CN1238762A

CN1238762A - Piperidine compounds

Info

Publication number: CN1238762A
Application number: CN97199952A
Authority: CN
Inventors: C·U·金; M·A·威廉斯
Original assignee: Gilead Sciences Inc
Current assignee: Gilead Sciences Inc
Priority date: 1996-10-21
Filing date: 1997-10-17
Publication date: 1999-12-15
Also published as: WO1998017647A1; CA2268756A1; AU4979597A; KR20000052702A; AU743333B2; JP2001502690A; EP0938475A1

Abstract

Novel compounds are described. The compounds generally comprise an acidic group, a basic group, a substituted amino or N-acyl and a group having an optionally hydroxylated alkane moiety. Pharmaceutical compositions comprising the inhibitors of the invention are also described. Methods of inhibiting neuraminidase in samples suspected of containing neuraminidase are also described. Antigenic materials, polymers, antibodies, conjugates of the compounds of the invention with labels, and assay methods for detecting neuraminidaseactivity are also described.

Description

Piperidine compounds

Invention field

Neuraminidase (being also referred to as sialidase, acylneuraminate hydrolase, and EC3.2.1.18) is animal body and enzyme common in multiple-microorganism.It is a kind of glycosylhydrolase, can from glycoprotein, glycolipid and oligosaccharides broken ends α -one glycosidic bond even sialic acid.Microorganism of many comprising neuraminidase is the pathogenic original of the mankind and other animals including poultry, horse, pig and sea dog.Microorganism with N-acetylneuraminic acid enzyme includes the species of bacterium such as comma bacillus, clostridium perfringens and streptococcus, and virus such as influenza virus and parainfluenza virus.

Influenza neuraminidase and influenza virus it is pathogenic relevant.It is thought that this enzyme not only assists to escape in the virion self-infection cell newly synthesized, also contribute to viral (by its hydrolysing activity) and be moved through respiratory mucus.

Description of Related Art

Von Itzstein, L.M. etc. exist《It is natural》, 363 (6428):The Theoretical Design of the influenza virus replication inhibitors based on sialidase is elaborated in 418-423 (1993).

Colman, P.M. et al. are in International Patent Publication WO 92/06691 (international application no PCT/AU90/00501, publication date：On April 30th, 1992) in, von Itzstein, L.M. et al. are in European Patent Publication 0539204A1 (EP application numbers 92309684.6, publication date：On April 28th, 1993), and von Itzstein, L.M. et al. are in international patent application WO91/16320 (international application no PCT/AU91/00161, publication date：On October 31st, 1991) in disclose can combine neuraminidase compound, it is said that its have interior resisting virus activity.

Umezawz, H. et al. are in antibiotic magazine (J.Antibotics) 27:Siastatin B separation is disclosed in 963-969 (1974).Nishimura, Y. et al. can will (J.Am.Chem.Soc.) 110 in American Chemical Society:7249-7250 (1988) and Japanization Society report (Bull.Chem.Soc.Jpn) 65:978-986 discloses the fully synthetic of siastatin B in (1992).Nishimura, Y. et al. are in antibiotic magazine 45 (10):1662-1668(1992)；46(2)300-309(1993)；46(12):1883-1889(1993)；47(1):101-107(1994)；With natural products communication (Nat.Prod.Lett.) 1 (1):39-44(1992)；And Japanese patent application 92-287381 (on October 26th, 1992)；90-201437 (July 31 nineteen ninety)；88-125020 (on May 24th, 1988) and the synthesis conversion reaction that siastatin B (including some dehydrogenation siastatin B analogues) is disclosed in 50046895 (on April 25th, 1975).Zbiral, E. et al. are in chemical record (Liebigs Ann.Chem.) 129-134 (1991), and vonItzstein, L.M. et al. are in carbohydrate compound research (Carbohydrate Res.) 244:The synthesis conversion reaction of C4- hydroxyls in sialic acid to amino group is disclosed in 181-185 (1993).

Goal of the invention

The embodiment that the present invention is selected can meet following one or more purposes：

The main object of the present invention is to suppress bacterium and virus, particularly suppresses influenza virus.More specifically, it is an object of the invention to suppress, glycolytic ferment such as neuraminidase, particularly selective depression be viral or bacillary neuraminidase.

It is a further object of the present invention to provide the neuraminidase inhibitor with following properties：Delay urination speed, entered in nose or pulmonary secretions by systemic circulation, be enough to realize effectively treat oral administration biaavailability, efficiently, clinically acceptable toxicity and other required pharmacological properties.

Another object of the present invention there is provided the inexpensive improved method of synthesis neuraminidase inhibitor.

It is yet another object of the invention to provide the improved method for applying known and new neuraminidase inhibitor.

It is a further object of the present invention to provide be used to prepare polymer, surfactant or immunogene and for the composition in other commercial runs and product.

Above-mentioned these purposes and other purposes will be apparent for those of ordinary skill in the art after integrally the present invention is considered.

Summary of the invention

The invention provides the compound with formula (Ⅸ) or material (composition)：

Wherein：

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂Or-(CR₁R₁)_m1W₂；

T₁For-NR₁W₃, or heterocycle；

J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂And J_2aIt independently is H or R₁；

R₁It independently is H or C_1-12Alkyl；

R₂It independently is R₃Or R₄, wherein each R₄Independently by 0-3 R₃Substituent group；

R₃It independently is F, Cl, Br, I ,-CN, N₃,-NO₂,-OR_6a-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R_6b)₂),=O,=S,=N(R₁) or=N (R_6b)；

R₄It independently is C_1-12Alkyl, C_2-12Alkenyl, or C_2-12Alkynyl；

R₅It independently is R₄, wherein each R₁By 0-3 R₃Group is replaced；

R_5aIt independently is C_1-12Alkylidene, C_2-12Alkylene group, or C_2-12Alkynylene, any alkylidene, alkylene group or alkynylene are by 0-3 R₃Group is replaced；

R_6aIt independently is H or into ether or into the group of ester；

R_6bIt independently is H, amino protecting group or carboxylated compound residue；

R_6cIt independently is H or the residue containing amino-compound；

W₁For the group comprising acidic hydrogen, by protection acidic-group, or the group comprising acidic hydrogen R_6cAcid amides；

W₂To include alkaline hetero atom or protected alkaline heteroatomic group, or alkaline heteroatomic R_6bAcid amides；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

W₅For carbocyclic ring or heterocycle, wherein W₅Independently by 0-3 R₂Group is replaced；

W₆For-R₅,-W₅,-R_5aW₅,-C(O)OR_6a,-C(O)R_6c,-C(O)N(R_6b)₂,-C(NR_6b)(N(R_6b)₂),-C(NR_6b)(N(H)(R_6b)),-C(N(H)(N(R_6b)₂),-C(S)N(R_6b)₂, or-C (O) R₂；With

Each m₁It independently is integer 0-2；

But condition is not include following compounds：Wherein J_1aFor H, each J₂For H, J_2aFor H and T₁For-N (H) (Ac) and：

E₁For-CO₂H or-CO₂CH₃,

G₁For-OBoc, and

W₆For Boc；

E₁For-CO₂H or-CO₂CH₃,

G₁For-OH, and

W₆For H；

E₁For-CO₂H,-CO₂CH₃Or-CO₂Bn

G₁For-OH, and

W₆For Boc；

E₁For-CONH₂,

G₁For-OH, and

W₆For Boc or H；

E₁For-CO₂H or-CO₂CH₃,

G₁For OH, and

W₆For Bn；Or

E₁For-CO₂H or-CO₂CH₃,

G₁For-OH, and

W₆For-CH₂CH(OH)CH₂(OH)；Wherein Bn is benzyl and Boc is-CO₂C(CH₃)₃；And their salt, solvate, the enantiomer of fractionation and the diastereomer of purifying.

Another embodiment of the present invention provides compound or material with formula (Ⅹ)：

Wherein：

One Z₁For W₆, and another Z₁For G₁；

Z₂For H or W₆；

E₁For-(CR₁R₁)_m1W₁；

G₁For-OH ,-OR_6a, or-(CR₁R₁)_m1W₂；

T₁For-NR₁W₃, or heterocycle；

J₁And J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂For H or R₁；

R₁It independently is H or C_1-12Alkyl；

R₂It independently is R₃Or R₄, wherein each R₄Independently by 0-3 R₃Group is replaced；

R₃It independently is F, Cl, Br, I ,-CN, N₃,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R₆b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R_6b)₂),=O,=S,=N(R₁) or=N (R_6b)；

R₄It independently is C_1-12Alkyl, C_2-12Alkenyl, or C_2-12Alkynyl；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Group is replaced；

R_6aIt independently is H or into ether or into the group of ester；

R_6cIt independently is H or the residue containing amino-compound；

W₂For H or include alkaline hetero atom or protected alkaline heteroatomic group, or alkaline heteroatomic R_6bAcid amides；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

Each m₁It independently is integer 0-2；And their salt, solvate, the enantiomer split and the diastereomer of purifying.

Another embodiment of the present invention provides the present composition for further comprising pharmaceutical acceptable carrier.

In the another embodiment of the present invention, using including the use of the compounds of this invention or compositions-treated may be containing neuraminidase sample the step of method suppress the activity of neuraminidase.

Another embodiment of the present invention provides the method for suppressing neuraminidase activity, the step of this method includes to contact with the present composition containing the sample of neuraminidase.

Invention is auspicious to be stated

The material of the present invention

The compounds of this invention does not include hitherto known compound.But as shown by hereafter other embodiments further, be antiviral purpose and using being only used for producing in the past and prepared the known compound of intermediate also within the scope of the present invention as antiviral compound.In the U.S., this paper compound or composition is including being obvious compound by the foreseeable compounds of 35USC § 102 or by 35USC § 103.Particularly, claims hereof, which will be understood that, eliminates compound that is being predicted in following documents or not possessing novelty in contrast：WO96/26933 (on September 6th, 1996)；Nishimura, Y. et al. " American Chemical Society's meeting will " 110:7249-7250(1988)；" Japanization Society report " 65:978-986 (1992), (disclosing the fully synthetic of siastatin B)；Nishimura, Y. et al. " antibiotic magazine " 45 (10):1662-1668(1992)；46(2):300-309(1993)；46(12):1883-1889(1993)；47(1):101-107(1994)；" natural products communication " 1 (1):39-44(1992)；With Japanese patent application 92-287381 (on October 26th, 1992)；90-201437 (July 31 nineteen ninety)；88-125020 (on May 24th, 1988) and 50046895 (on April 25th, 1975).

In further embodiment, the compounds of this invention is wherein W₆It is not -CH₂OH,-CH₂OAc, or-CH₂OCH₂Ph compound.

In further embodiment, the compounds of this invention is wherein E₁It is not -CH₂OH,-CH₂OTMS, or-CHO compound.

In further embodiment, the compounds of this invention is wherein W₆It is not polyhydroxyalkanes, especially-CH (OH) CH (OH) CH₂OH compound.In further embodiment, W₆For branched group R described below₅Or for by least one group R₅The carbocyclic ring replaced.

When compound described herein is by same group (such as " R₁" or " R_6a") when repeatedly replacing, it will be appreciated that these groups to each other can be with identical or different, i.e., each group is independent selection.

" heterocycle " used herein includes but is not limited to Paquette, Leo A., " contemporary heterocyclic chemistry principle " (Priniciples of Modern Heterocyclic Chemistry) (W.A.Benjamin, New York, 1968), the particularly the 1st, 3,4,6,7 and 9 chapters；" heterocyclic compound chemical series book series " (The Chemistry of HeterocyclicCompounds, A series of Monographs) (John Wiley ＆ Sons, New York, 1950 so far), the particularly the 13rd, 14,16, volume 19 and 28；And " American Chemical Society's meeting will ", 82:Those heterocycles described in 5566 (1960).

The example of heterocycle includes but is not limited to pyridine radicals,Thiazolyl,Tetrahydro-thienyl,The oxidized tetrahydro-thienyl of sulphur,Pyrimidine radicals,Furyl,Thienyl,Pyrrole radicals,Pyrazolyl,Imidazole radicals,Tetrazole radical,Benzofuranyl,Thianaphthenyl,Indyl,indolenyl,Quinolyl,Isoquinolyl,Benzimidazolyl,Piperidyl,4- piperidone bases,Pyrrolidinyl,2-Pyrrolidone base,Pyrrolinyl,Tetrahydrofuran is,Tetrahydric quinoline group,Tetrahydro isoquinolyl,Decahydroquinolyl,Octahydro quinolyl,Azocine base,Triazine radical,6H-1,2,5- thiadiazine bases,2H,6H-1,5,2- dithiazine bases,Thienyl,Thienyl,Pyranose,Isobenzofuran-base,Benzopyranyl,Xanthyl,Phenoxthine base (phenoxathiinyl),2H- pyrrole radicals,Isothiazolyl,Isoxazolyl,Pyrazinyl,Pyridazinyl,Indolizine base,Isoindolyl,3H- indyls,1H- indazolyls,Purine radicals,4H- quinolizine bases,2,3- phthalazinyls,1,5- phthalazinyls,Quinoxalinyl,Quinazolyl,1,2- phthalazinyls,Pteridine radicals,4aH- carbazyls,Carbazyl,B-carboline base,Phenanthridinyl,Acridinyl,Pyrimidine radicals,Phenanthroline,Phenazinyl,Phenothiazinyl,Furazanyl,Phenoxazine group,Isochroman base,Chromanyl,Imidazolidinyl,Imidazolinyl,Pyrazolidinyl,Pyrazolinyl,Piperazinyl,Indolinyl,Isoindolinyl,Quininuclidinyl,Morpholinyl,Oxazole alkyl,BTA base,Benzoisoxazole base,Hydroxyindole base,Benzoxazole quinoline base and isatinoyl (isatinoyl).

As non-limiting examples, the heterocycle by following position keys even is included by the example of the heterocycle of carbon key even：The 2 of pyridine, 3, 4, 5, or 6 upper keys connect, the 3 of pyridazine, 4, 5 or 6 upper keys connect, the 2 of pyrimidine, 4, 5 or 6 upper keys connect, the 2 of pyrazine, 3, 5 or 6 upper keys connect, in furans, tetrahydrofuran, thio-furan, thiophene, pyrroles or the 2 of nafoxidine, 3, 4, or 5 upper keys connect, oxazoles, the 2 of imidazoles or thiazole, 4, or 5 upper keys connect, isoxazoles, pyrazoles, or the 3 of isothiazole, 4 or 5 upper keys connect, key connects on 2 or 3 of aziridine, the 2 of azetidine, 3, or 4 upper keys connect, the 2 of quinoline, 3, 4, 5, 6, 7 or 8 upper keys are even or the 1 of isoquinolin, 3, 4, 5, 6, 7 or 8 upper keys connect.More typically, 2- pyridine radicals, 3- pyridine radicals, 4- pyridine radicals are included by the heterocycle of carbon key thereon even, 5- pyridine radicals, 6- pyridine radicals, 3- pyridazinyls, 4- pyridazinyls, 5- pyridazinyls, 6- pyridazinyls, 2- pyrimidine radicals, 4- pyrimidine radicals, 5- pyrimidine radicals, 6- pyrimidine radicals, 2- pyrazinyls, 3- pyrazinyls, 5- pyrazinyls, 6- pyrazinyls, 2- thiazolyls, 4- thiazolyls or 5- thiazolyls.

It is used as non-limiting examples, the example of the heterocycle of nitrogen key even includes aziridine, azetidine, pyrroles, pyrrolidines, 2- pyrrolins, 3- pyrrolins, imidazoles, imidazolidine, the 2- imidazolines by 1 key even, 3- imidazolines, pyrazoles, pyrazoline, 2- pyrazolines, 3- pyrazolines, piperidines, piperazine, indoles, indoline, 1H- indazoles, pass through the iso-indoles of 2 keys even, or isoindoline, pass through the morpholine of 4 keys even, and carbazole or B-carboline by 9 keys even.More typical nitrogen key, which connects heterocycle, includes 1- '-aziridinos, 1- azetidinyls, 1- pyrrole radicals, 1- imidazole radicals, 1- pyrazolyls and 1- piperidyls.

" alkyl " used herein, unless otherwise indicated, refer to containing just, the C of secondary, uncle or cyclic carbon atoms₁-C₁₂Alkyl.The example includes methyl (Me ,-CH₃), ethyl (Et ,-CH₂CH₃), 1- propyl group (n-Pr, n-propyl ,-CH₂CH₂CH₃), 2- propyl group (i-Pr, isopropyl ,-CH (CH₃)₂), 1- butyl (n-Bu, normal-butyl ,-CH₂CH₂CH₂CH₃), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH₂CH(CH₃)₂), 2- butyl (s-Bu, sec-butyl ,-CH (CH₃)CH₂CH₃), 2- methyl-2-propyls (t-Bu, the tert-butyl group ,-C (CH₃)₃), 1- amyl group (n-pentyl ,-CH₂CH₂CH₂CH₂CH₃), 2- amyl groups (- CH (CH₃)CH₂CH₂CH₃), 3- amyl groups (- CH (CH₂CH₃)₂), 2- methyl -2- butyl (- C (CH₃)₂CH₂CH₃), 3- methyl -2- butyl (- CH (CH₃)CH(CH₃)₂), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), 1- hexyls (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- hexyls (- CH (CH₃)CH₂CH₂CH₂CH₃), 3- hexyls (- CH (CH₂CH₃)(CH₂CH₂CH₃)), 2- methyl -2- amyl groups (- C (CH₃)₂CH₂CH₂CH₃), 3- methyl -2- amyl groups (- CH (CH₃)CH(CH₃)CH₂CH₃), 4- methyl -2- amyl groups (- CH (CH₃)CH₂CH(CH₃)₂), 3- methyl -3- amyl groups (- C (CH₃)(CH₂CH₃)₂), 2- methyl -3- amyl groups (- CH (CH₂CH₃)CH(CH₃)₂), 2,3- dimethyl -2- butyl (- C (CH₃)₂CH(CH₃)₂), 3,3- dimethyl -2- butyl (- CH (CH₃)C(CH₃)₃).Group 2-5 during the example of alkyl group is shown in Table 2,7,9, and shown in 100-399.

The material of the present invention includes following formula (Ⅸ) or the compound of (Ⅹ)：

Or

In a typical implementation, the compound of selecting type Ⅸ.

J₁And J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃, typically R₁Or F, it is more typically H or F, is more typically H.

J₂And J_2aIt independently is H or R₁, typically H.

Z in formula Ⅹ₁One of be W₆, and another is G₁。

Z in formula Ⅹ₂For H or W₆, typically H.

E₁For-(CR₁R₁)_m1W₁。

Typically, R₁For H or C_1-12Alkyl, usually H or C_1-4Or C_5-10Alkyl, more typically for H or containing 1, the alkyl of 2,3,4,5,6,7,8,9,10,11 or 12 carbon atoms, be more typically the H or C selected from methyl, ethyl, n-propyl and isopropyl_1-3Alkyl.Most typical R₁For H.

M1 is integer 0-2, typically 0 or 1, most typically about 0.

M2 is integer 0-1.

M3 is integer 1-3.

W₁For the group comprising acidic hydrogen, the R of the group by protection acidic-group or comprising acidic hydrogen_6cAcid amides, wherein the described group comprising acidic hydrogen in this article refers to produce the group of anion or its corresponding salt or solvate by alkali containing the hydrogen atom that can be removed.The acid or alkaline principle of organic matter is known, and defines W with this₁.It is not detailed herein.But refer to Streitwieser, A. and Heathcock, C.H. " organic chemistry introduction, the second edition " (Macmillan, New York, 1981), p.60-64.Usually, the pK values of acidic-group of the present invention are all lower than water, usually less than pK=10, typically lower than pK=8, and often less than pK=6.They include the acid of tetrazolium and carbon, sulphur, phosphorus and nitrogen, typically carboxylic acid, sulfuric acid, sulfonic acid, sulfinic acid, phosphoric acid and phosphonic acids, and these sour R_6cAcid amides and R_6bEster (R_6cAnd R_6bIt is defined as follows).Typical W₁For-CO₂H,-CO₂R_6a,-OSO₃H,-SO₃H,-SO₂H,-OPO₃H₂,-PO₃(R_6a)₂,-PO₃H₂,-PO₃(H)(R_6a) and-OPO₃(R_6a)₂。E₁Generally W₁, and W₁Typically-CO₂H,-CO₂R_6a,-CO₂R₄Or CO₂R₁, most typically about CO₂R₁₄, wherein R₁₄For just or the secondary C in end₁-C₆Alkyl.

W₁Can also be by protection acidic-group, in this article refer to by commonly used in the art for the above-mentioned acidic-group of one of group for protecting this kind of group protection, and the R that sees below_6aDescribed in.More typically by protection W₁For CO₂R₁,-SO₃R₁,-S(O)OR₁,-P(O)(OR₁)₂,-C(O)NHSO₂R₄, or-SO₂NHC(O)-R₄, wherein R₁And R₄It is defined as above.

Most typically, E₁Selected from-C (O) O (CH₂)_bCH((CH₂)_cCH₃)₂, wherein b=0-4, c=0-4, and b+c=1-4, or selected from following groups：

With

Representational E₁Group list is in 3a-3b.

G in formula Ⅹ₁For-OH, OR_6a, or-(CR₁R₁)_m1W₂, the G in formula Ⅸ₁For-N₃,-CN,-OH,OR_6a,-NO₂Or-(CR₁R₁)_m1W₂, wherein R₁It is defined as above with m1.Generally, the G in formula (Ⅸ)₁For-(CR₁R₁)_m1W₂, and the G in formula (Ⅹ)₁For H.

W in formula (Ⅹ)₂For H or comprising alkaline hetero atom, by the alkaline hetero atom of protection or alkaline heteroatomic R_6bW in the group of acid amides, formula (Ⅸ)₂Comprising hetero atom, to be protected alkaline hetero atom or alkaline heteroatomic R_6bThe group of acid amides.W₂Alkaline hetero atom is generally comprised, this alkaline hetero atom herein refers to not for carbon and (there can be W above by acidic hydrogen₁Described in acid range) protonation atom.The general principle of alkalescence is shown in described in Streitwieser and Heathcock (as described above), and provides the receptible definition of those of ordinary skill in the art to the alkaline hetero atom of term.Typically, alkaline heteroatomic correspondence protonated form used in the compounds of this invention has W above₁PK values in the scope of part.Alkaline hetero atom includes hetero atom common in organic chemistry, and they have the electronics pair of the property such as shared, non-key company, n-type.As example but be not that restricted typical alkaline hetero atom includes the oxygen in such as alcohol, amine, amidine, guanidine, thioether etc. (being usually amine, amidine and guanidine), nitrogen, and sulphur atom.Usual W₂For amino or aminoalkyl (generally C₁-C₆Low alkyl group), such as amino methyl, amino-ethyl or aminopropyl；Amidino groups, or Amidinylalkyl such as amidinomethyl, amidinoethyl, or amidino groups propyl group；Or guanidine radicals, or guanidine alkylation such as guanidine methyl, guanidine ethyl, or guanidine propyl group (in each case, alkyl therein is used for bridging alkali subtituent and carbocyclic ring).More typically, W₂For amino, amidino groups, guanidine radicals, heterocycle, by 1 or 2 amino or the heterocycle of guanidine radicals (being usually 1) substitution, or the C replaced by amino or guanidine radicals₂-C₃Alkyl, or second substituent group by amino and selected from hydroxyl and amino this alkyl.It can be used as W₂Heterocycle generally comprise and contain 1 or 2 hetero atom in 5 or 6 yuan of rings containing N or S, its middle ring.This kind of heterocycle is generally substituted on ring carbon atom.They can be saturation or undersaturated, and can be through low alkyl group (ml=1 or 2) or warp-NR₁- be bonded on parent nucleus cyclohexene.More typically, W₂For-NHR₁,-C(NH)(NH₂),-NR₁-C(NR₁)(NR₁R₃),-NH-C(NH)(NHR₃),-NH-C(NH)(NHR₁),-NH-C(NH)NH₂,-CH(CH₂NHR₁)(CH₂OH),-CH(CH₂NHR₁)(CH₂NHR₁),-CH(NHR₁)-(CR₁R₁)_m2-CH(NHR₁)R₁,-CH(OH)-(CR₁R₁)_m2-CH(NHR₁)R₁, or-CH (NHR₁)-(CR₁R₁)_m2-CH(OH)R₁,-(CR₁R₁)_m2-S-C(NH)NH₂,-N=C(NHR₁)(R₃),-N=C(SR₁)N(R₁)₂,-N(R₁)C(NH)N(R₁) C=N, or-N=C (NHR₁)(R₁)；Wherein each m2 is usually 0, and generally R₁For H and R₃For C (O) N (R₁)₂。

W₂It is optionally by the alkaline hetero atom of protection, that is, in this article refers to by R_6bThe above-mentioned alkaline hetero atom of (such as any such group commonly used in the art) substitution.This kind of group is auspicious to be set forth in Greene described below (in the book drawn herein).Such as this kind of group includes but is not limited to acid amides, carbamate, amido-acetal, imines; enamine, N- alkyl or N- arylphosphinyls, N- alkyl or N- aryl sulfonyl kias or sulfonyl, N- alkyl or N- arylsilyl groups; thioether, thioesters, disulphide, sulfhydryl etc..In some embodiments, protection group R_6bCan in physiological conditions be broken, typically be broken in vivo, so alkaline hetero atom with organic acid or for example naturally occurring amino acid of amino acid or hereafter R_6aDescribed in polypeptide formation acid amides.

Typically, the G in formula (Ⅹ)₁For the G in H, and formula (Ⅸ)₁Selected from following groups：

With

G₁The further example of group is listed in Table 4 below.

T₁For-NR₁W₃,-R₃,-R₅Or heterocycle.Typically, T₁For-NR₁W₃Or heterocycle.Usual T₁It is selected from：

With

Typical T₁Group list is in table 5.

W₃For W₄Or W₅, wherein W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅, or-SO₂W₅.Typically, W₃For-C (O) R₅Or W₅。

R₂It independently is R as defined below₃Or R₄, its condition is each R₄Independently by 0-3 R₃Substituent group；

R₃It independently is F, Cl, Br, I ,-CN, N₃,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R_6b)₂,=O,=S,=N(R₁),=N(R_6b) or W₅。R₃Typically F, Cl ,-CN, N₃,NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-NR₁C(O)R₁,-N(R_6b)C(O)R₁,-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂, or=O.It is more typical to include R_6bR₃Group includes-C (O) N (R_6b)₂Or-C (O) N (R_6b)(R₁).More typically R₃For F, CL ,-CN, N₃,-OR₁,-N(R₁)₂,-SR₁,-C(O)OR₁,-OC(O)R₁, or=O.More typically R₃For F ,-OR₁,-N(R₁)₂, or=O.In this application, "=O " represents the oxygen atom (oxo) with double bond key even, and "=S ", "=N (R_6b) " and "=N (R₁) " represent sulphur and nitrogen analog.

R₄For C₁-C₁₂Alkyl, and C₂-C₁₂Alkynyl or alkenyl.Alkyl R₄Typically there is 1,2,3,4,5,6,7,8,9,10,11, or 12 carbon atoms, and alkenyl and alkynyl R₄It is general that there are 2,3,4,5,6,7,8,9,10,11, or 12 carbon atoms.R₄Usually alkyl (as defined above).Work as R₄During for alkenyl, it is generally vinyl (- CH=CH₂), 1- propyl- 1- alkenyls (- CH=CHCH₃), 1- propyl- 2- alkenyls (- CH₂CH=CH₂), 2- propyl- 1- alkenyls (- C (=CH₂)(CH₃)), 1- but-1-enes base (- CH=CHCH₂CH₃), 1- but-2-ene bases (- CH₂CH=CHCH₃), 1- butyl- 3- alkenyls (- CH₂CH₂CH=CH₂), 2- methyl isophthalic acids -propyl- 1- alkenyls (- CH=C (CH₃)₂), 2- methyl isophthalic acids -propyl- 2- alkenyls (- CH₂C(=CH₂)(CH₃)), 2- but-1-enes base (- C (=CH₂)CH₂CH₃), 2- but-2-enes base (- C (CH₃)=CHCH₃), 2- butyl- 3- alkenyls (- CH (CH₃)CH=CH₂), amyl- 1- the alkenyls (- C=CHCH of 1-₂CH₂CH₃), amyl- 2- the alkenyls (- CHCH=CHCH of 1-₂CH₃), amyl- 3- the alkenyls (- CHCH of 1-₂CH=CHCH₃), amyl- 4- the alkenyls (- CHCH of 1-₂CH₂CH=CH₂), amyl- 1- alkenyls (- the C (=CH of 2-₂)CH₂CH₂CH₃), the amyl- 2- alkenyls (- C (CH of 2-₃)=CH₂CH₂CH₃), the amyl- 3- alkenyls (- CH (CH of 2-₃)CH=CHCH₃), the amyl- 4- alkenyls (- CH (CH of 2-₃)CH₂CH=CH₂) or 3- methyl isophthalic acids-but-2-ene base (- CH₂CH=C(CH₃)₂).More typically R₄Alkenyl contains 2,3 or 4 carbon atoms.Work as R₄During for alkynyl, it is typically acetenyl (- C ≡ CH), 1- propyl- 1- alkynyls (- C ≡ CCH₃), 1- the third 2- alkynyls (- CH₂C ≡ CH), 1- butyl- 1- alkynyls (- C ≡ CCH₂CH₃), 1- butyl- 2- alkynyls (- CH₂C≡CCH₃), 1- butyl- 3- alkynyls (- CH₂CH₂C ≡ CH), 2- butyl- 3- alkynyls (CH (CH₃) C ≡ CH), the amyl- 1- alkynyls of 1- (- C ≡ CCH₂CH₂CH₃), amyl- 2- the alkynyls (- CH of 1-₂C≡CCH₂CH₃), amyl- 3- the alkynyls (- CH of 1-₂CH₂C≡CCH₃) or amyl- 4- the alkynyls (- CH of 1-₂CH₂CH₂C≡CH).More typically, R₄Alkynyl has 2,3 or 4 carbon atoms.

R₅For R₄(being as defined above), or by 0-3 R₃The R of substituent group₄.Typical R₅For the C replaced by 0-3 fluorine atom₁-C₄Alkyl.

R_5aIt independently is C₁-C₁₂Alkylidene, C₂-C₁₂Alkylene group, or C₂-C₁₂Any one in alkynylene, alkylidene, alkylene group or alkynylene is by 0-3 R₃Substituent group.As above R₄Described in, R_5aWith 1,2,3,4,5,6,7,8,9,10,11,12 carbon atom (when for alkylidene) and 2,3,4,5,6,7,8,9,10,11, or twelve carbon atom (when for alkylene group or alkynylene).Each typical R₄Group is typical R_5aGroup, its condition is the R₄A hydrogen atom in group is removed and formed the open valency of carbon atom, passes through the carbon atom Article 2 key and R_5aConnection.

R₁₄For just or the secondary C in end₁-C₆Alkyl.

W₅For carbocyclic ring or heterocycle, its condition is each R₅Independently by 0-3 R₂Group is replaced.W₅Carbocyclic ring and T₁And W₅Heterocycle is stable chemical constitution.At a temperature of -78 DEG C to 200 DEG C, these structures can be isolated with appropriate yield from reactant mixture, and with adequate purity.Each W₅Independently by 0-3 R₂Substituent group.Typically, T₁And W₅It is to include monocyclic or bicyclic carbocyclic or miscellaneous ring filling, insatiable hunger and/or aromatic rings, more typically, T₁Or W₅With 3-10 annular atom, more typically, with 3-7 annular atom, and usually 3-6 annular atom.T₁With W₅Ring be saturation when containing 3 annular atoms, be saturation or monounsaturated when containing 4 annular atoms, be that saturation or single-or two are undersaturated when containing 5 annular atoms, be saturation when containing 6 annular atoms, single-or two unsaturated, or armaticity.Undersaturated W₅Ring includes inner and outer unsaturated (wherein in outside coupling collar atom).

Work as W₅During for carbocyclic ring, monocyclic typically containing 3-7 carbon or bicyclic containing 7-12 carbon.More typical ground W₅Monocycle carbocyclic ring has 3-6 annular atom, more typically containing 5 or 6 annular atoms.W₅Bicyclic carbocycle typically containing 7-12 annular atom, is arranged in two rings [4,5], [5,5], [5,6] or [6,6] system, more typically containing 9 or 10 annular atoms for being arranged in two rings [5,6] or [6,6] system.The example includes cyclopropyl, cyclobutyl, cyclopenta, the amyl- 1- alkenyls of 1- rings, the amyl- 2- alkenyls of 1- rings, the amyl- 3- alkenyls of 1- rings, cyclohexyl, 1- hexamethylene -1- alkenyls, 1- hexamethylene -2- alkenyls, 1- hexamethylene -3- alkenyls, phenyl, spiryl and naphthyl.

T₁Or W₅Heterocycle is typically monocyclic or containing 7-10 annular atom (4-9 carbon atom and the 1-3 hetero atoms for being selected from N, O, P, and S) two rings with 3-7 annular atom (2-6 carbon atom and the 1-3 hetero atoms for being selected from N, O, P and S).More typically, T₁And W₅Single heterocycle has 3-6 annular atom (2-5 carbon atom and the 1-2 hetero atoms for being selected from N, O and S), more typically containing 5 or 6 annular atoms (3-5 carbon atom and the 1-2 hetero atoms for being selected from N and S).T₁And W₅Double heterocycles have 7-10 annular atom (6-9 carbon atom and the 1-2 hetero atoms for being selected from N, O and S), are arranged in two rings [4,5], [5,5], [5,, or [6,6] system 6], more typically containing 9 or 10 annular atoms (8-9 carbon atom and the 1-2 hetero atoms for being selected from N and S), it is arranged in two rings [5,6] or [6,6] system.

Typical T₁And W₅Heterocycle is selected from pyridine radicals, pyridazinyl, pyrimidine radicals, pyrazinyl, cyanuro , oxazolyls, imidazole radicals, thiazolyl , isoxazolyls, pyrazolyl, isothiazolyl, furyl, thio-furan base, thienyl, or pyrrole radicals.

More typical is heterocycle T₁And W₅Enter line unit by its carbon atom or nitrogen-atoms to connect.More typically, T₁Heterocycle is bonded in the cyclohexene ring of the compounds of this invention by its nitrogen-atoms with the covalent stablized, W₅Heterocycle is connected in the cyclohexene ring of the compounds of this invention by its carbon or nitrogen-atoms through stable covalent bond key.Stable covalent bond refers to above-mentioned chemically stable structure.

W₅It is optionally selected from：

With

W₆For-R₅,-W₅,-R_5aW₅,-C(O)OR_6a,-C(O)R_6c,-C(O)N(R_6b)₂,-C(NR_6b)(N(R_6b)₂),-C(N(R_6b)(N(H)(R_6b)),-C(N(H)(N(R_6b)₂),-C(S)N(R_6b)₂, or-C (O) R₂, typical W₆For-R₅,-W₅, or-R_5aW₅；In some embodiments, W₆For R₁,-C(O)-R₁,-CHR₁W₇,-CH(R₁)_aW₇,-CH(W₇)₂, (wherein W₇For unit price, a is 0 or 1, but works as W₇0) or-C (O) W a is during for divalence₇.In certain embodiments, W₆For-CHR₁W₇Or-C (O) W₇, or W₆For-(CH₂)_m1CH((CH₂)_m3R₃)₂；-(CH₂)_m1C((CH₂)_m3R₃)₃；-(CH₂)_m1CH((CH₂)_m3R_5aW₅)₂；-(CH₂)_m1CH((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)；-(CH₂)_m1C((CH₂)_m3R₃)₂(CH₂)_m3R_5aW₅)；-(CH₂)_m1C((CH₂)_m3R_5aW₅)₃Or-(CH₂)_m1C((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)₂；And m therein₃For integer 1-3.

W₇For R₃Or R₅, but typically by 0-3 R₃The C that group is replaced₁-C₁₂Alkyl, the latter (i.e. R₃) it is selected generally from-NR₁(R_6b),-N(R_6b)₂,-OR_6a, or SR_6a.More typically, W₇For-OR₁Or by OR₁Substituted C₃-C₁₂Alkyl.

Usually, W₆For R₁-,-CHR₁W₇,

Representational W₆Group is listed in Table 2 below.

One embodiment of the present invention includes following formula: compound：Or

Wherein each R₁And R_6bTypically H, and W₂It is typically chosen from：

With And W₆For one of following groups：

With

Wherein R₇For H ,-CH₃,-CH₂CH₃,-CH₂CH₂CH₃,-OCH₃,-OAc(-O-C(O)CH₃),-OH,-NH₂, or-SH, typically H ,-CH₃Or-CH₂CH₃。

Another embodiment of the present invention is related to formula (XX) or (XX a) compound and its salt, solvate, the enantiomer split and the diastereomer of purifying：Wherein

A₃For N, N (O) or N (S)；

Z₃For H, W₆,G₁Or R_3a；

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂Or-(CR₁R₁)_m1W₂；

G₂For G₁Or-X₁W₆；

T₁For-NR₁W₃Or heterocycle；

J₁For R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂For H or R₁；

Work as X₁For Lian Jianshi, J₃For J₁；And work as X₁For-O- ,-N (H)-,-N (W₆)-,-N(OH)-,-N(OW₆)-,-N(NH₂)-,-N(N(H)(W₆))-,-N(N(W₆)₂)-,-N(H)N(W₆)-,-S- ,-SO-, or-SO₂- when, J₃It is then J₂；

R₁It independently is H or C₁-C₁₂Alkyl；

R₃It independently is F, Cl, Br, I ,-CN, N₃,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R_6b)₂),=O,=S,=N(R₁),=N(R_6b) or W₅；

R_3aIt independently is-CN, N₃,-NO,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O))R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂) or-N (R_6b)C(N(R_6b))(N(R_6b)₂)；

R₄It independently is C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, or C₂-C₁₂Alkynyl；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Substituent group；

R_5aIt independently is C₁-C₁₂Alkylidene, C₂-C₁₂Alkylene group, or C_2-12Any one in alkynylene, these alkylidenes, alkylene group or alkynylene is by 0-3 R₃Substituent group；

R_6aIt independently is H or into ether or into ester group；

R_6cIt independently is H or the residue containing amino-compound；

W₂For comprising alkaline hetero atom or by the alkaline heteroatomic group of protection, or alkaline heteroatomic R_6bAcid amides；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

W₆For-R₅,-W₅,-R_5aW₅,-C(O)OR_6a,-C(O)R_6c,-C(O)N(R_6b)₂,-C(NR_6b)(N(R_6b)₂),-C(NR_6b)(N(H)(R_6b)),-C(N(H)(N(R_6b)₂),-C(S)N(R_6b)₂, or-C (O) R₂；

X₁For even key ,-O- ,-N (H)-,-N (W₆)-,-N(OH)-,-N(OW₆)-,-N(NH₂)-,-N(N(H)(W₆)),-N(N(W₆)₂)-,-N(H)N(W₆)-,-S- ,-SO-, or-SO₂-；With

Each m₁It independently is integer 0-2；But condition is, wherein not including following formula (XX) compound：Wherein A₃For N, J₁,J₂,J_2aAnd J₃Respectively H, and T₁For-N (H) (Ac), and：

E₁For-CO₂H or-CO₂CH₃,

G₂For-OBoc, and

Z₃For Boc；

E₁For-CO₂H or-CO₂CH₃,

G₂For-OH, and

Z₃For H；

E₁For-CO₂H,-CO₂CH₃Or-CO₂Bn

G₂For-OH, and

Z₃For Boc；

E₁For-CONH₂,

G₂For-OH, and

Z₃For Boc or H；

E₁For-CO₂H or-CO₂CH₃,

G₂For OH, and

Z₃For Bn；Or

E₁For-CO₂H or-CO₂CH₃,

G₂For-OH, and

Z₃For-CH₂CH(OH)CH₂(OH)；Wherein Bn is benzyl, and Boc is-CO₂C(CH₃)₃；Wherein enter-walk exclusion following formula (VII) or (VIII) compound：

Wherein

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂, or-(CR₁R₁)_m1W₂；

T₁For-NR₁W₃, heterocycle or and G₁The group with following structures is formed together：

U₁For-X₁W₆；

J₁And J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂And J_2aIt independently is H or R₁；

R₁It independently is H or C₁-C₁₂Alkyl；

R₃It independently is F, Cl, Br, I ,-CN, N₃,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R_6b)₂),=O,=S,=N(R₁) or=N (R_6b)；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Substituent group；

R_5aIt independently is C₁-C₁₂Alkylidene, C₂-C₁₂Alkylene group, or C_2-12Any one in alkynylene, these alkylidenes, alkylene group or alkynylene is by 0-3 R₃Group is replaced；

R_6aIt independently is H or into ether or into ester group；

R_6cIt independently is H or the residue containing amino-compound；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

X₁For even key ,-O- ,-N (H)-,-N (W₆)-,-S- ,-SO-, or-SO₂-；With

Each m₁It independently is integer 0-2.

Typically A₃For N or N (O), more typical A₃For N.

In a typical implementation, Z₃With G₂One of be G₁Or R_3a, and another is W₆Or-X₁W₆.It is more typical to be, Z₃For W₆Or R_3aAnd G₂For G₁Or-X₁W₆.More typically, Z₃For W₆And G₂For G₁；Or Z₃For R_3aAnd G₂For-X₁W₆。

Work as X₁For Lian Jianshi, J₃For J₁, and work as X₁For-O- ,-N (H)-,-N (W₆)-,-N(OH)-,-N(OW₆)-,-N(NH₂)-,-N(N(H)(W₆))-,-N(N(W₆)₂-,-N(H)N(W₆)-,-S- ,-SO-, or-SO₂- when, J₃It is then J₂.Above-mentioned J₁And J₂Representative instance also be J₃Representative instance.

One embodiment of the present invention includes formula (Ⅹ Ⅺ) or (Ⅹ Ⅺ a) compound：Embodiment of the present invention also includes formula (Ⅹ Ⅻ) or (Ⅹ Ⅻ a) compound：

One embodiment of the invention includes formula (XX III) or (XX III a) compound：

Embodiment of the present invention includes formula (XX IV) or (XX IV a) compound：One of Z₁For W, and another Z₁It is then G₁；And Z₂For H or W₆.Typically, Z₂For H.

Embodiment of the present invention includes formula (XX V) or (XX V a) compound：

Embodiment of the present invention includes formula (XX VI) or (XX VI a) compound：

Embodiment of the present invention includes formula (XX VII) or (XX VII a) compound：

Embodiment of the present invention includes formula (XX VIII) or (XX VIII a) compound：

Embodiment of the present invention includes formula (XX Ⅸ) or (XX Ⅸ a) compound：

Embodiment of the present invention includes formula (XXX) or (XXX a) compound：

It is important that, it should be appreciated that the representative instance with the formula (XXX) described in accessory claim and (XXX a) is also respectively formula (Ⅹ Ⅺ)-(XXX) being described just above and (Ⅹ Ⅺ a)-(XXX a) example above.

Group R_6aAnd R_6bFor insignificant functional group, therefore it can change in relative broad range.When they are not H, its effect is used as female medicine intermediate.It is not intended that it does not have bioactivity.On the contrary, the major function of these groups is that female medicine is changed into prodrug, by converting prodrug in vivo, so as to disengage female medicine.Because active prodrugs can more effectively be absorbed than female medicine, thus actually these prodrugs have the effect for being better than female medicine in vivo.When not being hydrogen, R_6aAnd R_6bStill it can be either removed (under prodrug situation) in vivo (in the case of chemical intermediate) in vitro.For chemical intermediate, the preceding functionality product (such as alcohol) of gained whether be it is physiologically acceptable be not particularly critical, if but in general the product be pharmacy it is harmless it is certain more preferably.

R_6aFor H or into ether or into ester group." into ether group " refers to can be in parent molecule and with the group that stable covalent bond is formed between following formula group：

&Integral; - O - V_{a} {(V_{1})}_{3},

&Integral; - O - V_{a} (V_{1}) (V_{2})

&Integral; - O - V_{a} (V_{3})

&Integral; - O - V_{b} {(V_{1})}_{2}

&Integral; - O - V_{b} (V_{2})

, or

&Integral; - O - V_{c} (V_{1})

Wherein V_aFor tetrad, C and Si are typically chosen from；V_bFor triad, B, Al, N, and P are typically chosen from, more typically selected from N and P；V_cFor bivalent, O, S, and Se are typically chosen from, is more typically S；V₁To be connected in V by stable covalent single bond key_a,V_bOr V_cGroup, typical V₁For W₆Group, more typical V₁For H, R₂,W₅, or-R_5aW₅, it is more typically H or R₂；V₂To be connected in V with stable double covalent bonds key_aOr V_bGroup, condition is V₂It is not=O ,=S or=N-, typical V₂For=C (V₁)₂, wherein V₁As described above；V₃To be connected in V with stable covalent three keys key_aGroup, typical V₃For ≡ C (V₁), wherein V₁It is as defined above.

" into ester group " refers to that the group of stable covalent bond can be formed between parent molecule and following formula group：

&Integral; - O - V_{a} (V_{1}) (V_{4}), &Integral; - O - V_{b} (V_{4}), &Integral; - O - V_{d} {(V_{1})}_{2} (V_{4}),

&Integral; - O - V_{d} {(V_{4})}_{2}, &Integral; - O - V_{e} {(V_{1})}_{3} (V_{4})

, or

&Integral; - O - V_{e} (V_{1}) {(V_{4})}_{2}

Wherein V_a,V_b, and V₁It is as defined above；V_dFor pentavalent atom, P and N are typically chosen from；V_eFor hexad, typically S；And V₄To be connected in V with stable double covalent bonds key_a,V_b,V_dOr V_eGroup, condition is at least one V₄For=O ,=S or=N-V₁, when not for=O ,=S or=N- when, typical V₄For=C (V₁)₂, wherein V₁It is as defined above.

The protection group of-OH functional groups (whether hydroxyl, sour or other functional groups) for " into ether or into ester group " instantiation.

Especially interesting-OH functional groups be can serve as in synthesis flow as described herein protection group into ether or into ester group.However, it will be apparent to those skilled in the art that the protection group of some hydroxyls and sulfydryl is not into ether group nor into ester group, and including R below_6cDescribed in acid amides in.R_6cHydroxyl or sulfydryl, parent molecule hydrolysis generation hydroxyl or sulfydryl can be protected.

In being acted on into ester, R_6aTypically key is connected on any acidic-group, such as, but not limited to-CO₂H or-C (S) OH groups, so as to form-CO₂R_6a.For example, R_6aIt can derive from a large amount of ester groups in WO 95/07920.

R_6aExample include：

C₃-C₁₂Heterocycle (as described above) or C₆-C₁₂Aryl.These aryl are optionally polycyclic or monocyclic.The example includes phenyl, spiryl, 2- and 3- pyrrole radicals, 2- and 3- thienyls, 2- and 4- imidazole radicals, 2-, 4- and 5- oxazolyls, 3- and 4- isoxazolyls, 2-, 4- and 5- thiazolyl, 3-, 4- and 5- isothiazolyl, 3- and 4- pyrazolyls, 1-, 2-, 3- and 4- pyridine radicals, and 1-, 2-, 4- and 5- pyrimidine radicals.

The C replaced by following groups₃-C₁₂Heterocycle or C₆-C₁₂Aryl：Halogen, R₁,R₁-O-C₁-C₁₂Alkylidene, C₁-C₁₂Alkoxy, CN, NO₂, OH, carboxyl, carboxyl ester, mercaptan, thioesters, C₁-C₁₂Haloalkyl (1-6 halogen atom), C₂-C₁₂Alkenyl or C₂-C₁₂Alkynyl.This kind of group includes 2-, 3- and 4- alkoxyl phenyl (C₁-C₁₂Alkyl), 2-, 3- and 4- methoxyphenyls, 2-, 3- and 4- ethoxyl phenenyls, 2,3-, 2,4-, 2,5-, 2,6-, 3,4-, with 3,5- diethoxy phenyl, 2- and 3- carbethoxyl group -4- hydroxy phenyls, 2- and 3- ethyoxyl 4- hydroxy phenyls, 2- and 3- ethyoxyl -5- hydroxy phenyls, 2- and 3- ethyoxyl -6- hydroxy phenyls, 2-, 3- and 4-O- acetylphenyls, 2-, 3- and 4- dimethylamino phenyls, 2-, 3- and 4- methyl mercapto phenyl, 2-, 3- and 4- halogenophenyls (including 2-, 3- and 4- fluorophenyls and 2-, 3- and 4- chlorphenyls), 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- 3,5-dimethylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and double (carboxy ethyl) phenyl of 3,5-, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- Dimethoxyphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- and 3,5- dihalogenated phenyl (including 2,4- difluorophenyl and 3,5- difluorophenyl), 2-, 3- and 4- haloalkylphenyls (1-5 halogen atom, C₁-C₁₂Alkyl, including 4- trifluoromethyls), 2-, 3- and 4- cyano-phenyl, 2-, 3- and 4- nitrobenzophenone, 2-, 3- and 4- haloalkyl benzyl (1-5 halogen atom, C₁-C₁₂Alkyl, including 4- trifluoromethyl benzyls and 2-, 3- and 4- trichloromethyl phenyl and 2-, 3- and 4- trichloromethyl phenyl), 4-N- methyl piperidine bases, 3-N- methyl piperidine bases, 1- ethyl piperazidine bases, benzyl, alkylated salicylamide base phenyl (C₁-C₄Alkyl, including 2-, 3- and 4- ethyl salicyl phenyl), 2-, 3- and 4- acetylphenyl, 1,8- dihydroxy naphthyl (- C₁₀H₆- OH) and aryloxyethyl [C₆-C₉Aryl (including Phenoxyethyl)], 2,2 '-dihydroxybiphenyl base, 2-, 3- and 4-N, N- dialkyl amido phenol ,-C₆H₁₄CH₂-N(CH₃)₂, trimethoxy benzyl, triethoxy benzyl, 2- Alkylpyridyls (C_1-4Alkyl)；The C of 2- carboxyl phenyls₄-C₈Ester；And C₁-C₄Alkylidene-C₃-C₆Aryl (including benzyl ,-CH₂- pyrrole radicals ,-CH₂- thienyl ,-CH₂- imidazole radicals ,-CH₂- oxazolyls ,-CH₂- isoxazolyls ,-CH₂- thiazolyl ,-CH₂- isothiazolyl ,-CH₂- pyrazolyl ,-CH₂- pyridine radicals and-CH₂- pyrimidine radicals), its aryl moiety is selected from halogen, C by 3-5 halogen atom or 1-2₁-C₁₂Alkoxy (including methoxyl group and ethyoxyl), cyano group, nitro, OH, C₁-C₁₂Haloalkyl (1-6 halogen atom；Including-CH₂CCl₃), C₁-C₁₂Alkyl (including methyl and ethyl), C₂-C₁₂Alkenyl or C₂-C₁₂The atom or substituent group of alkynyl；

Alkoxyethyl [C₁-C₆Alkyl, including-CH₂-CH₂-O-CH₃(methoxy ethyl)]；

By any group described in aryl moiety above, particularly OH or the alkyl (including-CH replaced by 1-3 halogen atom₃,-CH(CH₃)₂,-C(CH₃)₃,-CH₂CH₃,-(CH₂)₂CH₃,-(CH₂)₃CH₃,-(CH₂)₄CH₃,-(CH₂)₅CH₃,-CH₂CH₂F,-CH₂CH₂Cl,-CH₂CF₃, and-CH₂CCl₃)

- N-2- propylmorpholin generations, 2,3- dihydro -6- hydroxyl indenes, sesamol, catechol monoesters,-CH₂-C(O)-N(R¹)₂,-CH₂-S(O)(R¹),-CH₂-S(O)₂(R¹),-CH₂-CH(OC(O)CH₂R¹)-CH₂(OC(O)CH₂R¹), cholesteryl, enolpyruvate (HOOC-C (=CH₂) -), glycerine；

5 or 6 carbon monose, disaccharide or oligosaccharides (3-9 monosaccharide residue)；

(aliphatic acid wherein comprising glyceride lipid is generally naturally occurring saturation or unsaturation C to α-D- β-diglyceride that triglycerides is such as connected on parent compound acyl group by the glyceryl oxygen atom key of triglycerides_6-26,C_6-18Or C_6-10Aliphatic acid, such as linoleic acid, laurate, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, the aliphatic acid such as leukotrienes)；

The phosphatide of carboxyl is connected in by the phosphate portion key of phosphatide；

2- benzos [c] furanonyl is (see Clayton et al. chemical antimicrobial (Antimicrob.Agents Chemo) 5 (6):Fig. 1 in 67O-671 [1974])；

Cyclic carbonate such as (5-Rd-2- oxos-1,3- Dioxol-4 -yl) methyl ester (Sakamoto et al., chemicals journal (Chem.Pharm.Bull.) 32 (6):2241-2248 [1984], wherein Rd are R₁,R₄Or aryl；With

Oh group in the compounds of this invention is optionally replaced by one of group III, IV or V described in WO 94/21604, or isopropyl.

As further embodiment ,-C (O) O- and-P (O) (O-) can be for example connected in via oxygen key by being listed in Table A₂The R of group_6aThe example of ester moiety.In addition several R be also list_6cAmidate, its direct key is connected in-C (O)-or-P (O)₂.Structure 1-5,8-10 and 16,17,19-22 ester is by making the compound as described herein via free hydroxyl group and corresponding halide (such as chloride or acyl chlorides) and N, N- dicyclohexyl-N- morpholines carbodiimide (or other alkali such as DBN, triethylamine, CsCO₃, N, accelerine etc.) react and synthesize in DMF (or other solvents such as acetonitrile or 1-METHYLPYRROLIDONE).Work as W₁During for phosphonate ester, structure 5-7,11,12,21, and 23-26 ester passes through alcohol or alkoxide (or corresponding amine, in the case of such as 13,14 and 15 etc compound) react and synthesize with monochloro phosphonate ester or dichloro phosphonate ester (or other reactive phosphonates).

Table A 1.-CH₂-C(O)-N(R₁)₂10.-CH₂-O-C(O)-C(CH₃)₃2.-CH₂-S(O)(R₁) 11.-CH₂-CCl₃3.-CH₂-S(O)₂(R₁) 12.-C₆H₅4.-CH₂-O-C(O)-CH₂-C₆H₅13.-NH-CH₂-C(O)O-CH₂CH₃5.3- cholesteryl 14.-N (CH₃)-CH₂-C(O)O-CH₂CH₃6.3- pyridine radicals 15.-NHR₁7.N- ethyl morpholines are for 16.-CH₂-O-C(O)-C₁₀H₁₅8.-CH₂-O-C(O)-C₆H₅17.-CH₂-O-C(O)-CH(CH₃)₂9.-CH₂-O-C(O)-CH₂CH₃18.-CH₂-C#H(OC(O)CH₂R₁)-CH₂-

-(OC(O)CH₂R₁)

#- chiral centres are (R), (S) or racemic modification.

Other esters being applicable herein are recorded in EP 632,048.

R_6aAlso include " dibasic acid esters " formation functional group, such as：-CH₂OC(O)OCH₃,

-CH₂SCOCH₃,-CH₂OCON(CH₃)₂, or structure-CH (R₁Or W₅)O((CO)R₃₇Or-CH (R₁Or W₅)((CO)OR₃₈) alkyl-or aryl-acyloxyalkyl radicals (key is connected on the oxygen of acidic-group), wherein R₃₇And R₃₈For alkyl, aryl, or alkaryl (referring to USP 4,968,788).Usual R₃₇And R₃₈For the big group of steric hindrance such as branched alkyl, orthosubstituted aryl, meta substituted aryl, or its combination, including n-, sec-, iso and tertiary C_1-6Alkyl.The example has oxy acid methyl neopentyl.These groups are particularly in oral prodrugs.This kind of useful R_6aThe example of group includes alkyl acyloxy methyl ester and its derivative, including-CH (CH₂CH₂OCH₃)OC(O)C(CH₃)₃,

-CH₂OC(O)C₁₀H₁₅,-CH₂OC(O)C(CH₃)₃,-CH(CH₂OCH₃)OC(C)C(CH₃)₃,-CH(CH(CH₃)₂)OC(O)C(CH₃)₃,-CH₂OC(O)CH₂CH(CH₃)₂,-CH₂OC(O)C₆H₁₁,-CH₂OC(O)C₆H₅,-CH₂OC(O)C₁₀H₁₅,-CH₂OC(O)CH₂CH₃,-CH₂OC(O)CH(CH₃)₂,-CH₂OC(O)C(CH₃)₃With-CH₂OC(O)CH₂C₆H₅。

In view of prodrug purpose, selected ester is generally those for being previously used for antibiotic medicine, particularly cyclic carbonate, dibasic acid esters, or 2- benzos [c] furanone base ester, aryl ester or Arrcostab.

It is as described herein, R_6a,R_6cAnd R_6bGroup thus can be used as protection group (PRT) optionally for preventing in synthesis step in the side reaction by shield group in synthesis.Determine which group is to be protected and property of PRT is usual must be depending on the reaction chemistry (such as acid, alkalescence, oxidisability, reproducibility or other conditions) of confrontation to be protected and predetermined compound direction depending on.If compound is replaced by multiple PRT, these PRT groups are not required certain identical (but typically different).Usually, PRT will be used for protecting carboxyl, hydroxyl or amino.The order that deprotection obtains free group depends on predetermined compound direction and involved reaction condition, and can be carried out with any order determined by those skilled in the art.

A large amount of R have been recorded in following documents_6aHydroxyl protecting group and R_6cAcid amides formation group and the reaction of corresponding chemical cracking：" protection group in organic chemistry ", Theodora W.Greene (JohnWiley ＆ Sons, Inc., New York, 1991, ISBN 0-471-62301-6) (" Greene ").Also reference can be made to Kocienski, Philip J. " protection group " (Georg ThiemeVerlag Stuttgart, New York, 1994), entire contents are incorporated herein by reference.Particularly chapter 1, protection group：Summary, p.1-20, chapter 2, hydroxyl protecting group, p.21-94, and chapter 3, glycerol protection base, p.95-117, and chapter 4, carboxyl-protecting group, p.118-154, and chapter 5, carbonyl-protection base, p.155-184.For R_6aCarboxylic acid, phosphonic acids, phosphonate ester, sulfonic acid and W₁Other protection groups of acid see below described Greene parts.These groups for example include but is not limited to ester, acid amides, hydrazides etc..

In some embodiments, R_6aBy the ester that protection acidic-group is the acidic-group, and R_6aFor the residue of hydroxyl function thing.In other embodiments, using R_6cAmino-compound protects acid functional group.Suitable hydroxyl or the residue containing amido functional group are shown in upper described or see WO95/07920.Particularly importantly amino acid, amino-acid ester, polypeptide or fragrant and mellow residue.The amino acid residue of typical amino acid, polypeptide and carboxyl esterification is recorded in group L1 or L2 in 11-18 pages of WO95/07920 and its related content.The clearly teaching amidatioon of phosphonic acids in WO95/07920, it is to be understood that, these amidates can be formed by the amino acid residue described in any acidic group and WO95/07920 as described herein.

For protecting W₁The typical R of acidic functionality_6aEster is also recorded in WO95/07920, it should also be understood that the phosphonate ester identical ester that can be also formed in being disclosed with WO95/07920 with this paper acidic-group.Typical ester group is at least described in p89-93 (R in WO95/07920³¹Or R³⁵Under), in p105 table and p.21-23 (it is used as R).The especially interesting ester for following groups：Unsubstituted aryl such as phenyl or aralkyl such as benzyl, or hydroxyl-, halogen-, alkoxy-, the aryl or alkylaryl of carboxyl-and/or the substitution of Arrcostab carboxyl, especially phenyl, O-ethoxyl base, or C₁-C₄Arrcostab carboxyl phenyl (salicylic acid C₁-C₁₂Arrcostab).

By protection acidic-group W₁(particularly when using the ester or acid amides in WO95/07920) can be used as oral prodrugs.But W₁Acidic-group, which it is not absolutely required to protection, just can be such that the compounds of this invention is effectively applied by oral route.When whole body or when orally administering with blocking group, the particularly the compounds of this invention of amino acid amide or substitution and unsubstituting aromatic yl ester, it is particular enable to hydrolytic cleavage in vivo and produces free acid.

One or more acid hydroxy groups can be protected.If protecting more than one acid hydroxy group group, identical or different protection group can be used, such as ester can be similar and different, or the acid amides and ester of mixing can be used.

Typical R_6aHydroxyl protecting group is recorded in Greene (p.14-118), including ether (methyl)；Substituent methyl ether (methoxy, methylthiomethyl, tertiary butylthio methyl, (phenyldimethylsilyl) methoxy, benzyloxymethyl, p- Methoxybenzyloxymethyl, (4- methoxyphenoxies) methyl, o-methoxyphenol methyl, t-butoxymethyl, 4- amylene epoxide methyl, silanyloxymethyl, 2- methoxvethoxvmethvls, 2, 2, 2- tri-chloroethoxy ylmethyls, double (2- chloroethoxies) methyl, 2- (trimethyl silyl) ethoxyl methyl, THP trtrahydropyranyl, 3- bromine THP trtrahydropyranyls, tetrahydro thiapyran base, 1- methoxycyclohexyls, 4- methoxyl group THP trtrahydropyranyls, 4- methoxyl group tetrahydro thiapyran bases, S, S- titanium dioxide 4- methoxyl group tetrahydro thiapyran bases, 1- [(the chloro- 4- methyl of 2-) phenyl] -4- methoxy piperide -4- bases, 35, 1, 4- dioxane -2- bases, tetrahydrofuran base, tetrahydrochysene thio-furan base, 2, 3, 3a, 4, 5, 6, 7, 7a- octahydros -7, 8, 8- trimethyls -4, 7- methylenebenzofuran -2- bases))；Replace ethylether (1- ethoxyethyl groups, 1- (2- chloroethoxies) ethyl, 1- methyl isophthalic acids-methoxy ethyl, 1- methyl isophthalic acids-Benzyloxyethyl, 1- methyl isophthalic acids-benzyloxy -2- fluoro ethyls, 2,2,2- trichloroethyls, 2- trimethylsilyethyls, 2- (phenylseleno) ethyl, the tert-butyl group, pi-allyl, p- chlorphenyl, p- methoxyphenyl, 2,4- dinitrophenyls, benzyl)；Substituted benzylic ether (p- methoxy-benzyl, 3, 4- dimethoxy-benzyls, o- nitrobenzyl, p- nitrobenzyl, p- halogeno-benzyl, 2, 6- dichloro benzyls, p- cyanobenzyls, p- phenylbenzyl, 2- and 4- picolyls, 3- methyl -2- picolyl N-oxides, diphenyl methyl, p, p '-dinitro benzhydryl, 5- dibenzocycloheptyls, trityl group, Alpha-Naphthyl benzhydryl, p- methyoxyphenyldiphenylmethyl base, two (p- methoxyphenyl) phenyl methyls, three (p- methoxyphenyl) methyl, 4- (4 '-Bromophenacyl epoxide) phenyl diphenyl methyl, 4, 4 ', 4 "-three (4, the chlorophthalimido phenyl of 5- bis-) methyl, 4, 4 ', 4 "-three (acetyl propionyl phenyl) methyl, 4, 4 ', 4 "-three (benzoyloxyphenyl) methyl, 3- (imidazoles -1- Ji Jia) double (4 ', 4 "-Dimethoxyphenyl) methyl, 1, double (4- methoxyphenyls) -1 '-pyrenylmethies of 1-, 9- anthryls, 9- (9- phenyl) xanthyl, 9- (9- phenyl -10- oxos) anthryl, 1, 3- benzo dithiolane -2- bases, benzisothia oxazolyl S, S- titanium dioxides)；Silyl ether (trimethyl silyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethyl isopropyl silyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzyl silicyl, three-p-xylene base silicyl, triphenyl-silyl, diphenylmethylsilyl, tert-butyl group butylmethoxyphenylsilyl)；Ester (formic acid esters, benzoyl formate, acetic acid esters, chloracetate, dichloroacetic acid ester, trichloroacetic esters, trifluoro-acetate, methoxyacetic acid ester, triphenylmethoxy acetic acid esters, benzyloxy yl acetate, p- tomatotone ester, p- polyphenyl yl acetate, 3- phenylpropionic acid esters, LA ester (levulinate), 4, 4- (ethylene sulfenyl) valerate, pivalate, adamantate, crotonates, 4- methoxyl group crotonates, benzoic ether, p- phenylbenzoate, 2, 4, 6- trimethylbenzoic acids ester (Mesitoate))；Carbonic ester (methyl, 9- fluorenyl methyls, ethyl, 2; 2,2- trichloroethyls, 2- (trimethyl silyl) ethyl, 2- (phenyl sulfonyl) ethyl; 2- (triphenylphosphine oxide group) ethyl, isobutyl group, vinyl, pi-allyl; p- nitrobenzophenone, benzyl, p- methoxy-benzyl, 3; 4- dimethoxy-benzyls, o-nitrophenyl, p- nitrobenzophenone; S- benzyl sulfocarbonates, 4- ethyoxyl -1- naphthyls, dithiocarbonic acids methyl esters)；With group (the 2- iodobenzoic acid esters for assisting fracture property, 4- azido butyrates, 4- nitro-4-methyl penetenoic acids, o- (two bromomethyls) benzoic ether, 2- formylbenzene sulfonates, 2- (methylthiomethoxy) ethyl carbonate ester, 4- (methylthiomethoxy) butyrate, 2- (methylthiomethoxymethyl) benzoic ether), other esters (2, the chloro- 4- methylphenoxyacetates of 6- bis-, 2, the chloro- 4- (1 of 6- bis-, 1, 3, 3- tetramethyl butyls) phenoxyacetic acid ester, 2, 4- double (1, 1- dimethyl propyls) phenoxyacetic acid ester, chloro diphenyl acetic acid ester, isobutyrate, monosuccinic acid ester, (E) -2- methyl-2-butenes acid esters (Tigloate), O- (methoxycarbonyl) benzoic ether, p- many benzoic ethers, α-naphthoicacid ester, nitrate, N, N, N ', N '-tetramethyl diaminourea alkyl phosphonates, N- carbanilates, borate, dimethyl disulfide phosphino-, 2, 4- dinitrophenyl sulfinic acid ester)；With sulphonic acid ester (sulfuric ester, methanesulfonates, benzylsulfonate, and tosylate).

More typical R_6aHydroxyl protecting group includes the methyl ether of substitution, substituted benzylic ether, silyl ether, and the esters including sulphonic acid ester, more typically including trialkylsilyl ethers, tosylate and acetic acid esters.

Typical 1,2- glycerol protections base (usual the two OH groups and R_6aProtection functional groups) the 118-142 pages of Greene is recorded in, and including cyclic acetal and ketal (methylene, ethylidene, 1- t butylethylidenes; 1- phenyl-ethylenes, (4- methoxyphenyls) ethylidene, 2,2; 2- trichloroethylidenes, acetone solvate (isopropylidene), cyclopentylene; cyclohexylidene, cycloheptylidene, benzal; p- benzylidene, 2,4- dimethoxybenzylidenegroup groups; 3,4- dimethoxybenzylidenegroup groups, 2- nitrobenzals)；Cyclic ortho ester (methoxymethylene, ethoxymeyhylene, dimethoxymethylene, 1- methoxyethlyens, 1- ethoxyethylidenes, 1,2- dimethoxyethylidene, α-benzylidene, 1- (N, N- dimethylamino) ethidene derivant, α-(N, N- dimethylaminos) benzylidene derivatives, 2- oxacyclopentylidenes)；Silyl derivative (di-t-butyl silicylene, 1,3- (1,1,3,3- tetra isopropyl disiloxanes are pitched), and four-tert-butoxy disiloxane -1,3- y-bend), cyclic carbonate, cycliborate, ethyl-boron dihydroxide ester and phenyl boronate.

More typical 1,2- glycerol protections base includes those shown in table B, more typically epoxides, acetone solvate, cyclic acetal and ketal.Table B

Wherein R⁹For C₁-C₆Alkyl.

R_6bFor H, the residue of amino protecting group or carboxylated compound, particularly H ,-C (O) R₄, amino acid, polypeptide or be-C (O) R₄, amino acid or polypeptide protection group.Into the R of acid amides_6bSee in such as group Gl.Work as R_6bDuring for amino acid or polypeptide, its structure is R₁₅NHCH(R₁₆) C (O)-, wherein R₁₅For H, amino acid or polypeptid residue, or R₅, and R₁₆It is defined as below.

R₁₆(the C replaced for low alkyl group or by following groups₁-C₆) low alkyl group：Amino, carboxyl, acid amides, carboxyl ester, hydroxyl, C₆-C₇Aryl, guanidine radicals, imidazole radicals, indyl, sulfydryl, sulfoxide and/or alkyl phosphate.R₁₆Proline residue (R can also be formed together with amino acid α N₁₆=-(CH₂)₃-).But R₁₆The usually side base of naturally occurring amino acid, such as H ,-CH₃,-CH(CH₃)₂,-CH₂-CH(CH₃)₂,-CHCH₃-CH₂-CH₃,-CH₂-C₆H₅,-CH₂CH₂-S-CH₃,-CH₂OH,-CH(OH)-CH₃,-CH₂-SH,-CH₂-C₆H₄OH,-CH₂-CO-NH₂,-CH₂-CH₂-CO-NH₂,-CH₂-COOH,-CH₂-CH₂-COOH,-(CH₂)₄-NH₂With-(CH₂)₃-NH-C(NH₂)-NH₂。R₁₆Also 1- guanidine radicals propyl- 3- bases, benzyl, 4- hydroxybenzyls, imidazol-4 yl, indol-3-yl, methoxyphenyl and ethoxyl phenenyl are included.

In most cases R_6bFor carboxylic acid residues, but any typical amino protecting group described in the 315-385 pages of Greene is all useful.They include carbamate (methyl and ethyl; 9- fluorenyl methyls, 9- (2- sulfo groups) fluorenyl methyl, 9- (2; 7- dibromos) fluorenyl methyl; 2,7- di-t-butyls-[9- (10,10- dioxos -10; 10; the thio xanthene of 10,10- tetrahydrochysenes)] methyl, 4- methoxybenzoyls base)；Replace ethyl (2, 2, 2- trichloroethyls, 2- trimethylsilyethyls, 2- phenylethyls, 1- (1- adamantyls) -1- Methylethyls, 1, 1- dimethyl -2- halogenated ethyls, 1, 1- dimethyl -2, 2- dibromoethyls, 1, 1- dimethyl -2, 2, 2- trichloroethyls, 1- methyl isophthalic acids-(4- xenyls) ethyl, 1- (3, 5- di-tert-butyl-phenyls) -1- Methylethyls, 2- (2 '-and 4 '-pyridine radicals) ethyl, 2- (N, N- dicyclohexyls formamido group) ethyl, the tert-butyl group, 1- adamantyls, vinyl, pi-allyl, 1- isopropylallyls, cinnamyl, 4- nitrocinnamyl bases, 8- quinolyls, N- hydroxy piperidine bases, alkyl-dithio, benzyl, p- methoxy-benzyl, p- nitrobenzyl, p- bromobenzyl, p- chlorobenzyl, 2, 4- dichloro benzyls, 4- methanesulfinyl benzyls, 9- anthrylmethyls, diphenyl methyl)；Aid in the group (2-methylmercaptoethyl of fracture; 2- methysulfonylethyls; 2- (ptoluene-sulfonyl) ethyl; [2- (1; the own ring group of 3- dithias)] methyl; 4- methyl mercapto phenyl, 2,4- dimethylthiophenyls; 2- phosphorus base ethyls; 2- triphenylphosphonioisopropyls, 1,1- dimethyl -2- cyano ethyls; m- chloro- p- acyloxybenzyl; p- (dihydroxy boryl) benzyl, 5- benzoisoxazole ylmethyls, 2- (trifluoromethyl) -6- chromones ylmethyl)；It is capable of the group (m-nitro base, 3,5- dimethoxy-benzyls, o- nitrobenzyl, 3,4- dimethoxy -6- nitrobenzyls, phenyl (o-nitrophenyl) methyl) of photodissociation；Carbamide derivative (phenothiazinyl-(10)-carbonyl, N '-ptoluene-sulfonyl amino carbonyl, N '-phenylaminothiocarbonyl)；Other carbamate (tertiary pentyls, S- benzyl thiocarbamates, p- cyanobenzyls, cyclobutyl, cyclohexyl, cyclopenta, Cvclopropvlmethvl, p- decyloxy benzyl, diisopropyl methyl, 2, 2- benzhydryloxycarbonyl vinyl, o- (N, N- dimethylformamides base) benzyl, 1, 1- dimethyl -3- (N, N- dimethylformamides base) propyl group, 1, 1- alkynyl dimethyls, two (2- pyridine radicals) methyl, 2- furyl methyls, 2- iodine ethyls, isobornyl, isobutyl group, different nicotinoyl base, p- (p '-methoxyphenyl azo group) benzyl, 1- methyl-cyclobutyls, 1- methylcyclohexyls, 1- methyl isophthalic acids-Cvclopropvlmethvl, 1- methyl isophthalic acids-(3, 5- Dimethoxyphenyls) ethyl, 1- methyl isophthalic acids-(to phenylazo phenyl) ethyl, 1- methyl isophthalic acids-phenylethyl, 1- methyl isophthalic acids-(4- pyridine radicals) ethyl, phenyl, p- (phenylazo) benzyl, 2, 4, 6- tri-tert phenyl, 4- (trimethyl ammonium) benzyl, 2, 4, 6- trimethyl benzyls)；Acid amides (N- formoxyls, N- acetyl group, N- ChloroacetYls, N- tribromo-acetyl bases; N-TFA base, N- phenyl acetyls, N-3- PHENYLPROPIONYLs, N- picoline acyl groups; N-3- pyridinyl carboxamides, N- benzoyl phenylalanyls, N- benzoyls, the p- Phenylbenzoyls of N-)；Aid in acid amides (the N- o-nitrophenyl acetyl group of fracture, the o- nitro-phenoxy acetyl group of N-, N- acetoacetyls, (N '-dithiobenzyloxycarbonylamino) acetyl group, N-3- (p- hydroxy phenyl) propiono, N-3- (o-nitrophenyl) propiono, N-2- methyl -2- (o- nitro-phenoxy) propiono, N-2- methyl -2- (o- phenylazo phenoxy group) propiono, N-4- chlorobutyryls, N-3- methyl-3-nitro bytyries, the o- nitrocinnamyl acyl groups of N-, N- acetyl group methionine, the o- nitro benzoyls of N-, o- (benzoyloxymethyl) benzoyls of N-, 4, 5- diphenyl -3- oxazoline -2- ketone)；Cyclic Imide Derivatives (N phlhalimide, N- dithia succinyl groups, N-2,3- diphenyl maleoyls; N-2,5- dimethyl pyrrole, N-1,1; 4,4- tetramethyl xylene silylation aza-cyclopentane adducts, the 1 of 5- substitutions; 3- dimethyl -1,3,5- Trianacyclohexane -2- ketone; 1,3- dibenzyl -1,3 of 5- substitutions; 5- Trianacyclohexane -2- ketone, 3, the 5- dinitro -4- pyriconyls of 1- substitutions)；N- alkyl and N- arylamines (N- methyl, N- pi-allyls, N- [2- (trimethyl silyl) ethyoxyl] methyl, N-3- acetyloxypropyls, N- (1- isopropyl -4- nitro -2- oxo -3- pyrrolin -3- bases), quaternary ammonium salt, N- benzyls, N- bis- (4- methoxyphenyls) methyl, N-5- dibenzocycloheptyls, N- trityl groups, N- (4- methoxyphenyls) diphenyl methyl, N-9- phenylfluorenyls, N-2, the chloro- 9- fluorenyls methylene of 7- bis-, N- ferrocenyl methyl, N-2- picolyl amine N '-oxide), imine derivative (N-1, 1- dimethylthiomethylenes, N- benzals, N- is to benzylidene, N- diphenylmethylenes, N- [(2- pyridine radicals) base] methylene, N, (N ', N '-dimethylamino methylene, N, N '-isopropylidene, N- is to nitrobenzal, N- salicylidenes, N-5- chlorine salicylidenes, N- (5- chlorine-2-hydroxyls phenyl) phenylmethylene, N- cyclohexylidenes)；Enamine derivates (N- (5,5- dimethyl -3- oxo -1- cyclohexenyl groups))；N- metal derivatives (N- borane derivatives, N- diphenyl-borinic acids derivatives, N- [phenyl (pentacarbonyl chromium-or tungsten)] carbene base, N- copper or N- chelates of zinc)；N-N derivatives (N- nitros, N- nitrosos, N- oxides)；N-P derivatives (N- two phenenyl phosphinyls, N- dimethyl sulphur-based phosphinyls, N- hexichol sulfenyl phosphinyls, N- dialkyl phosphoryls, N- dibenzyl phosphoryls, N- diphenylphosphoryls)；N-Si derivatives；N-S derivatives；N- sulfinyl derivatives (N- phenylsulfinyl bases, N- ortho-nitrophenyl sulfinyls, N-2; 4- dinitro benzene sulfinyls, N- pentachlorobenzene sulfinyls, N-2- nitro -4- methoxybenzene sulfinyls; N- trityl group sulfinyls, N-3- nitropyridines sulfinyl)；With N- sulfonyl-derivatives (N- p-toluenesulfonyls, N- benzenesulfonyls, N-2, 3, 6- trimethyl -4- MethOxybenzenesulfonyls, N-2, 4, 6- trimethoxybenzenesulfonyls, N-2, 6- dimethyl -4- MethOxybenzenesulfonyls, N- pentamethylbenzene sulfonyls, N-2, 3, 5, 6- tetramethyl -4- MethOxybenzenesulfonyls, N-4- MethOxybenzenesulfonyls, N-2, 4, 6- trimethylphenysulfonyls, N-2, 6- dimethoxy-4 's-Methyl benzenesulfonyl base, N-2, 2, 5, 7, 8- pentamethyl benzodihydropyran -6- sulfonyls, N- mesyls, N- β-trimethyl silyl ethanesulfonyl, N-9- anthracene sulfonyls, N-4- (4 ', 8 '-dimethoxy menaphthyl) benzenesulfonyl, N- benzylsulphonyls, N- trifluoromethyl sulfonyls, N- benzoyls sulfonyl).

It is more typical that carbamate and acid amides, more typically-NHC (O) R are included by protection amino₁Or-N=CR₁N(R₁)₂.Also prodrug, particularly amino or-NH (R can be used as in G1 parts₅) another protection group be：

For example, see Alexander, J. etc. pharmaceutical chemistry magazine (J.Med.Chem.) 39:480-486(1996).

R_6cFor H or the residue containing amino-compound (particularly amino acid, polypeptide), protection group ,-NHSO₂R₄,NHC(O)R₄,-N(R₄)₂,NH₂Or-NH (R₄) (H), thus, such as W₁Carboxylic acid or phosphate group and the amine reaction generation acid amides, such as in-C (O) R_6c,-P(O)(R_6c)₂Or-P (O) (OH) (R_6c) in.Usually, R_6cWith structure R₁₇C(O)CH(R₁₆) NH-, wherein R₁₇For OH, OR_6a,OR₅, amino acid or polypeptid residue.

Amino acid is low molecular weight compound, less than about 1000MW, and includes at least one amino or imino group and at least one carboxyl.These usual amino acid are present in nature, you can in biomaterial such as bacterium or other microorganisms, plant, detectable in animal or people.Suitable amino acid is generally alpha amino acid, that is, is characterized in that the compound that an amino or imino group nitrogen are kept apart by the carbon atom of a substituted or unsubstituted alpha-carbon atom and a carboxyl.Particularly importantly hydrophobic residue, such as single-or di-alkyl or aryl amino acid, cycloalkylamino acid etc..These residues have contributes to Premeabilisation of cells by improving the distribution coefficient of parent drug.Typically, this residue does not include sulfydryl or guanidino substituent.

Naturally occurring amino acid residue is the residue particularly found naturally in its protein in plant, animal or microorganism.Most typical polypeptide is substantially made up of this kind of native amino acid residues.These amino acid are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, oxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxy-proline.

Work as R_6bAnd R_6cDuring for single amino acids residue or polypeptide, they are generally in R₃,W₆,W₁And/or W₂Upper substitution, but typically only in W₁Or W₂Upper substitution.These conjugates pass through the carboxyl (or C-terminal amino acid of polypeptide) and W in amino acid₂Between formed amido link and generate.Equally, can also be in W₁Conjugate is formed between the amino of amino acid or polypeptide.Generally, only one of which position introduces multiple amino acid also within the scope of the present invention by amino acid amide as described herein, but on more than one allowed position in parent molecule.Usual W₁Carboxyl amino acid amide.Usually; the alpha-amido or α-carboxylic group of amino acid or the terminal amino group or carboxyl of polypeptide are bonded on the functional group of parent compound; carboxyl or amino i.e. on amino acid side chain typically do not form amido link with parent compound (but, these groups need to be protected by synthesis of coupling thing as described below).

Contain carboxylic side-chain on amino acid or polypeptide, it should be understood that the carboxyl is optionally by such as R_6aClosing, by R₅It is esterified or by R_6cAmidatioon.Equally, amino side chain R₁₆Also optionally by R_6bClose or by R₅Substitution.

Ester or amido link that these and side-chain amino group or carboxyl are formed, it is the same as indicated in the ester or acid amides of parent molecule formation, optionally in hydrolysis under inner or in vitro acid condition (pH ＜ 3) or alkalescence condition (pH ＞ 10).On the other hand, they are basicly stable in the intestines and stomach of people, but can occur under blood or intracellular environment enzymatic hydrolysis.The amidate of these esters or amino acid or polypeptide also can be used as preparing the intermediate of the parent molecule comprising free amine group or carboxyl.The free acid or alkali of parent compound for example can be formed easily by routine hydrolysis method by the ester or amino acid or polypeptide-conjugate of the present invention.

When amino acid residue includes one or more chiral centres, any D, L, meso, revive formula, erythro form (if appropriate), racemate, position isomer (scalemates) or its mixture can be used.Usually, if non-enzymatic hydrolysis intermediate (such as in the case of acid amides being used as into the chemical intermediate of free acid or free alkali), D isomers is useful.On the other hand, because L isomers is easy to carry out non-enzymatic to urge to become reconciled enzymatic hydrolysis, thus it is more generally applicable.And more effectively can be transported in the gastrointestinal tract by amino acid or dipeptides movement system.

(its residue is with R for Suitable amino acids_6bAnd R_6cRepresent) example include it is following：

Glycine；

Aminopolycarboxylic acid, such as aspartic acid, beta-hydroxy aspartic acid, glutamic acid, beta-hydroxyglutamic acid, Beta-methyl aspartic acid, Beta-methyl glutamic acid, β, beta-dimethyl aspartic acid, γ-Hydroxy GIutaminic Acid, beta, gamma-dihydroxy glutamic acid, beta-phenyl glutamic acid, γ-methyleneglutaric acid, 3- aminoadipic acids, 2- diaminopimelic acids, 2- amino suberic acid and 2- amino decanedioic acid；

Amino acid amide such as glutamine and asparagine；

Polyamino-or polyacid base-monocarboxylic acid such as arginine, lysine, beta-amino alanine, gamma-amino butyrin, urinary ammonia acid, citrulling, homoarginine, Homocitrulline, oxylysine, allohydroxylysine and diaminobutyric acid；

Other alkaline amino acid residues such as histidine；

Diamino dicarboxylic acid such as α, α '-diaminosuccinic acid, α, α '-diaminourea glutaric acid, α, α '-diaminourea adipic acid, α, α '-diaminopimelic acid, α, α '-diaminourea-beta-hydroxy pimelic acid, α, α '-diaminourea suberic acid, α, α '-diaminourea azelaic acid, and α, α '-diaminourea decanedioic acid；

Imino acid, such as proline, hydroxy-proline, allohydroxyproline, γ-methylproline, piperidines -2- formic acid, 5- hydroxy piperidine -2- formic acid, and AzeOH；

Single-or di-alkyl (typically C₁-C₈Side chain or straight chain) amino acid such as alanine, valine, leucine, allylglycine, butyrin, norvaline, nor-leucine, heptyline, Alpha-Methyl serine, alpha-amido-Alpha-Methyl-γ-hydroxypentanoic acid, alpha-amido-Alpha-Methyl-δ-hydroxypentanoic acid, alpha-amido-Alpha-Methyl-ε-hydroxycaproic acid, isovaline, Alpha-Methyl glutamic acid, α-aminoacid, alpha-amido diethacetic acid, alpha-amido diisopropyl acetic acid, alpha-amido diη-propyl acetic acid, alpha-amido diisobutyl acetic acid, alpha-amido di-n-butylacetic acid, alpha-amido ethylisopropyl guanidine-acetic acid, alpha-amido-n-propyl acetic acid, alpha-amido diisoamyl acetic acid, Alpha-Methyl aspartic acid, Alpha-Methyl glutamic acid, 1- amino-cyclopropane -1- carboxylic acids, isoleucine, alloisoleucine, Terleu, Beta-methyl tryptophan, and pantonine-ethyl-β-phenylpropionic acid；

Beta-phenyl seryl-；

Aliphatic pantonine-carboxylic acid such as serine, beta-hydroxy leucine, beta-hydroxy nor-leucine, beta-hydroxy norvaline, and pantonine-hydroxy stearic acid；

Alpha-amido, α-, γ-, δ-or ε-carboxylic acid such as homoserine, γ-hydroxynorvaline, δ-hydroxynorvaline, and ε-hydroxyl nor-leucine residue；Canavanine and canaline；γ-hydroxyl ornithine；

2- hexoses propylhomoserin such as D- glucose propylhomoserin or D- galactolipin propylhomoserins；

Pantonine-mercaptan such as penicillamine, β-mercaptan norvaline or β-mercaptan butyrin；

Other sulfur-containing amino acid residues, including cysteine；The mercaptan ether of homocystine, beta-phenyl methionine, methionine, SACS, 2- mercaptan histidines, cystathionie, and cysteine or homocysteine；

Phenylalanine, tryptophan and cyclosubstituted a-amino acid such as phenyl-or cyclohexyl amino acids alpha-amido phenylacetic acid, alpha-amido cyclohexyl-acetic acid and pantonine-cyclohexylpropionic acid；The phenylalanine analogues and derivative (such as tyrosine of the phenyl replaced comprising aryl, low alkyl group, hydroxyl, guanidine radicals, alkoxy ether, nitro, sulphur or halogen, methyl-tyrosine and neighbour it is chloro-, to it is chloro-, 3, it is 4- dichloros, o-, m- or p- methyl -, 2,4,6- trimethyls -, 2- ethyoxyl -5- nitros -, 2- hydroxyl -5- nitros-and p- nitrophenylalanine)；Furyl-, thienyl-, pyridine radicals-, pyrimidine radicals-, purine radicals-or naphthylalanine；And including kynurenin, 3-hydroxykynurenine, tryptophan analog and derivative including 2- hydroxytryptophans and 4- carboxyl tryptophans；

The amino acid of alpha-amido substitution, including methyl amimoacetic acid (sarcosine), N- benzyl glycines, N- methylalanines, N- benzyl alanine, N- methyl phenylalanines, N- benzyl phenyl alanine, N- methylvalines and N- benzyl valines；With

Alpha-hydroxy and substitution Alpha-hydroxy amino acid, including serine, threonine, allothreonine, phosphoserine and phosphothreonine.

Polypeptide is amino acid polymer, and the carboxyl of one of amino acid monomer is connected by the amino or imino group key of amido link and another amino acid monomer.Polypeptide includes dipeptides, low molecular weight polypeptide (about 1500-5000MW) and protein.Protein optionally contains 3,5,10,50,75,100 or more residues, and suitable has substantially similar sequence with people, animal, plant or microprotein.They include enzyme (such as catalase) and immunogene such as KLH, or immune response to be produced any kind of antibody or protein.The property and species of polypeptide have very big difference.

The polypeptide amide compound is used as immunogene on the anti-polypeptide (being non-immunogenic such as in the animal body of administration) or the remainder of anti-the compounds of this invention is produced in the antibody of epitope.

The antibody that can be combined with non-peptidyl linker parent compound can be used for isolating the parent compound from mixture, such as when diagnosing or preparing parent compound.The conjugate of parent compound and polypeptide generally can have more immunogenicity in species than polypeptide, so that the polypeptide has more immunogenicity, promote to produce and resist its antibody.Therefore, polypeptide or protein may not necessarily be immunogenicity in the animal (such as rabbit, mouse, horse and rat) commonly used to produce antibody, but final coupled product should be immunogenicity at least one this kind of animal.Polypeptide contains peptidohydrolase cracking site on the peptide bond optionally between the first and second residues of neighbouring acidic heteroatom.The flank of these cracking sites has the structure (the specific residue sequence that such as peptidohydrolase is recognized) recognized by enzyme.

Peptidohydrolase for cracking polypeptide-conjugate of the present invention is known, especially including carboxypeptidase.Carboxypeptidase digests polypeptide by removing C- ends residue, and has specificity to specific C- terminal sequences in many cases.These enzymes and its substrate requirements are typically also known.For example, dipeptides (having selected a pair of residues and free carboxy termini) is connected on the phosphorus of compounds herein or carbon atom by its alpha-amido key.W wherein₁For in the embodiment of phosphonate ester, it is contemplated that this peptide will be cracked by appropriate peptidohydrolase, leave near-end amino acid residue carboxyl and self-catalysis cut off phosphono amine key.

Suitable two peptidyl (with its single-letter representation) is：AA,AR,AN,AD,AC,AE AQ,AG,AH,AI,AL,AK,AM,AF,AP,AS,AT,AW,AY,AV,RA,RR,RN,RD,RC,RE,RQ RG,RH,RI,RL,RK,RM,RF,RP,RS,RT,RW,RY,RV,NA,NR,NN,ND,NC,NE,NQ,NG,NH,NI,NL,NK,NM,NF,NP,NS,NT,NW,NY,NV,DA,DR,DN,DD,DC,DE,DQ,DG,DH,DI,DL,DK,DM,DF,DP,DS,DT,DW,DY,DV,CA,CR,CN,CD,CC,CE,CQ,CG,CH,CI,CL,CK,CM,CF,CP,CS,CT,CW,CY,CV,EA,ER,EN,ED,EC,EE,EQ,EG,EH,EI,EL,EK,EM,EF,EP,ES,ET,EW,EY,EV,QA,QR,QN,QD,QC,QE,QQ,QG,QH,QI,QL,QK,QM,QF,QP,QS,QT,QW,QY,QV,GA,GR,GN,GD,GC,GE,GQ,GG,GH,GI,GL,GK,GM,GF,GP,GS,GT,GW,GY,GV,HA,HR,HN,HD,HC,HE,HQ,HG,HH,HI,HL,HK,HM,HF,HP,HS,HT,HW,HY,HV,IA,IR,IN,ID,IC,IE,IQ,IG,IH,II,IL,IK,IM,IF,IP,IS,IT,IW,IY,IV,LA,LR,LN,LD,LC,LE,LQ,LG,LH,LI,LL,LK,LM,LF,LP,LS,LT,LW,LY,LV,KA,KR,KN,KD,KC,KE,KQ,KG,KH,KI,KL,KK,KM,KF,KP,KS,KT,KW,KY,KV,MA,MR,MN,MD,MC,ME,MQ,MG,MH,MI,ML,MK,MM,MF,MP,MS,MT,MW,MY,MV,FA,FR,FN,FD,FC,FE,FQ,FG,FH,FI,FL,FK,FM,FF,FP,FS,FT,FW,FY,FV,PA,PR,PN,PD,PC,PE,PQ,PG,PH,PI,PL,PK,PM,PF,PP,PS,PT,PW,PY,PV,SA,SR,SN,SD,SC,SE,SQ,SG,SH,SI,SL,SK,SM,SF,SP,SS,ST,SW,SY,SV,TA,TR,TN,TD,TC,TE,TO,TG,TH,TI,TL,TK,TM,TF,TP,TS,TT,TW,TY,TV,WA,WR,WN,WD,WC,WE,WQ,WG,WH,WI,WL,WK,WM,WF,WP,WS,WT,WW,WY,WV,YA,YR,YN,YD,YC,YE,YQ,YG,YH,YI,YL,YK,YM,YF,YP,YS,YT,YW,YY,YV,VA,VR,VN,VD,VC,VE,VQ VG,VH,VI,VL,VK,VM,VF,VP,VS,VT,VW,VY and VV.

Tripeptide residue also can be used as R_6bOr R_ycWork as W₁During for phosphonate ester, (wherein X4 is any amino acid residue to sequence-X4-pro-X5-, and X5 is amino acid residue, the carboxyl ester of proline, or hydrogen) X4 containing free carboxy is cracked into by luminal carboxypeptidase, it is contemplated that this X4 in itself can autocatalytic cleavage phosphono amine key.X5 carboxyl is optionally esterified by benzyl.

The species of dipeptides or tripeptides can be selected according to known transport properties and/or on the sensitiveness (it can influence the transhipment to intestinal mucosa or other cell types) of peptase.Lack alpha-amino dipeptides and tripeptides be the peptide transporter found in the brush edge film of intestinal mucosa cells transhipment matrix (Bai, J.P.F., " drug research " (Pharm Res.) 9:969-978(1992)).The peptide for being adapted to transhipment can be used for the bioavilability of enhancing amide compound.Dipeptides or tripeptides containing one or more D amino acids are also compatible with peptide transhipment, and in the amide compound available for the present invention.D amino acids can be used for reduction dipeptides or tripeptides by the possibility of protease hydrolytic, and this protease is common such as aminopeptidase N (EC3.4.11.2) in brush border.In addition, two-or tripeptides can also be selected according to the relevant antagonism of its protease hydrolytic to being found in enteric cavity.For example, the tripeptides or polypeptide for lacking asp and/or glu are aminopeptidase A (EC3.4.11.7) bad substrate, in hydrophobic amino acid (leu, tyr, phe, val, trp) N- ends side on lack amino acid residue two-or tripeptides be endopeptidase 24.11 (EC3.4.24.11) bad substrate, and free carboxy end penultimate position lack pro residues peptide be carboxypeptidase P (EC3.4.17) bad substrate.Also it can be selected using similar consideration more difficult or be easier to the peptide that is hydrolyzed by cytosol, kidney, liver, serum or other peptases.It is such a to be difficult cut-off polypeptide amide compound for immunogene or can be used to be bound on protein forms immunogene.Stereoisomer

The compounds of this invention is rich product or the optical isomer split on any or all asymmetric carbon atom.For example, obvious chiral centre occurs with chiral isomer or racemic mixture form in specification.Racemic and non-enantiomer mixture, and the single optical isomer (not conforming to its enantiomer or diastereomer substantially) that separation or synthesis are obtained is all within the scope of the present invention.

One or more are following to enumerate enantiomer richness product or pure isomers that method can be used in preparing this paper.These methods are listed with its substantially preferred sequence, i.e., those skilled in the art should first use following order：Stereoselectivesynthesis is carried out by chiral precursor, then Chromatographic resolution, then spontaneous crystallization again.

Stereoselectivesynthesis is described as follows.When appropriate chiral raw material is easy to get to and selected reactions steps are when will not cause the chiral position to occur undesirable racemization, the use of this kind of method is that comparison is easy.A kind of advantage of stereoselectivesynthesis is exactly that will not produce the undesirable enantiomer (thus reducing total synthesis yield) that must be removed from final product.Usually, it will be apparent to those skilled in the art that for the enantiomer richness product needed by stereospecific reaction or pure isomers, it is necessary to use suitable raw material and reaction condition.If unexpected racemization effect occurs in stereospecific method is considered, people only need to use any of following separation method to separate required product.

If experimentally can not design or determine appropriate stereoselectivesynthesis method using conventional methods, those skilled in the art should turn to other methods.A kind of commonly used approach is the chromatogram enantiomer separation on chiral chromatogram resin.These resins are filled in pillar, commonly referred to as Pirkle posts, and being commercially available.This post includes chiral stationary phase.Racemate is formed into solution, is added on post, is then separated by HPLC.For example, with reference to chromatogram association proceedings-world chiral separation collection of thesis (Proceedings Chromatographic Society-International Symposium on Chiral Separations) (in September, 1987 3-4 days).Example available for the chiral column of screening optimal separation method includes DiacelChriacel OD, Regis Pirkle Covalent Dphenylglycine, Regis PirkleType 1A, Astec Cyclobond II, Astec Cyclobond III, Serva ChiralD-DL=Daltosil 100, Bakerbond DNBLeu, Sumipax OA-1000, Merck cellulosic triacetate posts,-the β of Astec Cyclobond I, or Regis Pirkle covalent bond D- naphthylalanine posts.But for each racemic mixture, these posts are not all highly effective.However, it will be apparent to those skilled in the art that to determine maximally effective stationary phase, it may be necessary to a certain amount of to carry out conventional screening.When using these posts, the compounds of this invention being neutralized preferably with wherein electric charge, for example, wherein acidic functionality such as carboxyl is esterified or amidated compound.

Another method needs to use the enantiomer in chiral auxiliary transformation mixture to turn into diastereomer, then passes through this conjugate of conventional pillar layer separation.Particularly when the compounds of this invention includes free carboxy, amino or hydroxyl that can be with chiral auxiliary forming salt or formation covalent bond, this is a kind of method being particularly suitable for.Chiral pure amino acid, organic acid or organic sulfonic acid can function well as chiral auxiliary, and all these is all well known in the art.They or can be bonded to functional group with these auxiliary agent forming salts with covalent manner (but for reversible).For example, pure D or L amino acid can be used to the carboxyl of amidatioon the compounds of this invention, then separated again by chromatography.

Enzymatic Resolution is another valuable method.In this kind of method, a kind of is the covalence derivative for preparing enantiomer in racemic mixture, generally (such as carboxylic acid) lower alkyl esters, and this derivative then is carried out into enzymatic lysis, is generally hydrolyzed.To complete this method, it is necessary to which selection can carry out the enzyme of three-dimensional single-minded cracking, therefore usually require to carry out the conventional several enzymes of screening.If cracking ester, esterase, phosphate, and lipase are selected, and determine their activity to derivative.Typical lipase comes from liver, pancreas or other animal organs, and including pig liver esterase.

If isolating mixture of enantiomers from solution or fused mass in aggregation (i.e. the mixture of enantiomer-pure crystal) form, this crystal can be mechanically separated, so as to produce the product of enantiomer richness product.But this method is infeasible for extensive prepare, and for true racemic compound also without application value.

Asymmetric syntheses is the another method for obtaining enantiomer richness product thing.For example, make chiral protecting group and the radical reaction to be protected, and balanced reaction mixture.If reaction is that enantiomer is single-minded, product will be enriched in corresponding enantiomer.

The further teaching of relevant mixture of enantiomers separation is found in such as, but not limited to JeanJacques, Andre Collet, and Samuel H.《Enantiomer, racemic modification and its fractionation》(Krieger publishing company, Malabar, FL, 1991, ISBN 0-89464-618-4).Particularly Part II, the fractionation of mixture of enantiomers, pp.217-435；More particularly chapter 4, direct crystallization is split, pp.217-251, chapter 5, the formation of diastereomer is with separating, pp.251-369, chapter 6 crystallizes the asymmetric transformation of induction, pp.369-378, and chapter 7, experimental method and fractionation technology (Experimental Aspects and Art ofResolutions), pp.378-435；Especially 5.1.4. is saved, the fractionation of alcohol, alcohol is converted into salt derivative, pp.263-266, 5.2.3. is saved, alcohol, mercaptan, with the covalence derivative of phenol, pp.332-335, 5.1.1. is saved, the fractionation of acid, pp.257-259, 5.1.2. is saved, the fractionation of alkali, pp.259-260, 5.1.3. is saved, the fractionation of amino acid, pp.261-263, 5.2.1 is saved, the covalence derivative of acid, pp.329, 5.2.2 is saved, the covalence derivative of amine, pp.330-331, 5.2.4 is saved, aldehyde, ketone, with the covalence derivative of sulfoxide, pp.335-339, and 5.2.7 sections, the chromatographic behavior of covalent diastereomeric, content in pp.348-354 is quoted as the example of this area.

In some cases, the compounds of this invention can also different tautomeric forms presence.For example, for imidazoles, guanidine, amidine and tetrazole systems, there may be enamine tautomers, and their all possible dynamic isomer is all within the scope of the present invention.Example compound

As non-limiting examples, examples of compounds is hereinafter listed with forms mode (table 6).Generally, each compound is expressed as replacing kernel form, and core therein is represented with capitalization, and each substituent is then represented with lowercase and numeral successively.Table 1 is the list of each seed nucleus, and their difference essentially consists in the position of ring unsaturated bond and the property of ring substituents.Each core all gives an alphabet symbol in table 1, and this symbol appears in first of each compound name.Equally, table 2,3,4 and 5 lists selected Q respectively₁,Q₂,Q₃And Q₄Substituent, and equally represented with letter or number symbol.Therefore, various name compounds can be expressed as follows：The capitalization of the core in table 1 is represented, is then expression Q₁The numeral of substituent, represents Q₂The lowercase of substituent, represents Q₃The numeral of substituent, and represent Q₄The lowercase of substituent.For example, following structures have title as follows.

A.141.x.4.i table 1

Table 2aTable 2b

Table 2cTable 2d

Table 2e

Table 2f

Table 2g

Table 2hTable 2iTable 2j

Table 2kTable 2l

Table 2mTable 2n

Table 2o

Table 2p

Table 2q

Table 2r

Table 2sTable 2t

Table 2uTable 2v

Table 2w

Table 2x

Table 2yTable 2zTable aa

Table 2abTable 2acTable 3a

Table 3bTable 4a

Table 4bTable 4c

Table 5aTable 5bTable 5c

Table 6- example compounds are A.3.a.4.i； A.4.a.4.i； A.7.a.4.i； A.9.a.4.i； A.103.a.4.i； A.106.a.4.i； A.107.a.4.i； A.108.a.4.i；A.111.a.4.i； A.114.a.4.i； A.117.a.4.i； A.118.a.4.i； A.119.a.4.i； A.120.a.4.i； A.121.a.4.i；A.137.a.4.i； A.138.a.4.i； A.139.a.4.i； A.140.a.4.i； A.141.a.4.i； A.142.a.4.i； A.145.a.4.i；A.146.a.4.i； A.147.a.4.i； A.148.a.4.i； A.149.a.4.i； A.150.a.4.i； A.151.a.4.i； A.165.a.4.i；A.166.a.4.i； A.167.a.4.i； A.168.a.4.i； A.169.a.4.i； A.170.a.4.i； A.171.a.4.i； A.172.a.4.i；A.173.a.4.i； A.174.a.4.i； A.175.a.4.i； A.176.a.4.i； A.188.a.4.i； A.189.a.4.i； A.190.a.4.i；A.196.a.4.i； A.202.a.4.i； A.205.a.4.i； A.206.a.4.i； A.207.a.4.i； A.208.a.4.i； A.209.a.4.i；A.210.a.4.i； A.211.a.4.i； A.212.a.4.i； A.213.a.4.i； A.700.a.4.i； A.701.a.4.i； A.702.a.4.i；A.703.a.4.i； A.704.a.4.i； A.705.a.4.i； A.706.a.4.i； A.707.a.4.i； A.708.a.4.i； A.709.a.4.i；A.710.a.4.i； A.711.a.4.i； A.712.a.4.i； A.713.a.4.i； A.714.a.4.i； A.715.a.4.i； A.716.a.4.i；A.717.a.4.i； A.718.a.4.i； A.719.a.4.i； A.720.a.4.i； A.721.a.4.i； A.722.a.4.i； A.723.a.4.i；A.724.a.4.i； A.3.a.4.o； A.4.a.4.o； A.7.a.4.o； A.9.a.4.o； A.103.a.4.o； A.106.a.4.o；A.107.a.4.o； A.108.a.4.o； A.111.a.4.o； A.114.a.4.o； A.117.a.4.o； A.118.a.4.o；A.119.a.4.o； A.120.a.4.o； A.121.a.4.o； A.137.a.4.o； A.138.a.4.o； A.139.a.4.o；A.140.a.4.o； A.141.a.4.o； A.142.a.4.o； A.145.a.4.o； A.146.a.4.o； A.147.a.4.o；A.148.a.4.o； A.149.a.4.o； A.150.a.4.o； A.151.a.4.o； A.165.a.4.o； A.166.a.4.o；A.167.a.4.o； A.168.a.4.o； A.169.a.4.o； A.170.a.4.o； A.171.a.4.o； A.172.a.4.o；A.173.a.4.o； A.174.a.4.o； A.175.a.4.o； A.176.a.4.o； A.188.a.4.o； A.189.a.4.o；A.190.a.4.o； A.196.a.4.o； A.202.a.4.o； A.205.a.4.o； A.206.a.4.o； A.207.a.4.o；A.208.a.4.o； A.209.a.4.o； A.210.a.4.o； A.211.a.4.o； A.212.a.4.o； A.213.a.4.o；A.700.a.4.o； A.701.a.4.o； A.702.a.4.o； A.703.a.4.o； A.704.a.4.o； A.705.a.4.o；A.706.a.4.o； A.707.a.4.o； A.708.a.4.o； A.709.a.4.o； A.710.a.4.o； A.711.a.4.o；A.712.a.4.o； A.713.a.4.o； A.714.a.4.o； A.715.a.4.o； A.716.a.4.o； A.717.a.4.o；A.718.a.4.o； A.719.a.4.o； A.720.a.4.o； A.721.a.4.o； A.722.a.4.o； A.723.a.4.o；A.724.a.4.o； A.172.b.4.i； A.173.b.4.i； A.174.b.4.i； A.175.b.4.i； A.176.b.4.i； A.188.b.4.i；A.189.b.4.i； A.190.b.4.i； A.196.b.4.i； A.202.b.4.i； A.205.b.4.i； A.206.b.4.i； A.207.b.4.i；A.208.b.4.i； A.209.b.4.i； A.210.b.4.i； A.211.b.4.i； A.212.b.4.i； A.213.b.4.i； A.700.b.4.i；A.701.b.4.i； A.702.b.4.i； A.703.b.4.i； A.704.b.4.i； A.705.b.4.i； A.706.b.4.i； A.707.b.4.i；A.708.b.4.i； A.709.b.4.i； A.710.b.4.i； A.711.b.4.i； A.712.b.4.i； A.713.b.4.i； A.714.b.4.i；A.715.b.4.i； A.716.b.4.i； A.717.b.4.i； A.718.b.4.i； A.719.b.4.i； A.720.b.4.i； A.721.b.4.i；A.722.b.4.i； A.723.b.4.i； A.724.b.4.i； A.3.b.4.o； A.4.b.4.o； A.7.b.4.o； A.9.b.4.o；A.103.b.4.o； A.106.b.4.o； A.107.b.4.o； A.108.b.4.o； A.111.b.4.o； A.114.b.4.o；A.117.b.4.o； A.118.b.4.o； A.119.b.4.o； A.120.b.4.o； A.121.b.4.o； A.137.b.4.o；A.138.b.4.o； A.139.b.4.o； A.140.b.4.o； A.141.b.4.o； A.142.b.4.o； A.145.b.4.o；A.146.b.4.o； A.147.b.4.o； A.148.b.4.o； A.149.b.4.o； A.150.b.4.o； A.151.b.4.o；A.165.b.4.o； A.166.b.4.o； A.167.b.4.o； A.168.b.4.o； A.169.b.4.o； A.170.b.4.o；A.171.b.4.o； A.172.b.4.o； A.173.b.4.o； A.174.b.4.o； A.175.b.4.o； A.176.b.4.o；A.188.b.4.o； A.189.b.4.o； A.190.b.4.o； A.196.b.4.o； A.202.b.4.o； A.205.b.4.o；A.206.b.4.o； A.207.b.4.o； A.208.b.4.o； A.209.b.4.o； A.210.b.4.o； A.211.b.4.o；A.212.b.4.o； A.213.b.4.o； A.700.b.4.o； A.701.b.4.o； A.702.b.4.o； A.703.b.4.o；A.704.b.4.o； A.705.b.4.o； A.706.b.4.o； A.707.b.4.o； A.708.b.4.o； A.709.b.4.o；A.710.b.4.o； A.711.b.4.o； A.712.b.4.o； A.713.b.4.o； A.714.b.4.o； A.715.b.4.o；A.716.b.4.o； A.717.b.4.o； A.718.b.4.o； A.719.b.4.o； A.720.b.4.o； A.721.b.4.o；A.722.b.4.o； A.723.b.4.o； A.724.b.4.o； A.172.x.4.i； A.173.x.4.i； A.174.x.4.i； A.175.x.4.i；A.176.x.4.i； A.188.x.4.i； A.189.x.4.i； A.190.x.4.i； A.196.x.4.i； A.202.x.4.i； A.205.x.4.i；A.206.x.4.i； A.207.x.4.i； A.208.x.4.i； A.209.x.4.i； A.210.x.4.i； A.211.x.4.i； A.212.x.4.i；A.213.x.4.i； A.700.x.4.i； A.701.x.4.i； A.702.x.4.i； A.703.x.4.i； A.704.x.4.i； A.705.x.4.i；A.706.x.4.i； A.707.x.4.i； A.708.x.4.i； A.709.x.4.i； A.710.x.4.i； A.711.x.4.i； A.712.x.4.i；A.713.x.4.i； A.714.x.4.i； A.715.x.4.i； A.716.x.4.i； A.717.x.4.i； A.718.x.4.i； A.719.x.4.i；A.720.x.4.i； A.721.x.4.i； A.722.x.4.i； A.723.x.4.i； A.724.x.4.i； A.3.x.4.o； A.4.x.4.o；A.7.x.4.o； A.9.x.4.o； A.103.x.4.o； A.106.x.4.o； A.107.x.4.o； A.108.x.4.o； A.111.x.4.o；A.114.x.4.o； A.117.x.4.o； A.118.x.4.o； A.119.x.4.o； A.120.x.4.o； A.121.x.4.o；A.137.x.4.o； A.138.x.4.o； A.139.x.4.o； A.140.x.4.o； A.141.x.4.o； A.142.x.4.o；A.145.x.4.o； A.146.x.4.o； A.147.x.4.o； A.148.x.4.o； A.149.x.4.o； A.150.x.4.o；A.151.x.4.o； A.165.x.4.o； A.166.x.4.o； A.167.x.4.o； A.168.x.4.o； A.169.x.4.o；A.170.x.4.o； A.171.x.4.o； A.172.x.4.o； A.173.x.4.o； A.174.x.4.o； A.175.x.4.o；A.176.x.4.o； A.188.x.4.o； A.189.x.4.o； A.190.x.4.o； A.196.x.4.o； A.202.x.4.o；A.205.x.4.o； A.206.x.4.o； A.207.x.4.o； A.208.x.4.o； A.209.x.4.o； A.210.x.4.o；A.211.x.4.o； A.212.x.4.o； A.213.x.4.o； A.700.x.4.o； A.701.x.4.o； A.702.x.4.o；A.703.x.4.o； A.704.x.4.o； A.705.x.4.o； A.706.x.4.o； A.707.x.4.o； A.708.x.4.o；A.709.x.4.o； A.710.x.4.o； A.711.x.4.o； A.712.x.4.o； A.713.x.4.o； A.714.x.4.o；A.715.x.4.o； A.716.x.4.o； A.717.x.4.o； A.718.x.4.o； A.719.x.4.o； A.720.x.4.o；A.721.x.4.o； A.722.x.4.o； A.723.x.4.o； A.724.x.4.o； A.172.y.4.i； A.173.y.4.i； A.174.y.4.i；A.175.y.4.i； A.176.y.4.i； A.188.y.4.i； A.189.y.4.i； A.190.y.4.i； A.196.y.4.i； A.202.y.4.i；A.205.y.4.i； A.206.y.4.i； A.207.y.4.i； A.208.y.4.i； A.209.y.4.i； A.210.y.4.i； A.211.y.4.i；A.212.y.4.i； A.213.y.4.i； A.700.y.4.i； A.701.y.4.i； A.702.y.4.i； A.703.y.4.i； A.704.y.4.i；A.705.y.4.i； A.706.y.4.i； A.707.y.4.i； A.708.y.4.i； A.709.y.4.i； A.710.y.4.i； A.711.y.4.i；A.712.y.4.i； A.713.y.4.i； A.714.y.4.i； A.715.y.4.i； A.716.y.4.i； A.717.y.4.i； A.718.y.4.i；A.719.y.4.i； A.720.y.4.i； A.721.y.4.i； A.722.y.4.i； A.723.y.4.i； A.724.y.4.i； A.3.y.4.o；A.4.y.4.o； A.7.y.4.o； A.9.y.4.o； A.103.y.4.o； A.106.y.4.o； A.107.y.4.o； A.108.y.4.o；A.111.y.4.o； A.114.y.4.o； A.117.y.4.o； A.118.y.4.o； A.119.y.4.o； A.120.y.4.o；A.121.y.4.o； A.137.y.4.o； A.138.y.4.o； A.139.y.4.o； A.140.y.4.o； A.141.y.4.o；A.142.y.4.o； A.145.y.4.o； A.146.y.4.o； A.147.y.4.o； A.148.y.4.o； A.149.y.4.o；A.150.y.4.o； A.151.y.4.o； A.165.y.4.o； A.166.y.4.o； A.167.y.4.o； A.168.y.4.o；A.169.y.4.o； A.170.y.4.o； A.171.y.4.o； A.172.y.4.o； A.173.y.4.o； A.174.y.4.o；A.175.y.4.o； A.176.y.4.o； A.188.y.4.o； A.189.y.4.o； A.190.y.4.o； A.196.y.4.o；A.202.y.4.o； A.205.y.4.o； A.206.y.4.o； A.207.y.4.o； A.208.y.4.o； A.209.y.4.o；A.210.y.4.o； A.211.y.4.o； A.212.y.4.o； A.213.y.4.o； A.700.y.4.o； A.701.y.4.o；A.702.y.4.o； A.703.y.4.o； A.704.y.4.o； A.705.y.4.o； A.706.y.4.o； A.707.y.4.o；A.708.y.4.o； A.709.y.4.o； A.710.y.4.o； A.711.y.4.o； A.712.y.4.o； A.713.y.4.o；A.714.y.4.o； A.715.y.4.o； A.716.y.4.o； A.717.y.4.o； A.718.y.4.o； A.719.y.4.o；A.720.y.4.o； A.721.y.4.o； A.722.y.4.o； A.723.y.4.o； A.724.y.4.o； A.172.z.4.i； A.173.z.4.i；A.174.z.4.i； A.175.z.4.i； A.176.z.4.i； A.188.z.4.i； A.189.z.4.i； A.190.z.4.i； A.196.z.4.i；A.202.z.4.i； A.205.z.4.i； A.206.z.4.i； A.207.z.4.i； A.208.z.4.i； A.209.z.4.i； A.210.z.4.i；A.211.z.4.i； A.212.z.4.i； A.213.z.4.i； A.700.z.4.i； A.701.z.4.i； A.702.z.4.i； A.703.z.4.i；A.704.z.4.i； A.705.z.4.i； A.706.z.4.i； A.707.z.4.i； A.708.z.4.i； A.709.z.4.i； A.710.z.4.i；A.711.z.4.i； A.712.z.4.i； A.713.z.4.i； A.714.z.4.i； A.715.z.4.i； A.716.z.4.i； A.717.z.4.i；A.718.z.4.i； A.719.z.4.i； A.720.z.4.i； A.721.z.4.i； A.722.z.4.i； A.723.z.4.i； A.724.z.4.i；A.3.z.4.o； A.4.z.4.o； A.7.z.4.o； A.9.z.4.o； A.103.z.4.o； A.106.z.4.o； A.107.z.4.o；A.108.z.4.o； A.111.z.4.o； A.114.z.4.o； A.117.z.4.o； A.118.z.4.o； A.119.z.4.o；A.120.z.4.o； A.121.z.4.o； A.137.z.4.o； A.138.z.4.o； A.139.z.4.o； A.140.z.4.o；A.141.z.4.o； A.142.z.4.o； A.145.z.4.o； A.146.z.4.o； A.147.z.4.o； A.148.z.4.o；A.149.z.4.o； A.150.z.4.o； A.151.z.4.o； A.165.z.4.o； A.166.z.4.o； A.167.z.4.o；A.168.z.4.o； A.169.z.4.o； A.170.z.4.o； A.171.z.4.o； A.172.z.4.o； A.173.z.4.o；A.174.z.4.o； A.175.z.4.o； A.176.z.4.o； A.188.z.4.o； A.189.z.4.o； A.190.z.4.o；A.196.z.4.o； A.202.z.4.o； A.205.z.4.o； A.206.z.4.o； A.207.z.4.o； A.208.z.4.o；A.209.z.4.o； A.210.z.4.o； A.211.z.4.o； A.212.z.4.o； A.213.z.4.o； A.700.z.4.o；A.701.z.4.o； A.702.z.4.o； A.703.z.4.o； A.704.z.4.o； A.705.z.4.o； A.706.z.4.o；A.707.z.4.o； A.708.z.4.o； A.709.z.4.o； A.710.z.4.o； A.711.z.4.o； A.712.z.4.o；A.713.z.4.o； A.714.z.4.o； A.715.z.4.o； A.716.z.4.o； A.717.z.4.o； A.718.z.4.o；A.719.z.4.o； A.720.z.4.o； A.721.z.4.o； A.722.z.4.o； A.723.z.4.o； A.724.z.4.o；A.172.A.4.i； A.173.A.4.i； A.174.A.4.i； A.175.A.4.i； A.176.A.4.i； A.188.A.4.i；A.189.A.4.i； A.190.A.4.i； A.196.A.4.i； A.202.A.4.i； A.205.A.4.i； A.206.A.4.i；A.207.A.4.i； A.208.A.4.i； A.209.A.4.i； A.210.A.4.i； A.211.A.4.i； A.212.A.4.i；A.213.A.4.i； A.700.A.4.i； A.701.A.4.i； A.702.A.4.i； A.703.A.4.i； A.704.A.4.i；A.705.A.4.i； A.706.A.4.i； A.707.A.4.i； A.708.A.4.i； A.709.A.4.i； A.710.A.4.i；A.711.A.4.i； A.712.A.4.i； A.713.A.4.i； A.714.A.4.i； A.715.A.4.i； A.716.A.4.i；A.717.A.4.i； A.718.A.4.i； A.719.A.4.i； A.720.A.4.i； A.721.A.4.i； A.722.A.4.i；A.723.A.4.i； A.724.A.4.i； A.3.A.4.o； A.4.A.4.o； A.7.A.4.o； A.9.A.4.o； A.103.A.4.o；A.106.A.4.o； A.107.A.4.o； A.108.A.4.o； A.111.A.4.o； A.114.A.4.o；A.117.A.4.o；A.118.A.4.o； A.119.A.4.o； A.120.A.4.o； A.121.A.4.o； A.137.A.4.o； A.138.A.4.o；A.139.A.4.o； A.140.A.4.o； A.141.A.4.o； A.142.A.4.o； A.145.A.4.o； A.146.A.4.o；A.147.A.4.o； A.148.A.4.o； A.149.A.4.o； A.150.A.4.o； A.151.A.4.o； A.165.A.4.o；A.166.A.4.o； A.167.A.4.o； A.168.A.4.o； A.169.A.4.o； A.170.A.4.o； A.171.A.4.o；A.172.A.4.o； A.173.A.4.o； A.174.A.4.o； A.175.A.4.o； A.176.A.4.o； A.188.A.4.o；A.189.A.4.o； A.190.A.4.o； A.196.A.4.o； A.202.A.4.o； A.205.A.4.o； A.206.A.4.o；A.207.A.4.o； A.208.A.4.o； A.209.A.4.o； A.210.A.4.o； A.211.A.4.o； A.212.A.4.o；A.213.A.4.o； A.700.A.4.o； A.701.A.4.o； A.702.A.4.o； A.703.A.4.o； A.704.A.4.o；A.705.A.4.o； A.706.A.4.o； A.707.A.4.o； A.708.A.4.o； A.709.A.4.o； A.710.A.4.o；A.711.A.4.o； A.712.A.4.o； A.713.A.4.o； A.714.A.4.o； A.715.A.4.o； A.716.A.4.o；A.717.A.4.o； A.718.A.4.o； A.719.A.4.o； A.720.A.4.o； A.721.A.4.o； A.722.A.4.o；A.723.A.4.o； A.724.A.4.o； A.172.B.4.i； A.173.B.4.i； A.174.B.4.i； A.175.B.4.i； A.176.B.4.i；A.188.B.4.i； A.189.B.4.i； A.190.B.4.i； A.196.B.4.i； A.202.B.4.i； A.205.B.4.i； A.206.B.4.i；A.207.B.4.i； A.208.B.4.i； A.209.B.4.i； A.210.B.4.i； A.211.B.4.i； A.212.B.4.i； A.213.B.4.i；A.700.B.4.i； A.701.B.4.i； A.702.B.4.i； A.703.B.4.i； A.704.B.4.i； A.705.B.4.i； A.706.B.4.i；A.707.B.4.i； A.708.B.4.i； A.709.B.4.i； A.710.B.4.i； A.711.B.4.i； A.712.B.4.i； A.713.B.4.i；A.714.B.4.i； A.715.B.4.i； A.716.B.4.i； A.717.B.4.i； A.718.B.4.i； A.719.B.4.i； A.720.B.4.i；A.721.B.4.i； A.722.B.4.i； A.723.B.4.i； A.724.B.4.i； A.3.B.4.o； A.4.B.4.o； A.7.B.4.o；A.9.B.4.o； A.103.B.4.o； A.106.B.4.o； A.107.B.4.o； A.108.B.4.o； A.111.B.4.o； A.114.B.4.o；A.117.B.4.o； A.118.B.4.o； A.119.B.4.o； A.120.B.4.o； A.121.B.4.o； A.137.B.4.o；A.138.B.4.o； A.139.B.4.o； A.140.B.4.o； A.141.B.4.o； A.142.B.4.o； A.145.B.4.o；A.146.B.4.o； A.147.B.4.o； A.148.B.4.o； A.149.B.4.o； A.150.B.4.o； A.151.B.4.o；A.165.B.4.o； A.166.B.4.o； A.167.B.4.o； A.168.B.4.o； A.169.B.4.o； A.170.B.4.o；A.171.B.4.o； A.172.B.4.o； A.173.B.4.o； A.174.B.4.o； A.175.B.4.o； A.176.B.4.o；A.188.B.4.o； A.189.B.4.o； A.190.B.4.o； A.196.B.4.o； A.202.B.4.o； A.205.B.4.o；A.206.B.4.o； A.207.B.4.o； A.208.B.4.o； A.209.B.4.o； A.210.B.4.o； A.211.B.4.o；A.212.B.4.o； A.213.B.4.o； A.700.B.4.o； A.701.B.4.o； A.702.B.4.o； A.703.B.4.o；A.704.B.4.o； A.705.B.4.o； A.706.B.4.o； A.707.B.4.o； A.708.B.4.o； A.709.B.4.o；A.710.B.4.o； A.711.B.4.o； A.712.B.4.o； A.713.B.4.o； A.714.B.4.o； A.715.B.4.o；A.716.B.4.o； A.717.B.4.o； A.718.B.4.o； A.719.B.4.o； A.720.B.4.o； A.721.B.4.o；A.722.B.4.o； A.723.B.4.o； A.724.B.4.o； B.3.a.54.i； B.4.a.54.i； B.7.a.54.i； B.9.a.54.i；B.103.a.54.i； B.106.a.54.i； B.107.a..54.i；B.108.a.54.i； B.111.a.54.i； B.114.a.54.i；B.117.a.54.i； B.118.a.54.i； B.119.a.54.i； B.120.a.54.i； B.121.a.54.i； B.137.a.54.i；B.138.a.54.i； B.139.a.54.i； B.140.a..54.i；B.141.a.54.i； B.142.a.54.i； B.145.a.54.i；B.146.a.54.i； B.147.a.54.i； B.148.a.54.i； B.149.a.54.i； B.150.a.54.i； B.151.a.54.i；B.165.a.54.i； B.166.a.54.i； B.167.a.54.i； B.168.a.54.i； B.169.a.54.i； B.170.a.54.i；B.171.a.54.i； B.172.a.54.i； B.173.a.54.i； B.174.a.54.i； B.175.a.54.i； B.176.a.54.i；B.188.a.54.i； B.189.a.54.i； B.190.a.54.i； B.196.a.54.i； B.202.a.54.i； B.205.a.54.i；B.206.a.54.i； B.207.a.54.i； B.208.a.54.i； B.209.a.54.i； B.210.a.54.i； B.211.a.54.i；B.212.a.54.i； B.213.a.54.i； B.700.a.54.i； B.701.a.54.i； B.702.a.54.i； B.703.a.54.i；B.704.a.54.i； B.705.a.54.i； B.706.a.54.i； B.707.a.54.i； B.708.a.54.i； B.709.a.54.i；B.710.a.54.i； B.711.a.54.i； B.712.a.54.i； B.713.a.54.i； B.714.a.54.i； B.715.a.54.i；B.716.a.54.i； B.717.a.54.i； B.718.a.54.i； B.719.a.54.i； B.720.a.54.i； B.721.a.54.iB.722.a.54.i； B.723.a.54.i； B.724.a.54.i； B.3.a.54.o； B.4.a.54.o； B.7.a.54.o； B.9.a.54.o；B.103.a.54.o； B.106.a.54.o； B.107.a.54.o； B.108.a.54.o； B.111.a.54.o； B.114.a.54.o；B.117.a.54.o； B.118.a.54.o； B.119.a.54.o； B.120.a.54.o； B.121.a.54.o； B.137.a.54.o；B.138.a.54.o； B.139.a.54.o； B.140.a.54.o； B.141.a.54.o； B.142.a.54.o； B.145.a.54.o；B.146.a.54.o； B.147.a.54.o； B.148.a.54.o； B.149.a.54.o； B.150.a.54.o； B.151.a.54.o；B.165.a.54.o； B.166.a.54.o； B.167.a.54.o； B.168.a.54.o； B.169.a.54.o； B.170.a.54.o；B.171.a.54.o； B.172.a.54.o； B.173.a.54.o； B.174.a.54.o； B.175.a.54.o； B.176.a.54.o；B.188.a.54.o； B.189.a.54.o； B.190.a.54.o； B.196.a.54.o； B.202.a.54.o； B.205.a.54.o；B.206.a.54.o； B.207.a.54.o； B.208.a.54.o； B.209.a.54.o； B.210.a.54.o； B.211.a.54.o；B.212.a.54.o； B.213.a.54.o； B.700.a.54.o； B.701.a.54.o； B.702.a.54.o； B.703.a.54.o；B.704.a.54.o； B.705.a.54.o； B.706.a.54.o； B.707.a.54.o； B.708.a.54.o； B.709.a.54.o；B.710.a.54.o； B.711.a.54.o； B.712.a.54.o； B.713.a.54.o； B.714.a.54.o； B.715.a.54.o；B.716.a.54.o； B.717.a.54.o； B.718.a.54.o； B.719.a.54.o； B.720.a.54.o； B.721.a.54.o；B.722.a.54.o； B.723.a.54.o； B.724.a.54.o； B.172.b.54.i； B.173.b.54.i； B.174.b.54.i；B.175.b.54.i； B.176.b.54.i； B.188.b.54.i； B.189.b.54.i； B.190.b.54.i； B.196.b.54.i；B.202.b.54.i； B.205.b.54.i； B.206.b.54.i； B.207.b.54.i； B.208.b.54.i； B.209.b.54.i；B.210.b.54.i； B.211.b.54.i； B.212.b.54.i； B.213.b.54.i； B.700.b.54.i； B.701.b.54.i；B.702.b.54.i； B.703.b.54.i； B.704.b.54.i； B.705.b.54.i； B.706.b.54.i； B.707.b.54.i；B.708.b.54.i； B.709.b.54.i； B.710.b.54.i； B.711.b.54.i； B.712.b.54.i； B.713.b.54.i；B.714.b.54.i； B.715.b.54.i； B.716.b.54.i； B.717.b.54.i； B.718.b.54.i； B.719.b.54.i；B.720.b.54.i； B.721.b.54.i； B.722.b.54.i； B.723.b.54.i； B.724.b.54.i； B.3.b.54.o； B.4.b.54.o；B.7.b.54.o； B.9.b.54.o； B.103.b.5.4.o；B.106.b.54.o； B.107.b.54.o； B.108.b.54.o；B.111.b.54.o； B.114.b.54.o； B.117.b.54.o； B.118.b.54.o； B.119.b.54.o； B.120.b.54.o；B.121.b.54.o； B.137.b.54.o； B.138.b.54.o； B.139.b.54.o； B.140.b.54.o； B.141.b.54.o；B.142.b.54.o； B.145.b.54.o； B.146.b.54.o； B.147.b.54.o； B.148.b.54.o； B.149.b.54.o；B.150.b.54.o； B.151.b.54.o； B.165.b.54.o； B.166.b.54.o； B.167.b.54.o； B.168.b.54.o；B.169.b.54.o； B.170.b.54.o； B.171.b.54.o； B.172.b.54.o； B.173.b.54.o； B.174.b.54.o；B.175.b.54.o； B.176.b.54.o； B.188.b.54.o； B.189.b.54.o； B.190.b.54.o； B.196.b.54.o；B.202.b.54.o； B.205.b.54.o； B.206.b.54.o； B.207.b.54.o； B.208.b.54.o； B.209.b.54.o；B.210.b.54.o； B.211.b.54.o； B.212.b.54.o； B.213.b.54.o； B.700.b.54.o； B.701.b.54.o；B.702.b.54.o； B.703.b.54.o； B.704.b.54.o； B.705.b.54.o； B.706.b.54.o； B.707.b.54.o；B.708.b.54.o； B.709.b.54.o； B.710.b.54.o； B.711.b.54.o； B.712.b.54.o； B.713.b.54.o；B.714.b.54.o； B.715.b.54.o； B.716.b.54.o； B.717.b.54.o； B.718.b.54.o； B.719.b.54.o；B.720.b.54.o； B.721.b.54.o； B.722.b.54.o； B.723.b.54.o； B.724.b.54.o； B.172.x.54.i；B.173.x.54.i； B.174.x.54.i； B.175.x.54.i； B.176.x.54.i； B.188.x.54.i； B.189.x.54.i；B.190.x.54.i； B.196.x.54.i； B.202.x.54.i； B.205.x.54.i； B.206.x.54.i； B.207.x.54.i；B.208.x.54.i； B.209.x.54.i； B.210.x.54.i； B.211.x.54.i； B.212.x.54.i； B.213.x.54.i；B.700.x.54.i； B.701.x.54.i； B.702.x.54.i； B.703.x.54.i； B.704.x.54.i； B.705.x.54.i；B.706.x.54.i； B.707.x.54.i； B.708.X.54.i； B.709.X.54.i； B.710.x.54.i； B.711.x.54.i；B.712.x.54.i； B.713.x.54.i； B.714.x.54.i； B.715.x.54.i； B.716.x.54.i； B.717.x.54.i；B.718.x.54.i； B.719.x.54.i； B.720.x.54.i； B.721.x.54.i； B.722.x.54.i； B.723.x.54.i；B.724.x.54.i； B.3.x.54.o； B.4.x.54.o； B.7.x.54.o； B.9.x.54.o； B.103.x.54.o； B.106.x.54.o；B.107.x.54.o； B.108.x.54.o； B.111.x.54.o； B.114.x.54.o； B.117.x.54.o； B.118.x.54.o；B.119.x.54.o； B.120.x.54.o； B.121.x.54.o； B.137.x.54.o； B.138.x.54.o； B.139.x.54.o；B.140.x.54.o； B.141.x.54.o； B.142.x.54.o； B.145.x.54.o； B.146.x.54.o； B.147.x.54.o；B.148.x.54.o； B.149.x.54.o； B.150.x.54.o； B.151.x.54.o； B.165.x.54.o； B.166.x.54.o；B.167.x.54.o； B.168.x.54.o； B.169.x.54.o； B.170.x.54.o； B.171.x.54.o； B.172.x.54.o；B.173.x.54.o； B.174.x.54.o； B.175.x.54.o； B.176.x.54.o； B.188.x.54.o； B.189.x.54.o；B.190.x.54.o； B.196.x.54.o； B.202.x.54.o； B.205.x.54.o； B.206.x.54.o； B.207.x.54.o；B.208.x.54.o； B.209.x.54.o； B.210.x.54.o； B.211.x.54.o； B.212.x.54.o； B.213.x.54.o；B.700.x.54.o； B.701.x.54.o； B.702.x.54.o； B.703.x.54.o； B.704.x.54.o； B.705.x.54.o；B.706.x.54.o； B.707.x.54.o； B.708.x.54.o； B.709.x.54.o； B.710.x.54.o； B.711.x.54.o；B.712.x.54.o； B.713.x.54.o； B.714.x.54.o； B.715.x.54.o； B.716.x.54.o； B.717.x.54.o；B.718.x.54.o； B.719.x.54.o； B.720.x.54.o； B.721.x.54.o； B.722.x.54.o； B.723.x.54.o；B.724.x.54.o； B.172.y.54.i； B.173.y.54.i； B.174.y.54.i； B.175.y.54.i； B.176.y.54.i；B.188.y.54.i； B.189.y.54.i； B.190.y.54.i； B.196.y.54.i； B.202.y.54.i； B.205.y.54.i；B.206.y.54.i； B.207.y.54.i； B.208.y.54.i； B.209.y.54.i； B.210.y.54.i； B.211.y.54.i；B.212.y.54.i； B.213.y.54.i； B.700.y.54.i； B.701.y.54.i； B.702.y.54.i； B.703.y.54.i；B.704.y.54.i； B.705.y.54.i； B.706.y.54.i； B.707.y.54.i； B.708.y.54.i； B.709.y.54.i；B.710.y.54.i； B.711.y.54.i； B.712.y.54.i； B.713.y.54.i； B.714.y.54.i； B.715.y.54.i；B.716.y.54.i； B.717.y.54.i； B.718.y.54.i； B.719.y.54.i； B.720.y.54.i； B.721.y.54.i；B.722.y.54.i； B.723.y.54.i； B.724.y.54.i； B.3.y.54.o； B.4.y.54.o； B.7.y.54.o； B.9.y.54.o；B.103.y.54.o； B.106.y.54.o； B.107.y.54.o； B.108.y.54.o； B.111.y.54.o； B.114.y.54.o；B.117.y.54.o； B.118.y.54.o； B.119.y.54.o； B.120.y.54.o； B.121.y.54.o； B.137.y.54.o；B.138.y.54.o； B.139.y.54.o； B.140.y.54.o； B.141.y.54.o； B.142.y.54.o； B.145.y.54.o；B.146.y.54.o； B.147.y.54.o； B.148.y.54.o； B.149.y.54.o； B.150.y.54.o； B.151.y.54.o；B.165.y.54.o； B.166.y.54.o； B.167.y.54.o； B.168.y.54.o； B.169.y.54.o； B.170.y.54.o；B.171.y.54.o； B.172.y.54.o； B.173.y.54.o； B.174.y.54.o； B.175.y.54.o； B.176.y.54.o；B.188.y.54.o； B.189.y.54.o； B.190.y.54.o； B.196.y.54.o； B.202.y.54.o； B.205.y.54.o；B.206.y.54.o； B.207.y.54.o； B.208.y.54.o； B.209.y.54.o； B.210.y.54.o； B.211.y.54.o；B.212.y.54.o； B.213.y.54.o； B.700.y.54.o； B.701.y.54.o； B.702.y.54.o； B.703.y.54.o；B.704.y.54.o； B.705.y.54.o； B.706.y.54.o； B.707.y.54.o； B.708.y.54.o； B.709.y.54.o；B.710.y.54.o； B.711.y.54.o； B.712.y.54.o； B.713.y.54.o； B.714.y.54.o； B.715.y.54.o；B.716.y.54.o； B.717.y.54.o； B.718.y.54.o； B.719.y.54.o； B.720.y.54.o； B.721.y.54.o；B.722.y.54.o； B.723.y.54.o； B.724.y.54.o； B.172.z.54.i； B.173.z.54.i； B.174.z.54.i；B.175.z.54.i； B.176.z.54.i； B.188.z.54.i； B.189.z.54.i； B.190.z.54.i； B.196.z.54.i；B.202.z.54.i； B.205.z.54.i； B.206.z.54.i； B.207.z.54.i； B.208.z.54.i； B.209.z.54.i；B.210.z.54.i； B.211.z.54.i； B.212.z.54.i； B.213.z.54.i； B.700.z.54.i； B.701.z.54.i；B.702.z.54.i； B.703.z.54.i； B.704.z.54.i； B.705.z.54.i； B.706.z.54.i； B.707.z.54.i；B.708.z.54.i； B.709.z.54.i； B.710.z.54.i； B.711.z.54.i； B.712.z.54.i； B.713.z.54.i；B.714.z.54.i； B.715.z.54.i； B.716.z.54.i； B.717.z.54.i； B.718.z.54.i； B.719.z.54.i；B.720.z.54.i； B.721.z.54.i； B.722.z.54.i； B.723.z.54.i； B.724.z.54.i； B.3.z.54.o； B.4.z.54.o；B.7.z.54.o； B.9.z.54.o； B.103.z.54.o； B.106.z.54.o； B.107.z.54.o； B.108.z.54.o；B.111.z.54.o； B.114.z.54.o； B.117.z.54.o； B.118.z.54.o； B.119.z.54.o； B.120.z.54.o；B.121.z.54.o； B.137.z.54.o； B.138.z.54.o； B.139.z.54.o； B.140.z.54.o； B.141.z.54.o；B.142.z.54.o； B.145.z.54.o； B.146.z.54.o； B.147.z.54.o； B.148.z.54.o； B.149.z.54.o；B.150.z.54.o； B.151.z.54.o； B.165.z.54.o； B.166.z.54.o； B.167.z.54.o； B.168.z.54.o；B.169.z.54.o； B.170.z.54.o； B.171.z.54.o； B.172.z.54.o； B.173.z.54.o； B.174.z.54.o；B.175.z.54.o； B.176.z.54.o； B.188.z.54.o； B.189.z.54.o； B.190.z.54.o； B.196.z.54.o；B.202.z.54.o； B.205.z.54.o； B.206.z.54.o； B.207.z.54.o； B.208.z.54.o； B.209.z.54.o；B.210.z.54.o； B.211.z.54.o； B.212.z.54.o； B.213.z.54.o； B.700.z.54.o； B.701.z.54.o；B.702.z.54.o； B.703.z.54.o； B.704.z.54.o； B.705.z.54.o； B.706.z.54.o； B.707.z.54.o；B.708.z.54.o； B.709.z.54.o； B.710.z.54.o； B.711.z.54.o； B.712.z.54.o； B.713.z.54.o；B.714.z.54.o； B.715.z.54.o； B.716.z.54.o； B.717.z.54.o； B.718.z.54.o； B.719.z.54.o；B.720.z.54.o； B.721.z.54.o； B.722.z.54.o； B.723.z.54.o； B.724.z.54.o； B.172.A.54.i；B.175.A.54.i； B.174.A.54.i； B.175.A.54.i； B.176.A.54.i； B.188.A.54.i； B.189.A.54.i；B.190.A.54.i； B.196.A.54.i； B.202.A.54.i； B.205.A.54.i； B.206.A.54.i； B.207.A.54.i；B.208.A.54.i； B.209.A.54.i； B.210.A.54.i； B.211.A.54.i； B.212.A.54.i； B.213.A.54.i；B.700.A.54.i； B.701.A.54.i； B.702.A.54.i； B.703.A.54.i； B.704.A.54.i； B.705.A.54.i；B.706.A.54.i； B.707.A.54.i； B.708.A.54.i； B.709.A.54.i； B.710.A.54.i； B.711.A.54.i；B.712.A.54.i； B.713.A.54.i； B.714.A.54.i； B.715.A.54.i； B.716.A.54.i； B.717.A.54.i；B.718.A.54.i； B.719.A.54.i； B.720.A.54.i； B.721.A.54.i； B.722.A.54.i； B.723.A.54.i；B.724.A.54.i； B.3.A.54.o； B.4.A.54.o； B.7.A.54.o； B.9.A.54.o； B.103.A.54.o； B.106.A.54.o；B.107.A.54.o； B.108.A.54.o； B.111.A.54.o； B.114.A.54.o； B.117.A.54.o； B.118.A.54.o；B.119.A.54.o； B.120.A.54.o； B.121.A.54.o； B.137.A.54.o； B.138.A.54.o； B.139.A.54.o；B.140.A.54.o； B.141.A.54.o； B.142.A.54.o； B.145.A.54.o； B.146.A.54.o； B.147.A.54.o；B.148.A.54.o； B.149.A.54.o； B.150.A.54.o； B.151.A.54.o； B.165.A.54.o； B.166.A.54.o；B.167.A.54.o； B.168.A.54.o； B.169.A.54.o； B.170.A.54.o； B.171.A.54.o； B.172.A.54.o；B.173.A.54.o； B.174.A.54.o； B.175.A.54.o； B.176.A.54.o； B.188.A.54.o； B.189.A.54.o；B.190.A.54.o； B.196.A.54.o； B.202.A.54.o； B.205.A.54.o； B.206.A.54.o； B.207.A.54.o；B.208.A.54.o； B.209.A.54.o； B.210.A.54.o； B.211.A.54.o； B.212.A.54.o； B.213.A.54.o；B.700.A.54.o； B.701.A.54.o； B.702.A.54.o； B.703.A.54.o； B.704.A.54.o； B.705.A.54.o；B.706.A.54.o； B.707.A.54.o； B.708.A.54.o； B.709.A.54.o； B.710.A.54.o； B.711.A.54.o；B.712.A.54.o； B.713.A.54.o； B.714.A.54.o； B.715.A.54.o； B.716.A.54.o； B.717.A.54.o；B.718.A.54.o； B.719.A.54.o； B.720.A.54.o； B.721.A.54.o； B.722.A.54.o； B.723.A.54.o；B.724.A.54.o； B.172.B.54.i； B.173.B.54.i； B.174.B.54.i； B.175.B.54.i； B.176.B.54.i；B.188.B.54.i； B.189.B.54.i； B.190.B.54.i； B.196.B.54.i； B.202.B.54.i； B.205.B.54.i；B.206.B.54.i； B.207.B.54.i； B.208.B.54.i； B.209.B.54.i； B.210.B.54.i； B.211.B.54.i；B.212.B.54.i； B.213.B.54.i； B.700.B.54.i； B.701.B.54.i； B.702.B.54.i； B.703.B.54.i；B.704.B.54.i； B.705.B.54.i； B.706.B.54.i； B.707.B.54.i； B.708.B.54.i； B.709.B.54.i；B.710.B.54.i； B.711.B.54.i； B.712.B.54.i； B.713.B.54.i； B.714.B.54.i； B.715.B.54.i；B.716.B.54.i； B.717.B.54.i； B.718.B.54.i； B.719.B.54.i； B.720.B.54.i； B.721.B.54.i；B.722.B.54.i； B.723.B.54.i； B.724.B.54.i； B.3.B.54.o； B.4.B.54.o； B.7.B.54.o； B.9.B.54.o；B.103.B.54.o； B.106.B.54.o； B.107.B.54.o； B.108.B.54.o； B.111.B.54.o； B.114.B.54.o；B.117.B.54.o； B.118.B.54.o； B.119.B.54.o； B.120.B.54.o； B.121.B.54.o； B.137.B.54.o；B.138.B.54.o； B.139.B.54.o； B.140.B.54.o； B.141.B.54.o； B.142.B.54.o； B.145.B.54.o；B.146.B.54.o； B.147.B.54.o； B.148.B.54.o； B.149.B.54.o； B.150.B.54.o； B.151.B.54.o；B.165.B.54.o； B.166.B.54.o； B.167.B.54.o； B.168.B.54.o； B.169.B.54.o； B.170.B.54.o；B.171.B.54.o； B.172.B.54.o； B.173.B.54.o； B.174.B.54.o； B.175.B.54.o； B.176.B.54.o；B.188.B.54.o； B.189.B.54.o； B.190.B.54.o； B.196.B.54.o； B.202.B.54.o； B.205.B.54.o；B.206.B.54.o； B.207.B.54.o； B.208.B.54.o； B.209.B.54.o； B.210.B.54.o； B.211.B.54.o；B.212.B.54.o； B.213.B.54.o； B.700.B.54.o； B.701.B.54.o； B.702.B.54.o； B.703.B.54.o；B.704.B.54.o； B.705.B.54.o； B.706.B.54.o； B.707.B.54.o； B.708.B.54.o； B.709.B.54.o；B.710.B.54.o； B.711.B.54.o； B.712.B.54.o； B.713.B.54.o； B.714.B.54.o； B.715.B.54.o；B.716.B.54.o； B.717.B.54.o； B.718.B.54.o； B.719.B.54.o； B.720.B.54.o； B.721.B.54.o；B.722.B.54.o； B.723.B.54.o； B.724.B.54.o C.3.a.54.i； C.4.a.54.i； C.7.a.54.i； C.9.a.54.i；C.103.a.54.i； C.106.a.54.i； C.107.a.54.i； C.108.a.54.i； C.111.a.54.i； C.114.a.54.i；C.117.a.54.i； C.118.a.54.i； C.119.a.54.i； C.120.a.54.i； C.121.a.54.i； C.137.a.54.i；C.138.a.54.i； C.139.a.54.i； C.140.a.54.i； C.141.a.54.i； C.142.a.54.i； C.145.a.54.i；C.146.a.54.i； C.147.a.54.i； C.148.a.54.i； C.149.a.54.i； C.150.a.54.i； C.151.a.54.i；C.165.a.54.i； C.166.a.54.i； C.167.a.54.i； C.168.a.54.i； C.169.a.54.i； C.170.a.54.i；C.171.a.54.i； C.172.a.54.i； C.173.a.54.i； C.174.a.54.i； C.175.a.54.i； C.176.a.54.i；C.188.a.54.i； C.189.a.54.i； C.190.a.54.i； C.196.a.54.i； C.202.a.54.i； C.205.a.54.i；C.206.a.54.i； C.207.a.54.i； C.208.a.54.i； C.209.a.54.i； C.210.a.54.i； C.211.a.54.i；C.212.a.54.i； C.213.a.54.i； C.700.a.54.i； C.701.a.54.i； C.702.a.54.i； C.703.a.54.i；C.704.a.54.i； C.705.a.54.i； C.706.a.54.i； C.707.a.54.i； C.708.a.54.i； C.709.a.54.i；C.710.a.54.i； C.711.a.54.i； C.712.a.54.i； C.713.a.54.i； C.714.a.54.i； C.715.a.54.i；C.716.a.54.i； C.717.a.54.i； C.718.a.54.i； C.719.a.54.i； C.720.a.54.i； C.721.a.54.i；C.722.a.54.i； C.723.a.54.i； C.724.a.54.i； C.3.a.54.o； C.4.a.54.o； C.7.a.54.o； C.9.a.54.o；C.103.a.54.o； C.106.a.54.o； C.107.a.54.o； C.108.a.54.0； C.111.a.54.o； C.114.a.54.o；C.117.a.54.o； C.118.a.54.o； C.119.a.54.o； C.120.a.54.o； C.121.a.54.o； C.137.a.54.o；C.138.a.54.o； C.139.a.54.o； C.140.a.54.o； C.141.a.54.o； C.142.a.54.o； C.145.a.54.o；C.146.a.54.o； C.147.a.54.o； C.148.a.54.o； C.149.a.54.o； C.150.a.54.o； C.151.a.54.o；C.165.a.54.o； C.166.a.54.o； C.167.a.54.o； C.168.a.54.o； C.169.a.54.o； C.170.a.54.o；C.171.a.54.o； C.172.a.54.o； C.173.a.54.o； C.174.a.54.o； C.175.a.54.o； C.176.a.54.o；C.188.a.54.o； C.189.a.54.o； C.190.a.54.o； C.196.a.54.o； C.202.a.54.o； C.205.a.54.o；C.206.a.54.o； C.207.a.54.o； C.208.a.54.o； C.209.a.54.o； C.210.a.54.o； C.211.a.54.o；C.212.a.54.o； C.213.a.54.o； C.700.a.54.o； C.701.a.54.o； C.702.a.54.o； C.703.a.54.o；C.704.a.54.o； C.705.a.54.o； C.706.a.54.o； C.707.a.54.o； C.708.a.54.o； C.709.a.54.o；C.710.a.54.o； C.711.a.54.o； C.712.a.54.o； C.713.a.54.o； C.714.a.54.o； C.715.a.54.o；C.716.a.54.o； C.717.a.54.o； C.718.a.54.o； C.719.a.54.o； C.720.a.54.o； C.721.a.54.o；C.722.a.54.o； C.723.a.54.o； C.724.a.54.o； C.172.b.54.i； C.173.b.54.i； C.174.b.54.i；C.175.b.54.i； C.176.b.54.i； C.188.b.54.i； C.189.b.54.i； C.190.b.54.i； C.196.b.54.i；C.202.b.54.i； C.205.b.54.i； C.206.b.54.i； C.207.b.54.i； C.208.b.54.i； C.209.b.54.i；C.210.b.54.i； C.211.b.54.i； C.212.b.54.i； C.213.b.54.i； C.700.b.54.i； C.701.b.54.i；C.702.b.54.i； C.703.b.54.i； C.704.b.54.i； C.705.b.54.i； C.706.b.54.i； C.707.b.54.i；C.708.b.54.i； C.709.b.54.i； C.710.b.54.i； C.711.b.54.i； C.712.b.54.i； C.713.b.54.i；C.714.b.54.i； C.715.b.54.i； C.716.b.54.i； C.717.b.54.i； C.718.b.54.i； C.719.b.54.i；C.720.b.54.i； C.721.b.54.i； C.722.b.54.i； C.723.b.54.i； C.724.b.54.i； C.3.b.54.o； C.4.b.54.o；C.7.b.54.o； C.9.b.54.o； C.103.b.54.o； C.106.b.54.o； C.107.b.54.o； C.108.b.54.o；C.111.b.54.o； C.114.b.54.o； C.117.b.54.o； C.118.b.54.o； C.119.b.54.o； C.120.b.54.o；C.121.b.54.o； C.137.b.54.o； C.138.b.54.o； C.139.b.54.o； C.140.b.54.o； C.141.b.54.o；C.142.b.54.o； C.145.b.54.o； C.146.b.54.o； C.147.b.54.o； C.148.b.54.o； C.149.b.54.o；C.150.b.54.o； C.151.b.54.o； C.165.b.54.o； C.166.b.54.o； C.167.b.54.o； C.168.b.54.o；C.169.b.54.o； C.170.b.54.o； C.171.b.54.o； C.172.b.54.o； C.173.b.54.o； C.174.b.54.o；C.175.b.54.o； C.176.b.54.o； C.188.b.54.o； C.189.b.54.o； C.190.b.54.o； C.196.b.54.o；C.202.b.54.o； C.205.b.54.o； C.206.b.54.o； C.207.b.54.o； C.208.b.54.o； C.209.b.54.o；C.210.b.54.o； C.211.b.54.o； C.212.b.54.o； C.213.b.54.o； C.700.b.54.o； C.701.b.54.o；C.702.b.54.o； C.703.b.54.o； C.704.b.54.o； C.705.b.54.o； C.706.b.54.o； C.707.b.54.o；C.708.b.54.o； C.709.b.54.o； C.710.b.54.o； C.711.b.54.o； C.712.b.54.o； C.713.b.54.o；C.714.b.54.o； C.715.b.54.o； C.716.b.54.o； C.717.b.54.o； C.718.b.54.o； C.719.b.54.o；C.720.b.54.o； C.721.b.54.o； C.722.b.54.o； C.723.b.54.o； C.724.b.54.o； C.172.x.54.i；C.173.x.54.i； C.174.x.54.i； C.175.x.54.i； C.176.x.54.i； C.188.x.54.i； C.189.x.54.i；C.190.x.54.i； C.196.x.54.i； C.202.x.54.i； C.205.x.54.i； C.206.x.54.i； C.207.x.54.i；C.208.x.54.i； C.209.x.54.i； C.210.x.54.i； C.211.x.54.i； C.212.x.54.i； C.213.x.54.i；C.700.x.54.i； C.701.x.54.i； C.702.x.54.i； C.703.x.54.i； C.704.x.54.i； C.705.x.54.i；C.706.x.54.i； C.707.x.54.i； C.708.x.54.i； C.709.x.54.i； C.710.x.54.i； C.711.x.54.i；C.712.x.54.i； C.713.x.54.i； C.714.x.54.i； C.715.x.54.i； C.716.x.54.i； C.717.x.54.i；C.718.x.54.i； C.719.x.54.i； C.720.x.54.i； C.721.x.54.i； C.722.x.54.i； C.723.x.54.i；C.724.x.54.i； C.3.x.54.o； C.4.x.54.o； C.7. x.54.o； C.9.x.54.o； C.103.x.54.o； C.106.x.54.o；C.107.x.54.o； C.108.x.54.o； C.111.x.54.o； C.114.x.54.o； C.117.x.54.o； C.118.x.54.o；C.119.x.54.o； C.120.x.54.o； C.121.x.54.o； C.137.x.54.o； C.138.x.54.o； C.139.x.54.o；C.140.x.54.o； C.141.x.54.o； C.142.x.54.o； C.145.x.54.o； C.146.x.54.o； C.147.x.54.o；C.148.x.54.o； C.149.x.54.o； C.150.x.54.o； C.151.x.54.o； C.165.x.54.o； C.166.x.54.o；C.167.x.54.o； C.168.x.54.o； C.169.x.54.o； C.170.x.54.o； C.171.x.54.o； C.172.x.54.o；C.173.x.54.o； C.174.x.54.o； C.175.x.54.o； C.176.x.54.o； C.188.x.54.o； C.189.x.54.o；C.190.x.54.o； C.196.x.54.o； C.202.x.54.o； C.205.x.54.o； C.206.x.54.o； C.207.x.54.o；C.208.x.54.o； C.209.x.54.o； C.210.x.54.o； C.211.x.54.o； C.212.x.54.o； C.213.x.54.o；C.700.x.54.o； C.701.x.54.o； C.702.x.54.o； C.703.x.54.o； C.704.x.54.o； C.705.x.54.o；C.706.x.54.o； C.707.x.54.o； C.708.x.54.o； C.709.x.54.o； C.710.x.54.o； C.711.x.54.o；C.712.x.54.o； C.713.x.54.o； C.714.x.54.o； C.715.x.54.o； C.716.x.54.o； C.717.x.54.o；C.718.x.54.o； C.719.x.54.o； C.720.x.54.o； C.721.x.54.o； C.722.x.54.o； C.723.x.54.o；C.724.x.54.o； C.172.y.54.i； C.173.y.54.i； C.174.y.54.i； C.175.y.54.i； C.176.y.54.i；C.188.y.54.i； C.189.y.54.i； C.190.y.54.i； C.196.y.54.i； C.202.y.54.i； C.205.y.54.i；C.206.y.54.i； C.207.y.54.i； C.208.y.54.i； C.209.y.54.i； C.210.y.54.i； C.211.y.54.i；C.212.y.54.i； C.213.y.54.i； C.700.y.54.i； C.701.y.54.i； C.702.y.54.i； C.703.y.54.i；C.704.y.54.i； C.705.y.54.i； C.706.y.54.i； C.707.y.54.i； C.708.y.54.i； C.709.y.54.i；C.710.y.54.i； C.711.y.54.i； C.712.y.54.i； C.713.y.54.i； C.714.y.54.i； C.715.y；54.i；C.716.y.54.i； C.717.y.54.i； C.718.y.54.i； C.719.y.54.i； C.720.y.54.i； C.721.y.54.i；C.722.y.54.i； C.723.y.54.i； C.724.y.54.i； C.3.y.54.o； C.4.y.54.o； C.7.y.54.o； C.9.y.54.o；C.103.y.54.o； C.106.y.54.o； C.107.y.54.o； C.108.y.54.o； C.111.y.54.o； C.114.y.54.o；C.117.y.54.o； C.118.y.54.o； C.119.y.54.o； C.120.y.54.o； C.121.y.54.o； C.137.y.54.o；C.138.y.54.o； C.139.y.54.o； C.140.y.54.o； C.141.y.54.o； C.142.y.54.o； C.145.y.54.o；C.146.y.54.o； C.147.y.54.o； C.148.y.54.o； C.149.y.54.o； C.150.y.54.o； C.151.y.54.o；C.165.y.54.o； C.166.y.54.o； C.167.y.54.o； C.168.y.54.o； C.169.y.54.o； C.170.y.54.o；C.171.y.54.o； C.172.y.54.o； C.173.y.54.o； C.174.y.54.o； C.175.y.54.o； C.176.y.54.o；C.188.y.54.o； C.189.y.54.o； C.190.y.54.o； C.196.y.54.o； C.202.y.54.o； C.205.y.54.o；C.206.y.54.o； C.207.y.54.o； C.208.y.54.o； C.209.y.54.o； C.210.y.54.o； C.211.y.54.o；C.212.y.54.o； C.213.y.54.o； C.700.y.54.o； C.701.y.54.o； C.702.y.54.o； C.703.y.54.o；C.704.y.54.o； C.705.y.54.o； C.706.y.54.o； C.707.y.54.o； C.708.y.54.o； C.709.y.54.o；C.710.y.54.o； C.711.y.54.o； C.712.y.54.o； C.713.y.54.o； C.714.y.54.o； C.715.y.54.o；C.716.y.54.o； C.717.y.54.o； C.718.y.54.o； C.719.y.54.o； C.720.y.54.o； C.721.y.54.o；C.722.y.54.o； C.723.y.54.o； C.724.y.54.o； C.172.z.54.i； C.173.z.54.i； C.174.z.54.i；C.175.z.54.i； C.176.z.54.i； C.188.z.54.i； C.189.z.54.i； C.190.z.54.i； C.196.z.54.i；C.202.z.54.i； C.205.z.54.i； C.206.z.54.i； C.207.z.54.i； C.208.z.54.i； C.209.z.54.i；C.210.z.54.i； C.211.z.54.i； C.212.z.54.i； C.213.z.54.i； C.700.z.54.i； C.701.z.54.i；C.702.z.54.i； C.703.z.54.i； C.704.z.54.i； C.705.z.54.i； C.706.z.54.i； C.707.z.54.i；C.708.z.54.i； C.709.z.54.i； C.710.z.54.i； C.711.z.54.i； C.712.z.54.i； C.713.z.54.i；C.714.z.54.i； C.715.z.54.i； C.716.z.54.i； C.717.z.54.i； C.718.z.54.i； C.719.z.54.i；C.720.z.54.i； C.721.z.54.i； C.722.z.54.i； C.723.z.54.i； C.724.z.54.i； C.3.z.54.o； C.4.z.54.o；C.7.z.54.o； C.9.z.54.o； C.103.z.54.o； C.106.z.54.o； C.107.z.54.o； C.108.z.54.o；C.111.z.54.o； C.114.z.54.o； C.117.z.54.o； C.118.z.54.o； C.119.z.54.o； C.120.z.54.o；C.121.z.54.o； C.137.z.54.o； C.138.z.54.o； C.139.z.54.o； C.140.z.54.o； C.141.z.54.o；C.142.z.54.o； C.145.z.54.o； C.146.z.54.o； C.147.z.54.o； C.148.z.54.o； C.149.z.54.o；C.150.z.54.o； C.151.z.54.o； C.165.z.54.o； C.166.z.54.o； C.167.z.54.o； C.168.z.54.o；C.169.z.54.o； C.170.z.54.o； C.171.z.54.o； C.172.z.54.o； C.173.z.54.o； C.174.z.54.o；C.175.z.54.o； C.176.z.54.o； C.188.z.54.o； C.189.z.54.o； C.190.z.54.o； C.196.z.54.o；C.202.z.54.o；C.205.z.54.o；C.206.z.54.o；C.207.z.54.o；C.208.z.54.o；C.209.z.54.oC.210.z.54.o；C.211.z.54.o；C.212.z.54.o；C.213.z.54.o；C.700.z.54.o；C.701.z.54.oC.702.z.54.o；C.703.z.54.o；C.704.z.54.o；C.705.z.54.o；C.706.z.54.o；C.707.z.54.oC.708.z.54.o；C.709.z.54.o；C.710.z.54.o；C.711.z.54.o；C.712.z.54.o；C.713.z.54.oC.714.z.54.o；C.715.z.54.o；C.716.z.54.o；C.717.z.54.o；C.718.z.54.o；C.719.z.54.oC.720.z.54.o；C.721.z.54.o；C.722.z.54.o；C.723.z.54.o；C.724.z.54.o；C.172.A.54.i；C.173.A.54.i；C.174.A.54.i；C.175.A.54.i；C.176.A.54.i；C.188.A.54.i；C.189.A.54.i；C.190.A.54.i；C.196.A.54.i；C.202.A.54.i；C.205.A.54.i；C.206.A.54.i；C.207.A.54.i；C.208.A.54.i；C.209.A.54.i；C.210.A.54.i；C.211.A.54.i；C.212.A.54.i；C.213.A.54.i；C.700.A.54.i；C.701.A.54.i；C.702.A.54.i；C.703.A.54.i；C.704.A.54.i；C.705.A.54.i；C.706.A.54.i；C.707.A.54.i；C.708.A.54.i；C.709.A.54.i；C.710.A.54.i；C.711.A.54.i；C.712.A.54.i；C.713.A.54.i；C.714.A.54.i；C.715.A.54.i；C.716.A.54.i；C.717.A.54.i；C.718.A.54.i；C.719.A.54.i；C.720.A.54.i；C.721.A.54.i；C.722.A.54.i；C.723.A.54.iC.724.A.54.i；C.3.A.54.o； C.4.A.54.o； C.7.A.54.o； C.9.A.54.o； C.103.A.54.o；C.106.A.54.o；C.107.A.54.o；C.108.A.54.o；C.111.A.54.o；C.114.A.54.o；C.117.A.54.o；C.118.A.54.o；C.119.A.54.o；C.120.A.54.o；C.121.A.54.o；C.137.A.54.o；C.138.A.54.o；C.139.A.54.o；C.140.A.54.o；C.141.A.54.o；C.142.A.54.o；C.145.A.54.o；C.146.A.54.o；C.147.A.54.o；C.148.A.54.o；C.149.A.54.o；C.150.A.54.o；C.151.A.54.o；C.165.A.54.o；C.166.A.54.o；C.167.A.54.o；C.168.A.54.o；C.169.A.54.o；C.170.A.54.o；C.171.A.54.o；C.172.A.54.o；C.173.A.54.o；C.174.A.54.o；C.175.A.54.o；C.176.A.54.o；C.188.A.54.o；C.189.A.54.o；C.190.A.54.o；C.196.A.54.o；C.202.A.54.o；C.205.A.54.o；C.206.A.54.o；C.207.A.54.o；C.208.A.54.o；C.209.A.54.o；C.210.A.54.o；C.211.A.54.o；C.212.A.54.o；C.213.A.54.o；C.700.A.54.o；C.701.A.54.o；C.702.A.54.o；C.703.A.54.o；C.704.A.54.o；C.705.A.54.o；C.706.A.54.o；C.707.A.54.o；C.708.A.54.o；C.709.A.54.o；C.710.A.54.o；C.711.A.54.o；C.712.A.54.o；C.713.A.54.o；C.714.A.54.o；C.715.A.54.o；C.716.A.54.o；C.717.A.54.o；C.718.A.54.o；C.719.A.54.o；C.720.A.54.o；C.721.A.54.o；C.722.A.54.o；C.723.A.54.o；C.724.A.54.o；C.172.B.54.i；C.173.B.54.i；C.174.B.54.i；C.175.B.54.i；C.176.B.54.i；C.188.B.54.i；C.189.B.54.i；C.190.B.54.i；C.196.B.54.i；C.202.B.54.i；C.205.B.54.i；C.206.B.54.i；C.207.B.54.i；C.208.B.54.i；C.209.B.54.i；C.210.B.54.i；C.211.B.54.i；C.212.B.54.i；C.213.B.54.i；C.700.B.54.i；C.701.B.54.i；C.702.B.54.i；C.703.B.54.i；C.704.B.54.i；C.705.B.54.i；C.706.B.54.i；C.707.B.54.i；C.708.B.54.i；C.709.B.54.i；C.710.B.54.i；C.711.B.54.i；C.712.B.54.i；C.713.B.54.i；C.714.B.54.i；C.715.B.54.i；C.716.B.54.i；C.717.B.54.i；C.718.B.54.i；C.719.B.54.i；C.720.B.54.i；C.721.B.54.i；C.722.B.54.i；C.723.B.54.i；C.724.B.54.i；C.3.B.54.o； C.4.B.54.o； C.7.B.54.o；C.9.B.54.o； C.103.B.54.o；C.106.B.54.o；C.107.B.54.o；C.108.B.54.o；C.111.B.54.o；C.114.B.54.o；C.117.B.54.o；C.118.B.54.o；C.119.B.54.o；C.120.B.54.o；C.121.B.54.9；C.137.B.54.o；C.138.B.54.o；C.139.B.54.o；C.140.B.54.o；C.141.B.54.o；C.142.B.54.o；C.145.B.54.o；C.146.B.54.o；C.147.B.54.o；C.148.B.54.o；C.149.B.54.o；C.150.B.54.o；C.151.B.54.o；C.165.B.54.o；C.166.B.54.o；C.167.B.54.o；C.168.B.54.o；C.169.B.54.o；C.170.B.54.o；C.171.B.54.o；C.172.B.54.o；C.173.B.54.o；C.174.B.54.o；C.175.B.54.o；C.176.B.54.o；C.188.B.54.o；C.189.B.54.o；C.190.B.54.o；C.196.B.54.o；C.202.B.54.o；C.205.B.54.o；C.206.B.54.o；C.207.B.54.o；C.208.B.54.o；C.209.B.54.o；C.210.B.54.o；C.211.B.54.o；C.212.B.54.o；C.213.B.54.o；C.700.B.54.o；C.701.B.54.o；C.702.B.54.o；C.703.B.54.o；C.704.B.54.o；C.705.B.54.o；C.706.B.54.o；C.707.B.54.o；C.708.B.54.o；C.709.B.54.o；C.710.B.54.o；C.711.B.54.o；C.712.B.54.o；C.713.B.54.o；C.714.B.54.o；C.715.B.54.o；C.716.B.54.o；C.717.B.54.o；C.718.B.54.o；C.719.B.54.o；C.720.B.54.o；C.721.B.54.o；C.722.B.54.o；C.723.B.54.o；C.724.B.54.o；D.3.a.4.i； D.4.a.4.i； D.7.a.4.i；D.9.a.4.i； D.103.a.4.i； D.106.a.4.i； D.107.a.4.i； D.108.a.4.i； D.111.a.4.i； D.114.a.4.i；D.117.a.4.i； D.118.a.4.i； D.119.a.4.i； D.120.a.4.i； D.121.a.4.i； D.137.a.4.i； D.138.a.4.i；D.139.a.4.i； D.140.a.4.i； D.141.a.4.i； D.142.a.4.i； D.145.a.4.i； D.146.a.4.i； D.147.a.4.i；D.148.a.4.i； D.149.a.4.i； D.150.a.4.i； D.151.a.4.i； D.165.a.4.i； D.166.a.4.i； D.167.a.4.i；D.168.a.4.i； D.169.a.4.i； D.170.a.4.i； D.171.a.4.i； D.172.a.4.i； D.173.a.4.i； D.174.a.4.i；D.175.a.4.i； D.176.a.4.i； D.188.a.4.i； D.189.a.4.i； D.190.a.4.i； D.196.a.4.i； D.202.a.4.i；D.205.a.4.i； D.206.a.4.i； D.207.a.4.i； D.208.a.4.i； D.209.a.4.i； D.210.a.4.i； D.211.a.4.i；D.212.a.4.i； D.213.a.4.i； D.700.a.4.i； D.701.a.4.i； D.702.a.4.i； D.703.a.4.i； D.704.a.4.i；D.705.a.4.i； D.706.a.4.i； D.707.a.4.i； D.708.a.4.i； D.709.a.4.i； D.710.a.4.i； D.711.a.4.i；D.712.a.4.i； D.713.a.4.i； D.714.a.4.i； D.715.a.4.i； D.716.a.4.i； D.717.a.4.i； D.718.a.4.i；D.719.a.4.i； D.720.a.4.i； D.721.a.4.i； D.722.a.4.i； D.723.a.4.i； D.724.a.4.i； D.3.a.4.o；D.4.a.4.o； D.7.a.4.o； D.9.a.4.o； D.103.a.4.o； D.106.a.4.o； D.107.a.4.o； D.108.a.4.o；D.111.a.4.o； D.114.a.4.o； D.117.a.4.o； D.118.a.4.o； D.119.a.4.o； D.120.a.4.o；D.121.a.4.o； D.137.a.4.o； D.138.a.4.o； D.139.a.4.o； D.140.a.4.o； D.141.a.4.o；D.142.a.4.o； D.145.a.4.o； D.146.a.4.o； D.147.a.4.o； D.148.a.4.o； D.149.a.4.o；D.150.a.4.o； D.151.a.4.o； D.165.a.4.o； D.166.a.4.o； D.167.a.4.o； D.168.a.4.o；D.169.a.4.o； D.170.a.4.o； D.171.a.4.o； D.172.a.4.o； D.173.a.4.o； D.174.a.4.o；D.175.a.4.o； D.176.a.4.o； D.188.a.4.o； D.189.a.4.o； D.190.a.4.o； D.196.a.4.o；D.202.a.4.o； D.205.a.4.o； D.206.a.4.o； D.207.a.4.o； D.208.a.4.o； D.209.a.4.o；D.210.a.4.o； D.211.a.4.o； D.212.a.4.o； D.213.a.4.o； D.700.a.4.o； D.701.a.4.o；D.702.a.4.o； D.703.a.4.o； D.704.a.4.o； D.705.a.4.o； D.706.a.4.o； D.707.a.4.o；D.708.a.4.o； D.709.a.4.o； D.710.a.4.o； D.711.a.4.o； D.712.a.4.o； D.713.a.4.o；D.714.a.4.o； D.715.a.4.o； D.716.a.4.o； D.717.a.4.o； D.718.a.4.o； D.719.a.4.o；D.720.a.4.o； D.721.a.4.o； D.722.a.4.o； D.723.a.4.o； D.724.a.4.o； D.172.b.4.i； D.173.b.4.i；D.174.b.4.i； D.175.b.4.i； D.176.b.4.i； D.188.b.4.i； D.189.b.4.i； D.190.b.4.i； D.196.b.4.i；D.202.b.4.i； D.205.b.4.i； D.206.b.4.i； D.207.b.4.i； D.208.b.4.i； D.209.b.4.i； D.210.b.4.i；D.211.b.4.i； D.212.b.4.i； D.213.b.4.i； D.700.b.4.i； D.701.b.4.i； D.702.b.4.i； D.703.b.4.i；D.704.b.4.i； D.705.b.4.i； D.706.b.4.i； D.707.b.4.i； D.708.b.4.i； D.709.b.4.i； D.710.b.4.i；D.711.b.4.i； D.712.b.4.i； D.713.b.4.i； D.714.b.4.i； D.715.b.4.i； D.716.b.4.i； D.717.b.4.i；D.718.b.4.i； D.719.b.4.i； D.720.b.4.i； D.721.b.4.i； D.722.b.4.i； D.723.b.4.i； D.724.b.4.i；D.3.b.4.o； D.4.b.4.o； D.7.b.4.o； D.9.b.4.o； D.103.b.4.o； D.106.b.4.o； D.107.b.4.o；D.108.b.4.o； D.111.b.4.o； D.114.b.4.o； D.117.b.4.o； D.118.b.4.o； D.119.b.4.o；D.120.b.4.o； D.121.b.4.o； D.137.b.4.o； D.138.b.4.o； D.139.b.4.o； D.140.b.4.o；D.141.b.4.o； D.142.b.4.o； D.145.b.4.o； D.146.b.4.o； D.147.b.4.o； D.148.b.4.o；D.149.b.4.o； D.150.b.4.o； D.151.b.4.o； D.165.b.4.o； D.166.b.4.o； D.167.b.4.o；D.168.b.4.o； D.169.b.4.o； D.170.b.4.o； D.171.b.4.o； D.172.b.4.o； D.173.b.4.o；D.174.b.4.o； D.175.b.4.o； D.176.b.4.o； D.188.b.4.o； D.189.b.4.o； D.190.b.4.o；D.196.b.4.o； D.202.b.4.o； D.205.b.4.o； D.206.b.4.o； D.207.b.4.o； D.208.b.4.o；D.209.b.4.o； D.210.b.4.o； D.211.b.4.o； D.212.b.4.o； D.213.b.4.o； D.700.b.4.o；D.701.b.4.o； D.702.b.4.o； D.703.b.4.o； D.704.b.4.o； D.705.b.4.o； D.706.b.4.o；D.707.b.4.o； D.708.b.4.o； D.709.b.4.o； D.710.b.4.o； D.711.b.4.o； D.712.b.4.o；D.713.b.4.o； D.714.b.4.o； D.715.b.4.o； D.716.b.4.o； D.717.b.4.o； D.718.b.4.o；D.719.b.4.o； D.720.b.4.o； D.721.b.4.o； D.722.b.4.o； D.723.b.4.o； D.724.b.4.o； D.172.x.4.i；D.173.x.4.i； D.174.x.4.i； D.175.x.4.i； D.176.x.4.i； D.188.x.4.i； D.189.x.4.i； D.190.x.4.i；D.196.x.4.i； D.202.x.4.i； D.205.x.4.i； D.206.x.4.i； D.207.x.4.i； D.208.x.4.i； D.209.x.4.i；D.210.x.4.i； D.211.x.4.i； D.212.x.4.i； D.213.x.4.i； D.700.x.4.i； D.701.x.4.i； D.702.x.4.i；D.703.x.4.i； D.704.x.4.i； D.705.x.4.i； D.706.x.4.i； D.707.x.4.i； D.708.x.4.i； D.709.x.4.i；D.710.x.4.i； D.711.x.4.i； D.712.x.4.i； D.713.x.4.i； D.714.x.4.i； D.715.x.4.i； D.716.x.4.i；D.717.x.4.i； D.718.x.4.i； D.719.x.4.i； D.720.x.4.i； D.721.x.4.i； D.722.x.4.i； D.723.x.4.i；D.724.x.4.i； D.3.x.4.o； D.4.x.4.o； D.7.x.4.o； D.9.x.4.o； D.103.x.4.o； D.106.x.4.o；D.107.x.4.o； D.108.x.4.o； D.111.x.4.o； D.114.x.4.o； D.117.x.4.o； D.118.x.4.o；D.119.x.4.o； D.120.x.4.o； D.121.x.4.o； D.137.x.4.o； D.138.x.4.o； D.139.x.4.o；D.140.x.4.o； D.141.x.4.o； D.142.x.4.o； D.145.x.4.o； D.146.x.4.o； D.147.x.4.o；D.148.x.4.o； D.149.x.4.o； D.150.x.4.o； D.151.x.4.o； D.165.x.4.o； D.166.x.4.o；D.167.x.4.o； D.168.x.4.o； D.169.x.4.o； D.170.x.4.o； D.171.x.4.o； D.172.x.4.o；D.173.x.4.o； D.174.x.4.o； D.175.x.4.o； D.176.x.4.o； D.188.x.4.o； D.189.x.4.o；D.190.x.4.o； D.196.x.4.o； D.202.x.4.o； D.205.x.4.o； D.206.x.4.o； D.207.x.4.o；D.208.x.4.o； D.209.x.4.o； D.210.x.4.o； D.211.x.4.o； D.212.x.4.o； D.213.x.4.o；D.700.x.4.o； D.701.x.4.o； D.702.x.4.o； D.703.x.4.o； D.704.x.4.o； D.705.x.4.o；D.706.x.4.o； D.707.x.4.o； D.708.x.4.o； D.709.x.4.o； D.710.x.4.o； D.711.x.4.o；D.712.x.4.o； D.713.x.4.o； D.714.x.4.o； D.715.x.4.o； D.716.x.4.o； D.717.x.4.o；D.718.x.4.o； D.719.x.4.o； D.720.x.4.o； D.721.x.4.o； D.722.x.4.o； D.723.x.4.o；D.724.x.4.o； D.172.y.4.i； D.173.y.4.i； D.174.y.4.i； D.175.y.4.i； D.176.y.4.i； D.188.y.4.i；D.189.y.4.i； D.190.y.4.i； D.196.y.4.i； D.202.y.4.i； D.205.y.4.i； D.206.y.4.i； D.207.y.4.i；D.208.y.4.i； D.209.y.4.i； D.210.y.4.i； D.211.y.4.i； D.212.y.4.i； D.213.y.4.i； D.700.y.4.i；D.701.y.4.i； D.702.y.4.i； D.703.y.4.i； D.704.y.4.i； D.705.y.4.i； D.706.y.4.i； D.707.y.4.i；D.708.y.4.i； D.709.y.4.i； D.710.y.4.i； D.711.y.4.i； D.712.y.4.i； D.713.y.4.i； D.714.y.4.i；D.715.y.4.i； D.716.y.4.i； D.717.y.4.i； D.718.y.4.i； D.719.y.4.i； D.720.y.4.i； D.721.y.4.i；D.722.y.4.i； D.723.y.4.i； D.724.y.4.i； D.3.y.4.o； D.4.y.4.o； D.7.y.4.o； D.9.y.4.o；D.103.y.4.o； D.106.y.4.o； D.107.y.4.o； D.108.y.4.o； D.111.y.4.o； D.114.y.4.o；D.117.y.4.o； D.118.y.4.o； D.119.y.4.o； D.120.y.4.o； D.121.y.4.o； D.137.y.4.o；D.138.y.4.o； D.139.y.4.o； D.140.y.4.o； D.141.y.4.o； D.142.y.4.o； D.145.y.4.o；D.146.y.4.o； D.147.y.4.o； D.148.y.4.o； D.149.y.4.o； D.150.y.4.o； D.151.y.4.o；D.165.y.4.o； D.166.y.4.o； D.167.y.4.o； D.168.y.4.o； D.169.y.4.o； D.170.y.4.o；D.171.y.4.o； D.172.y.4.o； D.173.y.4.o； D.174.y.4.o； D.175.y.4.o； D.176.y.4.o；D.188.y.4.o； D.189.y.4.o； D.190.y.4.o； D.196.y.4.o； D.202.y.4.o； D.205.y.4.o；D.206.y.4.o； D.207.y.4.o； D.208.y.4.o； D.209.y.4.o； D.210.y.4.o； D.211.y.4.o；D.212.y.4.o； D.213.y.4.o； D.700.y.4.o； D.701.y.4.o； D.702.y.4.o； D.703.y.4.o；D.704.y.4.o； D.705.y.4.o； D.706.y.4.o； D.707.y.4.o； D.708.y.4.o； D.709.y.4.o；D.710.y.4.o； D.711.y.4.o； D.712.y.4.o； D.713.y.4.o； D.714.y.4.o； D.715.y.4.o；D.716.y.4.o； D.717.y.4.o； D.718.y.4.o； D.719.y.4.o； D.720.y.4.o； D.721.y.4.o；D.722.y.4.o； D.723.y.4.o； D.724.y.4.o； D.172.z.4.i； D.173.z.4.i； D.174.z.4.i； D.175.z.4.i；D.176.z.4.i； D.188.z.4.i； D.189.z.4.i； D.190.z.4.i； D.196.z.4.i； D.202.z.4.i； D.205.z.4.i；D.206.z.4.i； D.207.z.4.i； D.208.z.4.i； D.209.z.4.i； D.210.z.4.i； D.211.z.4.i； D.212.z.4.i；D.213.z.4.i； D.700.z.4.i； D.701.z.4.i； D.702.z.4.i； D.703.z.4.i； D.704.z.4.i； D.705.z.4.i；D.706.z.4.i； D.707.z.4.i； D.708.z.4.i； D.709.z.4.i； D.710.z.4.i； D.711.z.4.i； D.712.z.4.i；D.713.z.4.i； D.714.z.4.i； D.715.z.4.i； D.716.z.4.i； D.717.z.4.i； D.718.z.4.i； D.719.z.4.i；D.720.z.4.i； D.721.z.4.i； D.722.z.4.i； D.723.z.4.i； D.724.z.4.i； D.3.z.4.o； D.4.z.4.o；D.7.z.4.o； D.9.z.4.o； D.103.z.4.o； D.106.z.4.o； D.107.z.4.o； D.108.z.4.o； D.111.z.4.o；D.114.z.4.o； D.117.z.4.o； D.118.z.4.o； D.119.z.4.o； D.120.z.4.o； D.121.z.4.o；D.137.z.4.o； D.138.z.4.o； D.139.z.4.o； D.140.z.4.o； D.141.z.4.o； D.142.z.4.o；D.145.z.4.o； D.146.z.4.o； D.147.z.4.o； D.148.z.4.o； D.149.z.4.o； D.150.z.4.o；D.151.z.4.o； D.165.z.4.o； D.166.z.4.o； D.167.z.4.o； D.168.z.4.o； D.169.z.4.o；D.170.z.4.o； D.171.z.4.o； D.172.z.4.o； D.173.z.4.o； D.174.z.4.o； D.175.z.4.o；D.176.z.4.o； D.188.z.4.o； D.189.z.4.o； D.190.z.4.o； D.196.z.4.o； D.202.z.4.o；D.205.z.4.o； D.206.z.4.o； D.207.z.4.o； D.208.z.4.o； D.209.z.4.o； D.210.z.4.o；D.211.z.4.o； D.212.z.4.o； D.213.z.4.o； D.700.z.4.o； D.701.z.4.o； D.702.z.4.o；D.703.z.4.o； D.704.z.4.o； D.705.z.4.o； D.706.z.4.o； D.707.z.4.o； D.708.z.4.o；D.709.z.4.o； D.710.z.4.o； D.711.z.4.o； D.712.z.4.o； D.713.z.4.o； D.714.z.4.o；D.715.z.4.o； D.716.z.4.o； D.717.z.4.o； D.718.z.4.o； D.719.z.4.o； D.720.z.4.o；D.721.z.4.o； D.722.z.4.o； D.723.z.4.o； D.724.z.4.o； D.172.A.4.i； D.173.A.4.i； D.174.A.4.i； D.175.A.4.i； D.176.A.4.i； D.188.A.4.i； D.189.A.4.i； D.190.A.4.i；D.196.A.4.i； D.202.A.4.i； D.205.A.4.i； D.206.A.4.i； D.207.A.4.i； D.208.A.4.i；D.209.A.4.i； D.210.A.4.i； D.211.A.4.i； D.212.A.4.i； D.213.A.4.i； D.700.A.4.i；D.701.A.4.i； D.702.A.4.i； D.703.A.4.i； D.704.A.4.i； D.705.A.4.i； D.706.A.4.i；D.707.A.4.i； D.708.A.4.i； D.709.A.4.i； D.710.A.4.i； D.711.A.4.i； D.712.A.4.i；D.713.A.4.i； D.714.A.4.i； D.715.A.4.i； D.716.A.4.i； D.717.A.4.i； D.718.A.4.i；D.719.A.4.i； D.720.A.4.i； D.721.A.4.i； D.722.A.4.i； D.723.A.4.i； D.724.A.4.i； D.3.A.4.o；D.4.A.4.o； D.7.A.4.o； D.9.A.4.o； D.103.A.4.o； D.106.A.4.o； D.107.A.4.o； D.108.A.4.o；D.111.A.4.o； D.114.A.4.o； D.117.A.4.o； D.118.A.4.o； D.119.A.4.o； D.120.A.4.o；D.121.A.4.o； D.137.A.4.o； D.138.A.4.o； D.139.A.4.o； D.140.A.4.o； D.141.A.4.o；D.142.A.4.o； D.145.A.4.o； D.146.A.4.o； D.147.A.4.o； D.148.A.4.o； D.149.A.4.o；D.150.A.4.o； D.151.A.4.o； D.165.A.4.o； D.166.A.4.o； D.167.A.4.o； D.168.A.4.o；D.169.A.4.o； D.170.A.4.o； D.171.A.4.o； D.172.A.4.o； D.173.A.4.o； D.174.A.4.o；D.175.A.4.o； D.176.A.4.o； D.188.A.4.o； D.189.A.4.o； D.190.A.4.o； D.196.A.4.o；D.202.A.4.o； D.205.A.4.o； D.206.A.4.o； D.207.A.4.o； D.208.A.4.o； D.209.A.4.o；D.210.A.4.o； D.211.A.4.o； D.212.A.4.o； D.213.A.4.o； D.700.A.4.o； D.701.A.4.o；D.702.A.4.o； D.703.A.4.o； D.704.A.4.o； D.705.A.4.o； D.706.A.4.o； D.707.A.4.o；D.708.A.4.o； D.709.A.4.o； D.710.A.4.o； D.711.A.4.o； D.712.A.4.o； D.713.A.4.o；D.714.A.4.o； D.715.A.4.o； D.716.A.4.o； D.717.A.4.o； D.718.A.4.o； D.719.A.4.o；D.720.A.4.o； D.721.A.4.o； D.722.A.4.o； D.723.A.4.o； D.724.A.4.o； D.172.B.4.i；D.173.B.4.i； D.174.B.4.i； D.175.B.4.i； D.176.B.4.i； D.188.B.4.i； D.189.B.4.i； D.190.B.4.i；D.196.B.4.i； D.202.B.4.i； D.205.B.4.i； D.206.B.4.i； D.207.B.4.i； D.208.B.4.i； D.209.B.4.i；D.210.B.4.i； D.211.B.4.i； D.212.B.4.i； D.213.B.4.i； D.700.B.4.i； D.701.B.4.i； D.702.B.4.i；D.703.B.4.i； D.704.B.4.i； D.705.B.4.i； D.706.B.4.i； D.707.B.4.i； D.708.B.4.i； D.709.B.4.i；D.710.B.4.i； D.711.B.4.i； D.712.B.4.i； D.713.B.4.i； D.714.B.4.i； D.715.B.4.i； D.716.B.4.i；D.717.B.4.i； D.718.B.4.i； D.719.B.4.i； D.720.B.4.i； D.721.B.4.i； D.722.B.4.i； D.723.B.4.i；D.724.B.4.i； D.3.B.4.o； D.4.B.4.o； D.7.B.4.o； D.9.B.4.o； D.103.B.4.o； D.106.B.4.o；D.107.B.4.o； D.108.B.4.o； D.111.B.4.o； D.114.B.4.o； D.117.B.4.o； D.118.B.4.o；D.119.B.4.o； D.120.B.4.o； D.121.B.4.o； D.137.B.4.o； D.138.B.4.o； D.139.B.4.o；D.140.B.4.o； D.141.B.4.o； D.142.B.4.o； D.145.B.4.o； D.146.B.4.o； D.147.B.4.o；D.148.B.4.o； D.149.B.4.o； D.150.B.4.o； D.151.B.4.o； D.165.B.4.o； D.166.B.4.o；D.167.B.4.o； D.168.B.4.o； D.169.B.4.o； D.170.B.4.o； D.171.B.4.o； D.172.B.4.o；D.173.B.4.o； D.174.B.4.o； D.175.B.4.o； D.176.B.4.o； D.188.B.4.o； D.189.B.4.o；D.190.B.4.o； D.196.B.4.o； D.202.B.4.o； D.205.B.4.o； D.206.B.4.o； D.207.B.4.o；D.208.B.4.o； D.209.B.4.o； D.210.B.4.o； D.211.B.4.o； D.212.B.4.o； D.213.B.4.o；D.700.B.4.o； D.701.B.4.o； D.702.B.4.o； D.703.B.4.o； D.704.B.4.o； D.705.B.4.o；D.706.B.4.o； D.707.B.4.o； D.708.B.4.o； D.709.B.4.o； D.710.B.4.o； D.711.B.4.o；D.712.B.4.o； D.713.B.4.o； D.714.B.4.o； D.715.B.4.o； D.716.B.4.o； D.717.B.4.o；D.718.B.4.o； D.719.B.4.o； D.720.B.4.o； D.721.B.4.o； D.722.B.4.o； D.723.B.4.o；D.724.B.4.o； E.3.a.54.i； E.4.a.54.i； E.7.a.54.i； E.9.a.54.i； E.103.a.54.i； E.106.a.54.i；E.107.a.54.i； E.108.a.54.i； E.111.a.54.i； E.114.a.54.i； E.117.a.54.i； E.118.a.54.i；E.119.a.54.i； E.120.a.54.i； E.121.a.54.i； E.137.a.54.i； E.138.a.54.i； E.139.a.54.i；E.140.a.54.i； E.141.a.54.i； E.142.a.54.i； E.145.a.54.i； E.146.a.54.i； E.147.a.54.i；E.148.a.54.i； E.149.a.54.i； E.150.a.54.i； E.151.a.54.i； E.165.a.54.i； E.166.a.54.i；E.167.a.54.i； E.168.a.54.i； E.169.a.54.i； E.170.a.54.i； E.171.a.54.i； E.172.a.54.i；E.173.a.54.i； E.174.a.54.i； E.175.a.54.i； E.176.a.54.i； E.188.a.54.i； E.189.a.54.i；E.190.a.54.i； E.196.a.54.i； E.202.a.54.i； E.205.a.54.i； E.206.a.54.i； E.207.a.54.i；E.208.a.54.i； E.209.a.54.i； E.210.a.54.i； E.211.a.54.i； E.212.a.54.i； E.213.a.54.i；E.700.a.54.i； E.701.a.54.i； E.702.a.54.i； E.703.a.54.i； E.704.a.54.i； E.705.a.54.i；E.706.a.54.i； E.707.a.54.i； E.708.a.54.i； E.709.a.54.i； E.710.a.54.i； E.711.a.54.i；E.712.a.54.i； E.713.a.54.i； E.714.a.54.i； E.715.a.54.i； E.716.a.54.i； E.717.a.54.i；E.718.a.54.i； E.719.a.54.i； E.720.a.54.i； E.721.a.54.i； E.722.a.54.i； E.723.a.54.i；E.724.a.54.i； E.3.a.54.o； E.4.a.54.o； E.7.a.54.o； E.9.a.54.o； E.103.a.54.o； E.106.a.54.o；E.107.a.54.o； E.108.a.54.o； E.111.a.54.o； E.114.a.54.o； E.117.a.54.o； E.118.a.54.o；E.119.a.54.o； E.120.a.54.o； E.121.a.54.o； E.137.a.54.o； E.138.a.54.o； E.139.a.54.o；E.140.a.54.o； E.141.a.54.o； E.142.a.54.o； E.145.a.54.o； E.146.a.54.o； E.147.a.54.o；E.148.a.54.o； E.149.a.54.o； E.150.a.54.o； E.151.a.54.o； E.165.a.54.o； E.166.a.54.o；E.167.a.54.o； E.168.a.54.o； E.169.a.54.o； E.170.a.54.o； E.171.a.54.o； E.172.a.54.o；E.173.a.54.o； E.174.a.54.o； E.175.a.54.o； E.176.a.54.o； E.188.a.54.o； E.189.a.54.o；E.190.a.54.o； E.196.a.54.o； E.202.a.54.o； E.205.a.54.o； E.206.a.54.o； E.207.a.54.o；E.208.a.54.o； E.209.a.54.o； E.210.a.54.o； E.211.a.54.o； E.212.a.54.o； E.213.a.54.o；E.700.a.54.o； E.701.a.54.o； E.702.a.54.o； E.703.a.54.o； E.704.a.54.o； E.705.a.54.o；E.706.a.54.o； E.707.a.54.o； E.708.a.54.o； E.709.a.54.o； E.710.a.54.o； E.711.a.54.o；E.712.a.54.o； E.713.a.54.o； E.714.a.54.o； E.715.a.54.o； E.716.a.54.o； E.717.a.54.o；E.718.a.54.o； E.719.a.54.o； E.720.a.54.o； E.721.a.54.o； E.722.a.54.o； E.723.a.54.o；E.724.a.54.o； E.172.b.54.i； E.173.b.54.i； E.174.b.54.i； E.175.b.54.i； E.176.b.54.i；E.188.b.54.i； E.189.b.54.i； E.190.b.54.i； E.196.b.54.i； E.202.b.54.i； E.205.b.54.i；E.206.b.54.i； E.207.b.54.i； E.208.b.54.i； E.209.b.54.i； E.210.b.54.i； E.211.b.54.i；E.212.b.54.i； E.213.b.54.i； E.700.b.54.i； E.701.b.54.i； E.702.b.54.i； E.703.b.54.i；E.704.b.54.i； E.705.b.54.i； E.706.b.54.i； E.707.b.54.i； E.705.b.54.i； E.709.b.54.i；E.710.b.54.i； E.711.b.54.i； E.712.b.54.i； E.713.b.54.i； E.714.b.54.i； E.715.b.54.i；E.716.b.54.i； E.717.b.54.i； E.718.b.54.i； E.719.b.54.i； E.720.b.54.i； E.721.b.54.i；E.722.b.54.i； E.723.b.54.i； E.724.b.54.i； E.3.b.54.o； E.4.b.54.o； E.7.b.54.o； E.9.b.54.o；E.103.b.54.o； E.106.b.54.o； E.107.b.54.o； E.108.b.54.o； E.111.b.54.o； E.114.b.54.o；E.117.b.54.o； E.118.b.54.o； E.119.b.54.o； E.120.b.54.o； E.121.b.54.o； E.137.b.54.o；E.138.b.54.o； E.139.b.54.o； E.140.b.54.o； E.141.b.54.o； E.142.b.54.o； E.145.b.54.o；E.146.b.54.o； E.147.b.54.o； E.148.b.54.o； E.149.b.54.o； E.150.b.54.o； E.151.b.54.o；E.165.b.54.o； E.166.b.54.o； E.167.b.54.o； E.168.b.54.o； E.169.b.54.o； E.170.b.54.o；E.171.b.54.o； E.172.b.54.o； E.173.b.54.o； E.174.b.54.o； E.175.b.54.o； E.176.b.54.o；E.188.b.54.o； E.189.b.54.o； E.190.b.54.o； E.196.b.54.o； E.202.b.54.o； E.205.b.54.o；E.206.b.54.o； E.207.b.54.o； E.208.b.54.o； E.209.b.54.o； E.210.b.54.o； E.211.b.54.o；E.212.b.54.o； E.213.b.54.o； E.700.b.54.o； E.701.b.54.o； E.702.b.54.o； E.703.b.54.o；E.704.b.54.o； E.705.b.54.o； E.706.b.54.o；.E.707.b.54.o； E.708.b.54.o； E.709.b.54.o；E.710.b.54.o； E.711.b.54.o； E.712.b.54.o； E.713.b.54.o； E.714.b.54.o； E.715.b.54.o；E.716.b.54.o； E.717.b.54.o； E.718.b.54.o； E.719.b.54.o； E.720.b.54.o； E.721.b.54.o；E.722.b.54.o； E.723.b.54.o； E.724.b.54.o； E.172.x.54.i； E.173.x.54.i； E.174.x.54.i；E.175.x.54.i； E.176.x.54.i； E.188.x.54.i； E.189.x.54.i； E.190.x.54.i； E.196.x.54.i；E.202.x.54.i； E.205.x.54.i； E.206.x.54.i； E.207.x.54.i； E.208.x.54.i； E.209.x.54.i；E.210.x.54.i； E.211.x.54.i； E.212.x.54.i； E.213.x.54.i； E.700.x.54.i； E.701.x.54.i；E.702.x.54.i； E.703.x.54.i； E.704.x.54.i； E.705.x.54.i； E.706.x.54.i； E.707.x.54.i；E.708.x.54.i； E.709.x.54.i； E.710.x.54.i； E.711.x.54.i； E.712.x.54.i； E.713.x.54.i；E.714.x.54.i； E.715.x.54.i； E.716.x.54.i； E.717.x.54.i； E.718.x.54.i； E.719.x.54.i；E.720.x.54.i； E.721.x.54.i； E.722.x.54.i； E.723.x.54.i； E.724.x.54.i； E.3.x.54.o； E.4.x.54.o；E.7.x.54.o； E.9.x.54.o； E.103.x.54.o； E.106.x.54.o； E.107.x.54.o； E.108.x.54.o；E.111.x.54.o； E.114.x.54.o； E.117.x.54.o； E.118.x.54.o； E.119.x.54.o； E.120.x.54.o；E.121.x.54.o； E.137.x.54.o； E.138.x.54.o； E.139.x.54.o； E.140.x.54.o； E.141.x.54.o；E.142.x.54.o； E.145.x.54.o； E.146.x.54.o； E.147.x.54.o； E.148.x.54.o； E.149.x.54.o；E.150.x.54.o； E.151.x.54.o； E.165.x.54.o； E.166.x.54.o； E.167.x.54.o； E.168.x.54.o；E.169.x.54.o； E.170.x.54.o； E.171.x.54.o； E.172.x.54.o； E.173.x.54.o； E.174.x.54.o；E.175.x.54.o； E.176.x.54.o； E.188.x.54.o； E.189.x.54.o； E.190.x.54.o； E.196.x.54.o；E.202.x.54.o； E.205.x.54.o； E.206.x.54.o； E.207.x.54.o； E.208.x.54.o； E.209.x.54.o；E.210.x.54.o； E.211.x.54.o； E.212.x.54.o； E.213.x.54.o； E.700.x.54.o； E.701.x.54.o；E.702.x.54.o； E.703.x.54.o； E.704.x.54.o； E.705.x.54.o； E.706.x.54.o； E.707.x.54.o；E.708.x.54.o； E.709.x.54.o； E.710.x.54.o； E.711.x.54.o； E.712.x.54.o； E.713.x.54.o；E.714.x.54.o； E.715.x.54.o； E.716.x.54.o； E.717.x.54.o； E.718.x.54.o； E.719.x.54.o；E.720.x.54.o； E.721.x.54.o； E.722.x.54.o； E.723.x.54.o； E.724.x.54.o； E.172.y.54.i；E.173.y.54.i； E.174.y.54.i； E.175.y.54.i； E.176.y.54.i； E.188.y.54.i； E.189.y.54.i；E.190.y.54.i； E.196.y.54.i； E.202.y.54.i； E.205.y.54.i； E.206.y.54.i； E.207.y.54.i；E.208.y.54.i； E.209.y.54.i； E.210.y.54.i； E.211.y.54.i； E.212.y.54.i； E.213.y.54.i；E.700.y.54.i； E.701.y.54.i； E.702.y.54.i； E.703.y.54.i； E.704.y.54.i； E.705.y.54.i；E.706.y.54.i； E.707.y.54.i； E.708.y.54.i； E.709.y.54.i； E.710.y.54.i； E.711.y.54.i；E.712.y.54.i； E.713.y.54.i； E.714.y.54.i； E.715.y.54.i； E.716.y.54.i； E.717.y.54.i；E.718.y.54.i； E.719.y.54.i； E.720.y.54.i； E.721.y.54.i； E.722.y.54.i； E.723.y.54.i；E.724.y.54.i； E.3.y.54.o； E.4.y.54.o； E.7.y.54.o； E.9.y.54.o； E.103.y.54.o； E.106.y.54.o；E.107.y.54.o； E.108.y.54.o； E.111.y.54.o； E.114.y.54.o； E.117.y.54.o； E.118.y.54.o；E.119.y.54.o； E.120.y.54.o； E.121.y.54.o； E.137.y.54.o； E.138.y.54.o； E.139.y.54.o；E.140.y.54.o； E.141.y.54.o； E.142.y.54.o； E.145.y.54.o； E.146.y.54.o； E.147.y.54.o；E.148.y.54.o； E.149.y.54.o； E.150.y.54.o； E.151.y.54.o； E.165.y.54.o； E.166.y.54.o；E.167.y.54.o； E.168.y.54.o； E.169.y.54.o； E.170.y.54.o； E.171.y.54.o； E.172.y.54.o；E.173.y.54.o； E.174.y.54.o； E.175.y.54.o； E.176.y.54.o； E.188.y.54.o； E.189.y.54.o；E.190.y.54.o； E.196.y.54.o； E.202.y.54.o； E.205.y.54.o； E.206.y.54.o； E.207.y.54.o；E.208.y.54.o； E.209.y.54.o； E.210.y.54.o； E.211.y.54.o； E.212.y.54.o； E.213.y.54.o；E.700.y.54.o； E.701.y.54.o； E.702.y.54.o； E.703.y.54.o； E.704.y.54.o； E.705.y.54.o；E.706.y.54.o； E.707.y.54.o； E.708.y.54.o； E.709.y.54.o； E.710.y.54.o； E.711.y.54.o；E.712.y.54.o； E.713.y.54.o； E.714.y.54.o； E.715.y.54.o； E.716.y.54.o； E.717.y.54.o；E.718.y.54.o； E.719.y.54.o； E.720.y.54.o； E.721.y.54.o； E.722.y.54.o； E.723.y.54.o；E.724.y.54.o； E.172.z.54.i； E.173.z.54.i； E.174.z.54.i； E.175.z.54.i； E.176.z.54.i；E.188.z.54.i； E.189.z.54.i； E.190.z.54.i； E.196.z.54.i； E.202.z.54.i； E.205.z.54.i；E.206.z.54.i； E.207.z.54.i； E.208.z.54.i； E.209.z.54.i； E.210.z.54.i； E.211.z.54.i；E.212.z.54.i； E.213.z.54.i； E.700.z.54.i； E.701.z.54.i； E.702.z.54.i； E.703.z.54.i；E.704.z.54.i； E.705.z.54.i； E.706.z.54.i； E.707.z.54.i； E.708.z.54.i； E.709.z.54.i；E.710.z.54.i； E.711.z.54.i； E.712.z.54.i； E.713.z.54.i； E.714.z.54.i； E.715.z.54.i；E.716.z.54.i； E.717.z.54.i； E.718.z.54.i； E.719.z.54.i； E.720.z.54.i； E.721.z.54.i；E.722.z.54.i； E.723.z.54.i； E.724.z.54.i； E.3.z.54.o； E.4.z.54.o； E.7.z.54.o； E.9.z.54.o；E.103.z.54.o； E.106.z.54.o； E.107.z.54.o； E.108.z.54.o； E.111.z.54.o； E.114.z.54.o；E.117.z.54.o； E.118.z.54.o； E.119.z.54.o； E.120.z.54.o； E.121.z.54.o； E.137.z.54.o；E.138.z.54.o； E.139.z.54.o； E.140.z.54.o； E.141.z.54.o； E.142.z.54.o； E.145.z.54.o；E.146.z.54.o； E.147.z.54.o； E.148.z.54.o； E.149.z.54.o； E.150.z.54.o； E.151.z.54.o；E.165.z.54.o； E.166.z.54.o； E.167.z.54.o； E.168.z.54.o； E.169.z.54.o； E.170.z.54.o；E.171.z.54.o； E.172.z.54.o； E.173.z.54.o； E.174.z.54.o； E.175.z.54.o； E.176.z.54.o；E.188.z.54.o； E.189.z.54.o； E.190.z.54.o； E.196.z.54.o； E.202.z.54.o； E.205.z.54.o；E.206.z.54.o； E.207.z.54.o； E.208.z.54.o； E.209.z.54.o； E.210.z.54.o； E.211.z.54.o；E.212.z.54.o； E.213.z.54.o； E.700.z.54.o； E.701.z.54.o； E.702.z.54.o； E.703.z.54.o；E.704.z.54.o； E.705.z.54.o； E.706.z.54.o； E.707.z.54.o； E.708.z.54.o； E.709.z.54.o；E.710.z.54.o； E.711.z.54.o； E.712.z.54.o； E.713.z.54.o； E.714.z.54.o； E.715.z.54.o；E.716.z.54.o； E.717.z.54.o； E.718.z.54.o； E.719.z.54.o； E.720.z.54.o； E.721.z.54.o；E.722.z.54.o； E.723.z.54.o； E.724.z.54.o； E.172.A.54.i； E.173.A.54.i； E.174.A.54.i；E.175.A.54.i； E.176.A.54.i； E.188.A.54.i； E.189.A.54.i； E.190.A.54.i； E.196.A.54.i；E.202.A.54.i； E.205.A.54.i； E.206.A.54.i； E.207.A.54.i； E.208.A.54.i； E.209.A.54.i；E.210.A.54.i； E.211.A.54.i； E.212.A.54.i； E.213.A.54.i； E.700.A.54.i； E.701.A.54.i；E.702.A.54.i； E.703.A.54.i； E.704.A.54.i； E.705.A.54.i； E.706.A.54.i； E.707.A.54.i；E.708.A.54.i； E.709.A.54.i； E.710.A.54.i； E.711.A.54.i； E.712.A.54.i； E.713.A.54.i；E.714.A.54.i； E.715.A.54.i； E.716.A.54.i； E.717.A.54.i； E.718.A.54.i； E.719.A.54.i；E.720.A.54.i； E.721.A.54.i； E.722.A.54.i； E.723.A.54.i； E.724.A.54.i； E.3.A.54.o；E.4.A.54.o； E.7.A.54.o； E.9.A.54.o； E.103.A.54.o； E.106.A.54.o； E.107.A.54.o；E.108.A.54.o； E.111.A.54.o； E.114.A.54.o； E.117.A.54.o； E.118.A.54.o； E.119.A.54.o；E.120.A.54.o； E.121.A.54.o； E.137.A.54.o； E.138.A.54.o； E.139.A.54.o； E.140.A.54.o；E.141.A.54.o； E.142.A.54.o； E.145.A.54.o； E.146.A.54.o； E.147.A.54.o； E.148.A.54.o；E.149.A.54.o； E.150.A.54.o； E.151.A.54.o； E.165.A.54.o； E.166.A.54.o； E.167.A.54.o；E.168.A.54.o； E.169.A.54.o； E.170.A.54.o； E.171.A.54.o； E.172.A.54.o； E.173.A.54.o；E.174.A.54.o； E.175.A.54.o； E.176.A.54.o； E.188.A.54.o； E.189.A.54.o； E.190.A.54.o；E.196.A.54.o； E.202.A.54.o； E.205.A.54.o； E.206.A.54.o； E.207.A.54.o； E.208.A.54.o；E.209.A.54.o； E.210.A.54.o； E.211.A.54.o； E.212.A.54.o； E.213.A.54.o； E.700.A.54.o；E.701.A.54.o； E.702.A.54.o； E.703.A.54.o； E.704.A.54.o； E.705.A.54.o； E.706.A.54.o；E.707.A.54.o； E.708.A.54.o； E.709.A.54.o； E.710.A.54.o； E.711.A.54.o； E.712.A.54.o；E.713.A.54.o； E.714.A.54.o； E.715.A.54.o； E.716.A.54.o； E.717.A.54.o； E.718.A.54.o；E.719.A.54.o； E.720.A.54.o； E.721.A.54.o； E.722.A.54.o； E.723.A.54.o； E.724.A.54.o；E.172.B.54.i； E.173.B.54.i； E.174.B.54.i； E.175.B.54.i； E.176.B.54.i； E.188.B.54.i；E.189.B.54.i； E.190.B.54.i； E.196.B.54.i； E.202.B.54.i； E.205.B.54.i； E.206.B.54.i；E.207.B.54.i； E.208.B.54.i； E.209.B.54.i； E.210.B.54.i； E.211.B.54.i； E.212.B.54.i；E.213.B.54.i； E.700.B.54.i； E.701.B.54.i； E.702.B.54.i； E.703.B.54.i； E.704.B.54.i；E.705.B.54.i； E.706.B.54.i； E.707.B.54.i； E.708.B.54.i； E.709.B.54.i； E.710.B.54.i；E.711.B.54.i； E.712.B.54.i； E.713.B.54.i； E.714.B.54.i； E.715.B.54.i； E.716.B.54.i；E.717.B.54.i； E.718.B.54.i； E.719.B.54.i； E.720.B.54.i； E.721.B.54.i； E.722.B.54.i；E.723.B.54.i； E.724.B.54.i； E.3.B.54.o； E.4.B.54.o； E.7.B.54.o； E.9.B.54.o； E.103.B.54.o；E.106.B.54.o； E.107.B.54.o； E.108.B.54.o； E.111.B.54.o； E.114.B.54.o； E.117.B.54.o；E.118.B.54.o； E.119.B.54.o； E.120.B.54.o； E.121.B.54.o； E.137.B.54.o； E.138.B.54.o；E.139.B.54.o； E.140.B.54.o； E.141.B.54.o； E.142.B.54.o； E.145.B.54.o； E.146.B.54.o；E.147.B.54.o； E.148.B.54.o； E.149.B.54.o； E.150.B.54.o； E.151.B.54.o； E.165.B.54.o；E.166.B.54.o； E.167.B.54.o； E.168.B.54.o； E.169.B.54.o； E.170.B.54.o； E.171.B.54.o；E.172.B.54.o； E.173.B.54.o； E.174.B.54.o； E.175.B.54.o； E.176.B.54.o； E.188.B.54.o；E.189.B.54.o； E.190.B.54.o； E.196.B.54.o； E.202.B.54.o； E.205.B.54.o； E.206.B.54.o；E.207.B.54.o； E.208.B.54.o； E.209.B.54.o； E.210.B.54.o； E.211.B.54.o； E.212.B.54.o；E.213.B.54.o； E.700.B.54.o； E.701.B.54.o； E.702.B.54.o； E.703.B.54.o； E.704.B.54.o；E.705.B.54.o； E.706.B.54.o； E.707.B.54.o； E.708.B.54.o； E.709.B.54.o； E.710.B.54.o；E.711.B.54.o； E.712.B.54.o； E.713.B.54.o； E.714.B.54.o； E.715.B.54.o； E.716.B.54.o；E.717.B.54.o； E.718.B.54.o； E.719.B.54.o； E.720.B.54.o； E.721.B.54.o； E.722.B.54.o；E.723.B.54.o； E.724.B.54.o； F.3.a.54.i； F.4.a.54.i； F.7.a.54.i； F.9.a.54.i； F.103.a.54.i；F.106.a.54.i； F.107.a.54.i； F.108.a.54.i； F.111.a.54.i； F.114.a.54.i； F.117.a.54.i；F.118.a.54.i； F.119.a.54.i； F.120.a.54.i； F.121.a.54.i； F.137.a.54.i； F.138.a.54.i；F.139.a.54.i； F.140.a.54.i； F.141.a.54.i； F.142.a.54.i； F.145.a.54.i； F.146.a.54.i；F.147.a.54.i； F.148.a.54.i； F.149.a.54.i； F.150.a.54.i； F.151.a.54.i； F.165.a.54.i；F.166.a.54.i； F.167.a.54.i； F.168.a.54.i； F.169.a.54.i； F.170.a.54.i； F.171.a.54.i；F.172.a.54.i； F.173.a.54.i； F.174.a.54.i； F.175.a.54.i； F.176.a.54.i； F.188.a.54.i；F.189.a.54.i； F.190.a.54.i； F.196.a.54.i； F.202.a.54.i； F.205.a.54.i； F.206.a.54.i；F.207.a.54.i； F.208.a.54.i； F.209.a.54.i； F.210.a.54.i； F.211.a.54.i； F.212.a.54.i；F.213.a.54.i； F.700.a.54.i； F.701.a.54.i； F.702.a.54.i； F.703.a.54.i； F.704.a.54.i；F.705.a.54.i； F.706.a.54.i； F.707.a.54.i； F.708.a.54.i； F.709.a.54.i； F.710.a.54.i；F.711.a.54.i； F.712.a.54.i； F.713.a.54.i； F.714.a.54.i； F.715.a.54.i； F.716.a.54.i；F.717.a.54.i； F.718.a.54.i； F.719.a.54.i； F.720.a.54.i； F.721.a.54.i； F.722.a.54.iF.723.a.54.i； F.724.a.54.i； F.3.a.54.o； F.4.a.54.o； F.7.a.54.o； F.9.a.54.o； F.103.a.54.o；F.106.a.54.o； F.107.a.54.o； F.108.a.54.o； F.111.a.54.o； F.114.a.54.o； F.117.a.54.o；F.118.a.54.o； F.119.a.54.o； F.120.a.54.o； F.121.a.54.o； F.137.a.54.o； F.138.a.54.o；F.139.a.54.o； F.140.a.54.o； F.141.a.54.o； F.142.a.54.o； F.145.a.54.o； F.146.a.54.o；F.147.a.54.o； F.148.a.54.o； F.149.a.54.o； F.150.a.54.o； F.151.a.54.o； F.165.a.54.o；F.166.a.54.o； F.167.a.54.o； F.168.a.54.o； F.169.a.54.o； F.170.a.54.o； F.171.a.54.o；F.172.a.54.o； F.173.a.54.o； F.174.a.54.o； F.175.a.54.o； F.176.a.54.o； F.188.a.54.o；F.189.a.54.o； F.190.a.54.o； F.196.a.54.o； F.202.a.54.o； F.205.a.54.o； F.206.a.54.o；F.207.a.54.o； F.208.a.54.o； F.209.a.54.o； F.210.a.54.o； F.211.a.54.o； F.212.a.54.o；F.213.a.54.o； F.700.a.54.o； F.701.a.54.o； F.702.a.54.o； F.703.a.54.o； F.704.a.54.o；F.705.a.54.o； F.706.a.54.o； F.707.a.54.o； F.708.a.54.o； F.709.a.54.o； F.710.a.54.o；F.711.a.54.o； F.712.a.54.o； F.713.a.54.o； F.714.a.54.o； F.715.a.54.o； F.716.a.54.o；F.717.a.54.o； F.718.a.54.o； F.719.a.54.o； F.720.a.54.o； F.721.a.54.o； F.722.a.54.o；F.723.a.54.o； F.724.a.54.o； F.172.b.54.i； F.173.b.54.i； F.174.b.54.i； F.175.b.54.i；F.176.b.54.i； F.188.b.54.i； F.189.b.54.i； F.190.b.54.i； F.196.b.54.i； F.202.b.54.i；F.205.b.54.i； F.206.b.54.i； F.207.b.54.i； F.208.b.54.i； F.209.b.54.i； F.210.b.54.i；F.211.b.54.i； F.212.b.54.i； F.213.b.54.i； F.700.b.54.i； F.701.b.54.i； F.702.b.54.i；F.703.b.54.i； F.704.b.54.i； F.705.b.54.i； F.706.b.54.i； F.707.b.54.i； F.708.b.54.i；F.709.b.54.i； F.710.b.54.i； F.711.b.54.i； F.712.b.54.i； F.713.b.54.i； F.714.b.54.i；F.715.b.54.i； F.716.b.54.i； F.717.b.54.i； F.718.b.54.i； F.719.b.54.i； F.720.b.54.i；F.721.b.54.i； F.722.b.54.i； F.723.b.54.i； F.724.b.54.i； F.3.b.54.o； F.4.b.54.o； F.7.b.54.o；F.9.b.54.o； F.103.b.54.o； F.106.b.54.o； F.107.b.54.o； F.108.b.54.o； F.111.b.54.o；F.114.b.54.o； F.117.b.54.o； F.118.b.54.o； F.119.b.54.o； F.120.b.54.o； F.121.b.54.o；F.137.b.54.o； F.138.b.54.o； F.139.b.54.o； F.140.b.54.o； F.141.b.54.o； F.142.b.54.o； F.145.b.54.o； F.146.b.54.o； F.147.b.54.o； F.148.b.54.o； F.149.b.54.o； F.150.b.54.o；F.151.b.54.o； F.165.b.54.o； F.166.b.54.o； F.167.b.54.o； F.168.b.54.o； F.169.b.54.o；F.170.b.54.o； F.171.b.54.o； F.172.b.54.o； F.173.b.54.o； F.174.b.54.o； F.175.b.54.o；F.176.b.54.o； F.188.b.54.o； F.189.b.54.o； F.190.b.54.o； F.196.b.54.o； F.202.b.54.o；F.205.b.54.o； F.206.b.54.o； F.207.b.54.o； F.208.b.54.o； F.209.b.54.o； F.210.b.54.o；F.211.b.54.o； F.212.b.54.o； F.213.b.54.o； F.700.b.54.o； F.701.b.54.o； F.702.b.54.o；F.703.b.54.o； F.704.b.54.o； F.705.b.54.o； F.706.b.54.o； F.707.b.54.o； F.708.b.54.o；F.709.b.54.o； F.710.b.54.o； F.711.b.54.o； F.712.b.54.o； F.713.b.54.o； F.714.b.54.o；F.715.b.54.o； F.716.b.54.o； F.717.b.54.o； F.718.b.54.o； F.719.b.54.o； F.720.b.54.o；F.721.b.54.o； F.722.b.54.o； F.723.b.54.o； F.724.b.54.o； F.172.x.54.i； F.173.x.54.i；F.174.x.54.i； F.175.x.54.i； F.176.x.54.i； F.188.x.54.i； F.189.x.54.i； F.190.x.54.i；F.196.x.54.i； F.202.x.54.i； F.205.x.54.i； F.206.x.54.i； F.207.x.54.i； F.208.x.54.i；F.209.x.54.i； F.210.x.54.i； F.211.x.54.i； F.212.x.54.i； F.213.x.54.i； F.700.x.54.i；F.701.x.54.i； F.702.x.54.i； F.703.x.54.i； F.704.x.54.i； F.705.x.54.i； F.706.x.54.i；F.707.x.54.i； F.708.x.54.i； F.709.x.54.i； F.710.x.54.i； F.711.x.54.i； F.712.x.54.i；F.713.x.54.i； F.714.x.54.i； F.715.x.54.i； F.716.x.54.i； F.717.x.54.i； F.718.x.54.i；F.719.x.54.i； F.720.x.54.i； F.721.x.54.i； F.722.x.54.i； F.723.x.54.i； F.724.x.54.i； F.3.x.54.o；F.4.x.54.o； F.7.x.54.o； F.9.x.54.o； F.103.x.54.o； F.106.x.54.o； F.107.x.54.o； F.108.x.54.o；F.111.x.54.o； F.114.x.54.o； F.117.x.54.o； F.118.x.54.o； F.119.x.54.o； F.120.x.54.o；F.121.x.54.o； F.137.x.54.o； F.138.x.54.o； F.139.x.54.o； F.140.x.54.o； F.141.x.54.o；F.142.x.54.o； F.145.x.54.o； F.146.x.54.o； F.147.x.54.o； F.148.x.54.o； F.149.x.54.o；F.150.x.54.o； F.151.x.54.o； F.165.x.54.o； F.166.x.54.o； F.167.x.54.o； F.168.x.54.o；F.169.x.54.o； F.170.x.54.o； F.171.x.54.o； F.172.x.54.o； F.173.x.54.o； F.174.x.54.o；F.175.x.54.o； F.176.x.54.o； F.188.x.54.o； F.189.x.54.o； F.190.x.54.o； F.196.x.54.o；F.202.x.54.o； F.205.x.54.o； F.206.x.54.o； F.207.x.54.o； F.208.x.54.o； F.209.x.54.o；F.210 x.54.o； F.211.x.54.o； F.212.x.54.o； F.213.x.54.o； F.700.x.54.o； F.701.x.54.o；F.702.x.54.o； F.703.x.54.o； F.704.x.54.o； F.705.x.54.o； F.706.x.54.o； F.707.x.54.o；F.708.x.54.o； F.709.x.54.o； F.710.x.54.o； F.711.x.54.o； F.712.x.54.o； F.713.x.54.o；F.714.x.54.o； F.715.x.54.o； F.716.x.54.o； F.717.x.54.o； F.718.x.54.o； F.719.x.54.o；F.720.x.54.o； F.721.x.54.o； F.722.x.54.o； F.723.x.54.o； F.724.x.54.o； F.172.y.54.i；F.173.y.54.i； F.174.y.54.i； F.175.y.54.i； F.176.y.54.i； F.188.y.54.i； F.189.y.54.i；F.190.y.54.i； F.196.y.54.i； F.202.y.54.i； F.205.y.54.i； F.206.y.54.i； F.207.y.54.i；F.208.y.54.i； F.209.y.54.i； F.210.y.54.i； F.211.y.54.i； F.212.y.54.i； F.213.y.54.i；F.700.y.54.i； F.701.y.54.i； F.702.y.54.i； F.703.y.54.i； F.704.y.54.i； F.705.y.54.i；F.706.y.54.i； F.707.y.54.i； F.708.y.54.i； F.709.y.54.i； F.710.y.54.i； F.711.y.54.i；F.712.y.54.i； F.713.y.54.i； F.714.y.54.i； F.715.y.54.i； F.716.y.54.i； F.717.y.54.i；F.718.y.54.i； F.719.y.54.i； F.720.y.54.i； F.721.y.54.i； F.722.y.54.i； F.723.y.54.i；F.724.y.54.i； F.3.y.54.o； F.4.y.54.o； F.7.y.54.o； F.9.y.54.o； F.103.y.54.o； F.106.y.54.o；F.107.y.54.o； F.108.y.54.o； F.111.y.54.o； F.114.y.54.o； F.117.y.54.o； F.118.y.54.o；F.119.y.54.o； F.120.y.54.o； F.121.y.54.o； F.137.y.54.o； F.138.y.54.o； F.139.y.54.o；F.140.y.54.o； F.141.y.54.o； F.142.y.54.o； F.145.y.54.o； F.146.y.54.o； F.147.y.54.o；F.148.y.54.o； F.149.y.54.o； F.150.y.54.o； F.151.y.54.o； F.165.y.54.o； F.166.y.54.o；F.167.y.54.o； F.168.y.54.o； F.169.y.54.o； F.170.y.54.o； F.171.y.54.o； F.172.y.54.o；F.173.y.54.o； F.174.y.54.o； F.175.y.54.o； F.176.y.54.o； F.188.y.54.o； F.189.y.54.o；F.190.y.54.o； F.196.y.54.o； F.202.y.54.o； F.205.y.54.o； F.206.y.54.o； F.207.y.54.o；F.208.y.54.o； F.209.y.54.o； F.210.y.54.o； F.211.y.54.o； F.212.y.54.o； F.213.y.54.o；F.700.y.54.o； F.701.y.54.o； F.702.y.54.o； F.703.y.54.o； F.704.y.54.o； F.705.y.54.o；F.706.y.54.o； F.707.y.54.o； F.708.y.54.o； F.709.y.54.o； F.710.y.54.o； F.711.y.54.o；F.712.y.54.o； F.713.y.54.o； F.714.y.54.o； F.715.y.54.o； F.716.y.54.o； F.717.y.54.o；F.718.y.54.o； F.719.y.54.o； F.720.y.54.o； F.721.y.54.o； F.722.y.54.o； F.723.y.54.o；F.724.y.54.o； F.172.z.54.i； F.173.z.54.i； F.174.z.54.i； F.175.z.54.i； F.176.z.54.i；F.188.z.54.i； F.189.z.54.i； F.190.z.54.i； F.196.z.54.i； F.202.z.54.i； F.205.z.54.i；F.206.z.54.i； F.207.z.54.i； F.208.z.54.i； F.209.z.54.i； F.210.z.54.i； F.211.z.54.i；F.212.z.54.i； F.213.z.54.i； F.700.z.54.i； F.701.z.54.i； F.702.z.54.i； F.703.z.54.i；F.704.z.54.i； F.705.z.54.i； F.706.z.54.i； F.707.z.54.i； F.708.z.54.i； F.709.z.54.i；F.710.z.54.i； F.711.z.54.i； F.712.z.54.i； F.713.z.54.i； F.714.z.54.i； F.715.z.54.i；F.716.z.54.i； F.717.z.54.i； F.718.z.54.i； F.719.z.54.i； F.720.z.54.i； F.721.z.54.i；F.722.z.54.i； F.723.z.54.i； F.724.z.54.i； F.3.z.54.o； F.4.z.54.o； F.7.z.54.o； F.9.z.54.o；F.103.z.54.o； F.106.z.54.o； F.107.z.54.o； F.108.z.54.o； F.111.z.54.o； F.114.z.54.o；F.117.z.54.o； F.118.z.54.o； F.119.z.54.o； F.120.z.54.o； F.121.z.54.o； F.137.z.54.o；F.138.z.54.o； F.139.z.54.o； F.140.z.54.o； F.141.z.54.o； F.142.z.54.o； F.145.z.54.o；F.146.z.54.o； F.147.z.54.o； F.148.z.54.o； F.149.z.54.o； F.150.z.54.o； F.151.z.54.o；F.165.z.54.o； F.166.z.54.o； F.167.z.54.o； F.168.z.54.o； F.169.z.54.o； F.170.z.54.o；F.171.z.54.o； F.172.z.54.o； F.173.z.54.o； F.174.z.54.o； F.175.z.54.o； F.176.z.54.o；F.188.z.54.o； F.189.z.54.o； F.190.z.54.o； F.196.z.54.o； F.202.z.54.o； F.205.z.54.o；F.206.z.54.o； F.207.z.54.o； F.208.z.54.o； F.209.z.54.o； F.210.z.54.o； F.211.z.54.o；F.212.z.54.o； F.213.z.54.o； F.700.z.54.o； F.701.z.54.o； F.702.z.54.o； F.703.z.54.o；F.704.z.54.o； F.705.z.54.o； F.706.z.54.o； F.707.z.54.o； F.708.z.54.o； F.709.z.54.o；F.710.z.54.o； F.711.z.54.o； F.712.z.54.o； F.713.z.54.o； F.714.z.54.o； F.715.z.54.o；F.716.z.54.o； F.717.z.54.o； F.718.z.54.o； F.719.z.54.o； F.720.z.54.o； F.721.z.54.o；F.722.z.54.o； F.723.z.54.o； F.724.z.54.o； F.172.A.54.i； F.173.A.54.i； F.174.A.54.i；F.175.A.54.i； F.176.A.54.i； F.188.A.54.i； F.189.A.54.i； F.190.A.54.i； F.196.A.54.i；F.202.A.54.i； F.205.A.54.i； F.206.A.54.i； F.207.A.54.i； F.208.A.54.i； F.209.A.54.i；F.210.A.54.i； F.211.A.54.i； F.212.A.54.i； F.213.A.54.i； F.700.A.54.i； F.701.A.54.i；F.702.A.54.i； F.703.A.54.i； F.704.A.54.i； F.705.A.54.i； F.706.A.54.i； F.707.A.54.i；F.708.A.54.i； F.709.A.54.i； F.710.A.54.i； F.711.A.54.i； F.712.A.54.i； F.713.A.54.i；F.714.A.54.i； F.715.A.54.i； F.716.A.54.i； F.717.A.54.i； F.718.A.54.i； F.719.A.54.i；F.720.A.54.i； F.721.A.54.i； F.722.A.54.i； F.723.A.54.i； F.724.A.54.i； F.3.A.54.o；F.4.A.54.o； F.7.A.54.o； F.9.A.54.o； F.103.A.54.o； F.106.A.54.o； F.107.A.54.o；F.108.A.54.o； F.111.A.54.o； F.114.A.54.o； F.117.A.54.o； F.118.A.54.o； F.119.A.54.o；F.120.A.54.o； F.121.A.54.o； F.137.A.54.o； F.138.A.54.o； F.139.A.54.o； F.140.A.54.o；F.141.A.54.o； F.142.A.54.o； F.145.A.54.o； F.146.A.54.o； F.147.A.54.o； F.148.A.54.o；F.149.A.54.o； F.150.A.54.o； F.151.A.54.o； F.165.A.54.o； F.166.A.54.o； F.167.A.54.o；F.168.A.54.o； F.169.A.54.o； F.170.A.54.o； F.171.A.54.o； F.172.A.54.o； F.173.A.54.o；F.174.A.54.o； F.175.A.54.o； F.176.A.54.o； F.188.A.54.o； F.189.A.54.o； F.190.A.54.o；F.196.A.54.o； F.202.A.54.o； F.205.A.54.o； F.206.A.54.o； F.207.A.54.o； F.208.A.54.o；F.209.A.54.o； F.210.A.54.o； F.211.A.54.o； F.212.A.54.o； F.213.A.54.o； F.700.A.54.o；F.701.A.54.o； F.702.A.54.o； F.703.A.54.o； F.704.A.54.o； F.705.A.54.o； F.706.A.54.o；F.707.A.54.o； F.708.A.54.o； F.709.A.54.o； F.710.A.54.o； F.711.A.54.o； F.712.A.54.o；F.713.A.54.o； F.714.A.54.o； F.715.A.54.o； F.716.A.54.o； F.717.A.54.o； F.718.A.54.o；F.719.A.54.o； F.720.A.54.o； F.721.A.54.o； F.722.A.54.o； F.723.A.54.o； F.724.A.54.o；F.172.B.54.i； F.173.B.54.i； F.174.B.54.i； F.175.B.54.i； F.176.B.54.i； F.188.B.54.i；F.189.B.54.i； F.190.B.54.i； F.196.B.54.i； F.202.B.54.i； F.205.B.54.i； F.206.B.54.i；F.207.B.54.i； F.208.B.54.i； F.209.B.54.i； F.210.B.54.i； F.211.B.54.i； F.212.B.54.i；F.213.B.54.i； F.700.B.54.i； F.701.B.54.i； F.702.B.54.i； F.703.B.54.i； F.704.B.54.i；F.705.B.54.i； F.706.B.54.i； F.707.B.54.i； F.708.B.54.i； F.709.B.54.i； F.710.B.54.i；F.711.B.54.i； F.712.B.54.i； F.713.B.54.i； F.714.B.54.i； F.715.B.54.i； F.716.B.54.i；F.717.B.54.i； F.718.B.54.i； F.719.B.54.i； F.720.B.54.i； F.721.B.54.i； F.722.B.54.i；F.723.B.54.i； F.724.B.54.i； F.3.B.54.o； F.4.B.54.o； F.7.B.54.o； F.9.B.54.o； F.103.B.54.o；F.106.B.54.o； F.107.B.54.o； F.108.B.54.o； F.111.B.54.o； F.114.B.54.o； F.117.B.54.o；F.118.B.54.o； F.119.B.54.o； F.120.B.54.o； F.121.B.54.o； F.137.B.54.o； F.138.B.54.o；F.139.B.54.o； F.140.B.54.o； F.141.B.54.o； F.142.B.54.o； F.145.B.54.o； F.146.B.54.o；F.147.B.54.o； F.148.B.54.o； F.149.B.54.o； F.150.B.54.o； F.151.B.54.o； F.165.B.54.o；F.166.B.54.o； F.167.B.54.o； F.168.B.54.o； F.169.B.54.o； F.170.B.54.o； F.171.B.54.o；F.172.B.54.o； F.173.B.54.o； F.174.B.54.o； F.175.B.54.o； F.176.B.54.o； F.188.B.54.o；F.189.B.54.o； F.190.B.54.o； F.196.B.54.o； F.202.B.54.o； F.205.B.54.o； F.206.B.54.o；F.207.B.54.o； F.208.B.54.o； F.209.B.54.o； F.210.B.54.o； F.211.B.54.o； F.212.B.54.o；F.213.B.54.o； F.700.B.54.o； F.701.B.54.o； F.702.B.54.o； F.703.B.54.o； F.704.B.54.o；F.705.B.54.o； F.706.B.54.o； F.707.B.54.o； F.708.B.54.o； F.709.B.54.o； F.710.B.54.o；F.711.B.54.o； F.712.B.54.o； F.713.B.54.o； F.714.B.54.o； F.715.B.54.o； F.716.B.54.o；F.717.B.54.o； F.718.B.54.o； F.719.B.54.o； F.720.B.54.o； F.721.B.54.o； F.722.B.54.o；F.723.B.54.o；F.724.B.54.o. salt and hydrate

The present composition optionally includes the salt of compound described herein, especially containing such as Na⁺,Li⁺,K⁺,Ca⁺⁺And Mg⁺⁺Pharmaceutically acceptable nontoxic salts.These salt may include that by suitable cation (such as alkali and alkaline earth metal ions ion or ammonium and quaternary ammonium ion) and acid anion group (be typically W₁Carboxylic acid) salt with reference to obtained from.If necessary to water soluble salt, then preferred monovalent salt.

Metal salt is general to be reacted and is made by metal hydroxides and the compounds of this invention.The example of the metal salt prepared in this way has containing Li⁺,Na⁺, and K⁺Salt.The appropriate metallic compound by adding, can be settled out the metal salt of indissoluble from readily soluble salting liquid.

In addition, also can be by by some organic acids and inorganic acid (such as HCl, HBr, H₂SO₄,H₃PO₄) or organic sulfonic acid add to basic center (typically group G₁Amine) or acidic-group such as E₁It is upper to form salt.Finally, it is to be understood that present subject matter thing includes unionization and zwitterionic form, and is combined with the compounds of this invention of the hydrate forms of stoichiometry water.

Also include parent compound and salt formed by one or more amino acid within the scope of the present invention.Any of above amino acid is all suitable for, the naturally occurring amino acid constituted especially as protein, but typical amino acid is with the amino acid (such as lysine, arginine or glutamic acid) containing alkalescence or acidic-group side chain, or for the amino acid containing neutral group pendant, such as glycine, serine, threonine, alanine, isoleucine, or leucine.The suppressing method of neuraminidase

Another aspect of the present invention be related to suppress neuraminidase activity method, it include with the compounds of this invention processing may be containing neuraminidase sample the step of.

As described below, material of the present invention can be used as the inhibitor of neuraminidase, intermediate as this kind of inhibitor or with other purposes.The inhibitor is incorporated on the position on the surface of neuraminidase or in hole (position has the structure that only neuraminidase just has).The combination of these materials and neuraminidase has different degrees of invertibity.The compound of those substantial Irreversible bindings is the desirable material that uses in the inventive method.In a typical implementation, the combination of the material and neuraminidase, which has, is less than 10^-4M, typically less than 10^-6M, is more typically 10⁸M binding constant.Once after mark, the material of substantial Irreversible binding can be used as detecting the probe of neuraminidase.Therefore, the invention further relates to detect the method for neuraminidase that may be in the sample containing neuraminidase, this method comprises the following steps：With the compositions-treated sample of the compounds of this invention including being incorporated into label；Observe effect of the sample to label activity.Appropriate label is well known in diagnostic field, and including free radical stably, fluorogen, isotope, enzyme, chemiluminescent groups and chromophore.Compounds herein is marked in a usual manner using functional group such as hydroxyl or amino.

In the present invention, may the sample containing neuraminidase include natural or artificial material, such as live organism；Tissue or cell culture；Biological sample such as biomaterial sample (blood, serum, urine, myelencephalon body, tears, phlegm, saliva, tissue sample etc.)；Laboratory sample；Food, water, or air sample；Accessory substance sample such as cell extract, particularly recombinant cell (it can synthesize the glycoprotein of needs) etc..Typically, sample is under a cloud containing that can produce the organism of neuraminidase, common for pathogenic organisms, such as virus.Sample can be included in including in any medium including water and organic solvent/aqueous mixtures.Sample includes Living Organism such as people, and artificial material such as cell culture.

The process step of the present invention includes the compounds of this invention being added in sample, or compound precursor is added in sample.This, which adds step, includes any application process described above.

If desired, the method for direct or indirect detection neuraminidase activity can be included using the observation of any method using the activity of the neuraminidase after compound.Quantitative, qualitative and sxemiquantitative the method for determining neuraminidase activity is all taken into account.Typically can be using any of above-mentioned screening technique, but it is also possible to apply other methods, the method for for example observing the physiological property of active organism.

Organism comprising neuraminidase includes bacterium (comma bacillus, clostridium perfringens, streptococcus pneumonia and Arthrobacter sialophilus) and virus (particularly myxovirus or paramyxoviridae, such as influenza virus A and B, parainfluenza virus, parotitis disease virus, NDV, poultry plague virus, and sendai virus).The inhibitory action for the neuraminidase activity for occurring or finding in these organisms is also within the purpose of the present invention.The virology of influenza virus is recorded in " basic virology " (FundamentalVirology) (Raben publishing houses, New York, 1986), the 24th chapter.The compounds of this invention can be used for treating or preventing animal (such as duck, rodent or pig) or this kind of infection of people.

However, when screening can suppress the compound of influenza virus, should be borne in mind that enzymatic determination result might not be consistent with the result of cell culture assays, as shown in the table 1 in Chandler etc. (ibid).Therefore, determination method should be reduced from plaque is main screening technique.The screening of neuraminidase inhibitor

Some the compounds of this invention have selectivity to specific organism, and such as bacterium is to (verses) neuraminidase or the neuraminidase of influenza virus to parainfluenza virus.These compounds can be determined by conventional screening.

Using any conventional method for evaluating enzymatic activity, inhibitory activity of the screening the compounds of this invention to neuraminidase.In the present invention, the compound for suppressing neuraminidase in vitro is typically first screened, then screening has the compound of activity in vivo from the compound for showing inhibitory activity again.The compound used in vivo preferably has less than about 5 × 10^-6M external Ki (inhibition constant), typically less than about 1 × 10^-7M, more preferably less than about 5 × 10^-8M。

Applicable in-vitro screening method has had a detailed description, and repeats no more here.But Itzstein, M. et al. exist《It is natural》, 363 (6428):418-423 (1993), particularly the 420th page, the part in first paragraph of the 3rd full section into the 2nd column of page 421 in the 2nd column describe Potier M. et al. and existed《Analytical biochemistry》(Analyt.Biochem.)94:A kind of suitable external test method described in 287-296 (1979), the method is by Chong, A.K.J. et al.《Acta Biochimica et Biophysica Sinica》(Biochem.Biophys.Acta),1077:65-71 (1991) is improved；And the row of page 34 the 13rd the 16th row of page-the 35 in Colman, P.M. et al. International Patent Publication WO92/06691 (international application no PCT/AU90/00501, publication date on April 30th, 1992) describes another useful in-vitro screening method.

Internal screening method has also been documented, referring to von Itzstein, M. et al., magazine as described above, part in the first paragraph on first full section the 2nd column of page-the 423 on particularly page 421 the 2nd column, and page 36 of Colman, P.M. et al. above-mentioned International Patent Publication, described applicable internal screening method in 1-38 rows.

In screening test used herein, with more than 1 μM (micromole) IC₅₀The compound of value is considered as emitting neuraminidase activity without influenza.Pharmaceutical preparation and method of administration

The compounds of this invention can be prepared together with conventional carrier and excipient, and depending on the selection of these carriers or excipient is according to conventional practice.Tablet includes excipient, glidant, filler, adhesive etc..Sterile form is made in aqua, and generally should also be isotonic when being conveyed with non-oral routes.All formulations all optionally contain excipient, as described in " pharmaceutical excipient handbook " (Handbook of Pharmaceutical Excipients) (1986).Excipient includes ascorbic acid and other antioxidants, chelating agent such as EDTA, carbohydrate such as dextrin, hydroxy alkyl cellulose, hydroxyalky methyl celluloses, stearic acid etc..The pH of preparation is in the range of about 3- about 11, but typically about 7-10.

One or more the compounds of this invention (hereinafter referred to as active component) are suitable for by any approach administration for controlling illness.Suitable approach includes oral, rectum, intranasal, local (including buccal and sublingual), the approach such as vagina and non-bowel (including subcutaneous, intramuscular, intravenous, intracutaneous, intrathecal and Epidural cavity).It can be appreciated that it is preferred that approach by with for example being changed by the illness of medicine person.The advantage of the compounds of this invention is that they have oral bioavailability, and can be with oral administration；From without via intrapulmonary or intra-nasal route administration.

Although active component can be administered alone, preferably they exist with pharmaceutical dosage forms.Invention formulation is either for animals or for a person to use all including at least one above-mentioned active component, and one or more acceptable carriers and optional other therapeutic components.Carrier must be " acceptable ", you can compatible with other compositions in preparation and to harmless by medicine person.

Preparation includes those preparations suitable for foregoing method of administration.Suitably the preparation exists in a unit, and is prepared using known any method in pharmaceutical field.Generally these technologies and preparation can be found from Remington Pharmaceutical Sciences (Mack Publishing Co., Easton, PA).These methods include the step of mixed active composition is with carrier (constituting one or more auxiliary elements).Usually, preparation is by uniform and be sufficiently mixed active component and liquid-carrier or subdivided solids carrier or both, then, if necessary to again prepare product shaping.

It is adapted to oral invention formulation and separate unit, such as capsule, cachet or tablet is made, each of which includes predetermined amounts of active ingredients；Pulvis or granule is made；Or solution or suspension are made in liquid, aqueous or on-aqueous liquid；Or oil-in-water liq emulsion or water-in-oil liquid emulsion is made.Bolus, electuary or paste can also be made in active component.

Tablet can be by suppressing or being molded, and is optionally mixed with one or more auxiliary elements.Compressed tablets can be by suppressing active component into free-flowing form such as powder or particle in suitable machine, and is wherein optionally mixed with adhesive, lubricant, inert diluent, preservative, surfactant or dispersant.Molded tablet can be made by the divided active component that molding is moistened with inert liquid diluent in appropriate machine.Tablet is optionally coated or indentation, and can optionally be configured to can slow or controlled release active component therein form.In one embodiment, it is avoided that sour water solution occurs for medicine using enteric coating.

For the infection of eyes or other outside organizations such as mouth and skin, the preparation is preferably applied with topical ointments or cream, the active component of the amount comprising such as 0.075-20%w/w (is included in the active principle in the range of 0.1%-20% in these preparations, it is incremented by with 0.1%w/w amounts, such as 0.6%w/w, 0.7%w/w etc.), preferably 0.2-15%w/w, most preferably 0.5-10%w/w.When being configured to ointment, active component can be shared with paraffin or water-miscible ointment agent matrix.On the other hand, active component can also be configured to creme together with oil-in-water type ointment bases.

If desired, cream base may include for example, at least 30%w/w polyalcohols, the i.e. alcohol with two or more hydroxyls, such as propane diols, butane -1,3- glycol, mannitol, D-sorbite, glycerine and polyethylene glycol (including PEG400) and its mixture.Topical preparation, which preferably includes, can strengthen the compound that active component absorbs or permeated through skin or other undamaged portions.The example of such dermal penetration enhancer includes dimethyl sulfoxide and related analogs.

The oil phase of emulsion of the present invention can be made up of principal component in a known manner.Although this mutually can only include emulsifying agent, the mixture that at least one emulsifying agent is formed with fat or oil or with fat and oil is wherein preferably included.It is preferred that hydrophilic emulsifying agent with the lipophilic emulsifier of used as stabilizers with being used in combination.Further preferably include oil and both fat.So-called emulsifying wax is together constituted with or without the emulsifying agent of stabilizer, this wax forms so-called emulsifying ointment base together with oil and fat, and then forms the oiliness dispersed phase of creme.

Include tween suitable for the emulsifying agent and emulsion stabilizer of invention formulation^60, sapn^80, cetostearyl alcohol, benzylalcohol, myristyl alcohol, glyceryl monostearate and NaLS.

The suitable oil or fat of preparation regard required cosmetic property and selected.Creme is preferably non-greasy, the product that does not dye and can wash away, but also with d spiss, is gone out so as to avoid oneself from managing interior or other container internal leakages.Straight or branched, unitary or binary alkyl ester such as two-different adipate ester can be used, Standamul 7061, the propylene glycol diesters of coconut fatty acid, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, palmitic acid 2- ethylhexyls or the branched ester for making Crodamol CAP, latter three are preferred ester.These esters can be used alone or be used in combination, then depending on required property.On the other hand, high-melting-point lipid can also be used, such as white soft vaseline and/or atoleine or other mineral oil.

Also include eye drops suitable for the local preparation for imposing on eyes, wherein active component is dissolved in or is suspended in suitable carrier, is especially suitable for the aqueous solvent of active component.Activity component concentration in this kind of preparation is preferably 0.5-20%, more favourable for 0.5-10%, about particularly 1.5%w/w.

Being adapted to the preparation of local application in oral cavity includes lozenge, and it includes being contained in the active component in flavoured base, and this matrix is usually sucrose and Arabic gum or bassora gum；Pastille, it includes the active component being mixed in inert base such as gelatin and glycerine or sucrose and Arabic gum；And including the gargle for the active component being dissolved in appropriate liquid carrier.

The preparation for being adapted to rectally can be the suppository form that is formed with the suitable matrix including such as cocoa butter or salicylate.

Being adapted to the particle that the preparation of intrapulmonary or intranasal administration has in such as 0.1-500 micrometer ranges, (including particle diameter is in 0.1-500 micrometer ranges, and in cumulative trend, such as 0.5,1,30 microns, 35 microns etc.), this preparation is quickly sucked by nasal passage or direct oral cavity sucks and reaches alveolar sac.Suitable preparation includes the aqueous or oily emulsion of inventive compound.The preparation that suitable aerosol or dry powder mode are administered can be prepared conventionally, and can be applied together with the compound for being previously used for treatment or prevention influenza A or B infection of other therapeutic agents as described below.

The preparation for being adapted to vagina administration can be pessary, cotton wool, creme, gel, paste, foam or spray, also include suitable carrier as known in the art in these preparations in addition to the active ingredient (s.

Being adapted to the preparation of parenterai administration includes aqueous and non-aqueous aseptic parenteral solution, wherein antioxidant can be contained, buffer, bateriostatics, and preparation can be made with being in isotonic solute by the blood of medicine person；And aqueous or non-aqueous sterile suspensions, wherein suspending agent and thickener can be included.

These preparations can exist with unit dose or multi-dose container (such as sealed ampoule and phial) form, and can be preserved under lyophilisation condition, in this case, sterile liquid carrier (such as water for injection) need to be added using preceding.It is interim to be prepared with parenteral solution and suspension by above-mentioned various aseptic powderies, particle and tablet.It is preferred that unit dose formulations in the active component comprising daily dose or unit day sub-doses (as described above) or its appropriate partial amount.

It should be appreciated that the other conventional substances for being adapted to the preparation type can also be included in addition to the active component pointed out specifically above, in invention formulation, for example, being adapted to that in the preparation of oral administration flavor enhancement can be included.

Invention further provides veterinary composition, it includes at least one above-mentioned active component and Veterinary carriers.

Veterinary carriers, to be adapted to the material using this composition, can be solid, liquid or gaseous material, and be inertia or be veterinarily acceptable, and can be compatible with active component.These veterinary compositions can be applied by oral, non-bowel or other any desired approach.

The compounds of this invention can be used for providing wherein comprising controlled release medicament (" controlled release formulation ") of one or more the compounds of this invention as active component, release wherein by controlling or adjusting active component can reduce administration number of times, or improve the pharmacokinetics or toxic characteristic of given activity composition.

The effective dose of active component is at least dependent on following factors：By the property for controlling illness, toxicity, the compound is to be used to prevent (low dosage) to be also resistant to active influenza infection, medication, and pharmaceutical dosage forms.The effective dose should be determined by attending doctor according to routine dose amendment scheme.It is expected that effective dose be about 0.0001- about 100mg, typically about 0.01- about 10mg per kg body weight per day, be more typically about 0.01- about 5mg, more typically about 0.05- about 0.5mg.For example, for the adult of about 70 kg body weights, the selected daily dose of inhalation is 1mg-1000mg, preferably 5mg-500mg, it is possible to which single dose or multiple dose mode are taken.

Inventive compound can also be used with other active ingredient combinations.This drug combination is selected according to by pharmacological properties when controlling illness, the cross reactivity of each active component and being used in combination.For example, when the virus infection for the treatment of respiratory system, particularly influenza infection when, the composition of the present invention can be used in combination with antiviral agent (such as amantadine, Rimantadine and ribavirin), viscous dissolving medicine, expectorant, bronchodilator, antibiotic, alexipyretic or anodyne.Generally, what is together applied with the compounds of this invention is antibiotic, antipyretic and anodyne.Enteric is protected

Another embodiment of the present invention is related to the intestines forms of protection of the compounds of this invention.Terminology used here " enteric protection " refers in order to avoid the compounds of this invention and gastrointestinal part, particularly on the gastrointestinal tract, is more specifically contacted with stomach and oesophagus, and the present invention is protected.Mucosa tissue and the contact rate of the compounds of this invention are so reduced, so that mucosa tissue is protected, and contact of the compounds of this invention with mucosa tissue can then produce the Ru Evil hearts etc side effect；On the other hand, the compounds of this invention can also be so protected not influence one or more illnesss in intestines and stomach, particularly on the gastrointestinal tract.

These enteric forms of protection include, but not limited to, e.g. enteric coating excipient, such as enteric coated tablet, enteric coated granule, enteric coating bead, enteric coating particle, enteric coating microparticle and enteric coated capsule.In preferred embodiments, it is that the compounds of this invention is placed in suitable excipient such as tablet, particle or capsule, and excipient is coated with pharmaceutically acceptable enteric coating thing.In another preferred embodiment; it is particle, granule, microparticle, spheroid, microsphere or the jelly that the compounds of this invention is first made to casing protection; then pharmaceutically acceptable formulation is made in particle, granule, microparticle, spheroid, microsphere or the jelly again protected these enterics; such as tablet; granule, capsule or suspension.

One aspect of the present invention is related to the enteric coated dosage forms of the compounds of this invention, they can effectively convey pharmaceutical composition to people or other mammals enteron aisle, can preferably be transported to small enteral, the composition includes the active component and optional pharmaceutically acceptable excipient of about 0.1-1000mg therapeutically effective amounts.

Term " excipient " used herein includes pharmaceutically useful pharmaceutical excipient.Many excipient be in pharmaceutical arts described herein it is known, such as tablet, coated tablet, capsule, hard capsule, soft capsule, particle, microparticle, spheroid, microsphere, colloid, microencapsulation, sustained release, semi-solid, suppository or granule excipient.

Term " pharmaceutically acceptable excipient " used herein includes any physiological inertia well known by persons skilled in the art, the material of parmacodynamics-less activity, and their physics and chemical property with selected particular compound of the present invention are compatible.These excipient record other parts herein.These excipient can be with, but is not required to provide enteric protection.

Term " unit dose " used herein typically refers to host's single administration to being treated or the compounds of this invention of following amounts is administered.It should be appreciated that treat or prevent dosage can with a unit dose to use, or can also two or more (amounts for increasing to compound required in the stipulated time altogether) this unit dose multiple dose form to use.

Usually, for the oral unit dosage form of the present composition, per unit dose preferably comprises about 1- about 1000 milligrams of (mg), typically about 10-500mg, it is more typically about 50- about 300mg, is more typically 75mg the compounds of this invention.Actual content changes with selected reactive compound.

In a typical implementation; enteric protection is coated on the excipient of inclusion compound; or be coated in the compound of no excipient; protection can prevent the compounds of this invention to be exposed to, contact or repeatedly be exposed to the Evil hearts caused by oral cavity, oesophagus or stomach; but compound can be discharged when formulation is by lower gastrointestinal tract proximal part for absorption; or in some embodiments, substantially only discharged in colon.

For acquisition optimal absorption effect, the relative scale of protection and the compounds of this invention changes with selected compounds.The minimum or maximum (pressing percent weight) of enteric protection are unimportant.Typically, included in enteric protection examples of compounds and be less than about 50wt.% enteric coating things.It is more typically about 1%- about 25%, more typically about 1%- about 15%, more typically about 1%- about 10% (being weight ratio).Correlation technique：

Enteric protection and correlation technique are all elaborated in a large amount of monographs.These monographs include：" theory and practice of industrial pharmaceutical " (Theory and Practice of IndustrialPharmacy), the third edition, Lea ＆ Febiger, Philadelphia, 1986 (ISBN0-8121-09775-5)；Lehmann,K.；“Practical Course in LaquerCoating,”,Eudragit,1989；Lieberman；Lachman,L.；Schwartz, " pharmaceutical dosage form：Tablet ", 1990, Dekker (ISBN:0-8247-8289-5)；Lee, Ping I.Editor Good, William R.Editor, " controlled-release technologies：Medicinal application ", ACS Symposium Ser.Vol.348 (ISBN:0-608-03871-7)；Wilson, Billie E., Shannon, Margaret T., " Rapid Dose Calculation：A kind of method for simplifying " (Dosage Calculation:A Simplified Approach),1996,Appleton & Lange(ISBN:0-8385-9297-X)；Lieberman, Herbert A.Editor Rieger, Martin M., " pharmaceutical dosage form：- dispersion " (Pharmaceutical Dosage Forms-Disperse Systems) 1996, Dekker (ISBN:0-8247-9387-0)；" basic test of pharmaceutical dosage form " (Basic Tests forPharmaceutical Dosage Forms), 1995, World Health (ISBN:92-4-154418-X)；Karsa, D.R. are edited；Stephenson, R.A. are edited, " pharmaceutical preparation excipient and induction system：' 94 Britain chemistry meeting preparation symposium collection of thesis ", 1995, CRC Pr (ISBN:0-85404-715-8)；Ansel,Howard C.；Popovich,Nichoals G.；Allen, Lyoyd V., " pharmaceutical dosage form and drug delivery sixth version ", 1994, Williams ＆ Wilkins (ISBN:0-683-01930-9)；" improved medicine transmits handbook：Equipment manufacturer and medicine, product supplier and service, information source " (The Sourcebook for Innovative Drug Delivery:Manufacturers ofDevices & Pharmaceuticals,Suppliers of Products & Services,Sources of Information),1987,Cannon Comns(ISBN:0-9618649-0-7)；Chiellini,E.,Editor；Giusti,G.Editor；Migliaresi,C.,Editor；Nicolais, L., the Editor, " polymer II in medicine：Biochemical drug and medicinal application " (Polymers in Medicine II:Biomedical& Pharmaceutical Applications),1986,Plenum(ISBN:0-306-42390-1)；" medicinal aerosol：A kind of transition delivery system " (PharmaceuticalAerosol:A Drug Delivery System in Transition),1994,Technomic(ISBN:0-87762-971-4)；Avid；Lieberman,L.；Lachman, " pharmaceutical dosage form：Non-bowel medicament, is revised and enlarged for the second time；Correction " (Pharmaceutical DosageForms:Parenteral Medication,2nd Expanded；Revised ed.),1992,Dekker(ISBN:0-8247-9020-0)；Laffer,U.,Editor；Bachmann,I.Editor；Metzger, U., Editor, " " drug delivery implant system " (Implantable DrugDelivery Systems), 199l, S Karger (ISBN:3-8055-5434-6)；Borchardt,Ronald T.,Editor；Repta,Arnold J.,Editor；Stella, Valentino J., Editor, " targeted delivery of drugs：A kind of multi-disciplinary method " (Directed DrugDelivery:A Multidisciplinary Approach),1985,Humana(ISBN:0-89603-089-X)；Anderson, James M., the Editor, " progress 5 of delivery system：The international delivery system latest developments conference Papers collection in 5th Yancheng lake, UT, U.S.A.1991 25-28 days 2 months " (Advances in Drug Delivery Systems 5:Proceedings of the Fifth Internationl Symposium on RecentAdvances in Drug Delivery Systems,Salt Lake City,UT,U.S.A.,February 25-28,1991),Elsevier(ISBN:0-444-88664-8)；Turco,Salvatore J.；King, Robert R., " sterile formulation：It is prepared and clinical practice ", 1987, Williams ＆ Wilkins (ISBN:0-8121-1067-6)；Tomlinson,E.,Editor；Dayis S.S., Editor, " position specific drug delivery：Cell biology, medical science and materia medica " (Site-Specific Drug Delivery:Cell Biology,Medical & Pharmaceutical Aspects),1986,Wiley(ISBN:0-471-91236-0)；Hess, H., Editot, " pharmaceutical dosage form and its application ", 1986, Hogrefe ＆ Huber Pubs (ISBN:3-456-81422-4)；Avis；Lieberman；Lachman, " pharmaceutical dosage form, volume 2 ", 1986, Dekker (ISBN:0-8247-7085-4)；Cartensen, Jens T., " solid-state drug and solid dosage " (Pharmaceutics ofSolids ＆ Solid Dosage Forms), 1977, Wiley (ISBN:0-471-13726-X)；Robinson, Joseph R., Editor, " administration through eye system " (Ophthalmic DrugDelivery Systems), 1980, Am Pharm Assn (ISBN:0-917330-32-3)；Ansel, Howard C., " pharmaceutical dosage form introduction, the 4th edition " (Introduction toPharmaceutical Dosage Forms, 4th ed), 1985, Williams ＆ Wilkins (ISBN:0-8121-0956-2)；" high-tech delivery system " (High Tech.DrugDelivery Systems), 1984, Intl Res Dev (ISBN:0-88694-622-0)；Swarbrick, James, " pharmaceutical science new ideas：Formulation is designed and bioavailability " (Current Concepts in Pharmaceutical Sciences:Dosage FormDesign & Bioavailability),1985,Lea & Febiger(ISBN:0-318-79917-0)；Sprowls, Joseph B.Editor, " prescription pharmacy：Formulation and the excipient substance second edition " (Prescription Pharmacy:Dosage Formulation &Pharmaceutical Adjuncts,2nd ed),1970,Lippincott(ISBN:0-397-52050-6)；And Polderman, J., Editor, " preparation is prepared with formulation：37th world F.I.P. pharmaceutical science conference collection of thesis, Hague, Detch, in September, 1977 " (Formulation ＆ Preparation of Dosage Forms:Proceedings ofthe 37th International Congress of Pharmaceutical Sciencesof F.I.P.,The Hague,Netherlands,September,1977),Elsevier(ISBN:0-444-80033-6).Specific embodiment：

In another embodiment, the present composition is enteric coated tablet formulation.In this embodiment, using conventional method, stiff sheet agent is made in component formula, then tablet is coated with enteric coating thing using routine techniques.

In preferred embodiments, the compounds of this invention is enteric coating powder form form.In this embodiment, recipe ingredient is filled into hard or soft shell capsule or its equivalent, then conventionally uses enteric coating thing coated capsule.

In one embodiment, the present composition is the liquid suspension form of the enteric coating particle of the compounds of this invention.In this embodiment, the inhibitor suspension of liquid form is injected into hard or soft shell capsule or its equivalent, then using conventional method enteric coating thing coated capsule.

As the alternative of the embodiment above, capsule or other dose containers itself are made up of enteric protective agent or composition, or are integrally formed with container.

In another embodiment, enteric protection is used to apply the compounds of this invention to colon.Transmission system is by the following three layers tablet constituted：1) core of reactive compound of the present invention is included；2) cladding not the expanding of core, erodible polymeric layer (conjugate of core and erodible polymeric layer is referred to as " bi-layer matrix piece ")；With the enteric coating thing 3) being applied on bi-layer matrix piece.The composition of this segmented intestine targeted transport system and the effect of component are further stated that in U.S.P.5, in 482,718, the content of the document is all hereby incorporated by reference herein, 2nd column particularly therein, 29 rows to the 4th column, the content of the 12nd row is specially incorporated herein herein.

Another embodiment of the present invention be related to the enteric protection emulsion of the compounds of this invention, suspension, tablet, coated tablet, hard shell capsules, Perle, microencapsulation, sustained release, liquid, semisolid, suppository and aerosol dosage form." theory and practice of industrial pharmaceutical " (Theory and Practice of Industrial Pharmacy), the third edition, Lea ＆Febiger, following part in Philadelphia, 1986 (ISBN 0-8121-0977-5) describes each of these standard dosage forms in detail：Emulsion and liquid suspension dosage form (pp.100-122), tablet (pp.293-345), coated tablet (pp.346-373), hard shell capsules (pp.374-397), Perle (pp.398-411), microencapsulation (pp.412-430), sustained release forms (pp.430-456), liquor (pp.457-478), drug suspension (pp.479-501), emulsion (pp.502-533), semi-solid (pp.534-563), suppository (pp.564-587), and medicinal aerosol (pp.589-618).

Another embodiment includes the following formulations for the compounds of this invention that enteric is protected：Sustained release, controlled release, particle, microencapsulation, many particles, particulate, colloid, intranasal, suction, oral mucosa, colon, intracutaneous, percutaneous, intraocular, part and special livestock formulation.Each of these formulation technologies is all documented in " medicine and pharmaceutical science " (the Drugs and the Pharmaceutical Sciences) that James Swarbrick are edited, Marcel Dekker, New York in detail.Material：

Conventional enteric protection polymer or polymeric blends used herein are insoluble under below about 5.5pH values (i.e. pH value common in stomach), but are dissolved under about 5.5 or higher pH value (i.e. pH conditions present in small intestine and large intestine).The effect of specific enteric protection materials can be using known USP methods measurement.

Include acetate cellulose available for the representational enteric protection polymer in this embodiment; methyl acrylate-methacrylic acid copolymer; cellulose acetate succinate; HPMCP; polyvinyl acetate phthalate, and Eudragit S100.Another example is the anionic property polymers of carboxylic acid (the entitled Eudragit (r) of commercially available product) based on methacrylic acid and methacrylate.Typical example includes acetate cellulose (" CAP "), Cellulose acetotrimellitate, HPMCP (" HPMCP "), hydroxypropyl methyl cellulose phthalic acid succinate, polyvinyl acetate phthalate (" PVAP "), methacrylic acid, and methacrylate.More typical protection is selected from PVAP and/or HPMCP, particularly PVAP.Known PVAP trade name Sureteric (r), is the production of Colorcon companies.

Enteric protection materials can be used and individually or together with Conventional plasticizers are applied to well known to a person skilled in the art method on excipient; these plasticizer such as acetylated monoglyceride; propane diols; glycerine, glycerol triacetate, polyethylene glycol; triethyl citrate; ATBC, diethyl phthalate, or dibutyl phthalate.The representative instance example 1 of enteric protection：The A.141.x.4.i capsule of enteric protection

In this representative instance, A.141.x.4.i the compound of 100mg/ capsule phos-phate forms is mixed into (capsule composition in No. 4 White-opalescent hard gelatin capsule shells with Ac-Di-Sol (Croscarmellose Sodium) (2.6mg/ capsules)：Gelatin NF, titanium dioxide USP), then this capsule of enteric coating.

Using well known to a person skilled in the art method, following enteric coating formula is imposed on capsule.Component %w/w preparations A：HPMCP (" HPMCP ")

The preparation B of 5.0 triacetin, 0.5 ethanol USP, 7.9 water 15.5：The formulation C of 72.75 water of HPMCP 10.0 titanium dioxide, 0.2 dimethyl polysiloxane, 0.05 triethyl citrate, 1.0 ethanol USP 16.00：The preparation D of 44.9 denatured alcohol of acetate cellulose (" CAP ") 8.5 diethyl phthalate, 1.5 titanium dioxide, 0.2 acetone 44.9：PVAP-J (" PVAP ")

The preparation E of 5.0 acetylated glycerides, 0.8 dichloromethane, 47.1 denatured alcohol 47.1：Methacrylic acid or methacrylate (Eudragit (r) S or L, Rohm Pharma, GMBH production, Wetterstadt, West Germany)

8.0 acetone, 46.0 absolute ethyl alcohol, 46.0 plasticizer are appropriate

Typically enteric polymer (with or without plasticizer) is dissolved in solvent described in every kind of formula, suspension/solution is formed.Optionally, opacifier such as titanium dioxide is added.In appropriate containers, it can be deposited on excipient in enteric protection coatingss but under conditions of insoluble or fragmentation excipient, with film coating suspension/solution spraying excipient.About 1-50%, typically 1-15%, the excipient that more typically 5-10% weight enteric polymer coatings thing is finally coated will have sufficient enteric to protect.Example 2：Enteric protects tablet

In another representative instance, core piece is encapsulated in enteric coating.Optionally, using sub- coating.Core piece：

The core piece of the present invention can be formed by the following method：(a) including such as diluent, adhesive, disintegrant and optional one or more are selected from compression aid, flavor enhancement, flavoring agent, sweetener, dyestuff, pigment, mixed active composition and pharmaceutically acceptable excipient in the mixture of the component of buffer system and preservative；(b) gained mixture is with lubricator lubricated；Utilize known to those skilled in the art various into chip technology compacting gained lubrication mixture, formed needed for tablet form (c).Term " tablet " used herein refers to include with the variously-shaped compacting with size or shaped pharmaceutical preparation.

Typical diluents available for this example include lactose or microcrystalline cellulose.

Typical adhesive available for this example includes but is not limited to polyvinylpyrrolidone.Polyvinylpyrrolidone can " Avicel " trade name bought from ISP companies.

Any of disintegrant can be some modified starches, or modified cellulosic polymeric.Typically, using Ac-Di-Sol.A class Ac-Di-Sols NF can be bought with " Ac-di-sol " trade name from the market.

Typical lubricant includes magnesium stearate, stearic acid, hydrogenated vegetable oil or talcum.

Flavor enhancement includes Remington Pharmaceutical Sciences (Remington ' s PharmaceuticalSciences), the 18th edition, Mack publishing company, those described in 1990, pp.1288-1300.

Typical sweetener includes saccharin, aspartyl phenylalanine methyl ester, or edible monose or disaccharides, such as glucose or sucrose.

Dyestuff and pigment include those described in the pharmaceutical excipient handbook (Handbook of Pharmaceutical Excipients) that american pharmaceutical association is edited with pharmacy association of Britain, pp.81-90,1986.

Typical preservative includes methyl hydroxybenzoate, propylben, cetylpyridinium chloride, and its salt, sorbic acid and its salt, thimerosal, or geramine.Enteric coating：

A kind of Eudragit L-30-D (r), methacrylic acid copolymer is produced, it is suitable enteric polymer by Rohm PharmaGmbH (Weiterstadt West Germany).EudragitL-30-D (r) has about 1: 1 free carboxy and ester group ratio, and soluble under the conditions of optionally greater than 5.5pH.Usually, the Eudragit L-30-D (r) included in enteric coating percentage amounts are higher, and active component is got in near-end in the release of lower gastrointestinal tract.Enteric coating discharged in lower gastrointestinal tract compound position can by those skilled in the art by control apply enteric coating constitute and thickness and be controlled by.

Typically comprise plasticizer, such as those described above.Other additives such as talcum or silica are used as improving the antitack agent of art for coating.Sub- coating：

In order that the interaction between the compounds of this invention and enteric coating is minimized, the sub- coating of enhancing stability is used optionally on core piece.Can also use does not influence 10-300 microns of thick enteric films of individual layer of product stability.This sub- coating suppresses active ingredient migration in core piece in enteric coating, so as to improve the stability of storage period and product, once but outer layer enteric coating rupture, sub- coating will be dissolved in intestinal juice rapidly.

Include hydroxypropyl methyl cellulose, hydroxypropyl cellulose, Hydroxypropyl ethyl cellulose, or polyvinylpyrrolidone available for the sub- coated polymeric of typical case in this example.The metabolin of the compounds of this invention

Also within the scope of the present invention, but these products should be new and for prior art or non-obvious to the interior metabolism product of compound described herein.These products can be reacted and produce for example, by oxidation, reduction, hydrolysis, amidatioon, esterification etc., and these reactions are mainly caused by enzymatic processes.Therefore, the present invention is included as the new and non-obvious compound produced by following methods, and methods described includes making the compounds of this invention and mammalian animal for a period of time, to be enough to produce its metabolite.These compounds can typically be differentiated by following manner：Prepare radio-labeled (such as C¹⁴Or H³) the compounds of this invention, with detectable dosage (such as larger than about 0.5mg/kg) parenteral administration in mammal, such as rat, mouse, cavy, monkey, or people, (it is typically about -30 hours 30 seconds) after metabolism is enough time for occurring, then from urine, its converted product is isolated in blood or other biological samples.These products are easily separated (other, using can be isolated with antibody that the epitope remained in metabolite is combined) because being labeled.Metabolite structures in a usual manner, for example, are determined by MS or NMR analyses.Usually, the analysis of metabolin can be according to well known to a person skilled in the art the completion of the same procedure of conventional drug metabolism research institute.These converted products, as long as other places are not found in vivo, even if themselves does not possess neuraminic acid enzyme inhibition activity, it can also be used to the diagnostic analysis of the compounds of this invention therapeutic administratp.Other purposes of the compounds of this invention

The compounds of this invention, or the bioactive substance that they are produced by hydrolysis in vivo or metabolism is used as immunogene or is used for and protein molecule, the antibody of protein, compound or its metabolite can be specifically incorporated into prepare so as to which they can be used as the component of immunogenic composition, the metabolite still retains the epitope (paratope) recognized by immunogene.Intermediate when thus immunogenic composition can be used as the antibody (be used to diagnosing, the analysis of the method such as quality control or the compound or its new metabolite) preparation.The compound can be used for the antibody for producing the anti-polypeptide for being originally used for non-immunogenic, and at this moment these compounds use haptens site as, stimulate the immune response with unmodified protein cross reaction.

Valuable hydrolysate includes the product after the above-mentioned acid hydrolysis with basic group by protection.As described above, acidity or alkaline amide comprising immunogenic polypeptide (such as albumin or keyhole limpet hemacyanin) generally can be used as immunogene.Above-mentioned metabolite can retain substantial extent with the compounds of this invention immune cross-reactivity.Therefore, antibody of the invention can be incorporated on unprotected the compounds of this invention, without being incorporated into by protection compound；In addition, in the presence of having metabolite, the antibody can be combined in by protection compound and/or metabolite without being incorporated into protected the compounds of this invention, or can specifically with therein any or all three combinations.Preferably substantially with natural materials cross reaction does not occur for antibody.Substantive cross reactivity is the reactivity to specific analyte under the conditions of the particular analysis of interference measurement result is enough.

The immunogene of the present invention includes the compounds of this invention of epitope needed for providing, and it is combined with immunogenic substance.Herein, this combination represents covalent bond formation immunogenic conjugate (when possible) or forms the mixture of Non-covalent binding material, or is the above-mentioned combination of both.Immunogenic substance includes adjuvant, such as Freund adjuvants, such as immunogenic protein, virus, bacterium, yeast, animals and plants polypeptide, particularly keyhole limpet hemacyanin, seralbumin, bovine thyroglobulin or soybean trypsin inhibitor, and immunogenic polysaccharide.Typically, the compound with required epitope structure is coupled to immunogenic polypeptide or polysaccharide using multifunctional (being usually two functions) bridging agent by covalent bond.The method for preparing haptens immunogene is that this area is common in itself, in view of the functional group on the precursor or hydrolysate for crosslinking and the possibility of the production antibody special to the epitope (rather than immunogenic substance), it is previously used for being coupled any method of the haptens to immunogenic polypeptide etc. and is suitable for this.

Typically, the polypeptide is coupled to site of the compounds of this invention away from epitope to be identified.

Conjugate is prepared in conventional manner.For example, crosslinking agent n-hydroxysuccinimide, succinic anhydride or alkyl N=C=N alkyl can be used for the conjugate for preparing the present invention.The conjugate is included with valence link or containing 1-100, and typically containing 1-25, the linking group more typically containing 1-10 carbon atom is connected to the compounds of this invention of immunogenic substance.Conjugate is isolated from raw material and accessory substance using technologies such as chromatograms, is then sterile filtered and storage of bottling.

The compounds of this invention can be crosslinked for example, by following any one or more groups：W₆Hydroxyl；E₁Carboxyl；W₆,E₁,G₁, or T₁Carbon atom (substitution H)；And G₁Amino.It is included in the acid amides for also having polypeptide within these compounds, wherein polypeptide serves as above-mentioned R_6cOr R_6bGroup.

Typically, animal is produced this immune conjugate or derivative and be immunized and prepared with conventional method antiserum or monoclonal antibody.

The compounds of this invention can be used for the structural intergrity for keeping glycoprotein in recombinant cell culture thing, i.e., be added in the fermentate for generating glycoprotein to be recycled to suppress the cracking of the neuraminic acid enzymatic for wanting glycoprotein by them.This point the protein carried out in heterologous host cell is re-combined into it is especially important because the cell can produce unfavorable degraded to the sugar moieties of synthesized protein.

The compounds of this invention is multi-functional.Thus they are a class unique monomers of synthetic polymer.Polyamide and polyester are for example included but is not limited to as the polymer prepared by the compounds of this invention.

The compounds of this invention is used as the monomer for preparing the polymer with unique functional pendant groups.The compounds of this invention can be used in homopolymer, or as the comonomer with the monomer copolymerization outside the scope of the invention.The purposes of the homopolymer of the compounds of this invention has：Cation-exchanger (polyester or polyamide), acid functional group E therein are used as when preparing molecular sieve (polyamide), fabric, fiber, diaphragm, article shaped and other items₁By W₆In hydroxy esterification so that pendant basic group G₁Just acidic functionality can be combined, for example, needs the acidic functionality in the polypeptide of purifying.Polyamide is by being crosslinked E₁With G₁And prepare, and W₆The effect of hydrophilic or hydrophobicity affinity groups is still freely played with neighbouring part on ring, and (this depends on selected W₆Group).The method for preparing these polymer by the compounds of this invention is known per se.

The compounds of this invention also can be used as the unique multifunctional surfactant of a class.Particularly work as W₆Without hydrophilic, and it is such as alkyl or during alkoxy, the compounds of this invention has the property of difunctionality surfactant.Thus there is useful interfacial activity, surface to coat for they, emulsion modified, rheological characteristic is modified and the gentle property in surface.

As with particular geometric configuration and while being loaded with the polyfunctional compound of polarity and nonpolar moiety, the compounds of this invention can be used as the unique consisting of phase-transferring agent of a class.As non-limiting examples, the compounds of this invention can be used in phase transfer catalyst and liquid liquid ion extractuin (LIX).

Group W in the compounds of this invention₆,E₁,G₁, and T₁Inside optionally include asymmetric carbon atom.Thus, they are unique chiral accessories that a class can be used for synthesizing or splitting other optically active substances.For example, can be by the racemic mixture of carboxylic acid into its enantiomer component by following manner：1) with wherein W₆For the compounds of this invention formation non-enantiomer ester or the mixture of acid amides of asymmetric hydroxyl alkane or amino alkane group；2) diastereomer is separated；With 3) hydrolysis ester structure.Racemic alcohol by with E₁Acidic-group is separated into ester.Further, if replacing racemic raw material using optical activity acid or alcohol, this method may further be used to split the compounds of this invention in itself.

When preparing affine adsorbing base, immobilised enzymes or immunological assay reagents for technology controlling and process, the compounds of this invention can be used as linker or interval base.At this moment compound includes multiple functional groups for being suitable for use as being crosslinked the site of target substance.For example, being typically that compatibility reagent such as hormone, peptide, antibody, medicine are connected on insoluble matter.These insoluble reagents are then used for the binding partner that these compatibility reagents are adsorbed from the sample, diagnosis sample and other not pure mixtures that have prepared in a known way.Similar, immobilised enzymes can be used for carrying out catalyzed conversion, and can easily reclaim enzyme.When preparing diagnostic reagent, difunctional compound is usually used in linking parsing thing and detectable group.

Many functional groups in the compounds of this invention are suitable for using in cross-linking reaction.For example, group E₁Carboxylic acid or phosphonic acids can be intended to cross-linking reagent alcohol or amine form ester or acid amides respectively.Suitable position is by OH, NHR₁, SH, azido (if desired, being reduced into amino before crosslinking), CN, NO₂, amino, guanidine radicals, the substituted G such as halogen₁Position.When being reacted with crosslinking agent, to prevent difunctional compound of the present invention from polymerizeing ,if needed can suitably protecting reactive group.Usually, compound described here is connected to through carboxylic acid or phosphonic acids in the hydroxyl or amino group of the first connexon, then passes through T again₁Or G₁Group is connected in other zygotes with covalent bond key.For example, the carboxylic acid of the first zygote such as steroid hormone and the compounds of this invention is esterified, then pass through G₁This conjugate is crosslinking on the Sepaharose of cyanogen bromide-activated by hydroxyl, so that being fixed steroid.Other coupled chemical reactions are also known.For example, see Maggio " enzyme immunoassay (EIA) " (Enzyme-Immunoassay) (CRC, 1988, pp.71-135) and wherein cited document.

As described above, wherein W₁Or G₁Carboxyl, hydroxyl or the protected present invention treatment useful compound of amino can be used for oral or slow release formulation.In these purposes, protection group removes (such as by hydrolysis or mode of oxidizing) in vivo, as a result produces free carboxy, amino or hydroxyl.The suitable esters or acid amides for being adapted to this purposes are selected according to the substrate specificity of esterase and/or carboxypeptidase, it is contemplated that these enzymes, which are present in, needs the intracellular of hydrolysis precursor.If the specificity of these enzymes is unknown, need to screen multiple the compounds of this invention, until the substrate specificity needed for finding.This can be learnt by the appearance of free cpds or antiviral activity.The acid amides or ester of the present invention is generally selected with following principle：(I) is not hydrolyzed in upper enteron aisle or relatively slowly hydrolyzed, (II) permeable enteron aisle and cell, and (III) is hydrolyzed in cell cytoplasm and/or body circulation.Screening test preferably uses the sensitive tissue of the cell of particular tissues, i.e. popularity cold infections, such as pulmonary branches feed channel mucous membrane.Analytic approach as known in the art can be adopted to determine vivo biodistribution availability, and these analyses include intestinal lumen stability, cell permeability, liver homogenate stability and plasma stability analysis.However, even if ester, acid amides or other protection derivatives do not translate into free carboxy, amino or oh group in vivo, they are still useful chemical intermediate.Prepare the exemplary process of the compounds of this invention

The invention further relates to prepare the method for pharmaceutical composition.These synthetics use any usability methods in organic synthesis to prepare.Many this methods are all as known in the art.Many known methods all have a detailed description in the following documents：" methodology of organic synthesis complete works of " (Compendium of Organic Synthetic Methods) (John Wiley ＆ Sons, New York), Vol.1, Ian T.Harrison and Shuyen Harrison, 1971；Vol.2, Ian T.Harrison and Shuyen Harrison, 1974；Vol.3, Louis S.Hegedus and Leroy Wade, 1977；Vol.4,Leroy G.Wade,Jr.,1980；Vol.5,Leroy,G.Wade,Jr.,1984；And Vol.6, Michael B.Smith；And March, J., " Advanced Organic Chemistry, the third edition ", (John Wiley ＆ Sons, NewYork, 1985), " comprehensive organic synthesis.Selectivity, strategy and the efficiency volume 9 of modern organic chemistry " (Comprehensive Organic Synthesis.Selectivity; the Volumes of Strategy＆ Efficiency in Modern Organic Chemistry.In 9); BarryM.Trost chief editors (Pergamon publishing houses; New York, print for 1993).

A large amount of illustrative methods for preparing pharmaceutical composition are provided below.These methods are used for the property for illustrating these preparation methods, rather than for limiting the scope of usability methods.

Generally, reaction condition such as temperature, the reaction time, solvent, post-processing step etc. is all well known in the art for the specific reaction to be carried out.The detailed description to this reaction condition is all contained in cited reference (including wherein cited data).Typical reaction temperature is -100 DEG C to 200 DEG C, and solvent is non-proton or protonic solvent, and the reaction time is -10 days 10 seconds.Post processing is main to be included decomposing any unreacted reagent, is then distributed in water/organic layer system (extraction), is finally separating the liquid layer comprising product.

Oxidation is typically being carried out with reduction reaction close under room temperature (about 20 DEG C), but when being reduced using metal hydride, temperature is often reduced to 0 DEG C to -100 DEG C, reduction is generally aprotic with solvent, and for oxidation reaction, then proton or non-protonic solvent all can be used.The reaction time is adjusted to obtain required conversion ratio.

Condensation reaction is typically carried out at a temperature of close to room temperature, but for non-equilibrium, dynamics Controlling condensation reaction, usually using low temperature (0 DEG C to -100 DEG C).Solvent can be (being common in the reaction of dynamics Controlling) of protic (being common in balanced reaction) or aprotic.

Standard synthetic techniques as be azeotroped off byproduct of reaction and using anhydrous response condition (such as inert gas environment) be all in this area it is common, and just use as applicable.

The exemplary method for preparing the compounds of this invention is shown in reaction process hereinafter.

The particular content of these exemplary methods sees below described.Each product in following methods can be optionally separated before it is used for subsequent processes, isolation, and/or purifying.

Term " processing " is abutment, mixes, react, is allowed to react, is contacted, and other be processed commonly used in the art for the one or more chemical substances of expression changes into the term of one or more other chemical substances.It means that " synonymous with following content with the processing of compound 2 compound 1 "：" compound 1 is reacted with compound 2 ", " contact compound 1 " with compound 2, " compound l with compound 2 react ", and the energy reasonable representation commonly used in organic synthesis is by compound 1 compound 2 " processing " and compound 2 " reaction ", other statement languages of " reacting ".

" processing " represents to make the reasonable and common mode that organic chemistry material is reacted.Unless otherwise indicated, it is commonly referred to as normal concentration (0.01M-10M, typically 0.1M-1M), (- 100 DEG C to 250 DEG C of temperature, typically -78 DEG C to 150 DEG C, it it is more typically -78 DEG C to 100C, it it is more typically 0 DEG C -100 DEG C), reaction vessel (is typically made up) of glass, plastics, metal, solvent, pressure, atmosphere (typically air (for the reaction insensitive to oxygen and water) or nitrogen or argon gas (reaction to oxygen or water sensitive)) etc..For giving method, it can select " to handle " condition and device according to the understanding to similar reaction known in organic synthesis field.Specifically, the ordinary skill in organic synthesis field can reasonably select to be expected to successfully carry out the condition and device of the chemical reaction of methods described based on ability domain knowledge.Reaction process 1

In one embodiment, the compounds of this invention is prepared as shown in reaction process 1.Siastatin B (1) (Umezawa, the H. etc., " antibiotic magazine " (J.Antibiotics), 27 obtained by natural material:963-969 (1974)) or ribose (Nishimura, Y. et al., " American Chemical Society's meeting will ", 110:7249-7250,1988)；" Japanization association journal " (Bull.Chem.Soc.Jpn), 65:978-986,1992) can any of two kinds of enantiomers obtain.(Nishimura, Y. et al., " antibiotic magazine ", 46 (2) can be completed using known method to the conversion of compound 2:300-309,1993).The standard reductive alkylation reaction for forming 3 completes (Nishimura, Y. et al., " antibiotic magazine ", 45 (10) using known method:1662-1668,1992).The reaction that alcohol 3 changes into amine 4 is completed by the following method：Zbiral, et al. E. in " chemical record " (Liebigs Ann.Chem.), 129-134 (1991) methods described, and von Itzstein, et al. M. in " carbohydrate compound research " (Carbohydrate Res.), 244:Method described in 181-185 (1993).Deprotection obtains compound 5.

As non-limiting examples, wherein R can be prepared according to the method for reaction process 1¹For the compound 5 of following groups：Ethyl (Et ,-CH₂CH₃), 1- propyl group (n-Pr, n-propyl ,-CH₂CH₂CH₃), 1- butyl (n-Bu, normal-butyl ,-CH₂CH₂CH₂CH₃), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH₂CH(CH₃)₂), 1- amyl group (n-pentyl ,-CH₂CH₂CH₂CH₂CH₃), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), 1- hexyls (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- ethyl -1- butyl (- CH₂CH(CH₂CH₃)₂), 2- ethyl -4- phenyl -1- butyl (- CH₂CH(CH₂CH₃)(CH₂CH₂)), or 2- (2- phenylethyls) -4- phenyl -1- butyl (- CH Ph₂CH(CH₂CH₂Ph)₂).Reaction process 2

In another embodiment, the compounds of this invention can be prepared as shown in reaction process 2.Siastatin B (6) prepares (Nishimura, Y. et al., " American Chemical Society's meeting will ", 110 by ribose:7249-7250,1988)；" Japanization association journal " (Bull.Chem.Soc.Jpn), 65:978-986,1992).To by the conversion of protection compound 7 use known method complete (for example, Pg is Boc, Nishimura, Y. et al. " antibiotic magazine ", 46 (2):300-309,1993).The reaction that alcohol 7 is converted into amine 8 is completed by the following method：Zbiral, E. et al. are in " chemical record " (Liebigs Ann.Chem.), 129-134 (1991) methods described, and von Itzstein, M. et al. in " carbohydrate compound research " (CarbohydrateRes.), 244:Method described in 181-185 (1993).The standard reductive alkylation for forming 9 completes (Nishimura, Y. et al., " antibiotic magazine ", 45 (10) using known method:1662-1668,1992).Deprotection obtains compound 10a.Compound 10a is equal to compound 10b.

As non-limiting examples, wherein R can be prepared according to the method for reaction process 2²For H and R³For the compound 10b of following groups：Ethyl (Et ,-CH₂CH₃), 1- propyl group (n-Pr, n-propyl ,-CH₂CH₂CH₃), 1- butyl (n-Bu, normal-butyl ,-CH₂CH₂CH₂CH₃), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH₂CH(CH₃)₂), 1- amyl group (n-pentyl ,-CH₂CH₂CH₂CH₂CH₃), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), 1- hexyls (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- ethyl -1- butyl (- CH₂CH(CH₂CH₃)₂), 2- ethyl -4- phenyl -1- butyl (- CH₂CH(CH₂CH₃)(CH₂CH₂)), or 2- (2- phenylethyls) -4- phenyl -1- butyl (- CH Ph₂CH(CH₂CH₂Ph)₂).Reaction process 3

In another embodiment, the compounds of this invention can be prepared as shown in reaction process 3.Siastatin B (1) (Umezawa, H. etc., " antibiotic magazine " (J.Antibiotics), 27 derived from natural material:963-969 (1974)) or ribose (Nishimura, Y. et al., " American Chemical Society's meeting will ", 110:7249-7250,1988)；" Japanization association journal " (Bull.Chem.Soc.Jpn), 65:978-986,1992) can any of two kinds of enantiomers form obtain.To by the conversion of protection compound 11 use known method complete (for example, Pg is Boc, Nishimura, Y. et al. " antibiotic magazine ", 46 (2):300-309,1993).Alcohol 11 is completed by the following method to the conversion of amine：Zbiral, E. et al. are in " chemical record " (Liebigs Ann.Chem.), 129-134 (1991) methods described, and von Itzstein, M. et al. in " carbohydrate compound research " (CarbohydrateRes.), 244:Method described in 181-185 (1993).The standard reductive alkylation for forming 12 completes (Nishimura, Y. et al., " antibiotic magazine ", 45 (10) using known method:1662-1668,1992).Deprotection obtains compound 13.

As non-limiting examples, wherein R can be made according to the method for reaction process 3²For H and R³For the compound 13 of following groups：Ethyl (Et ,-CH₂CH₃), 1- propyl group (n-Pr, n-propyl ,-CH₂CH₂CH₃), 1- butyl (n-Bu, normal-butyl ,-CH₂CH₂CH₂CH₃), 2- methyl isophthalic acids-propyl group (i-Bu, isobutyl group ,-CH₂CH(CH₃)₂), 1- amyl group (n-pentyl ,-CH₂CH₂CH₂CH₂CH₃), 3- methyl isophthalic acids-butyl (- CH₂CH₂CH(CH₃)₂), 2-methyl-1-butene base (- CH₂CH(CH₃)CH₂CH₃), 1- hexyls (- CH₂CH₂CH₂CH₂CH₂CH₃), 2- ethyl -1- butyl (- CH₂CH(CH₂CH₃)₂), 2- ethyl -4- phenyl -1- butyl (- CH₂CH(CH₂CH₃)(CH₂CH₂)), or 2- (2- phenylethyls) -4- phenyl -1- butyl (- CH Ph₂CH(CH₂CH₂Ph)₂).Reaction process 4Reaction process 5Reaction process 6Reaction process 7

Reaction process 4 sees below described in embodiment part.

Reaction process 5 and 6 is described as follows：

Described in such as " protection group in organic synthesis " second edition, T.W.Greene and P.G.M.Wuts, John ＆ Sons, New York, NY, 1991, by handling acetone solvate 111 with acid catalyst in methyl alcohol, so as to be converted into glycol 112.

By handling glycol 112 with p-toluenesulfonyl chloride in pyridine solvent, primary product tosylate is obtained, and then handled in methyl alcohol with potassium carbonate and be converted into epoxides 113.The case history of this conversion is in " Journal of Organic Chemistry " (J.Org.Chem.), 57:In 86 (1992).

By using alkali process, epoxides 113 can be converted into allyl alcohol 114 and 115." organic reaction " (Org.Reac.) 29 is shown in the reaction that epoxides is isomerizated into allyl alcohol:345 (1983) are described.Then the allyl alcohol is separated by standard chromatographic techniques.On the other hand, the synthesis of allyl alcohol also can be such as " American Chemical Society's meeting will " 101:Carried out described in 2738 (1979) by the sequential reaction with trifluoromethanesulfonic acid trimethyl silyl ester and DBU.

Utilize MnO₂, allyl alcohol 114 is oxidized to corresponding aldehyde 116.This kind of oxidation reaction is shown in " synthesis " (Synthesis), described in 601 (1986).This oxidation reaction can also use pyridine SO₃Compound/DMSO/Et₃N is completed.The case history of this conversion is in " synthesis ", 274 (1988).

Such as " American Chemical Society's meeting will " 90:Described in 5616 (1968), by using Cymag, MnO in methanol solvate₂And acetic acid treatment, α, beta-unsaturated aldehyde 116 can be oxidized to carboxylate methyl ester 117.

The reaction that the deprotection of silyl ether 117 forms alcohol 118 is carried out using tetrabutyl ammonium fluoride.The reaction that methyl esters is hydrolyzed into carboxylic acid 119 is carried out using potassium hydroxide.Both deprotection methods are recorded in " protection group in organic synthesis " second edition, T.W.Greene and P.G.M.Wuts, Hohn Wiley ＆ Sons, New York, NY, 1991.

According to similar mode described in 114, allyl alcohol 115 is changed into carboxylic acid 121.

Such as " Britain's Society will chemical communication " (J.Chem.Soc.Chem.Commun.), 18:Described in 2197 (1994), pyridine SO is used₃Compound/DMSO/Et₃N oxide diols 112, obtain Alpha-hydroxy aldehyde 122.Also described in this bibliography and use NaClO₂/NaH2PO₄/ 2- methyl-2-butenes change into Alpha-hydroxy aldehyde the oxidation of corresponding alpha-hydroxy carboxylic acid compounds.Carboxylic acid is handled with diazomethane, carboxylate 123 is obtained.This carboxylic esterification reaction is shown in described in " Tet Lett " 1397 (1973).

Utilize SOCl₂And pyridine, alpha-hydroxy esters 123 are dehydrated to the mixture for forming beta-unsaturated esters 117 and 120.The case history of similar reaction is in " Journal of Organic Chemistry " 60:In 2753 (1995).

Using already described condition, the deprotection of hydroxy ester 117 and 120 is formed 119 and 121 respectively.

The exemplary initial substance of modification has been described in detail and has formed different E₁The reaction of group, will not be repeated here.Referring to Fleet, et al. G.W.J. " J.Chem.Soc.Perkin Trans.I ", 905-908 (1984), Fleet, G.W.J. et al., " Britain's chemistry meeting will chemical communication ", 849-850 (1983), Yee, Ying K. et al., " pharmaceutical chemistry magazine " (J.Med.Chem.), 33:2437-2451(1990)；Olson, R.E. et al. " biological organic is communicated with pharmaceutical chemistry " (Bioorganic ＆ Medicinal Chemistry Letters), 4 (18):2229-2234(1994)；Santella, J.B. III et al., " biological organic is communicated with pharmaceutical chemistry ", 4 (18):2235-2240(1994)；Judd, D.B. et al. " pharmaceutical chemistry magazine ", 37:3108-3120 (1994) and De Lombaert, S. et al., " biological organic is communicated with pharmaceutical chemistry ", 5 (2):151-154(1994).

The E of carboxylic acid compound of the present invention₁Sulfur analogs are prepared using either standard method.As non-limiting examples, carboxylic acid is reduced into alcohol using standard method.Alcohol is changed into halide or sulphonic acid ester with standard method again, gained compound and NaSH reactions are then produced into sulfide product.Such reaction is recorded in Patai, " mercaptan chemistry " (The Chemistry of the ThiolGroup) (John Wiley, New York 1974), particularly pt.2, the 721-735 pages.

The various analogs of specific Exemplary materials generated above can be obtained by changing above-mentioned each reaction process.The document of the above-cited appropriate methodology of organic synthesis of explanation is suitable for these modification methods.

It is preferably that reaction product is separated from each other and/or separated with initial substance in above-mentioned each exemplary reaction process.The expection product of each step or series of steps is separated and/or purified with technology commonly used in the art and (hereafter referred to collectively as separated) to required purity.Typically, this kind of separation includes multiphase extraction, or is crystallized with solvent or solvent mixture, distillation, distillation or chromatography.Chromatography may include a variety of methods, such as including size exclusion or ion-exchange chromatography, it is high, in or low pressure liquid phase chromatography, small-scale and preparation of lamina or thick layer chromatography, and thin layer and Rapid chromatographic technique on a small scale.

Another kind of separation method includes using agent treatment mixture, and selected reagent should be able to combine with being expected product, unreacted starting material, byproduct of reaction etc. or can separate them.This kind of reagent includes adsorbent or absorbent, such as activated carbon, molecular sieve, Ion Exchange Medium etc..On the other hand, the reagent can be acid in the case of alkaline matter, and can be then alkali in the case of acidity, or they can also be bonding agent such as antibody, associated proteins, selectivity chelator such as crown ether, liquid liquid ion extractuin agent (Ⅸ) etc..

The selection of suitable partition method depends on the property of involved material.Such as boiling point and molecular weight when distilling and distil, whether there is the property such as the stability of material in acid and alkaline medium in polarized functional group, multiphase extraction process during chromatographic isolation.Those skilled in the art can reach required separating resulting using best-of-breed technology.Embodiment

The following example reference reaction flow.Embodiment 1：Alcohol 101：Added few drops 1 into magnesium chips (0.90g, 37.2mmo1)/THF (50mL), 2- Bromofumes then added 2- bromopropenes (4.5g, 37.2mmol) as initiator in 1 hour.0.68g (5.6mmol) 2- bromopropenes are added, 1.5h is stirred.At -30 DEG C, in 15 minutes by sleeve pipe to adding above-mentioned Grignard reagent in CuI (0.7g, 3.7mmol)/THF (30mL) pulpous states liquid, and be stirred for 20 minutes at -30 DEG C.Then THF (40ml) solution of epoxides 100 (9.4g, 29.8mmol) is added into grignard/CuI mixtures, is stirred 1 hour at -30 DEG C.Add saturation NH at 0 DEG C₄Cl (100mL) terminating reaction, is subsequently added into 1N NH₄The solid that OH is settled out with dissolving.Salt solution is added, product is extracted in ether.Organic phase salt water washing, dries (MgSO₄), filter and evaporation solvent, obtain alcohol 101 (11.8g), the product is suitable to further conversion：¹H NMR(CDCl₃) δ 7.51-7.27 (m, 15H), 4.84 (s, 1H), 4.77 (d, 1H, J=0.9), 3.97 (m, 1H), 3.20 (m, 2H), 2.30 (m, 1H), 2.21 (d, 2H, J=6.6), 1.76 (s, 3H) embodiments 2：Silyl ether 102：T-butyldiphenylsilyl chlorine (2.0g, 7.4mmol) is added into DMF (5mL) solution of alcohol 101 (1.77g, 4.9mmol) and imidazoles (1.5g, 22mmol).It is stirred at room temperature after 1 hour, is diluted with water reactant mixture, and with several parts of extracted by ether.By organic extract water and salt water washing, the drying (MgSO of merging₄), filter and evaporate.Residue obtains silyl ether 102 (2.85g, 97%), is a grease by silica gel column chromatography (20/1- hexane/ethyl acetates)：¹H NMR(CDCl₃) δ 7.73-7.65 (m, 4H), 7.49-7.20 (m, 21H), 4.56 (s, 1H), 4.50 (s, 1H), 4.02-3.98 (m, 1H), 3.11 (m, 2H), 2.45 (dd, 1H, J=7.5,13.5), 2.10 (dd, 1H, J=5.4,13.5), 1.35 (s, 3H), 1.09 (s, 9H) embodiments 3：Epoxides 103:At 0 DEG C, sodium acid carbonate (31g, 371mmol) and MCPBA (32g, 50-60% MCPBA w/w) are added into 102 (44.3g, 74.2mmol) dichloromethane (600mL) solution.After 0 DEG C is stirred 1 hour, 100mL water is added, and be stirred for mixture 1 hour.It is evaporated off after dichloromethane, is diluted with water reactant, uses extracted by ether.By the organic phase cold sodium thiosulfate of 0.5M, saturated sodium bicarbonate solution, salt water washing, and dry (MgSO₄), filtering and evaporation.Residue passes through silica gel column chromatography (2/1-CH₂Cl₂/ hexane), obtain epoxides 103 (35.2g), the non-enantiomer mixture for being 1.5: 1.Embodiment 4：Allyl alcohol 104:At 0 DEG C, epoxides 103 (33.5g)/ether (150mL) is added into ether (400mL) solution of diethyl lithamide (being formed by the hexane solution of 11.5mL diethylamine and 52mL 2.1M butyl lithiums).Reactant is warmed to room temperature, is stirred 17 hours.Cooling reaction is then poured into mixture of ice and water (500mL) to 0 DEG C.Organic phase water, salt water washing, and dry (MgSO₄), filtering and evaporate.Crude product obtains allyl alcohol 104 (15.4g, 46%), is a grease by silica gel column chromatography (3/1- hexane/ethyl acetates)：¹H NMR(CDCl₃) δ 7.75-7.65 (m, 4H), 7.53-7.22 (m, 21H), 4.90 (m, 1H), 4.71 (s, 1H), 4.03 (m, 1H), 3.73 (d, 2H, J=5.1), 3.16 (d, 2H, J=5.1), 2.53 (dd, 1H, J=6.9,13.8), 2.25 (dd, 1H, J=5.1,13.8), 1.54 (br t, 1H, J=6), 1.12 (s, 9H) embodiments 5：Pi-allyl azide 105:At 0 DEG C, triethylamine (7.45mL, 53.5mmol) is added into alcohol 104 (13.1g, 21.4mmol) dichloromethane (100mL) solution, mesyl chloride (1.82g, 23.5mmol) is subsequently added into.After 0 DEG C is kept for 30 minutes, cold water is added, and evaporates dichloromethane, then by residue distribution among ether and water.Organic phase water, salt water washing, dry (MgSO afterwards₄), filter and evaporate.Crude product methanesulfonates is dissolved in DMF (100mL), sodium azide (2.8g, 42.8mmol) is added, is stirred at room temperature 30 minutes.Volatile materials is evaporated off, residue is assigned within ether and water.Organic phase water and salt water washing, dry (MgSO afterwards₄), filter and evaporate.Crude product obtains pi-allyl azide 105 (11.9g, 87%), is a grease by silica gel column chromatography (10/1- hexane/ethyl acetates)：¹H NMR(CDCl₃) δ 7.71-7.60 (m, 4H), 7.51-7.21 (m, 21H), 4.89 (d, 1H, J=1.5), 4.78 (s, 1H), 3.97 (m, 1H), 3.36 (s, 2H), 3.10 (d, 2H, J=5.1), 2.56 (dd, 1H, J=6.3,13.8), 2.20 (dd, 1H, J=5.1,13.8), 1.08 (s, 9H) embodiments 6：Carbamate 106:At 0 DEG C, trimethyl-phosphine (2.3mL, 22mmol) is added in the solution of acetonitrile (100mL) and water (5mL) to azide 105 (9.3g, 14.6mmol).After 0 DEG C is stirred 2 hours, warm reactant to room temperature is stirred 18 hours.Potassium carbonate (4.0g, 29.2mmol) and water (20mL) are added into this solution, benzyl chloroformate (3.1mL, 95% purity ,~21mmol) is subsequently added into.Solvent is evaporated off after stirring reaction 1.5h.Add water, organic matter is extracted in ether.The organic extract merged with salt water washing, dries (MgSO₄), filter and evaporate.By residue by silica gel column chromatography (3/1- hexane/ethyl acetates), carbamate 106 (10.6,97%) is obtained, is a sticky oil thing：¹H NMR(CDCl₃) δ 7.72-7.60 (m, 4H), 7.51-7.20 (m, 26H), 5.08 (br s, 2H), 4.76 (s, 1H), 4.66 (s, 1H), 4.50 (m, 1H), 3.99 (m, 1H), 3.45 (dd, 1H, J=5.7,16), 3.33 (dd, 1H, J=5.7,16), 3.12 (d, 2H), 2.48 (dd, 1H, J=6.6,13.8), 2.16 (dd, 1H, J=6,13.8), 1.08 (s, 9H) embodiments 7：Alcohol 107:At 0 DEG C, formic acid (25mL) is added to solution of 106 (10.6g, the 14.2mmol) in dichloromethane (20mL) and methanol (20mL) is interior.This solution is stirred into 2.5h at 0 DEG C, is then poured under agitation in saturated solution of sodium bicarbonate (600mL).Aqueous phase NaCl saturations, and extracted with ethyl acetate.Dry (MgSO₄) merge organic extract, filter and evaporate.By residual crude by silica gel column chromatography (2/1- hexane/ethyl acetates), alcohol 107 (5.9g, 83%) is obtained, is a grease：¹H NMR(CDCl₃) δ 7.73-7.68 (m, 4H), 7.50-7.34 (m, 11H), 5.09 (s, 2H), 4.92 (d, 1H, J=1.2), 4.79 (s, 1H), 4.68 (m, 1H), 3.92 (m, 1H), 3.60-3.39 (m, 4H), 2.36 (dd, 1H, J=8.4,13.5), 2.15 (dd, 1H, J=4.8,13.5), 1.94 (br t, 1H), 1.10 (s, 9H) embodiments 8：Phthalimide adduct 108:At -78 DEG C, oxalyl chloride (0.39mL, 4.5mmol) is added into DMSO (0.76mL, 10.8mmol) dichloromethane (4mL) solution.After stirring 5 minutes, dichloromethane (5m1) solution of alcohol 107 (2.19g, 4.3mmol) is added, is stirred 25 minutes.Triethylamine (3mL, 21.5mmol) is added, reaction is stirred 30 minutes at -78 DEG C, then warmed to room temperature.After 1 hour, add diethyl ether diluting reaction thing, filtering, and evaporates.Ethyl acetate is dissolved the residue in, with water, salt water washing, and (MgSO is dried₄) organic phase, filtering, and evaporate.Thereafter the interior addition triphenyl phasphine (2.2g of solution to residue in DMF (20mL), 8.3mmol) with phthalimide (1.22g, 8.3mmol), this solution is cooled down to 0 DEG C, add diethylazodicarboxylate (1.3mL, 8.3mmol).Reactant is stirred 1 hour at 0 DEG C, stirring 3.5h is then warmed to room temperature.The excessive diethylazodicarboxylate of hydrolyzable, and evaporate DMF.Residue passes through silica gel column chromatography (2% ethyl acetate/dichloromethane).Mixing portion is chromatographed to (1% ethyl acetate/dichloromethane) again, phthalimide 108 (1.95g, 72%) is obtained, is a foam thing.¹H NMR(CDCl₃) δ 7.83-7.08 (m, 19H), 5.98 (br d, 1H, J=6.9), 5.22 (d, 1H, J=12.3), 4.97 (d, 1H, J=12.3), 4.88 (s, 1H), 4.71 (s, 1H), 4.60-4.52 (m, 2H), 4.20 (br d, 1H, J=16.2), 2.54 (dd, 1H, J=4,15.6), 2.41-2.33 (m, 1H), 0.98 (s, 9H) embodiments 9：Acetamide 109:At 40 DEG C, 108 (4.2g, 6.7mmol) methanol (100mL) solution is handled 5 hours with hydrazine monohydrate (1.6mL, 33mmol).Solvent is evaporated off, residue is suspended in ethyl acetate, solid residue is filtered to remove.Evaporation filtrate obtains a residue, and then is dissolved in pyridine (30mL), and is cooled to 0 DEG C.Acetic anhydride (6.9mL, 73mmol) is added, and warms reaction to being stirred at room temperature 2 hours.It is evaporated off after volatility thing, dissolves the residue in ethyl acetate, and with water and salt water washing.Dry (MgSO₄) organic phase, filtering, evaporation and silica gel column chromatography (1/1 hexane-ethylacetate), obtain 2.7g clean products.Precipitated with ether/hexane, obtain acetamide 109 (1.89g, 52%), be white solid.¹H NMR(CD₃OD) δ 7.69-7.62 (m, 4H), 7.45-7.32 (m, 11H), 6.23 (d, 1H, J=2.4), 5.22 (br d, 1H), 5.04 (br s, 2H), 4.76 (s, 1H), 4.56 (d, 1H, J=14.4), 4.03 (br s, 1H), 3.73 (br d, 1H), 2.43 (br d, 1H), 2.10 (br d, 1H), 1.93 (s, 3H), 1.02 (s, 9H) embodiments 10：Acetone solvate 110：4- methylmorpholine N-oxides (291mg, 2.5mmol) and 0.04M OsO are added into 109 (478mg, 0.88mmol) acetone (3mL) solution₄The aqueous solution (1mL).Reaction 16 hours is stirred at room temperature, 0 DEG C is subsequently cooled to, is handled with 10 hypo solutions (10mL).Plus salt solution diluted mixture, and extracted with ethyl acetate.Dry (MgSO₄) merge organic extract, filter and evaporate, then dissolve the residue in ethyl acetate, filtered by silicagel pad.Filtrate is evaporated, and gained residue is dissolved in acetone (10mL), is handled with dimethoxy propane (5mL) and the p- toluenesulfonic acid of catalytic amount.After stirring 15 minutes at room temperature, saturated sodium bicarbonate solution is added, then evaporation solvent, product is extracted in ethyl acetate, and the organic extract merged is dried with magnesium sulfate, filtering is followed by evaporated.Residue obtains acetone solvate 110 (465mg, 85%), is white solid by silica gel column chromatography (1/1 hexane-ethylacetate).¹H NMR(CD₃OD) δ 7.62 (br s, 4H), 7.51-7.23 (m, 11H), 6.05 (br s, 1H), 5.20 (br d, 1H), 5.05 (br d, 1H), 4.11 (m, 3H), 3.71 (br s, 1H), 2.85 (br d, 1H), 2.04 (m, 1H), 1.91 (s, 3H), 1.62 (m, 1H), 1.41 (s, 3H), 1.18 (br s, 3H), 1.04 (s, 9H) embodiments 11:N- alkyl derivatives 111：110 (465mg, 0.75mmol) solution are handled with 10%Pd/C (90mg), and stirring 4 hours in nitrogen atmosphere (hydrogen balloon).(diatomite) catalyst is filtered out, and evaporates filtrate, a residue is obtained, the product is used without purification.2- ethyl butyraldehydes (0.83mL, 67mmol) are added into amine (324mg, 0.67mmol) methanol (4mL) solution, and cool down this solution to 0 DEG C.Then 1.34mL NaCNBH are added into this solution₃/ZnCl₂Reagent is (by NaCNBH₃(314mg, 5mmol) and ZnCl₂(340mg, 2.5mmol) is made in methanol (10mL)).Reaction is stirred 40 minutes at 0 DEG C, is then evaporated.Residue is assigned within ether and 0.1N NaOH.Dry (MgSO₄) organic phase, filter and evaporate.Residue (2/1- hexane/ethyl acetates), obtains N- alkyl derivatives 111 (212mg, 56%), is white solid obtained by silica gel column chromatography.With hexane recrystallization analysis sample, fine acicular thing is obtained：mp 136-138℃；¹H NMR(CDCl₃)δ7.76-7.66(m,4H),7.50-7.36(m,6H),5.58(d,1H,J=9),4.84(dd,1H,J=2.7,9),4.26(d,1H,J=9),4.01(d,1H,J=3.3),3.74(d,1H,J=8.7),2.61(d,1H,J=11.7),2.37(dd,1H,J=6,12.3),2.30(d,1H,J=12),2.20(dd,1H,J=5.7,12.6),1.92(s,3H),1.69(dd,1H,J=3.3,14.1),1.54-1.28(m,9H),1.17(s,3H),1.13(s,9H),0.96-0.82(m,6H).

Above cited various documents and patent quote position at it respectively and are incorporated herein by reference.The paragraph or number of pages specifically quoted in above-mentioned works are then also specifically incorporated herein by reference.We are described in detail to the present invention, and those skilled in the art are sufficient to prepare accordingly and using the subject matter in the claims below.Obviously, to some modifications of the method and composition of the claims below all within the scope of the present invention or spirit.

Claims

1. a kind of composition, it includes formula (Ⅸ) compound and its salt, solvate, the enantiomer split and purifying diastereomer：

Wherein：

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂Or-(CR₁R₁)_m1W₂；

T₁For-NR₁W₃, or heterocycle；

J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂And J_2aIt independently is H or R₁；

R₁It independently is H or C_1-12Alkyl；

R₄It independently is C_1-12Alkyl, C_2-12Alkenyl, or C_2-12Alkynyl；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Group is replaced；

R_6aIt independently is H or into ether or into the group of ester；

R_6cIt independently is H or the residue containing amino-compound；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

Each m₁It independently is integer 0-2；

E₁For-CO₂H or-CO₂CH₃,

G₁For-OBoc, and

W₆For Boc；

E₁For-CO₂H or-CO₂CH₃,

G₁For-OH, and

W₆For H；

E₁For-CO₂H,-CO₂CH₃Or-CO₂Bn

G₁For-OH, and

W₆For Boc；

E₁For-CONH₂,

G₁For-OH, and

W₆For Boc or H；

E₁For-CO₂H or-CO₂CH₃,

G₁For OH, and

W₆For Bn；Or

E₁For-CO₂H or-CO₂CH₃,

G₁For-OH, and

W₆For-CH₂CH(OH)CH₂(OH)；Wherein Bn is benzyl and Boc is-CO₂C(CH₃)₃。

2. a kind of composition, it includes formula (Ⅹ) compound and its salt, solvate, the enantiomer split and purifying diastereomer：

Wherein：

One Z₁For W₆, and another Z₁For G₁；

Z₂For H or W₆；

E₁For-(CR₁R₁)_m1W₁；

G₁For-OH ,-OR_6a, or-(CR₁R₁)_m1W₂；

T₁For-NR₁W₃, or heterocycle；

J₁And J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂For H or R₁；

R₁It independently is H or C_1-12Alkyl；

R₄It independently is C_1-12Alkyl, C_2-12Alkenyl, or C_2-12Alkynyl；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Group is replaced；

R_6aIt independently is H or into ether or into the group of ester；

R_6cIt independently is H or the residue containing amino-compound；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

Each m₁It independently is integer 0-2；

3. the composition of claim 1, wherein further excluding wherein G₁For-OH ,-OR_6aCompound.

4. the composition of claim 1, wherein G₁For-NR₁W₃。

5. the composition of claim 1, compound therein has formula：

6. the composition of claim 2, wherein compound have formula：

7. the composition of claim 6, wherein G₁For R_6b。

8. the composition of claim 6, wherein R₁For H.

9. the composition of claim 2, wherein compound have formula：

10. the composition of claim 1 or 2, wherein R_6aFor H or hydroxyl or sulfhydryl protected base.

11. the composition of claim 1 or 2, wherein W₆For by 1-3 OR_6aOr SR_6aSubstituted C₁-C₃Alkyl, OR therein_6aOr SR_6aGroup is hydrolysis-stable in gastro-intestinal Fluid.

12. the composition of claim 1 or 2, wherein W₆For：-(CH₂)_m1CH((CH₂)_m3R₃)₂,-(CH₂)_m1C((CH₂)_m3R₃)₃；-(CH₂)_m1CH((CH₂)_m3R_5aW₅)₂；-(CH₂)_m1CH((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)；-(CH₂)_m1C((CH₂)_m3R₃)₂(CH₂)_m3R_5aW₅),(CH₂)_m1C((CH₂)_m3R_5aW₅)₃Or-(CH₂)_m1C((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)₂, and m₃For 1-3 integer.

13. the composition of claim 1 or 2, wherein W₆For-R₅,-W₅Or-R_5aW₅。

14. the composition of claim 1 or 2, wherein W₆For R₅。

15. the composition of claim 14, wherein the R₅For by 0-3-OR₁The R replaced₄。

16. the composition of claim 14, wherein the R₅For by 0-3-NO₂Or N₃The R that group is replaced₄。

17. the composition of claim 15, wherein there are described-OR₁, and at least one described R₁For C₄-C₁₂。

18. the composition of claim 1 or 2, wherein W₆For side chain R₅Group.

19. the composition of claim 18, wherein the R₅For side chain R₄Group.

20. the composition of claim 1 or 2, wherein W₆For R_5e, wherein R_5eFor by 1-3 OR_1aOr SR_1aThe C replaced₁-C₁₂Just or secondary alkyl, and R therein_1aFor C₁-C₄Alkyl.

21. the composition of claim 20, its condition is to work as W₆For by 1-3 R₃The R that group is replaced₅, and at least one R₃Group is OH, COOH, NH₂,C(O)H,C(O)NH₂,S(O)₂OH,S(O)OH,N(H)(C(O)OH),C(N(H))NH₂,N(H)(C(NH₂) N (H)) ,=O, or during=N (H), the then R₅By single OH, COOH, NH₂,C(O)H,C(O)NH₂,S(O)₂OH,S(O)OH,N(H)(C(O)OH),C(N(H))NH₂,N(H)(C(NH₂) N (H)) ,=O, or=N (H) group are replaced.

22. the composition of claim 21, wherein the R₅For by 0-3 R₃The C that group is replaced₄-C₈Alkyl.

23. the composition of claim 21, wherein the R₅By 0-2 R₃Substituent group.

24. the composition of claim 23, wherein the R₅By 1-2 R₃Substituent group, and at least one described R₃Group is-OH ,-COOH ,-NH₂,-C(O)H,-C(O)NH₂,-S(O)₂OH,-S(O)OH,-N(H)(C(O)OH),-C(N(H))NH₂,-N(H)(C(NH₂) N (H)) ,=O, or=N (H).

25. the composition of claim 1 or 2, wherein W₆For the R containing 1-7 carbon atom₄。

26. the composition of claim 1 or 2, wherein the W₆It is not the C for by OH or being protected OH to replace₁-C₃Alkyl, wherein described protected OH systems by aralkyl, acyl group, silicon protection group or oxinane are protected.

27. the composition of claim 26, wherein aralkyl protection group are benzyl, trityl or diphenyl methyl；Acyl group is acetyl group；And silicon protection group is trimethyl silyl.

28. the composition of claim 1, wherein G₁For-NHR₁,-N(R_6b)(R₁),-N(R_6b)₂,-N(H)(R₅),-N(R_6b)(R₅),-N(R₅)₂-C(NH)(NH₂),-N(R₁)C(NR₁)(NR₁R₃),-NHC(NH)(NHR₃),-NHC(NH)(NHR₁),-NHC(NH)NH₂),-CH(CH₂NHR₁)(CH₂OH),-CH(CH₂NHR₁)(CH₂NHR₁),-CH(NHR₁)-(CR₁R₁)_m2-CH(NHR₁)R₁,-CH(OH)-(CR₁R₁)_m2-CH(NHR₁)R₁, or-CH (NHR₁)-(CR₁R₁)_m2-CH(OH)R₁,-(CR₁R₁)_m2-S-C(NH)NH₂,-N=C(NHR₁)(R₃) or-N=C (NHR₁)(R₁)；And m2 independently is integer O-1.

29. the composition of claim 2, wherein G₁For H ,-NHR₁,-N(R_6b)(R₁),-N(R_6b)₂,-N(H)(R₅),-N(R_6b)(R₅),-N(R₅)₂,-C(NH)(NH₂),-CH(CH₂NHR₁)(CH₂OH),-CH(CH₂NHR₁)(CH₂NHR₁),-CH(NHR₁)-(CR₁R₁)_m2-CH(NHR₁)R₁,-CH(OH)-(CR₁R₁)_m2-CH(NHR₁)R₁, or-CH (NHR₁)-(CR₁R₁)_m2-CH(OH)R₁, or-(CR₁R₁)_m2-S-C(NH)NH₂；And m2 independently is 0-1 integer.

30. the composition of claim 1 or 2, wherein W₁For-CO₂R₁。

31. the composition of claim 1 or 2, wherein E₁It is selected from：The phenethyl ester of carboxyl,

With

32. the composition of claim 1, wherein G₁For amino, amidino groups or guanidine radicals, or by C₁-C₆Alkyl-substituted amino, amidino groups or guanidine radicals.

33. the composition of claim 1, wherein G₁It is selected from：C₁-C₆Monoalkylamine,

With

34. the composition of claim 1 or 2, wherein W₃For-C (O)-R₅。

35. the composition of claim 1 or 2, wherein W₆For by 0-3 F, Br, Cl, N₃、NO₂Or the C of CN substitutions₁-C₆Alkyl.

36. the composition of claim 1 or 2, wherein W₅It is selected from：

With

37. the composition of claim 1 or 2, wherein T₁It is selected from：

With

38. the composition of claim 2, wherein J₁For H, C₁-C₂Alkyl or F.

39. the composition of claim 1 or 2, wherein J_1aFor H.

40. the composition of claim 1, wherein J_2aFor H or C₁-C₂Alkyl.

41. the composition of claim 1, wherein J_2aFor H.

42. the composition of claim 1 or 2, wherein W₆For the secondary or tertiary alkyl containing 4-12 carbon atom, and the W₆To be unsubstituted or by NO₂,N₃,F,Br,Cl,OR₁Or SR₁Replaced.

43. the composition of claim 42, the compound is replaced by nitro, azido or F.

44. the composition of claim 1 or 2, wherein W₆For-(CH₂)_m1CH(R₁)_aW₇, and W therein₇For by 0-3 R₃Substituted C₁-C₄Alkyl, a is 0 or 1, and when a is 0, then W₇CH is connected in by double bond key.

45. the composition of claim 44, wherein W₆For-CH₂CH(R₁)W₇。

46. the composition of claim 45, wherein W₇For-CH₂OR₁, and R₁For C₄-C₁₂Alkyl.

47. the composition of claim 1 or 2, wherein W₆For (CH₃CH₂)₂CH-,(CH₃CH₂)(CH₃)(H)C-,(CH₃)₂(H)C-,(CH₃)₂CHCH₂-,CH₃(CH₂)₄-,CH₃(CH₂)₃-,CH₃(CH₂)₂-,(CH₃CH₂)(CH₃)₂C-,(CH₃CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂CH₂)(H)C-,(PhCH₂CH₂)(CH₃CH₂)(H)C-,(PhCH₂CH₂)(PhCH₂CH₂)(H)C-,(PhCH₂)(CH₃CH₂)(H)C-,(PhCH₂)(PhCH₂) (H) C-, cyclohexyl-or cyclopenta-.

48. the composition of claim 1, wherein：E₁For-COOR₅,

Or

G₁For-N (R₅)₂,-NH(R₅)₂,

Or And W₆For C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, or C₂-C₁₂Alkynyl, and W₆Replaced by 0-3 selected from following group：F,Cl,Br,I,-CN,NO₂,N₃,-OR_6a,-NR_6bR_6b,-SR_6a,-O-C(O)R_6a, or-NR_6b-C(O)R_6a。

49. the composition of claim 48, wherein W₆It is selected from

(CH₃CH₂)₂CH-,(CH₃CH₂)(CH₃)(H)C-,(CH₃)₂(H)C-,(CH₃)₂CHCH₂-,CH₃(CH₂)₄-,CH₃(CH₂)₃-,CH₃(CH₂)₂-,(CH₃CH₂)(CH₃)₂C-,(CH₃CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂CH₂)(H)C-,(PhCH₂CH₂)(CH₃CH₂)(H)C-,(PhCH₂CH₂)(PhCH₂CH₂)(H)C-,(PhCH₂)(CH₃CH₂)(H)C-,(PhCH₂)(PhCH₂) (H) C-, cyclohexyl-or cyclopenta-.

50. the composition of claim 2, wherein：

E₁For-COOR₅,

Or

G₁For H；With

W₆For C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, or C₂-C₁₂Alkynyl, and W₆Replaced by 0-3 selected from following group：F,Cl,Br,I,-CN,NO₂,N₃,-OR_6a,-NR_6bR_6b,-SR_6a,-O-C(O)R_6a, or-NR_6b-C(O)R_6a。

51. the composition of claim 50, wherein W₆It is selected from

52. formula (XX) or (XX a) compound and its salt, solvate, the enantiomer split and the diastereomer of purifying：

Wherein

A₃For N, N (O) or N (S)；

Z₃For H, W₆,G₁Or R_3a；

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂Or-(CR₁R₁)_m1W₂；

G₂For G₁Or-X₁W₆；

T₁For-NR₁W₃Or heterocycle；

J₁For R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂For H or R₁；

R₁It independently is H or C₁-C₁₂Alkyl；

R_3aIt independently is-CN, N₃,-NO,-NO₂,-OR_6a,-OR₁,-N(R₁)₂,-N(R₁)(R_6b),-N(R_6b)₂,-SR₁,-SR_6a,-S(O)R₁,-S(O)₂R₁,-S(O)OR₁,-S(O)OR_6a,-S(O)₂OR₁,-S(O)₂OR_6a,-C(O)OR₁,-C(O)R_6c,-C(O)OR_6a,-OC(O)R₁,-N(R₁)(C(O)R₁),-N(R_6b)(C(O)R₁),-N(R₁)(C(O)OR₁),-N(R_6b)(C(O)OR₁),-C(O)N(R₁)₂,-C(O)N(R_6b)(R₁),-C(O)N(R_6b)₂,-C(NR₁)(N(R₁)₂),-C(N(R_6b))(N(R₁)₂),-C(N(R₁))(N(R₁)(R_6b)),-C(N(R_6b))(N(R₁)(R_6b)),-C(N(R₁))(N(R_6b)₂),-C(N(R_6b))(N(R_6b)₂),-N(R₁)C(N(R₁))(N(R₁)₂),-N(R₁)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)₂),-N(R_6b)C(N(R_6b))(N(R₁)₂),-N(R_6b)C(N(R₁))(N(R₁)(R_6b)),-N(R₁)C(N(R_6b))(N(R₁)(R_6b)),-N(R₁)C(N(R₁))(N(R_6b)₂),-N(R_6b)C(N(R_6b))(N(R₁)(R_6b)),-N(R_6b)C(N(R₁))(N(R_6b)₂),-N(R₁)C(N(R_6b))(N(R_6b)₂) or-N (R_6b)C(N(R_6b))(N(R_6b)₂)；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Substituent group；

R_6aIt independently is H or into ether or into ester group；

R_6cIt independently is H or the residue containing amino-compound；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

E₁For-CO₂H or-CO₂CH₃,

G₂For-OBoc, and

Z₃For Boc；

E₁For-CO₂H or-CO₂CH₃,

G₂For-OH, and

Z₃For H；

E₁For-CO₂H,-CO₂CH₃Or-CO₂Bn

G₂For-OH, and

Z₃For Boc；

E₁For-CONH₂,

G₂For-OH, and

Z₃For Boc or H；

E₁For-CO₂H or-CO₂CH₃,

G₂For OH, and

Z₃For Bn；Or

E₁For-CO₂H or-CO₂CH₃,

G₂For-OH, and

Z₃For-CH₂CH(OH)CH₂(OH)；Wherein Bn is benzyl, and Boc is-CO₂C(CH₃)₃；Further exclude following formula (VII) or (VIII) compound：Wherein

E₁For-(CR₁R₁)_m1W₁；

G₁For N₃,-CN,-OH,-OR_6a,-NO₂, or-(CR₁R₁)_m1W₂；

U₁For-X₁W₆；

J₁And J_1aIt independently is R₁,Br,Cl,F,I,CN,NO₂Or N₃；

J₂And J_2aIt independently is H or R₁；

R₁It independently is H or C₁-C₁₂Alkyl；

R₅It independently is R₄, wherein each R₄By 0-3 R₃Substituent group；

R_6aIt independently is H or into ether or into ester group；

R_6cIt independently is H or the residue containing amino-compound；

W₃For W₄Or W₅；

W₄For R₅Or-C (O) R₅,-C(O)W₅,-SO₂R₅Or-SO₂W₅；

X₁For even key ,-O- ,-N (H)-,-N (W₆)-,-S- ,-SO-, or-SO₂-；With

Each m₁It independently is integer 0-2.

53. the compound of claim 52, the compound includes formula (Ⅹ Ⅺ) or (Ⅹ Ⅺ a) compound：

54. the compound of claim 53, the compound includes formula (Ⅹ Ⅻ) or (Ⅹ Ⅻ a) compound：

55. the compound of claim 54, the compound includes formula (XX III) or (XX III a) compound：

56. the compound of claim 52, the compound includes formula (XX IV) or (XX IV a) compound：Wherein

One Z₁For W₆, and another is then G₁；With

Z₂For H or W₆。

57. the compound of claim 56, the compound includes formula (XX V) or (XX V a) compound：

58. the compound of claim 57, the compound includes formula (XX VI) or (XX VI a) compound：

59. the compound of claim 58, the compound includes making (XX VII) or (XX VII a) compound：

60. the compound of claim 52, the compound includes formula (XX VIII) or (XX VIII a) compound：

61. the compound of claim 60, the compound includes formula (XX Ⅸ) or (XX Ⅸ a) compound：

62. the compound of claim 61, the compound includes formula (XXX) or (XXX a) compound：

63. the compound of claim 52, wherein G₂For G₁。

64. the compound of claim 63, wherein G₁For N₃,-CN,-NO₂, or-(CR₁R₁)_m1W₂。

65. the compound of claim 64, wherein G₁For N₃,-CN or-NO₂。

66. the compound of claim 64, wherein G₁For-(CR₁R₁)_m1W₂。

67. the compound of claim 66, wherein G₁For amino, amidino groups or guanidine radicals, or by C₁-C₆Alkyl-substituted amino, amidino groups or guanidine radicals.

68. the compound of claim 66, wherein G₁It is selected from：C₁-C₆Monoalkylamine,

With

69. the compound of claim 52, wherein G₂For-X₁W₆。

70. the compound of claim 52, wherein W₂For amino, aminoalkyl, amidino groups, Amidinylalkyl, guanidine radicals or guanidine alkylation.

71. the compound of claim 52, wherein W₂For amino, amidino groups, guanidine radicals, heterocycle, the heterocycle replaced by 1 or 2 amino or guanidine radicals, the C replaced by amino or guanidine radicals₂-C₃Alkyl, or this alkyl that second group by amino and selected from hydroxyl and amino is replaced.

72. the compound of claim 71, wherein the heterocycle is 5 or 6 circle heterocycles containing 1 or 2 N or S atom.

73. the compound of claim 52, wherein G₂For-NHR₁,-C(NH)(NH₂),-NR₁-C(NR₁)(NR₁R₃),-NH-C(NH)(NHR₃),-NH-C(NH)(NHR₁),-NH-C(NH)NH₂,-CH(CH₂NHR₁)(CH₂OH),-CH(CH₂NHR₁)(CH₂NHR₁),-CH(NHR₁)-(CR₁R₁)_m2-CH(NHR₁)R₁,-CH(OH)-(CR₁R₁)_m2-CH(NHR₁)R₁, or-CH (NHR₁)-(CR₁R₁)_m2-CH(OH)R₁,-C(R₁R₁)_m2-S-C(NH)NH₂,-N=C(NHR₁)(R₃),-N=C(SR₁)N(R₁)₂,-N(R₁)C(NH)N(R₁) C=N, or-N=C (NHR₁)(R₁)。

74. the compound of claim 52, wherein G₂For-NHR₁,-N(R_6b)(R₁),-N(R_6b)₂,-N(H)(R₅),-N(R_6b)(R₅),-N(R₅)₂,-C(NH)(NH₂),-CH(CH₂NHR₁)(CH₂OH),-CH(CH₂NHR₁)(CH₂NHR₁),-CH(NHR₁)-(CR₁R₁)_m2-CH(NHR₁)R₁,-CH(OH)-(CR₁R₁)_m2-CH(NHR₁)R₁, or-CH (NHR₁)-(CR₁R₁)_m2-CH(OH)R₁, or-C (R₁R₁)_m2-S-C(NH)NH₂；And m2 independently is integer 0 or 1.

75. the compound of claim 52, wherein G₂For-NHR₁。

76. the compound of claim 52, wherein E₁For W₁。

77. the compound of claim 76, wherein W₁For-CO₂R₅。

78. the compound of claim 77, wherein R₅For R₄。

79. the compound of claim 78, wherein R₄For R₁。

80. the compound of claim 1,2 or 52, wherein E₁For-COOH, or carboxyl ester or carboxylic acid amides of the hydrolyzable as-COOH in vivo.

81. the compound of claim 52, wherein E₁It is selected from：Carboxyl styrene ester, With

82. the compound of claim 52, wherein T₁For-N (R₁)(W₃)。

83. the compound of claim 82, wherein R₁For H.

84. the compound of claim 83, wherein W₃For-C (O)-R₅。

85. the compound of claim 84, wherein T₁It is selected from：

With

86. the compound of claim 52, wherein J₁For H, C₁-C₂Alkyl or F.

87. the compound of claim 86, wherein J₁For H.

88. the compound of claim 52, wherein J₂For H or C₁-C₂Alkyl.

89. the compound of claim 88, wherein J₂For H.

90. the compound of claim 52, wherein J_2aFor H or C₁-C₂Alkyl.

91. the compound of claim 90, wherein J_2aFor H.

92. the compound of claim 5, wherein R_6aFor H or hydroxyl or sulfydryl protection group.

93. the compound of claim 52, wherein A₃For N.

94. the compound of claim 52, wherein Z₃For R_3a, and G₂For-X₁W₆。

95. the compound of claim 52, wherein Z₃For W₆, and G₂For G₁。

96. the compound of claim 94 or 95, wherein W₆For by 1-3 OR_6aOr SR_6aSubstituted C₁-C₃Alkyl.

97. the compound of claim 96, wherein the OR_6aOr SR_6aGroup is hydrolysis-stable in gastro-intestinal Fluid.

98. the compound of claim 94 or 95, wherein W₆For：-(CH₂)_m1CH((CH₂)_m3R₃)₂,-(CH₂)_m1C((CH₂)_m3R₃)₃,-(CH₂)_m1CH((CH₂)_m3R_5aW₅)₂；-(CH₂)_m1CH((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)；-(CH₂)_m1C((CH₂)_m3R₃)₂(CH₂)_m3R_5aW₅),(CH₂)_m1C((CH₂)_m3R_5aW₅)₃Or-(CH₂)_m1C((CH₂)_m3R₃)((CH₂)_m3R_5aW₅)₂, and m₃For integer 1-3.

99. the compound of claim 94 or 95, wherein W₆For-R₅,-W₅Or-R_5aW₅。

100. the compound of claim 99, wherein W₆For R₅。

101. the compound of claim 100, wherein the R₅For by O-3-OR₁Substituted R₄。

102. the compound of claim 101, wherein there are described-OR₁, and at least one described R₁For C₁-C₁₂Alkyl.

103. the compound of claim 100, wherein the R₅For by 0-3-NO₂Or N₃The R that group is replaced₄。

104. the compound of claim 94 or 95, wherein W₆For side chain R₅Group.

105. the compound of claim 104, wherein the R₅For side chain R₄Group.

106. the compound of claim 94 or 95, wherein W₆For R_5e, wherein R_5eFor by 1-3 OR_1aOr SR_1aThe C replaced₁-C₁₂Just or secondary alkyl, and R therein_1aFor C₁-C₄Alkyl.

107. the compound of claim 94 or 95, wherein W₆For by 1-3 R₃The R that group is replaced₄, and wherein at least one R₃Group is OH, COOH, NH₂,C(O)H,C(O)NH₂,S(O)₂OH,S(O)OH,N(H)(C(O)OH),C(N(H))NH₂,N(H)(C(NH₂) N (H)) ,=O, or=N (H).

108. the compound of claim 94 or 95, wherein W₆For by 0-3 R₃The C that group is replaced₁-C₁₀Alkyl.

109. the compound of claim 108, wherein W₆For by 0-3 R₃The C that group is replaced₂-C₈Alkyl.

110. the compound of claim 108, wherein W₆For by 0-3 R₃The C that group is replaced₃-C₈Alkyl.

111. the compound of claim 108, wherein W₆For by 0-2 R₃The C of substituent group₄-C₈Alkyl.

112. the compound of claim 108, wherein W₆For by 0-1 R₃The C of substituent group₄-C₆Alkyl.

113. the compound of claim 108, wherein the W₆For by 0-2 R₃Substituent group.

114. the compound of claim 113, wherein R₃Group is F, Br, Cl ,-OH ,-COOH ,-NH₂,-C(O)H,-C(O)NH₂,-S(O)₂OH,-S(O)OH,-N(H)(C(O)OH),-C(N(H))NH₂,-N(H)C((NH₂) N (H)) ,=O, or=NH.

115. the compound of claim 94 or 95, wherein W₆For the secondary or tertiary alkyl containing 1-12 carbon atom, and the W₆To be unsubstituted or by NO₂,N₃,F,Br,Cl,OR₁Or SR₁Replaced.

116. the compound of claim 115, the compound is replaced by nitro, azido or F.

117. the compound of claim 94 or 95, wherein W₆For-(CH₂)_m1CH(R₁)_aW₇, wherein W₇For by 0-3 R₃Substituted C₁-C₄Alkyl, a is 0 or 1, and when a is 0, then W₇It is connected by double bond with CH.

118. the compound of claim 117, wherein W₆For-CH₂CH(R₁)W₇。

119. the compound of claim 118, wherein W₇For-CH₂OR₁, and R₁For C₄-C₁₂Alkyl.

120. the compound of claim 94 or 95, wherein W₆For (CH₃CH₂)₂CH-,(CH₃CH₂)(CH₃)(H)C-,(CH₃)₂(H)C-,(CH₃)₂CHCH₂-,CH₃(CH₂)₄-,CH₃(CH₂)₃-,CH₃(CH₂)₂-,(CH₃CH₂)(CH₃)₂C-,(CH₃CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂)(H)C-,(CH₃CH₂CH₂)(CH₃CH₂CH₂)(H)C-,(PhCH₂CH₂)(CH₃CH₂)(H)C-,(PhCH₂CH₂)(PhCH₂CH₂)(H)C-,(PhCH₂)(CH₃CH₂)(H)C-,(PhCH₂)(PhCH₂) (H) C-, cyclohexyl-or cyclopenta-.

121. the compound of claim 94 or 95, wherein：

E₁For-COOR₅,

Or

G₁For-N (R₅)₂,-NH(R₅)₂,

Or

And W₆For C₁-C₁₂Alkyl, C₂-C₁₂Alkenyl, or C₂-C₁₂Alkynyl, and W₆Replaced by 0-3 selected from following group：F,Cl,Br,I,-CN,NO₂,N₃,-OR_6a,-NR_6bR_6b,-SR_6a,-O-C(O)R_6a, or-NR_6b-C(O)R_6a。

122. the compound of claim 121, wherein W₆It is selected from

123. the compound of claim 1,2 or 52, it further comprises pharmaceutical acceptable carrier.

124. a kind of method for suppressing neuraminidase activity, this method includes making may the compound of the sample containing neuraminidase and claim 1,2 or 52 the step of contact.

125. the compound described in table 6.