CN101541781B

CN101541781B - Morpholino pyrimidine derivatives useful in the treatment of proliferative disorders

Info

Publication number: CN101541781B
Application number: CN200780039262.7A
Authority: CN
Inventors: M·R·V·芬利; J·莫里斯; K·G·皮克
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2006-08-24
Filing date: 2007-08-21
Publication date: 2014-01-08
Anticipated expiration: 2027-08-21
Also published as: ZA200901015B; CN101541781A; BRPI0715609A2; RU2009110255A; CN101558046A; ES2393215T3; RU2440349C2; TW200817384A; GB0616747D0

Abstract

A compound of formula (I) or a pharamaceutically acceptable salt 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

The morpholino pyrimidine derivatives that is used for the treatment of hyperplasia

The present invention relates to morpholino pyrimidine derivatives, their preparation method, the pharmaceutical composition that comprises them and their purposes in treatment, for example treat hyperplasia, and for example cancer, especially treat the disease that mTOR kinases and/or one or more PI3K enzymes mediate.

At present, people fully recognize that the imbalance of oncogene and tumor suppressor gene impels the formation of malignant tumour, for example, and by improving the approach of cell proliferation or raising cell survival.Equally, the signal path of known PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), and the imbalance in path is the origin cause of formation of wide spectrum human cancer and other disease.

The Mammals 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, but plays on the contrary the effect of serine-threonine kinase.Many understanding to the mTOR signal are based on the use rapamycin.At first rapamycin is combined albumen (FKBP12) combination with 12kDa immunophilin FK506-, and this mixture suppress the mTOR signal (Tee and Blenis, Seminars in Cell andDevelopmental Biology, 2005,16,29-37).MTOR albumen (approaches the C-end by the repressor zone of catalysis kinases zone (the FKBP12-rapamycin connects (FRB) zone), supposition, and there are 20 the continuous HEAT of repetition primitives at the most at the N-end) and FRAP-ATM-TRRAP (FAT) and FAT C-stub area composition (Huang and Houghton, Current Opinion in Pharmacology, 2003,3,371-377).

The mTOR kinases is the crucial conditioning agent of Growth of Cells, and show and there is the effect of regulating many cell functions, comprise translate, transcribe, mRNA circulation, protein stability, actin cytoskeleton restructuring reorganisation and autophagy (Jacinto and Hall, NatureReviews Molecular and Cell Biology, 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 be integrated, to regulate Growth of Cells.The mTOR kinases is by the PI3K-Akt path, by growth factor activation.The function that the mTOR kinases the most fully characterizes in mammalian cell is to regulate to translate, it is by two paths, i.e. the activation of core candy body S6K1 (with raising carry 5 '-mRNAs in few pyrimidine zone, end (TOP) translates) and the inhibition (translating with the dependent mRNA of permission CAP-) of 4E-BP1 carry out.

Usually, the investigator uses rapamycin and relevant forms of rapamycin analogs (based on them for mTOR the specificity as target in born of the same parents) to be suppressed, and has probed into physiology and the pathological effect of mTOR.Yet, latest data proposes, rapamycin demonstrates variable restraining effect to the mTOR semiotic function, and think, directly suppressing mTOR kinases zone can show basically than the anticancer activity obtained with rapamycin anticancer activity (people such as Edinger, Cancer Research, 2003 widely, 63,8451-8460).For this reason, can use effectively and the optionally inhibitor of mTOR kinase activity, in order to more thoroughly understand the mTOR kinase function, and provide the therapeutical agent of use.

Have now considerable evidence to show, the path upstream of mTOR is the PI3K path for example, is activated continually (Vivanco and Sawyers, Nature Reviews Cancer, 2002,2,489-501 in cancer; Bjornsti and Houghton, Nature Reviews Cancer, 2004,4,335-348; The people such as Inoki, Nature Genetics, 2005,37,19-24).The component in the PI3K path for example, suddenlyd change in different human tumors comprises the activation sudden change of growth factor receptors and amplification and/or the overexpression of PI3K and Akt.

Illustrate on evidence that in addition endothelial cell proliferation also depends on the mTOR signal.Endothelial cell proliferation be by the vascular endothelial growth factor of PI3K-Akt-mTOR signal path (VEGF) activation, stimulated (Dancey, Expert Opinion on Investigational Drugs, 2005,14,313-328).In addition, the impact of the expression by the factor on hypoxia inducible-1 α (HIF-1 α), think the mTOR kinase signal can partly control VEGF synthetic (people such as Hudson, Molecularand Cellular Biology, 2002,22,7004-7014).Therefore, tumor-blood-vessel growth depends on the mTOR kinase signal in two ways: the hypoxia inducible of the VEGF by tumour and stroma cell synthetic, and breed and the VEGF of survive (by the PI3K-Akt-mTOR signal) encourages by endothelium.

These find to disclose the kinase whose pharmacological inhibitor of mTOR should have therapeutic value, can be used for treating various forms of cancers, comprises noumenal tumour for example cancer and sarcoma, and the malignant tumour of leukemia and lymph.Especially, the kinase whose inhibitor of mTOR should have therapeutics and be worth, and can be used for treating 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 cholangiocarcinoma, the bone cancer, bladder cancer, head 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, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

Except tumorigenicity, explanation on evidence, the mTOR kinases plays a role in a series of progonoma syndromess.Nearest research shows, tumor suppressor protein for example TSC1, TSC2, PTEN and LKB1 is controlled the mTOR kinase signal consumingly.The forfeiture of these tumor suppressor proteins can cause a large amount of progonoma illnesss, this be due to the mTOR kinase signal increase (Tee and Blenis, Seminars in Cell and Developmental Biology, 2005,16,29-37).Setting up with the kinase whose dysregulation of mTOR the syndromes that molecule contacts comprises: Peutz-Jeghers syndrome (PJS), the Cowden disease, Bannayan-Riley-Ruvalcaba syndromes (BRRS), the Proteus syndromes, Lhermitte-Duclos disease and tuberous sclerosis (TSC) (people such as Inoki, Nature Genetics, 2005,37,19-24).Patient with these syndromess forms specifically optimum paramnesia tumour in many organs.

Up-to-date research has shown effect (the Easton &amp of mTOR kinases in Other diseases; Houghton, Expert Opinion on Therapeutic Targets, 2004,8,551-564).Show, by T cell proliferation, B cell and the antibody that suppresses antigen induction, produce, rapamycin is effective immunosuppressor (Sehgal, Transplantation Proceedings, 2003,35,7S-14S) and thus the mTOR kinase inhibitor is also useful immunosuppressor.The kinase activity that suppresses mTOR also can be effective to prevention of restenosis, in the treatment of vascular system disease, this restenosis is subject to normal cell in vascular system to produce the control (people such as Morice of undesirable propagation in the response process to introducing support, New England Journal of Medicine, 2002,346,1773-1780).In addition, 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 raising of mTOR kinase activity is relevant with cardiac hypertrophy, and this is important as Major Risk Factors in heart failure clinically, and is result (the Tee &amp of myocardial cell's cell size increase; Blenis, Seminars in Cell andDevelopmental Biology, 2005,16,29-37).Thus, except cancer, estimate that the mTOR kinase inhibitor has the value of prevention and treatment various diseases.

Believe equally, many these morpholino pyrimidine derivatives have and suppress active for kinase whose phosphatidylinositols (PI) 3-kinases family.

Phosphatidylinositols (PI) 3-kinases (PI3Ks) is ubiquitous lipid kinase, and it can be as signal converter and protein transportation route in the downstream of cell surface receptor and the intracellular membrane formed.All PI3Ks are the dual specificity enzymes, have the lipid kinase activity, and it can be in the 3-hydroxy position by the phosphoinositide phosphorylation, and has less characterization protein kinase activity.The lipid products of PI3K-catalyzed reaction (comprises phosphatidylinositols 3,4,5-triguaiacyl phosphate [PI (3,4,5) P ₃], phosphatidylinositols 3,4-bisphosphate [PI (3,4) P ₂] and phosphatidylinositols 3-Monophosphate [PI (3) P]) form the second messenger in various signal transduction pathways, comprise that on cell proliferation, adhesion, survival, cytoskeleton are reset and current those the indispensable approach of vesica.In all cells, structurally have PI (3) P, and its level can not change significantly along with the excitation of agonist.On the contrary, in most cells, nominally there is not PI (3,4) P ₂and PI (3,4,5) P ₃, but they can assemble rapidly under the excitation of agonist.

The 3-phosphoinositide second messenger's that PI3K-produces downstream effect is that for example, target molecule by comprising 3-phosphoinositide connecting zone (pleckstrin homology (PH) zone and definite FYVE and phox zone recently) mediates.The albumen target better characterized for PI3K comprises PDK1 and protein kinase B (PKB).In addition, for example Btk and Itk rely on the PI3K activity to Tyrosylprotein kinase.

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

The heterodimer that I class PI3Ks is comprised of p110 catalytic subunit and regulator subunit.Based on adjusting side and regulation mechanism, this family is further divided into to Ia class and Ib fermentoid.The Ia fermentoid comprises regulator subunit (the p85 α with five uniquenesses, p55 α, p50 α, p85 β and p55 γ) (the p110 α of catalytic subunit of three uniquenesses of dimerization, p110 β and p110 δ), all catalytic subunits can interact with all regulator subunits, form various heterodimers.In the response of the excitation of the somatomedin to receptor tyrosine kinase, by its regulator subunit SH ₂zone and activated receptor or for example interaction of the concrete phosphate tyrosine residues of IRS-1 of adaptor protein, activate Ia class PI3Ks usually.Structurally express p110 α and p110 β in all cell types, and p110 δ expression more is confined to leukocytes and some epithelial cells.On the contrary, single Ib fermentoid comprises the catalytic subunit with the interactional p110 γ of p101 regulator subunit.In addition, as if in the response to g protein coupled receptor system (GPCRs), classification Ib enzyme is activated, and its expression is limited to white corpuscle and myocardial cell.

Have now considerable evidence to show, in multiple human cancer, Ia class PI3K enzyme can contribute to directly or indirectly to cause tumour (Vivanco and Sawyers, Nature ReviewsCancer, 2002,2,489-501).For example, in some tumours, p110 α subunit is increased, such as ovarian tumor (people such as Shayesteh, Nature Genetics, 1999,21,99-102) and cervix neoplasms (people such as Ma, Oncogene, 2000,19,2739-2744).In recent years, activation in the catalytic site of p110 α catalytic subunit sudden change is relevant with various other tumours, those tumours of and breast and lung regional such as colorectum people such as (, Science, 2004,304,554) Samuels.In cancer for example in ovary and colorectal carcinoma, also determined the Tumor-assaciated in p85 α regulator subunit sudden change (people such as Philp, Cancer Research, 2001,61,7426-7429).Except direct impact, it is believed that, the activation of Ia class PI3Ks contributes to the tumorigenic situation occurred in the signal path upstream, for example, via the ligand dependent of receptor tyrosine kinase, GPCR system or integrin or the activation of part dependent/non-dependent (people such as Vara, CancerTreatment Reviews, 2004,30,193-204).The example in this stream signal path comprises the overexpression (people such as Harari of receptor tyrosine kinase erbB2 in the various tumours of the activation that causes path that PI3K mediates, 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 contribute to tumorigenicity (movable institute causes by various downstream signals) indirectly.For example, the PI mediated by PI3K (3,4,5) P ₃the imbalance generated, PTEN tumor suppression Phosphoric acid esterase (its catalysis PI (3,4,5) P ₃pI (4,5) P is got back in conversion ₂) forfeiture (Simpson and Parsons, the Exp relevant to a wide range of tumour of effect.Cell Res.，2001，264，29-41)。In addition, it is believed that, the increase of the effect of activity that other PI3K mediates, will help lend some impetus to various cancers, and for example activation by Akt (Nicholson and Anderson, Cellular Signalling, 2002,14,381-395).

Effect in mediation propagation in tumour cell and survival signal, explanation on evidence, Ia class PI3K enzyme contributes to tumorigenicity in the stroma cell of Tumor-assaciated.For example, know, to front angiogenic factor for example in the response of VEGF, PI3K signal in the generation angiokinesis of mediation endotheliocyte, play an important role (people such as Abid, Arterioscler.Thromb。Vasc。Biol.，2004，24，294-300)。Because I class PI3K enzyme also relate to reactivity and migration (Sawyer, Expert Opinion Investig.Drugs, 2004,13,1-19), by inhibition tumor cell, invade and metastasis, the PI3K enzyme inhibitors should provide the treatment benefit.In addition, I class PI3K enzyme in the immunocyte of the pre-neoplastic generation effect that contributes to inflammatory cell is regulated, play an important role (Coussens and Werb, Nature, 2002,420,860-867).

These find expression, and the pharmacological inhibitor of I class PI3K enzyme has therapeutic value, can be used for treating various diseases, comprises the various forms Cancerous disease, comprises noumenal tumour for example cancer and sarcoma, and the malignant tumour of leukemia and lymph.Especially, the inhibitor of I class PI3K enzyme should have therapeutics and be worth, and can be used for treating 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 cholangiocarcinoma, the bone cancer, bladder cancer, head 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, uterine neck and carcinoma vulvae, and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

PI3K γ (Ib class PI3K) is activated by GPCRs, and this finally is proven in the mouse that lacks enzyme.Thus, in for example, response to various chemotaxis materials (IL-8, C5a, fMLP and MIP-1a) excitation, derived from neutrophil and the scavenger cell of the animal that lacks PI3K γ, can not produce PI (3,4,5) P ₃, and be intact (people such as Hirsch, Science, 2000,287 (5455), 1049-1053 by protein tyrosine kinase coupled receptor to the signal of Ia class PI3Ks; The people such as Li, Science, 2002,287 (5455), 1046-1049; The people such as Sasaki, Science 2002,287 (5455), 1040-1046).In addition, in without the PI3K gamma cells, PI (3,4,5) P ₃the phosphorylation of the PKB of mediation is not to originate from these GPCR parts.Combine, result shows, at least in the hematopoietic cell of having a rest, and unique PI3K heterogeneous that PI3K γ is activated in the GPCRs body.When the neutrophil to deriving from mouse marrow with derive from wild-type and PI3K γ ^-/-when the peritoneal macrophages of mouse carries out in vitro tests, observe (but not eliminating fully) performance of reduction in chemotaxis and adherence test.Yet, this be converted into IL-8 drive neutrophil be penetrated into sharply weakening in tissue (people such as Hirsch, Science, 2000,287 (5455), 1049-1053.).Up-to-date data propose, and PI3K γ is relevant with the path finding process, and irrelevant with the generation (for reactivity) of mechanical force, (people such as Hannigan, Proc because not weakening of the random migration in the cell that lacks PI3K γ.Nat。Acad。of Sciences of U.S.A.，2002，99(6)，3603-8)。The data of contact PI3K γ and respiratory system disease pathology show, PI3K γ permeates and cause aspect the neutrophil activation of acute lung injury having central role (people such as Yum, J at the lung of regulating endotaxin induction.Immunology，2001，167(11)，6601-8)。Although PI3K γ expresses at the white cell camber, as if its forfeiture does not hinder hematopoiesis, and can grow and reproducible these truely imply that this PI3K heterogeneous can be used as potential drug targets without the mouse of PI3K γ.Research for the stunning mouse also confirms, PI3K γ be necessity of activating of mast cell toughener (people such as Laffargue, Immunity, 2002,16 (3), 441-451).

Thus, except tumorigenicity, explanation on evidence, I class PI3K enzyme in Other diseases, play a role (people such as Wymann, Trends in Pharmacological Science, 2003,24,366-376).In immune cell, Ia class PI3K enzyme and simple Ib fermentoid all have important effect (Koyasu, Nature Immunology, 2003,4,313-319), and they are treatment targets of inflammatory and irritated indication thus.Up-to-date report shows, the mouse that lacks PI3K and PI3K can grow, but have the inflammatory that weakens and anaphylactic response (people such as Ali, Nature, 2004,431 (7011), 1007-11).By the anti-inflammatory effect or directly affect the myocardial cell, the restraining effect of PI3K also can be used for Cardiovarscular (people such as Prasad, Trends inCardiovascular Medicine, 2003,13,206-212).Thus, except cancer, the inhibitor of expectation I class PI3K enzyme has the value of prevention and treatment various diseases.

Differentiate some compounds of the kinases (PI3KKs) that inhibition PI3Ks is relevant with phosphatidylinositols (PI) kinases, comprised wortmannin and quercetin derivative L Y ²94002.These compounds are suitable PI3Ks and PI3KKs specific inhibitors (with respect to other kinases), but they lack usefulness, and show selectivity seldom in PI3K family.

Correspondingly, desirable, effectively mTOR and/or PI3K inhibitor are provided further, be used for the treatment of cancer, inflammatory or obstructive respiratory tract disease, immunity or cardiovascular disorder.

Morpholino pyrimidine derivatives and PI3K inhibitor are known in the art.

International Patent Application WO 2004/048365 discloses the compound that has the PI3K enzyme inhibition activity and can be used for treating cancer.These compounds are pyrimidines that virtue is amino and heteroaryl amino replaces, and with regard to their virtue amino and heteroaryl amino substituting group, it is different from compound of the present invention.These substituting groups are not equivalent to of the present invention-XR ¹substituting group.The inhibitor of the PI3K activity that is used for the treatment of cancer is also disclosed in european patent application 1,277 738, it mentions the bicyclic heteroaryl compounds that the 4-morpholino replaces, for example quinazoline and pyrido [3,2-d] pyrimidine derivatives, with the tricyclic heteroaryl compounds of 4-morpholino replacement, rather than the pyrimidine derivatives of monocycle.

Registered chemical compound lot on the chemical abstracts database; 4-morpholine-4-base-6-(phenyl sulfonyl methyl)-2-pyridin-4-yl-pyrimidine and 4-{6-[(benzene sulfonyl for example) methyl]-2-pyridine-2-yl pyrimidines-4-yl } morpholine; but do not indicate applicability, and do not propose these compounds and there is mTOR and/or PI3K and suppress active or useful curative properties.

Unexpectedly, we find that some morpholino pyrimidine derivatives has useful curative properties.Do not wish to be bound by theory, it is believed that, the therepic use of this derivative stems from their for example, inhibition activity for mTOR kinases and/or one or more PI3K enzymes (Ia fermentoid and/or Ib fermentoid).Because the signal path of PI3K/mTOR family mediation has central role in many cell processes (comprising propagation and survival), with because the imbalance in these paths is origin causes of formation of wide spectrum human cancer and other disease, so people expect that this derivative has therepic use.Especially, people expect that this derivative has antiproliferative and/or apoptosis performance, and this refers to that they can be used for treating hyperplasia, for example cancer.Compound of the present invention also can be effective to suppress the cell proliferation without control, and this cell proliferation without control comes from 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 for the mTOR kinases, but this compound for example, also can have effective inhibition activity for one or more PI3K enzymes (Ia fermentoid and/or Ib fermentoid).

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

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

¹y and Y ²n or CR independently ⁸, condition is, ¹y and Y ²one of be N, and another is CR ⁸;

X is selected from following connection base :-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-;

R ¹to be selected from following group: hydrogen, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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 ²to be selected from following group: C _1-6alkyl, carbocylic radical and heterocyclic radical, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical 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 ¹², and-NR ¹¹cOCONR ¹²r ¹⁶;

When existing, each R ³independently 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 ⁵hydrogen or C independently _1-6alkyl;

Or R ¹and R ⁴form 4-to 10-unit carbocyclic ring or heterocycle together with the atom be connected with them, wherein 1,2 or 3 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 ⁷independently 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, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 ¹¹, R ¹², R ¹⁷and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 ¹⁵, R ¹⁶and R ¹⁹be hydrogen independently or be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 is as the medicine for the treatment of hyperplasia.

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

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ⁴and R ⁵hydrogen 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, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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 ¹¹, R ¹², R ¹⁷and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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 ¹⁵, R ¹⁶and R ¹⁹be hydrogen independently or be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces 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.

Medicine as the treatment hyperplasia.

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ¹to be selected from following group: C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

Or X-R ¹be-CR ⁶r ⁷oH;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces 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 is as the medicine for the treatment of hyperplasia.

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

X is selected from following connection base :-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-;

Or X-R ¹be-CR ⁶r ⁷oH;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces 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

Medicine as the treatment hyperplasia.

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ¹to be selected from following group: hydrogen, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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 independently hydrogen or _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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

Be used for the treatment of the purposes in the medicine of hyperplasia in manufacture.

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ¹to be selected from following group: C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

Or X-R ¹be-CR ⁶r ⁷oH;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

Or X-R ¹be-CR ⁶r ⁷oH

When existing, each R ³independently 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 ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces 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 is used for the treatment of the purposes in the medicine of hyperplasia in manufacture.

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

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

X is selected from following connection base :-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 ¹to be selected from following group: hydrogen, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

When existing, each R ³independently 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 ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 3-to 10-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 or 2 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ¹to be selected from following group: hydrogen, C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

R ¹to be selected from following group: C _1-6alkyl, C _2-6thiazolinyl, C _2-6alkynyl, carbocylic radical, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

Or X-R ¹be-CR ⁶r ⁷oH;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

Or R ¹and R ⁴form 4-to 10-unit's carbocyclic ring or heterocycle together with the atom be connected with them,

Wherein 1,2 or 3 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Formula (I)

Or its pharmacologically acceptable salt; Wherein

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

Or X-R ¹be-CR ⁶r ⁷oH;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

R ¹¹, R ¹², R ¹⁷and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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 C1 _-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;

The compound of some formula (I) can exist with stereoisomeric forms in any ratio.Be appreciated that all geometry and optically active isomer and its mixture of the formula of the present invention includes (I) compound, comprise raceme.Tautomer and its mixture also form one aspect of the present invention.Solvate and its mixture also form one aspect of the present invention.For example, the suitable solvent compound of formula (I) compound is for example hydrate, for example hydrate of semihydrate, monohydrate, dihydrate or trihydrate or its other number.

The compound that the present invention relates to formula defined herein (I) with and salt.Salt for pharmaceutical composition is pharmacologically acceptable salt, but other salt can be for the preparation of the compound of formula (I) and their pharmacologically acceptable salt.Pharmacologically acceptable salt of the present invention can for example comprise the acid salt of formula defined herein (I) compound, and this formula (I) compound is fully alkaline, in order to form this salt.This acid salt is including, but not limited to fumarate, mesylate, hydrochloride, hydrobromate, Citrate trianion and maleate, and the salt formed with phosphoric acid and sulfuric acid.In addition, if formula (I) compound is fully acid, salt is basic salt, example including, but not limited to: an alkali metal salt is sodium or sylvite for example, alkaline earth salt is calcium or magnesium salts for example, or organic amine salt triethylamine, thanomin, diethanolamine, trolamine, morpholine, N-methyl piperidine, N-ethylpiperidine, dibenzylamine or amino acid lysine salt for example for example.

Also can provide with the form of hydrolyzable ester in body the compound of formula (I).In the body of the formula that comprises carboxyl or hydroxyl (I) compound, the ester of cleavable for example is: in human or animal body, cleavable produces the pharmaceutically acceptable ester of parent acid or alcohol.This ester can by for example intravenously give the experimental animal test compound and subsequently the body fluid of check test animal identified.

The suitable pharmaceutically acceptable ester of carboxyl comprises C _1-6the alkoxy methyl ester is methoxymethyl ester for example, C _1-6the alkanoyloxymethyl ester is valeryl oxygen ylmethyl ester for example, phthalidyl ester, C _3-8cyclo alkoxy carbonyl oxygen base C _1-6alkyl ester is 1-cyclohexyl-carbonyl oxygen base ethyl ester for example, and 1,3-dioxole-2-ketone group methyl ester is the 5-methyl isophthalic acid for example, 3-dioxole-2-ketone group methyl ester, and C _1-6the alkoxy-carbonyl oxy ethyl ester is 1-methoxycarbonyl oxygen base ethyl ester for example; With the ester that can form on any carboxyl of the compounds of this invention.

The suitable pharmaceutically acceptable ester of hydroxyl comprises inorganic ester for example phosphoric acid ester (comprising the phosphoramidic acid cyclic ester) and α-acyloxyalkyl group ether, and conduct is because the related compound of the result that obtains parent hydroxy is decomposed in hydrolysis in the body of ester.The example of α-acyloxyalkyl group ether comprises acetoxyl group methoxy-ether and 2,2-dimethyl propylene acyloxy methoxy-ether.For hydroxyl, in organizer, the selection of the group of hydrolyzable ester comprises C _1-10alkyloyl, formyl radical for example, ethanoyl, benzoyl, phenylacetyl, the benzoyl of replacement and phenylacetyl; C _1-10carbalkoxy (obtaining alkyl carbonate), for example ethoxycarbonyl; 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 comprise aminomethyl, C _1-4alkylamino methyl and two-(C _1-4alkyl) aminomethyl, with morpholino or the piperazinyl of the 3-that is connected base shack nitrogen-atoms and benzoyl basic ring by methylene radical or 4-position.In other useful body, hydrolyzable ester comprises for example R ^ac (O) OC _1-6alkyl-CO-, wherein R ^abenzyloxy-C for example _1-4alkyl or phenyl.In this ester, the suitable substituent on phenyl comprises for example 4-C _1-4piperazinyl-C _1-4alkyl, piperazinyl-C _1-4alkyl and morpholino-C _1-4alkyl.

Also can be with the compound of prodrug form giving construction (I), it decomposes in human or animal body, obtains the compound of formula (I).The various forms of prodrug is known in this area.For example, this prodrug derivatives referring to:

a)Design of Prodrugs，H。Bundgaard compiles, (Elsevier, 1985) and Methods in Enzymology, and Vol.42, p.309-396, K.Widder, wait volume (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 etc., Journal of Pharmaceutical Sciences, 77,285 (1988); With

E) N.Kakeya etc., Chem Pharm Bull, 32,692 (1984).

General terms " C in this specification sheets _p-qalkyl " comprise straight chain and branched-chain alkyl.Yet, speak of indivedual alkyl for example " propyl group " only specifically for straight chain pattern (being n-propyl and sec.-propyl), speak of indivedual branched-chain alkyls for example " tertiary butyl " only specifically for the side chain pattern.

C _p-qprefix C in alkyl and other term (wherein p and q are integers) _p-qshow the carbon atom scope existed in group, for example C _1-4alkyl comprises C ₁alkyl (methyl), C ₂alkyl (ethyl), C ₃alkyl (propyl group of n-propyl and sec.-propyl form) and C ₄alkyl (normal-butyl, sec-butyl, isobutyl-and the tertiary butyl).

Term C _p-qcomprise-O-C of alkoxyl group _p-qalkyl.

Term C _p-qcomprise-C of alkyloyl (O) alkyl.

Term halogen comprises fluorine, chlorine, bromine and iodine.

" carbocyclic ring " is monocycle, dicyclo or the three-loop system of saturated, the unsaturated or fractional saturation that comprises 3 to 14 annular atomses, wherein encircles CH ₂group can be replaced by the C=O group." carbocyclic ring " comprises " aryl ", " C _p-qcycloalkyl " and " C _p-qcycloalkenyl group ".

" aryl " is the carbocyclic ring system of aromatic series monocycle, dicyclo or three rings.

" C _p-qcycloalkenyl group " be monocycle, dicyclo or the three ring carbocyclic ring ring systems of the unsaturated or fractional saturation that comprises 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 carbocyclic ring ring 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, the unsaturated or fractional saturation that comprises 3 to 14 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, and 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 ", " Heterocyclylalkyl " and " heterocycloalkenyl ".

" heteroaryl " is the heterocyclic radical of aromatic series monocycle, dicyclo or three rings, 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.

" heterocycloalkenyl " is monocycle, dicyclo or the tricyclic heterocyclic basic ring system with unsaturated or fractional saturation of 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, and wherein nuclear nitrogen or sulphur atom can be oxidized, wherein encircle CH ₂group can be replaced by the C=O group.

" Heterocyclylalkyl " is saturated monocycle, dicyclo or the tricyclic heterocyclic system with 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, and 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 be used the combination term, the group that comprises an above functional group with description.Unless this paper describes in addition, otherwise can understand according to this area explain this term.For example, carbocyclic ring C _p-qalkyl comprises by the cyclosubstituted C of carbon _p-qalkyl, heterocyclic radical C _p-qalkyl comprises the C replaced by heterocyclic radical _p-qalkyl, two (C _p-qalkyl) amino comprises by 2 C _p-qthe amino that alkyl (can be identical or different) replaces.

Halo C _p-qthe C that alkyl is replaced by 1 or 1 above halogenic substituent (especially 1,2 or 3 halogenic substituent) _p-qalkyl.Equally, wrap halogen-containing other and be generally called for example halo C _p-qalkoxyl group can comprise 1 or 1 above halogenic substituent, especially 1,2 or 3 halogenic substituent.

Hydroxyl C _p-qthe C that alkyl is replaced by 1 or 1 above hydroxyl substituent (especially 1,2 or 3 hydroxyl substituent) _p-qalkyl.Equally, other that comprises hydroxyl is generally called for example hydroxyl C _p-qalkoxyl group can comprise 1 or 1 above hydroxyl substituent, especially 1,2 or 3 hydroxyl substituent.

C _p-qalkoxy C _p-qalkyl is by 1 or 1 above C _p-qthe C that alkoxy substituent replaces _p-qalkyl, especially 1,2 or 3 C _p-qalkoxy substituent.Equally, comprise C _p-qother of alkoxyl group is generally called for example C _p-qalkoxy C _p-qalkoxyl group can comprise 1 or 1 above C _p-qalkoxy substituent (1,2 or 3 C especially _p-qalkoxy substituent).

If optional substituting group is selected from " 1 or 2 ", " 1,2 or 3 " or " 1,2,3 or 4 " individual group or substituting group, should be appreciated that, this definition comprises and is selected from all substituting groups that illustrate group, all substituting groups are identical, or substituting group is selected from two or more groups that illustrate, substituting group is not identical.

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

Any part of any R group or this group or substituent suitable meaning comprise:

C _1-4alkyl: methyl, ethyl, propyl group, butyl, 2-methyl-propyl and tertiary fourth

Base;

C _1-6alkyl: C _1-4alkyl, amyl group, 2,2-dimethylpropyl, the 3-methyl butyl and

Hexyl;

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

C _3-6cycloalkyl C _1-4alkyl: the cyclopropyl methyl, the cyclopropyl ethyl, cyclobutylmethyl, encircle penta

Ylmethyl and cyclohexyl methyl;

Aryl: phenyl and naphthyl;

Aryl C _1-4alkyl: benzyl, styroyl, naphthyl methyl and naphthyl ethyl;

Carbocyclic ring: aryl, cyclohexenyl and C _3-6cycloalkyl;

Halogen: fluorine, chlorine, bromine and iodine;

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

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

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

Heteroaryl: pyridyl, imidazolyl, quinolyl, the cinnolines base, pyrimidyl,

Thienyl, pyrryl, pyrazolyl, thiazolyl, thiazolyl,

Triazolyl ， oxazolyl ， isoxazolyl, furyl, pyridazinyl,

Pyrazinyl, indyl, benzofuryl, dibenzofuran group

And benzothienyl;

Heteroaryl C _1-4alkyl: pyrryl methyl, pyrryl ethyl, imidazolyl methyl, imidazoles

The base ethyl, pyrazolyl methyl, pyrazolyl ethyl, furyl first

Base, the furyl ethyl, thienyl methyl, thienyl ethyl,

Pyridylmethyl, pyridyl ethyl, pyrazinyl methyl, pyrazine

The base ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrimidyl third

Base, the pyrimidyl butyl, the imidazolyl propyl group, the imidazolyl butyl,

The quinolyl propyl group, 1,3,4-triazolyl propyl group is with the oxazolyl methyl;

Heterocyclic radical: heteroaryl, pyrrolidyl, isoquinolyl, quinoxalinyl, benzene

Benzothiazolyl, benzoxazolyl, piperidyl, piperazinyl, nitrogen

The heterocycle butane group, morpholinyl, tetrahydro isoquinolyl, tetrahydrochysene quinoline

The quinoline base, indolinyl, dihydro-2H-pyranyl and tetrahydrochysene furan

The base of muttering.

It should be noted that the example given for the term used in specification sheets is not restrictive.

M, X, ¹y and Y ², R ¹, R ²and R ³concrete meaning as follows.If suitable, this meaning can be combined with any aspect of the present invention or its part and any definition, claim or embodiment defined herein.

m

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

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

Further, m is 0 or 1.

In yet another aspect, m is 0, so that R ³do not exist.

In yet another aspect, m is 1, and R ³it is methyl.

¹ y and Y ²

In one aspect of the invention, ¹y is N, and Y ²cR ⁸.

In another aspect of the present invention, ¹y is N, and Y ²cH.

Of the present invention aspect another, ¹y is CR ⁸, and Y ²n.

Further, ¹y is CH or CF, and Y ²n.

Further, ¹y is CH, and Y ²n.

X

In one aspect of the invention, X is selected from following connection base :-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 connection base :-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-and-NR ⁴c (O)-.

Further, X is selected from following connection base :-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)-.

Further, X is selected from following connection base :-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 connection base :-SCR ⁶r ⁷-,-S (O) CR ⁶r ⁷-and-S (O) ₂cR ⁶r ⁷-.

In yet another aspect, X is selected from following connection base :-NR ⁴cH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-,-S (O) ₂c (CH ₃) ₂-,-C (O) NR ⁴-and-NR ⁴c (O)-.

In yet another aspect, X is selected from following connection base :-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 connection base :-NR ⁴cH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-and-S (O) ₂c (CH ₃) ₂-.

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

Further, X is selected from following connection base :-NHCH ₂-,-N (CH ₃) CH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-,-S (O) ₂c (CH ₃) ₂-,-C (O) NH-,-C (O) N (CH ₃)-,-NHC (O)-and-N (CH ₃) C (O)-.

Further, X is selected from following connection base :-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)-.

Further, X is selected from following connection base :-NHCH ₂-,-N (CH ₃) CH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-and-S (O) ₂c (CH ₃) ₂-.

Further, X is selected from following connection base :-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-SCH ₂-,-SCH (CH ₃)-or-SC (CH ₃) ₂-.

In yet another aspect, X is-S (O) CH ₂-,-S (O) CH (CH ₃)-or-S (O) C (CH ₃) ₂-.

In yet another aspect, X is-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-or-S (O) ₂c (CH ₃) ₂-.

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

In yet another aspect, X is-S (O) ₂c (CH ₃) ₂-.

R ¹

In one aspect of the invention, R ¹to be selected from following group: C _1-4alkyl, C _3-10cycloalkyl, aryl, C _3-10cycloalkyl 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 optionally is selected from following substituted radical and replaces 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 ¹it is to be selected from following group: adamantyl, methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopentyl, cyclohexyl, phenyl, benzyl, oxetanyl, styroyl, pyrrolidyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, the pyrrolidyl methyl, the pyrrolidyl ethyl, the pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, the imidazolyl ethyl, the pyrazolyl methyl, the pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, the pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optionally by 1, 2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹r ¹⁰,-NR ⁹r ¹⁰with-NR ⁹cOR ¹⁰.

In yet another aspect, R ¹it is to be selected from following group: adamantyl, 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, the pyrrolidyl ethyl, the pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, the imidazolyl ethyl, the pyrazolyl methyl, the pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, the pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optionally by 1, 2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹r ¹⁰,-NR ⁹r ¹⁰with-NR ⁹cOR ¹⁰.

Further, R ¹to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrrolidyl, pyrazolyl ethyl, furyl methyl, oxetanyl, imidazolyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group optionally is selected from following substituted radical by 1 or 2 and replaces: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NMe ₂,-NHCOCH ₃,-CONH ₂with-CONHCH ₃.

Further, R ¹to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group optionally is selected from following substituted radical by 1 or 2 and replaces: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH ₃,-CONH ₂with-CONHCH ₃.

In yet another aspect, R ¹to be selected from following group: methyl, ethyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nC (O) CH ₃, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.

In yet another aspect, R ¹to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nC (O) CH ₃,-CH ₂cONH ₂, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.

In yet another aspect, R ¹to be selected from following group: methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂oMe ,-CH ₂cH ₂nMe ₂,-CH ₂cH ₂nC (O) CH ₃,-CH ₂cONH ₂, phenyl, 3,5-difluorophenyl, the 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2-trifluoromethyl, the 2-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, trimethylene oxide-3-base, 2-oxo-pyrrolidine-3-base, 1-Methylimidazole-5-ylmethyl, 1-methylpyrrolidin-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.

In yet another aspect, R ¹methyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, 3,5-difluorophenyl, pyridin-4-yl or cyclopropyl.

In yet another aspect, R ¹methyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl.

In yet another aspect, R ¹methyl or cyclopropyl.

In yet another aspect, R ¹it is methyl.

X-R ¹

In one embodiment, X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH.

In one embodiment, X-R ¹be-CH ₂oH.

R ²

In one aspect of the invention, R ²be selected from carbocyclic ring or heterocyclic radical, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from carbocyclic ring or heterocyclic radical, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from carbocyclic ring or heterocyclic radical, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 5 or 6 yuan of carbocyclic rings or heterocyclic radical, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹².

In one aspect of the invention, R ²be selected from 6 yuan of aryl and 5 or 6 yuan of heteroaryls, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical 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, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical 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, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical 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, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical 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, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²by-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally by one or more phenyl or pyridyl that replace independently selected from following substituted radical: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²by-NHCONR ¹⁸r ¹⁹replace, and optionally by one or more phenyl or pyridyl that replace independently selected from following substituted radical: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²by-NHCONHR ¹⁹replace, and optionally by one or more phenyl or pyridyl that replace independently selected from following substituted radical: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂.

In yet another aspect, R ²optionally by-NR ¹⁷cONR ¹⁸r ¹⁹the phenyl or the pyridyl that replace.

In yet another aspect, R ²optionally by-NHCONR ¹⁸r ¹⁹the phenyl or the pyridyl that replace.

In yet another aspect, R ²optionally by-NHCONHR ¹⁹the phenyl or the pyridyl that replace.

In yet another aspect, R ²be

A wherein ¹and A ²be selected from CH or N, condition is, at least one A ¹or A ²cH.

In yet another aspect, R ²be

In yet another aspect, R ²be

R ⁴

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

In yet another aspect, R ⁴hydrogen.

r ⁴ and R ¹

In another aspect of the present invention, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) CR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴s (O) ₂cR ⁶r ⁷-,-NR ⁴c (O)-,-NR ⁴c (O) NR ⁵-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 4-to 10-unit heterocycle together with the atom be connected with them, wherein 1,2 or 3 ring carbon atom is optionally replaced by N, O or S, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In another aspect of the present invention, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) CR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴s (O) ₂cR ⁶r ⁷-,-NR ⁴c (O)-,-NR ⁴c (O) NR ⁵-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 4-, 5-, 6-or 7-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In another aspect of the present invention, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) CR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴s (O) ₂cR ⁶r ⁷-,-NR ⁴c (O)-,-NR ⁴c (O) NR ⁵-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 5-or 6-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In another aspect of the present invention, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) CR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴s (O) ₂cR ⁶r ⁷-,-NR ⁴c (O)-,-NR ⁴c (O) NR ⁵-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 6-or 7-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In another aspect of the present invention, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) CR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴s (O) ₂cR ⁶r ⁷-,-NR ⁴c (O)-,-NR ⁴c (O) NR ⁵-or-NR ⁴s (O) ₂-, R ¹and R ⁴form piperidines together with the atom be connected with them, morpholine, azetidine, azepine

, Diazesuberane and parathiazan ring, this ring optionally is selected from following substituted radical and replaces by one or more: halogen, hydroxyl, oxo and C _1-6alkyl.

In another aspect of the present invention, as X while being following :-NR ⁴c (O)-, R ¹and R ⁴form piperidines together with the atom be connected with them, morpholine, azetidine, azepine

In another aspect of the present invention, as X while being following :-NR ⁴c (O)-, R ¹and R ⁴form 1-methyl-piperidines together with the atom be connected with them, 4-hydroxy-piperdine, morpholine, 3-methylmorpholine, 3-hydroxyl azetidine, azepine , Isosorbide-5-Nitrae-Diazesuberane and parathiazan-1,1-dioxide ring.

R ⁵

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

In yet another aspect, R ⁵hydrogen.

In yet another aspect, R ⁵it is methyl.

R ⁶

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

In yet another aspect, R ⁶hydrogen.

In yet another aspect, R ⁶it is methyl.

R ⁷

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

In yet another aspect, R ⁷hydrogen.

In yet another aspect, R ⁷it is methyl.

R ⁸

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

In yet another aspect, R ⁸hydrogen or fluorine.

Further, R ⁸hydrogen.

R ⁹

In one aspect of the invention, R ⁹be hydrogen or optionally by 1,2 or 3, be selected from the C that following substituted radical replaces _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 ⁹hydrogen or the C that optionally replaced by 1,2 or 3 halogenic substituent _1-4alkyl.

Further, R ⁹hydrogen, methyl or trifluoromethyl.

R ¹⁰

In one aspect of the invention, R ¹⁰hydrogen.

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 optionally replaced by 1,2 or 3 group that is selected from halogen, hydroxyl and cyano group.

In yet another aspect, R ¹¹the methyl, phenyl or the pyrrolidyl that are hydrogen, are optionally replaced by hydroxyl or cyano group.

In yet another aspect, R ¹¹hydrogen or methyl.

R ¹²

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

R ¹⁷

In one aspect of the invention, R ¹⁷be hydrogen or be selected from C _1-4the group of the assorted alkyl of alkyl, aryl and ring, this group is optionally replaced by 1,2 or 3 group that is selected from halogen, hydroxyl and cyano group.

In yet another aspect, R ¹⁷the methyl, phenyl or the pyrrolidyl that are hydrogen, are optionally replaced by hydroxyl or cyano group.

In yet another aspect, R ¹⁷hydrogen or methyl.

In yet another aspect, R ¹⁷hydrogen.

R ¹⁸

In one aspect of the invention, R ¹⁸hydrogen or methyl.

In one aspect of the invention, R ¹⁸hydrogen.

R ¹⁹

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, phenyl, naphthyl, pyrryl, imidazolyl ， isoxazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azaindolyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, phenyl C _1-6alkyl, naphthyl C _1-6alkyl, pyrryl C _1-6alkyl, imidazolyl C _1-6alkyl ， isoxazolyl C _1-6alkyl, pyrazolyl C _1-6alkyl, furyl C _1-6alkyl, thienyl C _1-6alkyl, pyridyl C _1-6alkyl, pyrimidyl C _1-6alkyl, pyridazinyl C _1-6alkyl, azaindolyl C _1-6alkyl, indyl C _1-6alkyl, quinolyl C _1-6alkyl, benzimidazolyl-C _1-6alkyl, benzofuryl C _1-6alkyl, dibenzofuran group C _1-6alkyl, benzothienyl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, phenyl, naphthyl, pyrryl, imidazolyl ， isoxazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl, azaindolyl, indyl, quinolyl, benzimidazolyl-, benzofuryl, dibenzofuran group, benzothienyl, phenyl C _1-6alkyl, naphthyl C _1-6alkyl, pyrryl C _1-6alkyl, imidazolyl C _1-6alkyl ， isoxazolyl C _1-6alkyl, pyrazolyl C _1-6alkyl, furyl C _1-6alkyl, thienyl C _1-6alkyl, pyridyl C _1-6alkyl, pyrimidyl C _1-6alkyl, pyridazinyl C _1-6alkyl, azaindolyl C _1-6alkyl, indyl C _1-6alkyl, quinolyl C _1-6alkyl, benzimidazolyl-C _1-6alkyl, benzofuryl C _1-6alkyl, dibenzofuran group C _1-6alkyl, benzothienyl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl ， isoxazolyl, pyrazolyl, the pyrazolyl methyl, pyridyl and pyrimidyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl ， isoxazolyl, pyrazolyl, the pyrazolyl methyl, pyridyl and pyrimidyl, this group optionally is selected from following substituted radical and replaces 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.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl) ， isoxazole-3-base, 6-oxo-1H-pyridine-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyridyl-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.

In one aspect of the invention, R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl) ， isoxazole-3-base, 6-oxo-1H-pyridine-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.

In another aspect of the present invention, R ¹⁹to be selected from following group: methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH and 1H-pyrazole-3-yl.

r ¹⁸ and R ¹⁹

In one aspect of the invention, R ¹⁸and R ¹⁹form 6-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 C1 _-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.

In one aspect of the invention, R ¹⁸and R ¹⁹form 6-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces 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.

In one aspect of the invention, R ¹⁸and R ¹⁹form the morpholine ring together with the nitrogen-atoms be connected with them.

Hypotype or its pharmacologically acceptable salt of formula (I) compound are provided in one aspect of the invention;

M is 0,1 or 2;

X is selected from following connection base :-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 ¹to be selected from following group: C _1-6alkyl, carbocyclic ring, carbocyclic ring C _1-6alkyl, heterocyclic radical and heterocyclic radical C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹r ¹⁰,-NR ⁹r ¹⁰with-NR ⁹cOR ¹⁰;

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ²be selected from aryl and heteroaryl, this group quilt-NR ¹⁷cONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹²;

When existing, each R ³it is methyl;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

Or, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴c (O)-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 4-, 5-, 6-or 7-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 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 optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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 ¹¹, R ¹², R ¹⁷and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocylic radical and heterocyclic radical, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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; With

R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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;

Or R ¹⁸and R ¹⁹form 6-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

In another aspect of the present invention, provide hypotype or its pharmacologically acceptable salt of formula (I) compound;

M is 0,1 or 2;

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

When existing, each R ³it is methyl;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

Or, as X while being following :-NR ⁴cR ⁶r ⁷-,-NR ⁴c (O) NR ⁵cR ⁶r ⁷-,-NR ⁴c (O)-or-NR ⁴s (O) ₂-, R ¹and R ⁴form 4-, 5-, 6-or 7-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, C _1-6alkyl, C _1-6alkoxyl group, halogen C _1-6alkyl, halogen C _1-6alkoxyl group, hydroxyl C _1-6alkyl, hydroxyl C1 _-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 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 optionally is selected from following substituted radical and replaces 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 ¹¹, R ¹², R ¹⁷and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocylic radical and heterocyclic radical, this group optionally is selected from following substituted radical and replaces 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; With

R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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;

Or R ¹⁸and R ¹⁹form 6-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces 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.

M is 0,1 or 2;

X is selected from following connection base :-NR ⁴cH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-,-S (O) ₂c (CH ₃) ₂-,-C (O) NR ⁴-and-NR ⁴c (O)-;

R ¹it is to be selected from following group: adamantyl, 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, the pyrrolidyl ethyl, the pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, the imidazolyl ethyl, the pyrazolyl methyl, the pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, pyridylmethyl, the pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optionally by 1, 2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹r ¹⁰,-NR ⁹r ¹⁰with-NR ⁹cOR ¹⁰,

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ²be selected from 5 or 6 yuan of aryl and heteroaryl, this group quilt-NHCONR ¹⁸r ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹²;

When existing, each R ³it is methyl;

R ⁴hydrogen or C _1-6alkyl;

Or, as X while being following :-NR ⁴cH ₂-or-NR ⁴c (O)-, R ¹and R ⁴form 5-or 6-unit heterocycle together with the atom be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces 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 ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

R ¹¹, R ¹²and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocylic radical and heterocyclic radical, this group optionally is selected from following substituted radical and replaces 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; With

In another specific category of formula (I) compound or pharmaceutically acceptable salt thereof;

M is 0 or 1;

¹y is CH, Y ²n;

X is selected from following connection base :-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-and-S (O) ₂c (CH ₃) ₂-;

R ¹to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrrolidyl, pyrazolyl ethyl, furyl methyl, oxetanyl, imidazolyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group optionally is selected from following substituted radical by 1 or 2 and replaces: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NMe ₂,-NHCOCH ₃,-CONH ₂with-CONHCH ₃;

Or-XR ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ²be selected from phenyl, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyridazinyl and thiazolyl, this group quilt-NHCONHR ¹⁹replace, and optionally replaced independently selected from following substituted radical by one or more: halogen, cyano group, nitro ,-R ¹¹,-OR ¹¹,-COR ¹¹,-CONR ¹¹r ¹²,-NR ¹¹r ¹²with-NR ¹¹cOR ¹²;

When existing, R ³it is methyl;

R ¹¹, R ¹²and R ¹⁸be hydrogen independently or be selected from following group: C _1-6alkyl, carbocylic radical and heterocyclic radical, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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; With

R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

M is 0 or 1;

¹y is CH, and Y ²n;

R ¹to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrazolyl ethyl, furyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group optionally is selected from following substituted radical by 1 or 2 and replaces: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NHCOCH ₃,-CONH ₂with-CONHCH ₃;

Or-XR ¹be-C (CH ₃) ₂oH or-CH ₂oH;

When existing, R ³it is methyl;

R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces 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.

In the further specific category of formula (I) compound or pharmaceutically acceptable salt thereof;

M is 1;

¹y is CH, and Y ²n.

R ²by-NHCONHR ¹⁹replace, and optionally by one or more phenyl or pyridyl that replace independently selected from following substituted radical: fluorine, methyl, methoxyl group, methylol, cyano methyl ,-CONH ₂,-CONHCH ₃with-CON (CH ₃) ₂;

R ³it is methyl; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl ， isoxazolyl, pyrazolyl, the pyrazolyl methyl, pyridyl and pyrimidyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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.

M is 1;

¹y is CH, and Y ²n.

R ³it is methyl; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl ， isoxazolyl, pyrazolyl, the pyrazolyl methyl, pyridyl and pyrimidyl, this group optionally is selected from following substituted radical and replaces 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.

M is 1;

¹y is CH, and Y ²n.

R ¹to be selected from following group: methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂oMe ,-CH ₂cH ₂nMe ₂,-CH ₂cH ₂nC (O) CH ₃,-CH ₂cONH ₂, phenyl, 3,5-difluorophenyl, the 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2-trifluoromethyl, the 2-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, trimethylene oxide-3-base, 2-oxo-pyrrolidine-3-base, 1-Methylimidazole-5-ylmethyl, 1-methylpyrrolidin-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;

R ²be

A wherein ¹and A ²be selected from CH or N, condition is, at least one A ¹or A ²cH;

R ¹⁷hydrogen;

R ¹⁸hydrogen;

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl) ， isoxazole-3-base, 6-oxo-1H-pyridine-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyridyl-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl; With

R ³it is methyl.

M is 1;

¹y is CH, and Y ²n.

R ¹to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nC (O) CH ₃,-CH ₂cONH ₂, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen;

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl) ， isoxazole-3-base, 6-oxo-1H-pyridine-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;

With, R ³it is methyl.

M is 1;

¹y is CH, and Y ²n.

R ¹methyl or cyclopropyl;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen;

R ¹⁹methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH and 1H-pyrazole-3-yl;

With, R ³it is methyl.

M is 1;

X is-S (O) ₂c (CH ₃) ₂-connection base;

¹y is CH, Y ²n.

R ¹ethyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen;

R ¹⁹methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH,

-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH and 1H-pyrazole-3-yl;

With, R ³it is methyl.

In one aspect of the invention, provide the hypotype of formula (I) compound, the compound of its Chinese style (I) is formula (Ia) or compound (Ib)

Or its pharmacologically acceptable salt;

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ³it is methyl;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or R ¹⁸and R ¹⁹form 6-unit heterocycle together with the nitrogen-atoms be connected with them, wherein 1 ring carbon atom is optionally replaced by N or O, and this ring optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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

In another aspect of the present invention, the hypotype of formula (I) compound is provided, the compound of its Chinese style (I) is formula (Ia) or compound (Ib)

Or its pharmacologically acceptable salt;

X is selected from following connection base :-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-;

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ³it is methyl;

R ⁴and R ⁵hydrogen or C independently _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

Or its pharmacologically acceptable salt;

Or X-R ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ³it is methyl;

R ⁴hydrogen or C _1-6alkyl;

R ⁸be selected from hydrogen, halogen, cyano group and C _1-6alkyl;

In another specific category of formula (I) compound, the compound of formula (I) is formula (Ia) or compound (Ib),

Or its pharmacologically acceptable salt;

¹y is CH, Y ²n;

Or-XR ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ³it is methyl;

R ¹⁹be hydrogen or be selected from following group: C _1-6alkyl, C _3-6cycloalkyl, aryl, heteroaryl, aryl C _1-6alkyl and heteroaryl C _1-6alkyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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

Or its pharmacologically acceptable salt;

¹y is CH, Y ²n;

Or-XR ¹be-C (CH ₃) ₂oH or-CH ₂oH;

R ³it is methyl;

In the further specific category of formula (I) compound, the compound of formula (I) is formula (Ia) or compound (Ib),

Or its pharmacologically acceptable salt;

¹y is CH, Y ²n.

R ³it is methyl; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazoles methyl ， isoxazolyl, pyrazolyl, the pyrazolyl methyl, pyridyl and pyrimidyl, this group optionally is selected from following substituted radical and replaces by one or more: halogen, cyano group, nitro, hydroxyl, oxo, 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

Or its pharmacologically acceptable salt;

¹y is CH, Y ²n.

R ³it is methyl; With

Or its pharmacologically acceptable salt;

M is 1;

¹y is CH, Y ²n.

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl) ， isoxazole-3-base, 6-oxo-1H-pyridine-2-base, 5-methyl-isoxazole-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyridyl-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl;

With, R ³it is methyl.

Or its pharmacologically acceptable salt;

M is 1;

¹y is CH, Y ²n.

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

With, R ³it is methyl.

Or its pharmacologically acceptable salt;

M is 1;

¹y is CH, Y ²n.

R ¹methyl or cyclopropyl;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH and 1H-pyrazole-3-yl;

With, R ³it is methyl.

Or its pharmacologically acceptable salt;

M is 1;

X is-S (O) ₂c (CH ₃) ₂-connection base;

¹y is CH, Y ²n.

R ¹methyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

With, R ³it is methyl.

Another aspect of the present invention provides a kind of compound of any one that is selected from embodiment or combination or its pharmacologically acceptable salt of compound.

The present invention also provides the method for preparation formula (I) compound or pharmaceutically acceptable salt thereof.

The compound of formula (I), wherein X=-S (O) ₂cR ⁶r ⁷-, can be prepared as follows: incite somebody to action wherein X=SCR ⁶r ⁷-formula (I) compound oxidation, for example use

at room temperature, in the mixed solvent system of water and ethanol.

The compound of formula (I), wherein R ¹x=R ¹oCR ⁶r ⁷-, can be prepared as follows: optionally at suitable alkali for example triethylamine and solvent for example under the existence of tetrahydrofuran (THF) or DMF, wherein R ¹x=HOCR ⁶r ⁷-formula (I) compound and L wherein ¹formula (II) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted.

The compound of formula (I), wherein R ¹x=R ¹r ⁴nCR ⁶r ⁷-, can be prepared as follows: optionally at suitable alkali for example triethylamine and solvent for example under the existence of tetrahydrofuran (THF) or DMF, wherein R ¹x=HR ⁴nCR ⁶r ⁷-formula (I) compound and L wherein ¹formula (II) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted; Or at suitable reductive agent NaCNBH for example ₃existence under, R wherein ¹x=HR ⁴nCR ⁶r ⁷-formula (I) compound with the compound of formula (III), reacted.

The compound of formula (I), wherein X ¹=-S (O) ₂cR ⁶r ⁷-,-SCR ⁶r ⁷-,-OCR ⁶r ⁷-,-R ⁴nCR ⁶r ⁷-,-S (O) CR ⁶r ⁷-, can be prepared as follows: optionally at suitable alkali for example triethylamine and solvent for example under the existence of tetrahydrofuran (THF) or DMF, wherein L ¹formula (IV) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted with the compound of formula (V).

The compound of formula (I), wherein X=-SCR ⁶r ⁷-, can be prepared as follows: at suitable solvent for example in ethanol, L wherein ¹formula (IV) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted with thiocarbamide; the compound of production (VI); it is subsequently at suitable alkali sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, with the compound of formula (II), react.

The compound of formula (I), wherein X=-R ⁴nC (O)-, can be prepared as follows: the compound of formula (VII) and formula R ¹r ⁴the amine of NH is reacted, and before this reaction, utilizes the known in the literature method to carry out the suitable activation of carboxylic acid, for example uses for example HATU of coupler, or is converted into chloride of acid.

The compound of formula (I), wherein X=-S (O) ₂cR ⁶r ⁷-, can be prepared as follows: at suitable alkali for example under the existence of sodium hydride or potassium tert.-butoxide, at suitable solvent for example in tetrahydrofuran (THF) or DMF, the compound of formula (I) (X=-S (O) wherein ₂cH ₂-) carry out consecutive reaction with the compound of formula (VIII), then with the compound of formula (IX) (L wherein ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.)) reaction.

The compound of formula (I), wherein R ¹x=-HOCR ⁶r ⁷-, can be prepared as follows: in suitable solvent, the suitable organometallic compound of the compound of formula (X) and formula (XI) and formula (XII) for example Grignard reagent is reacted.If R ⁶and R ⁷different, can use the known in the literature technology, for example the compound of formula (X) is converted into to the Weinreb acid amides, in step subsequently, react with the organometallic reagent of formula (XI), then react with the organometallic reagent of formula (XII).

The compound of formula (I) can be by the compound of formula (XIII) (L wherein ²be leavings group (for example halogen, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.) for example, with suitable organometallic reagent (boric acid R ²b (OH) ₂or boron ester R ²b (OR) ₂etc.) preparation, for example, under the existence of suitable metal catalyzer (palladium or copper), at suitable solvent, for example in Isosorbide-5-Nitrae-dioxs, carry out.Perhaps, if R ²by nitrogen, oxygen or sulphur atom, with pyrimidine ring, be connected, the compound of formula (I) can be by the compound of formula (XIII) (L wherein ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.)), by with required amine, alcohol or thiol reactant preparation, in appropriate base, for example under the existence of salt of wormwood, at suitable solvent, for example in DMF, carry out.

Should be understood that and utilize above-listed or for example oxidation of known in the literature technology, alkylation, reduction amination etc., the compound of formula (XIII) can be transformed into the compound of another kind of formula (XIII).

The compound of formula (XIII), wherein X ¹=-S (O) ₂cR ⁶r ⁷-,-SCR ⁶r ⁷-,-OCR ⁶r ⁷-,-R ⁴nCR ⁶r ⁷-,-S (O) CR ⁶r ⁷-, can be prepared as follows: optionally at suitable alkali for example triethylamine and solvent for example under the existence of tetrahydrofuran (THF) or DMF, wherein L ¹formula (XIV) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted with the compound of formula (V).

The compound of formula (XIII), wherein X=-SCR ⁶r ⁷-, can be prepared as follows: at suitable solvent for example in ethanol, L wherein ¹formula (XIV) compound that is leavings group (for example halogen, tosyl group, methylsulfonyl etc.) is reacted with thiocarbamide; the compound of production (XV); it is subsequently at suitable alkali sodium hydroxide and solvent N for example for example; under the existence of dinethylformamide, with the compound of formula (II), react.

The compound of formula (XIII), wherein X=-R ⁴nC (O)-, can be prepared as follows: the compound of formula (XVI) and formula R ¹r ⁴the amine of NH is reacted, and before this reaction, utilizes the known in the literature method to carry out the suitable activation of carboxylic acid, for example uses for example HATU of coupler, or is converted into chloride of acid.

The compound of formula (XIII), wherein X=-S (O) ₂cR ⁶r ⁷-, can be prepared as follows: at suitable alkali for example under the existence of sodium hydride or potassium tert.-butoxide, at suitable solvent for example in tetrahydrofuran (THF) or DMF, the compound of formula (XIII) (X=-S (O) wherein ₂cH ₂-) with the compound of formula (VIII), reacted, then sequentially with the compound of formula (IX) (L wherein ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.)) reaction.

The compound of formula (XIII), wherein R ¹x=HOCR ⁶r ⁷-, can be prepared as follows: in suitable solvent, the suitable organometallic reagent of the compound of formula (XVII) and formula (XI) and formula (XII) for example Grignard reagent is reacted.If R ⁶and R ⁷different, can use the known in the literature technology, for example the compound of formula (XVII) is converted into to the Weinreb acid amides, in step subsequently, react with the organometallic reagent of formula (XI), then react with the organometallic reagent of formula (XII).

The compound of formula (IV) can be by the compound of formula (XIV) (L wherein ²be leavings group (for example halogen, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.)) with suitable organometallic reagent (boric acid R for example ²b (OH) ₂or boron ester R ²b (OR) ₂etc.) preparation, for example, under the existence of suitable metal catalyzer (palladium or copper), at suitable solvent, for example in Isosorbide-5-Nitrae-dioxs, carry out.Perhaps, if R ²by nitrogen, oxygen or sulphur atom, with pyrimidine ring, be connected, the compound of formula (IV) can be by the compound of formula (XIV) (L wherein ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.)) preparation, by with required amine, alcohol or thiol reactant, in appropriate base, for example under the existence of salt of wormwood, at suitable solvent, for example in DMF, carry out.

The compound of formula (X) can be by the compound of formula (XVII) (L wherein ²be leavings group (for example halogen, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), and R be hydrogen or C _1-4alkyl) for example, with suitable organometallic reagent (boric acid R ²b (OH) ₂or boron ester R ²b (OR) ₂etc.), for example, under the existence of suitable metal catalyzer (palladium or copper), at suitable solvent, for example in Isosorbide-5-Nitrae-dioxs, prepare.Perhaps, if R ²by nitrogen, oxygen or sulphur atom, with pyrimidine ring, be connected, the compound of formula (X) can be by the compound of formula (XVII) (L wherein ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.)), by with required amine, alcohol or thiol reactant, in appropriate base, for example under the existence of salt of wormwood, at suitable solvent, for example in DMF, prepare.

The compound of formula (XVIII) can be by the compound of formula (XIX) (L wherein ²be leavings group (for example halogen, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.) for example, with suitable organometallic reagent (boric acid R ²b (OH) ₂or boron ester R ²b (OR) ₂etc.), for example, under the existence of suitable metal catalyzer (palladium or copper), at suitable solvent, for example in Isosorbide-5-Nitrae-dioxs, prepare.Perhaps, if R ²by nitrogen, oxygen or sulphur atom, with pyrimidine ring, be connected, the compound of formula (XVIII) can be by the compound of formula (XIX) (L wherein ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.)), by with required amine, alcohol or thiol reactant, in appropriate base, for example under the existence of salt of wormwood, at suitable solvent, for example in DMF, prepare.

The compound of formula (XX) can be by the compound of formula (XXI) (L wherein ²be leavings group (for example halogen, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.) for example, with suitable organometallic reagent (boric acid R ²b (OH) ₂or boron ester R ²b (OR) ₂etc.), for example, under the existence of suitable metal catalyzer (palladium or copper), at suitable solvent, for example in Isosorbide-5-Nitrae-dioxs, prepare.Perhaps, if R ²by nitrogen, oxygen or sulphur atom, with pyrimidine ring, be connected, the compound of formula (XX) can be by the compound of formula (XXI) (L wherein ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.)), by with required amine, alcohol or thiol reactant, in appropriate base, for example under the existence of salt of wormwood, at suitable solvent, for example in DMF, prepare.

The compound of formula (I), wherein L ¹it is leavings group (halogen for example; tosyl group; methylsulfonyl etc.); can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine; at suitable solvent N for example; in dinethylformamide, the compound of formula (XXII) is reacted with the compound of formula (XXIII).

Should be understood that and utilize above-listed or for example oxidation of known in the literature technology, alkylation, reduction amination etc., the compound of formula (XXII) can be transformed into the compound of another kind of formula (XXII).

The compound of formula (IV), wherein L ¹it is leavings group (halogen for example; tosyl group; methylsulfonyl etc.); can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine; at suitable solvent N for example; in dinethylformamide, the compound of formula (XXIV) is reacted with the compound of formula (XXIII).

The compound of formula (X), wherein L ¹be leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and R is hydrogen or C _1-4alkyl can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXV) is reacted with the compound of formula (XXIII).

The compound of formula (XVIII), wherein L ¹it is leavings group (halogen for example; tosyl group; methylsulfonyl etc.); can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine; at suitable solvent N for example; in dinethylformamide, the compound of formula (XXVI) is reacted with the compound of formula (XXIII).

The compound of formula (XX), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXVII) is reacted with the compound of formula (XXIII).

The compound of formula (XIII), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXVIII) is reacted with the compound of formula (XXIII).

The compound of formula (XIV), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXIX) is reacted with the compound of formula (XXIII).

The compound of formula (XVII), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), and R be hydrogen or C _1-4alkyl can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXX) is reacted with the compound of formula (XXIII).

The compound of formula (XIX), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXXI) is reacted with the compound of formula (XXIII).

The compound of formula (XXI), wherein L ¹leavings group (for example halogen, tosyl group, methylsulfonyl etc.), and L ²leavings group (halogen for example, tosyl group, methylsulfonyl ,-SMe ,-S (O) ₂me etc.), can be prepared as follows: optionally at suitable alkali for example under the existence of triethylamine, at suitable solvent, for example in DMF, the compound of formula (XXXII) is reacted with the compound of formula (XXIII).

The compound of formula (I), wherein R ¹x=H ₂nCH ₂-, can be by the preparation of the compound of formula (XVIII), at suitable solvent for example in ethanol, utilize reduction for example with hydrogen and suitable catalyst for example palladium/carbon carry out hydrogenation.

The compound of formula (I), wherein R ¹x=H ₂nC (O)-, can utilize hydrolysis by the preparation of the compound of formula (XVIII), for example at suitable solvent, for example in the water-ethanol mixture, use sodium hydroxide hydrolysis.

The compound of formula (I), wherein R ¹x=H ₂nCR ⁶r ⁷-, can utilize and organometallic compound (XI) and reacting (XII), by the compound preparation of formula (XVIII).

The compound of formula (XIII), wherein R ¹x=H ₂nCH ₂-, can be by the preparation of the compound of formula (XIX), for example in ethanol, utilize reduction at suitable solvent, for example with hydrogen and suitable catalyst for example palladium/carbon carry out hydrogenation.

The compound of formula (XIII), wherein R ¹x=H ₂nC (O)-, can utilize hydrolysis by the preparation of the compound of formula (XIX), for example at suitable solvent, for example in the water-ethanol mixture, use sodium hydroxide hydrolysis.

The compound of formula (XIII), wherein R ¹x=H ₂nCR ⁶r ⁷-, can utilize and organometallic reagent (XI) and reacting (XII), by the compound preparation of formula (XIX).

Should be understood that and can introduce R with the form of carbocyclic ring or heterocyclic amine in initial any step ²group (is optionally protected with nitrogen; this protecting group is including, but not limited to nitro; tert.-butoxy carbamate etc.); by with isocyanic ester (or activating group for example phenoxy group carbamate etc.) direct reaction; or by the activation (for example, with phosgene or formation phenoxy group carbamate etc.) of amine; and reacted, or utilize subsequently known in the literature other forms the method for urea, the R of above-mentioned introducing with suitable amine ²group can be converted into urea in synthesis step (after suitable deprotection) subsequently.

Should understand, in compound of the present invention, can introduce some various ring substituents, this can pass through the substitution reaction of standard aromatics, or produce (before aforesaid method or after aforesaid method immediately) by the modification of conventional functional group, and this is also included within method of the present invention aspect.For example, utilize the substitution reaction of standard aromatics or conventional modified with functional group, the compound of formula (I) can change other formula (I) compound into.This reaction and modification for example comprise: 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 well-known at chemical field.The object lesson of aromatics substitution reaction comprises: use concentrated nitric acid to introduce nitro, for example use acyl halide and Lewis acid (for example aluminum chloride), under Friedel Crafts condition, introduce acyl group; Use haloalkane and Lewis acid (for example aluminum chloride), under Friedel Crafts condition, introduce alkyl; With the introducing halogen group.The object lesson of modifying comprises: by for example with nickel catalyzator, carrying out catalytic hydrogenation or processing with iron under the existence of hydrochloric acid (heating), nitroreduction is amino; Alkylthio is oxidized to alkyl sulphinyl or alkyl sulphonyl.

Should also be understood that in some reactions of mentioning at this paper any sensitive group in the possible necessary/compound that needs protection.Situation about must or need protection and suitable guard method are known to 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 Wileyand Sons, 1991) according to standard practices.Thus, if reactant comprises group for example amino, carboxyl or hydroxyl, this group of protection in some reactions that need to mention at this paper.

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

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

The appropriate protection base of carboxyl is 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 process to remove; or benzyl for example, its can be for example by with catalyzer for example carbon carry palladium hydrogenation and remove.

In the traditional method of using chemical field to know synthetic, can be in office what easily step remove protecting group.

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

biological test

Can use following test determination the compounds of this invention as the mTOR kinase inhibitor, as the PI3 kinase inhibitor, as the Activated in Vitro inhibitor in PI3 kinase signal path with as the effect of the in-vitro multiplication inhibitor of MDA-MB-468 human breast adenocarcinoma cell.

(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 to come by recombinant chou mTOR the ability of phosphorylation.

In the HEK293 cell, the C end disappearance (EMBL accession designation number L34075) that will comprise the mTOR of mTOR amino-acid residue 1362 to 2549 stably is expressed as the fusions of FLAG mark, as people such as Vilella-Bach at Journal of Biochemistry, 1999, as described in 274,4266-4272.The mTOR of HEK293 FLAG mark (1362-2549) stabilized cell is tied up to Dulbecco modification Eagle ' s growth medium (DMEM; InvitrogenLimited, Paisley, UK Catalogue No.41966-029) in use 5%CO ₂keep under 37 ℃ routinely, merge the fetus calf serum (FCS that growth medium comprises 10% heat inactivation until reach 70-90%; Sigma, Poole, Dorset, UK, Catalogue No.F0392), 1%L-glutamine (Gibco, Catalogue No.25030-024) and 2mg/mlGeneticin (G418 vitriol; Invitrogen Limited, UK Catalogue No.10131-027).After expressing in warm-blooded animal HEK293 clone, the Application standard purification technique, used the FLAG Epitope tag, by the protein purification of expressing.

In DMSO, test compound is prepared as to the 10mM stock solution, and is diluted to as required in water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into to the hole of the Greiner white polystyrene plate of 384 hole lower volume (LV) (Greiner Bio-one).By the mTOR enzyme of recombinant chou purifying, biotinylated 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 ₂; Bachem UK Ltd), 30 μ l mixtures of ATP (20 μ M) and buffered soln [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)] at room temperature stir 90 minutes.

Use 5%DMSO to replace test compound, create the control wells that produces minimum signal (being equivalent to maximum enzyme activity).By adding EDTA (83mM) to replace test compound, create and produce the minimum signal control wells of (being equivalent to the enzyme fully suppressed).At room temperature, these testing liquids are cultivated 2 hours.

By adding EDTA (50mM), bovine serum albumin (BSA; 0.5mg/mL) and Tris-HCl pH7.4 damping fluid (50mM) (comprise p70 S6K (T389) 1A5 monoclonal antibody (Cell Signalling Technology, Catalogue No.9206B)) and 10 μ l mixtures of AlphaScreen streptavidin donor stop each reaction, add A protein receptor bead (200ng; Perkin Elmer, Catalogue No. is respectively 6760002B and 6760137R), and at room temperature, in the dark will test plate and place about 20 hours.Use the PackardEnvision instrument, read the signal (being caused by laser excitation at 680nm) obtained.

Due to the phosphorylation of mTOR mediation, original position has formed the biotinylation peptide of phosphorylation.The biotinylation peptide of phosphorylation (it is relevant to AlphaScreen streptavidin donor bead) forms mixture with p70 S6K (T389) 1A5 monoclonal antibody (it is relevant with Alphascreen albumin A acceptor bead).Once, in 680nm laser excitation, the donor bead: acceptor bead mixture just produces the signal that can measure.Correspondingly, the existence of mTOR kinase activity can produce test signal.Under the existence of mTOR kinase inhibitor, strength of signal reduces.

For given test compound, the mTOR enzyme suppresses can be with IC ₅₀value representation.

(b) external PI3K enzyme test

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

Application standard molecular biology and PCR clone technology are separated the DNA fragmentation of coding mankind's PI3K catalysis and regulator subunit from the cDNA storehouse.By selected DNA fragmentation for generation of rhabdovirus expression vector.Especially, the full length DNA of each p110 α, p110 β and p110 δ Ia type mankind PI3K p110 heterogeneous (the EMBLAccession Nos. of p110 α, p110 β and p110 δ is respectively HSU79143, S67334, Y10055) is subcloned into to pDEST10 carrier (Invitrogen Limited, Fountain Drive, Paisley, UK) in.Carrier is the entrance adaptive version of the Fastbac1 that comprises the 6-His Epitope tag.The intercepting form of type I b mankind PI3K p110 γ heterogeneous (being equivalent to amino-acid residue 144-1102 (EMBL Accession No.X8336A)) and total length mankind p85 α regulator subunit (EMBL Accession No.HSP13KIN) also are subcloned in the pFastBac1 carrier that comprises the 6-His Epitope tag.By p85 α regulator subunit co expression Ia type p110 structure.After Application standard baculovirus expression technology is expressed in rhabdovirus system, the Application standard purification technique, used the His Epitope tag, by the protein purification of expressing.

Application standard molecular biology and PCR clone technology, from cDNA storehouse DNA isolation (it is equivalent to the amino acid 263 to 380 of the general acceptor in human phosphatase inositol (Grp1) PH zone).The DNA fragmentation obtained is subcloned into to pGEX 4T1 coli expression carrier and (comprises GST Epitope tag (Amersham Pharmacia Biotech, Rainham, Essex, UK)) in, as people such as Gray at Analytical Biochemistry, described in 2003,313:234-245.Express the Grp1 PH zone of GST mark, and Application standard technology purifying.

In DMSO, test compound is prepared as to the 10mM stock solution, and is diluted to as required in water, obtain a series of final experimental concentration.Each diluted chemical compound thing of equal portions (2 μ l) is put into to white polystyrene plate (the Greiner Bio-one of Greiner 384 hole lower volume (LV), Brunel Way, Stonehouse, Gloucestershire, UK Catalogue No.784075) hole in.By the PI3K enzyme (15ng) of each selected recombinant chou purifying, DiC8-PI (4,5) P2 matrix (40 μ M; Cell Signals Inc., Kinnear Road, Columbus, USA, CatalogueNo.901), Adenosine Triphosphate (ATP; 4M) and buffered soln [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 stir 20 minutes.

Use 5%DMSO to replace test compound, create the control wells that produces minimum signal (being equivalent to maximum enzyme activity).Add wortmannin (6 μ M; Calbiochem/MerckBioscience, Padge Road, Beeston, Nottingham, UK, Catalogue No.681675) replace test compound, establishment can produce the control wells of peak signal (enzyme that is equivalent to suppress fully).At room temperature, also these testing liquids are stirred to the companion 20 minutes.

Stop each reaction by the mixture that adds 10 μ l EDTA (100mM), bovine serum albumin (BSA, 0.045%) and Tris-HCl pH7.6 damping fluid (40mM).

Add biotinylated-DiC8-PI (3,4,5) P3 (50nM; Cell Signals Inc., Catalogue 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 BioscienceLimited, Station Road, Pangbourne, Berkshire, UK, Catalogue No.6760603M), at room temperature, in the dark will test plate and place about 5 to 20 hours.Use Packard AlphaQuest instrument, read the signal (being caused by laser excitation at 680nm) obtained.

Due to the phosphorylation of the PI3K of PI (4,5) P2 mediation, original position forms PI (3,4,5) P3.GST-Grp1 PH region protein (it is relevant to the anti-GST donor of AlphaScreen bead) forms mixture with biotinylated PI (3,4,5) P3 (it is relevant to Alphascreen Streptavidn acceptor bead).Enzyme living PI (3,4,5) P3 and biotinylated PI (3,4,5) the P3 competition of hastening parturition is combined with the PH region protein.Once, in 680nm laser excitation, the donor bead: acceptor bead mixture just produces the signal that can measure.Correspondingly, the PI3K enzymic activity forms PI (3,4,5) P3 and competes with biotinylated PI (3,4,5) P3 subsequently, causes signal to reduce.Under the existence of PI3K enzyme inhibitors, strength of signal is recovered.

For given test compound, the PI3K enzyme suppresses with IC ₅₀value representation.

(c) external phosphate-Ser473 Akt test

This test determination test compound suppresses Serine 473 and suppress the ability of phosphorylation in Akt, uses Acumen Explorer technology (Acumen Bioscience Limited), plate reader (feature that can be used for Fast Measurement image that laser scanning produces) to be estimated.

In DMEM (FCS that comprises 10% heat inactivation and 1%L-glutamine), MDA-MB-468 human breast gland cell system (LGC Promochem, Teddington, Middlesex, UK, Catalogue No.HTB-132) is used to 5%CO ₂routine remains on 37 ℃, until reach the fusion of 70-90%.

For this test, use ' Accutase ' (Innovative Cell Technologies Inc., SanDiego, CA, USA; Catalogue No.AT104), the Application standard tissue culture method separates cell from culturing bottle, and is resuspended in medium, obtains every mL 1.7x10 ⁵individual cell.Aliquot sample (90 μ l) is seeded into to black Packard 96 hole plate (PerkinElmer, Boston, MA, USA; Catalogue No.6005182), in inner 60 holes of each, obtain the density of every hole～15000 cell.Equal portions (90 μ l) substratum medium is placed in external holes, to prevent fringing effect.By cell 5%CO ₂37 ℃ of lower overnight incubation, make them bonding.

At the 2nd day, process cell with test compound, and use 5%CO ₂under 37 ℃, cultivate 2 hours.In DMSO, test compound is prepared as to the 10mM stock solution, and uses as required the growth medium serial dilution, obtain a series of concentration (its be required final experimental concentration 10 times).Each diluted chemical compound thing of equal portions (10 μ l) is placed on to (in triplicate) in hole, obtains the concentration finally needed.As the minimum response contrast, each plate comprises having 100 μ MLY ²the hole of the final concn of 94002 (Calbiochem, Beeston, UK, Catalogue No.440202).As the peak response contrast, hole comprises 1%DMSO and replaces test compound.After cultivation, by room temperature using 1.6% formalin (Sigma, Poole, Dorset, UK, Catalogue No.F1635), process 1 hour, the inclusion of plate is fixed.

Use Tecan 96 holes to wash dish device (pumping velocity 10mm/sec), carry out all suction and washing steps subsequently.Remove stationary liquid, with phosphate-buffered saline (PBS; 50 μ l; Gibco, Catalogue No.10010015) inclusion of washing plate.At room temperature, with the cell permeabilization damping fluid (mixture that comprises PBS and 0.5%Tween-20) of equal portions (50 μ l), the inclusion of plate is processed 10 minutes.Remove ' saturatingization ' damping fluid, at room temperature, in the mixture of PBS and 0.05%Tween-20, with comprising 5% skim-milk [' Marvel ' (registered trademark); Premier Beverages, Stafford, GB] equal portions (50 μ l) sealing damping fluid process 1 hour, by nonspecific binding site sealing.Remove ' sealing ' damping fluid, and at room temperature with the anti-phosphate-Akt of rabbit (SeR473) antibody-solutions (every hole 50 μ l; Cell Signalling, Hitchin, Herts, U.K., Catalogue No 9277) (in ' sealing ' damping fluid, diluting) by cell cultures 1 hour.In the mixture of PBS and 0.05%Tween-20, washed cell is three times.Subsequently, at room temperature, with goat anti-rabbit igg (every hole 50 μ l of Alexafluor488 mark; Molecular Probes Invitrogen Limited, Paisley, UK, Catalogue No.A11008) (in ' sealing ' damping fluid, being diluted to 1: 500) by cell cultures 1 hour.With the mixture washed cell of PBS and 0.05%Tween-20 3 times.The PBS of equal portions (50 μ l) is joined in each hole, with black plate sealer, seal plate, and the determination and analysis fluorescent signal.

The fluorescent agent quantitative response data analysis that each compound is obtained, and the inhibition kilsyth basalt of the Serine 473 in Akt is shown to IC ₅₀value.

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

This test determination test compound suppresses the ability of cell proliferation, uses the CellomicsArrayscan technology to be estimated.According to the next conventional maintenance MDA-MB-468 human breast gland cell system (LGC Promochem, Catalogue No.HTB-132) described in this paper biology mensuration (b).

For this proliferation test, to use Accutase that cell is removed from culturing bottle, and be seeded in the hole, 60 of inside of black Packard 96 hole plates, density is 8000, every hole cell, in the complete growth medium of 100 μ l.External holes comprises the aseptic PBS of 100 μ l.By cell 5%CO ₂37 ℃ of lower overnight incubation, make them bonding.

At the 2nd day, process cell with test compound, and use 5%CO ₂under 37 ℃, cultivate 48 hours.In DMSO, test compound is prepared as to the 10mM stock solution, and uses as required the growth medium serial dilution, obtain series of experiments concentration.Each diluted chemical compound thing of equal portions (50 μ l) is placed in hole, uses 5%CO ₂under 37 ℃, cultivate 2 days.Each plate comprises the control wells without test compound.

At the 4th day, add the reagent (Sigma, Catalogue No.B9285) (finally diluting 1: 1000) of BrdU mark, 37 ℃ of culturing cells 2 hours.Remove medium, by room temperature, process 30 minutes with the mixture (90% ethanol, 5% Glacial acetic acid and 5% water) of 100 μ l ethanol and Glacial acetic acid, the cell in each hole is fixed.Wash cell in each hole twice with PBS (100 μ l).Aqueous hydrochloric acid (2M, 100 μ l) is joined in each hole.After at room temperature 20 minutes, use twice of PBS washed cell.By hydrogen peroxide (3%, 50 μ l; Sigma, CatalogueNo.H1009) join in each hole.After at room temperature 10 minutes, with PBS washing hole again.

By at room temperature with the anti-BrdU antibody of mouse (50 μ l; Caltag, Burlingame, CA, US; Catalogue No.MD5200) (in the PBS that comprises 1%BSA and 0.05%Tween-20, be diluted to 1: 40) and cultivate the combination that detects BrdU in 1 hour.Remove unconjugated antibody by the PBS washed twice.Visual for introduced BrdU, at room temperature, process cell 1 hour with PBS (50 μ l) and 0.05%Tween-20 damping fluid (1: 1000 dilution of the goat anti-mouse IgG that comprises Alexa fluor 488 marks).For nuclear visual, add 1: 1000 dilution (Molecular Probes, the Catalogue No.H of Hoechst pigment (stain) ₃570).Each plate is washed with PBS successively.Subsequently, PBS (100 μ l) is joined in each hole, analyze plate with the Cellomics matrix-scanning, thereby estimate the number of total cell number and BrdU positive cell.

The fluorescent agent quantitative response data analysis that each compound is obtained, and by the inhibition degree of MDA-MB-468 Growth of Cells with IC ₅₀value representation.

Although the pharmacology performance of formula (I) compound resemble expectation with structural modification, change, people usually believe activity that formula (I) compound has can be in one or more above-mentioned tests (a) in (d), be proven under following concentration or dosage :-

Test (a) :-for chemical compound lot, for the kinase whose IC of mTOR ₅₀value is less than 10 μ M, especially 0.001-0.5 μ M; For example 34b measures IC in two situations ₅₀value, value is 0.155 and 0.093 μ M.

Test (b) :-for chemical compound lot, for the IC of p110 γ Ib type mankind PI3K ₅₀value is less than 10 μ M, especially 0.001-0.5 μ M; For chemical compound lot,

IC for p110 α Ia type mankind PI3K ₅₀value is less than 10 μ M, especially 0.001-0.5 μ M; For example 34b measures IC in two situations ₅₀value, value is 91.2 and 57.8 μ M.

Test (c) :-for chemical compound lot, for the IC of the Serine 473 in Akt ₅₀value is less than 10 μ M, especially 0.1-20 μ M; For example 34b measures IC in two situations ₅₀value, value is 1.361 and 0.654 μ M.

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

Compound of the present invention is favourable, because they have pharmacological activity.Especially, the compounds of this invention is regulated (especially 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 classification Ib PI3K enzyme (PI3K γ).More particularly, compound adjusting of the present invention (especially suppressing) mTOR kinases.More particularly, one or more PI3K enzymes of compound adjusting of the present invention (especially suppressing).The test method that can list with this paper and the test method in experimental section are carried out the rejection of proof formula (I) compound.Correspondingly, formula (I) compound can be for the treatment of the condition/disease in (treatment or prevention) people and inhuman animal, and this condition/disease is by mTOR kinases and/or the mediation of one or more PI3K enzymes, especially kinase mediated by mTOR.

The present invention also provides pharmaceutical composition, the combination that it comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable diluent or carrier.

Composition of the present invention can also be the form that is suitable for orally using (tablet for example, lozenge, hard or soft capsule, moisture or oily suspensions, emulsion, dispersible powder or particle, slurries or elixir), local type of service (emulsifiable paste for example, ointment, gelifying agent or moisture or oily solution or suspension), inhalation form (for example finely divided powder or liquid aerosol), be blown into form of medication (for example finely divided powder) or administered parenterally form (intravenously for example, subcutaneous, the aseptic aqueous solution of intraperitoneal or intramuscularly or oily solution, or for the suppository of rectal administration).

Can utilize conventional pharmaceutical vehicle well known in the art, by ordinary method, obtain composition of the present invention.Thus, the composition for oral design can comprise for example one or more tinting materials, sweeting agent, seasonings and/or sanitas.

Can with the amount of active ingredients that produces single formulation, need to change with one or more mixed with excipients, this depends on treated host and concrete mode of administration.For example, it (is more suitably 1 to 250mg that the preparation designed for human oral for example comprises the promoting agent of 1mg to 1g usually, for example 1 to 100mg), promoting agent and suitable and facilitate the vehicle of quantity to be mixed, vehicle can be total composition weight about 5 to about 98% between change.

According to the character of morbid state and severity, animal or patient's age and sex and route of administration, according to well-known medical principle, be used for the treatment of or prevent the amount nature difference of the formula I compound of purpose.

In the process of formula (I) compound that uses treatment or prevention purpose, usually give per daily dose, scope is for example to accept 1mg/kg to 100mg/kg body weight, if necessary, with the dosage form administration separated.Usually, when using parenteral route, give low dosage.Thus, for example, for intravenous administration, normally used dosage range is 1mg/kg to 25mg/kg body weight for example.Equally, for inhalation, the dosage range of use is 1mg/kg to 25mg/kg body weight for example.Typically, unit dosage comprises about 10mg to 0.5g compound of the present invention.

Stating as this paper, known mTOR kinases and PI3K enzyme have effect in tumorigenicity and many Other diseases.We have found that, the compound of formula (I) has the effective antitumour activity, thinks that this anti-tumor activity obtains by suppressing mTOR kinases and/or one or more PI3K enzymes.

Correspondingly, compound of the present invention is valuable anti-tumor agents.Especially, compound of the present invention suppress and/or treatment entity and/or liquid tumor disease in as antiproliferative, apoptosis and/or anti-intrusion medicament, be valuable.Especially, expect that compound of the present invention can be effective to prevention or treatment to suppressing for example those tumours of classification IaPI3K enzyme and classification Ib PI3K enzyme sensitivity of mTOR and/or one or more PI3K enzymes.Further, expect that compound of the present invention can be effective to prevention or treatment separately or part by mTOR and/or one or more PI3K enzymes those tumours of classification Ia PI3K enzyme and the mediation of classification Ib PI3K enzyme for example.Thus, this compound can produce mTOR enzyme inhibition in the warm-blooded animal of this treatment of needs.Some compound can produce PI3K enzyme inhibition in the warm-blooded animal of this treatment of needs.

As this paper statement, the inhibitor of mTOR kinases and/or one or more PI3K enzymes has therapeutic value, be used for the treatment of hyperplasia, cancer for example, especially for example cancer and sarcoma and leukemia and lymph malignant tumour of noumenal tumour, in particular for treating for example breast cancer, colorectal carcinoma, lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer and bronchioalveolar carcinoma disease) and prostate cancer, cholangiocarcinoma, the bone cancer, bladder cancer, 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, uterine neck and carcinoma vulvae, and leukemia [comprising acute lymph leukemia (ALL) and chronic myelogenic leukemia (CML)], multiple myeloma and lymphoma.

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein for example in the people, to be used as medicine warm-blooded animal.

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example in the people for generation of anti-proliferative effect.

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example in the people for generation of the apoptosis effect.

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

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example in the people for generation of the purposes of anti-proliferative effect.

According to the further feature of this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine for warm-blooded animal for example the people produce anti-proliferative effect.

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein warm-blooded animal for example in the people for generation of the purposes of apoptosis effect.

According to the further feature of this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine for warm-blooded animal for example the people produce the apoptosis effect.

According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine warm-blooded animal for example in the people as anti-intrusion medicament, for suppressing and/or treatment hyperplasia cancer for example.

Further feature according to this aspect of the present invention, the warm-blooded animal provided in this treatment of needs for example produces the method for anti-proliferative effect in the people, and the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.

Further feature according to this aspect of the present invention, the warm-blooded animal provided in this treatment of needs for example in the people by suppressing and/or treatment noumenal tumour disease produces the method for anti-intrusion effect, the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.

According to further aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine warm-blooded animal for example in the people for prevention or treatment hyperplasia cancer for example.

Further feature according to this aspect of the present invention, the warm-blooded animal provided in this treatment of needs for example prevents or treats for example method of cancer of hyperplasia in the people, and the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.

According to further aspect of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, for preventing or for example treating, to suppressing the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (classification Ia enzyme and/or classification Ib PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.

Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine is for prevention or treat for example, tumour to inhibition mTOR kinases and/or one or more PI3K enzymes (classification Ia enzyme and/or classification IbPI3K enzyme) sensitivity, and mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability.

Further feature according to this aspect of the present invention, provide prevention or treatment for example, to suppressing the method for the responsive tumour of mTOR kinases and/or one or more PI3K enzymes (classification Ia enzyme and/or classification Ib PI3K enzyme), mTOR kinases and/or one or more PI3K enzymes participate in causing the signal transduction step of tumor cell proliferation, survival, intrusion and transfer ability, and the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives described animal effective dose.

According to further aspect of the present invention, provide formula (I) compound or pharmaceutically acceptable salt thereof defined herein, for example, for mTOR kinase inhibition effect and/or PI3K enzyme inhibition (classification Ia PI3K enzyme or classification Ib PI3K enzyme inhibition) are provided.

Further feature according to this aspect of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, and this medicine for example, for providing mTOR kinase inhibition effect and/or PI3K enzyme inhibition (classification Ia PI3K enzyme or classification Ib PI3K enzyme inhibition).

According to further aspect of the present invention, a kind of method is provided, for example, for mTOR kinase inhibition effect and/or PI3K enzyme inhibition (classification Ia PI3K enzyme or classification Ib PI3K enzyme inhibition) are provided, the method comprises the formula I compound or pharmaceutically acceptable salt thereof defined herein that gives significant quantity.

According to further feature of the present invention, provide the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in treatment cancer, inflammatory diseases, obstructive respiratory tract disease, Immunological diseases or cardiovascular disorder defined herein.

According to further feature of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, be used for the treatment of noumenal tumour for example cancer and sarcoma and leukemia and lymph malignant tumour.

According to further feature of the present invention, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, has been 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, formula (I) compound or pharmaceutically acceptable salt thereof defined herein is provided, has been used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, 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, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, and this medicine is 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, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, this medicine is used for the treatment of noumenal tumour for example cancer and sarcoma and leukemia and lymph malignant tumour.

According to further feature of the present invention, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, and this medicine is 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, the purposes of formula (I) compound or pharmaceutically acceptable salt thereof in preparing medicine defined herein is provided, and this medicine is used for the treatment of cholangiocarcinoma, bone cancer, bladder cancer, 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, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphoma.

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

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

According to further feature of the present invention, the warm-blooded animal provided in this kind for the treatment of 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 in the people, and the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.

According to further feature of the present invention, the warm-blooded animal provided in this kind for the treatment of of needs is for example treated cholangiocarcinoma, bone cancer, bladder cancer, 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, uterine neck and carcinoma vulvae and leukemia (comprising ALL and CML), multiple myeloma and lymphadenomatous method in the people, and the method comprises formula defined herein (I) compound or pharmaceutically acceptable salt thereof that gives significant quantity.

Stating as this paper, after the compound of giving construction (I), by one or more metabolites that form, can partly bring into play the interior effect of body of formula (I) compound within human or animal body.

The invention further relates to combined therapy, wherein by the compound or pharmaceutically acceptable salt thereof of formula (I) or, the pharmaceutical composition that comprises formula (I) compound or preparation simultaneously or in a sequence, or give with the combination preparation form with controlling other treatment that tumor disease was used.

Especially, treatment defined herein can be used as monotherapy, or, except compound of the present invention, can also comprise routine operation or radiotherapy or chemotherapy.Correspondingly, compound of the present invention can also be used with the existing therapeutic combination for the treatment of cancer.

In combination for suitable medicament comprise:

(i) antiproliferative/antitumour drug and its combination, for example alkylating agent that for example Medical oncology is used (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Metabolic antagonist (antifolate for example, for example 5 FU 5 fluorouracil and Tegafur of 5-FU for example, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea and gemcitabine); Antitumor antibiotics (anthracycline antibiotics for example, Dx for example, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, Mitomycin-C, actinomycin and mithramycin); Antimitotic agent (vinca alkaloids for example, vincristin for example, vincaleucoblastine, desacetyl vinblastine amide and Vinorelbine, and Japanese yew class medicine, for example Paclitaxel and taxotere (taxotere)); For example, for example, with local isomerase inhibitors (epipodophyllotoxin, Etoposide and teniposide, amsacrine, Hycamtin and camptothecine);

(ii) cytostatic agent, estrogen antagonist (Tamoxifen for example for example, Toremifene Citrate, Raloxifene, droloxifene and iodoxyfene), estrogen receptor negative regulator agent (for example fulvestrant), androgen antagonist (bicalutamide for example, flutamide, Nilutamide and acetic acid Sai Pulong), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogen (for example megestrol), aromatase inhibitor is (for example, as Anastrozole, letrozole, vorozole and Exemestane) and the inhibitor of 5α-reductase finasteride for example,

(iii) anti-intrusion medicament (c-Src kinases man group inhibitor for example, 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-(the chloro-6-aminomethyl phenyl of 2-)-2-{6-[4-(2-hydroxyethyl) piperazine-1-yl]-2-methylpyrimidine-4-base amino thiazole-5-carboxamides (Dasatinib, BMS-354825; J.Med.Chem., 2004,47,6658-6661), and the inhibitors of metalloproteinase inhibitor of Marimastat (marimastat) and upar function for example);

(iv) inhibitor of somatomedin function: for example, this inhibitor comprises growth factor antibodies and growth factor receptor antibody (for example, former times monoclonal antibody [C225] is wanted in anti-erbB 2 antibody Herceptin [Herceptin] and anti-erbB1 antibody west), this inhibitor also comprises for example tyrosine kinase inhibitor, the inhibitor of epidermal growth factor family (EGFR family tyrosine kinase inhibitor N-(the chloro-4-fluorophenyl of 3-)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example for example for example, ZD1839), N-(3-ethynyl phenyl)-6, 7-bis-(2-methoxy ethoxy) quinazoline-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(the chloro-4-fluorophenyl of 3-)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033) and erbB2 tyrosine kinase inhibitor, lapatinibditosylate for example), the inhibitor of pHGF family, the inhibitor of PDGF 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 (BAY43-9006)) with by the inhibitor of MEK and/or the kinase whose cell signal of Akt,

(v) anti-angiogenic formation medicament, for example suppress those medicaments of vascular endothelial growth factor effect, [anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (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 in WO 01/32651), 4-(the fluoro-2 methyl indole of 4--5-base oxygen base)-6-methoxyl group-7-(3-pyrrolidin-1-yl propoxy-) quinazoline (AZD2171; Embodiment 240 in WO 00/47212), PTK787 (vatalanib) (PTK787; WO 98/35985) and SU11248 (Sutent (Sunitinib); WO 01/60814), and the compound by other mechanism work (linomide for example, integrin (v (inhibitor of 3 functions and angiostatin)];

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

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

(viii) gene therapy method, comprise for example method of abnormal p53 or abnormal BRCA1 or BRCA2 of aberrant gene of replacing, GDEPT (the direct enzyme precursor pharmacotherapy of gene) method, for example use those methods of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase, for example, with the method for increase patient for chemotherapy or radiocurable tolerance, multi-drug resistant gene therapy; With

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

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

Except as otherwise noted, starting raw material is commercially available.All solvents and commercial reagent are the laboratory grades, and can be used as it is.

In an embodiment, record on Bruker DPX 300 (300MHz), Bruker DRX 400 (400MHz) instrument or Bruker DRX 500 (500MHz) instrument ¹h NMR spectrum.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; The m multiplet; Br, broad peak.

Use silica gel (0.04-0.063mm, Merck) to carry out column chromatography.Usually, KromasilKR-100-5-C18 reversed-phase column (250x20mm, Akzo Nobel), for the preparation of HPLC, is used as elutriant, flow velocity 10mL/min with the mixture of acetonitrile and water [comprising 0.1% trifluoroacetic acid (TFA)].

Following method is analyzed for liquid chromatography (LC)/mass spectrum (MS):

HPLC:Agilent 1100 or Waters Alliance HT (2790 & 2795)

Mass spectrograph: Waters ZQ ESCi

the HPLC post

The standard HPLC post used is Phemonenex Gemini C18 5 μ m, 50x2mm.

acid HPLC method

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

Mobile phase B: acetonitrile

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

Use 5mL flow velocity Fast-Balance 0.45min after each method.

four kinds of general HPLC methods are suitable:

5 minutes monitoring acid methods

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

early stage the wash-out compound acid method in early stage

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Rational curve (curve)	Flow velocity/ml/min
						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

mid-term the wash-out compound acid method in mid-term

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Rational curve (curve)	Flow velocity/ml/min
						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 later stage acid method of later stage wash-out compound

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase C:	Rational curve (curve)	Flow velocity/ml/min
						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 the needed ionization of compound or chromatographic separation.In the case, four kinds of corresponding alkali formula HPLC methods are suitable.

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

Mobile phase B: acetonitrile

Moving phase D:0.1%880 ammonia/acetonitrile

Each method back is Fast-Balance, uses the 5mL flow velocity, 0.45min.

minute (minute) monitoring alkali formula method

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

early stage the wash-out compound alkali formula method in early stage

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Rational curve (curve)	Flow velocity/ml/min
						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

mid-term the wash-out compound alkali formula method in mid-term

Time/minute	Mobile phase A:	Mobile phase B:	Moving phase D:	Rational curve (curve)	Flow velocity/ml/min
						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 later stage alkali formula method of later stage wash-out compound

Following method is analyzed for liquid chromatography (LC)/mass spectrum (MS):

Instrument: Agilent 1100; Post: Waters ' Symmetry ' 2.1x30mm; Chemi-ionization (APCI) is used in mass spectroscopy; Flow velocity: 0.7 ml/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.

Following method is analyzed for LC:

Method A: instrument: Agilent 1100; Post: Kromasil C18 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.1%TFA/ water, solvent B:0.08%TFA/ acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, record the retention time of product.

Method B: instrument: Agilent 1100; Post: Waters ' Xterra ' C8 reverse phase silica gel, 100x3mm, 5 μ m particle diameters; Solvent orange 2 A: 0.015M ammonia/water, solvent B: acetonitrile; Flow velocity: 1 ml/min; Solvent gradient: 10-100% solvent B, 20 minutes, 100% solvent B then, 1 minute; Absorbing wavelength: 220,254 and 280nm.Usually, record the retention time of product.

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

The HPLC high performance 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 I-hydroxybenzotriazole;

HOAT 1-hydroxyl-7-azepine benzotriazole;

The NMP NMP;

The DMSO methyl-sulphoxide;

The DMF DMF;

The DMA N,N-dimethylacetamide;

The THF tetrahydrofuran (THF);

DME 1, the 2-glycol dimethyl ether;

The DCCI dicyclohexylcarbodiimide;

MeOH methyl alcohol;

The MeCN acetonitrile;

The DCM methylene dichloride;

The DIPEA DIPEA;

DBU 1,8-diazabicyclo [5.4.0] 11-7-alkene;

RT room temperature (about 17 to 25 ℃);

The tR retention time;

M/z mass/charge ratio.

Chemical name utilizes software to produce, and this software application Lexichem Toolkit (v.1.40) (being obtained from OpenEye Scientific Software (www.eyesopen.com)), meet the name of IUPAC with generation.

embodiment 1:

1-ethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] urea

By 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline (100mg, 0.28mmol) is dissolved in diox (4mL).Add ethyl isocyanate (0.109mL, 1.38mmol), and 70 ℃ of reacting by heating 4 hours.Reaction completes, and evaporate to dryness.The oil obtained by chromatogram purification; with 10-50% ethyl acetate/isohexane wash-out; obtain 3-ethyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] urea light yellow oil (113mg, 94%).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.99 (t, 3H), 1.25 (d, 3H), 3.11 (q, 2H), (3.20 s, 3H), 3.29 (m, 2H), 3.5 (m, 1H), (3.67 m, 1H), 3.78 (m, 1H), 3.99 (m, 1H), 4.16 (m, 1H), 4.47 (s, 2H), (6.18 t, 1H), 6.78 (s, 1H), 7.50 (d, 2H), 8.21 (d, 2H), 8.68 (s, 1H)

the LCMS spectrum:mH+434, retention time 1.37 minutes, method: 5 minutes acids

To be similar to preparation 3-ethyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] mode of urea, by suitable isocyanic ester and suitable aniline reaction, prepare and be shown in the compound in table.

Embodiment 1a: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.28 (d, 3H), 3.21 (s, 3H), 3.4 (m, 2H), (3.5 m, 1H), 3.65 (m, 1H), 3.71 (s, 3H), (3.8 d, 1H), 3.99 (m, 1H), 4.2 (m, 1H), (4.50 s, 2H), 6.79 (s, 1H), 6.89 (d, 2H), (7.38 d, 2H), 7.55 (d, 2H), 8.25 (d, 2H), 8.50 (s, 1H), 8.83 (s, 1H)

Embodiment 1b: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (d, 3H), 3.21 (s, 2H), 3.28-3.38 (m, 2H), (3.35 t, 1H), 3.67 (d, 1H), 3.69 (d, 1H), 4.18-4.22 (m, 1H), 4.50 (s, 3H), (6.79 s, 1H), 7.00 (m, 1H), 7.31 (m, 2H) 7.47 (d, 2H), 7.59 (d, 2H), 8.27 (d, 2H), 8.71 (s, 1H), 8.91 (s, 1H)

Embodiment 1c: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.10 (d, 6H), 1.24 (d, 3H), 3.29 (s, 3H), 3.49 (m, 1H), 3.64-3.66 (m, 1H), (3.77 m, 2H), 4.18-4.21 (m, 1H), 4.49 (s, 3H), 6.08 (d, 1H), 6.79, (s, 1H), 7.48 (d, 2H), (8.22 d, 2H), 8.51 (s, 1H)

Embodiment 1d: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.27 (m, 3H), 3.22 (s, 3H), (3.35-3.36 m, 1H), 3.41 (s, 1H), (3.51 d, 2H), 3.65-3.68 (m, 1H), (3.79 d, 1H), 3.98-4.02 (m, 1H), (4.18 s, 1H), 4.50 (s, 2H), 6.80 (s, 1H), (7.12-7.16 m, 2H), 7.47-7.50 (m, 2H), 7.57 (d, 2H), (8.27 d, 2H), 8.75 (s, 1H), 8.92 (s, 1H)

Embodiment 1e: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.27 (m, 3H), 3.21 (s, 3H), (3.25 t, 1H), 3.48-3.54 (m, 1H), (3.64-3.68 m, 1H), 3.79 (d, 1H), (3.98-4.02 m, 1H), 4.19 (s, 1H), (4.50 m, 1H), 4.51 (s, 2H), (6.84 s, 1H), 7.16 (d, 2H), (7.47-7.51 m, 2H), 8.08-8.12 (m, 1H), 8.13-8.15 (m, 1H), (8.31 t, 1H), 8.77 (d, 1H), 9.17 (s, 1H)

Embodiment 1f: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.26 (d, 3H), 3.21 (s, 3H), 3.24-3.26 (m, 1H), (3.52 t, 1H), 3.66 (t, 1H), 3.79 (d, 1H), (3.99-4.02 m, 2H), 4.18 (m, 1H), 4.52 (s, 3H), (6.84 s, 1H), 7.02 (t, 1H), 7.30-7.34 (m, 2H), (7.48 d, 2H), 8.08-8.15 (m, 2H), 8.34 (t, 1H), 8.79 (d, 1H), 9.15 (s, 1H)

Embodiment 1g: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.27 (m, 3H), 3.24 (s, 3H), (3.30 m, 1H), 3.49-3.53 (m, 1H), (3.65-3.69 m, 1H), 3.80 (d, 1H), (3.98 s, 3H), 4.00 (m, 1H), (4.02 m, 1H), 4.48 (m, 1H), (4.52 s, 2H), 6.82 (s, 1H), (7.12-7.17 m, 2H), 7.47-7.51 (m, 2H), 7.96 (s, 2H), (8.27 s, 1H), 8.42 (s, 1H), 9.45 (d, 1H)

Embodiment 1h: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.26 (d, 3H), 3.24 (s, 3H), (3.30 m, 1H), 3.49-3.55 (m, 1H), (3.65-3.69 m, 1H), 3.74 (s, 3H), (3.80 d, 1H), 3.97 (s, 3H), (4.00 m, 1H), 4.02 (m, 1H), (4.18-4.22 m, 1H), 4.47-4.49 (m, 1H), (4.52 s, 2H), 6.81 (s, 1H), 6.88-6.91 (m, 2H, 7.36-7.40 (m, 2H), (7.95 s, 2H), 8.28 (d, 1H), (8.36 s, 1H), 9.23 (s, 1H)

Embodiment 1i: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.27 (d, 3H), 3.21 (s, 3H), (3.25 m, 1H), 3.48-3.55 (m, 1H), (3.65-3.69 m, 1H), 3.79 (d, 1H), (3.98-4.02 m, 1H), 4.20 (s, 1H), (4.52 s, 3H), 6.87 (s, 1H), 7.14-7.21 (m, 2H), (7.56-7.60 m, 2H), 7.61-7.64 (m, 1H), 8.57-8.59 (m, 1H), (9.21-9.21 m, 1H), 9.70 (s, 1H), 10.52 (s, 1H)

Embodiment 1j: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.12 (t, 3H), 1.25-1.26 (m, 3H), (3.20 s, 3H), 3.22-3.24 (m, 2H), (3.26 m, 1H), 3.47-3.54 (m, 1H), (3.64-3.67 m, 1H), 3.78 (d, 1H), (3.97-4.01 m, 1H), 4.18 (s, 1H), 4.50 (s, 3H), (6.84 s, 1H), 7.48 (d, 1H), 8.10 (d, 1H), (8.48-8.51 m, 1H), 9.11 (m, 1H), 9.41 (s, 1H)

Test (a): embodiment (1) 0.0062 μ M; Embodiment (1a) 0.062 μ M; Embodiment (1b) 0.013 μ M; Embodiment (1c) 0.078 μ M; Embodiment (1d) 0.042 μ M; Embodiment (1e) 0.32 μ M; Embodiment (1f) 0.36 μ M; Embodiment (1g) 0.96 μ M; Embodiment (1h) 1.2 μ M; Embodiment (1i) 0.55 μ M; Embodiment (1j) 0.043 μ M.

Aniline 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline and the fluoro-4-[4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of aniline is described below.

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

By N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] carboxylamine tertiary butyl ester (1.09g; 2.35mmol) be dissolved in methyl alcohol (5mL), add 4M hydrochloric acid/diox (5mL).At room temperature stirred solution spends the night, and then mixture is evaporated to dun oil, and is dissolved in ethyl acetate (10mL).Add water (5mL), then add sodium hydrogen carbonate solution, until reach pH neutral (～2mL).Separation of phases, water (10mL) washing organic phase.Use the dried over mgso organic layer, evaporation, obtain light yellow foam (805mg).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.23 (3H, d), 3.31 (3H, s), 3.5 (1H, m), 3.64 (1H, m), (3.78 1H, m), 4.13 (1H, m), 4.49 (2H, m), 5.57 (2H, s), 6.61 (2H, d), 6.68 (1H, s), 8.08 (1H, d)

the LCMS spectrum:mH+363, retention time 1.02 minutes, method: 5 minutes acids

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] ammonia base formic acid tertiary butyl ester

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.0g, 3.27mmol) is dissolved in 7: 3: 2 DME of 18%DMF: water: in the mixture of ethanol (7mL) solution.Then incite somebody to action [4-[(2-methyl-prop-2-yl) oxygen base carbonylamino] phenyl] boric acid (1.165g, 4.91mmol), two (triphenylphosphine) palladium catalyst (115mg of 2M sodium carbonate solution (4mL) and dichloro, 0.16mmol) join in this solution, and in nitrogen atmosphere, 90 ℃ of backflows 5 hours.Make reaction be cooled to room temperature, then distribute between ethyl acetate and water.Use the dried over mgso organism, filter, be concentrated into dry.Crude product oil is dissolved in methylene dichloride, filters, remove insoluble substance.Be settled out beige solid from filtrate, again filter liquor.Analyze solid, find that it is excessive boric acid, filtrate comprises product and some impurity.Utilize silica gel chromatography purifying filtrate, with 0-40% ethyl acetate/isohexane wash-out, obtain needed compound orange oil (530mg).

the LCMS spectrum:mH+463, retention time 2.23 minutes, method: 5 minutes acids

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine

The chloro-6-of 2,4-bis-(sulfonyloxy methyl ylmethyl) pyrimidine (30g, 0.13mol) is dissolved in methylene dichloride, in-5 ℃ of stirrings (in nitrogen atmosphere).Add triethylamine (17.4mL, 0.13mol), obtain the brown solution of clarification.(3S)-3-methylmorpholine is dissolved in methylene dichloride, dropwise adds, keep reaction lower than-5 ℃.Then remove cooling bath, stir the mixture 1 hour.Reflux reaction mixture 2 hours, then wash reaction mixture with water, drying, then evaporation.Purify crude product with preparative HPLC, obtain needed material solid (19.3g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21-1.23 (m, 3H), 3.11 (s, 3H), (3.19-3.26 m, 1H), 3.42-3.49 (m, 1H), (3.58-3.62 1H, m), 3.73 (d, 1H), 3.92-3.96 (m, 2H), (4.27-4.31 m, 1H), 4.45 (s, 2H), 6.92 (s, 1H)

the LCMS spectrum:mH+306, retention time 1.42 minutes, method: 5 minutes acids

the chloro-6-of 2,4-bis-(sulfonyloxy methyl ylmethyl) pyrimidine

By 6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2,4-diketone (132g, 0.65mol) joins in phosphorus oxychloride (1.2L), and, by mixture reflux 16 hours, then is cooled to room temperature.Vacuum is removed excessive phosphorus oxychloride, by resistates and toluene (2x500mL) azeotropic, and is dissolved in methylene dichloride.Then this mixture is poured at leisure to ice (4L) upper, stirs 20 minutes, then use methylene dichloride (3x1L) (leach undissolvable atrament, and remove) and ethyl acetate (2x1L) to extract.The united extraction thing, drying, then evaporation, remain needed material dun solid (51g).This material just need not be further purified and can use.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.13 (s, 3H), 4.79 (s, 2H), 7.87 (s, 1H)

the LCMS spectrum:mH+239, retention time 1.21 minutes, method: 5 minutes acids

6-(sulfonyloxy methyl ylmethyl)-1H-pyrimidine-2, the 4-diketone

By 6-(chloromethyl)-1H-pyrimidine-2,4-diketone (175g, 1.09mol) is dissolved in DMF (2L), adds methyl-sulfinic acid sodium salt (133.5g, 1.31mol).Reaction is heated to 125 ℃, keeps 2 hours, then cooling, filtering suspension liquid, vacuum concentration, obtain yellow solid.Crude product is washed with water, filter, then grind with toluene.Cross filter solid, then isohexane grinds, remaining needed compound yellow solid (250g).This material just need not be further purified and can use.

6-(chloromethyl)-1H-pyrimidine-2, the 4-diketone is commercially available material.

the fluoro-4-[4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (860mg) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in ethanol (total solvent volume 21mL)).Then two (triphenylphosphine) palladiums (99mg) of 4-valeryl boron-2-fluoroaniline (1.005g), 2M sodium carbonate (4mL) and dichloro are joined in solution, and in nitrogen atmosphere, 90 ℃ of reflux 5 hours.Distribute reactant between DCM (50mL) and water (50mL).Use the dried over mgso organic extraction, filter vacuum concentration.Brown oil is dissolved in methylene dichloride, filters, remove powder mass, and be loaded on Companion and carry out purifying, use 0-50% ethyl acetate/isohexane gradient, with 20 minutes.Obtain the purified product light yellow oil.

the LCMS spectrum:mH+381, retention time 1.32 minutes, method: 5 minutes acids

5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyridine-2-amine

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (363mg, 1.19mmol) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (7mL)) in solution.By 5-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) two (triphenylphosphine) palladiums (42mg) of pyridine-2-amine (496mg, 2.25mmol), 2M sodium carbonate solution (2mL) and dichloro join in solution, in nitrogen atmosphere, 90 ℃ of reflux 90 minutes.Distribute reactant between ethyl acetate (50mL) and water (50mL), use the dried over mgso organism, filter, vacuum concentration, obtain needed product yellow oil (410mg), and it just need not be further purified and can use.

the LCMS spectrum:mH+364, retention time 0.89 minute, method: 5 minutes acids

2-methoxyl group-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] benzene amine

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (700mg, 2.29mmol) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (7mL)) in solution.Then two (triphenylphosphine) palladiums (81mg) of (4-amino-3-methoxyl group-phenyl) boric acid (574mg, 3.43mmol), 2M sodium carbonate solution (4mL) and dichloro are joined in solution, reflux 1 hour at 90 ℃.Reaction is cooled to room temperature, is distributed between ethyl acetate (50mL) and water (50mL), use the dried over mgso organism, filter vacuum concentration.Resistates is dissolved in methylene dichloride, filters, remove insoluble substance.Use companion purifying filtrate.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (d, 3H), 3.17-3.21 (m, 1H), 3.23 (s, 3H), 3.47-3.54 (m, 1H), 3.64-3.67 (m, 1H), (3.78 d, 1H), 3.83 (s, 3H), 3.97-4.01 (m, 1H), 4.16 (d, 1H), 4.46 (s, 3H), (5.23 s, 2H), 6.68-6.70 (m, 1H), 6.69 (s, 1H), 7.77 (m, 1H), 7.97 (s, 1H)

the LCMS spectrum:mH+393, retention time 1.17 minutes, method: 5 minutes acid methods

embodiment 2:

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] azetidine-1-carboxylic acid amides

20% methylene dichloride for toluene solution (0.245mL, 0.50mmol) (0.5mL) dilution by phosgene.By 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline (150mg, 0.41mmol) is dissolved in methylene dichloride (2mL) and pyridine (0.5mL).It was dropwise joined in phosgene solution with 2 minutes.To react and at room temperature stir 1 hour.Then add azetidine (0.034mL, 0.50mmol), and at room temperature stir the mixture 1 hour.Distribute reactant between water and ethyl acetate (25mL separately).Use the dried over mgso organic layer, evaporate to dryness.Use the chromatogram purification yellow oil, with 10-70% ethyl acetate/isohexane wash-out, obtain the yellow foam (50mg, 25%) of needed material.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (d, 3H), 2.16-2.24 (m, 2H), 3.19-3.23 (m, 4H), 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), (3.79 d, 1H), 3.99 (t, 5H), (4.17 s, 1H), 4.49 (s, 3H), (6.79 s, 1H), 7.62-7.64 (m, 2H), (8.20-8.23 m, 2H), 8.57 (s, 1H)

the LCMS spectrum:mH+446, retention time 1.37 minutes, method: 5 minutes acids

According to being similar to N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] mode of azetidine-1-carboxylic acid amides, by 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline and suitable amine prepares following compounds.

Embodiment 2a: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (d, 3H), 3.00 (s, 3H), 3.21 (s, 3H), (3.23-3.27 m, 2H), 3.45 (m, 2H), 3.51 (s, 4H), (3.53 m, 1H), 3.64-3.68 (m, 1H), 3.79 (d, 1H), 3.98-4.02 (m, 1H), 4.17-4.21 (m, 1H), (4.50 s, 3H), 6.79 (s, 1H), 7.58 (s, 2H), 8.21-8.23 (m, 2H), 8.47 (s, 1H)

Embodiment 2b: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24-1.26 (m, 3H), 2.96 (s, 6H), 3.21 (s, 3H), 3.25 (d, 1H), 3.48-3.54 (m, 1H), (3.64-3.68 m, 1H), 3.79 (d, 1H), 3.98-4.02 (m, 1H), 4.19 (d, 1H), 4.49 (s, 3H), (6.79 s, 1H), 7.58-7.62 (m, 2H), (8.20-8.23 m, 2H), 8.50 (s, 1H)

Embodiment 2c: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.27 (m, 3H), 2.97 (s, 6H), 3.18 (m, 1H), (3.23 s, 3H), 3.48-3.55 (m, 1H), 3.65-3.69 (m, 1H), (3.79 d, 1H), 3.93 (s, 3H), 3.98-4.02 (m, 1H), 4.20 (d, 1H), 4.47 (s, 1H), (4.51 s, 2H), 6.82 (s, 1H), 7.52 (s, 1H), 7.91-7.94 (m, 2H), 8.00 (s, 1H)

Embodiment 2d: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (d, 3H), 2.66-2.67 (d, 3H), 3.21 (s, 3H), (3.23 d, 1H), 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), (3.79 d, 1H), 3.97-4.01 (m, 1H), 4.18 (d, 1H), 4.48 (m, 1H), 4.49 (s, 2H), (6.08 q, 1H), 6.78 (s, 1H), 7.49-7.53 (m, 2H), 8.20-8.22 (m, 2H), 8.76 (s, 1H)

Embodiment 2e: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24-1.26 (m, 3H), 2.69 (d, 3H), (3.23-3.24 m, 1H), 3.26-3.27 (m, 1H), (3.20 s, 3H), 3.47-3.54 (m, 1H), (3.64-3.67 m, 1H), 3.79 (d, 1H), (3.97-4.01 m, 1H), 4.16-4.20 (m, 1H), 4.50 (s, 2H), (6.57 q, 1H), 6.82 (s, 1H), 8.02-8.09 (m, 1H), (8.05-8.07 m, 1H), 8.29 (m, 1H), 8.55 (d, 1H)

Embodiment 2f: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.27 (m, 3H), 2.96 (s, 6H), 3.20 (s, 3H), 3.48-3.55 (m, 1H), 3.64-3.68 (m, 1H), (3.79 d, 1H), 3.98-4.02 (m, 1H), 4.21 (t, 1H), 4.40 (m, 1H), 4.51 (s, 2H), (6.85 s, 1H), 7.68 (t, 1H), (8.02-8.11 m, 2H), 8.15 (s, 1H)

Test (a): embodiment (2) 0.31 μ M; Embodiment (2a) 2.3 μ M; Embodiment (2b) 0.29 μ M; Embodiment (2c) 1.2 μ M; Embodiment (2d) 0.0068 μ M; Embodiment (2e) 0.038 μ M; Embodiment (2f) 1.7 μ M.

embodiment 3:

1-[2-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl]-the 3-phenylurea

By 2-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline (130mg, 0.34mmol) is dissolved in Isosorbide-5-Nitrae-diox (4mL).Add phenyl isocyanate (0.038mL, 0.34mmol), and 70 ℃ of reacting by heating 3 hours.By the reaction mixture evaporate to dryness, and the resistates obtained is ground by ethyl acetate, obtain needed compound paste solid (42mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (s, 3H), 2.34 (s, 3H), 3.21 (s, 3H), (3.23-3.26 m, 1H), 3.48-3.55 (m, 1H), 3.64-3.68 (m, 1H), (3.79 d, 1H), 4.00 (d, 1H), 4.20 (d, 1H), (4.50 s, 3H), 6.79 (s, 1H), 6.97-7.01 (m, 1H), (7.31 d, 2H), 7.47-7.50 (m, 2H), 8.08 (s, 2H), 8.13 (d, 2H), 9.13 (s, 1H)

the LCMS spectrum:mH+496, retention time 2.08 minutes, method: 5 minutes similar modes of acid method prepare following compounds by suitable aniline and isocyanic ester.

Embodiment 3a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.25 (d, 3H), (3.09-3.14 m, 2H), 3.19-3.24 (m, 1H), (3.25 s, 3H), 3.47-3.54 (m, 1H), (3.64-3.68 m, 1H), 3.78 (d, 1H), (3.92 s, 3H), 3.97-4.01 (m, H), 4.17-4.20 (m, 1H), (4.50 s, 3H), 6.78 (s, 1H), 6.95 (t, 1H), (7.87-7.90 m, 2H), 8.06 (s, 1H), 8.21-8.24 (m, 1H)

Embodiment 3b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (d, 3H), 3.20 (s, 3H), (3.25 d, 1H), 3.48-3.54 (m, 1H), (3.64-3.68 m, 1H), 3.79 (d, 1H), (3.98-4.02 m, 1H), 4.20 (d, 1H), (4.48 m, 1H), 4.52 (s, 2H), (6.84 s, 1H), 7.02 (t, 1H), (7.32 d, 2H), 7.49 (d, 2H), (8.24-8.27 m, 1H), 8.34 (d, 1H), (8.34-8.37 m, 1H), 8.49 (s, 1H), 9.52 (s, 1H)

Embodiment 3c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.27 (d, 3H), 3.23 (s, 3H), (3.26 m, 1H), 3.49-3.56 (m, 1H), (3.65-3.69 m, 1H), 3.80 (d, 1H), (3.99-4.03 m, 1H), 4.20 (d, 1H), (4.53 s, 3H), 6.87 (s, 1H), (6.98 t, 1H), 7.29 (t, 2H), (7.40 t, 1H), 7.47 (d, 2H), (7.71-7.74 m, 1H), 7.95 (d, 1H), (8.31 s, 1H), 8.65 (s, 1H), 8.82 (s, 1H)

Embodiment 3d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (d, 3H), 3.21 (s, 3H), 3.34 (s, 3H), (3.39 m, 1H), 3.50 (d, 1H), 3.66 (d, 1H), (3.79 d, 1H), 4.00 (d, 1H), 4.17 (d, 1H), 4.52 (s, 3H), 6.85 (s, 1H), (6.96 t, 1H), 7.24 (t, 2H), 7.44 (m, 4H), 8.33 (s, 1H), 8.35 (s, 2H)

Test (a): embodiment (3) 1.5 μ M; Embodiment (3a) 0.1 μ M; Embodiment (3b) 0.44 μ M; Embodiment (3c) 3.3 μ M; Embodiment (3d) 2.9 μ M.

2-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of aniline is described below.

2-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

By the bromo-2-aminotoluene of 4-(1.00g, 5.37mmol), potassium acetate (1.59g, 16.1mmol) and 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1,3,2-dioxa boron heterocycle pentane (1.64g, 6.45mmol) be dissolved in Isosorbide-5-Nitrae-dioxs (20mL), and by degassed 5 minutes of solution.Add two (triphenylphosphine) palladiums (264mg, 0.32mmol) of dichloro, 90 ℃ of stirring reactions 4 hours.Add the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.65g, 5.37mmol), ethanol (1.5mL), 2M aqueous sodium carbonate (3mL) and two (triphenylphosphine) palladiums (264mg) of dichloro.Keep reaction 18 hours at 90 ℃, then be cooled to room temperature.Add water (15mL) and ethyl acetate (15mL), filtering mixt, remove insoluble impurities.Separation of phases, extract water layer by second section ethyl acetate (15mL).By the organism dry (MgSO4) merged, and vacuum concentration.Resistates is carried out to silica gel chromatography, with 0-3% methyl alcohol/DCM wash-out, obtain the cream-coloured foam of needed compound (290mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-1.24 (m, 3H), 3.16-3.19 (m, 1H), 3.20 (s, 3H), 3.46-3.52 (m, 1H), 3.62-3.66 (m, 1H), (3.77 d, 1H), 3.90 (s, 1H), 3.96-4.00 (m, 1H), 4.14-4.18 (m, 1H), 4.43 (s, 2H), (4.45 s, 1H), 5.32 (s, 2H), 6.63 (s, 1H), 6.66 (s, 1H), 7.91-7.94 (m, 2H)

the LCMS spectrum:mH+377, retention time 1.21 minutes, method: 5 minutes acids

The chloro-4-[4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of aniline is described below.

the chloro-4-[4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

The bromo-2-chloroaniline of 4-(1.00g, 4.84mmol), potassium acetate (1.58g, 14.5mmol) and two (valeryl) two boron (1.64g, 5.81mmol) are dissolved in Isosorbide-5-Nitrae-dioxs (20mL).By solution in nitrogen atmosphere degassed 5 minutes.Add [1,1 '-bis-(diphenylphosphino) ferrocene] (213mg, 0.29mmol).90 ℃ of stirring reactions 4 hours.Add ethanol (1.5mL), the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.49g; 4.84mmol), 2M sodium carbonate solution (5.4mL) and [1; 1 '-bis-(diphenylphosphino) ferrocene] (213mg), continue heating 18 hours.The evaporate to dryness reaction distributes resistates between water (15mL) and ethyl acetate (15mL).Filtering mixt, remove insoluble substance, and separation of phases, with ethyl acetate (15mL) washing water layer.By the organism dried over mgso merged, evaporation, obtain yellow oil.Purify crude product with silica gel chromatography, with 0-4% methyl alcohol/DCM wash-out, obtain needed material paste foam (1.1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-1.24 (m, 3H), 3.18 (s, 3H), 3.19-3.21 (m, 1H), 3.45-3.52 (m, 1H), 3.62-3.65 (m, 1H), (3.77 d, 1H), 3.96-4.00 (m, 1H), 4.13-4.17 (m, 1H), 4.46 (s, 3H), 5.82 (s, 2H), (6.72 s, 1H), 6.85 (d, 1H), (8.00-8.03 m, 1H), 8.14 (d, 1H)

the LCMS spectrum:mH+397, retention time 1.64 minutes, method: 5 minutes acid methods

3-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of aniline is described below.

3-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.50g, 4.91mmol) is dissolved in 18%DMF (at 7: 3: 2 glycol dimethyl ethers: water: in ethanol (15mL)).Two (triphenylphosphine) palladiums (173mg, 0.25mmol) of (3-aminophenyl) boric acid (1.01g, 7.36mmol), 2M sodium carbonate (5mL) and dichloro are joined in this solution.Under nitrogen atmosphere, will react at 90 ℃ and reflux 18 hours, then will react cooling, and distribute between ethyl acetate (50mL) and water (50mL).Use the dried over mgso organic layer, filter vacuum-drying.The brown oil obtained is dissolved in DCM, filters, remove insoluble substance, then filtrate is carried out to silica gel chromatography, with 0-4% methyl alcohol/DCM wash-out, obtain needed product yellow oil (1.61g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.26 (m, 3H), 2.90 (s, 3H), 3.19-3.26 (m, 1H), 3.47-3.54 (m, 1H), 3.64-3.68 (m, 1H), (3.77-3.80 m, 1H), 3.99 (d, 1H), 4.17 (s, 1H), 4.49 (s, 3H), 6.67-6.70 (m, 1H), (6.81 s, 1H), 7.11 (d, 1H), 7.50-7.52 (m, 1H), 7.57-7.58 (m, 1H), 7.96 (s, 1H)

the LCMS spectrum:mH+364, retention time 0.93 minute, method: 5 minutes acid methods

N-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of aniline is described below

N-methyl-4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.01g, 3.30mmol) is dissolved in 18%DMF (at 7: 3: 2 glycol dimethyl ethers: water: in ethanol (7mL)).By N-methyl-4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) aniline (1.00g, 4.29mmol), two (triphenylphosphine) palladiums (116mg, 0.16mmol) of 2M sodium carbonate solution (4mL) and dichloro join in this solution.Under nitrogen atmosphere, will react at 90 ℃ and reflux 3 hours, then cooling mixture, and distribution between ethyl acetate (30mL) and water (30mL).Use the dried over mgso organic layer, filter evaporate to dryness.Brown oil is dissolved in DCM, filters, remove insoluble substance, then filtrate is carried out to silica gel chromatography, with 0-4% methyl alcohol/DCM wash-out, obtain the yellow foam (1.12g, 90%) of needed product.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (d, 3H), 2.74 (d, 3H), 3.06-3.17 (m, 1H), 3.21 (s, 3H), 3.46-3.52 (m, 1H), (3.62-3.66 m, 1H), 3.77 (d, 1H), 3.96-4.00 (m, 1H), 4.14 (d, 1H), 4.44 (s, 2H), (4.46 s, 1H), 6.14 (q, 1H), 6.57-6.61 (m, 2H), 6.67 (s, 1H), 8.10-8.13 (m, 2H)

the LCMS spectrum:mH+377, retention time 1.33 minutes, method: 5 minutes acid methods

embodiment 4:

The fluoro-4-[4-[(3S of 1-ethyl-3-[2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] urea

Two (trichloromethyl) carbonic ethers (44mg, 0.16mmol) are dissolved in DCM (0.25mL), obtain colourless solution.By the fluoro-4-[4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] aniline (140mg, 0.39mmol) is dissolved in DCM (2.0mL) and pyridine (0.2mL).At 0 ℃, the solution obtained is dropwise joined in two (trichloromethyl) carbonate solution, make mixture be warming up to room temperature, then stir 10 minutes.Add ethamine (2M, in THF, 0.5mL, 1.0mmol), at room temperature stir the mixture 1 hour.Add water (5mL), with DCM (5mL), extract water layer.By the organic layer dry (MgSO4) merged, vacuum concentration.Purify crude product oil with preparative HPLC, obtain needed material white solid (149mg, 84%).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.08 (t, 3H), 1.25 (d, 3H), 3.13-3.18 (m, 2H), (3.20 s, 3H), 3.22-3.27 (m, 1H), 3.47-3.53 (m, 1H) 3.63-3.67 (m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.16-4.20 (m, 1H), 4.49 (m, 3H), (6.68 t, 1H), 6.81 (s, 1H), 8.01-8.08 (m, 2H), 8.29 (t, 1H), 8.47 (d, 1H)

mass spectrum:

Use similar mode, use suitable aniline and amine to prepare following compounds.

^*silica gel chromatography, with 0-5% methyl alcohol/DCM wash-out

Embodiment 4a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (d, 3H), 2.16-2.24 (m, 2H), 3.20 (s, 3H), 3.23-3.26 (m, 1H), 3.47-3.54 (m, 1H), (3.63-3.67 m, 1H), 3.78 (d, 1H), 4.00 (t, 5H), 4.19 (d, 1H), 4.50 (s, 3H), (6.84 s, 1H), 7.83-7.87 (m, 1H, 8.04 (d, 1H6), 8.08-8.10 (m, 1H), 8.18 (s, 1H)

Embodiment 4b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.12 (d, 6H), 1.25 (d, 3H), 3.20 (s, 3H), 3.24 (d, 1H), 3.47-3.53 (m, 1H), (3.63-3.67 m, 1H), 3.74-3.82 (m, 2H), 3.97-4.01 (m, 1H), 4.18 (d, 1H), 4.49 (s, 3H), (6.63 d, 1H), 6.81 (s, 1H), 8.01-8.08 (m, 2H), 8.29 (t, 1H), 8.37 (d, 1H)

Embodiment 4c: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.26 (m, 3H), 2.66-2.67 (m, 3H), 3.18 (d, 1H), (3.23 s, 3H), 3.48-3.55 (m, 1H), 3.65-3.68 (m, 1H), 3.79 (d, 1H), 3.92 (s, 3H), (3.98-4.02 m, 1H) 4.19 (s, 1H), 4.50 (s, 2H), (6.79 s, H.), 6.85 (d, 1H), 7.90 (s, 1H), 8.11 (s, 1H), 8.22-8.24 (m, 1H)

Embodiment 4d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (d, 3H), 3.19-3.24 (m, 2H), 3.21 (s, 3H), (3.27 s, 3H), 3.40 (t, 2H), 3.47-3.53 (m, 1H), (3.63-3.67 m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.17 (s, 1H), 4.49 (s, 3H), (6.27 t, 1H), 6.77 (s, 1H), 7.47-7.51 (m, 2H), 8.19-8.23 (m, 2H), 8.78 (s, 1H)

Embodiment 4e: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25-1.26 (m, 3H), 3.23 (s, 3H), (3.27 s, 1H), 3.28-3.21 (m, 2H), (3.38-3.40 m, 2H), 3.51 (d, 1H), (3.66 d, 1H), 3.77 (s, 1H), (3.92 s, 3H), 4.00 (d, 1H), 4.17-4.21 (m, 1H), (4.50 s, 3H), 6.79 (s, 1H), 7.12 (s, 1H), (7.88-7.90 m, 2H), 8.22-8.24 (m, 1H), 8.26 (1s, H)

Embodiment 4f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.26 (m, 3H.), 2.97 (s, 3H), 3.20 (s, 3H), 3.23-3.26 (m, 1H), 3.47-3.56 (m, 5H), (3.64-3.67 m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.17-4.21 (m, 1H), 4.50 (s, 3H), (6.84 s, 1H), 7.82 (t, 1H), (8.02-8.10 m, 2H), 8.41 (s, 1H)

Embodiment 4g: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (d, 3H), 3.20 (s, 3H), 3.23 (m, 1H), (3.29 m, 2H), 3.30 (s, 3H), 3.41 (t, 2H), (3.51 d, 1H), 3.65 (d, 1H), 3.78 (d, 1H), (3.97-4.01 m, 1H), 4.19 (d, 1H), 4.50 (s, 3H), (6.82 s, 1H), 6.87 (t, 1H), 8.02-8.09 (m, 2H), 8.29 (t, 1H), 8.63 (d, 1H)

Test (a): embodiment (4) 0.031 μ M; Embodiment (4a) 1 μ M; Embodiment (4b) 0.14 μ M; Embodiment (4c) 0.8 μ M; Embodiment (4d) 0.17 μ M; Embodiment (4e) 0.6 μ M; Embodiment (4f) 0.68 μ M; Embodiment (4g) 0.83 μ M.

embodiment 5:

1-ethyl-3-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 1-[4-[4-[(dimethyl-tertiary butyl-silyl) the oxygen ylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-ethyl-urea (104mg) is dissolved in THF (10mL), add TBAF (1.0M solution, 0.22mL).At room temperature stirring reaction is 1 hour, then downwards by the SCX-2 post.Use the methanol wash post, with the needed material of 7N ammonia/methanol-eluted fractions.The vacuum concentration fraction, obtain needed compound white solid (76mg).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.23 (3H, d), 3.11-3.16 (2H, m), (3.19-3.23 1H, m), 3.49 (1H, d), 3.62-3.66 (1H, m), (3.77 1H, d), 3.95-3.99 (1H, m), 4.16 (1H, d), (4.45 2H, d), 4.48 (1H, s), 5.38 (1H, s), (6.14 1H, t), 6.66 (1H, s), 7.46 (2H, d), 8.19 (2H, d), 8.62 (1H, s)

mass spectrum:m+H ⁺372.

Test (a): 0.063 μ M.

1-[4-[4-[(dimethyl-tertiary butyl-silyl) oxygen ylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-preparation of 3-ethyl-urea is described below.

1-[4-[4-[(dimethyl-tertiary butyl-silyl) oxygen ylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-ethyl-urea

By 4-[4-[(dimethyl-tertiary butyl-silyl) the oxygen ylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (250mg) is dissolved in Isosorbide-5-Nitrae-dioxs (4mL), adds ethyl isocyanate (0.144mL).In microwave reactor, reaction is heated to 120 ℃, keep 1 hour.The vacuum concentration reaction, then carry out silica gel chromatography to resistates, with 2.5% methyl alcohol/DCM wash-out, obtains needed compound white solid (106mg).

mass spectrum:m+H ⁺486.

4-[4-[(dimethyl-tertiary butyl-silyl) oxygen ylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] phonetic pyridine-2-yl] aniline

Will [2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (1.54g) is dissolved in DCM (60mL), adds tert-butyldimethylsilyl chloride (928mg) and imidazoles.Mixture is at room temperature stirred 0.5 hour, then filter vacuum concentration.Resistates is carried out to silica gel chromatography, with 1% methyl alcohol/DCM wash-out, obtain needed compound white solid (1.61g).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.12-0.13 (6H, m), 0.94-0.95 (9H, m), 1.21 (3H, d), 3.13-3.20 (1H, m), 3.46-3.52 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.13 (1H, d), 4.37-4.39 (1H, m), (4.60 2H, s), 5.48 (2H, d), 6.50 (1H, s), 6.57-6.59 (2H, m), 8.02-8.04 (2H, m)

mass spectrum:m+H ⁺415.

[2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol

By N-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] carboxylamine tertiary butyl ester (1.20g) is dissolved in 4M hydrochloric acid/diox (5mL) is with in diox (5mL).Stirring reaction 18 hours, then add DCM (10mL), helps dissolved substance.40 ℃ of further stirring reactions 18 hours, evaporate to dryness then.Solid suspension, in DCM (20mL), is added to the mixture of saturated sodium bicarbonate aqueous solution (6mL) and water (4mL).Separation of organic substances, dry (MgSO4), vacuum concentration, obtain needed compound (648mg) light yellow solid.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.21 (3H, d), 3.16 (1H, d), 3.48 (1H, d), 3.61-3.65 (1H, m), 3.75 (1H, d), (3.95 1H, d), 4.13 (1H, d), (4.41 2H, d), 4.45 (1H, s), (5.32 1H, t), 5.47 (2H, s), (6.57-6.59 3H, m), 8.02-8.04 (2H, m)

mass spectrum:m+H ⁺301.

n-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] the carboxylamine uncle butyl ester

Will [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] (18%DMF, at 7: 3: 2 DME: water: in ethanol) mixture (35mL) was degassed for methyl alcohol (2.44g), (4-Boc-aminophenyl) boric acid (4.76g), 2M sodium carbonate solution (10mL) and solvent mixture.Add two (triphenylphosphine) palladiums (300mg) of dichloro, 80 ℃ of reacting by heating 3 hours.To react cooling, and vacuum concentration.Resistates is distributed between ethyl acetate (200mL) and water (200mL), with salt solution (100mL) washing organism, dry (MgSO4).Crude product is carried out to silica gel chromatography, with 2.5% methyl alcohol/DCM wash-out, obtain needed compound white solid (4.00g).

mass spectrum:m+H ⁺401.

[the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol

By the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester (3.15g) is dissolved in anhydrous THF (20mL), and is cooled to 0 ℃ in nitrogen atmosphere.(2.0M, in THF, 6.09mL) dropwise to add wherein lithium borohydride solution.Solution is risen to room temperature, stir 1 hour.Water (20mL) cancellation reaction, then evaporate to dryness.Resistates is dissolved in ethyl acetate (150mL) to water (150mL), then salt solution (50mL) washing.The vacuum concentration organism, obtain needed compound white solid (2.44g).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.20-1.21 (3H, m), 3.18-3.22 (1H, m), (3.40-3.47 1H, m), 3.56-3.60 (1H, m), (3.71 1H, d), 3.91-3.94 (1H, m), 3.98 (1H, d), (4.35 3H, d), 5.51 (1H, t), 6.74 (1H, s)

mass spectrum:m+H ⁺244.

the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester

2,6-dichloro pyrimidine-4-carboxylate methyl ester (5.00g) is dissolved in DCM (120mL).(3S)-3-methylmorpholine (2.49g) is dissolved in triethylamine (3.70mL), and with 10 minutes, DCM (10mL) is dropwise joined in this solution.At room temperature stirring reaction is 1 hour, vacuum concentrated mixture then, and be dissolved in DCM (300mL).Water (150mL) washing organism, dry (MgSO4).Crude product is carried out to silica gel chromatography, with 2.5% methyl alcohol/DCM wash-out, obtain needed compound white solid (3.15g).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.22-1.24 (3H, m), 3.25 (1H, d), (3.41-3.48 1H, m), 3.57-3.61 (1H, m), (3.71 1H, d), 3.87 (3H, s), 3.91-3.95 (1H, m), (4.25 1H, s), 4.45 (1H, s), 7.29 (1H, s)

mass spectrum:m+H ⁺272.

embodiment 6:

1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-phenylurea

1-(the bromo-phenyl of 4-)-3-phenylurea (960mg), potassium acetate (969mg), two (valeryl) two boron (1.01g) are dissolved in 1,4 diox (50mL).By degassed 5 minutes of solution, then add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (162mg), reaction is heated to 80 ℃, keep 3 hours.Further add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (162mg), 80 ℃ of other stirring reactions 3 hours.Add [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (803mg), ethanol (3.75mL), 2M sodium carbonate solution (6.9mL) and 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (162mg), continue heating 16 hours.Add more ethanol (5mL) and 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (162mg), stirring reaction is 5 hours in addition, then cooling, with the neutralization of 2M hydrochloric acid.Reaction mixture, by three SCX-2 posts, is loaded to sample at every turn, use methanol wash, then with 7N ammonia/methyl alcohol, remove needed material.Vacuum concentrated solution, carry out silica gel chromatography to resistates, with 5% methyl alcohol/DCM wash-out, obtains needed material white solid (398mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.24 (3H, d), 3.20-3.24 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.18 1H, d), 4.47 (2H, d), (4.50 1H, s), 5.39 (1H, t), (6.68 1H, s), 6.97-7.01 (1H, m), (7.28-7.31 1H, m), 7.30 (1H, s), (7.46-7.48 2H, m), 7.52-7.56 (2H, m), (8.25-8.27 2H, m), 8.68 (1H, s), 8.87 (1H, s)

mass spectrum:m+H ⁺419.

Test (a): 0.56 μ M.

[the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl had before been described] preparation of methyl alcohol.

embodiment 7:

3-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl]-1-third-2-base-urea

At 70 ℃, by 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline (70mg, 0.2mmol) and isocyanic acid isopropyl esters (0.1mL, 1mmol) heat 4 hours in diox (2mL).Evaporation reaction mixture, use the ethyl acetate grinding residues.Filtering suspension liquid, with ethyl acetate and diethyl ether washing white solid, then spend the night 60 ℃ of vacuum-dryings, obtains title compound (38mg).

the LCMS spectrum:mH+434, retention time 1.66 minutes, method: alkali formula monitoring.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.11 (d, 6H), 3.2 (s, 3H), 3.7 (m, 8H), 3.76 (m, 1H), 4.48 (s, 2H), 6.05 (d, 1H), 6.8 (s, 1H), 7.48 (d, 2H), 8.2 (d, 2H), 8.54 (s, 1H)

Use similar mode, use suitable isocyanic ester, by XXX, prepare following compounds.

^*be further purified compound with preparative HPLC

Embodiment 7a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 2.25 (s, 3H), 3.21 (s, 3H), 3.71 (s, 8H), 4.49 (s, 2H), (6.83 s, 1H), 7.09 (d, 2H), 7.34 (d, 2H), 7.56 (d, 2H), 8.26 (d, 2H), 8.6 (s, 1H), 8.88 (s, 1H)

Embodiment 7b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.22 (s, 3H), 3.70 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7.34 (d, 2H), 7.50 (d, 2H), 7.56 (d, 2H), (8.28 d, 2H), 8.84 (s, 1H), 8.95 (s, 1H)

Embodiment 7c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7.59 (d, 2H), 7.65 (m, 4H), 8.3 (d, 2H), 9.40 (s, 1H), 9.13 (s, 1H)

Embodiment 7d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 2.23 (s, 6H), 3.21 (s, 3H), 3.72 (bs, 8H), 4.49 (s, 2H), (6.64 s, 1H), 6.85 (s, 1H), 7.08 (s, 2H), 7.55 (d, 2H), 8.28 (d, 2H), 8.58 (s, 1H), 8.92 (s, 1H)

Embodiment 7e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H), (7.05 m, 1H), 7.22 (m, 2H), 7.59 (d, 2H), 8.24 (d, 1H), 8.3 (d, 2H), 8.38 (s, 1H), 9.60 (s, 1H)

Embodiment 7f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.22 (s, 3H), 3.70 (bs, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7.12 (m, 2H), 7.48 (m, 2H), 7.55 (d, 2H), (8.26 d, 2H), 8.73 (s, 1H), 8.90 (s, 1H)

Embodiment 7g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (s, 3H), 3.72 (s, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7.34 (m, 2H), 7.56 (m, 2H), 7.8 (m, 1H), (8.28 m, 2H), 8.95 (s, 1H), 9.05 (s, 1H)

Embodiment 7i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.22 (s, 3H), 3.70 (bs, 8H), 4.49 (s, 2H), 6.84 (s, 1H), 7.34 (d, 2H), 7.50 (d, 2H), 7.56 (d, 2H), (8.28 d, 2H), 8.84 (s, 1H), 8.95 (s, 1H)

Embodiment 7j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.88 (m, 3H), 1.39 (m, 4H), (1.43 m, 2H), 3.08 (m, 2H), (3.21 s, 3H), 3.70 (bs, 8H), (4.47 s, 2H), 6.2 (t, 1H), (6.81 s, 1H), 7.49 (d, 2H), (8.20 d, 2H), 8.66 (s, 1H)

Embodiment 7m: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.05 (t, 3H), 3.12 (q, 2H), 3.21 (s, 3H), 3.7 (bs, 8H), 4.46 (s, 2H), 6.19 (t, 1H), 6.8 (s, 1H), (7.50 d, 2H), 8.21 (d, 2H), 8.69 (s, 1H)

Embodiment 7n: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.87 (m, 3H), 1.45 (m, 2H), 3.05 (m, 2H), 3.20 (s, 3H), (3.70 bs, 8H), 4.45 (s, 2H), 6.14 (t, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.69 (s, 1H)

Embodiment 7o: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (t, 3H), 2.55 (q, 2H), 3.21 (s, 3H), 3.70 (bs, 8H), 4.49 (s, 2H), (6.85 m, 2H), 7.19 (t, 2H), (7.27 d, 1H), 7.33 (s, 1H), (7.56 d, 2H), 8.26 (d, 2H), (8.68 s, 1H), 8.92 (s, 1H)

Embodiment 7p: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.20 (s, 3H), 3.70 (bs, 8H), (4.31 d, 1H), 4.47 (s, 2H), (6.28 d, 1h), 6.40 (d, 1H), (6.61 t, 1H), 6.82 (s, 1H), (7.51 d, 2H), 7.59 (s, 1H), (8.22 d, 2H), 8.77 (s, 1H)

Embodiment 7q: ¹h NMR (400.13MHz, DMSO-d ₆) δ 2.98 (t, 2H), 3.21 (s, 3H), 3.38 (m, 2H), 3.70 (bs, 8H), 4.47 (s, 2H), (6.29 t, 1H), 6.81 (s, 1H), (6.93 d, 1H), 6.97 (m, 1H), (7.36 m, 1 H), 7.50 (d, 2H), (8.21 d, 2H), 8.80 (s, 1H)

Test (a): embodiment (7) 0.17 μ M; Embodiment (7a) 0.28 μ M; Embodiment (7b) 0.42 μ M; Embodiment (7c) 1.7 μ M; Embodiment (7d) 2.6 μ M; Embodiment (7e) 2.6 μ M; Embodiment (7f) 0.029 μ M; Embodiment (7g) 1.3 μ M; Embodiment (7h) 0.24 μ M; Embodiment (7i) 0.032 μ M; Embodiment (7j) 1.9 μ M; Embodiment (7k) 0.72 μ M; Embodiment (7l) 7 μ M; Embodiment (7m) 0.081 μ M; Embodiment (7n) 0.2 μ M; Embodiment (7o) 1.7 μ M; Embodiment (7p) 3.8 μ M; Embodiment (7q) 1.7 μ M; Embodiment (7r) 0.19 μ M.

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] preparation of aniline is described below:

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

By 2-methyl sulfenyl-4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (1.00g; 3.3mmol), 4-aminophenyl boric acid (904mg; 6.60mmol), sulphur is luxuriant-2-copper carboxylate (I) (1.64g, 8.58mmol), Pd (PPh ₃) ₄(153mg, 0.04 equivalent, 0.13mmol) join in microwave container, and add Isosorbide-5-Nitrae-dioxs (20mL).Use N ₂system is degassed, the sealing and in microwave reactor, 130 ℃ the heating 1 hour.Once cooling, reactant is poured into water, to filter and collect the precipitation obtained, vacuum-drying, obtain title compound off-white color solid (988mg).

the LCMS spectrum:mH+349.41, retention time 1.43 methods: acid monitoring

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)

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

By 2-methyl sulfenyl-6-(sulfonyloxy methyl ylmethyl) pyrimidine-4-alcohol (15g, 63.97mmol) about 1 hour of reflux in the inferior phosphorus of oxychlorination (100ml).The inferior phosphorus of evaporation oxychlorination, use in sodium hydroxide solution and resistates, and extract in ethyl acetate.Then with sal epsom by the mixture drying obtained, filter, evaporate to dryness, obtain crude product chlorine product.Then it is dissolved in DCM, adds morpholine (319mmol, 28ml), at room temperature stirring reaction.Once complete, collect the precipitation white solid obtained.Concentrated filtrate, obtain more solids, obtains merging productive rate 13.7g.

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..

the LCMS spectrum:mH+304.50, retention time 1.49 minutes, method: alkali formula monitoring.

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

6-(chloromethyl)-2-methyl sulfenyl-pyrimidine-4-alcohol (19.07g, 100mmol) is suspended in acetonitrile (400mL).In this stirred suspension, add the methyl-sulfinic acid sodium salt(12.255g, 120mmol) and DMF (100mL).Then reaction is heated to 100 ℃, obtains the suspension of black, monitor with LCMS.Once complete, except desolventizing, and products obtained therefrom joined to 1: in 1MeOH: DCM (200ml), with acetic acid (10ml) acidifying.The precipitation that collection obtains, water (200ml) and MeOH (100ml) washing, vacuum-drying is spent the night, and obtains title compound white solid 16.45g.

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..

the LCMS spectrum:mH+235.2, retention time 0.5 minute, method: 5 minutes early stages alkali formula method

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

By S-methyl-2-sulfo-pseudo-urea vitriol (20g, 71.85mmol), 4-chloracetyl vinyl acetic monomer (10.755mL, 79.04mmol) and sodium carbonate (13.925g, 107.78mmol) water-soluble (100mL) in, and at room temperature stir and spend the night.With TLC monitoring reaction, once complete, collect reaction precipitation, use in 6N hydrochloric acid and supernatant liquor, obtain more reaction precipitations, equally by its collection.Then the precipitation that water (x3) washing is assembled, obtain the off-white color solid.At 60 ℃ by its vacuum-drying 48 hours, obtain needed compound light yellow/white solid 43.2g.

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

mass spectrum:m ⁺190

4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] aniline can also be by the chloro-6-of 2,4-bis-(sulfonyloxy methyl ylmethyl) pyrimidine preparation, as described below

The chloro-4-of 2-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine (5g, 17.1mmol) is dissolved in to DMF: DME: water: ethanol (16.5mL: 41mL: 18mL: in mixture 12mL).Add 4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) aniline (5.62g, 25.6mmol), two (triphenylphosphine) palladiums (600mg) of 2M aqueous sodium carbonate (25mL) and dichloro, under nitrogen atmosphere, and mixture is refluxed 5 hours.Mixture is cooling, and dilute with water, extract in DCM.By organic layer Na ₂sO ₄drying, filter, evaporation.Crude product is dissolved in the hot DCM of minimum, then adds hexane, filtering-depositing, obtain needed material (1.6g).

the LCMS spectrum:mH+349, retention time 1.48 minutes, method: alkali formula monitoring.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.20 (3H, s), 3.67-3.72 (8H, m), 4.43 (2H, s), 5.55-5.56 (2H, m), 6.59 (2H, d), 6.70 (1H, s), 8.03 (2H, d)

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

DCM (230mL) suspension of the chloro-6-of 2,4-bis-(sulfonyloxy methyl ylmethyl) pyrimidine (10.56g) is carried out to magnetic stirring (in nitrogen atmosphere), and be cooled to-5 ℃.Add triethylamine (6.78mL), then dropwise add DCM (30mL) solution of morpholine (3.85mL), keep temperature of reaction lower than-5 ℃.At room temperature stirring reaction is 1 hour, then water (300mL) washing organic mixture.Dry (MgSO4) organic phase, filter, and is evaporated to brown solid, and it is utilized to silica gel chromatography, with 50% ethyl acetate/DCM wash-out, obtains needed material (6.81g) white solid.

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)

mass spectrum:mH+292.

embodiment 8:

3-cyclopropyl-1-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] urea

At 50-70 ℃; by N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] phenyl carbamate (94mg; 0.2mmol), cyclopropylamine (0.069mL; 1mmol) and the mixture of triethylamine (0.090mL, 0.65mmol) in NMP (1-2mL), heat 2 hours.Then directly use preparative HPLC (alkali formula monitoring method) purified mixture, obtain needed material.

the LCMS spectrum:mH+432, retention time 2.42 minutes, method: alkali formula monitoring.

Use similar mode, use NMP or DMF as solvent, by required phenyl carbamate and suitable amine, prepare following compounds.

Embodiment 8g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.11 (d, 6H), 1.26 (d, 3H), (3.23 s, 3H), 3.25 (d, 1H), (3.48-3.55 m, 1H), 3.65-3.68 (m, 1H), (3.76 d, 1H), 3.80 (t, 1H), (3.98-4.02 m, 1H), 4.18 (d, 1H), (4.48 m, 1H), 4.52 (s, 2H), (5.98 d, 1H), 6.85 (s, 1H), (7.32 t, 1H), 7.65-7.68 (m, 1H), (7.86-7.88 m, 1H), 8.20 (t, 1H), 8.43 (s, 1H)

Embodiment 8h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.26 (d, 3H), (3.09-3.14 m, 2H), 3.22 (s, 3H), (3.24 m, 1H), 3.48-3.55 (m, 1H), (3.65-3.68 m, 1H), 3.79 (d, 1H), (3.98-4.02 m, 1H), 4.18 (s, 1H), (4.51 s, 3H), 6.08 (t, 1H), (6.85 s, 1H), 7.32 (t, 1H), 7.64-7.67 (m, 1H), (7.86-7.88 m, 1H), 8.23 (t, 1H), 8.55 (s, 1H)

Embodiment 8i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.09 (t, 3H), 1.25 (d, 3H), (3.15 m, 2H), 3.19 (s, 3H), (3.20-3.26 m, 1H), 3.47-3.53 (m, 1H), (3.63-3.67 m, 1H), 3.78 (d, 1H), (3.97-4.01 m, 1H), 4.18 (d, 1H), (4.46 s, 1H), 4.50 (s, 2H), (6.82 s, 1H), 7.13 (t, 1H), 8.14 (s, 1H), (8.17-8.20 m, 1H), 8.28 (d, 1H), 8.33 (d, 1H)

Embodiment 8j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (d, 3H), 2.26 (s, 3H), 2.68 (d, 3H), (3.20 s, 3H), 3.22-3.26 (m, 1H), 3.47-3.54 (m, 1H), (3.63-3.67 m, 1H), 3.78 (d, 1H), 3.97-4.01 (m, 1H), 4.19 (d, 1H), 4.49 (s, 3H), (6.56 q, 1H), 6.77 (s, 1H), 7.79 (s, 1H), 8.02 (s, 1H), 8.06-8.09 (m, 2H)

Test (a): embodiment (8) 0.031 μ M; Embodiment (8a) 0.47 μ M; Embodiment (8b) 0.42 μ M; Embodiment (8c) 2.2 μ M; Embodiment (8d) 0.57 μ M; Embodiment (8e) 0.28 μ M; Embodiment (8f) 0.3 μ M; Embodiment (8g) 0.96 μ M; Embodiment (8h) 0.92 μ M; Embodiment (8i) 1.4 μ M; Embodiment (8j) 0.16 μ M.

N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] phenyl carbamate

At 0-5 ℃; by phenyl chloroformate (1.33mL; 10.6mmol) join sodium bicarbonate (1.34g; 15.9mmol) and 4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] in the mixture of diox (150mL) of aniline (3.7g, 10.6mmol).Stirring at room reaction 3 hours, evaporation, then be dissolved in DCM.Wash organic mixture with water, use Na ₂sO ₄drying, filter, and evaporation, obtain light yellow foam, and it is ground with hexane/ether, then filters, and obtains needed material white solid (5.4g).

the LCMS spectrum:mH+470, retention time 2.18, method: alkali formula monitoring.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.22 (3H, s), 3.58 (4H, s), 3.73 (4H, s), 4.50 (2H, s), 6.88 (1H, s), 7.24-7.30 (3H, m), 7.43-7.47 (2H, m), (7.63 2H, d), 8.30 (2H, d), 10.45 (1H, s).

Use similar mode, by suitable aniline, prepare following phenyl carbamate.

The preparation of needed aniline above before having described.

embodiment 9:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base sulfanylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (78mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (34mg), then add immediately sodium permanganate (40mg).At room temperature stirring reaction is 2 hours.Reactant is loaded on the SCX-2 post, uses the methanol wash post, with the needed material of 7N ammonia/methanol-eluted fractions.The vacuum concentration fraction, obtain needed compound light yellow solid (77mg).

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.31-1.38 (6H, m), (3.18-3.24 1H, m), 3.48-3.58 (2H, m), (3.64-3.68 1H, m), 3.79 (1H, d), (3.98-4.01 1H, m), 4.18 (1H, d), (4.48 3H, s), 6.79 (1H, s), (6.97-7.01 1H, m), 7.28-7.31 (1H, m), (7.31 1H, d), 7.46-7.49 (2H, m), 7.56-7.58 (2H, m), (8.25 2H, d), 8.73 (1H, s), 8.92 (1H, s)

mass spectrum:m+H ⁺510..

Test (a): 0.59 μ M.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base sulfanylmethyl) pyrimidine-2-base] benzene base]-the 3-phenylurea

Isopropyl mercaptan (0.075mL) is dissolved in acetonitrile (5mL) and 1,8-diazabicyclo [5.4.0], 11-7-alkene (0.12mL).At room temperature stirring reaction is 15 minutes, then adds 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-acetonitrile (5mL) solution of 3-phenylurea (228mg).Stirring reaction 30 minutes, then vacuum concentration.Resistates is carried out to silica gel chromatography, with 2.5% methyl alcohol/DCM wash-out, obtain needed compound (78mg) colloid.

mass spectrum:m+H ⁺478.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] benzene base]-the 3-phenylurea

By 1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-phenylurea (388mg) is dissolved in DCM (15mL) and triethylamine (0.194mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.108mL), and 0 ℃ of stirring reaction 90 minutes.The vacuum concentration reaction mixture distributes between DCM (20mL) and water (10mL).With salt solution (10mL) washing organic phase, dry (MgSO ₄), vacuum concentration, obtain needed compound (273mg) solid.

1-[4-[4-(methylol)-6-[(3S had before been described)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-preparation of 3-phenylurea.

embodiment 10:

3-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea

By 3-(4-bromophenyl)-1,1-dimethyl-urea (825mg), potassium acetate (998mg) and two (valeryl) two boron (1.03g) are dissolved in 1,4 diox (45mL).By degassed 5 minutes of solution, then add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (167mg), reaction is heated to 85 ℃, keep 3 hours.Add [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (828mg), ethanol (3.75mL), 2M sodium carbonate solution (8.53mL) and 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (167mg), continue heating 16 hours.Cooling reaction, evaporate to dryness distributes resistates between ethyl acetate (125mL) and water (100mL).Use the dried over mgso organism, filter vacuum concentration.Crude product is carried out to silica gel chromatography, with 5% methyl alcohol/DCM wash-out, obtain needed material white solid (737mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.22-1.24 (3H, m), 2.95 (6H, s), 3.16-3.23 (1H, m), 3.46-3.53 (1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), 4.18 (1H, d), 4.45-4.50 (3H, m), 5.38 (1H, t), (6.66 1H, s), 7.55-7.59 (2H, m), (8.18-8.22 2H, m), 8.45 (1H, s)

mass spectrum:m+H ⁺372.

Test (a): 19 μ M.

3-(4-bromophenyl)-1, the preparation of 1-dimethyl-urea is described below.

3-(4-bromophenyl)-1,1-dimethyl-urea

4-bromophenyl isocyanic ester (1.00g) is dissolved in THF (30mL).By dimethylamine, (2.0M, in THF, 2.78mL) joined in solution, stirring at room reaction 2 hours.Filter reaction, vacuum concentration, carry out silica gel chromatography to resistates, with 5% methyl alcohol/DCM wash-out, obtains needed material white solid (830mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 2.90 (6H, s), 7.37-7.40 (2H, m), 7.45-7.47 (2H, m), 8.37 (1H, s)

mass spectrum:m+H ⁺244.

embodiment 11:

N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenylamino formamido group) phenyl] pyrimidine-4-yl] methyl sulphonyl] ethyl] ethanamide

By N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenylamino formamido group) phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] ethanamide (100mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (40mg), then add immediately sodium permanganate (47mg).At room temperature stirring reaction is 2 hours.Further add 3-chlorine peroxybenzoic acid (4mg) and sodium permanganate (4mg), extra stirring reaction 1 hour.Reactant is loaded on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, remove needed material.Separate needed material white solid (102mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.25 (3H, d), 1.84 (3H, s), 3.18-3.24 (1H, m), 3.48-3.54 (2H, m), 3.52 (1H, s), (3.58 2H, q), 3.64-3.68 (1H, m), (3.79 1H, d), 3.98-4.01 (1H, m), (4.18 1H, d), 4.49 (1H, s), (4.53 2H, s), 6.80 (1H, s), (6.99 1H, t), 7.31 (2H, d), (7.46-7.49 2H, m), 7.57 (2H, d), (8.16 1H, t), 8.27 (2H, d), (8.70 1H, s), 8.92 (1H, s)

mass spectrum:m+H ⁺553.

Test (a): 0.14 μ M.

N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenylamino formamido group) phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] preparation of ethanamide is described below.

n-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenylamino formamido group) phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] ethanamide

N-acetylcysteamine (0.086mL) is dissolved in acetonitrile (5mL).Then DBU (0.120mL) is joined in this solution, stirring at room 15 minutes.By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-acetonitrile (5mL) solution of 3-phenylurea (228mg) joins in reaction, stirs 30 minutes.The vacuum concentration reaction, purifying crude product resistates on silica gel, with 5% methyl alcohol/DCM wash-out, obtain needed compound white solid (100mg).

mass spectrum:m+H ⁺521.

1-[4-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-preparation of 3-phenylurea.

embodiment 12:

1-[4-[4-(benzenesulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl]-3-phenylurea (62mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (26mg), then add immediately sodium permanganate (30mg).Stirring at room reaction 2 hours, then further add 3-chlorine peroxybenzoic acid (4mg) and sodium permanganate (4mg).Extra stirring reaction 1 hour, then be loaded into reactant on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, removes needed material.Separate needed material light yellow solid (64mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.20 (3H, d), 3.14-3.21 (1H, m), (3.45-3.52 1H, m), 3.61-3.65 (1H, m), (3.77 1H, d), 3.96-3.99 (1H, m), (4.10 1H, d), 4.38 (1H, s), (4.71 2H, s), 6.63 (1H, s), (6.99 1H, m), 7.31 (2H, d), (7.46 4H, t), 7.63 (2H, t), (7.73-7.78 1H, m), 7.82 (1H, d), (7.82-7.84 1H, m), 7.87 (2H, d), (8.69 1H, s), 8.87 (1H, s).

mass spectrum:m+H ⁺544.

Test (a): 0.23 μ M.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl]-preparation of 3-phenylurea is described below.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl]-3-benzene the base urea

Phenylmercaptan (0.029mL) is dissolved in acetonitrile (3mL).Then DBU (0.043mL) is joined in this solution, stirring at room 15 minutes.By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (80mg) joins in reaction, stirs 30 minutes.The vacuum concentration reaction, carry out silica gel chromatography to resistates, with 5% methyl alcohol/DCM wash-out, obtains needed material white solid (62mg). mass spectrum:m+H ⁺512.

embodiment 13:

3-[4-[4-(cyano methyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea

By 3-[4-[4-(cyano methyl sulfenyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea (162mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (79mg), then add immediately sodium permanganate (92mg).At room temperature stirring reaction is 2 hours.Further add 3-chlorine peroxybenzoic acid (40mg) and sodium permanganate (45mg), stirring reaction 1 hour, then further add 3-chlorine peroxybenzoic acid (40mg) and sodium permanganate (45mg), stirring reaction 1 hour.Reactant is loaded on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, remove needed material.Separate needed material white solid (17mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.25 (3H, d), 2.96 (6H, s), 3.18 (1H, d), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), (3.79 1H, d), 3.98-4.01 (1H, m), 4.17 (1H, s), 4.46 (1H, d), 4.74 (2H, s), (5.10 2H, d), 6.82 (1H, s), 7.59-7.61 (2H, m), 8.21-8.23 (2H, m), 8.49 (1H, s)

mass spectrum:m+H ⁺459.

Test (a): 2.1 μ M.

3-[4-[4-(cyano methyl sulfenyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1, the preparation of 1-dimethyl-urea is described below.

3-[4-[4-(cyano methyl sulfenyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base]-1,1-dimethyl-urea

By 3-[4-[4-(amidino sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea (0.38mmol) is dissolved in DMF (2mL).With bromoacetonitrile (0.030mL), it is processed, then use sodium hydroxide (61mg)/water (1mL) to process, stirring at room 15 minutes.The vacuum concentration reaction mixture, be loaded into SCX-2 by resistates upper, uses methanol wash, with 7N ammonia/methyl alcohol, removes needed material.Separate needed material, its further chromatogram purification just can use.

mass spectrum:m+H ⁺427.

3-[4-[4-(amidino sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base]-1,1-dimethyl-urea

By 3-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea (140mg) is dissolved in DCM (5mL) and triethylamine (0.079mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.044mL), and stirring at room reaction 15 minutes.Removal of solvent under reduced pressure, supplement with ethanol (5mL), then adds thiocarbamide (32mg).Then reaction is heated to 70 ℃, keeps 30 minutes, cooling, vacuum concentration, obtain needed material, and it just need not be further purified and can use.

mass spectrum:m+H ⁺430.

embodiment 14:

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

By 1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base sulfanylmethyl) pyrimidine-2-base] phenyl] urea (163mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (79mg), then add immediately sodium permanganate (92mg).Stirring at room reaction 2 hours, then further add 3-chlorine peroxybenzoic acid (20mg) and sodium permanganate (25mg).Stirring reaction 1 hour, then be loaded on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, removes needed material.Separate needed material white solid (90mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.25 (3H, d), 1.35-1.37 (6H, m), 2.95 (6H, s), 3.21-3.26 (2H, m), 3.47-3.54 (2H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.24 (1H, m) 4.45-4.47 (2H, m), (6.78 1H, s), 7.58-7.61 (2H, m), (8.17-8.20 2H, m), 8.48 (1H, s)

mass spectrum:m+H ⁺462.

Test (a): 0.42 μ M.

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base sulfanylmethyl) pyrimidine-2-base] phenyl] preparation of urea is described below.

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base sulfanylmethyl) pyrimidine -2-yl] phenyl] urea

By 3-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea (140mg) is dissolved in DCM (5mL) and triethylamine (0.079mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.044mL), and, stirring at room reaction 15 minutes, then vacuum concentration, obtain methanesulfonates, it just need not be further purified and can use.Isopropyl mercaptan (0.062mL) is dissolved in acetonitrile (5mL).Then DBU (0.099mL) is joined in this solution, stirring at room 5 minutes.Crude product methanesulfonates obtained above is suspended in acetonitrile (5mL), and joins in thiol solution.To react stirring at room 1 hour, then further add DBU (0.099mL), stirring at room reaction 30 minutes.The vacuum concentration reaction mixture, obtain needed material, and it just need not be further purified and can use.

mass spectrum:m+H ⁺430.

embodiment 15:

3-[4-[4-(benzenesulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea

By 1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl] urea (158mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (89mg), then add immediately sodium permanganate (96mg).Stirring at room reaction 16 hours, then further add 3-chlorine peroxybenzoic acid (20mg) and sodium permanganate (25mg).Stirring reaction 1 hour, then be loaded on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, removes needed material.Separate needed material white solid (90mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.20 (3H, d), 2.95 (6H, s), 3.13-3.20 (1H, m), (3.44-3.51 1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.07 (1H, t), 4.36 (1H, s), 4.70 (2H, s), 6.62 (1H, s), (7.47-7.49 2H, m), 7.62 (2H, t), 7.72-7.75 (1H, m), 7.79-7.84 (4H, m), 8.43 (1H, s)

mass spectrum:m+H ⁺496.

Test (a): 1 μ M.

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl] preparation of urea is described below.

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenyl sulfenyl methyl) pyrimidine-2-base] phenyl] urea

Phenylmercaptan (0.062mL) is dissolved in acetonitrile (5mL).Then DBU (0.141mL) is joined in this solution, stirring at room 5 minutes.By 1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (154mg) is suspended in acetonitrile (5mL), and joins in mercaptan.Stirring at room reaction 1 hour, then vacuum concentration, obtained needed material, and it just need not be further purified and can use.

mass spectrum:m+H ⁺464.

1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) is phonetic pyridine-2-yl] phenyl] urea

By 3-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-1,1-dimethyl-urea (384mg) is dissolved in DCM (12mL) and triethylamine (0.216mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.121mL), and, stirring at room reaction 15 minutes, then vacuum concentration, obtain needed material.

mass spectrum:m+H ⁺450.

embodiment 16:

N-[2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethyl] ethanamide

By N-[2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] ethanamide (158mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (116mg), then add immediately sodium permanganate (134mg).Stirring at room reaction 1 hour, then be loaded on the SCX-2 post, use the methanol wash post, remove needed material with 7N ammonia/methyl alcohol.Separate needed material white solid (84mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.25 (3H, d), 1.83 (3H, s), (2.96 6H, s), 3.20-3.25 (1H, m), (3.47-3.50 1H, m), 3.52 (2H, d), (3.57 2H, q), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), (4.51 3H, m), 6.78 (1H, s), 7.58-7.61 (2H, m), (8.16-8.19 1H, m), 8.19-8.22 (2H, m), 8.49 (1H, s)

mass spectrum:m+H ⁺505.

Test (a): 4 μ M.

N-[2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] preparation of ethanamide is described below.

n-[2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4- base] the methyl sulfenyl] ethyl] ethanamide

N-acetylcysteamine (0.064mL) is dissolved in acetonitrile (5mL).Then DBU (0.141mL) is joined in this solution, stirring at room 5 minutes.By 1,1-dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (154mg) is suspended in acetonitrile (5mL), and joins in mercaptan.Stirring at room reaction 1 hour, then vacuum concentration, obtained needed material.

mass spectrum:m+H ⁺473.

embodiment 17:

2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethanamide

By 2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] ethanamide (158mg) is dissolved in Isosorbide-5-Nitrae-dioxs (6mL) and water (1mL).Solution is cooled to 0 ℃, adds 3-chlorine peroxybenzoic acid (75%) (123mg), then add immediately sodium permanganate (143mg).Stirring at room reaction 1 hour, then be loaded on the SCX-2 post, use the methanol wash post, remove needed material with 7N ammonia/methyl alcohol.Separate needed material white solid (55mg).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.25 (3H, d), 2.96 (6H, s), (3.22-3.26 1H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.18 (1H, d), (4.27 2H, s), 4.47 (1H, s), 4.67 (2H, s), (6.77 1H, s), 7.53 (1H, s), 7.58-7.61 (2H, m), (7.79 1H, s), 8.17-8.21 (2H, m), 8.49 (1H, s)

mass spectrum:m+H ⁺477.

Test (a): 1.1 μ M.

2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] preparation of ethanamide is described below.

2-[[2-[4-(dimethylamino formamido group) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] ethanamide

By dimethyl-3-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (154mg) is dissolved in ethanol (5mL), and adds thiocarbamide (29mg).Then reaction is heated to 70 ℃, keeps 30 minutes, then vacuum concentration.Resistates is dissolved in DMF (2mL), processes with 2-bromoacetamide (52mg), then use sodium hydroxide (55mg)/water (1mL) to process, stirring at room 30 minutes.The vacuum concentration reaction mixture, then be loaded on the SCX-2 post, uses the methanol wash post, with 7N ammonia/methyl alcohol, removes needed material.Needed material just need not be further purified and can use.

mass spectrum:m+H ⁺445.

embodiment 18:

1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-methyl-urea

1-(4-bromophenyl)-3-methyl-urea (2.50g), potassium acetate (3.21g) and two (valeryl) two boron (3.33g) are dissolved in 1,4 diox (120mL).By degassed 5 minutes of solution, then add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (535mg), reaction is heated to 90 ℃, keep 3 hours.Further add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (250mg), continue heating 1 hour.Further add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (250mg), continue heating 1 hour.Add [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (2.66mg), ethanol (9.5mL), 2M sodium carbonate solution (27.3mL) and 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (II) methylene dichloride adducts (535mg), continue heating 16 hours.Cooling reaction, evaporate to dryness then distributes resistates between ethyl acetate (250mL) and water (100mL).Use the dried over mgso organism, filter vacuum concentration.Crude product is carried out to silica gel chromatography, with 5% methyl alcohol/DCM wash-out, obtain needed material brown solid (1.25g).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.23 (3H, d), 2.66 (3H, d), 3.18-3.23 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), 3.76 (1H, d), (3.96-3.99 1H, m), 4.16 (1H, d), 4.45 (2H, d), 4.49 (1H, d), 5.38 (1H, t), (6.05 1H, q), 6.66 (1H, s), 7.46-7.48 (2H, m), 8.18-8.21 (2H, m), 8.69 (1H, s)

mass spectrum:m+H ⁺358.

Test (a): 0.12 μ M.

The preparation of 1-(4-bromophenyl)-3-methyl-urea is described below.

1-(4-bromophenyl)-3-methyl-urea

4-bromophenyl isocyanic ester (2.50g) is dissolved in THF (75mL).By methylamine, (2.0M, in THF, 75mL) joined in solution, stirring at room reaction 1 hour.Filter reaction, vacuum-drying.Crude product is carried out to silica gel chromatography, with 5% methyl alcohol/DCM wash-out, obtain needed material white solid (2.65g).

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 2.64 (3H, d), 6.03 (1H, d), 7.37 (4H, s), 8.61 (1H, s)

mass spectrum:m+H ⁺229.

embodiment 19:

1-[4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-methyl-urea

By 1-[4-[4-(cyclohexyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-methyl-urea (0.35mmol) is dissolved in Isosorbide-5-Nitrae-dioxs (5mL) and water (1mL).3-chlorine peroxybenzoic acid (75%) (121mg) is joined in this solution, then add immediately sodium permanganate (140mg), stirring at room reaction 1 hour.Further add 3-chlorine peroxybenzoic acid (75%) (121mg) and sodium permanganate (140mg), stirring at room reaction 1 hour.Further add 3-chlorine peroxybenzoic acid (75%) (121mg) and sodium permanganate (140mg), the other stirring reaction of room temperature 1 hour, then be loaded on the SCX-3 post.Use the methanol wash post, with 7N ammonia/methyl alcohol, remove needed material.With preparative HPLC (alkali formula) purifying crude product, obtain needed material (74mg) white solid.

the NMR spectrum: ¹h NMR (DMSO-d ₆) δ 1.18-1.32 (7H, m), 1.42 (1H, d), (1.48 1H, d), 1.68 (1H, d), (1.89 2H, d), 2.25 (3H, d), (2.32-2.34 1H, m), 2.66 (3H, d), (3.46-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.17 1H, d), 4.43 (3H, s), 6.08 (1H, t), (6.77 1H, s), 7.50-7.52 (2H, m), 8.19-8.21 (2H, m)

mass spectrum:m+H ⁺488.

Use similar mode, by suitable sulfide, prepare following compounds.

Embodiment 19a: ¹h NMR (DMSO-d ₆) δ 1.18 (3H, d), 2.66 (3H, q), (3.11-3.19 1H, m), 3.43-3.50 (1H, m), (3.60-3.63 1H, m), 3.75 (1H, d), (3.94-3.98 1H, m), 4.08 (1H, d), (4.35 1H, s), 4.69 (2H, s), (6.04 1H, q), 6.59 (1H, s), (7.36-7.38 2H, m), 7.61 (2H, t), 7.71-7.75 (1H, m), (7.79-7.81 3H, m), 7.82 (1H, s), 8.69 (1H, s)

Embodiment 19b: ¹h NMR (DMSO-d ₆) δ 1.20 (3H, d), 2.66 (3H, d), (3.14-3.21 1H, m), 3.45-3.51 (1H, m), (3.61-3.65 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.11 (1H, d), (4.37 1H, s), 4.71 (2H, s), 6.04 (1H, q), (6.64 1H, s), 7.37-7.41 (2H, m), 7.43-7.48 (2H, m), (7.77-7.80 2H, m), 7.85-7.89 (2H, m), 8.71 (1H, s)

Embodiment 19c: ¹h NMR (DMSO-d ₆) δ 1.18 (3H, d), 2.13 (3H, s), 2.60-2.61 (3H, m), (2.67 3H, q), 2.68 (1H, s), 3.44-3.49 (1H, m), (4.08 1H, d), 4.35 (1H, s), 4.60 (2H, s), (6.05 1H, q), 6.54 (1H, s), 7.37-7.39 (2H, m), (7.70 2H, d), 7.77 (2H, d), 7.82 (2H, d), 8.68 (1H, s), 10.37 (1H, s)

Embodiment 19d: ¹h NMR (DMSO-d ₆) δ 1.24 (3H, d), 1.35-1.37 (7H, m), 2.66-2.69 (3H, m), 3.21-3.25 (1H, m), 3.47-3.54 (2H, m), (3.63-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.46 (3H, s), 6.08 (1H, q), (6.77 1H, s), 7.49-7.51 (2H, m), (8.17-8.19 2H, m), 8.73 (1H, s)

Embodiment 19e: ¹h NMR (DMSO-d ₆) δ 1.24 (3H, d), 2.66 (2H, s), 2.68 (2H, q), (3.21-3.26 1H, m), 3.51 (3H, t), 3.63-3.67 (1H, m), (3.78 1H, d), 3.89-3.94 (2H, m), 3.97-4.01 (1H, m), 4.50 (3H, s), 5.18 (1H, t), (6.07 1H, d), 6.76 (1H, s), 7.49-7.51 (2H, m), 8.20-8.22 (2H, m), 8.74 (1H, s)

Embodiment 19f: ¹h NMR (DMSO-d ₆) δ 1.20-1.25 (3H, m), 2.66 (3H, t), (3.15-3.21 1H, m), 3.45-3.51 (1H, m), (3.61-3.65 1H, m), 3.77 (1H, t), (3.95-3.99 1H, m), 4.11 (1H, d), (4.39 1H, s), 4.87 (2H, s), (6.05 1H, q), 6.71 (1H, s), (7.35-7.37 2H, m), 7.64-7.66 (2H, m), 7.81-7.82 (2H, m), (8.70 1H, d), 8.90 (1H, d), 8.91 (1H, s)

Test (a): embodiment (19) 0.25 μ M; Embodiment (19a) 0.0047 μ M; Embodiment (19b) 0.033 μ M; Embodiment (19c) 0.022 μ M; Embodiment (19d) 0.066 μ M; Embodiment (19e) 0.011 μ M; Embodiment (19f) 0.027 μ M.

1-[4-[4-(cyclohexyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-preparation of 3-methyl-urea is described below.

1-[4-[4-(cyclohexyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base]-3-methyl-urea

Cyclohexylmercaptan (0.61mmol) is dissolved in acetonitrile (4mL).Then add DBU (0.050mL), stirring at room solution 5 minutes.By 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (151mg) is dissolved in acetonitrile (2mL); add DBU (0.054mL), stirring at room reaction 2 hours.The vacuum concentration reaction mixture, obtain needed material, and it just need not be further purified and can use.

Use similar fashion, by 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea and suitable mercaptan prepares following sulfide.

3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] preparation of urea is described below.

the 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2- base] phenyl] urea

By 1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-methyl-urea (1.24g) partly is dissolved in DCM (30mL) and triethylamine (0.724mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.405mL), and, stirring at room reaction 15 minutes, then vacuum concentration, obtain needed material.

mass spectrum:m+H ⁺436.

embodiment 20:

3-[4-[4-(benzenesulfonyl methyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl]-1-methyl-urea

By (4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) phenyl carbamate (250mg, 0.45mmol) is dissolved in DMF (5mL).Add triethylamine (0.188mL, 1.35mmol), (2M, in THF, 1.1mL), and 50 ℃ of heated solutions 1 hour then to add methylamine.Reaction is cooled to room temperature, and vacuum concentration.Purify with silica gel chromatography the oil obtained, with 0-5% methyl alcohol/DCM wash-out, obtain needed material white solid (120mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 2.66 (d, 3H), 3.63 (m, 4H), 3.70 (m, 4H), 4.69 (s, 2H), (6.05 m, 1H), 6.65 (s, 1H), 7.38 (d, 2H), 7.63 (t, 2H), 7.74 (d, 1H), 7.80 (m, 3H), 8.69 (s, 1H)

the LCMS spectrum:mH+468, retention time 1.76 minutes, method: 5 minutes alkali formulas

With being similar to preparation N '-(4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) mode of urea, by suitable amine and suitable urethane reaction, and carry out silica gel chromatography or preparative HPLC purifying, preparation is shown in the compound in table.

Embodiment 20a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.00 (t, 3H), 3.05 (m, 2H), 3.56 (s, 4H), 3.63 (m, 4H), (4.62 s, 2H), 6.07 (t, 1H), 6.59 (s, 1H), 7.30 (d, 2H), 7.55 (t, 2H), 7.71 (m, 5H), 8.54 (s, 1H)

Embodiment 20b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), 2.55 (m, 1H), 3.64 (m, 4H), 3.71 (m, 4H), (4.69 s, 2H), 6.41 (d, 1H), (6.66 s, 1H), 7.38 (d, 2H), (7.63 t, 2H), 7.75 (m, 1H), (7.81 m, 4H), 8.49 (s, 1H)

Embodiment 20c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 2.20 (s, 6H), 2.38 (t, 2H), 3.20 (m, 2H), 3.63 (s, 4H), 3.70 (s, 4H), (4.69 s, 2H), 6.17 (s, 1H), (6.65 s, 1H), 7.37 (d, 2H), (7.62 t, 2H), 7.75 (t, 1H), (7.81 t, 4H), 8.87 (s, 1H)

Embodiment 20d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.49 (m, 2H), 1.86 (m, 2H), 2.32 (s, 3H), 2.84 (m, 2H), 3.54 (m, 2H), (3.63 s, 4H), 3.70 (m, 4H), 4.69 (s, 2H), 6.46 (d, 1H), 6.65 (s, 1H), (7.35 d, 2H), 7.63 (t, 2H), 7.74 (t, 2H), 7.81 (m, 3H), 8.76 (s, 1H)

Embodiment 20e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.27 (m, 2H), 3.29 (s, 3H), 3.40 (t, 2H), 3.63 (s, 4H), 3.71 (m, 4H), (4.69 s, 2H), 6.25 (t, 1H), (6.66 s, 1H), 7.35 (d, 2H), (7.62 t, 1H), 7.75 (m, 2H), (7.81 m, 4H), 8.73 (s, 1H)

Embodiment 20f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.15 (t, 3H), 1.25 (d, 3H), 3.12 (m, 3H), (3.47 t, 1H), 3.62 (d, 1H), 3.76 (d, 1H), (3.96 d, 1H), 4.08 (d, 1H), 4.36 (s, 1H), (4.70 s, 2H), 6.14 (t, 1H), 6.60 (s, 1H), (7.38 d, 2H), 7.62 (t, 2H), 7.74 (t, 1H), 7.81 (m, 4H), 8.62 (s, 1H)

Embodiment 20g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), (1.20 d, 3H), 2.55 (m, 1H), (3.16 m, 1H), 3.47 (m, 1H), (3.62 m, 1H), 3.75 (d, 1H), (3.97 m, 1H), 4.09 (d, 1H), (4.36 s, 1H), 4.70 (s, 2H), (6.42 d, 1H), 6.60 (s, 1H), (7.39 d, 2H), 7.63 (t, 2H), (7.75 t, 1H), 7.82 (m, 4H), 8.49 (s, 1H)

Embodiment 20h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (d, 3H), 2.23 (s, 6H), (2.40 t, 2H), 3.21 (m, 3H), (3.47 m, 1H), 3.62 (m, 1H), (3.75 d, 1H), 3.96 (m, 1H), (4.08 d, 1H), 4.36 (s, 1H), (4.70 s, 2H), 6.21 (t, 1H), (6.60 s, 1H), 7.40 (d, 2H), (7.62 t, 2H), 7.75 (t, 1H), (7.82 m, 3H), 7.96 (s, 1H), 8.90 (s, 1H)

Embodiment 20i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (d, 3H), 1.40 (m, 2H), 1.79 (m, 2H), 2.02 (t, 2H), 2.16 (s, 3H), (2.64 m, 2H), 3.16 (m, 1H), (3.47 m, 2H), 3.62 (m, 1H), (3.75 d, 1H), 3.96 (m, 1H), (4.08 d, 1H), 4.35 (s, 1H), (4.69 s, 2H), 6.16 (d, 1H), (6.60 s, 1H), 7.35 (d, 2H), (7.65 t, 2H), 7.74 (t, 1H), (7.81 m, 4H), 8.52 (s, 1H)

Embodiment 20j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (d, 3H), 3.15 (t, 1H), 3.29 (m, 5H), (3.40 t, 2H), 3.47 (t, 1H), 3.62 (d, 1H), (3.75 d, 1H), 3.96 (d, 1H), 4.08 (d, 1H), (4.36 s, 1H), 4.70 (s, 2H), 6.25 (t, 1H), (6.60 s, 1H), 7.37 (d, 2H), 7.62 (t, 2H), (7.74 t, 1H), 7.82 (d, 4H), 8.73 (s, 1H)

Embodiment 20k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.36 (d, 6H), 2.66 (s, 3H), 3.51 (m, 1H), 3.72 (s, 8H), 4.47 (s, 2H), 6.09 (s, 1H), 6.83 (s, 1H), (7.51 d, 2H), 8.18 (d, 2H), 8.76 (s, 1H)

Embodiment 20l: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.35 (d, 6H), 3.12 (m, 2H), 3.51 (m, 1H), (3.72 s, 8H), 4.47 (s, 2H), 6.18 (s, 1H), 6.83 (s, 1H), 7.51 (d, 2H), 8.18 (d, 2H), 8.68 (s, 1H)

Embodiment 20m: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), (1.38 d, 6H), 2.56 (m, 1H), (3.51 m, 1H), 3.72 (s, 8H), (4.46 s, 2H), 6.45 (s, 1H), (6.82 s, 1H), 7.51 (d, 2H), (8.19 d, 2H), 8.55 (s, 1H)

Embodiment 20n: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.36 (d, 6H), 2.85 (d, 6H), (3.20 m, 2H), 3.46 (m, 2H), (3.51 m, 1H), 3.72 (s, 8H), (4.46 s, 2H), 6.56 (t, 1H), (6.83 s, 1H), 7.55 (d, 2H), (8.21 d, 2H), 9.10 (s, 1H)

Embodiment 20o: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.36 (d, 6H), 1.57 (m, 2H), 1.97 (d, 2H), 2.59 (s, 1H), 2.78 (s, 2H), (3.16 d, 2H), 3.29 (s, 3H), 3.50 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), (6.44 d, 1H), 6.81 (s, 1H), 7.49 (d, 2H), 8.20 (d, 2H), 8.65 (s, 1H)

Embodiment 20p: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.38 (d, 6H), 3.28 (m, 2H), (3.29 s, 3H), 3.40 (t, 2H), (3.51 m, 1H), 3.72 (s, 8H), (4.46 s, 2H), 6.28 (t, 1H), (6.81 s, 1H), 7.49 (d, 2H), (8.20 d, 2H), 8.77 (s, 1H)

Embodiment 20q: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.24 (d, 3H), 1.36 (m, 6H), (3.13 m, 2H), 3.23 (m, 1H), 3.51 (m, 2H), (3.65 m, 1H), 3.72 (d, 1H), 3.99 (m, 1H), 4.17 (d, 1H), 4.46 (s, 3H), (6.17 t, 1H), 6.77 (s, 1H), 7.50 (d, 2H), 8.18 (d, 2H), 8.65 (s, 1H)

Embodiment 20r: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.25 (d, 3H), (1.37 d, 6H), 2.57 (m, 2H), 3.23 (m, 1H), (3.50 m, 2H), 3.65 (m, 1H), 3.78 (d, 1H), (3.99 m, 1H), 4.17 (d, 1H), 4.46 (s, 2H), (6.44 d, 1H), 6.77 (s, 1H), 7.51 (d, 2H), 8.19 (d, 2H), 8.53 (s, 1H)

Embodiment 20s: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (d, 3H), 1.36 (m, 6H), 2.18 (s, 6H), (2.34 t, 2H), 3.21 (m, 2H), 3.50 (m, 2H), (3.65 m, 1H), 3.76 (d, 1H), 3.99 (m, 1H), (4.06 q, 2H), 4.17 (d, 1H), 4.46 (s, 2H), (6.17 t, 1H), 6.77 (s, 1H), 7.49 (d, 2H), 8.18 (d, 2H), 8.89 (s, 1H)

Embodiment 20t: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (d, 3H), 1.36 (m, 6H), 1.42 (m, 2H), 1.80 (m, 2H), 2.03 (t, 2H), (2.17 s, 3H), 2.65 (d, 2H), (3.18 d, 1H), 3.23 (m, 1H), (3.50 m, 2H), 3.65 (m, 1H), (3.76 d, 1H), 3.98 (m, 1H), (4.06 m, 1H), 4.17 (d, 1H), (4.46 s, 2H), 6.19 (d, 1H), (6.77 s, 1H), 7.48 (d, 2H), (8.18 d, 2H), 8.56 (s, 1H)

Embodiment 20u: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (d, 4H), 1.36 (m, 6H), 3.18 (d, 3H), (3.24 m, 2H), 3.40 (t, 2H), 3.50 (m, 2H), (3.65 m, 1H), 3.78 (d, 1H), 3.99 (m, 1H), (4.06 m, 1H), 4.17 (d, 1H), 4.46 (s, 2H), (6.28 t, 1H), 6.77 (s, 1H), 7.49 (d, 2H), 8.19 (d, 2H), 8.77 (s, 1H)

Test (a): embodiment (20) 0.043 μ M; Embodiment (20a) 0.15 μ M; Embodiment (20b) 0.17 μ M; Embodiment (20c) 1 μ M; Embodiment (20d) 1.6 μ M; Embodiment (20e) 2.1 μ M; Embodiment (20f) 0.035 μ M; Embodiment (20g) 0.039 μ M; Embodiment (20h) 0.44 μ M; Embodiment (20i) 0.7 μ M; Embodiment (20j) 0.75 μ M; Embodiment (20k) 0.036 μ M; Embodiment (20l) 0.074 μ M; Embodiment (20m) 0.081 μ M; Embodiment (20n) 0.86 μ M; Embodiment (20o) 1.3 μ M; Embodiment (20p) 0.91 μ M; Embodiment (20q) 0.039 μ M; Embodiment (20r) 0.094 μ M; Embodiment (20s) 0.62 μ M; Embodiment (20t) 0.6 μ M; Embodiment (20u) 0.27 μ M.

The preparation of following carbamate is described below: (4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) phenyl carbamate; (4-{4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) phenyl carbamate; (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) phenyl carbamate, (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate.

(4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) phenyl carbamate

By (4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amine (1g, 2.44mmol) is dissolved in diox (10mL).Add sodium bicarbonate (307mg, 3.65mmol), then add phenyl chloroformate (0.307mL, 2.44mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 10mL DCM and 10mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (790mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.64 (s, 4H), 3.70 (m, 4H), 4.71 (s, 2H), 6.70 (s, 1H), (7.27 m, 3H), 7.45 (t, 2H), 7.51 (d, 2H), 7.62 (t, 2H), 7.74 (m, 1H), 7.85 (m, 4H), 10.38 (s, 1H)

the LCMS spectrum:mH+531, retention time 2.61 minutes, method: 5 minutes alkali formulas

(4-{4-morpholine-4-base-6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amine

By the chloro-6-[(benzene sulfonyl of 4-{2-) methyl] pyrimidine-4-yl } morpholine (3.3g, 9.33mmol) is dissolved in 18%DMF solution (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (36mL)).Then add that [4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] amine (3.07g, 13.99mmol), 2M sodium carbonate solution (12mL) and two (triphenylphosphine) palladium catalyst (328mg of dichloro, 0.47mmol), under nitrogen atmosphere, at 90 ℃, will react and reflux 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.Crude product oil is dissolved in DCM, filters, remove insoluble substance.Be settled out beige solid from filtrate, again filter liquor.Analyze solid, find needed material (2.2g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.60 (m, 4H), 3.69 (m, 4H), 4.64 (s, 2H), 5.50 (s, 2H), 6.48 (d, 2H), 6.54 (s, 1H), 7.63 (m, 4H), 7.74 (t, 1H), 7.82 (m, 2H)

the LCMS spectrum:mH+411, retention time 1.70 minutes, method: 5 minutes alkali formulas

the chloro-6-[(benzene sulfonyl of 4-{2-) methyl] pyrimidine-4-yl } morpholine

By the chloro-6-[(benzene sulfonyl of 2,4-bis-) methyl] pyrimidine (6g, 19.8mmol) is dissolved in DCM (50mL), and in-5 ℃ of stirrings (in nitrogen atmosphere).Add triethylamine (3.06mL, 21.8mmol), obtain the brown solution of clarification.Morpholine (1.65mL, 19.8mmol) is dissolved in DCM, and dropwise adds, keep reaction lower than-5 ℃.Then remove cooling bath, at room temperature stirred reaction mixture is 1 hour.Then water (50mL) washing reaction mixture, use dried over mgso, filters vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (4g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.53 (s, 4H), 3.65 (t, 4H), 4.61 (s, 2H), 6.71 (s, 1H), 7.64 (t, 2H), 7.77 (m, 3H)

the LCMS spectrum:mH+354, retention time 1.50 minutes, method: 5 minutes alkali formulas

the chloro-6-[(benzene sulfonyl of 2,4-bis-) methyl] pyrimidine

By the 6-[(benzene sulfonyl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (13.3g, 49mmol) joins in phosphorus oxychloride (100mL), and by mixture reflux 16 hours.Then reaction is cooled to room temperature, vacuum is removed excessive phosphorus oxychloride.By resistates and toluene (2x100mL) azeotropic, and be dissolved in DCM.Then this mixture is poured at leisure to ice (1L) upper, stirs 20 minutes, then use DCM (3x500mL) to extract, the united extraction thing, use dried over mgso, and then vacuum concentration, obtain needed material brown solid (12g).This material just need not be further purified and can use.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 4.97 (s, 2H), 7.65 (t, 2H), 7.72 (s, 1H), 7.79 (m, 3H)

the LCMS spectrum:m-H 301, retention time 2.08 minutes, method: 5 minutes alkali formulas

the 6-[(benzene sulfonyl) methyl] pyrimidine-2,4 (1H, 3H)-diketone

By 6-(chloromethyl)-1H-pyrimidine-2,4-diketone (8g, 50mmol) is dissolved in DMF (200mL), adds benzene sulfinic acid sodium salt (9.8g, 60mmol).Reaction is heated to 125 ℃, keeps 2 hours, then cooling, filtering suspension liquid, vacuum concentration, obtain yellow solid.Water (100mL) washing crude product, filter, and then with acetonitrile, grinds, and obtains needed material paste solid (13.2g).This material just need not be further purified and can use.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 4.46 (s, 2H), 7.69 (t, 2H), 7.81 (m, 1H), 7.87 (m, 3H), 10.85 (s, 1H), 11.11 (s, 1H)

(4-{4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amino first acid phenenyl ester

By (4-{4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amine (2g, 4.71mmol) is dissolved in diox (20mL).Add sodium bicarbonate (594mg, 7.07mmol), then add phenyl chloroformate (0.593mL, 4.71mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 20mL DCM and 20mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (1.1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (d, 3H), 3.17 (m, 1H), 3.48 (m, 1H), (3.63 m, 1H), 3.76 (d, 1H), 3.97 (m, 1H), (4.11 d, 1H), 4.37 (s, 1H), 4.72 (s, 2H), (6.65 s, 1H), 7.27 (m, 3H), 7.45 (t, 2H), (7.51 d, 2H), 7.62 (t, 2H), 7.74 (t, 1H), (7.82 d, 2H), 7.90 (d, 2H), 10.38 (s, 1H)

the LCMS spectrum:mH+545, retention time 2.7 minutes, method: 5 minutes alkali formulas

(4-{4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amine

By (4-{4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) carboxylamine tertiary butyl ester (3.1g, 5.91mmol) is dissolved in DCM (20mL), adds trifluoroacetic acid (10mL).At room temperature stirred reaction mixture is 2 hours, then uses DCM (20mL) dilution, with saturated sodium bicarbonate aqueous solution (20mL) washing.Collect organic phase, use dried over mgso, filter, vacuum concentration, obtain needed material beige solid (2.5g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (d, 3H), 3.24 (m, 1H), 3.47 (m, 1H), 3.62 (m, 1H), 3.78 (d, 1H), (3.98 m, 1H), 4.14 (s, 1H), 4.37 (s, 1H), 4.75 (s, 2H), 6.56 (s, 1H), (6.67 d, 3H), 7.65 (m, 2H), (7.78 m, 3H), 7.84 (m, 3H)

the LCMS spectrum:mH+425, retention time 2.03 minutes, method: 5 minutes alkali formulas

(4-{4-[(S)-3-methylmorpholine-4-yl]-the 6-[(benzene sulfonyl) methyl] pyrimidine-2-base } phenyl) amino first the acid tertiary butyl ester

By the chloro-6-[(benzene sulfonyl of (3S)-4-{2-) methyl] pyrimidine-4-yl }-3-methylmorpholine (3.2g, 8.70mmol) is dissolved in 18%DMF solution (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (36mL)).Then add that [4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] carboxylamine tertiary butyl ester (4.16g, 13.05mmol), 2M sodium carbonate solution (8mL) and two (triphenylphosphine) palladium catalyst (306mg of dichloro, 0.43mmol), under nitrogen atmosphere, at 90 ℃, will react and reflux 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.The crude product solid is carried out to silica gel chromatography, with 0-30% ethyl acetate/DCM wash-out, obtain needed material beige solid (3.1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (d, 3H), 1.49 (s, 9H), 3.16 (m, 1H), (3.47 m, 1H), 3.62 (m, 1H), 3.75 (d, 1H), (3.97 m, 1H), 4.10 (d, 1H), 4.35 (s, 1H), 4.70 (s, 2H), 6.62 (s, 1H), (7.44 d, 2H), 7.63 (d, 2H), 7.74 (m, 1H), 7.82 (m, 4H), 9.49 (s, 1H)

the LCMS spectrum:mH+525, retention time 2.80 minutes, method: 5 minutes alkali formulas

(3S) the chloro-6-[(benzene sulfonyl of-4-{2-) methyl] pyrimidine-4-yl }-the 3-methylmorpholine

By the chloro-6-[(benzene sulfonyl of 2,4-bis-) methyl] pyrimidine (2.8g, 9.24mmol) is dissolved in DCM (20mL), in-5 ℃ of stirrings (in nitrogen atmosphere).Add triethylamine (1.42mL, 10.17mmol), obtain the brown solution of clarification.(3S)-3-methylmorpholine (935mg, 9.24mmol) is dissolved in DCM, and dropwise adds, keep reaction lower than-5 ℃.Then remove cooling bath, at room temperature stirred reaction mixture is 1 hour.Then water (50mL) washing reaction mixture, use dried over mgso, filters vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (2.6g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.15 (d, 3H), 3.15 (m, 1H), 3.42 (m, 1H), 3.56 (m, 1H), 3.72 (d, 1H), (3.92 m, 2H), 4.15 (s, 1H), (4.62 s, 2H), 6.66 (s, 1H), (7.74 t, 1H), 7.76 (t, 1H), (7.78 d, 1H), 7.80 (m, 2H)

the LCMS spectrum:mH+368, retention time 1.95 minutes, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) phenyl carbamate

By (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amine (1.5g, 3.98mmol) is dissolved in diox (10mL).Add sodium bicarbonate (503mg, 5.98mmol), then add phenyl chloroformate (0.502mL, 3.98mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 10mL DCM and 10mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (1.5g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.30 (d, 6H), 3.45 (m, 1H), 3.65 (s, 8H), 4.40 (s, 2H), 6.78 (s, 1H), 7.20 (m, 3H), 7.38 (t, 2H), (7.56 d, 2H), 8.22 (d, 2H), 10.37 (s, 1H)

the LCMS spectrum:mH+497, retention time 2.54 minutes, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amine

By (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) carboxylamine tertiary butyl ester (2.7g, 5.67mmol) is dissolved in DCM (20mL), adds trifluoroacetic acid (10mL).At room temperature stirred reaction mixture is 2 hours, then uses DCM (20mL) dilution, with saturated sodium bicarbonate aqueous solution (20mL) washing.Collect organic phase, use dried over mgso, filter, vacuum concentration, obtain needed material paste solid (2.1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.35 (d, 6H), 3.50 (m, 1H), 3.67 (m, 4H), 3.72 (m, 4H), 4.41 (s, 2H), 5.57 (s, 2H), 6.60 (d, 2H), 6.70 (s, 1H), 8.03 (d, 2H)

the LCMS spectrum:mH+377, retention time 1.61 minutes, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) the tertiary fourth of carboxylamine the base ester

By the chloro-6-[(sec.-propyl of 4-{2-alkylsulfonyl) methyl] pyrimidine-4-yl } morpholine (1.5g, 4.69mmol) is dissolved in 18%DMF solution (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (36mL)).Then add the 4-[(tertbutyloxycarbonyl) amino] phenyl boric acid (1.67g, 7.04mmol), two (triphenylphosphine) palladium catalyst (165mg of 2M sodium carbonate solution (12mL) and dichloro, 0.23mmol), under nitrogen atmosphere, 90 ℃ of back flow reaction 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.Crude product oil is dissolved in DCM, filters, remove insoluble substance.Be settled out brown solid from filtrate, again filter liquor.Analyze solid, find needed material (1.9g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.36 (d, 6H), 1.50 (s, 9H), 3.52 (m, 1H), 3.72 (s, 8H), 4.46 (s, 2H), 6.83 (s, 1H), 7.57 (d, 2H), 8.22 (d, 2H), 9.56 (s, 1H)

the LCMS spectrum:mH+477, retention time 2.50 minutes, method: 5 minutes alkali formulas

the chloro-6-[(benzene sulfonyl of 4-{2-) methyl] pyrimidine-4-yl } morpholine

By the chloro-6-[(sec.-propyl of 2,4-bis-alkylsulfonyl) methyl] pyrimidine (2.65g, 9.85mmol) is dissolved in DCM (50mL), in-5 ℃ of stirrings (in nitrogen atmosphere).Add triethylamine (1.5mL, 10.84mmol), obtain the brown solution of clarification.Morpholine (0.86mL, 9.85mmol) is dissolved in DCM, and dropwise adds, keep reaction lower than-5 ℃.Then remove cooling bath, at room temperature stirred reaction mixture is 1 hour.Then water (50mL) washing reaction mixture, use dried over mgso, filters vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material (2.5g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.30 (d, 6H), 3.42 (m, 1H), 3.62 (s, 4H), 3.68 (m, 4H), 4.42 (s, 2H), 6.95 (s, 1H)

the LCMS spectrum:mH+320, retention time 1.51 minutes, method: 5 minutes alkali formulas

the chloro-6-[(sec.-propyl of 2,4-bis-alkylsulfonyl) methyl] pyrimidine

By the chloro-6-[(isopropyl of 2,4-bis-sulfenyl) methyl] pyrimidine (6.2g, 26.16mmol) is dissolved in DCM (100mL), with within 10 minutes, adding in batches 3,5-, bis-chloroperoxybenzoic acids (13.5g, 78.4mmol).At room temperature stirring reaction is 4 hours.Then use saturated sodium bicarbonate aqueous solution (50mL) washing reaction mixture, use dried over mgso, filter, vacuum concentration, obtain the paste solid.By the normal-phase chromatography purifying, with 0-50% ethyl acetate/isohexane wash-out, obtain needed material paste solid (5.3g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (d, 6H), 3.43 (m, 1H), 4.77 (s, 2H), 7.87 (s, 1H)

the LCMS spectrum:m-H 267, retention time 1.64 minutes, method: 5 minutes alkali formulas

the chloro-6-[(isopropyl of 2,4-bis-sulfenyl) methyl] pyrimidine

By 6-[(isopropyl sulfenyl) methyl] pyrimidine-2,4 (1H, 3H)-diketone (8g, 40mmol) joins in phosphorus oxychloride (100mL), and by mixture reflux 16 hours.Then reaction is cooled to room temperature, vacuum is removed excessive phosphorus oxychloride.By resistates and toluene (2x100mL) azeotropic, and be dissolved in DCM.Then this mixture is poured at leisure to ice (1L) upper, stirs 20 minutes, then use DCM (3x500mL) to extract, the united extraction thing, use dried over mgso, and then vacuum concentration, obtain needed material brown oil (6.5g).This material just need not be further purified and can use.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (d, 6H), 2.96 (m, 1H), 3.85 (s, 2H), 7.82 (s, 1H)

the LCMS spectrum:retention time 2.51 minutes, method: 5 minutes alkali formulas

6-[(isopropyl sulfenyl) methyl] pyrimidine-2,4 (1H, 3H)-diketone

By 6-(chloromethyl)-1H-pyrimidine-2,4-diketone (8g, 50mmol) is dissolved in acetonitrile (200mL), adds 1,8-diazabicyclo [5.4.0] 11-7-alkene (13mL, 87.19mmol), and at room temperature stirring reaction is 15 minutes.Then add isopropyl mercaptan (8.1mL, 87.19mmol), at room temperature further stirring reaction is 2 hours.Solvent removed in vacuo, be dissolved in the brown oil obtained in DCM, washes with water.Use the dried over mgso organic phase, filter vacuum concentration.The oil obtained is carried out to silica gel chromatography, with 0-10% methyl alcohol/DCM wash-out, obtain needed material white solid (8g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (d, 6H), 2.90 (m, 1H), 3.42 (s, 2H), 5.49 (s, 1H), 10.82 (s, 1H), 10.94 (s, 1H)

the LCMS spectrum:m-H 199, retention time 0.63 minute, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate

By (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) amine (1.5g, 3.84mmol) is dissolved in diox (10mL).Add sodium bicarbonate (485mg, 5.76mmol), then add phenyl chloroformate (0.484mL, 3.84mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 10mL DCM and 10mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (1.8g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.18 (d, 3H), 1.30 (m, 6H), 3.17 (m, 2H), 3.44 (m, 2H), 3.58 (m, 1H), (3.70 d, 1H), 3.92 (m, 1H), 4.12 (d, 1H), 4.41 (s, 2H), 6.74 (s, 1H), (7.20 m, 3H), 7.38 (t, 2H), 7.56 (d, 2H), 8.22 (d, 2H), 10.37 (s, 1H)

the LCMS spectrum:mH+511, retention time 2.67 minutes, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) amine

By (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) carboxylamine tertiary butyl ester (3.2g; 6.52mmol) be dissolved in DCM (20mL), add trifluoroacetic acid (10mL).At room temperature stirred reaction mixture is 2 hours, then uses DCM (20mL) dilution, with saturated sodium bicarbonate aqueous solution (20mL) washing.Collect organic phase, use dried over mgso, filter, vacuum concentration, obtain needed material paste solid (2.4g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (d, 3H), 1.35 (m, 6H), 3.19 (m, 1H), 3.49 (m, 2H), 3.64 (m, 1H), (3.77 d, 1H), 3.97 (m, 1H), 4.14 (d, 1H), 4.41 (s, 2H), 4.45 (m, 1H), (5.56 s, 2H), 6.60 (d, 2H), (6.66 s, 1H), 8.02 (d, 2H)

the LCMS spectrum:mH+391, retention time 1.84 minutes, method: 5 minutes alkali formulas

(4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) the carboxylamine tertiary butyl ester

By the chloro-6-[(sec.-propyl of (3S)-4-{2-alkylsulfonyl) methyl] pyrimidine-4-yl }-3-methylmorpholine (2.0g, 5.99mmol) is dissolved in 18%DMF solution (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (16mL)).Then add the 4-[(tertbutyloxycarbonyl) amino] phenyl boric acid (2.13g, 8.99mmol), two (triphenylphosphine) palladium catalyst (211mg of 2M sodium carbonate solution (8mL) and dichloro, 0.30mmol), under nitrogen atmosphere, 90 ℃ of back flow reaction 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material brown solid (3.2g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.36 (m, 6H), 1.50 (s, 9H), 3.24 (m, 4H), 3.51 (m, 2H), 3.65 (m, 1H), (3.78 d, 1H), 3.99 (m, 1H), (4.18 d, 1H), 4.47 (s, 2H), (6.79 s, 1H), 7.57 (d, 2H), (8.21 d, 2H), 9.55 (s, 1H)

the LCMS spectrum:mH+491, retention time 2.67 minutes, method: 5 minutes alkali formulas

(3S) the chloro-6-[(sec.-propyl of-4-{2-alkylsulfonyl) methyl] pyrimidine-4-yl }-the 3-methylmorpholine

By the chloro-6-[(sec.-propyl of 2,4-bis-alkylsulfonyl) methyl] pyrimidine (2.65g, 9.85mmol) is dissolved in DCM (50mL), in-5 ℃ of stirrings (in nitrogen atmosphere).Add triethylamine (1.5mL, 10.84mmol), obtain the brown solution of clarification.3S-3-methylmorpholine (997mg, 9.85mmol) is dissolved in DCM, and dropwise adds, keep reaction lower than-5 ℃.Then remove cooling bath, at room temperature stirred reaction mixture is 1 hour.Then water (50mL) washing reaction mixture, use dried over mgso, filters vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (2g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (d, 3H), 1.31 (d, 6H), 3.22 (m, 1H), 3.43 (m, 2H), 3.60 (m, 1H), 3.74 (d, 1H), 3.98 (m, 1H), (4.30 s, 1H), 4.43 (s, 2H), 6.91 (s, 1H)

the LCMS spectrum:mH+332, retention time 1.70 minutes, method: 5 minutes alkali formulas

embodiment 21:

3-methyl isophthalic acid-[4-[4-(2-methyl sulphonyl third-2-yl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] urea

Will (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) phenyl carbamate (116mg, 0.22mmol) is dissolved in DMF (3mL).Add triethylamine (0.098mL, 0.7mmol), then add methylamine (2M, in THF, 0.6mL, 1.17mmol).Mixture is stirred 1 hour under 50 ℃.Concentration response, by the preparative HPLC purifying, obtain needed material white solid (54mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.77 (s, 6H), 2.66 (d, 3H), 3.04 (s, 3H), 3.73 (s, 8H), 6.06 (m, 1H), 6.79 (s, 1H), 7.51 (d, 2H), 8.24 (d, 2H), 8.74 (s, 1H)

the LCMS spectrum:mH+434, retention time 1.64 minutes, method: 5 minutes alkali formulas

Use similar mode, by (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) phenyl carbamate or (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate and suitable amine prepares following compounds.

Embodiment 21a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.77 (s, 6H), 3.04 (s, 3H), 3.13 (m, 2H), 3.73 (s, 8H), 6.15 (t, 1H), 6.79 (s, 1H), (7.50 d, 2H), 8.24 (d, 2H), 8.66 (s, 1H)

Embodiment 21b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.77 (s, 6H), 2.57 (m, 1H), (3.04 s, 3H), 3.73 (s, 8H), 6.43 (d, 1H), 6.79 (s, 1H), 7.51 (d, 2H), 8.24 (d, 2H), 8.54 (s, 1H)

Embodiment 21c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.77 (s, 6H), 2.18 (s, 6H), 2.34 (t, 2H), 3.04 (s, 3H), (3.19 m, 2H), 3.73 (s, 8H), 6.15 (t, 1H), 6.79 (s, 1H), 7.49 (d, 2H), 8.24 (d, 2H), 8.90 (s, 1H)

Embodiment 21d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.40 (m, 2H), 1.77 (s, 6H), 2.03 (m, 2H), 2.17 (s, 3H), 2.45 (m, 2H), (2.67 m, 2H), 3.04 (s, 3H), 3.47 (m, 1H), 3.73 (s, 8H), 6.18 (d, 1H), (6.79 s, 1H), 7.48 (d, 2H), (8.24 d, 2H), 8.57 (s, 1H)

Embodiment 21e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.77 (s, 6H), 3.04 (s, 3H), 3.27 (m, 2H), 3.29 (s, 3H), (3.40 t, 2H), 3.73 (s, 8H), 6.26 (t, 1H), 6.79 (s, 1H), 7.49 (d, 2H), 8.24 (d, 2H), 8.79 (s, 1H)

Embodiment 21f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16 (d, 3H), 1.70 (s, 6H), 2.59 (d, 3H), (2.96 s, 3H), 3.16 (m, 1H), 3.43 (m, 1H), (3.58 m, 1H), 3.70 (d, 1H), 3.91 (m, 1H), 4.16 (d, 1H), 4.53 (s, 1H), (5.99 m, 1H), 6.66 (s, 1H), 7.44 (d, 2H), 8.16 (d, 2H), 8.67 (s, 1H)

Embodiment 21g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.00 (t, 3H), 1.16 (d, 3H), 1.70 (d, 6H), (2.96 s, 3H), 3.06 (m, 2H), 3.16 (m, 1H), (3.43 m, 1H), 3.58 (m, 1H), 3.70 (d, 1H), (3.91 m, 1H), 4.16 (d, 1H), 4.52 (s, 1H), (6.09 t, 1H), 6.67 (s, 1H), 7.43 (d, 2H), 8.16 (d, 2H), 8.59 (s, 1H)

Embodiment 21h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (m, 2H), 0.65 (m, 2H), 1.23 (d, 3H), (1.78 d, 6H), 2.56 (m, 1H), 3.03 (s, 3H), (3.23 m, 1H), 3.50 (m, 1H), 3.65 (m, 1H), (3.78 d, 1H), 3.98 (m, 1H), 4.23 (d, 1H), (4.60 s, 1H), 6.43 (d, 1H), 6.74 (s, 1H), (7.51 d, 2H), 8.24 (d, 2H), 8.54 (s, 1H)

Embodiment 21i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (d, 3H), 1.77 (d, 6H), 2.18 (s, 6H), (2.34 t, 2H), 3.03 (s, 3H), 3.19 (m, 3H), (3.49 m, 1H), 3.65 (m, 1H), 3.77 (d, 1H), (3.98 m, 1H), 4.23 (d, 1H), 4.59 (s, 1H), (6.16 t, 1H), 6.73 (s, 1H), 7.49 (d, 2H), 8.23 (d, 2H), 8.90 (s, 1H)

Embodiment 21j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (s, 3H), 1.41 (m, 2H), (1.78 d, 6H), 1.81 (m, 2H), (2.02 t, 2H), 2.16 (s, 3H), (2.64 m, 2H), 3.03 (s, 3H), (3.22 m, 1H), 3.50 (m, 2H), (3.65 m, 1H), 3.78 (d, 1H), (3.98 m, 1H), 4.23 (d, 1H), (4.61 s, 1H), 6.18 (d, 1H), (6.74 s, 1H), 7.48 (d, 2H), (8.23 d, 2H), 8.57 (s, 1H)

Embodiment 21k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (d, 3H), 1.77 (d, 6H), 3.03 (s, 3H), (3.21 m, 2H), 3.27 (m, 1H), 3.40 (t, 2H), (3.48 m, 2H), 3.65 (m, 1H), 3.72 (d, 1H), (3.97 m, 1H), 4.23 (d, 1H), 4.60 (s, 1H), (6.26 t, 1H), 6.74 (s, 1H), 6.86 (s, 1H), (7.49 d, 2H), 8.24 (d, 2H), 8.78 (s, 1H)

Test (a): embodiment (21) 0.05 μ M; Embodiment (21a) 0.73 μ M; Embodiment (21b) 0.36 μ M; Embodiment (21c) 0.48 μ M; Embodiment (21d) 0.27 μ M; Embodiment (21e) 1 μ M; Embodiment (21f) 0.017 μ M; Embodiment (21g) 0.02 μ M; Embodiment (21h) 0.028 μ M; Embodiment (21i) 0.076 μ M; Embodiment (21j) 0.51 μ M; Embodiment (21k) 0.31 μ M.

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) phenyl carbamate and (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) preparation of phenyl carbamate is described below.

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amino first acid phenenyl ester

Will (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amine (1.5g, 3.98mmol) is dissolved in diox (15mL).Add sodium bicarbonate (503mg, 5.98mmol), then add phenyl chloroformate (0.502mL, 3.98mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 20mL DCM and 20mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (700mg).

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amine

Will (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) carboxylamine tertiary butyl ester (2.6g, 5.46mmol) is dissolved in DCM (20mL), and adds trifluoroacetic acid (10mL).At room temperature stirred reaction mixture is 2 hours, then uses DCM (20mL) dilution, with saturated sodium bicarbonate aqueous solution (20mL) washing.Collect organic phase, use dried over mgso, filter, vacuum concentration, obtain needed material paste solid (2.1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.75 (s, 6H), 3.03 (s, 3H), 3.71 (s, 8H), 5.56 (s, 2H), 6.61 (d, 2H), 6.69 (s, 1H), 8.07 (d, 2H)

the LCMS spectrum:mH+377, retention time 1.84 minutes, method: 5 minutes alkali formulas

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-morpholine-4-yl pyrimidines-2-yl } phenyl) amino first the acid tertiary butyl ester

By the chloro-6-[1-methyl isophthalic acid of (3S)-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl }-3-methylmorpholine (1.75g, 5.47mmol) is dissolved in 18%DMF (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (18mL)) in solution.Then add that [4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] carboxylamine tertiary butyl ester (2.62g, 8.2mmol), 2M sodium carbonate solution (8mL) and two (triphenylphosphine) palladium catalyst (192mg of dichloro, 0.27mmol), under nitrogen atmosphere, at 90 ℃, will react and reflux 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-30% ethyl acetate/DCM wash-out, obtain needed material white solid (2.6g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.50 (s, 9H), 1.77 (s, 6H), 3.04 (s, 3H), 3.73 (s, 8H), 6.80 (s, 1H), 7.57 (d, 2H), 8.26 (d, 2H), 9.54 (s, 1H)

the LCMS spectrum:mH+477, retention time 2.66 minutes, method: 5 minutes alkali formulas

the chloro-6-[1 methyl isophthalic acid of 4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl } morpholine

By the chloro-6-[(methyl sulphonyl of 4-{2-) methyl] pyrimidine-4-yl } morpholine (2.9g, 9.94mmol) is dissolved in DMF (20mL), and reaction is cooled to-5 ℃.Sodium tert-butoxide (956mg, 9.94mmol) is joined in reaction, then add methyl iodide (0.6mL, 9.94mmol), maintain the temperature at-5 ℃.Then the sodium tert-butoxide (956mg, 9.94mmol) and the methyl iodide (0.6mL, 9.94mmol) that add second equivalent ,-5 ℃ of stirring reactions 1 hour, then at room temperature stir 4 hours.Add DCM (20mL), with the 2M HCl aqueous solution (20mL) washing reaction.Use the dried over mgso organic phase, filter vacuum concentration.Crude product is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (1.7g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.68 (s, 6H), 2.99 (s, 3H), 3.67 (s, 8H), 6.91 (s, 1H)

the LCMS spectrum:mH+320, retention time 1.67 minutes, method: 5 minutes alkali formulas

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate

Will (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) amine (3.6g, 8.77mmol) is dissolved in diox (20mL).Add sodium bicarbonate (1.1g, 13.15mmol), then add phenyl chloroformate (1.1mL, 8.77mmol), at room temperature stirring reaction is 2 hours.Solvent removed in vacuo, and the oil obtained is distributed between 20mL DCM and 20mL water.Use the dried over mgso organic phase, filter vacuum concentration.The paste solid obtained is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material white solid (2g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (d, 3H), 1.78 (d, 6H), 3.04 (s, 3H), (3.24 m, 1H), 3.51 (m, 1H), 3.65 (m, 1H), (3.78 d, 1H), 3.96 (m, 1H), 4.25 (d, 1H), 4.61 (s, 1H), 6.77 (s, 1H), (7.27 m, 3H), 7.45 (m, 2H), 7.64 (d, 2H), 8.34 (d, 2H), 10.43 (s, 1H)

the LCMS spectrum:mH+511, retention time 2.7 minutes, method: 5 minutes alkali formulas

(4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) amine

By the chloro-6-[1-methyl isophthalic acid of (3S)-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl }-3-methylmorpholine (2.2g, 6.59mmol) is dissolved in 18%DMF (at 7: 3: 2 glycol dimethyl ethers: water: in the mixture of ethanol (18mL)) in solution.Then add that [4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] amine (2.17g, 9.89mmol), 2M sodium carbonate solution (8mL) and two (triphenylphosphine) palladium catalyst (232mg of dichloro, 0.33mmol), under nitrogen atmosphere, at 90 ℃, will react and reflux 2 hours.The cooling reaction to room temperature then distributed between ethyl acetate (20mL) and water (20mL).Use the dried over mgso organism, filter vacuum concentration.The crude product solid is carried out to silica gel chromatography, with 0-10% methyl alcohol/DCM wash-out, obtain needed material brown oil (3.6g).

the LCMS spectrum:mH+389, retention time 1.00 minutes, method: 5 minutes alkali formulas

(3S) the chloro-6-[1-methyl isophthalic acid of-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl }-the 3-methylmorpholine

By the chloro-6-[(methyl sulphonyl of (3S)-4-{2-) methyl] pyrimidine-4-yl }-3-methylmorpholine (2.1g, 6.87mmol) is dissolved in DMF (20mL), and reaction is cooled to-5 ℃.Sodium tert-butoxide (650mg, 6.87mmol) is joined in reaction, then add methyl iodide (0.4mL, 6.87mmol), maintain the temperature at-5 ℃.Then the sodium tert-butoxide (650mg, 6.87mmol) and the methyl iodide (0.4mL, 6.87mmol) that add second equivalent ,-5 ℃ of stirring reactions 1 hour, then at room temperature stir 4 hours.Add DCM (20mL), with 2M aqueous hydrochloric acid (20mL) washing reaction.Use the dried over mgso organic phase, filter vacuum concentration.The crude product solid is carried out to silica gel chromatography, with 0-50% ethyl acetate/DCM wash-out, obtain needed material (2.2g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (d, 3H), 1.68 (s, 6H), 2.74 (s, 3H), 3.21 (m, 1H), (3.45 m, 1H), 3.59 (m, 1H), 3.73 (d, 1H), 3.94 (m, 1H), 4.07 (d, 1H), 4.45 (s, 1H), 6.86 (s, 1H)

the LCMS spectrum:mH+334, retention time 1.85 minutes, method: 5 minutes alkali formulas

embodiment 22:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl]-3-(1,2-oxazole-3-yl) urea

By N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate (170mg, 0.35mmol) is dissolved in DMF (1.5mL).Add triethylamine (0.147mL, 1.06mmol).Add 1,2-oxazole-3-amine (198mg, 2.35mmol), 60 ℃ of stirring reactions 2 hours.The evaporate to dryness reaction, by the reverse-phase chromatography purifying, obtain needed material white solid (81mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.26 (3H, m), 3.21 (3H, s), 3.23-3.26 (1H, m), (3.47-3.54 1H, m), 3.64-3.68 (1H, m), 3.79 (1H, d), (3.98-4.01 1H, m), 4.17-4.20 (1H, m), 4.50 (3H, s), 6.81 (1H, s), 6.87 (1H, d), (7.58 2H, d), 8.29 (2H, d), 8.75 (1H, d), 9.07 (1H, s), 9.62 (1H, s)

the LCMS spectrum:mH+473, retention time 1.63 minutes, method: acid monitoring.

Use similar mode, by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 22a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.22 (3H, s), 3.24-3.26 (1H, m), (3.48-3.55 1H, m), 3.65-3.68 (1H, m), 3.79 (1H, d), (3.98-4.02 1H, m), 4.20 (1H, d), 4.51 (3H, s), 6.82 (1H, s), 7.16 (1H, t), (7.71-7.73 2H, m), 8.30-8.33 (2H, m), 8.70 (2H, d), 10.21 (1H, s), 11.63 (1H, s)

Embodiment 22b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.26 (3H, m), 2.23 (6H, s), 3.21 (3H, s), (3.23 1H, d), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.17-4.20 (1H, m), 4.49 (3H, s), 6.79 (1H, s), (7.08 3H, d), 7.55-7.59 (2H, m), 7.78 (1H, s), 8.23-8.27 (2H, m), 9.00 (1H, s)

Embodiment 22c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.22 (3H, s), 3.24 (1H, d), 3.48-3.55 (1H, m), 3.64-3.68 (1H, m), (3.79 1H, d), 3.98-4.02 (1H, m), 4.19 (1H, d), 4.51 (3H, s), 6.24 (1H, d), (6.81 1H, s), 7.56 (1H, t), 7.70 (2H, d), 8.28-8.30 (2H, m), 9.28 (1H, s)

Embodiment 22d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.38 (3H, d), 3.21 (3H, s), (3.23 1H, m), 3.47-3.54 (1H, m), 3.64-3.68 (1H, m), (3.79 1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.50 (3H, s), 6.57 (1H, d), (6.81 1H, s), 7.56 (2H, d), 8.27-8.29 (2H, m), 9.05 (1H, d), 9.46 (1H, s)

Embodiment 22e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.37 (3H, s), 3.21 (3H, s), (3.22-3.26 1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.18 (1H, s), 4.49 (3H, s), 6.80 (1H, s), (7.55-7.58 2H, m), 8.18 (1H, s), 8.25-8.27 (2H, m), 8.67 (1H, d), 8.99 (1H, s)

Embodiment 22f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 3.21 (3H, s), (3.22-3.26 1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.77-3.30 (1H, m) 3.79 (3H, s), 3.97-4.01 (1H, m), (4.18 1H, s), 4.49 (3H, s), 6.79 (1H, s), (7.38 1H, d), 7.53-7.57 (2H, m), 7.76 (1H, s), (8.23-8.26 2H, m), 8.39 (1H, s), 8.84 (1H, s)

Embodiment 22g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 3.21 (3H, s), (3.23-3.26 1H, m), 3.47-3.54 (1H, m), (3.64-3.68 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.18 (1H, d), (4.50 3H, s), 6.25-6.27 (1H, m), (6.46 1H, d), 6.81 (1H, s), (7.25 1H, d), 7.55-7.57 (2H, m), 8.27-8.29 (2H, m), (8.92 1H, s), 9.05 (1H, s), 11.04 (1H, s)

Embodiment 22h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.01 (3H, s), 2.10 (3H, s), (3.21 3H, s), 3.25 (1H, d), 3.47-3.54 (1H, m), (3.64 3H, s), 3.66-3.70 (1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.18 (1H, d), 4.49 (3H, s), (6.78 1H, s), 7.48 (1H, s), 7.53-7.57 (2H, m), 8.22-8.24 (2H, m), 8.80 (1H, s)

Embodiment 22i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.03 (3H, s), 2.09 (3H, s), (3.21 3H, s), 3.25 (1H, d), 3.47-3.54 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.18 1H, d), 4.49 (3H, s), 6.78 (1H, s), (7.44 1H, s), 7.55 (2H, d), 8.23 (2H, d), 8.81 (1H, s), 12.04 (1H, s)

Test (a): embodiment (22a) 0.06 μ M; Embodiment (22b) 1.6 μ M; Embodiment (22d) 0.0048 μ M; Embodiment (22e) 0.56 μ M; Embodiment (22f) 0.091 μ M; Embodiment (22g) 0.0045 μ M; Embodiment (22h) 1.5 μ M; Embodiment (22i) 4.3 μ M.

Test (c): embodiment (22c) 0.21 μ M.

N-[4-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate.

embodiment 23:

The 3-methyl isophthalic acid-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] urea

By N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] phenyl carbamate (220mg, 0.45mmol) is dissolved in DMF (3mL).Add triethylamine (0.188mL, 1.35mmol), then add 2M methylamine/THF (1.2mL, 2.25mmol).Mixture is stirred 3 hours under 50 ℃.The evaporate to dryness reaction mixture, by the normal-phase chromatography purifying, used 0-6% methyl alcohol/DCM gradient, obtains oil, and it is ground with diethyl ether, obtains needed material white solid (153mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.17 (3H, d), 1.20-1.27 (2H, m), (1.77 2H, d), 2.54 (3H, d), (2.99 2H, d), 3.08 (1H, d), (3.12 3H, s), 3.37-3.40 (1H, m), (3.43 1H, d), 3.57 (1H, d), (3.71 1H, d), 3.91 (1H, d), (3.94 1H, d), 4.23 (2H, s), (4.26 1H, d), 4.42 (2H, d), (5.57 1H, q), 5.83 (1H, d), 6.14 (1H, s)

the LCMS spectrum:mH+427, retention time 0.85 minute, method: 5 minutes acid methods

Use similar mode, by N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 23a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.98 (3H, t), 1.13-1.18 (3H, m), (1.20-1.26 2H, m), 1.77 (2H, d), (2.97-3.03 4H, m), 3.05-3.10 (1H, m), (3.12 3H, s), 3.38-3.45 (1H, m), (3.55-3.59 1H, m), 3.63 (1H, t), (3.71 1H, d), 3.92 (1H, d), (3.92 1H, d), 4.23 (2H, s), (4.27 1H, m), 4.41 (2H, d), (5.64 1H, t), 5.77 (1H, d), 6.14 (1H, s)

Test (a): embodiment (23) 5.6 μ M; Embodiment (23a) 3.7 μ M.

N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] preparation of phenyl carbamate is described below.

n-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidines base] phenyl carbamate

By 1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] piperidines-4-amine (500mg, 1.35mmol) is dissolved in diox (10mL).Add sodium bicarbonate (171mg, 1.50mmol).Then with within 2 minutes, dropwise adding Phenyl Chloroformate 99 (0.171mL, 1.35mmol).Slurries are at room temperature stirred 3 hours.Add phenyl chloroformate (0.021mL, 0.27mmol) and sodium bicarbonate (21mg, 0.12mmol).At room temperature continue to stir 1 hour, the evaporate to dryness reaction mixture, and distribute between water (10mL) and ethyl acetate (10mL).Extract water by the ethyl acetate (10mL) of second section.The organism merged by dried over mgso, evaporation, obtain needed material foam (701mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.18 (3H, d), 1.34-1.44 (2H, m), (1.86 2H, d), 2.99 (2H, d), (3.11 1H, d), 3.13 (3H, s), (3.40-3.46 1H, m), 3.60 (2H, d), (3.72 2H, d), 3.91-3.96 (2H, m), (4.25 2H, s), 4.28 (1H, m), (4.52 2H, d), 6.16 (1H, s), 7.10 (2H, d), (7.20 1H, t), 7.38 (2H, t), 7.76 (1H, d)

the LCMS spectrum:mH+490, retention time 1.58 minutes, method: acid monitoring.

1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] piperidines-4-amine

By N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] carboxylamine tertiary butyl ester (1.30g, 2.77mmol) is dissolved in methyl alcohol (10mL).Add 4M hydrochloric acid/diox (10mL).To react and at room temperature stir 3 hours.Add saturated sodium bicarbonate aqueous solution, until reach pH7, vacuum is removed organic solvent.Add water (20mL), product is extracted in ethyl acetate (50mL).Extract water layer by the ethyl acetate (25mL) of second section.The organism that evaporation merges, obtain the yellow foam (1.05g) of needed material.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.17 (3H, d), 1.69-1.73 (2H, m), 2.75-2.80 (1H, m), (2.87-2.94 2H, m), 3.07 (1H, d), 3.11 (1H, m), (3.12 3H, s), 3.39-3.45 (1H, m), 3.55-3.62 (1H, m), 3.69-3.73 (1H, m), 3.90-3.94 (2H, m), (4.22 2H, s), 4.26 (1H, s), 4.43 (1H, s), 4.46 (1H, d), 6.12 (1H, s)

the LCMS spectrum:mH+370, retention time 0.48 minute, method: acid monitoring.

n-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidines base] the carboxylamine tertiary butyl ester

The chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.00g; 3.27mmol), salt of wormwood (498mg; 3.60mmol) and N-(4-piperidyl) carboxylamine tertiary butyl ester (721mg, 3.60mmol).Add acetonitrile (10mL), and by mixture reflux 4 hours.The evaporation acetonitrile, remaining white solid distributes it between water (40mL) and ethyl acetate (60mL).Separation of phases, extract water layer by second section ethyl acetate (40mL).The organism that evaporate to dryness merges, obtain needed material paste solid (1.32g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16-1.18 (3H, m), 1.23-1.31 (2H, m), (1.39 9H, s), 1.74 (2H, d), (2.91 2H, t), 3.06-3.09 (1H, m), (3.11 3H, s), 3.39-3.44 (1H, m), (3.49 1H, s), 3.55-3.59 (1H, m), (3.71 1H, d), 3.90 (1H, d), (3.94 1H, d), 4.23 (2H, s), 4.26 (1H, d), (4.50 2H, d), 6.14 (1H, s), 6.78 (1H, d)

the LCMS spectrum:mH+470, retention time 1.39 minutes, method: acid monitoring.

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-preparation of 6-(sulfonyloxy methyl ylmethyl) pyrimidine.

embodiment 24:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl]-3-(2-pyridine-2-base ethyl) urea

By N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate (242mg, 0.50mmol) is dissolved in DMF (1.5mL).Add triethylamine (0.209mL, 1.50mmol).Add 2-pyridine-2-base ethamine (306mg, 2.50mmol).40 ℃ of stirring reactions 2 hours.By reverse-phase chromatography purification reaction mixture, obtain needed material white solid (239mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.94 (2H, t), (3.21 3H, s), 3.22-3.26 (1H, m), (3.48 1H, d), 3.50-3.54 (2H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.00 1H, m), 4.17 (1H, d), (4.48 3H, s), 6.26 (1H, t), (6.77 1H, s), 7.22-7.26 (1H, m), (7.30 1H, d), 7.47-7.51 (2H, m), (7.71-7.75 1H, m), 8.19-8.22 (2H, m), (8.52-8.54 1H, m), 8.77 (1H, s)

the LCMS spectrum: MH+511, retention time 1.67 minutes, method: 5 minutes alkali formula methods

Use similar mode, by suitable carbamate and suitable amine, prepare following compounds.

Embodiment 24a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.21 (3H, s), (3.22-3.26 1H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), (4.35 2H, d), 4.48 (3H, s), (6.77 1H, t), 6.78 (1H, s), (7.35-7.38 1H, m), 7.52 (2H, d), (7.71-7.74 1H, m), 8.22 (2H, d), (8.46-8.47 1H, m), 8.55 (1H, d), 8.88 (1H, s)

Embodiment 24b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.67 (2H, t), (3.21 3H, s), 3.24 (1H, d), (3.34-3.39 2H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.00 1H, m), 4.17 (1H, d), (4.48 3H, s), 6.23 (1H, t), (6.77 1H, s), 6.83 (1H, s), (7.49-7.51 2H, m), 7.55 (1H, d), (8.21 2H, s), 8.79 (1H, s), 11.81 (1H, s)

Embodiment 24c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.48 (3H, s), (3.21 3H, s), 3.22-3.26 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), (4.17 1H, d), 4.45 (2H, d), 4.49 (3H, s), (6.78 1H, s), 6.85 (1H, t), 7.50-7.53 (2H, m), (8.21-8.23 2H, m), 8.49-8.51 (2H, m), 9.01 (1H, s)

Embodiment 24d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.21 (3H, s), (3.25 1H, d), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), (4.44 2H, d), 4.49 (3H, s), (6.78 1H, s), 6.84 (1H, t), (7.27-7.30 1H, m), 7.37 (1H, d), (7.51-7.55 2H, m), 7.76-7.80 (1H, m), (8.22 2H, d), 8.53-8.55 (1H, m), 9.04 (1H, s)

Embodiment 24e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.21 (3H, s), (3.23-3.26 1H, m), 3.50-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97 1H, d), 4.00-4.19 (1H, m), (4.36 2H, d), 4.48 (2H, s), (4.49 1H, s), 6.78 (1H, s), (6.81 1H, t), 7.30-7.31 (2H, m), 7.51-7.55 (2H, m), (8.21-8.24 2H, m), 8.51-8.52 (2H, m), 8.96 (1H, s)

Embodiment 24f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.21 (3H, s), (3.24 1H, d), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.74 (3H, s), (3.78 1H, d), 3.97-4.01 (1H, m), (4.17 1H, d), 4.25 (2H, d), (4.48-4.48 2H, m), 6.59 (1H, t), (6.78 1H, s), 6.89-6.92 (2H, m), 7.23-7.26 (2H, m), (7.50-7.52 2H, m), 8.20-8.23 (2H, m), 8.76 (1H, s)

Embodiment 24g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.24 (1H, d), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.76 1H, s), 3.79 (3H, s), (3.97-4.01 1H, m), 4.13 (2H, d), (4.19 1H, s), 4.48 (2H, s), (4.49 1H, s), 6.42 (1H, t), (6.77 1H, s), 7.35 (1H, s), 7.49-7.51 (2H, m), (7.59 1H, s), 8.20-8.22 (2H, m), 8.69 (1H, s)

Embodiment 24h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.38 (3H, s), 3.25 (1H, d), (3.48-3.53 1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), 4.32 (2H, d), (4.48 2H, s), 4.49 (1H, s), 6.16 (1H, d), (6.71 1H, t), 6.78 (1H, s), 7.50-7.53 (2H, m), 8.21-8.24 (2H, m), 8.91 (1H, s)

Embodiment 24i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.88 (6H, s), (3.21 3H, s), 3.25 (1H, d), (3.50-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.17 1H, d), 4.25 (2H, d), (4.48 1H, d), 4.49 (2H, s), (6.59 2H, t), 6.63 (1H, d), (6.68 1H, d), 6.78 (1H, s), (7.14 1H, t), 7.51 (2H, d), (8.22 2H, d), 8.77 (1H, s)

Embodiment 24j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.21 (3H, d), (3.23-3.26 1H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, s), (4.49 1H, d), 4.49 (2H, s), (4.54 2H, d), 6.78 (1H, s), (6.80 1H, t), 7.50-7.54 (2H, m), 7.79 (1H, d), (8.21-8.24 2H, m), 8.87 (1H, s), 8.97 (1H, d)

Embodiment 24k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.69 (3H, d), 3.19 (1H, d), (3.25 3H, s), 3.48 (1H, d), 3.63 (1H, d), (3.77 1H, d), 3.96-3.99 (1H, m), 4.12 (1H, s), 4.44 (1H, m), 4.48 (2H, s), (6.49 1H, d), 6.72 (1H, s), 6.78 (1H, s), 8.44 (1H, d), 9.30 (1H, s)

Embodiment 24l: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.08 (3H, t), 1.25 (3H, d), 3.12-3.19 (2H, m), (3.23 3H, s), 3.24 (1H, m), 3.45-3.52 (1H, m), (3.62-3.65 1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), (4.12 1H, s), 4.45 (1H, m), 4.48 (2H, s), (6.46 1H, d), 6.78 (1H, s), 6.89 (1H, s), 8.44 (1H, d), 9.22 (1H, s)

Embodiment 24m: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.39-0.43 (2H, m), 0.64-0.69 (2H, m), (1.25 3H, d), 2.56-2.60 (1H, m), (3.22 3H, s), 3.25 (1H, m), (3.45-3.52 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.95-3.99 (1H, m), (4.12 1H, s), 4.45 (1H, s), (4.48 2H, s), 6.47 (1H, d), 6.78 (1H, s), (7.09 1H, s), 8.44 (1H, d), 9.16 (1H, s)

Embodiment 24n: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16 (3H, d), 1.18-1.24 (2H, m), (1.64 6H, s), 1.77 (2H, d), (2.54 3H, d), 2.98 (3H, s), (3.02 2H, t), 3.08-3.12 (1H, m), (3.39-3.45 1H, m), 3.55-3.60 (1H, m), (3.62-3.66 1H, m), 3.69-3.74 (1H, m), (3.90-3.93 1H, m), 3.98 (1H, d), (4.36 1H, d), 4.42 (2H, d), (5.57 1H, q), 5.82 (1H, s), 6.14 (1H, s)

Embodiment 24o: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.98 (3H, t), 1.15 (3H, t), (1.20-1.27 2H, m), 1.64 (6H, s), (1.77 2H, d), 2.98 (4H, s), (3.00-3.02 2H, m), 3.05 (1H, d), (3.08-3.12 1H, m), 3.39-3.45 (1H, m), (3.55-3.60 1H, m), 3.64 (1H, d), (3.71 1H, d), 3.90-3.93 (1H, m), (3.99 1H, d), 4.36 (1H, d), (4.42 2H, d), 5.64 (1H, t), (5.76 1H, d), 6.14 (1H, s)

Embodiment 24p: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.29-0.33 (2H, m), 0.53-0.57 (2H, m), 1.16 (3H, d), 1.31 (2H, m), 1.64 (6H, s), 1.76 (2H, d), 2.09 (3H, s), 2.37-2.43 (1H, m), 2.75 (1H, s), 2.98 (3H, s), 2.96-3.01 (1H, m), 3.05-3.12 (1H, m), 3.39-3.45 (1H, m), 3.55-3.59 (1H, m), 3.66 (1H, t), 3.71 (1H, d), 3.90-3.93 (1H, m), 3.99 (1H, d), 4.36 (1H, d), 4.44 (2H, d), 5.72 (1H, d), 5.97 (1H, d), 6.14 (1H, s)

Embodiment 24q: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16 (3H, d), 1.18-1.27 (2H, m), 1.64 (6H, s), 1.78 (2H, d), 2.98 (3H, s), (3.00 1H, s), 3.03 (1H, d), 3.08-3.12 (1H, m), 3.39-3.45 (1H, m), 3.58 (1H, d), (3.65 1H, t), 3.71 (1H, t), (3.78 3H, s), 3.89-3.93 (1H, m), (4.00 3H, d), 4.35 (1H, s), (4.41 2H, d), 5.82 (1H, d), (5.89 1H, t), 6.14 (1H, s), (7.28 1H, s), 7.51 (1H, s)

Embodiment 24r: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.47-0.50 (2H, m), 0.66-0.71 (2H, m), 1.25 (3H, d), (2.61-2.67 1H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), 4.19 (1H, d), 4.49 (3H, d), 6.83 (1H, s), (7.54 1H, d), 8.10 (1H, s), 8.48-8.51 (1H, m), 9.09 (1H, d), 9.32 (1H, s)

Embodiment 24s: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.78 (6H, s), 3.04 (3H, s), (3.19-3.25 1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.25 (1H, d), (4.61 1H, s), 6.77 (1H, s), 6.87 (1H, d), (7.58 2H, d), 8.31 (2H, d), 8.75 (1H, d), 9.07 (1H, s), 9.61 (1H, s)

Embodiment 24t: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.78 (6H, d), 2.38 (3H, d), (3.04 3H, s), 3.19-3.25 (1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.24 1H, d), 4.61 (1H, d), 6.57 (1H, d), (6.77 1H, s), 7.55-7.58 (2H, m), 8.31 (2H, d), 9.05 (1H, s), 9.46 (1H, s)

Embodiment 24u: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.78 (6H, d), (3.04 3H, s), 3.19-3.25 (1H, m), (3.47-3.53 1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.83 (3H, s), (3.97-4.00 1H, m), 4.24 (1H, d), (4.61 1H, s), 6.76 (1H, s), (6.80 1H, d), 7.57 (2H, d), (7.83-7.86 1H, m), 8.21 (1H, d), (8.29 2H, d), 8.62 (1H, s), 8.97 (1H, s)

Embodiment 24v: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.79 (6H, d), 3.04 (3H, s), (3.19-3.26 1H, m), 3.47-3.54 (1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), 4.25 (1H, d), (4.63 1H, s), 5.42 (1H, s), 5.90 (1H, d), (6.78 1H, s), 7.84 (2H, d), 8.06 (1H, d), 8.34 (2H, d), 9.84 (1H, s)

Embodiment 24w: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.78 (6H, d), (3.04 3H, s), 3.20-3.25 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.24 1H, d), 4.61 (1H, s), (6.76 1H, s), 6.99 (1H, t), (7.30 2H, d), 7.47 (2H, d), 7.57 (2H, d), (8.30 2H, d), 8.71 (1H, s), 8.91 (1H, s)

Embodiment 24x: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.78 (6H, d), (3.04 3H, s), 3.20-3.25 (1H, m), (3.27 3H, s), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.24 (1H, d), (4.61 1H, s), 6.76 (1H, s), (6.99 1H, t), 7.30 (2H, d), (7.47 2H, d), 7.57 (2H, d), (8.30 2H, d), 8.71 (1H, s), 8.91 (1H, s)

Embodiment 24y: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.78 (6H, d), (3.04 3H, s), 3.19-3.26 (1H, m), (3.48-3.54 1H, m), 3.64-3.68 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.25 1H, d), 4.62 (1H, s), (6.77 1H, s), 7.61 (2H, d), (7.71-7.76 1H, m), 7.78-7.82 (1H, m), 8.29 (1H, d), (8.32 2H, d), 9.38 (1H, s), 9.87 (1H, s)

Embodiment 24z: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.77 (6H, s), (3.00 3H, s), 3.02-3.23 (1H, m), (3.46-3.51 1H, m), 3.64 (1H, d), (3.76 1H, d), 3.80 (3H, s), (3.95-3.98 1H, m), 4.28 (1H, m), (4.29 2H, d), 4.63 (1H, s), (6.83 1H, s), 7.39 (1H, s), 7.63 (1H, s), (9.25 1H, t), 9.36 (2H, s), 10.09 (1H, s)

Embodiment 24aa: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), (1.25 3H, d), 2.53-2.59 (1H, m), (3.21 3H, s), 3.25 (1H, d), (3.47-3.54 1H, m), 3.64-3.68 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), (4.49 3H, s), 6.44 (1H, d), 6.78 (1H, s), (7.52 2H, d), 8.22 (2H, d), 8.55 (1H, s)

Embodiment 24ab: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.79 (6H, d), 2.66 (3H, d), 3.02 (3H, s), 3.20-3.27 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.27 (1H, d), (4.63 1H, s), 6.27 (1H, q), 6.86 (1H, s), 7.95-8.01 (2H, m), 8.14 (1H, s)

Embodiment 24ac: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.25 (3H, d), 1.79 (6H, d), (3.01 3H, s), 3.09-3.15 (2H, m), 3.20-3.27 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.27 (1H, d), (4.63 1H, s), 6.36 (1H, t), 6.85 (1H, s), 7.95-8.01 (2H, m), 8.05 (1H, s)

Embodiment 24ad: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.43-0.47 (2H, m), 0.63-0.67 (2H, m), (1.25 3H, d), 1.79 (6H, d), (2.53-2.58 1H, m), 3.02 (3H, s), (3.20-3.27 1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.27 1H, d), 4.63 (1H, s), 6.66 (1H, d), (6.86 1H, s), 7.97 (2H, d), 8.00 (1H, s)

Embodiment 24ae: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.79 (6H, d), (3.02 3H, s), 3.20-3.27 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.81 (3H, s), (3.97-4.01 1H, m), 4.12 (2H, d), (4.27 1H, d), 4.63 (1H, s), (6.63 1H, t), 6.86 (1H, s), 7.35 (1H, d), (7.58 1H, s), 7.97-8.01 (2H, m), 8.09 (1H, s)

Embodiment 24af: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.15 (3H, t), 1.25 (3H, d), 1.78 (6H, d), (3.02 3H, s), 3.20-3.24 (1H, m), 3.27-3.29 (2H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.28 (1H, d), (4.64 1H, s), 6.84 (1H, s), 9.06 (1H, t), 9.39 (2H, s), 10.01 (1H, s)

Embodiment 24ag: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.54-0.57 (2H, m), 0.70-0.74 (2H, m), (1.25 3H, d), 1.78 (3H, s), (1.78 3H, s), 2.68-2.73 (1H, m), (3.02 3H, s), 3.19-3.27 (1H, m), (3.46-3.53 1H, m), 3.63-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.28 1H, d), 4.63 (1H, s), 6.84 (1H, s), (9.13 1H, d), 9.38 (2H, s), 10.07 (1H, s)

Embodiment 24ah: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.78 (3H, s), (1.78 3H, s), 2.76 (3H, d), (3.03 3H, s), 3.20-3.26 (1H, m), (3.47-3.54 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.25 1H, d), 4.62 (1H, s), (6.80 1H, s), 7.42-7.45 (1H, m), 8.15 (1H, d), (8.52-8.55 1H, m), 9.14 (1H, d), 9.48 (1H, s)

Embodiment 24ai: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.12 (3H, t), 1.24 (3H, d), (1.78 3H, s), 1.78 (3H, s), (3.02 3H, s), 3.19-3.23 (2H, m), (3.24-3.26 1H, m), 3.47-3.54 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.25 (1H, d), (4.61 1H, s), 6.80 (1H, s), (7.46-7.49 1H, m), 8.17 (1H, t), (8.52-8.55 1H, m), 9.14 (1H, d), 9.40 (1H, s)

Embodiment 24aj: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.47-0.51 (2H, m), 0.67-0.71 (2H, m), (1.24 3H, d), 1.78 (3H, s), (1.78 3H, s), 2.61-2.67 (1H, m), (3.02 3H, s), 3.19-3.26 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.26 1H, d), 4.62 (1H, s), (6.80 1H, s), 7.53 (1H, d), (8.16 1H, s), 8.53-8.56 (1H, m), (9.13 1H, d), 9.33 (1H, s)

Embodiment 24ak: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.90 (3H, t), 1.24 (3H, d), (1.42-1.49 2H, m), 1.78 (6H, d), (3.04 3H, s), 3.18-3.25 (1H, m), (3.47-3.54 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), 4.24 (1H, d), (4.61 1H, d), 6.21 (1H, t), 6.74 (1H, s), (7.49-7.52 2H, m), 8.23-8.25 (2H, m), 8.66 (1H, s))

Embodiment 24al: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.12 (6H, d), 1.24 (3H, d), (1.77 3H, s), 1.78 (3H, s), (3.04 3H, s), 3.21-3.24 (1H, m), (3.48-3.53 1H, m), 3.63-3.67 (1H, m), (3.76-3.81 2H, m), 3.97-4.00 (1H, m), 4.24 (1H, d), (4.60 1H, d), 6.07 (1H, d), 6.74 (1H, s), (7.47-7.51 2H, m), 8.23 (2H, d), 8.55 (1H, s)

Embodiment 24am: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.59-1.66 (2H, m), (1.78 6H, d), 1.84-1.89 (2H, m), (2.19-2.25 2H, m), 3.04 (3H, s), (3.21-3.25 1H, m), 3.48-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.00 1H, m), 4.15 (1H, q), (4.23 1H, d), 4.60 (1H, d), (6.47 1H, d), 6.74 (1H, s), (7.49 2H, d), 8.24 (2H, d), 8.58 (1H, s)

Embodiment 24an: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.25-1.25 (5H, m), (1.78 6H, s), 3.04 (3H, s), (3.19-3.24 1H, m), 3.40 (2H, d), (3.50 1H, d), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.24 1H, d), 4.59 (1H, s), (4.96 1H, t), 6.01 (1H, s), 6.74 (1H, s), (7.46 2H, d), 8.23 (2H, d), 8.74 (1H, s)

Embodiment 24ao: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.78 (6H, d), (3.04 3H, s), 3.19-3.25 (1H, m), (3.47-3.54 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), (4.24 1H, d), 4.36 (2H, d), (4.60 1H, d), 6.75 (1H, s), (6.78 1H, t), 7.36-7.39 (1H, m), (7.53 2H, d), 7.72-7.75 (1H, m), (8.25 2H, d), 8.46-8.48 (1H, m), (8.55 1H, d), 8.88 (1H, s)

Embodiment 24ap: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.24 (3H, d), (1.77 3H, s), 1.78 (3H, s), (3.04 3H, s), 3.19-3.25 (1H, m), (3.34-3.42 2H, m), 3.47-3.54 (1H, m), (3.65 1H, d), 3.70-3.74 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), (4.24 1H, d), 4.60 (1H, s), (4.79 1H, t), 6.10 (1H, d), (6.74 1H, s), 7.49 (2H, d), (8.24 2H, d), 8.73 (1H, s)

Embodiment 24aq: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.18-0.22 (2H, m), 0.42-0.47 (2H, m), (0.94-0.98 1H, m), 1.24 (3H, d), (1.77 3H, s), 1.78 (3H, s), (3.00 2H, t), 3.04 (3H, s), (3.18-3.25 1H, m), 3.47-3.54 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.00 1H, m), 4.24 (1H, d), (4.60 1H, s), 6.27 (1H, t), (6.74 1H, s), 7.50 (2H, d), (8.24 2H, d), 8.70 (1H, s)

Embodiment 24ar: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 3.04 (3H, s), (3.20-3.24 1H, m), 3.46-3.52 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.24 (1H, d), (4.36 2H, d), 4.60 (1H, s), (6.74 1H, s), 6.83 (1H, t), (7.30-7.31 2H, m), 7.51-7.55 (2H, m), (8.23-8.26 2H, m), 8.51-8.52 (2H, m), 9.01 (1H, s)

Embodiment 24as: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.56-1.62 (2H, m), (1.76 3H, s), 1.77 (3H, s), (3.04 3H, s), 3.14-3.19 (2H, m), (3.20-3.24 1H, m), 3.44-3.47 (2H, m), (3.49-3.52 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.22 1H, s), 4.52 (1H, t), (4.59 1H, s), 6.22 (1H, t), (6.74 1H, s), 7.48-7.51 (2H, m), (8.23 2H, d), 8.75 (1H, s)

Embodiment 24at: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.88 (6H, d), 1.22 (3H, t), (1.66-1.73 1H, m), 1.74-1.76 (3H, m), (1.77 3H, s), 2.94 (2H, t), (3.04 3H, s), 3.20-3.24 (1H, m), (3.46-3.53 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.22 1H, s), 4.60 (1H, s), (6.26 1H, t), 6.74 (1H, s), (7.48-7.51 2H, m), 8.23 (2H, d), 8.68 (1H, s)

Embodiment 24au: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 3.04 (3H, s), (3.17-3.24 1H, m), 3.46-3.53 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.24 (1H, d), (4.32 2H, d), 4.60 (1H, s), (6.64 1H, t), 6.74 (1H, s), (6.83 1H, s), 7.04 (1H, s), (7.50-7.53 2H, m), 8.22-8.26 (2H, m), (8.96 1H, s), 11.87 (1H, s)

Embodiment 24av: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 3.04 (3H, s), (3.17-3.24 1H, m), 3.46-3.53 (1H, m), (3.62-3.66 1H, m), 3.76 (1H, s), (3.79 3H, s), 3.96-4.00 (1H, m), (4.12 2H, d), 4.23 (1H, s), (4.60 1H, s), 6.44 (1H, t), (6.74 1H, s), 7.35 (1H, s), (7.50 2H, d), 7.60 (1H, s), (8.24 2H, d), 8.74 (1H, s)

Embodiment 24aw: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 2.38 (3H, d), (3.04 3H, s), 3.17-3.24 (1H, m), (3.46-3.53 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.24 1H, d), 4.32 (2H, d), (4.60 1H, s), 6.16 (1H, d), (6.71 1H, s), 6.74 (1H, s), (7.52 2H, d), 8.25 (2H, d), 8.96 (1H, s)

Embodiment 24ax: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.44 (3H, d), 1.76 (3H, s), 1.76 (3H, s), 3.03 (3H, s), (3.19-3.24 1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), 3.77 (1H, d), 3.95-3.99 (1H, m), (4.23 1H, d), 4.59 (1H, s), (4.88 1H, t), 6.74 (1H, s), (6.81 1H, d), 7.36-7.39 (1H, m), (7.48 2H, d), 7.75-7.78 (1H, m), (8.23 2H, d), 8.45-8.47 (1H, m), (8.59 1H, d), 8.71 (1H, s)

Embodiment 24ay: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 3.04 (3H, s), (3.17-3.24 1H, m), 3.46-3.53 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.22-4.33 (1H, m), (4.28 2H, d), 4.60 (1H, s), (6.18 1H, s), 6.52 (1H, s), (6.74 1H, s), 7.51 (2H, d), (7.67 1H, s), 8.25 (2H, d), (8.84 1H, s), 12.64 (1H, s)

Embodiment 24az: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.76 (5H, m), 1.77 (3H, s), 3.20 (1H, d), (3.47-3.53 1H, m), 3.62-3.66 (1H, m), 3.76-3.80 (4H, m), (3.96-4.00 1H, m), 4.23 (2H, d), 4.25 (1H, s), (4.60 1H, s), 6.14 (1H, d), 6.52 (1H, t), (6.74 1H, s), 7.51 (2H, d), 7.61 (1H, d), 8.24 (2H, d), 8.84 (1H, s)

Embodiment 24ba: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), (2.95 6H, s), 3.04 (3H, s), 3.20-3.24 (1H, m), (3.49 1H, d), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, s), (4.60 1H, s), 6.75 (1H, s), 7.59 (2H, d), 8.23 (2H, d), 8.52 (1H, s)

Embodiment 24bb: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), (3.04 3H, s), 3.17-3.24 (1H, m), 3.45 (4H, t), (3.49-3.52 1H, m), 3.61-3.63 (4H, m), 3.65 (1H, s), (3.77 1H, d), 3.96-4.00 (1H, m), 4.25 (1H, d), (4.60 1H, s), 6.75 (1H, s), 7.59 (2H, d), 8.25 (2H, d), 8.77 (1H, s)

Embodiment 24bc: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.29-1.38 (2H, m), 1.75-1.77 (2H, m), 1.77 (3H, s), 1.77 (3H, s), (3.04 4H, s), 3.07-3.11 (2H, m), (3.16-3.24 1H, m), 3.46-3.53 (1H, m), (3.62-3.66 1H, m), 3.67-3.70 (1H, m), (3.77 1H, d), 3.85 (2H, q), (3.96-4.00 1H, m), 4.24 (1H, d), (4.60 1H, s), 4.74 (1H, d), (6.74 1H, s), 7.58 (2H, d), (8.23 2H, d), 8.72 (1H, s)

Embodiment 24bd: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.33-1.41 (2H, m), 1.69-1.73 (1H, m), 1.77 (3H, s), 1.77 (3H, s), 1.85-1.88 (1H, m), 2.74-2.79 (1H, m), 2.91-2.97 (1H, m), 3.04 (3H, s), 3.17-3.24 (1H, m), 3.45-3.53 (2H, m), 3.62-3.66 (1H, m), 3.76 (1H, s), 3.79 (1H, t), 3.93-4.00 (2H, m), 4.24 (1H, d), 4.60 (1H, s), 4.88 (1H, d), 6.74 (1H, s), 7.57-7.59 (2H, m), 8.21-8.24 (2H, m), 8.69 (1H, s)

Embodiment 24be: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, t), 1.76 (3H, s), 1.77 (3H, s), (2.15-2.23 2H, m), 3.04 (3H, s), 3.18-3.24 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.98 (5H, t), 4.22 (1H, s), (4.60 1H, s), 6.74 (1H, s), 7.62 (2H, d), 8.22-8.25 (2H, m), 8.59 (1H, s)

Embodiment 24bf: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (3H, s), (1.77 3H, s), 3.04 (3H, s), (3.16-3.24 1H, m), 3.46-3.53 (1H, m), (3.62-3.66 1H, m), 3.71-3.75 (2H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.14-4.18 2H, m), 4.24 (1H, d), (4.41-4.46 1H, m), 4.60 (1H, s), (5.66 1H, d), 6.74 (1H, s), (7.62 2H, d), 8.22-8.25 (2H, m), 8.64 (1H, s)

Embodiment 24bg: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.68-0.72 (2H, m), 0.90 (2H, d), (1.23 3H, d), 1.77 (3H, s), (1.78 3H, s), 2.70-2.74 (1H, m), (2.87 3H, s), 3.04 (3H, d), (3.17-3.24 1H, m), 3.46-3.53 (1H, m), (3.63-3.66 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.25 (1H, d), (4.59 1H, s), 6.75 (1H, s), (7.63-7.66 2H, m), 8.24 (2H, d), 8.43 (1H, s)

Embodiment 24bh: ¹h NMR (400.13MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (3H, s), 1.77 (3H, s), 2.80 (3H, d), 3.02 (3H, s), 3.18-3.26 (1H, m), 3.46-3.52 (1H, m), (3.62-3.65 1H, m), 3.77 (1H, d), 3.95-3.99 (1H, m), (4.27 1H, d), 4.63 (1H, s), 6.84 (1H, s), (8.98 1H, d), 9.37 (2H, s), 10.11 (1H, s)

Embodiment 24bi: ¹h NMR (400.13MHz, DMSO-d6) δ 1.24 (3H, d), 1.78 (6H, d), (3.02 3H, s), 3.18-3.26 (1H, m), (3.46-3.53 1H, m), 3.63-3.66 (1H, m), (3.77 1H, d), 3.80 (3H, s), (3.96-4.00 1H, m), 4.24 (2H, d), (4.27 1H, m), 4.61 (1H, s), (6.79 1H, s), 7.38 (1H, s), (7.49-7.52 1H, m), 7.62 (1H, s), (8.36 1H, s), 8.53-8.56 (1H, m), (9.12 1H, d), 9.45 (1H, s).

Embodiment 24bj: ¹h NMR (400.13MHz, DMSO-d6) δ 1.23 (3H, d), 1.77 (6H, d), 3.03 (3H, s), 3.17 (2H, q), 3.23 (1H, d), 3.46 (2H, q), 3.49-3.53 (1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.23 (1H, d), 4.60 (1H, d), 4.73 (1H, t), 6.25 (1H, t), 6.74 (1H, s), (7.50 2H, d), 8.24 (2H, d), 8.81 (1H, s)

Test (a): embodiment (24) 0.34 μ M; Embodiment (24a) 0.082 μ M; Embodiment (24b) 0.038 μ M; Embodiment (24c) 0.56 μ M; Embodiment (24d) 4.4 μ M; Embodiment (24e) 0.81 μ M; Embodiment (24f) 4.5 μ M; Embodiment (24g) 0.31 μ M; Embodiment (24h) 4.4 μ M; Embodiment (24i) 0.33 μ M; Embodiment (24j) 0.22 μ M; Embodiment (24k) 0.18 μ M; Embodiment (24l) 0.84 μ M; Embodiment (24m) 0.65 μ M; Embodiment (24n) 3.2 μ M; Embodiment (24o) 3.4 μ M; Embodiment (24p) 0.89 μ M; Embodiment (24q) 5.8 μ M; Embodiment (24r) 0.34 μ M; Embodiment (24s) 0.0047 μ M; Embodiment (24t) 0.012 μ M; Embodiment (24u) 0.12 μ M; Embodiment (24v) 0.055 μ M; Embodiment (24w) 0.034 μ M; Embodiment (24x) 0.1 μ M; Embodiment (24y) 2.2 μ M; Embodiment (24z) 0.37 μ M; Embodiment (24aa) 0.11 μ M; Embodiment (24ab) 0.042 μ M; Embodiment (24ac) 0.048 μ M; Embodiment (24ad) 0.51 μ M; Embodiment (24ae) 0.24 μ M; Embodiment (24bh) 0.012 μ M; Embodiment (24bi) 0.43 μ M; Embodiment (24bj) 0.051 μ M.

Test (c): embodiment (24af) 1.4 μ M; Embodiment (24ag) 0.32 μ M; Embodiment (24ah) 0.51 μ M; Embodiment (24ai) 0.26 μ M; Embodiment (24aj) 0.45 μ M; Embodiment (24ak) 0.21 μ M; Embodiment (24al) 0.038 μ M; Embodiment (24am) 0.21 μ M; Embodiment (24an) 1.8 μ M; Embodiment (24ao) 0.24 μ M; Embodiment (24ap) 0.077 μ M; Embodiment (24aq) 2 μ M; Embodiment (24ar) 0.049 μ M; Embodiment (24as) 0.22 μ M; Embodiment (24at) 0.089 μ M; Embodiment (24au) 2.4 μ M; Embodiment (24av) 4.9 μ M; Embodiment (24aw) 3.4 μ M; Embodiment (24ax) 0.64 μ M; Embodiment (24ay) 7.9 μ M; Embodiment (24az) 5.6 μ M; Embodiment (24ba) 5.1 μ M; Embodiment (24bb) 7.8 μ M; Embodiment (24bc) 0.69 μ M; Embodiment (24bd) 3.2 μ M; Embodiment (24be) 4.9 μ M; Embodiment (24bf) 6.7 μ M; Embodiment (24bg) 2.4 μ M.

N-[4-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate and (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) preparation of phenyl carbamate.

With with previously described N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-the 4-piperidyl] similar fashion of phenyl carbamate, prepare following carbamate by suitable amine or aniline.

(S)-2, the fluoro-4-of 6-bis-(4-(3-methylmorpholine generation)-6-(2-(methyl sulphonyl) third-2-yl) pyrimidine-2-base) phenylcarbamic acid phenylester: ¹h NMR (400.13MHz, DMSO-d6) δ 1.25 (3H, d), 1.79 (6H, d), 3.00 (3H, s), 3.20-3.27 (1H, m), 3.47-3.55 (1H, m), 3.58 (15H, s), 3 65 (1H, d), 3.75 (1H, d), 3.97-4.01 (1H, m), 4.28 (1H, d), 4.63 (1H, s), (6.88 1H, s), 7.21 (2H, d), 7.27 (1H, t), (7.44 2H, t), 8.08 (2H, d), 9.96 (1H, s)

1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of pyrazoles-3-amine is described below.

1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyrazoles-3-amine

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine (1.00g), 1H-pyrazoles-3-amine (300mg) and salt of wormwood (498mg) is dissolved in butyronitrile (20mL).By mixture reflux 24 hours.To react with ethyl acetate (20mL) dilution, and water (20mL) washing.Extract water by ethyl acetate (20mL).By the organic extraction dried over mgso merged, evaporation.Purify crude product with silica gel chromatography, with 0-5% methyl alcohol/DCM wash-out, obtain needed material (635mg).

the NMR spectrum: 1H NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 3.20 (3H, s), 3.24 (1H, m), 3.43-3.50 (1H, m), 3.60-3.64 (1H, m), (3.75 1H, d), 3.94-3.98 (1H, m), 4.06-4.12 (1H, m), 4.43 (1H, s), 4.43 (2H, s), (5.25 2H, s), 5.75 (1H, s), 5.80 (1H, d), 6.66 (1H, s), 8.26 (1H, d)

the LCMS spectrum: MH+490, retention time 1.58 minutes, method: acid monitoring

With with 1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] two-stage process like piperidines-4-amine, by the chloro-6-[1-methyl isophthalic acid of (3S)-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl-3-methylmorpholine and N-(4-piperidyl) carboxylamine tertiary butyl ester prepare 1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] piperidines-4-amine.

1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] piperidines-4-amine: ¹h NMR (400.13MHz, DMSO-d6) δ 1.27 (3H, d), 1.75 (6H, s), 1.83-1.87 (2H, m), 2.88 (1H, d), 2.91 (5H, s), 2.94 (1H, d), 3.17-3.25 (1H, m), (3.50-3.57 1H, m), 3.68 (1H, d), 3.70 (2H, s), (3.75-3.77 1H, m), 3.92 (1H, s), 3.95-3.99 (2H, m), (4.30 1H, d), 4.61 (2H, d), 6.06 (1H, s)

N-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-the 4-piperidyl] the carboxylamine tertiary butyl ester: ¹h NMR (400.13MHz, DMSO-d6) δ 1.25 (5H, d), 1.27 (2H, d), 1.30-1.35 (2H, m), 1.45 (9H, s), 1.54 (6H, s), 1.98 (2H, d), 2.04 (4H, s), 2.90 (3H, s), 2.95-3.01 (2H, m), 3.17-3.24 (1H, m), 3.50-3.57 (1H, m), (3.66-3.70 2H, m), 3.76 (1H, d), 3.95-3.99 (2H, m), (4.29 1H, d), 4.56 (2H, d), 6.07 (1H, s)

The chloro-6-[1-methyl isophthalic acid of (3S)-4-{2--(methyl sulphonyl) ethyl had before been described] pyrimidine-4-yl }-preparation of 3-methylmorpholine.

With with (4-{4-[1-methyl isophthalic acid-(methyl sulphonyl) ethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base phenyl) mode like amine, by the chloro-6-[1-methyl isophthalic acid of previously described (3S)-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl-the 3-methylmorpholine prepares 5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] pyrimidine-2-amine and 5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] pyridine-2-amine.

5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] pyrimidine-2-amine: ¹h NMR (400.13MHz, DMSO-d6) δ 1.23 (3H, d), 1.75-1.76 (6H, m), (3.00 3H, s), 3.16-3.23 (1H, m), 3.45-3.52 (1H, m), 3.61-3.65 (1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.22 (1H, d), (4.57 1H, s), 6.74 (1H, s), (7.11 2H, s), 9.09 (2H, s)

5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] pyridine-2-amine: ¹h NMR (400.13MHz, CDCl ₃) δ 1.33 (3H, d), 1.86 (6H, s), 2.93 (3H, s), 3.31-3.35 (1H, m), 3.56-3.62 (1H, m), (3.72-3.75 1H, m), 3.82 (1H, d), 4.02-4.05 (1H, m), 4.12 (1H, d), 4.48-4.50 (1H, m), (4.83 2H, s), 6.52-6.55 (1H, m), 6.59 (1H, s), 8.35-8.38 (1H, m), 9.08-9.09 (1H, m)

The fluoro-4-[4-[(3S of 2,6-bis-)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base] preparation of aniline is described below.

the fluoro-4-[4-[(3S of 2,6-bis-)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2- base] aniline

4-is bromo-2, the fluoro-aniline of 6-bis-(400mg, 1.92mmol), potassium acetate (566mg, 5.77mmol) and 4,4,5,5-tetramethyl--2-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl)-1,3,2-dioxa boron heterocycle pentane (587mg, 2.31mmol) be dissolved in 1,4 diox (5mL).By degassed 10 minutes of solution, then add 1,1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (95mg, 0.12mmol), will react at 90 ℃ and stir 3 hours.Add the chloro-6-[1-methyl isophthalic acid of (3S)-4-{2--(methyl sulphonyl) ethyl] pyrimidine-4-yl }-3-methylmorpholine (450mg; 1.35mmol), ethanol (1mL); 2M sodium carbonate (1mL) and 1; 1 '-bis-(diphenylphosphino) ferrocene dichloro palladium (95mg; 0.12mmol), continue heating 18 hours.The cooling reaction to room temperature, then add water (50mL), then adds ethyl acetate (50mL).Remove by filter undissolved solid.Separation of phases, extract water by second section ethyl acetate (30mL).The organism merged by dried over mgso, filter evaporate to dryness.Crude product is dissolved in DCM (25mL), filters, remove insoluble substance, with silica gel chromatography, purify filtrate, use 0-35% ethyl acetate/isohexane wash-out, obtain needed material type white solid (402mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.76 (6H, d), 3.00 (3H, s), 3.17-3.24 (1H, m), 3.45-3.51 (1H, m), (3.62-3.65 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.22 (1H, d), (4.57 1H, s), 5.70 (2H, d), (6.73 1H, s), 7.83-7.85 (2H, m)

the LCMS spectrum: MH+427, retention time 2.35 minutes, method: acid monitoring

N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyridine-2-yl] preparation of phenyl carbamate is described below.

n-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyridine-2- base] phenyl carbamate

By 5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyridine-2-amine (770mg; 2.12mmol) be dissolved in diox (10mL); and add sodium bicarbonate (267mg, 3.18mmol), obtain faint yellow slurries.With within 10 minutes, dropwise adding phenyl chloroformate (0.267mL, 2.12mmol), use water-bath to control heat release, in stirring at room mixture 16 hours.Further add sodium bicarbonate (267mg, 3.18mmol) and phenyl chloroformate (0.267mL, 2.12mmol), in stirring at room mixture 2 hours.Again add phenyl chloroformate (0.267mL, 2.12mmol), in stirring at room mixture 1 hour, then be heated to 35 ℃, keep 16 hours.The evaporate to dryness reaction distributes resistates between water (15mL) and ethyl acetate (20mL).Leach white solid, and water (5mL), DCM (5mL) and methyl alcohol (5mL) washing.40 ℃ of vacuum-drying solids 5 hours, obtain product white solid (117mg).

the LCMS spectrum: MH+484, retention time 2.32 minutes, method: acid monitoring

5-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] preparation of pyridine-2-amine.

embodiment 25:

1-[1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyrazole-3-yl]-the 3-phenylurea

By 1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyrazoles-3-amine (90mg, 0.26mmol) is dissolved in diox (4mL).Phenylcarbimide (0.024mL, 0.22mmol) is joined in the solution obtained.Mixture is heated 2 hours at 80 ℃.Leach solid, with diethyl ether (5mL) washing, obtain needed material white solid (66mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.23 (3H, s), (3.40 1H, m), 3.47-3.54 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), (3.98 1H, d), 4.14 (1H, s), (4.47 1H, m), 4.51 (2H, d), (6.60 1H, d), 6.81 (1H, s), (7.01 1H, t), 7.29-7.33 (2H, m), 7.47 (2H, d), (8.51 1H, d), 9.18 (1H, s), 9.50 (1H, s)

the LCMS spectrum: MH+472, retention time 1.86 minutes, method: 5 minutes acid methods

Use similar mode, by 1-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] pyrazoles-3-amine and suitable isocyanic ester prepare following compounds.

Embodiment 25a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.47-3.53 (1H, m), 3.56 (1H, d), (3.63-3.67 1H, m), 3.73 (3H, s), 3.78 (1H, d), (3.96-4.00 1H, m), 4.14 (1H, s), 4.47 (1H, m), (4.50 2H, s), 6.57 (1H, d), 6.81 (1H, s), (6.87-6.91 2H, m), 7.35-7.39 (2H, m), 8.50 (1H, d), 9.04 (1H, s), 9.42 (1H, s)

Embodiment 25b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.26 (1H, m), 3.46-3.53 (1H, m), (3.58 3H, s), 3.63-3.67 (1H, m), 3.78 (1H, d), (3.96-4.00 1H, m), 4.14 (1H, s), 4.46 (1H, m), (4.50 2H, s), 6.59 (1H, d), 6.81 (1H, s), (7.13-7.18 2H, m), 7.45-7.50 (2H, m), 8.51 (1H, d), 9.17 (1H, s), 9.51 (1H, s)

Test (a): embodiment (25) 1.9 μ M; Embodiment (25a) 4.4 μ M; Embodiment (25b) 4.4 μ M.

embodiment 26:

N-methyl-2-[[2-[4-(methyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethanamide

By N-methyl-2-[[2-[4-(methyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] ethanamide (0.35mmol) is dissolved in Isosorbide-5-Nitrae-dioxs (5mL) and water (1mL).M-CPBA (75%) (121mg) is joined in this solution, then add immediately sodium permanganate (140mg), stirring at room reaction 1 hour.M-CPBA (75%) (121mg) is further joined in this solution, then add immediately sodium permanganate (140mg), stirring at room reaction 1 hour.M-CPBA (75%) (121mg) is further joined in this solution again, then add immediately sodium permanganate (140mg), stirring at room reaction 1 hour.Reactant is loaded on SCX-3 (10g) post, uses the methanol wash post, with 7N ammonia/methanol-eluted fractions product.Be further purified material with preparative HPLC (alkali formula), obtain needed material (30mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23-1.25 (3H, m), 2.66-2.70 (3H, m), (2.68 1H, d), 3.21-3.26 (1H, m), (3.46-3.53 3H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), (4.17 1H, d), 4.29 (2H, s), (4.47 1H, s), 4.67 (2H, s), (6.07 1H, q), 6.76 (1H, s), 7.48-7.52 (2H, m), (8.17-8.20 2H, m), 8.31 (1H, t), 8.74 (1H, s)

mass spectrum:m+H ⁺477.

Use similar mode, by suitable thioether, prepare following compounds.

Embodiment 26a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.66 (3H, d), (3.18-3.26 1H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.97-4.00 1H, m), 4.17 (1H, d), (4.27 2H, s), 4.48 (1H, s), 4.66 (2H, s), (6.07 1H, q), 6.76 (1H, s), 7.48-7.52 (3H, m), (7.79 1H, s), 8.17-8.21 (2H, m), 8.74 (1H, s)

Embodiment 26b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.83 (3H, s), (2.66 2H, s), 2.68 (2H, q), (3.21-3.26 1H, m), 3.47-3.53 (2H, m), (3.52 1H, s), 3.57 (2H, q), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), (4.51 2H, s), 6.06 (1H, q), 6.77 (1H, s), (7.48-7.52 2H, m), 8.14-8.21 (3H, m), 8.74 (1H, s)

Test (a): embodiment (26) 0.029 μ M; Embodiment (26a) 0.037 μ M; Embodiment (26b) 0.041 μ M.

N-methyl-2-[[2-[4-(methyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] the methyl sulfenyl] preparation of ethanamide is described below.

n-methyl-2-[[2-[4-(methyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine -4-yl] the methyl sulfenyl] ethanamide

N-methyl-2-sulfenyl-ethanamide (0.61mmol) is dissolved in acetonitrile (4mL).Then DBU (0.050mL) is joined in this solution, and stirring at room solution 5 minutes.Add 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] acetonitrile (2mL) and DBU (0.054mL) solution of urea (151mg); stirring at room reaction 2 hours; then vacuum concentration, used by step neutrality subsequently.

Prepare following sulfide by similar fashion.

3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base had before been described] phenyl] preparation of urea.

embodiment 27:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(morpholine-4-ylmethyl) pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-phenylurea (90mg) is dissolved in DCM (5mL) and triethylamine (0.045mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.026mL), and stirring at room reaction 1 hour.Add morpholine (0.2mL), in room temperature, will react and place 72 hours, then vacuum concentration, with preparative HPLC (alkali formula) purifying, obtain needed compound (64mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (3H, d), 3.17 (4H, t), 3.46-3.52 (4H, m), (3.63 4H, d), 3.65 (1H, s), 3.76 (1H, d), (3.95-3.98 1H, m), 4.14 (1H, d), 4.49 (1H, s), (6.64 1H, s), 6.97 (1H, t), 7.29 (2H, d), (7.45 2H, d), 7.53 (2H, d), 8.25 (2H, d), 8.68 (1H, s), 8.87 (1H, s).

mass spectrum:m+H ⁺489.

Test (a): 0.19 μ M.

embodiment 28:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(phenoxymethyl) pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-phenylurea is dissolved in DCM (5mL), adds phenol (41mg), and stirring at room reaction 1 hour.Add DBU (0.2mL), stir the mixture 18 hours, then vacuum concentration, with preparative HPLC (alkali formula) purifying, obtain needed material (26mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19-1.21 (3H, m), 3.18 (1H, s), (3.47-3.52 1H, m), 3.62-3.66 (1H, m), (3.76 1H, d), 3.95-3.99 (1H, m), (4.16 1H, s), 4.51 (1H, s), (5.08 2H, s), 6.72 (1H, s), (6.96-7.01 2H, m), 7.07-7.10 (2H, m), (7.28-7.35 4H, m), 7.48 (2H, d), 7.57 (2H, d), (8.28 2H, d), 8.75 (1H, s), 8.95 (1H, s)

mass spectrum:m+H ⁺496.

Test (a): 4.7 μ M.

embodiment 29:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(2-oxo-pyrrolidine-3-yl) the alkylsulfonyl methyl] pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(2-oxo-pyrrolidine-3-yl) sulfanylmethyl] pyrimidine-2-base] phenyl]-3-phenylurea (0.26mmol) is dissolved in Isosorbide-5-Nitrae-dioxs (5mL) and water (1mL).M-CPBA (75%) (113mg) is joined in this solution, then add immediately sodium permanganate (125mg), stirring at room solution 1 hour.Reactant is loaded on SCX-2 (10g) post, uses the methanol wash post, with 7N ammonia/methanol-eluted fractions product.Be further purified material with preparative HPLC (alkali formula), obtain needed material (18mg) look solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.32-2.34 (1H, m), 2.47 (1H, d), 3.24 (2H, t), 3.34 (2H, d), 3.51 (1H, t), 3.66 (1H, d), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.49 (1H, s), 4.58-4.63 (2H, m), 5.01 (1H, d), 6.79 (1H, s), 6.97-7.01 (1H, m), 7.28-7.32 (1H, m), 7.30 (1H, s), 7.46-7.48 (2H, m), 7.56-7.58 (2H, m), 8.24-8.27 (2H, m), 8.38 (1H, s), 8.72 (1H, s), 8.92 (1H, s)

mass spectrum:m+H ⁺551.

Test (a): 0.56 μ M.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(2-oxo-pyrrolidine-3-yl) sulfanylmethyl] pyrimidine-2-base] phenyl]-preparation of 3-phenylurea is described below.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(2-oxo-pyrrolidine-3-yl) sulfanylmethyl] phonetic pyridine-2-yl] phenyl]-the 3-phenylurea

By 1-[4-[4-(amidino sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-phenylurea (125mg) is dissolved in DMF (3mL).Then use the bromo-pyrrolidin-2-one of 3-(48mg) treatment soln, then use sodium hydroxide (42mg)/water (1mL) to process, be heated to 40 ℃, stir 24 hours.With a small amount of methyl alcohol diluting reaction, and it is upper to be loaded into SCX-2 post (20g), by the post methanol wash, with the needed product of 7N ammonia/methanol-eluted fractions, obtains needed material, and it need not just further characterize and can use.

1-[4-[4-(amidino sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (865mg) is dissolved in ethanol (30mL), and adds thiocarbamide (146mg).Then reaction is heated to 70 ℃, keeps 30 minutes, cooling, vacuum concentration, obtain needed material, and it need not just further characterize and can use.

embodiment 30:

1-[4-[4-(phenylamino methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-phenylurea

To be dissolved in the 1-[4-[4-[(3S in DCM (5mL) solution)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (105mg; 0.21mmol) join aniline (0.097mL; 1.06mmol) in, stirring at room 18 hours.The vacuum-drying mixture, with preparative HPLC (alkali formula) purifying, obtain needed material (41mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.15 (3H, d), 3.12-3.18 (1H, m), 3.43-3.50 (1H, m), 3.59-3.63 (1H, m), 3.74 (1H, d), 3.93-3.97 (1H, m), 4.10 (1H, d), 4.24 (2H, d), 4.39 (1H, s), 6.20 (1H, t), 6.55 (1H, d), 6.60 (1H, s), 6.63 (1H, d), 6.65 (1H, s), 6.97-7.01 (1H, m), 7.06-7.10 (2H, m), 7.28-7.32 (1H, m), 7.30 (1H, s), 7.46-7.49 (2H, m), 7.55-7.57 (2H, m), 8.29-8.31 (2H, m), 8.69 (1H, s), 8.88 (1H, s).

mass spectrum:m+H ⁺495.

Prepare following compounds by similar fashion.

Embodiment 30a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 2.22 (3H, s), 2.44 (2H, d), 2.53 (2H, d), 2.56 (2H, s), 2.60-2.61 (1H, m), 2.67-2.69 (1H, m), 3.15-3.23 (1H, m), 3.46-3.54 (3H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.15 (1H, d), 4.47-4.49 (1H, m), 6.63 (1H, s), 6.97-7.01 (1H, m), 7.28-7.32 (1H, m), 7.30 (1H, s), 7.46-7.48 (2H, m), 7.53-7.56 (2H, m), 8.25-8.27 (2H, m), 8.69 (1H, s), 8.88 (1H, s)

Embodiment 30b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.30-0.31 (2H, m), 0.37-0.40 (2H, m), (1.23 3H, d), 2.14-2.19 (1H, m), (3.15-3.23 1H, m), 3.46-3.53 (1H, m), (3.63-3.66 1H, m), 3.72 (2H, s), (3.77 1H, d), 3.96-4.00 (1H, m), (4.17 1H, d), 4.51 (1H, d), (6.67 1H, s), 6.99-7.01 (1H, m), (7.28-7.32 2H, m), 7.46-7.48 (2H, m), (7.53-7.56 2H, m), 8.28 (2H, d), (8.69 1H, s), 8.87 (1H, s)

Embodiment 30d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.41 (2H, t), 0.45-0.49 (2H, m), 1.21 (3H, d), 1.90-1.95 (1H, m), 2.34 (3H, s), 3.14-3.21 (1H, m), 3.46-3.53 (1H, m), 3.63 (3H, t), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.13 (1H, d), 4.49 (1H, s), 6.54 (1H, s), 6.97-7.01 (1H, m), 7.28-7.32 (1H, m), 7.30 (1H, s), 7.46-7.48 (2H, m), 7.54-7.56 (2H, m), 8.26-8.28 (2H, m), 8.69 (1H, s), 8.87 (1H, s)

Test (a): embodiment (30) 0.9 μ M; Embodiment (30a) 0.12 μ M; Embodiment (30b) 0.18 μ M; Embodiment (30c) 1.1 μ M; Embodiment (30d) 0.28 μ M.

embodiment 31:

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[(1-methyl-4-piperidyl) the oxygen ylmethyl] pyrimidine-2-base] phenyl]-the 3-phenylurea

To be dissolved in the 1-[4-[4-[(3S in DCM (5mL) and triethylamine (0.045mL) solution)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (105mg) joins in 4-hydroxyl-1-methyl piperidine (5 equivalent).Add DBU (0.158mL), and stirring at room 18 hours.The vacuum-drying mixture, with preparative HPLC (alkali formula) purifying, obtain needed material (64mg) white solid.

mass spectrum:m+H ⁺517.

Test (a): 0.35 μ M.

embodiment 32:

1-[4-[4-(methoxymethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-phenylurea

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-phenylurea (90mg) is dissolved in DCM (5mL) and triethylamine (0.045mL) solution.Sodium methylate (33%, in methyl alcohol) (0.073mL) is joined in reaction, in stirring at room mixture 18 hours, then water cancellation, and distribute.Use the dried over mgso organic phase, evaporation, obtain colloid, and it,, with preparative HPLC (alkali formula) purifying, is obtained to needed compound (32mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 3.34 (1H, d), (3.43 3H, s), 3.49 (1H, t), (3.63-3.66 1H, m), 3.76 (1H, d), (3.97 1H, d), 4.19 (1H, d), (4.41 2H, s), 4.51 (1H, d), (6.59 1H, s), 6.99 (1H, t), (7.30 2H, t), 7.46-7.48 (2H, m), 7.55 (2H, d), (8.26 2H, d), 8.69 (1H, s), 8.88 (1H, s)

mass spectrum:m+H ⁺434.

Test (a): 0.0062 μ M.

embodiment 33:

The 3-methyl isophthalic acid-[4-[4-[(1-Methylimidazole-2-yl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 3-methyl isophthalic acid-[4-[4-[(1-Methylimidazole-2-yl) sulfanylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea (0.23mmol) is dissolved in Isosorbide-5-Nitrae-dioxs (4mL) and water (1mL).M-CPBA (75%) (80mg) is joined in this solution, then add immediately sodium permanganate (92mg).Stirring at room reaction 18 hours, then be loaded into SCX-2 post (10g) upper, use the methanol wash post, with 7N ammonia/methanol-eluted fractions product.The vacuum-drying reaction, with preparative HPLC (alkali formula) purifying, obtain needed material (37mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.17-1.22 (3H, m), 2.66 (3H, d), (2.68 1H, t), 3.14-3.22 (1H, m), (3.45-3.49 1H, m), 3.62 (3H, s), (3.77 1H, d), 3.96-3.99 (1H, m), (4.09-4.12 1H, m), 4.41 (1H, s), (4.75 2H, s), 6.07 (1H, q), (6.61 1H, s), 7.20 (1H, d), 7.43-7.47 (2H, m), (7.43-7.49 1H, m), 7.95-7.97 (2H, m), 8.72 (1H, s)

mass spectrum:m+H ⁺486.

Use similar mode, by suitable thioether, prepare following compounds.

Embodiment 33a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, q), 2.65-2.68 (3H, m), (2.68 1H, d), 3.17 (1H, d), (3.44-3.51 1H, m), 3.61-3.65 (1H, m), (3.76 1H, d), 3.95-3.99 (1H, m), (4.09 1H, t), 4.88 (2H, s), (6.05 1H, q), 6.71 (1H, s), (7.33-7.35 2H, m), 7.44-7.48 (1H, m), (7.65-7.69 1H, m), 7.67 (1H, s), (7.71-7.77 2H, m), 7.83-7.85 (1H, m), 8.68 (1H, s).

Embodiment 33b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.18 (3H, d), 2.66-2.69 (3H, m), (3.12-3.21 1H, m), 3.43-3.50 (1H, m), (3.59-3.63 1H, m), 3.75 (1H, d), (3.94-3.98 1H, m), 4.05 (4H, m), (4.37 1H, s), 4.70-4.77 (2H, m), (6.04 1H, q), 6.61 (1H, s), (7.01-7.05 1H, m), 7.34-7.36 (2H, m), 7.39 (1H, d), (7.54-7.57 1H, m), 7.67-7.74 (3H, m), 8.67 (1H, s).

Embodiment 33c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (3H, d), 2.66 (3H, d), (3.12-3.20 1H, m), 3.43-3.50 (1H, m), (3.60-3.63 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.08 (1H, d), (4.36 1H, s), 4.71 (2H, s), 6.06 (1H, q), (6.47 1H, s), 7.34 (2H, s), 7.42-7.44 (2H, m), (7.95-7.97 2H, m), 8.70 (1H, s), 13.52 (1H, s)

Embodiment 33d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (3H, d), 2.66-2.69 (3H, m), (3.12-3.21 1H, m), 3.44-3.48 (1H, m), (3.60-3.64 1H, m), 3.75 (1H, d), (3.94-3.98 1H, m), 4.05 (1H, t), (4.33 1H, s), 4.44 (2H, s), (6.06 1H, t), 6.12 (2H, d), (6.41 1H, s), 6.58-6.62 (2H, m), 7.34-7.38 (2H, m), (7.42-7.46 2H, m), 7.99-8.01 (2H, m), 8.70 (1H, s)

Embodiment 33e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19 (3H, d), 2.67 (6H, m), (3.14-3.18 1H, m), 3.44-3.50 (1H, m), (3.60-3.64 1H, m), 3.76 (1H, d), (3.94-3.98 1H, m), 4.06 (1H, q), (4.37 1H, s), 4.66 (2H, s), (6.05 1H, d), 6.60 (1H, s), (7.34 1H, d), 7.36-7.38 (2H, m), (7.47 1H, d), 7.56-7.60 (1H, m), (7.66-7.68 1H, m), 7.77-7.80 (2H, m), 8.69 (1H, s)

Embodiment 33f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (3H, d), 2.65-2.68 (3H, m), (3.16-3.21 1H, m), 3.44-3.51 (1H, m), (3.60-3.64 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.11 (1H, d), (4.38 1H, s), 4.80-4.88 (2H, m), (6.04 1H, q), 6.68 (1H, s), (7.34-7.36 2H, m), 7.64-7.67 (2H, m), (7.78-7.81 1H, m), 7.88-7.90 (1H, m), (8.07-8.12 1H, m), 8.69 (1H, s), 8.92-8.94 (1H, m)

Embodiment 33g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (3H, d), 2.67 (3H, q), 3.16-3.21 (1H, m), 3.45-3.52 (1H, m), 3.62-3.65 (1H, m), (3.77 1H, d), 3.96-3.99 (1H, m), 4.40 (2H, s), 4.91 (2H, d), 6.06 (1H, d), (6.70 1H, s), 7.40-7.42 (2H, m), 7.84 (2H, d), 8.27-8.29 (2H, m), 8.71 (1H, s).

Embodiment 33h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21-1.27 (3H, m), 2.52-2.61 (3H, m), 2.66-2.69 (3H, m), 3.15-3.22 (1H, m), 3.45-3.52 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.13 (1H, d), 4.40 (1H, s), (4.87 2H, d), 6.05 (1H, q), 6.70 (1H, s), 7.41-7.43 (2H, m), 7.82 (1H, S)

Test (a): embodiment (33) 0.84 μ M; Embodiment (33a) 0.06 μ M; Embodiment (33b) 0.066 μ M; Embodiment (33c) 0.0014 μ M; Embodiment (33d) 0.00031 μ M; Embodiment (33e) 0.088 μ M; Embodiment (33f) 0.27 μ M; Embodiment (33g) 0.021 μ M; Embodiment (33h) 0.048 μ M.

3-methyl isophthalic acid-[4-[4-[(1-Methylimidazole-2-yl) sulfanylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of urea is described below.

the 3-methyl isophthalic acid-[4-[4-[(1-Methylimidazole-2-yl) sulfanylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

Thiamazole (0.23mmol) is dissolved in acetonitrile (2mL), adds DBU (0.035mL), stirring at room reaction 5 minutes.Add 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] acetonitrile (2mL) solution and the DBU (0.034mL) of urea (100mg); in stirring at room mixture 18 hours; then vacuum concentration, obtain needed material.This material just need not be further purified and can use.

Prepare following sulfide by similar fashion.

embodiment 34:

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

By N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] phenyl carbamate (110mg) is dissolved in DMF (2mL), adds triethylamine (0.098mL).Add 2-aminopyrimidine (108mg), 40 ℃ of stirring reactions 2 hours.By preparative HPLC (alkali formula) purifying crude mixture, yet, only from mixture, isolate [4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] urea (8mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (3H, s), 3.71-3.72 (8H, m), 4.48 (2H, s), 5.91 (2H, s), 6.81 (1H, s), 7.49-7.51 (2H, m), 8.20-8.23 (2H, m), 8.76 (1H, s)

mass spectrum:m+H ⁺392.

Prepare following compounds by similar approach.

Embodiment 34a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (3H, s), 3.73 (8H, s), 4.50 (2H, s), (6.85-6.87 2H, m), 7.56-7.59 (2H, m), 8.28-8.31 (2H, m), (8.75 1H, d), 9.07 (1H, s), 9.62 (1H, s)

Embodiment 34b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.15-3.25 (3H, s), 3.21-3.26 (3H, S), (3.73 8H, s), 4.49 (2H, s), (6.56 1H, s), 6.85 (1H, s), 7.55-7.57 (2H, m), (8.28-8.30 2H, m), 9.05 (1H, s), 9.47 (1H, s)

Embodiment 34c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 3.21 (3H, s), 3.72 (3H, s), (3.74 8H, s), 4.49 (2H, s), (6.25 1H, d), 6.84 (1H, s), (7.54-7.56 2H, m), 7.57 (1H, d), (8.26-8.28 2H, m), 8.93 (1H, s), 9.18 (1H, s).

Test (a): embodiment (34) 0.21 μ M; Embodiment (34a) 0.042 μ M; Embodiment (34b) 0.12 μ M; Embodiment (34c) 0.72 μ M.

N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base had before been described] phenyl] preparation of phenyl carbamate.

embodiment 35:

3-(1-hydroxyl third-2-yl)-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] urea

By N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate (110mg; 0.23mmol) and DMF (2mL) solution of triethylamine (0.079mL, 0.68mmol) join in 2-aminopropan-1-ols (1.14mmol).40 ℃ of stirring reactions 2 hours, then use preparative HPLC (alkali formula) purifying, obtain needed material solid (22mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.24 (3H, d), (3.21 3H, s), 3.37-3.43 (2H, m), (3.47-3.53 2H, m), 3.63-3.67 (1H, m), (3.72 1H, d), 3.78 (1H, d), (3.97-4.01 1H, m), 4.15-4.19 (1H, m), 4.48 (3H, s), (4.78 1H, t), 6.09-6.11 (1H, m), 6.77 (1H, s), (7.47-7.49 2H, m), 8.20-8.22 (2H, m), 8.71 (1H, s)

mass spectrum:m+H ⁺463.

Prepare following compounds by similar fashion.

Embodiment 35a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.54-1.62 (2H, m), (2.10-2.14 6H, s), 2.23 (2H, d), (2.32-2.34 1H, m), 2.44-2.47 (1H, m), (3.07-3.15 2H, m), 3.21 (3H, s), (3.63-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), (4.48 3H, s), 6.32 (1H, t), 6.77 (1H, s), (7.48-7.52 2H, m), 8.19-8.21 (2H, m), 8.79 (1H, s)

Embodiment 35b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.68 (2H, t), 3.15 (2H, d), (3.21 3H, s), 3.25 (4H, s), 3.38 (2H, t), (3.50 1H, d), 3.67 (1H, d), 3.76-3.79 (1H, m), (4.01 1H, m), 4.17 (1H, d), 4.48 (3H, s), (6.21 1H, s), 6.77 (1H, s), 7.48-7.51 (2H, m), 8.19-8.22 (2H, m), 8.70 (1H, s)

Embodiment 35c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.85-1.88 (4H, m), 3.21 (3H, s), 3.40 (5H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), 4.48 (3H, s), (6.78 1H, s), 7.63-7.66 (2H, m), (8.19-8.22 2H, m), 8.31 (1H, s)

Embodiment 35d: ¹h NMR (400.13MHz, DMSO-d ₆) δ δ 1.25 (3H, d), 3.21 (3H, s), 3.33-3.34 (1H, m), 3.46 (5H, t), 3.61-3.63 (4H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.19 (1H, d), 4.49 (3H, s), (6.79 1H, s), 7.57-7.61 (2H, m), (8.21-8.23 2H, m), 8.74 (1H, s)

Embodiment 35e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19-1.30 (4H, m), 1.31-1.39 (1H, m), (1.67 2H, d), 1.71-1.72 (1H, m), (1.74-1.78 2H, m), 3.09-3.12 (1H, m), (3.22 3H, d), 3.48 (1H, d), (3.63-3.67 1H, m), 3.78 (1H, d), (3.84 1H, d), 3.83-3.88 (1H, m), (3.97-4.01 1H, m), 4.19 (1H, d), (4.48-4.51 3H, m), 4.69 (1H, s), (6.76 1H, t), 7.57-7.59 (2H, m), (8.19-8.22 2H, m), 8.69 (1H, s)

Embodiment 35f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.31 (9, s), 3.20 (3H, s), 3.22 (1H, d), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.17 (1H, d), 4.48 (3H, s), (6.06 1H, s), 6.77 (1H, s), 7.43-7.47 (2H, m), 8.19-8.21 (2H, m), 8.48 (1H, s)

Embodiment 35g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.18 (6H, s), 2.34 (2ht), (3.17-3.25 5H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.17 1H, d), 4.48 (3H, s), 6.16 (1H, t), 6.77 (1H, s), 7.47-7.51 (2H, m), (8.19-8.22 2H, m), 8.89 (1H, s)

Embodiment 35h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H d), 3.21 (5H, t), 3.46 (3H, t), (3.52 1H, d), 3.63-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.15-4.19 (1H, m), (4.48 3H, s), 4.73 (1H, s), 6.26 (1H, t), 6.77 (1H, s), 7.48-7.50 (2H, m), (8.21 2H, d), 8.82 (1H, s)

Embodiment 35i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.38 (2H, d), (1.70 1H, d), 1.89 (1H, s), (2.74-2.78 1H, m), 2.96 (1H, s), (3.20 3H, s), 3.47-3.50 (1H, m), (3.51 1H, s), 3.66-3.67 (1H, m), (3.77-3.80 2H, m), 3.98 (2H, d), (4.17 1H, d), 4.48 (3H, s), (4.83 1H, d), 6.78 (1H, s), (7.57-7.59 2H, m), 8.19-8.21 (2H, m), 8.66 (1H, s)

Embodiment 35j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 2.26 (6H, s), 2.67-2.69 (2H, m), (2.95 3H, s), 3.21 (3H, s), 3.40 (3H, t), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), 4.18 (1H, d), (4.49 3H, s), 6.78 (1H, s), 7.50-7.53 (2H, m), 8.20-8.23 (2H, m), 9.51 (1H, s)

Embodiment 35k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 2.39 (2H, d), 2.41 (4H, d), (3.21 3H, s), 3.24 (2H, t), 3.47-3.53 (1H, m), (3.58-3.63 5H, m), 3.67 (1H, d), 3.78 (1H, d), (3.97-4.01 1H, m), 4.17 (1H, d), 4.48 (3H, s), (6.17 1H, t), 6.77 (1H, s), 7.49-7.51 (2H, m), 8.21 (2H, d), 8.88 (1H, s)

Embodiment 35l: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.25 (3H, d), 3.19-3.23 (3H, m), 3.26 (1H, s), (3.63-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.16-4.19 1H, m), 4.32 (2H, d), 4.48 (3H, s), 6.63 (1H, t), 6.78 (1H, s), (6.93 2H, s), 7.51-7.53 (2H, m), 8.22 (2H, d), 8.93 (1H, s), 11.84 (1H, s)

Embodiment 35m: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.69-0.73 (2H, m), 0.88-0.93 (2H, m), (1.25 3H, d), 2.70-2.76 (1H, m), (2.88 3H, s), 3.21 (3H, s), (3.22-3.25 1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), 3.97-4.01 (1H, m), (4.19 1H, d), 4.49 (3H, s), 6.79 (1H, s), (7.62-7.65 2H, m), 8.21-8.23 (2H, m), 8.39 (1H, s)

Embodiment 35n: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.25 (3H, d), (3.15-3.23 1H, m), 3.20 (3H, s), (3.36-3.42 2H, m), 3.50 (1H, d), (3.53-3.57 1H, m), 3.64-3.68 (2H, m), (3.75 1H, s), 3.78 (2H, d), (3.85-3.88 1H, m), 3.97-4.01 (1H, m), (4.20 2H, d), 4.49 (3H, s), 6.79 (1H, s), (7.58-7.61 2H, m), 8.21-8.23 (2H, m), 8.65 (1H, s).

Test (a): embodiment (35) 0.064 μ M; Embodiment (35a) 6.4 μ M; Embodiment (35b) 0.42 μ M; Embodiment (35c) 3.4 μ M; Embodiment (35d) 3.2 μ M; Embodiment (35e) 2.5 μ M; Embodiment (35f) 0.82 μ M; Embodiment (35g) 0.66 μ M; Embodiment (35h) 0.024 μ M; Embodiment (35i) 0.77 μ M; Embodiment (35j) 3.6 μ M; Embodiment (35k) 1.2 μ M; Embodiment (35l) 0.47 μ M; Embodiment (35m) 2 μ M; Embodiment (35n) 1.1 μ M.

embodiment 36:

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-carbonyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid (95mg) is dissolved in DMF (3mL), and adds (3S)-3-methylmorpholine.Add DIPEA (0.125mL) and HATU (137mg), stirring at room reaction 3 hours, then vacuum concentration, and distribution between DCM (25mL) and water (25mL).Use the dried over mgso organic layer, filter, evaporate to dryness, obtain needed material solid (88mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 6H, m), 2.52-2.61 (1H, m), (3.23-3.29 2H, m) 3.41-3.42 (1H, m), 3.46-3.47 (1H, m), 3.50-3.55 (2H, m), 3.60 (2H, d), 3.70-3.81 (2H, m), 3.97 (2H, d), 4.17 (1H, s), (4.53 1H, s), 6.43 (1H, s), 6.74 (1H, d), (7.51 2H, d), 8.20 (2H, t), 8.54 (1H, s)

mass spectrum:m+H ⁺480.

Prepare following sample by similar fashion.

Embodiment 36a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.39-0.44 (2H, m), 0.56-0.61 (2H, m), (0.65-0.68 2H, m), 0.74-0.76 (2H, m), (1.24 3H, d), 2.52-2.59 (1H, m), (2.53-2.61 1H, m), 3.25 (1H, s), (3.50 1H, d), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.25 1H, s), 4.53 (1H, s), (6.42-6.43 1H, m), 7.12 (1H, d), (7.51 2H, d), 8.38-8.41 (2H, m), (8.56 1H, s), 8.69 (1H, d).

Embodiment 36b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 3H, d), 2.25-2.26 (3H, m), (2.40-2.48 2H, m), 2.43-2.48 (2H, m), (2.52-2.61 1H, m), 3.18-3.25 (1H, m), (3.46-3.52 3H, m), 3.62-3.66 (3H, m), (3.76 1H, d), 3.95-3.99 (1H, m), (4.22 1H, d), 4.55 (1H, s), (6.44 1H, d), 6.73 (1H, s), (7.50-7.52 2H, m), 8.18-8.20 (2H, m), 8.54 (1H, s).

Test (a): embodiment (36) 0.062 μ M; Embodiment (36a) 2.9 μ M; Embodiment (36b) 0.18 μ M.

2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine-4-carboxylic acid is described below.

2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid

By 2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] in pyrimidine-4-carboxylate methyl ester (350mg) water-soluble (15mL) (containing sodium hydroxide (67mg)), and stirring at room reaction 1 hour.Further add 2 Equivalent Hydrogen sodium oxides and THF (3mL).Stirring reaction is 1 hour in addition, and then THF is removed in decompression, with ethyl acetate (15mL) dispensing water solution.With concentrated hydrochloric acid acidified aqueous solution water layer, filtering-depositing, in vacuum drying oven, 50 ℃ of dryings 18 hours, obtain needed material (350mg) white solid.

The NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.60-0.64 (2H, m), 1.22 (3H, d), (2.52-2.58 1H, m), 3.17-3.21 (1H, m), 3.46-3.53 (1H, m), (3.63-3.66 1H, m), 3.75 (1H, d), 3.95-3.99 (1H, m), 4.14-4.17 (1H, m), 4.48 (1H, d), (6.92 1H, s), 7.28 (1H, s), 7.56 (2H, d), 8.22 (2H, d), 9.41 (1H, s)

Mass spectrum: M+H ⁺398.

2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester

By 6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenyloxycarbonyl amino) phenyl] pyrimidine-4-carboxylate methyl ester (547mg) is dissolved in DMF (8mL) and triethylamine (0.59mL), then adds cyclopropylamine (0.491mL).40 ℃ of stirring reactions 2 hours, vacuum-drying mixture then, and distribute between DCM (50mL) and water (50mL).Use the dried over mgso organic layer, vacuum-drying, then carry out silica gel chromatography, with 5% methyl alcohol/DCM wash-out, obtains needed material (351mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), (1.25 3H, d), 2.52-2.58 (1H, m), (2.67-2.69 1H, m), 3.47-3.53 (1H, m), (3.63-3.67 1H, m), 3.76 (1H, d), (3.91 3H, s), 3.96-4.00 (1H, m), 4.23-4.27 (1H, m), (4.58 1H, s), 6.43 (1H, d), 7.14 (1H, s), (7.51-7.53 2H, m), 8.22-8.25 (2H, m), 8.56 (1H, s)

mass spectrum:m+H ⁺412.

6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(phenyloxycarbonyl amino) phenyl] pyrimidine-4-carboxylate methyl ester

By 2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester (400mg) is dissolved in diox (10mL) and sodium bicarbonate (154mg), dropwise adds phenyl chloroformate (0.154mL).In stirring at room mixture 16 hours, then diox was removed in decompression, and resistates is distributed between water (50mL) and ethyl acetate (50mL).Use the dried over mgso organic layer, filter, evaporation, obtain needed material brown foam (624mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.11 (1H, s), (3.47-3.54 1H, m), 3.58 (1H, s), (3.63-3.67 1H, m), 3.73 (1H, d), 3.91 (3H, s), (396-4.00 1H, m), 4.27 (1H, s), 6.73-6.78 (1H, m), (7.14-7.20 1H, m), 7.24-7.30 (2H, m), 7.43-7.48 (2H, m), (7.64-7.66 2H, m), 8.32-8.34 (2H, m), 10.46 (1H, s)

mass spectrum:m+H ⁺449.

2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester

By 2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid (1.15g) is dissolved in methyl alcohol (15mL), adds sulfuric acid (0.01mL), 80 ℃ of reacting by heating 24 hours.A small amount of activated molecular sieve 4A is joined in reaction, stir 2 hours.Filter reaction, vacuum-drying, then be suspended in ethyl acetate (250mL), with saturated sodium bicarbonate solution (250mL) washing once.Filter organic layer, use dried over mgso, vacuum-drying, obtain needed material brown solid (405mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 3.08 (1H, s), 3.45-3.52 (1H, m), 3.62-3.66 (1H, m), 3.75 (1H, d), (3.89 3H, s), 3.97 (1H, d), (4.21 1H, d), 4.55 (1H, s), (5.59 2H, d), 6.59-6.63 (2H, m), (7.04 1H, s), 8.06-8.08 (2H, m)

mass spectrum:m+H ⁺329.

2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid

By the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester (1.00g) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (10mL)).Then add (4-aminophenyl) pinacol borate (1.21g) and 2M sodium carbonate (5mL), and by degassed 5 minutes of solution.Add two (triphenylphosphine) palladium catalysts (130mg) of dichloro, 90 ℃, will react backflow 18 hours in nitrogen atmosphere.Cooling reaction, vacuum concentration distributes resistates between ethyl acetate (100mL) and water (100mL).Filter water, vacuum reduces volume.By the solution obtained concentrated hydrochloric acid acidifying, vacuum-drying, obtain needed material.

mass spectrum:m+H ⁺315.

The chloro-6-[(3S of 2-had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine-4-carboxylate methyl ester.

embodiment 37:

3-cyclopropyl-1-[4-[4-(2-hydroxyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By the chloro-6-[(3S of 2-[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] propan-2-ol (70mg) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (4mL)), add 4-(3-cyclopropyl urea groups) phenyl-boron dihydroxide (98mg) and 2M sodium carbonate (1mL).Add two (triphenylphosphine) palladium catalysts (10mg) of dichloro, 100 ℃, in microwave reactor heated solution 0.5 hour.Use the concentrated hydrochloric acid acidifying mixture, directly be loaded into SCX-2 post (10g) upper, use the methanol wash post, then use 7N ammonia/methanol-eluted fractions product, obtain needed material (55mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.62-0.67 (2H, m), (1.23 3H, d), 1.45 (6H, s), (2.54 1H, t), 3.19-3.23 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96 (1H, d), (4.14-4.17 1H, m), 4.50 (1H, s), (5.17 1H, s), 6.41 (1H, d), 6.80 (1H, s), (7.48 2H, d), 8.23 (2H, d), 8.50 (1H, s)

mass spectrum:m+H ⁺412.

Test (a): 0.051 μ M.

The chloro-6-[(3S of 2-[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] preparation of propan-2-ol is described below.

the chloro-6-[(3S of 2-[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] propan-2-ol

By the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylate methyl ester (300mg) is dissolved in anhydrous THF, and is cooled to-78 ℃.With within 2 minutes, dropwise adding methyl-magnesium-bromide (3.0M in diethyl ether, 0.74mL), then ,-78 ℃ of stirring reactions 20 minutes, then to be warming up to room temperature.Further stirring reaction is 20 minutes, then water (2mL) cancellation.Reaction is reduced to dry, and distributes between ethyl acetate (50mL) and water (50mL), use the dried over mgso organic layer, vacuum-drying, obtain needed material white solid (291mg).

the NMR spectrum: (400.13MHz, DMSO-d ₆) δ 1.16-1.23 (3H, m), 1.36 (6H, s), (3.15-3.23 1H, m), 3.40-3.47 (1H, m), (3.56-3.60 1H, m), 3.71 (1H, d), 3.91-3.94 (2H, m), (4.34 1H, s), 5.28 (1H, s), 6.87 (1H, s).

mass spectrum:m+H ⁺272.

embodiment 38:

1-[4-[4-(2-hydroxyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea

By the chloro-6-[(3S of 2-[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] propan-2-ol (70mg) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (4mL)).Add the 3-[(1-methyl-pyrazol-4-yl) methyl]-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] urea (115mg) and 2M sodium carbonate (1mL).Add two (triphenylphosphine) palladium catalysts (10mg) of dichloro, 100 ℃, in microwave reactor heated solution 0.5 hour.Use the concentrated hydrochloric acid acidifying mixture, directly be loaded into SCX-2 post (10g) upper, use the methanol wash post, then use 7N ammonia/methanol-eluted fractions product, obtain needed material (55mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.45 (6H, s), (3.16-3.23 1H, m), 3.46-3.52 (1H, m), (3.62-3.66 1H, m), 3.78-3.80 (1H, m), (3.75-3.81 3H, s), 3.96-3.99 (1H, m), (4.13 3H, d), 4.49-4.52 (1H, m), (5.17 1H, s), 6.39 (1H, t), (6.80 1H, s), 7.35 (1H, s), 7.47-7.49 (2H, m), (7.59 1H, s), 8.22-8.24 (2H, m), 8.65 (1H, s)

mass spectrum:m+H ⁺466.

Test (a): 1.3 μ M.

The chloro-6-[(3S of 2-[2-had before been described)-3-methylmorpholine-4-yl] pyrimidine-4-yl] preparation of propan-2-ol.

The 3-[(1-methyl-pyrazol-4-yl) methyl]-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] preparation of urea is described below.

the 3-[(1-methyl-pyrazol-4-yl) methyl]-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron Polymorphs alkane-2-yl) phenyl] urea

(4-aminophenyl) pinacol borate (200mg) is dissolved in anhydrous THF (5mL), adds sodium bicarbonate (116mg), then dropwise add phenyl chloroformate (0.115mL).Mixture is at room temperature stirred 1 hour.Add (1-methyl-pyrazol-4-yl) methylamine (102mg), stirring at room reaction 2 hours, then be heated to 40 ℃, keep 16 hours.The vacuum concentration reaction mixture distributes resistates between DCM (25mL) and water (25mL).Use the dried over mgso organism, filter vacuum-drying.Material is carried out to silica gel chromatography, use eluent ethyl acetate, obtain needed material (232mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.28 (12H, s), 3.79 (3H, s), 4.11 (2H, d), 6.39 (1H, t), 7.34 (1H, s), 7.39-7.41 (2H, m), 7.52-7.54 (2H, m), 7.59 (1H, s), 8.56 (1H, s)

mass spectrum:m+H ⁺357.

embodiment 39:

1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-(1,2-oxazole-3-yl) urea

Will [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (500mg) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (10mL)).Then by 3-(1,2-oxazole-3-yl)-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] urea (811mg) and 2M aqueous sodium carbonate (4mL) join in solution, and by degassed 5 minutes of the mixture obtained.Add two (triphenylphosphine) palladium catalysts (73mg) of dichloro, 90 ℃, in nitrogen atmosphere, solution is refluxed 7 hours.Cooling reaction, then with the concentrated hydrochloric acid neutralization, and it is upper directly to be loaded into SCX-2 post (50g), uses the methanol wash post, with 7N ammonia/methanol-eluted fractions product.Material is further carried out to the silica gel chromatography purifying, with 5% methyl alcohol/DCM wash-out, obtain needed material white solid (318mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.20-3.24 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.16-4.19 1H, m), 4.47 (2H, d), (4.50 1H, s), 5.40 (1H, t), 6.69 (1H, s), (6.87 1H, d), 7.53-7.56 (2H, m), 8.27-8.29 (2H, m), (8.75-8.75 1H, m), 9.03 (1H, d), 9.60 (1H, s)

mass spectrum:m+H ⁺411.

Test (a): 0.075 μ M.

3-(1,2-oxazole-3-yl)-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] preparation of urea is described below.

3-(1,2-oxazole-3-yl)-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) benzene base] urea

(4-aminophenyl) pinacol borate (1g) is dissolved in anhydrous THF (30mL), adds sodium bicarbonate (576mg), then dropwise add phenyl chloroformate (0.575mL).Then mixture is at room temperature stirred 1 hour.Add 3-An isoxazole (0.506mL), 40 ℃ of stirring reactions 16 hours.Add more 3-An isoxazole (0.506mL) and sodium bicarbonate (576mg), reaction is heated to 75 ℃, keep 8 hours.Then vacuum concentrated mixture, and distribution between DCM (50mL) and water (50mL).Use the dried over mgso organic layer, filter vacuum-drying.Resistates is carried out to silica gel chromatography, use eluent ethyl acetate, obtain needed compound white solid (1.05g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.29 (12h, s), 5.89 (1H, d), 6.86 (1H, d), 7.47-7.49 (2H, m), 7.61-7.63 (2H, m), 8.32 (1H, t), 8.75 (1H, d)

mass spectrum:m+H ⁺330.

embodiment 40:

N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-2-[4-(1,2-oxazole-3-base carboxamide amino) phenyl] pyrimidine-4-yl] methyl sulphonyl] ethyl] ethanamide

By 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-(1; 2-oxazole-3-yl) urea (89mg; 0.18mmol) partly be dissolved in acetonitrile (4mL); and add N-(2-sulfenyl ethyl) ethanamide (0.034mL, 0.32mmol).Add DBU (0.055mL, 0.36mmol), in stirring at room reaction 6 hours, then vacuum-drying.Material is dissolved in Isosorbide-5-Nitrae-dioxs (2mL), adds m-CPBA (75%) Isosorbide-5-Nitrae-dioxs (2mL) solution (158mg), then add immediately water (1mL) solution of sodium permanganate (175mg).Stirring at room reaction 1 hour, then be loaded into SCX-2 post (10g) upper, use the methanol wash post, with 7N ammonia/methanol-eluted fractions product.Be further purified material with preparative HPLC (alkali formula), obtain needed material (13mg) solid.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.26 (3H, d), 1.84 (3H, s), (3.24 1H, d), 3.52 (2H, t), (3.54 1H, s), 3.58 (2H, t), (3.65-3.68 1H, m), 3.79 (1H, d), (3.98-4.02 1H, m), 4.20 (1H, s), (4.54 3H, m), 6.82 (1H, s), (6.88 1H, d), 7.56-7.59 (2H, m), (8.16-8.17 1H, m), 8.28-8.31 (2H, m), (8.76-8.77 1H, m), 9.09 (1H, d), 9.62 (1H, s)

mass spectrum:m+H ⁺544.

Use similar fashion, by 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-3-(1,2-oxazole-3-yl) urea and suitable mercaptan prepares following compounds.

Embodiment 40a: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.26 (3H, d), 3.24 (1H, d), 3.53 (3H, t), (3.65-3.68 1H, m), 3.79 (1H, d), 3.93 (2H, q), (3.98-4.02 1H, m), 4.20 (1H, s), 4.51 (3H, d), (5.20 1H, t), 6.80 (1H, s), 6.88-6.88 (1H, m), (7.58 2H, d), 8.29-8.31 (2H, m), 8.76 (1H, s), 9.09 (1H, d), 9.64 (1H, s).

Test (c): embodiment (40) 0.1 μ M; Embodiment (40a) 0.055 μ M.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-preparation of 3-(1,2-oxazole-3-yl) urea is described below.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] benzene base]-3-(1,2-oxazole-3-yl) urea

By 1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-(1,2-oxazole-3-yl) urea (300mg) partly is dissolved in DCM (10mL) and triethylamine (0.153mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.086mL), and stirring at room reaction 45 minutes.Then water (2mL) washing reaction, use dried over mgso.Vacuum-drying solution, obtain needed material yellow solid.

mass spectrum:m+H ⁺489.

embodiment 41:

1-[4-[4-(2-hydroxyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-(1,2-oxazole-3-yl) urea

By the chloro-6-[(3S of 2-[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] propan-2-ol (160mg, 0.59mmol) join 3-(1,2-oxazole-3-yl)-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] the 18%DMF solution of urea (242mg) and two (triphenylphosphine) palladium catalysts (21mg) of dichloro is (at 7: 3: 2 DME: water: in the mixture of ethanol (6mL)).In microwave reactor, reaction is heated to 100 ℃, keep 30 minutes, and be cooled to room temperature.With 2M hydrochloric acid acidizing reaction mixture, and it is upper that crude product is loaded into to SCX post (10g), with the needed material of 7N ammonia/methanol-eluted fractions.Be further purified material with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (52mg) white solid.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.47 (6H, s), (3.18-3.25 1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.16-4.19 (1H, m), (4.51-4.53 1H, m), 5.20 (1H, s), 6.84 (1H, s), (6.88 1H, d), 7.55-7.57 (2H, m), 8.30-8.32 (2H, m), (8.76 1H, d), 9.06 (1H, s), 9.61 (1H, s)

mass spectrum: M+H ⁺439.4

Test (c): 0.047 μ M.

The chloro-6-[(3S of 2-[2-had before been described)-3-methylmorpholine-4-yl] pyrimidine-4-yl] propan-2-ol and 3-(1,2-oxazole-3-yl)-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] preparation of urea.

embodiment 42:

3-cyclopropyl-1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

Will [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (3.30g) is dissolved in 18%DMF (at 7: 3: 2 DME: water: in the mixture of ethanol (50mL)), then add 4-(3-cyclopropyl urea groups) phenyl-boron dihydroxide (4.92g) and 2M sodium carbonate (5mL), and by degassed 5 minutes of solution.Then two (triphenylphosphine) palladium catalysts (476mg) of dichloro are joined in solution, 90 ℃, under nitrogen atmosphere, reflux 7 hours.Cooling reaction, evaporation distributes resistates between DCM (200mL) and water (200mL).Use the dried over mgso organic layer, evaporation, purify with silica gel chromatography, with 5% methyl alcohol/DCM wash-out, obtains needed material (4.33g) yellow solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.23 3H, d), 2.54-2.58 (1H, m), (3.17-3.22 1H, m), 3.46-3.52 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), (3.96-3.99 1H, m), 4.15-4.18 (1H, m), (4.45 2H, d), 4.49 (1H, d), (5.38 1H, t), 6.41 (1H, d), (6.66 1H, s), 7.46-7.50 (2H, m), 8.18-8.22 (2H, m), (8.49 1H, s)

mass spectrum:m+H ⁺384.

Test (a): 0.19 μ M.

embodiment 43:

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

By 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (100mg; 0.24mmol) partly be dissolved in acetonitrile (4mL), and add pyridine-4-mercaptan (0.38mmol).Stirring at room reaction 1 hour, then add DBU (0.065mL, 0.43mmol), stirring at room reaction 18 hours.The evaporate to dryness reaction, and be dissolved in Isosorbide-5-Nitrae-dioxs (2mL).By m-CPBA (75%), 1,4 diox (2mL) solution (94mg) joined in reaction, then adds immediately water (1mL) solution of sodium permanganate (104mg), stirring at room 1 hour.By further m-CPBA (75%), 1,4 diox (2mL) solution (94mg) joined in reaction, then adds immediately water (0.5mL) solution of sodium permanganate (104mg), stirring at room reaction 1 hour.Reaction mixture is loaded on SCX-2 (10g) post, uses the methanol wash post, with 7N ammonia/methanol-eluted fractions product.Be further purified material with preparative HPLC (alkali formula), obtain needed material solid (10mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.21 3H, d), 2.58-2.61 (1H, m), (3.15-3.25 1H, m), 3.45-3.52 (1H, m), (3.61-3.65 1H, m), 3.77 (1H, d), (3.96-3.99 1H, m), 4.10-4.14 (1H, m), (4.38 1H, s), 4.86 (2H, t), (6.41-6.42 1H, m), 6.71 (1H, s), (7.37 2H, d), 7.66 (2H, d), (7.81-7.82 2H, m), 8.50 (1H, s), 8.90-8.91 (2H, m)

mass spectrum:m+H ⁺509.

Use similar mode, use suitable mercaptan to prepare following compounds.

Embodiment 43a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.23-1.25 3H, m), 2.57-2.60 (1H, m), (2.67-2.70 3H, m), 3.19-3.25 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.15-4.19 1H, m), 4.29 (2H, s), (4.48 1H, s), 4.67 (2H, s), (6.43-6.44 1H, m), 6.77 (1H, s), (7.50 2H, d), 8.19 (2H, d), (8.31 1H, t), 8.54 (1H, s)

Embodiment 43b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.20 3H, d), 2.52-2.60 (1H, m), (3.15-3.20 1H, m), 3.45-3.51 (1H, m), (3.61-3.65 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.10-4.13 (1H, m), (4.38 1H, s), 4.71 (2H, s), (6.40 1H, d), 6.65 (1H, s), (7.38-7.41 2H, m), 7.43-7.48 (2H, m), (7.79 2H, d), 7.85-7.89 (2H, m), 8.51 (1H, s)

Embodiment 43c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.19 (3H, d), 2.13 (3H, s), 2.53-2.61 (1H, m), (3.15-3.20 1H, m), 3.43-3.50 (1H, m), (3.60-3.63 1H, m), 3.75 (1H, d), (3.94-3.98 1H, m), 4.09 (1H, s), (4.34 1H, s), 4.60 (2H, s), (6.41-6.42 1H, m), 6.55 (1H, s), (7.39 2H, d), 7.70 (2H, d), (7.77 2H, d), 7.83 (2H, d), (8.48 1H, s), 10.37 (1H, s)

Embodiment 43d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 3H, d), 2.59-2.61 (1H, m), (3.15-3.20 1H, m), 3.51 (3H, t), (3.63-3.67 1H, m), 3.78 (1H, d), (3.92 2H, q), 3.97-4.01 (1H, m), (4.16-4.19 1H, m), 4.50 (3H, s), (5.18 1H, t), 6.44 (1H, d), 6.76 (1H, s), (7.50-7.52 2H, m), 8.21-8.23 (2H, m), 8.54 (1H, s)

Embodiment 43e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.20 3H, d), 2.52-2.61 (1H, m), (3.15-3.20 1H, m), 3.45-3.52 (1H, m), (3.62-3.65 1H, m), 3.77 (1H, d), (3.96-3.99 1H, m), 4.12 (1H, d), (4.40 2H, s), 4.90-4.91 (1H, m), (6.42 1H, d), 6.71 (1H, s), 7.40-7.43 (2H, m), (7.84 2H, d), 8.27-8.29 (2H, m), 8.50 (1H, s)

Embodiment 43f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.20-1.22 3H, m), 2.53 (1H, m), (3.17 1H, d), 3.49 (1H, d), (3.62-3.66 1H, m), 3.77 (1H, d), (3.95-3.99 1H, m), 4.12 (1H, d), (4.40 1H, s), 4.74-4.75 (2H, m), (6.42-6.42 1H, m), 6.70 (1H, s), (7.37 2H, d), 7.72 (2H, d), (7.80 1H, d), 7.90 (2H, t), (8.08 1H, d), 8.48 (1H, s)

Embodiment 43g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.42 (2H, d), 0.63-0.67 (2H, m), 1.23 (3H, d), (2.53 1H, d), 2.80 (3H, s), 3.20 (1H, d), (3.48 1H, d), 3.62-3.66 (1H, m), 3.77 (1H, d), (4.12 1H, d), 4.40 (2H, s), 5.04 (2H, t), (6.44 1H, s), 6.80 (1H, s), 7.43 (2H, d), 7.79 (2H, d), 8.53 (1H, s)

Embodiment 43i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.21 3H, d), 2.60-2.61 (1H, m), (3.20 1H, d), 3.34-3.39 (3H, s), (3.45-3.52 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.12 1H, d), 4.41 (1H, s), (4.86-4.87 2H, m), 6.41-6.42 (1H, m), (6.71 1H, s), 7.41-7.44 (2H, m), (7.82 1H, d), 7.87 (2H, d), 8.51 (1H, s)

Embodiment 43j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 3H, t), 1.83 (3H, s), (2.52-2.60 1H, m), 3.19-3.25 (1H, m), (3.47-3.50 2H, m), 3.52 (2H, d), (3.56 2H, d), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.12 1H, d), 4.50 (2H, d), (6.43 1H, d), 6.78 (1H, s), (7.50 2H, d), 8.19-8.22 (2H, m), (8.54 1H, s), 9.00 (1H, s)

Embodiment 43k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 3H, d), 1.67 (6H, d), (2.03 6H, s), 2.12 (3H, s), (2.53-2.60 1H, m), 3.20-3.24 (1H, m), (3.47-3.51 1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.12 1H, d), 4.39-4.45 (3H, m), (6.43 1H, d), 6.73 (1H, s), (7.49-7.51 2H, m), 8.22 (2H, d), 8.53 (1H, s)

Test (a): embodiment (43) 0.076 μ M; Embodiment (43a) 0.087 μ M; Embodiment (43b) 0.15 μ M; Embodiment (43c) 0.013 μ M; Embodiment (43d) 0.011 μ M; Embodiment (43e) 0.13 μ M; Embodiment (43f) 0.11 μ M; Embodiment (43h) 0.0071 μ M; Embodiment (43i) 0.058 μ M; Embodiment (43j) 1.8 μ M.

Test (c): embodiment (43g) 1.9 μ M; Embodiment (43k) 2.9 μ M

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] preparation of urea is described below.

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine -2-yl] phenyl] urea

By 3-cyclopropyl-1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea (1.83g) partly is dissolved in DCM (50mL) and triethylamine (1mL), and solution is cooled to 0 ℃.Add methylsulfonyl chloride (0.56mL), and stirring at room reaction 45 minutes.Then water (10mL) washing reaction, use the dried over mgso organism.Vacuum-drying solution, obtain needed material yellow solid.

mass spectrum:m+H ⁺462.

embodiment 44:

3-cyclopropyl-1-[4-[4-(3-hydroxypropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

At 20 ℃, by sodium permanganate monohydrate (38mg, 0.24mmol) join m-CPBA (33.2mg, 0.19mmol) and 3-cyclopropyl-1-[4-[4-(3-hydroxypropyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea is (in 44mg, 0.10mmol) diox (2mL) and water (1mL) solution.The solution obtained is stirred 45 minutes at 20 ℃, and mixture is loaded on SCX-3 (5g) post, the needed product of wash-out from post, used 7M ammonia/methyl alcohol.Be further purified material with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material (19mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.24 3H, d), 1.92-1.99 (2H, m), (2.53-2.60 1H, m), 3.18-3.26 (1H, m), (3.39 2H, q), 3.47-3.50 (1H, m), (3.55 2H, q), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), (4.16-4.19 1H, m), 4.46 (3H, s), (4.72 1H, t), 6.43 (1H, d), (6.78 1H, s), 7.49-7.51 (2H, m), (8.20-8.23 2H, m), 8.53 (1H, s)

mass spectrum:m+H ⁺490

Test (a): 1.8 μ M.

3-cyclopropyl-1-[4-[4-(3-hydroxypropyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of urea is described below.

3-cyclopropyl-1-[4-[4-(3-hydroxypropyl sulfanylmethyl)-6-[(3S)-3-methylmorpholine-4-yl] phonetic pyridine-2-yl] phenyl] urea

By 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (100mg) partly is dissolved in acetonitrile (4mL), and join in 3-sulfenyl third-1-alcohol (0.38mmol).To react and at room temperature stir 1 hour.DBU (0.065ul) is joined in reaction, in stirring at room mixture 18 hours.Vacuum concentrated mixture, with preparative HPLC (alkali formula) purifying, obtain needed material (44mg) white solid.

mass spectrum:m+H ⁺458.

3-cyclopropyl-1-[4-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] preparation of urea.

embodiment 45:

1-(2-hydroxyethyl)-1-methyl-3-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] urea

By N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] phenyl carbamate (94mg; 2mmol) and the NMP of triethylamine (0.09ml, 9.2mmol) (1mL) solution join in 2-methylamino ethanol (10mmol).70 ℃ of heated mixt 2 hours, use the preparative HPLC purification reaction, obtain needed compound.

the LCMS spectrum: MH+450, retention time 2.07 minutes.

Use similar mode, by N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Test (a): embodiment (45) 0.66 μ M; Embodiment (45a) 0.63 μ M; Embodiment (45b) 0.12 μ M; Embodiment (45c) 0.082 μ M; Embodiment (45d) 0.56 μ M; Embodiment (45e) 0.56 μ M; Embodiment (45f) 1.6 μ M; Embodiment (45g) 0.041 μ M; Embodiment (45h) 0.14 μ M; Embodiment (45i) 3 μ M; Embodiment (45j) 0.72 μ M; Embodiment (45k) 0.049 μ M; Embodiment (45l) 1.1 μ M; Embodiment (45m) 0.17 μ M; Embodiment (45n) 0.63 μ M; Embodiment (45o) 0.9 μ M; Embodiment (45p) 0.92 μ M; Embodiment (45q) 0.032 μ M; Embodiment (45r) 0.41 μ M; Embodiment (45s) 0.3 μ M; Embodiment (45t) 0.082 μ M; Embodiment (45u) 0.42 μ M; Embodiment (45v) 1.2 μ M; Embodiment (45w) 0.74 μ M; Embodiment (45x) 1.1 μ M; Embodiment (45y) 1.2 μ M; Embodiment (45z) 1 μ M; Embodiment (45aa) 0.83 μ M; Embodiment (45ab) 0.39 μ M.

N-[4-[4-(sulfonyloxy methyl ylmethyl)-6-morpholine-4-base-pyrimidine-2-base had before been described] phenyl] phenyl carbamate and N-[4-[4-[(3 S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate.

embodiment 46:

The 3-methyl isophthalic acid-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1,3-thiazoles-2-yl] urea

At 70 ℃; by N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1; the 3-thiazol-2-yl] phenyl carbamate (100mg; 0.2mmol), the mixture of methylamine (1mmol) and triethylamine (0.085mL, 0.6mmol) heats 2 hours in NMP (2mL).Use the preparative HPLC purifying substance, obtain needed material white solid (27mg).

the LCMS spectrum: MH+427, retention time 1.44 minutes

Prepare following compounds by similar fashion.

Test (a): embodiment (46) 0.14 μ M; Embodiment (46a) 0.35 μ M; Embodiment (46b) 0.0061 μ M; Embodiment (46c) 0.45 μ M; Embodiment (46d) 0.85 μ M; Embodiment (46e) 0.71 μ M; Embodiment (46f) 1.2 μ M; Embodiment (46g) 0.73 μ M; Embodiment (46h) 0.063 μ M; Embodiment (46i) 0.097 μ M.

N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1,3-thiazoles-2-yl] preparation of phenyl carbamate is described below.

n-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1, the 3-thiophene azoles-2-yl] phenyl carbamate

By 5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1; 3-thiazole-2-amine (1g; 2.71mmol), (0.511mL) dioxane solution at room temperature stirs 2 hours, then vacuum concentration for sodium bicarbonate (342mg) and phenyl chloroformate.Resistates is distributed between DCM and water, use the dried over sodium sulfate organic layer, evaporation, obtain foam.By the mixture milled foam of hexane and diethyl ether, obtain needed material white solid (1.1g).

the LCMS spectrum: MH+490, retention time 2.17, method: acid monitoring.

5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1,3-thiazoles-2- amine

By N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1; the 3-thiazol-2-yl]-N-[(2-methyl-prop-2-yl) the oxygen carbonyl] DCM (15mL) solution of carboxylamine tertiary butyl ester (1.7g, 2.9mmol) and TFA (8mL) at room temperature stirs 16 hours.Removal of solvent under reduced pressure, make resistates be alkalescence with ammonia soln.Extract product by ethyl acetate, use the dried over sodium sulfate organism, filter, evaporation, obtain needed material white solid (1g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16-1.22 (3H, m), 3.13-3.18 (1H, m), 3.19 (3H, s), 3.43-3.50 (1H, m), 3.60-3.63 (1H, m), (3.75 1H, d), 3.94-3.97 (1H, dd), 4.04 (1H, d), 4.37 (1H, s), 4.40 (2H, s), (5.75 1H, s), 6.64 (1H, s), (7.40 2H, s), 7.73 (1H, s)

the LCMS spectrum: MH+370, retention time 1.38 minutes, method: alkali formula monitoring

n-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(sulfonyloxy methyl ylmethyl) pyrimidine-2-base]-1, the 3-thiophene azoles-2-yl]-N-[(2-methyl-prop-2-yl) the oxygen carbonyl] the carboxylamine tertiary butyl ester

At 105 ℃; in nitrogen atmosphere; by N-[(2-methyl-prop-2-yl) the oxygen carbonyl]-N-(5-tributyl stannyl-1; the 3-thiazol-2-yl) carboxylamine tertiary butyl ester (3g; 5.1mmol), the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-mixture of 6-(sulfonyloxy methyl ylmethyl) pyrimidine (1g, 3.2mmol) and tetrakis triphenylphosphine palladium (50mg) heats 2 hours in toluene (10mL).Mixture is carried out to silica gel chromatography, obtain needed material (1.7g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.53 (9H, s), (3.18 3H, s), 3.55 (1H, t), (3.62 1H, d), 3.75 (1H, d), (3.98 1H, d), 4.10 (1H, s), (3.90 1H, s), 3.98 (2H, s), (6.80 1H, s), 8.18 (1H, s)

the LCMS spectrum: MH+570, retention time 2.89 minutes, method: alkali formula monitoring

n-[(2-methyl-prop-2-yl) oxygen carbonyl]-the amino first of N-(5-tributyl stannyl-1,3-thiazoles-2-yl) the acid tertiary butyl ester

At 0 ℃, n-Butyl Lithium (1.6M, in hexane, 30mL, 0.48mol) is joined in THF (480mL) solution of Diisopropylamine (6.7mL, 0.48mol).Stir the mixture 30 minutes at 0 ℃, then be cooled to-78 ℃.Add N-[(2-methyl-prop-2-yl) the oxygen carbonyl]-N-(1,3-thiazoles-2-yl) carboxylamine tertiary butyl ester (12g, 0.05mol), stirred solution 30 minutes.Add tributyltin chloride (16.3mL), stirred solution 30 minutes, then be warming up to room temperature.With saturated aqueous ammonium chloride (20mL) cancellation reaction, by ethyl acetate, extract product.Use the dried over sodium sulfate organism, vacuum concentration, utilize silica gel chromatography, with 5-15% ethyl acetate/hexane wash-out, obtains needed material clarified oil (9g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.49 (18H, s), 7.50 (1H, d), 7.55 (1H, d)

n-[(2-methyl-prop-2-yl) oxygen carbonyl]-N-(1,3-thiazoles-2-yl) carboxylamine tertiary butyl ester

THF (100mL) the solution return stirring of 2-aminothiazole (5g, 0.05mol), (2-methyl-prop-2-yl) oxygen carbonyl tertiary butyl carbonic ether (27.8g, 0.15mol) and DMAP (100mg) is spent the night.Mixture is cooling, and vacuum concentration.Resistates is carried out to silica gel chromatography, with 8% ethyl acetate/hexane wash-out, obtain needed material white solid (12g).

the LCMS spectrum: MH-299, retention time 2.6 minutes, method: alkali formula monitoring

embodiment 47:

The 3-methyl isophthalic acid-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-1,3-thiazoles-2-yl] urea

By N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-1; the 3-thiazol-2-yl] phenyl carbamate (200mg; 0.39mmol), NMP (3mL) solution of methylamine (1.5mmol) and triethylamine (0.163mL, 1.16mmol) is 70 ℃ of heating 2 hours.Mixture is carried out to silica gel chromatography, with 0-5% methanol/ethyl acetate wash-out, obtain needed material.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.70 (6H, s), 3.19 (3H, s), 3.20 (1H, dd), 3.45 (1H, dd), (3.62 1H, d), 3.75 (1H, d), 3.96 (1H, d), 4.18 (1H, d), 4.52 (1H, s), (6.40 1H, s), 6.65 (1H, s), (8.09 1H, s), 10.70 (1H, s)

the LCMS spectrum: MH+455, retention time 1.78 minutes.

Prepare following compounds by similar fashion.

Embodiment 47a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.45 (2H, q), 0.68 (2H, q), 1.20 (3H, d), (1.70 6H, s), 3.05 (3H, s), 3.20 (1H, dd), (3.48 1H, dd), 3.62 (1H, d), 3.75 (1H, d), 3.98 (1H, dd), 4.18 (1H, d), (4.55 1H, s), 6.68 (1H, s), 6.75 (1H, s), 8.05 (1H, s), 11.0 (1H, s).

Embodiment 47b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.70 (6H, s), 3.03 (3H, s), (3.20 1H, dd), 3.48 (1H, dd), 3.65 (1H, d), (3.70-3.80 4H, m), 3.99 (1H, dd), 4.15 (1H, d), 4.53 (1H, s), 6.70 (1H, s), (7.42 1H, s), 7.82 (1H, s), 8.10 (1H, s), 8.72 (1H, s), 10.75 (1H, s)

Embodiment 47c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.70 (6H, s), 2.68 (3H, s), (3.05 3H, s), 3.18 (1H, dd), 3.48 (1H, dd), (3.62 1H, d), 3.75 (1H, d), 3.98 (1H, d), (4.05 1H, q), 4.18 (2H, s), 4.51 (1H, s), (6.68 1H, s), 6.78 (1H, s), 7.35 (1H, s), (7.62 1H, s), 8.09 (1H, s), 10.60 (1H, s).

Test (a): embodiment (47) 0.26 μ M; Embodiment (47a) 1.2 μ M; Embodiment (47b) 0.41 μ M; Embodiment (47c) 1.4 μ M; Embodiment (47d) 0.97 μ M.

N-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-1,3-thiazoles-2-yl] preparation of phenyl carbamate is described below.

n-[5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2- base]-1,3-thiazoles-2-yl] phenyl carbamate

By 5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-1; 3-thiazole-2-amine (1.05g; 2.6mmol), phenyl chloroformate (618mg; 3.9mmol) and sodium bicarbonate (311mg; 3.9mmol) mixture diox (10mL) in, at room temperature stir 2 hours; then with the ethyl acetate dilution, water (150mL) and salt solution (100mL) wash.Use the dried over mgso organism, vacuum concentration.By the resistates recrystallization, obtain needed product beige solid (1g) with diethyl ether and hexane.

5-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine-2-base]-1,3-thiazoles-2-amine

At 110 ℃; under nitrogen atmosphere; by the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine (1.2g; 3.6mmol), N-[(2-methyl-prop-2-yl) the oxygen carbonyl]-N-(5-tributyl stannyl-1; the 3-thiazol-2-yl) carboxylamine tertiary butyl ester (3.1g, 5.2mmol) and tetrakis triphenylphosphine palladium (200mg) the mixture heated overnight in toluene (30mL).Mixture is diluted by ethyl acetate, wash with water.Use the dried over mgso organism, filter, evaporation.Resistates is dissolved in DCM (50mL), adds trifluoroacetic acid (15mL).After stirring 2 hours, evaporating mixture, add water.With ammonia soln, make mixture be alkalescence, extract by ethyl acetate.Use the dried over mgso organism, filter, evaporation, obtain solid.By the mixture grinding residues of diethyl ether and hexane, obtain needed material (1.05g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.18 (3H, d), 1.65 (6H, s), 3.0 (3H, s), 3.15 (3H, dd), 3.45 (1H, dd), (3.60 1H, dd), 3.71 (1H, d), (3.95 1H, dd), 4.10 (1H, d), (4.50 1H, S), 6.60 (1H, s), (7.35 2H, s), 7.75 (1H, s).

the LCMS spectrum: MH+398 retention time 1.76 minutes, method: alkali formula monitoring

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-6-(2-methyl sulphonyl third-2-yl) pyrimidine and N-[(2-methyl-prop-2-yl) the oxygen carbonyl]-preparation of N-(5-tributyl stannyl-1,3-thiazoles-2-yl) carboxylamine tertiary butyl ester.

embodiment 48:

3-cyclobutyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

By cyclobutyl amine (0.074mL; 0.87mmol) join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] phenyl carbamate (0.095g; 0.17mmol) and triethylamine (0.073mL; 0.52mmol) DMF (3mL) solution in, then in nitrogen atmosphere, be heated to 50 ℃.The solution obtained 50 ℃ of stirrings 2 hours.Solvent removed in vacuo, purify crude product with preparative HPLC, obtains needed material white solid (0.089g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20-1.22 (3H, d), 1.59-1.66 (2H, m), (1.82-1.92 2H, m), 2.18-2.25 (2H, m), (3.15-3.22 1H, td), 3.45-3.52 (1H, td), (3.62-3.65 1H, td), 3.75-3.78 (1H, d), (3.96-3.99 1H, dd), 4.09-4.17 (2H, m), (4.39 1H, bs), 4.87 (2H, s), (6.52-6.54 1H, d), 6.71 (1H, s), (7.33-7.35 2H, d), 7.64-7.67 (2H, d), (7.80-7.82 2H, q), 8.61 (1H, s), 8.90-8.91 (2H, q).

the LCMS spectrum: MH+523 retention time 1.96 minutes

Use similar mode, by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 48a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.05-1.09 (3H, t), 1.20-1.22 (3H, d), (3.09-3.16 2H, m), 3.16-3.22 (1H, td), (3.45-3.52 1H, td), 3.62-3.65 (1H, dd), (3.75-3.78 1H, d), 3.96-3.99 (1H, dd), (4.10-4.14 1H, d), 4.39 (1H, bs), (4.88 2H, s), 6.14-6.17 (1H, t), (6.71 1H, s), 7.35-7.37 (2H, d), 7.65-7.67 (2H, d), (7.81-7.82 2H, d), 8.64 (1H, s), 8.90-8.91 (2H, d).

Embodiment 48b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20-1.21 (3H, d), 2.41 (2H, bs), (2.74 3H, s), 2.90 (3H, s), (3.15-3.23 1H, td), 3.2-3.4 (2H, m), (3.45-3.51 1H, td), 3.61-3.65 (1H, dd), (3.75-3.78 1H, d), 3.96-3.99 (1H, dd), (4.10-4.13 1H, d), 4.39 (1H, bs), (4.87 2H, s), 6.25 (1H, t), (6.72 1H, s), 7.35-7.37 (2H, d), (7.65-7.67 2H, d), 7.81-7.82 (2H, q), (7.96 1H, s), 8.89-8.91 (2H, d).

Test (c): embodiment (48) 0.038 μ M; Embodiment (48a) 0.25 μ M.

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] benzene base] phenyl carbamate

In room temperature; by phenyl chloroformate (0.029mL; 0.23mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] aniline (0.097g; 0.23mmol) and sodium bicarbonate (in 0.029g, 0.34mmol) dioxane solution.The slurries that obtain are at room temperature stirred 2 hours.Add extra phenyl chloroformate (2X0.005ml), so that reacted.Then water is joined in reaction, cross filter solid, dry in vacuum drying oven, obtain needed material type white solid (0.098g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21-1.23 (3H, d), 3.16-3.24 (1H, td), (3.46-3.52 1H, td), 3.62-3.66 (1H, dd), (3.76-3.79 1H, d), 3.96-4.00 (1H, dd), 4.13-4.16 (1H, bd), (4.41 1H, bs), 4.90 (2H, s), 6.76 (s, 1H), (7.23-7.31 3H, m), 7.43-7.51 (4H, m), 7.74-7.77 (2H, m), (7.81-7.83 2H, dd), 8.90-8.92 (2H, dd), 10.39 (1H, s).

the LCMS spectrum: MH+546 retention time 2.35 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine) palladium (the II) (0.039g of trans-dichloro; 0.06mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine (0.411g; 1.11mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3,2-dioxa boron heterocycle pentane-2-yl) aniline (0.366g, 1.67mmol) and sodium carbonate (0.233mL; 5.56mmol) mixture (in 18%DMF, DMF was at 7: 3: 2 DME: water: in the mixture of ethanol (100ml)).The solution obtained 90 ℃ of stirrings 5 hours.To react cooling, with ethyl acetate and water dilution.With ethyl acetate abstraction reaction mixture, by the dry (MgSO of the organism merged ₄), filter evaporation.Crude product is carried out to silica gel chromatography, with 0-5% methyl alcohol/DCM wash-out, obtain needed material white solid (0.453g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.19-1.20 (3H, d), 3.12-3.19 (1H, td), 3.44-3.50 (1H, td), (3.61-3.64 1H, dd), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), (4.07-4.11 1H, d), 4.37 (1H, bs), 4.83 (2H, s), (5.50-5.52 2H, d), 6.45-6.47 (2H, d), 6.60 (1H, s), (7.48-7.50 2H, d), 7.80-7.81 (2H, q), 8.89-8.90 (2H, q).

the LCMS spectrum: MH+426 retention time 1.80 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine

At 55 ℃, in during 5 minutes, in air atmosphere, by superoxol (1.799mL, 58.19mmol) dropwise join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl sulfanylmethyl) pyrimidine (0.980g, 2.91mmol), (0.075mL) diox (200mL) is felt and is mixed in solution for sodium tungstate dihydrate (0.005mL, 0.06mmol) and 2N sulfuric acid.The solution obtained 55 ℃ of stirrings 3 hours.Add water (200mL), cooling reaction, cross filter solid, washes with water, and dried overnight in 50 ℃ of vacuum drying ovens, obtain needed material white solid (0.580g).Extract water layer with DCM, obtain extra material.Dry (MgSO ₄) extract, to filter, evaporation, utilize silica gel chromatography, with 0-3% methyl alcohol/DCM wash-out, obtains the needed material (0.144g) of part in addition.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.17-1.19 (3H, d), 3.14-3.22 (1H, td), (3.40-3.47 1H, td), 3.56-3.60 (1H, dd), (3.71-3.74 1H, d), 3.90 (1H, bs), (3.91-3.95 1H, dd), 4.20 (1H, bs), (4.79 2H, s), 6.79 (1H, s), (7.77-7.79 2H, q), 8.92-8.93 (2H, q).

LCMS spectrum: MH+369 retention time 1.39 minutes

the chloro-4-[(3 S of 2-)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl sulfanylmethyl) pyrimidine

In room temperature, under air conditions, 4-mercaptopyridine (0.752g, 6.77mmol) is joined to the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] in acetonitrile (100mL) solution of pyrimidine (1.596g, 4.51mmol).Then add DBU (0.3mL, 2.01mmol), and by the solution that obtains stirring at room 2 minutes.Except desolventizing, add DCM.Wash continuously reaction mixture with water, dry (MgSO ₄) organic layer, filter evaporation.Crude product is carried out to silica gel chromatography, with 0-2% methyl alcohol/DCM wash-out.Impure fraction is carried out to silica gel chromatography in addition, with 0-4.5% methyl alcohol/DCM wash-out, and merge with initial pure fraction, obtain the yellow colloid (0.980g) of needed material.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.14-1.16 (3H, d), 3.11-3.18 (1H, td), (3.37-3.44 1H, td), 3.53-3.57 (1H, dd), (3.64-3.67 1H, d), 3.86-3.90 (2H, dd), (4.01 2H, s), 4.14 (1H, bs), (6.43 1H, s), 7.04-7.06 (2H, d), 8.29-8.30 (2H, d).

the LCMS spectrum: MH+337 retention time 1.62 minutes

the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, sodium iodide (1.006mL, 24.61mmol) is joined to the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-the DCM solution of 6-(methyl sulphonyl oxygen ylmethyl) pyrimidine (1.584g, 4.92mmol) in.The solution obtained is refluxed 18 hours at 40 ℃.Reaction mixture is diluted with DCM, wash with water.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed product (1.596g).

the NMR spectrum: ¹h NMR (400.13MHz, CDCl ₃) δ 1.27-1.28 (3H, d), 3.20-3.27 (1H, td), 3.46-3.53 (1H, td), (3.62-3.65 1H, dd), 3.72-3.75 (1H, d), 3.93-3.97 (2H, dd), (4.17 2H, s), 4.26 (1H, bs), 6.41 (1H, s).

the LCMS spectrum: MH+354 retention time 1.85 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine

At 0 ℃, in during 2 minutes, by methylsulfonyl chloride (0.488mL, 6.31mmol) dropwise join [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (1.025g, 4.21mmol) and the DCM of triethylamine (0.880mL, 6.31mmol) in solution.During 2 hours, the solution obtained is warmed to room temperature gradually.By DCM for reaction mixture (50mL) dilution, wash with water.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material (1.584g), and it just need not be further purified and can use.

the LCMS spectrum: MH+322 retention time 1.60 minutes

embodiment 49:

3-cyclopropyl-1-[4-[4-[(cyclopropylamino) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (107mg; 0.23mmol) be dissolved in DCM (5mL), and join in cyclopropylamine (1.16mmol).Triethylamine (0.162mL, 1.16mmol) is joined in solution, stirring at room 18 hours.The evaporate to dryness reaction, with preparative HPLC (alkali formula) purifying, obtain needed material (27mg) white solid.

the NMR spectrum: 1H NMR (400.13MHz, DMSO-d ₆) δ 0.29-0.31 (2H, m), 0.34-0.44 (4H, m), (0.62-0.67 2H, m), 1.21-1.27 (3H, m), (2.13-2.17 1H, m), 2.53-2.58 (1H, m), (3.14-3.21 1H, m), 3.45-3.52 (1H, m), (3.62-3.65 1H, m), 3.71 (2H, d), (3.75 1H, s), 3.95-3.99 (1H, m), (4.14-4.17 1H, m), 4.49-4.51 (1H, m), (6.46 1H, d), 6.65 (1H, s), (7.47-7.50 2H, m), 8.21-8.23 (2H, m), 8.55 (1H, s).

mass spectrum:m+H ⁺423.

Use similar fashion, by 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea and suitable amine prepares following compounds.

Embodiment 49a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.21-1.27 3H, m), 2.30 (3H, s), (2.53-2.58 1H, m), 3.14-3.21 (1H, m), (3.46-3.58 7H, m), 3.62-3.66 (1H, m), (3.76 1H, d), 3.95-3.99 (1H, m), (4.15-4.18 1H, m), 4.45 (1H, t), (4.48 1H, s), 6.42 (1H, d), 6.73 (1H, s), (7.47-7.49 2H, m), 8.19-8.21 (2H, m), 8.50 (1H, s).

Embodiment 49b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.21 3H, d), 2.17 (3H, s), (2.30-2.37 8H, m), 2.53-2.58 (1H, m), (3.14-3.21 1H, m), 3.47-3.50 (3H, m), (3.63-3.66 1H, m), 3.76 (1H, d), (3.95-3.99 1H, m), 4.12-4.15 (1H, m), (4.45-4.47 1H, m), 6.43 (1H, d), 6.61 (1H, s), (7.46-7.50 2H, m), 8.19-8.21 (2H, m), 8.51 (1H, s).

Embodiment 49c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.21-1.26 3H, m), 3.14-3.22 (1H, m), (3.26 3H, s), 3.39-3.49 (5H, m), (3.62-3.66 2H, m), 3.67 (2H, s), (3.76 1H, d), 3.95-3.99 (1H, m), 4.16 (1H, d), (4.48 1H, s), 6.54 (1H, s), 6.66 (1H, s), (7.50 2H, d), 8.19 (2H, q), 8.62 (1H, s).

Embodiment 49d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.21-1.22 3H, m), 2.25 (6H, s), (2.52-2.57 1H, m), 3.17 (1H, d), (3.42 2H, s), 3.46-3.50 (1H, m), (3.62-3.66 1H, m), 3.75 (1H, d), (3.95-3.98 1H, m), 4.14-4.18 (1H, m), (4.46-4.48 1H, m), 6.44 (1H, d), 6.61 (1H, s), (7.47-7.50 2H, m), 8.19-8.22 (2H, m), 8.53 (1H, s).

Embodiment 49e: there is no wave spectrum

Embodiment 49f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.21 3H, d), 2.52-2.57 (1H, m), (3.14-3.21 1H, m), 3.49 (2H, s), (3.50 2H, t), 3.63 (7H, m), (3.66 1H, d), 3.76 (1H, d), (3.95-3.99 1H, m), 4.13-4.16 (1H, m), (4.49 1H, d), 6.42 (1H, d), 6.64 (1H, s), (7.47-7.49 2H, m), 8.19-8.21 (2H, m), 8.51 (1H, s).

Embodiment 49g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.22 3H, d), 2.13 (6H, s), (2.32-2.35 2H, m), 2.52-2.57 (1H, m), (2.62 2H, t), 3.14-3.22 (1H, m), (3.45-3.52 1H, m), 3.62-3.66 (1H, m), (3.67 3H, s), 3.76 (1H, d), (3.95-3.99 1H, m), 4.14-4.18 (1H, m), (4.49 1H, s), 6.42 (1H, d), (6.65 1H, s), 7.48 (2H, d), (8.22 2H, d), 8.50 (1H, s).

Embodiment 49h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 1.24 (3H, d), 1.46 (1H, d), 1.73-1.77 (2H, m), 2.27 (4H, s), 2.37 (1H, d), 2.43 (1H, s), 2.56-2.61 (2H, m), 2.73-2.76 (3H, m), 3.14-3.21 (1H, m), 3.47-3.53 (1H, m), 3.59-3.68 (3H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.14-4.17 (1H, m), 4.45 (1H, s), 6.43 (1H, d), 6.65 (1H, s), 7.47-7.49 (2H, m), 8.19-8.21 (2H, m), 8.51 (1H, s)

Embodiment 49i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 1.01 (6H, s), 1.21-1.27 (3H, m), 1.36 (1H, t), 2.07 (1H, t), 2.52-2.57 (1H, m), 3.15-3.21 (1H, m), 3.23 (2H, d), 3.45-3.52 (1H, m), 3.62-3.65 (3H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.12-4.16 (1H, m), 4.50-4.52 (1H, m), 6.49 (1H, s), 6.69 (1H, s), 7.47-7.50 (2H, m), 8.16-8.22 (2H, m), 8.56 (1H, s)

Embodiment 49j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 1.21-1.27 (3H, m), 2.53-2.58 (1H, m), 2.68 (2H, q), 3.09 (2H, s), 3.18 (1H, t), 3.20 (2H, t), 3.46-3.53 (1H, m), 3.57 (2H, s), 3.62-3.66 (1H, m), 3.75 (1H, d), 3.95-3.99 (1H, m), 4.15-4.18 (1H, m), 4.48-4.51 (1H, m), 6.44 (1H, d), 6.63 (1H, s), 7.48-7.50 (2H, m), 7.74 (1H, s), 8.19-8.22 (2H, m), 8.53 (1H, s)

Test (a): embodiment (49) 0.033 μ M; Embodiment (49a) 0.15 μ M; Embodiment (49b) 0.014 μ M; Embodiment (49c) 0.04 μ M; Embodiment (49e) 0.032 μ M; Embodiment (49f) 0.2 μ M; Embodiment (4,9g0 0.087 μ M; Embodiment (49h) 0.18 μ M; Embodiment (49i) 0.016 μ M; Embodiment (49k) 0.014 μ M; Embodiment (49l) 1.6 μ M.

Test (c): embodiment (49d) 0.62 μ M; Embodiment (49j) 0.13 μ M.

embodiment 50:

3-cyclopropyl-1-[4-[4-[(1,1-dioxo-Isosorbide-5-Nitrae-thiazan-4-yl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (107mg; 0.23mmol) be dissolved in DCM (5ml), and join in parathiazan (1.16mmol).Triethylamine (0.162mL, 1.16mmol) is joined in solution, stirring at room 18 hours.The evaporate to dryness reaction, and be dissolved in the mixture of Isosorbide-5-Nitrae-dioxs (4mL) and water (1mL).Form with single part joined metachloroperbenzoic acid (100mg, 0.58mmol) and sodium permanganate (110mg, 0.69mmol) in solution, stirring at room 1 hour.Crude product solution is loaded on the SCX-2 post, with 7N ammonia/separating methanol, evaporate to dryness.With preparative HPLC (alkali formula) purifying solid, obtain needed material white solid (11mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.22 3H, d), 2.53-2.58 (1H, m), (3.00 1H, s), 3.02 (3H, t), (3.15-3.22 5H, m), 3.50 (1H, d), (3.63-3.67 1H, m), 3.70 (2H, s), (3.77 1H, d), 3.96-3.99 (1H, m), (4.18 1H, s), 4.53 (1H, s), (6.42 1H, d), 6.70 (1H, s), (7.47-7.50 2H, m), 8.19-8.21 (2H, m), 8.50 (1H, s).

mass spectrum:m+H ⁺501.

Test (a): 0.0016 μ M.

embodiment 51:

1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea

Will [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (1.00g, 4.10mmol) join the 3-[(1-methyl-pyrazol-4-yl) methyl]-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] urea (2.193g, 6.16mmol) and sodium carbonate (8.21mL, 16.41mmol) in, the latter is in 18%DMF (at DME: EtOH: in water 7: 2: 3 (18mL)), and by degassed 5 minutes of solution.Two (triphenylphosphine) palladiums (II) (0.144g, 0.21mmol) of dichloro are joined in mixture.The solution obtained is stirred 18 hours at 85 ℃.To react cooling, neutralize with concentrated hydrochloric acid.Use the ion-exchange chromatogram purification crude product, use SCX-2 (50g) post, then further purify with fast silica gel chromatogram, gradient 0, to 7% methyl alcohol/DCM, obtains needed material white solid (963mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 3.19-3.23 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), (3.78 1H, d), 3.79 (3H, s), (3.96-3.99 1H, m), 4.13 (3H, d), (4.45-4.50 3H, m), 5.38 (1H, t), (6.39 1H, t), 6.66 (1H, s), 7.35 (1H, s), (7.45-7.49 2H, m), 7.59 (1H, s), 8.19-8.21 (2H, m), (8.64 1H, s), m/z the LCMS spectrum: MH+438, retention time 1.37 minutes

Before described [the chloro-6-[(3S of 2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl alcohol (1.00g, 4.10mmol) and the 3-[(1-methyl-pyrazol-4-yl) methyl]-1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) phenyl] preparation of urea.

embodiment 52:

1-4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methylpiperazine-1-yl) methyl] pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea

In room temperature; in nitrogen atmosphere; by 1-methylpiperazine (0.067mL; 0.60mmol) join triethylamine (0.084mL; 0.60mmol) and 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] in DCM (5mL) solution of urea (155mg, 0.30mmol).By the solution that obtains stirring at room 18 hours.Reaction mixture is evaporated.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (65mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21 (3H, d), 2.17 (3H, s), (2.35 8H, s), 3.14-3.21 (1H, m), (3.47-3.50 3H, m), 3.62-3.66 (1H, m), (3.77 1H, s), 3.79 (3H, s), (3.95-3.99 1H, m), 4.13 (3H, d), (4.46 1H, d), 6.42 (1H, t), (6.61 1H, s), 7.35 (1H, s), 7.47 (2H, d), (7.59 1H, s), 8.20 (2H, d), 8.66 (1H, s).

the LCMS spectrum: MH+520, retention time 1.49 minutes.

Use similar mode, by 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea and suitable amine prepares following compounds.

Embodiment 52a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.28-0.33 (2H, m), 0.37-0.39 (1H, m), 1.21-1.26 (3H, m), 1.36 (1H, t), 2.13-2.17 (1H, m), 2.82 (1H, s), 3.14-3.21 (1H, m), 3.43-3.51 (1H, m), 3.62-3.65 (1H, m), 3.71 (2H, d), 3.77-3.79 (4H, m), 3.95-3.99 (1H, m), 4.12-4.17 (3H, m), 4.50 (1H, d), 6.55 (1H, s), 6.64 (1H, s), 7.35 (1H, s), 7.48 (2H, d), 7.59 (1H, s), 8.17-8.23 (2H, m), 8.79 (1H, s).

Embodiment 52b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40 (2H, t), 0.44-0.49 (2H, m), (1.20 3H, d), 1.89-1.94 (1H, m), (2.33 3H, s), 3.16-3.20 (2H, m), (3.45-3.52 1H, m), 3.65 (3H, d), (3.79 3H, s), 3.94-3.98 (1H, m), (4.13 3H, d), 4.46 (1H, s), (6.40 1H, t), 6.52 (1H, s), (7.35 1H, s), 7.46-7.49 (2H, m), (7.59 1H, s), 8.21 (2H, d), 8.64 (1H, s).

Test (a): embodiment (52) 1.4 μ M; Embodiment (52a) 0.33 μ M; Embodiment (52b) 0.57 μ M.

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] preparation of urea is described below

1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] benzene base]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea

At 0 ℃, in nitrogen atmosphere, in during 10 minutes, by methylsulfonyl chloride (0.246mL, 3.15mmol) dropwise join triethylamine (0.440mL, 3.15mmol) and 1-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] in DCM (30mL) solution of urea (920mg, 2.10mmol).The solution obtained is stirred 45 minutes at 20 ℃.Water (10mL) washing reaction mixture.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material, and it just need not be further purified and can use.

the LCMS spectrum: MH+516, retention time 1.72 minutes

Before described-[4-[4-(methylol)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] preparation of urea.

embodiment 53:

N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-the 2-[4-[(1-methyl-pyrazol-4-yl) methyl carboxamide amino] phenyl] pyrimidine-4-yl] methyl sulphonyl] ethyl] ethanamide

In room temperature, in nitrogen atmosphere, to be dissolved in the metachloroperbenzoic acid acid (156mg of diox (2mL), 0.90mmol), the sodium permanganate monohydrate (192mg of water-soluble (1mL), 1.20mmol) dropwise join N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-the 2-[4-[(1-methyl-pyrazol-4-yl) methyl carboxamide amino] phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] ethanamide is (in 162mg, 0.30mmol) diox (6mL) and water (2mL) solution.By the solution that obtains stirring at room 1 hour.Use the ion-exchange chromatogram purification crude product, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol, the pure fraction of evaporate to dryness.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (61mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.83 (3H, s), (3.18 1H, m), 3.50-3.58 (6H, m), (3.66-3.67 1H, m), 3.76 (1H, s), (3.80 3H, s), 3.97 (1H, s), (4.13 2H, d), 4.51 (3H, m), (6.40 1H, d), 6.78 (1H, s), (7.35 1H, s), 7.48-7.51 (2H, m), 7.59 (1H, s), (8.15 1H, s), 8.21 (2H, d), 8.69 (1H, s).

the LCMS spectrum: MH+571, retention time 1.42 minutes.

Use similar mode, by suitable thioether, prepare following compounds.

Embodiment 53a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.19-3.25 (1H, m), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.76 1H, s), 3.79 (3H, s), (3.97-4.00 1H, m), 4.13 (3H, d), (4.27 2H, s), 4.48 (1H, s), (4.67 2H, s), 6.42 (1H, t), (6.76 1H, s), 7.35 (1H, s), (7.48-7.52 3H, m), 7.59 (1H, s), (7.79 1H, s), 8.20 (2H, d), 8.69 (1H, s).

Embodiment 53b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24 (3H, d), 3.22 (1H, d), 3.51 (3H, t), (3.63-3.67 1H, m), 3.80 (4H, s), 3.92 (2H, q), (3.97-4.01 1H, m), 4.13 (3H, d), 4.50 (3H, s), (5.18 1H, t), 6.42 (1H, t), 6.76 (1H, s), (7.35 1H, s), 7.49-7.51 (2H, m), 7.59 (1H, s), 8.22 (2H, d), 8.68 (1H, s).

Embodiment 53c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.20-1.26 (3H, m), 3.15-3.22 (1H, m), (3.45-3.52 1H, m), 3.61-3.65 (1H, m), (3.78 1H, s), 3.80 (3H, s), (3.95-3.99 1H, m), 4.12 (3H, d), (4.39 1H, s), 4.87 (2H, s), (6.39 1H, t), 6.71 (1H, s), (7.34-7.39 3H, m), 7.59 (1H, s), 7.66 (2H, d), (7.81-7.82 2H, m), 8.64 (1H, s), 8.90-8.91 (2H, m).

Test (a): embodiment (53) 0.64 μ M; Embodiment (53a) 0.6 μ M; Embodiment (53c) 0.03 μ M.

Test (c): embodiment (53b) 3 μ M.

N-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-the 2-[4-[(1-methyl-pyrazol-4-yl) methyl carboxamide amino] phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] preparation of ethanamide is described below.

n-[2-[[6-[(3S)-3-methylmorpholine-4-yl]-the 2-[4-[(1-methyl-pyrazol-4-yl) methyl carboxamide ammonia base] phenyl] pyrimidine-4-yl] the methyl sulfenyl] ethyl] ethanamide

In nitrogen atmosphere; by N-acetylcysteamine (0.056mL; 0.53mmol) join DBU (0.091mL; 0.60mmol) and 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] in acetonitrile (4mL) solution of urea (155mg, 0.30mmol).By the solution that obtains stirring at room 5 hours.Evaporation reaction mixture, obtain needed material, and it just need not be further purified and can use.

the LCMS spectrum: MH+539, retention time 1.66 minutes

Use similar fashion, by 1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] urea and suitable mercaptan prepares following sulfide.

1-[4-[4-[(3S had before been described)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl]-the 3-[(1-methyl-pyrazol-4-yl) methyl] preparation of urea.

embodiment 54:

3-cyclopropyl-1-[4-[4-(methoxymethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By 3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(methyl sulphonyl oxygen ylmethyl) pyrimidine-2-base] phenyl] urea (75mg; 0.16mmol) and salt of wormwood (90mg; 0.65mmol) be suspended in methyl alcohol (3mL), and be sealed in microwave tube.In microwave reactor, reaction is heated to 100 ℃, keep 10 minutes, and be cooled to room temperature.Use the ion-exchange chromatogram purification crude product, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol.Be further purified crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (15mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.22 3H, d), 2.54-2.58 (1H, m), (3.18-3.23 1H, m), 3.40 (3H, s), (3.45-3.52 1H, m), 3.62-3.66 (1H, m), (3.75 1H, d), 3.95-3.98 (1H, m), (4.16-4.19 1H, m), 4.39 (2H, s), (4.50 1H, s), 6.42 (1H, d), 6.57 (1H, s), (7.47-7.50 2H, m), 8.19-8.21 (2H, m), 8.51 (1H, s).

the LCMS spectrum: MH+398, retention time 1.86 minutes.

Test (c): 0.11 μ M

embodiment 55:

3-cyclopropyl-1-[4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By [4-(3-cyclopropyl urea groups) phenyl] boric acid, pinacol ester (80mg; 0.26mmol), sodium carbonate (1.055mL; 2.11mmol), two (triphenylphosphine) palladium (the II) (14.8mg of dichloro; 0.02mmol) and the chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (70mg; 0.21mmol) be suspended in 18%DMF (at DME: ethanol: in water 7: 2: 3 mixture (4mL)), and be sealed in microwave tube.In microwave reactor, reaction is heated to 100 ℃, keep 10 minutes, and be cooled to room temperature.Use the ion-exchange chromatogram purification crude product, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol.Be further purified crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain the colourless colloid of needed material (33.0mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.41-0.43 (2H, m), 0.64-0.66 (2H, m), (0.98-1.01 2H, m), 1.04-1.08 (2H, m), (1.24 3H, d), 2.56 (1H, s), (2.86 1H, d), 3.18 (1H, d), (3.50 1H, d), 3.67 (1H, d), (3.76-3.79 1H, m), 4.50 (2H, s), (6.43 1H, d), 6.77 (1H, s), (7.49-7.51 2H, m), 7.55-7.57 (1H, m), (7.60-7.65 2H, m), 8.21-8.23 (2H, m), 8.53 (1H, s).

the LCMS spectrum: MH+472, retention time 1.80 minutes.

Test (a): 0.062 μ M.

The chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine is described below.

the chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, will be as a cyclopropane-sulfinic acid, sodium salt (381mg, 2.97mmol) joins the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] in acetonitrile (20mL) solution of pyrimidine (700mg, 1.98mmol).The suspension obtained 90 ℃ of stirrings 3 hours.The evaporate to dryness reaction mixture, and be dissolved in again in DCM (50mL) water (50mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient is 0 to 40% ethyl acetate/DCM, obtains needed material white solid (458mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.95-0.98 (2H, m), 1.02-1.06 (2H, m), (1.18-1.23 3H, m), 2.77-2.83 (1H, m), (3.19-3.25 1H, m), 3.42-3.49 (1H, m), (3.58-3.62 1H, m), 3.73 (1H, d), (3.92-3.96 2H, m), 4.30 (1H, s), (4.48 2H, s), 6.92 (1H, s).

the LCMS spectrum: MH+332, retention time 1.68 minutes

The chloro-4-of 2-(iodomethyl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 56:

3-cyclopropyl-1-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By [4-(3-cyclopropyl urea groups) phenyl] boric acid; pinacol ester (199mg; 0.66mmol); the chloro-4-of 2-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (190mg; 0.53mmol), sodium carbonate (1.320mL; 2.64mmol) and two (triphenylphosphine) palladium (the II) (37.1mg of dichloro; 0.05mmol) be suspended in 18%DMF (at DME: in water: EtOH 7: 3: 2 solution (4mL)), and be sealed in microwave tube.In microwave reactor, reaction is heated to 100 ℃, keep 20 minutes, and be cooled to room temperature.Use the ion-exchange chromatogram purification crude product, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol, the pure fraction of evaporate to dryness.Be further purified crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (85mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), 0.78-0.83 (1H, m), 0.81 (1H, d), 0.95 (2H, d), 1.23 (3H, d), 1.81 (6H, d), 2.56 (1H, q), 2.73-2.77 (1H, m), 3.20-3.24 (1H, m), 3.48-3.53 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.20-4.23 (1H, m), 4.57-4.59 (1H, m), 6.42 (1H, d), 6.77 (1H, s), 7.49-7.51 (2H, m), 8.23-8.25 (2H, m), 8.52 (1H, s).

the LCMS spectrum: MH+500, retention time 2.04 minutes

Test (a): 2.4 μ M.

The chloro-4-of 2-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine is described below.

the chloro-4-of 2-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At-10 ℃; by methyl iodide (0.033mL; 0.53mmol) join sodium tert-butoxide (50.7mg; 0.53mmol) and the chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] in DMF (2mL) solution of pyrimidine (175mg, 0.53mmol).The dense suspension that obtains, stirring at room 15 minutes, is stirred being easy to.Methyl iodide (0.033mL, 0.53mmol) and sodium tert-butoxide (50.7mg, 0.53mmol) are joined in reaction again to the suspension obtained in stirring at room 15 minutes.By DCM for reaction mixture (20mL) dilution, and water (20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material (153mg).

the LCMS spectrum: MH+360, retention time 2.13 minutes

The chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 57:

1-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-methyl-urea

By methylamine (0.699mL; 1.40mmol) join N-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (150mg; 0.28mmol) and DMF (2mL) solution of triethylamine (0.117mL, 0.84mmol) in.The solution obtained 40 ℃ of stirrings 2 hours.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (74.0mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.77-0.85 (2H, m), 0.91-0.98 (2H, m), (1.22-1.23 3H, m), 1.81 (6H, d), (2.67 3H, t), 2.72-2.78 (1H, m), (3.20-3.24 1H, m), 3.47-3.54 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.20-4.23 (1H, m), (4.57-4.59 1H, m), 6.06 (1H, q), 6.77 (1H, s), (7.48-7.52 2H, m), 8.22-8.25 (2H, m), 8.72 (1H, s).

the LCMS spectrum: MH+474, retention time 1.92 minutes

Test (c): embodiment (57) 0.25 μ M; Embodiment (57a) 0.064 μ M; Embodiment (57b) 0.089 μ M; Embodiment (57c) 0.36 μ M; Embodiment (57d) 0.84 μ M; Embodiment (57e) 0.38 μ M; Embodiment (57f) 0.72 μ M; Embodiment (57g) 0.095 μ M; Embodiment (57h) 0.066 μ M; Embodiment (57i) 0.27 μ M; Embodiment (57j) 0.07 μ M; Embodiment (57k) 0.34 μ M; Embodiment (57l) 0.088 μ M.

Use similar fashion, by N-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 57a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.79-0.83 (2H, m), 0.94-0.97 (2H, m), (1.22 3H, d), 1.24 (6H, s), (1.81 6H, d), 2.74-2.78 (1H, m), (3.21 1H, t), 3.39 (2H, d), (3.50 1H, d), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.20-4.23 1H, m), 4.56-4.59 (1H, m), (4.95 1H, t), 6.00 (1H, s), (6.76 1H, s), 7.44-7.46 (2H, m), (8.22 2H, d), 8.72 (1H, s).

Embodiment 57b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.79-0.84 (2H, m), 0.95 (2H, d), (1.23 3H, d), 1.81 (6H, d), (2.18 6H, s), 2.34 (2H, t), (2.73-2.77 1H, m), 3.17-3.23 (3H, m), (3.47-3.54 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.19-4.23 1H, m), 4.58 (1H, d), (6.15 1H, t), 6.77 (1H, s), (7.47-7.50 2H, m), 8.22-8.24 (2H, m), 8.88 (1H, s).

Embodiment 57c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.81-0.83 (2H, m), 0.96 (2H, d), (1.22-1.24 3H, m), 1.82 (6H, d), (2.73-2.77 1H, m), 3.21-3.25 (1H, m), (3.47-3.51 1H, m), 3.64-3.68 (1H, m), (3.76 1H, s), 3.79 (3H, s), (3.97-4.00 1H, m), 4.22 (1H, d), (4.57-4.60 1H, m), 6.78 (1H, s), (7.38 1H, d), 7.53-7.56 (2H, m), (7.76 1H, s), 8.27 (2H, d), (8.38 1H, s), 8.82 (1H, s)

Embodiment 57d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.97-1.01 (2H, m), 1.03-1.09 (2H, m), (1.23-1.25 3H, m), 2.67 (3H, t), (2.83-2.90 1H, m), 3.18 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.20 (1H, d), (4.50 3H, m), 6.06 (1H, q), 6.77 (1H, s), (7.48-7.51 2H, m), 8.20-8.23 (2H, m), 8.72 (1H, s).

Embodiment 57e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.98-1.01 (2H, m), 1.05-1.09 (2H, m), (1.23 3H, d), 1.25 (6H, s), (2.85-2.89 1H, m), 3.18 (1H, d), (3.39 2H, d), 3.47-3.51 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.15-4.18 (1H, m), (4.47 1H, s), 4.50 (2H, s), (4.95 1H, t), 6.00 (1H, s), (6.77 1H, s), 7.43-7.47 (2H, m), (8.21 2H, d), 8.72 (1H, s).

Embodiment 57f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.99-1.01 (2H, m), 1.05-1.08 (2H, m), (1.24 3H, d), 2.18 (6H, s), (2.34 2H, t), 2.86 (1H, d), (3.17 1H, d), 3.20 (2H, m), (3.51 1H, s), 3.66-3.67 (1H, m), (3.76-3.79 1H, m), 4.02 (1H, d), (4.20 1H, d), 4.50 (3H, m), (6.15 1H, s), 6.77 (1H, s), (7.47-7.49 2H, m), 8.20-8.23 (2H, m), 8.88 (1H, s).

Embodiment 57g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.99-1.02 (2H, m), 1.04-1.10 (2H, m), (1.25 3H, d), 2.85-2.89 (1H, m), (3.18 2H, m), 3.48-3.51 (1H, m), (3.64-3.68 1H, m), 3.77 (1H, s), (3.79 3H, s), 3.97-4.01 (1H, m), (4.48 1H, s), 4.51 (2H, s), (6.78 1H, d), 7.38-7.39 (1H, m), (7.53-7.55 2H, m), 7.76 (1H, s), (8.24-8.27 2H, m), 8.38 (1H, s), 8.82 (1H, s).

Embodiment 57h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.77-0.84 (2H, m), 0.91-0.96 (2H, m), 1.22-1.23 (3H, m), 1.59-1.64 (2H, m), 1.80 (6H, s), 1.81-1.85 (2H, m), 2.17-2.25 (2H, m), 2.73-2.77 (1H, m), 3.16-3.24 (1H, m), 3.47-3.53 (1H, m), 3.63-3.67 (1H, m), 3.77 (1H, d), 3.96-4.00 (1H, m), 4.11 (1H, m), 4.19 (1H, m), 4.56-4.59 (1H, m), 6.46 (1H, d), 6.77 (1H, s), 7.46-7.49 (2H, m), 8.24 (2H, d), 8.55 (1H, s).

Embodiment 57i: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.77-0.83 (2H, m), 0.94 (2H, t), (1.23 3H, d), 1.81 (6H, d), (2.73-2.77 1H, m), 3.18 (2H, d), (3.20-3.24 1H, m), 3.46 (2H, q), (3.48-3.53 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.21 1H, d), 4.58 (1H, d), (4.72 1H, t), 6.25 (1H, t), (6.75 1H, d), 7.47-7.50 (2H, m), (8.23-8.25 2H, m), 8.79 (1H, s).

Embodiment 57j: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.97-1.01 (2H, m), 1.03-1.10 (2H, m), (1.04-1.09 3H, m), 1.23-1.25 (3H, m), (2.85-2.89 1H, m), 3.09-3.16 (2H, m), (3.21-3.25 1H, m), 3.47-3.54 (1H, m), (3.64-3.67 1H, m), 3.78 (1H, d), (3.97-4.01 1H, m), 4.15 (1H, d), (4.50 3H, m), 6.16 (1H, t), 6.77 (1H, s), (7.47-7.50 2H, m), 8.20-8.23 (2H, m), 8.65 (1H, s).

Embodiment 57k: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.78-0.83 (2H, m), 0.95 (2H, d), (1.07 3H, t), 1.23 (3H, d), (1.81 6H, d), 2.75 (1H, d), (3.15 2H, d), 3.18 (1H, s), (3.50 1H, d), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.19-4.23 1H, m), 4.58 (1H, d), (6.16 1H, t), 6.74-6.77 (1H, m), (7.48-7.50 2H, m), 8.23 (2H, d), 8.65 (1H, s).

Embodiment 57l: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.97-1.03 (2H, m), 1.03-1.09 (2H, m), (1.23-1.25 3H, m), 1.57-1.66 (2H, m), (1.83-1.88 2H, m), 2.17-2.24 (2H, m), (2.83-2.88 1H, m), 3.21-3.25 (1H, m), (3.47-3.54 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.00 (1H, m), (4.14 2H, m), 4.50 (3H, m), (6.45 1H, d), 6.77 (1H, s), (7.45-7.49 2H, m), 8.20-8.23 (2H, m), 8.55 (1H, s).

N-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

In nitrogen atmosphere; by phenyl chloroformate (0.215mL; 1.71mmol) dropwise join 4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (712mg; 1.71mmol) and sodium bicarbonate (in 215mg, 2.56mmol) diox (15mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture, and be dissolved in again in ethyl acetate (100mL) water (100mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material (983mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.77-0.84 (2H, m), 0.95 (2H, t), (1.23 3H, s), 1.82 (6H, d), (2.74-2.78 1H, m), 3.18-3.25 (1H, m), (3.47-3.54 1H, m), 3.64-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.23 1H, d), 4.59 (1H, s), (6.80 1H, s), 7.22-7.30 (3H, m), 7.40-7.48 (2H, m), (7.55-7.64 2H, m), 8.35 (2H, d), 10.42 (1H, s).

the LCMS spectrum: MH+537, retention time 2.87 minutes

4-[4-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (96mg of dichloro; 0.14mmol) join (4-aminophenyl) pinacol borate (747mg; 3.41mmol), the chloro-4-of 2-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (982mg; 2.73mmol) and the 18%DMF of sodium carbonate (6.82mL, 13.64mmol) (at DME: water: in ethanol 7: 3: 2 (20mL)) solution in.The solution obtained 80 ℃ of stirrings 16 hours.Use the ion-exchange chromatogram purification crude product, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol.Be further purified crude product with fast silica gel chromatogram, gradient 0, to 2.5% methyl alcohol/DCM, obtains needed material yellow crystal solid (712mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.79-0.83 (2H, m), 0.94-0.96 (2H, s), 1.21 (3H, d), (1.79 6H, d), 2.74 (1H, m), 3.17 (1H, d), (3.49 1H, d), 3.62-3.66 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.16-4.19 (1H, m), (4.54 1H, d), 5.51-5.53 (2H, m), 6.59 (2H, t), 6.67 (1H, s), 8.07 (2H, d).

the LCMS spectrum: MH+417, retention time 2.22 minutes

The chloro-4-of 2-(2-cyclopropyl alkylsulfonyl third-2-yl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

N-[4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

By phenyl chloroformate (0.315mL; 2.50mmol) dropwise join 4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (972mg; 2.50mmol) and sodium bicarbonate (in 315mg, 3.75mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture, and be dissolved in again in ethyl acetate (100mL) water (100mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material (1.35g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.98-1.03 (2H, m), 1.06-1.10 (2H, m), (1.26 3H, d), 2.86-2.93 (1H, m), (3.48-3.52 1H, m), 3.58 (1H, s), (3.64-3.68 1H, m), 3.77-3.80 (1H, m), (3.98-4.06 1H, m), 4.17 (1H, d), (4.50 1H, s), 4.56 (2H, s), (6.86 1H, s), 7.24-7.29 (3H, m), 7.43-7.47 (2H, m), (7.65 2H, d), 8.31 (2H, d), 10.47 (1H, s).

the LCMS spectrum: MH+509, retention time 2.29 minutes.

4-[4-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (96mg of dichloro; 0.14mmol) join (4-aminophenyl) pinacol borate (747mg; 3.41mmol), the chloro-4-of 2-(cyclopropyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (905mg; 2.73mmol) and the 18%DMF of sodium carbonate (6.82mL, 13.64mmol) (at DME: water: in ethanol 7: 3: 2 (20mL)) solution in.The solution obtained 80 ℃ of stirrings 6 hours.With ion-exchange chromatogram purification crude product reactant, use the SCX post.The needed product of wash-out in post, used 7M ammonia/methyl alcohol.Be further purified crude product with fast silica gel chromatogram, gradient 0, to 2.5% methyl alcohol/DCM, obtains needed material yellow solid (972mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.97-1.02 (2H, m), 1.03-1.10 (2H, m), 1.23 (3H, d), 2.81-2.87 (1H, m), 3.15-3.22 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.12-4.15 (1H, m), (4.45 3H, s), 5.53 (2H, d), 6.58-6.61 (2H, m), 6.66 (1H, s), 8.03-8.07 (2H, m).

the LCMS spectrum: MH+389, retention time 1.82 minutes.

embodiment 58:

The 3-methyl isophthalic acid-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] urea

By methylamine (2M solution; in THF) (0.55ml; 1.10mmol) join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate (125mg; 0.22mmol) and the DMF (4mL) of triethylamine (0.092mL, 0.66mmol) in.The solution obtained is spent the night 50 ℃ of stirrings.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material (91mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-1.23 (3H, d), 1.82-1.83 (6H, d), (2.66-2.67 3H, d), 3.15-3.23 (1H, td), (3.47-3.53 1H, td), 3.63-3.53 (1H, dd), (3.76-3.79 1H, d), 3.96-4.00 (1H, dd), (4.18-4.21 1H, d), 4.57 (1H, bs), 6.03-6.07 (1H, q), (6.71 1H, s), 7.35-7.37 (2H, d), 7.47-7.48 (2H, q), (7.65-7.68 2H, d), 8.70 (1H, s), 8.74-8.75 (2H, q).

the LCMS spectrum: MH+511, retention time 2.03 minutes

Use similar fashion, by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 58a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.05-1.09 (3H, t), 1.22-1.23 (3H, d), (1.82-1.83 6H, d), 3.09-3.22 (3H, m), (3.47-3.53 1H, td), 3.63-3.67 (1H, dd), (3.76-3.79 1H, d), 3.96-3.99 (1H, dd), (4.18-4.22 1H, d), 4.57 (1H, bs), 6.13-6.15 (1H, t), (6.71 1H, s), 7.34-7.36 (2H, d), 7.47-7.48 (2H, q), (7.65-7.68 2H, d), 8.62 (1H, s), 8.74-8.75 (2H, q).

Embodiment 58b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.68 (2H, m), 1.22-1.23 (3H, d), 1.82-1.83 (6H, d), 2.54-2.59 (1H, m), 3.15-3.23 (1H, td), 3.47-3.53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.18-4.21 (1H, d), 4.57 (1H, bs), 6.41-6.42 (1H, d), 6.72 (1H, s), 7.35-7.38 (2H, d), 7.47-7.48 (2H, q), 7.66-7.68 (2H, d), 8.50 (1H, s), 8.74-8.75 (2H, q).

Embodiment 58c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-1.23 (3H, d), 1.58-1.66 (2H, m), 1.82-1.83 (6H, d), 1.83-1.89 (2H, m), 2.18-2.25 (2H, m), 3.15-3.22 (1H, td), 3.47-3.53 (1H, td), 3.63-3.67 (1H, dd), 3.76-3.79 (1H, d), 3.96-4.00 (1H, dd), 4.11-421 (2H, m), 4.57 (1H, bs), 6.43-6.45 (1H, d), 6.72 (1H, s), 7.32-7.34 (2H, d), 7.46-7.48 (2H, q), 7.65-7.68 (2H, d), 8.83 (1H, s), 8.74-8.75 (2H, q).

Embodiment 58d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-1.23 (3H, d), 1.82-1.83 (6H, d), (3.16-3.23 3H, m), 3.44-3.48 (2H, q), (3.48-3.53 1H, td), 3.63-3.67 (1H, dd), (3.76-3.79 1H, d), 3.96-4.00 (1H, dd), (4.18-4.22 1H, d), 4.56 (1H, bs), (4.71-4.74 1H, t), 6.22-6.25 (1H, t), (6.72 1H, s), 7.33-7.36 (2H, d), 7.47-7.48 (2H, q), (7.66-7.68 2H, d), 8.74-8.75 (2H, q), 8.77 (1H, s).

Embodiment 58e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22-123 (3H, d), 1.82-1.83 (6H, d), (2.19 6H, s), 2.32-2.36 (2H, t), (3.15-3.22 3H, m), 3.47-3.53 (1H, td), (3.63-3.67 1H, dd), 3.76-3.79 (1H, d), (3.96-4.00 1H, dd), 4.18-4.21 (1H, d), (4.56 1H, bs), 6.13-6.15 (1H, t), (6.72 1H, s), 7.33-7.35 (2H, d), 7.47-7.48 (2H, q), (7.66-7.68 2H, d), 8.74-8.75 (2H, q), 8.85 (1H, s).

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2- base] phenyl] phenyl carbamate

In room temperature; under air conditions; by phenyl chloroformate (0.177mL; 1.41mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline (0.640g; 1.41mmol) and sodium bicarbonate (in 0.178g, 2.12mmol) diox (175mL).The slurries that obtain are at room temperature stirred 2 hours.Add the phenyl chloroformate (2x0.005mL) of two other part, react in stirring at room.Then water is joined in reaction, cross filter solid, dry in 55 ℃ of vacuum drying ovens, obtain needed material type brown solid (0.758g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23-1.24 (3H, d), 1.83-1.84 (6H, d), 3.17-3.24 (1H, td), (3.48-3.53 1H, td), 3.64-3.67 (1H, dd), 3.76-3.79 (1H, d), (3.97-4.00 1H, dd), 4.21-4.24 (1H, d), 4.59 (1H, bs), (6.76 1H, s), 7.24-7.31 (3H, m), 7.43-7.50 (6H, m), (7.75-7.78 2H, d), 8.74-8.76 (2H, d), 10.39 (1H, s).

the LCMS spectrum: MH+572, retention time 2.82 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine) palladium (the II) (0.050g of trans-dichloro; 0.07mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine (0.560g; 1.41mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) 18%DMF of aniline (0.464g, 2.12mmol) and sodium carbonate (3.53mL, 7.05mmol) is (at DME: water: in the mixture (30mL) of ethanol (7: 3: 2)).The solution obtained 80 ℃ of stirrings 5 hours.Make to react cooling, and distribute between ethyl acetate and water.Extract water layer twice by ethyl acetate, dry (MgSO ₄) organism that merges, to filter, evaporation, obtain needed material (0.640g), and it just need not be further purified and can use.

the LCMS spectrum: MH+454, retention time 2.18 minutes

The chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-pyridin-4-yl alkylsulfonyl third-2-yl) pyrimidine

At 0 ℃; under air conditions; by methyl iodide (0.164mL; 2.63mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine (0.970g; 2.63mmol) and DMF (15mL) mixture of sodium tert-butoxide (0.253g, 2.63mmol) in.Add extra sodium tert-butoxide (0.253g, 2.63mmol) and methyl iodide (0.164mL, 2.63mmol), at 0 ℃ by the solution stirring that obtains 1 hour.Make solution be warmed at leisure room temperature.Add water and ethyl acetate, separation solution.Extract water layer twice by ethyl acetate, dry (MgSO ₄) organism that merges, filter, be evaporated on silica gel.Crude product is carried out to silica gel chromatography, with 0-60% ethyl acetate/DCM wash-out, obtain needed material yellow oil, when standing, it solidifies (0.56g).

the NMR spectrum: ¹h NMR (400.13MHz, CDCl ₃) δ 1.27-1.29 (3H, d), 1.71-1.72 (6H, d), (3.22-3.29 1H, td), 3.48-3.54 (1H, td), (3.64-3.67 1H, dd), 3.73-3.76 (1H, d), (3.95-3.98 2H, dd), 4.29 (1H, bs), (6.63 1H, s), 7.39-7.41 (2H, dd), 8.78-8.79 (2H, dd).

the LCMS spectrum: MH+397, retention time 1.73 minutes

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-preparation of 6-(pyridin-4-yl alkylsulfonyl methyl) pyrimidine.

embodiment 59:

3-ethyl-1-[4-[4-(2-hydroxyethyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

By N-[4-[4-(2-hydroxyethyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (0.073g; 0.14mmol), ethamine (0.70mmol) and triethylamine (0.42mmol) mix, and 50 ℃, in air atmosphere heated overnight.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (0.047g) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.06-1.09 (3H, t), 1.24-1.25 (3H, d), (3.10-3.17 2H, m), 3.19-3.26 (1H, td), (3.47-3.53 3H, m), 3.64-3.67 (1H, dd), (3.77-3.80 1H, d), 3.90-3.94 (2H, q), (3.97-4.01 1H, dd), 4.15-4.19 (1H, d), (4.48 1H, bs), 4.50 (2H, s), (5.17-5.20 1H, t), 6.15-6.18 (1H, t), 6.76 (1H, s), (7.49-7.51 2H, d), 8.20-8.23 (2H, d), 8.66 (1H, s).

the LCMS spectrum: MH+464, retention time 1.62 minutes

Use similar fashion, by N-[4-[4-(2-hydroxyethyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 59a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.25 (3H, d), 1.57-1.69 (2H, m), (1.82-1.92 2H, m), 2.18-2.25 (2H, m), (3.18-3.27 1H, td), 3.47-3.53 (3H, m), (3.64-3.67 1H, dd), 3.77-3.79 (1H, d), (3.90-3.94 2H, q), 3.97-4.01 (1H, dd), (4.10-4.18 2H, m), 4.47 (1H, bs), (4.50 2H, s), 5.17-5.20 (1H, t), (6.46-6.48 1H, d), 6.76 (1H, s), (7.47-7.49 2H, d), 8.20-8.22 (2H, d), 8.56 (1H, s).

Embodiment 59b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.35-1.37 (3H, d), 3.37 (6H, s), (2.56-2.59 2H, t), 3.31-3.38 (5H, m), (3.49 2H, s), 3.56-3.63 (1H, td), (3.72-3.76 1H, dd), 3.82-3.85 (1H, d), (4.03-4.07 1H, dd), 4.14-4.17 (2H, t), 4.17-4.20 (1H, d), (4.42-4.43 2H, d), 4.48 (1H, bs), 5.61 (1H, bs), (6.45 1H, s), 7.46-7.48 (2H, d), 8.19-8.21 (2H, d).

Test (c): embodiment (59a) 0.037 μ M; Embodiment (57b) 0.043 μ M.

N-[4-[4-(2-hydroxyethyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(2-hydroxyethyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

In room temperature; under air conditions; by phenyl chloroformate (0.046mL; 0.36mmol) join 2-[[2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethanol (0.143g; 0.36mmol) and sodium bicarbonate (in 0.046g, 0.55mmol) diox (20mL) mixture.The slurries that obtain are at room temperature stirred 2 hours.Add water, with DCM, extract mixture three times.Dry (MgSO ₄) organism that merges, filtering, vacuum concentration, obtain needed material (0.228g) yellow solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.24-1.26 (3H, d), 3.20-3.26 (1H, td), (3.51-3.54 3H, m), 3.58 (1H, s), (3.64-3.68 1H, dd), 3.77-3.80 (1H, d), (3.90-3.95 2H, m), 3.97-4.01 (1H, dd), (4.18-4.21 1H, d), 4.48 (1H, bs), (4.52 2H, s), 5.18-5.20 (1H, t), (6.80 1H, s), 7.25-7.30 (3H, m), 7.43-7.47 (2H, t), (7.63-7.65 3H, d), 8.31-8.33 (2H, d), 10.44 (1H, s).

the LCMS spectrum: MH+513, retention time 2.28 minutes

2-[[2-(4-aminophenyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] second alcohol

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine) palladium (the II) (0.013g of trans-dichloro; 0.02mmol) join the chloro-6-[(3S of 2-[[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethanol (0.122g; 0.36mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) 18%DMF of aniline (0.119g, 0.54mmol) and sodium carbonate (0.908mL, 1.82mmol) is (at DME: water: in the mixture (10mL) of ethanol (7: 3: 2)) in solution.The solution obtained 80 ℃ of stirrings 2 hours.Make to react cooling, and distribute between ethyl acetate and water.With ethyl acetate abstraction reaction mixture twice, dry (MgSO ₄) organism that merges, filtering, vacuum concentration, obtain needed material (0.143g).

the LCMS spectrum: MH+393, retention time 1.30 minutes

the chloro-6-[(3S of 2-[[2-)-3-methylmorpholine-4-yl] pyrimidine-4-yl] methyl sulphonyl] ethanol

By 30% aqueous hydrogen peroxide solution (0.225mL, 7.29mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[2-(oxane-2-base oxygen base) the ethyl sulfanylmethyl] pyrimidine (0.141g, 0.36mmol), sodium tungstate dihydrate (2.4mg, 0.0073mmol) (in water (0.2mL) and 2N sulfuric acid (0.011mL)) 1, in the stirred solution of 4-diox (1.4mL) and methyl alcohol (1.4mL), and be heated to 55 ℃ under air conditions.By the solution stirring that obtains 4 hours, then add water (50mL), cooling reaction at 55 ℃.Add 10% aqueous solution of Sodium Pyrosulfite, then with DCM, extract complete soln.Dry (MgSO ₄) organism, filtering, vacuum concentration, obtain the opaque oil of needed material (0.198g).

the LCMS spectrum: MH+336, retention time 1.18 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[2-(oxane-2-base oxygen base) the ethyl sulfanylmethyl] phonetic pyridine

In room temperature, under air conditions, by DIPEA (0.211g, 1.63mmol) dropwise join the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (0.231g, 0.65mmol) and the acetonitrile solution of 2-(tetrahydrochysene-2H-pyrans-2-base oxygen base) sulfur alcohol (0.133g, 0.82mmol) in.By the solution that obtains stirring at room 1 hour.Except desolventizing, use the DCM diluted reaction mixture, wash with water.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with flash chromatography on silica gel, with 0-2% methyl alcohol/DCM wash-out, obtain needed material water white oil (0.141g).

The NMR spectrum: ¹h NMR (400.13MHz, CDCl ₃) δ 1.24-1.26 (3H, d), 1.40-1.55 (4H, m), (1.60-1.67 1H, m), 1.69-1.77 (1H, m), (2.68-2.71 2H, t), 3.17-3.24 (1H, td), (3.41-3.47 2H, m), 3.50-3.58 (1H, m), 3.59 (2H, s), (3.62-3.63 1H, d), 3.69-3.72 (1H, d), 3.76-3.86 (2H, m), (3.91-3.95 1H, dd), 3.97 (1H, bs), 4.25 (1H, bs)<4.52-4.54 (1H, t), 6.44 (1H, s).

The LCMS spectrum: m/z (ES+) (M+H) +=386; HPLC tR=2.11min.MH+386, retention time 2.11 minutes

embodiment 60:

3-cyclobutyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(third-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

By cyclobutyl amine (70mg; 0.98mmol) join (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate (100mg; 0.20mmol) and DMF (2mL) solution of triethylamine (0.082mL, 0.59mmol) in.The solution obtained 50 ℃ of stirrings 2 hours.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (57mg) white solid.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.35 (3H, d), (1.37 3H, d), 1.57-1.68 (2H, m), (1.81-1.91 2H, m), 2.18-2.25 (2H, m), (3.18-3.25 1H, m), 3.25-3.27 (1H, m), (3.47-3.54 2H, m), 3.65 (1H, dd), (3.78 1H, d), 3.99 (1H, dd), (4.11-4.17 2H, m), 4.46 (2H, s), (6.47 1H, d), 6.77 (1H, s), (7.48 2H, d), 8.18 (2H, d), 8.55 (1H, s)

the LCMS spectrum: MH+488, retention time 1.99 minutes.

Use similar fashion, by (4-{4-[(sec.-propyl alkylsulfonyl) methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) phenyl carbamate or N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 60a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (3H, t), 1.25 (3H, d), (1.35 3H, d), 1.37 (3H, d), (1.43-1.49 2H, m), 3.04-3.07 (1H, m), (3.21-3.26 1H, m), 3.47-3.52 (2H, m), (3.64-3.67 1H, m), 3.67-3.87 (3H, m), (3.98-4.00 1H, m), 4.20 (1H, d), (4.47 2H, s), 6.23 (1H, t), 6.79 (1H, s), (7.50 2H, d), 8.18 (2H, d), 8.66 (1H, s)

Embodiment 60b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (6H, d), 1.25 (3H, d), (1.35 3H, d), 1.37 (3H, d), (1.71 1H, quintet), 2.95 (2H, t), (3.20-3.27 1H, m), 3.47-3.54 (3H, m), (3.65 1H, dd), 3.78 (1H, d), (3.99 1H, dd), 4.19 (1H, d), (4.47 2H, s), 6.27 (1H, t), 6.79 (1H, s), (7.50 2H, d), 8.18 (2H, d), 8.66 (1H, s)

Embodiment 60c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.35-1.37 (6H, m), 1.60 (2H, quintets), (3.17 2H, q), 3.21-3.25 (1H, m), 3.45-3.54 (4H, m), (3.63-3.67 1H, m), 3.78 (1H, d), 3.97-4.00 (1H, m), 4.17 (1H, d), 4.46-4.49 (3H, m), (6.21 1H, t), 6.77 (1H, s), 7.49 (2H, d), 8.18 (2H, d), 8.70 (1H, s)

Embodiment 60d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.36 (3H, d), 1.38 (3H, d), (3.20-3.27 2H, m), 3.48-3.55 (2H, m), 3.66 (1H, dd), (3.79 1H, d), 4.00 (1H, dd), 4.19 (1H, d), 4.48 (2H, s), 6.80 (1H, s), (7.59 2H, d), 7.64-7.70 (4H, m), 8.27 (2H, d), 9.04 (1H, s), 9.15 (1H, s)

Embodiment 60e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.37 (3H, d), (1.38 3H, d), 3.20-3.24 (1H, m), (3.27 1H, s), 3.48-3.56 (2H, m), (3.66 1H, dd), 3.79 (1H, d), (4.00 1H, dd), 4.19 (1H, d), (4.49 2H, s), 6.81 (1H, s), (7.02-705 1H, m), 7.55 (1H, d), (7.65 2H, d), 7.75-7.79 (1H, m), (8.27-8.31 3H, m), 9.47 (1H, s), 10.63 (1H, s)

Embodiment 60f: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.11 (6H, d), 1.24 (3H, d), 1.35 (3H, d), (1.37 3H, d), 3.19-3.25 (2H, m), 3.47-3.54 (2H, m), (3.65 1H, dd), 3.73-3.82 (2H, m), 3.99 (1H, dd), 4.17 (1H, d), 4.46 (2H, s), (6.07 1H, d), 6.77 (1H, s), 7.48 (2H, d), 8.18 (2H, d), 8.52 (1H, s)

Embodiment 60g: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.24 (6H, s), (1.35 3H, d), 1.37 (3H, d), (3.18 1H, d), 3.22-3.27 (1H, m), (3.39 1H, d), 3.47-3.55 (2H, m), (3.64-3.66 1H, m), 3.78 (1H, d), (3.98-4.00 1H, m), 4.17 (1H, d), (4.46 2H, s), 4.95 (1H, t), (6.01 1H, s), 6.77 (1H, s), (7.46 2H, d), 8.17 (2H, d), 8.73 (1H, s)

Embodiment 60h: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.36 (3H, d), (1.38 3H, d), 3.18-3.25 (2H, m), (3.48-3.54 2H, m), 3.66 (1H, dd), (3.78 1H, d), 3.79 (3H, s), (3.99 1H, dd), 4.18 (1H, d), (4.47 2H, s), 6.78 (1H, s), (7.39 1H, s), 7.55 (2H, d), 7.76 (1H, s), (8.22 2H, d), 8.40 (1H, s), 8.83 (1H, s)

Embodiment 60i: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), (1.79 6H, d), 2.66 (3H, d), 3.16-3.24 (1H, m), (3.50 1H, dt), 3.65 (1H, dd), 3.70-3.78 (2H, m), (3.98 1H, dd), 4.22 (1H, d), 4.56 (1H, s), (6.06-6.08 1H, m), 6.78 (1H, s), 7.51 (2H, d), 8.23 (2H, d), 8.74 (1H, s)

Embodiment 60j: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.09 (3H, d), (1.12 3H, d), 1.22 (3H, d), (1.79 6H, d), 3.10-3.15 (2H, m), (3.16-3.24 1H, m), 3.50 (1H, dt), (3.65 1H, dd), 3.70-3.78 (2H, m), (3.98 1H, dd), 4.22 (1H, d), (4.56 1H, s), 6.16 (1H, t), 6.78 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.66 (1H, s)

Embodiment 60k: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.08-1.13 (12H, m), 1.22 (3H, d), 1.79 (6H, d), 3.18-3.24 (2H, m), 3.50 (1H, dt), (3.65 1H, dd), 3.70-3.82 (2H, m), 3.98 (1H, dd), 4.22 (1H, d), 4.55 (1H, s), (6.06 1H, d), 6.78 (1H, s), 7.49 (2H, d), 8.23 (2H, d), 8.53 (1H, s)

Embodiment 60l: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.33-0.37 (2H, m), 0.56-0.60 (2H, m), (1.02 3H, d), 1.05 (3H, d), (1.15 3H, d), 1.73 (6H, d), (2.47-2.52 1H, m), 3.14 (1H, dt), (3.43 1H, dt), 3.58 (1H, dd), (3.63-3.72 2H, m), 3.89-3.92 (1H, m), (4.16 1H, d), 4.50 (1H, s), (6.36 1H, d), 6.72 (1H, s), (7.44 2H, d), 8.16 (2H, d), 8.46 (1H, s)

Embodiment 60m: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), (1.22 3H, d), 1.57-1.66 (2H, m), (1.79 6H, d), 1.83-1.90 (2H, m), (2.18-2.25 2H, m), 3.20 (1H, dt), (3.50 1H, dt), 3.65 (1H, dd), (3.70-3.78 2H, m), 3.98 (1H, dd), (4.12-4.18 1H, m), 4.22 (1H, d), (4.55 1H, s), 6.46 (1H, d), (6.78 1H, s), 7.48 (2H, d), (8.23 2H, d), 8.56 (1H, s)

Embodiment 60n: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), 1.22 (3H, d), (1.79 6H, d), 3.16-3.24 (2H, m), 3.44-3.53 (3H, m), (3.65 1H, dd), 3.70-3.78 (2H, m), 3.98 (1H, dd), (4.22 1H, d), 4.55 (1H, s), 4.73 (1H, t), (6.26 1H, t), 6.78 (1H, s), 7.50 (2H, d), 8.24 (2H, s), 8.80 (1H, s)

Embodiment 60o: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.13 (3H, d), (1.22 3H, d), 1.24 (6H, s), (1.79 6H, d), 3.17-3.24 (1H, m), (3.39 2H, d), 3.50 (1H, dt), (3.65 1H, dd), 3.71-3.78 (2H, m), (3.98 1H, dd), 4.22 (1H, d), (4.56 1H, s), 4.95 (1H, t), (6.01 1H, s), 6.78 (1H, s), (7.46 2H, d), 8.22 (2H, d), 8.73 (1H, s)

Embodiment 60p: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), (1.22 3H, d), 1.79 (6H, d), (2.18 6H, s), 2.32-2.35 (2H, m), (3.17-3.22 3H, m), 3.50 (1H, dt), (3.66 1H, dd), 3.70-3.78 (2H, m), (3.98 1H, dd), 4.22 (1H, d), (4.57 1H, s), 6.16 (1H, t), 6.78 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.89 (1H, s)

Embodiment 60q: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (3H, t), 1.09 (3H, d), (1.12 3H, d), 1.22 (3H, d), (1.41-1.50 2H, m), 1.79 (6H, d), (3.04-3.09 2H, m), 3.18-3.24 (2H, m), (3.50 1H, dt), 3.65 (1H, dd), (3.70-3.78 1H, m), 3.98 (1H, dd), (4.22 1H, d), 4.56 (1H, s), (6.21 1H, t), 6.78 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.65 (1H, s)

Embodiment 60r: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (6H, d), 1.09 (3H, d), (1.12 3H, d), 1.22 (3H, d), (1.67-1.74 1H, m), 1.79 (6H, d), (2.95 2H, t), 3.22 (1H, dd), (3.50 1H, dt), 3.65 (1H, dd), (3.70-3.79 2H, m), 3.98 (1H, dd), (4.22 1H, d), 4.55 (1H, s), (6.25 1H, t), 6.78 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.64 (1H, s)

Embodiment 60s: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), (1.22 3H, d), 1.60 (2H, quintets), (1.79 6H, d), 3.15-3.24 (3H, m), (3.45-3.53 3H, m), 3.65 (1H, dd), (3.70-3.78 2H, m), 3.98 (1H, dd), (4.22 1H, d), 4.47 (1H, t), (4.55 1H, s), 6.21 (1H, t), 6.78 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.71 (1H, s)

Embodiment 60t: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.10 (3H, d), 1.13 (3H, d), (1.23 3H, d), 1.81 (6H, d), (3.22-3.25 1H, m), 3.66 (1H, dd), (3.71-3.79 1H, m), 3.97-4.00 (2H, m), (4.04-4.08 1H, m), 4.24 (1H, d), 4.57 (1H, s), (6.82 1H, s), 7.59 (2H, d), 7.64-7.70 (4H, m), (8.31 2H, d), 9.04 (1H, s), 9.14 (1H, s)

Embodiment 60u: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.10 (3H, d), 1.14 (3H, d), (1.24 3H, d), 1.81 (6H, d), (3.18-3.27 1H, m), 3.51 (1H, dt), (3.66 1H, ddd), 3.73-3.80 (2H, m), (3.99 1H, dd), 4.24 (1H, d), (4.57 1H, s), 6.82 (1H, s), (7.02-7.05 1H, m), 7.57 (1H, t), (7.65 2H, d), 7.74-7.79 (1H, m), (8.29-8.33 3H, m), 9.45 (1H, s), 10.59 (1H, s)

Embodiment 60v: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.13 (3H, d), (1.23 3H, d), 1.80 (6H, d), (3.18-3.24 2H, m), 3.51 (1H, dt), (3.64-3.68 1H, m), 3.71-3.78 (1H, m), (3.79 3H, s), 3.98 (1H, dd), (4.23 1H, d), 4.56 (1H, s), (6.80 1H, s), 7.39 (1H, s), (7.55 2H, d), 7.76 (1H, s), (8.27 2H, d), 8.39 (1H, s), 8.84 (1H, s)

Test (c): embodiment (60) 1.0 μ M; Embodiment (60a) 3.3 μ M; Embodiment (60b) 1.8 μ M; Embodiment (60b) 1.8 μ M; Embodiment (60c) 0.77 μ M; Embodiment (60d) 0.59 μ M; Embodiment (60e) 1.3 μ M; Embodiment (60f) 0.87 μ M; Embodiment (60g) 0.22 μ M; Embodiment (60h) 1.9 μ M; Embodiment (60i) 0.12 μ M; Embodiment (60j) 0.19 μ M; Embodiment (60k) 0.18 μ M; Embodiment (60l) 0.064 μ M; Embodiment (60m) 0.059 μ M; Embodiment (60n) 0.15 μ M; Embodiment (60o) 0.086 μ M; Embodiment (60p) 0.14 μ M; Embodiment (60q) 0.16 μ M; Embodiment (60r) 0.21 μ M; Embodiment (60s) 0.3 μ M; Embodiment (60t) 1.4 μ M; Embodiment (60u) 0.16 μ M; Embodiment (60v) 0.27 μ M.

(4-{4-[(sec.-propyl alkylsulfonyl) methyl had before been described]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base } phenyl) preparation of phenyl carbamate.

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate

In nitrogen atmosphere; by phenyl chloroformate (0.42mL; 3.34mmol) dropwise join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline (1.4g; 3.34mmol) and sodium carbonate (in 0.421g, 5.02mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture, and be dissolved in again in DCM (50mL) water (50mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and it is ground with diethyl ether, obtains needed product (1.57g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), 1.23 (3H, d), (1.80 6H, d), 3.17-3.25 (1H, m), 3.47-3.54 (1H, m), (3.66 1H, dd), 3.72-3.79 (2H, m), 3.97-4.00 (1H, m), (4.24 1H, d), 4.57 (1H, s), 6.82 (1H, s), (7.25 3H, d), 7.45 (2H, t), 7.64 (2H, d), 8.34 (2H, d), 10.43 (1H, s)

the LCMS spectrum: MH+539, retention time 2.76 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (116mg of dichloro; 0.17mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine (1.2g; 3.32mmol) and the 18%DMF of sodium carbonate (5mL, 10.00mmol) (at DME: water: in the mixture (20mL) of ethanol (7: 3: 2)) in solution.The solution obtained 90 ℃ of stirrings 4 hours.By ethyl acetate for reaction mixture (20mL) dilution, and water (2x20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 5, to 60% ethyl acetate/isohexane, obtains needed material paste solid (1.40g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.09 (3H, d), 1.12 (3H, d), 1.21 (3H, d), 1.77 (6H, d), 3.13-3.21 (1H, m), (3.46-3.52 1H, m), 3.62-3.66 (1H, m), 3.69-3.77 (2H, m), 3.97 (1H, dd), 4.19 (1H, d), (4.53 1H, d), 5.55 (2H, s), 6.61 (2H, d), 6.69 (1H, s), 8.06 (2H, d)

the LCMS spectrum: MH+419, retention time 2.11 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-third-2-base alkylsulfonyl third-2-yl) pyrimidine

At-10 ℃; by methyl iodide (0.23mL; 3.75mmol) join sodium tert-butoxide (360mg; 3.75mmol) and the chloro-6-[(sec.-propyl of (3S)-4-{2-alkylsulfonyl) methyl] pyrimidine-4-yl-DMF (2mL) mixture of 3-methylmorpholine (2.5g, 7.49mmol) in.The dense suspension that obtains, stirring at room 15 minutes, is stirred being easy to.Methyl iodide (0.23mL, 3.75mmol) and sodium tert-butoxide (360mg, 3.75mmol) are joined in reaction again to the suspension obtained in stirring at room 15 minutes.By DCM for reaction mixture (20mL) dilution, and water (20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 50% ethyl acetate/DCM, obtains needed material beige solid (1.20g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.11 (3H, d), 1.14 (3H, d), 1.20 (3H, d), 1.70 (6H, s), 3.16-3.24 (1H, m), (3.41-3.48 1H, m), 3.59 (1H, dd), (3.67 1H, q), 3.72 (1H, d), (3.94 1H, dd), 4.06 (1H, d), (4.42 1H, s), 6.91 (1H, s)

the LCMS spectrum: MH+362, retention time 2.08 minutes

The chloro-6-[(sec.-propyl of (3S)-4-{2-alkylsulfonyl had before been described) methyl] pyrimidine-4-yl }-preparation of 3-methylmorpholine.

embodiment 61:

3-cyclobutyl-1-[4-[4-[(4-fluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

Cyclobutyl amine (0.96mmol) is joined to the N-[4-[4-[(4-fluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (120mg; 0.21mmol) and DMF (2mL) solution of triethylamine (0.090mL, 0.59mmol) in.The solution obtained 50 ℃ of stirrings 3 hours.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of MeCN as elutriant, obtain needed material (117mg) white solid.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.57-1.66 (2H, m), (1.81-1.91 2H, m), 2.18-2.24 (2H, m), (3.17 1H, dt), 3.47 (1H, dt), (3.63 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.08-4.19 (2H, m), (4.38 1H, s), 4.71 (2H, s), (6.42 1H, d), 6.64 (1H, s), (7.36 2H, d), 7.46 (2H, t), (7.78 2H, d), 7.85-7.89 (2H, m), 8.53 (1H, s)

the LCMS spectrum: MH+540, retention time 2.25 minutes

Use similar fashion, by the N-[4-[4-[(4-fluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 61a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.20 (3H, d), 3.09-3.21 (3H, m), (3.49 1H, dd), 3.63 (1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.11 (1H, d), 4.37 (1H, s), (4.71 2H, s), 6.13 (1H, t), 6.64 (1H, s), (7.38 2H, d), 7.46 (2H, t), 7.78 (2H, d), 7.85-7.88 (2H, m), 8.64 (1H, s)

Embodiment 61b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.11 (6H, d), 1.20 (3H, d), 3.18 (1H, dt), (3.48 1H, dt), 3.63 (1H, dd), 3.73-3.81 (2H, m), (3.97 1H, dd), 4.11 (1H, d), 4.38 (1H, s), (4.71 2H, s), 6.03 (1H, d), 6.64 (1H, s), (7.36 2H, d), 7.46 (2H, t), 7.79 (2H, d), 7.85-7.89 (2H, m), 8.51 (1H, s)

Embodiment 61c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 3.13-3.21 (3H, m), 3.44-3.50 (3H, m), (3.63 1H, dd), 3.76 (1H, d), 3.97 (1H, dd), (4.11 1H, d), 4.37 (1H, s), 4.71-4.74 (3H, m), 6.22 (1H, t), 6.64 (1H, s), (7.38 2H, d), 7.46 (2H, t), 7.79 (2H, d), 7.85-7.89 (2H, m), 8.78 (1H, s)

Embodiment 61d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.24 (6H, s), (3.14-3.20 2H, m), 3.39 (1H, d), (3.48 1H, t), 3.63 (1H, d), (3.76 1H, d), 3.97 (1H, d), (4.11 1H, d), 4.37 (1H, s), (4.72 2H, s), 4.95 (1H, s), (5.98 1H, s), 6.64 (1H, s), (7.34 2H, d), 7.46 (2H, t), (7.78 2H, d), 7.86-7.89 (2H, m), 8.72 (1H, s)

Embodiment 61e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 2.18 (6H, s), (2.34 2H, t), 3.14-3.21 (3H, m), (3.48 1H, dt), 3.63 (1H, d), (3.76 1H, d), 3.97 (1H, d), (4.04-4.12 1H, m), 4.37 (1H, s), (4.71 2H, s), 6.13 (1H, t), (6.64 1H, s), 7.37 (2H, d), 7.46 (2H, t), (7.78 2H, d), 7.85-7.89 (2H, m), 8.86 (1H, s)

Embodiment 61f: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (3H, t), 1.20 (3H, d), (1.46 2H, sextet), 3.06 (2H, q), (3.17 1H, dt), 3.48 (1H, dt), (3.63 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.11 (1H, d), (4.37 1H, s), 4.71 (2H, s), (6.17 1H, t), 6.64 (1H, s), (7.38 2H, d), 7.46 (2H, t), (7.79 2H, d), 7.86-7.89 (2H, m), 8.62 (1H, s)

Embodiment 61g: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.89 (6H, d), 1.20 (3H, d), (1.67-1.72 1H, m), 2.94 (2H, t), (3.17 1H, t), 3.48 (1H, t), (3.63 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.11 (1H, d), (4.38 1H, s), 4.72 (2H, s), (6.21 1H, t), 6.65 (1H, s), (7.38 2H, d), 7.46 (2H, t), (7.79 2H, d), 7.85-7.89 (2H, m), 8.62 (1H, s)

Embodiment 61h: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.60 (2H, quintets), (3.14-3.21 3H, m), 3.45-3.51 (3H, m), (3.63 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.11 (1H, d), (4.38 1H, s), 4.47 (1H, t), (4.71 2H, s), 6.17 (1H, t), (6.64 1H, s), 7.38 (2H, d), 7.46 (2H, t), (7.78 2H, d), 7.85-7.89 (2H, m), 8.68 (1H, s)

Embodiment 61i: ¹h NMR (400.132MHz, DMSO-d ₆) δ 9.10 (1H, s), 9.02 (1H, s), 7.86-7.89 (4H, m), 7.64-7.70 (4H, m), 7.45-7.49 (4H, m), (6.68 1H, s), 4.73 (2H, s), 4.39 (1H, s), 4.13 (1H, d), 3.98 (1H, d), (3.77 1H, d), 3.64 (1H, dd), 3.49 (1H, td), 3.19 (1H, td), 1.21 (3H, d)

Embodiment 61j: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 3.19 (1H, dt), 3.50 (1H, dt), (3.64 1H, d), 3.77 (1H, d), 3.98 (1H, d), (4.12 1H, d), 4.39 (1H, s), 4.74 (2H, s), (6.68 1H, s), 7.02-7.05 (1H, m), 7.45-7.59 (5H, m), (7.75-7.79 1H, m), 7.86-7.90 (4H, m), 8.30 (1H, d), 9.42 (1H, s), 10.52 (1H, s)

Embodiment 61k: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.27 (3H, d), 1.84 (6H, d), 2.71 (3H, d), (3.19-3.26 1H, m), 3.52-3.57 (1H, m), 3.70 (1H, dd), (3.82 1H, d), 4.02 (1H, dd), 4.22 (1H, d), (4.59 1H, s), 6.09-6.10 (1H, m), 6.73 (1H, s), (7.36 2H, t), 7.44 (2H, d), 7.60-7.63 (2H, m), 7.83 (2H, d), 8.76 (1H, s)

Embodiment 61l: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.22 (3H, d), 1.79 (6H, d), (3.09-3.20 3H, m), 3.50 (1H, t), 3.65 (1H, d), (3.77 1H, d), 3.98 (1H, d), 4.17 (1H, d), (4.55 1H, s), 6.13 (1H, t), 6.68 (1H, s), (7.31 2H, t), 7.38 (2H, d), 7.54-7.58 (2H, m), 7.78 (2H, d), 8.62 (1H, s)

Embodiment 61m: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.11 (6H, d), 1.22 (3H, d), 1.79 (6H, d), (3.11-3.20 1H, m), 3.50 (1H, t), 3.65 (1H, d), (3.75-3.80 2H, m), 3.98 (1H, d), 4.17 (1H, d), (4.54 1H, s), 6.03 (1H, d), 6.68 (1H, s), (7.31 2H, t), 7.36 (2H, d), 7.54-7.58 (2H, m), 7.78 (2H, d), 8.50 (1H, s)

Embodiment 61n: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.57-1.66 (2H, m), (1.78 6H, d), 1.82-1.91 (2H, m), (2.14-2.25 2H, m), 3.17 (1H, dt), (3.49 1H, dt), 3.64 (1H, dd), (3.77 1H, d), 3.97 (1H, dd), (4.09-4.18 2H, m), 4.54 (1H, s), (6.43 1H, d), 6.68 (1H, s), (7.31 2H, t), 7.36 (2H, d), (7.54-7.58 2H, m), 7.78 (2H, d), 8.53 (1H, s)

Embodiment 61o: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.79 (6H, d), (2.18 6H, s), 2.34 (2H, t), (3.13-3.21 3H, m), 3.50 (1H, t), (3.64 1H, d), 3.77 (1H, d), (3.98 1H, d), 4.17 (1H, d), (4.55 1H, s), 6.14 (1H, t), (6.67 1H, s), 7.31 (2H, t), 7.37 (2H, d), (7.54-7.58 2H, m), 7.78 (2H, d), 8.85 (1H, s)

Embodiment 61p: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.79 (6H, d), 3.14-3.21 (3H, m), (3.44-3.53 3H, m), 3.65 (1H, dd), 3.77 (1H, d), (3.98 1H, dd), 4.17 (1H, d), 4.55 (1H, s), (4.72 1H, t), 6.23 (1H, t), 6.68 (1H, s), (7.31 2H, t), 7.37 (2H, d), 7.54-7.58 (2H, m), 7.78 (2H, d), 8.77 (1H, s)

Embodiment 61q: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.62-0.67 (2H, m), (1.22 3H, d), 1.79 (6H, d), (2.54-2.58 1H, m), 3.17 (1H, dt), (3.49 1H, dt), 3.65 (1H, dd), (3.77 1H, d), 3.97 (1H, dd), (4.17 1H, d), 4.55 (1H, s), (6.40 1H, d), 6.68 (1H, s), (7.31 2H, t), 7.39 (2H, d), (7.54-7.58 2H, m), 7.79 (2H, d), 8.50 (1H, s)

Test (c): embodiment (61) 0.33 μ M; Embodiment (61a) 0.75 μ M; Embodiment (61b) 0.038 μ M; Embodiment (61c) 0.41 μ M; Embodiment (61d) 0.18 μ M; Embodiment (61e) 0.12 μ M; Embodiment (61g) 0.45 μ M; Embodiment (61h) 0.79 μ M; Embodiment (61k) 0.12 μ M; Embodiment (61l) 0.099 μ M; Embodiment (61m) 0.03 μ M; Embodiment (61n) 0.038 μ M; Embodiment (61o) 0.045 μ M; Embodiment (61q) 0.077 μ M;

The N-[4-[4-[(4-fluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

the N-[4-[4-[(4-fluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base] phenyl carbamate

In nitrogen atmosphere; by phenyl chloroformate (0.474mL; 3.77mmol) dropwise join the 4-[4-[(4-fluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.67g; 3.77mmol) and sodium bicarbonate (in 476mg, 5.66mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture, and be dissolved in again in DCM (50mL) water (50mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and it is ground with diethyl ether, obtains needed product (1.90g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 3.15-3.22 (1H, m), 3.35 (1H, s), (3.45-3.52 1H, m), 3.63 (1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.13 (1H, d), 4.39 (1H, s), 4.73 (2H, s), 6.69 (1H, s), (7.24-7.26 2H, m), 7.43-7.48 (4H, m), 7.53 (2H, d), 7.86-7.90 (4H, m), 10.39 (1H, s)

the LCMS spectrum: MH+563, retention time 2.65 minutes

the 4-[4-[(4-fluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (136mg of dichloro; 0.19mmol) join 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.107g; 5.05mmol) and the chloro-4-[(4-fluorophenyl of 2-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.50g; 3.89mmol) and the 18%DMF of sodium carbonate (5mL, 10.00mmol) (at DME: water: ethanol (7: 3: 2) (20mL) in) solution in.The solution obtained 90 ℃ of stirrings 4 hours.By ethyl acetate for reaction mixture (20mL) dilution, and water (2x20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 5, to 60% ethyl acetate/isohexane, obtains needed material paste solid (1.670g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18 (3H, d), 3.10-3.18 (1H, m), 3.44-3.50 (1H, m), 3.62 (1H, dd), 3.75 (1H, d), (3.96 1H, dd), 4.07 (1H, d), 4.35 (1H, s), 4.67 (2H, s), 5.52 (2H, s), (6.49 2H, d), 6.53 (1H, s), 7.45 (2H, t), 7.62 (2H, d), 7.84-7.88 (2H, m)

the LCMS spectrum: MH+443, retention time 1.96 minutes

the chloro-4-[(4-fluorophenyl of 2-) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At 0 ℃; by triethylamine (1.117mL; 8.01mmol) join 2; the chloro-6-[(4-fluorophenyl of 4-bis-) alkylsulfonyl methyl] pyrimidine (2.34g; 7.29mmol) DCM (36.4mL) solution in; then with the DCM that adds (3S)-3-methylmorpholine (0.737g, 7.29mmol) in 15 minutes (20mL) solution.Then will react and at room temperature stir 16 hours.Water (50mL) washing reaction mixture, dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 50% ethyl acetate/DCM, obtains needed material beige solid (1.530g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.17 (3H, d), 3.13-3.20 (1H, m), (3.27-3.28 1H, m), 3.39-3.46 (1H, m), (3.57 1H, dd), 3.72 (1H, d), (3.93 1H, dd), 4.17 (1H, s), (4.65 2H, s), 6.71 (1H, s), (7.48 2H, t), 7.83-7.87 (2H, m)

the LCMS spectrum: MH+386, retention time 1.94 minutes

the chloro-6-[(4-fluorophenyl of 2,4-bis-) alkylsulfonyl methyl] pyrimidine

3-chlorine peroxybenzoic acid (3.78g, 21.89mmol) is joined to the chloro-6-[(4-fluorophenyl of 2,4-bis-in batches) sulfanylmethyl] in DCM (36.5mL) solution of pyrimidine (2.11g, 7.30mmol), at room temperature stirring reaction is 2 hours.With saturated sodium bicarbonate aqueous solution (50mL) washing reaction mixture, dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed product (2.35g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 4.99 (2H, s), 7.48-7.52 (2H, m), 7.76 (1H, s), 7.85-7.88 (2H, m)

the LCMS spectrum: MH+319, retention time 2.01 minutes

the chloro-6-[(4-fluorophenyl of 2,4-bis-) sulfanylmethyl] pyrimidine

Phosphorus oxychloride (15.2g, 99.1mmol) is joined to the 6-[(4-fluorophenyl) sulfanylmethyl]-1H-pyrimidine-2, in 4-diketone (2.5g, 9.91mmol), and by the solution return stirring that obtains 7 hours.Then will react cooling, phosphorus oxychloride is removed in decompression, obtains brown oil.It is dissolved in DCM, adds frozen water (50mL), then add solid sodium bicarbonate (until stopping bubbling).Extract water layer with DCM (2x50mL), dry (MgSO ₄) organism, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 40% ethyl acetate/isohexane, obtains the yellow colloid (2.11g) of needed material.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 4.21 (2H, s), 7.09-7.14 (2H, m), 7.34-7.38 (2H, m), 7.58 (1H, s)

the LCMS spectrum: M-H+287, retention time 2.51 minutes

the 6-[(4-fluorophenyl) sulfanylmethyl]-1H-pyrimidine-2, the 4-diketone

In room temperature, DBU (4.02mL, 26.91mmol) is joined in DMF (90mL) solution of 4-fluoro thiophenol (3.45g, 26.91mmol).The solution obtained is stirred 15 minutes at 20 ℃.Then add 6-(chloromethyl)-1H-pyrimidine-2,4-diketone (2.88g, 17.94mmol), stirring reaction 4 hours.Concentrated reaction mixture, with DCM (100mL) dilution, water (100mL) washing.With 2M hcl acidifying water layer, obtain white solid, by its filtration, wash with water, then vacuum-drying, obtain needed product (2.5g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 3.80 (2H, s), 5.20 (1H, s), 7.18-7.23 (2H, m), 7.45-7.49 (2H, m), 10.90 (1H, s), 10.93 (1H, s)

the LCMS spectrum: M-H-251, retention time 0.80 minute

N-[4-[4-[2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2- base] phenyl] phenyl carbamate

In nitrogen atmosphere; by phenyl chloroformate (0.482mL; 3.83mmol) dropwise join 4-[4-[2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.8g; 3.83mmol) and sodium bicarbonate (in 0.482g, 5.74mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture, and be dissolved in again in DCM (50mL) water (50mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and it is ground with diethyl ether, obtains needed material white solid (2.26g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.80 (6H, d), 3.18 (1H, dt), (3.50 1H, dt), 3.65 (1H, dd), 3.77 (1H, d), (3.98 1H, dd), 4.19 (1H, d), 4.55 (1H, s), 6.72 (1H, s), 7.24-7.33 (5H, m), (7.45 2H, t), 7.52 (2H, d), 7.55-7.58 (2H, m), 7.88 (2H, d), 10.39 (1H, s)

the LCMS spectrum: MH+591, retention time 3.10 minutes

4-[4-[2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (170mg of dichloro; 0.24mmol) join 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.376g; 6.28mmol) and the chloro-4-[2-of 2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (2g; 4.83mmol) and the 18%DMF of sodium carbonate (5mL, 10.00mmol) (at DME: water: ethanol (7: 3: 2) (20mL) in) solution in.The solution obtained 90 ℃ of stirrings 4 hours.By ethyl acetate for reaction mixture (20mL) dilution, and water (2x20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 5, to 60% ethyl acetate/isohexane, obtains needed material paste solid (1.80g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.76 (6H, d), 3.14 (1H, dt), 3.48 (1H, dt), 3.63 (1H, dd), (3.76 1H, d), 3.96 (1H, dd), 4.13 (1H, d), 4.51 (1H, d), 5.50 (2H, s), (6.49 2H, d), 6.58 (1H, s), 7.31 (2H, t), 7.54-7.57 (2H, m), 7.62 (2H, d)

the LCMS spectrum: MH+471, retention time 2.57 minutes

the chloro-4-[2-of 2-(4-fluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At-10 ℃; by methyl iodide (0.32mL; 5.20mmol) join sodium tert-butoxide (498mg; 5.20mmol) and the chloro-4-[(4-fluorophenyl of 2-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] in DMF (2mL) solution of pyrimidine (2g, 5.18mmol).The dense suspension that obtains, stirring at room 15 minutes, is stirred being easy to.Methyl iodide (0.32mL, 5.20mmol) and sodium tert-butoxide (498mg, 5.20mmol) are joined in reaction again to the suspension obtained in stirring at room 15 minutes.By DCM for reaction mixture (20mL) dilution, and water (20mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0 is to 50% ethyl acetate/DCM.The pure fraction of evaporate to dryness, obtain required product white solid (2.00g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 1.67 (6H, d), (3.17 1H, dt), 3.43 (1H, dt), (3.58 1H, dd), 3.72 (1H, d), (3.93 1H, dd), 4.01 (1H, d), (4.38 1H, s), 6.75 (1H, s), (7.44 2H, t), 7.58-7.61 (2H, m)

the LCMS spectrum: MH+414, retention time 2.35 minutes

The chloro-4-[(4-fluorophenyl of 2-had before been described) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 62:

3-cyclopropyl-1-[4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] urea

To N-[4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (150mg; 0.29mmol) DMF (2mL) solution in add triethylamine (0.120mL; 0.86mmol); then add cyclopropylamine (0.100mL; 1.44mmol), 50 ℃ of reacting by heating 2 hours.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material (85mg) white solid.

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.14 3H, t), 1.23 (3H, d), (1.79 6H, s), 2.55 (1H, m), (3.17-3.21 1H, m), 3.23 (2H, d), (3.46-3.50 1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.23 1H, d), 4.59 (1H, s), (6.43 1H, d), 6.75 (1H, s), (7.51 2H, d), 8.23 (2H, d), 8.54 (1H, s).

the LCMS spectrum: MH+488, retention time 2.19 minutes

Use similar fashion, by N-[4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 62a: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.14 (3H, t), 1.23 (3H, d), (1.54-1.68 2H, m), 1.78 (6H, s), (1.83-1.90 2H, d), 2.18-2.25 (2H, m), (3.17-3.21 1H, m), 3.23 (2H, q), (3.46-3.53 1H, m), 3.63-3.66 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), (4.15 1H, q), 4.22 (1H, d), (4.59 1H, s), 6.46 (1H, d), (6.75 1H, s), 7.48 (2H, d), (8.22 2H, d), 8.56 (1H, s)

Embodiment 62b: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.14 (3H, t), (1.23 3H, d), 1.78 (6H, d), (3.09-3.16 2H, m), 3.18 (1H, m), (3.22 2H, t), 3.46-3.53 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.23 (1H, d), (4.58 1H, s), 6.16 (1H, t), 6.75 (1H, d), (7.50 2H, d), 8.22 (2H, d), 8.66 (1H, s)

Embodiment 62c: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.14 (3H, t), (1.23 3H, d), 1.78 (6H, d), (3.09-3.16 2H, m), 3.18 (1H, m), (3.22 2H, t), 3.46-3.53 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.23 (1H, d), (4.58 1H, s), 6.16 (1H, t), 6.75 (1H, d), (7.50 2H, d), 8.22 (2H, d), 8.66 (1H, s)

Embodiment 62d: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.14 (3H, t), 1.22-1.24 (3H, m), (1.78 6H, s), 3.17 (1H, t), (3.20-3.22 2H, s), 3.24 (2H, m), (3.46 2H, q), 3.48 (1H, m), (3.63-3.66 1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.21-4.24 (1H, m), (4.57-4.60 1H, m), 4.73 (1H, t), (6.25 1H, t), 6.75 (1H, s), (7.48-7.51 2H, m), 8.23 (2H, d), 8.80 (1H, s)

Embodiment 62e: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.14 (3H, t), 1.27 (3H, d), 1.78 (6H, m), (2.68 3H, d), 3.18 (1H, m), 3.24 (2H, m), (3.46-3.53 1H, m), 3.63-3.66 (1H, m), 3.77 (1H, d), (3.96-4.00 1H, m), 4.23 (1H, d), 4.59 (1H, s), (6.07 1H, t), 6.75 (1H, s), 7.51 (2H, d), 8.22 (2H, d), 8.74 (1H, s)

Embodiment 62f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23-1.25 (3H, m), 1.35 (3H, t), (1.59-1.66 2H, m), 1.83-1.86 (2H, m), (2.19-2.23 2H, m), 3.18 (1H, m), (3.33 2H, m), 3.47-3.50 (1H, m), (3.66 1H, d), 3.76-3.79 (1H, m), (3.96 1H, d), 4.14 (2H, d), (4.45 3H, m), 6.47 (1H, d), 6.78 (1H, s), (7.47-7.49 2H, m), 8.18-8.20 (2H, m), 8.56 (1H, s)

Embodiment 62g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.24 (3H, d), (1.35 3H, t), 3.09-3.16 (2H, m), (3.21-3.26 1H, m), 3.33 (2H, d), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.14 (1H, d), (4.45 3H, s), 6.17 (1H, t), 6.77 (1H, s), (7.48-7.51 2H, m), 8.18-8.20 (2H, m), 8.66 (1H, s)

Embodiment 62h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23-1.25 (3H, m), 1.35 (3H, t), (2.18 6H, s), 2.34 (2H, t), (3.20 3H, q), 3.33 (2H, d), (3.47-3.53 1H, m), 3.63-3.67 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.14 (1H, d), (4.45 3H, s), 6.16 (1H, t), 6.77 (1H, s), (7.47-7.51 2H, m), 8.18-8.20 (2H, m), 8.89 (1H, s)

N-[4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

N-[4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

In nitrogen atmosphere; by phenyl chloroformate (0.373mL; 2.97mmol) dropwise join 4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.20g; 2.97mmol) and sodium bicarbonate (in 0.374g, 4.45mmol) diox (25mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture distributes between ethyl acetate (150mL) and water (150mL).Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material white solid (1.40g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.14 (3H, t), 1.24 (3H, d), 1.79 (6H, d), (3.24 3H, q), 3.47-3.54 (1H, m), 3.63-3.67 (1H, m), (3.77 1H, d), 3.96-4.00 (1H, m), 4.24 (1H, d), 4.60 (1H, s), 6.74-6.79 (2H, m), (7.24-7.27 2H, m), 7.43-7.47 (2H, m), 7.61-7.64 (2H, m), 8.33 (2H, d), 10.43 (1H, s)

the LCMS spectrum: MH+525, retention time 2.84 minutes

4-[4-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (0.360g of dichloro; 0.51mmol) join the chloro-4-of 2-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.784g; 5.13mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.404g; 6.41mmol) and the 18%DMF of sodium carbonate (12.82mL, 25.64mmol) (at DME: water: in the mixture (25mL) of ethanol (7: 3: 2)) in de-gassed solution.The solution obtained 85 ℃ of stirrings 2 hours.Concentrated reaction mixture, and distribute between DCM (150mL) and water (100mL), with salt solution (100mL) washing organism, dry (MgSO ₄), to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 2.5% methyl alcohol/DCM, obtains needed material brown solid (1.20g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.13 (3H, t), 1.21 (3H, d), 1.76 (6H, d), 3.14-3.18 (1H, m), 3.23 (2H, q), (3.45-3.52 1H, m), 3.62-3.65 (1H, m), 3.76 (1H, d), 3.95-3.99 (1H, m), 4.17-4.21 (1H, m), (4.54-4.56 1H, m), 5.54 (2H, d), 6.61 (1H, d), 6.62 (2H, t), 8.06 (2H, d)

the LCMS spectrum: MH+405, retention time 2.14 minutes

the chloro-4-of 2-(2-ethylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At-5 ℃; by methyl iodide (0.321mL; 5.13mmol) join sodium tert-butoxide (0.493g; 5.13mmol) and the chloro-4-of 2-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] in DMF (75mL) solution of pyrimidine (1.64g, 5.13mmol).Solution is stirred 15 minutes at-5 ℃.Further add methyl iodide (0.321mL, 5.13mmol) and sodium tert-butoxide (0.493g, 5.13mmol) ,-5 ℃ of stirring reactions 15 minutes.With DCM (200mL) diluted reaction mixture, water (2x100mL) and salt solution (100mL) washing.Dry (MgSO ₄) organism, to filter, evaporation, obtain needed material brown solid (1.784g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.16 (3H, t), 1.21 (3H, d), (1.69 6H, s), 3.15-3.19 (2H, m), (3.14-3.24 1H, m), 3.41-3.48 (1H, m), (3.57-3.61 1H, m), 3.72 (1H, d), (3.92-3.95 1H, m), 4.05-4.44 (2H, m), 6.87 (1H, s)

the LCMS spectrum: MH+348, retention time 1.79 minutes

the chloro-4-of 2-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, a ethyl sulfinic acid sodium salt (3.94g, 33.94mmol) is joined to the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] in acetonitrile (250mL) solution of pyrimidine (12.0g, 33.94mmol).At 80 ℃ by the suspension agitation that obtains 16 hours.The evaporate to dryness reaction mixture distributes resistates between DCM (250mL) and water (200mL).Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 40% ethyl acetate/DCM, obtains needed material yellow solid (5.94g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, m), 1.28 (3H, t), (3.22 2H, d), 3.32 (1H, s), (3.42-3.49 1H, m), 3.58-3.62 (1H, m), (3.73 1H, d), 3.92-3.96 (2H, m), (4.25-4.31 1H, m), 4.43 (2H, s), 6.92 (1H, s)

the LCMS spectrum: MH+320, retention time 1.46 minutes.

N-[4-[4-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] ammonia the base phenyl formate

In nitrogen atmosphere; by phenyl chloroformate (0.207mL; 1.65mmol) dropwise join 4-[4-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (620mg; 1.65mmol) and sodium bicarbonate (in 208mg, 2.47mmol) diox (15mL) mixture.The suspension obtained is at room temperature stirred 2 hours.The evaporate to dryness reaction mixture distributes resistates between ethyl acetate (200mL) and water (200mL).Dry (MgSO ₄) organic layer, to filter, evaporation, obtain needed material white solid (885mg).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.21-1.29 (3H, m), 1.35 (3H, t), 3.20-3.28 (2H, m), 3.47-3.54 (2H, m), 3.64-3.68 (1H, m), (3.78 1H, d), 3.97-4.01 (1H, m), 4.20 (1H, d), 4.48 (3H, s), 6.83 (1H, s), (7.24-7.30 3H, m), 7.42-7.48 (2H, m), 7.64 (2H, d), 8.28-8.30 (2H, m), 10.45 (1H, s)

the LCMS spectrum: MH+497, retention time 2.57 minutes

4-[4-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By two (triphenylphosphine) palladium (the II) (0.162g of dichloro; 0.23mmol) join the chloro-4-of 2-(ethylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (0.74g; 2.31mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.634g; 2.89mmol) and the 18%DMF of sodium carbonate (5.78mL, 11.57mmol) (at DME: water: in the mixture (20mL) of ethanol (7: 3: 2)) in de-gassed solution.The solution obtained 85 ℃ of stirrings 30 minutes.Concentrated reaction mixture, with DCM (100mL) dilution, then water (100mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0 is to 2.5% methyl alcohol/DCM.The material of acquisition is further purified, uses the SCX post, by 7M ammonia/methanol-eluted fractions, obtain needed material yellow solid (0.62g).

the NMR spectrum: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.34 (3H, t), 3.16-3.19 (1H, m), 3.32 (2H, m), 3.45-3.52 (1H, m), (3.62-3.66 1H, m), 3.77 (1H, d), 3.96-3.99 (1H, m), 4.12 (1H, s), 4.42 (3H, d), (5.56 2H, s), 6.59-6.62 (2H, m), (6.67 1H, s), 8.01-8.04 (2H, m)

the LCMS spectrum: MH+377, retention time 1.83 minutes

The chloro-4-of 2-(ethylsulfonyl methyl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 63:

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(morpholine-4-carbonyl) pyrimidine-2-base] phenyl] urea

In room temperature, in nitrogen atmosphere, in during 30 minutes, by 2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid (100mg, 0.25mmol) join morpholine (0.066mL, 0.75mmol), in dry DMF (3mL) solution of DIPEA (0.132mL, 0.75mmol) and HATU (144mg, 0.38mmol).By the solution stirring that obtains 3 hours, with preparative HPLC, purify crude product in room temperature, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material (98mg) white solid.

the NMR spectrum: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.68 (2H, m), (1.23-1.25 3H, d), 2.54-2.59 (1H, m), (3.18-3.27 1H, m), 3.46-3.49 (3H, m), 3.60-3.69 (7H, m), (3.74-3.77 1H, d), 3.95-3.99 (1H, dd), 4.21-4.24 (1H, d), (4.56 1H, s), 6.43-6.44 (1H, d), 6.77 (1H, s), (7.50-7.52 2H, d), 8.18-8.20 (2H, d), 8.54 (1H, s)

the LCMS spectrum: MH+467, retention time 1.69 minutes

Use similar fashion, use suitable amine, by 2-[4-(cyclopropyl carboxamide amino) phenyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-4-carboxylic acid prepares following compounds.

Embodiment 63a: ¹h NMR (400MHz, CDCl ₃) δ 0.68-0.68 (2H, d), 0.86-0.87 (2H, d), 1.34-1.35 (3H, d), 1.86-1.90 (1H, m), 1.94-2.02 (1H, m), 2.62-2.64 (1H, t), 2.99-3.04 (2H, m), 3.06-3.11 (2H, m), 3.30-3.37 (1H, td), 3.56-3.59 (1H, d), 3.63-3.68 (3H, m), 3.72-3.75 (1H, d), 3.78-3.84 (3H, m), 4.02-4.06 (1H, dd), 4.15-4.18 (1H, d), 4.49 (1H, s), 4.98-4.99 (1H, d), 6.62-6.64 (1H, d), 7.07-7.08 (1H, d), 7.48-7.50 (2H, d), 8.30-8.33 (2H, m)

Embodiment 63b: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.23-1.24 (3H, d), 1.64-1.70 (2H, m), 1.75-1.80 (2H, m), 2.54-2.58 (1H, m), 3.2-3.21 (1H, d), 3.36-3.44 (2H, dt), 3.46-3.53 (1H, m), 3.57-3.60 (1H, q), 3.62-3.65 (2H, m), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), 4.21-4.24 (1H, d), 4.54 (1H, s), 6.43-6.44 (1H, d), 6.70-6.71 (1H, d), 7.49-7.51 (2H, d), 8.18-8.20 (2H, d), 8.45 (1H, s)

Embodiment 63c: ¹h NMR (400MHz, CDCl ₃) δ 0.68-0.72 (2H, m), 0.86-0.90 (2H, m), 1.13-1.15 (3H, dd), 1.27-1.29 (3H, d), 1.35-1.37 (3H, d), 2.54-2.61 (1H, t), 2.62-2.66 (1H, m), 2.82-2.91 (1H, m), 3.31-3.39 (1H, td), 3.57-3.63 (1H, td), 3.73-3.76 (3H, m), 3.82-3.85 (1H, d), 4.03-4.07 (1H, dd), 4.11-4.18 (2H, m), 4.51 (1H, s), 4.56-4.60 (1H, dd), 4.96 (1H, s), 6.69 (1H, s), 7.069 (1H, s), 7.51-7.53 (2H, d), 8.31-8.33 (2H, d),

Embodiment 63d: ¹h NMR (400MHz, DMSO-d ₆) δ 0.42-0.44 (2H, m), 0.63-0.68 (2H, m), (1.23-1.25 3H, d), 2.54-2.59 (1H, m), (2.99-3.01 6H, d), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd), (3.74-3.77 1H, d), 3.95-3.99 (1H, dd), 4.21-4.24 (1H, d), (4.55 1H, s), 6.43-6.44 (1H, d), 6.71 (1H, s), (7.49-7.51 2H, d), 8.19-8.21 (2H, d), 8.54 (1H, s)

Embodiment 63e: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.67 (2H, m), 1.23-1.25 (3H, d), 2.32-2.34 (1H, m), 2.54-2.61 (1H, m), 3.03 (3H, s), 3.18-3.25 (1H, td), 3.36-3.41 (1H, q), 3.49-3.50 (1H, d), 3.52-3.54 (1H, d), 3.57 (1H, s), 3.63-3.66 (1H, dd), 3.74-3.77 (1H, d), 3.95-3.99 (1H, dd), 4.21-4.23 (1H, d), 4.52 (1H, s), 4.74 (1H, s), 6.45-6.46 (1H, d), 6.70 (1H, s), 7.50-7.52 (2H, d), 8.17-8.20 (2H, m), 8.56 (1H, s)

Embodiment 63f: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), (1.24-1.26 3H, d), 2.33-2.35 (1H, m), (2.67-2.69 1H, m), 2.70 (1H, s), (2.74 2H, s), 2.90 (3H, s), (3.49-3.53 2H, m), 3.63-3.67 (1H, dd), (3.76-3.78 1H, d), 3.96-4.00 (1H, dd), (4.35 1H, s), 4.56-4.58 (1H, d), (6.43-6.44 1H, d), 7.13 (1H, s), (7.52-7.54 2H, d), 7.96 (1H, s), (8.38-8.40 2H, d), 8.57 (1H, s)

Embodiment 63g: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d), 2.20 (2H, s), 2.27 (1H, s), 2.33-2.35 (2H, m), 2.67-2.69 (3H, m), 2.74 (1H, s), 2.90-2.91 (2H, d), 2.97 (2H, s), 3.17-3.21 (1H, m), 3.47-3.52 (1H, m), 3.63-3.66 (1H, dd), 3.74-3.77 (1H, d), 3.96-3.98 (1H, dd), 4.22-4.24 (1H, d), 4.32-4.34 (1H, d), 4.56 (1H, s), 6.43-6.45 (1H, m), 6.69-6.70 (1H, d), 7.49-7.53 (2H, dd), 8.19-8.21 (2H, dd), 8.54 (1H, s),

Embodiment 63h: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), 1.23-1.24 (3H, d), 1.43 (2H, s), 1.74-1.84 (2H, d), 2.53-2.57 (1H, m), 3.14-3.18 (1H, m), 3.21-2.24 (2H, m), 3.46-3.52 (1H, td), 3.56 (1H, m), 3.62-3.66 (1H, dd), 3.74-3.77 (2H, d), 3.95-3.98 (1H, dd), 4.00-4.04 (1H, m), 4.21 (1H, d), 4.55 (1H, s), 4.77-4.78 (1H, d), 6.43-6.44 (1H, d), 6.71 (1H, s), 7.49-7.52 (2H, d), 8.18-8.20 (2H, d), 8.54 (1H, s)

Embodiment 63i: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.68 (2H, m), (1.23-1.24 3H, d), 1.60-1.61 (4H, d), (1.74-1.75 4H, d), 2.67-2.69 (1H, m), (3.17-3.25 1H, m), 3.37-3.40 (1H, t) 3.56-3.59 (1H, t), 3.62-3.65 (1H, dd), 3.74-3.77 (1H, d), 3.94-3.99 (1H, dd), 4.22-4.24 (1H, d), 4.54 (1H, s), 6.43-6.44 (1H, d), 6.69 (1H, s), (7.49-7.51 2H, d), 8.18-2.20 (2H, d), 8.53 (1H, s)

Embodiment 63j: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), (1.15-1.19 3H, t), 1.24-1.26 (3H, d), (2.56-2.60 1H, m), 3.25-3.26 (1H, m), (3.33-3.42 2H, m), 3.47-3.53 (1H, td), (3.64-3.67 1H, dd), 3.75-3.78 (1H, d), (3.96-4.00 1H, dd), 4.35-4.27 (1H, d), (4.57 1H, s), 6.43-6.44 (1H, d), (7.13 1H, s), 7.52-7.54 (2H, d), 8.40-8.42 (2H, d), (8.57 1H, s) 8.91-8.93 (1H, t)

Embodiment 63k: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.22-1.25 (3H, m), 2.01 (2H, s), 2.24 (2H, s), 2.55-2.58 (1H, m), 2.99-3.01 (3H, d), 3.27 (3H, s), 3.35-3.39 (3H, m), 3.46-3.49 (1H, dd), 3.52-3.56 (1H, td), 3.62-3.66 (1H, dd), 3.74-3.77 (1H, d), 3.96-3.98 (1H, d), 4.21-4.24 (1H, d), 4.55 (1H, s), 6.43-6.44 (1H, d), 6.68-6.70 (1H, d), 7.50-7.52 (2H, d), 8.20-8.22 (2H, d), 8.54 (1H, s)

Embodiment 63l: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d), 2.55-2.58 (1H, m), 3.02 (3H, s), 3.19 (2H, s), 3.24-3.25 (1H, m), 3.46-3.47 (1H, d), 3.49-3.54 (3H, m), 3.59-3.60 (1H, d), 3.61-3.66 (2H, dd), 3.74-3.78 (1H, d), 3.95-3.98 (1H, dd), 4.21-4.22 (1H, d), 4.51 (1H, s), 6.44 (1H, s), 6.69-6.71 (1H, s), 7.50-7.52 (2H, d), 8.18-8.20 (2H, d), 8.55 (1H, s)

Embodiment 63m: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), 1.24-1.25 (3H, d), 1.74-1.78 (4H, m), 1.97-2.04 (3H, m), 2.55-2.61 (1H, m), 2.76-2.79 (2H, d), 3.21-3.26 (1H, m), 3.27 (1H, s), 3.47-3.53 (1H, td), 3.63-3.67 (1H, dd), 3.73-3.78 (2H, d), 3.80-3.84 (1H, m), 3.96-4.00 (1H, dd), 4.24-4.27 (1H, d), 4.58 (1H, s), 6.44-6.45 (1H, d), 7.12 (1H, s), 7.52-7.54 (2H, d), 8.38-8.40 (2H, d), 8.51-8.54 (1H, d), 8.57 (1H, s)

Embodiment 63n: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), 1.23-1.25 (3H, d), 2.56-2.59 (1H, m), 3.19-3.23 (1H, dd), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd), 3.75-378 (1H, d), 3.80-3.84 (1H, m), 3.96-3.99 (1H, dd), 4.23 (1H, s), 4.26-4-31 (1H, qd), 4.42-4.47 (1H, m), 4.53-4.58 (2H, m), 4.88-4.94 (1H, m), 5.72-5.73 (1H, d), 6.44-6.45 (1H, d), 7.04 (1H, s), 7.52-7.54 (2H, d), 8.20-8.23 (2H, d), 8.56 (1H, s)

Embodiment 63o: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.68 (2H, m), 1.24-1.26 (3H, d), 2.55-2.59 (1H, m), 3.21-3.25 (1H, m), 3.47-3.53 (1H, td), 3.63-3.64 (1H, d), 3.66 (3H, s), 3.75-3.78 (1H, d), 3.96-4.00 (1H, dd), 4.24-4.28 (1H, d), 4.52-4.54 (2H, d), 4.58 (1H, s), 6.42-6.44 (1H, d), 6.65 (1H, s), 7.15 (1H, s), 7.50-7.51 (1H, t), 7.52-7.53 (2H, d), 8.38-8.40 (2H, d), 8.56 (1H, s)

Embodiment 63p: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.63-0.68 (2H, m), 1.25-1.27 (3H, d), 2.56-2.59 (1H, m), 2.91 (3H, s), 3.03 (3H, s), 3.20-3.24 (1H, m), 2.48-3.54 (1H, td), 3.64-3.68 (1H, dd), 3.76-3.79 (1H, d), 3.97-4.00 (1H, dd), 4.18-4.20 (2H, d), 4.26 (1H, d), 4.59 (1H, s), 6.46-6.47 (1H, d), 7.14 (1H, s), 7.54-7.56 (2H, d), 8.34-8.36 (2H, d), 8.59 (1H, s), 8.99-9.02 (1H, t)

Embodiment 63q: ¹h NMR (400MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.49-0.53 (4H, m), 0.63-0.67 (2H, m), 1.22-1.24 (3H, d), 2.55-2.61 (2H, m), 2.87-2.88 (1H, d), 2.93 (2.95 (1H, m), 3.17-3.25 (1H, td), 3.27 (1H, s), 3.47-3.54 (1H, td), 3.62-3.67 (1H, dd), 3.75-3.78 (1H, d), 3.94-3.98 (1H, dd), 4.21-4.24 (1H, d), 4.52 (1H, s), 6.42-6.43 (1H, d), 6.73 (1H, s), 7.49-7.51 (2H, d), 8.19-8.22 (2H, d), 8.53 (1H, s)

Embodiment 63r: ¹h NMR (400MHz, DMSO-d ₆) δ 0.14-0.18 (1H, m), 0.30-0.34 (1H, m), 0.40-0.43 (2H, m), 0.44-0.48 (1H, dq), 0.51-0.56 (1H, dq), 0.63-0.67 (2H, m), 1.06-1.10 (1H, m), 1.22-1.25 (3H, m), 2.54-2.59 (1H, m), 3.03-3.06 (3H, d), 3.16-3.19 (1H, m), 3.20-3.25 (1H, m), 3.35-3.37 (1H, m), 3.46-3.53 (1H, td), 3.62-3.66 (1H, dd), 3.74-3.77 (1H, d), 3.95-3.98 (1H, dd), 4.22-4.24 (1H, d), 4.55 (1H, s) 6.44-6.45 (1H, d), 6.70-6.71 (1H, d), 7.49-7.59 (2H, dd), 8.18-8.21 (2H, dd), 8.54-8.55 (1H, d)

Embodiment 63s: ¹h NMR (400MHz, DMSO-d ₆) δ 0.41-0.45 (2H, m), 0.64-0.68 (2H, m), (1.24-1.25 3H, d), 2.55-2.60 (1H, m), (3.17-3.25 1H, m), 3.47-3.54 (1H, td), (3.63-3.67 1H, dd), 3.75-3.78 (1H, d), (3.96-4.00 1H, dd), 4.25-4.27 (1H, d), (4.57 1H, s), 4.74-4.80 (4H, m), (5.04-5.13 1H, m), 6.44-6.45 (1H, d), (7.11 1H, s), 7.53-7.55 (2H, d), (8.46-8.48 2H, d), 8.58 (1H, s), 9.38-9.40 (1H, d)

Test (c): embodiment (63) 0.41 μ M; Embodiment (63a) 0.092 μ M; Embodiment (63b) 0.5 μ M; Embodiment (63c) 0.26 μ M.

2-[4-(cyclopropyl carboxamide amino) phenyl had before been described]-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine-4-carboxylic acid.

embodiment 64:

1-[4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-cyclopropyl-urea

By triethylamine (0.175mL; 1.25mmol) join N-[4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (200mg; 0.31mmol) and NMP (2mL) mixture of cyclopropylamine (1.25mmol) in, and 75 ℃ of heating 6 hours.With preparative HPLC purification reaction mixture, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material solid (136mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.39-0.44 (2H, m), 0.63-0.67 (2H, m), (1.22 3H, d), 1.40-1.48 (4H, m), (1.52-1.59 4H, m), 1.70-1.80 (6H, m), (3.16-3.24 1H, m), 3.46-3.54 (1H, m), (3.65 1H, d), 3.77 (1H, d), (3.91-4.01 2H, m), 4.23 (1H, d), (4.60 1H, s), 6.44 (1H, d), 6.77 (1H, s), (7.51 2H, d), 8.24 (2H, d), 8.55 (1H, s)

the LCMS spectrum: MH+528, retention time 2.43 minutes

Use similar fashion, by N-[4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 64a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.39-1.68 (10H, m), (1.69-1.80 6H, m), 1.86 (2H, q), (2.17-2.25 2H, m), 3.16-3.24 (1H, m), (3.46-3.55 1H, m), 3.65 (1H, dd), (3.77 1H, d), 3.95 (1H, quintets), (4.14 1H, q), 4.22 (1H, d), (4.60 1H, s), 6.46 (1H, d), 6.78 (1H, s), (7.48 2H, d), 8.23 (2H, d), 8.57 (1H, s)

Embodiment 64b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.22 (3H, d), (1.41-1.48 4H, m), 1.51-1.57 (4H, m), (1.70-1.79 6H, m), 3.12 (2H, q), (3.16-3.24 1H, m), 3.50 (1H, dd), (3.65 1H, d), 3.77 (1H, d), (3.91-4.00 2H, m), 4.22 (1H, d), (4.60 1H, s), 6.17 (1H, t), 6.77 (1H, s), (7.49 2H, d), 8.22 (2H, d), 8.67 (1H, s)

Embodiment 64c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.41-1.48 (4H, m), (1.52-1.58 4H, m), 1.69-1.79 (6H, m), (2.19 6H, s), 2.33 (2H, t), (3.16-3.24 3H, m), 3.50 (1H, td), (3.65 1H, dd), 3.77 (1H, d), (3.90-4.01 2H, m), 4.22 (1H, d), (4.59 1H, s), 6.15 (1H, t), 6.78 (1H, s), (7.49 2H, d), 8.23 (2H, d), 8.90 (1H, s)

Embodiment 64d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.41-1.47 (4H, m), (1.50-1.58 4H, m), 1.70-1.79 (6H, m), (3.15-3.24 3H, m), 3.44-3.54 (3H, m), (3.65 1H, dd), 3.77 (1H, d), (3.91-4.00 2H, m), 4.22 (1H, d), 4.60 (1H, s), (4.73 1H, t), 6.26 (1H, t), 6.77 (1H, s), (7.49 2H, d), 8.23 (2H, d), 8.82 (1H, s)

Embodiment 64e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.41-1.49 (4H, m), (1.51-1.58 4H, m), 1.68-1.81 (6H, m), (2.67 3H, d), 3.16-3.24 (1H, m), (3.50 1H, td), 3.65 (1H, dd), (3.77 1H, d), 3.91-4.00 (2H, m), 4.22 (1H, d), (4.60 1H, s), 6.07 (1H, t), 6.77 (1H, s), (7.50 2H, d), 8.23 (2H, d), 8.75 (1H, s)

Embodiment 64f: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.57-1.74 (6H, m), (1.82-1.90 2H, m), 1.93-2.07 (4H, m), (2.17-2.25 2H, m), 3.16-3.27 (1H, m), (3.50 1H, td), 3.65 (1H, dd), (3.73-3.83 1H, m), 3.99 (1H, dd), (4.10-4.20 2H, m), 4.45 (2H, s), (4.49 1H, s), 6.47 (1H, d), 6.79 (1H, s), (7.47 2H, d), 8.19 (2H, d), 8.56 (1H, s)

Embodiment 64g: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.24 (3H, d), (1.60-1.74 4H, m), 1.89-2.06 (4H, m), (3.09-3.16 2H, m), 3.18-3.26 (1H, m), (3.46-3.54 1H, m), 3.65 (1H, dd), (3.75-3.83 2H, m), 3.99 (1H, dd), (4.17 1H, d), 4.43 (2H, s), (4.49 1H, s), 6.16 (1H, t), 6.79 (1H, s), (7.49 2H, d), 8.19 (2H, d), 8.66 (1H, s)

Embodiment 64h: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.60-1.74 (4H, m), (1.91-2.07 4H, m), 2.19 (6H, s), (2.34 2H, t), 3.16-3.22 (3H, m), (3.50 2H, td), 3.65 (2H, dd), (3.74-3.83 2H, m), 3.99 (2H, dd), (4.16 1H, d), 4.44 (2H, s), (4.51 1H, s), 6.17 (1H, t), 6.78 (1H, s), (7.49 2H, d), 8.19 (2H, d), 8.89 (1H, s)

N-[4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

At 5 ℃; in nitrogen atmosphere; by phenyl chloroformate (0.635mL; 5.06mmol) join 4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.5g; 3.37mmol) and sodium bicarbonate (in 0.425g, 5.06mmol) diox (20mL) mixture.The mixture obtained is at room temperature stirred 2 hours.With ethyl acetate (200mL) diluted reaction mixture, water (125mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and crude product is ground with the mixture of diethyl ether and isohexane, obtains needed material white solid (1.30g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.23 (3H, d), 1.41-1.47 (2H, m), (1.50-1.57 2H, m), 1.69-1.78 (4H, m), (1.79 6H, d), 3.21 (1H, td), (3.51 1H, td), 3.65 (1H, dd), (3.77 1H, d), 3.92-4.01 (2H, m), (4.24 1H, d), 4.62 (1H, s), (6.82 1H, s), 7.23-7.31 (3H, m), 7.42-7.48 (2H, m), (7.64 2H, d), 8.34 (2H, d), 10.45 (1H, s)

the LCMS spectrum: MH+565, retention time 3.0 minutes

4-[4-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

In room temperature; by two (triphenylphosphine) Palladous chloride (II) (200mg; 0.28mmol) join the chloro-4-of 2-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.66g; 4.28mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.406g; 6.42mmol) and the mixture of ethanol (5mL), DMF (10mL), water (7mL) and the DME (25mL) of sodium carbonate (10mL, 20.00mmol) in.The mixture obtained is degassed, then at 95 ℃, stir 18 hours.Make reaction mixture cooling, with ethyl acetate (200mL) dilution, then water (2x150mL) and salt solution (150mL) washing.Dry (Na ₂sO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 10, to 60% ethyl acetate/isohexane, grinds with the mixture of diethyl ether and isohexane the resistates obtained, and obtains the pink solid (1.52g) of needed material.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.41-1.50 (2H, m), 1.52-1.60 (2H, m), 1.69-1.80 (10H, m), 3.17 (1H, td), (3.49 1H, td), 3.64 (1H, dd), 3.76 (1H, d), 3.90-3.99 (2H, m), 4.18 (1H, d), (4.56 1H, s), 5.57 (2H, s), 6.61 (2H, d), 6.68 (1H, s), 8.06 (2H, d)

the LCMS spectrum: MH+445, retention time 2.42 minutes

the chloro-4-of 2-(2-cyclopentyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At-5 ℃; sodium tert-butoxide (5.56mmol) is joined to the chloro-4-of 2-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (2g; 5.56mmol) DMF (10mL) solution in, then at-5 ℃, dropwise add methyl iodide (0.365mL).Add extra sodium tert-butoxide (5.56mmol) and methyl iodide (0.365mL), and spend the night at-5 ℃ of stirring reactions.By ethyl acetate for reaction mixture (250mL) dilution, and water (2x150mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and its mixture with diethyl ether and isohexane is ground, and obtains needed material paste solid (1.66g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (4H, d), 1.46-1.61 (6H, m), 1.69-1.84 (12H, m), 1.70 (9H, s), 3.20 (3H, td), (3.45 1H, td), 3.60 (1H, dd), (3.75 1H, s), 3.85 (2H, q), (3.96 1H, d), 4.06 (1H, d), (4.46 1H, s), 6.90 (1H, s)

the LCMS spectrum: MH+388, retention time 2.47 minutes

the chloro-4-of 2-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At 55 ℃, under air conditions, by hydrogen peroxide (19.54mL, 632mmol) join the chloro-4-of 2-(cyclopentyl sulfenyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (10.36g, 31.60mmol), sodium tungstate dihydrate (0.208g, 0.63mmol) (being dissolved in the water of minimum quantity) and 2M sulphuric acid soln be (in 0.177mL) diox (100mL) solution.The solution obtained 55 ℃ of stirrings 2 hours.By ethyl acetate for reaction mixture (100mL) dilution, and wash with water, then with 10% metabisulfite solution washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 5, to 70% ethyl acetate/isohexane, obtains the colourless colloid of needed material (9.7g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.64 (4H, m), (1.95 4H, m), 3.24 (1H, m), (3.45 1H, td), 3.60 (1H, dd), (3.71 1H, m), 3.95 (2H, m), (4.35 1H, s), 4.40 (2H, s), 6.91 (1H, s)

mass spectrum: MH+360

the chloro-4-of 2-(cyclopentyl sulfenyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, in nitrogen atmosphere, DIPEA (9.62mL, 55.57mmol) is joined in DMF (80mL) solution of pentamethylene mercaptan (5.93mL, 55.57mmol).By the solution that obtains stirring at room 20 minutes.By the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (13.1g, 37.05mmol) joins in reaction, stirring at room 2 hours.By ethyl acetate for reaction mixture (500mL) dilution, and water (2x200mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 30% ethyl acetate/isohexane, obtains the colourless colloid of needed material (11.13g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.43 (2H, m), 1.53 (2H, m), 1.65 (2H, m), (1.94 2H, m), 3.16 (2H, m), 3.44 (1H, td), 3.71 (1H, d), 3.95 (2H, m), 4.35 (1H, s), 6.79 (1H, s)

mass spectrum: MH+328

N-[4-[4-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

At 5 ℃; in nitrogen atmosphere; by phenyl chloroformate (0.759mL; 6.05mmol) join 4-[4-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.68g; 4.03mmol) and sodium bicarbonate (in 0.508g, 6.05mmol) diox (20mL) solution.The mixture obtained is at room temperature stirred 2 hours.By ethyl acetate for reaction mixture (200mL) dilution, and water (125mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and its mixture with diethyl ether and isohexane is ground, and obtains needed material white solid (2.10g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.25 (3H, d), 1.57-1.76 (4H, m), (1.93-2.08 4H, m), 3.24 (1H, td), (3.47-3.54 1H, m), 3.66 (1H, dd), (3.75-3.84 2H, m), 3.99 (1H, dd), (4.20 1H, d), 4.47 (2H, s), 4.52 (1H, s), (6.84 1H, s), 7.24-7.31 (3H, m), 7.42-7.48 (2H, m), (7.64 2H, d), 8.29 (2H, d), 10.47 (1H, s)

the LCMS spectrum: MH+537, retention time 2.75 minutes

4-[4-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

In room temperature; by two (triphenylphosphine) Palladous chloride (II) (118mg; 0.17mmol) join the chloro-4-of 2-(cyclopentyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.67g; 4.64mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.525g; 6.96mmol) and the mixture of ethanol (6mL), DMF (10mL), water (6mL) and the DME (20mL) of sodium carbonate (10mL, 20.00mmol) in.The mixture obtained is degassed, then at 95 ℃, stir 18 hours.By ethyl acetate for reaction mixture (400mL) dilution, and water (2x150mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 10, to 60% ethyl acetate/isohexane, obtains needed material paste crystalline solid (1.680g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.58-1.73 (4H, m), 1.93-2.06 (4H, m), 3.19 (1H, td), 3.49 (1H, td), (3.64 1H, dd), 3.74-3.82 (2H, m), 3.97 (1H, dd), 4.14 (1H, d), 4.39 (2H, s), (4.47 1H, s), 5.57 (2H, s), 6.60 (2H, d), 6.67 (1H, s), 8.03 (2H, d)

the LCMS spectrum: MH+417, retention time 2.09 minutes

The chloro-4-of 2-(cyclopentyl alkylsulfonyl methyl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 65:

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] phenyl] urea

By triethylamine (0.197mL; 1.40mmol) join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] phenyl] phenyl carbamate (200mg; 0.35mmol) and NMP (2mL) mixture of cyclopropylamine (1.40mmol) in, and 75 ℃ of heating 6 hours.With preparative HPLC purification reaction mixture, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material, solid (163mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.40-0.43 (2H, m), 0.63-0.66 (2H, m), (1.20 3H, d), 1.84 (6H, d), (3.11-3.19 1H, m), 3.49 (1H, dd), (3.64 1H, dd), 3.76 (1H, d), (3.97 1H, d), 4.13 (1H, d), (4.62 1H, s), 6.41 (1H, d), (6.67 1H, s), 7.32 (2H, d), (7.59 2H, d), 7.78 (1H, d), (7.82-7.91 2H, m), 7.97 (1H, d), 8.48 (1H, s)

the LCMS spectrum: MH+604, retention time 2.59 minutes

Use similar fashion, by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 65a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.57-1.68 (4H, m), (1.84 6H, d), 2.18-2.25 (2H, m), (3.12-3.18 1H, m), 3.45-3.53 (1H, m), (3.64 1H, d), 3.76 (1H, d), (3.97 1H, d), 4.09-4.18 (2H, m), (4.60 1H, s), 6.43 (1H, d), (6.66 1H, s), 7.29 (2H, d), (7.59 2H, d), 7.78 (1H, d), (7.82-7.91 2H, m), 7.97 (1H, d), 8.50 (1H, s)

Embodiment 65b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.06 (3H, t), 1.20 (3H, d), (1.82 6H, d), 3.08-3.19 (2H, m), (3.49 1H, dd), 3.64 (1H, dd), (3.77 1H, d), 3.94-3.99 (1H, m), (4.12 1H, d), 4.62 (1H, s), (6.14 1H, t), 6.68 (1H, s), (7.30 2H, d), 7.59 (2H, d), 7.77-7.80 (1H, m), (7.82-7.91 2H, m), 7.97 (1H, d), 8.60 (1H, s)

Embodiment 65c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.84 (6H, d), (2.20 6H, s), 2.34 (2H, t), (3.09-3.21 3H, m), 3.49 (1H, td), (3.64 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.12 (1H, d), (4.61 1H, s), 6.14 (1H, t), (6.67 1H, s), 7.30 (2H, d), (7.59 2H, d), 7.78 (2H, dd), (7.82-7.91 2H, m), 7.97 (2H, d), 8.83 (1H, s)

Embodiment 65d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 1.85 (6H, d), (3.11-3.20 3H, m), 3.43-3.53 (3H, m), (3.64 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.13 (1H, d), (4.60 1H, s), 4.72 (1H, t), (6.23 1H, t), 6.67 (1H, s), (7.30 2H, d), 7.59 (2H, d), 7.78 (1H, dd), (7.82-7.91 2H, m), 7.95-7.99 (1H, m), 8.74 (1H, s)

Embodiment 65e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.20 (3H, d), 1.84 (6H, d), (2.66 3H, d), 3.15 (1H, td), (3.49 1H, td), 3.64 (1H, dd), (3.77 1H, d), 3.97 (1H, dd), (4.12 1H, d), 4.61 (1H, s), (6.02-6.07 1H, m), 6.66 (1H, s), (7.31 2H, d), 7.59 (2H, d), 7.76-7.80 (1H, m), (7.82-7.91 2H, m), 7.95-7.99 (1H, m), 8.67 (1H, s)

Embodiment 65f: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.10 (3H, t), 1.20 (3H, d), (1.58-1.67 2H, m), 1.81-1.92 (2H, m), (2.16-2.25 2H, m), 3.12-3.22 (1H, m), (3.44-3.52 1H, m), 3.63 (1H, d), (3.97 1H, d), 4.06-4.17 (2H, m), (4.44 1H, s), 4.77 (2H, s), (6.45 1H, d), 6.71 (1H, s), (7.33 2H, d), 7.71 (2H, d), (7.76-7.82 1H, m), 7.87-7.93 (2H, m), (8.09 1H, d), 8.52 (1H, s)

Embodiment 65g: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.21 (3H, d), (3.08-3.22 3H, m), 3.48 (1H, td), (3.64 1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.11 (1H, d), (4.44 1H, s), 4.78 (2H, s), (6.15 1H, t), 6.70 (1H, s), (7.35 2H, d), 7.72 (2H, d), 7.79 (1H, t), (7.87-7.93 2H, m), 8.08 (1H, d), 8.61 (1H, s)

Embodiment 65h: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 2.19 (6H, s), (2.33 2H, t), 3.13-3.22 (3H, m), (3.44-3.53 1H, m), 3.64 (1H, dd), (3.76 1H, d), 3.97 (1H, dd), (4.10 1H, d), 4.44 (1H, s), (4.76 2H, s), 6.14 (1H, t), (6.70 1H, s), 7.34 (2H, d), (7.71 2H, d), 7.79 (1H, t), (7.87-7.92 2H, m), 8.08 (1H, d), 8.84 (1H, s)

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] phenyl] phenyl carbamate

At 5 ℃; in nitrogen atmosphere; by phenyl chloroformate (0.542mL; 4.32mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine-2-base] aniline (1.5g; 2.88mmol) and sodium bicarbonate (in 0.363g, 4.32mmol) diox (20mL) mixture.At room temperature the mixture obtained is stirred 2 hours, then use ethyl acetate (200mL) dilution, water (125mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and its mixture with diethyl ether and isohexane is ground, and obtains needed material white solid (1.38g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.85 (6H, d), 3.16 (1H, td), (3.45-3.54 1H, m), 3.65 (1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.15 (1H, d), 4.63 (1H, s), (6.71 1H, s), 7.23-7.29 (3H, m), 7.42-7.47 (4H, m), (7.69 2H, d), 7.78 (1H, d), 7.82-7.92 (2H, m), 7.98 (1H, d), 10.37 (1H, s)

the LCMS spectrum: MH+641, retention time 3.08 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] phonetic pyridine-2-yl] aniline

In room temperature; by two (triphenylphosphine) Palladous chloride (II) (200mg; 0.28mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine (1.91g; 4.12mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.353g; 6.18mmol) and the mixture of ethanol (5mL), DMF (10mL), water (7mL) and the DME (25mL) of sodium carbonate (10mL, 20.00mmol) in.The mixture obtained is degassed, then at 95 ℃, stir 18 hours.Make reaction mixture cooling, with ethyl acetate (200mL) dilution, then water (2x200mL) and salt solution (100mL) washing.Dry (Na ₂sO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 10, to 60% ethyl acetate/isohexane, grinds with the mixture of diethyl ether and isohexane the material obtained, and obtains needed material white solid (1.50g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18 (3H, d), 1.82 (6H, d), 3.12 (1H, td), 3.47 (1H, td), 3.63 (1H, dd), (3.75 1H, d), 3.95 (1H, dd), 4.08 (1H, d), 4.57 (1H, s), 5.47 (2H, s), (6.42 2H, d), 6.56 (1H, s), 7.44 (2H, d), 7.78-7.89 (3H, m), 7.92-7.96 (1H, m)

the LCMS spectrum: MH+521, retention time 2.56 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[2-[2-(trifluoromethyl) phenyl] alkylsulfonyl third-2-yl] pyrimidine

At-5 ℃; sodium tert-butoxide (4.59mmol) is joined to the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine (2g; 4.59mmol) DMF (10mL) solution in, then at-5 ℃, dropwise add methyl iodide (0.030mL).Add extra sodium tert-butoxide (4.59mmol) and methyl iodide (0.030mL), and spend the night at-5 ℃ of stirring reactions.Vacuum is removed organism, between ethyl acetate (200mL) and water (100mL), distributes resistates.Water (100mL) washing organic layer, dry (MgSO ₄), to filter, evaporation, obtain crude product, and crude product is ground with the mixture of diethyl ether and isohexane, obtains needed material paste solid (1.91g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.17 (3H, d), 3.13 (1H, td), 3.41 (1H, td), 3.57 (1H, dd), 3.71 (1H, d), 3.89-3.98 (2H, m), 4.46 (1H, s), 6.72 (1H, s), 7.87-8.02 (4H, m)

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine

In room temperature, in nitrogen atmosphere, 2-(trifluoromethyl) benzene sulfinic acid sodium salt (10.24g, 44mmol) is joined to the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] in acetonitrile (500mL) solution of pyrimidine (13g, 36.77mmol).At 80 ℃, the mixture obtained is stirred 3 hours.Add extra 2-(trifluoromethyl) benzene sulfinic acid sodium salt (10.2g, 44mmol), 80 ℃ of reacting by heating 1 hour.Reaction mixture is cooling, and vacuum concentration.Material is dissolved in ethyl acetate (500mL) to water (200mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0 is to 40% ethyl acetate/isohexane, obtain needed material orange/paste solid (9.48g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18 (3H, d), 3.17 (1H, td), (3.43 1H, td), 3.58 (1H, dd), (3.72 1H, d), 3.93 (2H, m), (4.27 1H, s), 4.68 (2H, s), (6.79 1H, s), 7.94 (3H, m), 8.08 (1H, d)

the LCMS spectrum: MH+436; Retention time 2.35 minutes

2-(trifluoromethyl) benzene sulfinic acid sodium salt

S-WAT (3.92mL, 81.88mmol) is soluble in water, stirring at room 10 minutes.Add sodium bicarbonate (13.74g, 163.52mmol), and stir the mixture 1 hour at 50 ℃.2-(trifluoromethyl) benzene-1-SULPHURYL CHLORIDE (12.62mL, 81.76mmol) is dropwise joined in reaction mixture, then stir 18 hours at 50 ℃.The evaporate to dryness reaction mixture, be suspended in resistates in methyl alcohol (250mL), stirring at room 20 minutes.Solids removed by filtration, evaporation filtrate, obtain needed material (20.00g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 7.40 (1H, d), 7.51 (1H, d), 7.64 (1H, d), 8.05 (1H, d)

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine -2-yl] phenyl] phenyl carbamate

At 5 ℃; in nitrogen atmosphere; by phenyl chloroformate (0.535mL; 4.26mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine-2-base] aniline (1.4g; 2.84mmol) and sodium bicarbonate (in 0.358g, 4.26mmol) diox (20mL) mixture.At room temperature the mixture obtained is stirred 2 hours, then use ethyl acetate (200mL) diluted reaction mixture, water (125mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and its mixture with diethyl ether and isohexane is ground, and obtains needed material white solid (1.70g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 3.19 (1H, td), 3.49 (1H, td), (3.64 1H, dd), 3.77 (1H, d), 3.98 (1H, dd), (4.13 1H, d), 4.47 (1H, s), 4.79 (2H, s), 6.75 (1H, s), 7.23-7.31 (3H, m), (7.42-7.51 4H, m), 7.77-7.83 (2H, m), 7.87-7.92 (2H, m), 8.09 (1H, d), 10.39 (1H, s)

the LCMS spectrum: MH+613, retention time 2.92 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine-2- base] aniline

In room temperature; by two (triphenylphosphine) Palladous chloride (II) (300mg; 0.43mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] pyrimidine (1.66g; 3.81mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (1.252g; 5.71mmol) and the mixture of ethanol (6mL), DMF (10mL), water (6mL) and the DME (20mL) of sodium carbonate (10mL, 20.00mmol) in.The mixture obtained is degassed, then at 95 ℃, stir 18 hours.Reaction mixture is cooling, then use ethyl acetate (400mL) dilution, water (2x200mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 10, to 60% ethyl acetate/isohexane, obtains needed material paste crystalline solid (1.40g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 3.14 (1H, td), 3.47 (1H, td), (3.62 1H, dd), 3.75 (1H, d), 3.96 (1H, dd), (4.04-4.11 1H, m), 4.41 (1H, s), 4.72 (2H, s), 5.51 (2H, s), 6.47 (2H, d), (6.59 1H, s), 7.56 (2H, d), 7.76-7.81 (1H, m), 7.86-7.92 (2H, m), 8.07 (1H, d)

the LCMS spectrum: MH+493, retention time 2.35 minutes

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-6-[[2-(trifluoromethyl) phenyl] the alkylsulfonyl methyl] preparation of pyrimidine.

embodiment 66:

3-ethyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

By ethylamine hydrochloride (86.4mg; 1.03mmol) join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] phenyl carbamate (120mg; 0.23mmol) and DMF (2mL) solution of triethylamine (0.21mL, 1.49mmol) in.In room temperature, make reaction mixture sat 65 hours.Purify crude product with preparative HPLC, use polarity water decrescence (to contain 1%NH ₃) and the mixture of acetonitrile as elutriant, obtain needed material (79.0mg) colorless solid.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.25 (3H, d), 1.39 (9H, s), 3.10-3.25 (3H, m), 3.45-3.54 (1H, m), (3.63-3.69 1H, m), 3.79 (1H, d), 3.95-4.03 (1H, m), 4.18 (1H, d), 4.46 (3H, s), (6.18 1H, t), 6.75 (1H, s), 7.50 (2H, m), 8.21 (2H, d), 8.68 (1H, s)

the LCMS spectrum: MH+476, retention time 2.04 minutes

Use similar fashion, by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 66a: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24 (3H, d), 1.39 (9H, s), 1.54-1.69 (2H, m), (1.79-1.92 2H, m), 2.15-2.27 (2H, m), 3.15-3.25 (1H, m), (3.51 1H, t), 3.66 (1H, d), 3.78 (1H, d), (3.99 1H, d), 4.10-4.22 (2H, m), 4.46 (3H, s), (6.46 1H, d), 6.75 (1H, s), 7.48 (2H, d), 8.21 (2H, d), 8.1 (1H, s)

Embodiment 66b: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.24-1.25 (3H, m), 1.39 (9H, s), 2.19 (6H, s), (2.34 2H, t), 3.19-3.25 (1H, m), 3.45-3.56 (1H, m), (3.62-3.68 1H, m), 3.79 (1H, d), 3.95-4.02 (1H, m), (4.08 2H, q), 4.18 (1H, d), 4.46 (3H, s), (6.17 1H, t), 6.75 (1H, s), 7.49 (2H, d), 8.21 (2H, d), 8.90 (1H, s)

Embodiment 66c: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.41-0.44 (2H, m), 0.63-0.68 (2H, m), (1.15 9H, s), 1.21 (3H, d), (1.85 3H, s), 1.88 (3H, s), (2.55-2.59 1H, m), 3.18 (1H, dt), (3.51 1H, dt), 3.66 (1H, dd), (3.78 1H, d), 3.99 (1H, dd), (4.22 1H, d), 4.51 (1H, br, s), 6.44 (1H, d), 6.88 (1H, s), 7.52 (2H, d), 8.27 (2H, d), 8.55 (1H, s)

Embodiment 66d: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.15 (9H, s), 1.21 (3H, d), (1.58-1.68 2H, m), 1.80-1.91 (8H, m), (2.15-2.25 2H, m), 3.12-3.23 (1H, m), (3.45-3.55 1H, m), 3.62-3.68 (1H, m), (3.78 1H, d), 3.94-4.02 (1H, m), (4.08-4.26 2H, m), 4.51 (1H, br, s), 6.47 (1H, d), 6.88 (1H, s), (7.49 2H, d), 8.26 (2H, d), 8.58 (1H, s)

Embodiment 66e: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.15 (9H, s), 1.21 (3H, d), (1.85 3H, s), 1.88 (3H, s), 3.10-3.24 (3H, m), (3.44-3.55 1H, m), 3.62-3.68 (1H, m), 3.78 (1H, d), (3.94-4.01 1H, m), 4.22 (1H, d), 4.51 (1H, br, s), 6.17 (1H, t), 6.88 (1H, s), 7.51 (2H, d), 8.26 (2H, d), 8.67 (1H, s)

Embodiment 66f: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.15 (9H, s), 1.21 (3H, d), (1.85 3H, s), 1.88 (3H, s), (2.19 6H, s), 2.35 (2H, t), (3.13-3.23 3H, m), 3.45-3.54 (1H, m), (3.62-3.68 1H, m), 3.78 (1H, d), (3.94-4.01 1H, m), 4.22 (1H, d), (4.52 1H, br, s), 6.17 (1H, t), 6.88 (1H, s), (7.50 2H, d), 8.26 (2H, d), 8.91 (1H, s)

Embodiment 66g: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.15 (9H, s), 1.21 (3H, d), 1.85 (3H, s), (1.88 3H, s), 3.12-3.22 (3H, m), 3.43-3.54 (3H, m), (3.62-3.68 1H, m), 3.78 (1H, d), 3.95-4.01 (1H, m), (4.22 1H, d), 4.51 (1H, br, s), 4.74 (1H, t), 6.27 (1H, t), 6.88 (1H, s), 7.50 (2H, d), 8.27 (2H, d), 8.82 (1H, s)

Embodiment 66h: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.15 (9H, s), 1.21 (3H, d), (1.85 3H, s), 1.88 (3H, s), (2.67 3H, d), 3.14-3.23 (1H, m), (3.46-3.55 1H, m), 3.63-3.69 (1H, m), (3.78 1H, d), 3.96-4.02 (1H, m), (4.22 1H, d), 4.52 (1H, br, s), 6.06-6.12 (1H, m), 6.88 (1H, s), (7.52 2H, d), 8.26 (2H, d), 8.77 (1H, s)

Test (c): embodiment (66c) 0.15 μ M; Embodiment (66d) 0.16 μ M; Embodiment (66e) 0.26 μ M; Embodiment (66f) 0.04 μ M; Embodiment (66g) 0.3 μ M.

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] phenyl carbamate

In room temperature; by phenyl chloroformate (0.368mL; 2.93mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline (1.153g; 2.67mmol) and sodium bicarbonate (in 0.336g, 4.00mmol) diox (20mL) mixture.The slurries that obtain are at room temperature stirred 2 hours.Reaction mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, filter concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 20%-70% ethyl acetate/isohexane wash-out, obtain needed material and connect subdiaphanous solid (1.42g).

the NMR spectrum: ¹h NMR (400.13MHz, CDCl ₃) δ 1.25 (9H, s), 1.32 (3H, d), 1.95 (3H, s), (1.97 3H, s), 3.31 (1H, dt), 3.61 (1H, dt), (3.76 1H, dd), 3.83 (1H, d), 4.05 (1H, dd), (4.18 1H, d), 4.47 (1H, br), 6.88 (1H, s), (7.10 1H, br, s), 7.20-7.27 (3H, m), 7.41 (2H, t), 7.55 (2H, d), 8.43 (2H, d)

the LCMS spectrum: MH+553, retention time 3.05 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine)-palladium (the II) (0.103g of dichloro; 0.15mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine (1.10g; 2.93mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) in the solution of DMF (6mL), DME (5mL), ethanol (5mL) and the water (12.5mL) of aniline (0.833g, 3.80mmol) and 2M aqueous sodium carbonate (5.27mL, 10.53mmol).With nitrogen purging reaction 15 minutes, and the mixture obtained is stirred 16 hours at 80 ℃.Reaction mixture is diluted by ethyl acetate, wash with water.Dry (MgSO ₄) organic solution, filter concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-100% ethyl acetate/isohexane wash-out, obtain needed material yellow solid (1.19g).

the NMR spectrum: ¹h NMR (400MHz, CDCl ₃) δ 1.24 (9H, s), 1.30 (3H, d), 1.93 (3H, s), 1.95 (3H, s), 3.28 (1H, dt), (3.60 1H, dt), 3.75 (1H, dd), 3.82 (1H, d), 3.90 (2H, s), 4.03 (1H, dd), (4.16 1H, d), 4.46 (1H, br), 6.72 (2H, d), 6.79 (1H, s), 8.26 (2H, d)

the LCMS spectrum: MH+433, retention time 2.42 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-tertiary butyl alkylsulfonyl third-2-yl) pyrimidine

At 0 ℃; in nitrogen atmosphere; sodium tert-butoxide (0.345g, 3.59mmol) is joined to the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-DMF (30mL) solution of 6-(tertiary butyl alkylsulfonyl methyl) pyrimidine (1.250g, 3.59mmol) in.Add methyl iodide (0.224mL, 3.59mmol), and the solution obtained is stirred 15 minutes at 0 ℃.Further add sodium tert-butoxide (0.345g, 3.59mmol), then add methyl iodide (0.224mL, 3.59mmol), at 0 ℃ by the solution stirring that obtains 1 hour.With DCM (100mL) diluting reaction, water (100mL) and salt solution (100mL) washing.Dry (MgSO ₄) organic layer, filtering, evaporating solvent, obtain colloid, and it is crystallization at leisure.Crude product is carried out to silica gel chromatography, with 0-40% ethyl acetate/DCM wash-out, obtain needed material colorless solid (1.14g).

the NMR spectrum: ¹h NMR (400MHz, CDCl ₃) δ 1.28 (9H, s), 1.30 (3H, d), (1.84 3H, s), 1.86 (3H, s), (3.27 1H, dt), 3.54 (1H, dt), (3.69 1H, dd), 3.79 (1H, d), (3.99-4.05 2H, m), 4.30 (1H, br, s), 6.89 (1H, s).

the LCMS spectrum: MH+376,378, retention time 2.52 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine

By hydrogen peroxide (9.48mL, 107.30mmol) (35% aqueous solution) solution dropwise joins the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(tertiary butyl sulfanylmethyl) pyrimidine (9.82g, 31.1mmol), sodium tungstate dihydrate (0.205g, 0.62mmol) and sulfuric acid (0.6mL, in 1M, 0.6mmol) diox (80mL) stirred solution.55 ℃, under air conditions by mixture heating 1 hour.When reaction completes, dilute with water solution, cooling.Add sodium metabisulfite solution (10%w/v), to destroy remaining superoxide.Extract solution with DCM, dry (MgSO ₄), filter, obtain needed material and approach colourless colloid (9.34g).

the NMR spectrum: ¹h NMR (399.9MHz, CDCl ₃) δ 1.33 (3H, d), 1.44 (9H, s), 3.29 (1H, dt), 3.54 (1H, dt), 3.69 (1H, dd), 3.78 (1H, d), 3.97-4.13 (2H, m), (4.21 2H, s), 4.30 (1H, br, s), 6.71 (1H, s).

the LCMS spectrum: MH+348,350, retention time 1.82 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(tertiary butyl sulfanylmethyl) pyrimidine

In room temperature, in nitrogen atmosphere, N-ethyl diisopropyl amine (8.61mL, 49.78mmol) is joined in DMF (55mL) solution of 2-methyl-2-propylmercaptan (4.21mL, 37.33mmol).By the solution that obtains stirring at room 20 minutes.By the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (11.00g, 31.11mmol) once joins in reaction mixture.Mixture is at room temperature stirred 4 hours.Reaction mixture is placed in the water-bath of 60 ℃ to 1.5 hours, then distributes between ethyl acetate and water.With extra water washing organic layer, dry (MgSO then ₄), to filter, evaporation, obtain the yellow colloid (10.02g) of needed material.

the NMR spectrum: 1H NMR (399.9MHz, CDCl3) δ 1.31 (3H, d), 1.34 (9H, s), 3.27 (1H, dt), 3.54 (1H, dt), 3.66-3.71 (3H, m), (3.78 1H, d), 3.97-4.07 (2H, m), 4.31 (1H, br, s), 6.56 (1H, s)

the LCMS spectrum: MH+316,318, retention time 2.61 minutes

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] phenyl] phenyl carbamate

By phenyl chloroformate (0.227mL; 1.81mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] aniline (665mg; 1.64mmol) and sodium bicarbonate (in 207mg, 2.47mmol) diox (12mL) solution.The slurries that obtain are at room temperature stirred 1 hour.Mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-80% ethyl acetate/isohexane wash-out, obtain the yellow dry film (860mg) of needed material.

the NMR spectrum: ¹h NMR (400MHz, CDCl ₃) δ 1.34 (3H, d), 1.44 (9H, s), 332 (1H, dt), (3.60 1H, dt), 3.75 (1H, dd), 3.82 (1H, d), (4.04 1H, dd), 4.20 (1H, d), 4.34 (2H, s), 4.46 (1H, br), 6.68 (1H, s), (7.10 1H, s), 7.19-7.27 (3H, m), 7.40 (2H, t), 7.53 (2H, d), 8.37 (2H, d)

the LCMS spectrum: MH+525, retention time 2.69 minutes.

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine)-palladium (the II) (63mg of dichloro; 0.09mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(tertiary butyl alkylsulfonyl methyl) pyrimidine (626mg; 1.8mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) in the mixture of DMF (3.75mL), DME (5mL), ethanol (5mL) and the water (12.5mL) of aniline (513mg, 2.34mmol) and 2M aqueous sodium carbonate (3.24mL, 6.48mmol).With nitrogen purging reaction mixture 15 minutes, and the mixture obtained is stirred 16 hours at 80 ℃.Mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, filter concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-100% ethyl acetate/isohexane wash-out, obtain needed material yellow solid (681mg).

the NMR spectrum: ¹h NMR (400MHz, CDCl ₃) δ 1.32 (3H, d), 1.43 (9H, s), 3.30 (1H, m), 3.60 (1H, m), 3.74 (1H, dd), (3.81 1H, d), 3.89 (2H, s), 4.03 (1H, dd), 4.18 (1H, d), 4.31 (2H, d), (4.44 1H, br), 6.61 (1H, s), (6.71 2H, d), 8.21 (2H, d)

the LCMS spectrum: MH+405, retention time 1.98 minutes

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-preparation of 6-(tertiary butyl alkylsulfonyl methyl) pyrimidine.

embodiment 67:

1-[4-[4-[(3, the 5-difluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-ethyl-urea

In room temperature; by N-[4-[4-[(3; the 5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (120mg; 0.207mmol) join ethylamine hydrochloride (86mg; 1.03mmol) and DMF (1.5mL) mixture of triethylamine (0.2mL, 1.49mmol) in.In room temperature, make reaction mixture sat 65 hours.Purify crude product with preparative HPLC, use the mixture of water (containing 1% ammonia) decrescence of polarity and acetonitrile as elutriant, obtain needed material (19.0mg) colorless solid.

the NMR spectrum: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.22 (3H, d), 3.09-3.3 (3H, m), (3.44-3.3 1H, m), 3.61-3.67 (1H, m), 3.78 (1H, d), (3.94-4.01 1H, m), 4.09-4.18 (1H, m), 4.41 (1H, br, s), 4.87 (2H, s), 6.16 (1H, t), (6.71 1H, s), 7.40 (2H, d), 7.58-7.64 (2H, m), 7.72-7.83 (3H, m), 8.65 (1H, s).

the LCMS spectrum: MH+532, retention time 2.29 minutes

Use similar fashion; by N-[4-[4-[(3; the 5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[2-(3,5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 67a: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.56-1.70 (2H, m), (1.80-1.94 2H, m), 2.15-2.27 (2H, m), (3.14-3.24 1H, m), 3.44-3.53 (1H, m), (3.61-3.67 1H, m), 3.77 (1H, d), (3.95-4.02 1H, m), 4.08-4.20 (2H, m), (4.41 1H, br, s), 4.87 (2H, s), 6.46 (1H, d), 6.71 (1H, s), 7.38 (2H, d), (7.59-7.64 2H, m), 7.72-7.83 (3H, m), 8.55 (1H, s).

Embodiment 67b: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.22 (3H, d), 2.19 (6H, s), (2.34 2H, t), 3.14-3.23 (3H, m), (3.44-3.54 1H, m), 3.62-3.66 (1H, m), (3.77 1H, d), 3.94-4.00 (1H, m), (4.06-4.14 1H, m), 4.41 (1H, br, s), 4.87 (2H, s), (6.16 1H, t), 6.71 (1H, s), 7.39 (2H, d), (7.58-7.64 2H, m), 7.74-7.83 (3H, m), 8.88 (1H, s).

Embodiment 67c: ¹h NMR (399.9MHz, DMSO-d ₆) δ 0.39-0.45 (2H, m), 0.62-0.69 (2H, m), (1.23 3H, d), 1.82 (6H, s), (2.54-2.60 1H, m), 3.13-3.22 (1H, m), (3.46-3.54 1H, m), 3.62-3.68 (1H, m), (3.78 1H, d), 3.95-4.00 (1H, m), (4.18 1H, d), 4.59 (1H, br, s), 6.43 (1H, s), 6.71 (1H, s), 7.16-7.23 (2H, d), 7.41 (2H, d), 7.60-7.67 (1H, m), 7.84 (2H, d), 8.53 (1H, s).

Embodiment 67d: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.56-1.69 (2H, m), (1.78-1.92 8H, m), 2.17-2.26 (2H, m), (3.12-3.22 1H, m), 3.46-3.53 (1H, m), (3.61-3.68 1H, m), 3.78 (1H, d), (3.95-4.02 1H, m), 4.10-4.22 (2H, m), (4.59 1H, br, s), 6.46 (1H, d), 6.71 (1H, s), 7.15-7.23 (2H, m), 7.38 (2H, d), (7.60-7.68 1H, m), 7.84 (2H, d), 8.55 (1H, s).

Embodiment 67e: ¹h NMR (399.9MHz, DMSO-d ₆) δ 1.08 (3H, t), 1.23 (3H, d), 1.83 (6H, s), (3.09-3.22 3H, m), 3.50 (1H, t), 3.66 (1H, d), (3.78 1H, d), 3.99 (1H, d), 4.19 (1H, d), (4.60 1H, br, s), 6.16 (1H, s), 6.71 (1H, s), 7.21 (2H, s), 7.41 (2H, d), 7.59-7.69 (1H, m), 7.84 (2H, d), 8.65 (1H, s).

Embodiment 67f: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.80-1.83 (6H, m), (2.18 6H, s), 2.34 (2H, t), (3.12-3.23 3H, m), 3.44-3.54 (1H, m), (3.63-3.67 1H, m), 3.77 (1H, d), (3.94-4.01 1H, m), 4.18 (1H, d), (4.59 1H, br, s), 6.15 (1H, t), 6.70 (1H, s), 7.15-7.23 (2H, m), 7.39 (2H, d), (7.59-7.66 1H, m), 7.84 (2H, d), 8.86 (1H, s).

Embodiment 67g: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.80-1.83 (6H, m), (3.12-3.23 3H, m), 3.40-3.53 (3H, m), (3.62-3.67 1H, m), 3.77 (1H, d), (3.95-4.01 1H, m), 4.18 (1H, d), (4.59 1H, br, s), 4.73 (1H, t), 6.24 (1H, t), (6.70 1H, s), 7.16-7.23 (2H, m), 7.39 (2H, d), (7.59-7.66 1H, m), 7.84 (2H, d), 8.78 (1H, s).

Embodiment 67h: ¹h NMR (400.13MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.82 (6H, s), (2.66 3H, d), 3.12-3.22 (1H, m), (3.44-3.54 1H, m), 3.60-3.68 (1H, m), (3.77 1H, d), 3.93-4.00 (1H, m), (4.18 1H, d), 4.58 (1H, br, s), 6.03-6.09 (1H, m), (6.70 1H, s), 7.14-7.23 (2H, m), 7.40 (2H, d), (7.63 1H, t), 7.83 (2H, d), 8.71 (1H, s).

N-[4-[4-[2-(3,5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[2-(3,5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine -2-yl] phenyl] phenyl carbamate

By phenyl chloroformate (0.413mL; 3.29mmol) join 4-[4-[2-(3; the 5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.46g; 2.99mmol) and sodium bicarbonate (in 0.377g, 4.48mmol) diox (25mL) solution.The slurries that obtain are at room temperature stirred 1 hour.Mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, filter concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-80% ethyl acetate/isohexane wash-out, obtain colourless colloid.Grind this material with diethyl ether, obtain needed material colourless crystallization solid (1.808g).

the NMR spectrum: ¹h NMR (399.9MHz, CDCl ₃) δ 1.36 (3H, d), 1.89 (6H, s), 3.34 (1H, dt), (3.63 1H, dt), 3.79 (1H, dd), 3.86 (1H, d), (4.08 1H, dd), 4.14 (1H, d), 4.48-4.58 (1H, m), 6.66 (1H, s), 6.88-6.95 (1H, m), (7.04 1H, s), 7.08-7.13 (2H, m), 7.19-7.28 (3H, m), 7.38-7.44 (4H, m), 7.98 (2H, d).

the LCMS spectrum: MH+609, retention time 3.26 minutes

4-[4-[2-(3,5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2- base] aniline

In room temperature; nitrogen gas stream is passed through to the chloro-4-[2-(3 of 2-; the 5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.4g; 3.24mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.923g; 4.21mmol) and DMF (6mL), DME (5mL), ethanol (5mL) and water (12.5mL) solution of 2M aqueous sodium carbonate (5.83mL, 11.67mmol).By two (triphenylphosphine) palladium (II) (0.114g, the 0.16mmol) reaction mixture of dichloro, at 80 ℃, stir 1 hour.Reaction mixture is diluted by ethyl acetate, wash with water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-60% ethyl acetate/isohexane wash-out, obtain needed material light yellow solid (1.496g).

the NMR spectrum: ¹h NMR (400MHz, CDCl ₃) δ 1.34 (3H, d), 1.88 (6H, s), 3.32 (1H, dt), 3.63 (1H, dt), 3.77 (1H, dd), (3.82 1H, s), 3.86 (2H, s), 4.05 (1H, dd), 4.12 (1H, d), 4.46-4.54 (1H, m), (6.57-6.62 3H, m), 6.88-6.93 (1H, m), (7.08-7.12 2H, m), 7.82 (2H, d).

the LCMS spectrum: MH+489, retention time 2.77 minutes

the chloro-4-[2-of 2-(3,5-difluorophenyl) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At 0 ℃; in nitrogen atmosphere, sodium tert-butoxide (0.336g, 3.49mmol) is joined to the chloro-4-[(3 of 2-; the 5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] in DMF (30mL) mixture of pyrimidine (1.41g, 3.49mmol).Add methyl iodide (0.217mL, 3.49mmol), and the solution obtained is stirred 15 minutes at 0 ℃.Add sodium tert-butoxide (0.336g, 3.49mmol), then add methyl iodide (0.217mL, 3.49mmol), at 0 ℃ by the solution stirring that obtains 1 hour.Reactant is poured in water (100mL).The precipitation that filtering separation obtains, vacuum-drying, obtain needed product colorless solid (1.434g).

the NMR spectrum: ¹h NMR (399.9MHz, CDCl ₃) δ 1.34 (3H, d), 1.77 (6H, s), (3.32 1H, dt), 3.58 (1H, dt), (3.72 1H, dd), 3.81 (1H, d), (3.97-4.05 2H, m), 4.36 (1H, br, s), 6.69 (1H, s), 7.07-7.16 (3H, m).

the LCMS spectrum: MH+432,434, retention time 2.78 minutes

the chloro-4-[(3 of 2-, the 5-difluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

By sodium tungstate dihydrate (199mg, 0.60mmol) solution in water (2mL) joins the chloro-4-[(3 of 2-, the 5-difluorophenyl) sulfanylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (11.23g, 30.2mmol) and 2M sulfuric acid (in 0.302mL, 0.60mmol) diox (40mL) stirred solution.Add hydrogen peroxide (3.22mL, 104.19mmol), in the stirring at room mixture overnight.Filter collecting precipitation, vacuum-drying.Filtrate is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 5%-20% ethyl acetate/DCM wash-out, the product and the sedimentable matter that obtain are merged, obtain needed material and approach colorless solid (11.27g).

the NMR spectrum: 1H NMR (400MHz, CDCl ₃) δ 1.34 (3H, s), 3.31 (1H, dt), 3.56 (1H, dt), 3.71 (1H, dd), 3.80 (1H, d), 3.98-4.10 (2H, m), 4.31 (2H, s), (6.55 1H, s), 7.12 (1H, tt), 7.30-7.36 (2H, m).

the LCMS spectrum: MH+404,406, retention time 2.32 minutes

the chloro-4-[(3 of 2-, the 5-difluorophenyl) sulfanylmethyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, in nitrogen atmosphere, DIPEA (8.07mL, 46.67mmol) is joined in DMF (55mL) solution of 3,5-difluoro thiophenol (5.00g, 34.22mmol).By the solution that obtains stirring at room 20 minutes.By the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (11.00g, 31.11mmol) joins in reaction mixture once.Mixture is at room temperature stirred 4 hours.Reaction mixture is heated 1.5 hours in the water-bath of 60 ℃, then distribute between ethyl acetate and water.Water further washs organic solution, dry (MgSO ₄), to filter, evaporation, obtain needed material colloid (12.24g).

the NMR spectrum: ¹h NMR (399.9MHz, CDCl ₃) δ 1.27 (3H, d), 3.24 (1H, dt), (3.52 1H, dt), 3.66 (1H, dd), (3.76 1H, d), 3.96-4.04 (4H, m), (4.21 1H, br, s), (6.41 1H, s), 6.59-6.66 (1H, m), 6.80-6.86 (2H, m).

the LCMS spectrum: MH+372,374, retention time 2.66 minutes

N-[4-[4-[(3,5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3, the 5-difluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2- base] phenyl] phenyl carbamate

By phenyl chloroformate (0.208mL; 1.66mmol) join 4-[4-[(3; the 5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (693mg; 1.50mmol) and sodium bicarbonate (in 190mg, 2.26mmol) diox (10mL) mixture.The slurries that obtain are at room temperature stirred 1 hour.Mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-80% ethyl acetate/isohexane wash-out, obtain the yellow dry film (827mg) of needed product.

the NMR spectrum: ¹h NMR (399.9MHz, CDCl ₃) δ 1.35 (3H, d), 3.33 (1H, dt), (3.61 1H, dt), 3.76 (1H, dd), (3.83 1H, d), 4.16 (1H, d), (4.38-4.48 3H, m), 6.48 (1H, s), (698-7.08 2H, m), 7.19-7.28 (4H, m), (7.32-7.47 5H, m), 8.02 (2H, d).

the LCMS spectrum: MH+581, retention time 2.91 minutes

4-[4-[(3, the 5-difluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

Nitrogen gas stream is passed through to the chloro-4-[(3 of 2-; the 5-difluorophenyl) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (0.727g; 1.8mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.513g; 2.34mmol) and DMF (3.75mL), the DME (5mL) of 2M aqueous sodium carbonate (3.24mL, 6.48mmol), ethanol (5mL) and water (12.5mL) mixture 15 minutes.By two (triphenylphosphine) palladium (II) (0.063g, the 0.09mmol) reaction mixture of dichloro, at 80 ℃, stir the mixture 16 hours.Mixture is distributed between ethyl acetate and water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 25%-60% ethyl acetate/isohexane wash-out, obtain needed product yellow solid (0.735g).

the NMR spectrum:: ¹h NMR (400MHz, CDCl ₃) δ 1.33 (3H, t), 3.31 (1H, dt), 3.60 (1H, dt), 3.75 (1H, dd), 3.80-3.93 (3H, m), (4.01-4.08 1H, dd), 4.15 (1H, d), (4.40 3H, s), 6.40 (1H, s), (6.62 2H, d), 7.01 (1H, tt), (7.32-7.38 2H, m), 7.85 (2H, d).

the LCMS spectrum: MH+461, retention time 2.46 minutes

The chloro-4-[(3 of 2-had before been described, the 5-difluorophenyl) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 68:

1-[4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-cyclopropyl-urea

To cyclopropylamine (53mg; 0.93mmol) DMF (2mL) solution in add triethylamine (0.09mL; 0.64mmol); then add N-[4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate (118mg, 0.20mmol).The mixture obtained is heated to 50 ℃, stirs 2 hours.Reaction mixture, with further dilution of DMF (1mL), then with preparative HPLC, purify the crude product reaction mixture, use the mixture of water (containing 1% ammonia soln) decrescence of polarity and acetonitrile as elutriant, obtain needed material white solid (75mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.00-1.19 3H, m), 1.22 (3H, d), (1.24-1.37 2H, m), 1.47-1.53 (1H, m), (1.64-1.82 10H, m), 2.53-2.59 (1H, m), (3.20 1H, td), 3.50 (1H, td), (3.65 1H, dd), 3.71-3.78 (2H, m), (3.98 1H, dd), 4.23 (1H, d), (4.56-4.62 1H, m), 6.44 (1H, d), (6.75 1H, s), 7.52 (2H, d), (8.25 2H, d), 8.55 (1H, s).

the LCMS spectrum: MH+542, retention time 2.37 minutes

Use similar fashion, by N-[4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 68a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.02-1.18 (3H, m), 1.22 (3H, d), (1.25-1.35 2H, m), 1.47-1.53 (1H, m), (1.57-1.91 14H, m), 2.18-2.25 (2H, m), (3.20 1H, td), 3.50 (1H, td), (3.65 1H, dd), 3.70-3.78 (2H, m), (3.98 1H, dd), 4.11-4.26 (2H, m), (4.55-4.61 1H, m), 6.48 (1H, d), 6.75 (1H, s), (7.49 2H, d), 8.24 (2H, d), 8.58 (1H, s).

Embodiment 68b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.99-1.17 (6H, m), 1.22 (3H, d), (1.25-1.36 2H, m), 1.47-1.53 (1H, m), (1.64-1.84 10H, m), 3.10-3.16 (2H, m), (3.20 1H, td), 3.50 (1H, td), (3.65 1H, dd), 3.71-3.78 (2H, m), (3.98 1H, dd), 4.23 (1H, d), (4.55-4.62 1H, m), 6.17 (1H, t), 6.75 (1H, s), (7.51 2H, d), 8.25 (2H, d), 8.68 (1H, s).

Embodiment 68c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.99-1.19 (3H, m), 1.22 (3H, d), (1.25-1.37 2H, m), 1.48-1.53 (1H, m), (1.64-1.84 10H, m), 2.18 (6H, s), (2.34 2H, t), 3.17-3.24 (3H, m), (3.50 1H, td), 3.65 (1H, dd), (3.70-3.78 2H, m), 3.98 (1H, dd), (4.23 1H, d), 4.56-4.62 (1H, m), (6.17 1H, t), 6.75 (1H, s), (7.50 2H, d), 8.25 (2H, d), 8.91 (1H, s).

Embodiment 68d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.99-1.18 (3H, m), 1.22 (3H, d), (1.25-1.37 2H, m), 1.47-1.53 (1H, m), (1.63-1.84 10H, m), 3.16-3.24 (3H, m), (3.44-3.53 3H, m), 3.65 (1H, dd), (3.70-3.78 2H, m), 3.98 (1H, dd), (4.23 1H, d), 4.56-4.63 (1H, m), (4.73 1H, t), 6.26 (1H, t), 6.75 (1H, s), (7.50 2H, d), 8.25 (2H, d), 8.82 (1H, s).

Embodiment 68e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.00-1.18 (3H, m), 1.22 (3H, d), (1.25-1.36 2H, m), 1.47-1.52 (1H, m), (1.64-1.84 10H, m), 2.66 (3H, d), (3.20 1H, td), 3.50 (1H, td), (3.65 1H, dd), 3.71-3.78 (2H, m), (3.98 1H, dd), 4.23 (1H, d), (4.56-4.61 1H, m), 6.08 (1H, q), 6.75 (1H, s), (7.52 2H, d), 8.25 (2H, d), 8.76 (1H, s).

Embodiment 68f: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18-1.31 (6H, m), 1.41-1.49 (2H, m), (1.57-1.69 3H, m), 1.82-1.92 (4H, m), (2.18-2.28 4H, m), 3.22 (1H, td), (3.34 1H, tt), 3.50 (1H, td), (3.65 1H, dd), 3.78 (1H, d), (3.99 1H, dd), 4.09-4.22 (2H, m), (4.40-4.51 3H, m), 6.48 (1H, d), 6.77 (1H, s), (7.48 2H, d), 8.19 (2H, d), 8.58 (1H, s).

Embodiment 68g: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.15-1.33 (6H, m), (1.39-1.50 2H, m), 1.65-1.71 (1H, m), (1.86-1.92 2H, m), 2.21-2.28 (2H, m), (3.09-3.16 2H, m), 3.22 (1H, td), (3.34 1H, tt), 3.50 (1H, td), (3.65 1H, dd), 3.78 (1H, d), (3.99 1H, dd), 4.13-4.21 (1H, m), (4.40-4.51 3H, m), 6.18 (1H, t), (6.77 1H, s), 7.50 (2H, d), (8.20 2H, d), 8.68 (1H, s).

Embodiment 68h: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.16-1.33 (6H, m), 1.39-1.50 (2H, m), (1.65-1.71 1H, m), 1.86-1.92 (2H, m), (2.18 6H, s), 2.21-2.27 (2H, m), (2.34 2H, t), 3.17-3.26 (3H, m), (3.34 1H, tt), 3.50 (1H, td), (3.65 1H, dd), 3.78 (1H, d), (3.99 1H, dd), 4.14-4.21 (1H, m), (4.40-4.51 3H, m), 6.18 (1H, t), (6.77 1H, s), 7.49 (2H, d), (8.20 2H, d), 8.90 (1H, s).

N-[4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

To 4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (1.1g; 2.40mmol) 1; add sodium bicarbonate (0.302g, 3.60mmol) in 4-diox (12mL) solution.Then dropwise add phenyl chloroformate (0.316mL, 2.52mmol), and by the mixture that obtains stirring at room 3 hours.The mixture that evaporate to dryness obtains distributes resistates between water (10mL) and DCM (10mL).Separate organic layer, evaporate to dryness.Use the diethyl ether grinding residues, obtain needed material solid (1.328g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.99-1.18 (3H, m), 1.20-1.37 (5H, m), (1.46-1.52 1H, m), 1.63-1.83 (10H, m), (3.21 1H, td), 3.51 (1H, td), 3.65 (1H, dd), (3.69-3.79 3H, m), 3.98 (1H, dd), 4.21-4.28 (1H, m), (4.56-4.64 1H, m), 7.24-7.30 (3H, m), 7.45 (2H, t), (7.65 2H, d), 8.36 (2H, d), 10.43 (1H, s).

the LCMS spectrum: MH+579, retention time 3.11 minutes

4-[4-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By the chloro-4-of 2-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.18g; 2.94mmol), 2M aqueous sodium carbonate (5.5mL; 11.00mmol) and 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.907g; 4.14mmol) nitrogen purging 10 minutes for mixture in DMF (5mL), water (12.50mL), ethanol (5.00mL) and DME (5.00mL) mixture; then use two (triphenylphosphine) Palladous chloride (II) (0.111g, 0.16mmol) to process.To stir the mixture and be heated to 80 ℃, stir 2.5 hours in nitrogen atmosphere.Reaction mixture, process with ethyl acetate (50mL) and water (50mL).Separate organic layer, by ethyl acetate (2x30mL), extract again the aqueous solution.The organism merged with the salt water washing, dry (MgSO ₄), evaporation, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 25, to 75% ethyl acetate/isohexane, obtains needed material (1.130g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.99-1.23 (6H, m), 1.25-1.36 (2H, m), 1.47-1.53 (1H, m), 1.65-1.83 (10H, m), 3.18 (1H, td), (3.49 1H, td), 3.64 (1H, dd), 3.73-3.81 (2H, m), 3.97 (1H, dd), 4.19 (1H, d), (4.52-4.58 1H, m), 5.54-5.57 (2H, m), 6.62 (2H, d), 6.64 (1H, s), 8.08 (2H, d).

the LCMS spectrum: MH+459, retention time 2.56 minutes

the chloro-4-of 2-(2-cyclohexyl alkylsulfonyl third-2-yl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

By the chloro-4-of 2-of cooling (ice/water bath) (cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (1.26g; 3.37mmol) DMF (16mL) sodium tert-butoxide for solution (0.324g, 3.37mmol) process.Mixture is stirred 5 minutes at 0 ℃.Then add methyl iodide (0.210mL, 3.37mmol), and mixture is further stirred 10 minutes at 0 ℃.Then further add sodium tert-butoxide (0.324g, 3.37mmol), continue to stir 5 minutes, then add more methyl iodide (0.210mL, 3.37mmol).The mixture obtained is further stirred 15 minutes at 0 ℃.Then remove cooling bath, the order reaction heats up, and is stirred to room temperature.Water (75mL) is joined in reaction mixture, and suction strainer is collected the precipitation obtained, and with more water (40mL) washing, drying, obtain needed material (1.180g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.04-1.15 (1H, m), 1.19-1.37 (7H, m), 1.54-1.60 (1H, m), 1.69 (6H, s), 1.70-1.80 (4H, m), (3.17-3.25 1H, m), 3.45 (1H, td), (3.52-3.62 2H, m), 3.72 (1H, d), (3.94 1H, dd), 4.07 (1H, d), (4.39-4.48 1H, m), 6.89 (1H, s).

the LCMS spectrum: MH+402, retention time 2.72 minutes

the chloro-4-of 2-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

To cooling (ice/water bath) 2, add triethylamine (0.820mL, 5.88mmol) in DCM (25mL) solution of the chloro-6-of 4-bis-(cyclohexyl alkylsulfonyl methyl) pyrimidine (1.65g, 5.34mmol).With 8 minutes, the solution obtained is dropwise processed with DCM (5mL) solution of (3S)-3-methylmorpholine (609mg, 6.02mmol).At 6 ℃, stir the mixture 30 minutes.Then remove cooling bath, stirred reaction mixture spends the night.Then add water (25mL), stirred reaction mixture 5 minutes.Then separate organic layer, dry (MgSO ₄), evaporation, obtain the crude product brown oil, and crude product is purified with fast silica gel chromatogram, and gradient 25, to 75% ethyl acetate/isohexane, obtains needed material (1.440g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.15-1.45 (8H, m), 1.63-1.68 (1H, m), (1.81-1.87 2H, m), 2.11-2.17 (2H, m), (3.15-3.25 2H, m), 3.45 (1H, td), (3.60 1H, dd), 3.73 (1H, d), (3.92-4.01 2H, m), 4.30 (1H, br s), (4.39 2H, s), 6.90 (1H, s).

the LCMS spectrum: MH+374, retention time 2.24 minutes

the chloro-6-of 2,4-bis-(cyclohexyl alkylsulfonyl methyl) pyrimidine

During 20 minutes, in nitrogen atmosphere, to 2, the chloro-6-of 4-bis-(cyclohexyl sulfanylmethyl) pyrimidine (1.53g, 5.52mmol) DCM (28mL) stirred solution in add 3-chlorine peroxybenzoic acid (3.09g in batches, 13.80mmol), in order to control temperature lower than 28 ℃.The suspension that obtains, stirring at room 3 hours, is then added to saturated sodium bicarbonate aqueous solution (40mL), stirred reaction mixture 5 minutes.Then separate organic layer, dry (MgSO ₄), evaporate to dryness.The solid obtained is dissolved in DCM (40mL) again, adds saturated sodium bicarbonate aqueous solution (40mL).Stir the mixture 15 minutes, then separate organic layer, dry (MgSO ₄), evaporation, obtain needed material (1.650g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.12-1.46 (5H, m), 1.61-1.69 (1H, m), 1.80-1.88 (2H, m), 2.10-2.17 (2H, m), 3.22 (1H, tt), 4.73 (2H, s), 7.85 (1H, s).

the LCMS spectrum: M-H-307, retention time 2.26 minutes

the chloro-6-of 2,4-bis-(cyclohexyl sulfanylmethyl) pyrimidine

During 15 minutes, by 6-(cyclohexyl sulfanylmethyl)-1H-pyrimidine-2, phosphorus oxychloride (15mL, the 160.93mmol) suspension of 4-diketone (3.6g, 14.98mmol) is heated to 100 ℃.The dark orange solution obtained is stirred 7 hours at 100 ℃.Then reaction mixture, then evaporate, and obtains the brown oil of thickness, and it is distributed between DCM (20mL) and frozen water (20mL).Then carefully and in batches added solid sodium bicarbonate with 30 minutes, in order to control bubbling.During adding, add water (30mL) and the DCM of further equal portions.Once stop bubbling and the pH value be adjusted to 8, mixture is proceeded in separating funnel, separate organic layer.Extract again water layer with DCM (2x50mL), the organic layer merged with salt solution (100mL) washing, dry (MgSO ₄), evaporation, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 10, to 40% ethyl acetate/isohexane, obtains needed material (1.60g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18-1.31 (5H, m), 1.51-1.58 (1H, m), 1.63-1.71 (2H, m), 1.86-1.93 (2H, m), 2.70-2.77 (1H, m), 3.85 (2H, s), 7.81 (1H, s).

the LCMS spectrum: M-H-275, retention time 3.04 minutes

6-(cyclohexyl sulfanylmethyl)-1H-pyrimidine-2, the 4-diketone

By the DMF of hexanaphthene mercaptan (10mL, 81.74mmol) (150mL) 1,8-diazabicyclo [5.4.0] 11-7-alkene (14mL, 93.80mmol) processing for solution.By the solution that obtains stirring at room 20 minutes.Then, in nitrogen atmosphere, add in batches 6-(chloromethyl) pyrimidine-2,4 (1H, 3H)-diketone (10g, 62.28mmol) in during 30 minutes, in order to keep internal temperature lower than 35 ℃.By the solution that obtains in stirred overnight at room temperature.Then the evaporate to dryness reaction mixture distributes resistates between DCM (100mL) and water (150mL).Form precipitation during mixing, it is removed by suction strainer, 55 ℃ of vacuum-dryings 2 hours, obtain needed material (6.45g).By dropwise adding 2M hydrochloric acid, filtrate is adjusted to pH2, obtain extra needed material (3.62g), remove precipitation, water (100mL) washing precipitation, dry in vacuum drying oven.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.16-1.34 (5H, m), 1.51-1.58 (1H, m), 1.63-1.72 (2H, m), (1.87-1.96 2H, m), 2.65-2.72 (1H, m), 3.41 (2H, s), 5.49 (1H, s), 10.75-10.96 (2H, m).

the LCMS spectrum: MH+241, retention time 0.99 minute

N-[4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate

By sodium bicarbonate (113mg; 1.35mmol) join 4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (370mg; 0.86mmol) Isosorbide-5-Nitrae-dioxs (5mL) solution in.Dropwise add phenyl chloroformate (0.124mL, 0.99mmol), and by the mixture that obtains stirring at room 5 hours.The mixture that evaporate to dryness obtains distributes resistates between DCM (5mL) and water (5mL).Separate organic layer, evaporate to dryness.Grind the crude product resistates with diethyl ether, obtain needed material (429mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.16-1.33 (6H, m), 1.40-1.50 (2H, m), (1.64-1.70 1H, m), 1.85-1.92 (2H, m), (2.21-2.28 2H, m), 3.19-3.36 (2H, m), (3.50 1H, td), 3.65 (1H, dd), (3.78 1H, d), 3.99 (1H, dd), (4.16-4.23 1H, m), 4.43-4.52 (3H, m), (6.81 1H, s), 7.24-7.30 (3H, m), 7.43-7.47 (2H, m), (7.63 2H, d), 8.30 (2H, d), 10.44 (1H, s).

the LCMS spectrum: MH+551, retention time 2.88 minutes

4-[4-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

By the chloro-4-of 2-(cyclohexyl alkylsulfonyl methyl)-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (437mg; 1.17mmol), 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (381mg; 1.74mmol) and 2M aqueous sodium carbonate (0.60mL; 1.20mmol) nitrogen purging 5 minutes for mixture in DMF (2mL), ethanol (2mL), water (5mL) and DME (2mL) mixture; then add two (triphenylphosphine) Palladous chloride (II) (41.0mg, 0.06mmol).In nitrogen atmosphere, reaction mixture is heated to 80 ℃, stir 3.5 hours.Reaction mixture is distributed between ethyl acetate (25mL) and water (30mL).Separate organic layer, by ethyl acetate (2x25mL), extract again the aqueous solution.By saturated brine for organic extraction (50mL) washing merged, dry (MgSO ₄), to filter, evaporation, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 25, to 75% ethyl acetate/isohexane, obtains needed material (402mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.16-1.32 (6H, m), 1.38-1.50 (2H, m), (1.64-1.70 1H, m), 1.85-1.92 (2H, m), (2.20-2.27 2H, m), 3.19 (1H, td), (3.31-3.40 1H, m), 3.48 (1H, td), (3.64 1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.10-4.18 (1H, m), (4.38 2H, s), 4.40-4.48 (1H, m), 5.57 (2H, s), (6.61 2H, d), 6.66 (1H, s), 8.04 (2H, d).

the LCMS spectrum: MH+431, retention time 2.33 minutes

The chloro-4-of 2-(cyclohexyl alkylsulfonyl methyl)-6-[(3S had before been described)-3-methylmorpholine-4-yl] preparation of pyrimidine.

embodiment 69:

3-cyclopropyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine-2-base] phenyl] urea

To cyclopropylamine (53mg; 0.93mmol) in add N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine-2-base] phenyl] phenyl carbamate (54mg; 0.09mmol) DMA (2mL) and triethylamine (0.045mL, 0.32mmol) solution.The mixture obtained is heated to 50 ℃, keeps 16 hours.Reaction mixture is cooling, and pour in water (30mL).Collect the precipitation obtained through suction strainer, dry under the suction filtration condition, obtain crude product, crude product to be purified with fast silica gel chromatogram, gradient 25 is to 75% ethyl acetate/isohexane.The fraction that evaporate to dryness contains product, grind with isohexane/diethyl ether, 50 ℃ of vacuum-dryings 1 hour, obtains needed material white solid (38mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 0.40-0.44 (2H, m), 0.63-0.67 (2H, m), (1.21 3H, d), 1.92 (6H, s), (2.42 3H, s), 2.53-2.59 (1H, m), (3.16 1H, td), 3.49 (1H, td), (3.64 1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.13-4.20 (1H, m), (4.52-4.58 1H, m), 6.40-6.42 (1H, m), (6.69 1H, s), 7.42 (2H, d), (7.68 1H, d), 7.87 (2H, d), 8.51 (1H, s)

the LCMS spectrum: MH+557, retention time 2.33 minutes

Use similar fashion; by N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 69a: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.57-1.68 (2H, m), (1.80-1.92 2H, m), 1.92 (6H, s), (2.18-2.25 2H, m), 2.41-2.42 (3H, m), (3.16 1H, td), 3.49 (1H, td), (3.64 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.11-4.19 (2H, m), (4.51-4.58 1H, m), 6.44 (1H, d), (6.69 1H, s), 7.39 (2H, d), (7.68 1H, d), 7.87 (2H, d), 8.53 (1H, s).

Embodiment 69b: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.07 (3H, t), 1.21 (3H, d), (1.92 6H, s), 2.41-2.42 (3H, m), (3.09-3.20 3H, m), 3.49 (1H, td), (3.64 1H, dd), 3.77 (1H, d), (3.97 1H, dd), 4.14-4.19 (1H, m), 4.52-4.58 (1H, m), (6.14 1H, t), 6.69 (1H, s), 7.41 (2H, d), (7.68 1H, d), 7.87 (2H, d), 8.63 (1H, s).

Embodiment 69c: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.92 (6H, s), (2.20 6H, s), 2.33-2.40 (2H, m), (2.42 3H, s), 3.12-3.22 (3H, m), (3.49 1H, td), 3.64 (1H, dd), (3.76 1H, d), 3.97 (1H, dd), (4.16 1H, d), 4.51-4.57 (1H, m), (6.15 1H, t), 6.69 (1H, s), 7.40 (2H, d), (7.68 1H, s), 7.87 (2H, d), 8.87 (1H, s).

Embodiment 69d: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.92 (6H, s), 2.41 (3H, s), (3.13-3.21 3H, m), 3.44-3.52 (3H, m), 3.64 (1H, dd), (3.77 1H, d), 3.97 (1H, dd), 4.13-4.19 (1H, m), (4.52-4.57 1H, m), 4.72 (1H, t), 6.24 (1H, t), (6.69 1H, s), 7.40 (2H, d), 7.68 (1H, s), 7.87 (2H, d), 8.78 (1H, s).

Embodiment 69e: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.21 (3H, d), 1.92 (6H, s), (2.41-2.42 3H, m), 2.66 (3H, d), (3.12-3.20 1H, m), 3.49 (1H, td), (3.64 1H, dd), 3.76 (1H, d), (3.97 1H, dd), 4.13-4.19 (1H, m), 4.51-4.57 (1H, m), (6.05 1H, q), 6.69 (1H, s), 7.42 (2H, d), (7.68 1H, d), 7.87 (2H, d), 8.72 (1H, s).

Embodiment 69f: there is no the NMR spectrum

Embodiment 69g: there is no the NMR spectrum

Embodiment 69h: there is no the NMR spectrum

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third -2-yl] pyrimidine-2-base] phenyl] phenyl carbamate

To 4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine-2-base] aniline (340mg; 0.72mmol) 1; add sodium bicarbonate (90mg, 1.08mmol) in 4-diox (4mL) solution.Then dropwise add phenyl chloroformate (0.104mL, 0.86mmol), and by the mixture that obtains stirring at room 6 hours.Then evaporation reaction mixture distributes resistates between DCM (5mL) and water (5mL).Separate organic layer, with more DCM (5mL), extract again the aqueous solution.Organic layer is merged, and evaporate to dryness, obtain the amber colloid, and it is received in diethyl ether (5mL), by supersound process, ground.Suction filtration is collected the solid obtained, and drying, obtain needed material (334mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 1.93 (6H, s), 2.41 (3H, s), (3.17 1H, td), 3.49 (1H, td), 3.64 (1H, dd), (3.77 1H, d), 3.98 (1H, dd), 4.15-4.22 (1H, m), (4.53-4.59 1H, m), 6.73 (1H, s), 7.24-7.30 (3H, m), (7.45 2H, t), 7.55 (2H, d), 7.68 (1H, m), 7.97 (2H, d), 10.39 (1H, s).

the LCMS spectrum: MH+594, retention time 2.91 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third-2- base] pyrimidine-2-base] aniline

By the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third-2-yl] pyrimidine (480mg, 1.15mmol), 4-(4, 4, 5, 5-tetramethyl--1, 3, 2-dioxa boron heterocycle pentane-2-yl) aniline (378mg, 1.73mmol) and 2M aqueous sodium carbonate (2.8mL, 5.60mmol) at DMF (2mL), 1, 2-glycol dimethyl ether (2mL), mixture in ethanol (2mL) and water (5mL) mixture is used nitrogen purging 10 minutes, then add two (triphenylphosphine) Palladous chloride (II) (54mg, 0.08mmol).Reaction mixture is heated to 85 ℃, at this temperature, in nitrogen atmosphere, stirs 3 hours.Then reaction mixture is distributed between ethyl acetate (50mL) and water (30mL).Separate organic layer, by ethyl acetate (25mL), extract again water layer.By salt solution for organic layer (50mL) washing merged, dry (MgSO ₄), to filter, evaporation, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 25, to 75% ethyl acetate/isohexane, obtains needed material (367mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 1.90 (6H, s), 2.43 (3H, s), 3.13 (1H, td), 3.48 (1H, td), (3.63 1H, dd), 3.75 (1H, d), 3.96 (1H, dd), 4.09-4.15 (1H, m), 4.47-4.54 (1H, m), (5.50 2H, s), 6.52 (1H, d), (6.58 2H, s), 7.68-7.72 (3H, m).

the LCMS spectrum: MH+474, retention time 2.31 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-the 6-[2-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) alkylsulfonyl] third -2-yl] pyrimidine

The chloro-4-[(3S of 2-to cooling (ice/water bath))-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl methyl] pyrimidine (612mg; 1.57mmol) DMF (8mL) solution in add sodium tert-butoxide (157mg, 1.63mmol).In nitrogen atmosphere, stir the mixture 5 minutes, then add methyl iodide (0.100mL, 1.61mmol).In cooling bath, further stirred reaction mixture is 10 minutes, then further adds sodium tert-butoxide (157mg, 1.63mmol).After further stirring 5 minutes, add more methyl iodide (0.100mL, 1.61mmol), in nitrogen atmosphere, in cooling bath, stirred reaction mixture 20 minutes.Then remove cooling bath, continue to stir 2 hours.Then add water (25mL), filter and collect the precipitation obtained, water (50mL) washing, 50 ℃ of vacuum-dryings 2 hours, obtain needed material (487mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 1.79 (6H, d), (2.46 3H, s), 3.15 (1H, td), (3.43 1H, td), 3.58 (1H, dd), (3.72 1H, d), 3.93 (1H, dd), (3.96-4.03 1H, m), 4.35-4.44 (1H, m), (6.78 1H, s), 7.89 (1H, s).

the LCMS spectrum: MH+417, retention time 2.28 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] phonetic pyridine

To cooling (ice/water bath) 2, the chloro-6-[(4-methyl isophthalic acid of 4-bis-, 3-thiazol-2-yl) the alkylsulfonyl methyl] add triethylamine (0.45mL, 3.23mmol) in DCM (12mL) solution of pyrimidine (901mg, 2.78mmol).By DCM (2.5mL) solution-treated of the solution obtained dropwise being used in 3 minutes to (3S)-3-methylmorpholine (319mg, 3.15mmol).In nitrogen atmosphere, reaction mixture is stirred 24 hours, make reaction be warming up to room temperature.Water (20mL) is joined in reaction mixture, stir 15 minutes.Then separate organic layer, dry (MgSO ₄), evaporation, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 25, to 75% ethyl acetate/isohexane, obtains needed material (615mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.18 (3H, d), 2.49 (3H, s), (3.18 1H, td), 3.43 (1H, td), (3.58 1H, dd), 3.72 (1H, d), (3.86-3.96 2H, m), 4.16-4.28 (1H, m), (4.82 2H, s), 6.80 (1H, s), 7.89 (1H, d).

the LCMS spectrum: MH+389, retention time 1.89 minutes

the chloro-6-[(4-methyl isophthalic acid of 2,4-bis-, the 3-thiazol-2-yl) the alkylsulfonyl methyl] pyrimidine

With 10 minutes, to cooling (ice/water bath) 2, the chloro-6-[(4-methyl isophthalic acid of 4-bis-, 3-thiazol-2-yl) sulfanylmethyl] pyrimidine (867mg, 2.97mmol) DCM (15mL) solution in add 3-chlorine peroxybenzoic acid (1.42g, 6.34mmol) in batches.The suspension obtained is stirred 15 minutes in cooling bath.Then remove cooling bath, make reaction mixture be warming up to room temperature, stir 22 hours.Reaction not exclusively, further adds 3-chlorine peroxybenzoic acid (162mg, 0.72mmol), further stirs the mixture 1 hour.Saturated sodium bicarbonate aqueous solution (20mL) is joined in reaction mixture, stir 30 minutes.Separate organic layer, dry (MgSO ₄), to filter, evaporation, obtain needed material (912mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 2.48 (3H, d), 5.19 (2H, s), 7.84 (1H, s), 7.94-7.95 (1H, m).

the LCMS spectrum: M-H-322, retention time 1.47 minutes

the chloro-6-[(4-methyl isophthalic acid of 2,4-bis-, the 3-thiazol-2-yl) sulfanylmethyl] pyrimidine

By the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) sulfanylmethyl]-1H-pyrimidine-2, phosphorus oxychloride (6mL, the 64.37mmol) suspension of 4-diketone (1.4g, 5.48mmol) is heated to 100 ℃, stirs 6 hours.Then reaction mixture, then evaporate, and distribute resistates between DCM (30mL) and frozen water (30mL).Then carefully and in batches added sodium bicarbonate with 30 minutes, in order to control bubbling.Once stop bubbling and the pH value be adjusted to 8, process mixture with more DCM (30mL) and water (20mL), proceed in separating funnel, separate organic layer.Further extract again water layer with DCM (2x50mL), the organic extraction merged with the salt water washing, dry (MgSO ₄), evaporate to dryness, obtain crude product, and crude product is purified with fast silica gel chromatogram, and gradient 10, to 20% ethyl acetate/isohexane, obtains needed material (0.90g).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 2.31 (3H, d), 4.55 (2H, s), 7.23-7.24 (1H, m), 7.83 (1H, s).

the LCMS spectrum: MH+292, retention time 2.33 minutes

the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) sulfanylmethyl]-1H-pyrimidine-2, the 4-diketone

DMF (15mL) solution of 4-methylthiazol-2-mercaptan (1.01g, 7.70mmol) is joined in 1,8-diazabicyclo [5.4.0] 11-7-alkene (1.4mL, 9.38mmol).By the solution that obtains stirring at room 30 minutes.Then, in during 10 minutes, in nitrogen atmosphere, add 6-(chloromethyl) pyrimidine-2,4 (1H, 3H)-diketone (1g, 6.23mmol) in batches.By the solution that obtains stirring at room 19 hours.Then the evaporate to dryness reaction mixture distributes resistates between DCM (20mL) and water (20mL).Suction filtration is collected solid precipitation, and water (20mL) washing, 60 ℃ of vacuum-dryings 2 hours, obtain needed material (1.07g, 67%).By with 2M hydrochloric acid, regulating filtrate to pH2, obtain extra needed material (0.330g), filtering-depositing, water (20mL) washing precipitation, dry in vacuum drying oven.

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 2.34 (3H, d), 4.08 (2H, s), 5.43 (1H, s), 7.27 (1H, m), 11.01 (2H, s).

the LCMS spectrum: MH+256, retention time 0.53 minute

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] pyrimidine-2-base] phenyl] phenyl carbamate

At 5 ℃; in nitrogen atmosphere; by phenyl chloroformate (0.190mL; 1.51mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl methyl] pyrimidine-2-base] aniline (450mg; 1.01mmol), sodium bicarbonate is (in 127mg, 1.51mmol) diox (10mL) mixture.The mixture obtained is at room temperature stirred 2 hours.By ethyl acetate for reaction mixture (200mL) dilution, and water (125mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product, and its mixture with diethyl ether and isohexane is ground, and obtains needed material (360mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.22 (3H, d), 2.53 (3H, s) [it is fuzzy that DMSO makes it], (3.20 1H, td), 3.49 (1H, td), (3.64 1H, dd), 3.77 (1H, d), (3.98 1H, dd), 4.15 (1H, d), (4.45 1H, s), 4.93 (2H, s), 6.77 (1H, s), (7.22-7.32 3H, m), 7.43-7.47 (2H, m), 7.56 (2H, d), (7.84 1H, s), 7.97 (2H, d), 10.43 (1H, s).

the LCMS spectrum: MH+566, retention time 2.66 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] pyrimidine -2-yl] aniline

In room temperature; in nitrogen atmosphere; by two (triphenylphosphine) Palladous chloride (II) (54.4mg; 0.08mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid; the 3-thiazol-2-yl) alkylsulfonyl methyl] pyrimidine (600mg; 1.55mmol), 4-(4; 4; 5; 5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) aniline (510mg; 2.33mmol) and the mixture of sodium carbonate (5mL, 10.00mmol) in DMF (6mL), DME (12mL), ethanol (3mL) and water (3.5mL) in.By the reaction mixture exhaust, with nitrogen, refill, carry out several times, at 95 ℃, the mixture obtained is stirred 18 hours.By ethyl acetate for reaction mixture (250mL) dilution, and water (2x150mL) washing.Dry (Na ₂sO ₄) organic layer, to filter, evaporation, obtain crude product, and it is purified with fast silica gel chromatogram, and gradient 10, to 70% ethyl acetate/isohexane, obtains needed material (450mg).

the NMR spectrum: ¹h NMR (400.132MHz, DMSO-d ₆) δ 1.19 (3H, d), 253 (3H, s), 3.15 (1H, td), 3.47 (1H, td), 3.62 (1H, dd), (3.75 1H, d), 3.96 (1H, dd), 4.09 (1H, d), 4.40 (1H, s), 4.83 (2H, s), (5.54 2H, s), 6.52 (2H, d), 6.60 (1H, s), 7.70 (2H, d), 7.81 (1H, s).

the LCMS spectrum: MH+446, retention time 2.0 minutes

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-the 6-[(4-methyl isophthalic acid, the 3-thiazol-2-yl) the alkylsulfonyl methyl] preparation of pyrimidine.

embodiment 70:

3-ethyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] urea

In room temperature; in nitrogen atmosphere; methanol solution (0.471mL by a 2M ethamine; 0.94mmol) join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] in DMF (2mL) solution of phenyl carbamate (120mg, 0.21mmol).By the solution that obtains stirring at room 60 minutes.The evaporate to dryness reaction mixture, purify crude product with fast silica gel chromatogram, and gradient 0, to 7% methyl alcohol/DCM, obtains needed material white foam (103mg).

the NMR spectrum: ¹h NMR (399.902MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.21 (d, 3H), (1.88 s, 6H), 3.09-3.21 (m, 3H), (3.45-3.53 m, 1H), 3.61-3.66 (m, 1H), (3.77 d, 1H), 3.95-4.00 (m, 1H), (4.15 d, 1H), 4.53 (s, 1H), (6.15 t, 1H), 6.66 (s, 1H), (7.35 d, 2H), 7.61-7.66 (m, 2H), 7.71 (d, 2H), (7.88-7.93 m, 1H), 8.61 (s, 1H), 8.74-8.76 (m, 1H)

the LCMS spectrum: MH+525.56, retention time 2.14 minutes

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2- base] phenyl] phenyl carbamate

In room temperature; by phenyl chloroformate (0.432mL; 3.44mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] aniline (1.3g; 2.87mmol) and sodium bicarbonate (in 0.482g, 5.73mmol) diox (20mL) mixture.The slurries that obtain, stirring at room 1 hour, are then distributed to reaction mixture between ethyl acetate and water.Dry (MgSO ₄) organic solution, concentrating under reduced pressure.Resistates is carried out to silica gel chromatography, with 0%-20% ethyl acetate/DCM wash-out, obtain the yellow dry film (1.62g) of needed material.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.27 (d, 3H), 1.90 (s, 6H), 3.25 (m, 1H), 3.55 (m, 1H), 3.70 (m, 1H), (4.03 m, 2H), 4.39-4.46 (m, 1H), (6.60 s, 1H), 6.93 (s, 1H), (7.12-7.22 m, 12H), 7.32 (m, 5H), (7.57 m, 2H), 7.82 (d, 2H).

the LCMS spectrum: MH+574.52, retention time 2.85 minutes (acid monitoring).

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine-2-base] benzene amine

In room temperature; in nitrogen atmosphere; by tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.773g; 3.53mmol) and the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine (1.4g, 3.53mmol) is suspended in the mixture of DME (10mL), ethanol (10.00mL), DMF (10.00mL) and water (10mL).Use the nitrogen purging mixture, add two (triphenylphosphine) Palladous chlorides (II) (0.124g, 0.18mmol).In nitrogen atmosphere, the suspension obtained is stirred 90 minutes at 80 ℃.Concentrated reaction mixture, with ethyl acetate (150mL) dilution, water (2x150mL) and saturated brine (100mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 40% ethyl acetate/DCM, obtains the yellow foam (1.210g) of needed material.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.25 (d, 3H), 1.89 (s, 6H), 3.22 (m, 1H), 3.54 (m, 1H), 3.66-3.80 (m, 4H), (3.97 m, 1H), 4.05 (m, 1H), (4.42 s, 1H), 6.46-6.53 (m, 3H), (7.28 m, 1H), 7.55 (m, 2H), (7.64 d, 2H), 8.61 (d, 1H).

the LCMS spectrum: MH+454.58, retention time 1.88 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(2-pyridine-2-base alkylsulfonyl third-2-yl) pyrimidine

At 0 ℃; in nitrogen atmosphere; by methyl iodide (1.266mL; 20.33mmol) join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine (2.5g; 6.78mmol) and DMF (50mL) solution of sodium tert-butoxide (1.954g, 20.33mmol) in.Make solution be warmed at leisure room temperature, stirring at room 1 hour.Add water and ethyl acetate, agitation of solutions, separate.By the dry (MgSO of the ethyl acetate layer merged ₄), filter.Evaporation filtrate, purify crude product with fast silica gel chromatogram, and gradient 0, to 60% ethyl acetate/DCM, obtains needed material yellow oil, solidifies (1.77g) when it is standing.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.26 (d, 3H), 1.77 (s, 6H), 3.22 (m, 1H), 3.49 (m, 1H), 3.64 (m, 1H), (3.74 d, 1H), 3.89-3.98 (m, 2H), (4.27 s, 1H), 6.67 (s, 1H), (7.46 m, 1H), 7.73 (m, 1H), (7.80 d, 1H), 7.82 (m, 1H).

the LCMS spectrum: MH+397.38, retention time 2.04 minutes.

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine

By 35% aqueous hydrogen peroxide solution (8.26mL, 93.53mmol) dropwise join the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridine-2-base sulfanylmethyl) pyrimidine (10.5g, 31.17mmol), sodium tungstate dihydrate (0.206g, 0.62mmol) and 2N sulfuric acid (in 0.6mL) diox (300mL) stirred solution, then solution is heated to 55 ℃.55 ℃ of stirred solutions 4 hours.Further add hydrogen peroxide (8.26mL), and stir the mixture 18 hours at 50 ℃.Add 3-chlorine peroxybenzoic acid (5.38g, 31.17mmol), and at room temperature stir the mixture 2 hours.Water (500mL) diluting soln, and be cooled to 20 ℃.Add 10% sodium metabisulfite solution, to destroy any residue superoxide, by ethyl acetate, extract solution.By the dry (MgSO of organic layer ₄), filter.Purify crude product with fast silica gel chromatogram, gradient 0, to 50% ethyl acetate/DCM, obtains the yellow colloid (10.5g) of needed material.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.24 (d, 3H), 3.20 (m, 1H), (3.46 m, 1H), 3.61 (d, 1H), (3.71 d, 1H), 3.90-3.98 (m, 2H), (4.21 s, 1H), 4.51 (s, 2H), (6.50 s, 1H), 7.51-7.53 (m, 1H), (7.86-7.95 m, 2H), 8.72-8.74 (m, 1H)

the LCMS spectrum: MH+369.37, retention time 1.73 minutes

the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-6-(pyridine-2-base sulfanylmethyl) pyrimidine

In room temperature, in nitrogen atmosphere, DIPEA (8.77mL, 50.71mmol) is joined in DMF (300mL) solution of 2-mercaptopyridine (3.80g, 34.22mmol).By the solution that obtains stirring at room 15 minutes.With within 5 minutes, add the chloro-4-of 2-(iodomethyl)-6-[(3S in batches)-3-methylmorpholine-4-yl] pyrimidine (11g, 31.11mmol), in stirring at room mixture 3 hours.The evaporate to dryness reaction mixture, and be dissolved in again in DCM (200mL), with saturated sodium bicarbonate solution (100mL) and the washing of saturated brine (50mL) order.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 20% ethyl acetate/DCM, obtains needed material brown oil (10.50g).NMR shows the m-chlorobenzoic acid that has 0.6eq..Just need not be further purified and can use this material in step subsequently.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.23 (d, 3H), 3.17-3.25 (m, 1H), 3.46-3.54 (m, 1H), 3.62-3.67 (m, 1H), 3.74 (d, 1H), (3.93-4.01 m, 2H), 4.20 (s, 1H), (4.29-4.38 m, 2H), 6.60 (s, 1H), (6.99-7.02 m, 1H), 7.20 (d, 1H), (7.47-7.51 m, 1H), 8.40-8.42 (m, 1H).

the LCMS spectrum: MH+337.48, retention time 2.19 minutes.

embodiment 71:

3-ethyl-1-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl] urea

In room temperature; in nitrogen atmosphere; methanol solution (0.495mL by 2M ethamine; 0.99mmol) once join N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl] in DMF (2mL) solution of phenyl carbamate (120mg, 0.22mmol).By the solution that obtains stirring at room 60 minutes.The evaporate to dryness reaction mixture, purify crude product with fast silica gel chromatogram, and gradient 0, to 7% methyl alcohol/DCM, obtains needed material white foam (83mg).

the NMR spectrum: ¹h NMR (399.902MHz, DMSO-d ₆) δ 1.07 (t, 3H), 1.20 (d, 3H), (3.09-3.22 m, 3H), 3.44-3.52 (m, 1H), (3.61-3.65 m, 1H), 3.76 (d, 1H), (3.95-4.00 m, 1H), 4.12 (d, 1H), (4.40 s, 1H), 4.85 (q, 2H), (6.14 t, 1H), 6.69 (s, 1H), (7.35 d, 2H), 7.66 (d, 2H), (7.79-7.82 m, 1H), 7.90 (d, 1H), (8.08-8.13 m, 1H), 8.62 (s, 1H), 8.93 (d, 1H).

the LCMS spectrum: MH+497.49, retention time 1.66 minutes

N-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] benzene base] phenyl carbamate

In room temperature; by phenyl chloroformate (0.390mL; 3.10mmol) join 4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] aniline (1.1g; 2.59mmol) and sodium bicarbonate (in 0.434g, 5.17mmol) diox (25mL) mixture.The slurries that obtain are at room temperature stirred 1 hour.Mixture is distributed between ethyl acetate and water.Separate organic solution, dry (MgSO ₄), concentrating under reduced pressure.Purify resistates with fast silica gel chromatogram, use gradient elution 0%-20% ethyl acetate/DCM, obtain the yellow foam (1.130g) of needed material.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.25 (d, 3H), 3.23 (m, 1H), (3.52 m, 1H), 3.65-3.68 (m, 1H), (3.75 d, 1H), 3.95-3.99 (m, 1H), (4.05-4.11 m, 2H), 4.31-4.38 (m, 1H), (4.63 q, 2H), 6.39 (s, 1H), 6.95 (s, 1H), (7.13 m, 2H), 7.17-7.21 (m, 1H), 7.34 (m, 4H), (7.48 m, 1H), 7.75-7.85 (m, 4H), 8.77-8.79 (m, 1H).

the LCMS spectrum: MH+546.49, retention time 2.54 minutes

4-[4-[(3S)-3-methylmorpholine-4-yl]-6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by sodium carbonate (7.32mL; 14.64mmol) join 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.891g; 4.07mmol) and the chloro-4-[(3S of 2-)-3-methylmorpholine-4-yl]-mixture of DME (10mL), ethanol (10.00mL), DMF (10.00mL) and the water (10mL) of 6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine (1.5g, 4.07mmol) in.With nitrogen purging mixture three times, add two (triphenylphosphine) Palladous chlorides (II) (0.143g, 0.20mmol), again use the nitrogen purging mixture.At 80 ℃ by the suspension agitation that obtains 90 minutes.The evaporate to dryness reaction mixture, and be suspended in ethyl acetate (150mL) water (2x150mL) and saturated brine (100mL) washing.Dry (MgSO ₄) organic layer, to filter, evaporation, obtain crude product.Purify crude product with fast silica gel chromatogram, gradient 0, to 40% ethyl acetate/DCM, obtains the yellow foam (1.21g) of needed material.

the NMR spectrum: ¹h NMR (399.902MHz, CDCl ₃) δ 1.23 (d, 3H), 3.16-3.24 (m, 1H), 3.47-3.55 (m, 1H), (3.63-3.68 m, 1H), 3.71-3.80 (m, 3H), 3.92-3.98 (m, 1H), (4.02-4.09 m, 1H), 4.30-4.37 (m, 1H), 4.59 (q, 2H), (6.32 s, 1H), 6.48-6.53 (m, 2H), 7.44-7.49 (m, 1H), (7.67 d, 2H), 7.73-7.83 (m, 2H), 8.77-8.79 (m, 1H).

the LCMS spectrum: MH+426.48, retention time 1.24 minutes (acid monitoring).

The chloro-4-[(3S of 2-had before been described)-3-methylmorpholine-4-yl]-preparation of 6-(pyridine-2-base alkylsulfonyl methyl) pyrimidine.

embodiment 72:

1-[4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl]-3-cyclopropyl-urea

By cyclopropylamine (0.139mL; 1.98mmol) join N-[4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] in DMF (2mL) solution of phenyl carbamate (150mg, 0.25mmol).The solution obtained 60 ℃ of stirrings 5 hours.The evaporate to dryness reaction mixture distributes resistates between ethyl acetate (30mL) and water (30mL).Water (2x30mL) and saturated brine (30mL) washing organic layer, dry (MgSO ₄), filter evaporate to dryness.Purify resistates with fast silica gel chromatogram, gradient 30 is to 60% ethyl acetate/isohexane.The pure fraction of evaporate to dryness, use the diethyl ether grinding residues, obtains required material white solid (92mg).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 0.70 (2H, s), 0.88 (2H, s), 1.34 (3H, d), 1.86 (6H, s), 2.63 (1H, t), 3.33 (1H, td), 3.63 (1H, td), 3.78 (2H, dd), 3.85 (2H, d), 4.06 (1H, dd), 4.14 (1H, d), 4.49 (1H, d), 4.88 (1H, s), 6.63 (1H, s), 6.93 (1H, s), 7.30 (4H, d), 7.39 (2H, d), 7.47 (2H, d), 7.87 (2H, d).

the LCMS spectrum: MH+570,572, retention time 2.63 minutes

Use similar fashion, by N-[4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate or N-[4-[4-[(4-chloro-phenyl-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] phenyl carbamate and suitable amine prepares following compounds.

Embodiment 72a: ¹h NMR (399.902MHz, CDCl3) δ 1.34 (3H, d), 1.72 (2H, m), (1.86 2H, m), 1.86 (6H, s), (2.39 2H, m), 3.32 (1H, ddd), (3.63 1H, ddd), 3.77 (1H, dd), (3.85 1H, d), 4.06 (1H, dd), (4.14 1H, d), 4.31 (1H, dtt), (4.49 1H, br.d), 4.86 (1H, d), (6.29 1H, s), 6.63 (1H, s), (7.27 2H, d), 7.29 (2H, d), (7.47 2H, d), 7.86 (2H, d).

Embodiment 72b: ¹h NMR (399.902MHz, CDCl3) δ 1.34 (3H, d), 1.86 (6H, s), 2.86 (3H, d), 3.32 (1H, ddd), 3.62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H, dd), 4.13 (1H, d), 4.48 (1H, br.d), 4.81 (1H, q), (6.52 1H, s), 6.62 (1H, s), 7.28 (2H, d), (7.29 2H, d), 7.47 (2H, d), 7.87 (2H, d).

Embodiment 72c: ¹h NMR (399.902MHz, CDCl3) δ 1.17 (3H, t), 1.34 (3H, d), 1.86 (6H, s), 3.32 (2H, dq), 3.32 (1H, ddd), 3.62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H, dd), 4.13 (1H, d), 4.49 (1H, br.d), 4.78 (1H, t), 6.46 (1H, s), 6.62 (1H, s), 7.28 (2H, d), (7.29 2H, d), 7.47 (2H, d), 7.86 (2H, d) .-

Embodiment 72d: ¹h NMR (399.90MHz, CDCl3) δ 1.34 (3H, d), 1.85 (6H, s), 2.32 (6H, s), 2.53 (2H, t), 3.31 (1H, ddd), 3.33 (2H, dt), 3.62 (1H, ddd), 3.77 (1H, dd), 3.84 (1H, d), 4.06 (1H, dd), 4.14 (1H, d), 4.49 (1H, br.d), 5.29 (1H, br.s), 6.61 (1H, s), 7.29 (2H, d), 7.33 (2H, d), 7.47 (2H, d), 7.83 (2H, d), 8.41 (1H, v.br.s).

Embodiment 72e: ¹h NMR (399.902MHz, CDCl3) δ 1.33 (3H, d), 1.71 (2H, m), (1.84 2H, m), 2.37 (2H, m), (3.30 1H, ddd), 3.59 (1H, ddd), (3.74 1H, dd), 3.82 (1H, d), (4.04 1H, dd), 4.14 (1H, d), (4.30 2H, dtt), 4.38 (2H, s), (4.39 1H, d), 4.97 (1H, d), (6.44 1H, s), 6.49 (1H, s), (7.31 2H, d), 7.43 (2H, d), (7.70 2H, d), 7.87 (2H, d).

Embodiment 72f: ¹h NMR (399.902MHz, CDCl3) δ 1.17 (3H, t), 1.33 (3H, d), 3.30 (1H, ddd), 3.32 (2H, dq), 3.60 (1H, ddd), 3.74 (1H, dd), 3.83 (1H, d), 4.05 (1H, dd), 4.15 (1H, d), 4.38 (2H, s), 4.42 (1H, br.d), 4.77 (1H, t), 6.44 (1H, s), 6.47 (1H, s), 7.31 (2H, d), (7.43 2H, d), 7.70 (2H, d), 7.88 (2H, d).

N-[4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

n-[4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2- base] phenyl] phenyl carbamate

In room temperature; by phenyl chloroformate (0.256mL; 2.04mmol) dropwise join 4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (850mg; 1.85mmol) and sodium bicarbonate (in 233mg, 2.78mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.With ethyl acetate (100mL) diluted reaction mixture, water (2x100mL) and saturated brine (50mL) washing.Dry (MgSO ₄) organic layer, filter evaporation.Purify crude product with fast silica gel chromatogram, gradient 30 is to 50% ethyl acetate/isohexane.The pure fraction of evaporate to dryness, obtain required material white solid (955mg).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.34 (3H, d), 3.32 (1H, ddd), 3.61 (1H, ddd), 3.75 (1H, dd), 3.84 (1H, d), 4.05 (1H, dd), 4.16 (1H, br.d), 4.38 (2H, s), 4.43 (1H, br.d), 6.46 (1H, s), 7.03 (1H, s), 7.21 (2H, d), 7.25 (1H, dd), 7.40 (2H, d), 7.43 (2H, dd), (7.45 2H, d), 7.70 (2H, d), 7.92 (2H, d)

the LCMS spectrum: MH+579,581, retention time 2.94 minutes

4-[4-[2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

In room temperature; in nitrogen atmosphere; by sodium carbonate (2M; in water; 6.69mL; 13.38mmol) join 4-(4; 4; 5; 5-tetramethyl--1,3,2-dioxa boron heterocycle pentane-2-yl) aniline (0.815g; 3.72mmol) and the chloro-4-[2-of 2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] in the mixture of DME (10mL), ethanol (10.00mL), DMF (10.00mL) and water (20mL) of pyrimidine (1.60g, 3.72mmol).Mixture is degassed, use nitrogen purging three times.Add two (triphenylphosphine) Palladous chloride (II) (0.130g, 0.19mmol), mixture is degassed, further use nitrogen purging three times.In nitrogen atmosphere, at 80 ℃ by the suspension agitation that obtains 90 minutes.Concentrated reaction mixture, with ethyl acetate (150mL) dilution, water (2x150mL) and saturated brine (100mL) washing.Dry (MgSO ₄) organic layer, filter evaporation.Purify crude product with fast silica gel chromatogram, gradient 30, to 45% ethyl acetate/isohexane, obtains needed material white solid (1.502g).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.33 (3H, d), 1.84 (6H, s), 3.31 (1H, ddd), 3.62 (1H, ddd), 3.77 (1H, dd), (3.84 1H, d), 3.86 (2H, s), 4.05 (1H, dd), 4.13 (1H, br.d), 4.48 (1H, br.d), (6.57 1H, s), 6.60 (2H, d), 7.30 (2H, d), 7.47 (2H, d), 7.72 (2H, d).

the LCMS spectrum: MH+487,489, retention time 2.64 minutes

the chloro-4-[2-of 2-(4-chloro-phenyl-) alkylsulfonyl third-2-yl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

At 0 ℃; in during 5 minutes; in nitrogen atmosphere; by methyl-iodide (0.310mL; 4.97mmol) dropwise join the chloro-4-[(4-chloro-phenyl-of 2-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine (2.00g; 4.97mmol) and DMF (50mL) mixture of sodium tert-butoxide (0.478g, 4.97mmol) in.The solution obtained is stirred 15 minutes at 0 ℃.At 0 ℃, add sodium tert-butoxide (0.478g, 4.97mmol), then add methyl-iodide (0.310mL, 4.97mmol), at 0 ℃, mixture is further stirred 1 hour.Mixture is poured into fast in the water (700mL) of stirring; Filter and collect the precipitation obtained, wash with water, vacuum-drying, obtain needed material white solid (1.79g)

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.34 (3H, d), 1.74 (6H, s), 3.30 (1H, ddd), 3.57 (1H, ddd), 3.72 (dd, 1H), 3.81 (1H, d), 4.02 (2H, m), 4.33 (1H, br.s), 6.71 (1H, s), 7.45 (2H, d), 7.50 (2H, d).

the LCMS spectrum: MH+430,432, retention time 2.68 minutes

the chloro-4-[(4-chloro-phenyl-of 2-) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine

In room temperature, 4-chlorobenzene-sulfinic acid sodium salt (5.39g, 27.15mmol) is once joined to the chloro-4-of 2-(iodomethyl)-6-[(3S)-3-methylmorpholine-4-yl] in acetonitrile (400mL) solution of pyrimidine (8.00g, 22.63mmol).By the suspension that obtains 85 ℃ of return stirrings 5 hours.Concentrated reaction mixture, with DCM (400mL) dilution, water (400mL) washing.Dry (MgSO ₄) organic layer, filter evaporation.Purify crude product with fast silica gel chromatogram, gradient 25, to 40% ethyl acetate/isohexane, obtains needed material white solid (6.90g).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.33 (3H, d), 3.30 (1H, ddd), 3.55 (1H, ddd), 3.70 (1H, dd), 3.80 (1H, d), 4.02 (2H, m), 4.28 (1H, br.s), 4.29 (2H, s), 6.55 (1H, s), 7.51 (2H, d), 7.70 (2H, d).

the LCMS spectrum: MH+402,404, retention time 2.26 minutes

The N-[4-[4-[(4-chloro-phenyl-) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] phenyl] preparation of phenyl carbamate is described below.

the N-[4-[4-[(4-chloro-phenyl-) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] benzene base] phenyl carbamate

In room temperature; by phenyl chloroformate (0.256mL; 2.04mmol) dropwise join the 4-[4-[(4-chloro-phenyl-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline (850mg; 1.85mmol) and sodium bicarbonate (in 233mg, 2.78mmol) diox (20mL) mixture.The suspension obtained is at room temperature stirred 2 hours.With ethyl acetate (100mL) diluted reaction mixture, water (2x100mL) and saturated brine (50mL) washing.Dry (MgSO ₄) organic layer, filter evaporation.Purify crude product with fast silica gel chromatogram, gradient 30, to 50% ethyl acetate/isohexane, obtains needed material white solid (955mg).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.34 (3H, d), 3.32 (1H, ddd), 3.61 (1H, ddd), 3.75 (1H, dd), 3.84 (1H, d), 4.05 (1H, dd), 4.16 (1H, br.d), 4.38 (2H, s), 4.43 (1H, br.d), 6.46 (1H, s), 7.03 (1H, s), 7.21 (2H, d), 7.25 (1H, dd), 7.40 (2H, d), 7.43 (2H, dd), (7.45 2H, d), 7.70 (2H, d), 7.92 (2H, d).

the LCMS spectrum: MH+579,581, retention time 2.94 minutes

the 4-[4-[(4-chloro-phenyl-) alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] pyrimidine-2-base] aniline

In room temperature; by sodium carbonate (2M; in water; 4.47mL; 8.95mmol) join 4-(4; 4; 5; 5-tetramethyl--1; 3; 2-dioxa boron heterocycle pentane-2-yl) aniline (0.572g, 2.61mmol) and the chloro-4-[(4-chloro-phenyl-of 2-) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] in DME (6.00mL), DMF (6.00mL) ethanol (6.00mL) and water (14.00mL) mixture of pyrimidine (1.00g, 2.49mmol).Mixture is degassed, use nitrogen purging three times.Add two (triphenylphosphine) Palladous chloride (II) (0.0870g, 0.120mmol), mixture is degassed, further use nitrogen purging three times.In nitrogen atmosphere, at 80 ℃ by the suspension agitation that obtains 90 minutes.Concentrated reaction mixture, with ethyl acetate (100mL) dilution, water (2x100mL) washing.Dry (MgSO ₄) organic layer, filter evaporation.Purify crude product with fast silica gel chromatogram, gradient 30, to 60% ethyl acetate/isohexane, obtains needed material white solid (0.980g).

the NMR spectrum: ¹h NMR (399.902MHz, CDCl3) δ 1.33 (3H, d), 3.30 (1H, ddd), 3.60 (1H, ddd), 3.74 (1H, dd), 3.82 (1H, d), (3.87 2H, s), 4.04 (1H, dd), 4.15 (1H, m), 4.36 (2H, s), 4.42 (1H, br.s), (6.39 1H, s), 6.62 (2H, d), 7.44 (2H, d), 7.69 (2H, d), 7.73 (2H, d).

the LCMS spectrum: MH+459,461, retention time 2.34 minutes

The chloro-4-[(4-chloro-phenyl-of 2-had before been described) the alkylsulfonyl methyl]-6-[(3S)-3-methylmorpholine-4-yl] preparation of pyrimidine.

Claims

1. the compound of formula (I):

Formula (I)

Or its pharmacologically acceptable salt; Wherein

M is 0 or 1;

¹y is CH, and Y ²n;

X is selected from following connection base :-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)-; With

R ¹to be selected from following group: adamantyl, methyl, ethyl ,-CH ₂cH ₂oH, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, oxetanyl, styroyl, pyrrolidyl, 2-oxo-pyrrolidine-3 base, pyrryl, imidazolyl, pyrazolyl, furyl, thienyl, pyridyl, pyrimidyl, pyrazinyl, the pyrrolidyl methyl, the pyrrolidyl ethyl, the pyrryl methyl, the pyrryl ethyl, imidazolyl methyl, the imidazolyl ethyl, the pyrazolyl methyl, the pyrazolyl ethyl, furyl methyl, the furyl ethyl, thienyl methyl, thienyl ethyl, thiazol-2-yl, 4-methylthiazol-2-base, the thiadiazolyl group methyl, the 3-methyl isophthalic acid, 3, 4-thiadiazoles-2 base, pyridylmethyl, the pyridyl ethyl, Pyrimidylmethyl, pyrimidinylethyl, pyrazinyl methyl and pyrazinyl ethyl, this group is optionally by 1, 2 or 3 are selected from following substituted radical and replace: halogen, cyano group, nitro, R ⁹,-OR ⁹,-COR ⁹,-CONR ⁹r ¹⁰,-NR ⁹r ¹⁰with-NR ⁹cOR ¹⁰,

Or-X-R ¹for-C (CH ₃) ₂oH or-CH ₂oH;

R ²be

A wherein ¹and A ²be selected from CH or N, condition is, A ¹or A ²in at least one is CH;

When existing, each R ³be methyl independently;

R ⁴hydrogen or C _1-6alkyl;

R ⁶and R ⁷independently selected from hydrogen, and C _1-6alkyl;

R ⁹and R ¹⁰be hydrogen independently or be selected from C _1-6the group of alkyl, this group is optionally replaced by halogen or hydroxyl;

R ¹⁷and R ¹⁸hydrogen;

R ¹⁹be hydrogen or be selected from following group: methyl, CH ₂(cyclopropyl), ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, thienyl, imidazolyl methyl, different the azoles base, pyrazolyl, the pyrazolyl methyl, pyridyl, 6-oxo-1H-pyridine 2-base and pyrimidyl, this group optionally is selected from following substituted radical and replaces 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.

2. according to the compound or pharmaceutically acceptable salt thereof of claim 1, the compound of its Chinese style (I) is formula (Ia) or compound (Ib)

Or its pharmacologically acceptable salt, wherein R ¹, R ², R ³, X, Y ¹and Y ²as the definition to the desired formula of claim 1 (I) compound.

3. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X is selected from following connection base :-NR ⁴cH ₂-,-OCH ₂-,-OCH (CH ₃)-,-OC (CH ₃) ₂-,-SCH ₂-,-SCH (CH ₃)-,-SC (CH ₃) ₂-,-S (O) CH ₂-,-S (O) CH (CH ₃)-,-S (O) C (CH ₃) ₂-,-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-,-S (O) ₂c (CH ₃) ₂-,-C (O) NR ⁴-and-NR ⁴c (O)-.

4. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X is-S (O) ₂cH ₂-,-S (O) ₂cH (CH ₃)-or-S (O) ₂c (CH ₃) ₂-.

5. according to the compound or pharmaceutically acceptable salt thereof of claim 1, wherein X is-S (O) ₂c (CH ₃) ₂-.

6. according to the compound or pharmaceutically acceptable salt thereof of any one in claim 1-5, R wherein ¹to be selected from following group: methyl, ethyl, propyl group, butyl, isobutyl-, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl, styroyl, pyridyl, pyrrolidyl, pyrazolyl ethyl, furyl methyl, oxetanyl, imidazolyl methyl, thienyl methyl, thiazolyl methyl, thiadiazolyl group methyl and pyrazinyl ethyl, this group optionally is selected from following substituted radical by 1 or 2 and replaces: amino, halogen, cyano group, methyl, methoxyl group, trifluoromethyl, trifluoromethoxy ,-NMe ₂,-NHCOCH ₃,-CONH ₂with-CONHCH ₃.

7. according to the compound or pharmaceutically acceptable salt thereof of claim 6, R wherein ¹to be selected from following group: methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂oMe ,-CH ₂cH ₂nMe ₂,-CH ₂cH ₂nHC (O) CH ₃,-CH ₂cONH ₂, phenyl, 3,5-difluorophenyl, the 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2-trifluoromethyl, the 2-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, trimethylene oxide-3-base, 2-oxo-pyrrolidine-3-base, 1-Methylimidazole-5-ylmethyl, 1-methylpyrrolidin-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.

8. according to the compound or pharmaceutically acceptable salt thereof of claim 6, R wherein ¹to be selected from following group: methyl, sec.-propyl, cyclopropyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nHC (O) CH ₃, phenyl, 4-fluorophenyl, the 2-chloro-phenyl-, 2-trifluoromethyl, 2-p-methoxy-phenyl, the 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, 2-oxo-pyrrolidine-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base.

9. according to the compound or pharmaceutically acceptable salt thereof of claim 6, R wherein ¹methyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, 3,5-difluorophenyl, pyridin-4-yl or cyclopropyl.

10. according to the compound or pharmaceutically acceptable salt thereof of claim 6, R wherein ¹methyl, ethyl, sec.-propyl, the tertiary butyl, 4-fluorophenyl, pyridin-4-yl or cyclopropyl.

11. according to the compound or pharmaceutically acceptable salt thereof of any one in claim 1-5, wherein R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl), different

azoles-3-base, 6-oxo-1H-pyridine-2-base, the 5-methyl is different

azoles-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyridyl-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl.

12. according to the compound or pharmaceutically acceptable salt thereof of claim 11, wherein R ¹⁹to be selected from following group: methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH and 1H-pyrazole-3-yl.

13., according to the compound or pharmaceutically acceptable salt thereof of claim 1, the compound of its Chinese style (I) is formula (Ia) or compound or pharmaceutically acceptable salt thereof (Ib):

¹y is CH, and Y ²n; With

R ¹to be selected from following group: methyl, ethyl, sec.-propyl, the tertiary butyl, cyclopropyl, cyclopentyl, cyclohexyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂oMe ,-CH ₂cH ₂nMe ₂,-CH ₂cH ₂nHC (O) CH ₃,-CH ₂cONH ₂, phenyl, 3,5-difluorophenyl, the 4-fluorophenyl, 2-chloro-phenyl-, 4-chloro-phenyl-, 2-trifluoromethyl, the 2-p-methoxy-phenyl, 2-aminomethyl phenyl, 4-acetamido phenyl, 4-aminophenyl, pyridin-4-yl, pyridine-2-base, trimethylene oxide-3-base, 2-oxo-pyrrolidine-3-base, 1-Methylimidazole-5-ylmethyl, 1-methylpyrrolidin-3-base, thiazol-2-yl, 4-methylthiazol-2-base and 3-methyl isophthalic acid, 3,4-thiadiazoles-2-base;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, sec.-propyl, butyl, isobutyl-, the tertiary butyl, amyl group, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl ,-CH ₂(cyclopropyl) ,-CH ₂cH ₂nMe ₂,-CH (CH ₃) CH ₂oH ,-C (CH ₃) ₂cH ₂oH ,-CH ₂cH ₂oH ,-CH ₂cH ₂cH ₂oH, 4-aminomethyl phenyl, 4-chloro-phenyl-, 4-trifluoromethyl, 4-fluorophenyl, 4-p-methoxy-phenyl, 3,4-difluorophenyl, thiophene-2-base ,-CH ₂(imidazoles-2-yl) ,-CH ₂(imidazo-3-yl), different

azoles-3-base, 6-oxo-1H-pyridine-2-base, the 5-methyl is different

azoles-3-base, 1-methyl-pyrazol-4-yl ,-CH ₂(1-methyl-pyrazol-4-yl), 6-methoxypyridine-3-base, 5-fluorine pyridine-2-base, pyridyl-2-base, pyrimidine-2-base and 1H-pyrazole-3-yl; With

R ³it is methyl

14., according to the compound or pharmaceutically acceptable salt thereof of claim 1, the compound of its Chinese style (I) is formula (Ia) or compound or pharmaceutically acceptable salt thereof (Ib):

¹y is CH, and Y ²n;

R ¹methyl or cyclopropyl;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

R ¹⁹be hydrogen or be selected from following group: methyl, ethyl, propyl group, cyclopropyl, cyclobutyl ,-CH ₂cH ₂oH ,-CH ₂cH ₂nMe ₂,-C (Me) ₂cH ₂oH, and 1H-pyrazole-3-yl; With

R ³it is methyl.

15., according to the compound or pharmaceutically acceptable salt thereof of claim 1, the compound of its Chinese style (I) is formula (Ia) or compound or pharmaceutically acceptable salt thereof (Ib):

X connects base-S (O) ₂c (CH ₃) ₂-;

¹y is CH, and Y ²n;

R ²be

R ¹⁷hydrogen;

R ¹⁸hydrogen; With

R ³it is methyl.

16. according to formula (I) compound or pharmaceutically acceptable salt thereof of claim 1 or 15, as the medicine in the treatment of hyperplasia.

17. the purposes of the defined formula of claim 1 or 15 (I) compound or pharmaceutically acceptable salt thereof in preparing medicine, this medicine is used for the treatment of hyperplasia.

18. the purposes of the defined formula of claim 1 or 15 (I) compound or pharmaceutically acceptable salt thereof in medicine preparation, this medicine in warm-blooded animal for generation of anti-proliferative effect.

19. a pharmaceutical composition, it comprises the defined formula of claim 1 or 15 (I) compound or pharmaceutically acceptable salt thereof, with pharmaceutically acceptable diluent or carrier, is combined.