CN1336930A - Bridged heterocyclic derivatives - Google Patents

Abstract

This invention relates to novel N-heterocyclic carboxylic acids and carboxylic acid isosteres, their preparation and use for treating neurological disorders including physically damaged nerves and neurodegenerative diseases, for treating alopecia and promoting hair growth, for treating vision disorders and/or improving vision, and for treating memory impairment and/or enhancing memory performance by administering such compounds.

Description

Bridged heterocyclic derivatives

The application requires the interim U.S. Patent application No.60/101 of application on September 18th, 1998, the U.S. Patent application No.09/159 of application on September 23rd, 077 and 1998, and the interests of 105 the applying date, their full content is introduced the present invention with for referencial use.Background of invention

Invention field

The present invention relates generally to novel bridged heterocyclic derivatives, its preparation, and the use lower molecular weight, micromolecular bridged heterocyclic derivatives is used for maybe preventing and/or treating neurologic disease from the animal that this treatment is benefited to the needs treatment and comprises physical damnification nerve and neurodegenerative disease; Treatment alopecia and promotion hair growth; Treat the vision illness and/or improve vision; Treatment memory impairment and/or hypermnesis function.

Description of related art A. neuroimmunophilin

Peptide acyl-prolyl isomerase (" PPIases ") is the enzyme that gang extensively exists, can catalysis and the peptide substrate in the adjacent cis of proline residue and the mutual conversion of trans amide key rotational isomer.Referring to, for example, Galat, A., Eur.J.Biochem. (1993) 216:689-707 and Kay, J.E., Biochem.J. (1996) 314:361-385.PPIases is owing to the interaction with some immunosuppressive drugs is called as immunophilin.Schreiber, S.L., Science (1991) 251:283-278; Rosen, M.K., and Schreiber, S.L., Angew.Chem.Intl.Ed.Engi. (1992) 31:384-400.

Find PPIases, ring-type affinity thing A can be used as the intracellular protein target of powerful immunosuppressive drug cyclosporin A.Find subsequently structure independently macrolide immunosuppressant FK506 can with a kind of different PPIase enzyme combination of the FK506-of being called as conjugated protein.Rapamycin, another kind of macrolide medicine, it is the analog of FK506, also can interact with FKBP.

All these three kinds of medicines with they separately immunophilin combine, and restrain PPIase activity separately.But the restraining effect of immunophilin enzymic activity is not the cause of the immunosuppressive effect that observed.The combination of medicine and immunophilin causes the formation of " activatory complex compound ", and itself and defluent protein interact, and restrains the hyperplasia of T-thymus dependent cells.Schreiber, supra; Rosen, et al., supra.FK506 and FKBP form medicine-protein complex in conjunction with meeting, and it is the powerful inhibitor of the dependent protein phosphatase of calcium-calmodulin.Bierer，B.E.，Mattila，P.S.，Standaert，R.F.，Herzenberg，L.A.，Burakoff，S.J.，Crabtree，G.，Schreiber，S.L，Proc.Natl.Acad.Sci.USA(1990)87：9231-9235；Liu，J.，Farmer，J.D.，lane，W.S.，Friedman，J.Weissman，I.，Schreiber，S.L.；Cell(1991)66：807-815。

Separately FK506 or FKBP to the calcium neurine without any slight restraining effect.Suppress the calcium neurine and just blocked signalling channel, activated T-cell receptor induces the genetic transcription of interleukin to suppress immune response by these passages.Although the structure dissimilarity of FK506 and cyclosporin A (and ring-type affinity thing and FKBP), cyclosporin A-ring-type affinity thing complex compound also can suppress the calcium neurine, so cyclosporin A has the identical mechanism of action with FK506.

In addition, although rapamycin and FK506 have similar structure and with identical immunophilin (FKBP) combination, the mechanism of action of rapamycin is different with FK506's.The complex compound of FKBP12 and rapamycin and the protein interaction that is called FRAP or RAFT, thereby disabling signal passage, these signalling channels originate from the IL-2 acceptor of T-cell surface, and enter the cell cycle of nuclear.Sabatini，D.M.，Erdjument-Bromage，H.，Lui，M.；Tempst，P.，Snyder，S.H.，Cell(1994)78：35-43；Brown，E.J.，Albers，M.W.，Shin，T.B.，Ichikawa，K.，Keith，C.T.，Lane，W.S.，Schreiber，S.L.Nature(1994)，369：756-758；Brown，E.J.，Beal，P.A.，Keith，C.T.，Chen，J.，Shin，T.B.，Schreiber，S.L.，Nature(1995)377：441-446。

Therefore, all three kinds of medicines produce identical effect--inhibition T-hyperplasia-but by different sensing passages.The appearance of S-Neoral (" CsA ") indicates the breakthrough of organ transplantation, and this medicine becomes main pharmaceutical prod.Rapamycin (" Wyeth-Ayerst Laboratories subsequently ") and the discovery of FK506 further improve interest to these medicines and cytosis.The interactional discovery of immunophilin and CsA has caused the research of the immunosuppressive action mechanism of immunophilin adjusting.B. immunophilin and neural system

Because at first to the interest of immunophilin be mainly derived from its with the immunosuppressive drug interaction mechanism in the role, the research to these protein and their effects the earliest mainly concentrates on immune tissue.Had in 1992 and report that 30-50 that the content of FKBP12 in the brain is higher than immuning tissue doubly.Steiner，J.P.，Dawson，T.M.，Fotuhi，M.，Glatt，C.E.，Snowman，A.M.，Cohen，N.，Snyder，S.H.，Nature(1992)358：584-587。This discovery suggestion immunophilin role in nervous system activity.FKBP and ring-type affinity thing extensively are present in the brain, and almost completely all in neurone.The distribution of the distribution of immunophilin and calcium neurine is closely similar in the brain, and suggestion has the neurological association of potential.Steiner，J.P.，Dawson，T.M.，Fotuhi，M.，Glatt，C.E.，Snowman，A.M.，Cohen，N.，Snyder，S.H.，Nature(1992)358：584-587。Dawson，T.M.，Steiner，J.P.，Lyons，W.E.，Fotuhi，M.，Blue，M.，Snyder，S.H.，Neuroscience(1994)62：569-580。

The existence that studies confirm that FK506 has subsequently changed the phosphorylation level of several known calcium neurine substrates.Steiner，J.P.，Dawson，T.M.，Fotuhi，M.，Glatt，C.E.，Snowman，A.M.，Cohen，N.，Snyder，S.H.，Nature(1992)358：584-587。The protein that a kind of FK506 of being subjected to treatment influences, GAP-43 regulates the prominent growth of neurone.Lyons，W.E.，Steiner，J.P.，Snyder，S.H.，Dawson，T.M.，J.Neurosci.(1995)15：2985-2994。This research discloses FKBP12 and GAP-43 is used to improve impaired face of white mouse or sciatic nerve.Find also that simultaneously the content of FKBP12 in new life's neuronic growth cone is very high.Test FK506 is to determine whether it is effective to nerve growth or regeneration.In the PCI2 cell or Sensory neurone culture experiment in dorsal root ganglion, FK506 promotes the growth of prominent (spinous process) under the consumption of inferior nmole.Lyons，W.E.，George，E.B.，Dawson，T.M.，Steiner，J.P.，Snyder，S.H.，Proc.Natl.Acad.Sci.USA(1994)91：3191-3195。Confirmation FK506 functions in vivo such as Gold are neurotrophy reagent.For the sciatic nerve of white mouse crushing, the regeneration of FK506 promoting nerve and functional restoration.Geold，B.G.，Storm-Dickerson，T.，Austin，D.R.，restorative?neurol.Neurosci.，(19940?6：287；Geold，B.G.，Katoh，K.，Storm-Dickerson，T.，Neurosci.(1995)15：7509-7516。Also can be referring to, Snyder, S.H., Sabatini, D.M., Nature Medicine (1995) 1:32-37 (FK506 strengthens the regeneration of the impaired face nerve of white mouse)

Except that FK506, rapamycin and S-Neoral also produce powerful neurotrophy effect for outer PCI2 cell of organism and chicken Sensory neurone.Steiner，J.P.，Connolly，M.A.，Valentine，H.L.，Hamilton，G.S.，Dawson，T.M.，Hester，L.，Snyder，S.H.，Nature?Medicine(1997)3：421-428。As mentioned above, the immunosuppression mechanism of rapamycin is different with FK506 or S-Neoral.Observation finds that rapamycin has the neurotrophy effect of similar FK506 and S-Neoral, advises that therefore the neurotization effect of these compounds is subjected to the adjusting of another kind of mechanism, rather than passes through to suppress the T-proliferation of cells.

According to the known FK506 of prior art, the analogue of rapamycin and S-Neoral and different separately immunophilin combinations, but do not have immunosuppressive activity.Therefore FK506 analogue L-685,818 combine with FKBP but can not with the interaction of calcium neurine, so be non-inhibitive ability of immunity.Dumont，F.J.，Staruch，M.J.，Koprak，S.L，J.Exp.Med.(1992)176：751-760。

Similarly, 6-methyl-alanyl cyclosporin A (6-[Mel-ala-CsA) combines with ring-type affinity thing, but equally also lacks the ability that suppresses the calcium neurine.Forms of rapamycin analogs WAY-124,466 combine with FKBP but can not interact with RAFT, is non-inhibitive ability of immunity equally.Ocain，T.D.，Longhi，D.，steffan，R.J.，Caccese，R.G.，Sehgal，S.N.，Biochem.Biophys.Res.Commun.(1993)192：1340-1346；Sigal，N.H.，Dumont，F.，Durette，P.，Siekierka，J.J.，Peterson，L.，Rich，D.，J.Exp.Med.(1991)173：619-628。These nonimmunosuppressive compounds show as powerful neurotrophy reagent outside organism, wherein a kind of compound L-685,818 is the same with FK506 to promote form and functional restoration effectively to the sciatic nerve of white mouse crushing.Teiner，J.P.，Connolly，M.A.，Valentine，H.L.，Hamilton，G.S.，Dawson，T.M.，Hester，L.，Snyder，S.H.，Nature?Medicine(1997)3：421-428。These results confirm that the neurotrophy character of immunosuppressive drug can separate with they zone of action in immunity system.

In the research of researchist for the mechanism of action of FK506 and similar medicine, minimum FKBP-calmodulin binding domain CaM has good avidity (setting forth as Holt etc.) for FKBP among the published job description FK506 in BioMed.Chem.Lett. (1994) 4:315-320.The neurotrophy calmodulin binding domain CaM of proposal FK506 such as Hamilton mainly is positioned at the calmodulin binding domain CaM of immune affinity body, thereby has synthesized a series of compounds, its can efficiently promote spinous process from Sensory neurone to outgrowth.Hamilton，G.S.，Huang，W.，Connolly，M.A.，Ross，D.T.，Guo，H.，Valentine，H.L.，Suzdak，P.D.，Steiner，J.P.，BioMed.Chem.Lett.(1997)。These compounds are effective for the neurodegenerative disease of animal model.C.FKBP12 inhibitor/part

Many investigators are at the early stage FK506 that the explores nineties, and the immunosuppression mechanism of S-Neoral and rapamycin is to seek not have the s-generation immunosuppression reagent of early stage poisonous side effect of medicine.A kind of important compound, and 506BD (for " FK506 calmodulin binding domain CaM " referring to Bierer, B.E., Somers, P.K., wandless, T-J., Burakoff, S.J., Schreiber, S.L, Science (1990) 250:556-559), kept FK506 and FKBP12 in conjunction with the time part that contacts, and in medicine-protein complex, prolong the big loop section of the FK506 that very big change is arranged from FKBP12.Discover that 506BD is high affinity part and inhibitor for FK506, but can not suppress the T-proliferation of cells, confirm that the immunosuppressive action of FK506 is not simply to suppress the gyrase activity to cause for the first time.

Except that the Macrocyclic analogs of multiple FK506 and rapamycin, synthetic and estimate some and simplify after compound, the medicine FKBP-calmodulin binding domain CaM that these compounds represented are cut.The non-macrocylc compound of FKBP-calmodulin binding domain CaM that contains cut FK506 is less with respect to the avidity of parent compound and FKBP12.These structures still have the avidity of nmole for protein.Referring to, as, Hamilton, G.S., Steiner, J.P., Curr.Pharm.Design (1997) 3:405-428; Teague, S.J., Stocks, M.J., BioMed.Chem.Lett., (1993) 3:1947-1950; Teague, S.J., Cooper, M.E., Donald, D.K., Furber, M., BioMed.Chem.Lett., (1994) 4:1581-1584.

Holt etc. disclose some simple piperidines acid esters FKBP12 inhibitor, and it has excellent avidity for FKBP12.Initial studies confirm that with effect is fine in this regard as the pyranose ring in the alternative FK506 analogue of simple alkyl such as cyclohexyl and dimethyl amyl group.Holt，et?al.，BioMed.Chem.Lett.，(1994)4：315-320。Simple compounds has good avidity (Ki value be respectively 250 and 50nM) for FKBP12.The simple analog thing of these FK506 calmodulin binding domain CaMs of these structural validations is almost the same with the FK506 corresponding section with the combination of immunophilin.Holt，D.A.，Luengo，J.I.，Yamashita，D.S.，oh，H.J.，Konialian，A.L.，Yen，H.K.，Rozamus，L.W.，Brandt，M.，Bossard，M.J.，Levy，M.A.，Eggleston，D.S.，Liang，J.，Schultz，LW.，Stout，T.J.，Clardy，I.，J.Am.Chem.Soc.(1993)115：9925-9938。

Armistead etc. have also described some piperidines acid esters FKBP12 inhibitor.These molecules studies confirm that with the X-ray structure of the complex compound of FKBP the binding pattern of these simple structures is relevant with FK506.Armistead，D.M.，Badia，M.C.，Deininger，D.D.，Duffy，J.P.，Saunders，J.O.，Tung，R.D.，Thomson，J.A.，DeCenzo，M.T.，Futer，O.，Livingston，D.J.，Murckko，M.A.，Yamashita，M.M.，Navia，M.A.，ActaCryst.(1995)D51：522-528。

According to known effector-region mode, the FKBP12 part that lacks the effector element does not have activity to immunosuppression reagent, just can not suppress the outer and intravital lymphocytic hyperplasia of organism.The neuroprotective of D.FKBP12 part and neurotization effect

Steiner etc. are at USP No.5, and a large amount of neurotrophy behaviors of compound have as described above been described in 696,135 (publication on December 9th, 1997).Cultivate the chicken Sensory neurone as biological in-vitro evaluation, can be used for measuring in the compound promoted neurone spinous process to the ability of outgrowth (fibrous extension).Also test compounds and FKBP12 bonded ability are with the ability that suppresses its enzyme (gyrase) catalytic activity.The data acknowledgement chemical compound lot is powerful especially nerve growth reagent, promotes the neurofibril shape of cultivating to extend, and just reaches half maximum effect sometimes when pmol concentration.These simple FKBP12 parts are suitable for the effect and the FK506 of nervous tissue, sometimes even stronger.

Wherein some compound can promote the peripheroneural regeneration of damage in the organism.Steiner.J.P.，Connolly，M.A.，Valentine，H.L.，Hamilton，G.S.，Dawson，T.M.，Hester，L，Snyder，S.H.，Nature?Medicine(1997)3：421-428。The sciatic nerve tweezers fragmentation of rat in the living animal test, animal is by these compounds of subcutaneous use, discovery is with respect to comparing animals, and the neural of damage obviously regenerated, thereby forms more aixs cylinder and the aixs cylinder that contains more myelins in the animal body that carries out pharmacological agent.Impaired minimizing (with respect to comparison minimizing 90%) that causes the minimizing (reducing 50%) of the quantity of aixs cylinder and the degree that myelin forms with the vehicle treatment of the organ of animal with respect to comparison.Use the FKBP12 ligands for treating can reduce the minimizing (reducing by 25% and 5%) of the quantity of aixs cylinder and the minimizing (reducing by 65% and 50%) of the degree that myelin forms with respect to comparison with respect to comparison.Gold etc. has reported similar result subsequently.Gold，B.G.，Zeleney-Pooley，M.，wang，M.S.，Chaturvedi，P.，Arnistead，D.M.，Exp.Neurobiol.(1997)147：269-278。

Wherein some compound exhibits promotes to suffer from the recovery of the dopaminergic nervus centralis of pathology in the living animal of Parkinson's disease.Hamilton，G.S.，Huang，W.，Connolly，M.A.，Ross，D.T.，Guo，H.，Valentine，H.L.，Suzdak，P.D.，Steiner，J.P.，BioMed.Chem.Lett.(1997)。N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (" MPTP ") is a kind of neurotoxin, the dopaminergic neurone of alternative damage.Gerlach，M.，Riederer，P.，Przuntek，H.，Youdim，M.B.，Eur.J.Pharmacol.(1991)208：273-286。Former motion responds the dopaminergic passage of black substance-striatum for controls movement in the brain.

Parkinson's disease is serious neurodegenerative illness, comes from the sex change of motor passage.The animal of the black substance-striatum passage pathology that is caused by MPTP is used as the living animal sample of Parkinson's disease.The mouse of handling with MPTP and vehicle is with respect to the functional dopaminergic end of pathology animal significantly sacrificing 60-70% not.With respect to comparison; use the pathology animal of MPTP to be right after the surprising recovery that use FKBP12 part shows the dopaminergic end of striatum that TH-pollutes, illustrate that the FKBP12 part all has powerful neuroprotective and neurotization effect for peripheral nerve and nervus centralis.

Other has the compound of avidity also to have similar neurotrophic activity described above to FKBP12.Known following patent of those skilled in the art and patent application, they provide the neurotrophic compound that lacks immunosuppressive activity:

Hamilton etc., U.S. Pat P No.5,614,547 (on March 25th, 1997)

Steiner etc., U.S. Pat P No.5,696,135 (on December 9th, 1997)

Hamilton etc., U.S. Pat P No.5,721,256 (on February 24th, 1998)

Hamilton etc., U.S. Pat P No.5,786,378 (on July 28th, 1998)

Hamilton etc., U.S. Pat P No.5,795,908 (on Augusts 18th, 1998)

Steiner etc., U.S. Pat P No.5,798,355 (on Augusts 25th, 1998)

Steiner etc., U.S. Pat P No.5,801,197 (on September 1st, 1998)

Li etc., U.S. Pat P No.5,801,187 (on September 1st, 1998)

These molecules are effective part and inhibitor for FKBP12, also are the outer powerful neurotrophy reagent of organism, can promote the neurite outgrowth of the Sensory neurone of cultivation under nmole or inferior nmole consumption.

In addition, known these compounds are FK506 for example, and S-Neoral and rapamycin etc. has immunosuppressive activity, also can have tangible neurotrophic activity.Therefore, these compounds also have other activity to a certain extent, comprise neurotrophic activity, and these compounds can comprise in " sensorineurotrophic compound " that is this use.Following publication provides some compounds to have immunosuppressive activity and other may be active, and can comprise equally in " sensorineurotrophic compound " that is this use.

Armistead etc., U.S. Pat P No.5,192,773 (on March 9th, 1993)

Armistead etc., U.S. Pat P No.5,330,993 (on July 19th, 1994)

Armistead etc., U.S. Pat P No.5,516,797 (on Mays 14th, 1996)

Armistead etc., U.S. Pat P No.5,620,971 (on April 15th, 1997)

Armistead etc., U.S. Pat P No.5,622,970 (on April 22nd, 1997)

Armistead etc., U.S. Pat P No.5,665,774 (on September 9th, 1997)

Zelle etc., U.S. Pat P No.5,780,484 (on July 14th, 1998)

The neurotization of FKBP12 part and neuroprotective are not limited to the dopaminergic neurone of central nervous system.Mouse with after chlorine Amphetamine (" PCA ") is handled has provide protection with the treatment of fkbp ligand body.To the chlorine Amphetamine is a kind of to discharging the hurtful reagent of neurone meeting of neurotransmitters varies.Steiner，J.P.，Hamilton，G.S.，Ross，D.T.，Valentine，H.L.，Guo，H.，Connolly，M.A.，Liang，S.，Ramsey，C.，Li，J.H.，Huang，W.，Howotnick，A.，Suzdak，P.D.，Proc.Natl.Acad.Sci.USA(1997)94：2019-2024。With respect to comparison, the cortical density of the varies fiber of the mouse of PCA pathology reduces 90%.With respect to pathology, the animal of non-drug therapy, accept in the animal cortex of part varies in the neural bigger somatesthesia cortex that distributes of varies can nerve distribute and improve twice.

Similarly, the vault of the band fringe of crosscut rat, these parts can cause the remaining germinating growth with cholinergic aixs cylinder.Guo，H.，Spicer，D.M.，Howorth，P.，Hamilton，G.S.，Suzdak，P.D.，Ross，D.T.，，Soc.Neurosci.，Abstr.(1997)677.12。Crosscut causes the deafferentation of digitation of hippocamps 75-80%.Subcutaneous use FKBP12 part makes hippocampal CAl, the prominent germinating growth that produces four times of the remnants (nerve) of the remainder in CA3 and dentation gyrus zone, make that cholinergic neural the distribution obviously recovered in all three zones, quantitatively learn by cholinacetyltranslase (ChAT) density.

Take all factors into consideration, the specific ligand of the data declaration FKBP12 of known references, preferably nonimmunosuppressive, comprise that gang is called as the powerful neurotrophy compound of " neuroimmunophilin " or " nerve immunity affinity ligands ", the potential therepic use is arranged for the treatment and the prevention of neurodegenerative disorders.Therefore, according to the present invention, sensorineurotrophic compound comprises that those are called as the compound of neuroimmunophilin, and it has binding ability to FKBP, but and does not require so.Whether the most basic mechanism and these compounds of effect have other activity, as immunosuppressive activity, whether not neurophic to compound, can not promote hair growth for the objective of the invention is, recover vision, or improve memory, and whether above compound is to neurocyte, hair follicle, ocular tissue or brain cell have desired effects and play a decisive role.

The disclosure of also not working before the present invention is used these compounds to be used for the treatment of or is prevented the neuroscience illness, baldness, vision illness, memory impairment and associated conditions.According to following more detailed description, the present invention is mainly used in this purpose.In order to understand the present invention better, below comprise physical damnification nerve and neurodegenerative disease, to the treatment memory impairment and/or to the hypermnesis function to preventing and/or treating neurologic disease; To treatment alopecia and promotion hair growth; With to treatment vision illness and/or improve vision and discuss: 1. prevent and/or treat neuropathic conditions

Have been found that the immunosuppressor of pmol concentration such as FK506 and rapamycin can stimulate the PCI2 cell and be called neurite outgrowth in the Sensory neurone of back root neural section cell (DRGs).Lyons etc., Proc.of Natl.Acad.Sci., 1994 91 volume 3191-3195 pages or leaves.In the living animal test, FK506 shows the stimulating neuronal regeneration after the face nerve damage and causes functional rehabilitation in the animal of injury of sciatic nerve.

There are several neurotrophic factors that influence the specific neurone colony in the central nervous system to determine.For example, supposed that Alzheimer's is minimizing or the loss that comes from nerve growth factor (NGF).Suggestion is given birth to neural factor (BDNF), neuroglia neural factor, ciliary neurotrophic factor and neurotrophin-3 with exogenesis nerve growth factor or other neurotrophin such as brain and is treated the survival of person with Alzheimer's disease with raising sex change neurone colony thus.

Owing to the conveying of large protein neuralward aims of systems and the difficulty of biological availability have hindered the clinical application of these protein in various neural morbid state.On the contrary, the immune suppressant drug with neurotrophic activity is less relatively, and has good biological availability and specificity.But when taking for a long time, immunosuppressor shows many potential severe side effect, comprise filtering weakening of nephrotoxicity such as glomerulus and irreversible interstitial fibers sex change (Kopp etc., 1991, J.Am.Soc.Nephrol.1:162); Neurological deficit such as unconscious tremble or unspecific cerebellum angina such as non-localized headache (De Groen etc., 1987, N.Engl.J.Med.317:861); And hypertension and complication thereof (Kahan etc., 1989, N.Engl.J.Med.321:1725).

Therefore need can be used for the micromolecular compound that neurotrophic effect is provided and can be used for treating neurodegenerative disorders.2. treatment alopecia and promotion hair growth

Trichomadesis has multiple situation.These situations comprise male pattern alopecia, senile alopecia, alopecia areata, the disease of following basic skin lesion or tumour and system disorders such as nutrition disorder and endocrine regulation.The reason that produces trichomadesis is very complicated, but it is unusual to be attributable to age, inherited genetic factors, male hormone activation, the leiphemia that is delivered to hair follicle and scalp in some cases.

Immunosuppressive drug FK506, rapamycin and S-Neoral are well-known as effective T cell special immune inhibitor, and very effective to prevention transplant rejection after the organ transplantation.FK506 (Yamamoto etc., J.Invest.Dermatol.1994,102,160-164; Jiang etc., J.Invest.Dermatol.1995,104,523-525) and S-Neoral (Iwabuchi etc., J.Dermatol.Sci.1995,9, topical application 64-69) but non-ly orally rely on the existing report of mode stimulating hair growth with dosage.A kind of trichomadesis of form, spot takes off, and known is relevant with autoimmune activity; Therefore expectation proof topical application immunomodulatory compounds can be effective to treating such alopecia.The hair growth hormesis of FK506 is the theme (Honbo etc., EP 0 423 714 A2) that covers the international monopoly that is used for stimulating hair growth of FK506 and dependency structure thereof.People such as Honbo disclose relatively large tricyclic compound, and its immunosuppressive effect is known, as the purposes of hair revitalizing agent.

The hair growth of FK506 and related reagent and recovery effects be open (Goulet etc., USP5,258,389 in many United States Patent (USP)s; Luly etc., USP5,457,111; Goulet etc., USP5,532,248; Goulet etc., USP5,189,042; Ok etc., USP5,208,241; Rupprecht etc., USP5,284,840; And Organ etc., USP5,284,877).The compound that the claimed FK506 of these patents is relevant.Though method that they do not have claimed hair to recover, they disclose the known application that FK506 is used for hair growth.Be similar to FK506 (and in people's such as Honbo patent desired variation range), desired compound is all relatively large in these patents.And these patents of quoting are all relevant with the immunomodulatory compounds that is used for the autoimmunity relative disease, and wherein the effect of FK506 is well-known.

Some other U.S. Patent Publication be used for the S-Neoral that hair recovers and purposes (Hauer etc., USP5,342,625 of related compound; Eberle, USP5,284,826; With Hewitt etc., USP4,996,193).These patents are also relevant with the compound that is used for the treatment of autoimmune disorders, and quoted the known application that the S-Neoral that is used for hair growth and related immune suppress compound.

But defined immunosuppressive compounds suppresses immunity system and shows other toxic side effect.Therefore need can be used as the micromolecular compound that hair recovers compound.

Hamilton and Steiner be at U.S. Pat P No.5, disclosed novel pyrrolidine carbonate in 614,547, and it can combine with immunophilin FKBP12 and neuroactive growth, but does not have immunosuppressive action.The effect and the FK506 that unexpectedly find these non-inhibitive ability of immunity compound promoted hair growths are similar.So these small molecule structures and non-immunosuppression character make the related immune inhibition compound in they and FK506 and the prior art make a distinction.3. treat the vision illness and/or improve eyesight

Vision system comprises eyeball, ocular adnexa and visual channel.The dysfunction meeting of vision system causes permanent or temporary transient impaired vision, that is to say, departs from or multinomial normal function of eyes.Impaired vision can embody from many aspects, and comprises the disorderly and imbalance of very large-scale vision.These disorderly and imbalances comprise the part or all of loss of vision without limitation, to needing to proofread and correct with the vision resolution capability of distant place things, lose the visual field nearby, the impaired ocular motility that does not have diplopia (double vision), impaired or the distortion color perception, limited regulating power to light and shade, the adaptability that weakens, metamorphopsic distortion, impaired Binocular vision, adaptive local paralysis, iridoplegia, trichoma, ectropion, lagophthalmos and scar scar.Referring to " doctor's application manual one ophthalmology ", 16 editions, 6:47 (1998).Multiple eye disease, disease, wound and complication have disadvantageous effect to vision system, comprise the gene illness without limitation; With the aging illness relevant with sex change; With to eye, the head or other body part by the relevant illness of physical trauma that external force causes; The illness that causes by environmental factors; The illness that has multiple disease to cause; Combination with above each situation.

Vision system is a complex system that comprises a plurality of parts.Impaired vision can comprise whole vision system, and arbitrary parts, or the combination of various parts depend on the trickle person's character of surrounding environment.Eye contains lens, and lens is suspended in the ribbon of Qin Shi (Zinn), focuses on by ciliary body.Ciliary body is secreted water-soluble body fluid, is full of posterior chamber of the eye, flows into anterior chamber of the eye by pupil, mainly discharges by executing tired Mu Shi (Schlemm) passage.Iris is controlled the optical throughput that enters eyes by the size of regulating its central opening-pupil.Visual pattern focuses on the retina, and central fovea is the sharpest part of visual sensitivity in the retinal area.Conjunctiva is the mucous membrane between eyelid and eyeball, and terminates in limbus conjunctiva place significantly, and the edge and the cornea of conjunctiva are overlapping.Cornea is positioned at the front portion of eye, is as clear as crystal layer of fibers; Its refraction to light is very important, and is covered by epithelial cell, and these epithelial cells and conjunctival epithelial cell are all different aspect a lot.

Retina is positioned at an innermost layer, to photaesthesia, contains two kinds of photoreceptors, and cone mainly is responsible for the color vision under the light, and rhabdos is necessary to the vision under the dim light, but can't experience color.When light by cornea, lens, and vitreous humor arrive retina from the inboard; That be exactly light earlier by ganglion cell and nerve fiber, plexiform layers inside and outside, the inside and outside and interior outer limiting membrane of stratum nucleare arrives the photoreceptor layer at last.Photoreceptor is positioned at the inboard near the amphiblestroid outside and outermost pigment epithelial layer.The pigment epithelium confluent monolayer cells plays barrier on the anatomy for the liquid and the material of eye outside, form " blood-retina " barrier, provide nutritive substance to the photoreceptor cell, oxygen, functional useful matter source is as the phagocytosis material of vitamin A and degradation production.Pigment epithelial layer and photoreceptor layer do not have related on the anatomy, only can distinguish under pathological conditions.

When rhabdos and cone are subjected to light stimulus, signal is delivered to the light nerve fiber by the successive neurone of retina own, arrives pallium at last.Rhabdos and cone all contain the molecule that decomposes after contacting with light, during these molecules can stimulate the nerve fiber that links to each other with eye.The contained molecule of rhabdos contains three kinds of photosensitive moleculars rhodopsin in the cone, be generically and collectively referred to as porphyropsin, and is slightly different with the composition of rhodopsin, respectively to red, and indigo plant, or green glow is the most responsive.

Rhabdos or cone do not produce action potential.But produce photoinduced membrane hyperpolarization in rhabdos or pyramidal cell's outside photosensitive fragment, it is delivered to the synaptosome by interior segments from outside fragment by the direct conduction of voltage itself, and this process is called electronic conduction.In synaptosome, the release of the transmitter molecule that membrane potential control is unknown.Under the light situation seldom, rhabdos and pyramidal cell's film meeting depolarize, thus the release of transmitter reaches maximum value.Photoinduced super utmost point effect meeting causes that the release of transmitter molecule obviously reduces.

Rhabdos and pyramidal cell discharge transmitter and produce signal in bipolar neuron and horizontal cells.Signal in two kinds of cells all passes through electronic conduction but not the action potential transmission.

Shaft-like bipolar neuron links to each other with at least 50 staff cells, and the bipolar neuron of short and small disperse only links to each other with one or several pyramidal cell.When the rhabdos that links to each other with the depolarize bipolar cell contacts with light with the pyramidal cell, bipolar cell is upset.The release of transmitter molecule has suppressed unpolarized bipolar cell.Therefore in the dark, rhabdos and pyramidal cell secrete a large amount of transmitter molecules, and unpolarized bipolar cell is suppressed.Under light, rhabdos and pyramidal cell secrete the transmitter molecule and reduce, thereby the inhibition of depolarize bipolar cell has also been reduced, and make bipolar cell be excited.In this way, positive negative signal can be delivered to amacrine neurocyte and ganglion cell from rhabdos and cone by different bipolar cells.

Advise that as they titles horizontal cell is horizontal protrusion in retina, with rhabdos, cone, horizontal cell, or the combination of other cell type formation cynapse that is connected.Although inferred the mechanism in some photoreceptor set of signals, the function of horizontal cell is still unclear.

All types of bipolar cells link to each other with ganglion cell with two kinds of basic forms.A-type ganglion cell mainly links to each other with the rhabdos bipolar cell, and B-type ganglion cell mainly links to each other with the bipolar cell of short and small disperse.A-type ganglion cell is described mainly to contrast gradient, the perceptual sensitization of light intensity and motion, and B-type ganglion cell is main relevant with color vision and visual sensitivity.

As horizontal cell, the formation cynapse that flatly is connected of amacrine neurocyte with some other cells, these cells refer to bipolar cell, ganglion cell and other amacrine neurocyte.The function of amacrine neurocyte is also unclear.

The aixs cylinder of ganglion cell is imported signal the nerve fiber layer of eye into, pools fiber in this aixs cylinder, further converges on the discus nervi optici again, leaves eye from discus nervi optici with the optic nerve form.Ganglion cell transmits signal to brain by optic nerve fiber with the form of action potential.Also can be even without these cells of irriate with the average baselining speed transmission impulsion continuously of about 5 per seconds.Visual signalling is added on the baseline that ganglion cell stimulates.These signals can be provocable, and the quantity of impulsion is brought up to and is higher than baseline rate, and is also suppressible, and the quantity of impulsion is reduced to and is lower than baseline rate.

As the part of central nervous system, some aspect of eye can be regarded the extension of brain as; Its regenerative power is very limited like this.Limited regenerative power makes improves eyesight, solves the problem of vision system dysfunction, and/or treatment or these the challenging work of prevention ophthalmic diseases are more complicated.The illness of many eyes, as retinal photic injury, the ophthalmic injuries that retinal ischemia causes, the macular degeneration relevant with the age, other illness of the eye disease that free radical causes and some is considered to irremediable fully.Other ophthalmic diseases as the illness that is caused by permanent impaired vision, to proofread and correct with ophthalmological instrument and/or operation, has obtained success in various degree only.

Immunosuppressive drug FK506, rapamycin and S-Neoral are known as powerful single-minded T-cellular immunization inhibitor, and to the opposing autoimmunity, (organ) transplanted or (skin, muscle) transplant rejection, inflammation, anaphylaxis, other autoimmunity or immunoregulatory disease and communicable disease are effective.Find S-Neoral, FK506, rapamycin, buspirone, Spiropitan, and/or the use of their derivative is effective to the treatment of some ophthalmic diseasess in these types.Some eye diseases or visual problem are known relevant with autoimmunity or immunoregulatory activity; Therefore wish to confirm that immunomodulatory compounds is effective to the treatment of the eye disease of these types or visual problem.

Some United States Patent (USP)s have disclosed FK506, and rapamycin and relevant reagent are used for the treatment of the result of treatment of ophthalmic diseases.(Guolet etc., USP 5,532, and 248; MochizukiUSP 5,514, and 686; Luly etc., USP 5,457, and 111; Russo etc., USP 5,441, and 937; Kulkarni, USP5,387,589; Asakura etc., USP5,368,865; Guolet etc., USP 5,258, and 389; Armistead etc., USP 5,192, and 773; Guolet etc., USP 5,189, and 042; And Fehr, USP5,011,844).The compound that these patent application protections are relevant with FK506 or rapamycin, and it is relevant to disclose the immunosuppressive action of the known application of these compounds for treating eye diseases relevant with FK506 or rapamycin and known FK506 and rapamycin.The compound of these Patent publish is sizable molecules.In addition, the immunomodulatory compounds that the patent of being quoted relates to only limits to treat autoimmunity or relevant disease, or immunoregulatory disease, is known for the curative effect of these treatment of diseases FK506 and rapamycin.

Other United States Patent (USP) disclose use S-Neoral, Spiropitan, buspirone, their derivative and other inhibitive ability of immunity compound be used for the treatment of ophthalmic diseases (Sharpe etc., USP 5,703,088; Sharpe etc., USP 5,693, and 645; Sullivan, USP 5,688, and 765; Sullivan, USP 5,620, and 921; Sharpe etc., USP 5,574, and 041; Eberle, USP5,284,826; Sharpe etc., USP 5,244, and 902; Chiou etc., USP 5,198, and 454 and 5,194,434; And Kaswan, USP 4,839, and 342).It is effective to the treatment of autoimmune disorders that these patents also relate to compound, and S-Neoral, Spiropitan, buspirone are used in explanation, their derivative and other inhibitive ability of immunity compound are used for the treatment of eye inflammation and other immunoregulatory ophthalmic diseases.

According to definition, the inhibitive ability of immunity compound that discloses in the prior art can suppress immunity system, and other toxic side effect is also arranged.Therefore need non-immunosuppressant, micromolecular compound and composition and the method for using these compounds, this just helps to improve eyesight; Prevention, treatment, and/or the dysfunction of repairing impaired vision or vision system; And prevention, treatment, and/or solve ophthalmic diseases.

Some patents have also disclosed non-immunosuppressant and have been used for permission or promote wound healing (no matter being that wound or operation cause); Control intraocular pressure (causing because of glaucoma usually); Control neurodegenerative eye disorders, comprise retinal neurons damage or wound, retinal ganglial cells damage or wound, and macular degeneration; Exsule length excites nerve; The oxidative damage that prevention or minimizing cause because of free radical; The oxygen and the nutrition supplement that cause owing to low volume of blood flow are impaired impaired with the waste discharge with treating.These non-immunosuppressive substances can be divided into two classes: naturally occurring molecule, and as albumen, glycoprotein, peptide, hormone, and somatomedin; With the synthetic molecule.

In the non-inhibitive ability of immunity molecule of naturally occurring this gang; some hormone; somatomedin; be applied patent with signaling molecule; the supplement use of the naturally occurring characteristic of claimed these molecules; with attack to specific cells, wherein specific molecular not natural existence in ripe individuality.These patents apply for that usually protection is used for reducing or prevention eye disease symptom, or are used to suppress or reverse the method for vision loss.

Louis etc. are especially at USP 5,736,516 and 5,641, the neurotrophic factor (GDNF) that disclose to use glial cell-line to derive from 749 stops or reverses the retinal neurons that caused by glaucoma (in other words, or other retinal diseases or wound that causes by sex change or wound photoreceptor) and the sex change of retinal ganglial cells.O'Brien etc. are at USP5, disclose in 714,459 and 5,700,909 and use glycoprotein, excite nerve exsule length and promote myelin to form of Saponin/TSM and its derivative.LaVail etc. are at USP5,667, disclose the pathology of using multiple neurotrophin to stop or reverse retinal neurons in 968, these neurotrophins comprise the neurotrophic factor that is derived from by brain, ciliary neurotrophic factor, neurotrophy thing-3 or neurotrophy thing-4, the former albumen somatomedin of acidity or alkaline fiber, interleukin, tumor necrosis factor-alpha, insulin-like growth factor-2 and other somatomedin.Wong etc. are at USP 5,632, disclose in 984 and use Interferon, rabbit, and Intederon Alpha-2a especially is by reducing hemorrhage and placing restrictions on revascularization treatment macular degeneration symptom.At last, Wallace etc. are at USP5, disclose in 441,937 and use lung-derived neurotrophic factor (NTF) to be used to keep ciliary ganglion and parasympathetic neuron cell.

The key feature of the factor that derives from from specific cells system is that they are positioned specific clone and tissue; Using these molecules to carry out whole body therapeutic and have very big risk, may be that the clone of non-activity causes effect unconscious but that have potentially dangerous to these molecules of genetic marker wherein.Similarly, hormone and somatomedin often can activate a lot of genes in many clones; Once more, ground, non-location uses these molecules to have very big risk, may evoke inappropriate and proemial response.

In this molecule of synthetic, the compound of most patent protections is inhibitive abilities of immunity, and can be used for treating aforesaid inflammation, autoimmunity and supersensitivity response.Wherein other are non-inhibitive abilities of immunity, it is said treatment cytopathy and can promote the ability of cell regeneration sometimes, and the most common is their antioxidation property.

Tso etc. are especially at USP 5,527, disclose in 533 and use astaxanthin, and a kind of carotenoid antioxidant is used to prevent or reduces photoreceptor have the damage that causes because of free radical.Similarly, Babcock etc. are at USP 5,252, disclose the ability of using the antioxidant amino steroid to improve the opposing oxidative damage in 319, and are used for the treatment of eye disease and wound.Freeman is at USP 5,468, discloses in 752 to use antiviral phosphoryl methoxy base alkyl cytosine to reduce unusual intraocular pressure to raise.

Hamilton and Steiner be at USP 5,614, disclosed the novel pyrrolidine carbonate in 547, and it can combine with immunophilin FKBP12 and the growth of exciting nerve, but does not have immunosuppressive action.Find that unexpectedly these non-immunosuppressive compounds can promote the raising of vision and solve eye disease.And their new small molecule structures and non-immunosuppressive properties make a distinction they and FK506 of the prior art and related immune inhibitor.

In addition, these compounds are because their new small molecule structures and do not have the effect of general whole body to make a distinction with the non-immunosuppressive compounds that is used for the treatment of the vision illness.Naturally occurring hormone, somatomedin, cytokine and signaling molecule are normally multi-functional, and can activate several genes in different clones; And these compounds can not.Unforeseeable when therefore having avoided whole body to use, the side effect with potentially dangerous.Similarly, these compounds also can avoid unforeseeable other side effect one of potential can not introduce clone-specific molecular in the clone that its itself do not contain them.

Regardless of reason, need prevention really or treat neurologic disease, comprise physical damnification nerve and neurodegenerative disease; Treatment alopecia and promotion hair growth; Be used for the treatment of the vision illness and/or improve vision; Be used for the treatment of memory impairment and/or memory.The invention provides such method.

The invention summary

The present invention is based on the discovery of some bridged heterocyclic derivatives, these compounds can be used for treating neurodegenerative disease; The treatment alopecia reduces illness with relevant hair, is used for the treatment of the vision illness and/or improves eyesight; Be used for the treatment of memory impairment and/or memory.Therefore, provide gang novel heterocyclic derivatives compound, its primary structure contains one or more bridging parts and/or its substituting group.

These regeneration of compound stimulating neuronal and growths, thus effective to treating neurologic illness and neurodegenerative disease.These compounds also can promote hair growth, thereby it is effective that the treatment hair is reduced illness.These compounds also to treatment vision illness, improve eyesight, the treatment memory impairment, or memory is effective.The preferred characteristics of these compounds are there is not immunosuppressive activity and/or are non-inhibitive abilities of immunity among the present invention.

The present invention provides the method for treatment neurodegenerative disorders especially, comprises that the patient uses a certain amount of The compounds of this invention according to the needs of curative effect.By the mode of example, treatable illness is relevant with the sex change of wound or cell.Therefore, use the The compounds of this invention of treatment significant quantity can promote specific nerve, hair, eye, or the protection of brain cell, survival, or regeneration.

The invention still further relates to pharmaceutical composition, said composition contains:

(i) bridged heterocyclic derivatives of significant quantity, its primary structure contain one or more bridging parts and/or its substituting group, are used for the treatment of the neurodegenerative disease of animal, and the treatment alopecia reduces illness with relevant hair, treat the vision illness and/or improve eyesight; Or treatment memory impairment and/or memory; With

(ii) medicine acceptable carrier.

And then consider that The compounds of this invention can be independent, make up or be used in combination with another treatment reagent of significant quantity or for effective other reagent of this treatment for diseases of enumerating continuously or simultaneously.

The present invention also provides The compounds of this invention in the purposes that is used for the treatment of in the manufacturing of the medicine of this illness of enumerating or pharmaceutical composition.Such pharmaceutical composition comprises the part that is fit to particular disorder, and whole body is oral, the injection prescription.Further consider that compound of the present invention can be used for the treatment of the illness of enumerating in this with another therapeutical agent.Multiple formula of medicine and different medicine-feeding technologies are below more at large described.

Brief Description Of Drawings

Fig. 1 is the photo with 6 week of vehicle treatment back mouse.Fig. 1 demonstration is less than 3% the new hair of shaving region growing when using vehicle (contrast).

Fig. 2 is with 10 μ M related compounds, the photo of GPI 1046 treatments 6 week back mouse.Fig. 2 shows the unusual effect when the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body of use N-heterocyclic derivatives, wherein 90% the new hair of shaving region growing.

Fig. 3 is the photo with 30 μ M GPI, 1046 treatments, 6 week back mouse.Fig. 3 shows the excellent ability when the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body of use N-heterocyclic derivatives, wherein the shaving zone new hair of almost completely growing.

Fig. 4 is used for describing using vehicle, and FK506 treats mouse with the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body of multiple relevant heterocyclic derivatives, treats the histogram of the relative hair growth factor of the mouse of each compound of determining after 14 days.Fig. 4 confirms that non-inhibitive ability of immunity neuroimmunophilin fkbp ligand physical efficiency significantly promotes early stage hair growth.

Fig. 5 A, 5B and 5C show GPI 1046 protection retinal ganglial cellses, prevent the retina local hemorrhage and sex change.

Fig. 6 shows optic nerve aixs cylinder and the myelinic degeneration that GPI 1046 protections occur because of the retina local hemorrhage.

Fig. 7 shows that GPI 1046 provides appropriateness protection, can prevent the death of retinal ganglial cells behind the optic nerve transection.

Fig. 8 shows that GPI 1046 influences the process of cross-section backsight neural axon sex change significantly during treating.

Fig. 9 shows with GPI 1046 treatments more obvious to the effect comparison ganglion cell body of optic nerve aixs cylinder.

Figure 10 can prevent myelinic degeneration on proximal stump with GPI 1046 treatments after 28 days after showing optic nerve transection.

Figure 11 shows the mesoglia (large dark cell with fibrous processes) of FKBP-12 immunohistochemistry mark and produces myelinic cell between optic nerve fiber bundle and some optic nerve aixs cylinders.

Figure 12 can prevent myelinic degeneration on the stump far away with GPI 1046 treatments after 28 days after showing optic nerve transection.

Figure 13 is presented at the generation that can reduce inside and outside amphiblestroid neovascularity afterwards with GPI 1046 treatments after 28 days in 8 weeks of diabetes outbreak that streptozocin causes, and prevents the neuronal degeneration of inner nuclear layer (INL) and ganglion-cell layer (GCL).

Invention Xiang Shu definition

" thiazolinyl " Shi contains the Zhi chain of the fixed carbon number of Zhi or the aliphatic unsaturated hydrocarbon of Zhi chain. For example, C₂-C ₆The alkenyl hydrocarbon chain of Zhi chain or Zhi chain contains 2-6 to has Zhi Tan Yuan of Shao Yi Shuan key, include but not limited to Qu for basic as Yi thiazolinyl, acrylic, Yi acrylic, cyclobutenyl, isobutenyl, Shu cyclobutenyl, Zheng pentenyl, n-hexylene base etc. Also is included in the Shi of scope Zhong of the present invention, and " thiazolinyl " also can Qi Zhong of Zhi Suo be Shuoed what the Tan Yuan Xuan Ze ground of Ren of thiazolinyl by O, NH, S or SO₂The aliphatic unsaturated hydrocarbon in Ti generation. For example, the Tan 2 of 4-pentenyl can become (2-propylene) Yang methyl for Xing by Yong O Ti.

" alcoxyl base " Shi group-OR, Qi Zhong R are the Wan base of this place definition. The Shi R Wei Zhi chain of You Xuan or the saturated hydrocarbon chain that contains 1-6 Tan Yuan of Zhi chain.

" Wan yl " Shi contains the Zhi chain of the fixed carbon number of Zhi or the saturated hydrocarbon chain of Zhi chain. For example, C₁-C ₆Zhi chain or branched alkyl hydrocarbon chain contain 1-6 Tan Yuan, include but not limited to Qu for basic as methyl, Yi base, propyl group, Yi propyl group, butyl, isobutyl base, Shu butyl, Zheng Wu base, n-hexyl etc. Also is included in the Shi of scope Zhong of the present invention, and " Wan yl " also can Qi Zhong of Zhi Suo be Shuoed what the Tan Yuan Xuan Ze ground of Ren of Wan base by O, NH, S or SO₂The hydrocarbon chain in Ti generation. For example, the Tan 2 of Zheng Wu base can become the propoxyl group methyl for Xing by Yong O Ti.

Zhi obtains the Shi of Zhu Yi, Zai Zheng Shen Qing Zhong " R " or " R_n" (Qi Zhong n Wei Shuo Zi) Yong Zuo Zhis fixed multiple Wan base (or Qi Ta) Qu for base. Full Wen Zhong R group Shi independence Xuan Ze. Yin this, R Shang Shi Shi for example₁Shi branched alkyl and do not require the molecule Zhong R of the Xiang Tong of another place of Zai somewhere₁The branched alkyl of Shi Xiang Tong, for example do not forbid R₁Shi Zhi alkyl group. " the R of Suo You_n" for " R of Qi Ta_n" Shi independence Xuan Ze all, Wu the Lun Shu Yu no Shi Yong of " independent Xuan Ze " Shi or unconsciously ignore.

" Tuo sends out " Shi hair growth is not enough and Mao sends out Tuo Luo part or all of, comprises non-limitingly that Xiong Zheng Tuo sends out that (Xiong sexual type Tuo sends out), the malicious Tuo of Zhong send out, alopecia senilis, areatus alopecia, alopecia areata and trichologia. When producing Tuo, multilated hair cycle Shi sends out. The most common Xian Xiang Shi You Yu hyperplasia Zhong Zhi and cause hair growth or Zai Sheng stage to shorten. Zhe will cause starting too early of Tuiization stage, and Sui Zhi causes a large amount of Mao to send out Wei Yu stage telogen Zhong, and between Qi, Mao Nang separates from the Nang Tou of Pi skin, trichomadesis. Tuo has sent out many Zhong cause of disease, comprises that Yi passes Yin the secondary action of Su, Nian age, region and systemic disease, febrile state, stress, hormone Wen Ti, Yi and Yao Wu etc.

" aralkyl " Shi Yong aryl, heteroaryl, Tan ring or the cyclosubstituted Wan base of Za or alkene (alkenyl) chain, perhaps also can Shi Yong Wan base or Yi or a plurality of aryl, heteroaryl, Tan ring or the Za ring in alkenyl Qu generation, the Wan base/thiazolinyl in namely ' Ar Qu generation ' or ' Ar ' in Wan base/thiazolinyl Qu generation.

" aryl " or " fragrance " Shi aromatic carbon cyclic group or monocycle heterocyclic radical, as phenyl ring; A plurality of rings are as xenyl; Or condensed ring, Qi Zhong Zhi Shao Yi ring is aromatic rings, as Nai base, 1,2,3,4-tetralyl, En base or phenanthryl, Ta can Wei Wei Qu generation or Yong Yi or a plurality of Qian Mian definition Qu for basic Qu generation. The phenyl ring Qu partly that is connected to the aryl moiety of Zhong compound of the present invention can be connected to ortho-, meta-or p-Wei direction for base, You Xuan Zai contraposition.

The example of the typical aryl moiety that is included in the scope of the present invention can include, but not limited to Xia the row group:

It should be noted that " Ar " or " Ar in whole application _n" (wherein n be numeral) as specifying multiple ring-type (or other) substituting group.The Ar group is independent the selection in full.Therefore, Ar in fact for example ₂Be phenyl somewhere and do not require Ar in another identical molecule in place ₂Be phenyl, for example do not forbid Ar ₂It is pyridyl.All " Ar _n" with respect to other " Ar _n" all be independent the selection, no matter whether term " is independently selected " to use or unconsciously ignore.

" bridged ring " or " bridged ring part " refers to carbocyclic ring or the heterocycle that two or more atoms are shared by two or more ring structures, and wherein the atom of Gong Xianging is C, N, and S or other heteroatoms are arranged according to reasonably replacement mode chemically.Perhaps, " bridging " compound also refers to carbocyclic ring or heterocycle structure, wherein on the main ring on arbitrary position atom and the main ring another atom link to each other by chemical bond or the atom that is not included on the main ring structure division.First and second atoms can be adjacent on main ring also can be non-conterminous.The specific non-limiting example that below contains the bridged ring structure among explanation the present invention:

The present invention also considers other carbocyclic ring or heterocyclic bridged ring structure, and the atom that comprises bridge joint on the bridged ring is carbon or heteroatoms, arranges according to reasonably replacement mode chemically, is not described here.

" carbocyclic ring " or " isocyclic " is meant organic loop section that ring skeleton wherein only is made up of carbon atom, one or morely is selected from the heteroatoms of nitrogen, oxygen or sulphur and can contains or organic loop section of carbon atoms not and term " heterocycle " or " heterocyclic " are meant that wherein ring skeleton contains.Term " carbocyclic ring " is meant and contains the isocyclic part that specifies number carbon atom.So term " C ₃-C ₈Cycloalkyl " be meant that wherein three to eight carbon atoms form three, four, five, six, seven or the organic ring substituents of octatomic ring, comprise, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, suberyl or ring octyl group.

" isocyclic " or " heterocyclic " used herein comprise the monocycle system, and condensed ring (for example, two rings, three ring or other similar bridged ring system or substituting groups are as adamantyl) or many rings condense system.Thereby those skilled in the art can understand that the ring structure that is formed by A and B (or J and K) in this description can comprise two rings among the present invention, or three rings, or polycyclic condensed ring and/or bridged ring system.

Without limitation, the example of preferred carbocyclic ring and heterocyclic moiety comprises phenyl, benzyl, naphthyl, indenyl, the Azulene base, fluorenyl, anthryl, indyl, pseudoindoyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, tetrahydrofuran base, THP trtrahydropyranyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, tetrahydric quinoline group, quinazolyl, furyl, thienyl, imidazolyl ， oxazolyl, benzoxazolyl, thiazolyl isoxazolyl, different triazolyl ， oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, trithian base, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidyl, thienyl, tetrahydro isoquinolyl, the cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridyl, phenazinyl, phenothiazinyl, fen is the piperazine base oh, and adamantyl.

" memory " refers to improve or improve mental capacity, and record keeps or memory experience in the past knowledge, idea, sensation, idea and impression thus.

" eye " refers to the structure on the relevant anatomy with human or animal's vision, comprises the structure on the following anatomy: lens, vitreum, ciliary body, back room, anterior chamber, pupil, cornea, iris, Schlemm road, Zinn band, limbus, conjunctiva, choroid, retina, retinal centre blood vessel, optic nerve, fovea centralis, macula lutea, and sclera.

N-heterocyclic derivatives neuroimmunophilin fkbp ligand body (2S)-1-that " GPI 1046 " refer to be correlated with (3,3-dimethyl-1,2 ,-dioxo amyl group-)-2-pyrrolidyl carboxylic acid 3-(3-pyridyl)-1-propyl ester, molecular formula is as follows

" halogen " is meant at least a in fluorine, chlorine, bromine or the iodine part.

" heterocycle " or " heterocyclic " refers to have single ring, a plurality of ring or a plurality of condensed ring (for example two rings, three ring or other similar bridged ring system or substituting groups), and has at least one heteroatoms as nitrogen, oxygen or sulphur, saturated, unsaturated or fragrant carbon ring group at least one ring therein.This term also comprises " heteroaryl ", refers to that wherein at least one ring is the heterocycle of aromatic nucleus.Any heterocyclic radical or heteroaryl can be unsubstituted, are perhaps optionally replaced by one or more previously defined groups.And, two or the trinucleated heteroaryl moieties can contain at least one all or part of saturated ring.

In the full text of the present invention, useful carbocyclic ring and heterocycle comprise, for example, but are not limited to phenyl, benzyl, naphthyl, indenyl, Azulene base, fluorenyl, anthryl, indyl, pseudoindoyl, indolinyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl-, benzothiazolyl, tetrahydrofuran base, THP trtrahydropyranyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, tetrahydric quinoline group, quinazolyl, furyl, thienyl, imidazolyl ， oxazolyl benzoxazolyl, thiazolyl ， isoxazolyl, different triazolyl ， oxadiazole base, triazolyl, thiadiazolyl group, pyridazinyl, pyrimidyl, pyrazinyl, triazinyl, trithian base, indolizinyl, pyrazolyl, pyrazolinyl, pyrazolidyl, thienyl, tetrahydro isoquinolyl, cinnolines base, phthalazinyl, quinazolyl, quinoxalinyl, naphthyridinyl, pteridyl, carbazyl, acridyl, phenazinyl, phenothiazinyl and fen be the piperazine base oh.

Those skilled in the art will appreciate that these heterocyclic moieties can exist with the form of a plurality of isomer, all these isomer all comprise in the present invention.For example, the 1,3,5-triazines part can become 1,2 by isomery, the 4-triazine group.This positional isomers is contemplated within the scope of the present invention.Similarly, this heterocyclic radical or heteroaryl can be bonded on the other parts of The compounds of this invention.Be connected to point on these other parts and can not be interpreted as qualification protection domain of the present invention.Therefore, for instance, the pyridyl part can be bonded on other group by 2-, 3-or the 4-position of pyridyl.All these configurations all are considered to be in protection scope of the present invention.

The heterocyclic radical that is included in the scope of the present invention or the example of heteroaryl moieties can include, but not limited to following groups:

" isomer " is meant to have identical molecular formula and comprise the different compound of cyclic isomers as (different) indoles and other circular part isomeric forms." steric isomer " only is meant isomer different on the atoms in space arrangement mode." enantiomer " is meant a pair of steric isomer that can not the eclipsed mirror image of being each other." diastereomer " is meant and is not the steric isomer of mirror image each other." racemic mixture " is meant the mixture of the independent enantiomer of umbers such as containing." non-racemic mixture " is meant and contains the independent enantiomer that do not wait umber or the mixture of steric isomer.

But " isostere " is meant to have different molecular formula the different compounds that show identical or similar character.For example tetrazolium is a kind of isostere of carboxylic acid, although because they have diverse molecular formula, and the character of tetrazolium imitation carboxylic acid.Tetrazolium is a kind of in many isosteres that may substitute carboxylic acid.Other isostere that belongs to carboxylic acid of the present invention comprises-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³CN.R wherein ³Be hydrogen, hydroxyl, halogen, halo C ₁-C ₆Alkyl, thiocarbonyl, C ₁-C ₆Alkoxyl group, itrile group, nitro, imino-, C ₁-C ₆Alkylamino, the amino C that replaces ₁-C ₆Alkyl, sulfydryl, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, alkylsulfonyl, C ₁-C ₆The straight or branched alkyl, C ₁-C ₆Straight or branched alkane thiazolinyl or alkane alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle, and CO ₂R ⁴R wherein ⁴Be hydrogen, C ₁-C ₉Straight or branched alkyl or alkane thiazolinyl.In addition, the isostere of carboxylic acid can comprise the carbocyclic ring of 5-7 unit and contain the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded heterocycle, any atom in the wherein said ring structure can optionally be substituted in one or more positions.Following array structure is the example that belongs to the indefiniteness of preferred carbocyclic ring of the present invention and heterocycle isostere:

With-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³CN.R wherein ³Be hydrogen, hydroxyl, halogen, halo C ₁-C ₆Alkyl, thiocarbonyl, C ₁-C ₆Alkoxyl group, itrile group, nitro, imino-, C ₁-C ₆Alkylamino, the amino C that replaces ₁-C ₆Alkyl, sulfydryl, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, alkylsulfonyl, C ₁-C ₆The straight or branched alkyl, C ₁-C ₆Straight or branched alkane thiazolinyl or alkane alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle, and CO ₂R ⁴R wherein ⁴Be hydrogen, C ₁-C ₉Straight or branched alkyl or alkane thiazolinyl.Atom on the wherein said ring structure can be optionally by R ₁At a place or many places replace, according in this definition.It is considered herein that chemical substituting group be added on the isostere of carboxylic acid in the time compound of the present invention still keep the character of carboxylic acid isostere.

The present invention relates to work as the isostere of carboxylic acid with being selected from R ³One or more part selectivity when replacing, this substituting group can not be eliminated the carboxylic acid isostere character of The compounds of this invention.If the invention still further relates to one or more R ³Substituting group destroys the carboxylic acid isostere character of The compounds of this invention, the one or more R on carbocyclic ring or heterocyclic carboxylic acid isostere so ³Substituent displacement will be not keep or with the carboxylic acid isostere character of The compounds of this invention be that one or more atoms place of one carries out.

The carboxylic acid isostere of other that does not exemplify especially in this manual or describe is also included among the present invention.

" memory impairment " refers to the experience to the past, knowledge, and idea, sensation, the record of idea and impression keeps or the ability of memory is lost gradually.Memory impairment can influence short-term or secular imformation memory, the judgement of spatial relation, the strategy of memory (exercise) and the recovery and the generation of language.The general reason that causes memory impairment is aging, serious head trauma, big cerebral anoxia or local asphyxia, the nutritive disease that alcoholism causes, and drug intoxication.Non-exclusively, the example of memory impairment comprises optimumly to be forgotten, forgetful and lack the illness of memory capability, memory lacks as Korsakoff ' mental anomaly, dementia and learning disorder arbitrarily.

" neopsis (Neopsic) factor " and " neopsics (neopsics) " refer to can be used for treating impaired vision, the prevention vision degeneration, or promote vision regenerated compound.

" neopsis (Neopsis) " refers to can be used for treating impaired vision, the prevention vision degeneration, or promote vision regenerated process.

" neurotrophy " includes but not limited to: the ability and/or the prevention of stimulating neuronal regeneration or growth or treat neurodegenerative ability.

" non-immunosuppression " is meant when not causing immune response with compound of the present invention when comparing as FK506 or cyclosporin A in the same old way.Measuring immunosuppressant test knows for those of ordinary skills.Specific and the infinite example of the test of knowing comprises PMA and OKT3 test, wherein uses mitogen to stimulate the hyperplasia of human body peripheral blood lymphocytes (PBC).Compound is added in this pilot system and suppresses this outgrowth ability to estimate it.

" (ophthalmological) of ophthalmology " refers to any relevant with eye or relevant, but do not limit, and can with " (ocular) of eyes ", " eye (ophthalmic) ", " (ophthalmologic) of vision " and other term exchange and use, but do not limit.

Term used herein " medicine acceptable carrier " is meant any carrier, thinner, vehicle, suspension agent, lubricant, auxiliary agent, vehicle, transmission system, emulsifying agent, disintegrating agent, absorption agent, sanitas, tensio-active agent, tinting material, seasonings or sweeting agent.For these purposes, compound of the present invention can take, suck that spraying is taken, take the part, rectum is taken, nose obey, buccally is taken, vagina is taken or take by the reservoir of implantation to contain conventional oral, the non-enteron aisle of atoxic medicine acceptable carrier, auxiliary agent or vectorial dosage form.The injection or the input technology of the non-enteron aisle of term used herein comprises subcutaneous, intravenous, intramuscular, endoperitoneal, intravaginal, intraventricular, intrasternal and encephalic.

Term used herein " the acceptable salt of medicine " is meant treats required organic or inorganic salt as required to warm-blooded animal.These characteristics according to employed The compounds of this invention can be acid or alkaline additive salt.

If The compounds of this invention contains acidic moiety, can handle The compounds of this invention with basic cpd and form salt, especially available mineral alkali.Preferred inorganic salt are them and the salt of basic metal and alkaline-earth metal formation, for example lithium, sodium, potassium, barium and calcium.Preferably the salt of organic bases comprises, for example, and ammonium salt, dibenzyl ammonium salt, benzyl ammonium salt, 2-hydroxyethyl ammonium salt, two (2-hydroxyethyl) ammonium salt, phenylethyl benzyl amine, diphenyl ethylene diamine etc.Other salt of acidic moiety comprises, for example those and PROCAINE HCL, PHARMA GRADE, the salt that quinine and N-methylglucosamine form, and with basic aminoacids such as Padil, ornithine, Histidine, phenylglycine, the salt that Methionin and arginine form.Basic salt, ester or solvate comprise magnesium salts; The salt that forms with organic bases such as dicyclohexylamine, N-methyl D-glycosamine.The salt of particularly preferred The compounds of this invention is sodium salt or sylvite.

For the basic moiety of The compounds of this invention, handle desirable The compounds of this invention with acidic cpd and form salt, especially available mineral acid.Preferably the inorganic salt of type comprise like this, for example, and hydrogen chlorate, hydrobromate, hydriodate, vitriol, phosphoric acid salt or similar salt.Preferably the organic salt of type comprises like this, for example, and with formic acid, acetate, succsinic acid, citric acid, lactic acid, toxilic acid, FUMARIC ACID TECH GRADE, palmitinic acid, cholic acid is pounced on acid, tetrahydroxyadipic acid, d-L-glutamic acid, d-dextrocamphoric acid, pentanedioic acid, oxyacetic acid, phthalic acid, tartrate, lauric acid, stearic acid, Whitfield's ointment, methylsulfonic acid, Phenylsulfonic acid, tosic acid, Sorbic Acid, puric acid, phenylformic acid, the salt that styracin and similar organic acid form.Other organic acid is a lipid acid, alginic acid, day (door) winter propylhomoserin, Phenylsulfonic acid, heavy sulfuric acid, butyric acid, camphorsulfonic acid, cyclopentanepropanoiacid acid, two Portugals (grape) saccharic acid, dodecyl sulfate, ethyl sulfonic acid, glucose enanthic acid, Phosphoric acid glycerol esters, hemisulfic acid, enanthic acid, caproic acid, the 2-ethylenehydrinsulfonic acid, methylsulfonic acid, naphthoic acid, 2-naphthene sulfonic acid, nicotinic acid, oxalic acid, thiocyanic acid, toluenesulphonic acids and undeeanoic acid.The salt of particularly preferred such type is the hydrochloride and the vitriol of The compounds of this invention.In addition, the group that contains basic nitrogen can be quaternized with these reagent, as: 1) muriate of low-carbon alkyl halogenide such as methyl, ethyl, propyl group and butyl, bromide and iodide; 2) vitriol of dialkyl sulfate such as dimethyl, diethyl, dibutyl and diamyl; 3) chain alkyl such as decyl, dodecyl, tetradecyl and the octadecyl that replaces with one or more halogens such as chlorine, bromine and iodine; With 4) aryl or aralkyl halogenide such as benzyl and styroyl bromination thing etc.

The scope of protection of present invention comprises the acceptable ester of the pharmacology of carboxylic acid or hydroxyl group, comprises easy the to be metabolic ester or the prodrug of The compounds of this invention.Easy metabolic ester can for example improve the blood standard and prolong the effect of the non-esterified form of compound.Prodrug form is not the activity form of molecule when using, but in vivo or after the bio-transformation, as metabolism, for example enzyme catalysis or hydrolysis are decomposed, becoming has therapeutic activity.The ester of The compounds of this invention comprises, methyl esters for example, ethyl ester, propyl ester, and butyl ester, and other suitable ester that is formed by acidic moiety and hydroxyl containing portion.Easy metabolic ester can comprise, for example, and methoxyl group methyl esters, oxyethyl group methyl esters, the different third oxygen methyl esters, a-methoxyl group ethyl ester and as a-(C1-C4 alkyl) ethyl ester; For example, methoxyl group ethyl ester, ethoxy ethyl ester, third 2-ethoxyethyl acetate, different third 2-ethoxyethyl acetate etc.; Some 2-oxo-4-(1, the 3-dicyclopentenyl) methyl esters is as 5-methyl-2-oxo-4-(1, the 3-dicyclopentenyl) methyl esters; The acyloxy methyl esters is as pivaloyl oxygen base methyl esters, a-acetoxyl group methyl esters etc.; Ethoxycarbonyl-1-methyl esters; Or a-acyloxy-a-replaces methyl esters, as a-acetoxyl group ethyl ester.

In addition, compound of the present invention can exist with crystalline solid forms, and it can separate out from common solvent in crystallization, ethanol for example, N, dinethylformamide, water etc.Therefore the crystallized form of The compounds of this invention can exist with the solvate of compound of the present invention and/or hydrate or the acceptable salt form of their pharmacology.All these may form all be considered in protection scope of the present invention.

" hair cycle " is meant the life cycle of hair follicle, comprises three phases:

(1) the regeneration stage is active hair vegetative period, as hair of scalp, can continue about 3 to 5 years;

(2) catagen phase for growth stops and the hair follicle atrophy phase, as hair of scalp, can continue for 1 to two week;

(3) stage telogen, the later stage hair of scalp for hair separates gradually and comes off at last can continue about 3 to 4 months.

The hair follicle of general 80-90% is in the regeneration stage, is less than 1% hair follicle and is in catagen phase, and remaining hair follicle is in stage telogen.The diameter of hair is even in stage telogen, has bulbous a little non-pigmented.In the regeneration stage, hair has big colored bulb at its root on the contrary.

Term used herein " prevention neurodegeneration " comprises when taking these compounds simultaneously, suppress or prevention is diagnosed as patient's the neurodegenerative ability of suffering from neurodegenerative disease or having the new neurodegenerative disease danger of development recently, and suppress or prevention has suffered or had the further neurodegenerative ability of patient of neurodegenerative disease symptom.

Term used herein " prevention vision degeneration " comprises when taking these compounds simultaneously, suppress or prevention is diagnosed as patient's the ability of vision degeneration of suffering from the degenerative disease that influence vision or having the new degenerative disease danger that influences vision of development recently, and suppress or prevent to have suffered or had the ability of the further vision degeneration of patient that influences the degenerative disease of vision symptom.

" main ring structure " refers to the five-ring described in the molecular formula accompanying drawing herein, six-ring or seven-members ring structure, or refer to specified ring structure in addition as " atom that A and B (or J and K) are connected with them is together ".Whether the number of the ring structure that no matter replaces what or structure determine to have only a ring structure to be applicable to such definition in the molecule arbitrarily among the application.

The growth that " promotion hair growth " is meant maintenance, brings out, stimulates, quickens or recovers hair.

No matter " promote vision regeneration " be meant eye disease, and whether disease or wound exist, keep, improve, stimulate, quicken the recovery or the recovery of the one or more assemblies among the human visual system, and improve or the enhancing vision.

Term used herein " treatment " has covered animal especially people's disease and/or any treatment of illness, comprising:

(i) prevention may suffer from but also not be diagnosed as the generation of disease and/or illness;

(ii) suppress disease and/or illness, promptly stop its development; Or

(iii) palliate a disease and/or illness, even disease and/or illness disappear.

" treatment alopecia " is meant:

(i) the animal alopecia that prevention may alopecia; And/or

(ii) suppress, delay or reduce alopecia; And/or

(iii) promote hair growth; And/or

(iv) prolong the regeneration stage of hair cycle; And/or

(v) hair being transformed makes it be grown to terminal hair.Terminal hair is thick coloured long hair, and wherein the bulb of hair follicle is buried in skin.On the contrary, hair is a bob thin, thin, no color, and wherein the bulb of hair follicle is positioned at the upper layer of skin.Along with alopecia, hair becomes the hair type by the terminal hair type.

Term used herein " vision " is meant that people or other animal generate the ability of image, can with " eyesight ", " eyesight " and other term exchange use, without limits.

" vision illness " is meant the illness influential or relevant to vision arbitrarily, includes but not limited to impaired vision, orbital disorder, lacrimal apparatus's illness, the illness of eyelid, disorder of conjunctiva, disorder of cornea, cataract, uveal illness, the illness of optic nerve or visual channel, eye disorders that free radical causes or disease, immunologically-mediated eye disorders or disease, eye wound, and eye disorders, disease, the symptom of wound and complication.

" impaired vision " is meant sight function disorder arbitrarily, includes but not limited to, vision is (as eyes, maincenter, peripheral, scotopia) interference or reduction, to the visual sensitivity of far and near object, the visual field, eye maneuvering ability, colour perception is to the adaptation of light and shade, regulating power, the interference or the reduction of refractive power and aspect such as shed tears.Referring to " doctor's application manual (PDR)-ophthalmology ", the 16 edition, 6:47 (1988).

" warm-blooded animal " comprises and comprises the people by Mammals, horse, pig, ox, mouse, a member in dog or the cat.For the people, the term of Shi Yonging " warm-blooded animal " also can refer to one " patient " herein.In addition, the term " needed warm-blooded animal " that herein uses is meant because gene or envrionment conditions or its easily ill physique and the warm-blooded animal of easy ill disease.This term also refers to a homoiothermy

Animal is because of contacting with specific gene or envrionment conditions or easily ill wound that has suffered or damage.Envrionment conditions also comprises wound or the infringement of using curative compounds for treating and other type.

In the illustrated throughout of the present invention in addition, mark:

Or Wherein W or Y are H ₂, or similarly mark represents that two hydrogen atoms link to each other with mark carbon, each hydrogen atom is with singly-bound and carbon atom bonding.Compound of the present invention

Find that surprisingly The compounds of this invention is neurotrophic, and can treat alopecia, and can treat vision and memory illness.Thereby provide a class new bridged heterocyclic derivatives.A favourable feature of The compounds of this invention is that they do not produce any tangible immunosuppressive activity.Method treatment neurotrophy illness of the present invention

The present invention relates to the application of any compound described herein in pharmaceutical preparation, this medicine is used for the treatment of disease as the peripheral neuropathy that caused by physical damnification or morbid state, brain physical damnification, spinal cord physical damnification, apoplexy, Alzheimer's, Parkinson's disease and the amyotrophic lateral sclerosis relevant with brain injury.The present invention also relates to be used for the treatment of the isostere application of compound of the carboxylic acid and the carboxylic acid of above-mentioned neuropathy, neurologic disease and nerve injury.

As neurotrophy reagent, to carrying out the neuroscience treatment of conditions, or, regularly use The compounds of this invention as the multiple periphery nervosa relevant and the patient of neuroscience illness with neurodegeneration because of other reason needs stimulating neuronal regeneration and growth.The compounds of this invention also can use the Mammals except that the people, is used for the treatment of the neuropathic conditions of multiple animal.

New compound of the present invention has excellent neurotrophic activity.This activity promotes neuron regeneration for stimulating injured neurons, and the prevention neurodegeneration is useful with some neuroscience illnesss relevant with neuronal degeneration and peripheral neuropathy of treatment.Treatable neuroscience illness includes but not limited to: trigeminal neuralgia, glossopharyngeal neuralgia, Bell ' s paralysis, myasthenia gravis, muscular dystrophy, amyotrophic lateral sclerosis, gradual muscular dystrophy, progressive bulbar inherited muscular atrophy, hernia, no spinal disc break or sagging illness cervical spondylosis, nerve plexus disorder, thoracic outlet destruction syndrome, by lead, dapsone, tick, porphyria, or Gullain-Barre syndrome, the peripheral neuropathy that Alzheimer's and Parkinson's disease cause.Treatment alopecia and promotion hair growth

The present invention also relates to treat alopecia or the trichogenous method of animal, this method comprises the The compounds of this invention of using significant quantity to said animal.The present invention also relates to the application in alopecia that is used for the treatment of animal or trichogenous pharmaceutical preparation of The compounds of this invention and composition.

The inventive method is specially adapted to treat male pattern alopecia, senile alopecia, areatus alopecia, owing to the alopecia that skin lesion or tumour cause, be used for the alopecia that cancer is levied alopecia that treatment as chemotherapy and radiotherapy cause and caused owing to system disorders such as nutrition disorder and endocrine regulation.Treatment vision and memory illness

The invention provides and be used for animal and treat the vision illness, improve vision, the treatment memory impairment, or strengthen the method for memory, this method comprises the The compounds of this invention of using significant quantity to said animal.

The inventive method is specially adapted to treat eye disease, includes but not limited to the vision illness, disease, wound, and complication, genopathy; With aging or the relevant vision illness of sex change; Relate to because of external force causes eye head, or the vision illness of the physical trauma of human body other parts; The illness that causes by environmental factors; The illness that has numerous disease to cause; Combination with above these illnesss.

The compositions and methods of the invention especially are fit to improve vision, or proofread and correct, and treatment, or vision (eyesight) damage or the dysfunction of prevention vision system include but not limited to permanent or provisional impaired vision.The present invention also is fit to prevention and treatment ophthalmic diseases and illness, the eye of treatment damage or wound, and prevention and treatment can cause vision to lack, vision loss, or watch or form the disease of the decline of image ability, illness and wound and symptom that causes thus and complication.Eye disease that The compounds of this invention can treat or prevent or illness are not limited by the cause of said disease or illness.Therefore, no matter whether disease or illness cause that by gene or environmental factors and other influence said composition and method all are suitable for.The compositions and methods of the invention especially are suitable for eye problem or vision loss or the shortage relevant with following situation, but are not limited to: aging, and cell or physiology sex change, central nervous system or neuroscience illness, vascular defects, muscle is damaged, contacts with hostile environment conditioned disjunction material.

The compositions and methods of the invention especially are suitable for but are not limited to and proofread and correct, treatment, or improve impaired vision.Impaired vision in various degree is meant or several normal functions that depart from eye, comprises (1) visual sensitivity to far and near object; (2) visual field; (3) there is not the eye maneuvering ability of diplopia.Referring to " doctor's application manual (PDR)-ophthalmology ", the 16 edition, 6:47 (1988).It is faulty not having the cooperation vision of these three functions.

The compositions and methods of the invention also are suitable for and proofread and correct, treatment, or improve other eye functions, and include but not limited to, colour perception, to the adaptation of light and shade, regulating power, metamorphopsia, and binocular vision.The compositions and methods of the invention especially be suitable for to be proofreaied and correct, treatment, or improve the vision disorder and include but not limited to, the local paralysis of adapt, iridoplegia, trichoma, ectropion, epiphora, lagophthalmos, scar scar, vitreous opacity, non-reactive pupil, cornea or other vectorial light scattering disturbance and the permanent distortion of eye socket.

The compositions and methods of the invention are suitable for and improve vision or treatment vision loss very much.From slight can be with said the compositions and methods of the invention treatment to vision loss completely.Use the compositions and methods of the invention treatment eye disorders, disease and wound can be improved vision.Be not limited thereto but be to use the compositions and methods of the invention to improve vision, can be used to does not have these illnesss yet, improves vision when disease and wound.

The compositions and methods of the invention also are applicable to disease and illness and consequent symptom and the complication that causes thus in the following non-limiting examples.

The vision illness includes, but are not limited to following:

Impaired vision, as visual sensitivity to far and near object, the reduction of the visual field and eye maneuvering ability;

The eye socket illness, as orbital cellulitis, phlegmon near the eyes, cavernous sinus thrombophlebitis, exophthalmos;

Lacrimal apparatus disease, as dacryostenosis, congenital dacryostenosis, dacryocystitis (polarity or chronic);

The eyelid illness, as palpebral edema, blepharitis, ptosis, Bell ' s paralysis, winking spasm, sty (hordeolum), external hordeolum, internal hordeolum (tarsus hordeolum), chalazion, trichoma (entropion), ectropion (ectropion of lid), tumour (optimum or pernicious), xanthelasma, rodent cancer knurl, the squamous cell carcinoma knurl, carcinoma of meibomian gland knurl, and melanoma;

Disorder of conjunctiva, as pinguecula, pterygium, or other anything superfluous or useless, acute conjunctivitis, chronic conjunctivitis, adult gonococcus conjunctivitis, baby's conjunctivitis, trachoma (granular conjunctivitis or trachoma), conjunctivitis (inclusion blennorrhea or swimming pool conjunctivitis), baby's inclusion conjunctivitis, the inclusion conjunctivitis of the adult, vernal keratoconjunctivitis, keratoconjunctivitis sicca (keratitis sicca or dry eye symptoms), sclera extexine inflammation, scleritis, cicatricial pemphigoid (eye cicatricial pemphigoid or benign mucosal pemphigoid), and subconjunctival hemorrhage;

Disorder of cornea, as superficial punctate keratitis, keratohelcosis, callous ulcer, recurrent corneal erosion, corneal epithelium basilar membrane malnutrition, the endothelial cell malnutrition, herpes simplex keratitis (herpes simplex keratoconjunctivitis), dendritic keratitis, disciform keratitis, the ophthalmology zoster, herpetic keratoconjunctivitis (herpetic or eczematous keratoconjunctivitis), interstitial keratitis (parenchymatous keratitis), periphery ulcerative keratitis (marginality keratolysis or periphery rheumatic ulcer), keratomalacia (keratitis sicca), xerophthalmia, keratoconus, bullous keratopathy;

Cataract comprises developmental character or congenital cataract, childhood or adult cataract, nuclear sclerosis, posterior subcapsular cataract.

The uveal tract illness is as uveitis (uveal tract or amphiblestroid inflammation), anterior uveitis, intermediate uveitis, posterior uveitis, iritis, cyclitis, choroiditis, ankylosing spondylitis, Lai Teershi (Reiter ' s) syndromes, chest inflammation (pars planitis), toxoplasmosis, cytomegalovirus (CMV), acute retina gangrene, toxocariasis, the birdshot choroidopathy, reticuloendothelial cytomycosis (the eye reticuloendothelial cytomycosis of supposition), Bei Qieteshi (behcet ' s) symptom, sympathetic ophthalmia, the Vogt-Koyanagi-Harada symptom, sarcoidosis, reticulum cell sarcoma, large celllymphoma, toxoplasma virus, interior ophthalmia and pernicious melanoma of choroid;

Retinal disorder, as blood vessel retinopathy (as arteriosclerotic retinopathy and hypertensive retinopathy), a retinal centre or an obstruction of artery, diabetic retinopathy (proliferative retinopathy or non-proliferative retinopathy), ageing macular degeneration (with aging relevant macular degeneration or senile macular degeneration SMD), the neovascularization macular degeneration, detachment of retina, retinitis pigmentosa, photic retina wound, the eye wound that the retina local hemorrhage causes, and glaucoma (primary glaucoma, chronic open angle glaucoma, acute or chronic angle closure glaucoma, congenital (baby) glaucoma, secondary glaucoma, pure glaucoma);

Optic nerve or visual channel disease, as papilloedema (papilledema), papillitis optica (optic neuritis), ischemic optic neuropathy, toxic amblyopia, optic atrophy, the damage of high visual channel, eye maneuvering ability illness (is paralysed as the 3rd cranial nerve, the paralysis of the 4th cranial nerve, the paralysis of the 6th cranial nerve, internuclear ophthamoplegia, and paralysis of gaze);

Eye disorders that free radical causes and disease; With

Immunoregulatory disease, as Graves ' illness in eye, keratoconus, dystrophia epithelialis corneae, walleye, Ocular pemphigus, Mooren ' s ulcer, scleritis, and sarcoidosis.Referring to " Merck handbook ", the 16 edition, 217:2365-2397 (1992) and " ophthalmology reference book ", Cassel, Billig, and Randall, Johns Hopkins University press (1998).

The compositions and methods of the invention also can be used in following consequent non-limiting eye wound and consequent symptom and complication: conjunctiva and corneal foreign body wound, corneal abrasion, the intraocular foreign body wound, cut, eyelid cracking, wound, eyelid is wounded (black eye), the eyeball wound, the iris cracking, cataract, lens dislocation, glaucoma, vitreous hemorrhage, orbital floor fracture, retinal hemorrhage or peel off, and ophthalmorrhexis, hyphema (traumatic hyphema), burn ambustio palpebrae, chemical burns, the chemical burns and the UV-light of cornea and conjunctiva burn (sunlight is burnt).Referring to " Merck handbook ", the 16 edition, 217:2365-2397 (1992).

The compositions and methods of the invention also are applicable to and treat and/or prevent following nonrestrictive eye disease, the symptom of eye disorders or eye wound and the example of complication: subconjunctival hemorrhage, vitreous hemorrhage, retinal hemorrhage, floating matter, detachment of retina, photophobia, eye throe, dim spot (negativity or reality), the refractive power mistake, emmetropia EM, ametropia, the long sight long sight, myopia myopia, astigmatism, (two) anisometropia, aniseikonia, presbyopia, hemorrhage, recurrent hemorrhage, sympathetic ophthalmia, the inflammation of eye, swelling, and red and swollen, the eye inflammation, keratohelcosis and formation scar scar, iridocyclitis, perforation of eyeball, eyelid distortion, ophthalmoptosis (disease), eye maneuvering ability is impaired, eyelid swelled, chemosis, vision loss comprises partially or completely and loses one's sight optic neuritis, heating, dispirited, thrombus (property) phlebitis, form cavernous sinus thrombosis, panophthalmitis, meninx and brain infect, papilloedema, (the headache of serious brain symptom, consciousness reduces, and spasm), the cranial nerve paralysis, epiphora (chronic or shed tears constantly), a large amount of mucus and purulence adverse current, cryptomere hyperplasia under the conjunctiva, vascularization of cornea, conjunctiva, cornea and eyelid cicatrize, pannus, hypopyon, the posterior chamber of the eye empyema, lagophthalmos, phlysis, RI, two temporo half-blindness, the homonymy hemianopsia.Referring to " Merck handbook ", the 16 edition, 217:2365-2397 (1992).

The compounds of this invention can with significant quantity be used for the treatment of the vision illness, improve vision, treatment memory impairment, or one or more factors of strengthening memory are used together.

One preferred embodiment in, the factor of using with The compounds of this invention is selected from by the immunosuppressor that is used for the treatment of autoimmunity, inflammation and immunoregulatory illness; The Wound healing agent that is used for the wound healing that causes by wound or operation; Be used for the treatment of the glaucoma medicine that abnormal intraocular pressure increases; Be used for the treatment of neurodegenerative disorders or the neurotrophic factor of the exsule length that excites nerve and somatomedin; Can effectively limit or suppress the compound that hemorrhage and vascularization is used for the treatment of macular degeneration; With being used for the treatment of because of oxidation ocular tissue is caused in the group that the antioxidant of damage forms.Pharmaceutical composition of the present invention

The present invention relates to a kind of pharmaceutical composition, said composition contains:

(i) a kind of bridged heterocyclic compound of significant quantity; With

(ii) a kind of medicine acceptable carrier.

More than generalized discussion relate to the effectiveness and the use of The compounds of this invention, also can apply to pharmaceutical composition of the present invention.

Pharmaceutical composition generally include the treatment significant quantity in the The compounds of this invention of this description, mix mutually with the material of one or more pharmacology or the acceptable preparation usefulness of physiology.The material of suitable preparation usefulness includes but not limited to, antioxidant, sanitas, tinting material, seasonings and thinner, emulsifying agent, suspension agent, solvent, filler, extender, damping fluid, transmission vehicle, diluent, vehicle and/or pharmaceutical auxiliary agent.For example, suitable vehicle can be that water is used for injection, and physiological salt solution or artificial perilymph may replenish other material in the composition that uses common non-enteron aisle use.It is more typical vehicle that neutral buffered salts solution or salts solution mix with blood relation's albumin.

Primary solvent in the vehicle can be water miscible or non-water-soluble in essence.In addition, vehicle can contain the acceptable vehicle of other pharmacology and be used for modifying, and regulates or keep the pH value of prescription, osmotic pressure, viscosity, transparency, color, aseptic degree, stability, dissolution rate, or smell.Similarly, vehicle can also contain the acceptable vehicle of other pharmacology and be used for modifying, or keeps the rate of release of treatment product, or promotes the treatment product to absorb or infiltration by eardrum.These vehicle usually and be used to prepare medicament traditionally can potion, also can multi-agent.

After therapeutic composition prepares, be kept in the aseptic bottle with solution, suspension, colloid, emulsion, solid or dehydration or freeze dried powder type immediately.These prescriptions can as freeze dried, be preserved with the restorative form that needs to recombinate before operable form or the use at any time.

Optimum formula of medicine can be determined according to the mode of using and the dosage of needs by those skilled in the art.Referring to, for example " Remington ' the s medical science ", the 18 edition, (1990, Mack publishing company, Easton, PA 18042), the 1435-1712 page or leaf, disclosed content quotation is for referencial use in this.Such prescription can influence the physical condition of treatment reagent of the present invention, stability, clearance rate in rate of release and the organism in the organism.

Other effective method of application can be used,, spraying can be sucked as eye slowly-releasing prescription, or the Orally active prescription.For example, in the prescription of sustainable release, The compounds of this invention can be prepared into particulate polymkeric substance (as poly(lactic acid), polyglycolic acid etc.) or liposome and combine or unite.Also can use hyaluronic acid, it has the effect that prolongs the time length in the circulation.These compositions exist with the aqueous solution form that contains the pyrogen-free matter of The compounds of this invention in the acceptable vehicle of pharmacology usually.Preferred vehicle is sterile distilled water.

The specific prescription that contains The compounds of this invention can orally use.The The compounds of this invention of taking by this way can be made capsule, or prepares or do not contain these carriers with the carrier used always of preparation solid chemicals.Capsule can be designed to the significant part at intestines and stomach place release formulation, the maximum and previous whole body degraded minimum of bioavailability this moment.Also can use other vehicle to be beneficial to the absorption of The compounds of this invention.Also can use diluent, seasonings, low melt wax, vegetable oil, lubricant, suspension agent, tablet disintegrant and caking agent.

The prescription of topical formulations comprise solution, suspension or the finish that those skilled in the art know (referring to, for example " Remington ' s medical science ", the 18 edition, the 86th chapter, 1581-1592 page or leaf, Mack publishing company, 1990).Can use other pattern, comprise injection.The ways and means that is suitable for the production preparation of different use patterns is widely known by the people.

In the treatment to vision or sacred disease or wound, the advantage of the local prescription that uses is that contained reagent can promote to treat reagent and permeates in position and transmit.Prior art has been understood these reagent.Another preparation also comprises the prescription of The compounds of this invention and a kind of reagent, and as injectable microballoon or liposome, it provides slow or lasting release molecule to make and can transmit with the form of supply injection.Other suitable means of introducing The compounds of this invention comprise the implantable drug delivery devices that contains The compounds of this invention, or the passage of implanting, and can transmit The compounds of this invention continuously by it.

Preparation of the present invention, especially topical formulations can comprise other component, for example the known acceptable sanitas of prior art, nutrition agent, cosolvent, complexing agent, buffer reagent or other pH control reagent, antiseptic-germicide, oxidation inhibitor and tensio-active agent.Suitable preservatives comprises benzalkonium chloride, thiomersal(ate), phenylethyl alcohol, methyl p-hydroxybenzoate, propylparaben, chlorhexidine, Sorbic Acid etc.Hydrogen peroxide also can be used as sanitas.Suitable cosolvent includes but not limited to glycerine, propylene glycol and polyoxyethylene glycol.Suitable complexing agent comprises caffeine, polyethylene-pyrrolidone, b-cyclodextrin or hydroxypropyl b-cyclodextrin.Damping fluid can be traditional buffered soln, as borate, and Citrate trianion, phosphoric acid salt, supercarbonate, or tris.

Other component of prescription can comprise the material that can prolong the residence time of employed treatment reagent, refers in particular to can make local contact maximization and promote the material that treatment reagent absorbs.These suitable materials comprise the material of polymkeric substance or gel formation, and it can improve the viscosity of preparation.The prescription suitability that is used for the direct invention of sustained release (for example continuing or lasting release) can be determined with known several different methods.Another kind of preparation comprises that also the The compounds of this invention of significant quantity mixes mutually with the acceptable vehicle of atoxic treatment.For example The compounds of this invention can be made tablet.Tablet dissolved in sterilized water, or in other suitable vehicle, is made the treatment solution of unitary dose.Suitable vehicle includes but not limited to, inert diluent, and as lime carbonate, yellow soda ash or Calcium hydrogen carbonate, lactose, or calcium phosphate; Or caking agent, as starch, gel, or Sudan Gum-arabic.Neurotrophy spare illness

The present invention also relates to a kind of pharmaceutical composition, said composition contains:

(i) a kind of bridged heterocyclic compound of significant quantity is used for the treatment of the neurodegenerative disease of animal, neuroscience illness, and nerve injury, or nerve growth in promoting; With

(ii) a kind of medicine acceptable carrier.

As neurotrophy reagent, this compound can use with other neurotrophy reagent, other neurotrophy reagent has for example neurotrophic growth factor, brain derived somatomedin, neuroglia deutero-somatomedin, ciliary neurotrophic factor, insulin-like growth factor and its active derivative, acid fiber archeocyte somatomedin, alkaline fiber archeocyte somatomedin simplified, platelet-derived somatomedin, neurotrophy thing-3 and neurotrophy thing 4/5.The dosage of other neurotrophy medicine depends on the factor of prior statement and the neurotrophy effect of drug regimen,

Neurotrophy compound of the present invention can be termly to carrying out the neuroscience treatment for diseases or needing the patient of stimulating neuronal regeneration and growth to use because of other reason, so-called other reason has, as multiple periphery nervosa or the neuroscience illness relevant with neurodegeneration.Compound of the present invention can use the Mammals except that the people, is used for the treatment of mammiferous neuroscience illness, alopecia and hair growth

The present invention also relates to a kind of pharmaceutical composition, this pharmaceutical composition contains:

(i) a kind of bridged heterocyclic compound of significant quantity is used for the treatment of the alopecia of animal, or promotes hair growth; With

(ii) a kind of pharmacology acceptable carrier.

The compounds of this invention can use the treatment alopecia or the effective factor of promotion hair growth with one or more.Vision and memory illness

The present invention also relates to a kind of pharmaceutical composition, said composition contains:

(i) a kind of bridged heterocyclic compound of significant quantity is used for the treatment of the vision illness of animal, improves vision, the treatment memory impairment, or strengthen memory; With

(ii) a kind of medicine acceptable carrier.

The compounds of this invention can with one or more to treatment vision illness, improve vision, treatment memory impairment, or strengthen the effective factor of memory and use together.Use route

Compound of the present invention can take, suck that spraying is taken, take the part, rectum is taken, nose obey, buccally is taken, vagina is taken or take by the reservoir of implantation to contain conventional oral, the non-enteron aisle of atoxic pharmacology acceptable carrier, auxiliary agent or vectorial dosage form.The injection or the input technology of the non-enteron aisle of term used herein comprises subcutaneous, intravenous, intramuscular, endoperitoneal, intravaginal, intraventricular, intrasternal and encephalic.

For oral, compound of the present invention can provide with any appropriate formulation form well known in the art.For example, can use conventional equipment well known in the art and technology that composition is made tablet, pulvis, granula, bead, masticable lozenge, capsule, liquor, aqeous suspension or solution or similar dosage form.Tablet form preferably.Tablet can contain carrier such as lactose and W-Gum, and/or lubricant such as Magnesium Stearate.Capsule can contain the thinner that comprises lactose and dried corn starch.Aqeous suspension can contain and emulsification of activeconstituents bonded and suspension agent.

When preparation was combined with the dosage form of composition of the present invention, this compound also can be mixed with conventional vehicle such as tackiness agent, comprises the starch of gelatin, pre-gelledization etc.; Lubricant such as hydrogenated vegetable oil, stearic acid etc.; Thinner such as lactose, seminose and sucrose; Disintegrating agent such as carboxymethyl cellulose and primojel; Suspension agent such as Povidone, polyvinyl alcohol etc.; Absorption agent such as silicon-dioxide; Sanitas such as methyl p-hydroxybenzoate, propylparaben and Sodium Benzoate; Tensio-active agent such as sodium lauryl sulphate, tween 80 etc.; Tinting material such as F.D.﹠amp; C. dyestuff or color lake; Seasonings and sweeting agent.

The compounds of this invention can be taken with the form of sterile injectable preparation such as sterile injectable aqueous or oily suspension.These suspension can use suitable dispersion agent or wetting agent and suspension agent to prepare according to technology well known in the art.Sterile injectable preparation also can be at nontoxic non-enteron aisle acceptable diluent or solution or the suspension in the solvent, as the solution in 1,3 butylene glycol.Operable in acceptable vehicle and solvent is water, Ringer's solution isotonic sodium chlorrde solution.In addition, aseptic expressed oil is conventional solvent or the suspension vehicle of using.For this reason, the expressed oil of any gentleness be can use, synthetic list or two glyceryl ester comprised.Lipid acid such as oleic acid and its glyceride derivative comprise sweet oil and Semen Ricini oil, and particularly the ethylating variant of its polyoxy can be used for the preparation of injectable formulation.These oil solutions or suspension also can contain long-chain alcohol thinner or dispersion agent.

The compounds of this invention also can topical, is particularly treating under the situation of accessible position or organ by topical application, comprises the neurologic disease of eye, skin or enteron aisle lower end.Can prepare suitable topical formulations easily to each this position.

Topical application for eyes or eye usefulness; The compounds of this invention can be mixed with adjusting in the isoosmotic stroke-physiological saline solution micronize suspension of pH; the solution of pH that perhaps preferably has been mixed with adjusting in isoosmotic stroke-physiological saline solution wherein contains or does not contain sanitas such as benzyl alkylammonium muriate.Perhaps for eye usefulness, this compound also can be formulated in ointment such as the vaseline ointment.

Topical application for skin, The compounds of this invention can be formulated in a kind of suitable, contain in the ointment that is dispersed or dissolved in this compound in for example a kind of mixture, this mixture contains one or more following materials: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Perhaps, this compound also can be formulated in a kind of suitable, contain in the lotion or emulsifiable paste that is dispersed or dissolved in this active compound in for example a kind of mixture, this mixture contains one or more following materials: mineral oil, sorbitan monostearate, polysorbate60, spermaceti ester type waxes, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.

Take for part, enteron aisle lower end, can adopt enteron aisle suppository formulations (face as follows) or suitable enema agent.

The compounds of this invention also can be taken by rectum with the form of suppository.These compositions can prepare by medicament is mixed with a kind of suitable non-irritating excipient, and this vehicle is a solid at room temperature, and is liquid under rectal temperature, thereby will melt at internal rectum and discharge medicament.This material comprises Oleum Cocois, beeswax and polyoxyethylene glycol.

Component of the present invention and method also can be used the technology of sustained release.Therefore, for example, The compounds of this invention can join in the hydrophobic polymeric matrix and discharge in the time of a couple of days inner control.The film of this sustained release is well known in the art.Particularly preferably be transdermal delivery system.Other can be used for the example that generally is used for the polymkeric substance of this purpose of the present invention comprise can external application or in nondegradable vinyl-vinyl acetate copolymer and the degradable lactic acid-ethanol copolymer used.Some hydrogel such as hemacol or poly-(vinyl alcohol) also can use, but in order to shorten deenergized period, should use other polymkeric substance delivery systme those delivery systmes as mentioned above.

Can imagine that it is advantageous using continuously or continue to transmit sensorineurotrophic compound under the specified conditions.When finishing continuous use, so just can consider to adopt other to carry out continuously or near successive use pattern by mechanical means such as infusion pump.For example, such use means have subcutaneous or intramuscular injection, and oral tablets and auristillae.

Those skilled in the art have known multiple continuing-or control-transmission means, liposome vectors for example, biological erodible particle or pearl and supply injection.

For the central nervous system target effective is treated, The compounds of this invention should be easy to penetrate blood brain barrier when take the periphery.The compound that can not penetrate blood brain barrier can be taken effectively by the suitable transmission system that approach in the ventricle or other are suitable for being administered into brain.

In order effectively to treat alopecia or to promote hair growth, compound that uses in the inventive method and pharmaceutical composition must can be easy to act on target site.For this purpose, compound preferably topical in skin.

For topical in skin, The compounds of this invention can be formulated in a kind of suitable, contain in the ointment that is dispersed or dissolved in this compound in for example a kind of mixture, this mixture contains one or more following materials: mineral oil, petrosio, white vaseline, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Perhaps, this compound also can be formulated in a kind of suitable, contain in the lotion or emulsifiable paste that is dispersed or dissolved in this active compound in for example a kind of mixture, this mixture contains one or more following materials: mineral oil, sorbitan monostearate, polysorbate60, spermaceti ester type waxes, cetostearyl alcohol, 2-Standamul G, phenylcarbinol and water.

The compounds of this invention can use with other hair revitalizing agent.The concrete dosage level of other hair revitalizing agent depends on foregoing factor and medicine bonded validity.Other route of administration of knowing in the pharmaceutical field also belongs to the scope of the invention.

For the treatment of vision symptom, sensorineurotrophic compound can be oral, and whole body uses, or is directly used in eye, especially after carrying out the intrusive mood surgical operation, or topical application, insertion, injection or implantation.For example can use and contain the implant that molecule is embedded in the slow release on the polymeric matrix and transmit The compounds of this invention.Known, The compounds of this invention can be used for eye, also can promote the The compounds of this invention infiltration or transmit the local use of the reagent that passes through the eye film with one or more.The frequency of medication depends on the medical kinetic parameter of The compounds of this invention and the method for using.

The method of treatment above-mentioned symptom also comprises the instructions about how to take medicine of final medicament, and it is considered to determine after the multiple factor that influences pharmaceutical activity by the doctor in charge.These influence factors have, as severity, medicine time and other clinical factor well known to those skilled in the art of age, healthy state, body weight, sex, diet, specified disease.

The present invention also is included in known other using method of field of medicaments.Dosage

The available dosage level is the extremely approximately 10000mg active compound component order of magnitude of about 0.1mg when the above-mentioned disease of treatment, is preferably about 0.1mg to about 1000mg level.Any concrete patient's given dose level depends on various changing factors, activity, patient's age, body weight, healthy state, sex and diet, medicine time, discharge rate, the medicine that comprises used specific compound in conjunction with and the severity of the specified disease of treatment and take mode.Be typically, the suitable dose that the effect of external dosage is taken the patient provides the guidance of usefulness.The Animal Model Study also is helpful.The method of determining the suitable dose level is well known in the art.

With reference to body weight, body surface area or organ size can be calculated given dose.Be necessary to calculate more accurately with definite proper dosage in order to treat above-mentioned each disease, and these work are conventional for the one skilled in the art, nor surpass the routine work scope, especially with reference to dosage information described herein and evaluation.Use evaluation and the rational dosage-response data set up can determine proper dosage.The one skilled in the art thinks that local using dosage of the present invention is little with respect to systemic injection or oral dosage.

Described compound can use with other reagent, is used to prevent and/or treat neurodegenerative disease, comprises physical damnification nerve and neurodegenerative disease; Treatment alopecia and promotion hair growth; Treat the vision illness and/or improve eyesight; Memory with treatment memory impairment and/or enhancing animal.The specific dosage level of these reagent depends on the factor of prior statement and the effect of pharmaceutical composition.

The compound that following molecular formula I-LXVII describes has asymmetric center, therefore can generate the mixture of steric isomer, perhaps independent R-and S-steric isomer.Use optically active initial substance, resolution of racemic or non-racemic mixture in the synthetic appropriate step; The compound that perhaps splits molecular formula I-LXVII can obtain independent stereoisomerism.The compound that is appreciated that molecular formula I-LXVII comprises independent stereoisomerism and mixture (racemize or non-racemic).The preferred S-steric isomer that uses in pharmaceutical composition of the present invention and the method.

Be used for compound of the present invention and comprise multiple structure type.What at first consider as noted, is to have desirable active those compounds of describing in this specification sheets.Therefore non-limiting as describing, the example of following structural as compound is provided, be used to prevent and/or treat neurologic illness comprise physical damnification nerve and neurodegenerative disease; Be used for the treatment of alopecia and promote hair growth; Be used for the treatment of the vision illness and/or improve eyesight; Remember impairment and/or hypermnesis function with being used for the treatment of.

The invention provides a kind of general formula I ':

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A is hydrogen, C ₁Or C ₂Alkyl or benzyl, B are C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or

A and B, the atom that is connected with them form saturated, the undersaturated or fragrant heterocycle or the carbocyclic ring of a kind of 5-7 unit together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

V is CH, S or N;

X is O, CH ₂, or S;

M is 0 or 1;

G is Or

R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nThe C that replaces ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl is by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound;

Perhaps, R ₁Be general formula independently: Part,

Wherein:

R ₃Independently for optionally by C ₃-C ₈Cycloalkyl or Ar ₁The C that replaces ₁-C ₉The straight or branched alkyl;

X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

R ₂Independently or be hydrogen or for P;

Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

U or be O or for N, its precondition is:

When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

W and Y are O, S, CH independently ₂Or H ₂

Z is C (R ₁) ₂, O, S, directly key or NR ₁Perhaps

Z-R ₁Be independently

Or

Wherein:

C and D are hydrogen, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino C ₁-C ₆Alkyl, sulfydryl, sulphur-(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, or S (O) _pSubstitute;

C ' and D ' are hydrogen, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein

Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

J is O, NR ₁, S or (CR ₁) ₂

K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

K " is C (R ₁) ₂, O, S, directly key or NR ₁

L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

N is 1 or 2;

P is 0,1 or 2;

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

Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.

In addition, the invention provides and be used to prevent and/or treat neurologic illness comprise physical damnification nerve and neurodegenerative disease; Be used for the treatment of alopecia and promote hair growth; Be used for the treatment of the vision illness and/or improve eyesight; With the method that is used for the treatment of memory impairment and/or hypermnesis function, its according to patient's needs to the patient take general formula I ' compound.

The present invention also is provided for preventing and/or treats neurologic illness comprising physical damnification nerve and neurodegenerative disease; Be used for the treatment of alopecia and promote hair growth; Be used for the treatment of the vision illness and/or improve eyesight; With the general formula I of the pharmaceutical products that is used for the treatment of memory impairment and/or hypermnesis function ' compound.

In addition, the present invention also is provided for preventing and/or treats neurologic illness comprising physical damnification nerve and neurodegenerative disease; Be used for the treatment of alopecia and promote hair growth; Be used for the treatment of the vision illness and/or improve eyesight; With the preparation that is used for the treatment of memory impairment and/or hypermnesis function, said preparation contain general formula I ' compound and associated medicine acceptable carrier, thinner or vehicle.

More particularly, the invention provides the compound that describes below, and the method that describes below, purposes and preparation.

I. heterocyclic thioesters and ketone

General formula I

Particularly, the Hete rocyclic derivatives of bridging can be a general formula I

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A and B, nitrogen-atoms that is connected respectively with them and carbon atom form the saturated or unsaturated heterocycle of a kind of 5-7 unit together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₂Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

X or be O or for S;

Z or be S, CH ₂, CHR ₁, perhaps be CR ₁R ₃

W and Y are O, S, CH independently ₂Or H ₂

R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

General formula I I

The Hete rocyclic derivatives of bridging also can be general formula I I

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 1 or 2;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, any two or more atoms of pyrrolidine ring (working as n=1) or piperidine ring (working as n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X is O or S;

Z is selected from by S, CH ₂, CHR ₁, and CR ₁R ₃In the group of being formed;

R ₁And R ₃Be independently selected from by C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part and Ar ₁In the group of being formed, wherein said alkyl, thiazolinyl or Ar ₁For unsubstituted or be independently selected from by halogen, nitro, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, bridged ring part, hydroxyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, amino and Ar ₁Substituting group in the group of being formed replaces;

R ₂Be independently selected from by C ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁In the group of being formed; With

Ar ₁Be phenyl, benzyl, pyridyl, fluorenyl, sulfo-indyl or naphthyl independently, wherein said Ar ₁For not replacing, perhaps be independently selected from by halogen, trifluoromethyl, hydroxyl, nitro, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces.

The compound of preferred general formula I I is listed in the Table I. Table I numbering n X Z R ₁R ₂11 O CH ₂3-phenyl propyl 1,1-dimethyl propyl 21 O CH ₂3-(3-pyridyl) propyl group 1,1-dimethyl propyl 31 O CH ₂The 3-phenyl propyl tertiary butyl 41 O CH ₂3-(3-pyridyl) the propyl group tertiary butyl 51 O CH ₂3-(3-pyridyl) propyl group cyclohexyl 61 O CH ₂3-(3-pyridyl) propyl group cyclopentyl 71 O CH ₂3-(3-pyridyl) propyl group suberyl 81 O CH ₂2-(9-fluorenyl) ethyl 1,1-dimethyl propyl 91 O S 2-phenylethyls 1,1-dimethyl propyl 10 2 O S 2-phenylethyls 1,1-dimethyl propyl 11 1 O S methyl (2-sulfo-indyl) 1, the 1-dimethyl propyl 12 1 O S 2-phenylethyl cyclohexyl 13 2 O S 2-phenylethyl tertiary butyls 14 2 O S 2-phenyl ethyl phenyls 15 1 O CH ₂3-(4-p-methoxy-phenyl) propyl group 1,1-dimethyl propyl 16 2 O CH ₂4-(4-p-methoxy-phenyl) butyl 1,1-dimethyl propyl 17 2 O CH ₂4-phenyl butyl 1,1-dimethyl propyl 18 2 O CH ₂4-phenyl butyl phenyl 19 2 O CH ₂4-phenyl butyl cyclohexyl 20 1 S CH ₂3-phenyl propyl 1,1-dimethyl propyl 21 1 S S 2-phenylethyls 1,1-dimethyl propyl 22 2 S CH ₂3-phenyl propyl 1,1-dimethyl propyl 23 2 S S 2-phenylethyls 1,1-dimethyl propyl 24 2 O CHR ₁3-phenyl propyl 1,1-dimethyl propyl 25 2 O CHR ₁3-phenyl propyl cyclohexyl 26 2 O CHR ₁3-phenyl propyl phenyl 27 2 O CHR ₁3-phenyl propyl 3,4, the 5-trimethoxyphenyl 28 1 O S 2-phenylethyl cyclopentyl 29 2 O S 3-phenyl propyl tertiary butyls 30 1 O S 3-phenyl propyl 1,1-dimethyl propyl 31 1 O S 3-(3-pyridyl) propyl group 1,1-dimethyl propyl 32 1 O S 3-phenyl propyl cyclohexyl 33 1 O S 4-phenyl butyl cyclohexyl 34 1 O S 4-phenyl butyls 1,1-dimethyl propyl 35 1 O S 3-(3-pyridyl) propyl group cyclohexyl 36 1 O S 3,3-diphenyl propyl 1,1-dimethyl propyl 37 1 O S 3,3-diphenyl propyl cyclohexyl 38 1 O S 3-(4-p-methoxy-phenyl) propyl group 1, the 1-dimethyl propyl 39 2 O S 4-phenyl butyl tertiary butyls 40 2 O S 1,5-phenylbenzene amyl group 1,1-dimethyl propyl 41 2 O S 1,5-phenylbenzene amyl group phenyl 42 2 O S 3-(4-p-methoxy-phenyl) propyl group 1,1-dimethyl propyl 43 2 O S 3-(4-p-methoxy-phenyl) propyl group phenyl 44 2 O S 3-(1-naphthyl) propyl group 1,1-dimethyl propyl 45 1 O S 3,3-two (4-fluorine) phenyl propyl 1,1-dimethyl propyl 46 1 O S 4,4-two (4-fluorine) phenyl butyl 1,1-dimethyl propyl 47 1 O S 3-(1-naphthyl) propyl group 1,1-dimethyl propyl 48 1 O S 2,2-diphenyl-ethyl 1,1-dimethyl propyl 49 2 O S 2,2-diphenyl-ethyl 1,1-dimethyl propyl 50 2 O S 3,3-diphenyl propyl 1,1-dimethyl propyl 51 1 O S 3-(the 4-{ trifluoromethyl } phenyl) propyl group 1,1-dimethyl propyl 52 1 O S 3-(2-naphthyl) propyl group 1,1-dimethyl propyl 53 2 O S 3-(1-naphthyl) propyl group 1,1-dimethyl propyl 54 1 O S 3-(3-chlorine) phenyl propyl 1,1-dimethyl propyl 55 1 O S 3-(the 3-{ trifluoromethyl } phenyl) propyl group 1,1-dimethyl propyl 56 1 O S 3-(2-xenyl) propyl group 1,1-dimethyl propyl 57 1 O S 3-(2-fluorophenyl) propyl group 1,1-dimethyl propyl 58 1 O S 3-(3-fluorophenyl) propyl group 1,1-dimethyl propyl 59 2 O S 4-phenyl butyls 1,1-dimethyl propyl 60 2 O S 3-phenyl propyl 1,1-dimethyl propyl 61 1 O S 3-(2-chlorine) phenyl propyl 1,1-dimethyl propyl 62 2 O S 3-(3-chlorine) phenyl propyl 1,1-dimethyl propyl 63 2 O S 3-(2-fluorine) phenyl propyl 1,1-dimethyl propyl 64 2 O S 3-(3-fluorine) phenyl propyl 1,1-dimethyl propyl 65 1 O S 3-(2, the 5-Dimethoxyphenyl) propyl group 1,1-dimethyl propyl 66 1 O CH ₂3-phenyl propyl cyclohexyl 67 1 O CH ₂The 3-phenylethyl tertiary butyl 68 2 O CH ₂4-phenyl butyl cyclohexyl 69 2 O CHR ₁The 2-phenylethyl tertiary butyl 70 1 O CH ₂3,3-two (4-fluorine) phenyl propyl 1,1-dimethyl propyl 71 2 O CH ₂3-phenyl propyl 1, the 1-dimethyl propyl

The preferred compound name of table 1 is as follows:

1 (2S)-2-({ 1-oxo-5-phenyl }-amyl group)-1-(3,3-dimethyl-1,2-dioxo amyl group) tetramethyleneimine

23, the 3-dimethyl-1-[(2S)-and 2-(5-(3-pyridyl) pentanoyl)-1-tetramethyleneimine] 1, the 2-diacetylmethane

3 (2S)-2-({ 1-oxo-4-phenyl }-butyl)-1-(3,3-dimethyl-1,2-dioxo butyl) tetramethyleneimine

9 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 2-phenyl-1-ethyl ester

10 1-(3,3-dimethyl-1,2-dioxo amyl group)-2-piperidines thiocarboxylic acid 2-phenyl-1-ethyl ester

11 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid (3-sulfo-indyl) methyl ester

12 (2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 2-phenyl-1-ethyl ester

14 1-(2-phenyl-1,2-dioxo ethyl)-2-piperidines thiocarboxylic acid 2-phenyl-1-ethyl ester

28 (2S)-1-(1-cyclopentyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 2-phenyl-1-ethyl ester

29 1-(3,3-dimethyl-1,2-dioxo butyl)-2-piperidines thiocarboxylic acid 3-phenyl-1-propyl diester

30 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 3-phenyl-1-propyl diester

31 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 3-(3-pyridyl)-1-propyl diester

32 (2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 3-phenyl-1-propyl diester

33 (2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 4-phenyl-1-butyl ester

34 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 4-phenyl-1-butyl ester

35 (2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 3-(3-pyridyl)-1-propyl diester

36 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 3,3-phenylbenzene-1-propyl diester

37 (2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-2-tetramethyleneimine thiocarboxylic acid 3,3-phenylbenzene-1-propyl diester

38 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 3-(p-methoxyphenyl)-1-propyl diester

39 1-(1,2-dioxo-3,3-dimethylbutyl)-2-piperidines thiocarboxylic acid 4-phenyl-1-butyl ester

40 1-(3,3-dimethyl-1,2-dioxo amyl group)-2-piperidines thiocarboxylic acid 1,5-phenylbenzene-3-amyl group ester

41 1-(3-phenyl-1,2-dioxo ethyl)-2-piperidines thiocarboxylic acid 1,5-phenylbenzene-3-sulfydryl amyl group ester

42 1-(1,2-dioxo-3,3-dimethyl amyl group) piperidines-2-thiocarboxylic acid 3-(p-methoxyphenyl)-1-propyl diester

43 1-(2-phenyl-1,2-dioxo ethyl) piperidines-2-thiocarboxylic acid 3-(p-methoxyphenyl)-1-propyl diester

44 1-(3,3-dimethyl-1,2-dioxo amyl group) piperidines-2-thiocarboxylic acid 3-(1-naphthyl)-1-propyl diester

45 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 3,3-two (right-fluorophenyl)-1-propyl diester

46 1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 4,4-two (right-fluorophenyl) butyl ester

47 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(1-naphthyl) propyl diester

48 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl) tetrahydrochysene-1H-2-tetramethyleneimine thiocarboxylic acid 2,2-diphenyl-ethyl ester

49 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 2,2-diphenyl-ethyl ester

50 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3,3-diphenyl propyl ester

51 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-[4-(trifluoromethyl) phenyl] propyl diester

52 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(2-naphthyl) propyl diester

53 (2R, S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3-(2-naphthyl) propyl diester

54 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(3-chloro-phenyl-) propyl diester

55 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-[3-(trifluoromethyl) phenyl] propyl diester

56 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(1-xenyl) propyl diester

57 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(2-fluorophenyl) propyl diester

58 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(3-fluorophenyl) propyl diester

59 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 4-phenyl butyl ester

60 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3-phenyl propyl ester

61 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(2-chloro-phenyl-) propyl diester

62 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3-(2-chloro-phenyl-) propyl diester

63 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3-(2-fluorophenyl) propyl diester

64 1-(3,3-dimethyl-2-oxo pentanoyl)-2-piperidines thiocarboxylic acid 3-(3-fluorophenyl) propyl diester

65 (2S)-1-(3,3-dimethyl-2-oxo pentanoyl)-2-tetramethyleneimine thiocarboxylic acid 3-(3, the 4-Dimethoxyphenyl) propyl diester

66 (2S)-2-({ 1-oxo-4-phenyl }-butyl)-1-(2-cyclohexyl-1,2-dioxo ethyl) tetramethyleneimine

67 2-({ 1-oxo-4-phenyl }-butyl)-1-(3,3-dimethyl-1,2-dioxo butyl) tetramethyleneimine

68 2-({ 1-oxo-6-phenyl }-hexyl)-1-(2-cyclohexyl-1,2-dioxo ethyl) piperidines

69 2-(the 1-oxo-[2-{2 '-phenyl } ethyl]-the 4-phenyl }-butyl)-1-(3,3-dimethyl-1,2-dioxo butyl) piperidines

70 1-{ (2S)-2-[5,5-two (4-fluorophenyl) pentanoyl]-the 2-tetramethyleneimine }-3,3-dimethyl-1,2-diacetylmethane

71 3,3-dimethyl-1-[2-(4-phenyl pentanoyl) piperidines]-1, the 2-diacetylmethane

General formula III

And bridged heterocyclic derivatives can be a general formula III: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A, B and C are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein A, B and C any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X is O or S;

Z is S, CH ₂, CHR ₁Or CR ₁R ₃

R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, bridged ring part, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl and Ar ₂Substituting group in the group of being formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

The compound of preferred general formula III is listed in the Table II.

Table II numbering A B C X Z R ₁R ₂72 CH ₂S CH ₂O S 2-phenylethyl 1,1-dimethyl propyl 73 CH ₂S CH ₂O CH ₂2-phenyl propyl 1,1-dimethyl propyl 74 CH ₂CH ₂NH O S 2-phenylethyl 1,1-dimethyl propyl 75 CH ₂S CH ₂S S 2-phenylethyl 1, the 1-dimethyl propyl

General formula I V

Perhaps, bridged heterocyclic derivatives also can be general formula I V: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A, B, C and D are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein A, B, C and D any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X is O or S;

Z is S, CH ₂, CHR ₁Or CR ₁R ₃

R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

The compound of preferred general formula I V is listed in the Table III.

Table III numbering A B C D X Z R ₁R ₂76 CH ₂CH ₂O CH ₂O CH ₂3-phenyl propyl 1,1-dimethyl propyl 77 CH ₂CH ₂O CH ₂O S 2-phenylethyl 1,1-dimethyl propyl 78 CH ₂CH ₂S CH ₂O CH ₂3-phenyl propyl 1,1-dimethyl propyl 79 CH ₂CH ₂S CH ₂O S 2-phenylethyl 1, the 1-dimethyl propyl

General formula V

Bridged heterocyclic derivatives also can further be general formula V:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

A and B with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₄Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R ₄Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, R wherein ₄Perhaps, perhaps be selected from by halogen, halo-C by one or more for not replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₄Substituting group in the group of being formed replaces;

Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; With

R ₁, R ₂, W, X, Y and Z in the general formula I of front definition.

II. heterocyclic ester and acid amides

General formula VI

In addition, bridged heterocyclic derivatives can be general formula VI: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A and B, nitrogen-atoms that is connected respectively with them and carbon atom form the saturated or unsaturated heterocycle of a kind of 5-7 unit together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₁Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

X is O or S;

Z is O, NH or NR ₁

W and Y are O, S, CH independently ₂Or H ₂

R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

Suitable carbocyclic ring or heterocyclic ring include but not limited to naphthyl, indyl, furyl, thiazolyl, thienyl, pyridyl, quinolyl, isoquinolyl, fluorenyl and phenyl.

General formula VII

Bridged heterocyclic derivatives also can be general formula VII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A, B and C are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein A, B and C any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl or bridged ring part, they are independently selected from by (Ar by one or more ₁) _nWith by (Ar ₁) _nThe C that is replaced ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁With

Ar ₁Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, ring wherein or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

The compound of preferred general formula VII is: In the particularly preferred embodiment of general formula VII compound:

A is CH ₂

B is CH ₂Or S;

C is CH ₂Or NH;

Two or more A, B and C, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R ₁Be independently selected from the group of forming by 3-phenyl propyl and 3-(3-pyridyl) propyl group; With

R ₂Be independently selected from by 1, in the group that 1-dimethyl propyl, cyclohexyl and the tertiary butyl are formed.

The object lesson of this embodiment is listed in the Table IV:

Table IV numbering A B C R ₁R ₂80 CH ₂S CH ₂3-phenyl propyl 1,1-dimethyl propyl 81 CH ₂S CH ₂3-(3-pyridyl) propyl group 1,1-dimethyl propyl 82 CH ₂S CH ₂3-phenyl propyl cyclohexyl 83 CH ₂S CH ₂The 3-phenyl propyl tertiary butyl 84 CH ₂CH ₂NH 3-phenyl propyl 1,1-dimethyl propyl 85 CH ₂CH ₂NH 3-phenyl propyl cyclohexyl 86 CH ₂CH ₂The NH 3-phenyl propyl tertiary butyl

General formula VIII

In a kind of further embodiment of the present invention, bridged heterocyclic derivatives can be general formula VIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A, B, C and D are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein A, B, C and D any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be C independently ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _nWith by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁With

Ar ₁Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, ring wherein or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

In the particularly preferred embodiment of general formula VIII compound:

A is CH ₂

B is CH ₂

C is S, O or NH;

D is CH ₂

Two or more A, B, C and D, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R ₁Be independently selected from the group of forming by 3-phenyl propyl and (3,4, the 5-trimethoxy) phenyl propyl; With

R ₂Be independently selected from by 1,1-dimethyl propyl, cyclohexyl, the tertiary butyl, phenyl and 3,4 are in the group that the 5-trimethoxyphenyl is formed.

The object lesson of this embodiment is listed in the Table V:

Table V numbering A B C D R ₁R ₂87 CH ₂CH ₂S CH ₂3-phenyl propyl 1,1-dimethyl propyl 88 CH ₂CH ₂O CH ₂3-phenyl propyl 1,1-dimethyl propyl 89 CH ₂CH ₂S CH ₂3-phenyl propyl cyclohexyl 90 CH ₂CH ₂O CH ₂3-phenyl propyl cyclohexyl 91 CH ₂CH ₂S CH ₂3-phenyl propyl phenyl 92 CH ₂CH ₂O CH ₂3-phenyl propyl phenyl 93 CH ₂CH ₂NH CH ₂3-phenyl propyl 1,1-dimethyl propyl 94 CH ₂CH ₂NH CH ₂3-phenyl propyl phenyl

General formula I X

In addition, bridged heterocyclic derivatives can be general formula I X:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

A and B with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, wherein R or for replacing perhaps is independently selected from by halogen, halo-C by one or more ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₄Substituting group in the group of being formed replaces;

Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

X is O or S;

Z is O, NH or NR ₁

W and Y are O, S, CH independently ₂Or H ₂

R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl and Ar ₂Substituting group in the group of being formed replaces;

N is 1 or 2;

R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl and hydroxyl are formed replaces; With

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.

The N-oxide compound of heterocyclic ester, acid amides, monothioester and ketone

General formula X

The Hete rocyclic derivatives of bridging can further be a general formula X: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A and B, nitrogen-atoms that is connected respectively with them and carbon atom form the saturated or unsaturated heterocycle of a kind of 5-7 unit together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₁Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

W is O, S, CH ₂Or H ₂

R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by bridged ring part or C ₁-C ₆Straight or branched alkyl or C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl; With

R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.

General formula X I

And bridged heterocyclic derivatives can be general formula X I:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

W is O, S, CH ₂Or H ₂

R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

Said aromatic amine is pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl or Y-Z.

General formula X II

And bridged heterocyclic derivatives can be general formula X II:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F and G are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

W is O, S, CH ₂Or H ₂

R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

Said aromatic amine is pyridyl, pyrimidyl, quinolyl or isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.

General formula X III

Bridged heterocyclic derivatives also can be general formula X III: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 1,2 or 3, forms the heterocyclic ring of a 5-7 unit;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, wherein mainly ring (when n is 1,2 or 3) any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

W is O, S, CH ₂Or H ₂

R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

Said aromatic amine is pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.

The example of the general formula X III compound when W is O is listed in the Table VI:

Table VI numbering n X Y Z R95 1 O (CH ₂) ₃3-pyridyl N-oxide compound 1,1-dimethyl propyl 96 1 O (CH ₂) ₃2-pyridyl N-oxide compound 1,1-dimethyl propyl 97 1 O (CH ₂) ₃4-pyridyl N-oxide compound 1,1-dimethyl propyl 98 1 O (CH ₂) ₃2-quinolyl N-oxide compound 1,1-dimethyl propyl 99 1 O (CH ₂) ₃3-quinolyl N-oxide compound 1,1-dimethyl propyl 100 1 O (CH ₂) ₃4-quinolyl N-oxide compound 1, the 1-dimethyl propyl

The compound of preferred general formula X III is selected from the group of being made up of following material and the acceptable salt of their medicine, ester and solvate:

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-pyridyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4-pyridyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-quinolyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-quinolyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-quinolyl)-1-propyl diester, the N-oxide compound;

(2S)-and 1-(1,1-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4-quinolyl)-1-propyl diester, the N-oxide compound;

General formula X IV

In addition, bridged heterocyclic derivatives can be general formula X IV:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

A and B with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₇Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R ₇Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, R wherein ₇Perhaps, perhaps be independently selected from by halogen, halo-C by one or more for not replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, bridged ring part, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl and Ar ₄Substituting group in the group of being formed replaces;

Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; With

R, W, X, Y and Z in the general formula X of front definition.

IV. the urea and the carbamate bridged heterocyclic derivatives of the N-of heterocyclic thioesters connection can further be general formula X V: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A and B, nitrogen-atoms that is connected respectively with them and carbon atom form saturated, the undersaturated heterocycle of a kind of 5-7 unit together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₃Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₃Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆Substituting group in the group that-ester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group optionally are independently selected from by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or the substituting group in the group formed of alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

W is O or S; With

U or be O or for N, its precondition is:

When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, C ₃-C ₈Cycloalkyl, bridged ring part, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, C ₃-C ₁₀Cycloalkyl, bridged ring part, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl is independently selected from by Ar, bridged ring part and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.

In the preferred embodiment of general formula X V, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

General formula X VI

And bridged heterocyclic derivatives can be general formula X VI:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₃

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group optionally are independently selected from by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl or alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Replace;

W is O or S; With

U or be O or for N, its precondition is:

When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, C ₃-C ₈Cycloalkyl, bridged ring part, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₃Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.

In the preferred embodiment of general formula X VI, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

General formula X VII

Bridged heterocyclic derivatives also can be general formula X VII: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F and G are CH independently ₂, O, S, SO, SO ₂, NH and NR ₃

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

W is O or S; With

U or be O or for N, its precondition is:

When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.

In the preferred embodiment of general formula X VII, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

General formula X VIII

Bridged heterocyclic derivatives also can be general formula X VIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 1,2 or 3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, wherein mainly ring (when n is 1,2 or 3) any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond:

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₂-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

W is O or S; With

U or be O or for N, its precondition is:

When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.

In the preferred embodiment of general formula X VIII, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

U is that N and X are that the example of compound of the general formula X VIII of O is listed in the Table VII.

Numbering n W Y Z C D R ₁R ₂101 1 O (CH ₂) ₂CH 3-pyridyl H H 2-methyl butyl 102 1 O (CH ₂) ₂CH 3-pyridyl H H 1,1-dimethyl propyl 103 1 O (CH ₂) ₂CH 4-p-methoxy-phenyl H H 1,1-dimethyl propyl 104 1 O CH ₂ CH phenyl H H 1,1-dimethyl propyl 105 1 S (CH ₂) ₂CH 4-p-methoxy-phenyl H H cyclohexyl 106 1 O (CH ₂) ₂CH 3-pyridyl H H cyclohexyl 107 1 S (CH ₂) ₂CH 3-pyridyl H H cyclohexyl 108 1 S (CH ₂) ₂CH 3-pyridyl H H 1-adamantyl 109 1 S (CH ₂) ₂CH 3-pyridyl H H 1,1-dimethyl propyl 110 1 O (CH ₂) ₂ CH phenyl H 1,1-dimethyl propyl 111 2 O (CH ₂) ₂ CH phenyl H H 1,1-dimethyl propyl 112 2 O (CH ₂) ₂The direct key CH of the direct key CH of the direct key CH of CH phenyl H H phenyl 113 2 O 2-phenylethyl 2-phenylethyl H phenyl 114 2 O 2-phenylethyl 2-phenylethyl H cyclohexyl 115 2 S 2-phenylethyl 2-phenylethyl H cyclohexyl 116 2 O (CH ₂) ₂CH 4-p-methoxy-phenyl H H cyclohexyl

The compound of most preferred general formula X VIII is selected from the group of being made up of following material and the acceptable salt of their medicine, ester and solvate:

The 2S-1-[(2-methyl butyl) formamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-propyl diester;

2S-1-[(1 ', 1 '-dimethyl propyl) formamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-propyl diester;

The 2S-1-[(cyclohexyl) thiocarbamoyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-propyl diester;

General formula X IX

In addition, bridged heterocyclic derivatives can be general formula X IX: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₃Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute; With

A, B, R ₁, R ₂, U, W and X in the general formula X V definition.

V. the sulphonamide that connects of the N-of heterocyclic thioesters

General formula X X

Bridged heterocyclic derivatives can further be general formula X X: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A and B, nitrogen-atoms that is connected respectively with them and carbon atom form saturated, the undersaturated heterocycle of a kind of 5-7 unit together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₂Heteroatoms in the group of being formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical 1 amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.

In a kind of preferred embodiment of general formula X X, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

In the another kind of preferred embodiment of general formula X X, A forms a kind of 6 yuan saturated or unsaturated heterocycle or heterocyclic bridged loop section with B with nitrogen-atoms and the carbon atom that they are connected respectively; R ₂Be C ₄-C ₇Branched-chain alkyl, C ₄-C ₇Cycloalkyl, phenyl or 3,4, the 5-trimethoxyphenyl.

In the another kind of preferred embodiment of general formula X X, this compound is selected from the group of being made up of following material and the acceptable salt of their medicine, ester and solvate:

(2S)-N-(benzenesulfonyl) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

(2S)-N-(α-tosyl group) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

(2S)-N-(α-tosyl group) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

N-(ptoluene-sulfonyl) nipecotic acid 1,5-phenylbenzene-3-amyl group thiol esters.

General formula X XI

And bridged heterocyclic derivatives can be general formula X XI:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.

In a kind of preferred embodiment of general formula X XI, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

General formula X XII

Bridged heterocyclic derivatives also can be general formula X XII: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

E, F and G are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl or hydroxyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.

In a kind of preferred embodiment of general formula X XII, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

General formula X XIII

In addition, bridged heterocyclic derivatives can be general formula X XIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 1,2 or 3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, wherein mainly ring (when n is 1,2 or 3) any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl or hydroxyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.

In a kind of preferred embodiment of general formula X XIII, Ar is independently selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.

The example of the compound of general formula X XIII is listed in the Table VIII.

Table VIII numbering n Y Z C D R ₁117 1 CH ₂CH phenyl H phenyl 118 1 CH ₂CH phenyl H Alpha-Methyl phenyl 119 1 CH ₂CH phenyl H 4-aminomethyl phenyl 120 1 (CH ₂) ₂CH is right-p-methoxy-phenyl H phenyl 121 1 (CH ₂) ₂CH is right-p-methoxy-phenyl H Alpha-Methyl phenyl 122 1 (CH ₂) ₂CH is right-p-methoxy-phenyl H 4-aminomethyl phenyl 123 1 (CH ₂) ₂CH phenyl phenyl 124 1 (CH ₂) ₂CH phenyl Alpha-Methyl phenyl 125 1 (CH ₂) ₂CH phenyl 4-aminomethyl phenyl 126 2 (CH ₂) ₃CH phenyl H phenyl 127 2 (CH ₂) ₃CH phenyl H Alpha-Methyl phenyl 128 2 (CH ₂) ₃CH phenyl H 4-aminomethyl phenyl 129 2 (CH ₂) ₃ CH phenyl H 3,4, the 5-front three

Oxygen base phenyl 130 2 (CH ₂) ₃the key CH 3-that key CH 3-phenylethyl 3-phenylethyl 4-methyl phenyl 135 2 Zhi that key CH 3-phenyl propyl group 3-phenyl propyl group 4-methyl phenyl 134 2 Zhi that key CH 3-phenyl propyl group 3-phenyl propyl group Alpha-Methyl phenyl 133 2 Zhi that key CH 3-phenyl propyl group 3-phenyl propyl group phenyl 132 2 Zhi that CH phenyl H cyclohexyl 131 2 Zhi connect connect connect connect connect, the key CH 3-that (4-methoxyphenyl) propyl group 3-phenyl propyl group 4-methyl phenyl 136 2 Zhi connect, (2-Bi Ding yl) propyl group 3-phenyl propyl group 4-methyl phenyl

The compound of most preferred general formula X XIII is selected from the group of being made up of following material and the acceptable salt of their medicine, ester and solvate:

(2S)-N-(benzenesulfonyl) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

(2S)-N-(α-tosyl group) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

(2S)-N-(α-tosyl group) tetramethyleneimine-2-carboxylic acid 3-(right-p-methoxy-phenyl)-1-propyl group thiol esters;

N-(ptoluene-sulfonyl) nipecotic acid 1,5-phenylbenzene-3-amyl group thiol esters.

General formula X XIV

In addition, bridged heterocyclic derivatives can be general formula X XIV:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

A, B, C, D, R ₁, X, Y and Z in the general formula X X of front definition.

Pyrrolidin derivatives

General formula X XV

Bridged heterocyclic derivatives also can be general formula X XV: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, wherein mainly ring (when t is 1,2 or 3) any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl wherein said Ar ₁For not replacing, perhaps be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

X is O, S, CH ₂Or H ₂

Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z ₁-C ₆Alkyl; With

Each Z is C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment

Wherein:

R ₃Be C independently ₁-C ₉The straight or branched alkyl, it is not for replacing or by C ₃-C ₈Cycloalkyl, bridged ring part or Ar ₁Replace;

X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed;

N is 1 or 2; With

T is 1,2 or 3.

In a kind of preferred embodiment of general formula X XV, Z and R ₁For lipophilic.

In the another kind of preferred embodiment of general formula X XV, this compound is selected from the group of being made up of following material and the acceptable salt of medicine, ester or solvate:

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-phenyl-1-third-2-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3,4, the 5-trimethoxyphenyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3,4, the 5-trimethoxyphenyl)-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-dichlorophenyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-dichlorophenyl)-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-methylenedioxyphenyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-methylenedioxyphenyl)-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-cyclohexyl-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-cyclohexyl-1-third-2-(E)-alkenyl esters;

(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1,3-phenylbenzene-1-propyl diester;

(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1,3-phenylbenzene-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1-cyclohexyl-3-phenyl-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1-cyclohexyl-3-phenyl-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1-(4, the 5-dichlorophenyl)-3-phenyl-1-propyl diester;

(2S)-1-(1,2-dioxo-2-cyclohexyl) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-1-(1,2-dioxo-4-cyclohexyl) butyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-and 1-(1,2-dioxo-2-[2-furyl]) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-and 1-(1,2-dioxo-2-[2-thienyl]) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-and 1-(1,2-dioxo-2-[2-thiazolyl]) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-1-(1,2-dioxo-2-phenyl) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 1,7-phenylbenzene-4-heptyl ester;

(2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

3-phenyl-1-propyl group (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid acid amides;

1[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-phenylalanine ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-leucine ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-phenylglycocoll ethyl ester;

1-[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-phenylalanine phenylester;

1-[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-phenylalanine benzyl ester;

1-[1-(3,3-dimethyl-1,2-dioxo amyl group)-L-proline(Pro)]-L-Isoleucine ethyl ester;

General formula X XVI

In addition, bridged heterocyclic derivatives can be general formula X XVI: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl wherein said Ar ₁For not replacing, perhaps be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

Z is C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment Wherein:

R ₃Independently for not replacing or by C ₃-C ₈The C that cycloalkyl replaced ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; With

R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed.

In a kind of preferred embodiment of general formula X XVI, R ₁Be independently selected from by C ₁-C ₉In the group that straight or branched alkyl, 2-cyclohexyl, 4-cyclohexyl, 2-furyl, 2-thienyl, 2-thiazolyl and 4-hydroxybutyl are formed.

In the another kind of preferred embodiment of general formula X XVI, Z and R ₁For lipophilic.

General formula X XVII

And bridged heterocyclic derivatives can be general formula X XVII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

Z ' is a fragment Wherein:

R ₃Be C independently ₁-C ₉Straight or branched alkyl or unsubstituted Ar ₁, wherein said alkyl is not for replacing or by C ₃-C ₈Cycloalkyl, bridged ring part or Ar ₁Replace;

X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; With

R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed; With

Ar ₁Such as among the general formula X XVI definition.

In a kind of preferred embodiment of general formula X XVII, Z ' is lipophilic.

General formula X XVIII

Bridged heterocyclic derivatives also can be general formula X XVIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₆Cycloalkyl, bridged ring part or Ar ₁, wherein said alkyl or alkenyl or for replacing, perhaps by C ₃-C ₆Cycloalkyl or Ar ₂Replace;

Ar ₁And Ar ₂Be independently selected from the group of forming by 2-furyl, 2-thienyl and phenyl;

X is selected from the group of being made up of oxygen and sulphur;

Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z independently ₁-C ₆Alkyl; With

Each Z is hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by 2-furyl, 2-thienyl, C by one or more ₃-C ₆Substituting group in the group that cycloalkyl, pyridyl and phenyl are formed replaces, and each substituting group has one or more being independently selected from by hydrogen and C ₁-C ₄Substituting group in the group that alkoxyl group is formed; With

N is 1 or 2.

In a kind of preferred embodiment of general formula X XVIII, Z and R ₁For lipophilic.

In the another kind of preferred embodiment of general formula X XVIII, this compound is selected from the group of being made up of following material and the acceptable salt of medicine, ester or solvate:

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2, the 5-Dimethoxyphenyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2, the 5-Dimethoxyphenyl)-1-third-2-(E)-alkenyl esters;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 2-(3,4, the 5-trimethoxyphenyl)-1-ethyl ester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-pyridyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4-pyridyl)-1-propyl diester;

(2S)-1-(the 2-tertiary butyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-1-(2-cyclohexyl ethyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl diester;

(2S)-1-(2-cyclohexyl ethyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-1-(the 2-tertiary butyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl diester;

(2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-N-([2-thienyl]-1,2-dioxo ethyl) pyrrolidine carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-and 1-(3,3-dimethyl-1,2-dioxo butyl)-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl diester;

(2S)-and 1-cyclohexyl-1,2-dioxo ethyl-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl diester;

(2S)-and 1-(2-thienyl)-1,2-dioxo ethyl-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl diester;

In the another kind of preferred embodiment of general formula X XVIII, this compound is selected from the group of being made up of following material and the acceptable salt of medicine, ester or solvate:

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-pyridyl)-1-propyl diester;

(2S)-1-(2-cyclohexyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester;

In the another kind of preferred embodiment of general formula X XVIII, this compound is (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl diester and the acceptable salt of medicine, ester or solvate.

General formula X XIX

In addition, bridged heterocyclic derivatives can be general formula X XIX: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

A and B with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed; Or

A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R or for replacing perhaps is independently selected from by halogen, halo-C by one or more ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

X is O, S, CH ₂Or H ₂

Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z ₁-C ₆Alkyl; With

Each Z is C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment Wherein:

R ₃Independently for not replacing or by C ₃-C ₈The C that cycloalkyl replaced ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed; With

N is 1 or 2.

Other bridged heterocyclic derivatives that belongs to the scope of the invention is that those can have immunosuppressant, non-immunosuppressant or other active compound, as long as they also can be used to prevent and/or treat neurologic illness comprise physical damnification nerve and neurodegenerative disease; Be used for the treatment of alopecia and promote hair growth; Be used for the treatment of the vision illness and/or improve eyesight; Remember impairment and/or hypermnesis function with being used for the treatment of.For example these compounds can include, but not limited to following compound:

Compound 167

People such as Ocain are incorporated into the present invention as a reference at Biochemical and Biophysical Research Communcations (1993) 3:192, in a kind of example of the nipecotic acid derivative of being represented by general formula X XX is disclosed.This compound passes through 4-phenyl-1,2,4-triazoline-3, and 5-diketone and Wyeth-Ayerst Laboratories react and prepare.

General formula (XXX)

" WAY-124,466 "

Compound 168

People such as Chakraborty are incorporated into the present invention as a reference at Chemistry and Biology (1995) 2:157-161, in a kind of example of the nipecotic acid derivative of being represented by general formula X XXI is disclosed.

General formula (XXXI)

RAP-Pa

Compound 169-171

People such as Ikeda are incorporated into the present invention as a reference at J.Am.Chem.Soc. (1994) 116:4143-4144, in the example of the nipecotic acid derivative of being represented by general formula X XXII and Table X II is disclosed.

General formula (XXXII)

Table X II

Compound structure

169????????????????n＝1

170????????????????n＝2

171????????????????n＝3

Compound 172-175

People such as Wang are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4:1161-1166,9, be incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X XXIII and Table X III is disclosed.

General formula (XXXIII)

Table X III

Compound structure

172???????????X＝H，H

173???????????X＝CH ₂

174???????????X＝H，CH ₃

175???????????X＝O

Compound 176

People such as Birkenshaw are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (21): 2501-2506 is incorporated into the present invention as a reference, in a kind of example of the nipecotic acid derivative of being represented by general formula X XXIV is disclosed.

General formula (XXXIV)

Compound 177-187

People such as Holt are incorporated into the present invention as a reference at J.Am.Chem.Soc. (1993) 115:9925-9938, in the example of the nipecotic acid derivative of being represented by general formula X XXV and Table X IV and XV is disclosed.

General formula (XXXV)

Table X V compound R ₂

Compound 188-196

People such as Caffery are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (21): 2507-2510 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X XXIII-XXXVIII and Table X VI-XVIII is disclosed.

General formula X XXVI

Table X VI

Compound structure

188???????????????y＝1

189???????????????y＝2

190???????????????y＝3

General formula X XXVII

Table X VII

Compound structure

191???????????n＝1

192???????????n＝2

193???????????n＝3

General formula X XXVIII

Table X VIII

Compound structure

194???????????n＝1

195???????????n＝2

196???????????n＝3

Compound 197

People such as Teague are at Bioorganic﹠amp; Medicinal Chemistry Letters (1993) 3 (10): 1947-1950 is incorporated into the present invention as a reference, in a kind of example of the nipecotic acid derivative of being represented by general formula X XXIX is disclosed.

General formula X XXIX

Compound 198-200

People such as Yamashita are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (2): 325-328 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X L and Table X IX is disclosed.

General formula X L

Table X IX

Compound structure

198 R=phenyl

199 R=N (allyl group) ₂

200

Compound 201-221

People such as Holt are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (2): 315-320 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X LI and Table X X-XXII is disclosed.

General formula X LI

Table X X compound R

Table X XI compound number R

Table X XII compound number structure

Compound 222-234

People such as Holt are at Bioorganic﹠amp; Medicinal Chemistry Letters (1993) 3 (10): 1977-1980 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X LII and XLIII and Table X XIII-XXV is disclosed.

General formula X LII

Table X XIII

Compound structure

222???????????X＝OH

223 X=O methyl

224 X=O-sec.-propyls

225 X=O benzyls

226 X=OCH (methyl) phenyl

227 X=OCH ₂The CHCH phenyl

228 X=OCH ₂CH ₂CH ₂(3, the 4-O methyl ₂) phenyl

229 X=NH benzyls

230 X=NHCH ₂CH ₂CH ₂Phenyl

General formula X LIII

Table X XIV

Compound structure

231 R=methyl

232 R=benzyls

Table X XV

Compound structure

Compound 235-249

People such as Hauske are at J.﹠amp; Med.Chem. (1992) 35:4284-4296 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X LIV-XLVII and Table X XVI-XXIX is disclosed.

General formula X LIV

Table X XVI compound structure 235 n=2

R ₁＝

R ₂=phenoxy group the tertiary butyl 236 n=2

R ₁＝

R ₂=phenoxy group the tertiary butyl

General formula X LV

Table X XVII

Compound structure

237 R ₁=m-methoxyphenyl

R ₃=Xie Ansuan-oxygen-tertiary butyl

238 R ₁=m-methoxyphenyl

R ₃=leucine-oxygen-tertiary butyl

239 R ₁=m-methoxyphenyl

R ₃=Isoleucine-oxygen-tertiary butyl

240 R ₁=m-methoxyphenyl

R ₃=six hydrogen-phenylalanine-oxygen-tertiary butyl

241 R ₁=m-methoxyphenyl

R ₃=allyl group L-Ala-oxygen-the tertiary butyl

240 R ₁=betanaphthyl

R ₃=Xie Ansuan-oxygen-tertiary butyl

General formula X LVI

Table X XVIII

Compound structure

243 R ₁=CH ₂(CO)-m-methoxyphenyl

R ₄＝CH ₂Ph

R ₅＝OCH ₃

244 R ₁=CH ₂(CO)-betanaphthyl

R ₄＝CH ₂Ph

R ₅＝OCH ₃

General formula X LVII

Table X XIX

Compound structure

245 R ₁=m-methoxyphenyl

X=is anti--CH=CH-

R ₄＝H

Y＝OC(O)Ph

246 R ₁=m-methoxyphenyl

X=is anti--CH=CH-

R ₄＝H

Y＝OC(O)CF ₃

247 R ₁=m-methoxyphenyl

X=is anti--CH=CH-

R ₄＝-

Y＝-

248 R ₁=m-methoxyphenyl

X=is anti--CH=CH-

R ₄＝H

Y＝OCH ₂CH＝CH ₂

249 R ₁=m-methoxyphenyl

X＝C＝O

R ₄＝H

Y＝Ph

Compound 250

People such as Teague are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (13): 1581-1584 is incorporated into the present invention as a reference, in a kind of example of the nipecotic acid derivative of being represented by general formula X LVIII is disclosed.

General formula X LVIII

SLB506

Compound 251-254

People such as Stocks are at Bioorganic﹠amp; Medicinal Chemistry Letters (1994) 4 (12): 1457-1460 is incorporated into the present invention as a reference, in the example of the nipecotic acid derivative of being represented by general formula X LIX and Table X XX and XXXI is disclosed.

Table X XX

The compound number structure

General formula X LIX

Table X XXI

Compound structure

252????????R ₁＝H

R ₂=O methyl

R ₃=CH ₂The O methyl

253????????R ₁＝H

R ₂＝H

R ₃＝H

254 R ₁=methyl

R ₂＝H

R ₃＝H

Compound 255-276

The example of other nipecotic acid derivative is represented by general formula L-LIV and Table X XXII-XXXVI.

General formula L

Table X XXII

Compound structure

255 R=3, the 4-dichloro

256 R=3,4, the 5-trimethoxy

257???????R＝H

258 R=3-(2, the 5-dimethoxy) phenyl propyl

259 R=3-(3,4-methylene radical dioxy) phenyl propyl

General formula LI

Table X XXIII

Compound structure

260 R=4-(right-methoxyl group) butyl

261 R=3-phenyl propyl

262 R=3-(3-pyridyl) propyl group

General formula LII

Table X XXIV

Compound structure

263 R=3-(3-pyridyl) propyl group

264 R=1,7-phenylbenzene-4-heptyl

265 R=4-(4-methoxyl group) butyl

266 R=1-phenyl-6-(4-p-methoxy-phenyl)-4-hexyl

267 R=3-(2, the 5-dimethoxy) phenyl propyl

268 R=3-(3,4-methylene radical dioxy) phenyl propyl

269 R=1,5-phenylbenzene amyl group

General formula LIII

Table X XXV

Compound structure

270 R=4-(4-first-oxygen base) butyl

271 R=3-cyclohexyl propyl group

272 R=3-phenyl propyl

General formula LIV

Table X XXVI

Compound structure

273 R=3-cyclohexyl propyl group

274 R=3-phenyl propyl

275 R=4-(4-methoxyl group) butyl

276 R=1,7-phenylbenzene-4-heptyl

The title of some compounds of Que Dinging is listed among the following Table X XXVII above.

Table X XXVII compound title 172 (2S)-1-[2-(3,4, the 5-trimethoxyphenyl) ethanoyl] six hydrogen-2-Pyridinecarboxylic Acid 4-(4-methoxy

The base phenyl) butyl ester 173 (2S)-1-[2-(3,4, the 5-trimethoxyphenyl) acryl] six hydrogen-2-Pyridinecarboxylic Acid 4-(4-first

Oxygen base phenyl) butyl ester 174 (2S)-1-[2-(3,4, the 5-trimethoxyphenyl) propionyl] six hydrogen-2-Pyridinecarboxylic Acid 4-(4-methoxy

The base phenyl) butyl ester 175 (2S)-1-[2-oxo-2-(3,4, the 5-trimethoxyphenyl) ethanoyl] six hydrogen-2-Pyridinecarboxylic Acid 4-

(4-p-methoxy-phenyl) butyl ester 177 (2S)-1-(3; 3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid 3-cyclohexyl propyl ester 178 (2S)-1-(3; 3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid 3-amyl group propyl ester 179 (2S)-1-(3; 3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid 3-(3; 4, the 5-front three

Oxygen base phenyl) propyl ester 180 (2S)-1-(3,3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid (1R)-2, the 2-diformazan

Base-1-styroyl-3-butene esters 181 (2S)-1-(3,3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid (1R)-1, the 3-hexichol

Base propyl ester 182 (2S)-1-(3,3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid (1R)-1-cyclohexyl

-3-phenyl propyl ester 183 (2S)-1-(3,3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid (1S)-1, the 3-hexichol

Base propyl ester 184 (2S)-1-(3,3-dimethyl-2-oxo-pentanoyl) six hydrogen-2-Pyridinecarboxylic Acid (1S)-1-cyclohexyl

-3-phenyl propyl ester 185 (22aS)-15,15-dimethyl perhydro pyrido [2,1-c] [1,9,4] dioxy azepine nonadecane-

1,12,16,17-tetraketone 186 (24aS)-17,17-dimethyl perhydro pyrido [2,1-c] [1,9,4] dioxy azepine heneicosane-

1; 14; 18; 19-tetraketone 201 1-(2-oxo-3-phenyl propionyl)-2 piperidine carboxylic acid ethyl ester 202 1-pyruvoyl-2 piperidine carboxylic acid ethyl ester 203 1-(2-oxobutanoyl)-2 piperidine carboxylic acid ethyl ester 204 1-(3-methyl-2-oxobutanoyl)-2 piperidine carboxylic acid ethyl ester 205 1-(4-methyl-2-oxo pentanoyl)-2 piperidine carboxylic acid ethyl ester 206 1-(3; 3-dimethyl-2-oxobutanoyl)-2 piperidine carboxylic acid ethyl ester 207 1-(3; 3-dimethyl-2-oxo pentanoyl)-and 2 piperidine carboxylic acid ethyl ester 208 4-[2-(ethoxy carbonyl) piperidino-(1-position only)]-2; 2-dimethyl-3; 4-dioxo butylacetic acid ester 209 1-[2-(2-hydroxy tetrahydro-2H-2-pyranyl)-2-oxo ethanoyl]-2 piperidine carboxylic acid ethyl ester 210 1-[2-(2-methoxyl group tetrahydrochysene-2H-2-pyranyl)-2-oxo ethanoyl]-2 piperidine carboxylic acid ethyl ester 211 1-[2-(1-hydroxy-cyclohexyl)-2-oxo ethanoyl]-2 piperidine carboxylic acid ethyl ester 212 1-[2-(1-methoxyl group cyclohexyl)-2-oxo ethanoyl]-2 piperidine carboxylic acid ethyl ester 213 1-(2-cyclohexyl)-2-oxo ethanoyl)-2 piperidine carboxylic acid ethyl ester 214 1-(2-oxo-2-piperidino-(1-position only) ethanoyl)-2 piperidine carboxylic acid ethyl ester 215 1-[2-(3; 4-dihydro-2H-6-pyranyl)-2-oxo ethanoyl]-2 piperidine carboxylic acid ethyl ester 216 1-(2-oxo-2-phenyl acetyl)-2 piperidine carboxylic acid ethyl ester 217 1-(4-methyl-2-oxo-1-sulfo-amyl group)-2 piperidine carboxylic acid ethyl ester 218 1-(2-hydroxyl-3; 3-dimethyl-penten acyl group)-2 piperidine carboxylic acid 3-phenyl propyl ester 219 1-(3; 3-dimethyl butyrate acyl group)-2 piperidine carboxylic acid (1R)-1-phenyl-3-(3; 4, the 5-trimethoxy

Phenyl) propyl ester 220 1-(benzyl alkylsulfonyl)-2 piperidine carboxylic acid (1R)-1,3-phenylbenzene propyl ester 221 1-(benzyl alkylsulfonyl)-2 piperidine carboxylic acid 3-(3,4; the 5-trimethoxyphenyl) propyl ester 222 1-(2-[(2R, 3R, 6S)-6-[(2S; 3E; 5E, 7E, 9S; 11R)-2; 13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid 223 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid methyl esters 224 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid isopropyl ester 225 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid benzyl ester 226 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid 1-phenyl chlorocarbonate 227 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid (Z)-3-phenyl-2-propenyl ester 228 1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-dimethoxy-3,9,11-

Trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-2H-2-pyrrole

The base of muttering]-2-oxo ethanoyl)-2 piperidine carboxylic acid 3-(3, the 4-Dimethoxyphenyl) propyl ester 229 N2-benzyl-1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2, the 13-dimethoxy

-3,9,11-trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxy-3-methyl tetrahydrochysene-

The 2H-2-pyranyl]-2-oxo ethanoyl)-2 piperidine carboxylic acid ester 230 N2-(3-phenyl propyl)-1-(2-[(2R, 3R, 6S)-and 6-[(2S, 3E, 5E, 7E, 9S, 11R)-2,13-

Dimethoxy-3,9,11-trimethylammonium-12-oxo-3,5,7-three (trialkenyl in the last of the ten Heavenly stems)]-2-hydroxyl-3-first

Base tetrahydrochysene-2H-2-pyranyl]-2-oxo ethanoyl)-2 piperidine carboxylic acid ester 231 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid (E)-3-(3, the 4-dichlorophenyl)-2-

Propenyl ester 232 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid (E)-3-(3,4, the 5-trimethoxy-benzene

Base)-2-propenyl ester 233 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid (E)-3-phenyl-2-propenyl ester 234 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid (E)-3-((3-(2, the 5-dimethoxy)

Phenyl propyl)-phenyl)-2-propenyl ester 235 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid (E)-3-(1,3-benzo dioxolane

-5-yl)-2-propenyl ester 236 1-(2-oxo-2-phenyl acetyl)-2 piperidine carboxylic acid 4-(4-p-methoxy-phenyl) butyl ester 237 1-(2-oxo-2-phenyl acetyl)-2 piperidine carboxylic acid 3-phenyl propyl ester 238 1-(2-oxo-2-phenyl acetyl)-2 piperidine carboxylic acid 3-(3-pyridyl) propyl ester 239 1-(3; 3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 3-(3-pyridyl) propyl ester 240 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 4-phenyl-1-(3-phenyl propyl)

Butyl ester 241 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 4-(4-p-methoxy-phenyl) butyl ester 242 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 1-(4-anisole ethyl)-4-

Butyloxy phenyl 243 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 3-(2, the 5-Dimethoxyphenyl) third

Ester 244 1-(3,3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 3-(1,3-benzo dioxolane-5-

Base) propyl ester 245 1-(3; 3-dimethyl-2-oxo pentanoyl)-2 piperidine carboxylic acid 1-phenyl-3-phenyl propyl ester 246 1-(2-cyclohexyl)-2-oxo ethanoyl)-2 piperidine carboxylic acid 4-(4-p-methoxy-phenyl) butyl ester 247 1-(2-cyclohexyl)-2-oxo ethanoyl)-2 piperidine carboxylic acid 3-cyclohexyl propyl ester 248 1-(2-cyclohexyl)-2-oxo ethanoyl)-2 piperidine carboxylic acid 3-phenyl propyl ester 249 1-(3; the 3-dimethyl)-the 2-oxobutanoyl)-2 piperidine carboxylic acid 3-cyclohexyl propyl ester 250 1-(3; the 3-dimethyl)-the 2-oxobutanoyl)-2 piperidine carboxylic acid 3-phenyl propyl ester 251 1-(3; the 3-dimethyl)-the 2-oxobutanoyl)-2 piperidine carboxylic acid 4-(4-p-methoxy-phenyl) butyl ester 252 1-(3, the 3-dimethyl)-2-oxobutanoyl)-2 piperidine carboxylic acid 4-phenyl-1-(3-phenyl propyl)

Butyl ester

General formula LV

In a kind of further embodiment, provide general formula LV:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

M is 0-3;

A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

B and D be hydrogen, Ar independently, by C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, by C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl or the C that is replaced by Ar ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein in each case, one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be fragment Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

Ar is independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed;

L or be hydrogen or for U; M or be oxygen or for CH-U, its precondition is when L is hydrogen, M is CH-U, perhaps when M was oxygen, L was U;

U is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

J is hydrogen, C ₁Or C ₂Alkyl, or benzyl;

K is C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or

J and K form a kind of by oxygen, sulphur, SO or SO together ₂The heterocyclic ring of the 5-7 unit that replaces, or

J forms a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part with the atom that K is connected with them.

The representational material of general formula LV is listed among the Table X XXVIII:

Table X XXVIII compound n m B D L253 20 3-phenyl propyl 3-(3-pyridyl) propyl group phenyl 254 20 3-phenyl propyl 3-(2-pyridyl) propyl group phenyl 255 20 3-phenyl propyl 2-(4-p-methoxy-phenyl) ethylphenyls 256 20 3-phenyl propyl 3-phenyl propyl phenyl 257 20 3-phenyl propyl 3-phenyl propyl 3,4,5-trimethoxyphenyl 258 20 3-phenyl propyl 2-(3-pyridyl) propyl group 3,4,5-trimethoxyphenyl 259 20 3-phenyl propyl 3-(2-pyridyl) propyl group 3,4,5-trimethoxyphenyl 260 20 3-phenyl propyl 3-(4-p-methoxy-phenyl) propyl group 3,4,5-trimethoxyphenyl 261 20 3-phenyl propyl 3-(3-pyridyl) propyl group 3-isopropyl phenyls

General formula (LVI)

USP5,330,993, be incorporated into the present invention as a reference, a kind of general formula LVI is disclosed: Example or the acceptable salt of its medicine, ester or the solvate of nipecotic acid derivative, wherein:

A is O, NH or N-(C ₁-C ₄Alkyl);

B is hydrogen, CHL-Ar, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, C ₅-C ₇The C that cycloalkenyl group, Ar replace ₁-C ₆Alkyl or C ₂-C ₆Thiazolinyl perhaps is Wherein L and Q are hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cyclohexyl;

Ar is independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they contain 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, CF ₃, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), in the group that O-benzyl, O-phenyl, amino and phenyl are formed;

D or be hydrogen or for U; E is oxygen or CH-U, and its precondition is when D is hydrogen, and E is CH-U, and perhaps when E was oxygen, D was U;

U is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, 2-indyl, 3-indyl, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

J is hydrogen, C ₁Or C ₂Alkyl, or benzyl;

K is C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl ethyl; Or

J and K form a kind of by oxygen, sulphur, SO or SO together ₂The heterocyclic ring of the 5-7 unit that replaces, or

In bridged heterocyclic derivatives of the present invention, J forms a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part with the atom that K is connected with them.

General formula LVII

A kind of preferred bridged heterocyclic derivatives is general formula LVII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 2;

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of piperidine ring (when n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

D is phenyl, methoxyl group, 2-furyl or 3,4, the 5-trimethoxyphenyl; With

B is benzyl, 3-phenyl propyl, 4-(4-p-methoxy-phenyl) butyl, 4-phenyl butyl, styroyl, 3-cyclohexyl propyl group, 4-cyclohexyl butyl, 3-cyclopentyl propyl group, 4-cyclohexyl butyl, 3-phenoxy benzyl, 3-(3-indyl) propyl group or 4-(4-p-methoxy-phenyl) butyl;

Its precondition is:

When D was phenyl, B was benzyl, 3-phenyl propyl, 4-(4-p-methoxy-phenyl) butyl, 4-phenyl butyl, styroyl or 4-cyclohexyl butyl;

When D was methoxyl group, B was benzyl, 4-cyclohexyl butyl, 3-cyclohexyl propyl group or 3-cyclopentyl propyl group;

When D was the 2-furyl, B was a benzyl; With

When D is 3,4, during the 5-trimethoxyphenyl, B is 4-cyclohexyl butyl, 3-phenoxy benzyl, 4-phenyl butyl, 3-(3-indyl) propyl group or 4-(4-p-methoxy-phenyl) butyl.

The representational material of general formula LVII is listed among the Table X XXIX:

Table X XXIX compd B D n262 benzyl phenyl 2263 3-phenyl propyl phenyl, 2264 4-(4-p-methoxy-phenyl) butyl phenyl 2265 4-phenyl butyl phenyl 2266 styroyl phenyl 2267 4-cyclohexyl butyl phenyls 2268 benzyl methoxyl groups 2269 4-cyclohexyl butyl methoxyl groups 2 270 3-cyclohexyl propyl group methoxyl groups 2271 3-cyclopentyl propyl group methoxyl groups 2272 benzyl 2-furyls 2273 4-cyclohexyl butyl 3,4,5-trimethoxyphenyl 2274 3-phenoxy benzyls 3,4,5-trimethoxyphenyl 2275 4-phenyl butyls 3,4,5-trimethoxyphenyl 2276 3-(3-indyl) propyl group 3,4,5-trimethoxyphenyl 2277 4-(4-p-methoxy-phenyl) butyl 3,4,5-trimethoxyphenyl 2

General formula LVIII bridged heterocyclic derivatives also can be general formula LVIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

J and K with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed; Or

J and K, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₂-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R perhaps is selected from by halogen, halo-C by one or more independently or for replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; With

A, B, D, L, M and m in the general formula LV of front definition.

VI. small molecules sulphonamide

General formula LIX

In a kind of other embodiment, provide general formula LIX:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

B and D are Ar, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be

Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

Its precondition is that B and D not all are hydrogen;

Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

J is hydrogen, C ₁Or C ₂Alkyl, or benzyl; K is C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or J and K form a kind of by oxygen, sulphur, SO or SO together ₂The heterocyclic ring of the 5-7 unit that replaces, or

J forms a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part with the atom that K is connected with them;

N is 0-3; With

The stereochemistry of 1 and 2 carbon atom positions is R or S.

General formula LX

In the preferred embodiment of general formula LIX, J and K combine, and bridged heterocyclic derivatives is general formula LX: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

N is 1 or 2;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, any two or more atoms of pyrrolidine ring (when n=1) or piperidine ring (when n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond; With

M is 0 or 1.

In a kind of preferred embodiment, B is selected from the group of being made up of hydrogen, benzyl, 2-phenylethyl and 3-phenyl propyl;

D is selected from the group of being made up of phenyl, 3-phenyl propyl, 3-Phenoxyphenyl and 4-Phenoxyphenyl; With

E is selected from by phenyl, 4-aminomethyl phenyl, 4-p-methoxy-phenyl, 2-thienyl, 2,4,6-triisopropyl phenyl, 4-fluorophenyl, 3-p-methoxy-phenyl, 2-p-methoxy-phenyl, 3,5-Dimethoxyphenyl, 3,4,5-trimethoxyphenyl, methyl, 1-naphthyl, 8-quinolyl, 1-(5-N, N dimethylamine base)-naphthyl, 4-iodine substituted phenyl, 2,4, in the group that 6-trimethylphenyl, benzyl, 4-nitrophenyl, 2-nitrophenyl, 4-chloro-phenyl-and E-styryl are formed.

General formula LXI

The example of another kind of bridged heterocyclic derivatives is general formula LXI: Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of main piperidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond; With

B and D are Ar, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by O, S, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be

Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

Its precondition is that B and D not all are hydrogen;

Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With

M is 0-3.

General formula LXII

The further example of bridged heterocyclic derivatives is general formula LXII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

Main ring structure optionally comprises Br, and wherein Br is heterocyclic bridged loop section, and any two or more atoms of main piperidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond; With

B and D are Ar, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by O, S, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

Its precondition is that B and D not all are hydrogen;

Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With

M is 0-3.

General formula LXIII

The further example of bridged heterocyclic derivatives is general formula LXIII:

Compound or the acceptable salt of its medicine, ester or solvate, wherein:

V is CH, N or S;

J and K with V and the carbon atom that they connect respectively, form saturated, the undersaturated heterocycle of a kind of 5-7 unit, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed; Or

J and K, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together;

R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R perhaps is selected from by halogen, halo-C by one or more independently or for replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; With

A, B, D, E and n in the general formula LIX of front definition.

The representational material of general formula LIX-LXIII is listed among the Table X L:

Table X I compound structure and title

4-phenyl-1-butyl-1-(benzyl alkylsulfonyl)-(2R, S)-the pipecolinic acid ester

1,5-phenylbenzene-3-amyl group-N-(α-tosyl group)-piperidines acid esters

1,7-phenylbenzene-4-heptyl-N-(ptoluene-sulfonyl)-piperidines acid esters

3-(3-pyridyl)-1-propyl group-(2S)-N-(α-tosyl group)-tetramethyleneimine-2-carboxylicesters

4-phenyl-1-butyl-N-(ptoluene-sulfonyl)-piperidines acid esters

4-phenyl-1-butyl-N-(benzenesulfonyl)-piperidines acid esters

4-phenyl-1-butyl-N-(α-tosyl group)-piperidines acid esters

VII. carboxylic acid isostere

The preferred embodiment of another kind of the present invention is compound or the acceptable salt of its medicine, ester or the solvate of general formula LXIV: Wherein:

N is 1-3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

X or be O or for S;

R ₁Be independently selected from by C ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring or heterocycle are formed;

D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl; With

R ₂Be carboxylic acid or carboxylic acid isostere independently.

A kind of preferred embodiment of the present invention is R wherein ₂Independently for containing the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded carbocyclic ring or heterocycle, wherein its one or more regioselectivities ground of the atom of any said ring structure is by R ³Replace.

Particularly preferred embodiment of the present invention is R wherein ₂Be independently selected from following group:

Wherein its one or more positions of the atom of said ring structure can be optionally by R ³Replace.

The preferred embodiment of another kind of the present invention is R wherein ₂Be independently selected from by-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ₃,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³In the group that CN formed, R wherein ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

Preferred embodiment of the present invention is: (2S)-and 1-(1,2-dioxo-3,3-dimethyl amyl group)-2-hydroxymethyl pyrrolidine; (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine tetrazolium; (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile; (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-aminocarboxyl piperidines.

Compound of the present invention is in particular general formula LXIV, and wherein n is 1, and X is O, and D is a key, R ₁Be 1,1-dimethyl propyl, and R ₂For-CN, called after (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile.

The specific embodiment of the present invention is listed among Table X LI, XLII and the LXIII.The present invention expects to use the compound of following Table X LI, XLII and LXIII.

Table X LI

When D is a key and R ₂During for COOH, numbering X N R ₁285 O 13,4,5-trimethylphenyl 286 O 23,4,5-trimethylphenyl 287 O 1 tertiary butyl 287 O 3 tertiary butyls 288 O 1 cyclopentyl 289 O 2 cyclopentyl 290 O 3 cyclopentyl 291 O 1 cyclohexyl 292 O 2 cyclohexyl 293 O 3 cyclohexyl 294 O 1 suberyl 295 O 2 suberyl 296 O 3 suberyl 297 O 1 2-thienyl 298 O 2 2-thienyls 299 O 3 2-thienyls 300 O 1 2-furyl 301 O 2 2-furyls 302 O 3 2-furyls 303 O 3 phenyl 304 O 11,1-dimethyl amyl group 305 O 21,1-dimethyl hexyl 306 O 3 ethyls 307

Table X LII numbering X n R ₁D R ₂308 S 11,1-dimethyl propyl CH ₂COOH309 S 11,1-dimethyl propyl singly-bound COOH310 O 11,1-dimethyl propyl CH ₂OH311 O 11,1-dimethyl propyl singly-bound SO ₃H312 O 11,1-dimethyl propyl CH ₂CN313 O 11,1-dimethyl propyl singly-bound CN314 O 11,1-dimethyl propyl singly-bound tetrazyl 315 S 1 phenyl (CH ₂) ₂ COOH316 S 1 phenyl (CH ₂) ₃ COOH317 S 2 phenyl CH ₂COOH318 O 11,1-dimethyl propyl singly-bound CONH ₂319 O 21,1-dimethyl propyl singly-bound CONH ₂320 S, 2 2-furyl singly-bound PO ₃H ₂321 O, 2 propyl group (CH ₂) ₂ COOH322 O 1 propyl group (CH ₂) ₃ COOH323 O 1 tertiary butyl (CH ₂) ₄ COOH324 O 1 methyl (CH ₂) ₅ COOH325 O 2 phenyl (CH ₂) ₆COOH326 O 23,4,5-trimethoxyphenyl CH ₂COOH327 O 23,4,5-trimethoxyphenyl CH ₂Tetrazyl

Table X LIII numbering n X D R₂         R ₁328 1 S singly-bound COOH phenyl 329 1 O singly-bound COOH α-methylbenzyl 330 2 O singly-bound COOH 4-methyl Bian base 331 1 O singly-bound Si Zuo base Bian base 332 1 O singly-bound SO₃H α-methylbenzyl 333 1 O CH₂COOH 4-methyl Bian base 334 1 O singly-bound SO₂HN methyl Bian base 335 1 O singly-bound CN α-methylbenzyl 336 1 O singly-bound PO₃H ₂4-methyl Bian base 337 2 O singly-bound COOH Bian base 338 2 O singly-bound COOH α-methylbenzyl 339 2 O singly-bound COOH 4-methyl Bian base 340 2 S singly-bound COOH 3,4,5-trimethoxy phenyl, 341 2 O singly-bound COOH cyclohexyl 342 2 O singly-bound PO₂H Yi base Yi propyl group 343 2 O singly-bound PO₃H propyl group Yi base 344 2 O singly-bound PO₃(Yi yl)₂The methyl 345 2 O singly-bound methoxyl group Shu butyl 346 1 O singly-bound ethyoxyl Zheng Wu base 347 2 O singly-bound propoxyl group n-hexyl 348 1 O singly-bound butoxy cyclohexyl 349 1 O singly-bound Wu Yang base cyclopenta 350 1 own Yang base of O singly-bound n-heptyl 351 1 O singly-bound methyl mercapto n-octyl 352 1 O singly-bound Yi sulfenyl n-nonyl 353 2 O singly-bound rosickyite base 2-Yin Duo base 354 2 O singly-bound butylthio 2-Fu Nan base 355 2 O singly-bound NHCO methyl 2-Sai Zuo base 356 2 O singly-bound NHCO Yi base 2-Sai fen base 357 1 O CH₂N (methyl)₂2-Bi Ding base 358 1 O (CH₂) ₂N (methyl) Yi base 1,1-dimethyl propyl group 359 1 O (CH₂) ₃CON (methyl)₂1,1-dimethyl propyl group, 360 1 O (CH₂) ₄CONH methyl 1,1-dimethyl propyl group 361 1 O (CH₂) ₅CONH Yi base 1,1-dimethyl propyl group 362 1 O (CH₂) ₆CONH propyl group 1,1-dimethyl propyl group 363 1 O singly-bound CONH (O) methyl Bian base 364 1 O singly-bound CONH (O) Yi base Alpha-Methyl phenyl 365 1 O singly-bound CONH (O) propyl group 4-methyl phenyl 366 1 O (CH₂) ₂COOH Bian base 367 1 O singly-bound COOH Alpha-Methyl phenyl 368 1 O singly-bound COOH 4-methyl phenyl 369 1 O CH₂COOH 1,1-dimethyl propyl group 370 1 O (CH₂) ₂COOH 1,1-dimethyl propyl group 371 1 O (CH₂) ₃COOH 1,1-dimethyl propyl group 372 1 O (CH₂) ₄COOH 1,1-dimethyl propyl group 373 1 O (CH₂) ₅COOH 1,1-dimethyl propyl group 374 1 O (CH₂) ₆COOH Yi propyl group 375 1 O (CH₂) ₇COOH Shu butyl 376 1 O (CH₂) ₈COOH 1,1-dimethyl propyl group 377 1 O (CH₂) ₉COOH Bian base 378 1 O (CH₂) ₁₀COOH 1,1-dimethyl propyl group 379 1 O C₂H ₂COOH cyclohexyl methyl 380 1 O 2-OH, Yi base COOH 1,1-dimethyl propyl group 381 1 O 2-butylidene COOH 1,1-dimethyl propyl group 382 1 S Yi propyl group COOH 1,1-dimethyl propyl group 383 2 S Shu butyl COOH phenyl 384 2 O 2-NO₂-hexyl COOH 1,1-dimethyl propyl group 385 1 O (CH₂) ₂CN 1,1-dimethyl propyl group 386 1 O (CH₂) ₃CN 1,1-dimethyl propyl group 387 3 O singly-bound CONHNHSO₂Methyl Bian base 388 3 O singly-bound CONHNHSO₂Yi base Alpha-Methyl phenyl 389 3 O singly-bound CONHSO₂Methyl 4-methyl phenyl 390 1 O singly-bound CONHNHSO₂Ethylo benzene base 391 2 O singly-bound CON (methyl) CN Alpha-Methyl phenyl 392 1 O singly-bound CON (Yi yl) CN 4-methyl phenyl 393 1 O (CH₂) ₂COOH methyl 394 1 O (CH₂) ₃COOH Yi base 395 1 O (CH₂) ₄COOH Zheng propyl group 396 1 O (CH₂) ₅COOH Shu butyl 397 1 O (CH₂) ₆COOH Wu base 398 1 O (CH₂) ₇COOH hexyl 399 1 O (CH₂) ₈COOH heptyl 400 1 O (CH₂) ₉COOH Xin base 401 1 O C₂H ₂COOH cyclohexyl 402 2 O singly-bounds1,1-dimethyl propyl group, 403 1 O singly-bounds

1,1-dimethyl propyl group, 404 1 O singly-bounds

1,1-dimethyl propyl group, 405 1 O singly-bounds

1,1-dimethyl propyl group, 406 1 O singly-bounds1,1-dimethyl propyl group, 407 1 O singly-bounds1,1-dimethyl propyl group, 408 1 O singly-bounds1,1-dimethyl propyl group, 409 1 O singly-bounds

1,1-dimethyl propyl group, 410 1 O singly-bounds

1,1-dimethyl propyl group, 411 1 O singly-bounds

1,1-dimethyl propyl group, 412 1 O singly-bounds

1,1-dimethyl propyl group, 413 1 O singly-bounds1,1-dimethyl propyl group, 414 1 O singly-bounds

1,1-dimethyl propyl group, 415 1 O singly-bounds

1,1-dimethyl propyl group, 416 1 O singly-bounds

1,1-dimethyl propyl group, 417 1 O singly-bounds

1,1-dimethyl propyl group, 418 1 O singly-bounds

1,1-dimethyl propyl group, 419 1 O singly-bounds

1,1-dimethyl propyl group, 420 1 O singly-bounds1,1-dimethyl propyl group, 421 1 O singly-bound COOH 1,1-dimethyl propyl group 422 2 O singly-bound COOH 1,1-dimethyl propyl group

General formula LXV

The preferred embodiment of another kind of the present invention is compound or the acceptable salt of its medicine, ester or the solvate of general formula LXV:

Wherein:

X, Y and Z are independently selected from the group of being made up of C, O, S or N, and its precondition is that X, Y and Z not all are C;

N is 1-3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

A is selected from by L ₁, L ₂, L ₃Or L ₄In the group of being formed, wherein R ₁Be independently selected from by hydrogen, C with E ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

R ₂Isostere for carboxylic acid or carboxylic acid;

The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

This embodiment of the present invention preferred embodiment be R wherein ₂Independently for containing the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded carbocyclic ring or heterocycle, wherein its one or more regioselectivities ground of the atom of any said ring structure is by R ³Replace.

Particularly preferred embodiment of the present invention is to use wherein R ₂Be independently selected from those compounds in following group: Wherein its one or more positions of the atom of said ring structure can be optionally by R ³Replace.

The preferred embodiment of another kind of the present invention is R wherein ₂Be independently selected from by-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³In the group that CN formed.

This embodiment of the present invention preferred embodiment be compound (2S)-1-(phenyl methyl) formamyl-2-methylol (4-thiazolidine); (2S)-1-(1, the 1-dimethyl propyl) formamyl-2-(4-thiazolidine) tetrazolium and (2S)-1-(phenyl methyl) formamyl-2-(4-thiazolidine) carbon nitrile.

Following array structure is the example of the indefiniteness of the preferred carbocyclic ring that reckons with of the present invention and heterocycle isostere:

Wherein its one or more positions of the atom of said ring structure can be optionally by R ³Replace, wherein R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.The present invention expects that when chemical substituting group joins in the isostere of carboxylic acid compound of the present invention still keeps the character of carboxylic acid isostere.Particularly, the present invention expects to work as the isostere of carboxylic acid with being selected from R ³One or more part selectivity when replacing, this substituting group can not be eliminated the carboxylic acid isostere character of The compounds of this invention.The present invention also expects if one or more R ³Substituting group destroys the carboxylic acid isostere character of The compounds of this invention, the one or more R on carbocyclic ring or heterocyclic carboxylic acid isostere so ³Substituent displacement will be not keep or with the carboxylic acid isostere character of The compounds of this invention be that one or more atoms place of one carries out.

The carboxylic acid isostere of other that does not exemplify especially in this manual or describe is also included among the present invention.

Be used for compound of the present invention and be in particular general formula LXV, wherein n is 1, and X is O, and D is a key, R ₁Be 1,1-dimethyl propyl, and R ₂For-CN, called after (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile.

The specific embodiment of the present invention is listed among Table X LIV, XLV and the LXVI.The present invention expects to use the compound of following Table X LIV, XLV and LXVI to be used for the compositions and methods of the invention.

Table X LIV Numbering n D R ₂A Y R ₁423 1 singly-bound COOH H S benzyls, 424 1 singly-bound COOH H S α-Jia Jibianjis, 425 1 singly-bound COOH H S 4-methyl-benzyls, 426 1 singly-bound tetrazolium H S benzyls, 427 1 singly-bound SO ₃H H O α-Jia Jibianji 428 1 CH ₂COOH H O 4-methyl-benzyl 429 1 singly-bound SO ₂HN methyl H O benzyl 430 1 singly-bound CN H N α-Jia Jibianjis 431 1 singly-bound PO ₃H ₂H N 4-methyl-benzyl 432 2 singly-bound COOH H N benzyls 433 2 singly-bound COOH H S α-Jia Jibianjis 434 2 singly-bound COOH H S 4-methyl-benzyls 435 2 singly-bound COOH H S 3,4,5-trimethoxyphenyl 436 2 singly-bound COOH H S cyclohexyl 437 2 singly-bound PO ₂H ethyl H O sec.-propyl 438 2 singly-bound PO ₃H propyl group H O ethyl 439 2 singly-bound PO ₃(ethyl) ₂The H N methyl 440 2 singly-bound methoxyl group H S Shu butyl 441 2 singly-bound ethyoxyl H S Zheng Wu base 442 2 singly-bound propoxyl group H S n-hexyl 443 1 singly-bound butoxy H O cyclohexyl 444 1 singly-bound Wu Yang base H N cyclopenta 445 1 own Yang base of singly-bound H S n-heptyl 446 1 singly-bound methyl mercapto H S n-octyl 447 1 singly-bound Yi sulfenyl H O n-nonyl 448 2 singly-bound rosickyite base H N 2-Yin Duo base 449 2 singly-bound butylthio H O 2-Fu Nan base 450 2 singly-bound NHCO methyl H S 2-Sai Zuo base 451 2 singly-bound NHCO Yi base H S 2-Sai fen base 452 1 CH₂N (methyl) ₂H N 2-pyridyl 453 1 (CH ₂) ₂N (methyl) ethyl H S 1,1-dimethyl propyl 454 1 (CH ₂) ₃CON (methyl) ₂H O 1,1-dimethyl propyl 455 1 (CH ₂) ₄CONH methyl H N 1,1-dimethyl propyl 456 1 (CH ₂) ₅CONH ethyl H S 1,1-dimethyl propyl 457 1 (CH ₂) ₆CONH propyl group H S 1, the 1-dimethyl propyl

Table X LV

Numbering n D R ₂Y R ₁458 singly-bound CONH, (O) methyl S benzyl 459 singly-bound CONH, (O) ethyl S Alpha-Methyl phenyl 460 1 singly-bound CONH, (O) propyl group S 4-aminomethyl phenyl 461 2 singly-bound COOH S benzyls 462 2 singly-bound COOH O Alpha-Methyl phenyl 463 2 singly-bound COOH O 4-aminomethyl phenyls 464 1 CH ₂COOH N benzyl 465 1 (CH ₂) ₂COOH N benzyl 466 1 (CH ₂) ₃COOH N benzyl 467 1 (CH ₂) ₄COOH S benzyl 468 1 (CH ₂) ₅COOH S benzyl 469 1 (CH ₂) ₆COOH S benzyl 470 1 (CH ₂) ₇COOH S benzyl 471 1 (CH ₂) ₈COOH O benzyl 472 1 (CH ₂) ₉COOH O benzyl 473 1 (CH ₂) ₁₀COOH O benzyl 474 1 C ₂H ₂COOH N benzyl 475 1 2-hydroxyethyl COOH N benzyls 476 1 2-butylidene COOH S benzyls 477 1 sec.-propyl COOH S benzyls 478 1 tertiary butyl COOH S benzyls 479 1 2-nitro COOH S benzyl hexyls 480 3 (CH ₂) ₂CN S benzyl 481 1 (CH ₂) ₃CN S benzyl 482 3 singly-bound CONHNHSO ₂Methyl N benzyl 483 3 singly-bound CONHNHSO ₂Ethyl n Alpha-Methyl phenyl 484 3 singly-bound CONHSO ₂Methyl N 4-aminomethyl phenyl 485 2 singly-bound CONHNHSO ₂Ethyl n phenyl 486 2 singly-bound CON (methyl) CN O Alpha-Methyl phenyl 487 2 singly-bound CON (ethyl) CN O 4-aminomethyl phenyls 488 1 (CH ₂) ₂COOH O methyl 489 1 (CH ₂) ₃COOH O ethyl 490 1 (CH ₂) ₄COOH N n-propyl 491 1 (CH ₂) ₅The COOH N tertiary butyl 492 1 (CH ₂) ₆COOH N amyl group 493 1 (CH ₂) ₇COOH S hexyl 494 1 (CH ₂) ₈COOH S heptyl 495 1 (CH ₂) ₉COOH S octyl group 496 1 (CH ₂) ₁₀COOH S nonyl 497 1 C ₂H ₂COOH S cyclohexyl

Table X LVI

Numbering n X D R ₂Y R ₁498 1 O singly-bounds

O 1,1-dimethyl propyl 499 1 O singly-bounds

S 1,1-dimethyl propyl 500 1 O singly-bounds

S 1,1-dimethyl propyl 501 1 O singly-bounds

O 1,1-dimethyl propyl 502 1 O singly-bounds

N 1,1-dimethyl propyl 503 1 O singly-bounds S 1,1-dimethyl propyl 504 1 O singly-bounds

N 1,1-dimethyl propyl 505 1 O singly-bounds N 1,1-dimethyl propyl 506 1 O singly-bounds S 1,1-dimethyl propyl 507 1 O singly-bounds

O 1,1-dimethyl propyl 508 1 O singly-bounds

S 1,1-dimethyl propyl 509 1 O singly-bounds

S 1,1-dimethyl propyl 510 1 O singly-bounds

O 1,1-dimethyl propyl 511 1 O singly-bounds S 1,1-dimethyl propyl 512 1 O singly-bounds

O 1,1-dimethyl propyl 513 1 O singly-bounds S 1,1-dimethyl propyl 514 1 O singly-bounds N 1,1-dimethyl propyl 515 1 O singly-bounds O 1,1-dimethyl propyl 516 1 O singly-bounds

S 1, the 1-dimethyl propyl

Also exemplify compound 517-610 among the present invention, and be defined as the 3-position that wherein Y is positioned at the heterocyclic ring of compound 423-516, and n, A, D, Y, X, R ₁And R ₂Identical with the defined maintenance of compound 423-516 among Table X LIV, XLV and the XLVI.

The compound 611 that exemplifies is defined as the 3-position (3-thiazolidine) that S is positioned at the heterocyclic ring, and n is 1, R ₁Be 1,1-dimethyl propyl, D are a key, R ₂Be COOH.

The compound 612 that exemplifies is defined as the 2-position (2-oxygen pentanoyl) that O is positioned at the heterocyclic ring, and n is 1, R ₁Be 1,1-dimethyl propyl, D are a key, R ₂Be COOH (being 3-(3,3-dimethyl-2-oxygen pentanoyl)-1,3-oxazolidine-4-carboxylic acid).

The present invention also comprises heteroatoms O, the N of heterogeneous ring compound and the ring position that S is positioned at other.The present invention also comprises the heteroatomic heterocycle that contains 3 or more be independently selected from O, N and S.

Table X LVII Numbering n D R ₂L R ₁613 1 CH ₂OH 1,2-dioxo Ethylbenzyl 614 1 singly-bounds-CN 1,2-dioxo ethyl 1,1-dimethyl propyl 615 1 singly-bound tetrazoliums 1,2-dioxo ethyl 1,1-dimethyl propyl 616 2 singly-bound CONH ₂1,2-dioxo ethyl 1,1-dimethyl propyl 617 1 singly-bound COOH 1,2-dioxo ethyl 1,1-dimethyl propyl 618 2 singly-bound COOH 1,2-dioxo ethyl 1,1-dimethyl propyl

General formula LXVI

The preferred embodiment of another kind of the present invention provides compound or the acceptable salt of its medicine, ester or the solvate of general formula LXVI:

Wherein:

N is 1-3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be independently selected from by hydrogen, C with A ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl;

R ₂Be carboxylic acid or carboxylic acid isostere independently;

The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

The preferred compound that is used for this embodiment of the present invention is (2S)-1-(cyclohexyl) formamyl-pyrrolidine 2 carboxylic acid.

Other the preferred compound that is used for this embodiment of the present invention is R wherein ₂Independently for containing the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded carbocyclic ring or heterocyclic compound, wherein its one or more regioselectivities ground of the atom of any said ring structure is by R ³Replace.

Particularly preferred embodiment of the present invention is to use wherein R ₂Be independently selected from those compounds in following group:

Wherein its one or more positions of the atom of said ring structure can be optionally by R ³Replace.

The preferred embodiment of another kind of the present invention is R wherein ₂Be independently selected from by-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³In the group that CN formed.

But " isostere " is meant to have different molecular formula the different compounds that show identical or similar character.For example tetrazolium is a kind of isostere of carboxylic acid, although because they have diverse molecular formula, and the character of tetrazolium imitation carboxylic acid.Tetrazolium is a kind of in many isosteres that may substitute carboxylic acid.Other isostere that belongs to carboxylic acid of the present invention comprises-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³CN, wherein R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

In addition, the isostere of carboxylic acid can comprise the carbocyclic ring of 5-7 unit and contain the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded heterocycle, any atom in the wherein said ring structure can optionally be substituted in one or more positions.Following array structure is the example that belongs to the indefiniteness of preferred carbocyclic ring of the present invention and heterocycle isostere: Atom on the wherein said ring structure can be optionally at one or more position R ³Replace, wherein R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.The present invention expects that when chemical substituting group joins in the isostere of carboxylic acid compound of the present invention still keeps the character of carboxylic acid isostere.

The present invention expects to work as the isostere of carboxylic acid with being selected from R ³One or more part selectivity when replacing, this substituting group can not be eliminated the carboxylic acid isostere character of The compounds of this invention.The present invention also expects if one or more R ³Substituting group destroys the carboxylic acid isostere character of The compounds of this invention, the one or more R on carbocyclic ring or heterocyclic carboxylic acid isostere so ³Substituent displacement will be not keep or with the carboxylic acid isostere character of The compounds of this invention be that one or more atoms place of one carries out.

Compound of the present invention is in particular general formula LXVI, and wherein n is 1, and X is O, and D is a key, R ₁Be 1,1-dimethyl propyl, and R ₂For-CN, called after (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile.

The embodiment of The compounds of this invention is listed among the Table X LVIII.The present invention expects to use the compound of following Table X LVIII to be used for the compositions and methods of the invention.

Table X LVIIINumbering n D R₂       A    R ₁619 1 singly-bound COOH H cyclohexyl 620 1 singly-bound COOH H α-methylbenzyl 621 1 singly-bound COOH H 4-methyl Bian base 622 1 singly-bound Si Zuo H Bian base 623 1 singly-bound SO₃H H α-methylbenzyl 624 1 CH₂COOH H 4-methyl Bian base 625 1 singly-bound SO₂HN methyl H Bian base 626 1 singly-bound CN H α-methylbenzyl 627 1 singly-bound PO₃H ₂H 4-methyl Bian base 628 2 singly-bound COOH H Bian base 629 2 singly-bound COOH H α-methylbenzyl 630 2 singly-bound COOH H 2-butyl 631 2 singly-bound COOH H 2-butyl 632 2 singly-bound COOH H cyclohexyl 633 2 singly-bound PO₂H Yi base H Yi propyl group 634 2 singly-bound PO₃H propyl group H Yi base 635 2 singly-bound PO₃(Yi yl)₂The H methyl 636 2 singly-bound methoxyl group H Shu butyl 637 2 singly-bound ethyoxyl H Zheng Wu base 638 2 singly-bound propoxyl group H n-hexyl 639 1 singly-bound butoxy H cyclohexyl 640 1 singly-bound Wu Yang base H cyclopenta 641 1 own Yang base of singly-bound H n-heptyl 642 1 singly-bound methyl mercapto H n-octyl 643 1 singly-bound Yi sulfenyl H n-hexyl 644 2 singly-bound rosickyite base H n-hexyl 645 2 singly-bound butylthio H n-hexyl 646 2 singly-bound NHCO methyl H n-hexyl 647 2 singly-bound NHCO Yi base H 2-Sai fen base 648 1 CH₂N (methyl)₂H adamantyl 649 1 (CH₂) ₂N (methyl) Yi base H adamantyl 650 1 (CH₂) ₃CON (methyl)₂H adamantyl 651 1 (CH₂) ₄CONH methyl H adamantyl 652 1 (CH₂) ₅CONH Yi base H adamantyl 653 1 (CH₂) ₆CONH propyl group H adamantyl 654 1 singly-bound CONH (O) methyl H Bian base 655 1 singly-bound CONH (O) Yi base H Alpha-Methyl phenyl 656 1 singly-bound CONH (O) propyl group H 4-methyl phenyl 657 2 singly-bound COOH H Bian base 658 2 singly-bound COOH H Alpha-Methyl phenyl 659 2 singly-bound COOH H 4-methyl phenyl 660 1 CH₂COOH methylcyclohexyl 661 1 (CH₂) ₂COOH Yi basic ring hexyl 662 1 (CH₂) ₃COOH propyl group cyclohexyl 663 1 (CH₂) ₄COOH butyl cyclohexyl 664 1 (CH₂) ₅COOH H cyclohexyl 665 1 (CH₂) ₆COOH H cyclohexyl 666 1 (CH₂) ₇COOH H cyclohexyl 667 1 (CH₂) ₈COOH H cyclohexyl 668 1 (CH₂) ₉COOH H cyclohexyl 669 1 (CH₂) ₁₀COOH H cyclohexyl 670 1 C₂H ₂COOH H cyclohexyl 671 1 2-Qiang base Yi base COOH H cyclohexyl 672 1 2-butylidene COOH H cyclohexyl 673 1 Yi propyl group COOH H cyclohexyl 674 1 Shu butyl COOH H cyclohexyl 675 1 2-Xiao base hexyl COOH H cyclohexyl 676 3 (CH₂) ₂CN H cyclohexyl 677 1 (CH₂) ₃CN H cyclohexyl 678 3 singly-bound CONHNHSO₂Methyl H Bian base 679 3 singly-bound CONHNHSO₂Yi base H Alpha-Methyl phenyl 680 3 singly-bound CONHSO₂Methyl H 4-methyl phenyl 681 2 singly-bound CONHNHSO₂Yi base H phenyl 682 2 singly-bound CON (methyl) CN H Alpha-Methyl phenyl 683 2 singly-bound CON (Yi yl) CN H 4-methyl phenyl 684 1 (CH₂) ₂COOH H methyl 685 1 (CH₂) ₃COOH H Yi base 686 1 (CH₂) ₄COOH H Zheng propyl group 687 1 (CH₂) ₅COOH H Shu butyl 688 1 (CH₂) ₆COOH H Wu base 689 1 (CH₂) ₇COOH H hexyl 690 1 (CH₂) ₈COOH H heptyl 691 1 (CH₂) ₉COOH H Xin base 692 1 (CH₂) ₁₀COOH H Ren base 693 1 C₂H ₂COOH H cyclohexyl 694 1 singly-bounds

H cyclohexyl 695 1 singly-boundsH cyclohexyl 696 1 singly-bounds

H cyclohexyl 697 1 singly-bounds

H cyclohexyl 698 1 singly-bounds

H cyclohexyl 699 1 singly-bounds

H cyclohexyl 700 1 singly-bounds

H cyclohexyl 701 1 singly-boundsH cyclohexyl 702 1 singly-bounds

H cyclohexyl 703 1 singly-bounds

H cyclohexyl 704 1 singly-bounds

H cyclohexyl 705 1 singly-bounds

H cyclohexyl 706 1 singly-boundsH cyclohexyl 707 1 singly-bounds

H cyclohexyl 708 1 singly-bounds

H cyclohexyl 709 1 singly-boundsH cyclohexyl 710 1 singly-bounds

H cyclohexyl 711 1 singly-boundsH cyclohexyl 712 1 singly-bounds

H cyclohexyl Table I LNumbering n D R₂   L                R ₁ 713    1  CH ₂OH 1, and the 2-dioxy is for Ethylbenzyl 714 1 singly-bounds-CN 1, and the 2-dioxy is for Yi base 1, and 1-dimethyl propyl group 715 1 singly-bound Si Zuo 1,2-dioxy are for Yi base 1,1-dimethyl propyl group 716 2 singly-bound CONH₂1,2-dioxy is for Yi base 1, and 1-dimethyl propyl group 717 1 singly-bound COOH 1,2-dioxy are for Yi base 1, and 1-dimethyl propyl group 718 2 singly-bound COOH 1,2-dioxy are for Yi base 1,1-dimethyl propyl group Tong Shi LXVII

The preferred embodiment of another kind of the present invention is compound or the acceptable salt of its medicine, ester or the solvate of general formula LXVII: Wherein:

N is 1-3;

Main ring structure optionally comprises Br, wherein Br is heterocyclic bridged loop section, main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

R ₁Be independently selected from by hydrogen, C ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl;

R ₂Be carboxylic acid or carboxylic acid isostere independently;

The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

Preferred embodiment of the present invention is to use wherein R ₂Independently for containing the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded carbocyclic ring or heterocyclic compound, wherein its one or more regioselectivities ground of any atom of said ring structure is by R ³Replace.

The particularly preferred embodiment of The compounds of this invention is to use wherein R ₂Be independently selected from those compounds in following group:

Wherein its one or more positions of the atom of said ring structure can be optionally by R ³Replace.

The preferred embodiment of another kind of the present invention is R wherein ₂Be independently selected from by-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³In the group that CN formed.

Preferred embodiment of the present invention is a following compounds: (2S)-and 1-(phenyl methyl) alkylsulfonyl-2-hydroxymethyl pyrrolidine; (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine tetrazolium; (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carbon nitrile; With compound 719-821.

But " isostere " is meant to have different molecular formula the different compounds that show identical or similar character.For example tetrazolium is a kind of isostere of carboxylic acid, although because they have diverse molecular formula, and the character of tetrazolium imitation carboxylic acid.Tetrazolium is a kind of in many isosteres that may substitute carboxylic acid.Other isostere that belongs to carboxylic acid of the present invention comprises-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³CN, wherein R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.

In addition, the isostere of carboxylic acid can comprise the carbocyclic ring of 5-7 unit and contain the CH that is in any chemically stable oxidation state ₂, O, S or N any bonded heterocycle, any atom in the wherein said ring structure can optionally be substituted in one or more positions.Following array structure is the example that belongs to the indefiniteness of preferred carbocyclic ring of the present invention and heterocycle isostere. Atom on the wherein said ring structure can be optionally at one or more position R ³Replace.The present invention expects that when chemical substituting group joins in the isostere of carboxylic acid compound of the present invention still keeps the character of carboxylic acid isostere.

The present invention expects to work as the isostere of carboxylic acid with being selected from R ³One or more part selectivity when replacing, this substituting group can not be eliminated the carboxylic acid isostere character of The compounds of this invention.The present invention also expects if one or more R ³Substituting group destroys the carboxylic acid isostere character of The compounds of this invention, the one or more R on carbocyclic ring or heterocyclic carboxylic acid isostere so ³Substituent displacement will be not keep or with the carboxylic acid isostere character of The compounds of this invention be that one or more atoms place of one carries out.

The carboxylic acid isostere of other that does not exemplify especially in this manual or describe is also included among the present invention.

Compound of the present invention is in particular general formula LXVII, and wherein n is 1, and D is a key, R ₁Be phenyl methyl, and R ₂For-CN, called after (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carbon nitrile.

The specific embodiment of the present invention is listed among table L and the LI.The present invention expects to use the compound of following table L and LI to be used for the compositions and methods of the invention.

Table L

Numbering n D R ₂R ₁719 1 singly-bound COOH benzyls, 720 1 singly-bound COOH α-Jia Jibianjis, 721 1 singly-bound COOH 4-methyl-benzyls, 722 1 singly-bound tetrazolium benzyls, 723 1 singly-bound SO ₃H α-Jia Jibianji 724 1 CH ₂COOH 4-methyl-benzyl 725 1 singly-bound SO ₂HN methyl-benzyl 726 1 singly-bound CN α-Jia Jibianjis 727 1 singly-bound PO ₃H ₂4-methyl-benzyl 728 2 singly-bound COOH benzyls 729 2 singly-bound COOH α-Jia Jibianjis 730 2 singly-bound COOH 4-methyl-benzyls 731 2 singly-bound COOH 3,4,5-trimethoxyphenyl 732 2 singly-bound COOH cyclohexyl 733 2 singly-bound PO ₂H ethyl sec.-propyl 734 2 singly-bound PO ₃H propyl group ethyl 735 2 singly-bound PO ₃(ethyl) ₂The methyl 736 2 singly-bound methoxyl group Shu butyl 737 2 singly-bound ethyoxyl Zheng Wu base 738 2 singly-bound propoxyl group n-hexyl 739 1 singly-bound butoxy cyclohexyl 740 1 singly-bound Wu Yang base cyclopenta 741 1 own Yang base of singly-bound n-heptyl 742 1 singly-bound methyl mercapto n-octyl 743 1 singly-bound Yi sulfenyl n-nonyl 744 2 singly-bound rosickyite base 2-Yin Duo base 745 2 singly-bound butylthio 2-Fu Nan base 746 2 singly-bound NHCO methyl 2-Sai Zuo base 747 2 singly-bound NHCO Yi base 2-Sai fen base 748 1 CH₂N (methyl) ₂2-pyridyl 749 1 (CH ₂) ₂N (methyl) Ethylbenzyl 750 1 (CH ₂) ₃CON (methyl) ₂Benzyl 751 1 (CH ₂) ₄CONH methyl-benzyl 752 1 (CH ₂) ₅CONH Ethylbenzyl 753 1 (CH ₂) ₆CONH propyl group 1,1-dimethyl propyl 754 1 singly-bound CONH (O) methyl-benzyls 755 1 singly-bound CONH (O) ethyl Alpha-Methyl phenyl 756 1 singly-bound CONH (O) propyl group 4-aminomethyl phenyls 757 2 singly-bound COOH benzyls 758 2 singly-bound COOH Alpha-Methyl phenyl 759 2 singly-bound COOH 4-aminomethyl phenyls 760 1 CH ₂COOH benzyl 761 1 (CH ₂) ₂COOH benzyl 762 1 (CH ₂) ₃COOH benzyl 763 1 (CH ₂) ₄COOH benzyl 764 1 (CH ₂) ₅COOH benzyl 765 1 (CH ₂) ₆COOH benzyl 766 1 (CH ₂) ₇COOH benzyl 767 1 (CH ₂) ₈COOH benzyl 768 1 (CH ₂) ₉COOH benzyl 769 1 (CH ₂) ₁₀COOH benzyl 770 1 C ₂H ₂The COOH benzyl

1 2-hydroxyl second COOH benzyl 771

Base 772 1 2-butylidene COOH benzyls 773 1 sec.-propyl COOH benzyls 774 1 tertiary butyl COOH benzyls

The own COOH benzyl 775 of 1 2-nitro

Base 776 3 (CH ₂) ₂CN benzyl 777 1 (CH ₂) ₃CN benzyl 778 3 singly-bound CONHNHSO ₂Methyl-benzyl 779 3 singly-bound CONHNHSO ₂Ethyl Alpha-Methyl phenyl 780 3 singly-bound CONHSO ₂Methyl 4-aminomethyl phenyl 781 2 singly-bound CONHNHSO ₂Ethylphenyl 782 2 singly-bound CON (methyl) CN Alpha-Methyl phenyl 783 2 singly-bound CON (ethyl) CN 4-aminomethyl phenyls 784 1 (CH ₂) ₂COOH methyl 785 1 (CH ₂) ₃COOH ethyl 786 1 (CH ₂) ₄COOH n-propyl 787 1 (CH ₂) ₅The COOH tertiary butyl 788 1 (CH ₂) ₆COOH amyl group 789 1 (CH ₂) ₇COOH hexyl 790 1 (CH ₂) ₈COOH heptyl 791 1 (CH ₂) ₉COOH octyl group 792 1 (CH ₂) ₁₀COOH nonyl 793 1 C ₂H ₂COOH cyclohexyl 794 1 singly-bounds

Benzyl 795 1 singly-bounds

Benzyl 796 1 singly-bounds

Benzyl 797 1 singly-bounds

Benzyl 798 1 singly-bounds

Benzyl 799 1 singly-bounds

Benzyl 800 1 singly-bounds

Benzyl 801 1 singly-bounds

Benzyl 802 1 singly-bounds Benzyl 803 1 singly-bounds

Benzyl 804 1 singly-bounds Benzyl 805 1 singly-bounds

Benzyl 806 1 singly-bounds

Benzyl 807 1 singly-bounds Benzyl 808 1 singly-bounds Benzyl 809 1 singly-bounds Benzyl 810 1 singly-bounds Benzyl 811 1 singly-bounds

Benzyl 812 1 singly-bounds

Benzyl 813 1 singly-bound CH ₂OH benzyl 814 1 singly-bound CONH ₂Benzyl 815 1 singly-bound CN benzyls

Table LI Numbering n D R ₂L R ₁816 1 CH ₂OH 1,2-dioxo Ethylbenzyl 817 1 singly-bounds-CN 1,2-dioxo ethyl 1,1-dimethyl propyl 818 1 singly-bound tetrazoliums 1,2-dioxo ethyl 1,1-dimethyl propyl 819 2 singly-bound CONH ₂1,2-dioxo ethyl 1,1-dimethyl propyl 820 1 singly-bound COOH 1,2-dioxo ethyl 1,1-dimethyl propyl 821 2 singly-bound COOH 1,2-dioxo ethyl 1,1-dimethyl propyl The compounds of this invention synthetic

The compound that is used for method and composition of the present invention can adopt the general synthetic route that describes below to prepare easily by vitochemical standard technique.

In the preparation of The compounds of this invention, it will be appreciated by those skilled in the art that when desired response when another part of molecule carries out, the different activities functional group of starting raw material or intermediate can protect or block.After desired response is finished, perhaps in any time of hope, these blocking groups generally will pass through, and for example, hydrolysis or hydrogenolysis means remove.This protection and deprotection steps are conventional in organic chemistry.Those skilled in the art can be with reference to " blocking group in the organic chemistry ", McOmie, ed., Plenum Press, New York, NewYork; " blocking group in the organic synthesis ", Greene, ed., John Wiley﹠amp; Sons, New York, the instruction of relevant blocking group among the N.Y. (1981), they can be used for the preparation of The compounds of this invention.

Product and intermediate can adopt the purification technique of one or more standards to carry out isolated or purified, comprise, for example, one or more simple solvent evaporations, recrystallization, distillation, distillation, filtration, chromatography comprise tlc, HPLC (as reversed-phase HPLC) method, column chromatography, flash chromatography method, radial chromatography, grinding or the like.

As described in response path I, the cyclic amino acid 1 with suitable blocking group P protection on amino acid whose nitrogen can react with mercaptan RSH, generates monothioester 2.After removing blocking group, free amine 3 can generate last urea or thiocarbamide respectively with multiple isocyanic ester or lsothiocyanates reaction.

Response path I

Isocyanic ester (R ' NCO) or lsothiocyanates (R ' NCS) 4 can be easily from the corresponding amine that obtains easily by preparing with carbonyl chloride or thiophosgene reaction, II describes as response path.

Response path II

Mercaptan R-SH can be prepared by two step substitution reactions of sulphur by halogenide from corresponding alcohol that obtains easily or halogenide easily, and III describes as response path.Halogenide can react with thiocarbamide, and corresponding alkyl thiourea salt hydrolysis obtains mercaptan RSH.If as parent material, can at first they be converted into corresponding halogenide by standard method with alcohol.

Response path III

The compound of general formula X X to XXIV can adopt the general synthetic route that describes below to prepare easily by vitochemical standard method.As described in response path IV, the cyclic amino acid 1 with suitable blocking group P protection on amino acid whose nitrogen can react with mercaptan RSH, generates monothioester 2.After removing blocking group, free amine 3 can generate last product 5 with good productive rate with multiple SULPHURYL CHLORIDE 4 reactions.

Response path IV

Mercaptan R-SH can be prepared by two step substitution reactions of sulphur by halogen from corresponding alcohol that obtains easily or halogenide easily, and V describes as response path.Halogenide can react with thiocarbamide, and corresponding alkyl thiourea salt hydrolysis obtains mercaptan RSH.If as parent material, can at first they be converted into corresponding halogenide by standard method with alcohol.

Response path V

The compound of general formula X XV to XXIX can be prepared by the various synthetic order that is used to set up chemical transformation.The general route such as the response path VI that are used for The compounds of this invention describe.N-(1,2-dioxo ethyl) proline derivative can be by preparing L-proline methyl ester and the reaction of methyl oxalyl chloride, and VI describes as response path.The gained oxamate can obtain midbody compound with various carbon nucleophile reactions.With these intermediates and various alcohol, acid amides or the reaction of protected amino-acid residue, obtain propyl ester of the present invention and acid amides then.

Response path VI

The prepared in various methods that the alcohol that replaces can be known by organic synthesis field those of ordinary skill.As described in response path VII, alkyl or aryl aldehyde can obtain various anti-cinnamates by turning to phenyl propanol with (triphenyl-positive phosphinidene) methyl acetate reaction homology; The latter can by with excessive lithium hydride reactive aluminum, perhaps then the reduction reaction of double bond reduction reaction by shortening and the saturated ester by appropriate reductant is reduced to saturated alcohol.Perhaps also can be that anti-cinnamate can be reduced to (E)-allylic alcohol by using diisobutyl aluminium hydride.

Response path VII

Alcohol than long-chain can be by phenyl aldehyde and the more homologation preparation of high-grade aldehyde.Perhaps these aldehyde can be by corresponding toluylic acid and more high-grade acid and phenylethyl alcohol and the more preparation that is converted of high-grade alcohol.

General synthetic being shown among response path VIII and the IX of the carboxylic acid isostere of general formula LXV:

N-(1,2-dioxo ethyl) proline derivative can be by preparing L-proline methyl ester and the reaction of methyl oxalyl chloride, and VIII describes as response path.The gained oxamate can obtain being used for compound of the present invention with various carbon nucleophile reactions, and IX describes as response path.

Response path VIII

Response path IX

The compound of general formula LXV can prepare easily by the general synthetic route that is used for derovatives, sulfone amide derivative and urea or carbamate derivatives that vitochemical standard method is shown in response path X.

Cyclic amino acid 1 with suitable blocking group P protection on amino acid whose nitrogen can react with mercaptan RSH, generates monothioester 2.After removing blocking group, free amine 3 can generate last urea or thiocarbamide respectively with multiple isocyanic ester or lsothiocyanates reaction.

Response path X

The response path that another kind is used for preparing urea or carbamate is shown in following response path XI.

Response path XI

Isocyanic ester (R ' NCO) or lsothiocyanates (R ' NCS) can be easily from the corresponding amine that obtains easily by preparing with carbonyl chloride or thiophosgene reaction, describe as following response path XII.

Response path XII

Mercaptan R-SH can be prepared by two step substitution reactions of sulphur by halogenide from corresponding alcohol that obtains easily or halogenide easily, describes as following response path XIII.Halogenide can react with thiocarbamide, and corresponding alkyl thiourea salt hydrolysis obtains mercaptan RSH.If as parent material, can at first they be converted into corresponding halogenide by standard method with alcohol.

Response path XIII

N-(1,2-dioxo ethyl) proline derivative can be described as following response path XIV by L-proline methyl ester and the reaction of methyl oxalyl chloride are prepared.The gained oxamate can obtain compound of the present invention or be used for compound of the present invention with various carbon nucleophile reactions.

Response path XIV

The synthesis path that is used to prepare sulfone amide derivative is well known in the art, and compound of the present invention can adopt response path as shown below to synthesize.

Response path XV

Response path XVI

The general synthetic of the carboxylic acid isostere of general formula LXVI can be finished by the various synthetic order that is used to set up chemical transformation.The example such as the response path XVII that are used for a kind of general route of synthetic The compounds of this invention describe.

Response path XVII

The compound of general formula LXVII can prepare by the various synthetic order that is used to set up chemical transformation.Being used for the example of general route of synthetic these compounds such as response path XVIII, XIX and XX describes.

Response path XVIII

Response path XIX

Response path XX

Avidity to FKBP12

The compound that is used for the inventive method and pharmaceutical composition can have the avidity to the conjugated protein particularly FKBP12 of FK506.The restraining effect of prolyl peptidyl cis-trans isomerization enzymic activity that can measure FKBP is as the index of this avidity.K _iProcess of the test

To the combination of FKBP12 be used for the inventive method and the active restraining effect of peptidyl prolyl cis-trans isomerization enzyme (rotamerism enzyme) of the compound of pharmaceutical composition can be passed through document (Harding etc., Nature, 1989,341:758-760; Holt etc., J.Am.Chem.Soc., 115:9923-9938) the middle currently known methods of describing is estimated.These numerical value obtain with the form of apparent Ki and the numerical value of representational compound is listed among the Table I X-XVI.

In the Quimotrase coupling is measured, at the model reaction thing N-succinyl--Ala-Ala-proline(Pro)-phenylalanine-cis-trans isomerizationization of the L-Ala in the p-nitroanilide-proline(Pro) key is detected by spectrophotometric analysis, from the reactant of transoid, discharge p-nitroanilide.Measured the restraining effect that causes by the inhibitor that adds different concns, as the function of the variation of main rate constant data have been analyzed, obtained apparent K with inhibitor concentration to this reaction _iValue.

In the plastics cuvette, add 950 milliliters of ice-cold mensuration damping fluid (25mMHEPES, pH7.8,100mM NaCl), (2.5mM is at the Tris-Cl of the pH7.5 of 10mM for 10 milliliters of FKBP, 100mM NaCl, in the 1mM dithiothreitol (DTT)), the test compounds of 25 milliliters of Quimotrases (50mg/ml is in 1mM HCl) and 10 milliliters of different concns in methyl-sulphoxide.By adding 5 milliliters of reactants (N-succinyl--L-Ala-phenylalanine-proline(Pro)-phenylalanine-to p-nitroanilide, 5mg/ml is in the Halothane solution of 2.35mM LiCl).

The absorption that detects 390nm place in time of 90 seconds with spectrophotometer is to time relation, from the numerical evaluation rate constant of absorption to the time.

Table LII vitro test result-Shi I to XIV compound K _i(nM) 1 31 2 210 3 85 9 10410 1211 29912 44214 31328 10829 5930 1131 8.732 36233 169834 3435 6236 737 6838 8.939 34740 122641 36642 2843 25944 18845 3146 757

47???????????????????????21

48???????????????????????127

49???????????????????????1334

50???????????????????????55

51???????????????????????33

52???????????????????????6

53???????????????????????261

54???????????????????????37

55???????????????????????30

56???????????????????????880

57???????????????????????57

58???????????????????????79

59???????????????????????962

60???????????????????????90

61???????????????????????139

62???????????????????????196

63???????????????????????82

64???????????????????????163

65???????????????????????68

66???????????????????????306

67???????????????????????177

68???????????????????????284

69???????????????????????49

70???????????????????????457

71???????????????????????788

80???????????????????????215

The parent of 81 638 embodiment 6 (not oxidation) compound 7.5

95 (embodiment 6) 225

Table LIII vitro test result-Shi XV to XXIV compound K _i(nM)101 +++102 ++103 ++104 ++105 ++106 +107 ++108 +++109 +++110 +++111 ++112 +++113 +++114 +++115 +++116 ++117 +++118 ++119 ++120 ++121 ++122 +123 ++124 +++125 +++126 +++127 ++128 +++129 +++130 +++131 +++132 ++

The relative capacity of compound grades according to following grade: ++ ++ expression K _iOr ED50 is less than 1nM; +++expression K _iOr ED50 is 1-50nM; ++ expression K _iOr ED50 is 51-200nM; + expression K _iOr ED50 is 201-500nM.

Table LIV

Vitro test result-Shi XXV to XXIX numbering Z R ₁K _i137 1,1-dimethyl propyl 3-phenyl propyl 42,138 1,1-dimethyl propyl 3-phenyl-third-2-(E)-thiazolinyl 125,139 1,1-dimethyl propyl 3-(3,4, the 5-trimethoxyphenyl) propyl group 200,140 1,1-dimethyl propyl 3-(3,4, the 5-trimethoxyphenyl)-third-2-(E)-thiazolinyl 65,141 1,1-dimethyl propyl 3-(4,5-methylene radical dioxy base) phenyl propyl 170,142 1,1-dimethyl propyl 3-(4,5-methylene radical dioxy base) phenyl third-2-(E)-thiazolinyl 160,143 1,1-dimethyl propyl 3-cyclohexyl propyl group 200,144 1,1-dimethyl propyl 3-cyclohexyl third-2-(E)-thiazolinyl 600,145 1,1-dimethyl propyl (1R)-1,3-phenylbenzene-1-propyl group 52146 2-furyl 3-phenyl propyl 4000147 2-thienyl 3-phenyl propyl 92148 2-thiazolyl 3-phenyl propyl 100149 phenyl 3-phenyl propyl 1,970,150 1,1-dimethyl propyl 3-(2, the 5-dimethoxy) phenyl propyl 250,151 1,1-dimethyl propyl 3-(2, the 5-dimethoxy) phenyl third-2-(E)-thiazolinyl 450,152 1,1-dimethyl propyl 2-(3,4, the 5-trimethoxyphenyl) ethyl 120,153 1,1-dimethyl propyl 3-(3-pyridyl) propyl group 5,154 1,1-dimethyl propyl 3-(2-pyridyl) propyl group 195,155 1,1-dimethyl propyl 3-(4-pyridyl) propyl group 23156 cyclohexyl 3-phenyl propyl 82157 tertiary butyl 3-phenyl propyl 95158 cyclohexyl ethyl 3-phenyl propyl 1025159 cyclohexyl ethyl 3-(3-pyridyl) propyl group 1400160 tertiary butyl 3-(3-pyridyl) propyl group 3,161 1,1-dimethyl propyl 3,3-diphenyl propyl 5162 cyclohexyl 3-(3-pyridyl) propyl group 9163 2-thienyl 3-(3-pyridyl) propyl group 1000164 tertiary butyls 3,3-diphenyl propyl 5165 cyclohexyl 3,3-diphenyl propyl 20166 2-thienyls 3,3-diphenyl propyl 150

Table LV vitro test result-Shi XXXIII to LIV compound K _i(mM) the parkinsonian MPTP Mo Xing of 172 140,175 13,177 170,178 250,179 25,181 17,185 12202＞10,000,207 1300216＞10,000,255 1,800,256 28,257 39,258 75,259 70,260 165,261 740,262 725,263 130,264 30,265 60,266 15,267 12,268 120,269 20,270 103,271 760,272 210,273 32,274 2,275 24,276 5 mouse

The dopaminergic neuronic MPTP infringement of mouse is as parkinsonian animal model.4 weeks, big male CD1 white mouse carried out 5 days peritoneal injection medication with the MPTP of 30mg/kg.The compounds of this invention (4mg/kg), perhaps vehicle is carried out 5 days subcutaneous administration with MPTP, and is ending to carry out after MPTP handles 5 days use again.Carrying out the MPTP processing after 18 days, kill this animal, and cutting striatum and homogenate.With anti-tyrosine hydroxylase Ig sagging and crown brain section is carried out immunostaining, with dopaminergic neuronic survival of quantitative assay and recovery.When handling this animal, compare a large amount of losses of observing functional dopaminergic end with the animal that does not have infringement with MPTP and vehicle.In another record, test compound is only used after MPTP induces infringement.Therefore, after animal was handled 5 days with MPTP, the back began oral drug therapy at the 8th day in the past at other 3 days.This animal is with The compounds of this invention oral administration (4mg/kg), totally 5 days once a day.In the time of the 18th day, kill this animal and also analyze according to the method described above.Table LVI provides the dopaminergic neuronic recovery percentage ratio in first (parallel taking) example in the animal of having accepted carboxylic acid or carboxylic acid isostere.

Following table LVI has shown the tangible neuron regeneration effect of the related compound of carboxylic acid of the present invention or carboxylic acid isostere, described the neurotrophy ability of carboxylic acid isostere, shown that the undermined animal capable of having accepted carboxylic acid or carboxylic acid isostere compounds produces the soiled dopaminergic neuronic obvious recovery of TH-as a time-like.

Table LVI-MPTP neurodegeneration model

Recovery rate %

Compd A 26.7%

Compd B ND

Compound C 24.4%

Compound D 23.2%

Compd E 19.6%

Compound F 17-hydroxy-corticosterone 34.1%

Compound G 46.5%

Compound H 14.0%

Compound I ND

With the quantitative assay of anti-tyrosine hydroxylase immunoglobulin (Ig) the percentage ratio of the striatal neural distribution density in the brain section, the dopaminergic neurone of its deixis.Only with the vehicle pre-treatment and during handling the striatal neural distribution density of oral vectorial animal be 23%, showing not have normally the striatum tissue that damages.With the MPTP pre-treatment and during handling the striatal neural distribution density of oral vectorial animal be reduced to 5%, show that MPTP has brought out infringement.Surprisingly, with the MPTP pre-treatment and during handling the striatal neural distribution density of the animal of oral 0.4mg/kg compound increase 8-13%, showing after having brought out the MPTP infringement has substantial neuron regeneration.

Embodiment

The following examples are description of this invention, but are not limitation of the invention.Except as otherwise noted, all percentage ratios all are as 100 weight % benchmark with last compound.Synthetic (the 2S)-2-({ 1-oxo-5-phenyl }-amyl group) of embodiment 1-1-(3,3-dimethyl-1,2-dioxo amyl group) tetramethyleneimine (1) (2S)-2-(1-oxo-4-phenyl) butyl-N-benzyl-pyrrole alkane

1-chloro-4 phenyl butanes (1.78 grams; 10.5 mmole) be dissolved in 20 milliliters of tetrahydrofuran THFs, add among the THF of 50 milliliters of backflows that contain 0.24 gram (10 mmole) magnesium cutting object.After adding, mixture refluxed 5 hours again, slowly added subsequently in the reflux solution of N-benzyl-L-ethyl prolinate (2.30 grams, 10 mmoles) in 100 milliliters of THF.After refluxing again 2 hours, mixture cooling and with 5 milliliters 2N salt acid treatment.Reaction mixture dilutes with ether (100 milliliters), and uses saturated sodium bicarbonate, water and salt water washing.The organic phase drying concentrates and chromatographic separation, and with 5: 1 ethylene dichloride: eluent ethyl acetate obtained the 2.05 buttery ketone (64%) that restrain. ¹H?NMR(CDCl ₃，300MHz)：d1.49-2.18(m，8H)；2.32-2.46(m，1H)；2.56-2.65(m，2H)；2.97-3.06(m，1H)；3.17-3.34(m，1H)；3.44-3.62(m，1H)；4.02-4.23(m，2H)7.01-7.44(m，10H)。(2S)-2-(1-oxo-4-phenyl) butyl pyrrolidine

Hydrogenation spends the night under 40 bar pressures in the Paar vibrator with described ketone compound (500 milligrams) and palladium hydroxide (loading on the carbon 20%, 50 milligram).Remove by filter catalyzer, and solvent removed in vacuo.Obtain (230 milligrams of yellow oily unhindered aminas; 100%). ¹H?NMR(CDCl ₃，300MHz)：d1.75-2.34(m，10H)；2.55(m，2H)；2.95(dm，1H)；3.45-3.95(m，1H)；4.05(m，1H)；7.37(m，5H)。(2S)-2-(1-oxo-4-phenyl) butyl-1-(1,2-dioxo-2-methoxy ethyl) tetramethyleneimine

Under 0 ℃, to (230 milligrams of (2S)-2-(1-oxo-4-phenyl) butyl pyrrolidines; 1.0 drip (135 milligrams of methyl oxalyl chlorides in ethylene dichloride mmole) (20 milliliters) solution; 1.1 mmole).Stirring is after 3 hours down at 0 ℃, and reaction stops with saturated ammonium chloride solution, organic phase water and salt water washing, drying and concentrated.With the silicagel column thick residue of purifying, with 20: 1 ethylene dichloride: eluent ethyl acetate obtains 300 milligrams clarification buttery barkite (98%). ¹HNMR (CDCl ₃, 300MHz): d 1.68 (m, 4H); 1.91-2.38 (m, 4H); 2.64 (t, 2H); 3.66-3.80 (m, 2H); 3.77,3.85 (s, 3H amounts to); 4.16 (m, 2H); 4.90 (m, 1H); 7.16 (m, 3H); 7.27 (m, 2H).(2S)-2-({ 1-oxo-5-phenyl }-amyl group)-1-(3,3-dimethyl-1,2-dioxo amyl group) tetramethyleneimine (1)

(250 milligrams of above-mentioned barkites; 0.79 anhydrous diethyl ether mmole) (15 milliliters) solution is cooled to-78 ℃, adds chlorination 1 then, 1-dimethyl propyl magnesium (0.8 milliliter 1.0M diethyl ether solution; 0.8 mmole).The gained mixture adds 2 milliliters of saturated ammonium chloride solution termination reactions after-78 ℃ are stirred 2 hours, add 100 milliliters of ethyl acetate subsequently.Organic phase salt water washing, drying concentrates and purifies with silicagel column, and with 50: 1 ethylene dichloride: eluent ethyl acetate obtained 120 milligrams clarification oily compound (1). ¹H?NMR(CDCl ₃，300MHz)：d0.87(t，3H，J＝7.5)；1.22(s，3H)；1.25(s，3H)；1.67(m，4H)；1.70-2.33(m，6H)；2.61(t，2H，J＝7.1)；3.52(m，2H)；4.17(t，2H，J＝6.2)；4.52(m，1H)；7.16-7.49(m，5H)。C ₂₂H ₃₁NO ₃-H ₂The calculated value of O ultimate analysis: C, 70.37; H, 8.86; N, 3..73.Actual measurement: C, 70.48; H, 8.35; N, 3.69.The synthetic 1-(3,3-dimethyl-1,2-dioxo amyl group) of embodiment 2-2-piperidines thiocarboxylic acid 2-phenyl-1-ethyl esters (10) (2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters

L-proline methyl ester hydrochloride (3.08 grams; 18.60 anhydrous methylene chloride solution mmole) is cooled to 0 ℃ also with triethylamine (3.92 grams; 38.74 mmole; 2.1 equivalent) handle.Under nitrogen atmosphere, stir formed slurry 15 minutes, drip methyl oxalyl chloride (3.20 grams; 26.12 methylene dichloride mmole) (45 milliliters) solution.The gained mixture stirred 1.5 hours at 0 ℃.After the solids removed by filtration, organic phase washes with water, uses dried over mgso and concentrated.Use the silicagel column thick residue of purifying,, obtain 3.52 gram red oily products (88%) with the hexane wash-out that contains 50% ethyl acetate.The mixture of suitable-anti-amic rotational isomer; Provide the data of trans rotational isomer. ¹H NMR (CDCl ₃): d1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79,3.84 (s, 3H amounts to); (4.86 dd, 1H, J=8.4,33).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters

(2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters (2.35 grams; 10.90 30 milliliters of THF solution mmole) are cooled to-78 ℃, use 14.2 milliliters 1.0M chlorination 1 then, the THF solution-treated of 1-dimethyl propyl magnesium.The gained uniform mixture is after-78 ℃ are stirred 3 hours, in the mixture impouring saturated ammonium chloride solution (100 milliliters) and use ethyl acetate extraction.Organic phase washes with water, and drying concentrates and removes the crude product that desolvates and purifies with silicagel column, obtains the colorless oil barkite of 2.10 grams (75%) with the hexane wash-out that contains 25% ethyl acetate. ¹H NMR (CDCl ₃): d0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); (4.52 dm, 1H, J=8.4,3.4).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid

(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters (2.10 grams; 8.23 mmole), 1N lithium hydroxide (15 milliliters), and the mixture of methyl alcohol (50 milliliters) at room temperature stirs subsequently and spends the night 0 ℃ of following stirring 30 minutes.Mixture is 1 with the 1N hcl acidifying to the pH value, dilute with water, 100 milliliters of dichloromethane extractions.Organic extract salt water washing obtains snow-white solid 1.73 grams (87%), and need not to purify after concentrating. ¹H NMR (CDCl ₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); (3.53 dd, 2H, J=10.4,7.3); (4.55 dd, 1H, J=8.6,4.1).1-(3,3-dimethyl-1,2-dioxo amyl group)-2-piperidines thiocarboxylic acid 2-phenyl-1-ethyl ester (10)

With (226 milligrams of dicyclohexyl carbodiimides; 1.1 mmole) add (241 milligrams of (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid; 1.0 in ethylene dichloride mmole) (10 milliliters) solution.The gained mixture stirred 5 minutes, and solution is cooled to 0 ℃, and with containing (138 milligrams of phenyl mercaptan; 1.0 mmole) and 5 milliliters of dichloroethane solutions of 4-dimethylamino pyridine (6 milligrams) handle.Mixture can be in stirred overnight at room temperature.Solids removed by filtration and vacuum concentrated filtrate; Crude product separates (10: 1 hexane: ethyl acetate) obtain the oily compound (10) of 320 milligrams (84%) with flash chromatography. ¹H?NMR(CDCl ₃，300MHz)：d0.85(t，3H，J＝7.5)；1.29(s，3H)；1.31(s，3H)；1.70-2.32(m，6H)；2.92(t，2H，J＝7.4)；3.22(t，2H，J＝7.4)；3.58(m，2H)；4.72(m，1H)；7.23-7.34(m，5H)。C ₂₀H ₂₇NO ₃S-0.4H ₂The calculated value of O ultimate analysis: C, 65.15; H, 7.60; N, 3.80.Actual measurement: C, 65.41; H, 7.49; N, 3.72.Embodiment 3 synthetic (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 2-phenyl-1-ethyl ester (9) 1-(1,2-dioxo-2-methoxy ethyl)-2 piperidine carboxylic acid methyl esters

Nipecotic acid methyl esters hydrochloride (8.50 grams; 47.31 anhydrous methylene chloride mmole) (100 milliliters) solution is cooled to 0 ℃, and (10.5 restrain with triethylamine; 103 mmoles; 2.1 equivalent) handle.Under nitrogen atmosphere, stir formed slurry 15 minutes, drip methyl oxalyl chloride (8.50 grams; 69.4 methylene dichloride mmole) (75 milliliters) solution.Reaction mixture stirred 1.5 hours at 0 ℃.After the solids removed by filtration, organic phase washes with water, uses dried over mgso and concentrated.Use the silicagel column thick residue of purifying,, obtain 9.34 gram (86%) red oily products with the hexane wash-out that contains 50% ethyl acetate.The mixture of suitable-anti-amic rotational isomer; Provide the data of trans rotational isomer. ¹HNMR (CDCl ₃): d1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m, 1H); 3.55 (m, 1H); 3.76 (s, 3H); 3.85,3.87 (s, 3H amounts to); 4.52 (dd, 1H).1-(1,2-dioxo-3,3-dimethyl amyl group)-2 piperidine carboxylic acid methyl esters

1-(1,2-dioxo-2-methoxy ethyl)-2 piperidine carboxylic acid methyl esters (3.80 grams; 16.57 the solution of 75 milliliters of THF mmole) is cooled to-78 ℃, uses 20.7 milliliters 1.0M chlorination 1 then, the THF solution-treated of 1-dimethyl propyl magnesium.The gained uniform mixture is after-78 ℃ are stirred 3 hours, mixture impouring saturated ammonium chloride solution (100 milliliters) and use ethyl acetate extraction.Organic phase washes with water, and drying concentrates and removes the crude product that desolvates and purifies with silicagel column, obtains the colorless oil barkite of 3.32 grams (74%) with the hexane wash-out that contains 25% ethyl acetate. ¹H NMR (CDCl ₃): d0.88 (t, 3H); 1.21,1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41 (m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).1-(1,2-dioxo-3,3-dimethyl amyl group)-2 piperidine carboxylic acid

1-(1,2-dioxo-3,3-dimethyl amyl group)-2 piperidine carboxylic acid methyl esters (3.30 grams; 12.25 mmole), 1N lithium hydroxide (15 milliliters), and the mixture of methyl alcohol (60 milliliters) at room temperature stirs subsequently and spends the night 0 ℃ of following stirring 30 minutes.Mixture is 1 with the 1N hcl acidifying to the pH value, dilute with water, 100 milliliters of dichloromethane extractions.Organic extract salt water washing obtains snow-white solid 2.80 grams (87%), and need not to purify after concentrating. ¹H NMR (CDCl ₃): d0.89 (t, 3H); 1.21,1.24 (s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42 (m, 1H); 5.31 (d, 1H).(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-tetramethyleneimine thiocarboxylic acid 2-phenyl-1-ethyl ester (9)

With (226 milligrams of dicyclohexyl carbodiimides; 1.1 mmole) join (255 milligrams of 1-(1,2-dioxo-3,3-dimethyl amyl group)-2 piperidine carboxylic acid; 1.0 in ethylene dichloride mmole) (10 milliliters) solution.The gained mixture stirred 5 minutes, and solution is cooled to 0 ℃, and with containing (138 milligrams of phenyl mercaptan; 1.0 mmole) and 5 milliliters of dichloroethane solutions of 4-dimethylamino pyridine (6 milligrams) handle.Mixture can at room temperature stir and spend the night.Solids removed by filtration and vacuum concentrated filtrate; Crude product separates (10: 1 hexane: ethyl acetate) obtain the oily compound (9) of 300 milligrams (80%) with flash chromatography. ¹H?NMR(CDCl ₃，300MHz)：d0.94(t，3H，J＝7.5)；1.27(s，3H)；1.30(s，3H)；1.34-1.88(m，7H)；2.45(m，1H)；2.90(t，2H，J＝7.7)；3.26(t，2H，J＝7.7)；3.27(m，1H)；3.38(m，1H)；5.34(m，1H)；7.24-7.36(m，5H)。C ₂₁H ₂₉NO ₃The calculated value of S ultimate analysis: C, 67.17; H, 7.78; N, 3.73.Actual measurement: C, 67.02; H, 7.83; N, 3.78.Embodiment 4 synthetic (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-(4-thiazolidine) carboxylic acid 3-phenyl-1-propyl ester (80) 1-(1,2-dioxo-2-methoxy ethyl) 2-(4-thiazolidine) carboxylicesterss

L-sulphur proline(Pro) (1.51 grams; 11.34 the solution of anhydrous methylene chloride mmole) (40 milliliters) is cooled to 0 ℃, and (2.41 restrain with 3.3 milliliters of triethylamines; 23.81 mmole) handle.Mixture stirred 30 minutes, dripped methyl oxalyl chloride (1.81 grams; 14.74 solution mmole).Reaction mixture stirred 1.5 hours at 0 ℃.Remove after the solid by diatomite filtration, dry and concentrate.Use the silicagel column thick residue of purifying,, obtain 2.0 gram orange barkites with the methylene dichloride wash-out that contains 10% methyl alcohol.(2S)-1-(1,2-dioxo-2-methoxy ethyl) 2-(4-thiazolidine) carboxylic acid 3-phenyl-1-propyl ester

(500 milligrams of 1-(1,2-dioxo-2-methoxy ethyl)-2-(4-thiazolidine) carboxylicesters; 2.25 mmole), 3-phenyl-1-propyl alcohol is (465 milligrams; 3.42 mmole), dicyclohexyl carbodiimide is (750 milligrams; 3.65 mmole), the 4-dimethylamino pyridine is (95 milligrams; 0.75 mmole) and (175 milligrams of camphorsulfonic acids; 0.75 mmole) in 30 milliliters methylene dichloride, stir and spend the night.Remove solid by diatomite filtration, and chromatographic separation (25% ethyl acetate/hexane) obtains 690 milligrams of materials. ¹H?NMR(CDCl ₃，300?MHz)：d1.92-2.01(m，2H)；2.61-2.69(m，2H)；3.34(m，1H)；4.11-4.25(m，2H)；4.73(m，1H)；5.34(m，1H)；7.12(m，3H)；7.23(m，2H)。(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-(4-thiazolidine) thiocarboxylic acid 3-phenyl-1-propyl ester (80)

(2S)-(670 milligrams of 1-(1,2-dioxo-2-methoxy ethyl) 2-(4-thiazolidine) carboxylic acid 3-phenyl-1-propyl ester; 1.98 the solution of 10 milliliters of THF mmole) is cooled to-78 ℃, uses 2.3 milliliters 1.0M chlorination 1 then, the diethyl ether solution of 1-dimethyl propyl magnesium is handled.Mixture mixture impouring saturated ammonium chloride solution, and was used ethyl acetate extraction after stirring 3 hours.Organic phase washes with water, and drying concentrates and crude product is purified with silicagel column, obtains the compound of 380 milligrams yellow oily embodiment 4 with the hexane wash-out that contains 25% ethyl acetate. ¹HNMR(CDCl ₃，300MHz)：d0.86(t，3H)；1.21(s，3H)；1.26(s，3H)；1.62-1.91(m，3H)；2.01(m，2H)；2.71(m，2H)；3.26-3.33(m，2H)；4.19(m，2H)；4.58(m，1H)；7.19(m，3H)；7.30(m，2H)。C ₂₀H ₂₇NO ₄The calculated value of S ultimate analysis: C, 63.63; H, 7.23; N, 3.71.Actual measurement: C, 64.29; H, 7.39; N, 3.46.Embodiment 5 (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-(4-thiazolidine) carboxylic acid 3-(3-pyridyl)-1-propyl ester (81)

According to the compound of the synthetic embodiment 5 of the method for embodiment 4, in the end a step is used 3-(3-pyridyl)-1-propyl alcohol, obtains (2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-2-(4-thiazolidine) carboxylic acid 3-(3-pyridyl)-1-propyl ester. ¹H?NMR(CDCl ₃，300MHz)：d0.89(t，3H，J＝7.3)；1.25(s，3H)；1.28(s，3H)；1.77(q，2H，J＝7.3)；2.03(tt，2H，J＝6.4，7.5)；2.72(t，2H，J＝7.5)；3.20(dd，1H，J＝4.0，11.8)；3.23(dd，1H，J＝7.0，11.8)；4.23(t，2H，J＝6.4)；4.55(d，2H，J＝8.9)；5.08(dd，1H，J＝4.0，7.01)；7.24(m，1H)；8.48(m，2H)。C ₁₉H ₂₆N ₂O ₄S-0.5H ₂The calculated value of O ultimate analysis: C, 58.89; H, 7.02; N, 7.23.Actual measurement: C, 58.83; H, 7.05; N, 7.19.Synthetic (the 2S)-1-(3,3-dimethyl-1,2-dioxo amyl group) of embodiment 6-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, N-oxide compound (95) (2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters

L-proline methyl ester hydrochloride (3.08 grams; 18.60 anhydrous methylene chloride solution mmole) is cooled to 0 ℃ also with triethylamine (3.92 grams; 38.74 mmole; 2.1 equivalent) handle.Under nitrogen atmosphere, stir formed slurry 15 minutes, drip methyl oxalyl chloride (3.20 grams; 26.12 methylene dichloride mmole) (45 milliliters) solution.Reaction mixture stirred 1.5 hours at 0 ℃.After the solids removed by filtration, organic phase washes with water, uses dried over mgso and concentrated.Use the silicagel column thick residue of purifying,, obtain 3.52 gram (88%) red oily products with the hexane wash-out that contains 50% ethyl acetate.The mixture of the rotational isomer of suitable-anti-acid amides; Provide the data of trans rotational isomer. ¹H NMR (CDCl ₃): d1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79,3.84 (s, 3H amounts to); (4.86 dd, 1H, J=8.4,3.3).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters

(2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters (2.35 grams; 10.90 30 milliliters of THF solution mmole) are cooled to-78 ℃, use 14.2 milliliters 1.0M chlorination 1 then, the THF solution-treated of 1-dimethyl propyl magnesium.The uniform mixture of gained is after-78 ℃ are stirred 3 hours, mixture impouring saturated ammonium chloride solution (100 milliliters) and use ethyl acetate extraction.Organic phase washes with water, and drying concentrates, and removes the crude product that desolvates and purify with silicagel column, obtains the colorless oil barkite of 2.10 grams (75%) with the hexane wash-out that contains 25% ethyl acetate. ¹H NMR (CDCl ₃): d 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); (4.52 dm, 1H, J=8.4,3.4).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid

(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters (2.10 grams; 8.23 mmole), 1N lithium hydroxide (15 milliliters), and the mixture of methyl alcohol (50 milliliters) at room temperature stirs subsequently and spends the night 0 ℃ of following stirring 30 minutes.Mixture is 1 with the 1N hcl acidifying to the pH value, dilute with water, 100 milliliters of dichloromethane extractions.Organic extract salt water washing obtains snow-white solid 1.73 grams (87%), and need not to purify after concentrating. ¹H NMR (CDCl ₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); (3.53 dd, 2H, J=10.4,7.3); (4.55 dd, 1H, J=8.6,4.1).(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester

(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid (4.58 grams; 19 mmoles), 3-pyridine propyl alcohol (3.91 grams; 28.5 dicyclohexyl carbodiimide (6.27 grams mmole); 30.4 camphorsulfonic acid (1.47 grams mmole); 6.33 mmole) and (773 milligrams of 4-dimethylamino pyridines; 6.33 mmole) in 100 milliliters methylene dichloride, stir under the nitrogen atmosphere and spend the night.Reaction mixture is removed the solid final vacuum by diatomite filtration and is concentrated.Crude product grinds with several parts of ether, and the ether part is removed the solid final vacuum by diatomite filtration and concentrated.Spissated filtrate obtains 5.47 gram colorless oil GPI1046 (partially hydrated) with flash chromatography post purification (the component wash-out contains 25% ethyl acetate/hexane to pure ethyl acetate). ¹H NMR (CDCl ₃, 300MHz): d0.85 (t, 3H); 1.23,1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53 (m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45.C ₂₀H ₂₈NO ₄-0.25H ₂The calculated value of O ultimate analysis: C, 65.82; H, 7.87; N, 7.68.Actual measurement: C, 66.01; H, 7.85; N, 7.64.(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, N-oxide compound (95)

(2S)-(190 milligrams of 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester; 0.52 mmole) and-chlorine peroxybenzoic acid (material of 160 milligrams 57-86%, 0.53 mmole) stirred under the room temperature 3 hours in methylene dichloride (20 milliliters).Reaction mixture dilutes with methylene dichloride, and washs secondary with the 1N sodium hydroxide solution.Organic extract is dry and concentrate, and the crude product chromatographic separation with the eluent ethyl acetate that contains 10% methyl alcohol, obtains the compound 95 among 130 milligrams the embodiment 6. ¹H?NMR(CDCl ₃，300MHz)：d?0.83(t，3H)；1.21(s，3H)；1.25(s，3H)；1.75-2.23(m，8H)；2.69(t，2H，J＝7.5)；3.52(t，2H，J＝6.3)；4.17(dd，2H，J＝6.3)；4.51(m，1H)；7.16-7.22(m，2H)；8.06-8.11(m，2H)。C ₂₀H ₂₈N ₂O ₅-0.75H ₂The calculated value of O ultimate analysis: C, 61.60; H, 7.63; N, 7.18.Actual measurement: C, 61.79; H, 7.58; N, 7.23.Embodiment 7 synthetic (2S)-1-[(2-methyl butyls) carbamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester (101) 3-(3-pyridyl)-1-propyl chloride

To 3-(3-pyridyl)-1-propyl alcohol (10 grams; 72.4 be added dropwise to thionyl chloride (12.9 grams in chloroform mmole) (100 milliliters) solution; 108.6 chloroform mmole) (50 milliliters) solution.The gained mixture refluxed 1 hour, in ice-cold 50% potassium hydroxide aqueous solution (150 milliliters) of impouring subsequently.Be separated, the organic phase drying concentrates and purifies with silicagel column, with the hexane wash-out that contains 40% ethyl acetate, obtains the clarification oily muriate of 10 grams (65%). ¹H?NMR(CDCl ₃，300?MHz)：d?2.02-2.11(m，2H)；2.77(m，2H)；3.51(m，2H)；7.20(m，1H)；7.49(m，1H)；8.45(m，2H)。3-(3-pyridyl)-1-propyl group mercaptan

3-(3-pyridyl)-1-propyl chloride (3 grams; 19.4 mmole) and thiocarbamide (1.48 the gram; 19.4 mmole) mixture in ethanol (10 milliliters) refluxed 24 hours.The 0.75N aqueous sodium hydroxide solution that adds 15 milliliters, mixture continue to reflux 2 hours.Cool to room temperature, solvent removed in vacuo.With containing the hexane wash-out of 50% ethyl acetate, the chromatographic separation thick mercaptan product of purifying obtains 1.2 gram clarified liq 3-(3-pyridyl)-1-propyl group mercaptan on silicagel column. ¹H?NMR(300MHz，CDCl ₃)：d?1.34(m，1H)；1.90(m，2H)；2.52(m，2H)；2.71(m，2H)；7.81(m，1H)；7.47(m，1H)；8.42(m，2H)。N-(uncle's fourth oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester

N-(uncle's fourth oxygen carbonic acyl radical)-(S)-L-proline(Pro) (3.0 grams; 13.9 3-(3-pyridyl)-1-propyl group mercaptan (3.20 grams mmole); 20.9 dicyclohexyl carbodiimide (4.59 grams mmole); 22.24 camphorsulfonic acid (1.08 grams mmole); 4.63 mmole) and the 4-dimethylamino pyridine (0.60 the gram; 4.63 mmole) mixture in 100 milliliters anhydrous methylene chloride stirs and spends the night.Reaction mixture dilutes with methylene dichloride (50 milliliters) and water (100 milliliters), and is separated.Dried over mgso is used in organic phase water (3 * 100 milliliters) washing, concentrates.Thick residue is purified with the pure ethyl acetate wash-out on silicagel column, obtains the heavy-gravity oily thioesters of 4.60 grams (95%). ¹HNMR(300MHz，CDCl ₃)：d1.45(s，9H)；1.70-2.05(m，5H)；2.32(m，1H)；2.71(t，2H)；2.85(m，2H)；3.50(m，2H)；4.18(m，1H)；7.24(m，1H)；7.51(m，1H)；8.48(m，2H)。Tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester

N-(uncle's fourth oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester (4.60 grams; 13.1 mmole) stirred 3 hours under the solution room temperature in methylene dichloride (60 milliliters) and trifluoroacetic acid (6 milliliters).Adding saturated potassium carbonate is alkalescence until the pH value, reaction mixture dichloromethane extraction three times.Merge organic extract liquid, drying obtains 2.36 gram heavy-gravity oily free amines (75%) after concentrating. ¹H NMR (300MHz, CDCl ₃): d1.87-2.20 (m, 6H); 2.79 (m, 2H); (3.03-3.15 m, 4H amounts to); 3.84 (m, 1H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57 (m, 2H).2S-1-[(2-methyl-butyl) carbamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester (101)

To contain (113 milligrams of 2-methylbutylamines; 1.3 mmole) and (132 milligrams of triethylamines; 1.3 adding, methylene dichloride mmole) (5 milliliters) solution contains (128 milligrams of triphosgene; 0.43 in methylene dichloride mmole) (5 milliliters) solution.The gained mixture refluxed 1 hour, then cool to room temperature.Add and to contain (300 milligrams of tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester; 1.3 methylene dichloride mmole) (5 milliliters) solution, gained mixture continue to stir 1 hour, water and 1: 1 ethyl acetate and the mixture of hexane distribute again.The organic phase drying concentrates and purifies (50% ethyl acetate/hexane) with column chromatography, obtains the compound (compound 101, Table VII) of 250 milligrams of (55%) oily embodiment 7. ¹H?NMR(CDCl ₃，300MHZ)：d0.89-0.93(m，6H)；1.10-1.20(m，1H)；1.27(s，1H)；1.36-1.60(m，2H)；1.72(s，2H)；1.97-2.28(m，6H)；2.70-2.75(m，2H)；2.92-3.54(m，6H)；4.45-4.47(m，1H)；7.21-7.29(m，1H)；7.53-7.56(dd，1H)；8.46-8.48(s，2H)。Embodiment 8 Synthetic 2 S-1-[(1 ', 1 '-dimethyl propyl) carbamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-propyl ester (102)

According to the description of embodiment 7,, obtain the compound (compound 102, Table VII) of embodiment 8 with tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester and the isocyanate reaction that produces by uncle's amylamine and triphosgene. ¹H?NMR(CDCl ₃，300MHZ)：d0.83(t，3H)；1.27(s，6H)；1.64-1.71(m，2H)；1.91-2.02(m，7H)；2.66-2.71(t，2H)；2.85(m，2H)；3.29-3.42(m，2H)；4.11(br，1H)；4.37-4.41(m，1H)。Embodiment 9 Synthetic 2 S-1-[(cyclohexyl) thiocarbamyl] tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester (107)

(120 milligrams of cyclohexyl lsothiocyanates; 0.9 mmole), tetramethyleneimine-2-carboxylic acid 3-(3-pyridyl)-1-rosickyite ester is (200 milligrams; 0.9 mmole) and (90 milligrams of triethylamines; 0.9 mmole) mixture in 20 milliliters of methylene dichloride stirred 1 hour, and water and 1: 1 the ethyl acetate and the mixture distribution of hexane.The organic phase drying concentrates and purifies (50% ethyl acetate/hexane) with column chromatography, obtains the compound (compound 107, Table VII) of 160 milligrams of (47%) embodiment 9. ¹H?NMR(CDCl ₃，300MHZ)：d1.16-1.40(m，6H)；1.50-1.71(m，4H)；1.95-2.08(m，7H)；2.70-2.75(t，2H)；3.03(m，2H)；3.40-3.60(m，2H)；4.95-4.98(d，1H)；5.26-5.29(d，1H)；7.17-7.25(m，1H)。Embodiment 10 synthetic (2S)-N-(benzenesulfonyl) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-rosickyite ester (120) 3-(p-methoxyphenyl)-1-propyl bromides

3-(p-methoxyphenyl)-1-propyl alcohol (16.6 grams; 0.1 250 milliliters of toluene solutions mole) are cooled to 0 ℃, drip 26 milliliters of phosphorus tribromides (0.27 mole) then.After dropwising, reaction is at room temperature stirred and was carried out 1 hour, refluxes 1 hour again.In the reactant cooling back impouring ice, be separated, organic phase is washed with saturated sodium bicarbonate (3X) and salt solution (3X).Drying, the crude product that boils off solvent carries out chromatographic separation with 10% ethyl acetate/hexane wash-out, obtains 3-(the p-methoxyphenyl)-1-propyl bromide of 14 grams (61%).3-(p-methoxyphenyl)-1-propyl group mercaptan

3-(p-methoxyphenyl)-1-propyl bromide (14 grams; 61 mmoles) and thiocarbamide (5.1 the gram; 67 mmoles) mixture in ethanol (150 milliliters) refluxed 48 hours.Boil off solvent and obtain transparent glassy compound, it is dissolved in 50 ml waters, and handle with 100 milliliter of 40% aqueous sodium hydroxide solution.The gained mixture continues to stir 2 hours.Product merges organic extract liquid with extracted with diethyl ether (3X), with sodium bicarbonate and salt water washing, drying concentrates, and uses the hexane wash-out that contains 2% ether on silicagel column, the crude product of chromatographic separation purification mercaptan obtains 10.2 gram clarified liq 3-(p-methoxyphenyl)-1-propyl group mercaptan. ¹H?NMR(300MHz，CDCl ₃)：d?1.34(t，1H)；1.88-1.92(m，2H)；2.49-2.53(m，2H)；2.64-2.69(m，2H)；3.77(s，3H)；6.80-6.84(m，2H)；7.06-7.24(m，2H)。N-(uncle's fourth oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters

N-(uncle's fourth oxygen carbonic acyl radical)-(S)-proline(Pro) (2.0 grams; 9.29 3-(p-methoxyphenyl)-1-propyl group mercaptan (1.86 grams mmole); 10.22 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide hydrochloride (1.96 grams mmole); 10.22 mmole) and the mixture of 4-dimethylamino pyridine (catalytic amount) in 50 milliliters anhydrous methylene chloride stir and to spend the night.Reaction mixture dilutes with methylene dichloride (50 milliliters) and water (100 milliliters), and is separated.Dried over mgso is used in organic phase water (3 * 100 milliliters) washing, concentrates, and obtains the heavy-gravity oily product of 3.05 grams (100%). ¹H?NMR(300MHz，CDCl ₃)：d1.15(s，9H)；1.84-2.31(m，6H)；2.61(m，2H)；2.83(m，2H)；3.51(m，2H)；3.75(s，3H)；6.79(d，2H，J＝8.04)；7.05(m，2H)。Tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters

N-(uncle's fourth oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters (3.0 grams; 8.94 mmole) stirred 3 hours under the solution room temperature in methylene dichloride (60 milliliters) and trifluoroacetic acid (6 milliliters).Adding saturated potassium carbonate is alkalescence until the pH value, reaction mixture dichloromethane extraction (3X).Merge organic extract liquid, drying obtains 1.73 gram heavy-gravity oily free amines (69%) after concentrating. ¹H?NMR(300?MHz，CDCl ₃)：d1.80-2.23(m，6H)；2.62(m，2H)；2.81(m，2H)；3.01(m，2H)；3.75(s，3H)；3.89(m，1H)；6.81(m，2H)；7.06(m，2H)。(2S)-N-(benzenesulfonyl) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-rosickyite ester (120)

To contain (567 milligrams of tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters; 2.03 mmole) and (358 milligrams of benzene sulfonyl chlorides; 2.03 (290 milligrams of diisopropylethylamine of methylene dichloride mmole) (5 milliliters) solution; 2.23 mmole) handle, and at room temperature stir and spend the night.The reaction mixture solids removed by filtration, and directly use silicagel column, the hexane wash-out with containing 25% ethyl acetate obtains 540 milligrams compound 120 (Table VIII). ¹H?NMR(300MHz，CDCl ₃)：d1.65-1.89(m，6H)；2.61(t，2H，J＝7.3)；2.87(t，2H，J＝7.6)；3.26(m，1H)；3.54(m，1H)；3.76(s，3H)；4.34(dd，1H，J＝2.7，8.6)；6，79(d，2H，J＝8.7)；7.06(d，2H，J＝8.6)；7.49-7.59(m，3H)；7.86(dd，2H，J＝1.5，6.8)。Embodiment 11 synthetic (2S)-N-(a-tosyl group) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-rosickyite esters (121)

To contain (645 milligrams of tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters; 2.30 mmole) and (440 milligrams of a-toluene sulfonyl chlorides; 2.30 (330 milligrams of diisopropylethylamine of methylene dichloride mmole) (5 milliliters) solution; 2.53 mmole) handle, and at room temperature stir and spend the night.Obtain the compound 121 (Table VIII) of embodiment 11 according to the description purification of embodiment 10. ¹HNMR(300MHz，CDCl ₃)：d1.65-2.25(m，8H)；2.65(t，2H)；2.89-2.96(m，2H)；3.55-3.73(m，2H)；3.80(s，3H)；4.32(s，2H)；4.70-4.81(m，1H)；6.83(d，2H)；7.09(d，2H)；7.14(m，3H)；7.26(m，2H)。Embodiment 12 (Synthetic 2 S)-N-(p-toluenesulfonyl) tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-rosickyite ester (122)

To contain (645 milligrams of tetramethyleneimine-2-carboxylic acid 3-(p-methoxyphenyl)-1-thioesters; 2.30 mmole) and (425 milligrams of Tosyl chlorides; 2.23 (330 milligrams of diisopropylethylamine of methylene dichloride mmole) (5 milliliters) solution; 2.53 mmole) handle, and at room temperature stir and spend the night.Obtain the compound 122 (Table VIII) of embodiment 12 according to the description purification of embodiment 10. ¹HNMR(300MHz，CDCl ₃)：d1.67-1.94(m，6H)；2.40(s，3H)；2.61(t，2H，J＝7.3)；2.84(m，2H，J＝7.2)；3.22(m，1H)；3.52(m，1H)；3.76(s，3H)；4.32(dd，1H，J＝2.9，8.5)；6.79(d，2H，J＝6.5)；7.07(d，2H，J＝6.5)；7.29(d，2H，J＝6.5)；7.74(d，2H，J＝6.5)。Embodiment 13 synthetic N-(p-toluenesulfonyl) nipecotic acids 1,5-phenylbenzene-3-penta thioesters (134) 3-phenyl-1-propionic aldehyde

Oxalyl chloride (2.90 grams; 2.29 methylene dichloride mmole) (50 milliliters) solution is cooled to-78 ℃, with the solution-treated of methyl-sulphoxide (3.4 milliliters) in 10 milliliters of methylene dichloride.Stir after 5 minutes, add 3-phenyl-1-propyl alcohol (2.72 grams; 20 mmoles) solution in 20 milliliters of methylene dichloride, the gained mixture stirred 15 minutes at-78 ℃, and with 14 milliliters of triethylamines processing, restir 15 minutes is then in impouring 100 ml waters.Be separated, organic phase is dry and concentrated, and thick resistates is purified with containing the hexane wash-out of 10% ethyl acetate on silicagel column, obtains the clarification oily aldehyde of 1.27 grams (47%). ¹H?NMR(300MHz，CDCl ₃)：d2.80(m，2H)；2.98(m，2H)；7.27(m，5H)；9.81(2，1H)。1,5-phenylbenzene-3-amylalcohol

2-(bromotrifluoromethane) benzene (1.73 grams; 9.33 add under ether mmole) (10 milliliters) solution stirring and contain (250 milligrams of magnesium cutting objects; 10.18 in 5 milliliters of ether mmole).Reaction causes with heat gun, and the reinforced back mixture that finishes heated 30 minutes with oil bath.Add and contain 3-phenyl-1-propionic aldehyde (1.25 grams; 9.33 10 milliliters of ether mmole) continue to reflux 1 hour.The reactant cooling, and, use ethyl acetate extraction 2 times with the saturated ammonium chloride termination, merging organic phase, drying concentrates.(hexane that contains 10% ethyl acetate) chromatography is purified on silicagel column, obtains the phenylbenzene alcohol of 1.42 grams (63%). ¹H?NMR(300MHz，CDCl ₃)：d1.84(m，4H)；2.61-2.76(m，4H)；3.65(m，1H)；7.19-7.29(m，10H)。1,5-phenylbenzene-3-bromo pentane silane

Under 0 ℃, triphenylphosphine (1.31 grams; 5 mmoles) adding contains 1 in batches, 5-phenylbenzene-3-amylalcohol (1.20 grams; 5 moles) and carbon tetrabromide (1.67 grams; 5 mmoles) in methylene dichloride (20 milliliters) solution.At room temperature stirred 18 hours, mixture grinds solids removed by filtration after concentrating with ether.Filtrate is by layer of silica gel, with 10: 1 hexane: the methylene dichloride wash-out, obtain the oily bromide of 1.35 grams (90%), need not purification. ¹H?NMR(300MHz，CDCl ₃)：d?2.11-2.18(m，4H)；2.73(m，2H)；2.86(m，2H)；3.95(m，1H)；7.16-7.30(m，10H)。1,5-phenylbenzene-3-amyl mercaptan

Method according to embodiment 10 changes into mercaptan with bromide, and 1,5-phenylbenzene-3-bromo pentane silane changes into 1,5-phenylbenzene-3-amyl mercaptan, total recovery 35%. ¹H?NMR(300MHz，CDCl ₃)：d?1.79(m，2H)；1.98(m，2H)；2.71(m，3H)；2.80(m，2H)；7.16-7.28(m，10H)。N-(uncle-Ding oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 1,5-phenylbenzene-3-amyl group thioesters

N-(uncle-Ding oxygen carbonic acyl radical)-(S)-nipecotic acid (2.11 grams; 9.29 mmole), 1,5-phenylbenzene-3-amyl mercaptan (2.58 grams; 10.22 the hydrochloride of 1-(3-dimethylamino-propyl)-3-ethyl carbodiimide (1.96 grams mmole); 10.22 mmole) and the mixture of 4-dimethylamino pyridine (catalytic amount) in 50 milliliters anhydrous methylene chloride stir and to spend the night.Reaction mixture dilutes with methylene dichloride (50 milliliters) and water (100 milliliters), and is separated.Dried over mgso is used in organic phase water (3 * 100 milliliters) washing, concentrates, and obtains the heavy-gravity oily product of 870 milligrams (20%), need not to purify to use.Tetramethyleneimine-2-carboxylic acid 1,5-phenylbenzene-3-amyl group thioesters

N-(uncle-Ding oxygen carbonic acyl radical) tetramethyleneimine-2-carboxylic acid 1, (850 milligrams of 5-phenylbenzene-3-amyl group thioesters; 1.8 mmole) stirred 3 hours under the solution room temperature in methylene dichloride (10 milliliters) and trifluoroacetic acid (1 milliliter).Adding saturated potassium carbonate is alkalescence until the pH value, the reaction mixture dichloromethane extraction.Merge organic extract liquid, drying obtains 480 milligrams of heavy-gravity oily free amines (72%) after concentrating, and need not to purify and can use.N-(p-toluenesulfonyl) nipecotic acid 1,5-phenylbenzene-3-amyl group thioesters (134)

According to the description of embodiment 12, make tetramethyleneimine-2-carboxylic acid 1, (850 milligrams of 5-phenylbenzene-3-amyl group thioesters; 1.8 mmole) with synthetic N-(p-tosyl group) nipecotic acid 1 of Tosyl chloride reaction, 5-phenylbenzene-3-amyl group thioesters (18), yield 65%. ¹H?NMR(300MHz，CDCl ₃)：d0.80(m，4H)；1.23-1.97(m，5H)；2.15(d，1H)；2.61-2.69(m，4H)；3.23(m，1H)；3.44(dm，1H)；4.27(s，2H)；4.53(d，1H，J＝4.5)；5.06(m，1H)；7.16-7.34(m，15H)。Synthetic (the 2S)-1-(3,3-dimethyl-1,2-dioxo amyl group) of embodiment 14-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester (137) (2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters

L-proline methyl ester hydrochloride (3.08 grams; 18.60 anhydrous methylene chloride solution mmole) is cooled to 0 ℃ also with triethylamine (3.92 grams; 38.74 mmole; 2.1 equivalent) handle.Under nitrogen atmosphere, stir formed slurry 15 minutes, drip methyl oxalyl chloride (3.20 grams; 26.12 methylene dichloride mmole) (45 milliliters) solution.The gained reaction mixture stirred 1.5 hours at 0 ℃.After the solids removed by filtration, organic phase washes with water, uses dried over mgso and concentrated.The use silicagel column is the thick residue of purifying with the hexane wash-out that contains 50% ethyl acetate, obtains 3.52 gram (88%) red oily products.The mixture of suitable-anti-amic rotational isomer; Provide the data of trans rotational isomer. ¹H NMR (CDCl ₃): d1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79,3.84 (s, 3H amounts to); (4.86 dd, 1H, J=8.4,3.3).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters

(2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters (2.35 grams; 10.90 30 milliliters of THF solution mmole) are cooled to-78 ℃, use 14.2 milliliters 1.0M chlorination 1 then, the THF solution-treated of 1-dimethyl propyl magnesium.The gained uniform mixture is after-78 ℃ are stirred 3 hours, mixture impouring saturated ammonium chloride solution (100 milliliters) and use ethyl acetate extraction.Organic phase washes with water, and drying concentrates, and removes the crude product that desolvates and purify with containing the hexane wash-out of 25% ethyl acetate on silicagel column, obtains the colorless oil barkite of 2.10 grams (75%). ¹H NMR (CDCl ₃): d0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); (4.52 dm, 1H, J=8.4,3.4).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid synthetic

(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters (2.10 grams; 8.23 mmole), 1N lithium hydroxide (15 milliliters), and the mixture of methyl alcohol (50 milliliters) at room temperature stirs subsequently and spends the night 0 ℃ of following stirring 30 minutes.Mixture is 1 with the 1N hcl acidifying to the pH value, dilute with water, 100 milliliters of dichloromethane extractions.Organic extract salt water washing obtains snow-white solid 1.73 grams (87%), and need not to purify after concentrating. ¹H NMR (CDCl ₃): d0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); (3.53 dd, 2H, J=10.4,7.3); (4.55 dd, 1H, J=8.6,4.1).(2S)-1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester

(2S)-(600 milligrams of 1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid; 2.49 mmole), 3-phenyl-1-propyl alcohol is (508 milligrams; 3.73 mmole), dicyclohexyl carbodiimide is (822 milligrams; 3.98 mmole), camphorsulfonic acid is (190 milligrams; 0.8 mmole) and (100 milligrams of 4-dimethylamino pyridines; 0.8 mmole) mixture in 20 milliliters methylene dichloride stirs and spends the night.Reaction mixture is removed the solid final vacuum by diatomite filtration and is concentrated.Crude product obtains 720 milligrams of (80%) colorless oil embodiment 14 compounds with flash distillation post purification (containing 25% ethyl acetate/hexane to pure ethyl acetate). ¹H?NMR(CDCl ₃)：d0.84(t，3H)；1.19(s，3H)；1.23(s，3H)；1.70(dm，2H)；1.98(m，5H)；2.22(m，1H)；2.64(m，2H)；3.47(m，2H)；4.14(m，2H)；4.51(d，1H)；7.16(m，3H)；7.26(m，2H)。Embodiment 15

The compound that is used for illustration below the method preparation of use embodiment 14.

Compound 138:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-phenyl-1-third-2-(E)-alkene ester, yield 80%. ¹H?NMR(360MHz，CDCl ₃)：d0.86(t，3H)；1.21(s，3H)；1.25(s，3H)；1.54-2.10(m，5H)；2.10-2.37(m，1H)；3.52-3.55(m，2H)；4.56(dd，1H，J＝3.8，8.9)；4.78-4.83(m，2H)；6.27(m，1H)；6.67(dd，1H，J＝15.9)；7.13-7.50(m，5H)。

Compound 139:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3,4, the 5-trimethoxyphenyl)-1-propyl ester, yield 61%. ¹H?NMR(CDCl ₃)：d?0.84(t，3H)；1.15(s，3H)；1.24(s，3H)；1.71(dm，2H)；1.98(m，5H)；2.24(m，1H)；2.63(m，2H)；3.51(t，2H)；3.79(s，3H)；3.83(s，3H)；4.14(m，2H)；4.52(m，1H)；6.36(s，2H)。

Compound 140:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3,4, the 5-trimethoxyphenyl)-1-third-2-(E)-alkene ester, yield 66%. ¹H?NMR(CDCl ₃)：d?0.85(t，3H)；1.22(s，3H)；1.25(s，3H)；1.50-2.11(m，5H)；2.11-2.40(m，1H)；3.55(m，2H)；3.85(s，3H)；3.88(s，6H)；4.56(dd，1H)；4.81(m，2H)；6.22(m，1H)；6.58(d，1H，J＝16)；6.63(s，2H)。

Compound 141:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-methylenedioxyphenyl)-1-propyl ester, yield 82%. ¹H?NMR(360MHz，CDCl ₃)：d0.86(t，3H)；1.22(s，3H)；1.25(s，3H)；1.60-2.10(m，5H)；3.36-3.79(m，2H)；4.53(dd，1H，J＝3.8，8.6)；4.61-4.89(m，2H)；5.96(s，2H)；6.10(m，1H)；6.57(dd，1H，J＝6.2，15.8)；6.75(d，1H，J＝8.0)；6.83(dd，1H，J＝1.3，8.0)；6.93(s，1H)。

Compound 142:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4, the 5-methylenedioxyphenyl)-1-third-2-(E)-alkene ester, yield 82%. ¹HNMR(360MHz，CDCl ₃)：d0.86(t，3H)；1.22(s，3H)；1.25(s，3H)；1.60-2.10(m，5H)；2.10-2.39(m，1H)；3.36-3.79(m，2H)；4.53(dd，1H，J＝3.8，8.6)；4.61-4.89(m，2H)；5.96(s，2H)；6.10(m，1H)；6.57(dd，1H，J＝6.2，15.8)；6.75(d，1H，J＝8.0)；6.83(dd，1H，J＝1.3，8.0)；6.93(s，1H)。

Compound 144:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-cyclohexyl-1-third-2-(E)-alkene ester, yield 92%. ¹H NMR (CDCl ₃): d0.86 (t, 3H); (1.13-1.40 m+2 is unimodal, and 9H amounts to); 1.50-1.87 (m, 8H); 1.87-2.44 (m, 6H); 3.34-3.82 (m, 2H); 4.40-4.76 (m, 3H); 5.35-5.60 (m, 1H); (5.60-5.82 dd, 1H, J=6.5,16).

Compound 145:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid (1R)-1,3-phenylbenzene-1-propyl ester, yield 90%. ¹H?NMR(360MHz，CDCl ₃)：d0.85(t，3H)；1.20(s，3H)；1.23(s，3H)；1.49-2.39(m，7H)；2.46-2.86(m，2H)；3.25-3.80(m，2H)；4.42-4.82(m，1H)；5.82(td，1H，J＝1.8，6.7)；7.05-7.21(m，3H)；7.21-7.46(m，7H)。

Compound 146:(2S)-1-(1,2-dioxo-2-[2-furyl] ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 99%. ¹H?NMR(300MHz，CDCl ₃)：d1.66-2.41(m，6H)；2.72(t，2H，J＝7.5)；3.75(m，2H)；4.21(m，2H)；4.61(m，1H)；6.58(m，1H)；7.16-7.29(m，5H)；7.73(m，2H)。

Compound 147:(2S)-1-(1,2-dioxo-2-[2-thienyl] ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 81%. ¹H?NMR(300MHz，CDCl ₃)：d1.88-2.41(m，6H)；2.72(dm，2H)；3.72(m，2H)；4.05(m，1H)；4.22(m，1H)；4.64(m，1H)；7.13-7.29(m，6H)；7.75(dm，1H)；8.05(m，1H)。

Compound 149:(2S)-and 1-(1,2-dioxo-2-phenyl) ethyl-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 99%. ¹H?NMR(300MHz，CDCl ₃)：d?1.97-2.32(m，6H)；2.74(t，2H，J＝7.5)；3.57(m，2H)；4.24(m，2H)；4.67(m，1H)；6.95-7.28(m，5H)；7.51-7.64(m，3H)；8.03-8.09(m，2H)。

Compound 150:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2, the 5-Dimethoxyphenyl)-1-propyl ester, yield 99%. ¹H?NMR(300MHz，CDCl ₃)：d0.87(t，3H)；1.22(s，3H)；1.26(s，3H)；1.69(m，2H)；1.96(m，5H)；2.24(m，1H)；2.68(m，2H)；3.55(m，2H)；3.75(s，3H)；3.77(s，3H)；4.17(m，2H)；4.53(d，1H)；6.72(m，3H)。

Compound 151:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2, the 5-Dimethoxyphenyl)-1-third-2-(E)-alkene ester, yield 99%. ¹HNMR(300MHz，CDCl ³)：d0.87(t，3H)；1.22(s，3H)；1.26(s，3H)；1.67(m，2H)；1.78(m，1H)；2.07(m，2H)；2.26(m，1H)；3.52(m，2H)；3.78(s，3H)；3.80(s，3H)；4.54(m，1H)；4.81(m，2H)；6.29(dt，1H，J＝15.9)；6.98(s，1H)。

Compound 152:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3,4, the 5-trimethoxyphenyl)-1-ethyl ester, yield 97%. ¹H?NMR(300MHz，CDCl ₃)：d0.84(t，3H)；1.15(s，3H)；1.24(s，3H)；1.71(dm，2H)；1.98(m，5H)；2.24(m，1H)；2.63(m，2H)；3.51(t，2H)；3.79(s，3H)；3.83(s，3H)；4.14(m，2H)；4.52(m，1H)；6.36(s，2H)。

Compound 153:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, yield 80%. ¹H NMR (CDCl ₃, 300MHz): d0.85 (t, 3H); 1.23,1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53 (m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45.

Compound 154:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(2-pyridyl)-1-propyl ester, yield 88%. ¹H NMR (CDCl ₃, 300MHz): d0.84 (t, 3H); 1.22,1.27 (s, 3H each); 1.68-2.32 (m, 8H); 2.88 (t, 2H, J=7.5); 3.52 (m, 2H); 4.20 (m, 2H); 4.51 (m, 1H); 7.09-7.19 (m, 2H); 7.59 (m, 1H); 8.53 (d, 1H, J=4.9).

Compound 155:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3-(4-pyridyl)-1-propyl ester, yield 91%. ¹H?NMR(CDCl ₃，300MHz)：d6.92-6.80(m，4H)；6.28(m，1H)；5.25(d，1H，J＝5.7)；4.12(m，1H)；4.08(s，3H)；3.79(s，3H)；3.30(m，2H)；2.33(m，1H)；1.85-1.22(m，7H)；1.25(s，3H)；1.23(s，3H)；0.89(t，3H，J＝7.5)。

Compound 156:(2S)-and 1-(2-cyclohexyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 91%. ¹H NMR (CDCl ₃, 300MHz): d1.09-1.33 (m, 5H); 1.62-2.33 (m, 12H); 2.69 (t, 2H, J=7.5); 3.15 (dm, 1H); 3.68 (m, 2H); 4.16 (m, 2H); 4.53,4.84 (d, 1H amounts to); 7.19 (m, 3H); 7.29 (m, 2H).

Compound 157:(2S)-and 1-(the 2-tertiary butyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 92%. ¹H?NMR(CDCl ₃，300MHz)：d?1.29(s，9H)；1.94-2.03(m，5H)；2.21(m，1H)；2.69(m，2H)；3.50-3.52(m，2H)；4.16(m，2H)；4.53(m，1H)；7.19(m，3H)；7.30(m，2H)。

Compound 158:(2S)-and 1-(2-cyclohexyl-ethyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-phenyl-1-propyl ester, yield 97%. ¹H?NMR(CDCl ₃，300MHz)：d0.88(m，2H)；1.16(m，4H)；1.43-1.51(m，2H)；1.67(m，5H)；1.94-2.01(m，6H)；2.66-2.87(m，4H)；3.62-3.77(m，2H)；4.15(m，2H)；4.86(m，1H)；7.17-7.32(m，5H)。

Compound 159:(2S)-and 1-(2-cyclohexyl ethyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, yield 70%. ¹H?NMR(CDCl ₃，300MHz)：d0.87(m，2H)；1.16(m，4H)；1.49(m，2H)；1.68(m，4H)；1.95-2.32(m，7H)；2.71(m，2H)；2.85(m，2H)；3.63-3.78(m，2H)；4.19(m，2H)；5.30(m，1H)；7.23(m，1H)；7.53(m，1H)；8.46(m，2H)。

Compound 160:(2S)-and 1-(the 2-tertiary butyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, yield 83%. ¹H?NMR(CDCl ₃，300MHz)：d1.29(s，9H)；1.95-2.04(m，5H)；2.31(m，1H)；2.72(t，2H，J＝7.5)；3.52(m，2H)；4.18(m，2H)；4.52(m，1H)；7.19-7.25(m，1H)；7.53(m，1H)；8.46(m，2H)。

Compound 161:(2S)-and 1-(3,3-dimethyl-1,2-dioxo amyl group)-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl ester, yield 99%. ¹H NMR (CDCl ₃, 300MHz): d0.85 (t, 3H); 1.21,1.26 (s, 3H each); 1.68-2.04 (m, 5H); 2.31 (m, 1H); 2.40 (m, 2H); 3.51 (m, 2H); 4.08 (m, 3H); 4.52 (m, 1H); 7.18-7.31 (m, 10H).

Compound 162:(2S)-and 1-(2-cyclohexyl-1,2-dioxo ethyl)-pyrrolidine 2 carboxylic acid 3-(3-pyridyl)-1-propyl ester, yield 88%. ¹H?NMR(CDCl ₃，300MHz)：d1.24-1.28(m，5H)；1.88-2.35(m，11H)；2.72(t，2H，J＝7.5)；3.00-3.33(dm，1H)；3.69(m，2H)；4.19(m，2H)；4.55(m，1H)；7.20-7.24(m，1H)；7.53(m，1H)；8.47(m，2H)。

Compound 163:(2S)-and N-([2-thienyl] is glyoxyl-based) pyrrolidine carboxylic acid 3-(3-pyridyl)-1-propyl ester, yield 49%. ¹H?NMR(CDCl ₃，300MHz)：d1.81-2.39(m，6H)；2.72(dm，2H)；3.73(m，2H)；4.21(m，2H)；4.95(m，1H)；7.19(m，2H)；7.61(m，1H)；7.80(d，1H)；8.04(d，1H)；8.46(m，2H)。

Compound 164:(2S)-and l-(3,3-dimethyl-1,2-dioxo butyl)-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl ester, yield 99%. ¹H?NMR(CDCl ₃，300MHz)：d1.27(s，9H)；1.96(m，2H)；2.44(m，4H)；3.49(m，lH)；3.64(m，1H)；4.08(m，4H)；4.53(dd，1H)；7.24(m，10H)。

Compound 165:(2S)-and 1-cyclohexyl acetaldehyde acyl group-pyrrolidine 2 carboxylic acid 3,3-phenylbenzene-1-propyl ester, yield 91%. ¹H?NMR(CDCl ₃，300MHz)：d1.32(m，6H)；1.54-2.41(m，10H)；3.20(dm，lH)；3.69(m，2H)；4.12(m，4H)；4.52(d，1H)；7.28(m，10H)。

Compound 165:(2S)-and 1-(2-thienyl) is glyoxyl-based-pyrrolidine 2 carboxylic acid 3, and 3-phenylbenzene-1-propyl ester, yield 75%. ¹H NMR (CDCl ₃, 300MHz): d2.04 (m, 3H); 2.26 (m, 2H); 2.48 (m, 1H); 3.70 (m, 2H); (3.82-4.18 m, 3H amounts to); 4.64 (m, 1H); 7.25 (m, 11H); 7.76 (dd, 1H); 8.03 (m, lH).Embodiment 16

The general method of acrylic ester synthesizing uses (3,4, the 5-trimethoxy)-trans cinnamic acid methyl esters as illustration.

Contain 3,4,5-TMB (5.0 grams; 25.48 mmole) and (triphenyl phosphoranediyl) methyl acetate (10.0 the gram; 29.91 refluxing, THF mmole) (250 milliliters) solution spends the night.Cooling, reaction mixture dilutes with 200 milliliters of ethyl acetate, and with 2 * 200 milliliters of washings, drying, and vacuum concentration.Thick residue carries out chromatographic separation with containing the hexane wash-out of 25% ethyl acetate on silicagel column, obtain the laurate of 5.63 gram (88%) white crystals. ¹HNMR(300MHz；CDCl ₃)：d3.78(s，3H)；3.85(s，6H)；6.32(d，1H，J＝16)；6.72(s，2H)；7.59(d，1H，J＝16)。Embodiment 17

From the general method of the synthetic saturated alcohol of acrylate, use (3,4, the 5-trimethoxy)-phenyl propanol as illustration.

Under argon atmospher, under condition of stirring, containing (3,4, the 5-trimethoxy)-trans cinnamic acid methyl esters (1.81 grams; 7.17 tetrahydrofuran THF mmole) (30 milliliters) drips of solution is added in THF (35 milliliters) solution that contains lithium aluminium hydride (14 mmole).Dropwise, mixture is elevated to 75 ℃, heats 4 hours.After the cooling, carefully add 15 milliliters of 2N sodium hydroxide and 50 ml water termination reactions.The gained mixture is removed solid by diatomite, and filter cake washs with ethyl acetate.Be associated with the machine component, washing, drying, vacuum concentration carries out chromatography with eluent ethyl acetate and purifies on silicagel column, obtain the clarification buttery alcohol of 0.86 gram (53%). ¹HNMR(300MHz；CDCl ₃)：d1.23(br，1H)；1.87(m，2H)；2.61(t，2H，J＝7.1)；3.66(t，2H)；3.80(s，3H)；3.83(s，6H)；6.40(s，2H)。Embodiment 18

From acrylate synthetic anti--general method of allyl alcohol, carry out illustration with (3,4, the 5-trimethoxy)-phenyl third-2-(E)-enol.

Contain (3,4, the 5-trimethoxy)-trans cinnamic acid methyl esters (1.35 grams; 5.35 toluene mmole) (25 milliliters) solution is cooled to-10 ℃, and with the toluene that contains the hydrogenation diisobutyl aluminum (11.25 milliliters 1.0M solution; 11.25 mmole) handle.Reaction mixture stirred 3 hours at 0 ℃, used 3 ml methanol termination reactions again, and regulating pH with 1N hydrochloric acid subsequently is 1.The reaction mixture ethyl acetate extraction, organic phase washes with water, drying, vacuum concentration is purified with the hexane wash-out that contains 25% ethyl acetate on silicagel column, obtains 0.96 gram (80%) heavy-gravity oily compound. ¹H?NMR(360MHz，CDCl ₃)：d3.85(s，3H)；3.87(s，6H)；4.32(d，2H，J＝5.6)；6.29(dt，1H，J＝15.8，5.7)，6.54(d，1H，J＝15.8)；6.61(s，2H)。Synthetic (the 2S)-1-(3,3-dimethyl-1,2-dioxo amyl group) of embodiment 19-pyrrolidine 2 carboxylic acid esters (421) (2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid ester synthetic

L-proline methyl ester hydrochloride (3.08 grams; 18.60 anhydrous methylene chloride solution mmole) is cooled to 0 ℃ also with triethylamine (3.92 grams; 38.74 mmole; 2.1 equivalent) handle.Stirred formed slurry 15 minutes under nitrogen atmosphere, dropping contains methyl oxalyl chloride (3.20 grams; 26.12 methylene dichloride mmole) (45 milliliters) solution.Reaction mixture stirred 1.5 hours at 0 ℃.After the solids removed by filtration, organic phase washes with water, uses dried over mgso and concentrated.On silicagel column with containing the hexane wash-out of 50% ethyl acetate the thick residue of purifying, obtain 3.52 gram (88%) red oily products.The mixture of suitable-anti-amic rotational isomer; Provide the data of trans rotational isomer. ¹H NMR (CDCl ₃): d1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79,3.84 (s, 3H amounts to); (4.86 dd, 1H, J=8.4,3.3).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid ester synthetic

(2S)-1-(1,2-dioxo-2-methoxy ethyl)-pyrrolidine 2 carboxylic acid methyl esters (2.35 grams; 10.90 30 milliliters of THF solution mmole) are cooled to-78 ℃, use 14.2 milliliters 1.0M chlorination 1 then, the THF solution-treated of 1-dimethyl propyl magnesium.The gained uniform mixture is after-78 ℃ are stirred 3 hours, mixture impouring saturated ammonium chloride solution (100 milliliters) and use ethyl acetate extraction.Organic phase washes with water, and drying concentrates and removes the crude product that desolvates and purifies with silicagel column, obtains the colorless oil barkite of 2.10 grams (75%) with the hexane wash-out that contains 25% ethyl acetate. ¹H NMR (CDCl ₃): d 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54 (m, 2H); 3.76 (s, 3H); (4.52 dm, 1H, J=8.4,3.4).(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid synthetic

(2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid methyl esters (2.10 grams; 8.23 mmole), 1N lithium hydroxide (15 milliliters), and the mixture of methyl alcohol (50 milliliters) at room temperature stirs subsequently and spends the night 0 ℃ of following stirring 30 minutes.Mixture is 1 with the 1N hcl acidifying to the pH value, dilute with water, 100 milliliters of dichloromethane extractions.Organic extract salt water washing obtains snow-white solid 1.73 grams (87%), and need not to purify after concentrating. ¹H NMR (CDCl ₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m, 1H); (3.53 dd, 2H, J=10.4,7.3); (4.55 dd, 1H, J=8.6,4.1).Embodiment 20 synthetic (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carboxylic acid amides (318)

Under-10 ℃ of stirrings, isobutyl chlorocarbonate (20 mmoles; 2.7 milliliter) add 50 milliliters of methylene dichloride that contain (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-pyrrolidine 2 carboxylic acid (4.89 grams, 20 mmoles) (obtaining) from embodiment 19.Drip ammonia (20 mmoles, 10 milliliters 2M ethanolic soln) after 5 minutes.Stir 30 minutes afterreaction temperature recoveries down to room temperature at-10 ℃.The mixture dilute with water is with 200 milliliters of dichloromethane extractions.After organic extract liquid concentrates, purify, obtain 4.0 gram white solid product (81.8% productive rate) with silicagel column. ¹H NMR (CDCl ₃): d0.91 (t, 3H, J=7.5); 1.28 (s, 6H, each); 1.63-1.84 (m, 2H); 1.95-2.22 (m, 3H); 2.46 (m, 1H); 3.55-3.67 (m, 2H); 4.67 (t, 1H, J=7.8); 5.51-5.53 (br, 1H, NH); 6.80 (br, 1H, NH).Embodiment 21 synthetic (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitriles (313)

Under 0 ℃, in containing 0.465 milliliter the solution of 10 milliliters of acetonitriles of dimethyl formamide DMF (6 mmole), add the oxalyl chloride of 0.48 milliliter (5.5 mmole).Form white precipitate at once, and be attended by the gas generation.Behind reinforced the finishing, add again contain 1.2 grams (5 mmole) (2S)-2.5 milliliters of acetonitrile solutions of 1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carboxylic acid amides (obtaining) from embodiment 20.After the mixture homogeneous, add 0.9 milliliter of (11 mmole) pyridine.After 5 minutes, the mixture dilute with water is used 200 milliliters of ethyl acetate extractions again.Organic phase concentrates, and further purifies with silicagel column, obtains 0.8 gram white solid product (yield 72%). ¹H?NMR(CDCl ₃)：d0.87(t，3H，J＝7.5)；1.22(s，3H)；1.24(s，3H)；1.80(m，2H)；2.03-2.23(m，4H)；3.55(m，2H)；4.73(m，1H)。Embodiment 22 synthetic (2S)-1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine tetrazoliums (314)

(2S)-(222 milligrams of 1-(1,2-dioxo-3,3-dimethyl amyl group)-2-tetramethyleneimine carbon nitrile, 1 mmole) (obtains) from embodiment 21, sodiumazide (81 milligrams, 1 mmole) and the mixture of ammonium chloride (70 milligrams, 1.3 mmoles) in 3 milliliters of DMF stirred 16 hours down at 130 ℃.Mixture concentrates, and further purifies with silicagel column, obtains 200 milligrams of white solid product (yield 75.5%). ¹H?NMR(CDCl ₃)：d0.88(t，3H，J＝7.5)；1.22(s，6H)；1.68(m，2H)；2.05-2.36(m，3H)；2.85(m，1H)；3.54(m，1H)；3.75(m，1H)；5.40(m，1H)。Embodiment 23 synthetic 3-(3,3-dimethyl-2-oxo pentanoyl)-1,3-oxazolidine-4-carboxylic acid (612) 1,3-oxazolidine-4-carboxylate methyl ester

According to synthetic this compound of the method that provides among J.Med.Chem. (1990) 33:1459-1469.2-[4-(methoxycarbonyl) 3-(1, the 3-oxazolidinyl)]-2-carbonylic acetic acid methyl esters

To ice-cold 1,3-oxazolidine-4-carboxylate methyl ester (0.65 gram, 4.98mM) add in the solution triethylamine (0.76 milliliter, 5.45mM) and the methyl oxalyl chloride (0.5 milliliter, 5.45mM).Mixture stirred 2 hours down at 0 ℃, mixture water subsequently, and anhydrous magnesium sulfate drying use in the salt water washing, filters, and evaporates.Gained light yellow liquid body and function 30% ethyl acetate/hexane, 50% ethyl acetate/hexane and last 75% ethyl acetate/hexane flash distillation wash-out.Obtain clarifying oily product (0.52 gram, 48%).Ultimate analysis (C ₈H ₁₁NO ₆) C, H, N; ¹H NMR (CDCl ₃, 400MHz): d (2 rotational isomers 1: 1) 3.78 (s, 1.5H); 3.79 (s, 1.5H); 3.87 (s, 1.5H); 3.91 (s, 1.5H); 4.14-4.36 (m, 2H); (4.70 dd, 0.5H, J=4.1,6.8); (5.08 dd, 0.5H, J=3.1,6.7); 5.10 (d, 0.5H, J=5.9); 5.27 (d, 0.5H, J=5.8); (5.36 dd, 1H, J=5.3,17.8).3-(3,3-dimethyl-2-oxo pentanoyl)-1,3-oxazolidine-4-carboxylate methyl ester

Contain 2-[4-(methoxycarbonyl) 3-(1, the 3-oxazolidinyl)]-2-carbonylic acetic acid methyl esters (0.84 gram after THF 3.87mM) (50 milliliters) solution is cooled to-78 ℃, adds chlorination 1, and 1-dimethyl propyl magnesium (the THF solution of 1M, 8 milliliters, 8mM).Mixture reacted 3 hours down at-78 ℃, used saturated ammonium chloride (50 milliliters) termination reaction, and extracted with ethyl acetate (100 milliliters).Separate obtaining organic phase,, use anhydrous magnesium sulfate drying, filter and evaporation with salt solution (100 milliliters) washing.Gained light yellow liquid body and function 20% ethyl acetate/hexane flash distillation wash-out.Obtain clarifying oil (3) (0.61 gram, 61%). ¹H?NMR(CDCl ₃，400MHz)：d?0.85(t，3H，J＝7.5)；1.25(s，3H)；1.26(s，3H)；1.67-1.94(m，2H)；3.79(s，3H)；4.12-4.3](m，2H)；4.64(dd，1H，J＝4.1，6.8)；5.04(dd，2H，J＝4.9，9.4)。3-(3,3-dimethyl-2-oxo pentanoyl)-1,3-oxazolidine-4-carboxylic acid (612)

3-(3,3-dimethyl-2-oxo pentanoyl)-1,3-oxazolidine-4-carboxylate methyl ester (3) (0.6 gram 2.33mM) is dissolved in methyl alcohol (25 milliliters), and the adding lithium hydroxide (aqueous solution of 1M, 10 milliliters, 10mM).Mixture at room temperature stirs and spends the night.Resistates evaporation back is distributed with ethyl acetate (50 milliliters) and 2N hydrochloric acid (50 milliliters).Water extracts (2 * 25 milliliters) 2 times again with ethyl acetate.Extraction liquid is used anhydrous magnesium sulfate drying with salt solution (50 milliliters) washing, filters and evaporation.Obtain clarifying oily product (0.49 gram, 86%).Ultimate analysis (C ₁₁H ₁₇NO ₅) C, H, N; ¹HNMR (CDCl ₃, 400MHz): d0.84 (t, 3H, J=7.5); 1.25 (s, 6H); 1.70-1.95 (m, 2H); 4.22-4.29 (m, 2H); (4.66 dd, 1H, J=4.6,6.5); (5.04 dd, 2H, J=5.0,8.9); 7.67 (bs, 1H).Synthetic (2S)-1-(the N-cyclohexyl carboxyamide base) tetramethyleneimine of embodiment 24-2-carboxylic acids (619) (2S)-1-(N-cyclohexyl carboxyamide base) tetramethyleneimine-2-carboxylate methyl ester

Cyclohexyl isocyanate (3.88 grams; 31 mmoles) and L-proline ester hydrochloride (5.0 the gram; 30.19 mmole) and the mixture of triethylamine (9 milliliters) in methylene dichloride (150 milliliters) at room temperature stir and spend the night.Reaction mixture washs with hydrochloric acid (2 * 100 milliliters) and the water (1 * 100 milliliter) of 1N.The organic phase drying concentrates, and use silicagel column (containing 50% ethyl acetate/hexane) obtains heavy-gravity oily urea after purifying. ¹HNMR(CDCl ₃，400MHz)：d1.09-1.15(m，3H)；1.33(m，2H)；1.68(m，3H)；1.93-2.05(m，6H)；3.33(m，1H)；3.43(m，1H)；3.46(m，1H)；3.73(s，3H)；4.39(m，1H)；4.41(m，1H)。(2S)-1-(N-cyclohexyl carboxyamide base) tetramethyleneimine-2-carboxylic acid (619)

(2S)-1-(N-cyclohexyl carboxyamide base) tetramethyleneimine-2-carboxylate methyl ester (3.50 gram) is dissolved in the methyl alcohol (60 milliliters), is cooled to 0 ℃, and handles with 2N lithium hydroxide (20 milliliters).After stirring is spent the night, mixture ether and water dispenser.Abandon ether layer, water layer is 1 with the 1N hcl acidifying to the pH value, and uses dichloromethane extraction.Dry also except that obtaining snow-white solid 2.20 grams after desolvating. ¹H?NMR(CDCl ₃，400MHz)：d1.14-1.18(m，3H)；1.36-1.38(m，2H)；1.71-1.75(m，3H)；1.95-2.04(m，5H)；2.62(m，1H)；3.16(m，1H)；3.30-3.33(m，1H)；3.67(m，1H)；4.38(br，1H)；4.46(m，1H)。Embodiment 25 synthetic (2S)-N-(benzyl alkylsulfonyl)-pyrrolidine 2 carboxylic acids (719)

Contain L-proline methyl ester hydrochloride (5.0 grams; 30.19 200 milliliters of dichloromethane solutions mmole) are cooled to 0 ℃, add triethylamine (35 milliliters) and benzene sulfonyl chloride (5.75 grams; 30.19 mmole).Mixture stirred 1 hour down at 0 ℃, and with 2 * 100 milliliters water washing.The organic phase drying concentrates, and uses the N-sulphonamide methyl esters that obtains 8.14 grams (5%) behind the 50% ethyl acetate/hexane elution chromatography, and it is dissolved in 120 ml methanol, is cooled to 0 ℃, and with 40 milliliters of 1N lithium hydroxides processing.Mixture stirred 1 hour down at 0 ℃, stirred under the room temperature then and spent the night.Reaction mixture is 1 with the 1N hcl acidifying to the pH value, and uses the dichloromethane extraction product.Obtain white solid (2S)-N-(benzyl alkylsulfonyl)-pyrrolidine 2 carboxylic acid (A) 4.25 grams after dry and concentrated. ¹HNMR(CDCl ₃，400MHz)：d1.85-1.90(m，2H)；2.08(m，1H)；2.1?8(m，1?H)；3.04(m，1H)；3.27(m，1H)；4.32-4.35(m，2H)；4.45(m，1H)；4.45(m，2H)；7.36(m，3H)；7.48(m，2H)；10.98(br，1H)。Embodiment 26 synthetic (2S)-1-(phenyl methanesulfonamide acyl group)-2-hydroxymethyl pyrrolidines (813)

Under 0 ℃, stir the a-toluene sulfonyl chloride that in 30 milliliters of dichloromethane solutions that contain (2S)-(+)-2-pyrrolidine carbinol (1.01 grams, 10 mmoles) and triethylamine (1.5 milliliters, 11 mmoles), adds 1.9 grams (10 mmole) down.Temperature of reaction goes back up to room temperature gradually, and stirring is spent the night.The reaction mixture dilute with water, and with 200 milliliters of dichloromethane extractions.After organic phase concentrates, use silicagel column to purify, obtain 1.5 gram white solid product (58.9%). ¹H NMR (CDCl ₃): d01.71-1.88 (m, 4H); 2.05 (br, 1H; OH); 3.22 (m, 2H); 3.47 (m, 2H); 3.67 (m, 1H); 4.35 (s, 2H); (7.26-7.44 m, 5H, aromatics).Embodiment 27 synthetic (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carboxylic acid amides (814)

Under 0 ℃, stir down to containing L-proline(Pro) acid amides (2.28 grams; 20 Bo moles) the a-toluene sulfonyl chloride that adds 3.92 grams (20 mmole) and in 40 milliliters of dichloromethane solutions of triethylamine (5.76 milliliters, 42 mmoles).Temperature of reaction goes back up to room temperature gradually, and stirring is spent the night.The reaction mixture dilute with water, and with 200 milliliters of dichloromethane extractions.After organic phase concentrates, use silicagel column to purify, obtain 3.0 gram white solid product (55.7%). ¹H NMR (CDCl ₃): d01.89 (m, 3H); 2.25 (m, 1H); 3.40 (m, 1H); 3.50 (m, 1H); 3.96 (m, 1H); 4.35 (s, 2H); (7.39-7.45 m, 5H, aromatics).Embodiment 28 synthetic (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carbon nitriles (815)

In the solution of 10 milliliters of acetonitriles that contain 0.67 milliliter of (8.7 mmole) DMF, under 0 ℃, add the oxalyl chloride of 0.70 milliliter (8.0 mmole).Form white precipitate at once, and be attended by the gas generation.Reinforced finishing, add again contain 2.0 grams (7.5 mmole) (2S)-5.0 milliliters of acetonitrile solutions of 1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carboxylic acid amides.After the mixture homogeneous, add 1.35 milliliters of (16.5 mmole) pyridines.After 5 minutes, the mixture dilute with water is used 200 milliliters of ethyl acetate extractions again.Organic phase concentrates, and further purifies with silicagel column, obtains 1.5 gram white solid product (yield 80%). ¹H NMR (CDCl ₃): d1.92 (m, 2H); 2.01 (m, 1H); 2.11 (m, 1H); 3.45 (m, 2H); 4.35 (s, 2H); 4.65 (m, 1H); (7.26-7.45 m, 5H, aromatics).Embodiment 29 synthetic (2S)-1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine tetrazoliums (722)

(2S)-and 1-(phenyl methyl) alkylsulfonyl-2-tetramethyleneimine carbon nitrile (250 milligrams, 1 mmole), sodiumazide (81 milligrams, 1.3 mmoles) and the mixture of ammonium chloride (70 milligrams, 1.3 mmoles) in 3 milliliters of DMF stirred 16 hours down at 130 ℃.Mixture concentrates, and purifies with silicagel column, obtains 120 milligrams of white solid product (yield 41.1%). ¹H NMR (CDCl ₃): d01.95 (m, 2H); 2.21 (m, 1H); 2.90 (m, 1H); 3.40 (m, 2H); 4.27 (s, 2H); 5.04 (m, 1H); (7.36-7.41 m, 5H, aromatics); 8.05 (s, 1H, NH).FKBP neuroimmunophilin GPI-1046 is used to improve the survival rate of retinal ganglial cells and suppresses aixs cylinder withered behind embodiment 30 optic nerve transections

The cross-section meeting of Mammals optic nerve causes the abortive regeneration of short period of time, but intercepted neurone is most of dead, and the aixs cylinder of the residual ganglion cell outside the optic nerve head can be withered.The purpose of present embodiment is to detect the neuroprotective of GPI-1046 after optic nerve transection.

The retinal ganglial cells of bull Sprague Dawley mouse is by the LGNd injection fluorescent yellow mark that drives in the wrong direction, after four days optic nerve behind the eyeball 5 millimeters cross-section.The GPI-1046 of every treated animal acceptance or 10 milligrams/kg/day or vectorial treatment 28 days.90 days all test animals and comparing animals are all dead after cross-section.

Detected by RT97 neurofilament immunohistochemistry, have only the ganglion cell colony survival of 10% FG mark after 90 days, fewer than half also keeps the aixs cylinder above optic nerve head in these neurones.GPI-1046 treatment provides the perikaryon neuroprotective of appropriateness, and the ganglion cell colony of protection 25% has kept by nearly all on the cross-section neural contiguous residue and protected neuronic aixs cylinder.These presentation of results produce essential change with FKBP neuroimmunophilin part GPI-1046 to the treatment that central nervous system CNS manages wound in pathological process.

These results have confirmed that also small molecules FKBP neuroimmunophilin part GPI-1046 strengthens the growth of the spinous process in the culture, strengthen stimulating the interior growth of CNS after peripheral nerve regeneration and the part deafferentation.Embodiment 31 neuroimmunophilin parts promote the relevant peripheral sensory neuropathy of diabetes that causes with streptozocin to recover

In the 30-40% diabetic subject, peripheral neurophaty is the common II-type diabetic complication that makes people's weakness.Known neurotrophic factor such as nerve growth factor (NGF) can promote in the growth and sophisticated neuronal survival in the peripheral nervous system (PNS).Select part such as the small molecules GPI-1046 of some neuroimmunophilin FKBP-12, it has shown can promote to repair or regenerate (Proc, Nat'l Acad.Sci.USA 94,019-2024,1997) in central or peripheral nervous system.

Present embodiment is estimated the potential result of treatment of GPI-1046, investigates its ability to the raising sensory function of the diabetic mice suffering from streptozocin and cause.Present method comprises the use male Wistar rats, to its injection streptozocin (65 milligrams of/kilogram i.v.).First three week of experiment and detect blood sugar concentration last week weekly one time.Use heat dish and back to measure the esthesioneurosis signal of animal weekly along the jump device test method.Begin after six weeks with GPI-1046 or vehicle treatment.

The gained result confirms to have illustrated with GPI-1046 effective in cure to the animal that is in preclinical damaged with 10 milligrams of/kilogram s.c with the performance testing that carry out along the jump device heat dish and back.This result illustrates that also GPI-1046 can improve the behavior sequela of diabetes esthesioneurosis, alleviates the misery of suffering from diabetes type peripheral nerve patient.Embodiment 32 usefulness C57 Black 6 mouse carry out the hair growth live test

Test A: with the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body of C57 Black 6 mouse checking N-heterocyclic derivatives, the hair restorability of GPI 1046.With reference to Fig. 1 and Fig. 2 of accompanying drawing, C57 Black 6 mouse big near 7 weeks go out the hair that wherein all existence are removed in about 2 inches * 2 inches zone in its buttocks shaving.Note not making following skin layer to produce otch or cause scratch.Pinkish skin shows the stage anagen that this animal being in.With reference to Fig. 2,3 and 4, every group of 4 mouse are dissolved in the GPI 1046 (Fig. 3) of 10 μ M in the vehicle or the GPI 1046 (Fig. 4) of 30 μ M and handle by the propylene glycol vehicle (Fig. 2) of topical application 20%.This animal per 48 hours is handled (using altogether 3 times) with vehicle or GPI 1046 in 5 days the course of treatment, allow hair growth continue for 6 week.The percentage ratio quantitative assay hair growth that the hair of newly being grown by its shaving zone in during this period covers.

Fig. 2 show the animal of handling with vehicle have only a spot of spot or bunch hair growth, only be less than the hair of 3% shaving zone newly being grown and cover.On the contrary, Fig. 3 has shown with the animal display of GPI 1046 processing of 10 μ M outstanding hair growth, and the hair that all animals are newly grown above 90% shaving zone covers.In addition, Fig. 4 shows that the nearly all hair of handling with the GPI1046 of 30 μ M of animal all regenerates, and the shaving zone and not the shaving zone can not distinguish.

Test B: with C57 Black 6 mouse checking lower molecular weight, the hair restorability of the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body of micromolecular N-heterocyclic derivatives.The biggest C57 Black 6 mouse of 55-75 go out the hair that wherein all existence are removed in about 2 inches * 2 inches zone in its buttocks shaving.Note not making following skin layer to produce otch or cause scratch.Pinkish skin shows the stage anagen that this animal being in.With reference to Fig. 2,3 and 4, every group of 5 mouse, to shaving zone topical application vehicle, FK506, or a kind of lower molecular weight, (GPI 1605 for the neuroimmunophilin fkbp ligand body of micromolecular non-inhibitive ability of immunity N-heterocyclic derivatives, GPI 1046, GPI 1312, and GPI 1572, and GPI 1389, GPI 1511 and GPI 1234).Time animal is treated assessing hair growth after the treatment beginning 14 days on every Wendesdays.The percentage ratio quantitative assay hair growth that the hair of newly being grown by its shaving zone covers, being kept the score by blind test obtains 0 grade (not growth) to 5 grades (shaving zone hair is grown fully).

After Fig. 5 showed 14 days, the animal of handling with vehicle had only the hair of tuftlet to begin growth.On the contrary, use lower molecular weight, the animal display that the neuroimmunophilin fkbp ligand body of micromolecular non-inhibitive ability of immunity N-heterocyclic derivatives is handled outstanding hair growth.Embodiment 33 usefulness C57 Black 6 mouse carry out the hair growth live test

Hair restorability with C57 Black 6 mouse checking N-Hete rocyclic derivatives.With reference to Fig. 1 and Fig. 2 of accompanying drawing, C57 Black 6 mouse big near 7 weeks go out the hair that wherein all existence are removed in about 2 inches * 2 inches zone in its buttocks shaving.Note not making following skin layer to produce otch or cause scratch.Pinkish skin shows the stage anagen that this animal being in.With reference to Fig. 2, every group of 4 mouse are handled (Fig. 2) by the propylene glycol vehicle of topical application 20%, perhaps handle with the respective compound that is dissolved in this vehicle.This animal per 48 hours is handled (using altogether 3 times) with vehicle or N-Hete rocyclic derivatives in 5 days the course of treatment, allow hair growth continue for 6 week.The percentage ratio quantitative assay hair growth that the hair of newly being grown by its shaving zone in during this period covers.

Fig. 2 show the animal of handling with vehicle have only a spot of spot or bunch hair growth, only be less than the hair of 3% shaving zone newly being grown and cover.

On the contrary, Fig. 3 shows that two kinds of compounds wherein have the hair of newly being grown greater than 25% shaving zone to cover with the N-Hete rocyclic derivatives outstanding hair growth that has been compd A, compd B and the compound G animal display of handling for 2 weeks in all animals.

Fig. 3 shows the corresponding hair growth situation of handling C57 Black 6 mouse of back 14 days shaving with N-heterocyclic carboxylic acid or carboxylic acid isostere.Mouse is gone out 2 inches * 2 inches zone in its back shaving remove wherein all hairs.Note not making following skin layer to produce otch or cause scratch.With concentration is the shaving zone that every milliliter 1 micromolar compound carefully is applied in mouse (every group of 5 mouse), and per week is used 3 times.Estimate its hair growth situation in beginning 14 days after the drug treating.The relative grade of assessing hair growth is as follows:

0=is growth not;

1=begins to have the growth of Xiao Cong;

2=is coated with＜hair growth of 25% shaving area;

3=is coated with＞25% shaving area but be lower than the hair growth of 50% shaving area;

4=is coated with＞50% shaving area but be lower than the hair growth of 75% shaving area;

5=shaving area is hair growth completely.The live test of embodiment 34 retinal ganglial cellses and optic nerve aixs cylinder

In the vision loss pattern, cut off the mechanical trauma of optic nerve simulation with surgical operation to optic nerve, measure the degree that retinal ganglial cells and optic nerve axonal degeneration reduce or prevent.By the relatively treatment of the neuroimmunophilin fkbp ligand body of the N-heterocyclic derivatives of 14 days and 28 days, the neuroimmunophilin fkbp ligand body of some N-heterocyclic derivatives of test determination is to the effect of retinal ganglial cells and optic nerve aixs cylinder density.Is to be mutually related with the neuroimmunophilin fkbp ligand body of N-heterocyclic derivatives to the effect of retinal ganglial cells and the treatment of optic nerve aixs cylinder.Surgical procedures

Bull Sprague Dawley mouse (March is big, the 225-250 gram) is anaesthetized with the mixture of ketamine (87 milligrams/kilogram) and xylazine (13 milligrams/kilogram).Retinal ganglial cells is by the marker fluorescent yellow (FG of the retrograde transportation of fluorescence, 0.5 the three-dimensional locating injection in both sides 2.5% salts solution of microlitre) is (behind the β 4.5 millimeters of LGNd, 3.5 millimeters of sides, following 4.6 millimeters of endorchis) mark is in advance carried out in cooperation down.After four days, FG mark mouse carries out the micrurgy second time, and the 4-5 millimeter cuts off both sides optic nerve in the socket of the eye behind the eye socket.

Experimental animal is divided into six test group, every group of six mouse (12 eyes).One group of neuroimmunophilin fkbp ligand body (10 milligrams/kg/day sc) that is received in the N-heterocyclic derivatives in the PEG vehicle (20% propylene glycol, 20% ethanol and 60% salt) 14 days.Second winding is subjected to the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body dosage 28 days of identical N-heterocyclic derivatives.The group of each treatment has corresponding vacation/operation and cross-section comparative group, and it accepts the vehicle dosage of 14 days or 28 days.

All animal optic nerve transections are dead after 90 days, and pericardium perfusion formaldehyde solution.Remove all eye and optic nerve residues.If the optic nerve vascular system is impaired or retina in do not have the FG mark, example is got rid of outside research.The retinal ganglial cells counting

From eyeball, take out retina, prepare to be used for holistic approach.Select the most intensive 5 the strongest eyeballs of FG mark to carry out quantitative analysis in every group with 20 times of object lens.Select 5 zones to obtain digital picture from retinal centre (optic nerve head radius 3-4 millimeter).Every group 5 example, 5 400 microns * 400 microns zones of every example are labeled as greatly (＞18 microns) to FG, and medium (12-16 micron) and little (＜10 microns) ganglion cell and mesoglia are counted.The detection of optic nerve

The vicinity and the distal stump of optic nerve are identified, and measure, and transfer in the 30% saccharate solution.The contiguous residue of five nerves is blocked, and appends on the dry pan, downcuts 10 microns cross sections in cryostat; Every group keeps 1/10 part.The part that contains 1-2 millimeter zone behind the eye socket is to RT97 neurofilament immunohistochemical reaction.Use 63 times of oil immersion lens, Dage81 camera and Simple Image Analysis program carry out optic nerve aixs cylinder density analysis.Count in three 200 microns * 200 microns zones to each nerve, measures neurological region with 10 times of eyepieces in each example.

As the vivid description of Table I and II, can provide moderate neuroprotective to retinal ganglial cells with the treatment that the neuroimmunophilin fkbp ligand body of N-heterocyclic derivatives carried out 14 days to the retinal ganglial cells after cross-section 28 days.But, treated afterwards in cross-section 90 days, have only 5% ganglion cell colony survival.

For the animal groups of only accepting vehicle or carrying out the non-inhibitive ability of immunity neuroimmunophilin fkbp ligand body treatment of 14 days N-heterocyclic derivatives, optic nerve transection remain in after 90 days aixs cylinder number on the contiguous residue of optic nerve only have survival the ganglion cell number near half.These presentation of results surpassed the ganglion cell aixs cylinder of half from the optic nerve head retraction, and the treatment of carrying out with the neuroimmunophilin fkbp ligand body of N-heterocyclic derivatives after the optic nerve transection, were not sufficient to suppress this retraction at preceding 14 days.

As the vivid description of Table I and II, to the neuroimmunophilin fkbp ligand body extension treatment of cross-section retinal ganglial cells with the N-heterocyclic derivatives, 28 days therapeutic process can the appropriate neuroprotective that improves retinal ganglial cells.Pregnable retinal ganglial cells near 12% is protected.Observing optic nerve aixs cylinder density has similar portions (～50%) to be retained.These results have confirmed this surprising phenomenon, with after neuroimmunophilin fkbp ligand body extension treatment time to 28 of N-heterocyclic derivatives day, almost can suppress the degeneration of spinous process impaired in the retinal ganglial cells of all survivals to cross-section retinal ganglial cells.All the other results are by Table III and IV, and Fig. 5-13 illustrates.

[inserting blank page, Table I-IV]

Fig. 5 .GPI1046 protection retinal ganglial cells prevents sex change after the retinal ischemia

The retinal ganglial cells of adult rats is by the two side injection fluorescent yellows mark that drives in the wrong direction in their lateral bending nucleus.The ganglion cell that is labeled in the normal mice retina is white image (Fig. 5 A) with respect to black background.Amphiblestroid vitreous chamber injection physiological saline to each eye is higher than arteriotony until intraocular pressure, and whole retina can local asphyxia.The local asphyxia outbreak extensive sex change of retinal ganglial cells afterwards in 28 days is confirmed (Fig. 5 B) by a large amount of minimizing of the cell of fluorescent yellow mark.1 hour use GPI 1046 (10 milligrams/kilogram s.c.), and were pressed 10 milligrams/kg/day in later four days and use significant protect (Fig. 5 C) of the pregnable ganglion cell of major part colony generation before the local asphyxia outbreak.

Fig. 6 .GPI1046 prevents the sex change after retinal ischemia of optic nerve aixs cylinder and myelin

The optic nerve that detects in the identical retinal ischemia example finds that 1046 pairs of optic nerve elements of GPI produce outstanding protection and prevent the local asphyxia sex change.The myelin (white ring) in the Resins, epoxy announcement normal mice optic nerve of the Toluidine blue staining of embedding optic nerve cross section and the details of optic nerve aixs cylinder (black center).Retinal ischemia's outbreak was checked optic nerve with the vehicle treatment after 28 days after 1 hour, it is characterized in that optic nerve density reduces and occur the myelin figure of a large amount of sex change (ring that brilliant white is full of).In case sex change, also can obviously reduce the myelin figure density of sex change with the GPI 1046 treatment most optic nerve aixs cylinders of protection.

Moderate protection is provided Fig. 7 .GPI 1046 in case ganglion cell is dead behind optic nerve transection

Locate optic nerve and cut off fully and can produce a large amount of retinal ganglion cells degenerations for 5 millimeters behind the eyeball, the minimizing (table 1) of 90 days at least 87% common ganglion cell colony after the wound.For treat example (big white image) with vehicle, seldom have fluorescent yellow in advance the ganglion cell of mark remain in the mesoglia colony, mesoglia can be engulfed the relic of degenerating cell, and occupies the position (Fig. 7 A) of fluorescent yellow mark.Can improve the cross-section back 90 days still density of the retinal ganglial cells of survival in 14 days a little with GPI 1046 treatments, but not obvious (table 1).But treat with GPI 1046 originally 28 days after cross-section, can produce appropriateness but significant protection (table 1, Fig. 7 B) 12.6% pregnable ganglion cell colony.

The treatment cycle of Fig. 8 .GPI 1046 is the process of the cross-section backsight neural axon of influence sex change obviously

The optic nerve aixs cylinder density that detects the contiguous residue of optic nerve in same instance shows that the treatment of GPI1046 provides more outstanding protection.Seldom there is the ganglion cell aixs cylinder to be retained in (Fig. 8 B) in the optic nerve after cross-section 90 days, 5.6% of normal population is only arranged.The minimizing of aixs cylinder reflected the dead of retinal ganglial cells and near the aixs cylinder in the ganglion cell colony of 70% little survival degenerate or " black dead " to retina itself (table 1).Behind optic nerve transection, originally 14 days produce protection (Fig. 8 D a small amount of but unconspicuous 5.3% optic nerve aixs cylinder with GPI 1046 treatments; table 1); but the optic nerve aixs cylinder of the retinal ganglial cells that can stay most (81.4%) with GPI 1046 treatment of same dose 28 days provides protection (Fig. 8 C, table 1).

The treatment of Fig. 9 .GPI 1046 is better than effect to the ganglion cell body to the effect of optic nerve aixs cylinder

Data and high magnification micrographs (Fig. 9 A﹠amp of ganglion cell protection in the sketch explanatory view 7; B, top).Obviously improved in 28 days with GPI 1046 treatment big, the density of medium and little optic nerve aixs cylinder, especially medium and little optic nerve aixs cylinder density (Fig. 9 C﹠amp; D, the bottom).

Figure 10. prevented myelinic degeneration on the contiguous residue in 28 days with GPI 1046 treatments behind the optic nerve transection

Medullated aixs cylinder bundle in the normal optic nerve of myelin basic protein immunohistochemistry mark (" island " of dark mark) (Figure 10 A, upper left).In the example with the vehicle treatment, obviously there is myelinic degeneration widely after cross-section 90 days, is characterised in that the minimizing of pencil tissue and many highdensity sex change myelin figures (Figure 10 B, upper right) occur.Treat the pattern (Figure 10 C, lower-left) that did not change myelinic degeneration in 14 days, the quantitative recovery (table 1) that only produces myelin density inapparent 1.6% with GPI 1046 behind the optic nerve transection.Prolong GPI 1046 behind the optic nerve transection and treat the reservation of significantly using the painted pencil pattern of myelin basic protein in 28 days in the place's generation of the contiguous residue of optic nerve, and the density of sex change myelin figure reduces (Figure 10 D, the bottom right), there is 70% myelin density to recover (table 1).

The mesoglia of Figure 11 .FKBP-12 immunohistochemistry mark (with the huge black cell of fibrous spinous process), it can produce myelin, between the bundle of optic nerve fiber and some optic nerve aixs cylinders.

Figure 12. GPI 1046 treatments prevented myelinic degeneration on the distal stump in 28 days behind the optic nerve transection

The cut-out fully of optic nerve causes the sex change of distal portions (with the unconnected aixs cylinder part of ganglion cell body) and the sex change of myelin.After cross-section 90 days (Figure 12 B), the myelin basic protein immunohistochemistry shows that pencil tissue (being present in the normal optic nerve) almost completely loses (Figure 12 A) and many highdensity sex change myelin figures occur.The cross-sectional area of the distal stump that the quantitative data explanation is cross-section reduces 31%, and its myelin reduces near 1/2 (table 1).Behind the optic nerve transection with GPI 1046 treatment originally the atrophy that can not prevent distal stump in 14 days but can improve myelin density a little, sex change myelin density still very high (Figure 12 C, table 1).The pencil pattern that can protect the myelin mark in 28 days highlightedly for the treatment of originally with GPI 1046 behind the optic nerve transection; reduce sex change myelin figure density; prevent cross-section nerve distal stump the cross section atrophy and keep the myelin level normal level～99% (Figure 12 D, table 1).

Figure 13. 8 all GPI of using 1046 treat the degree of the neovascularity generation outside reducing in the retina in 28 days after the outbreak of streptozocin initiation diabetes, prevent the neuronal degeneration of inner nuclear layer (INL) and ganglion-cell layer (GCL)

The negative-appearing image of the purple painted tangent retina part of tolyl has shown the perikaryon (Figure 13 A) of three cellular layers.If the animal retina that streptozocin is handled only uses vehicle (Figure 13 B) can show that the cell of ONL and INL reduces, the thickness of outer plexus vasculosus layer (dark areas between ONL and the INL) reduces and the size and the density of retinal vessel (big black ring-type profile) obviously increase.The treatment of GPI 1046 has reduced ONL, the generation (being exactly to prevent blood vessel hyperplasia) of neovascularity among the OPL, INL and photoreceptor layer (PR, the grey fuzzy zone on the ONL layer).With respect to the comparative group of handling with streptozocin/vehicle, although can not preventing the neurone among the ONL, reduces GPI 1046, can suppress the neuronic minimizing among INL and the GCL.Embodiment 35

Table V is illustrated representational compound in the different immunophilin series prevents the ganglion cell axonal degeneration behind optic nerve transection effect.

Representational compound prevents ganglion cell in the different immunophilin series of Table V behind optic nerve transection

The effect of axonal degeneration

Embodiment 36Morris water maze/aging and recall tests process

Old and feeble rodent shows significant individual difference aspect the finishing of multiple study of behaviour task, these study of behaviour tasks comprise the spatial discrimination in the T-labyrinth after variation of two kinds of selections, spatial discrimination in the ring-shaped platform task, passive avoidance, radial maze task and the space navigation ability in the pond.

In all these tasks, rat that some are old and feeble or mouse are the same with most young comparing animals performances, and other shows the damage of serious memory function with respect to young animal.For example, Fisher and colleague find that the part rat is increased in the memory impairment of having outstanding performance in the space navigation aspect with the age, (Fisher etc., 1991b) 8% December is big, 45% 18 months are big, show as damaged aspect all 30 months big rats big and 90% were finished in the space of Morris water maze task with respect to young comparing animals in 53%24 months.

Particularly, accepted by many investigators by space learning and memory capability reduction with the age increase for rodent, is considered to the attracting relevant animal models of senile dementia.Hippocampal choline function is widely studied as a component of rodentine space learning, and notices that the hippocampal choline function of reduction is consistent with the development of learning and memory damage.Other neurotransmission system system demonstration is relevant with space learning in addition, and reduces with the age increase, and for example dopaminergic and norepinephrine activated is serotonergic, the glutamate activated system.

The defective relevant with the age that reports that digitation of hippocamps long-term potentiation (LTP) causes also arranged, the minimizing of theta rhythm frequency, the plasticity-of the digitation of hippocamps position units that experience relies on reduces the phenomenon with the minimizing of digitation of hippocamps protein kinase, and this is identical of views to can be used as cause that the rodent study of behaviour relevant with the age damage with the pathology that are not dominant separately.But taked the kinds of experiments treatment means to be used to improve memory function to the rodent of aging, this fact is tended to cholinergic hypothesis to a certain extent.

Morris water maze task is widely used in laboratory animal, in order to estimate the formation and the reservation of spatial memory.The ability of animal usage space visual information is depended in test, to determine the buried escape platform in the tank.Importantly tank itself lacks as far as possible that specific visual signature-therefore, tank is an original shape, keeps smooth all around, and the color homogeneous is dim, uses water-soluble pigment of non-toxicity or milk powder to make water opaque.Guarantee that like this animal only relies on the visual cues by means of the farther place, or the clue in the labyrinth that provides according to the experimenter is navigated.

Keeping certain height in the trough inner water position, initiatively swims to impel animal.Mouse or rat are detested the swimming part of test very much, thereby can climb to, or rest on the escape platform, and they can be transferred in the rest cage of insulation like this.

If platform is a visible, (being higher than the water surface in other words), being placed on animal in the groove and can very fast association finding platform and climb up.Can guarantee that with the visible platform test laboratory animal does not become blind, and have enough motivations and energy to finish the work that this is for comprising that old and feeble rodentine experiment is extremely important.If platform is sightless, (submergence in other words is lower than the water surface) is placed on the location of visual cues in test trough at a distance in the intact animal meeting use test room in the groove, around the position of the very fast definite platform of meeting and this zone, up to finding platform.

The path of animal, speed and swimming time are passed through under the camera record of top, Computer Analysis after being used for.Repeatedly in the process of continuously tested, space learning can be defined as from be placed on groove until the swimming distance that escapes on the invisible platform, or the time runs off.

Test also can do to change the evaluation with some other aspect that adapts to spatial memory slightly: the task of a) finishing hint, animal according to cortical functional ability that a visual cues is directly related with escape platform (in other words, a ball is suspended on the escape platform, and animal is found platform according to this clue; B) finish space tasks, wherein the animal ability of grasping the position of buried escape platform according to the combination of distant place visual cues depends on digitation of hippocamps function (vision by paper tower divider and door and ceiling light be arranged in trilateral determine position in its groove) in other words; C) complete successfully the memory of space tasks, it mainly depends on the function (several in other words weeks back animals must remember the locus) of cortex; D) inverse task that relies on of digitation of hippocamps, wherein animal must regain new space platform position (between the swim test, platform moves on to new location in other words, and animal must be abandoned previous searching strategy and obtains new position).

The difference of Morris water maze method changes and is used for a collection of laboratory animal their spatial memory behaviors successively and remembers decay with normal aging characterizing completely.In addition, a series of like this successive recall tests (for example have more understanding to the functional completeness of the specific brain system of the acquisition that relates to spatial memory and reservation, the rat of digitation of hippocamps choline function damage can be remembered to obtain the position of platform before several weeks, but still rests on the original space position after platform moves).

Systematically use effective FKBP-part GPI 1046 treatments to space learning and memory impairments in the medium-term and long-term rodent midium or long term of using 1046 pairs of space learnings of GPI and memory impairments present embodiment to be presented at aging of the rodent of aging.

Present method comprise use March big (youth) and the 18-19 month big (old) male C57BL/6N-Nia mouse, be put in the known common Morris water maze, carry out 4 every day and test 3-4 days visible platform training stage.Obtaining test with rear space carries out according to following: all mouse carry out 4 tests (unit), totally 5 days every day.The longest swimming time is 90 seconds.If the task of mouse in the unit 4 or 5 in the stage of acquisition finished more than the 1S.D. of the mean value that is higher than " youth " mouse, then incorporate in " old impaired " and organize, be less than 0.5 S.D. if task is finished the mean value that is higher than " youth " mouse, then do not incorporate in " old impaired " and organize.Year mouse is divided into to statistics similarly, and " GPI1046 " and " vehicle " organizes.

Obtaining training 10 milligrams/kilogram GPI beginning in back 3 days every day 1046 treatments, memory keeps test phase and also continues medication.Memory keeps test and adopts the method identical with the acquisition stage, begins after 3 weeks of medication.The swimming distance is analyzed with 7 * 5ANOVA, consideration group and unit (1-5) factor in the analysis, and the test of different units is as the repetition means.

The result shows the contrast of arranging by careful, is obtaining later stage in stage " youth " group and " old impaired-vehicle and GPI 1046 " treatment group has significant difference, is respectively F _1.58=26.75, P=0.0001, and F _1.58=17.70, P=0.0001.And two groups " old impaired " group does not have significant difference, F _1.58=0.67, P=0.42.But in memory kept test process, " old impaired-vehicle " treatment treated animal performance obviously was worse than " old impaired-GPI 1046 " treatment group and " youth " animal, is respectively F _1.69=8.11, P=0.006, and F _1.69=25.45, P=0.0001.Keep in the test process " youth " group and " old impaired-GPI1046 " treatment group no longer includes the significant difference on the statistics, F in memory _1.69=3.09, P=0.08.In brief, systematically there is the mouse of the spatial memory damage relevant to treat and obviously improves the spatial memory behavior with aging with 1046 couples of GPI.Embodiment 37

A patient suffers from the senile alopecia disease.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 38

A patient suffers from the male pattern alopecia disease.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 39

A patient suffers from the areatus alopecia disease.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 40

A patient suffers from the epilation that is caused by skin injury.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 41

A patient suffers from the epilation that is caused by tumour.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 42

Patient suffers from the epilation that is caused by system disorders such as nutrition disorder or endocrine regulation.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 43

A patient suffers from the epilation that is caused by chemotherapy.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 44

A patient suffers from the epilation that is caused by radiotherapy.Use bridged heterocyclic derivatives can for this patient, or contain the pharmaceutical composition of this compound.The natural on-off cycles of hair growth that expection takes place after treatment increases.Embodiment 45

A patient suffers from neurodegenerative disease.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 46

The disease of neurotic of patient.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 47

A patient suffers stroke.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 48

A patient suffers from Parkinson's disease.Use for this patient and contain N-heterocyclic carboxylic acid or carboxylic acid isostere, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 49

A patient suffers from Alzheimer's.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 50

A patient suffers from peripheral neuropathy.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 51

A patient suffers from amyotrophic lateral sclerosis.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 52

A patient suffers from spinal injury.Use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.The healthy state that is contemplated that this patient improves or recovers.Embodiment 53

A patient has the danger of suffering from neurodegenerative disease or neurologic disease.Prophylactically use bridged heterocyclic derivatives for this patient, or contain the pharmaceutical composition of this compound.Compare with those patients that do not carry out pretreat, be contemplated that to prevent some or all of these diseases or disorderly generation, perhaps its situation has obtained tangible improvement or recovery.Embodiment 54

A patient suffers from macular degeneration.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 55

A patient suffers from glaucoma, causes discus nervi optici to become recessed and nerve fiber is caused damage.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 56

A patient suffers from cataract, needs operation.After the operation, use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 57

A patient suffers from and diabetes type neuropathy, optic nerve local asphyxia, perhaps relevant retina blood supply damage or the retardance of arteria retina or vein obstruction.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 58

A patient suffers from retina and peels off.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 59

A patient suffers from the tissue injury that is caused by the inflammation relevant with uveitis or conjunctivitis.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 60

Patient's trouble contacts caused photoreceptor damage by long-term or short-term with UV-light.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 61

A patient suffers from optic neuritis.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 62

A patient suffers from and the relevant tissue injury of " dry eyes " illness.Use above definite pyrrolidin derivatives for this patient, separately or and one or more other neopsis factors together, or contain the pharmaceutical composition of this compound.The minimizing vision loss of expection taking place after treatment, prevent vision degeneration, and/or promotes vision regeneration.Embodiment 63

Preparation contains the lotion of the part use of following composition.

	(％)
		95% ethanol	80.0
The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	10.0
		The alpha-tocopherol acetic ester	0.01
The oxyethane of hardened castor oil (40 moles) adducts	0.5
		Purified water	9.0
Spices and dyestuff	In right amount

Oxyethane (40 moles) adducts, spices and the dyestuff of the immunophilin fkbp ligand body of the nonimmunosuppressive N-heterocyclic derivatives of adding, alpha-tocopherol acetic ester, hardened castor oil in 95% ethanol.The gained mixture is stirred and dissolving, and purified water is joined in this mixture, obtain transparent liquid lotion.

5 milliliters of these lotions can be used once or secondary at the position that obvious bald head or alopecia are arranged every day.Embodiment 64

Preparation contains the lotion of the part use of following composition.

	(％)
		95% ethanol	80.0
The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	0.005
		Hinokitiol	0.01
The oxyethane of hardened castor oil (40 moles) adducts	0.5
		Purified water	19.0
Spices and dyestuff	In right amount

Oxyethane (40 moles) adducts, spices and the dyestuff of the immunophilin fkbp ligand body of the nonimmunosuppressive N-heterocyclic derivatives of adding, Hinokitiol, hardened castor oil in 95% ethanol.With gained mixture stirring and dissolving, and purified water joined in this mixture, obtain transparent liquid lotion.

This lotion can be sprayed once to four times at the position that obvious bald head or alopecia are arranged every day.Embodiment 65

Prepare a kind of emulsion mutually with B mutually from A with following composition.

(A phase)	(％)
		Spermaceti	0.5
Hexadecanol	2.0
		Vaseline	5.0
Squalane	10.0
		Polyoxyethylene (10 moles) monostearate	2.0
Dehydrated sorbitol mono-fatty acid ester	1.0
		The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	0.01
(B phase)	(％)
		Glycerine	10.0
Purified water	69.0
		Spices, dyestuff and sanitas	In right amount

With A mutually with B heat fused and remain on 80 ℃ respectively mutually.Then two-phase is mixed also under agitation being cooled to normal temperature, obtain a kind of emulsion.

This emulsion can be sprayed once to four times at the position that obvious bald head or alopecia are arranged every day.Embodiment 66

Prepare a kind of emulsifiable paste mutually with B mutually from A with following composition.

(A phase)	(％)
		Liquid paraffin	5.0
Cetostearyl alcohol	5.5
		Vaseline	5.5
Zerol	33.0
		Polyoxyethylene (20 moles) 2-octyl group lauryl ether	3.0
Propylparaben	0.3
		(B phase)	％
The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	0.8
		Glycerine	7.0
Dipropylene glycol	20.0
		Macrogol 4000	5.0
Hexamethyl phosphoric acid sodium	0.005
		Purified water	44.895

With A heat phase fusing and remain on 70 ℃.With B be added to A mutually in and mixture stirred, obtain a kind of emulsion.Then this emulsion cooling is obtained a kind of emulsifiable paste.

This emulsifiable paste can be used once to four times at the position that obvious bald head or alopecia are arranged every day.Embodiment 67

Preparation contains a kind of local liquid that uses of following composition.

	(％)
		The polyoxyethylene butyl ether	20.0
Ethanol	50.0
		The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	0.001
Propylene glycol	5.0
		Polyoxyethylene hardened castor oil derivative (80 moles of adductss of oxyethane)	0.4
Spices	In right amount
		Purified water	In right amount

The immunophilin fkbp ligand body and the spices that in ethanol, add polyoxyethylene butyl ether, propylene glycol, polyoxyethylene hardened castor oil, nonimmunosuppressive N-heterocyclic derivatives.The gained mixture is stirred, and purified water is joined in this mixture, obtain a kind of liquid.

This liquid can be used once to four times at the position with obvious bald head or alopecia every day.Embodiment 68

Preparation contains a kind of shampoo of following composition.

	(％)
		Sodium lauryl sulphate	5.0
The dodecyl sulphate triethanol ammonium	5.0
		Trimethyl-glycine dodecyl dimethyl Glycinates	6.0
Unister E 275	2.0
		Polyoxyethylene glycol	5.0
The immunophilin fkbp ligand body of nonimmunosuppressive N-heterocyclic derivatives	5.0
		Ethanol	2.0
Spices	0.3
		Purified water	69.7

In the 69.7g purified water, add 5.0g sodium lauryl sulphate, 5.0g dodecyl sulphate triethanol ammonium, 6.0g trimethyl-glycine dodecyl dimethyl Glycinates.Add the immunophilin fkbp ligand body of the nonimmunosuppressive N-heterocyclic derivatives of 5.0g then in 2.0g ethanol, 5.0g polyoxyethylene glycol and 2.0g Unister E 275 obtain a kind of mixture, stir then, and add 0.3g spices.With the gained mixture heating up, cooling obtains a kind of shampoo then.

This shampoo can be used for having one's hair wash once a day or secondary.

Claims (80)

1. General formula I ': Compound or the acceptable salt of its medicine, ester or solvate, wherein:

   A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom;

   V is CH, S or N;

   X is O, CH ₂, or S;

   M is 0 or 1;

   G is Or

   

   R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

   The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nThe C that replaces ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl is by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

   Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound;

   Perhaps, R ₁Be general formula independently: Part,

   Wherein:

   R ₃Independently for optionally by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

   X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

   R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

   R ₂Independently or be hydrogen or for P;

   Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

   P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

   U or be O or for N, its precondition is:

   When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

   When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

   W and Y are O, S, CH independently ₂Or H ₂

   Z is C (R ₁) ₂, O, S, directly key or NR ₁Perhaps

   Z-R ₁Be independently Or

   

   Wherein:

   C and D are hydrogen, bridged ring part, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, or S (O) _pSubstitute;

   C ' and D ' are hydrogen, bridged ring part, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be

   

   Wherein

   Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

   T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

   J is O, NR ₁, S or (CR ₁) ₂

   K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

   Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

   K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

   K " is C (R ₁) ₂, O, S, directly key or NR ₁

   L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, bridged ring part and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

   L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

   N is 1 or 2;

   P is 0,1 or 2;

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

   Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

   Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

   Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

   R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.
2. 2. the compound of claim 1, wherein this compound is a general formula I

   

   Or the acceptable salt of its medicine, ester or solvate, wherein:

   A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₂Heteroatoms in the group of being formed;

   X or be O or for S;

   Z or be S, CH ₂, CHR ₁, perhaps be CR ₁R ₃

   W and Y are O, S, CH independently ₂Or H ₂

   R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part, and Ar ₂Substituting group in the group of being formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

   Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
3. 3. the compound of claim 2, wherein this compound is general formula I I:

   

   Or the acceptable salt of its medicine, ester or solvate, wherein:

   N is 1 or 2;

   Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring (working as n=1) or piperidine ring (working as n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

   X is O or S;

   Z is selected from by S, CH ₂, CHR ₁, and CR ₁R ₃In the group of being formed;

   R ₁And R ₃Be independently selected from by C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part and Ar ₁In the group of being formed, wherein said alkyl, thiazolinyl or Ar ₁For unsubstituted or be independently selected from by halogen, nitro, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, bridged ring part, hydroxyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, amino and Ar ₁Substituting group in the group of being formed replaces;

   R ₂Be independently selected from by C ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁In the group of being formed; With

   Ar ₁Be phenyl, benzyl, pyridyl, fluorenyl, sulfo-indyl or naphthyl independently, wherein said Ar ₁For not replacing, perhaps be independently selected from by halogen, trifluoromethyl, hydroxyl, nitro, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces.
4. 4. the compound of claim 2, wherein this compound is a general formula III:

   

   Or the acceptable salt of its medicine, ester or solvate, wherein:

   A, B and C are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

   Br is heterocyclic bridged loop section, wherein A, B and C any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

   X is O or S;

   Z is S, CH ₂, CHR ₁Or CR ₁R ₃

   R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, bridged ring part, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl and Ar ₂Substituting group in the group of being formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

   Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
5. 5. the compound of claim 2, wherein this compound is general formula I V: Or the acceptable salt of its medicine, ester or solvate, wherein:

   A, B, C and D are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

   Br is heterocyclic bridged loop section, wherein A, B, C and D any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

   X is O or S;

   Z is S, CH ₂, CHR ₁Or CR ₁R ₃

   R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

   Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
6. 6. the compound of claim 1, wherein this compound is general formula V:

   

   Or the acceptable salt of its medicine, ester or solvate, wherein:

   V is CH, N or S;

   A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₄Heteroatoms in the group of being formed;

   X or be O or for S;

   Z or be S, CH ₂, CHR ₁, perhaps be CR ₁R ₃

   W and Y are O, S, CH independently ₂Or H ₂

   R ₁And R ₃Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces;

   R ₄Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, R wherein ₄Perhaps, perhaps be independently selected from by halogen, halo-C by one or more for not replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₄Substituting group in the group of being formed replaces; With

   Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
7. 7. the compound of claim 1, wherein this compound is general formula VI:

   

   Or the acceptable salt of its medicine, ester or solvate, wherein:

   The atom that A and B are connected with them forms a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₁Heteroatoms in the group of being formed;

   X is O or S;

   Z is O, NH or NR ₁

   W and Y are O, S, CH independently ₂Or H ₂

   R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl, bridged ring part and hydroxyl are formed replaces; With

   Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein said ring or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
8. 8. the compound of claim 7, wherein this compound is general formula VII: Or the acceptable salt of its medicine, ester or solvate, wherein:

   A, B and C are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

   Br is heterocyclic bridged loop section, wherein A, B and C any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

   R ₁Be C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl or bridged ring part, they are independently selected from by (Ar by one or more ₁) _nWith by (Ar ₁) _nThe C that is replaced ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces;

   N is 1 or 2;

   R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁With

   Ar ₁Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, ring wherein or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
9. 9. the compound of claim 8, wherein this compound is a general formula: Or the acceptable salt of its medicine, ester or solvate, wherein:

   Br is heterocyclic bridged loop section, wherein A, B and C any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond.
10. 10. the compound of claim 8, wherein:

    A is CH ₂

    B is CH ₂Or S;

    C is CH ₂Or NH;

    R ₁Be selected from the group of forming by 3-phenyl propyl and 3-(3-pyridyl) propyl group; With

    R ₂Be selected from by 1, in the group that 1-dimethyl propyl, cyclohexyl and the tertiary butyl are formed.
11. 11. the compound of claim 7, wherein this compound is general formula VIII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A, B, C and D are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

    Br is heterocyclic bridged loop section, wherein A, B, C and D any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be C independently ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _nWith by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces;

    N is 1 or 2;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁With

    Ar ₁Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, ring wherein or for replacing perhaps is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
12. 12. the compound of claim 11, wherein:

    A is CH ₂

    B is CH ₂

    C is S, O or NH;

    D is CH ₂

    R ₁Be selected from the group of forming by 3-phenyl propyl and (3,4, the 5-trimethoxy) phenyl propyl; With

    R ₂Be selected from by 1,1-dimethyl propyl, cyclohexyl, the tertiary butyl, phenyl and 3,4 are in the group that the 5-trimethoxyphenyl is formed.
13. 13. the compound of claim 1, wherein this compound is general formula I X:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed;

    R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, wherein R or for replacing perhaps is independently selected from by halogen, halo-C by one or more ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₄Substituting group in the group of being formed replaces;

    Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

    X is O or S;

    Z is O, NH or NR ₁

    W and Y are O, S, CH independently ₂Or H ₂

    R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl or bridged ring part, wherein said alkyl or alkenyl is independently selected from by (Ar by one or more ₁) _n, by (Ar ₁) _nThe C that replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl and Ar ₂Substituting group in the group of being formed replaces;

    N is 1 or 2;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group or for replacing perhaps are independently selected from by C by one or more ₁-C ₄Straight or branched alkyl, C ₂-C ₄Substituting group in the group that straight or branched thiazolinyl and hydroxyl are formed replaces; With

    Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps be independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S.
14. 14. the compound of claim 1, wherein this compound is a general formula X:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₁Heteroatoms in the group of being formed;

    W is O, S, CH ₂Or H ₂

    R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

    Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by bridged ring part or C ₁-C ₆Straight or branched alkyl or C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

    Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl; With

    R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.
15. 15. the compound of claim 14, wherein this compound is general formula X I:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

    Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    W is O, S, CH ₂Or H ₂

    R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

    Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

    Said aromatic amine is pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

    Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.
16. 16. the compound of claim 14, wherein this compound is general formula X II: Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F and G are CH independently ₂, O, S, SO, SO ₂, NH or NR ₁

    Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    W is O, S, CH ₂Or H ₂

    R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

    Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

    Said aromatic amine is pyridyl, pyrimidyl, quinolyl or isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

    Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.
17. 17. the compound of claim 14, wherein this compound is general formula X III:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1,2 or 3, forms the heterocyclic ring of a 5-7 unit;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n is 1,2 or 3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    W is O, S, CH ₂Or H ₂

    R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₁Substituting group in the group of being formed replaces;

    Ar ₁Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

    Said aromatic amine is pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by C ₁-C ₆Straight or branched alkyl, bridged ring part and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

    Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.
18. 18. the compound of claim 1, wherein this compound is general formula X IV: Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₇Heteroatoms in the group of being formed;

    R ₇Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₃, R wherein ₇Perhaps, perhaps be independently selected from by halogen, halo-C by one or more for not replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, bridged ring part, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl and Ar ₄Substituting group in the group of being formed replaces;

    Ar ₃And Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

    W is O, S, CH ₂Or H ₂

    R is C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁They optionally are independently selected from by C by one or more ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 1-indyl, 2-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they have one or more being independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, NH, NR ₁, S, CH, CR ₁, or CR ₁R ₃

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound;

    Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, or they are for not replacing, and perhaps are independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Said tertiary amine is NR ₄R ₅R ₆, R wherein ₄, R ₅, and R ₆Be independently selected from by bridged ring part or C ₁-C ₆Straight or branched alkyl or C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in cycloalkenyl group, bridged ring part, the group that hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Any carbon atom of wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar is optionally used O, NH, NR ₁, S, SO or SO ₂Substitute;

    Ar independently is selected from the group of being made up of pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl; With

    R ₁And R ₃Be hydrogen, C independently ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part or Y-Z.
19. 19. the compound of claim 1, wherein this compound is general formula X V:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₃Heteroatoms in the group of being formed; Or

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₃Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆Substituting group in the group that-ester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; The optionally selected free C of wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or the substituting group in the group formed of alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    W is O or S; With

    U or be O or for N, its precondition is:

    When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, C ₃-C ₈Cycloalkyl, bridged ring part, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, C ₃-C ₁₀Cycloalkyl, bridged ring part, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl is independently selected from by Ar, bridged ring part and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.
20. 20. the compound of claim 19, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
21. 21. the compound of claim 19, wherein this compound is general formula X VI-

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₃

    Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Replace;

    W is O or S; With

    U or be O or for N, its precondition is:

    When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, C ₃-C ₈Cycloalkyl, bridged ring part, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.
22. 22. the compound of claim 21, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
23. 23. the compound of claim 19, wherein this compound is general formula X VII: Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F and G are CH independently ₂, O, S, SO, SO ₂, NH and NR ₃

    Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps optionally be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    W is O or S; With

    U or be O or for N, its precondition is:

    When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.
24. 24. the compound of claim 23, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
25. 25. the compound of claim 19, wherein this compound is general formula X VIII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1,2 or 3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n is 1,2 or 3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₃Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆-ester, thioformamide base, trifluoromethyl and comprise fat and group that the carboxylic acid of aromatic structure and heterocyclic moiety are formed in substituting group replace; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    W is O or S; With

    U or be O or for N, its precondition is:

    When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together.
26. 26. the compound of claim 25, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
27. 27. the compound of claim 1, wherein this compound is general formula X IX: Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₃Heteroatoms in the group of being formed; Or

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₃Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps be independently selected from by C by one or more ₁-C ₆-alkylamino, amido, amino, amino-C ₁-C ₆-alkyl, azo-group, benzyloxy, C ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, C ₁-C ₆-ester, formylaniline base, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, sulfo--C ₁-C ₆-alkyl, thiocarbonyl, sulfo-cyano group, sulfo--C ₁-C ₆Substituting group in the group that-ester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    W is O or S; With

    U or be O or for N, its precondition is:

    When U is O, R ₁Be lone-pair electron, R ₂Be selected from by Ar, C ₃-C ₈Cycloalkyl, bridged ring part, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U is N, R ₁And R ₂Be independently selected from by hydrogen, Ar, C ₃-C ₁₀Cycloalkyl, bridged ring part, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl is independently selected from by Ar, bridged ring part and C by one or more ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ₁And R ₂Form a kind of 5-unit in the group of forming by tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
28. 28. the compound of claim 1, wherein this compound is general formula X X-

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₂Heteroatoms in the group of being formed;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

    R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
29. 29. the compound of claim 28, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
30. 30. the compound of claim 29, wherein A forms a kind of 6 yuan saturated or unsaturated bridged heterocyclic ring with B with nitrogen-atoms and the carbon atom that they are connected respectively; R ₂Be C ₄-C ₇Branched-chain alkyl, C ₄-C ₇Cycloalkyl, phenyl or 3,4, the 5-trimethoxyphenyl.
31. 31. the compound of claim 28, wherein this compound is general formula X XI:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F, G and J are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

    Br is heterocyclic bridged loop section, wherein E, F, G and J any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

    R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
32. 32. the compound of claim 31, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
33. 33. the compound of claim 28, wherein this compound is general formula X XII: Or the acceptable salt of its medicine, ester or solvate, wherein:

    E, F and G are CH independently ₂, O, S, SO, SO ₂, NH or NR ₂

    Br is heterocyclic bridged loop section, wherein E, F and G any two or more or by chemical bond, perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl or hydroxyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

    R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
34. 34. the compound of claim 33, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
35. 35. the compound of claim 28, wherein this compound is general formula X XIII: Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1,2 or 3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n is 1,2 or 3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl or hydroxyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute: and

    R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
36. 36. the compound of claim 35, wherein Ar is selected from the group of being made up of phenyl, benzyl, naphthyl, indyl, pyridyl, pyrryl, pyrrolidyl, pyridyl, pyrimidyl, purine radicals, quinolyl, isoquinolyl, furyl, fluorenyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, pyrazolyl and thienyl.
37. 37. the compound of claim 1, wherein this compound is general formula X XIV:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, N, NH and NR ₂Heteroatoms in the group of being formed;

    X or be O or for S;

    Y is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the Sauerstoffatom that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute;

    R ₂Be independently selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein is at nitrogen-atoms and contain and form bridge between the carbon atom of said heteroatomic said alkyl or alkenyl chain to form a kind of ring, and wherein said ring optionally is fused on the Ar base;

    Ar be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Z is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl is at its one or more regioselectivities ground quilt amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-ester, sulfo--C ₁-C ₆-ester, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, alkylsulfonyl or replaced with the oxygen that forms carbonyl, perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute;

    C and D are hydrogen, Ar, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, hydroxyl, ketonic oxygen and Ar formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Alkyl or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₂, S, SO or SO ₂Substitute; With

    R ₁Be independently selected from by Ar, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by Ar, bridged ring part, C by one or more ₃-C ₈Cycloalkyl, amino, halogen, halo-C ₁-C ₆-alkyl, hydroxyl, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, carbonyl, thiocarbonyl, C ₁-C ₆Ester group, sulfo--C ₁-C ₆Ester group, C ₁-C ₆Alkoxyl group, C ₂-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--C ₁-C ₆Substituting group in the group that alkyl and alkylsulfonyl are formed replaces; Wherein any carbon atom of said alkyl or alkenyl is optionally used O, NH, NR ₃, S, SO or SO ₂Substitute.
38. 38. the compound of claim 1, wherein this compound is general formula X XV:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when t is 1,2 or 3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl wherein said Ar ₁For not replacing, perhaps be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    X is O, S, CH ₂Or H ₂

    Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z ₁-C ₆Alkyl; With

    Each Z is C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment

    

    Wherein:

    R ₃Be C independently ₁-C ₉The straight or branched alkyl, it is not for replacing or by C ₃-C ₈Cycloalkyl, bridged ring part or Ar ₁Replace;

    X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed;

    N is 1 or 2; With

    T is 1,2 or 3.
39. 39. the compound of claim 38, wherein this compound is general formula X XVI;

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl wherein said Ar ₁For not replacing, perhaps be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces;

    Z is C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment

    

    Wherein:

    R ₃Be C independently ₁-C ₉The straight or branched alkyl, it is not for replacing or by C ₃-C ₈Cycloalkyl, bridged ring part or Ar ₁Replace;

    X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; With

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed.
40. 40. the compound of claim 38, wherein this compound is general formula X XVII: Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    Z ' is a fragment Wherein:

    R ₃Be C independently ₁-C ₉Straight or branched alkyl or unsubstituted Ar ₁, wherein said alkyl is not for replacing or by C ₃-C ₈Cycloalkyl, bridged ring part or Ar ₁Replace;

    X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; With

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed; With

    Ar ₁Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-indyl, 3-indyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl wherein said Ar ₁For not replacing, perhaps be independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces.
41. 41. the compound of claim 38, wherein this compound is general formula X XVIII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be C independently ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₆Cycloalkyl, bridged ring part or Ar ₁, wherein said alkyl or alkenyl or for replacing, perhaps by C ₃-C ₆Cycloalkyl or Ar ₂Replace;

    Ar ₁And Ar ₂Be independently selected from the group of forming by 2-furyl, 2-thienyl and phenyl;

    X is selected from the group of being made up of oxygen and sulphur;

    Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z independently ₁-C ₆Alkyl; With

    Each Z is hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by 2-furyl, 2-thienyl, C by one or more ₃-C ₆Substituting group in the group that cycloalkyl, pyridyl and phenyl are formed replaces, and each substituting group has one or more being independently selected from by hydrogen and C ₁-C ₄Substituting group in the group that alkoxyl group is formed; With

    N is 1 or 2.
42. 42. the compound of claim 1, wherein this compound is general formula X XIX: Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more being independently selected from by O, S, SO, SO ₂, the heteroatoms in the group that N, NH and NR formed; Or

    R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R or for replacing perhaps is independently selected from by halogen, halo-C by one or more ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    R ₁Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said R ₁Perhaps, perhaps be independently selected from by C by one or more for not replacing ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein should ring or for replacement, perhaps replaced by one or more substituting group; Wherein independent ring is a 5-8 unit ring; Wherein said heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

    X is O, S, CH ₂Or H ₂

    Y is O or NR ₂, R wherein ₂Be direct key, hydrogen or the C that is connected with Z ₁-C ₆Alkyl; With

    Each Z is C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, wherein said Z is independently selected from by Ar by one or more ₁, C ₃-C ₈Cycloalkyl and by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆Substituting group in the group that the straight or branched thiazolinyl is formed replaces, and perhaps Z is a fragment

    

    Wherein:

    R ₃Independently for not replacing or by C ₃-C ₈The C that cycloalkyl replaced ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

    X ₂Be O or NR ₅, R wherein ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, bridged ring part, the C that is replaced by phenyl ₁-C ₅Straight or branched alkyl and the C that is replaced by phenyl ₂-C ₅In the group of being formed in the group that the straight or branched thiazolinyl is formed; With

    N is 1 or 2.
43. 43. the compound of claim 1, wherein this compound is general formula LV:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    M is 0-3;

    A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

    B and D be hydrogen, bridged ring part, Ar independently, by C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, by C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl or the C that is replaced by Ar ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein in each case, one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be fragment

    

    Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Ar is independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed;

    L or be hydrogen or for U; M or be oxygen or for CH-U, its precondition is when L is hydrogen, M is CH-U, perhaps when M was oxygen, L was U;

    U is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

    J is hydrogen, C ₁Or C ₂Alkyl, or benzyl;

    K is C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or

    J forms a kind of by oxygen, sulphur, SO or SO with the atom that K is connected with them ₂Saturated, the undersaturated or fragrant heterocycle or the carbocyclic ring bridged ring part that replace.
44. 44. the compound of claim 43, wherein this compound is general formula LVI:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A is O, NH or N-(C ₁-C ₄Alkyl);

    B is hydrogen, CHL-Ar, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, C ₅-C ₇The C that cycloalkenyl group, Ar replace ₁-C ₆Alkyl or C ₂-C ₆Thiazolinyl perhaps is

    

    Wherein L and Q are hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cyclohexyl;

    Ar is independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, they contain 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, CF ₃, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), in the group that O-benzyl, O-phenyl, amino and phenyl are formed;

    D or be hydrogen or for U; E is oxygen or CH-U, and its precondition is when D is hydrogen, and E is CH-U, and perhaps when E was oxygen, D was U;

    U is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, 2-indyl, 3-indyl, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

    J is hydrogen, C ₁Or C ₂Alkyl, or benzyl;

    K is C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl ethyl; Or

    J forms a kind of by oxygen, sulphur, SO or SO with the atom that K is connected with them ₂Saturated, the undersaturated or fragrant heterocycle or the carbocyclic ring bridged ring part that replace.
45. 45. the compound of claim 43, wherein this compound is general formula LVII: Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 2;

    Br is heterocyclic bridged loop section, and any two or more atoms of piperidine ring (when n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    D is phenyl, methoxyl group, 2-furyl or 3,4, the 5-trimethoxyphenyl; With

    B is benzyl, 3-phenyl propyl, 4-(4-p-methoxy-phenyl) butyl, 4-phenyl butyl, styroyl, 3-cyclohexyl propyl group, 4-cyclohexyl butyl, 3-cyclopentyl propyl group, 4-cyclohexyl butyl, 3-phenoxy benzyl, 3-(3-indyl) propyl group or 4-(4-p-methoxy-phenyl) butyl.
46. 46. the compound of claim 1, wherein this compound is general formula LVIII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R perhaps is independently selected from by halogen, halo-C by one or more independently or for replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

    M is 0-3;

    A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

    B and D be hydrogen, bridged ring part, Ar independently, by C ₅-C ₇The C of cycloalkyl substituted ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, by C ₅-C ₇The C that cycloalkenyl group replaces ₁-C ₆Straight or branched alkyl or C ₂-C ₆Straight or branched thiazolinyl or the C that is replaced by Ar ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein in each case, one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be fragment Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Ar is independently selected from the group of being made up of 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed;

    L or be hydrogen or for U; M or be oxygen or be ^CH-U, its precondition is when L is hydrogen, M is ^CH-U, perhaps when M was oxygen, L was U;

    U is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With

    J forms a kind of by oxygen, sulphur, SO or SO with the atom that K is connected with them ₂Saturated, the undersaturated or fragrant heterocycle or the carbocyclic ring bridged ring part that replace.
47. 47. the compound of claim 1, wherein this compound is general formula LIX:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

    B and D are Ar, bridged ring part, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Its precondition is that B and D not all are hydrogen;

    Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

    E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar;

    J forms a kind of by oxygen, sulphur, SO or SO with the atom that K is connected with them ₂Saturated, the undersaturated or fragrant heterocycle or the carbocyclic ring bridged ring part that replace; With

    N is 0-3.
48. 48. the compound of claim 47, wherein this compound is general formula LX:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1 or 2;

    Br is heterocyclic bridged loop section, and any two or more atoms of pyrrolidine ring (when n=1) or piperidine ring (when n=2) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    B and D are Ar, bridged ring part, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Its precondition is that B and D not all are hydrogen; With

    M is 0 or 1.
49. 49. the compound of claim 47, wherein this compound is general formula LXI: Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and any two or more atoms of wherein main piperidine ring or by chemical bond are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    B and D are Ar, bridged ring part, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by O, S, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Its precondition is that B and D not all are hydrogen;

    Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

    E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With m be 0-3.
50. 50. the compound of claim 49, wherein this compound is general formula LXII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    Br is heterocyclic bridged loop section, and any two or more atoms of wherein main piperidine ring or by chemical bond are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond; With

    B and D are Ar, bridged ring part, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by O, S, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be

    

    Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Its precondition is that B and D not all are hydrogen;

    Ar is independently selected from the group of being made up of phenyl, 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Wherein Ar contains 1-3 substituting group, and this substituting group is independently selected from by hydrogen, halogen, hydroxyl, nitro, trifluoromethyl, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, 1, in the group that 2-methylene radical dioxy base, amino, carbonyl and phenyl are formed;

    E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With

    M is 0-3.
51. 51. the compound of claim 1, wherein this compound is general formula LXIII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    V is CH, N or S;

    A is CH ₂, O, NH or N-(C ₁-C ₄Alkyl);

    B and D are Ar, bridged ring part, hydrogen, C independently ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is not for replacing or by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar or is independently selected from by hydrogen, hydroxyl, O-(C by one or more 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    Its precondition is that B and D not all are hydrogen;

    R is C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein R perhaps is selected from by halogen, halo-C by one or more independently or for replacing ₁-C ₆Alkyl, carbonyl, carboxyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Alkene oxygen base, phenoxy group, benzyloxy, sulfo--C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, amino, C ₁-C ₆Alkylamino, amino-C ₁-C ₆Alkyl, amino carboxyl, bridged ring part and Ar ₂Substituting group in the group of being formed replaces;

    Ar ₁And Ar ₂Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring; The size of wherein independent ring is a 5-8 unit; Heterocyclic ring wherein contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S;

    E is C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₂-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar or Ar; With

    J forms a kind of one or more being selected from by oxygen, sulphur, SO, SO of containing with the atom that K is connected with them ₂, heteroatomic saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part in the group that N, NH and NR formed; With

    N is 0-3.
52. 52. the compound of claim 1, wherein this compound is general formula LXIV: Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1-3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    X or be O or for S;

    R ₁Be independently selected from by C ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring or heterocycle are formed;

    D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl; With

    R ₂Be carboxylic acid or carboxylic acid isostere independently.
53. 53. the compound of claim 52, wherein R ₂Be selected from following group:

    By-COOH ,-SO ₃H ,-SO ₂HNR ³,-PO ₂(R ³) ₂,-CN ,-PO ₃(R ³) ₂,-OR ³,-SR ³,-NHCOR ³,-N (R ³) ₂,-CON (R ³) ₂,-CONH (O) R ³,-CONHNHSO ₂R ³,-COHNSO ₂R ³With-CONR ³In the group that CN formed, R wherein ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.
54. 54. the compound of claim 1, wherein this compound is general formula LXV:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    X, Y and Z are independently selected from the group of being made up of C, O, S or N, and its precondition is that X, Y and Z not all are C;

    N is 1-3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    A is selected from by L ₁, L ₂, L ₃Or L ₄In the group of being formed, L wherein ₁For L ₂For L ₃For

    

    And L ₄For

    

    R ₁Be independently selected from by hydrogen, C with E ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

    R ₂Isostere for carboxylic acid or carboxylic acid;

    The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

    R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.
55. 55. the compound of claim 54, wherein this compound is general formula LXVI:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1-3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be independently selected from by hydrogen, C with A ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

    D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl;

    R ₂Be carboxylic acid or carboxylic acid isostere independently;

    The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

    R ³Be hydrogen, hydroxyl, halogen, halo-C ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.
56. 56. the compound of claim 54, wherein this compound is general formula LXVII:

    

    Or the acceptable salt of its medicine, ester or solvate, wherein:

    N is 1-3;

    Br is heterocyclic bridged loop section, and main any two or more atoms of ring (when n=1-3) or by chemical bond wherein are perhaps by the bonding each other of the atom that does not contain main ring structure part beyond the chemical bond;

    R ₁Be independently selected from by hydrogen, C ₁-C ₉Straight or branched alkyl, C ₂-C ₉In the group that straight or branched thiazolinyl, bridged ring part, aryl, heteroaryl, carbocyclic ring and heterocycle are formed;

    D is a key, perhaps is C ₁-C ₁₀Straight or branched alkyl, C ₂-C ₁₀Thiazolinyl or C ₂-C ₁₀Alkynyl;

    R ₂Be carboxylic acid or carboxylic acid isostere independently;

    The isostere of wherein said alkyl, thiazolinyl, alkynyl, aryl, heteroaryl, carbocyclic ring, heterocycle or carboxylic acid is optionally by one or more R that are selected from ³Substituting group replace, wherein

    R ³Be hydrogen, hydroxyl, halogen, halo-C independently ₁-C ₆-alkyl, thiocarbonyl, C ₁-C ₆-alkoxyl group, C ₂-C ₆-alkene oxygen base, C ₁-C ₆-alkyl-aryloxy, aryloxy, aryl-C ₁-C ₆-alkoxyl group, cyano group, nitro, imino-, C ₁-C ₆-alkylamino, amino-C ₁-C ₆-alkyl, sulfydryl, sulfo--C ₁-C ₆-alkyl, C ₁-C ₆-alkylthio, alkylsulfonyl, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched alkenyl or alkynyl, bridged ring part, aryl, heteroaryl, carbocyclic ring, heterocycle or CO ₂R ⁴, R wherein ⁴Be hydrogen or C ₁-C ₉The straight or branched alkyl or alkenyl.
57. 57. a pharmaceutical composition, said composition contains:

    A. a kind of bridged heterocyclic derivatives of significant quantity; With

    B. medicine acceptable carrier.
58. 58. the pharmaceutical composition of claim 57, bridged heterocyclic derivatives wherein be general formula I ':

    

    Compound or the acceptable salt of its medicine, ester or solvate, wherein:

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom;

    V is CH, S or N;

    X is O, CH ₂, or S;

    M is 0 or 1;

    G is

    

    Or

    

    R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

    The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nThe C that replaces ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl is by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

    Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound;

    Perhaps, R ₁Be general formula independently:

    

    Part,

    Wherein:

    R ₃Independently for optionally by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

    X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

    R ₂Independently or be hydrogen or for P;

    Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

    P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

    U or be O or for N, its precondition is:

    When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

    W and Y are O, S, CH independently ₂Or H ₂

    Z is C (P ₁) ₂, O, S, directly key or NR ₁Perhaps

    Z-R ₁Be independently Or

    

    Wherein:

    C and D are hydrogen, bridged ring part, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, or S (O) _pSubstitute;

    C ' and D ' are hydrogen, bridged ring part, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be

    

    Wherein

    Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    J is O, NR ₁, S or (CR ₁) ₂

    K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

    Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

    K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    K " is C (R ₁) ₂, O, S, directly key or NR ₁

    L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, bridged ring part and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

    L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    N is 1 or 2;

    P is 0,1 or 2;

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

    Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

    R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.
59. 59. a method for the treatment of the neurologic illness of animal, this method comprises:

    Use a kind of bridged heterocyclic derivatives of significant quantity for this animal.
60. 60. the method for claim 59, bridged heterocyclic derivatives wherein be general formula I ':

    

    Compound or the acceptable salt of its medicine, ester or solvate, wherein:

    A is hydrogen, C ₁Or C ₂Alkyl or benzyl, B are C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom;

    V is CH, S or N;

    X is O, CH ₂, or S;

    M is 0 or 1;

    G is

    

    Or

    R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

    The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nThe C that replaces ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl is by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

    Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound;

    Perhaps, R ₁Be general formula independently:

    

    Part,

    Wherein:

    R ₃Independently for optionally by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

    X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

    R ₂Independently or be hydrogen or for P;

    Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

    P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

    U or be O or for N, its precondition is:

    When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

    W and Y are O, S, CH independently ₂Or H ₂Z is C (R ₁) ₂, O, S, directly key or NR ₁Perhaps Z-R ₁Be independently

    

    Or

    

    Wherein:

    C and D are hydrogen, bridged ring part, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, or S (O) _pSubstitute;

    C ' and D ' are hydrogen, bridged ring part, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein

    Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    J is O, NR ₁, S or (CR ₁) ₂

    K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

    Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

    K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    K " is C (R ₁) ₂, O, S, directly key or NR ₁

    L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, bridged ring part and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

    L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    N is 1 or 2;

    P is 0,1 or 2;

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

    Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

    R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.
61. 61. the method for claim 60, wherein said neurologic illness are selected from the Peripheral nerve disease that caused by physical damnification or morbid state, brain physical damnification, spinal cord physical damnification, the apoplexy relevant with brain injury and relevant neurologic illness is formed with neurodegeneration the group.
62. 62. the method for claim 60, wherein said neurologic illness is selected from the group of being made up of Alzheimer's, Parkinson's disease and amyotrophic lateral sclerosis.
63. 63. the method for claim 60, wherein said neurologic illness is an Alzheimer's.
64. 64. the method for claim 60, wherein said neurologic illness is a Parkinson's disease.
65. 65. the method for claim 60, wherein said neurologic illness is amyotrophic lateral sclerosis.
66. 66. the method for claim 59, wherein said bridged heterocyclic derivatives right and wrong are immunosuppressant.
67. 67. the method for claim 59, wherein said bridged heterocyclic derivatives has affinity to FKBP type immunophilin.
68. 68. the method for claim 67, wherein said FKBP type immunophilin is FKBP-12.
69. 69. an alopecia or a trichogenous method for the treatment of animal, this method comprises a kind of bridged heterocyclic derivatives of using significant quantity to said animal.
70. 70. the method for claim 69, wherein said bridged heterocyclic derivatives right and wrong are immunosuppressant.
71. 71. the method for claim 69, wherein said bridged heterocyclic derivatives has affinity to FKBP type immunophilin.
72. 72. the method for claim 71, wherein said FKBP type immunophilin is FKBP-12.
73. 73. the method for claim 69, wherein said bridged heterocyclic derivatives be general formula I ':

    

    Compound or the acceptable salt of its medicine, ester or solvate, wherein:

    A is hydrogen, C ₁Or C ₂Alkyl or benzyl, B are C ₁-C ₄Straight or branched alkyl, benzyl or cyclohexyl methyl; Or

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom;

    V is CH, S or N;

    X is O, CH ₂, or S; M is 0 or 1; G is

    

    Or

    

    R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

    The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nThe C that replaces ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl is by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

    Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound; Perhaps, R ₁Be general formula independently: Part,

    Wherein:

    R ₃Independently for optionally by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

    X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

    R ₂Independently or be hydrogen or for P;

    Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

    P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

    U or be O or for N, its precondition is:

    When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together;

    W and Y are O, S, CH independently ₂Or H ₂

    Z is C (R ₁) ₂, O, S, directly key or NR ₁Perhaps

    Z-R ₁Be independently Or

    

    Wherein:

    C and D are hydrogen, bridged ring part, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl with O, NR ₅, or S (O) _pSubstitute;

    C ' and D ' are hydrogen, bridged ring part, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein

    Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    J is O, NR ₁, S or (CR ₁) ₂

    K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

    Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

    K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    K " is C (R ₁) ₂, O, S, directly key or NR ₁

    L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, bridged ring part and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

    L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    N is 1 or 2;

    P is 0,1 or 2;

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

    Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

    R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.
74. 74. a vision illness for the treatment of animal, the eyesight of improving, the treatment memory impairment relevant with the age, the method for hypermnesis function, this method comprises a kind of bridged heterocyclic derivatives of using significant quantity to said animal.
75. 75. the method for claim 74, wherein said bridged heterocyclic derivatives are immunosuppressant or non-immunosuppressant.
76. 76. the method for claim 74, wherein said bridged heterocyclic derivatives has affinity to FKBP type immunophilin.
77. 77. the method for claim 76, wherein said FKBP type immunophilin is FKBP-12.
78. 78. the method for claim 74, wherein said vision illness is selected from by eyesight and detracts; The eye socket illness; Lacrimal apparatus's illness; The eyelid illness; Disorder of conjunctiva; Disorder of cornea; Cataract; The uveal tract illness; Retinal disorder; Optic nerve or visual pathway illness; Eye disease and disease that free radical causes; The eye disease and the disease of immunology mediation; Ocular injury; In the group that the symptom of ophthalmic diseases, eye disease or ocular injury and complication are formed.
79. 79. the method for claim 74, this method are to improve congenital visual disturbance under the situation without any ophthalmology illness, i or I.
80. 80. the method for claim 74, wherein said bridged heterocyclic derivatives be general formula 1 ':

    

    Compound or the acceptable salt of its medicine, ester or solvate, wherein:

    A and B, the atom that is connected with them form a kind of saturated, undersaturated or fragrant heterocycle or carbocyclic ring bridged ring part together, and this ring contains one or more O, C (R ₁) ₂, S (O) _p, N, NR ₁, or NR ₅Atom;

    V is CH, S or N;

    X is O, CH ₂, or S;

    M is 0 or 1;

    G is Or

    

    R ₁Be hydrogen, C independently ₁-C ₉Straight or branched alkyl or C ₂-C ₉Straight or branched alkenyl or alkynyl, C ₃-C ₉Cycloalkyl, C ₅-C ₇The isostere of cycloalkenyl group, carboxylic acid or carboxylic acid, N (R ₄) _n, Ar ₁, Ar ₄, bridged ring part or K-L, wherein said alkyl, cycloalkyl, cycloalkenyl group, alkynyl, thiazolinyl, Ar ₁, Ar ₄, or bridged ring part optionally replaced by one or more substituting groups, these substituting groups be independently selected from by:

    The 2-furyl, 2-thienyl, pyridyl, phenyl, C ₃-C ₆The wherein said furyl of cycloalkyl, thienyl, pyridyl, phenyl or cycloalkyl are optionally by C ₁-C ₄Alkoxyl group replaces, (Ar ₁) _n, halogen, halo C ₁-C ₆Alkyl, carbonyl, thiocarbonyl, C ₁-C ₆The sulfo-ester group, cyano group, imino-, COOR ₆R wherein ₆Be C independently ₁-C ₉The straight or branched alkyl or alkenyl, hydroxyl, nitro, trifluoromethyl, C ₁-C ₆Alkoxyl group, C ₂-C ₄Alkene oxygen base, C ₁-C ₆Aryloxy alkyl, C ₁-C ₆Aryloxy, aryl C ₁-C ₆Alkoxyl group, phenoxy group, benzyloxy, sulfo-C ₁-C ₆Alkyl, C ₁-C ₆Alkylthio, sulfydryl, alkylsulfonyl, amino, (C ₁-C ₆) list or dialkyl amino, amino C ₁-C ₆Alkyl, amino carboxyl is optionally by (Ar ₁) _nWith by C ₃-C ₈The C of cycloalkyl substituted ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The C that the straight or branched thiazolinyl is replaced ₃-C ₈Cycloalkyl, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, and Ar ₂In the group of being formed, wherein any carbon atom on the alkyl or alkenyl can optionally be used O, NR ₅, or S (O) _pSubstitute;

    Ar ₁Or Ar ₂, independently, for a kind of aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C with one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein independent ring is a 5-8 unit ring; Wherein heterocyclic ring contains 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or tertiary amine optionally are oxidized to corresponding N-oxide compound;

    Perhaps, R ₁Be general formula independently:

    

    Part,

    Wherein:

    R ₃Independently for optionally by C ₃-C ₈The C of cycloalkyl substituted ₁-C ₉Straight or branched alkyl, bridged ring part or Ar ₁

    X ₂Be O or NR ₆, R wherein ₆Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed;

    R ₄Be independently selected from by phenyl, benzyl, C ₁-C ₅Straight or branched alkyl, C ₂-C ₅Straight or branched thiazolinyl, the C that replaces with phenyl ₁-C ₅Straight or branched alkyl, the C that replaces with phenyl ₂-C ₅In the group that straight or branched thiazolinyl and bridged ring part are formed;

    R ₂Be C independently ₁-C ₉Straight or branched alkyl, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part or Ar ₁, wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or bridged ring part optionally are selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, (Ar ₁) _nSubstituting group in the group of forming with hydroxyl replaces; Perhaps

    R ₂Independently or be hydrogen or for P;

    Y or be oxygen or for CH-P, its precondition is to work as R ₂Y is CH-P during for hydrogen, perhaps R when Y is oxygen ₂Be P;

    P is hydrogen, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₅-C ₇Cycloalkyl, use C ₁-C ₄Straight or branched alkyl or C ₂-C ₄The C of straight or branched alkenyl substituted ₅-C ₇Cycloalkenyl group, (C ₁-C ₄Alkyl or C ₂-C ₄Thiazolinyl)-Ar ₅, or Ar ₅

    U or be O or for N, its precondition is:

    When U was O, R ' was lone-pair electron, and R " is selected from by Ar ₄, bridged ring part, C ₃-C ₈Cycloalkyl, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; With

    When U was N, R ' and R " were independently selected from by hydrogen, Ar ₄, bridged ring part, C ₃-C ₁₀Cycloalkyl, C ₇-C ₁₂Two or trinucleated carbocyclic ring, C ₁-C ₉Straight or branched alkyl and C ₂-C ₉In the group that the straight or branched thiazolinyl is formed, wherein said alkyl or alkenyl optionally is independently selected from by Ar by one or more ₄And C ₃-C ₈Substituting group in the group that cycloalkyl is formed replaces; Perhaps R ' and R " form a kind of 5-unit in the group of being made up of tetramethyleneimine, imidazolidine, pyrazolidine, piperidines and piperazine or heterocyclic ring of 6-unit of being selected from together; W and Y are O, S, CH independently ₂Or H ₂Z is C (R ₁) ₂, O, S, directly key or NR ₁Perhaps Z-R ₁Be independently

    

    Or

    

    Wherein:

    C and D are hydrogen, bridged ring part, Ar independently ₄, Ar ₁, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, Ar ₁And Ar ₄Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl or cycloalkenyl group are optionally by C ₁-C ₆Alkyl, C ₂-C ₆Thiazolinyl, hydroxyl, amino, halogen, haloalkyl, thiocarbonyl, C ₁-C ₆Ester group, C ₁-C ₆Sulfo-ester group, C ₁-C ₆Alkoxyl group, C ₁-C ₆Alkene oxygen base, cyano group, nitro, imino-, C ₁-C ₆Alkylamino radical, amino-C ₁-C ₆Alkyl, sulfydryl, sulfo--(C ₁-C ₆Alkyl) or alkylsulfonyl replace; Wherein any carbon atom of said alkyl or alkenyl is replaced the formation carbonyl on its one or more regioselectivities ground by oxygen; Perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, or S (O) _pSubstitute;

    C ' and D ' are hydrogen, bridged ring part, Ar independently ₅, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl is optionally by C ₅-C ₇Cycloalkyl, C ₅-C ₇Cycloalkenyl group or Ar ₅Replace; Wherein one of said alkyl or alkenyl or two carbon atoms can be independently selected from by oxygen, sulphur, SO and SO ₂In the group of being formed one or two heteroatomss according to chemically reasonably substitute mode replace, perhaps be Wherein

    Q is hydrogen, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; With

    T is Ar ₅Or be independently selected from by hydrogen, hydroxyl, O-(C at 3 or 4 ₁-C ₄Alkyl), O-(C ₂-C ₄Thiazolinyl) and the C that substituting group replaced in the group formed of carbonyl ₅-C ₇Cycloalkyl;

    J is O, NR ₁, S or (CR ₁) ₂

    K is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, bridged ring part, hydroxyl, ketonic oxygen and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Any carbon atom optionally use O, NR or S (O) _pSubstitute;

    Wherein R is selected from by hydrogen, C ₁-C ₄Straight or branched alkyl, C ₃-C ₄Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₃On the base;

    K ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    K " is C (R ₁) ₂, O, S, directly key or NR ₁

    L is aromatic amine or the tertiary amine that is oxidized to corresponding N-oxide compound; Said aromatic amine is selected from the group of being made up of pyridyl, pyrimidyl, quinolyl and isoquinolyl, and said aromatic amine optionally is independently selected from by halogen, hydroxyl, nitro, trifluoromethyl, C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₁-C ₄Alkoxyl group, C ₂-C ₄Substituting group in alkene oxygen base, phenoxy group, benzyloxy and the amino group of being formed replaces; Wherein said tertiary amine is NR _xR _yR _z, R wherein _x, R _y, and R _zBe independently selected from by C ₁-C ₆Straight or branched alkyl and C ₂-C ₆In the group that the straight or branched thiazolinyl is formed; Wherein said alkyl or alkenyl optionally is independently selected from by C by one or more ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Cycloalkenyl group, hydroxyl, ketonic oxygen, bridged ring part and Ar ₃Substituting group in the group of being formed replaces; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₃Optionally by C ₁-C ₄Alkyl, C ₂-C ₄Thiazolinyl, hydroxyl or ketonic oxygen replace; Wherein said alkyl, thiazolinyl, cycloalkyl, cycloalkenyl group or Ar ₂Any carbon atom optionally use O, NR ', S (O) _pSubstitute;

    L ' is direct key, C ₁-C ₆Straight or branched alkyl or C ₂-C ₆The straight or branched thiazolinyl; Wherein any carbon atom of said alkyl or alkenyl replaces by amino, halogen, haloalkyl, thiocarbonyl, ester, monothioester, alkoxyl group, alkene oxygen base, cyano group, nitro, imino-, alkylamino, aminoalkyl, sulfydryl, alkylthio, alkylsulfonyl or with the Sauerstoffatom that forms carbonyl on its one or more regioselectivities ground, and perhaps wherein any carbon atom of said alkyl or alkenyl is optionally used O, NR ₅, S (O) _pSubstitute;

    N is 1 or 2;

    P is 0,1 or 2;

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

    Ar ₃Independently be selected from the group of forming by pyrrolidyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, quinolyl and isoquinolyl;

    Ar ₄Be independently aliphatic or fragrant single, two or trinucleated carbocyclic ring or heterocyclic ring, wherein this ring optionally is independently selected from by alkylamino, amido, amino, aminoalkyl group, azo-group, benzyloxy, C by one or more ₁-C ₉Straight or branched alkyl, C ₁-C ₉Alkoxyl group, C ₂-C ₉Alkene oxygen base, C ₂-C ₉Straight or branched thiazolinyl, C ₃-C ₈Cycloalkyl, C ₅-C ₇Substituting group in the group that cycloalkenyl group, carbonyl, carboxyl, cyano group, diazo, ester, formylaniline base, halogen, haloalkyl, hydroxyl, imino-, isocyano-, different amino, inferior amino, nitro, nitroso-group, phenoxy group, sulfydryl, alkylsulfonyl sulfoxylic acid base, sulphur, alkylthio, thiocarbonyl, sulfo-cyano group, monothioester, thioformamide base, trifluoromethyl and carboxylic acid and heterocyclic moiety are formed replaces; Wherein independent fat or aromatic nucleus are that 5-8 unit ring and wherein said heterocyclic ring contain 1-6 heteroatoms that is independently selected from the group of being made up of O, N and S; Wherein any aromatic amine or alkyl amine optionally are oxidized to corresponding N-oxide compound;

    Ar ₅Be independently selected from the group of forming by 1-naphthyl, 2-naphthyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, its single ring of monocycle and bicyclic heterocyclic system has 5 or 6 yuan size, contain 1-4 total heteroatoms in single or two rings, this heteroatoms is independently selected from the group of being made up of oxygen, nitrogen and sulphur; Ar wherein ₅Optionally contain 1-3 substituting group, this substituting group is independently selected from by hydrogen, halogen, hydroxyl, methylol, nitro, CF ₃, trifluoromethoxy, C ₁-C ₆Straight or branched alkyl, C ₂-C ₆Straight or branched thiazolinyl, O-(C ₁-C ₄The straight or branched alkyl), O-(C ₂-C ₄The straight or branched thiazolinyl), O-benzyl, O-phenyl, amino, 1, in the group that 2-methylene radical dioxy base, carbonyl and phenyl are formed; With

    R ₅Be independently selected from by hydrogen, C ₁-C ₆Straight or branched alkyl, C ₃-C ₆Straight or branched alkenyl or alkynyl, bridged ring part and C ₁-C ₄In the group that the bridging alkyl is formed, bridging alkyl wherein forms bridge to form a kind of ring between nitrogen-atoms and the said carbon atom that contains said heteroatomic alkyl or alkenyl chain, and wherein said ring optionally is fused to Ar ₄Or Ar ₁On the base.

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