CN105246482A

CN105246482A - Combination of kinase inhibitors and uses thereof

Info

Publication number: CN105246482A
Application number: CN201480026545.8A
Authority: CN
Inventors: 刘异; 任平达; 卡塔洋·杰森; 昕·郭; C·罗梅尔; T·E·威尔森
Original assignee: Intellikine LLC
Current assignee: Intellikine LLC
Priority date: 2013-03-15
Filing date: 2014-03-12
Publication date: 2016-01-13
Also published as: EP2968340A1; CA2906542A1; WO2014151147A1; EP2968340A4; HK1219421A1; JP2016512835A

Abstract

The present invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In another aspect, the invention provides for a method for treating a disease condition associated with PI3-kinase a and/or mTOR in a subject. In yet another aspect, a method of inhibiting phosphorylation of both Akt (S473) and Akt (T308) in a cell is set forth. The present invention also provides a pharmaceutical kit effective for treating a disease condition associated with PI3 -kinase alpha and/or mTOR in a subject.

Description

Combination of inhibitors of kinases and uses thereof

The cross reference of related application

This application claims the rights and interests of the U.S. Patent Application No. 14/099,644 that U.S. Patent Application No. 13/843,816 and 2013 on December of submitting on March 15th, 2013 is submitted to for 6, its separately by reference entirety be incorporated to herein.

Background of invention

Kinsase signaling pathway plays central role in numerous biological process.Find that the defect of the various components of signal transduction pathway causes numerous disease, comprise the cancer of various ways, inflammatory conditions, metabolism disorder, blood vessel and neuronal disease (Gaestel etc., CurrentMedicinalChemistry (2007) 14:2214-2234).In recent years, the kinases be associated with oncogenic signals pathway has become the important drugs target in the treatment of the various diseases comprising eurypalynous cancer perhaps.

The mammal target of rapamycin (mTOR), also referred to as the mechanicalness target of rapamycin, for regulating cell growth, translation control, the serine/threonine protein kitase of angiogenesis and/or cell survival.MTOR is by FKBP12-rapamycin associated protein 1 (FRAP1) gene code.MTOR is the catalytic subunit of two complex mTORC1 and mTORC2.MTORC1 is made up of the regulation and control associated protein (Raptor) of mTOR, mTOR, mammal LST8/G-albumen β-subunit sample albumen (mLST8/G β L), PRAS40 and DEPTOR.The protein kinase interaction protein 1 (mSIN1) that mTOR complex 2 (mTORC2) stress be activated by the rapamycin insensitivity companion (Rictor) of mTOR, mTOR, G β L and mammal is formed.

Except its subunit, by mTORC1 and mTORC2, the different sensitivity of rapamycin and analog (also referred to as forms of rapamycin analogs (rapalog)) thereof are distinguished them.Rapamycin combines and allosteric ground suppresses mTORC1, but mTORC2 is usually insensitive to rapamycin.Due to this rapamycin insensitivity mTOR intracellular signaling mediated by mTORC2, usually demonstrate only part with the cancerous cell of forms of rapamycin analogs treatment and suppress mTOR intracellular signaling, this can cause the survival rate of raising and the resistance to rapamycin treatment.

Another group kinases related in the cell function of imbalance usually in disease is the enzyme of phosphatidylinositol-3-kinase (PI3-kinases or PI3K) family.These lipid kinases by the 3-position di of the inositol ring of phosphatidylinositols (PtdIns), thus activate the signal cascade be associated with the process of such as Growth of Cells, propagation, differentiation, motion, survival and transmitter loss.The destruction relating to these processes of PI3K causes numerous disease, comprise cancer, contact dermatitis, rheumatoid arthritis, osteoarthritis, inflammatory bowel, chronic obstructive pulmonary disease, psoriasis, multiple sclerosis, asthma, the disease relevant to diabetic complication, and the struvite complication of cardiovascular system, as acute coronary syndrome.

PI3K family comprises the kinases that 15 kinds have differing substrate specificity, expression pattern and regulation and control model.I class PI3K (p110 α, p110 β, p110 δ and p110 γ) is activated by tyrosine kinase or G-G-protein linked receptor usually, to generate phosphatidylinositols-3,4,5-triphosphoric acid (PIP ₃), it engages downstream effect thing, as those in Akt/PDK1 approach, mTOR, Tec family kinase and Rho family GTP enzyme.

α (α) isoform of I type PI3K has participated in multiple human cancer.Angiogenesis has demonstrated the α isoform optionally needing PI3K in the control of endothelial cell migration.(Graupera etc., Nature2008; 453; 662-6).It is believed that at many human cancers, as the sudden change of the gene of coding PI3K α occurred in pulmonary carcinoma, gastric cancer, carcinoma of endometrium, ovarian cancer, bladder cancer, breast carcinoma, colon cancer, the brain cancer and skin carcinoma or causing the sudden change of rise of PI3K α.Usually, the sudden change of the gene of coding PI3K α concentrates on the point mutation in the some focuses in spiral and kinase domain (as E542K, E545K and H1047R).These sudden changes many have demonstrated as carcinogenecity gain-of-function mutation.Although other PI3K isoforms as PI3K δ or PI3K γ are mainly expressed in hematopoietic cell, PI3K α, together with PI3K β, composing type ground is expressed.

δ (δ) isoform of I class PI3K especially participates in various diseases and biological process.PI3K δ mainly expresses, as T-cell, dendritic cell, neutrophil cell, mastocyte, B-cell and macrophage comprising in leukocytic hematopoietic cell.PI3K δ relates generally to immune system function, as T-cell function, B-cell activation, Mast cell activation, Dendritic Cell Function and neutrophil activity.Due to its mass action in function of immune system, PI3K δ also relates to the various diseases relevant to less desirable immunne response, as atopic reaction, diseases associated with inflammation, inflammation mediated angiogenesis, rheumatoid arthritis, autoimmune disease, as lupus, asthma, emphysema and other respiratory tract diseases.Other I class PI3K relating to function of immune system comprise PI3K γ, and it works and has participated in inflammation, rheumatoid arthritis and autoimmune disease as lupus in leukocyte intracellular signaling.

PI3K β mainly participates in various types of cancer, comprises PTEN-negative cancer (.CancerResearch (2010) 70 (3): 1164-1172 such as Edgar) and HER2-process LAN cancer, as breast carcinoma and ovarian cancer.

Summary of the invention

Due to the different basic functions of mTOR and PI3K, the medicine of the kinase isoforms of broad range and complex is suppressed to cause harmful side effect with low specific binding.Such as, the extra-inhibitory of PI3K β can cause the destruction of ill effect to metabolic pathway and insulin signal transduction.Alternatively, the extra-inhibitory of PI3K δ and/or PI3K γ can destroy or reduce immunologic function.The disclosure provides a kind of efficient targeting disease-linked pathway, with the alternative method of limit adverse side effect.

Therefore, the invention provides a kind of method for treating the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises to described experimenter simultaneously or the PI3-kinases alpha inhibitor of administering therapeutic effective dose and the combination of mTOR inhibitors successively, wherein PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) by vitro kinase, wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.In one aspect, described combination comprises the PI3-kinases alpha inhibitor for the treatment of effective dose and the mTOR inhibitors for the treatment of effective dose.In yet another aspect, described combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein PI3-kinases alpha inhibitor and/or mTOR inhibitors exist with sub-therapeutic dose.

The present invention also provides a kind of method for treating the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises to described experimenter simultaneously or use following combination successively: (a) is according to the PI3-kinases alpha inhibitor of the treatment effective dose of the first dosage regimen, and (b) is according to the mTOR inhibitors of the treatment effective dose of the second dosage regimen, wherein PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) by vitro kinase, wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, wherein each dosage regimen comprises the repetition period that the treatment phase is then the rest period independently, wherein at least one dosage regimen has a rest period more than 0 day.In certain methods, the first dosage regimen and the second dosage regimen are identical and use simultaneously.In certain methods, the first dosage regimen and the second dosage regimen are different.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of at least 1 day independently, are then at least one cycles of the rest period of at least 1 day.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of 2,3,4,5,6 or 7 Consecutive Days independently, are then at least one cycles of the rest period of at least 1 day.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of 2,3,4,5,6 or 7 Consecutive Days independently, are then at least one cycles of the rest period of at least 3,4 or 5 Consecutive Days.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of at least 1 day independently, are then at least one cycles of the rest period of 6 Consecutive Days.In certain methods, first dosage regimen and/or the second dosage regimen comprise the treatment phase of 3 Consecutive Days independently, then be at least one cycle of 7 days of the rest period of 4 Consecutive Days, optionally, the first dosage regimen and the second dosage regimen are identical and use simultaneously.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of 5 Consecutive Days independently, are then at least one cycles of 7 days of the rest period of 2 Consecutive Days.In certain methods, the first dosage regimen and/or the second dosage regimen comprise the treatment phase of 1 Consecutive Days independently, are then at least one cycles of 7 days of the rest period of 6 Consecutive Days.In certain methods, the first dosage regimen and/or the second dosage regimen comprise at least one cycle of 7 days independently, at least 3 treatment phases on the next day of between the described cycle was included in 7 days.

In certain methods, the second dosage regimen has the rest period of 0 day.In certain methods, the first dosage regimen has the rest period of 0 day.In certain methods, the first dosage regimen has the rest period of 0 day, and the second dosage regimen comprises the treatment phase of 5 Consecutive Days, is then at least one cycle of 7 days of the rest period of 2 Consecutive Days.In certain methods, the first dosage regimen has the rest period of 0 day, and the second dosage regimen comprises the treatment phase of 1 Consecutive Days, is then at least one cycle of 7 days of the rest period of 6 Consecutive Days.

The present invention also provides a kind of method for treating the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises to described experimenter simultaneously or use following combination successively: (a) treats the PI3-kinases alpha inhibitor of effective dose, and (b) treats the mTOR inhibitors of effective dose, wherein PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) by vitro kinase, wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, wherein the clinical and therapeutic effect of the treatment of disease condition continues at least the same with the phase of using persistent period action period grown.In certain methods, described combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein PI3-kinases alpha inhibitor and/or mTOR inhibitors exist with sub-therapeutic dose.In certain methods, clinical and therapeutic effect is selected from by the following group formed: lasting tumor regression, downtrod tumor regrowth length, the minimizing of propagation, the apoptosis of increase, or the downward of target protein activity.In certain methods, clinical and therapeutic effect is that lasting tumor regression and downtrod tumor regrowth are long.In certain methods, persistent period action period is at least 30 days.In certain methods, persistent period action period is at least 5 days.In certain methods, PI3-kinases alpha inhibitor is used according to the first intermittent dosing regimen, and described scheme comprises the treatment phase, is then repetition period of rest period.In certain methods, mTOR inhibitors is used according to the second intermittent dosing regimen, and described scheme comprises the treatment phase, is then repetition period of rest period.

The present invention also provides a kind of method for the treatment of the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises to experimenter simultaneously or use following combination successively: the PI3-kinases alpha inhibitor for the treatment of effective dose according to (a) of intermittent ann, and (b) treats the mTOR inhibitors of effective dose, described scheme is effective in and realizes (a) higher curative effect, similar or the better toleration of (b) PI3-kinases alpha inhibitor and/or mTOR inhibitors, and (c) is compared with the PI3-kinases alpha inhibitor using dose,equivalent once a day and/or mTOR inhibitors, similar or less area under curve, wherein PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) by vitro kinase, and wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

In some embodiments, the disease condition be associated with PI3-kinases α and/or mTOR can include but not limited to tumprigenicity condition of illness, autoimmune disease, diseases associated with inflammation, fibrotic conditions and nephropathy.Such as, tumprigenicity condition of illness can be NSCLC, incidence ESCC, cancer of pancreas, breast carcinoma and ovarian cancer, renal cell carcinoma, carcinoma of prostate, neuroendocrine carcinoma, carcinoma of endometrium and other forms of cancer.

The present invention further provides the method for the phosphorylation of Akt (S473) in a kind of T suppression cell and Akt (T308), it comprises makes cell contact with mTOR inhibitors with the PI3-kinases alpha inhibitor of effective dose, described mTOR inhibitors optionally suppresses mTORC1 and mTORC2 active for one or more I type phosphatidylinositol-3-kinases (PI3-kinases), as by measuring determined based on the mensuration of cell or vitro kinase, wherein PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) by vitro kinase, wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.In some embodiments, for the every other I type phosphatidylinositol-3-kinase (PI3-kinases) be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α.

Such as, the PI3-kinases alpha inhibitor utilized in subject methods suppresses PI3-kinases α with the IC50 value of about 500nM or less, 400nM or less, 300nM or less, 200nM or less, 100nM or less, 10nM or less, 1nM or less, as determined in kinase assays in vitro.In another case, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, the IC50 value had than its for be selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta one, two kinds, three kinds or every other I type PI3-kinase whose IC50 value little at least 2,5,10,50,100,1000 times.In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α with the IC50 value being less than about 200nM, and described IC50 value is less at least 2,5 or 10 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α and/or PI3-kinase beta, and the IC50 value had is less at least 5 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.In other embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α and/or PI3-kinase beta, and the IC50 value had is less at least 50 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.In other embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, and the IC50 value had is less at least 50 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.

In some embodiments of the inventive method, mTOR inhibitors combines and directly suppresses mTORC1 and mTORC2.Such as, mTOR inhibitors is with about 500nM or less, 400nM or less, 300nM or less, 200nM or less, 100nM or less, 50nM or less, 10nM or less, or the IC50 value of 1nM or less suppresses mTORC1 and mTORC2, as determined in kinase assays in vitro.In another embodiment, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 10nM or less, as determined in kinase assays in vitro, and mTOR inhibitors is to the essentially no activity of one or more I type PI3-kinases being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.Alternatively, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro, and this IC50 value is less at least 2,5 or 10 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some embodiments, mTor inhibitor optionally suppresses mTORC1.Such as, mTor inhibitor suppresses mTORC1 with the IC50 value of about 1000nM or less, 500nM or less, 100nM or less, 50nM or less, 10nM or less, as determined in kinases in vitro.In some embodiments, mTor inhibitor is the analog of rapamycin or rapamycin.In other embodiments, mTor inhibitor is sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), CCI-779 (CCI-779), Zuo Tamosi (ABT-578) or than Ao Mosi (biolimus) A9 (Wu meter Mo Si (umirolimus)).

In some embodiments, mTOR inhibitors is formula I:

Or its pharmaceutically acceptable salt, wherein:

X ₁for N or C-E ¹, X ₂for N or C, X ₃for N or C, X ₄for C-R ⁹or N, X ₅for N or C-E ¹, X ₆for C or N and X ₇for C or N; And be adjacent wherein no more than two nitrogen ring atom;

R ₁for H ,-L-C _1-10alkyl ,-L-C _3-8cycloalkyl ,-L-C _1-10alkyl-C _3-8cycloalkyl ,-L-aryl ,-L-heteroaryl ,-L-C _1-10alkylaryl ,-L-C _1-10miscellaneous alkyl aryl ,-L-C _1-10alkyl heterocyclic ,-L-C _2-10thiazolinyl ,-L-C _2-10alkynyl ,-L-C _2-10thiazolinyl-C _3-8cycloalkyl ,-L-C _2-10alkynyl-C _3-8cycloalkyl ,-L-alkyl ,-L-alkylaryl ,-L-mix the alkyl-heterocyclyl groups ,-L-of miscellaneous alkyl aryl ,-L-that mix that mix that mix mixes alkyl-C _3-8cycloalkyl ,-L-aralkyl ,-L-heteroarylalkyl or-L-heterocyclic radical, wherein each is unsubstituted or by one or more independently R ³replace;

L be non-existent ,-(C=O)-,-C (=O) O-,-C (=O) N (R ³¹)-,-S-,-S (O)-,-S (O) ₂-,-S (O) ₂n (R ³¹)-or-N (R ³¹)-;

E ¹and E ²be-(W independently ¹) _j-R ⁴;

M ₁be 5,6,7,8,9 or-10 yuan of ring systems, wherein ring system be monocycle or dicyclo, by R ₅to replace and in addition optionally by one or more-(W ²) _k-R ²replace;

Each k is 0 or 1;

E ¹in j or E ²in j be 0 or 1 independently;

W ¹for-O-,-NR ⁷-,-S (O) _0-2-,-C (O)-,-C (O) N (R ⁷)-,-N (R ⁷) C (O)-,-N (R ⁷) S (O)-,-N (R ⁷) S (O) ₂-,-C (O) O-,-CH (R ⁷) N (C (O) OR ⁸)-,-CH (R ⁷) N (C (O) R ⁸)-,-CH (R ⁷) N (SO ₂r ⁸)-,-CH (R ⁷) N (R ⁸)-,-CH (R ⁷) C (O) N (R ⁸)-,-CH (R ⁷) N (R ⁸) C (O)-,-CH (R ⁷) N (R ⁸) S (O)-or-CH (R ⁷) N (R ⁸) S (O) ₂-;

W ²for-O-,-NR ⁷-,-S (O) _0-2-,-C (O)-,-C (O) N (R ⁷)-,-N (R ⁷) C (O)-,-N (R ⁷) C (O) N (R ⁸)-,-N (R ⁷) S (O)-,-N (R ⁷) S (O) ₂-,-C (O) O-,-CH (R ⁷) N (C (O) OR ⁸)-,-CH (R ⁷) N (C (O) R ⁸)-,-CH (R ⁷) N (SO ₂r ⁸)-,-CH (R ⁷) N (R ⁸)-,-CH (R ⁷) C (O) N (R ⁸)-,-CH (R ⁷) N (R ⁸) C (O)-,-CH (R ⁷) N (R ⁸) S (O)-or-CH (R ⁷) N (R ⁸) S (O) ₂-;

R ²for hydrogen, halogen ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl (such as, the monocyclic aryl of bicyclic aryl, unsubstituted aryl or replacement), heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _1-10alkyl-C _2-10thiazolinyl, C _1-10alkyl-C _2-1 ₀alkynyl, C _1-10alkylaryl (such as, C _2-10alkyl-monocyclic aryl, C _1-10the monocyclic aryl of alkyl-replacement or C _1-10alkyl bicyclic aryl), C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical, assorted alkyl, heterocyclic radical-C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl (such as, monocyclic aryl-C _2-10monocyclic aryl-the C of alkyl, replacement _1-10alkyl or bicyclic aryl-C _1-10alkyl), aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said bicyclic aryl or heteroaryl moieties is unsubstituted, or each wherein in bicyclic aryl, heteroaryl moieties or monocyclic aryl part is by one or more independently alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties be unsubstituted or by one or more alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ³and R ⁴be hydrogen, halogen ,-OH ,-R independently ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³ ¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl, heteroaryl, C _1-4alkyl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3- ₈cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C ₁ _-10alkyl-C _2-10thiazolinyl, C _1-10alkyl-C _2-10alkynyl, C _1-10alkylaryl, C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl-C _3-8cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical, heterocyclic radical-C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, assorted alkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said aryl or heteroaryl moieties is unsubstituted or by one or more independently halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³ ¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties is unsubstituted or by one or more halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ⁵for hydrogen, halogen ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²;

R ³¹, R ³²and R ³³in each be H or C independently _1-10alkyl, wherein C _1-10alkyl is unsubstituted or is replaced by one or more aryl, assorted alkyl, heterocyclic radical or heteroaryl, and each in wherein said aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace;

-NR ³⁴r ³⁵,-C (=O) NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵in R ³⁴and R ³⁵saturated or the undersaturated ring of 3-10 unit is formed together with the nitrogen-atoms attached by it; Wherein said ring is unsubstituted or by one or more-NR independently ³¹r ³², hydroxyl, halogen, oxo base, aryl, heteroaryl, C _1-6alkyl or O-aryl replace, and wherein said 3-10 unit is saturated or undersaturated ring contains 0,1 or 2 more hetero atoms except nitrogen-atoms independently;

R ⁷and R ⁸in each be hydrogen, C independently _1-10alkyl, C _2-10thiazolinyl, aryl, heteroaryl, heterocyclic radical or C _3-10cycloalkyl, wherein each outside dehydrogenation is unsubstituted or by one or more independently R ⁶replace;

R ⁶for halogeno-group ,-OR ³¹,-SH ,-NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl; Aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, each in wherein said alkyl, thiazolinyl, alkynyl, aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-10alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-10thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace; And

R ⁹for H, halogeno-group ,-OR ³¹,-SH ,-NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl; Aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, each in wherein said alkyl, thiazolinyl, alkynyl, aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-10alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-10thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace.In other embodiments, mTOR inhibitors is following formula: compound:

In other embodiments, PI3-kinases alpha inhibitor is following formula: compound:

Or its pharmaceutically acceptable salt, wherein:

W ^{1 '}for N, NR ^{3 '}or CR ^{3 '}; W ^{2 '}for N, NR ^{4 '}, CR ^{4 '}or C=O; W ^{3 '}for N, NR ^{5 '}or CR ^{5 '}; W ^{4 '}for N, wherein no more than two atom N with to be no more than two C=O groups adjacent;

W ^{5 '}for N;

W ^{6 '}for N or CR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

R ^{1 '}and R ^{2 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen;

R ^{3 '}and R ^{4 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{5 '}, R ^{6 '}, R ^{7 '}and R ^{8 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen;

R ^{9 '}for alkyl or halogeno-group; And

R ^{10 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.

Or its pharmaceutically acceptable salt, wherein:

X is O or S or N;

W ^{1 '}for S, N, NR ^{3 '}or CR ^{3 '}; W ^{2 '}for N or CR ^{4 '}; W ^{3 '}for S, N or CR ^{5 '}; W ^{4 '}for N or C, and W ^{7 '}for N or C, wherein no more than two atom N with to be no more than two C=O groups adjacent;

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

Or R ^{3 '}and R ^{4 '}form annulus together; And

R ^{5 '}, R ^{7 '}and R ^{8 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen.

For any method of the present invention, PI3-kinases alpha inhibitor and/or mTOR inhibitors can parenteral, per os, intraperitoneal, intravenous, intra-arterial, percutaneous, intramuscular, with liposomal form, through in the local delivery of conduit or support, subcutaneous, fat or use in sheath.In some embodiments, PI3-kinases alpha inhibitor and/or mTOR inhibitors are jointly applied to experimenter in same preparation.In other embodiments, PI3-kinases alpha inhibitor and/or mTOR inhibitors are jointly applied to experimenter in different preparation.

The present invention also provides a kind of pharmaceutical composition, and it comprises the combination of a certain amount of PI3-kinases alpha inhibitor and a certain amount of mTOR inhibitors, and wherein said being combined in experimenter in need provides synergistic therapeutic action.Such as, pharmaceutical composition is prepared with oral dose.In some embodiments, at least one in described amount is used as sub-therapeutic dose.In other embodiments, pharmaceutical composition is formulated as tablet or capsule.Such as, PI3-kinases alpha inhibitor and mTOR inhibitors are packed as independent tablet.In other embodiments, PI3-kinases alpha inhibitor and mTOR inhibitors are formulated as single peroral dosage form.

The present invention also provides a kind of medicinal reagent box, it comprises (i) and to be placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day are used in expection, wherein the mTOR inhibitors that the PI3-kinases alpha inhibitor of effective dose and/or (b) treat effective dose is treated by daily dose unit each self-contained (a), wherein daily dose unit comprises the PI3-kinases alpha inhibitor and/or mTOR inhibitors that are effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, and (ii) to be placed in packaging unit and expection use the time period of a time period or multiple at least 1 day not containing multiple daily dose units of activating agent.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein not containing the daily dose unit of activating agent is at least 1.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein not containing the daily dose unit of activating agent is at least 3,4 or 5, or the multiple of 3,4 or 5.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is at least 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is 3, or the multiple of 3, and the number wherein not containing the daily dose unit of activating agent is 4, or the multiple of 4.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is 5, or the multiple of 5, and the number wherein not containing the daily dose unit of activating agent is 2, or the multiple of 2.In some test kits, the number comprising the daily dose unit of PI3-kinases alpha inhibitor and/or mTOR inhibitors is 1, or the multiple of 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.

The present invention further provides a kind of medicinal reagent box being effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, it comprises (i) and to be placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the wherein each self-contained following combination of daily dose unit are used in expection: (a) treats the mTOR inhibitors that the PI3-kinases alpha inhibitor of effective dose and (b) treat effective dose; And (ii) is placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the wherein PI3-kinases alpha inhibitor of each self-contained treatment effective dose of daily dose unit are used in expection.In some test kits, the number comprising the daily dose unit of described combination is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is at least 1.In some test kits, the number comprising the daily dose unit of described combination is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is at least 3,4 or 5, or the multiple of 3,4 or 5.In some test kits, the number comprising the daily dose unit of described combination is at least 1, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is 6, or the multiple of 6.In some test kits, the number comprising the daily dose unit of described combination is 3, or the multiple of 3, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is 4, or the multiple of 4.In some test kits, the number comprising the daily dose unit of described combination is 5, or the multiple of 5, and the number wherein not containing the daily dose unit of activating agent is 2, or the multiple of 2.In some test kits, the number comprising the daily dose unit of described combination is 1, or the multiple of 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.

The present invention further provides a kind of medicinal reagent box being effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, it comprises (i) and to be placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the wherein each self-contained following combination of daily dose unit are used in expection: (a) treats the mTOR inhibitors that the PI3-kinases alpha inhibitor of effective dose and (b) treat effective dose; And (ii) is placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the wherein mTOR inhibitors of each self-contained treatment effective dose of daily dose unit are used in expection.

The present invention also provides a kind of method, and it comprises: (a) determines the sudden change that there is the PI3-kinases α be associated with the disease condition alpha mediated by PI3-kinases in experimenter; And (b) uses pharmaceutical composition of the present invention to described experimenter.Such as, sudden change is in the nucleotide sequence of coding PI3-kinases α.Exemplary mutations can comprise the point mutation of the nucleotide sequence of the PI3-kinases α that can cause encoding, the disappearance of frameshit and/or translation, insertion, translation without limitation.In another example, sudden change is in the aminoacid sequence of PI3-kinases α.

In some embodiments of any method of the present invention, experimenter or cell comprise the sudden change of the PI3-kinases α be associated with the disease condition alpha mediated by PI3-kinases.

Be incorporated to by reference

The all announcements mentioned in this manual, patent and patent application are incorporated herein by reference, and its degree is specific and indicating individually and being incorporated to way of reference as each independent announcement, patent or patent application.

Accompanying drawing is sketched

Novel feature of the present invention is specifically set forth enclosing in claim.Make use of the detailed description of the illustrative embodiment of principle of the present invention and accompanying drawing thereof by reference to following elaboration and will obtain better understanding to the features and advantages of the present invention:

Fig. 1 is the schematic diagram of the multiple and different signal transduction path activated in human cancer.

Fig. 2 uses the synergistic figure of combined therapy to tumor weight of PI3-kinases alpha inhibitor (compd A) and mTor inhibitor (compd B) in clinical front breast cancer model for illustrating.

Fig. 3 describes to use the combined therapy of compd A and compd B lowering the synergistic Western blotting in Akt and S6 phosphorylation.

Fig. 4 illustrates to use the synergistic figure of the combined therapy of compd A and rapamycin in the gross tumor volume reducing clinical front breast cancer model.

Fig. 5 illustrates A) diagram of unlike signal pathway that mediated by mTORC1 and mTORC2, and B) describe mTORC1-dependency NRDG1 phosphorylation to compd B, instead of the Western blotting of the sensitivity of rapamycin.

Fig. 6 illustrates A) to be depicted in PTEN-saltant type negative control tumor model compd B higher than the optionally figure of compd A, B) compd B in PTEN mutant cell is shown, instead of compd A is to the Western blotting of the Selective depression of Akt, S6 and 4EBP phosphorylation, and C) describe compared to mTOR and other PI3K isoforms, compd A suppresses the specificity of PI3K α, and compared to PI3K isoform, compd B suppresses the specific chart of mTOR.

Fig. 7 describes compd B to the Western blotting (upper figure) of serine 473 from the different suppression of the Akt phosphorylation at threonine 308 place.What also illustrate is the comparison that Pan-PI3K inhibitor suppresses relative to the Akt phosphorylation of compd B.

Fig. 8 is for illustrating Pan-PI3K inhibitor, instead of compd A blocks the figure of B cell function in vivo.By mice with TNP-Ficoll immunity and use following process: 1) vehicle; 2) 70mg/kgGDC0941; 3) 30mg/kg compd A; 4) 60mg/kg compd A; Or 5) 120mg/kg compd A, continue 7 days.Antibody produces the percentage ratio of the matched group be measured as with vehicle process.

Fig. 9 illustrates, Zuo Tu, illustrates the figure using 70mg/kgPan-PI3K inhibitor and 60mg/kg compd A to reduce the tumor weight of breast cancer model, and right figure, illustrate compared with 60mg/kg compd A, 70mg/kgPan-PI3K inhibitor reduces the figure of the existence of MZB cell in mouse spleen.

Figure 10 illustrates the frequency that PI3K α suddenlys change in various human cancer.

Figure 11 be in the cell line being depicted in the PI3K alpha active with rising compd A to the Western blotting of the suppression of PI3K approach.Left column illustrates the data from the MDA-MB-361 breast cancer cell carrying PIK3CA sudden change.Middle column illustrates the data from the MDA-MB-453 breast cancer cell carrying PIK3CA sudden change.The right side lists out the data from the SKBr3 breast cancer cell carrying HER2 sudden change.

Figure 12 illustrates A in PTEN-mutant cell system) Western blotting of compd A to the suppression of the Akt phosphorylation at serine 473 place is shown; And B) compd A is to the suppression of the reduction of the Akt phosphorylation at serine 473 place.

Figure 13 illustrates that compd A preferentially suppresses the chart of the propagation of carrying the tumor cell that PI3K α suddenlys change.

Figure 14 is the equivalent line chart describing addition or the Synergistic anti-cancer activity realized by the combination of compd A and compd B.External combinative analysis confirms that this is combined in addition between tumor type or hereditary form or cooperative effect.

Figure 15 is depicted in the Western blotting by compd A, compd B or its combination cell death inducing in mammary glandular cell cancerous cell.The PARP of cracking is the biomarker of apoptosis.Result shows, and compared with single medicament, apoptosis and approach regulation and control (TORC1 and TORC2 substrate) are greatly induced in the combination by compd A and compd B.Left column illustrates the data from the MDA-MB-361 breast cancer cell carrying PIK3CA and HER2 sudden change.The right side lists out the data from the HCC-1419 breast cancer cell carrying HER2 sudden change.

Figure 16 illustrates that the intermittent dosing regimen of the combination of compd A and compd B causes Tumor growth inhibition, is similar to viewed on QD timetable in vivo.

The persistency that Figure 17 illustrates the increase that the combination of compd A and compd B causes in-vivo tumour to control and the tumor regression continued, and single medicament control arm shows regrowth.

Figure 18 illustrates that the combination of compd A and compd B causes the increase of Tumor growth inhibition in PTEN deficiency model, shows that this is combined in different genotype and has purposes.

Figure 19 illustrates that compd A and being combined in KRAS/PIK3CA colon models of compd B show activity, and single medicament is not imitated.

Detailed Description Of The Invention

Some aspects of the present invention hereinafter with reference for illustration of exemplary application be described.Should be understood that numerous detail, relation and method are set forth and complete understanding of the present invention is provided.But those of ordinary skill in the art will easily recognize, the present invention can or utilize additive method to be implemented under neither one or multiple described detail.The present invention does not limit by the order of shown action or event, because some actions different order can occur and/or occur with other actions or event simultaneously.In addition, the action and shown by not all or event are all that to implement method according to the present invention necessary.

Term used herein is only for describing the object of specific embodiments and not being intended to for restriction of the present invention.As used herein, unless the context clearly dictates otherwise, otherwise singulative "/kind " and " described " are intended to also comprise plural form.In addition, " comprise (including, includes) " at term, " having (having, has, with) " or its variant for describing in detail and/or the degree of claim, described term is intended to be similar to the mode that term " comprises " and is included.

Term " about " or " approximately " mean to be within the acceptable error scope of the determined particular value of those of ordinary skill in the art, and it depends in part on this value and how to measure and to determine, that is, the restriction of measuring system.Such as, " about " can mean according to the practice of this area 1 or be greater than 1 standard deviation within.Alternatively, " about " gratifying shows being up to 20%, being preferably up to 10%, being more preferably up to 5% of definite value, and is more preferably up to the scope of 1%.Alternatively, particularly relative to biology system or process for, described term can mean within the order of magnitude of value, preferably within 5 times, and more preferably within 2 times.When applying for and describe occurrence in claim, unless otherwise stated, otherwise should suppose that term " about " means within the acceptable error scope of particular value.

As used herein, " treatment (Treatment, treating) ", " alleviating (palliating) " and " alleviating (ameliorating) " use interchangeably.These terms refer to the method for obtaining useful or expected result, and described result includes but not limited to treatment benefit and/or prevention benefit.Treatment benefit means elimination or the alleviation of the potential disease for the treatment of.In addition, treating benefit is realize, to make to observe in patients improvement, although patient still may suffer from this potential disease by eradicating or alleviate physiological signs that one or more and potential disease is associated.For prevention benefit, compositions can be applied to the patient of the risk being in development specified disease, or report there is the patient of one or more physiological signs of this disease, even if also do not do the diagnosis of this disease.

As used herein, term " tumprigenicity condition of illness " refers to the cell existing and have abnormal growth characteristics, described feature is as the oncogenic signals conduction of uncontrolled proliferation, immortality, metastatic potential, fast growth and growth rate, multilated, and some characteristic morphological feature.This comprises following misgrowth: the tumor cell (tumor) that (1) is bred by expression mutated tyrosine kinase or process LAN receptor tyrosine kinase; (2) wherein there is the optimum and malignant cell of other proliferative diseasees of aberrant tyrosine kinase activation; (3) any tumor of being bred by receptor tyrosine kinase; (4) any tumor of being bred by aberrant serine/threonine kinase activation; And wherein there is the optimum of other proliferative diseasees of aberrant serine/threonine kinase activation and malignant cell in (5).

Term " effective dose " or " treatment effective dose " refer to the amount of inhibitor as herein described of the expection application being enough to realize including but not limited to disease treatment, as hereafter define.Treatment effective dose can according to expection application (external or body in), or the experimenter treated and disease condition are (such as, the body weight of experimenter and age), the order of severity of disease condition, mode of using etc. and change, this easily can be determined by those of ordinary skill in the art.This term is also applied to dosage, and it is by the specific reaction in inducing target cell, such as, and the minimizing of target protein propagation or the downward of activity.Concrete dosage is by according to following and change: selected particular compound, the dosage regimen (no matter whether using with other compound combinations) followed, the time of using, the tissue used, and its physical delivery system of carrying.

" the sub-therapeutic dose " of medicament or therapy is for being less than the amount of the effective dose of described medicament or therapy, but the result that can produce when the another kind of medicament or therapy with effective or sub-therapeutic dose combines desired by doctor, this is because the synergism of the effective effect of such as gained or the side effect of reduction.

" collaborative effective therapeutic dose " of medicament or therapy for produce when the another kind of medicament or therapy with effective or sub-therapeutic dose combines compare be used alone in two kinds of medicaments or therapy any one time larger effect amount.In some embodiments, the medicament of collaborative effective therapeutic dose or therapy produce the larger effect of addition effect when each ratio in two kinds of medicaments or therapy is used alone when combinationally using.

As used herein, " medicament " or " bioactivator " refers to biology, pharmacy or chemical compound or other parts.Limiting examples comprises simple or complicated organic or inorganic molecule, peptide, protein, oligonucleotide, antibody, antibody derivatives, antibody fragment, vitamin derivative, carbohydrate, toxin, or chemotherapy compound.Multiple compounds can be synthesis, such as, and the organic compound of micromolecule and oligomer (such as, oligopeptide and oligonucleotide) and the synthesis based on multiple core texture.In addition, multiple natural resources can be provided for the compound screened, as plant or animal extracts etc.Technical staff can easily recognize, the structural property of medicament of the present invention does not limit.

As used herein, term " agonist " refers to and can cause by suppressing the activity of target protein or expression or the compound of biological function of intensifier target albumen.Therefore, term " agonist " defines in the context of the biological action of target polypeptide.Although preferred agonist herein interacts (such as with target specifically, in conjunction with), but by with target polypeptide other members that are the signal transduction pathway of its member interact cause or the compound of biologic activity of intensifier target polypeptide also particularly including within defining at this.

Term " antagonist " and " inhibitor " use interchangeably, and they refer to the compound that can be suppressed the biological function of target protein by the activity of suppression target protein or expression.Therefore, term " antagonist " and " inhibitor " define in the context of the biological action of target protein.Although preferred antagonist herein interacts (such as with target specifically, in conjunction with), but by interacting the compound of the biologic activity suppressing target protein also particularly including within defining at this with target protein other members that are the signal transduction pathway of its member.The preferred biologic activity that antagonist suppresses and the development of tumor, growth or diffusion, or the undesirable immunne response as showed in autoimmune disease is associated.

Phrase " combines and directly suppresses the kinase whose mTOR inhibitors of mTORC1 and mTORC2 " in use: refer to herein with the mutual effect of mTORC1 and mTORC2 composite bulk phase and reduce the mTOR inhibitors of its kinase activity.

" anticarcinogen ", " antitumor agent " or " chemotherapeutics " refer to any medicament being applicable to treat tumprigenicity condition of illness.One class anticarcinogen comprises chemotherapeutics." chemotherapy " means to use one or more chemotherapeutics and/or other medicaments by multiple method to cancer patient, and described method comprises intravenous, per os, intramuscular, intraperitoneal, intravesical, subcutaneous, percutaneous, buccal, or suck or with suppository form.

Term " cell proliferation " refers to the phenomenon that cell quantity changes due to division.This term also contains Growth of Cells, changes cellular morphology (such as, size increases) by Growth of Cells, consistent with proliferation signal.

Term " is used " jointly, " with ... combined administration " and grammatical equivalents thereof thereof are contained and used two or more medicaments to animal, is present in animal body to make two kinds of medicaments and/or its metabolite simultaneously.Jointly use to comprise and use with separate compositions form simultaneously, use at different time with separate compositions form, or use with the composition forms that wherein there are two kinds of medicaments.The medicament jointly used can be in same preparation.The medicament jointly used also can be in different preparation.

As used herein, " therapeutic effect " contains treatment benefit as above and/or prevention benefit.Preventive effect comprise postpone or eliminate a disease or condition of illness appearance, postpone or eliminate a disease or condition of illness paresthesia epilepsy, slow down, stop or the progress of reverse disease or condition of illness, or its any combination.

Term " pharmaceutically acceptable salt " refers to the salt derived from multiple organic and inorganic counterion well known in the art.Pharmaceutically acceptable acid-addition salts can use mineral acid and organic acid to be formed.Can comprise such as from the mineral acid of its salt derivative, hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc.Can comprise such as from the organic acid of its salt derivative, acetic acid, propanoic acid, glycolic, acetone acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, p-toluenesulfonic acid, salicylic acid etc.Pharmaceutically acceptable base addition salts can use inorganic base and organic base to be formed.Can comprise such as from the inorganic base of its salt derivative, sodium, potassium, lithium, ammonium, calcium, magnesium, ferrum, zinc, copper, manganese, aluminum etc.Can comprise such as from the organic base of its salt derivative, primary amine, secondary amine and tertiary amine, replacement amine (comprising naturally occurring replacement amine), cyclammonium, deacidite etc., especially as 2-aminopropane., trimethylamine, diethylamine, triethylamine, tripropyl amine (TPA) and ethanolamine.In some embodiments, pharmaceutically acceptable base addition salts is selected from ammonium salt, potassium salt, sodium salt, calcium salt and magnesium salt.

" pharmaceutically acceptable carrier " or " pharmaceutically acceptable excipient " comprise any and all solvents, disperse medium, coating, antibacterial agent and antifungal, etc. blend absorption delay agent etc.The use in pharmaceutically active substance of described medium and reagent is well-known in the art.Unless the medium of any routine or reagent incompatible with active component, otherwise cover its purposes in therapeutic combination of the present invention.The active component supplemented also can mix in described compositions.

" signal transduction " during it, stimulates or suppress signal to be passed in cell and at described intracellular delivery to cause the process of replying in born of the same parents.The regulator of signal transduction pathway refers to the compound regulating and map to the activity of one or more cell proteins of same signal specific transduction pathway.Regulator can increase (agonist) or check the activity of (antagonist) signal transduction molecule.

Term " Selective depression (selectiveinhibition or selectivelyinhibit) " refers to compared with the signaling activity that misses the target when being applied to bioactivator, described medicament can optionally reduce target signaling activity by the direct or indirect interaction with target.

" experimenter " refers to animal, as mammal, and such as people.Method as herein described is applicable to clinical front human body therapy and veterinary's application.In some embodiments, experimenter is mammal, and in some embodiments, experimenter behaves.

Term " in body " refers to the event occurred in the health of experimenter.

Term " external " refers to the event of the health outside occurring in experimenter.Such as, any mensuration that the outside that external test is encompassed in experimenter's mensuration is carried out.External test contains the mensuration based on cell, wherein adopts the cell of survival or death.External test also contains cell-less measurement, does not wherein adopt intact cell.

When this paper scope of application is used for the physical characteristic as molecular weight or the chemical characteristic as chemical formula, all combinations of scope and sub-portfolio and specific embodiments are wherein intended to be included.Term " about " means the approximation that the number of indication or numerical range are in experimental variability (or in statistical experiment errors) when index order or numerical range, and therefore described number or numerical range can change between 1% and 15% of such as described number or numerical range.Term " comprises (comprising) " (and relational language, as " comprising (comprise or comprises) " or " having (having) " or " comprising (including) ") comprise those embodiments, such as, " to be made up of described feature " or any embodiment formed of material, compositions, method or process etc. of " being substantially made up of described feature ".

Below abbreviation and term have indicated implication in the whole text: PI3K=phosphoinositide-3-kinases; PI=phosphatidylinositols.

Unless otherwise stated, otherwise the junctional complex of compound name portion be in the rightmost side describe part.That is, substituent group title starts with end section, continues with any coupling part, and terminates with this coupling part.Such as, heteroarylthio C _1-4alkyl has and is connected to C by sulfenyl sulfur _1-4the heteroaryl of alkyl group, described C _1-4alkyl group is connected to is with this substituent chemical substance.At expression such as "-L-C _1-10alkyl-C _3-8cycloalkyl " formula time, this condition is inapplicable.In this case, end group connects C for being attached to _1-10the C of moieties _3-8cycloalkyl, described connection C _1-10moieties is attached to element L, and described element is connected to self is with this substituent chemical substance.

" alkyl " refers to and is only made up of carbon and hydrogen atom, not containing unsaturated part, hydrocarbon chain radical (such as, the C with the straight of one to ten carbon atom or branching ₁-C ₁₀alkyl).No matter when occur in this article, numerical range refers to each integer in given range as " 1 to 10 ", such as, " 1 to 10 carbon atom " means alkyl can by 1 carbon atom, 2 carbon atoms, 3 carbon atoms etc., until and comprise 10 carbon atoms composition, but the appearance of the term " alkyl " of not specifying numerical range is also contained in this definition.In some embodiments, it is C ₁-C ₄alkyl.Typical alkyl comprises but is limited to never in any form: methyl, ethyl, propyl group, isopropyl, normal-butyl, isobutyl group, sec-butyl, isobutyl group, the tert-butyl group, amyl group, isopentyl, neopentyl, hexyl, heptyl (septyl), octyl group, nonyl, decyl etc.Alkyl is attached to the remainder of molecule by singly-bound, such as, methyl (Me), ethyl (Et), n-pro-pyl, 1-Methylethyl (isopropyl), normal-butyl, n-pentyl, 1,1-dimethyl ethyl (tert-butyl group), 3-methylhexyl, 2-methylhexyl etc.Unless clearly stated in addition in the description, otherwise alkyl is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂,-N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term " halogeno-group " or " halogen " refer to fluoro base, chloro base, bromo base or iodo base.

Term " haloalkyl " refers to the alkyl replaced by one or more halogeno-group, such as chloromethyl, 2-bromoethyl, 3-iodo propyl group, trifluoromethyl, perfluoro propyl, 8-chloro nonyl etc.

" acyl group " refer to group (alkyl)-C (O)-, (aryl)-C (O)-, (heteroaryl)-C (O)-, (assorted alkyl)-C (O)-and (Heterocyclylalkyl)-C (O)-, wherein said group is attached to precursor structure by carbonyl functional group.In some embodiments, described acyl group is C ₁-C ₁₀carboxyl groups, it refers to that the chain of the alkyl of acyloxy, aryl, heteroaryl or heterocycloalkyl portion or annular atoms add the carbonyl carbon of acyl group, and namely three other rings or chain atom add the sum of carbonyl.If R group is heteroaryl or Heterocyclylalkyl, so heterocycle or chain atom are that the sum of chain or annular atoms contributes.Unless clearly stated in addition in the description, otherwise " R " of acyloxy is optionally replaced by one or more substituent group, and described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a, SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂, N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

" cycloalkyl " refers to monocycle only containing carbon and hydrogen or polycyclic moiety and can be saturated or fractional saturation.Cycloalkyl comprises group (that is, the C with 3 to 10 annular atomses ₂-C ₁₀cycloalkyl).No matter when appear at herein, the numerical range as " 3 to 10 " refers to each integer in given range; Such as, " 3 to 10 carbon atoms " means cycloalkyl can by 3 carbon atoms etc., until and comprise 10 carbon atoms compositions.In some embodiments, described cycloalkyl is C ₃-C ₈group of naphthene base.In some embodiments, described cycloalkyl is C ₃-C ₅group of naphthene base.The illustrative examples of cycloalkyl includes but not limited to lower part: cyclopropyl, cyclobutyl, cyclopenta, cyclopentenyl, cyclohexyl, cyclohexenyl group, suberyl, ring octyl group, ring nonyl, ring decyl, norborny etc.Unless clearly stated in addition in the description, otherwise cycloalkyl is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂, N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each Ra is hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term " C _1-10alkyl-C _3-8cycloalkyl " such as, for describing the side chain of the connecting ring alkyl be attached to containing 3 to 8 carbon or straight chain and alkyl containing 1 to 10 carbon atom, 2-methylcyclopropyl groups etc.Any portion of described part is what do not replace or replace.

Term " bicyclic alkyl " refers to the structure be made up of two cycloalkyl moieties not replacing or replace with two or more shared atoms.If cycloalkyl moiety accurately has two shared atoms, so they are called as " condensing ".Example includes but not limited to dicyclo [3.1.0] hexyl, perhydro naphthyl etc.If cycloalkyl moiety has more than two shared atoms, so they are called as " bridge joint ".Example includes but not limited to dicyclo [2.2.1] hexyl (" norborny "), dicyclo [2.2.2] octyl group etc.

As used herein, term " hetero atom " or " ring hetero atom " are intended to comprise oxygen (O), nitrogen (N), sulfur (S), phosphorus (P) and silicon (Si).

" assorted alkyl ", " assorted thiazolinyl " and " assorted alkynyl " comprise the alkyl of optional replacement, thiazolinyl and alkynyl group and have one or more backbone atoms, and described backbone atoms is selected from the atom outside de-carbon, such as, and oxygen, nitrogen, sulfur, phosphorus and combination thereof.Can numerical range be provided, such as, C ₁-C ₄assorted alkyl, it refers to total chain length, is that 4 atoms are long in this example.Such as ,-CH ₂oCH ₂cH ₃group is called " C ₄" assorted alkyl, it is included in the hetero atom center in atom chain length description.The connection to the remainder of molecule is realized by the hetero atom in assorted alkyl chain or carbon.Assorted alkyl can be replaced by one or more substituent group, and described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, nitro, oxo base, thio group, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term " assorted alkylaryl " refers to as assorted alkyl defined above, and it is attached to aryl and can be attached at end points or the branched fraction attachment by assorted alkyl, such as benzyloxymethyl part.Any portion of described part is what do not replace or replace.

Term " assorted miscellaneous alkyl aryl " refers to the assorted alkyl being attached to heteroaryl moieties similarly, such as, and ethoxyl methyl pyridine radicals.Any portion of described part is what do not replace or replace.

Term " assorted alkyl-heterocyclyl groups " refer to be attached to heterocyclic radical as assorted alkyl defined above, such as, 4 (3-aminopropyl)-N-piperazinyl.Any portion of described part is what do not replace or replace.

Term " assorted alkyl-C _3-8cycloalkyl " refer to the cyclic alkyl be attached to containing 3 to 8 carbon as assorted alkyl defined above, such as, 1-aminobutyl-4-cyclohexyl.Any portion of described part is what do not replace or replace.

Term " assorted bicyclic alkyl " refers to the bicyclic alkyl structure not replacing or replaces, and to be wherein independently selected from the hetero atom of oxygen, nitrogen and sulfur alternative at least one carbon atom.

Term " assorted spirane base " refers to the spirane based structures not replacing or replaces, and to be wherein independently selected from the hetero atom of oxygen, nitrogen and sulfur alternative at least one carbon atom.

" alkene " part refers to the group be made up of at least two carbon atoms and at least one carbon-to-carbon double bond, and " alkynes " part refers to the group be made up of at least two carbon atoms and at least one carbon-to-carbon triple bond.No matter moieties be saturated or undersaturated, can be side chain, straight chain or ring-type.

" thiazolinyl " refers to and is only made up of carbon and hydrogen atom, has hydrocarbon chain radical (that is a, C of the straight of two to ten carbon atoms or branching containing at least one double bond ₂-C ₁₀thiazolinyl).No matter when appear at herein, the numerical range as " 2 to 10 " refers to each integer in given range; Such as, " 2 to 10 carbon atoms " means thiazolinyl can by 2 carbon atoms, 3 carbon atoms etc., until and comprise 10 carbon atoms compositions.In certain embodiments, thiazolinyl comprises two to eight carbon atoms.In other embodiments, thiazolinyl comprises two to five carbon atoms (such as, C ₂-C ₅thiazolinyl).Thiazolinyl is attached to the remainder of molecule by singly-bound, such as vinyl (ethenyl) (namely, vinyl (vinyl)), the third-1-thiazolinyl (that is, pi-allyl), but-1-ene base, penta-1-thiazolinyl, penta-Isosorbide-5-Nitrae-dialkylene etc.Unless clearly stated in addition in the description, otherwise thiazolinyl is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂, N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term " C _2-10thiazolinyl-assorted alkyl " refer to the group having and be attached to the alkenyl part containing 2 to 10 carbon atoms and for side chain or straight chain connecting assorted alkyl, such as, allyloxy etc.Any portion of described part is what do not replace or replace.

Term " C _2-10alkynyl-assorted alkyl " refer to have be attached to connect assorted alkyl do not replace or replace, containing 2 to 10 carbon atoms and be the group of the alkynyl moiety of side chain or straight chain, such as, 4-fourth-1-alkynyloxy group etc.Any portion of described part is what do not replace or replace.

Term " haloalkenyl group " refers to the thiazolinyl replaced by one or more halogeno-group.

Except as otherwise noted, otherwise term " cycloalkenyl group " refers to cyclic aliphatic 3 to 8 ring structure, is optionally replaced by alkyl, hydroxyl and halogeno-group, there is 1 or 2 ethylene linkage, as methyl cyclopropene base, trifluoromethyl cyclopropanyl, cyclopentenyl, cyclohexenyl group, 1，4-cyclohexadiene base etc.

" alkynyl " refers to and is only made up of carbon and hydrogen atom, containing at least one triple bond, hydrocarbon chain radical (that is, the C with the straight of two to ten carbon atoms or branching ₂-C ₁₀alkynyl).No matter when appear at herein, the numerical range as " 2 to 10 " refers to each integer in given range; Such as, " 2 to 10 carbon atoms " means alkynyl can by 2 carbon atoms, 3 carbon atoms etc., until and comprise 10 carbon atoms compositions.In certain embodiments, alkynyl comprises two to eight carbon atoms.In other embodiments, alkynyl comprises two to five carbon atoms (such as, C ₂-C ₅alkynyl).Alkynyl is attached to the remainder of molecule by singly-bound, such as, and acetenyl, propinyl, butynyl, pentynyl, hexin base etc.Unless clearly stated in addition in the description, otherwise alkynyl is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a, SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂, N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term C _2-10alkynyl-C _3-8cycloalkyl refers to the group of the alkynyl containing 2 to 10 carbon atoms and for side chain or straight chain containing the connecting ring alkyl be attached to containing 3 to 8 carbon, such as, and 3-third-3-alkynes-ring penta-1 base etc.Any portion of described part is what do not replace or replace.

Term " halo alkynyl " refers to the alkynyl replaced by one or more independently halogeno-group.

" amino " or " amine " refers to-N (R ^a) ₂group, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently, unless clearly stated in addition in description.As-N (R ^a) ₂group has the R outside two dehydrogenations ^atime, they can combine with nitrogen-atoms, to form 4-, 5-, 6-or 7-ring.Such as ,-N (R ^a) ₂be intended to include but not limited to 1-pyrrolidinyl and 4-morpholinyl.Unless clearly stated in addition in the description, otherwise amino is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂,-N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^aindependently for hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl and each in these parts can be optional as herein defined to replace.

" amide " or " acylamino-" refers to have formula-C (O) N (R) ₂or the chemical part of-NHC (O) R, wherein R is selected from by the following group formed: hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by ring bond with carbon) and heteroalicyclyl (by ring bond with carbon), and each in described part self can be optional replacement.In some embodiments, it is C ₁-C ₄acylamino-or amide group, it comprises amidocarbonylation at the sum of the carbon of group.-the N (R) of amide ₂r ^{2 '}optionally form 4-, 5-, 6-or 7-ring together with the nitrogen attached by it.Unless clearly stated in addition in the description, otherwise acylamino-is optionally such as replaced for one or more in the substituent group described by alkyl, cycloalkyl, aryl, heteroaryl or Heterocyclylalkyl herein independently.Amide can be aminoacid or peptide molecule, and it is attached to formula (I) compound, thus forms prodrug.Any amine, hydroxyl or carboxylic side-chain on compound as herein described all can be amidated.To prepare the program of described amide and special groups be well known by persons skilled in the art and can find easily in list of references source, described list of references source is as Greene and Wuts, ProtectiveGroupsinOrganicSynthesis, 3rd edition, JohnWiley & Sons, NewYork, N.Y., 1999, it is incorporated to herein with way of reference entirety.

" aromatics " or " aryl " refers to aromatic group (such as, the C with six to ten annular atomses ₆-C ₁₀aromatics or C ₆-C ₁₀aryl), it comprises at least one ring of the pi-electron system with conjugation, and described ring is carbocyclic ring (such as, phenyl, fluorenyl and naphthyl).To be formed by the benzene derivative replaced and the divalent group on annular atoms with free valency is called the phenylene group of replacement.Divalent group derived from monovalence multi-ring alkyl (its title ends up with "-Ji " by removing a hydrogen atom from the carbon atom with free valency) is named by adding "-Ya " to the title of the univalent perssad of correspondence, such as, the naphthyl with two attachment point is called naphthylene.No matter when appear at herein, the numerical range as " 6 to 10 " refers to each integer in given range; Such as, " 6 to 10 annular atomses " means aryl can by 6 annular atomses, 7 annular atomses etc., until and comprise 10 annular atomses compositions.This term comprises monocycle or condensed ring multi-ring (that is, sharing the right ring of adjacent annular atoms) group.Unless clearly stated in addition in the description, otherwise aryl moiety is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, trifluoromethyl, trifluoromethoxy, nitro, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-OC (O) N (R ^a) ₂,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) C (O) N (R ^a) ₂, N (R ^a) C (NR ^a) N (R ^a) ₂,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

" heteroaryl " or alternatively " heteroaromatic " refer to 5-to 18-unit aromatic group (such as, C ₅-C ₁₃heteroaryl), it comprises one or more ring hetero atom of being selected from nitrogen, oxygen and sulfur and can be monocycle, dicyclo, three rings or Fourth Ring ring system.No matter when appear at herein, the numerical range as " 5 to 18 " refers to each integer in given range; Such as, " 5 to 18 annular atomses " means heteroaryl can by 5 annular atomses, 6 annular atomses etc., until and comprise 18 annular atomses compositions.Divalent group derived from monovalence heteroaryl groups (its title ends up with "-Ji " by removing a hydrogen atom from the atom with free valency) is named by adding "-Ya " to the title of the univalent perssad of correspondence, such as, the pyridine radicals with two attachment point is called pyridylidene." heteroaromatic " or " heteroaryl " part containing N refer in the skeletal atom of its medium ring at least one be the aromatic group of nitrogen-atoms.Polyheteroaromatic can be and condenses or non-condensed.Hetero atom in heteroaryl groups is optional oxidation.One or more nitrogen-atoms, if existed, for optionally quaternised.Heteroaryl is attached to the remainder of molecule by any one atom of ring.The example of heteroaryl includes but not limited to: azepine base (azepinyl), acridinyl, benzimidazolyl, benzindole base, 1,3-benzodioxole group, benzofuranyl, benzoxazolyl, benzo [d] thiazolyl, diazosulfide base, benzo [b] [Isosorbide-5-Nitrae] Dioxepane base, benzo [b] [Isosorbide-5-Nitrae] oxazinyl, Isosorbide-5-Nitrae-benzo dioxane base (Isosorbide-5-Nitrae-benzodioxanyl), benzo naphtho-furan base, benzoxazolyl, benzodioxole group, benzo dioxine base (benzodioxinyl), benzoxazolyl, benzopyranyl, .alpha.-5:6-benzopyran ketone group, benzofuranyl, benzofuran ketone group, benzofuraxan base, benzothiazolyl, benzothienyl (benzo thio-phenyl), benzothiophene is [3,2-d] pyrimidine radicals also, benzotriazole base, benzo [4,6] imidazo [1,2-a] pyridine radicals, carbazyl, cinnolines base, cyclopenta [d] pyrimidine radicals, 6,7-dihydro-5H-cyclopenta [4,5] thieno [2,3-d] pyrimidine radicals, 5,6-dihydrobenzo [h] quinazolyl, 5,6-dihydrobenzo [h] cinnolines base, 6,7-dihydro-5H-benzo [6,7] cyclohepta [1,2-c] pyridazinyl, dibenzofuran group, dibenzo thio-phenyl, furyl, furazan base, furanonyl, furo [3,2-c] pyridine radicals, 5,6,7,8,9,10-six hydrogen ring pungent [d] pyrimidine radicals, 5,6,7,8,9,10-six hydrogen ring pungent [d] is rattled away and is chanted in a loud voice base, 5,6,7,8,9,10-six hydrogen ring pungent [d] pyridine radicals, isothiazolyl, imidazole radicals, indazolyl, indyl, indazolyl, isoindolyl, indolinyl, iso-dihydro-indole-group, isoquinolyl, indolizinyl, isoxazolyl, 5,8-endo-methylene group-5,6,7,8-tetrahydro quinazoline base, naphthyridinyl, 1,6-naphthyridines ketone group, oxadiazolyl, 2-oxo aza ring heptantriene base, oxazolyl, Oxyranyle, 5,6,6a, 7,8,9,10,10a-octahydro benzo [h] quinazolyl, 1-phenyl-1H-pyrrole radicals, phenazinyl, phenothiazinyl, phenoxazine group, phthalazinyl, pteridyl, purine radicals, pyranose, pyrrole radicals, pyrazolyl, pyrazolo [3,4-d] pyrimidine radicals, pyridine radicals, pyrido [3,2-d] pyrimidine radicals, pyrido [3,4-d] pyrimidine radicals, pyrazinyl, pyrimidine radicals, pyridazinyl, pyrrole radicals, quinazolyl, quinoxalinyl, quinolyl, isoquinolyl, tetrahydric quinoline group, 5,6,7,8-tetrahydro quinazoline base, 5,6,7,8-tetrahydro benzo [4,5] thieno [2,3-d] pyrimidine radicals, 6,7,8,9-tetrahydrochysene-5H-cyclohepta [4,5] thieno [2,3-d] pyrimidine radicals, 5,6,7,8-tetrahydropyridine is [4,5-c] pyridazinyl also, thiazolyl, thiadiazolyl group, thiapyran base (thiapyranyl), triazolyl, tetrazole radical, triazine radical, thieno [2,3-d] pyrimidine radicals, thieno [3,2-d] pyrimidine radicals, thieno [2,3-c] pyridine radicals, and thio-phenyl (i.e. thienyl).Unless clearly stated in addition in the description, otherwise heteroaryl moieties is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, nitro, oxo base, thio group, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, hetercycloalkylalkyl, heteroaryl or heteroaryl alkyl independently.

Term " aryl-alkyl ", " aryl alkyl " and " aralkyl " can be side chain or straight chain for describing wherein alkyl chain, thus form the group of coupling part with the terminal aryl group as above of aryl-alkyl part.The example of aryl-alkyl includes but not limited to: the optional benzyl replaced, phenethyl, phenylpropyl and benzene butyl, as 4-chlorobenzyl, 2, 4-dibromo-benzyl, 2-methyl-benzyl, 2-(3-fluorophenyl) ethyl, 2-(4-aminomethyl phenyl) ethyl, 2-(4-(trifluoromethyl) phenyl) ethyl, 2-(2-methoxyphenyl) ethyl, 2-(3-nitrobenzophenone) ethyl, 2-(2, 4-Dichlorobenzene base) ethyl, 2-(3, 5-Dimethoxyphenyl) ethyl, 3-phenylpropyl, 3-(3-chlorphenyl) propyl group, 3-(2-aminomethyl phenyl) propyl group, 3-(4-methoxyphenyl) propyl group, 3-(4-(trifluoromethyl) phenyl) propyl group, 3-(2, 4-Dichlorobenzene base) propyl group, 4-benzene butyl, 4-(4-chlorphenyl) butyl, 4-(2-aminomethyl phenyl) butyl, 4-(2, 4-Dichlorobenzene base) butyl, 4-(2-methoxyphenyl) butyl, and 10-phenyl decyl.Any portion of described part is what do not replace or replace.

As used herein, term " C _1-10alkylaryl " refer to that wherein aryl substitutes a hydrogen on alkyl as mentioned above containing the side chain of 1 to 10 carbon atom or the alkyl of non-branched, such as, 3-phenylpropyl.Any portion of described part is what do not replace or replace.

Term " C _2-10alkyl monocyclic aryl " refer to containing be attached to the side chain of the connection aryl only with a ring or straight chain and the group of end alkyl containing 2 to 10 atoms, such as, 2-phenethyl.Any portion of described part is what do not replace or replace.

Term " C _1-10alkyl bicyclic aryl " refer to containing be attached to the side chain of biarc connecting aryl or straight chain and the group of end alkyl containing 2 to 10 atoms, such as, 2-(1-naphthyl)-ethyl.Any portion of described part is what do not replace or replace.

Term " aryl-cycloalkyl " and " cycloalkyl aryl " are attached to the group of cycloalkyl for describing wherein terminal aryl group, such as, and phenylcyclopentyl etc.Any portion of described part is what do not replace or replace.

Term " heteroaryl-C _3-8cycloalkyl " and " heteroaryl-C _3-8cycloalkyl " group of the cycloalkyl containing 3 to 8 carbon, such as pyridine-2-base-cyclopenta etc. is attached to for describing wherein terminal hetaryl group.Any portion of described part is what do not replace or replace.

Term " heteroaryl-assorted alkyl " refers to that wherein terminal hetaryl group is attached to the group connecting assorted alkyl, such as, and the sub-methoxyl group of pyridine-2-base etc.Any portion of described part is what do not replace or replace.

Term " aryl-thiazolinyl ", " aryl alkenyl " and " arylalkenyl " can be side chain or straight chain for describing wherein alkenylene chain, thus form the group of the coupling part of arylalkenyl part, such as styryl (2-phenyl vinyl), cinnamyl group etc. with terminal aryl group part as defined above.Any portion of described part is what do not replace or replace.

Term " aryl-C _2-10thiazolinyl " mean the aryl alkenyl as above that wherein alkenyl part contains 2 to 10 carbon atoms, such as, styryl (2-phenyl vinyl) etc.Any portion of described part is what do not replace or replace.

Term " C _2-10thiazolinyl-aryl " for describing wherein containing 2 to 10 carbon atoms and the thiazolinyl that can be side chain or straight chain is attached to aryl moiety, thus form the group of the coupling part of thiazolinyl-aryl moiety, and such as, 3-acrylic-naphthalene-1-base etc.Any portion of described part is what do not replace or replace.

Term " aryl-alkynyl ", " aromatic yl polysulfide yl " and " sweet-smelling alkynyl " can be side chain or straight chain for describing wherein alkynyl chain, thus form the group of the coupling part of aryl-alkynyl moiety, such as 3-phenyl-1-propinyl etc. with terminal aryl group part as defined above.Any portion of described part is what do not replace or replace.

Term " aryl-C _2-10alkynyl " mean the aromatic yl polysulfide yl as above that wherein alkynyl moiety contains 2 to 10 carbon, such as, 3-phenyl-1-propinyl etc.Any portion of described part is what do not replace or replace.

Term " C _2-10alkynyl-aryl " mean containing the alkynyl moiety being attached to aromatic linked group group, all as defined above, wherein alkynyl moiety contains 2 to 10 carbon for described alkynyl moiety and aromatic linked group, such as 3-propinyl-naphthalene-1-base.Any portion of described part is what do not replace or replace.

Term " aryl-oxygen base ", " aryloxy " with " aryloxy group " for describing the terminal aryl group being attached to and being connected oxygen atom.Typical aryl-oxygen base comprises phenoxy group, 3,4-dichlorophenoxies etc.Any portion of described part is what do not replace or replace.

The group that term " aryl-oxyalkyl ", " aromatic yloxy yl alkyl " and " aryloxy alkyl " are replaced by terminal aryl group-oxygen base for describing wherein alkyl, such as pentafluorophenoxymethyl etc.Any portion of described part is what do not replace or replace.

Term " C _1-10alkoxy-C _1-10alkyl " refer to wherein containing 1 to 10 carbon atom and an oxygen atom in side chain or straight chain alkoxyl and be attached to the group of the connection alkyl of side chain containing 1 to 10 carbon atom or straight chain, such as methoxy-propyl etc.Any portion of described part is what do not replace or replace.

Term " C _1-10alkoxy-C _2-10thiazolinyl " refer to wherein containing 1 to 10 carbon atom and an oxygen atom in side chain or straight chain alkoxyl and be attached to the group of the connection thiazolinyl of side chain containing 1 to 10 carbon atom or straight chain, such as 3-methoxyl group but-2-ene-1-base etc.Any portion of described part is what do not replace or replace.

Term " C _1-10alkoxy-C _2-10alkynyl " refer to wherein containing 1 to 10 carbon atom and an oxygen atom in side chain or straight chain alkoxyl and be attached to the group of the connection alkynyl of side chain containing 1 to 10 carbon atom or straight chain, such as 3-methoxyl group fourth-2-alkynes-1-base etc.Any portion of described part is what do not replace or replace.

Term " heterocycloalkenyl " refers to the cycloalkenyl group structure not replacing or replace, wherein at least one carbon atom be selected from oxygen, nitrogen and sulfur hetero atom substitute.

Term " heteroaryl-oxygen base ", " heteroaryl-oxygen base ", " heteroaryl oxygen base ", " heteroaryl oxygen base ", " heteroaryloxy (hetaroxy) " with " heteroaryloxy (eteroaroxy) " for describing the terminal hetaryl group not replacing or replace being attached to and being connected oxygen atom.Typical heteroaryl-oxygen base comprises 4,6-dimethoxypyridin-2-base oxygen base etc.

Term " heteroaryl alkyl ", " heteroaryl alkyl ", " heteroaryl-alkyl ", " heteroaryl-alkyl ", " heteroarylalkyl (hetaralkyl) " and " heteroarylalkyl (heteroaralkyl) " can be side chain or straight chain for describing wherein alkyl chain, thus form the group of the coupling part of Heteroarylallcyl moieties, such as 3-furyl methyl, thenyl, furfuryl group etc. with terminal hetaryl group part as defined above.Any portion of described part is what do not replace or replace.

Term " heteroaryl-C _1-10alkyl " heteroaryl alkyl as above of 1 to 10 carbon atom is contained for describing wherein alkyl.Any portion of described part is what do not replace or replace.

Term " C _1-10alkyl-heteroaryl " for describing the alkyl being attached to heteroaryl as above, wherein alkyl contains 1 to 10 carbon atom.Any portion of described part is what do not replace or replace.

Term " heteroarylalkenyl ", " heteroarylalkenyl ", " heteroaryl-alkenyl ", " heteroaryl-alkenyl ", " impure aromatic ene base (hetaralkenyl) " and " impure aromatic ene base (heteroaralkenyl) " can be side chain or straight chain for describing wherein alkenylene chain, thus form the heteroarylalkenyl of the coupling part of impure aromatic ene base section, such as 3-(4-pyridine radicals)-1-acrylic with terminal hetaryl group part as defined above.Any portion of described part is what do not replace or replace.

Term " heteroaryl-C _2-10thiazolinyl " group as above of 2 to 10 carbon atoms is contained for describing wherein thiazolinyl.Any portion of described part is what do not replace or replace.

Term " C _2-10alkenyl-heteroaryl " connect the side chain of heteroaryl or straight chain and the group of thiazolinyl containing 2 to 10 carbon atoms for describing containing being attached to, such as 2-styryl-4-pyridine radicals etc.Any portion of described part is what do not replace or replace.

Term " heteroaryl alkynyl ", " heteroaryl alkynyl ", " heteroaryl-alkynyl ", " heteroaryl-alkynyl ", " hetaryne base (hetaralkynyl) " and " hetaryne base (heteroaralkynyl) " can be side chain or straight chain for describing wherein alkynyl chain, thus form the group of the coupling part of hetaryne base section, such as 4-(2-thienyl)-ethyl acetylene base etc. with heteroaryl moieties as defined above.Any portion of described part is what do not replace or replace.

Term " heteroaryl-C _2-10alkynyl " the heteroaryl alkynyl as above of 2 to 10 carbon atoms is contained for describing wherein alkynyl.Any portion of described part is what do not replace or replace.

Term " C _2-10alkynyl-heteroaryl " such as, for describing the group containing being attached to the alkynyl containing 2 to 10 carbon atoms and for side chain or straight chain connecting heteroaryl, 4 (fourth-1-alkynyl) thiophene-2-base etc.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical " refers to containing 1,2,3 or 4 heteroatomic four, five, six or heptatomic rings independently selected from nitrogen, oxygen and sulfur.Four-membered ring has 0 double bond, and five-membered ring has 0 to 2 double bond, and hexatomic ring and heptatomic ring have 0 to 3 double bond.Term " heterocyclic radical " also comprises bicyclic radicals, and wherein heterocyclic ring is fused to another monocyclic heterocycles base, or four to seven yuan of aromatics or non-aromatic carbocycle ring.Heterocyclic radical is attached to parent molecular moiety by any carbon atom in group or nitrogen-atoms.

" Heterocyclylalkyl " refers to stable 3-to 18-unit non-aromatic cyclic radical, and it comprises the hetero atom that 2 to 12 carbon atoms and 1 to 6 are selected from nitrogen, oxygen and sulfur.No matter when appear at herein, the numerical range as " 3 to 18 " refers to each integer in given range; Such as, " 3 to 18 annular atomses " means Heterocyclylalkyl can by 3 annular atomses, 4 annular atomses etc., until and comprise 18 annular atomses compositions.In some embodiments, described Heterocyclylalkyl is C ₅-C ₁₀heterocyclylalkyl.In some embodiments, described Heterocyclylalkyl is C ₄-C ₁₀heterocyclylalkyl.In some embodiments, described Heterocyclylalkyl is C ₃-C ₁₀heterocyclylalkyl.Unless clearly stated in addition in the description, otherwise heterocycloalkyl is monocycle, dicyclo, three rings or Fourth Ring ring system, and it can comprise and condensing or bridge joint ring system.Hetero atom in heterocycloalkyl can be optional oxidation.One or more nitrogen-atoms, if existed, for optionally quaternised.Heterocycloalkyl is partially or completely saturated.Heterocyclylalkyl is attached to the remainder of molecule by any one atom of ring.The example of described heterocycloalkyl includes but not limited to: dioxolanyl, thienyl [1, 3] dithiane base, Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidinyl, isothiazole alkyl, isoxazole alkyl, morpholinyl, octahydro indyl, octahydro isoindolyl, 2-oxopiperazinyl, 2-oxo-piperidine base, 2-oxo-pyrrolidine base, oxazolidinyl, piperidyl, piperazinyl, 4-piperidone base, pyrrolidinyl, pyrazolidinyl, quininuclidinyl, thiazolidinyl, tetrahydrofuran base, trithiane base, THP trtrahydropyranyl, thio-morpholinyl (thiomorpholinyl), thiamorpholinyl (thiamorpholinyl), 1-oxo-thiomorpholin base, and 1, 1-dioxo-thiomorpholinyl.Unless clearly stated in addition in the description, otherwise heterocycloalkyl portion is optionally replaced by one or more substituent group, described substituent group is independently: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, hydroxyl, halogeno-group, cyano group, nitro, oxo base, thio group, trimethyl silyl ,-OR ^a,-SR ^a,-OC (O)-R ^a,-N (R ^a) ₂,-C (O) R ^a,-C (O) OR ^a,-C (O) N (R ^a) ₂,-N (R ^a) C (O) OR ^a,-N (R ^a) C (O) R ^a,-N (R ^a) S (O) _tr ^a(wherein t is 1 or 2) ,-S (O) _toR ^a(wherein t is 1 or 2) ,-S (O) _tn (R ^a) ₂(wherein t is 1 or 2) or PO ₃(R ^a) ₂, wherein each R ^abe hydrogen, alkyl, fluoro-alkyl, carbocylic radical, carbocylic radical alkyl, aryl, aralkyl, Heterocyclylalkyl, heteroaryl or heteroaryl alkyl independently.

" Heterocyclylalkyl " also comprises bicyclic ring system, and a non-aromatic ring wherein usually with 3 to 7 annular atomses is except 1-3 independently selected from the hetero atom of oxygen, sulfur and nitrogen and comprise except at least one aforementioned heteroatomic combination containing at least 2 carbon atoms; And another ring usually with 3 to 7 annular atomses optionally containing 1-3 independently selected from the hetero atom of oxygen, sulfur and nitrogen and for aromatics.

Term " cycloheteroalkylalkyl (heterocyclylalkyl) ", " heterocyclyl-alkyl (heterocyclyl-alkyl) ", " cycloheteroalkylalkyl (hetcyclylalkyl) " and " heterocyclyl-alkyl (hetcyclyl-alkyl) " can be side chain or straight chain for describing wherein alkyl chain, thus form the group of the coupling part of cycloheteroalkylalkyl part, such as 3-piperidino methyl etc. with end heterocyclyl moieties as defined above.Term " assorted cycloalkylidene " refers to the divalent derivative of Heterocyclylalkyl.

Term " C _1-10alkyl-heterocyclyl groups " refer to that wherein moieties contains the group as defined above of 1 to 10 carbon atom.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _1-10alkyl " refer to containing being attached to containing 1 to 10 carbon atom and the group of end heterocyclic radical for the connection alkyl of side chain or straight chain, such as, 4-morpholinyl ethyl etc.Any portion of described part is what do not replace or replace.

Term " heterocyclylalkenyl (heterocyclylalkenyl) ", " heterocyclic radical-thiazolinyl (heterocyclyl-alkenyl) ", " heterocyclylalkenyl (hetcyclylalkenyl) " and " heterocyclic radical-thiazolinyl (hetcyclyl-alkenyl) " can be side chain or straight chain for describing wherein alkenylene chain, thus form the group of the coupling part of heterocyclylalkenyl part, such as 2-morpholinyl-1-acrylic etc. with end heterocyclyl moieties as defined above.Term " assorted sub-cycloalkenyl group " refers to the divalent derivative of heterocyclylalkenyl.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _2-10thiazolinyl " refer to that wherein thiazolinyl contains 2 to 10 carbon atoms and is the group as defined above of side chain or straight chain, such as, 4-(N-piperazinyl)-but-2-ene-1-base etc.Any portion of described part is what do not replace or replace.

Term " heterocyclylalkynyl (heterocyclylalkynyl) ", " heterocyclic radical-alkynyl (heterocyclyl-alkynyl) ", " heterocyclylalkynyl (hetcyclylalkynyl) " and " heterocyclic radical-alkynyl (hetcyclyl-alkynyl) can be side chain or straight chain for describing wherein alkynyl chain; thus form the group of the coupling part of heterocyclylalkynyl part, such as 2-pyrrolidinyl-ethyl acetylene base etc. with end heterocyclyl moieties as defined above.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _2-10alkynyl " refer to that wherein alkynyl contains 2 to 10 carbon atoms and is the group as defined above of side chain or straight chain, such as, 4-(N-piperazinyl)-Ding-2-alkynes-1-base etc.

Term " aryl-heterocyclic " refers to the group containing being attached to the terminal aryl group connecting heterocyclic radical, such as, and N4-(4-phenyl)-piperazinyl etc.Any portion of described part is what do not replace or replace.

Term " heteroaryl-heterocyclyl " refers to the group containing being attached to the terminal hetaryl group connecting heterocyclic radical, such as, and N4-(4-pyridine radicals)-piperazinyl etc.Any portion of described part is what do not replace or replace.

Term " carboxyalkyl " refers to the terminal carboxyl group (-COOH) being attached to branched-chain or straight-chain alkyl as defined above.

Term " carboxyalkenyl " refers to the terminal carboxyl group (-COOH) being attached to side chain or straight-chain alkenyl as defined above.

Term " carboxyalkynyl " refers to the terminal carboxyl group (-COOH) being attached to side chain or straight-chain alkynyl as defined above.

Term " carboxyl cycloalkyl " refers to the terminal carboxyl group (-COOH) being attached to cyclic aliphatic ring structure as defined above.

Term " carboxyl cycloalkenyl group " refers to the terminal carboxyl group (-COOH) being attached to the cyclic aliphatic ring structure as defined above with ethylene linkage.

Term " cycloalkyl-alkyl " and " cycloalkyl-alkyl " refer to the alkyl of end-rings being as defined above attached to alkyl, such as Cvclopropvlmethvl, cyclohexyl-ethyl etc.Any portion of described part is what do not replace or replace.

Term " cycloalkyl alkenyl " and " cycloalkyl-alkenyl " refer to the alkyl of end-rings being as defined above attached to thiazolinyl, such as cyclohexylvinyl, cycloheptylallyl etc." any portion of described part is what do not replace or replace.

Term " cycloalkylalkynyl " and " cycloalkyl-alkynyl " refer to the alkyl of end-rings being as defined above attached to alkynyl, such as cyclopropylpropargyl, 4-cyclopenta-2-butyne base etc.Any portion of described part is what do not replace or replace.

Term " cycloalkenyl alkyl " and " cycloalkenyl-alkyl " refer to the thiazolinyl of end-rings being as defined above attached to alkyl, such as 2-(cyclopentenes-1-base) ethyl etc.Any portion of described part is what do not replace or replace.

Term " cycloalkenylalkenyl " and " cycloalkenyl-alkenyl " refer to the thiazolinyl of end-rings being as defined above attached to thiazolinyl, such as 1-(cyclohexene-3-base) pi-allyl etc.

Term " cycloalkenylalkynyl " and " cycloalkenyl group-alkynyl " refer to the thiazolinyl of end-rings being as defined above attached to alkynyl, such as 1-(cyclohexene-3-base) propargyl etc.Any portion of described part is what do not replace or replace.

Term " alkoxyl " refers to radical-O-alkyl, and it comprises 1 to 8 carbon atom, has straight chain, side chain, cyclic configuration or its combination, is attached to precursor structure by oxygen.Example comprises methoxyl group, ethyoxyl, propoxyl group, isopropoxy, ring propoxyl group, cyclohexyloxy etc." lower alkoxy " refers to the alkoxyl containing 1 to 6 carbon.In some embodiments, C ₁-C ₄alkyl is contain to have the straight chain of 1 to 4 carbon atom and the alkyl of branched alkyl.

Term " halogenated alkoxy " refers to the alkoxyl replaced by one or more halogeno-group, such as chloromethoxy, trifluoromethoxy, difluoro-methoxy, perfluoroisobutoxy etc.

Term " alkoxy alkoxy alkyl " refers to the partially substituted alkyl of alkoxy, and described alkoxy portion is replaced by the second alkoxy portion then, such as Methoxymethoxymethyl, isopropoxymethoxyethyl etc.This part is replaced by other substituent group or is not replaced by other substituent groups.

Term " alkylthio group " comprises the side chain and straight chained alkyl, such as methyl mercapto etc. that are attached to and connect sulphur atom.

Term " alkoxyalkyl " refers to the alkyl that alkoxy replaces, such as i-propoxymethyl etc.Any portion of described part is what do not replace or replace.

Term " alkoxyalkenyl " refers to the thiazolinyl that alkoxy replaces, such as 3-methoxyallyl etc.Any portion of described part is what do not replace or replace.

Term " alkoxyalkynyl " refers to the alkynyl that alkoxy replaces, such as 3-methoxyl group propargyl etc.Any portion of described part is what do not replace or replace.

Term " C _2-10thiazolinyl C _3-8cycloalkyl " refer to the thiazolinyl as defined above replaced by three to octatomic ring alkyl, such as 4-(cyclopropyl)-crotyl etc.Any portion of described part is what do not replace or replace.

Term " C _2-10alkynyl C _3-8cycloalkyl " refer to the alkynyl as defined above replaced by three to octatomic ring alkyl, such as 4-(cyclopropyl)-2-butyne base etc.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _1-10alkyl " refer to the heterocyclic radical as defined above replaced by the alkyl as defined above with 1 to 10 carbon, such as, 4-(N-methyl)-piperazinyl etc.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _2-10thiazolinyl " refer to by the heterocyclic radical as defined above with the alkenyl substituted as defined above of 2 to 10 carbon, such as, 4-(N-pi-allyl)-piperazinyl etc.In wherein heterocyclic radical is also included within by the part of alkenyl substituted on carbon atom.Any portion of described part is what do not replace or replace.

Term " heterocyclic radical-C _2-10alkynyl " refer to by the heterocyclic radical as defined above with the alkynyl substituted as defined above of 2 to 10 carbon, such as, 4-(N-propargyl)-piperazinyl etc.In wherein heterocyclic radical is also included within by the part of alkenyl substituted on carbon atom.Any portion of described part is what do not replace or replace.

Term " oxo base " refers to carbon atom with the oxygen of double bond bonding.It will be understood by those skilled in the art that " oxo base " needs the second key from the atom attached by described oxo base.Therefore, should be understood that oxo base can not be displaced on aryl or heteroaryl ring, unless it forms a part for aromatic systems as tautomer.

Term " oligomer " refers to low-molecular weight polymer, and its number-average molecular weight is less than about 5000g/mol usually, and its degree of polymerization (average number of the monomeric unit of every bar chain) is greater than 1 and is generally equal to or is less than about 50.

" sulfonamido (sulfonamidyl or sulfonamido) " refers to-S (=O) ₂-NR ' R ' group, wherein each R ' is independently selected from by the following group formed: hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (by ring bond with carbon) and heteroalicyclyl (by ring bond with carbon).-S (=O) ₂r ' group in the-NR ' R ' of-NR ' R ' group can form 4-, 5-, 6-or 7-ring together with the nitrogen attached by it.Sulfonamido is optionally replaced for the substituent group described by alkyl, cycloalkyl, aryl, heteroaryl respectively by one or more.

Described compound can contain one or more asymmetric center and can therefore produce diastereomer and optical isomer.The present invention includes all described possible diastereomers and racemic mixture thereof, its substantially pure fractionation enantiomer, all possible geometric isomer, and its pharmaceutically acceptable salt.The spatial chemistry that compound can some position not determined illustrates.The present invention includes all stereoisomers and the pharmaceutically acceptable salt thereof of disclosed compound.In addition, in the mixture of stereoisomer and the particular stereoisomer of separation are also included within.In the process of the synthesis program for the preparation of described compound, or in the process using racemization well known by persons skilled in the art or epimerization program, the product of described program can be the mixture of stereoisomer.

The present invention includes the state that the isomer of all modes of inhibitor of the present invention and conformation are restricted.

For alkyl, assorted alkyl, cycloalkyl, Heterocyclylalkyl unit price and bivalence deriveding group (comprise and are commonly referred to alkylidene, thiazolinyl, assorted alkylidene, assorted thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, those groups of cycloalkenyl group and heterocycloalkenyl) substituent group to can be in multiple group one or more, described group is selected from, but be not limited to: alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl,-OR ',=O,=NR ',=N-OR ',-NR ' R ",-SR ',-halogen,-SiR ' R " R " ',-OC (O) R ',-C (O) R ',-CO ₂r ' ,-C (O) NR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R " ' ,-NR " C (O) OR ' ,-NR-C (NR ' R ")=NR ' " ,-S (O) R ' ,-S (O) ₂r ' ,-S (O) ₂nR ' R " ,-NRSO ₂r ' ,-CN and-NO ₂, quantitative range is 0 to (2m '+1), and wherein m ' is the sum of carbon atom in described group.R ', R ", R " ' and R " " preferably refer to hydrogen, substituted or unsubstituted assorted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl separately independently (such as, aryl by 1-3 halogen substiuted), substituted or unsubstituted alkyl, alkoxyl or thio alkoxy, or aryl alkyl.Such as, when inhibitor of the present invention comprises more than one R group, in R group each is chosen as each R ', R independently ", R ' " with group, when these groups more than one exist.

As R ' and R " or R " and R " ' is attached to same nitrogen-atoms time, they can combine with nitrogen-atoms, form 4-, 5-, 6-or 7-ring.Such as ,-NR ' R " be intended to include but not limited to 1-pyrrolidinyl, 4-piperazinyl and 4-morpholinyl.By substituent above discussion, it will be understood by those skilled in the art that term " alkyl " is intended to comprise the group of the carbon atom with the group be bonded to except hydrogen group, as haloalkyl (such as ,-CF ₃with-CH ₂cF ₃) and acyl group (such as ,-C (O) CH ₃,-C (O) CF ₃,-C (O) CH ₂oCH ₃deng).

Be similar to above for the substituent group described by alkyl group, illustrative substituents for aryl and heteroaryl (and divalent derivative) is different, and is selected from such as: halogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl ,-OR ' ,-NR ' R " ,-SR ' ,-halogen ,-SiR ' R " R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO ₂r ' ,-C (O) NR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R " ' ,-NR " C (O) OR ' ,-NR-C (NR ' R " R ' ")=NR " " ,-NR-C (NR ' R ")=NR ' " ,-S (O) R ' ,-S (O) ₂r ' ,-S (O) ₂nR ' R " ,-NRSO ₂r ' ,-CN and-NO ₂,-R ' ,-N ₃,-CH (Ph) ₂, fluoro (C ₁-C ₄) alcoxyl is for base and fluoro (C ₁-C ₄) alkyl, quantitative range is the sum that 0 to aromatic ring fastens open valency; And wherein R ', R ", R " ' and R " " preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted assorted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl and substituted or unsubstituted heteroaryl.Such as, when inhibitor of the present invention comprises more than one R group, in R group each is chosen as each R ', R independently ", R ' " with group, when these groups more than one exist.

As used herein ,-S (O) _(0-2)-context in 0-2 be integer 0,1 and 2.

Two in substituent group on the adjacent atom of aryl or heteroaryl ring optionally formed there is formula-T-C (O)-(CRR ') _qthe ring of-U-, wherein T and U is-NR-,-O-,-CRR '-or singly-bound independently, and q is the integer of 0 to 3.Alternatively, two in the substituent group on the adjacent atom of aryl or heteroaryl ring can optionally be had formula-A-(CH ₂) _rthe substituent group of-B-substitutes, wherein A and B be independently-CRR '-,-O-,-NR-,-S-,-S (O)-,-S (O) ₂-,-S (O) ₂nR '-or singly-bound, and r is the integer of 1 to 4.One in the singly-bound of the new ring of such formation can optionally be substituted by double bond.Alternatively, two in the substituent group on the adjacent atom of aryl or heteroaryl ring can optionally be had formula-(CRR ') _s-X '-(C " R " ') _d-substituent group substitute, wherein s and d is the integer of 0 to 3 independently, and X ' be-O-,-NR '-,-S-,-S (O)-,-S (O) ₂-or-S (O) ₂nR '-.Substituent R, R ', R " and R ' " preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted Heterocyclylalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

Unless otherwise stated, otherwise the structure described herein is also intended to comprise only different in the existence of the atom of one or more isotope enrichment compounds.Such as, there is structure of the present invention, just instead of hydrogen by deuterium or tritium, or by ¹³c-or ¹⁴the carbon of C-enrichment substitutes carbon compound within the scope of the invention.

Compound of the present invention also can contain the atom isotope of unnatural proportions in the one or more atoms forming described compound.Such as, described compound using radiation isotope as tritium ( ³h), iodine-125 ( ¹²⁵i) or carbon-14 ( ¹⁴c) radio-labeled is carried out.No matter whether all isotopic variations of compound of the present invention, be radioactive, all contain within the scope of the invention.

As used herein, term " treatment phase " is defined as the time period of the pharmaceutical composition wherein using daily dose according to dosage regimen to experimenter.Term " rest period " refers to period according to dosage regimen not to the time period of experimenter's drug administration compositions.Such as, if pharmaceutical composition basis gives in every day, if so use stopping such as some natural law or all numbers every day, then the rest period will be there is.If press a different time top application dosage, so the rest period occurs in administration when stopping a period of time.In some dosage regimens, when the concentration that the rest period occurs in pharmaceutical composition remains on sub-treatment level.Preferably, during the rest period, the plasma concentration of pharmaceutical composition remains on sub-treatment level.Combination treatment can have the different dosing regimes for different compound, such as, for a dosage regimen of the first compound and another dosage regimen for the second compound.Under described combination treatment, experimenter can stand the rest period for the first compound, stands the treatment phase for the second compound simultaneously.In some combination treatments, the rest period refers to that period does not use the time period of any pharmaceutical composition to experimenter.

Term " intermittent dosing regimen " refer to comprise drug administration compositions, be then the dosage regimen of rest period.

Term " effect duration " refers to the continuation of at least one in PI3-kinases alpha inhibitor and/or the mTOR inhibitors clinical and/or therapeutic effect after it uses stopping.Clinical sustainable with the described continuation of therapeutic effect at least with phase of using the same time period grown of PI3-kinases alpha inhibitor and/or mTOR inhibitors.Term " persistent period action period " refers to the time period started immediately after the phase of using.The feature in this period after occurring in the phase of using is not use PI3-kinases alpha inhibitor or mTOR inhibitors, but the inhibitor treatment of using and clinical effectiveness still continue.The length depending on dosage and use, at least the same with the phase of the using length of duration lasts action period, but sustainable most as many as use phase length about 5 or more is doubly.In some versions, persistent period action period is at least 5,10,20,30 days.In some versions, persistent period action period is at least one moon, three months, six months or 1 year.

The invention provides the disease condition being used for the treatment of and being associated with PI3-kinases α and/or mTOR, especially the method for tumprigenicity condition of illness, autoimmune disease, diseases associated with inflammation, fibrotic conditions and nephropathy, it provides phase of using the same persistent period action period grown at least with PI3-kinases alpha inhibitor or mTOR inhibitors.Extend to the clinical of persistent period action period from the phase of using and can comprise lasting tumor regression, downtrod tumor regrowth length, the minimizing of propagation, the apoptosis of increase with therapeutic effect, or the downward of target protein activity, or its combination.The phase of using refers to the time period being wherein administered to regimen (such as, intermittent dosing regimen) to experimenter.The phase of using can be about 1 to about 52 week, or about 4 to about 24 weeks, or about 6 to about 12 weeks, or about 8 weeks, or about 4 weeks.The phase of using can comprise one or more treatment phase and one or more rest period.Use the phase for each, there is corresponding persistent period action period, it continues at least the same with the phase of using length.

Method

In one aspect, the invention provides a kind of method for treating the disease condition be associated with PI3-kinases α and/or mTOR in experimenter.The while that described method generally including or successively to the PI3-kinases alpha inhibitor of experimenter's administering therapeutic effective dose and the combination of mTOR inhibitors.

As used herein, the treatment PI3-kinases alpha inhibitor of effective dose and the combination of mTOR inhibitors refer to the combination of PI3-kinases alpha inhibitor and mTOR inhibitors, and wherein said combination is enough to the expection application realizing including but not limited to disease treatment as herein defined.What contain in this subject methods is combinationally use the treatment PI3-kinases alpha inhibitor of effective dose and/or mTOR inhibitors to realize described treatment.What also contain in subject methods is combinationally use the PI3-kinases alpha inhibitor of sub-therapeutic dose and/or mTOR inhibitors to treat disease expectancy condition of illness.Each inhibitor, although exist with sub-therapeutic dose, collaborative generation useful effect and/or reduction side effect in expection application.

Therefore, in independent but related aspect, the invention provides a kind of method for treating the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises simultaneously or uses the PI3-kinases alpha inhibitor of collaborative effective therapeutic dose and the combination of mTOR inhibitors to experimenter successively.

The treatment effective dose of motif compound combination can according to expection application (external or body in), or the experimenter treated and disease condition are (such as, the body weight of experimenter and age), the order of severity of disease condition, mode of using etc. and change, this easily can be determined by those of ordinary skill in the art.This term is also applied to dosage, and it is by the specific reaction in inducing target cell, such as, and the minimizing of target protein propagation or the downward of activity.Concrete dosage is by according to following and change: selected specific compound, the dosage regimen (no matter whether using with other compound combinations) followed, the time of using, the tissue used, and its physical delivery system of carrying.

The PI3-kinases alpha inhibitor utilized in the inventive method shows the Selective depression relative to one or more I type phosphatidylinositol-3-kinases (PI3-kinases) (comprising such as, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta) PI3-kinases α usually.

The Selective depression of PI3-kinases α is determined by method in external or body.Any mensuration as known in the art can be used, include but not limited to immunoassay, immunoprecipitation, fluorescence or the mensuration based on cell.In some embodiments, use external test to determine the Selective depression of PI3-kinases α, this realizes relative to the mensuration of other PI3-kinases as the activity of PI3K α albumen for the activity of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta by measuring.Such as, the time-resolved FRET of the PIP3 product that indirect inspection can be used to be formed by the activity of PI3-K measures the IC50 value determined for test compounds PI3-kinases α and/or any other PI3-kinases.

As used herein, term " IC50 " refers to the half maximum inhibition concentration of inhibitor when suppressing biology or biochemical function.This quantitative measurement instruction suppress the special inhibitor needed for bioprocess (or the component of process, i.e. enzyme, cell, cell receptor or microorganism) of half number.In other words, its half maximum (50%) inhibition concentration (IC) (50%IC or IC50) EC50 being material refers to the plasma concentration needed for 50% obtaining maximum effect in vivo.

By determining and building dose response curve and check the inhibitor of variable concentrations to the mensuration being used for carrying out IC50 of inverse agonist activity.Be applicable to carry out these external tests measured be called " vitro kinase mensuration ".

In some embodiments, vitro kinase measures and comprises usage flag ATP as phosphodonor, and is captured on suitable filter by peptide substrate after kinase reaction.Split out by unreacted labelling ATP and metabolite from radioactive peptide substrate by multiple technologies, described technology comprises trichloroacetic acid precipitation and a large amount of washings.The interpolation of some positively charged residues allows to be captured on cellulose phosphate paper, then washs.The radioactivity of mixing in peptide substrate is detected by scinticounting.This measures relatively simply, quite sensitive, and can carry out for the sequence of peptide substrates and concentration the requirement adjusting to meet mensuration.

Other exemplary kinase assays are specified in U.S. Patent number 5,759, and 787 and Application U.S. Serial No 12/728, in 926, it is all incorporated herein by reference.

In other embodiments, the mensuration based on cell is used to determine the Selective depression of PI3-kinases α.Such as, if inhibitor is in the cell of expressing PI3-kinases α, preferably in the cell of the high level of the exception showing PI3-kinases α or activity, optionally lower PI3-signal transduction of kinases, so can show described inhibitor for PI3-kinases α for optionally.There is PI3-kinases α to suddenly change and the various kinds of cell therefore showing described PI3-kinases α exception is known in the art.The limiting examples of carrying the cell line of described sudden change comprise the point mutation of the nucleotide sequence carrying PI3-kinases α gene, disappearance, replacement or translation those.The example of described cell line includes but not limited to: BT20 (H1047R sudden change), MCF-7 (E545K sudden change), MDA-MB-361 (E545K sudden change), MDA-MB-453 (H1047R sudden change), T47D (H1047R sudden change), Hec-1A (G1049R sudden change) and HCT-116 (H1047R sudden change).Other cell lines in PI3K α albumen with sudden change can be used in, as carried the cell of the sudden change in p85, C2, spiral or kinase domain.

In addition, the suppression of PI3-kinases alpha active is determined by the minimizing of the signal transduction of PI3-kinases α approach.Extensive multiple reading result can be utilized to establish the minimizing of the Output rusults of described signal transduction path.Some non-restrictive illustrative read result and comprise (1) and including but not limited to the reduction of residue place Akt phosphorylation of S473 and T308; (2) reduction that activates of Akt, phosphorylation as the Akt substrate by including but not limited to FoxO1/O3aT24/32, GSK3 α/β S21/9 and TSC2T1462 reduce prove; (3) reduction of the phosphorylation of the signal transduction molecule (including but not limited to ribosome S 6 S240/244,70S6KT389 and 4EBP1T37/46) in PI3-kinases α downstream; (4) normal or tumor cell, mouse embryo fibroblasts, leukemic blasts, cancer stem cell is included but not limited to, and the suppression of the cell proliferation of the cell of mediation autoimmune response; (5) induction of apoptosis or cell cycle arrest; (6) reduction of cell chemotaxis; And the increase of the combination of (7) 4EBP1 and eIF4E.Term " eIF4E " refers to and participates in instructing ribosome to the 24-kD eukaryotic translation initiation factor with people's gene seat 4q21-q25 of the cap of mRNA.

In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α for the one be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, two or three other I type phosphatidylinositol-3-kinases (PI3-kinases).In other embodiments, some theme inhibitor optionally suppress PI3-kinases α and PI3-kinases γ compared with remaining I type PI3-kinases.In other embodiments, some theme inhibitor optionally suppress PI3-kinases α and PI3-kinase beta compared with remaining I type PI3-kinases.In other embodiments, some theme inhibitor optionally suppress PI3-kinases α and PI3-kinase delta compared with remaining I type PI3-kinases.

In some embodiments, described subject methods utilizes the PI3-kinases alpha inhibitor of the IC50 value about or be less than with predetermined value, as in kinase assays in vitro determine.In some embodiments, PI3-kinases alpha inhibitor is with about 1nM or less, 2nM or less, 5nM or less, 7nM or less, 10nM or less, 20nM or less, 30nM or less, 40nM or less, 50nM or less, 60nM or less, 70nM or less, 80nM or less, 90nM or less, 100nM or less, 120nM or less, 140nM or less, 150nM or less, 160nM or less, 170nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1 μM or less, 1.2 μMs or less, 1.3 μMs or less, 1.4 μMs or less, 1.5 μMs or less, 1.6 μMs or less, 1.7 μMs or less, 1.8 μMs or less, 1.9 μMs or less, 2 μMs or less, 5 μMs or less, 10 μMs or less, 15 μMs or less, 20 μMs or less, 25 μMs or less, 30 μMs or less, 40 μMs or less, 50 μMs, 60 μMs, 70 μMs, 80 μMs, 90 μMs, 100 μMs, 200 μMs, 300 μMs, the IC50 value of 400 μMs or 500 μMs or less suppresses PI3-kinases α.

In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, the IC50 value had than it for being selected from the one of the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, two or three other I type PI3-kinase whose IC50 value is little at least 2,3,4,5,6,7,8,9,10,15,20,25,30,35,40,45,50,100 or 1000 times.

In some embodiments, PI3-kinases alpha inhibitor is to be less than about 1nM, 2nM, 5nM, 7nM, 10nM, 20nM, 30nM, 40nM, 50nM, 60nM, 70nM, 80nM, 90nM, 100nM, 120nM, 140nM, 150nM, 160nM, 170nM, 180nM, 190nM, 200nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM, 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM, 1.9 μM, 2 μMs, 5 μMs, 10 μMs, 15 μMs, 20 μMs, 25 μMs, 30 μMs, 40 μMs, 50 μMs, 60 μMs, 70 μMs, 80 μMs, 90 μMs, 100 μMs, 200 μMs, 300 μMs, the IC50 value of 400 μMs or 500 μMs optionally suppresses PI3-kinases α, and described IC50 value than it for being selected from by PI3-kinase beta, the one of the group of PI3-kinases γ and PI3-kinase delta composition, the kinase whose IC50 value little at least 2 of two or three other I type PI3-, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times.In some embodiments, PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 100nM or less, as determined in kinase assays in vitro.

In some cases, PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 200nM or less, as determined in kinase assays in vitro, and this IC50 value is less at least 5,10,15,20,25,50,100 or 1000 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α with the IC50 value being less than about 100nM, and described IC50 value is less at least 5,10,15,20,25,50 or 100,1000 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some cases, PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 50nM or less, as determined in kinase assays in vitro, and this IC50 value is less at least 5,10,15,20,25,50,100 or 1000 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α with the IC50 value being less than about 20nM, and described IC50 value is less at least 5,10,15,20,25,50 or 100,1000 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some cases, PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 20nM or less, as determined in kinase assays in vitro, and this IC50 value is less at least 100 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

Alternatively, PI3-kinases alpha inhibitor with about 10 μMs or less, 5 μMs or less, 2.5 μMs or less, 1 μM or less, 500nM or less, 100nM or less, 75nM or less, 50nM or less, 25nM or less, 10nM or less, 5nM or less, 1nM or less, 500pM or less or 100pM or less EC50 value suppress PI3-kinases α, as determined in measured by vitro kinase.

In some embodiments, PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, the EC50 value had than it for being selected from the one of the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, two or three other I type PI3-kinase whose EC50 value is little at least 5,10,15,20,25,50,100 or 1000 times.

In some embodiments, PI3-kinases alpha inhibitor is with about 10 μMs or less, 5 μMs or less, 2.5 μMs or less, 1 μM or less, 500nM or less, 100nM or less, 75nM or less, 50nM or less, 25nM or less, 10nM or less, 5nM or less, 1nM or less, 500pM or less, or the EC50 value of 100pM or less suppresses PI3-kinases α, as determined in measured by vitro kinase, and described EC50 value than it for being selected from by PI3-kinase beta, the one of the group of PI3-kinases γ and PI3-kinase delta composition, the kinase whose EC50 value little at least 5 of two or three other I type PI3-, 10, 15, 20, 25, 50 or 100, 1000 times.

The mTOR inhibitors that utilizes in subject methods is generally high selectivity for target molecule.In one aspect, mTOR inhibitors combines and directly suppresses mTORC1 and mTORC2.Described ability can use known in this area or any method as herein described to determine.Such as, the suppression of mTorC1 and/or mTorC2 activity is determined by the minimizing of the signal transduction of PI3K/Akt/mTor approach.Extensive multiple reading result can be utilized to establish the minimizing of the Output rusults of described signal transduction path.Some non-restrictive illustrative read result and comprise (1) and including but not limited to the reduction of residue place Akt phosphorylation of S473 and T308; (2) reduction that activates of Akt, phosphorylation as the Akt substrate by including but not limited to FoxO1/O3aT24/32, GSK3 α/β S21/9 and TSC2T1462 reduce prove; (3) reduction of the phosphorylation of the signal transduction molecule (including but not limited to ribosome S 6 S240/244,70S6KT389 and 4EBP1T37/46) in mTor downstream; (4) normal or tumor cell, mouse embryo fibroblasts, leukemic blasts, cancer stem cell is included but not limited to, and the suppression of the cell proliferation of the cell of mediation autoimmune response; (5) induction of apoptosis or cell cycle arrest; (6) reduction of cell chemotaxis; And the increase of the combination of (7) 4EBP1 and eIF4E.

MTor is present in the complex of two types, the mTorC1 namely containing raptor subunit and the mTorC2 containing rictor.As is known in the art, " rictor " refers to the cell growth control albumen with people's gene seat 5p13.1.These complexs are are differently regulated and controled and have different substrates to be composed.Such as, mTorC1 by S6K (S6K) and 4EBP1 phosphorylation, thus promotes that the translation of increase and ribosome biology generate, to be conducive to Growth of Cells and cell cycle progress.S6K also works and weakens the activation of PI3K/Akt in feedback approach.Therefore, the suppression (such as, by bioactivator as discussed herein) of mTorC1 causes the activation of 4EBP1, thus the suppression causing RNA to translate (such as, reducing).

MTorC2 for rapamycin and selective depressant normally insensitive, and be considered to by by some agc kinases as the C-of Akt holds hydrophobic motif phosphorylation to carry out growth regulation factor signal transduction.In many cellular context, mTorC2 is required for the phosphorylation in the S473 site of Akt.Therefore, mTorC1 active part is controlled by Akt, and Akt own partial is controlled by mTorC2.

The factors stimulated growth of PI3K causes the activation of Akt by the phosphorylation at two critical sites S473 and T308 place.Report, Akt activates the phosphorylation needing S473 and T308Active completely.Akt promotes cell survival and propagation in many ways, comprises and checks apoptosis, promotion glucose uptake and change cellular metabolism.In two phosphorylation sites on Akt, the activation cycli phosphate at the T308 place mediated by PDK1 be it is believed that and to be absolutely necessary for kinase activity, and the hydrophobic motif phosphorylation at S473 place strengthens Akt kinase activity.

Selectivity mTor suppresses also by mTor gene, the i.e. expression (such as passing through RT-PCR) of its downstream signal conduction gene, or protein expression level (such as by immunocytochemistry, immunohistochemistry, Western blotting) is determined compared with other PI3-kinases or protein kinase.

The mensuration based on cell for establishing the Selective depression of mTorC1 and/or mTorC2 can take various ways.This will depend on that biological activity and/or the signal transduction studied read result usually.Such as, medicament suppresses mTorC1 and/or mTorC2 the ability of stream substrates phosphorylation to be determined by polytype kinase assays as known in the art.Representative mensuration includes but not limited to the immunoblotting that use antibody carries out and immunoprecipitation, and described antibody is as identified the anti-phosphotyrosine of phosphorylated protein, anti-phosphoserine or anti-phosphothreonine antibody.Alternatively, the antibody of the specific phosphorylation form identifying kinase substrate specifically (such as, anti-phosphoric acid AKTS473 or anti-phosphoric acid AKTT308) can be used.In addition, by high throughput chemical luminescence assays, as AlphaScreen ^tM(can purchased from PerkinElmer) and eTag ^tMmeasure (Chan-Hui etc. (2003) ClinicalImmunology111:162-174) and detect kinase activity.In yet another aspect, the single cell measurements of the flow cytometry as described in Phosflow experiment can be used to measure the phosphorylation of multiple downstreams mTOR substrate in mixed cellularity group.

An advantage of immunoblotting and Phosflow method is the phosphorylation simultaneously can measuring multiple kinase substrate.This provide and can measure effect and optionally advantage simultaneously.Such as, cell can be made to contact with the mTOR inhibitors of various concentration and mTOR and other kinase whose substrate phosphorylation levels can be measured.In one aspect, in so-called " comprehensive kinases investigation ", a large amount of kinase substrate is measured.Expection selectivity mTOR inhibitors suppresses the phosphorylation of mTOR substrate, and does not suppress the phosphorylation of other kinase whose substrates.Alternatively, selectivity mTOR inhibitors suppresses the phosphorylation of other kinase whose substrates by anticipation or the mechanism do not envisioned such as feedback loop or rich remaining property.

The inhibition of mTorC1 and/or mTorC2 or PI3-kinases α forms mensuration by cell colonies or other forms of cell proliferating determining is established.The cell proliferating determining of broad range can obtain in this area, and many test kits that can be used as wherein obtain.The limiting examples of cell proliferating determining comprise measure for titrtated thymidine picked-up, BrdU (5 '-bromo-2 '-BrdU) picked-up (test kit that Calbiochem sells), MTS picked-up (test kit that Promega sells), MTT picked-up (test kit that CaymanChemical sells), the test of Dye uptake (Invitrogen sale).

Apoptosis and cell cycle arrest analysis can use illustrative any method and additive method known in the art herein to carry out.Many diverse ways are designed to detect apoptosis.Exemplary mensuration includes but not limited to that TUNEL (TdT-mediation dUTPNick-EndLabeling) analyzes, ISEL (In situ terminal labeling) and for the fracture that detects DNA in cell mass or separate cell DNA ladder fractional analysis, measure serous coat change, detect apoptosis-related protein such as the Annexin-V of p53 and Fas and analyze.

Based on the mensuration of cell usually by target cell (such as, in culture medium) to carry out when being exposed to test compounds and then carrying out measuring for the reading result studied, described test compounds is possible mTorC1 and/or mTorC2 selective depressant or PI3-kinases alpha inhibitor.Depend on the character of candidate mTor inhibitor or PI3-kinases alpha inhibitor, they can be added directly in cell or with carrier and be combined.Such as, when reagent is nucleic acid, added in cell culture by method well known in the art, described method includes but not limited to calcium phosphate precipitation, microinjection or electroporation.Alternatively, nucleic acid can be mixed for mixing in expression in cell or insertion vector.Carrier containing promoter and cloning site is well known in the art, and polynucleotide can be operatively attached in described cloning site.Described carrier can external or in vitro transcription RNA, and can be commercially available from the source of such as Stratagene (LaJolla, CA) and PromegaBiotech (Madison, WI).In order to optimization expression and/or in vitro transcription, may need to remove, add or change 5 ' and/or 3 ' the untranslated part of clone, with eliminate extra, may unsuitable alternative translation initiation codon or other on transcriptional level or translation skill, may disturb or reduce the sequence of expression.Alternatively, 5 ' of start codon can be close to and insert total ribosome binding site with Enhanced expressing.The example of carrier be virus as other recombinant vectors conventional in baculovirus and retrovirus, phage, adenovirus, adeno-associated virus, cosmid, plasmid, fungal vector and this area, have described for the expression in multiple eucaryon and prokaryotic hosts to described carrier and it can be used for gene therapy and simple protein expression.Wherein there are some non-virus carriers, comprise the virus protein DNA complex of DNA/ liposome compound and targeting.In order to strengthen sending cell, can by nucleic acid of the present invention or protein-conjugate in conjunction with the antibody of cell surface antigen or its binding fragment.The liposome also comprising targeting antibodies or its fragment can be used in the method for the invention.The upper acceptable carrier of the other biological that is combined with motif compound can be utilized, be included in such as REMINGTON ' SPHARMACEUTICALSCIENCES, describe in the 19th edition (2000) those.

Theme medicament also can be utilized to carry out the phosphorylation of Akt in T suppression cell (S473) and Akt (T308).Therefore, the invention provides a kind of method, it comprises the following steps: cell is contacted with the described bioactivator of effective dose, to make the Akt phosphorylation suppressing residue S473 and T308 place simultaneously.In one aspect, when in suitable molar concentration, when preferably testing under identical molar concentration, compared to the phosphorylation of the T308 of Akt, bioactivator more effectively suppresses the phosphorylation of the S473 of Akt.

The suppression of Akt phosphorylation can use any method as known in the art or as herein described to determine.Representative mensuration includes but not limited to the immunoblotting that use antibody carries out and immunoprecipitation, and described antibody is as identified the anti-phosphotyrosine antibody of specific phosphorylated protein.ELISA kit based on cell also can be buied (SuperArrayBiosciences), and described test kit carries out quantitatively relative to the amount of total Akt albumen to (in S473 place phosphorylation) Akt of activation.

When practical matter method, the cell of any expression PI3-kinases α, mTorC1, mTorC2 and/or Akt can be utilized.Its propagation the limiting examples of repressed particular cell types can comprise fibroblast, skeletal tissue's (bone and cartilage) cell, epithelial tissue (such as liver, lung, breast, skin, bladder and kidney) cell, cardiac muscle and smooth muscle cell, neurocyte (neuroglia and neuron), endocrine cell (adrenal gland, hypophysis, islet cells), melanocyte, and many dissimilar hematopoietic cells (such as, B-cell or the cytophyletic cell of T-, and corresponding stem cell, lymphoblast).What also pay close attention to is the cell showing tumor tendency or phenotype.What especially pay close attention to is the type of the cell of differential expression (process LAN or low expression) Disease-causing gene.The parafunctional disease type comprising gene includes but not limited to autoimmune disease, cancer, obesity, hypertension, diabetes, neuron and/or muscular-degenerative disease, heart disease, endocrine regulation, and its any combination.

In some embodiments, mTOR inhibitors is with about 1nM, 2nM, 5nM, 7nM, 10nM, 20nM, 30nM, 40nM, 50nM, 60nM, 70nM, 80nM, 90nM, 100nM, 120nM, 140nM, 150nM, 160nM, 170nM, 180nM, 190nM, 200nM, 225nM, 250nM, 275nM, 300nM, 325nM, 350nM, 375nM, 400nM, 425nM, 450nM, 475nM, 500nM, 550nM, 600nM, 650nM, 700nM, 750nM, 800nM, 850nM, 900nM, 950nM, 1 μM, 1.2 μM, 1.3 μM, 1.4 μM, 1.5 μM, 1.6 μM, 1.7 μM, 1.8 μM, 1.9 μM, 2 μMs, 5 μMs, 10 μMs, 15 μMs, 20 μMs, 25 μMs, 30 μMs, 40 μMs, 50 μMs, 60 μMs, 70 μMs, 80 μMs, 90 μMs, 100 μMs, 200 μMs, 300 μMs, the IC50 value of 400 μMs or 500 μMs or less suppresses mTORC1 and mTORC2, as determined in kinase assays in vitro, and described IC50 value than it for being selected from by PI3-kinases α, PI3-kinase beta, the kinase whose IC50 value little at least 2 of every other I type PI3-of the group of PI3-kinases γ and PI3-kinase delta composition, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 100 or 1000 times.Such as, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 200,100,75,50,25,10,5,1 or 0.5nM or less, as determined in kinase assays in vitro.In one case, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro.Alternatively, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 10nM or less, as determined in kinase assays in vitro.

In some embodiments, the invention provides the purposes of mTOR inhibitors, wherein mTOR inhibitors directly combine and with about or the IC50 value being less than predetermined value suppress mTORC1 and mTORC2, as determined in kinase assays in vitro.In some embodiments, mTOR inhibitors is with about 1nM or less, 2nM or less, 5nM or less, 7nM or less, 10nM or less, 20nM or less, 30nM or less, 40nM or less, 50nM or less, 60nM or less, 70nM or less, 80nM or less, 90nM or less, 100nM or less, 120nM or less, 140nM or less, 150nM or less, 160nM or less, 170nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1 μM or less, 1.2 μMs or less, 1.3 μMs or less, 1.4 μMs or less, 1.5 μMs or less, 1.6 μMs or less, 1.7 μMs or less, 1.8 μMs or less, 1.9 μMs or less, 2 μMs or less, 5 μMs or less, 10 μMs or less, 15 μMs or less, 20 μMs or less, 25 μMs or less, 30 μMs or less, 40 μMs or less, 50 μMs or less, 60 μMs or less, 70 μMs or less, 80 μMs or less, 90 μMs or less, 100 μMs or less, 200 μMs or less, 300 μMs or less, the IC50 value of 400 μMs or less or 500 μMs or less suppresses mTORC1 and mTORC2.

In some embodiments, mTOR inhibitors is with about 1nM or less, 2nM or less, 5nM or less, 7nM or less, 10nM or less, 20nM or less, 30nM or less, 40nM or less, 50nM or less, 60nM or less, 70nM or less, 80nM or less, 90nM or less, 100nM or less, 120nM or less, 140nM or less, 150nM or less, 160nM or less, 170nM or less, 180nM or less, 190nM or less, 200nM or less, 225nM or less, 250nM or less, 275nM or less, 300nM or less, 325nM or less, 350nM or less, 375nM or less, 400nM or less, 425nM or less, 450nM or less, 475nM or less, 500nM or less, 550nM or less, 600nM or less, 650nM or less, 700nM or less, 750nM or less, 800nM or less, 850nM or less, 900nM or less, 950nM or less, 1 μM or less, 1.2 μMs or less, 1.3 μMs or less, 1.4 μMs or less, 1.5 μMs or less, 1.6 μMs or less, 1.7 μMs or less, 1.8 μMs or less, 1.9 μMs or less, 2 μMs or less, 5 μMs or less, 10 μMs or less, 15 μMs or less, 20 μMs or less, 25 μMs or less, 30 μMs or less, 40 μMs or less, 50 μMs or less, 60 μMs or less, 70 μMs or less, 80 μMs or less, 90 μMs or less, 100 μMs or less, 200 μMs or less, 300 μMs or less, the IC50 value of 400 μMs or less or 500 μMs or less suppresses mTORC1 and mTORC2, and mTOR inhibitors is to being selected from by PI3-kinases α, PI3-kinase beta, the essentially no activity of one or more I type PI3-kinases of the group of PI3-kinases γ and PI3-kinase delta composition.In some embodiments, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 10nM or less, as determined in kinase assays in vitro, and mTOR inhibitors is to the essentially no activity of one or more I type PI3-kinases being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

As used herein, term " essentially no activity " refers to that inhibitor suppresses the activity of described target be less than the maximum activity of its target when there is not this inhibitor about 1%, 5%, 10%, 15% or 20%, as determined by external enzymatic mensuration (such as in vitro kinase assays in).

In other embodiments, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 1000,500,100,75,50,25,10,5,1 or 0.5nM or less, as determined in kinase assays in vitro, and described IC50 value is less at least 2,5,10,15,20,50,100 or 100 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.Such as, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro, and described IC50 value is less at least 5 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some embodiments, mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro, and described IC50 value is less at least 5 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

In some embodiments, the mTOR inhibitors utilized in subject methods optionally suppresses one in mTORC1 and mTORC2 with about 1000,500,100,75,50,25,10,5,1 or the IC50 value of 0.5nM or less, as determined in kinase assays in vitro.Such as, the mTOR inhibitors utilized in subject methods optionally suppresses mTORC1 with the IC50 value of about 1000,500,100,75,50,25,10,5,1 or 0.5nM or less, as determined in kinase assays in vitro.Such as, rapamycin and rapamycin derivative or analog have demonstrated and have mainly suppressed mTORC1, instead of mTORC2.Suitable mTORC1 inhibitor compound comprises such as, sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), CCI-779 (CCI-779), Zuo Tamosi (ABT-578), and do not take charge of A9 (Wu meter Mo Si) than Austria.

The PI3-kinases alpha inhibitor or the mTOR inhibitors that are applicable to subject methods can be selected from polytype molecule.Such as, inhibitor can be biological or chemical compound, as simple or complicated organic or inorganic molecule, peptide, peptide mimics, protein (such as antibody), liposome or polynucleotide (such as siRNA, Microrna, antisense, fit, ribozyme or three spirillums).Some Exemplary types being applicable to the chemical compound of subject methods describe in detail in lower part.

The Selective depression of cell target is diversified as a kind of advantage for the treatment of the mode of the disease condition mediated by described target.Because the survival of healthy cell depends on the signal transduction path be activated in cancer, so the suppression of these approach can cause harmful side effect during treatment of cancer.In order to make the success of the method for Therapeutic cancer not cause too much injury to healthy cell, need the specificity of the very height of one or more abnormal signal conductive components of targeting.In addition, the survival of cancer cell can be dependent on overactive intracellular signaling (being called the additive hypothesis of oncogene).In this way, cancerous cell is frequently observed by selecting to overcome the Drug inhibition that pharmaceutically-active sudden change adapts to abnormal signal conductive components in identical approach.Therefore, if the signal transduction path that cancer therapy targeting is overall, or targeting to be advanced by leaps and bounds interior component more than a kind of intracellular signaling, and so described cancer therapy more successfully can overcome resistance problems.

Be not bound by theory, the Selective depression of PI3-kinases α provides treats targetedly to the having more of disease condition kinase mediated by PI3-, and do not destroy by one or more other I type phosphatidylinositol-3-kinases, i.e. one or more approach of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta participation.

Some signal transduction paths containing PI3K and mTOR are shown in Figure 1.The main downstream effect thing of of PI3K and mTOR intracellular signaling is Akt serine/threonine kinase.Akt has the protein structure domain being called as PH domain or pleckstrin homology domain (PleckstrinHomologydomain), its with high-affinity in conjunction with phosphoinositide.When the PH domain of Akt, it is in conjunction with PIP3 (phosphatidylinositols (3,4,5)-triphosphoric acid, PtdIns (3,4,5) P3) or PIP2 (phosphatidylinositols (3,4)-diphosphonic acid, PtdIns (3,4) P2) in any one.PI3K is in response to the signal from chemical messenger by PIP2 phosphorylation, and described signal is as ligand binding G-protein-coupled receptor or receptor tyrosine kinase.PIP2 is converted into PIP3 by the phosphorylation of being undertaken by PI3K, thus raises to cell membrane by Akt, at described cell membrane place by mTORC2 by described Akt in serine 473 (S473) place phosphorylation.Akt is in another site, and the phosphorylation at threonine 308 (T308) place does not directly depend on mTORC2, but needs PI3K active.Therefore, lack by inspection Akt threonine 308 phosphorylation state in the cell of mTORC2 activity by for the PI3K of Akt active with mTOR activity in separate.

This subject methods is applicable to treat the disease condition be associated with PI3-kinases α and/or mTOR.Any disease condition directly or indirectly caused by abnormal activity or the expression of PI3-kinases α and/or mTOR can be disease expectancy condition of illness.

Report the complicated and diversified disease condition be associated with PI3-kinases α and/or mTOR.PI3-kinases α take part in such as multiple human cancer.Angiogenesis has demonstrated the α isoform optionally needing PI3K in the control of endothelial cell migration.(Graupera etc., Nature, 2008:453; 662-6).It is believed that at many human cancers, as the sudden change of the gene of coding PI3K α occurred in pulmonary carcinoma, gastric cancer, carcinoma of endometrium, ovarian cancer, bladder cancer, breast carcinoma, colon cancer, the brain cancer and skin carcinoma or causing the sudden change of rise of PI3K α.Usually, the sudden change of the gene of coding PI3K α concentrates on the point mutation in the some focuses in spiral and kinase domain (as E542K, E545K and H1047R).These sudden changes many have demonstrated as carcinogenecity gain-of-function mutation.Because the high frequency of PI3K α suddenlys change, the targeting of this approach provides valuable therapy apparatus meeting.Although other PI3K isoforms as PI3K δ or PI3K γ are mainly expressed in hematopoietic cell, PI3K α, together with PI3K β, composing type ground is expressed.

The disease condition be associated with PI3-kinases α and/or mTOR also characterizes by the high activity level of the exception of the downstream courier of PI3-kinases α and/or expression.Such as, the amount existence that protein or courier as PIP2, PIP3, PDK, Akt, PTEN, PRAS40, GSK-3 β, p21, p27 can be abnormal, this identifies by mensuration as known in the art.

The imbalance of mTOR approach become various human diseases common theme and therefore the medicine of targeting mTOR there is therapeutic value.The disease be associated for the imbalance of mTORC1 includes but not limited to Tuberous sclerosis complex (TSC) and LAM (LAM), and both cause by the sudden change of TSC1 or TSC2 tumor suppressor gene.There is patient evolution's benign tumor of TSC, but, epilepsy, mental retardation and death can be caused when described benign tumor is present in brain.LAM is serious pulmonary disease.The suppression of mTORC1 can help to suffer from and be suddenlyd change the syndromic patient of the carcinogenic tendency of Peutz-Jeghers caused by LKB1.MTORC1 also can work in the generation of distributed cancers.Some tumor suppressor genes, especially PTEN, p53, VHL activate relevant with the inactivation of NF1 to mTORC1.Rapamycin and analog (such as CCI-779, RAD001 and AP23573) thereof suppress TORC1 and have demonstrated to regulate active anticancer in II clinical trial phase.But, due to from S6K1 to insulin/negative signal of PI3K/Akt approach, notice that the inhibitor of mTORC1 is important as forms of rapamycin analogs can activate PKB/Akt.If continue to keep when acting on chronic rapamycin treatment this, so it can be the survival-signal that cancerous cell provides increase, and this may be undesirable clinically.PI3K/Akt approach is activated in many cancers.The Akt of activation is by coming modulating apoptosis in platelets, cell proliferation and metabolism by the protein phosphorylation of such as BAD, FOXO, NF-KB, p21Cip1, p27Kip1, GSK3 β and other protein.Akt is also by carrying out Promote cell's growth by TSC2 phosphorylation.Akt activation can by overall growth promoting effects, propagation and survival, and apoptosis inhibit approach promotes cell transformation and the resistance to apoptosis simultaneously.The inhibitor of mTORC1 and mTORC2 and the combination of PI3-kinases alpha inhibitor are of value to the treatment of the tumor of the Akt phosphorylation with rising, and should lower Growth of Cells, cell survival and cell proliferation.

When wishing, before treatment, diagnostic assay is used to test experimenter to be treated, to measure the sensitivity of tumor cell to PI3K alpha kinase inhibitor.Any tumor cell measuring experimenter as known in the art can be adopted the method for the sensitivity of PI3K alpha kinase inhibitor.When using diagnostic assay test subject before treatment to measure the sensitivity of tumor cell to PI3K alpha kinase inhibitor, in one embodiment, when experimenter be accredited as its tumor cell be predicted to be to the PI3K alpha kinase inhibitor as single medicament, there is the experimenter of hyposensitivity time, time at the same time or successively to the combination of the PI3K alpha kinase inhibitor of experimenter's administering therapeutic effective dose and mTOR inhibitors, may show the sensitivity of enhancing under the existence of mTOR inhibitors, or vice versa.In another embodiment, when experimenter be accredited as its tumor cell be predicted to be to the PI3K alpha kinase inhibitor as single medicament, there is the experimenter of hypersensitivity time, but time at the same time or successively to the combination of the PI3K alpha kinase inhibitor of experimenter's administering therapeutic effective dose and mTOR inhibitors, based on result as herein described, under the existence of mTOR inhibitors, also may show the sensitivity of enhancing.In these methods, using doctor in view of experimenter is to possible reactive prediction of the combination of PI3K alpha kinase inhibitor and mTOR inhibitors, when being judged as suitable in conjunction with any other situation about this individual subjects, or can treating one or more other anticarcinogen with PI3K alpha kinase inhibitor is together with mTOR inhibitors while or in turn jointly use.

Therefore, in some embodiments, the invention provides a kind of method, it comprises: (a) determines the sudden change that there is the PI3-kinases α be associated with the disease condition alpha mediated by PI3-kinases in experimenter, and (b) uses pharmaceutical composition of the present invention to described experimenter.

In another embodiment, the invention provides the method for the phosphorylation of Akt (S473) in a kind of T suppression cell and Akt (T308), it comprises makes cell contact with mTOR inhibitors with the PI3-kinases alpha inhibitor of effective dose, described mTOR inhibitors is the bioactivator optionally suppressing mTORC1 and mTORC2 activity for one or more I type phosphatidylinositol-3-kinases (PI3-kinases), as by measuring determined based on the mensuration of cell or vitro kinase, wherein PI3-kinases alpha inhibitor shows and measures by vitro kinase the Selective depression of PI3-kinases α for one or more I type phosphatidylinositol-3-kinases (PI3-kinases) determined, wherein one or more I type PI3-kinases are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

The data presented in following this paper embodiment confirm, the antitumous effect of the combination of mTOR inhibitors and PI3K alpha inhibitor is better than the antitumous effect of arbitrary inhibitor self, and mTOR inhibitors and PI3K alpha inhibitor jointly use the tumprigenicity condition of illness effectively can treated and be associated with PI3-kinases α and/or mTOR.The limiting examples of described condition of illness includes but not limited to: acanthoma, acinic cell carcinoma, acoustic neuroma, acral lentiginous melanoma, acrospiroma, acute eosinophilic leukemia, acute lymphoblastic leukemia, acute megakaryoblastic leukemia, acute monocytic leukemia, acute myeloblastic leukemia with maturation, acute myeloid dendritic cell leukemia, acute myeloid leukemia, acute promyelocytic leukemia, ameloblastoma, adenocarcinoma, adenoid cystic carcinoma, adenoma, adenomatoid odontogenic tumor, adrenocortical carcinoma, adult T-cell leukemia, aggressive NK chronic myeloid leukemia, AIDS associated cancer, AIDS associated lymphoma, alveolar soft part sarcoma, ameloblastic fibroma, anus cancer, primary cutaneous type, anaplastic thyroid carcinomas, angioimmunoblastic T cell lymphoma, angiomyoliopma, angiosarcoma, vermiform appendix cancer, astrocytoma, atypical monster sample/Rhabdoid tumor, basal cell carcinoma, basaloid carcinoma, B cell leukemia, B cell lymphoma, Bellini duct carcinoma, cancer of bile ducts, bladder cancer, blastoma, osteocarcinoma, bone tumor, brain stem glioma, the cerebral tumor, breast carcinoma, brenner tumor, tumor of bronchus, bronchioloalveolar carcinoma, brown tumor, Burkitt lymphoma, the cancer that original site is not clear, carcinoid tumor, tumor, cancer in situ, carcinoma of penis, carcinoma of unknown primary site, carcinosarcoma, the graceful disease of Karst Lay, central nervous system's embryo tumor, cerebellar astrocytoma, cerebral astrocytoma, cervical cancer, cancer of biliary duct, chondroma, chondrosarcoma, chordoma, choriocarcinoma, papilloma of choroid plexus, chronic lymphocytic leukemia, chronic monocytic leukemia, chronic granulocytic leukemia, chronic myeloproliferative disease, chronic neutrophilic leukemia, clear cell tumor, colon cancer, colorectal carcinoma, craniopharyngioma, cutaneous T cell lymphoma, degos' disease, dermatofibrosarcoma protuberans, dermoid cyst, short fibroproliferative small circle cell tumor, diffuse large B cell lymphoma, Dysembryoplastic neuroepithelial tumor, embryonal carcinoma, endodermal sinus tumor, carcinoma of endometrium, endometrium uterus carcinoma, endometrioid tumor, the T-cell lymphoma relevant to enteropathy, ependymoblastoma, ependymoma, epithelioid sarcoma, erythroleukemia, the esophageal carcinoma, esthesioneuroblastoma, You Wenshi family tumor, You Wenshi family sarcoma, ewing's sarcoma, extracranial germ cell tumor, Extragonadal germ cell tumor, cholangiocarcinoma, extramammary Paget, carcinoma of fallopian tube, fetus in fetu, fibroma, fibrosarcoma, follicular lymphoma, follicular thyroid carcinoma, carcinoma of gallbladder, carcinoma of gallbladder, ganglioglioma, ganglioneuroma, gastric cancer, gastric lymphoma, human primary gastrointestinal cancers, gastrointestinal associated cancers tumor, gastrointestinal stromal tumor, gastrointestinal stromal tumor, germinoma, germinoma, gestational choriocarcinoma, gestational trophoblastic neoplasms, giant cell tumor of bone, glioblastoma multiforme, glioma, gliomatosis cerebri, glomus tumor, glucagonoma of pancreas, gonadoblastoma, granulosa cell tumor, hairy cell, hairy cell, head and neck cancer, head and neck cancer, heart cancer, hemangioblastoma, hemangiopericytoma, angiosarcoma, Malignancy, hepatocarcinoma, liver splenic t-cell lymphoma, heritability mammary gland-ovarian cancer syndrome, Hodgkin lymphoma, hodgkin's lymphomas, hypopharyngeal cancer, hypothalamic gliomas, inflammatory breast cancer, intraocular melanoma, islet-cell carcinoma, islet cell tumor, juvenile myelomonocytic leukemia, Kaposi sarcoma, Kaposi sarcoma, renal carcinoma, hilar cholangiocarcinoma, krukenberg tumor, laryngeal carcinoma, laryngeal carcinoma, lentigo maligna melanoma, leukemia, leukemia, lip and oral cancer, liposarcoma, pulmonary carcinoma, xanthofibroma, lymphangioma, lymphangiosarcoma, lymphepithelioma, LL, lymphoma, macroglobulinemia, malignant fibrohistiocytoma, malignant fibrohistiocytoma, malignant fibrous histiocytoma of bone, glioblastoma, malignant mesothe, Malignant Peripheral Nerve Sheath Tumors, Malignant Rhabdoid Tumor, triton tumor, MALT lymphoma, mantle cell lymphoma, mast cell leukemia, vertical diaphragm germinoma, mediastinum tumor, medullary thyroid carcinoma, medulloblastoma, medulloepithelioma, melanoma, meningioma, Michael cell carcinoma, mesothelioma, the cervical metastasis scale cancer that primary tumor is not clear, transitivity urothelium cancer, Seedling Le Shi mixed tumor, monocytic leukemia, oral cancer, mucinous tumor, multiple endocrine neoplasia syndrome, multiple myeloma, mycosis fungoides, myeloproliferative disorder is sick, myelodysplastic syndrome, marrow series leukemia, medullary system sarcoma, myeloproliferative disease, myxoma, tumor of nasal cavity, nasopharyngeal carcinoma, rhinopharyngocele, superfluous raw tumor, schwannoma, neuroblastoma, neurofibroma, neuroma, nodular melanoma, non-Hodgkin lymphoma, non-Hodgkin lymphoma, non-melanoma skin carcinoma, nonsmall-cell lung cancer, eye neoplasms, prominent astrocytoma less, oligodendroglioma, oncocytoma, vagina nervi optici meningioma, oral cancer, oral cancer, oropharynx cancer, osteosarcoma, ovarian cancer, ovarian cancer, epithelial ovarian cancer, ovarian germ cell tumor, the low potential malignant tumor of ovary, mammary Paget disease, pulmonary sulcus tumor, cancer of pancreas, cancer of pancreas, papillary thyroid carcinoma, papillomatosis, paraganglioma, nasal sinus cancer, parathyroid carcinoma, carcinoma of penis, epithelioid cell tumor around blood vessel, nasopharyngeal carcinoma, pheochromocytoma, middle differentiation pinus parenchymal tumor, pineocytoma, pituicytoma, pituitary adenoma, pituitary tumor, plasmocytoma, pleuropulinonary blastoma, polyembryoma, forerunner T-lymphoblastic lymphoma, primary central nervous system lymphoma, lymphoma primary effusion, primary hepatoma, primary hepatocarcinoma, Primary peritoneal carcinoma, intramedullary primitive neuroectodermal tumor, carcinoma of prostate, pseudomyxoma peritonei, rectal cancer, renal cell carcinoma, relate to the respiratory cancer of the NUT gene on chromosome 15, retinoblastoma, rhabdomyoma, rhabdomyosarcoma, Richter transforms, sacrococcygeal teratoma, salivary-gland carcinoma, sarcoma, Schwann cell tumor, sebaceous gland carcinoma, secondary tumor, spermocytoma, serosity tumor, sertoli-Leydig cell tumour, sex cord-stromal tumor, Sai Zeli syndrome, signet-ring cell carcinoma, skin carcinoma, blue small round cell tumor, small cell carcinoma, small cell lung cancer, smallcelllymphoma, carcinoma of small intestine, soft tissue sarcoma, somatostatinoma, soot wart, spinal cord tumor, tumor of spinal cord, splenic marginal zone lymphoma, squamous cell carcinoma, gastric cancer, superficial spreading melanoma, Supratentorial primitive neuroectodermal tumour, superficial epithelium-mesenchymoma, synovial sarcoma, T cell acute lymphoblastic leukemia, T cell large granular lymphocyte leukemia, T cell leukemia, t cell lymphoma, T cell prolymphocytic leukemia, teratoma, latter stage lymphatic cancer, carcinoma of testis, thecoma, laryngeal carcinoma, thymic carcinoma, thymoma, thyroid carcinoma, renal pelvis and ureteral transitional cell carcinoma, transitional cell carcinoma, carcinoma of urachus, carcinoma of urethra, genitourinary system tumor, sarcoma of uterus, uveal melanoma, cancer of vagina, Fan-Mo two Cotard, verrucous carcinoma, depending on road glioma, carcinoma vulvae, Waldenstrom's macroglobulinemia, papillary cystadenoma lymphomatosum, wilms' tumor or its any combination.

In other embodiments, use the method for PI3K alpha inhibitor as herein described and mTOR inhibitors to be applied to the treatment of heart conditions, comprise atherosclerosis, cardiac hypertrophy, cardiac myocyte dysiunction, blood pressure rising and vasoconstriction.The invention still further relates to a kind of in mammal treatment and the method for the disease that blood vessel occurs or angiogenesis is relevant, described method comprises PI3K alpha inhibitor of the present invention and the mTOR inhibitors for the treatment of effective dose to described administration, or its any pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant.

In some embodiments, described method is used for the treatment of the disease be selected from by the following group formed: tumor-blood-vessel growth, chronic inflammation disease (as rheumatoid arthritis), atherosclerosis, inflammatory bowel, dermatosis (as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi sarcoma and ovarian cancer, breast carcinoma, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, colon cancer and epidermoid carcinoma.

In some embodiments, the invention provides the purposes that PI3K alpha inhibitor and mTOR inhibitors are used for the treatment of the disease condition be associated with PI3-kinases α and/or mTOR, described disease condition includes but not limited to and undesirable, active excessive, harmful in mammal or condition of illness that disadvantageous immunne response is relevant, is referred to as " autoimmune disease ".Autoimmune disorder includes but not limited to: Crohn disease, ulcerative colitis, psoriasis, arthritic psoriasis, adolescent arthritis and ankylosing spondylitis, other limiting examples of autoimmune disorder comprise autoimmune diabetes, multiple sclerosis, systemic lupus erythematosus (sle) (SLE), rheumatoid spondylitis, gouty arthritis, allergy, autoimmune uveitis, nephrotic syndrome, multisystem autoimmune disease, autoimmune hearing loss, adult respiratory distress syndrome, shock lung, chronic pulmonary inflammatory disease, lung sarcosis, pulmonary fibrosis, silicosis, idiopathic interstitial lung disease, chronic obstructive pulmonary disease, asthma, stenosis, spondyloarthropathy, conjunctivo-urethro-synovial syndrome, autoimmune hepatitis, inflammatory skin disorder, trunk, the vasculitis of Moderate vessel or thin vessels, endometriosis, prostatitis and siogren's syndrome.Undesirable immunne response also can be associated with such as asthma, emphysema, bronchitis, psoriasis, allergy, anaphylaxis, autoimmune disease, rheumatoid arthritis, graft versus host disease, transplant rejection, injury of lung and lupus erythematosus or cause described disease.Pharmaceutical composition of the present invention can be used for treating other respiratory tract diseases, includes but not limited to encroach on the lobe of the lung, pleural space, bronchus, trachea, upper respiratory tract or the disease of N&M for breathing.Compositions of the present invention can be further used for treating multiple organ failure, MOF.

The present invention also provides the method using PI3K alpha inhibitor and mTOR inhibitors to treat hepatopathy (comprising diabetes), pancreatitis or nephropathy (comprising the nephropathy of proliferative glomerulonephritis and diabetes-induced) or pain in mammal.

The present invention also provides a kind of method using PI3K alpha inhibitor and mTOR inhibitors nitric oxide.The present invention further provides a kind of method using PI3K alpha inhibitor and mTOR inhibitors nervous system disease or neurodegenerative disease, described disease includes but not limited to Alzheimer, Huntington Chorea, CNS wound and apoplexy.

The present invention further provides a kind of method that the PI3K of use alpha inhibitor and mTOR inhibitors prevent mammiferous blastocyte from implanting.

The invention still further relates to a kind of PI3K alpha inhibitor and mTOR inhibitors of using in mammal, treat the method to the disease that blood vessel occurs or angiogenesis is relevant, described disease can show as tumor-blood-vessel growth, chronic inflammation disease (as rheumatoid arthritis), inflammatory bowel, atherosclerosis, dermatosis is (as psoriasis, eczema and scleroderma), diabetes, diabetic retinopathy, retinopathy of prematurity, age-related macular degeneration, hemangioma, glioma, melanoma, Kaposi sarcoma and ovarian cancer, breast carcinoma, pulmonary carcinoma, cancer of pancreas, carcinoma of prostate, colon cancer and epidermoid carcinoma.

The present invention further provides a kind of method that the PI3K of use alpha inhibitor and mTOR inhibitors relate to the disease of platelet aggregation or platelet adhesion, described disease includes but not limited to Bernard Soulier syndrome, thrombocytasthenia, Scott Cotard, von Willebrand, Hermansky-Pudlak syndrome and GPS.

In some embodiments, the method using PI3K alpha inhibitor and mTOR inhibitors disease is provided, described disease is skeletal muscle atrophy, skeletal muscle is loose, leukocyte recruitment in cancerous tissue, invade transfer, melanoma, Kaposi sarcoma, acute and chronic bacterial and viral infection, septicemia, glomerular sclerosis, glomerule, nephritis, or Progressive symmetric erythrokeratodermia renal fibrosis.

Some embodiment contemplates human experimenter, suffers from or be in the experimenter of the risk developing or obtain the disease condition be associated with PI3-kinases α and/or mTOR as being diagnosed as.Some other embodiment contemplates non-human subject, such as non-human primate, as macaque, chimpanzee, gorilla, black guenon, orangutan, baboon or other non-human primate, comprising can the known described non-human subject as preclinical models (comprising the preclinical models for inflammatory conditions) in this area.Some other embodiment contemplates as mammiferous non-human subject, such as, and mice, rat, rabbit, pig, sheep, horse, cattle, goat, gerbil jird, hamster, Cavia porcellus or other mammals.Also contemplate other embodiments, wherein experimenter or biogenetic derivation can be nonmammalian vertebrates, such as, and other level vertebrate animals, or birds, Amphibian or reptile species, or other experimenter or biogenetic derivation.In certain embodiments of the invention, transgenic animal are utilized.Transgenic animal are non-human animal, one or more cells of wherein said animal comprise nucleic acid, described nucleic acid be non-endogenous (namely, heterologous) and be present in as extra-chromosomal element in the part of its cell or be stably incorporated into (that is, in the genome sequence of its most of or all cells) in its germline DNA.

exemplary mTor inhibitor compound

In one aspect, the invention provides a kind of formula I of the inhibitor for mTor:

Or its pharmaceutically acceptable salt, wherein:

E ¹and E ²be-(W independently ¹) _j-R ⁴;

Each k is 0 or 1;

E ¹in j or E ²in j be 0 or 1 independently;

R ⁹for H, halogeno-group ,-OR ³¹,-SH ,-NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl; Aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, each in wherein said alkyl, thiazolinyl, alkynyl, aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-10alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-10thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace.

M ₁be 5,6,7,8,9 or 10 yuan of ring systems, wherein ring system is monocycle or dicyclo.Monocycle M ₁ring is unsubstituted or by one or more R ⁵substituent group (comprises 0,1,2,3,4 or 5 R ⁵substituent group) replace.In some embodiments, monocycle M ₁ring is aromatics (comprising phenyl) or heteroaromatic (including but not limited to pyridine radicals, pyrrole radicals, imidazole radicals, thiazolyl or pyrimidine radicals).Monocycle M ₁ring can be 5 or 6 rings (including but not limited to pyridine radicals, pyrrole radicals, imidazole radicals, thiazolyl or pyrimidine radicals).In some embodiments, M ₂for having heteroatomic five yuan of heteroaromatic group, wherein hetero atom is N, S or O.In another embodiment, M ₂for having two heteroatomic five yuan of heteroaromatic group, wherein hetero atom is nitrogen and oxygen or nitrogen and sulfur.

Dicyclo M ₁ring is unsubstituted or by one or more R ⁵substituent group (comprises 0,1,2,3,4,5,6 or 7 R ⁵substituent group) replace.Dicyclo M ₁ring is 7,8,9 or 10 yuan of aromatics or heteroaromatic.Aromatics dicyclo M ₁the example of ring comprises naphthyl.In other embodiments, dicyclo M ₁ring is heteroaromatic and includes but not limited to benzothiazolyl, quinolyl, quinazolyl, benzoxazolyl and benzimidazolyl.

The present invention also provides wherein M ₁for having the compound of the part of formula M1-A or formula M1-B structure:

Wherein W ₁, W ₂and W ₇be N or C-R independently ⁵; W ₄and W ₁₀be N-R independently ⁵, O or S; W ₆and W ₈be N or C-R independently ⁵; W ₅and W ₉be N or C-R independently ²; And W ₃for C or N, condition is no more than two N and/or N-R ⁵be adjacent and do not have two O or S to be adjacent.

In some embodiments of the present invention, formula M1-AM ₁part is formula M1-A1, formula M1-A2, formula M1-A3 or formula M1-A4 part:

Wherein W ₄for N-R ⁵, O or S; W ₆for N or C-R ⁵and W ₅for N or C-R ².

Formula M1-AM ₁some limiting examples of part comprise:

Wherein R ⁵for-(W ¹) _k-R ⁵³or R ⁵⁵; Each k be independently 0 or 1, n be 0,1,2 or 3, and-(W ¹) _k-R ⁵³and R ⁵⁵as defined above.

In other embodiments of the present invention, formula M1-BM ₁part is formula M1-B1, formula M1-B2, formula M1-B3 or formula M1-B4 part:

Wherein W ₁₀for N-R ⁵, O or S; W ₈for N or C-R ⁵, and W ₅for N or C-R ².

Formula M1-BM ₁some limiting examples of part comprise:

Wherein R ' ⁵for-(W ¹) _k-R ⁵³or R ⁵⁵; K be 0 or 1, n be 0,1,2 or 3, and-(W ¹) _k-R ⁵³and R ⁵⁵as defined above.

The present invention also provides wherein M ₁for having the compound of the part of formula M1-C or formula M1-D structure:

Wherein W ₁₂, W ₁₃, W ₁₄and W ₁₅be N or C-R independently ⁵; W ₁₁and W ₁₈be N-R independently ⁵, O or S; W ₁₆and W ₁₇be N or C-R independently ⁵; It is adjacent that condition is no more than two N.

In other embodiments of the present invention, there is the M of formula M1-C or formula M1-D ₁part is formula M1-C1 or formula M1-D1 part:

Wherein W ₁₁and W ₁₈for N-R ⁵, O or S, and W ₁₆and W ₁₇for N or C-R ⁵.

Formula M1-C and formula M1-DM ₁some limiting examples of part comprise:

Wherein R ' ⁵for-(W ¹) _k-R ⁵³or R ⁵⁵; K is 0 or 1, and-(W ¹) _k-R ⁵³and R ⁵⁵as defined above.

The present invention also provides wherein M ₁for having the compound of the part of formula M1-E structure:

Wherein X ₁₁, X ₁₂, X ₁₃, X ₁₄, X ₁₅, X ₁₆and X ₁₇be N or C-R independently ⁵, it is adjacent that condition is no more than two N.

In some embodiments of the present invention, there is the M of formula M1-E structure ₁part is for having the part of formula M1-E1, M1-E2, M1-E3, M1-E4, M1-E5, M1-E6, M1-E7 or M1-E8 structure:

In some embodiments of the present invention, there is the M of formula M1-E structure ₁part is for having the part of following structure:

Formula M1-EM ₁some limiting examples of part comprise:

Wherein R ' ⁵for-(W ¹) _k-R ⁵³or R ⁵⁵; K be 0 or 1, n be 0,1,2 or 3, and-(W ¹) _k-R ⁵³or R ⁵⁵as defined above.In some embodiments, k is 0 and R ⁵for R ⁵³.

In some embodiments, R ⁵³for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₈cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments, R ⁵³for monocycle or bicyclic aryl, wherein R ⁵³aryl is what do not replace or replace.Some examples of aryl include but not limited to phenyl, naphthyl or fluorenyl.In some other embodiments, R ⁵³for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ⁵³include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ⁵³include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base and purine radicals.In addition, R ⁵³can be alkyl-cycloalkyl (including but not limited to cyclopropylethyl, cyclopentyl ethyl and cyclobutylpropyl) ,-alkylaryl (including but not limited to benzyl, phenethyl and phenyl napthyl) ,-miscellaneous alkyl aryl (including but not limited to pyridylmethyl, pyrrolylethyl and imidazolylpropyl) or-alkyl heterocyclic (limiting examples is morpholinyl methyl, 1-piperizinylmethyl and azetidinyl propyl group).For each in alkyl-cycloalkyl, alkylaryl, miscellaneous alkyl aryl or-alkyl heterocyclic, this part is connected to M by the moieties of this part ₁.In other embodiments, R ⁵³for the C not replacing or replace ₂-C ₁₀thiazolinyl (including but not limited to thiazolinyl, such as vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl not replacing or replace (include but not limited to the C not replacing or replace ₂-C ₁₀alkynyl, as acetenyl, propargyl, butynyl or pentynyl).

Other embodiments provide wherein R ⁵³for alkenyl aryl, alkenyl heteroaryl, thiazolinyl are mixed the R of alkyl or alkenyl heterocyclic radical ⁵³, each wherein in thiazolinyl, aryl, heteroaryl, assorted alkyl or heterocyclic radical as described herein and wherein alkenyl aryl, alkenyl heteroaryl, thiazolinyl alkyl or alkenyl heterocyclyl moieties of mixing be attached to M by thiazolinyl ₁.Some limiting examples comprise styryl, 3-pyridine radicals pi-allyl, 2-methoxy ethoxy vinyl and morpholinyl pi-allyl.In other embodiments, R ⁵³for-alkynyl aryl ,-alkynyl heteroaryl ,-alkynyl are mixed alkyl ,-alkynyl heterocyclic radical ,-alkynyl cycloalkyl or-alkynyl C _3-8cycloalkenyl group, each wherein in alkynyl, aryl, heteroaryl, assorted alkyl and heterocyclic radical as described herein and wherein mix alkyl or alkynyl heterocyclyl moieties of alkynyl aryl, alkynyl heteroaryl, alkynyl be attached to M by alkynyl ₁.Alternatively, R ⁵³for-alkoxyalkyl ,-alkoxyalkenyl or-alkoxyalkynyl, each wherein in alkoxyl, alkyl, thiazolinyl and alkynyl is as described herein and wherein-alkoxyalkyl ,-alkoxyalkenyl or-alkoxyalkynyl part are attached to M by alkoxyl ₁.In other embodiments, R ⁵³for-cycloheteroalkylalkyl ,-heterocyclylalkenyl or-heterocyclylalkynyl, wherein heterocyclic radical, alkyl, alkenyl or alkynyl is as described herein and wherein-cycloheteroalkylalkyl ,-heterocyclylalkenyl or-heterocyclylalkynyl are attached to M by the heterocyclyl moieties of this part ₁.In addition, R ⁵³can be aryl-thiazolinyl, aryl-alkynyl or aryl-heterocyclic, wherein aryl, thiazolinyl, alkynyl or heterocyclic radical are as described herein and wherein aryl-thiazolinyl, aryl-alkynyl or aryl heterocyclic base section are attached to M by the aryl moiety of this part ₁.In some other embodiments, R ⁵³for heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each wherein in heteroaryl, alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl and heterocyclic radical is as described herein and wherein heteroaryl-alkyl, heteroaryl-alkenyl, heteroaryl-alkynyl, heteroaryl-cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl part are attached to M by the heteroaryl moieties of this part ₁.

For formation R ⁵³part or all of aryl or heteroaryl moieties in each, aryl or heteroaryl are unsubstituted or by one or more independently halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NNR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²substituent group replaces.In addition, R is formed ⁵³part or all of alkyl, cycloalkyl, heterocyclic radical or assorted moieties in each be unsubstituted or by one or more halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NNR ³⁴r ³⁵, or-C (=O) NR ³¹r ³²substituent group replaces.

In other embodiments, R ⁵for-W ¹-R ⁵³.In some embodiments, R ⁵for-OR ⁵³, include but not limited to-O-alkyl (including but not limited to methoxy or ethoxy) ,-O-aryl (including but not limited to phenoxy group) ,-O-heteroaryl (including but not limited to pyridyloxy) and-O-heterocyclic oxy group (including but not limited to 4-N-piperidines oxygen base).In some embodiments, R ⁵for-NR ⁶r ⁵³, include but not limited to anilino-, diethylamino and 4-N-piperidyl amino.In other embodiments, R ⁵for-S (O) _0-2r ⁵³, include but not limited to phenyl sulfonyl and pyridyl sulfonyl.The present invention also provides wherein R ⁵for-C (O) (including but not limited to acetyl group, benzoyl and picolinoyl (pyridinoyl)) or-C (O) OR ⁵³the compound of (including but not limited to carboxyethyl and carboxyl benzyl).In other embodiments, R ⁵for-C (O) N (R ⁶) R ⁵³(including but not limited to C (O) NH (cyclopropyl) and C (O) N (Me) (phenyl)) or-CH (R ⁶) N (R ⁷) R ⁵³(include but not limited to-CH ₂-NH-pyrrolidinyl, CH ₂-NH cyclopropyl and CH ₂-anilino-).Alternatively, R ⁵for-N (R ⁶) C (O) R ⁵³(including but not limited to-NHC (O) phenyl ,-NHC (O) cyclopenta and-NHC (O) piperidyl) or-N (R ⁶) S (O) ₂r ⁵³(include but not limited to-NHS (O) ₂phenyl ,-NHS (O) ₂piperazinyl and-NHS (O) ₂methyl).In addition, R ⁵for-N (R ⁶) S (O) R ⁵³,-CH (R ⁶) N (C (O) OR ⁷) R ⁵³,-CH (R ⁷) N (C (O) R ⁷) R ⁵³,-CH (R ⁶) N (SO ₂r ⁷) R ⁵³,-CH (R ⁶) N (R ⁷) R ⁵³,-CH (R ⁶) C (O) N (R ⁷) R ⁵³,-CH (R ⁶) N (R ⁷) C (O) R ⁵³,-CH (R ⁶) N (R ⁷) S (O) R ⁵³or CH (R ⁶) N (R ⁷) S (O) ₂r ⁵³.

Alternatively, R ⁵for R ⁵⁵.R ⁵⁵for halogeno-group ,-OH ,-NO ₂,-CF ₃,-OCF ₃or-CN.In some other embodiments, R ⁵⁵for-R ³¹,-OR ³¹(including but not limited to methoxyl group, ethyoxyl and butoxy) ,-C (O) R ³¹(limiting examples comprises acetyl group, propiono or valeryl) or-CO ₂r ³¹(including but not limited to carboxymethyl, carboxyethyl and carboxylic propyl group).In further embodiment, R ⁵⁵for-NR ³¹r ³²,-C (=O) NR ³¹r ³²,-SO ₂nR ³¹r ³²or-S (O) _0-2r ³¹.In other embodiments, R ⁵⁵for-NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵, wherein R ³⁴r ³⁵with R ³⁴r ³⁵attached nitrogen forms annulus together.The annulus of such formation can be and not replace or replace, and wherein substituent group is selected from by alkyl ,-C (O) alkyl ,-S (O) ₂alkyl and-S (O) ₂the group of aryl composition.Example includes but not limited to morpholinyl, piperazinyl or-SO ₂-(4-N-thyl-piperazin-1-base.In addition, R ⁵⁵for-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-C (=O) NNR ³⁴r ³⁵,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²; .In another embodiment, R ⁵⁵for-O-aryl, include but not limited to phenoxy group and naphthoxy.

The present invention further provides a kind of compound for mTor inhibitor, wherein said compound has formula I-A:

Or its pharmaceutically acceptable salt, wherein:

X ₁for N or C-E ¹, X ₂for N, X ₃for C, and X ₄for C-R ⁹or N; Or X ₁for N or C-E ¹, X ₂for C, X ₃for N, and X ₄for C-R ⁹or N;

M ₁for having the part of formula M1-F1 or M1-F2 structure:

K is 0 or 1;

E ¹and E ²be-(W independently ¹) _j-R ⁴;

(that is, at E in often kind of situation ¹in or E ²in j) j be 0 or 1 independently

R ³¹, R ³²and R ³³, in each case, be H or C independently _1-10alkyl, wherein C _1-10alkyl is unsubstituted or is replaced by one or more aryl, assorted alkyl, heterocyclic radical or heteroaryl, and each in wherein said aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace;

R ⁷and R ⁸be hydrogen, C independently of one another _1-10alkyl, C _2-10thiazolinyl, aryl, heteroaryl, heterocyclic radical or C _3-10cycloalkyl, wherein each outside dehydrogenation is unsubstituted or by one or more independently R ⁶replace;

In some embodiments, X ₄for C-R ⁹.

The present invention also provides one inhibitor as defined above, and wherein said compound has formula I:

Or its pharmaceutically acceptable salt, and wherein substituent group is as defined above.

In various embodiments, formula I-B compound or its pharmaceutically acceptable salt are the compound with formula I-B1 or formula I-B2 structure:

Or its pharmaceutically acceptable salt.

In the various embodiments of formula I-B1, X ₁for N and X ₂for N.In other embodiments, X ₁for C-E ¹and X ₂for N.In other embodiments, X ₁for NH and X ₂for C.In further embodiment, X ₁for CH-E ¹and X ₂for C.

In the various embodiments of formula I-B2, X ₁for N and X ₂for C.In further embodiment, X ₁for C-E ¹and X ₂for C.

In various embodiments, X ₁for C-(W ¹) _j-R ⁴, wherein j is 0.

In another embodiment, X ₁for CH.In another embodiment, X ₁for C-halogen, wherein halogen is Cl, F, Br or I.

At X ₁various embodiments in, it is C-(W ¹) _j-R ⁴.At X ₁various embodiments in, j is 1, and W ¹for-O-.At X ₁various embodiments in, j is 1, and W ¹for-NR ⁷-.At X ₁various embodiments in, j is 1, and W ¹for-NH-.At X ₁various embodiments in, j is 1, and W ¹for-S (O) _0-2-.At X ₁various embodiments in, j is 1, and W ¹for-C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) N (R ⁷)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O) ₂-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) O-.At X ₁various embodiments in, j is 1, and W ¹for CH (R ⁷) N (C (O) OR ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (C (O) R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (SO ₂r ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) C (O) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O) ₂-.

In another embodiment, X ₁for CH ₂.In another embodiment, X ₁for CH-halogen, wherein halogen is Cl, F, Br or I.

In another embodiment, X ₁for N.

In various embodiments, X ₂for N.In other embodiments, X ₂for C.

In various embodiments, E ²for-(W ¹) _j-R ⁴, wherein j is 0.

In another embodiment, E ²for CH.In another embodiment, E ²for C-halogen, wherein halogen is Cl, F, Br or I.

At E ²various embodiments in, it is-(W ¹) _j-R ⁴.At E ²various embodiments in, j is 1, and W ¹for-O-.At E ²various embodiments in, j is 1, and W ¹for-NR ⁷-.At E ²various embodiments in, j is 1, and W ¹for-NH-.At E ²various embodiments in, j is 1, and W ¹for-S (O) _0-2-.At E ²various embodiments in, j is 1, and W ¹for-C (O)-.At E ²various embodiments in, j is 1, and W ¹for-C (O) N (R ⁷)-.At E ²various embodiments in, j is 1, and W ¹for-N (R ⁷) C (O)-.At E ²various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O)-.At E ²various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O) ₂-.At E ²various embodiments in, j is 1, and W ¹for-C (O) O-.At E ²various embodiments in, j is 1, and W ¹for CH (R ⁷) N (C (O) OR ⁸)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (C (O) R ⁸)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (SO ₂r ⁸)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) C (O) N (R ⁸)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) C (O)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O)-.At E ²various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O) ₂-.

In various embodiments, M is worked as ₁during for formula M1-F1 part, M ₁for quilt-(W ₂) _k-R ₂the benzoxazolyl replaced.In some embodiments, M ₁for quilt-(W on 2-position ²) _j-R ²the benzoxazolyl replaced.In some embodiments, M ₁for optional on 2-position quilt-(W ²) _j-R ²the 5-benzoxazolyl replaced or 6-benzoxazole base section.Exemplary formula M1-F1M ₁part includes but not limited to following:

and

In various embodiments, M is worked as ₁during for formula M1-F2 part, formula M1-F2 is the benzoxazole base section of the azepine-replacement of the structure of of having in following formula:

Exemplary formula M1-F2M ₁part includes but not limited to following:

and

At M ₁various embodiments in, k is 0.At M ₁other embodiments in, k is 1, and W ²be selected from following in one :-O-,-NR ⁷,-S (O) _0-2-,-C (O)-,-C (O) N (R ⁷)-,-N (R ⁷) C (O)-or-N (R ⁷) C (O) N (R ⁸)-.At M ₁another embodiment in, k is 1, and W ²for-N (R ⁷) S (O)-,-N (R ⁷) S (O) ₂-,-C (O) O-,-CH (R ⁷) N (C (O) OR ⁸)-,-CH (R ⁷) N (C (O) R ⁸)-or-CH (R ⁷) N (SO ₂r ⁸)-.At M ₁another embodiment in, k is 1, and W ²for-CH (R ⁷) N (R ⁸)-,-CH (R ⁷) C (O) N (R ⁸)-,-CH (R ⁷) N (R ⁸) C (O)-or-CH (R ⁷) N (R ⁸) S (O)-.At M ₁another embodiment in, k is 1, and W ²for-CH (R ⁷) N (R ⁸) S (O) ₂-.

The invention provides the inhibitor of a kind of mTor, it is formula I-C or formula I-D compound:

Or its pharmaceutically acceptable salt, wherein X ₁for N or C-E ¹, X ₂for N, and X ₃for C; Or X ₁for N or C-E ¹, X ₂for C, and X ₃for N;

R ₁for-H ,-L-C _1-10alkyl ,-L-C _3-8cycloalkyl ,-L-C _1-10alkyl-C _3-8cycloalkyl ,-L-aryl ,-L-heteroaryl ,-L-C _1-10alkylaryl ,-L-C _1-10miscellaneous alkyl aryl ,-L-C _1-10alkyl heterocyclic ,-L-C _2-10thiazolinyl ,-L-C _2-10alkynyl ,-L-C _2-10thiazolinyl-C _3-8cycloalkyl ,-L-C _2-10alkynyl-C _3-8cycloalkyl ,-L-alkyl ,-L-alkylaryl ,-L-mix the alkyl-heterocyclyl groups ,-L-of miscellaneous alkyl aryl ,-L-that mix that mix that mix mixes alkyl-C _3-8cycloalkyl ,-L-aralkyl ,-L-heteroarylalkyl or-L-heterocyclic radical, wherein each is unsubstituted or by one or more independently R ³replace;

E ¹and E ²be-(W independently ¹) _j-R ⁴;

E ¹in j or E ²in j be 0 or 1 independently;

K is 0 or 1;

R ²for hydrogen, halogen ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl (such as, the monocyclic aryl of bicyclic aryl, unsubstituted aryl or replacement), heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _1-10alkyl-C _2-10thiazolinyl, C _1-10alkyl-C _2-1 ₀alkynyl, C _1-10alkylaryl (such as, C _2-10alkyl-monocyclic aryl, C _1-10the monocyclic aryl of alkyl-replacement or C _1-10alkyl bicyclic aryl), C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical-C _1- ₁₀alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl (such as, monocyclic aryl-C _2-10monocyclic aryl-the C of alkyl, replacement _1-10alkyl or bicyclic aryl-C _1-10alkyl), aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said bicyclic aryl or heteroaryl moieties is unsubstituted, or each wherein in bicyclic aryl, heteroaryl moieties or monocyclic aryl part is by one or more independently alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties be unsubstituted or by one or more alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ³and R ⁴be hydrogen, halogen ,-OH ,-R independently ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³ ¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C ₁ _-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _1-10alkyl-C _2- ₁₀thiazolinyl, C _1-10alkyl-C _2-10alkynyl, C _1-10alkylaryl, C _1-10miscellaneous alkyl aryl, C _1-1 ₀alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2- ₁₀thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-1 ₀alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical-C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said aryl or heteroaryl moieties be unsubstituted or by one or more independently alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties be unsubstituted or by one or more alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

-NR ³⁴r ³⁵,-C (=O) NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵in R ³⁴and R ³⁵saturated or the undersaturated ring of 3-10 unit is formed together with the nitrogen-atoms attached by it; Wherein said ring is unsubstituted or by one or more-NR independently ³¹r ³², hydroxyl, halogen, oxo base, aryl, heteroaryl, C _1-6alkyl or O-aryl replace, and wherein said 3-10 unit is saturated or undersaturated ring contains 0,1 or 2 more hetero atoms except nitrogen-atoms independently; And

R ⁷and R ⁸be hydrogen, C independently of one another _1-10alkyl, C _2-10thiazolinyl, aryl, heteroaryl, heterocyclic radical or C _3-10cycloalkyl, each wherein outside dehydrogenation is unsubstituted or by one or more independently R ⁶replace; And R ⁶for halogeno-group ,-OR ³¹,-SH, NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl or C _2-10alkynyl; Or R ⁶for aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, wherein each is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-10alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-10thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace.

In the various embodiments of formula I-C compound, described compound has formula I-C1 or formula I-C2 structure:

Or its pharmaceutically acceptable salt.

In some embodiments of formula I-Cl, X ₁for N and X ₂for N.In other embodiments, X ₁for C-E ¹and X ₂for N.In other embodiments, X ₁for NH and X ₂for C.In further embodiment, X ₁for CH-E ¹and X ₂for C.

In some embodiments of formula I-C2, X ₁for N and X ₂for C.In other embodiments, X ₁for NH and X ₂for C.In further embodiment, X ₁for CH-E ¹and X ₂for C.

In the various embodiments of formula I-D compound, described compound has formula I-Dl or formula I-D2 structure:

Or its pharmaceutically acceptable salt.

In some embodiments of formula I-D1, X ₁for N and X ₂for N.In other embodiments, X ₁for C-E ¹and X ₂for N.In other embodiments, X ₁for NH and X ₂for C.In further embodiment, X ₁for CH-E ¹and X ₂for C.

In some embodiments of formula I-D2, X ₁for N and X ₂for C.In further embodiment, X ₁for C-E ¹and X ₂for C.

In various embodiments, X ₁for C-(W ¹) _j-R ⁴, wherein j is 0.

At X ₁various embodiments in, it is C-(W ¹) _j-R ⁴.At X ₁various embodiments in, j is 1, and W ¹for-O-.At X ₁various embodiments in, j is 1, and W ¹for-NR ⁷-.At X ₁various embodiments in, j is 1, and W ¹for-NH-.In the various embodiments of X1, j is 1, and W ¹for-S (O) _0-2-.At X ₁various embodiments in, j is 1, and W ¹for-C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) N (R ⁷)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O) ₂-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) O-.At X ₁various embodiments in, j is 1, and W ¹for CH (R ⁷) N (C (O) OR ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (C (O) R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (SO ₂r ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) C (O) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O) ₂-.

In various embodiments, X ₁for CH-(W ¹) _j-R ⁴, wherein j is 0.

At X ₁various embodiments in, it is CH-(W ¹) _j-R ⁴.At X ₁various embodiments in, j is 1, and W ¹for-O-.At X ₁various embodiments in, j is 1, and W ¹for-NR ⁷-.At X ₁various embodiments in, j is 1, and W ¹for-NH-.At X ₁various embodiments in, j is 1, and W ¹for-S (O) _0-2-.At X ₁various embodiments in, j is 1, and W ¹for-C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) N (R ⁷)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-N (R ⁷) S (O) ₂-.At X ₁various embodiments in, j is 1, and W ¹for-C (O) O-.At X ₁various embodiments in, j is 1, and W ¹for CH (R ⁷) N (C (O) OR ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (C (O) R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (SO ₂r ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) C (O) N (R ⁸)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) C (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O)-.At X ₁various embodiments in, j is 1, and W ¹for-CH (R ⁷) N (R ⁸) S (O) ₂-.

In another embodiment, X ₁for N.

In various embodiments, X ₂for N.In other embodiments, X ₂for C.

In various embodiments, E ²for-(W ¹) _j-R ⁴, wherein j is 0.

In various embodiments, k is 0.In other embodiments, k is 1 and W ²for-O-.In another embodiment, k is 1 and W ²for-NR ⁷-.In another embodiment, k is 1, and W ²for-S (O) _0-2-.In another embodiment, k is 1 and W ²for-C (O)-.In another embodiment, k is 1 and W ²for-C (O) N (R ⁷)-.In another embodiment, k is 1 and W ²for-N (R ⁷) C (O)-.In another embodiment, k is 1 and W ²for-N (R ⁷) C (O) N (R ⁸)-.In another embodiment, k is 1 and W ²for-N (R ⁷) S (O)-.In another embodiment, k is 1 and W ²for-N (R ⁷) S (O) ₂-.In another embodiment, k is 1 and W ²for-C (O) O-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (C (O) OR ⁸)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (C (O) R ⁸)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (SO ₂r ⁸)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (R ⁸)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) C (O) N (R ⁸)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (R ⁸) C (O)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (R ⁸) S (O)-.In another embodiment, k is 1 and W ²for-CH (R ⁷) N (R ⁸) S (O) ₂-.

The present invention also provides a kind of formula I-E compound for mTor inhibitor:

Or its pharmaceutically acceptable salt, wherein: X ₁for N or C-E ¹, X ₂for N, and X ₃for C; Or X ₁for N or C-E ¹, X ₂for C, and X ₃for N;

M ₁for having the part of formula M1-F1 or formula M1-F2 structure:

K is 0 or 1;

E ¹and E ²be-(W independently ¹) _j-R ⁴;

E ¹in j or E ²in j be 0 or 1 independently;

In the various embodiments of formula I-E compound, described compound has formula I-E1 or formula I-E2 structure:

Or its pharmaceutically acceptable salt.

In some embodiments of formula I-E1, X ₁for N and X ₂for N.In other embodiments, X ₁for C-E ¹and X ₂for N.In other embodiments, X ₁for NH and X ₂for C.In further embodiment, X ₁for CH-E ¹and X ₂for C.

In some embodiments of formula I-E2, X ₁for N and X ₂for C.In further embodiment, X ₁for C-E ¹and X ₂for C.

In various embodiments, X ₁for C-(W ¹) _j-R ⁴, wherein j is 0.

In another embodiment, X ₁for N.

In various embodiments, X ₂for N.In other embodiments, X ₂for C.

In various embodiments, E ²for-(W ¹) _j-R ⁴, wherein j is 0.

In various embodiments, M is worked as ₁during for formula I-E1 part, M ₁for quilt-(W ₂) _k-R ₂the benzoxazolyl replaced.In some embodiments, M ₁for quilt-(W on 2-position ₂) _k-R ₂the benzoxazole base section replaced.In some embodiments, M ₁for optionally by-(W ₂) _k-R ₂the 5-benzoxazolyl replaced or 6-benzoxazole base section.Exemplary formula I-E1M ₁part includes but not limited to following:

and

In various embodiments, M is worked as ₁during for formula I-E2 part, formula I-E2 is the benzoxazole base section of the azepine-replacement of the structure of of having in following formula:

Exemplary formula I-E2M ₁part includes but not limited to following:

and

At M ₁various embodiments in, k is 0.At M ₁other embodiments in, k is 1 and W ²for-O-.At M ₁another embodiment in, k is 1 and W ²for-NR ⁷-.At M ₁another embodiment in, k is 1 and W ²for-S (O) _0-2-.At M ₁another embodiment in, k is 1 and W ²for-C (O)-.At M ₁another embodiment in, k is 1 and W ²for-C (O) N (R ⁷)-.At M ₁another embodiment in, k is 1 and W ²for-N (R ⁷) C (O)-.In another embodiment, k is 1 and W ²for-N (R ⁷) C (O) N (R ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-N (R ⁷) S (O)-.At M ₁another embodiment in, k is 1 and W ²for-N (R ⁷) S (O) ₂-.At M ₁another embodiment in, k is 1 and W ²for-C (O) O-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (C (O) OR ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (C (O) R ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (SO ₂r ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (R ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) C (O) N (R ⁸)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (R ⁸) C (O)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (R ⁸) S (O)-.At M ₁another embodiment in, k is 1 and W ²for-CH (R ⁷) N (R ⁸) S (O) _2-.

The other embodiments comprising I-A, I-B, I-C, I-D, I-E and other formula I are hereafter described.

In the various embodiments of formula I, L does not exist.In another embodiment, L be-(C=O)-.In another embodiment, L is-C (=O) O-.In another embodiment, L is-C (=O) NR ³¹-.In another embodiment, L is-S-.In one embodiment, L be-S (O)-.In another embodiment, L is-S (O) ₂-.In another embodiment, L is-S (O) ₂nR ³¹-.In another embodiment, L is-NR ³¹-.

In the various embodiments of formula I, R ₁for-L-C _1-10alkyl, it is unsubstituted.In another embodiment, R ₁for-L-C _1-10alkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for the unsubstituted C of-L- _1-10alkyl, wherein L does not exist.In another embodiment, R ₁for-L-C _1-10alkyl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for-L-C _3-8cycloalkyl, it is unsubstituted.In another embodiment, R ₁for-L-C _3-8cycloalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _3-8cycloalkyl, it is unsubstituted, and L does not exist.In another embodiment, R ₁for-L-C _3-8cycloalkyl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for H.

In the various embodiments of formula I, R ₁for-L-aryl, it is unsubstituted.In another embodiment, R ₁for-L-aryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-aryl, it is unsubstituted, and L does not exist.In another embodiment, R ₁for-L-aryl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for-L-heteroaryl, it is unsubstituted.In another embodiment, R ₁for-L-heteroaryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-heteroaryl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-heteroaryl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for-L-C _1-10alkyl-C _3-8cycloalkyl, it is unsubstituted.In another embodiment, R ₁for-L-C _1-10alkyl-C _3-8cycloalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _1-10alkyl-C _3-8cycloalkyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _1-10alkyl-C _3-8cycloalkyl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for-L-C _1-10alkylaryl, it is unsubstituted.In another embodiment, R ₁for-L-C _1-10alkylaryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _1-10alkylaryl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _1-10alkylaryl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _1-10miscellaneous alkyl aryl, it is unsubstituted.In another embodiment, R ₁for-L-C _1-10miscellaneous alkyl aryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _1-10miscellaneous alkyl aryl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _1-10miscellaneous alkyl aryl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _1-10alkyl heterocyclic, it is unsubstituted.In another embodiment, R ₁for-L-C _1-10alkyl heterocyclic, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _1-10alkyl heterocyclic, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _1-10alkyl heterocyclic, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _2-10thiazolinyl, it is unsubstituted.In another embodiment, R ₁for-L-C _2-10thiazolinyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _2-10thiazolinyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _2-10thiazolinyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _2-10alkynyl, it is unsubstituted.In another embodiment, R ₁for-L-C _2-10alkynyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _2-10alkynyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _2-10alkynyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _2-10thiazolinyl-C _3-8cycloalkyl, it is unsubstituted.In another embodiment, R ₁for-L-C _2-10thiazolinyl-C _3-8cycloalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _2-10thiazolinyl-C _3-8cycloalkyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _2-10thiazolinyl-C _3-8cycloalkyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-C _2-10alkynyl-C _3-8cycloalkyl, it is unsubstituted.In another embodiment, R ₁for-L-C _2-10alkynyl-C _3-8cycloalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-C _2-10alkynyl-C _3-8cycloalkyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-C _2-10alkynyl-C _3-8cycloalkyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-mixes alkyl, it is unsubstituted.In another embodiment, R ₁for-L-mixes alkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-mixes alkyl, it does not exist for unsubstituted and L.In another embodiment, R ₁for-L-mixes alkyl, it is by one or more independently R ³replace, and L does not exist.

In the various embodiments of formula I, R ₁for-L-mixes alkylaryl, it is unsubstituted.In another embodiment, R ₁for-L-mixes alkylaryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-mixes alkylaryl, it does not exist for unsubstituted and L.In another embodiment, R ₁for-L-mixes alkylaryl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-mixes miscellaneous alkyl aryl, it is unsubstituted.In another embodiment, R ₁for-L-mixes miscellaneous alkyl aryl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-mixes miscellaneous alkyl aryl, it does not exist for unsubstituted and L.In another embodiment, R ₁for-L-mixes miscellaneous alkyl aryl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula compound, R ₁for-L-mixes alkyl-heterocyclyl groups, it is unsubstituted.In another embodiment, R ₁for-L-mixes alkyl-heterocyclyl groups, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-mixes alkyl-heterocyclyl groups, it does not exist for unsubstituted and L.In another embodiment, R ₁for-L-mixes alkyl-heterocyclyl groups, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-mixes alkyl-C _3-8cycloalkyl, it is unsubstituted.In another embodiment, R ₁for-L-mixes alkyl-C _3-8cycloalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-mixes alkyl-C _3-8cycloalkyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-mixes alkyl-C _3-8cycloalkyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-aralkyl, it is unsubstituted.In another embodiment, R ₁for-L-aralkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-aralkyl, it is unsubstituted.In another embodiment, R ₁for-L-aralkyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-heteroarylalkyl, it is unsubstituted.In another embodiment, R ₁for-L-heteroarylalkyl, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-heteroarylalkyl, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-heteroarylalkyl, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁for-L-heterocyclic radical, it is unsubstituted.In another embodiment, R ₁for-L-heterocyclic radical, it is by one or more independently R ³replace.In another embodiment, R ₁for-L-heterocyclic radical, it is unsubstituted and L does not exist.In another embodiment, R ₁for-L-heterocyclic radical, it is by one or more independently R ³replace, wherein L does not exist.

In the various embodiments of formula I, R ₁substituent group for as follows:

In the various embodiments of formula I, R ²for hydrogen.In another embodiment, R ²for halogen.In another embodiment, R ²for-OH.In another embodiment, R ²for-R ³¹.In another embodiment, R ²for-CF ₃.In another embodiment, R ²for-OCF ₃.In another embodiment, R ²for-OR ³¹.In another embodiment, R ²for-NR ³¹r ³².In another embodiment, R ²for-NR ³⁴r ³⁵.In another embodiment, R ²for-C (O) R ³¹.In another embodiment, R ²for-CO ₂r ³¹.In another embodiment, R ²for-C (=O) NR ³¹r ³².In another embodiment, R ²for-C (=O) NR ³⁴r ³⁵.In another embodiment, R ²for-NO ₂.In another embodiment, R ²for-CN.In another embodiment, R ²for-S (O) _0-2r ³.In another embodiment, R ²for-SO ₂nR ³¹r3 ².In another embodiment, R ²for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ²for-NR ³¹c (=O) R ³².In another embodiment, R ²for-NR ³¹c (=O) OR ³².In another embodiment, R ²for-NR ³¹c (=O) NR ³²r ³³.In another embodiment, R ²for-NR ³¹s (O) _0-2r ³².In another embodiment, R ²for-C (=S) OR ³¹.In another embodiment, R ²for-C (=O) SR ³¹.In another embodiment, R ²for-NR ³¹c (=NR ³²) NR ³³r ³².In another embodiment, R ²for-NR ³¹c (=NR ³²) OR ³³.In another embodiment, R ²for-NR ³¹c (=NR ³²) SR ³³.In another embodiment, R ²for-OC (=O) OR ³³.In another embodiment, R ²for-OC (=O) NR ³¹r ³².In another embodiment, R ²for-OC (=O) SR ³¹.In another embodiment, R ²for-SC (=O) OR ³¹.In another embodiment, R ²for-P (O) OR ³¹oR ³².In another embodiment, R ²for-SC (=O) NR ³¹r ³².In another embodiment, R ₂for monocyclic aryl.In another embodiment, R ₂for bicyclic aryl.In another embodiment, R ²for the monocyclic aryl replaced.In another embodiment, R ²for heteroaryl.In another embodiment, R ²for C _1-4alkyl.In another embodiment, R ²for C _1-10alkyl.In another embodiment, R ²for C _3-8cycloalkyl.In another embodiment, R ²for C _3-8cycloalkyl-C _1-10alkyl.In another embodiment, R ²for C _1-10alkyl-C _3-8cycloalkyl.In another embodiment, R ²for C _1-10alkyl-monocyclic aryl.In another embodiment, R ²for C _2-10alkyl-monocyclic aryl.In another embodiment, R ²for monocyclic aryl-C _2-10alkyl.In another embodiment, R ²for C _1-10alkyl-bicyclic aryl.In another embodiment, R ²for bicyclic aryl-C _1-10alkyl.In another embodiment, R ²for-C _1-10miscellaneous alkyl aryl.In another embodiment, R ²for-C _1-10alkyl heterocyclic.In another embodiment, R ²for-C _2-10thiazolinyl.In another embodiment, R ²for-C _2-10alkynyl.In another embodiment, R ²for C _2-10alkenyl aryl.In another embodiment, R ²for C _2-10alkenyl heteroaryl.In another embodiment, R ²for C _2-10thiazolinyl is mixed alkyl.In another embodiment, R ²for C _2-10thiazolinyl heterocyclic radical.In another embodiment, R ²for-C _2-10alkynyl aryl.In another embodiment, R ²for-C _2-10alkynyl heteroaryl.In another embodiment, R ²for-C _2-10alkynyl is mixed alkyl.In another embodiment, R ²for-C _2-10alkynyl heterocyclic radical.In another embodiment, R ²for-C _2-10alkynyl C _3-8cycloalkyl.In another embodiment, R ²for-C _2-10alkynyl C _3-8cycloalkenyl group.In another embodiment, R ²for-C _1-10alkoxy-C _1-10alkyl.In another embodiment, R ²for-C _1-10alkoxy-C _2-10thiazolinyl.In another embodiment, R ²for-C _1-10alkoxy-C _2-10alkynyl.In another embodiment, R ²for-heterocyclic radical C _1-10alkyl.In another embodiment, R ²for heterocyclic radical C _2-10thiazolinyl.In another embodiment, R ²for heterocyclic radical C _2-10alkynyl.In another embodiment, R ²for aryl-C _2-10alkyl.In another embodiment, R ²for aryl-C _1-10alkyl.In another embodiment, R ²for aryl-C _2-10thiazolinyl.In another embodiment, R ²for aryl-C _2-10alkynyl.In another embodiment, R ²for aryl-heterocyclic.In another embodiment, R ²for heteroaryl-C _1-10alkyl.In another embodiment, R ²for heteroaryl-C _2-10thiazolinyl.In another embodiment, R ²for heteroaryl-C _2-10alkynyl.。In another embodiment, R ²for heteroaryl-C _3-8cycloalkyl.In another embodiment, R ²for heteroaryl-assorted alkyl.In another embodiment, R ²for heteroaryl-heterocyclyl.

In the various embodiments of formula I, work as R ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is unsubstituted.In various embodiments, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently halogeno-group.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently-OH.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-R ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-CF ₃replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently-OCF.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OR ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³⁴r ³⁵replace.In another embodiment, R is worked as ⁴for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (O) R ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-CO ₂r ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) NR ³⁴r ³⁵replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NO ₂replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently-CN.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-S (O) _0-2r ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SO ₂nR ³¹r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SO ₂nR ³⁴r ³⁵replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently NR ³¹c (=O) R ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) OR ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) NR ³²r ³³replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹s (O) _0-2r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=S) OR ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) SR ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) NR ³³r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) OR ³³replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) SR ³³replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) OR ³³replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) SR ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) OR ³¹replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-P (O) OR ³¹oR ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently alkyl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently assorted alkyl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently alkenyl substituted.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently alkynyl substituted.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently cycloalkyl substituted.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently Heterocyclylalkyl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently aryl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently aryl alkyl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently heteroaryl.In another embodiment, R is worked as ²for bicyclic aryl, monocyclic aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, monocyclic aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is replaced by one or more independently heteroaryl alkyl.

In the various embodiments of formula I, R ³for hydrogen.In another embodiment, R ³for halogen.In another embodiment, R ³for-OH.In another embodiment, R ³for-R ³¹.In another embodiment, R ³for-CF ₃.In another embodiment, R ³for-OCF ₃.In another embodiment, R ³for-OR ³¹.In another embodiment, R ³for-NR ³¹r ³².In another embodiment, R ³for-NR ³⁴r ³⁵.In another embodiment, R ³for-C (O) R ³¹.In another embodiment, R ³for-CO ₂r ³¹.In another embodiment, R ³for-C (=O) NR ³¹r ³².In another embodiment, R ³for-C (=O) NR ³⁴r ³⁵.In another embodiment, R ³for-NO ₂.In another embodiment, R ³for-CN.In another embodiment, R ³for-S (O) _0-2r ³.In another embodiment, R ³for-SO ₂nR ³¹r ³².In another embodiment, R ³for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ³for-NR ³¹c (=O) R ³².In another embodiment, R ³for-NR ³¹c (=O) OR ³².In another embodiment, R ³for-NR ³¹c (=O) NR ³²r ³³.In another embodiment, R ³for-NR ³¹s (O) _0-2r ³².In another embodiment, R ³for-C (=S) OR ³¹.In another embodiment, R ³for-C (=O) SR ³¹.In another embodiment, R ³for-NR ³¹c (=NR ³²) NR ³³r ³².In another embodiment, R ³for-NR ³¹c (=NR ³²) OR ³³.In another embodiment, R ³for-NR ³¹c (=NR ³²) SR ³³.In another embodiment, R ³for-OC (=O) OR ³³.In another embodiment, R ³for-OC (=O) NR ³¹r ³².In another embodiment, R ³for-OC (=O) SR ³¹.In another embodiment, R ³for-SC (=O) OR ³¹.In another embodiment, R ³for-P (O) OR ³¹oR ³².In another embodiment, R ³for-SC (=O) NR ³¹r ³².In another embodiment, R ³for aryl.In another embodiment, R ²for heteroaryl.In another embodiment, R ³for C _1-4alkyl.In another embodiment, R ³for C _1-10alkyl.In another embodiment, R ³for C _3-8cycloalkyl.In another embodiment, R ³for C ^3-8cycloalkyl-C _1-10alkyl.In another embodiment, R ³for-C _1-10alkyl-C _3-8cycloalkyl.In another embodiment, R ³for C _2-10alkyl-monocyclic aryl.In another embodiment, R ³for monocyclic aryl-C _2-10alkyl.In another embodiment, R ³for C _1-10alkyl-bicyclic aryl.In another embodiment, R ³for bicyclic aryl-C _1-10alkyl.In another embodiment, R ³for C _1-10miscellaneous alkyl aryl.In another embodiment, R ³for C _1-10alkyl heterocyclic.In another embodiment, R ³for C _2-10thiazolinyl.In another embodiment, R ³for C _2-10alkynyl.In another embodiment, R ³for C _2-10alkenyl aryl.In another embodiment, R ³for C _2-10alkenyl heteroaryl.In another embodiment, R ³for C _2-10thiazolinyl is mixed alkyl.In another embodiment, R ³for C _2-10thiazolinyl heterocyclic radical.In another embodiment, R ³for-C _2-10alkynyl aryl.In another embodiment, R ³for-C _2-10alkynyl heteroaryl.In another embodiment, R ³for-C _2-10alkynyl is mixed alkyl.In another embodiment, R ³for C _2-10alkynyl heterocyclic radical.In another embodiment, R ³for-C _2-10alkynyl C _3-8cycloalkyl.In another embodiment, R ³for C _2-10alkynyl C _3-8cycloalkenyl group.In another embodiment, R ³for-C _1-10alkoxy-C _1-10alkyl.In another embodiment, R ³for C _1-10alkoxy-C _2-10thiazolinyl.In another embodiment, R ³for-C _1-10alkoxy-C _2-10alkynyl.In another embodiment, R ³for heterocyclic radical-C _1-10alkyl.In another embodiment, R ³for-heterocyclic radical C _2-10thiazolinyl.In another embodiment, R ³for heterocyclic radical-C _2-10alkynyl.In another embodiment, R ³for aryl-C _1-10alkyl.In another embodiment, R ³for aryl-C _2-10thiazolinyl.In another embodiment, R ³for aryl-C _2-10alkynyl.In another embodiment, R ³for aryl-heterocyclic.In another embodiment, R ³for heteroaryl-C _1-10alkyl.In another embodiment, R ³for heteroaryl-C _2-10thiazolinyl.In another embodiment, R ³for heteroaryl-C _2-10alkynyl.。In another embodiment, R ³for heteroaryl-C _3-8cycloalkyl.In another embodiment, R ³for heteroaryl-assorted alkyl.In another embodiment, R ³for heteroaryl-heterocyclyl.

In the various embodiments of formula I, work as R ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is unsubstituted.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently halogeno-group.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-OH.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-R ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-CF ₃replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-OCF.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-OR ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³¹r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³⁴r ³⁵replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-C (O) R ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-CO ₂r ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-C (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) NR ³⁴r ³⁵replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NO ₂replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-CN.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-S (O) _0-2r ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-SO ₂nR ³¹r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-SO ₂nR ³⁴r ³⁵replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently NR ³¹c (=O) R ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) OR ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) NR ³²r ³³replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹s (O) _0-2r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=S) OR ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) SR ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³¹c (=NR ³²) NR ³³r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) OR ³³replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) SR ³³replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) OR ³³replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) SR ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) OR ³¹replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-P (O) OR ³¹oR ³²replace.In another embodiment, R is worked as ³for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) NR ³¹r ³²replace.

In the various embodiments of formula I, R ⁴for hydrogen.In another embodiment, R ⁴for halogen.In another embodiment, R ⁴for-OH.In another embodiment, R ⁴for-R ³¹.In another embodiment, R ⁴for-CF ₃.In another embodiment, R ⁴for-OCF ₃.In another embodiment, R ⁴for-OR ³¹.In another embodiment, R ⁴for-NR ³¹r ³².In another embodiment, R ⁴for-NR ³⁴r ³⁵.In another embodiment, R ⁴for-C (O) R ³¹.In another embodiment, R ⁴for-CO ₂r ³¹.In another embodiment, R ⁴for-C (=O) NR ³¹r ³².In another embodiment, R ⁴for-C (=O) NR ³⁴r ³⁵.In another embodiment, R ⁴for-NO ₂.In another embodiment, R ⁴for-CN.In another embodiment, R ⁴for-S (O) _0-2r ³.In another embodiment, R ⁴for-SO ₂nR ³¹r ³².In another embodiment, R ⁴for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ⁴for-NR ³¹c (=O) R ³².In another embodiment, R ⁴for-NR ³¹c (=O) OR ³².In another embodiment, R ⁴for-NR ³¹c (=O) NR ³²r ³³.In another embodiment, R ⁴for-NR ³¹s (O) _0-2r ³².In another embodiment, R ⁴for-C (=S) OR ³¹.In another embodiment, R ⁴for-C (=O) SR ³¹.In another embodiment, R ⁴for-NR ³¹c (=NR ³²) NR ³³r ³².In another embodiment, R ⁴for-NR ³¹c (=NR ³²) OR ³³.In another embodiment, R ⁴for-NR ³¹c (=NR ³²) SR ³³.In another embodiment, R ⁴for-OC (=O) OR ³³.In another embodiment, R ⁴for-OC (=O) NR ³¹r ³².In another embodiment, R ⁴for-OC (=O) SR ³¹.In another embodiment, R ⁴for-SC (=O) OR ³¹.In another embodiment, R ⁴for-P (O) OR ³¹oR ³².In another embodiment, R ⁴for-SC (=O) NR ³¹r ³².In another embodiment, R ⁴for aryl.In another embodiment, R ⁴for heteroaryl.In another embodiment, R ⁴for C _1-4alkyl.In another embodiment, R ⁴for C _1-10alkyl.In another embodiment, R ⁴for C _3-8cycloalkyl.In another embodiment, R ⁴for C _1-10alkyl-C _3-8cycloalkyl.In another embodiment, R ⁴for C _1-10alkylaryl.In another embodiment, R ⁴for C _1-10miscellaneous alkyl aryl.In another embodiment, R ⁴for C _1-10alkyl heterocyclic.In another embodiment, R ⁴for C _2-10thiazolinyl.In another embodiment, R ⁴for C _2-10alkynyl.In another embodiment, R ⁴for C _2-10alkynyl-C _3-8cycloalkyl.R ⁴for C _2-10thiazolinyl-C _3-8cycloalkyl.In another embodiment, R ⁴for C _2-10alkenyl aryl.In another embodiment, R ⁴for C _2-10alkenyl-heteroaryl.In another embodiment, R ⁴for C _2-10thiazolinyl is mixed alkyl.In another embodiment, R ⁴for C _2-10thiazolinyl heterocyclic radical.In another embodiment, R ⁴for-C _2-10alkynyl aryl.In another embodiment, R ⁴for C _2-10alkynyl heteroaryl.In another embodiment, R ⁴for C _2-10alkynyl is mixed alkyl.In another embodiment, R4 is C _2-10alkynyl heterocyclic radical.In another embodiment, R ⁴for C _2-10alkynyl C _3-8cycloalkyl.In another embodiment, R ⁴for heterocyclic radical C _1-10alkyl.In another embodiment, R ⁴for heterocyclic radical C _2-10thiazolinyl.In another embodiment, R ⁴for heterocyclic radical-C _2-10alkynyl.In another embodiment, R ⁴for aryl-C _1-10alkyl.In another embodiment, R ⁴for aryl-C _2-10thiazolinyl.In another embodiment, R ⁴for aryl-C _2-10alkynyl.In another embodiment, R ⁴for aryl-heterocyclic.In another embodiment, R ⁴for heteroaryl-C _1-10alkyl.In another embodiment, R ⁴for heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁴for heteroaryl-C _2-10alkynyl.In another embodiment, R ⁴for C _3-8cycloalkyl-C _1-10alkyl.In another embodiment, R ⁴for C _3-8cycloalkyl-C _2-10thiazolinyl.In another embodiment, R ⁴for C _3-8cycloalkyl-C _2-10alkynyl.

In the various embodiments of formula I, work as R ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is unsubstituted.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently halogeno-group.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-OH.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-R ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-CF ₃replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-OCF.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-OR ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³¹r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³⁴r ³⁵replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-C (O) R ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-CO ₂r ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-C (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) NR ³⁴r ³⁵replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NO ₂replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is replaced by one or more independently-CN.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-S (O) _0-2r ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-SO ₂nR ³¹r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-SO ₂nR ³⁴r ³⁵replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently NR ³¹c (=O) R ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) OR ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=O) NR ³²r ³³replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹s (O) _0-2r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=S) OR ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-C (=O) SR ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-NR ³¹c (=NR ³²) NR ³³r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) OR ³³replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-NR ³¹c (=NR ³²) SR ³³replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) OR ³³replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) NR ³¹r ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-OC (=O) SR ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) OR ³¹replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, heterocyclic radical, heterocyclic radical C _1-10when alkyl or assorted alkyl, it is by one or more independently-P (O) OR ³¹oR ³²replace.In another embodiment, R is worked as ⁴for aryl, heteroaryl, C _1-10alkyl, cycloalkyl, heterocyclic radical, assorted alkyl, C _2-10thiazolinyl, C _2-10alkynyl, aryl-C _2-10alkyl, heterocyclic radical C _1-10alkyl or C _3-8cycloalkyl-C _1-10during alkyl, it is by one or more independently-SC (=O) NR ³¹r ³²replace.

In the various embodiments of formula I, R ⁵for hydrogen.In another embodiment, R ⁵for halogen.In another embodiment, R ⁵for-OH.In another embodiment, R ⁵for-R ³¹.In another embodiment, R ⁵for-CF ₃.In another embodiment, R ⁵for-OCF ₃.In another embodiment, R ⁵for-OR ³¹.In another embodiment, R ⁵for-NR ³¹r ³².In another embodiment, R ⁵for-NR ³⁴r ³⁵.In another embodiment, R ⁵for-C (O) R ³¹.In another embodiment, R ⁵for-CO ₂r ³¹.In another embodiment, R ⁵for-C (=O) NR ³¹r ³².In another embodiment, R ⁵for-C (=O) NR ³⁴r ³⁵.In another embodiment, R ⁵for-NO ₂.In another embodiment, R ⁵for-CN.In another embodiment, R ⁵for-S (O) _0-2r ³¹.In another embodiment, R ⁵for-SO ₂nR ³¹r ³².In another embodiment, R ⁵for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ⁵for-NR ³¹c (=O) R ³².In another embodiment, R ⁵for-NR ³¹c (=O) OR ³².In another embodiment, R ⁵for-NR ³¹c (=O) NR ³²r ³³.In another embodiment, R ⁵for-NR ³¹s (O) _0-2r ³².In another embodiment, R ⁵for-C (=S) OR ³¹.In another embodiment, R ⁵for-C (=O) SR ³¹.In another embodiment, R ⁵for-NR ³¹c (=NR ³²) NR ³³r ³².In another embodiment, R ⁵for-NR ³¹c (=NR ³²) OR ³³.In another embodiment, R ⁵for-NR ³¹c (=NR ³²) SR ³³.In another embodiment, R ⁵for-OC (=O) OR ³³.In another embodiment, R ⁵for-OC (=O) NR ³¹r ³².In another embodiment, R ⁵for-OC (=O) SR ³¹.In another embodiment, R ⁵for-SC (=O) OR ³¹.In another embodiment, R ⁵for-P (O) OR ³¹oR ³².In another embodiment, R ⁵for or-SC (=O) NR ³¹r ³².

In the various embodiments of formula I, R ⁷for hydrogen.In another embodiment, R ⁷for unsubstituted C _1-10alkyl.In another embodiment, R ⁷for unsubstituted C ₂-C ₁₀thiazolinyl.In another embodiment, R ⁷for unsubstituted aryl.In another embodiment, R ⁷for unsubstituted heteroaryl.In another embodiment, R ⁷for unsubstituted heterocyclic radical.In another embodiment, R ⁷for unsubstituted C _3-10cycloalkyl.In another embodiment, R ⁷for by one or more independently R ⁶the C replaced _1-10alkyl.In another embodiment, R ⁷for by one or more independently R ⁶the C replaced _2-10thiazolinyl.In another embodiment, R ⁷for by one or more independently R ⁶the aryl replaced.In another embodiment, R ⁷for by one or more independently R ⁶the heteroaryl replaced.In another embodiment, R ⁷for by one or more independently R ⁶the heterocyclic radical replaced.In another embodiment, R ⁷for by one or more independently R ⁶the C replaced _3-10cycloalkyl.

In the various embodiments of formula I, R ⁸for hydrogen.In another embodiment, R ⁸for unsubstituted C _1-10alkyl.In another embodiment, R ⁸for unsubstituted C _2-10thiazolinyl.In another embodiment, R ⁸for unsubstituted aryl.In another embodiment, R ⁸for unsubstituted heteroaryl.In another embodiment, R ⁸for unsubstituted heterocyclic radical.In another embodiment, R ⁸for unsubstituted C _3-10cycloalkyl.In another embodiment, R ⁸for by one or more independently R ⁶the C replaced _1-10alkyl.In another embodiment, R ⁸for by one or more independently R ⁶the C replaced _2-10thiazolinyl.In another embodiment, R ⁸for by one or more independently R ⁶the aryl replaced.In another embodiment, R ⁸for by one or more independently R ⁶the heteroaryl replaced.In another embodiment, R ⁸for by one or more independently R ⁶the heterocyclic radical replaced.In another embodiment, R ⁸for by one or more independently R ⁶the C replaced _3-10cycloalkyl.

In the various embodiments of formula I, R ⁶for halogeno-group, in another embodiment, R ⁶for-OR ³¹.In another embodiment, R ⁶for-SH.In another embodiment, R ⁶for NH ₂.In another embodiment, R ⁶for-NR ³⁴r ³⁵.In another embodiment, R ⁶for-NR ³¹r ³².In another embodiment, R ⁶for-CO ₂r ³¹.In another embodiment, R ⁶for-CO ₂aryl.In another embodiment, R ⁶for-C (=O) NR ³¹r ³².In another embodiment, R ⁶for C (=O) NR ³⁴r ³⁵.In another embodiment, R ⁶for-NO ₂.In another embodiment, R ⁶for-CN.In another embodiment, R ⁶for-S (O) _0-2c _1-10alkyl.In another embodiment, R ⁶for-S (O) _0-2aryl.In another embodiment, R ⁶for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ⁶for-SO ₂nR ³¹r ³².In another embodiment, R ⁶for C _1-10alkyl.In another embodiment, R ⁶for C _2-10thiazolinyl.In another embodiment, R ⁶for C _2-10alkynyl.In another embodiment, R ⁶for unsubstituted aryl-C _1-10alkyl.In another embodiment, R ⁶for unsubstituted aryl-C _2-10thiazolinyl.In another embodiment, R ⁶for unsubstituted aryl-C _2-10alkynyl.In another embodiment, R ⁶for unsubstituted heteroaryl-C _1-10alkyl.In another embodiment, R ⁶for unsubstituted heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for the aryl-C replaced by one or more independently halogeno-group _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for the aryl-C replaced by one or more independently cyano group _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for the aryl-C replaced by one or more independently nitro _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-OC _1-10aryl-the C that alkyl replaces _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-C _1-10aryl-the C that alkyl replaces _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-C _2-10aryl-the C of alkenyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-C _2-10aryl-the C of alkynyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by independently one or more-(halogeno-group) C _1-10aryl-the C that alkyl replaces _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by independently one or more-(halogeno-group) C _2-10aryl-the C of alkenyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by independently one or more-(halogeno-group) C _2-10aryl-the C of alkynyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for the aryl-C replaced by one or more independently-COOH _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-C (=O) NR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-C (=O) NR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-SO ₂nR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-SO ₂nR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-NR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁶for by one or more independently-NR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.

In the various embodiments of formula I, R ⁹for H.In another embodiment, R ⁹for halogeno-group.In another embodiment, R ⁹for-OR ³¹.In another embodiment, R ⁹for-SH.In another embodiment, R ⁹for NH ₂.In another embodiment, R ⁹for-NR ³⁴r ³⁵.In another embodiment, R ⁹for-NR ³¹r ³².In another embodiment, R ⁹for-CO ₂r ³¹.In another embodiment, R ⁹for-CO ₂aryl.In another embodiment, R ⁹for-C (=O) NR ³¹r ³².In another embodiment, R ⁹for C (=O) NR ³⁴r ³⁵.In another embodiment, R ⁹for-NO ₂.In another embodiment, R ⁹for-CN.In another embodiment, R ⁹for-S (O) _0-2c _1-10alkyl.In another embodiment, R ⁹for-S (O) _0-2aryl.In another embodiment, R ⁹for-SO ₂nR ³⁴r ³⁵.In another embodiment, R ⁹for-SO ₂nR ³¹r ³².In another embodiment, R ⁹for C _1-10alkyl.In another embodiment, R ⁹for C _2-10thiazolinyl.In another embodiment, R ⁹for C _2-10alkynyl.In another embodiment, R ⁹for unsubstituted aryl-C _1-10alkyl.In another embodiment, R ⁹for unsubstituted aryl-C _2-10thiazolinyl.In another embodiment, R ⁹for unsubstituted aryl-C _2-10alkynyl.In another embodiment, R ⁹for unsubstituted heteroaryl-C _1-10alkyl.In another embodiment, R ⁹for unsubstituted heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for the aryl-C replaced by one or more independently halogeno-group _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for the aryl-C replaced by one or more independently cyano group _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for the aryl-C replaced by one or more independently nitro _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-OC _1-10aryl-the C that alkyl replaces _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-C _2-10aryl-the C of alkenyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-C _2-10aryl-the C of alkenyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-C _2-10aryl-the C of alkynyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by independently one or more-(halogeno-group) C _1-10aryl-the C that alkyl replaces _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by independently one or more-(halogeno-group) C _2-10aryl-the C of alkenyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by independently one or more-(halogeno-group) C _2-10aryl-the C of alkynyl substituted _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for the aryl-C replaced by one or more independently-COOH _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-C (=O) NR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-C (=O) NR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-SO ₂nR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-SO ₂nR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-NR ³¹r ³²aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.In another embodiment, R ⁹for by one or more independently-NR ³⁴r ³⁵aryl-the C replaced _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl or heteroaryl-C _2-10thiazolinyl.

In the various embodiments of formula I, R ³¹for H.In some embodiments, R ³¹for unsubstituted C _1-10alkyl.In some embodiments, R ³¹for the C replaced _1-10alkyl.In some embodiments, R ³¹for the C replaced by one or more aryl _1-10alkyl.In some embodiments, R ³¹for the C replaced by one or more assorted alkyl _1-10alkyl.In some embodiments, R ³¹for the C replaced by one or more heterocyclic radical _1-10alkyl.In some embodiments, R ³¹for the C replaced by one or more heteroaryl _1-10alkyl.In some embodiments, R is worked as ³¹for the C replaced by one or more aryl _1-10during alkyl, each in described aryl substituent is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³¹for the C replaced by one or more assorted alkyl _1-10during alkyl, each in described assorted alkyl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵substituent group replaces.In some embodiments, R is worked as ³¹for the C replaced by one or more heterocyclic radical _1-10during alkyl, each in described heterocyclic radical is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³¹for the C replaced by one or more heteroaryl _1-10during alkyl, each in described heteroaryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³¹for the C replaced _1-10during alkyl, it is replaced by the combination of aryl, assorted alkyl, heterocyclic radical or heteroaryl.

In the various embodiments of formula I, R ³²for H.In some embodiments, R ³²for unsubstituted C _1-10alkyl.In some embodiments, R ³²for the C replaced _1-10alkyl.In some embodiments, R ³²for the C replaced by one or more aryl _1-10alkyl.In some embodiments, R ³²for the C replaced by one or more assorted alkyl _1-10alkyl.In some embodiments, R ³²for the C replaced by one or more heterocyclic radical _1-10alkyl.In some embodiments, R ³²for the C replaced by one or more heteroaryl _1-10alkyl.In some embodiments, R is worked as ³²for the C replaced by one or more aryl _1-10during alkyl, each in described aryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³²for the C replaced by one or more assorted alkyl _1-10during alkyl, each in described assorted alkyl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³²for the C replaced by one or more heterocyclic radical _1-10during alkyl, each in described heterocyclic radical is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³²for the C replaced by one or more heteroaryl _1-10during alkyl, each in described heteroaryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³²for the C replaced _1-10during alkyl, it is replaced by the combination of aryl, assorted alkyl, heterocyclic radical or heteroaryl.

In the various embodiments of formula I, R ³³for unsubstituted C _1-10alkyl.In some embodiments, R ³³for the C replaced _1-10alkyl.In some embodiments, R ³³for the C replaced by one or more aryl _1-10alkyl.In some embodiments, R ³³for the C replaced by one or more assorted alkyl _1-10alkyl.In some embodiments, R ³³for the C replaced by one or more heterocyclic radical _1-10alkyl.In some embodiments, R ³³for the C replaced by one or more heteroaryl _1-10alkyl.In some embodiments, R is worked as ³³for the C replaced by one or more aryl _1-10during alkyl, each in described aryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³³for the C replaced by one or more assorted alkyl _1-10during alkyl, each in described assorted alkyl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³³for the C replaced by one or more heterocyclic radical _1-10during alkyl, each in described heterocyclic radical is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³³for the C replaced by one or more heteroaryl _1-10during alkyl, each in described heteroaryl is unsubstituted or by one or more halogeno-group ,-OH ,-C _1-10alkyl ,-CF ₃,-O-aryl ,-OCF ₃,-OC _1-10alkyl ,-NH ₂,-N (C _1-10alkyl) (C _1-10alkyl) ,-NH (C _1-10alkyl) ,-NH (aryl) ,-NR ³⁴r ³⁵,-C (O) (C _1-10alkyl) ,-C (O) (C _1-10alkyl-aryl-group) ,-C (O) (aryl) ,-CO ₂-C _1-10alkyl ,-CO ₂-C _1-10alkylaryl ,-CO ₂-aryl ,-C (=O) N (C _1-10alkyl) (C _1-10alkyl) ,-C (=O) NH (C _1-10alkyl) ,-C (=O) NR ³⁴r ³⁵,-C (=O) NH ₂,-OCF ₃,-O (C _1-10alkyl) ,-O-aryl ,-N (aryl) (C _1-10alkyl) ,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2c _1-10alkylaryl ,-S (O) _0-2aryl ,-SO ₂n (aryl) ,-SO ₂n (C _1-10alkyl) (C _1-10alkyl) ,-SO ₂nH (C _1-10alkyl) or-SO ₂nR ³⁴r ³⁵replace.In some embodiments, R is worked as ³³for the C replaced _1-10during alkyl, it is replaced by the combination of aryl, assorted alkyl, heterocyclic radical or heteroaryl.

In the various embodiments of formula I ,-NR ³⁴r ³⁵,-C (=O) NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵in R ³⁴and R ³⁵saturated or the undersaturated ring of 3-10 unit is formed together with the nitrogen-atoms attached by it; Wherein said ring is unsubstituted or by one or more-NR independently ³¹r ³², hydroxyl, halogen, oxo base, aryl, heteroaryl, C _1-6alkyl or O-aryl replace, and wherein said 3-10 unit is saturated or undersaturated ring independently containing 0,1 or 2 more denitrogenate outside hetero atom.

In some embodiments ,-NR ³⁴r ³⁵,-C (=O) NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵in R ³⁴and R ³⁵formed together with the nitrogen-atoms attached by it:

In another embodiment, X ₁for C-NH ₂.

In various embodiments, X ₁for C--NH-R ⁴, wherein-NH-R ⁴for:

In one embodiment, the invention provides a kind of formula I-C1 inhibitor, wherein R ⁵for H.In another embodiment, the invention provides a kind of formula I-C2 inhibitor, wherein R ⁵for H.

In some embodiments, the invention provides a kind of formula I-C1a inhibitor:

Or its pharmaceutically acceptable salt, wherein:

E ²for-H;

X ₁and X ₂for N;

R ₁for-L-C _1-10alkyl ,-L-C _3-8cycloalkyl ,-L-C _1-10alkyl heterocyclic or-L-heterocyclic radical, wherein each is unsubstituted or by one or more independently R ³replace;

R ³for hydrogen ,-OH ,-OR ³¹,-NR ³¹r ³²,-C (O) R ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵, aryl, heteroaryl, C _1-4alkyl, C _1-10alkyl, C _3-8cycloalkyl or heterocyclic radical, each in wherein said aryl or heteroaryl moieties is unsubstituted or by one or more independently alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³ ²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl or heterocyclyl moieties be unsubstituted or by one or more alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

-(W ²) _k-be-NH-,-N (H) C (O)-or-N (H) S (O) ₂-;

R ²for hydrogen, halogen ,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³ ¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵, bicyclic aryl, the monocyclic aryl of replacement, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-1 ₀thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _2-10alkyl-monocyclic aryl, monocyclic aryl-C _2-10alkyl, C _1-10alkyl bicyclic aryl, bicyclic aryl-C _1-10the C of alkyl, replacement _1-10aryl-the C of alkylaryl, replacement _1-10alkyl, C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2- ₁₀thiazolinyl, C _2-10alkynyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy C _2-10thiazolinyl, C _1-10alkoxy C _2-10alkynyl, heterocyclic radical, heterocyclic radical C _1-10alkyl, heterocyclic radical C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said bicyclic aryl or heteroaryl moieties is unsubstituted, or each wherein in bicyclic aryl, heteroaryl moieties or monocyclic aryl part is by one or more independently halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³ ⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³ ¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties is unsubstituted or by one or more halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ³¹, R ³²and R ³³, in each case, be H or C independently _1-10alkyl, wherein C _1-10alkyl is unsubstituted; And

-NR ³⁴r ³⁵,-C (=O) NR ³⁴r ³⁵or-SO ₂nR ³⁴r ³⁵in R ³⁴and R ³⁵saturated or the undersaturated ring of 3-10 unit is formed together with the nitrogen-atoms attached by it; Wherein said ring is unsubstituted or by one or more-NR independently ³¹r ³², hydroxyl, halogen, oxo base, aryl, heteroaryl, C _1-6alkyl or O-aryl replace, and wherein said 3-10 unit is saturated or undersaturated ring independently containing 0,1 or 2 more denitrogenate outside hetero atom.

In yet another aspect, formula I-C1 inhibitor is formula I-C1a compound:

Or its pharmaceutically acceptable salt, wherein: E ²for-H; X ₁for CH and X ₂for N;

-(W ²) _k-be-NH-,-N (H) C (O)-or-N (H) S (O) ₂-;

R ²for hydrogen, halogen ,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³ ¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵, bicyclic aryl, the monocyclic aryl of replacement, heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _2-10alkyl-monocyclic aryl, monocyclic aryl-C _2-10alkyl, C _1-10alkyl bicyclic aryl, bicyclic aryl--C _1-10the C of alkyl, replacement _1-10aryl-the C of alkylaryl, replacement _1-10alkyl, C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, heterocyclic radical, heterocyclic radical C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1- ₁₀alkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said bicyclic aryl or heteroaryl moieties is unsubstituted, or each wherein in bicyclic aryl, heteroaryl moieties or monocyclic aryl part is by one or more independently halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³ ³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties is unsubstituted or by one or more halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

Or its pharmaceutically acceptable salt, wherein:

M ₁for quilt-(W ²) _k-R ²the benzothiazolyl replaced;

K is 0 or 1;

E ¹and E ²be-(W independently ¹) _j-R ⁴;

(that is, at E in often kind of situation ¹in or E ²in j) j be 0 or 1 independently;

In some embodiments, X ₄for C-R ⁹.

The present invention also provides one inhibitor as defined above, and wherein said compound has formula I-B:

In various embodiments, formula I-B compound or its pharmaceutically acceptable salt are the inhibitor with formula I-B1 or formula I-B2 structure:

Or its pharmaceutically acceptable salt.

In various embodiments, X ₁for C-(W ¹) _j-R ⁴, wherein j is 0.

In another embodiment, X ₁for N.

In various embodiments, X ₂for N.In other embodiments, X ₂for C.

In various embodiments, E ²for-(W ¹) _j-R ⁴, wherein j is 0.

In the various embodiments of formula I-A, I-B, I-B1 and I-B2, M ₁for:

In some embodiments of the present invention, M ₁for quilt-(W ²) _k-R ²the benzothiazolyl replaced.W ²can be-O-,-S (O) _0-2-(include but not limited to-S-,-S (O)-and-S (O) ₂-) ,-C (O)-or-C (O) O-.In other embodiments, W ¹for-NR ⁶-or-CH (R ⁶) N (R ⁷)-, be R wherein ⁶and R ⁷be hydrogen, the C that do not replace or replace independently of one another ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), the C that do not replace or replace ₂-C ₁₀thiazolinyl (including but not limited to thiazolinyl, such as vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl).In addition, W is worked as ²for-NR ⁶-or-CH (R ⁶) N (R ⁷)-time, R ⁶and R ⁷aryl (comprising phenyl and naphthyl) independently of one another for not replacing or replacing.In other embodiments, W is worked as ²for-NR ⁶-or-CH (R ⁶) N (R ⁷)-time, R ⁶and R ⁷be heteroaryl independently of one another, wherein said heteroaryl is what do not replace or replace.R ⁶and R ⁷heteroaryl is bicyclic heteroaryl, and includes but not limited to imidazole radicals, pyrrole radicals, oxazolyl, thiazolyl and pyridine radicals.In some other embodiments, work as W ²for-NR ⁶-or-CH (R ⁶) N (R ⁷)-time, R ⁶and R ⁷be the heterocyclic radical (including but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl) not replacing or replace or the C not replacing or replace independently of one another _3-8cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta).Non-restrictive illustrative W ²comprise-NH-,-N (cyclopropyl) and-N (4-N-piperidyl).

Such as, exemplary mTor inhibitor of the present invention has following formula:

reaction process-mTor inhibitor compound

MTor inhibitor compound disclosed herein is prepared by following route.The commercially available acquisition of material used herein or prepared by synthetic method generally known in the art.These flow processs are not limited to listed compound or are subject to the restriction of any specified substituent adopted for illustration purposes.Numbering must not correspond to the numbering in claim or other tables.

flow process A

In one embodiment, by making functionalized heterocycle A-1 and Methanamide condensation, to provide pyrazolopyrimidine A-2 to synthesize compound.With N-iodosuccinimide process pyrazolopyrimidine, this introduces iodine substituent group in pyrazole ring, as in A-3.By making pyrazolopyrimidine A3 and formula R ₁-Lg compound reacts under the existence of alkali as potassium carbonate introduces R ₁substituent group, with production A-4 compound.Other alkali being suitable for using in this step include but not limited to sodium hydride and potassium tert-butoxide.Formula R ₁-Lg compound has as the R for formula I-A compound ₁the part R defined ₁, and wherein-Lg is suitable leaving group, as halogenide (comprising bromine, iodine and chlorine), toluenesulfonic acid ester group or other suitable leaving groups.

Thereafter introduce corresponding to M by making aryl or heteroaryl-boronic acids and formula A-4 compound react ₁substituent group, to obtain compd A-5.

Flow process A-1

Alternatively, Mitsunobu chemical method can be used to obtain alkylation pyrazolopyrimidine A-4, as shown in flow process A-1.Make iodopyrazol theta and pyrimidine A-3 and suitable alcohol react, to produce pyrazolopyrimidine A-4 under the existence of triphenylphosphine and diisopropyl azodicarboxylate (DIAD).

Flow process B

Compound of the present invention is by the reaction process synthesis represented general in flow process B.The coupling of through type A compound and formula B compound is synthesized, with production C compound.Coupling step is usually by using such as palladium catalyst to carry out catalysis, and described palladium catalyst includes but not limited to tetrakis triphenylphosphine palladium.Coupling is carried out usually under the existence of suitable alkali, and the limiting examples of described alkali is sodium carbonate.For the example Wei diox aqueous solution of suitable solvent reacted.

Formula A compound for flow process B has formula A structure, wherein T ₁for trifluoromethanesulfonic acid ester group or halogeno-group (comprising bromine, chlorine and iodine), and wherein R ₁, X ₁, X ₂, X ₃, R ₃₁and R ₃₂as for formula I-A compound define.For boric acid with such as formula the acid derivative described in B, M is M ₁or M ₂.M ₁as for formula I-A compound define.Such as, M ₁can be 5-benzoxazolyl or 6-benzoxazole base section, include but not limited to those M disclosed herein ₁part.M ₂for at M ₂moiety to formula A compound dicyclo core after synthesis transform to form M ₁part.

For formula B compound, G is hydrogen or R _g1, wherein R _g1for alkyl, thiazolinyl or aryl.Alternatively, B (OG) ₂form 5-or 6-membered cyclic moiety together.In some embodiments, formula B compound is the compound with formula E structure.

Wherein G is H or R _g1, R _g1for alkyl, thiazolinyl or aryl.Alternatively, form 5-or 6-membered cyclic moiety, and R ₂for R _g2part, wherein R _g2part is H, acyl group or amino protecting group, and described amino protecting agent includes but not limited to t-butyl carbamate base (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethoxycarbonyl groups (FMOC), p-methoxy-benzyl (PMB) etc.

Flow process C

In some embodiments, formula B compound is formula B ' compound, and wherein G is R _g1, or be formula B " compound, wherein G is hydrogen.Flow process C illustrates for the synthesis of for the formula B ' compound of reaction process C or the optionally formula B " exemplary flow of compound.React to carry out this to react by making formula D compound and trialkyl borate or boronic acid derivatives, with production B ' compound.Reaction is usually carried out in the solvent of such as diox or oxolane.Trialkyl borate includes but not limited to tri-isopropylborate and boronic acid derivatives includes but not limited to two (pinacol) two boron.

When use trialkyl borate react time, interpolation borate before, first by alkali as n-BuLi adds in formula D compound, to generate anion.When use boronic acid derivatives as two (pinacol) two boron react time, use palladium catalyst and alkali.Typical palladium catalyst includes but not limited to (diphenylphosphino) ferrocene Palladous chloride..Suitable alkali includes but not limited to potassium acetate.

Formula D compound for flow process C is wherein T ₂for halogeno-group or another leaving group and M for as above in flow process B define compound.Formula B ' compound can be converted into formula B " compound further by with sour example hydrochloric acid process.

At formula B, B ', B " or E compound an embodiment in, G group is hydrogen.At formula B, B ', B " or E compound another embodiment in, G group is R _g1.

In some embodiments, when such as, M ₁during for 2-N-acetyl group-benzoxazole-5-base, after coupling reaction, do not carry out M ₁the further synthesis of part transforms.

Some exemplary formula B compounds by flow process C synthesis include but not limited to following formula: compound:

In other embodiments of the present invention, by formula F compounds accepted way of doing sth E compound, as shown in flow process C-1:

Flow process C-1

Flow process C-1 shows the exemplary flow for the synthesis of formula E compound.React to carry out this to react by making formula F compound and trialkyl borate or boronic acid derivatives, with production E compound.Reaction condition is as above described in flow process C.

Formula F compound for flow process C-1 is wherein T ₂for halogeno-group (comprising Br, Cl and I) or another leaving group (including but not limited to trifluoromethanesulfonic acid ester group, toluenesulfonic acid ester group and methanesulfonic acid ester group), and G _ppart is the compound of H, acyl group or amino protecting group, and described amino protecting group includes but not limited to t-butyl carbamate base (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethoxycarbonyl groups (FMOC), p-methoxy-benzyl (PMB) etc.

Wherein G is that the formula E compound of alkyl is by being further converted to sour example hydrochloric acid process the formula E compound that wherein G is hydrogen.

When needed, after formula B compound is coupled to formula A compound, carry out benzoxazolyl (that is, the M of formula C ₁) on substituent go protection (such as, from amino-substituent remove Boc protection).

Some exemplary compounds with described protecting group include but not limited to following formula: compound:

M ₂to M ₁exemplary conversion undertaken by flow process D as shown below.

Flow process D

In step 1, formula 3-1 compound and boric acid 3-2 is made at tetrakis triphenylphosphine palladium and suitable alkali as reacted in aqueous/ORGANIC SOLVENT MIXTURES under sodium carbonates' presence, with production 3-3 compound.In step 2, formula 3-3 compound is made to react in as the acetic acid of solvent with the nitric acid of about 2 equivalents, with production 3-4 compound.The next one that two alternative conversions can be used to realize step 3 transforms.In first method, in water, process formula 3-4 compound, with production 3-5 compound with sodium dithionite and sodium hydroxide.Alternatively, palladium on carbon reduction-type 3-4 compound in a hydrogen atmosphere is in a suitable solvent used, with production 3-5 compound.

In step 4, the Bromine cyanide. of compound 3-5 and about 1.2 equivalents is made to react, with production 3-6 compound in the solvent of such as methanol/tetrahydrofuran compound.Formula 3-6 compound replaces by other or derivative conversion further.

The formula 3-1 compound that can be used for the method for flow process D is the compound with formula 3-1 structure, wherein T ₁for trifluoromethanesulfonic acid ester group or halogeno-group (comprising bromine, chlorine and iodine), and wherein R ₁, X ₁, X ₂, X ₃, R ₃₁and R ₃₂as for formula I-A compound define.

The exemplary compounds with pyrazolopyrimidine core is synthesized by flow process E.

Flow process E

In the step 1 of flow process E, make the compd A-2 in dimethyl formamide (DMF) and N-halosuccinimides (NT ₁s) react at about 80 DEG C, to provide compound 4-1, wherein T ₁for iodine or bromine.In step 2, the compound 4-1 in formula DMF and compound R is made ₁t _xreact in the presence of potassium carbonate, to provide compound 4-2.In step 4, palladium catalyst such as tetrakis triphenylphosphine palladium is used under sodium carbonates' presence, to make compound 4-2 and the coupling of formula B compound, to produce as directed Pyrazolopyrimidine compound.

Be applicable to the formula R of reaction process E ₁t _xcompound is wherein R ₁for cycloalkyl or alkyl and T _xfor the compound of halogeno-group (comprising bromine, iodine or chlorine) or leaving group (including but not limited to methanesulfonic acid ester group or toluenesulfonic acid ester group).

Reaction process F-M illustrates the method for synthesis borane reagent, and described borane reagent can be used for being prepared in the intermediate used in the synthesis of compound of the present invention, as described in above reaction process A, B and E, to introduce M ₁substituent group.

reaction process F

reaction process G

reaction process H

reaction process I

reaction process J

reaction process K

reaction process L

reaction process M

reaction process N

In substituting synthetic method, by formula N-1 compound and the coupling of formula N-2 compound with production C compound.Coupling step is usually by using such as palladium catalyst to carry out catalysis, and described palladium catalyst includes but not limited to tetrakis triphenylphosphine palladium.Coupling is carried out usually under the existence of suitable alkali, and the limiting examples of described alkali is sodium carbonate.For the example Wei diox aqueous solution of suitable solvent reacted.

The formula N-1 compound being applicable to flow process N has formula N-1 structure, and wherein G is hydrogen or R _g1, wherein R _g1for alkyl, thiazolinyl or aryl.Alternatively, the B (OG) of formula N-1 compound ₂form 5-or 6-membered cyclic moiety together.The R of formula N-1 compound ₁, X ₁, X ₂, X ₃, R ₃₁and R ₃₂as for formula I-A compound define.

Formula N-2 compound for flow process N has formula N-2 structure, wherein T ₁for trifluoromethanesulfonic acid ester group or halogeno-group (comprising bromine, chlorine and iodine).The M of formula N-2 compound is M ₁or M ₂.M ₁as for formula I define.Such as, M ₁can be 5-benzoxazolyl or 6-benzoxazole base section, include but not limited to those M disclosed herein ₁part.M ₂for at M ₂moiety to formula N-1 compound dicyclo core after synthesis transform to form M ₁part.

Flow process N-1

Formula N-1 compound can synthesize as shown in flow process N-1.Formula N-1 compound and trialkyl borate or boronic acid derivatives are reacted, with production N-1 compound.Reaction is usually carried out in the solvent of such as diox or oxolane.Trialkyl borate includes but not limited to tri-isopropylborate and boronic acid derivatives includes but not limited to two (pinacol) two boron.

When use trialkyl borate react time, interpolation borate before, first by alkali as n-BuLi adds in formula N-3 compound, to generate anion.When use boronic acid derivatives as two (pinacol) two boron react time, use palladium catalyst and alkali.Typical palladium catalyst includes but not limited to (diphenylphosphino) ferrocene) Palladous chloride..Suitable alkali includes but not limited to potassium acetate.

The formula N-3 compound being applicable to flow process N-1 is wherein T ₂for halogeno-group or another leaving group are as the compound of methanesulfonic acid ester group, toluenesulfonic acid ester group or trifluoromethanesulfonic acid ester group.The X of formula N-3 compound ₁, X ₂, X ₃, R ₁, R ₃₁and R ₃₂as for formula I-A compound define.

In some embodiments of the present invention, formula A, B, B ', B ", C, C ", D, E, E ", 3-1,3-2,3-3,3-4,3-5,3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " compound provides as its salt, includes but not limited to hydrochlorate, acetate, formates, nitrate, sulfate and borate.

In some embodiments of the present invention, formula A, B, B ', B ", C, C ", D, E, E ", 3-1,3-2,3-3,3-4,3-5,3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " compound synthesis in use palladium compound, include but not limited to (diphenylphosphino) ferrocene) Palladous chloride. and tetrakis triphenylphosphine palladium.When at formula A, B, B ', B ", C, C ", D, E, E ", 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " compound synthesis in when there is palladium compound, it is with at formula A, B, B ', B ", C, D, E, 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, about 0.005 molar equivalent of N-1 or N-3 compound is to about 0.5 molar equivalent, about 0.05 molar equivalent is to about 0.20 molar equivalent, about 0.05 molar equivalent is to about 0.25 molar equivalent, about 0.07 molar equivalent extremely about 0.15 molar equivalent or about 0.8 molar equivalent exists to the amount in the scope of about 0.1 molar equivalent.In some embodiments, palladium compound, includes but not limited to (diphenylphosphino) ferrocene) Palladous chloride. and tetrakis triphenylphosphine palladium be for synthesis type A, B, B ', B ", C, C ", D, E, E ", 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " the formula A of compound, B, B ', B ", C, C ", D, E, E ", 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " parent material about 0.07, about 0.08, about 0.09, about 0.10, about 0.11, about 0.12, about 0.13, about 0.14 or about 0.15 molar equivalent is present in formula A, B, B ', B ", C, C ", D, E, E ", 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, N-1 ", N-3 ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", N-1 " or N-3 " compound synthesis in.

In some embodiments of above reaction process B, D, E, N or N-1, another embodiment of formula A, C, 3-1,3-3,3-4,3-5,3-6, A-2,4-1,4-2, N-1 and N-3 compound is as shown in following flow process B ', D ', E ', N ' or N-1 '.In these substituting synthesis of production C, 3-1,3-3,3-4,3-5,3-6, A-2,4-1,4-2, N-1 or N-3 compound, use the compound comprising amino-moiety, described amino-moiety has the R existed during one or more synthesis step _g2part, wherein R _g2for amino protecting group, include but not limited to t-butyl carbamate base (Boc), carboxybenzyl (Cbz), benzyl (Bz), fluorenylmethoxycarbonyl groups (FMOC), p-methoxy-benzyl (PMB) etc.These compounds comprise formula A ", C ", 3-1 ", 3-3 ", 3-4 ", 3-5 ", 3-6 ", A-2 ", 4-1 ", 4-2 ", N-1 " or N-3 " compound.

At the some place of any expectation, suitable method is used to remove R _g2part, formula C, 3-1,3-3,3-4,3-5,3-6, A-2,4-1,4-2, N-1 or N-3 compound have alternative R on amino-moiety thus _g2the R of part ₃₁hydrogen.For formula C " compound is to the conversion (that is, as in the step 4 of flow process E ') of C compound and formula 3-6 " compound to the conversion (that is, as in the step 5 of flow process D ') of formula 3-6 compound specifically illustrates this and transforms.This illustrates the selection of conditioning step never in any form, comprising NR ₃₁r _g2the compound of part can be converted into and comprise NR ₃₁r ₃₂the compound of part, wherein R ₃₂part is hydrogen.

Flow process B '

Flow process D '

Flow process E '

Flow process N ' and N-1 "

In addition, the present invention contain A, B, B ', B ", the synthetic method of C, E, 3-1,3-2,3-3,3-4,3-5,3-6, N-1 or N-3 compound, wherein M, M ₁or R ₁in one or more there is the protecting group existed during one or more synthesis step.Be applicable to M, M ₁or R ₁the protecting group of part and the method mixing and remove and the reagent being applicable to described conversion are well known in the art.

Wherein X ₄for C-R ⁹compound of the present invention by be similar to above shown in flow process described in one method preparation.

Reaction process O, P and Q illustrate the method for synthesis borane reagent, and described borane reagent can be used for being prepared in the intermediate used in the synthesis of compound of the present invention, as described in above reaction process 1 and 2, to introduce benzothiazolyl substituent group.

flow process O

Use such as nitric acid treatment formula O-1 compound, with production O-2 compound.Use reducing agent as stannous chloride process formula O-2 compound, with production O-3 compound.Use the Chile saltpeter in acid and copper bromide process O-3 compound, with production O-4 compound.Use alkali as butyl lithium and three isopropoxy boron process O-4 compounds, with production O-5 compound.

flow process P

Use the acetic acid solution process formula P-1 compound of such as potassium thiocyanate and bromine, with production P-2 compound.Use acetylation reagent as chloroacetic chloride process formula P-2 compound, with production P-3 compound.Make P-3 compound with such as two (pinacol) two boron (compound P-4) react under the existence of catalyst as Palladous chloride., with production P-5 compound.

flow process Q

Formula P-2 compound and such as methyl carbamic acid chlorine are reacted, with production Q-1 compound.Make formula Q-1 compound and two (pinacol) two boron (compound P-4) at catalyst as Pd ₂(dba) ₃, 2-chloro hexyl phosphino--2,4,6-triisopropyl diphenyl, alkali as reacted under the existence of potassium acetate, with production Q-2 compound.

For exemplary compounds more of the present invention of mTor inhibitor are hereafter describing.Compound illustrated by compound of the present invention is limited to herein never in any form.

Exemplary compounds of the present invention comprises those of subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a or 16b, wherein substituent R ₁, X ₁as described below with V.

In some embodiments, R is worked as ₁for H and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for H and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for CH ₃and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for CH ₃and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for Et and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for Et and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for iPr and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for iPr and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In one embodiment, R ₁for iPr, X ₁for N, and V is NH ₂.In another embodiment, R ₁for iPr, X ₁for N, and V is NHCOMe.In other embodiments, R is worked as ₁for cyclobutyl and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for cyclobutyl and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for cyclopenta and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for cyclopenta and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for phenyl and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for phenyl and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for pyridine-2-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for pyridine-2-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methylamino hexamethylene-4-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methylamino hexamethylene-4-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methyl piperidine-4-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methyl piperidine-4-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methylamino ring fourth-3-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for N-methylamino ring fourth-3-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for the tert-butyl group and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for the tert-butyl group and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 1-cyano group-Ding-4-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 1-cyano group-Ding-4-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 1-cyano group-propyl-3-base and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 1-cyano group-propyl-3-base and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 3-azetidinyl and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for 3-azetidinyl and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.

In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.

In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.

In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for CH, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.In other embodiments, R is worked as ₁for and X ₁during for N, V is phenyl amino, benzyl, phenyl, NHMe, NH ₂, NHEt, NHCOH, NHCOMe, NHCOEt, NHCOiPr, NHCOOMe, CONHMe or NHSO ₂me.

In mentioned embodiment, pyridine-2-base is n-methylamino hexamethylene-4-base is n-methyl piperidine-4-base is and N-methylamino ring fourth-3-base is

Exemplary compounds of the present invention comprises those of subclass 1a, 1b, 2a, 2b, 3a, 3b, 4a, 4b, 5a, 5b, 6a, 6b, 7a, 7b, 8a, 8b, 9a, 9b, 10a, 10b, 11a, 11b, 12a, 12b, 13a, 13b, 14a, 14b, 15a, 15b, 16a or 16b, wherein substituent R ₁, X ₁as described below with V.In some embodiments, R is worked as ₁for H and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for H and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for CH ₃and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for CH ₃and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for Et and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for Et and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for iPr and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for iPr and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for cyclobutyl and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for cyclobutyl and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for cyclopenta and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for cyclopenta and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for phenyl and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for phenyl and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for pyridine-2-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for pyridine-2-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for N-methylamino hexamethylene-4-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for N-methylamino hexamethylene-4-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for N-methyl piperidine-4-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for N-methyl piperidine-4-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In some embodiments, R is worked as ₁for N-methylamino ring fourth-3-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for N-methylamino ring fourth-3-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for the tert-butyl group and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for the tert-butyl group and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 1-cyano group-Ding-4-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 1-cyano group-Ding-4-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 1-cyano group-propyl-3-base and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 1-cyano group-propyl-3-base and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 3-azetidinyl and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for 3-azetidinyl and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.

In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.

In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for CH, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.In other embodiments, R is worked as ₁for and X ₁during for N, V is cyclopropanecarbonyl amino, cyclopropylamino, morpholinoethyl amino, Hydroxy-ethylamino or N-morpholino.

In mentioned embodiment, cyclopropanecarbonyl amino is cyclopropylamino is 2-morpholinoethyl amino is hydroxy-ethylamino is and N-morpholine on behalf of

The biological activity of table 1. some exemplary mTor inhibitor compounds of the present invention.

Table 1 illustrates the biological activity of some compounds of the present invention in mTOR and PI3K kinase assays.The scale used in table 1 is as follows: ++++be less than 100nM; +++ be less than 1.0 μMs; ++ be less than 10 μMs; And+be greater than 10 μMs.

In other embodiments, the invention provides following compound:

Any compound above can demonstrate at about 0.5nM and 25 μM (IC ₅₀) between mTOR or PI3K suppress measure in biological activity.

For the of the present invention other compound of mTor inhibitor illustrates in table 2.

The external IC of table 2. exemplary mTor inhibitor compound of the present invention ₅₀value.

In above table 2, +++ +++ the IC of+instruction 5nM or less ₅₀; +++ +++ the IC of instruction 10nM or less ₅₀; +++ ++ the IC of instruction 25nM or less ₅₀; +++ the IC of+instruction 50nm or less ₅₀; +++ the IC of instruction 100nM or less ₅₀; ++ the IC of instruction 500nM or less ₅₀; And+instruction is greater than the IC of 500nM ₅₀.

exemplary PI3K alpha inhibitor compound

In one aspect, the invention provides a kind of PI3K alpha inhibitor, it is formula I:

Or its pharmaceutically acceptable salt, wherein

W ^{5 '}for N;

W ^{6 '}for N or CR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{9 '}for alkyl or halogeno-group; And

Such as, the invention provides a kind of PI3K alpha inhibitor, it is formula I:

Or its pharmaceutically acceptable salt, wherein

X is O or S or N;

W ^{1 '}for N, NR ^{3 '}, CR ^{3 '}or C=O; W ^{2 '}for N, NR ^{4 '}, CR ^{4 '}or C=O; W ^{3 '}for N, NR ^{5 '}or CR ^{5 '}; W ^{4 '}for N, C=O or CR ^{6 '}, wherein no more than two atom N with to be no more than two C=O groups adjacent;

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

Or R ^{3 '}and R ^{4 '}form annulus together; And

R ^{5 '}, R ^{6 '}, R ^{7 '}and R ^{8 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen.

In some embodiments, formula II compound exists as tautomer, and described tautomer is contained in the present invention.

In some embodiments, formula II compound has following formula:

Such as, formula II compound is:

In some embodiments of formula II compound, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}; W ^{1 '}for N, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}; Or W ^{1 '}for CR ^{3 '}, W ^{2 '}for N, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.The formula of described embodiment illustrates following:

In some embodiments, X is O.In other embodiments, X is S.

In some embodiments, R ^{1 '}for hydrogen.In other embodiments, R ^{1 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.

In some embodiments, R ^{2 '}for hydrogen.In other embodiments, R ^{2 '}for the alkyl such as not replacing or replace (includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{2 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{2 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{2 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{2 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{2 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{2 '}for the compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{2 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{2 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{2 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{2 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{2 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{2 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the sulfonamido not replacing or replace or the C not replacing or replace ₁-C ₄sulfonamido.In other embodiments, R ^{2 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{2 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{2 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

In some embodiments of formula II compound, W ^{1 '}for CR ³.R ^{3 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{3 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{3 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{3 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{3 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{3 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides formula II compound, wherein R ^{3 '}for the heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{3 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{3 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{3 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{3 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{3 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{3 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{3 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{3 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

The R of formula II compound ^{3 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

The present invention also provides formula II compound, wherein works as R ^{3 '}for by alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group and NR ' R " (wherein R ' and R " forms annulus together with nitrogen) member of the group that forms time, so R ^{3 '}optionally by the one or more replacements in following substituent group: alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, heterocyclylalkoxy groups, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.Each in above substituent group can be replaced by one or more substituent group further, described substituent group is selected from by the following group formed: alkyl, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, oxo base, phosphate-based, urea groups, and carbonate group.

Such as, the invention provides compound, wherein work as R ^{3 '}during for alkyl, alkyl is by NR ' R, and " replace, wherein R ' " forms annulus with R together with nitrogen.The annulus of such formation can be and not replace or replace.Non-restrictive illustrative annulus includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl and thio-morpholinyl.In other examples of formula II compound, work as R ^{3 '}during for alkyl, alkyl is replaced by Heterocyclylalkyl, and described Heterocyclylalkyl comprises oxetanyl, azetidinyl, tetrahydrofuran base, pyrrole radicals, THP trtrahydropyranyl, piperidyl, morpholinyl and piperazinyl.All Heterocycloalkyl substituents listed above can be and not replace or replace.

In other examples of formula II compound, work as R ^{3 '}during for alkyl, alkyl is replaced by 5,6,7,8,9 or 10 yuan of monocycles or bicyclic heteroaryl, and described heteroaryl is what do not replace or replace.Bicyclic heteroaryl includes but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl includes but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In other embodiments of formula II compound, R ^{3 '}for-NHR ^{3 "},-N (CH ₃) R ^{3 "},-N (CH ₂cH ₃) R ^{3 "},-N (CH (CH ₃) ₂) R ^{3 "}or-OR ^{3 "}, wherein R ^{3 "}for the Heterocyclylalkyl (its limiting examples comprises 4-NH piperidin-1-yl, 4-methyl piperidine-1-base, 4-ethyl piperidine-1-base, 4-isopropyl-piperidin-1-yl and pyrrolidin-3-yl) not replacing or replace, the monocyclic aryl not replacing or replace, or the bicyclic heteroaryl not replacing or replace (include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl, Yi is Ji oxazolyl).In an example, R ^{3 '}for-O-aryl, i.e. phenoxy group.In another example, R ^{3 '}for-O-(4-methyl) piperidin-1-yl or-O-(4-isopropyl) piperidin-1-yl.

In some embodiments of formula II compound, R ^{3 '}for with in lower part:

In some embodiments of formula II compound, W ^{1 '}for NR ^{3 '}, wherein R ^{3 '}for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments of formula II compound, R ^{3 '}for the Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl) not replacing or replace, or the C not replacing or replace ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl).Alternatively, R ^{3 '}for the bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) not replacing or replace or the monocyclic aryl not replacing or replace.

In other embodiments, W ^{1 '}for C=O.

In some embodiments of formula II compound, W ^{2 '}for CR ^{4 '}.R ^{4 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{4 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{4 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{4 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{4 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{4 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

The present invention also provides wherein R ^{4 '}for the formula II compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{4 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{4 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{4 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{4 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{4 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{4 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In some embodiments, R ^{4 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{4 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{4 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

The R of formula II compound ^{4 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

The present invention also provides formula II compound, wherein works as R ^{4 '}for by alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group and NR ' R " (wherein R ' and R " forms annulus together with nitrogen) member of the group that forms time, so R ^{4 '}optionally by the one or more replacements in following substituent group: alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.Each in above substituent group can be replaced by one or more substituent group further, described substituent group is selected from by the following group formed: alkyl, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, oxo base, phosphate-based, urea groups, and carbonate group.

Such as, the invention provides and wherein work as R ^{4 '}during for alkyl, alkyl is by NR ' R, and " compound replaced, wherein R ' " forms annulus with R together with nitrogen.The annulus of such formation can be and not replace or replace.Non-restrictive illustrative annulus includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide and thio-morpholinyl.In other examples of formula II compound, work as R ^{4 '}during for alkyl, alkyl is replaced by Heterocyclylalkyl, and described Heterocyclylalkyl comprises oxetanyl, azetidinyl, tetrahydrofuran base, pyrrole radicals, THP trtrahydropyranyl, piperidyl, morpholinyl and piperazinyl.All Heterocycloalkyl substituents listed above can be and not replace or replace.

In other examples of formula II compound, work as R ^{4 '}during for alkyl, alkyl is replaced by 5,6,7,8,9 or 10 yuan of monocycles or bicyclic heteroaryl, and described heteroaryl is what do not replace or replace.Bicyclic heteroaryl includes but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl includes but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula II compound, W ^{2 '}for NR ^{4 '}, wherein R ^{4 '}for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments of formula II compound, R ^{4 '}for the Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl) not replacing or replace, or the C not replacing or replace ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl).Alternatively, R ^{4 '}for the bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) not replacing or replace or the monocyclic aryl not replacing or replace.

In some embodiments, R ^{3 '}and R ^{4 '}form annulus together.Described part can have such as 3 to 8 annular atomses.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace.In some embodiments, substituent group is C ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl) or C ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl); Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl), C ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl); Bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) or the monocyclic aryl not replacing or replace.Annulus can have one or more substituent group, and it can be identical or different.

In some embodiments, by R ^{3 '}and R ^{4 '}the annulus formed is replaced by least one following substituent group:

In some embodiments of formula II compound, W ^{3 '}for CR ^{5 '}.R ^{5 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{5 '}for H.In other embodiments, R ^{5 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{5 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{5 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{5 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{5 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula II compound, W ^{3 '}for N or NR ^{5 '}, wherein R ^{5 '}for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments of formula II compound, R ^{5 '}for the Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl) not replacing or replace, or the C not replacing or replace ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl).Alternatively, R ^{5 '}for the bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) not replacing or replace or the monocyclic aryl not replacing or replace.

In some embodiments of formula II compound, W ^{4 '}for CR ^{6 '}.R ^{6 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{6 '}for H.In other embodiments, R ^{6 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{6 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{6 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{6 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{6 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula II compound, W ^{4 '}for N or NR ^{6 '}, wherein R ^{6 '}for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments of formula II compound, R ^{6 '}for the Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl) not replacing or replace, or the C not replacing or replace ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl).Alternatively, R ^{6 '}for the bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) not replacing or replace or the monocyclic aryl not replacing or replace.

In other embodiments, W ^{4 '}for C=O.

In some embodiments of formula II compound, W ^{5 '}for N.In other embodiments of formula II compound, W ^{5 '}for CR ^{7 '}.R ^{7 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{7 '}for H.In other embodiments, R ^{7 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{7 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{7 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{7 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{7 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula II compound, W ^{6 '}for N.In other embodiments of formula II compound, W ^{6 '}for CR ^{8 '}.R ^{8 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{8 '}for H.In other embodiments, R ^{8 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{8 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{8 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{8 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{8 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments, formula II compound has following formula:

In other embodiments, formula II compound is:

Such as, formula II compound is:

In some embodiments, formula II compound is:

In yet another aspect, the invention provides sub-formula IIa compound.

In one embodiment, R ^{1 '}, R ^{3 '}, R ^{4 '}, R ^{5 '}and R ^{8 '}for hydrogen.In another embodiment, R ^{1 '}, R ^{3 '}, R ^{5 '}and R ^{8 '}for hydrogen and R ^{4 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, Heterocyclylalkyl oxygen base, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R ^{4 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{4 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{4 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{4 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{4 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{4 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In yet another aspect, the invention provides sub-formula IIa ' and IIb ' compound, wherein W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In one embodiment, R ^{1 '}, R ^{3 '}, R ^{4 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen.In another embodiment, R ^{1 '}, R ^{4 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen and R ^{3 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, Heterocyclylalkyl oxygen base, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R3 ' can be such as, and hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{3 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{3 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{3 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{3 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{3 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{3 '}for the formula II compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{3 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{3 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{3 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{3 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{3 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{3 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{3 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{3 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.In some embodiments, R ^{3 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

In yet another aspect, the invention provides sub-formula IIb compound:

In one embodiment, R ^{1 '}, R ^{4 '}, R ^{5 '}and R ^{8 '}for hydrogen.In another embodiment, R ^{1 '}, R ^{5 '}and R ^{8 '}for hydrogen and R ^{4 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, Heterocyclylalkyl oxygen base, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R4 ' can be such as, and hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{4 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{4 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{4 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{4 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{4 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In yet another aspect, the invention provides sub-formula IIc and IId compound, wherein W ^{1 '}for N, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.

In one embodiment, R ^{1 '}, R ^{4 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen.In another embodiment, R ^{1 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen and R ^{4 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, Heterocyclylalkyl oxygen base, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R ^{4 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{4 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{4 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{4 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{4 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{4 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{4 '}for the formula II compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{4 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{4 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{4 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{4 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{4 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{4 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{4 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{4 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.In some embodiments, R ^{4 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

In yet another aspect, the invention provides sub-formula IIe and IIf compound, wherein W ^{1 '}for CR ^{3 '}, W ^{2 '}for N, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.

In one embodiment, R ^{1 '}, R ^{3 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen.In another embodiment, R ^{1 '}, R ^{5 '}, R ^{7 '}and R ^{8 '}for hydrogen and R ^{3 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, Heterocyclylalkyl oxygen base, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R ^{3 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{3 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{3 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{3 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{3 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{3 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{3 '}for the formula II compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{3 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{3 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{3 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{3 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{3 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{3 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{3 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{3 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.In some embodiments, R ^{3 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

In some embodiments, substituent R ^{3 '}, R ^{4 '}, R ^{5 '}, R ^{6 '}or R ^{8 '}can be any substituent group shown in table 1:

The R of table 1. formula II compound ^{3 '}, R ^{4 '}, R ^{5 '}, R ^{6 '}, R ^{8 '}part, includes but not limited to following independently of one another:

In yet another aspect, the invention provides a kind of PI3K alpha inhibitor, it is formula III compound:

Or its pharmaceutically acceptable salt, wherein:

X is O or S or N;

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

Or R ^{3 '}and R ^{4 '}form annulus together; And

In some embodiments, formula III compound exists as tautomer, and described tautomer is contained in the present invention.

In some embodiments, PI3K alpha inhibitor is formula III compound, and it has formula:

In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for N, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for NR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for C, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for S, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for C, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for S, W ^{4 '}for C, W ^{5 " '}for N, and W ^{6 '}for N.

In other embodiments, formula III inhibitor is the compound according in following formula:

Wherein for each in above formula, the R variable of each correspondence comprises " symbol (prime) is divided at angle " (').

In some embodiments, X is O.In other embodiments, X is S.

In some embodiments, R ^{2 '}for hydrogen.In other embodiments, R ^{2 '}for the alkyl such as not replacing or replace (includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{2 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{2 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{2 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{2 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{2 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{2 '}for the compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{2 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{2 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula III compound, R ^{2 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{2 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{2 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{2 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{2 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{2 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{2 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

In some embodiments of formula III compound, W ^{1 '}for CR ³.R ^{3 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{3 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{3 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{3 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{3 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{3 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{3 '}for the formula III compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{3 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{3 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula III compound, R ^{3 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{3 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{3 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{3 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{3 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{3 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

The R of formula III compound ^{3 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

The present invention also provides formula III compound, wherein works as R ^{3 '}for by alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group and NR ' R " (wherein R ' and R " forms annulus together with nitrogen) member of the group that forms time, so R ^{3 '}optionally by the one or more replacements in following substituent group: alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, heterocyclylalkoxy groups, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.Each in above substituent group can be replaced by one or more substituent group further, described substituent group is selected from by the following group formed: alkyl, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, oxo base, phosphate-based, urea groups, and carbonate group.

Such as, the invention provides and wherein work as R ^{3 '}during for alkyl, alkyl is by NR ' R, and " compound replaced, wherein R ' " forms annulus with R together with nitrogen.The annulus of such formation can be and not replace or replace.Non-restrictive illustrative annulus includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl and thio-morpholinyl.In other examples of formula III compound, work as R ^{3 '}during for alkyl, alkyl is replaced by Heterocyclylalkyl, and described Heterocyclylalkyl comprises oxetanyl, azetidinyl, tetrahydrofuran base, pyrrole radicals, THP trtrahydropyranyl, piperidyl, morpholinyl and piperazinyl.All Heterocycloalkyl substituents listed above can be and not replace or replace.

In other examples of formula III compound, work as R ^{3 '}during for alkyl, alkyl is replaced by 5,6,7,8,9 or 10 yuan of monocycles or bicyclic heteroaryl, and described heteroaryl is what do not replace or replace.Bicyclic heteroaryl includes but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl includes but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In other embodiments of formula III compound, R ^{3 '}for-NHR ^{3 "},-N (CH ₃) R ^{3 "},-N (CH ₂cH ₃) R ^{3 "},-N (CH (CH ₃) ₂) R ^{3 "}or-OR ^{3 "}, wherein R ^{3 "}for the Heterocyclylalkyl (its limiting examples comprises 4-NH piperidin-1-yl, 4-methyl piperidine-1-base, 4-ethyl piperidine-1-base, 4-isopropyl-piperidin-1-yl and pyrrolidin-3-yl) not replacing or replace, the monocyclic aryl not replacing or replace, or the bicyclic heteroaryl not replacing or replace (include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl, Yi is Ji oxazolyl).In an example, R ^{3 '}for-O-aryl, i.e. phenoxy group.In another example, R ^{3 '}for-O-(4-methyl) piperidin-1-yl or-O-(4-isopropyl) piperidin-1-yl.

In some embodiments of formula III compound, R ^{3 '}for with in lower part:

In some embodiments of formula III compound, W ^{1 '}for NR ^{3 '}, wherein R ^{3 '}for hydrogen, the C that do not replace or replace ₁-C ₁₀alkyl (includes but not limited to-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl), or the C not replacing or replace ₃-C ₇cycloalkyl (including but not limited to cyclopropyl, cyclobutyl, cyclopenta and cyclohexyl).In other embodiments of formula III compound, R ^{3 '}for the Heterocyclylalkyl (including but not limited to oxetanyl, tetrahydrofuran base, pyrrolidinyl, THP trtrahydropyranyl, piperidyl and piperazinyl) not replacing or replace, or the C not replacing or replace ₂-C ₁₀assorted alkyl (including but not limited to methoxy ethoxy, methoxy and diethylamino ethyl).Alternatively, R ^{3 '}for the bicyclic heteroaryl (including but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl) not replacing or replace or the monocyclic aryl not replacing or replace.

In other embodiments, W ^{1 '}for N.In other embodiments, W ^{1 '}for S.

In some embodiments of formula III compound, W ^{2 '}for CR ^{4 '}.R ^{4 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R4 ' is that the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{4 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{4 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{4 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{4 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

The present invention also provides wherein R ^{4 '}for the formula III compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{4 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{4 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula III compound, R ^{4 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{4 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{4 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{4 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In some embodiments, R ^{4 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{4 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{4 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.

The R of formula III compound ^{4 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

The present invention also provides formula III compound, wherein works as R ^{4 '}for by alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, Heterocyclylalkyl oxygen base, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group and NR ' R " (wherein R ' and R " forms annulus together with nitrogen) member of the group that forms time, so R ^{4 '}optionally by the one or more replacements in following substituent group: alkyl, thiazolinyl, alkynyl, cycloalkyl, assorted alkyl, Heterocyclylalkyl, heterocyclylalkoxy groups, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, acyl group, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.Each in above substituent group can be replaced by one or more substituent group further, described substituent group is selected from by the following group formed: alkyl, alkoxyl, acylamino-, amino, sulfonamido, acyloxy, alkoxy carbonyl group, halogeno-group, cyano group, hydroxyl, nitro, oxo base, phosphate-based, urea groups, and carbonate group.

Such as, the invention provides and wherein work as R ^{4 '}during for alkyl, alkyl is by NR ' R, and " compound replaced, wherein R ' " forms annulus with R together with nitrogen.The annulus of such formation can be and not replace or replace.Non-restrictive illustrative annulus includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide and thio-morpholinyl.In other examples of formula III compound, work as R ^{4 '}during for alkyl, alkyl is replaced by Heterocyclylalkyl, and described Heterocyclylalkyl comprises oxetanyl, azetidinyl, tetrahydrofuran base, pyrrole radicals, THP trtrahydropyranyl, piperidyl, morpholinyl and piperazinyl.All Heterocycloalkyl substituents listed above can be and not replace or replace.

In other examples of formula III compound, work as R ^{4 '}during for alkyl, alkyl is replaced by 5,6,7,8,9 or 10 yuan of monocycles or bicyclic heteroaryl, and described heteroaryl is what do not replace or replace.Bicyclic heteroaryl includes but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl includes but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.In some embodiments of formula III compound, W ^{2 '}for N.

In some embodiments of formula III compound, W ^{3 '}for CR ^{5 '}.R ^{5 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{5 '}for H.In other embodiments, R ^{5 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{5 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{5 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{5 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{5 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.In some embodiments of formula III compound, W ^{3 '}for N.In other embodiments, W ^{3 '}for S.

In some embodiments of formula III compound, W ^{4 '}for C.In other embodiments, W ^{4 '}for N.

In some embodiments of formula III compound, W ^{5 '}for N.In other embodiments of formula III compound, W ^{5 '}for CR ^{7 '}.R ^{7 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{7 '}for H.In other embodiments, R ^{7 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{7 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{7 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{7 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{7 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula III compound, W ^{6 '}for N.In other embodiments of formula III compound, W ^{6 '}for CR ^{8 '}.R ^{8 '}can be such as, hydrogen, or the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In one embodiment, R ^{8 '}for H.In other embodiments, R ^{8 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{8 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{8 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{8 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{8 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.

In some embodiments of formula III compound, W ^{7 '}for C.In other embodiments, W ^{7 '}for N.

The present invention also provides formula III compound, its as by following subclass define:

Wherein for each in above formula, the R variable of each correspondence comprises angle and divides symbol (" prime) " (').

In some embodiments of subclass IIIa-IIIj compound, R ^{1 '}for hydrogen.In other embodiments of subclass IIIa-III1 compound, R ^{2 '}for the NH of NHCO (alkyl) ₂.In other embodiments of subclass IIIa-III1 compound, R ^{4 '}for hydrogen.In other embodiments of subclass IIIc-IIAnd if IIIi-III1 compound, R ^{7 '}for hydrogen.In other embodiments of subclass IIIa-IIIh and IIIk-III1 compound, R ^{8 '}for hydrogen.

In some embodiments of subclass IIIa to III1 compound, R ^{3 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.R ^{3 '}can be such as, hydrogen, the alkyl not replacing or replace (include but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl and heptyl).In other embodiments, R ^{3 '}for the thiazolinyl not replacing or replace (includes but not limited to the C not replacing or replace ₂-C ₅thiazolinyl, such as, vinyl, pi-allyl, 1-metering system-1-base, cyclobutenyl or pentenyl) or the alkynyl that do not replace or replace (include but not limited to the C not replacing or replace ₂-C ₅alkynyl, as acetenyl, propargyl, butynyl or pentynyl).Alternatively, R ^{3 '}for the aryl (including but not limited to monocycle or bicyclic aryl) not replacing or replace or the aryl alkyl not replacing or replace, (include but not limited to be connected to monocycle or the bicyclic aryl of alkyl, wherein alkyl includes but not limited to CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group).In some other embodiments, R ^{3 '}for the heteroaryl not replacing or replace, include but not limited to monocycle and bicyclic heteroaryl.Bicyclic heteroaryl R ^{3 '}include but not limited to pyrrole radicals, thienyl, furyl, pyridine radicals, pyranose, pyrimidine radicals, pyrazinyl, pyridazinyl, imidazole radicals, thiazolyl, pyrazolyl He oxazolyl.Bicyclic heteroaryl R ^{3 '}include but not limited to benzo thio-phenyl, benzofuranyl, indyl, quinolyl, isoquinolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, quinazolyl, azaindolyl, pyrazolopyrimidine base, purine radicals, pyrrolo-[1,2-b] pyridazinyl, pyrrolo-pyrimidine radicals, indazolyl, pyrazolyl pyridine radicals, imidazo [1,2-a] pyridine radicals and pyrrolo-[1,2-f] [1,2,4] triazine radical.The present invention also provides wherein R ^{3 '}for the formula II compound of heteroaryl alkyl not replacing or replace, described heteroaryl alkyl includes but not limited to the monocycle as above and the bicyclic heteroaryl that are connected to alkyl, and described alkyl includes but not limited to CH then ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, sec-butyl and amyl group.In some embodiments, R ^{3 '}for the cycloalkyl (including but not limited to cyclopropyl, cyclobutyl and cyclopenta) not replacing or replace or the assorted alkyl (limiting examples comprises ethoxyl methyl, methoxy and diethylamino methyl) not replacing or replace.In some other embodiments, R ^{3 '}for the Heterocyclylalkyl not replacing or replace, it includes but not limited to pyrrolidinyl, tetrahydrofuran base, piperidyl, THP trtrahydropyranyl, thiazolidinyl, imidazolidinyl, morpholinyl and piperazinyl.In other embodiments of formula II compound, R ^{3 '}for the alkoxyl not replacing or replace, include but not limited to C ₁-C ₄alkoxyl, as methoxyl group, ethyoxyl, propoxyl group or butoxy.R ^{3 '}also can be the Heterocyclylalkyl oxygen base not replacing or replace, include but not limited to 4-NH piperidin-1-yl-oxygen base, 4-methyl piperidine-1-base-oxygen base, 4-ethyl piperidine-1-base-oxygen base, 4-isopropyl-piperidin-1-yl-oxygen base and pyrrolidin-3-yl-oxygen base.In other embodiments, R ^{3 '}for the amino not replacing or replace, the amino wherein replaced includes but not limited to dimethylamino, diethylamino, diisopropylaminoethyl, N-methyl N-ethylamino and dibutylamino.In some embodiments, R ^{3 '}for the acyl group not replacing or replace, the acyloxy not replacing or replace, the C that do not replace or replace ₁-C ₄acyloxy, the alkoxy carbonyl group not replacing or replace, the acylamino-not replacing or replace or the sulfonamido not replacing or replace.In other embodiments, R ^{3 '}for halogeno-group, it is-I ,-F ,-Cl or-Br.In some embodiments, R ^{3 '}be selected from the group be made up of cyano group, hydroxyl, nitro, phosphate-based, urea groups and carbonate group.Also be contemplated that R ^{3 '}for-CH ₃,-CH ₂cH ₃, n-pro-pyl, isopropyl, normal-butyl, the tert-butyl group, sec-butyl, amyl group, hexyl, heptyl ,-OCH ₃,-OCH ₂cH ₃or-CF ₃.In some embodiments, R ^{3 '}also can be NR ' R ", wherein R ' and R " forms the annulus with 3 to 8 annular atomses together with nitrogen.The annulus of such formation also can comprise one or more hetero atom, and described hetero atom is selected from the group be made up of S, O and N.The annulus of such formation is what do not replace or replace, includes but not limited to morpholinyl, azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, isothiazole alkyl 1,2, dioxide, and thio-morpholinyl.Other non-restrictive illustrative annulus is as follows:

The present invention further provides a kind of PI3K alpha inhibitor, it is formula IV compound:

Or its pharmaceutically acceptable salt, wherein

W ^{1 '}for CR ^{3 '}, W ^{2 '}for by R ^{2 '}replace C-benzoxazolyl and W ^{3 '}for S;

W ^{1 '}for CR ^{3 '}, W ^{2 '}for by R ^{2 '}replace C-benzoxazolyl and W ^{3 '}for CR ^{5 '};

W ^{1 '}for N or CR ^{3 '}, W ^{2 '}for CR ^{4 '}and W ^{3 '}for by R ²the C-benzoxazolyl replaced;

W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}and W ^{3 '}for by R ²the C-benzoxazolyl replaced; Or

W ^{1 '}for N or NR ^{3 '}, W ^{2 '}for NR ^{4 '}and W ^{3 '}for by R ²the C-benzoxazolyl replaced;

X is N;

In some embodiments of formula IV compound, described compound is:

And wherein W ^{1 '}for CR ^{3 '}or NR ^{3 '}and W ^{2 '}for CR ^{4 '}.

In yet another aspect, the invention provides a kind of PI3K alpha inhibitor, it is formula V compound:

Or its pharmaceutically acceptable salt, wherein

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{a '}in one be N, and another is O, NR ^{10 '}or S;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{9 '}for alkyl or halogeno-group; And

In some embodiments of formula IV compound, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}; W ^{1 '}for N, W ^{2 '}for CR ^{4 '}, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}; Or W ^{1 '}for CR ^{3 '}, W ^{2 '}for N, W ^{3 '}for CR ^{5 '}, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In some embodiments of formula IV compound, W ^{b '}for N.In other embodiments, W ^{a '}for CR ^{9 '}and R ^{9 '}for alkyl.

The present invention also provides a kind of PI3K alpha inhibitor, and it is formula VI compound:

Or its pharmaceutically acceptable salt, wherein

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{5 '}, R ^{7 '}and R ^{8 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen;

R ^{9 '}for alkyl or halogeno-group; And

In some embodiments of formula VI compound, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for N, W ^{5 '}for N, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for NR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for C, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for S, W ^{2 '}for CR ^{4 '}, W ^{3 '}for N, W ^{4 '}for C, W ^{5 '}for CR ^{7 '}, and W ^{6 '}for CR ^{8 '}.In other embodiments, W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '}, W ^{3 '}for S, W ^{4 '}for C, W ^{5 '}for N, and W ^{6 '}for N.

In some embodiments of formula VI compound, W ^{b '}for N.In other embodiments, W ^{a '}for CR ^{9 '}and R ^{9 '}for alkyl.

The present invention further provides the PI3K alpha inhibitor for formula VI-A and VI-B compound:

Or its pharmaceutically acceptable salt, wherein

W ^{1 '}for CR ^{3 '};

And R ^{3 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen.

Also be provided as the PI3K alpha inhibitor of formula VI-C and VI-D compound herein:

Or its pharmaceutically acceptable salt, wherein

W ^{1 '}for CR ^{3 '};

W ^{5 '}for N or CR ^{7 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

R ^{3 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen;

R ^{7 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen;

R ^{9 '}for alkyl or halogeno-group; And

In some embodiments of formula V-C or V-D compound, W ^{b '}for N.In other embodiments, W ^{a '}for CR ^{9 '}and R ^{9 '}for alkyl.

The present invention also provides a kind of PI3K alpha inhibitor for formula VII compound:

Or its pharmaceutically acceptable salt, wherein

W ^{1 '}for CR ^{3 '}, W ^{2 '}for CR ^{4 '};

W ^{a '}for CH or N;

R ^{1 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen;

R ^{3 '}for alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen;

R ^{4 '}for hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R ", wherein R ' " forms annulus with R together with nitrogen;

Or R ^{3 '}and R ^{4 '}form annulus together; And

R ^{10 '}and R ^{11 '}be hydrogen, alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, alkoxyl, heterocyclylalkoxy groups, acylamino-, amino, acyl group, acyloxy, alkoxy carbonyl group, sulfonamido, halogeno-group, cyano group, hydroxyl, nitro, phosphate-based, urea groups, carbonate group or NR ' R independently ", wherein R ' " forms annulus with R together with nitrogen.

The present invention further provides a kind of PI3K alpha inhibitor, it is formula VIII compound:

Or its pharmaceutically acceptable salt, wherein

X ₁for CR ^{3 '}, NR ^{3 '}or S;

X ₂for CR ^{4 '}, NR ^{4 '}, CR ^{4 '} cR ^{5 '}or CR ^{4 '} nR ^{5 '};

X ₃and X ₄be C or N independently;

X ₅for CR ^{6 '}, NR ^{6 '}or S;

X ₄for CR ^{7 '}, NR ^{7 '}, CR ^{7 '} cR ^{8 '}or CR ^{7 '} nR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{9 '}for alkyl or halogeno-group; And

In some embodiments of formula VIII compound, W ^{b '}for N.In other embodiments, W ^{a '}for CR ^{9 '}and R ^{9 '}for alkyl.

In some embodiments, mTor inhibitor is as U.S. Patent number 7,651,687 or 7,585, and the compound described in 868; Or the compound as described in international patent application WO2007/079164, WO2007/061737, WO2007/106503, WO2007/134828 or WO2011/025889, described patent and patent application hereby by reference entirety be incorporated to.

In other embodiments, mTor inhibitor is NVP-BEZ235 (Novartis), BGT226 (Novartis), XL765 (Sanofi-Aventis, Exelixis), GDC0980 (Genentech), SF1126 (Semafore), PKI587 (Wyeth), PF04691502 (Pfizer) or GSK2126458 (GlaxoSmithKline).In other embodiments, mTor inhibitor is CC223 (Celgene), OSI027 (OSIPharmaceuticals), AZD8055 (AstraZeneca), AZD2014 (AstraZeneca) or Palomid529 (PalomaPharmaceuticals).

The structure of exemplary mTor inhibitor illustrates following:

reaction process-PI3K alpha inhibitor compound

In general, compound of the present invention is prepared by following reaction process:

Flow process A ':

Such as, compound of the present invention is prepared by following reaction process:

Flow process A ":

Flow process B ':

Compound of the present invention is by " synthesizing with the reaction process represented general in B ' at flow process A ', A.The coupling of through type A compound and formula B compound is synthesized, with production C compound.Coupling step is usually by using palladium catalyst to carry out catalysis, and described palladium catalyst includes but not limited to tetrakis triphenylphosphine palladium.Coupling is carried out usually under the existence of suitable alkali, and the limiting examples of described alkali is sodium carbonate.For the example Wei diox aqueous solution of suitable solvent reacted.

For flow process A ' or A " formula A compound there is formula A structure, wherein T ₁for halogeno-group, comprise bromine, chlorine, fluorine and iodine, and wherein all the other substituent groups define for the formula I of compound of the present invention and II.For boric acid with as the acid derivative shown in formula B, X is O or S, and benzoxazole or benzothiazole portion being attachable are in 4-, 5-, 6-or 7-position.

For formula B compound, G is hydrogen or R _g1, wherein R _g1for alkyl, thiazolinyl or aryl.Alternatively, B (OG) ₂form 5-or 6-membered cyclic moiety together.In some embodiments, formula B compound is the compound of the structure with formula E:

Wherein G is H or R _g1, R _g1for alkyl, thiazolinyl or aryl.Alternatively, B (OG) ₂form 5-or 6-membered cyclic moiety together, and R _g2for H, t-butyl carbamate base or aryl.

Flow process C ':

Flow process C ' shows for the synthesis of for the formula B ' compound of reaction process C ' or the optionally formula B " exemplary flow of compound.M is heterocyclic moiety, as benzoxazolyl or benzothiazolyl moiety, described by B.React to carry out this to react by making formula D compound and trialkyl borate or boronic acid derivatives, with production B ' compound.Trialkyl borate includes but not limited to tri-isopropylborate and boronic acid derivatives includes but not limited to two (pinacol) two boron.Reaction is carried out usually in the presence of base, and limiting examples is potassium acetate.Reaction can be carried out in the solvent of such as diox or oxolane.

Formula D compound for flow process C ' is wherein T ₂for halogeno-group or another leaving group and M compound as defined above.Formula B ' compound can be converted into formula B " compound further by with sour example hydrochloric acid process.

Some exemplary formula B compounds by flow process C ' synthesis include but not limited to following formula: compound:

Following reaction process illustrates the preparation of some compounds of the present invention.

Flow process D ': 5-(7-(3-(4-isopropyl piperazine-1-base) azetidine-1-base)-naphthyridine-2-base) benzo [synthesis of d] oxazole-2-amine

The synthesis of flow process E ': 2-amino-1-(4-(6-(2-amino benzo [d] oxazole-5-base)-naphthyridine-3-base) piperazine-1-base)-2-methyl-prop-1-ketone

[the synthesis of d] oxazole-2-amine of flow process F ': 5-(3-morpholino pyrido [2,3-b] pyrazine-6-base) benzo

[the synthesis of d] oxazole-2-amine of flow process G ': 5-(6-morpholino-naphthyridine-3-base) benzo

Reaction process H ':

Reaction process I ':

Reaction process J ':

Reaction process K ':

Reaction process L ':

Reaction process M ':

Reaction process N ':

Reaction process O ':

Reaction process P ':

Reaction process Q ':

Reaction process R ':

Reaction process S ':

Reaction process T ':

Reaction process U ':

Reaction process V ':

Reaction process W ':

Reaction process X ':

Reaction process Y ':

Reaction process Z ':

Reaction process AA ':

Reaction process AB ':

Reaction process AC ':

Reaction process AD ':

Reaction process AE ':

Reaction process AF ':

Reaction process AG ':

Reaction process AH ':

Reaction process AI ':

Reaction process AJ ':

Table 3 illustrates exemplary PI3K alpha inhibitor of the present invention.

The external IC of table 3. selected compounds of the present invention ₅₀data.Employ following symbol :+(being greater than 10 micromoles), ++ (being less than 10 micromoles), +++ (being less than 1 micromole) and ++++(being less than 100nM).

* start with compound 438, Proliferation data uses MDA-MB-361 cell line to obtain.

Table 4 illustrates exemplary PI3K alpha inhibitor in addition of the present invention.

The external IC of table 4. selected compounds of the present invention ₅₀data.Employ following symbol :+(being greater than 10 micromoles), ++ (being less than 10 micromoles), +++ (being less than 1 micromole) and ++++(being less than 100nM).

In some embodiments, the invention provides a kind of combined therapy, it comprises the mTor inhibitor that can be compound as herein provided and also PI3K alpha inhibitor as herein provided.In some embodiments, mTor inhibitor is formula I, formula I-A, formula I-B1, formula I-C, formula I-C1a compound, or the compound of table 1 or table 2, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.Such as, mTor inhibitor is formula I, wherein M1 is bicyclic heteroaryl system, comprise such as, benzothiazolyl, quinolyl, quinazolyl, benzoxazolyl and benzimidazolyl, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.In other embodiments, mTor inhibitor is formula I, wherein M1 has formula M1-A, M1-B, M1-C or M1-D, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.In other embodiments, mTor inhibitor has formula I-B1 and M1 has formula M1-F1, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.In other embodiments, mTor inhibitor has formula I-C, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.In other embodiments, mTor inhibitor has formula I-C1a, and PI3K alpha inhibitor is the compound of formula II, sub-formula IIa, sub-formula IIb, formula III, subclass IIIc, subclass IIId, formula VI-B, formula VI-C, formula VI-D or table 3.

In some embodiments, mTor inhibitor is formula I, formula I-A, formula I-B1, formula I-C, formula I-C1a compound, or the compound of table 1 or table 2, and PI3K alpha inhibitor is formula II or formula III compound.In other embodiments, mTor inhibitor is formula I, formula I-A, formula I-B1, formula I-C, formula I-C1a compound, or the compound of table 1 or table 2, and PI3K alpha inhibitor is sub-formula IIa or sub-formula IIb compound.In other embodiments, mTor inhibitor is formula I, formula I-A, formula I-B1, formula I-C, formula I-C1a compound, or the compound of table 1 or table 2, and PI3K alpha inhibitor is formula III, subclass IIIc or subclass IIId compound.In other embodiments, mTor inhibitor is formula I, formula I-A, formula I-B1, formula I-C, formula I-C1a compound, or the compound of table 1 or table 2, and PI3K alpha inhibitor is the compound of formula VI-B, VI-C, VI-D compound or table 3.

In some embodiments, mTor inhibitor is formula I, and wherein M1 has formula M1-A, M1-B, M1-C or M1-D, and PI3K alpha inhibitor is subclass IIIc or subclass IIId compound.In other embodiments, mTor inhibitor is formula I-C compound and PI3K alpha inhibitor is subclass IIIc or subclass IIId compound.

In some embodiments, mTor inhibitor is the compound of table 1 or 2 and PI3K alpha inhibitor is the compound of table 3.

Pharmaceutical composition and using

In one aspect, the invention provides a kind of combined therapy utilizing PI3K alpha inhibitor and mTor inhibitor.The therapeutic agent (comprising compound) being provided for combination treatment of the present invention can simultaneously or separate administration.This combined administration comprises such as, uses while being in two kinds of medicaments of same dosage form, is in while separating dosage form and uses and separate administration.Such as, multiple therapeutic agent can be prepared together with same dosage form and use simultaneously.Alternatively, can use multiple therapeutic agent, wherein two kinds of medicaments are present in preparation separately simultaneously.In a further alternative, inhibitor of the present invention can and then any above-mentioned pharmacy application, or vice versa.In separate administration scheme, inhibitor of the present invention and any above-mentioned medicament can be separated by a few minutes, or several hours, or several days use.Term " combined therapy " also comprises uses therapeutic agent as described herein further in combination with other biological reactive compound or composition and non-drug therapy (such as, perform the operation or radiotherapy).

Using by any method of compound delivery to action site being realized of compound of the present invention.By any accepted mode of using the medicament with similar effectiveness with single dose or multiple dose to use the inhibitor of the present invention of effective dose, these methods of application comprise rectally, buccal administration, intranasal and transdermal routes of administration, intra-arterial injection administration, intravenous administration, Intraperitoneal medication, parenteral, intramuscular administration, subcutaneous administration, oral administration, topical, as inhalant administration, or by the device that floods or be coated with (as support, such as, or insert the cylindrical polymeric of tremulous pulse) administration.Use each inhibitor successively or in fact simultaneously or therapeutic agent realizes by any suitable approach, described approach as indicated above and include but not limited to peroral route, intravenous route, intramuscular route and directly absorbed by mucosal tissue.Therapeutic agent is by identical approach or used by different approaches.Such as, the first therapeutic agent of selected combination is used by intravenous injection, and the other treatment agent of combination can oral administration.Or such as, all therapeutic agents can oral administration or all therapeutic agents all be used by intravenous injection.The order of administering therapeutic agent is not strict crucial.

In some embodiments, using of inhibitor of the present invention can realize with a dosage continuously or off and in whole therapeutic process.The method determining the most effectively to use means and dosage is known for those skilled in the art and is changed along with the compositions be used for the treatment of, therapeutic purposes, the target cell treated or tissue and the experimenter that treats.Single or multiple is used and can be performed according to the dosage level selected by treating physician and pattern.

Each inhibitor of using or the amount of compound will depend on treated mammal, the order of severity of disease or condition of illness, application rate, the disposal of compound and the judgement of prescriber.But effective dose is within the scope of about 0.001 to about 100mg/kg body weight/day, and preferably about 1 to about 35mg/kg/ day, use with single dose or the dosage that separates.For the people of 70kg, this will be equivalent to about 0.05 to 7g/ day, be preferably about 0.05 to about 2.5g/ day.In some cases, the dosage level lower than above-mentioned range lower limit may be enough, and may use the larger dosage not causing any adverse side effect in other cases, such as, run through use all day by described larger dosage being divided into several low dose.

In some embodiments, combined therapy of the present invention is used with the single dose comprising at least PI3K alpha inhibitor and mTor inhibitor.Typically, use described in and undertaken by injection (such as intravenous injection), to introduce medicament fast.But, other approach can be used as one sees fit.The single dose of combined therapy of the present invention also can be used for treating acute pathologies.

In some embodiments, combined therapy of the present invention is used with multiple dose.Administration can be about once a day, twice, three times, four times, five times, more than six times or six times.Administration can be about monthly, once every two weeks, once in a week or every other day once.In another embodiment, PI3K alpha inhibitor is used together with mTor inhibitor, about once a day to about every day 6 times.In another embodiment, PI3K alpha inhibitor and using of mTor inhibitor continue to be less than about 7 days.In another embodiment, use described in and continue to be greater than about 6 days, 10 days, 14 days, 28 days, two months, six months or 1 year.In some cases, as long as necessity, just realize continuing medication and keeping.

As long as necessity, use combined therapy of the present invention with regard to sustainable.In some embodiments, pharmacy application of the present invention is greater than 1,2,3,4,5,6,7,14 or 28 day.In some embodiments, pharmacy application of the present invention is less than 28,14,7,6,5,4,3,2 or 1 days.In some embodiments, medicament of the present invention is used chronically on the basis of carrying out, such as, be used for the treatment of chronic effect.

When treatment of the present invention combination as comprise one or more compounds and the compositions that is shorter than another kind of compound of a kind of half-life of compound is used time, can correspondingly unit of adjustment's dosage form.

In some embodiments, combined therapy of the present invention is tested, to evaluate the side effect profile (profile) of pharmacokinetic property and expection.The many measure of this object is become known in this area.Such as, oral availability is evaluated in drug development early stage period by carrying out Caco-2 permeability mensuration.In addition, the oral pharmacokinetics in people can carry out approximate obtaining from the result extrapolation of the mensuration mice, rat or monkey.In some embodiments, compound of the present invention demonstrates good oral availability within the scope of multiple organism species.

Other measure the effect of inspection inhibitor in liver function and metabolism.Cytochrome P450 (CYP) albumen is participate in the Major Enzymes that metabolism is applied to the medicine of mammalian organism.Therefore, the less desirable interaction of drug candidates can be the important sources of disadvantageous drug interaction.Generally speaking, wish medicine not with CYP isozyme as CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 interact.In some embodiments, for CYP1A2, CYP2C9, CYP2C19, CYP2D6 or CYP3A4, inhibitor of the present invention shows the IC50 being greater than 10 μMs.In addition, the hepatomicrosome regulating liver-QI cellular metabolism that end user's preparation carries out measures the vitro half-lives that can be used for estimating medicine candidate thing.

Cardiac toxicity is also the significant consideration of assessing compound.Such as, hERG is the gene of encoded K v11.1 potassium-channel, and described Kv11.1 potassium-channel is the protein of the current of polarization again related in the heart action potential in mediate cardiac.Suppress hERG gene outcome can cause the increase of sudden death risk by drug candidates and be therefore undesirable characteristic.In some embodiments, when using under suitable concentration, inhibitor of the present invention shows the hERG suppression being less than 10%.

Ames by Ames test (Amestest) or improvement is tested, and uses the mutagenicity of such as liver S9 system measurement compound.In some embodiments, compound demonstrates negative active in described test.

Also other undesirable interactions of inhibitor are determined by receptor group screening (receptorpanelscreen).In some embodiments, for combined therapy of the present invention, can't detect significant interaction.Theme pharmaceutical composition can prepare the combination of the therapeutic agent of the present invention providing treatment effective dose, or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant.When hope, described pharmaceutical composition contains its pharmaceutically acceptable salt and/or co-ordination complex, and one or more pharmaceutically acceptable excipient, carrier (comprising inert solid diluent and filler), diluent (comprising aseptic aqueous solution and various organic solvent), penetration enhancer, solubilizing agent and adjuvant.

Theme pharmaceutical composition can be used as the combined administration of PI3K alpha inhibitor and mTor inhibitor, or with the further combined administration of one or more other medicaments, its also the usual form with pharmaceutical composition use.When hope, subject combination and one or more other medicaments can be mixed into preparation and maybe two kinds of components can be mixed with independent preparation to combinationally use respectively or simultaneously.

In some embodiments, the concentration of one or more compounds provided in pharmaceutical composition of the present invention is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of the present invention is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%19%, 18.75%, 18.50%, 18.25%18%, 17.75%, 17.50%, 17.25%17%, 16.75%, 16.50%, 16.25%16%, 15.75%, 15.50%, 15.25%15%, 14.75%, 14.50%, 14.25%14%, 13.75%, 13.50%, 13.25%13%, 12.75%, 12.50%, 12.25%12%, 11.75%, 11.50%, 11.25%11%, 10.75%, 10.50%, 10.25%10%, 9.75%, 9.50%, 9.25%9%, 8.75%, 8.50%, 8.25%8%, 7.75%, 7.50%, 7.25%7%, 6.75%, 6.50%, 6.25%6%, 5.75%, 5.50%, 5.25%5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002% or 0.0001%w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of the present invention is in following scope: about 0.0001% to about 50%, about 0.001% to about 40%, about 0.01% to about 30%, about 0.02% to about 29%, about 0.03% to about 28%, about 0.04% to about 27%, about 0.05% to about 26%, about 0.06% to about 25%, about 0.07% to about 24%, about 0.08% to about 23%, about 0.09% to about 22%, about 0.1% to about 21%, about 0.2% to about 20%, about 0.3% to about 19%, about 0.4% to about 18%, about 0.5% to about 17%, about 0.6% to about 16%, about 0.7% to about 15%, about 0.8% to about 14%, about 0.9% to about 12%, about 1% to about 10%w/w, w/v or v/v.

In some embodiments, the concentration of one or more compounds of the present invention is in following scope: about 0.001% to about 10%, about 0.01% to about 5%, about 0.02% to about 4.5%, about 0.03% to about 4%, about 0.04% to about 3.5%, about 0.05% to about 3%, about 0.06% to about 2.5%, about 0.07% to about 2%, about 0.08% to about 1.5%, about 0.09% to about 1%, about 0.1% to about 0.9%w/w, w/v drum v/v.

In some embodiments, the amount of one or more compounds of the present invention is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.1g, 0.09g, 0.08g, 0.07g, 0.06g, 0.05g, 0.04g, 0.03g, 0.02g, 0.01g, 0.009g, 0.008g, 0.007g, 0.006g, 0.005g, 0.004g, 0.003g, 0.002g, 0.001g, 0.0009g, 0.0008g, 0.0007g, 0.0006g, 0.0005g, 0.0004g, 0.0003g, 0.0002g or 0.0001g.

In some embodiments, the amount of one or more compounds of the present invention is greater than 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.015g, 0.02g, 0.025g, 0.03g, 0.035g, 0.04g, 0.045g, 0.05g, 0.055g, 0.06g, 0.065g, 0.07g, 0.075g, 0.08g, 0.085g, 0.09g, 0.095g, 0.1g, 0.15g, 0.2g, 0.25g, 0.3g, 0.35g, 0.4g, 0.45g, 0.5g, 0.55g, 0.6g, 0.65g, 0.7g, 0.75g, 0.8g, 0.85g, 0.9g, 0.95g, 1g, 1.5g, 2g, 2.5, 3g, 3.5, 4g, 4.5g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g or 10g.

In some embodiments, the amount of one or more compounds of the present invention is in following scope: 0.0001-10g, 0.0005-9g, 0.001-8g, 0.005-7g, 0.01-6g, 0.05-5g, 0.1-4g, 0.5-4g or 1-3g.

Combined therapy according to the present invention is effective in wide dosage range.Such as, in the treatment of adult, every day 0.01 to 1000mg, 0.5 to 100mg, 1 to 50mg dosage, and every day 5 to 40mg dosage be the example of operable dosage.Exemplary dose is 10 to 30mg every day.Exact dose is by the form depending on route of administration, administered compound adopts, experimenter to be treated, the body weight of experimenter to be treated and the preference of attending doctor and experience.

Pharmaceutical composition of the present invention usually containing active component (such as, inhibitor of the present invention or its pharmaceutically acceptable salt and/or co-ordination complex, and one or more pharmaceutically acceptable excipient, carrier (including but not limited to inert solid diluent and filler), diluent, aseptic aqueous solution and various organic solvent, penetration enhancer, solubilizing agent and adjuvant.

Described below is non-restrictive illustrative pharmaceutical composition and preparation method thereof.

for Orally administered pharmaceutical composition.in some embodiments, the invention provides a kind of for Orally administered pharmaceutical composition, it contains at least one therapeutic agent and is suitable for Orally administered pharmaceutical excipient.

In some embodiments, the invention provides a kind of for Orally administered solid composite medicament, it contains: (i) is the compound of PI3K alpha inhibitor; (ii) be the second compound of mTor inhibitor; And (iii) is suitable for Orally administered pharmaceutical excipient.In some embodiments, compositions also contains: (iv) the 3rd medicament or even the 4th medicament.In some embodiments, each compound or medicament exist to treat effective dose.In other embodiments, one or more compounds or medicament exist with sub-therapeutic dose, and compound or medicament act on synergistically, to provide treatment drug composition effective.

In some embodiments, the invention provides a kind of pharmaceutical composition, it comprises the combination of PI3-kinases alpha inhibitor and mTOR inhibitors.PI3-kinases alpha inhibitor and mTOR inhibitors can be used as single peroral dosage form packaging.In other embodiments, PI3-kinases alpha inhibitor and mTOR inhibitors can be used as separately dosage form such as tablet and pack.

In one embodiment, the invention provides a kind of peroral dosage form, it comprises the inhibitor of the present invention of 100mg to 1.5g.Peroral dosage form can be tablet, in liquid form, with namely release or slow release pattern preparation.

In some embodiments, described pharmaceutical composition can be the composition of liquid medicine being suitable for orally using.Be suitable for Orally administered pharmaceutical composition of the present invention can be used as discrete dosage form (as capsule, cachet or tablet) or liquid agent or aerosol spray (separately containing scheduled volume in powder or the active component of particle form) or solution in aqueous or non-aqueous liquid or suspensoid, oil in water emulsion or water-in-oil liquid Emulsion exist, comprise liquid dosage form (such as, suspensoid or serosity) and oral dosage form (such as, tablet or bulk powder).As used herein, term " tablet " is often referred to tablet, caplet, capsule (comprising Perle) and lozenge.Peroral dosage form can be formulated as the tablet of individuality to be treated or patient's orally ingestible, pill, dragee, capsule, Emulsion, lipotropy and hydrophilic suspension agent, liquid, gel, syrup, serosity, suspensoid etc.Described dosage form is prepared by any practice of pharmacy, but all methods include and make active component and carrier-bound step, and it forms the composition of one or more necessity.In one embodiment, inhibitor packages of the present invention is contained in capsule.Be suitable for Orally administered capsule and comprise the fit capsule that obtained by gelatin and by gelatin and the obtained soft seal capsule of plasticiser (as glycerol or Sorbitol).Described fit capsule can containing the active component mixed as Talcum or magnesium stearate and optional stabilizer as starch and/or lubricant as lactose, binding agent with filler.Optionally; for the present composition that orally uses by following acquisition: inhibitor is mixed with solid excipient; optionally grind gained mixture; and (if necessary) after adding suitable auxiliary agent, processing granular mixture is to obtain tablet or dragee core.Suitable excipient is in particular filler as sugar, comprises lactose, sucrose, mannitol or Sorbitol; Cellulose preparation, as, such as, corn starch, wheaten starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl cellulose, and/or polyvinyl pyrrolidone (PVP).Generally speaking, compositions is by evenly and closely the solid carrier of active component and liquid-carrier or segmentation or both being mixed, and then, where necessary, is that desired appearance is formed by product shaping.Such as, prepare tablet by suppressing or being molded, optionally use one or more auxiliary elements.Compressed tablets is in the active component (optionally with mixed with excipients, such as, but not limited to binding agent, lubricant, inert diluent and/or surfactant or dispersant) of free-flowing form as powder or granule by compacting in suitable machine to be prepared.Molded tablet is prepared by being molded the mixture of the powder compound with inert liquid diluent moistening in suitable machine.

The anhydrous pharmaceutical composition and dosage form that comprise active component are contained in the present invention further, this is because water can promote the degraded of some compounds.Such as, water (such as 5%) can be added as the long-term method of preserving of simulation in pharmaceutical field, to measure feature, as the stability that shelf life or preparation are passed in time.Anhydrous pharmaceutical composition of the present invention and dosage form can use anhydrous or containing low-moisture composition and low moisture or low-moisture conditions preparation.If expected at manufacture, packaging and/or a large amount of contact wetting of lay up period and/or dampness, so can prepare lactinated pharmaceutical composition of the present invention and dosage form anhydrously.Can prepare and store anhydrous pharmaceutical composition, to make its anhydrous nature of maintenance.Therefore, the known material preventing from being exposed to water can be used to pack anhydrous composition, can be contained in suitable prescription test kit (formularykit) to make it.Paper tinsel, plastics etc. that the example of suitable packaging includes but not limited to seal, unit-dose container, blister package (blisterpack) and band pack (strippack).

Conveniently active component and pharmaceutical carrier can be blended in closely in mixture by pharmaceutical compounding techniques.Described carrier can take various ways, and this depends on the dosage form wishing to use.In the preparation of the compositions for peroral dosage form, any conventional medicinal medium all can be used as carrier, with regard to oral liquid (as suspensoid, solution and elixir) or aerosol, have such as water, glycol, oil, alcohol, flavoring agent, antiseptic, coloring agent etc.; Or in some embodiments not using lactose, just like the carrier of starch, saccharide, microcrystalline Cellulose, diluent, granulating agent, lubricant, binding agent and disintegrating agent with regard to oral solid formulation.Such as, for solid orally ingestible, suitable carrier comprises powder, capsule and tablet.If wished, by the moisture of standard or not aqueous techniques to tablet coating.

The binding agent being applicable to pharmaceutical composition and dosage form includes but not limited to corn starch, potato starch or other starch, gelatin, natural and synthetic colloidal substance (as arabic gum), sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its derivates (such as, ethyl cellulose, cellulose acetate, carboxymethylcellulose calcium, sodium carboxymethyl cellulose), polyvinylpyrrolidone, methylcellulose, pre-gelatinized starch, hydroxypropyl emthylcellulose, microcrystalline Cellulose and composition thereof.

The example being applicable to the filler of pharmaceutical composition disclosed herein and dosage form includes but not limited to Talcum, calcium carbonate (such as, granule or powder), microcrystalline Cellulose, Powderd cellulose, dextrates (dextrate), Kaolin, mannitol, silicic acid, Sorbitol, starch, pre-gelatinized starch and composition thereof.

Disintegrating agent can be used in the compositions of the present invention to provide the tablet of the disintegrate when being exposed to aqueous environment.Too much disintegrating agent may produce can the tablet of disintegrate in bottle.May be not enough to very little disintegrate occurs and speed and the degree that therefore may change release of active ingredients from described dosage form.Therefore, enough disintegrating agents (neither not many again very little, to avoid the release adversely changing active component) can be used to form the dosage form of compound disclosed herein.The amount of disintegrating agent used can change based on preparation type and method of application, and those skilled in the art can easily distinguish.The disintegrating agent of about 0.5 to about 15 percentage by weight can be used in pharmaceutical composition, or the disintegrating agent of about 1 to about 5 percentage by weight.The disintegrating agent that can be used to be formed pharmaceutical composition of the present invention and dosage form includes but not limited to aga agar, alginic acid, calcium carbonate, microcrystalline Cellulose, cross-linking sodium carboxymethyl cellulose, crospovidone, polacrilin potassium (polacrilinpotassium), primojel, Rhizoma Solani tuber osi or tapioca, other starch, pre-gelatinized starch, other starch, clay, other Algins, other celluloses, natural gum or its mixture.

The lubricant that can be used to be formed pharmaceutical composition of the present invention and dosage form includes but not limited to calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, Sorbitol, mannitol, Polyethylene Glycol, other glycol, stearic acid, sodium lauryl sulphate, Talcum, hydrogenated vegetable oil (such as, Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, sunflower oil, Oleum sesami, olive oil, Semen Maydis oil and Oleum Glycines), zinc stearate, ethyl oleate, ethyl laurate (ethylaureate), agar or its mixture.Other lubricant comprises coagulated aerosol or its mixture of such as fine silica gel (syloidsilicagel), synthetic silica.Optionally add lubricant with the amount being less than about 1 percentage by weight of pharmaceutical composition.

Lubricant also can be combined with tissue barrier, and described tissue barrier includes but not limited to polysaccharide, poly polysaccharide (polyglycan), seprafilm, interceed and hyaluronic acid.

When wishing Orally administered aqueous suspensions and/or elixir, primary activity composition wherein and various sweetener or flavoring agent, coloring agent or dyestuff and (if wanting) emulsifying agent and/or suspending agent and described diluent (as water, ethanol, propylene glycol, glycerol and various combination thereof) can be mixed.

Tablet can be not coating, or by known technology coating, to delay disintegrate in the gastrointestinal tract and absorption and to provide the continuous action of long period thus.Such as, time delay material can be used, as glyceryl monostearate or distearin.Preparation for orally using also can be used as hard gelatin capsule to be existed, wherein active component and inert solid diluent are (such as, calcium carbonate, calcium phosphate or Kaolin) mixing, or exist as Perle, wherein active component mixes with water or oily medium (such as, Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil).

The surfactant that can be used to be formed pharmaceutical composition of the present invention and dosage form includes but not limited to hydrophilic surfactant active, lipophilic surfactant and composition thereof.That is, the mixture of hydrophilic surfactant active can be used, the mixture of lipophilic surfactant can be used maybe can to use the mixture of at least one hydrophilic surfactant active and at least one lipophilic surfactant.

Suitable hydrophilic surfactant active can have the HLB value of at least 10 usually, and suitable lipophilic surfactant can have or be less than the HLB value of about 10 usually.Hydrophile-lipophile balance value (" HLB " value) is used to characterize the relative hydropathy of non-ionic amphiphilic compound and hydrophobic empirical parameter.Having compared with the surfactant of low hlb is more lipophilic or hydrophobic, and in oil, have larger dissolubility, and to have compared with the surfactant of high hlb be more hydrophilic, and has larger dissolubility in aqueous.It has been generally acknowledged that hydrophilic surfactant active is that those have compound and anion, cation or the zwitterionic compound (HLB scale is usually inapplicable to these compounds) of the HLB value being greater than about 10.Similarly, lipotropy (i.e. hydrophobicity) surfactant is the compound with the HLB value being equal to or less than about 10.But the HLB value of surfactant is only the rough guide of preparation being generally used for realizing industry, pharmacy and cosmetic emulsions.

Hydrophilic surfactant active can be ion or non-ionic.Suitable ionic surfactant includes but not limited to alkylammonium salt; Fusidate; The derivative of fatty acid of aminoacid, oligopeptide and polypeptide; The glyceride ester derivatives of aminoacid, oligopeptide and polypeptide; Lecithin and hydrolecithin; LYSOLECITHIN SUNLECITHIN A and hydrogenated lyso lecithin; Phospholipid and derivant thereof; Lysophosphatide and derivant thereof; Carnitine fatty acid ester salt; Alkyl sulfate; Soap; Docusate sodium (sodiumdocusate); Acyl lactylates (acylactylates); The monoacylated tartrate of monoglyceride and two glyceride and diacetylation tartrate; The monoglyceride of succinylation and two glyceride; The citrate of monoglyceride and two glyceride; With and composition thereof.

Within above-mentioned group, ionic surfactant comprises, such as: lecithin, LYSOLECITHIN SUNLECITHIN A, phospholipid, lysophosphatide and derivant thereof; Carnitine fatty acid ester salt; Alkyl sulfate; Soap; Docusate sodium; Acyl lactylates; The monoacylated tartrate of monoglyceride and two glyceride and diacetylation tartrate; The monoglyceride of succinylation and two glyceride; The citrate of monoglyceride and two glyceride; With and composition thereof.

Ionic surfactant can be the ionized form of following compound: lecithin, LYSOLECITHIN SUNLECITHIN A, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, phosphatidyl glycerol, phosphatidic acid, Phosphatidylserine, LYSO-PHOSPHATIDYLCHOLINE LYSOPC, lysophosphatidyl ethanolamine, lysophosphatidyl glycerol, lysophosphatidic acid, hemolytic phosphatidylserine, PEG-PHOSPHATIDYL ETHANOLAMINE, PVP-PHOSPHATIDYL ETHANOLAMINE, fatty acid lactoyl ester, stearoyl-2-lactate, stearoyl lactylates, succinated monoglyceride, list/diacetylation the tartrate of list/bis-glyceride, the citrate of list/bis-glyceride, CHOLYLSARCOSINE, caproate, caprylate, caprate, laruate, myristate, palmitate, oleate, ricinate, linoleate, linolenate, stearate, lauryl sulfate, tetradecyl sulfate (teracecylsulfate), many storehouses fat salt, C12, palmitoyl carnitine, C14 and salt with and composition thereof.

Hydrophilic non-ionic surfactant can include but not limited to alkyl androstanediol; Alkylmaltosides; Alkyl glucosides sulfur glycosides; Polyethylene glycol glycerol dodecyl ester (laurylmacrogolglyceride); Polyoxyethylene alkyl ether (as polyethylene glycol alkyl ether); Polyoxyethylene alkylphenol (as polyalkylene glycol alkyl phenol); Polyoxyethylene alkylphenol fatty acid ester (as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diester); Polyethylene glycol glycerol fatty acid ester; Polyglyceryl fatty acid ester; Polyoxyethylene sorbitan fatty acid esters (as Polyethylene Glycol sorbitan fatty acid esters); The hydrophilic product of transesterification reaction of polyhydric alcohol and at least one member of the group to be made up of glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterin; Polyoxyethylene sterin and derivant thereof and analog; Polyoxyethylated vitamin and derivant thereof; Polyox-yethylene-polyoxypropylene block copolymer; With and composition thereof; Polyethylene Glycol sorbitan fatty acid esters and polyhydric alcohol and the hydrophilic product of transesterification reaction of at least one member of group be made up of triglyceride, vegetable oil and hydrogenated vegetable oil.Polyhydric alcohol can be glycerol, ethylene glycol, Polyethylene Glycol, Sorbitol, propylene glycol, tetramethylolmethane or saccharide.

Other hydrophilic non-ionic surfactants include but not limited to PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, , PEG-32 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate, PEG-100 stearate, PEG-20 dilaurate, PEG-25 glycerol trioleate, PEG-32 dioleate, PEG-20 glycerol monolaurate, PEG-30 glycerol monolaurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 glycerol monolaurate, PEG-40 glycerol monolaurate, PEG-40 palm-kernel oil, PEG-50 castor oil hydrogenated, PEG-40 Oleum Ricini, Cremophor ELP, PEG-60 Oleum Ricini, Cremophor RH40, PEG-60 castor oil hydrogenated, PEG-60 Semen Maydis oil, PEG-6 capric acid/caprylin, PEG-8 capric acid/caprylin, Natrulon H-10 laurate, PEG-30 cholesterol, PEG-25 plant sterol, PEG-30 soyasterol, PEG-20 trioleate, PEG-40 sorbitanoleate, PEG-80 sorbitan laurate esters, TWEEN-20, polysorbate 80, POE-9 lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, Natrulon H-10 oleate, tween (Tween) 40, tween (Tween) 60, sucrose monostearate, sucrose monolaurate, sucrose palmitic acid ester, PEG10-100 nonylphenol series (nonylphenolseries), PEG15-100 octyl phenol series (octylphenolseries) and poloxamer (poloxamers).

Suitable lipophilic surfactant comprises (mode by means of only citing): fatty alcohol; Fatty acid glyceride; Acetylated glycerol fatty acid esters; Lower alcohol fatty acid esters; Methyl glycol fatty acid ester; Sorbitan fatty acid esters; Polyethylene Glycol sorbitan fatty acid esters; Sterol and sterol derivative; Polyoxyethylated sterol and sterol derivative; Polyethylene glycol alkyl ether; Sugar ester; Sugar ether; The lactic acid derivative of monoglyceride and two glyceride; The hydrophobicity product of transesterification reaction of polyhydric alcohol and at least one member of the group to be made up of glyceride, vegetable oil, hydrogenated vegetable oil, fatty acid and sterol; Fat soluble vitamin/vitamin derivative; With and composition thereof.Within this group, preferred lipophilic surfactant comprises fatty acid glyceride, methyl glycol fatty acid ester and composition thereof, or polyhydric alcohol and the hydrophobicity product of transesterification reaction of at least one member of group that is made up of vegetable oil, hydrogenated vegetable oil and triglyceride.

In one embodiment, described compositions can comprise solubilizing agent, to guarantee good solubilising and/or the dissolving of the compounds of this invention and to make the precipitation of the compounds of this invention minimize.This compositions for parenteral use (such as composition for injection) is particular importance.Also solubilizing agent can be added to improve the dissolubility of hydrophilic medicament and/or other components (as surfactant) or to make compositions remain stable or uniform solution or dispersion.

The example of suitable solubilizing agent includes but not limited to following: alcohol and polyhydric alcohol, as ethanol, isopropyl alcohol, butanols, benzylalcohol, ethylene glycol, propylene glycol, butanediol and isomer, glycerol, tetramethylolmethane, Sorbitol, mannitol, TC (transcutol), dimethyl isosorbite, Polyethylene Glycol, polypropylene glycol, polyvinyl alcohol, hydroxypropyl emthylcellulose and other cellulose derivatives, cyclodextrin and cyclodextrin derivative; There is the polyglycol ether of the mean molecule quantity of about 200 to about 6000, as tetrahydrofurfuryl alcohol PEG ether (Tetrahydrofurfuryl polyethylene glycol ether (glycofurol)) or methoxyl group PEG; Amide and other nitrogen-containing compounds, as 2-Pyrrolidone, 2-piperidones, epsilon-caprolactams, N-alkyl pyrrolidone, N-hydroxyalkylpyrrolidone, N-Alkylpiperidine ketone, N-alkyl caprolactam, dimethyl acetylamide and polyvinylpyrrolidone; Ester, as ethyl propionate, tributyl citrate, acetyl triethyl citrate, tributyl 2-acetylcitrate, triethyl citrate, ethyl oleate, ethyl caprilate, ethyl n-butyrate., glycerol triacetate, single propylene glycol acetate, propylene glycol diacetate, 6-caprolactone and isomer, δ-valerolactone and isomer, beta-butyrolactone and isomer thereof; And other solubilizing agents known in the art, as dimethyl acetylamide, dimethyl isosorbite, N-Methyl pyrrolidone, monooctanoin, TC and water.

Also the mixture of solubilizing agent can be used.Example includes but not limited to glycerol triacetate, triethyl citrate, ethyl oleate, ethyl caprilate, dimethyl acetylamide, N-Methyl pyrrolidone, NHP, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxypropyl cyclodextrin, ethanol, Macrogol 200-100, Tetrahydrofurfuryl polyethylene glycol ether, TC, propylene glycol and dimethyl isosorbite.Particularly preferred solubilizing agent comprises Sorbitol, glycerol, glycerol triacetate, ethanol, PEG-400, Tetrahydrofurfuryl polyethylene glycol ether and propylene glycol.

The amount of the solubilizing agent that can comprise is not limited especially.The amount of given solubilizing agent can be defined as biologically acceptable amount, and it easily can be determined by those skilled in the art.In some cases, the amount comprised considerably beyond the biologically solubilizing agent of acceptable amount can be favourable, such as, maximize to make drug level, wherein before providing compositions to experimenter, use routine techniques, as the solubilizing agent of distilling or evaporative removal is excessive.Therefore, if existed, the weight ratio of solubilizing agent can be based on medicine and other excipient gross weights 10 % by weight, 25 % by weight, 50 % by weight, 100 % by weight or at most about 200 % by weight.If wanted, the solubilizing agent of seldom amount also can be used, as 5%, 2%, 1% or even less.Typically, solubilizing agent can about 1 % by weight to about 100 % by weight amount exist, more typically with about 5 % by weight to about 25 % by weight amount exist.

Described compositions can comprise one or more pharmaceutically acceptable additive and excipient further.Described additive and excipient include but not limited to antitack agent (detackifiers), defoamer, buffer agent, polymer, antioxidant, antiseptic, chelating agen, viscosity modifier, tension regulator (tonicifier), flavoring agent, coloring agent, flavour enhancer, opacifier, suspending agent, binding agent, filler, plasticizer, lubricant with and composition thereof.

In addition, acid or alkali can be incorporated in described compositions, so that processing, enhanced stability or for other reasons.The example of pharmaceutically acceptable alkali comprises aminoacid, amino-acid ester, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium bicarbonate, aluminium hydroxide, calcium carbonate, magnesium hydroxide, aluminium-magnesium silicate, synthetic aluminium silicate, synthesis two hydroconite (hydrocalcite), magaldrate, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, three (methylol) aminomethane (TRIS) etc.Alkali for the salt of pharmaceutically acceptable acid is also suitable, described acid as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, aminoacid, ascorbic acid, benzoic acid, boric acid, butanoic acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid (hydroquinosulfonicacid), arabo-ascorbic acid, lactic acid, maleic acid, oxalic acid, to bromo-benzene sulfonic acid, propanoic acid, p-methyl benzenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, TGA, toluenesulfonic acid, uric acid etc.Also the salt of polyprotic acid can be used, as sodium phosphate, sodium hydrogen phosphate and sodium dihydrogen phosphate.When described alkali is salt, cation can be any routine and pharmaceutically acceptable cation, as ammonium, alkali metal, alkaline-earth metal etc.Example can include but not limited to sodium, potassium, lithium, magnesium, calcium and ammonium.

Suitable acid is the acid of pharmaceutically acceptable organic or inorganic.The example of suitable mineral acid comprises hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, nitric acid, boric acid, phosphoric acid etc.Suitable organic acid example comprise acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, aminoacid, ascorbic acid, benzoic acid, boric acid, butanoic acid, carbonic acid, citric acid, fatty acid, formic acid, fumaric acid, gluconic acid, hydroquinone sulfonic acid, arabo-ascorbic acid, lactic acid, maleic acid, methanesulfonic acid, oxalic acid, to bromo-benzene sulfonic acid, propanoic acid, p-methyl benzenesulfonic acid, salicylic acid, stearic acid, succinic acid, tannic acid, tartaric acid, TGA, toluenesulfonic acid, uric acid etc.

medicinal composition for injections.In some embodiments, the invention provides a kind of medicinal composition for injections containing at least one the compounds of this invention and be suitable for the pharmaceutical excipient injected.Such as, a kind of medicinal composition for injections comprising at least one PI3K alpha inhibitor and mTor inhibitor is provided.Also providing package containing PI3K alpha inhibitor pharmaceutical composition and comprise the pharmaceutical composition of mTor inhibitor, wherein PI3K alpha inhibitor separate with mTor inhibitor or together with use.PI3K alpha inhibitor and mTor inhibitor can separate prepares and can comprise the 3rd therapeutic agent.Medicament component in the composition and amount are as described herein.

New compositions of the present invention comprise aqueous or Oil suspensions or Emulsion (using Oleum sesami, Semen Maydis oil, Oleum Gossypii semen or Oleum Arachidis hypogaeae semen) by injecting the combining form of using, and elixir, mannitol, dextrose or aseptic aqueous solution and similar acceptable vehicle.

Aqueous solution in saline is usually also for injection.Also (and suitable mixture), cyclodextrin derivative and the vegetable oil such as ethanol, glycerol, propylene glycol, liquid macrogol can be used.Suitable mobility can such as by using for keeping the coating of the particle diameter of needs with regard to dispersion (as lecithin) and being kept by use surfactant.To microbial action prevent realize by various antibacterial agent and antifungal (such as, p-Hydroxybenzoate, methaform, phenol, sorbic acid, thimerosal (thimerosal) etc.).

By the compounds of this invention of the aequum in suitable solvent and various other compositions (as required) of as above enumerating being merged, then filtration sterilization prepares aseptic parenteral solution.Usually, by various sterilizing activity composition is incorporated into containing basic disperse medium and from enumerate above those needed for other compositions sterile carrier in prepare dispersion.With regard to the sterilized powder for the preparation of aseptic parenteral solution, some desirable preparation method is vacuum drying and Freeze Drying Technique, and it obtains the powder of described active component and the composition of any other hope from the solution of its previous aseptic filtration.

for the pharmaceutical composition that local (such as percutaneous) is sent.In some embodiments, the invention provides a kind of pharmaceutical composition for dermal delivery, its pharmaceutical excipient containing at least one the compounds of this invention and be suitable for dermal delivery.Such as, a kind of pharmaceutical composition for local delivery comprising at least one PI3K alpha inhibitor and mTor inhibitor is provided.Also providing package containing PI3K alpha inhibitor the pharmaceutical composition for local delivery and comprise the pharmaceutical composition for local delivery of mTor inhibitor, wherein PI3K alpha inhibitor separate with mTor inhibitor or together with use.PI3K alpha inhibitor and mTor inhibitor separately can be prepared and can be comprised the 3rd therapeutic agent.

The present composition can be mixed be suitable for that local (local/topical) uses in the preparation of solid, semisolid or liquid form, as gel (gels), water soluble gel (jellies), ointment, lotion, suspensoid, foam, powder, serosity (slurries), ointment, solution, oil preparation, paste, suppository, spray, Emulsion, saline solution agent, solution based on dimethyl sulfoxine (DMSO).In general, the carrier with higher density can provide the region extending and be exposed to active component.By contrast, pharmaceutical solutions can provide active component more directly to expose selection area.

Described pharmaceutical composition also can comprise suitable solid-state or gel phase carriers or excipient, and it is the infiltration allowing to increase treatment molecule transdermal horny layer permeability barrier, or promotes the compound of transdermal horny layer permeability barrier delivery treatments molecule.Known many these of technical staff in topical formulations field penetrate enhancing molecule.The example of described carrier and excipient includes but not limited to wetting agent (such as carbamide), glycols (such as propylene glycol), alcohols (such as ethanol), fatty acid (such as oleic acid), surfactant (such as isopropyl myristate and sodium lauryl sulphate), ketopyrrolidine, glyceryl monolaurate, sulfoxide, terpene (such as menthol), amine, amide, alkane, alkanol, water, calcium carbonate, calcium phosphate, various saccharide, starch, cellulose derivative, gelatin and polymer (as Polyethylene Glycol).

The another kind of exemplary formulation used in the methods of the invention uses transdermal delivery device (" paster (patch) ").Described transdermal patch can be used for continuously or discontinuously with controlled quentity controlled variable infusion inhibitor of the present invention (together with another kind of medicament or not together with another kind of medicament).

Well known in the art for the structure of the transdermal patch of drug delivery with medicament and use.See, such as U.S. Patent number 5,023,252,4,992,445 and 5,001,139.The described paster of drug delivery with medicament continuously, pulsedly or as required can be configured to.

for the pharmaceutical composition sucked.Compositions for sucking or being blown into is included in solution in pharmaceutically acceptable aqueous or organic solvent or its mixture and suspension and powder.Liquid or solid compositions can containing pharmaceutically acceptable excipient suitable as above.Preferably, described compositions is used by mouth or nasal respiratory route, for local or general action.Compositions in preferably pharmaceutically acceptable solvent is by using noble gas spraying.Maybe can be connected to the sprayer unit of face shield (facemasktent) or intermittent positive pressure breathing (IPPB) machine from sprayer unit and directly suck spray solution.Solution, suspensoid or dust composition can be used from the device sending described preparation by rights, preferably per os or per nasal.Such as, a kind of pharmaceutical composition for local delivery comprising at least one PI3K alpha inhibitor and mTor inhibitor is provided.Also providing package containing PI3K alpha inhibitor the pharmaceutical composition for local delivery and comprise the pharmaceutical composition for local delivery of mTor inhibitor, wherein PI3K alpha inhibitor separate with mTor inhibitor or together with use.The compositions comprising PI3K alpha inhibitor and mTor inhibitor separately can be prepared and can be comprised the 3rd therapeutic agent.

other drug compositions.Also and can be suitable in Sublingual, buccal, rectum, bone by compositions as herein described, ophthalmic, intranasal, one or more pharmaceutically acceptable excipient pharmaceutical compositions of using in epidural or spinal column.Preparation for described pharmaceutical composition is well-known in the art.See, such as, Anderson, PhilipO.; Knoben, JamesE.; Troutman, WilliamG write, HandbookofClinicalDrugData, the tenth edition, McGraw-Hill, 2002; Pratt and Taylor writes, PrinciplesofDrugAction, the third edition, ChurchillLivingston, NewYork, 1990; Katzung, writes, BasicandClinicalPharmacology, the 9th edition, McGrawHill, 20037ybg; Goodman and Gilman writes, ThePharmacologicalBasisofTherapeutics, the tenth edition, McGrawHill, 2001; RemingtonsPharmaceuticalSciences, the 20 edition, LippincottWilliams & Wilkins., 2000; Martindale, TheExtraPharmacopoeia, the 32 edition (ThePharmaceuticalPress, London, 1999); All these are all incorporated to herein with way of reference entirety.

Using by any method of compound delivery to action site being realized of each compound of the present invention or pharmaceutical composition.These methods comprise oral route, intraduodenal route, parenteral injection (comprising intravenous, intra-arterial, subcutaneous, intramuscular, Ink vessel transfusing, intraperitoneal or infusion), locally (such as percutaneous application), rectal administration, through the local delivery of conduit or support or by sucking.Also can administered compound in (intraadiposally) or sheath in fat.

The amount of application of each compound will depend on treated mammal, the order of severity of disease or condition of illness, application rate, the disposal of compound and the judgement of prescriber.But effective dose is within the scope of about 0.001 to about 100mg/kg body weight/day, and preferably about 1 to about 35mg/kg/ day, use with single dose or the dosage that separates.For the people of 70kg, this will be equivalent to about 0.05 to 7g/ day, be preferably about 0.05 to about 2.5g/ day.In some cases, the dosage level lower than above-mentioned range lower limit may be enough, and may use the larger dosage not causing any adverse side effect in other cases, such as, run through use all day by described larger dosage being divided into several low dose.

In some embodiments, inhibitor of the present invention is used with single dose.Typically, use described in and undertaken by injection (such as intravenous injection), to introduce medicament fast.But, other approach can be used as one sees fit.The single dose of inhibitor of the present invention also can be used for treating acute pathologies.

In some embodiments, inhibitor of the present invention is used with multiple dose.Administration can be about once a day, twice, three times, four times, five times, more than six times or six times.Administration can be about monthly, once every two weeks, once in a week or every other day once.In another embodiment, inhibitor of the present invention is used together with another kind of medicament, about once a day to about every day six times.In another embodiment, inhibitor of the present invention and using of medicament continue to be less than about 7 days.In another embodiment, use described in and continue to be greater than about 6 days, 10 days, 14 days, 28 days, two months, six months or 1 year.In some cases, as long as necessity, just realize continuing medication and keeping.

As long as necessity, use medicament of the present invention with regard to sustainable.In some embodiments, pharmacy application of the present invention is greater than 1,2,3,4,5,6,7,14 or 28 day.In some embodiments, pharmacy application of the present invention is less than 28,14,7,6,5,4,3,2 or 1 days.In some embodiments, medicament of the present invention is chronic administration on the basis of carrying out, such as, be used for the treatment of chronic effect.

By any accepted mode of using the medicament with similar effectiveness with single dose or multiple dose to use the inhibitor of the present invention of effective dose, described method of application comprises rectally, buccal administration, intranasal and transdermal routes of administration, intra-arterial injection administration, intravenous administration, Intraperitoneal medication, parenteral, intramuscular administration, subcutaneous administration, oral administration, topical or as inhalant administration.

The present composition also can be sent via the device (as support, or such as inserting the cylindrical polymeric of tremulous pulse) of dipping or coating.Described application process such as can contribute to prevention or improve in operation as the restenosis after balloon angioplasty.Not bound by theory, the migration that the compounds of this invention can slow down or suppress to promote the smooth muscle cell of restenosis in arterial wall and propagation.Inhibitor of the present invention is by the pillar such as from support, from stent graft, use from graft or from the lid of support or the local delivery of cover.In some embodiments, inhibitor of the present invention is mixed with substrate.Described substrate can be polymeric matrix, and can be used to compound to be bonded to support.The polymeric matrix being suitable for described purposes comprises such as based on polyester or the copolyesters of lactone, as polylactide, polycaprolactone Acetic acid, hydroxy-, bimol. cyclic ester, poe, polyanhydride, the acid of polychlorostyrene base, polysaccharide, polyphosphazene, poly-(ether-ester) copolymer (such as PEO-PLLA); Polydimethylsiloxane, poly-(ethane-acetic acid ethyenyl ester), based on the polymer of acrylate or copolymer (such as poly-methylmethacrylic acid hydroxyl ethyl ester, polyvinyl pyrrolidone), fluorinated polymer (as politef and cellulose esters).That suitable substrate can be non-degradable or can pass in time and degrade, thus discharge one or more compounds.The compounds of this invention is coated on the surface of support by various method, as dipping/spin coating, spraying, dip-coating and/or brushing.Described compound can be applied in a solvent and solvent can be made to evaporate, thus forms compound layer on support.Or described compound can be arranged in the main body of support or graft, such as, in microchannel or micropore.When implanted, described compound from the main diffusion of support out to contact arterial wall.Described support is by immersing the support manufactured containing described micropore or microchannel in the solution of the compounds of this invention in suitable solvent, and then prepared by evaporating solvent.Excess drug on rack surface is removed by the washing of other simple solvent.In other embodiments, the compounds of this invention can be covalently attached to support or graft.The covalent linker of vivo degradation can be used in, thus cause the release of the compounds of this invention.Any biolabile key all can be used for described object, as ester, amide or acid anhydride key.In addition, the compounds of this invention can be used in the Balloon used during angioplasty.Also can come outside blood vessel, to use described compound, to reduce restenosis via pericardium or via tunica adventitia application invention formulation.

Can as described in the multiple holder device of use be disclosed in such as below with reference in document, all described lists of references are incorporated to hereby by reference: U.S. Patent number 5451233; U.S. Patent number 5040548; U.S. Patent number 5061273; U.S. Patent number 5496346; U.S. Patent number 5292331; U.S. Patent number 5674278; U.S. Patent number 3657744; U.S. Patent number 4739762; U.S. Patent number 5195984; U.S. Patent number 5292331; U.S. Patent number 5674278; U.S. Patent number 5879382; U.S. Patent number 6344053.

The compounds of this invention can be used by multiple dosage.It is well known in the art that due to the difference of compound pharmacokinetics between experimenter, individualization of dosage regimen is required for optimal treatment.The administration of inhibitor of the present invention can be determined by normal experiment according to content disclosed herein.

Theme pharmaceutical composition can be and is such as suitable for Orally administered form (as tablet, capsule, pill, powder, slow releasing preparation, solution, suspensoid), be suitable for the form (as sterile solution agent, suspensoid or Emulsion) of parental injection, be suitable for the form (as ointment or ointment) of local application or be suitable for the form (as suppository) of rectal administration.Described pharmaceutical composition can be the unit dosage forms of the single administration being suitable for exact dose.Described pharmaceutical composition using comprise conventional pharmaceutical carrier or excipient and as active component according to inhibitor of the present invention.In addition, it can comprise other drug or medicinal medicament, carrier, adjuvant etc.

Exemplary parenteral administration forms comprises the solution of reactive compound in aseptic aqueous solution (such as aqueous solution of propylene glycol or aqueous dextrose) or suspensoid.If wish, can suitably cushion described dosage form.

The present invention also provides test kit.Described test kit is included in inhibitor as of the invention described herein in suitable package or compound, and can comprise the written material of operation instruction, clinical research discussion, side effect list etc.Described test kit also can comprise information, as the summary of scientific literature reference, package insert material, clinical test results and/or these similar information, it is pointed out or confirms activity and/or the advantage of described compositions, and/or its describe administration, use, side effect, drug interaction or other information useful to health care supplier.Described information based on the result of various research, such as, can use the research relating to the research of the laboratory animal of In vivo model and the clinical trial based on the mankind.Described test kit also can contain another kind of medicament.In some embodiments, the compounds of this invention and described medicament provide as the independent compositions in the independent container in test kit.In some embodiments, the compounds of this invention and described medicament provide as the single compositions in the container of test kit.Suitable packaging and for additional article (such as, for liquid preparation measuring cup, make the minimized foil packages of air exposure etc.) be known in the art and can be included in described test kit.Test kit as herein described can be provided, sells and/or promotes to health care providers, comprise doctor, nurse, pharmacists, prescription teacher etc.In some embodiments, also can by test kit direct marketing to consumer.

In some embodiments, experimenter be need Therapeutic cancer or pre-cancer condition of illness or the people of focus, wherein cancer is preferably NSCL, breast carcinoma, colon cancer or cancer of pancreas.Combined therapy of the present invention can be used, or the pharmaceutically acceptable salt of therapeutic agent, ester, prodrug, solvate, hydrate or derivant, the experimenter that method according to the present invention is treated comprises such as, has been diagnosed as and has suffered from psoriasis; Restenosis; Atherosclerosis; BPH; Breast carcinoma is as the duct carcinoma in the tracheal tissue in mammary gland, medullary carcinoma, mucinous carcinoma, tubular carcinoma and inflammatory breast cancer; Ovarian cancer, comprises epithelial ovarian tumor, as the adenocarcinoma in ovary and from ovarian metastasis to abdominal cavity in adenocarcinoma; Uterus carcinoma; Cervical cancer, as the adenocarcinoma in cervical epithelium, comprises squamous cell carcinoma and adenocarcinoma; Carcinoma of prostate, as being selected from following carcinoma of prostate: adenocarcinoma or the adenocarcinoma transferred in bone; Cancer of pancreas, as the Epithelial cancer in ductus pancreaticus tissue and the adenocarcinoma in ductus pancreaticus; Bladder cancer, as the transitional cell carcinoma in bladder, bladder transitional cell carcinoma (transitional cell carcinoma), the tumor of Urothelial Cell (theurothelialcellsthatlinethebladder), squamous cell carcinoma, adenocarcinoma and small cell carcinoma along bladder arrangement; Leukemia, as acute myelogenous leukemia (AML), acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic lymphocytic leukemia, hairy cell, myelodysplasia, bone marrow proliferative disease, acute myeloid leukaemia (AML), chronic myelogenous leukemia (CML), mastocytosis, chronic lymphocytic leukemia (CLL), multiple myeloma (MM) and myelodysplastic syndrome (MDS); Osteocarcinoma; Pulmonary carcinoma, as nonsmall-cell lung cancer (NSCLC, it is divided into squamous cell carcinoma, adenocarcinoma and maxicell undifferentiated carcinoma) and small cell lung cancer; Skin carcinoma, as basal cell carcinoma, melanoma, squamous cell carcinoma and actinic keratosis (it is the skin condition of illness sometimes developing into squamous cell carcinoma); Eyes retina blastoma; Skin or ophthalmic (eye) melanoma; Primary hepatocarcinoma (cancer started in liver); Renal carcinoma; Thyroid carcinoma, as mastoid process thyroid carcinoma, vesicle thyroid carcinoma, medullary thyroid carcinoma and degeneration thyroid carcinoma; The lymphoma relevant to AIDS, as diffuse large B cell lymphoma, B cell immunoblastic lymphoma and small non-cleaved cell lymphoma; Kaposi sarcoma; The cancer of virus induction, comprises hepatitis B virus (HBV), hepatitis C virus (HCV) and hepatocarcinoma; 1 type mankind lymphotropic virus (HTLV-1) and adult T cell leukemia/lymphoma; With human papillomavirus (HPV) and cervical cancer; Central nervous system cancer (CNS), as primary brain tumor (it comprises glioma (astrocytoma, anaplastic astrocytoma or glioblastoma multiforme), oligodendroglioma, ependymoma, meningioma, lymphoma, Schwann-cell tumor (Schwannoma) and medulloblastoma); Peripheral nervous system (PNS) cancer, as acoustic neuroma and pernicious peripheral nervous sheath tumor (MPNST), comprise neurofibroma and Schwann-cell tumor, malignant fibrous glucagonoma, malignant fibrohistiocytoma, malignant meningioma, malignant mesothe and pernicious mixed type Miller tumor (malignantmixedM ü lleriantumor); Oral cavity and oropharynx cancer, as hypopharyngeal cancer, laryngeal carcinoma, nasopharyngeal carcinoma and oropharynx cancer; Gastric cancer, as lymphoma, Gastric stromal tumors and carcinoid tumor; Carcinoma of testis, as germinoma (GCT, it comprises spermocytoma and nonseminoma) and gonadal stromal tumor (it comprises Leydig's cell tumor and sertoli cell tumor); Thymic carcinoma, as thymoma, thymic carcinoma, Hodgkin (Hodgkindisease), non-Hodgkin lymphoma carcinoid or carcinoid tumor; Rectal cancer; And colon cancer.

The invention still further relates to a kind of method for the treatment of diabetes in mammal, it comprises the combined therapy of the present invention to described administration treatment effective dose.

In addition, combined therapy as herein described can be used for Acne treatment.

In addition, combined therapy as herein described can be used for treating arteriosclerosis, comprises atherosclerosis.Arteriosclerosis describes general terms that is medium or aortic any sclerosis.Atherosclerosis is the arteriosclerosis caused by atheromatous plaque particularly.

In addition, combined therapy as herein described can be used for treating glomerulonephritis.Glomerulonephritis is constitutional or Secondary cases autoimmune nephrosis, it is characterized by glomerule inflammation.It may be asymptomatic or with hematuria and/or albuminuria.There are many types identified, are divided into acute, subacute or chronic glomerulonephritis.Reason is for infecting (antibacterial, virus or parasitic disease substance), autoimmune or paraneoplastic.

In addition, combined therapy as herein described can be used for treating following disease: bursitis, lupus, acute disseminated encephalomyelitis (ADEM), Addison's disease, antiphospholipid antibody syndrome (APS), aplastic anemia, autoimmune hepatitis, celiac disease, Crohn disease, diabetes (1 type), Goodpasture's syndrome, Graves' disease, Ji-Ba syndrome (GBS), Hashimoto's disease, inflammatory bowel, lupus erythematosus, myasthenia gravis, opsoclonus-myoclonic syndrome (OMS), optic neuritis, atrophic thyroiditis, osteoarthritis, uveoretinitis, pemphigus, polyarthritis, primary biliary cirrhosis, conjunctivo-urethro-synovial syndrome, aortic arch syndrome, temporal arteritis, warm autoimmune hemolytic anemia, Wegner granulomatosis, alopecia universalis, Chagas' disease (Chagas ' disease), chronic fatigue syndrome, autonomic nerve function is abnormal, endometriosis, hidradenitis suppurativa, interstitial cystitis, neuromyotonia, sarcoidosis, scleroderma, ulcerative colitis, vitiligo, vulvodynia, appendicitis, arteritis, arthritis, blepharitis, bronchiolitis, bronchitis, cervicitis, cholangitis, cholecystitis, chorioamnionitis, colitis, conjunctivitis, cystitis, dacryoadenitis, dermatomyositis, endocarditis, endometritis, intestinal is scorching, enterocolitis, epicondylitis, epididymitis, fascitis, fibrositis, gastritis, gastroenteritis, gingivitis, hepatitis, hidradenitis, ileitis, iritis, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, umbilicus is scorching, oophoritis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendinitis, tonsillitis, uveitis, vaginitis, vasculitis or vulvitis.

The invention still further relates to a kind of method of Cardiovarscular in mammal, it comprises the combined therapy of the present invention to described administration treatment effective dose.The example of cardiovascular pathologies includes but not limited to atherosclerosis, restenosis, vascular occlusion, carotid obstructive disease or ischemia condition of illness.

In yet another aspect, the invention provides the method destroyed leukocyte function or destroy osteoclast function.Described method comprises makes leukocyte or osteoclast contact with the combined therapy of the present invention of function destruction amount.

In another aspect of the present invention, provide the method by treating ocular disease to the treatment of one or more subject combination of experimenter's ophthalmic applications.There is provided further via eye drop, intraocular injection, intravitreal injection, partly or by using pharmacological eluting arrangement, microcapsule, implant or microfluidic device to use the method for combined therapy of the present invention.In some cases, combined therapy is used with improving together with the carrier of intraocular penetration of described compound or excipient, as have colloidal particle (its have by interfacial film around oily core) oil and aqueous emulsion.

In some cases, described colloidal particle comprises at least one cation reagent and at least one non-ionic surface active agent, as poloxamer (poloxamer), Tai Luoshamu (tyloxapol), polysorbate, castor oil derivatives, sorbitan ester or polyglycol distearate (polyoxylstearate).In some cases, cation reagent is alkylamine, alkyl amine, quaternary ammonium compound, cation lipid, amino alcohol, Guanoctine, cationic compound or its mixture.In some cases, cation reagent is Guanoctine, as chlorhexidine, polychlorostyrene propyl group biguanide, phenformin, alkyl biguanide or its mixture.In some cases, quaternary ammonium compound is that benzene pricks halogen ammonium (behenalkoniumhalide), Laura halogen ammonium (lauralkoniumhalide), cetrimonium bromide, cetyl trimethyl ammonium halide, tetradecyltrimethylammonium ammonium halide, trimethyl ammonium halide, western bent halogen ammonium, benzyl rope halogen ammonium, halogenation docosyl dimethyl benzyl ammonium (behenalkoniumhalide), halogenation cetyldimethylbenzylammonium (cetalkoniumhalide), halogenation cetyl dimethylethyl ammonium (cetethyldimoniumhalide), cetylpyridinium halide (cetylpyridiniumhalide), benzyl halide dodecyldimethylamine (benzododeciniumhalide), halogenation chlorallyl hexamethylenamine (chlorallylmethenaminehalide), halogenation myristyl benzyl dimethyl ammonium (rnyristylalkoniumhalide), halogenation octadecyl dimethyl benzyl ammonium (stearalkoniumhalide) or its two or more mixture.In some cases, cation reagent is benzalkonium chloride, lauralkonium chloride, benzododecinium bromide, benzethonium chloride, cetyl trimethyl ammonium bromide, Tetradecyl Trimethyl Ammonium Bromide, Dodecyl trimethyl ammonium chloride or its two or more mixture.In some cases, oil phase is mineral oil and light mineral oil, medium chain triglyceride (MCT), Oleum Cocois; Hydrogenated oil and fat, comprises cotmar, hydrogenated palm oil, castor oil hydrogenated or oil with hydrogenated soybean; Polyoxyethylene hydrogenated Oleum Ricini derivant, comprises polyoxyethylene-40 castor oil hydrogenated (poluoxyl-40hydrogenatedcastoroil), polyoxyethylene-60 castor oil hydrogenated (poluoxyl-60hydrogenatedcastoroil) or polyoxyethylene-100 castor oil hydrogenated (poluoxyl-100hydrogenatedcastoroil).

The present invention further provides by making kinases contact with the compositions of mTor inhibitor the method regulating PI3K and/or mTOR kinase activity with the PI3K alpha inhibitor that comprises of effective dose.Adjustment can be suppression or activated protein kinase is active.In some embodiments, the invention provides by making kinases contact with the compositions of mTor inhibitor the method suppressing kinase activity with the PI3K alpha inhibitor that comprises of effective dose in the solution.In some embodiments, the invention provides the method suppressing kinase activity by contacting cell, tissue or the organ of expressing kinase targets.In some embodiments, the invention provides and suppress experimenter (to include but not limited to rodent and mammal (such as, people)) in the method for kinase activity, it is realized by the compositions comprising PI3K alpha inhibitor and mTor inhibitor using effective dose to experimenter.In some embodiments, suppress percentage ratio more than 50%, 60%, 70%, 80% or 90%.

Other combination treatments

Present invention also offers the method for other combination treatments, in other combination treatments described, except PI3K alpha inhibitor and mTor inhibitor, other compositions also using other approach of known adjustment or these approach or the medicament even covering several groups of target enzymes or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant.In one aspect, this therapy includes but not limited to comprise PI3K alpha inhibitor and mTor inhibitor and chemotherapeutant, therapeutic antibodies and radiocurable combination, to provide therapeutic effect that is collaborative or that be added when needed.

For the treatment of autoimmune disease, motif compound or pharmaceutical composition and conventional prescription drugs (can be included but not limited to with ) combinationally use.For the treatment of respiratory tract disease, motif compound or pharmaceutical composition and conventional prescription drugs (can be included but not limited to with ) combined administration.

The compounds of this invention can with prepare or use together with the symptom (such as encephalomyelitis, asthma and other diseases described herein) alleviating inflammatory condition effectively other medicaments.These medicaments comprise NSAID (non-steroidal anti-inflammatory drug) (NSAID), such as aspirin; Ibuprofen; Naproxen; Indometacin; Nabumetone; Tolmetin; Cortical steroid is for reducing immune inflammation and inhibit activities.The most frequently used prescription drugs of the type is prednisone (Prednisone).It also may be very useful in the individuality of lupus that chloroquine (Aralen) or hydroxychloroquine (Plaquenil) suffer from some.They are prescriptions of skin and joint symptoms through being usually used in lupus.Azathioprine (Imuran) and cyclophosphamide (Cytoxan) inflammation-inhibiting and tend to Immunosuppression system.Other medicaments (such as methotrexate and cyclosporin) are for controlling the symptom of lupus.Anticoagulant is used for anti-Hemostatic Oral Liquid rapid solidification.Their scope is from preventing the aspirin of very low dosage of platelet stickness to heparin/warfarin sodium.

In one aspect of the method, the present invention also relates to method and the pharmaceutical composition for suppressing the abnormal cell growth in mammal, it comprises the inhibitor a certain amount of of the present invention or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant that combine with a certain amount of anticarcinogen (such as chemotherapeutant).That current many chemotherapeutants are known in the art and can combinationally use with the compounds of this invention.

In some embodiments, described chemotherapeutant is selected from by the following group formed: mitotic inhibitor, alkylating agent, antimetabolite, embedding antibiotic (intercalatingantibiotics), growth factor receptor inhibitors, cell cycle inhibitor, enzyme, topoisomerase enzyme inhibitor, biological response modifier, hormone antagonist, angiogenesis inhibitor, immunotherapeutic agent, apoptosis agent and androgen antagonist.Limiting examples is chemotherapeutant, cytotoxic agent and non-peptide micromolecule, such as imatinib mesylate (Gleevec, imatinib mesylate), Bortezomib (Velcade, bortezomib), Kang Shi get (Casodex, bicalutamide), Iressa (Iressa, gefitinib) and doxorubicin (Adriamycin) and a large amount of chemotherapeutant.The limiting examples of chemotherapeutant comprises alkylating agent, and such as thiophene is for sending (thiotepa) and cyclophosphamide (CYTOXAN ^tM); Alkylsulfonate, such as busulfan (busulfan), an improsulfan (improsulfan) and piposulfan (piposulfan); Aziridines, such as benzo DOPA (benzodopa), carboquone, U.S. appropriate DOPA (meturedopa) and urea DOPA (uredopa); Ethylenimine and methylmelamine, comprise altretamine, triethylenemelamine, triethylenephosphoramide, triethylene thiophosphoramide and trimethylolmelamine; Chlormethine, such as chlorambucil, chlornaphazine, cyclophosphamide (cholophosphamide), estramustine, ifosfamide, chlormethine, mechlorethaminoxide hydrochlorate, melphalan (melphalan), novoembichin, phenesterin, PM, trofosfamide, uracil mustard; Nitroso ureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, Ranimustine; Oxygen azo-cycle is Phosphorus; Nitroso ureas; Triazenes; Antibiotic, such as pentolinli tartras preparation, D actinomycin D and bleomycin, comprise aklavine, D actinomycin D, anthramycin (authramycin), azaserine, bleomycin, D actinomycin D, Calicheamicin, carubicin (carabicin), carminomycin, carzinophillin, Casodex ^tM, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxn-l-norieucin, doxorubicin, epirubicin, esorubicin, idarubicin, marcellomycin, mitomycin, mycophenolic acid, nogalamycin, Olivomycin, peplomycin, porfiromycin, puromycin, triferricdoxorubicin, rodorubicin, streptonigrin, streptozocin, tubercidin, ubenimex, zinostatin, left softly compare star; Antimetabolite, such as methotrexate and 5-fluorouracil (5-FU); Folacin, such as 9,10-dimethylpteroylglutamic acid, methotrexate, Pteropterin, trimetrexate; Purine analogue, such as fludarabine, Ismipur, ITG, thioguanine; Pyrimidine analogue, such as ancitabine (ancitabine), azacitidine, 6-azauridine, carmofur (carmofur), cytosine arabinoside, two uracil deoxyriboside, doxifluridine, enocitabine (enocitabine), floxuridine; Androgen, such as calusterone, Masterone, epitiostanol, mepitiostane, testolactone; Antiadrenergic drug, such as aminoglutethimide (aminoglutethimide), mitotane (mitotane), Qu Luosi smooth (trilostane); Folic acid supplement, such as folinic acid; Aceglatone; Aldophosphamide glucosides; Aminolevulinic acid; Amsacrine; Bestrabucil; Bisantrene (bisantrene); Edatrexate (edatraxate); Defosfamide; Demecolcine; Diaziquone; Eflornithine (elfomithine); Elliptinium acetate; Etoglucid (etoglucid); Ganite (Fujisawa).; Hydroxyurea; Lentinan; Lonidamine (lonidamine); Mitoguazone; Mitoxantrone; Mopidamol; C-283; Pentostatin (pentostatin); Phenamet; Pirarubicin; Podophyllinic acid; 2-ethyl hydrazides; Procarbazine; PSK.R ^tM; Razoxane (razoxane); Sizofiran (sizofiran); Spirogermanium; Acid is helped for slave; Triaziquone; 2,2 ', 2 "-RA3s; Urethane; Vindesine; Dacarbazine (dacarbazine); Mannomustine; Mitobronitol; Mitolactol; Pipobroman (pipobroman); Gacytosine; Cytosine arabinoside (" Ara-C "); Cyclophosphamide; Thiophene is for group; Taxane, such as paclitaxel (TAXOL ^tM, Bristol-MyersSquibbOncology, Princeton, N.J.) and docetaxel (TAXOTERE ^tM, Rhone-PoulencRorer, Antony, France); Tretinoin; Ai Sipeila mycin; Capecitabine; And the pharmaceutically acceptable salt of any above-mentioned chemotherapeutant, acid or derivant.Be applicable to chemotherapy cell modulator also comprise to adjustment or the effective antihormone of Tumor suppression hormonal action as estrogen antagonist, comprise such as zitazonium (Nolvadex ^tM), the aromatase of raloxifene, suppression 4 (5)-imidazoles, 4-hydroxy tamoxifen, trioxifene, keoxifene, LY117018, onapristone and toremifene (fareston); And androgen antagonist, as flutamide, nilutamide, bicalutamide, leuprorelin and goserelin; Chlorambucil; Gemcitabine; 6-thioguanine; Purinethol; Methotrexate; Platinum or platinum analogs and complex are as cisplatin and carboplatin; Anti-microtubule medicine, as Diterpenes, comprises paclitaxel and docetaxel, or vinca alkaloids, comprises vinblastine, vincristine, vinflunine, vindesine and vinorelbine; Etoposide (VP-16); Ifosfamide; Ametycin; Mitoxantrone; Vincristine; Vinorelbine; Nvelbine; Mitoxantrone; Teniposide; Daunorubicin; Aminopterin; Xeloda; Ibandronate; Topoisomerase I and Topoisomerase II inhibitors, comprise camptothecine (such as, camptothecin-11), topotecan, irinotecan and epipodophyllotoxin; Topoisomerase enzyme inhibitor RFS2000; Ebomycin A or epothilone B; α-difluorometylornithine (DMFO); Histone deacetylase inhibitor; The compound of Cell differentiation inducing activity process; Gonadorelin agonist; Methionine aminopeptidase inhibitor; The compound of targeting/reduction protein or lipid kinase activity; The compound of targeting, reduction or Profilin matter or lipid phosphatase activity; Androgen antagonist; Diphosphate; Biological response modifier; Anti proliferative antibody; Heparanase inhibitors; Ras Ras oncogenic isoforms inhibitor; Telomerase inhibitor; Proteasome inhibitor; Be used for the treatment of the compound of malignant hematologic disease; Targeting, reduction or suppress the compound of Flt-3 activity; Hsp90 inhibitor; Temozolomide hsp90 inhibitor is as the 17-AAG (17-AAG from ConformaTherapeutics, NSC330507), 17-DMAG (17-Dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; Temozolomide spindle kinesin inhibitor, as SB715992 or SB743921 from GlaxoSmithKline or the pentamidine/chlorpromazine from CombinatoRx; Mek inhibitor is as the ARRY142886 from ArrayPioPharma, the AZD6244 from AstraZeneca, PD181461 or PD0325901, folinic acid, EDG bonding agent, leukemia compound, ribonucleotide reductase inhibitor, S adenosylmethionine decarboxylase inhibitor, antiproliferation antibodies or other chemotherapy compounds from Pfizer.When needed, compound of the present invention or pharmaceutical composition can with conventional prescription anticarcinogen (such as with ) combinationally use.Provided hereinafter other information about the compound that can be combined with compound of the present invention.

Proteasome inhibitor comprises the compound of targeting, reduction or proteasome enzyme inhibition activity.The compound of targeting, reduction or proteasome enzyme inhibition activity comprises such as proteasome inhibitor (Bortezomid, Velcade ^tM) and MLN341.Matrix metallo-proteinase inhibitor (" MMP " inhibitor) includes but not limited to collagen peptidomimetic and non-petidomimetic inhibitors, tetracycline derivant, such as hydroxamic acid peptidomimetic inhibitors batimastat and oral bio useful analogs marimastat (BB-2516) thereof, Pu Masita (AG3340), metastat (NSC683551) BMS-279251, BAY12-9566, TAA211, MMI270B or AAJ996.The compound being used for the treatment of malignant hematologic disease includes but not limited to FMS-sample tyrosine kinase inhibitor, such as targeting, reduction or the compound suppressing FMS-sample tyrosine kinase receptor (Flt-3R) active; Interferon, 1-b-D-arabinofuranosyl cytosine (ara-c) and busulfan (bisulfan); And ALK inhibitor, such as targeting, reduction or suppress the compound of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase.Targeting, reduction or the compound suppressing the active compound of FMS-sample tyrosine kinase receptor (Flt-3R) to be in particular to suppress Flt-3R receptor kinase family member, protein or antibody, such as PKC412, midostaurin, staurosporine derivant, SU11248 and MLN518.

Hsp90 inhibitor comprises such as from the 17-AAG (17-AAG of ConformaTherapeutics, NSC330507), 17-DMAG (17-Dimethylaminoethylamino-17-demethoxy-geldanamycin, NSC707545), IPI-504, CNF1010, CNF2024, CNF1010; Temozolomide spindle kinesin inhibitor, as SB715992 or SB743921 from GlaxoSmithKline or the pentamidine/chlorpromazine from CombinatoRx; Mek inhibitor, such as from ARRY142886, the AZD6244 from AstraZeneca of ArrayPioPharma, the PD181461 from Pfizer, folinic acid, EDG bonding agent, leukemia compound, ribonucleotide reductase inhibitor, S adenosylmethionine decarboxylase inhibitor, antiproliferation antibodies or other chemotherapy compounds.

Histone deacetylase inhibitor (or " hdac inhibitor ") comprises and suppresses histidine deacetylase and the compound with antiproliferative activity.This comprises compound, particularly N-hydroxyl-3-[4-[[(2-ethoxy) [2-(1H-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-propionic acid amide. disclosed in WO02/22577, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-base)-ethyl] is amino] methyl] phenyl]-2E-2-propionic acid amide. and pharmaceutically acceptable salt thereof.It is also particularly including Vorinostat (SAHA).

The diphosphate used with compound combination of the present invention includes but not limited to, etidronic acid, clodronic acid, tiludronic acid, pamidronic acid, alendronic acid, ibandronic acid, risedronic acid and zoledronic acid.

Compound of the present invention also with targeting or can reduce the compound of protein or lipid kinase activity, protein or lipid phosphatase activity or other anti-angiogenic compounds are combined.This compounds includes but not limited to protein tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitors, such as: targeting, reduction or the compound suppressing platelet-derived growth factor receptor (PDGFR) active, as targeting, reduction or the compound suppressing PDGFR activity, particularly suppress the compound of pdgf receptor, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib, SU101, SU6668 and GFB-111; Targeting, reduction or the compound suppressing fibroblast growth factor receptor (FGFR) active; Targeting, reduction or the compound suppressing insulin like growth factor receptor I (IGF-IR) active, as targeting, reduction or the compound suppressing IGF-IR activity, particularly suppress the compound of IGF-I kinase activation, as those compounds disclosed in WO02/092599 or if the antibody of OSI906 or targeting IGF-I receptor extracellular domain is as CP-751871, R1507, AVE1642, IMC-A12, AMG479, MK-0646, SCH717454 or its somatomedin; Targeting, reduction or suppress the compound of Trk receptor tyrosine kinase family active or liver to join protein B 4 inhibitor; Targeting, reduction or suppress the compound of AxI receptor tyrosine kinase family active; Targeting, reduction or suppress the compound of Ret receptor tyrosine kinase activity; Targeting, reduction or suppress the compound of Kit/SCFR receptor tyrosine kinase activity, such as imatinib; Targeting, reduction or the compound suppressing C-kit receptor tyrosine kinase-(part PDGFR family) active, as targeting, reduction or the compound suppressing c-Kit receptor tyrosine kinase family active, particularly suppress the compound of c-Kit receptor, such as imatinib; Targeting, reduction or suppress c-Ab1 family member, its gene fusion product (such as, BCR-AbI kinases) and the compound of mutant activity, as targeting, reduction or the compound suppressing c-Ab1 family member and gene fusion product activity thereof, such as N-phenyl-2-pyrimidine-amine derivatives, such as imatinib or nilotinib (AMN107); PD180970; AG957; NSC680410; From the PD173955 of ParkeDavis; Or Dasatinib (BMS-354825); The compound of the activity of targeting, reduction or Profilin kinase c (PKC) and serine/threonine kinase Raf family member, MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family member and/or cyclin-dependent kinase family (CDK) member and be in particular US5,093, those staurosporine derivant, such as midostaurins disclosed in 330; The example of other compounds comprises such as UCN-01, Safingol, BAY43-9006, bryostatin 1, perifosine; Llmofosine; RO318220 and RO320432; GO6976; Isis3521; LY333531/LY379196; Isoquinoline compound, as disclosed those in WO00/09495; FTI; PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor); The compound of targeting, reduction or Profilin matter tyrosine kinase inhibitor activity, such as the compound of targeting, reduction or Profilin matter tyrosine kinase inhibitor activity comprises imatinib mesylate (GLEEVEC) or tyrphostin.Tyrphostin is preferably low-molecular-weight (Mr < 1500) compound or its pharmaceutically acceptable salt, be in particular and be selected from benzylidene Cyanoacetyl-Cyacetazid classification or S-aryl phenylpropyl alcohol dintrile or other compound of compound Double bottom thing quinolines, more particularly for being selected from by any compound of the following group formed: tyrphostin A23/RG-50810; AG99; Tyrphostin AG213; Tyrphostin AG1748; Tyrphostin AG490; Tyrphostin B44; Tyrphostin B44 (+) enantiomer; Tyrphostin AG555; AG494; Tyrphostin AG556, AG957 and adaphostin (4-{ [(2,5-dihydroxy phenyl) methyl] is amino }-benzoic acid diamantane (obsolete) ester; NSC680410, adaphostin).

Compound of the present invention also can combinationally use with the following: targeting, reduce or suppress the epidermal growth factor family (EGFR of receptor tyrosine kinase, ErbB2, ErbB3, ErbB4 is as homodimer or heterodimer) and the compound of mutant activity, such as targeting, reduce or suppress the compound of Epidermal Growth Factor Receptor Family activity to be in particular to suppress EGF receptor tyrosine kinase family member such as EGF receptor, ErbB2, ErbB3 and ErbB4 or the compound be combined with EGF or EGF associated ligands, protein or antibody, and be in particular WO97/02266 (such as, the compound of embodiment 39) or EP0564409, WO99/03854, EP0520722, EP0566226, EP0787722, EP0837063, US5,747,498, WO98/10767, WO97/30034, WO97/49688, WO97/38983 and especially WO96/30347 (such as, being called the compound of CP358774), general those disclosed compound especially in WO96/33980 (such as, compound ZD1839) and WO95/03283 (such as, compound ZM105180), protein or monoclonal antibody, such as, trastuzumab (Herceptin disclosed in WO03/013541 ^tM), Cetuximab (Erbitux ^tM), Iressa, Erlotinib, OSI-774, C1-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, E6.3 or E7.6.3 and 7H-pyrrolo--[2,3-d] pyrimidine derivatives, and targeting, reduction or suppress the compound of c-Met receptor active, as targeting, reduction or the compound suppressing c-Met activity, the antibody particularly suppressing the compound of c-Met kinase activation or targeting c-Met extracellular domain or be combined with HGF.Other anti-angiogenic compounds comprise the compound its activity to another kind of mechanism, such as, suppress uncorrelated with protein or lipid kinase, such as Sa Li polyamines (THALOMID) and TNP-470.

Non-receptor kinase angiogenesis inhibitor also can be applicable to being combined with compound of the present invention.Angiogenesis is usually relevant to erbB21EGFR intracellular signaling, because the inhibitor of erbB2 and EGFR has shown inhibiting angiogenesis, has been mainly vegf expression.Therefore, nonreceptor tyrosine kinase inhibitor can use with compound combination of the present invention.Such as, VEGFR (receptor tyrosine kinase) can not be identified but the anti-VEGF antibodies of binding partner; By integrin (the α v β 3) micromolecular inhibitor of inhibiting angiogenesis; Endostatin and angiostatin (non-RTK) are also provable to be applicable to and disclosure compound combination.(see Bruns, C.J. etc. (2000), CancerRes., 60:2926-2935; Schreiber, A.B., Winkler, M.E. and Derynck, R. (1986), Science, 232:1250-1253; Yen, L. etc. (2000), Oncogene19:3460-3469).

The compound of targeting, reduction or Profilin matter or lipid phosphatase activity comprises the inhibitor of such as phosphatase 1, phosphatase 2A or CDC25, such as okadaic acid or derivatives thereof.The compound of Cell differentiation inducing activity process is such as tretinoin, α-γ-or Delta-Tocopherol or α-γ-or δ-tocotrienol.Cyclooxygenase-2 inhibitors includes but not limited to that the 2-arylaminophenylacetic acid that such as Cox-2 inhibitor, 5-alkyl replace and derivant thereof are as celecoxib (CELEBREX), rofecoxib (VIOXX), Etoricoxib, valdecoxib or 5-alkyl-2-arylaminophenylacetic acid such as 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid and lumiracoxib.

Heparanase inhibitors comprises targeting, reduction or suppresses the compound of heparin sulfate degraded, includes but not limited to PI-88.Biological response modifier comprises lymphokine and interferon, such as interferon gamma.Ras Ras oncogenic isoforms inhibitor comprises H-Ras, K-Ras, N-Ras and targeting, reduction or suppresses other compounds of Ras carcinogenic activity.Farnesyl transferase inhibitor includes but not limited to such as L-744832, DK8G557 and R115777 (Zarnestra).

Telomerase inhibitor comprises targeting, reduction or suppresses the compound of telomerase activation.Targeting, reduction or suppress the compound of telomerase activation definitely such as, for suppressing the compound of telornerase receptor, telomere chalone.Methionine aminopeptidase inhibitor is such as targeting, reduction or the compound suppressing methionine aminopeptidase activity.Targeting, reduction or suppress the compound of methionine aminopeptidase activity to be such as bengamide or derivatives thereof.

Antiproliferation antibodies includes but not limited to trastuzumab (Herceptin ^tM), trastuzumab-DM1, Erbitux, bevacizumab (Avastin ^tM), Rituximab pRO64553 (anti-CD 40) and 2C4 antibody.Antibody one word mean such as intact monoclonal antibodies, polyclonal antibody, by the multi-specificity antibody of at least 2 complete antibody forms and antibody fragment, as long as they show required biological activity.

For the treatment of acute myeloid leukaemia (AML), compound of the present invention can combinationally use with standard leukemia therapies, particularly combinationally uses with the therapy being used for the treatment of AML.Specifically, compound of the present invention with such as farnesyl transferase inhibitor and/or can be applicable to the other drug combined administration for the treatment of AML, as daunorubicin, doxorubicin, Ara-C, VP-16, teniposide, mitoxantrone, idarubicin, carboplatin and PKC412.

The leukemia compound used with compound combination of the present invention comprises such as Ara-C, and it is a kind of pyrimidine analogue, is 2 '-Alpha-hydroxy ribose (galactoside) derivant of deoxycytidine.Also comprise the purine analogue of hypoxanthine, 6-MP (6-MP) and fludarabine phosphate.Targeting, reduction or inhibition of histone deacetylase (HDAC) inhibitor such as the compound of the activity of sodium butyrate and Vorinostat (SAHA) suppresses the enzymatic activity being called deacetylase protein enzyme.Specificity hdac inhibitor comprises MS275, SAHA, FK228 (being FR901228 originally), Trichostatin A and US6, 552, compound disclosed in 065, be in particular Λ/-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-base)-ethyl]-amino] methyl] phenyl]-2E-2-propionic acid amide. or its pharmaceutically acceptable salt and Λ/-hydroxyl-3-[4-[(2-ethoxy) { 2-(1/-/-indol-3-yl) ethyl]-amino] methyl] phenyl]-2E-2-propionic acid amide. or its pharmaceutically acceptable salt such as lactate.

Somatostatin receptor antagonist comprise targeting, treatment or Developing restraint inhibin receptor compound as octreotide and SOM230 (SOM230).Tumor cell destruction method comprises the method for such as ionizing radiation, such as, as the ionizing radiation that electromagnetic radiation (as X-ray and gamma-rays) or particle (alpha-particle and beta-particle) occur.Be not limited in radiation therapy provide ionizing radiation in radiation therapy and described ionizing radiation is known in this area.Write see Hellman, PrinciplesofRadiationTherapy, Cancer, inPrinciplesandPracticeofOncology, Devita etc., the 4th edition, the 1st volume, 248-275 page (1993).EDG bonding agent comprises the immunosuppressant of adjustment lymphocyte recirculation as FTY720.

Ribonucleotide reductase inhibitors comprises pyrimidine or the similar thing of purine nucleotides, include but not limited to, fludarabine and/or cytosine arabinoside (ara-C), 6-thioguanine, 5-fluorouracil, cladribine, 6-MP (special and ara-C combines for ALL) and/or pentostatin.Ribonucleotide reductase inhibitors is such as hydroxyurea or 2-hydroxyl-1/-/-iso-indoles-1,3-derovatives, as at Nandy etc., ActaOncologica, PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or PL-8 mentioned in the 33rd volume the 8th phase 953-961 page (1994).

S adenosylmethionine decarboxylase inhibitor includes but not limited to US5,461, and compound disclosed in 076.

Specifically also comprise those compounds of VEGF disclosed in WO98/35958, protein or monoclonal antibody such as 1-(4-chloroanilino)-4-(4-pyridylmethyl) phthalazines or its pharmaceutically acceptable salt, such as succinate, or those disclosed in WO00/09495, WO00/27820, WO00/59509, WO98/11223, WO00/27819 and EP0769947; By Prewett etc., CancerRes, the 59th volume, 5209-5218 page (1999); Yuan etc., ProcNatlAcadSciUSA, the 93rd volume 14765-14770 page (1996); Zhu etc., CancerRes, the 58th volume 3209-3214 page (1998); And Mordenti etc., ToxicolPathol, those described in the 27th volume the 1st phase 14-21 page (1999); Those described in WO00/37502 and WO94/10202; By O ' Reilly etc., Cell, the angiostatin (ANGIOSTATIN) described in the 79th volume 315-328 page (1994); By O ' Reilly etc., Cell, the endostatin (ENDOSTATIN) described in the 88th volume 277-285 page (1997); Anthranilic amides; ZD4190; ZD6474; SU5416; SU6668; Bevacizumab; Or anti-VEGF antibodies or anti-VEGF receptor antibody, such as rhuMAb and RHUFab, VEGF are fit, such as Macugon; FLT-4 inhibitor, FLT-3 inhibitor, VEGFR-2IgGI antibody, Angiozyme (RPI4610) and bevacizumab (Avastin ^tM).

Compound of the present invention is also suitable for the co-therapy compound doing to combinationally use as anti-inflammatory drug, bronchiectasis medicine or antihistamine drug with other drug, particularly be applicable to treat obstructive or inflammatory airways diseases those diseases as mentioned above, such as, be suitable for the synergist making this type of Drug therapy activity or the mode being suitable for work this type of medicine required dosage of minimizing or potential side effect.Inhibitor of the present invention can mix with other drug in fixing pharmaceutical composition or it can before other drug, with the while of other drug or use individually after other drug.Therefore, the present invention includes the combination of inhibitor of the present invention and anti-inflammatory drug, bronchiectasis medicine, antihistamine drug or cough suppressing medicine, compound of the present invention and described medicine are in same pharmaceutical composition or are in different pharmaceutical compositions.Applicable anti-inflammatory drug comprises steroid, is in particular glucocorticoid as budesonide, beclomethasone, fluticasone propionate, furancarboxylic acid ciclesonide or saccharic acid mometasone or the steroid as described in WO02/88167, WO02/12266, WO02/100879, WO02/00679 (definitely for embodiment 3,11,14,17,19,26,34,37,39,51,60,67,72,73,90,99 and 101 those), WO03/035668, WO03/048181, WO03/062259, WO03/064445, WO03/072592, non-steroidal glucocorticoid receptor stimulating agent, those as described in WO00/00531, WO02/10143, WO03/082280, WO03/082787, WO03/104195, WO04/005229, LTB4 antagonist, those as described in LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO4057, SB209247 and US5451700, LTD4 antagonist, as montelukast and zafirlukast, PDE4 inhibitor, as cilomilast ( glaxoSmithKline), roflumilast (BykGulden), V-11294A (Napp), BAY19-8004 (Bayer), SCH-351591 (Schering-Plough), arofylline (AlmirallProdesfarma), PD189659/PD168787 (Parke-DaVis), AWD-12-281 (AstaMedica), CDC-801 (Celgene), SeICID (TM) CC-10004 (Celgene), VM554/UM565 (Vernalis), T-440 (Tanabe), KW-4490 (KyowaHakkoKogyo), and WO92/19594, WO93/19749, WO93/19750, WO93/19751, WO98/18796, WO99/16766, WO01/13953, WO03/104204, WO03/104205, WO03/39544, WO04/000814, WO04/000839, WO04/005258, WO04/018450, WO04/018451, WO04/018457, WO04/018465, WO04/018431, WO04/018449, WO04/018450, WO04/018451, WO04/018457, WO04/018465, WO04/019944, WO04/019945, those described in WO04/045607 and WO04/037805, A2a agonist, as EP409595A2, EP1052264, EP1241176, WO94/17090, WO96/02543, WO96/02553, WO98/28319, WO99/24449, WO99/24450, WO99/24451, WO99/38877, WO99/41267, WO99/67263, WO99/67264, WO99/67265, WO99/67266, WO00/23457, WO00/77018, WO00/78774, WO01/23399, WO01/27130, WO01/27131, WO01/60835, WO01/94368, WO02/00676, WO02/22630, WO02/96462, WO03/086408, WO04/039762, WO04/039766, those described in WO04/045618 and WO04/046083, A2b antagonist, those as described in WO02/42298, and β-2 adrenoreceptor agonists, as albuterol (salbutamol), orciprenaline, terbutaline, salmaterol, fenoterol, procaterol and be in particular formoterol and pharmaceutically acceptable salt thereof, the formula I (free or salt or solvate form thereof) of WO0075114 (this file is incorporated to herein by reference), the formula I (free or salt or solvate form thereof) of the compound being preferably embodiment and WO04/16601 and the compound of WO04/033412.Applicable bronchiectasis medicine comprises anticholinergic or antimuscarinic compounds, be in particular ipratropium bromide, oxitropium bromide, tiotropium salts and CHF4226 (Chiesi) and glycopyrronium bromide, and those described in WO01/04118, WO02/51841, WO02/53564, WO03/00840, WO03/87094, WO04/05285, WO02/00652, WO03/53966, EP424021, US5171744, US3714357, WO03/33495 and WO04/018422.

Applicable antihistamine drug comprise described in cetirizine hydrochloride, acetaminophen, tavehil, promethazine, loratadine, loratadine, diphhydramine hydrochloride and fexofenadine hydrochloride, acrivastine, astemizole, azelastine, ebastine, epinastine, mizolastine and terfenadine and WO03/099807, WO04/026841 and JP2004107299 those.

Other of compound of the present invention and anti-inflammatory drug are useful to be combined as and chemokine receptors such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCR1, CXCR2, CXCR3, CXCR4, the antagonist of CXCR5, be in particular CCR-5 antagonist as Schering-Plough antagonist SC-351125, SCH-55700 and SCH-D, Takeda antagonist is as TAK-770, and US6166037 (being in particular claim 18 and 19), WO00/66558 (being in particular claim 8), WO00/66559 (being in particular claim 9), CCR-5 antagonist-combination described in WO04/018425 and WO04/026873.

Anti-microtubule agent or antimitotic agent are included in fissional M phase or mitotic phase to the activated phase-specific agent of tumor cell microtubule tool.The example of anti-microtubule agent includes but not limited to Diterpenes and vinca alkaloids.The Diterpenes being derived from natural source is the G at cell cycle ₂the phase specific anticarcinogen that/M phase works.Think that Diterpenes makes it stablize by being combined with microtubule 'beta '-tubulin subunit.Then breaks down proteins seems to be inhibited, and simultaneously mitosis stops and cell death subsequently.The example of Diterpenes includes but not limited to paclitaxel and analog docetaxel thereof.Paclitaxel, 5 β, 20-epoxy radicals-1,2 α, 4,7 β, 10 β, the ester of 13 α-six-hydroxy taxane-11-alkene-9-ketone 4,10-oxalic acid 2-benzoic acid 13-alcohol and (2R, 3S)-N-benzoyl-3-phenylisoserine; Can be used as Injectable solution for the natural diterpene product that is separated from Pacific yew yewtree commercially available.It is terpenes taxane family member.Its a kind of active mechanism relate to paclitaxel in conjunction with tubulin thus anticancer growth ability.Be used for the treatment of refractory ovarian and be used for the treatment of breast carcinoma pacific yew alcohol approved is clinical.It is a kind of possible drug candidate being used for the treatment of cutaneous tumor and tumor of head and neck.Described compound also shows the possibility for the treatment of POLYCYSTIC KIDNEY DISEASE, pulmonary carcinoma and malaria.Paclitaxel treatment experimenter is used to cause above threshold concentration (the 50nM) (Kearns with administration, C.M. etc., SeminarsinOncology, 3 (6) 16-23 pages, 1995) bone marrow depression (many cells pedigree, Ignoff, R.J. etc. that persistent period is relevant, CancerChemotherapyPocketGuide, 1998).Docetaxel, (2R, 3S)--N-carboxyl-3-phenylisoserine, the N-tert-butyl ester, 13-alcohol and 5 β-20-epoxy radicals-1,2 α, 4,7 β, 10 β, 13 α-six hydrogen taxane-1-1-alkene-9-ketone 4-acetic acid 2-benzoate trihydrates; As Injectable emulsions commercially available.Docetaxel is instructed to be used for the treatment of breast carcinoma.Docetaxel is the semi-synthetic derivant of taxane, uses the natural precursor 10-deacetyl-baccatin III extracted from European yew tree needle to prepare.Docetaxel dose-limiting toxicity is neutropenia.

Other compounds of scalable apoptosis (such as, BCL-2 inhibitor) can use together.

Vinca alkaloids comprises the phase specific anti-tumor agents being derived from periwinkle.Vinca alkaloids is by acting on M phase (mitotic phase) of cell cycle with tubulin specific binding.Therefore, in conjunction with tubulin molecule can not aggregate into microtubule.Think that mitosis stopped in metaphase of cell division, subsequently cell death occurs.The example of vinca alkaloids includes but not limited to vincaleucoblastine, vincristine and vinorelbine.Vincaleucoblastine (vincaleucoblastine sulfate) is as Injectable solution commercially available.Although it has the indication of possibility as two gamma therapies of various solid tumor, it mainly indicates treatment carcinoma of testis and respective lymphoma, comprises Hodgkin and lymphocyte and histocytic lymphoma.Bone marrow depression is the dose-limiting side effect of vincaleucoblastine.Vincristine (22-oxo-vincaleucoblastine sulfate) is as Injectable solution commercially available.Vincristine is instructed to be used for the treatment of acute leukemia and finds in the therapeutic scheme for Huo Qijin malignant lymphoma and non-Hodgkin′s malignant lymphoma.Alopecia and action of nervous system are the modal side effect of vincristine and in less degree, occur the effect of bone marrow depression stomach function regulating esoenteritis.Vinorelbine 3 ', 4 '-two dehydrogenation-4 '-deoxidation-C '-NVB [R--(R*, R*)-2,3 dihydroxybutanedioic acid (1: 2) (salt)] is as Injectable solution vinorelbine tartrate commercially available, it is a kind of semisynthetic vinca alkaloids.Vinorelbine be indicated as single medicament or with other chemotherapeutants as cisplatin combination, treat various solid tumor, be in particular nonsmall-cell lung cancer, advanced breast cancer and hormone-refractory prostate cancer.Bone marrow depression is the dose-limiting side effect of modal vinorelbine.

Platinum coordinates complex to comprise the interactional non-phase specific anticarcinogen with DNA.Platinum complex enters tumor cell, carries out hydration and is formed in chain and interchain linkage with DNA, thus producing bad biological agent to tumor.The example of platinum coordination complex includes but not limited to cisplatin and carboplatin.Cisplatin (cis-diammine dichloro platinum) is as Injectable solution commercially available.Cisplatin mainly indicates treatment metastatic testicular cancer and ovarian cancer and advanced bladder carcinoma.The major dose-limiting side effect of cisplatin is the nephrotoxicity and ototoxicity that control by hydration and diuresis.(carboplatin, platinum, diamidogen [1,1-Tetramethylene .-dicarboxylic ester (2-)-O, O '] conduct commercially available) as Injectable solution.Carboplatin is mainly designated as a line and the second line treatment of advanced ovarian cancer.Bone marrow depression is the dose-limiting toxicity of carboplatin.

Alkylating agent comprises non-phase specific anticancer agents and strong electrophilic reagent.Usually, alkylating agent is come and DNA alkylation by nucleophilic moiety such as phosphate, amino, sulfydryl, hydroxyl, carboxyl and the imidazole radicals via DNA molecular, thus forms covalent bond.This type of alkylation destroys nucleic acid function, causes cell death.The example of alkylating agent includes but not limited to that chlormethine is as cyclophosphamide, melphalan and chlorambucil; Alkylsulfonate is as busulfan; Nitroso ureas is as carmustine; And triazenes is as dacarbazine.Cyclophosphamide 2-[two (2-chloroethyl) is amino] tetrahydrochysene-2H-1,3,2- azoles phosphine 2-oxide monohydrate is as Injectable solution or tablet commercially available.Cyclophosphamide be designated as single medicament or with other chemotherapeutic combination, treatment malignant lymphoma, multiple myeloma and leukemia.Alopecia, Nausea and vomiting and leukopenia are the side effect of modal cyclophosphamide dose dependent.Melphalan 4-[two (2-chloroethyl) is amino]-L-Phe is as Injectable solution or tablet commercially available.The epithelial ovarian cancer that melphalan instruction is used for palliative treatment multiple myeloma and can not cuts.Bone marrow depression is the dose-limiting side effect of modal melphalan.Chlorambucil 4-[two (2-chloroethyl) is amino] benzenebutanoic acid conduct tablet is commercially available.Chlorambucil instruction palliative treatment chronic lymphatic leukemia and malignant lymphoma are as lymphosarcoma, giant follicular lymphoma and Hodgkin.Bone marrow depression is the dose-limiting side effect of modal chlorambucil.The conduct of busulfan Busulfan tABLETS is commercially available.Busulfan instruction palliative treatment chronic granulocytic leukemia.Bone marrow depression is the dose-limiting side effect of modal busulfan.[two (2-chloroethyl)-1-nitroso ureas is as the freeze-dried drug of single bottle for carmustine 1,3- commercially available.Carmustine instruction as single medicament or with other pharmaceutical agent combinations palliative treatment cerebral tumor, multiple myeloma, Hodgkin and non-Hodgkin lymphoma.The bone marrow depression postponed is the dose-limiting side effect of modal carmustine.Dacarbazine 5-(3,3-dimethyl-1-triazenyl)-imidazoles-4-Methanamide is as single bottle medicine commercially available.Dacarbazine instruction is treated metastatic malignant melanoma and is used for second line treatment Hodgkin with other pharmaceutical agent combinations.Nausea and vomiting and apositia are the side effect of modal dacarbazine dose dependent.

Antitumor antibiotics comprises non-phase-specific agent, and it combines or inserts DNA.Usually, this type of effect causes stable DNA complex or chain to break, thus destroys the general utility functions of nucleic acid, and then causes cell death.The example of antibiotic anti-tumor agents includes but not limited to, D actinomycin D is if dactinomycin, anthracycline are as daunorubicin and doxorubicin; And bleomycin.Dactinomycin also referred to as actinomycin D, as injectable forms commercially available.Dactinomycin instruction treatment wilm tumor and rhabdomyosarcoma.Nausea and vomiting and apositia are the side effect of modal dactinomycin dose dependent.Daunorubicin (8S-is cis-)-8-acetyl group-10-[(amino-2,3,6-tri-deoxy of 3--α-L-lysol-pyranohexose base) oxygen base]-7; 8,9,10-tetrahydrochysene-6; 8,11-trihydroxy-1-methoxyl group-5,12 naphthalenedione hydrochlorate is as liposome injectable forms or as injectable commercially available.Daunorubicin instruction is for alleviating the induction in acute nonlymphocytic leukemia and HIV dependency Kaposi sarcoma treatment in late period.Bone marrow depression is the dose-limiting side effect of modal daunorubicin.Doxorubicin (8S, 10S)-10-[(amino-2,3,6-tri-deoxy of 3--α-L-lysol-pyranohexose base) oxygen base]-8-glycollyl, 7,8,9,10-tetrahydrochysene-6,8,11-trihydroxy-1-methoxyl group-5,12 naphthalenedione hydrochlorate is as injectable forms or commercially available.Doxorubicin mainly indicates treatment acute lymphoblastic leukemia and acute myeloblastic leukemia, but is also the useful component in some solid tumors and lymphoma treating.Bone marrow depression is the dose-limiting side effect of modal doxorubicin.Bleomycin is the mixture of the cytotoxicity glycopeptide antibiotics be separated in trailing wheel branch streptomycete bacterial strain, can be used as commercially available.Bleomycin instruction is the palliative treatment of squamous cell carcinoma, lymphoma and carcinoma of testis as its single medicament or with other pharmaceutical agent combinations.Pulmonary and dermal toxicity are the restricted side effect of modal bleomycin dose.

Topoisomerase II inhibitors includes but not limited to, epipodophyllotoxin.Epipodophyllotoxin is the phase specific anti-tumor agents being derived from mandrake plant.Epipodophyllotoxin affects cell by forming ternary complexes with topoisomerase II and DNA usually within the S phase and G2 phase of cell cycle, thus causes DNA break.Chain interruption accumulation also causes cell death subsequently.The example of epipodophyllotoxin includes but not limited to, etoposide and teniposide.Etoposide 4 '-demethylation-epipodophyllotoxin 9 [4,6-0-(R)-ethylidene-β-D-pyranglucoside] is as Injectable solution or capsule commercially available and be commonly referred to VP-16.Etoposide instruction treats carcinoma of testis and nonsmall-cell lung cancer as single medicament or with other chemotherapeutic combination.Bone marrow depression is modal etoposide side effect.Leukopenic sickness rate is often more serious than thrombocytopenia.Teniposide 4 '-demethylation-epipodophyllotoxin 9 [4,6-0-(R)-thenylidene-β-D-pyranglucoside] is as Injectable solution commercially available and be commonly referred to VM-26.Teniposide instruction treats acute leukemia as single medicament or with other chemotherapeutic combination.Bone marrow depression is the dose-limiting side effect of modal teniposide.Teniposide can induce leukopenia and thrombocytopenia.Other Topoisomerase II inhibitors comprise epirubicin, idarubicin, Nemorubicin, mitoxantrone and losoxantrone.

Antimetabolite oncology pharmacy comprises phase specific anti-tumor agents, and it is by suppressing DNA synthesis or the S phase (DNA synthesis) by suppressing purine or pyrimidine bases synthesis to act on cell cycle, thus restricted dna synthesis.Therefore, the S phase can not proceed and cell death subsequently.The example of antimetabolite oncology pharmacy includes but not limited to, fluorouracil, methotrexate, cytarabine, mercaptopurine, thioguanine and gemcitabine.5-fluorouracil 5-fluoro-2,4-(1H, 3H) hybar X is commercially available as fluorouracil.Using 5-fluorouracil makes thymidylic acid synthesis be inhibited and also be incorporated in both RNA and DNA.Its result is generally cell death.5-fluorouracil instruction treats breast carcinoma, colon and rectum carcinoma, gastric cancer and cancer of pancreas as single medicament or with other chemotherapeutic combination.Bone marrow depression and mucositis are the dose-limiting side effect of 5-fluorouracil.Other fluoropyrimidine analogues comprise floxuridine (BrdU) and floxuridine monophosphate.The conduct of cytarabine 4-amino-1-β-D-R furyl glycosyl-2 (1H)-pyrimidone commercially available and be commonly referred to Ara-C.Think that cytarabine suppresses DNA chain lengthening by DNA chain cytarabine end being incorporated into growth, thus show cell cycle specific in the S-phase.Cytarabine instruction treats acute leukemia as single medicament or with other chemotherapeutic combination.Other cytidine analogs comprise U-18496 and 2 ', 2 '-difluoro deoxycytidine (gemcitabine).Cytarabine induction leukopenia, thrombocytopenia and mucositis.The conduct of mercaptopurine 1,7-dihydro-6H-purine-6-thioketone monohydrate commercially available.Mercaptopurine shows cell cycle specific by suppressing DNA synthesis via some non-specific mechanism in the S phase.Mercaptopurine instruction treats acute leukemia as single medicament or with other chemotherapeutic combination.Expection bone marrow depression stomach function regulating esoenteritis is the side effect of high dose mercaptopurine.Useful mercaptopurine analog is azathioprine.Amino-1, the 7-dihydro-6H-purine-6-thioketone conduct of thioguanine 2- commercially available.Thioguanine shows cell cycle specific by suppressing DNA synthesis via some non-specific mechanism in the S phase.Thioguanine instruction treats acute leukemia as single medicament or with other chemotherapeutic combination.Bone marrow depression, comprises leukopenia, thrombocytopenia and anemia, is the dose-limiting side effect that modal thioguanine is used.But, there is gastrointestinal side-effect and described gastrointestinal side-effect can be dose-limiting.Other purine analogues comprise pentostatin, erythro hydroxynonyl adenine, fludarabine phosphate and cladribine.Gemcitabine 2 '-deoxy-2 ', 2 '-difluoro cytidine mono-hydrochloric salts (beta-isomer) conduct commercially available.Gemcitabine is shown cell cycle specific in the S-phase and is undertaken by G1/S boundary by blocking cell progression.Gemcitabine instruction is treated local advanced non small cell lung cancer with cisplatin combination and treats Local advanced pancreatic carcinoma separately.Bone marrow depression, comprises leukopenia, thrombocytopenia and anemia, is the dose-limiting side effect that modal gemcitabine is used.Methotrexate N-[4-[[(2,4-diaminourea-6-pteridyl) methyl] methylamino] benzoyl]-Pidolidone is commercially available as methotrexate sodium.Methotrexate suppresses DNA to synthesize, repair and/or copy by suppressing the dihydrofolate reductase required for purine nucleotides and thymidylic acid synthesis, thus shows cell cycle action specificity in the S phase.Methotrexate is designated as single medicament or treats choriocarcinoma, meningeal leukemia, non-Hodgkin lymphoma and breast carcinoma, head cancer, cervical region cancer, ovarian cancer and bladder cancer with other chemotherapeutic combination.Expection bone marrow depression (leukopenia, thrombocytopenia and anemia) and mucositis are that methotrexate uses independent side effect.

Topoisomerase I inhibitor comprises camptothecin as camptothecine and camptothecin derivative.Think that camptothecine cellular cytoxicity activity is relevant to its topoisomerase I inhibit activities.The example of camptothecine includes but not limited to, irinotecan and topotecan.Topotecan HCl, (4S)-4,11-diethyl-4-hydroxyl-9-[(4-piperidinyl piperidine base) ketonic oxygen base]-1H-pyrans also [3 ', 4 ', 6,7] indolizino [1,2-b] quinoline-3,14 (4H, 12H)-child's hydrochlorate, as Injectable solution commercially available.Topotecan is the derivant of camptothecine, and it and active metabolite SN-38 thereof are combined with topoisomerase I-DNA complex.Think due to topoisomerase I: DNA: topotecan or SN-38 ternary complexes and replicative enzyme interact and cause unrepairable double-strand break and occur cytotoxicity.Topotecan instruction treatment transitivity colon cancer or rectal cancer.The dose-limiting side effect of topotecan HCl is bone marrow depression, comprises neutropenia and GI effect, comprises diarrhoea.Topotecan HCl, (S)-10-[(dimethylamino) methyl]-4-ethyl-4,9-dihydroxy-1H-pyrans also [3 ', 4 ', 6,7]-indolizino [1,2-b] quinoline-3,14-(4H, 12H)-diketone mono-hydrochloric salts, as Injectable solution commercially available.Topotecan is be combined with topoisomerase I-DNA complex and prevent topoisomerase I from causing strand to connect the camptothecin derivative of fracture again in response to DNA molecular torsional strain.Topotecan instruction second line treatment Metastatic carcinoma in the ovary and small cell lung cancer.The dose-limiting side effect of topotecan HCl is bone marrow depression, is mainly neutropenia.

Hormone and hormone analogs are the useful compound being used for the treatment of certain cancers, and in these cancers, hormone and growth of cancers and/or grow exists relation between lacking.The example of the hormone and hormone analogs that are applicable to treatment of cancer includes but not limited to, is applicable to the adrenocortical steroid for the treatment of malignant lymphoma and acute leukemia as prednisone and prednisolone; Be applicable to treat adrenocortical carcinoma and the aminoglutethimide of hormone-dependent type breast carcinoma containing estrogen receptor and other aromatase inhibitors as aminoglutethimide, Rogletimide, (.+-.)-Pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, Anastrozole, letrozole, Formestane, atamestane and exemestane; Be applicable to the progesterone for the treatment of hormone-dependent type breast carcinoma and carcinoma of endometrium as megestrol acetate; Be applicable to the estrogen for the treatment of carcinoma of prostate and benign prostatauxe, androgen and androgen antagonist, if Drogenil, nilutamide, bicalutamide, cyproterone acetate and 5α-reductase are as finasteride and dutasteride; Be applicable to the anti-estrogens for the treatment of hormone-dependent type breast carcinoma and other susceptibility cancers, as fulvestrant, tamoxifen, toremifene, raloxifene, droloxifene, idoxifene and selective estrogen receptor modulators (SERMS), such as U.S. Patent number 5,681,835,5,877,219 and 6,207, those described in 716; And stimulating lutropin (LH) and/or follicle-stimulating hormone (FSH) release for gonadotropin-releasing hormone (GnRH) and the analog thereof for the treatment of carcinoma of prostate, such as LHRH agonist and antagonist are as 1: PN: WO02056903 PAGE: 25 claimed protein, goserelin, goserelin acetate and leuprorelin.SH2/SH3 domain blocker is the medicament of SH2 or the SH3 domain destroyed in various enzyme or adaptin, and these enzymes or adaptin comprise PI3-Kp85 subunit, Src family kinase, adapter molecule (Shc, Crk, Nck, Grb2) and Ras-GAP.As the SH2/SH3 domain of cancer therapy drug target in Smithgall, T.E. (1995), discuss in JournalofPharmacologicalandToxicologicalMethods.34 (3) 125-32.Serine/threonine kinase inhibitor, comprise map kinase cascade blocker, comprise the blocker of Raf kinases (RAFK), mitogen or extracellular signal-regulated kinase (MEK) and extracellular signal-regulated kinase (ERK); And Protein kinase C family member blocker, comprise PKC (α, β, γ, ε, μ, λ, blocker ζ).IkB kinase families (IKKa, IKKb), PKB family kinase, Akt kinase families member and TGF beta receptor kinases.This type of serine/threonine kinase and inhibitor thereof are described in Yamamoto, T., Taya, S., Kaibuchi, K.., (1999), JournalofBiochemistry.126 (5) 799-803; Brodt, P., Samani, A. and Navab, R. (2000), BiochemicalPharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) CancerSurveys.27:41-64; Philip, P.A. and Harris, A.L. (1995), the BioorganicandMedicinalChemistryLetters such as CancerTreatmentandResearch.78:3-27, Lackey, K., (10), 2000,223-226; U.S. Patent number 6,268,391; And Martinez-Iacaci, L., etc., Int.J.Cancer (2000), 88 (1), 44-52.

Also the interested compound used together with compound of the present invention is for inositol signal transduction inhibitor is as phospholipase C blocker and myo-mositol analog.This type of signal suppressing agent is described in Powis, G. and Kozikowski, A., and (1994) NewMolecularTargetsforCancerChemotherapy edits, PaulWorkman and DavidKerr, CRC publishing house 1994, London.

Another group inhibitor is that signal transduction pathway inhibitor is as Ras oncogene inhibitor.This type of inhibitor comprises inhibitor and antisense oligonucleotide, ribozyme and the immunotherapy of farnesyl tranfering enzyme, Herba Pelargonii Graveolentis acyl Herba Pelargonii Graveolentis acyltransferase and CAAX protease.This type of inhibitor has shown the intracellular ras activation of retardance containing wild saltant type ras, thus is used as antiproliferative.Ras oncogene suppresses at Scharovsky, O.G., Rozados, V.R., Gervasoni, S.I., Matar, P. (2000), JournalofBiomedicaiScience.7 (4) 292-8; Ashby, M.N. (1998), CurrentOpinioninLipidology.9 (2) 99-102; And BioChim.Biophys.Acta, discuss in (19899) 1423 (3): 19-30.

The invention still further relates to a kind of method for using described compound or pharmaceutical composition and other tumor therapeuticing methods to combine, other tumor therapeuticing methods described comprise operation, ionizing radiation, optical dynamic therapy or implant, such as, use corticosteroid, hormone or be used as radiosterilization.

A kind of such method can be the radiotherapy such as suppressing abnormal cell growth or treatment mammal to breed too much disease.Using radiocurable technology is known in this area, and uses in these technology combination treatment that can describe in this article.The compounds of this invention using in this combination treatment can as described hereinly be determined.

Radiotherapy is by the combined administration of a kind of or method in several method, and described method includes but not limited to external beam treatment, internal-radiation therapy, implant X-ray therapy, stereotaxic radiosurgery operation, systemic radiation therapy, X-ray therapy and lasting or temporary transient interstitial brachytherapy.As used herein, term " brachytherapy " refers to by embedding health, tumor or other hyperproliferative tissue disease site places or near the radiotherapy sent of spatially limited active material.Described term is intended to include but not limited to be exposed to radiosiotope (radiosiotope of such as At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32 and Lu).The radioactive source being suitable for use as cell modulator of the present invention comprises solid and liquid.As limiting examples, described radioactive source can be radionuclide, such as I-125, I-131, Yb-169, Ir-192 (as solid source), I-125 (as solid source) or radiation photon, beta-particle, gamma-rays or other treatment ray other radionuclides.Described active material also can, for the fluid be made up of any solution (solution of such as I-125 or I-131) of radionuclide, maybe can use the suitable fluid slurry containing Solid radionuclides (such as Au-198, Y-90) small-particle to prepare radioactive fluid.In addition, described radionuclide can be contained in gel or radioactive microsphere.

Be not bound by any theory, the compounds of this invention can make abnormal cell kill and/or suppress the radiotherapy of this type of Growth of Cells more responsive to being used for.Therefore, the invention further relates to and make the abnormal cell in mammal become responsive method to radiotherapy, described method comprises a certain amount of the compounds of this invention of administration or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant, and described amount can make abnormal cell become responsive to radiotherapy effectively.The amount of described compound, salt or solvate in the method can measure according to the method for the effective dose for determining this compounds described herein.

Optical dynamic therapy comprises the therapy using some chemicals treatment or the prophylaxis of cancer being called photosensitive compounds.The example of optical dynamic therapy comprises use compound and such as treats as the compound of the fast Da Er of dimension and porfimer sodium.Vascular study sex steroid comprises the compound of retardance or inhibiting angiogenesis, such as, as anecortave, triamcinolone acetonide, hydrocortisone, 11-α-Biao hydrocortisone (epihydrocotisol), corticosterone, 17 α-hydroxyprogesterone, cortex fat ketone, deoxycorticosterone, Testosterone, estrone and dexamethasone.

Implant containing corticosteroid comprises the compound of such as fluocinolone acetonide and dexamethasone.Other chemotherapy compounds include but not limited to, plant alkaloid, hormonal compounds and antagonist; Biological response modifier, preferably lymphokine or interferons; Antisense oligonucleotide or oligonucleotide derivative; ShRNA or siRNA; Or various compound or there is the compound of other or unknown role mechanism.

Compound of the present invention or pharmaceutical composition can use with a certain amount of one or more combinations of substances being selected from anti-angiogenic agent, signal transduction inhibitor and antiproliferative.

Anti-angiogenic agent (such as MMP-2 (matrix-metalloprotienase 2) inhibitor, MMP-9 (matrix-metalloprotienase 9) inhibitor and COX-11 (cyclooxygenase 11) inhibitor) can use with the compounds of this invention described herein and pharmaceutical composition.The example of useful COX-II inhibitor comprises CELEBREX ^tM(alecoxib), valdecoxib and rofecoxib.The example of useful matrix-metalloprotienase inhibitor is described in WO96/33172 (on October 24th, 1996 is open), WO96/27583 (on March 7th, 1996 is open), No. 97304971.1st, european patent application (submission on July 8th, 1997), No. 99308617.2nd, european patent application (submission on October 29th, 1999), WO98/07697 (on February 26th, 1998 is open), WO98/03516 (on January 29th, 1998 is open), WO98/34918 (on August 13rd, 1998 is open), WO98/34915 (on August 13rd, 1998 is open), WO98/33768 (on August 6th, 1998 is open), WO98/30566 (on July 16th, 1998 is open), European patent discloses 606,046 (on July 13rd, 1994 is open), European patent discloses 931,788 (on July 28th, 1999 is open), WO90/05719 (May 31 nineteen ninety is open), WO99/52910 (on October 21st, 1999 is open), WO99/52889 (on October 21st, 1999 is open), WO99/29667 (on June 17th, 1999), No. PCT/IB98/01113rd, PCT international application (submission on July 21st, 1998), No. 99302232.1st, european patent application (submission on March 25th, 1999), No. 9912961.1st, UK Patent Application (submission on June 3rd, 1999), U.S. Provisional Application the 60/148th, No. 464 (submission on August 12nd, 1999), United States Patent (USP) 5,863,949 (on January 26th, 1999 is open), United States Patent (USP) 5,861,510 (on January 19th, 1999 is open) and European patent disclose 780, and 386 (on June 25th, 1997 is open), all these is incorporated to herein with way of reference entirety at this.In some embodiments, MMP-2 and MMP-9 inhibitor almost or not do not suppress MMP-1 activity or relative to other matrix-metalloprotienase (that is, MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12 and MMP-13) Selective depression MMP-2 and/or AMP-9.Be AG-3340, RO32-3555 and RS13-0830 to some instantiations of the useful MMP inhibitor of the present invention.

The present invention also relates to a kind of method and pharmaceutical composition of cardiovascular disease for the treatment of in mammal, described pharmaceutical composition comprises a certain amount of inhibitor of the present invention or its pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate or derivant or its isotope-labeled derivant, and a certain amount of one or more are used for the treatment of the therapeutic agent of cardiovascular disease.

Example medicament for cardiovascular disease application is antithrombotic agents, such as prostacyclin and salicylic acid salt; Thrombolytics, such as streptokinase, urokinase, tissue plasminogen activator (TPA) and anisoyl-plasminogen streptokinase activator complex (APSAC); Anti-platelet agents, such as aspirin (ASA) and clopidogrel; Vasodilation, such as nitrate, calcium channel blocker; Antiproliferative, such as colchicine and alkylating agent; Intercalator; Growth regulator, such as interleukin, transforming growth factor-β and platelet-derived growth factor congener; Growth factor monoclonal antibody; Steroidal and NSAID (non-steroidal anti-inflammatory drug); And to other medicaments of the healing response of blood vessel or organ injury after scalable blood vessel elasticity, function, arteriosclerosis and intervention.Antibiotic also can be included in the compositions or coating that the present invention includes.In addition, coating can be used for realizing treating to centrality in blood vessel wall sending.By activating agent is merged in the polymer of swellable, can when described polymers swell release bioactive agent.

The medicine can used with compound combination described herein comprises such as, such as, by sucking any suitable medicine effectively sent, analgesic, codeine, paramorphane, Ergotamine, fentanyl or morphine; Anginal preparations, such as diltiazem; Anti-allergic agent, such as cromoglycate, ketotifen or nedocromil; Anti-infective, such as cephalosporins, penicillins, streptomycin, sulfonamides, Tetracyclines or pentamidine; Antihistaminic, such as methapyrilene; Anti-inflammatory agent, such as beclometasone, flunisolide, budesonide, tipredane, triamcinolone acetonide or fluticasone; Cough medicine, such as narcotine; Bronchodilator, amino-3, the 5-bis-chloro-α of such as ephedrine, epinephrine, fenoterol, formoterol, isoproterenol, orciprenaline, phyenlephrinium, phenylpropanolamine, pirbuterol, reproterol, rimiterol, salbutamol, salmaterol, terbutaline, isoetarine, tulobuterol, orciprenaline or (-)-4--[[[6-[2-(2-pyridine radicals) ethyoxyl] hexyl] is amino] methyl] benzyl alcohol; Diuretic, such as amiloride; Anticholinergic, such as ipratropium, atropine or oxitropine; Hormones, such as cortisone, hydrocortisone or prednisolone; Xanthine, such as aminophylline, Oxtriphylline, theophylline-lysine or theophylline; And therapeutic protein and peptide, such as insulin or glucagon.It is clear to the skilled person that, in appropriate circumstances, described medicine can in the form of salts (such as alkali metal salt or amine salt or as acid-addition salts) or use, to make activity and/or the optimal stability of medicine as ester (such as lower alkyl esters) or as solvate (such as hydrate).

Other exemplary treatment agent that can be used for combination treatment include but not limited to medicament as above, radiotherapy, hormone antagonist, hormone and their releasing factor, thyroid and antithyroid drug, estrogens and progestogens, androgens, thyroliberin; Adrenocortical steroid and their synthetic analogues; The synthesis of adrenocortical hormones and the inhibitor of effect, insulin, oral hypoglycemic and endocrine pancreas pharmacology, affect the medicament that calcification and bone upgrade: calcium, phosphate, parathyroid hormone, vitamin D, calcitonin, vitamin (such as water soluble vitamins, compound vitamin B, ascorbic acid, fatsoluble vitamin, vitamin A, K and E), somatomedin, cytokine class, chemotactic factor class, agonists of muscarinic receptors and antagonist; Anticholinesterase; Act on the medicament of neuromuscular junction and/or autonomic ganglion; Catecholamines, sympathomimetic and 3 adrenergic receptor agonists or antagonist; And 5-hydroxy tryptamine (5-HT, serotonin) receptor stimulating agent and antagonist.

Therapeutic agent also can comprise the medicament for pain and inflammation, such as histamine and histamine antagonist, Kallidin I and brad ykinin antagonists, 5-hydroxy tryptamine (serotonin), the lipid matter generated is transformed by the biology of the optional water hydrolysis products of membrane phospholipid, Eicosanoids, prostaglandins, thromboxanes, leukotrienes, aspirin, non-steroidal anti-inflammatory agent, pain relieving-antipyretic, suppress the medicament of prostaglandins and thromboxanes synthesis, the selective depressant of cyclooxygenase can be induced, the selective depressant of COX-2 can be induced, autacoid, paracrine hormone, somatostatin, gastrin, mediation relates to the interactional cytokine of humoral and cellular immune response reaction, the autacoid that lipid is derivative, Eicosanoids, beta-adrenergic agonist, ipratropium, glucocorticoids, methylxanthine, sodium channel inhibitor, opioid receptor agonists, calcium channel blocker, membrane stabilizer and leukotriene inhibitors.

The other therapeutic agent comprised herein comprises diuretic, vassopressin, the kidney that affects water are preserved medicament, Chymosin, angiotensin, to useful medicament, hypotensive agent, angiotensin converting enzyme inhibitor, the B-adrenergic receptor antagonist for the treatment of myocardial ischemia, be used for the treatment of the medicament of hypercholesterolemia and be used for the treatment of the medicament of dyslipidemia.

The other treatment agent comprised comprises the medicine for controlling gastric acidity, the medicament being used for the treatment of peptic ulcer, the medicament being used for the treatment of gastroesophageal reflux disease, short digestive tract power reinforcing medicine, Bendectin, the medicament for irritable bowel syndrome, the medicament for suffering from diarrhoea, the medicament for constipation, the medicament for inflammatory bowel, the medicament for biliary diseases, the medicament for pancreatic diseases.Be used for the treatment of the therapeutic agent of protozoan infection, be used for the treatment of malaria, the medicine of amebiasis, giardiasis, trichomoniasis, african trypanosomiasis and/or leishmaniasis, and/or for verminotic chemotherapeutical medicine.Other treatment agent comprises antimicrobial, sulfonamides, trimethoprim-sulfalene azoles quinolinones and for the medicament of urinary tract infection, penicillins, cephalosporins and other beta-Lactam antibiotic classes, the medicament comprising aminoglycoside, protein synthesis inhibitor, the chemotherapeutical medicine for pulmonary tuberculosis, Mycobacterium avium compound bacteria group disease and leprosy, antifungal, antiviral agent (comprising non-anti-retroviral agent and antiretroviral agent agent).

The example of the therapeutic antibodies that can combine with motif compound includes but not limited to anti-receptor tyrosine kinase antibody (Cetuximab, handkerchief wood monoclonal antibody, Herceptin), anti-CD 20 antibodies (Rituximab, tositumomab) and other antibody (such as A Lun pearl monoclonal antibody, Avastin and lucky trastuzumab).

In addition, method herein comprises for immunoregulatory therapeutic agent (such as immunomodulator, immunosuppressant, toleragen and immunopotentiating agent).In addition, also comprise and act on that blood and blood form the therapeutic agent of organ, blood generates preparation, somatomedin, minerals and vitamins, anticoagulant, thrombolytic and antiplatelet drug.

The other treatment agent can combined with motif compound is found in " ThePharmacologicalBasisofTherapeutics " of Goodman and Gilman, tenth edition, Hardman, Limbird and Gilman write, or Physician ' sDeskReference, both is all incorporated to herein with way of reference entirety at this.

The embodiment below provided and preparation method further illustrate and illustrate the compounds of this invention and prepare the method for this compounds.Should be appreciated that scope of the present invention is limited to the scope of following examples and preparation never in any form.In the examples below, unless otherwise noted, the molecule with single chiral center exists as racemic mixture.Unless otherwise noted, the molecule with two or more chiral centres exists as the racemic mixture of diastereomer.Single enantiomer/diastereomer obtains by method known to those skilled in the art.

therapeutic scheme

Present invention also offers a kind of therapeutic scheme, in described therapeutic scheme, use the combination of PI3-kinases alpha inhibitor and/or mTOR inhibitors to experimenter.In some versions, described combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein said PI3-kinases alpha inhibitor and/or mTOR inhibitors exist with sub-therapeutic dose.In some versions, compared with the PI3-kinases alpha inhibitor of once-a-day administration dose,equivalent and/or mTOR inhibitors, described scheme is effective in and realizes (a) higher therapeutic efficiency, (b) PI3-kinases alpha inhibitor and/or mTOR inhibitors is similar or better toleration and (c) similar or less area under curve.Term as used herein " dose,equivalent " points to experimenter to use single dose or the multiple dose of a period of time, and described a period of time comprises one day, several days, one week, one month or for more time.In some versions, such as one week inner evaluation equivalence within the treatment cycle time.Term dose,equivalent is not limited to the equal number of the compound using fixed time section, and refers to the dosage causing tolerance level similar.As an example, when relatively the solution of the present invention (using weekly PI3-kinases alpha inhibitor and/or mTOR inhibitors that accumulated dose is 50mg off and on) and a kind of scheme (wherein daily PI3-kinases alpha inhibitor and/or mTOR inhibitors), because dose-limiting toxicity and/or restricted toleration are by using the accumulated dose that only can realize being less than 50mg (such as, about 40-45mg) every day.In the case, in intermittent ann, use weekly the accumulated dose of about 40-45mg weekly that accumulation 50mg dosage " equivalence " was used every day.

Such as, dosage regimen is effective in the PI3-kinases alpha inhibitor/mTOR inhibitors plasma concentration realizing being greater than about 80,90,100,100,120,130,140,150 or 160nM in 7 days time of application sections, continues to be longer than the persistent period of about 5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 or 35 hours.In some cases, described scheme is effective in the PI3-kinases alpha inhibitor/mTOR inhibitors plasma concentration realizing being greater than about 100nM in 7 days time of application sections, continues to be longer than the persistent period of about 20,21,22,23,24,25,26,27,28,29,30,31,32,33,34 or 35 hours.In other cases, described scheme is effective in the PI3-kinases alpha inhibitor/mTOR inhibitors plasma concentration realizing being greater than about 100nM in 7 days time of application sections, continues to be longer than the persistent period of about 20 or about 30 hours.

The present invention also provides a kind of therapeutic scheme, the Cmax about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 60%, 70%, 80%, 90%, 100%, 150%, 200%, 250% or 300% that its Cmax effectively realized realizes than the PI3-kinases alpha inhibitor/mTOR inhibitors of once-a-day administration dose,equivalent.Such as, the Cmax realized is greater than about 100,200,250,300,350,400,450,500,550 or 600nM.In some cases, the Cmax realized is greater than about 200,250,300,350,400,450,500,550 or 600nM.Such as, Cmax is greater than 200nM.Or Cmax is greater than 300nM.In other cases, the Cmax realized is between 200 and 600nM.In other cases, the Cmax realized is between 200 and 500nM.In other cases, the Cmax realized is between 200 and 500nM.

In some embodiments, intermittent therapy scheme of the present invention realizes suppressing with PI3-kinases alpha inhibitor/mTOR inhibitors better approach that is similar or ratio of once-a-day administration dose,equivalent.Approach suppresses the phosphorylation that can be measured as the protein being such as selected from p4EBP1, pS6 and pRAS40 to reduce percentage ratio.In some embodiments, approach suppresses the phosphorylation being measured as p4EBP1 to reduce 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or larger.Such as, the phosphorylation of p4EBP1 reduces at least 60%.In other embodiments, approach suppresses the phosphorylation being measured as pS6 to reduce 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or larger.Such as, the phosphorylation of pS6 reduces at least 60%.In other embodiments, approach suppresses the phosphorylation being measured as pRAS40 to reduce 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or larger.Such as, the phosphorylation of pRAS40 reduces at least 60%.In other embodiments, approach suppresses the phosphorylation being measured as p4EBP1, pS6 and pRAS40 to reduce 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or larger.Such as, the phosphorylation of p4EBP1, pS6 and pRAS40 reduces at least 60%.In some embodiments, approach of measuring in peripheral blood cells suppresses.In other embodiments, measure approach with biopsy such as Skin biopsy to suppress.

In some embodiments, intermittent therapy scheme of the present invention realizes better tolerance level that is similar with the PI3-kinases alpha inhibitor/mTOR inhibitors of once-a-day administration dose,equivalent or ratio.Tolerance level can be measured as the generation of such as 3 grades or more senior adverse events or not occur.In some embodiments, adverse events is erythra, hyperglycemia, lymphopenia, diarrhoea, gamma glutamyltransferase increase, hypokalemia, hyponatremia, pruritus wind, thrombocytopenia, epigastric pain, anemia, aspartate transaminase increase, weakness, catheter related infection, cellulitis, disease progression, Enteral fistulas, gastroenteritis, acute pancreatitis, pleural effusion, erythematous eruption, sleepy or urinary tract infection.Such as, adverse events is erythra.

In some embodiments, given medication comprises one or many and uses PI3-kinases alpha inhibitor/mTOR inhibitors, wherein use at least one times PI3-kinases alpha inhibitor/mTOR inhibitors as described herein those, can every day, weekly, every two weeks, monthly, per bimester, annual, every half a year or any other time period repeat or circulate.The dosage regimen repeated or cycle can repeat, and continue the set time section determined when scheme starts; Can stop, extend or otherwise adjust based on therapeutical effect measured value, described measured value is as the level (such as, reducing at least 50%, 60%, 70%, 80%, 90%, 95%, 99% or 100%) reduced under the existence of detectable disease tissue; Or can stop, extend or otherwise adjust for other reasons, as determined by medical expert.

In some dosage regimens, described dosage regimen is intermittent ann.Preferably, described intermittent ann comprises at least one cycle that the treatment phase of at least 1 day is then the rest period of at least 1 day.Such as, intermittent dosing regimen can comprise at least one cycle that the treatment phase of 2,3,4,5,6 or 7 Consecutive Days is then the rest period of at least 1 day.In some versions, at least one 7 day cycle of intermittent dosing regimen comprises the treatment phase of 2,3,4,5,6 or 7 Consecutive Days be then treatment phase at least one cycle, at least 1 day of the rest period of at least 3,4 or 5 Consecutive Days is then at least one cycle of the rest period of 6 Consecutive Days, the treatment phase of 3 Consecutive Days is then at least one 7 day cycle of the rest period of 4 Consecutive Days, the treatment phase of 5 Consecutive Days, to be then at least one 7 day cycle of the rest period of 2 Consecutive Days or the treatment phase of 1 Consecutive Days be then rest period of 6 Consecutive Days.In some versions, intermittent dosing regimen comprises at least one 7 day cycle, at least 3 treatment phases next day of between the described cycle was included in 7 days.

In some combined therapy schemes, use (a) according to the PI3-kinases alpha inhibitor of the treatment effective dose of the first dosage regimen and (b) according to the combination of the mTOR inhibitors of the treatment effective dose of the second dosage regimen to experimenter.First dosage regimen and the second medication can be different or can be identical and use simultaneously.Each dosage regimen comprises the repetition period that the treatment phase is then the rest period independently.Preferably, at least one dosage period has a rest period more than 0 day.In some assembled schemes, one of first scheme and the second dosage regimen are not intermittent ann, are continuous scheme.Such as, in some schemes, first scheme or alternative plan have the rest period of 0 day.Preferably, the first dosage regimen has the rest period of 0 and the second dosage regimen is intermittent ann.Such as, at least one 7 day cycle of the second dosage regimen can comprise the treatment phase of 5 Consecutive Days to be then at least one 7 day cycle of the rest period of 2 Consecutive Days or the treatment phase of 1 Consecutive Days be then rest period of 6 Consecutive Days.

In some combined therapy schemes, the treatment phase that the first and/or second dosage regimen comprises at least 1 day independently is then at least one cycle of the rest period of at least 1 day.Such as, the first and/or second dosage regimen can comprise at least one cycle that the treatment phase of 2,3,4,5,6 or 7 Consecutive Days is then the rest period of at least 1 day independently.In some versions, the first and/or second dosage regimen comprises the treatment phase of 2,3,4,5,6 or 7 Consecutive Days independently, is then at least one cycle of the rest period of at least 3,4 or 5 Consecutive Days.Preferably, the first and/or second dosage regimen comprises the treatment phase of at least 1 day independently, is then at least one cycle of the rest period of 6 Consecutive Days.More preferably, at least one 7 day cycle of the first and/or second dosage regimen comprises the treatment phase of 3 Consecutive Days independently be then at least one 7 day cycle of the rest period of 4 Consecutive Days or the treatment phase of 5 Consecutive Days be then at least one 7 day cycle of the rest period of 2 Consecutive Days or the treatment phase of 1 Consecutive Days to be then at least one 7 day cycle of the rest period of 6 Consecutive Days or the treatment phase of 1 Consecutive Days be then rest period of 6 Consecutive Days.Optionally, the first dosage regimen and the second dosage regimen are identical and use simultaneously.

In some schemes, PI3-kinases alpha inhibitor/mTOR inhibitors and/or any additional procedures compound of the present invention are used with multiple dose.Dosage regimen can be about every day or weekly, twice, three times, four times, five times, more than six times or six times.Dosage regimen can be about monthly, once every two weeks, once in a week or every other day once.In some schemes, using PI3-kinases alpha inhibitor/mTOR inhibitors is then cycle of rest period (intermittently) repeat to exceed about 6,10,14,28 days, two months, six months or 1 year.In some schemes, as long as necessary, just continue to repeat to comprise the dosage period used PI3-kinases alpha inhibitor/mTOR inhibitors and then have a rest.As long as necessary, use therapeutic scheme of the present invention with regard to sustainable.In some schemes, PI3-kinases alpha inhibitor/mTOR inhibitors of the present invention was used more than 1,2,3,4,5,6,7,14 or 28 day.In some schemes, PI3-kinases alpha inhibitor/mTOR inhibitors of the present invention is used and is less than 28,14,7,6,5,4,3,2 or 1 days.In some versions, PI3-kinases alpha inhibitor/mTOR inhibitors of the present invention is used chronically on the basis of carrying out, such as, be used for the treatment of chronic effect.

The amount of the PI3-kinases alpha inhibitor/mTOR inhibitors used herein can change according to the application of expection (external or body in) or the experimenter treated and disease condition (order of severity, method of application etc. of the body weight of such as experimenter and age, disease condition), and it easily can be determined by persons skilled in the art.

Dosage form of the present invention points to the substance preparation of the medicine that patient uses.When dosage form is solid, dosage form can be single capsule, tablet or pill, or alternately comprises multiple capsule, tablet or pill.Dosage form can use one or many to experimenter every day.The method of the most effective method of application and dosage of determining is known for those skilled in the art and is changed along with the compositions be used for the treatment of, therapeutic purposes, the target cell treated and the experimenter that treats.Dosage level selected by doctor and mode can be treated perform single or multiple and use (such as, about or exceed about 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,25,30 or more dosage).

Inhibitor can any applicable amount be used.In some versions, described combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein said PI3-kinases alpha inhibitor and/or mTOR inhibitors exist with sub-therapeutic dose.Comprise in the scheme of combination treatment at some, it is about 0.1 that every circumferential experimenter uses scope, 0.2, 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, 10.0, 10.5, 11.0, 11.5, 12.0, 12.5, 13.0, 13.5, 14.0, 14.5, 15.0, 15.5, 16.0, 16.5, 17.0, 17.5, 18.0, 18.5, 19.0, 19.5, 20.0, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69 or the mTor inhibitor of 70mg.Such as, every circumferential experimenter uses the mTOR inhibitors that scope is about 0.1,0.2,0.5,1,1.5,2.0,2.5,3.0,3.5,4.0,4.5,5.0,5.5,6.0,6.5,7.0,7.5,8.0,8.5,9.0,9.5,10.0,10.5,11.0,11.5,12.0,12.5,13.0,13.5,14.0,14.5,15.0,15.5,16.0,16.5,17.0,17.5,18.0,18.5,19.0,19.5 or 20.0mg.In some versions, every circumferential experimenter uses the mTOR inhibitors that scope is about 1.0,1.5,2.0,2.5,3.0,3.5,4.0,4.5 or 5.0mg.Comprise in the scheme of combination treatment at some, every circumferential experimenter's practical range is about 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 650, 700, 750, 800, 850, 900, 950 or the PI3-kinases alpha inhibitor of 1000mg.Such as, every circumferential experimenter uses the PI3-kinases alpha inhibitor that scope is about 100,110,120,130,140,150,160,170,180,190,200,210,220,230,240,250,260,270,280,290,300,310,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490 or 500mg.In some versions, every circumferential experimenter's practical range is the PI3-kinases alpha inhibitor of about 300,310,320,330,340,350,360,370,380,390,400,410,420,430,440,450,460,470,480,490 or 500mg.

In some embodiments, every day uses to experimenter the inhibitor that scope is about 0.1mg/kg-50mg/kg, such as daily about, to be less than about or more than about 0.1mg/kg, 0.2mg/kg, 0.3mg/kg, 0.4mg/kg, 5mg/kg, 6mg/kg, 7mg/kg, 8mg/kg, 9mg/kg, 10mg/kg, 11mg/kg, 12mg/kg, 13mg/kg, 14mg/kg, 15mg/kg, 16mg/kg, 17mg/kg, 18mg/kg, 19mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg or 50mg/kg.In some embodiments, every day uses to experimenter the inhibitor that scope is about 0.1mg/kg-400mg/kg, such as daily about, is less than about or is greater than about 1mg/kg, 5mg/kg, 10mg/kg, 15mg/kg, 20mg/kg, 25mg/kg, 30mg/kg, 35mg/kg, 40mg/kg, 45mg/kg, 50mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 300mg/kg, 350mg/kg or 400mg/kg.In some embodiments, monthly use to experimenter the inhibitor that scope is about 0.1mg/kg-1500mg/kg, such as, monthly use about, be less than about or be greater than about 50mg/kg, 100mg/kg, 150mg/kg, 200mg/kg, 250mg/kg, 300mg/kg, 350mg/kg, 400mg/kg, 450mg/kg, 500mg/kg, 550mg/kg, 600mg/kg, 650mg/kg, 700mg/kg, 750mg/kg, 800mg/kg, 850mg/kg, 900mg/kg, 950mg/kg or 1000mg/kg.In some embodiments, every circumferential experimenter uses scope for about 0.1mg/m ²-200mg/m ²inhibitor, such as use weekly about, be less than about or be greater than about 5mg/m ², 10mg/m ², 15mg/m ², 20mg/m ², 25mg/m ², 30mg/m ², 35mg/m ², 40mg/m ², 45mg/m ², 50mg/m ², 55mg/m ², 60mg/m ², 65mg/m ², 70mg/m ², 75mg/m ², 100mg/m ², 125mg/m ², 150mg/m ², 175mg/m ²or 200mg/m ².Target dosage can be used by single dose.Or target dosage can about or more than about 1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,25,30 or more dosage be used.Such as, the dosage of about 20mg/kg can be used with the dose delivery of about 20mg/kg or the dosage of about 6.67mg/kg that can use every three weeks of period of one week weekly weekly, and these natural law can be continuous or discrete.Application program can any scheme according to the present invention repeat, and comprises any application program as herein described.In some embodiments, scope is used for about 0.1mg/m to experimenter ²-500mg/m ²inhibitor, such as about, be less than about or be greater than about 5mg/m ², 10mg/m ², 15mg/m ², 20mg/m ², 25mg/m ², 30mg/m ², 35mg/m ², 40mg/m ², 45mg/m ², 50mg/m ², 55mg/m ², 60mg/m ², 65mg/m ², 70mg/m ², 75mg/m ², 100mg/m ², 130mg/m ², 135mg/m ², 155mg/m ², 175mg/m ², 200mg/m ², 225mg/m ², 250mg/m ², 300mg/m ², 350mg/m ², 400mg/m ², 420mg/m ², 450mg/m ²or 500mg/m ².

The dosage of PI3-kinases alpha inhibitor or mTOR inhibitors can be about, at least about or at the most about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000mg or mg/kg, or any scope derived thus.Contain, the dosage of mg/kg refers to that the inhibitor mg of every kg experimenter's TBW measures.Contain, when giving multiple dosage to patient, the amount of dosage can change or they can be identical.

The amount of application of often kind of compound will depend on treated mammal, the order of severity of disease or condition of illness, application rate, the character of compound and the judgement of prescriber.

Embodiment

The expression of embodiment 1:p110 α/p85 α, p110 β/p85 α, p110 δ/p85 α and p110 γ and inhibition test:

Available for measuring commercial kit or the system of PI3-K activity.Commercial kit or system can be used for the inhibitor and/or the agonist that screen PI3K (including but not limited to PI3-kinases α, β, δ and γ).Example system is PI3-kinases (mankind) HTRF from Upstate ^tMpilot system.Can test according to the step of manufacturer's suggestion.Briefly, described test is time-resolved fluorescence test (timeresolvedFRETassay) of the PIP3 product that indirect inspection is formed by PI3-K activity.Kinase reaction is carried out in microtitration plate (such as 384 hole microtitration plates).Total reaction volume is about 20ul/ hole.In a first step, in each hole, add the test compounds of 2ul in 20% dimethyl sulfoxine, obtain 2%DMSO ultimate density.Then in each hole, about 14.5ul kinases/PIP2 mixture (diluting in 1X reaction buffer) is added to make kinases ultimate density for 0.25-0.3ug/ml and PIP2 ultimate density is 10 μMs.By plate sealing and incubated at room 15 minutes.In order to initiation reaction, in each hole, adding 3.5ulATP (diluting in 1X reaction buffer) to make ATP ultimate density is 10 μMs.By plate sealing and incubated at room 1 hour.By adding 5ul stop buffer and carry out cessation reaction subsequently to adding 5ul detection mixture in each hole in each hole.Plate is sealed, incubated at room 1 hour, and reads on suitable plate reader subsequently.Analytical data also uses GraphPadPrism5 to obtain IC50.For PI3K α, β, δ and γ, provide the inhibitor nM concentration reaching IC50.The PI3K α that concentration ratio β, δ and γ are lower suppresses to provide the specificity evidence in this group kinases.Similar test and other tests known in the art can be used for measuring other kinase whose suppression percentage ratio, and other kinases described include but not limited to PI3KII type kinase, phosphoinositide-4 kinases (PI4K) and phosphoinositide-5 kinases (PI5K).

The expression of embodiment 2:Ab1 and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of Ab1 or cross-reactive can be measured according to the method for any step known in the art or following discloses.Such as, compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to recombinant full-lenght Ab1 or Ab1 (T315I) (Upstate) ₂, 200 μMs of ATP (2.5 μ Ci γ-32P-ATP) and 0.5mg/mLBSA test in measure in triplicate.Use the Ab1 peptide substrates EAIYAAPFAKKK passing through and optimize as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 3:Hck and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of Hck or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to recombinant full-lenght Hck ₂, 200 μMs of ATP (2.5 μ Ci γ-32P-ATP) and 0.5mg/mLBSA test in measure in triplicate.Use the Src family kinase peptide substrates EIYGEFKKK optimized as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

Embodiment 4: the expression of Insulin receptor INSR (IR) and inhibition test

The shortage of one or more the compounds of this invention to the cross-reactive of IR receptor kinase or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound described herein can contain 25mMHEPES (pH7.4), 10mMMgCl to IRK domain (Upstate) ₂, 10mMMnCl ₂, 200 μMs of ATP (2.5 μ Ci γ-32P-ATP) and 0.5mg/mLBSA test in measure in triplicate.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 5:Src and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of Src or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to recombinant full-lenght Src or Src (T338I) ₂, 200 μMs of ATP (2.5 μ Ci γ-32P-ATP) and 0.5mg/mLBSA test in measure in triplicate.Use the Src family kinase peptide substrates EIYGEFKKK optimized as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 6:DNA-PK (DNAK) and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of DNAK or cross-reactive can be measured according to any step known in the art.DNA-PK can buy and use DNA-PK pilot system (Promega) to test according to the explanation of manufacturer from Promega.

The expression of embodiment 7:mTOR and inhibition test

The shortage of one or more the compounds of this invention to the cross-reactive of mTor or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 50mMHEPES (pH7.5), 1mMEGTA, 10mMMgCl to restructuring mTOR (Invitrogen) ₂, 2.5mM, 0.01%Tween, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use rat restructuring PHAS-1/4EBP1 (Calbiochem; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

Commercially available for measuring other test kit or the system of mTOR activity.Such as, the LanthaScreen of Invitrogen can be used ^tMkinase assay tests mTOR inhibitors disclosed herein.The time resolution FRET fluorescence platform by the 4EBP1 of the GFP labelling of mTOR tyrosine phosphorylation is measured in this test.Described kinase reaction is carried out in white 384 hole microtitration plates.Total reaction volume is 20ul/ hole, and reaction buffer consists of 50mMHEPES (pH7.5), 0.01% TWEEN-20,1mMEGTA, 10mMMnCl ₂and 2mMDTT.In a first step, in each hole, add the test compounds of 2ul in 20% dimethyl sulfoxide solution, obtain 2%DMSO ultimate density.Then in each hole, the diluent of 8ulmTOR in reaction buffer is added to make ultimate density for 60ng/ml.In order to initiation reaction, in each hole, add 10ulATP/GFP-4EBP1 mixture (diluting in reaction buffer) to make ATP ultimate density be 10 μMs and GFP-4EBP1 ultimate density is 0.5 μM.By plate sealing and incubated at room 1 hour.By adding the anti-pT464EBP1 antibody/EDTA mixture (diluting in TR-FRET buffer) of 10ulTb-to make antibody ultimate density for 1.3nM and EDTA ultimate density carrys out cessation reaction for 6.7mM in each hole.Plate is sealed, incubated at room 1 hour, and subsequently for LanthaScreen ^tMthe plate reader device of TR-FRET reads.Analytical data also uses GraphPadPrism5 to obtain IC50.

Embodiment 8: the expression of vascular endothelial growth receptor and inhibition test

The shortage of one or more the compounds of this invention to the cross-reactive of vegf receptor or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring KDR receptor kinase domain (Invitrogen) ₂, 0.1%BME, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 9:Ephrin receptor B4 (EphB4) and inhibition test

The shortage of one or more the compounds of this invention to the cross-reactive of EphB4 or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring Ephrin receptor B4 kinase domain (Invitrogen) ₂, 0.1%BME, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

Embodiment 10: the expression of EGF-R ELISA (EGFR) and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of EGFR or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring EGF receptor kinase domain (Invitrogen) ₂, 0.1%BME, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The kinase whose expression of embodiment 11:KIT and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of KIT or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring KIT kinase domain (Invitrogen) ₂, 1mMDTT, 10mMMnCl ₂, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 12:RET and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of RET or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound described herein can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring RET kinase domain (Invitrogen) ₂, 2.5mMDTT, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use the Ab1 peptide substrates EAIYAAPFAKKK passing through and optimize as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

Embodiment 13: the expression of platelet derived growth factor B (PDGFR) and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of PDGFR or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring PDG receptor kinase domain (Invitrogen) ₂, 2.5mMDTT, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use the Ab1 peptide substrates EAIYAAPFAKKK passing through and optimize as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 14:FMS related tyrosine kinases 3 (FLT-3) and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of FLT-3 or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring FLT-3 kinase domain (Invitrogen) ₂, 2.5mMDTT, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use the Ab1 peptide substrates EAIYAAPFAKKK passing through and optimize as phosphate acceptors (200 μMs).By cessation reaction on point sample to cellulose phosphate sheet, described cellulose phosphate sheet is with 0.5% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

The expression of embodiment 15:TEK receptor tyrosine kinase (TIE2) and inhibition test

The shortage of one or more the compounds of this invention to the kinase whose cross-reactive of TIE2 or cross-reactive can be measured according to the method for any step known in the art or following discloses.Compound as herein described can contain 25mMHEPES (pH7.4), 10mMMgCl to restructuring TIE2 kinase domain (Invitrogen) ₂, 2mMDTT, 10mMMnCl ₂, 10 μMs of ATP (2.5 μ Ci μ-32P-ATP) and 3 μ g/mLBSA test in test.Use PolyE-Y (Sigma; 2mg/mL) as substrate.By cessation reaction on point sample to nitrocellulose, described nitrocellulose 1MNaCl/1% phosphoric acid washing (about 6 times, each 5-10 minute).Dry and the radioactivity amount be quantitatively transferred by Phosphorescence imaging by sheet.

Embodiment 16:B cell activation and proliferation test

One or more motif compounds suppress the ability of B cell activation and propagation to measure according to standard step known in the art.Such as, set up body outer cell proliferation test, measure living cells metabolize active.In 96 hole microtitration plates, use AlamarBlue to reduce carry out described test.Balb/c spleen B cell is through Ficoll-Paque ^tMpLUS is gradient-purified, then uses MACSB cell separation test kit (Miletenyi) to carry out Magnetic cell sorting.By cell with 90ul and 50,000 cells/well is layered in B cell culture medium (RPMI+10%FBS+Penn/Strep+50 μM of bME+5mMHEPES).Compound disclosed herein is diluted in B cell culture medium and adds with 10ul volume.By plate at 37C and 5%CO ₂30 minutes are hatched under the condition of (0.2%DMSO ultimate density).Add 50ulB cytositimulation mixture (stimulationcocktail) subsequently, described mixture in B cell culture medium containing 10ug/mlLPS or 5ug/mlF (ab ') 2 donkey anti-mouse IgM and 2ng/ml recombined small-mouse IL4.By plate at 37 DEG C and 5%CO ₂condition under hatch 72 hours.AlamarBlue reagent that volume is 15 μ L is added and by plate at 37C and 5%CO in each hole ₂condition under hatch 5 hours.560Ex/590Em reads AlamarBlue fluorescence, and uses GraphPadPrism5 to calculate IC50 value or EC50 value.

Embodiment 17: tumor cell line proliferation test

The ability of one or more motif compound inhibition tumor cell systems propagation measures according to standard step known in the art.Such as, body outer cell proliferation test can be carried out, to measure living cells metabolize activity.In 96 hole microtitration plates, use AlamarBlue to reduce carry out described test.Human tumor cell line derives from ATCC (such as MCF7, U-87MG, MDA-MB-468, PC-3), fusion is grown in T75 flask, trypsin treatment is carried out with 0.25% trypsin, wash once with tumor cell culture base (DMEM+10%FBS), and with 90ul and 5,000 cells/well is layered in tumor cell culture base.Compound disclosed herein is diluted in tumor cell culture base and adds with 10ul volume.By plate at 37C and 5%CO ₂condition under hatch 72 hours.AlamarBlue reagent that volume is 10uL is added and by plate at 37C and 5%CO in each hole ₂condition under hatch 3 hours.Read AlamarBlue fluorescence at 560Ex/590Em, and use GraphPadPrism5 to calculate IC50 value.Expected results shows the potent inhibitor that some compounds of the present invention are tumor cell line propagation under test conditions.

Embodiment 18: anti-tumor in vivo is active

Compound described herein can be evaluated in people and Mus tumor model group.

The tumor model of tolerance paclitaxel

1. clinical sources Ovarian Cancer Model.

This tumor model is set up by the tumor biopsy thing of ovarian cancer patients.Tumor biopsy thing takes from patient.

Every 2 days x5 schemes are used to use compound as herein described to the nude mouse with staged tumors (stagedtumor).

2.A2780Tax human ovarian cancer xenograft (sudden change tubulin).

A2780Tax is the human ovarian cancer model of tolerance paclitaxel.It derives from the sensitivity A2780 maternal (sensitiveparentA2780line) by cell and paclitaxel and verapamil (a kind of MDR reversal agents) are jointly hatched and obtained.Show its tolerance mechanism and MDR to have nothing to do and owing to the sudden change in the gene of coding for beta-tubulin.

Every 2 days x5 schemes can be used to use compound as herein described to the nude mouse with staged tumors.

3.HCT116/VM46 human colon carcinoma xenograft (multidrug resistant).

HCT116/VM46 tolerates colon cancer from the MDR of the maternal development of sensitivity HCT116.(grow in nude mouse) in vivo, HCT116/VM46 as one man shows the height endurability to paclitaxel.

5.M5076 Mus sarcoma model

M5076 is mouse fibrosarcoma, and it tolerates paclitaxel in vivo inherently.

In multidrug resistant human colon carcinoma xenograft HCT/VM46 or any other model known in the art (comprising those models as herein described), one or more the compounds of this invention can combinationally use in vivo with other treatment agent.

Expected results shows the potent inhibitor that one or more compounds of the present invention are tumor growth in vivo under test conditions.

Embodiment 19: Microsomal Stability is tested

The stability of one or more motif compounds measures according to standard step known in the art.Such as, the stability of one or more motif compounds is set up by vitro tests.Specifically, establish Microsomal in vitro stability test, stability when it measures one or more motif compounds and mice, the hepatomicrosome of rat or people reacts.The reaction of microsome and compound is carried out in 1.5mL microcentrifugal tube (Eppendorftube).Often pipe is containing the 10.0mg/mlNADPH of 0.1 μ L; 75 μ L20.0mg/ml mices, rat or people's hepatomicrosome; 0.4 μ L0.2M phosphate buffer and 425 μ LddH ₂o.Negative control (without NADPH) pipe is containing 75 μ L20.0mg/mL mices, rat or people's hepatomicrosome; 0.4 μ L0.2M phosphate buffer and 525 μ LddH ₂o.By adding 1.0 μ L10.0mM test compounds initiation reactions.Incubation reaction pipe at 37 DEG C.When reaction carries out 0,5,10,15,30 and 60 minute, collect 100 μ L samples in the new microcentrifugal tube containing 300 μ L cold methanols.With 15,000rpm Centrifuge A sample to remove deproteinize.The supernatant of Centrifuge A sample is transferred in new pipe.The concentration of stable compound after reacting with microsome in supernatant is measured by liquid chromatography/mass spectrometry (LC-MS).

Embodiment 20: plasma stability assay

The stability of one or more motif compounds in blood plasma measures see such as RapidCommun.MassSpectrom., 10:1019-1026 according to standard step known in the art.Following steps are HPLC-MS/MS tests of end user's blood plasma; Also other species be can use, monkey, Canis familiaris L., rat and mouse comprised.Before the use freezing heparinised human plasma is thawed in psychrolusia and 4 DEG C with 2000rpm centrifugal 10 minutes.Motif compound is added to the aliquot of blood plasma warm in advance from 400 μMs of storing solutions to obtain the final test volume (containing 5 μMs of test compounds and 0.5%DMSO) of 400 μ L (or being determined as 800 μ L for the half-life).Reactant is hatched (with shake) 0 minute and 60 minutes at 37 DEG C, or hatches 0,15,30,45 and 60 minute to determine the half-life at 37C.By shifting 50 μ L mixtures incubated and mix 5 minutes cessation reactions by shake in the ice-cold acetonitrile of 200 μ L.By sample 4 DEG C with 6000xg centrifugal 15 minutes and 120 μ L supernatant are transferred in clean pipe.Subsequently by sample evaporate to dryness and present HPLC-MS/MS analyze.

When needed, one or more contrasts or reference compound (5 μMs) are tested with test compounds simultaneously: a kind of compound (propoxycaine) has low plasma stability, and another kind of compound (Propantheline) has medium plasma stability.

Sample to be dissolved in again in acetonitrile/methanol/water (1/1/2, v/v/v) and to use Selective reaction monitoring (SRM) to analyze via (RP) HPLC-MS/MS.HPLC condition forms by having the binary LC pump of automatic sampler, mixing module, C12,2x20mm post and Gradient program.The peak area corresponding with analyzing thing is by HPLC-MS/MS record.Remaining parent compound is reported as plasma stability relative to the ratio (being expressed as percentage ratio) of zero-time remaining amount after 60 minutes.When determining the half-life, the half-life is estimated (being assumed to be first order kinetics) relative to the slope of the initial linear scope of the loaarithmic curve of time by residue compound (%).

Embodiment 21: chemical stability

The chemical stability of one or more motif compounds measures according to standard step known in the art.Below describe the illustrative steps of the chemical stability for determining motif compound in detail.For the acquiescence buffer of chemical stability test to be pH be 7.4 phosphate buffered saline (PBS) (PBS); Other suitable buffer can be used.Motif compound is added the aliquot of PBS to (in duplicate) to obtain the final test volume of 400 μ L, wherein containing 5 μMs of test compounds and 1%DMSO (total sample volume preparing 700 μ L is used for determining the half-life) from 100 μMs of storing solutions.Reactant is hatched (with jolting) 0 minute and 24 hours at 37 DEG C; In order to determine the half-life, by sample incubation 0,2,4,6 and 24 hours.By adding 100 μ L mixtures incubated and vortex carrys out cessation reaction in 5 minutes to 100 μ L acetonitriles immediately.Then by sample preservation at-20 DEG C, until analyzed by HPLC-MS/MS.When needed, control compound or reference compound such as chlorambucil (5 μMs) and related subject compound are tested, because this compound was hydrolyzed in a large number through 24 hours simultaneously.Selective reaction monitoring (SRM) is used to analyze sample via (RP) HPLC-MS/MS.HPLC condition forms by having the binary LC pump of automatic sampler, mixing module, C12,2x20mm post and Gradient program.The peak area corresponding with analyzing thing is by HPLC-MS/MS record.Remaining parent compound is reported as chemical stability relative to the ratio (being expressed as percentage ratio) of zero-time remaining amount after 24 hours.When determining the half-life, the half-life is estimated (being assumed to be first order kinetics) relative to the slope of the initial linear scope of the loaarithmic curve of time by residue compound (%).

Embodiment 22:Akt kinase assay

Usually make cell (including but not limited to L6 sarcoplast, B-ALL cell, B cell, T cell, leukaemia, medullary cell, p190 transducer cell, Philadelphia Chromosome Positive cell (Ph+) and the mouse embryo fibroblasts) growth in cell growth medium (being such as supplemented with hyclone and/or antibiotic DMEM) comprising Akt/mTOR path component, and grow to fusion.

In order to the effect that one or more compounds more disclosed herein activate Akt, make described cell lack serum spend the night and hatch about 1 minute to about 1 hour together with one or more compounds disclosed herein or about 0.1%DMSO, use insulin (such as 100nM) to stimulate afterwards about 1 minute to about 1 hour.By cell being scraped molten born of the same parents in ice-cold molten born of the same parents' buffer, described molten born of the same parents' buffer is containing detergent (such as sodium lauryl sulphate) and protease inhibitor (such as PMSF).After making cell and molten born of the same parents' Buffer fluid contacts, by the ultrasonic of short duration process of solution, pass through centrifugal clarification, resolved by SDS-PAGE, to transfer in nitrocellulose or PVDF and to use the antibody (CellSignalingTechnologies) for phosphoric acid-AktS473, phosphoric acid-AktT308, Akt and beta-actin to carry out immunoblotting.

Embodiment 23: the kinase signal transduction in blood

Phosflow method (MethodsEnzymol.2007 is used in blood cell; 434:131-54) measure PI3K/Akt/mTor intracellular signaling.The advantage of the method is it is unicellular test in essence, therefore can detect that cell is heterogeneous but not colony is average.This allows to distinguish by the intracellular signaling state in the different groups of other tag definitions simultaneously.Phosflow is also highly quantitative.For testing the effect of one or more compounds disclosed herein, stimulate splenocyte or the peripheral blood lymphocytes of end differentiation with AntiCD3 McAb, to cause φt cell receptor intracellular signaling.Subsequently by fixing for cell also colored surfaces labelling and endocellular phosphorus albumen.Be contemplated that inhibitor disclosed herein suppresses the phosphorylation of the AntiCD3 McAb mediation of Akt-S473 and S6, and rapamycin suppresses S6 phosphorylation under test conditions and strengthens Akt phosphorylation.

Similarly, 15 minutes are hatched together with the inhibitors of kinases of the aliquot of whole blood and vehicle (such as 0.1%DMSO) or various concentration, add stimulus object subsequently with crosslinked φt cell receptor (TCR) (there is the AntiCD3 McAb of second antibody) or B-cell receptor (BCR), wherein use anti-κ light chain antibody (Fab ' 2 fragment).After about 5 minutes and 15 minutes, sample is fixed (such as with 4% cold paraformaldehyde) and for Phosflow.Use padding, use and distinguish T cell and B cell for cell surface marker known in the art.Then by by fixed cell with together with the special traget antibody of the phospho-isoform of these protein, hatch the phosphorylation level measuring kinase substrate Akt and S6.Subsequently by flow cytometry analysis cell colony.

Expected results shows the potent selective depressant that one or more compounds of the present invention are one or more one or more members under test conditions in hemocyte in PI3K, mTOR and Akt intracellular signaling.

Embodiment 24: colony-forming test

Be layered on just using the murine myeloid cells of p190BCR-Ab1 Retroviral Transformation (being called p190 transducer cell herein) under the existence of various pharmaceutical composition together with the recombined human IL-7 in about 30% serum in M3630 methylcellulose medium and also keep about 7 days, and by range estimation, the colony number formed is counted under the microscope.

Or, obtain human peripheral blood mononuclear cell from the Philadelphia Chromosome Positive (Ph+) of ID or recurrence and negative (Ph-) patient.Be separated living cells and enrichment CD19+CD34+B cell precursors.After liquid culture spends the night, be layered on by cell in methocultGF+H4435 (StemCellTechnologies), described methocultGF+H4435 is supplemented with the known chemotherapeutant of cytokine (IL-3, IL-6, IL-7, G-CSF, GM-CSF, CF, Flt3 part and erythropoietin) and various concentration and the combination of any compound disclosed herein.By microscopic counting colony after 12-14 days.The method can be used for the evidence testing superposition or synergistic activity.

Expected results shows the potent selective depressant that one or more compounds of the present invention are p190 transducer cell Colony forming under test conditions.

Embodiment 25: inhibitors of kinases acts in the body of leukaemia

With γ-source with two dosage (about 4 hours, interval, each approximately 5Gy) the female test mice of mortality eradiation.After second radiation dose about 1 hour, with about 1x10 ⁶individual leukaemia (such as Ph+ people or Mus cell or p190 transduction medullary cell) intravenous injection mice.By these cells and about 5x10 ⁶the normal marrow cell (donor mice from 3-5 age in week) of radiation protection dosage is used together.Be provided in the antibiotic in water to experimenter and monitor every day.After about 14 days, making ill mice euthanasia and collecting lymphatic organ for analyzing.Within about 10 days after leukemic cell injection, start kinase inhibitor for treating and every day continued treatment, until mice is ill or reach the maximum of after transplanting about 35 days.Inhibitor is used by oral administration gavage.

Large after the 10th day (before treatment) and euthanasia (after treatment) collection peripheral blood cells, make itself and the anti-hCD4 antibody contacts of labelling and pass through Flow cytometry.The method can be used for proving, under test conditions, compared with treating with known chemotherapeutant (such as Gleevec) individually, the cooperative effect of the combination of one or more compounds disclosed herein and known chemotherapeutant reduces leukemic blood cells significantly and counts.

Embodiment 26: the treatment of lupus model mice

The mice lacking the Inhibitory receptor Fc γ RIIb of the PI3K intracellular signaling in antagonism B cell develops into lupus with high penetrance.Fc γ RIIb knock-out mice (R2KO, JacksonLabs) valid model of human diseases is regarded as, because some lupus patient show the function of Fc γ RIIb or express reduction (S.Bolland and J.V.Ravtech2000.Immunity12:277-285).

R2KO mice develops within the about 4-6 monthly age has antinuclear antibody, glomerulonephritis and albuminuretic lupoid acne disease.For these experiments, use forms of rapamycin analogs RAD001 (can LCLaboratories be derived from) as baseline composition and oral administration.This compound shows and alleviates lupus symptoms (J.ClinInvest.117:2186-2196 such as T.Wu) in B6.Sle1z.Sle3z model.

Lupus model mice (such as R2KO, BXSB or MLR/lpr) was treated when about 2 monthly age, continues about 2 months.Following dosage is given: the RAD001 of vehicle, about 10mg/kg or the compound disclosed herein of about 1mg/kg to about 500mg/kg to mice.Obtain blood sample and urine sample at about whole test period, and test antinuclear antibody (with serum dilution) or the protein concentration (with urine) of these samples.Also by anti-ssDNA and the Anti-hCG action of ELISA test sera.Make animal the 60th day time euthanasia collection organization for measuring the heavy and kidney diaseases of spleen.Glomerulonephritis is evaluated in the kidney segment dyeed with H & E.Other animals are studied after stopped treatment about two months (using identical terminal).

This model set up in the art can be used for proving that inhibitors of kinases disclosed herein can suppress or postpone lupifom outbreak in lupus model mice.

Embodiment 27: Os Mus implantation of marrow is tested

With the female test mice of gamma ray projector mortality eradiation.After radiation dose about 1 hour, (be such as described in CancerGenetCytogenet.2005 August with culture of transduceing from the p190 that goes down to posterity in early days; 161 (1): 51-6) about 1x106 leukemic cell injection mice.These cells are used together with the normal marrow cell (donor mice from 3-5 age in week) of about 5x106 radiation protection dosage.Be provided in the antibiotic in water to experimenter and monitor every day.After about 14 days, make ill mice euthanasia and collect lymphatic organ for flow cytometer and/or magnetite gathering.Started treatment at about 10th day and every day continued treatment, until mice is ill or reach the maximum of after transplanting about 35 days.By oral gavage (oral) administration.In preliminary experiment, determine and not there is therapeutic but the dosage of leukemia shown effect delay about a week or less chemotherapeutant; Control experiment is vehicle treatment or postpones but do not treat the chemotherapeutant (such as with the imatinib of about 70mg/kg administered twice every day) that leukemia generates to treat with previously demonstrating in the model.For the first stage, use and express the p190 cell of eGFP, and after death analyze to be limited to and by flow cytometer, the percent of leukaemia in bone marrow, spleen and lymph node (LN) is counted.In second stage, use express people CD4 anury form p190 cell, and after death analyze to comprise magnetic sorting carried out to the hCD4+ cell from spleen, then immunoblotting assay is carried out to key signal conduction terminal: pAkt-T308 and S473; PS6 and p4EBP-1.As the contrast of immune-blotting method, hatch under the cell of sorting in this article disclosed inhibitors of kinases existence or non-existent situation, carry out molten born of the same parents subsequently.Optionally, when without sorting in advance, " Phosflow " is used to detect pAkt-S473 and pS6-S235/236 in hCD4 gated cells (hCD4-gatedcell).If (such as) drug-treated mice does not develop into clinical leukemia at the time point of 35 days, so the research of these intracellular signaling is useful especially.Generate Kaplan-Meier survival curve and carry out data analysis according to means known in the art.Individually and the result analyzed cumulatively from p190 cell.

Started to obtain peripheral blood sample (100-200 μ l) from all mices once in a week before the 10th day is about to start treatment.Blood plasma is for measuring drug level, and the leukemia labelling (eGFP or hCD4) of analysis of cells as described herein and intracellular signaling biomarker.

This ordinary test known in the art can be used for proving that the compound disclosed herein of dose therapeutically effective can be used for suppressing the propagation of leukaemia.

Embodiment 28: the Arthritis Assay that the expansionary II Collagen Type VI of rat brings out

In order to study the compounds of this invention to the arthritic effect of autoimmune disease, use collagen-induced expansionary arthritis model.At the 0th day to Female Lewis rats injectable collagen.The 4mg/ml solution of cattle II Collagen Type VI is prepared in 0.01N acetic acid.By the isopyknic collagen of manual mixing emulsifying and Freund ' s Freund's incomplete adjuvant, until the beadlet of emulsified material keeps its form in water.In span each inject time, at three subcutaneous site of back, each rodent is injected to the mixture of 300 μ l.

Started Orally administered compound at the 0th day and last till the 16th day, every day is with 12 h apart vehicle (5%NMP, 85%PEG400,10%Solutol) or the compounds of this invention in vehicle or placebo (such as methotrexate) carry out.By rat the 0th, 3,6,9-17 days weighs, and carried out the caliper measurements (calipermeasurement) of ankle joint at 9-17 days.Weigh final body weight, subsequently at the 17th angel's animal euthanasia.After euthanasia, draw blood and remove rear solid end and knee joint.Blood is used for pharmacokinetic studies and the test of anti-II Collagen Type VI antibody ELISA through processing further.Rear solid end is weighed, is kept in 10% formalin subsequently together with knee joint.Microphotograph is used for pawl described in post processing and knee joint.Also liver, spleen and thymus are weighed.Prepare sciatic nerve and be used for histopathology.

Knee joint and ankle joint are fixed 1-2 days and decalcification 4-5 days.Ankle joint is longitudinally cut in half, knee joint is cut in half along face amount.Subsequently joint processed, embed, cut into slices and use Toluidine blue staining.According to following standard, given a mark in joint:

Knee joint and Ankle Joint Inflammation

0=is normal

The minimum infiltration of 1=inflammatory cell in synovial membrane/periarticular tissues

2=mild infiltration

3=is with the moderate infiltration of intermediate edema

4=is with the remarkable infiltration of remarkable edema

5=is with the severe infiltration of Severe edema

Ankle joint nebula

0=is normal

The minimum infiltration of 1=pannus in cartilage and subchondral bone

2=mild infiltration (infecting the tibia or the shank that are less than 1/4 in marginal zone)

3=moderate infiltration (infecting the tibia of 1/4-1/3 or little shank in marginal zone)

4=significantly infiltrates (infecting tibia or the shank of 1/2-3/4 in marginal zone)

5=severe infiltration (infecting the tibia or the shank that are greater than 3/4 in marginal zone, total gross distortion)

Knee joint nebula

0=is normal

1=pannus is minimum infiltration in cartilage and subchondral bone

2=mild infiltration (spread all over area under the surface of tibia or femur or cartilage at the most 1/4)

3=moderate infiltration (spread all under the surface of tibia or femur or cartilage area be greater than 1/4 but be less than 1/2)

4=significantly infiltrates (spreading all over 1/2 to 3/4 of tibia or femoral surface)

5=severe infiltration (being greater than 3/4 of covering surfaces)

Cartilage injury's (ankle joint focuses on little shank)

0=is normal

1=is minimum=lose Toluidine blue staining with being minimal to moderate, and destroy without obvious chondrocyte loss or collagen

2=is slight=lose Toluidine blue staining mildly, and there is Focal slight (shallow table) chondrocyte loss and/or collagen destruction

3=moderate=moderate ground loss Toluidine blue staining, and there is how Focal moderate (deeply reaching middle level (middlezone)) chondrocyte loss and/or collagen destruction, infect the less shank to the 1/2-3/4 degree of depth

4=significantly=lose Toluidine blue staining significantly, and have how Focal remarkable (deeply reaching deep layer (deepzone)) chondrocyte loss and/or collagen destroys, 1 or more how little shank have the cartilage loss of through thickness

5=is serious=seriously divergence loss Toluidine blue staining, and there is how Focal serious (deeply reaching tidemark (tidemark)) chondrocyte loss and/or collagen destroys

Cartilage injury's (knee joint focuses on femur ankle)

0=is normal

3=moderate=moderate ground loss Toluidine blue staining, and moderate (deeply the reaching middle level) chondrocyte with how Focal extremely diffusion loses and/or collagen destroys

4=significantly=lose Toluidine blue staining significantly, and there is the how Focal loss of remarkable (deeply the reaching deep layer) chondrocyte to diffusion and/or collagen destroys, or completely or close to the sub-thread bone surface lost completely

5=is serious=seriously divergence loss Toluidine blue staining, and there is on two femurs and/or tibia how Focal serious (deeply reaching tidemark) chondrocyte loss and/or collagen destroys

Bone resorption (Resorption) (ankle joint)

0=is normal

1=is minimum=absorption of small size, and not obvious in low range, osteoclast is little

2=is slight=absorption of larger area, and not obvious in low range, osteoclast is more, 1/4 to be absorbed in being less than of marginal zone tibia or shank

3=moderate=marrow girder (medullarytrabecular) and cortical bone obviously absorb but without full-thickness defects (fullthicknessdefects) in cortex, have lost some marrow girders, in low range, infringement obviously, osteoclast is more, in 1/4 to 1/3 pathological changes of marginal zone tibia or shank

4=significantly=in cortical bone full-thickness defects, usually with the distortion of residue cortex surface profile, lose marrow bone (medullarybone) significantly, a large amount of osteoclast, in the 1/2-3/4 pathological changes of marginal zone tibia or shank

5=is serious=in cortical bone full-thickness defects, usually with the distortion of residue cortex surface profile, lose marrow bone significantly, a large amount of osteoclast, be greater than 3/4 pathological changes, total gross distortion at marginal zone tibia or shank

Bone resorption (Resorption) (knee joint)

0=is normal

2=is slight=absorption of larger area, and limitedly lose subchondral bone, relate to 1/4 of tibia or femoral surface (inner side (medial) or outside (lateral))

3=moderate=absorb subchondral bone significantly, relates to being greater than 1/4 but being less than 1/2 of tibia or femoral surface (inner side or outside)

4=significantly=absorb subchondral bone significantly, relate to being more than or equal to 1/2 but being less than 3/4 of tibia or femoral surface (inner side or outside)

5=is serious=due to relate to tibia or femoral surface (inner side or outside) be greater than 3/4 destruction, whole joint deformity

Use Si Shi t inspection or other proper methods (ANOVA (ANOVAwithpost-test) with rear inspection) to evaluate the statistical analysis of body weight/pawl weight, pawl AUC parameter and histopathological parameters, significance is set in the significance level of 5%.Use the heavy suppression ratio percent of following formulae discovery pawl and AUC:

Suppression ratio %=A-B/AX100

A=disease control average-normal mean value

B=treats average-normal mean value

Expected results display is relative to only vectorial contrast or relative to methotrexate contrast, and compound display arthritis induction ankle diameter of the present invention increases and significantly to reduce along with the time and at least one in the above inflammation, pannus, cartilage injury and bone resorption type or multiple ankle histopathology reduce.Expected results shows, and one or more the compounds of this invention can be used for treatment and ameliorate osteoarthritis disease symptoms.

Result also expects display, selected test compounds significantly reduces serum anti-II Collagen Type VI level with 10,20 and 60mg/kg dosage level, this shows that one or more the compounds of this invention not only can be used for treatment and ameliorate osteoarthritis disease symptoms, and can be used for suppression of autoimmune responses itself.

Embodiment 29: the Arthritis Assay that the II Collagen Type VI set up of rat brings out

In order to check the dose response usefulness of the compounds of this invention in the arthritic inflammation, cartilage destruction and the bone resorption that suppress the II Collagen Type VI that 10 days set up in rat to bring out, by compound once a day or every day twice Orally administered, continue 6 days.

At the 0th day Female Lewis rats anaesthetized and give collagen (prepare as mentioned above and use) injection.At the 6th day, by Animal Anesthesia and give second time collagen injection.The caliper measurements of normal (premorbid) right ankle joint and left ankle joint is carried out at the 9th day.At 10-11 days, usually there is arthritis and rat is divided into treatment group at random.Random packet is carried out after ankle swelling is obviously set up and be there is the evidence of bilateral disease.

After the animal selecting this research of participation, start treatment by oral route.Give animal vector thing, tester (Embrel) or compound dosage, every day twice or (be respectively BID or QD) once a day.The oral solution administration of 2.5ml/kg (BID) or 5ml/kg (QD) volume is used at 1-6 days.Rat weighing for 1-7 days after arthritis is set up also is carried out the caliper measurements of ankle joint every day.Weighed final body weight at the 7th day and make animal euthanasia.

Expected results display for selected test compounds under test conditions average ankle diameter increase along with time decreased.

Embodiment 30: the Arthritis Assay that adjuvant brings out

The insertion of sheath inner catheter is carried out to rat

(IT) conduit in sheath is implanted to the Lewis rat (200-250g) of isoflurane anesthesia.After 6 day convalescent period, all animals (except showing sensation or dyskinesia those (being less than 5% of sum)) are all for experiment.IT is used, injects 10 μ l medicine or saline by conduit, then inject 10 μ l isotonic saline solutions.

Adjuvant arthritis and Drug therapy

Implant (n=6/ group) after a couple of days at conduit, at the 0th day, at tail base portion place, immunity inoculation is carried out to Lewis rat with 0.1ml complete Freund ' s adjuvant (CFA).Usually started medicine (such as one or more the compounds of this invention or vehicle) treatment also to continue, until the 20th day every day at the 8th day.Arthritic clinical sign started at the 10th day usually, every other day measured pawl swelling by water displaced volume measurement method (waterdisplacementplethysmometry).

These results show that one or more the compounds of this invention can be used for treating one or more disease as herein described or diseases.

Embodiment 31: rodent pharmacokinetic trial

In order to study the pharmacokinetics of the compounds of this invention, the mice in all for a group 4-10 ages is divided into groups according to following table:

The compounds of this invention to be dissolved in suitable vehicle (such as 5%1-N-methyl-2-2-pyrrolidone N-, 85% PEG400,10%Solutor) and every day Orally administered with 12 h apart.After using last compound, by all animals at CO ₂in 2 hours implement euthanasia.Collect blood immediately and remain on and be separated with blood plasma on ice.With 5000rpm centrifugal 10 minutes separated plasmas.The plasma freezing of collection is detected for pharmacokinetics.

The pharmacokinetic parameter of outcome expectancy display the compounds of this invention (such as absorb, distribute, metabolism, excretion and toxicity).

Embodiment 32:Basotest tests

OrpegenPharmaBasotest test kit is used to carry out basotest test.By Heparinised whole blood test compounds or solvent 37C preincubate 20 minutes.With after through 20 minutes, by blood test kit stimulate buffer hatch (with the cell of sensitization for responding), then use allergen (dirt demodicid mite extract or careless extract) to hatch.Threshing course is stopped by hatching blood sample on ice.Subsequently with anti-IgE-PE labeled cell to detect basophilic granulocyte, and with anti-gp53-FITC labeled cell to detect gp53 (on the basophil of activation the glycoprotein of expressing).After dyeing, make hemolysis by adding solvent soln.Cell is washed, and passes through flow cytometry analysis.When testing in this experiment, the Basohil activation that test compounds is induced with the control of the concentration allergen of sub-micromolar scope.Expected results is presented at the Basohil activation that one or more compounds of the present invention under test condition can suppress allergen to be induced.

Embodiment 33: use compound Tumor suppression of the present invention to grow

cell line

Interested cell line (A549, U87, ZR-75-1 and 786-O) is obtained from American Type Culture Collection center (ATCC, Manassas, VA).Cell proliferation is also preserved go down to posterity in early days (such as, the 3rd generation) at low temperatures.A sample aliquot is used to breed further, to obtain the enough cells (in the about the 9th generation) for a TGI research.

animal

Female athymic nude mice is supplied by Harlan.Mice received when age week in 4 week age to 6.All mices all adapt to about one day to two weeks before operation.Mice is supported in miniature isolation cage and under maintaining specific pathogen-free conditions.The HIGH PRESSURE TREATMENT freely obtained water is provided with radiation murine diet mice.

tumor xenograft models

With 0.01 to 0.5ml tumor cell (about 1.0x10 ⁵to 1.0x10 ⁸individual cell/mice) subcutaneous vaccination is in mice right flank.5 to 10 days after inoculation, use caliper measurements tumor and calculate tumor weight, such as, using zooscopy management software as StudyDirectorV.1.6.70 (research log).StudyDirector is used the mice that tumor size is about 120mg to be matched in pairs (the 1st day) in desired group.Its body weight is recorded when mice mates in pairs.Carry out weekly one to four gross tumor volume and measured body weight and carry out gross examination of skeletal muscle at least one times weekly.At the 1st day, use compound of the present invention and reference compound and vehicle by oral feeding or intravenous injection, as indicated.In experiment last day, put to death mice and in the end its tumor of 1-4 hr collections after dosage.Cut off tumor and be cut into two parts.The tumor of 1/3rd being fixed in formalin and being embedded in paraffin mass, the tumor of its excess-three divided two is temporarily freezing and at being kept at-80 DEG C.

data and statistical analysis

Following formulae discovery median tumor growth is utilized to suppress (TGI):

The tumor from initial size recovery in the 1st day is removed from calculate.For the tumor recovered relative to tumor weight display in the 1st day, use and calculate individual tumor contraction (TS) with following formula.Calculate and report that the average tumor often organized shrinks.

This models show compound of the present invention can be used whether can to grow as human renal carcinoma cell growth, breast cancer cell growth, lung cancer cell growth or spongioblast tumor cell growth by inhibition tumor cell under test conditions.

Embodiment 34:PI3K approach and the suppression with the tumor cell proliferation that PI3K α suddenlys change

The cell comprising one or more sudden change in PI3K α (includes but not limited to that breast cancer cell (such as, MDA-MB-361, T47D, SKOV-3)) and in PTEN, comprise one or more sudden change cell (including but not limited to prostate gland cancer cell (such as, PC3)) usually growth in cell growth medium (as being supplemented with fetal bovine serum and/or antibiotic DMEM), grow to fusion.Then with the test compounds process cell of various concentration, continue about 2 hours and cracking in cell lysis buffer solution subsequently.Make pyrolysis product stand SDS-PAGE, then carry out western blot analysis, to detect downstream signal conduction labelling, include but not limited to pAKT (S473), pAKT (T308), pS6 and p4E-BP1.At the compound of the present invention of various dose as under compd A (compound 54 of table 3) or compd B (compound 1 of table 1), also measure degree of cell proliferation (and Proliferation Ability).Beta-actin can be used as house keeping protein, to determine applicable carrying capacity.Fig. 7 illustrates and to be depicted in PC3 model compd B to the Western blotting (upper figure) of serine 473 from the different suppression of the Akt phosphorylation at threonine 308 place.What also illustrate is the comparison that Pan-PI3K inhibitor suppresses relative to the Akt phosphorylation of compd B in SKOV-3 model.Figure 12 shows and describes MDA-MB-361 cell relative to the Western blotting of compd A in PC3 cell to the suppression of the Akt phosphorylation at serine 473 place, and this indicates compound of the present invention preferably can have the tumor proliferation of the cell of sudden change relative to the Carbazole alkaloid in PTEN approach with sudden change in PI3K α approach.Compd A suppresses pAKT, wherein IC50 for MDA-MB-361 cell be ~ 1000nM and IC50 are ~ 10,000nM for PC3 cell.Similarly, compd A antiproliferative effect, wherein IC50 for MDA-MB-361 cell for ~ 1900 and IC50 for PC3 cell for being greater than 10,000nM.

Figure 11 to show in the cell line being depicted in the PI3K alpha active with rising compd A to the Western blotting of the suppression of PI3K approach.Make its cracking subsequently with compd A process MDA-MB-361 (PIK3CA-E545K), the MDA-MB-453 (PIK3CA-H1047R) of variable concentrations and SK-Br3 (Her2) cell 2h.Make pyrolysis product stand SDS-PAGE, then carry out western blot analysis as described above, to detect downstream pathway labelling.Left column illustrates the data from the MDA-MB-361 breast cancer cell carrying PIK3CA sudden change.Middle column illustrates the data from the MDA-MB-453 breast cancer cell carrying PIK3CA sudden change.The right side lists out the data from the SKBr3 breast cancer cell carrying HER2 sudden change.

Figure 13 shows compd A to the effect of carrying the tumor cell proliferation that PI3K α suddenlys change.By cell with every hole 5000-10,000 is seeded in 96 hole flat underside 90ul growth mediums.Add compound (10 times of ultimate density) or the DMSO (contrast) of beforehand dilution.Prepare described compound, extend to 14nM (8 point curve) via 3 times of serial dilutions from ultimate density 30 μMs to make dosage range.Final DMSO concentration is 0.3%.By cell at 37 DEG C at C _o272 hours are hatched in couveuse.After 72 hours, CellTiter-GloLuminescent reagent (Promega, PR-G7573) is used to measure propagation.Add CellTiter-Glo reagent with every hole 100 μ L, this equals the culture volume existed in every hole.Content is mixed 30 minutes, with cell lysis on orbital shaker.PerkinElmerEnVision plate reader read luminous.Contrary flexure dose response nonlinear regression and fitting formation curve and IC is used in GraphPadPrism ₅₀value.% is suppressed to be calculated as: 1-(cell+inhibitor)-background signal)/(cell+DMSO)-background signal) X100.

Embodiment 35: extracorporeal blood vessel generates and suppresses

Pipe is used to form test, such as evaluating the Agiogenesis inhibition test compounds exists by using pipe to form test kit (such as, commercially available from Invitrogen).Endothelial cell line can be used as Human umbilical vein endothelial cells (HUVEC) in-vitro measurements angiogenesis ability.Illustrate in compound existence according to test kit or carry out described test under lacking.In brief, gel-type vehicle is applied to cell culture surface, cell is added the substrate covering surfaces being attended by somatomedin, some of them sample also accepts inhibitor compound, by cell at 37 DEG C and 5%CO ₂in hatch the time (as spending the night) that enough control samples (not adding compound) form tubular construction, use cell-permeable dyestuff (such as, calcein) staining cell, and check that cell is to distinguish that pipe forms degree.Pipe forms any minimizing instruction Agiogenesis inhibition relative to not suppressing compared with control cells.Suppression degree is formed, the IC50 value that computer tube is formed based on institute's proof load and respective tube.Any kinds of schemes known in the art can be used to measure the IC50 value of cell survival, and described method such as distinguishes the colouring method of living cells and dead cell, and (such as, Image-iTDEADGreen viability stain can be commercially available from Invitrogen.

Embodiment 36: effect in the body in breast tumor xenograft mouse model

Carry the tumor (150-250mm being derived from human breast cancer cell MDA-MB-361 (PI3K α/HER2 cancer) and implanting ³) nude mouse be divided into and do not treat matched group (only vehicle) and treatment group.The mice for the treatment of group is divided into the mice of combination accepting 60mg/kg (60mpk) PI3K alpha inhibitor (compd A), 0.3mg/kgmTor inhibitor (compd B) or compd A and compd B further.Also comprise and accept separately or accept the group of 5mg/kg paclitaxel (intravenous) in combination with compd B.The mice for the treatment of group accepts the dosage of restriction every day by oral lavation, continue 30 days, calculate tumor weight (such as, every 2-5 days) within this period as described above.Regular monitoring blood glucose after administering therapeutic.Latter 2 hours of final treatment, collect tumor and pass through western blot analysis protein described above.The effect of the also location/vigor of assessing compound edge region B cell in spleen at the end for the treatment of.Fig. 2 shows the combined therapy of compd A and compd B in clinical front breast cancer model to the synergism of tumor weight.These results are supported by Fig. 3 further, also shown is the Western blotting result of the kinase activity of various labelling level.

Carry out similar experiment, wherein carry the nude mouse being derived from the tumor that human breast cancer cell MDA-MB-361 (PI3K α/HER2 cancer) implants and be divided into and do not treat matched group (only vehicle) and treatment group.Then the mice for the treatment of group is divided into the mice of combination accepting 60mg/kg (60mpk) PI3K alpha inhibitor (compd A), mTor inhibitor (rapamycin, intraperitoneal 0.5mg/kg) or compd A and rapamycin further.The treatment using compound on tumor (MDA-MB-361) is interrupted at the 30th day.Within every 2-5 days, measure tumor.Fig. 4 shows the synergism using the combined therapy of compd A and rapamycin in clinical front breast cancer model.

Using 786-O cell, there is the human renal carcinoma cell line of the PI3K α that do not suddenly change instead of the similar experiment of MDA cell for proving the specificity of test compounds further.Using 60 and the Orally administered compd A of 120mg/kg and by compd A as the solution of 1mg/kg Orally administered (QD).Such as, by PI3K alpha inhibitor with mTor is had to specific inhibitors of kinases and compares.The inhibitor (compd B) having an affinity to mTor is in the model effective in and suppresses kinase activity (being measured by the western blot analysis of marker downstream) and tumor growth, and has the activity (comparison diagram 2 and Fig. 6) of reduction compared with the activity seen in tumor that PI3K alpha inhibitor (compd A) is originated with MDA when still showing some anti-tumor activities.Fig. 6 C also provides the biochemical activity data of two kinds of inhibitor compared.Use PI3 kinases it is active that test kit (MilliporeCorporation) tests PI3 kinases α, β, γ and δ.Restructuring PI3K α, PI3K β, the PI3K γ and PI3K δ of purification is obtained from MilliporeCorporation.The restructuring PI3K of purification is used to analyze under 10 μMs of ATP exist phosphatidylinositols-4,5-diphosphonic acid (PIP2) to the phosphorylation of phosphatidylinositols-3,4,5-triphosphoric acid (PIP3).Emission index is converted into and suppresses percentage ratio and import in GraphPadPrism software.The scope of application is that 20 μMs of calculating of the concentration to 0.1nM (12-point curve) realize inhibition of enzyme activity 50% (IC ₅₀) required for compd A or the concentration of compd B.Nonlinear regression model (NLRM) available in GraphPadPrism5 is used to measure IC ₅₀value.

Fig. 9 shows and describes to use 70mg/kgPan-PI3K inhibitor and 60mg/kg compd A to reduce the curve chart (left figure) of the tumor weight in breast cancer model, and illustrates that 70mg/kgPan-PI3K inhibitor reduces the curve chart (right figure) of the existence of MZB cell in mouse spleen compared with 60mg/kg compd A.In the end 2 hr collections spleens after dosage, are processed and with suitable antibody staining (marginal zone B cells: B220+; CD23-; CD21hi), GuavaCytosoft5.2 software is used to analyze dyeing on GUAVAEasyCyteFACS instrument.The display of these data is compared with Pan-PI3K inhibitor, and the compound of selectivity PI3K alpha inhibitor such as compd A does not affect the location/viability of marginal area B cell.

Embodiment 37:TNP-Ficoll non-T cell dependency B cell activation experiments

The effect in non-T cell dependency antibody tormation is being suppressed, use TNP-FicollB cell activation assay as described herein in order to test the compounds of this invention.The compounds of this invention is dissolved in suitable vehicle (such as 5%1-N-methyl-2-2-pyrrolidone N-, 85% PEG400,10%Solutor).TNP-Ficoll treatment before about 1 hour, to 4-10 week age Mouse oral administered compound.In order to study the effect that described compound activates B cell, a group mice is divided into groups according to following table:

After the 7th day last administered compound, by CO ₂middle maintenance 2 hours, makes four animals in group 1 and eight animal euthanasias in group 2 to 7.Collect blood by cardiac puncture immediately, and 37 DEG C keep 1 hour with grumeleuse, then 4 DEG C of overnight incubation to make clot retracts.Next day, within centrifugal 10 minutes, collect serum by decant with 3000rpm.Then for further analysis at collected serum being chilled in-80 DEG C.

By the anti-TNP antibody titer of ELISA serum analysis sample as described herein.Be applied on NuncMaxisorb microtitration plate by the TNP-BSA in phosphate-buffered saline (PBS), 100 μ l/ holes, concentration is 10 μ g/ml.Maxisorb plate is removed solution incubated at room 1.5 hours.Add to every hole 200 μ l/ holes blocking-up buffer (blockingbuffer) (1%BSA such as in PBS) and incubated at room 1 hour.With the PBS0.05%Tween-20 (lavation buffer solution) in 200 μ l/ holes, plate is washed once.1: 2 diluent of serum in blocking-up buffer from every mice is added in each hole in the first row (1) of microtitration plate.Subsequently the serum in each hole of row 1 diluted 3 times in blocking-up buffer and add row 2 to.Serum in each hole of row 2 is diluted 3 times in blocking-up buffer and adds row 3 to.This step is repeated in 12 row of microtitration plate.By microtitration plate incubated at room 1 hour.Remove serum deprivation from described plate and with lavation buffer solution, plate washed three times.The goat anti-mouse igg 3-HRP in 100 μ l/ holes (diluting in blocking-up buffer with 1: 250) to be added in each hole and incubated at room 1 hour.From microtitration plate removing anti-mouse IgG3-HRP, and with lavation buffer solution, plate is washed 6 times.By HRP substrate (200 μ lABTS solution+30%H ₂o ₂+ 10ml citrate buffer solution) to add in each hole with 100 μ l/ holes, lucifuge is hatched 2-20 minute and is measured the amount of anti-TNPIgG3 by spectrophotography at 405nm place.Similarly, anti-mouse IgM-HRP and anti-mouse Ig-HRP is used to measure anti-TNPIgM and total anti-TNPAb respectively.

Fig. 8 shows display Pan-PI3K inhibitor instead of PI3K alpha inhibitor such as compd A blocks the curve chart of B cell function in vivo.By mice with TNP-Ficoll immunity and use following treatment: 1) vehicle, 2) 70mg/kgGDC0941,3) 30mg/kg compd A, 4) 60mg/kg compd A or 5) 120mg/kg compd A, continue 7 days.Use ELISA to measure percentage ratio that antibody generation and described antibody generation are expressed as the matched group with vehicle process.

The interaction in vitro of embodiment 38. pairs of mTOR approach

As described in embodiment 34,786-O cell is used to carry out experiment in vitro, the compd B of described cell variable concentrations or rapamycin treatment.Then cell lysis make pyrolysis product stand SDS-PAGE, then carries out western blot analysis, to detect downstream pathway labelling pNDRG1.The instruction of result shown in Fig. 5 rapamycin is relative to the not same-action of compd B to mTORC1 and mTORC2.

The In Vitro Anti of embodiment 39. compd B and compd A in the human cell line cultivated breeds combination research

Method and material

Compd B is prepared as the stock solution in 100% dimethyl sulfoxine (DMSO) and at being kept at about 25 DEG C.Compd A is prepared as 100%DMSO) in stock solution and at being kept at about 25 DEG C.From American Type Culture Collection center (ATCC) (Manassas, VA, USA) obtain the cell line of this institute use in and list Mikroorganismen preservation center (DeutscheSammlungvonMikroorganismenundZellkulturenGmbH in the following table, DSMZ, Germany).

The human tumor cell line used in cell proliferation test

ATCC=American Type Culture Collection center; DMEM=Dulbecco ' sModifiedEagle culture medium; EMEM=Eagle ' sModifiedEagle culture medium; Glu=glutamate, Glu; IMDM=Iscove ' sModifiedDulbecco ' s culture medium; NT=does not test; Institute (RoswellParkMemorialInstitute) is commemorated in RPMI=Loews dimension park.

The tumor tissues source that a cell line is originated.

B provides genotype by http://www.sanger.ac.uk/genetics/CGP/cosmic.

The lower multiple cell of c paving is with the optimum linear growth guaranteeing 72 hours.

D growth medium is used for culture of tumor cell.

Experimental design

Cell culture and compounds for treating: evaluate each combination in 6 × 11 substrate containing indivedual 96-orifice plate of two kinds of compounds as single medicament of variable dose and the mixture containing two kinds of test compounds right.Inoculating cell at the 5%CO of 37 DEG C ₂in hatch 24 hours, carry out compound treatment afterwards.After 72 hours, ATP level is measured to assess cell survival.According to composite substrate plate figure, diluted chemical compound plate is used to be transferred in bread board by compound.Backfill institute is porose, to obtain constant percentage DMSO.

In porose by plate, final DMSO concentration keeps constant and maintains being less than 0.5% time.The dose concentration scope of often kind of targeting medicament is that non-activity is to maximum effectiveness (being defined as causing maximum growth to suppress).Compd B maximum concentration scope is 100 to 10,000nM and the maximum concentration scope of compd A is 15,000 to 50,000nM.These cell survival data sets are used to calculate generation 50% effect (EC ₅₀) value single drug concentration and inhibitor composite reaction is classified.Untreated control and single compound contrast is used separately as with the cell that vehicle (DMSO) processes.After adding compound, be incorporated in mixed for bread board in moistening cell culture chamber at 37 DEG C and 5%CO ₂under hatch 72 hours.

CellTiter- cell proliferation test: use ATP detectable CellTiter- (Promega, Madison, WI, USA) assesses the compound activity in cell line.After hatching 72 hours, according to PromegaLuminescenceATP detection system the process of package insert scheme described in plate.In brief, 25 μ L lysis/substrate solutions (providing in a kit form) to be added in every hole and described plate is at room temperature mixed 30 minutes.The many label counter of PHERAstar (BMGLabtech, Ortenberg, Germany) is used to measure according to ATP luminescence assays 96-hole scheme luminous.Double reagent (Double-Agent) method is used to analyze luminous value.

Statistical analysis: use double reagent software analysis data, described software is that inner exploitation generates EC ₅₀curve also evaluates synergistic a kind of program.In brief, each plate representing single medicine combination is analyzed separately.First, carry out normalization viability measured value (luminous value) by scaled data, be 0 to make the intermediate value of negative control and the intermediate value of positive control for 100.A some holes on plate only contains a kind of medicine and double reagent uses these data to calculate single medicine EC by making this data fitting Hill equation (HillAV.JPhysiol.40:iv-vii, 1910) ₅₀.

Several different quality examination is carried out to each plate.The change of positive control and the meansigma methods of negative control are checked and is defined as lower.Also by reaction surface Fitting Analysis surplus value, to guarantee that residual sum of square is enough little.The multiple threshold values determined all are passed through/not being passed through in all quality examinations based on making, and same threshold is also for all plates.If plate not by any one quality examination, then removes this plate from analysis.

For combinative analysis, double reagent makes data and models fitting.This allows us to assess the cell survival rate of any dosage combination.In this study, with Minto (Minto etc., Anesthesiology.2000; 92:1603-16) Response surface model like described model class is used for the relation between description standard viability and drug level.Experiment is repeated for every group, Stochastic choice two plates.By minimizing residual sum of square by data and models fitting.If some data points have large surplus value, then these points are labeled as exceptional value and removing from analysis.Then second time matching remaining data.Based on the reaction surface of matching, generate constant existence and try hard to (being called equivalent line chart).Profile in equivalence line chart is 90% to 10% viability, and wherein viability is separated 10%.

Combinatorial index (Chou, T.C., Talalay, P.Adv.EnzymeReg.1984.22:27-55; Berenbaum, M.C.J.Theor.Biol.1985; 114:413-31) with non-linear mixing (PetersonJJ, NovikSJ, JReceptSignalTransductRes.2007; 27 (2-3): 125-46) as drug synergism measured value.For calculation combination index, use 50% equivalent line chart (there is the Dose contour of 50% viability).If it curves inwardly, then combinatorial index will be less than 1, and this indicates synergism.If can not determine combinatorial index, then use non-linear mixing.By considering to intersect with two concentration axles and being parallel to the surperficial fragment of dose response of mechanical axis of surviving, find non-linear mixing.In this study, the IC of often kind of independent medicine is selected ₅₀value (or if there is no IC ₅₀, be then maximum dose level value) between fragment.Use Cramer-Rao lower limit (Cramer, Mathematicalmethodsofstatistics.1946.Princeton, NJ:PrincetonUniv.Press; Rao, BulletinoftheCalcuttaMathematicalSociety.1945; 37:81-89) determine the standard error of these measured values.After first time completes the analysis of indivedual plate, in the upper combined result of repeat plate (not carrying out on the same day).Experiment is repeated for given synergism measured value and one group, uses calculated with weighted average method population mean and standard error.

After calculating meansigma methods that often group repeats to test, standard error and p-value, need to explain these values.Therefore, standardization program is created to form a kind of conclusion (call) (synergism, summation action, secondary summation action, antagonism or uncertain) in each case.If exceed half to repeat experiment and there is combinatorial index, these measured values are so used to reach a conclusion (makethecall).If major part repeats experiment there is not combinatorial index, the similar step based on non-linear mixing is so used to reach a conclusion.When p-value is greater than 0.05, the estimated value of combinatorial index statistically can't be different from 1.But, if standard error is also very large, so too uncertain so that few of information of estimated value.Therefore, conclusion is " uncertain ".In addition, conclusion is " summation action ".When p value is less than 0.05, the estimated value of combinatorial index is statistically different from 1.But if meansigma methods is close to 1, so difference does not have practical significant.Therefore, based on meansigma methods, result is classified.

The statistical analysis of vitro data

Normalization.First, carry out normalization viability measured value (luminous value) by scaled data, be 0 to make the intermediate value of negative control and the intermediate value of positive control for 100.More formally say,

Wherein V _ifor i ^ththe normalization viability in hole, U _ifor original viability measured value, intermediate value (U _-) for the intermediate value of negative control and intermediate value (U ₊) be the intermediate value of positive control.After normalization, contrast is abandoned.

Response surface model and matching.The Response surface model similar with the model (C.F.Minto etc., Anesthesiology, 2000,92,1603-1616) of Minto etc. is used to describe relation between normalization viability and drug level.For given plate, order

C＝(C _A/I ₁)+(C _B/I ₂)

x＝(C _A/I ₁)/C

E _max＝E ₁+E ₂x+E ₃x ²+E ₄x ³

I＝1+I ₃x(1-x)

S＝S ₁+S ₂x+S ₃x ²+S ₄x ³

V=100-E _max(1+ (I/C) ⁵) ^-1+ error

Wherein E ₁, E ₂, E ₃, E ₄, I ₁, I ₂, I ₃, S ₁, S ₂, S ₃and S ₄for parameter, C _aand C _bfor the respective concentration of medicine A and medicine B, and V is normalization viability measured value.Suppose that error amount is for independently and for identically distributed normal random variable.This model is the extension (A.V.Hill, J.Physiol., 1910,40, iv-vii) of Hill equation, is generally used for the effect of simulating single medicine.Maximum possible method and statistical software program R (RDevelopmentCoreTeam, 2008, ISBN3-900051-07-0, URLhttp: //www.R-project.org) is used to make data and this models fitting.

Quality examination.The quality examination of three types is applied to these plates.First, check whether positive control change and negative control intermediate value are little.Then, check new data whether with the data consistent of testing from previous single medicine.Finally, analyze the surplus value from reaction surface matching, to guarantee that residual sum of square is enough little.All these quality examinations all pass through based on making/multiple threshold values not by determining, and same threshold is also for all plates in testing.If plate not by any one quality examination, then removes this plate from analysis.

Measure synergism.By combinatorial index (M.C.Berenbaum, J.Theor.Biol., 1985,114,413-431) with non-linear mixing (J.J.Peterson and S.J.Novik, JournalofReceptorsandSignalTransduction, 2007,27:125-146.) as drug synergism measured value.Combinatorial index calculates based on equivalent line chart, and described equivalent line chart is the dose response surface fragment with constant viability.For analysis of the present invention, use 50% equivalent line chart, it is the Dose contour with 50% viability.EC50 _aand EC50 _bbe defined as the corresponding dosage that independent medicine A and medicine B has 50% viability.For the point (D along 50% equivalent line chart _a, D _b), combinatorial index is defined as (D _a/ EC50 _a)+(D _b/ EC50 _b).Due to (D _a, D _b) selection can be arbitrarily, use restriction D _a/ D _b=EC50 _a/ EC50 _b.

In some cases, combinatorial index is used, because EC50 _aor EC50 _bdo not exist.In such cases, non-linear mixing is used to substitute measured value as synergism.By considering to intersect with two concentration axles and being parallel to the surperficial fragment of dose response of mechanical axis of surviving, find non-linear mixing.V _aand V _bpower for survival, wherein said fragment is intersected with medicine A and medicine B axle respectively.V _maxand V _minfor the minimum and maximum viability along fragment.Wherein

NLB _S＝min(V _A，V _B)-V _min

NLB _A＝V _max-max(V _A，V _B)

Defining non-linear mixed number is NLB _s, condition is NLB in addition _s> NLB _awith-NLB _a.Because being chosen as of described fragment is arbitrary, so the fragment between the EC50 value (if there is no EC50 is then maximum dose level value) of the independent often kind of medicine of selection.Use Cramer-Rao lower limit (HCramer, 1946.MathematicalMethodsofStatistics; C.R.Rao, BulletinoftheCalcuttaMathematicalSociety, 1945,37:81-89) find the standard error of combinatorial index and non-linear both mixing.

Summary repeats experiment. and after the analysis completing indivedual plate, combination repeats the result of testing.Experiment is repeated for given synergism measured value and one group, uses calculated with weighted average method population mean and standard error.By with the corresponding blank averages of summation action compared with population mean.Blank averages is 1 for combinatorial index and is mixed into 0 for non-linear.Then, the Z-inspection of two sizes is carried out based on the meansigma methods estimated and standard error.This produces the p-value of aesthetic feeling synergism measured value and each cell line.

After calculating meansigma methods that often group repeats to test, standard error and p-value, need to explain these values.Therefore, standardization program is created to form a kind of conclusion (synergism, summation action, secondary summation action, antagonism or uncertain) in each case.If exceed half to repeat experiment and there is combinatorial index, these measured values are so used to reach a conclusion (makethecall).If major part repeats experiment there is not combinatorial index, the similar step based on non-linear mixing is so used to reach a conclusion.When p-value is greater than 0.05, the estimated value of combinatorial index statistically can't be different from 1.But, if standard error is also very large, so too uncertain so that few of information of estimated value.Therefore, conclusion is " uncertain ".In addition, conclusion is " summation action ".When p-value is less than 0.05, the estimated value of combinatorial index is statistically different from 1.But if meansigma methods is close to 1, so difference does not have practical significant.Therefore, based on meansigma methods, result is classified.Two tables describe the mode drawing these conclusions below.

Explain combinatorial index.When p-value is greater than 0.05, the estimated value of combinatorial index statistically can't be different from 1.But, if standard error is also very large, so too uncertain so that few of information of estimated value.Therefore, conclusion is " uncertain ".In addition, conclusion is " summation action ".When p-value is less than 0.05, the estimated value of combinatorial index is statistically different from 1.But if meansigma methods is close to 1, so difference does not have practical significant.Therefore, based on meansigma methods, result is classified.

P-value	Standard error	Meansigma methods	Conclusion
				＞0.05	＞0.25	Any value	Uncertain
＞0.05	＜0.25	Any value	Summation action
				＜0.05	Any value	0.7 to 1.3	Summation action

＜0.05	Any value	0 to 0.7	Synergism
				＜0.05	Any value	1.3 to 2	Secondary summation action
＜0.05	Any value	＞2	Antagonism

Explain non-linear mixing.In the mode similar with combinatorial index, non-linear mixing is classified.

P-value	Standard error	Meansigma methods	Conclusion
				＞0.05	＞15	Any value	Uncertain
＞0.05	＜15	Any value	Summation action
				＜0.05	Any value	-15 to 15	Summation action
＜0.05	Any value	＞15	Synergism
				＜0.05	Any value	＜-15	Antagonism

The statistical analysis of data in body

Analyze the measured value of tumor models.All gross tumor volumes are at log ₁₀value 1 is all added before conversion.Whether these values in comparison therapy group are statistically remarkable with the dynamic difference assessed along with time variations.In order to more paired treatment group, use maximum possible method by following linear regression Mixed effect model and data fitting:

Y _ijk-Y _iOk=Y _iOk+ treatment _i+ natural law _j+ natural law _j ²+ (treatment * natural law) _ij+ treatment * natural law ²) _ij+ e _ijk

Wherein Y _ijkfor at i ^thk in treatment ^ththe j of animal ^ththe log of time point ₁₀tumor value, Y _iOkfor at i ^thk in treatment ^ththe animal log of the 0th day ₁₀tumor value, natural law _jcentered by time point and processing as continuous variable, and e _ijkfor remainder error.Usage space power law covariance matrix explains the repeated measures of same animals along with time variations.If interaction item and natural law _j ²item is not statistically evident, then remove them.

Use possible ratio test to assess given paired treatment group and whether show statistically evident difference.X 2 test is used to test the difference of described value compared with the model (simplified model) without any treatment item the-2log of full model probability.Inspection degree of freedom is calculated as the difference between full model degree of freedom and simplified model degree of freedom.

Except statistical significance, find the measured value of often kind of effect-size for the treatment of.The log tumor value (Y of prediction is obtained from above model _ijk-Y _iOk) difference of reduced time, with area (AUC) value under the averaged curve calculating each treatment group.Then dAUC value is calculated as:

For synergism analysis, use the AUC value of observed log tumor value mathematic interpolation every animal.When removing treatment group animal from research, then by all time points thereafter after last tumor value of observing.The synergism score of the combination for the treatment of A and treatment B is defined as

100* (average (AUC _aB)-average (AUC _a)-average (AUC _b)+average (AUC _ctl))/average (AUC _ctl)

Wherein AUC _aB, AUC _a, AUC _band AUC _ctlbe respectively the AUC value of combination group, A group, B combination control animals.Based on the standard error of the change calculations synergism score of AUC value in animal.Sided t-inspection is used to determine whether synergism score is significantly different from zero.If P-value is lower than 0.05 and synergism score is less than zero, be combined as collaborative described in so thinking.If P-value is greater than 0.05, be combined as additive described in so thinking.

Results and discussions

Use CellTiter- cell proliferation test, to evaluate the growth of tumor cell line under single compound and compound combination existence.Experiment is repeated for every group, develops equivalent line chart based on normalization data.Representative equivalent line chart has been shown in Figure 14.

Double reagent program determination synergism is used to analyze.For calculation combination index, combinationally use 50% equivalent line chart (there is the Dose contour of 50% viability) to each.Compd B and compd A show the synergism of cell survival in MCF-7 HCC70 and MDA-MB-453.Described being combined in the every other cell line of test shows common summation action.These results show that, relative to the single medicament reaction of often kind in tested all cells system model, the larger suppression of combination display of compd B and compd A, this can be considered at least additive and is considered as synergism even in some cases.What is interesting is, occurring in the different genotype irrelevant with PIK3CA mutation status appears in the instruction of synergism and summation action.

Embodiment 40 compd B and compd A be the inhibitory action to the cellular signal transduction in human tumor cell line as single medicament or combination

Method and material: by compd B with Intellikine (LaJolla, CA, USA) synthesis and as the storing solution supply of 10mM in 100% dimethyl sulfoxine (DMSO), with corresponding cell line growth medium dilution.By compd A using Intellikine synthesis and as the storing solution supply of 10mM in 100%DMSO, with corresponding cell line growth medium dilution.Following table lists the cell line that this institute uses.

the tumor cell line used in western blot test

ATCC=American Type Culture Collection center; EMEM=Eagle ' s MEM, FBS=fetal bovine serum; Institute is commemorated in RPMI=Loews dimension park; SCLC=small cell lung cancer.

The tumor tissues source that a cell line is originated.

B growth medium is used for culture of tumor cell.

Experimental design

Cell culture and compd B/Compound A treatment

Cell process: all cells system all to maintain in the growth medium shown below be set in the moistening 5%CO2 cell culture couveuse of 37 DEG C purchased from ATCC (American Type Culture Collection center).

MDA-MB-361: human breast cancer cell is growth in Eagle ' the s MEM (EMEM) being supplemented with 20% fetal bovine serum (FBS), 1 × Pen .-Strep and 2mM glutamine.

HCC-1419: human breast cancer cell grows in the RPMI being supplemented with 10%FBS, 1 × Pen .-Strep and 2mM glutamine.

H1048: human small cell lung carcinoma cell grows in the HITES with 5%FBS, 1 × Pen .-Strep, 5mL100 × ITS mixture, 10nM hydrocortisone, 10nM β estradiol, 4.5mML-glutamine.

Before treatment, by cell with 2 × 10 ⁵individual cells/well to be layered in the 12-orifice plate of normal growth medium and to grow to 80% fusion.Be set to 37 DEG C and there is the CO of normal growth medium containing the inhibitor with DMSO dilution ₂by cell process 2 hours or 24 hours in couveuse.

● prepare drug dilution liquid by 10mMDMSO stock solution

● final DMSO ≤0.2%

● be 5,10,20,30 or 100nM and be 1 and 3 μM for compd A for the treatment of the final drug level of cell for compd B.

Cell process for western blot analysis: extract culture medium out, use 1XPBS washed cell, prepared ice-cold 1X cell lysis buffer solution by 10 × storing solution and 100 μMs of 4-(2-amino-ethyl) benzene sulfonyl fluorine hydrochlorate (AEBSF) and added 1mM sodium orthovanadate (NaVO4).Cell lysis is carried out by adding 1 × cell lysis buffer solution (12 porocyte plate every hole 100 μ L).Cell is hatched 20 to 30 minutes on ice to allow complete cracking, and pyrolysis product is transferred in micro centrifugal pipe, supersound process 10 second, and with 14 at 4 DEG C, 000 × g microcentrifugation 10 minutes.Clarified supernatant is transferred in fresh tube, and at being kept at-20 DEG C, for western blot analysis.By sample and 4X lDS sample buffer and 10 × sample reducing agent mixes, and continues within 5 minutes, to be heated to 95 DEG C to 100 DEG C, and is loaded into on Novex4-12%Bis-TrisMidiGel.Load molecular weight marker, gel electrophoresis 40 minutes under 200V.

Immunoblotting: by gel electrotransfer to nitrocellulose membrane, and at room temperature in blocking-up buffer (Tris buffer saline adds 0.5%Tween-20 (TBS/T)+5% bovine serum albumin (BSA)), hatch 1 hour.Under gentle agitation, film primary antibodie (pAKT (T308), pAKT (S473), pS6 (S235/236), p4E-BP1 (T37/46), PARP (or cracking PARP) or beta-actin) is blocked overnight incubation in buffer at 15mL being set in the refrigerator of 4 DEG C.Trace TBS/T is washed three times.At room temperature film horseradish peroxidase-(HRP-) is puted together two anti-(anti-rabbit IgG) under gentle agitation and hatch 1 hour in 15mL blocking-up buffer.Before detecting by BioRadWesternC detectable, trace TBS/T is washed three times.At room temperature film 5mLWesternC reagent (equal-volume reagent A and reagent B) is hatched 3-5 minute.From film, discharge excessive developer solution, be placed on slide, and at ChemiDocXRS ^tMthe upper imaging of system (BioRad).

Results and discussions: use from different tissues/disease and there is the gene mutation of advanced activation PI3K approach or there is HER2 amplification MDA-MB-361 (mammary gland; PI3K α E545K/HER2), HCC-1419 (mammary gland; And NCI-H1048 (SCLC HER2); PI3K α E545K/K111R) human tumor cell line, by using western blot analysis assessment downstream Phospoprotein, assessing compound B or compd A suppress the ability of PI3 kinsase signaling pathway as single medicament or combination.In this analysis, compd B or compd A effectively suppress the phosphorylation of downstream targets with dose dependent fashion; Comprise AKT (the Ser/Thr protein kinase regulated by PI3K), S6 (the Ser/Thr protein kinase regulated by p70S6 kinases) and 4E-BP1 (the Ser/Thr protein kinase regulated by PI3K/AKT/mTOR protein kinase) (Figure 15).The phosphorylation of marker downstream pAKT (473 and 308), pS6, p4E-BP1 is more effectively transplanted in the combination of compd B and compd A than single pharmaceutical treatment.In addition, more maxicell apoptosis is induced in the combination of compd B and compd A, (Figure 15, left column) indicated by PARP cracking.Therefore, research at present provides mechanism principle, to make therapeutical effect maximize for being total to the many nodes of targeting in PI3K approach.

For MDA-MB-361 cell line (Figure 15, left column), by cell with containing with the cell culture medium process 2 hours (A) of the inhibitor of DMSO dilution or 20 hours (B), and there are 100 μMs of AEBSF and 1mMNaVO ₄freezing 1X cell lysis buffer solution in cracking.Cell lysis is carried out by adding 1X cell lysis buffer solution (12 porocyte plate every hole 100 μ l).? novex4-12%Bis-TrisMidiGel runs sample, transferred in nitrocellulose membrane, by anti-phosphoprotein specific antibody, (Cell Signaling Technologies pAKT (T308), pAKT (S473), pS6 (S235/236), p4E-BPl (T37/46), PARP and beta-actin detection, and at ChemiDocXRS ^tMimaging in system.For HCC-1419 cell line (Figure 15, right row), by cell with containing with the cell culture medium process 2 hours (A) of the inhibitor of DMSO dilution or 24 hours (B), and there are 100 μMs of AEBSF and 1mMNaVO ₄freezing 1X cell lysis buffer solution in cracking.Cell lysis is carried out by adding 1X cell lysis buffer solution (12 porocyte plate every hole 100 μ l).? novex4-12%Bis-TrisMidiGel runs sample, transferred in nitrocellulose membrane, by anti-phosphoprotein specific antibody, (Cell Signaling Technologies pAKT (T308), pAKT (S473), pS6 (S235/236), p4E-BP1 (T37/46), cPARP and beta-actin detection, and at ChemiDocXRS ^tMimaging in system.

Carrying out self-organizing/disease and having in the human tumor cell line of different genetic mutation (PI3K α suddenlys change and/or HER2 amplifies), compd B and compd A suppress the phosphorylation of downstream targets effectively with dose dependent fashion; Comprise AKT, S6 and 4E-BP1.Upon combination, the suppression of downstream phosphoprotein target more obviously and cause apoptotic induction larger.

Embodiment 41 uses multiple dose scheme to carrying the female nude mice of MDA-MB-361 human breast carcinoma xenograft as single medicament or the anti-tumor in vivo activity combining Orally administered compd B and compd A

Method and material

Test article and contrast article: use in this study and following tests article: within the every 5-7 of compd B days, keep in Dark Place at about 25 DEG C with 100%PEG400 (RugerChemical) preparation.The every 5-7 of compd A days with 100%PEG400 preparation and keep in Dark Place at about 25 DEG C.The contrast article used in this research are 100%PEG400.

Test macro: passing at the low grows in Dulbecco ' sModifiedEagle ' sMedium (DMEM) culture medium being supplemented with 20% fetal bovine serum (FBS) and 1X penicillin/streptomycin (Invitrogen) for MDA-MB-361 cell, merges until realize about 80%.Before injection, cell is separated with Trypsin (Invitrogen), wash twice with phosphate buffered saline (PBS) (PBS), and be resuspended in RPMI (institute is commemorated in the Loews dimension park) culture medium (Invitrogen) without supplement.By cell in the DMEM culture medium having 50%Matrigel (BDBiosciences) without supplement resuspended to ultimate density be 10.0 × 10 ⁷individual cell/mL.By MDA-MB-361 cell, (every animal injects 10.0 × 10 with 0.1-mL injected slurry volume ⁶individual cell) SC implantation female athymic nude mouse flank.Following table describes the animal that this institute uses.

test macro

Experimental design: with 10.0 × 10 ⁶mDA-MB-361 cell SC inoculates 4-5 female athymic nude mouse flank in age in week (cell suspending liquid in serum-free DMEM and 50%Matrigel).Use slide gauge monitoring tumor growth.Use formula V=W ²× L/2 calculates average T V (MTV).When MTV reaches about 280mm ³time, animal is divided at random 14 treatment groups (n=5/ group).Then with the combination to mice PO administration PEG400, compd B, compd A or compd B and compd A of several dosage and scheme.Measure weekly twice tumor growth and body weight.TGI percentage ratio and body weight change is calculated at the 28th day.Start treatment at the 0th day, continue 28 days.Within 28 days, pass through afterwards to use in treatment equation 1calculate TGI percentage ratio and determine anti-tumor activity: MTV × 100 of TGI percentage ratio=(MTV of mean tumour volume [the MTV]-treatment group of matched group)/matched group.

Blood glucose measurement: use 15,30,60,90,120 and 1440 minutes after Abbott ' s " FreestyleLite " Handheld blood sugar monitoring instrument (AbbottLaboratories) administration the last time (the 28th day) to measure blood sugar level by afterbody kink.

Insulin is measured: use MesoscaleDiscovery ' sMouse/Rat Insulin Kit (Rockville, MD, USA) to measure insulin.The plasma sample of collection in 120 minutes after last administration is thawed on ice and makes kit reagent be warming up to room temperature.150 μ LBlockerA solution are added in every hole, covers these plates, then at room temperature in deck vibrator (300-1000rpm), hatch 1 hour.After first time hatches, described hole phosphate buffered saline (PBS)+Tween20 (PBS-T) is washed three times, in described hole, then adds 40 μ L1X antibody test solution in duplicate, add the unknown clean sample of 10 μ L or standard substance subsequently.Then cover plate and at room temperature in deck vibrator (300-1000rpm), hatch 2 hours.After second time is hatched, described hole PBS-T is washed three times, then 150 μ L1XReadBufferT is added every hole.On SECTOR imager, use MSDDiscoveryWorkbench software (MesoScaleDiscovery) to analyze described plate immediately.The concentration of the standard curve determination unknown sample generated based on it by software application 4-parameter logistic model.

Statistical analysis

Area under curve changes: use linear hybrid effect regression model to assess between paired treatment group tumor growth trend along with the difference of time variations.These specifications of a model are in the fact of multiple point in time measurement every animal.The independent model of matching for comparing at every turn, and uses area under curve (AUC) value of each treatment group of the predictor calculation of described model.Then the reduction percentage ratio (△ AUC) of AUC relative to reference group is calculated.Statistically evident p value show 2 treatment groups along with the trend of time variations be different.

Combined therapy effect: the synergism of the AUC value assessment drug regimen observed by use.Calculate single treatment group and the AUC both the combination group change relative to contrast.Then in the AUC change observed in charge-coupled by comparable group and two kinds of single medicaments, viewed change summation assesses the interaction between two kinds of compounds.Result can be divided into four classes: concertedness, additivity, secondary additivity and Antagonism.Other details about combinative analysis are provided in annex.All p values being less than 0.05 are all considered to significant.

Results and discussions

Compared with treating with vehicle, use as single medicament with 0.3mg/kgQD, 1.0mg/kgQD3/4 to stop using and the compd B used of 3.0mg/kgQWPO significantly suppress tumor growth, wherein TGI value is respectively 71.1%, 63.6%, 52.7% (△ AUCp < 0.001).

Compared with treating with vehicle, as single medicament with 60mg/kgQD, 70mg/kgQD3 use/4 stop using, 140mg/kgQD3 uses/4 to stop using and compd A that 210mg/kgQWPO uses significantly suppress tumor growth, wherein TGI value is respectively 84.5%, 76.0%, 84.2% and 64.7% (△ AUCp < 0.001).

Compared with treating with vehicle, 0.3mg/kgQD compd B and the 60mg/kgQD compd A of combined administration significantly suppress tumor growth, and wherein TGI value is 93.9% (△ AUCp < 0.001).Graphically illustrate in Figure 16 often group along with the mean tumour volume of time variations.MDA-MB-361 human breast cancer cell is implanted in female nude mice mammary fat pad.About 280mm is reached at mean tumour volume (MTV) ³afterwards, start to treat (combination that PO uses vehicle QD × 28 day, compd B 0.3mg/kgQD × 28 day, compd A 60mg/kgQD × 28 day or compd B and compd A).Data are depicted as meansigma methods; Error bars represents average standard error (SEM) (n=5).Vehicle=PEG400.Clamp are used to monitor weekly twice tumor growth.Use formula (length x width ²)/2 calculate gross tumor volume.The average maximum BW change of this dosage group is 7.8% on the 28th day in treatment.

Compared with treating with vehicle, 0.3mg/kgQD compd B and the 210mg/kgQW compd A of combined administration significantly suppress tumor growth, and wherein TGI value is 88.7% (△ AUCp < 0.001).The average maximum BW change of this dosage group is 3.8% on the 15th day in treatment.

Compared with treating with vehicle, the 1.0mg/kgQD3 of combined administration uses/and 4 stop using compd Bs and 70mg/kgQD3 use/4 to stop using or 210mg/kgQW compd A significantly suppress tumor growth, and wherein TGI value is respectively 88.2% and 85.9% (△ AUCp < 0.001).The average maximum BW change of these dosage groups is respectively-7.8% (the 11st day) and-6.0% (the 4th day).

Compared with treating with vehicle, the 1.0mg/kgQD3 of combined administration uses/4 stop using compd Bs and 140mg/kgQD3 use/4 compd As of stopping using significantly suppress tumor growth, wherein TGI value is 91.1% (△ AUCp < 0.001).Graphically illustrate in Figure 16 often group along with the mean tumour volume of time variations.MDA-MB-361 human breast cancer cell is implanted in female nude mice flank.About 280mm is reached at mean tumour volume (MTV) ³time, start to treat (POa/kgQD3 uses/4 stop using × 28 days or the combination of compd B and compd A).Data are depicted as meansigma methods; Error bars represents average standard error (SEM) (n=5).Vehicle=PEG400.Clamp are used to monitor weekly twice tumor growth.Use formula (length x width ²)/2 calculate gross tumor volume.The average maximum BW of these dosage groups is changed to-14.3% (the 11st day).

Compared with treating with vehicle, 3.0mg/kgQW compd B and the 210mg/kgQW compd A of combined administration significantly suppress tumor growth, and wherein TGI value is 85.7% (△ AUCp < 0.001).The average maximum BW change of this dosage group is-12.3% on the 11st day in treatment.

Be greater than owing to losing weight 15% thus do not have mice from research removing, and compound B-11 .0mg/kgQD3 use/4 stop using with compd A 140mg/kgQD3 use/4 stop using dosage groups in visible maximum BW lose.

As shown in the table, it is what be added that synergism analysis discloses all unitized dose groups.

compd B alone or in combination and compd A are to the effect of nude mouse stable state blood sugar level

QD=once a day; QD3 uses/4 to stop using=daily once, continue 3 days, then within 4 days, stop using; QW=is weekly

* relative to the multiple of vehicle control: the blood glucose of the nude mouse of tumor is carried in the measurements in 15,30,60,90 and 120 minutes of blood glucose average A UC/ vehicle control blood glucose average A UC after last dosage (the 28th day) of the repeated doses antitumor activity of MDA-MB-361 human breast carcinoma xenotransplantation female mice of process.Data are depicted as meansigma methods; (n=3).Vehicle control=PEG400 (PEG400).Collect blood by cutting tail and use Abbott " Freestyle " Handheld blood Sugar Monitoring instrument to measure blood glucose.

In this study by measuring the effect that stable state blood glucose and plasma insulin level assessing compound B, compd A and combination thereof regulate blood glucose/insulin.Compd B or the single medicament group of compd A cause the control level of blood glucose average A UC relative to 0-2 after administration hour to increase 1.02-1.34 doubly, within 2 hours, return to baseline values upon administration.The blood sugar level of the combination arm of 1.0mg/kg compd B (QD3 use/4 stop using)+70mg/kg compd A (QD3 use/4 stop using) and 1.0mg/kg compd B (QD3 use/4 stop using)+140mg/kg compd A (QD3 use/4 inactive) is used to cause the contrast of blood sugar level average A UC relative to 0-2 after administration hour to increase by 1.22 times and 1.62 times respectively.3.0mg/kg compd B (QW) makes blood sugar level increase 1.26-relative to contrast doubly and with 210mg/kg compd A (QW) combine and make blood sugar level relative to contrasting and increase 1.32-times.As shown in the table, the combination of two kinds of medicaments causes stable state blood sugar level and dosage and frequency to increase pro rata, within 2 hours, returns to baseline values upon administration.

As shown in the table, the visible icotype of plasma insulin level, it increases as many as 8 times pro rata relative to contrast and dosage and frequency, but level increases lasting long period section (being greater than 2 hours after administration).

compd B and compd A are as single medicament or combine nude mouse plasma insulin water flat effect

* relative to the multiple of vehicle control: the Mean plasma insulin/vehicle control Mean plasma insulin of process

Within 120 minutes after last dosage (the 28th day) of the repeated doses antitumor activity of MDA-MB-361 human breast carcinoma xenotransplantation female mice, measure the plasma insulin carrying the nude mouse of tumor.Data are depicted as meansigma methods; Error bars represents average standard error (SEM) (n=3).Vehicle=PEG400 (PEG400).MesoscaleDiscovery ' s mice/rat insulin test kit (Rockville, MD, USA) is used to measure insulin.

All combinations of compd B and compd A cause significantly (△ AUC, p < 0.001) TGI and the interaction that synergism analyzes indication compound B and compd A is what be added in MDA-MB-361 human breast carcinoma model.Tolerate all treatments, and average weight limit alleviates not > 15%.In addition, the combination of compd B and compd A causes blood glucose and plasma insulin level and dosage and frequency to increase pro rata.

Embodiment 42 compd B and compd A as single medicament or combination by oral administration to the anti-tumor activity after the female nude mice carrying MDA-MB-361 xenograft

Every 5 to 7 days of test article compd B is with 5%N-crassitude (NMP) (Sigma-Aldrich)+95% PEG400 (PEG400) (RugerChemicalCo, Inc.) preparation keeping in Dark Place in about 25 DEG C (room temperatures).Every 5 to 7 days of test article compd A is with 5%NMP+95%PEG400 preparation and keep in Dark Place in about 25 DEG C (room temperatures).The contrast article used in this research are 5%NMP+95%PEG400.Compound is dissolved in NMP completely via supersound process, then adds the PEG400 of proper volume, and by final solution vortex and supersound process, to guarantee thorough mixing.

Pass at the low and be supplemented with 20% fetal bovine serum (FBS) and 1X penicillin/streptomycin (Invitrogen for MDA-MB-361 cell, Carlsbad, CA, USA) grow in Eagle ' s MEM (EMEM) culture medium, merge until realize about 80%.Before injection, by cell with trypsin Invitrogen) be separated, wash twice with phosphate buffered saline (PBS) (PBS), and the Loews dimension park be resuspended in without supplement is commemorated in institute (RPMI) culture medium (Invitrogen).With without supplement RPMI culture medium by resuspended for cell to ultimate density for 5 × 10 ⁷individual cell/mL.By MDA-MB-361 cell, (every animal injects 5.0 × 10 with 0.1-mL injected slurry volume ⁶individual cell) SC implantation female athymic nu/nu nude mouse flank.Following table describes the animal that this institute uses.

test macro

Experimental design: with 5.0 × 10 ⁶mDA-MB-361 cell SC inoculates 5 to 6 all age female (athymism nu/nu) nude mouse flanks.Use slide gauge monitoring tumor growth.Use formula V=W ²× L ÷ 2 calculates MTV.When MTV reaches about 235mm ³time, animal is divided at random 4 treatment groups (n=8/ group).Treatment is started at the 0th day.Then to combination (using) QD of mice PO administration vehicle, compd B, compd A or compd B and compd A simultaneously, 30 days are continued.Measure weekly twice tumor growth and body weight.TGI percentage ratio and body weight change is calculated at the 29th day.The 29th angel often organize four mice euthanasia and collection organization for pharmacodynamic studies.All the other mices continued research until the 65th day, and within every 9 to 11 days, measured tumor size and the body weight of these mices.

By using equation 1calculate TGI percentage ratio and determine anti-tumor activity: TGI percentage ratio)=(matched group MTV-treatment group MTV) ÷ matched group MTV × 100

1000mm is reached by calculating given treatment group MTV ³time reach 1000mm divided by matched group MTV ³time determine tumor growth delay.

Blood glucose measurement: used by afterbody kink hand-held blood sugar monitoring instrument (AbbottLaboratories) administration the last time (the 29th day) measures blood sugar level in 5,15,30,60 and 90 minutes afterwards.

Statistical analysis

The change of area under tumor volume vs's time graph: use linear hybrid effect regression model to assess between paired treatment group tumor growth trend along with the difference of time variations.These specifications of a model are in the fact of multiple point in time measurement every animal.The independent model of matching for comparing at every turn, and uses the AUC of each treatment group of the predictor calculation of described model.Then the reduction percentage ratio (Δ AUC) of AUC relative to reference group is calculated.Statistically evident p value show 2 treatment groups along with the trend of time variations be different.

Use linear hybrid effect regression model to carry out statistical analysis, the difference of tumor Production trend between control sample and treatment sample considered by described model.Difference between mice is treated to stochastic effect, and the transmutability using the symmetrical covariance structure of compound to simulate every mice to repeat between measurement of tumor value.Carry out treatment by the matched curve calculating Δ AUC used a model to compare.Use the significance of permutation tests assessment Δ AUC.All p values being less than 0.05 are all considered to significant.

Synergism is analyzed: whether the effect using combination score to calculate to solve combined therapy is greater than additions (working in coordination with), addition or the problem of secondary addition (antagonism) relative to single treatment.If combination score is less than 0, then the effect of combined therapy is considered to synergism, if combination score equals 0, is then considered to be added, and if combination score is greater than 0, is then considered to antagonism.Whether combination score is significantly different from 0 to use standard error (SE) and 95% confidence interval (CI) (being calculated as 2 × SE) to determine.All p values being less than 0.05 are all considered to significant.

Results and discussions:

In the mice of carrying MDA-MB-361 human breast carcinoma xenograft, continue to significantly suppress tumor growth (TGI=71.1% with the compd B of 0.3mg/kgPO administration compared with the matched group of the 29th day in 30 days in QD scheme; Δ AUC, p < 0.001).The compd A used with 60.0mg/kgPO in QD scheme significantly suppress tumor growth (TGI=77.4% compared with the matched group of the 29th day; Δ AUC, p < 0.001).In the mice of carrying MDA-MB-61 human breast carcinoma xenograft, the 0.3mg/kg compd B that QD scheme for duration is used for 30 days significantly suppress tumor growth (TGI=93.0% with the combination of 60mg/kgPO compd A compared with the matched group of the 29th day; Δ AUC, p < 0.001).As shown in the table, synergism analysis instruction combined therapy act as addition.

combination score calculates (Log-conversion) (synergism analysis)

SEM=average standard error.

Attention: under being used in the concentration curve of XX days, area (AUC) carries out combination score calculating (synergism analysis).Score < 0 indicates synergism, and score=0 indicates summation action, and score > 0 indicates time addition (antagonism) effect.Be different from 0 to assess based on synergism score whether remarkable (p < 0.05).

The 29th angel often organize four mice euthanasia and collection organization for pharmacodynamic studies.In continuation until in all the other 4 mices of each dosage group of the 65th day, tumor regrowth long delay exceedes the research period of each dosage group.In matched group, TV reaches 1000mm ³time be 50 days; But, within 65 day period, do not have treatment group to reach TV1000mm ³.The combination of compd B (0.3mg/kg) and compd A (60mg/kg) causes tumor regrowth length to minimize, and wherein MTV reached 56.8mm at the 65th day ³, MTV reached 50.9mm at the 29th day by contrast ³.As shown in the table, in compd B (0.3mg/kg) group in single drug dose group MTV by 210.9mm ³be increased to 400mm ³, and from 165mm in compd A (60mg/kg) group ³be increased to 500mm ³.Figure 17 shows the tumor regrowth length often organizing all the other 4 mices, and (PO=is oral; QD=once a day).In fig. 17, subcutaneous for MDA-MB-361 human breast cancer cell (SC) is implanted in female nude mice flank.About 235mm is reached at mean tumour volume (MTV) ³start after (the 0th day) treatment and continual cure until the 29th day.Until the 65th day, for determining that the data of regrowth are depicted as meansigma methods; Error bars represents average standard error (SEM) (n=4).Vehicle=5%N-crassitude (NMP)+95% PEG400 (PEG400).Use clamp to measure weekly twice tumor growth, until the 29th day, then within every 9 to 11 days, measure once, until the 65th day.Use formula (length x width ²) ÷ 2 calculates gross tumor volume.

tumor regrowth is long to be analyzed

BW=body weight; MTV=mean tumour volume; N/A=is inapplicable; TGI=Tumor growth inhibition;

TV=gross tumor volume.

A was the 29th day n=8 mice.

B was the 65th day n=4 mice.

C calculated the %TGI of the 65th day at the 65th day based on matched group (n=4).

In treatments period, often organize average weight limit change percentage ratio be no more than and alleviate 13%.In combination group, saw maximum alleviating (13%) at the 4th day, recover at the second day measured.

In order to assessing compound B, compd A and combination thereof may act on blood glucose regulation, use last dosage (the 29th day) during this research after, measure stable state blood sugar level.The slight increase of stable state blood sugar level is all shown in two kinds of single medicaments and combination thereof, and returns to normal level in one hour upon administration.

The combination Tumor suppression of compd B and compd A grows and it act as addition.Extend research interval any treatment group TV not regrowth to 1000mm ³, reached 1000mm with wherein TV at the 50th day ³matched group different.Described combination does not cause body weight significantly to alleviate and it is of short duration to acting as of blood sugar level in this study.

Embodiment 43 uses multiple dose scheme to carrying the female nude mice of HCC70 human breast carcinoma xenograft as single medicament or the anti-tumor in vivo activity combining Orally administered compd B and compd A

Method and material

Article are tested: the every 5-7 of compd B days with 5%N-crassitude (NMP) (Sigma below using in this study, St.Louis, MO, USA)+95%PEG400 (RugerChemical, Linden, NJ, USA) prepare and keep in Dark Place at about 25 DEG C.The every 5-7 of compd A days with 5%NMP+95%PEG400 preparation and keep in Dark Place at about 25 DEG C.The contrast article used in this research are 5%NMP+95%PEG400.By supersound process, compound is dissolved in NMP completely, then adds the PEG400 of proper volume.By solution vortex supersound process again, to guarantee to mix completely.

Test macro: pass at the low for HCC70 cell (ATCC) in the middle growth of the RPMI (LifeTechnologies) being supplemented with 10% fetal bovine serum (FBS) (PAALaboratoriesPtyLtd) and 1X Pen .-Strep (LifeTechnologies) and with 5.0x10 in serum-free RPMI and 50%Matrigel (BDBiosciences) ⁷the concentration supply of individual cell/mL.By HCC70 cell (5.0x10 ⁶individual cell/animal, 0.1-mL injected slurry volume) in subcutaneous implantation (SC) female athymic nude mouse flank.Following table describes the animal that this institute uses.

test macro

Experimental design:

With 5.0 × 10 ⁶hCC70 cell SC inoculates female athymic nude mouse flank in five week age (cell suspending liquid in serum-free RPMI and 50%Matrigel).Use slide gauge monitoring tumor growth.Use formula V=W ²× L/2 calculates average T V (MTV).When MTV reaches about 160 to 180mm ³time, animal is divided at random 13 treatment groups (n=5/ group).Then with the combination to mice PO administration PEG400, compd B, compd A or compd B and compd A of several dosage and scheme.Measure weekly twice tumor growth and body weight.TGI percentage ratio and body weight change is calculated at the 35th day.Start treatment at the 0th day, continue 28 days.By using equation 1calculate TGI percentage ratio and determine anti-tumor activity: MTV × 100 of TGI percentage ratio=(MTV of mean tumour volume [the MTV]-treatment group of matched group)/matched group.

Statistical analysis

Area under curve changes: use linear hybrid effect regression model to assess between paired treatment group tumor growth trend along with the difference of time.These specifications of a model are in the fact of multiple point in time measurement every animal.The independent model of matching to compare at every turn, and uses area under curve (AUC) value of each treatment group of the predictor calculation of described model.Then the reduction percentage ratio (△ AUC) of AUC relative to reference group is calculated.Statistically evident p value show 2 treatment groups along with the trend of time be different.

Results and discussions

Compared with treating with vehicle, use as single medicament with 0.3mg/kgQD, 1.0mg/kgQD3/4 to stop using and the compd B used of 3.0mg/kgQWPO significantly suppress tumor growth, wherein TGI value is respectively 36.9% (△ AUCp < 0.05), 47.2% (△ AUCp < 0.001) and 35.8% (△ AUCp < 0.001).

Compared with treating with vehicle, use as single medicament with 140mg/kgQD3/4 to stop using and the compd As used of 420mg/kgQWPO significantly suppress tumor growth, wherein TGI value is respectively 41.0% (△ AUCp < 0.001) and 40.8% (△ AUCp < 0.001).When compd A with 70mg/kgQD3 use/4 stop using and 210mg/kgQW use time, Tumor growth inhibition is minimum, and wherein TGI value is respectively 19.4% and 21.0%, but this is significantly different from contrast (p > 0.05).

Compared with treating with vehicle, 0.3mg/kgQD compd B and the 420mg/kgQW compd A of combined administration significantly suppress tumor growth, and wherein TGI value is 69.6% (△ AUCp < 0.001).Graphically illustrate in Figure 18 often group along with the mean tumour volume of time variations.The average maximum BW change of this dosage group is-2.4% on the 3rd day in treatment.In figure 18, HCC70 human breast cancer cell is implanted in female nude mice mammary fat pad.About 160 to 180mm is reached at mean tumour volume (MTV) ³afterwards, start to treat (combination that PO uses vehicle QD × 28 day, compd B 0.3mg/kgQD × 28 day, compd A 420mg/kgQW × 28 day or compd B and compd A).Data are depicted as meansigma methods; Error bars represents meansigma methods standard deviation (SEM) (n=5).Vehicle=PEG400.Clamp are used to monitor weekly twice tumor growth.Use formula (length x width ²)/2 calculate gross tumor volume.

Compared with treating with vehicle, the 1.0mg/kgQD3 of combined administration uses/and 4 stop using compd Bs and 70mg/kgQD3 use/4 to stop using or 140mg/kgQD3 uses/4 to stop using or 210mg/kgQW compd A significantly suppress tumor growth, and wherein TGI value is respectively 67.2% (△ AUCp < 0.001), 68.4% (△ AUCp < 0.001) and 59.0% (△ AUCp < 0.001).The average maximum BW change of these dosage groups is respectively-11.1% (the 3rd day) ,-18.8% (the 3rd day) and-10.7% (the 3rd day).

Compared with treating with vehicle, 3.0mg/kgQW compd B and the 420mg/kgQW compd A of combined administration significantly suppress tumor growth, and wherein TGI value is 61.7% (△ AUCp < 0.001).The average maximum BW change of this dosage group is-16.2% on the 3rd day in treatment.

Be greater than owing to losing weight 20% thus do not have mice from research removing, and compound B-11 .0mg/kgQD3 use/4 stop using with compd A 140mg/kgQD3 use/4 stop using dosage groups in visible maximum BW lose.

combination is compared (Log-conversion) (synergism analysis)

Attention: synergism analysis is carried out to area under concentration versus time curve (AUC) value at the 35th day.Score < 0 indicates synergism, and score=0 indicates summation action, and score > 0 indicates time addition (antagonism) effect.Be different from 0 to assess based on synergism score whether remarkable (p < 0.05).

All combinations of compd B and compd A cause significantly (p < 0.001) TGI and the interaction that synergism analyzes indication compound B and compd A is what be added in HCC-70 human breast carcinoma model.TGI scope be 59.0% (compound B-11 .0mg/kgQD3 uses/4 stop using+compd A 210mg/kgQW) to 69.6% (compd B 0.3mg/kgQD+ compd A 420mg/kgQW).

Tolerate all treatments, and average weight limit alleviates not > 18.8%.Compound B-11 .0mg/kgQD3 uses/4 to stop using+compd A 140mg/kgQD3 uses/at the 3rd day, 4 groups of stopping using occur that maximum average weight limit alleviates.These results show that these treatments can be combined and significantly can not increase toxicity, are confirmed by acceptable body weight change.In HCC-70 model in Ren Sanyin breast carcinoma in repeatedly therapeutic scheme, compd B shows anti-tumor activity with the combination of compd A compared with single medicament to be increased.

Embodiment 44 is to carrying the female nude mice of HCT-116 human colorectal cancer xenograft as single medicament or the anti-tumor in vivo activity combining Orally administered compd B and compd A

Method and material: below using in this study, test article: compd B also at room temperature keeps in Dark Place with PEG400 (TCAL, SanDiego, CA, USA) preparation for every 7 days.Compd A also at room temperature keeps in Dark Place with PEG400 (TCAL, SanDiego, CA, USA) preparation for every 7 days.The vehicle used in this research is PEG400 (Sigma, St.Louis, MO, USA).

Test macro: pass at the low generation (the 8th generation) HCT-116 cell (American Type Culture Collection center ATCC, Manassas, VA, USA) there is 10% fetal bovine serum (FBS) (PAALaboratoriesPtyLtd, Morningside, Queensland, Australia) McCoy ' s5A (ATCC) culture medium in growth and with 5.0 × 10 ⁷the concentration supply of individual cell/mL.By HCT-116 cell (5.0 × 10 ⁶/ animal, 0.1-mL injected slurry volume) SC implantation female athymic nude mouse flank.Following table describes the animal that this institute uses.

test macro

Experimental design: with 5.0 × 10 ⁶hCT-116 cell SC inoculate female 9 to 10 week age female FoxnlnuHsd: athymic nude mice flank.Use slide gauge monitoring tumor growth.Use formula V=W ²× L/2 calculates MTV.When MTV reaches about 160 to 170mm ³time, animal is divided at random 4 treatment groups (n=5/ group).Then to the combination (using) of mice PO administration PEG400, compd B, compd A or compd B and compd A simultaneously.Measure weekly twice tumor growth and body weight.TGI percentage ratio and body weight change is calculated when within the 21st day, animal is treated.Treatment is started at the 0th day.By using equation 1calculate TGI percentage ratio and determine anti-tumor activity: MTV × 100 of % Tumor growth inhibition (TGI)=(MTV of mean tumour volume [the MTV]-treatment group of matched group)/matched group.

Statistical analysis

Area under curve changes: use linear hybrid effect regression model to assess between paired treatment group tumor growth trend along with the difference of time.These specifications of a model are in the fact of multiple point in time measurement every animal.The independent model of matching to compare at every turn, and uses area under curve (AUC) value of each treatment group of the predictor calculation of described model.Then the reduction percentage ratio (Δ AUC) of AUC relative to reference group is calculated.Statistically evident p value show 2 treatment groups along with the trend of time be different.All p values being less than 0.05 are all considered to significant.

Results and discussions: in the nude mouse of carrying HCT-116 people's colorectal tumor xenograft, compared with treating with vehicle, QD5 use/2 stop using and to continue in schemes within 21 days, inhibit tumor growth (TGI=4.5%) with the compd B of 0.6mg/kgPO administration but be not significantly different from contrast (Δ AUC, p > 0.05).Compared with treating with vehicle, the compd A continuing to use with 120mg/kgPO for 21 days in QD scheme significantly suppress tumor growth (TGI=8.2%, Δ AUC, p < 0.05).Continue 21 days QD5 use/2 stop using the 0.6mg/kg compd B used in schemes and in QD scheme the combination of the 120mg/kg compd A that PO uses cause tumor growth significantly to suppress 60.8% (Δ AUC, p < 0.001).Graphically illustrate in Figure 19 often group along with the mean tumour volume of time variations.In Figure 19, HCT-116 human colorectal cancer cell SC is implanted in female nude mice flank.About 160 to 170mm is reached at mean tumour volume (MTV) ³start treatment afterwards.Data are depicted as meansigma methods; Error bars represents meansigma methods standard deviation (SEM) (n=5).Vehicle=PEG400.Clamp are used to monitor weekly twice tumor growth.Use formula (length x width ²)/2 calculate gross tumor volume.

As shown in the table, synergism analysis disclose 0.6mg/kg compd B (QD5 use/2 stop using continue 21 days PO in schemes and use) and being combined as synergistic (p=0.003) of 120mg/kg compd A (lasting 21 days POQD use).

combination is compared (Log-conversion) (synergism analysis)

SEM=average standard error.

Attention: synergism analysis is carried out to area under concentration curve (AUC) value at the 21st day.Score < 0 indicates synergism, and score=0 indicates summation action, and score > 0 indicates time addition (antagonism) effect.Be different from 0 to assess based on synergism score whether remarkable (p < 0.05).

At the 6th day, in the mice with compd B and compd A combination medicine-feeding, visible maximum average weight changed percentage ratio is-0.7%.Mice is not had to remove from research and comprise all mices when calculating.

This research shows, in the mice of carrying HCT-116 human colorectal cancer xenograft compd B (0.6mg/kg) and the combined therapy of compd A (120mg/kg) be tolerance and cause compared with single pharmaceutical treatment time antitumor action statistically significantly (p=0.003) increase.

Although illustrate and describe the preferred embodiments of the invention herein, for a person skilled in the art will be apparent, described embodiment only provides as an example.Numerous change, change and substitute without departing from the present invention now expect by those skilled in the art.Should be understood that the various replacement schemes of embodiment of the present invention as herein described can be used for carrying out the present invention.Intention is, following claims define scope of the present invention and therefore can contain and are in method and structure in these Claims scope and its equivalent.

Claims

1. the method for the disease condition be associated with PI3-kinases α and/or mTOR for treatment in experimenter, it comprises to described experimenter simultaneously or use following combination successively: (a) is according to the PI3-kinases alpha inhibitor of the treatment effective dose of the first dosage regimen, and (b) is according to the mTOR inhibitors of the treatment effective dose of the second dosage regimen, wherein said PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidyl-inositol 3-kinases (PI3-kinases) by vitro kinase, one or more I type PI3-kinases wherein said are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, wherein each dosage regimen comprises the repetition period that the treatment phase is then the rest period independently, wherein at least one dosage regimen has a rest period more than 0 day.

2. method according to claim 1, wherein said combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein said PI3-kinases alpha inhibitor and/or described mTOR inhibitors exist with sub-therapeutic dose.

3. method according to claim 1, the described disease condition be wherein associated with PI3-kinases α and/or mTOR is selected from by the following group formed: tumprigenicity condition of illness, autoimmune disease, diseases associated with inflammation, fibrotic conditions and nephropathy.

4. method according to claim 3, wherein said tumprigenicity condition of illness is selected from by the following group formed: NSCLC, incidence ESCC, cancer of pancreas, breast carcinoma and ovarian cancer, renal cell carcinoma, carcinoma of prostate, neuroendocrine carcinoma and carcinoma of endometrium.

5. method according to claim 1, wherein said first dosage regimen and described second dosage regimen are identical and use simultaneously.

6. method according to claim 1, wherein said first dosage regimen and described second dosage regimen are different.

7. method according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of at least 1 day independently, are then at least one cycles of the rest period of at least 1 day.

8. method according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of 2,3,4,5,6 or 7 Consecutive Days independently, are then at least one cycles of the rest period of at least 1 day.

9. method according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of 2,3,4,5,6 or 7 Consecutive Days independently, are then at least one cycles of the rest period of at least 3,4 or 5 Consecutive Days.

10. method according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of at least 1 day independently, are then at least one cycles of the rest period of 6 Consecutive Days.

11. methods according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of 3 Consecutive Days independently, are then at least one cycles of 7 days of the rest period of 4 Consecutive Days.

12. methods according to claim 11, wherein said first dosage regimen and described second dosage regimen are identical and use simultaneously.

13. methods according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of 5 Consecutive Days independently, are then at least one cycles of 7 days of the rest period of 2 Consecutive Days.

14. methods according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise the treatment phase of 1 Consecutive Days independently, are then at least one cycles of 7 days of the rest period of 6 Consecutive Days.

15. methods according to claim 1, wherein said first dosage regimen and/or described second dosage regimen comprise at least one cycle of 7 days independently, at least 3 treatment phases on the next day of between the described cycle was included in 7 days.

16. methods according to claim 1, one in wherein said first dosage regimen and described second dosage regimen has rest period of 0 day.

17. methods according to claim 1, wherein said second dosage regimen has the rest period of 0 day.

18. methods according to claim 1, wherein said first dosage regimen has the rest period of 0 day.

19. methods according to claim 18, wherein said second dosage regimen comprises the treatment phase of 5 Consecutive Days, is then at least one cycle of 7 days of the rest period of 2 Consecutive Days.

20. methods according to claim 18, wherein said second dosage regimen comprises the treatment phase of 1 Consecutive Days, is then at least one cycle of 7 days of the rest period of 6 Consecutive Days.

21. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α for the every other I type phosphatidyl-inositol 3-kinase (PI3-kinases) be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

22. methods according to claim 1, wherein said PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 100nM or less, as determined in kinase assays in vitro.

23. methods according to claim 1, wherein said PI3-kinases alpha inhibitor suppresses PI3-kinases α with the IC50 value of about 10nM or less, as determined in kinase assays in vitro.

24. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, and the IC50 value had is less at least 5 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

25. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α with the IC50 value being less than about 200nM, and described IC50 value is less at least 5 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

26. methods according to claim 1, wherein said mTOR inhibitors combines and directly suppresses mTORC1 and mTORC2.

27. methods according to claim 1, wherein said mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro.

28. methods according to claim 1, wherein said mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 10nM or less, as determined in kinase assays in vitro.

29. methods according to claim 1, wherein said mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 10nM or less, as determined in kinase assays in vitro, and described mTOR inhibitors is to the essentially no activity of one or more I type PI3-kinases being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

30. methods according to claim 1, wherein said mTOR inhibitors suppresses mTORC1 and mTORC2 with the IC50 value of about 100nM or less, as determined in kinase assays in vitro, and described IC50 value is less at least 5 times for the every other I type PI3-kinase whose IC50 value being selected from the group be made up of PI3-kinases α, PI3-kinase beta, PI3-kinases γ and PI3-kinase delta than it.

31. methods according to claim 1, wherein said mTOR inhibitors is formula I:

Or its pharmaceutically acceptable salt, wherein:

E ¹and E ²be-(W independently ¹) _j-R ⁴;

M ₁be 5,6,7,8,9 or 10 yuan of ring systems, wherein ring system be monocycle or dicyclo, by R ₅to replace and in addition optionally by one or more-(W ²) _k-R ²replace;

Each k is 0 or 1;

E ¹in j or E ²in j be 0 or 1 independently;

R ²for hydrogen, halogen ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl (such as, the monocyclic aryl of bicyclic aryl, unsubstituted aryl or replacement), heteroaryl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _1-10alkyl-C _2-10thiazolinyl, C _1-10alkyl-C _2-10alkynyl, C _1-1 ₀alkylaryl (such as, C _2-10alkyl-monocyclic aryl, C _1-10the monocyclic aryl of alkyl-replacement or C _1-10alkyl bicyclic aryl), C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3- ₈cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical, assorted alkyl, heterocyclic radical-C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl (such as, monocyclic aryl-C _2-10monocyclic aryl-the C of alkyl, replacement _1-10alkyl or bicyclic aryl-C _1-10alkyl), aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said bicyclic aryl or heteroaryl moieties is unsubstituted, or each wherein in bicyclic aryl, heteroaryl moieties or monocyclic aryl part is by one or more independently alkyl, assorted alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties be unsubstituted or by one or more alkyl, mix alkyl, thiazolinyl, alkynyl, cycloalkyl, Heterocyclylalkyl, aryl, aryl alkyl, heteroaryl, heteroaryl alkyl, halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ³and R ⁴be hydrogen, halogen ,-OH ,-R independently ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²,-SC (=O) NR ³¹r ³², aryl, heteroaryl, C _1-4alkyl, C _1-10alkyl, C _3-8cycloalkyl, C _1-10alkyl-C _3-8cycloalkyl, C _3-8cycloalkyl-C _1-10alkyl, C _3-8cycloalkyl-C _2-10thiazolinyl, C _3-8cycloalkyl-C _2-10alkynyl, C _1-10alkyl-C _2-10thiazolinyl, C _1-10alkyl-C _2-10alkynyl, C _1-10alkylaryl, C _1-10miscellaneous alkyl aryl, C _1-10alkyl heterocyclic, C _2-10thiazolinyl, C _2-10alkynyl, C _2-10thiazolinyl-C _1-10alkyl, C _2-10alkynyl-C _1-10alkyl, C _2-10alkenyl aryl, C _2-10alkenyl heteroaryl, C _2-10thiazolinyl is mixed alkyl, C _2-10thiazolinyl heterocyclic radical, C _2-10thiazolinyl-C _3-8cycloalkyl, C _2-10alkynyl-C _3-8cycloalkyl, C _2-10alkynyl aryl, C _2-10alkynyl heteroaryl, C _2-10alkynyl is mixed alkyl, C _2-10alkynyl heterocyclic radical, C _2-10alkynyl-C _3-8cycloalkenyl group, C _1-10alkoxy C _1-10alkyl, C _1-10alkoxy-C _2-10thiazolinyl, C _1-10alkoxy-C _2-10alkynyl, heterocyclic radical, heterocyclic radical-C _1-10alkyl, heterocyclic radical-C _2-10thiazolinyl, heterocyclic radical-C _2-10alkynyl, aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, aryl-heterocyclic, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, heteroaryl-C _3-8cycloalkyl, assorted alkyl, heteroaryl-assorted alkyl or heteroaryl-heterocyclyl, each in wherein said aryl or heteroaryl moieties is unsubstituted or by one or more independently halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-NR ³¹r ³²,-NR ³⁴r ³⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2r ³¹,-SO ₂nR ³¹r ³²,-SO ₂nR ³⁴r ³⁵,-NR ³¹c (=O) R ³²,-NR ³ ¹c (=O) OR ³²,-NR ³¹c (=O) NR ³²r ³³,-NR ³¹s (O) _0-2r ³²,-C (=S) OR ³¹,-C (=O) SR ³¹,-NR ³¹c (=NR ³²) NR ³³r ³²,-NR ³¹c (=NR ³²) OR ³³,-NR ³¹c (=NR ³ ²) SR ³³,-OC (=O) OR ³³,-OC (=O) NR ³¹r ³²,-OC (=O) SR ³¹,-SC (=O) OR ³¹,-P (O) OR ³¹oR ³²or-SC (=O) NR ³¹r ³²replace, and each in wherein said alkyl, cycloalkyl, heterocyclic radical or assorted moieties is unsubstituted or by one or more halogeno-group ,-OH ,-R ³¹,-CF ₃,-OCF ₃,-OR ³¹,-O-aryl ,-NR ³¹r ³²,-NR ³⁴r ³ ⁵,-C (O) R ³¹,-CO ₂r ³¹,-C (=O) NR ³⁴r ³⁵or-C (=O) NR ³¹r ³²replace;

R ⁶for halogeno-group ,-OR ³¹,-SH ,-NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³ ¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) ₀ _-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl; Aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, each in wherein said alkyl, thiazolinyl, alkynyl, aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-10alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-10thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace; And

R ⁹for H, halogeno-group ,-OR ³¹,-SH ,-NH ₂,-NR ³⁴r ³⁵,-NR ³¹r ³²,-CO ₂r ³¹,-CO ₂aryl ,-C (=O) NR ³¹r ³², C (=O) NR ³⁴r ³⁵,-NO ₂,-CN ,-S (O) _0-2c _1-10alkyl ,-S (O) _0-2aryl ,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³², C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl; Aryl-C _1-10alkyl, aryl-C _2-10thiazolinyl, aryl-C _2-10alkynyl, heteroaryl-C _1-10alkyl, heteroaryl-C _2-10thiazolinyl, heteroaryl-C _2-10alkynyl, each in wherein said alkyl, thiazolinyl, alkynyl, aryl, assorted alkyl, heterocyclic radical or heteroaryl is unsubstituted or by one or more independently halogeno-group, cyano group, nitro ,-OC _1-1 ₀alkyl, C _1-10alkyl, C _2-10thiazolinyl, C _2-10alkynyl, halo C _1-10alkyl, halo C _2-1 ₀thiazolinyl, halo C _2-10alkynyl ,-COOH ,-C (=O) NR ³¹r ³²,-C (=O) NR ³⁴r ³⁵,-SO ₂nR ³⁴r ³⁵,-SO ₂nR ³¹r ³²,-NR ³¹r ³²or-NR ³⁴r ³⁵replace.

32. methods according to claim 1, wherein said PI3-kinases alpha inhibitor is following formula: compound:

Or its pharmaceutically acceptable salt, wherein

W ^{5 '}for N;

W ^{6 '}for N or CR ^{8 '};

W ^{a '}and W ^{b '}be N or CR independently ^{9 '};

W ^{c '}and W ^{d '}in one be N, and another is O, NR ^{10 '}or S;

Or R ^{3 '}and R ^{4 '}form annulus together;

R ^{9 '}for alkyl or halogeno-group; And

33. methods according to claim 1, wherein said PI3-kinases alpha inhibitor is following formula: compound:

Or its pharmaceutically acceptable salt, wherein:

X is O or S or N;

W ^{5 '}for N or CR ^{7 '};

W ^{6 '}for N or CR ^{8 '};

Or R ^{3 '}and R ^{4 '}form annulus together; And

34. methods according to claim 1, wherein said mTOR inhibitors is following formula: compound:

35. methods according to claim 1, wherein said PI3-kinases alpha inhibitor and/or described mTOR inhibitors parenteral, per os, intraperitoneal, intravenous, intra-arterial, percutaneous, intramuscular, with liposomal form, through in the local delivery of conduit or support, subcutaneous, fat or use in sheath.

36. methods according to claim 1, wherein said PI3-kinases alpha inhibitor and/or described mTOR inhibitors are jointly applied to described experimenter in same preparation.

37. methods according to claim 1, wherein said PI3-kinases alpha inhibitor and/or described mTOR inhibitors are jointly applied to described experimenter in different preparation.

38. methods according to claim 1, wherein said experimenter or cell are included in the sudden change be associated with the disease condition alpha mediated by PI3-kinases in the nucleotide sequence of coding PI3-kinases α.

39. methods according to claim 1, wherein said mTor inhibitor optionally suppresses mTORC1.

40. according to method according to claim 39, and wherein said mTor inhibitor suppresses mTORC1 with the IC50 value of about 1000nM or less, as determined in kinase assays in vitro.

41. according to method according to claim 39, and wherein said mTor inhibitor is the analog of rapamycin or rapamycin.

42. methods according to claim 41, wherein said mTor inhibitor is sirolimus (rapamycin), deforolimus (AP23573, MK-8669), everolimus (RAD-001), CCI-779 (CCI-779), Zuo Tamosi (ABT-578) or do not take charge of A9 (Wu meter Mo Si) than Austria.

43. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α and PI3-kinase beta, and the IC50 value had is less at least 5 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.

44. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α and PI3-kinase beta, and the IC50 value had is less at least 50 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.

45. methods according to claim 1, wherein said PI3-kinases alpha inhibitor optionally suppresses PI3-kinases α, and the IC50 value had is less at least 50 times than its IC50 value for PI3-kinases γ or PI3-kinase delta.

46. 1 kinds for treating the method for the disease condition be associated with PI3-kinases α and/or mTOR in experimenter, it comprises to described experimenter simultaneously or use following combination successively: (a) treats the PI3-kinases alpha inhibitor of effective dose, and (b) treats the mTOR inhibitors of effective dose, wherein said PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidyl-inositol 3-kinases (PI3-kinases) by vitro kinase, one or more I type PI3-kinases wherein said are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta, clinical and the therapeutic effect of the treatment of wherein said disease condition continues at least the same with the phase of using persistent period action period grown.

47. methods according to claim 46, wherein said combination comprises PI3-kinases alpha inhibitor and the mTOR inhibitors of collaborative effective therapeutic dose, and wherein said PI3-kinases alpha inhibitor and/or described mTOR inhibitors exist with sub-therapeutic dose.

48. methods according to claim 46, wherein said clinical and therapeutic effect is selected from by the following group formed: lasting tumor regression, downtrod tumor regrowth are long, the minimizing of propagation, the apoptosis of increase, or the downward of target protein activity.

49. methods according to claim 46, wherein said clinical and therapeutic effect is that lasting tumor regression and downtrod tumor regrowth are long.

50. methods according to claim 46, wherein said persistent period action period is at least 30 days.

51. methods according to claim 46, wherein said persistent period action period is at least 5 days.

52. methods according to claim 46, wherein said PI3-kinases alpha inhibitor is used according to the first intermittent dosing regimen, and described scheme comprises the repetition period that the treatment phase is then the rest period.

53. methods according to claim 46, wherein said mTOR inhibitors is used according to the second intermittent dosing regimen, and described scheme comprises the repetition period that the treatment phase is then the rest period.

The method of 54. 1 kinds of disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, it comprises to described experimenter simultaneously or use following combination successively: the PI3-kinases alpha inhibitor for the treatment of effective dose according to (a) of intermittent ann, and (b) treats the mTOR inhibitors of effective dose, described scheme is effective in and realizes (a) higher curative effect, similar or the better toleration of (b) described PI3-kinases alpha inhibitor and/or mTOR inhibitors, and (c) is compared with the described PI3-kinases alpha inhibitor using dose,equivalent once a day and/or mTOR inhibitors, similar or less area under curve, wherein said PI3-kinases alpha inhibitor shows the Selective depression being measured determined PI3-kinases α for one or more I type phosphatidyl-inositol 3-kinases (PI3-kinases) by vitro kinase, and one or more I type PI3-kinases wherein said are selected from by the following group formed: PI3-kinase beta, PI3-kinases γ and PI3-kinase delta.

55. 1 kinds of medicinal reagent boxes, it comprises:

I () is placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day are used in expection, and the mTOR inhibitors that the PI3-kinases alpha inhibitor of effective dose and/or (b) treat effective dose is treated by wherein said daily dose unit each self-contained (a); The described daily dose unit wherein comprising described PI3-kinases alpha inhibitor and/or mTOR inhibitors is effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, and

(ii) to be placed in packaging unit and expection use the time period of a time period or multiple at least 1 day not containing multiple daily dose units of activating agent.

56. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein not containing the daily dose unit of activating agent is at least 1.

57. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein not containing the daily dose unit of activating agent is at least 3,4 or 5, or the multiple of 3,4 or 5.

58. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is at least 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.

59. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is 3, or the multiple of 3, and the number wherein not containing the daily dose unit of activating agent is 4, or the multiple of 4.

60. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is 5, or the multiple of 5, and the number wherein not containing the daily dose unit of activating agent is 2, or the multiple of 2.

61. test kits according to claim 55, the number wherein comprising the daily dose unit of described PI3-kinases alpha inhibitor and/or mTOR inhibitors is 1, or the multiple of 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.

62. 1 kinds of medicinal reagent boxes being effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, it comprises

I () is placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, each self-contained following combination of wherein said daily dose unit are used in expection: (a) treats the mTOR inhibitors that the PI3-kinases alpha inhibitor of effective dose and (b) treat effective dose; And

(ii) to be placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the PI3-kinases alpha inhibitor of each self-contained treatment effective dose of wherein said daily dose unit are used in expection.

63. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is at least 1.

64. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is 2,3,4,5,6 or 7, or the multiple of 2,3,4,5,6 or 7, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is at least 3,4 or 5, or the multiple of 3,4 or 5.

65. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is at least 1, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is 6, or the multiple of 6.

66. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is 3, or the multiple of 3, and the number wherein only comprising the daily dose unit of PI3-kinases alpha inhibitor is 4, or the multiple of 4.

67. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is 5, or the multiple of 5, and the number wherein not containing the daily dose unit of activating agent is 2, or the multiple of 2.

68. test kits according to claim 62, the number wherein comprising the daily dose unit of described combination is 1, or the multiple of 1, and the number wherein not containing the daily dose unit of activating agent is 6, or the multiple of 6.

69. 1 kinds of medicinal reagent boxes being effective in the disease condition that treatment is associated with PI3-kinases α and/or mTOR in experimenter, it comprises

(ii) to be placed in packaging unit and multiple daily dose units of the time period of a time period or multiple at least 1 day, the mTOR inhibitors of each self-contained treatment effective dose of wherein said daily dose unit are used in expection.