阅读说明：本技术 有酪氨酸激酶抑制剂的组合产品和其应用 (There are combination product and its application of tyrosine kinase inhibitor ) 是由 R·提耶德 C·沙特奈-里沃戴 M·伊托 B·彭 龚瑛 M·阿基莫夫 于 2013-04-03 设计创作，主要内容包括：本发明涉及药物产品,包括以下组合：(i)MET抑制剂和(ii)EGFR抑制剂,或其各自药学上可接受盐、或其前药,所述成分共同发挥作用治疗增殖性疾病,以及涉及对应的药物制剂、用途、方法、工艺、商业包装和相关发明实施方式。(The present invention relates to drug products, including following combination: (i) MET inhibitor and (ii) EGFR inhibitor, or its respectively pharmaceutically-acceptable salts or its prodrug, the ingredient plays a role jointly treats proliferative diseases, and is related to corresponding pharmaceutical preparation, purposes, method, technique, commercial packing and related invention embodiment.)

1. a kind of for treating the pharmaceutical composition for having the object of EGFR mutation, c-MET amplification, the combination includes (i) MET junket Histidine kinase inhibitor and (ii) EGFR tyrosine kinase inhibitor or its respectively pharmaceutically-acceptable salts or its respective prodrug, With at least one pharmaceutically acceptable carrier, which is characterized in that wherein the MET tyrosine kinase inhibitor is the fluoro- N- first of 2- Base -4- [(7- quinoline -6- base-methyl)-imidazo [1,2-b] triazine -2- base] benzamide or its pharmaceutically-acceptable salts.

2. combination as claimed in claim 1, which is characterized in that the EGFR tyrosine kinase inhibitor is that Erlotinib, Ji Fei are replaced Buddhist nun, Lapatinib, Canertinib, pelitinib, linatinib or Cetuximab or its respective pharmaceutically-acceptable salts.

3. combination as claimed in claim 1, which is characterized in that the EGFR tyrosine kinase inhibitor is Erlotinib or it is each From pharmaceutically-acceptable salts.

4. combination as claimed in claim 1, which is characterized in that the EGFR tyrosine kinase inhibitor is Gefitinib or it is each From pharmaceutically-acceptable salts.

5. such as combination of any of claims 1-4, which is characterized in that the combination includes other auxiliary agents.

6. such as combination of any of claims 1-4, which is characterized in that including a certain amount of, the amount is common for the combination Effectively antagonize the disease that EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediate, especially cancer, the combination Including combined partner (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor or its respectively pharmaceutically may be used Receive salt, and at least one pharmaceutically acceptable carrier material, and optional other auxiliary agents or its pharmaceutically-acceptable salts.

7. such as combination of any of claims 1-4, which is characterized in that the combination uses combination product form.

8. combination of any of claims 1-4 is in preparation for treating EGFR tyrosine kinase activity and/or MET junket The disease that histidine kinase activity mediates, especially cancer, drug in purposes.

9. a kind of containing the drug products of combination or commercial packing as described in any one of claim 1-4, especially together with its Treat the disease that EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediate, especially cancer, in simultaneously, separately or The specification sequentially used, the disease mediated particularly for treatment EGFR tyrosine kinase activity and/or MET tyrosine kinase activity Disease, especially cancer.

Background of invention

It is designed to that the drug for individual molecule target is often unsuitable for prevention and treatment and has more than one target as the cause of disease (more bases Because of disease) disease, such as cancer or other proliferative diseases.

To prevent and treat this kind of disease, a kind of method is using single multiple target point drug --- however, this needs to cause disease aobvious The existing target is all considered drug hits.On the other hand, multiple target point drug may cause unwanted side effect, because It can also have an impact to the target that disease shows is not involved in.

Another different method is to use pharmaceutical composition as multiple target point drug.At its best, this can produce conjunction And efficiency such as synergistic effect, thus caused side effect when single medicine is used alone can be reduced.

Once in a while, such drug component (combined partner) can influence independent target to generate combined effect, and thus a It can realize and/or consider respectively that it is individually imitated beyond single compound in body cell or in intracellular generate of difference of different tissues Combined effect when fruit, approach are identical or different.Alternatively, the ability that another component reaches its target can be changed in a kind of component, Such as by inhibiting efflux pump.Alternatively, different loci of the combined partner in combination with same target.It is logical that these targets connect variant Cross substantial increase to combination come in handy or possibility interaction type useless come hinder search for appropriate combination.

However, cooperating needed for may not being found using this kind of drug in many cases or even acting synergistically.Due at To (r=2) pharmaceutical composition number according to formula n！/(r！(n-r)！) increase with test agent number n (such as 2000 kinds of test Reagent can generate 1,999,000 kinds of distinct pairs combinations), need efficient suitable screening technique.

Additionally, it is contemplated that a critical demands are the ways that identification accidentally participates in or aided disease shows before any combination Diameter, enzyme, metabolism state etc..

In many cases, or even not know that given disease is multigenic disease.

Therefore, the search of appropriate combination and amount can be properly described as looked for a needle in a haystack.

Proto-oncogene (MET) encodes albumen hepatocyte growth factor receptor (HGFR), and the receptor has tyrosine kinase It is active and most important to embryonic development and wound healing.After by hepatocyte growth factor receptor (HGFR) stimulation, MET induces number Kind biological respinse, leads to infiltrative growth.Abnormal MET activation is including kidney, liver cancer, gastric cancer, breast cancer and the cancer of the brain Start tumour growth in Several Kinds of Malignancy type, form new blood vessel (angiogenesis) and shift.Known some MET kinase inhibitions The inhibitor of agent or HGF induction MET (=HGFR) activation.C-MET (or c-MET signal path) is in normal tissue and the mankind Biological function in malignant tumour such as cancer has had been well documented (Christensen, J.G. etc., Cancer Lett.2005,225 (1):1-26；Corso, S. etc., Trends in Mol.Med.2005,11 (6): 284-292).

C-Met (c-MET) access of imbalance plays an important role and is sometimes in tumour forms, grows, maintains and develops The origin cause of formation (in the case where gene alteration) (Birchmeier, C. etc., Nat.Rev.Mol.Cell.Biol.2003,4 (12): 915-925；Boccaccio, C. etc., Nat.Rev.Cancer 2006,6 (8): 637-645；Christensen, J.G. etc., Cancer Lett.2005,225(1):1-26).HGF and/or c-Met is overexpressed in most human cancers, and usually It is related to bad clinical effectiveness, such as disease more invasion, disease development, metastases and patient's shortened survival.In addition, The high patient of HGF/c-Met protein level is more tolerant to chemotherapy and radiation.Other than abnormal HGF/c-Met expression, c-Met receptor is also It can be activated in cancer patient by gene mutation (embryonal system and body cell) and gene magnification.Although gene magnification and mutation are to suffer from The most common gene alteration reported in person, the receptor can also be activated by missing, truncation, gene rearrangement.

The kinds cancer that c-MET is participated in includes but is not limited to: cancer (such as bladder cancer, breast cancer, cervical carcinoma, liver and gallbladder cast liver Cancer, colorectal cancer, the cancer of the esophagus, gastric cancer, head and neck cancer, kidney, liver cancer, lung cancer, nasopharyngeal carcinoma, oophoroma, cancer of pancreas, prostate cancer, Thyroid cancer)；Musculoskeletal sarcoma (such as osteosarcoma, synovial sarcoma, rhabdomyosarcoma)；Soft tissue sarcoma's (such as MFH/ fiber meat Tumor, leiomyosarcoma, Kaposi sarcoma)；(such as Huppert's disease, lymthoma, human adult T cell are white for Malignancy Blood disease, acute myeloid leukaemia, chronic myelogenous leukemia)；With other tumors (such as glioblastoma, astrocytoma, melanocyte Tumor, celiothelioma and the nephroblastoma (www.vai.org/met/；Christensen, J.G. etc., Cancer Lett.2005, 225(1):1-26)。

Activation c-MET access causes tumour formation and development and can be the sight of the good targets of effective cancer interventional therapy Point is further strengthened (Birchmeier, C. etc., Nat.Rev.Mol.Cell by several preclinical studies Biol.2003,4(12):915-925；Christensen, J.G. etc., Cancer Lett.2005,225 (1): 1-26； Corso, S. etc., Trends in Mol.Med.2005,11 (6): 284-292).For example, researches show that tpr-met to merge base Cause, c-met are overexpressed and activation c-met is mutated the carcinogenicity turn that (referred to herein, generally, as MET) results in a variety of model cell systems Change and the tumour in mouse is caused to be formed and shifted.Importantly, significant antitumor (sometimes tumor regression) and anti-rotation are moved Activity passes through reagent and shows in vitro and in vivo, the reagent specific Damage and/or blocking HGF/c-MET signal transduction.This A little reagents include anti-HGF and anti-C-met antibodies, HGF peptide antagonists, inveigle c-Met receptor, c-Met peptide antagonists, dominant C-Met mutation, c-Met specific antisense oligonucleotides and ribozyme and selective small molecule c-Met kinase inhibitor (Christensen, J.G. etc., Cancer Lett.2005,225 (1): 1-26).

Other than effect fixed in cancer, abnormal HGF/MET signal transduction also participates in atherosclerosis, lung fiber Change, kidney fibrosis and regeneration, hepatopathy, allergic disorder, inflammatory and autoimmune disease, cranial vascular disease, cardiovascular disease, with The relevant illness of organ transplant (Ma, H. etc., Atherosclerosis.2002,164 (1): 79-87；Crestani, B. etc., Lab.Invest.2002,82(8):1015-1022；Sequra-Flores, A.A. etc., Rev.Gastroenterol.Mex.2004,69(4)243-250；Morishita, R. etc., Curr.Gene Ther.2004,4 (2)199-206；Morishita, R. etc., Endocr.J.2002,49 (3) 273-284；Liu,Y.,Curr.Opin.Nephr ol.Hypertens.2002,11(1):23-30；Matsumoto, K. etc., Kidney Int.2001,59 (6): 2023-2038； Balkovetz, D.F. etc., Int.Rev.Cytol.1999,186:225-250；Miyazawa, T. etc., J.Cereb.Blood Flow Metab.1998,18(4)345-348；Koch, A.E. etc., Arthritis Rheum.1996,39 (9): 1566- 1575；Futamatsu, H. etc., Circ.Res.2005,96 (8) 823-830；Eguchi, S. etc., Clin.Transplant.1999,13(6)536-544)。

EGF-R ELISA (EGFR, aka ErbB-1；HER1 in people) it is epidermal growth factor family ligand Receptor.Known several types of cancers is excessively active dependent on EGFR or is overexpressed, as lung cancer, cancer of anus, glioblastoma multiforme and Many other (mainly) epitheliomas.

Cancer often relies on the gene alteration of receptor tyrosine kinase (RTK), such as passes through point mutation, gene magnification or dyeing Body transposition, cause these RTK activity it is out of control and thus become carcinogenicity.The cell Proliferation of cancer cell depends on these exceptions The activity of RTK.

When proliferative diseases caused by treating, usually using the inhibitor of involved oncogene RTK.However, it is general, After the treatment of certain time, the drug resistance to drug used is observed.A kind of mechanism of drug resistance may include target RTK, influence to control Treat the combination or activity of agent.Another mechanism is when main kinases is suppressed, and compensatory activation continues to press on the substitution of cancer growth Kinases.One clear example for covering 2 kinds of mechanism types is in the non-small cell carcinoma (NSCLC) for carry activation EGFR mutation to table The acquired resistance of skin growth factor receptor (EGFR) Gefitinib and Erlotinib is (see Lynch, T.J., etc.N Engl J Med,350:2129-2139,2004；Or Paez, J.G., etc. Science, 304:1497-1500,2004).For example, MET is living Change can compensate activity of EGFR loss (passing through inhibition) by activated downstream signaling molecule such as HER3, can compensate for as MET is expanded, or Its ligand hepatocyte growth factor can activate MET (see Engelman, J.A., etc. Science, 316:1039-1043,2007； Yano, S., etc. Cancer Res, 68:9479-9487,2008；And Turke, A.B., etc., Cancer Cell, 17:77-88, 2010).The EGFR that it is known that MET dependence cancer cell line (it, which is proliferated, depends on MET activity) can be induced by ligand is activated Influence from MET inhibitor (see Bachleitner-Hofmann, T., etc. .Mol Cancer Ther, 7:3499-3508, 2008)。

The general description of invention

Cancer cell is initially used according to MET and/or EGFR (i.e. its activity), observe by ligand mediated activation substitution by The bypass of body tyrosine kinase (RTK) relies on.(i.e. with corresponding selection inhibitor for treating MET- or FGFR- dependent cell system With the MET dependent cell system of MET inhibitor and with the FGFR dependent cell system of FGFR inhibitor) and be added on cell simultaneously When clear, it was found that by-pass mechanism, the cell transfecting have the cDNA for encoding a variety of secretory proteins.It can be seen that MET and FGFR RTK can compensate respective loss, thus " can succour " proliferative cell, as long as one of these RTK are inhibited by suitable drug.

Have been surprisingly found that the joint inhibition of these RTK can cause Synergistic anti-cancer active, especially when MET and FGFR RTK has It when active and then according to the present invention, can be simultaneously or common sequentially suppressed.

The specific descriptions of invention

According to first embodiment, the present invention relates to a certain pharmaceutical composition (such as combination products), including (i) MET inhibitor (ii) EGFR inhibitor or its respectively pharmaceutically-acceptable salts or its respective prodrug, and at least one pharmaceutically acceptable load Body.

Another embodiment of the present invention provides a certain amount of combination (such as combination product), which effectively treats EGFR jointly The disease that tyrosine kinase activity and/or MET tyrosine kinase activity mediate, especially cancer, the combination include combined partner (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor or its respective pharmaceutically-acceptable salts, and extremely A kind of few pharmaceutically acceptable carrier material.

Another embodiment be related to using the present invention combination (such as combination product) treatment EGFR tyrosine kinase activity and/or The disease that MET tyrosine-kinase activity mediates, especially cancer.

Another embodiment is related to using following combination: (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine-kinase Enzyme inhibitor or its respective pharmaceutically-acceptable salts, for producing for treating EGFR tyrosine kinase activity and/or MET junket The disease that histidine kinase activity mediates, especially cancer, drug or drug products.

Another embodiment is related to following combined therapy EGFR tyrosine kinase activity and/or MET tyrosine-kinase enzyme activity Property the disease that mediates, especially cancer, method: (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibit Agent or its respective pharmaceutically-acceptable salts.

Another embodiment is related to treating the disease that EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediate Disease, especially cancer, method, the method includes such as warm-blooded animal of the object to needs especially people give it is a effective amount of containing (i) combination of EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor or combination product.

Another embodiment of the present invention is related to drug products or commercial packing containing combination product of the present invention, especially Its together with treatment EGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediate disease (especially cancer) in its Simultaneously, the specification for separately or sequentially using (especially common active), particularly for treating EGFR tyrosine-kinase enzyme activity Property and/or the disease that mediates of MET tyrosine kinase activity, especially cancer.

Another embodiment of the present invention is related to using (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine-kinase Enzyme inhibitor or its respectively pharmaceutically-acceptable salts to prepare combination (such as combination product) of the present invention.

Following definition shows the particularly embodiment with general features or expression, can be used for described in the context Replace a kind of, more than one or all general features or expression in embodiment of the present invention, thus generates the present invention particularly Embodiment.

In useful MET tyrosine kinase inhibitor of the present invention, WO 2011/018454 (is incorporated by reference this Text, especially with respect to the compound disclosed in classes of compounds and its) those disclosed is specific embodiment, especially formula Those of (i),

Wherein

Y is C or N；

X is CH or N；

B is CH or N；

A is ring；

To which when X is CH and B is N, ring A is ring Ai or ring Aii；

When X is N and B is N, ring A is Aiii；

With when X is N and B is N or X is N and when B is CH, ring A is Ai；

R¹It is the group selected from i, ii and iii:

Wherein R⁵It is heteroaryl；

R⁶It is hydrogen, deuterium, OH, methyl or halogen；

R⁷It is hydrogen, deuterium, halogen or (C₁-C₃) alkyl, wherein (the C₁-C₃) alkyl is optionally independently selected from OH and halogen One or more substituent groups replace；

Or R⁶And R⁷Carbon in connection is formed together cyclopropyl, wherein the cyclopropyl is optionally replaced by methyl；

N is 0,1 or 2；

R²It is hydrogen, NH₂Or (C₁-C₄) alkyl, wherein (the C₁-C₄) alkyl is optionally independently selected from OH, NH₂And halogen One or more substituent groups of element replace；

R³It is hydrogen ,-CONH₂、-CONH(C₁-C₄) alkyl ,-CONH phenyl, wherein the phenyl of the CONH phenyl is optionally With one or more halogens ,-(C₁-C₄) alkyl ,-CO (C₁-C₄) alkyl ,-CO₂(C₁-C₄) alkyl, phenyl, heteroaryl ,-CO be miscellaneous Aryl ,-CSNH₂、-CSNH(C₁-C₄) alkyl ,-CSNH benzyl ,-SO₂(C₁-C₄) alkyl or-COCH₂Heterocycle replaces, described miscellaneous Ring group is optionally by (C₁-C₃) alkyl substitution；

R⁴It is hydrogen or (C₁-C₃) alkyl；

Or R³And R⁴Nitrogen in connection is formed together 5 or 6 yuan of saturations or the unsaturated monocyclic groups in part comprising 1 In conjunction with R³And R⁴Ring N atom and optional 1 additional ring heteroatom for being independently selected from N, O and S, wherein the monocyclic groups Replaced with 1 or 2=O substituent group；

Or its pharmaceutically-acceptable salts.

It is especially preferred as the compound of formula I group of MET tyrosine kinase inhibitor, entitled (E) -2- (1- (3- ((7- fluorine Quinoline -6- base) methyl) imidazo [1,2-b] pyridazine -6- base) ethylidene) semicarbazides (hereinafter also referred to Cpd.A), under having Formula:

Referring to WO 11 018454, embodiment 1.

In useful MET tyrosine kinase inhibitor of the present invention, WO 2008/064157 (is incorporated by reference this Text, especially with respect to disclosed compound and classes of compounds) inhibitor disclosed in those is also referred to specific embodiment And its production divides method, especially with the compound of formula III:

Or its pharmaceutically-acceptable salts or its prodrug, in which:

A is N or CR³；

Cy¹It is aryl, heteroaryl, naphthenic base or Heterocyclylalkyl, is respectively optionally replaced with 1,2,3,4 or 5-W-X-Y-Z；

Cy²It is aryl, heteroaryl, naphthenic base or Heterocyclylalkyl, respectively optionally with 1,2,3,4 or 5-W '-X '-Y '-Z ' Replace；

L¹It is (CR⁴R⁵)_m,(CR⁴R⁵)_p(cyclic alkylene)-(CR⁴R⁵)_q,(CR⁴R⁵)_p(arlydene)-(CR⁴R⁵)_q, (CR⁴R⁵)_p(heterocyclic hydrocarbylene)-(CR⁴R⁵)_q,(CR⁴R⁵)_p(heteroarylidene)-(CR⁴R⁵)_q,(CR⁴R⁵)_pO(CR⁴R⁵)_q, (CR⁴R⁵)_pS(CR⁴R⁵)_q,(CR⁴R⁵)_pC(O)(CR⁴R⁵)_q,(CR⁴R⁵)_pC(O)NR⁶(CR⁴R⁵)_q,(CR⁴R⁵)_pC(O)O(CR⁴R⁵)_q, (CR⁴R⁵)_pOC(O)(CR⁴R⁵)_q,(CR⁴R⁵)_pOC(O)NR⁶(CR⁴R⁵)_q,(CR⁴R⁵)_pNR⁶(CR⁴R⁵)_q,(CR⁴R⁵)_pNR⁶C(O)NR⁶ (CR⁴R⁵)_q,(CR⁴R⁵)_pS(O)(CR⁴R⁵)_q,(CR⁴R⁵)_pS(O)NR⁶(CR⁴R⁵)_q,(CR⁴R⁵)_pS(O)₂(CR⁴R⁵)_q, or (CR⁴R⁵)_pS(O)₂NR⁶(CR⁴R⁵)_q, wherein the cyclic alkylene, arlydene, heterocyclic hydrocarbylene or heteroarylidene are optionally independently selected from 1,2 or 3 substituent group below replaces: Cy³, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenated sulphur Alkyl (halosulfanyl), CN, NO₂,N₃,OR^a,SR^a,C(O)R^b,C(O)NR^cR^d,C(O)OR^a,OC(O)R^b,OC(O)NR^cR^d, NR^cR^d,NR^cC(O)R^b,NR^cC(O)NR^cR^d,NR^cC(O)OR^a, C (=NR^g)NR^cR^d,NR^cC (=NR^g)NR^cR^d,P(R^f)₂,P (OR^e)₂,P(O)R^eR^f,P(O)OR^eOR^f,S(O)R^b,S(O)NR^cR^d,S(O)₂R^b,NR^cS(O)₂R^bWith S (O)₂NR^cR^d；

L²It is (CR⁷R⁸)_r,(CR⁷R⁸)_s(cyclic alkylene)-(CR⁷R⁸)_t,(CR⁷R⁸)_s(arlydene)-(CR⁷R⁸)_t, (CR⁷R⁸)_s(heterocyclic hydrocarbylene)-(CR⁷R⁸)_t,(CR⁷R⁸)_s(heteroarylidene)-(CR⁷R⁸)_t,(CR⁷R⁸)_sO(CR⁷R⁸)_t, (CR⁷R⁸)_sS(CR⁷R⁸)_t,(CR⁷R⁸)_sC(O)(CR⁷R⁸)_t,(CR⁷R⁸)_sC(O)NR⁹(CR⁷R⁸)_t,(CR⁷R⁸)_sC(O)O(CR⁷R⁸)_t, (CR⁷R⁸)_sOC(O)(CR⁷R⁸)_t,(CR⁷R⁸)_sOC(O)NR⁹(CR⁷R⁸)_t,(CR⁷R⁸)_sNR⁹(CR⁷R⁸)_t,(CR⁷R⁸)_sNR⁹C(O)NR⁹ (CR⁷R⁸)_t,(CR⁷R⁸)_sS(O)(CR⁷R⁸)_t,(CR⁷R⁸)_sS(O)NR⁷(CR⁸R⁹)_t,(CR⁷R⁸)_sS(O)₂(CR⁷R⁸)_t, or (CR⁷R⁸)_sS(O)₂NR⁹(CR⁷R⁸)_t, wherein the cyclic alkylene, arlydene, heterocyclic hydrocarbylene or heteroarylidene are optionally independently selected from 1,2 or 3 substituent group below replaces: Cy⁴, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenated sulphur Alkyl, CN, NO₂,N₃,OR^a1,SR^a1,C(O)R^b1,C(O)NR^c1R^d1,C(O)OR^a1,OC(O)R^b1,OC(O)NR^c1R^d1,NR^c1R^d1, NR^c1C(O)R^b1,NR^c1C(O)NR^c1R^d1,NR^c1C(O)OR^a1, C (=NR^g)NR^c1R^d1,NR^c1C (=NR^g)NR^c1R^d1,P(R^f1)₂,P (OR^e1)₂,P(O)R^e1R^f1,P(O)OR^e1OR^f1,S(O)R^b1,S(O)NR^c1R^d1,S(O)₂R^b1,NR^c1S(O)₂R^b1With S (O)₂NR^c1R^d1；

R¹It is H or-W "-X "-Y "-Z "；

R²It is H, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, CN, NO₂,OR^A,SR^A,C(O)R^B,C (O)NR^CR^D,C(O)OR^A,OC(O)R^B,OC(O)NR^CR^D,NR^CR^D,NR^CC(O)R^B,NR^CC(O)NR^CR^D,NR^CC(O)OR^A,S(O) R^B,S(O)NR^CR^D,S(O)₂R^B,NR^CS(O)₂R^BOr S (O)₂NR^CR^D；

R³It is H, naphthenic base, aryl, Heterocyclylalkyl, heteroaryl, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogen Substituted alkyl, CN, NO₂,OR^A,SR^A,C(O)R^B,C(O)NR^CR^D,C(O)OR^A,OC(O)R^B,OC(O)NR^CR^D,NR^CR^D,NR^CC(O) R^B,NR^CC(O)NR^CR^D,NR^CC(O)OR^A,S(O)R^B,S(O)NR^CR^D,S(O)₂R^B,NR^CS(O)₂R^BWith S (O)₂NR^CR^D；It is wherein described Naphthenic base, aryl, Heterocyclylalkyl, heteroaryl or C_1-6Alkyl is optionally independently selected from 1,2 or 3 substituent group below and is replaced: Cy⁵, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenosulfanes base, CN, NO₂,N₃,OR^a1,SR^a1,C (O)R^b1,C(O)NR^c1R^d1,C(O)OR^a1,OC(O)R^b1,OC(O)NR^c1R^d1,NR^c1R^d1,NR^c1C(O)R^b1,NR^c1C(O)NR^c1R^d1, NR^c1C(O)OR^a1, C (=NR^g)NR^c1R^d1,NR^c1C (=NR^g)NR^c1R^d1,P(R^f1)₂,P(OR^e1)₂,P(O)R^e1R^f1,P(O) OR^e1OR^f1,S(O)R^b1,S(O)NR^c1R^d1,S(O)₂R^b1,NR^c1S(O)₂R^b1With S (O)₂NR^c1R^d1；

Or R²With-L²-Cy²It is joined together to form the group with following formula:

Its middle ring B is fused aromatic rings or fused heteroaromatic ring, is respectively optionally replaced with 1,2 or 3-W '-X '-Y '-Z '；

R⁴And R⁵It is independently selected from H, halogen, OH, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Alkoxy, alkoxyalkyl, cyanogen Base alkyl, Heterocyclylalkyl, naphthenic base, C_1-6Halogenated alkyl, CN and NO₂；

Or R⁴And R⁵C atom in connection is formed together 3,4,5,6 or 7- member naphthenic base or heterocycloalkyl ring, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: halogen, OH, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Alkane Oxygroup, alkoxyalkyl, cyanoalkyl, Heterocyclylalkyl, naphthenic base, C_1-6Halogenated alkyl, CN and NO₂；

R⁶It is H, C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl；

R⁷And R⁸It is independently selected from H, halogen, OH, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Alkoxy, C_1-6Halogenated alkyl, CN and NO₂；

Or R⁷And R⁸C atom in connection is formed together 3,4,5,6 or 7- member naphthenic base or heterocycloalkyl ring, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: halogen, OH, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Alkane Oxygroup, C_1-6Halogenated alkyl, CN and NO₂；

R⁹It is H, C_1-6Alkyl, C_2-6Alkenyl or C_2-6Alkynyl；

W, W ' and W " independently lacks or is independently selected from C_1-6Alkylene, C_2-6Alkenylene, C_2-6Alkynylene, O, S, NR^h、CO、 COO、CONR^h、SO、SO₂、SONR^hAnd NR^hCONRⁱ, wherein each C_1-6Alkylene, C_2-6Alkenylene and C_2-6Alkynylene is optionally only It founds 1,2 or 3 substituent group selected from the following to replace: halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, OH, C_1-6Alkoxy, C_1-6It is halogenated Alkoxy, amino, C_1-6Alkyl amino and C_2-8Dialkyl amido；

X, X ' and X " independently lacks or is independently selected from C_1-6Alkylene, C_2-6Alkenylene, C_2-6Alkynylene, arlydene, ring Asia hydrocarbon Base, heteroarylidene and heterocyclic hydrocarbylene, wherein each C_1-6Alkylene, C_2-6Alkenylene, C_2-6Alkynylene, arlydene, cyclic alkylene, Heteroarylidene and heterocyclic hydrocarbylene are optionally independently selected from 1,2 or 3 substituent group below and are replaced: halogen, CN, NO₂、OH、 C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-8Alkoxyalkyl, C_1-6Alkoxy, C_1-6Halogenated alkoxy, C_2-8Alkoxyalkoxy group, naphthenic base, Heterocyclylalkyl, C (O) OR^j、C(O)NR^hRⁱ, amino, C_1-6Alkyl amino and C_2-8Dialkyl amido；

Y, Y ' and Y " independently lacks or is independently selected from C_1-6Alkylene, C_2-6Alkenylene, C_2-6Alkynylene, O, S, NR^h、CO、 COO、CONR^h、SO、SO₂、SONR^hAnd NR^hCONRⁱ, wherein each C_1-6Alkylene, C_2-6Alkenylene and C_2-6Alkynylene is optionally only It founds 1,2 or 3 substituent group selected from the following to replace: halogen, C_1-6Alkyl, C_1-6Halogenated alkyl, OH, C_1-6Alkoxy, C_1-6It is halogenated Alkoxy, amino, C_1-6Alkyl amino and C_2-8Dialkyl amido；

Z, Z ' and Z " is independently selected from H, halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenosulfanes Base, CN, NO₂、N₃、OR^a2、SR^a2、C(O)R^b2、C(O)NR^c2R^d2、C(O)OR^a2、OC(O)R^b2、OC(O)NR^c2R^d2、NR^c2R^d2、 NR^c2C(O)R^b2、NR^c2C(O)NR^c2R^d2、NR^c2C(O)OR^a2, C (=NR^g)NR^c2R^d2、NR^c2C (=NR^g)NR^c2R^d2、P(R^f2)₂、P (OR^e2)₂、P(O)R^e2R^f2、P(O)OR^e2OR^f2、S(O)R^b2、S(O)NR^c2R^d2、S(O)₂R^b2、NR^c2S(O)₂R^b2、S(O)₂NR^c2R^d2、 Aryl, naphthenic base, heteroaryl and Heterocyclylalkyl, wherein the C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, naphthenic base, heteroaryl Base and Heterocyclylalkyl are optionally independently selected from 1,2,3,4 or 5 substituent group below and are replaced: halogen, C_1-6Alkyl, C_2-6Alkene Base, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenosulfanes base, CN, NO₂、N₃、OR^a2、SR^a2、C(O)R^b2、C(O)NR^c2R^d2、C(O) OR^a2、OC(O)R^b2、OC(O)NR^c2R^d2、NR^c2R^d2、NR^c2C(O)R^b2、NR^c2C(O)NR^c2R^d2、NR^c2C(O)OR^a2, C (=NR^g) NR^c2R^d2、NR^c2C (=NR^g)NR^c2R^d2、P(R^f2)₂、P(OR^e2)₂、P(O)R^e2R^f2、P(O)OR^e2OR^f2、S(O)R^b2、S(O) NR^c2R^d2、S(O)₂R^b2、NR^c2S(O)₂R^b2With S (O)₂NR^c2R^d2；

Wherein atom 2 mutually o- W-X-Y-Z in connection optional formation 4-20 member naphthenic base fused rings or 4-20 together Membered heterocycloalkyl fused rings are respectively optionally independently selected from 1,2 or 3 substituent group below and are replaced: halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenosulfanes base, CN, NO₂、OR^a3、SR^a3、C(O)R^b3、C(O)NR^c3R^d3、C(O) OR^a3、OC(O)R^b3、OC(O)NR^c3R^d3、NR^c3R^d3、NR^c3C(O)R^b3、NR^c3C(O)NR^c3R^d3、NR^c3C(O)OR^a3, C (=NR^g) NR^c3R^d3、NR^c3C (=NR^g)NR^c3R^d3、S(O)R^b3、S(O)NR^c3R^d3、S(O)₂R^b3、NR^c3S(O)₂R^b3、S(O)₂NR^c3R^d3, virtue Base, naphthenic base, heteroaryl and Heterocyclylalkyl；

Wherein atom 2 mutually o- W '-X '-Y '-Z ' in connection together optional formation 4-20 member naphthenic base fused rings or 4-20 membered heterocycloalkyl fused rings are respectively optionally independently selected from 1,2 or 3 substituent group below and are replaced: halogen, C_1-6Alkane Base, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenosulfanes base, CN, NO₂、OR^a3、SR^a3、C(O)R^b3、C(O)NR^c3R^d3、C (O)OR^a3、OC(O)R^b3、OC(O)NR^c3R^d3、NR^c3R^d3、NR^c3C(O)R^b3、NR^c3C(O)NR^c3R^d3、NR^c3C(O)OR^a3, C (= NR^g)NR^c3R^d3、NR^c3C (=NR^g)NR^c3R^d3、S(O)R^b3、S(O)NR^c3R^d3、S(O)₂R^b3、NR^c3S(O)₂R^b3、S(O)₂NR^c3R^d3、 Aryl, naphthenic base, heteroaryl and Heterocyclylalkyl；

Cy³、Cy⁴And Cy⁵It is independently selected from aryl, naphthenic base, heteroaryl and Heterocyclylalkyl, is respectively optionally independently selected from 1,2,3,4 or 5 substituent group below replaces: halogen, C_1-6Alkyl, C_2-6Alkenyl, C_2-6Alkynyl, C_1-6Halogenated alkyl, halogenated sulphur Alkyl, CN, NO₂、N₃、OR^a4,SR^a4、C(O)R^b4、C(O)NR^c4R^d4、C(O)OR^a4、OC(O)R^b4、OC(O)NR^c4R^d4、NR^c4R^d4、 NR^c4C(O)R^b4、NR^c4C(O)NR^c4R^d4、NR^c4C(O)OR^a4, C (=NR^g)NR^c4R^d4、NR^c4C (=NR^g)NR^c4R^d4、P(R^f4)₂、P (OR⁴)₂、P(O)R^e4R^f4、P(O)OR^e4OR^f4、S(O)R^b4、S(O)NR^c4R^d4、S(O)₂R^b4、NR^c4S(O)₂R^b4With S (O)₂NR^c4R^d4；

R^AIt is H, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl, wherein described C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally independently selected from below 1,2 Or 3 substituent groups replace: OH, CN, amino, halogen and C_1-4Alkyl；

R^BIt is H, C_1-4Alkyl, C_2-4Alkenyl, C_2-4Alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl, wherein described C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynyl, naphthenic base, Heterocyclylalkyl, aryl or heteroaryl are optionally independently selected from below 1,2 or 3 substituent groups replace: OH, CN, amino, halogen and C_1-4Alkyl；

R^CAnd R^DIt is independently selected from H, C_1-4Alkyl, C_2-4Alkenyl or C_2-4Alkynyl, wherein the C_1-4Alkyl, C_2-4Alkenyl or C_2-4 Alkynyl is optionally independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen and C_1-4Alkyl；

Or R^CAnd R^DN atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively optional Ground is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen and C_1-4Alkyl；

R^a、R^a1、R^a2、R^a3And R^a4It is independently selected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, ring Alkyl, heteroaryl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl and hetercycloalkylalkyl, wherein the C_1-6 Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl, aryl alkyl, heteroaryl Alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, Amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

R^b、R^b1、R^b2、R^b3And R^b4It is independently selected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, ring Alkyl, heteroaryl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl and hetercycloalkylalkyl, wherein the C_1-6 Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl, aryl alkyl, heteroaryl Alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, Amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

R^cAnd R^dIt is independently selected from H, C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkanes Base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl, wherein the C_1-10Alkyl, C_1-6 Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkanes Base alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

Or R^cAnd R^dN atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively optional Ground is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogen Substituted alkyl and C_1-6Halogenated alkoxy；

R^c1And R^d1It is independently selected from H, C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkanes Base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl, wherein the C_1-10Alkyl, C_1-6 Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkanes Base alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

Or R^c1And R^d1N atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6 Halogenated alkyl and C_1-6Halogenated alkoxy；

R^c2And R^d2It is independently selected from H, C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkanes Base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, cycloalkyl aryl, aryl-heterocyclic alkane Base, aryl heteroaryl, biaryl, Heteroarylcycloalkyl, heteroarylheterocycloalkyl, Heteroarylaryl and two heteroaryls, wherein institute State C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, aryl alkyl, Heteroaryl alkyl, cycloalkyl-alkyl, hetercycloalkylalkyl, cycloalkyl aryl, arylheterocycloalkyl, aryl heteroaryl, biaryl, Heteroarylcycloalkyl, heteroarylheterocycloalkyl, Heteroarylaryl and two heteroaryls are respectively optionally independently selected from below 1,2 Or 3 substituent groups replace: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl, C_1-6Halogenated alkoxy, Hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C (O) OR^a4、C(O)R^b4、S(O)₂R^b3, alkoxyalkyl and alkyloxy-alkoxy；

Or R^c2And R^d2N atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6 Halogenated alkyl, C_1-6Halogenated alkoxy, hydroxyalkyl, cyanoalkyl, aryl, heteroaryl, C (O) OR^a4、C(O)R^b4、S(O)₂R^b3, alkane Oxyalkyl and alkyloxy-alkoxy；

R^c3And R^d3It is independently selected from H, C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, cycloalkanes Base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl, wherein the C_1-10Alkyl, C_1-6 Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkanes Base alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

Or R^c3And R^d3N atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6 Halogenated alkyl and C_1-6Halogenated alkoxy；

R^c4And R^d4It is independently selected from H, C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-66Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, ring Alkyl, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl, wherein the C_1-10Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, heteroaryl, naphthenic base, Heterocyclylalkyl, aryl alkyl, heteroaryl alkyl, Cycloalkyl-alkyl or hetercycloalkylalkyl are optionally independently selected from 1,2 or 3 substituent group below and are replaced: OH, CN, amino, Halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6Halogenated alkyl and C_1-6Halogenated alkoxy；

Or R^c4And R^d4N atom in connection is formed together 4-, 5-, 6- or 7- membered heterocycloalkyl or heteroaryl, respectively may be used Selection of land is independently selected from 1,2 or 3 substituent group below and is replaced: OH, CN, amino, halogen, C_1-6Alkyl, C_1-6Alkoxy, C_1-6 Halogenated alkyl and C_1-6Halogenated alkoxy；

R^e、R^e1、R^e2And R^e4It is independently selected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, (C_1-6Alkoxy)-C_1-6Alkane Base, C_2-6Alkynyl, aryl, naphthenic base, heteroaryl, Heterocyclylalkyl, aryl alkyl, cycloalkyl-alkyl, heteroaryl alkyl and heterocycle alkane Base alkyl；

R^f、R^f1、R^f2And R^f4It is independently selected from H, C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, cycloalkanes Base, heteroaryl and Heterocyclylalkyl；

R^gIt is H, CN and NO₂；

R^hAnd RⁱIt is independently selected from H and C_1-6Alkyl；

R^jIt is H, C_1-6Alkyl, C_1-6Halogenated alkyl, C_2-6Alkenyl, C_2-6Alkynyl, aryl, naphthenic base, heteroaryl, heterocycle alkane Base, aryl alkyl, heteroaryl alkyl, cycloalkyl-alkyl or hetercycloalkylalkyl；

M is 0,1,2,3,4,5 or 6；

P is 0,1,2,3 or 4；

Q is 0,1,2,3 or 4；

R is 0,1,2,3,4,5 or 6；

S is 0,1,2,3 or 4；With

T is 0,1,2,3 or 4.

In some embodiments, useful formula III compound of the present invention has formula III A:

In some embodiments, useful formula III compound of the present invention has formula III B:

Especially wherein:

A is CH or N, especially N；

L¹It is (CR⁴R⁵)_m, wherein each R⁴And R⁵It is H or C independently of one another_1-6Alkyl and m are 0,1 or 2,

L²It is (CR⁷R⁸)_r, wherein each R⁷And R⁸It is H or C independently of one another_1-6Alkyl and r are 0,1 or 2,

R¹It is H, halogen or C_1-6Alkyl；

R²It is H, halogen or C_1-6Alkyl；With

Cy²It is aryl, especially phenyl, wherein the aryl or phenyl are unsubstituted or be independently selected from the 1-3 of the following group Group replaces :-C (=O)-NR^c2R^d2And halogen, wherein R^c2And R^d2It is independently selected from H, C_1-10Alkyl and C_1-6Halogenated alkyl；

Wherein the compound can also or alternatively exist in the form of pharmaceutically-acceptable salts.

Particularly preferred formula III compound group, the entitled fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-methyl)-imidazo [1,2-b] triazine -2- base] benzamide (hereinafter also referred to Cpd.B), there is following formula:

Referring to WO 2008/064157, embodiment 7.This is most preferred MET tyrosine kinase inhibitor.

Although two kinds of MET inhibitor (compound A and compound B) of special interest mentioned above, the scope of the invention Including other MET inhibitor.

For example, this kind of other MET inhibitor (also including to the active compound of HGF or antibody) be selected from it is following (including Its pharmaceutically-acceptable salts and its prodrug):

Gram azoles replaces Buddhist nun (Pfizer (Pfizer)) (aka PF02341066) (a kind of highly preferred compound), has following formula

Card is rich to replace Buddhist nun (Exelixis) (aka XL-184) (a kind of highly preferred compound), has following formula

Tivatinib (A Kuli (ArQule), Japanese Daiichi Pharmaceutical Co., Ltd. (daiichi), Kyowa Co., Ltd. (Kyowa)) (aka ARQ-197) (a kind of highly preferred compound) has following formula

A kind of foretinib (Exelixis, GlaxoSmithKline PLC (GlaxoSmithKline)) (aka XL-880) (height Preferred compound), there is following formula

MGCD-265 (MG company (MethylGene)) (a kind of highly preferred compound) has following formula

AMG-208 (Amgen (Amgen)) (seeing also WO 2008/008539) has following formula

AMG-337 (Amgen)；

JNJ-38877605 (Johson & Johnson (Johnson&Johnson)) (aka BVT051) (sees also WO 2007/ 075567), there is following formula

MK-8033 (Merck & Co., Inc. (Merck&Co)) has following formula

E-7050 (defends material (Eisai)), has following formula

EMD-1204831 (Merck Xue Lannuo (Merck Serono))；

EMD-1214063 (Merck Xue Lannuo) (sees also WO 2007/019933), has following formula

Amuvatinib (supergene company (SuperGen)) (aka MP-470) has following formula

LY-2875358 (Li Lai company (Eli Lilly))；

BMS-817378 (Bristol-Myers Squibb Co. (BristolMyersSquibb), first sign medicine company (Simcere)), tool There is following formula

DP-3590(Deciphera)；

(Suzhou Ace roc object researches and develops Co., Ltd (Suzhou Ascepion to ASP-08001 Pharmaceuticals))；

HM-5016504 (and Huang is medical (Hutchison Medipharma))；

PF-4217903 (Pfizer) (seeing also US2007/0265272) has following formula

Or

SGX523 (SGX) (seeing also WO 2008/051808) has following formula

Or antibody or relevant molecule, such as

For ficlatuzumab (AVEO) monoclonal antibody (preferably) of HGF；For the onartuzumab (Roche of MET (Roche)) monoclonal antibody (preferably)；For rilotuzumab (Amgen) monoclonal antibody (preferably) of HGF；For the Tak-701 of HGF (military field pharmacy (Takeda)) monoclonal antibody；For LA-480 (Li Lai company) monoclonal antibody of MET；And/or the LY.2875358 for MET (Li Lai company) monoclonal antibody.

In useful EGFR tyrosine kinase inhibitor of the present invention, those of specifically mentioned quinazoline amine type.

Particularly, WO 96/30347 (being totally incorporated herein by reference, be related to generic and specific compound disclosed in it) is public The EGFR tyrosine kinase inhibitor opened refers to especially thering is 4- (replacing phenylamino) quinoline azoles of following formula in this as first group Quinoline derivant

With its pharmaceutically-acceptable salts and prodrug, wherein

Each Ra, Rb, Rc and Rd are independently selected from hydrogen, halogen, hydroxyl, amino, hydroxylamino, carboxyl, C_1-8Alkoxy carbonyl group, nitro, Guanidine radicals, urea groups, carbamyl, cyano, trifluoromethyl, (R⁶)₂N- carbonyl and phenyl-W- alkyl, wherein W is selected from singly-bound, O, S and NH；

Or each Ra or Rb are independently selected from cyano-C_1-8Alkyl and R9, wherein R9 is selected from R5, R5O, (R5)₂N, R7C (=O), R5ONH, A and R5Y；Wherein

R5 is C_1-8Alkyl；

R6 is hydrogen or R5, wherein then its is identical or different if there is more than one R5；

R7 is R5, R5O or (R6)₂N；

A be selected from piperidyl, morpholino, pyrrolidinyl and 4-R6- piperazine -1- base, imidazoles -1- base, 4- pyridone -1- base, Carboxyl-C_1-8Alkyl, phenoxy group, phenyl, benzenesulfonyl, C_2-8Alkenyl, (R5)₂N- carbonyl-C_1-8Alkyl；With

Y is selected from S, SO, SO₂；R5, R5O and (R5)₂Moieties in N optionally replace through halogen or R9, and wherein R9 is such as Upper definition, and wherein gained group optionally replaces through halogen or R9, on condition that nitrogen, oxygen or sulphur atom and another hetero atom cannot Same carbon atom is connected, further on condition that Ra and Rb cannot include more than 3 R9 units.

Or each Ra or Rb are independently selected from R5- sulfonamido, phthalimido-C_1-8Alkyl sulfonyl amino, benzamide Base, benzenesulfonylamino, 3- phenylcarbamido, 2- oxo-pyrrolidine -1- base, 2,5- dioxo pyrrolidin -1- base and R10-C_2-4Alkanol Base amino, wherein R10 is selected from halogen, R5O, C_2-4Alkanol hydroxyl, B7C (=O) and (R6)₂N；And the wherein benzene of Ra or Rb Formamide or benzenesulfonylamino or phenyl or phenoxy group or anilino- or benzenesulfonyl (phenylsulfanyl) substituent group can Choosing carries 1 or 2 halogen, C_1-8Alkyl, cyano, mesyl or C_1-8Alkoxy substituent；

Or any 2 Ra and Rb carbon in connection includes 5-8 member ring together, containing at least 1 or 2 selected from oxygen, sulphur or The hetero atom of nitrogen；And wherein the alkyl group and moieties of alkoxy or alkyl amino can be straight chain, if or by least three Carbon is constituted, then can be branch or annular；

Each Rc and Rd is independently selected from hydrogen, optionally substituted C_1-8Alkyl, halogen, hydroxyl, can be chosen optionally substituted amino The hydroxyl in generation；Or azido or R11- acetenyl are come from, wherein R11 is selected from hydrogen, optionally substituted C_1-8Alkyl, wherein described take Dai Ji is selected from hydrogen, amino, hydroxyl, R5O, R5NH and (R5)₂N；

And X is N or C (CN), on condition that substituent R 5 cannot include another substituent R 5；Especially with following formula Compound

The entitled Erlotinib of its INN (withSale, the Roche of Basel, SUI)=N- (3- acetylenylbenzene Base) -6,7- bis--(2- methoxy ethoxy) quinazoline -4- amine or its pharmaceutically-acceptable salts.For example, the reality of WO 9630347 It applies example 20 and discloses the compound and its manufacture.

Particularly, WO 96/33980 or US 5,616,582 (are totally incorporated herein by reference, are related to generic disclosed in it And specific compound) disclosed in EGFR tyrosine kinase inhibitor referred in this as second group, especially with following formula 4- (replacing phenylamino) quinazoline derivant

Wherein

X is N；

Ra is C_1-8Alkoxy；

Rb is two-(C_1-8Alkyl)-amino-C_1-Alkoxy, pyrrolidin-1-yl-C_1-8Alkoxy, piperidines-C_1-8Alkoxy, Morpholino-C_1-8Alkoxy, piperazine -1- base-C_1-8Alkoxy, 4-C_1-8Alkyl piperazine -1- base-C_1-8Alkoxy, imidazoles -1- base - C_1-8Alkoxy, two-(C_1-8Alkoxy -C_1-8Alkyl)-amino-C_1-8Alkoxy, thiomorpholine generation-C_1-8Alkoxy, 1- oxygen thiomorpholine Generation-C_1-8Alkoxy or 1,1- oxygen thiomorpholine-C_1-8Alkoxy, and wherein any of the above-described includes the CH2 for being not connected with N or O atom The Rb substituent group of (methylene) group can be selected on the CH2 group and carry hydroxyl substituent；

And each Rc and Rd are halogen, trifluoromethyl or C independently of one another_1-8Alkyl；

Or its pharmaceutically-acceptable salts or prodrug, especially with the compound of following formula

The entitled Gefitinib of its INN (withSale, AstraZeneca (AstraZeneca))=N- (the chloro- 4- of 3- Fluorophenyl) -7- methoxyl group -6- [3- (morpholine -4- base) propoxyl group] quinazoline -4- amine or its pharmaceutically-acceptable salts, referring to W =96/33980 embodiment 1.Embodiment of the present invention particularly preferably this compound or its pharmaceutically-acceptable salts.

Particularly, 6 US, 391,874, US 7,157,466, US 6,828,320, US 6,713,485 and especially US 6,727,256 (=WO9935146) (being totally incorporated herein by reference, be related to generic and specific compound disclosed in it) are disclosed EGFR tyrosine kinase inhibitor refers to that 4- (replacing phenylamino) quinazoline especially with following formula spreads out in this as third group Biology

Wherein X is N；

Ra's and Rb first is that group CH₃SO₂CH₂CH₂NHCH₂- Ar-, wherein Ar is selected from phenyl, furyl, thiophenyl, pyrroles Base and thiazolyl are respectively optionally replaced by 1 or 2 substituent group selected from the group below: 1 or 2 halogen, C_1-8Alkyl and C_1-8Alcoxyl Base；Another in Ra and Rb is selected from hydrogen, halogen, hydroxyl, C_1-8Alkyl, C_1-8Alkoxy, C_1-8Alkyl amino and two (C_1-8Alkane Base) amino；

One of Rc and Rd represent benzyl, it is halogenated-, dihalo-or three halogeno-benzyls, three halogenated methylbenzyls, benzoyl, pyrrole Pyridine methyl, pyridomethoxy, phenoxy group, benzyloxy, it is halogenated-, dihalo-or phenyl trihalide oxygroup, trihalomethyl group phenoxy group, Benzene sulfonyl or hydrogen；

It is in Rc and Rd the other is hydrogen or hydroxyl, halogen, C_1-8Alkyl, C_2-8Alkenyl, C_2-8Alkynyl, C_1-8Alkoxy, ammonia Base, C_1-8Alkyl amino, two (C_1-8Alkyl) amino, C_1-8Sulfanyl, C_1-8Alkyl sulphinyl, C_1-8Alkyl sulphonyl, C_1-8Alkane Base carbonyl, carboxyl, carbamyl, C_1-8Alkoxy carbonyl, C_1-8Silane alcohol base amino, N- (C_1-8Alkyl) carbamyl, N, bis- (C of N-_1-8Alkane Base) carbamyl, cyano, nitro or trifluoromethyl；

Or its pharmaceutically-acceptable salts or prodrug, especially with the compound of following formula

The entitled Lapatinib of its INN (with(U.S.),(Europe) sale, GlaxoSmithKline PLC), Entitled N- [the chloro- 4- of 3- (3- fluorine benzyloxy) phenyl] -6- { 5- [4- (mesyl) -2- nitrogen butyl] -2- furyl } quinazoline - 4- amine or its pharmaceutically-acceptable salts or prodrug, see, for example, WO9935146 (embodiment 29).

Particularly, WO97/38983 or especially WO2000031048 (are totally incorporated herein by reference, are related to disclosed in it Generic and specific compound) disclosed in EGFR tyrosine kinase inhibitor referred in this as the 4th group, especially have following formula 4- (replace phenylamino) quinazoline derivant

Or its pharmaceutically-acceptable salts or prodrug, wherein

X is N,

Ra is-D-E-F and Rb is-SR^4*, halogen ,-OR^4*、-NHR^3*Or hydrogen, or

Rb is-D-E-F and Ra is-SR^4*, halogen ,-OR^4*、-NHR^3*Or hydrogen,

Wherein, respectively,

D is-N (R^2*)-、-O-、-CH(R^2*)-、-N(R^2*)-NH-、-N(R^2*)-O-、-CH(R^2*)-NH-、-CH(R^2*)- O-、-CH(R^2*)-CH₂-、-NH-CH(R^2*)-、-O-CH(R^2*)-、-S-CH(R^2*)-or missing；

E is-C (=O)-,-S (=O)₂,-P (=O) (OR^2*)-or-S (=O)-,

F is-C (R^1*)=CHR^5*、-C≡C-R^5*Or-C (R^1*)=C=CHR^5*；

On condition that when E is S (=O)₂Or when-S (=O)-, D is not-NH-CH (R^2*)-or-O-CH (R^2*)-；

R^1*It is hydrogen, halogen or C_1-8Alkyl,

R^2*、R^3*And R^4*It is independently hydrogen, C_1-8Alkyl ,-(CH₂)_n*- N- piperidyl ,-(CH₂)_n*- N- piperazinyl ,- (CH₂)_n*-N₁Piperazinyl (N₄-C_1-6Alkyl) ,-(CH₂)_n*- N- pyrrolidinyl ,-(CH₂)_n*- N- pyridyl group ,-(CH₂)_n*- N- miaow Oxazolyl ,-(CH₂)_n*- N- morpholinyl ,-(CH₂)_n*- N- thiomorpholine ,-(CH₂)_n*- N- hexahydro azatropylidene base or substituted C_1-8Alkane Base, wherein the substituent group is selected from-OH ,-NH₂Or-N (B*) (A*), wherein A* and B* is independently hydrogen, C_1-8Alkyl ,- (CH₂)_n*-OH,-(CH₂)_n*- N- piperidyl ,-(CH₂)_n*- N- piperazinyl ,-(CH₂)_n*-N₁Piperazinyl (N₄-C_1-8Alkyl) ,- (CH₂)_n*- N- pyrrolidinyl ,-(CH₂)_n*- N- pyridyl group and-(CH₂)_n*TMSIM N imidazole base；

Rc and Rd is independently hydrogen, halogen, C_1-8Alkyl, C_3-8Naphthenic base, C_1-8Alkoxy, C_3-8Cycloalkyloxy, nitro, C_1-8Perfluoroalkyl, hydroxyl, C_1-8Acyloxy, amino ,-NH (C_1-8Alkyl) ,-N (C_1-8Alkyl)₂,-NH(C_3-8Naphthenic base) ,-NH (C_3-8Naphthenic base)₂, methylol, C_1-8Acyl group, cyano, azido, C_1-8Alkylthio, C_1-8Sulfinylalkyl, C_1-8Sulfonyl Alkyl, C_3-8Sulphur naphthenic base, C_3-8Sulfinyl naphthenic base, C_3-8Sulfonyl naphthenic base, sulfydryl, C_1-8Alkoxy carbonyl group, C_3-8Cycloalkanes oxygen Carbonyl, C_2-8Alkenyl, C_4-8Cycloalkenyl or C_2-8Alkynyl；

R^5*It is hydrogen, halogen, C_1-6Perfluoroalkyl, the fluoro- C of 1,1- bis-_1-6Alkyl, C_1-6Alkyl ,-(CH₂)_n*- N- piperidyl ,- (CH₂)_n*- N- piperazinyl ,-(CH₂)_n*-N₁Piperazinyl (N₄-C_1-8Alkyl) ,-(CH₂)_n*- N- pyrrolidinyl ,-(CH₂)_n*- N- pyrrole Piperidinyl ,-(CH₂)_n*TMSIM N imidazole base ,-(CH₂)_n*- N- morpholinyl ,-(CH₂)_n*- N- thiomorpholine ,-CH=CH₂,-CH=CH- C_1-8Alkyl ,-(CH₂)_n*- N- hexahydro azatropylidene base ,-(CH₂)_n*-NH₂、-(CH₂)_n*-NH-(C_1-8) alkyl ,-(CH₂)_n*-N(C_1-8 Alkyl)₂, -1- oxo-C_1-8Alkyl, carboxyl, C_1-8Alkoxy carbonyl group, N-C_1-8Alkyl-carbamyl, phenyl or substituted phenyl, Middle phenyl can have 1-3 to be independently selected from the substituent group of Rc and Rd or the monocycle heteroaryl selected from pyridyl group, thienyl and imidazole radicals Base, and R^5*In each C_1-8Alkyl can use-OH ,-NH₂Or NA*B* replaces, wherein A* and B* are as defined above；

R^6*It is hydrogen or C_1-8Alkyl；

It is 1-8 with n*, especially 1-4；Especially with the compound of following formula

The entitled Canertinib of its INN (Pfizer) (as being used as dihydrochloride) N- [4- [(the chloro- 4- fluorophenyl of 3-) ammonia Base] -7- (3- morpholine -4- base propoxyl group) quinazoline -6- base] propyl- 2- acrylamide or its pharmaceutically-acceptable salts or prodrug, tool Body is referring to WO2000031048.

Particularly, WO2005028443 (being totally incorporated herein by reference, be related to generic and specific compound disclosed in it) Disclosed EGFR tyrosine kinase inhibitor refers to especially thering is 4- (replacing phenylamino) quinoline of following formula in this as the 5th group Oxazoline derivative

Wherein X is C-CN；

Ra is C_1-8Alkoxy；

Rb is that [N '-is mono- or N ', N '-two (C by amino-or N-_1-8Alkyl)] amino }-C_4-8Enoyl-)-amino；

Rc is halogen or R₂**-(CH₂)_n**-R₃**-

Wherein R₂* is pyridyl group, thiophenyl, pyrimidine radicals, thiazolyl or phenyl, is respectively optionally selected from C_1-8Alkyl, C_1-8Up to 3 substituent groups of alkoxy and halogen replace, R₃* is-O- or-S- and n** is 0-8, preferably 0 or 1；

It is halogen with Rd；

Or its pharmaceutically-acceptable salts or prodrug, especially with the compound of following formula

The entitled pelitinib of its INN (Wyeth (Wyeth), be subordinate under Pfizer), entitled 2E)-N- [4- [(3- Chloro- 4- fluorophenyl) amino] -3- cyano -7- ethyoxyl -6- quinoline] -4- (dimethylamino) -2- crotonamide, referring to WO2005028443 (embodiment 20), or the compound with following formula

The entitled linatinib of its INN (Pfizer (Pfizer Inc.)), (2E)-N- [4- [[chloro- 4- [(pyridine-of 3- 2- yl) methoxyl group] phenyl] amino] -3- cyano -7- ethoxyquinoline -6- base] -4- (dimethylamino) but-2-enamides, referring to Such as the embodiment 2 of WO2005028443；

Or its respectively pharmaceutically-acceptable salts or prodrug.

In possible EGFR inhibitor, it is also mentioned antibody such as Cetuximab(Imclone Systems Inc. (ImClone Systems), Bristol Myers Squibb and Merck Group (Merck KgaA)), the antibody is chimeric (mouse/people) Monoclonal antibody works as EGF-R ELISA (EGFR) inhibitor, can such as intravenous administration.

The particular implementation of embodiment of the present invention is related to the EGRF inhibitor with following formula in each situation

Wherein

X is N or C (CN)；

Ra is selected from C_1-8Alkoxy or (C_1-8Alkoxy, 1- piperidin-1-yl, 1- piperazine -1- base, 4-C_1-8Alkyl-piperazin -1- Base, morpholine -1- base, thiomorpholine generation -1- base, S- oxo-thiomorpholin -1- base or S, S- dioxy thiomorpholine -1- base)-C_1-8Alkane Oxygroup；

Rb is selected from C_3-8Enoyl-, { [N '-is mono- or N ', N '-two (C by amino-or N-_1-8Alkyl)] amino }-C_4-8Alkene acyl Base)-amino, [(C_1-8Alkyl sulphonyl-C_1-8Alkyl amino)-C_1-8Alkyl]-furyl or (C_1-8Alkoxy, 1- piperidines -1- Base, 1- piperazine -1- base, 4-C_1-8Alkyl-piperazin -1- base, morpholine -1- base, thiomorpholine -1- base, S- oxo-thiomorpholin -1- Base or S, S- dioxy thiomorpholine -1- base)-C_1-8Alkoxy；

Rc is halogen or C_2-8Alkynyl；With

Rd is hydrogen, pyridyl group-C_1-8Phenyl-the C that alkoxy or unsubstituted or halogen replace_1-8Alkoxy；

Especially wherein:

X is N or C (CN)；

Ra is methoxyl group, ethyoxyl, 3- morpholino propoxyl group or 2- methoxy ethoxy；

Rb is 4- (dimethylamino)-but-2-ene acylamino-, propyl- 2- alkene acylamino-, 5- [(2- methylsulfonyl-ethyl)-amino Methyl]-furans -2- base, 2- methoxy ethoxy or 3- morpholino propoxyl group；

Rc is chlorine or acetenyl；With

Rd is hydrogen, fluorine, pyridine -2- ylmethoxy or 3- fluorophenyl-methoxyl group；

Or its respectively pharmaceutically-acceptable salts or prodrug.

If not stated otherwise, following definition is as used herein more wide up and down for being limited by specific variants Thus general expression limits more specific embodiment of the present invention, one of them, more than one or it is all expression by following Definition is to limit:

Before and in following definition, C_1-8Preferably C_1-6, more preferable C_1-4, it is former to have respectively referred to 1-8,1-6 or 1-4 carbon The straight chain or linear fraction of son.

Before and in following definition, C_2-8Preferably C_2-6, more preferable C_2-4, it is former to have respectively referred to 2-8,2-6 or 2-4 carbon The straight chain or linear fraction of son.

Before and in following definition, C_3-8Preferably C_3-6, more preferable C_3-4, it is former to have respectively referred to 3-8,3-6 or 3-4 carbon The part of son.

Before and in following definition, C_4-8Preferably C_4-6, more preferable C₄, respectively refer to 4-8,4-6 or 4 carbon atoms Straight chain or linear fraction.

" rudimentary ", which refers to, up to 8, the group of especially up to 6 carbon atoms, unless otherwise indicated.For example, lower alkyl Base refers to C_1-8Alkyl, such as C_1-6Alkyl, such as methyl, ethyl, n-propyl, isopropyl, normal-butyl, sec-butyl, isobutyl group or tert-butyl.

In the different places of this specification, useful compound substituent of the present invention is disclosed with group or range format. The present invention be especially intended to include member in described group and range each or each sub-combination.For example, term " C_1-6Alkyl " is specific Mean to separately disclose methyl, ethyl, C₃Alkyl, C₄Alkyl, C₅Alkyl and C₆Alkyl.

Useful compound of the present invention should also be stable." stabilization " used herein refers to that compound is strong enough Reach the purity of useful degree to withstand from reaction mixture separation, and can preferably be formulated into effective therapeutic agent.

It will also be understood that certain features of the invention describe in different embodiments for clarity, it can also be single It combines and provides in embodiment.On the contrary, various features of the invention describe in single embodiment for brevity, also It can separate or with the offer of any suitable sub-combination.

The term as used herein " alkyl " (and alkoxy, aryl alkyl, heteroaryl alkyl, halogenated alkyl etc.) refers to straight chain Or the saturated hydrocarbons group of branch.Alkyl example includes methyl (Me), ethyl (Et), propyl (such as n-propyl and isopropyl), butyl (such as normal-butyl, isobutyl group, tert-butyl), amyl (such as n-pentyl, isopentyl, neopentyl).Alkyl may include 1- about 20,2- About 20,1- about 10,1- about 8, about 3 1- about 6,1- about 4 or 1- carbon atoms.

The term as used herein " alkylene " refers to connection alkyl.

The term as used herein " alkenyl " refers to the alkyl with one or more carbon-carbon double bonds.Exemplary alkenyl groups include ethylene Base, acrylic etc..

The term as used herein " alkenylene " refers to connection alkenyl.

The term as used herein " alkynyl " refers to the alkyl with one or more triple carbon-carbon bonds.Exemplary alkynyl includes acetylene Base, propinyl etc..

The term as used herein " alkynylene " refers to connection alkynyl.

The term as used herein " halogenated alkyl " refers to the alkyl with one or more halogenic substituents.Exemplary alkyl halide Base includes CF₃、C₂F₅、CHF₂、CCl₃、CHCl₂、C₂Cl₅Deng.

" aryl " used herein refer to monocycle or it is polycyclic (as have 2,3 or 4 condensed ring) aromatic hydrocarbon, such as phenyl, naphthalene, Anthryl, phenanthryl, indanyl, indenyl etc..In some embodiments, aryl has about 20 carbon atoms of 6-.

" arlydene " used herein refers to connection aryl.

" naphthenic base " used herein refers to the non-aromatic carbocyclic ring including cyclisation alkyl, alkenyl and alkynyl.Naphthenic base may include Monocycle or polycyclic (as having 2,3 or 4 condensed ring) ring system, include loop coil.In some embodiments, naphthenic base can have 3- about 20 carbon atom, 3- about 10 carbon atoms of about 14 carbon atoms, 3- or 3-7 carbon atom.Naphthenic base can also have 0,1,2 or 3 A double bond and/or 0,1 or 2 three key.Naphthenic base definition further includes having one or more and cycloalkyl ring condensed (i.e. therewith altogether Have key) the part, such as pentane, amylene, hexane of aromatic ring etc. benzo derivative.Ring with one or more fused aromatic rings Alkyl can be connected by fragrance or nonaromatic components.One or more ring carbons of naphthenic base can aoxidize, such as with oxygen Generation or sulphur bridge substituent group.Exemplary cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclopentenyl, ring Hexenyl, cyclohexadienyl, cycloheptatriene base, norcamphanyl, drop Fu base (norpinyl), norcarane base (norcarnyl), adamantane Base etc..

" cyclic alkylene " used herein refers to connection naphthenic base.

" heteroaryl " used herein refers to at least one heteroatom ring members such as aromatic heterocycle of sulphur, oxygen or nitrogen.It is miscellaneous Aryl includes monocycle and polycyclic (as having 2,3 or 4 condensed ring) system.Any ring-forming N atom in heteroaryl can also aoxidize to be formed N- oxo moieties.Heteroaryl example includes but is not limited to pyridyl group, N- oxo pyridine base, pyrimidine radicals, pyrazinyl, pyridazinyl, three Piperazine base, furyl, quinolyl, isoquinolyl, thienyl, imidazole radicals, thiazolyl, indyl, pyrrole radicals, oxazolyl, benzo furan It mutters base, benzothienyl, benzothiazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazole radical, indazolyl, 1,2,4- thiadiazoles Base, isothiazolyl, benzothienyl, purine radicals, carbazyl, benzimidazolyl, indoline base etc..In some embodiments, Heteroaryl has about 20 carbon atoms of 1-, and in further embodiments, and heteroaryl has about 20 carbon atoms of about 3-.Some In embodiment, heteroaryl includes 3- about 14,3- about 7 or 5-6 ring member nitrogen atoms.In some embodiments, heteroaryl With 1- about 4,1- about 3 or 1-2 hetero atom.

" heteroarylidene " used herein refers to connection heteroaryl.

" Heterocyclylalkyl " or " heterocycle " used herein refer to wherein one or more ring member nitrogen atoms be hetero atom such as O, N or The non-aromatic carbocyclic ring of S atom.Heterocyclylalkyl may include monocycle or polycyclic (as having 2,3 or 4 condensed ring) ring system and loop coil.Show Example property " Heterocyclylalkyl " includes morpholino, thiomorpholine generation, piperazinyl, tetrahydrofuran base, tetrahydro-thienyl, 2,3- dihydrobenzo furan It mutters base, 1,3- benzodioxole, phendioxin, 4- dioxanes, piperidyl, pyrrolidinyl, isoxazolidinyl, different tetrahydro-thiazoles base, pyrrole Azoles piperidinyl, oxazolidinyl, tetrahydro-thiazoles base, imidazolidinyl etc..The definition of Heterocyclylalkyl further include have it is one or more with it is non- The part of the aromatic ring of aromatic heterocycle condensed (sharing key therewith), such as phthalimidyl (phthalimidyl), naphthalene The benzo derivative of dicarboximide base and heterocycle.Heterocyclylalkyl with one or more fused aromatic rings can by fragrance or Nonaromatic components connection.The definition of Heterocyclylalkyl further includes wherein one or more ring member nitrogen atoms 1 or 2 oxo or sulphur bridge base The part that group replaces.In some embodiments, Heterocyclylalkyl has about 20 carbon atoms of 1-, in other embodiments, miscellaneous Naphthenic base has about 20 carbon atoms of about 3-.In some embodiments, Heterocyclylalkyl includes 3- about 20,3- about 14,3- About 7 or 5-6 ring member nitrogen atoms.In some embodiments, Heterocyclylalkyl has 1- about 4,1- about 3 or 1-2 a miscellaneous Atom.In some embodiments, Heterocyclylalkyl includes 0-3 double bond.In some embodiments, Heterocyclylalkyl includes 0-2 A three key.

" heterocyclic hydrocarbylene " used herein refers to connection Heterocyclylalkyl.

" biaryl " used herein refers to the aryl replaced by another aryl.

" two heteroaryls " used herein refers to the heteroaryl replaced by another heteroaryl.

Used herein " halogenated " or " halogen " includes fluorine, chlorine, bromine and iodine.

" alkoxy " used herein refers to-O- alkyl.Exemplary alkoxy radicals include methoxyl group, ethyoxyl, propoxyl group (as just Propoxyl group and isopropoxy), tert-butoxy etc..

" acyl group " used herein includes organic group, corresponding to the residue for the organic acid for for example removing hydroxyl, that is, is had Formula R^AThe group of-C (O)-, wherein R^AIt can be specifically aliphatic or substituted aliphatic, or can be for example substituted or unsubstituted It is mono- or bicyclic.Therefore, R can be selected from rudimentary C₁-C₆Alkyl, C₃-C₇Naphthenic base, phenyl, benzyl or phenethyl.Wherein, exemplary Acyl group is alkyl-carbonyl.Acyl group example includes but is not limited to acetyl group, propiono and bytyry.For example, lower acyl is formic acid Base or lower alkylcarbonyl, especially acetyl group.

MET and FGFR inhibitor can be produced as described in above-mentioned patent application and patent, and the patent application and patent are also led to It crosses reference to be included in, more particularly to its manufacturing method.

Useful compound of the present invention may also include all same of atom appeared in intermediary or final compound Position element.Isotope includes having those of same atoms ordinal number but mass number difference atom.The same of the compounds of this invention can be mixed The plain example in position includes the isotope of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, respectively for example²H、³H、¹¹C、¹³C、¹⁴C、¹⁵N、¹⁸F ³¹P、³²P、³⁵S、³⁶Cl、¹²⁵I.There are many compounds of this invention of isotope labelling, such as incorporation radioactive isotope is such as³H、¹³C and¹⁴C Those of.The compound of this isotope labelling (is preferably used for being metabolized research¹⁴C), Reaction kinetics research (such as with²H Or³H), detection or imaging technique [such as positron emission tomography (PET) or Single Photon Emission Computed imaging (SPECT), including drug or substrate tissue distribution assays], or be used for radiation treatment patient.Particularly, with regard to PET or SPECT It is specific preferred for research¹⁸F or labeled compound.In addition, (i.e. with higher isotope such as deuterium²H) replace and can provide metabolism surely Certain treatment advantages of qualitative higher generation, such as Half-life in vivo increases or dose requirements are reduced.This hair of isotope labelling Bright compound and its prodrug can generally be prepared as follows: being replaced nonisotopic labels reagent with existing isotope labeling reagent, completed Process disclosed in following proposal or embodiment and preparation.

In addition, (i.e. with higher isotope especially deuterium²H or D) replace can provide the certain of the higher generation of metabolic stability Treatment advantage, such as Half-life in vivo increases or dose requirements reduce or improvment of therapeutic index.It should be understood that the deuterium quilt under this background It is regarded as the substituent group of formula (i) compound.The concentration of the higher isotope especially deuterium can be determined by isotope enrichment factor. The term as used herein " isotope enrichment factor " refers to the ratio between isotope abundance and specified natural abundance of isotopes.If this hair The substituent group of bright compound is shown deuterium, and the compound has certain isotope enrichment factor for each specified D-atom, The specified D-atom be at least 3500 (the 52.5% deuterium incorporation at each specified D-atom), at least 4000 (incorporations of 60% deuterium), At least 4500 (incorporations of 67.5% deuterium), at least 5000 (incorporations of 75% deuterium), at least 5500 (incorporations of 82.5% deuterium), at least 6000 (incorporation of 90% deuterium), at least 6333.3 (incorporations of 95% deuterium), at least 6466.7 (incorporations of 97% deuterium), at least 6600 (99% deuterium is mixed Enter) or at least 6633.3 (incorporations of 99.5% deuterium).In the compounds of this invention, it is not specially designated as any of specific isotope Atom is intended to represent any stable isotope of the atom.Unless otherwise indicated, a certain position is specially designated as " H " or " hydrogen " When, it should be understood that the position has hydrogen at its natural abundance isotopic composition.Therefore, it in the compounds of this invention, specifies It is intended to represent deuterium for any atom of deuterium (D), such as within the above range.

Isotope labelling MET and/or the EGFR tyrosine kinase inhibitor of part combination product formed according to the present invention Close object generally can by routine techniques well known by persons skilled in the art or with appended " embodiment and preparation " the similar work Skill preparation, non-marked reagent previously used is replaced using suitable isotope labeling reagent.

Embodiment of the present invention further includes the pharmaceutically-acceptable salts according to the useful compound of invention described herein.Herein " pharmaceutically-acceptable salts " used refer to the derivative of disclosed compound, wherein by the way that existing acid or alkali are partially converted into it Salt form modifies parent compound.The example of pharmaceutically-acceptable salts includes but is not limited to the mineral of alkaline residue such as amine or has Machine hydrochlorate；The alkali or organic salt of acidic residues such as carboxylic acid；Etc..Pharmaceutically-acceptable salts of the invention include parent compound Conventional non-toxic salts, the compound is such as from nontoxic inorganic or organic acid.Pharmaceutically-acceptable salts of the invention can lead to Conventional chemical processes are crossed to synthesize from the parent compound containing alkalinity or acidic moiety.Generally, by making the trips of these compounds It reacts, can be prepared in the mixture of water or organic solvent or both from acid or alkali form and the appropriate base of stoichiometry or acid This kind of salt；Generally it is preferred to non-aqueous media such as ether, ethyl acetate, ethyl alcohol, isopropanol or acetonitrile.The list of acceptable acid addition salts referring to Remington ' s Pharmaceutical Sciences (" Remington pharmaceutical science "), the 17th edition, Pennsylvania Yi Si The Mike publishing company (Mack Publishing Company) paused, page 1985,1418 and Journal of Pharmaceutical Science, 66,2 (1977) are respectively incorporated herein by reference in their entirety.

Herein using phrase it is " pharmaceutically acceptable " expression those of in scope of sound medical judgment compound, material, Composition and/or dosage form, it is suitable for contact humans and animals tissue, without excessive toxicity, stimulation, allergy or its Its problem or complication, and there is reasonable benefit/risk ratio.

The invention also includes the prodrugs of useful compound of the present invention." prodrug " used herein, which is showed, gives mammal Any covalently bound carrier of active parent drug is discharged when object.It can be made by functional group present in modified compound Standby prodrug, to cut the modification by routine operation or in vivo from parent compound.Prodrug includes wherein hydroxyl, ammonia Base, sulfydryl or carboxyl combine the compound of any group, and the group is respectively cut to form trip when giving mammalian object From hydroxyl, amino, sulfydryl or carboxyl.The example of prodrug includes but is not limited to the acetic acid of pure and mild amine functional group in the compounds of this invention Salt, formates and benzoic acid salt derivative.The preparation and application of prodrug are referring to T.Higuchi and V.Stella, " Pro-drugs as Novel Delivery Systems (prodrug as new delivery system), " A.C.S.Symposium Series is (" Americanized Association's disquisition series of books ") volume 14, and it is embodied in Bioreversible Carriers in Drug Design (" bioreversible carrier in drug design "), Edward B.Roche is compiled, american pharmaceutical association and Pei Geman publishing house (American Pharmaceutical Association and Pergamon Press), 1987, it is complete all to pass through reference Text is included in herein.

Useful compound of the present invention (=it is included in combination, especially combination product according to the present invention respectively, or according to this Invention uses, also optional including following other auxiliary agents, i.e., all active constituents) and its pharmaceutically-acceptable salts or prodrug also can Exist as tautomer, N- oxide or solvate such as hydrate.All these variants and its any one or 2 The combination of kind or more (being less than) all such variants is included herein and interprets, wherein referring to that combination product of the present invention includes Compound, such as EGFR tyrosine kinase inhibitor and/or MET tyrosine kinase inhibitor.

According to first embodiment above and hereafter, the present invention relates to pharmaceutical composition, especially pharmaceutical combination product, packets Include the combined partner and at least one pharmaceutically acceptable carrier.

" combination " refers to the independent companion's preparation for being with or without use in conjunction specification, or refers to combination product.Therefore, described group Closing companion can be distinct pharmaceutical dosage form or pharmaceutical composition, can also sell independently of one another, and its use in conjunction is said Bright book provides in packaging facilities such as pamphlet or other information form, and it is (such as oral to be such as supplied to doctor and medical worker Communication, writing communication etc.), for simultaneously or sequentially using with common active, being especially discussed further below.

" combination product " refers in particular to the fixed Combination of a dosage unit form, or the complete kit being administered in combination, wherein EGFR tyrosine kinase inhibitor and MET tyrosine kinase inhibitor (and for example following another drugs of optional another combined partner, Also referred to as " auxiliary agent ") it individually can separately be given in same time or certain time interval, especially these time intervals allow Combined partner display cooperation (=joint) such as synergistic effect.The term as used herein " administration altogether " or " administering drug combinations " etc. are intended to wrap It includes to the single object (such as patient) of needs and gives selected combined partner, and be intended to include therapeutic scheme, wherein the reagent is not It by identical administration route and/or must be administered simultaneously.

Therefore, the term as used herein " combination product " refers to the drug by mixing or combining the generation of more than one active constituents Product, including fixed and non-fixed combinations active constituent (it can also be combined).

Term " fixed Combination " refers to active constituent such as EGFR tyrosine kinase inhibitor and MET tyrosine kinase inhibitor, All patient is given simultaneously using single entities or dosage form.In other terms: active constituent exists with a kind of dosage form, such as in piece In agent or capsule.

Term " non-fixed combinations " refer to active constituent be all used as corpus separatum simultaneously, it is synchronous or sequentially give patient, and do not have There is specific time limitation, wherein the administration provides 2 kinds of compounds for the treatment of effective level in patient's body.The latter is also applied to Cocktail therapy such as gives 3 kinds or more.Therefore, term " non-fixed combinations " is especially fixed for following meaning Adopted " complete kit ": combined partner (i) EGFR tyrosine kinase inhibitor defined herein and (ii) MET tyrosine kinase inhibit Agent (and other one or more auxiliary agents if it exists) can be administered independently of one another or using the fixed group of the different difference of combined partner amount It closes, i.e., simultaneously or in different time points, wherein the combined partner also acts as distinct pharmaceutical dosage form or pharmaceutical preparation, It can also sell independently of one another, and the specification about its use in conjunction possibility is in packaging facilities such as pamphlet etc. or other It is provided in message form, is such as supplied to doctor and medical worker.Then, independent formulations or complete kit part can for example be given simultaneously Medicine intersects in chronological order, i.e., time interval is equal or different in different time points and for complete kit any part. Most preferably, time interval is selected, combination is used only to be greater than when part to the effect of treated disease described in use in conjunction Companion (i) and the effect that can be realized any in (ii), thus play a role jointly.Combination companion to be administered with combination formulations The ratio between companion (i) and combined partner (ii) total amount are variable, such as in order to meet patient subgroups demand or single patient demand to be treated, Different demands may be attributed to age, gender, weight of patient etc..

The invention further relates to (i) MET inhibitor and (ii) EGFR inhibitor or its pharmaceutically-acceptable salts, are answered with combining The disease especially cancer mediated for treating EGFR tyrosine kinase activity and/or MET tyrosine kinase activity, method.

In another embodiment, according to the MET inhibitor that uses of previous paragraphs and EGFR inhibitor select as follows: MET Tyrosine kinase inhibitor is selected from (E) -2- (1- (3- ((7- fluorine quinoline -6- base) methyl) imidazo [1,2-b] pyridazine -6- base) Ethylidene) semicarbazides and/or (especially or) the fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-methyl)-imidazo [1,2-b] three Piperazine -2- base] benzamide or its respectively pharmaceutically-acceptable salts or prodrug,

And EGFR inhibitor is Gefitinib and/or (especially or) Tarceva or its pharmaceutically-acceptable salts or preceding Medicine.

The preferred preparation of combined partner (i) and (ii) or use in any invention embodiment is with common (preventative or special It is not therapeutic) it is active.This is specific to mean there is at least one beneficial effect, such as the phase of combined partner (i) and (ii) Mutual improvement effect, especially acts synergistically, and is more than such as synergistic effect, additional meritorious effects are (as any single compound Not found other therapeutic effects), side effect is less, and one or both of the combined partner (i) of non-treatment dosage and (ii) generate Combination therapy effect, and very preferably combined partner (i) and (ii) significant synergistic effect.

For example, term " common active (in treatment) " can indicate the compound can at a time interval individually or Sequentially (by it is long-term it is staggered in a manner of, especially sequence-specific fashion) give, so that it is preferably special in warm-blooded animal to be treated It is not that still display (preferably cooperates with) interaction (combination therapy effect) in people.Combination therapy effect can be by tracking blood water It puts down and shows that 2 kinds of compounds are at least all present in the blood of people to be treated in certain time intervals to measure, but this is not precluded Following situations: the compound plays a role jointly, although it does not occur simultaneously in blood.

Therefore, the present invention relates to the combination products for simultaneously, separately or sequentially using, such as combination formulations or drug to fix Combination or the preparation and combined combination.

In combination therapy of the invention, useful compound of the present invention can be manufactured and/or be matched by same or different vendor System.In addition, the combined partner can be pooled in combination therapy: (i) lets pass to before doctor in combination product (such as containing this hair In the medicine box situation of bright compound and another therapeutic agent)；(ii) by doctor's (or under physician guidance) before facing administration； (iii) sufferers themselves, such as during sequential administration the compounds of this invention and another therapeutic agent.

In some embodiments, any of above method includes further giving one or more other (such as thirds) to help Agent, especially chemotherapeutics.

Therefore, the present invention is related to combination product, especially pharmaceutical composition in another embodiment, including treatment is effectively Amount (i) EGFR tyrosine kinase inhibitor and (ii) MET tyrosine kinase inhibitor or its respectively pharmaceutically-acceptable salts, With at least one third therapeutically active agent (auxiliary agent), such as another compound (i) and/or (ii) or different auxiliary agents.It is described additionally to help Agent is preferably selected from anticancer agent；Anti-inflammatory agent.

Equally in this case, the combined partner for forming corresponding product of the present invention can be fixed to form fixed drug combination Object or its can separate or in pairs administration (i.e. prior to, concurrently with, or after other medicines substance).

Additionally or alternatively, combination product of the present invention can with chemotherapy, radiotherapy, immunotherapy, operation intervention or The combination of these methods is combined in (especially) oncotherapy.Long-term treatment is equally possible, as in above-mentioned other treatments Complementary therapy in the background of strategy.Other possible treatments are the treatments of the maintenance patient's states after tumor regression, or even It is chemopreventive therapy, such as in risky patient.

Possibility anticancer agent (as being used for chemotherapy) as auxiliary agent includes but is not limited to aromatase inhibitor；Antiestrogen； Topoisomerase I inhibitor；Topoisomerase II inhibitors；Micro-pipe reactive compound；Alkylated compound；Histone deacetylase Inhibitor；The compound of Cell differentiation inducing activity process；Cyclooxygenase-2 inhibitor；MMP inhibitor；MTOR inhibitors；Antitumor activity Antimetabolite；Molybdenum compound；The compound of targeting/reduction protein kinase or rouge kinase activity；Anti-angiogenesis compound；Target Xiang Yu, reduction inhibit phosphoprotein phosphatase or the active compound of lipid phosphatase；Gonadorelin agonist；It is anti-male sharp Plain medicine；Methionine aminopeptidase inhibitor；Bis-phosphonic acids；Biological response conditioning agent；Anti proliferative antibody；Heparanase inhibits Agent；Ras carcinogenic isoform inhibitor；Telomerase inhibitor；Proteasome inhibitor；For treating the change of hematologic malignancies Close object；Target, reduce or inhibit the active compound of Flt-3；Hsp90 inhibitor；Drive albumen spindle protein inhibitor； Mek inhibitor；Folinic acid；EDG bonding agent；Anti-leukemia compound；Nucleotide reducing enzyme inhibitor；S-adenosylmethionine is de- Decarboxylase inhibitor；Inhibit the steroids of blood vessel；Corticosteroid；Other chemotherapy compounds (defined below)；Light-sensitive compound.

Furthermore or or in addition, combination product of the present invention can be combined with other tumor therapeuticing methods, including operation, Ionising radiation, optical dynamic therapy, transplanting as with corticosteroid, hormone or its can be used as radiosensitizer.

The term as used herein " aromatase inhibitor " is related to inhibiting estrogen production, i.e., hero is stayed alkene diketone and testosterone bottom Object is separately converted to the compound of oestrone and estradiol.The term includes but is not limited to steroid, especially atamestane, according to Xi Meitan and formestane, and especially non-steroid, especially aminoglutethimide, Rogletimide, Pyridoglutethimide, Trilostane, Testolactone, ketoconazole, Vorozole, Fadrozole, Anastrozole and Letrozole.

The term as used herein " antiestrogen " is related to the chemical combination of the antagonising oestrogen effect on Estrogen Receptor Object.The term includes but is not limited to tamoxifen, fulvestrant, Raloxifene and RALOXIFENE HCL.

The term as used herein " antiandrogen " is related to any substance that can inhibit male sex hormone biological effect, including but It is not limited to Bicalutamide (CASODEX), it can be such as US 4,636,505 preparations.

The term as used herein " gonadorelin agonist " includes but is not limited to abarelix, Goserelin and second Sour Goserelin.The term as used herein " topoisomerase I inhibitor " include but is not limited to topotecan, gefitinib, she It is vertical to replace health, camptothecine and the like, 9-nitrocamptothecin and macromolecular camptothecin conjugate PNU-166148 (W099/17804 In compound Al).

The term as used herein " Topoisomerase II inhibitors " includes but is not limited to anthracycline, such as adriamycin (including rouge Liposome preparation, such as CAELYX), daunorubicin, Epi-ADM, idarubicin and Nemorubicin, the mitoxantrone of Anthraquinones And the Etoposide and Teniposide of Losoxantrone and podophyllotoxin class.

Term " micro-pipe reactive compound " is related to microtubule stabilization chemical combination object, microtubule destabilizing conjunction object and tubulin polymerization Inhibitor, including but not limited to taxanes such as taxol and docetaxel, vinca alkaloids such as vinblastine (especially sulphur Sour vinblastine), vincristin (especially vincristine sulfate) and vinorelbine, circle suberite lactone, colchicin and Epothilones and its derivative such as epothilone B or D or derivatives thereof.

The term as used herein " alkylated compound " includes but is not limited to cyclophosphamide, ifosfamide, phenylalanine nitrogen Mustard or nitroso ureas (BCNU or Gliadel).

Term " histone deacetylase inhibitor " or " hdac inhibitor " are related to inhibition of histone deacetylase and have There is the compound of antiproliferative activity.This includes compound disclosed in WO 02/22577, especially N- hydroxyl -3- [4- [[(2- Ethoxy) [2- (1H- indol-3-yl) ethyl]-amino] methyl] phenyl] -2E-2- propylene acid amide, N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] phenyl] -2E-2- acrylamide and its pharmaceutically-acceptable salts. It is gone back particularly including Vorinostat (SAHA).Targeting, reduction or inhibition of histone deacetylase (HDAC) inhibit The compound of agent such as sodium butyrate and Vorinostat (SAHA) can inhibit the enzymatic activity of referred to as histone deacetylase. Specific hdac inhibitor includes MS275, SAHA, FK228 (pervious FR901228), Trichostatin A and US 6,552,065 Disclosed compound, especially N- hydroxyl -3- [4- [[[2- (2- Methyl-1H-indole -3- base)-ethyl]-amino] methyl] benzene Base] -2E-2- acrylamide or its pharmaceutically-acceptable salts and N- hydroxyl -3- [4- [(2- ethoxy) [2- (1H- indoles -3- Base) ethyl]-amino] methyl] phenyl] -2E-2- propylene acid amide or its pharmaceutically-acceptable salts, especially lactate.

Term " antitumor activity antimetabolite " include but is not limited to 5 FU 5 fluorouracil or 5-FU, capecitabine, gemcitabine, DNA demethylation compound such as 5-azacitidine and Decitabine, methotrexate (MTX) and Edatrexate and antifol are as trained Beautiful Qu Sai.

The term as used herein " molybdenum compound " includes but is not limited to card molybdenum, along molybdenum, cis-platinum and Ao Shali molybdenum.

The term as used herein " compound of targeting/reduction protein kinase or rouge kinase activity "；Or " targeting/reduction Phosphoprotein phosphatase or the active compound of lipid phosphatase "；Or " other anti-angiogenesis compounds " includes but is not limited to C-Met tyrosine kinase and/or serine and/or threonine kinase inhibitor or lipid kinase inhibitors, such as:

A) platelet derived growth factor receptor (PDGFR) active compound is targeted, reduces or inhibits, such as target, The active compound of PDGFR is reduced or inhibited, the compound of pdgf receptor, such as N- phenyl -2- pyrimidine-amine is especially inhibited to spread out Biology, such as Imatinib, SU101, SU6668 and GFB-111；

B) target, reduce or inhibit insulin-like growth factor receptor I (IGF-IR) active compound, such as targeting, drop The low or inhibition active compound of IGF-IR, especially inhibits the compound of IGF-I kinase activation, such as WO 02/092599 Those disclosed compound, or the antibody of targeting IGF-I receptor or its growth factor extracellular domain；

C) targeting, reduction or the compound for inhibiting Trk receptor tyrosine kinase family active；Or ephrins (ephrin) Kinase families inhibitor；

D) targeting, reduction or the compound for inhibiting Axl Receptor Tyrosine Kinase family active；

E) targeting, reduction or the compound for inhibiting Ret receptor tyrosine kinase activity；

F) targeting, reduction or the compound for inhibiting Kit/SCFR receptor tyrosine kinase activity, such as Imatinib；

G) C-kit receptor tyrosine kinase-(a part of PDGFR family) active compound is targeted, reduces or inhibits, Such as targeting, the compound for reducing or inhibiting C-Kit receptor tyrosine kinase family active, especially inhibition C-Kit receptor Compound, such as Imatinib；

H) target, reduce or inhibit C-Abl family member, its gene fusion product (such as BCR-Abl kinases) and mutation The active compound of body, such as targeting, reduction or inhibition c-Abl family member and the active compound of its gene fusion product, Such as N- phenyl-2-pyrimidine-amine derivatives, such as Imatinib or nilotinib (AMN107)；PD180970；AG957；NSC 680410；The PD173955 of dimension (ParkeDavis) is worn from Parker；Or Dasatinib (BMS-354825)；

I) target, reduce or inhibit protein kinase C (PKC) and serine/threonine kinase Raf family member and MEK, SRC, JAK, FAK, PDK1, PKB/Akt and Ras/MAPK family member and/or cell cycle protein dependent kinase family (CDK) compound of member activity, especially US 5,093,330 those disclosed staurosporine derivatives, such as midostaurin； The example of other compounds includes such as UCN-01, Safingol, BAY 43-9006, bryostatin I, perifosine；Emol good fortune Newly；RO 318220 and RO 320432；G0 6976；Isis 3521；LY333531/LY379196；Isoquinoline compound, such as 00/09495 those disclosed of WO；FTIs；PD184352 or QAN697 (P13K inhibitor) or AT7519 (CDK inhibitor)；

J) the active compound of protein tyrosine kinase inhibitor is targeted, reduced or inhibited, such as targets, reduce or inhibits The active compound of protein tyrosine kinase inhibitor, including imatinib mesylate (GLEEVEC) or tyrphostirio.Junket Propylhomoserin phosphorylation inhibitor (Tyrphostin) is preferably low molecular weight (Mr < 1500) compound or pharmaceutically acceptable salt thereof, especially Compound selected from benzal malononitrile class or S- aryl phenylpropyl alcohol dintrile or Double bottom object quinolines, is more particularly selected from Any compound of the following group: tyrphostin A23/RG-50810；AG 99；Tyrphostin AG 213；Tyrphostin AG1748；Tyrphostin AG 490；Tyrphostin B44； Tyrphostin B44 (+) enantiomter；Tyrphostin AG 555；AG 494；Tyrosine phosphatase Change inhibitor AG 556, AG957 and adaphostin (4- { [(2,5- dihydroxy phenyl) methyl] amino }-benzoic acid adamantane Base ester；NSC 680410,adaphostin)；

K) target, reduce or inhibit receptor tyrosine kinase epidermal growth factor family (EGFR, ErbB2, ErbB3, ErbB4 is homopolymer or heterodimer) and its mutant active compound, such as targeting, reduce or inhibition epidermal growth The compound of factor acceptor family active, especially inhibition EGF receptor family tyrosine kinase member such as EGF receptor, ErbB2, ErbB3 and ErbB4 or compound, protein or antibody in conjunction with EGF or EGF associated ligands, especially under General and specific those disclosed compound, protein or monoclonal antibody in column document: WO 97/02266, such as embodiment 39 compound or EP 0 564 409, WO 99/03854, EP 0520722, EP 0 566 226, EP 0 787 722, EP 0 837063, US 5,747,498, WO 98/10767, WO 97/30034, WO 97/49688, WO 97/38983, especially It is WO 96/30347 (such as the compound for being known as CP 358774), WO96/33980 (such as compound ZD 1839) and WO 95/03283 (such as compound ZM105180)；Such as trastuzumab (Herceptin^TM), Cetuximab (Erbitux^TM)、 Iressa, Erlotinib, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2.11, 7H- pyrrolo- [2,3-d] pyrimidine derivatives disclosed in E6.3 or E7.6.3 and WO 03/013541；With

L) it targets, reduce or inhibit the compound of C-Met receptor active, such as target, reduce or inhibit c-Met active Compound especially inhibits the compound of C-Met kinase activation, or targeting C-Met extracellular domain or anti-in conjunction with HGF Body；

M) targeting, reduction or the compound for inhibiting Ron receptor active.

Other anti-angiogenesis compounds include the compound with other activity mechanisms, for example, with protein kinase or rouge The unrelated mechanism of kinase inhibitory activity, such as Thalidomide (THAL0MID) and TNP-470.

Term " targeting reduces or inhibit phosphoprotein phosphatase or the active compound of lipid phosphatase " includes but is not limited to phosphorus Sour enzyme 1, the inhibitor, such as okadaic acid of phosphatase 2A or CDC25 or derivatives thereof.

Term " compound of Cell differentiation inducing activity process " includes but is not limited to such as retinoic acid, α-, γ-or Delta-Tocopherol Or α-, γ-or δ-tocotrienols.

The term as used herein " cyclooxygenase-2 inhibitor " includes but is not limited to that such as Cox-2 inhibitor, 5- alkyl replace 2- arylaminophenylacetic acid and derivative, such as celecoxib (CELEBREX), rofecoxib (VIOXX), etoricoxib, Valdecoxib or 5- alkyl -2- arylaminophenylacetic acid, such as 5- methyl -2- (2 '-chloro- 6 '-fluoroanilino) phenylacetic acid, Shandong Rice examines former times (Iumiracoxib).

The term as used herein " bis-phosphonic acids " include but is not limited to Etidronic Acid (etridonic acid), Clodronate, Tiludronic Acid, pamidronic acid, alendronic acid, ibandronic acid, Risedronic Acid and zoledronic acid.

Term " mTOR inhibitors " is related to inhibiting the mammal target (mTOR) of rapamycin and has antiproliferative living The compound of property, such as sirolimusEverolimus (Certican^TM), CCI-779 and ABT578.

The term as used herein " heparanase inhibitors " refers to the chemical combination targeted, reduced or inhibited the degradation of heparin sulfate Object.The term includes but is not limited to PI-88.

The term as used herein " biological response conditioning agent " refers to lymphokine or interferon, such as interferon gamma.

The term as used herein " Ras carcinogenic isoform inhibitor " (such as H-Ras, K-Ras or N-Ras) refers to targeting, drop Compound that is low or inhibiting Ras carcinogenic activity, such as " farnesyl transferase inhibitor ", such as L-744832, DK8G557 or Rl15777(Zarnestra)。

The term as used herein " telomerase inhibitor " refers to the compound targeted, lowered or inhibited telomerase activity.Target To, to reduce or inhibit the compound of telomerase activation specific be the compound for inhibiting telornerase receptor, such as telomere chalone (telomestatin)。

The term as used herein " methionine aminopeptidase inhibitor " refers to targeting, reduction or inhibits methionine aminopeptidase Active compound.Targeting reduces or the active compound of methionine aminopeptidase is inhibited to have such as bengamide or its derivative Object.

The term as used herein " proteasome inhibitor " refers to targeting, reduction or the active chemical combination of protease inhibition body Object.Targeting, reduction or the active compound of protease inhibition body include such as bortezomib (Velcade^TM) and MLN341.

The term as used herein " Matrix Metalloproteinase Inhibitors " or (" MMP inhibitor ") include but is not limited to that collagen is quasi- Peptide and non-peptidomimetic inhibitor, tetracycline derivant, for example, hydroxamic acid peptidomimetic inhibitor Batimastat and its it is oral can biology benefit Analog Marimastat (BB-2516), prinomastat (AG3340), metastat (NSC 683551) BMS- 279251, BAY 12-9566, TAA211, MMI270B or AAJ996.

The term as used herein " for treating the drug of hematologic malignancies " includes but is not limited to FMS- sample tyrosine Kinase inhibitor, such as targeting, reduction or inhibition FMS- sample tyrosine kinase receptor (Flt-3R) active compound；Interference Element, 1-b-D- arabino-furanosylcytosine (ara-c) and busulfan (bisulfan)；With ALK inhibitor, such as targeting, Reduce or inhibit the compound of anaplastic lymphoma kinase.

Specific term " targeting reduces or inhibit FMS- sample tyrosine kinase receptor (Flt-3R) active compound " is suppression Compound, protein or the antibody of Flt-3R receptor kinase family member processed, such as PKC412, midostaurin, staurosporin are derivative Object, SU11248 and MLN518.

The term as used herein " HSP90 inhibitor " includes but is not limited to targeting, the endogenous sexual gland for reducing or inhibiting HSP90 The compound of guanosine triphosphate enzymatic activity；Via the degradation of Ubiquitin-proteasome access, targeting, reduce or inhibit HSP90 client protein Compound.The specific active compound of endogenous adenosine triphosphatase of targeting, reduction or inhibition HSP90 is to inhibit HSP90 Atpase activity compound, protein or antibody, such as 17- allyl amino, 17- de-methoxy Ge Erde be mould Element (17AAG, 17-DMAG), geldanamycin derivant；Other compounds relevant to geldanamycin；Radicicol and Hdac inhibitor；From Conforma treatment company (Conforma Therapeutics) IPI-504, CNF1010, CNF2024,CNF1010；Temozolomide, AUY922 from Novartis Co., Ltd (Novartis).

The term as used herein " anti proliferative antibody " include but is not limited to Erbitux, bevacizumab, Rituximab, PROM553 (anti-CD40) and 2C4 antibody." antibody " means for example complete monoclonal antibody, polyclonal antibody, by least two The multi-specificity antibody and antibody fragment that complete antibody is formed, as long as they show required biological activity.

Term " antileukemie compound " includes such as pyrimidine analogue Ara-C, it is the 2'- Alpha-hydroxy of deoxycytidine Ribose (cytarabine) derivative.It further include purine analogue hypoxanthine, Ismipur (6-MP) and fludarabine phosphate. For the treatment of acute myeloid leukaemia (AML), formula (i) compound can be combined with standard leukemia therapies, especially with Therapy for treating AML is combined.Specifically, formula (i) compound can be with such as farnesyl transferase inhibitor and/or other For treating the administered in combination of AML, such as daunorubicin, adriamycin, Ara-C, VP-16, Teniposide, mitoxantrone, Idarubicin, card molybdenum and PKC412.

" the somatostatin receptor antagonist " used herein refer to targeting, reduction or inhibit somatostatin by The compound of body, such as Octreotide and SOM230.

" tumor cell damage means " refer to the means such as ionising radiation.Term " ionization spoke mentioned in context Penetrate " mean the ionising radiation occurred in the form of electromagnetic radiation (such as X-ray and gamma-rays) or particle (such as α and β particle).Ionization Radiation is to provide in (but being not limited to) radiotherapy, and be known in the art.Referring to Hellman, Principles of Radiation Therapy (radiotherapy principle) is embodied in Cancer, Principles and Practice of Oncology (" cancer: oncology principle and practice "), Devita etc. are compiled, and the 4th edition, volume 1,248-275 pages (1993).

The term as used herein " EDG bonding agent " refers to the immunosuppressant for adjusting lymphocyte recirculation, such as FTY720.

Term " driving albumen spindle protein inhibitor " is known in the art and including from GlaxoSmithKline PLC SB715992 or SB743921, pentamidinum/chlorpromazine from CombinatoRx.

Term " mek inhibitor " is known in the art and including from A Lai biopharmaceutical company (Array PioPharma) ARRY142886 comes from AZD6244, the PD181461 from Pfizer of AstraZeneca (AstraZeneca), sub- Folic acid.

Term " ribonucleotide reductase inhibitors " includes but is not limited to pyrimidine or purine nucleoside analogs, including but not It is limited to fludarabine and/or cytarabine (ara-C), 6- thioguanine, 5 FU 5 fluorouracil, Cladribine, Ismipur is (outstanding It is combined with ara-C for anti-ALL) and/or Pentostatin.Specific ribonucleotide reductase inhibitors are hydroxycarbamide or 2- Hydroxyl -1H- iso-indoles -1,3- derovatives, such as Nandy etc., Acta Oncologica, volume 33, the 8th phase, 953- PL-1, PL-2, PL-3, PL-4, PL-5, PL-6, PL-7 or the PL-8 referred in page 961 (1994).

The term as used herein " S adenosylmethionine decarboxylase inhibitor " includes but is not limited to public in US5,461,076 The compound opened.

The also specific monoclonal including those compounds, protein or VEGF/VEGFR disclosed in WO 98/35958 is anti- Body, such as 1- (4- chloroanilino) -4- (4- pyridylmethyl) phthalazines or its pharmaceutically-acceptable salts such as succinate, Huo Zhe It is public in WO 00/09495, WO 00/27820, WO 00/59509, WO 98/11223, WO 00/27819 and EP 0 769 947 Those of open；Those of as described in following documents: Prewett etc., Cancer Res, volume 59,5209-5218 pages (1999)； Yuan etc., Proc Natl Acad Sci USA, volume 93,14765-14770 pages (1996)；Zhu etc., Cancer Res, the Volume 58,3209-3214 pages (1998)；With Mordenti etc., Toxicol Pathol, volume 27, the 1st phase, 14-21 pages (1999)；W000/37502 and W094/10202；Angiostatin (ANGIOSTATIN), O ' Reilly etc., Cell, volume 79, Described in 315-328 pages (1994)；Endostatin (ENDOSTATIN), O ' Reilly etc., Cell, volume 88,277-285 pages (1997) described in；Anthranilic amides；ZD4190；ZD6474；SU5416；SU6668；Bevacizumab；Or anti-vegf is anti- Body or anti-vegf receptor antibody, such as rhuMAb and RHUFab, VEGF aptamer such as Macugon；FLT-4 inhibitor, FLT-3 inhibit Agent, VEGFR-2IgGl antibody, blood vessel enzyme (Angiozyme) (RPI 4610) and bevacizumab.

" photodynamic therapy " used herein, which refers to using certain chemicals for being referred to as light-sensitive compound, to be treated or prevented The therapy of cancer.The example of photodynamic therapy includes the treatment carried out with drugs such as Verteporfin and Porfimer Sodiums.

" steroids for inhibiting blood vessel " used herein refers to blocking or inhibits the drug of angiogenesis, such as anecortave, song Anxi dragon, hydrocortisone, 11- α-table hydrogen cortisol (epihydrocotisol), deoxidation cortisone, 17- α-light progesterone, skin Matter ketone, deoxycortone, testosterone, oestrone and dexamethasone.

" corticosteroid " used herein includes but is not limited to the compounds such as fluocinolone acetonide, dexamethasone；Especially Implantation material form.

Other chemotherapeutics include but is not limited to plant alkaloid, hormonal compounds and antagonist；Biological response conditioning agent, it is excellent Select lymphokine or interferon；Antisense oligonucleotides or oligonucleotide derivative；ShRNA or SiRNA；Or mixed compounds or Compound with other mechanisms of action or unknown role mechanism.

Combination product of the present invention can also be combined with one or more other medicines or including it, the drug is selected from anti- Scorching medicine；Antihistamine；Bronchodilators, NSAID；Chemokine receptor anagonists.

Suitable anti-inflammatory drug includes steroids, especially glucocorticoids for example budesonide, beclomethasone dipropionate, Steroids described in fluticasone propionate, ciclesonide or mometasone furoate or following documents: WO 02/88167, WO 02/ 12266, WO 02/100879, WO 02/00679 (especially embodiment 3,11,14,17,19,26,34,37,39,51,60, 67, those of in 72,73,90,99 and 101), WO 03/035668, WO 03/04818U, 03/062259 WO, WO 03/ 064445,03/072592 WO, non-steroid glucocorticoid receptor agonist, those of as described in following documents: WO 00/00531,WO 02/10143,WO 03/082280,WO 03/082787,WO 03/104195,WO 04/005229；

LTB4 antagonist, as LY293111, CGS025019C, CP-195543, SC-53228, BIIL284, ONO 4057, Those of described in SB 209247 and US 5451700；LTD4 antagonist, such as montelukast and zafirlukast；PDE4 inhibitor, Such as cilomilast, roflumilast (hectogram (Byk Gulden)), V-11294A (Napp), BAY19-8004 (Bayer (Bayer)), SCH-351591 (Schering Plough (Schering-Plough)), arofylline (the limited public affairs of Amelia medical Take charge of (AlmiralI Prodesfarma)), PD 189659/PD168787 (Parker-Davis (Parke-Davis)), AWD- 12-281 (Ace reaches Pharmacy stock Co., Ltd (Asta Medica)), CDC-801 (Sai Er gene (Celgene)), SelCID (TM) CC-10004 (Sai Er gene), VM554/UM565 (Vernalis), T-440 (field side (Tanabe)), KW-4490 (consonance Fermentation industry Co., Ltd. (Kyowa Hakko Kogyo)) and following documents disclosed in those: WO 92/19594, WO 93/ 19749、WO 93/19750、WO 93/19751、WO 98/18796、WO 99/16766、WO 01/13953、WO 03/ 104204、WO 03/104205、WO 03/39544、WO 04/000814、WO 04/000839、WO 04/005258、WO 04/ 018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/018431、WO 04/018449、WO 04/018450、WO 04/018451、WO 04/018457、WO 04/018465、WO 04/019944、WO 04/019945、WO 04/045607 and WO 04/037805；A2a agonist, as disclosed in following documents those: EP 409595A2, EP 1052264、EP 1241176、WO 94/17090、WO 96/02543、WO 96/02553、WO 98/28319、WO 99/ 24449、WO 99/24450、WO 99/24451、WO 99/38877、WO 99/41267、WO 99/67263、WO 99/ 67264、WO 99/67265、WO 99/67266、WO 00/23457、WO 00/77018、WO 00/78774、WO 01/ 23399、WO 01/27130、WO 01/27131、WO 01/60835、WO 01/94368、WO 02/00676、WO 02/ 22630, WO 02/96462, WO 03/086408, WO 04/039762, WO 04/039766, WO 04/045618 and WO 04/ 046083；A2b antagonist, those of as described in WO 02/42298；And beta-2-adrenoceptor agonist, such as Aerolin (salbutamol), orciprenaline, Terbutaline, salmeterol, fenoterol, Procaterol and especially Formoterol and its medicine The compound of formula I (free or salt or solvate form thereof) of acceptable salt and WO 0075114 on, the document passes through introducing It is included in herein, preferably the compound of embodiment, especially with the compound of following formula

With compound of formula I (the free or salt or solvate shape of its pharmaceutically-acceptable salts and WO 04/16601 Formula) and WO 04/033412 compound.

Suitable bronchodilators includes anticholinergic or antimuscarinic compounds, especially Ipratropium Bromide, oxygen support Bromine ammonium, tiotropium salt and CHF 4226 (Kai Xi (Chiesi)) and glycopyrronium, there are also WO 01/04118, WO 02/51841, WO 02/53564、WO 03/00840,WO 03/87094、WO 04/05285、WO 02/00652、WO 03/53966、EP 424021, those of described in US 5171744, US 3714357, WO 03/33495 and WO 04/018422.

Suitable chemokine receptor anagonists include such as CCR-1, CCR-2, CCR-3, CCR-4, CCR-5, CCR-6, CCR-7, CCR-8, CCR-9 and CCR10, CXCRl, CXCR2, CXCR3, CXCR4, CXCR5, especially CCR-5 antagonist are such as first Antagonist SC-351125, SCH-55700 and SCH-D of Ling Baoya, antagonist such as the N- [[4- [[[6,7- of military field (Takeda) Dihydro -2- (4- aminomethyl phenyl) -5H- benzo ring heptene -8- base] carbonyl] amino] phenyl] methyl] tetrahydro-N, N- dimethyl - CCR-5 antagonist described in 2H- pyrans -4- ammonium chloride (TAK-770) and following documents: US 6166037 (especially want by right Ask 18 and 19), WO 00/66558 (especially claim 8), WO 00/66559 (especially claim 9), WO 04/ 018425 and WO04/026873.

Suitable antihistamine drug include Cetirizine Hydrochloride, paracetamol, clemastine fumarate, fenazil, Loratadine, Desloratadine, diphenhydramine and fexofenadine hydrochloride, Acrivastine (activastine), astemizole, Nitrogen generation sting, Ebastine, epinastine, Mizolastine and tefenadine (tefenadine) and WO 03/099807, WO Those of disclosed in 04/026841 and JP 2004107299.

The structure of the active constituent determined by Code Number, common name or trade name can be from standard outline " The Merck The current edition of Index (" Merck index ") " or from database such as Patents International (international monopoly) (such as IMS World Publications (IMS World Publications)) is obtained.Its corresponding contents is incorporated by reference herein.

Term " pharmaceutically effectively " is preferably directed to for disease or disorder is in progress in the treatment or (more broadly) is also preventing Upper effective amount, as disclosed herein.

The term as used herein " commercial packing " especially defines " complete kit ", in this sense such as the group of contextual definition Point (a) MET tyrosine kinase inhibitor and (b) FGFR tyrosine kinase inhibitor and optional other auxiliary agent energy separate administrables or Using component (a) the different fixed Combinations different with (b) amount, i.e., while or in different time points.In addition, these terms include Commercial packing contains and (especially combines) component (a) and (b) and specification as active constituent, and the specification is used for Delay proliferative diseases develop or treatment proliferative diseases in its simultaneously, it is sequentially (long-term staggeredly, preferably suitable with temporal Sequence) or (less preferably) be used separately.Then, complete kit part can for example be administered simultaneously or intersect in chronological order, that is, exist Different time points and time interval is equal or different for complete kit any part.Most preferably, time interval is selected, from And the effect of treated disease is greater than when part described in use in conjunction, any meeting in combined partner (a) and (b) is used only The effect (as being measured according to standard method) of realization.Combined partner (a) and combined partner (b) to be administered with combination formulations is total The ratio between amount is variable, such as in order to meet patient subgroups demand or single patient demand to be treated, different demands may be attributed to trouble Specific age of person, gender, weight etc..Preferably, there is at least one beneficial effect, such as combined partner (a) and (b's) is mutual Therefore improvement effect can be realized with each combination medicine of lower dosage respectively especially more than synergistic effect, only with individual Drug without be treated in combination in the case where tolerance it is lower, generate less or non-effective dose of additional meritorious effects such as side effect The combination therapy effect that one or both of combined partner (a) and (b) of amount generate, and very preferably combined partner (a) and (b) Significant synergistic effect.

Using component (a) and in the case where (b) and commercial packing, while any combination, sequentially and it is used separately It is also possible, it is meant that component (a) and (b) can be administered simultaneously a time point, then only give a kind of host's poison for a long time Property lower component, such as being administered daily more than 3-4 weeks, in latter time point and then give another component or after more when Between point (in the Subsequent pharmacological combined therapy process for optimal effectiveness) give the combination, etc. of 2 kinds of components.

Combination product of the present invention is suitable for treating a variety of diseases, and the disease is respectively by EGFR and/or MET tyrosine-kinase Enzymatic activity mediates and depends particularly on the activity.Therefore, can be used to treat can be by EGFR tyrosine kinase for the combination product Any disease of inhibitor and MET treatment with tyrosine kinase inhibitors.

Term " disease that FGFR tyrosine kinase activity and/or MET tyrosine kinase activity mediate " refers in particular to a certain disease Disease, wherein the activity of one or both of described kinases cause include one of 2 kinds of kinases regulatory pathway activity it is abnormal, especially its Described in one or both of kinases excessive activity, such as due to the overexpression of another control access, mutation or lacked relatively in cell Weary activity, such as wherein before or subsequent controlling element there is amplification, composing type activation and/or excessive activation.

EGFR inhibitor for example can be used for treating it is one or more response activity of EGFR inhibit diseases, especially tumor or Tumor disease, especially solid tumor, more particularly to those of EGFR kinases cancer, including it is breast cancer, gastric cancer, lung cancer, preceding Column gland cancer, bladder cancer and carcinoma of endometrium.Other cancers include kidney, liver cancer, adrenal, gastric cancer, oophoroma, colon cancer, The carcinoma of the rectum, cancer of pancreas, carcinoma of vagina or thyroid cancer, sarcoma, the kinds of tumors and leukaemia of glioblastoma and incidence And Huppert's disease.Particularly preferred breast cancer or oophoroma；Lung cancer, such as NSCLC or SCLC；Head and neck cancer, kidney, Colon and rectum Cancer, cancer of pancreas, bladder cancer, gastric cancer or prostate cancer；Or glioma；Specifically mentioned glioma or colon and rectum carcinoma or knot are straight Intestinal cancer, or particularly refer to lung cancer.It further include the disease dependent on EGFR ligand, the ligand such as EGF；TGF-α；HB-EGF； Amphiregulin；Epiregulin；Cytokine.

MET inhibitor for example can be used for treating MET related disease, especially shows while activating MET and FGFR sign Cancer, including the gene magnification at the residue of instruction activation, activated mutant, homologous RTK ligand expression, RTK phosphorylation, such as Wherein the cancer is selected from the cancer of the brain, gastric cancer, anogenital cancer, urinary organ cancer, prostate cancer, (urine) bladder cancer (shallow and flesh Layer wellability), breast cancer, cervical carcinoma, colon cancer, colorectal cancer, (including glioblastoma, modification star are thin for glioma Born of the same parents' tumor, dash forward less astrocytoma, oligodendroglioma), the cancer of the esophagus, gastric cancer, human primary gastrointestinal cancers, liver cancer, the liver including children HCC it is thin It is born of the same parents' cancer (HCC), head and neck cancer (including head and neck squamous cell carcinoma, nasopharyngeal carcinoma), Xu Telai Schwann Cells cancer, epithelioma, cutaneum carcinoma, black Plain tumor (including chromoma), celiothelioma, lymthoma, myeloma (including Huppert's disease), leukaemia, lung cancer (including Non-small cell lung cancer (including all histological subtypes: gland cancer, squamous cell carcinoma, bronchovesicular cancer, large cell carcinoma and adenosquamous carcinoma Mixed type), Small Cell Lung Cancer), oophoroma, cancer of pancreas, prostate cancer, kidney (including but not limited to papillary clear-cell carcinoma), Intestinal cancer, clear-cell carcinoma (including heredity and sporadic papillary clear-cell carcinoma I type and II type and hyaline cell nephrocyte Cancer)；Sarcoma, especially osteosarcoma, clear cell sarcoma and soft tissue sarcoma (including alveolar shape and (such as Embryo) striated muscle Sarcoma, alveolar shape soft sarcoma)；Thyroid cancer (papillary and other hypotypes).

MET inhibitor can also be used in, for example, treating cancer, wherein the cancer is gastric cancer, colon cancer, liver cancer, genitals Cancer, urinary organ cancer, melanoma or prostate cancer.In a particular implementation, the cancer is liver cancer or the cancer of the esophagus.

MET inhibitor can also be used in, for example, treatment colon cancer, including the metastatic tumor in such as liver, and treatment non-small cell Lung cancer.

MET inhibitor can also be used in, for example, treatment heredity papillary clear-cell carcinoma (Schmidt, L. etc. .Nat.Genet.16,68-73,1997) and other proliferative diseases, wherein c-MET passes through mutation (Jeffers and Vande Woude.Oncogene 18,5120-5125,1999；And references cited therein) or chromosomal rearrangement (such as TPR-MET； The .Nature such as Cooper 311,29-33,1984；Park. equal .Cell 45,895-904,1986) and overexpression or composing type Activation.

MET inhibitor can also be used in, for example, treating other cancers and illness presented herein or known in the art.

MET inhibitor is for example further adapted for treating one or more inflammation.

In another embodiment, the inflammation is attributed to infection.In one embodiment, the treatment method is Block pathogenic infection.In a particular implementation, the infection is bacterium infection, such as listeria (Listeria) The infection of bacterium.See, for example, Shen etc., Cell 103:501-10, (2000), wherein bacterial surface protein passes through bind receptor Extracellular domain activates c-Met kinases, to simulate the effect of cognate ligand HGF/SF.

Combination product of the invention is especially suitable for any cancer of the above-mentioned acceptable EGFR or Met inhibitor for treating for the treatment of, It is especially selected from cancer below: gland cancer (especially breast cancer or more particularly adenocarcinoma of lung), rhabdomyosarcoma, osteosarcoma, wing Guang cancer, colorectal cancer and glioma.

The compounds of this invention of term " therapeutically effective amount " refers to the chemical combination of the present invention that can cause object organisms or medical response Object dosage, such as enzyme or protein active reduce or inhibit or alleviate symptom, improvement illness, slow down or postpone progression of disease or pre- Anti- disease etc..In a non-limiting embodiment, term " therapeutically effective amount ", which is showed, effectively plays following make when giving object The compounds of this invention dosage: (1) at least partly alleviate, inhibit, prevention and/or improve illness or disorder or disease (i) by CMet (MET) is mediated and/or is characterized as cMet and/or activity of EGFR (normal or abnormal) by activity of EGFR mediation or (ii)；Or (2) reduce or inhibit cMet and/or activity of EGFR；Or (3) reduce or inhibit cMet and/or EGFR expression.In another non-limit In property embodiment processed, term " therapeutically effective amount " is showed effectively to be sent out when giving cell or tissue or acellular biomaterials or medium It waves the compounds of this invention dosage of following effect: at least partially reducing or inhibiting cMet and/or activity of EGFR；Or it at least partly drops Low or inhibition cMet and/or EGFR expression.

The term as used herein " object " refers to animal.In general, the animal is mammal.Object also refers to such as primate Animal (such as people), ox, sheep, goat, horse, dog, cat, rabbit, rat, mouse, fish, bird.In some embodiments, described right Like primate.In other embodiments, the object is people.

"and/or" refers to list each or 2 or all components or is characterized in possible variant, in particular by substitution or Wherein 2 kinds or a variety of of accumulation mode.

The term as used herein " inhibition ", " inhibiting effect " or " oppressive " refers to reduction or inhibits given illness, symptom or disorderly The Baseline activity of random or disease or bioactivity or process is remarkably decreased.

In one embodiment, the term as used herein " treatment ", " processing " or " treating " any disease or disorder refer to Improve disease or disorder (slowing down or block or reduce disease development or its at least one clinical symptoms).In another embodiment party In formula, " treatment ", " processing " or " treating " refers to alleviation or improves at least one physical parameter, possibly can not distinguish including patient Those parameters.In another embodiment, " treatment ", " processing " or " treating " refer to physically (as stabilization can distinguish symptom), it is raw (such as stablizing physical parameter) adjusts disease or disorder in reason, or both.In another embodiment, " treatment ", " processing " or " right To " refer to that preventing or delaying disease or disorder occurs or develop or be in progress.

For example, term " treatment " includes to needing the warm-blooded animal (preferably people) of the treatment preventative or especially treat Property give the combined partner, it is intended to cure disease or to disease regression or progression of disease delay work.

As used herein, object " needs " is treated, as long as the object can obtain biology, medicine or life from this kind for the treatment of Benefit in bioplasm amount.

The term as used herein "one", "an", similar terms used in " described " and the context of the invention (especially In the content of claim) it should be interpreted that and cover odd number and plural number, unless otherwise indicated herein or it is apparently contradicted in the context.

Combination of the present invention can prepare in a known way and be suitable for intestines administration as orally or rectally and stomach and intestine Mammal including people (warm-blooded animal) is given outside, at least one pharmacologically active component including therapeutically effective amount Companion, one or more pharmaceutically acceptable carriers, are particularly suited for intestines or parenteral administration alone or in combination.In the present invention An embodiment in, the oral administration of one or more active constituents.

The term as used herein " carrier " or " pharmaceutically acceptable carrier " include any and all solvents, decentralized medium, Coating, surfactant, antioxidant, preservative (such as antibacterial agent, antifungal agent), isotonic agent, absorption delaying agent, salt, anti-corrosion Agent, drug, drug stabilizing agent, adhesive, excipient, disintegrating agent, lubricant, sweetener, flavoring agent, dyestuff etc. and a combination thereof, It is known to those skilled in the art (see, for example, " Remington pharmaceutical science ", the 18th edition Mike printing firm (Mack Printing Company), 1990,1289-1329 pages).Unless any routine carrier is incompatible with the active constituent, otherwise Consider its application in treatment or pharmaceutical composition.

Pharmaceutical combination product of the present invention (as fixed Combination, or as medicine box, is such as made as fixed Combination and individually The combination of agent with one or both of for combined partner, or as the medicine box of combined partner body preparation) include group of the invention Close companion (at least one MET tyrosine kinase inhibitor, at least one EGFR tyrosine kinase inhibitor and optional one kind or A variety of other auxiliary agents) and one or more pharmaceutically acceptable carrier materials (carrier, excipient).The combination product or structure At its combined partner can be formulated for specific administration approach be such as administered orally, parenteral and rectally.In addition, this The combination product of invention can be made solid form (including but not limited to capsule, tablet, pill, granule, powder or suppository) or Liquid form (including but not limited to solution, suspension or emulsion).The combination product and/or combination thereof companion can receive routine Pharmaceutical operation is as sterilized and/or can include conventional inert diluent, lubricant or buffer and adjuvant such as preservative, stabilization Agent, wetting agent, emulsifier and buffer etc..

In one embodiment, described pharmaceutical composition is tablet or gelatine capsule, containing the active constituent and One or more common vectors, such as one or more carriers selected from the group below:

A) diluent, such as lactose, dextrose, sucrose, mannitol, sorbierite, cellulose and/or glycine；

B) lubricant, such as silica, talcum, stearic acid, its magnesium or calcium salt and/or polyethylene glycol；Also for tablet Have

C) adhesive, for example, aluminium-magnesium silicate, gelatinized corn starch, gelatin, bassora gum, methylcellulose, sodium carboxymethylcellulose and/ Or polyvinylpyrrolidone；If necessary

D) disintegrating agent, such as starch, agar, alginic acid or its sodium salt or effervescent agent mixture；With

E) adsorbent, colorant, flavoring agent and sweetener.

According to methods known in the art, tablet can be film coating or enteric coating.

For the suitable compositionss of oral administration particularly including a effective amount of one or more or (in fixed Combination preparation feelings In condition) each combined partner (active constituent), form is tablet, pastille, aqueous or Oil suspensions, dispersible powder or particle Agent, emulsion, hard capsule or soft capsule or syrup or elixir.Appointing for pharmaceutical composition is used to prepare according to known in the art Where method prepares the composition for being intended for oral use, and such composition can containing selected from sweetener, flavoring agent, One or more reagents of toner and preservative are in order to provide pharmaceutical elegant and palatable preparation.Tablet can contain and be suitable for Prepare the active constituent that excipient mixing is subjected on the non-toxic pharmaceutical of tablet.These excipient are such as inert diluents, such as Calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate；Granulation and disintegrating agent, such as cornstarch or alginic acid；Adhesive, such as Starch, gelatin or Arabic gum；And lubricant, such as magnesium stearate, stearic acid or talcum.Tablet is uncoated or by known Therefore technology coatings provide lasting effect to delay disintegration and absorption in the gastrointestinal tract in the longer time.For example, Time delay material such as glycerin monostearate or glycerol distearate can be used.Preparation for oral use can also be with glutoid The form of capsule exists, wherein mixing active constituent with inert solid diluent such as calcium carbonate, calcium phosphate or kaolin；Or with The form of Perle exists, wherein mixing active constituent with water or oil medium such as peanut oil, atoleine or olive oil.

Certain injectables composition (be used in particular for for example antibody be used as EGFR inhibitor when) be aqueous isotonic solutions or Suspension, suppository are advantageously prepared by fat emulsion or suspension.The composition can sterilize and/or contain adjuvant, such as Preservative, stabilizer, wetting agent or emulsifier, solubilizer, salt and/or buffer for adjusting osmotic pressure.In addition, they Other therapeutically valuable substances can be contained.The composition be respectively according to it is conventional mixing, granulation or coating method come Preparation, and contain about 0.1-75% or the active constituent containing about 1-50%.

Suitable compositionss for transdermal application include a effective amount of one or more active constituents and suitable carrier.It is applicable in In the carrier of transdermal delivery include the acceptable solvent of absorbable pharmacology to assist passing through host skin.For example, transdermal dress Be set to form of bandage comprising backing film, containing optionally with the compound reservoirs of carrier, optional rate control barrier with In delivering compound in the extended period to host skin under controlled, set rate, and device is fixed to the work of skin Tool.

Composition suitable for topical application in such as skin and eyes include aqueous solution, suspension, ointment, cream, Gelling agent or sprayable preparation, such as being delivered by aerosol etc..Such local delivery system will be particularly suitable for Corium application, such as the treatment of cutaneum carcinoma, such as the preventative purposes in suncream, lotion, spray.Therefore it Particularly suitable for local use, including cosmetics, preparation well known in the art.It can promote containing solubilizer, stabilizer, tension Agent, buffer and preservative.

As used herein, topical application can also refer to sucking or intranasal application.They are convenient to (single in dry powder form Solely, as mixture, such as the dry mixture with lactose, such as the blending constituent particle with phosphatide) from Diskus Delivering, or presented from pressurizing vessel, pump, spraying, atomizer or sprayer with aerosol spray, using or be not used suitably Propellant.

The present invention relates to complete kit or fixed drug compositions comprising effective quantity especially states disease in the treatment One of in a effective amount of at least one MET tyrosine kinase inhibitor, at least one tyrosine kinase EGFR inhibitor or it is each From pharmaceutically-acceptable salts, and optional at least one other auxiliary agent or its pharmaceutically-acceptable salts and one or more medicines Acceptable carriers on, the carrier is suitable for part, intestines is for example oral or rectal or parenteral and can be inorganic Or organically, solid or liquid.

In all formulations, the active constituent of part combination product formed according to the present invention can be made so that 0.5-95 weight % is corresponding The relative quantity of agent (about described preparation itself, i.e., without packaging and pamphlet) exists, such as respectively 1-90,5-95,10-98 Or 10-60 or 40-80 weight %.

Active ingredient agent amount applied to warm-blooded animal depends on many factors, type, kind, age including patient, Weight, gender and medical conditions；The seriousness of treated illness；Administration route；The hepatic and renal function of patient；And it is used specific Compound.Doctor, clinician or animal doctor with common skill can easily determine and prescription prevention, confrontation or prevention illness A effective amount of drug needed for progress.Realize that the best precision of drug concentration is wanted in the range of generating effect without toxicity Seek dynamic (dynamical) scheme of the availability for target position based on drug.This includes distribution, balance and the elimination for considering drug.Wait give Give that warm-blooded animal such as weight is about each combined partner of 70kg people or the dosage of its pharmaceutically-acceptable salts is preferably that everyone is every Its about 3mg to about 5g, more preferably from about 10mg are to about 1.5g, such as are divided into the preferred 1-3 single doses that may, for example, be same size Amount, it is such as daily using once or twice.In general, children receive the half of adult human dose.

For example, pharmaceutical combination product of the invention can be the about 1-1000mg active constituent for about 50-70kg object Unit dose, or for any active constituent or especially active constituent summation about 1-500mg or about 1-250mg or The unit dose of about 1-150mg or about 0.5-100mg or about 1-50mg；Or just any active constituent or especially activity It (particularly for EGFR inhibitor) is respectively 50-900,60-850,75-800 or 100-600mg for ingredient summation.Treatment has Imitate the compound of dosage, pharmaceutical composition or combinations thereof depend on object kind, weight, age and individual treated illness, Disorder or disease or its seriousness.Doctor, clinician or (animal applications) animal doctor with common skill can easily determine Prevent, treat or inhibit a effective amount of each active constituent needed for disorder or progression of disease.

Only certain exemplary embodiments of this invention also provides in the claim and embodiment being totally incorporated herein by reference.

Summary of the invention

This disclosure relates to pharmaceutical composition, such as product, including following combination: (i) MET inhibitor and (ii) EGFR (ErbB-1) Inhibitor or its respectively pharmaceutically-acceptable salts or its prodrug, the ingredient plays a role jointly treats proliferative diseases, with And it is related to corresponding pharmaceutical preparation, purposes, method, technique, commercial packing and related invention embodiment.

Brief description

The fluoro- N- methyl -4- of Fig. 1: MET inhibitor 2- [(7- quinoline -6- base-methyl)-imidazo [1,2-b] triazine -2- Base] benzamide and the combination of EGFR inhibitor Gefitinib in vitro effects diagram, the combination overcomes HCC827GR lung cancer To the resistance of single agents Gefitinib in cell；Dot: Gefitinib；Square: the fluoro- N- methyl -4- of 2- [(7- quinoline -6- Base-methyl)-imidazo [1,2-b] triazine -2- base] benzamide；Triangle: Gefitinib and fluoro- N- methyl-the 4- [(7- of 2- Quinoline -6- base-methyl)-imidazo [1,2-b] triazine -2- base] benzamide combination.

Fig. 2: HCC827 cell is assigned to the in vitro effects figure of the external source HGF (hepatocyte growth factor) of gefitinib resistant Show.

Fig. 3: the fluoro- N- methyl -4- of (internal) MET inhibitor 2- [(7- quinoline -6- base-first in the mouse that embodiment provides Base)-imidazo [1,2-b] triazine -2- base] benzamide and EGFR inhibitor Gefitinib the first combination experiment diagram.Lotus There is the female Nude mice of the HCC827GR5 subcutaneous transplantation object fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-methyl)-imidazoles And [1,2-b] triazine -2- base] benzamide, Gefitinib, the combination of 2 kinds of reagents or carrier compare with shown dosage and scheme Treatment.Treatment starts after tumor cell transplantation and continuously continues 13 days for 11 days.The statistics of Δ gross tumor volume and Δ weight is carried out, With One-way ANOVA, subsequent Deng Nite method (p < 0.05 * is compareed compared to carrier) to compare treatment group and carrier control group, and One-way ANOVA, subsequent Du's Kjeldahl method are for comparing (p < 0.05 * between relevant group) in pairs.Left side: with the tumour body of time Product.Right figure: with the weight of time.

Fig. 4: the fluoro- N- methyl -4- of (internal) MET inhibitor 2- [(7- quinoline -6- base-first in the mouse that embodiment provides Base)-imidazo [1,2-b] triazine -2- base] benzamide and EGFR inhibitor Gefitinib the second combination experiment diagram.Lotus There is the female Nude mice of the HCC827GR5 subcutaneous transplantation object fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-methyl)-imidazoles And [1,2-b] triazine -2- base] benzamide, Gefitinib, the combination of 2 kinds of reagents or carrier compare with shown dosage and scheme Treatment.Treatment starts after tumor cell transplantation and continuously continues 13 days for 11 days.The statistics of Δ gross tumor volume and Δ weight is carried out, With One-way ANOVA, subsequent Deng Nite method (p < 0.05 * is compareed compared to carrier) to compare each group and carrier and unidirectional variance Analysis, subsequent Du's Kjeldahl method are used in pairs relatively (p < 0.05 * between relevant group).

Fig. 5: as the tumor Volume Changes figure of time is shown after (internal) treatment is interrupted in mouse, such as the more detailed institute of embodiment It states.Lotus has the female Nude mice of the HCC827GR5 subcutaneous transplantation object fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-first Base)-imidazo [1,2-b] triazine -2- base] benzamide, Gefitinib, the combination of 2 kinds of reagents or carrier compare with shown agent Amount and Regimen Chemotherapy.Treatment starts after tumor cell transplantation and continuously continues 13 days for 11 days.It is (thin at the end of second Efficacy experiments The 24th day after born of the same parents' injection), the fluoro- N- methyl -4- of 2- [(7- quinoline -6- base-methyl)-imidazo [1,2-b] triazine -2- base] will be used The group and combination partner of benzamide treatment are at 2 groups, every group of each 4 animal.4 are observed in no any treatment (left figure) Animal, and another 2 groups of 4 animals keep before daily treatment (right figure).A gross tumor volume and weight are only recorded weekly. Horizontal line is set as 100 and 500mm³Gross tumor volume.

Embodiment

The following example illustrates the present invention and provides particular implementation, but is not intended to limit the scope of the invention.

The abbreviation of company and cells depositories

ATCC=American Type Culture Collection, Virginia, USA Manassas

The trade mark of hundred Kang Te of Amimed=(BioConcept), Switzerland A Ershiweier

Applied Biosystems=Applied Biosystems, Inc. (Applied Biosystems), California, US Sub- state Foster city

Gibco=belongs to Life Technologies, Inc. (Life Technologies Corporation), USA New York Glan moral Island

Pepro Tech=is sent general Tyke (PeproTech), New Jersey Lip river Ji Shan

Quiagen=Kai Jie company (Quiagen AG), Heerden, Germany

TPP=TPP company (Techno Plastic Products AG), Switzerland spy Lhasa fourth root

Other abbreviations

DMSO=dimethyl sulfoxide