CN102268000A

CN102268000A - Novel spiroheterocyclic compound and application of same serving as therapeutic agent

Info

Publication number: CN102268000A
Application number: CN2011101204765A
Authority: CN
Inventors: 李校堃; 梁广; 赵承光; 吴建章; 蔡跃飘; 王怡
Original assignee: Wenzhou Medical College
Current assignee: Wenzhou Medical College
Priority date: 2011-05-05
Filing date: 2011-05-05
Publication date: 2011-12-07

Abstract

The invention relates to a spiroheterocyclic compound shown as a formula (I), and a stereoisomer, an enantiomer, a tautomer or a mixture thereof, or a pharmaceutically acceptable salt, a solvate or a pre-drug thereof, wherein (II, k, j, P, Q, R1, R2 and R3) are defined in the specifications; and the spiroheterocyclic compound can be used for treating and/or preventing diseases or disease states, such as cancer, mediated by a fibroblast growth factor and an acceptor signal path thereof. The invention further discloses a medicinal composition comprising the compound and a method for using the compound.

Description

The novel spiroheterocyclic compound of one class and as the purposes of therapeutical agent

Technical field

The present invention relates to spiroheterocyclic compound.Particularly, the present invention relates to following spiroheterocyclic compound, its for the fibroblast growth factor acceptor inhibitor and therefore can be used for treating such as the disease of fibroblast growth factor such as cancer and the mediation of receptor signal path thereof or morbid state and with fibroblast growth factor and relevant other disease and the morbid state of receptor signal path mediation thereof.

Background technology

With the Tyrosylprotein kinase is the focus and the field, forward position of molecular targeted antitumor drug research and development having become the current life science and the pharmaceutical science of target spot.Malignant tumour is a most serious class disease of present harm humans life and health, the research of antitumor drug is the important topic in medicament research and development field always, the treatment common drug of clinical tumor is a conventional cell toxicity class medicine, but there are shortcomings such as selectivity is low, toxic side effect is big in such medicine.In recent years, the researchist constantly explores and furthers investigate the effect of all kinds of Tyrosylprotein kinases in tumour cell malignant proliferation process, and verified effective inhibition tyrosine protein kinase can reach the purpose for the treatment of tumour.Many effective tyrosine kinase inhibitor medicines go on the market successively, and more high reactivity inhibitor molecules also are in clinical experimental stage.Therefore, Tyrosylprotein kinase has become the important target spot of novel molecular targeting anti-tumor medicament research and development.

Fibroblast growth factor acceptor (fibroblast growth factor receptor, FGFRs) be the Tyrosylprotein kinase receptor that a class is worn film, it and fibroblast growth factor (fibroblast growth factor receptor, FGFs) can mediate many bars transduction paths in conjunction with the FGF/FGFR signal transmission that is constituted, extracellular signal is delivered in the born of the same parents, to propagation, differentiation and the apoptosis of normal cell and tumour cell, and important regulatory role is all brought into play in aspects such as growth of tumor and transfer.Many research reports, the unusual rise that multiple pathology such as tumour and FGF/FGFR express is closely related.The generation of FGF/FGFR and tumour and the relation of development are mainly as follows: (1) is in kinds of tumor cells such as bladder cancer, cancer of the stomach, colorectal carcinoma, carcinoma of endometrium, prostate cancer, fibroma, rhabdosarcoma, neurospongioma and melanoma, all find sudden change or the high level expression of FGF/FGFR, the highest normal value that can exceed is more than 100 times; (2) FGF is strong mitogenic factor, can promote the rapid abnormal propagation of tumour cell; (3) FGF is one of the strongest angiogenesis factor, and angiogenesis not only provides nutrient and oxygen for tumour cell, promotes its growth, the more important thing is also to provide the foundation for invasion by tumor cells, transfer and diffusion; (4) FGF can mediate the antitumor drug resistance of wide spectrum, and tumour cell to the resistance of chemotherapeutics and in the metastatic tumo(u)r treatment the limited curative effect of chemotherapy be topmost clinically two challenges.Therefore, FGFR is regarded as one of treatment of diseases targets such as tumour and receives much concern.

In sum, more and more signal path tailor-made really using in tumor vessel takes place that studies show that the FGFR mediation, therefore optionally suppress FGFR Mediated Signal Transduction approach, can reach the purpose of treatment tumour, for the targeted therapy tumour has been opened up a practical way.And, with FGF/FGFR the signal transmission that the inhibitor medicaments of target can be blocked FGF, suppress the generation of tumor tissues new vessel, suppress growth, division and the transfer of tumour cell, and do not kill and wound normal cell, be different from the traditional tumour treatment.Therefore, the novel antitumor drug of seeking efficient, low toxicity, wide spectrum or single-minded characteristic is the target that many medicine workers pursue, and also is current vast medical worker and scientific research personnel's urgent task.

Up to now, the medicine of many effective target Tyrosylprotein kinases goes on the market successively and is applied to clinically, and has 150 micromolecular inhibitors at Tyrosylprotein kinase also carrying out clinical trial approximately.FGFR is one of important tyrosine kinase receptor.For the FGFR inhibitor, scientist has found that in succession some high reactivities such as SU5402 and CHR258 and selective binding are in the reversible inhibitor (as Fig. 1) of SRCA TP binding sites such as FGFR, VEGFR or PDGFR.The inhibitor NP603 that obtains according to FGFR1 inhibitor SU6668 and PD173074 structure design is to the 503nhibiting concentration of FGFR1 even can reach 0.4 μ M.

Summary of the invention

For example the present invention relates to be used for the treatment of and/or prevent fibroblast growth factor and the disease of receptor signal path mediation or the spiroheterocyclic compounds of morbid state such as tumour.The compounds of this invention also is used for the treatment of the disease or the morbid state of other fibroblast growth factor and the mediation of receptor signal path thereof, including but not limited to craniosynostosis, dwarfing, ripe fetal rickets, Kalman's syndromes and Fa Yifu syndromes etc.

Therefore, an aspect of of the present present invention provides general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvate or prodrug:

Wherein:

P is 1 to 4;

J and k all are 0,1,2 or 3 independently;

Q is-C (R ^1a) H-,-C (O)-,-O-,-S-,-N (R ⁵)-,-CF ₂-,-C (O) O-,-C (O) N (R ⁵)-or-N (R ⁵) C (O)-;

R ^1aFor hydrogen or-OR ⁵

Be condensed hetero-aromatic ring, condensed aromatic ring or condensed heterocycle;

R ¹For hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, aryl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heteroaryl, heterocyclic radical ,-R ⁸-OR ⁵,-R ⁸-CN ,-R ⁹-P (O) (OR ⁵) ₂Or-R ⁹-O-R ⁹-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

R ⁷For hydrogen, alkyl, haloalkyl ,-R ⁹-CN ,-R ⁹-OR ⁵,-R ⁹-N (R ⁴) R ⁵, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl;

Or R ⁶And R ⁷And connected nitrogen forms heterocyclic radical or heteroaryl together;

And R wherein ⁶And R ⁷Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaryl groups can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl ,-R ⁸-CN ,-R ⁸-OR ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹For randomly by-R ⁸-OR ⁵,-C (O) OR ⁵, the aralkyl that replaces of halogen, haloalkyl, alkyl, nitro, cyano group, aryl (optional by cyano replaces), aralkyl (randomly being replaced by one or more alkyl groups), heterocyclic radical or heteroaryl replaces;

Or R ¹For-R ⁹-N (R ¹⁰) R ¹¹,-R ⁹-N (R ¹²) C (O) R ¹¹, or-R ⁹-N (R ¹⁰) C (O) N (R ¹⁰) R ¹¹, wherein:

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

Each-R ¹¹For hydrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ⁹-OC (O) R ⁵,-R ⁹-C (O) OR ⁵,-R ⁹-C (O) N (R ⁴) R ⁵,-R ⁹-C (O) R ⁵,-R ⁹-OR ⁵Or-R ⁹-CN;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

And R wherein ¹⁰With R ¹¹Each aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl group can be randomly by one or more be selected from alkyl, cyclic hydrocarbon radical, aryl, aralkyl, halogen, haloalkyl, nitro ,-R ⁸-CN ,-R ⁸-OR ⁵,-R ⁸-C (O) R ⁵, heterocyclic radical and heteroaryl substituting group replace;

Or R ¹Be heterocyclic radical alkyl or heteroaralkyl, wherein said heterocyclic radical alkyl or heteroaryl groups randomly by one or more be selected from alkyl, halogen, haloalkyl ,-R ⁸-OR ⁵,-R ⁸-C (O) OR ⁵, aryl and aralkyl substituting group replace;

Or R ¹And R ²And can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, and remaining R with its direct-connected nitrogen or carboatomic ring atom ¹Group defines as mentioned;

R ²Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) nR ⁴,-N (R ⁵) S (O) nN (R ⁴) R ⁵,-R ⁸-S (O) nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (N=C (R ⁴) R ⁵) N (R ⁴) R ⁵, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently;

Or R ²And R ¹And can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl, and remaining R with its direct-connected carbon or azo-cycle atom ²Group defines as mentioned;

Each R ³All be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) nR ⁴,-N (R5) S (O) n (R ⁴) R ⁵,-R ⁸-S (O) nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently;

And each R wherein ²Each cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl and heteroaralkyl group can be randomly by one or more be selected from alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-S (O) mR ⁴,-R ⁸-C (O) R ⁴,-R ⁸-C (O) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴And-N (R ⁵) S (O) nR ⁴Substituting group replace, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently:

Or two adjacent R ³Group with its direct-connected condensed hetero-aromatic ring or condensed heterocycle atom can form the condensed ring that is selected from cyclic hydrocarbon radical, aryl, heterocyclic radical and heteroaryl, and remaining R ³The definition as mentioned if group exists;

Each R ⁴And R ⁵Be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, haloalkyl, alkoxyalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical and heteroaryl;

Or work as R ⁴And R ⁵When all being connected on the identical nitrogen-atoms, R ⁴And R ⁵And connected nitrogen-atoms can form heterocyclic radical or heteroaryl together; And

Each R ⁸Be the alkylidene chain of valence bond or straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched; And each R ⁹Be the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched.

On the other hand, the invention provides the treatment Mammals, be preferably the method for tumour among the mankind, wherein said method comprises the invention described above compound of its Mammals of needs being treated significant quantity.

On the other hand, the invention provides treatment or palliate a disease, the method for the seriousness of morbid state or obstacle, it is closely related that wherein said disease state relates to the unusual rise that FGF/FGFR expresses.

On the other hand, the invention provides by suppressing Mammals, be preferably among the mankind through the inoblast factor acceptor, with the method for the treatment inoblast factor and receptor-mediated disease or morbid state, wherein said method comprises the invention described above compound of its Mammals of needs being treated significant quantity.

On the other hand, the invention provides the pharmaceutical composition that comprises the invention described above compound and pharmaceutically-acceptable excipients.In one embodiment, the present invention relates to pharmaceutical composition, wherein be included in the The compounds of this invention in the drug acceptable carrier, and its amount is giving animal, be preferably Mammals, when most preferably being the mankind, treatment and pain diseases associated or morbid state effectively.

On the other hand, the invention provides with the present invention in one or more other compounds or one or more other accepted therapy or it is arbitrarily in conjunction with the pharmacotherapy that combines, improving the effect of existing or future pharmacotherapy, or reduce the side effect relevant with accepting therapy.In one embodiment, the present invention relates to The compounds of this invention and the pharmaceutical composition that therapy that established or future combines are used for the listed indication of the present invention.

The total number of carbon atoms that Ming Ming some chemical group front shorthand notation indication of being put herein exists at indicated chemical group.For example, C ₇-C ₁₂Alkyl is described below literary composition and definedly has the alkyl group of 7 to 12 carbon atoms altogether, and C ₄-C ₁₂The cyclic hydrocarbon radical alkyl is described below the civilian defined cyclic hydrocarbon radical alkyl group of 4 to 12 carbon atoms altogether that has.Carbon sum in the shorthand notation does not comprise the carbon in the substituting group that may be present in described group. and for example, following term has indicated implication:

" C ₁-C ₁₀Alkyl " be meant as the defined alkyl that contains one to ten carbon atom hereinafter.C ₁-C ₁₀Alkyl can be randomly as hereinafter alkyl group being substituted defined.

" C ₂-C ₁₂Alkynyl " be meant as the defined alkynyl that contains two to 12 carbon atoms hereinafter.C ₂-C ₁₂Alkynyl can be randomly as hereinafter alkenyl group being substituted defined.

" C ₁-C ₁₂Alkoxyl group " be meant as the defined alkoxyl group that contains one to 12 carbon atom hereinafter.C ₁-C ₁₂The alkyl of alkoxyl group partly can be randomly as hereinafter alkyl group being substituted defined.

" C ₂-C ₁₂Alkoxyalkyl " be meant as the defined alkoxyalkyl that contains two to 12 carbon atoms hereinafter.C ₂-C ₁₂Each alkyl of alkoxyalkyl partly can be randomly as hereinafter alkyl group being substituted defined.

" C ₇-C ₁₂Aralkyl " be meant as the defined aralkyl that contains seven to 12 carbon atoms hereinafter.C ₇-C ₁₂The aryl of aralkyl partly can be randomly as hereinafter aromatic yl group being substituted defined.C ₇-C ₁₂The alkyl of aralkyl partly can be randomly as hereinafter alkyl group being substituted defined.

" C ₇-C ₁₂Aryl alkenyl " be meant as the defined aryl alkenyl that contains seven to 12 carbon atoms hereinafter.C ₇-C ₁₂The aryl of aryl alkenyl partly can be randomly as hereinafter aromatic yl group being substituted defined.C ₇-C ₁₂The thiazolinyl of aryl alkenyl partly can be randomly as hereinafter alkenyl group being substituted defined.

" C ₃-C ₁₂Cyclic hydrocarbon radical " be meant as the defined cyclic hydrocarbon radical that contains three to 12 carbon atoms hereinafter.C ₇-C ₁₂Cyclic hydrocarbon radical can be randomly as hereinafter the cyclic hydrocarbon radical group being substituted defined.

" C ₄-C ₁₂The cyclic hydrocarbon radical alkyl " be meant as the defined cyclic hydrocarbon radical alkyl that contains four to 12 carbon atoms hereinafter.C ₄-C ₁₂Cyclic hydrocarbon radical can be randomly as hereinafter the cyclic hydrocarbon radical group being substituted defined.

Except that aforementioned, when in specification sheets that is used in this patent and the appended claim, unless opposite appointment is arranged, following term has indicated meaning:

" amido " is meant-the NH group.

" cyano group " is meant-the CN group.

" hydroxyl " is meant-the OH group.

" imines tomb " is meant=the NH substituting group.

" nitro " is meant-the NO group.

" ketone group " is meant=the O substituting group.

" thioketones base " is meant=the S substituting group.

" trifluoromethyl " is meant-CF ₃Group.

" alkyl " is meant the hydrocarbon chain group of straight or branched, only form with nitrogen-atoms by broken, do not contain nonsaturation, has one to 12 carbon atom, be preferably one to eight carbon atom or to six carbon atom, and its be connected to molecule by singly-bound all the other partly, for example methyl, ethyl, n-propyl, 1-methylethyl (sec.-propyl), normal-butyl, n-pentyl, 1,1-dimethyl ethyl (tertiary butyl), 3-methyl hexyl, 2-methyl hexyl etc.Unless clearly address in addition in this specification sheets, alkyl can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, ketone group, TMS ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" thiazolinyl " is meant the hydrocarbon chain group of straight or branched, only form by carbon and nitrogen-atoms, contain at least one two key, have two to 12 carbon atoms, be preferably one to eight carbon atom, and its be connected to molecule by singly-bound all the other partly, for example vinyl, third-1-thiazolinyl, but-1-ene base, penta-1-thiazolinyl, penta-1,4-dialkylene etc.Unless clearly address in addition in this specification sheets, thiazolinyl can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, ketone group, TMS ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Independent is hydrogen, pit foundation, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced by one or more halogen groups), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" alkylidene group " or " alkylidene chain " is meant the bivalent hydrocarbon chain of straight or branched, link all the other part and groups of molecule, only form, do not contain nonsaturation by carbon and nitrogen, and have one to 12 carbon atom, for example methylene radical, ethylidene, propylidene, just-butylidene etc.Alkylidene chain be connected to molecule by singly-bound all the other partly, and be connected to described group by Dan Jian.Alkylidene chain to molecule all the other partly reach can be by carbon of intrachain or any two carbon to the tie point of this group. unless clearly address in addition in this specification sheets, alkylidene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, ketone group, TMS ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" alkenylene " and " alkenylene chain " is meant the bivalent hydrocarbon chain of straight or branched, link all the other part and groups of molecule, only form, contain at least one two key by carbon and hydrogen, and have two to 12 carbon atoms, for example vinylidene, propenylidene, just-crotonylidene etc.The alkenylene chain is connected to all the other parts of molecule by Dan Jian, and is connected to described group by two keys or singly-bound.The alkenylene chain partly reaches tie point to this group to all the other of molecule, can be by carbon of intrachain or any two carbon. unless clearly address in addition in this specification sheets, the alkenylene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, ketone group, TMS ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" alkynylene " or " alkynylene chain " is meant the bivalent hydrocarbon chain of straight or branched, and all the other that link molecule partly and groups only are made up of carbon and nitrogen, contains at least one and three is good for, and have two to 12 carbon atoms, for example inferior proyl, just-butynelene etc.Inferior piece base chain be connected to molecule by Dan Jian all the other partly, and be connected to described group by two strong or singly-bounds.The alkynylene chain partly reaches tie point to this group to all the other of molecule, can be by one of intrachain broken or any two carbon. unless clearly address in addition in this specification sheets, the alkynylene chain can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkenyl group, cyano group, nitro, aryl, cyclic hydrocarbon radical, heterocyclic radical, heteroaryl, ketone group, TMS ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" alkynyl " is meant the hydrocarbon chain group of straight or branched, only form by carbon and hydrogen atom, contain at least one three key, have two to 12 carbon atoms, be preferably one to eight carbon atom, and it is connected to all the other part, for example ethynyl, proyl, butynyl, pentynyl, hexin bases etc. of molecule by singly-bound.Unless clearly address in addition in this specification sheets, alkynyl can randomly be replaced by one of following groups: alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-OR ¹⁴,-OC (O)-R ¹⁴,-N (R ¹⁴) ₂,-C (O) R ¹⁴,-C (O) OR ¹⁴,-C (O) N (R ¹⁴) ₂,-N (R ¹⁴) C (O) OR " ,-N (R ¹⁴) C (O) R ¹⁶,-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-S (O) _tN (R ¹⁴) 2 (wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted, unless otherwise noted.

" C ₂-C ₁₂Alkynyl " be meant the alkynyl that contains two to 12 carbon atoms as defined above.C ₂-C ₁₂Alkynyl can randomly be substituted alkynyl is defined as mentioned like that.

" alkoxyl group " is meant formula-OR _aGroup, wherein R _aAlkyl for defining as mentioned contains one to 12 carbon atom.The alkyl of alkoxyl group partly can randomly be substituted alkyl group is defined as mentioned like that.

" C ₁-C ₁₂Alkoxyl group " be meant the alkoxyl group that contains one to 12 carbon atom as defined above.C ₁-C ₁₂The alkyl of alkoxyl group partly can randomly be substituted alkyl group is defined as mentioned like that.

" alkoxyalkyl " is meant formula-R _a-O-R _aGroup, wherein each R _aBe the alkyl that defines as mentioned independently.Sauerstoffatom can be good for any the breaking that is bonded in any alkyl.Each alkyl of alkoxyalkyl partly can randomly be substituted alkyl group is defined as mentioned like that.

" C ₂-C ₁₂Alkoxyalkyl " be meant the alkoxyalkyl that contains two to 12 carbon atoms as defined above.C ₂-C ₁₂Each alkyl of alkoxyalkyl partly can randomly be substituted alkyl group is defined as mentioned like that.

" aryl " is meant aromatic monocyclic or polynuclear hydrocarbon loop systems, only is made up of nitrogen and carbon, and contains 6 to 19 carbon atoms, and wherein said loop systems can be partly saturated.Aromatic yl group includes but not limited to the group as fluorenyl, phenyl and naphthyl.Unless clearly address in addition in this specification sheets, term " aryl " or prefix " virtue-" (as in " aralkyl ") mean comprise the aryl that is randomly replaced, this substituting group by one or more substituting groups be independently selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, nitro, aryl, heteroaryl, heteroaralkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR " ,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted.

" aralkyl " is meant formula-R _aR _bGroup, wherein R _aBe the alkyl group that defines as mentioned, and R _bBe the one or more aryl that define as mentioned, for example benzyl, diphenyl-methyl etc.Aryl can be randomly being substituted like that as hereinbefore defined.

" C ₇-C ₁₂Aralkyl " be meant the aromatic alkyl group as defined above that contains seven to 12 carbon atoms.C ₇-C ₁₂The aryl of aralkyl partly can randomly be substituted aromatic yl group is defined as mentioned like that.C ₇-C ₁₂The alkyl of aralkyl partly can randomly be substituted alkyl group is defined as mentioned like that.

" aryloxy " is meant formula-OR _bGroup, wherein R _bBe the aryl that defines as mentioned.The aryl of aryloxy partly can be randomly being substituted like that as hereinbefore defined.

" aryl alkenyl " is meant formula-R _cR _bGroup, wherein R _cBe the thiazolinyl that defines as mentioned, and R _bBe one or more aryl of definition as mentioned, its can be randomly being substituted like that as hereinbefore defined.The aryl of aryl alkenyl partly can randomly be substituted aromatic yl group is defined as mentioned like that.The thiazolinyl of aryl alkenyl partly can randomly be substituted alkenyl group is defined as mentioned like that.

" C ₇-C ₁₂Arylalkenyl " be meant the arylalkenyl of the above-mentioned definition that contains seven to 12 carbon atoms.C ₇-C ₁₂The aryl of arylalkenyl partly can randomly be substituted aromatic yl group is defined as mentioned like that.C ₇-C ₁₂The thiazolinyl of arylalkenyl partly can randomly be substituted alkenyl group is defined as mentioned like that.

" aralkoxy " is meant formula-OR _bGroup, wherein R _bBe the aralkyl that defines as mentioned.The aralkyl of aralkoxy partly can be randomly being substituted like that as hereinbefore defined.

" cyclic hydrocarbon radical " is meant stable non-aromatic monocyclic or multi-ring alkyl, only is made up of carbon and nitrogen-atoms, and it can comprise through condensing or the loop systems of bridge joint, has three to 15 carbon atoms, be preferably to have three to ten carbon atoms, and it is saturated or undersaturated.And be connected to molecule by singly-bound all the other partly.Monocyclic groups comprises for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl and ring octyl group.Many cyclic groups for example comprise adamantyl, fall the thatch alkyl, decahydro base, 7 how, 7-dimethyl-dicyclo [2.2.1] heptane base etc.Unless clearly address in addition in this manual, term " cyclic hydrocarbon radical " means and comprises the cyclic hydrocarbon radical that is randomly replaced by one or more substituting groups, this substituting group is independently selected from alkyl, thiazolinyl, halogen, halo pit foundation, haloalkenyl group, cyano group, nitro, ketone group, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR " ,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted.

" C ₃-C ₁₂Cyclic hydrocarbon radical " be meant the cyclic hydrocarbon radical of above-mentioned definition with three to 12 carbon atoms.C ₃-C ₁₂Cyclic hydrocarbon radical can randomly be substituted cyclic hydrocarbon radical is defined as mentioned like that.

" cyclic hydrocarbon radical alkyl " is meant formula-R _aR _dGroup, wherein R _aBe the alkyl that defines as mentioned, and R _dBe the cyclic hydrocarbon radical that defines as mentioned.Alkyl and cyclic hydrocarbon radical can be randomly being substituted like that as hereinbefore defined.

" C ₄-C ₁₂The cyclic hydrocarbon radical alkyl " be meant the cyclic hydrocarbon radical alkyl of above-mentioned definition with four to 12 carbon atoms.C ₄-C ₁₂The cyclic hydrocarbon radical alkyl can randomly be substituted the cyclic hydrocarbon radical alkyl is defined as mentioned like that.

" halogen " is meant bromine, chlorine, fluorine or iodine.

" haloalkyl " is meant the alkyl of definition as mentioned that is replaced by the halogen of one or more definition as mentioned, for example trifluoromethyl, difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl, 1-methyl fluoride-2-fluoro ethyl, 3-bromo-2-fluoropropyl, 1-brooethyl-2-bromotrifluoromethane etc.The alkyl of haloalkyl partly can randomly be substituted alkyl group is defined as mentioned like that.

" condense " be meant with The compounds of this invention in any ring structure as herein described of ring structure condensed that exists. if the condensed ring is heterocycle or hetero-aromatic ring, then becomes condensed heterocycle or the condensed hetero-aromatic ring any carbon atom on the ring structure that exists partly and all can be replaced by nitrogen-atoms.

" heterocyclic radical " or " heterocycle " is meant stable 3-to 18-unit non-aromatic ring group, and it comprises two to 17 carbon atoms and one to ten heteroatoms that is selected from nitrogen, oxygen and sulphur.Unless clearly address in addition in this specification sheets, heterocyclic radical can be monocycle, dicyclo, three ring or tetracyclic loop systems, and it can comprise the loop systems of condensed or bridge joint; And the nitrogen in heterocyclic radical, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternary ammoniated; And heterocyclic radical can be partly or is saturated fully.The example of these heterocyclic radicals includes but not limited to dioxolanyl, thiophene [1,3] dithiane base, the Decahydroisoquinolinpreparation base, imidazolinyl, imidazolidyl, isothiazole alkyl; isoxazole alkyl, morpholinyl, eight azepindole bases, eight nitrogen pseudoindoyl, 2-ketone group piperazinyl, 2-keto piperidine base, 2-Ketopyrroles alkyl oxazolidinyl, piperidyl, piperazinyl, 4-piperazine ketone group, the pyrroline alkyl, pyrazolidyl, thiazolidyl, tetrahydrofuran base, the trithian base, THP trtrahydropyranyl, thio-morpholinyl (thiomorpholinyl), thio-morpholinyl (thiamorpholinyl), 1-ketone group-thio-morpholinyl and 1,1-diketo-thio-morpholinyl.Unless clearly address in addition in this specification sheets, term " heterocyclic radical " mean comprise the heterocyclic radical as hereinbefore defined that is randomly replaced, this substituting group by one or more substituting groups be selected from alkyl, thiazolinyl, halogen, haloalkyl, haloalkenyl group, cyano group, ketone group, thioketones base, nitro, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR " ,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-R ¹⁵-S (O) _tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted.

" heterocyclic radical alkyl " is meant formula-R _aR _eGroup, wherein R _aBe the alkyl that defines as mentioned, and R _eBe the heterocyclic radical or the heterocycle of definition as mentioned, and if heterocyclic radical is a nitrogen heterocycle, then heterocyclic radical can be connected to alkyl on this nitrogen-atoms.The alkyl of heterocyclic radical alkyl partly can randomly be substituted alkyl is defined as mentioned like that.The heterocyclic radical of heterocyclic radical alkyl partly can randomly be substituted heterocyclic radical is defined as mentioned like that.

" heteroaryl " or " heteroaryl ring " is meant 5-to 18-unit aromatic ring group, and it comprises three to 17 carbon atoms and one to ten heteroatoms that is selected from nitrogen, oxygen and sulphur.For purpose of the present invention, heteroaryl can be monocycle, dicyclo, three ring or tetracyclic loop systems, and it can comprise the loop systems of condensed or bridge joint; And the nitrogen in heteroaryl, carbon or sulphur atom can be randomly oxidized; Nitrogen-atoms can be randomly by quaternized.Example includes but not limited to the azepine base, acridyl, benzimidazolyl-, benzothiazolyl, the benzindole base, the benzo dioxolanyl, benzofuryl, benzo is bent azoles base (benzooxazolyl), benzothiazolyl, the diazosulfide base, benzo [b] [1,4] dioxane heptyl, 1,4-benzo two is bent alkyl, benzo aphthofurans base, benzo is bent azoles base (benzoxazolyl), the benzo dioxolanyl, benzo two is bent thiazolinyl, benzopyranyl, the chromene ketone group, benzofuryl, the cumarone ketone group, benzothienyl (benzo thiophenyl), the benzotriazole base, benzo [4,6] imidazo [1,2-a] pyridyl, carbazyl, Zen quinoline base, dibenzofuran group, dibenzofuran group, furyl, furanonyl, isothiazolyl, imidazolyl, indazolyl, indyl, iso indazolyl, indolinyl, iso-dihydro-indole-group, isoquinolyl, the indolizine base, different azoles base in the wrong, naphthyl, phthalazinyl, the bisoxazoline base, 2-ketone group azepine base, bend the azoles base, Oxyranyle, 1-phenyl-1H-pyrryl, phenazinyl, the piperazine base is bent in fen, the 2 base, pteridyl, purine radicals, pyrryl, pyrazolyl, pyridyl, pyrazinyl, pyrimidyl, pyridazinyl, pyrryl, quinazolyl, quinoxalinyl, quinolyl (quinolinyl), the quinoline cyclic group, isoquinolyl (isoquinolinyl), tetrahydric quinoline group (tetrahydroquinolinyl), thiazolyl, thiadiazolyl group, triazolyl, tetrazyl, triazinyl and thiophenyl (being thienyl).Unless clearly address in addition in this specification sheets, term " heteroaryl " mean comprise randomly the heteroaryl of definition as mentioned that is replaced by one or more substituting groups, described substituting group be selected from alkyl, thiazolinyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, atmosphere base, ketone group, thioketones tomb, slightly base, ketone group, aryl, aralkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, heterocycle plug, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ¹⁵-OR ¹⁴,-R ¹⁵-OC (O)-R ¹⁴,-R ¹⁵-N (R ¹⁴) ₂,-R ¹⁵-C (O) R ¹⁴,-R ¹⁵-C (O) OR ¹⁴,-R ¹⁵-C (O) N (R ¹⁴) ₂,-R ¹⁵-N (R ¹⁴) C (O) OR " ,-R ¹⁵-N (R ¹⁴) C (O) R ¹⁶,-R ¹⁵-N (R ¹⁴) S (O) _tR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tOR ¹⁶(wherein t is 1 to 2) ,-R ¹⁵-S (O) _tR ¹⁶(wherein t is 1 to 2) reaches-R ¹⁵-S (O) ^tN (R ¹⁴) ₂(wherein t is 1 to 2), wherein each R ¹⁴Be nitrogen, alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl (randomly being replaced), aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl independently by one or more halogen groups; And each R ¹⁶Be alkyl, haloalkyl, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl or heteroaralkyl, and wherein each above-mentioned substituting group is unsubstituted.

" heteroaralkyl " is meant formula-R ^aR _fGroup, wherein R _aBe the alkyl that defines as mentioned, and R _fHeteroaryl or hetero-aromatic ring base for definition as mentioned.The heteroaryl of heteroaralkyl partly can randomly be substituted heteroaryl is defined as mentioned like that.The alkyl of heteroaralkyl partly can randomly be substituted alkyl is defined as mentioned like that.

" heteroaryl thiazolinyl " is meant formula-R _bR _fGroup, wherein-R ^bBe the thiazolinyl that defines as mentioned, and Rf being the heteroaryl or the hetero-aromatic ring base of definition as mentioned. the heteroaryl of heteroaryl thiazolinyl partly can randomly be substituted heteroaryl is defined as mentioned like that.The thiazolinyl of heteroaryl thiazolinyl partly can randomly be substituted thiazolinyl is defined as mentioned like that.

" tri haloalkyl " is meant the alkyl of definition as mentioned, and it is replaced by three halogens that define as mentioned, for example trifluoromethyl.The alkyl of tri haloalkyl partly can randomly be substituted alkyl is defined as mentioned like that.

" three halogenated alkoxies " is meant formula-OR _gGroup, wherein R _gBe the tri haloalkyl that defines as mentioned.The tri haloalkyl of three halogenated alkoxies partly can randomly be substituted tri haloalkyl is defined as mentioned like that.

" analgesia " is meant and do not have pain when responding the stimulation that causes pain under the normal circumstances.

" allodynia " is meant sensation harmless under the normal circumstances, as pressure or slight contact, is perceived as the morbid state of extreme pain.

" prodrug " is for represent can be under physiological condition or be converted to the compound of bioactive compounds of the present invention by dense dose of decomposition.Therefore, term " prodrug " is meant that the medicine of The compounds of this invention can accept metabolic precursor thereof.Prodrug can be a non-activity when being given the patient who needs, but is converted to active compound of the present invention in vivo.Prodrug promptly is transformed into parent compound of the present invention usually in vivo, for example by hydrolysis in blood. preceding drug compound often provides the advantage of solubleness, histocompatibility or delay release (referring to Bundgard in mammalian organism, H., Design of Prodrugs (prodrug design) (1985), pp.7-9,21-24, (Elsevier, Amsterdam)).

Discussion about prodrug is provided in Higuchi, T., et al, " Pro-drugs as Novel Delivery Systems (prodrug is as novel transmission system) ", A.C.S.Symposium Series, Vol.14 and Bioreversible Carriers in Drug Design (bioreversible carrier in the medicinal design), Ed.Edward B.Roche, American Pharmaceutical Association andPergamon Press, 1987, these both all with the form of reference and in this paper.

Term " prodrug " also means and comprises when these prodrugs are given mammalian object, can discharge any covalently bound carrier of active compound of the present invention in vivo.The prodrug of The compounds of this invention can prepare by the functional group that modification is present on the The compounds of this invention, its mode make in routine operation or in vivo the material of these modifieds become parent compound of the present invention by division.Prodrug comprises compound of the present invention, and wherein hydroxyl, amido or thin base are combined on any group, and when the prodrug of The compounds of this invention was given mammalian object, it division took place forms free hydroxyl, free amino or free sulfhydryl group with division.The example of prodrug includes but not limited to acetic ester, manthanoate and the benzoate derivatives of the alcohol functional group in the The compounds of this invention, becomes the amide derivatives of amine functional group etc.

The purpose of invention disclosed herein also comprises the medicine of all isotope-labeled formulas (I) can accept compound, and wherein one or more are former in the former in displacement of different atomic masses or total mass number arranged by it.The isotopic example that can be gone into disastrously in the disclosed compound comprises the isotropic substance of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine and iodine, as is respectively ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I reaches ¹²⁵I.These radio-labeled compounds can be by characterizing for example active position on the sodium channel or pattern, or the binding affinity of the pharmacology vital role position on the sodium channel is used to help to measure or measure when characterizing the effectiveness of compound.Some is with isotope-labeled formula (I) compound, and for example those are gone into radioactivity disastrously and live plain compound together, can be used for medicine and 1 or the research of substrate tissue distribution.The radio isotope tritium, that is, ³H and carbon-14, promptly ¹⁴C is owing to it is easy to go into disastrously and ready-made detection method, so be particularly useful for this purpose.

With heavier isotropic substance such as deuterium.Promptly ²H replaces, and can provide a little treatment of dress advantages owing to its higher metabolism temperature stability, for example increases the dosage requirement of interior transformation period of body or reduction.And it is therefore preferred in some cases.

With positron send out the envelope isotropic substance as ¹¹C, ¹⁸F, ¹⁵O, ¹³N replaces, and can be used for positive electricity in emission tomography video picture (PEI) research, captures with check substrate acceptor.The routine techniques that isotope-labeled formula (I) compound can be familiar with by ability city technician usually or example and the similar method described in the preparation by hereinafter.Use suitable isotope-labeled reagent to replace the reagent of previous used un-marked and prepare.

Invention disclosed herein also means the interior metabolism product that comprises disclosed compound.Mainly due to enzyme process,, administered compound obtains these products by being carried out oxidation, reduction, hydrolysis, amidation, esterification etc.Therefore, the present invention includes the compound that produces by a kind of method, this method comprises makes compound of the present invention contact for some time with Mammals.Be enough to produce its meta-bolites during this period of time.These products are confirmed usually in the following manner, give animal with radio-labeled compound of the present invention respectively can detect dosage, as rat, mouse, cavy, monkey or people, allow the enough time that metabolism takes place.And from urine, blood or other biological sample, separate its converted product.

" stable compound " is in order to represent enough steadily and surely to separate and be mixed with useful purity the compound of effective therapeutical agent from reaction mixture with " rock steady structure ".

" Mammals " comprises people and domestic animal such as laboratory animal and household pet (for example cat, dog, pig, ox, sheep, goat, horse, rabbit), and non-performing animal, as wildlife etc.

" optional " or " randomly " means incident or the situation described subsequently and can take place or can not take place, and specification sheets comprises situation and nonevent situation that this incident or situation take place.For example " aryl that is randomly replaced " means described aryl and can be substituted or can not be substituted, and specification sheets comprises substituted aryl and do not have substituent aryl.

" drug acceptable carrier, thinner or vehicle " includes but not limited to that any is adjuvant, carrier, vehicle, glidant, sweeting agent, thinner, sanitas, dyestuff/tinting material, odorant, tensio-active agent, wetting agent, dispersion agent, suspension agent, stablizer, isotonic agent, solvent or the emulsifying agent that can accept to be used for people or domestic animal by united States food and drug administration's approval.

" the acceptable salt of medicine " comprises the salt of bronsted lowry acids and bases bronsted lowry addition.

" the acceptable acid salt of medicine " is meant the biological effectiveness of the free alkali of maintenance and the salt of character, it can be not expect biologically or in others, and itself and inorganic acids and organic acid form, this inorganic acids as, but be not limited to, hydrochloric acid, the acid of hydrogen Australia, sulfuric acid, acid slightly, phosphoric acid etc., this organic acid as, but be not limited to, acetate, 2, the 2-dichloro acetic acid, hexanodioic acid, alginic acid, bad hematic acid of Hangzhoupro, aspartic acid, Phenylsulfonic acid, phenylformic acid, the 4-acetaminobenzoic acid, dextrocamphoric acid, camphor-10-sulfonic acid, capric acid, caproic acid, sad, carbonic acid, styracin, citric acid, the hexanaphthene amidosulfonic acid, dodecyl sulphate, ethane-1, the 2-disulfonic acid, ethane sulfonic acid, the 2-hydroxyethanesulfonic acid, formic acid, FUMARIC ACID TECH GRADE, tetrahydroxyadipic acid, gentisinic acid, glucoheptonic acid, glyconic acid, glucuronic acid, L-glutamic acid, pentanedioic acid, 2-ketone group-pentanedioic acid, Phosphoric acid glycerol esters, oxyacetic acid, urobenzoic acid, isopropylformic acid, lactic acid, lactobionic acid, lauric acid, maleic acid, oxysuccinic acid, propanedioic acid, the liquor-saturated acid of phenyl second, methanesulfonic, glactaric acid, naphthalene-1, the 5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxyl-2-naphthoic acid, nicotinic acid, oleic acid, vitamin B13, oxalic acid, the palm fibre eleostearic acid, pamoic acid, propionic acid, Pyrrolidonecarboxylic acid, pyruvic acid, Whitfield's ointment, 4-amido Whitfield's ointment, sebacic acid, stearic acid, succsinic acid, tartrate, thiocyanic acid, to a toluenesulphonic acids, trifluoracetic acid, undecylenic acid etc.

" the acceptable base addition salt of medicine " is meant the biological effectiveness that keeps free acid and the salt of character, and it can be not expect biologically or in others.These salt prepare by adding mineral alkali or organic bases in free acid.Salt derived from mineral alkali includes but not limited to sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminium salt etc.Preferred inorganic salt are ammonium, sodium, potassium, calcium and magnesium salts.Salt derived from organic bases includes but not limited to following salt, primary, the second month in a season and tertiary amine, the replacement amine that comprises natural replacement amine, cyclic amine and deacidite, for example ammonia, Isopropylamine, Trimethylamine 99, diethylamine, triethylamine, tripropyl amine, diethanolamine, thanomin, dimethylethanolamine, the 2-dimethylamino-ethanol, 2-diethylin ethanol, dicyclohexylamine, Methionin, arginine, Histidine, caffeine, PROCAINE HCL, PHARMA GRADE, Hai Baming (hydrabamine), choline, trimethyl-glycine, benzene bright (benethamine), benzyl star (benzathine), quadrol, glucosamine, methylglucosamine, Theobromine, trolamine, tromethane, purine, piperazine, piperidines, N-ethylpiperidine, versamid 900 etc.Especially preferred organic bases is Isopropylamine, diethylamine, thanomin, Trimethylamine 99, dicyclohexylamine, choline and caffeine.

Usually, crystallization effect meeting produces the solvate of The compounds of this invention.Term used herein " solvate " is meant that the aggregate solvent that comprises one or more The compounds of this invention molecules and one or more solvent molecules can be water, and this moment, solvate can be hydrate.Perhaps, solvent can be organic solvent.Therefore, The compounds of this invention can exist by hydrate forms, comprises monohydrate, dihydrate, semihydrate, sesquialter hydrate, trihydrate, tetrahydrate etc., and exists with the corresponding solvent form.The compounds of this invention can be true dense thinner thing, and in other situation, The compounds of this invention can only keep accidental water or add the mixture of a part of accidental solvent for water.

" pharmaceutical composition " is meant in The compounds of this invention and this area that being used to of accepting usually transmit bioactive compounds to the Mammals preparation of people's medium for example.Described medium comprises all drug acceptable carriers for its use, thinner or vehicle.

" treatment significant quantity " is meant the amount of The compounds of this invention, when it is given Mammals, be preferably man-hour, be enough to as hereinafter defining ground Mammals, be preferably philtrum and realize that the treatment to the disease of sodium channel mediation or morbid state constitutes the amount of the The compounds of this invention of " treatment significant quantity ", change according to compound, morbid state and seriousness thereof, administering mode and the mammiferous age that will treat, but can determine according to its own knowledge and present disclosure by persons skilled in the art routinely.

The disease paid close attention to suffering from or the Mammals of morbid state are contained in " treatment " used herein or " treatment ", are preferably the disease of being paid close attention to of philtrum or the treatment of morbid state, and comprise:

(i) ward off disease or morbid state betides in the Mammals, especially easily suffer from this morbid state when these Mammalss, but be not diagnosed as yet when suffering from this morbid state;

(ii) suppress disease or morbid state, promptly stop its development;

(iii) alleviate disease or morbid state, promptly cause disappearing of described disease or morbid state; Or

(iv) alleviate the symptom that disease thus or morbid state cause, i.e. alleviating pain rather than handle basic disease or morbid state.

Term used herein " disease ", with " morbid state " commutative use, perhaps, can be difference, be that this specified disease or morbid state may not have known pathogenic agent (therefore not working out nosetiology as yet), and therefore it be not considered to disease as yet, and only be morbid state or the syndrome of not expecting, wherein specific symptoms combination is more or less confirmed by the clinicist.

The compounds of this invention or the acceptable salt of its medicine can contain one or more asymmetric centers, and therefore can cause enantiomer, diastereomer and other steric isomer, its according to the absolute stereo chemistry be defined as (R)-or (S)-, or to amino acid be (D)-or (L)-.The present invention expectation comprises the isomer that all these are possible, with and racemize and optically pure form.Optical activity (+) and (-), (R)-with (S)-or (D)-can use chiral synthon or chiral reagent preparation, or use routine techniques such as chromatography and fractional crystallization solution with (L)-isomer.The routine techniques of the single enantiomer of preparation/separation comprises from the chirality of suitable optical purity precursor synthetic, or use chirality high pressure lipuid chromatography (HPLC) (HPLC) for example to the fractionation of racemic modification (the perhaps racemic modification of salt or derivative) when described compound herein contains two strong or other how much asymmetric centers of alkene, and unless otherwise, these compound expectations comprise E and Z geometrical isomer.Similarly, also expectation comprises all tautomeric forms.

" steric isomer " is meant by forming by identical valence bond bonded same atoms, but the compound with not interchangeable different three-dimensional structures.Various steric isomers and composition thereof are contained in the present invention's expectation, and comprise " enantiomer ", and it is meant two kinds of steric isomers, and its molecule each other can not the eclipsed mirror image.

" tautomer " is meant that proton is passed to another atom of same molecular from an atom of molecule.The present invention includes the tautomer of any described compound.

The midbody compound of formula (I) and all polymorphic forms of aforementioned species and crystal habit thereof are also within the scope of the invention.

Chemical name draft used herein and structure iron are the correction form of I.U.P.A.C. naming system, use 9.07 editions software programs of ACD/ name, wherein The compounds of this invention be referred to herein as the centronucleus structure derivative to the employed complicated chemical title of this paper, substituting group name is in group front that it connected.For example, the cyclopropyl ethyl comprises and has the substituent ethyl skeleton of cyclopropyl confirmed all chemical bonds in chemical structural drawing, is combined with enough hydrogen atoms to finish the carbon atom of valence state except some is assumed that.

Therefore, general formula (I) compound for example, wherein P is 1, and j is 0, and k is 1, and Q is-C (R ^1a) H-R ^1aBe hydrogen, A is the condensed pyrrole ring, R ¹Be methyl, R ²Be hydrogen, each R ³All independently be selected from hydrogen, i.e. following formula: compound:

Called after in this article: 1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2-fluorophenyl) methylene radical cyclopentanone.

Correspondingly, in second aspect, the invention provides pharmaceutical composition, it contains general formula (I) compound of effective dose, and pharmaceutically acceptable carrier.The preferred low dose pharmaceutical compositions of the present invention is preferred for prevention or treatment cancer.Pharmaceutically acceptable carrier used herein refers to nontoxic weighting agent, stablizer, thinner, adjuvant or other pharmaceutical adjuncts.For example, thinner, vehicle are as water, physiological saline etc.; Weighting agent is as starch, sucrose etc.; Tackiness agent is as derivatived cellulose, alginate, gelatin and/or polyvinylpyrrolidone; Wetting agent is as glycerine; Disintegrating agent is as agar, lime carbonate and/or sodium bicarbonate; Absorption enhancer is as quaternary ammonium compound; Tensio-active agent is as cetyl alcohol; Absorption carrier is as kaolin and/or soap clay; Lubricant is as talcum powder, calcium stearate/magnesium, polyoxyethylene glycol etc.In addition, pharmaceutical composition of the present invention can also further contain other auxiliary material, as flavouring agent, sweeting agent etc.Known technology according to this area, can pharmaceutical composition be made various formulations according to the needs of therapeutic purpose, route of administration, preferred said composition is a unit dosage form, as freeze-dried, tablet, capsule, pulvis, emulsion agent, aqueous injection or sprays, more preferably this pharmaceutical composition be injection type (as, lyophilized injectable powder) or oral dosage form (as, tablet, capsule).Wherein, pharmaceutically acceptable carrier mentioned above is meant the pharmaceutical carrier of pharmaceutical field routine,

Correspondingly, in the third aspect, the invention provides kit, it comprises the pharmaceutical composition of second aspect present invention, and the label of indication low dosage administration.Kit all is a kind of common product for masses, can easily find in pharmacy.Usually, kit comprises the container that the pharmaceutical composition of face is put in the present invention second is housed that in other words, the pharmaceutical composition of second aspect present invention is contained in the container of kit of the present invention.Container can be the container commonly used of pharmaceutical composition that can hold general formula (I) compound and second aspect present invention such as bottle, box, syringe etc.Medicine can include only a container, also can comprise a plurality of containers.Label can be attached on the said vesse, perhaps directly prints on the said vesse, also can exist with form independently, as the kit front cover of stating container or the specification sheets that directly provides can be provided.Label indication is with the compound of low dosage (in general formula (I) compound one or more) administration, wherein, the indication of label specifically can be represented with per weight dosage, also can represent with the absolute dosage of specific crowd, as " adult's consumption " or " children's consumption ", at this moment need simply to convert according to the body weight situation.If what adorn in the container is compositions such as medicine, preparation, then can be according to the content of compound in the unit form of administration (as, a pin), and low dosage is converted into content, with the label indication, this is easily to people.As required, as conveniently transporting, depositing, kit can further be packed in the into bigger packing, and this also within the scope of the invention.

For the ease of understanding, the present invention has quoted open source literature, and these documents are in order more clearly to describe the present invention, its in full content all include this paper in and carry out reference.Below will describe in detail the present invention by specific embodiment and accompanying drawing.It needs to be noted that these descriptions only are exemplary descriptions, do not constitute limitation of the scope of the invention.According to the argumentation of this specification sheets, many variations of the present invention, change have been obviously all concerning one of ordinary skill in the art.

Description of drawings

Fig. 1 mtt assay mensuration part active analogue thereof suppresses active OD value to the increment of U251 and A549 cell

Fig. 2 part of compounds is to the inhibition activity of chicken embryo CAM vasculogenesis

Fig. 3 bFGF is to the influence of ERK1/2 phosphorylation level among the U251

Fig. 4 bFGF is to the influence of FGFR1 phosphorylation level among the U251

Fig. 5 part of compounds is to the influence of FGFR among the U251 and ERK1/2 phosphorylation level

Embodiment

The present invention further specifies in following embodiment.These embodiment are for illustrative purposes, rather than are used for limiting the scope of the invention.

The synthetic logical method and the part of compounds structure elucidation of embodiment 1 compound (I)

The corresponding substituted benzaldehyde of 10mmol is dissolved in the 10mL dehydrated alcohol, adds corresponding cyclopentanone, acetone or pimelinketone behind the stirring at room 5min, continue to stir 10min, solution no change.Sodium Metal 99.5 is dissolved in methyl alcohol, is configured to the sodium methylate/methanol solution of 18% (w/v).Slowly drip this sodium methoxide solution 1.5mL (containing sodium methylate 5mmol) in reaction soln, behind the stirring reaction 2-5h, a large amount of insoluble yellows appear, with TLC detection reaction liquid, the black splotch that no longer occurs raw material 2-bromobenzaldehyde under the 320nm ultraviolet lamp, the distinct displaing yellow of product spot.Stopped reaction, with reacting liquid filtering, product washes with water earlier, subsequently with ice ethanol, ice acetone wash twice, 30 ℃ of vacuum-drying after spending the night yellow powder shape product, after silica gel chromatography purity all greater than 98% compound.

Get the 1mmol above-claimed cpd in 10ml methyl alcohol, and add the amino acid of 1mmol and isatin/acenaphthenequinone of 1mmol, stirring at room a large amount of insoluble yellows occur behind the reaction 2-5h, and TLC point plate is monitored to raw material point and disappeared.Stopped reaction, with reacting liquid filtering, product washes with water, suction filtration, after the dried overnight yellow or red powder shape product, after silica gel chromatography purity all greater than 98% compound.

Sic65:1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-6 '-(2-fluorophenyl) methylene radical pimelinketone, yield 80.65%, fusing point 84.3-85.3 ℃. ¹H-NMR (CDCl ₃) δ: 1.182 (2H, m, 3 '-CH ₂); 1.204,1.778 (2H, m, 4 ' CH ₂); 2.139 (3H, s, N-CH ₃); 2.255 (2H, m, 5 '-CH ₂); 3.451,3.996 (2H, m, 5-CH ₂); 5.137 (1H, m, 4-CH); 7.403 (1H, s, Ar-CH=); 7.831 (1H, s, N-H); 6.732,7.821 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.20,23.00,28.67,31.09,34.83,40.70,56.56,62.67,109.27,114.87,115.02,115.62,115.86,123.14,123.44,123.75,123.84,128.20,129.36,130.04,130.74,131.64,138.51,141.21,159.83,160.88,161.71,162.51,171.11,200.65.ESI-MS m/z:485.3 (M+1) ⁺, calcd for C ₃₀H ₂₆F ₂N ₂O ₂: 484.54.

Sac65:1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-6 '-(2-fluorophenyl) methylene radical pimelinketone, yield 78.77%, fusing point 88.9-90.9 ℃ ¹H-NMR (CDCl ₃) δ: 0.523,1.082 (2H, m, 3 '-CH ₂); 1185,1.900 (2H, m, 4 '-CH ₂); 1.971,2.124 (2H, m, 5 '-CH ₂); 2.111 (3H, s, N-CH ₃); 3.539,4.077 (2H, m, 5-CH ₂); 5.220 (1H, m, 4-CH); 7.552 (1H, s, Ar-CH=); 6.937,8.067 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.80,28.15,31.03,34.78,41.29,57.44,64.02,114.94,115.09,115.41,115.55,120.11,123.37,123.40,123.74,124.04,125.17,125.73,127.80,128.22,129.07,129.96,130.42,131.06,131.26,131.99,132.30,138.51,142.39,161.43,159.77,201.50,207.81ESI-MSm/z:520.3) ⁺, calcd for C ₃₄H ₂₇F ₂NO ₂: 519.58.

Saa65:1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ' 1-5 '-(2-fluorophenyl) methylene radical cyclopentanone, yield 79.60%, fusing point 93.2-97.0 ℃ .1H-NMR (CDCl3) δ: 1.230 (2H, m, 3 '-CH2); 1.883,2.083 (2H, m, 4 '-CH2); 2.165 (3H, s, N-CH3); 3.655,4.144 (2H, m, 5-CH2); 4.833 (1H, m, 4-CH); 7.547 (1H, s, Ar-CH=); 6.751-7.896 (14H, m, Ar-H). δ C:(150MHZ, CDCl3): 26.32,26.53,29.67,34.96,40.00,58.87,65.57,114.93,115.08,115.90,120.23,123.49,124.27,124.90,125.14,125.73,127.91,128.96,129.63,130.132.13,137.42,138.97,142.97,160.48,162.16,206.07,208.21.ESI-MS m/z:506.3 (M+1)+, calcd for C33H25F2NO2:505.55.

Sia65:1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2-fluorophenyl) methylene radical cyclopentanone, yield 71.28%, fusing point 176.0-178.5 ℃. ¹H-NMR (CDCl ₃) δ: 1.241,2.097 (2H, m, 3 '-CH ₂); 2.226,2.319 (2H, m, 4 '-CH ₂); 2.226 (3H, s, N-CH ₃); 3.553,4.045 (2H, m, 5-CH ₂); 4.772 (1H, m, 4-CH); 7.567 (1H, s, Ar-CH=); 7.930 (1H, s, N-H); 6.769-7.815 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 26.10,26.53,30.29,35.03,39.19,58.23,64.81,109.20,114.89,115.04,123.09,124.07,125.54,126.41,127.98,128.33,129.48,130.13,131.05,137.13,138.97,141.33,160.54,160.92,162.22,162.60,195.55,205.49.ESI-MS m/z:471.3 (M+1) ⁺, calcd forC ₂₉H ₂₄F ₂N ₂O ₂: 470.51.

Sia64:1-methyl-4-(2-chloro-phenyl-) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2-chloro-phenyl-) methylene radical cyclopentanone, yield 87.41%, fusing point 146.2-148.2 ℃. ¹H-NMR (CDCl ₃) δ: 1.189,2.000 (2H, m, 3 '-CH ₂); 2.022,2.257 (2H, m, 4 '-CH ₂); 2.221 (3H, s, N-CH ₃); 3.583,4.045 (2H, m, 5-CH ₂); 4.934 (1H, m, 4-CH); 7.594 (1H, s, Ar-CH=); 8.085 (1H, s, N-H); 6.778-8.073 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 25.98,26.55,30.32,35.02,43.62,58.70,64.82,109.19,123.33,125.56,126.27,126.61,126.87,127.92,128.04,129.16,129.44,129.65,129.85,130.04,131.39,133.17,135.22,141.31,157.85,159.86,178.58,206.98.ESI-MS m/z:503.4M ⁺, calcd for C ₂₉H ₂₄Cl ₂N ₂O ₂: 503.4.

Saa64:1-methyl-4-(2-chloro-phenyl-) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(2-chloro-phenyl-) methylene radical cyclopentanone, yield 76.2%, fusing point 77.5-79.8 ℃. ¹H-NMR (CDCl ₃) δ: 1.153,1.237 (2H, m, 3 '-CH ₂); 1.756,2.067 (2H, m, 4 '-CH ₂); 2.167 (3H, s, N-CH ₃); 3.702,4.142 (2H, m, 5-CH ₂); 4.983 (1H, m, 4-CH); 7.570 (1H, s, Ar-CH=); 6.609-8.206 (14H, m, Ar-H) .ESI-MS m/z:538.4M ⁺, calcd forC ₃₃H ₂₅Cl ₂NO ₂: 538.5.

Sac64:1-methyl-4-(2-chloro-phenyl-) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-6 '-(2-chloro-phenyl-) methylene radical pimelinketone, δ _C:(150MHZ, CDCl ₃): 19.55,27.90,31.04,34.90,46.13,58.26,63.50,120.33,125.26,125.93,126.13,126.92,127.95,128.02,129.33,129.42,129.63,129.66,130.47,130.62,131.38,132.20,132.34,134.49,134.98,135.64,136.11,136.45,137.77,137.93,142.74,201.37,207.56.ESI-MS m/z:552.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 552.49.

Sic64:1-methyl-4-(2-chloro-phenyl-) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-6 '-(2-chloro-phenyl-) methylene radical pimelinketone, yield 64.31%, fusing point 182.6-184.4. ¹H-NMR (CDCl ₃) δ: 1.150 (2H, m, 3 '-CH ₂); 1.308 (2H, m, 4 ' CH ₂); 1.702 (2H, m, 5 '-CH ₂); 2.183 (3H, s, N-CH ₃); 3.565,4.065 (2H, m, 5-CH ₂); 5.178 (1H, s, 4-CH); 7.752 (1H, s, Ar-CH=); 6.776-7.836 (12H, m, Ar-H); 8.027 (1H, s, N-H). δ _C:(150MHZ, CDCl ₃): 18.94,28.27,30.97,34.97,45.50,57.13,62.07,109.34,123.68,125.56,126.02,126.70,126.87,127.91,128.80,129.16,139.36,129.60,130.38,131.23,134.40,134.98,135.88,136.29,137.45,137.57,141.30,168.0,200.55.ESI-MS m/z:517.4 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 517.45.

Sic06:1-methyl-4-(2-bromophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-6 '-(2-bromophenyl) methylene radical pimelinketone, yield 82.6%, fusing point 183.3-185.3 ℃. ¹H-NMR (CDCl ₃) δ: 1.147,1.966 (2H, m, 3 '-CH ₂); 1.163,1.317 (2H, m, 4 ' CH ₂); 2.157 (3H, s, N-CH ₃); 2.292 (2H, m, 5 '-CH ₂); 3.494,4.020 (2H, m, 5-CH ₂); 5.108 (1H, m, 4-CH); 7.548 (1H, s, Ar-CH=); 8.066 (1H, s, N-H); 6.753-8.054 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 18.78,27.93,28.28,30.91,34.90,48.37,57.59,61.96,123.78,125.26,126.65,126.87,127.26,127.82,128.22,128.80,129.37,129.51,130.41,130.52,131.70,132.52,132.85,136.29,137.25,138.02,141.35,168.1,200.44.ESI-MS m/z:607.1 (M+1) ⁺, calcd for C ₃₀H ₂₆Br ₂N ₂O ₂: 606.35.

Sac06:1-methyl-4-(2-bromophenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-6 '-(2-bromophenyl) methylene radical pimelinketone, yield 45.2%, fusing point 88.1-89.8 ℃. ¹H-NMR (CDCl ₃) δ: 0.432,1.052 (2H, m, 3 '-CH ₂); 1.136,1.781 (2H, m, 4 '-CH ₂); 1.809,2.189 (2H, m, 5 '-CH ₂); 2.049 (3H, s, N-CH ₃); 3.657,4.063 (2H, m, 5-CH ₂); 5.203 (1H, m, 4-CH); 7.529 (1H, s, Ar-CH=); 6.936-8.217 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.26,27.42,28.28,30.84,34.75,48.86,58.62,63.25,120.21,125.14,125.82,126.62,126.87,127.84,128.20,129.44,129.60,129.70,130.37,130.49,130.52,131.68,132.07,132.19,132.79,135.97,136.15,136.40,137.31,137.67,139.54,142.66,201.10,207.45.ESI-MS m/z:642.1 (M+1) ⁺, calcd for C ₃₄H ₂₇Br ₂NO ₂: 641.39.

Saa06:1-methyl-4-(2-bromophenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(2-bromophenyl) methylene radical cyclopentanone, yield 84.41%, fusing point 121.7-123.6 ℃. ¹H-NMR (CDCl ₃) δ: 1.194 (2H, m, 3 '-CH ₂); 1.759,1.998 (2H, m, 4 '-CH ₂); 2.167 (3H, s, N-CH ₃); 3.731,4.131 (2H, m, 5-CH ₂); 4.973 (1H, m, 4-CH); 7.538 (1H, br s, Ar-CH=); 7.013-8.232 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 26.05,26.17,29.70,34.91,43.37,59.77,65.56,120.22,125.10,125.63,126.39,126.80,127.22,127.93,129.18,129.56,129.86,130.11,130.39,131.68,131.99,132.15,132.34,132.64,133.41,135.40,135.60,135.81,139.25,143.03,206.07,208.90.ESI-MS m/z:628.1 (M+1) ⁺, calcd forC ₃₃H ₂₅Br ₂NO ₂: 627.37.

Sia06:1-methyl-4-(2-bromophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2-bromophenyl) methylene radical cyclopentanone, yield 85.19%, fusing point 106.5-107.9 ℃. ¹H-NMR (CDCl ₃) δ: 1.222,2.240 (2H, m, 3 '-CH ₂); 1.987,2.007 (2H, m, 4 '-CH ₂); 2.223 (3H, s, N-CH ₃); 3.628,4.016 (2H, m, 5-CH ₂); 4.914 (1H, m, 4-CH); 7.519 (1H, s, Ar-CH=); 8.112 (1H, s, N-H); 6.783-7.886 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 26.05,26.42,29.70,34.91,47.37,59.77,65.55,120.22,125.10,125.63,126.44,127.22,127.93,128.25,129.18,129.86,130.11,131.68,132.15,132.59,132.99,133.41,135.40,135.81,138.08,139.32,143.02,206.07,208.90.ESI-MS m/z:593.1 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 592.32.

Sic75:1-methyl-4-(2, the 6-difluorophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-6 '-(2, the 6-difluorophenyl) methylene radical pimelinketone, yield 79.42%, fusing point 166.2-168.2 ℃. ¹H-NMR (CDCl ₃) δ: 1.295-1.440 (2H, m, 3 '-CH ₂); 1.444,1.747 (2H, m, 4 '-CH ₂); 2.130 (3H, s, N-CH ₃); 2.598-2.607 (2H, m, 5 '-CH ₂); 3.247,4.411 (2H, m, 5-CH ₂); 5.352 (1H, s, 4-CH); 6.608,7.353 (10H, m, Ar-H); 7.632 (1H, s, Ar-CH=); 7.897 (1H, s, N-H). δ _C:(150MHZ, CDCl ₃): 19.51,22.59,28.95,30.02,34.57,40.01,53.85,64.35,109.29,111.08,113.17,114.46,123.39,124.33,125.57,126.28,128.63,129.21,130.31,141.28,159.59,160.99,161.77,163.37,178.30,199.20.ESI-MS m/z:520.3 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 520.

Sia75:1-methyl-4-(2, the 6-difluorophenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2, the 6-difluorophenyl) methylene radical cyclopentanone, yield 80.18%, fusing point 87.6-90.2 ℃. ¹H-NMR (CDCl ₃) δ: 1.322,1.743 (2H, m, 3 '-CH ₂); 1.743,2.115 (2H, m, 4 '-CH ₂); 2.244 (3H, s, N-CH ₃); 3.519,4.386 (2H, m, 5-CH ₂); 5.021 (1H, m, 4-CH); 6.775-7.289 (12H, m, Ar-H); 7.502 (1H, s, Ar-CH=); 8.0112 (1H, s, N-H) .ESI-MS m/z:507.3 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 506.49.

Sia50:-methyl-4-(2, the 5-3,5-dimethylphenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2, the 5-3,5-dimethylphenyl) methylene radical cyclopentanone, yield 87.82%, fusing point 185.5-189.0 ℃. ¹H-NMR (CDCl ₃) δ: 1.222,2.240 (2H, m, 3 '-CH ₂); 1.987,2.007 (2H, m, 4 '-CH ₂); 2.223 (3H, s, N-CH ₃); 3.628,4.016 (2H, m, 5-CH ₂); 4.914 (1H, m, 4-CH); 7.519 (1H, s, Ar-CH=); 8.112 (1H, s, N-H); 6.783-7.886 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.41,20.34,20.94,21.38,25.80,26.54,31.04,35.15,43.19,59.53,65.28,109.19,123.05,127.27,128.83,129.33,129.91,130.17,130.38,131.15,131.56,132.05,134.41,134.85,135.18,135.37,135.94,136.19,137.54,138.03,141.49,178.44,206.67.ESI-MS m/z:593.1 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 592.32.

Saa50:1-methyl-4-(2, the 5-3,5-dimethylphenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(2, the 5-3,5-dimethylphenyl) methylene radical cyclopentanone, yield 81.5%, fusing point 70.3-72.8 ℃. ¹H-NMR (CDCl ₃) δ: 1.068,1.228 (2H, m, 3 '-CH ₂); 1.902,1.980 (2H, m, 4 '-CH ₂); 2.054 (3H, s, N-CH ₃); 2.111-2.445 (12H, m, Ar-CH ₃); 3.616,4.186 (2H, m, 5-CH ₂); 4.724,4.753 (1H, m, 4-CH); 7.376,7.401 (1H, br s, Ar-CH=); 6.874-8.101 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.35,20.79,21.14,25.96,30.48,34.97,43.94,60.29,66.28,120.25,124.77,124.97,127.25,127.92,128.60,128.98,129.54,129.94,130.10,130.37,130.54,131.84,131.89,132.19, .134.15,134.53,134.73,135.20,135.54,136.19,136.56,137.71,142.84,207.45,208.50.ESI-MS m/z:526.3 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 525.5.

Sic19:1-methyl-4-(2, the 3-Dimethoxyphenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-6 '-(2, the 3-Dimethoxyphenyl) methylene radical pimelinketone, yield 33.7%, fusing point 178.4-181.2 ℃. ¹H-NMR (CDCl ₃) δ: 1.168,2.036 (2H, m, 3 '-CH ₂); 1.288 (2H, m, 4 ' CH ₂); 2.133 (3H, s, N-CH ₃); 2.235 (2H, m, 5 '-CH ₂); 3.397,4.037 (2H, m, 5-CH ₂); 5.082 (1H, m, 4-CH); 3.746,3.853 (12H, s, O-CH ₃* 4); 7.353 (1H, s, Ar-CH=); 7.632 (1H, s, N-H); 6.608-7.340 (10H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.09,28.39,30.42,34.93,42.38,55.62,55.79,59.62,60.95,62.42,109.16,110.56,112.38,121.55,122.06,123.15,123.73,127.82,128.80,129.13,130.54,133.82,134.10,137.31,141.38,147.90,148.19,152.57,152.69,153.14,168.0,200.73.ESI-MS m/z:569.3 (M+1) ⁺, calcd for C ₃₄H ₃₆N ₂O ₆: 568.66.

Sac19:1-methyl-4-(2, the 3-Dimethoxyphenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-6 '-(2, the 3-Dimethoxyphenyl) methylene radical pimelinketone, yield 85.37%, fusing point 67.4-67.9 ℃. ¹H-NMR (CDCl ₃) δ: 0.556,1.860 (2H, m, 3 '-CH ₂); 1.052,1.281 (2H, m, 4 '-CH ₂); 1.888,2.141 (2H, m, 5 '-CH ₂); 2.041 (3H, s, N-CH ₃); 3.491,4.112 (2H, m, 5-CH ₂); 5.175 (1H, m, 4-CH); 7.474 (1H, s, Ar-CH=); 6.500-8.043 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 19.60,23.31,27.75,28.74,30.38,34.87,42.82,55.62,57.40,59.66,60.88,63.70,119.94,121.59,121.98,122.16,123.10,123.44,123.80,124.97,125.83,127.70,129.20,130.36,130.43,130.48,131.80,132.36,132.48,132.64,133.81,137.30,142.43,147.94,152.63,190.34,201.44.ESI-MS m/z:604.3 (M+1) ⁺, calcd for C ₃₈H ₃₇NO ₆: 603.70.

Sia19:1-methyl-4-(2, the 3-Dimethoxyphenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2, the 3-Dimethoxyphenyl) methylene radical cyclopentanone, yield 89.95%, fusing point 130.3-133.6 ℃. ¹H-NMR (CDCl ₃) δ: 1.748,1.743 (2H, m, 3 '-CH ₂); 2.061 (2H, m, 4 '-CH ₂); 2.316 (3H, s, N-CH ₃); 2.344,3.039 (2H, m, 5-CH ₂); 3.653,3.724,3.838 (12H, m ,-OCH ₃); 4.804 (1H, m, 4-CH); 6.583-7.586 (10H, m, Ar-H); 7.586 (1H, s, Ar-CH=); 7.955 (1H, s, N-H). δ _C:(150MHZ, CDCl ₃): 26.51,30.21,35.12,40.85,55.59,58.30,60.26,61.36,64.91,109.05,110.55,113.51,121.63,122.95,123.76,127.99,128.25,129.21,130.01,133.65,136.97,138.64,141.45,147.87,148.86,149.30,152.55,152.79,153.04,178.36,206.07.ESI-MS m/z:555.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 554.63.

Saa19:1-methyl-4-(2, the 3-Dimethoxyphenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(2, the 3-Dimethoxyphenyl) methylene radical cyclopentanone, yield 69.24%, fusing point 74.2-75.9 ℃. ¹H-NMR (CDCl ₃) δ: 1.212 (2H, m, 3 '-CH ₂); 1.690 (2H, m, 4 '-CH ₂); 2.142 (3H, s, N-CH ₃); 3.589,4.170 (2H, m, 5-CH ₂); 848 (1H, m, 4-CH); 3.549,3.891 (12H, m ,-OCH ₃); 7.536 (1H, m, Ar-CH=); 6.308-8.066 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 26.76,29.63,35.03,41.18,55.59,59.00,60.24,61.23,65.77,110.57,112.95,120.08,121.41,121.63,121.90,123.35,124.03,124.84,127.59,127.86,128.96,129.88,130.32,131.90,132.17,133.85,136.10,137.34,142.92,147.92,148.72,152.59,152.72,206.93,208.86.ESI-MS m/z:590.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 589.68.

Sia01:1-methyl-4-(4-ethoxyl phenenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(4-ethoxyl phenenyl) methylene radical cyclopentanone, yield 82.4%, fusing point 98.6-102.1 ℃. ¹H-NMR (CDCl ₃) δ: 1.368,1.452 (2H, m, 3 '-CH ₂); 1.387 (6H, m ,-CH ₃); 2.102,2.198 (2H, m, 4 '-CH ₂); 2.142 (3H, s, N-CH ₃); 3.085,3.545 (2H, m, 5-CH ₂); 3.978,3.989 (4H, s, O-CH ₂); 4.288 (1H, S, 4-CH); 7.261 (1H, s, Ar-CH=); 7.930 (1H, s, N-H); 6.731-7.565 (12H, m, Ar-H); 7.952 (1H, m, NH) δ _C:(150MHZ, CDCl ₃): 14.70,26.23,26.49,30.57,35.06,48.57,60.08,63.34,65.53,109.07,113.86,114.23,114.79,122.87,126.64,127.91,128.00,129.24,131.35,132.07,133.17,135.22,141.31,157.85,159.86,178.58,206.98.ESI-MS m/z:523.3 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 522.6.

Saa01:1-methyl-4-(4-p-methoxy-phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(4-p-methoxy-phenyl) methylene radical cyclopentanone, yield 72.51%, fusing point 98.5-100.4 ℃. ¹H-NMR (CDCl ₃) δ: 1.290,1.437 (6H, m, CH ₃-N-CH ₃) 1.290,1.437 (2H, m, 3 '-CH ₂); 1.683,1.934 (2H, m, 4 '-CH ₂); 2.141 (3H, s, N-CH ₃); 3.077 (2H, m, 5-CH ₂); 3.652 (1H, m, 4-CH); 3.952-4.086 (6H, m ,-OCH ₃); 7.260 (1H, s, Ar-CH=); 6.697-8.053 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 14.80,26.54,26.62,30.06,35.13,49.44,60.85,63.50,66.65,114.46,114.58,114.93,120.20,124.89,125.05,127.91,128.03,128.78,128.98,130.41,131.47,131.82,132.09,132.27,132.65,133.36,133.45,133.54,135.35,136.28,142.32,158.00,159.92,207.81,208.95.ESI-MS m/z:558.3 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 557.

Sioa1:1-methyl-4-(3-methoxyl group-4-hydroxy phenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(3-methoxyl group-4-hydroxy phenyl) methylene radical cyclopentanone, yield 85.67%, fusing point 125.9-127.8 ℃. ¹H-NMR (CDCl ₃) δ: 1.121,1.902 (2H, m, 3 '-CH ₂); 2.052,2.352 (2H, m, 4 '-CH ₂); 1.976 (3H, s, N-CH ₃); 2.487 (2H, m, 5-CH ₂); 3.052 (1H, m, 4-CH); 3.360 (3H, s ,-OCH ₃); 3.709 (3H, s ,-OCH ₃); 3.822,3.996 (2H, m ,-OH); 7.231 (1H, s, Ar-CH=); 6.631-7.343 (10H, m, Ar-H).; 8.799 (1H, s, NH). δ _C:(150MHZ, CDCl ₃): 26.04,30.97,34.85,48.66,55.91,60.24,65.21,77.28,109.61,114.25,115.49,116.16,121.90,122.81,124.40,126.41,127.14,129.58,131.11,132.75,133.26,133.38,135.20,143.28,145.73,147.91,148.16,148.97,178.48,206.32.ESI-MS m/z:527.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 526.58.

Sina1:1-methyl-4-(4-diethylin phenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(4-diethylin phenyl) methylene radical cyclopentanone, yield 50.16%, fusing point 131.4-133.7 ℃. ¹H-NMR (CDCl ₃) δ: 1.159 (12H, s, CH ₃); 1.238,1.452 (2H, m, 3 '-CH ₂); 1.743 (2H, s, 4 '-CH ₂); 2.356,3.546 (2H, m, 5-CH ₂); 2.212 (3H, s, N-CH ₃); 3.337 (8H, s, N-CH ₂-); 4.281 (1H, s, 4-CH); 7.097 (1H, s, Ar-CH=); 6.539-7.367 (12H, m, Ar-H); 7.944 (H, s, N-H). δ _C:(150MHZ, CDCl ₃): 12.58,26.47,30.58,35.15,44.36,48.71,60.08,65.63,77.95,108.03,110.99,111.32,111.67,122.63,122.80,126.32,126.54,128.99,130.31,131.24,132.64,134.32,141.24,146.64,148.37,178.81,207.03.ESI-MS m/z:577.5 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 576.77.

Sana1:1-methyl-4-(4-diethylin phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(4-diethylin phenyl) methylene radical cyclopentanone, yield 85.05%, fusing point 79.6-80.7 ℃. ¹H-NMR (CDCl ₃) δ: 1.092-1.214 (12H, m, CH ₃); 1.39 (2H, m, 3 '-CH ₂); 1.912,2.138 (2H, m, 4 '-CH ₂); 2.138 (3H, s, N-CH ₃); 3.281-3.396 (8H, m, N-CH ₂-); 3.060,4.051 (2H, m, 5-CH ₂); 4.351 (1H, m, 4-CH); 7.260 (1H, s, Ar-CH=); 6.447-8.034 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 12.55,26.63,29.92,35.12,44.33,49.43,60.70,66.65,80.93,110.92,111.32,111.75,119.83,122.51,123.50,124.73,127.60,128.90,130.23,130.52,131.23,132.27,132.88,133.51,134.13,136.51,142.78,146.66,148.30,207.70,209.04.ESI-MS m/z:612.6 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 611.81.

Saoa2:1-methyl-4-(4-hydroxy phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(4-hydroxy phenyl) methylene radical cyclopentanone, yield 79.25%, fusing point 132.2-135.1 ℃. ¹H-NMR (CDCl ₃) δ: 1.085,1.202 (2H, m, 3 '-CH ₂); 1.846,2.102 (2H, m, 4 '-CH ₂); 1.967 (3H, s, N-CH ₃); 2.506 (2H, m, 5-CH ₂); 3.012 (1H, m, 4-CH); 3.803,4.187 (2H, m ,-OH); 7.208 (1H, s, Ar-CH=); 6.621-8.228 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 26.22,30.03,34.85,48.75,60.47,66.43,80.40,115.68,116.14,116.39,120.74,124.40,125.51,126.18,127.11,128.78,129.02,130.07,130.30,131.16,131.93,132.26,132.80,132.83,133.19,133.27,135.04,136.38,142.39,156.64,159.42,206.43,208.53.ESI-MSm/z:467.3 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 466.53.

Saoa1:1-methyl-4-(3-methoxyl group-4-hydroxy phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(3-methoxyl group-4-hydroxy phenyl) methylene radical cyclopentanone, yield 90.81%, fusing point 100.3-103.7 ℃. ¹H-NMR (CDCl ₃) δ: 1.102,1.212 (2H, m, 3 '-CH ₂); 1.855,2.152 (2H, m, 4 '-CH ₂); 1.966 (3H, s, N-CH ₃); 2.486 (2H, m, 5-CH ₂); 3.052 (1H, m, 4-CH); 3.590 (3H, s ,-OCH ₃); 3.824 (3H, s ,-OCH ₃); 3.839,4.150 (2H, m ,-OH); 7.067 (1H, s, Ar-CH=); 6.526-9.545 (12H, m, Ar-H) .ESI-MSm/z:562.4 (M+1) ⁺, calcd forC ₂₉H ₂₄Br ₂N ₂O ₂: 561.62.

Sioc1:1-methyl-4-(3-methoxyl group-4-hydroxy phenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(3-methoxyl group-4-hydroxy phenyl) methylene radical pimelinketone, yield 73.99%, fusing point 117.9-118.9 ℃. ¹H-NMR (CDCl ₃) δ: 1.290,1.308 (2H, m, 3 '-CH ₂); 1.639 (4H, m, 4 ', 5 '-CH ₂); 2.183 (3H, s, N-CH ₃); 2.426,3.520 (2H, m, 5-CH ₂); 3.052 (1H, m, 4-CH); 3.948 (3H, s ,-OCH ₃); 3.709 (3H, s ,-OCH ₃); 5.587 (1H, s ,-OH); 5.774 (1H, s ,-OH); 7.021 (1H, s, Ar-CH=); 6.702-7.548 (10H, m, Ar-H).; 7.720 (1H, s, NH) .ESI-MS m/z:541.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 540.61.

Saoc1:1-methyl-4-(3-methoxyl group-4-hydroxy phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(3-methoxyl group-4-hydroxy phenyl) methylene radical pimelinketone, yield 90.33%, fusing point 89.9-91.7 ℃. ¹H-NMR (CDCl ₃) δ: 1.142,1.296 (2H, m, 3 '-CH ₂); 1.697 (2H, m, 4 '-CH ₂); 2.169,2.180 (2H, m, 5 '-CH ₂); 2.080 (3H, s, N-CH ₃); 3.571,3.948 (2H, m, 5-CH ₂); 3.847 (3H, s ,-OCH ₃); 4.005 (3H, s ,-OCH ₃); 4.881 (1H, m, 4-CH); 5.612 (2H, m ,-OH); 7.190 (1H, s, Ar-CH=); 6.591-8.0674 (12H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 20.04,28.14,30.58,34.84,49.84,55.87,59.06,64.98,80.37,112.53,112.83,113.28,113.97,114.44,120.21,123.31,124.08,125.02,125.22,127.91,128.67,130.33,131.84,132.46,136.97,138.26,142.31,144.48,146.00,203.38,207.30.ESI-MS m/z:576.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 575.65.

Saa63:1-methyl-4-(2-p-methoxy-phenyl) pyrrolo-(spiral shell-[2.2 "] acenaphthene-1 "-ketone)-spiral shell [3.2 ']-5 '-(2-p-methoxy-phenyl) methylene radical cyclopentanone, yield 76.2%, fusing point 77.5-79.8 ℃. ¹H-NMR (CDCl ₃) δ: 1.227,1.351 (2H, m, 3 '-CH ₂); 1.697 (2H, m, 4 '-CH ₂); 2.166 (3H, s, N-CH ₃); 3.589,4.227 (2H, m, 5-CH ₂); 4.814 (1H, m, 4-CH); 3.635-3.819 (6H, m ,-OCH ₃); 7.563 (1H, m, Ar-CH=); 6.670-8.076 (14H, m, Ar-H). δ _C:(150MHZ, CDCl ₃): 20.49,26.68,29.29,36.19,41.36,55.08,58.14,65.41,67.01,109.90,109.98,110.58,119.91,120.65,124.82,125.14,126.54,127.20,127.74,128.13,129.03,129.29,129.68,130.27,130.31,130.75,131.81,132.17,136.05,143.05,155.70,158.01,207.17,208.95.ESI-MS m/z:530.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 529.62.

Sia63:1-methyl-4-(2-p-methoxy-phenyl) pyrrolo-(spiral shell-[2.3 "] oxindole)-spiral shell [3.2 ']-5 '-(2-p-methoxy-phenyl) methylene radical cyclopentanone, yield 76.2%, fusing point 77.5-79.8 ℃. ¹H-NMR (CDCl ₃) δ: 1.284 (2H, m, 3 '-CH ₂); 1.849 (2H, m, 4 '-CH ₂); 2.264 (3H, s, N-CH ₃); 2.594,3.514 (2H, m, 5-CH ₂); 3.514 (3H, m ,-OCH ₃); 3.837 (3H, m ,-OCH ₃); 4.780 (1H, m, 4-CH); 6.776-7.837 (12H, m, Ar-H); 7.460 (1H, s, Ar-CH=); 7.849 (1H, s, N-H). δ _C:(150MHZ, CDCl ₃): 20.49,26.47,29.87,35.29,40.48,55.13,64.50,66.96,109.00,109.98,110.63,120.00,120.50,122.96,124.88,126.55,127.62,128.13,128.31,129.17,129.69,130.38,130.77,133.89,141.51,135.69,157.97,172.00,208.81.ESI-MS m/z:495.4 (M+1) ⁺, calcd for C ₂₉H ₂₄Br ₂N ₂O ₂: 494.58.

Embodiment 2 compounds (I) vitro kinase activity analytical test

Caliper-EZ Reader is that the mobility detection technique with the micro-fluid chip technology is the detection platform of core, and it has real-time kinetic measurement function.Micro-fluid chip is integrated into steps such as specimen preparation, biochemical reaction and detection on the chip exactly, with the feature set of microminiaturized, integrated, automatization; This detection platform is applied to the ultimate principle of capillary electrophoresis in the microfluidic environment, is not adding detection zymetology experiment under the situation that stops reagent.

We will carry out the screening of FGFR kinase inhibiting activity to institute's synthetic compound on Caliper-EZ Reader platform.Experimental procedure following (20 μ M):

1. dispose 1.25 * the kinases ealkaline buffer and stop damping fluid.

A.1.25 * kinases ealkaline buffer: 62.5mM HEPES, pH 7.5,0.001875%Brij-35,12.5mM MgCl2,2.5mM DTT

B. stop damping fluid: 100mM HEPES, pH 7.5,0.015%Brij-35,0.2%Coating Reagent#3,50mMEDTA

2. the target compound of configuration finite concentration gradient is to be measured.

A. prepare 20mM compound mother liquor.

B. get 5 μ L, 20mM compound mother liquor is in 96 orifice plates, and adding DMSO 96ML, and making the compound final concentration is 1mM, gets 2 holes and adds 100 μ L DMSO as control group.

C. take out among the b, add another 96-orifice plate on each orifice plate solution 5 μ L, and add 45 μ L water.

E. take out among the c, each orifice plate solution 10 μ L is added to adjacent two holes of 384 hole analysis plates respectively.As: get 10 μ L in 96 orifice plates among the A1 and be added to 384 hole analysis plates A1 respectively, each 5 μ L analogizes in proper order in the A2 hole.Get 5 μ l of250mM EDTA in A23 and A24 hole, as minimum control group.Each hole adds 95 μ L, 10%DMSO again.

3. dispose 2.5 * enzyme solution: promptly FGFRs (FGFR1,2 and 3) (6nM) is joined in 1.25 * kinases ealkaline buffer.

4. dispose 2.5 * polypeptide solution: promptly FAM-labeled polypeptide and ATP (262 μ M) are joined in 1.25 * kinases ealkaline buffer.

5. get 10 μ L, 2.5 * enzyme solution to 384 orifice plates that contain the finite concentration compound, at room temperature hatch 10min.

6. get 10 μ L, 2.5 * polypeptide solution to above-mentioned 384 orifice plates, add 25 μ l after hatching specified time at 28 ℃ and stop damping fluid and finish enzymatic reaction.

7. on Caliper, collect data, be worth inhibiting rate according to conversion.

Percent?inhibition＝(max-conversion)/(max-min)*100.“max”stands?for?DMSO?control；“min”stands?for?low?control.

Table 1 part of compounds (I) is to the activity of FGFR1 ^*

Embodiment 3 part of compounds suppress experiment to bFGF inductive FGFR1 high expression tumour cell proliferation

Choose FGFR1 tyrosine-kinase enzyme inhibition activity compound preferably, adopt mtt assay, measured their proliferation inhibition activities to bFGF inductive FGFR1 high expression tumour cell U251 and A549, its activity data is seen Fig. 1.BFGF can both stimulate the cell proliferation of every kind of tumour cell.Compound has all shown every kind of tumour cell and has suppressed bFGF inductive cell-proliferation activity preferably, has generally all shown dose-effect relationship preferably, and the restraining effect of A549 is quite obvious.

Every kind of cell includes: blank group does not add bFGF and compound; Negative group only adds bFGF (20ng/mL), does not add compound; The dosing test group adds bFGF (20ng/mL), adds with DMSO dissolved compound, and compound is provided with 1 μ M, 5 μ M, three concentration of 10 μ M.Blank group and negative group all add the DMSO with dosing test group equal volume.

The configuration of compound mother liquor:

1) centrifugal 20 second.(sample is fully sunk to the bottom)

2) testing sample is made into the mother liquor of 20mM, 4 ℃ of preservations with DMSO.

The configuration of bFGF working fluid: the dilution of frozen mother liquor [bFGF of 0.1mg/ml]

1) the EP pipe that contains 0.1mg/ml bFGF of taking-up 5ul is put-20 ℃ of temperature equilibriums earlier from-80 ℃ of refrigerators, is placed into 4 ℃ of temperature equilibriums again, finally takes out again.

2) low-temperature centrifugation is 20 seconds.

3) be diluted to desired concn with substratum or PBS.

Experimental procedure:

1, cell is cultivated in the culturing bottle of the nutrient solution that contains 10% foetal calf serum (FCS), culture condition is 37 ℃, 5%CO ₂, the cell of the phase growth of taking the logarithm is made into cell suspension with the DMEM of 10% foetal calf serum (FCS) after 0.25% trypsin solution digestion;

2, with cell with 5000/hole, the perfect medium that every hole 100 μ l contain 10% foetal calf serum (FCS) is inoculated in 96 orifice plates, changes the hungry nutrient solution that contains 0.4% foetal calf serum with 100 μ l/ holes after the incubated overnight, 37 ℃, 5%CO ₂The hungry 24h that cultivates under the condition.

3, hungry cultivate 24h after, change the hungry nutrient solution that promptly contains 0.4% foetal calf serum with the fresh hungry substratum in 100 μ l/ holes, every hole adds 1 μ l compound mother liquor, every hole adds the bFGF working fluid of 1ul, 37 ℃, 5%CO after hatching hour ₂Continue to cultivate 48h.

4, mtt assay detects: add 20 μ l/ hole MTT (5ng/ml), and 37 ℃, 5%CO ₂Stop with 100 μ l/ hole DMSO after cultivating 4h, lucifuge about micro oscillator concussion 5min, detects the OD value on the microplate reader.

Be blank with PBS during mensuration, the negative contrast of bFGF is contrast with PD173074, and (bFGF+ testing sample) is experimental group, and every kind of sample is established each 3 multiple holes of 5 extent of dilution.

Embodiment 4 part of compounds are to bFGF inductive chicken embryo CAM angiogenesis inhibiting activity

Adopt chick embryo allantois (CAM) experiment, the blood vessel hyperplasia of having tested the part active compound suppresses active.Find that compound has certain restraining effect to bFGF inductive chicken embryo CAM vasculogenesis, its effect has dose-effect relationship (Fig. 2) preferably.

Plant egg and hatched 6 days for 37 ℃, open an osculum directly over the egg air chamber, filter paper is placed the few position of vessel density on the chorioallantoic membrane, dosing is (20 μ L/ egg) to filter paper, seals damaged eggshell position with strile gauze dressing; After 24 hours, add the bFGF (20 μ L/ egg) of 20ng/ml; Continue to cultivate 3 days, and opened eggshell on the air chamber, the top chorioallantoic membrane is exposed as far as possible, with 4% Paraformaldehyde 96 fixing half an hour, machine is taken pictures.

The influence of the short proliferation signal molecule activation of part in the embodiment 5bFGF inductive FGFR1 high expression tumour cell

Select the neuroglial cytoma (U251) of FGFR1 high expression level, 20ng/mLbFGF stimulates U251, has measured the variation of short proliferation signal molecule P-FGFR and p-Erk1/2.At first, bFGF can obviously improve the phosphorylation level of Erk1/2 as shown in Figure 3, has just reached maximum horizontal in 20 minutes.To the influence of FGFR1 phosphorylation level experiment, also can clearly find out that bFGF also can obviously improve the phosphorylation level of FGFR1 for bFGF by Fig. 4, dosing in 5 minutes phosphorylation level reach maximum.BFGF can obviously improve the phosphorylation level of Erk1/2 and FGFR as shown in Figure 5, and compound can obviously reduce the level of p-FGFR1 and p-Erk1/2.

Claims

1. general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvate or prodrug:

Wherein:

P is 1 to 4;

J and k all are 0,1,2 or 3 independently;

R ^1aFor hydrogen or-OR ⁵

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Each R ³All be independently selected from hydrogen, alkyl, thiazolinyl, alkynyl, alkoxyl group, halogen, haloalkyl, haloalkenyl group, halogenated alkoxy, cyclic hydrocarbon radical, cyclic hydrocarbon radical alkyl, aryl, aralkyl, aryl alkenyl, heterocyclic radical, heterocyclic radical alkyl, heteroaryl, heteroaralkyl ,-R ⁸-CN ,-R ⁸-NO ₂,-R ⁸-OR ⁵,-R ⁸-N (R ⁴) R ⁵,-N=C (R ⁴) R ⁵,-S (O) mR ⁴,-R ⁸-C (O) R ⁴,-C (S) R ⁴,-C (R ⁴) ₂C (O) R ⁵,-R ⁸-C (O) OR ⁴,-C (S) OR ⁴,-R ⁸-C (O) N (R ⁴) R ⁵,-C (S) N (R ⁴) R ⁵,-N (R ⁵) C (O) R ⁴,-N (R ⁵) C (S) R ⁴,-N (R ⁵) C (O) OR ⁴,-N (R ⁵) C (S) OR ⁴,-N (R ⁵) C (O) N (R ⁴) R ⁵,-N (R ⁵) C (S) N (R ⁴) R ⁵,-N (R ⁵) S (O) nR ⁴,-N (R ⁵) S (O) n (R ⁴) R ⁵,-R ⁸-S (O) nN (R ⁴) R ⁵,-N (R ⁵) C (=NR ⁵) N (R ⁴) R ⁵And-N (R ⁵) C (=N-CN) N (R ⁴) R ⁵, wherein each m is 0,1 or 2 independently, and each n is 1 or 2 independently;

Each R ⁸Be the alkylidene chain of valence bond or straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched; And

Each R ⁹Be the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched.

2. compound as claimed in claim 1, wherein:

P is 1 or 2;

At least one is 1 among j and the k, and another is 0 or 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed hetero-aromatic ring or condensed aromatic ring;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

3. compound as claimed in claim 2, wherein

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

For being selected from phenyl, pyrimidyl, pyrazinyl, pyridyl and pyrryl condensed hetero-aromatic ring or aromatic ring;

Or R1 is quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

Each R ³All be independently selected from hydrogen and alkyl;

4. compound as claimed in claim 3 is in the base

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed benzopyrrole ring;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ²Be hydrogen;

Or R ²And R ¹And can form the condensed ring that is selected from cyclic hydrocarbon radical, heterocyclic radical, aryl or heteroaryl with its direct-connected carbon or azo-cycle atom;

Each R ³All be independently selected from hydrogen and alkyl;

Each R ₉Be the alkylidene chain of straight or branched, the alkenylene chain of straight or branched or the alkynylene chain of straight or branched.

5. compound of answering according to claim 4, wherein

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be the condensed pyrrole ring;

R ¹Be hydrogen or alkyl;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen and alkyl;

6. compound as claimed in claim 5, wherein

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be the condensed pyrrole ring;

R ¹Be hydrogen or alkyl;

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen and alkyl;

7. compound as claimed in claim 6, wherein

P is 1;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be the condensed pyrrole ring;

R ¹Be methyl;

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen;

8. compound as claimed in claim 7 is selected from following:

1-methyl-4-(2-chloro-phenyl-) pyrroles (spiral shell-[2.3 "] indoles)-spiral shell [3.2 ']-5 '-(2-chloro-phenyl-methylene radical) cyclopentanone.

1-methyl-4-(2-fluorophenyl) pyrrolo-(spiral shell-[2.3 "] indoles)-spiral shell [3.2 ']-5 '-(2-fluorophenyl methylene radical) cyclopentanone.

1-methyl-4-(2-bromophenyl) pyrrolo-(spiral shell-[2.3 "] indoles)-spiral shell [3.2 ']-5 '-(2-bromophenyl methylene radical) cyclopentanone.

9. compound as claimed in claim 3 is in the base

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed naphtho-pentamethylene ring;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen and alkyl;

10. compound of answering according to claim 4, wherein

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed naphtho-pentamethylene ring;

R ¹Be hydrogen or alkyl;

Or R ¹Be quilt-C (O) N (R ⁶) R ⁷The aralkyl that replaces, wherein:

R ⁶Be hydrogen, alkyl, aryl or aralkyl; And

Each-R ¹⁰Be hydrogen, alkyl, aryl or aralkyl;

R ¹²For hydrogen, alkyl, aryl, aralkyl or-C (O) R ⁵

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen and alkyl;

11. compound as claimed in claim 5, wherein

P is 1 or 2;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed naphtho-pentamethylene ring;

R ¹Be hydrogen or alkyl;

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen and alkyl;

12. compound as claimed in claim 6, wherein

P is 1;

J be 0 and k be 1;

Q is-C (R ^1a) H-, and R ^1aBe hydrogen;

Be condensed naphtho-pentamethylene ring;

R ¹Be methyl;

R ²Be hydrogen;

Each R ³All be independently selected from hydrogen;

13. compound as claimed in claim 12 is selected from following:

1-methyl-4-(2-chloro-phenyl-) pyrroles (spiral shell-[2.2 "] acenaphthenequinone-1 "-ketone)-spiral shell [3.2 ']-5 '-2-chlorobenzene methylene radical cyclopentanone.

1-methyl-4-(2-fluorophenyl) pyrroles (spiral shell-[2.2 "] acenaphthenequinone-1 "-ketone)-spiral shell [3.2 ']-5 '-2-fluorobenzene methylene radical cyclopentanone.

1-methyl-4-(2-bromophenyl) pyrroles (spiral shell-[2.2 "] acenaphthenequinone-1 "-ketone)-spiral shell [3.2 ']-5 '-2-bromobenzene methylene radical cyclopentanone.

14. treatment, prevent or improve the method for disease in the Mammals or morbid state, wherein said disease or morbid state are selected from misgrowth, polycystic kidney disease, pain, depression, cardiovascular disorder, respiratory tract disease and mental disorder or its combination of cell, comprise general formula (I) compound of the Mammals of the described method of needs being treated significant quantity, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvate or prodrug.

15. method as claimed in claim 14, the cause of disease of described disease is caused by the overexpression of the defective in the signal pathway upstream of protein kinase, protein kinase or the unusual protein kinase of regulating at least in part, and this method comprises provides any one desired formula (I) compound among the claim 1-13 of significant quantity to described Mammals.

16. method as claimed in claim 15 is a kind of method for the treatment of or eradicating the tumour in the Mammals or suppress its growth, this method comprises any one desired formula (I) compound among the claim 1-13 of described administration significant quantity.

17. according to the method for claim 16, wherein this tumour is selected from mammary gland, kidney, bladder, oral cavity, throat, oesophagus, stomach, colon, ovum fine strain of millet, lung, pancreas, skin, liver, prostate gland or cerebral tumor.

18. according to the method for claim 16, wherein this tumour express FGFr or wherein this tumour partly depend on the FGFr approach at least.

19. pharmaceutical composition, it comprises pharmaceutically-acceptable excipients and general formula (I) compound, its steric isomer, enantiomer, tautomer or its mixture, or the acceptable salt of its medicine, solvate or prodrug.