CN101189243A

CN101189243A - Substituted heterocycles and their use as CHK1, PDK1 and PAK inhibitors

Info

Publication number: CN101189243A
Application number: CNA2006800198622A
Authority: CN
Inventors: K·达利; N·赫伦; A·赫德; S·乔安尼迪斯; J·W·简特卡; P·莱恩; J·斯科特; D·托德; M·瓦斯宾德; D·余; Y·余
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-04-06
Filing date: 2006-04-05
Publication date: 2008-05-28
Also published as: ZA200708186B

Abstract

This invention relates to novel compounds of Formula (I) and to their pharmaceutical compositions and to their methods of use. These novel compounds possess CHK1 kinase inhibitory activity, PDK1 inhibitory activity and Pak kinase inhibitory activity and are accordingly useful in the treatment and/or prophylaxis of cancer.

Description

The heterocycle that replaces and as the application of CHK1, PDK1 and PAK inhibitor

Invention field

The present invention relates to the heterocycle of new replacement, their medicinal compositions and using method.In addition, the present invention relates to treat with preventing cancer methods of treatment.

Background of invention

Chemotherapy and radiating irradiation are the main selections for the treatment of cancer now, but the application of these two kinds of means is owing to its severe side effect and frequent tumor cell resistance that takes place for healthy tissues is subjected to strict restriction.Therefore, be starved of in the effect that does not increase the such treatment of improvement under the toxicity situation relevant with them.A kind of method that reaches this purpose is to use such as those at specificity sensitive medicaments described herein.

Individual cells accurately copies by making its karyomit(e), then with these separation (segregating) to each cell that separates and duplicate.Dna replication dna, chromosome segregation and the circulation that separates are by keeping each step in order and guarantee that the intracellular mechanism that each step is accurately carried out regulates.The key of these processes is that (Nov 3 for Hartwell etc., Science in the cell cycle check point, 1989,246 (4930): 629-34), in these check points, cell can be stagnated to guarantee that the DNA repair mechanism carried out if having time before continuing to enter mitotic division by circulation.Two such check points were arranged in the cell cycle---by the G1/S check point of p53 adjusting and the G2/M check point of monitoring by Ser/Thr kinases check point kinases 1 (CHK1).In addition, recently Chk1 also is accredited as very important in S phase phase check point (PNAS such as Zhao, on November 12nd, 2002,99 (23): 14795-14800; Sorsensen etc., Cancer Cell, in March, 2003, volume 3:247-258 and Senggupta etc., Journal of Cell Biology, volume 166,6,801-813).

Because the cell cycle arrest that is caused by these check points is extremely important mechanism, they can overcome the damage that causes by radiotherapy or chemotherapy by this mechanism cell, so will be increased the susceptibility of tumour cell to the dna damage treatment by the elimination of new medicine.In addition, the specificity by the G1/S check point of p53 sudden change of the tumour in most of tumours is eliminated, and can be developed so that the tumor-selective medicine to be provided.The chemotherapy sensitive agent of G2/M check point is eliminated in design or an approach of radiotherapy sensitive agent is, key of development G2/M regulates the inhibitor of kinase c HK1, and this approach has been presented in the test of many conceptual approaches effectively.(Koniaras etc., Oncogene, 2001,20:7453; Luo etc., Neoplasia, 2001,3:411; Busby etc., Cancer Res., 2000,60:2108; Jackson etc., Cancer Res., 2000,60:566).

Some kinases belongs to serine/threonine kinase family and is positioned at cell and transmits relevant with the biochemical signals that influences growth of tumour cell such as those.Such serine/threonine kinase signal transmission path comprise downstream such as PDK-1, the AKT of Raf-MEK-ERK cascade reaction and those PI3K and mTOR (Blume-Jensen and Hunter, Nature, 2001, 411, 355).These serine/threonine kinase paths have also shown to be regulated other serine/threonine kinase and is regulated by described other serine/threonine kinase, and described other serine/threonine kinase also regulate tumor growth and invasion other serine/threonine kinase and regulated by described other serine/threonine kinase.Such kinases family is p21-activated protein kinase (Pak) family of serine/threonine kinase in the cell.

Pak kinases family as the downstream effect device of little p21 Rho GTP enzyme, Rac and Cdc42 work (Bokoch, Annual Review of Biochemistry, 2003, 72, 741-781).Six kinds of people Pak kinases that just in time divide to go into two subfamilies have been identified.First subfamily (group I) comprises Pak1 (Pak α), Pak2 (Pak γ, hPak65) and Pak3 (Pak β).Another subfamily (group II) comprises Pak4, Pak5 and Pak6.The group I Paks of family shares 93% identity in their kinases territory, and group II Paks kinases territory shows 54% identity more distinctively with group I kinases territory.Organize 1 Pak kinases can by multiple GTP enzyme-dependence and-ind mechanism activates.Organize 1 Pak kinases and activated (GTP-bonded) p21 (Rac/Cdc42) and interact, suppress the GTP enzymic activity of p21 and cause automatic phosphorylation of kinases and activation.The guanine nucleotide exchange factor (GEFs) and the GTP enzyme-activator (GAPs) of the GTP-GDP bonding state of the Rho family of adjusting GTP enzyme are the important determinants that is transmitted by Pak activated downstream signal.

Pak kinases family related to cell survival, conversion, propagation and cell movement adjusting (Bokoch, Annual Review of Biochemistry, 2003, 72, 741-781; Kumar and Hung, Cancer Research, 2005, 65, 2511-2515).The Pak1 signal downstream of Ras path and the activation of Pak have been presented in the cell transformation works.As in the fairly simple eukaryotic cell, Paks regulates the MAPK signal path in mammalian cell, and for example, Pak1 makes Raf1 and Mek1 phosphorylation.Paks plays an important role in the growth factor signal transmission that the cytoskeleton of transfer that causes influencing the somatomedin mediation and invasion and attack is rebuild.Also by making the Bad inactivation promote cell survival, prompting Pak1 can relate to cancer cell survival and evolution (progression) in the Pak1 activation.

Have new data point out Pak kinases family to the tumour of a variety of human cancers take place generation effect directly or indirectly (Vadlamudi and Kumar, 2003, Cancer and Metastasis Reviews, 2003, 22, 385-393; Kumar and Hung, Cancer Research, 2005, 65, 2511-2515).For example, existing be reported in the ovary breast tumor Pak1 gene amplification and corresponding Pak 1 protein upwards-regulate (Schraml etc., American Journal of Pathology, 2003, 163, 985-992).The deterioration transfer of existing report Pak1 expression increasing colorectal carcinoma (Carter etc., Clinical Cancer Research, 2004, 10, 3448-3456).In addition, determined Pak4 gene amplification and sudden change in the colorectum kinases (Parsons etc., Nature, 2005, 436, 792).New data prompting Pak1 relates to the evolution of mammary cancer.For example, the genetically modified expression of (constitutively active) Pak1 of the constitutively activate in the mouse mammary gland bring out the breast epithelium hyperplasia (Wang etc., The EMBO Journal, 2002, 21, 5437-5447).At last, also can participate in the excessive activation of Pak signal cascade reaction in the cancer to the active adjusting of Pak by Rac/Cdc42 and guanine exchange factor (GEFs).For example, the new data of the keying action of relevant GEF Vav1 in the tumour of pancreatic cancer takes place discloses, and is target with the Rac-Pak signal path in the treatment pancreatic neoplasm, exist possible chance (Fernandez-Zapico etc., Cancer Cell, 2005, 7, 39-49).

These results suggest, the Pak inhibitor on the pharmacology should have therapeutic value for the Cancerous disease of treatment various ways.

Also show on evidence, Pak in regulating neurocyte projection and normal brain development, work (Hofmann etc., Journal of Cell Science, 2004, 117, 4343-4354; Nikolic, The International Journal of Biochemistry, 2002, 34, 731-745).The Pak inhibitor can be used for treating nerve degenerative diseases and the disease relevant with the neurotization defective.In addition, the Pak inhibitor also can have the potential purposes in treatment joint disease or arthralgia.

Known adjusting cell survival and apoptosis (Yao and Cooper, Oncogene, 1996,13, the 343-351 of relating in itself of phosphatidylinositols 3 ' OH kinases (PI3K) path; Franke etc., Oncogene, 2003,22,8983-8998).As the part of this path, protein kinase-1 (PDK1) that phosphoinositide relies on and Akt in signal conducts, play a crucial role (Vanhaesebroeck and Alessi, Biochem.J., 2000,346,561-576).The activation of PI3K causes producing the PH structural domain (pleckstrin homology) that is incorporated into PDK1 and Akt and goes up to act on activated (3,4,5) the triphosphoric acid phosphatidylinositols of film associating (membrane association) and Akt.The transgenation of PI3K path kinases such as PI3K, Akt, mTOR and the many human cancers closely related (Philp etc., Cancer Res., 2001,61, the 7426-7429 that comprise colorectal carcinoma, mammary cancer and prostate cancer; Bellacosa etc., Int.J.Cancer, 1995,64,280-285).By the sudden change of the lipid Phosphoric acid esterase PTEN that goes back archeocyte PIP3 or the confusion of this path that disappearance causes, comprise the relevant (Steck etc. of mammary cancer, prostate cancer, carcinoma of endometrium and melanoma with the various human tumour with the neuroglia blastoma, Nat.Genetics, 1997,15,356-362).

Derive from tool PTEN that hypomorph PDK1 knocks out lack background mouse in body evidence strong hint, PDK be present in a lot of tumor types (Bayascas etc., Curr.Biol., 2005,15,1839-1846).Have again, use the PDK1 inhibitor, 7-hydroxyl Si Tuosibolin (stauro-sporine) body research consistent with these results (Sato etc., Oncogene, 2002,21,1727-1738).Therefore can expect that the inhibitor of the protein kinase-1 (PDK1) that phosphoinositide relies on will be used for the treatment of such as cancer, for example the disease of colorectal carcinoma, mammary cancer or prostate cancer.

The invention summary

Therefore according to the present invention, the applicant discloses new compound at this, and described compound is effective kinase c HK1 inhibitor and has the prevention cell cycle in the ability to stagnating in the G2/M check point in the replying of dna damage.Some compound of the present invention still is the PDK1 inhibitor.Therefore The compounds of this invention is because its antiproliferative (such as anticancer disease) is active but useful, and therefore is used for the treatment of in the method for human or animal body.

Some compound of the present invention still is the Pak kinase inhibitor, for example one or more Pak1, Pak 2, Pak 3, Pak 4, Pak 5 and Pak 6 kinases, particularly Pak 1, Pak 2 or Pak 4 kinase whose inhibitor.Compound with Pak kinase activity is also expected for example to pass through to suppress cell survival, cell transformation or cell movement, is used to suppress tumour and takes place.

The invention still further relates to the method that is used to prepare described compound, relate to the medicinal compositions that comprises described compound and relate to their application in the preparation medicine, described medicine is used for producing anticarcinogenic effect warm-blooded animal such as the people, for example anti-proliferative effect.

The present invention includes the pharmacy acceptable salt of such compound.According to the present invention, the applicant provides medicinal compositions and use the method for such compound in cancer therapy in addition.

Such characteristic is desirably in treatment and cell cycle arrest, cell proliferation, cell survival, have value in the morbid state that cell transformation or cell movement are correlated with, described morbid state has such as cancer (noumenal tumour and leukemia), fiber proliferative and branch voltinism illness, psoriatic, rheumatoid class sacroiliitis, Kaposi, vascular tumor, acute and chronic nephropathy, sebaceous cyst, atherosclerosis, arterial restenosis, autoimmune disorder, neurodegenerative disorders and disease such as Parkinson's disease and the Alzheimer relevant with the neurotization defective, acute and chronic inflammation is such as osteoarthritis, rheumatoid class sacroiliitis or arthralgia, osteopathy and the outgrowth disease of eye of companion's retinal vessel.

Detailed Description Of The Invention

Therefore, the invention provides formula (I) compound or its pharmacy acceptable salt,

(I)

Wherein:

A and D independently are selected from N, CH, S, O and NR separately ⁴

L is selected from NR ⁵, O and S;

X and Y independently are selected from N and CH separately;

R ¹Be selected from cyano group, halo; C _1-6Alkyl ,-NR ¹¹R ¹², C _1-6Alkoxyl group, C _2-6Thiazolinyl, C _2-6Alkynyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical, OR ⁶-CO carbocylic radical ,-the CO heterocyclic radical ,-CO (C _1-6Alkyl) ,-CONR ²⁸R ²⁹,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical, S (O) _yNR ²⁸R ²⁹With-(C _1-6Alkyl) S (O) _yNR ²⁸R ²⁹, wherein x independently is that 0-2 and y independently are 1 or 2; R wherein ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group;

R ²Be selected from (C _1-3Alkyl) NR ⁷R ⁸, contain at least one nitrogen-atoms 4-to 7-unit heterocycle ,-the CO carbocylic radical ,-the CO heterocyclic radical ,-CO (C _1-6Alkyl) ,-CONR ²⁸R ²⁹,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-CO ₂Heterocyclic radical ,-CO ₂NR ²⁸R ²⁹,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCycloalkyl ,-S (O) _xCycloalkenyl group ,-S (O) _xHeterocyclic radical, S (O) _yNR ²⁸R ²⁹With-(C _1-6Alkyl) S (O) _yNR ²⁸R ²⁹, wherein x independently is 1 or 2 and R wherein for 0-2 and y independently ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; Wherein if heterocyclic radical also contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group;

R ³Be selected from H, benzyl, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical, OR ⁶, CHO ,-the CO carbocylic radical ,-CO (C _1-6Alkyl) ,-CONR ²⁸R ²⁹,-S (O) x (C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical, S (O) _yNR ²⁸R ²⁹With-(C _1-6Alkyl) S (O) _yNR ²⁸R ²⁹, wherein x independently is 0-2, y independently is 1 or 2 and R wherein ³Can be by one or more R on one or more carbon atoms ¹⁵The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then described nitrogen can be selected from R ¹⁶Optional replacement of group;

R ⁴Be selected from H, C _1-3Alkyl, cyclopropyl and CF ₃

R ⁵Be selected from H, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, heterocyclic radical and OR ⁶R wherein ⁵Can be by one or more R on carbon ¹⁷The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁸Optional replacement of group;

R ⁶Be selected from H, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical; R wherein ⁶Can be by one or more R on carbon ¹⁹The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ²⁴Optional replacement of group;

R ⁷And R ⁸Independently be selected from H, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical; R wherein ⁷And R ⁸Independently of one another can be by one or more R on carbon ²⁰The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ²¹Optional replacement of group;

R ¹¹And R ¹²Independently be selected from H, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical, wherein R ¹¹And R ¹²Independently of one another can be by one or more R on carbon ³²The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ³³Optional replacement of group;

R ⁹, R ¹³, R ¹⁵, R ¹⁷, R ¹⁹, R ²⁰, R ³²And R ³⁴Independently be selected from separately halo, nitro ,-NR ²⁸R ²⁹, cyano group, isocyano-, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl, ketone group (=O) ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-the O heterocyclic radical ,-the O aryl ,-OC (O) C _1-6Alkyl ,-NHCHO ,-N (C _1-6Alkyl) CHO ,-NHCONR ²⁸R ²⁹,-N (C _1-6Alkyl) CONR ²⁸R ²⁹,-NHCO (C _1-6Alkyl) ,-the NHCO carbocylic radical ,-NHCO (heterocyclic radical) ,-NHCO ₂(C _1-6Alkyl);-NHCO ₂H ,-N (C _1-6Alkyl) CO (C _1-6Alkyl) ,-NHSO ₂(C _1-6Alkyl), carboxyl ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-the CO aryl ,-CO ₂H ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-CO ₂Heterocyclic radical ,-OC (O) (NR ²⁸R ²⁹), sulfydryl ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _xNR ²⁸R ²⁹Wherein x independently is 0-2, wherein R ⁹, R ¹³, R ¹⁵, R ¹⁷, R ¹⁹, R ²⁰, R ³²And R ³⁴Independently of one another can be by one or more R on carbon ²²If optional replace and wherein heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ²³Optional replacement of group;

R ¹⁰, R ¹⁴, R ¹⁶, R ¹⁸, R ²¹, R ²⁴, R ³³And R ³⁵Independently be selected from cyano group, C separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-CO carbocylic radical-CO aryl ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-CO ₂Heterocyclic radical ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _yNR ²⁸R ²⁹Wherein x independently is that 0-2 and y independently are 1 or 2; R wherein ¹⁰, R ¹⁴, R ¹⁶, R ¹⁸, R ²¹, R ²⁴, R ³³And R ³⁵Independently of one another can be by one or more R on carbon ²⁵If optional replace and wherein described heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ²⁶Optional replacement of group;

R ²²And R ²⁵Independently be selected from separately halo, nitro ,-NR ²⁸R ²⁹, cyano group, isocyano-, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl, ketone group (=O) ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-the O heterocyclic radical ,-the O aryl ,-OC (O) C _1-6Alkyl ,-NHCHO ,-N (C _1-6Alkyl) CHO ,-NHCONR ²⁸R ²⁹,-N (C _1-6Alkyl) CONR ²⁸R ²⁹,-NHCO (C _1-6Alkyl) ,-the NHCO carbocylic radical ,-NHCO (heterocyclic radical) ,-NHCO ₂(C _1-6Alkyl);-NHCO ₂H ,-N (C _1-6Alkyl) CO (C _1-6Alkyl) ,-NHSO ₂(C _1-6Alkyl), carboxyl ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂H ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-OC (O) (NR ²⁸R ²⁹), sulfydryl ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _xNR ²⁸R ²⁹Wherein x independently is 0-2, wherein R ²²And R ²⁵Can be by one or more R on carbon ³⁶If optional replace and wherein described heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ²⁷Optional replacement of group;

R ²³And R ²⁶Independently be selected from cyano group, C separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _yNR ²⁸R ²⁹Wherein x independently is that 0-2 and y independently are 1 or 2; R wherein ²³And R ²⁶Independently of one another can be by one or more R on carbon ³⁰If optional replace and wherein described heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ³¹Optional replacement of group;

R ²⁸And R ²⁹Independently be selected from H, amino, cyano group, C separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl ,-O (C _1-6Alkyl) ,-the O aryl ,-the OCO alkyl ,-amidino groups ,-CHO ,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-SO (C _1-6Alkyl) ,-SO ₂(C _1-6Alkyl), R wherein ²⁸And R ²⁹Independently of one another can be by one or more R on carbon ³⁴The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ³⁵Optional replacement of group;

R ³⁰And R ³⁶Independently be selected from separately halo, nitro ,-NR ²⁸R ²⁹, cyano group, isocyano-, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl, ketone group (=O) ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-OC (O) C _1-6Alkyl ,-NHCHO ,-N (C _1-6Alkyl) CHO ,-NHCONR ²⁸R ²⁹,-N (C _1-6Alkyl) CONR ²⁸R ²⁹,-NHCO (C _1-6Alkyl) ,-the NHCO carbocylic radical ,-NHCO (heterocyclic radical) ,-NHCO ₂(C _1-6Alkyl);-NHCO ₂H ,-N (C _1-6Alkyl) CO (C _1-6Alkyl) ,-NHSO ₂(C _1-6Alkyl), carboxyl ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂H ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-OC (O) (NR ²⁸R ²⁹), sulfydryl ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _xNR ²⁸R ²⁹Wherein x independently is 0-2;

R ²⁷And R ³¹Independently be selected from cyano group, C separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-(C _1-6Alkyl)-O-(C _1-6Alkyl) ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _yNR ²⁸R ²⁹Wherein x independently is that 0-2 and y independently are 1 or 2;

As used in this application term " optional replace ", mean replace be choose wantonly and therefore, might not be substituted by specified atom.In case it is essential replacing, then such replacement means any amount of hydrogen on the specified atom and is selected from specified group and replaces, and condition is that the normal valency and the replacement that are no more than specified atom cause stable compound.

When ring is presented in the ring structure, it is meant that loop systems is an aromatics.

Term " hydrocarbon " uses separately or uses as prefix or suffix, refers to the structure of 14 carbon atoms of as many as of any only carbon containing and hydrogen atom.

Term " hydrocarbyl group " or " alkyl (hydrocarbyl) " use separately or use as prefix or suffix, refer to anyly to remove one or more hydrogen and the structure that forms by hydrocarbon.

Term " alkyl " uses separately or uses as prefix or suffix, unless refer in particular in addition, refers to and contains 1 to the unit price straight or branched alkyl of about 12 carbon atoms and comprise straight chain and branched-chain alkyl.When mentioning single alkyl such as " propyl group ", then only refer in particular to linear form, when mentioning single branched-chain alkyl such as " sec.-propyl ", then only refer in particular to the side chain form.For example, " C _1-6Alkyl " comprise C _1-4Alkyl, C _1-3Alkyl, propyl group, sec.-propyl and tert-butyl.Similarly convention is applicable to other group, for example " phenyl C _1-6Alkyl " comprise phenyl C _1-4Alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

Term " thiazolinyl " uses separately or uses as prefix or suffix, unless refer in particular in addition, refers to that to have at least one carbon-to-carbon two strong and contain at least 2 to the unit price straight or branched alkyl of about 12 carbon atoms at most.

Term " alkynyl " uses separately or uses as prefix or suffix, unless refer in particular in addition, refers to that to have at least one carbon-to-carbon three strong and contain at least 2 to the unit price straight or branched alkyl of about 12 carbon atoms at most.

Term " cycloalkyl " uses separately or uses as prefix or suffix, refer to saturated, comprise and contain at least 3 to the alkyl unit price rings of about 12 carbon atoms at most.When cycloalkyl comprises more than a ring, then ring can be condensed or uncondensed and comprise bicyclic group.Between generally referring to, shares on the condensed ring at least two rings of two atoms.Cycloalkyl as an example comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and norcamphyl (norboranyl).

Term " cycloalkenyl group " uses separately or uses as prefix or suffix, refers to comprise to contain at least 3 alkyl unit price rings to maximum about 12 carbon atoms, but does not comprise the aromatic ring system.When cycloalkenyl group contained more than when ring, then ring can be condensed or uncondensed and comprise bicyclic group.Cycloalkenyl group as an example comprises cyclohexenyl and cycloheptenyl.

Term " aryl " uses separately or uses as prefix or suffix, refer to and have aromatic character (as, 4n+2 delocalized electron) and comprise 6, wherein this group is positioned on the carbon of aromatic ring to the maximum alkyl of one or more many unsaturated carbocyclics of about 14 carbon atoms.Aryl as an example comprises phenyl, naphthyl and indenyl.

Term " alkoxyl group " uses separately or uses as prefix or suffix, refers to the group of general formula for-O-R, wherein-and R is selected from alkyl.Alkoxyl group as an example comprises methoxyl group, oxyethyl group, propoxy-, isopropoxy, butoxy, uncle-butoxy, isobutoxy, cyclo propyl methoxy, allyloxy and propargyloxy.

That term " carbocylic radical " refers to is saturated, fractional saturation with undersaturated, monocycle, dicyclo or encircle carbocyclic ring more.These can comprise the dicyclo or the multi-loop system of condensed or bridging.Carbocylic radical can have 3-12 carbon atom, i.e. C in its ring structure _3-12Carbocylic radical and in specific embodiment in its ring structure, having the monocycle of 3-7 carbon atom or having the dicyclo of 7-10 carbon atom.The carbocylic radical example that is fit to comprises cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl, cyclohexenyl, cyclopentadienyl, indanyl, phenyl and naphthyl.

" heterocyclic radical " is saturated, fractional saturation or undersaturated monocycle or the dicyclo that contains 4-12 atom (wherein at least one atom is selected from nitrogen, sulphur or oxygen), unless refer in particular in addition, it can be, and carbon or nitrogen connects, wherein-and CH ₂-group can be by optional oxidation formation S-oxide compound by-C (O)-optional displacement and epithio atom.Heterocyclic radical can comprise more than a ring.When heterocyclic radical comprised more than a ring, this ring can be condensed.Between generally referring to, shares on the condensed ring at least two rings of two atoms.Heterocyclic radical can be aromatics.The example of heterocyclic radical comprises, but be not limited to, the 1H-indazolyl, 2-pyrroles's ketone group, 2H, 6H-1,5,2-dithiazine base, the 2H-pyrryl, the 3H-indyl, the 4-piperidone base, the 4aH-carbazyl, the 4H-quinolizinyl, 6H-1,2,5-thiadiazine base, acridyl, azepan base (azepanyl), azetidinyl, the azacyclopropane base, the azocine base, benzimidazolyl-, benzofuryl, benzofuryl, benzimidazole thiophanate is for furyl, benzothienyl (benzothiophenyl), the benzodioxole base, Benzoxazinyl, dihydrobenzo  piperazine base, 3,4-dihydro-1, the 4-Benzoxazinyl, the benzoxazol base, benzo thio-phenyl (benzthiophenyl), benzothiazolyl, the benzotriazole base, the benzo tetrazyl, benzisoxa  azoles base, benzothiazole, the benzisothiazole base, benzimidazolyl-, benzimidazoline ketone group (benzimidazalonyl), carbazyl, the 4aH-carbazyl, the b-carbolinyl, chromanyl, benzopyranyl, the cinnolines base, decahydroquinolyl, 2H, 6H-1,5,2-dithiazine base, the dioxolane base, furyl, 2,3-dihydrofuran base, 2,5-dihydrofuran base, dihydrofuran also [2,3-b] tetrahydrofuran base, furyl, the furazan base, homopiperidinyl, imidazolyl, imidazolidyl, imidazolidyl, imidazolinyl, imidazolyl, the 1H-indazolyl, indolenyl, indolinyl, the indolizine base, indyl, isobenzofuran-base, the isochroman base, iso indazolyl, iso-dihydro-indole-group, pseudoindoyl, isoquinolyl, isothiazolyl, different  azoles base, morpholinyl, naphthyridinyl, the octahydro isoquinolyl, the  di azoly, 1,2,3- di azoly, 1,2,4- di azoly, 1,2,5- di azoly, 1,3,4- di azoly, the  oxazolidinyl,  azoles base, Oxyranyle,  oxazolidinyl perimidinyl, phenanthridinyl, phenanthroline, the phenarsazine base, phenazinyl, phenothiazinyl, fen  thiophene base (phenoxathiinyl), fen  piperazine base, phthalazinyl, piperazinyl, piperidyl, piperidyl, pteridyl, piperidone base, the 4-piperidone base, purine radicals, pyranyl, pyrrolidyl, pyrrolinyl, pyrrolidyl, pyrazinyl, pyrazolidyl, pyrazolinyl, pyrazolyl, pyridazinyl, pyrido  azoles base, the pyridine-imidazole base, the pyrido thiazolyl, pyridyl, N-oxide compound-pyridyl, pyridyl, pyrimidyl, pyrrolidyl, pyrrolinyl, pyrryl, pyridyl, quinazolyl, quinolyl, the 4H-quinolizinyl, quinoxalinyl, quinuclidinyl, carbolinyl, tetrahydrofuran base, tetrahydro isoquinolyl, tetrahydro-thienyl, the sulfo-tetrahydric quinoline group, 6H-1,2,5-thiadiazine base, 1,2, the 3-thiadiazolyl group, 1,2, the 4-thiadiazolyl group, 1,2, the 5-thiadiazolyl group, 1,3, the 4-thiadiazolyl group, thianthrenyl, thiazolyl, thienyl, the thieno-thiazolyl, thieno- azoles base, the Thienoimidazole base, thiophenyl, thiiranes group, triazinyl, 1,2, the 3-triazolyl, 1,2, the 4-triazolyl, 1,2, the 5-triazolyl, 1,3,4-triazolyl and oxa-anthryl (xanthenyl).In one aspect of the invention, " heterocyclic radical " is saturated, fractional saturation or the undersaturated monocycle that contains 5,6 or 7 atoms (wherein at least one atom is selected from nitrogen, sulphur or oxygen), unless refer in particular in addition, it can be, and carbon or nitrogen connects, wherein-and CH ₂-group can be by optional oxidation formation S-oxide compound by-C (O)-optional displacement and epithio atom.The specific examples of heterocyclic radical comprises azepan base, 1H-indazolyl, piperidyl, 1H-pyrazolyl, pyrimidyl, pyrrolidyl, pyridyl and thienyl.

As " 4-to the 7-unit heterocycle that contains at least one nitrogen-atoms " that be used for this paper means 4-, 5-, 6-or the 7-unit heterocycle that contains at least one nitrogen-atoms.4-to the 7-unit heterocycle that contains at least one nitrogen-atoms as an example includes, but are not limited to piperidyl, azetidinyl, azepan base, pyrrolidyl, pyrazolidyl, piperazinyl, imidazolyl, morpholinyl, indolinyl and thio-morpholinyl.

Term " halo " means fluoro, chloro, bromo and iodo.

When any variable (as, R ²⁸, R ²⁹Deng) when occurring in any formula of compound more than once, its definition when occurring each time all is independent of its definition when other occurs each time.

Some formula (I) compound can have chiral centre and/or rotamerism center (E-and Z-isomer) stereoisomeric forms in any ratio that also therefore these compounds can be concrete or how much form and exist.Should be appreciated that the present invention comprises all such optical isomer, diastereomer and geometrical isomers of having CHK1, Pak or PDK1 kinase inhibiting activity and composition thereof.The present invention also comprise all have CHK1, Pak or PDK1 kinase inhibiting activity the tautomeric form of formula (I) compound.How for example to prepare the optical activity form, by being familiar with this area by the form of resolution of racemic or by synthesizing from optical starting raw material.When needs, can realize the separation of racemic raw material by methods known in the art.Unless specifically indicate special stereochemistry or isomeric form, structures all chirality forms, the diastereo-isomerism form, racemic form and all rotamerism forms are all wanted.

Below be further embodiment of the present invention for the substituting group that is included in the variable group in the formula (I).Special substituting group so in due course can be with using in any definition, claims or the embodiment of above or hereinafter definition.

X is N.

Y is CH.

X is that CH and Y are CH.

D is S.

A is S.

A is N.

A is NR ⁵

D is N.

D is NR ⁵

A is O.

D is O.

A is that N and D are O.

A is that S and D are N.

X is that N and A are S.

X is that N and D are S.

X is that N and A are O.

X is that N and D are O.

X is N; A is S; With Y be CH.

X is N; D is S; With Y be CH.

X is N; A is S; D is that CH and Y are CH.

X is N; D is S; A is that CH and Y are CH.

At least one A or D are S.

X is N; A is S; D is that N and Y are CH.

X is N; D is S; A is that N and Y are CH.

A is CH; D is NR ⁴X is CH; With Y be CH.

A is CH; D is NH; X is CH; With Y be CH.

L is NR ⁵

L is NR ⁵And R ⁵Be H.

L is NR ⁵And R ⁵Be cyclopropyl, wherein R ⁵Can be by one or more R on carbon ¹⁷The optional replacement.

L is NR ⁵And R ⁵Be H or C _1-3Alkyl, wherein R ⁵Can be by one or more R on carbon ¹⁷The optional replacement.

L is NH.

L is O.

L is S.

R ¹Be selected from C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl and heterocyclic radical, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group.

R ¹Be aryl, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement.

R ¹Be aryl, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement, wherein R ⁹Be selected from halo, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, heterocyclic radical ,-O (C _1-6Alkyl) ,-CO (C _1-6Alkyl) ,-CONR ²⁸R ²⁹With-NHCO (heterocyclic radical) R wherein ⁹Can be by one or more R on carbon ²²If optional replace and wherein heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ²³Optional replacement of group.

R ¹Be heterocyclic radical, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group.

R ¹Be aryl, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement, wherein R ⁹Be selected from halo and C _1-6Alkyl and R wherein ⁹Can be by one or more R on carbon ²²The optional replacement, wherein R ²²Be selected from halo ,-NR ²⁸R ²⁹, cyano group, isocyano-, aryl, cycloalkyl, cycloalkenyl group and R wherein ²²Can be by one or more R on carbon ³⁶If optional replace and wherein described heterocyclic radical contain-the NH-part, then the nitrogen of described part can be selected from R ²⁷Optional replacement of group.

R ¹Be aromatic heterocyclic radical, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group.

R ¹Be selected from benzimidazolyl-, Benzoxazinyl, dihydrobenzo  piperazine base, imidazolinyl, thienyl, pyrazolyl; Pyradinyl and pyrimidyl, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group.

R ²For containing 4-to the 7-unit heterocycle of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²For containing 4-to the 7-unit saturated heterocyclic of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²For containing the 4-unit heterocycle of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²For containing the 5-unit heterocycle of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²For containing the 6-unit heterocycle of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²For containing the 7-unit heterocycle of at least one nitrogen-atoms, wherein said heterocyclic radical can be by one or more R on one or more carbon atoms ¹³The optional replacement; If wherein described in addition heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

R ²Be selected from piperidyl, azetidinyl, azepan base, pyrrolidyl, pyrazolidyl, piperazinyl, imidazolyl, morpholinyl, indolinyl and thio-morpholinyl, wherein said piperidyl, azetidinyl, azepan base, pyrrolidyl, pyrazolidyl, piperazinyl, imidazolyl, morpholinyl, indolinyl and thio-morpholinyl can be by one or more R on one or more carbon atoms ¹³The optional replacement; Can on N, be selected from R with other wherein said piperidyl, azepan base, pyrrolidyl, pyrazolidyl, piperazinyl, imidazolyl, morpholinyl, indolinyl and thio-morpholinyl ¹⁴Optional replacement of group.

R ²Be selected from tetramethyleneimine-3-base, piperidines-3-base and azepan-3-base, wherein said tetramethyleneimine-3-base, piperidines-3-base and azepan-3-base can be by one or more R on one or more carbon atoms ¹³The optional replacement; With other wherein said tetramethyleneimine-3-base, piperidines-3-base, or azepan-3-base can be selected from R on N ¹⁴Optional replacement of group.

R ³Be selected from H, benzyl, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl, heterocyclic radical and OR ⁶, R wherein ³Can be by one or more R on one or more carbon atoms ¹⁵The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then described nitrogen can be selected from R ¹⁶Optional replacement of group.

R ³For on one or more carbon atoms by one or more R ¹⁵The optional pyrazinyl that replaces.

R ³Be H.

R ³Be methyl.

R ⁴Be H.

Another aspect of the present invention provides formula (I) compound or its pharmacy acceptable salt, wherein:

A is CH;

D is S;

L is NR ⁵

X is N;

Y is CH;

R ¹Be selected from C _1-6Alkyl, aryl and heterocyclic radical, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group;

R ²For containing 4-to 7-unit heterocycle, the wherein R of at least one nitrogen-atoms ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; Wherein if heterocyclic radical also contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group;

R ³Be H;

R ⁵Be H or C _1-3Alkyl.

A is CH;

D is S;

L is NR ⁵

X is N;

Y is CH;

R ¹Be selected from aryl and heterocyclic radical, wherein R ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group;

R ²Be (C _1-3Alkyl) NR ⁷R ⁸, R wherein ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement;

R ³Be H;

R ⁵Be H or C _1-3Alkyl;

R ⁷And R ⁸Independently be selected from H, C _1-6Alkyl, cycloalkyl, cycloalkenyl group, aryl and heterocyclic radical; R wherein ⁷And R ⁸Independently of one another can be by one or more R on carbon ²⁰The optional replacement; If wherein described heterocyclic radical contains-the NH-part, then the nitrogen of described part can be selected from R ²¹Optional replacement of group.

In still another aspect of the invention, provide formula (I) compound or its pharmacy acceptable salt, wherein:

A is CH;

D is S;

L is NR ⁵

X is N;

Y is CH;

R ²For containing 4-to 7-unit heterocycle, the wherein R of at least one nitrogen-atoms ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; If also contain with heterocyclic radical-the NH-part, then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group;

R ³Be H;

R ⁵Be H or C _1-3Alkyl.

One side more of the present invention provides formula (I) compound or its pharmacy acceptable salt, wherein:

A is CH;

D is NR ⁴

L is NR ⁵

X is CH;

Y is CH;

R ³Be H;

R ⁴Be H, C _1-3Alkyl, cyclopropyl and CF ₃

R ⁵Be H or C _1-3Alkyl.

A is CH;

D is NR ⁴

L is NR ⁵

X is CH;

Y is CH;

R ³Be H;

R ⁴Be H, C _1-3Alkyl, cyclopropyl and CF ₃

R ⁵Be H or C _1-3Alkyl;

Provide formula (I) compound or its pharmacy acceptable salt also on the one hand of the present invention, wherein:

A is CH;

D is NR ⁴

L is NR ⁵

X is CH;

Y is CH;

R ³Be H;

R ⁴Be H, C _1-3Alkyl, cyclopropyl and CF ₃

R ⁵Be H or C _1-3Alkyl.

In further embodiment of the present invention, useful especially The compounds of this invention is arbitrary embodiment compound or its pharmacy acceptable salt.

Other embodiments of the present invention relate to and prepare wherein that X is N, and Y is CH, and A is CH, and D is S, R ³For H and L are NR ⁵Formula (I) compound or the method for its pharmacy acceptable salt, this method comprises:

A. make wherein that Z is a halo, as formula (II) compound of bromo, chloro or iodo

With R wherein ²And R ⁵As formula (III) amine of definition in formula (I) reacting down of alkali below,

NHR ²R ⁵

(III)

Obtain formula (IV) compound

B. make formula (IV) compound and R wherein ¹As definition and R ' in formula (I) be that formula V compound or (V ') of H or methyl reacts,

R ¹B(OR’) ₂

(V) (V’)

Obtain formula (VI) compound

C. make formula (VI) compound hydrolysis, form suc as formula formula (I) compound shown in (IA)

D. and then if desired:

I) a kind of formula (I) compound is converted into another kind of formula (I) compound;

Ii) remove any blocking group;

Iii) form pharmacy acceptable salt.

Another other embodiments of the present invention relate to and prepare wherein that X is N, and Y is CH, and A is CH, and D is S, R ³For H and L are formula (I) compound of O or the method for its pharmacy acceptable salt, this method comprises:

With R wherein ²As formula (the III ') alcohol of definition in formula (I), the alkali below such as the existence of sodium hydride be reaction down,

R ²OH

(III’)

Obtain formula (IV ') compound

B. make formula (IV ') compound and R wherein ¹As definition and R ' in formula (I) be that formula V or (V ') compound of H or methyl reacts,

R ¹B(OR’) ₂

(V) (V’)

Obtain formula (VI ') compound

C. make formula (VI ') compound hydrolysis form the compound that is shown as formula (IB) according to formula (I)

D. and then if desired:

Ii) remove any blocking group;

Iii) form pharmacy acceptable salt.

Another other embodiments of the present invention relate to and prepare wherein that X is CH, and Y is CH, and A is CH, and D is NR ⁴With L be NR ⁵And R ⁵Be formula (I) compound of H or the method for its pharmacy acceptable salt, this method comprises:

A. make wherein R " be formula (VII) compound of H, methyl, ethyl or benzyl

With formula (VIII) reactive ketone, wherein R ¹As definition in formula (I)

Obtain formula (IX) indoles

B. make formula (IX) indoles and R wherein ³Formula (X) amine reaction as definition in formula (I)

R ³NH ₂

(X)

Obtain formula (XI) compound

C. make the reduction of formula (XI) compound, form formula (XII) amine

D. make formula (XII) compound and suitable R ²Aldehyde, ketone, carboxylic acid or the reaction of alkylsulfonyl chlorine,

R wherein ²As definition in formula (I), form suc as formula formula (I) compound shown in (IC)

Perhaps as selecting, make the reaction of formula (XII) compound and Sodium Nitrite and copper halide, form formula (XIII) compound, wherein Z is a halo, as bromo, chloro or iodo,

E. make formula (XIII) compound and R wherein ²And R ⁵As formula (III) amine of definition in formula (I),

NHR ²R ⁵

(III)

At catalyzer, the existence reaction down as palladium or copper deutero-catalyzer obtains suc as formula formula (I) compound shown in (ID)

D. and then if desired:

Ii) remove any blocking group;

Iii) form the formula (IC) or (ID) pharmacy acceptable salt of compound.

Should be appreciated that above and in some reactions of hereinafter mentioning, any sensitive groups of protection in the compound need/wanted.The example of the protection that needs or want and suitable guard method are for known to the those skilled in the art.But the establishing criteria working method is used GPF (General Protection False group (in order to set forth referring to T.W.Green and P.G.M.Wuts ProtectiveGroups in Organic Synthesis, the 3rd edition, John Wiley and Sons, 1999).Thereby if comprise group in the reagent such as amino, carboxyl or hydroxyl, then this group is worth protection in some reactions that this paper mentions.

The blocking group that is fit to that is used for amino or alkylamino is, for example, acyl group, for example alkyloyl is such as ethanoyl; alkoxy carbonyl, for example methoxycarbonyl, ethoxy carbonyl or uncle-butoxy carbonyl, aryl methoxy carbonyl; for example benzyloxycarbonyl, or aroyl, for example benzoyl.The protective condition that goes of above blocking group will be different different because of the selection of blocking group necessarily.Like this, for example, acyl group such as alkyloyl or alkoxy carbonyl or aroyl can be for example, and by using the alkali that is fit to such as alkali metal hydroxide, for example lithium hydroxide or the hydrolysis of lithium hydroxide sodium are removed.Perhaps; acyl group is such as uncle-butoxy carbonyl; can be for example; remove by handling with the sour example hydrochloric acid, sulfuric acid or the phosphoric acid that are fit to or trifluoroacetic acid; with aryl methoxy carbonyl such as benzyloxycarbonyl can be for example, by catalyzer such as palladium on carbon on hydrogenation or with Lewis acid for example three (trifluoroacetic acid) boron (boron tris (trifluoroacetate)) handle and remove.The alternative blocking group that is fit to that is used for primary amino is, for example, and available alkylamine, for example dimethylaminopropyl amine or handle the phthaloyl of removing with hydrazine.

The blocking group that is fit to that is used for hydroxyl is, acyl group for example, and for example alkyloyl is such as ethanoyl, aroyl, for example benzoyl, or arylmethyl, for example benzyl.The protective condition that goes of above blocking group will be different different because of the selection of blocking group necessarily.Thereby for example, acyl group such as alkyloyl or aroyl can be for example, and by using the alkali that is fit to such as alkali metal hydroxide, for example lithium hydroxide or the hydrolysis of lithium hydroxide sodium are removed.Perhaps, arylmethyl is such as benzyl, can be for example, by catalyzer such as palladium on carbon on hydrogenation remove.

Being used for the suitable blocking group of carboxyl is; for example; esterified group; for example can be by methyl or the ethyl of removing with alkali such as sodium hydroxide hydrolysis; or for example can be by handling the tert-butyl of removing with sour for example organic acid such as trifluoroacetic acid; or for example can be for example, by catalyzer such as palladium on carbon on the benzyl removed of hydrogenation.

Blocking group can be removed by the routine techniques that adopts chemical field to be familiar with in any stage easily in synthetic.

In other embodiments, the present invention relates to aforementioned in preparation with the formula (IV) of the intermediate of form the basis formula (I) compound, (IV '), (VI), (VI '), (IX), (XI), (XII) and (XIII) compound.

R wherein ¹, R ², R ³And R ⁵As definition and Z in formula (I) is halo, as bromo, chloro and iodo.

In a further embodiment, the present invention relates to suc as formula (IA), (IB), (IC) and formula (I) compound and the pharmacy acceptable salt thereof (ID)

Wherein variable groups is as definition in formula (I).

According to one side more of the present invention, provide the medicinal compositions that comprises formula (I) compound or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier, thinner or vehicle.

Another aspect of the present invention provides formula (I) compound or its pharmacy acceptable salt that define as the preamble as medicine.

In another embodiment, the invention provides the application in the preparation medicine of formula (I) compound or its pharmacy acceptable salt.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt preparation be used for the treatment of or the medicine of preventing cancer in application.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt preparation be used for the treatment of or the medicine of prophylaxis of tumours disease in application, described neoplastic disease has such as mammary cancer, ovarian cancer, lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer and bronchovesicular cancer), colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma comprise CLL and CML, and the tumour of maincenter and peripheral nervous system and other tumor type are such as melanoma, multiple myeloma, fibrosarcoma and osteosarcoma and malignant brain tumor.

In a further embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt is used for the treatment of or prevents to comprise application in the medicine of proliferative disease of autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder in preparation.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt are used for suppressing the medicine of CHK1 kinase activity in preparation application.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt and be used to suppress the Pak kinase activity, for example suppress the application in the medicine of Pak1, Pak2 or Pak4 kinase activity in preparation.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt are used for suppressing the medicine of PDK1 kinase activity in preparation application.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt are used for the medicine of restrictive cell propagation in preparation application.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt are used for limiting tumorigenic medicine in preparation application.

In another aspect of the present invention, formula (I) compound or its pharmacy acceptable salt as the preamble definition are provided, it is used for the method by the therapy for treating human or animal body.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt, the illness that it is used for the treatment of or prevention is relevant with cancer.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt, it is used for the treatment of or the prophylaxis of tumours disease, described neoplastic disease has for example mammary cancer, ovarian cancer, lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer and bronchovesicular cancer), colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma comprise CLL and CML, and the tumour of maincenter and peripheral nervous system and other tumor type are such as melanoma, multiple myeloma, fibrosarcoma and osteosarcoma and malignant brain tumor.

In another embodiment, the invention provides formula (I) compound or its pharmacy acceptable salt, it is used for the treatment of or prevents to comprise the proliferative disease of autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder.

In one side more of the present invention, provide to comprise as formula (I) compound of preamble definition or the medicinal compositions of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier, said composition is used for producing the CHK1 kinase inhibitory activity warm-blooded animal such as people.

In one side more of the present invention, provide to comprise as formula (I) compound of preamble definition or the medicinal compositions of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier, said composition is used for producing Pak kinase inhibitory activity (for example Pak1, Pak2 or Pak4 kinase inhibitory activity) warm-blooded animal such as people.

In one side more of the present invention, provide to comprise as formula (I) compound of preamble definition or the medicinal compositions of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier, said composition is used for producing the PDK1 kinase inhibitory activity warm-blooded animal such as people.

Provide to comprise as formula (I) compound of preamble definition or the medicinal compositions of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier more on the one hand of the present invention, said composition is used for producing antitumous effect warm-blooded animal such as the people.

In one side more of the present invention, it provides and comprises as formula (I) compound of preamble definition or the medicinal compositions of its pharmacy acceptable salt and pharmaceutically acceptable diluent or carrier, and said composition is used for treating or preventing to comprise warm-blooded animal such as people the proliferative disease of autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder.

In another embodiment, the invention provides the method for restrictive cell propagation in the human or animal, described method comprises formula (I) compound or its pharmacy acceptable salt that gives the effective therapeutic dose of described human or animal.

In another embodiment, the invention provides the tumorigenic method of restriction in the human or animal, described method comprises formula (I) compound or its pharmacy acceptable salt that gives the effective therapeutic dose of described human or animal.

In a further embodiment, the invention provides and suppress the kinase whose method of CHK1, described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the animal or human of described inhibition.

In a further embodiment, the invention provides and suppress the inhibiting method of Pak kinases (for example Pak1, Pak2 or Pak4 kinases), described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the animal or human of described inhibition.

In a further embodiment, the invention provides and suppress the kinase whose method of PDK1, described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the animal or human of described inhibition.

In another embodiment, the invention provides the method that the human or animal of cancer is suffered from treatment, described method comprises formula (I) compound or its pharmacy acceptable salt that gives the effective therapeutic dose of described human or animal.

In further embodiment, the invention provides the prophylactic treatment method for cancer, described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the human or animal of such treatment.

In another embodiment, the invention provides treatment and suffer from the human or animal's of neoplastic disease method, described neoplastic disease has for example mammary cancer, ovarian cancer, lung cancer (comprises small cell lung cancer, nonsmall-cell lung cancer and bronchovesicular cancer), colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma comprise CLL and CML, and the tumour of maincenter and peripheral nervous system and other tumor type are such as melanoma, multiple myeloma, fibrosarcoma and osteosarcoma and malignant brain tumor.

In another embodiment, the invention provides treatment and suffer from the human or animal's of proliferative disease such as autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder method, described method comprises formula (I) compound or its pharmacy acceptable salt that gives the effective therapeutic dose of described human or animal.

One embodiment of the invention provide by giving the treatment method for cancer of human or animal's formula (I) compound or its pharmacy acceptable salt and antitumour drug.

One embodiment of the invention provide by giving the treatment method for cancer of human or animal's formula (I) compound or its pharmacy acceptable salt and dna damage agent.

One embodiment of the invention provide the method for the treatment infection relevant with cancer, and described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the human or animal of such treatment.

The present invention's embodiment again is provided for the method for the prophylactic treatment infection relevant with cancer, and described method comprises formula (I) compound or its pharmacy acceptable salt that needs the effective therapeutic dose of the human or animal of such treatment.

As used herein, phrase " blocking group " means the temporary transient substituting group of protecting reactive functional groups potentially not to be subjected to unwanted chemical conversion.The example of such blocking group comprise carboxylic acid the ester class, alcohol silyl ether and be respectively aldehyde and the acetal of ketone and ketal.The existing summary of blocking group chemical field (Greene, T.W; Wuts, P.G.M.ProtectiveGroups in Organic Synthesis, the 3rd edition; Wiley:New York, 1999).

As used herein, " pharmaceutically acceptable " be used in this paper refer within medical judgment scope reliably, be suitable for use in contact with humans and animals tissue and do not have too much toxicity, pungency, anaphylaxis or other problem or complication, have and rational suitable those compounds, raw material, composition and/or the formulation of income/risk-ratio.

As used herein, " pharmacy acceptable salt " refers to the derivative of disclosed compound, and wherein parent compound is modified by forming hydrochlorate or alkali salt.The example of pharmacy acceptable salt includes, but are not limited to the mineral salt or the organic acid salt of alkaline residue such as amine; The basic salt of acidic residues such as carboxylic acid or organic salt etc.Pharmacy acceptable salt for example comprises, the non-toxic salts or the quaternary ammonium salt of the routine of the parent compound that is formed by nontoxic mineral acid or organic acid.For example, the non-toxic salts of such routine comprises that those are derived from all example hydrochloric acids of mineral acid, Hydrogen bromide, sulfuric acid, thionamic acid, phosphoric acid, nitric acid etc.; With salt from organic acid such as acetate, propionic acid, Succinic Acid, oxyacetic acid, stearic acid, lactic acid, maleic acid, tartrate, citric acid, xitix, palmitinic acid, maleic acid, hydroxy-maleic acid, toluylic acid, L-glutamic acid, phenylformic acid, Whitfield's ointment, Sulphanilic Acid, 2-ethoxybenzoic acid, FUMARIC ACID TECH GRADE, toluenesulphonic acids, methanesulfonic, ethane sulfonic acid, oxalic acid, isethionic acid etc.

Can be from containing the parent compound of alkalescence or acidic moiety, by the synthetic pharmacy acceptable salt of the present invention of the chemical process of routine.Usually, the suitable alkali of free acid by making these compounds or alkali form and the amount of calculating by chemical equivalent or acid are in water or in organic solvent or react in the mixture of water and organic solvent, can prepare such salt; Usually, non-water-soluble matchmaker such as ether, ethyl acetate, ethanol, Virahol or acetonitrile are preferred.The list of the salt that is fit to is at Remington ' s Pharmaceutical Sciences, and the 17th edition, Mack publishing company, Easton, Pa. can find in 1985, the 1418 pages, and its disclosure is incorporated into this paper by reference.

" stable compound " and " stable structure " mean compound enough firmly to isolate useful purity from reaction mixture and to be prepared into effective therapeutical agent.

The anticancer disease treatment of this paper definition can be used as independent therapy or except The compounds of this invention, can comprise conventional operation and/or radiotherapy and/or chemotherapy.Such chemotherapy can comprise the antitumour drug of one or more following kinds:

(i) antiproliferative/antitumor drug and combination thereof are as used in the medical science oncology, such as alkylating agent or platinum agent (for example cis-platinum, carboplatin, oxaliplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan and nitrosourea); Antimetabolite (for example gemcitabine and fludarabine, and antifol such as fluorinated pyrimidine class such as 5 FU 5 fluorouracil and Tegafur, Raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea); Antitumor antibiotics (for example anthracycline drug such as Zorubicin, bleomycin, Dx, Daunorubicin, epirubicin, Yi Darou are than star, Mitomycin-C, dactinomycin and mithramycin); Antimitotic agent (for example vinca alkaloids such as vincristine(VCR), vinealeucoblastine(VLB), vindesine and vinorelbine and Japanese yew class medicine such as taxol and taxotere); And topoisomerase enzyme inhibitor (for example showing podophyllin class (epipodophyllotoxins)) as etoposide and teniposide, amsacrine, topotecan, Rinotecan and camptothecine;

(ii) cytostatics such as estrogen antagonist agent (tamoxifen for example, toremifene, raloxifene, droloxifene and iodoxyfene), the downward conditioning agent of estrogen receptor (for example fulvestrant), antiandrogen (bicalutamide for example, flutamide, Nilutamide and acetate cyproterone), lhrh antagonist or LHRH agonist (goserelin for example, Leuprolide and buserelin), progestogens (for example acetate megestrol), aromatase inhibitor (for example resembles Anastrozole, letrozole, vorazole and Exemestane) and the 5 inhibitor such as finasteride;

The medicine (for example inhibitors of metalloproteinase such as Marimastat and urokinase type plasminogen activators function of receptors inhibitor) that (iii) suppresses the cancer cell invasion and attack;

(iv) somatomedin depressant of functions, for example such inhibitor comprises growth factor antibodies, growth factor receptor antibody (for example anti-erbb2 antibody Herceptin [Herceptin ^TM] and anti-erbb1 antibody Cetuximab [C225]), farnesyl transferase inhibitor, tyrosine kinase inhibitor and serine/threonine kinase inhibitor, for example the inhibitor of epidermal growth factor family (for example EGFR family tyrosine kinase inhibitor such as N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholine propoxy-) quinazoline-4-amine (Gefitinib), N-(3-ethynyl phenyl)-6, two (2-methoxy ethoxy) quinazolines of 7--4-amine (erlotinib (erlotinib), OSI-774) and 6-acrylamido- N-(3-chloro-4-fluorophenyl)-7-(3-morpholine propoxy-) quinazoline-4-amine (CI 1033)), for example thrombocyte derivation growth factor family inhibitor and for example pHGF man group inhibitor;

(v) the anti-angiogenic rebirth agent suppresses the medicine of the effect of vascular endothelial growth factor such as those, (anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF (bevacizumab) [Avastin for example ^TM], such as those disclosed compounds in International Patent Application WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354) and (beta 2 integrin alpha v β 3 depressant of functions linomide and the angiostatins for example of the compound by other machine-processed generation effect;

(vi) blood vessel injury agent such as combretastatin A4 and in International Patent Application WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 and WO 02/08213 disclosed compound;

(vii) antisense therapy, for example those relate to the medicine of above listed target, such as antisense oligonucleotide (antiras antisense) ISIS 2503;

(viii) gene therapy means, comprise means, GDEPT (enzyme precursor-pharmacotherapy of the gene targeting) means of for example replacing aberrant gene such as unusual p53 or unusual BRCA1 or BRCA2 use Isocytosine deaminase, thymidine kinase or bacterium nitroreductase such as those and make the patient to chemotherapy or radiotherapy tolerance enhanced means such as multiple-drug resistance gene therapy; With

(ix) immunotherapy means, comprise for example strengthen the patient tumors cell immunogenicity external and body in means, such as the transfectional cell factor such as interleukin-22, interleukin 4 or rHuGM-CSF, make the incompetent means that lower of T-cell, the means of the dendritic cell of immunocyte such as the cytokine transfection of use transfection, the means of the means of the tumor cell line of use cytokine transfection and use antiidiotypic antibody.

Such combination therapy can be by simultaneously, single composition sequential or that separately give therapy is reached.Such associating product uses the The compounds of this invention of the dosage range of describing before this paper wherein and the other medicines promoting agent in the dosage range of its approval.

Can be by oral, parenteral, suck clothes, intravaginal, rectum, suck, be blown into, in hypogloeeis, intramuscular, subcutaneous, local, the nose, in the intraperitoneal, pleura, in the intravenously, exterior dura, sheath, give The compounds of this invention in the cerebrovascular and by being injected into intraarticular.

When decision is suitable for concrete patient's single treatment plan and dosage level most, dosage will depend on severity, patient's age and the body weight of route of administration, disease and the other factors of being considered usually by the attending doctor.

The significant quantity that is used for the treatment of the The compounds of this invention of infection, be the amount that is enough to reach following effect, promptly in warm-blooded animal particularly in the people symptomatic alleviation infection symptoms, the progress of slowing down infection or reduction suffer from the risk that the patient of infection symptoms is further worsened.

In order to prepare medicinal compositions from The compounds of this invention, inert, pharmaceutically acceptable carrier can or be solid or are liquid.The preparation of solid form comprises pulvis, tablet, dispersible granules agent, capsule, flat jelly and suppository.

Solid carrier can be one or more materials, and it also can be used as thinner, correctives, solubilizing agent, slipping agent, suspending agent, tackiness agent or tablet disintegrant; It also can be coating material.

In pulvis, carrier is through the broken solid of fine powder, its with mix mutually through the broken activeconstituents of fine powder.In tablet, activeconstituents mixes with the ratio that is fit to mutually with the carrier with essential adhesion characteristic, and is pressed into required shape and size.

In order to prepare suppository composition, at first make the mixture melt of low melt wax such as glycerin fatty acid ester and theobroma oil and pass through and for example stir activeconstituents is disperseed wherein.Then with in the mould of the size of the homogeneous mixture impouring of fusing convenient (uses) and let alone cooling and curing.

The carrier that is fit to comprises magnesiumcarbonate, Magnesium Stearate, talcum powder, lactose, Icing Sugar, pectin, dextrin, starch, tragacanth gum, methylcellulose gum, Xylo-Mucine, low-melting wax, cocoa wet goods.

Some The compounds of this invention can form salt with various inorganic and organic bronsted lowry acids and bases bronsted lowries, and such salt is also within the scope of the invention.The example of such acid salt comprises acetate, adipate, ascorbate salt, benzoate, benzene sulfonate, supercarbonate, hydrosulfate, butyrates, camphorate, camsilate, choline, Citrate trianion, cyclohexyl-n-sulfonate, two quadrols, ethane sulfonate, fumarate, glutaminate, glycollate, Hemisulphate, 2-hydroxyethyl sulfonate, enanthate, hexanoate, hydrochloride, hydrobromate, hydriodate, hydroxy-maleic acid salt, lactic acid salt, malate, maleic acid salt, methane sulfonates, meglumine, the 2-naphthalenesulfonate, nitrate, oxalate, embonate, persulphate, phenylacetate, phosphoric acid salt, diphosphate, picrate, pivalate, propionic salt, quinate, salicylate, stearate, succinate, sulfamate, sulfanilate, vitriol, tartrate, tosylate (right-tosylate), trifluoroacetate and undecane hydrochlorate.Alkali salt comprises salt that ammonium salt, an alkali metal salt such as sodium salt, lithium salts and sylvite, alkaline earth salt such as aluminium salt, calcium salt and magnesium salts, salt such as the dicyclohexyl amine salt that is become with organic bases, N-methyl D-glycosamine form and the salt that forms with amino acid such as arginine, Methionin, ornithine etc.Equally, available following reagent makes the group that contains basic nitrogen quaternized: elementary alkyl halide, such as the halogenide of methyl, ethyl, propyl group and butyl; Dialkyl sulfate such as dimethyl, diethyl, dibutyl; The vitriol of diamyl; Long-chain (alkyl) halogenide is such as decyl, dodecyl, tetradecyl and octadecyl halogenide; Arylalkyl halogenide such as benzyl bromide and other.Although such as when the isolated or purified product, other salt also is useful, preferred nontoxic, physiology is acceptable salt.

Available ordinary method forms salt, described method is for example product and the one or more normal suitable acid by making free alkali form, in undissolved solvent of salt or solvent, or react in such as water at solvent, described solvent is removed in a vacuum, or removes or remove by the negatively charged ion that is present in the salt with another anionresin on the ion exchange resin that is fit to by lyophilize.

Comprise the people in order to make formula (I) compound or its pharmacy acceptable salt be applied to therapeutic treatment (comprising prophylactic treatment) Mammals, establishing criteria pharmacy standard is mixed with medicinal compositions with it usually.

Except The compounds of this invention, medicinal compositions of the present invention also can comprise one or more on one or more disease illnesss of relating to of treatment this paper valuable drug, or give (simultaneously or sequential) jointly with described medicine.

The term composition is intended to comprise the preparation of activeconstituents or pharmacy acceptable salt and pharmaceutically acceptable carrier.For example can the present invention be mixed with following form by means known in the art, for example, (the comprising intravenously, intramuscular or infusion) of the pulvis of tablet, capsule, water-based or oily solution agent, suspension agent, emulsion, ointment, salve, gelifying agent, nasal spray, suppository, trickle pulverizing or the aerosol that is used to suck or sprays and parenteral application sterilization water-based or oily solution agent or suspension agent or sterilization emulsion.

The composition of liquid form comprises solution, suspension agent and emulsion.The aqua sterilisa of active compound or water-propylene glycol solution can be mentioned as the example of the liquid preparation that is suitable for parenteral admin.Also the liquid composition preparation can be formed in the solution in the polyoxyethylene glycol aqueous solution.By activeconstituents being dissolved in the water and adding tinting material, correctives, stablizer and the thickening material that is fit to when needed, can prepare the aqueous pharmaceutical that is used for oral administration.Be scattered in by activeconstituents and add cohesive material such as natural synthetic gum, resin, methylcellulose gum, Xylo-Mucine and other known suspending agent in pharmaceutical formulations field in the water simultaneously, can prepare and be used for oral aqueous suspension agent trickle pulverizing.

Medicinal compositions can unit dosage forms exist.In such form, composition is divided into the unitary dose of the activeconstituents that contains appropriate amount.Unit dosage can be packaged preparation, and packing contains the preparation of discontinuous amount, for example, the tablet of packing, capsule and be contained in bottle or ampoule in pulvis.Unit dosage also can be capsule, flat jelly or tablet itself, and perhaps it can be the form of any of these packing of suitable quantity.

Formula (I) compound has been presented at vitro inhibition check point kinase activity.The kinase whose inhibitor in check point has shown makes cell be evolved into mitosis metaphase inadequately, causes affected apoptosis, and therefore, has antiproliferative effect.Formula (I) compound also has been presented at vitro inhibition Pak kinases and PDK1 kinase activity.Therefore, believe that formula (I) compound and pharmacy acceptable salt thereof can be used for treating neoplastic disease as described above.In addition, formula (I) compound and pharmacy acceptable salt thereof are also expected and are used for the treatment of other proliferative disease and other disease as described above.Expection formula (I) compound will be most possible and wide in range dna damage agent combined utilization, but also can be used as single medicinal application or with another antitumor drug combined utilization as described above.

In a word, determine that by one or more analytical methods described below it is 100 micromoles or lower IC that formula (I) compound has ₅₀Or EC ₅₀Value.For example, in check point described below kinases 1 is analyzed, the IC of embodiment 5 compounds ₅₀Value is the IC of 0.016 μ M, embodiment 16 compounds ₅₀Value is the IC of 0.55 μ M and embodiment 157 compounds ₅₀Value is 0.15 μ M.As embodiment further, the IC of embodiment 10 compounds in Pak 1 enzyme is analyzed ₅₀Value is 0.73 μ M and the IC in Pak 4 enzymes are analyzed ₅₀Value is 0.14 μ M; The IC of same compound in the PDK1 enzyme is analyzed ₅₀Value is 0.35 μ M.The IC of embodiment 14 compounds in Pak 1 enzyme is analyzed ₅₀Value is 0.60 μ M and the IC in Pak 4 enzymes are analyzed ₅₀Value is 0.10 μ M; The IC of same compound in the PDK1 enzyme is analyzed ₅₀Value is 0.16 μ M.

Detect the analysis of 1 inhibition of check point kinases and effect

Check point kinases 1 is analyzed: this analyzed in vitro detection compound is to the kinase whose restraining effect of CHK1.Express in baculovirus and through GST label purifying in the kinases territory.Then the protein of purifying and biotinylated peptide substrates (Cdc25C) are applied to 384 holes get close to automatically flicker detection method (Scintillation Proximity Assay) (SPA) in.Especially, mixing peptide, enzyme and reaction buffer also, five equilibrium joins in 384 orifice plates that contain series compound and contrast diluent.Add ATP cold and heat then and start reaction.After 2 hours, add SPA pearl slurries, CsCl ₂With the EDTA termination reaction with catch biotinylated peptide.On Topcount, plate is counted then.Analytical data is also measured the IC of each individualized compound ₅₀

Eliminating (Abrogation) analyzes: this cell analysis detects the ability that the CHK1 inhibitor is eliminated the G2/M check point that causes the DNA-damage.Test is effectively to the compound of antienzyme (＜2 μ M) in cell analysis.In brief, at the 1st day HT29 cell (colon carcinoma cell line, p53 null) is elaborated in 96 orifice plates.Next day, handle cell 2 hours to cause dna damage with camptothecine.After 2 hours, remove camptothecine and with test compound with make cell fixation handle cell again 18 hours, the elimination check point at spindle poison (spindle poison) R 17934 (nocodazole) in mitotic division stage.Also use the Hoechst dye marker with formaldehyde fixed cell, dyeing to present mitotic peculiar sign phosphohistone H3 then, can detect cell count like this.Adopt mitotic index rules (Mitotic Index protocol) to go up scanning board at Array Scan (Cellomics).As the positive control of eliminating, use the 4mM caffeine.In 12 some test compounds (in triplicate) dose-response relationship.Analytical data is also measured the EC of each compound ₅₀

Detect the analysis of Pak kinase inhibitory activity:

(a) External Pak1 enzyme is analyzed

This analytical applications get close to flicker detection analysis (SPA) technology (Antonsson etc., Analytical Biochemistry, 1999, 267: 294-299) the determination test compound suppresses the ability by the phosphorylation of reorganization Pak1.The Pak1 protein of overall length is expressed as the GST fusion and adopts the standard purification technology to use GST label purifying in intestinal bacteria (E.coli).

With test compound be prepared as the stock solution of 10mM in DMSO and when needed in water dilution obtain the whole analytical concentration of sequence.The aliquots containig (5 μ l) of each diluted chemical compound liquid is elaborated in each hole of the flat white polystyrene board in matrix (Matrix) 384-hole (catalog number (Cat.No.) 4316).Reorganization purifying Pak1 enzyme (30nM), the biotinylated peptide substrates of 3 μ M (vitamin H-Ahx-Lys-Lys-Glu-Gln-Ser-Lys-Arg-Ser-Thr-Met-Val-Gly-Thr-Pro-Tyr-Trp-Met-Ala-Pro-Glu-NH with 20 μ l ₂Bachem UK Ltd), Triphosaden (ATP; 3 μ M), ³³The Triphosaden of P-mark ( ³³P-ATP; 33 nCi/ holes) and the buffering solution [comprise Tris-HCl pH 7.5 damping fluids (50mM), EGTA (0.1mM), bSA (0.1mg/ml), dithiothreitol (DTT) (DTT; 5mM) and magnesium acetate (10mM)] mixture in incubated at room 120 minutes.

By using 5%DMSO alternate test compound, set up the control wells that produces peak signal corresponding to maximum enzyme activity.By being added in EDTA (62.5mM) the alternate test compound among the 5%DMSO, set up the control wells that produces minimum signal corresponding to whole inhibitory enzymes.These analytical solution were also at room temperature hatched 120 minutes.

PVT SPA pearl slurries (AmershamBiosciences, the catalog number (Cat.No.) RPQ0205 of the Streptavidin bag quilt by adding 30 μ l; 250 μ g/ holes) mixture in the 50mM Tris-HCl pH7.5 damping fluid that contains 0.05% sodiumazide adds the 2.83M cesium chloride (final analysis concentration is 1M) of 30 μ l subsequently, makes each reaction terminating and catches biotinylated peptide.Then plate was placed 2 hours at worktable, on Topcount, counted then.

Because the phosphorylation of Pak1 mediation, original position forms the biotinylated peptide of radiolabeled phosphorylation.The SPA pearl contains can be stimulated radiative scintillator.This stimulation only takes place when Streptavidin surface bonding on the SPA pearl causes the blue emission that can detect on scintillation counter with being coated at the peptide of radiolabeled phosphorylation.Therefore, the existence of Pak1 kinase activity produces analytical signal.In the presence of the Pak1 kinase inhibitor, signal strength weakening.

Pak1 enzyme for given test compound suppresses to use IC ₅₀Value representation.

(b) External Pak2 enzyme is analyzed

This analytical applications get close to flicker detection analysis (SPA) technology (Antonsson etc., Analytical Biochemistry, 1999, 267: 294-299) the determination test compound suppresses the ability by the phosphorylation of reorganization Pak2.Terminal and the terminal His of C-of N- ₆Ni is expressed and adopted to the Pak2 protein of the overall length of mark in intestinal bacteria (E.coli) ^2+/NTA-agarose purifying.

The stock solution that test compound is prepared as the DMSO of 10 mM also dilutes in water when needed and obtains the whole analytical concentration of sequence.The aliquots containig (5 μ l) of each diluted chemical compound liquid is elaborated in each hole of the flat white polystyrene board in matrix (Matrix) 384-hole (catalog number (Cat.No.) 4316).Reorganization purifying Pak2 enzyme (15ng), the biotinylated peptide substrates of 1 μ M (vitamin H-Ahx-Lys-Lys-Glu-Gln-Ser-Lys-Arg-Ser-Thr-Met-Val-Gly-Thr-Pro-Tyr-Trp-Met-Ala-Pro-Glu-NH with 20 μ l ₂Bachem UK Ltd), Triphosaden (ATP; 2 μ M), ³³The Triphosaden of P-mark ( ³³P-ATP; 33 nCi/ holes) and the buffering solution [comprise Tris-HCl pH 7.5 damping fluids (50mM), EGTA (0.1mM), bSA (0.1mg/ml), dithiothreitol (DTT) (DTT; 5mM) and magnesium acetate (10mM)] mixture in incubated at room 120 minutes.

As the result of the phosphorylation of Pak2 mediation, original position forms the biotinylated peptide of radiolabeled phosphorylation.The SPA pearl contains can be stimulated radiative scintillator.This stimulation only takes place when Streptavidin surface bonding on the SPA pearl causes the blue emission that can detect on scintillation counter with being coated at the peptide of radiolabeled phosphorylation.Therefore, the existence of Pak2 kinase activity produces analytical signal.In the presence of the Pak2 kinase inhibitor, signal strength weakening.Pak2 enzyme for given test compound suppresses to use IC ₅₀Value representation.

(c) External Pak4 enzyme is analyzed

This analytical applications get close to flicker detection analysis (SPA) technology (Antonsson etc., Analytical Biochemistry, 1999, 267: 294-299) the determination test compound suppresses the ability by the phosphorylation of reorganization Pak4.The kinases territory of Pak4 (amino acid 291-591) is expressed as the GST fusion and adopts the standard purification technology to use GST label purifying in intestinal bacteria (E.coli).

The stock solution that test compound is prepared as the DMSO of 10mM also dilutes in water when needed and obtains the whole analytical concentration of sequence.The aliquots containig (5 μ l) of each diluted chemical compound liquid is elaborated in each hole of the flat white polystyrene board in matrix (Matrix) 384-hole (catalog number (Cat.No.) 4316).Reorganization purifying Pak4 enzyme (10nM), the biotinylated peptide substrates of 1 μ M (vitamin H-Ahx-Lys-Lys-Glu-Val-Pro-Arg-Arg-Lys-Ser-Leu-Val-Gly-Thr-Pro-Tyr-Trp-Met-Ala-Pro-Glu-NH with 20 μ l ₂Bachem UK Ltd), Triphosaden (ATP; 2 μ M), ³³The Triphosaden of P-mark ( ³³P-ATP; 33 nCi/ holes) and the buffering solution [comprise Tris-HCl pH 7.5 damping fluids (50mM), EGTA (0.1mM), bSA (0.1mg/ml), dithiothreitol (DTT) (DTT; 5mM) and magnesium acetate (10mM)] mixture in incubated at room 120 minutes.

Because the phosphorylation of Pak4 mediation, original position forms the biotinylated peptide of radiolabeled phosphorylation.The SPA pearl contains can be stimulated radiative scintillator.This stimulation only takes place when Streptavidin surface bonding on the SPA pearl causes the blue emission that can detect on scintillation counter with being coated at the peptide of radiolabeled phosphorylation.Therefore, the existence of Pak4 kinase activity produces analytical signal.In the presence of the Pak4 kinase inhibitor, signal strength weakening.

Pak4 enzyme for given test compound suppresses to use IC ₅₀Value representation.The concrete field of activity of this compound is at 10nM-20 μ M.

Detect the analysis of PDK1 kinase inhibition:

(a) the PDK1 enzyme is analyzed:

This this analysis and utilization alpha scanning (Alphascreen) technology (Ullman, EF wait Proc.Natl.Acad.Sci.USA, volume 91, the 5426-5430 pages or leaves, 1994) determination test compound suppresses the ability of PDK1 enzymic activity.The PDK1 enzyme of 6His mark is in expressed in insect cells and adopt the NiNTA pearl and conventional method of purifying protein purifying.

The stock solution that test compound is prepared as the DMSO of 10mM also dilutes in water when needed and obtains the whole analytical concentration of sequence.The compound of 2 μ l integral multiples is distributed in 384 orifice plates (catalog number (Cat.No.) 784075) of GreinerBio-One lower volume.For activation analysis, the mixture that in each hole, adds the following material of 5 μ l, 48nM native peptides (vitamin H-Ahx-Ile-Lys-Asp-Gly-Ala-Thr-Met-Lys-Thr-Phe-Cys-Gly-Thr-Pro-Glu-Tyr-Leu-Ala-Pro-Glu-Val-Arg-Arg-Glu-Pro-Arg-Ile-Leu-Ser-Glu-Glu-Glu-Gln-Glu-Met-Phe-Arg-Asp-Phe-Asp-Tyr-Ile-Ala-Asp-Trp-NH ₂, BachemUK Ltd) and the reaction buffer that contains Tris-HCl pH7.4 (60 mM), magnesium acetate (12mM), EGTA (120 μ M), DTT (1.2mM) and bSA (0.12mg/ml) of 12 μ M Triphosadens (ATP).Start reaction by the solution that contains the proteic reaction buffer of 20ng/ml purification of Recombinant PDK1 that adds 5 μ l prepared fresh, at room temperature hatched 45 minutes.

Contain Tris-HCl pH 7.4 (50mM), bSA (1mg/ml), EDTA (90mM), anti-phosphatide Akt T308 antibody, R﹠amp by what add 5 μ l; D system, catalog number (Cat.No.) RF8871, (200ng/ml), alpha scans the Streptavidin donor bead, Perkin Elmer catalog number (Cat.No.) 6760002B (30 μ g/ml) and alpha are scanned the albumin A acceptor bead, the solution of Perkin Elmer catalog number (Cat.No.) 6760137R (30 μ g/ml) stops each reaction.Seal all plates then and shine overnight incubation under the condition, read to read plate on the plate device (Perkin Elmer) at Envision afterwards in low light.

Also can use with the similar condition of activation analysis under the manual analysis detection compound, but different be peptide [vitamin H-Ahx-Ile-Lys-Asp-Gly-Ala-Thr-Met-Lys-(p) Thr-Phe-Cys-Gly-Thr-Pro-Glu-Tyr-Leu-Ala-Pro-Glu-Val-Arg-Arg-Glu-Pro-Arg-Ile-Leu-Ser-Glu-Glu-Glu-Gln-Glu-Met-Phe-Arg-Asp-Phe-Asp-Tyr-Ile-Ala-Asp-Trp-NH in the 2nM phosphorylation ₂, Bachem UK Ltd) and the existence of 18nM native peptides under carry out.

By using 6%DMSO alternate test compound, set up the control wells that produces peak signal corresponding to maximum enzyme activity.Be used for activation analysis or be used for manual analysis by the control wells that adds EDTA (0.5M) foundation generation minimum signal by adding 1.008mM Xylene Brilliant Cyanine G (Coomassieblue) alternate test compound.

In activation analysis,, form the biotinylated peptide of phosphorylation, subsequently with anti-phosphatide (phospho) Akt T308 antibodies by making the PDK1 activation.Catch this mixture via the interaction of itself and vitamin H and protein A acceptor bead via the interaction of itself and antibody by the Streptavidin donor bead then.The getting close to of donor bead and acceptor bead can make now singlet oxygen from donor bead by the exciting of 680nm, be transferred to acceptor bead, produce emission at 520-620nm.In the linearity range of analyzing, strength of signal and PDK1 enzyme active proportional.Therefore, the existence of PDK1 activity inhibitor will make the emission at 520-620nm reduce.

The PDK1 inhibitor activity is reported IC with the result of duplicate detection ₅₀Value.

(b) PDK1 cell analysis:

As the part of PI3K path, Akt is that independent (pocketindependent) substrate of the PIF pocket of PDK and the phosphorylation of T308 on Akt1 provide cell PDK1 active direct detection.Can in analysis, use and have the PI3K path (as PTEN, PI3K) Tu Bian cell type, with or avoid needing to stimulate or make the maximization of path flow.Cell analysis utilizes specificity phosphorylation antibody, to survey the phosphorylation of Akt1 to T308.

Breast cancer cell line MDA-MB-468 cell (PTEN null) is inoculated in 96 orifice plates (Packard View plate, Perkin Elmer catalog number (Cat.No.) 1450-573), and density is among every hole 90 μ l 10 ⁴Individual cell, and in 37 ℃, 5%CO ₂Following grow overnight.The stock solution that test compound is prepared as the DMSO of 10mM also dilutes in cell culture medium when needed and obtains the whole analytical concentration of sequence.In each hole, add the compound of 10 μ l then and make cell in 37 ℃, 5%CO ₂Under hatch 2hrs.The phosphate buffered saline (PBS) (PBS) that adds 20 μ l, 10% formaldehyde then in each hole makes cell fixation, hatches under room temperature 20 minutes.After removing substratum and fixing, with 100 μ l PBS, 0.05% polysorbate washed cell, then by adding 100 μ l PBS, the infiltration of 0.5% polysorbas20 and under room temperature, hatching 10 minutes.After removing the infiltration damping fluid, cell dyeing is used to manifest phosphorylation (phospho) Akt1 T308, phosphorylation Akt2 T309 and phosphorylation Akt3 T305.

Briefly, with the sealing damping fluid (PBS of cell in 100 μ l, 0.05% polysorbas20,5%BSA), under room temperature, hatch 1hr, then under 4 ℃, spend the night with anti-phosphorylation Akt T308 antibody (Cell SignallingTechnologies, the catalog number (Cat.No.) 4056) solution-dyed of sealing damping fluid at every hole 40 μ l by 1/1000 dilution.Behind the PBS of 250 μ l, the washing of 0.05% polysorbas20 3 times, under room temperature, cell is contained with goat anti-rabbit igg (H+L)/Alexa Fluor 488 conjugates (Molecular Probes, catalog number (Cat.No.) A11008) the solution-dyed 1hr of sealing damping fluid by 1/1000 dilution with 40 μ l.After with PBS, the washing of 0.05% polysorbate of the PBS of 250 μ l, 0.05% polysorbas20,100 μ l 3 times, add 1 μ M propidium iodide and read to read plate on the plate device (TTP Labtech) at Acumen Explorer.

All detect by the IC that carries out in duplicate and quantitatively signal is used to assess compound ₅₀Value.Adopt the effect of propidium iodide dyeing monitoring pair cell quantity.

Synthetic

Many methods that the technician is familiar with in the available organic synthesis field prepare The compounds of this invention.More particularly, can adopt reaction described herein and technology to prepare the new compound of the present invention.Should be appreciated that in synthetic method described below, the reaction conditions of all proposals comprises solvent selection, reaction atmosphere, temperature of reaction, duration of experiment and subsequent disposal, all select to be suitable for the standard conditions of this reaction.The technician should be appreciated that in the organic synthesis field, and the functional group of the existence in the molecule on the different positions must adapt to reagent and proposed reacting phase.Like this for the substituent restriction that does not adapt with reaction conditions, will be conspicuous to those skilled in the art, thereby must use alternative methods.

Unless refer else, be included in the starting raw material of embodiment herein or commercially available or easily prepare from known raw material with standard method.The general method of synthetic The compounds of this invention is as follows: from general synthetic method synthesis type (I) compound that can describe among following flow process 1-10.The general method that is used for synthesizing thiofuran and pyridine formula (I) compound is described in flow process 1.Make the nitrile that replaces by aryl obtain esters of unsaturated carboxylic acids with the Knovenagel type method with the oxoethanoic acid condensation.Obtain acylazide with reaction of sodium azide after producing acyl chlorides.Acylazide is reset through Curtius, adopts very high temperature to carry out the electrophilic cyclisation of thiphene ring subsequently, obtains Thienopyridinone.By selecting and N-bromo-or iodo-succinimide reaction, optionally make the 5-position bromination or the iodate of thiphene ring then.Use Phosphorus Oxychloride dehydration and aromizing to obtain the chloro-pyridine intermediate, it can react the experience nucleophilic displacement by making amine and salt of wormwood in NMP.Perhaps, the chloro-pyridine intermediate can obtain corresponding aryl ethers or sulfide (flow process 2) with oxygen or the reaction of sulphur nucleophilic reagent.In the Suzuki of Pd-mediation reaction, can make the bromo that obtains-or iodo-thienopyridine and boric acid or ester under the standard coupling condition, react.By making the nitrile partial hydrolysis, can finally produce required thienopyridine methane amide with concentrated hydrochloric acid or PPA.Synthetic permission hydrolysis before the Suzuki coupling of the modification that in flow process 3, shows.

Flow process 1

Flow process 3

Bromo among the flow process 1-3, chloro or iodo-thienopyridine also can be used in the linked reaction of other Pd-mediation, for example with the Stille coupling (flow process 4) of aryl stannane, with the Sonogashiri coupling (flow process 5) and the Buchwald amination (flow process 6) of alkynes class, form formula (I) compound.

Flow process 4

Flow process 5

Flow process 6

Employing is at the alternative route of synthesis of flow process 7 general introductions, but other heterogeneous ring compound of production (I).Heteroaryl aldehyde can experience the condensation of aldol (Aldol) type with propanedioic acid, obtains unsaturated carboxylic acid.Be similar to flow process 1, behind the generation acyl chlorides, form acylazide and, provide heterocycle 5-6 ring condensed pyridine via the cyclisation of Curtius isocyanate intermediate.With the cupric cyanide displacement, provide the nitrile pyridine after the pyridine ring bromination.As preceding making Phosphorus Oxychloride and amine replacement(metathesis)reaction, provide the nitrile precursor.Be required methane amide by the hydrolysis nitrile then, form target formula (I) compound.

Flow process 7

According to steps outlined in flow process 8, the acid amides that can synthesize replacement is essential formula (I) compound.The amino-nitrile that produces in each from above flow process 1-7 can be a carboxylic acid by being used alternatingly that 6 N aqueous hydrochloric acids substitute concentrated acid and by complete hydrolysis.Method such as the anhydride reaction with blended acid that can adopt any standard to form acid amides then makes acid and amine coupling, or use acid amides coupling agent/dewatering agent such as, but be not limited to 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride (EDCI), O-(1H-benzotriazole-1-yl)-N, N, N ', N '-tetramethyl-urea  hexafluoro-phosphoric acid salt (HBTU) or benzotriazole-1-base oxygen base three (dimethylamino)  hexafluoro-phosphoric acid salt (BOP).

Flow process 8

The synthetic conversion that use is described in flow process 9 and 10, but the non-pyridinyl compounds of synthesis type (I).Show in the flow process 9, reflux and use MeOH and anhydrous hydrochloric acid can make 3-nitro anthranilate (anthranilate) esterification of derivatives down.Can make the amino ester experience adopt the one still process (one-pot) of the uncle-Ding potassium oxide in DMSO to transform then, it comprises by producing enamine, deprotonation effect, replace in the adjacent nucleophilic aromatic that activates nitro with the aryl ketones reaction, is subsequently oxidized to the indoles intermediate.By forming mixed acid anhydride, with the amine reaction, the carboxylic acid product of this step can be converted into acid amides subsequently with chloro-formic ester.Make nitro hydrogenation obtain anils, it can be converted into formula (I) benzazolyl compounds by carrying out reductive amination with ketone or aldehyde.Perhaps, by diazotisation methods, can make aniline be converted into halide derivative, the displacement with amine or alcohol by Pd or Cu mediation is converted into formula (I) compound then.

Flow process 9

Another approach of the non-pyridinyl compounds of synthesis type (I) is summarized in flow process 10.The nucleophilic aromatic of carrying out fluorine with amine, alcohol or mercaptan replaces, and produces aniline subsequently, carries out the intramolecularly electrophilic aromatics replacement of acetal subsequently with strong acid, can obtain different 5-6 condensed ring systems.The conversion of describing in flow process 1-9 before using, the aniline that obtains can be made with extra care is non-pyridinyl compounds all thionaphthene or cumarone suc as formula (I).

Flow process 10

Embodiment

The present invention will quote following illustrative embodiment at this and further describe, unless refer else:

(i) temperature that provides in degree centigrade (℃); Unless refer else, promptly be meant in 18-25 ℃ of scope and carry out in operating under the room temperature or under the envrionment temperature;

(ii) solution is through anhydrous sodium sulphate or dried over mgso; The evaporation of organic solvent under reduced pressure (4.5-30mmHg), use rotatory evaporator to carry out under 60 ℃ the bath temperature in being up to;

(iii) chromatography means quick silica gel column chromatography; Thin-layer chromatography (TLC) carries out on silica-gel plate;

(iv) usually, carrying out TLC or liquid chromatography (LC)/mass spectrum (LC/MS) and given reaction times after the reaction process uses for illustrative purposes only;

(v) end product has gratifying proton magnetic resonance (PMR) (NMR) frequency spectrum and/or mass-spectrometric data;

(yield that vi) provides is used for illustrative purposes only and is essential by complicated available those yield of method exploitation; More if desired raw materials can repeat preparation;

(vii) when providing nucleus magnetic resonance (NMR) data, its form with delta (δ) value is represented main diagnostic proton, unless refer else, marks as interior with the several of per 1,000,000 (ppm) branch that provide with respect to tetramethylsilane (TMS), at d ₆The 300MHz of-DMSO measures;

(viii) chemical symbol has its common implication;

(ix) the solvent ratio is with volume: volume (v/v) term provides;

(x) Rochelle salt (Rochelle ' s Salt) is a sodium-potassium tartrate;

(xi) Hunig ' s alkali is diisopropyl ethyl amine (DIEA);

(xii) use following one or more kind methods to carry out the purifying of compound:

A) flash chromatography on the conventional silica gel;

B) flash chromatography on silica gel of use MPLC separation system: the quick column casing of the positive of prefill, flow velocity, 30-40ml/min;

C) use anti-phase C18 post, 100 * 20mm, 5 μ M (or bigger) and water (0.1%TFA) and MeCN (0.1%TFA) combination are as the preparation HPLC system of moving phase wash-out;

D) use chiral column, as Diacel ^Post (AD, OD, AS and/or OJ stationary phase), 250 * 20mm, 10 μ M (or bigger) and with the combination of hexane, Virahol, EtOH and/or MeOH (containing 0.1% diisopropylethylamine) chirality preparation HPLC system as the moving phase wash-out; With

(xiii) use following abbreviation:

Concentrate under the CIV vacuum;

RT and rt room temperature;

Uncle BOC-butoxy carbonyl;

BOP benzotriazole-1-base oxygen base three (dimethylamino)  hexafluorophosphate;

Bu ₃The N Tributylamine;

The CBZ benzyloxycarbonyl;

DMF N, dinethylformamide;

The DMSO methyl-sulphoxide;

NMP N-N-methyl-2-2-pyrrolidone N-;

The EtOAc ethyl acetate;

The ether ether;

EtOH ethanol;

The THF tetrahydrofuran (THF);

MeOH methyl alcohol;

The MeCN acetonitrile;

The PPA polyphosphoric acid;

The TFA trifluoroacetic acid; With

The TEA triethylamine.

The most compounds for preparing in following examples is separated into hydrochloride and is proved that by the NMR data this will be conspicuous to those skilled in the art based on the method that is used to prepare compound.

Embodiment 1

The 2-phenyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

Step 1:

(2Z)-3-cyano group-3-(2-thienyl) vinylformic acidTo the 2-thienyl acetonitrile that stirs (24.8g, add in MeOH 0.20mol) (300mL) solution oxoethanoic acid monohydrate (18.5g, 0.20mol) and salt of wormwood (25.5g, 0.20mol).Place reacting slurry under the nitrogen atmosphere and be heated to backflow.Make reaction mixture be cooled to rt behind the 2h, obtain product after filtration.With a large amount of MeOH washing leaching cakes, dried overnight in vacuum drying oven then obtains the title compound of the sylvite of 43.1g (99%) white crystals. ¹H NMR δ7.95(d，3H)，7.75(d，1H)，7.30(dd，1H)，7.05(s，1H)，3.0-4.0(br s，1H)。LCMS(ES，M+H＝180，M-H＝178)。

Step 2:

(2Z)-3-cyano group-3-(2-thienyl) acrylate chloride(2.6mL is 30mmol) in the CH of 10mL to the oxalyl chloride that stirs ₂Cl ₂Add the CH that is dissolved in 20mL in the solution ₂Cl ₂(2Z)-3-cyano group-3-(2-thienyl) vinylformic acid sylvite (2.2g is 12.3mmol) in the solution.The CH that adds additional quantity ₂Cl ₂Reaction mixture until the viscosity nonuniformity can stir easily.React on stir about 1h under the rt.Remove solid after filtration also with a large amount of CH ₂Cl ₂Washing.Filtrate and ishes are merged, concentrate the 2.0g title compound that obtains being used for next step under the vacuum.

Step 3:

(2Z)-3-cyano group-3-(2-thienyl) acryloyl trinitrideIn 0 ℃, the sodiumazide (2.0g in 50: 50 dioxane/water (20mL) to quick stirring, in suspension 30mmol), add (2Z)-3-cyano group-3-(2-thienyl) acrylate chloride (2.0g, 12.3mmol) solution of the dioxane that is dissolved in 10mL.In 0 ℃ of reaction stirred 30 minutes, and then make it reach rt after stirring 1-2h.Adding～100mL water is to reactant then.The throw out that forms washes with water after filtration, and dried overnight in vacuum drying oven obtains being further purified the title trinitride of the white solid (2.0g) that promptly is used for next step.

Step 4:

4-oxo-4,5-dihydro-thiophene be [3,2-c] pyridine-7-nitrile alsoUnder nitrogen gas stream, with phenyl ether (260mL) and Bu ₃The mixture heating up to 210 of N (53mL) ℃.In 2h, (acutely produce N ₂Gas), (15.0g is 73.5mmol) in CH dropwise to add (2Z)-3-cyano group-3-(2-thienyl) acryloyl trinitride ₂Cl ₂Slurries (30mL).After finishing adding,, make reaction be cooled to rt then, place ice bath then in 210 ℃ of restir reactant 10min.Add the hexane (500mL) and the filtering precipitate of bleeding down, with a large amount of hexane wash.The solid dried overnight (not heating) in vacuum drying oven that obtains is obtained light brown solid-like title compound (9.89g, 76%). ¹HNMRδ12.4(br s，1H)，8.29(d，1H)，7.82(d，1H)，7.58(d，1H)。LCMS(ES，M+H＝177，M-H＝175)。

Step 5:

2-bromo-4-oxo-4,5-dihydro-thiophene be [3,2-c] pyridine-7-nitrile alsoWith N-bromosuccinimide (1.6g 9mmol) adds 4-oxo-4, the 5-dihydro-thiophene also [3,2-c] pyridine-7-nitrile (0.8 g, 4.5mmol) DMF/ acetate (20mL) with the solution in 50: 50 the mixture in.The reaction mixture of this black is heated to 80 ℃ of meter 12h.After being cooled to rt, stir down reactant is joined～100mL water in.Use saturated NaHCO ₃Regulate the pH to 9-10 of muddy solution.After filtration, wash with water, drying obtains product (1.1g, 100%) in vacuum drying oven. ¹H NMRδ12.6(br s，1H)，8.38(d，1H)，7.77(s，1H)。LCMS(ES，M+H＝255，M-H＝253)。

Step 6:

2-bromo-4-chloro thiophene is [3,2-c] pyridine-7-nitrile alsoWith 2-bromo-4-oxo-4, the 5-dihydro-thiophene also [3,2-c] pyridine-7-nitrile (1.1g 4.5mmol) is dissolved in POCl ₃Solution (10mL) is heated to reflux and spends the night.After being cooled to rt, under the vacuum reactant is concentrated into drying.Slowly and carefully with solid suspension in～50-100mL water.After filtration, water, saturated NaHCO subsequently ₃, water washing, drying obtains product (1.0g, 83%) in vacuum drying oven. ¹H NMRδ9.10(s，1H)，8.20(s，1H)。LCMS(ES，M+H＝275)。

Step 7:

(3S)-and 3-[(7-cyano group-2-bromo thiophene [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid uncle fourth EsterTo the 2-bromo-4-chloro thiophene that stirs also [3,2-c] pyridine-7-nitrile (0.48g, 1.76mmol) and (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (0.40g, 2.0mmol) in the solution of NMP (5mL), add salt of wormwood (0.5g, 3.52mmol).With the mixture heating up to 80 of nonuniformity ℃ meter 2h, be cooled to rt, add to then～water of 50mL in.Product (880mg) separates after filtration and is dry.Through using MPLC (SiO ₂The 30-50%EtOAc/ hexane gradient) is further purified and obtains 0.54g, 70% glassy yellow crystalline solid-like title compound. ¹H NMRδ8.36(s，1H)，8.08(s，1H)，7.68(m，1H)，4.02(m，1H)，3.74(m，1H)，3.50(m，1H)，2.70-3.20(m，2H)，1.91(m，1H)，1.74(m，1H)，1.54(m，1H)，1.30-1.45(m，1H)，1.21(s，9H)。LCMS(ES，M+H＝437，439；M-H，435，437)。

Step 8:

(3S)-and 3-{[7-cyano group-2-(phenyl) thieno-[3,2-c] pyridin-4-yl] amino } piperidines-1-carboxylic acid uncle Butyl esterWith (3S)-3-[(7-cyano group-2-bromo thiophene [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid tert-butyl ester (0.18g.0.41mmol), phenyl-boron dihydroxide (0.076g, 0.62mmol), tetrakis triphenylphosphine palladium (0) (Pd (PPh3) ₄) (0.10g, (0.41g 1.25mmol) is dissolved in water (1mL) and dioxane (3mL) for mixture 0.062mmol) and cesium carbonate.This reaction mixture is stirred 1h under 80 ℃ of nitrogen atmosphere, make it be cooled to rt then.With removing dioxane under pipette removal water and the vacuum.Resistates is through MPLC (SiO ₂The 30-60%EtOAc/ hexane) purifying obtains title compound (140mg, 78%). ¹H NMRδ8.41(s，1H)，8.34(br s，1H)，7.74(s，1H)，7.73(d，2H)，7.52(dd，2H)，7.42(dd，1H)，4.12(m，1H)，3.81(m，1H)，3.60(m，1H)，2.6-3.2(m，2H)，2.01(m，1H)，1.82(m，1H)，1.62(m，1H)，1.40-1.50(m，1H)，1.24(s，9H)。LCMS(ES，M+H＝435；M-H，433)。

Step 9:

The 2-phenyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide.With (3S)-3-{[7-cyano group-2-(phenyl) thieno-[3,2-c] pyridin-4-yl] amino } (80mg, 0.18mmol) (dense, 4mL) stirring is 24 hours for solution and 12 N HCl for piperidines-1-carboxylic acid tert-butyl ester.Add entry (10-20mL) and use saturated NaHCO ₃The pH to 10-11 of regulator solution.This raw material separates after filtration and uses a small amount of cold water washing.This raw material drying is then through MPLC (SiO ₂NH ₄OH/MeOH/CH ₂Cl ₂2: 10: 88) purifying obtains title compound (24mg, 38%). ¹H NMRδ8.58(s，1H)，8.27(s，1H)，7.98(br s，1H)，7.79(d，2H)，7.55(dd，2H)，7.43(dd，1H)，7.34(br s，1H)，7.25(d，2H)，4.22(m，1H)，3.21(d，1H)，2.91(d，1H)，2.48(m，2H)，2.05(m，1H)，1.76(m，1H)，1.55(m，2H)。LCMS(ES，M+H＝353)。

With mode similar to Example 1, adopt suitable starting raw material to prepare embodiment 2-51.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	2	4-[(3S)-piperidines-3-base is amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	358.49	359	9.72 (s, 1H), 9.08 (s, 1H), 8.79 (s, 1H), 8.55 (s, 1H), 8.40 (s, 1H), 7.96 (s, 1H), 7.78 (t, 1H), 7.72 (s, 1H), 7.54 (d, 1H), 4.63 (m, 1H), 3.19 (m, 2H), 3.02 (m, 2H), 2.06 (m, 2H), 1.81 (m, 2H).
3	2-(3-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	370.45	371	8.59 (s, 1H) 8.34 (s, 1H) 7.98 (s, 1H) 7.51-7.64 (m, 3 H), 7.37 (s, 1H) 7.21-7.30 (m, 3H) 4.22 (s, 1H) 3.19 (d, 1H) 2.90 (d, 1H) 2.38-2.53 (m, 2H) 2.04 (m, 1H) 1.75 (m, 1 H) 1.54 (m, 2H)	2		358.49	359
3		370.45	371		4	2-(2,4 difluorobenzene base)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	388.44	389	9.61 (s, 1H), 9.01 (s, 1H), 8.80 (s, 1H), 8.59 (s, 1H), 8.42 (m, 1H), 7.92 (m, 1H), 7.67 (s, 1H), 7.52 (m, 1H), 7.30 (m, 1H), 4.63 (m, 1H), 3.20 (m, 2H), 2.99 (m, 2H), 2.08 (m, 2H), 1.80 (m, 2H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else	5	2-(3-p-methoxy-phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	382.49	383	9.02 (s, 1H), 8.82 (s, 1H), 8.55 (s, 1H), 8.37 (s, 1H), 8.12 (s, 1H), 7.43 (t, 2H), 7.32 (m, 2H), 6.98 (d, 1H), 4.53 (m, 1H), 3.86 (s, 3H), 3.21 (m, 2H), 2.97 (m, 2H), 2.04 (m, 2H), 1.74 (m, 2H).
6	2-(4-aminomethyl phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	366.49	367	9.61 (s, 1H), 9.02 (s, 1H), 8.76 (s, 1H), 8.54 (s, 1H), 8.39 (s, 1H), 7.70 (d, 2H), 7.34 (d, 2H), 4.61 (m, 1H), 3.19 (m, 2H), 2.36 (s, 3H), 2.07 (m, 2H), 1.80 (m, 2H).	5		382.49	383
6		366.49	367		7	2-(3, the 4-Dimethoxyphenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	412.51	413	9.25 (s, 1H), 8.88 (s, 1H), 8.51 (s, 1H), 8.45 (s, 1H), 8.21 (s, 1H), 7.55 (s, 1H), 7.32 (d, 2H), 7.10 (d, 1H), 4.55 (m, 1H), 3.88 (s, 3H), 3.82 (s, 3H), 3.19 (m, 2H), 2.99 (m, 2H), 2.02 (m, 2H), 1.77 (m, 2H).
8	2-(2-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	370.45	371	1.77-1.44 (m, 4H), 2.87 (m, 2H), 3.12 (m, 2H), 4.19 (m, 1H), 7.46-7.31 (m, 5H), 7.81 (m, 2H), 7.94 (br s, 1H), 8.26 (s, 1H), 8.53 (s, 1H)	7		412.51	413
8		370.45	371		9	4-[(3S)-piperidines-3-base is amino]-2-(2-thienyl) thieno-[3,2-c] pyridine-7-methane amide	358.49	359	9.42 (s, 1H), 8.94 (s, 1H), 8.55 (s, 1H), 8.34 (s, 2H), 7.65 (d, 1H), 7.46 (d, 1H), 7.40 (m, 1H), 7.17 (m, 1H), 4.57 (m, 1H), 3.50 (m, 1H), 3.21 (m, 1H), 2.96 (m, 2H), 2.05 (m, 2H), 1.76 (m, 2H).
10	2-(3, the 5-difluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	388.44	389	9.72 (s, 1H), 9.43 (s, 1H), 9.16 (s, 2H), 8.61 (s, 1H), 8.51 (s, 1H), 7.74 (s, 1H), 7.47 (d, 2H), 7.33 (m, 1H), 4.67 (m, 1H), 3.28 (m, 2H), 3.04 (m, 2H), 2.06 (m, 2H), 1.83 (m, 2H).	9		358.49	359

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	11	2-(3, the 4-dichlorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	421.35	421	9.45 (s, 1H), 9.04 (s, 1H), 8.77 (s, 1H), 8.59 (s, 1H), 8.28 (m, 1H), 7.97 (s, 1H), 7.77 (m, 2H), 7.59 (m, 2H), 4.60 (m, 1H), 3.24 (m, 2H), 3.01 (m, 2H), 2.01 (m, 2H), 1.78 (m, 2H).
12	4-[(3S)-piperidines-3-base is amino]-2-[3-(trifluoromethyl) phenyl] thieno-[3,2-c] pyridine-7-methane amide	420.46	421	9.62 (s, 1H), 9.08 (s, 1H), 8.97 (s, 1H), 8.61 (s, 1H), 8.42 (m, 1H), 8.07 (s, 2H), 7.79 (s, 2H), 7.69 (s, 1H), 4.64 (m, 1H), 3.21 (m, 2H), 3.03 (m, 2H), 2 05 (m, 2H), 1.81 (m, 2H).	11		421.35	421
12		420.46	421		13	4-[(3S)-azepan-3-base is amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	1.71-1.58 (m, 1H), 1.94-1.83 (m, 4H), 2.17-2.07 (m, 1H), and 3.31-3.20 (m, 2H), 3.45-3.31 (m, 2H), 4.71 (m, 1H), 7.31 (m, 2H), 7.43 (m, 2H), 7.51 (m, 2H), 7.76 (m, 2H), 8.23 (br s, 1H), 8.46 (m, 1H), 8.54 (s, 1H), 9.10 (br s, 1H), 9.31 (br s, 1H)
14	2-(4-chloro-phenyl-)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	386.91	388	9.29 (s, 1H), 8.94 (s, 1H), 8.56 (s, 2H), 8.23 (s, 1H), 7.76 (d, 2H), 7.60 (d, 3H), 4.57 (m, 1H), 3.45 (m, 2H), 3.01 (m, 2H), 2.03 (m, 2H), 1.77 (m, 2H).	13		366.49	367
14		386.91	388		15	The 2-phenyl-4-[(3S)-tetramethyleneimine-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	338.43	339	2.20-2.12 (m, 2H), 3.55-3.22 (m, 3H), 4.09 (m, 1H), 4.76 (m, 1H), 7.50-7.32 (m, 3H), 7.90-7.75 (m, 3H), 8.23-8.07 (m, 2H), 8.56 (s, 1H), 9.05-8.90 (m, 2H)
16	The 4-[(2-amino-ethyl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	312.4	313	3.16 (m, 2H), 3.82 (m, 2H), 7.31 (m, 1H), 7.40 (m, 1H), 7.51 (m, 2H), 8.00 (brs, 2H), 8.20 (br s, 1H), 8.32 (br s, 1H), 8.53 (s, 1H)	15		338.43	339

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	17	The 2-phenyl-4-[(3R)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	352.46	353	1.73-1.66 (m, 2H), 2.01-1.95 (m, 2H), 3.00-2.95 (2H), 3.15 (m, 1H), 3.24 (m, 1H), 4.56 (m, 1H), 7.46 (m, 3H), 7.75-7.73 (m, 3H), 8.02 (br s, 1H), 8.37 (s, 1H), 8.55 (s, 1H), 8 96 (br s, 1H), 9.27 (br s, 1H)
18	2-(4-tert-butyl-phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	408.57	409	8.51 (s, 1H), 8.16 (s, 1H), 7.93 (br s, 1H), 7.67 (d, 2H), 7.51 (d, 2H), 7.28 (brs, 1H), 7.16 (d, 2H), 4.17 (m, 1H), 3.13 (d, 1H), 2.83 (d, 1H), 2.44 (m, 2H), 1.99 (m, 1H), 1.67 (m, 1H), 1.51 (m, 2H), 1.32 (s, 9H)	17		352.46	353
18		408.57	409		19	2-(4-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	370.45	371	1.77-1.66 (m, 2H), 2.13-1.92 (m, 2H), 2.84 (m, 2H), 3.25 (m, 1H), 3.49 (m, 1H), 4.49 (m, 1H), 7.35 (m, 2H), 7.54 (brs, 1H), 7.73 (m, 2H), 8.04 (br s, 1H), 8.11 (s, 1H), 8.54 (s, 1H), 8.72 (br s, 2H)
20	2-(4-acetylphenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	394.5	395	9.40 (s, 1H), 8.97 (s, 1H), 8.82 (s, 1H), 8.59 (s, 1H), 8.29 (s, 1H), 8.04 (d, 2H), 7.91 (d, 2H), 7.60 (m, 1H), 4.60 (m, 1H), 3.21 (m, 2H), 3.02 (m, 2H), 2.62 (s, 3H), 2.03 (m, 2H), 1.79 (m, 2H).	19		370.45	371
20		394.5	395		21	2-(3-chloro-4-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	404.9	406	9.73 (s, 1H), 9.45 (s, 1H), 9.13 (s, 1H), 9.03 (s, 1H), 8.60 (s, 1H), 8.52 (s, 1H), 7.97 (d, 1H), 7.78 (m, 1H), 7.59 (t, 1H), 4.66 (m, 1H), 3.48 (m, 2H), 3.22 (m, 2H), 2.02 (m, 2H), 1.83 (m, 2H).
22	4-[(3S)-piperidines-3-base is amino]-2-(3,4, the 5-trifluorophenyl) thieno-s [3,2-c] pyridine-7-methane amide	406.43	407	9.35 (s, 1H), 8.94 (s, 1H), 8.61 (s, 2H), 8.26 (s, 1H), 7.70 (m, 1H), 7.52 (m, 2H), 7.39 (d, 2H), 4.58 (m, 1H), 3.19 (m, 2H), 2.98 (m, 2H), 2.04 (m, 2H), 1.77 (m, 2H).	21		404.9	406

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else	23	2-(4-chloro-3-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	404.9	406	9.41 (s, 1H), 8.96 (s, 1H), 8.68 (s, 1H), 8.61 (s, 1H), 8.28 (s, 1H), 7.83 (t, 1H), 7.66 (t, 1H), 7.58 (s, 1H), 7.39 (t, 1H), 4.59 (m, 1H), 3.21 (m, 2H), 3.00 (m, 2H), 2.04 (m, 2H), 1.79 (m, 2H).
24	The 2-{4-[(methylamino) carbonyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	409.51	410	9.56 (s, 1H), 9.01 (s, 1H), 8.90 (s, 1H), 8.58 (d, 2H), 7.96 (d, 2H), 7.88 (d, 2H), 7.68 (m, 1H), 4.60 (m, 1H), 3.21 (m, 2H), 3.02 (m, 2H), 2.82 (d, 3H), 2.04 (m, 2H), 1.80 (m, 2H).	23		404.9	406
24		409.51	410		25	2-(2,6-difluoro pyridine-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	389.43	390	9.32 (s, 1H), 8.93 (s, 1H), 8.61 (s, 1H), 8.54 (m, 1H), 8.24 (s, 1H), 7.71 (d, 1H), 7.54 (m, 1H), 7.40 (d, 1H), 4.58 (m, 1H), 3.18 (m, 2H), 3.03 (m, 2H), 2.03 (m, 2H), 1.76 (m, 2H).
26	4-[(3S)-piperidines-3-base is amino]-2-[4-(piperidines-1-base carbonyl) phenyl] thieno-[3,2-c] pyridine-7-methane amide	463.6	464	9.46 (s, 1H), 8.97 (s, 1H), 8.80 (s, 1H), 8.57 (s, 1H), 8.31 (s, 1H), 7.83 (d, 2H), 7.68 (m, 1H), 7.51 (d, 2H), 4.59 (m, 1H), 3.33 (m, 4H), 3 21 (m, 2H), 3 03 (m, 2H), 2.05 (m, 2H), 1.79 (m, 2H), 1.58 (m, 6H).	25		389.43	390
26		463.6	464		27	2-(3-{[(methyl sulphonyl) amino] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	459.59	460	9.46 (s, 1H), 8.96 (s, 1H), 8.67 (s, 1H), 8.56 (s, 1H), 8 32 (s, 1H), 7.71 (m, 4H), 7.51 (t, 1H), 7.41 (d, 1H), 4.59 (m, 1H), 4.24 (d, 2H), 3.22 (m, 2H), 3.03 (m, 2H), 2.92 (s, 3H), 2.08 (m, 2H), 1.79 (m, 2H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	28	2-[4-(sec.-propyl alkylsulfonyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	458.6	459	9.41 (s, 1H), 9.00 (s, 1H), 8.89 (s, 1H), 8.61 (s, 1H), 8.30 (m, 1H), 8.01 (q, 3H), 7.71 (d, 1H), 7.62 (s, 1H), 4.60 (s, 1H), 3.35 (m, 2H), 3.00 (m, 2H), 2.04 (m, 2H), 1.79 (m, 2H), 1.65 (m, 1H), 1.21 (s, 3H), 1.19 (s, 3H).
29	2-(3-chloro-phenyl-)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	386.91	387	9.56 (s, 1H), 9.01 (s, 1H), 8.88 (s, 1H), 8.58 (s, 1H), 8.37 (s, 1H), 7.82 (s, 1H), 7.73 (d, 1H), 7.62 (brs, 1H), 7.55 (t, 1H), 7.50 (d, 1H), 4.63 (m, 1H), 3.48 (d, 2H), 3.17 (m, 2H), 2.06 (m, 2H), 1.81 (m, 2H).	28		458.6	459
29		386.91	387		30	2-(3, the 4-difluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	388.44	389	9.36 (s, 1H), 8.95 (s, 1H), 8.65 (s, 1H), 8.57 (s, 1H), 8.23 (s, 1H), 7.79 (t, 1H), 7.59 (m, 3H), 4.58 (m, 1H), 3.17 (d, 2H), 3.02 (m, 2H), 2.00 (m, 2H), 1.77 (m, 2H).
31	2-(5-ethanoyl-2-thienyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	400.53	401	9.25 (s, 1H), 8.94 (s, 1H), 8.60 (s, 1H), 8.47 (s, 1H), 8.19 (s, 1H), 7.96 (d, 1H), 7.54 (d, 2H), 4.56 (s, 1H), 3.17 (d, 2H), 2.99 (m, 2H), 2.56 (s, 3H), 2.02 (m, 2H), 1.76 (m, 2H).	30		388.44	389
31		400.53	401		32	The 2-{3-[(dimethylamino) carbonyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	423.54	424	9.53 (s, 1H), 9.00 (s, 1H), 8.81 (s, 1H), 8.56 (s, 1H), 8.33 (s, 1H), 7.83 (d, 1H), 7.77 (s, 1H), 7.58 (t, 2H), 7.44 (d, 1H), 4.60 (s, 1H), 3.52 (d, 2H), 3.17 (m, 2H), 3.00 (d, 6H), 2.05 (m, 2H), 1.79 (m, 2H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else	33	2-(2-fluorinated pyridine-4-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	371.44	372	9.50 (s, 1H), 9.15 (s, 1H), 9.06 (s, 1H), 8.63 (s, 1H), 8.35 (d, 1H), 7.77 (d, 1H), 7.63 (m, 1H), 7.47 (s, 1H), 4.63 (s, 1H), 3.49 (d, 2H), 3.16 (m, 2H), 2.02 (m, 2H), 1.80 (m, 2H).
34	2-[2-(4-methylpiperazine-1-yl) pyridin-4-yl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	451.6	452	11.20 (s, 1H), 9.82 (s, 1H), 9.62 (s, 1H), 9.14 (s, 1H), 9.01 (s, 1H), 8.55 (d, 3H), 7.99 (d, 1H), 7.73 (m, 1H), 7.12 (d, 1H), 4.68 (s, 1H), 4.50 (d, 2H), 3.49 (d, 4H), 3.36 (d, 2H), 3.11 (m, 4H), 2.79 (d, 3H), 2.05 (m, 2H), 1.86 (m, 2H).	33		371.44	372
34		451.6	452		35	2-[3-(acetylamino) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	409.51	410	10.18 (s, 1H), 9 42 (s, 1H), 8.95 (d, 1H), 8.60 (s, 1H), 8.54 (s, 1H), 8.34 (brs, 1H), 7.69 (brs, 1H), 7.46 (m, 3H), 4.58 (s, 1H), 3.49 (d, 2H), 3.00 (m, 2H), 2.08 (s, 3H), 2.05 (m, 2H), 1.77 (m, 2H).
36	4-[(3S)-piperidines-3-base is amino]-2-quinoline-3-base thieno-[3,2-c] pyridine-7-methane amide	403.51	404	9.54 (s, 1H), 9.41 (s, 1H), 9.10 (s, 1H), 9.02 (s, 1H), 8.85 (s, 1H), 8.61 (s, 1H), 8.37 (brs, 1H), 8.16 (m, 2H), 7.86 (t, 1H), 7.73 (t, 1H), 7.70 (brs, 1H), 4.65 (s, 1H), 3.49 (d, 2H), 3.19 (m, 2H), 2.08 (m, 2H), 1.82 (m, 2H).	35		409.51	410
36		403.51	404		37	2-(6-fluoro-2-picoline-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	385.47	386	9.37 (s, 1H), 8.93 (s, 1H), 8.59 (s, 1H), 8.28 (s, 1H), 8.18 (brs, 1H), 8.06 (t, 1H), 7.52 (brs, 1H), 7.17 (m, 1H), 4.59 (s, 1H), 3.17 (d, 2H), 2.99 (m, 2H), 2.62 (s, 3H), 2.05 (m, 2H), 1.75 (m, 2H).
38	2-(5-fluoro-6-oxo-1,6-dihydropyridine-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	387.44	388	12.54 (s, 1H), 9.39 (s, 1H), 8.94 (s, 1H), 8.54 (s, 1H), 8.48 (s, 1H), 8.18 (brs, 1H), 7.76 (d, 2H), 7.66 (s, 1H), 7.55 (s, 1H), 4.57 (s, 1H), 3.17 (d, 2H), 3.03 (m, 2H), 2.05 (m, 2H), 1.77 (m, 2H).	37		385.47	386

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	39	2-(5-chloro-6-oxo-1,6-dihydropyridine-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	403.89	404	12.54 (s, 1H), 9.08 (s, 1H), 8.87 (s, 1H), 8.54 (s, 1H), 8.18 (s, 1H), 8.09 (s, 1H), 7.70 (m, 3H), 7.45 (s, 1H), 4.51 (s, 1H), 3.59 (d, 2H), 2.95 (m, 2H), 2.01 (m, 2H), 1.72 (m, 2H).
40	2-(6-morpholine-4-yl pyridines-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	438.55	439	9.56 (s, 1H), 8.99 (s, 1H), 8.72 (s, 1H), 8.51 (s, 2H), 8.37 (s, 1H), 8.00 (d, 1H), 7.67 (m, 1H), 7.10 (d, 1H), 4.60 (s, 1H), 3.73 (m, 2H), 3.59 (m, 4H), 3.49 (m, 2H), 3.17 (m, 2H), 3.04 (m, 2H), 2.04 (m, 2H), 1.80 (m, 2H).	39		403.89	404
40		438.55	439		41	2-[4-(dimethylamino) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.53	396	9.26 (br s, 1H), 8.82 (br s, 1H), 8.44 (s, 1H), 8.29 (m, 2H), 7.60 (m, 3H), 6.85 (d, 2H), 4.50 (m, 1H), 3.18 (m, 2H), 3.11 (m, 2H), 2.97 (s, 6H), 2.02 (m, 2H), 1.75 (m, 2H)
42	2-[3-(dimethylamino) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.53	396	9.40 (br s, 1H), 8.92 (br s, 1H), 8.61 (m, 1H), 8.51 (s, 1H), 8.28 (m, 1H), 7.60 (m, 1H), 7.33 (m, 2H), 7.16 (m, 1H), 6.87 (m, 1H), 4.56 (m, 1H), 3.47 (m, 2H), 3.15 (m, 2H), 3.00 (s, 6H), 2.00 (m, 2H), 1.78 (m, 2H)	41		395.53	396
42		395.53	396		43	4-[methyl (piperidines-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	9.26 (br s, 1H), 8.92 (br s, 1H), 8.59 (s, 1H), 8.18 (br s, 1H), 7.94 (s, 1H), 7.85 (m, 2H), 7.46 (m, 2H), 7.40 (m, 1H), 4.83 (m, 1H), 3.42 (m, 1H), 3.29 (s, 3H), 3.22 (m, 2H), 2.89 (m, 1H), 2.00-1.79 (m, 4H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	44	2-[3-(amino methyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	381.5	382	9.20(br s，1H)，8.82(br s，1H)，8.49(s，1H)，8.46(m，1H)，8.24(m，3H)，8.06(brs，1H)，7.80(s，1H)，7.74(d，1H)，7.49(t，1H)，7.40(m，2H)，4.48(m，1H)，4.03(dd，2H)，3.13(m，2H)，2.91(m，2H)，1.94(m，2H)，1.68(m，2H)
45	The 2-pyridin-3-yl-4-[(3S)-tetramethyleneimine-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	339.42	340	9.50(br s，3H)，9.19(s，1H)，9.10(s，H)，8.73(d，1H)，8.62(s，1H)，8.45(d，2H)，7.82(dd，1H)，7.73(br s，1H)，4.99m，1H)，3.50(m，2H)，3.33(m，2H)，2.35(m，1H)，2.26(m，1H)	44		381.5	382
45		339.42	340		46	The 2-pyridin-3-yl-4-[(3R)-tetramethyleneimine-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	339.42	340	9.70(br s，2H)，9.54(br s，1H)，9.19(s，1H)，9.09(s，1H)，8.73(d，1H)，8.66(s，1H)，8.43(d，2H)，7.80(dd，1H)，7.73(brs，1H)，5.05(m，1H)，3.50(m，2H)，3.33m，2H)，2.35(m，1H)，2.26(m，1H)
47	2-(4-methyl-3,4-dihydro-2H-1,4-benzoxazine-7-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	423.54	424	9.70(m，1H)，8.95(m，1H)，8.65(m，H)，8.44(m，2H)，7.73(m，1H)，7.22(d，1H)，7.08(s，1H)，6.78(d，1H)，4.58(m，1H)，4.26(m，2H)，3.47(m，2H)，3.23(m，2H)，3.03(m，2H)，2.90(s，3H)，2.00(m，2H)，1.80(m，2H)	46		339.42	340
47		423.54	424		48	2-(3 '-bromo biphenyl-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	507.45	508	8.90(m，2H)，8.56(s，1H)，8.36(m，1H)，7.97(d，2H)，7.76(m，2H)，7.68(m，1H)，7.60(m，3H)，7.47(m，2H)，4.55(m，1H)，3.24(m，2H)，2.91(m，2H)，2.00(m，2H)，1.74(m，2H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	49	2-(1-benzyl-1H-pyrazoles-4-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	432.55	433	9.45(br s，1H)，8.90(m，1H)，8.48(s，1H)，8.41-8.14(m，2H)，8.33(s，1H)，7.85(s，1H)，7.61(s，1H)，7.39-7.27(m，5H)，5.38(s，2H)，4.54(m，1H)，3.47(m，1H)，3.18(m，1H)，3.08(m，1H)，2.97(m，1H)，2.05(m，1H)，1.97(m，1H)，1.77(m，2H)
50	2-(1-methyl isophthalic acid H-pyrazoles-4-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	356.45	357	9.44(br s，1H)，8.89(m，1H)，8.47(s，1H)，8.45-8.20(m，2H)，8.18(s，1H)，7.80(s，1H)，7.63(br s，1H)，4.54(m，1H)，3.89(s，3H)，3.47(m，1H)，3.20(m，1H)，3.10(m，1H)，2.99(m，1H)，2.05(m，1H)，1.97(m，1H)，1.78(m，2H)	49		432.55	433
50		356.45	357		51	2-[2-(benzyloxy) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	458.58	459	8.55(s，1H)，8.33(s，1H)，7.77(br s，2H)，7.78(d，1H)，7.54(d，2H)，7.36(t，2H)，7.30(t，2H)，7.23(d，1H)，7.19(brs，1H)，7.08(t，1H)，5 36(s，2H)，4.61(brs，1H)，3.45(dd，1H)，3.20(s，3H)，3.15-3.20(m，1H)，2.02-2.09(m，2H)，1.76-1.85(m，2H)

Embodiment 52

2-[1-(1,3-benzothiazole-2-ylmethyl)-1H-pyrazoles-4-yl]-4-[(3S)-piperidines-3-base is amino] thiophene Fen is [3,2-c] pyridine-7-methane amide also

In mode similar to Example 1 but use 2-{[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-base (dioxaborolan-2-yl))-the 1H-pyrazol-1-yl] methyl }-1,3-benzothiazole (synthetic as described below) is as the preparation of the starting raw material in step 8. ¹H NMRδ9.11(br，1H)，8.81(br，1H)，8.50(s，1H)，8.44(s，1H)，8.10(br，2H)，8.08(d，1H)，8.01(d，1H)，7.94(s，1H)，7.55-7.42(m，3H)，5.92(s，2H)，4.51(br，1H)，3.46(m，1H)，3.20(m，1H)，2.95(m，2H)，2.09-1.92(m，2H)，1.82-1.65(m，2H)。LCMS(ES，M+H＝490)。

2-{[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl)-1H-pyrazol-1-yl] methyl }- 1, the 3-benzothiazoleIn 23 ℃, to 4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl)-and the 1H-pyrazoles (100mg, 0.515mmol) and 2-(bromomethyl)-1,3-benzothiazole (118mg, 0.515mmol) the solution of DMF (1.7mL) in add NaH (60% disperse in oil, 23mg, 0.567mmol).The reaction mixture stirring is spent the night.By adding NH ₄The Cl quencher is reacted and product is extracted with EtOAc.Organic layer salt water washing is through Na ₂SO ₄Concentrate under drying and the vacuum.

With mode similar to Example 1, adopt suitable starting raw material to prepare embodiment 53-57.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	53	4-[(3S)-piperidines-3-base is amino]-2-[1-(pyridine-2-ylmethyl)-1H-pyrazoles-4-yl] thieno-[3,2-c] pyridine-7-methane amide	433.54	434	9.63(br，1H)，8.96(br，1H)，8.63(d，1H)，8.50(s，1H)，8.47(br，2H)，8.40(s，1H)，7.96(m，1H)，7.90(s，1H)，7.69(br，1H)，7.48(dd，1H)，7.32(d，1H)，5.58(s，2H)，4.59(m，1H)，3.47(m，1H)，3.18(m，2H)，2.99(m，1H)，2.12-1.91(m，2H)，1.85-1.72(m，2H)
54	4-[(3S)-piperidines-3-base is amino]-2-[1-(pyridin-3-yl methyl)-1H-pyrazoles-4-yl] thieno-[3,2-c] pyridine-7-methane amide	433.54	434	9.31(br，1H)，8.87(br，1H)，8.77(s，1H)，8.72(d，1H)，8.49(s，1H)，8.40(s，1H)，8.32-8.08(m，3H)，7.88(s，1H)，7.75(m，1H)，7.53(br，1H)，5.55(s，2H)，4.53(m，1H)，3.46(m，1H)，3.19(m，1H)，2.99(m，2H)，2.10-1.90(m，2H)，1.83-1.67(m，2H)	53		433.54	434
54		433.54	434		55	2-[1-(2-amino-ethyl)-1H-pyrazoles-4-yl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	385.49	386	9.21(br，1H)，8.87(br，1H)，8.50(s，1H)，8.23(s，1H)，8.04(br，4H)，7.88(s，1H)，7.49-7.21(m，1H)，4.54(m，1H)，4.42(t，2H)，3.31(m，2H)，3.19(m，2H)，2.95(m，2H)，2.05-1.91(m，2H)，1.81-1.67(m，2H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	56	4-[(3S)-piperidines-3-base is amino]-2-[1-(pyridin-4-yl methyl)-1H-pyrazoles-4-yl] thieno-[3,2-c] pyridine-7-methane amide	433.54	434	9.36(br，1H)，8.92(br，1H)，8.79(d，2H)，8.51(s，1H)，8.42(s，1H)，8.24(br，2H)，7.95(s，1H)，7.60(d，2H)，7.52(br，1H)，5.70(s，2H)，4.55(m，1H)，3.46(m，1H)，3.18(m，1H)，3.00(m，2H)，2.08-1.90(m，2H)，1.82-1.67(m，2H)
57	4-[(3S)-piperidines-3-base is amino]-2-[1-(1,3-thiazoles-4-ylmethyl)-1H-pyrazoles-4-yl] thieno-[3,2-c] pyridine-7-methane amide	439.57	440	9.54(br，1H)，9.10(s，1H)，8.92(br，1H)，8.48(s，1H)，8.38(br，1H)，8.30(s，1H)，7.85(s，1H)，7.68(br，1H)，7.65(s，1H)，5.53(s，1H)，4.56(m，1H)，3.47(m，1H)，3.17(m，2H)，2.99(m，1H)，2.12-1.92(m，2H)，1.84-1.70(m，2H)	56		433.54	434

Embodiment 58

The 4-{ methyl [(3S)-and piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use (3S)-3-(methylamino) piperidines-1-carboxylic acid tert-butyl ester (synthetic as described below) as the preparation of the starting raw material in step 7. ¹H NMR δ9.26(br s，1H)，8.92(br s，1H)，8.59(s，1H)，8.18(br s，1H)，7.94(s，1H)，7.85(m，2H)，7.46(m，2H)，7.40(m，1H)，4.83(m，1H)，3.42(m，1H)，3.29(s，3H)，3.22(m，2H)，2.89(m，1H)，2.00-1.79(m，4H)。LCMS(ES，M+H＝367)。

(3S)-3-(methylamino) piperidines-1-carboxylic acid tert-butyl esterTo formaldehyde (37%, aq.; 0.37ml 4.7mmol) in 20ml contain add in the anhydrous MeOH solution of 3  molecular sieves (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (1.0g, 5mmol).In N ₂, reaction stirred～30h under the rt, add solid NaBH then ₄(304mg, 8mmol).Reaction stirred is spent the night under rt, uses 1N NaOH (～10ml) quencher then.Separate each and also extract remaining water layer mutually with ether (3x).The organic layer that water and salt water washing merge, dry and evaporation obtains water white oil (1.04g, 100%).LCMS(ES，M+H＝215)。

With with embodiment 58 similar modes, adopt suitable starting raw material to prepare embodiment 59-63.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	59	2-(3-fluorophenyl)-4-{ methyl [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide	384.48	385	Add D ₂O:1.76 (m, 1H), 1.94 (m, 3H), 2.84 (m, 1H), 3.17 (m, 2H), 3 24 (s, 3H), 3.40 (m, 1H), 4.75 (m, 1H), 7.19 (m, 1H), 7.52 (m, 1H), 7.60 (d, 1H), 7.67 (d, 1H), 7.92 (s, 1H), 8.52 (s, 1H)
60	2-(4-fluorophenyl)-4-{ methyl [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide	384.48	385	Add D ₂O:1.75 (m, 1H), 1.96 (m, 3H), 2.86 (m, 1H), 3.21 (m, 2H), 3.26 (s, 3H), 3.42 (m, 1H), 4.75 (m, 1H), 7.30 (m, 2H), 7.85 (m, 3H), 8.55 (s, 1H)	59		384.48	385
60		384.48	385		61	The 4-{ methyl [(3S)-and piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	Add D ₂O:1.76 (m, 1H), 1.95 (m, 3H), 2.84 (m, 1H), 3.18 (m, 2H), 3.23 (s, 3H), 3 401 (m, 1H), 4.69 (m, 1H), 7.61 (m, 2H), 7.75 (s, 1H), 7.92 (s, 1H), 8.50 (s, 1H)
62	4-{ (2-hydroxyethyl) [(3S)-and piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	396.51	397	Add D ₂O:8.57 (s, 1H), 7.80 (s, 1H), 7.77 (m, 2H), 7.49 (m, 2H), 7.39 (m, 1H), 4.59 (m, 1H), 3.77 (m, 1H), 3.69 (m, 1H), 3.54 (m, 2H), 3.39 (m, 1H), 3.20 (m, 2H), 2.82 (m, 1H), 1.89 (m, 3H), 1.70 (m, 1H).	61		372.52	373
62		396.51	397		63	4-{ (2-hydroxyethyl) [(3S)-and piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	402.54	403	D ₂O adds: 8.56 (s, 1H), 7.96 (s, 1H), 7.68 (m, 2H), 7.61 (m, 1H), 4.67 (m, 1H), 3.88 (m, 1H), 3.73 (m, 1H), 3.54 (m, 3H), 3.21 (m, 2H), 2.83 (m, 1H), 1.90 (m, 3H), 1.74 (m, 1H).

Embodiment 64

2-[2-(benzyloxy) phenyl]-the 4-{ methyl [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide

(3S)-and 3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) (methyl) amino] piperidines-1-carboxylic acid uncle Butyl esterUnder nitrogen atmosphere, with (3S)-3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid tert-butyl ester (240mg) is dissolved in NMP (10mL).Add sodium hydride (63mg) and will react placement 20min.Dropwise add methyl iodide (108 μ L) and will react on rt and stirred 1 hour down.In case (LCMS 452.69 M+H) are finished in reaction, will extract in the reaction mixture impouring water (120mL) and with EtOAc.Organic layer water and salt water washing are through MgSO ₄Drying, vacuum concentration.Resistates through silicagel column with 30-50%EtOAc/ different-hexane wash-out purifying.Merge the product flow point and obtain yellow jelly (245mg, 91%) through vacuum concentration. (3S)-and 3-[[7-(aminocarboxyl)-2-bromo thiophene [3,2-c] pyridin-4-yl also] (methyl) amino] piperidines- The 1-carboxylic acid tert-butyl esterWith (3S)-3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) (methyl) amino] piperidines-1-carboxylic acid tert-butyl ester (245mg) is dissolved in uncle-butanols (10mL), adds the KOH (110mg) of powder.The reaction mixture that obtains is heated to 80 ℃ of meter 30min, and LCMS confirms to finish reaction (468.93 M+H).Reaction mixture through vacuum concentration and with the MeOH azeotropic.Resistates is dissolved in CH ₂Cl ₂, water and salt water washing and through MgSO ₄Drying with the MeOH dilution, is used ion exchange column afterwards and is used MeOH and MeOH/NH ₃The priority wash-out.Product wash-out in alkaline flow point also is concentrated into yellow solid (207mg) in a vacuum. (3S)-and 3-[{7-(aminocarboxyl)-2-[2-(benzyloxy) phenyl] thieno-[3,2-c] pyridin-4-yl } (first Base) amino] piperidines-1-carboxylic acid tert-butyl ester. to (3S)-3-[[7-(aminocarboxyl)-2-bromo thiophene [3,2-c] pyridin-4-yl also] (methyl) amino] add 2-benzyloxy phenyl-boron dihydroxide (151mg), Pd (PPh in the piperidines-1-carboxylic acid tert-butyl ester (207 mg) ₃) ₄(51mg) and cesium carbonate (432mg).This mixture is at the dioxane of 10mL: H ₂Form slurries among the O (4: 1), be heated to 80 ℃ of meter 1h.The LCMS Indicator Reaction is finished (573.09 M+H).Reaction mixture concentrates and is dissolved in CH under vacuum ₂Cl ₂, water, salt water washing and through MgSO ₄Dry.Resistates is purifying on the 40g silicagel column, and with 30-100%EtOAc/ hexane wash-out.Merge the product flow point, concentrate in a vacuum and obtain colourless glutinous product (182mg).

2-[2-(benzyloxy) phenyl]-the 4-{ methyl [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7- Methane amideWith (3S)-3-[{7-(aminocarboxyl)-2-[2-(benzyloxy) phenyl] thieno-[3,2-c] pyridin-4-yl } (methyl) amino] piperidines-1-carboxylic acid tert-butyl ester (182mg) is dissolved among the MeOH 6ml, adds the dioxane solution of the 4.0M HCl of 1.5mL.Under room temperature, stir this reaction mixture 3hr then.The LCMS Indicator Reaction is finished (472.87 M+H).After reaction is finished with reaction mixture in 30 ℃ bathe temperature down, under the vacuum careful concentrate and with resistates at CH ₂Cl ₂With several MeOH/NH ₃With saturated NaHCO ₃Between distribute.With salt water washing organism with through MgSO ₄Drying, dried load are on silica gel, and purifying on the 12g silicagel column is used 1-12%MeOH/NH afterwards ₃/ CH ₂Cl ₂Wash-out.Merge the cleanest product flow point and vacuum concentration, obtain white solid, it is through grinding with ether, and filtration and drying obtain title product 85mg. ¹H NMR(500MHz，DMSO-d ₆)δ1.40-1.55(m，1H)，1.62-1.75(m，2H)，1.75-1.84(m，1H)，2.32-2.43(m，1H)，2.60-2.70(m，1H)，2.79-2.87(m，1H)，2.87-2.97(m，1H)，2.91(s，3H)，4.36-4.46(m，1H)，5.28(s，2H)，7.09(t，1H)，7.25-7.32(m，1H)，7.32-7.46(m，5H)，7.55(d，2H)，7.73(d，1H)，7.82-8.04(m，1H)，7.99(s，1H)，8.55(s，1H)。LCMS(ES，M+H＝473)。

Embodiment 65

2-phenyl-4-{ (2-phenylethyl) [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use (3S)-3-[(2-phenylethyl) amino] piperidines-1-carboxylic acid tert-butyl ester (synthetic as described below) prepares as the starting raw material in the step 7. ¹H NMR (adds D ₂O) δ 8.63 (s, 1H), 767 (m, 2H), 7.53 (s, 1H), 7.44 (m, 3H), 7.14-7.23 (m, 5H), 4.50 (m, 1H), 3.85 (m, 2H), 3.15 (m, 3H), 2.80 (m, 3H), 1.80-1.87 (m, 3H), 1.66 (m, 1H).LCMS(ES，M+H＝457)。

(3S)-and the 3-[(2-phenylethyl) amino] piperidines-1-carboxylic acid tert-butyl esterWith (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (1g, 5mmol), (2-bromoethyl) benzene (925mg, 0.69ml, 5mmol) and salt of wormwood (1.73g 12.5mmol) is added in the microwave heating pipe and adds DMF (6mL).

This mixture is heated 1h in 90 ℃.Each distributes between EtOAc and water.Water and salt water washing organic layer, dry and evaporation.Mixture through MPLC (EtOAC/ hexane) purifying obtain 794mg (52%) colourless oil sample title compound LCMS (ES, M+H=305).

With with the mode that is similar to embodiment 65, adopt suitable starting raw material to prepare embodiment 66-68.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	66	4-{ (4-hydroxybutyl) [(3S)-and piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	430.59	431	Add D ₂O:8.53 (s, 1H), 7.92 (s, 1H), 7.65 (m, 1H), 7.57 (m, 2H), 4.53 (m, 1H), 3.60 (m, 2H), 3 35 (m, 2H), 3.21 (m, 3H), 3.21 (m, 1H), 2.81 (m, 1H), 1.96 (m, 3H), 1.74 (m, 1H), 1.45 (m, 3H).
67	2-(3-fluorophenyl)-4-{ (2-phenylethyl) [(3S)-and piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide	474.6	475	Add D ₂O:8.71 (s, 1H), 7.68 (s, 1H), 7.58 (m, 3H), 7.28 (m, 4H), 7.21 (m, 2H), 4.59 (m, 1H), 3.80 (m, 2H), 3.20 (m, 3H), 2.86 (m, 3H), 1.92 (m, 3H), 1.70 (m, 1H)	66		430.59	431
67		474.6	475		68	4-{ (2-phenylethyl) [(3S)-and piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	462.64	475	Add D ₂O:8.74 (s, 1H), 7.97 (s, 1H), 7.77 (dd, 1H), 7.59 (d, 1H), 7.56 (s, 1H), 7.34 (m, 3H), 7.24 (m, 2H), 4.57 (m, 1H), 3.95 (m, 2H), 3.25 (m, 3H), 2.86 (m, 3H), 1.98 (m, 3H), 1.75 (m, 1H)

Embodiment 69

4-{[is trans-pipecoline-3-yl] and amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use trans-3-amino-2-methyl piperidines-1-benzyl carboxylate (synthetic as described below) to prepare as the starting raw material in the step 7. ¹H NMRδ9.47(m，1H)，9.04(m，1H)，8.59(m，1H)，8.45(s，1H)，8.25(m，1H)，7.71(d，2H)，7.56(m，1H)，7.45(m，2H)，7.35(m，1H)，4.34(m，1H)，3.42(m，1H)，3.22(m，1H)，2.82(m，1H)，2.07(m，1H)，1.83(m，2H)，1.59(m，1H)，1.26(d，3H)。LCMS(ES，M+H＝367)。

((1S)-1-ethanoyl-4-{[(benzyloxy) carbonyl] amino } butyl) t-butyl carbamateThe N that contains to assembling magnetic stirring bar and feed hopper ⁵-[(benzyloxy) carbonyl]-N ²(36.6g adds anhydrous THF (100mL) to-(uncle-butoxy carbonyl)-L-ornithine in 3-neck flask 100mmol).(1.6M is in ether to have filled MeLi in the feed hopper; 275mL; 440mmol), slowly add (above 20 minutes) subsequently to being cooled in 0 ℃ the reaction mixture.Then this solution is warmed to rt.Behind the restir 5h, by reactant being inclined to quencher reaction to the ice/water mixture that stirs.(3 * 100mL) extract aqueous mixture with EtOAc.Use the organic layer of salt water washing merging then, through Na ₂SO ₄Drying concentrates under filtration and the vacuum and obtains yellow oil (6.0g, 98%).Use MPLC (SiO ₂The 25-60%EtOAc/ hexane) behind the purifying, separating clarifying oil sample product (5.2g, 14%). ¹H NMRδ7.35(m，5H)，7.25(m，2H)，5.00(s，2H)，3.85(m，1H)，2.98(dd，2H)，2.05(s，3H)，1.63(m，1H)，1.39(s，9H)，1.34(m，3H)。LCMS(ES，M+H＝365)。

[trans-pipecoline-the 3-yl] t-butyl carbamateTo ((the 1S)-1-ethanoyl-4-{[(benzyloxy) carbonyl that stirs] amino } butyl) (3.9g 10.7mmol) adds 10%Pd/C (0.1mmol) to t-butyl carbamate in the solution of MeOH (200mL).Under normal atmosphere, make the mixture hydrogenation 3 days (or 40 psi spend the night) of nonuniformity.Behind diatomite filtration, isolate clarification oil sample product and evaporated filtrate, obtain need not purifying and promptly be used for next step title compound (2.3g; 100%).LCMS(ES，M+H＝215)。

Trans-uncle 3-[(-butoxy carbonyl) amino]-pipecoline-1-benzyl carboxylateTo the CH that is cooled to 0 ℃ that is dissolved in that stirs ₂Cl ₂[trans-pipecoline-the 3-yl] t-butyl carbamate (40mL) (2.3g, 10.7mmol) and diisopropyl ethyl amine (2.1mL, in solution 12mmol), add benzyl chloroformate (1.7mL, 12mmol).Then reaction mixture is warmed to rt and restir 1h.Use CH then ₂Cl ₂Dilute this mixture and use 1N HCl and salt water washing, through Na ₂SO ₄Drying concentrates under filtration and the vacuum, obtains yellow oil.Through using MPLC (SiO ₂The 10-40%EtOAc/ hexane) behind the purifying, isolates crystalline solid-like title compound (trans diastereomer) (1.8g). ¹H NMRδ7.34(m，5H)，6.99(d，1H)，5.04(s，2H)，4.28(dd，1H)，3.83(m，1H)，3.37(m，1H)，2.86(m，1H)，1.77(m，2H)，1.46(m，1H)，1.36(s，9H)，1.33(m，1H)，1.11(d，3H)。LCMS(ES，M+H＝349)。The also cis diastereomer of separation and purification, cis-uncle 3-[(-butoxy carbonyl) amino]-pipecoline-1-benzyl carboxylate (1.3g). ¹H NMRδ7.35(m，5H)，6.97(d，1H)，5.07(s，2H)，4.44(m，1H)，3.80(m，1H)，3.40(m，1H)，2.78(m，1H)，1.63(m，1H)，1.49(m，2H)，1.39(s，9H)，1.36(m，1H)，0.96(d，3H)。LCMS(ES，M+H＝349)。

Trans-3-amino-2-methyl piperidines-1-benzyl carboxylateTrans-uncle 3-[(-butoxy carbonyl in being dissolved in MeOH (10mL)) amino]-pipecoline-1-benzyl carboxylate (1.8g, (4 N are in dioxane 5.2mmol) to add HCl in the solution; 20mL).After rt stirs 1h down, reactant is concentrated under vacuum, be dissolved in again among the MeOH, concentrate the hydrochloride (1.46g, 1 00%) that obtains clarifying crystalline solid-like title compound then under the vacuum. ¹H NMRδ8.27(br s，3H)，7.39(m，3H)，7.35(m，1H)，7.32(m，1H)，5.09(s，2H)，4.36(dd，1H)，3.88(m，1H)，3.26(m，1H)，2.92(m，1H)，1.79(m，3H)，1.48(m，1H)，1.16(d，3H)。LCMS(ES，M+H＝249)。

Embodiment 70

4-{[cis-pipecoline-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use cis-3-amino-2-methyl piperidines-1-benzyl carboxylate (following description) to prepare as the starting raw material in the step 7. ¹H NMRδ9.79(m，1H)，8.95(m，2H)，8.51(s，1H)，8.15(m，1H)，7.78(d，2H)，7.49(m，3H)，7.38(m，1H)，4.73(m，1H)，3.71(m，1H)，3.28(m，1H)，3.00(m，1H)，1.95(m，2H)，1.82(m，1H)，1.69(m，1H)，1.30(d，3H)。LCMS(ES，M+H＝367)。

Cis-3-amino-2-methyl piperidines-1-carboxylic acid benzyl esterTo the cis-uncle 3-[(-butoxy carbonyl that is dissolved in MeOH (10mL)) amino]-pipecoline-1-benzyl carboxylate (1.2g, (4N is in dioxane to add HCl in solution 3.4mmol); 20mL).After rt stirs 1h down, reactant is concentrated under vacuum, be dissolved in again among the MeOH, concentrate under the vacuum then and obtain the hydrochloride (0.97g, 100%) of clarification crystalline solid-like title compound. ¹H NMRδ8.39(br s，3H)，7.36(m，3H)，7.33(m，2H)，5.09(s，2H)，4.61(dd，1H)，3.83(m，1H)，3.26(m，1H)，2.86(m，1H)，1.72(m，3H)，1.41(m，1H)，1.10(d，3H)。LCMS(ES，M+H＝249)。

Prepare following examples 71-74 in a similar fashion.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	71	2-(3-fluorophenyl)-4-{[is trans-pipecoline-3-yl] and amino } thieno-[3,2-c] pyridine-7-methane amide	384.48	385	9.50 (s, 1H), 9.11 (s, 1H), 8.71 (s, 1H), 8.55 (s, 1H), 8.30 (s, 1H), 7.60 (m, 5H), 7.27 (t, 1H), 4.42 (s, 1H), 3.31 (m, 2H), 2.94 (m, 1H), 2.11 (m, 1H), 1.91 (m, 2H), 1.68 (m, 1H), 1.33 (d, 3H).
72	4-{[is trans-pipecoline-3-yl] and amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	9.45 (s, 1H), 9.03 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8 30 (s, 1H), 7.91 (s, 1H), 7.74 (d, 1H), 7.60 (s, 1H), 7.50 (d, 2H), 4.40 (s, 1H), 3 31 (m, 2H), 2.92 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.66 (m, 1H), 1.32 (d, 3H).	71		384.48	385
72		372.52	373		73	2-(4-fluorophenyl)-4-{[is trans-pipecoline-3-yl] and amino } thieno-[3,2-c] pyridine-7-methane amide	384.48	385	9.55 (s, 1H), 9.15 (s, 1H), 8.71 (s, 1H), 8.52 (s, 1H), 8 41 (s, 1H), 7.82 (t, 2H), 7.67 (s, 1H), 7.38 (t, 2H), 4.37 (s, 1H), 3.31 (d, 2H), 2.94 (m, 1H), 2.14 (m, 1H), 1.91 (m, 2H), 1.66 (m, 1H), 1.34 (d, 3H).
74	2-(2-fluorophenyl)-4-{[is trans-pipecoline-3-yl] and amino } thieno-[3,2-c] pyridine-7-methane amide	384.48	385	9.75 (d, 1H), 9.22 (d, 1H), 8.87 (s, 1H), 8.55 (s, 1H), 8.45 (m, 1H), 7.91 (t, 2H), 7.67 (s, 1H), 7.43 (m, 3H), 4.39 (d, 1H), 3.26 (d, 2H), 2.89 (m, 1H), 2.18 (d, 1H), 1.92 (s, 2H), 1.66 (m, 1H), 1.36 (d, 3H).	73		384.48	385

Separate embodiment 69 by the chirality preparation HPLC, preparation following examples 75-76.

Embodiment

The IUPAC title

MW(g/mol)

MS(ES，M+H)

¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	75	4-{[(2S, 3R)-pipecoline-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	9.47 (m, 1H), 9.04 (m, 1H), 8.59 (m, 1H), 8.45 (s, 1H), 8.25 (m, 1H), 7.71 (d, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.35 (m, 1H), 4.34 (m, 1H), 3.42 (m, 1H), 3.22 (m, 1H), 2.82 (m, 1H), 2.07 (m, 1H), 1.83 (m, 2H), 1.59 (m, 1H), 1.26 (d, 3H).
76	4-{[(2R, 3S)-pipecoline-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	9.47 (m, 1H), 9.04 (m, 1H), 8.59 (m, 1H), 8.45 (s, 1H), 8.25 (m, 1H), 7.71 (d, 2H), 7.56 (m, 1H), 7.45 (m, 2H), 7.35 (m, 1H), 4.34 (m, 1H), 3.42 (m, 1H), 3.22 (m, 1H), 2.82 (m, 1H), 2.07 (m, 1H), 1.83 (m, 2H), 1.59 (m, 1H), 1.26 (d, 3H).	75		366.49	367

Separate embodiment 72 by the chirality preparation HPLC, preparation following examples 77-78.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300 MHz; d ₆-DMSO; δ ppm), unless refer else	77	4-{[(2S, 3R)-pipecoline-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	9.45 (s, 1H), 9.03 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.74 (d, 1H), 7.60 (s, 1H), 7.50 (d, 2H), 4.40 (s, 1H), 3.31 (m, 2H), 2.92 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.66 (m, 1H), 1.32 (d, 3H).
78	4-{[(2R, 3 S)-pipecoline-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	9.45 (s, 1H), 9.03 (s, 1H), 8.51 (s, 1H), 8.36 (s, 1H), 8.30 (s, 1H), 7.91 (s, 1H), 7.74 (d, 1H), 7.60 (s, 1H), 7.50 (d, 2H), 4.40 (s, 1H), 3.31 (m, 2H), 2.92 (m, 1H), 2.09 (m, 1H), 1.90 (m, 2H), 1.66 (m, 1H), 1.32 (d, 3H).	77		372.52	373

Embodiment 79

4-{ methyl [trans-pipecoline-the 3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use trans-2-methyl-3-(methylamino) piperidines-1-benzyl carboxylate (synthetic as described below) to prepare as the starting raw material in the step 7. ¹H NMR δ9.57(m，1H)，8.92(m，1H)，8.61(s，1H)，8.14(br s，1H)，7.97(s，1H)，7.87(d，2H)，7.50(m，3H)，7.40(m，1H)，4.82(m，1H)，3.55(m，1H)，3.29(s，3H)，3.23(m，1H)，2.94(m，1H)，1.97(m，4H)，1.21(d，3H)。LCMS(ES，M+H＝381)。

Trans-uncle 3-[(-butoxy carbonyl) (methyl) amino]-pipecoline-1-benzyl carboxylateIn N ₂Under the atmosphere, to trans-uncle 3-[(-butoxy carbonyl) amino]-pipecoline-1-benzyl carboxylate (0.10g, (60% in vegetables oil 0.29mmol) to add sodium hydride in the solution of the anhydrous THF of 10mL; 8mg, 0.32mmol).Stirred this solution 30 minutes, add then methyl iodide (0.017mL, 0.287mmol).Reaction stirred mixture 2 hours, the MeOH that slowly adds 10mL reacts with quencher.With content CIV, resistates is dissolved in 30mL CH ₂Cl ₂In, water (2x) washing.The CIV organic layer obtains the 0.16g title product. ¹H NMRδ1.14(d，3H)1.38(s，9H)1.54(m，1H)1.68(m，3H)2.73(s，3H)3.06(m，1H)3.74(m，1H)3.84(m，1H)4.04(m，1H)5.07(s，2H)7.34(m，5H)。LCMS(ES，M+H＝363)。

Benzyl is trans-2-methyl-3-(methylamino) piperidines-1-carboxylicestersTo the trans-uncle 3-[(-butoxy carbonyl that is dissolved in MeOH (4mL)) (methyl) amino]-(4N is in dioxane to add HCl in pipecoline-1-benzyl carboxylate (0.16g0.45mmol) solution; 4mL).After rt stirs 2h down, with concentrating under the reactant vacuum, be dissolved in MeOH again, concentrate the hydrochloride (0.12g) that obtains oiliness crystalline solid-like title compound then under the vacuum.LCMS(ES，M+H＝263)。

Embodiment 80

4-{[is trans-2-(2-hydroxyethyl) piperidines-3-yl] and amino }-2-phenyl thieno-[3,2-c] pyridine-7-

Methane amide

In mode similar to Example 1, but use trans-3-amino-2-(2-hydroxyethyl) piperidines-1-benzyl carboxylate (synthetic as described below) to prepare as the starting raw material in the step 7. ¹HNMRδ9.57(m，1H)，8.92(m，1H)，8.61(s，1H)，8.14(br s，1H)，7.97(s，1H)，7.87(d，2H)，7.50(m，3H)，7.40(m，1H)，4.82(m，1H)，3.55(m，1H)，3.29(s，3H)，3.23(m，1H)，2.94(m，1H)，1.97(m，4H)，1.21(d，3H)。LCMS(ES，M+H＝381)。

Trans-uncle 3-[(-butoxy carbonyl) amino]-2-(2-oxyethyl group-2-oxoethyl) piperidines-1-benzyl carboxylate EsterAt exsiccant and N ₂Under the condition that purifies, will uncle 3-[(-butoxy carbonyl) and amino] piperidines-2-yl } ethyl acetate (prepare according to the method for in following document, describing: Tetrahedron Lett, 1993,34,3593-3594) (0.45g 1.6mmol) is dissolved in 10mL CH ₂Cl ₂In.Add 0.28mL (1.6mmol) DIEA, add 0.22mL (1.59mmol) benzyl chloroformate then.Stir this solution 30min.Water and salt solution abstraction reaction mixture successively then.Concentrate organic layer and resistates through MPLC; 0-50%EtOAc/ hexane purifying.The wash-out title compound (43-48%, 0.41g).LCMS(ES，M+H＝421)。

Trans-3-amino-2-(2-hydroxyethyl) piperidines-1-benzyl carboxylateAt the exsiccant and the N that use dry solvent ₂Under the condition that purifies, with trans-uncle 3-[(-butoxy carbonyl) amino]-2-(2-oxyethyl group-2-oxoethyl) piperidines-1-benzyl carboxylate (0.41g) is dissolved among 9mL THF and the 1mLMeOH.In this reactant, add 0.073g NaBH ₄And stirring 16hr.Add NaBH ₄After observe gas and take place.Reaction is with the dilution of 25mL water and use CH ₂Cl ₂Extract.Concentrate organic extraction and resistates is dissolved in the dioxane solution of 4mL 4 N HCl.Stir this solution 16hr, after high vacuum goes down to desolventize, obtain title compound, 0.20g.LCMS(ES，M+H＝279)。

Embodiment 81

4-{[(3S)-and 5-benzyl piepridine-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use benzyl (3S)-5-benzyl piepridine-3-amine (synthetic as described below) as the preparation of the starting raw material in step 7. ¹H NMRδ8.64(s，1H)，8.19(m，1H)，8.04(m，2H)，7.59(m，2H)，7.56(m，2H)，7.43(m，3H)，7.30(m，3H)，7.22(m，2H)，3.99(m，2H)，3.72(m，3H)，3.37(d，1H)，2.91(m，1H)，2.70(m，1H)，1.99(m，1H)，1.69(m，1H)。LCMS(ES，M+H＝443)。

4-benzyl-N-(uncle-butoxy carbonyl)-L-L-glutamic acid dimethyl estersIn-78 ℃, (6.55g is 23.8mmol) in the solution of 30mLTHF dropwise to add N-(uncle-butoxy carbonyl)-L-L-glutamic acid dimethyl esters in hexamethyl dimethyl silanyl Lithium Azide (1M is in THF for 50.0mL, 50.0mmol) solution.The solution that stirring obtains 30 minutes, add subsequently bromotoluene (5.65mL, 47.6mmol).In-78 ℃ of reaction stirred mixtures 1 hour, LCMS indication after this was converted into product fully then.Water (50mL) quencher reaction mixture, (3 * 100mL) extract with EtOAc.Organic layer obtains white solid sample title compound (5.68 grams, 65% yield) through dried over mgso, filtration and under reduced pressure concentrated behind rapid column chromatography (100% hexane is to 100%EtOAc) purifying.LCMS(ES，M+Na＝388)。

[(1S)-and 3-benzyl-4-hydroxyl-1-(hydroxymethyl) butyl] t-butyl carbamateIn 0 ℃, to contain 4-benzyl-N-(uncle-butoxy carbonyl)-L-glutamic acid dimethyl ester (5.68g, 15.5mmol) and calcium chloride (6.88g, 62.0mmol) in the EtOH of each 60mL and THF solution, add in batches NaBH4 (4.69g, 124mmol).Reaction mixture is warmed to rt and stirs and be converted into product fully until the LCMS indication in 12 hours.Use then saturated sodium bicarbonate (2 * 100mL) and water (2 * 100mL) quencher reaction mixtures, (3 * 100mL) extract to use EtOAc subsequently.The organic layer that merges obtains being directly used in the title compound of next reaction through dried over mgso, filtration and under reduced pressure concentrated.LCMS (ES, M+H-BOC group=210).

(2S)-and 4-benzyl-uncle 2-[(-butoxy carbonyl) amino]-the 5-[(methyl sulphonyl) the oxygen base] amyl group methane SulfonateWill [(1S)-and 3-benzyl-4-hydroxyl-1-(hydroxymethyl) butyl] (4.42g is 14.3mmol) in 100mL CH for t-butyl carbamate ₂Cl ₂Solution be cooled to 0 ℃, add thereafter TEA (7.97mL, 57.2mmol), add subsequently methane sulfonyl chloride (3.32mL, 42.9mmol).In 0 ℃ of reaction stirred mixture 1 hour, use CH ₂Cl ₂Dilution with the washing of saturated sodium bicarbonate sodium, through dried over mgso, concentrates under filtration and the vacuum, obtains being directly used in the title compound of next reaction.LCMS(ES，M+Na＝488)。

[(3S)-1,5-dibenzyl piperidines-3-yl] t-butyl carbamateTo (2S)-4-benzyl-uncle 2-[(-butoxy carbonyl) amino]-the 5-[(methyl sulphonyl) the oxygen base] add the benzyl amine of 30mL in the solution of amyl group methane sulfonate (14.3mmol).With reaction mixture be heated to 70 ℃ about 24 hours, this mixture is cooled among rt and the impouring 1N NaOH (100mL) thereafter.(4 * 100mL) extract mixture, and organic layer filters and CIV through dried over mgso with hexane.The oil that obtains obtains title compound through rapid column chromatography (100% hexane is to 100%EtOAc) purifying.LCMS (ES, M+H-BOC group=281).

[(3S)-and 5-benzyl piepridine-3-yl] t-butyl carbamateUnder nitrogen atmosphere, (3.28g 8.62mmol) adds 10%Pd/C (900mg) in the solution of 15mL EtOH to [(3S)-1,5-dibenzyl piperidines-3-yl] t-butyl carbamate.On Pa Er (Parr) device, use 50psi hydrogen treat reaction mixture 24 hours.Reaction mixture with a large amount of MeOH rinsings, concentrating under reduced pressure filtrate, obtains being directly used in the title compound of next reaction through diatomite filtration.LCMS(ES，M+H＝291)。

(3S)-5-benzyl piepridine-3-amine(1.59g adds the dioxane (5.0mL) of 4N HCl in solution 5.46mmol) to containing [(3S)-5-benzyl piepridine-3-yl] t-butyl carbamate of being dissolved in minimum MeOH.The solution that obtains was stirred 30 minutes down in rt.Concentrated reaction mixture under the decompression obtains title compound then.LCMS(ES，M+H＝191)。

To adopt suitable starting raw material to prepare embodiment 82 with embodiment 81 similar modes.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	82	4-{[(3S)-and 5-benzyl piepridine-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	448.61	449	8.63(s，1H)，8.17(m，1H)，8.03(m，3H)，7.84(s，1H)，7.73(m，1H)，7.60(m，1H)，7.37(m，2H)，7.27(m，2H)，7.20(m，2H)，3.99(m，2H)，3.83(m，2H)，3.38(m，2H)，2.94(m，1H)，2.72(m，1H)，1.95(m，1H)，1.68(m，1H)

Embodiment 83

4-[(2,6-lupetidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

Lupetidine-3-amineUnder nitrogen atmosphere, to containing 2,6-lutidine-3-amine (2.08g adds entry and 12N HCl (each 10mL) in high pressure vessel 17.0mmol), add subsequently platinum oxide (IV) (500mg, 2.20mmol).Down high pressure vessel is found time and mixture was placed 50psi Pa Er hydrogenator 48 hours in decompression then.Under nitrogen atmosphere, mixture is found time, on Celite pad, filter and with a large amount of MeOH rinsings.The filtrate of collecting is concentrated under vacuum, obtain being directly used in the title compound as isomer mixture of next reaction.LCMS(ES，M+H＝129)。

2-bromo-4-[(2,6-lupetidine-3-yl) amino] thieno-[3,2-c] pyridine-7-nitrileTo the lupetidine that is dissolved in NMP (10mL)-3-amine (1.23g, add in 4.50mmol) salt of wormwood (1.87g, 13.5mmol) and 2-bromo-4-chloro thiophene also [3,2-c] pyridine-7-nitrile (1.23g, 4.50mmol).With the mixture heating up to 80 that obtains ℃ and stirred 12 hours or be converted into product fully until the LCMS indication.Water (100mL) diluted mixture thing then, the solid that obtains after filtration, water (20mL) washing and decompression dry maximum 8 hours down.LCMS(ES，M+H＝366)。

4-[(2,6-lupetidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-nitrileTo containing 2-bromo-4-[(2,6-lupetidine-3-yl) amino] and thieno-[3,2-c] pyridine-7-nitrile (400mg, 1.09mmol), phenyl-boron dihydroxide (200mg, 1.64mmol), (1.06g 3.27mmol) and in the solution of dioxane/water (2mL/1mL) adds Pd (PPh to cesium carbonate ₃) ₄(126mg, 0.109mmol).Reactant was heated to 80 ℃ of meters 1 hour, makes reaction be cooled to rt subsequently, filter, with silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound.LCMS(ES，M+H＝363)。

4-[(2,6-lupetidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amideTo containing 4-[(2,6-lupetidine-3-yl) amino]-add the 12N HCl of 5.00mL in the flask of 2-phenyl thieno-[3,2-c] pyridine-7-nitrile.Reaction stirred mixture and monitor under rt by LCMS.Added the required product that extra 12N HCl is transformed fully in per 12 hours.To be transformed when complete, concentrate down with MeOH diluted reaction mixture and decompression and to obtain product, it is through preparation HPLC (5%-95%H ₂O/MeCN/0.1%TFA) purifying obtains the title compound as isomer mixture.The analytical data of the main isomer that is present in mixture is provided: ¹H NMR δ 9.96 (m, 1H), 9.19 (m, 1H), 9.02 (m, 1H), 8.50 (s, 1H), 8.21 (m, 1H), 7.79 (m, 2H), 7.49 (m, 2H), 7.35 (m, 2H), 4.74 (m, 1H), 3.67 (m, 1H), 3.27 (m, 1H), 1.84 (m, 4H), 1.36 (m, 6H).LCMS(ES，M+H＝381)。

Adopt suitable starting raw material to prepare following examples 84-94 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	84	4-[(2,6-lupetidine-3-yl) amino-2-(4-fluorophenyl) thieno-[3,2-c] pyridine-7-methane amide	398.5	399	9.93(m，1H)，9.15(m，1H)，9.04(m，1H)，8.51(s，1H)，8.21(m，1H)，7.85(m，2H)，7.57(m，1H)，7.34(m，1H)，7.15(m，1H)，4.72(m，1H)，3.67(m，1H)，3.26(m，1H)，1.83(m，4H)，1.34(m，6H)
85	4-[(2,6-lupetidine-3-yl) amino]-2-(3-fluorophenyl) thieno-[3,2-c] pyridine-7-methane amide	398.5	399	9.87(m，1H)，9.21(m，1H)，8.96(m，1H)，8.53(s，1H)，8.16(m，1H)，7.56(m，3H)，7.22(m，2H)，4.76(m，1H)，3.65(m，1H)，3.25(m，1H)，1.78(m，4H)，1.31(m，6H)	84		398.5	399
85		398.5	399		86	4-[(2,6-lupetidine-3-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	386.54	387	9.90(m，1H)，9.01(m，2H)，8.48(s，1H)，8.19(m，1H)，7.87(s，1H)，7.72(m，1H)，7.54(m，2H)，4.71(m，1H)，3.67(m，1H)，3.26(m，1H)，1.84(m，4H)，1.36(m，6H)
87	2-phenyl-4-{[6-(trifluoromethyl) piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide	420.46	421	8.83(m，1H)，8.54(m，1H)，8.25(m，1H)，7.76(m，2H)，7.51(m，3H)，7.40(m，1H)，4.65(m，1H)，4.44(m，1H)，3.68(m，1H)，3.53(m，1H)，2.14(m，2H)，2.02(m，2H)	86		386.54	387
87		420.46	421		88	4-[(4-methyl piperidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	8.67(s，1H)，8.24(s，1H)，8.06(m，2H)，7.88(m，3H)，7.62(m，1H)，7.51(m，2H)，7.42(m，1H)，4.12(m，1H)，3.98(m，1H)，3.52(m，1H)，3.41(m，1H)，3.18(m，1H)，2.10(m，1H)，1.92(m，2H)，1.06(d，3H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	89	4-[(4-methyl piperidine-3-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	8.65(s，1H)，8.17(m，1H)，8.01(m，3H)，7.72(m，2H)，7.67(m，1H)，7.56(m，1H)，4.08(m，1H)，3.94(m，1H)，3.53(m，1H)，3.38(m，1H)，3.17(m，1H)，2.09(m，1H)，1.89(m，1H)，1.72(m，1H)，1.06(d，3H)
90	2-(3-fluorophenyl)-4-[(4-methyl piperidine-3-yl) amino] thieno-[3,2-c] pyridine-7-methane amide	384.48	385	8.68(s，1H)，8.17(m，1H)，8.01(m，2H)，7.91(s，1H)，7.77(d，1H)，7.66(m，1H)，7.56(m，2H)，7.26(m，1H)，3.97(m，2H)，3.53(m，1H)，3.40(m，1H)，3.19(m，1H)，2.10(m，1H)，1.93(m，1H)，1.74(m，1H)，1.06(d，3H)	89		372.52	373
90		384.48	385		91	2-(3-fluorophenyl)-4-[(6-methyl piperidine-3-yl) amino] thieno-[3,2-c] pyridine-7-methane amide	384.48	385	9.38(m，1H)，9.08(m，1H)，8.88(m，1H)，8.55(s，1H)，8.15(m，1H)，7.56(m，4H)，7.24(m，1H)，4.60(m，1H)，3.49(m，1H)，3.32(m，2H)，1.87(m，4H)，1.33(d，3H)
92	2-(4-fluorophenyl)-4-[(6-methyl piperidine-3-yl) amino] thieno-[3,2-c] pyridine-7-methane amide	384.48	385	9.59(m，1H)，9.16(m，1H)，8.89(m，1H)，8.52(s，1H)，8.18(m，1H)，7.81(m，2H)，7.57(m，1H)，7.35(m，2H)，4.62(m，1H)，3.46(m，1H)，3.28(m，2H)，1.86(m，4H)，1.33(d，3H)	91		384.48	385
92		384.48	385		93	4-[(6-methyl piperidine-3-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	372.52	373	8.97(m，1H)，8.52(m，1H)，8.00(m，1H)，7.84(m，1H)，7.73(m，1H)，7.49(m，2H)，4.56(m，1H)，4.10(br s，2H)，3.47(m，1H)，3.29(m，2H)，1.89(m，4H)，1.32(d，3H)
94	4-[(6-methyl piperidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	366.49	367	9.84(m，1H)，9.41(m，1H)，9.18(m，1H)，8.53(s，1H)，8.40(m，1H)，7.72(m，3H)，7.51(m，3H)，4.72(m，1H)，3.21(m，3H)，1.89(m，4H)，1.34(m，3H)	93		372.52	373

Embodiment 95

The 2-{3-[(dimethylamino) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

(3S)-and 3-{[7-cyano group-2-(3-formyl radical phenyl)-1-thionaphthene-4-yl] amino } piperidines-1-carboxylic acid tert-butyl ester.With (3S)-3-[(7-cyano group-2-bromo thiophene [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid tert-butyl ester (and 500mg, 1.1mmol), 3-formyl radical phenyl-boron dihydroxide (257mg, 1.7mmol), cesium carbonate (1.12g, 3.4mmol) and Pd (PPh ₃) ₄(198mg, mixture 0.17mmol) is in dioxane (8.2mL) and H ₂Be heated to 80 ℃ among the O (2.7mL).Behind the 30min, make solution be cooled to rt, remove water layer and solution is concentrated under vacuum via pipette.Resistates is through MPLC (SiO ₂The 20-50%EtOAc/ hexane) purifying obtains title compound (185mg, 35%).LCMS(ES，M+H＝463)。

(3S)-and 3-[(7-cyano group-2-{4-[(dimethylamino) methyl] phenyl }-1-thionaphthene-4-yl) amino] Piperidines-1-carboxylic acid tert-butyl esterUnder rt; with (3S)-3-{[7-cyano group-2-(3-formyl radical phenyl)-1-thionaphthene-4-yl] amino } piperidines-1-carboxylic acid tert-butyl ester (50mg; 0.11mmol) and dimethyl amine (the 2 M solution in THF of 0.54mL, 1.1mmol) solution stirs in glycol dimethyl ether (0.54mL).Add acetate (2), add NaBH (OAc) subsequently ₃(92mg, 0.43mmol).This solution is heated to 80 ℃ of meter 30min.Make solution be cooled to rt then.Add entry (2), add 1M NaOH (1mL) subsequently.This product extracts through EtOAc.With salt water washing organic extraction, through MgSO ₄Concentrate under drying and the vacuum, obtain being directly used in next step title compound.LCMS(ES，M+H＝492)。

The 2-{3-[(dimethylamino) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyrrole Pyridine-7-methane amideWith (3S)-3-[(7-cyano group-2-{4-[(dimethylamino) methyl] phenyl }-1-thionaphthene-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester is dissolved among the 12M HCl (4mL) and maintenance is 17h under the rt.This solution concentrated under vacuum and with the MeOH azeotropic, obtain title compound (48mg, 98%) as hydrochloride. ¹H NMRδ10.62(br s，1H)，9.70(brs，1H)，9.07(m，2H)，8.57(s，1H)，8.44(br s，1H)，7.96(s，1H)，7.90(m，1H)，7.60(m，3H)，4.65(m，1H)，4.35(d，2H)，3.47(m，1H)，3.20(m，2H)，3.01(m，1H)，2.74(s，3H)，2.73(s，3H)，2.03(m，2H)，1.81(m，2H)。LCMS(ES，M+H＝410)。

In a similar fashion, from suitable feedstock production following examples 96-111.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	96	The 2-{4-[(dimethylamino) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	409.56	410	10.44(br s，1H)，9.44(br s，1H)，8.95(brs，1H)，8.76(br s，1H)，8.55(s，1H)，8.21(br s，1H)，7.85(d，2H)，7.66(d，2H)，7.52(br s，1H)，4.59(m，1H)，4.30(d，2H)，3.33(m，1H)，3.18(m，1H)，3.10(m，1H)，3.00(m，1H)，2.73(s，3H)，2.72(s，3H)，2.01(m，2H)，1.77(m，2H)
97	4-[(3S)-piperidines-3-base is amino]-2-[4-(piperidines-1-ylmethyl) phenyl] thieno-[3,2-c] pyridine-7-methane amide	449.62	450	10.34(br s，1H)，9.54(br s，1H)，8.99(brs，1H)，8.85(br s，1H)，8.56(s，1H)，8.26(br s，1H)，7.84(d，2H)，7.70(d，2H)，7.56(br s，1H)，4.61(m，1H)，4.28(d，2H)，3.45(m，1H)，3.31(m，2H)，3.16(m，1H)，3.02(m，1H)，2.85(m，2H)，2.01(m，2H)，1.77(m，8H)，1.36(m，1H)	96		409.56	410
97		449.62	450		98	2-[4-(morpholine-4-ylmethyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	451.59	452	11.53(br s，1H)，9.75(br s，1H)，9.11(m，2H)，8.57(s，1H)，8.44(br s，1H)，7.86(d，2H)，7.76(d，2H)，7.65(br s，1H)，4.66(m，1H)，4.36(m，2H)，3.96-2.95(m，12H)，2.02(m，2H)，1.81(m，2H)
99	4-[(3S)-piperidines-3-base is amino]-2-[3-(piperidines-1-ylmethyl) phenyl] thieno-[3,2-c] pyridine-7-methane amide	449.62	450	9.94(br s，1H)，9.28(br s，1H)，8.91(brs，1H)，8.56(m，2H)，8.16(br s，1H)，7.92(s，1H)，7.87(m，1H)，7.58(m，3H)，4.55(m，1H)，4.34(m，2H)，3.50-2.60(m，8H)，2.00(m，2H)，1.80-1.50(m，8H)	98		451.59	452
99		449.62	450		100	2-[3-(morpholine-4-ylmethyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyrrole	451.59	452	10.40(br s，1H)，9 05(br s，1H)，8.83(brs，1H)，8.57(s，1H)，8.41(br s，1H)，8.06(br s，1H)，7.92(s，1H)，7.87(m，1H)，

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else		Pyridine-7-methane amide			7.65-7.50(m，3H)，4.55(m，1H)，4.41(m，2H)，3.97(m，2H)，3.75-2.90(m，10H)，2.00(m，2H)，1.75(m，2H)
101	2-(3-{[4-(2-methoxyl group-ethyl) piperazine-1-yl] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2c] pyridine-7-methane amide	508.69	509	9.21(br s，1H)，8.86(br s，1H)，8.56(s，1H)，8.48(br s，1H)，8.20-7.70(m，4H)，7.65-7.30(m，3H)，4.56(m，2H)，3.75-2.88(m，17H)，3.28(s，3H)，2.00(m，2H)，1.75(m，2H)		Pyridine-7-methane amide
101		508.69	509		102	The 2-{3-[(methylamino) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.53	396	9.52(br s，1H)，9.15(m，2H)，9.01(br s，1H)，8.75(br s，1H)，8.57(s，1H)，8.26(br s，1H)，7.91(s，1H)，7.86(m，1H)，7.56(m，3H)，4.61(m，1H)，4.18(m，2H)，3.46(m，1H)，3.23-2.93(m，3H)，2.58(t，3H)，2.02(m，2H)，1.78(m，2H)
103	2-(4-{[4-(2-methoxy ethyl) piperazine-1-yl] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	508.69	509	12.75-11.20(m，1H)，9.75(br s，1H)，9.43(br s，1H)，9.11(m，2H)，8.57(s，1H)，8.44(br s，1H)，7.86(d，2H)，7.77(d，2H)，7.66(br s，1H)，4.66(m，1H)，4.41(m，2H)，3.80-2.93(m，16H)，3.27(s，3H)，2.02(m，2H)，1.82(m，2H)	102		395.53	396
103		508.69	509		104	The 2-{4-[(methylamino) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.53	396	9.25(br s，1H)，9.01(m，2H)，8.89(m，1H)，8.56(s，1H)，8.54(br s，1H)，8.09(br s，1H)，7 81(d，2H)，7.61(d，2H)，7.43(br s，1H)，4.57(m，1H)，4.15(m，2H)，3.18(m，2H)，2.98(m，2H)，2.57(t，1H)，2.00(m，2H)，1.74(m，2H)
105	2-[4-(piperazine-1-ylmethyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	450.61	451	8.91(br，2H)，8.55(s，1H)，8.45-7.10(m，8H)，4.57(m，1H)，3.57(m，2H)，3.44-2.56(m，12H)，1.99(m，2H)，1.74(m，2H)	104		395.53	396

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	106	2-(4-{[ethanoyl (methyl) amino] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	437.57	438	9.67(br s，1H)，9.41(br s，1H)，9.00(brs，1H)，8.92(br s，1H)，8.52(s，1H)，8.47(br s，1H)，7.82-7.63(m，3H)，7.35(d，2H)，4.69-4.48(m，3H)，3.47(m，1H)，3.26(m，1H)，3.17(m，1H)，3.02(m，1H)，2.97-2.77(m，3H)，2.10-1.93(m，5H)，1.81(m，2H)
107	2-{3-[(4-ethanoyl piperazine-1-yl) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	492.65	493	10.98(br s，1H)，9.46(br s，1H)，8.97(brs，1H)，8.76(br s，1H)，8.56(s，1H)，8.27(br s，1H)，7.94(s，1H)，7.89(m，1H)，7.61(m，3H)，4.59(m，1H)，4.41(m，2H)，4.10-2.80(m，12H)，2.10-1.95(m，5H)，1.78(m，2H)	106		437.57	438
107		492.65	493		108	2-(3-{[ethanoyl (methyl) amino] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	437.57	438	9.38(br s，1H)，8.90(m，2H)，8.60(br s，1H)，8.54(m，1H)，8.26(m，1H)，7.73-7.43(m，4H)，7.24(m，1H)，4.64(m，1H)，4.56(m，2H)，3.46(m，1H)，3.23-2.80(m，6H)，2.12-1.93(m，5H)，1.77(m，2H)
109	2-(3-{[methyl (methyl sulphonyl) amino] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	473.62	474	9.34(br s，1H)，8.94(br s，1H)，8.55(m，2H)，8.22(br s，1H)，7.71(m，2H)，7.52(m，2H)，7.37(m，1H)，4.56(m，1H)，4.31(m，2H)，3.46(m，1H)，3.19(m，1H)，3.13-2.90(m，5H)，2.71-2.53(m，3H)，2.01(m，2H)，1.77(m，2H)	108		437.57	438
109		473.62	474		110	2-{4-[(4-ethanoyl piperazine-1-yl) methyl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	492.65	493	11.37(br s，1H)，9.63(br s，1H)，9.02(m，1H)，8.56(s，1H)，8.39(br s，1H)，7.86(d，2H)，7.72(d，2H)，7.64(br s，1H)，4.63(m，1H)，4.40(m，2H)，4.03-2.86(m，12H)，2.09-1.95(m，2H)，2.02(s，3H)，1.81(m，2H)

Embodiment	The IUPAC title	MW(g/mol)	MS (ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS (ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	111	2-(4-{[methyl (methyl sulphonyl) amino] methyl } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	473.62	474	9.50(br，1H)，8.98(br，1H)，8.71(br，1H)，8.54(s，1H)，8.28(br，1H)，7.79(d，2H)，7.59(br s，1H)，7.46(d，2H)，4.59(br，1H)，4.28(s，2H)，3.48(m，1H)，3.16(m，2H)，2.98(m，1H)，2.97(s，3H)，2.69(s，3H)，2.10-1.93(m，2H)，1.85-1.71(m，2H)

Embodiment 112

2-(4-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl)-4-[(3S)-piperidines-3-base is amino] Thieno-[3,2-c] pyridine-7-methane amide

1-methyl-N-[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl]-the 1H-indoles- The 2-methane amideIn 0 ℃, (364mg is 2.08mmol) in CH to 1-Methyl-1H-indole-2-carboxylic acid ₂Cl ₂Dropwise add in the solution (5.00mL) oxalyl chloride (0.536mL, 6.24mmol).Spend the night in refluxing to stir down to these two DMF of solution adding with the solution that obtains, subsequently dark solution is concentrated under vacuum then.CH with 5mL ₂Cl ₂The resistates that obtains of dilution and dropwise be added to [4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl] in 0 ℃ (0.50g is 2.28mmol) in the CH of 5mL for amine ₂Cl ₂And N, (DIPEA, 0.56mL is in solution 3.12mmol) for the N-diisopropyl ethyl amine.The mixture that obtains stirred 3 hours down in rt.Water (100mL) extracts the mixture obtain and washs with saturated sodium-chloride then.Organic layer is through MgSO ₄Drying is filtered and decompression concentrates down, obtains title compound (0.417mg, 53% yield) behind column chromatography (0-100%EtOAc/ hexane). ¹H NMRδ10.45(s，1H)，7.82(m，2H)，7.67(m，2H)，7.58(d，1H)，7.56(m，2H)，7.36(m，2H)，4.01(s，3H)，1.29(s，12H)。LCMS(ES，M+H＝377)。

(3S)-and 3-{[7-cyano group-2-(4-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl) thieno- [3,2-c] pyridin-4-yl] amino } piperidines-1-carboxylic acid tert-butyl esterTo (3S)-3-[(2-bromo-7-cyano thiophene also [3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester (203mg, 0.464mmol) the middle cesium carbonate (452mg that adds, 1.39mmol), 1-methyl-N-[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl]-1H-indoles-2-methane amide (262mg, 0.696mmol), Pd (PPh ₃) ₄(53.6mg, 0.0464mmol) and dioxane/water (2mL/1mL).Reaction was heated to 80 ℃ of meters 1 hour, makes reactant be cooled to rt subsequently, filter and, obtain title compound (156mg, 56% yield) through silica gel column chromatography (0-100%EtOAc/ hexane) purifying.LCMS(ES，M+H＝607)。

2-(4-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl)-4-[(3S)-piperidines-3-base is amino] Thieno-[3,2-c] pyridine-7-methane amideTo containing (3S)-3-{[7-cyano group-2-(4-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl) thieno-[3,2-c] pyridin-4-yl] amino } add the 12 N HCl of 5.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.Reaction mixture is stirred down and monitors with LCMS in rt.Again to add the required product that 12N HCl is transformed fully in per 12 hours.To be transformed when complete, reaction mixture dilute with water and decompression concentrate down, obtain product, through silica gel column chromatography (CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹H NMRδ10.45(s，1H)，8.50(s，1H)，8.14(s，1H)，7.94(m，2H)，7.73(m，3H)，7.59(d，1H)，7.35(m，2H)，7.15(m，2H)，4.19(m，1H)，4.03(s，3H)，3.14(m，2H)，2.87(m，2H)，1.98(m，1H)，1.74(m，1H)，1.53(m，2H)。LCMS(ES，M+H＝525)。

Prepare following examples 113-115 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	113	2-(3-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	524.65	525	10.44(s，1H)，8.53(s，1H)，8.32(s，1H)，8.20(s，1H)，7.73(m，3H)，7.59(d，2H)，7.49(s，1H)，7.39(s，1H)，7.32(m，2H)，7.15(m，1H)，4.22(m，1H)，4.05(s，3H)，3.19(m，2H)，2.90(m，2H)，1.99(m，1H)，1.71(m，1H)，1.54(m，2H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	114	2-(4-fluoro-3-{[(1-Methyl-1H-indole-3-yl) carbonyl] amino } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	542.64	543	10.27(s，1H)，9.23(br s，1H)，8.90(br s，1H)，8.56(s，1H)，8.40(m，1H)，8.10(m，1H)，7.72(d，1H)，7.62(m，1H)，7.46(m，2H)，7.34(m，2H)，7.16(m，2H)，6.99(m，1H)，4.55(m，1H)，4.04(s，3H)，3.48(m，1H)，3.19(m，1H)，2.95(m，2H)，2.01(m，2H)，1.74(m，2H)
115	2-(3-fluoro-4-{[(1-Methyl-1H-indole-2-yl) carbonyl] amino } phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	542.64	543	10.2(s，1H)，8.81(m，1H)，8.57(m，1H)，8.33(m，1H)，8.04(m，1H)，7.81(t，1H)，7.65(m，6H)，7.34(m，1H)，7.14(m，1H)，6.95(m，1H)，4.53(m，1H)，4.03(s，3H)，3.49(m，2H)，3.24(m，1H)，2.95(m，1H)，2.02(m，2H)，1.69(m，2H)	114		542.64	543

Embodiment 116

2-bromo-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

To solid (3S)-3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) amino] (70mg adds the dense HCl of 4mL in 0.20mmol) and this solution was stirred 2 days down in rt piperidines-1-carboxylic acid tert-butyl ester.Vacuum is removed the title compound (78mg, 100%) that obtains after the drying under solvent and the high vacuum as hydrochloride. ¹H NMRδ1.50(m，2H)，1.67(m，1H)，1.93(m，1H)，2.81(m，2H)，3.11(m，1H)，3.24(m，1H)，4.11(m，1H)，7.20(m，1H)，7.34(m，1H)，7.95(br s，1H)，8.52(s，1H)。LCMS(ES，M+H＝356)。

Embodiment 117

The 2-phenyl-4-[(3S)-piperidines-3-base oxygen base] thieno-[3,2-c] pyridine-7-methane amide (3S)-and 3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) the oxygen base] piperidines-1-carboxylic acid uncle fourth Ester(1.4g 7mmol) slowly adds NaH (0.3g, 7mmol in batches in the solution of THF (10mL) to (the 3S)-3-hydroxy piperidine-1-carboxylic acid tert-butyl ester that stirs; 60% in mineral oil).After 15 minutes, the 2-bromo-4-chloro thiophene that will be suspended in THF (10mL) also [3,2-c] pyridine-7-nitrile (1.4g 5.1mmol) slowly adds in the preformed alkoxide solution.Reaction mixture stirs 1h down in rt, the water of usefulness～80mL dilution then.Be extracted into EtOAc, use saturated NaHCO subsequently ₃, saturated NaCl washing and through Na ₂SO ₄Drying obtains being directly used in next step brown solid product (～2g, 91%). ¹H NMRδ8.66(s，1H)，7.79(s，1H)，5.26(m，1H)，4.13(m，1H)，3.84(m，1H)，2.93(m，1H)，1.94(m，3H)，1.50(m，2H)，0.92(s，9H)。LCMS(ES，M+H＝438，440)。

(3S)-and 3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) the oxygen base] piperidines-1-carboxylic acid uncle fourth EsterWith (3S)-3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) the oxygen base] piperidines-1-carboxylic acid tert-butyl ester (2g.4.5mmol), phenyl-boron dihydroxide (0.83g, 6.8mmol), Pd (PPh3) ₄(0.8g, 0.68mmol) and cesium carbonate (4.4g, mixture 13.6mmol) are dissolved in water (5mL) and the dioxane (20mL).Under nitrogen atmosphere, in 80 ℃ of stirring 1h, make it be cooled to rt then this reaction mixture.Remove water with pipette, remove dioxane under the vacuum.Resistates is through MPLC (SiO ₂The 20-50%EtOAc/ hexane) purifying obtains title compound (1.0g, 45%; 2 steps). ¹H NMRδ8.62(s，1H)7.85(d，2H)7.42-7.54(m，3H)6.74(d，1H)5.29(s，1H)4.15(m，1H)3.83(m，1H)3.35(m，1H)2.97(m，1H)1.98(s，3H)1.52(s，1H)0.90(s，9H)。LCMS(ES，M+H＝436)。

The 2-phenyl-4-[(3S)-piperidines-3-base oxygen base] thieno-[3,2-c] pyridine-7-methane amideWith (3S)-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) the oxygen base] (1.0g, 2.3mmol) (dense, 15mL) solution stirring is 12 hours with 12 N HCl for piperidines-1-carboxylic acid tert-butyl ester.Add entry (100mL), make solution concentration under the vacuum to dry.The white solid that obtains is dissolved in the MeOH of 100mL, concentrates under the vacuum and dry under high vacuum, obtain title compound (0.86g, 96%). ¹H NMRδ9.56(d，1H)9.10(s，1H)8.67(s，1H)8.32(s，1H)8.28(s，1H)7.87(d，2H)7.66(s，1H)7.49(t，2H)7.40(t，1H)，5.64(s，1H)3.41(s，2H)3.17-3.28(m，1H)3.03(d，1H)1.91-2.06(m，3H)1.65-1.79(m，1H)。LCMS(ES，M+H＝354)。

In a similar fashion, prepare embodiment 118-128 from suitable starting raw material.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	118	4-[2-(cyclohexyl amino) oxyethyl group]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	395.52	396	8.79(br s，2H)，8.67(s，1H)，8.30(br s，1H)，8.02(m，1H)，7.82(d，2H)，7.72(m，1H)，7.5 1(m，2H)，7.43(m，1H)，4.75(m，1H)，3.49(m，2H)，3.15(m，1H)，2.08(m，2H)，1.76(m，2H)，1.59(m，1H)，1.26(m，5H)
119	4-[2-(methylamino) oxyethyl group]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	327.41	328	8.48(s，1H)，8.28(m，1H)，8.21(m，1H)，7.85(d，2H)，7.56(m，4H)，7.41(m，1H)，3.93(m，2H)，3.78(m，2H)，3 50(s，3H)	118		395.52	396
119		327.41	328		120	The 2-phenyl-4-[(3S)-tetramethyleneimine-3-base oxygen base] thieno-[3,2-c] pyridine-7-methane amide	339.42	340	8.45(m，1H)，8.22(m，1H)，7.89(m，2H)，7.69(m，1H)，7.46(m，3H)，4.52(m，1H)，4.08(m，2H)，3.63(m，2H)，2.08(m，2H)
121	4-{[(2R)-and the 2-aminopropyl] the oxygen base }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	327.41	328	8.66(s，1H)，8.30(m，2H)，8.18(s，1H)，7.84(m，2H)，7.72(m，1H)，7.48(m，4H)，4.66(m，1H)，4.45(m，1H)，3.76(m，1H)，1.36(d，3H)	120		339.42	340
121		327.41	328		122	4-[2-(sec.-propyl amino) oxyethyl group]-2-phenyl-thieno-[3,2-c] pyridine-7-methane amide	355.46	356	8.89(br s，1H)，8.68(s，1H)，8.30(m，1H)，8.06(m，1H)，7.80(m，3H)，7.46(m，3H)，4.75(m，1H)，3.89(m，2H)，3.46(m，2H)，1.30-1.22(d，6H)
123	4-{[(2S)-and the 2-aminopropyl] the oxygen base }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	327.41	328	8.66(s，1H)，8.23(m，3H)，7.83(d，2H)，7.71(m，1H)，7.49(m，4H)，4.66(m，1H)，4.46(m，1H)，3.75(m，1H)，1.36(d，3H)	122		355.46	356

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	124	4-{[(2S)-and 2-amino-4-methyl amyl] the oxygen base }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	369.49	370	8.67(s，1H)，8.30(m，2H)，8.21(s，1H)，7.84(m，2H)，7.71(m，1H)，7.52(m，2H)，7.43(m，2H)，4.70(m，1H)，4.51(m，1H)，3.48(m，1H)，1.80(m，1H)，1.62(m，2H)，0.94(m，6H)
125	4-(2-amino-3-hydroxyl propoxy-)-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	343.41	344	8.67(s，1H)，8.35(m，3H)，8.18(s，1H)，7.84(m，3H)，7.71(s，1H)，7.48(m，3H)，4.64(m，2H)，3.78(m，2H)，3.08(m，1H)	124		369.49	370
125		343.41	344		126	4-[(3S)-piperidines-3-base oxygen base]-2-pyridin-3-yl thieno-[3,2-c] pyridine-7-methane amide	354.43	355	9.57(m，2H)，9.44(s，1H)，9.02(s，1H)，8.87(d，1H)，8.8 1(d，1H)，8.78(s，1H)，8.41(br s，1H)，8.00(dd，1H)，7.78(br s，1H)，5.67(m，1H)，3.43(s，2H)，3.22(m，1H)，3.05(m，1H)，1.99(m，3H)，1.73(m，1H)
127	4-[(3R)-piperidines-3-base oxygen base]-2-pyridin-3-yl thieno-[3,2-c] pyridine-7-methane amide	354.43	355	9.35(m，1H)，9.27(s，1H)，9.12(m，1H)，8.73(s，1H)，8.72(m，1H)，8.67(s，1H)，8.56(d，1H)，8.36(m，1H)，7.78(m，2H)，5.67(m，1H)，3.43(s，2H)，3.22(m，1H)，3.05(m，1H)，1.99(m，3H)，1.73(m，1H)	126		354.43	355
127		354.43	355		128	4-{[(3S)-and 1-methyl-piperidines-3-yl] the oxygen base }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	367.47	368	8.63(s，1H)，8.20(br s，1H)，7.85(d，2H)，7.70(s，1H)，7.63(s，1H)，7.48(m，2H)，7.40(m，1H)，5.33(m，1H)，3.16(m，2H)，2.95(m，2H)，2.20(s，3H)，2.08(m，2H)，1.83(m，2H)

Embodiment 129

2-phenyl-4-(piperidines-3-base sulfo-) thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 17, but use 3-sulfhydryl piperidine-1-benzyl carboxylate (synthetic as described below) to prepare as the starting raw material in the first step. ¹H NMRδ9.23(br，2H)，8.91(s，1H)，8.45(s，1H)，7.88(d，2H)，7.83(br，1H)，7.82(s，1H)，7.50(t，2H)，7.43(t，1H)，4.41(m，1H)，3.63(m，1H)，3.23(m，1H)，3.09(m，1H)，2.94(m，1H)，2.22-2.13(m，1H)，1.96-1.72(m，3H)。LCMS(ES，M+H＝370)。

3-(ethanoyl sulfo-) piperidines-1-benzyl carboxylateIn 0 ℃, to triphenylphosphine (3.40g, 13.0mmol) and diisopropyl azodiformate (2.65mL, 13.7mmol) THF (10mL) solution in add 3-hydroxy piperidine-1-benzyl carboxylate (2.57g, 10.9mmol), add subsequently thiol-acetic acid (1.00mL, 14.0mmol).Reaction mixture is heated to 70 ℃ of meter 18h.After the cooling, reaction mixture is concentrated under vacuum, (gradient: the 5-20%EtOAc/ hexane) purifying obtains required yellow oil sample product (1.02g, 3.49mmol, 32%) through MPLC. ¹H NMRδ7.41-7.27(m，5H)，5.12-5.01(m，2H)，3.75(m，1H)，3.58-3.13(m，4H)，2.28(br s，3H)，1.91(m，1H)，1.65-1.43(m，3H)。LCMS(ES，M+Na＝316)。

3-sulfhydryl piperidine-1-benzyl carboxylate(541mg adds NaSMe (582mg, MeOH 8.31mmol) (10mL) solution in MeOH 1.85mmol) (20mL) solution to 3-(ethanoyl sulfo-(acetylthio)) piperidines-1-benzyl carboxylate.Mixture is stirred 2h, the completely consumed of lcms analysis indication this moment starting raw material.With reaction mixture in concentrating under the vacuum and resistates being distributed between EtOAc and 0.5M HCl.Concentrate organic layer, obtain yellow oil sample free mercaptan (463mg, 1.85mmol,＞98%). ¹H NMRδ7.41-7.26(m，5H)，5.13-5.00(m，2H)，3.98(m，1H)，3.76(m，1H)，2.90(m，1H)，2.80(m，1H)，2.70(d，1H)，1.99(m，1H)，1.65(m，1H)，1.40(m，2H)。LCMS(ES，M+Na＝274)。

Embodiment 130

4-{[(3S)-and 1-methyl piperidine-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

(3S)-1-methyl piperidine-3-amineIn 0 ℃, to (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (8.89g, dropwise add in THF 44.4mmol) (176mL) solution 1M lithium aluminum hydride THF (88.0mL, 88.8mmol).Make the grey solution that obtains be warmed to rt, under nitrogen atmosphere, stir and spend the night.In 0 ℃, 10% Rochelle salt solution is added in the mixture until stopping foaming.With a large amount of EtOAc, use 1/1 MeOH/CH subsequently ₂Cl ₂The mixture that extraction obtains.The organic layer that merges is through MgSO ₄Drying concentrates under filtration and the vacuum, obtains being directly used in the title compound of next reaction.GCMS (m/z 114)。

2-bromo-4-{[(3S)-and 1-methyl piperidine-3-yl] amino } thieno-[3,2-c] pyridine-7-nitrileTo 2-bromo-4-chloro thiophene also [3,2-c] pyridine-7-nitrile (400mg, add in NMP 1.46mmol) (2.0mL) solution salt of wormwood (605mg, 4.38mmol) and (3S)-1-methyl piperidine-3-amine (333mg, 2.92mmol).Reaction mixture is heated to 130 ℃ to be finished until the LCMS Indicator Reaction.Make reaction mixture be cooled to rt, add the water of about 100mL.The solid that obtains is also vacuum-drying after filtration, obtains title compound.LCMS(ES，M+H＝353)。

4-{[(3S)-and 1-methyl piperidine-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-nitrileTo 2-bromo-4-{[(3S)-1-methyl piperidine-3-yl] amino thieno-[3,2-c] pyridine-7-nitrile (512mg, add in 1.46mmol) cesium carbonate (1.43g, 4.38mmol), phenyl-boron dihydroxide (306mg, 2.19mmol), Pd (PPh ₃) ₄(169mg, 0.146mmol) and dioxane/water (4mL/2mL).Reaction is heated to 80 ℃ of meters 1 hour, makes reaction be cooled to rt subsequently, filter, adopt silica gel column chromatography (100% hexane is to 100%EtOAc) purifying, obtain title compound.LCMS(ES，M+H＝349)。

To containing 4-{[(3S)-1-methyl piperidine-3-yl] amino }-add the 12 N HCl of 5.00mL in the flask of 2-phenyl thieno-[3,2-c] pyridine-7-nitrile.Reaction stirred mixture and monitor under rt with LCMS.Add 12N HCl again, be converted into required product after 12 hours fully.To be transformed when complete, dilute with water reaction mixture and decompression concentrate down, obtain product, through with silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹H NMRδ8.52(s，1H)，8.20(s，1H)，7.74-7.71(m，3H)，7.48-7.36(m，4H)，7.21(d，1H)，4.28(m，1H)，2.96(m，2H)，2.69(m，2H)，1.93-1.55(m，4H)。LCMS(ES，M+H＝367)。

Embodiment 131

2-(4-cyano-phenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

With solid 2-bromo-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide (75mg, 0.2mmol), 4-cyano-phenyl boric acid (44.1mg, 0.30mmol), cesium carbonate (260mg, 0.80mmol), Pd (PPh ₃) ₄(23mg 0.02mmol) is dissolved in the water of the dioxane of 2ml and 0.5ml.Reaction mixture was heated to 80 ℃ of meters 2 hours.Remove solvent in the vacuum, resistates is through preparation HPLC (H ₂O/CH ₃The CN/0.1%TFA gradient) purifying.To obtain after the freeze-drying that trifluoroacetate is dissolved among the MeOH and with the dioxane processing of 4 N HCl, then stirred for several hour under rt.Remove solvent in the vacuum and under high vacuum, after the drying, isolate title compound (44mg, 54%) as hydrochloride, ¹H NMR δ 9.36 (s, 1H), 8.97 (s, 1H), 8.83 (s, 1H), 8.60 (s, 1H), 8.22 (s, 1H), 7.96 (q, 4H), 7.56 (s, 1H), 4.60 (m, 1H), 3.21 (m, 2H), 3.02 (m, 2H), 2.05 (m, 2H), 1.77 (m, 2H).LCMS(ES，M+H＝378)。

Prepare following examples 132 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	132	(4-{7-(aminocarboxyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-2-yl } phenyl) acetate	410.5	411	8.74(s，2H)，8.55(s，1H)，8.15(s，1H)，8.05(s，1H)，7.69(d，2H)，7.58(s，1H)，7.39(d，2H)，4.50(s，1H)，3.24(m，2H)，2.89(m，2H)，2.08(m，2H)，1.76(m，2H)

Embodiment 133

4-{[(2S)-and 2-amino-3-hydroxypropyl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide 3-amino-N-[(benzyloxy) carbonyl]-the L-alanine methyl esterContain 3-amino-N-[(benzyloxy to the equipment magnetic stirring bar) carbonyl]-(5.0g adds anhydrous MeOH (100mL) to the L-alanine methyl ester in flask 21.0mmol).Stir down that bubbling fed HCl gas about 10 minutes in solution/slurries.This exothermic reaction is converted into clarification/colourless from muddy white after about 2 minutes.This solution stirring is spent the night, and vacuum concentration and drying obtain the title compound (6.0g, 98%) as the white crystals hydrochloride afterwards. ¹H NMRδ3.05(t，1H)，3.19(t，1H)，3.70(s，3H)，4.45(m，1H)，5.10(s，2H)，7.38(m，5H)，7.95(d，1H)，8.35(br s，3H)。LCMS(ES，M+H＝253)。

The N-[(benzyloxy) carbonyl]-3-[(2-bromo-7-cyano thiophene [3-2-c] pyridin-4-yl also) amino]-L-third The propylhomoserin methyl estersTo the 4-chloro-2-bromo-thieno-[3 that stirs, 2-c] pyridine-7-nitrile (0.53g, 1.9mmol) and 3-amino-N-[(benzyloxy) carbonyl]-L-alanine methyl ester hydrochloride (0.66g, add in the solution of NMP 2.3mmol) (4mL) salt of wormwood (0.44g, 3.2mmol).With the mixture heating up to 80 of nonuniformity ℃ meter 2h, be cooled to rt, be added to then～water of 50mL in.Product (1.2g) separates after filtration and is dry, obtains the burgundy solid.Adopt MPLC (SiO ₂The 0-100%EtOAc/ hexane) this solid of purifying obtains title compound (0.41g).LCMS(ES，M+H＝489，491；M-H＝487，489)。

The N-[(benzyloxy) carbonyl]-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-L- Alanine methyl esterTo purify with nitrogen, contain the N-[(benzyloxy) carbonyl]-3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) amino]-add in the flask of L-alanine methyl ester (0.41g.0.85mmol) phenyl-boron dihydroxide (0.21g, 1.7mmol), Pd (PPh3) ₄(0.10g, 0.085mmol), cesium carbonate (0.83g, 2.5mmol), water (2mL) and dioxane (6mL).This reaction mixture was heated to 80 ℃ of meters 15 minutes, makes it be cooled to rt then.Through MPLC (SiO ₂The 0-50%EtOAc/ hexane) purifying obtains title compound (89mg).LCMS(ES，M+H＝487)。 [(1S)-and 2-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-1-(hydroxymethyl) second Base] benzyl carbamateUnder nitrogen atmosphere, to containing the N-[(benzyloxy that is dissolved in THF (9.5mL)/MeOH (0.5mL)) carbonyl]-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-(89mg in flask 0.18mmol), adds NaBH to the L-alanine methyl ester ₄(0.014g, 0.37mmol).Reaction stirred and monitor under rt with LCMS.After 40 minutes, reaction is finished.Concentrated solvent under the vacuum obtains being directly used in next step title compound, 83mg (100%).LCMS(ES，M+H＝459)。

4-{[((2S)-and 2-amino-3-hydroxypropyl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-formyl AmineIn the flask of equipment magnetic stirring bar, add [(1S)-and 2-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-1-(hydroxymethyl) ethyl] (83mg is 0.18mmol) with 12 N HCl (5mL) for benzyl carbamate.These slurries were stirred 24 hours.Vacuum is removed solvent and is used MPLC (SiO ₂50-100%NH ₄OH/MeOH/CH ₂Cl ₂(1: 7: 92)) the purifying resistates, obtain title compound (23mg). ¹H NMRδ1.35(s，2H)，2.75(m，1H)，3.16(m，2H)，3.33(m，1H)，3.87(q，1H)，4.45(t，1H)，7.04(s，1H)，7.14(t，1H)，7.28(m，3H)，7.50(d，2H)，7.68(s，1H)，7.94(s，1H)，8.30(s，1H)。LCMS(ES，M+H＝343)。

Being similar to the mode of embodiment 133, in first step, adopt 3-amino-N-[(benzyloxy) carbonyl]-the D-alanine methyl ester substitutes 3-amino-N-[(benzyloxy) carbonyl]-the L-alanine methyl ester prepares following examples 134.

Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	134	4-{[(2R)-and 2-amino-3-hydroxypropyl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	342.42	343	8.57(s，1H)，8.21(s，1H)，7.97(br s，1H)，7.77(d，2H)，7.61(t，1H)，7.54(t，2H)，7.42(t，1H)，7.34(s，1H)，4.76(t，1H)，3.62(m，1H)，3.46(m，2H)，3.30(m，1H)，3.05(t，1H)，2.0(br s，2H)

Embodiment 135

3-{[7-(aminocarboxyl)-2-phenyl thieno-[3,2-c] pyridin-4-yl l amino }-the D-L-Ala

With the N-[(benzyloxy) carbonyl]-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-the D-L-Ala (54mg, 0.11mmol) [for intermediate] with the embodiment 134 for preparing of mode that is similar to preparation embodiment 133 be dissolved in the 12N HCl of 4mL and stir and spend the night.Reaction mixture is dry under evaporation and high vacuum.Behind the preparation HPLC purifying, isolate title product (19mg, 48%) as trifluoroacetate. ¹H NMRδ8.65(m，2H)，8.40(m，1H)，8.1-8.3(br s，1H)，7.82(m，2H)，7.59(m，2H)，7.49(m，1H)，4.45(m，1H)，4.17(m，2H)，4.08(m，2H)，3.90(br s，2H)。LCMS(ES，M+H＝357)。

Embodiment 136

4-[(3S)-piperidines-3-base is amino]-2-pyridin-4-yl thieno-[3,2-c] pyridine-7-methane amide

3-[(4-cyano group-2-pyridin-4-yl thieno-[3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid The tert-butyl esterTo 3-[(2-bromo-7-cyano thiophene [3,2-c] pyridin-4-yl also) amino] (183mg, N 0.418mmol) add Pd (PPh in dinethylformamide (2.00mL) solution to piperidines-1-carboxylic acid tert-butyl ester ₃) ₄(19.3mg, 0.017mmol), cupric iodide (15.9mg, 0.084mmol) and 4-(tributyl stannyl) pyridine (185mg, 0.502mmol).The reaction stirred mixture is complete until the LCMS Indicator Reaction under 80 ℃, nitrogen atmosphere.The black reaction mixture that filtration obtains is used the EtOAc rinsing, and decompression concentrates down, with silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂) purifying, obtain 103mg title compound (51% yield).LCMS(ES，M+H＝436)。

4-[(3S)-piperidines-3-base is amino]-2-pyridin-4-yl thieno-[3,2-c] pyridine-7-methane amideTo containing 3-[(7-cyano group-2-pyridin-4-yl thieno-[3,2-c] pyridin-4-yl) amino] add the 12N HCl of 2.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.The reaction stirred mixture is monitored with LCMS under rt.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, the dilute with water reaction mixture also under reduced pressure concentrates, and obtains product, and it is through silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹H NMRδ1.70-1.56(m，2H)，1.99-1.78(m，2H)，2.98-2.89(2H)，3.09(m，1H)，3.24(m，1H)，4.22(m，1H)，7.38(m，1H)，7.66(d，2H)，7.97(m，1H)，8.47(s，1H)，8.57(s，1H)，8.64(d，2H)。LCMS(ES，M+H＝354)。

Adopt suitable starting raw material to prepare following examples 137 in a similar fashion.

Embodiment

The IUPAC title

MW (g/mol)

MS(ES，M+H)

¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else

137

4-[(3S)-piperidines-3-base is amino]-2-pyridin-3-yl thieno-[3,2-c] pyridine-7-methane amide

353.45

354

1.54(m，2H)，1.70(m，1H)，1.99(m，1H)，2.75(m，2H)，3.15(m，1H)，3.24(m，1H)，4.17(m，1H)，7.24(m，1H)，7.52(m，1 H)，7.93(m，1H)，8.09(m，1H)，8.30(s，1H)，8.54(br s，2H)，8.95(s，1H)

Embodiment 138

2-(phenylacetylene base)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

2-iodo-4-oxo-4,5-dihydro-thiophene be [3,2-c] pyridine-7-nitrile alsoWith N-iodosuccinimide (10.2g 44mmol) joins 4-oxo-4, the 5-dihydro-thiophene also [3,2-c] pyridine-7-nitrile (4.0g is 22mmol) in the solution in the mixture of 50: 50 DMF/ acetate (32mL).With this black reaction mixture heating up to 80 ℃ meter 12h.After being cooled to rt, while stirring reactant is added to～water of 150mL.Use saturated NaHCO ₃With the pH regulator of this turbid solution to 9-10.After filtration, wash with water and in vacuum drying oven drying obtain product (5.0g, 76%). ¹H NMRδ12.5(br s，1H)，8.31(d，1H)，7.83(s，1H)。LCMS(ES，M+H＝303，M-H＝301)。

4-chloro-2-iodo thieno-[3,2-c] pyridine-7-nitrileTo be dissolved in POCl ₃2-iodo-4-oxo-4 (50mL), 5-dihydro-thiophene also [3,2-c] pyridine-7-nitrile (5.0g, solution 16.6mmol) are heated to reflux and spend the night.After being cooled to rt, under the vacuum reactant is concentrated into drying.This solid slowly and carefully is suspended in～water of 300mL in.After filtration, water, saturated NaHCO subsequently ₃, water washing and in vacuum drying oven drying obtain product (4.3 g, 84%). ¹H NMRδ8.80(s，1H)，8.05(s，1H)。LCMS(ES，M+H＝321)。

(3S)-and 3-[(7-cyano group-2-iodo thieno-[3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid uncle fourth EsterTo 4-chloro-2-iodo thieno-[3, the 2-c] pyridine-7-nitrile that stirs (2.5g, 7.8mmol) and (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (1.9g, add in NMP 9.4mmol) (14mL) solution salt of wormwood (2.2g, 15.6mmol).With this nonuniformity mixture heating up to 80 ℃ meter 2h, be cooled to rt, be added to then～water of 100-150mL in.Filter and dry obtain need not purifying and be directly used in next step, burgundy solid product (4.4g, 100%).LCMS(ES，M+H＝485；M-H，483)。

(3S)-and 3-{[7-cyano group-2-(phenylacetylene base) thieno-[3,2-c] pyridin-4-yl] amino } piperidines-1- Carboxylic acid tert-butyl esterTo (3S)-3-[(7-cyano group-2-iodo thieno-[3,2-c] pyridin-4-yl) amino] (150mg adds PdCl to piperidines-1-carboxylic acid tert-butyl ester among N 310mmol), dinethylformamide (1.00mL) ₂(PPh ₃) ₂(16.1mg, 0.023mmol), cupric iodide (4.40mg, 0.023mmol), TEA (0.130mL, 0.930mmol) and phenylacetylene (81.7 μ L, 0.744mmol).The reaction stirred mixture is complete until the LCMS Indicator Reaction under rt, nitrogen atmosphere.Add 10mL water in the reaction mixture that obtains, (4 * 20mL) extract mixture, and organic layer is through MgSO to use EtOAc subsequently ₄Drying, the concentrated solvent down that filters and reduce pressure obtains black residue, through preparation HPLC (5-95%MeCN, H ₂O, 0.1%TFA) purifying obtains title compound.LCMS(ES，M+H＝459)。

To containing (3S)-3-{[7-cyano group-2-(phenylacetylene base) thieno-[3,2-c] pyridin-4-yl] amino } add the 12N HCl of 1.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.Reaction stirred mixture and monitor under rt with LCMS.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, reaction mixture is cooled to 0 ℃, dropwise handle until reaching pH 12 with 6NNaOH.With EtOAc and CH ₂Cl ₂/ MeOH (1/1) extracts mixture, and organic layer concentrates under filtration and the vacuum and obtains product through dried over mgso, and it is through preparation HPLC (5-95%MeCN, H ₂O, 0.1%TFA) purifying obtains title compound. ¹H NMR δ 1.99-1.63 (m, 4H), 2.91-2.83 (m, 2H), 3.3 1-3.20 (m, 2H), 4.48 (m, 1H), 7.26 (m, 1H), 7.48 (m, 3H), 7.55 (m, 2H), 8.10 (s, 1H), 8.71-8.57 (overlapping m and s, 2H).LCMS(ES，M+H＝377)。

Being similar to the mode of embodiment 1, in step 8, use (3S)-3-[(7-cyano group-2-iodo thieno-[3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester prepares following examples 139-145.

Embodiment

The IUPAC title

MW (g/mol)

MS(ES，M+H)

¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	139	2-(6-fluoro-5-picoline-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	385.47	386	1.82-1.62 (m, 2H), 2.11-1.94 (m, 2H), 2.32 (s, 3H), 2.91 (m, 2H), 3.20 (m, 1H), 3.45 (m, 1H), 4.50 (m, 1H), 7.51 (m, and 1H) 8.03 (m, 1H), 8.17 (overlapping s and m, 2H), 8.40 (s, 1H), 8.57 (s, 1H), 8.69 (s, 1H)
140	2-[4-(aminocarboxyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.49	396	1.78-1.64(m，2H)，2.00-1.96(m，2H)，2.93-2.88(m，2H)，3.23(m，1H)，3.51(m，1H)，4.50(m，1H)，7.43(br s，1H)，7.62(m，1H)，7.80(m，2H)，8.05-7.98(m，4H)，8.30(s，1H)，8.56(s，1H)，8.76(br s，2H)	139		385.47	386
140		395.49	396		141	2-[3-(aminocarboxyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.49	396	1.80-1.66(m，2H)，2.09-1.94(m，2H)，2.92(m，2H)，3.21(m，2H)，4.49(m，1H)，7.56(m，3H)，7.87(m，2H)，8.17(s，1H)，8.28(s，1H)，8.36(br s，1H)，8.56(s，1H)，8.80(br m，2H)
142	4-[(3S)-piperidines-3-base is amino]-2-pyrimidine-5-base thieno-[3,2-c] pyridine-7-methane amide	354.44	355	1.80-1.70(m，2H)，2.08-1.91(m，2H)，3.15-2.96(m，3H)，3.41(m，]H)，4.62(m，1H)，7.54(m，1H)，8.20(m，1H)，8.62(s，1H)，8.91(s，1H)，9.17(br s，3H)，9.50(br s，1H)	141		395.49	396
142		354.44	355		143	4-[(3S)-piperidines-3-base is amino]-2-(1H-pyrazoles-4-yl) thieno-[3,2-c] pyridine-7-methane amide	342.43	343	1.81-1.57(m，2H)，2.10-1.91(m，2H)，2.90(m，2H)，3.24(m，1H)，3.47(m，1H)，4.47(m，1H)，7.64(m，1H)，7.82(m，1H)，8.03(m，3H)，8.53(m，1H)，8.78(m，2H)
144	2-[2-(aminocarboxyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	395.49	396	1.74-1.61(m，2H)，2.00-1.92(M，2H)，2.92-2.82(m，2H)，3.24(m，1H)，3.48(m，1H)，4.51(m，1H)，7.60-7.42(m，6H)，7.75(m，2H)，8.01(m，1H)，8.53(s，1H)，8.67(br s，2H)	143		342.43	343

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	145	2-(6-methoxypyridine-3-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c]-pyridine-7-methane amide	383.47	384	8.70(m，2H)，8.53(m，2H)，8.04(m，2H)，7.48-7.36(m，2H)，6.98(d，1H)，4.48(m，1H)，3.90(s，3H)，3.31(m，1H)，3.27(m，1H)，2.88(m，2H)，2.19-1.69(m，4H)

Embodiment 146

2-(1H-indazole-1-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

(3S)-and 3-{[7-cyano group-2-(1H-indazole-1-yl) thieno-[3,2-c] pyridin-4-yl] amino } piperazine Pyridine-1-carboxylic acid tert-butyl esterUnder the nitrogen atmosphere, to CuI (2.7mg, 0.014mmol), indazole (79.2mg, 0.670mmol) and cesium carbonate (191mg adds (3S)-3-[(7-cyano group-2-iodo thieno-[3,2-c] pyridin-4-yl in solution 0.586mmol)) amino] piperidines-1-carboxylic acid tert-butyl ester (135mg, 0.279mmol), anti-form-1, the 2-cyclohexane diamine (4.2L, 0.056mmol) and anhydrous 1,4-dioxane (1.0mL).In 110 ℃ of reaction stirred mixtures 24 hours, make reactant be cooled to rt and use CH at this time point ₂Cl ₂Dilution.Filtering this mixture goes down to desolventize with decompression.With preparation HPLC (5-95%MeCN, H ₂O, 0.1%TFA) the purifying black residue obtains title compound.LCMS(ES，M+H＝475)。

2-(1H-indazole-1-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-formyl AmineTo containing (3S)-3-{[7-cyano group-2-(1H-indazole-1-yl) thieno-[3,2-c] pyridin-4-yl] amino } add the 12N HCl of 1.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.Reaction stirred mixture and monitor under rt with LCMS.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, make reaction mixture be cooled to 0 ℃ and dropwise handle until reaching pH 12 with 6NNaOH.With EtOAc and CH ₂Cl ₂/ MeOH (1/1) extracts mixture, and organic layer concentrates under filtration and the vacuum and obtains title compound through dried over mgso. ¹H NMRδ1.73-1.61(m，2H)，2.00-1.80(m，2H)，3.02-2.92(m，2H)，3.24(m，1H)，3.38(m，1H)，4.28(m，1H)，7.38(m，2H)，7.94(t，1H)，7.96(d，1H)，8.03(s，1H)，8.20(d，1H)，8.46(s，1H)，8.55(s，1H)。LCMS(ES，M+H＝393)。

Prepare following examples 147 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	147	2-(1H-imidazoles-1-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	342.43	343	1.82-1.70(m，2H)，2.03-1.94(m，2H)，2.97-2.92(m，2H)，3.24(m，1H)，3.38(m，1H)，4.24(m，1H)，7.27(m，1H)，7.43(m，1H)，7.66(s，1H)，7.89(s，1H)，8.06(br s，1H)，8.16(s，1H)，8.58(s，1H)

Embodiment 148

2-phenyl-4-[(3S)-piperidines-3-base is amino] [1,3] thiazole [4,5-c] pyridine-7-methane amide also

2-phenyl-thiazole-5-formaldehydeTo 2-chloro propionic aldehyde (malonaldehyde) (500mg, 4.69mmol) in the solution of 5.00mL acetone, add thiobenzamide (643mg, 4.69mmol).The reaction stirred mixture is finished until the LCMS Indicator Reaction under room temperature.Decompression is concentrated reaction mixture down, obtains being directly used in next step solid. ¹H NMRδ7.57(m，3H)，8.09(d，2H)，8.78(s，1H)，10.1(s，1H)。LCMS(ES，M+H＝190)。(2E)-3-(2-phenyl-1,3-thiazoles-5-yl) vinylformic acid.To 2-phenyl-thiazole-5-formaldehyde (888mg, add in 4.69mmol) propanedioic acid (684mg, 6.57mmol), pyridine (0.859mL) and piperidines (0.046mL).The mixture heating up that obtains to refluxing 6 hours, is cooled to rt subsequently.With in the reaction mixture impouring water (20mL) and after stirring 10 minutes, filter the solid that obtains, dry down with water rinse and decompression, obtain title compound (899mg, 83% yield). ¹H NMR δ6.25(d，2H)，7.53(m，3H)，7.83(d，1H)，7.95(m，2H)，8.26(s，1H)，12.57(br s，1H)。LCMS(ES，M+H＝232)。

(2E)-3-(2-phenyl-1,3-thiazoles-5-yl) acryloyl trinitrideIn 0 ℃, to (2E)-3-(2-phenyl-1,3-thiazoles-5-yl) vinylformic acid (899mg, 3.89mmol) in the solution of 15.0mL acetone, dropwise add isobutyl chloroformate (0.661mL, 5.05mmol).The solution that obtains in 0 ℃ of stirring 1 hour adds sodiumazide (328mg, 5.05mmol) solution in 3.00mL water subsequently.In 0 ℃ of reaction stirred 30 minutes, make reactant be warmed to rt subsequently and stirred 30 minutes.Add entry (50mL) to the solution that obtains.Filter yellow solid, wash with water subsequently, obtain the title compound of 884mg (89% yield). ¹H NMRδ6.40(d，1H)，7.55(m，3H)，7.99(m，2H)，8.06(s，1H)，8.40(s，1H)。2-phenyl [1,3] thiazole is [4,5-c] pyridines-4 (5H)-ketone also.In 230 ℃, in the solution of phenyl ether (3.60mL) and Tributylamine (0.900mL), dropwise be incorporated in the CH of about 5.00mL ₂Cl ₂In 5-[(1E)-3-oxo-3-(21 ⁵-three nitrogen-1-alkene-2-alkynes-1-base (triaz-1-en-2-yn-1-y1)) third-1-alkene-1-yl]-2-phenyl-1,3-thiazoles.Stirred the mixture 30 minutes in 230 ℃, make reactant be cooled to rt subsequently, then add the 50mL hexane, obtain yellow solid.With the solid that hexane wash obtains, decompression drying down obtains title compound (84% yield). ¹H NMRδ6.96(d，1H)，7.36(m，1H)，7.55(m，3H)，8.01(m，2H)，11.76(br s，1H)。

7-bromo-2-phenyl [1,3] thiazole is [4,5-c] pyridines-4 (5H)-ketone alsoTo 2-phenyl [1,3] thiazole also [4,5-c] pyridines-4 (5H)-ketone (600mg, 2.61mmol) in the solution of acetate (8.00mL), dropwise add bromine (0.144mL, 2.81mmol).This reaction mixture is heated to backflow 30 minutes.After 30 minutes, make solution be cooled to rt and add 40mL water.Filter remaining solid, dry down with water rinse and decompression, obtain title compound (728mg, 90% yield). ¹H NMR δ7.56(m，3H)，7.72(s，1H)，8.06(m，2H)。LCMS(ES，M+H＝309)。 4-chloro-2-phenyl [1,3] thiazole is [4,5-c] pyridine-7-nitrile alsoTo 7-bromo-2-phenyl [1,3] thiazole also [4,5-c] pyridines-4 (5H)-ketone (728mg, 2.35mmol) in the N of about 10.0mL, add in the dinethylformamide (DMF) cupric cyanide (I) (464mg, 5.18mmol).Reaction stirred is 10 hours under refluxing, and is cooled to rt subsequently.(4.57g 28.2mmol) is dissolved among the dense HCl of 1.30mL, adds the water of 7.30mL then with the solution of iron(ic) chloride (III).Stir these mixtures 15 minutes in 70 ℃, be cooled to rt subsequently.Adding entry (40.0mL) and crossing filter solid also reduces pressure dry down.Handle the solid that obtains and refluxed 4 hours with the Phosphorus Oxychloride of 7.00mL, make reaction be cooled to rt subsequently.Vacuum is removed solvent.Resistates is dissolved in CH ₂Cl ₂, use saturated NaHCO ₃Washing, organic layer is through MgSO ₄Drying is filtered and decompression concentrates down.The solid that obtains is through silica gel column chromatography (100%CH ₂Cl ₂) purifying, obtain title compound (189mg, 30% yield). ¹HNMRδ7.83-7.74(m，3H)，8.22(d，2H)，8.95(s，1H)。LCMS(ES，M-H＝272)。

(3S)-and 3-[(7-cyano group-2-phenyl [1,3] thiazole [4,5-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid The tert-butyl esterTo 4-chloro-2-phenyl [1,3] thiazole also [4,5-c] pyridine-7-nitrile (189mg, add in NMP 0.690mmol) (3.0mL) solution salt of wormwood (229mg, 1.66mmol) and (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (691mg, 3.45mmol).Reaction mixture is heated to 100 ℃ to be finished until the LCMS Indicator Reaction.Filter reaction mixture obtains viscous oil then, and it is through silica gel column chromatography (100% hexane is to 100%EtOAc) purifying, is concentrated into driedly, obtains the title compound (85% yield) of 255mg. ¹H NMRδ1.35(s，9H)，1.96-1.69(m，4H)，2.90(m，2H)，4.07-3.66(m，2H)，4.16(m，1H)，7.61(m，3H)，7.96(br s，1H)，8.15(m，2H)，8.49(s，1H)。LCMS(ES，M+H＝436)。

2-phenyl-4-[(3S)-piperidines-3-base is amino] [1,3] thiazole [4,5-c] pyridine-7-methane amide alsoTo (3S)-3-[(7-cyano group-2-phenyl [1,3] thiazole [4,5-c] pyridin-4-yl also) amino] add the 12N HCl of 3.00mL in piperidines-1-carboxylic acid tert-butyl ester (255mg).Stir this turbid solution down in rt, by LCMS monitoring reaction performance.Reaction mixture is cooled to 0 ℃, dropwise handles until reaching pH 12 with 6 N NaOH.With EtOAc and CH ₂Cl ₂/ MeOH (1/1) extracts mixture, and organic layer concentrates under filtration and the vacuum and obtains product through dried over mgso, and it is through preparation HPLC (5-95%MeCN, H ₂O, 0.1%TFA) purifying obtains the title compound (48% yield) of 100mg. ¹H NMR δ 1.99-1.65 (m, 4H), 2.91-2.83 (m, 2H), 3.24 (m, 1H), 3.38 (m, 1H), 4.56 (m, 1H), 5.2-6.2 (br s, 2H), 7.47 (m, 3H), 7.65 (d, 1H), 8.12 (m, 2H), 8.67-8.61 (overlapping m and s, 2H).LCMS(ES，M+H＝354)。

To be similar to the mode of embodiment 148, adopt suitable starting raw material to prepare following examples 149-155.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	149	The 4-[(2-amino-ethyl) amino]-2-(4-p-methoxy-phenyl) [1,3] thiazole [4,5-c] pyridine-7-methane amide also	343.41	344	(400.132MHz) 2.93(m，2H)，3.66(m，2H)，3.86(s，3H)，7.12(d，2H)，7.44(brs，1H)，7.67(br t，1H)，8.06(br s，3H)，8.09(d，3H)，8.61(s，1H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	150	4-{[2-(dimethylamino) ethyl] amino }-2-(4-p-methoxy-phenyl) [1,3] thiazole [4,5-c] pyridine-7-methane amide also	371.46	372	(400.132MHz)2.23(s，6H)，2.55(t，2H)，3.67(dt，2H)，3.86(s，3H)，7.12(d，2H)，7.37(t，1H)，7.39(br s，1H)，8.00(br s，1H)，8.07(d，2H)，8.62(s，1H)
151	2-(4-p-methoxy-phenyl)-4-(piperidin-4-yl amino) [1,3] thiazole is [4,5-c] pyridine-7-methane amide also	383.47	384	(400.132MHz) 1.56(m，2H)，1.90(m，2H)，2.59(m，2H)，3.01(m，2H)，3.86(s，3H)，4.22(m，1H)，7.11(d，2H)，7.20(d，1H)，7.38(br s，1H)，7.97(br s，1H)，8.11(d，2H)，8.59(s，1H)	150		371.46	372
151		383.47	384		152	2-(4-p-methoxy-phenyl)-4-[(3S)-piperidines-3-base is amino] [1,3] thiazole [4,5-c] pyridine-7-methane amide also	383.47	384	(400.132MHz) 1.50(m，1H)，1.69(m，2H)，1.70(m，2H)，1.91(m，1H)，2.57(m，1H)，2.64(m，1H)，2.82(m，1H)，3.09(m，1H)，3.86(s，3H)，4.26(m，1H)，7.12(d，2H)，7.17(d，1H)，7.38(br s，1H)，8.00(br s，1H)，8.09(d，2H)，8.60(s，1H)
153	The 4-[(3-aminopropyl) amino]-2-(4-p-methoxy-phenyl) [1,3] thiazole [4,5-c] pyridine-7-methane amide also	357.44	358	(400.132MHz)1.73(m，2H)，1.76(br s，2H)，2.66(t，2H)，3.64(dt，2H)，3.86(s，3H)，7.12(d，2H)，7.36(br s，1H)，7.74(t，1H)，7.97(br s，1H)，8.08(d，2H)，8.60(s，1H)	152		383.47	384
153		357.44	358		154	2-(4-p-methoxy-phenyl)-4-(tetramethyleneimine-3-base is amino) [1,3] thiazole is [4,5-c] pyridine-7-methane amide also	369.45	370	(400.132MHz) 2.11(m，1H)，2.55(m，1H)，2.81(m，2H)，3.00(m，1H)，3.07(dd，1H)，3.86(s，3H)，4.68(m，1H)，7.11(d，2H)，7.35(d，1H)，7.38(br s，1H)，8.00(br s，1H)，8.10(d，2H)，8.62(s，1H)
155	4-(azetidine-3-base is amino)-2-(4-p-methoxy-phenyl) [1,3] thiazole is [4,5-c] pyridine-7-methane amide also	355.42	356	(400.132MHz) 3.71(d，4H)，3.87(s，3H)，5.01(m，1H)，7.13(d，2H)，7.41(brs，1H)，7.90(d，1H)，8.00(br s，1H)，8.12(d，2H)，8.60(s，1H)	154		369.45	370

Embodiment 156

The 2-phenyl-4-[(3S)-piperidines-3-base is amino] furo [3,2-c] pyridine-7-methane amide (2E)-3-(5-phenyl-2-furyl) vinylformic acidWith 5-phenyl-2-furyl aldehyde (2.82g, 16.4mmol) with propanedioic acid (2.4g, 23.0mmol), the processing of pyridine (3ml) and piperidines (0.16ml).In reflux mixture 6 hours, be cooled to rt afterwards.During stir on the limit then with in the mixture impouring water (50ml).The yellow solid that filtration obtains washes with water with dry air and obtains title compound (3.5g, 99%). ¹H NMRδ12.39(br s，1H)，7.83(d，2H)，7.47(t，2H)，7.38(t，2H)，7.13(d，1H)，7.05(d，1H)，6.33(d，1H)。LCMS(ES，M+H＝215)。

(2E)-3-(5-phenyl-2-furyl) acryloyl trinitrideIn 0 ℃, to (2E)-3-(5-phenyl-2-furyl) vinylformic acid (1.63g, 7.6mmol) and Et ₃(1.40ml 9.9mmol) in the solution of acetone (20ml), dropwise adds ClCO to N ₂IBu (1.3ml, 9.9mmol).Behind 0 ℃ of stirring 1h, (the mixture 30min that obtains in 0 ℃ of stirring stirs 30min down in rt then again, adds entry (100ml) then for 643mg, water 9.9mmol) (5ml) solution to add sodiumazide.Filtration obtains yellow solid sample title compound, and it washes with water and air-dry (1.21g, 67%). ¹H NMRδ7.88(d，2H)，7.60(d，1H)，7.48(t，2H)，7.39(t，1H)，7.22(d，2H)，6.44(d，1H)。LCMS(ES，M+H＝240)。

The 2-benzofurane is [3,2-c] pyridines-4 (5H)-ketone alsoIn 230 ℃, to the phenyl ether (36.4ml) and the Bu that stir ₃(2.29g is 9.56mmol) in CH dropwise to add (2E)-3-(5-phenyl-2-furyl) acryloyl trinitride in the mixture of N (9.1ml) ₂Cl ₂Solution (18ml).The speed of control liquid feeding makes internal temperature be kept above 190 ℃ like this.After the adding, the brown solution that obtains is stirred 30min, be cooled to rt afterwards.Add hexane (90ml) and filter yellow solid,, obtain title compound (1.3g, 64.5%) with hexane wash with at air drying. ¹H NMRδ11.51(s，1H)，7.84(d，2H)，7.48(t，3H)，7.37(m，2H)，6.70(d，1H)。LCMS(ES，M+H＝212)。

7-bromo-2-benzofurane is [3,2-c] pyridines-4 (5H)-ketone alsoUnder rt, with bromine (320mg, 1.93mmol) handle the 2-benzofurane also [3,2-c] pyridines-4 (5H)-ketone (369mg, 1.75mmol) in the solution of acetate (5ml) and with the mixture that obtains in reflux 30min.After being cooled to rt, add entry (20ml) to mixture.The yellow solid that forms washes with water and at air drying, obtains being directly used in next step title compound and 6 after filtration, and 7-two bromo-2-benzofuranes are the mixture of [3,2-c] pyridines-4 (5H)-ketone compound (2: 1,400mg, 52%) also.4-oxo-2-phenyl-4,5-dihydrofuran be [3,2-c] pyridine-7-nitrile also.With 7-bromo-2-benzofurane also [3,2-c] pyridines-4 (5H)-ketone (472mg, 1.63mmol) and CuCN (320mg, 3.58mmol) in the mixture of DMF in the heating down 16 hours that refluxes, be cooled to rt afterwards.Add FeCl then ₃(3.32g is 20mmol) in the solution of dense HCl (0.9ml) and water (5ml), to decompose this copper composition.In 70 ℃ of this mixture meter of stirring 15min, make it be cooled to rt then.Add entry (35ml), the yellow solid of formation is filtered, wash with water and at air drying.Title compound and 4-oxo-2-phenyl-4,5-dihydrofuran be [3,2-c] pyridine-6 also, and the mixture of 7-dintrile need not purifying and is used for next step.

4-chloro-2-benzofurane is [3,2-c] pyridine-7-nitrile alsoUse POCl ₃(5ml) handle crude product 4-oxo-2-phenyl-4, the 5-dihydrofuran is [3,2-c] pyridine-7-nitrile also, and this mixture was heated 4 hours down in refluxing.Decompression goes down to desolventize, and makes resistates at CH ₂Cl ₂And distribute between the sodium bicarbonate aqueous solution.Separate organic phase and through dried over mgso.Remove solvent, with after silica gel column chromatography (elutriant: CH ₂Cl ₂And MeOH) obtains white solid sample title compound (287 mg, the yield 69.7% of two steps). ¹H NMRδ8.35(s，1H)，8.06(d，2H)，7.86(s，1H)，7.57(m，3H)。LCMS(ES，M+H＝254)。

(3S)-and 3-[(7-cyano group-2-benzofurane [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid uncle fourth EsterTo 4-chloro-2-benzofurane also [3,2-c] pyridine-7-nitrile (287mg, 1.13mmol) and salt of wormwood (376mg, 2.72mmol) in the mixture of NMP (5ml), add (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (1.14g, 5.67mmol), the mixture that obtains in 110 ℃ of stirrings 16 hours.Cooling mixture and add entry (50ml) filters the throw out that forms and obtains title compound (178mg) then.

The 2-phenyl-4-[(3S)-piperidines-3-base is amino] furo [3,2-c] pyridine-7-methane amideHandle also [3,2-c] pyridin-4-yl of (3S)-3-[(7-cyano group-2-benzofurane with dense HCl (5ml)) amino] piperidines-1-carboxylic acid tert-butyl ester (178mg), and under rt, stir this mixture overnight.After removing solvent,, obtain title compound as trifluoroacetate with preparation HPLC purifying resistates.This salt is dissolved in MeOH (1ml), uses 4 N HCl/ dioxane (2ml) to fill then.After stirring is spent the night, filter white solid and the air-dry title compound (53mg) that obtains. ¹H NMRδ9.14(br s，1H)，8.89(brs，1H)，8.34(s，1H)，7.91(d，2H)，7.85(s，1H)，7.67(s，2H)，7.55(t，2H)，7.45(t，1H)，4.47(m，1H)，3.19(m，2H)，2.96(m，2H)，2.03(m，2H)，1.72(m，2H)。LCMS(ES，M+H＝337)。

Embodiment 157

The 2-methyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide (2E)-3-(5-methyl-2-thienyl) vinylformic acidTo 5-thiotolene-2-formaldehyde (13.1mL, add in 120mmol) propanedioic acid (17.5g, 168mmol), pyridine (22.0mL) and piperidines (118mL).The mixture heating up that obtains is spent the night to refluxing, be cooled to rt subsequently.With in the reaction mixture impouring water (200mL) and after stirring 10 minutes, filter the solid that obtains then, obtain title compound (13.2g, 66% yield) with drying under water rinse and the decompression. ¹H NMRδ12.3(s，1H)，7.68(d，1H)，7.32(s，1H)，6.86(s，1H)，6.03(d，1H)，3.36(s，3H)。LCMS(ES，M+H＝169)。

(2E)-3-(5-methyl-2-thienyl) acryloyl trinitrideIn 0 ℃, to (2E)-3-(5-methyl-2-thienyl) vinylformic acid (13.2g, in the solution of 300mL acetone 78.3mmol), dropwise add the chloroformic acid isobutyl (13.3mL, 102mmol).The solution that obtains in 0 ℃ of stirring 1 hour adds sodiumazide (6.63g, the aqueous solution of 64.0mL 102mmol) subsequently.Then in 0 ℃ of reaction stirred 30 minutes, make reactant be warmed to rt and restir 30 minutes subsequently.In the solution that obtains, add entry (500mL).Filter yellow solid, wash with water, obtain title compound (83% yield). ¹H NMRδ7.85(d，1H)，7.47(s，1H)，6.91(s，1H)，6.14(d，1H)，3.32(s，3H)。

The 2-thiotolene is [3,2-c] pyridines-4 (5H)-ketone alsoIn 230 ℃, in the solution of phenyl ether (149mL) and Tributylamine (37.0mL), dropwise be incorporated in the CH of about 5.00mL ₂Cl ₂In (2E)-3-(5-methyl-2-thienyl) acryloyl trinitride (7.60g, 39.3mmol).Stirred the mixture 30 minutes in 230 ℃, make reaction be cooled to rt subsequently, add the 200mL hexane subsequently, obtain yellow sample solid.The solid and the drying under reduced pressure that obtain with hexane wash obtain title compound (4.84g, 74% yield). ¹H NMRδ 11.3(s，1H)，7.14(s，2H)，6.73(d，1H)，3.32(s，3H)。

7-bromo-2-thiotolene is [3,2-c] pyridines-4 (5H)-ketone alsoTo the 2-thiotolene also [3,2-c] pyridines-4 (5H)-ketone (4.84g, 28.9mmol) in the solution of acetate (84.0mL), dropwise add bromine (1.64mL, 31.8mmol).Reaction mixture is heated to backflow 1 hour.After 1 hour, solution is cooled to rt, adds entry until forming solid.Filter remaining solid,, obtain title compound (6.01g, 85% yield) with dry under water rinse and the vacuum. ¹H NMRδ11.7(br s，1H)，7.47(s，1H)，7.30(s，1H)，3.38(s，3H)。LCMS(ES，M+H＝245)。

4-chloro-2-thiotolene is [3,2-c] pyridine-7-nitrile alsoTo 7-bromo-2-thiotolene also [3,2-c] pyridines-4 (5H)-ketone (2.76g, about 24.0mL N 11.3mmol), add in the solution of dinethylformamide (DMF) cupric cyanide (I) (2.22g, 24.9mmol).Reaction stirred is 10 hours under refluxing, and is cooled to rt subsequently.Add then iron(ic) chloride (III) solution in the water of the dense HCl be dissolved in 6.30mL and 35.0mL (11.0g, 67.8mmol).Stirred the mixture 15 minutes in 70 ℃, be cooled to rt subsequently.Add entry (192mL) and cross filter solid and drying under reduced pressure.Handle the solid that obtains and place with the Phosphorus Oxychloride of 34.0mL then and refluxed 4 hours, be cooled to rt with afterreaction.Vacuum is removed solvent.Resistates is dissolved in CH ₂Cl ₂, use saturated NaHCO ₃Washing and organic layer are through MgSO ₄Drying is filtered and the concentrated down title compound (943mg, 40% yield) that obtains of decompression. ¹H NMRδ8.78(s，1H)，7.49(s，1H)，3.33(s，3H)。LCMS(ES，M+H＝209)。

(3S)-and 3-[(7-cyano group-2-thiotolene [3,2-c] pyridin-4-yl also) amino] piperidines-1-carboxylic acid uncle fourth EsterTo 4-chloro-2-thiotolene also [3,2-c] pyridine-7-nitrile (943mg, add in the solution of NMP 4.52mmol) (5.0mL) salt of wormwood (1.49g, 10.8mmol) and (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (2.72g, 13.6mmol).Reaction mixture is heated to 130 ℃ to be finished until the LCMS Indicator Reaction.Reaction mixture is cooled to the water of rt and the about 100mL of adding.Solid that filtration obtains and vacuum-drying obtain title compound.LCMS(ES，M+Na＝395)。 The 2-methyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amideTo containing also [3,2-c] pyridin-4-yl of (3S)-3-[(7-cyano group-2-thiotolene) amino] add the 12N HCl of 5.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.Reaction stirred mixture and monitor under rt with LCMS.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, dilute with water reaction mixture and decompression concentrate down and obtain product, through silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹HNMRδ8.42(s，1H)，7.81(br s，1H)，7.41(s，1H)，7.14(s，1H)，7.14(br s，1H)，6.96(d，1H)，4.11(m，1H)，3.31(s，3H)，3.14(m，2H)，2.82(m，2H)，1.94(m，1 H)，1.52(m，1H)，1.36(m，2H)。LCMS(ES，M+H＝291)。

Embodiment 158

2-(3-fluorophenyl)-7-[(3S) piperidines-3-base is amino] thieno-[2,3-c] pyridine-4-methane amide (2Z)-3-cyano group-3-(3-thienyl) vinylformic acidIn 3-thiophene acetonitrile (166mmol), add oxoethanoic acid (174mmol), MeOH (332mL) and salt of wormwood (174mmol).The mixture heating up that obtains to refluxing 3 hours, is cooled to rt subsequently.The solid that filtration obtains with MeOH rinsing and dry in vacuum drying oven, obtains title compound (26.6g, 90% yield).LCMS(ES，M-H＝178)。

(2Z)-3-cyano group-3-(3-thienyl) acrylate chloride(27.3mL is 313mmol) in CH to oxalyl chloride ₂Cl ₂Portions adding (2Z)-3-cyano group-3-(3-thienyl) vinylformic acid in the solution (57mL) (26.6g, 149mmol).It is complete until the LCMS Indicator Reaction to stir the solution that obtains down in rt.Filter reaction mixture and use CH then ₂Cl ₂Rinsing.Collect filtrate, decompression concentrate down and vacuum under dry, obtain being directly used in the yellow solid sample title compound (18.5g, 63% yield) of next reaction.

(2Z)-3-cyano group-3-(3-thienyl) acryloyl trinitrideIn 0 ℃, to sodiumazide (12.2g, 187mmol) be incorporated in the solution of 1: 1 mixture in dioxane/water (23mL) (2Z)-3-cyano group-3-(3-thienyl) acrylate chloride in the dioxane of 33mL (18.5g, 93.5mmol).In 0 ℃ of reaction stirred 15 minutes, make reactant be warmed to rt subsequently.After about 1.5 hours, add entry (100mL) to the solid that reacts and filtration obtains, and dry in vacuum drying oven, obtain title compound (15.1g, 82% yield). ¹H NMRδ 8.24(s，1H)，7.76-7.71(m，2H)，7.25(s，1H)。LCMS(ES，M-H＝204)。

7-oxo-6,7-dihydro-thiophene be [2,3-c] pyridine-4-nitrile alsoIn 230 ℃, in the solution of phenyl ether (224mL) and Tributylamine (53.0mL), dropwise be incorporated in the CH of about 10mL ₂Cl ₂In (2Z)-3-cyano group-3-(3-thienyl) acryloyl trinitride.Stirred the mixture 30 minutes in 230 ℃, be cooled to rt, add the 500mL hexane subsequently, obtain yellow sample solid.Dry under solid that obtains with hexane wash and the vacuum, obtain title compound (4.61 g, 44% yield). ¹H NMR δ12.4(br s，1H)，8.26(m，2H)，7.42(d，1H)。

2-bromo-7-oxo-6,7-dihydro-thiophene be [2,3-c] pyridine-4-nitrile alsoTo 7-oxo-6, the 7-dioxy thiophene also [2,3-c] pyridine-4-nitrile (2.30g, 13.1mmol) add in the solution in 1/1 acetate/DMF (10mL) N-bromosuccinimide (11.6g, 65.3mmol).Reaction mixture was heated to 80 ℃ of meters 1 hour.Making solution be cooled to rt also dilutes with the water of 100mL.Use saturated sodium bicarbonate neutralization reaction then, the solid that subsequent filtration obtains, it is dry in vacuum drying oven, obtains title compound (3.20g, 96% yield). ¹H NMRδ12.7(br s，1H)，8.41(s，1H)，8.32(d，1H)。LCMS(ES，M+H＝256)。

2-bromo-7-chloro thiophene is [2,3-c] pyridine-4-nitrile alsoTo 2-bromo-7-oxo-6, the 7-dihydro-thiophene is [2,3-c] pyridine-4-nitrile (3.20g, 12.5mmol) middle Phosphorus Oxychloride that adds 45.0mL also.Reaction is heated to refluxes and spend the night, the LCMS Indicator Reaction is finished afterwards.Reaction is cooled under rt and the decompression removes volatile matter.The water that in the resistates that obtains, adds about 200mL.Filter black solid and, obtain title compound (2.80g, 82% yield) with dry under a large amount of water rinses and the vacuum. ¹H NMRδ8.97(s，1H)，8.71(s，1H)。

(3S)-and 3-[(2-bromo-4-cyano thiophene [2,3-c] pyridine-7-yl also) amino] piperidines-1-carboxylic acid uncle fourth EsterTo 2-bromo-7-chloro thiophene also [2,3-c] pyridine-4-nitrile (2.80g, add in NMP 10.2mmol) (10.0mL) solution salt of wormwood (4.23g, 30.6mmol) and (3S)-3-amino piperidine-1-carboxylic acid tert-butyl ester (4.92g, 24.6mmol).Reaction mixture is heated to 130 ℃ to be finished until the LCMS Indicator Reaction.Then reaction mixture is cooled to rt, adds the water of about 100mL.The solid that filtration obtains, vacuum-drying obtains title compound. ¹H NMRδ 8.47(s，1H)，8.35(s，1H)，7.90(br s，1H)，4.14(m，1H)，3.38(m，1H)，3.24(m，1H)，2.93(m，2H)，1.94-1.73(m，4H)，1.37(s，9H)。LCMS(ES，M+H＝33 8)。

(3S)-and 3-{[4-cyano group-2-(3-fluorophenyl) thieno-[2,3-c] pyridine-7-yl] amino } piperidines-1-carboxylic acid The tert-butyl esterTo (3S)-3-[(2-bromo-4-cyano thiophene [2,3-c] pyridine-7-yl also) amino] piperidines-1-carboxylic acid tert-butyl ester (and 428mg, add in 0.979mmol) cesium carbonate (957mg, 2.94mmol), 3-fluorophenyl boric acid (206mg, 1.47mmol), Pd (PPh ₃) ₄(113mg, 0.0979mmol) and dioxane/water (4mL/2mL).With this reactant be heated to 80 ℃ 1 hour, subsequently reaction is cooled to rt, filter and, obtain title compound (241mg, 54% yield) with silica gel column chromatography (100% hexane is to 100%EtOAc) purifying.LCMS(ES，M+H＝453)。 2-(3-fluorophenyl)-7-[(3S)-piperidines-3-base is amino] thieno-[2,3-c] pyridine-4-methane amideTo containing (3S)-3-{[4-cyano group-2-(3-fluorophenyl) thieno-[2,3-c] pyridine-7-yl] amino } add the PPA of about 2.00mL in the flask of piperidines-1-carboxylic acid tert-butyl ester.In 110 ℃ of reaction stirred mixtures 12 hours.Water diluted reaction mixture with 10.0mL also transfers to alkaline pH with 6N NaOH.Use then EtOAc (4 * 100mL), use CH subsequently ₂Cl ₂(1/1,4 * 100mL) extracts mixture to/MeOH, through MgSO ₄Dry and decompression concentrates down, obtains product, through silica gel column chromatography (100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹H NMRδ 8.01(s，1H)，7.91(s，1H)，7.51(s，1H)，7.38(m，1H)，7.36(m，4H)，7.34(br s，1H)，6.80(m，1H)，4.21(m，1H)，3.15(m，2H)，2.87(m，2H)，1.92-1.46(m，4H)。LCMS(ES，M+H＝371)。

Adopt suitable starting raw material to prepare following examples 159 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	159	The 2-phenyl-7-[(3S)-piperidines-3-base is amino] thieno-[2,3-c] pyridine-4-methane amide	352.46	353	8.01(s，1H)，7.86(s，1H)，7.68(m，1H)，7.49-7.24(m，5H)，7.12(br s，1H)，4.50(m，1H)，3.3-3.8(br s，2H)，3.15(m，2H)，2.87(m，2H)，2.01-1.20(m，4H)

Embodiment 160

2-phenyl-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide

2-amino-4-nitrobenzoic acid methyl esters(24g slowly adds thionyl chloride (96mL) in MeOH 0.132mol) (500mL) solution to 2-amino-4-nitrobenzoic acid.The solution backflow that obtains is spent the night.After cooling, the product of fractional crystallization after filtration is under high vacuum dry (22.9g, 88%). ¹H NMRδ7.90(d，1H)7.67(d，1H)7.25(dd，1H)7.13(s，2H)3.84(s，3H)。

4-nitro-2-phenyl-1H-indole-7-carboxylic acidTo be cooled to-15 ℃ 2-amino-4-nitrobenzoic acid methyl ester (2.2g, 11.2mmol) and methyl phenyl ketone (2.8g, add in DMSO 23.3mmol) (30mL) solution solid K OtBu (2.7g, 24mmol).Stir after 20 minutes, restir 2h under rt uses saturated NH then ₄Cl (200mL) quencher reaction, restir 1h under rt then.The filter red throw out, wash with water with high vacuum under dry, obtain title compound (2.85g, 90%). ¹H NMR δ12.05(s，1H)7.99(d，1H)7.89(d，2H)7.65(d，1H)7.50(t，2H) 7.44(s，1H)7.41(d，1H)7.30(br s，1H)。LCMS(ES，M-H＝281)。

4-nitro-2-phenyl-1H-indoles-7-methane amideIn-1 5 ℃, to 4-nitro-2-phenyl-1H-indole-7-carboxylic acid (0.60g, 2.1mmol) and the CH of N-methylmorpholine (2.3mmol) ₂Cl ₂Adding chloroformic acid isobutyl in the solution (20mL) (0.5mL, 3.8mmol).After stirring 1h, bubbling feeds NH in reaction mixture ₃(g) 10-15 minute, restir 1h under rt then.After removing solvent, resistates is through MPLC (SiO ₂The 50-100%EtOAc/ hexane) purifying obtains dark yellow solid-like product (0.50g, 85%). ¹H NMRδ11.72(s，1H)8.46(s，1H)8.11(d，1H)8.02(d，2H)7.92(s，1H)7.76(d，1H)7.50-7.57(m，3H)7.47(d，1H)。LCMS(ES，M+H＝282；M-H＝280)。

4-amino-2-phenyl-1H-indoles-7-methane amideTo (0.50g 17.8mmol) adds 10%Pd/C (30mg) in the solution with 4-nitro-2-phenyl-1H-indoles-7-methane amide nitrogen-purification, that stir, that be dissolved in MeOH (30mL).The nonuniformity mixture that obtains is added H ₂(g) balloon.After stirring is spent the night under the rt, and the filtering reaction thing (0.45u, Teflon).Filtrate concentrates under vacuum and obtains glassy yellow solid-like title compound (0.35g, 80%). ¹H NMRδ10.90(s，1H)7.74(d，3H)7.53(q，4H)7.35(t，1H) 7.12(d，1H)6.22(d，1H)6.10(s，2H)。LCMS(ES，M+H＝252；M-H＝250)。

3-{[7-(aminocarboxyl)-2-phenyl-1H-indoles-4-yl] amino } piperidines-1-carboxylic acid tert-butyl ester(0.60g, 2.4mmol) (0.6g adds Na in solution 2.8mmol) with 3-oxo-piperidine-1-carboxylic acid tert-butyl ester to the 4-amino that is dissolved in AcOH (15mL)-2-phenyl-1H-indoles-7-methane amide ₂SO ₄Mixture is stirred 1h down in rt, and slow then adding sodium triacetoxy borohydride (1.5g, 7.2mmol).Reaction stirred 1h under rt.Dilute this mixture with EtOAc and water, use saturated NaHCO ₃, 1N HCl and saturated NaCl washing.Organic layer is through Na ₂SO ₄Drying is filtered and CIV.Resistates is through MPLC (SiO ₂The 50-80%EtOAc/ hexane) purifying gets brown solid title product (0.3g, 30%).LCMS(ES，M+H＝435；M-H＝433)。2-phenyl-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide.The dioxane (10mL) of 4.0N HCl is added 3-{[7-(the aminocarboxyl)-2-phenyl-1H-indoles-4-yl that stirs] amino } (0.15g is in MeOH 0.35mmol) (10mL) solution for piperidines-1-carboxylic acid tert-butyl ester.Reaction stirred 2h under rt concentrates under the vacuum then and obtains hydrochloride.Use 2.0N NH ₃MeOH (10mL) solution dilution resistates and CIV.Resistates is through MPLC (SiO ₂10%MeOH/CH ₂Cl ₂/ 1.5%NH ₄OH-20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains pale solid sample title compound (90mg, 78%). ¹H NMRδ10.87(s，1H)7.69(d，2H)7.57(d，1H)7.45(t，2H)7.28(t，1H)7.20(s，1H)6.96(br s，1H)6.15(d，1H)6.02(d，1H)3.50(d，1H)3.30(s，2H)3.05-3.20(m，2H)2.84(d，1H)2.34-2.46(m，1H)1.98(s，1H)1.60-1.72(m，1H)1.43-1.58(m，2H)。LCMS(ES，M+H＝335；M-H＝333)。

By with preparation embodiment 158 similar modes, adopt suitable starting raw material to prepare following examples 161-169.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	161	2-(4-chloro-phenyl-)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	368.87	369	10.75 (s, 1H), 9.10 (m, 2H), 7.55 (d, 2H), 7.45 (d, 1H), 7.33 (d, 2H), 7.15 (d, 1H), 6.08 (d, 1H), 5.45 (br s, 3H), 3.83 (m, 1H), 3.21 (m, 1H), 3.03 (m, 1H), 2.73 (m, 1H), 2.65 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.51 (m, 1H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	162	2-(4-fluorophenyl)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	352.41	353	10.89 (s, 1H), 8.92 (m, 1H), 8.73 (m, 1H), 7.75 (d, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.30 (t, 2H), 7.15 (d, 1H), 7.04 (br s, 1H), 6.33 (br s, 1H), 6.23 (d, 1H), 3.91 (m, 1 H), 3.41 (m, 1H), 3.25 (m, 1H), 2.89 (m, 1H), 2.75 (m, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.66 (m, 1H).
163	2-(4-p-methoxy-phenyl)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	364.45	365	10.8 (s, 1H), 9.06 (m, 1H), 8.95 (m, 1H), 7.63 (m, 3H), 7.57 (d, 1H), 7.05 (m, 3H), 6 22 (d, 1H), 3.79 (s, 3H), 3.68 (m, 2H), 3.43 (m, 2H), 3.23 (m, 1H), 2.89 (m, 1H), 2.75 (m, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.66 (m, 1H).	162		352.41	353
163		364.45	365		164	2-[4-(dimethylamino) phenyl]-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	377.49	378	10.84 (s, 1H), 9.24 (m, 2H), 7.71 (m, 2H), 7.58 (d, 1H), 7.33 (m, 2H), 7.19 (m, 1H), 6.24 (d, 1H), 3.99 (m, 2H), 3.68 (m, 1H), 3.47 (m, 1H), 3.38 (m, 1H), 3.20 (m, 1H), 3.04 (s, 6H), 2.89 (m, 1H), 2.78 (m, 1H), 1.94 (m, 2H), 1.74 (m, 1H), 1.66 (m, 1H).
165	2-(3-chloro-phenyl-)-4-piperidines-3-base is amino)-1H-indoles-7-methane amide	368.87	369	10.98 (s, 1H), 9.19 (m, 1H), 9.08 (m, 1H), 7.79 (s, 1H), 7.66 (dd, 2H), 7.49 (t, 1H), 7.37 (s, 2H), 7.34 (s, 1H), 6.31 (br s, 2H), 6.26 (d, 1H), 4.00 (m, 1H), 3.41 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).	164		377.49	378
165		368.87	369		166	2-(3-fluorophenyl)-4-piperidines-3-base is amino)-1H-indoles-7-methane amide	352.41	353	10.98 (s, 1H), 9.19 (m, 1H), 9.08 (m, 1H), 7.63 (d, 2H), 7.56 (m, 2H), 7.50 (m, 1H), 7.34 (s, 1H), 7.13 (dt, 1H), 6.26 (d, 1H), 5.60 (br s, 2H), 4.00 (m, 1H), 3.41 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	167	2-(3-p-methoxy-phenyl)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	364.45	365	10.90 (s, 1H), 9.24 (m, 2H), 7.63 (d, 2H), 7.39 (t, 2H), 7.29 (s, 2H), 7.26 (s, 1H), 6.89 (dd, 2H), 6.26 (d, 1H), 4.01 (m, 1H), 3.85 (s, 3H), 3.41 (m, 1H), 3.23 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).
168	2-[3-(dimethylamino) phenyl]-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide	377.49	378	10.97 (s, 1H), 9.26 (m, 2H), 7.95 (br s, 2H), 7.49 (m, 3H), 7.33 (m, 2H), 6.26 (d, 1H), 4.03 (m, 1H), 3.68 (m, 1H), 3.48 (m, 1H), 3.41 (m, 1H), 3.23 (m, 1H), 3.12 (s, 6H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).	167		364.45	365
168		377.49	378		169	4-(piperidin-4-yl amino)-2-pyridin-4-yl-H-indoles-7-methane amide	335.41	336	1.41 (td, 2H), 1.95 (d, 2H), 2.61 (t, 2H), 3.01 (d, 2H), 3.47-3.61 (m, 2H), 6.16-6.21 (m, 2H), 7.52 (s, 1H), 7.61-7.67 (m, 3H), 8.58 (d, 2H), 11.05 (s, 1H);

Chirality preparation HPLC through embodiment 160 separates, preparation following examples 170-171.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	170	The 2-phenyl-4-[(3R)-piperidines-3-base is amino]-1H-indoles-7-methane amide	334.42	335	10.87 (s, 1H) 7.69 (d, 2H) 7.57 (d, 1H) 7.45 (t, 2H) 7.28 (t, 1H) 7.20 (s, 1H) 6.96 (br s, 1H) 6.15 (d, 1H) 6.02 (d, 1H) 3.50 (d, 1H) 3.30 (s, 2H) 3.05-3.20 (m, 2H) 2.84 (d, 1H) 2.34-2.46 (m, 1H) 1.98 (s, 1H) 1.60-1.72 (m, 1H) 1.43-1.58 (m, 2H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	171	The 2-phenyl-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide	334.42	335	10.87 (s, 1H) 7.69 (d, 2H) 7.57 (d, 1H) 7.45 (t, 2H) 7.28 (t, 1H) 7.20 (s, 1H) 6.96 (br s, 1H) 6.15 (d, 1H) 6.02 (d, 1H) 3.50 (d, 1H) 3.30 (s, 2H) 3.05-3.20 (m, 2H) 2.84 (d, 1H) 2.34-2.46 (m, 1H) 1.98 (s, 1H) 1.60-1.72 (m, 1H) 1.43-1.58 (m, 2H).

Chirality preparation HPLC through embodiment 166 separates, preparation following examples 172-173.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	172	2-(3-fluorophenyl)-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide	352.41	353	10.98 (s, 1H), 9.19 (m, 1H), 9.08 (m, 1H), 7.63 (d, 2H), 7.56 (m, 2H), 7.50 (m, 1H), 7.34 (s, 1H), 7.13 (dt, 1H), 6.26 (d, 1H), 5.60 (br s, 2H), 4.00 (m, 1H), 3.41 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).
173	2-(3-fluorophenyl)-4-[(3R)-piperidines-3-base is amino]-1H-indoles-7-methane amide	352.41	353	10.98 (s, 1H), 9.19 (m, 1H), 9.08 (m, 1H), 7.63 (d, 2H), 7.56 (m, 2H), 7.50 (m, 1H), 7.34 (s, 1H), 7.13 (dt, 1H), 6.26 (d, 1H), 5.60 (br s, 2H), 4.00 (m, 1H), 3.41 (m, 1H), 3.21 (m, 1H), 2.92 (m, 1H), 2.80 (m, 1H), 2.0 (m, 1H), 1.93 (m, 1H), 1.76 (m, 1H), 1.69 (m, 1H).	172		352.41	353

Chirality preparation HPLC through embodiment 161 separates, preparation following examples 174-175.

Embodiment

The IUPAC title

MW(g/mol)

MS(ES，M+H)

¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	174	2-(4-chloro-phenyl-)-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide	368.87	369	10.75 (s, 1H), 9.10 (m, 2H), 7.55 (d, 2H), 7.45 (d, 1H), 7.33 (d, 2H), 7.15 (d, 1H), 6.08 (d, 1H), 5.45 (br s, 3H), 3.83 (m, 1H), 3.21 (m, 1H), 3.03 (m, 1H), 2.73 (m, 1H), 2.65 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.51 (m, 1H).
175	2-(4-chloro-phenyl-)-4-[(3R)-piperidines-3-base is amino]-1H-indoles-7-methane amide	368.87	369	10.75 (s, 1H), 9.10 (m, 2H), 7.55 (d, 2H), 7.45 (d, 1H), 7.33 (d, 2H), 7.15 (d, 1H), 6.08 (d, 1H), 5.45 (br s, 3H), 3.83 (m, 1H), 3.21 (m, 1H), 3.03 (m, 1H), 2.73 (m, 1H), 2.65 (m, 1H), 1.80 (m, 2H), 1.62 (m, 1H), 1.51 (m, 1H).	174		368.87	369

Chirality preparation HPLC through embodiment 162 separates, preparation following examples 176-177.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	176	2-(4-fluorophenyl)-4-[(3 S)-piperidines-3-base is amino]-1H-indoles-7-methane amide	352.41	353	10.89 (s, 1H), 8.92 (m, 1H), 8.73 (m, 1H), 7.75 (d, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.30 (t, 2H), 7.15 (d, 1H), 7.04 (br s, 1H), 6.33 (br s, 1H), 6.23 (d, 1H), 3.91 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H), 2.89 (m, 1H), 2.75 (m, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.66 (m, 1H).
177	2-(4-fluorophenyl)-4-[(3R)-piperidines-3-base is amino]-1H-indoles-7-methane amide	352.41	353	10.89 (s, 1H), 8.92 (m, 1H), 8.73 (m, 1H), 7.75 (d, 1H), 7.74 (d, 1H), 7.60 (d, 1H), 7.30 (t, 2H), 7.15 (d, 1H), 7.04 (br s, 1H), 6.33 (br s, 1H), 6.23 (d, 1H), 3.91 (m, 1H), 3.41 (m, 1H), 3.25 (m, 1H), 2.89 (m, 1H), 2.75 (m, 1H), 2.03 (m, 1H), 1.94 (m, 1H), 1.74 (m, 1H), 1.66 (m, 1H).	176		352.41	353

Embodiment 178

N-methyl-2-phenyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide 4-{[(3S)-and 1-(uncle-butoxy carbonyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] Pyridine-7-carboxylic acidTo (3S)-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester (2.00 grams, 4.60mmol) in add 6 N HCl (50mL), the solution that obtains is heated to reflux spends the night or be converted into product fully until the LCMS indication.Then reaction mixture is cooled to rt, decompression concentrates down and obtained in dry 24 hours title compound in vacuum drying oven.LCMS(ES，M+H＝3 54)。

(3S)-3-(the 7-[(methylamino) carbonyl]-2-phenyl thieno-[3,2-c] pyridin-4-yl } amino) piperidines- The 1-carboxylic acid tert-butyl esterWith 4-{[(3S)-1-(uncle-butoxy carbonyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-carboxylic acid adds and to contain HATU (81.0mg, 0.213mmol), the methylamine (THF of 2 M, 0.200mL, 0.426mmol), (0.037mL is 0.213mmol) and in the round-bottomed flask of DMF (1.0mL) for DIPEA.Reaction stirred is 12 hours under rt, uses saturated NH subsequently ₄(2 * 20mL) washing reaction mixtures, (2 * 20mL) extract Cl solution with EtOAc.Merge organic layer, through dried over mgso, filtration and under reduced pressure concentrated.With MPLC (SiO ₂100% hexane is to 100%EtOAc) purified mixture, obtain title compound.LCMS(ES，M+H＝467)。

N-methyl-2-phenyl-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amideTo (3S)-3-({ 7-[(methylamino) carbonyl]-2-phenyl thieno-[3,2-c] pyridin-4-yl } amino) add the dioxane solution (5.0mL) of 4 N HCl in piperidines-1-carboxylic acid tert-butyl ester, reaction stirred is 20 minutes under rt, and the concentrating under reduced pressure reactant obtains title compound subsequently. ¹H NMR δ8.93(m，1H)，8.77(m，1H)，8.49(m，2H)，8.28(m，1H)，7.73(d，2H)，7.50(m，2H)，7.38(m，1H)，4.54(m，1H)，3.21(m，2H)，2.92(m，2H)，2.83(d，3H)，2.00(m，2H)，1.72(m，2H)。LCMS(ES，M+H＝367)。

Synthetic in a similar fashion embodiment 179.

Embodiment

The IUPAC title

MW (g/mol)

MS (ES， M+H)

¹H NMR (300MHz；d ₆-DMSO; δ ppm), unless refer else

Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS (ES， M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	179	The 2-phenyl-4-[(3S)-piperidines-3-base is amino]-N-pyridin-4-yl thieno-[3,2-c] pyridine-7-methane amide	429.55	430	11.57(s，1H)，9.03(s，1H)，8.72(d，1H)，8.43(s，1H)，8.36(d，2H)，8.10(m，1H)，7.76(m，2H)，7.68(m，1H)，7.62(s，1H)，7.52(m，2H)，7.41(m，1H)，4.63(m，1H)，3.21(m，2H)，2.98(m，2H)，2.00(m，2H)，1.76(m，2H)

Embodiment 180

The 2-phenyl-4-[(3S)-piperidines-3-base is amino]-N-pyrazine-2-base thieno-[3,2-c] pyridine-7-formyl Amine

4-{[(3S)-and 1-(uncle-butoxy carbonyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine- The 7-carboxylic acidTo (3S)-3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester (2.00 grams, 4.60mmol) in add 6N HCl (50mL), the solution that obtains is heated to reflux and spends the night or be converted into product fully until the LCMS indication.Then this reactant is cooled to rt, decompression concentrates down and in vacuum drying oven dry 24 hours, obtains title compound.LCMS(ES，M+H＝354)。

(3S)-3-(2-phenyl-7-[(pyrazine-2-base is amino) and carbonyl] thieno-[3,2-c] pyridin-4-yl } amino) Piperidines-1-carboxylic acid tert-butyl esterIn 0 ℃, to contain amino pyrazine (113mg, add in the round-bottomed flask of toluene 1.19mmol) (1.0mL) solution trimethyl aluminium (2.0M in hexane, 0.600mL, 1.19mmol).Stirred this solution 30 minutes down in rt, then its adding is contained 4-{[(3S)-1-(uncle-butoxy carbonyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-carboxylic acid (108mg, 0.238mmol), HATU (136mg, 0.358mmol), (0.064mL is 0.358mmol) and in the round-bottomed flask of DMF (1.0mL) for DIPEA.In 100 ℃ of reaction stirred 12 hours, use saturated NH subsequently ₄(2 * 20mL) washing reaction mixtures are also used EtOAc (2 * 20mL) extractions to Cl solution.Merge organic layer, through dried over mgso, filtration and under reduced pressure concentrated, (5% to 95%MeCN/ water/0.1%TFA) purifying obtains title compound to mixture through preparation HPLC.LCMS(ES，M+H＝531)。

The 2-phenyl-4-[(3S)-piperidines-3-base is amino]-N-pyrazine-2-base thieno-[3,2-c] pyridine-7-formyl AmineTo (3S)-3-({ 2-phenyl-7-[(pyrazine-2-base is amino) carbonyl] thieno-[3,2-c] pyridin-4-yl } amino) add the dioxane solution (5.0mL) of 4 N HCl in piperidines-1-carboxylic acid tert-butyl ester, reaction stirred is 20 minutes under rt, decompression subsequently is the concentration response thing down, obtains title compound. ¹H NMRδ11.12(s，1H)，9.44(s，1H)，8.94(s，1H)，8.80(br s，1H)，8.48(s，1H)，8.42(s，1H)，8.34(s，1H)，7.88(m，1H)，7.76(m，2H)，7.52(m，2H)，7.40(m，1H)，4.61(m，1H)，3.24(m，2H)，2.94(m，2H)，2.02(m，2H)，1.75(m，2H)。LCMS(ES，M+H＝431)。

Embodiment 181

4-{[2-(hydroxymethyl) piperidines-3-yl] the oxygen base }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) pyridine-3-alcoholTo 2-(hydroxymethyl) pyridine-3-alcohol (14.86g, 91.96mmol) in 150mL THF, add tert-butyldimethylsilyl chloride (15.2g, 101mmol) and N, the N-dimethyl aminopyridine (20.0g, 101mmol).Reaction stirred is 4 hours under rt, and (3 * 100mL) abstraction reaction things also wash with water to use EtOAc subsequently.The organic layer that merges is through dried over mgso, filtration and under reduced pressure concentrated, through MPLC (SiO ₂100% hexane is to 100%EtOAc) obtain white solid sample title compound behind the purifying.LCMS(ES，M+H＝240)。

2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-alcoholUnder nitrogen atmosphere, (4.00g, EtOH and the water of each 10mL of adding add platinum oxide (IV) (1.00g) subsequently in high pressure vessel 16.7mmol) to containing 2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) pyridine-3-alcohol.Find time under decompression high pressure vessel and placed 50psi Pa Er hydrogenator 24 hours.Under nitrogen atmosphere, extract mixture out then, filter and with a large amount of MeOH rinsings through Celite pad.Concentrate the filtrate of collecting under the vacuum, obtain title compound (about 10% less important diastereomer) as mixture of isomers.LCMS(ES，M+H＝246)。

2-bromo-4-{[2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-yl] the oxygen base } thiophene Fen is [3,2-c] pyridine-7-nitrile also(295mg, 1.20mmol) (30.0mg 1.20mmol), stirs the mixture that obtains 20 minutes down in rt middle adding sodium hydride to the 2-that is dissolved in 3.0mL THF ({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-alcohol.Add then 2-bromo-4-chloro thiophene also [3,2-c] pyridine-7-nitrile (293mg, the 1.07mmol) slurries in 3.0mL THF, and under rt reaction stirred 1 hour.(2 * 20mL) extract the mixture that obtains with sodium bicarbonate (10mL) dilution and with EtOAc.Merge organic layer,, obtain title compound through dried over mgso, filtration and under reduced pressure concentrated.LCMS(ES，M+H＝483)。

4-{[2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-yl] the oxygen base }-the 2-phenyl Thieno-[3,2-c] pyridine-7-nitrileTo 2-bromo-4-{[2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-yl] the oxygen base } thieno-[3,2-c] pyridine-7-nitrile (516mg, 1.07mmol) the middle phenyl-boron dihydroxide (194mg that adds, 1.61mmol), cesium carbonate (1.04g, 3.21mmol), dioxane/water (4 mL/2 mL), add Pd (PPh then ₃) ₄(1 24mg, 0.107mmol).This reactant was heated to 80 ℃ of meters 1 hour, makes reaction be cooled to rt subsequently, filter and with MPLC (SiO ₂, 100% hexane is to 100%EtOAc) and purifying, obtain title compound.LCMS(ES，M+H＝480)。

4-{[2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-yl] the oxygen base }-the 2-phenyl Thieno-[3,2-c] pyridine-7-methane amideTo containing 4-{[2-({ [tertiary butyl (dimethyl) silyl] oxygen base } methyl) piperidines-3-yl] the oxygen base }-add the 12N HCl of 5.00mL in the flask of 2-phenyl thieno-[3,2-c] pyridine-7-nitrile.Reaction stirred mixture and monitor under rt with LCMS.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, concentrate down with MeOH diluted reaction mixture and decompression and to obtain product, it is through MPLC (SiO ₂, 100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains the title compound (about 10% less important diastereomer) as mixture of isomers.The analytical data that is present in the main isomer in the mixture is provided: ¹H NMR δ 9.31 (m, 1H), 8.93 (m, 1H), 8.64 (s, 1H), 8.44 (s, 1H), 8.27 (m, 1H), 7.84 (d, 2H), 7.69 (m, 1H), 7.46 (m, 3H), 5.70 (m, 1H), 3.68 (m, 2H), 3.54 (m, 1H), 3.34 (m, 1H), 3.06 (m, 1H), 2.17 (m, 1H), 1.85 (m, 2H), 1.67 (m, 1H).LCMS(ES，M+H＝384)。

Embodiment 182

4-{[2-(hydroxymethyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

2-(methoxycarbonyl) nicotinic acidTo furo [3,4-b] pyridine-5,7-diketone (41.0g, 275mmol) the middle MeOH that adds 200mL.This reactant is heated to about 1 hour of backflow, and vacuum concentration obtains as mixture of isomers title compound and 3-(methoxycarbonyl) pyridine-2-carboxylic acids (being respectively 2.3: 1) subsequently.LCMS(ES，M+H＝182)。

Uncle 3-[(-butoxy carbonyl) amino] the pyridine-2-carboxylic acids methyl estersTo 2-(methoxycarbonyl) nicotinic acid and 3-(methoxycarbonyl) pyridine-2-carboxylic acids (10.46g, add in mixture 57.7mmol) uncle-butanols (100mL) and TEA (8.85mL, 63.5mmol).Reaction stirred is 5 minutes under rt, add then diphenyl phosphoryl azide (13.1mL, 60.6mmol).This reactant is heated to refluxes and stir about 4 hours.Reaction mixture is cooled to rt, is concentrated into drying, being dissolved in EtOAc and water and saturated sodium bicarbonate again (respectively is 2 * 20mL) washings.Merge organic layer, through dried over mgso, filtration and under reduced pressure concentrated.Mixture obtains title compound and uncle 2-[(-butoxy carbonyl through column chromatography purification (100% hexane is to 100%EtOAc)) amino] nicotinic acid methyl ester (9.24g, 64% yield).LCMS(ES，M+Na＝275)。[2-(hydroxymethyl) pyridin-3-yl] t-butyl carbamate.To uncle 3-[(-butoxy carbonyl) amino] pyridine-2-carboxylic acids methyl esters and uncle 2-[(-butoxy carbonyl) amino] nicotinic acid methyl ester (5.00g, 19.8mmol) the middle THF/MeOH (30mL/3mL) that adds, make the reaction be cooled to 0 ℃, add subsequently sodium borohydride (1.49g, 39.6mmol).Reaction is warmed to rt and stirred 4 hours.Then reaction mixture is dissolved among the EtOAc and and washs with saturated sodium hydrogen carbonate solution.Merge organic layer, through dried over mgso, filtration and under reduced pressure concentrated, (5-95%MeCN/ water/0.1%TFA) separate obtains title compound and [3-(hydroxymethyl) pyridine-2-yl] t-butyl carbamate through preparation HPLC.Required isomer is through 1D NOE NMR experiment confirm. ¹H NMRδ8.78(br s，1H)，8.17(m，1H)，8.10(d，1H)，7.27(dd，1H)，4.64(s，2H)，1.46(s，9H)。LCMS(ES，M+H＝225)。

[2-(hydroxymethyl) piperidines-3-yl] t-butyl carbamateUnder the nitrogen atmosphere, (1.46g, EtOH and the water of each 5mL of adding add platinum oxide (IV) (500mg) subsequently in high pressure vessel 6.51mmol) to containing [2-(hydroxymethyl) pyridin-3-yl] t-butyl carbamate.Find time under decompression high pressure vessel and placed 50psi Pa Er hydrogenator 24 hours.Under nitrogen atmosphere, extract mixture out then, filter and with a large amount of MeOH rinsings through Celite pad.Concentrate the filtrate of collecting under the vacuum, obtain title compound as mixture of isomers.MS m/z 231(M+H)。

3-amino-2-(hydroxymethyl) piperidines-1-benzyl carboxylateIn round-bottomed flask, add [2-(hydroxymethyl) piperidines-3-yl] t-butyl carbamate (785mg, 3.41mmol), DIPEA (0.653mL, 3.75mmol) and CH ₂Cl ₂(10mL).Flask is cooled to 0 ℃, and adding chlorocarbonic acid benzyl ester (benzyl chloridocarbonate) (0.504mL, 3.58mmol).Reactant is warmed to rt and stirred 12 hours, use CH subsequently ₂Cl ₂Extract this mixture with EtOAc and wash with saturated sodium bicarbonate.The organic layer that merges is through dried over mgso, filtration and under reduced pressure concentrated.Resistates is through MPLC (SiO ₂100% hexane is to 100%EtOAc to 20%MeOH/CH ₂Cl ₂) purifying and dioxane solution (5mL) processing of directly using 4N HCl 30 minutes.Decompression is concentrated reaction mixture down, obtains title compound.LCMS(ES，M+H＝265)。

3-[(2-bromo-7-cyano thiophene is [3,2-c] pyridin-4-yl also) amino]-2-(hydroxymethyl) piperidines-1-carboxylic Acid benzyl esterTo containing 3-amino-2-(hydroxymethyl) piperidines-1-benzyl carboxylate (246mg, 0.932mmol) round-bottomed flask in add 2-bromo-4-chloro thiophene also [3,2-c] pyridine-7-nitrile (128mg, 0.466mmol), salt of wormwood (100mg, 0.700mmol) and NMP (5.0mL).Reaction mixture is heated to 80 ℃, per hour finishes, subsequently mixture is cooled to rt with the LCMS monitoring reaction.Add entry (50mL) and filter the solid that obtains, drying under reduced pressure obtained title compound in 12 hours.LCMS(ES，M+H＝502)。

3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-2-(hydroxymethyl) piperidines-1- Benzyl carboxylateTo 3-[(2-bromo-7-cyano thiophene also [3,2-c] pyridin-4-yl) amino]-middle phenyl-boron dihydroxide (0.699mmol), cesium carbonate (0.932mmol), the dioxane/water (2.0mL/1.0mL) of adding of 2-(hydroxymethyl) piperidines-1-benzyl carboxylate (0.466mmol), add Pd (PPh3) 4 (0.0466mmol) then.Reactant was heated to 80 ℃ of meters 1 hour, subsequently reaction is cooled to rt, filter and with MPLC (SiO ₂100% hexane is to 100%EtOAc) purifying obtains title compound.LCMS(ES，M+H＝499)。

4-{[2-(hydroxymethyl) piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-formyl AmineTo containing 3-[(7-cyano group-2-phenyl thieno-[3,2-c] pyridin-4-yl) amino]-add the 12N HCl of 5.00mL in the flask of 2-(hydroxymethyl) piperidines-1-benzyl carboxylate.Reaction stirred mixture and monitor under rt with LCMS.Added 12N HCl in per 12 hours again, the required product that is transformed fully.To be transformed when complete, use the MeOH diluted reaction mixture, under reduced pressure concentrate and obtain product, (purifying of 5-95%MeCN/ water/0.1%TFA) obtains the title compound (approximately ratio is 1/1) as mixture of isomers through preparation HPLC for it. ¹H NMRδ9.95(m，1H)，9.21(m，1H)，8.98(m，1H)，8.70(m，1H)，8.51(m，1H)，8.38(m，1H)，8.15(m，1H)，7.77(m，2H)，7.44(m，3H)，4.88(m，1H)，3.76(m，1H)，3.28(m，2H)，2.96(m，2H)，2.10(m，2H)，1.87(m，2H)。LCMS(ES，M+H＝383)。

Embodiment 183

The 2-phenyl-7-[(3S)-piperidines-3-base oxygen base]-the 1H-h-benzimidazole-4-carboxamide

4-fluoro-3-nitrobenzamide(12.0g dropwise adds CH in 64.8mmol) to 4-fluoro-3-nitrobenzoic acid ₂Cl ₂(300mL), (16.7mL is 195mmol) with about 0.100mL DMF for oxalyl chloride.Down stirred this mixture 3 hours in rt, subsequently reaction is cooled to-78 ℃ and in solution bubbling feed liquid NH ₃About 20 minutes.The yellow solid that obtains is through MPLC (SiO ₂100% hexane is to 100%EtOAc) purifying, obtain title compound (9.00g, 76% yield).LCMS(ES，M-H＝183)。

(3S)-and 3-[4-(aminocarboxyl)-2-nitro-phenoxy] piperidines-1-carboxylic acid tert-butyl esterTo (the 3S)-3-hydroxy piperidine-1-carboxylic acid tert-butyl ester that contains the DMF that is dissolved in 5.00mL (3.97g, add in solution 19.7mmol) sodium hydride (473mg, 19.7mmol).Down stirred resulting solution 30 minutes in rt, add subsequently the 4-fluoro-3-nitrobenzoic acid that is dissolved in 5.00mL DMF (3.29g, 17.9mmol).Stir this mixture 12 hours down or be converted into product fully in rt until the LCMS indication.In reaction mixture, add 20mL water then, filter resulting solid and drying under reduced pressure, obtain title compound (4.15g, 63% yield).LCMS(ES，M+H＝366)。 (3S)-and 3-[2-amino-4-(aminocarboxyl) phenoxy group] piperidines-1-carboxylic acid tert-butyl ester

To (3S)-3-[4-(the aminocarboxyl)-2-nitro-phenoxy that is dissolved in 50mL MeOH] (4.15g adds 10%Pd/C (800mg) to piperidines-1-carboxylic acid tert-butyl ester in solution 11.4mmol).Filling hydrogen 12 hours or be converted into product fully in the mixture that obtains until LCMS indication.Through the diatomite filtration mixture and with a large amount of MeOH rinsings, through MPLC (SiO ₂100% hexane is to 100%EtOAc to 20%MeOH/CH ₂Cl ₂) obtain required product behind the purifying.LCMS(ES，M+H＝336)。

(3S)-and 3-(4-(aminocarboxyl)-2{[imino-(phenyl) methyl] amino } phenoxy group) piperidines-1-carboxylic acid The tert-butyl esterIn 0 ℃, with trimethyl aluminium (2M in hexane, 17.9mL 35.8mmol) adds (3S)-3-[2-amino-4-(aminocarboxyl) phenoxy group] (1.20g is in the solution of 20mL THF 3.58mmol) for piperidines-1-carboxylic acid tert-butyl ester.This mixture is warmed to rt and stirred 1 hour, add benzonitrile (3.66mL, 10mL THF solution 35.8mmol) subsequently.Indicate the starting raw material completely consumed in 60 ℃ of stirred solutions until LCMS.Mixture is cooled to 0 ℃.Dropwise add 10% Rochelle salt solution (about 20mL).(4 * 20mL) extract mixture, and organic layer concentrates under filtration and the vacuum and obtains a material, through MPLC (SiO through dried over mgso with EtOAc ₂CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂) purifying, obtain title compound (464mg, 30% yield).LCMS(ES，M+H＝439)。

(3S)-and 3-{[4-(aminocarboxyl)-2-phenyl-1H-benzoglyoxaline-7-yl] the oxygen base } piperidines-1-carboxylic acid uncle Butyl esterIn (the 3S)-3-that is dissolved in each 3.0mL MeOH and water (4-(aminocarboxyl)-2-{[imino-(phenyl) methyl] amino } phenoxy group) piperidines-1-carboxylic acid tert-butyl ester solution, dropwise add clorox (0.100mL, 1.17mmol).Stir resulting solution 5 minutes down in rt, add the 3.0mL aqueous solution of yellow soda ash (148mg) subsequently.Then solution is heated to and refluxes and finish with the LCMS monitoring reaction.Treat starting raw material one consumption, this mixture is cooled to rt, with EtOAc and CH ₂Cl ₂/ MeOH (1/1) extracts, and organic layer is through dried over mgso, filtration and under reduced pressure concentrated.The mixture that obtains is through MPLC (SiO ₂100%CH ₂Cl ₂To 20%MeOH/CH ₂Cl ₂) purifying, obtain title compound.LCMS(ES，M+H＝437)。

The 2-phenyl-7-[(3S)-piperidines-3-base oxygen base]-the 1H-h-benzimidazole-4-carboxamideTo (3S)-3-{[4-(aminocarboxyl)-2-phenyl-1H-benzoglyoxaline-7-yl] the oxygen base } piperidines-1-carboxylic acid tert-butyl ester (18.7mg, 0.043mmol) the middle dioxane solution that adds the 4.0N HCl of 5.0mL.Reaction stirred is about 30 minutes under rt, and vacuum decompression concentrates down, and is dry under the high vacuum, obtains title compound. ¹H NMRδ9.60(m，1H)，9.10(m，2H)，8.48(s，2H)，7.98(m，1H)，7.85(m，1H)，7.63(m，3H)，7.03(d，1H)，5.16(m，1H)，4.13(m，1H)，3.69(m，1H)，3.46(m，1H)，3.27(m，1H)，2.00(m，2H)，1.79(m，1H)，1.62(m，1H)。LCMS(ES，M+H＝337)。

Embodiment 184

2-{4-[4-(methyl sulphonyl) piperazine-1-yl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide

1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl] piperazineTo 4-[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl] piperazine-1-carboxylic acid tert-butyl ester (235mg, 0.656mmol) the middle dioxane solution that adds the 4N HCl of 5.0mL, the solution that stirring obtains under rt 2 hours, decompression subsequently concentrates this solution down, obtains white solid sample title compound. ¹H NMRδ9.14(br s，1H)，7.54(d，2H)，6.96(d，2H)，3.43(m，4H)，3.18(m，4H)，1.25(s，12H)。

(3S)-and 3-{[7-cyano group-2-(4-piperazine-1-base phenyl) thieno-[3,2-c] pyridin-4-yl] amino } piperidines -1-carboxylic acid tert-butyl esterTo 1-[4-(4,4,5,5-tetramethyl--1,3,2-dioxo bora penta ring-2-yl) phenyl] piperazine (58.0mg, 0.225mmol) in add (3S)-3-[(2-bromo-7-cyano thiophene also [3,2-c] pyridin-4-yl) amino] piperidines-1-carboxylic acid tert-butyl ester (361mg, 0.826mmol), cesium carbonate (806mg, 2.48mmol), Pd (PPh ₃) ₄(95.4mg, 0.0826mmol) and dioxane/water (2.0mL/1.0mL).In 80 ℃ of reaction stirred 30 minutes, be cooled to rt, filter, with a large amount of EtOAc rinsings, concentrated down through dried over mgso and decompression.With MPLC (SiO ₂100%CH ₂Cl ₂To 20%CH ₃OH/CH ₂Cl ₂/ 3%NH ₄OH) purified mixture obtains title compound.LCMS(ES，M+H＝519)。

(3S)-and 3-[(7-cyano group-2-{4-[4-(methyl sulphonyl) piperazine-1-yl] phenyl } thieno-[3,2-c] pyrrole Pyridine-4-yl) amino] piperidines-1-carboxylic acid tert-butyl esterTo (the 3S)-3-{[7-cyano group-2-that is dissolved in 5.0mL THF (4-piperazine-1-base phenyl) thieno-[3,2-c] pyridin-4-yl] amino } piperidines-1-carboxylic acid tert-butyl ester (74.0mg, 0.143mmol) in dropwise add TEA (0.0239mL, 0.172mmol), dropwise add then methane sulfonyl chloride (0.0133mL, 0.172mmol).Reaction stirred is about 1 hour under rt, uses (2 * 20mL) washings and with EtOAc (2 * 20mL) abstraction reaction mixtures of saturated sodium hydrogen carbonate solution subsequently.Organic layer is through dried over mgso, filtration and under reduced pressure concentrated, with MPLC (SiO ₂100%CH ₂Cl ₂To 20%CH ₃OH/CH ₂Cl ₂/ 3%NH ₄OH) obtain title compound behind the purifying.LCMS(ES，M+H＝597)。

2-{4-[4-(methyl sulphonyl) piperazine-1-yl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno- [3,2-c] pyridine-7-methane amideTo (3S)-3-[(7-cyano group-2-{4-[4-(methyl sulphonyl) piperazine-1-yl] phenyl } thieno-[3,2-c] pyridin-4-yl) amino] add about 5mL 12N HCl in piperidines-1-carboxylic acid tert-butyl ester and stir resulting solution 12 hours down or indicate and be converted into required product fully until LCMS in rt.With the reaction mixture that MeOH dilution obtains, decompression concentrates down and with MPLC (SiO ₂100%CH ₂Cl ₂To 20%CH ₃OH/CH ₂Cl ₂/ 3%NH ₄OH) purifying obtains title compound. ¹H NMRδ9.40(m，1H)，8.87(m，1H)，8.48(s，2H)，8.31(m，2H)，7.66(d，2H)，7.12(d，2H)，4.53(m，1H)，3.38(m，5H)，3.25(m，5H)，3.03(m，2H)，2.94(s，3H)，2.01(m，2H)，1.78(m，2H)。LCMS(ES，M+H＝515)。

In a similar fashion, adopt suitable starting raw material to prepare embodiment 185-189.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	185	2-[4-(4-ethanoyl piperazine-1-yl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	478.62	479	9.23 (m, 1H), 8.84 (m, 1H), 8.47 (s, 1H), 8.26 (m, 1H), 7.62 (d, 2H), 7.08 (d, 2H), 4.51 (m, 1H), 3.58 (m, 5H), 3.45 (m, 2H), 3.24 (m, 5H), 2.04 (overlapping s and m, 5H), 1.80 (m, 2H)
186	2-{3-[4-(methyl sulphonyl) piperazine-1-yl] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	514.67	515	9.56(m，1H)，8.94(m，2H)，8.51(s，1H)，8.42(m，1H)，7.69(m，1H)，7.39(m，2H)，7.24(m，1H)，7.06(m，1H)，4.59(m，1H)，3.50(m，1H)，3.32(m，8H)，3.08(m，2H)，2.95(s，3H)，2.74(m，1H)，1.79(m，4H)	185		478.62	479
186		514.67	515		187	2-[3-(4-ethanoyl piperazine-1-yl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide	478.62	479	9.44 (m, 1H), 8.92 (m, 1H), 8.72 (m, 1H), 8.51 (s, 1H), 8.32 (m, 1H), 7.63 (m, 1H), 7.36 (m, 2H), 7.22 (d, 1H), 7.04 (m, 1H), 4.56 (m, 1H), 3.61 (m, 4H), 3.46 (m, 2H), 3.24 (m, 5H), 3.01 (m, 1H), 2.01 (overlapping s and m, 5H), 1.78 (m, 2H)

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	188	(4-piperazine-1-base phenyl)-4-[(3S)-piperidines-3-base is amino for 2-] thieno-[3,2-c] pyridine-7-methane amide	436.58	437	9.82(m，1H)，9.36(m，1H)，9.08(m，1H)，8.91(m，1H)，8.57(m，1H)，8.49(s，1H)，7.76(m，1H)，7.69(d，2H)，7.11(d，2H)，4.64(m，1H)，3.49(m，5H)，.3.28(m，6H)，3.02(m，1H)，2.05(m，2H)，1.83(m，2H)
189	(3-piperazine-1-base phenyl)-4-[(3S)-piperidines-3-base is amino for 2-] thieno-[3,2-c] pyridine-7-methane amide	436.58	437	9.65(m，1H)，9.21(m，1H)，9.08(m，1H)，8.94(m，1H)，8.53(s，1H)，8.38(m，1H)，7.64(m，1H)，7.38(m，2H)，7.22(m，2H)，4.64(m，1H)，3.49(m，5H)，3.23(m，6H)，3.02(m，1H)，2.02(m，2H)，1.80(m，2H)	188		436.58	437

Embodiment 190

4-[(4-hydroxy piperidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use trans-3-amino-4-hydroxy piperidines-1-benzyl carboxylate (by at J.Med.Chem.1997, describing in 40,226 synthetic) to prepare as the starting raw material in the step 7. ¹H NMRδ9.29(m，1H)，8.85(m，1H)，8.60(m，1H)，8.51(s，1H)，8.19(m，1H)，7.77(d，2H)，7.56(m，1H)，7.50(dd，2H)，7.40(dd，1H)，4.42(m，1H)，4.0-4.3(br s，1H)，3.88(m，1H)，3.51(m，1H)，3.27(m，1H)，3.05(m，2H)，2.16(m，1H)，1.73(m，1H)。LCMS(ES，M+H＝369)。

Prepare embodiment 191 in a similar fashion.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	191	4-[(4-hydroxy piperidine-3-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	374.49	375	9.07(m，1H)，8.80(m，1H)，8.50(s，1H)，8.28(m，1H)，8.10(m，1H)，7.85(m，1H)，7.73(dd，1H)，7.48(dd，1H)，7.44(m，1H)，4.39(m，1H)，3.8-4.2(br s，1H)，3.8(m，1H)，3.49(m，1H)，3.27(m，1H)，3.01(m，2H)，2.14(m，1H)，1.71(m，1H)

Embodiment 192

4-[(3-hydroxy piperidine-4-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide

In mode similar to Example 1, but use trans-4-amino-3-hydroxy piperidine-1-benzyl carboxylate (by at J.Med.Chem.1997, describing in 40,226 synthetic) to prepare as the starting raw material in the step 7. ¹H NMR δ 8.85(m，1H)，8.73(m，1H)，8.48(s，1H)，8.36(br，1H)，8.08(m，1H)，7.75(d，2H)，7.55(br，1H)，7.51(t，2H)，7.40(t，1H)，5.74(br，1H)，4.33(m，1H)，3.93(m，1H)，3.38(m，2H)，3.04(m，1H)，2.86(m，1H)，2.27-2.16(m，1H)，1.90-1.67(m，1H)。LCMS(ES，M+H＝369)。

To prepare embodiment 193 with embodiment 192 similar modes.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	193	4-[(3-hydroxy piperidine-4-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	374.49	375	9.08(m，1H)，8.85(m，1H)，8.50-8.10(m，2H)，8.46(s，1H)，7.91(m，1H)，7.75(dd，1H)，7.63(br，1H)，7.49(dd，1H)，5.83(br，1H)，4.33(m，1H)，3.95(m，1H)，3.40(m，2H)，3.01(m，1H)，2.82(m，1H)，2.25-2.14(m，1H)，1.96-1.78(m，1H)

With with embodiment 58 similar modes, adopt suitable starting raw material to prepare embodiment 194-195.

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; D6-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; D6-DMSO; δ ppm), unless refer else	194	The 4-{ ethyl [(3S)-and piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	380.51	381	9.26 (m, 1H), 8.95 (m, 1H), 8.63 (s, 1H), 8.19 (m, 1H), 7.86 (m, 2H), 8.77 (s, 1H), 7.49 (m, 3H), 7.40 (m, 2H), 4.75 (m, 1H), 3 77 (m, 2H), 3.40 (m, 1H), 3.23 (m, 2H), 2.87 (m, 1H), 1.96 (m, 3H), 1.74 (m, 1H), 1.17 (t, 3H).

Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW (g/mol)	MS (ES, M+H)	¹H NMR (300MHz; d ₆-DMSO; δ ppm), unless refer else	195	The 4-{ ethyl [(3S)-and piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide	386.54	387	9.1 (m, 1H), 8.87 (m, 1H), 8.61 (s, 1H), 8.14 (m, 1H), 8.01 (s, 1H), 7.70 (m, 3H), 7.51 (m, 1H), 4.68 (m, 1H), 3.72 (m, 2H), 3.41 (m, 1H), 3.20 (m, 2H), 2.83 (m, 1H), 1.94 (m, 3H), 1.74 (m, 1H), 1.14 (t, 3H).

With with the similar mode of embodiment 69-70, adopt suitable starting raw material to prepare embodiment 196-197.

Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else
Embodiment	The IUPAC title	MW(g/mol)	MS(ES，M+H)	¹H NMR(300MHz；d ₆-DMSO; δ ppm), unless refer else	196	4-[(is trans-2-ethyl piperidine-3-yl) and amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	380.51	381	9.05(m，1H)，8.86(m，1H)，8.50(s，1H)，8.43(m，1H)，8.18(br s，1H)，7.75(d，2H)，7.49(d，2H)，7.39(dd，1H)，7.34(brs，1H)，6.68(br s，1H)，4.48(m，1H)，3.26(m，2H)，2.97(m，1H)，2.05(m，1H)，1.88(m，3H)，1.63(m，2H)，0.95(t，3H)
197	4-[(cis-2-ethyl piperidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide	380.51	381	10.20(m，1H)，9.30(m，1H)，9.19(m，1H)，8.52(s，1H)，8.39(br s，1H)，7.82(d，2H)，7.67(m，1H)，7.50(dd，2H)，7.41(dd，1H)，6.75(br s，1H)，4.96(m，1H)，3.50(m，1H)，3.31(m，1H)，3.00(m，1H)，2.05(m，2H)，1.80(m，4H)，0.86(t，3H)	196		380.51	381

Claims

1. formula (I) compound or its pharmacy acceptable salt,

Wherein:

A and D independently are selected from N, CH, S, O and NR separately ⁴

L is selected from NR ⁵, O and S;

X and Y independently are selected from N and CH separately;

R ²Be selected from (C _1-3Alkyl) NR ⁷R ⁸, contain at least one nitrogen-atoms 4-to 7-unit heterocycle ,-the CO carbocylic radical ,-the CO heterocyclic radical ,-CO (C _1-6Alkyl) ,-CONR ²⁸R ²⁹,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-CO ₂Heterocyclic radical ,-CO ₂NR ²⁸R ²⁹,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCycloalkyl ,-S (O) _xCycloalkenyl group ,-S (O) _xHeterocyclic radical, S (O) _yNR ²⁸R ²⁹With-(C _1-6Alkyl) S (O) _yNR ²⁸R ²⁹Wherein x independently is 1 or 2 and R wherein for 0-2 and y independently ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; Wherein if heterocyclic radical also contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group;

R ⁴Be selected from H, C _1-3Alkyl, cyclopropyl and CF ₃

R ³⁰And R ³⁶Independently be selected from separately halo, nitro ,-NR ²⁸R ²⁹, cyano group, isocyano-, C _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl, ketone group (=O) ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-OC (O) C _1-6Alkyl ,-NHCHO ,-N (C _1-6Alkyl) CHO ,-NHCONR ²⁸R ²⁹,-N (C _1-6Alkyl) CONR ²⁸R ²⁹,-NHCO (C _1-6Alkyl) ,-the NHCO carbocylic radical ,-NHCO (heterocyclic radical) ,-NHCO ₂(C _1-6Alkyl);-NHCO ₂H ,-N (C _1-6Alkyl) CO (C _1-6Alkyl) ,-NHSO ₂(C _1-6Alkyl), carboxyl ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂H ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-OC (O) (NR ²⁸R ²⁹), sulfydryl ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _xNR ²⁸R ²⁹Wherein x independently is O-2;

R ²⁷And R ³¹Independently be selected from cyano group, C separately _1-6Alkyl, C _2-6Thiazolinyl, C _2-6Alkynyl, aryl, cycloalkyl, cycloalkenyl group, heterocyclic radical, hydroxyl ,-O (C _1-6Alkyl) ,-the O carbocylic radical ,-(C _1-6Alkyl)-O-(C _1-6Alkyl) ,-amidino groups ,-CHO ,-CONR ²⁸R ²⁹,-CO (C _1-6Alkyl) ,-the CO heterocyclic radical ,-the CO cycloalkyl ,-the CO cycloalkenyl group ,-CO ₂(C _1-6Alkyl) ,-CO ₂Carbocylic radical ,-S (O) _x(C _1-6Alkyl) ,-S (O) _xCarbocylic radical ,-S (O) _xHeterocyclic radical and-S (O) _yNR ²⁸R ²⁹Wherein x independently is that 0-2 and y independently are 1 or 2.

2. according to compound or its pharmacy acceptable salt, the wherein R of claim 1 ²Be selected from (C _1-3Alkyl) NR ⁷R ⁸With 4-to the 7-unit heterocycle, the wherein R that contain at least one nitrogen-atoms ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; Wherein if heterocyclic radical also contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

3. according to compound or its pharmacy acceptable salt, the wherein R of claim 1 ²For containing 4-to 7-unit heterocycle, the wherein R of at least one nitrogen-atoms ²Can be by one or more R on one or more carbon atoms ¹³The optional replacement; Wherein if heterocyclic radical also contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁴Optional replacement of group.

4. according to compound or its pharmacy acceptable salt, the wherein R of claim 1 ¹Be selected from aryl and heterocyclic radical and R wherein ¹Can be by one or more R on one or more carbon atoms ⁹The optional replacement; Wherein if heterocyclic radical contains-the NH-part, and then the nitrogen of described part can be selected from R ¹⁰Optional replacement of group.

5. according to compound or its pharmacy acceptable salt, the wherein R of claim 1 ³Be H.

6. according to compound or its pharmacy acceptable salt of claim 1, wherein X is N; Y is CH; A is that CH and D are S.

7. according to compound or its pharmacy acceptable salt of claim 1, wherein X is CH; Y is CH; A is that CH and D are NR ⁴

8. according to compound or its pharmacy acceptable salt of claim 1, wherein L is NR ⁵

9. according to formula I compound or its pharmacy acceptable salt of claim 1, wherein

A is CH;

D is S;

L is NR ⁵

X is N;

Y is CH;

R ³Be H;

R ⁵Be H or C _1-3Alkyl.

10. according to formula I compound or its pharmacy acceptable salt of claim 1, wherein

A is CH;

D is NR ⁴

L is NR ⁵

X is CH;

Y is CH;

R ³Be H;

R ⁴Be H, C _1-3Alkyl, cyclopropyl and CF ₃

R ⁵Be H or C _1-3Alkyl.

11. according to formula I compound or its pharmacy acceptable salt of claim 1, described compound is selected from

1) 2-phenyl-4-[(3 S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

2) 4-[(3S)-piperidines-3-base is amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

3) 2-(3-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

4) 4-[(3S)-piperidines-3-base is amino]-2-(2-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

5) 2-(4-fluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

6) 2-(3, the 4-difluorophenyl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

7) 2-(1-benzyl-1H-pyrazoles-4-yl)-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

8) 4-{ methyl [(3S)-piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

9) 2-(3-fluorophenyl)-4-{ methyl [(3S)-piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide;

10) 2-(4-fluorophenyl)-4-{ methyl [(3S)-piperidines-3-yl] amino } thieno-[3,2-c] pyridine-7-methane amide;

11) 4-{ methyl [(3S)-piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

12) 4-{[trans-pipecoline-3-yl] amino-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

13) 2-(3-fluorophenyl)-4-{[trans-pipecoline-3-yl] amino thieno-[3,2-c] pyridine-7-methane amide;

14) 4-{[trans-pipecoline-3-yl] amino-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

15) 2-(4-fluorophenyl)-4-{[trans-pipecoline-3-yl] amino thieno-[3,2-c] pyridine-7-methane amide;

16) 4-{[(2R, 3S)-pipecoline-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

17) 4-{[(2R, 3S)-pipecoline-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

18) 4-{ methyl [trans-pipecoline-the 3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

19) 4-[(2,6-lupetidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

20) 4-[(2,6-lupetidine-3-yl) amino]-2-(3-fluorophenyl) thieno-[3,2-c] pyridine-7-methane amide;

21) 4-[(2,6-lupetidine-3-yl) amino]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

22) amino 4-[(6-methyl piperidine-3-yl)]-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

23) amino 4-[(6-methyl piperidine-3-yl)]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

24) methyl 2-{4-[(dimethylamino)] phenyl }-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

25) 4-[(3S)-piperidines-3-base is amino]-2-[4-(piperidines-1-ylmethyl) phenyl] thieno-[3,2-c] pyridine-7-methane amide;

26) 2-[4-(morpholine-4-ylmethyl) phenyl]-4-[(3S)-piperidines-3-base is amino] thieno-[3,2-c] pyridine-7-methane amide;

27) 2-(4-chloro-phenyl-)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide;

28) 2-(4-fluorophenyl)-4-(piperidines-3-base is amino)-1H-indoles-7-methane amide;

29) 2-phenyl-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide;

30) 2-(3-fluorophenyl)-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide;

31) 2-(4-chloro-phenyl-)-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide;

32) 2-(4-fluorophenyl)-4-[(3S)-piperidines-3-base is amino]-1H-indoles-7-methane amide;

33) 4-{ ethyl [(3S)-piperidines-3-yl] amino }-2-phenyl thieno-[3,2-c] pyridine-7-methane amide;

34) 4-{ ethyl [(3S)-piperidines-3-yl] amino }-2-(3-thienyl) thieno-[3,2-c] pyridine-7-methane amide;

35) 4-[(trans-2-ethyl piperidine-3-yl) amino]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide; With

36) amino 4-[(cis-2-ethyl piperidine-3-yl)]-2-phenyl thieno-[3,2-c] pyridine-7-methane amide.

12. formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11, the illness that described compound is used for the treatment of or prevention is relevant with cancer.

13. formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11, described compound is used for the treatment of or the prophylaxis of tumours disease, as mammary cancer, ovarian cancer, lung cancer, colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma, comprise CLL and CML, the tumour of maincenter and peripheral nervous system and other tumor type are such as melanoma, multiple myeloma, fibrosarcoma and osteosarcoma and malignant brain tumor.

14. formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11, described compound is used for the treatment of or prevents to comprise the proliferative disease of autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder.

15. the method for a restrictive cell propagation in the human or animal, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that gives the effective therapeutic dose of described human or animal.

16. the human or animal's of cancer method is suffered from a treatment, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that gives the effective therapeutic dose of described human or animal.

17. a prophylactic treatment method for cancer, described method comprise formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that needs the effective therapeutic dose of the human or animal of such treatment.

18. the human or animal's of neoplastic disease method is suffered from a treatment, described neoplastic disease is for example mammary cancer, ovarian cancer, colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma, comprise CLL and CML, the tumour of maincenter and peripheral nervous system and other tumor type be melanoma for example, multiple myeloma, fibrosarcoma and osteosarcoma, and malignant brain tumor, among the claim 1-11 requirement of any one or its pharmacy acceptable salt.

19. the human or animal's of proliferative disease such as autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder method is suffered from a treatment, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that gives the effective therapeutic dose of described human or animal.

20. a treatment method for cancer, described method comprises formula (I) compound or its pharmacy acceptable salt and the antitumour drug of any one requirement among the administration of human claim 1-11.

21. a treatment method for cancer, described method comprises formula (I) compound or its pharmacy acceptable salt and the dna damage agent of any one requirement among administration of human or the animal right requirement 1-11.

22. the method for the infection that a treatment is associated with cancer, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that needs the effective therapeutic dose of the human or animal of such treatment.

23. the method for the infection that a prophylactic treatment is associated with cancer, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that needs the effective therapeutic dose of the human or animal of such treatment.

24. a medicinal compositions, it comprises formula (I) compound or its pharmacy acceptable salt and at least a pharmaceutically acceptable carrier, thinner or the vehicle of any one requirement among the claim 1-11.

25. the formula of any one requirement (I) compound or its pharmacy acceptable salt application in the preparation medicine among the claim 1-11.

26. among the claim 1-11 formula of any one requirement (I) compound or its pharmacy acceptable salt preparation be used for the treatment of or the medicine of preventing cancer in application.

27. among the claim 1-11 formula of any one requirement (I) compound or its pharmacy acceptable salt preparation be used for the treatment of or the medicine of prophylaxis of tumours disease in application, described neoplastic disease is for example mammary cancer, ovarian cancer, lung cancer, colorectal carcinoma, the rectum cancer, prostate cancer, cancer of bile ducts, osteocarcinoma, bladder cancer, the incidence cancer, kidney, liver cancer, gastrointestinal tissue's cancer, the esophageal carcinoma, carcinoma of the pancreas, skin carcinoma, carcinoma of testis, thyroid carcinoma, uterus carcinoma, cervical cancer, the cancer of carcinoma of vagina or other tissue, and leukemia and lymphoma comprise CLL and CML, the tumour of maincenter and peripheral nervous system and other tumor type are such as melanoma, multiple myeloma, fibrosarcoma and osteosarcoma, and malignant brain tumor.

28. the formula of any one requirement (I) compound or its pharmacy acceptable salt are used for the treatment of or prevent application in the medicine of proliferative disease in preparation among the claim 1-11, described proliferative disease comprises autoimmune disorder, inflammation, nervous system disease and cardiovascular disorder.

29. one kind is suppressed the kinase whose method of CHK1, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that needs the effective therapeutic dose of the animal or human of described inhibition.

30. the formula of any one requirement (I) compound or its pharmacy acceptable salt are used for suppressing the application of the medicine of CHK1 kinase activity among the claim 1-11 in preparation.

31. the formula of any one requirement (I) compound or its pharmacy acceptable salt are used for the application of the medicine of restrictive cell propagation among the claim 1-11 in preparation.

32. one kind is suppressed the kinase whose method of Pak, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that needs the effective therapeutic dose of the animal or human of described inhibition.

33. the formula of any one requirement (I) compound or its pharmacy acceptable salt are used for suppressing the application of the medicine of Pak kinase activity among the claim 1-11 in preparation.

34. the tumorigenic method of restriction in the human or animal, described method comprises formula (I) compound or its pharmacy acceptable salt of any one requirement among the claim 1-11 that gives the effective therapeutic dose of described human or animal.

35. a medicinal compositions that is used for producing the Pak kinase inhibitory activity warm-blooded animal, it comprise with pharmaceutically acceptable diluent or carrier blended claim 1-11 in formula (I) compound or its pharmacy acceptable salt of any one definition.

36. the formula of any one requirement (I) compound or its pharmacy acceptable salt are used for limiting the application of tumorigenic medicine among the claim 1-11 in preparation.

37. formula (IV), (1V '), (VI), (VI '), (IX), (XI), (XII) and (XIII) compound, described compound is used as intermediate in the preparation of formula (I) compound or its salt of claim 1 definition

R wherein ¹, R ², R ³And R ⁵As definition and Z in formula (I) is halo.

38. one kind prepares formula (I) compound according to claim 1 or the method for its pharmacy acceptable salt, wherein X is N, and Y is CH, and A is CH, and D is S, R ³For H and L are NR ⁵, described method comprises:

A. make formula (II) compound

Wherein Z is a halo, as bromo, chloro or iodo, with R wherein ²And R ⁵Formula (III) amine as definition in formula (I) reacts in the presence of following alkali,

NHR ²R ⁵

(III)

Obtain formula (IV) compound

B. make formula (IV) compound and formula V or the reaction of (V ') compound,

R ¹B(OR’) ₂

(V) (V’)

R wherein ¹As definition and R ' in formula (I) is H or methyl, obtains formula (VI) compound

(VI)；

C. make formula (VI) compound hydrolysis, form the compound shown in the formula (IA) according to formula (I)

D. then if desired:

Ii) remove any blocking group;

Iii) form pharmacy acceptable salt.

39. the method for preparation formula (I) compound or its pharmacy acceptable salt, wherein X is N, and Y is CH, and A is CH, and D is S, R ³For H and L are O, described method comprises:

A. make formula (II) compound

Wherein Z is a halo, as bromo, chloro or iodo, with R wherein ²As formula (the III ') alcohol of definition in formula (I),

R ²OH

(III’)

In the presence of alkali, react, obtain formula (IV ') compound

B. make formula (IV ') compound and formula V or (V ') compound reaction,

R ¹B(OR’) ₂

(V) (V’)

R wherein ¹As definition and R ' in formula (I) is H or methyl, obtains formula (VI ') compound

C. hydrolyzing type (VI ') compound forms the compound according to formula (I) shown in the formula (IB)

D. then if desired:

Ii) remove any blocking group;

Iii) form pharmacy acceptable salt.

40. the method for preparation formula (I) compound or its pharmacy acceptable salt, wherein X is CH, and Y is CH, and A is CH, and D is NR ⁴With L be NR ⁵, described method comprises:

A. make wherein R " be formula (VII) compound of H, methyl, ethyl or benzyl

With R wherein ¹As formula (VIII) reactive ketone of definition in formula (I),

Obtain formula (IX) indoles

R ³NH ₂

(X)

Obtain formula (XI) compound

C. make the reduction of formula (XI) compound, form formula (XII) amine

D. make formula (XII) compound and suitable R ²Aldehyde, ketone, carboxylic acid or SULPHURYL CHLORIDE reaction, wherein R ²As definition in formula (I), form the compound shown in the formula (IC) according to formula (I)

Perhaps as selecting, make the reaction of formula (XII) compound and Sodium Nitrite and copper halide, form formula (XIII) compound, wherein Z is a halo,

NHR ²R ⁵

(III)

In the presence of catalyzer, react, obtain the compound shown in the formula (ID) according to formula (I)

F. then if desired:

Ii) remove any blocking group;

Iii) form the formula (IC) or (ID) pharmacy acceptable salt of compound.