TW200810821A - Process for the precipitation and isolation of 6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-amide compounds by controlled precipitation and pharmaceutical formulations containing same - Google Patents

Abstract

The present invention provides a method of continuous precipitation and isolation of an amorphous solid particulate form of 3-[2-(3-tert-Butyl-ureido)-3,3-dimethyl-butyryl]-6,6-dimethyl-3-aza-bicyclo[3.1.0]hexane-2-carboxylic acid (2-carbamoyl-1-cyclobutylmethyl-2-oxo-ethyl)-amide having controlled physical properties. The present invention provides also pharmaceutical formulations comprising the precipitated compound.

Description

200810821 IX. Description of the invention: [Technical field to which the invention pertains] The present invention is directed to a compound for the precipitation and isolation of therapeutic properties, more particularly precipitation and isolation of 3-[2-(3-tert-butyl-ureido) -3,3-dimercapto-butyryl]-6,6-dimercapto-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (2-aminomethylindol-1-ring) A method of butylmethyl-oxyl-ethyl)-guanamine and a pharmaceutical formulation containing the compound. [Prior Art]

The identification of any publication in this section or any section of this application is not an admission that the publication is prior art to the invention. A method of supplying a pharmaceutical compound in a solid form is to precipitate a compound (solvent/anti-solvent > method) from a solution by combining an anti-solvent and a compound solution of a compound to be used. Generally, when a precipitation is prepared using a solvent/anti-solvent precipitation method, the characteristics of the precipitated substance are shown to be present during the mixing of the solution and the anti-solvent, and the concentration gradient sensitivity generated increases with the particle velocity formed by the combined solution and the anti-solvent. And increase. Examples of the characteristics of the precipitated product include an initial particle size range provided by the precipitation method, a size of the precipitated particles (aggregates of the primary particles), a bulk surface and a bulk density, and an amount of the solvent included in the precipitated particles. These characteristics can be affected by the presence of a concentration gradient in the solvent/antisolvent precipitation process. The solvent/antisolvent precipitation process is typically carried out in a batch process. In general, smaller aliquots are made at slower rates under mixing conditions. The sample to be precipitated: the solution is introduced into a tank containing an anti-solvent for batch processing. In this type of batch method, the mixed shear in the anti-solvent tank is usually not; ^ provides sufficient 120556.doc 200810821 The mixing of the anti-solvent and the solution, which is unaffected by the concentration gradient, such that the method does not provide a consistent and controlled particle size range of particles with low solvent content. It is said that the nucleation rate is at the same order of magnitude or nucleation rate as the mixing rate. A solvent/antisolvent precipitation method that is faster than the mixing rate is a mixed controlled method. In a mixed controlled method for producing a sinking particle material, This worker has employed a method that includes a high velocity collision of a solvent and an antisolvent at substantially high convection to provide a better controlled particle size range and maintains a low solvent content in the precipitated material, see, for example, to the United States to Midler et al. Patent Nos. 5, 314, 5, 6 (the '506 patent) and No. 6,558,435 to Am_Ende et al., each teaching the use of a substantially tit-impact jet of a solution and an anti-solvent to produce a crystal of controlled size. U.S. Patent No. 6,302,958 to the disclosure of U.S. Patent No. 6,302,958 to the disclosure of U.S. Pat. Increasing the mixing rate to a point where the homogenization rate of the mixed φ liquid is less than the time of the crystal nucleation time in the mixing zone. Each of these solutions of mixed controlled precipitation requires precise mechanical and fluid dependent Precise control of the kinetics to control the physical state of the precipitated crystalline solid. U.S. Patent No. 7, 〇 12, 〇 66, to Saskena et al. , 〇66 Patent) describes 6,6-dimethyl-3-aza-bicyclohexane-guanidine compound of formula A, 120556.doc 200810821

Wherein R represents a moiety described as R3, Z, R4, w, and Y in the '066 patent, and R is described in the U.S. Patent. A specific example of one of the compounds described in the '066 patent is 3_[2.(氕2,2-butyl-ureido)-3,3-dimethyl-butanyl, 6,6-dimethyl-3-aza Bicyclo [3.1.0] hexane-2-decanoic acid (2. Aminomethyl decylcyclobutyl fluorenyloxy) ethyl decylamine (a compound of the formula ,, see, 〇 66 patent line 113, Example XXIV (lines 448 to 451) and line f 1259). These compounds have properties such as treatment of hepatitis C virus (HCV) protease inhibitors in HCV infection.

An active compound (API) for use in a pharmaceutical formulation, for example, in the form of agglomerated microparticles having an average size in the micrometer range, for example, in the form of agglomerated microparticles having an average size in the micrometer range, 120556.doc 200810821. The active compounds have a narrow particle size distribution, a consistent bulk density, a lower amount of solvent and a clearly defined melting point. Since crystallization kinetics can be used to ensure high purity and it can be used to ensure uniform physical properties, it is preferred if the compound can be crystallized. An attempt was made to provide a compound of formula B in crystalline form without success. • In the case of a compound suitable for medical use, the pharmaceutically active compound is usually purified and isolated by precipitating a solid compound from a solution of the compound. A general precipitation method (referred to herein as a solution/anti-solvent method) is carried out by mixing a solution of the desired compound into a sufficient amount of an anti-solvent to provide a solvent/anti-solvent mixture having a reduced solubility of the desired compound. Therefore, when a solution of the desired compound and an anti-solvent are mixed, the desired compound forms original particles which are aggregated and precipitated from a combined liquid which forms a slurry containing the sinking particles and the combined solvent and anti-solvent liquid. • When the solvent/antisolvent method is used to supply a compound of formula B in a batch crystallizer, an amorphous particulate material having a different initial particle size and a wide range of agglomerate sizes is precipitated, thereby requiring the production of the amorphous particulate material by the precipitation method. The particulate material is classified twice. In addition, the precipitated product of the compound of formula B provided from the batch crystallizer by the solution/antisolvent method provides a precipitated material having a wide range of solvent retention between batches, and generally provides for the need to extend the drying time to distill off the excess internal solvent or have A product in the form of a gel rather than a particle form (and therefore not suitable). SUMMARY OF THE INVENTION 120556.doc 200810821 In view of the foregoing, there is a need for a compound of formula A which provides solid, high purity, precipitated particulate form and/or agglomerated particulate form (eg 3-[2-(3-tert-butyl-)- Ureido)-3,3-dimethylbutanyl;|_6,6-dimethyl-3·aza-bicyclo[3.1.0]hexan-2-carboxylic acid (2-aminoindenyl-1- a method of cyclobutylindenyl-2-sideoxy-ethyl)-guanamine (compound of formula B) which consistently produces a solid having a narrow size range (e.g., from about 200 nm to about 300 nm) The agglomerate particles and precipitated particles of a narrow chord length range, and additionally provide a desired control content exceeding the amount of the solvent contained therein. The present invention provides these and other objects and/or advantages. Thus, in one aspect of the invention, a compound of formula A is precipitated in the form of amorphous solid particles comprising primary particles in the range of from about 200 nm to about 300 nm (eg, 3_[2·(3·third) Butyl-ureido)_3,3-dimethyl-butyl]-6,6-diamidino-3-aza-bicyclo[3 1〇]hexane_2-decanoic acid (2_aminocarbamidine) The S method of -1-cyclobutyl fluorenyl I pendant oxy-ethyl) amide (formula oxime compound), the method comprises introducing a liquid of the formula β compound/column flow under controlled spoiler conditions Used in the anti-solvent flow of the hydrazine compound. In some embodiments, it is preferred to maintain the Reynolds number of the solution stream (Reyn〇lds is maintained at least sufficient to provide a value for the turbulence, such as a value of at least about 2,000, more preferably a value of 5,500 to v, more preferably A value of at least about 1 Torr. In some embodiments, it is preferred to maintain the Reynolds number of the antisolvent stream at a value of at least about 9, _: preferably at least about 15, _, more preferably For at least about 2 〇, _, 士 - 实 ^ (4) ' & good combination does not exist in any parallel flow component in a known case 'preferably with respect to the anti-solvent flow is substantially 9 〇-angle The solvent stream and the anti-solvent stream are combined. In some embodiments, preferably 120556.doc 200810821 there is no flow of any stream collision component. In some embodiments, the method of the invention comprises utilizing a solution stream of formula B, Wherein the Reynolds number of the solution stream is maintained at a value of at least about 5,500, and the volume ratio of solvent stream to antisolvent stream is from about 1:15 to about 1:3 solution: antisolvent, preferably about 1:4 solution: antisolvent In some embodiments, it is preferred to maintain the area of the device where contact between the solution and the anti-solvent occurs at about -25 ° C. A temperature of about +25 ° C, preferably about -25 ° C to about + 20 ° C. It is preferred to maintain the contact zone between the solution and the anti-solvent at a temperature of about -15 ° C. In some embodiments, the antisolvent is preferably maintained at a temperature of from about -25 ° C to about +20 ° C, preferably at a temperature of from about -20 ° C. In some embodiments, preferably. The solution of the compound of formula B is maintained at a temperature of from about 10 ° C to about + 20 ° C, preferably at a temperature of about 〇 ° C. In some embodiments, the anti-solvent and solution are cooled to the desired temperature. And operating the zone of the combined solution with the anti-solvent at ambient temperature, such as a mixing tee. In some embodiments, the solution of the compound of Formula B preferably comprises methyl tert-butyl ether (MTBE) as a solvent. In some embodiments, the solution preferably contains a quantity of a compound of formula B to provide a solution of a compound of formula B having from about 80 mg/ml (0.15 M) to about 250 mg/ml (0.48 M), preferably about 166 mg. /ml to about 200 mg / ml of the compound of formula B, more preferably about 166 mg / ml of the compound of formula B. In some embodiments, the solvent is preferably selected from the group consisting of methyl third Ether (MTBE) and a mixture of ethyl acetate and MTBE. In some embodiments, the anti-solvent is preferably n-g. In some embodiments, it is preferred to dry the solution, for example, with a desiccant, prior to precipitation, Distillation or CUNO Filtration 120556.doc -11 - 200810821 Water is removed from the lysate μ. In some embodiments, the solvent is acetone and the antisolvent is water. In some embodiments, preferably by using a solution The continuous blending of the anti-solvent forms a slurry (initial slurry) of the solvent, anti-solvent and precipitated particles for the 'duplex' method. In some embodiments, the initial mass is preferably conducted from the zone of the combined solution and the anti-solvent to a sump that collects the initial slurry. In some embodiments, the static mixer is placed in the blending zone and the sump 2_tube as the case may be, and the method of conducting the continuous blending flow using the solution antisolvent via the conduit, preferably by One or more techniques selected from the group consisting of decantation, filtration, and centrifugation collect the killed solids. In some embodiments, it is preferred to collect the slurry formed by combining the solution and the anti-solvent stream in a sump, and additionally subjecting the collected slurry to a distillation step. In some implementations, it is preferred to remove a quantity, liquid to provide a volume having from about 90% to about 25% by volume of the initial slurry volume, more preferably about 90% of the initial slurry volume of φ. From 5% by volume to about 30% by volume, more preferably a residual slurry of about one-third of the initial slurry volume of the slurry volume. In some embodiments, the distillation step is performed in a controlled pressure/temperature distillation system to promote regenerable agglomeration of the precipitated solids (precipitated particles), whereby the condensed particles of the chord length, volume surface area, and bulk density are entangled in one In this embodiment, the steaming step is preferably carried out at a temperature of less than about 32 〇c under low pressure conditions, preferably at a pressure of greater than about 〇97 bar (gauge*). In some embodiments, it is preferred to distill from (iv) to about 22% by volume of the initial slurry volume at a temperature of less than about 30t. In some embodiments, 120556.doc -12. 200810821 distills a first volume of the initial slurry volume at a temperature of less than about 26 °C. In some embodiments, the first 8 volume percent initial slurry volume is preferably distilled at a temperature of less than about 25 °C. In some embodiments, the first 6 volume percent initial slurry volume is preferably distilled at a temperature of less than about 23 C. In some embodiments, it is preferably less than about 22. The first 4 volume% of the original slurry volume was distilled off at a temperature of 〇. In some embodiments, the first 2 vol% initial slurry volume is preferably distilled at a temperature of less than about 2 Å. In some embodiments, the method further comprises, after concentration of the initial slurry, isolating the agglomerated particles by filtration, followed by washing the filter cake with an anti-solvent aliquot. In some embodiments, the filter cake is preferably washed with about 4 times the volume of the cake volume of n-heptane. In some embodiments, the filter cake is preferably washed with an anti-solvent equal to the mass of the filter cake. In some embodiments, the filter cake is preferably washed with an anti-solvent equal to 2 aliquots of the mass of the filter cake. In some embodiments, the filter cake is preferably washed with an anti-solvent until the residual solvent content of the filter cake is less than about 1 to about 1.25 wt%. In some embodiments, the method further comprises, after washing the filter cake, drying the isolated agglomerated microparticles at a temperature of from about 25 ° C to about 45 ° C under ambient conditions for a period of time sufficient to reduce the total residual solvent to less than about 1 . The weight %, preferably less than about 0.8% by weight of the time. In some embodiments, it is preferred to select 3_[2 gas 3_t-butyl-urea-based 3,3-dimethyl-butanyl]-6,6-dimethyl-3-3 aza-bicyclo[3· 10] hexane 2 - formic acid (2-aminoformamido-1 - cyclobutylmethyl 2 - pendant oxy-ethyl > guanamine (compound of formula b) concentration, volume of solution and anti-solvent flow Comparing and combining the linear velocity of the stream to produce a precipitate of the compound of formula B having a titer of less than about 1 〇 micron 120556.doc -13 - 200810821

The primary particles, the median granule size (aggregation of the original particles) of about 1 micrometer to about 2.5 micrometers, preferably about 1 micrometer, preferably about 1 micrometer to about 5 micrometers, and less than about The solvent content is within 1% by weight. In some embodiments, the method of producing precipitated particles in the initial slurry having a volumetric surface area of from about 16 m2/g to about 33 m2/g, preferably from about 25 m2/g to about 32.5 m/g, is preferably selected. In some embodiments, it is preferred to provide process conditions for the slurry wherein the solids in the slurry have a softening point of from about 2 (TC to about 5 (rc, preferably from about 25 ° C to about 50 ° C.) In some embodiments, the initially collected slurry is subjected to a distillation step, preferably under conditions which produce agglomerated particles having a volume surface area in the range of from about 5 mVg to about 12 m2/g. In some embodiments, a preferred option is produced. Distillation step conditions for agglomerated microparticles having a median volumetric surface area of about 7 m2/g. Another aspect of the invention provides a pharmaceutical formulation having a bulk density of from about 0.4 mg/ml to about 0.6 mg/ml. Preferably, the bulk density of about 47 mg/mi and the knockdown of about 0.64 mg/ml and comprising agglomerated microparticles prepared in accordance with the present invention. In some embodiments, the particulate #pharmaceutical formulation preferably comprises up to 50% by weight of the API comprising the compound of the formula b prepared according to the process of the invention (preferably 50% by weight of API), up to 14% by weight of lactose monohydrate (preferably 14% by weight of lactose monohydrate), more Up to 6% by weight of crosslinked 竣methylcellulose sodium (preferably 6% by weight (four) Cellulose cellulose as much as % by weight of microcrystalline cellulose (preferably 1% by weight of microcrystalline cellulose, up to 重量% by weight of pregelatinized starch (relatively 祛糸) 曰U乂隹 is 15% by weight Gelatinized starch), up to 6% by weight of sodium lauryl sulfate (Zhuo, ^ (Huawei' is 3 wt% sodium lauryl sulfate) and Xi Da 2% by weight stearic acid town (preferably 2 wt% hard) Magnesium oleate) 120556.doc -14- 200810821 In some embodiments, preferably by preparing a granule pharmaceutical formulation: a method comprising the following steps (4) forming a first granule by a method comprising the following steps : (1) 払s is sufficient to provide up to 58% by weight, preferably 6% by weight of the first granules of the formula B according to the process of the invention, sufficient to provide up to 6.0% by weight, preferably 5.6 weight Microcrystalline cellulose at the top of the granules, enough to provide up to 18

% by weight, preferably 6% by weight of the first granules of pre-gel = 匕, powder, sufficient to provide up to 4% by weight, and the cross-linking of the amount of 3% to 3% by weight Methylcellulose is added in an amount sufficient to provide up to 6% by weight, preferably i5.6% by weight of the first granules of lactose monohydrate to provide a first dry blending mixture; (8), containing sufficient to provide up to 6 6 wt%, preferably ^ weight f % of the granulating fluid of the first granule (dissolved in water equal to about seven times the weight of sls) granules from the mixture of step "a(1)"; Step "Π" granules to provide a uniform particle size; (d) Drying the wet granules prepared in step (4) until the granules exhibit a loss on drying weight (LOD) of less than 2.5% by weight; w-milling the dried granules to provide graded granules = fine by making the graded particles from step »" sufficient to provide microcrystalline cellulose in an amount sufficient to provide 5'1% by weight of the second dry blended mixture, and sufficient to provide up to 6.2% by weight, preferably Sichuan weight% second dry 120556.doc -15- 200810821 The amount of the cross-linking of several f-cell cellulose nano-doses to form a first dry blending mixture; and by dry blending the second dry blending mixture with enough to provide up to 3 weights of Li Wei % granule product "amount of magnesium stearate to form a granule medicinal formulation product. In some of the examples, the capsules are preferably filled by a granule pharmaceutical formulation containing the desired amount of granules contained in the granule formulation to provide a capsule dosage form of the medicament. In some embodiments, a high shear mixer/granulation machine for blending and granulation is preferably used. A wet mill equipped with a sieve having a 0. 375 bore, a fluidized bed dryer and equipment The first pellet was prepared by a dry mill having a sieve having a 0.040 bore. In some embodiments, the dry blending operation is preferably carried out in a draw blender. In some embodiments, it is preferred to dry blend 4 〇 KgSB compound (API) (prepared according to the above precipitation method and used as prepared) with 4 () Kg microcrystalline cellulose, 11.2 Kg lactose monohydrate, 12 A mixture of 〇Kg pregelatinized starch and 2.4 Kg of croscarmellose sodium to form a first dry blending mixture to form a first granule. In some embodiments, it is preferred to provide a granulated fluid comprising 2.4 g of sodium lauryl sulfate dissolved in 48 Kg of water and preferably granulating the dry blended mixture until no free flowing powder is observed. In some embodiments, the particles are preferably dried in a fluid bed dryer until the loss on drying is less than about 2.5% by weight. In some embodiments, the dried granules are preferably ground in a teacher mill equipped with a 0.032 division to provide a particulate material having an average size of 32 mesh. In some embodiments, the dry abrasive granules are preferably blended with 4.0 Kg of additional microcrystalline cellulose and 2·4 Kg of additional crosslinked tempering 120556.doc -16 - 200810821 based cellulose sodium to provide a second dry blend. The mixture is then blended with 1.6 Kg of magnesium stearate and the second dry blended mixture to provide a particulate pharmaceutical formulation. In some embodiments, an aliquot of the above granule pharmaceutical formulation is optionally filled into a gelatin capsule to provide a dosage form having a component weight as indicated in the table below (each dosage having about 200 mg API). Component functional content (mg/capsule) Precipitation of compound of formula B e drug substance 200 microcrystalline cellulose binder/filler 40 lactose monohydrate filler 56 croscarmellose sodium disintegrant 24 pregelatinization Starch Adhesive 60 Sodium Lauryl Sulfate Surfactant 12 Magnesium Stearate Lubricant 8 Pure Water a Processing Aid (...) a Capsule Fill Net Weight 400 Hard Gelatin Capsule b Contains one capsule each a: Add For processing; evaporation during the manufacturing process. b : No. 0, blue, opaque, preservative-free, two-piece hard gelatin capsules. c: assuming a precipitation activity of 100% by weight - upregulating the actual formulation weight to reduce activity. Another aspect of the invention is the provision of a dosage form comprising a quantity of a particulate pharmaceutical formulation comprising up to 58% by weight of an API of a compound of formula B, up to 6% by weight of microcrystalline cellulose, up to 18 5% by weight of pregelatinized starch, up to 4% by weight of croscarmellose sodium, up to 16% by weight of lactose monohydrate and up to 6% by weight of sodium lauryl sulfate, further Characterized by a bulk density of from about 0.4 g/ml to about 0.6 g/ml, and wherein the particulate form of the API is from about 5 m2/g to about 12 m2/g by volume surface area and from about 0.15 g/ml to about 0.19 g. Agglomerated particles characterized by a bulk density of /ml, when 12060.doc -17- 200810821 This dosage form is further characterized by a Umax containing 800 mg API and exhibiting a Cmax of 2106 and an AUC of 7029 at about 3.0 hours. In some embodiments, the above pharmaceutical formulation is preferably provided by substituting one or more compounds selected from the group consisting of compounds of formula I-XXVIII as described herein for the API of formula B above. Such formulations are useful for inhibiting HCV protease and/or tissue protein activity and having good solubility characteristics to promote absorption of the compound of Formula I-XXVIII. In some embodiments, a population of HCV protease inhibitors, preferably mentioned in the following document (which is incorporated herein by reference), is also selected from at least one HCV protease inhibitor: US20040048802A1, US20040043949A1, US20040001853A1, US20030008828A1 US20020182227A1, US20020177725A1, US20020150947A1, US20050267018A1, US20020034732A1, US20010034019A1, US20050153877A1, US20050074465A1, US20050053921A1, US20040253577A1, US20040229936A1, US20040229840A1, US20040077551A1

EP1408031A1, WO9837180A2, US6696281B1, JP11137252A, W00111089A1, US6280940B1, EP1106702A1, US20050118603A1, JP2000007645A, W00053740A1, W00020400A1, W02004013349A2, W02005027871A2, W02002100900A2, W00155703A1, US20030125541A1, US20040039187A1, US6608027B1, US20030224977A1, W02003010141A2, W02003007945A1, W02002052015A2, WO0248375A2, WO0066623A2, W00009543A2, WO9907734A2, US6767991B1, US20030187018A1, US20030186895A1, 120556.doc -18- 200810821

W02004087741A1 W02004037855A1 US20040224900A1 W02004065367A1 W02004009121A1 W02004094452A2 W02003099274A1 W00040745A1, WO0248157A2, W00022160A1, ^ W02004039970A1 ^ W02004030670A1, W02005028501A1 ^ W02004064925A1, W02003066103A1, W02004015131A2 ^ W02003053349A2 US6586615B1, WO0248116A2, US20060051745A1, W02004039833A1, 'US20040229818A1,, W02004103996A1,, W02004093915A1,, W02005034850A2, > W02003099316A1 ,, W02002060926A2, W02002061048A2, W02005017125A2, W02004021871A2, W02004011647A1, W09816657A1, US5371017A, WO9849190A2, US5807829A, W00005243A2, W00208251A2, W02005067437A2, W09918856A1, W00004914A1, WO0212543A2, W09845040A1, W00140262A1, W00102424A2, W00196540A2, WO0164678A2 US5512391A, WO0218369A2, W09846597A1, W02005010029A1 WO2004113365A2, W02004093798A2, W02004072243A2

W09822496A2

JP11199509A W02004046159A1 WO9740168A1 W02005012288A1 W02004108687A2 US6187905B1 US20060110755A1 W02002093519A2 W09524414A1 W02003077729A2 W02005009418A2 W09963998A1 W02004003000A2 US20050037018A1 WO0063444A2, W09938888A2, W09964442A1, W00031129A1 WO0168818A2, WO9812308A1, W09522985A1, WO0132691A1

WO9708304A2, W02002079234A1, JP10298151A, JP09206076A 120556.doc -19- 200810821

JP09009961A, JP2001103993A, JP11127861A, JP11124400A, JP11124398A, W02003051910A2, W02004021861A2, W09800548A1, W02004026896A2, WO0116379A1, US5861297A, W02004007512A2, W02004003138A2, W02002057287A2, W02004009020A2, W02004000858A2, W02003105770A2, WO0114517A1, WO9805333A1, US6280728B1, EP1443116A1, US20040063911A1, W02003076466A1, W02002087500A2, W00190121A2, W02004016222A2, W09839030A1, WO9846630A1, WO0123331A1, W09824766A1, US6168942B1, WO0188113A2, W02005018330A1, W02005003147A2, W09115596A1, WO9719103A1, WO9708194A1, W02002055693A2, W02005030796A1, W02005021584A2, WO2004113295A1, WO2004113294A1, W02004113272A1, W02003062228A1 > WO0248172A2, W00208198A2, WO0181325A2, WO0177113A2, WO0158929A1, W09928482A2 , WO9743310A1, WO9636702A2, WO9635806A1, W09635717A2, US6326137B1, US6251583B1, US5990276A, US5759795A, US5714371A, US6524589B1, WO0208256A2, W00208187A1, W02003062265A2, US7012066B2, JP071846 48A, JP06315377A, W02002100851A2, W02002100846A1, W00039348A1, JP06319583A, JP11292840A, JP08205893A, WO0075338A2, W00075337A1, W02003059384A1, W02002063035A2, W02002070752A1, US6190920B1, W02002068933A2, WO0122984A1, JP04320693A, JP2003064094A, WO0179849A2, W00006710A1, W00001718A2, 120556.doc -20- 200810821 WO0238799A2 , W02005037860A2, W02005035525A2, W02005025517A2, W02005007681A2, W02003035060A1, W02003006490A1, WO0174768A2, W00107027A2, W00024725A1, W00012727A1, W09950230A1, WO9909148A1, W09817679A1, W09811134A1, W09634976A1, W02003087092A2, W02005028502A1, US5837464A, DE20201549U1, W02003090674A2, WO9727334A1, W00034308A2, US6127116A, US20030054000A1,

JP2001019699A, US6596545B1, US6329209B1, IT1299179, CA2370400, KR2002007244, KR165708, KR2000074387, KR2000033010, KR2000033011, KR2001107178, KR2001107179, ES2143918, KR2002014283, KR149198, KR2001068676. [Embodiment] A method of producing a compound of the formula B is described in U.S. Patent No. 7,012,066, issued to Saskena et al. In particular, the '066 patent specifically describes the preparation of compounds of formula B at line 113, example XXIV (lines 448 to 451) and line 1259. In particular, these subsections and the entire '〇66 patent are incorporated herein by reference. An improved method for the synthesis of a compound of formula B is described in U.S. Patent Application Serial No. 11/598,528, filed on Nov. 13, 2006, filed on /048613 ('613 application). Improvements to the method for preparing a compound of formula B as described in the '528 application description '066 patent, pages 10 to 13 and examples 1 to 2, which are incorporated herein by reference in its entirety by reference. The manner is incorporated herein. On pages 19 to 39, '613 Application 120556.doc -21-200810821, the description of the improvement of the method for preparing the compound of formula 6 described in the '066 patent, the pages (with the whole, 613) The application is hereby incorporated by reference. As used herein, the term "antisolvent," is a liquid that reduces the solubility of a compound of interest when the antisolvent is mixed with a solution comprising the solvent and the compound of interest. Thus, a sufficient amount of the anti-solvent is mixed with a solution containing the compound of interest to cause the compound of interest to precipitate out of solution and hindrance in the form of particulate matter. The term "string length" as used herein refers to the length of the theoretical green cord required to traverse a particle. Therefore, each particle has a chord length distribution characteristic of its size and shape. "Original Particles" as used herein is the initially formed particle nucleated by combining a solution with an anti-solvent. The initial particle size refers to the size of the original particles and is determined by scanning electron microscopy (SEM). As used herein, the term "sinking particles" refers to particles that are formed by agglomeration of the initial particles in a polymer. The term "agglomerated particles" as used herein refers to the agglomeration of precipitated particles. . As used herein, the terms particle, and "particle" are those which are formed by the sinking method, and "particle" refers to the aggregation or aggregation of particles or the aggregation or agglomeration of a mixture of components, such as solids and granulation. "Particles" prepared by agglomerating a mixture of fluid powders. "Median precipitate size", "median aggregate particle size, and f' particle size distribution" as used herein are laser diffraction (LC) Measured by measurement. Unless otherwise indicated, the abbreviation used herein, legs " means nano 0 120556.doc -22- 200810821 Unless otherwise stated, the abbreviation "M" as used herein means The term "Reynolds number" is used as a customary definition of fluid dynamics, and is a dimensionless parameter as defined below:

Re=pUL~=UL/v where P=fluid density viscosity coefficient ν=kinetic viscosity characteristic velocity characteristic length magnitude If known, the Thunder number reflects whether the fluid flows under laminar or turbulent conditions. In general, laminar flow conditions exist at Reynolds numbers less than about Re = 21 。. Above about Re = 2100, the flow begins to become disturbed, and at about Re = l〇, the flow becomes disordered.

When the substance is precipitated to provide an active pharmaceutical ingredient (API) for use in a medicament, it is necessary to closely control the average initial particle size and initial particle size range distribution, the average size (chord length) of the aggregate of the original particles (precipitated particles), and 2 The size range distribution of the polyparticulate material (the terms are as defined above). : The volumetric surface area and bulk density of the agglomerated particulate matter are closely controlled, and both the primary particles and the precipitated particles and the agglomerate particles are included: "The amount of solvent. These parameters affect the physical properties of the particulate matter produced, for example, for pharmaceutical agents. The softening point, bulk density and processing properties of the formulation are important. The pharmacological properties of the API are also affected, such as dissolution rate, release 120556.doc -23- 200810821 and bioavailability' and the particles are agglomerated at the end of the condensed particulate matter. The parameters used in the additional curing steps that can be experienced are also affected, such as particulate matter = drying time and maximum drying temperature experienced by precipitation of the precipitation slurry. As described above, the solution for the precipitation of the compound of formula B / anti-agent The method uses a solution having a high concentration of U dissolved therein to minimize the amount of depletion used for the sinking compound and to minimize the amount of formula B. When a batch of crystallizer of the prior art is used to carry out the compound of formula B When precipitating: The large concentration gradient when the mixture is mixed with the anti-solvent produces a large average particle size range and an undesirable large average initial particle size. Undesirable large average aggregate particle size precipitated material. In addition, the precipitated product lacks batch-to-batch consistency with respect to the average particle size and the amount of solvent contained. In addition, for the isolation and purification of active compounds on an industrial scale, The batch operation system is inefficient and inefficient. The present invention is a method for sinking an amorphous compound by solution/antisolvent technology, wherein the sinking has a controlled narrow size range of Lu (micron) And a controlled narrow volume surface area range (m2/g). The process of the invention optionally comprises distilling off some of the supernatant from the initially prepared flotation (initial slurry) to precipitate the precipitated compound Controlled agglomeration to provide a particulate material having a narrow size range and a narrow volumetric surface area range. Each of the aspects of the method is discussed in turn. Surprisingly, the present invention provides a consistently narrow range of sizes and a method of precipitating a solid having a narrow chord length. The method of the present invention comprises an antisolvent stream and a solution stream containing a compound to be precipitated, wherein The streams are at a substantially 90 degree angle (measured relative to the flow direction of the antisolvent stream) 120556.doc -24 - 200810821 directly combined with the antisolvent stream and the solution stream, and selected for providing an antisolvent stream Conditions are such that a Reynolds number of at least about 9,000 is obtained, and conditions for providing a solution stream are selected to obtain a Reynolds number (eg, Re- to about 2, 〇00) that is at least sufficient to generate a turbulence. Preferably, Providing an anti-solvent at a rate equal to at least about '00, preferably at least about 20,000, and supplying the solution at a Reynolds number equal to at least about 5,500. Thus, the inventors have surprisingly discovered that the method of the present invention can be used to provide An amorphous solid form of the b compound having a controlled initial particle size in the range from about 2 to about 2 and a volume surface area of from about 25 to about π A. Furthermore, when performing an optional subsequent coacervation step (described below), the inventors 2 surprisingly found that the method of the present invention provides a volumetric surface area having a desired chord length, from about 5 m2/g to about 8 mVg, and about (3) _ Particles having a bulk density of about (four) g/ml. Referring to Figure 1, the precipitation of the compound of formula B can be carried out continuously using a simple device according to the present invention. The simple device has a static mixing comprising a mixing tee and optionally an outlet end tube (7) connected to the three channels. The mixing chamber of h(3) where the anti-solvent stream passes through the straight conduit person σ(4) in the direction of the head (6) via the anti-solvent population line (7), and the solution stream containing the compound of formula B is lined up via the solution inlet 瞢螅A (8) In the branch of the Shuo (9) (7). In the example, the tee (1) is equipped with 1/2, the person ^: (7), 3/8 " static mixer (3) and 1/8, the standard of the population line (8) " steel two Official. Hunting provides a solution stream by means of a device that produces at least about 5,5 Torr and provides an appropriate amount of anti-solvent to achieve at least a continuous abundance rate to cause the <Reynolds number to be used in the present invention; 120556.doc -25- 200810821 Law. In some embodiments in which devices having such relative dimensions are used, it is preferred to establish conditions for the private use: _吝/, the desired Reynolds number of the house and the volume ratio of the antisolvent volume to the solution is maintained at about 3:1 antisolvent. : solution to about 15:1 anti-solvent: / combined machine (eg 'solution flow'). Preferably, the volume ratio of the anti-solvent to the solution supplied to the mixing tee is about 4:1 anti-solvent: solution ratio. The inventors have discovered that providing a solution to the mixing tee at a rate that produces a Reynolds number of at least about 5,5 Torr, preferably at least about 1 Torr, and producing at least about 9'000 ruts at least Preferably, the desired volume ratio can be conveniently achieved using the simple mixing device at a rate of about 15, preferably at least about 2, when the rate of Reynolds number of the crucible is provided to the mixing tee. In some embodiments, the anti-solvent is preferably supplied under conditions that produce a Reynolds number of at least 25,000. Using the compound of formula B, the inventors have surprisingly found that when the solution and the anti-solvent are combined in a simple apparatus under the above conditions, a sufficiently rapid mixing of the anti-solvent and the solution is achieved in the tee to consistently provide a narrow The particulate amorphous solid of the compound of formula B in the initial particle size range facilitates the supply of a particulate condensate having desirable physical properties suitable for use as an active pharmaceutical ingredient (API) in the supply of a medicament. Use, for example, a device with a mixing chamber consisting of a 3/8"nominal outer diameter pipe (equipped with a 3/8" inlet and outlet pipe) and a %"nominal outer diameter branch end pipe (equipped A vertical tee fitting with a 1/8"supply tube is constructed by supplying an anti-solvent flow rate of about 3300 ml/min to about 4200 mi/min through a mixed tee pipe and a mixed tee The branch end tube supplies a solution flow rate of from about 38 〇ml/min to about 880 ml/min to achieve the desired flow conditions, wherein the solution comprises MTBE and has from about 80 mg/mi to about 120556.doc -26 dissolved in MTBE. - 200810821 250 mg/ml of compound B. It should be understood that other diameters and configurations of the mixing chamber can be used by varying the supply rate of the anti-solvent and solution to achieve the minimum required number of errors and provide anti-solvent and solution. The desired volume ratio. Suitable mixing chambers for use in the method of the present invention are conveniently provided by standard commercially available 9-inch tee fittings, such as conventional vertical tee fittings, compression tee fittings, and SwagelokTM tee fittings. The anti-solvent and solution flow are strictly 90 degrees off , but preferably utilizes a vertical fitting that does not substantially supply any of the parallel flow components to the antisolvent stream (from the anti-solvent reference system) to the solution of the compound of formula B. It has an accessory that imparts access to some of the parallel flow characteristics. It should be understood that adjustments should be made to increase the Reynolds number of the combined anti-solvent and solution streams to provide a more disturbing mixing environment to compensate for the combined parallel flow components. Thus, for example, if the mixing chamber has a configuration of a gamma-type fitting, the fitting The input tube having less than 120 degrees apart (so that it forms an angle greater than 120 degrees with the common end tube) can be selected to cause an increase in the Reynolds number of the input stream. The two narrow-angle end tubes are used for solution and anti-solvent. Input, thereby canceling the parallel flow component of the combined flow. Conversely, if the tee is used with a common end pipe and a narrow angle end pipe is used as the inlet end pipe and thus the flow is merged with the collision component, an improvement can be utilized The degree to which the combined stream is merged with the collision component is selected using conditions that result in a reduced Reynolds number of the input stream. Therefore, there is a configuration of the end tube. A fitting of the tee configuration can be used in the method of the present invention while suitably changing the conditions to provide the Reynolds number necessary to configure the orientation of the substantially parallel flow or collision component of the combined stream. Use on the end tube as appropriate, for example

Convention of the 1-TU-3L-12-1 static mixer of the Corporation (Cary, IL) 120556.doc 27- 200810821 Static mixer to increase the mixing time and strength of the solution and the anti-solvent after the combined flow The physical properties of the resulting particles provide additional control. Different solvents may be used in combination with the anti-solvent depending on the compound to be precipitated. For compounds of formula B, the antisolvent is preferably selected from the group consisting of linear or branched chain hydrocarbons having from about 5 carbon atoms to about 12 carbon atoms, preferably from about 5 carbon atoms to about 8 carbon atoms. The group, more preferably a linear hydrocarbon having from about 5 to about 8 carbon atoms, more preferably n-heptane. For the compound of formula B, the solvent used to provide the solution of the compound of formula B is preferably selected from the group consisting of acetone, methyl tert-butyl ether (MTBE) and a mixture of ethyl acetate and MTBE, preferably more preferably MTBE. . When acetone is selected as the solvent, it is preferred to use water as a counter and a solvent. When MTBE or a mixture of MTBE and ethyl acetate is selected as the solvent, it is preferred to use n-heptane as the anti-solvent. In the case of the compound of the formula B according to the method of the present invention, MTBE is preferably used as a solvent and n-heptane is used as an anti-solvent. In some embodiments, when it is not necessary to carry out subsequent optional steps of distilling the supernatant from the initially formed slurry (described herein), it is preferred to strictly dry the solution and react before combining the streams and forming a precipitate. Examples of the solvent, whereby substantially removing the water from the initial formation of the slurry, can be used by filtration (eg, CUNO filtration), steaming, and contacting the solution or anti-solvent with a desiccant (eg, , molecular sieve).

Preferably, the method of sinking the present invention is carried out with a high concentration solution of the compound to be precipitated. In some embodiments, the solution of the compound of formula B preferably contains from about 80 g of the compound of formula B (0.15 M) per ml of solution to about mM mg^B of compound per ml of solution (0·48 Μ). In some embodiments, it is preferred to use a solution of about 166 mg of the compound of formula B (0.32 Torr) per milliliter of solution 120556.doc -28 - 200810821. In some embodiments, such concentrations are preferably utilized to maintain the solution at a temperature of from about -20 ° C to about +25 T:, preferably at a temperature of from about -10 ° C to about +20 t: and More preferably, the solution is maintained at 〇 ° C. In some embodiments of the precipitation method of the present invention, when the compound to be precipitated is a compound of formula B, it is preferred to maintain the solution of the antisolvent and the compound of formula B at about -25 ° C to about +25 ° C. It is preferably at a temperature of about -25 ° C to +20 ° C. In some embodiments, it is preferred to use a solution (0.32 M) of about 166 mg of the compound of formula B per ml of solution and maintain the solution at a temperature of about 0 °C. The precipitation process of the present invention can be carried out in a unit comprising a thermally controlled supply line, a mixing chamber (e.g., a cooling line-trace mixing tee) and piping to maintain any desired temperature. In some embodiments, it is preferred to maintain the supply line and mixing chamber at ambient temperature, typically about 25 ° C, and supply the mixing chamber with a solution of the anti-solvent and compound of formula B that has been maintained at the desired temperature such that The slurry produced during the stream combination is warmed to ambient temperature as it passes through the system. In some embodiments of the precipitation process, it is preferred to maintain the supply of the solution and the anti-solvent at a temperature of from about -25 ° C to about + 20 ° C. In some embodiments of the precipitation process, it is preferred to maintain the supply of the solution of the compound of formula B at a temperature of from about -10 ° C to about 20 ° C. In some embodiments, it is preferred to track the supply conduit for the solution of the compound of formula B up to the mixing chamber with the cooling line and thereby maintain the solution entering the mixing chamber at a temperature of about o °C. In some embodiments, it is preferred to track the anti-solvent supply line up to the mixing chamber with the cooling line so that the anti-solvent supply is maintained at a temperature of about -20 °C. When the solution of the compound of formula B is supplied to the mixing chamber at 120556.doc -29-200810821 ° C and the anti-solvent is supplied to the mixing chamber at -20 ° C, it is generally found that the resulting slurry has a temperature of about -15 ° C. . The process of the invention for precipitating a compound of formula B can be used as part of a continuous sinking process. For example, referring to Fig. 2, as schematically shown in Fig. 2, the inlet pipe end pipe of the mixing tee (1) can be supplied from the storage tank (2), and can be fed from the storage tank (3) via the check valve (6). The solution of the B compound is supplied to the mixed tee (1)

Agent and branch end tube inlet. The combined solution and anti-solvent (which produces a slurry upon precipitation of the compound) can be conducted from the outlet of the mixing tee (1), optionally via a static mixer (7), to the sump (8). Therefore, the compound can be continuously precipitated in the mixing tee by this method. Referring further to Figure 2, if the slurry formed in the mixing tee is conducted via a conduit having an outlet directed to one of the plurality of hoppers (8), the slurry collected as each tank reaches capacity can be fed-in and less At the same time, the method of mixing the sink in the tee is continued while the outlet of the mixing tee is directed to the new storage tank. Alternatively, the outlet of the mixing tee and the optional static mixer can be connected to the instrument for separation from liquids, such as straight-air clearing, eight-pass/yiyiyi, centrifugation. Machine or sedimentation tank for decanting the combined solvent and anti-solvent. When the storage tank (7) of the agent and the storage tank (7) of the compound solution of the formula B are supplied to the mixing apparatus, the flow rate of the reverse two (4) via the mixing tee can be controlled by any (four) pieces, for example, selected from, for example, section 1 Needle valves, metering pumps, flow meters and f-flow controllers =, it should be understood that other components that regulate the flow of liquids can be used / such as: (4). The </ br> (5) and other process monitors can be installed in the points in Figure 2 of h to help control the process. The difference between ..... 120556.doc -30 - 200810821 As described above and as indicated in Figure 2, in some embodiments of the prior developed method, the slurry produced in the mixing tee is directed to It is equipped with a hopper (8) in the agitator (10). After collecting a certain amount of slurry, some of the supernatant of the collected slurry is taken out from the tank under partial vacuum as appropriate, thereby concentrating the slurry and agglomerating the precipitated particles to provide agglomeration of the desired volume surface area and bulk density. particle. During the agglomeration, the high volume surface area precipitated particles are condensed to produce a particulate material having a reduced volume surface area (preferably a surface area of from about 5 m2/g to about 8 m2/g), and correspondingly the volume of the agglomerated particulate matter The density varies from about 25·25 g/ml to about 〇·35 in the range of the precipitated particulate matter to a volume density of about 15 g/ml to about 2 g/mi of the agglomerated particulate matter. As described herein, the change in volume surface area during distillation can be monitored by the PSD measurement probe (9). Another benefit of using the optional retort step is to reduce the amount of volatile components retained in the precipitated particles and agglomerated particles. Examples of volatile components which may be retained in the precipitated material include MTBE, acetic acid and water, the presence of each volatile component being produced by the preparation and treatment of a compound of formula B before or during the precipitation process. Additional advantages of the optional distillation step include The amount of liquid that must be treated to separate the precipitated particles from the slurry and reduce the amount of compound of formula B remaining in the slurry supernatant. The distillation must be carefully controlled during the optional distillation step. Temperature and pressure to maintain a narrow distribution of the chord length of the agglomerated particles in the isolated solid product. It is not desirable to limit the volatile components remaining in the precipitated solid (eg MTBE, water and a mixture of MTBE and water). The amount will increase the softening point of the solid, and thus reduce the reach, the viscosity of the precipitated solid 120556.doc -31 · 200810821 possibility 'at the same time allows the higher drying temperature of the collected precipitate. See Figure 3 to see the pulp The percentage of MTBE in the feed decreases, while the softening temperature of the fines in the slurry increases. A similar relationship exists between the softening temperature of the precipitated material and the amount of water present in the slurry. The inventors also found that it is associated with water or mtbe alone. In comparison, the combined water and mtbe have a synergistic effect of lowering the softening point of the precipitated material. Therefore, when mtbe is used as the solvent in the sinking method of the present invention, it is desirable to remove the water to the lowest possible amount. An optional vacuum distillation step is carried out while stirring the slurry by a mechanical agitator, preferably at a temperature below the softening point of the precipitated solid in the slurry. The supernatant is collected on the slurry to carry out the distillation step. In some embodiments, the temperature of the upper liquid is maintained at about 25 ° C until L has been taken up to > 1% by volume. The supernatant. In some embodiments, the temperature of the collected slurry is maintained at about 20 ° C or 20. (: below until at least about 2 vol% of the collected slurry has been distilled, and then with each distillation An additional 2% by volume of the initially collected slurry was heated from 2 (rc to 26 〇c in increments of rc. In some real φ examples, after 13% by volume of the initial collection of the slurry was distilled, the temperature was allowed to proceed. Maintained below 32 ° C or below 32 ° C until the slurry volume becomes about one third of the volume of the initial collection slurry. In some embodiments, it is preferred to leave the supernatant from the slurry until it is present in the slurry The amount of water in the remaining supernatant is about 3% by weight or less by 0.003% by weight. In some implementations, the distillation is continued until the amount of MTBE present in the slurry supernatant is less than about 0.2% by weight, preferably from about 12% by weight to about 0.2% by weight. In some embodiments, the volume of concentrated concentrate is preferably reduced to about one-third of the initially collected slurry volume. It should be understood that when the type and amount of volatile components present in the solution are different 120556.doc -32- 200810821 The type of the volatile components in the above-mentioned initial collection of crude water and the agglomeration step will be required (4) Describe the _ ^ = material and measure the U sample material. ❹Sampling batch A ^ softening temperature, then in the various stages & softening r charge (4) at the appropriate temperature into the steaming "(4) and Μ and maintain a satisfactory rate and cohesion to adjust the applied vacuum, Select the temperature/pressure of the condensate. The 解 batch-human/child's required solution is to remove the component (especially water) from the solution before performing the sinking method of the present invention. Anti-solvent: dissolve two... can be used for the sinking method, for example, under these conditions, the ratio of the (4) J. solution, preferably the 3:1 anti-solvent: solution can be used. Ratios are expected to be adjustable: square: two provides a sink with the desired particle size and volume surface area while maintaining the narrow particle size distribution provided by the precipitation method of the present invention. From the above discussion, we should understand that the method of the present invention can be applied to other blends. The human controlled precipitation method 'produces precipitated particulate matter having a narrow and controlled particle size, chord length, surface area and bulk density. Examples of other compounds include crystalline or amorphous compounds and structural formula 1 To a further compound of 111. ^ Next, a pharmaceutical formulation prepared from the precipitated particulate material provided by the present invention will be described. ^Pharmaceutical Formulations In some embodiments of the present invention, Into the formulation for use as a medicament for the treatment of HCV infection, preferably a compound of formula B 556.doc-33-200810821, in the form of a precipitated material. In some embodiments, it is preferred to prepare a medicament from the precipitated form of the compound. The precipitated form has an initial particle size of less than about 1 (μm), preferably an initial particle size of from about 200 nm to about 3 Å () nm, a value of from about 丨 microns to about 2.5 microns, preferably about 15 microns. a particle size (a cluster of primary particles), a precipitate particle size distribution of from about 1 micron to about 5 microns, and an internal solvent content of less than about 1% by weight. In some embodiments, preferably used in a pharmaceutical decoy. Agglomerated particles of the compound of formula B (condensed particles of precipitated particles) having a volumetric surface area ranging from about 5 m2/g to about 12 m2/g as described below, more preferably having a basis of about 7 m2/g Value volume surface area and about 0.15 g/ml to The agglomerated particles having a bulk density of 19 g/ml, for example, by containing precipitated particles (having from about 16 m2/g to about 33 m2/g, preferably from 25 m/g to about 32.5 m2/g) The initial precipitated slurry of the volumetric surface area is subjected to agglomerated particles prepared by the condensation step at a temperature below the softening point of the initial precipitated solid. In some embodiments, the pharmaceutical formulation is preferably prepared in the form of particles suitable for use as a capsule filler. To provide a φ agglomerated particulate material comprising a compound of formula B. In some embodiments, the formulation comprises particles comprising up to 58% by weight of a compound of formula B (API), up to 6 weight 〇/〇 Microcrystalline cellulose, up to 18% by weight of pregelatinized starch, up to 4% by weight of croscarmellose sodium, up to 16% by weight of lanthanum/Lactose lactose monohydrate and up to 6 % by weight of sodium lauryl sulfate. In some embodiments, the particles preferably have a bulk density of from about 0.4 g/ml to about 66 g/ml, more preferably a bulk density of about 0.468 g/ml. The phrase "weight of API" as used herein refers to the amount of active pharmaceutical ingredient (by weight) contained in a substance supplied to the API. Therefore, if the substance package 120556.doc -34- 200810821 contains 80% For active pharmaceutical ingredients, one gram of the substance must be used to provide 80 grams of API. Therefore, the weight used in the formulation refers to 1% of the mass of the substance used to provide the API to the composition. The theoretical weight of the material is adjusted accordingly, and the actual weight of the substance providing the weight of the API is adjusted accordingly. In some embodiments, it is preferred to incorporate the precipitated particulate material provided by the present invention into a medicine suitable for supplying medicine by a method comprising the following steps. In the granules of the formulation: (a) sufficient amount to provide a precipitated particulate material (API) prepared by the process according to the invention by blending particles sufficient to provide up to 58% by weight, preferably 55.6 % by weight of particles Up to 6% by weight, preferably 5.6 % by weight of the amount of microcrystalline cellulose, sufficient to provide up to 18% by weight, preferably 16.6% by weight of the amount of pregelatinized starch, sufficient to provide Up to 4% by weight Preferably, 3% by weight of granules of croscarmellose sodium and lactose monohydrate in an amount sufficient to provide up to 16% by weight, preferably 156% by weight of the granules, to provide a dry blended mixture; Lu (b) dry blended mixture from step ''a') using a granulating fluid comprising sodium laurate (SLS) in an amount sufficient to provide up to "% by weight, preferably 3% by weight of particles" The sodium lauryl sulfate is dissolved in water equal to about 12 times to about 13 times the weight of the SLS used; (the wet grinding is from the step "b&quot; particles to provide a uniform particle size; (4) the drying step (b) The prepared wet granules until the granules exhibit a loss on drying (LOD) of less than 2·5 wt❶/◦, preferably from about 15% by weight to about 重量%; and $(e) is ground through the sieve to dry the dried first granules To provide graded granules. 120556.doc -35- 200810821 In some embodiments, it is preferred to use a low shear or high shear mixer to dry blend the material in the step &quot;a&quot;, preferably using high shear mixing / granulator, which is also conveniently used in the next step &quot;b" While the dry blending mixture is granulated, in some embodiments, the granules from step &quot;b, are preferably wet milled in a wet mill equipped with a sieve having a 0.375 bore. In some embodiments, Preferably, the wet granules are dried in a device selected from the group consisting of a box and a fluidized bed dryer, and more preferably a mechanical bed dryer is used. In some embodiments, it is preferred to use a device equipped with a sieve having a 〇·040 bore. The mill is used for the dry grinding step &quot;e&quot;. T can be used to prepare the granules using other techniques, including the use of low or high potential jaw/granulator equipment and the use of manual or automatic screening equipment. Wet and dry grinding 'both. In some embodiments, the graded granules prepared above are preferably incorporated into a pharmaceutical composition comprising granules of granules, extragranular microcrystalline cellulose, and extragranular magnesium stearate. In some embodiments, the pharmaceutical composition is preferably 5% by weight of API (intragranular), 14% by weight of lactose monohydrate (in granules), 5% by weight of intragranular microcrystalline cellulose, and 5 parts by weight. . /. Extragranular microcrystalline cellulose, 3% by weight of intragranular crosslinked sodium carboxymethyl cellulose, 3 parts by weight. 〆〇 granules The outer granules are delayed by methylcellulose, 15% by weight of pregelatinized powder (in granules), 3 parts of sodium lauryl sulfate (in granules) and the weight. /〇 Magnesium stearate (extragranular). In some embodiments, a particulate pharmaceutical formulation containing graded particles is prepared by subjecting the API-containing particles to excipients to provide a particulate pharmaceutical formulation product from which the dosage form is made. In some embodiments, this is accomplished by using the above method to prepare granules using the steps of 120556.doc • 36-200810821 further comprising the following steps: (4): Steps from the granulation method described above &quot;e, a microcrystalline cellulose having an amount equal to the amount of microcrystalline cellulose in the scaly particles and an amount equal to the cross-linked methine of the weight of the crosslinked retort cellulose present in the classified granule Cellulose nano dry push to provide a homogeneous particle powder;

W: a self-drying blending step &quot;a&quot; of a homogeneous particulate powder with an amount of stearic acid that is sufficient to provide a 2% by weight dry blended product, thereby providing a particulate pharmaceutical formulation. In some embodiments, microcrystalline cellulose in an amount greater than that present in the particles can be used. In some embodiments, it is possible to use a mixture of sodium methionate m in an amount greater than that present in the granules, although it is understood that by using any suitable means for dry blending particulate matter: for homogenization The blend 'preferably uses a blending member selected from the group consisting of a drum blender and a traction blender, more preferably a draw blender, to perform the blending steps nan and "b&quot; as described above. In some embodiments Preferably, the capsule dosage form of the medicament is provided by filling the capsule with a particulate pharmaceutical formulation prepared according to the above method sufficient to provide a therapeutic serum level of A containing the particulate pharmaceutical formulation. In some embodiments Preferably, the granules used in the pharmaceutical formulation are formed by granulating the dry blending mixture by dry blending 40 Kg of the compound of formula B (API) according to the above precipitation method. Prepare the preparation as it is), 4.0 Kg microcrystalline cellulose, u, 2 § lactose monohydrate, 12_0 Kg pregelatinized starch and 2.4 Kg croscarmellose nano 120556.doc -37- 200810821 And made. In some implementations In one embodiment, it is preferred to provide a granulating fluid comprising 2.4 Kg of sodium lauryl sulfate dissolved in 48 Kg of water, and preferably the dry blended mixture is granulated until no free flowing powder is observed. In some embodiments, preferably. The granules are dried in a fluid bed dryer until the loss on drying is less than about 2.5% by weight. In some embodiments, the dried granules are preferably ground in a sieve mill equipped with a 0.032 吋 sieve to provide an average size of 32 mesh. Particulate matter. In some embodiments, the dry abrasive granules are preferably blended with 4.0 Kg of additional microcrystalline cellulose and 2.4 Kg of additional croscarmellose sodium to provide a second dry blended mixture, followed by blending 1.6. Kg magnesium stearate and the second dry blending mixture to provide a granular product. For use in the granule of the present invention, it is preferred to use microcrystalline cellulose equivalent to Avicel PH102, preferably using a fine fine nipple For hydrate, it is preferred to use pre-gelatinized starch 1500 from Colorcon, preferably NF-grade croscarmellose sodium; and preferably use NF-grade lauryl sulfur from Stepan. And NF grade magnesium stearate derived from plant test stearic acid. Suitable materials are commercially available, such as Avicel PHI02 microcrystalline cellulose from FMC, very fine lactose monohydrate from Foremost Farms, purchased from Colorcon's pregelatinized starch 1500, cross-linked methyl cellulose sodium NF grade from FMC, Stepanol WA-100 NF from Stepan, and plant-grade stearic acid from Greven. In some embodiments, an aliquot of a homogeneous powder is optionally filled into a gelatin capsule to provide a dosage form having a component weight as indicated in the table below (each dosage having an API of about 200 mg). 120556.doc -38 - 200810821

Exclusivity, this effect is performed by the excipients given in the above table. Alternative Embodiments In some embodiments, it is preferred to provide a pharmaceutical formulation of the above method comprising one or more compounds such as an API selected from the group consisting of compounds of formulas I-XXVIII as described herein. Such formulations are useful for inhibiting HCV protease and/or tissue protein activity and having good solubility characteristics to promote absorption of the compound of formula XXVHI. In some embodiments, at least one HCV protease inhibitor is selected from the group of HCV protease inhibitors referred to in the following document, which is incorporated herein by reference: US20040048802A1, US20040043949A1, US20040001853A1, US20030008828A1, US20020182227A1, US20020177725A1, US20020150947A1, US20050267018A1, US20020034732A1, US20010034019A1, 120556.doc-39-200810821 US20050153877A1, US20050074465A1, US20050053921A1 US20040253577A1, US20040229936A1, US20040229840A1 US20040077551A1, EP1408031A1, WO9837180A2, US6696281B1

JP11137252A W00111089A1 US6280940B1 EP1106702A1 US20050118603A1

JP2000007645A W00053740A1 W00020400A1 W02004013349A2 W02005027871A2 US20030125541A1 W02002100900A2, W00155703A1 US6608027B1 US20040039187A1 US20030224977A1 W02003010141A2 &gt; W02003007945A1 &gt; W02002052015A2 WO0248375A2, WO0066623A2, W00009543A2, WO9907734A2 US6767991B1 US20030187018A1 US20030186895A1 W02004087741A1, W02004039970A1, W02004039833A1 W02004037855A1 - W02004030670A1 &gt; US20040229818A1 US20040224900A1, W02005028501A1, W02004103996A1 W02004065367A1 &gt; W02004064925A1 &gt; W02004093915A1 W02005034850A2 W02004009121A1 &gt; W02003066103A1 W02004094452A2 &gt; W02004015131A2 - W02003099316A1 W02003099274A1 W02003053349A2, W02002060926A2 W00040745A1, US6586615B1, W02002061048A2, WO0248157A2 WO0248116A2 W02005017125A2 W00022160A1 US20060051745A1 &gt; W02004021871A2 &gt; W02004011647A1 W09816657A1, US5371017A, WO9849190A2, US5807829A W00005243A2, W00208251A2, W02005067437A2, W09918856A1 W00004914A1, WO0212543A2, W09845040A1, W00140262A1 120556.doc -40- 200 810821 W00102424A2, W00196540A2, WO0164678A2, US5512391A, WO0218369A2, W09846597A1, W02005010029A1, WO2004113365A2, W02004093798A2, W02004072243A2, W09822496A2, W02004046159A1, JP11199509A, W02005012288A1, W02004108687A2, WO9740168A1, US20060110755A1, W02002093519A2, US6187905B1, W02003077729A2, W09524414A1, W02005009418A2, W02004003000A2, US20050037018A1, W09963998A1 ,

WO0063444A2, W09938888A2, W09964442A1, W00031129A1, WO0168818A2, WO9812308A1, W09522985A1, WO0132691A1, WO9708304A2, W02002079234A1, JP10298151A, JP09206076A, JP09009961A, JP2001103993A, JP11127861A, JP11124400A, JP11124398A, W02003051910A2, W02004021861A2, W09800548A1, W02004026896A2, WO0116379A1, US5861297A, W02004007512A2, W02004003138A2, W02002057287A2, W02004009020A2, W02004000858A2, W02003105770A2, WO0114517A1, WO9805333A1, US6280728B1, EP1443116A1, US20040063911A1, W02003076466A1, W02002087500A2, W00190121A2, W02004016222A2, W09839030A1, WO9846630A1, WO0123331A1, W09824766A1, US6168942B1, WO0188113A2, W02005018330A1, W02005003147A2, W09115596A1, WO9719103A1, WO9708194A1, W02002055693A2, W02005030796A1, W02005021584A2, WO2004113295A1, WO2004113294A1 &gt; WO2004113272A1 &gt; W02003062228A1 &gt; 120556.doc -41- 200810821 WO0248172A2, W00208198A2, WO0181325A2, WO0177113A2, WO0158929A1, W0992 8482A2, WO9743310A1, WO9636702A2, WO9635806A1, W09635717A2, US6326137B1, US6251583B1, US5990276A, US5759795A, US5714371A, US6524589B1, WO0208256A2, W00208187A1, W02003062265A2, US7012066B2, JP07184648A, JP06315377A, W02002100851A2, W02002100846A1, W00039348A1, JP06319583A, JP11292840A, JP08205893A, WO0075338A2, W00075337A1, W02003059384A1,

W02002063035A2, W02002070752A1, US6190920B1, W02002068933A2, WO0122984A1, JP04320693A, JP2003064094A, WO0179849A2, W00006710A1, W00001718A2, WO0238799A2, W02005037860A2, W02005035525A2, W02005025517A2, W02005007681A2, W02003035060A1, W02003006490A1, WO0174768A2, W00107027A2, W00024725A1, W00012727A1, W09950230A1, WO9909148A1, W09817679A1, W09811134A1, W09634976A1 &gt; W02003087092A2 &gt; W02005028502A1 &gt; US5837464A, DE20201549U1, W02003090674A2, W09727334A1, W00034308A2, US6127116A, US20030054000A1, JP2001019699A, US6596545B1, US6329209B1, IT1299179, CA2370400, KR2002007244, KR165708, KR2000074387, KR2000033010, KR2000033011, KR2001107178, KR2001107179, ES2143918, KR2002014283 , KR149198, KR2001068676. Preferably, the HCV protease inhibitor is provided in a dose ranging from about 100 to about 4000 mg per day (eg, 100 mg, 150 mg, 200 mg, 250 120556.doc -42 - 200810821 mg, 300 mg, 350 mg per day, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1050 mg, 1100 mg, 1150 mg, 1200 mg , 1250 mg, 1300 mg, 1350 mg, 1400 mg, 1450 mg, 1500 mg, 1550 mg, 1600 mg, 1650 mg, 1700 mg, 1750 mg, 1800 mg, 1850 mg, 1900 mg, 1950 mg, 2000 mg, 2050 Mg, 2100 mg, 2150 mg, 2200 mg,

2250 mg, 2300 mg ' 2350 mg ' 2400 mg, 2450 mg, 2500 mg, 2550 mg, 2600 mg, 2650 mg, 2700 mg, 2750 mg, 2800 mg, 2850 mg, 2900 mg, 2950 mg, 3000 mg, 3050 mg , 3100 mg, 3150 mg, 3200 mg, 3250 mg, 3300 mg, 3350 mg, 3400 mg, 3450 mg, 3500 mg, 3550 mg, 3600 mg, 3650 mg, 3700 mg, 3750 mg, 3800 mg, 3850 mg, 3900 The amount of mg, 3 950 mg, 4000 mg) provides a formulation to patients in need. In a preferred embodiment, the HCV protease inhibitor is administered at a dose ranging from about 400 mg to about 2500 mg per day. In another preferred embodiment, the HCV protease inhibitor is administered at a dose ranging from about 1900 mg to about 4000 mg per day. In another preferred embodiment, the HCV protease inhibitor is administered at a dose ranging from about 1 〇 5 〇 mg to about 2850 mg per day. In one embodiment, wherein the HCV protease inhibitor is a chelate, a pharmaceutically acceptable salt, solvate or ester thereof, the HCV protease inhibitor is from about 1920 mg to about 4000 mg per day. Preferably, it is administered in a dose ranging from about 192 mg to about 3000 mg per day or from about 2560 mg to about 4000 mg per day. 120556.doc -43- 200810821 In one embodiment, wherein the HCV protease inhibitor is a compound of formula XXVII, a pharmaceutically acceptable salt, solvate or ester thereof, the HCV protease inhibitor is from about 1080 mg per day to A dosage range of about 3 125 mg, preferably from about 1800 to about 2813 mg per day, is administered. In one embodiment, wherein the HCV protease inhibitor is a compound of formula XXVIII, a pharmaceutically acceptable salt, solvate or ester thereof, the HCV protease inhibitor is from about 1 080 mg to about 3 125 mg per day, preferably It is administered in a dose range of about 1 800 to about 28 13 mg per day. It should be noted that the dose of the HCV protease inhibitor can be administered in a single dose per day (i.e., QD) or divided into 2 to 4 doses per day (i.e., BID, TID, or QID). In one embodiment, the HCV protease inhibitor is administered in a dosage range from about 600 mg QID to about 800 mg QID. In one embodiment, wherein the HCV protease inhibitor is a compound of formula I, a pharmaceutically acceptable salt, solvate or vinegar thereof, the HCV protease inhibitor is 800 mg TID, 600 mg QID or 800 mg QID Dosage is administered. In another embodiment, wherein the HCV protease inhibitor is a compound of formula XXVII, a pharmaceutically acceptable salt, solvate or ester thereof, the HCV protease inhibitor is administered at a dose of 75 0 mg TID. Also in another embodiment, wherein the HCV protease inhibitor is a compound of formula XXVIII, a pharmaceutically acceptable salt, solvate or ester thereof, the HCV protease inhibitor is administered at a dose of 750 mg TID. Preferably, the HCV protease inhibitor is administered orally. The structure of the compound of formula I is disclosed in PCT International Publication No. WO 03/062265, issued July 31, 2003. Non-limiting examples of certain compounds disclosed in this publication 120556.doc-44.200810821 include those compounds listed in pages 48-75 (incorporated herein by reference) or pharmaceutically acceptable Salt, solvate or i. In one embodiment, the API is selected from the group consisting of compounds of formula la:

Formula la, a pharmaceutically acceptable salt, solvate or vinegar thereof. The compounds of formula ia have recently been isolated as isomers/diastereomers of formulas lb and Ic, as disclosed in U.S. Patent Publication No. 2005/0249702, which is incorporated herein by reference. In one embodiment, at least one compound is of Formula Ic (a potent inhibitor of HCV NS3 serine protease), a pharmaceutically acceptable salt, solvate or ester thereof

The chemical name of the compound of formula Ic is (1,28,58)-indole[(18)-3-amino-1-(cyclobutylindenyl)-2,3-di-oxypropyl]-3 -[(2S)-2-[[[(l,l-dimethylethyl)amino]]]amino]-3,3-dimethyl-1-oxobutyl -6, 6-二曱120556.doc -45- 200810821 Base-3-azabicyclo[3.1.0]hexane-2-carboxamide. A method for the manufacture of a compound of formula I is disclosed in U.S. Patent Publication Nos. 2005/0059648, 2005/0020, 689, and U.S. Pat. Non-limiting examples of suitable compounds of formula II and methods for their manufacture are disclosed in U.S. Patent Application Serial No. 6,002, the entire disclosure of which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula III and methods for their manufacture are disclosed in International Patent Publication No. W002/08187 and U.S. Patent Publication No. 2002/0160962, page 3, paragraphs 22 to 132, which are incorporated by reference. In this article. Non-limiting examples of suitable compounds of formula IV and methods for their manufacture are disclosed in International Patent Publication No. WO 03/062228 and U.S. Patent Publication No. 2003/0207861, page 3, paragraphs 25 to 26, which are incorporated by reference. In this article. Non-limiting examples of suitable compounds of formula V and methods for their manufacture are disclosed in U.S. Patent Publication No. 2005/0119168, page 3, paragraph [0024] to page 215, paragraph [0833], which is incorporated herein by reference. in. Non-limiting examples of suitable compounds of formula VI and methods for their manufacture are disclosed in U.S. Patent Publication Serial No. 2005/0085425, page 3, paragraphs 0023 to 139, which is incorporated herein by reference. Non-limiting examples of suitable compounds of the formulae VII, VIII and IX and methods for their manufacture are disclosed in International Patent Publication No. WO2005/051980 and U.S. Patent Publication No. 2005/0164921, page 3, paragraph [0026] to page 113, section 120556. .doc -46.200810821 [0271], which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula X and methods for their manufacture are disclosed in International Patent Publication No. WO2005/085275 and U.S. Patent Publication No. 2005/0267043, page 4, paragraph [0026] to page 519, paragraph [0444]. It is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XI and methods for their manufacture are disclosed in International Patent Publication No. WO2005/087721 and U.S. Patent Publication No. 2005/028 8233, page 3, paragraph [0026] to page 280, paragraph [0508]. , which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XII and methods for their manufacture are disclosed in International Patent Publication No. WO2005/087725 and U.S. Patent Publication No. 2005/0245458, page 4, paragraph [0026] to page 194, paragraph [0374]. It is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XIII and methods for their manufacture are disclosed in International Patent Publication No. WO2005/085242 and U.S. Patent Publication No. 2005/0222047, page 3, paragraph [0026] to page 209, paragraph [0460]. It is incorporated herein by reference. Non-limiting examples of suitable compounds of the formula XIV and methods for their manufacture are disclosed in International Patent Publication No. WO2005/087781, page 8, line 20 to page 683, line 6, which is incorporated herein by reference. Non-limiting examples of suitable XV compounds and methods for their manufacture are disclosed in International Patent Publication No. WO2005/058821 and U.S. Patent Publication No. 2005/0153900, page 4, paragraph [0028] to page 83, paragraph [0279]. It is incorporated herein by reference. 120556.doc -47- 200810821 A non-limiting example of a suitable XVI compound and method of making the same is disclosed in International Patent Publication No. WO2005/087730 and U.S. Patent Publication No. 2005/0197301, page 3, paragraphs [0026] to 156. In paragraph [03 12], it is incorporated herein by reference. Non-limiting examples of suitable compounds of the formula XVII and methods for their manufacture are disclosed in International Patent Publication No. WO2005/085197 and U.S. Patent Publication No. 2005/0209164, page 3, paragraph [0026] to page 87, paragraph [0354]. , which is incorporated herein by reference. • Non-limiting examples of suitable compounds of formula XVIII and methods for their manufacture are disclosed in U.S. Patent Publication No. 2006/0046956, page 4, paragraph [0024] to page 50, paragraph [0282], which is incorporated by reference. In this article. Non-limiting examples of suitable compounds of the formula XIX and methods for their manufacture are disclosed in International Patent Publication No. WO2005/113581 and U.S. Patent Publication No. 2005/0272663, page 3, paragraphs [0026] to 76, which are incorporated by reference. Incorporated herein. Non-limiting examples of suitable compounds of formula XX and methods for their manufacture are disclosed in International Patent Publication No. WO20009558, page 4, line 17 to page 85, which is incorporated herein by reference. Non-limiting examples of suitable XXI compounds and methods for their manufacture are disclosed in International Patent Publication No. WO2000/09543, page 4, line 14 to page 124, which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XXII and methods for their manufacture are disclosed in International Patent Publication No. WO2000/59929 and U.S. Patent No. 6,608,027, at col. 65, line 65 to 141, line 20, each of which is incorporated by reference. 120556.doc -48- 200810821 is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XXIII and methods for their manufacture are disclosed in International Patent Publication No. WO 02/1 83 69, page 4, line 14 to page 311, which is incorporated herein by reference. Non-limiting examples of suitable compounds of the formula XXIV and methods for their manufacture are disclosed in U.S. Patent Publication Nos. 2002/0032175, 2004/0266731, and U.S. Patent No. 6,265,380, col. 3, lines 35 to 121, and 6,617,309. No. 3, pp. 40 to 121, each of which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XXV and methods for their manufacture are disclosed in International Patent Publication No. WO 1998/22496, pages 3 to 122, which is incorporated herein by reference. Non-limiting examples of suitable compounds of the formula XXVI and methods for their manufacture are disclosed in U.S. Patent No. 6,143,715, at col. 3, line 6 to column 62, line 20, which is incorporated herein by reference. Non-limiting examples of suitable compounds of formula XXVII and formula XXVIII and methods for their manufacture are disclosed in International Patent Publication No. WO 02/18369, page 4, line 4 to page 311, which is incorporated herein by reference. More specifically, see International Patent Publication No. WO 02/18369, Examples 17, 27, 86 and 126, which are incorporated herein by reference. In particular, for compound XXVII, see Example 27 of WO 02/18369 pages 146-153, which details the method of making the compound nCU described on page 90, and Example 126, which details the manufacture of Section 225 The method of the intermediate compound cxxxviii of the page. Similarly, for the compound XXVIIIa, see Example 21 of WO 02/18369, pp. 120556.doc-49-200810821 139-140, which details the preparation of the compound described on page 52" Method of BW", and Example 86, which details the method of making the intermediate compound Ixxxix on page 207. For each of the above alternative compounds, the isomers (if present) of the various compounds 'including the alignment Isomers, stereoisomers, rotamers, tautomers and racemates, as well as mixtures and racemic mixtures of such stereoisomers, are also considered to be part of the invention. The structure of the compound of I to XXVIII. The compound of the formula I has the following structure:

And including pharmaceutically acceptable salts, solvates or esters thereof; wherein in Formula I: Y is selected from the group consisting of alkyl, alkylaryl, heteroalkyl, heteroaryl, Arylheteroaryl, alkylheteroaryl, cycloalkyl, alkoxy, alkylaryloxy, aryloxy, heteroaryloxy, heterocycloalkoxy, cycloalkoxy, alkylamino An arylamino group, an alkylarylamino group, an arylamino group, a heteroarylamino group, a cycloalkylamino group and a heterocycloalkylamino group, which are limited to γ optionally substituted by X11 or X12; X11 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclic 120556.doc • 50- 200810821 yl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl , heteroaryl, alkylheteroaryl or heteroarylalkyl, the limitation is that X11 may be optionally substituted by X12; X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, aryl Thio group, amine group, alkylamino group, arylamine group, alkylsulfonyl group, arylsulfonyl group, alkylsulfonylamino group, arylsulfonylamino group, carboxyl group, alkoxycarbonyl group, carboxyindole Amine, alkoxy a carbonylamino group, an alkoxycarbonyloxy group, an alkylureido group, an aryl urea group, an i group, a cyano group or a nitro group, with the proviso that the alkyl group, the alkoxy group and the aryl group may be independently selected as appropriate a moiety selected from X12; R1 is COR5, wherein R5 is COR7, wherein R7 is NHR9, wherein R9 is selected from the group consisting of H, alkyl, aryl, heteroalkyl, heteroaryl, Cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, [CHCR'^lpCOOR11 ^ [C^R^^pCONR^R13 &gt; [CH(R1)]pS02R11 ^ [CH(Rr)] pCORn ^ [CHCR' ^pCHCO^R11 ^ CH(Rr)CONHCH(R2)COORu ^ CI^RqCONHCI^RqCONR12;^13,,CHCR1') CONHCH(R2,)CONHCH(R3,)COORh,CH(Rr)CONHCH (R2) CONHCH(R3')CONR12R13, CH(Rr)CONHCH(R2,)CONHCH(R3') CONHCH(R4)COORn,CH(R1,)CONHCH(R2,)CONHCH(R3) CONHCH(R4,)CONR12R13 ^ CH(R1,)CONHCH(R2,)CONHCH(R3) CONHCH(R4')CONHCH(R5)COORu and CHCR^CONHOHKRqCONHCH (R3')CONHCH(R4)CONHCH(R5')CONR12R13, where R1', R2' , R3·, R4', ^, ^^, ^^, 尺" and "' are independently selected from the group consisting of: H, , aryl, heteroalkyl 'heteroaryl, cycloalkyl, alkylaryl, alkylheteroaryl, arylalkyl and heteroarylalkyl; 1205 56.doc -51 - 200810821 Z series selected from Ο, N, CH or CR; w may or may not be present, and if w is present, w is selected from c=o, C=S, C(=N-CN) or S02; Q may or may not be present, And when Q is present, Q is CH, N, P, (CH2)P, (CHR)P, (CRR,) P, Ο, NR, S or S02; and when Q is not present, M may or may not exist Exist; when Q and M are not present, A is directly connected to L; A is Ο, CH2, (CHR)P, (CHR-CHR,) P, (CRR,) P, NR, ® s, so2 or - E is CH, N, CR or a double bond towards A, L or G; G may or may not be present, and when G is present, G is (CH2)P, (CHR)P or (CRR')P; And when G is absent, J exists and E directly links the broken atom bonded by G in formula I; J may or may not exist, and when J exists, J is (CH2)P, (CRRf)p, S02 , NH, NR or Ο; and when J is absent, G exists and E is directly bonded to the N of J as shown in formula I; L may or may not exist, and when L is present, L is CH , CR, Ο, S Or NR; and when L is not present, then Μ may or may not exist; and if Μ exists and L does not exist, Μ is directly and independently bonded to Ε, and J is directly and independently bonded to Ε; Μ may exist Or absent, and when Μ is present, Μ is Ο, NR, S, S02, (CH2)P, (CHR)P(CHR-CHR,)P or (CRR%; p is a number from 0 to 6; R, R, R2, R3 and R4 are independently selected from the group consisting of: 120556.doc -52- 200810821 Η ; CrCw alkyl; C2-C1G dilute; C3-C8 cycloalkyl; C3-C8 Heterocyclic alkyl, alkoxy, aryloxy, alkylthio, arylthio, amine, decylamine, ester, carboxylic acid, urethane, urea, ketone, aldehyde, cyano, nitro , halogen; (cycloalkyl)alkyl and (heterocycloalkyl)alkyl, wherein the cycloalkyl consists of 3 to 8 carbon atoms and oxime to 6 oxygen, nitrogen, sulfur or dish atoms, and the a group having 1 to 6 carbon atoms; an aryl group; a heteroaryl group; an alkylaryl group; and an alkylheteroaryl group;

Wherein the alkyl, heteroalkyl, alkenyl, heteroalkenyl, aryl, heteroaryl, cycloalkyl and heterocycloalkyl moieties are suitably substituted as appropriate and chemically, the term &quot;substituted" Optionally and chemically suitably one or more selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, halogen, hydroxy, thio, alkoxy, aryloxy Base, alkylthio, arylthio, amine, decyl, ester, decanoic acid, urethane, urea, ketone, aldehyde, cyano, nitro, sulfoximine, sulfoxide, sulfone, Sulfonyl urea, hydrazine and hydroxamic acid are substituted by a portion of the group consisting of:

In addition, the structure, wherein the single tgN-C-G-E-L small N represents a five- or six-membered annular ring is limited to when the unit N-C-G-E-L-J-N represents a five-membered ring

a ring-like structure, or when the double-kick structure of N, c, g, e, l, j, n, a, q, and Μ in formula I represents a five-membered f-shell structure, the five-membered ring The ring structure lacks a carbonyl group as a part of the ring.

120556.doc -53- 200810821 or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula II: Z is NH; X is alkylsulfonyl, heterocyclylsulfonyl, heterocycle Alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylcarbonyl, heterocyclylcarbonyl, heterocyclylalkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, alkoxycarbonyl, a heterocyclic oxycarbonyl group, an aryloxycarbonyl group, a heteroaryloxycarbonyl group, an alkylaminocarbonyl group, a heterocyclic aminocarbonyl group, an arylaminocarbonyl group or a heteroarylaminocarbonyl moiety, which is limited to X may additionally be substituted by R12 or R13; X1 is H; CVC4 linear alkyl; CVCU branched alkyl or CH2-aryl (substituted or unsubstituted); R12 is alkyl, alkenyl, Alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl or heteroaryl The alkyl moiety, with the proviso that R12 can be additionally substituted with R13 as appropriate. 0 R13 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, alkylamino, arylamine, alkyl thiol, aryl acid group, burned Base-stranded amine, aryl continued amine, weiki, oxydithiol, acesulfame, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, Halogen, cyano or nitro moieties, with the proviso that the alkyl, alkoxy and aryl groups may additionally be optionally substituted with a moiety independently selected from R13.

Pla, Plb, P2, P3, P4, P5 and P6 are independently: Η; &lt;^-(: 10 direct bond or branched bond base, C2-Ci〇 direct bond or branch bond thin base; C3-C8 a cycloalkyl group, a c3-c8 heterocyclic ring; a (cycloalkyl)alkyl group or a (heterocyclyl)alkyl group, wherein the ring 120556.doc -54- 200810821 alkyl group is composed of 3 to 8 carbon atoms and 0 to 6 Oxygen, nitrogen, sulfur or phosphorus atom, and the alkyl group has 1 to 6 carbon atoms; aryl, heteroaryl, arylalkyl or heteroarylalkyl group, wherein the alkyl group has 1 to 6 a carbon atom; wherein the alkyl, alkenyl, cycloalkyl, heterocyclyl; (cycloalkyl)alkyl and (heterocyclyl)alkyl moieties are optionally substituted by Rl3, and further wherein the pia and Plb are as appropriate Linked to each other to form a spiro or spiro heterocycle, wherein the spiro or spiroheterocycle contains 0 to 6 oxygen, nitrogen, sulfur or phosphorus atoms, and may be optionally substituted with R13;

Lanthanum, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl The restriction condition is that the Ρ1 can be replaced by a ruler. The compound of formula III has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in the formula: G is a carbonyl group; J and oxime may be the same or different and are independently selected from the group consisting of: Η, 烧基,院Alkyl, heteroalkyl, heteroaryl, arylheteroaryl, alkylheteroaryl, cycloalkyl, alkoxy, alkylaryloxy, aryloxy, heterooxy, heterocyclic Oxyl, cycloalkoxy, alkylamino, arylamine, calcination 120556.doc -55- 200810821 arylamino, arylamine, heteroarylamine, cycloalkylamine and hetero a cycloalkylamino group, which is limited to γ may be optionally substituted by X11 or χΐ2; X11 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclic, heterocyclic a group consisting of an alkyl group, an aryl group, an alkylaryl group, an arylalkyl group, a heteroaryl group, an alkylheteroaryl group or a heteroarylalkyl moiety, with the proviso that X11 may be optionally substituted with X12; X12 is hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, alkylamino, arylamine, alkylsulfonyl, arylsulfonyl, alkyl Sulfon Base, arylsulfonylamino group, carboxyl group, alkoxycarbonyl group, carboxy S basket amine group, alkoxycarbonylamino group, alkoxycarbonyloxy group, alkylureido group, aryl urea group, dentate, cyano group Or a nitro group, wherein the alkyl group, the alkoxy group and the aryl group may be optionally substituted with a moiety independently selected from X12; R1 is COR5 or C(OR)2, wherein R5 is selected from ruthenium, OH, a group consisting of OR8, NR9R10, CF3, C2F5, C3F7, CF2R6, R6 and COR7, wherein R7 is selected from the group consisting of ruthenium, OH, OR8, CHR9R10 and NR9R10, wherein R6, R8, R9 and R1G may be the same or different and Is independently selected from the group consisting of hydrazine, alkyl, aryl, heteroalkyl, heteroaryl, cycloalkyl, cycloalkyl, arylalkyl, heteroarylalkyl, CH(R1) COOR11, CH(Rr)CONR12R13, CH(R1,)CONHCH(R2) COOR11 &gt; CHCR'^CONHCHC^^CONR^R13 &gt; CH(Rr)CONHCH (R2,)Rf &gt; CHCR/^CONHCHC^^CONHCHC ^^COOR11 &gt; CH(Rr) C0NHCH(R2,)C0NHCH(R3,)C0NR12R13, CH(R1,)CONHCH(R2) CONHCH(R3,)CONHCH(R4,)COORn, CH(R1,)CONHCH(R2 120556.doc -56- 200810821 CONHCH(R3')CONHCH(R4')CON R12R13, CH(Rr)CONHCH(R2) CONHCH(R3,)CONHCH(R4,)CONHCH(R5,)COORn, and CH(Rr) CONHCH(R2,)CONHCH(R3,)CONHCH(R4,)CONHCH(R5 CONR12R13 wherein R1, R2, R3', R4', R5', R11, R12, r13 and r' may be the same or different and are independently selected from the group consisting of hydrazine, alkyl, aryl, heteroalkyl, heteroaryl a group consisting of a cycloalkyl group, an alkylaryl group, an alkylheteroaryl group, an arylalkyl group, and a heteroaralkyl group; the lanthanide is selected from the group consisting of ruthenium, osmium or CH; W may or may not be present, and if w is present , wherein w is selected from C = 0, C = S or S02; and R, Rf, R2, R3 and R4 are independently selected from the group consisting of: Η; CkCw alkyl; C2-C1G alkenyl; c3_Cyf&lt;;alkyl; C3-C8 heterocycloalkyl, alkoxy, aryloxy, thiol, arylthio, amine, amide, ester, carboxylic acid, urethane, urea, ketone, Aldehyde, cyano, nitro; oxygen, nitrogen, sulfur or atomic (wherein the oxygen, nitrogen, sulfur or phosphorus atom counts from 〇 to 6); (cycloalkyl)alkyl and (heterocycloalkyl)alkyl Wherein the cycloalkyl group consists of from 3 to 8 carbon atoms and from 0 to 6 oxygen, nitrogen, sulfur or phosphorus atoms And the alkyl group has 1 to 6 carbon atoms; an aryl group; a heteroaryl group; an alkylaryl group; and an alkylheteroaryl group; wherein the alkyl group, heteroalkyl group, alkenyl group, heteroalkenyl group, aryl group, The heteroaryl, cycloalkyl and heterocycloalkyl moieties may be optionally substituted, wherein the term, substituted, is optionally and chemically suitably selected from one or more selected from alkyl, alkenyl, fast radical, Aryl, aralkyl, cycloalkyl, heterocyclic, halogen, hydroxy, thio, alkoxy, aryloxy, alkylthio, arylthio, amine, hydrazine 120556.doc -57- 200810821 Amino , esters, carboxylic acids, urethanes, ureas, ketones, aldehydes, cyano groups, nitro groups, sulfonic acid amine groups, sulfoxides, hydrazines, sulfonyl ureas, hydrazine and hydroxamic acid Part of the group is replaced.

The compound of formula IV has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula IV: Y is selected from the group consisting of alkyl, alkylaryl, heteroalkyl, heteroaryl, aryl Heteroaryl, alkylheteroaryl, cycloalkyl, alkoxy, alkylaryloxy, aryloxy, heteroaryloxy, heterocycloalkoxy, cycloalkoxy, alkylamino, aromatic Amino group, alkylarylamino group, arylamino group, heteroarylamino group, cycloalkylamino group and heterocycloalkylamino group, the limitation condition is that γ may be substituted by X11 or X12; X11 is Alkyl, fluorenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkyl heteroaryl Or a heteroarylalkyl group, the limitation is that the oxime may be optionally substituted by X12; X12 is a hydroxyl group, an alkoxy group, an aryloxy group, a thio group, an alkylthio group, an aryl fluorenyl group, an amine group, an alkylamine Base, arylamine, alkylsulfonyl, aryl miscellaneous 120556.doc •58- 200810821 base, alkylsulfonylamino, arylsulfonylamino, carboxyl, alkoxycarbonyl, carboxamide Silk-based m-amine a group, an alkoxycarboxyoxy group, an alkyl group, an aryl urea group, an i group, a cyano group or a nitro group, wherein the alkyl group, the alkoxy group and the aryl group may be independently selected from the group consisting of Part 2 is substituted; R1 is selected from the following structure: I-&quot;&quot;&quot;(Rl1)k IN^^^(Rl1)k

Wherein k is a number which may be the same or different from 〇 to 5, and R11 represents an optional substituent wherein each substituent is independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, Cycloalkyl, alkylaryl, heteroalkyl, heteroaryl, arylheteroaryl, alkylheteroaryl, alkoxy, alkylaryloxy, φ aryloxy, heteroaryloxy, hetero Cycloalkoxy, cycloalkoxy, alkylamino, arylamino, alkylarylamino, arylamino, heteroarylamino, cycloalkylamino, heterocycloalkylamino , hydroxy, thio, alkylthio, arylthio, amine, alkylsulfonyl, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, carboxyl, alkoxycarbonyl, carboxy Amidino, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, _, cyano and nitro, the limitation of which is R11 (when R11矣Η) is visible The condition is replaced by X11 or X12; the lanthanide is selected from lanthanum, cerium, CH or CR; W may or may not be present, and if w is present, the W is selected from c=o, 120556.doc • 59- 200810821 〇S, C(=N-CN) or S(02); Q may or may not exist In, and when Q is present, Q is CH, N, P,

(CH2)p, (CHR)p, (CRR')P, ο, n(R), s or S(02); and when Q is not present, M may or may not exist; when Q&amp;M does not exist When A is directly bonded to L; A is Ο, CH2, (CHR)p, (CHR-CHR,)p '(CRR,)P, N(R), s, S(〇2) or one bond; E is CH, N, CR or a double bond towards A, L or G; G may or may not be present, and when (^ is present, G is (CH2)p, (CHR)p or (CRR')p; And when G is absent, j exists and E directly links the carbon atom to which the bond is attached; J may or may not exist, and when j is present, j is (CH2)p, (CHR)p or (CRR%, S(02), NH, N(R) or 〇; and when j is absent, G exists and E is directly bonded to the n of j as shown in formula I; l may or may not exist and When L is present, L is CH, C(R), 〇, s or N(R); and when L is not present, Μ may or may not exist; and if M is present [is not present, then Μ directly Independently linked to e, and J is directly and independently linked to e; Μ may or may not exist, and when Laos is present, μ is 〇, n(r), s, S(〇2), (CH2)P , (CHR)P(CHR-CHR')P4(CRR,)P ; p is a number from 0 to 6; R, R/, R, R3 and r4 may be the same or different and each independently selected from Η 'C^-Cio alkyl; c2_Ci decenyl; C3_C8 cycloalkyl; c3-C8 heterocycloalkyl, alkoxy , aryloxy, alkylthio, arylthio, amine, decyl, ester, carboxylic acid, amino phthalate, urea, ketone, aldehyde, cyano, nitrocellulose, 120556.doc -60- 200810821 A group of halogen, (cycloalkyl)alkyl and (heterocycloalkyl)alkyl groups, wherein the cycloalkyl group is from 3 to 8 carbon atoms, and up to 6 oxygen, nitrogen, sulfur or phosphorus atoms Composition, and the alkyl group has 1 to 6 carbon atoms; aryl; heteroaryl; alkylaryl; and alkylheteroaryl; &amp;, τ, thiol, helo, alkenyl, hetero Alkenyl / ,

The decyl and heterocycloalkyl moieties may be optionally substituted, wherein the term &quot;substituted&quot; means substituted by one or more moieties which may be the same or different, each substituent being independently selected from alkyl, alkenyl , alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, dentate, thiol, thio, methoxy, aryloxy, aryl, arylthio, amine, amidino, A group consisting of vinegar, citric acid, urethane, L. urea, ί, cyano, decyl, hydrazine, subhard, hard, succinct, fermented, and hydroquinone; In addition, the unit shows five members> Changyi's voice, gentleman's magnetic 4, clothing, or mouth structure or /, shell% % structure, the restriction condition is when the unit N_c

The five-membered annular ring structure, or the formula]; contains a double-ring structure of N, C, G, EJN y'Q and Μ, which represents a five-membered annular ring structure. The five-membered cyclic ring compound of the formula V has the following structure:

R1 is a carbonyl group. 120556.doc -61 - 200810821 or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in formula v: (1) R1 is -C(0)R5 or -B(OR)2; (2 R5 is Η, -OH, -OR8, -NR9R10, -C(0)0R8, -C(0)NR9R10, _CF3, -C2F5, C3F7, -CF2R6, -R6, _C(0)R7 or NR7S02R8 ; 3) R7 is H, -OH, -OR8 or -CHR9R1(); (4) R6, R8, R9 and R1() are independently selected from the group consisting of hydrazine, alkyl, alkenyl, aryl ,heteroalkyl,heteroaryl,cycloalkyl,arylalkyl,heteroarylalkyl, R14,-CI^R1 )01(1^)(:(0)01111, [CH(R1,)] pC(0)OR11 ^ -[CH(Rr)]pC(0)NR12R13 - .[CH(R1,)]pS(02)Rn --[CH(R1,)]pC(0)R11 ^ -[CH (R1,)]pS(02)NR12R13 ^ CH(R1,)C(0)N(H)CH(R2,)(Rt) &gt; CH(Rr)CH(Rr)C(0)NR12R13 &gt; - CHCR'^CHCR1,)8(02)^11 ^ &gt;CH(R1,)CH(R1,)S(02)NR12R13 ^ -CH(R1,)CH(R1,)C(0)R11 ^ - [ CH(R! )] pCH(OH)R11 ^ -CH(R1,)C(0)N(H)CH(R2,)C(0)0R11 &gt; C(0)N(H)CH(R2, )C(0)0R11 ^ -C(0)N(H)CH(R2,)C(0)Rn ^ CH(R1,)C(0)N(H)CH(R2,)C(0)NR12R13 ^ -CH(R1,)C(0)N(H)CH(R2,)R, ^ CH(Rr)C(0)N(H)CH(R2,)C(0)N(H CH(R3,)C(0)0Rn &gt; CH(R1,)C(0)N(H)CH(R2,)C(0)CH(R3,)NR12R13 ^CH(R1,)C(0 N(H)CH(R2,)C(0)N(H)CH(R3,)C(0)NR12R13 &gt; CH(R1,)C(0)N(H)CH(R2,)C( 0) N(H)CH(R3,)C(0)N(H)CH(R4,)C(0)0R11 &gt; H(R1,)C(0)N(H)CH(R2,)C (0)N(H)CH(R3,)C(0)N(H)CH(R4,)C(0)NR12R13 'CH(Rr)C(0)N(H)CH(R2,)C( 0) N(H)CH(R3,)C(0)N(H)CH(R4,)C(0)N(H)CH(R5')C(0)0Ru and)c(o)n( h)ch(r3')c(o)n (H)CH(R4,)C(0)N(H)CH(R5,)C(0)NR12R13; •62- 120556.doc 200810821 where R1, R2 And R3·, R4·, r5·, R11, Rl2 and r13 may be the same or different, and each part is independently selected from the group consisting of hydrazine, halogen, alkyl, aryl, heteroalkyl, hetero Aryl, cycloalkyl, alkoxy, aryloxy, alkenyl, alkynyl, alkylaryl, alkylheteroaryl, heterocycloalkyl, arylalkyl and heteroarylalkyl; or R12 and R13 is bonded together, wherein the combination is a cycloalkyl, heterocycloalkyl, aryl or heteroaryl group; R14 is present or absent and, if present, is selected from the group consisting of hydrazine, alkyl, aryl, heteroalkyl, Heteroaryl, cycloalkyl, alkyl a group consisting of an allyl group, an allyl group, an alkylheteroaryl group, an alkoxy group, an arylalkyl group, an alkenyl group, an alkynyl group, and a heteroaralkyl group; (5) the presence or absence of R and R' and, if present, The same or different, each moiety is independently selected from the group consisting of hydrazine, 0H, Cl_Cl decyl, C2-C1G alkenyl, C3-C8 cycloalkyl, (: 3-indole: 8 heterocycloalkane) Alkyl, alkoxy, aryloxy, alkylthio, arylthio, alkylamino, arylamino, amine, acid amine, arylthioamino, aryl, propylamino, aryl Amino fluorenyl, alkylamino group, heteroalkyl, alkenyl, alkynyl, (aryl)alkyl, heteroarylalkyl, ester, carboxylic acid, urethane, urea, hydrazine, , gas group, nitro, halogen, (cycloalkyl)alkyl, aryl, heteroaryl, (alkyl) aryl, alkyl, aryl, and a group, wherein the cycloalkyl group is composed of 3 to 8 carbon atoms, and 0 to 6 oxygen, nitrogen, sulfur or scale atoms, and the alkyl group has 1 to 6 carbon atoms; (6) L' is Η, OH, alkyl, miscible, aryl, heteroaryl, ring burning 120556.doc -63- 2 00810821 base or heterocyclic group; (7) Μ' is a hydrazine, alkyl, heteroalkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heterocyclic or amino acid side chain; or L The 'and Μ' keys are joined together to form a ring structure, wherein the part of the structural formula 1 is represented by the following formula:

And wherein the structural formula 2 is represented by the following formula:

Wherein in Formula 2: Ε exists or does not exist and if present is c, ch, Ν or C(R); J exists or does not exist, and when j exists, j is (CH2)p, (CHR-CHR ,) p, (CHR)P, (CRR')P, S(〇2), N(H), N(R) or ο; when J does not exist and G is present, l is directly bonded to the mark as a position a nitrogen atom of 2; P is a number from 〇 to 6; L is present or absent, and when l is present, B is c(H) or C(R); when L is absent, Μ is present or absent; % exists and L does not exist, then "directly and independently bonded to E, and J is directly and independently bonded to E; 120556.doc -64- 200810821 G exists or does not exist, and when G exists, G is (CH2 P, (CHR)P, (CHR-CHR')P or (CRR')p; when G is absent, J is present and E is directly attached to the carbon atom labeled as position 1; Q is present or absent, And when Q is present, q is NR, PR, (CR=CR), (CH2)p, (CHR)p, (CRR')p, (CHR-CHRf)p, 〇, NR, S, SO or S02 When Q is absent, M(1) is directly bonded to A or (11) is an independent substituent on L, and the independent substituent is selected from -〇R, -CH(R)(R'), s(O) 0_2R or -NRR' or Iii) absent; when both Q and deuterium are absent, deuterium is directly bonded to L or deuterium to an independent substituent on the indole, the independent substituent being selected from -0R, _CH(R)(R,) , s (〇V2r or 氺RR, or A does not exist; A exists or does not exist and if present, then A is 〇, 〇(r), (CHR)P, (CHR-CHR,)p, (CRR, ) p, n(r), NRR, SP, S(〇2), -OR, CH(R)(R, tNRR,; or human connected to M to form an alicyclic, aliphatic or heteroalicyclic bridge; Μ exists or does not exist, and when Μ exists, ^^ is halogen, 〇, 〇R, N(R), s, s(〇2), (CH2)p, (chr)p(chr rhyme R,) p or (CRR')p; or ]^ is attached to an eight-alicyclic, aliphatic or heteroalicyclic bridge; (8) Z' is represented by structural formula 3:

Wherein in Formula 3: the alkyl group and the alkyl group Y are selected from the group consisting of H, aryl, 120556.doc -65- 200810821, ketone, heteroalkyl, heteroaryl, arylheteroaryl , arylheteroaryl, cycloalkyl, alkoxy, alkylaryloxy, aryloxy, heteroaryloxy, heterocycloalkoxy, heteroalkyl-heteroaryl, heteroalkyl-heterocycle An alkyl group, a cycloalkoxy group, an alkylamino group, an arylamino group, an alkylarylamino group, an arylamino group, a heteroarylamino group, a cycloalkylamino group, and a heterocycloalkylamino group, and Y is unsubstituted or optionally substituted with one or two substituents which are the same or different and are independently selected from X11 or X12; X11 is alkyl, alkenyl, alkynyl, cycloalkyl, naphthenic Alkyl, heterocyclyl, heteroalkyl, aryl, alkyl, aryl, heteroaryl, alkyl or heteroaryl, and X11 unsubstituted or Wherein the case is substituted by one or more X12 moieties which are identical or different and independently selected; X12 is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, sulfhydryl, Sulfur-based, arylthio, amine , an alkylamino group, an arylamino group, an alkylsulfonyl group, an arylsulfonyl group, an alkylsulfonylamino group, an arylsulfinylamino group, a carboxyl group, an alkoxycarbonyl group, a carboxy oxime group, an alkane Alkylcarbonyl, aryl-Wilyl, heteroalkyl-based, aryl-carboxy, thiol urea, cycloalkyl hydrazino, heteroaryl-cycloalkylsulfonylamino, heteroaryl-sulfonate Amino, alkoxyamino, alkoxy-Wikioxy, decylureido, arylureido, _, gas or nitro' and the alkyl, alkoxy and aryl groups Substituted or optionally substituted by one or more moieties which are the same or different and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkane Alkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl or heteroarylalkyl; 120556.doc -66- 200810821 Z is hydrazine, N, C(H) or C (R); R31 is anthracene, hydroxy, aryl, alkyl, alkylaryl, heteroalkyl, heteroaryl, arylheteroaryl, alkylheteroaryl, cycloalkyl, alkoxy, alkane Alkyloxy, aryloxy, heteroaryloxy, heterocycloalkoxy, heterocycloalkyl -heteroaryl, cycloalkoxy, alkylamino, arylamine, alkylarylamine, arylamine, heteroarylamine, cycloalkylamino or heterocycloalkylamino And R31 is unsubstituted or optionally substituted by one or two substituents which are the same or different and independently selected from X13 or X14; X13 is alkyl, alkenyl, alkynyl, cycloalkyl, naphthenic Alkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl, heteroaryl, alkylheteroaryl or heteroarylalkyl, and R13 unsubstituted or The situation is substituted by one or more identical or different and independently selected X14 moieties; X14 is hydroxy, alkoxy, alkyl, alkenyl, alkynyl, aryl, aryloxy, thio, alkylthio, aryl Thio group, amine group, alkyl amine group, aryl amine group, alkyl group, aryl aryl group, alkyl group, aryl group, aryl group, carboxyl group, alkoxycarbonyl group, carboxy group Amine group, alkylcarbonyl group, arylcarbonyl group, heteroalkylcarbonyl group, heteroarylcarbonyl group, cycloalkylsulfonylamino group, heteroaryl-cycloalkyl acid group, heteroaryl acid group, burning Oxygenylamino group Alkoxycarbonyloxy, alkylureido, arylureido, halogen, cyano or schismyl' and the alkyl, alkoxy and aryl groups are unsubstituted or optionally substituted by one or more moieties, The same moiety or the same and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkyl ,heteroaryl,alkylheteroaryl or heteroarylalkyl; 120556.doc -67- 200810821 w may or may not be present, and if w is present, the boundary is c 〇), C(=s), C(=N-CN) or s(02); (9) X is represented by the structural formula 4. (O)e (CH)a — (C - C)b~ (〇)〇—(S)d — (A)f — r29 ^30^30 [29, where in Equation 4: Lu a is 2, 3, 4, 5, 6, 7, 8 or 9; b, e, d, e and f are 〇 , 1 ' 2, 3, 4 or 5; A is C, N, S or Ο; R and R29 are independent or absent, and if present, may be the same or different, each independently substituted by one or two Substituted, the substituents are independently selected from the group consisting of hydrazine, halo, alkyl, aryl, cycloalkyl, cycloalkylamine, ring Alkylaminocarbonyl, cyano, hydroxy, alkoxy, alkylthio, amine, - fluorenyl (alkyl), hydrazine (cycloalkyl), hydrazine (alkyl), carboxyl, c (o) Oalkyl, heteroaryl, aralkyl, alkylaryl, sulfhydryl, heteroaryl, alkyl, heteroaryl, light aryl, aryloxy, aralkyloxy Base, fluorenyl, aryl fluorenyl, nitro, aryloxycarbonyl, ketone group, alkyl group, aryl sulfonyl, heteroaryl fluorenyl, alkyl sulfinyl, aryl Sulfosyl, heteroarylsulfinyl, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkenyl, heterocyclyl, heterocycloalkenyl, YiYzN- , YiYzNC^O)- and YiYzNSCV 'where Yi&amp;Y2 may be the same or different and are independently selected from the group consisting of: hydrogen, alkyl, aryl and aralkyl; or 120556.doc -68- 200810821 R and R are bonded together to form an aliphatic or heteroaliphatic chain having from 〇 to 6 carbons; R is present or absent and, if present, one or two independently selected from ruthenium, alkyl, aryl Group of heteroaryl and cycloalkyl groups Substituted by the base; (10) D is represented by the formula 5: (〇)i II · —(CJH)g — (C)h — (N)j — (A)k—(C=C)1 — ( CH) m — • ^ ^33 ^34 wherein in Formula 5: R32, R33 and R34 are present or absent and, if present, independently substituted by one or two substituents independently selected from the group consisting of: : hydrazine, halo, alkyl, aryl, cycloalkyl, cycloalkylamino, spiroalkyl, cycloalkylamino, cyano, hydroxy, alkoxy, alkylthio, amine, _ΝΗ(alkyl), -ΝΗ(cycloalkyl), -Ν(alkyl)2,carboxy, -C(〇)〇-alkyl, hetero-aryl, aralkyl, alkylaryl, arene Base, heteroarylalkyl, alkylheteroaryl, heteroarylalkenyl, hydroxyalkyl, aryloxy, aralkyloxy, decyl, aryl, nitro, aryloxycarbonyl, aralkyloxy Carbonyl, alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, alkylsulfinyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroaryl Thio group, aralkylthio group, heteroaralkylthio group, cycloalkenyl group, heterocyclic group, heterocycloalkenyl group, Υιγ2Ν-alkyl group, Υ!Υ2Ν (:(0)- and Y^YzNSCV, wherein 丫 and γ2 may be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl and aralkyl; or 120556.doc-69 · 200810821 R and R are connected to each other so that the part g of the combination is 1, 2, 3, 4, 5, 6, 7, 8, or 9; h, 1, j, k, 1, 2 3, 4 or 5; and A is C, N, S or 〇, (Π) whose constraint is when Equation 2:

And conditional conclusions (i) and (ii) below w4ch or ν' apply: Conditional conclusion (1): z, not -NH-R36, wherein R36 is Η, C6 or 10 arylheteroaryl, -C (〇)-R37, -C(〇)_〇R37 or _c(〇) nhr37, wherein Han 37 is 〇1_6 alkyl or (:3-6 cycloalkyl; and conditional conclusion (ii): R1 does not An acid of -C(0)0H, _C(0)0H 120556.doc -70- 200810821 acceptable salt, -C(0)0H or -C(0)NHR38, wherein R38 is selected from a group consisting of Cw alkyl, C3_6 cycloalkyl, C6^1G aryl or C7-16 aralkyl. The compound of formula VI has the following structure:

And includes pharmaceutically acceptable salts, solvates or esters thereof; wherein in Formula VI: &quot;Cap&quot; is anthracene, alkyl, alkylaryl, heteroalkyl, heteroaryl, aryl heteroaryl , alkylheteroaryl, cycloalkyl, alkoxy, aryloxy, aryloxy, heteroaryloxy, heterocyclooxy, cycloalkoxy, amine, alkylamino, aromatic An amino group, a pyraryl aryl group, an arylamine group, a heteroarylamino group, a cycloalkylamino group, a carboxyalkylamino group, an arylalkoxy group or a heterocyclic amino group, wherein the alkane Base, alkylaryl, heteroalkyl, heteroaryl, arylheteroaryl, alkylheteroaryl, cycloalkyl, alkoxy, alkylaryloxy, aryloxy, heteroaryloxy, Heterocyclicoxy, cycloalkoxy, amine, alkylamino, arylamine, alkylarylamine, arylamine, heteroarylamine, cycloalkylamino, carboxyalkyl Each of the amine, arylalkoxy or heterocyclylamino groups may be unsubstituted or optionally substituted with one or two substituents which may be the same or different and independently selected from X1 and X2 120556.doc -71 - 200810821 P, for -N HR; χ1 is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclyl, aryl, alkylaryl, fluorenyl, aryl a heteroaryl group, a heteroarylamino group, an alkylheteroaryl group or a heteroarylalkyl group, and X may be unsubstituted or optionally independently one or more X2 moieties which may be the same or different and independently selected Substituted; hydrazine, alkyl, aryl, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, alkylamino, arylamine, alkylsulfonate Base, arylsulfonyl, alkylsulfonylamino, arylsulfonylamino, carboxyl, alkoxycarbonyl, decylamino, alkoxycarbonylamino, alkoxycarbonyloxy, alkylurea Or an aryl urea group, a halogen, a cyano group, a ketone, an ester or a nitro group, wherein the alkyl group, the alkoxy group and the aryl group are each unsubstituted or optionally substituted by one or more moieties, such Portions may be the same or different and are independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocyclylalkyl, aryl, alkylaryl, arylalkane Base, aryl heteroaryl a heteroaryl group, a heterocyclic amino group, an alkylheteroaryl group, and a heteroarylalkyl group; w may or may not exist, and when | is present, the bound is c(=0), C(=s ), C(=NH), C(=N-OH), C(=N-CN), S(O) or S(02); Q may or may not exist, and when Q is present, Q is N (R), P(R), CR=CR', (cH2)p, (CHR)P, (CRR,)p, (CHR-CHR%, Ο, s, S(o) or S(〇2) When Q is absent, M(i) is directly bonded to A or (ii) M is an independent substituent on L· and a is an independent substituent on E, wherein the independent substituent is selected from -OR, -CH(R,), S(0)〇-2R or -NRR,; when both Q and Μ are absent, Α directly linked to L or Α is selected from _OR, 120556.doc -72- 200810821 CH(R)(R'), -S(0)〇-2R or -NRR' independent substituent; A exists or does not exist and if present, then eight is _〇_, -〇(r ) Ch2_, (CHR)p-, -(CHR-CHR')p-, (CRR,)p, N(R), NRR,, s or S(〇2), and when Q does not exist, artificial _ 〇R, CH(R)(R,) or _NRR,; and when A is absent, q&amp;e is linked by a bond or 卩 is an independent substituent on M; E exists or does not exist If present, e is cH, N, C (R);

0 may or may not be present, and when G is present, G is (CH2)P, (CHR)P or (CRR)p, when g is absent, j is present and E is directly attached to the carbon atom labeled as position 1. On; J may or may not exist, and when j exists,: [for ((::11山,((::1111_)

CHR )p, (CHR)p, (CRR,)p, s(〇2), n(H), N(R) or 〇; when J is absent and G is present, L is directly bonded to the label as a position L on the nitrogen atom; L may or may not exist, and when L is present, L is CH, N or cr; when φ L is absent, Μ exists or does not exist; if 乂 exists and l does not exist, then M Directly and independently connected to E, and J is directly and independently bonded to E; Μ may or may not exist, and when μ is present, M is 〇, n(r), $, S(〇2), (CH2) p, (CHR)P, (CHR-CHR,)P or (CRR,)P; p is a number from 0 to 6; R, R and R3 may be the same or different, each of which is independently selected from the group consisting of the following groups Group: H, Cl_Cl decyl, C2_Ci decyl, C3_C8 cycloalkyl vC^C: 8 heterocyclic, alkoxy, aryloxy, alkylthio, arylthio, amine, decyl , arylthioamino group, arylarylamino group, arylamine group enemy 120556.doc -73- 200810821 group, alkylamino group, ketone group, heteroalkyl group, alkenyl group, alkenyl group, alkynyl group, aromatic Alkyl, heteroarylalkyl, ester, carboxylic acid, urethane, urea, ketone, aldehyde, cyano, nitro, _, (cycloalkane) An alkyl, aryl, heteroaryl, alkylaryl, alkylheteroaryl, alkylheteroaryl, and (heterocyclyl)alkyl; R in (CRR,) Combining to form a cycloalkyl or heterocyclic moiety; and R1 is a Wei group. The compound of formula VII has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula VII: Μ is 〇, n(H) or CH2; η is 〇-4; R1 is -or6, wherein R6 and R7 are the same Or different, each of which is independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl a group consisting of a heterocyclic group, a heterocyclic group, a heterocyclic alkyl group, a group, an amine group, an arylamine group, and an alkylamino group; 120556.doc -74- 200810821 R4 and R5 may be the same or different and each independently Selecting a group consisting of a ruthenium, an alkyl group, an aryl group and a cycloalkyl group; or R4 and R5 together forming a ring-shaped 5 to 7 member XS, and a part of the ring such that a portion thereof is from 0 to 2 of h / To indicate; X is selected from the group consisting of the following groups:

Wherein P is 1 to 2' q is 1-3 and P2 is alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamine or ring An alkyl group of φ; and R3 is selected from the group consisting of aryl, heterocyclic, heteroaryl,

120556.doc -75- 200810821

Wherein Y is 0, S or NH, and z is CH or N, and the R8 moieties may be the same or different, and each R8 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, A group consisting of a heterocyclic group, a hydroxyl group, an amine group, an arylamine group, an alkylamino group, a monoalkylamino group, a sulfhydryl group, a thiol group, an arylthio group, and an alkoxy group. The compound of the formula VIII has the following structure··

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula VIII: Μ is Ο, N(H) or CH2; R1 is -C(0)NHR6, wherein R6 is hydrogen, alkyl, Alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, hydroxy, An amine group, an arylamino group or an alkylamino group; P1 is selected from the group consisting of an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl halide group; 120556.doc -76 - 200810821 P3 is selected from an alkyl group a group consisting of a cycloalkyl group, an aryl group and an aryl group fused to a cyclyl group; R and R5 may be the same or different 'each of which is independently selected from the group consisting of an anthracene, an aryl group and a cycloalkyl group; or R4 and R5 together form a ring of 5 to 7 members

Part of the ring is such that part of the game is represented by k from 〇 to 2; x is selected from the group consisting of:

# wherein P is 1 to 2, q is 1 to 3 and p2 is a deutero, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamine or a cycloalkylamine group; and R3 is selected from the group consisting of aryl, heterocyclic, heteroaryl

120556.doc -77- 200810821

Wherein Y is 0, s or NH, and Z is CH or N, and R8 is partially the same or different. Each R8 is independently selected from the group consisting of hydrogen, an alkyl group, a heteroalkyl group, a cyclodyl group, a sulfhydryl group, a heteroaryl group, A group consisting of a heterocyclic group, a hydroxyl group, an amine group, an arylamine group, an alkylamine group, a monoalkyl group, a halogen group, a sulfur-burning group, an arylthio group, and an alkoxy group. The compound of formula IX has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula IX: Μ is 〇, N(H) or CH2; η is 0-4; Η 〇 R1 is -OR6, -NR6r7 or R6 and R7 may be the same or different, each of which is selected from the group consisting of hydrogen, alkane 120556.doc-78-200810821, alkenyl, alkynyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, aryl, a group consisting of a sulfhydryl group, a heteroaryl group, a heteroarylalkyl group, a heterocyclic group, a heterocyclic group, a sulfhydryl group, an amine group, an arylamine group, and an alkylamine group; R4 and R5 may be the same or Differently, each of them is independently selected from the group consisting of an anthracene, an alkyl group, an aryl group and a cycloalkyl group; or R4 and R5 together form a part of a ring of 5 to 7 members to make a part of the ring k is 〇 to 2 of 0 / to represent y X is selected from the group consisting of:

Wherein P is from 1 to 2' to 3 and p2 is alkyl, aryl, heteroaryl, heteroalkyl, cycloalkyl, dialkylamino, alkylamino, arylamine or cycloalkylamine a group consisting of the following groups: aryl, heterocyclic, heteroaryl R3, free radical, 120556.doc 79- 200810821

Wherein Y is 0, S or NH, and Z is CH or N, and the R8 moieties may be the same or not, and each r8 is independently selected from the group consisting of hydrogen, alkyl, heteroalkyl, cycloalkyl, aryl, heteroaryl A group consisting of a hetero group, a heterocyclic group, a hydroxyl group, an amine group, an arylamine group, an alkylamino group, a dialkylamino group, a leuco group, an alkylthio group, an arylthio group, and an alkoxy group.

The compound of formula X has the following structure:

Or a pharmaceutically acceptable salt, solvate or glycerin thereof; wherein in the formula X: R1 is NHR9, wherein R9 is η, alkyl, alkenyl-, alkynyl-, aryl, heteroalkyl- , heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl- or heteroarylalkyl; 120556.doc -80- 200810821 A may be the same or different from hydrazine, each of which is independently selected from r , 〇r, NHR, NRR', SR, S02R and halo; or A and Μ are interconnected such that the moiety shown in the above formula I:

Form three, four, six, seven or eight members of cycloalkyl, four to eight membered heterocyclic groups, six to ten members of aryl or five to ten members of heteroaryl; _ E is C ( H) or C(R); L is C(H), C(R), CH2C(R) or C(R)CH2; R, R2 and R3 may be the same or different, each of which is a ruthenium or an alkyl group. - alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl- a group of arylalkyl- and heteroarylalkyl-; or R and R/ in NRR' are interconnected such that NRR* forms a four to eight membered heterocyclic group; and the lanthanide is selected from the following:

Wherein G is ruthenium or osmium; and R15, R16, R17 and R18 may be the same or different, and each of 120556.doc -81 - 200810821 is independently selected from the group consisting of H, alkyl, miscible, dilute, heteropoly, and a group consisting of a hetero group, a heteroalkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, or R15 and Rl6 are bonded to each other to form a four member: an eight member cycloalkyl group, a heteroaryl or heterocyclic structure, and likewise r17 and Ri8 are independently bonded to each other to form a three to eight membered cycloalkyl or heterocyclic group; wherein the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic group Each may be unsubstituted or, as the case may be, independently substituted by one or more selected from the group consisting of: a thiol group, an oxy group, an aryloxy group, a thio group, a sulfur-burning group: a thio group, an amine group, an amidino group, Alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, sulfonylamino, alkyl, aryl, heteroaryl, alkylsulfonylamino, arylsulfonylamino , ketone, carboxyl, alkoxycarbonyl, carboguanamine, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyano and nitro. «ΙΑ* · Things.

In one embodiment, ''at least one compound' is a combination of structural formulas

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XI: 120556.doc -82 - 200810821 R1 is NHR9, wherein R9 is fluorene, alkyl-, alkenyl group Alkyl, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl or heteroarylalkyl; hydrazine and hydrazine may be the same or different, each independently selected from the group consisting of r, SR, SO# and halo; or A and Μ are interconnected (in other words, joined together) for the part shown in the above formula I:

Form three, four, six, seven or eight members of cycloalkyl, four to eight membered heterocyclic groups, six to ten members of aryl or five to ten members of heteroaryl; E is C (H Or C(R); L is C(H), C(R), CH2C(R) or C(R)CH2; R, R1, R2 and R3 may be the same or different, each of which is independently selected from the group consisting of Alkyl-, alkenyl, alkynyl, cycloalkyl, heteroalkyl, heterocyclyl, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkane a group of benzyl-, arylalkyl- and heteroarylalkyl- groups; or NRR, wherein R and R are interconnected such that NR9R1G forms a four- to eight-membered heterocyclic group; Y is selected from the following:

Where γ3〇 and γ31 are selected from 120556.doc -83 - 200810821 ΤΛΛ Τ2 Τ3 Τ3, +3, Τ3

Wherein u is 0_6; X is selected from Ο, NR15, NC(0)R16, s, S(O) and S〇2; G is NH or O; and R15, R16, R17, R18, R19, Tl , T2, T3 and T4 may be the same or different and each independently selected from H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclic, aryl a group consisting of arylalkyl, heteroaryl and heteroarylalkyl, or R17 and R18 are bonded to each other to form a three to eight membered cycloalkyl or heterocyclic group; wherein the alkyl, aryl, heteroaryl Each of the cycloalkyl or heterocyclic groups may be unsubstituted or, as the case may be, independently substituted with one or more moieties selected from the group consisting of hydroxy, alkoxy, aryloxy, thio, alkylthio, Arylthio, amine, decylamino, alkylamino, arylamine, alkyl, arylsulfonyl, sulfonylamino, alkyl, aryl, heteroaryl, alkyl Sulfonamide, arylsulfonylamino, ketone, carboxyl, alkoxycarbonyl, carboxylamido, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, aryl gland, _ Base, cyano and nitro. The compound of formula XII has the structure: 120556.doc -84- 200810821 M A L-E 〇

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XII: R1 is NHR9, wherein R9 is H, alkyl-, alkenyl-, alkynyl, aryl, heteroalkyl -heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl- or heteroarylalkyl; A and oxime may be the same or different, each independently selected from the ruler, 011, NHR, NRR1 , SR, S02R and halo; or Α and Μ are interconnected to make the moiety shown in formula I above:

Form three, four, six, seven or eight members of the ring, four to eight members of the heterocyclic group, six to ten members of the aryl or five to ten members of the heteroaryl; Ε for C (H Or C(R); L is C(H), C(R), CH2C(R) or C(R)CH2; R, IT, R2 and R3 may be the same or different, each of which is independently selected from Η, Anthracenyl-, roastyl-, fast-radical, lyophilic-, miscible-, heterorule-, aryl, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkane a group of aryl-, arylalkyl-120556.doc-85 - 200810821 and a heteroarylalkyl group; or NRR, a combination of a ruthenium and a ruthenium, such that the NRR' forms a four- to eight-membered heterocyclic group. ; and Y is selected from the following sections:

Wherein G is NH or 0; and Ri5, Rl6, Rl7, r18 and Rl9 may be the same or different, each independently selected from the group consisting of hydrazine, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl a group consisting of a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, or (i) Ri5 and Ri6 are bonded to each other to form a four- to eight-membered ring structure or rH Interconnected with Rl9 to form a four- to eight-membered cyclic structure, and (R) is also independently R17 and R!8 are independently bonded to each other to form a three- to eight-membered cycloalkyl or heterocyclic group; wherein the alkyl group, the aryl group, Each of the heteroaryl, cycloalkyl or heterocyclyl groups may be unsubstituted or, as the case may be, independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkane Thio group, aryl fluorenyl group, amine group, decylamino group, alkylamino group, arylamino group, alkylsulfonyl group, arylsulfonyl group, sulfonylamino group, alkylsulfonylamino group, aryl group Sulfonamide, alkyl, aryl, heteroaryl, ketone, carboxyl, alkoxycarbonyl, carboguanamine, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, aryl gland , S group, a cyano group and a nitro group. 120556.doc -86- 200810821

The compound of formula XIII has the structure: Μ A Ν

Or R3 or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XIII: R1 is NHR9, wherein R9 is fluorene, alkyl-, alkenyl-, alkynyl, aryl-, miscellaneous Base-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl- or heteroarylalkyl; hydrazine and hydrazine may be the same or different, each independently selected from the group consisting of r, 〇R, NHR , NRR', SR, S02R and halo; or A and Μ are interconnected (in other words, A_E-LM are connected together) to make the part shown in Formula I above: \_/ Knife forming three members, four members, six , seven or eight members of cycloalkyl, four to eight membered heterocyclic groups, six to ten members of aryl or five to ten members of heteroaryl; E is C(H) or C(R); Is C(H), C(R), CH2C(R) or C(R)CH2; R, R, R2 and R3 may be the same or different and each independently selected from hydrazine, alkyl-, alkenyl- , alkynyl...cycloalkyl-,heteroalkyl...heterocyclyl...aryl 120556.doc -87- 200810821 phenyl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl- a group of arylalkyl-, and heteroarylalkyl groups; or R in the NRR' is interconnected to form NRR, forming four members Eight heterocyclic group; and Y is selected from the following:

R/e Οχ//0 R19 17 R18 °Nx/P R19r1^S^n^VgV r2.乂〇r17 r18 °xv? R19 R15〆R15, or R16 Λ〇R17 R18 R20 ° 18 where G is NH or O, and RI5, Ri6, r, 7, R丨8, r19&amp;r2〇 may be the same or different' Each of them is independently selected from H, Ci_Ci 〇 alkyl, CrCi oxalate, c2-c10 alkenyl, c2-c10 heteroalkenyl, c2_Ci() block, C2_Ci〇 alkynyl, C3-C8 cycloalkyl a group of C3-C8 heterocyclic groups, aryl groups, heteroaryl groups or: (1) R15 and R16 may be bonded to each other to form a four to eight membered cycloalkyl or heterocyclic group ' or a core to form a five member to a human Please base or heterocyclic group ' or R15 and R2G are linked to each other to form five members, from shell to eight-membered cycloalkyl or heterocyclic group, and (ii) the same R17 and R18 are independently bonded to the group or heterocyclic group. Hu 八贝环烧120556.doc •88· 200810821 wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic groups may be unsubstituted or, as the case may be, independently composed of one or more selected from the group consisting of Part of the group is substituted: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, amine, alkylamino, arylamine, alkyl, aryl base Sulfonyl group, continuation with amine group, alkyl group, aryl group, ketone, carboxyl group, alkoxycarbonyl group, carboxy oxime group, alkoxycarbonylamino group, alkoxy group , a ureido group, an aryl group, a yl group, a cyano group and a nitro group. The compound of formula XIV has the following structure:

Or a pharmaceutically acceptable salt, solvate or glycerin thereof; wherein in formula XIV:

R1 is NHR9, wherein R9 is hydrazine, alkyl, alkenyl ... alkynyl...aryl, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl...arylalkyl or heteroarylalkyl And Α and Μ may be the same or different, each of which is independently selected from R, 〇R, NHR, NRR', SR, S02R and a halogen group; or A and M are linked to each other such that the moiety shown in Formula I above:

120556.doc -89- 200810821 Form three, four, six, seven or eight members of cycloalkyl, four to eight members of heterocyclic, six to ten aryl or five to ten members Base, E is C(H) or Ο; L is C(H), C=, CH2C= or C=CH2; R, R', R2 and R3 may be the same or different, each of which is independently selected from Η, a group consisting of a pyridyl group, a miscible group, a dilute group, a heterocyclic group, an alkynyl group, a heteroalkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroaryl group. Or NRR/where R and R' are linked to each other such that the NRR forms a four to eight membered heterocyclic group; and the lanthanide is selected from the following:

Wherein G is hydrazine or hydrazine; and R15, R16, R17 and R18 may be the same or different and each selected from the group consisting of hydrazine, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkane a group consisting of a heterocyclic group, a heterocyclic group, an aryl group and a heteroaryl group, or (i) R15 and R16 are bonded to each other to form a four- to eight-membered cyclic structure, and (R) is also independently R17 and R18 are independently bonded to each other to form a three-member An eight-membered cycloalkyl or heterocyclic group; 120556.doc • 90-200810821 wherein the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic group can each be unsubstituted or optionally independently one or more Substituting a moiety selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, decylamino, alkylamino, arylamine, alkane Sulfosyl group, aryl stone yellow base, acid-reductive amine group, alkyl amide group, aryl-based amine group, alkyl group, aryl group, heteroaryl group, ketone group, carboxyl group, alkoxycarbonyl group, carboxy group Amine group, alkoxyalkyl group, alkoxy group, alkoxy group, aryl group, aryl group, halogen group, nitrogen group and schlossyl group. The structural XV compound has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XV: R1 is NHR9, wherein R9 is hydrazine, alkyl-, aryl-, heteroalkyl-, heteroaryl-, ring An alkyl-, cycloalkyl-, arylalkyl or heteroarylalkyl group; Ε and J may be the same or different, each selected from the group consisting of R, OR, NHR, NRR7, SR, halo and S(02) a group consisting of R, or E and J may be directly linked to form a three to eight membered cycloalkyl or a three to eight member heterocyclic moiety; Z is N(H), -N(R) or hydrazine, the limitation thereof The condition is that when Z is Ο, G exists 120556.doc •91 · 200810821 or does not exist and if G exists and Z is 〇, then (} is c(=〇); G may exist or; j; exists 'and if G exists, then (d) and when G is not present, z is directly connected to γ; MS (

Y is selected from the group consisting of the following groups··

X =〇,S, NH

X=〇,S,NH 120556.doc -92- 200810821 •N, Vi, (?

F3c-A=0, NH; R, R7, R2, R3, 4 and r5 may be the same or different, each selected from the group consisting of H, alkyl-, alkenyl-, alkynyl- , cycloalkyl-, heteroalkyl (heterocyclyl), heteroaryl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl-, arylalkyl- and heteroaryl Alkyl group, wherein the heteroalkyl group, heteroaryl group and heterocyclic group each independently have (1) an oxygen, nitrogen, sulfur or a lining atom; wherein the alkyl group, heteroalkyl group, alkenyl group, alkynyl group, aryl group, Each of the heteroaryl, cycloalkyl and heterocyclyl moieties may be independently unsubstituted, independently of one or more selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, aryl, Cycloalkyl, heterocyclo-hetero, pyrenyl, hydroxy, thio, alkoxy, aryloxy, alkylthio, squary, amine, oxime, carboxylic acid, amine Formic acid vinegar, urea, _ soil ^ # slightly 11 base, nitro, sulfonamide, sulfoxide, hydrazine, sulfonyl urea, hydrazine and hydrazide structural formula XVI compound has the following structure:

0 R3 120556.doc -93 - 200810821 or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XVI: R1 is NHR9, wherein R9 is oxime, alkyl-, alkenyl-, alkynyl -, aryl, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl- or heteroarylalkyl; R2 and R3 may be the same or different, each selected from a group consisting of hydrazine, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and Heteroarylalkyl; a Y is selected from the following:

Wherein G is NH or hydrazine; and Rl5, R16, R17, R18, Rl9, ruthenium R22, R23, R24&amp; R25 may be the same or different, each selected from the group consisting of R and a group of groups. An anthracene, an alkyl group, a heteroalkyl group, an alkenyl group or a heteroalkyl group derived from the following groups, a heteroalkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a aryl group, an alkyne group and a heteroarylalkyl group. Or (i) R17 and R18 are independently bonded to each other to form a cycloalkyl or heterocyclic group; (ii) likewise, R15 and R19 are independently bonded to the octa-phase to form a four- to eight-membered heterocyclic group; Similarly, R15 and Rl6 are independently linked to form a four- to eight-membered heterocyclic group; (iv) Similarly, R15 and R20 are independently linked to each other from four to eight members; (V) Similarly, R22 is R23 is independently linked to each other to form a member to an eight-membered cycloalkyl group or a four-membered to eight-membered heterocyclic group; and (vi) likewise, R^ is independently bonded to each other to form a three- to eight-membered cycloalkyl group or a four- to eight-membered heterocyclic group.环环· wherein each of the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic groups may be unsubstituted or, as the case may be, independently passed through one or more selected from the group consisting of: Substituting: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, decylamino, alkylamino, arylamine, alkylsulfonyl, arylsulfonate Sulfhydryl, sulfonylamino, alkyl, aryl, heteroaryl, alkylsulfonylamino, arylsulfonylamino, ketone, carboxyl, alkoxycarbonyl, carboxamide, alkoxycarbonylamine Alkyl, alkoxycarbonyloxy, alkylureido, arylureido, yl, cyano and nitro. The compound of formula XVII has the following structure:

Μ A

.R1 Y, 120556.doc 200810821 or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XVII: R1 is NHR9, wherein R9 is H, alkyl-, alkenyl-, alkynyl , aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, heterocyclyl-, arylalkyl- or heteroarylalkyl; A and oxime may be the same or different, each independently selected From R, OR, NHR, NRRf, SR, S02R and halo; or A and Μ are interconnected to make the moiety shown in Formula I above:

Form three, four, six, seven or eight members of the ring, four to eight members of the heterocyclic group, six to ten members of the aryl or five to ten members of the heteroaryl; Ε for C (H Or Ο; L is C(H), C=, CH2C= or C=CH2; R, R/, R2 and R3 may be the same or different, each selected from the group consisting of hydrazine, alkyl - alkenyl-, alkynyl-, cycloalkyl-, heteroalkyl-, heterocyclyl-, aryl-, heteroaryl-, (cycloalkyl)alkyl-, (heterocyclyl)alkyl -, in the arylalkyl- and heteroarylalkyl or NRR', R is attached to the phase such that NRR1 forms a four-membered to eight-membered heterocyclic group; Y is selected from the following:

120556.doc -96- 200810821 where y3() is selected from; °w° V-/ Ο ο r T2 T3, D1 T3, T3 where u is 0-1; X is selected from Ο, NR15, NC (0) R16, s, S(O) and S02; G is NH or O; and R15, R16, R17, R18, R19, Tl, butyl 2 and butyl 3 may be the same or different, each selected from the group consisting of Group of groups: H, alkyl, heteroalkyl, dilute, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclic, aryl, arylalkyl, heteroaryl and heteroaryl An alkyl group; or R17 and R18 are bonded to each other to form a three to eight member cycloalkyl or heterocyclic group; wherein the alkyl, aryl, heteroaryl, cycloalkyl or heterocyclic group may be unsubstituted or otherwise The situation is independently substituted by one or more moieties selected from the group consisting of: hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, decylamine, alkylamine Alkyl, arylamino, alkylsulfonyl, aryl, fluorenyl, alkyl, aryl, heteroaryl, alkylsulfonyl, arylsulfonyl, ketone , carboxyl group, alkoxycarbonyl group, acid retardant amine group, alkoxycarbonylamino group Alkoxycarbonyl group, a ureido group, an aryl ureido group, a halogen group, a cyano group and a nitro group. 120556.doc -97- 200810821 The compound of formula XVIII has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XVIII: R8 is selected from the group consisting of alkyl-, aryl-, heteroalkyl-, heteroaryl-, cycloalkyl-, a group consisting of a heterocyclic-, arylalkyl-, heteroarylalkyl-, and heterocyclylalkyl group; R9 is selected from the group consisting of an anthracene, an alkyl group, an alkenyl group, an alkynyl group, an aryl group, and a cycloalkyl group. Groups; Α and Μ may be the same or different, each of which is independently selected from R, OR, N(H)R, N(RR), SR, S(02)R and a halogen group; or A and Μ are interconnected (for φ, AELM is connected together) so that the part shown in the above formula I:

Form three, four, five, six, seven or eight members of the ring base, four to eight members of the heterocyclic group, six to ten members of the aryl or five to ten members of the heteroaryl; C(H) or C(R); L is C(H), C(R), CH2C(R) or C(R)CH2; R and R' may be the same or different and each is selected from the group consisting of Composition 120556.doc -98- 200810821 Group · hydrazine, alkyl group, alkenyl group, alkynyl group, cycloalkyl group, heterodole group, heterocyclic group, aryl group, heteroaryl group _, ( Cycloalkyl)alkyl-, (heterocyclyl)alkyl-, arylalkyl- and heteroarylalkyl-; or R(R) in N(RR,) are interconnected such that N(RR' a four- to eight-membered heterocyclic group; R2 and R3 may be the same or different, each of which is selected from the group consisting of anthracene, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, a group consisting of a cycloalkyl group, a spiro-linked cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group; the oxime system is selected from the following:

120556.doc •99- 200810821 or different, each selected from H, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, aromatic a group consisting of an alkyl group, a heteroaryl group, and a heteroarylalkyl group, or (1) independently linked to each other to form a two to eight membered cycloalkyl or heterocyclic group; (ii) likewise, Ri5 is independent of Ri9 Interconnected to form a four-membered to eight-membered heterocyclic group; (iii) Similarly, the ruler "and !^6 are independently interconnected to form a four-membered to eight-membered heterocyclic group; and (iv) likewise, r1s and R are independently linked to each other to form four To eight members of heterocyclic groups;

Wherein the alkyl, aryl, heteroaryl, cycloalkyl, spiro-linked cycloalkyl and heterocyclyl groups may each be unsubstituted or, as the case may be, independently substituted with one or more moieties selected from the group consisting of: Hydroxy, alkoxy, aryloxy, thio, alkylthio, arylthio, amine, decylamino, alkylamino, arylamino, alkylsulfonyl, arylsulfonyl, Sulfonamide, alkyl, alkenyl, aryl, heteroaryl, alkylsulfonylamino, arylsulfonylamino, ketone, carboxyl, alkoxycarbonyl, carboxamide, alkoxycarbonylamine Alkyl, alkoxycarbonyloxy, alkylureido, arylureido, yl, cyano and nitro. The compound of structural formula XIX has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XIX: Z is selected from the group consisting of heterocyclyl, N(H)(alkyl), -N(alkyl)2, _N( H) (ring 120556.doc -100- 200810821 alkyl), -N(cycloalkyl)2, -N(H)(aryl), Ν(aryl)2, -N(H)(heterocycle) , N-(heteroaryl), -N(H)(heteroaryl) and Ν(a group of heteroaryl h; R1 is NHR9, wherein R9 is fluorene, alkyl-, dilute- , alkynyl-, aryl, heteroalkyl-, heteroaryl, cycloalkyl-, heterocyclyl, arylalkyl- or heteroarylalkyl; R2 and R3 may be the same or different, each Is selected from the group consisting of hydrazine, alkyl, heteroalkyl, alkenyl, heteroalkenyl, alkynyl, heteroalkynyl, cycloalkyl, heterocyclyl, aryl, arylalkyl, heteroaryl and heteroarylalkane Group of bases; • Lines are selected from the following:

120556.doc 101 - 200810821 wherein G is NH or hydrazine; and Rule 15, Ri6, Rl7, r18, r19, r2〇 and Han 21 may be the same or different 'each of which is selected from H, alkyl, miscible, dilute a group consisting of a base, a heteroalkenyl group, an alkynyl group, a heteroalkynyl group, a cycloalkyl group, a heterocyclic group, an aryl group, an arylalkyl group, a heteroaryl group, and a heteroarylalkyl group, or (丨汛^ and ... 8 Independently interconnected to form a two to eight membered cycloalkyl or heterocyclic group; (^) Similarly, Rl5 and R are independently bonded to each other to form a four to eight membered heterocyclic group; (iH)

Independently intercalated with R to form a four- to eight-membered heterocyclic group; (iv) likewise, r1s and R2G are independently bonded to each other to form a four- to eight-membered heterocyclic group; wherein the alkyl, aryl, heteroaryl, naphthenic Each of the groups or heterocyclic groups may be unsubstituted or, as the case may be, independently substituted with one or more moieties selected from the group consisting of: hydroxy, alkanoyl, aryloxy, thio, alkylthio, arylthio Amino, amidino, alkylamino, arylamino, alkylsulfonyl 'arylsulfonyl, sulfonylamino, alkyl, aryl, heteroaryl, alkylsulfonamide Base, arylsulfonylamino, ketone, carboxyl, alkoxycarbonyl, carboxylammonium, alkoxycarbonylamino, alkoxycarbonyloxy, alkylureido, arylureido, halo, cyanide Base and nitro group. The compound of formula XX has the following structure: P6 P5 P4 P3 P2 P1

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XX: 120556.doc -102- 200810821 a is 0 or 1; b is 0 or 1; Y is HSCw alkyl; B is Η, a sulfhydryl derivative of the formula R7-C(0)- or a sulfonyl derivative of the formula RrSO2, wherein: R7 is (1) optionally thiol, Ci-6 succinyloxy or Ci-6 oxynitride a substituted C1-lQ alkyl group, (ii) optionally substituted with a carboxyl group, a (Cw alkoxy)carbonyl group or a phenylmethoxy group; a 3-7 cycloalkyl group;

(in) a C6 or C1G aryl group substituted by (^.6 alkyl, hydroxy or amine (optionally substituted by Cl 6 alkyl) or (1:7-16 aryl; or (iv) The case is substituted by (^_6 alkyl, hydroxy, amine (optionally substituted by Cl-6 alkyl) or guanamine (optionally substituted by Cw alkyl); R6 (if present) is substituted by carboxyl group Cl-6 alkyl;

Rs, if present, is a C1-6 alkyl group optionally substituted by a carboxy group; R4 is C^o alkyl, Cm cycloalkyl or c4.1G (alkylcycloalkyl); R3 is C^oalkyl, C3·7 cycloalkyl or c4-1()(alkylcycloalkyl); R2 is CH2-R20, NH-R20, 〇_r20 or s_r2〇, wherein r2〇 is monosubstituted or disubstituted by Rn as the case may be. Or a trisubstituted saturated or unsaturated C3_7 cycloalkyl or C4-1G(alkylcycloalkyl) or Rm is optionally substituted by a Rn, disubstituted or disubstituted (:6 or &lt;:1() aryl Or (7-16 aralkyl, or Rm is Het or (lower alkyl)-Het monosubstituted, disubstituted or trisubstituted, as appropriate, wherein each Rn is independently a C1-6 alkyl group Substituted or disubstituted amine group; aryl group; Cw alkoxy group; optionally as Cl_6 alkane fluorenyl group; N02; OH; SH; halogenated by (^-6 alkyl, c6 or C1G aryl Base, (: 7-16 aromatic 120556.doc 200810821 alkyl, Het or (lower alkyl)_Het monosubstituted guanamine; carboxyl; carboxyl (low carbon alkyl); C64C1G aryl, (: 7-16 Aralkyl or Het, the aryl, aralkyl or Het is optionally substituted by r22; wherein 22 is (: 1-6 Alkyloxyl;Cl_6 alkoxy; optionally as a mono- or di-substituted alkyl group; sulfonyl; n〇2; OH; SH; halo; haloalkyl; carboxy; Lower alkyl) guanamine;

Ri is a C1-6 alkyl group or a C2_6 alkenyl group optionally substituted by halogen; and W is a trans- or n-substituted amine group. In the structures shown above for the compound of the formula XX, the terms P6, P5, P4, P3, P2 and P1 represent the respective amino acid moieties as is known to those skilled in the art. The structural formula XXI compound has the following structure··

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XXI: B is hydrazine, (: 6 or 0: 1 () aryl, (: 7-16 aralkyl; as appropriate) Alkyl substituted Het or (lower alkyl)-Het; C!-6 alkoxy; Cle6 alkyl fluorenyl; hydroxy; alkylalkyl; self group; functional alkyl; nitro; cyano; Alkyl;, as the case may be. 6. Alkyl-substituted amine; guanamine; or (lower alkyl) decylamine; or B is a fluorenyl derivative of the formula Ο(Ο)-; -C(〇)_的carboxy derivative 120556.doc -104- 200810821 Biological; formula r4-n(r5)-c(o)-decanamine derivative; SR4-N(R5)-C(S)- a thioguanamine derivative; or a sulfonyl derivative of the formula R4_S02 wherein R4 is (1) optionally via a carboxyl group, a Cw alkanoyl group, a hydroxyl group, a C1-6 alkoxy group, an amine group (optionally Cw alkyl group) Substituted or disubstituted), decylamino or (lower alkyl) decylamine substituted Cm alkyl; (ii) C3_7 cycloalkyl, C3-7 cycloalkoxy or C4_1G alkylcycloalkyl, both of which are considered In the case of a hydroxyl group, a carboxyl group, a (Cw alkoxy)carbonyl group, an amine group (optionally substituted or disubstituted by c!_6 alkyl group), hydrazine Substituted or (lower alkyl) decylamine substituted; (iii) optionally substituted or disubstituted amine group via Cw alkyl; guanamine; or (lower alkyl) decylamine; (iv) optionally a C6 alkyl group or a C7-16 aryl group substituted with a Cw alkyl group, a hydroxyl group, a decylamino group, a (lower alkyl) decylamine or an amine group (optionally substituted or disubstituted with a CN6 alkyl group); (V) Het or (low carbon) substituted by (^.6 alkyl, hydroxy, decylamino, (lower alkyl) decylamine or amine group (optionally Cw alkyl mono- or disubstituted)) Alkyl)-Het; R5 is hydrazine or C!-6 alkyl; the restriction is that when I is decylamine or thioguanamine, r4 is not _(π)cycloalkoxy; hydrazine is 11 or Ci -6 alkyl; ^ is ^^.8 alkyl, Cw cycloalkyl or ^^alkylcycloalkyl, all of which are optionally hydroxyl, Cw alkoxy, CrWialkyl, amidino, (low Carboalkyl) guanamine, C6 or C1G aryl or C716 aralkyl; R2 is CH2-R2, NH-R20, 0-R2 or S-R20, wherein R20 is saturated 120556.doc-105- 200810821 or unsaturated CM cycloalkyl or C4-1G (alkylcycloalkyl), which are optionally monosubstituted by Rn, Substituted or trisubstituted, or R2AC64Cig aryl or C7i4 arylalkyl group, which are optionally monosubstituted, disubstituted or trisubstituted by R21, or R2〇 is Het or (lower alkyl)-Het, which are optionally R2i monosubstituted, disubstituted or trisubstituted wherein each Ru is independently C!_6 alkyl; Cw alkoxy; lower thioalkyl; sulfonyl; N02; 〇H; SH; halo; haloalkyl; In the case of (^_6 alkyl, hydrazine 6 or (: 1 () aryl, C 4 aralkyl, Het or (lower alkane # base) _ Het monosubstituted or disubstituted amine; as the case (^ -6 alkyl, (6 or C10 alkyl, CVw aryl, Het or (lower alkyl)-Het monosubstituted amide group; buffer; carboxyl (lower alkyl); c: 6 or c1G aryl, C7-14 aralkyl or Het 'the aryl, arylalkyl or Het is optionally substituted by R22; wherein R22 is C!-6 alkyl; c^7 cycloalkyl; Cu alkoxy; Amino group which is mono- or disubstituted by Cw alkyl; sulfonyl; (lower alkyl) sulfonyl, N02; 〇H; SH; halo; haloalkyl; carboxy; decylamine; Base amine; or Het substituted by C16 alkyl;

• R1 is H; Cl_6 alkyl, cycloalkyl, 02-6 alkenyl or C2_6 alkynyl, all of which are optionally substituted by D. The compound of formula XXII has the following structure:

120556.doc -106. 200810821 or a pharmaceutically acceptable salt, solvate or vinegar thereof; wherein in formula XXII: w is CH or N, R21 is hydrazine, halo, Cw alkyl, C3-6 ring An alkyl group, a Cu haloalkyl group, an alkoxy group, a C3-6 cycloalkoxy group, a hydroxyl group or N(R23)2, wherein each R23 is independently H, Cw alkyl or C3-6 cycloalkyl; R22 is an anthracene or a halogen Base, Cu alkyl, C3-6 cycloalkyl, Cu haloalkyl, Cl. 6 thioalkyl, Ci-6 alkoxy, C3-6 cycloalkoxy, C2-7 alkoxyalkyl, C3 -6 cycloalkyl, Ceio aryl or Het' wherein Het is a five-, six- or seven-membered saturated or unsaturated heterocyclic ring containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur; , aryl or Het substituted by R24, wherein R24 is fluorene, halo, Cw alkyl, C3-6 cycloalkyl, Cw alkoxy, C3-6 cycloalkoxy, &gt;j〇2, N(R25)2, NH -C(0)-R25 or NH-C(0)-NH-R25, wherein each R25 is independently: Η, Cw alkyl or (:3_6 cycloalkyl; or R24 is NH-C(0)-0R26, Wherein R26 is Cle6 alkyl or c3_6 cycloalkyl; R3 is hydroxy, NH2 or a group of the formula _NH-R31 wherein R31 is (6 or 10 aryl, heteroaryl, -C(0)-R32, -C(0)-NHR32 or -C(0)-〇R32, wherein R32 is Cw alkyl or C3.6 cycloalkyl; D is a saturated or unsaturated extension chain of 5 to 10 atoms, Optionally containing from 1 to 3 heteroatoms independently selected from hydrazine, S or N-R41, wherein are η, Cw alkyl, C3_6 cycloalkyl or -C(0)-R42, wherein R42 is Cl-6 alkyl, C3 • 6 ring alkyl or Cwm aryl; R 4 is hydrazine or 1 to 3 substituents on any carbon atom of the chain D 120556.doc -107 - 200810821, the substituents are independently selected from π to 3 A group of beer consisting of a lower group: C!-6 alkyl, Ci-6 haloalkyl, Ci-6 alkoxy, _, tymidine, pendant oxy, thio and Ci-6 thio And A is a decylamine of the formula -C(0)-NH-R5, wherein R5 is selected from white, (3) Tianyuanji 'C3·6 cycloalkyl, Cww aryl and C7·6 aryl are formed. Group or A is a carboxylic acid. The compound of formula XXIII has the following structure:

Or a pharmaceutically acceptable salt, solvate or hydrate thereof; wherein in the formula XXIII: rq is a bond or a difluoromethylene group; R1 is hydrazine; and R2 and R9 are each independently substituted as appropriate a substituted cyclic group or an optionally substituted aromatic group; R3, R5 and R7 are each independently: substituted as appropriate (^- or ^^cycloalkylene or optionally substituted ( — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — — a substituent substituted, and wherein the methylene or ethylidene is substituted by a substituent of the genus; or; R, R6, R8 and r1g are each independently hydrogen or optionally substituted aliphatic 120556 .doc 200810821 is a substituted monocyclic azaheterocyclyl or substituted as appropriate

~ Han ~ part of the ring of the ring, L is -c (0) -, - 〇 c (〇) -, -NR1 〇 C (0) _, _s (〇) 2_ ^ &quot; NR10S (〇) 2 . ; , 2 The restrictions are

Replaced

L is -OC(O)- and R9 is an optionally substituted aliphatic; or at least one of R3, R5 and R7 is an exoethyl group, which is selected from an aliphatic group optionally substituted, optionally Substituted by a substituent of a substituted ring group or an optionally substituted aromatic group, and wherein the ethylidene group is further substituted with an aliphatic substituent; or R4 is an optionally substituted aliphatic group . The compound of formula XXIV has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in formula XXIV: W is:

120556.doc -109- 200810821 m is hydrazine or 1; R2 is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenyl An alkyl group, a heterocyclic group, a heterocyclic alkyl group, a heterocyclic alkenyl group, a heteroaryl group or a heteroarylalkyl group; wherein any R 2 carbon atom is optionally substituted by J; J is an alkyl group, an aryl group, an aromatic group , alkoxy, aryloxy, aryloxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclooxy, heterocyclylalkyl, ketone, hydroxy, amine, alkylamino , an alkylamino group, an aryl fluorenyl group, an arylalkyl fluorenyl group, a carboxyl group, a carboxyalkyl group, a carboxy oximinoalkyl group, a halogen group, a cyano group, a nitro group, a decyl group, a fluorenyl group, Anthracenyl or fluorenylamino and optionally substituted by 1-3 J1 groups; J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclooxy, ketone , hydroxy, amine, decylamino, aryl fluorenyl, weiji, fluorenyl, fluorenyl, halo, cyano, schlossyl, decyl, sulfonyl or sulfonate Amidino group; L is a pyridyl group, a dilute group or an alkynyl group Substituted by specthalin, and any hydrogen or halogen atom bonded to any terminal carbon atom is optionally substituted with a thiol group or a hydroxy group; A1 is a bond; R4 is a decyl group, a cycloalkyl group, an aryl group, an aralkyl group. a heterocyclic group, a heterocyclic group, a heterocyclic group, a heteroaryl group, a heteroarylalkyl group, a fluorenyl group or a fluorenyl group, and optionally substituted with 1-3 groups of J; R5 and R6 are independently Is hydrogen, alkyl, alkenyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkyl, cycloalkenyl, heterocyclic, heterocyclic US 120556.doc -110- 200810821 , heteroaryl or heteroaryl, and optionally substituted by 1 to 3 J groups; X is a bond, -C(H)(R7)-, -〇-, -S· or -N(R8)· R7 is hydrogen, alkyl, alkenyl, aryl, aralkyl, heterocyclyl, heterocyclyl, heteroaryl or heteroaryl, and optionally substituted by 1 to 3 j groups; R8 Is hydrogen, alkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, aralkyl fluorenyl, heterocyclanoyl, heteroaralkyl Sulfhydryl, _c(〇)Ri4, _s〇2Ri4 or carboxy

Anthracene amino group' and optionally substituted with 1 to 3 J groups; or r8 and z together with the atom to which they are bonded form a nitrogen-containing monocyclic or bicyclic ring system optionally substituted with 1 to 3 J groups; Alkyl, aryl, aralkyl, heterocyclic, heterocycloalkyl, heteroaryl or heteroaryl; Y is a bond, -cn2-, -c(0)-, -c(o)c (〇)-, , -S(0)2_4_S(0)(NR7)·, wherein R7 is as defined above; z is alkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, heterocycle a heterocyclic group, a heteroaryl group, a heteroaryl group, a 〇Nan 2 or _N(R2) 2, wherein any hindered atom is optionally substituted by J, wherein R 2 is as defined above; A 2 is a bond or 〇

R is alkyl, cycloalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroarylalkyl, carboxyalkyl or carboxyalkylaminoalkyl, and optionally 1-3 J groups substituted; Μ is alkyl, cycloalkyl, aryl, aralkyl, heterocyclic, heterocycloalkane 120556.doc -111 - 200810821 base, heteroaryl or heteroarylalkyl Any alkyl carbon atom substituted by id j groups as the case may be replaced by a hetero atom; V is a bond, _ch2-, -C(H)(RU)-, -〇_, _nN(Rll) · R11 is hydrogen or Cw alkyl; K is a bond, -ο-, winter...c(0), one s(〇), s(〇) η -S(0)(NR&quot;)-, where R&quot ; as defined above; or T is -R12, _alkyl_R12, _alkynyl _r12, seven Hans with -N(R12)2, -C(0)R12, ·&lt;:(=decane Base) R12 or R15

R12 is hydrogen, aryl, heteroaryl, cycloalkyl, heterocyclyl, cycloalkylene or heterocycloalkylene, and optionally substituted by 1-3 J groups or the first Han ^ and ^ 2 R12, together with the nitrogen to which it is combined, forms a mono- or bicyclic ring system which is optionally substituted with 1-3 J groups; ~ R1G is alkyl, cycloalkyl, aryl, aralkyl, heterocyclic, heterocyclic a base, a heteroaryl group, a heteroarylalkyl group, a carboxyalkyl group or a carboguanamine group, and optionally substituted with 1-3 hydrogen J groups; R15 is an alkyl group, a cycloalkyl group, an aryl group, an aralkyl group a base, a heterocyclic group, a heterocyclic alkyl group, a heteroaryl group, a heteroarylalkyl group, a carboxyalkyl group or a carboxyalkylamino group, and optionally substituted with 1-3 J groups; and R is hydrazine, An alkyl group, a aryl group, a heteroaryl group, a cycloalkyl group or a heterocyclic group. The compound of formula XXV has the following structure:

R9

E 120556.doc -112- 200810821 or a pharmaceutically acceptable salt, solvate or vinegar thereof; wherein in formula XXV: E represents CHO or B(OH)2; R1 represents lower alkyl, halogenated lower Carboalkyl, cyano lower alkyl, lower alkylalkylthio lower alkyl, aryl lower alkylthio lower alkyl, aryl lower alkyl, heteroaryl lower alkyl, lower carbon Alkenyl or lower alkynyl; R2 represents lower alkyl, hydroxy lower alkyl, carboxy lower alkyl, aryl lower alkyl, aminocarbonyl lower alkyl or lower cycloalkyl lower alkane And R 3 represents a hydrogen or lower alkyl group; or R 2 and R 3 together represent a dimethyl group or a trimethylene group optionally substituted by a hydroxyl group; R 4 represents a lower alkyl group, a hydroxy lower alkyl group, a lower carbocycle Lower alkylene, slow-base low-carbon alkyl, aryl low-carbon alkyl, low-carbon sulfur low-cracking base, cyano lower alkylthio-lower alkyl, low aryl lower alkylthio Carboalkyl, lower alkenyl, aryl or lower carboalkyl; R5 represents lower alkyl, hydroxy lower alkyl, lower alkylthio lower alkyl, aryl lower alkyl, aryl Lower alkyl alkane lower alkyl, cyanide Lower alkyl alkylthio lower alkyl or lower cycloalkyl; R6 represents hydrogen or lower alkyl; R7 represents lower alkyl, hydroxy lower alkyl, carboxy lower alkyl, aryl lower alkane a lower, lower alkylcycloalkyl or lower cycloalkyl; R 8 represents lower alkyl, hydroxy lower alkyl, carboxy lower alkyl or aryl lower alkyl; and R 9 represents lower alkane Carbocarbonyl, carboxy lower alkylcarbonyl, arylcarbonyl, 120556.doc -113- 200810821 lower alkylsulfonyl, arylsulfonyl, lower alkoxycarbonyl or aryl lower alkoxycarbonyl . The compound of formula XXVI has the following structure: P6 P5 P4 P3 P2 P1

Or a pharmaceutically acceptable salt, solvate or ester thereof; wherein in Formula XXVI: B is a fluorenyl derivative of the formula Ru-c(0)-, wherein Rn is optionally substituted by a carboxyl group 10 alkyl; or Rn is C6 or Cl〇 aryl or 07_16 aralkyl substituted by Ci-6 leumino group as appropriate; a is 0 or 1; R6 (if present) is carboxy (lower carbon) alkyl; Is 0 or 1; R5 (if present) is (1; 1-6 alkyl or slow (low carbon) alkyl; Y is hydrazine or C1 -6 alkyl; R4 is Ci-1G alkyl; C3-IG a cycloalkyl group; R3 is a Ci-1G alkyl group; a Cm cycloalkyl group; W is a group of the following formula:

120556.doc -114- 200810821 wherein R2 is optionally substituted by a carboxy group of CK1() alkyl or (33-7 cycloalkyl; C6 or 〇1() aryl; or (: 7-16 aryl; or W is a group of the following formula:

Where X is CH or N;

R/ is a C3 4 alkyl group which is bonded to form a five- or six-membered ring, which is optionally substituted by OH; SH ·, NH 2 ; carboxyl; r 12 ; 〇Ri2, SRi2, NHRl2 or nr12r12', wherein Rl2 and Ri2 , independently: ^C3_ie alkyl or acyclic C1-10 alkyl or cycloc3^alkenyl or acyclohexadecenyl, the alkyl or alkenyl group being optionally substituted by Njj2, 〇H, SH, halo or carboxy The alkyl or alkenyl group optionally contains at least one heteroatom independently selected from the group consisting of ruthenium, s and N; or independently (: 6 or &lt;: 1 () aryl or c?i6 aralkyl, Substituted by a group, NH2, OH, SH, _ group, a sulfhydryl or a ruthenium (low carbon) alkyl group; the Schiff aryl or aryl group optionally contains at least __ groups independently selected from 0, S and N a hetero atom; a cycloalkyl, cycloalkenyl, aryl or aryl group optionally fused to a second, 5 member, or 7 membered ring to form a ring system or a heterocyclic ring, and the second ring is optionally 衾NH 2 OH SH, 4 base, slow or slow (low carbon) alkyl substitution; ^

Ci. Or a heterocyclic ring; the second ring optionally contains at least one hetero atom selected from the group consisting of 0, S and N; Q is a group of the formula: 120556.doc -115- 200810821

R13 wherein Z is CH; X is O or S; R1 is H, optionally substituted by a thio or halo group, or a Ci 6 alkenyl group; and r13 is co-nh-r14, wherein R14 is hydrogen, a ring c3 i〇alkyl or acyclic alkyl or a ring C3-1G alkenyl or a non-cycloalkenyl group, the alkyl or alkenyl group being optionally substituted by NH2, OH, SH, halo or carboxy; the alkyl or alkene The base-view case contains at least one heteroatom independently selected from the group consisting of ruthenium, S&amp;N; or

Rm is (:6 or &lt;:1() aryl or c^6 aralkyl, which is optionally substituted by alkyl, brain 2, oxime H, SH, dentate, carboxyl or carboxyl (low carbon) alkyl Or substituted by another C3·7 alkyl group, (:6 or (:1) aryl or heterocyclic ring; the aryl or aralkyl group optionally contains at least one group independently selected from hydrazine, S&amp;N a hetero atom; * the cycloalkyl, cycloalkenyl, aryl or aralkyl group optionally fused to a second 5 member, 6 member or 7 membered ring to form a ring system or a heterocyclic ring, the second ring being optionally NH :, OH, SH, _ group, sulphonyl or a sulphonyl (lower carbon) alkyl group substituted or substituted by another CM% alkyl, C6 or C1 () aryl or heterocyclic ring; the second ring contains at least - A hetero atom independently selected from the group consisting of (4); 'The limiting condition is that when Z is CH, then Ru is not ... amino acid or its slightly, Q is a phosphonate of the formula: I20556.doc -116- 200810821

Wherein R15 and R16 are independently C6-2Q aryloxy; and the heart is as defined above. In the structure shown above for the compound of formula XXVI, the term? 6,? 5. P4, P3, P2 and P1 represent the respective amino acid moieties as is known to those skilled in the art. Thus, the actual structure of the compound of formula XXVI is:

The compound of formula XXVII has the following structure:

Or a pharmaceutically acceptable salt, solvate or ester thereof. The compound of formula XXVIII has the following structure:

〇 120556.doc -117 200810821 or a pharmaceutically acceptable salt, solvate or singly. The present invention provides a pharmaceutical formulation comprising at least one active compound selected from the group consisting of Formulas I to XXVIII, wherein at least one active compound initially contained in the formulation dissolves at least about 20°/◦ in 10 minutes. In selected embodiments, at least one active compound initially contained in the formulation is at least about 60% dissolved within 10 minutes; at least one active compound initially contained in the formulation is at least about 50% dissolved in 20 minutes; initially contained in At least one active compound in the formulation is dissolved in at least about 80% in 20 minutes; at least one active compound originally contained in the formulation is dissolved in at least about 65% in 30 minutes; at least one active initially contained in the formulation The compound is dissolved at least about 90% in 30 minutes; at least one active compound initially contained in the formulation dissolves at least about 80% in 45 minutes; at least one active compound initially contained in the formulation is at least about 95 in 45 minutes. % is dissolved; at least one active compound initially contained in the formulation dissolves at least about 85% in 60 minutes; at least one active compound initially contained in the formulation dissolves at least about 98% in 60 minutes. In one embodiment, the dissolution was tested in a USPII paddle mixer filled with 900 mL of Dissolved® medium at 37 ° C. The dissolution medium consisted of 0-5% sodium lauryl sulfate buffer buffered with a pH 6.8 sodium phosphate buffer. . EXAMPLES Next are examples of the process of the invention and comparative examples of particles precipitated by conventionally stirred batch reactors. For the subsequent examples, the compound of formula B is prepared according to the procedure described in the published International Patent Application No. WO 02/08244, which is incorporated herein by reference. 120556.doc -118- 200810821 Unless otherwise stated, all reagents are commercially available usp or food grade ua ua and are used as received. If indicated, the granularity information is obtained according to the following procedure. For the subsequent examples, the particle size information is obtained by measuring the particulate matter produced by the slurry using the focused beam reflectance measurement (FBRM), which is derived from the manufacturer's instructions for obtaining the measurements.

Mettler Toledo's Lasentec probe is used to perform this focused beam reflectance measurement. The slurry sample obtained from the hopper was subjected to vacuum distillation before vacuum distillation. The program and apparatus can measure particulate matter in the range of i microns up to the 丨〇〇〇 micron size. Quantitative Characterization of Initial Particle Size I by Scanning Electron Microscopy (SEM) I observed the aggregation of particles and the kinelation of aggregate morphology by SEM under different conditions to determine the softening point of the precipitated material. For the SEM measurement of the softening point and a, the slurry sample is periodically obtained at various temperature intervals when the slurry is heated. The solid in the sample is collected by filtration, vacuum dried for 1 to 2 hours, and the dried sample is examined using a conventional SEM. . Referring to Figure 7a, without undergoing softening, the micrograph of the microparticles showed a nodular particle appearance at a lower magnification. Referring to 7b', when examined at the same magnification, particles that have been exposed to temperatures above the softening point show the absence of nodular particle appearance. When examined by SEM in this way, the self-sinking hall shows the sample temperature at which the nodular particle appearance is lost to estimate the softening point. By means of the SEM view, the test also shows that the softening point can be measured by the FBRM measurement method (according to the manufacturer's instructions), and the FBRM measurement for the controlled addition of the sample is completed. Tian*, human, and therefore 'scrape the 3 slurry reactor at a rate between 200 rpm and 300 rpm. At a rate of π, - will be stirred 120556.doc -119 - 200810821 mixed slurry from -2 (TC heating to 15 (rc above.) FBRM m is continuously obtained during the heating cycle and the softening point is determined to be equivalent to heating The temperature of the maximum value in the particle count curve of the energy spectrum.

Example I

By connecting the pressure gauge (mechanical pressure gauge, purchased from c〇le) and the control valve (1 · 5 gallons / minute, maximum, water, purchased from r · $ Cmm &amp; Company) a certain length of 乂" steel pipe fastened to one of the three-way pipe of the official road end pipe used as an anti-solvent inlet, by the pipe end pipe and 1/4&quot; Νρτ thread knives know that there are 3/811 A three-way static pressure tube mixer (purchased from c〇le parmeri Koflo Corporation) is fastened to another pipe end pipe of the tee pipe by a non-recorded steel tee fitting for the press fitting. Used as an outlet. A steel ΝΡΤ X 1/8" press fitting adapter (commercially available) is used to assemble the branch end of the tee to be used as an inlet line for the solution of formula B. It will be equipped with a mechanical pressure gauge (Cole/Pannei: ) and flow control metering valve (υ gallons / min, maximum, water, from RS · Cmm &amp; Company) 1 / 8" 316 L stainless steel pipeline connected to the assembly of the tee fittings of the assembly of the tee fittings Connector. The control valve in the 3/8&quot; inlet line (anti-solvent supply) is connected to a supply tank containing approximately 2 〇 L. The control valve in the 1 / 8 '' inlet line (solution supply) is connected to a sump holding about 2.85 L of the compound of the formula B compound. A solution of formula B was prepared by dissolving 608·5 gSB of the compound in 2450 ml of methyl tert-butyl ether (ΜΤΒΕ). The outlet of the static mixer of the mixing tee was connected to a 5 L flask equipped with a mechanical stirrer, a Lasentec probe for particle size determination, and a 120556.doc-120-200810821 heat jacket. A precipitated slurry of the compound of formula b was prepared by providing a flow control valve to supply 3400 ml/min of n-heptane and 840 ml/min of MTBE/form B compound solution. The solution, anti-solvent and mixing tee were maintained at 2 °C. When the temperature of the reverse solvent and solution has stabilized, flow begins until the 丨〇.4 L anti-solvent and 2.85 L solution have passed through the mixing tee into the flask. The FBRM measurement performed in the slurry in the flask showed that the agglomerated particles had an average chord length of 15·8 μm and the particle chord length ranged from about 1 μm to about 11 μm. The resulting slurry was also evaluated to determine the softening point of the sinking chamber. Therefore, an aliquot was heated at a rate of 1 〇 / 111 丨 11 in a disturbed 3 L reactor, and a Lasentec® probe was used for FBRM measurement. The softening temperature was measured in this manner to be 36.2 °C. The microparticles prepared above were recovered by vacuum filtration and vacuum drying at room temperature (about 60 to 70 Torr) at 25 ° C for 2 hours, followed by drying at room temperature under vacuum at 35 ° C for 8 hours. The product was finally dried under room vacuum at 45t for an additional 16 hours. The dried microparticles were evaluated and found to have an initial particle size range of less than 1 micron up to about 2 microns. The specific surface area (BET absorption method) was determined to be about 19.11 m2/g. The bulk density of the isolated material was determined by weighing a 25 ml (open) sample. The bulk density was found to be 0.3 g/mi. A second conduit was conducted in the apparatus using a 2.7 L solution of the compound of formula B as a 0.24 hydrazine solution prepared by dissolving 456 § 3 compound in 3600 ml of MTBE. An anti-solvent flow control valve was provided to supply 3750 ml/min of n-heptane and a solution control valve was provided to supply a solution of 635 ml/min of the compound of formula B. Keep the solution, anti-solvent and mix 120556.doc • 121 - 200810821 all under the grab. When the temperature is stable, flow begins until 20.3 L of anti-solvent and 3.7 (10) liquid has passed through the mixing tee and into the hopper. The (25) aliquot of the 25 〇〇 μ aliquot entering the hopper was vacuumed at 32 ° C until it was reduced to approximately 870 mL of the original volume. The above-mentioned reading measurement method was used to determine the softening of the sink in the aggregate = ' and the softening point was found to be 51. The sink was recovered by vacuum filtration, washed with a 1 L of n-gum sample and the residual μ· was evaluated. Found thirsty cakes contain less than! % by weight of residual ΜΤΒΕ. Under room vacuum at 35. ^ Vacuum drying (4) for 8 hours, and then vacuum drying at valence. The isolated material was found to have an initial particle size of less than [micron] and a "micron agglomerate (four) degree with a particle size range of about 2 microns to about 30 microns. The BET surface area measurements indicate that the microparticles have an average volumetric surface area of (4) 1 〇 m 2 /g, while the sample is in the range of from about 5 m 2 /g to about 25 m 2 /g.

The thousand-volume density is 0A, /3 H and 疋 is 0·191 g/m3, and the bulk density is in the range of from about 15 g/cm to about 0.35 g/cm3. Using a vertical tee with a μ nominal way to make a larger number of mixed tees, using the same type of L-lily and left-force meter in the smaller mixing tee described in Example 1, Terminate the end tubes of the mixing tee with a press fitting and a branching end tube. Connect the mixing three = outlet to a static mixer with a 1/2&quot; outer diameter. By using 2, _claw-heptane 120556.doc -122- 200810821 at the temperature of 'C (so the Reynolds number is 97 〇〇) and keeping it at 5 °C (hence the Reynolds number is 2700) A 716 ml/min solution of MTBE solution of MsB compound was prepared to prepare a slurry. The output of the mixing tee is collected in a disturbed hopper. While the agitator is running, the contents of the sump are placed under a vacuum of about 3 Torr to 50 Torr (indoor vacuum), and are purged from the retort vacuum distillation paddle at a temperature of about 12 ° C to about 17 ° C. liquid. The volume of the slurry was reduced to about 4% by volume original volume (about 600 L·) by vacuum evaporation. The precipitated material was recovered by centrifugal filtration. The filter cake was washed with about 24 〇 [n-heptane. The wet cake was vacuum dried at 2 rc for 4 hours under room vacuum (about 30 to 50 Torr), followed by vacuum drying at 35 ° C for 1 hour and then vacuum drying at 45 ° C for 12 hours. Evaluate the hopper in the sump by placing a sample of about 50 〇 ml volume to a volume of about 7 〇〇 ml in a container and heating while monitoring the softening point of the particulate matter in the granule during the process of the sink. An aliquot of the slurry. The results of this study are reported in Figure 3. As shown in Fig. 3, as the concentration of the slurry caused by the distillation of MTBE and water is increased, the φ softening point of the generated particulate matter is increased. Analysis of the precipitate obtained from the slurry showed a volumetric surface area of 8.14 m2/g and a bulk density of 〇23 g/cm3, and a median particle size of 157 microns.

Example III A vertical tee with a 1" nominal OD line was used to make the mixing chamber, and the end tubes of the mixing chamber were terminated with a 1" press fitting and a %" branch end tube. The above example was used in this example. The same configuration of the flow meter and pressure gauge used in the device described in I. By using 20,000 ml/min n-heptane maintained at _2 (the temperature of rc (hence the Reynolds number of 23,650) and kept at temperature 120556.doc -123 - 200810821 (hence the Reynolds number is 10,650) A 5,000 ml/min solution containing 0.32 bismuth B compound MTBE solution to prepare a slurry. It is equipped with a temperature controlled jacket, vacuum line and agitating paddle The output of the mixing tee is collected in a stirred hopper for about 5.5 hours. When the vessel is sealed, the slurry is warmed from the collected temperature by operating the jacket temperature at 15 ° C. When the slurry has been When the temperature reaches 12.1 ° C, the vessel is evacuated until the pressure of -0.800 bar (gauge pressure) is reached and the distillation begins. During the distillation, the pressure and jacket temperature shown in the table below are maintained until the slurry volume has reached the initial collection. 33.33% of the volume of the slurry. The analysis of the sedimentation chamber shows that it has a volume surface area of 7.2 m2/g, a bulk density of 0.18 g/cm3, a median particle size of 1.46 micrometers, and a particle size range of 0.25 to 18 micrometers. HCV-Y distillation distribution pressure ( Gauge pressure 夹 jacket temperature 总 total batch volume % distilled Distilled batch volume (L) (X=320kg) -0.800 15 NA 9600L1 -0.905 20 0-2 0-190 -0.905 21 2-4 190-380 -0.905 22 4-6 380-580 -0.905 23 6-8 580-770 -0.905 25 8-10 770-960 -0.905 26 10-13 960-1250 -0.905 28 13-16 1250-1540 -0.908 28 16- 18 1540-1730 -0.910 30 18-22 1730-2110 -0.914 32 22-26 2110-2500 -0.918 32 26-30 2500-2880 -0.924 32 30-34 2880-3270 -0.932 32 34-38 3270-3650 - 0.938 32 38-42 3650-4030 -0.942 32 42-46 4030-4420 -0.950 32 46-52 4420-4990 -0.956 32 52-60 4990-5760 -0.970 32 60-66.67 5760-6400

1 collected initial slurry volume 120556.doc -124- 200810821 The graph shown in Figure 8 depicts the precipitation produced in Example II (antisolvent Reynolds number = 9700, solution Reynolds number = 2700) and the results produced in Example III Comparison of the chord length distribution of the precipitate (antisolvent Reynolds number = 23,650, solution Reynolds number = 10,650). As can be seen in Figure 8, the conditions used to generate higher Reynolds numbers in Example III resulted in higher nucleation rates (as evidenced by increased particle counts) and provided a narrower chord length distribution. Additional operations are performed as described in the following table. The resulting initial particle size and agglomerated particles prepared as shown in the following table were designated using the apparatus described in the following table: • Independent group operations indicated by the group of πΑη, '’B’' and nCn. Example * MTBE solution concentration of formula B (10) MTBE solution flow rate (ml/min) heptane flow rate (ml/min) observed initial particle size (micron) aggregate size (micron) BET surface area (m2/g) A1 0.23 635 4100 Micron to 2 micron 10-20 micron 30.19 A2 0.23 420 4125 submicron to 2 micron 10-20 micron 16.44 A3 0.41 640 4115 submicron to 2 micron 20-30 micron 17.41 B1 0.23 717 4200 submicron to 1 micron 10-20 micron 32.75 B2 0.23 717 4200 Submicron to 1 micron 10-20 micron 25.68 B3 0.23 717 4200 submicron to 1 micron 10-20 micron 32.00 B4 0.23 717 4200 submicron to 1 micron 24.24 C1 0.32 5000 20000 submicron to 2 micron 0.25- 25.5 micron 24.85 C2 0.32 5000 20000 submicron to 2 micron 0.25-18 micron 32.41 C3 0.32 5000 20000 submicron to 2 micron 10-20 micron C4 0.32 5000 20000 submicron to 2 micron 10-20 micron *Note: use has 1/ , a mixed tee with a nominal pipe outer diameter and a nominal 3/16" branch end pipe outer diameter for the batch indicated by ,, using a W nominal pipe outer diameter and a nominal 1/8'' Mixed tee pipe with outer diameter of the branch end Line consists ΠΒ "represents the batch, and having a" nominal pipe diameter and% "nominal mixing tee to the outer diameter of the tube end branches by '' C &quot; represents the batch. The slurry produced in each of Examples C1 and C2 was subjected to a distillation step. In the final particulate product, the volumetric surface area of the precipitate produced in C1 decreased from 24.8 5 m2/g to 6.13 m2/g, and the precipitate produced in C2 was from 32.41 m2/g -125-120556.doc 200810821 salt J 3 1 m / g. Figure 9 illustrates these two operations: the surface area of the volume decreases in m and then remains substantially the same throughout the remainder of the process.

Comparative Example I. A comparative example of precipitation of a composition was prepared using a 3 L stirred dish bottom batch reactor equipped with a 90 mm reversed curve impeller (4) (iv) w mpeller), which reactor was maintained at _2 Torr. Under the arm of i78〇 W n-heptane. A 330 ml volume of MTBE solution containing 132 mgs of B compound per ml of solution was introduced into the anti-solvent over a period of 29 min with stirring (550 rpm). The resulting slurry was distilled to a volume of 16 〇〇 ml under an indoor vacuum (30_60 Torr). The precipitate was collected by pressure filtration, washed with 4 liters of heptane and dried in a stirred filter drier under full vacuum at 35 C for 15 hrs and then at 550 hr. The filtrate contained about 5% by weight of 2 ΜΤΒΕ. The collected material had a bulk density of 0.16 g/ml, indicating a BET surface area of only 1.76 m2/g for a larger initial particle size. SEM examination of the particles showed that the particles were blended (melted). The softening point of the wet cake was determined to be less than about 30 °C. The precipitate prepared in accordance with the present invention is more uniform than the batch precipitated material and has an improved bulk density that allows for smaller dosage forms of equal amounts of active content. In addition, the elevated softening point of the isolated particulate matter allows for more aggressive drying conditions to reduce processing time. An example of the preparation of a pharmaceutical formulation using a precipitate prepared as described above. 0 Pharmaceutical Formulation I20556.doc -126- 200810821 An exemplary pharmaceutical formulation as described below is prepared in a laboratory scale apparatus (3 Kg order) and It is included in a low shear mixer granulated, dried in an oven, blended in a roller blender and manually filled into capsules, or prepared in industrial scale equipment (40 Kg or more), including ^ with his high shear granulator, Glatt fluidized bed dryer, B〇hle traction mixer, Quadro Comil screen mill (for both dry and wet grinding) &amp; B〇sch capsule filling machine. In all cases, it is operated according to GMP standard pharmaceutical manufacturing methods and industry standards including screening, granulation, grinding, fluid bed drying and powder mixing. Unless otherwise stated, 'all substances used in the formulation are commercially available items that meet the current requirements of the USP/NF. Active pharmaceutical ingredients for the preparation of pharmaceutical formulations were prepared according to Example II above. According to the above description of the sinker particulate matter, all APIs are used as they are and have a characteristic volume surface area, average chord length, average particle size, volume density, and volume surface area. Example IV-40 Preparation of Kg Pharmaceutical Formulations The granule pharmaceutical formulations of the present invention were prepared in batches at 40 Kg using the following procedure. 2.000 Kg microcrystalline cellulose (Avicel PH102, FMC), 1.200 Kg croscarmellose sodium (NF grade), 6.000 Kg pregelatinized powder 1500 (Colorcon), 4.586 Kg lactose monohydrate (NF , very fine grade, Foremost Farms) and 21.014 Kg of the compound of formula B prepared according to the above example π is placed in a Collette granulator/high speed mixer equipped with a mixing paddle and a modulating disk blade, wherein the compound of formula B has 8 · 14 m 2 /g median volume surface area and volume density of 0.23 g/cm3, and 1.57 micron median particles 120556.doc -127- 200810821 size. The weight of the API used reflects the adjusted quality from the theoretical 20 Kg to compensate for API activity. Thus, the 21.014 Kg API used has an activity equal to 20 Kg of theoretical material with 100% activity. The API and excipients present in the mixer were dry blended by operating the high shear mixer at 15.7 Torr/sec for 2 minutes to provide a homogeneous powder. The powder was sprayed onto a homogeneous powder using a solution containing 1.200 Kg of sodium lauryl sulfate (NF/USP, Stepan) dissolved in 17 Kg of pure water by spraying in a mixer/granulator at 3 Kg per minute. Wet granulation in which the mixer blades operate at 18.9 Torr/sec and • modulate the disk blades to operate at 2500 RPM. When all of the granulating fluid has been sprayed, the sump containing the granulating fluid and the line feeding the granulating fluid to the spraying device are washed by spraying an additional 8.10 Kg of pure water into the granulator/mixer. Thereafter, the granulator was operated with cooling water throughout the granulator jacket to maintain the pellets at temperatures below 30 °C until the mixer power demand rose to 11.1 kW. At the end of the granulation time, the wet granules thus produced were discharged into a Quadro Comil equipped with 0.375 pairs of square-porous sieves and circular impeller rods. Allow the entire amount of wet granules to pass through the mill. The milled wet granules were transferred to a ® Glatt WSG 60 fluid bed processor and dried at 55 ° C under a 1000 CFM flow until the sample showed a dry moisture loss of 2.2 wt%. The entire amount of dry granules prepared was dry milled/sifted using a Quadro Comil equipped with a larger sieve having a 0.040 inch aperture and a round bar impeller. A second batch of particulate material prepared substantially in the same manner as described above was also ground under the same conditions and combined with the first batch of abrasive to produce a combined weight of 69,560 g of abrasive. The entire amount of the ground material and 3,864 g of microcrystalline cellulose (outside the particle, Avicel PH102, the weight of the microcrystalline cellulose is equal to the microcrystalline cellulose present in the grain of 120556.doc-128 - 200810821) 2,319 g of croscarmellose sodium (outside the granules, NF grade, the weight of croscarmellose sodium is equal to the amount of intragranular croscarmellose sodium present in the abrasive) 400 L Bohle traction mixer. The traction mixer assembly was dry blended at 8 RPM for about 3 minutes to produce a homogeneous particulate blend. Magnesium stearate (1,546 g, Greven) was passed through a 30 mesh screen and added to a Bohle blender containing the particulate blend. Dry blending of the blender contents at 8 〇 RPM for 9 minutes resulted in a homogeneous granule pharmaceutical formulation having a bulk density of QMS g/ml and a knock-off of 0.642 g/ml, the pharmaceutical formulation comprising 50% by weight of API ( Within the granule) and comprising 10% by weight of microcrystalline cellulose (5 wt% granules, 5% by weight of granules), 14% by weight of lactose monohydrate (intragranular), 6% by weight of croscarmellose sodium In the % granules, 3 parts by weight / 〇 granules), 15% by weight of pregelatinized starch (in granules), 3% by weight of sodium lauryl sulfate (in granules) and 2% by weight of magnesium stearate (extragranular). PK results for granule pharmaceutical formulations 0.400 g portions (average) of granule pharmaceutical formulations prepared above were loaded to No. 0 using a Bosch capsule filling machine equipped with a 19 mm metering disc (equivalent to 2 gram per active capsule) In the capsule. Samples of these capsules were administered to healthy volunteers, administered in 4 capsules at a time or at a 1 hour dosing interval over a three hour period. The results are shown in Figure 1 'which shows a Cmax (single dose) of 2106 ng/ml at 3.1 hours and a Cmax (multiple dose) of 1631 ng/ml at 4.25 hours. The corresponding single-dose AUC was found to be 7029 ng.hr/ml and the corresponding multi-dose AUC was found to be 6410 ng.ml/hr, indicating that the formulation can provide Hcv eggs with therapeutic levels of API 120556.doc -129- 200810821 White enzyme inhibitor . Example v-Pharmaceutical Formulations As indicated in the table below, although the appropriate size equipment for larger (250 Kg) and smaller (3 Kg) batch sizes was used, additional batches of granules were prepared using the method described in Example IV. Medical formulations. Referring to the table below, the weights of the components used in each batch are reported (half of the reported croscarmellose sodium and microcrystalline cellulose are present in the product granules in the form of intragranular substances, and the other half According to the method described in Example IV, the particulate material is blended at the time of preparation, and thus it is an extragranular material). Batch 3 kg 40 kga 250 kga Component kg/batch kg/batch kg/batch SCH 503034 1.5 (50 wt%) 20 (50 wt%) Π5 (50 wt%) lactose monohydrate 0.27 (9 wt%) 5.6 ( 14% by weight) 35 (14% by weight) Microcrystalline cellulose 0.3 ((7)% by weight) 15% by weight) 15 25 (10 ii%) b Pregelatinized starch 0.45 (15% by weight) 6 (15% by weight) 37.5 (15% by weight) croscarmellose sodium (^: ^ 7 wt%) 15 . ·% by weight) &quot; ^(1)% by weight) 15 Tartaric acid 0.15 (5 wt%) ... Sodium lauryl sulfate 0·09 (3 wt%) 1.2 (3 wt%) 7.5 (3 wt%) Magnesium stearate 0.06 (2wt%) 0.8 (2wt%) 5 (2wt%) Total weight per batch 3 40 250 Processing equipment: granulator low shear mixer high shear granulator high shear granulator dryer Oven fluidized bed dryer fluidized bed dryer blender drum type blender drum type blender drum type blender capsule filling machine plastic machine (quantitative tray) capsule machine (quantitative tray) capsule machine (quantitative tray) )

a: The two blends can be combined into one blend before the capsule is obtained. b: - half inside the granule and half outside the granule. Capsule dissolution characteristics An aliquot of each granule pharmaceutical formulation prepared above was placed in a capsule and the dissolution characteristics were tested according to the following method. The dissolution test device used was 120556.doc • 130- 200810821 A USPII device paddle mixer filled with 900 mL of dissolution medium, the dissolution medium was buffered with 0.5% sodium lauryl sulfate buffered with a pH 6.8 sodium phosphate buffer. Solution composition. The dissolution test was carried out at 37 °C. The test was carried out while maintaining the dissolution medium at the test temperature and setting the paddle to 50 RPM. The test capsule is placed in the dissolution medium and the paddle is driven. An aliquot of the dissolution medium was periodically withdrawn and the active content was analyzed by HPLC. The total amount of active compound present in the dissolution medium is calculated by HPLC and reported as a percentage of the total amount of the active compound contained in the capsule dissolved in the dissolution medium. The results of representative samples taken from capsules prepared in each batch are shown in the table below as the average of 6 capsules. Source 3 kg Batch 40 kg Batch 250 kg Batch component mg/cap mg/cap Mg/cap Precipitated Formula B Compound 200 200 200 Lactose monohydrate 36 56 56 Microcrystalline cellulose 40 40 40 Pregelatinized Starch 60 60 60 croscarmellose sodium 24 24 24 sodium lauryl sulfate 12 12 12 tartaric acid 20 ... — magnesium stearate 8 8 8 capsule filling weight 400 400 400 dissolution time: dissolved API% dissolved API% dissolved API% 10 minutes 65 78 83 20 minutes 84 88 92 30 minutes 92 91 94 45 minutes 98 95 96 60 minutes 100 98 97

The comparative PK results will be prepared using the formulation described above for the 3 Kg batch and by the same method (although on a laboratory scale and in the fluid granulation, no lauryl 120556.doc -131 - 200810821 sodium sulfate is used) Formulations prepared capsules were administered to 12 healthy human volunteers. Therefore, each test subject received 2 capsules containing 2 mg of the API in a single administration form. Blood samples were collected from each volunteer before administration (0 hours) and 0.5, 1, u, 2, 2, 5, 3, 4, 5, 6, 7, 8, 9, 10, 12, and 24 hours after administration. The average concentration values of the subjects receiving the API are illustrated in Figure 6 in the form of traces represented by square data points. The serum drug levels of volunteers receiving active drugs are also reported in the table below, which contains results for each of the 3% SLS and no SLS formulations. The pharmacokinetic (PK) data from this study show that for a dosage form prepared with sodium lauryl sulfate in a granulating fluid, the mean maximum plasma concentration (Cmax) after a single administration is an average of 864 ng/ml, reaching a maximum concentration. The median time (hours) (Tmax) was 1.71 hours and Auc 24 (area under the plasma concentration time curve after 24 hours of administration, ng.hr/mL) was 2540.

120556.doc •132- 200810821 Referring to Figure 6, the existing formulation shows improved bioavailability at the time of administration when compared to a formulation that does not contain sodium lauryl sulfate (a trace with open loop data points). Example VI - Pharmaceutical Formulations Using Other APIs APIs will be prepared using the above precipitation methods for the structural formula 1 described herein (instead of the compound of formula B exemplified herein) and the compounds of formula π to XXVIII. The precipitated particulate material can be used in the pharmaceutical preparations of the above examples and V by substituting the API in the above method for incorporation into the pharmaceutical formulation. The above description of the present invention is intended to be illustrative, and not restrictive. Different variations or modifications may occur to those skilled in the art in the embodiments described herein. Such changes may be made without departing from the scope or spirit of the invention. BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 is a schematic cross-sectional view showing a three-way fitting device for combining a solution and an anti-solvent according to the present invention. φ Figure 2 presents a schematic flow diagram of an apparatus comprising a mixing tee for producing a precipitate in accordance with the present invention. Figure 3 presents a graphical representation of the effect of distillation on the softening point of the resulting precipitate. Figure 4 presents a schematic representation of the manufacturing process. Figure 5 presents a graphical representation of the softening point of a comparative particulate material prepared using a stirred batch process. Figure 6 presents a graphical representation of the bioavailability effect of using SLS in a formulation compared to formulations prepared without the use of SLS. Figure 7a shows SEM 25x magnification micrographs of morphological granules before exposure to temperatures above the softening temperature 120556.doc-133-200810821. Figure 7b presents a SEM 25x magnification micrograph showing the morphology of the particles after exposure to temperatures above the softening temperature. Figure 8 shows a comparison of the chord length of the precipitated agglomerates as a function of the Reynolds number obtained by combining the anti-solvent with the solution stream. Figure 9 shows the correlation between the treatment stage and the volume surface area in the precipitated and coagulated material. Figure 10 presents a comparison of Cmax and AUC between a single dose of 800 mg dose and a 3 hour multiple dose ® 200 mg dose (see Example V below, detailed). [Main component symbol description] 1 Mixing tee 2 Outlet pipe/storage tank 3 Static mixer/storage tank 4 Straight pipe inlet/control valve 5 Inlet line/pressure gauge 6 Arrow/check valve 7 Branch pipe/static Mixer 8 inlet line / hopper 9 arrow / probe 10 agitator 120556.doc • 134-

Claims (1)

200810821 X. Patent Application Range: A method of precipitating particles of a compound of formula a having a size range of from about 200 nm to about 300 nm, the method comprising introducing a solution stream of a compound of formula A into an antisolvent stream of a compound of formula A, wherein The anti-solvent stream is supplied under conditions that produce a Reyn 〇 ids number of at least about 9,000, and the solution is supplied under conditions that produce a Reynolds number of at least about 2, and wherein This stream is introduced in the presence of any parallel or collision component. • 2· 3. 4. 5. The method of claim 1, wherein the anti-solvent is supplied under conditions that produce a Reynolds number of from about 9, 〇〇〇 to about 25,000. The method of claim 2, wherein the solution containing the compound of formula a is supplied under conditions which produce a Reynolds number of at least about 10,000. The method of claim 3, wherein the compound of the formula A is 3[2-(3_t-butyl-ureido)·3,3-dimethyl-butanyl]_6,6-dimethyl-3-aza - Bicyclo [3.1 · oxime] hexane-2-carboxylic acid (2-aminocarbazyl 4 · cyclobutylmethyl 2 - oxoethoxy) ethyl decylamine (formula oxime compound), and the anti-solvent is at least The method of claim 1 wherein the hydrazine compound is a 3-[2_(3-third)-ureido group-3,3-didecyl butyl. Base]_6,6-dimethylazepine-double-written [3.1.0]hexan-2-carboxylic acid (2-aminomethyl)-cyclobutylindolyl-2-ylidene ethyl) B compound) 'The solution containing the fine chelate 4 is supplied under conditions of 5,500 or 5,5 or more Reynolds number, and the volume ratio of the liquid flow to the anti-solvent flow is maintained at about 1:15. To a liquid ratio of about 1:3: anti-solvent ratio. 120556.doc 200810821 6. The method of claim 5, wherein the ratio of the combined streams is maintained at a solution of about 1:4: anti-solvent ratio. The method of item 4, wherein the compound solution of the formula B comprises a compound dissolved in about 8 〇nig/miSB to about 25 〇 a methyl tertiary butyl ether (MTBE) solvent of the formula, and the anti-solvent is selected from linear or branched paraffins having from about 5 to about 12 carbon atoms. The method of claim 7, wherein the anti-solvent is heptane. 9. The method of claim 8, wherein the solution contains a compound of formula b in an amount of from about 8 mg/mi to about 2 (10) mg/ml. The method wherein the solution and the anti-solvent are maintained at a temperature of from about -20 C to about +25 ° C and combined. 11. In the method of claim H), the solution is maintained at about before mixing. Under the 〇 ° C overflow and maintaining the anti-solvent at a temperature of about _2 (rc). 12. The method of claim 1, wherein the solution comprises a compound of formula b of about i66. The method wherein the solution concentration, the temperature of the solution and the anti-solvent introduction, and the Reynolds number of the solution and the anti-solvent are selected to provide an initial particle size of less than about 1.0 micron and a median precipitation of from about 2.5 micrometers to about 2.5 micrometers. Particle size, precipitation particle size distribution from about i micrometer to about 5 micrometers, volume surface from about 25 m2/g to about 32·5 m2/g And a precipitated particle of about 2 Torr to a softening point of about 50 C. 14. A method of providing agglomerated particles comprising collecting precipitated particles and a solvent and an antisolvent provided by the method of claim η, and below The combined liquid is distilled at atmospheric pressure and at a temperature below the softening point of the precipitated particles. The combined liquid is at least 22, 556.doc 200810821% by volume. The method of claim 14, wherein the distillation condition is selected to produce about 5 m2/ g to a median volume surface area of about 12 m2 / g, about! Agglomerated median particle size of micron to about 2.5 microns, agglomerated particle size distribution of from about 1 micron to about 50 microns, and agglomerated particles of softening point of from about 20 °C to about 50 °C. 16· The species containing will contain 166 mg/ml compound 3-[2-(3-t-butyl-glycosyl)-3,3-methyl-butanyl]-6,6-dimercapto- 3-Aza-bicyclo[3.1.0]hexane-2-carboxylic acid (2-Aminomethyl-1-ylcyclobutyl-2-deoxy-ethyl)-decylamine (Compound B) a method in which a 0 ° C solution stream of a base butyl ether (MTBE) is combined with a -20 ° C heptane stream, wherein the solution stream is provided under conditions which produce a Reynolds number of 10650, the heptane stream being A supply of 23,650 Reynolds number is produced and the solution stream is combined with the anti-solvent stream at a substantially 90 degree angle, thereby providing a slurry comprising precipitated particles of the compound of formula B. 17. The method of claim 16, further comprising the step of collecting the slurry and distilling the supernatant from the collected slurry at a temperature below atmospheric pressure and at a temperature at which agglomerated particles having a softening point greater than about 25 t are formed. . A method for producing a classified particle comprising: (4) precipitating a particulate matter (Αρι) prepared according to the method of claim 17 by blending an amount sufficient to provide 55.6 wt% of the particles, sufficient to provide 5 6 3% by weight of microcrystalline cellulose, pregelatinized starch in an amount sufficient to provide 166% by weight of granules, sufficient amount of conjugated methylcellulose sodium sufficient to provide 3% by weight of granules, and sufficient to provide 156% by weight A particulate amount of lactose monohydrate to provide a dry blended mixture; I20556.doc 200810821 (b) using a granulation fluid comprising sodium lauryl sulfate in an amount sufficient to provide 6.6 wt% of the particles from the step &quot;a The dry blending mixture is agglomerated thereby providing - a first particle in which the sodium lauryl sulfate is dissolved in water equal to about 12 times to about 13 times the weight of the sodium lauryl sulfate used, (c) wet grinding the first particles from step "b" to provide a second particle of uniform size; (4) drying the second particles prepared in step (4) until the particles exhibit a loss on drying (LOD) of less than about 丨^ % to about 25 wt%; and (e) dry-milling the dried second granules via a sieve. 19. The method of claim 18, wherein the granulation step, b&quot; The amount is sufficient to provide 3.3% by weight of the amount of sodium lauryl sulfate. 20. The method of claim 18, wherein the wet milling step, v, is wetted with a sieve having 0. In the mill, the method of claim 20, wherein the drying step, dn is carried out in a fluidized bed dryer. 22. The method of claim 21, wherein the dry grinding step is performed in the equipment Processed in a screen mill having a sieve having a 0.040 bore. 23. A method for providing a granular pharmaceutical formulation comprising the steps of: (4) dry blending a graded particle from the step of claim 19 Microcrystalline cellulose in an amount equal to the amount of microcrystalline cellulose present in the graded granules and crosslinked carboxymethyl fibers in an amount equal to the weight of the crosslinked carboxymethyl fibers present in the graded granules 120556.doc 200810821 Sodium to provide homogeneous granule powder; and (b) dry A homogeneous granule powder from step "a" is combined with magnesium stearate in an amount sufficient to provide 2% by weight of dry blended product, thereby providing a granule pharmaceutical formulation. 24. A dosage form comprising as claimed in the capsule A granule pharmaceutical formulation as defined in claim 23. 25. The dosage form of claim 24, wherein the dissolution is performed using USPII filled with a 900 mL dissolution medium consisting of a 0.5% sodium lauryl sulfate solution buffered with a pH 6.8 sodium phosphate buffer. The test device paddle mixer (Paddle Stirrer), when tested at 37 ° C and set the paddle to 50 RPM, showed the following dissolution patterns on average: Time after injection: API % dissolved 10 minutes 80 20 minutes 90 30 minutes 93 45 minutes 96 60 minutes 98 26. A dosage form comprising a particulate pharmaceutical formulation as defined in claim 23, the pharmaceutical formulation comprising 800 mg API which exhibits a Cmax of 2106 ng at about 3.0 hours when administered in a single dose. Ml and AUC is 7029 ng hr/ml. 27. A precipitated particle prepared according to the method of claim 13. 28. An agglomerated particle prepared according to the method of claim 14. 120556.doc 200810821 29_ - Precipitated particles prepared according to the method of claim 4. 30. A graded particle prepared according to the method of claim 22. 31. A particulate pharmaceutical formulation prepared according to the method of claim 23. 32. A graded particle prepared according to the method of claim 18, wherein the compound of formula A is substituted by any structural formula to a structural formula of χχνπι. 33. A precipitated particle comprising a ruthenium compound having a primary particle size of less than about 1 micron, a precipitated particle size distribution of from about 1 micron to about 5 microns, and a volume of from about 25 m2/g to about 32.5 m2/g. The surface area is about 2 〇 to about 5 〇. 〇之 Softening point. 34· - 2 kinds of agglomerated particles comprising a compound of the formula β, having a median volume surface area of from about $ to about 12 m2/g, agglomerated particle size of from about m to about 25 microns, agglomerates from about 1 to about 50 microns Particle size distribution and about 2 ° C to about 5 (softening point of TC. 35. kinds of particles 'containing 55.6 wt% ΑΡΙ, 5.6 wt% microcrystalline cellulose 16. 6 weight i / 〇 pregelatinization Powdered, 3.3% by weight of crosslinked slow methylcellulose sodium, 15.6% by weight of lactose monohydrate and up to 6.6 % by weight of lauryl citrate, the granules having about 〇·4 "Μ to about 〇· 6 "Volume density of μ" wherein the API is agglomerated microparticles comprising a compound of formula 3 having a median volumetric surface area of from about 1 m to about 2 m, a particle size of about 1 micron to about 2.5 microns, about 丨 micron. To a particle size of about 5 micrometers of agglomerated particles, knife cloth, about 15 g / ml to about 0.19 g / ml volume density and about 20 ° C to about 5 (rc softening point. Wherein sodium lauryl sulfate is present in an amount to provide 3.3% by weight of particles. 120556.doc 200810821 37. A granule pharmaceutical formulation comprising 5 0% by weight API, 14% by weight, / lactose monohydrate (intragranular), 5% by weight of microcrystalline cellulose in the particle, 5% by weight of extragranular microcrystalline cellulose, 3% by weight of intragranular crosslinked carboxymethyl fiber Plain steel, 1% by weight of granules of diplomatic carboxymethylcellulose sodium, 15% by weight of pregelatinized powder (in granules), 3% by weight of sodium lauryl sulfate (in granules) and 2 parts by weight of 5°/. Magnesium hydride (extragranular) wherein the API is a reduced polyparticle comprising a compound of formula b having a median volume surface area of from about 5 m2/g to about 12 m2/g, agglomerates of from about 1 micron to about 2.5 microns The particle size, agglomerated particle size distribution of from about 1 micron to about 50 microns, a bulk density of from about 15 g/ml to about 19 g/ml, and about 2 Torr. 〇 to about 5 〇. Softening point of 〇. - A capsule comprising a granule pharmaceutical formulation according to claim 37, when used in a USPII dissolution test filled with 900 mL of dissolution medium consisting of a solution of 〇5〇/〇 lauryl sulphate buffer buffered with pH 6.8 sodium phosphate buffer Paddle Stirrer, when testing at 37 ° C and setting the paddle to 50 RPM The capsules have the following dissolution patterns on average: Time after injection: API % dissolved 10 minutes 80 20 minutes 90 30 minutes 93 45 minutes 96 60 minutes 98 120556.doc 1 9 - A dosage form comprising the granule pharmaceutical formulation of claim 37, the granule pharmaceutical formulation comprising 8 mg of API, which is administered to humans at about 3.0 hours of cma^21 〇6 ng/ml and AUC of 7029 ng.hr/ml.