CN103833753B - Alkynyl compound and its use method and purpose - Google Patents

Abstract

The invention provides a novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation, and a use of the novel substituted alkynyl compound and its pharmaceutically acceptable salt and medicinal preparation in adjustment of protein kinase activity and intercellular or intracellular signal response. The invention also relates to a pharmaceutical composition containing the novel substituted alkynyl compound and a method for treating high-proliferative diseases of mammals especially such as human by the pharmaceutical composition.

Description

Alkynyl compoundss and its using method and purposes

Invention field

The invention belongs to drug world and be particularly used for the compound for the treatment of cancer, compositionss and application thereof and make Use method.Especially, compound of the present invention is can be used as the substituted alkynyl compound of kinases inhibitor.

Background of invention

Protein kinase, as the important regulator of cell function, is the member that in gene family, quantity is maximum, function is the widest One of.They, by increasing phosphate group to substrate protein, adjust activity, position and the allomeric function of multiple protein, and participate in Layout many cellular processes.Kinases in the cooperation of signal transduction and sophisticated functions, such as: cell cycle, occupy very prominent Position.In 518 kinds of human kinase proteins, there are 478 kinds due to catalytic domain Sequences similar, be included into a superfamily, according to growth The similarity of sequence and biochemical activity, they are segmented into different groups, family or subfamily again.

Wherein said kinases partial list include abl, aatk, alk, akt, axl, bmx, bcr-abl, blk, brk, btk, csk、c-kit、c-met、c-src、c-fins、cdk1、cdk2、cdk3、cdk4、cdk5、cdk6、cdk7、cdk8、cdk9、 cdk10、craf1、csf1r、csk、ddr1、ddr2、epha、ephb、egfr、erbb2、erbb3、erbb4、erk、fak、fes、 fer、fgfr1、fgfr2、fgfr3、fgfr4、fgfr5、fgr、flt-1、fps、frk、fyn、gsg2、gsk、hck、ilk、 insrr、irak4、itk、igf-1r、ins-r、jak、ksr1、kdr、lmtk2、lmtk3、ltk、lck、lyn、matk、mertk、 mltk、mst1r、musk、npr1、ntrk、mek、plk4、ptk、p38、pdgfr、pik、pkc、pyk2、ret、ror1、ror2、 ryk、ros、ron、sgk493、src、srms、styk1、syk、tec、tek、tex14、tnk1、tnk2、tnni3k、txk、 Tyk2, tyro3, tie, tie2, trk, yes and zap70.

Receptor tyrosine kinase is the transmembrane protein that a type is enriched, can be used as cytokine, somatomedin, hormone Receptor with other signaling molecules.Receptor tyrosine kinase is expressed in polytype cell, plays the part of in various cellular processes Drill key player, including cell growth, differentiation and angiogenesis.The activation of kinases starts from extracellular regions and ligand binding, then Cause conformation change, lead to Receptor dimerization, mutual phosphorylation between the receptor of dimerization, outside subsequent autophosphorylation catalysis region Tyrosine residue.This autophosphorylation can stable activation receptor conformation, can build in the albumen of signal transduction in the cell again Vertical phosphorylation heap plot point.

Receptor tyrosine kinase (rtks) is highly active (by receptor in many human entity tumors and malignant hematologic disease Activated mutant, gene amplifies, the approach such as growth factor activation).The acceleration activation of rtk has promotion to make to various tumorigenesis factors With, such as hypertrophy, survival, intrusion, transfer and angiogenesis, therefore, the activity of suppression receptor tyrosine kinase is considered as cancer Effective scheme (the sharma ps for the treatment of;et al.“receptor tyrosine kinase inhibitors as potent weapons in war against cancers.”curr pharm des.2009,15,758).

Receptor tyrosine kinase anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (alk), belongs to Insulin receptor INSR superfamily, swells with multiple human bodies The generation of tumor is relevant.It is true that tentatively having confirmed alk presented in constitutively activate and oncogene fusion, to exist Nuclear phosphoprotein (npm)-alk- in primary cutaneous type (a kind of lymphadenomatous separate type of Fei Huojinsen) is the most Common (morris, s.w.;et al.“fusion of a kinase gene,alk,to a nucleolar protein gene,npm,in non-hodgkin's lymphoma.”science1994,263,1281).

Additionally, people are also found that alk fusion gene in Inflammatory myofibroblastic tumor (imts), and in esophageal squamous cell It has been found that alk fusion gene tpm4-alk in the subspecies of shape cell carcinoma.Research display, familial form and diversity nerve In blastoma, all there is the mutation of multiple alk genes.This mutation being present in neuroblastoma cell can cause group Molding alk phosphorylation and hypofunction.Contrary, the quick of cell strain can be suppressed using srna and small molecule alk inhibitor Increase (palmer, r.h.;et al.“anaplastic lymphoma kinase:signalling in development and disease.”biochem.j.2009,420,345).

Recent years, people confirm, in nonsmall-cell lung cancer (nsclc) cell, exist by part echinoderm micro-pipe phase Close albumen sample 4(eml4) multiple hypotypes of the fusion gene of gene and alk genomic constitution.About nsclc patient's quilt of 3-7% Detection eml4-alk fusion gene transcript.Internal and external test confirms, eml4-alk fusion gene albumen has carcinogenic The mankind are suffered from nsclc and have a major impact (soda, m. by activity of conversion;et al“identification of the transforming eml4-alk fusion gene in non-small-cell lung cancer.”nature2007, 448,561).

The fusion gene of alk shows obvious carcinogenecity, and the tyrosine kinase activity of its exception can strengthen cell proliferation And survival, lead to cytoskeleton rearrangement, so that cell shape is changed.During carcinogenic alk signal transduction, alk and downstream Interaction of molecules, then signal path in active cell, as most of normal and carcinogenic tyrosine kinase, alk melts Close gene and can activate multiple different paths, these paths are closely coupled, overlap, and eventually form a complicated signal Transduction network.According to the literature, the most related, and study more clearly path have three: ras-erk(extracellular signal adjust Kinases) path, jak3(janus kinases 3)-stat3 path and pi3k(phosphatidyl-inositol 3-kinase)-akt path.This three lead to Many sites in road can mediate the activation of alk.In a word, jak3-stat3 path and pi3k-akt path are deposited to cell Live and phenotypic alternation plays vital effect (chiarle, r.;et al.“the anaplastic lymphoma kinase in the pathogenesis of cancer.”nat.rev.cancer2008,8,11;barreca,a.;et al.“anaplastic lymphoma kinase(alk)in human cancer.”j.mol.endocrinol.2011,47, r11).

Completely, normal alk receptor be there is also with the generation of other malignancy diseases and associates, such as, glioblast Tumor, neuroblastoma, breast carcinoma, etc..In the collection of human cancer cell's strain is investigated, dirks et al. confirms, in god Through there is the expression of alk transcript in system cells strain and most of ectoderm solid cancer cell strain, these cell strains include Retinoblastoma, melanoma and breast carcinoma (dirks, p.b. " cancer ' s source in the peripheral nervous system.”nature medicine2008,14,373).

C-met, i.e. C-MET HGFr (hgfr), its main application point is in endotheliocyte, and has proven to It, in endotheliocyte, myogenous cell, all has expression in hematopoietic cell and motor neuron.The natural part of c-met is hepatocyte Somatomedin (hgf), it is a multi-functional growth factor, i.e. dispersion factor (sf).In fetus and adult, activate c-met The formation of some forms can be promoted, such as, invasive growth will lead to the fast-growth of cell, intercellular division, and carefully Born of the same parents to about migrate (peschard p.;park m.“from tpr-met to met,tumorigenesis and tubes.”oncogene2007,26,1276;stellrecht cm;gandhi v.“met receptor tyrosine kinase as a therapeutic anticancer target.”cancer letter2009,280,1).

There is lasting c-met stimulation, overexpression or variation in the human malignancies being widely present, including breast carcinoma, liver Cancer, pulmonary carcinoma, ovarian cancer, renal carcinoma, thyroid carcinoma, colon cancer, glioblastoma, carcinoma of prostate etc..C-met equally involves tremulous pulse medicated porridge Sample hardening and pulmonary fibrosiss.By the interaction of mesenchyma stroma of tumors, including hgf/c-met approach, make the invasion and attack of these cancerous cell The property speed of growth thoroughly improves.Therefore, a large amount of evidence display c-me signal responses are had with certain cancers advancing of disease speed Close, and improve its role status (migliore c. in developing with the cancer drug with c-met as major target class; giordano s.“molecular cancer therapy:can our expectation be met.” eur.j.cancer2008,44,641;benedetta peruzzi;donald p.bottaro.“targeting the c- met signaling pathway in cancer.”clinical cancer research2006,12,3657).Instantly, Medicine (joseph paul eder just in clinical studies for the exploitation of c-met signal path;et al.“novel therapeutic inhibitors of the c-met signaling pathway in cancer.”clinical cancer research2009,15,2207;“paolo m.;et al.drug development of met inhibitors:targeting oncogene addiction and expedience.”nature review drug discovery2008,7,504).

Clinically, there is alk the and/or c-met inhibitor of many treating cancers, such as: gram Zhuo replaces Buddhist nun (crizotinib), a kind of small molecule atp competitiveness alk inhibitor, meanwhile, may also act on c-met receptor tyrosine kinase. On August 26th, 2008, U.S. fda approval gram Zhuo replaces Buddhist nun's (trade nameCode name pf-02341066) for treatment local evening Phase or metastatic, there is the nonsmall-cell lung cancer of anaplastic lymphoma kinase ALK Alk receptor tyrosine kinase (alk) gene rearrangement.Alk (eml4-alk) base The rearrangement of cause, leads to cell mutation, promotes the malignant phenotype of lung carcinoma cell.Therefore, the kinases alk of mutation inhibiting is for treatment Cancer is effective.

Ke Zhuo replaces Buddhist nun to need daily 2 times, each 250mg.After single oral dose, gram Zhuo averagely arrives in 4-6 hour for Buddhist nun Reach the peak concentration of absorption, keep the dosage of 250mg bid., after 15 days, reach steady statue, average accumulated rate is 4.8fda-approved patient labeling,pfizer inc.february2012).

As other target treatment medicines, alk positive Patients with Non-small-cell Lung is replaced after Buddhist nun using gram Zhuo, still can answer Send out.It can be seen that, acquired drug-resistance is the bottleneck in target treatment (e.g., gram Zhuo replaces Buddhist nun), and it directly influences patient using after medicine Effect (alice t.shaw;et al.“crizotinib”nature review drug discovery2011,10, 897).

Therefore, to proliferative disease primary carcinoma, metastatic carcinoma etc. it is still necessary to effective treat, especially effective target To treatment, for example, effective tyrosine kinase inhibitor, including double target spot inhibitor (alk and/or c-met inhibitor), selection Property inhibitor etc..The drug effect of these inhibitor, oral administration biaavailability is required for improving further, and then is preferably administered Scheme, for example daily need to be administered orally once.

The invention provides some, by suppressing alk and/or c-met come treating cancer, are considered possess Clinical practicability Noval chemical compound.Compare existing alk and/or c-met inhibitor, preferred compounds of the invention has more preferable drug effect, medicine For property and/or toxicological characteristics.

Abstract of invention

The present invention relates to the method for new substituted alkynyl compound and treatment cell proliferation disorders.The compound of the present invention There is inhibitory action to protein tyrosine kinase activity.More satisfactory, the compound of the present invention can suppress as alk(bag Include alk fusion gene, such as: eml4-alk, npm-alk etc.), or the response of c-met receptor (C-MET HGFr) signal. Correspondingly, present invention also offers the inhibitor of some new protein tyrosine kinase receptor signals responses, such as alk receptor signal Response or the response of c-met receptor signal.

Especially, compound involved in the present invention, and its pharmaceutically acceptable compositionss, can be effective as Tyrosine kinase receptor, the such as inhibitor of alk or c-met.

On the one hand, the present invention relates to a kind of compound, it is the compound of structure shown in formula (i) or chemical combination shown in formula (i) The stereoisomer of thing, geometric isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically Acceptable salt or its prodrug:

Wherein: x, w₁, w₂, w₃, and y has implication as described in the present invention.

In some embodiments, each w₁, w₂And w₃It independently is n or cr^c；

X is following subformula:

OrWherein, described subformula (iia) and (iib) Unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced；Each z₁And z₂It independently is n or ch；

Each r¹It independently is d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-nr^ar^b, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, r^ao-c_1-4Alkylidene, c_3-10Cycloalkyl, c_3-10Cycloalkanes Base-c_1-4Alkylidene, c_3-10Heterocyclic radical, c_3-10Heterocyclic radical-c_1-4Alkylidene, c_6-10Aryl, comprises 1,2,3 or 4 and is independently selected from o, The heteroatomic 5-10 former molecular heteroaryl of s and n, c_6-10Aryl-c_1-4Alkylidene, or (5-10 is former molecular miscellaneous Aryl)-c_1-4Alkylidene, wherein, when in formula (iia), z₁And z₂When being ch simultaneously, r¹It is not -or^aOr-nr^ar^b, and each r¹Can With independently unsubstituted or further by r²Group is replaced；Or, the r in formula (iia) or (iib), on adjacent atom¹Base Group can be unified into c_4-10Cycloalkyl or c_3-10Heterocyclic radical, wherein, described c_4-10Cycloalkyl and c_3-10Heterocyclic radical is independently of one another not It is substituted or by 1,2,3 or 4 r²Group is replaced；

Each r²It independently is d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-nr^ar^b, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c₂-₆Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, r^ao-c_1-4Alkylidene, c_3-8Cycloalkyl, c_3-8Cycloalkanes Base-c_1-4Alkylidene, c_3-8Heterocyclic radical, or c_3-8Heterocyclic radical-c_1-4Alkylidene；

Y is c_6-10Aryl or comprise 1,2,3 or 4 and be independently selected from o, heteroatomic 5-10 of s and n former molecular miscellaneous Aryl, wherein, described c_6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or by 1,2,3 or 4 Individual substituent group is replaced, and described substituent group is independently selected from d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-s (=o) r^a,-s (=o)₂r^a,-nr^ar^b,-s (=o)₂nr^ar^b,-oc (=o) r^a, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4 Alkylidene, r^ao-c_1-4Alkylidene, c_3-8Cycloalkyl, c_3-8Cycloalkyl-c_1-4Alkylidene, c_3-8Heterocyclic radical, or c_3-8Heterocyclic radical-c_1-4 Alkylidene；

Each r^aAnd r^bIt independently is h, c_1-6Aliphatic, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-4Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-4Alkylidene, wherein, described c_1-6Aliphatic, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-4Alkylidene, c_3-6Heterocycle Base, and c_3-6Heterocyclic radical-c_1-4Alkylidene is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substituent group, described replacement Base is independently selected from d, f, cl, cn, n₃, oh, nh₂, c_1-6Alkoxyl, or c_1-6Alkyl amino；

Each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-6Alkyl-s (=o)₂Nh-, c_1-6Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-6Alkyl, c_1-6Alkoxyl, c_1-6Alkyl amino, c_3-6Cycloalkyl, c_3-6Heterocyclic radical, c_6-10Virtue Base, or comprise 1,2,3 or 4 and be independently selected from o, the heteroatomic 5-10 former molecular heteroaryl of s and n, wherein, described c_1-6Alkyl, c_1-6Alkoxyl, c_1-6Alkyl amino, c_3-6Cycloalkyl, c_3-6Heterocyclic radical, c_6-10Aryl, and 5-10 is individual former molecular Heteroaryl is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substituent group, described substituent group independently selected from d, f, Cl, cn, n₃, oh, nh₂, c_1-6Alkyl, c_3-6Cycloalkyl, c_1-6Haloalkyl, c_1-6Alkoxyl, or c_1-6Alkyl amino.

In other embodiment, each w₁And w₂It independently is cr^c；w₃For n or cr^c.

In other embodiment, x is following subformula:

OrWherein, described subformula (iia) and (iii) Unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced；Each z₁And z₂It independently is n or ch.

In other embodiment, each r¹It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-4Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, when in formula (iia), z₁And z₂When being ch simultaneously, r¹It is not -or^aOr-nr^ar^b, and Each r¹Can be independently unsubstituted or further by r²Group is replaced；Or, in formula (iia) or (iib), on adjacent atom R¹Group can be unified into c_5-6Cycloalkyl or c_3-6Heterocyclic radical, wherein, described c_5-6Cycloalkyl and c_3-6Heterocyclic radical is each independent Ground is unsubstituted or by 1,2,3 or 4 r²Group is replaced.

In other embodiment, each r²It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene.

In other embodiment, y is phenyl, and described phenyl is independently unsubstituted or by 1,2,3 or 4 substituent group Replaced, described substituent group is independently selected from d, f, cl, br, c_1-3Alkyl, c_1-3Haloalkyl, or c_2-6Alkynyl.

In other embodiment, each r^aAnd r^bIt independently is h, c_1-3Alkyl, c_3-6Cycloalkyl, or c_3-6Heterocyclic radical, its In, described c_1-3Alkyl, c_3-6Cycloalkyl, and c_3-6Heterocyclic radical is unsubstituted independently of one another or by 1,2,3 or 4 substituent group institute Replace, described substituent group is independently selected from d, f, n₃, oh, nh₂, c_1-3Alkoxyl, or c_1-3Alkyl amino.

In other embodiment, each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-3Alkyl-s (=o)₂Nh-, c_1-3Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-3Alkyl, c_1-3Alkoxyl, c_1-3Alkyl amino, c_3-6Cycloalkanes Base, or c_3-6Heterocyclic radical, wherein, described c_1-3Alkyl, c_1-3Alkoxyl, c_1-3Alkyl amino, c_3-6Cycloalkyl, and c_3-6Heterocyclic radical is each Replaced from independently unsubstituted or by 1,2,3 or 4 substituent group, described substituent group is independently selected from d, f, cl, cn, n₃, Oh, nh₂, c_1-3Alkyl, c_3-6Cycloalkyl, c_1-3Haloalkyl, c_1-3Alkoxyl, or c_1-3Alkyl amino.

In other embodiment, x is following subformula:

Wherein, described subformula is unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced, and each r¹Can With independently unsubstituted or further by r²Group is replaced；Or, the r in described each subformula, on adjacent atom¹Base Group can be unified into c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is unsubstituted or by 1,2,3 or 4 r²Group is replaced.

In other embodiment, each r¹It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-4Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, when x is for phenyl, r¹It is not -or^aOr-nr^ar^b, and each r¹Can independently not It is substituted or further by r²Group is replaced；Or, the r in described each subformula, on adjacent atom¹Group can be combined Become c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is independently unsubstituted or by 1,2,3 or 4 r²Group is replaced；Each r²Solely It is on the spot d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Sub- Alkyl, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene.

On the other hand, the present invention relates to a kind of pharmaceutical composition, it comprises the compounds of this invention, and pharmaceutically acceptable Carrier, excipient, diluent, adjuvant, vehicle, or combinations thereof.

In some embodiments, pharmaceutical composition of the present invention, further comprise additional therapeutic agent, described attached It is selected from chemotherapeutic agent with therapeutic agent, antiproliferative, for treating atherosclerotic medicine, for treating pulmonary fibrosiss Medicine, or combinations thereof.

In other embodiment, pharmaceutical composition of the present invention, wherein involved additional therapeutic agent be Ah Mycin (adriamycin), rapamycin (rapamycin), sirolimuss (temsirolimus), everolimuses (everolimus), ipsapirone (ixabepilone), gemcitabine (gemcitabin), cyclophosphamide (cyclophosphamide), dexamethasone (dexamethasone), etoposide (etoposide), fluorouracil (fluorouracil), Afatinib (afatinib), alisertib, amuvatinib, Axitinib (axitinib), ripple Relax and replace Buddhist nun (bosutinib), brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, a gram Zhuo replaces Buddhist nun (crizotinib), dabrafenib, dacomitinib, Dasatinib (dasatinib), danusertib, Dovitinib, Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), Ibrutinib, imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, Linifanib, linsitinib, Masitinib (masitinib), momelotinib, does not replace husky Buddhist nun (motesanib), comes that For Buddhist nun (neratinib), niraparib, AMN107 (nilotinib), oprozomib, olaparib, pazopanib (pazopanib), pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), relaxes Buddhist nun replace Buddhist nun (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, vemurafenib, vismodegib, volasertib, Interferon (an interferon), carboplatin (carboplatin), hycamtin (topotecan), paclitaxel (taxol), long Spring alkali (vinblastine), vincristine (vincristine), temozolomide (temozolomide), tositumomab (tositumomab), trabedectin, belimumab, bevacizumab (bevacizumab), brentuximab, Cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, Tositumomab, Herceptin (trastuzumab), or combinations thereof.

On the other hand, it is possible to use the compounds of this invention or pharmaceutical composition are preparing for protecting, processing, treat or subtract The purposes of the medicine of light patient's proliferative disease.

In some embodiments, proliferative disease of the present invention is metastatic carcinoma, colon cancer, adenocarcinoma of stomach, bladder cancer, breast Adenocarcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, skin carcinoma, thyroid carcinoma, head and neck cancer, carcinoma of prostate, cancer of pancreas, cns(central nervous system) Cancer, glioblastoma, myeloproliferative disease, atherosclerosiss or pulmonary fibrosiss.

On the other hand, the present invention relates to being prepared in biological sample using the compounds of this invention or pharmaceutical composition Suppression or the method for regulatory protein kinase activity, methods described comprises to connect with described biological sample using the compounds of this invention Touch.

Some embodiments wherein, kinases of the present invention is tyrosine kinase receptor.In other embodiment, Tyrosine kinase receptor of the present invention is alk, c-met, or combinations thereof.

On the other hand, the present invention provides some pharmaceutical compositions, and it comprises the present invention and suppresses as tyrosine kinase receptor The compound of agent, or its stereoisomer, geometric isomer, tautomer, solvate, metabolite, or it is pharmaceutically Acceptable salt, pharmaceutically acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.In some embodiments In, pharmaceutical composition provided by the present invention comprises to respond as alk receptor signal, and c-met receptor signal responds, or it is three-dimensional Isomer, geometric isomer, tautomer, solvate, metabolite, or its pharmaceutically acceptable salt, or pharmaceutically Acceptable carrier, diluent, adjuvant, vehicle, or combinations thereof.In other embodiments, medicine of the present invention Compositionss further comprise additional therapeutic agent.

On the other hand, the present invention relates to the method for suppression protein tyrosine kinase activity, the method comprises chemical combination of the present invention Thing or its pharmaceutical composition are contacted with described kinases.In some embodiments, the present invention relates to suppression alk receptor signal responds With the method for c-met receptor signal response, the method comprises the compounds of this invention or its pharmaceutical composition is contacted with described receptor. Other embodiment is, suppression protein kinase receptor activity in cell or multicellular organisms, particularly suppression alk or The activity of c-met receptor signal response.According to method of the present invention, the method comprises using the compounds of this invention or its medicine Compositions are administered to described multicellular organisms.In some embodiments, described multicellular organisms refer to that suckling is moved Thing.In other embodiment, described multicellular organisms refer to the mankind.In some embodiments, the method for the invention Further comprise additional therapeutic agent to contact with described kinases.

On the other hand, the present invention relates to a kind of method of suppression cell-proliferation activity, methods described comprises to use the present invention The effectively treatment amount of compound or its pharmaceutical composition energy Inhibit proliferaton and cells contacting.In some embodiments, institute of the present invention Method of stating further comprises additional therapeutic agent and cells contacting.

On the other hand, the present invention relates to a kind of method treating Patient cells' proliferative disease, methods described comprises to use The effectively treatment amount of the compounds of this invention or its pharmaceutical composition is administered to patient.In some embodiments, institute of the present invention State the administration that method further comprises additional therapeutic agent.

On the other hand, the present invention relates to a kind of method of suppression patient tumors growth, methods described comprises to use the present invention The effectively treatment amount of compound or its pharmaceutical composition is administered to patient.In some embodiments, the method for the invention Further comprise the administration of additional therapeutic agent.

On the other hand, the present invention relates to formula (i) comprised the preparation of compound, separate and purification method.

Content noted earlier only outlines certain aspects of the invention, but is not limited to these aspects.These aspects and its The content of his aspect is made more specific complete description below.

Detailed description of the invention book

Definition and general terms

The present invention will list the document corresponding to the content of the materialization determining in detail, and embodiment is all accompanied by structure Formula and the diagram of chemical formula.The present invention has and expectedly covers all of choice, variant and coordinate, and these may be as right It is included in existing invention field like that defined in requirement.Those skilled in the art will identify many similar or equivalent to This described method and material, these can apply in the practice of the present invention.The present invention is limited to absolutely not method and material Description.Have a lot of documents and similar material to distinguish with the present patent application or conflict, including but be not limited to term Definition, the usage of term, the technology of description, or the scope being controlled as the present patent application.

Should further appreciate that, some features of the present invention, for the sake of clarity, in the context of different embodiments In be described, it is also possible to provide in combination in single embodiment.On the contrary, for simplicity in single reality The multiple features applying the present invention described in scheme can also be provided separately or be provided with any suitable sub-portfolio.

Unless otherwise noted, technology used in the present invention and scientific terminology and the technical field of the invention technical staff Conventional understand that there is identical implication, unless otherwise noted, all patents cited in the open full content of the present invention are public Open publication and be integrally incorporated the present invention by reference.

The present invention is by defined below for application unless other aspects show.According to the purpose of the present invention, chemical element is according to unit Plain periodic chart, cas version and chemical drugss handbook, 75,^thEd, 1994 defining.In addition, organic chemistry General Principle is shown in " organic chemistry,"thomas sorrell,university science books,sausalito:1999, and"march's advanced organic chemistry,"by michael b.smith and jerry march, John wiley＆sons, new york:2007, therefore all of content has all merged list of references.

Term " study subject " used in the present invention refers to animal.Typically described animal is mammal.Tested right As also referring to primate (such as people, men and women does not limit), cattle, sheep, goat, horse, dog, cat, rabbit, rat, mice, fish, bird Deng.In certain embodiments, described study subject is primate.In other embodiments other, described tested right As if people.

Term " patient " used in the present invention refers to people's (including adult and child) or other animals.In some enforcements Scheme, " patient " refers to people.

Present invention additionally comprises isotope-labeled the compounds of this invention, its in addition to following facts with of the present invention those Compound phase is different from the former of natural common atomic quality or mass number with: one or more atoms by atomic mass or mass number Filial generation is replaced.The Exemplary isotopes also being introduced in the compounds of this invention include the same position of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine Element, such as²H,³H,¹³C,¹⁴C,¹⁵N,¹⁶O,¹⁷O,¹⁸O,³¹P,³²P,³⁶S,¹⁸F and³⁷cl.

Comprise other isotopic the compounds of this invention of aforementioned isotopes and/or other atoms and described compound Pharmaceutically acceptable salt is included within the scope of the present invention.The same position of isotope-labeled the compounds of this invention, such as radioactivity Element, such as³H and¹⁴C is incorporated in the compounds of this invention and can be used for medicine and/or substrate tissue distributional analysiss.Due to easily prepared with And detection, tritium generation, i.e.³H, and carbon-14, that is,¹⁴C, isotope is particularly preferred.Additionally, with the isotope of weight, such as deuterium, that is,²h Replace, it is possible to provide some are derived from advantage, the Half-life in vivo of such as increase or the minimizing in the bigger treatment of metabolic stability Volume requirements.Therefore, it is probably preferably in some cases.

The Stereochemical definitions of present invention use and convention are generally according to s.p.parker, ed., mcgraw-hill Dictionary of chemical terms (1984) mcgraw-hill book company, new york；and Eliel, e.and wilen, s., " stereochemistry of organic compounds ", john wiley＆sons, Inc., new york, 1994.The compounds of this invention can contain asymmetric center or chiral centre, therefore different with different solids Configuration formula exists.It is expected that all stereoisomeric forms in any ratio of the compounds of this invention, including but not limited to diastereo-isomerism Body, enantiomer and atropisomer (atropisomer) and their mixture such as racemic mixture, are also contained in this Within invention scope.Many organic compound are existed with optical active forms, and that is, they have makes the plane of linearly polarized light send out The ability of raw rotation.When description has optically active compound, represented with regard in molecule using prefix d and l or r and s The absolute configuration of molecule for chiral centre (or mulitiple chiral centers).Prefix d and l or (+) and (-) are for appointed compound The symbol of caused linearly polarized light rotation, wherein (-) or l represent that compound is left-handed.Prefix be (+) or the compound of d be Dextrorotation.For given chemical constitution, in addition to these stereoisomers each other mirror image, these stereoisomers are identical 's.Specific stereoisomer is alternatively referred to as enantiomer, and the so-called enantiomerism of mixture of described isomer The mixture of body.The 50:50 mixture of enantiomer is referred to as racemic mixture or racemic modification, when in chemical reaction or side When there is no stereo selectivity or stereospecificity in method, may occur in which described racemic mixture or racemic modification.

According to the selection of raw material and method, the compounds of this invention can be with one of possible isomer or theirs is mixed Presented in compound, such as pure optical isomer, or as isomer mixture, such as racemic modification and diastereomeric Isomer mixture, this depends on the quantity of asymmetric carbon atom.(r) of optical activity-or (s)-isomer can be closed using chiral Become son or chiral agents preparation, or split using routine techniquess.If this compound contains a double bond, substituent group may be e Or z configuration；If containing dibasic cycloalkyl in this compound, the substituent group of cycloalkyl may be cis or trans (cis- Or trans-) configuration.

The compounds of this invention can contain asymmetric center or chiral centre, is therefore deposited with different stereoisomer forms ?.It is expected that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomer, mapping Isomer and atropisomer (atropisomer) and geometry (or conformation) isomer and their mixture, such as raceme mix Compound, all within the scope of the present invention.

Unless otherwise noted, the structure of present invention description be also represented by all isomers including this structure (e.g., enantiomer, Diastereomer and geometry (or conformation)) form；For example, r the and s configuration of each asymmetric center, (z) and (e) double bond isomer, with And (z) and (e) conformer.Therefore, the single three-dimensional chemical isomer of the compounds of this invention and mixture of enantiomers, non- Mixture of enantiomers and geometric isomer (or conformer) mixture are within the scope of the present invention.

Term " tautomer " or " tautomeric form " refer to that Tong Guo the mental retardation with different-energy builds (low Energy barrier) mutual inversion of phases constitutional isomer.If tautomerism is possible (as in the solution), can reach The chemical equilibrium of tautomer.For example, (also referred to as proton translocation mutually makes a variation proton tautomer (protontautomer) Structure body (prototropic tautomer) includes migrating, by proton, the mutual inversion of phases to carry out, such as keto-enol isomerization and Imine-enamine isomerizations.Valence tautomerism body (valence tautomer) include by the restructuring of some bonding electronss Lai The mutual inversion of phases carrying out.The instantiation of ketoenol tautomerization is pentane -2,4- diketone and 4- hydroxyl amyl- 3- alkene -2- ketone is mutual The change of tautomeric.Another example tautomeric is phenol-keto tautomerism.One of phenol-keto tautomerism is specifically real Example is pyridine -4- alcohol and the change of pyridine -4 (1h) -one tautomer.

Unless otherwise noted, all tautomeric forms of the compounds of this invention are within the scope of the present invention.Separately Outward, unless other aspects show, the structural formula of compound described in the invention includes the richness of one or more different atoms Collection isotope.

Any asymmetric atom (for example, carbon etc.) of the compounds of this invention can be enriched with racemic modification or enantiomer Form exists, for example (r)-, (s)-or (r, s)-configuration exist.In certain embodiments, each asymmetric atom exists R ()-or (s)-configuration aspect has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, At least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess.As If possible, having the substituent group on the atom of unsaturated bond can be existed fruit with cis-(z)-or trans-(e)-form.

Therefore, as described in the present invention, the compound of the present invention can be with possible isomer, rotational isomeric Presented in one of body, atropisomer, tautomer form or its mixture, for example, substantially pure geometry (cis or trans) isomer, diastereomer, optical isomer (enantiomer), racemic modification or its form of mixtures.

According to the physical chemical differences of component, any isomer mixture of gained can be separated into pure or substantially pure Geometry or optical isomer, diastereomer, racemic modification, for example, carry out separating by chromatography and/or fractional crystallization.

With known method, the racemic modification of any gained end-product or intermediate can be passed through those skilled in the art Familiar method splits into optical antipode, e.g., by carrying out to its diastereoisomeric salt obtaining separating.Racemic product Thing can also be separated by chiral chromatogram, e.g., using the high pressure liquid chromatography (hplc) of chiral sorbent.Especially, mapping Isomer can prepare (e.g., jacques, et al., enantiomers, racemates and by asymmetric synthesis resolutions(wiley interscience,new york,1981);principles of asymmetric synthesis(2^nded.robert e.gawley,jeffrey aubé,elsevier,oxford,uk,2012);eliel, e.l.stereochemistry of carbon compounds(mcgraw-hill,ny,1962);and wilen, s.h.tables of resolving agents and optical resolutions p.268(e.l.eliel,ed., univ.of notre dame press,notre dame,in1972).

" nitrogen oxides " used in the present invention refer to when compound contains several amine functional group, by 1 or can be more than 1 Nitrogen-atoms oxidation formed n- oxide.The particular example of n- oxide is n- oxide or the nitrogen heterocyclic ring nitrogen-atoms of tertiary amine N- oxide.Available oxidant example, such as hydrogen peroxide or peracid (such as peroxycarboxylic acid) process corresponding amine and form n- oxide (referring to advanced organic chemistry, wiley interscience, the 4th edition, jerry march, pages). Especially, n- oxide can be prepared (syn.comm.1977,7,509-514) with the method for l.w.deady, wherein for example lazy Property solvent, such as, in dichloromethane, make amines react with m- chlorine benzylhydroperoxide (mcpba).

" solvate " used in the present invention refers to that one or more solvent molecules and the compound of the present invention are formed Associated complex.The solvent forming solvate includes, but is not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, acetic acid Ethyl ester, acetic acid, ethylaminoethanol.Term " hydrate " refers to that solvent molecule is the associated complex that water is formed.

" metabolite " used in the present invention refers to that specific compound or its salt passes through metabolism gained in vivo The product arriving.The metabolite of one compound can be identified by technology known to art, its activity is permissible Experimentally characterized by adopting as described in the present invention.Such product can be by being administered compound Through peroxidating, reduce, hydrolysis, amidated, desamido- acts on, esterification, degreasing, enzymatic lysises etc. method obtains.Accordingly Ground, the present invention includes the metabolite of compound, is fully contacted a period of time including by the compound of the present invention and mammal Produced metabolite.

" pharmaceutically acceptable salt " used in the present invention refers to the organic salt of compound and the inorganic salt of the present invention.Medicine On, acceptable salt is known to us in art, such as document: s.m.berge et al., describe pharmaceutically acceptable salts in detail in j.pharmaceutical sciences,66: 1-19,1977. it is described.The salt that pharmaceutically acceptable nontoxic acid is formed includes, but is not limited to, anti-with amino group The inorganic acid salt that should be formed has hydrochlorate, hydrobromate, phosphate, sulfate, perchlorate, and acylate such as acetate, Oxalates, maleate, tartrate, citrate, succinate, malonate, or by described on books document Additive method such as ion exchange is obtaining these salt.Other pharmaceutically acceptable salts include adipate, and alginate are anti-bad Hematic acid salt, aspartate, benzene sulfonate, benzoate, bisulphate, borate, butyrate, Camphora hydrochlorate, camphorsulfonic acid Salt, cyclopentyl propionate, digluconate, lauryl sulfate, esilate, formates, fumarate, Portugal heptan Sugar lime, glycerophosphate, gluconate, Hemisulphate, enanthate, caproate, hydriodate, 2- hydroxy-ethanesulfonate salt, Lactobionate, lactate, laruate, lauryl sulfate, malate, malonate, mesylate, 2- LOMAR PWA EINECS 246-676-2 Salt, nicotinate, nitrate, oleate, palmitate, pamoate, pectate, persulfate, 3- phenylpropionic acid salt, picric acid Salt, pivalate, propionate, stearate, rhodanate, tosilate, undecylate, valerate, etc..By suitable When the salt that obtains of alkali include alkali metal, alkaline-earth metal, ammonium and n⁺(c_1-4Alkyl)₄Salt.The present invention is also intended to contemplate any institute The quaternary ammonium salt that the compound of the group comprising n is formed.Water solublity or oil-soluble or dispersion product can pass through quaternization Obtain.Alkali metal or alkali salt include sodium, lithium, potassium, calcium, magnesium, etc..Pharmaceutically acceptable salt further includes suitably , nontoxic ammonium, the amine cation that quaternary ammonium salt and gegenions are formed, such as halogenide, hydroxide, carboxylate, sulphation Thing, phosphoric acid compound, nitric acid compound, c_1-8Azochlorosulfonate acid compound and aromatic sulphonic acid compound.

Term " prodrug " used in the present invention, represents a compound and is converted into the compound shown in formula (i) in vivo. Such conversion is hydrolyzed in blood by prodrug or is affected for precursor structure through enzymatic conversion in blood or tissue.This Bright pro-drug compounds can be ester, and in existing invention, ester can be used as the phenyl ester class that have of prodrug, aliphatic (c_1-24) esters, pivaloyloxymethyl esters, carbonic ester, carbamatess and amino acid esters.Such as in the present invention one Compound comprises oh group, you can be acylated the compound obtaining prodrug form.Other prodrug form bags Include phosphate ester, such as these phosphate compounds are to obtain through the di on parent.Complete with regard to prodrug Discussion may be referred to documents below: t.higuchi and v.stella, pro-drugs as novel delivery systems,vol.14of the a.c.s.symposium series,edward b.roche,ed.,bioreversible carriers in drug design,american pharmaceutical association and pergamon press,1987,j.rautio et al,prodrugs:design and clinical applications,nature review drug discovery,2008,7,255-270,and s.j.hecker et al,prodrugs of phosphates and phosphonates,journal of medicinal chemistry,2008,51,2328-2345, Every document is incorporated herein by this.

Term " optionally ", " optional " or " optional " refer to subsequently described event or situation can but may not occur, And this description includes wherein the situation of this event or situation, and the situation that this event or situation wherein do not occur.Picture Described in the invention, the compound of the present invention can optionally be replaced by one or more substituent groups, as formula above Compound, or as special example inside embodiment, subclass, and the class compound that the present invention is comprised.Should be appreciated that " optionally Replacing " this term and " substituted or non-substituted " this term can exchange use.In general, term " optionally " is no By whether before term " substituted ", represent that one or more of given structure hydrogen atom is taken by concrete substituent group Generation.Unless other aspects show, optional substituted radical can have a substituent group in group each commutable position Replaced.When in given structural formula, more than one position can be selected from one or more substituent groups of concrete group and taken Generation, then substituent group can replace in each position identical or differently.Wherein said substituent group can be, but does not limit In d, f, cl, br, i, cn, no₂, n₃, oh, nh₂, or^a, sr^a, s (=o) r^a, s (=o)₂r^a, s (=o)₂nr^ar^b, oc (=o) r^a, nr^ar^b, c_1-6Alkyl-s (=o)₂Nh, c_1-6Alkyl-c (=o) n (r^a), nhc (=o) nr^ar^b, c_1-6Alkyl, c_1-6Aliphatic, c_1-6Alkane Epoxide, c_1-6Alkyl amino, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, r^ao- c_1-4Alkylidene, c_3-10Cycloalkyl, c_3-10Cycloalkyl-c_1-4Alkylidene, c_3-10Heterocyclic radical, c_3-10Heterocyclic radical-c_1-4Alkylidene, c_6-10 Aryl, comprises 1,2,3 or 4 and is independently selected from o, the heteroatomic 5-10 former molecular heteroaryl of s or n, c_6-10Aryl- c_1-4Alkylidene, or (5-10 former molecular heteroaryl)-c_1-4Alkylidene, wherein, each r^aAnd r^bThere have to be fixed as described herein Justice.

In addition, it is necessary to explanation, unless otherwise explicitly pointed out, the describing mode that adopted in the present invention " each ... independently be " and " ... be each independently " and " ... independently be " can be exchanged, and all should be interpreted broadly, it both may be used To refer in different groups, do not affect it is also possible to represent in phase mutually between expressed concrete option between same-sign In same group, do not affect mutually between expressed concrete option between same-sign.

Different places in the present invention, the substituent group of the compound of the present invention presses group or scope is open.Specifically, this The all of individuality sub-portfolio of the bright member including this group and scope.For example, term " c_1-6Alkyl " explicitly indicates that respectively public Methyl, ethyl, c are opened₃Alkyl, c₄Alkyl, c₅Alkyl and c₆Alkyl.

In the different places of the present invention, describe connect substituent.When structure significant need linking group, for this base Markush (markush) variable that group lists is interpreted as linking group.For example, as fruit structure needs linking group, and this horse Storehouse assorted (markush) group definition lists variable " alkyl " or " aryl ", then it should be recognized that " alkyl " or " aryl " represents respectively Linking group alkylidene or arlydene.

Terminology used in the present invention " aliphatic " or " aliphatic group ", represent straight chain (non-branched) or side chain, replace or The non-substituted fully saturated or hydrocarbon chain containing one or more degrees of unsaturation.Unless otherwise detailed instructions, aliphatic group contains 1-20 carbon atom.Some of them embodiment is that aliphatic group contains 1-10 carbon atom, and other embodiment is, fatty Race's group contains 1-8 carbon atom.Other embodiment is that aliphatic group contains 1-6 carbon atom, other embodiment It is that aliphatic group contains 1-4 carbon atom, other embodiment is that aliphatic group contains 1-3 carbon atom, other Embodiment is that aliphatic group contains 1-2 carbon atom.Suitable aliphatic group includes, but not limited to straight or branched, takes Generation or non-substituted alkyl, thiazolinyl, or alkynyl.For example, c_1-6Aliphatic group, including non-branched or side chain, non-substituted or suitable The c replacing_1-6Alkyl, c_2-6Thiazolinyl, or c_2-6Alkynyl.Such example includes, but is not limited to, methyl, ethyl, propyl group, isopropyl Base, butyl, isobutyl group, the tert-butyl group, ethylene, propylene, butylene, 2-butylene, acetylene, propine, butine, 2-butyne, etc., wherein Described aliphatic group can be independently unsubstituted or replaced by one or more substituent groups described in the invention.

Terminology used in the present invention " alkyl " or " alkyl group ", represent the saturated straight chain containing 1-20 carbon atom or side chain Monovalence Hydrocarbon atomic group.Unless otherwise detailed instructions, alkyl group contains 1-20 carbon atom, and some of them are implemented Example is that alkyl group contains 1-10 carbon atom, and other embodiment is that alkyl group contains 1-8 carbon atom, in addition one A little embodiments are that alkyl group contains 1-6 carbon atom, and other embodiment is that alkyl group contains 1-4 carbon atom, Other embodiment is that alkyl group contains 1-3 carbon atom, and other embodiment is that it is former that alkyl group contains 1-2 carbon Son.

The example of alkyl group comprises, but is not limited to, methyl (me ,-ch₃), ethyl (et ,-ch₂ch₃), n-pro-pyl (n- Pr ,-ch₂ch₂ch₃), isopropyl (i-pr, i-propyl ,-ch (ch₃)₂), normal-butyl (n-bu, n-butyl ,- ch₂ch₂ch₂ch₃), isobutyl group (i-bu, i-butyl ,-ch₂ch(ch₃)₂), sec-butyl (s-bu, s-butyl ,-ch (ch₃) ch₂ch₃), the tert-butyl group (t-bu, t-butyl ,-c (ch₃)₃), n-pentyl (n-pentyl ,-ch₂ch₂ch₂ch₂ch₃), 2- amyl group (- ch(ch₃)ch₂ch₂ch₃), 3- amyl group (- ch (ch₂ch₃)₂), 2- methyl -2- butyl (- c (ch₃)₂ch₂ch₃), 3- methyl -2- fourth Base (- ch (ch₃)ch(ch₃)₂), 3- methyl isophthalic acid-butyl (- ch₂ch₂ch(ch₃)₂), 2-methyl-1-butene base (- ch₂ch(ch₃) ch₂ch₃), n-hexyl (- ch₂ch₂ch₂ch₂ch₂ch₃), 2- hexyl (- ch (ch₃)ch₂ch₂ch₂ch₃), 3- hexyl (- ch (ch₂ch₃)(ch₂ch₂ch₃)), 2- methyl -2- amyl group (- c (ch₃)₂ch₂ch₂ch₃), 3- methyl -2- amyl group (- ch (ch₃)ch (ch₃)ch₂ch₃), 4- methyl -2- amyl group (- ch (ch₃)ch₂ch(ch₃)₂), 3- methyl -3- amyl group (- c (ch₃)(ch₂ch₃)₂), 2- methyl -3- amyl group (- ch (ch₂ch₃)ch(ch₃)₂), 2,3- dimethyl -2- butyl (- c (ch₃)₂ch(ch₃)₂), 3,3- diformazans Base -2- butyl (- ch (ch₃)c(ch₃)₃), n-heptyl, n-octyl, etc..Wherein said alkyl group can independently not taken Generation or replaced by one or more substituent groups described in the invention.

Term " alkyl " used in the present invention and its prefix " alkane ", all comprise the saturated carbon chains of straight chain and side chain.

Terminology used in the present invention " alkylidene ", represents and eliminates two hydrogen atoms from straight or branched saturated hydrocarbon The saturation bivalent hydrocarbon radical obtaining.Unless otherwise detailed instructions, alkylidene group contains 1-10 carbon atom, some of them embodiment It is that alkylidene group contains 1-6 carbon atom, other embodiment is that alkylidene group contains 1-4 carbon atom, in addition Some embodiments are that alkylidene group contains 1-3 carbon atom, and other embodiment is that alkylidene group contains 1-2 carbon Atom.The example of alkylidene group includes, but is not limited to, methylene (- ch₂-), ethylidine (- ch₂ch₂-), secondary isopropyl (- ch(ch₃)ch₂-) etc..Wherein said alkylidene group can be independently unsubstituted or retouched by one or more present invention The substituent group stated is replaced.

Term " thiazolinyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom The monovalent hydrocarbon of straight or branched, wherein at least one position is undersaturated condition, and that is, a c-c is sp²Double bond, including group There are negation " just " or the positioning of " e " " z ", wherein specific example includes, but is not limited to, vinyl (- ch=ch₂), pi-allyl (-ch₂ch=ch₂) etc..Wherein said kiki alkenyl group can be independently unsubstituted or retouched by one or more present invention The substituent group stated is replaced.

Term " alkynyl " represents 2-12 carbon atom, or 2-8 carbon atom, or 2-6 carbon atom, or 2-4 carbon atom The monovalent hydrocarbon of straight or branched, wherein at least one position is undersaturated condition, and that is, a c-c is sp tri- key, wherein alkyl Group can be independently unsubstituted or replaced by one or more substituent groups described in the invention, specific example bag Include, but be not limited to, acetenyl (- c ≡ ch), propargyl (- ch₂C ≡ ch) etc..

Term " haloalkyl ", " halogenated alkenyl " or " halogenated alkoxy " represents alkyl, alkenyl or alkoxy base Replaced by one or more halogen atoms, such example comprises, but is not limited to, trifluoromethyl, trifluoromethoxy etc..

Term " carbocyclic ring ", " carbocylic radical ", " carbocyclic ring " or " annular aliphatic " has referred to that one or more junction points connect To the remainder of molecule, non-aromatic, saturation or partly undersaturated, including 3-12 carbon atom, or 3-10 carbon is former Son, or 3-8 carbon atom, or 3-6 carbon atom monocyclic, bicyclic and three-ring system.Suitable carbon ring group includes, but not It is limited to, cycloalkyl, cycloalkenyl group and cycloalkynyl radical.The example of carbon ring group includes, but is not limited to, cyclopropyl, cyclobutyl, ring penta Base, 1- cyclopenta -1- thiazolinyl, 1- cyclopenta -2- thiazolinyl, 1- cyclopenta -3- thiazolinyl, cyclohexyl, 1- cyclohexyl -1- thiazolinyl, 1- Cyclohexyl -2- thiazolinyl, 1- cyclohexyl -3- thiazolinyl, cyclohexadienyl, suberyl, cyclooctyl, cyclononyl, cyclodecyl, ring hendecane Base, cyclo-dodecyl, etc..Wherein said carbon ring group can be independently unsubstituted or retouched by one or more present invention The substituent group stated is replaced.

Term " cycloalkyl " refers to that one or more junction points are connected to the remainder of molecule, and saturation, containing 3-12 Monocyclic, the bicyclic or three-ring system of individual carbon atom.Its bicyclic system comprises that spiral shell is bicyclic and condensed-bicyclic.Some of them embodiment is Member ring systems containing 3-10 carbon atom, other embodiment is the member ring systems containing 3-8 carbon atom, and other embodiment is Member ring systems containing 3-6 carbon atom, other embodiment is the member ring systems containing 5-6 carbon atom, and described group of naphthene base Can be independently unsubstituted or replaced by one or more substituent groups described in the invention.

Term " cycloalkyl alkylidene " represents that alkyl group can be replaced by one or more groups of naphthene base, wherein alkane Base and group of naphthene base have implication as described in the present invention.Some of them embodiment is that cycloalkyl alkylidene group refers to " relatively Rudimentary cycloalkyl alkylidene " group, that is, group of naphthene base be connected to c_1-6Alkyl group on.Other embodiment is, ring Alkyl group is connected to c_1-4Alkyl group on.Other embodiment is that group of naphthene base is connected to c_1-3Alkyl group On.Other embodiment is that group of naphthene base is connected to c_1-2Alkyl group on.Such example includes, but does not limit In, cyclopropylethyl, cyclopentyl-methyl, cyclohexyl methyl etc..Described cycloalkyl alkylidene group can independently not taken Generation or replaced by one or more substituent groups described in the invention.

Term " heterocycle ", " heterocyclic radical " or " heterocycle " is used interchangeably herein, all referring to monocyclic, bicyclic, or three rings System, on its medium ring, one or more atoms are replaced by hetero atom individually optionally, and ring can be fully saturated or comprise One or more degrees of unsaturation, but be definitely not the fragrant same clan, and have one or more junction points to be connected to its remaining part of molecule Point.Its bicyclic system comprises that spiral shell is bicyclic and condensed-bicyclic, and wherein any one ring can be monocyclic carbocyclic ring or single heterocycle.One Or multiple ring hydrogen atom is replaced by one or more substituent groups described in the invention individually optionally.Some of them are real Applying example is, " heterocycle ", " heterocyclic radical " or " heterocycle " group be 3-7 former molecular monocyclic (2-6 carbon atom and selected from n, The 1-3 hetero atom of o, p, s, is optionally replaced by one or more oxygen atoms in this s or p, obtains as so, so₂, po, po₂ Group), other embodiment is, 3-6 former, and molecular monocyclic (2-5 carbon atom and be selected from n, the 1-3 of o, p, s is individual Hetero atom, is optionally replaced by one or more oxygen atoms in this s or p, obtains as s=o, so₂, po, po₂Group, work as institute When the ring stated is three-membered ring, only one of which hetero atom), or former molecular bicyclic (the 4-9 carbon atom and being selected from of 7-10 The 1-3 hetero atom of n, o, p, s, is optionally replaced by one or more oxygen atoms in this s or p, obtains as so, so₂, po, po₂Group).

Heterocyclic radical can be carbon-based or hetero atom base.The example of heterocycle includes, but is not limited to, pyrrolidinyl, tetrahydrochysene furan Mutter base, dihydrofuran base, tetrahydro-thienyl, THP trtrahydropyranyl, dihydro pyranyl, tetrahydro thiapyran base, piperidyl, morpholinyl, sulfur For morpholinyl, thiophene alkyl, piperazinyl, homopiperazine base, azelidinyl, oxetanylmethoxy, thietanyl, homopiperidinyl, Glycidyl, azacycloheptyl, oxepane base, thia suberyl, oxygen azatropylidene base, diazepine base, sulfur azatropylidene base, 2- Pyrrolinyl, 3- pyrrolinyl, indolinyl, 2h- pyranose, 4h- pyranose, dioxacyclohexyl, 1,3- dioxy amyl group, Pyrazolinyl, dithiane base, dithiode alkyl, dihydro-thiophene base, pyrazolidinyl imidazolinyl, imidazolidinyl, 1,2,3,4- tetra- Hydrogen isoquinoline base.The example of heterocyclic group also includes, the hybar X base and 1,1- that on ring, two carbon atoms are replaced by oxygen (=o) Dioxidothiomorpholinyl.The example of heterocyclic group also includes, hexahydro furyl simultaneously [2,3-b] furyl, etc..Described heterocyclic radical base Group can be independently unsubstituted or replaced by one or more substituent groups described in the invention.

Term " heterocycloalkylene " represents that alkyl group can be replaced by one or more heterocyclyl groups, wherein alkane Base and heterocyclyl groups have implication as described in the present invention.Some of them embodiment is that heterocycloalkylene group refers to " relatively Rudimentary heterocycloalkylene " group, that is, heterocyclyl groups be connected to c_1-6Alkyl group on.Other embodiment is, miscellaneous Cyclic groups are connected to c_1-4Alkyl group on.Other embodiment is that heterocyclyl groups are connected to c_1-3Alkyl group On.Other embodiment is that heterocyclyl groups are connected to c_1-2Alkyl group on.Such example includes, but does not limit In, 2- pyrrolidine ethyl, 3- azetidine methyl etc..Described heterocycloalkylene group can independently unsubstituted or Replaced by one or more substituent groups described in the invention.

Term " hetero atom " refers to o, s, n, p and si, including n, the form of any oxidation state of s and p；Primary, secondary, tertiary amine and season The form of ammonium salt；Or the form that the hydrogen on nitrogen-atoms in heterocycle is substituted, for example, n(is as in 3,4- dihydro -2h- pyrrole radicals N), nh(is as the nh in pyrrolidinyl) or the pyrrolidinyl that replaces as n- of nr(in nr).

Term " halogen " refers to f, cl, br or i.

Term " h " represents single hydrogen atom.Such atomic group can be connected with other groups, such as with oxygen atom phase Even, form oh group.

Term " d " or "²H " represents single D-atom.One such atomic group is connected with a methyl, forms list-deuterium Acute pyogenic infection of nails base (- cdh₂), two D-atoms are connected with a methyl, form double-deuterated methyl (- cd₂H), and three D-atoms with One methyl is connected, and forms three-deuterated methyl (- cd₃).

Term " n₃" represent a nitrine structure.This group can be connected with other groups, for example, with methyl group It is connected, triazonmethane (methyl azide, men can be formed₃)；And be connected with phenyl group, then form aziminobenzene (phn₃)

Term " aryl " can be used alone or as " aralkyl ", a big portion of " aralkoxy " or " aryloxy alkyl " Point, represent and contain 6-14 annular atom, or 6-12 annular atom, or 6-10 annular atom is monocyclic, the carbocyclic ring of bicyclic and three rings System, wherein, at least one member ring systems is aromatic, and each of which member ring systems comprise 3-7 former molecular ring, and have One or more attachment points are connected with the remainder of molecule.Term " aryl " can exchange with term " aromatic rings " and use, virtue Fragrant ring can include phenyl, naphthyl and anthracene.Described aromatic yl group can be independently unsubstituted or by one or more present invention Described substituent group is replaced.

Term " aryl alkylene " represent alkyl group can be replaced by one or more aromatic yl groups, wherein alkyl and Aromatic yl group has implication as described in the present invention, and some of them embodiment is that arylalkylene groups refer to the " virtue of lower level Base alkylidene " group, that is, aromatic yl group be connected to c_1-6Alkyl group on.Other embodiment is, arylalkylene groups Refer to containing c_1-4Alkyl " benzene alkylene ".Other embodiment is that arylalkylene groups refer to that aromatic yl group is connected to c_1-2Alkyl group on.Wherein instantiation includes benzyl, diphenyl methyl, phenethyl etc..Described arylalkylene groups Can be independently unsubstituted or replaced by one or more substituent groups described in the invention.

Term " heteroaryl " can be used alone or as " heteroaryl alkyl " or " heteroarylalkoxy " most, Represent and contain 5-14 annular atom, or 5-12 annular atom, or 5-10 annular atom is monocyclic, bicyclic, and three-ring system, wherein At least one member ring systems is aromatic, and at least one member ring systems comprises one or more hetero atoms, each of which ring body System comprises 5-7 former molecular ring, and has one or more attachment points to be connected with molecule remainder.Term " heteroaryl " can Used with exchanging with term " heteroaromatic " or " heteroaromaticss ".

Other embodiment is, heteroaromatic includes following monocyclic, but it is monocyclic to be not limited to these: 2- furyl, 3- Furyl, n- imidazole radicals, 2- imidazole radicals, 4- imidazole radicals, 5- imidazole radicals, 3- isoxazolyl, 4- isoxazolyl, 5- isoxazolyl, 2- oxazolyl, 4- oxazolyl, 5- oxazolyl, n- pyrrole radicals, 2- pyrrole radicals, 3- pyrrole radicals, 2- pyridine radicals, 3- pyridine radicals, 4- pyrrole Piperidinyl, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, pyridazinyl (as 3- pyridazinyl), 2- thiazolyl, 4- thiazolyl, 5- thiazole Base, tetrazole radical (as 5- tetrazole radical), triazolyl (as 2- triazolyl and 5- triazolyl), 2- thienyl, 3- thienyl, pyrazolyl (as 2- pyrazolyl), isothiazolyl, 1,2,3- di azoly, 1,2,5- di azoly, 1,2,4- di azoly, 1,2,3-triazoles Base, 1,2,3- thio biphosphole base, 1,3,4- thio biphosphole base, 1,2,5- thio biphosphole base, pyrazinyl, 1,3,5-triazines base；? Including following bicyclic, but it is bicyclic to be not limited to these: benzimidazolyl, benzofuranyl, benzothienyl, and indyl is (such as 2- indyl), purine radicals, quinolyl (such as 2- quinolyl, 3- quinolyl, 4- quinolyl), and isoquinolyl is (as 1- isoquinolin Base, 3- isoquinolyl or 4- isoquinolyl).Described heteroaryl groups can independently unsubstituted or by one or more send out Bright described substituent group is replaced.

Term " heteroarylalkylenyl " represents that alkyl group can be replaced by one or more heteroaryl groups, wherein alkane Base and heteroaryl groups have implication as described in the present invention, and some of them embodiment is that heteroarylalkylenyl group refers to " relatively Rudimentary heteroarylalkylenyl " group, that is, heteroaryl groups be connected to c_1-6Alkyl group on.Other embodiment is, miscellaneous Aromatic yl group is connected to c_1-4Alkyl group on.Other embodiment is that heteroaryl groups are connected to c_1-2Alkyl group On.Wherein instantiation includes 2- picolyl, 3- furylethyl etc..Described heteroarylalkylenyl group can independently not It is substituted or replaced by one or more substituent groups described in the invention.

No matter term " carboxyl ", be single use or be used in conjunction with other terms, such as " carboxyalkyl ", expression-co₂h；Term No matter " carbonyl ", be single use or be used in conjunction with other terms, such as " amino carbonyl " or " acyloxy ", represents-(c=o)-.

Term " alkylthio group " includes c_1-10The alkyl of straight or branched is connected on the sulphur atom of bivalence, and some of them are implemented Example is that alkylthio group is the c of lower level_1-3Alkylthio group, such example includes, but is not limited to methyl mercapto (ch₃s-).

Term " alkoxyl " represents that alkyl group is connected with molecule remainder by oxygen atom, and wherein alkyl group has Implication as described in the present invention.Unless otherwise detailed instructions, described alkoxy base contains 1-20 carbon atom, and some of them are real Applying example is, alkoxy base contains 1-10 carbon atom, and other embodiment is that alkoxy base contains 1-8 carbon atom, Other embodiment is that alkoxy base contains 1-6 carbon atom, and other embodiment is that alkoxy base contains 1-4 Individual carbon atom, other embodiment is that alkoxy base contains 1-3 carbon atom.

The example of alkoxy base comprises, but is not limited to, methoxyl group (meo ,-och₃), ethyoxyl (eto ,- och₂ch₃), 1- propoxyl group (n-pro, n- propoxyl group ,-och₂ch₂ch₃), 2- propoxyl group (i-pro, i- propoxyl group ,-och (ch₃)₂), 1- butoxy (n-buo, n- butoxy ,-och₂ch₂ch₂ch₃), 2- methyl-l- propoxyl group (i-buo, i- fourth oxygen Base ,-och₂ch(ch₃)₂), 2- butoxy (s-buo, s- butoxy ,-och (ch₃)ch₂ch₃), 2- methyl -2- propoxyl group (t- Buo, t- butoxy ,-oc (ch₃)₃), 1- amoxy (n- amoxy ,-och₂ch₂ch₂ch₂ch₃), 2- amoxy (- och (ch₃) ch₂ch₂ch₃), 3- amoxy (- och (ch₂ch₃)₂), 2- methyl -2- butoxy (- oc (ch₃)₂ch₂ch₃), 3- methyl -2- fourth Epoxide (- och (ch₃)ch(ch₃)₂), 3- methyl-l- butoxy (- och₂ch₂ch(ch₃)₂), 2- methyl-l- butoxy (- och₂ch(ch₃)ch₂ch₃), etc..Described alkoxy base can be independently unsubstituted or by one or more institutes of the present invention The substituent group of description is replaced.

" alkoxyalkyl " represents that alkyl group is replaced by one or more alkoxy bases, wherein alkyl group to term With alkoxy base, there is implication as described in the present invention, such example includes, but is not limited to methoxy, ethyoxyl Methyl, ethoxyethyl group etc..

Term " alkylamino " or " alkyl amino " inclusion " n- alkyl amino " and " n, n- dialkyl amido ", wherein amino base Group is separately replaced by one or two alkyl group.Some of them embodiment is that alkyl amino is one or two c_1-6Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Other embodiment is, alkyl amino be one or Two c_1-3Alkyl is connected to the alkylamino group of the lower level on nitrogen-atoms.Suitable alkylamino group can be single alkane Base amino or dialkyl amido, such example includes, but is not limited to, n- methylamino, n- ethylamino, n, n- dimethylamino, N, n- lignocaine etc..Described alkylamino radicals can be independently unsubstituted or by one or more described in the invention Substituent group is replaced.

Term " fragrant amino " represents that amino group is replaced by one or two aromatic yl group, and such example includes, but It is not limited to n- phenylamino.Some of them embodiment is that the aromatic ring on fragrant amino can be substituted further.

Term " hydroxy alkyl " includes the c being replaced by one or more hydroxyls_1-10Straight or branched alkyl group.Wherein Some embodiments are that hydroxy alkyl is the c being replaced by one or more oh groups_1-6" hydroxy alkyl of lower level ", so Example include, but is not limited to, methylol, ethoxy, hydroxypropyl, hydroxyl butyl and hydroxyl hexyl.

Term " aminoalkyl " includes the c being replaced by one or more amino_1-10Straight or branched alkyl group.Wherein Some embodiments are that aminoalkyl is the c being replaced by one or more amino groups_1-6" aminoalkyl of lower level ", so Example include, but is not limited to, aminomethyl, aminoethyl, aminopropyl, ammonia butyl and ammonia hexyl.

Term " cyanoalkyl " includes the c being replaced by one or more cyano group_1-10Straight or branched alkyl group.Wherein Some embodiments are that cyanoalkyl is the c being replaced by one or more cyano groups_1-6" cyanoalkyl of lower level ", so Example include, but is not limited to, cyano methyl, cyano ethyl, cyanopropyl, cyanobutyl and cyano group hexyl.

" alkyl amino alkyl " includes the alkyl group being replaced by alkylamino to term.Some of them embodiment is, alkylamino alkane Base is c_1-6The alkyl amino alkyl of lower level.Other embodiment is that alkyl amino alkyl is c_1-3The alkyl amino alkyl of lower level. Suitable alkyl amino alkyl group can be monoalkyl or dialkyl group replaces, and such embodiment includes, but is not limited to, n- Methylaminomethyl, n, n- dimethyl aminoethyl, n, n- diethylamino methyl etc..

Term " undersaturated " the expression part being used in the present invention contains one or more degrees of unsaturation.

Term "comprising" is open language, that is, include the content specified by the present invention, but be not precluded from otherwise Content.

Term " condensed-bicyclic ", " fused rings ", " condensed-bicyclic base " or " condensing ring group ", as shown in formula a-c, represent two Between five-membered ring, (formula a), between two hexatomic rings, (between formula b), and a five-membered ring and a hexatomic ring, (formula c) shares one The bridged-ring system of individual c-c key.Isolated or conjugation unsaturated bond can be comprised in system, but in core ring structure, do not include virtue Fragrant ring or hetero-aromatic ring (substituent group can be armaticity).Each ring in condensed-bicyclic can be carbocyclic ring or heterocycle.

The example of condensed-bicyclic includes, but not limited to hexahydro furyl simultaneously [2,3-b] furan -3- base, 3a- fluorine hexahydro furyl And [2,3-b] furan -3- base, (3as, 6ar) -3a, 6a- bis- deuterium hexahydro furyl simultaneously [2,3-b] furan -3- base, 5,5- difluoros six Hydrogen furo [2,3-b] furan -3- base, 4,4- difluoro hexahydro furyls simultaneously [2,3-b] furan -3- base, (3s) -6- hydroxyl hexahydro furan Mutter simultaneously [3,2-b] furan -3- base, (6r) -6- fluorine hexahydro furyl simultaneously [3,2-b] furan -3- base, 3- deuterium hexahydro furyl simultaneously [3,2- B] furan -3- base, 5,5- bis- deuterium hexahydro furyls simultaneously [3,2-b] furan -3- base, 6,6- difluoro hexahydro furyls simultaneously [3,2-b] furan - 3- base, (3ar, 6ar) -3a, 6a- bis- deuterium hexahydro furyl simultaneously [3,2-b] furan -3- base, octahydro Pentamethylene. simultaneously [c] pyrroles -5- base, (3ar, 6as) -3a, 6a- bis- deuterium octahydro Pentamethylene. simultaneously [c] pyrroles -5- base, 3a- fluorine two deuterium octahydro Pentamethylene. simultaneously [c] pyrroles -5- Base, 5- deuterium octahydro Pentamethylene. simultaneously [c] pyrroles -5- base, 1,1- bis- deuterium octahydro Pentamethylene. simultaneously [c] pyrroles -5- base, 5- amino octahydro is simultaneously Cyclopentadiene -2- base, 5- deuterium -5- amino octahydro pentalene -2- base, etc..Wherein said fused bicyclic radicals can be only On the spot unsubstituted or replaced by one or more substituent groups described in the invention.

Term " condensed-bicyclic base alkylidene " represents that alkyl is replaced by one or more condensed-bicyclic base groups, wherein alkane Base group and condensed-bicyclic base group have implication as described in the present invention, and such example includes, but are not limited to hexahydro furyl And [2,3-b] furan -3- ylmethyl, the hexahydro furyl simultaneously deuterated methyl of [2,3-b] furan -3- base two, (3ar, 6as) -3a, 6a- Two deuterium hexahydro furyls simultaneously [2,3-b] furan -3- ylmethyl etc..Wherein said condensed-bicyclic base alkylidene group can be independently Unsubstituted or replaced by one or more substituent groups described in the invention.

Term " volution base ", " volution ", it is special on another ring that " spiral shell bicyclic group " or " spiral shell is bicyclic " represents that a ring originates from Different ring-type carbon, and this member ring systems has one or more junction points to be connected with the remainder of molecule, for example, as disclosed below , the bridged-ring system (ring b and b ') of a saturation is referred to as " condensed-bicyclic ", otherwise ring a and ring b is in the member ring systems of two saturations In a shared carbon atom, then be referred to as " volution " or " spiral shell is bicyclic ".Each ring in volution can be carbocyclic ring or heterocycle.This The example of sample includes, but is not limited to 5- azaspiro [2.4] heptane -5- base, (r) -4- azaspiro [2.4] heptane -6- base etc.. Wherein said spiral shell cyclic groups can be independently unsubstituted or replaced by one or more substituent groups described in the invention.

Term " spiral shell bicyclic group alkylidene " represents that alkyl is replaced by one or more spiral shell bicyclic group groups, wherein alkyl base Group and spiral shell bicyclic group group have implication as described in the present invention.Wherein said spiral shell bicyclic group alkylidene group can independently not It is substituted or replaced by one or more substituent groups described in the invention.

As described in the invention, substituent group draws member ring systems (the below figure institute being formed on a ring being bonded the center of being connected to Show) represent substituent group any commutable position on ring and can replace.For example, formula e represents and any on b ring may be substituted Position, such as formula f-1, shown in f-2 and f-3.

As described herein, term " pharmaceutically acceptable carrier " includes any solvent, disperse medium, coating agents, Surfactant, antioxidant, preservative (such as antibacterial agent, antifungal), isotonic agent, salt, drug stabilizing agent, bonding Agent, excipient, dispersant, lubricant, sweeting agent, flavoring agent, coloring agent, or combinations thereof, these carriers are all affiliated technology Skilled person known (as remington's pharmaceutical sciences, 18th ed.mack Printing company, 1990, p.1289-1329 described).Except the incompatible situation of any conventional carrier and active component Outward, cover its purposes in treatment or pharmaceutical composition.

The as used in the present invention any disease of term " treatment " or disease, wherein some embodiment middle fingers improve disease Disease or the disease development of its at least one clinical symptoms (slow down or stop or palliate a disease or).In other embodiments In, " treatment " refers to relax or improve at least one body parameter, including the body parameter that may not be discovered by patient.Another In some embodiments, " treatment " refers to (for example stablize perceptible symptom) from body or physiologically (for example stablizes body Parameter) or above-mentioned two aspects adjust diseases or disease.In other embodiments, " treat " refer to prevent or postpone disease or The outbreak of disease, generation or deterioration.

When term " blocking group " or " pg " refer to a substituent group and other reacted with functional groups, it is commonly used to hinder Feature disconnected or that protection is special.For example, " blocking group of amino " refers to that a substituent group is connected to block with amino group Or in protection compound amino feature, suitable amido protecting group includes acetyl group, trifluoroacetyl group, tertbutyloxycarbonyl (boc, boc), benzyloxycarbonyl group (cbz) and 9- fluorenes methylene oxygen carbonyl (fmoc).Similarly, " hydroxy-protective group " refers to hydroxyl Substituent group is used for blocking or protect the feature of hydroxyl, and suitable blocking group includes acetyl group and silicyl." carboxy protective Group " refers to the substituent group of carboxyl for blocking or protecting the feature of carboxyl, general carboxyl-protecting group includes- ch₂ch₂so₂Ph, cyano ethyl, 2- (TMS) ethyl, 2- (TMS) ethoxyl methyl, 2- is (to toluene Sulfonyl) ethyl, 2- (p-nitrophenyl sulfonyl) ethyl, 2- (diphenylphosphino) ethyl, nitro-ethyl, etc..For protection The general description of group refers to document: t w.greene, protective groups in organic synthesis, john wiley&sons,new york,1991;and p.j.kocienski,protecting groups,thieme, stuttgart,2005.

The description of the compound of the present invention

Alkynyl compoundss according to the present invention, its pharmaceutically acceptable salt, and its pharmaceutical preparation, tyrosine kinase is subject to Body, the especially disease of alk and c-met regulation or the treatment of disease have potential purposes.Particularly, the present invention relates to one Plant compound, it is the stereoisomer of the compound of structure shown in formula (i) or compound shown in formula (i), geometric isomer, mutually Tautomeric, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or its prodrug:

Wherein: x, w₁, w₂, w₃, and y has implication as described in the present invention.

In some embodiments, each w₁, w₂And w₃It independently is n or cr^c；

X is following subformula:

OrWherein, described subformula (iia) and (iib) Unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced；Each z₁And z₂It independently is n or ch；

Each r¹It independently is d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-nr^ar^b, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, r^ao-c_1-4Alkylidene, c_3-10Cycloalkyl, c_3-10Cycloalkanes Base-c_1-4Alkylidene, c_3-10Heterocyclic radical, c_3-10Heterocyclic radical-c_1-4Alkylidene, c_6-10Aryl, comprises 1,2,3 or 4 and is independently selected from o, The heteroatomic 5-10 former molecular heteroaryl of s and n, c_6-10Aryl-c_1-4Alkylidene, or (5-10 is former molecular miscellaneous Aryl)-c_1-4Alkylidene, wherein, when in formula (iia), z₁And z₂When being ch simultaneously, r¹It is not -or^aOr-nr^ar^b, and each r¹Can With independently unsubstituted or further by r²Group is replaced；Or, the r in formula (iia) or (iib), on adjacent atom¹Base Group can be unified into c_4-10Cycloalkyl or c_3-10Heterocyclic radical, wherein, described c_4-10Cycloalkyl and c_3-10Heterocyclic radical is independently of one another not It is substituted or by 1,2,3 or 4 r²Group is replaced；

Each r²It independently is d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-nr^ar^b, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c₂-₆Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, rao-c_1-4Alkylidene, c_3-8Cycloalkyl, c_3-8Cycloalkanes Base-c_1-4Alkylidene, c_3-8Heterocyclic radical, or c_3-8Heterocyclic radical-c_1-4Alkylidene；

Y is c_6-10Aryl or comprise 1,2,3 or 4 and be independently selected from o, heteroatomic 5-10 of s and n former molecular miscellaneous Aryl, wherein, described c_6-10Aryl and 5-10 former molecular heteroaryl is unsubstituted independently of one another or by 1,2,3 or 4 Individual substituent group is replaced, and described substituent group is independently selected from d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-s (=o) r^a,-s (=o)₂r^a,-nr^ar^b,-s (=o)₂nr^ar^b,-oc (=o) r^a, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4 Alkylidene, r^ao-c_1-4Alkylidene, c_3-8Cycloalkyl, c_3-8Cycloalkyl-c_1-4Alkylidene, c_3-8Heterocyclic radical, or c_3-8Heterocyclic radical-c_1-4 Alkylidene；

Each r^aAnd r^bIt independently is h, c_1-6Aliphatic, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-4Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-4Alkylidene, wherein, described c_1-6Aliphatic, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-4Alkylidene, c_3-6Heterocycle Base, and c_3-6Heterocyclic radical-c_1-4Alkylidene is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substituent group, described replacement Base is independently selected from d, f, cl, cn, n₃, oh, nh₂, c_1-6Alkoxyl, or c_1-6Alkyl amino；

Each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-6Alkyl-s (=o)₂Nh-, c_1-6Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-6Alkyl, c_1-6Alkoxyl, c_1-6Alkyl amino, c_3-6Cycloalkyl, c_3-6Heterocyclic radical, c_6-10Virtue Base, or comprise 1,2,3 or 4 and be independently selected from o, the heteroatomic 5-10 former molecular heteroaryl of s and n, wherein, described c_1-6Alkyl, c_1-6Alkoxyl, c_1-6Alkyl amino, c_3-6Cycloalkyl, c_3-6Heterocyclic radical, c_6-10Aryl, and 5-10 is individual former molecular Heteroaryl is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substituent group, described substituent group independently selected from d, f, Cl, cn, n₃, oh, nh₂, c_1-6Alkyl, c_3-6Cycloalkyl, c_1-6Haloalkyl, c_1-6Alkoxyl, or c_1-6Alkyl amino.

In other embodiment, each w₁And w₂It independently is cr^c；w₃For n or cr^c.

In other embodiment, x is following subformula:

OrWherein, described subformula (iia) and (iii) Unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced；Each z₁And z₂It independently is n or ch.

In other embodiment, each r¹It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-4Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, when in formula (iia), z₁And z₂When being ch simultaneously, r¹It is not -or^aOr-nr^ar^b, and Each r¹Can be independently unsubstituted or further by r²Group is replaced；Or, in formula (iia) or (iib), on adjacent atom R¹Group can be unified into c_5-6Cycloalkyl or c_3-6Heterocyclic radical, wherein, described c_5-6Cycloalkyl and c_3-6Heterocyclic radical is each independent Ground is unsubstituted or by 1,2,3 or 4 r²Group is replaced.

In other embodiment, each r²It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene.

In other embodiment, y is phenyl, and described phenyl is independently unsubstituted or by 1,2,3 or 4 substituent group Replaced, described substituent group is independently selected from d, f, cl, br, c_1-3Alkyl, c_1-3Haloalkyl, or c_2-6Alkynyl.

In other embodiment, each r^aAnd r^bIt independently is h, c_1-3Alkyl, c_3-6Cycloalkyl, or c_3-6Heterocyclic radical, its In, described c_1-3Alkyl, c_3-6Cycloalkyl, and c_3-6Heterocyclic radical is unsubstituted independently of one another or by 1,2,3 or 4 substituent group institute Replace, described substituent group is independently selected from d, f, n₃, oh, nh₂, c_1-3Alkoxyl, or c_1-3Alkyl amino.

In other embodiment, each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-3Alkyl-s (=o)₂Nh-, c_1-3Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-3Alkyl, c_1-3Alkoxyl, c_1-3Alkyl amino, c_3-6Cycloalkanes Base, or c_3-6Heterocyclic radical, wherein, described c_1-3Alkyl, c_1-3Alkoxyl, c_1-3Alkyl amino, c_3-6Cycloalkyl, and c_3-6Heterocyclic radical is each Replaced from independently unsubstituted or by 1,2,3 or 4 substituent group, described substituent group is independently selected from d, f, cl, cn, n₃, Oh, nh₂, c_1-3Alkyl, c_3-6Cycloalkyl, c_1-3Haloalkyl, c_1-3Alkoxyl, or c_1-3Alkyl amino.

In other embodiment, x is following subformula:

Wherein, described subformula is unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced, and each r¹Can With independently unsubstituted or further by r²Group is replaced；Or, the r in described each subformula, on adjacent atom¹Base Group can be unified into c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is unsubstituted or by 1,2,3 or 4 r²Group is replaced.

In other embodiment, each r¹It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-4Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, Or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, when x is for phenyl, r¹It is not -or^aOr-nr^ar^b, and each r¹Can independently not It is substituted or further by r²Group is replaced；Or, the r in described each subformula, on adjacent atom¹Group can be combined Become c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is independently unsubstituted or by 1,2,3 or 4 r²Group is replaced；Each r²Solely It is on the spot d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Sub- Alkyl, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene.

In other embodiment, the present invention relates to the compound of one of or its stereoisomer, several What isomer, tautomer, nitrogen oxides, hydrate, solvate, metabolite, pharmaceutically acceptable salt or it Prodrug, but it is not limited to these compounds:

The present invention also comprises the compound of the present invention and its application of pharmaceutically acceptable salt, that is, be used for producing medicine product Product treat the disease of acute and chronic blood vessel generation mediation, described in the invention including those.The compound of the present invention is anti-in production Application in cancer drug.The compound of the present invention is equally used for producing a kind of medical supplies to mitigate, stop, control or treatment by The disease that alk or c-met is mediated.The present invention comprises pharmaceutical composition, and this pharmaceutical composition includes the chemical combination representated by formula (i) Thing and at least one pharmaceutically acceptable carrier, the effectively treatment consumption needed for the combination of adjuvant or diluent.

The present invention equally comprises to treat the disease that patient vessel occurs mediation, or the method sensitive to this disease, the method Comprise using the therapeutically effective amount of compound representated by formula (i), patient to be treated.

Unless other aspects show, all of stereoisomer of compound of the present invention, geometric isomer, tautomerism Body, nitrogen oxides, hydrate, solvate, metabolite, salt and pharmaceutically acceptable prodrug broadly fall into the model of the present invention Enclose.

In some embodiments, described salt refers to pharmaceutically acceptable salt.Term " pharmaceutically acceptable " refers to thing Matter or compositionss must be with the other compositions comprising preparation and/or the mammal treated with it chemically and/or in toxicology Compatible.

The salt of the compound of the present invention is also included for preparation or the intermediate of compound or formula (i) shown in purification formula (i) The salt of the detached enantiomer of shown compound, but it is not necessarily pharmaceutically acceptable salt.

Pharmaceutically useful acid-addition salts can be formed with mineral acid and organic acid, for example acetate, aspartate, benzoic acid Salt, benzene sulfonate, bromide/hydrobromate, bicarbonate/carbonate, disulfate/sulfate, camsilate, chlorination Thing/hydrochlorate, chloro theophylline salt, citrate, ethanedisulphonate, fumarate, gluceptate, gluconate, glucuronic acid Salt, hippurate, hydriodate/iodide, isethionate, lactate, lactobionate, lauryl sulfate, Fructus Mali pumilae Hydrochlorate, maleate, malonate, mandelate, mesylate, Methylsulfate, naphthoate, naphthalene sulfonate, nicotinate, Nitrate, octadecanoate, oleate, oxalates, palmitate, pamoate, phosphate/phosphor acid hydrogen salt/dihydric phosphate, poly- half Lactobionate, propionate, stearate, succinate, sulfosalicylate, tartrate, toluene fulfonate and trifluoroacetic acid Salt.

Such as hydrochloric acid, hydrobromic acid, sulphuric acid, nitric acid, phosphoric acid etc. can be included by its derivative mineral acid obtaining salt.

Can by its derivative organic acid obtaining salt include for example acetic acid, propanoic acid, hydroxyacetic acid, oxalic acid, maleic acid, the third two Acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethyl sulfonic acid, acetone acid, p-methyl benzenesulfonic acid, Sulfosalicylic acid etc..Pyrans saccharic acid, such as glucuronic acid and galacturonic acid；Alpha-hydroxy acid, such as citric acid and tartaric acid；Amino Acid, such as aspartic acid and glutamic acid；Aromatic acid, such as benzoic acid and cinnamic acid；Sulfonic acid, such as p-methyl benzenesulfonic acid and ethyl sulfonic acid, Etc..

Pharmaceutically acceptable base addition salts can be formed with inorganic base and organic base.

Can be included by its derivative inorganic base obtaining salt, the metal of i race to the xii race of such as ammonium salt and periodic chart.? In some embodiments, this salt is derived from sodium, potassium, lithium, ammonium, calcium, magnesium, ferrum, aluminum, silver, manganese, zinc and copper；Particularly suitable salt bag Include ammonium, potassium, sodium, calcium and magnesium salt.

Amine primary amine, secondary amine and tertiary amine can be included by its derivative organic base obtaining salt, replacing (includes naturally occurring The amine replacing), cyclic amine (as morpholine and piperazine etc.), alkali metal hydroxide, alkaline earth metal hydroxide or alkali ion hand over Change resin etc..Some organic amines, such as 2-aminopropane., benzathine benzylpenicillin (benzathine), choline salt (cholinate), diethanol Amine, diethylamine, lysine, meglumine (meglumine), piperazine and trometamol.Some aminoacid, such as glycine and smart ammonia Acid.

The officinal salt of the present invention can be synthesized by parent compound, alkalescence or acidic moiety with conventional chemical processes. In general, such salt can by make the free acid form of these compounds and stoichiometry suitable alkali (as na, ca, The hydroxide of mg or k, carbonate, bicarbonate etc.) reaction, or by making free alkali form and the chemistry of these compounds The suitable acid reaction of metered amount is being prepared.Such reaction is generally carried out in water or organic solvent or the mixture of the two. Usually, in the case of suitably, need using non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile.? Such as " remington ' s pharmaceutical sciences ", the 20th edition, mack publishing company, Easton, pa., (1985)；" pharmaceutical salts handbook: property, selection and application (handbook of pharmaceutical Salts:properties, selection, and use) ", stahl and wermuth (wiley-vch, weinheim, Germany, 2002) list of the suitable salt of other can be found in.

And, the compounds of this invention, can also be obtained with its hydrate forms including its salt, or include other for it The solvent of crystallization.The compounds of this invention can inherently or by design forming have the solvation of acceptable solvent (inclusion water) Thing；Therefore, the invention is intended to including solvation and unsolvated form.

On the other hand, the invention provides the preparation of compound shown in formula (i), separate the method with purification.Of the present inventionization Compound might have the form of several asymmetric centers or generally described raceme mixture.The present invention wraps further Containing racemic mixture, the mixture of partial racemization and separate the enantiomer that obtains and diastereomer.

The compound of the present invention can be with possible isomer, rotamer, atropisomer, tautomer Presented in a kind of form or its mixture, the present invention can comprise isomer further, rotamer, resistance turn isomery Body, the mixture of tautomer, or isomer, rotamer, atropisomer, the part mixing of tautomer Thing or the isomer separated, rotamer, atropisomer, tautomer.

Any structural formula that the present invention is given is also intended to the form and isotope mark representing that these compounds are not labeled The form of note.Isotope-labeled compound has the structure of the formula description that the present invention provides, except one or more atoms Replaced by the atom with selected atomic weight or mass number.The Exemplary isotopes being introduced in the compounds of this invention include The isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine and chlorine, such as²H,³H,¹¹C,¹³C,¹⁴C,¹⁵N,¹⁸F,³¹P,³²P,³⁶S,³⁷Cl and¹²⁵i.

On the other hand, compound of the present invention includes with compound defined in the various isotope-labeled present invention, For example, wherein there is radiosiotope, such as³H,¹⁴C and¹⁸Those compounds of f, or wherein there is non radioactive isotope, As²H and¹³c.Such isotope-labeled compound can be used for metabolism research and (uses¹⁴C), Reaction kinetics research (use example As²H or³H), detection or imaging technique, such as positron emission tomography (pet) or inclusion medicine or substrate tissue distribution are surveyed Fixed SPECT (single photon emission computed tomography) (spect), or can be used in the radiotherapy of patient.¹⁸F or the compound pair of labelling It is especially desirable for pet or spect research.Isotope-labeled formula (i) compound can pass through those skilled in the art Substituted using suitable isotope labeling reagent described by embodiment in familiar routine techniquess or the present invention and preparation process Originally used unmarked reagent is preparing.

Additionally, higher isotope particularly deuterium is (i.e.,²H or replacement d) can provide some treatment advantages, and these advantages are Brought by metabolic stability is higher.For example, Half-life in vivo increases or volume requirements reduce or therapeutic index obtains improving band Come.It should be appreciated that the deuterium in this context is seen as the substituent group of formula (i) compound.Isotope enrichment factor can be used To define the concentration of such higher isotope particularly deuterium.Term " isotope enrichment factor " used in the present invention refers to indication Fixed ratio between isotopic isotope abundance and natural abundance.If the substituent group of the compounds of this invention is designated as deuterium, This compound has at least 3500 (at each specified D-atom, 52.5% deuterium mixes), at least for each D-atom specified 4000 (60% deuterium mixes), at least 4500 (67.5% deuterium mixes), at least 5000 (75% deuterium mixes), at least 5500 (82.5% deuterium mix), at least 6000 (90% deuterium mixes), at least 6333.3 (95% deuterium mixes), at least 6466.7 (97% Deuterium mix), the isotope enrichment factor of at least 6600 (99% deuterium mix) or at least 6633.3 (99.5% deuterium mixes).This Invent pharmaceutically useful solvate and include the such as d that wherein recrystallisation solvent can be that isotope replaces₂O, acetone-d₆、dmso-d₆ Those solvates.

The compositionss of the compound of the present invention, preparation and administration

According on the other hand, the feature of the pharmaceutical composition of the present invention includes the compound of formula (i), listed by the present invention Compound, or the compound of embodiment 1-9, and pharmaceutically acceptable carrier, adjuvant, or excipient.The compositionss of the present invention The amount of middle compound can detectably suppress biological sample or protein kinase in the patient effectively.

There is free form in the compound of the present invention, or suitably, as pharmaceutically acceptable derivates.According to this Bright, pharmaceutically acceptable derivates include, but is not limited to, pharmaceutically acceptable prodrug, salt, ester, the salt of esters, or energy Directly or indirectly other any adducts or the derivant that need administration according to patient, described by other aspects of the present invention Compound, its metabolite or his residue.

As described in the invention, the pharmaceutically acceptable compositionss of the present invention comprise pharmaceutically acceptable load further Body, adjuvant, or excipient, these are applied as the present invention, including any solvent, diluent, or other liquid excipients, point Powder or suspending agent, surfactant, isotonic agent, thickening agent, emulsifying agent, preservative, solid binder or lubricant, etc., It is suitable for distinctive target formulation.As described by documents below: in remington:the science and practice of pharmacy,21st edition,2005,ed.d.b.troy,lippincott williams&wilkins, philadelphia,and encyclopedia of pharmaceutical technology,eds.j.swarbrick And j.c.boylan, 1988-1999, marcel dekker, new york, the content of comprehensive document herein, show different Carrier can be applicable to preparation and the preparation method known to them of pharmaceutically acceptable compositionss.Except any conventional carrier The incompatible scope of the compound of medium and the present invention, for example produced any bad biological effect or with pharmaceutically can connect What any other component of the compositionss being subject to produced in harmful manner interacts, and their purposes is also that the present invention is considered Scope.

Can include, but is not limited to as the material of pharmaceutically acceptable carrier, ion-exchanger, aluminum, aluminium stearate, ovum Phospholipid, serum albumin, such as human albumin, buffer substance such as phosphate, glycine, sorbic acid, potassium sorbate, saturation vegetable butter Partial glyceride mixtures, water, salt or the electrolyte of fat acid, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, chlorination Sodium, zinc salt, colloidal silicon, magnesium trisilicate, Polyvinylpyrrolidone, polyacrylate, wax, polyethylene-polyoxypropylene-blocking-up polymerization Body, lanoline, sugar, such as Lactose, dextrose and saccharose；Starch such as corn starch and potato starch；Cellulose and its derivant As sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate；Gum powder；Fructus Hordei Germinatus；Gelatin；Pulvis Talci；Adjuvant such as cacao bean Fat and suppository wax；Oil such as Oleum Arachidis hypogaeae semen, Oleum Gossypii semen, safflower oil, Oleum Sesami, olive oil, Semen Maydis oil and Oleum Glycines；Glycolss chemical combination Thing, such as propylene glycol and Polyethylene Glycol；Esters such as ethyl oleate and ethyl laurate；Agar；Buffer agent such as magnesium hydroxide and Aluminium hydroxide；Alginic acid；Pyrogen-free water；Isotonic salt；Lin Ge (family name) solution；Ethanol, phosphate buffer solution, and other are nontoxic Suitable lubricant such as sodium laurylsulfate and magnesium stearate, coloring agent, releasing agent, coating agents, sweeting agent, flavoring agent and perfume (or spice) Material, preservative and antioxidant.

The compositionss of the present invention can be oral administration, drug administration by injection, Aerosol inhalation, and local is administered, and per rectum is administered, Nose administration, buccal administration, vagina administration or be administered by implantable medicine box.Term used herein " through injection " includes Subcutaneous, vein, intramuscular, IA, in synovial membrane (chamber), intrasternal, in film, ophthalmic, in liver, focus Interior, and the injection of intracranial or infusion techniques.Preferably compositionss are oral administration, to Intraperitoneal medication or intravenous injection.This The injection system of the composition sterile of invention can be water or oleaginous suspension.These suspensions can be according to known skill Art adopts suitable dispersant, wetting agent and suspending agent to press formula manufacture.Aseptic injection can be aseptic parenteral solution or suspension Liquid, is the nontoxic acceptable diluent of injection or solvent, such as 1,3 butylene glycol solution.These acceptable excipient and solvent Can be water, Ringer's solution and isotonic sodium chlorrde solution.Further, aseptic nonvolatile oil can be made by convention For solvent or suspension media.

With this end in view, any gentle nonvolatile oil can be list or the DG of synthesis.Fat Acid, such as Oleic acid and its glyceride ester derivatives can be used for the preparation of injectable, as natural pharmaceutically acceptable oil Fat, such as olive oil or Oleum Ricini, particularly their polyoxyethylene deriv.These oil solutions or suspension can comprise long-chain Alcohol diluent or dispersant, such as carboxymethyl cellulose or similar dispersing agents, it is generally used for the medicine system of pharmaceutically acceptable dosage form Agent includes emulsion and suspension.Other conventional surfactants, such as Tweenses, spans and other emulsifying agents or biological medicament The hardening agent of efficiency, is generally used for pharmaceutically acceptable solid, liquid, or other dosage forms is it is possible to be applied to drug target The preparation of preparation.

The pharmaceutically acceptable compositionss of the present invention can be to carry out oral administration with any acceptable peroral dosage form, its In include, but is not limited to, capsule, tablet, water suspension or solution.Orally use with regard to tablet, carrier generally comprises breast Sugar and corn starch.Lubricant, such as magnesium stearate, all typically it is added.For capsule oral administration, suitable diluent bag Include Lactose and dry corn starch.When oral administration is for water suspension, its effective ingredient is made up of emulsifying agent and suspending agent. If expecting these dosage forms, some sweeting agents, flavoring agent or coloring agent can also be added.

In addition, the pharmaceutically acceptable compositionss of the present invention can in the form of suppository rectally.These can pass through Reagent is mixed with suitable non-perfusing accessory drugss and forms, this accessory drugss at room temperature be solid but at a temperature of rectum then For liquid, thus melting in the rectum and discharging medicine.Such material includes cocoa butter, Cera Flava, and polyethylene glycols.This When to invent pharmaceutically acceptable compositionss can be local administration, particularly local application, it is related to controlling of region or organ Treat target easily to reach, such as the disease of eye, skin or lower intestinal tract.Suitable topical preparations can prepare and be applied to These fields or organ.

Rectal suppository (see above content) or suitably enema can apply to the local application of lower intestine.Local skin Skin speckle is it is also possible that medication.For local application, pharmaceutically acceptable compositionss can be prepared into properly by formulation method Ointment, this ointment packets is suspended or dissolved in one or more carriers containing active component.It is supported that present invention local is administered Compound includes, but is not limited to mineral oil, liquid paraffin, white vaseline, propylene glycol, polyoxyethylene, polyoxypropylene compound, breast Change wax and water.In addition, pharmaceutically acceptable compositionss can be prepared into suitable lotion or Emulsion, this lotion or Emulsion comprise Active component is suspended in or is dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier includes, but is not limited to, ore deposit Thing oil, Arlacel-60 (Arlacel-60), Tween-60 (polysorbate 60), cetyl esters wax, palmityl alcohol, 2- Octyldodecanol, benzyl alcohol and water.

Preparation can be prepared into for ophthalmically acceptable, pharmaceutically acceptable compositionss, such as isotonic micronized suspension, ph The Sterile Saline or other aqueous solutions that adjust are it is preferable that the Sterile Saline of isosmotic solution and ph regulation or other aqueous solutions, permissible Add disinfection preservative such as benzalkonium chloride.In addition, for ophthalmically acceptable, pharmaceutically acceptable compositionss can be by pharmaceutical formulation system Standby one-tenth ointment such as vaseline oil.The pharmaceutically acceptable compositionss of the present invention can by the gaseous solvents of nose or inhalant carry out to Medicine.Such compositionss can prepare according to the known technology of pharmaceutical formulation, or can be prepared into saline solution, using benzene first Alcohol or other suitable preservative, absorption enhancer, fluorocarbon or other conventional solubilizing agents or dispersant are improving biology Availability.

The liquid dosage form of oral administration includes, but is not limited to, pharmaceutically acceptable Emulsion, microemulsion, solution, suspends Liquid, syrup and elixir.In addition to the active compound, liquid dosage form can comprise known general inert diluent, for example, water Or other solvents, solubilizing agent and emulsifying agent, such as ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3 butylene glycol, dimethylformamide, oils and fatss (particularly Semen Gossypii, Semen arachidis hypogaeae, Semen Maydiss, microorganism, Fructus Canarii albi, Semen Ricini And Oleum Sesami), glycerol, Tetrahydrofurfuryl Alcohol, Polyethylene Glycol, sorbitan alcohol fatty acid ester, and their mixture.Remove Outside inert diluent, Orally administered composition can also comprise adjuvant such as wetting agent, emulsifying agent or suspending agent, sweeting agent, seasoning Agent and aromatic.

Injection, such as aseptic parenteral solution or oleaginous suspension can according to known technology adopt suitable dispersant, Wetting agent and suspending agent are prepared by pharmaceutical formulation.Aseptic injection can be nontoxic through parenterally acceptable diluent Or aseptic parenteral solution, suspension or the emulsion that solvent is made, for example, 1,3 butylene glycol solution.Acceptable excipient and solvent Can be water, Lin Ge (family name) solution, u.s.p. and isotonic sodium chlorrde solution.In addition, aseptic nonvolatile oil is by convention As solvent or suspension media.With this end in view any gentle nonvolatile oil can include the list synthesizing or two glycosyl are sweet Oily diester.In addition, fatty acid such as Oleic acid can apply to injection.

Injection can be aseptic, such as defend filter by antibacterial and filter, or in the form of aseptic solid composite Mix biocide, biocide can be dissolved in or be scattered in disinfectant or other sterile injectable medium before use.In order to prolong The effect of the compound of the long present invention, it usually needs slow down the absorption of compound by subcutaneous injection or intramuscular injection.So Can realize solving the problems, such as crystal or amorphous material poorly water-soluble using liquid suspension.The absorbance of compound depends on Its dissolution, depends on grain size and crystal shape successively.Furthermore it is possible to be dissolved in oil vehicles by compound Or dispersion absorbs come the delay to complete compound injection administration.

Injection storage form is by biodegradable polymer, and such as many lactic acid-polyglycolide forms chemical combination The microcapsule matrix of thing completes.The controlled release ratio of compound depends on ratio and the particular polymer that compound forms polymer Property.Other biodegradable polymers include poly- (positive esters) and poly- (anhydride).Injection storage form can also be passed through Compound embeds the liposome compatible with bodily tissue or microemulsion prepares.

Some of them embodiment is that the compositionss of rectum or vagina administration are suppository, and suppository can be by by the present invention's The adjuvant of compound and suitable non-perfusing or carrier mix to prepare, such as cocoa butter, Polyethylene Glycol, or suppository is wax-like Thing, they for solid but are then liquid in room temperature under body temperature, therefore just melt release of active in vagina or sheath intracavity and close Thing.

The solid dosage formss of oral administration include capsule, tablet, pill, powder and granule.In these dosage forms, active ingredient Thing is mixed with least one pharmaceutically acceptable inert excipient or carrier, such as sodium citrate or calcium phosphate or filler or a) Filler such as starch, Lactose, sucrose, glucose, Mannitol and silicic acid, b) binding agent such as carboxymethyl cellulose, alginate, bright Glue, polyvidon, sucrose and arabic gum, c) wetting agent such as glycerol, d) disintegrating agent such as agar, Calcium Carbonate, potato starch Or tapioca, alginic acid, some silicate and sodium carbonate, e) block agent solution such as paraffin, f) absorption enhancer such as quaternary ammonium Compound, g) wetting agent such as hexadecanol and glyceryl monostearate, h) absorbent such as kaolin and Bentonite, i) lubricant such as Talcum Powder, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium laurylsulfate, and their mixture.As for capsule, tablet and ball Agent, these dosage forms can comprise buffer agent.

The solid composite of similar type can be that filler riddles soft or hard capsule, and the adjuvant being used has breast Sugared and high molecular Polyethylene Glycol etc..Solid dosage formss photo agent, lozenge, capsule, pill and granule can pass through coating, shell adding As on enteric coating and other drugs preparation, known coating method prepares.They optionally can comprise opacifier, or Preferably, in certain part of intestinal, arbitrarily, with the sole active agent in the method release composition of delay.As implantation Compositionss can comprise multimeric species and wax.

Reactive compound can form microcapsule formulations together with one or more excipient described in the invention.Solid Dosage form photo agent, lozenge, capsule, pill and granule can pass through coating or shell adding, such as enteric coating, controlled release coat and other public affairs The drug formulation process known.In these solid dosage formss, reactive compound can be mixed with least one inert diluent, such as sugarcane Sugar, Lactose or starch.Such dosage form can also comprise substance besides inert diluents as general application, such as Tableting lubricant and other compression aids such as magnesium stearate and Microcrystalline Cellulose.As for capsule, tablet and pill, these dosage forms can To comprise buffer agent.They optionally can comprise tranquilizer, or preferably, in certain part of intestinal, with any delay Sole active agent in method release composition.Applicable implant compositions can include, but is not limited to, polymer and Wax.

The compound of the present invention by local or the dosage form through percutaneous drug delivery include ointment, paste, Emulsion, lotion, coagulate Colloid, powder, solution, spray, inhalant, paster.Active component under sterile conditions with pharmaceutically acceptable carrier Mutually mix with any necessary preservative or necessary buffer agent.The pharmaceutical preparation of ophthalmology, ear drop and eye drop are all these The scope of bright consideration.In addition, present invention further contemplates that the application of transdermal patch, it is delivered to internal aspect in control compound has More advantages, such dosage form by dissolving or can disperse compound to prepare in suitable medium.Absorb and promote Enter agent can increase compound pass through skin flow, through-rate control thin film or by compound be scattered in polymer matrix or Gelatin is controlling its speed.

The compound of the present invention is preferably prepared into dosage unit form to mitigate the equal of dosage and dosage by pharmaceutical formulation Even property.Term " dosage " unit type " is suitably treated the physical dispersion unit of required medicine referred to herein as patient.However, should Understand that the compound of the present invention or the total daily usage of compositionss will judge to come according to reliable medical science scope by the doctor in charge Determine.For any one special patient or organism, specific effective dose level will depend upon that many factors include being controlled The disease treated and the seriousness of disease, the activity of particular compound, concrete composition used, the age of patient, body weight, health Situation, sex and dietary habit, administration time, the discharge rate of route of administration and particular compound used, treatment lasting when Between, medicinal application is combined in drug combination or with specific compound, and factor known to some other pharmaceutical field.

The change of the consumption of the compound of the present invention that can produce single dosage form composition in conjunction with carrier mass depends on Cure mainly and special mode of administration.Some of them embodiment is that compositionss can be prepared into dosage in 0.01- by formulation method The inhibitor of 200mg/kg body weight/day, is administered by the amount that patient accepts compositionss.

The compound of the present invention with only pharmaceutical agents or can combine other additional treatment (pharmacy one or more ) being administered, wherein drug combination causes acceptable untoward reaction for agent, this is for the treatment tool of high proliferative disease such as cancer There is special meaning.In this case, the compound of the present invention can be in conjunction with known cytotoxic agent, single transduction suppression Agent or other antitumor and anticancer agents, and their mixture and combination.As used in the present invention, the normal administration of additional therapeutic agent is controlled Treat special disease it is simply that known " suitably treating disease "." additional therapeutic agent " used in the present invention includes Chemo-Therapy Treat medicine or other antiproliferative medicines can be in conjunction with the compounds for treating proliferative disease of the present invention or cancer.

Chemotherapeutic agent or other anti-proliferative drugs include histon deacetylase (HDAC) (hdac) inhibitor, including but simultaneously It is not limited to, saha, ms-275, mgo103, and those compounds described by following patent: wo2006/010264, wo03/ 024448,wo2004/069823,us2006/0058298,us2005/0288282,wo00/71703,wo01/38322, Wo01/70675, wo03/006652, wo2004/035525, wo2005/030705, wo2005/092899, and demethylation examination Agent includes, but is not limited to, the miscellaneous nitrogen of 5- -2 '-deoxycytidine (5-aza-dc), azacitidine (vidaza), decitabine (decitabine) compound and described by documents below: us6,268137, us5,578,716, us5,919,772, us6, 054,439, us6,184,211, us6,020,318, us6,066,625, us6,506,735, us6,221,849, us6,953, 783,us11/393,380.

Other embodiment is that chemotherapeutics or other anti-proliferative drugs can increase in conjunction with the compounds for treating of the present invention Growing property disease and cancer.Known chemotherapeutics include, but is not limited to, can with anti-cancer agent in combination of the present invention use other Therapy or cancer therapy drug, operation, X-ray therapy (a little example such as gamma-radiation, neutron beam X-ray therapy, electron beam evaporation therapy, Proton therapy, brachytherapy and system isotope therapy), incretotherapy, taxaneses (paclitaxel (taxol), Docetaxel (taxotere) etc.), and platinum derivatives (cisplatin (cisplatin), carboplatin (carboplatin), difficult to understand Husky profit platinum (oxaliplatin), Satraplatin (satraplatin)), biological response modifier (interferon, interleukin), tumor Necrosin (tnf, trail receptor target thing), overheated and cryotherapy, the reagent mitigating any untoward reaction is (as emesis Medicine), and other approved chemotherapeutics, including but not limited to, alkylating drug (chlormethine (mechlorethamine), benzene fourth Sour chlormethine (chlorambucil), cyclophosphamide (cyclophosphamide), melphalan (melphalan), ifosfamide (ifosfamide)), antimetabolite (methotrexate (methotrexate), pemetrexed (pemetrexed) etc.), purine Antagonist and Pyrimidine antagonists (6-MP (6-mercaptopurine), 5-fluorouracil (5-fluorouracil), arabinose Cytidine (cytarabile), gemcitabine (gemcitabine)), spindle poison (vinblastine (vinblastine), Changchun New alkali (vincristine), vinorelbine (vinorelbine)), (etoposide (etoposide), Yi Li replaces podophyllotoxin Health (irinotecan), hycamtin (topotecan)), antibiotic (amycin (doxorubicin), bleomycin (bleomycin), mitomycin (mitomycin)), nitroso ureas (carmustine (carmustine), lomustine (lomustine)), (ksp passes through mitotic kinesin inhibitors to cell division cycle inhibitor, cenp-e and cdk suppresses Agent), enzyme (asparaginase (asparaginase)), hormone (tamoxifen (tamoxifen), leuprorelin (leuprolide), flutamide (flutamide), megestrol (megestrol), dexamethasone (dexamethasone) etc. Deng).Angiogenesis inhibitor reagent (Avastin (avastin) etc.).Monoclonal antibody (Baily monoclonal antibody (belimumab), brentuximab, Cetuximab (cetuximab), gemtuzumab Ozogamicin Mylotarg CDP 771 (gemtuzumab), her monoclonal antibody (ipilimumab), ofatumumab, handkerchief Buddhist nun's monoclonal antibody (panitumumab), Lucentis (ranibizumab), Rituximab (rituximab), tositumomab (tositumomab), Herceptin (trastuzumab)).Kinase inhibitor (imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Erlotinib (erlotinib), gefitinib (gefitinib), reach sand For Buddhist nun (dasatinib), AMN107 (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), Ruxolitinib, vemurafenib, vandetanib, pazopanib, etc.).The approach of Drug inhibition or activation cancer is such as Mtor, hif (hypoxia inducible factor) approach and other.The wide forum for the treatment of of cancer seeshttp:// www.nci.nih.gov/, fad accreditation oncologic inventory seehttp://www.fda.gov/cder/cancer/ druglist-rame.htm, and Merck Manual, the 18th edition .2006, all of content is all combined with list of references.

Other embodiment is that the compound of the present invention can be in conjunction with cytotoxic anticancer agent.Such anticarcinogen can To find the 13rd edition Merck index (2001) is inner.These anticarcinogen include, but are not limited to, asparaginase, win Mycin, carboplatin, carmustine, chlorambucil, cisplatin, l- asparaginase, cyclophosphamide, cytosine arabinoside, dacarbazine, put Line rhzomorph d, daunorubicin, amycin (doxorubicin), epirubicin, etoposide, 5-fluorouracil, hexamethyl melamine Amine, hydroxyurea, ifosfamide, irinotecan, folinic acid, lomustine, chlormethine, Ismipur, mesna, first ammonia butterfly Purine, mitomycin c, mitoxantrone, prednisolone, prednisone, procarbazine, raloxifene, streptozocin, tamoxifen, sulfur Guanine, hycamtin, vinblastine, vincristine, and vindesine.

Include, but is not limited to other suitable cytotoxic drugs of the compound drug combination of the present invention, these Admittedly it is applied to the compound of neoplastic disease treatment, as described in documents below: goodman and gilman's the pharmacological basis of therapeutics(ninth edition,1996,mcgraw-hill.)；This A little anticarcinogen include, but are not limited to, aminoglutethimide (aminoglutethimide), l- asparaginase, azathioprine, 5- Azacytidine, cladribine (cladribine), busulfan (busulfan), diethylstilbestrol, 2,2'- difluoro dCDP gallbladders Alkali, Docetaxel, red hydroxyl nonyl adenine (erythrohydroxynonyladenine), ethinylestradiol, 5- fluorine Uracil deoxynucleoside, floxuridine monophosphate, Fludarabine Phosphate (fludarabine phosphate), Fluoxymesterone Ketone (fluoxymesterone), flutamide (flutamide), hydroxyprogesterone caproate, idarubicin (idarubicin), interferon, Medroxyprogesterone acetate, megestrol acetate, melphalan (melphalan), mitotane (mitotane), paclitaxel, pentostatin (pentostatin), n- phosphate base-l- aspartic acid (pala), plicamycin (plicamycin), methyl cyclohexane nitrous Urea (semustine), teniposide (teniposide), testosterone propionate, phosphinothioylidynetrisaziridine (thiotepa), trimethyl melamine Amine, urine nucleoside and vinorelbine.

The cytotoxin class anticarcinogen of the compound use in conjunction of other suitable and present invention includes newfound cell Toxic substance, including, but be not limited to, oxaliplatin (oxaliplatin), gemcitabine (gemcitabine), card training His shore (capecitabine), Macrolide antineoplastic agent and its naturally occurring or synthetic derivant, temozolomide (temozolomide) (quinn et al., j.clin.oncology, 2003,21 (4), 646-651), tositumomab (bexxar), trabedectin (vidal et al., proceedings of the american society for Clinical oncology, 2004,23, abstract3181), and drive albumen spindle protein inhibitor eg5 (wood et al.,curr.opin.pharmacol.2001,1,370-377).

Other embodiment is that the compound of the present invention can be in conjunction with other signal transduction inhibitors.What is interesting is letter Number transduction inhibitor using egfr family as target, such as egfr, her-2 and her-4 (raymond et al., drugs, 2000, 60(suppl.l),15-23;Harari et al., oncogene, 2000,19 (53), 6102-6114) and the joining of each of which Body.Such reagent includes, but is not limited to, antibody therapy such as Herceptin (trastuzumab), Cetuximab (cetuximab), her monoclonal antibody (ipilimumab) and handkerchief trastuzumab (pertuzumab).Such therapy also includes, but It is not limited to, small molecule kinase inhibitors such as imatinib (imatinib), Sutent (sunitinib), Sorafenib (sorafenib), Erlotinib (erlotinib), gefitinib (gefitinib), Dasatinib (dasatinib), Ni Luo For Buddhist nun (nilotinib), Lapatinib (lapatinib), gram Zhuo replaces Buddhist nun (crizotinib), ruxolitinib, Vemurafenib, vandetanib, pazopanib, Afatinib (afatinib), amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), brivanib, canertinib, cabozantinib, AZD2171 (cediranib), dabrafenib, dacomitinib, danusertib, dovitinib, foretinib, Ganetespib, ibrutinib, iniparib, lenvatinib, linifanib, linsitinib, Masitinib (masitinib), momelotinib, does not replace husky Buddhist nun (motesanib), HKI-272 (neratinib), niraparib, Oprozomib, olaparib, pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, Rucaparib, saracatinib (saracatinib), saridegib, tandutinib, tasocitinib, telatinib, Tivantinib, tivozanib, tofacitinib, trametinib, vatalanib, veliparib, vismodegib, Volasertib, bms-540215, bms777607, jnj38877605, tki258, gdc-0941(folkes, et al., J.med.chem.2008,51,5522), bze235, etc..

Other embodiment is that the compound of the present invention can be with bonding histone deacetylase inhibitors.Such Reagent includes, but is not limited to, suberoylanilide hydroxamic acid (saha), laq-824 (ottmann et al., proceedings of the american society for clinical oncology,2004,23,abstract3024),lbh-589 (beck et al.,proceedings of the american society for clinical oncology,2004, 23,abstract3025),ms-275(ryan et al.,proceedings of the american association of cancer research,2004,45,abstract2452),fr-901228(piekarz et al.,proceedings Of the american society for clinical oncology, 2004,23, abstract3028) and mgcdoi03 (us6,897,220).

Other embodiment is that the compound of the present invention can be in conjunction with other anticarcinogen such as proteasome inhibitor and m- Tor inhibitor.These include, but are not limited to, bortezomib (bortezomib) (mackay et al., proceedings Of the american society for clinical oncology, 2004,23, abstract3109), and cci-779 (wu et al.,proceedings of the american association of cancer research,2004, 45,abstract3849).The compound of the present invention can be combined with other anticarcinogen such as topoisomerase enzyme inhibitor, including but It is not limited to camptothecine.

Those additional therapeutic agents separately can be administered with the compositionss of the compound comprising the present invention, as many dosage regimens A part.Or, those therapeutic agents can be a part for one-pack type, mixes formation list with the compound of the present invention Individual compositionss.If as a part for many dosage regimens, two activating agents can be simultaneously continuously or in a period of time for administration Interior mutual transmission, thus obtain destination agent activity.

(those comprise one and add the consumption of the compound of one-pack type and additional therapeutic agent can be produced in conjunction with carrier mass The compositionss of therapeutic agent are as described in the invention) change depend on cure mainly and special mode of administration.Normally, the present invention The amount of compositionss additional therapeutic agent will comprise therapeutic agent as the normal amount administered of unique activating agent less than compositionss.Separately On the one hand, the scope of the amount of existing disclosed compositionss additional therapeutic agent is about the 50%-100% of existing compositionss normal amount, bag The reagent containing is as sole active therapeutic agent.In the compositionss that those comprise additional therapeutic agent, additional therapeutic agent will be with this Bright compound plays synergism.

The compound of the present invention and the purposes of compositionss

The feature of the pharmaceutical composition of the present invention includes the compound shown in formula (i) or the compound listed by the present invention, And pharmaceutically acceptable carrier, adjuvant or excipient.In the compositionss of the present invention, the amount of compound can be visited effectively Geodetic suppresses the activity of protein kinase such as alk or c-met.The compounds of this invention will be treated to patient as antitumor drug Or reduce the illeffectss of alk and c-met signal response.

The compound of the present invention will be applied to, but be not limited to, using the compound of the present invention or the effective dose of compositionss Patient is administered to prevent or to treat patient's proliferative disease.Such disease includes cancer, especially metastatic carcinoma, and tremulous pulse is athero- Hardening and pulmonary fibrosiss.

The treatment being applied to tumor is included cancer and metastatic carcinoma by the compound of the present invention, further includes but is not limited to, Cancer such as bladder cancer, breast carcinoma, colon cancer, renal carcinoma, hepatocarcinoma, pulmonary carcinoma (inclusion small cell lung cancer), esophageal carcinoma, carcinoma of gallbladder, ovary Cancer, cancer of pancreas, gastric cancer, cervical cancer, thyroid carcinoma, carcinoma of prostate, and skin carcinoma (inclusion squamous cell carcinoma)；Lymphsystem hemopoietic Tumor (includes leukemia, the Cystic leukemia of acute lymphoblastic, acute lymphoblastic leukemia, b cell lymphoma, t cell Lymphoma, He Jiejin (family name) lymphoma, non-hodgkin's (family name) lymphoma, hairy cell leukemia and Burkitt lymphoma)；Bone marrow System hematopoetic tumor (includes acute and chronic myelocytic leukemia, myelodysplastic syndrome, and the white blood of promyelocyte Disease)；The tumor (inclusion fibrosarcoma and rhabdomyosarcoma, and other sarcomas, such as soft tissue and cartilage) of mesenchymal cell origin； Maincenter peripheral nervous system tumor (includes astrocytoma, neuroblastoma, glioma, and schwannoma)；And other Tumor (inclusion melanoma, spermocytoma, teratocarcinoma, osteosarcoma, xenoderoma pigmentosum, Keratoctanthoma, thyroid follicle tumor and Ka Bo Ji (family name) sarcoma).

The compound of the present invention can be additionally used in treating eye disease such as corneal graft rejection, and the new vesselses of eye are formed, Retinal neovascularazation includes damaging or metainfective new vesselses are formed；Diabetic retinopathy；Fine after crystalline lenses Dimensional tissue hypertrophy disease, and neovascular glaucoma；Retinal ischemia；Vitreous hemorrhage；Ulcer disease such as gastric ulcer；Pathology Situation such as hemangioma that learn but non-malignant, including baby's hemangioendothelioma, the blood vessel of nasopharynx and ANB is fine Dimension tumor；The disorderly such as endometriosis of female repro ductive system.These compounds are equally also used for treating edema and vascular permeability Too high situation.

The compound of the present invention can be used for processing the situation such as diabetic retinopathy related to diabetes and micro- blood Pipe disease.The compound of the present invention is equally used for the situation of cancer patient's blood flow minimizing.The compound of the present invention is to patient tumors Transfer reduces also beneficial effect.

The compound of the present invention, in addition to beneficial to human treatment, applies also for veterinary treatment house pet, introduced variety Animal and farm animal, including mammal, rodent etc..The example of other animal include horse, Canis familiaris L. and Cat.Here, the compound of the present invention includes its pharmaceutically acceptable derivates.

Plural form is being applied to compound, in the case of salt etc., it also means single compound, salt etc..

Comprise the compound of the present invention or the Therapeutic Method of compositionss administration, further include to patient's additional therapeutic agent The administration of (therapeutic alliance), wherein additional therapeutic agent are selected from: chemotherapy, antiproliferative or antiinflammatory, wherein additional therapeutic agent Be applied to treated disease, and additional therapeutic agent can with the compound of the present invention or compositionss administering drug combinations, the present invention's Compound or compositionss are as single dosage form, or separate compound or compositionss are as a part for multi-pharmaceuticss.Additional treatment Agent can be administered simultaneously with the compound of the present invention or not be administered simultaneously.The situation of the latter, administration can be staggered and be carried out as 6 little When, 12 hours, 1 day, 2 days, 3 days, 1 week, 2 weeks, 3 weeks, carry out within 1 month or 2 months.

The present invention equally comprises the cytostatic method to expression alk or c-met, and the method includes the present invention's Compound or compositionss and cells contacting, thus cell growth inhibiting.The cell that growth can be suppressed includes: breast cancer cell, Colorectal cancer cell, lung carcinoma cell, papillary carcinoma cell, prostate gland cancer cell, lymphoma cell, colon cancer cell, pancreas Cancerous cell, ovarian cancer cell, cervical cancer cell, central nervous system's cancerous cell, human osteosarcoma cell, kidney cancer cell, liver is thin Born of the same parents' cancerous cell, transitional cell bladder carcinoma cell line, stomach cancer cell, head or carcinoma of neck cell, melanoma cell and leukaemia.

The invention provides the method suppressing alk or c-met kinase activity in biological sample, the method includes this Bright compound or compositionss are contacted with biological sample.Term " biological sample " used in the present invention refers to the mark of vitro Originally, including but not limited to, cell culture or cell extraction；The biopsy thing obtaining from mammal or its extract Matter；Blood, saliva, urine, feces, seminal fluid, tear, or other living tissue liquid substances and its extract.Suppression biological sample Middle kinase activity, particularly alk or c-met kinase activity, can be used for multiple use known to one of ordinary skill in the art.So Purposes include, but be not limited to, hematometachysises, organ transplantation, biological sample storage and bioassay.

" effective dose " or " effective dose " of the compound of the present invention or pharmaceutically acceptable compositionss refer to process or Mitigate the effective dose that one or more present invention are previously mentioned the severity of disease.The method according to the invention, compound and combination Thing can be the order of severity that any dosage and any route of administration process to be efficiently used for or palliate a disease.Necessary standard Situation according to patient is changed by true amount, this depend on race, the age, the generic condition of patient, the order of severity of infection, Special factor, administering mode, etc..Compound or compositionss can be with one or more other therapeutic agents administering drug combinations, such as The present invention is discussed.

The compound of the present invention or its pharmaceutical composition can apply to the coating of implantable medical device, such as prosthese, Artificial valve, artificial blood vessel, stem and catheter.For example, vascular stem, have been used for overcoming restenosiss (vessel wall after injury Shrink again).However, patient will have the risk of clot formation or platelet activation using stem or other implantable devices.These Unfavorable effect can the pharmaceutically acceptable compositionss precoating device of compound by using comprising the present invention hinder Stop or mitigate.

The coating of suitable coating and implantable device be typically prepared method in document us6,099,562;us5,886, 026;And us5, it is described in 304,121, coating is typically biocompatible polymeric material such as hydrogel polymeric Body, poly- methyl two silicon ether, polycaprolactone, Polyethylene Glycol, polylactic acid, ethane-acetic acid ethyenyl ester, and its mixture.Coating can Optionally further to be covered by suitable coating, such as fluoro simethicone, polyase, Polyethylene Glycol, phospholipid, or Combinations thereof, carrys out the feature of performing combination thing control release.Another aspect of the present invention includes the compound using the present invention The implantable device of coating.The compound of the present invention can also be coated on the medical instruments in implantable, such as pearl, or To there is provided " medicine storage institute " with polymer or other molecular mixing, therefore to compare with pharmaceutical aqueous solution administering mode it is allowed to medicine Thing release has longer time limit.

General building-up process

For describing the present invention, it is listed below embodiment.But it is to be understood that the invention is not restricted to these embodiments, simply The method of the present invention is put into practice in offer.

Usually, the compound of the present invention can be prepared by method described in the invention, unless there are further Explanation, wherein shown in the definition of substituent group such as formula (i).Following reaction scheme and embodiment are used for being further illustrated this The content of invention.

The professional of art will be appreciated that chemical reaction described in the invention can be used to suitably prepare perhaps Other compounds of many present invention, and other methods of the compound for preparing the present invention are considered as the model in the present invention Within enclosing.For example, according to the present invention, the synthesis of the compound of those non-illustrations can be successfully by those skilled in the art Completed by method of modifying, such as suitable protection disturbs group, by using reagent known to other except described in the invention , or modification reaction condition being made some routines.In addition, reaction disclosed in this invention or known reaction condition are also generally acknowledged Ground is applied to the preparation of other compounds of the present invention.

The embodiments described below, unless other aspects show all of temperature and are set to degree Celsius.Reagent is bought in business Product supplier such as aldrich chemical company, arco chemical company and alfa chemical Company, not through being further purified, unless other aspects show during use.General reagent is from western Gansu Province, Shantou chemical industry Factory, Guangdong brilliance chemical reagent factory, Guangzhou Chemical Reagent Factory, Tianjin Hao Yuyu Chemical Company, Tianjin good fortune morning chemistry Chemical reagent work, Wuhan Xin Huayuan development in science and technology company limited, Qingdao Teng Long chemical reagent company limited, and Haiyang Chemical Plant, Qingdao's purchase Can buy.

Anhydrous tetrahydro furan, dioxane, toluene, ether is to be dried to obtain through metallic sodium backflow.Anhydrous methylene chloride It is to be dried to obtain through calcium hydride backflow with chloroform.Ethyl acetate, petroleum ether, normal hexane, n, n- dimethyl acetylamide and n, n- Dimethylformamide is to be dried in advance through anhydrous sodium sulfate to use.

Hereinafter reaction is usually to cover a drying tube under nitrogen or argon gas positive pressure or on anhydrous solvent (unless other aspects Show), reaction bulb all suitable rubber closures beyond the Great Wall, substrate is squeezed into by syringe.Glass drying oven is all dried.

Chromatographic column is to use silicagel column.Silica gel (300-400 mesh) is purchased from Haiyang Chemical Plant, Qingdao.The survey of proton nmr spectra Strip part is: under room temperature condition, the nuclear magnetic resonance spectrometer of Brooker (bruker) 400mhz or 600mhz, with cdcl₃、dmso-d₆、cd₃od Or acetone-d₆For solvent (in units of ppm), with tms (0ppm) or chloroform (7.26ppm) as reference standard.Many when occurring Weight peak when, by using following abbreviation: s (singlet, unimodal), d (doublet, bimodal), t (triplet, triple Peak), m (multiplet, multiplet), br (broadened, broad peak), dd (doublet of doublets, double doublet), Dt (doublet of triplets, double triplets).Coupling constant, is represented with hertz (hz).

The condition of Algorithm (ms) data is: agilent6120quadrupole hplc-ms (pillar model: Zorbax sb-c18,2.1x30mm, 3.5 μm, 6min, flow velocity is 0.6ml/min, and mobile phase: 5%-95% is (containing 0.1% formic acid ch₃Cn) in (h containing 0.1% formic acid₂O) ratio in)), detected with uv in 210/254nm, with electron spray ionisation pattern (esi).

The characteristic manner of compound purity is: agilent1260 preparative high performance liquid chromatography (pre-hplc) or Calesep pump250 preparative high performance liquid chromatography (pre-hplc) (pillar model: novasep, 50/80mm, dac), 210nm/254nm is detected with uv.

The use of brief word below runs through the present invention:

Atp adenosine triphosphate

acoh,hac,ch₃Cooh acetic acid, acetic acid

Aibn azodiisobutyronitrile

bbr₃Boron tribromide

bu₄Nf tetrabutyl ammonium fluoride

Double diphenyl phosphine -1,1'- the dinaphthalene of binap 2,2'-

Boc, boc tert-butoxycarbonyl

Bsa bovine serum albumin

N-buoh n-butyl alcohol

N-buli n-BuLi

(n-bu)₃Sncl tri-n-butyltin chloride

cdcl₃Deuterochloroform

ch₃Cook potassium acetate

chcl₃Chloroform

ch₂cl₂, dcm dichloromethane

ch₃so₂Cl, mscl paratoluensulfonyl chloride

cs₂co₃Cesium carbonate

Cu copper

Cui Hydro-Giene (Water Science).

Dcc n, n'- dicyclohexylcarbodiimide

Dast diethylaminosulfur trifluoride

Dbu 1,8- diazabicyclo [5.4.0] 11 carbon -7- alkene

Dead diethyl azodiformate

Diad diisopropyl azodiformate

Dibal diisobutyl aluminium hydride

Diea, dipea diisopropyl ethyl amine

Dmap DMAP

Dme glycol dimethyl ether

Dmf n, n- dimethylformamide

Dmso dimethyl sulfoxide

dmso-d₆, d₆The deuterated dimethyl sulfoxide of-dmso

Dppa diphenyl phosphate azide

Edci 1- (3- dimethylamino-propyl) -3- ethyl-carbodiimide hydrochloride

Etoac, ea ethyl acetate

et₂O ether

et₃N, tea triethylamine

Fbs hyclone

Fe ferrum

G gram

H hour

Hatu o- (7- nitrogen BTA)-n, n, n', n'- tetramethylurea hexafluorophosphoric acid ester

Hbr hydrobromic acid

Hbtu o- BTA-n, n, n', n'- tetramethylurea hexafluorophosphate

Hcl hydrochloric acid

h₂Hydrogen

h₂O water

h₂o₂Hydrogen peroxide

Hoac, acoh acetic acid

Hobt I-hydroxybenzotriazole

k₂co₃Potassium carbonate

Koh potassium hydroxide

Lihmds LHMDS

Lda lithium diisopropyl amido

Mcpba metachloroperbenzoic acid

Mecn, ch₃Cn acetonitrile

Mei iodomethane

Meoh, ch₃Oh methanol

2-methf 2- methyltetrahydrofuran

mgso₄Magnesium sulfate

Ml, ml milliliter

n₂Nitrogen

n-bu₄nhso₄4-butyl ammonium hydrogen sulfate

nabh₄Sodium borohydride

nabh₃Cn sodium cyanoborohydride

Nacl sodium chloride

naclo₂Sodium chlorite

Nah sodium hydride

nahco₃Sodium bicarbonate

na₂co₃Sodium carbonate

nah₂po₄Sodium dihydrogen phosphate

Nai sodium iodide

Nao (t-bu) sodium tert-butoxide

Naoh sodium hydroxide

na₂so₄Sodium sulfate

Nbs n- bromo-succinimide

Nis n- N-iodosuccinimide

nh₃Ammonia

nh₄C1 ammonia chloride

Nmp n- methyl pyrrolidone

Pbs phosphate buffered saline (PBS)

p(t-bu)₃Three (tert-butyl group) phosphine

Pd/c palladium/carbon

pd₂(dba)₃Double (dibenzyl subunit acetone) palladium

pd(dppf)cl₂Double (diphenylphosphino) the ferrocene palladium chloride of 1,1-

pd(dppf)cl₂·ch₂cl₂[double (diphenylphosphine) ferrocene of 1,1'-] palladium chloride dichloromethane complex

pd(oac)₂Palladium

pd(oh)₂Palladium dydroxide

pd(pph₃)₄Tetrakis triphenylphosphine palladium

pd(pph₃)₂cl₂Double (triphenylphosphine) palladium chloride

Pe petroleum ether (60-90 DEG C)

pocl₃Phosphorus oxychloride

phso₂Cl benzene sulfonyl chloride

Pybop 1h- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate

Rt, rt, r.t. room temperature

Rt retention time

Tbab tetrabutyl ammonium bromide

Tbaf tetrabutyl ammonium fluoride

tbahso₄4-butyl ammonium hydrogen sulfate

Tbtu o- (1h- benzotriazole -1- base)-n, n, n', n'- tetramethylurea Tetrafluoroboric acid ester

Tfa trifluoroacetic acid

Teac bis- (tetraethyl ammonium) carbonate

Thf oxolane

L microlitre of μ

Synthetic schemes set forth below gives the experimental procedure of compound disclosed in the preparation present invention.Wherein, each w₁, w₂, w₃, z₁, z₂, r¹, r²With y, there is definition as described in the present invention." pg " is suitable alkynyl blocking group.Ring " a " is by r²Appoint Choose generation, the heterocycle containing n.

Synthetic schemes 1

Compound as shown in chemical formula (i) formula can be prepared by the method described in synthetic schemes 1. First, compound (1) under suitable pd catalyst action, with connection boric acid pinacol ester (or acid) (2) reaction change into corresponding Borate (or acid) class compound (3).Then, compound (3) again with the heteroaryl compound of bromo (4) occur suzuki to be coupled Reacting generating compound (5).Next compound (5) in room temperature condition and nis occur iodide reaction generate compound (6).? Afterwards, iodo compound (6) under suitable pd catalyst action with alkynyl compoundss (7) there is coupling reaction, obtain final Kinase inhibitor (8).

Synthetic schemes 2

Other compounds in the present invention can be prepared by synthetic schemes 2.First, compound (6) in Asia Amino can be protected with suitable blocking group, such as with phso₂cl(9) in the basic conditions, in aprotic solvent Carry out reacting generating compound (10).Then, compound (10) be suitable for alkynyl compoundss (11) occur sonagashira even Connection reacting generating compound (12), alkynyl blocking group " pg " includes but is not limited to tms, tes or tips.Alkynyl blocking group " pg " can in the presence of the aqueous solution of alkali and tbaf etc. deprotection generate intermediate (13).Intermediate (13) finally by with change Compound (14) occur under pd catalysis coupling reaction generate final kinase inhibitor (8).

Kinase inhibitor (15) and (16) can also be by synthetic schemes 1 and the method preparation described in synthetic schemes 2 Obtain.

Specific embodiment

Following examples are used for the present invention is described, but are not limited to the scope of the present invention.

Embodiment 13- ((2- chlorphenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrrolo- [2,3-b] pyridine

Step 1) 4- (4- iodo- 1h- pyrazol-1-yl) piperidines -1- t-butyl formate

By compound 4-hydroxy phenylpiperidines -1- t-butyl formate (485mg, 2.41mmol) and dmap (29.4mg, 0.241mmol) it is dissolved in dcm (15ml), at 0 DEG C, in reactant liquor, be slowly added into et₃N (0.67ml, 4.82mmol) and mscl(0.223ml,2.897mmol).Reactant liquor, after room temperature condition stirring reaction 5 hours, adds nahco₃(25ml, 1m's) Aqueous solution, mixture is extracted with dcm (50mlx2).The organic faciess saline solution (25ml) merging is washed, and uses anhydrous na₂so₄It is dried, Concentrating under reduced pressure, the crude product obtaining is directly used in the next step without being further purified.

Iodo- for compound 4- 1h- pyrazoles (467.5mg, 2.41mmol) is dissolved in dry dmf (8ml), then at 0 DEG C, It is dividedly in some parts nah (60%, 193mg, 4.82mmol) in reactant liquor.Reactant liquor is warmed to room temperature, reaction 2 is stirred at room temperature After hour, add dmf (4ml) solution of above-mentioned crude product in reactant liquor.Reactant liquor after 100 DEG C of stirring reactions 12 hours, Add nh₄The aqueous solution (20ml) of cl is quenched reaction, and mixture is extracted with etoac (40ml x2).The organic faciess Sal merging Water (25ml) is washed, and uses anhydrous na₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column chromatography (pe/etoac (v/v)=4/1) purification Obtaining title compound is yellow solid (620mg, 68%).

Ms (esi, pos.ion) m/z:322.0 (m+1-56).

Step 2) 4- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1h- pyrazol-1-yl) piperazine Pyridine -1- t-butyl formate

Compound connection boric acid pinacol ester (281.6mg, 1.11mmol) is dissolved in dmso (6ml), then protects in nitrogen Under shield, sequentially add in reactant liquor 4- (4- iodo- 1h- pyrazol-1-yl) piperidines -1- t-butyl formate (298.8mg, 0.792mmol), potassium acetate (310.5mg, 3.17mol) and pd (pph₃)₂cl₂(33.36mg,0.0475mmol).Reactant liquor exists 80 DEG C of stirring reactions are after 3 hours, are cooled to room temperature, add water (20ml) that reaction is quenched, and mixture is with ethyl acetate (35mlx2) Extraction.The organic faciess saline solution (30mlx2) merging is washed, and uses anhydrous na₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column layer It is white solid (250mg, 83%) that analysis (pe/etoac (v/v)=2/1) purification obtains title compound.

Ms (esi, pos.ion) m/z:378.0 (m+1).

Step 3) 4- (4- (1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate

By bromo- for compound 5- 1h- pyrrolo- [2,3-b] pyridine (197.0mg, 1.0mmol) and 4- (4- (4,4,5,5- tetra- Methyl isophthalic acid, 3,2- dioxaborolanes -2- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (453mg, 1.2mmol) It is dissolved in dme (25ml), in reactant liquor, then add na₂co₃Aqueous solution (na₂co₃(318mg, 3.0mmol) is dissolved in In 2.5ml water).After substituting gas (nitrogen) three times, add pd (pph in reactant liquor₃)₂cl₂(70.2mg,0.1mmol).Again After substituting gas (nitrogen) three times, reactant liquor flows back overnight under nitrogen protection.Question response liquid is cooled to room temperature, adds ethyl acetate (10ml) dilute.Sucking filtration, insoluble matter ethyl acetate (15ml) is washed.By filtrate reduced in volume, residue is through silica gel column chromatography It is white solid (260mg, 71%) that (pe/etoac (v/v)=1/1) purification obtains title compound.

Ms (esi, pos.ion) m/z:368.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 1.90-2.08 (m, 2h), 2.14-2.25 (m, 2h), 2.92 (t,j=12.2hz,2h),4.20-4.42(m,3h),6.51(dd,j=3.4hz,1.6hz,1h),7.37(dd,j=3.2hz, 2.3hz,1h),7.70(s,1h),7.83(s,1h),8.02(d,j=2.0hz,1h),8.48(d,j=2.0hz,1h),10.45 (s,1h)；

¹³c nmr(100mhz,cdcl₃): δ 28.6,32.7,59.7,80.2,101.0,120.6,121.2,123.6, 126.0,136.7,141.1,154.8.

Step 4) 4- (4- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- formic acid The tert-butyl ester

By compound 4- (4- (1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) the tertiary fourth of piperidines -1- formic acid Ester (150mg, 0.41mmol) is dissolved in acetone (6ml), then adds nis (110mg, 0.49mmol) in reactant liquor.Reaction Liquid stirring reaction after 2 hours at ambient temperature, sucking filtration, filter cake acetone (10ml) is washed, and obtains title compound after vacuum drying Thing is white solid (150mg, 75%).

Ms (esi, pos.ion) m/z:494.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 1.90-2.10 (m, 2h), 2.16-2.28 (m, 2h), 2.90- 3.08(m,2h),4.15-4.50(m,3h),7.45(d,j=2.2hz,1h),7.75(s,1h),7.78(d,j=2.0hz,1h), 7.85(d,j=0.5hz,1h),8.47(d,j=2.0hz,1h),10.19(s,1h).

Step 5) 4- (4- (3- ((2- chlorphenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazoles - 1- yl) piperidines -1- t-butyl formate

Compound 4- (4- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrrole is sequentially added in microwave tube Azoles -1- base) piperidines -1- t-butyl formate (600mg, 1.22mmol), 1- chloro- 2- acetylenylbenzene (0.178ml, 1.46mmol), Cui (3mg, 0.016mmol), pd (pph₃)₂cl₂(60mg, 0.086mmol), et₃N (6ml) and dmf (20ml).By microwave tube After good seal, reactant liquor after 80 DEG C of stirring reactions 1 hour, is cooled to room temperature under microwave condition.By reactant liquor concentrating under reduced pressure, It is yellow solid (300mg, 49%) that residue obtains title compound through silica gel column chromatography (pe/etoac (v/v)=1/2) purification.

Ms (esi, pos.ion) m/z:502.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.43 (s, 9h), 1.76-1.91 (m, 2h), 2.02-2.11 (m, 2h), 2.80- 3.10(m,2h),4.00-4.12(m,2h),4.32-4.48(m,1h),7.41(dd,j=5.9hz,3.5hz,2h),7.58- 7.62(m,1h),7.71-7.75(m,1h),7.95(d,j=2.8hz,1h),7.99(d,j=0.4hz,1h),8.18(d,j= 2.0hz,1h),8.39(s,1h),8.62(d,j=2.0hz,1h),12.21(d,j=2.4hz,1h).

Step 6) 3- ((2- chlorphenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrrolo- [2,3-b] pyridine

By compound 4- (4- (3- ((2- chlorphenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrrole Azoles -1- base) piperidines -1- t-butyl formate (300mg, 0.60mmol) is dissolved in dcm (40ml), then at 0 DEG C, in reactant liquor Add the ethyl acetate solution (4.3ml, 12.9mmol, 3m) of hcl.Reactant liquor is warmed to room temperature, and continues under room temperature condition Stirring reaction 4 hours, then concentrating under reduced pressure.Water (100ml) is added to dissolve residue, the na of aqueous phase saturation₂co₃Aqueous solution Adjust ph to 10, then use dcm (100mlx5) to extract.The organic faciess saline solution (10ml) merging is washed, and uses anhydrous na₂so₄Dry Dry, concentrating under reduced pressure, residue with Ethyl acetate (6ml) is washed, and obtaining title compound after vacuum drying is beige solid (140mg,58%).

Ms (esi, pos.ion) m/z:402.0 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.75-1.90 (m, 2h), 1.92-2.03 (m, 2h), 2.53-2.66 (m, 2h),3.00-3.11(m,2h),4.10-4.28(m,1h),7.38-7.44(m,2h),7.57-7.62(m,1h),7.70-7.76 (m,1h),7.95(s,1h),7.97(s,1h),8.17(d,j=2.1hz,1h),8.34(s,1h),8.61(d,j=2.1hz, 1h),12.21(s,1h).

Embodiment 23- ((2,5- Dichlorobenzene base) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrrole Cough up simultaneously [2,3-b] pyridine

Step 1) 4- (4- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazoles -1- Base) piperidines -1- t-butyl formate

By compound 4- (4- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- first Tert-butyl acrylate (4.93g, 10mmol) is suspended in dcm (120ml), then sequentially adds phso in reactant liquor₂cl(2ml, 15mmol), n-bu₄nhso₄(0.44g, 1.29mmol) and the aqueous solution of 50%naoh (1.0g, 25mmol).Reactant liquor is in room temperature Under the conditions of stirring reaction after 16 hours, add dcm (100ml) dilution, washed with water (150ml), with the nahco of saturation₃Aqueous solution (100ml) wash.Divide the anhydrous na of organic faciess that liquid obtains₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column chromatography (dcm/ Meoh (v/v)=100/1) purification obtain title compound be white solid (6.1g, 96%).

Ms (esi, pos.ion) m/z:634.0 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 8.69 (d, j=2.0hz, 1h), 8.48 (s, 1h), 8.17-8.12 (m, 3h), 8.05(d,j=0.4hz,1h),7.91(d,j=2.1hz,1h),7.77-7.71(m,1h),7.68-7.65(m,2h),4.45- 4.32(m,1h),4.20-4.00(m,2h),3.05-2.85(br,2h),2.10-2.00(m,2h),1.88-1.72(m,2h), 1.43(s,9h).

Step 2) 4- (4- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyrrole Pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate

By compound 4- (4- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazoles -1- Base) piperidines -1- t-butyl formate (0.8g, 1.26mmol) is suspended in dmf (15ml), then sequentially adds pd in reactant liquor (pph₃)₂cl₂(44mg, 0.063mmol) and cui (12mg, 0.063mmol).Reactant liquor is substituted after gas (nitrogen) three times, then Add trimethyl silicane ethyl-acetylene (0.13g, 1.26mmol) and et₃n(3.50ml,25.25mmol).Reactant liquor is under nitrogen protection After 75 DEG C of stirring reactions 2 hours, it is cooled to room temperature, be subsequently adding dcm (150 ml) dilution.Mixed liquor with 5% nahco₃'s Aqueous solution (80ml) is washed, and is washed with water (80ml), is washed with saline solution (80mlx2).Divide the anhydrous na of organic faciess that liquid obtains₂so₄Dry Dry, concentrating under reduced pressure, it is pale yellow colored solid that residue obtains title compound through silica gel column chromatography (pe/etoac (v/v)=2/1) purification Body (0.6g, 83%).

Ms (esi, pos.ion) m/z:604.5 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 0.28 (s, 9h), 1.42 (s, 9h), 1.80 (m, 2h), 2.02 (m, 2h), 2.89 (s,2h),4.03(m,2h),4.38(m,1h),7.64(t,j=8.1hz,2h),7.74(t,j=7.5hz,1h),8.04(s, 1h),8.05(d,j=2.1hz,1h),8.15(m,2h),8.25(s,1h),8.45(s,1h),8.71(d,j=2.1hz,1h).

Step 3) 4- (4- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- T-butyl formate

By compound 4- (4- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] Pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (0.76g, 1.26mmol) is suspended in meoh (15ml), Then add koh (0.14g, 2.52mmol) in reactant liquor.Reactant liquor stirring reaction after 2 hours at ambient temperature, with food Saline (60ml) is washed, and mixture is extracted with dcm (50mlx3).The anhydrous na of organic faciess merging₂so₄It is dried, concentrating under reduced pressure, residual Staying thing to obtain title compound through silica gel column chromatography (pe/etoac (v/v)=1/2) purification is light yellow solid (0.17g, 34%).

Ms (esi, pos.ion) m/z:392.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 1.97 (m, 2h), 2.18 (m, 2h), 2.89 (m, 2h), 3.22 (s,1h),4.30(m,3h),7.57(d,j=2.3hz,1h),7.74(s,1h),7.85(d,j=0.6hz,1h),8.09(d,j= 2.0hz,1h),8.50(d,j=2.0hz,1h),9.44(s,1h).

Step 4) 4- (4- (3- ((2,5- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrrole Azoles -1- base) piperidines -1- t-butyl formate

By compound 4- (4- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines - 1- t-butyl formate (0.20g, 0.51mmol) is suspended in dmf (15ml), then sequentially adds pd (pph in reactant liquor₃)₂cl₂(36mg, 0.051mmol), cui (10mg, 0.051mmol) and the chloro- 2- bromobenzene (0.12g, 0.51mmol) of Isosorbide-5-Nitrae-two.Will be anti- After answering liquid to substitute gas (nitrogen) three times, add et₃n(1.4ml,10.2mmol).Reactant liquor stirs at 75 DEG C under nitrogen protection After reaction 2 hours, concentrating under reduced pressure, the residue obtaining dcm (100ml) dissolves, and mixed liquor saline solution (100ml x2) is washed. Divide the anhydrous na of organic faciess that liquid obtains₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column chromatography (pe/etoac (v/v)=1/ 2) purification obtains title compound is yellow solid (0.17g, 62%).

Ms (esi, pos.ion) m/z:536.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.42 (s, 9h), 1.86 (m, 2h), 2.04 (m, 2h), 2.95 (m, 2h), 4.05 (m,2h),4.39(m,1h),7.47(dd,j=8.7hz,2.6hz,1h),7.61(d,j=8.7hz,1h),7.83(d,j= 2.5hz,1h),7.97(d,j=2.6hz,1h),8.01(s,1h),8.21(d,j=1.9hz,1h),8.39(s,1h),8.62(s, 1h),12.27(s,1h).

Step 5) 3- ((2,5- Dichlorobenzene base) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrroles And [2,3-b] pyridine

By compound 4- (4- (3- ((2,5- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- Pyrazol-1-yl) piperidines -1- t-butyl formate (0.17g, 0.32mmol) is suspended in dcm (15ml), then in reactant liquor plus Enter the ethyl acetate solution (3.20ml, 12.8mmol, 4m) of hcl.Reactant liquor is stirred overnight at ambient temperature, then reduces pressure dense Contracting.Add the na of saturation₂co₃The ph of reactant liquor is adjusted to 12 by aqueous solution, and mixture is extracted with dcm/meoh (10/1,50mlx3). The organic faciess saline solution (80mlx3) merging is washed, and uses anhydrous na₂so₄It is dried, concentrating under reduced pressure, residue is tied with dcm (6ml) again It is faint yellow solid (85mg, 61%) that crystalline substance obtains title compound.

Ms (esi, pos.ion) m/z:436.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.82 (m, 2h), 1.98 (m, 2h), 3.03 (m, 2h), 4.20 (m, 2h), 7.46 (dd,j=8.7hz,2.5hz,1h),7.61(d,j=8.7hz,1h),7.83(d,j=2.5hz,1h),7.97(d,j=3.5hz, 2h),8.20(d,j=1.9hz,1h),8.33(s,1h),8.60(d,j=1.8hz,1h),12.27(s,1h).

Embodiment 33- ((2,5- difluorophenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrrole Cough up simultaneously [2,3-b] pyridine

Step 1) 4- (4- (3- ((2,5- difluorophenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrrole Azoles -1- base) piperidines -1- t-butyl formate

Compound 4- (4- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- is sequentially added in microwave tube Pyrazol-1-yl) piperidines -1- t-butyl formate (0.1g, 0.26mmol), the bromo- Isosorbide-5-Nitrae-difluorobenzene of 2- (58mg, 0.26mmol), pd (pph₃)₂cl₂(9.0mg, 0.013mmol), cui (2.0mg, 0.013mmol), et₃N (1ml) and dmf (4ml).By reactant liquor After substituting gas (nitrogen) three times, by the microwave seal of tube, then reactant liquor under microwave condition in 120 DEG C of stirring reactions 30 minutes. Question response liquid is cooled to room temperature, adds dcm (100ml) dilute reaction solution, and mixed liquor saline solution (100mlx3) is washed.Liquid is divided to obtain The anhydrous na of the organic faciess arriving₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column chromatography (pe/etoac (v/v)=1/2) purification Obtaining title compound is faint yellow solid (0.14g, 81%).

Ms (esi, pos.ion) m/z:504.2 (m+1)；

¹hnmr:(400hz,dmso-d₆): δ 1.43 (s, 9h), 1.84 (m, 2h), 2.05 (m, 2h), 2.95 (s, 2h), 4.06(m,2h),4.38(m,1h),7.31(m,1h),7.38(m,1h),7.62(m,1h),7.98(d,j=2.8hz,1h), 8.02(s,1h),8.19(d,j=1.8hz,1h),8.41(s,1h),8.62(d,j=1.8hz,1h),12.26(s,1h).

Step 2) 3- ((2,5- difluorophenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrroles And [2,3-b] pyridine

Title compound can be according to the method described by embodiment 2 step 5, with compound 4- (4- (3- ((2,5- difluoros Phenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (140mg, 0.28mmol), the ethyl acetate solution (2.5ml, 10mmol, 4m) of hcl and solvent dcm (10ml) prepare.Institute Obtain crude product to obtain title compound through preparative hplc purification is faint yellow solid (30mg, 26%).

Ms (esi, pos.ion) m/z:404.2 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.98 (m, 2h), 2.10 (m, 2h), 2.19 (m, 2h), 3.05 (m, 2h), 4.46(m,1h),5.32(s,1h),7.31(m,1h),7.39(m,1h),7.61(m,1h),7.99(s,1h),8.07(s,1h), 8.21(d,j=2.1hz,1h),8.38(s,1h),8.63(s,1h),12.26(s,1h).

Embodiment 43- ((2,6- Dichlorobenzene base) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrrole Cough up simultaneously [2,3-b] pyridine

Step 1) 4- (4- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrrole Azoles -1- base) piperidines -1- t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 4- (4- (3- acetenyl -1h- Pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (0.10g, 0.26mmol), 1,3- bis- Chloro- 2- bromobenzene (57mg, 0.26mmol), pd (pph₃)₂cl₂(9mg, 0.013mmol), cui (2mg, 0.013mmol), et₃n (1.43ml, 10.2mmol) and solvent dmf (4ml) prepare.Gained crude on silica gel column chromatography (pe/etoac (v/v)= 1/2) purification obtains title compound is faint yellow solid (0.07g, 51%).

Ms (esi, pos.ion) m/z:536.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.42 (s, 9h), 1.84 (m, 2h), 2.04 (m, 2h), 2.94 (m, 2h), 4.12 (m,2h),4.36(m,1h),7.40(t,j=8.3hz,1h),7.61(d,j=8.1hz,2h),7.94(s,1h),8.01(d,j= 2.7hz,1h),8.11(d,1h),8.36(s,1h),8.62(m,1h),12.31(s,1h).

Step 2) 3- ((2,6- Dichlorobenzene base) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- base) -1h- pyrroles And [2,3-b] pyridine

Title compound can be according to the method described by embodiment 2 step 5, with compound 4- (4- (3- ((2,6- dichloros Phenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (0.13g, 0.24mmol), the ethyl acetate solution (2.50ml, 10.0mmol, 4m) of hcl and solvent dcm (10ml) prepare.Gained is thick It is faint yellow solid (85mg, 80%) that product is recrystallized to give title compound through dcm (6ml).

Ms (esi, pos.ion) m/z:436.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.81 (m, 2h), 1.97 (m, 2h), 3.03 (m, 2h), 4.21 (m, 2h), 7.39 (t,j=8.2hz,1h),7.60(d,j=8.1hz,2h),7.92(s,1h),8.01(s,1h),8.10(d,j=2.0hz,1h), 8.30(s,1h),8.61(d,j=2.0hz,1h).

Embodiment 53- ((5- chloro- 2- (trifluoromethyl) phenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- Base) -1h- pyrrolo- [2,3-b] pyridine

Step 1) the bromo- 4- of 2- chloro- 1- (trifluoromethyl) benzene

40%hbr (2.20ml, 15.34mmol) is dissolved in h₂In o (2ml), then at 0 DEG C, add 2- ammonia in reactant liquor Base -4- chlorobenzotrifluoride (0.50g, 2.56mmol), next then at 0 DEG C, is added dropwise over the water of sodium nitrite in reactant liquor Solution (sodium nitrite (0.21g, 3.07mmol) is dissolved in 2ml water).Reactant liquor, after 0 DEG C of stirring reaction half an hour, adds The 40%hbr (2.20ml, 15.34mmol) of cuprous bromide (0.63g, 4.35mmol) and h₂The mixed solution of o (3ml).Reactant liquor After 75 DEG C of stirring reactions 3 hours, it is cooled to room temperature, then use ethyl acetate (40mlx4) to extract.The organic faciess food merging Saline (80mlx2) is washed, and uses anhydrous na₂so₄Be dried, obtain after concentrating under reduced pressure title compound be yellow liquid (0.76g, 100%).

gc-ms:257.9.

Step 2) 4- (4- (3- ((5- chloro- 2- (trifluoromethyl) phenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- Base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 4- (4- (3- acetenyl -1h- Pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- t-butyl formate (0.30g, 0.80mmol), 2- is bromo- 4- chloro- 1- (trifluoromethyl) benzene (0.62g, 2.40mmol), pd (pph₃)₂cl₂(28mg, 0.04mmol), cui (7mg, 0.04mmol), et₃N (2.20ml, 16.0mmol) and solvent dmf (10ml) prepares.Gained crude on silica gel column chromatography It is yellow solid (0.38g, 63%) that (pe/etoac (v/v)=1/2) purification obtains title compound.

Ms (esi, pos.ion) m/z:570.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 2.02 (m, 2h), 2.22 (m, 2h), 2.93 (m, 2h), 4.34 (m,2h),7.35(dd,j=8.4hz,1.1hz,1h),7.63(d,j=8.0hz,1h),7.65(m,2h),7.75(s,1h), 7.88(s,1h),8.15(s,1h),8.52(s,1h).

Step 3) 3- ((5- chloro- 2- (trifluoromethyl) phenyl) acetenyl) -5- (1- (piperidin-4-yl) -1h- pyrazoles -4- Base) -1h- pyrrolo- [2,3-b] pyridine

Title compound can be according to the method described by embodiment 2 step 5, with compound 4- (4- (3- ((the chloro- 2- of 5- (trifluoromethyl) phenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1h- pyrazol-1-yl) piperidines -1- formic acid uncle Butyl ester (0.38g, 0.67mmol), the ethyl acetate solution (6.67ml, 26.7mmol, 4m) of hcl and solvent dcm (30ml) system Standby obtain.It is yellow solid (0.17g, 54%) that gained crude product dcm (10ml) is recrystallized to give title compound.

Ms (esi, pos.ion) m/z:470.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 2.00 (m, 2h), 2.23 (m, 2h), 2.80 (m, 2h), 3.97 (m, 2h), 4.31 (m,1h),7.41(m,1h),7.63(s,1h),7.65(m,1h),7.68(s,1h),7.85(s,2h),8.19(d,j=2.0hz, 1h),8.45(d,j=1.9hz,1h).

Embodiment 63- ((2,6- Dichlorobenzene base) acetenyl) -5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3- B] pyridine

Step 1) 5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] pyridine

By compound 2- methoxyl group -5- bromopyridine (1.50g, 7.98mmol), pd (dppf) cl₂·ch₂cl₂(0.65g, 0.80mmol) and cs₂co₃(7.80g, 23.93mmol) is suspended in dme and h₂In the mixed solvent of o (5/1,96ml), Ran Houxiang 7- azaindole -5- pinacol borate (2.92g, 11.97mmol) is added in reactant liquor.Reactant liquor is substituted gas (nitrogen) three After secondary, it is stirred at reflux 4 hours, then reactant liquor will be pressed concentration, residue is through silica gel column chromatography (pe/etoac (v/v)=2/1) It is white solid (1.80g, 95%) that purification obtains title compound.

Ms (esi, pos.ion) m/z:226.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 4.00 (s, 3h), 6.57 (d, j=3.2hz, 1h), 6.85 (d, j=8.6hz, 1h),7.39(d,j=1.8hz,1h),7.81(dd,j=8.5hz,2.52hz,1h),8.06(d,j=2.1hz,1h),8.41(d,j =2.3hz,1h),8.48(d,j=2.0hz,1h),9.54(s,1h).

Step 2) the iodo- 5- of 3- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] pyridine

Compound 5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] pyridine (1.0g, 4.44mmol) is dissolved in In acetone (20ml), in reactant liquor, then add nis (1.2g, 5.33mmol).Reactant liquor stirring reaction 5 at ambient temperature After hour, most of acetone is first removed under reduced pressure, then sucking filtration, the acetone after filter cake cooling is washed, and finally by filtration cakes torrefaction, obtains Title compound is white solid (1.35g, 86%).

Ms (esi, pos.ion) m/z:352.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 4.00 (s, 3h), 6.87 (d, j=8.6hz, 1h), 7.48 (s, 1h), 7.83 (dd,j=8.6hz,2.56hz,1h),7.87(d,j=2.0hz,1h),8.42(d,j=2.2hz,1h),8.47(d,j=2.0hz, 1h),9.40(s,1h).

Step 3) the iodo- 5- of 3- (6- methoxypyridine -3- base) -1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine

By iodo- for compound 3- 5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] pyridine (0.12g, 0.34mmol) and n-bu₄nhso₄(0.02g, 0.2mmol) is dissolved in dcm (10ml), then sequentially adds in reactant liquor phso₂Cl (0.07ml, 0.51mmol) and the aqueous solution of 50%naoh (0.07g, 0.85mmol).Reactant liquor is stirred at room temperature After reaction 3 hours, add dcm (100ml) dilution, mixed liquor 5%nahco₃Aqueous solution (100mlx2) is washed.What point liquid obtained has The anhydrous na of machine phase₂so₄It is dried, concentrating under reduced pressure, residue is marked through silica gel column chromatography (pe/etoac (v/v)=4/1) purification Topic compound is faint yellow solid (0.145g, 94%).

Ms (esi, pos.ion) m/z:491.9 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 3.99 (s, 3h), 6.85 (d, j=8.6hz, 1h), 7.50 (t, j=8.0hz, 2h),7.59(t,j=7.4hz,1h),7.74(d,j=2.1hz,1h),7.77(dd,j=8.6hz,2.5hz,1h),7.91(s, 1h),8.22(d,j=7.4hz,2h),8.37(d,j=2.2hz,1h),8.59(d,j=2.0hz,1h).

Step 4) 5- (6- methoxypyridine -3- base) -1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- Pyrrolo- [2,3-b] pyridine

By iodo- for compound 3- 5- (6- methoxypyridine -3- base) -1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine (0.85g, 2.42mmol) and pd (pph₃)₂cl₂(84mg, 0.12mmol) is suspended in dmf (30ml), then in reactant liquor Add cui (23mg, 0.12mmol).Reactant liquor is substituted after gas (nitrogen) three times, sequentially adds trimethyl silicane ethyl-acetylene (0.68ml, 4.84mmol) and et₃n(6.75ml,48.4mmol).Reactant liquor, after 70 DEG C of stirring reactions 2 hours, is cooled to room Temperature.After reactant liquor concentrating under reduced pressure, dcm (200ml) is added to dissolve residue, the mixture water (100mlx3) obtaining is washed.Point The anhydrous na of the organic faciess that liquid obtains₂so₄It is dried, concentrating under reduced pressure, residue is through silica gel column chromatography (pe/etoac (v/v)=4/1) It is faint yellow solid (0.67g, 84%) that purification obtains title compound.

Ms (esi, pos.ion) m/z:462.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 0.27 (s, 9h), 3.99 (s, 3h), 6.85 (d, j=8.6hz, 1h), 7.48 (t, j=8.0hz,2h),7.58(t,j=7.4hz,1h),7.77(dd,j=8.6hz,2.6hz,1h),7.95(s,1h),7.99(d,j= 2.2hz,1h),8.19(d,j=7.4hz,2h),8.37(d,j=2.1hz,1h),8.60(d,j=2.0hz,1h).

Step 5) 3- acetenyl -5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] pyridine

By compound 5- (6- methoxypyridine -3- base) -1- (benzenesulfonyl) -3- ((TMS) acetenyl) - 1h- pyrrolo- [2,3-b] pyridine (0.67g, 1.45mmol) is suspended in thf (60ml), then adds four fourths in reactant liquor Base ammonium fluoride (0.76g, 2.90mmol).After reactant liquor is stirred at room temperature 1.5 hours of reaction, concentrating under reduced pressure, residue warp It is faint yellow solid (0.30g, 83%) that silica gel column chromatography (pe/etoac (v/v)=1/1) purification obtains title compound.

Ms (esi, pos.ion) m/z:250.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 3.23 (s, 1h), 4.00 (s, 3h), 6.86 (d, j=8.6hz, 1h), 7.62 (s, 1h),7.83(dd,j=8.6hz,2.5hz,1h),8.17(d,j=2.0hz,1h),8.43(d,j=2.3hz,1h),8.52(s, 1h),9.34(s,1h).

Step 6) 3- ((2,6- Dichlorobenzene base) acetenyl) -5- (6- methoxypyridine -3- base) -1h- pyrrolo- [2,3-b] Pyridine

Title compound can be according to the method described by embodiment 3 step 1, with compound 3- acetenyl -5- (6- methoxy Yl pyridines -3- base) -1h- pyrrolo- [2,3-b] pyridine (0.10g, 0.40mmol), 1,3- bis- chloro- 2- bromobenzene (90mg, 0.40mmol), pd (pph₃)₂cl₂(14mg, 0.02mmol), cui (4mg, 0.02mmol), et₃n(1.12ml,8.02mmol) Prepare with solvent dmf (4ml).Gained crude on silica gel column chromatography (pe/etoac (v/v)=1/2) purification obtains title Compound is white solid (26mg, 14%).

Ms (esi, pos.ion) m/z:394.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 3.91 (s, 3h), 6.94 (d, j=8.9hz, 1h), 7.37 (t, j=8.4hz, 1h),7.59(d,j=8.1hz,2h),8.07(d,j=2.6hz,1h),8.09(d,j=2.6hz,1h),8.17(d,j=2.0hz, 1h),8.52(d,j=2.2hz,1h),8.62(d,j=1.8hz,1h),12.47(s,1h).

Embodiment 73- ((2,6- Dichlorobenzene base) acetenyl) -5- (2- (piperazine -1- base) pyridin-4-yl) -1h- pyrrolo- [2,3-b] pyridine

Step 1) 4- (4- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) pyridine -2- base) piperazine - 1- t-butyl formate

By compound 2- (piperazine -1- base) pyridine -4- pinacol borate (0.55g, 1.90mmol) and dmap (23mg, 0.19mmol) it is suspended in thf (50ml), then at 0 DEG C, add et in reactant liquor₃N (0.4ml, 2.85mmol) and (boc)₂o(0.49ml,2.28mmol).Reactant liquor, after 0 DEG C of stirring reaction 15 minutes, is warmed to room temperature, and continues in room temperature condition Stirring reaction 4 hours, then concentrating under reduced pressure, residue obtains title through silica gel column chromatography (dcm/meoh (v/v)=10/1) purification Compound is faint yellow solid (0.58g, 78%).

Ms (esi, pos.ion) m/z:308.2 (m+1-82)；

¹h nmr(400mhz,cdcl₃): δ 1.33 (s, 12h), 1.48 (s, 9h), 3.54 (s, 8h), 6.96 (d, j= 4.8hz,1h),7.04(s,1h),8.20(d,j=4.8hz,1h).

Step 2) 4- (4- (1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 4- (4- (4,4,5,5- tetramethyls Base -1,3,2- dioxaborolanes -2- bases) pyridine -2- base) piperazine -1- t-butyl formate (0.37g, 0.99mmol), 5- Bromo-7-azaindole (0.15g, 0.76mmol), pd (dppf) cl₂·ch₂cl₂(60.0mg, 0.076mmol), cs₂co₃ (0.74g, 2.28mmol) and solvent dmf (10ml) and h₂O (2ml) prepares.Gained crude on silica gel column chromatography (pe/ Etoac (v/v)=1/2) purification obtain title compound be faint yellow solid (0.25g, 65%).

Ms (esi, pos.ion) m/z:380.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 3.60 (m, 8h), 6.58 (m, 1h), 6.87 (s, 1h), 6.93 (dd,j=5.2hz,1.3hz,1h),7.38(m,1h),8.15(d,j=1.8hz,1h),8.26(d,j=5.4hz,1h),8.55 (d,j=2.2hz,1h),9.15(s,1h).

Step 3) 4- (4- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) the tertiary fourth of piperazine -1- formic acid Ester

By compound 4- (4- (1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate (1.0g, 4.44mmol) is dissolved in acetone (35ml), then adds nis (1.2g, 5.33mmol) in reactant liquor.Reactant liquor exists Under room temperature, stirring reaction is after 1.5 hours, concentrating under reduced pressure, and residue obtains through silica gel column chromatography (pe/etoac (v/v)=1/1) purification It is faint yellow solid (0.26g, 97%) to title compound.

Ms (esi, pos.ion) m/z:506.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 3.61 (m, 8h), 6.87 (s, 1h), 6.94 (dd, j= 4.0hz,1.1hz,1h),7.50(d,j=2.3hz,1h),7.93(d,j=1.8hz,1h),8.28(d,j=5.2hz,1h),8.55 (d,j=2.0hz,1h),9.54(s,1h).

Step 4) 4- (4- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine Piperazine -1- t-butyl formate

Title compound can be according to the method described by embodiment 6 step 3, with compound 4- (4- (the iodo- 1h- pyrroles of 3- And [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate (0.33g, 0.65mmol), n-bu₄nhso₄ (0.022g, 0.065mmol), phso₂Cl (0.13ml, 0.98mmol), the aqueous solution of 50%naoh (0.13g, 1.63mmol) and Solvent dcm (30ml) prepares.Gained crude on silica gel column chromatography (pe/etoac (v/v)=2/1) purification obtains titled Compound is yellow solid (0.40g, 95%).

Ms (esi, pos.ion) m/z:646.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 3.59 (d, j=5.8hz, 8h), 6.78 (s, 1h), 6.84 (d, j=5.1hz,1h),7.49(m,2h),7.62(t,j=7.4hz,1h),7.80(d,j=2.0hz,1h),7.91(s,1h),8.22 (d,j=7.6hz,2h),8.26(d,j=5.2hz,1h),8.64(d,j=1.8hz,1h).

Step 5) 4- (4- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyrrole Pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate

By compound 4- (4- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) Piperazine -1- t-butyl formate (0.40g, 0.62mmol) is suspended in dmf (30ml), then sequentially adds pd in reactant liquor (pph₃)₂cl₂(22mg, 0.03mmol) and cui (6mg, 0.03mmol).Reactant liquor is substituted after gas (nitrogen) three times, more successively Add trimethyl silicane ethyl-acetylene (0.17ml, 1.24mmol) and et₃n(0.86ml,6.20mmol).Reactant liquor is anti-in 75 DEG C of stirrings After answering 2 hours, concentrating under reduced pressure, residue obtains title compound and is through silica gel column chromatography (pe/etoac (v/v)=3/1) purification Yellow solid (0.30g, 78%).

Ms (esi, pos.ion) m/z:616.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 0.28 (s, 9h), 1.49 (s, 9h), 3.60 (d, j=5.4hz, 8h), 6.78 (s, 1h),6.84(dd,j=5.1hz,1.08hz,1h),7.49(t,j=7.4hz,2h),7.61(t,j=7.4hz,1h),7.97(s, 1h),8.05(d,j=2.1hz,1h),8.20(d,j=7.4hz,2h),8.26(d,j=5.1hz,1h),8.64(d,j=2.0hz, 1h).

Step 6) 4- (4- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- formic acid The tert-butyl ester

By compound 4- (4- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] Pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate (0.30g, 0.49mmol) is suspended in thf (10ml), Ran Houxiang Tetrabutyl ammonium fluoride (the thf solution of 0.97ml, 0.97mmol, 1m) is added in reactant liquor.Reactant liquor is stirred at room temperature reaction After 1.5 hours, concentrating under reduced pressure, it is subsequently adding dcm (80ml) and residue is dissolved, the mixture obtaining is with saline solution (30mlx2) Wash.Divide the anhydrous na of organic faciess that liquid obtains₂so₄Be dried, concentrating under reduced pressure, residue through silica gel column chromatography (pe/etoac (v/v)= 1/1) purification obtains title compound is faint yellow solid (0.19g, 96%).

Ms (esi, pos.ion) m/z:404.3 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.50 (s, 9h), 3.25 (s, 1h), 3.61 (m, 8h), 6.88 (s, 1h), 6.95 (d,j=5.2hz,1h),7.69(s,1h),8.26(d,j=1.9hz,1h),8.28(d,j=5.2hz,1h),8.61(d,j= 1.8hz,1h),11.40(s,1h).

Step 7) 4- (4- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine - 2- yl) piperazine -1- t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 4- (4- (3- acetenyl -1h- Pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate (0.20g, 0.49mmol), 1,3- bis- is chloro- 2- bromobenzene (112mg, 0.49mmol), pd (pph₃)₂cl₂(17mg, 0.022mmol), cui (4mg, 0.022mmol), et₃n (1.40ml, 9.92mmol) and solvent dmf (10ml) prepare.Gained crude on silica gel column chromatography (pe/etoac (v/v) =1/2) purification obtains title compound is yellow solid (0.17g, 62%).

Ms (esi, pos.ion) m/z:548.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.49 (s, 9h), 3.63 (m, 8h), 6.89 (s, 1h), 6.95 (d, j=5.2hz, 1h),7.19(t,j=8.4hz,1h),7.38(d,j=8.1hz,2h),7.75(d,j=1.9hz,1h),8.28(d,j=5.2hz, 1h),8.39(d,j=1.8hz,1h),8.63(s,1h),9.79(s,1h).

Step 8) 3- ((2,6- Dichlorobenzene base) acetenyl) -5- (2- (piperazine -1- base) pyridin-4-yl) -1h- pyrrolo- [2,3-b] pyridine

Title compound can be according to the method described by embodiment 2 step 5, with compound 4- (4- (3- ((2,6- dichloros Phenyl) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) pyridine -2- base) piperazine -1- t-butyl formate (0.17g, 0.31mmol), the ethyl acetate solution (3.10ml, 12.4mmol, 4m) of hcl and solvent dcm (10ml) prepare.Gained is thick It is gray solid (47mg, 33%) that product obtains title compound through dcm (10ml) recrystallization purifying.

Ms (esi, pos.ion) m/z:448.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 3.03 (m, 4h), 3.61 (m, 4h), 6.93 (s, 1h), 6.97 (d, j=5.2hz, 1h),7.20(t,j=8.1hz, 1h),7.39(d,j=8.1hz,2h),7.76(s,1h),8.24(d,j=5.2hz,1h),8.40 (d,j=2.0hz,1h),8.55(d,j=1.9hz,1h).

Embodiment 86- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1,2,3, 4- tetrahydroisoquinoline

Step 1) 6- bromo- 3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 7 step 1, with bromo- 1,2,3, the 4- tetrahydrochysenes of compound 6- Isoquinolin (1.00g, 4.72mmol), (boc)₂O (1.21ml, 5.66mmol), dmap (58mg, 0.47mmol), et₃n (1.00ml, 7.07mmol) and solvent thf (45ml) prepare.Gained crude on silica gel column chromatography (pe/etoac (v/v) =20/1) purification obtains the liquid (1.38g, 93%) that title compound is colorless viscous.

Ms (esi, pos.ion) m/z:256.0 (m+1-56)；

¹h nmr(400mhz,cdcl₃): δ 1.48 (s, 9h), 2.80 (t, j=5.4hz, 2h), 3.61 (m, 2h), 4.50 (s, 2h),6.97(d,j=8.0hz,1h),7.29(d,j=7.4hz,2h).

Step 2) 6- (1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 7- azaindole -5- boric acid Pinacol ester (1.40g, 5.75mmol), 6- bromo- 3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (1.38g, 4.42mmol), pd (dppf) cl₂·ch₂cl₂(0.36g, 0.44mmol), cs₂co₃(4.32g, 13.26mmol) and solvent dmf (20ml) and h₂O (4ml) prepares.Gained crude on silica gel column chromatography (pe/etoac (v/v)=5/2) purification obtains Title compound is faint yellow solid (1.35g, 87%).

Ms (esi, pos.ion) m/z:350.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.51 (s, 9h), 2.93 (m, 2h), 3.70 (m, 2h), 4.64 (s, 2h), 6.56 (m,1h),7.22(d,j=7.9hz,1h),7.40(m,2h),7.46(d,j=7.8hz,1h),8.11(d,j=1.6hz,1h), 8.54(d,j=1.9hz,1h),9.84(s,1h).

Step 3) 6- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-formic acid uncle Butyl ester

By compound 6- (1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.50g, 1.43mmol) is suspended in acetone (10ml), then adds nis (0.39g, 1.72mmol) in reactant liquor.Reaction After liquid is stirred at room temperature reaction 1.5 hours, sucking filtration, the acetone (6ml) of filter cake cooling is washed.By filtrate reduced in volume, obtain Residue together with filter cake through silica gel column chromatography (pe/etoac (v/v)=2/1) purification obtain title compound be pale yellow colored solid Body (0.61g, 97%).

Ms (esi, pos.ion) m/z:476.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.51 (s, 9h), 2.94 (m, 2h), 3.71 (m, 2h), 4.65 (s, 2h), 7.23 (m,1h),7.43(m,1h),7.48(d,j=9.2hz,2h),7.90(d,j=1.8hz,1h),8.55(d,j=1.6hz,1h), 10.43(s,1h).

Step 4) 6- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline - 2 (1h)-t-butyl formates

Title compound can be according to the method described by embodiment 6 step 3, with compound 6- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.61g, 1.28mmol), n-bu₄nhso₄ (0.044g, 0.128mmol), phso₂Cl (0.25ml, 1.93mmol), the aqueous solution of 50%naoh (0.26g, 3.21mmo) and Solvent dcm (15ml) prepares.Gained crude on silica gel column chromatography (pe/etoac (v/v)=4/1) purification obtains titled Compound is yellow solid (0.70g, 88%).

Ms (esi, pos.ion) m/z:616.0 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.50 (s, 9h), 2.91 (t, j=5.2hz, 2h), 3.69 (m, 2h), 4.62 (s, 2h),7.22(d,j=7.3hz,1h),7.34(s,1h),7.39(d,j=7.9hz,1h),7.51(t,j=7.4hz,2h),7.61 (t,j=7.4hz,1h),7.77(d,j=2.0hz,1h),7.89(s,1h),8.23(m,2h),8.62(d,j=2.0hz,1h).

Step 5) 6- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyridine - 5- yl) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 6- (3- iodo- 1- (benzene sulfonyl Base) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.54g, 0.88mmol), trimethyl silicane ethyl-acetylene (0.25ml, 1.75mmol), pd (pph₃)₂cl₂(31mg, 0.044mmol), cui (8mg, 0.044mmol), et₃N (2.45ml, 17.55mmol) and solvent dmf (10ml) prepares.Gained crude product is through silicon It is yellow solid (0.46g, 89%) that plastic column chromatography (pe/etoac (v/v)=4/1) purification obtains title compound.

Ms (esi, pos.ion) m/z:586.3 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 0.28 (s, 9h), 1.50 (s, 9h), 2.91 (m, 2h), 3.69 (m, 2h), 4.62 (s,2h),7.22(d,j=7.9hz,1h),7.34(s,1h),7.39(d,j=8.1hz,1h),7.51(t,j=7.9hz,2h), 7.61(t,j=7.4hz,1h),7.94(s,1h),8.01(d,j=2.1hz,1h),8.21(m,2h),8.63(d,j=2.0hz, 1h).

Step 6) 6- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-first Tert-butyl acrylate

Title compound can be according to the method described by embodiment 7 step 6, with compound 6- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-formic acid uncle Butyl ester (0.58g, 0.99mmol), tetrabutyl ammonium fluoride (the thf solution of 2.0ml, 2.0mmol, 1m) and solvent thf (10ml) system Standby obtain.It is solid for brown color that gained crude on silica gel column chromatography (pe/etoac (v/v)=2/1) purification obtains title compound Body (0.27g, 73%).

Ms (esi, pos.ion) m/z:374.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.51 (s, 9h), 2.94 (m, 2h), 3.23 (s, 1h), 3.71 (m, 2h), 4.65 (s,2h),7.23(d,j=8.0hz,1h),7.44(s,1h),7.49(d,j=8.0hz,1h),7.65(d,j=1.5hz,1h), 8.22(d,j=1.9hz,1h),8.59(d,j=1.9hz,1h),10.81(s,1h).

Step 7) 6- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro Isoquinolin -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 6- (3- acetenyl -1h- pyrrole Cough up simultaneously [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.15g, 0.40mmol), 1,3- bis- Chloro- 2- bromobenzene (91mg, 0.40mmol), pd (pph₃)₂cl₂(14mg, 0.02mmol), cui (4mg, 0.02mmol), et₃n (1.12ml, 8.03mmol) and solvent dmf (3ml) prepare.Gained crude on silica gel column chromatography (pe/etoac (v/v)= 2/1) purification obtains title compound is yellow solid (0.08g, 38%).

Ms (esi, pos.ion) m/z:518.2 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 1.51 (s, 9h), 2.95 (m, 2h), 3.71 (m, 2h), 4.65 (s, 2h), 7.17 (t,j=8.1hz,1h),7.24(m,1h),7.37(d,j=8.1hz,2h),7.44(s,1h),7.49(d,j=8.1hz,1h), 7.75(d,j=1.6hz,1h),8.35(d,j=1.8hz,1h),8.61(m,1h),10.52(s,1h).

Step 8) 6- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1,2,3,4- Tetrahydroisoquinoline

Title compound can be according to the method described by embodiment 2 step 5, with compound 6- (3- ((2,6- dichloro-benzenes Base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.08g, 0.15mmol), the ethyl acetate solution (1.54ml, 6.16mmol, 4m) of hcl and solvent dcm (5ml) prepare.Gained is thick It is faint yellow solid (40mg, 62%) that product obtains title compound through dcm (6ml) recrystallization purifying.

Ms (esi, pos.ion) m/z:418.1 (m+1)；

¹h nmr(400mhz,cdcl₃): δ 2.80 (m, 2h), 3.00 (m, 2h), 3.91 (s, 2h), 7.15 (d, j=8.1hz, 1h),7.41(m,3h),7.60(d,j=8.1hz,2h),8.08(s,1h),8.17(d,j=2.1hz,1h),8.60(d,j= 2.1hz,1h),12.40(s,1h).

Embodiment 97- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1,2,3, 4 tetrahydroisoquinolines

Step 1) 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- base) -1h- pyrrolo- [2,3-b] pyrrole Pyridine

By bromo- for compound 5- 1h- pyrrolo- [2,3-b] pyridine (19.7g, 100mmol), connection boric acid pinacol ester (30.5g, 120mmol) is dissolved in Isosorbide-5-Nitrae-dioxane (400ml), then in reactant liquor add potassium acetate (19.6g, 200mmol).Reactant liquor is substituted after gas (nitrogen) three times, adds pd (dppf) cl₂·ch₂cl₂(1.6g,2mmol).Reactant liquor After being stirred overnight in 80 DEG C under nitrogen protection, it is cooled to room temperature, concentrating under reduced pressure, being subsequently adding ethyl acetate (500ml) will be residual Thing is stayed to dissolve, the mixture saline solution (300mlx3) obtaining is washed.Divide the anhydrous na of organic faciess that liquid obtains₂so₄It is dried, decompression Concentrate, the crude product that residue obtains after silica gel column chromatography (pe/etoac (v/v)=1/1) again use pe/etoac (10/1, 25ml) being recrystallized to give title compound is white solid (23.4g, 95.9%).

Ms (esi, pos.ion) m/z:245.2 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.31 (s, 12h), 6.48 (d, j=3.4hz, 1h), 7.47 (d, j=3.1hz, 1h),8.22(d,j=1.4hz,1h),8.44(d,j=1.4hz,1h),11.75(s,1h).

Step 2) 7- (1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 7- bromo- 3,4- dihydro isoquinoline Quinoline -2 (1h)-t-butyl formate (1.32g, 4.2mmol), 5- (4,4,5,5- tetramethyl -1,3,2- dioxaborolanes -2- Base) -1h- pyrrolo- [2,3-b] pyridine (1.14g, 4.65mmol), pd (dppf) cl₂·ch₂cl₂(0.35g, 0.42mmol), cs₂co₃(4.12g, 12.7mmol) and solvent dmf/h₂O (5/1,12ml) prepares.Gained crude on silica gel column chromatography It is brown liquid (1.68g, 100%) that (pe/etoac (v/v)=5/2) purification obtains title compound.

Ms (esi, pos.ion) m/z:350.2 (m+1).

Step 3) 7- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-formic acid uncle Butyl ester

By compound 7- (1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (1.68g, 4.8mmol) is dissolved in acetone (50ml), then adds nis (1.30g, 5.77mmol) in reactant liquor.Reactant liquor After room temperature condition stirring reaction 2 hours, remove partial solvent, sucking filtration, the acetone of filter cake cooling is washed, filtrate reduced in volume, It is brown that the residue obtaining obtains title compound through silica gel column chromatography (pe/etoac (v/v)=2/1) purification together with filter cake Solid (1.98g, 86.7%).

Ms (esi, pos.ion) m/z:476.1 (m+1).

Step 4) 7- (3- iodo- 1- (benzenesulfonyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline - 2 (1h)-t-butyl formates

Title compound can be according to the method described by embodiment 6 step 3, with compound 7- (3- iodo- 1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (1.98g, 4.17mmol), phso₂cl (0.81ml, 6.25mmol), n-bu₄nhso₄(0.142g, 0.42mmol), 50%naoh (0.42g, 10.43mmol) aqueous solution and Solvent dcm (60ml) prepares.Gained crude on silica gel column chromatography (pe/etoac (v/v)=4/1) purification obtains titled Compound is yellow solid (0.78g, 30.4%).

Ms (esi, pos.ion) m/z:616.0 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.43 (s, 9h), 2.81 (s, 2h), 4.02 (s, 2h), 4.58 (s, 2h), 7.26-7.28(d,j=8.2hz,1h),7.55-7.57(d,j=8.1hz,1h),7.61-7.62(d,j=4.3hz,1h),7.64- 7.66(d,j=8.5hz,2h),7.73-7.74(d,j=4.1hz,1h),7.92-7.93(d,j=4.0hz,1h),8.15-8.17 (d,j=8.3hz,2h),8.22(s,1h),8.69-8.70(d,j=4.6hz,1h).

Step 5) 7- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyridine - 5- yl) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 7- (3- iodo- 1- (benzene sulfonyl Base) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.78g, 1.27mmol), trimethyl silicane ethyl-acetylene (0.187g, 1.90mmol), pd (pph₃)₂cl₂(88.9mg, 0.13mmol), cui (24.13mg, 0.13mmol), et₃N (2.5g, 25.3mmol) and solvent dmf (15ml) prepares.Gained crude product is through silicon It is faint yellow solid (0.68g, 91.6%) that plastic column chromatography (pe/etoac (v/v)=4/1) purification obtains title compound.

Ms (esi, pos.ion) m/z:586.3 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 0.27 (s, 9h), 1.43 (s, 9h), 2.81 (s, 2h), 4.02 (s, 2h), 4.58(s,2h),7.26-7.28(d,j=8.2hz,1h),7.55-7.57(d,j=8.0hz,1h),7.61-7.62(d,j= 4.1hz,1h),7.63-7.65(d,j=8.4hz,2h),7.75-7.77(d,j=8.3hz,1h),8.10-8.11(d,j= 4.2hz,1h),8.15-8.17(d,j=8.3hz,2h),8.32(s,1h),8.71-8.72(d,j=4.6hz,1h).

Step 6) 7- (3- acetenyl -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-first Tert-butyl acrylate

By compound 7- (1- (benzenesulfonyl) -3- ((TMS) acetenyl) -1h- pyrrolo- [2,3-b] pyrrole Pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.68g, 1.16mmol) is suspended in thf (20ml), so Tetrabutyl ammonium fluoride (0.61g, 2.32mmol) is added in backward reactant liquor.After reactant liquor is stirred at room temperature reaction 2 hours, subtract Pressure concentrates, and it is faint yellow that the residue obtaining obtains title compound through silica gel column chromatography (pe/etoac (v/v)=2/1) purification Solid (0.31g, 71.5%).

Ms (esi, pos.ion) m/z:374.2 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.44 (s, 9h), 2.80-2.83 (m, 2h), 3.57-3.59 (m, 2h), 4.15(s,1h),4.46-4.60(m,2h),7.25-7.27(d,j=8.1hz,1h),7.54-7.56(d,j=8.2hz,1h), 7.59(s,1h),7.89-7.90(d,j=4.2hz,1h),8.13-8.14(d,j=4.2hz,1h),8.58-8.59(d,j= 4.6hz,1h),12.15(s,1h).

Step 7) 7- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro Isoquinolin -2 (1h)-t-butyl formate

Title compound can be according to the method described by embodiment 3 step 1, with compound 7- (3- acetenyl -1h- pyrrole Cough up simultaneously [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.31g, 0.83mmol), 1,3- bis- Chloro- 2- bromobenzene (0.19g, 0.83mmol), pd (pph₃)₂cl₂(29mg, 0.04mmol), cui (7.9mg, 0.04mmol), et₃n (1.83g, 16.6mmol) and solvent dmf (15ml) prepare.Gained crude on silica gel column chromatography (pe/etoac (v/v) =2/1) purification obtains title compound is faint yellow solid (0.15g, 36.5%).

Ms (esi, pos.ion) m/z:518.2 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 1.44 (s, 9h), 2.81-2.84 (m, 2h), 3.57-3.60 (m, 2h), 4.55-4.60(m,2h),7.28-7.20(d,j=8.2hz,1h),7.37-7.42(m,1h),7.51-7.56(m,2h),7.59- 7.61(d,j=8.2hz,2h),7.95(s,1h),8.08-8.09(d,j=4hz,1h),8.19-8.20(d,j=4.1hz,1h), 8.63-8.64(d,j=4.5hz,1h),12.43(s,1h).

Step 8) 7- (3- ((2,6- Dichlorobenzene base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -1,2,3,4- Tetrahydroisoquinoline

Title compound can be according to the method described by embodiment 2 step 5, with compound 7- (3- ((2,6- dichloro-benzenes Base) acetenyl) -1h- pyrrolo- [2,3-b] pyridine -5- base) -3,4- dihydro-isoquinoline -2 (1h)-t-butyl formate (0.15g, 0.3mmol), the ethyl acetate solution (4ml, 16.0mmol, 4m) of hcl and solvent dcm (15ml) prepare.Gained crude product Obtaining title compound through dcm (8ml) recrystallization purifying is faint yellow solid (110mg, 90.9%).

Ms (esi, pos.ion) m/z:418.1 (m+1)；

¹h nmr(400mhz,dmso-d₆): δ 2.70-2.73 (m, 2h), 2.95-2.98 (m, 2h), 3.92 (m, 2h), 7.17-7.19(d,j=8.3hz,1h),7.36-7.37(d,j=4hz,1h),7.39-7.44(m,2h),7.59-7.61(d,j= 8.2hz,2h),8.07(s,1h),8.16-8.17(d,j=4.2hz,1h),8.59-8.60(d,j=4.6hz,1h),12.30(s, 1h).

Biologic test

Bioanalytical method

The lc/ms/ms system of analysis includes agilent1200 series vacuum degassing furnace, binary syringe pump, and orifice plate is automatic Sampler, post calorstat, charged spray ionizes the agilent g6430 three-level level Four bar mass spectrograph in (esi) source.Quantitative analyses exist Carry out under mrm pattern, the parameter of mrm conversion is as shown in table a:

Table a

Many reaction detection scannings	490.2→383.1
		Fragmentation voltage	230v
Capillary voltage	55v
		Dryer temperature	350℃
Nebulizer	40psi

Exsiccator flow velocity

10l/min

Analysis uses agilent xdb-c18,2.1x30mm, 3.5 μm post, injects 5 μ l samples.Analysis condition: mobile phase Aqueous formic acid (a) for 0.1% and 0.1% formic acid methanol solution (b).Flow velocity is 0.4ml/min.Eluent gradient such as table b Shown:

Table b

Time	The gradient of mobile phase b
		0.5min	5%
1.0min	95%
		2.2min	95%
2.3min	5%
		5.0min	stop

Additionally, for the also agilent6330 series lc/ms/ms spectrogrph of analysis, equipped with the injection of g1312a binary Pump, g1367a automatic sampler and g1314c uv detector；Lc/ms/ms spectrogrph adopts esi radioactive source.Using titer pair Each analyte carries out suitable cation models treated and mrm conversion carries out optimal analysis.Use during analyzing Capcell mp-c18 post, specification is: 100x4.6mmi.d., 5 μm (phenomenex, torrance, california, usa).Mobile phase is 5mm ammonium acetate, 0.1% methanol aqueous solution (a): 5mm ammonium acetate, 0.1% methanol acetonitrile solution (b) (70/30, v/v)；Flow velocity is 0.6ml/min；Column temperature is maintained at room temperature；Inject 20 μ l samples.

Stability in embodiment a people and rat liver microsomes

People or rat liver microsomes are placed in incubation in polypropylen tubes, and guide its duplication.Typical incubation mixed liquor Including people or rat liver microsomes (0.5mg protein/ml), target compound (5 μm) and the nadph that cumulative volume is 200 μ l (1.0mm) kaliumphosphate buffer (pbs, 100mm, ph value is 7.4), by compound dissolution in dmso and using pbs, it is dilute Release so as to the concentration of final dmso solution is 0.05%.And be incubated in the water-bath communicating with air at 37 DEG C, incubate in advance Educate and add albumen in 3 minutes backward mixed liquors and start to react.In different time points (0,5,10,15,30 and 60 minute), plus Enter same volume ice-cold acetonitrile terminating reaction.Sample preserves until carrying out lc/ms/ms analysis at -80 DEG C.

Concentration in people or rat liver microsomes mixtures incubated for the compound is to be measured by the method for lc/ms/ms 's.The range of linearity of concentration range is determined by each test-compound.

Parallel incubation test be used the microsome of degeneration as negative control, hatches at 37 DEG C, reacts when different Between point (0,15 and 60 minute) terminate.

Dextromethorphan (70 μ μ), as positive control, is hatched at 37 DEG C, reaction different time point (0,5,10, 15,30 and 60 minutes) terminate.The positive and negative control sample is all included, to ensure microsome hatching in each assay method The integrity of system.

Additionally, stability data in people or rat liver microsomes for the compound of the present invention also can be obtained by tests below Arrive.People or rat liver microsomes are placed in incubation in polypropylen tubes, and guide its duplication.Typical mixtures incubated includes people Or rat liver microsomes (ultimate density: 0.5mg albumen/ml), compound (ultimate density: 1.5 μm) and cumulative volume are 30 μ l K- buffer solution (edta containing 1.0mm, 100mm, ph7.4).By compound dissolution in dmso, and diluted with k- buffer solution, The ultimate density making dmso is 0.2%.After preincubate 10 minutes, 15 μ l nadph (ultimate density: 2mm) are added to carry out enzymatic anti- Should, whole test is carried out in 37 DEG C of incubation tube.In different time points (0,15,30 and 60 minute), add 135 μ l acetonitriles (containing is) terminating reaction.It is centrifuged 10 minutes with 4000rpm, except Deproteinization, collect the supernatant, analyzed with lc-ms/ms.

In above-mentioned test, ketanserin (1 μm) is selected as positive control, hatches at 37 DEG C, and reaction is in the different time Point terminates for (0,15,30 and 60 minute).Positive control sample is all included, to ensure microsome hatching body in each assay method The integrity of system.

Data analysiss

For each reaction, concentration (as a percentage) in people or rat liver microsomes incubation for the compound is pressed The plotted as percentage of relative zero time point, to infer internal CLint cl with this_int(ref.:naritomi y, terashita s,kimura s,suzuki a,kagayama a,sugiyama y.prediction of human hepatic clearance from in vivo animal experiments and in vitro metabolic studies with liver microsomes from animals and humans.drug metabolism and disposition2001,29:1316-1324).

Stability data in people and rat liver microsomes for table 1 embodiment of the present invention

During by compound incubation in people and rat liver microsomes, compound of the present invention shows the good half-life (t_1/2).

Embodiment b mice, rat, dog and monkey are administered orally the Pharmacokinetic Evaluation after quantitation the compounds of this invention

The present invention to the compounds of this invention, commented by the pharmacokinetic in mice, rat, dog or monkey body Estimate.The compounds of this invention with the aqueous solution of aqueous solution or 2%hpmc+1% twen-80, the saline solution of 5%dmso+5%, 4%mc or Capsule form is administered.For intravenous administration, animal gives 1 or 2mg/kg dosage.For oral dose (p.o.), Rat and mice are 5 or 10mg/kg, and dog and monkey are 10mg/kg.It is 0.25,0.5,1.0,2.0,3.0,4.0 in time point, Take within 6.0,8.0,12 and 24 hours blood (0.3ml), and be centrifuged 10 minutes under 3,000 or 4,000rpm.Collect plasma solutions, and Preserve at -20 DEG C or -70 DEG C until carrying out above-mentioned lc/ms/ms analysis.

Embodiment c kinase assay

Kinase assay pass through detection mix γ-³³The myelin basic protein (mbp) of p-atp is come to complete.Prepare 20 μ g/ Mbp (sigma#m-1891) trishydroxymethylaminomethane buffer salt solution (tbs of ml;50mm tris ph8.0,138mm Nacl, 2.7mm kcl), it is coated white 384 orifice plates (greiner) of high associativity, every hole 60 μ l.4 DEG C, it is incubated 24 hours.Afterwards Wash plate 3 times with 100 μ l tbs.Kinase buffer liquid (the 5mm hepes ph7.6,15mm that kinase reaction is 34 μ l in cumulative volume Nacl, 0.01% bovine serum albumin (sigma#i-5506), 10mm mgcl₂, 1mm dtt, 0.02%tritonx-100) in enter OK.By compound dissolution in dmso, add in each hole, the ultimate density of dmso is 1%.Twice of each data determination, each change The mensure of compound is at least tested twice.Such as, the ultimate density of enzyme is 10nm or 20nm.Add and do not have markd atp (10 μm) and γ-³³Atp (every hole 2x10 of p labelling⁶Cpm, 3000ci/mmol) start to react.Concussion carries out 1 at room temperature for reflection Hour.384 orifice plates are cleaned with the pbs of 7x, are subsequently adding the scintillation solution of every hole 50 μ l.With the detection of wallac trilux enumerator Result.To those of ordinary skill in the art, this is only one of numerous detection methods, and other methods also may be used.

The ic that above-mentioned test method can be inhibited₅₀And/or inhibition constant k_i.ic₅₀It is defined as under test conditions, suppression Make compound concentration during 50% enzymatic activity.Make the curve comprising 10 concentration point using the extension rate of 1/2log, estimation ic₅₀Value (for example, a typical curve is made by following compound concentration: 10 μm, 3 μm, 1 μm, 0.3 μm, 0.1 μm, 0.03 μm, 0.01 μm, 0.003 μm, 0.001 μm, 0 μm).

Kinase assay in the present invention be by millipore company of Britain to complete (millipore uk ltd, dundee technology park,dundee dd21sw,uk).

Alk (h) kinase assays

People the alk mops for 7.0,0.2mm edta in 8mm ph value, 250 μm of kkkspgeyvniefg, 10mm magnesium acetate [γ -33p-atp] (specific activity about 500cpm/pmol, concentration determines according to demand) is incubated under conditions of existing.Add Start after mgatp mixture to react.Under room temperature, incubation is added thereto to 3% phosphoric acid solution and carrys out terminating reaction for 40 minutes afterwards.Will The reactant liquor of 10 μ l be in mottled be distributed on p30 filter, and clean 3 times in 5 minutes with 75mm phosphoric acid, and drying with Put at once before scinticounting in methanol solution and preserve.

C-met (h) kinase assays

People the c-met mops for 7.0,0.2mm edta in 8mm ph value, 250 μm of kkkspgeyvniefg, 10mm acetic acid Magnesium and [γ-³³P-atp] (specific activity about 500cpm/pmol, concentration determines according to demand) be incubated under conditions of existing.Plus Start after entering mgatp mixture to react.Under room temperature, incubation is added thereto to 3% phosphoric acid solution and carrys out terminating reaction for 40 minutes afterwards. The reactant liquor of 10 μ l is distributed on p30 filter in mottled, and was cleaned 3 times in 5 minutes with 75mm phosphoric acid, and be dried Preserve with putting at once before scinticounting in methanol solution.

The kinase inhibiting activity data of table 2 embodiment of the present invention

Compound of the present invention generally shows very high activity in the test of alk and c-met (h).

The kinase inhibiting activity of the compounds of this invention can also pass through kinomescan^tmTest, it is mainly based upon quantitation Determination sample and the test of the part fixing, active site guides and kinases competitive binding ability.It is complete that this is tested Become to need with reference to following three elements: the kinases of dna- labelling, fixing part and testing sample.Testing sample and fixed ligands The ability of competitive binding kinases can be determined by measuring the amount of the pcr in dna labelling.

For great majority test, the t7 phage strain of kinases-labelling is the large intestine bar that origin comes from bl21 bacterial strain Bacterium host prepare.First escherichia coli are cultivated exponential phase, are then infected with t7 phage, and by its Hatch until cracking in 32 DEG C under continuous concussion, lysate is centrifuged, sucking filtration, remove cell debriss.Remaining in hek-293 The kinases of intracellular generation and then with dna come labelling, for the detection of qpcr.It is coated with magnetic bead and the biology of Streptavidin After the smaller ligand of elementization reacts 30 minutes at room temperature, generate the affine resin for kinase assay.The magnetic bead being coordinated Blocked by excessive biotin, with blocking buffer (seablock^tm(pierce), 1%bsa, 0.05% tween 20,1mm Dtt) washing removes free part, to reduce non-specific binding.Association reaction be all by kinases, the affinity that has been coordinated Magnetic bead and testing sample in 1x combination buffer (20%seablock^tm, 0.17x pbs, 0.05% tween 20,6mm dtt) in Complete.All reactions are carried out in 96 orifice plates of the polystyrene for 0.135ml all in final volume.The orifice plate of test is all continuous Hatch 1 hour in room temperature condition under concussion, the magnetic bead of affinity is all washed with lavation buffer solution (1x pbs, 0.05% tween 20) Wash, be then resuspended in elution buffer (1x pbs, 0.05% tween 20,0.5 μm of non-biotinylated affinity ligands), and Hatch 30 minutes in room temperature condition under continuous concussion.Kinase concentration in eluent is measured by qpcr.

Kinase assay in the present invention is by the kinomescan of discoverx company^tmAnalysis Service is completing (42501albrae st.fremont, ca94538, usa).

Embodiment d Xenograft Tumor Models

The drug effect of the compounds of this invention is to be evaluated by the standard Murine models of transplantation tumor.Human tumor cells After (u87mg glioma cell, atcc) culture, collection, in rear veutro subcutaneous vaccination in the female nude mice body of 6-7 week old (balb/ca nu/nu, Hunan slac Animal Lab.) (for solvent group and each dosage group: n=6-10).When tumor body Amass and reach 100-250mm³When, animal is randomly divided into solvent control group (5%dmso+70%(30%),7%hcl (ph1),18%(30%);Or 7%dmso, 7%hcl (ph1), 70%(30%),16%(30%)) And compound group.Subsequently gastric infusion is carried out using compound on animals, any from 0 to 15 days after tumor cell inoculation Place starts, and generally carries out once daily in test.

Tumor growth inhibition (tgi) is analyzed

The crystallization growth of tumor is to be evaluated by the relation of gross tumor volume and time.The major axis of Subcutaneous tumor L () and short axle (w) measure weekly twice by caliper, the volume (tv) of tumor passes through formula (l × w²)/2) calculated. Tgi is calculated by the intermediate value of solvent group mouse tumor volume and the difference of medicine group mouse tumor volume-median, with solvent The percentage ratio of matched group gross tumor volume intermediate value representing, is calculated by following formula:

Primary statisticss analysis to be completed by repeating variance mensure analysis (rmanova).Followed by scheffe Psot hoc test method carries out multiple comparisons.Separate solvent (5%dmso+70%(30%),7%hcl(ph1),18%(30%);Or 7%dmso, 7%hcl (ph1), 70%(30%),16%(30%) it is) negative right According to.

Finally it should be noted that also other modes are used for implementing the present invention.Correspondingly, embodiments of the invention are To illustratively illustrate, but be not limited to content described in the invention it is also possible to be made within the scope of the present invention Modification or the equivalents added in the claims.All publications cited in the present invention or patent all will be used as these Bright list of references.

Claims (17)

1. a kind of compound, it is the stereoisomer of the compound of structure shown in formula (i) or compound shown in formula (i), geometry Isomer, tautomer, or pharmaceutically acceptable salt:

Wherein:

Each w₁, w₂And w₃It independently is n or cr^c；

X is following subformula:

Wherein, described subformula (iia) and (iii) are each From independently unsubstituted or by 1,2 or 3 r¹Group is replaced；Each z₁And z₂It independently is n or ch；

Each r¹It independently is c_3-10Cycloalkyl, c_3-10Cycloalkyl-c_1-4Alkylidene, c_3-10Heterocyclic radical, c_3-10Heterocyclic radical-c_1-4Alkylene Base, c_6-10Aryl, comprises 1,2,3 or 4 and is independently selected from o, the heteroatomic 5-10 former molecular heteroaryl of s and n, c_6-10 Aryl-c_1-4Alkylidene, or (5-10 former molecular heteroaryl)-c_1-4Alkylidene, wherein, each r¹Can independently not taken Generation or further by r²Group is replaced；Or, the r in formula (iia) or (iii), on adjacent atom¹Group can be unified into c_4-10Cycloalkyl or c_3-10Heterocyclic radical, wherein, described c_4-10Cycloalkyl and c_3-10Heterocyclic radical is unsubstituted independently of one another or by 1, 2,3 or 4 r²Group is replaced；

Each r²It independently is d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-nr^ar^b, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Alkene Base, c_2-6Alkynyl, nc-c_1-4Alkylidene, r^br^an-c_1-4Alkylidene, r^ao-c_1-4Alkylidene, c_3-8Cycloalkyl, c_3-8Cycloalkyl-c_1-4 Alkylidene, c_3-8Heterocyclic radical, or c_3-8Heterocyclic radical-c_1-4Alkylidene；

Y is c_6-10Aryl wherein, described c_6-10Aryl is unsubstituted or is replaced by 1,2,3 or 4 substituent group, described substituent group Independently selected from d, f, cl, br, i, cn, no₂, n₃,-or^a,-sr^a,-s (=o) r^a,-s (=o)₂r^a,-nr^ar^b,-s (=o)₂nr^ar^b,-oc (=o) r^a, c_1-6Alkyl, c_1-6Haloalkyl, c_2-6Thiazolinyl, c_2-6Alkynyl, nc-c_1-4Alkylidene or r^ao-c_1-4Alkylene Base；

Each r^aAnd r^bIt independently is h or c_1-6Aliphatic, wherein, described c_1-6Aliphatic is unsubstituted or is replaced by 1,2,3 or 4 Base is replaced, and described substituent group is independently selected from d, f, cl, cn, n₃, oh, nh₂, c_1-6Alkoxyl, or c_1-6Alkyl amino；

Each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-6Alkyl-s (=o)₂Nh-, c_1-6Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-6Alkyl, c_1-6Alkoxyl or c_1-6Alkyl amino, wherein, described c_1-6Alkyl, c_1-6Alkoxyl And c_1-6Alkyl amino is unsubstituted independently of one another or is replaced by 1,2,3 or 4 substituent group, and described substituent group is independently selected From d, f, cl, cn, n₃, oh, nh₂, c_1-6Alkyl, c_3-6Cycloalkyl, c_1-6Haloalkyl, c_1-6Alkoxyl, or c_1-6Alkyl amino.

2. compound according to claim 1, wherein, each w₁And w₂It independently is cr^c；w₃For n or cr^c.

3. compound according to claim 1, wherein, each r¹It independently is c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylene Base, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, each r¹Can be independently unsubstituted or further by r²Group Replaced；Or, the r in formula (iia) or (iii), on adjacent atom¹Group can be unified into c_5-6Cycloalkyl or c_3-6Heterocycle Base, wherein, described c_5-6Cycloalkyl and c_3-6Heterocyclic radical is unsubstituted independently of one another or by 1,2,3 or 4 r²Group is replaced.

4. compound according to claim 1, wherein, each r²It independently is d, f, cl ,-or^a,-nr^ar^b, c_1-4Alkyl, c_1-4 Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene.

5. compound according to claim 1, wherein, y is phenyl, and described phenyl is independently unsubstituted or by 1,2,3 Or 4 substituent groups are replaced, described substituent group is independently selected from d, f, cl, br, c_1-3Alkyl, c_1-3Haloalkyl, or c_2-6Alkynes Base.

6. compound according to claim 1, wherein, each r^aAnd r^bIt independently is h or c_1-3Alkyl, wherein, described c_1-3Alkane Base is unsubstituted or is replaced by 1,2,3 or 4 substituent group, and described substituent group is independently selected from d, f, n₃, oh, nh₂, c_1-3Alcoxyl Base, or c_1-3Alkyl amino.

7. compound according to claim 1, wherein, each r^cIt independently is h, d, f, cl, br, i, n₃, cn, nh₂, c_1-3Alkane Base-s (=o)₂Nh-, c_1-3Alkyl-c (=o) n (r^a)-,-nhc (=o) nr^ar^b, c_1-3Alkyl, c_1-3Alkoxyl or c_1-3Alkyl ammonia Base, wherein, described c_1-3Alkyl, c_1-3Alkoxyl and c_1-3Alkyl amino is unsubstituted independently of one another or is taken by 1,2,3 or 4 Replaced for base, described substituent group is independently selected from d, f, cl, cn, n₃, oh, nh₂, c_1-3Alkyl, c_3-6Cycloalkyl, c_1-3Alkyl halide Base, c_1-3Alkoxyl, or c_1-3Alkyl amino.

8. compound according to claim 1, wherein, x is following subformula:

Wherein, described subformula is unsubstituted independently of one another or by 1,2 or 3 r¹Group is replaced, and each r¹Can be only On the spot unsubstituted or further by r²Group is replaced；Or, the r in described each subformula, on adjacent atom¹Group can To be unified into c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is unsubstituted or by 1,2,3 or 4 r²Group is replaced.

9. compound according to claim 8, wherein, each r¹It independently is c_3-6Cycloalkyl, c_3-6Cycloalkyl-c_1-2Alkylene Base, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene, wherein, each r¹Can be independently unsubstituted or further by r²Group Replaced；Or, the r in described each subformula, on adjacent atom¹Group can be unified into c_4-6Heterocyclic radical, wherein, described c_4-6Heterocyclic radical is independently unsubstituted or by 1,2,3 or 4 r²Group is replaced；Each r²It independently is d, f, cl ,-or^a,- nr^ar^b, c_1-4Alkyl, c_1-4Haloalkyl, c_2-6Thiazolinyl, r^br^an-c_1-2Alkylidene, r^ao-c_1-2Alkylidene, c_3-6Cycloalkyl, c_3-6Ring Alkyl-c_1-2Alkylidene, c_3-6Heterocyclic radical, or c_3-6Heterocyclic radical-c_1-2Alkylidene.

10. compound according to claim 1, has a structure of one of:

A kind of 11. pharmaceutical compositions comprise the compound described in claim 1-10 any one, and pharmaceutically acceptable load Body, excipient, diluent, adjuvant, vehicle or combinations thereof.

12. pharmaceutical compositions according to claim 11, wherein further comprise additional therapeutic agent, and described adding is controlled Treat agent and be selected from chemotherapeutic agent, antiproliferative, for treating atherosclerotic medicine, for treating the medicine of pulmonary fibrosiss Thing, or combinations thereof.

13. pharmaceutical compositions according to claim 12, wherein said additional therapeutic agent is amycin (adriamycin), rapamycin (rapamycin), sirolimuss (temsirolimus), everolimuses (everolimus), Ipsapirone (ixabepilone), gemcitabine (gemcitabin), cyclophosphamide (cyclophosphamide), ground plug rice Loose (dexamethasone), etoposide (etoposide), fluorouracil (fluorouracil), Afatinib (afatinib), alisertib, amuvatinib, Axitinib (axitinib), SKI-606 (bosutinib), Brivanib, cabozantinib, AZD2171 (cediranib), crenolanib, gram Zhuo replaces Buddhist nun (crizotinib), Dabrafenib, dacomitinib, Dasatinib (dasatinib), danusertib, dovitinib, Erlotinib (erlotinib), foretinib, ganetespib, gefitinib (gefitinib), ibrutinib, imatinib (imatinib), iniparib, Lapatinib (lapatinib), lenvatinib, linifanib, linsitinib, Marseille For Buddhist nun (masitinib), momelotinib, do not replace husky Buddhist nun (motesanib), HKI-272 (neratinib), Niraparib, AMN107 (nilotinib), oprozomib, olaparib, pazopanib (pazopanib), Pictilisib, ponatinib, quizartinib, regorafenib, rigosertib, rucaparib, Ruxolitinib, saracatinib (saracatinib), saridegib, Sorafenib (sorafenib), Sutent (sunitinib), tasocitinib, telatinib, tivantinib, tivozanib, tofacitinib, Trametinib, ZD6474 (vandetanib), veliparib, vemurafenib, vismodegib, volasertib, Interferon (an interferon), carboplatin (carboplatin), hycamtin (topotecan), paclitaxel (taxol), long Spring alkali (vinblastine), vincristine (vincristine), temozolomide (temozolomide), tositumomab (tositumomab), trabedectin, belimumab, bevacizumab (bevacizumab), brentuximab, Cetuximab, gemtuzumab, ipilimumab, ofatumumab, panitumumab, ranibizumab, rituximab, Herceptin (trastuzumab), or combinations thereof.

A kind of 14. usage rights require described in compound or claim 11-13 any one described in 1-10 any one Pharmaceutical composition come to prepare for protect, process, treat or mitigate patient's proliferative disease medicine purposes.

15. according to claim 14 compound or pharmaceutical composition purposes, wherein said proliferative disease be transfer Cancer, colon cancer, adenocarcinoma of stomach, bladder cancer, breast carcinoma, renal carcinoma, hepatocarcinoma, pulmonary carcinoma, skin carcinoma, thyroid carcinoma, head and neck cancer, prostate Cancer, cancer of pancreas, the cancer of cns (central nervous system), glioblastoma, myeloproliferative disease, atherosclerosiss or lung fiber Change.

A kind of 16. usage rights require described in compound or claim 11-13 any one described in 1-10 any one The method to prepare the medicine for suppression in biological sample or regulation receptor tyrosine kinase activity for the pharmaceutical composition, described Method comprises described in compound or usage right requirement 11-13 any one that usage right requires described in 1-10 any one Pharmaceutical composition is contacted with described biological sample.

17. methods according to claim 16, wherein receptor tyrosine kinase are alk, c-met, or combinations thereof.