HK1120494B - Novel compounds and methods for synthesis and therapy - Google Patents
Novel compounds and methods for synthesis and therapy Download PDFInfo
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- HK1120494B HK1120494B HK08112143.3A HK08112143A HK1120494B HK 1120494 B HK1120494 B HK 1120494B HK 08112143 A HK08112143 A HK 08112143A HK 1120494 B HK1120494 B HK 1120494B
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Description
The invention is a divisional application of Chinese patent application 200510087659.6 with the application date of 1996, 2 and 26, and the original invention name is 'novel compound, its synthesis method and therapeutic application'.
Background
Technical Field
Neuraminidase (also known as sialidase, acylneuraminidase, and ec3.2.1.18) is a common enzyme in animals and many microorganisms. It is a glycohydrolase that cleaves terminal alpha-ketoglycoside-bonded sialic acids from glycoproteins, glycolipids and oligosaccharides. Many neuraminidase-containing microorganisms are pathogenic to humans and other animals, including poultry, horses, pigs and seals. These pathogenic organisms include influenza virus.
Neuraminidase is involved in the pathogenicity of influenza virus. It is thought to help the newly synthesized virion emerge from infected cells and to help the virus move (via its hydrolase activity) through the respiratory mucus.
Brief description of the related art
Itzstein, M.von et al in "Nature", 363 (6428): 418-423(1993) discloses the theoretical design of sialidase-based inhibitors of influenza virus replication.
Colman, P.M. et al in International Patent Publication No. WO 92/06691 (published int. App. No. PCT/AU 90/00501, 1992, 30.4.1992), Itzstein, L.M.von et al in European Patent Publication No. 0539204A 1 (published EP App. No.92309648.6, 1993, 28.4.1993), and Itzstein, L.M.von et al in International Publication No. WO 91/16320 (published int.App. No. PCT/AU 91/00161, 1991, 31.10) disclose compounds that bind neuraminidase and claim antiviral activity in vivo.
Object of the Invention
The present invention is primarily directed to the inhibition of viruses, particularly influenza viruses. It is particularly aimed at inhibiting the selective inhibition of glycolytic enzymes such as neuraminidase, in particular viral or bacterial neuraminidase.
It is another object of the present invention to provide neuraminidase inhibitors which inhibit the rate of urination, enter nasal or pulmonary secretions from the systemic circulation, have bioavailabilities sufficient to be therapeutically effective, have high potency, clinically acceptable toxicity profiles (profiles), and other desirable pharmaceutical properties.
It is another object to provide an improved method for the synthesis of a neuraminidase inhibitor which is less expensive.
Another object is to provide improved methods of administering known and novel neuraminidase inhibitors.
It is a further object to provide compositions for the preparation of polymers, surfactants or immunogens and for other industrial processes and articles.
These and other objects as described above will be readily apparent to those of ordinary skill in the art after considering the present invention as a whole.
Summary of The Invention
The present invention provides compounds or compositions having formula (I) or (II)
Wherein
A1is-C (J)1) or-N ═ N;
A2is-C (J)1)2-，-N(J1)-，-N(O)(J1)-，-N(O)＝，-S-，-S(O)-，-S(O)2-or-O-;
E1is- (CR)1R1)m1W1；
G1Is N3，-CN，-OH，-OR6a，-NO2Or is- (CR)1R1)m1W2；
T1is-NR1W3Heterocyclic ring, or with U1Or G1Together form a group having the structure:
U1is H or-X1W6；
J1And J1aIndependently is R1，Br，Cl，F，I，CN，NO2Or N3；
J2And J2aIndependently is H or R1；
R1Independently is H or C1-C12An alkyl group;
R2independently is R3Or R4Wherein each R4Independently with 0 to 3R3Substituted by groups;
R3independently of one another, F, Cl, Br, I, -CN, N3，-NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-S(O)R1，-S(O)2R1，-S(O)OR1，-S(O)OR6a，-S(O)2OR1，-S(O)2OR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-N(R1)(C(O)R1)，-N(R6b)(C(O)R1)，-N(R1)(C(O)OR1)，-N(R6b)(C(O)OR1)，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2，-C(NR1)(N(R1)2)，-C(N(R6b))(N(R1)2)，-C(N(R1))(N(R1)(R6b))，-C(N(R6b))(N(R1)(R6b))，-C(N(R1))(N(R6b)2)，-C(N(R6b))(N(R6b)2)，-N(R1)C(N(R1))(N(R1)2)，-N(R1)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)2)，-N(R6b)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)(R6b))，-N(R1)C(N(R1))N(R6b)2)，-N(R6b)C(N(R6b))(N(R1)(R6b))，-N(R6b)C(N(R1))(N(R6b)2)，-N(R1)C(N(R6b))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R6b)2)，＝O，＝S，＝N(R1) Or ═ N (R)6b)；
R4Independently is C1-C12Alkyl radical, C2-C12Alkenyl, or C2-C12An alkynyl group;
R5independently is R4Wherein each R4Is 0 to 3R3Substituted by a group;
R5aindependently is C1-C12Alkylene radical, C2-C12Alkenylene, or C2-C12Alkynylene, any alkylene, alkenylene or alkynylene substituted with 0 to 3R3Substituted by a group;
R6aindependently H or an ether-or ester-forming group;
R6bindependently is H, an amino protecting group or a residue of a carboxy-containing compound;
R6cindependently is H or a residue of an amino-containing compound;
W1r being an acidic hydrogen-containing group, a protected acidic group, or an acidic hydrogen-containing group6cAn amide;
W2is a group containing a basic heteroatom or a protected basic heteroatom, or R of the basic heteroatom6bAn amide;
W3is W4Or W5；
W4Is R5or-C (O) R5，-C(O)W5，-SO2R5or-SO2W5；
W5Is a carbocyclic or heterocyclic ring in which W5Independently by 0 to 3R 2Substituted by groups;
W6is-R5，-W5，-R5aW5，-C(O)OR6a，-C(O)R6c，-C(O)N(R6b)2，-C(NR6b)(N(H)(R6b))，-C(NR6b)(N(R6b)2)，-C(N(H)(N(R6b)2)，-C(S)N(R6b)2or-C (O) R2；
X1Is a bond, -O-, -N (H) -, -N (W)6)-，-N(OH)-，-N(OW6)-，-N(NH2)-，-N(N(H)(W6))-，-N(N(W6)2))-，-N(H)N(W6) -, -S-, -SO-, or-SO2-; and
each m1Independently an integer from 0 to 2; with the proviso that the following compounds are excluded;
(a)A1is-CH or-N and A2is-CH2-；
(b)E1Is COOH, P (O) (OH)2，SOOH，SO3H, or tetrazole;
(c)G1is CN, N (H) R20，N3，SR20，OR20Guanidino, -N (H) CN
(d)T1is-NHR20；
(e)R20Is H; c1-C4An acyl group; c1-C6Linear or cyclic alkyl, or halogen substituted analogues thereof; allyl or unsubstituted aryl, or by halogen, OH group, NO2Radical, NH2Aryl substituted with a group or a COOH group;
(f)J1is H and J1aIs H, F, Cl, Br or CN;
(g)J2is H and J2aIs H, CN or N3；
(h)U1Is CH2YR20a，CHYR20aCH2YR20aOr CHYR20aCHYR20aCH2YR20a；
(i)R20aIs H or C1-C4An acyl group;
(j) y is O, S, H or NH;
(k)0 to 2 YR20aIs H, and
(l)U1each Y moiety in the group is the same or different, and when Y is H, R20aIs a covalent bond, with the proviso that if G1Is N3Then U is1Is not-CH2OCH2Ph，
And pharmaceutically acceptable salts and solvates thereof;
and salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention relates to compounds of the formula:
wherein
E1Is- (CR)1R1)m1W1；
G1Is N3，-CN，-OH，-OR6a，-NO2Or is- (CR)1R1)m1W2；
T1is-NR1W3Heterocyclic ring, or with U1Or G1Together form a group having the structure:
U1is H or-X 1W6And if is-X1W6Then U is1Is branched chain;
J1and J1aIndependently is R1，Br，Cl，F，I，CN，NO2Or N3；
J2And J2aIndependently is H or R1；
R1Independently is H or C1-C12An alkyl group;
R2independently is R3Or R4Wherein each R4Independently with 0 to 3R3Substituted by groups;
R3independently of one another, F, Cl, Br, I, -CN, N3，-NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-S(O)R1，-S(O)2R1，-S(O)OR1，-S(O)OR6a，-S(O)2OR1，-S(O)2OR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-N(R1)(C(O)R1)，-N(R6b)(C(O)R1)，-N(R1)(C(O)OR1)，-N(R6b)(C(O)OR1)，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2，-C(NR1)(N(R1)2)，-C(N(R6b))(N(R1)2)，-C(N(R1))(N(R1)(R6b))，-C(N(R6b))(N(R1)(R6b))，-C(N(R1))(N(R6b)2)，-C(N(R6b))(N(R6b)2)，-N(R1)C(N(R1))(N(R1)2)，-N(R1)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)2)，-N(R6b)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)(R6b))，-N(R1)C(N(R1))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R1)(R6b))，-N(R6b)C(N(R1))(N(R6b)2)，-N(R1)C(N(R6b))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R6b)2)，＝O，＝S，＝N(R1) Or ═ N (R)6b)；
R4Independently is C1-C12Alkyl radical, C2-C12Alkenyl, or C2-C12An alkynyl group;
R5independently is R4WhereinEach R4Is 0 to 3R3Substituted by a group;
R5aindependently is C1-C12Alkylene radical, C2-C12Alkenylene, or C2-C12Alkynylene radical, and the alkynylene radical is substituted with 0 to 3R3Substituted by a group;
R6aindependently H or an ether-or ester-forming group;
R6bindependently is H, an amino protecting group or a residue of a carboxy-containing compound;
R6cindependently is H or a residue of an amino-containing compound;
W1is an acidic hydrogen-containing group, a protected acidic group, or an acidic hydrogen group-containing R6cAn amide;
W2is a group containing a basic heteroatom or a protected basic heteroatom, or R of the basic heteroatom6bAn amide;
W3is W4Or W5；
W4Is R5or-C (O) R5，-C(O)W5，-SO2R5or-SO2W5；
W5Is a carbocyclic or heterocyclic ring in which W5Independently 0 to 3R2Substituted by a group;
W6is-R5，-W5，-R5aW5，-C(O)OR6a，-C(O)R6c，-C(O)N(R6b)2，-C(NR6b)(N(R6b)2)，-C(S)N(R6b)2Or C (O) R2；
X1Is a bond, -O-, -N (H) -, -N (W)6)-，-N(OH)-，-N(OW6)-，-N(NH2)-，-N(N(H)(W6))-，-N(N(W6)2)-，-N(H)N(W6) -, -S-, -SO-, or-SO2-; and
each m1Independently an integer from 0 to 2;
and salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention relates to compounds of the formula:
wherein
E1Is- (CR)1R1)m1W1；
G1Is N3，-CN，-OH，-OR6a，-NO2Or is- (CR)1R1)m1W2；
T1is-NR1W3Heterocyclic ring, or with U1Or G1Together form a group having the structure:
U1is H or-X1W6；
J1And J1aIndependently is R1，Br，Cl，F，I，CN，NO2Or N3；
J2And J2aIndependently is H or R1；
R1Independently is H or C1-C12An alkyl group;
R2independently is R3Or R4Wherein each R4Independently by 0 to 3R3Substituted by a group;
R3independently of one another, F, Cl, Br, I, -CN, N3，-NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-S(O)R1，-S(O)2R1，-S(O)OR1，-S(O)OR6a，-S(O)2OR1，-S(O)2OR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-N(R1)(C(O)R1)，-N(R6b)(C(O)R1)，-N(R1)(C(O)OR1)，-N(R6b)(C(O)OR1)，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2，-C(NR1)(N(R1)2)，-C(N(R6b))(N(R1)2)，-C(N(R1))(N(R1)(R6b))，-C(N(R6b))(N(R1)(R6b))，-C(N(R1))(N(R6b)2)，-C(N(R6b))(N(R6b)2)，-N(R1)C(N(R1))(N(R1)2)，-N(R1)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)2)，-N(R6b)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)(R6b))，-N(R1)C(N(R1))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R1)(R6b))，-N(R6b)C(N(R1))N(R6b)2)，-N(R1)C(N(R6b))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R6b)2)，＝O，＝S，＝N(R1) Or ═ N (R)6b)；
R4Independently is C1-C12Alkyl radical, C2-C12Alkenyl, or C2-C12An alkynyl group;
R5independently is R4Wherein each R4Is 0 to 3R3Substituted by a group;
R5aindependently is C1-C12Alkylene radical, C2-C12Alkenylene, or C2-C12Alkynylene radical, and the alkynylene radical is substituted with 0 to 3R3Substituted by a group;
R6aindependently H or an ether-or ester-forming group;
R6bindependently is H, an amino protecting group or a residue of a carboxy-containing compound;
R6cindependently is H or a residue of an amino-containing compound;
W1is an acidic hydrogen-containing group, a protected acidic group, or an acidic hydrogen group-containing R6cAn amide;
W2is a group containing a basic heteroatom or a protected basic heteroatom, or R of the basic heteroatom6bAn amide;
W3is W4Or W5；
W4Is R5or-C (O) R5，-C(O)W5，-SO2R5or-SO2W5；
W5Is a carbocyclic or heterocyclic ring in which W5Independently 0 to 3R2Substituted by a group;
W6is-R5，-W5，-R5aW5，-C(O)OR6a，-C(O)R6c，-C(O)N(R6b)2，-C(NR6b)(N(R6b)2)，-C(S)N(R6b)2Or C (O) R2；
X1is-O-, -N (H) -, -N (W)6)-，-N(OH)-，-N(OW6)-，-N(NH2)-，-N(N(H)(W6))-，-N(N(W6)2)-，-N(H)N(W6) -, -S-, -SO-, or-SO2-; and
each m1Independently an integer from 0 to 2;
and salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention relates to compounds of the formula:
wherein
E1is-CO2R1；
G1is-NH2，-N(H)(R5) or-N (H) (C (N (H)) (NH)2))；
T1is-N (H) (C (O) CH3)；
U1is-OR60；
R1Is H or alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; and
R60is a branched alkyl group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; and salts, solvates, resolved enantiomers and purified diastereomers thereof.
Another embodiment of the invention relates to compounds of formula (VII) or (VIII):
wherein
E1Is- (CR)1R1)m1W1；
G1Is N3，-CN，-OH，-OR6a，-NO2Or is- (CR)1R1)m1W2；
T1is-NR1W3Heterocyclic ring, or with G1Together form a group having the structure
U1is-X1W6；
J1And J1aIndependently is R1，Br，Cl，F，I，CN，NO2Or N3；
J2And J2aIndependently is H or R1；
R1Independently is H or C1-C12An alkyl group;
R2independently is R3Or R4Wherein each R4Independently 0 to 3R3Substituted by a group;
R3independently of one another, F, Cl, Br, I, -CN, N3，-NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-S(O)R1，-S(O)2R1，-S(O)OR1，-S(O)OR6a，-S(O)2OR1，-S(O)2OR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-N(R1)(C(O)R1)，-N(R6b)(C(O)R1)，-N(R1)(C(O)OR1)，-N(R6b)(C(O)OR1)，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2，-C(NR1)(N(R1)2)，-C(N(R6b))(N(R1)2)，-C(N(R1))(N(R1)(R6b))，-C(N(R6b))(N(R1)(R6b))，-C(N(R1))(N(R6b)2)，-C(N(R6b))(N(R6b)2)，-N(R1)C(N(R1))(N(R1)2)，-N(R1)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)2)，-N(R6b)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)(R6b))，-N(R1)C(N(R1))(R6b)2)，-N(R6b)C(N(R6b))(N(R1)(R6b))，-N(R6b)C(N(R1))(N(R6b)2)，-N(R1)C(N(R6b))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R6b)2)，＝O，＝S，＝N(R1) Or ═ N (R)6b)；
R4Independently is C1-C12Alkyl radical, C2-C12Alkenyl, or C2-C12An alkynyl group;
R5independently is R4Wherein each R4Is 0 to 3R3Substituted by a group;
R5aindependently is C 1-C12Alkylene radical, C2-C12Alkenylene, or C2-C12Alkynylene, any alkylene, alkenylene or alkynylene substituted with 0 to 3R3Substituted by a group;
R6a(ii) a protecting group that is independently H or hydroxy or mercapto (thio);
R6bindependently is H, an amino protecting group or a residue of a carboxy-containing compound;
R6cindependently is H or a residue of an amino-containing compound;
W1is an acidic hydrogen-containing group, a protected acidic group, or an acidic hydrogen group-containing R6cAn amide;
W2is a group containing a basic heteroatom or a protected basic heteroatom, or R of the basic heteroatom6bAn amide;
W3is W4Or W5；
W4Is R5or-C (O) R5，-C(O)W5，-SO2R5or-SO2W5；
W5Is a carbocyclic or heterocyclic ring in which W5Independently 0 to 3R2Substituted by a group;
W6is-R5，-W5，-R5aW5，-C(O)OR6a，-C(O)R6c，-C(O)N(R6b)2，-C(NR6b)(N(R6b)2)，-C(NR6b)(N(H)(R6b))，-C(N(H)(N(R6b)2)，-C(S)N(R6b)2Or C (O) R2；
X1Is a bond, -O-, -N (H) -, -N (W)6) -, -S-, -SO-, or-SO2-; and
each m1Independently an integer from 0 to 2;
provided however that U is not included therein1Is H or-CH2CH(OH)CH2(OH) compounds;
and salts, solvates, resolved enantiomers and purified diastereomers thereof.
In another embodiment of the invention, a compound or composition is provided that further comprises a pharmaceutically acceptable carrier.
In another embodiment of the invention, neuraminidase activity is inhibited by a method comprising the step of treating a sample which may contain neuraminidase with a compound or composition of the invention.
In another embodiment, the invention provides a method of inhibiting neuraminidase activity comprising the step of contacting a sample which may contain neuraminidase with a composition of the invention.
Another embodiment of the invention is a method of treating or preventing viral infections, in particular influenza viral infections, in a host comprising administering to the host via a route other than topical administration to the respiratory tract a therapeutically effective amount of an antivirally active compound as described in WO 91/16320, WO 92/06691 or us patent 5360817.
In other embodiments, novel syntheses of the compounds of the invention are provided. In this embodiment, a method of using compound 281 is provided, wherein the method comprises using formula R5-X1Compound 281 is treated with compound H to form compound 281.1:
wherein
X1And R5As defined above;
R51is an acid stable protecting group of a carboxylic acid;
R54is an aziridine activating group.
In another embodiment, there is provided a process using a compound of the formula
Wherein the process comprises treating cinchona-acid with a geminal dialkoxyalkane or geminal dialkoxycycloalkane and an acid to form a compound of the formula:
treating compound 274 with a metal alkoxide and an alkanol to form a compound of the formula:
Treating compound 275 with a sulfonyl halide and an amine to form a compound of the formula:
treatment of compound 276 with a dehydrating agent followed by treatment with an acid and an alkanol provides a compound of the formula:
wherein
R50Is a 1, 2-diol protecting group;
R51is an acid stable protecting group of a carboxylic acid; and
R52is a hydroxyl activating group.
Brief description of the drawings
FIGS. 1 and 2 illustrate the arterial oxygen saturation (SaO) of mice infected with influenza-A2) The mice were treated with various i.p. doses of the following compounds: GG167 (4-guanidino-2, 4-dideoxy-2, 3-dehydro-N-acetylneuraminic acid), a known compound against influenza virus (figure 1), compound 203 of the invention (figure 2): the test compounds and saline controls were each at 50, 10, 2 and 0.5mpk (mg/kg/day), shown as squares, filled circles, triangles, diamonds and open circles, respectively. In all figures, compared to the saline control group,*P＜0.05，**P＜0.01。
FIGS. 3-5 compare SaO in influenza A infected mice2Levels, each of which was treated with p.o. doses of ribavirin (triangles), compound 203 (squares) and GG167 (filled circles), the saline control group being open circles. FIG. 3: compounds 203 and GG167 were each 150mpk, ribavirin was 100 mpk; FIG. 4: compounds 203 and GG167 were each 50mpk, ribavirin was 32 mpk; FIG. 5: compounds 203 and GG167 were each 10mpk, and ribavirin was 10 mpk.
FIGS. 6-8 illustrate SaO from mice infected with influenza-A2Levels, each treated with low p.o. doses of compounds 262 (circles) and 260 (filled squares) and GG167 (triangles); the saline control group was a hollow circle, while the uninfected control group was a hollow square. FIG. 6: each test compound is mpk; FIG. 7:each test compound was 1 mpk; FIG. 8: each test compound was 0.1 mpk.
Detailed Description
Composition of the invention
The compounds of the present invention do not include the compounds known hitherto. However, as will be seen in the other embodiments described below, it is within the scope of the present invention to use known compounds, which have previously only been known as intermediates for antiviral compounds, for antiviral purposes. In the united states, compounds or compositions herein do not include compounds expected from 35USC ξ 102 or compounds evident from 35USC ξ 103. In particular, the claims of the present application exclude WO 91/16320, WO 92/06691, US 5360817 or Chandler, MJ.Chem.Soc.Perkin Trans.11995, 1189-1197, or compounds which are not novel.
However, in one embodiment of the invention, compounds within the generic concept of WO 91/16320, WO 92/06691, or U.S. Pat. No. 5360817 are included which have the formula Ia in the (a) ' 320 application, the carbon for the group "A" in the (b) ' 320 application, and the R's in the (c) ' 320 and ' 691 applications 5is-CH2YR6，-CHYR6CH2YR6or-CHYR6CHYR6CH2YR6", wherein YR6It may not be OH or protected OH (where the protecting group is hydrolysable in the human gastrointestinal tract to yield free OH), i.e. the compound is hydrolytically stable in the gastrointestinal tract. Compounds excluded from this embodiment are those in which R is5Is acetyl or other C1-C4The carbonyl '320 or' 691 application.
Methods for determining the stability of compounds in alternative gastrointestinal secretions are known. By a compound stable in the gastrointestinal tract is meant: less than about 50 mol% of the protecting groups are deprotected after incubation in alternative intestinal or gastric fluid at 37 ℃ for 1 hour. Such compounds are suitable for use in the above embodiments. It should be noted that a compound that is stable in the gastrointestinal tract does not mean that it cannot be hydrolyzed in vivo. Generally, a prodrug (produgs) is stable in the digestive system, but is hydrolyzed to the parent drug (parent drug) in the digestive lumen, liver or other metabolic organs, or in general cells.
It is to be understood, however, that other embodiments of the invention detailed below contemplate the use of the compounds disclosed in WO 91/16320, WO 92/06691 or U.S. Pat. No. 5360817, including those disclosed in YR thereof6Either as free hydroxyl or protected by a readily hydrolyzable group such as acetyl. In this case, however, these compounds are used by a novel route of administration.
In another embodiment, the compounds herein exclude compounds wherein:
(a)E1is-CO2H，-P(O)(OH)2，-NO2，-SO2H，-SO3H, tetrazolyl, -CH2CHO, -CHO, or-CH (CHO)2；
(b)G1is-CN, N3，-NHR20，NR20，-OR20Guanidino, SR20，-N(R20)→O，-N(R20)(OR20)，-N(H)(R20)N(R20)2Unsubstituted pyrimidinyl, or unsubstituted (pyrimidinyl) methyl;
(c)T1is-NHR20，-NO2(ii) a And R is20Is H; c1-C4An acyl group; c1-C6Linear or cyclic alkyl, or halogen-substituted congeners thereof; allyl or unsubstituted aryl, or via halogen, OH group, NO2Radical, NH2Aryl substituted with a group or a COOH group;
(d) each J1Is H; and
(e)X1is a bond, -CH2-or-CH2CH2-；
In this example, W6Is not H, W7or-CH2W7Wherein W is7Is H, -OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1or-SR6a。
In another embodiment, the compounds of the invention are those in which U1Is not-CH2OH，-CH2OAc or-CH2OCH2Those of Ph.
In another embodiment, the compounds of the invention are those in which E1Is not-CH2OH，-CH2OTMS, or — CHO.
In another embodiment, the compounds of the invention are those in which U1Not directly bound to the nucleus via a carbon atom, or U1Not substituted by hydroxy groups or hydroxy esters, especially U1Not being a polyhydroxyalkane, in particular-CH (OH) CH2Those of OH. In another embodiment, U1Is a branched group R as described below5Or with at least one radical R5A substituted carbocyclic ring.
In another embodiment, the invention excludes compounds of the formula:
wherein:
1. in formula (V):
A2is-O-or-CH2-；
E1is-CO2H；
G1is-N (H) (C (NH)) (NH)2))；
T1is-N (H) (Ac); and
U1having the formula:
2. in formula (V):
A2is-O-or-CH2-；
E1is-CO2H；
G1is-NH2；
T1is-N (H) (Ac); and
U1is-CH2OH；
3. In formula (V):
A2is-CH2-；
E1is-CH2OH or-CH2OTMS；
G1is-N3；
T1is-N (H) (Ac); and
U1is-CH2OCH2Ph；
4. In formula (V):
A2is-CH2-；
E1is-CO2H or-CO2CH3；
G1is-N3；
T1is-N (H) (Ac); and
U1is-CH2OH；
5. In formula (V):
A2is-CH2-；
E1is-CO2H, -CHO, or-CH2OH；
G1is-N3：
T1is-N (H) (Ac); and
U1is-CH2OCH2Ph；
6. In formula (VI):
A2is-CH2-；
E1is-CO2H；
G1is-OCH3；
T1is-NH2(ii) a And
U1is-CH2OH; and
7. in formula (VI):
A2is-CH2-；
E1is-CO2H；
G1is-OCH3；
T1is-N (H) (Ac); and
U1is-CH2OAc。
When the compounds described herein are substituted with the same group (e.g., "R1"or" R6a') multiple substitution, it is understood that the groups may be the same or different, i.e., each group is independently selected.
"heterocycle" is included herein by way of example, but not limitation, Paquette, Leo a.; "Principles of Modern Heterocyclic Chemistry" (W.A. Benjamin, New York, 1968), in particular chapters 1, 3, 4, 6, 7 and 9; "The Chemistry of heterocyclic Compounds, A series of monograms" (John Wiley & Sons, New York, 1950 to date), especially volumes 13, 14, 16, 19 and 28; and "j.am.chem.soc.," 82: 5566(1960) said heterocycle.
Examples of heterocycles include, by way of example and not limitation, pyridyl, thiazolyl, tetrahydrothiophenyl, thiooxidated tetrahydrothiophenyl, pyrimidinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, thianaphthyl, indolyl, indolinyl (in-dolenyl), quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidinonyl, pyrrolinyl, tetrahydrofuryl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1, 2, 5-thiadiazinyl, 2H, 6H-1, 5, 2-dithiazinyl, thienyl, thianthrenyl, pyranyl, isobenzofuranyl, benzopyranyl, xanthenyl, oxathianthrenyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, 2, 3-diazanaphthyl, 1, 5-diazanaphthyl, quinoxalinyl, quinazolinyl, 1, 2-diazanaphthyl, pteridinyl, 4 aH-carbazolyl, β -carbolinyl, phenanthridinyl, acridinyl, pyrimidinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, azanyl, phenoxazinyl, isobenzopyranyl, dihydropyranyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl, oxazolidinyl, benzotriazolyl, benzisoxazolyl, oxindolyl, benzoxazolinyl and isatinoyl (isatinoyl).
By way of example and not limitation, carbon-bonded heterocycles are bonded at the 2, 3, 4, 5, or 6 positions of pyridine, the 3, 4, 5, or 6 positions of pyridazine, the 2, 4, 5, or 6 positions of pyrimidine, the 2, 3, 5, or 6 positions of pyrazine, furan, tetrahydrofuran, thiofuran, thiophene, 2, 3, 4, or 5 positions of pyrrole or tetrahydropyrrole, the 2, 4, or 5 positions of oxazole, imidazole, or thiazole, the 3, 4, or 5 positions of isoxazole, pyrazole, or isothiazole, the 2 or 3 positions of aziridine, the 2, 3, or 4 positions of azetidine, the 2, 3, 4, 5, 6, 7, or 8 positions of quinoline, the 1, 3, 4, 5, 6, 7, or 8 positions of isoquinoline. More specifically, the carbon-bonded heterocycle includes 2-pyridyl, 3-pyridyl, 4-pyridyl, 5-pyridyl, 6-pyridyl, 3-yl, 4-pyridazinyl, 5-pyridazinyl, 6-pyridazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 2-pyrazinyl, 3-pyrazinyl, 5-pyrazinyl, 6-pyrazinyl, 2-thiazolyl, 4-thiazolyl or 5-thiazolyl.
By way of example and not limitation, the nitrogen-bonded heterocycle is bonded to aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, 1-position of 1H-indazole, 2-position of isoindoline or isoindoline, 4-position of morpholine, 9-position of carbazole or β -carboline. More specific nitrogen-bonded heterocycles include 1-aziridine, 1-azetidinyl (azetedyl), 1-pyrrolyl, 1-imidazolyl, 1-pyrazolyl and 1-piperidinyl.
As used herein, unless otherwise indicated, "alkyl" refers to a C group containing n-, secondary-, tertiary-or ring carbon atoms1-C12A hydrocarbyl group. Examples are methyl (Me, -CH)3) Ethyl (Et, -CH)2CH3) 1-propyl (n-Pr, n-propyl, -CH)2CH2CH3) 2-propyl (i-Pr, isopropyl, -CH (CH)3)2) 1-butyl (n-Bu, n-butyl, -CH)2CH2CH2CH3) 2-methyl-1-propyl (i-Bu, isobutyl, -CH)2CH(CH3)2) 2-butyl (s-Bu, sec-butyl, -CH (CH)3)CH2CH3) 2-methyl-2-propyl (t-Bu, t-butyl, -C (CH)3)3) 1-pentyl (n-pentyl, -CH)2CH2CH2CH2CH3) 2-pentyl (-CH (CH)3)CH2CH2CH3) 3-pentyl (-CH (CH)2CH3)2) 2-methyl-2-butyl (-C (CH)3)2CH2CH3) 3-methyl-2-butyl (-CH (CH)3)CH(CH3)2) 3-methyl-1-butyl (-CH)2CH2CH(CH3)2) 2-methyl-1-butyl (-CH)2CH(CH3)CH2CH3) 1-hexyl (-CH)2CH2CH2CH2CH2CH3) 2-hexyl (-CH (CH)3)CH2CH2CH2CH3) 3-hexyl (-CH (CH)2CH3)(CH2CH2CH3) 2-methyl-2-pentyl (-C (CH)3)2CH2CH2CH3) 3-methyl-2-pentyl (-CH (CH)3)CH(CH3)CH2CH3) 4-methyl-2-pentyl (-CH (CH)3)CH2CH(CH3)2) 3-methyl-3-pentyl (-C (CH)3)(CH2CH3)2) 2-methyl-3-pentyl (-CH (CH)2CH3)CH(CH3)2) 2, 3-dimethyl-2-butyl (-C (CH)3)2CH(CH3)2) 3, 3-dimethyl-2-butyl (-CH (CH)3)C(CH3)3). Examples of alkyl groups are the groups 2-5, 7, 9 and 100-399 of Table 2.
The compositions of the present invention include a compound of one of the following formulas:
in typical embodiments, the compound of formula I is selected.
J1And J1aIndependently is R1，Br，Cl，F，I，CN，NO2Or N3Typically R 1Or F, more typically H or F, and even more typically H.
J2And J2aIndependently is H or R1Typically H.
A1is-C (J)1) or-N ═ typically-C (J)1) More typically-CH ═ CH.
A2is-C (J)1)2-，-N(J1)-，-N(O)(J1)-，-N(O)＝，-S-，-S(O)-，-S(O)2-or-O-, typically-C (J)1)2-，-N(J1) -, -S-or-O-, more typically-C (J)1)2-, or-O-, more typically-CH2-or-O-, more typically-CH2-。
E1Is- (CR)1R1)m1W1。
Typically, R1Is H or C1-C12Alkyl, typically H or C1-C4Or C5-C10Alkyl, more typically H or alkyl having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms, more typically H or C selected from methyl, ethyl, n-propyl and isopropyl1-C3An alkyl group. Most typical of R1Is H.
m1 is an integer from 0 to 2, typically 0 or 1, more typically 0.
m2 is an integer of 0 to 1.
m3 is an integer of 1 to 3.
W1Is an acidic hydrogen-containing group, a protected acidic group, or an acidic hydrogen group-containing R6cAmide, as used herein, refers to a group having a hydrogen atom which can be removed by a base to produce an anion or the corresponding salt or solvate. The general principle of acidity or basicity of organic substances is well known and W is defined as such1And will not be described in detail herein. However, reference is made to Streitwieser, a. and Heathcock, c.h.; introduction to Organic Chemistry, Secocndedition "(Macmillan, New York, 1981), pages 60-64. Typically, the acidic groups of the present invention have a PK value less than water, and typically less than PK-10, more preferably less than PK-8, and most preferably less than PK-6. They include tetrazoles and acids of carbon, sulfur, phosphorus and nitrogen, typically carboxylic acids, sulfuric acids, sulfonic acids, sulfinic acids, phosphoric acids and phosphonic acids, And R of these acids6cAmides with R6bEsters (R)6aAnd R6cAs defined below). W1Examples of (A) are-CO2H，-CO2R6a，-OSO3H，-SO3H，-SO2H，-OPO3H2，-PO3(R6a)2，-PO3H2，-PO3(H)(R6a) and-OPO3(R6a)2，W1Is typically E1，E1typically-CO2H，-CO2R6a，-CO2R4Or CO2R1Most typically CO2R14Wherein R is14Is a positive or terminal secondary C1-C6An alkyl group.
W1It may also be a protected acidic group, which in the present context means a protection which has been used for the groups customary in the art for protecting acidic groups and which will be described below at R6aThe above-mentioned acidic groups described below. More typically, protected W1is-CO2R1，-SO3R1，-S(O)OR1，-P(O)(OR1)2，-C(O)NHSO2R4or-SO2NHC(O)-R4Wherein R is1As defined above.
More typically, E1Selected from the group consisting of-C (O) O (CH)2)bCH((CH2)cCH3)2Wherein b is 0 to 4, c is 0 to 4, b + c is 1 to 4, or is selected from the group consisting of:
group E1Examples of (c) are listed in tables 3a to 3 b.
G1Is N3，-CN，-OH，OR6a，-NO2Or- (CR)1R1)m1W2Wherein R is1And m1 are as defined above. In general G1Is- (CR)1R1)m1W2。
W2Is a group containing a basic heteroatom or a protected basic heteroatom, or R of the basic heteroatom6bAn amide. W2Generally containing a basic heteroatom, which is referred to herein as not carbon and which may be substituted with acidic hydrogen (having W as described above)1Acidic range of) protonated atoms. The basic principle of basicity is as described in Streitwieser and Heathcock (cited above) and gives the term basic heteroatom a meaning understood by those of ordinary skill in the art. In general, the corresponding protonated form of the basic heteroatom used in the compounds of the present invention has the above-described W 1pK value in the range of (1). Basic heteroatoms include heteroatoms commonly found in organic compounds, which have unshared, unbound, n-type, etc. electron pairs. By way of example and not limitation, typical basic heteroatoms include oxygen, nitrogen and sulfur atoms of alcohols, amines, amidines, guanidines, sulfides and the like, typically amines, amidines and guanidines. Usually W2Is an amino group or an aminoalkyl group (typically lower alkyl group), for example, aminomethyl, aminoethyl, or aminopropyl; amidino or amidinoalkyl, such as amidinomethyl, amidinoethyl or amidinopropyl; or guanidino or guanidinoalkyl, such as guanidinomethyl, guanidinoethyl or guanidinopropyl (in each case, alkyl is used to bridge this basic substituent to the carbocyclic ring). More typically, W2Is amino, amidino, guanidino, heterocycle substituted by 1 or 2 amino or guanidino groups, usually 1, or C substituted by amino or guanidino2-C3Alkyl, or C substituted by amino with a second group selected from hydroxy and amino2-C3An alkyl group. Can be used as W2The heterocyclic ring of (a) typically comprises a 5 or 6 membered ring containing N or S, wherein the ring contains 1 or 2 heteroatoms. Such heterocycles are typically substituted on ring carbon atoms. Which may be saturated or unsaturated and may be via lower alkyl (m1 ═ 1 or 2) or-NR 1-bonding to core cyclohexene. More typically, W2is-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)R1or-CH (NHR)1)-(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 (NHR)1)(R1) (ii) a Wherein each m2 is typically 0, typically R1Is H, R3Is C (O) N (R)1)2。
W2Optionally protected basic heteroatom, which is referred to herein as R6bSuch as the basic heteroatoms described above protected by one of the groups commonly used in the art. Such groups are detailed in Greene (cited herein). By way of example, and not limitation, such groups include amides, carbamates, aminoacetals, imines, enamines, N-alkyl or N-arylphosphinyl, N-alkyl or N-arylsulfinyl or sulfonyl, N-alkyl or N-arylsilyl, thioethers, thioesters, disulfides, sulfinyl, and the like. In some embodiments, R6bA protecting group can be cleaved under physiological conditions, typically in vivo, wherein, for example, the basic heteroatom is cleaved with an organic acid or an amino acid, such as a naturally occurring amino acid or R hereinafter6aWherein said polypeptide forms an amide.
Typically, G1Selected from the following:
G1additional examples are listed in table 4.
T1is-NR1W3Or heterocyclic, or with U1Or G1Together form a group having the structure:
wherein R is6bAs defined below, R1And W1As defined above. Usually T1Selected from the following:
T1Examples of (2) are listed in Table 5.
W3Is W4Or W5Wherein W is4Is R1or-C (O) R5，-C(O)W5，-SO2R5or-SO2W5。W3typically-C (O) R5Or W5。
R2Independently R is defined as3Or R4Provided that each R is4Independently by 0 to 3R3Substituted by a group;
R3independently of one another, F, Cl, Br, I, -CN, N3，-NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-S(O)R1，-S(O)2R1，-S(O)OR1，-S(O)OR6a，-S(O)2OR1，-S(O)2OR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-N(R1)(C(O)R1)，-N(R6b)(C(O)R1)，-N(R1)(C(O)OR1)，-N(R6b)(C(O)OR1)，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2，-C(NR1)(N(R1)2)，-C(N(R6b))(N(R1)2)，-C(N(R1))(N(R1)(R6b))，-C(N(R6b))(N(R1)(R6b))，-C(N(R1))(N(R6b)2)，-C(N(R6b))(N(R6b)2)，-N(R1)C(N(R1))(N(R1)2)，-N(R1)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)2)，-N(R6b)C(N(R6b))(N(R1)2)，-N(R6b)C(N(R1))(N(R1)(R6b))，-N(R1)C(N(R6b))(N(R1)(R6b))，-N(R1)C(N(R1))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R1)(R6b))，-N(R6b)C(N(R1))(N(R6b)2)，-N(R1)C(N(R6b))(N(R6b)2)，-N(R6b)C(N(R6b))(N(R6b)2)，＝O，＝S，＝N(R1) Or ═ N (R)6b)。R3Typically F, Cl, -CN, N3，NO2，-OR6a，-OR1，-N(R1)2，-N(R1)(R6b)，-N(R6b)2，-SR1，-SR6a，-C(O)OR1，-C(O)R6c，-C(O)OR6a，-OC(O)R1，-NR1C(O)R1，-N(R6b)C(O)R1，-C(O)N(R1)2，-C(O)N(R6b)(R1)，-C(O)N(R6b)2Or ═ O. More typically, R is contained6bGroup R of3comprising-C (O) N (R)6b)2，-C(O)N(R6b)(R1)，-C(S)N(R6b)2or-C (S) N (R)6b)(R1). More typically, R3Is F, Cl, -CN, N3，-OR1，-N(R1)2，-SR1，-C(O)OR1，-OC(O)R1Or ═ O. More typically, R3Is F, -OR1，-N(R1)2Or ═ O. In the present application, "═ O" represents a double-bonded oxygen atom (oxo), "═ S", and "═ N (R)6b) And (R) is N1) "denotes sulfur and nitrogen analogs.
R4Is C1-C12Alkyl radical, C2-C12Alkynyl or C2-C12An alkenyl group. Typically, an alkyl radical R4Alkenyl and alkynyl radicals R having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms4Having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. R4Typically an alkyl group (as defined above). When R is4When alkenyl, it is typically vinyl (-CH ═ CH)2) 1-prop-1-enyl (-CH ═ CHCH)3) 1-prop-2-enyl (-CH)2CH＝CH2) 2-prop-1-enyl (-C (═ CH)2)(CH3) 1-but-1-enyl (-CH ═ CHCH) —)2CH3) 1-but-2-enyl (-CH)2CH＝CHCH3) 1-but-3-enyl (-CH) 2CH2CH＝CH2) 2-methyl-1-prop-1-enyl (-CH ═ C (CH)3)2) 2-methyl-1-prop-2-enyl (-CH)2C(＝CH2)(CH3) 2-but-1-enyl (-C (═ CH))2)CH2CH3) 2-but-2-enyl (-C (CH)3)＝CHCH3) 2-but-3-enyl (-CH (CH)3)CH＝CH2) 1-pent-1-enyl (-CH ═ CHCH)2CH2CH3) 1-pent-2-enyl (-CHCH ═ CHCH)2CH3) 1-pent-3-enyl (-CHCH)2CH＝CHCH3) 1-pent-4-enyl (-CHCH)2CH2CH＝CH2) 2-pent-1-enyl (-C (═ CH)2)CH2CH2CH3) 2-pent-2-enyl (-C (CH)3)＝CH2CH2CH3) 2-pentan-3-alkenyl (-CH (CH)3)CH＝CHCH3) 2-pent-4-enyl (-CH (CH)3)CH2CH＝CH2) Or 3-methyl-1-but-2-enyl (-CH)2CH＝C(CH3)2). More typically, R4Alkenyl has 2, 3 or 4 carbon atoms. When R is4When alkynyl, it is typically ethynyl (-CCH), 1-prop-1-ynyl (-CCCH)3) 1-prop-2-ynyl (-CH)2CCH), 1-but-1-ynyl (-CCCH)2CH3) 1-but-2-ynyl (-CH)2CCCH3) 1-but-3-ynyl (-CH)2CH2CCH), 2-but-3-ynyl (-CH (CH)3) CCH), 1-pent-1-ynyl (-CCCH)2CH2CH3) 1-pent-2-ynyl (-CH)2CCCH2CH3) 1-pent-3-ynyl (-CH)2CH2CCCH3) Or 1-pent-4-ynyl (-CH)2CH2CH2CCH). More typically, R4Alkynyl groups have 2, 3 or 4 carbon atoms.
R5Is R4(as defined above), or by 0 to 3R3Radical substituted R4. Typically, R5Is C substituted by 0 to 3 fluorine atoms1-C4An alkyl group.
R5aIs C1-C12Alkylene radical, C2-C12Alkenylene, or through 0 to 3R3Radical substituted C2-C12Alkynylene radical. Such as R4R is as defined in (1) 5aIs alkylene having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms; alkenylene or alkynylene having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Each typical R4The radicals being typical of R5aProvided that said R4One hydrogen atom in the group is removed to form an open valency of a carbon atom through which the second bond to R5aAre connected.
R10Is through 0 to 3R2Substituted C1-C12Alkyl, alkenyl, alkynyl.
R11Independently is H or R10。
R12Is C3-C10Cycloalkyl radicals, or C4-C10A cycloalkenyl group.
R14Is a positive or terminal secondary C1-C6An alkyl group.
W5Is carbocyclic or heterocyclic, provided that each W5Independently via 0 to 3R2Substituted by a group. W5Carbocycle and T1And W5Heterocycles are stable chemical structures. These structures can be isolated in measurable yields from reaction mixtures at-78 ℃ to 200 ℃ and have measurable purity. Each W5Independently by 0 to 3R2Substituted by a group. Typically, T1And W5Is a saturated, unsaturated or aromatic ring containing a monocyclic or bicyclic carbocyclic or heterocyclic ring. More typically, T1Or W5Having 3 to 10 ring atoms, more typically 3 to 7 ring atoms, and usually 3 to 6 ring atoms. T is1And W5The ring (b) is saturated when it contains 3 ring atoms; saturated or monounsaturated when containing 4 ring atoms; saturated, mono-unsaturated or di-unsaturated when containing 5 ring atoms; saturated, monounsaturated, diunsaturated, or aromatic when containing 6 ring atoms.
When W is5When carbocyclic, typically a 3 to 7 carbon monocyclic ring or a 7 to 12 carbon bicyclic ring. More typically, W5Monocyclic carbocycles have 3 to 6 ring atoms, more preferably 5 or 6 ring atoms. W5Bicyclic carbocycles have 7 to 12 ring atoms which are arranged as bicyclic [ 4, 5 ], [ 5, 6 ] or [ 6, 6 ] systems, more typically 9 or 10 ring atoms which are arranged as bicyclic [ 5, 6 ] or [ 6, 6 ] systems. Examples include cyclopropyl, cyclobutyl, cyclopentyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, cyclohexyl, 1-cyclohex-1-enyl, 1-cyclohex-2-enyl, 1-cyclohex-3-enyl, phenyl, spiroyl and naphthyl.
T1Or W5The heterocyclic ring is typically a monocyclic ring having 3 to 7 ring members (2 to 6 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S), or a bicyclic ring having 7 to 10 ring members (4 to 9 carbon atoms and 1 to 3 heteroatoms selected from N, O, P, S). More typically, T1And W5Heterocyclic monocyclic rings have 3 to 6 ring atoms (2 to 5 carbon atoms and 1 to 2 heteroatoms selected from N, O, S), more typically 5 or 6 ring atoms (3 to 5 carbon atoms and 1 to 2 heteroatoms selected from N and S). T is1And W5Heterobicyclic rings have 7 to 10 ring atoms (6 to 9 carbon atoms and 1 to 2 heteroatoms selected from N, O, S) and are arranged as bicyclic [ 4, 5 ], [ 5, 6 ] or [ 6, 6 ] systems, more typically 9 to 10 ring atoms (8 to 9 carbon atoms and 1 to 2 heteroatoms selected from N and S) and are arranged as bicyclic [ 5, 6 ] or [ 6, 6 ] systems.
Typically, T1And W5The heterocycle is selected from: pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, s-triazinyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, pyrazolyl, isothiazolyl, furyl, thiofuryl, thienyl or pyrrolyl.
More typically, T1And W5The heterocyclic ring is bonded via its carbon or nitrogen atom. More typically, T1The heterocyclic ring being bound by its nitrogen atom to the cyclohexene ring of the compounds of the invention by a stable covalent bond, W5The heterocyclic ring is bonded to the cyclohexene ring of the compounds of the invention by its carbon or nitrogen atom with a stable covalent bond. Stable covalent bonds refer to chemically stable structures as described above.
W5Is optionally selected from the following:
U1is H or-X1W6But typically the latter.
X1Is a bond, -CR5R5-，-(CR5R5)2-，-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-; typically, X1Is a bond, -CR5R5-，-(CR5R5)2-，-O-，-N(H)-，-N(R5)-，-N(OH)-，-N(OR5)-，-N(NH2)-，-N(N(H)(R5))-，-N(N(R5)2)-，-N(H)N(R5) -, -S-, -SO-, or-SO2-, more typically X1Is a bond, -CR1R1-，-(CR1R1)2-，-O-，-NR1-，-N(OR1)-，-N(NR1R1) -, -S-, -SO-, or-SO2-. Usually X1is-O-, -NH-, -S-, -SO-, or-SO-2-；
W6is-R5，-W5，-R5aW5，-C(O)OR6a，-C(O)R6c，-C(O)N(R6b)2，-C(NR6b)(N(R6b)2)，-C(NR6b)(N(H)(R6b))，-C(N(H)(N(R6b)2)，-C(S)N(R6b)2or-C (O) R2typically-R5，-W5or-R5aW5(ii) a In some embodiments, W6Is R1，-C(O)-R1，-CHR1W7，-CH(R1)aW7，-CH(W7)2(wherein a is 0 or 1, but when W is7When divalent, 0) or-C (O) W7. In some embodiments, W6is-CHR1W7or-C (O) W7Or W 6Is- (CH)2)m1CH((CH2)m3R3)2，-(CH2)m1C((CH2)m3R3)3；-(CH2)m1CH((CH2)m3R5aW5)2；-(CH2)m1CH((CH2)m3R3)((CH2)m3R5aW5)；-(CH2)m1C((CH2)m3R3)2(CH2)m3R5aW5)，(CH2)m1C((CH2)m3R5aW5)3Or- (CH)2)m1C((CH2)m3R3)((CH2)m3R5aW5)2(ii) a Wherein m3 is an integer from 1 to 3.
W7Is R3Or R5But is typically over 0 to 3R3Radical substituted C1-C12Alkyl radical, R3Is typically selected from-NR1(R6b)，-N(R6b)2，-OR6aOr SR6a. More typically, W7is-OR1OR via OR1Substituted C3-C12An alkyl group.
Usually, U1Is R1O-，-OCHR1W7，
U1Examples of groups are listed in table 2.
One embodiment of the invention includes compounds of the formula:
wherein E2Is E1But is typically selected from:
wherein G is2Is G1But is typically selected from:
wherein T is2Is R4Or R5. Usually T2Is C substituted by 0 to 3 fluorine atoms1-C2An alkyl group.
U2Is one of the following:
wherein R is7Is H, -CH3，-CH2CH3，-CH2CH2CH3，-OCH3，-OAc(-O-C(O)CH3)，-OH，-NH2or-SH, typically H, -CH3or-CH2CH3。
Radical R6aAnd R6bAre not critical functional groups and can vary widely. When it is not H, it functions as an intermediate of the parent drug, but it does not mean that it has no biological activity. Conversely, the primary function of these groups is to convert the parent drug into a prodrug, which is converted in vivo to release the parent drug. Since the active prodrug is more readily absorbed than the parent drug, in fact, the prodrug is present in vivoThe efficacy is higher than that of the mother medicine. R6aAnd R6bCan be removed in vitro (in the case of chemical intermediates) or in vivo (in the case of prodrugs). When used as chemical intermediates, it is not particularly important whether the resulting pro-functional (pro-functional) product, e.g., alcohol, is physiologically acceptable, although it is generally preferred that it be pharmaceutically innocuous.
R6aIs H or an ether-or ester-forming group. "Ether-forming group" refers to a group that can form a stable covalent bond between the parent molecule and a group of the formula:
wherein VaIs a tetravalent atom, typically selected from C and Si; vbIs a trivalent atom, generally selected from B, Al, N and P, more preferably N and P; vcIs a divalent atom, generally selected from O, S and Se, more preferably S; v1Is bonded to V with stable covalent single bondsa，VbOr VcA group of (A), preferably V1Is W6A radical, preferably H, R2，W5or-R5aW5Preferably H or R2；V2To be bonded to V with stable covalent double bondsaOr VbWith the proviso that V2Not being ═ O, ═ S or ═ N-, V2Preferably ═ C (V)1)2In which V is1As described above; v3Is bonded to V with a stable covalent triple bondaA group of (A), preferably V3Is ≡ C (V)1) In which V is1As described above.
"ester-forming group" refers to a group that can form a stable covalent bond between the parent molecule and a group of the formula:
wherein Va，VbAnd V1As described above; vdIs a pentavalent atom, preferably selected from P and N; veIs a hexavalent atom, preferably S; v4To be bonded to V with stable covalent double bondsa，Vb，VdOr VeProvided that at least one V is4Is ═ O, ═ S or ═ N-V1When not ═ O, ═ S or ═ N-, it is preferably ═ C (V)1)2In which V is1As described above.
Protecting groups for-OH functions (whether hydroxyl, acid or other functions) are specific examples of "ether-or ester-forming groups".
Among the ether-or ester-forming groups, particularly preferred are those which can serve as protecting groups in the synthetic reaction schemes described herein. However, as will be appreciated by those skilled in the art, certain hydroxy and mercapto protecting groups are not ether-or ester-forming groups and are included in R as described below6cIn the amide of (1). R6cCan protect hydroxyl or sulfhydryl, so as to hydrolyze parent molecule to generate hydroxyl or sulfhydryl.
When acting as an ester, typically R6aBonded to any acidic group (e.g., by way of example and not limitation, -CO2H or a-C (S) OH group, thereby forming-CO2R6a. For example, R6aA number of ester groups derived from WO 95/07920 can be deduced.
R6aExamples of (a) include:
C3-C12heterocyclic (as described above) or aryl. These aryl groups are optionally polycyclic or monocyclic. Examples are phenyl, spiroyl, 2-and 3-pyrrolyl, 2-and 3-thienyl, 2-and 4-imidazolyl, 2-, 4-and 5-oxazolyl, 3-and 4-isoxazolyl, 2-, 4-and 5-thiazolyl, 3-, 4-and 5-isothiazolyl, 3-and 4-pyrazolyl, 1-, 2-, 3-and 4-pyridyl, and 1-, 2-, 4-and 5-pyrimidinyl.
C substituted by 3-C12Heterocycle or aryl: halogen, R1，R1-O-C1-C12Alkylene radical, C1-C12Alkoxy, CN, NO2OH, carboxyl ester, thiol, thioester, C1-C12Haloalkyl (1-6 halogen atoms), C2-C12Alkenyl or C2-C12Alkynyl. Such groups include 2-, 3-and 4-alkoxyphenyl (C)1-C12Alkyl), 2-, 3-and 4-methoxyphenyl, 2-, 3-and 4-ethoxyphenyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-and 3, 5-diethoxyphenyl, 2-and 3-ethoxycarbonyl-4-hydroxyphenyl, 2-and 3-ethoxy-4-hydroxyphenyl, 2-, 3-and 4-O-acetylphenyl, 2-, 3-and 4-dimethylaminophenyl, 2-, 3-and 4-methylthiophenyl, 2-, 3-and 4-halophenyl radicals (including 2-, 3-and 4-fluorophenyl radicals and 2-, 3-and 4-chlorophenyl radicals), 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-and 3, 5-xylyl, 2, 3-, 2, 4-, 2, 5-, 2, 6-, 3, 4-and 3, 5-dicarboxyethylphenyl, 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-dihalophenyl (including 2, 4-difluorophenyl and 3, 5-difluorophenyl), 2-, 3-and 4-haloalkylphenyl (1 to 5 halogen atoms, C.sub.1-C12Alkyl, including 4-trifluoromethylphenyl), 2-, 3-and 4-cyanophenyl, 2-, 3-and 4-nitrophenyl, 2-, 3-and 4-haloalkylbenzyl (1 to 5 halogen atoms, C) 1-C12Alkyl, including 4-trifluoromethylbenzyl and 2-, 3-and 4-trichloromethylphenyl), 4-N-methylpiperidinyl, 3-N-methyl-piperidinyl, 1-ethylpiperazinyl, benzyl, alkylsalicylphenyl (C)1-C4Alkyl radicals including 2-, 3-and 4-ethylsalicylphenyl), 2-, 3-and 4-acetylphenyl, 1, 8-dihydroxynaphthyl (-C)10H6-OH) with aryloxyethyl [ C6-C6Aryl (including phenoxyethyl), 2, 2' -dihydroxybiphenyl, 2-, 3-and 4-N, N-dialkylaminophenols, -C6H4-CH2-N(CH3)2Trimethoxybenzyl, triethoxybenzyl, 2-alkylpyridyl (C)1-C4Alkyl groups);
2-carboxyphenyl radical C4-C8An ester; and C1-C4alkylene-C3-C6Aryl (including benzyl, -CH)2-pyrrolyl, -CH2-thienyl, -CH2-imidazolyl, -CH2-oxazolyl, -CH2-isoxazolyl, -CH2-thiazolyl, -CH2-isothiazolyl, -CH2-pyrazolyl, -CH2-pyridyl and-CH2-pyrimidinyl), the aryl part of which is substituted by 3 to 5 halogen atoms or 1 to 2 atoms or groups selected from: halogen, C1-C12Alkoxy (including methoxy and ethoxy), cyano, nitro, OH, C1-C12Haloalkyl (1 to 6 halogen atoms; including-CH)2，CCl3)，C1-C12Alkyl (including methyl and ethyl), C2-C12Alkenyl or C2-C12An alkynyl group;
alkoxyethyl radical [ C 1-C6Alkyl radicals including-CH2-CH2-O-CH3(methoxyethyl) ];
alkyl (-CH) substituted by a substituent of the above-mentioned aryl group (particularly OH) or 1 to 3 halogen atoms3，-CH(CH3)2，-C(CH3)3，-CH2CH3，-(CH2)2CH3，-(CH2)3CH3，-(CH2)4CH3，-(CH2)5CH3，-CH2CH2F，-CH2CH2Cl，-CH2CF3and-CH2CCl3)；
-N-2-propylmorpholinyl, 2, 3-dihydro-6-hydroxyindene, sesamol, catechol monoester, -CH2-C(O)-N(R1)2，-CH2-S(O)(R1)，-CH2-S(O)2(R1)，-CH2-CH(OC(O)CH2R1)-CH2(OC(O)CH2R1) Cholestyryl, enolpyruvate (HOOC-C (═ CH)2) -, glycerol;
a monosaccharide, disaccharide or oligosaccharide of 5 or 6 carbons (3 to 9 monosaccharide residues);
triglycerides, such as alpha-D-beta-diglycerides bonded to the acyl group of the parent compound herein via the glyceryl oxygen atom of the triglyceride (wherein the fatty acids making up the lipid glycerides are typically naturally occurring saturated or unsaturated C6-26，C6-18Or C6-10Fatty acids such as linoleic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, palmitoleic acid, linolenic acid, and the like);
a phospholipid bonded to a carboxyl group via a phosphate ester of the phospholipid;
2-benzo [ c ] furanone (Clayton et al, Antimicrob. AgentsChemo.5 (6): 670-671[1974 ]: FIG. 1);
cyclic carbonates, such as (5-Rd-2-oxo-1, 3-dioxol-4-yl) methyl ester (Sakamoto et al, chem. pharm. Bull.32(6)2241-]) Wherein Rd is R1，R4Or an aryl group; and
the hydroxyl groups of the compounds of the invention are optionally substituted by one of the groups III, IV or V disclosed in WO 94/21604, or by isopropyl.
As another specific exampleTable A shows R6aExamples of ester moieties which may be bonded via oxygen bonds to moieties such as-C (O) O-and-P (O) (O-)2A group. In addition, a plurality of R are also listed6cAmides directly bonded to-C (O) -or-P (O)2. Esters of structures 1 to 5, 8 to 10 and 16, 17, 19 to 22 are prepared by reacting compounds having free hydroxyl groups with the corresponding halides (chlorides or acid chlorides, etc.) and N, N-dicyclohexyl-N-morpholinecarboxamidine (or other bases such as DBU, triethylamine, CsCO)3N, N-dimethylaniline, etc.) in DMF (or other solvent such as acetonitrile or N-methylpyrrolidone). When W is1In the case of phosphonates, the esters of structures 5 to 7, 11, 12, 21 and 23 to 26 are synthesized by reacting alcohols or alkoxides (or corresponding amines, as in the case of compounds 13, 14 and 15) with monochlorophosphonate or dichlorophosphonate (or another activated phosphonate).
TABLE A
The # chiral center is (R), (S) or a racemate
Other esters suitable for use herein are described in EP 632048.
R6aAlso comprising "diester ester" (pendant) forming pre-functional groups, e.g.
Or the structure-CH (R)1Or W5)O((CO)R37) or-CH (R)1Or W5)((CO)OR38) Alkyl-or aryl-acyloxyalkyl (oxygen bonded to an acidic group) of (a), wherein R37And R38Is an alkyl, aryl, or alkaryl group (see U.S. patent 4968788). In general, R 37And R38Being bulky radicals, e.g. branched alkyl radicals, oA meta-substituted aryl group, or combinations thereof, including n-, secondary-, iso-and tertiary C1-C6An alkyl group. An example is pivaloyloxymethyl. It is particularly useful in oral prodrugs. Useful R's of this type6aExamples of groups are alkyl acyloxy methyl esters and derivatives thereof, including-CH (CH)2CH2OCH3)OC(O)C(CH3)3，-CH2OC(O)C10H15，-CH2OC(O)C(CH3)3，-CH(CH2OCH3)OC(O)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)3and-CH2OC(O)CH2C6H5。
When used as prodrugs, the esters selected are preferably those previously used in antibiotic drugs, in particular cyclic carbonates, diesters, or 2-benzo [ c ] furanone esters, aryl esters or alkyl esters.
It should be noted that R6a，R6cAnd R6bThe group may be optionally used to prevent side reactions with the protected group during the synthetic step, so it may serve as a protecting group (PRT) during synthesis.
The determination of which group is to be protected and the nature of the PRT generally will depend on the chemistry of the reaction (e.g., acidic, basic, oxidative, reductive or other conditions) to be protected against and the direction in which the synthesis is to be performed. Where multiple PRTs are substituted in a compound, the PRT groups need not be, and are typically not, identical. In general, PRT will be used to protect carboxyl, hydroxyl or amino groups. The order in which deprotection gives rise to free groups depends on the direction in which the synthesis is carried out and the reaction conditions and may occur in any order as determined by the person skilled in the art.
Very much of R6aHydroxy protecting group and R6cAmide-forming Groups and the corresponding chemical cleavage reactions are described in "Protective Groups in Organic Chemistry", TheodoraW.Greene (John Wiley)&Sons, Inc., New York, 1991, ISBN 0-471-. Reference may also be made to Kocienski, Philip j; "Pro-protecting Groups" (Georg Thieme Verlag Stuttgart, New York, 1994), which is incorporated herein by reference in its entirety. In particular Chapter 1, ProtectingGroups: an Overview, pages 1-20, Chapter 2, hydroxy protective-Groups, pages 21-94, Chapter 3, Diol protective Groups, pages 95-117, Chapter 4, carboxy protective Groups, pages 118-. For R6aCarboxylic acids, phosphonic esters, sulfonic acids and W1Other protecting groups for acids can be found in Greene, below. Such groups include, by way of example and not limitation, esters, amides, hydrazides, and the like.
In some embodiments, through R6aThe protected acid group is an ester of the acid group, and R6aIs a residue containing a hydroxyl functional group. In other embodiments, R6cAmino compounds are used to protect acid functional groups. Suitable hydroxyl-containing or amino-containing functional residues are described above or can be found in WO 95/07920. Particularly useful are amino acid, amino acid ester, polypeptide or aromatic alcohol residues. Typical amino acids, amino acid residues of polypeptides esterified with carboxyl groups are described on pages 11-18 and related contents of WO 95/07920 as group L 1Or L2. WO 95/07920 teaches amidates of phosphonic acids, but it is understood that these amidates are formed with any of the acidic groups described herein with the amino acid residues shown in WO 95/07920.
For protecting W1Typical R of acidic functional groups6aEsters are also described in WO 95/07920, and as such, it is understood that acids herein may be usedThe polar groups may also form the same esters as the phosphonates disclosed with the' 920 publication. Typical ester groups are defined at least on pages 89 to 93 of WO 95/07920 (at R)31Or R35Next), page 105 in the table, and pages 21-23 (R). Particularly preferred are esters of the following groups: unsubstituted aryl, e.g. phenyl or aralkyl (e.g. benzyl), or aryl or alkaryl substituted by hydroxy, halogen, alkoxy, carboxy and/or by alkylester carboxy, especially phenyl, o-ethoxyphenyl, or C1-C4Alkyl ester carboxyphenyl (salicylic acid C)1-C12Alkyl esters).
Protected acidic group W1Particularly with esters or amides of WO 95/07920, as oral prodrugs. However W1The acidic groups need not be protected to allow the compounds of the present invention to be used effectively in oral administration. When the compounds of the invention having a protecting group (particularly amino acid amides or substituted and unsubstituted aryl esters) are administered systemically or orally, they can be cleaved hydrolytically in vivo to give the free acid.
One or more acidic hydroxyl groups may be protected. Where more than one acidic hydroxyl group is protected, the same or different protecting groups may be used, for example, the esters may be the same or different, or mixed amidates and esters may be used.
Typical of R6aHydroxy protecting groups are described in Greene (pages 14-118) and include ethers (methyl); substituted methyl ethers (methoxymethyl, methylthiomethyl, tert-butylthiomethyl, (phenyldimethylsilyl) methoxymethyl, benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy) methyl, o-methoxyphenol methyl, t-butoxymethyl, 4-pentenyloxymethyl, siloxymethyl, 2-methoxyethoxymethyl, 2, 2, 2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl, 2- (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, 3-bromotetrahydropyranyl, tetrahydrothiopyranyl, 1-methoxycyclohexyl, 4-methoxytetrahydropyranyl, 4-methoxytetrahydrothiopyranyl S, S-dioxan bridge (dioxoid), 1- [ (2-chloro-4-methyl) phenyl ] -4-methoxypiperox.Pyridin-4-yl, 35, 1, 4-dioxan-2-yl, tetrahydrofuranyl, tetrahydrothiofuranyl, 2, 3, 3a, 4, 5, 6, 7, 7 a-octahydro-7, 8, 8-trimethyl-4, 7-methylenebenzofuran-2-yl) ]; substituted ethyl ethers (1-ethoxyethyl, 1- (2-chloroethoxy) ethyl, 1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl, 1-methyl-1-benzyloxy-2-fluoroethyl, 2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2- (phenylhydrogenselenyl) ethyl, tert-butyl, allyl, p-chlorophenyl, p-methoxyphenyl, 2, 4-dinitrophenyl, benzyl); substituted benzyl ethers (P-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, P-halobenzyl, 2, 6-dichlorobenzyl, P-cyanobenzyl, P-phenylbenzyl, 2-and 4-picolyl, 3-methyl-2-picolyl N-oxido, benzhydryl, P, P '-dinitrobenzhydryl, 5-dibenzocycloheptyl, trityl, alpha-naphthylbenzhydryl, P-methoxyphenylbenzhydryl, di (P-methoxyphenyl) benzyl, tri (P-methoxyphenyl) methyl, 4- (4' -bromobenzoylmethoxy) phenylbenzhydryl, 4, 4 '-tris (4, 5-dichlorophthalimidophenyl) methyl, 4, 4' -tris (acetylpropionyloxyphenyl) methyl, 4, 4 ', 4 "-tris (benzoyloxyphenyl) methyl, 3- (imidazol-1-ylmethyl) bis (4 ', 4" dimethoxyphenyl) methyl, 1, 1-bis (4-methoxyphenyl) -1 ' -pyrenylmethyl, 9-anthracenyl, 9- (9-phenyl) xanthenyl, 9- (9-phenyl-10-oxo) anthracenyl, 1, 3-benzodithian-2-yl, benzisothiazolyl S, S-dioxybridge); silyl ethers (trimethylsilyl, triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl, diethylisopropylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, tribenzylsilyl, tri-p-xylylsilyl, triphenylsilyl, diphenylmethylsilyl, t-butylmethoxyphenylsilyl); esters (formate, benzoylformate, acetate, chloroacetate, dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate, triphenylmethoxyacetate, phenoxyacetate, p-chlorophenoxyacetate, p-polyphenylacetate, 3-phenylpropane Acid esters, 4-oxopentanoate (levulinate), 4, 4- (ethylenedithio) pentanoate, pivalate, adamantanoate, crotonate, 4-methoxycrotonate, benzoate, p-phenylbenzoate, 2, 4, 6-trimethylbenzoate; carbonate (methyl, 9-fluorenylmethyl, ethyl, 2, 2, 2-trifluoroethyl, 2- (trimethylsilyl) ethyl, 2- (phenylsulfonyl) ethyl, 2- (triphenylphosphonio) ethyl, isobutyl, vinyl, allyl, p-nitrophenyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-nitrobenzyl, S-benzylthiocarbonate, 4-ethoxy-1-naphthyl, methyl dithiocarbonate); having a group that facilitates cleavage (2-iodobenzoate, 4-azidobutyrate, 4-nitro-4-methylpentanoate, o- (dibromomethyl) benzoate, 2-formylbenzenesulfonate, 2- (methylthiomethoxy) ethyl carbonate, 4- (methylthiomethoxymethyl) butyrate, 2- (methylthiomethoxy) benzoate); other esters (2, 6-dichloro-4-methylphenoxyacetate, 2, 6-dichloro-4- (1, 1, 3, 3-tetramethylbutyl) phenoxyacetate, 2, 4-bis (1, 1-dimethylpropyl) phenoxyacetate, chlorodiphenylacetate, isobutyrate, monosuccinate, (E) -2-methyl-2-butenoate (tiglic acid ester), o- (methoxycarbonyl) benzoate, p-benzoate, α -napthenate, nitrate, alkyl N, N' -tetramethylphosphorodiamidate, N-phenylcarbamate, borate, dimethylphosphinothioyl, 2, 4-dinitrophenylsulfenate); and sulfonates (sulfate, methanesulfonate, benzylsulfonate, tosylate).
More typically, R6aHydroxy protecting groups include substituted methyl ethers, substituted benzyl ethers, silyl ethers, and esters including sulfonic acid esters, preferably trialkylsilyl ethers, tosylates and acetates.
Typical 1, 2-diol protecting groups (so, usually, the di-OH group is associated with R6aCombined protecting groups) as described by Greene at pages 118-142, including cyclic acetals with ketals (methylene, ethylene, 1-tert-butylethylene, 1-phenylethylene, (4-methoxyphenyl) ethylene, 2,2-trichloroethylene, acetonide (isopropylidene), cyclopentylene, cyclohexylene, cycloheptylene, benzylidene, p-methoxybenzylidene, 2, 4-dimethoxybenzylidene, 3, 4-dimethoxybenzylidene, 2-nitrobenzylidene); cyclic orthoesters (methoxymethylene, ethoxymethylene, dimethoxymethylene, 1-methoxyethylene, 1-ethoxyethylene, 1, 2-dimethoxyethylene, α -methoxybenzylidene, 1- (N, N-dimethylamino) ethylidene derivative, α - (N, N-dimethylamino) benzylidene derivative, 2-oxocyclopentylidene); silyl derivatives (di-tert-butylsilylene, 1, 3- (1, 1, 3, 3-tetraisopropyldisilylenesiloxane), and tetra-tert-butoxydisiloxane-1, 3-diylidene), cyclic carbonates, cyclic borides (Boronate), ethyl borides, and phenyl borides.
More typically, the 1, 2-diol protecting groups include those shown in Table B, more preferably epoxides, acetonides, cyclic acetals, and aryl acetals.
TABLE B
Wherein R is9Is C1-C6An alkyl group.
R6bIs H, an amino protecting group or a residue of a compound containing a carboxyl group, in particular H, -C (O) R4Amino acid, polypeptide, or not-C (O) R4Amino acids, protecting groups for polypeptides. R forming amides6bFor example the group G1As shown therein. When R is6bWhen it is an amino acid or polypeptide, it has the structure R15NHCH(R16) C (O) -, wherein R15Is H, an amino acid or polypeptide residue, or R5And R is16As defined below.
R16Is lower alkyl or C substituted by1-C6Lower alkyl groups: amino, carboxyl, amide, carboxyl ester, hydroxyl，C6-C7Aryl, guanidino, imidazolyl, indolyl, mercapto, sulfoxide and/or alkylphosphate. R10Or combined with the alpha-N of the amino acid to form a proline residue (R)10＝-(CH2)3-). But R is10Pendant groups of generally naturally occurring amino acids, e.g. 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-NH2And- (CH)2)3-NH-C(NH2)-NH2。R10Also included are 1-guanidinopropane-3-yl, benzyl, 4-hydroxybenzyl, imidazol-4-yl, indol-3-yl, methoxyphenyl, and ethoxyphenyl.
Most of the time, R6bAre carboxylic acid residues, but any of the typical amino protecting groups described by Greene at page 315-385 can be used. They include carbamates (methyl, ethyl, 9-fluorenylmethyl, 9- (2-sulfo) fluorenylmethyl, 9- (2, 7-dibromo) fluorenylmethyl, 2, 7-di-tert-butyl- [ 9- (10, 10-dioxo-10, 10, 10, 10-tetrahydrothioxanthyl) ], methyl, 4-methoxybenzoylmethyl); substituted ethyl (2, 2, 2-trichloroethyl, 2-trimethylsilylethyl, 2-phenylethyl, 1- (1-adamantyl) -1-methylethyl, 1, 1-dimethyl-2-haloethyl, 1, 1-dimethyl-2, 2-dibromoethyl, 1, 1-dimethyl-2, 2, 2-trichloroethyl, 1-methyl-1- (4-biphenylyl) ethyl, 1- (3, 5-di-tert-butylphenyl) -1-methylethyl, 2- (2 '-and 4' -pyridyl) ethyl, 2- (N, N-dicyclohexylcarboxamido) ethyl, tert-butyl, 1-adamantyl, vinyl, allyl, 1-isopropylallyl, cinnamyl, 4-nitrocinnamyl, 8-quinolyl, N-hydroxypiperidinyl, alkanedithiol, benzyl, p-tolyl Oxybenzyl, p-nitrobenzyl, p-bromobenzyl, p-chlorobenzyl, 2, 4-dichlorobenzyl, 4-methylsulfinylbenzyl, 9-anthrylmethyl, diphenylmethyl); (ii) has a cleavage-assisting group (2-methylthioethyl, 2-methylsulfonylethyl, 2- (p-toluenesulfonyl) ethyl, [ 2- (1, 3-dithianyl) ] methyl, 4-methylthiophenyl, 2, 4-dimethylthiophenyl, 2-phosphonioethyl, 2-triphenylphosphonioisopropyl, 1, 1-dimethyl-2-cyanoethyl, m-chloro-p-acyloxybenzyl, p- (dihydroxyboryl) benzyl, 5-benzisoxazolylmethyl, 2- (trifluoromethyl) -6-chromonylmethyl); photolytic groups (m-nitrophenyl, 3, 5-dimethoxybenzyl, o-nitrobenzyl, 3, 4-dimethoxy-6-nitrobenzyl, phenyl (o-nitrophenyl) methyl); urea type derivatives (phenothiazinyl- (10) -carbonyl, N '-p-toluenesulfonylaminocarbonyl, N' -phenylaminothiocarbonyl); other carbamates (tert-amyl, S-benzylthiocarbamate, p-cyanobenzyl, cyclobutyl, cyclohexyl, cyclopentyl, cyclopropylmethyl, p-decyloxybenzyl, diisopropylmethyl, 2, 2-dimethoxycarbonylvinyl, o- (N, N-dimethylcarboxamido) benzyl, 1, 1-dimethyl-3- (N, N-dimethylcarboxamido) propyl, 1, 1-dimethylpropynyl, bis (2-pyridyl) methyl, 2-furylmethyl, 2-iodoethyl, isobornyl, isobutyl, isonicotinyl, p- (p-methoxyphenylazo) benzyl, 1-methylcyclobutyl, 1-methylcyclohexyl, 1-methyl-1-cyclopropylmethyl, 1-methyl-1- (3, 5-dimethoxyphenyl) ethyl, 1-methyl-1- (p-phenylazophenyl) ethyl, 1-methyl-1-phenylethyl, 1-methyl-1- (4-pyridyl) ethyl, phenyl, p- (phenylazo) benzyl, 2, 4, 6-tri-tert-butylphenyl, 4- (trimethylammonium) benzyl, 2, 4, 6-trimethylbenzyl); amides (N-formyl, N-acetyl, N-chloroacetyl, N-trichloroacetyl, N-trifluoroacetyl, N-phenylacetyl, N-3-phenylpropionyl, N-picolinoyl, N-3-pyridylcarboxamide, N-benzoylphenylalanyl, N-benzoyl, N-p-phenylbenzoyl); having a cleavage-assisting amide (N-o-nitroacetoyl, N-o-nitrophenoxyacetyl, N-acetoacetyl, (N' -dithiobenzyloxycarbonylamino) acetyl, N-3- (p-hydroxyphenyl) propionyl, N-3- (o-nitrophenyl) propionyl, N-2-methyl-2- (o-nitrophenoxy) propionyl, N-2-methyl-2- (o-phenylazophenoxy) propionyl, N-4-chlorobutyryl, N-3-methyl-3-nitrobutyryl, N-o-nitrocinnamoyl, N-acetylmethionine, N-o-nitrobenzoyl, N-o- (benzoyloxymethyl) benzoyl, 4, 5-diphenyl-3-oxazolin-2-one); cyclic imide derivatives (N-phthalimide, N-dithiosuccinyl, N-2, 3-diphenylmaleoyl, N-2, 5-dimethylpyrrolyl, N-1, 1, 4, 4-tetramethyldisilylazacyclopentane adduct, 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclohexan-2-one, 1-substituted 3, 5-dinitro-4-pyridonyl); n-alkyl and N-arylamine (N-methyl, N-allyl, N- [ 2- (trimethylsilyl) ethoxy ] methyl, N-3-acetoxypropyl, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl), quaternary ammonium salts, N-benzyl, N-bis (4-methoxyphenyl) methyl, N-5-dibenzocycloheptyl, N-triphenylmethyl, N- (4-methoxyphenyl) diphenylmethyl, N-9-phenylfluorenyl, N-2, 7-dichloro-9-fluorenylmethylene, N-ferrocenylmethyl, N-2-picolylamine N' -oxide), imine derivative (N-1, 1-dimethylthiomethylene, N-benzylidene, N-p-methoxybenzylidene, N-diphenylmethylene, N- [ (2-pyridyl) A methylene group, an N- (N ', N ' -dimethylamino) methylene group, an N, N ' -isopropylidene group, an N-p-nitrobenzylidene group, an N-salicylidene group, an N-5-chlorosalicylidene group, an N- (5-chloro-2-hydroxyphenyl) phenylmethylene group, an N-cyclohexylidene group); enamine derivatives (N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl)); n-metal derivatives (N-borane derivatives, N-diphenylboronic acid (borinic acid) derivatives, N- [ phenyl (chromium or tungsten pentacarbonyl) ], N-copper or N-zinc chelates); N-N derivatives (N-nitro, N-nitroso, N-oxide); N-P derivatives (N-diphenylphosphinyl oxide, N-dimethylphosphinyl oxide, N-diphenylphosphinyl oxide, N-dialkyl phosphoryl, N-dibenzylphosphoryl, N-diphenyl phosphoryl); derivatization of N-SiAn agent; N-S derivatives; n-sulfinyl derivatives (N-benzenesulfinyl, N-o-nitrobenzenesulfinyl, N-2, 4-dinitrobenzenesulfinyl, N-pentachlorophenylsulfinyl, N-2-nitro-4-methoxybenzenesulfinyl, N-triphenylmethylsulfinyl, N-3-nitropyridinylsulfinyl); and N-sulfonyl derivatives (N-p-toluenesulfonyl, N-benzenesulfonyl, N-2, 3, 6-trimethyl-4-methoxybenzenesulfonyl, N-2, 4, 6-trimethoxybenzenesulfonyl, N-2, 6-dimethyl-4-methoxybenzenesulfonyl, N-pentamethylbenzenesulfonyl, N-2, 3, 5, 6-tetramethyl-4-methoxybenzenesulfonyl, N-2, 4, 6-trimethylbenzenesulfonyl, N-2, 6-dimethoxy-4-methylbenzenesulfonyl, N-2, 2, 5, 7, 8-pentamethylbenzodihydropyran-6-sulfonyl, N-methylsulfonyl, n-beta-trimethylsilylethanesulfonyl, N-9-anthracenesulfonyl, N-4- (4 ', 8' -dimethoxynaphthylmethyl) benzenesulfonyl, N-benzylsulfonyl, N-trifluoromethylsulfonyl, N-benzoylmethylsulfonyl).
More typically, the protected amino group includes carbamates and amides, more preferably-NHC (O) R1or-N ═ CR1N(R1)2. Another protecting group, may also be used as G1Prodrugs of position, in particular for amino or-NH (R)5) The method comprises the following steps:
reference, for example, Alexander, j. et al;J.Med.Chem.1996，39，480-486。
R6cis H or a residue of an amino-containing compound (in particular an amino acid, a polypeptide), a protecting group, -NHSO2R4，NHC(O)R4，-N(R4)2，NH2or-NH (R)4) H, whereby W1With the abovementioned amines to form amides, e.g. in the form of-C (O) R6c，-P(O)(R6c)2or-P (O) (OH) (R)6c) In (1).In general R6cHaving R17C(O)CH(R16) Structure of NH-, wherein R17Is OH, OR6a，OR5Amino acid or polypeptide residues.
Amino acids are low molecular weight compounds, less than about 1000MW, and comprise at least one amino or imino group, and at least one carboxyl group. Usually, the amino acid is present in nature, i.e., it is detectable in biological substances such as bacteria or other microorganisms, plants, animals or humans. Suitable amino acids are typically alpha-amino acids, i.e. compounds in which one of the amino or imino nitrogen atoms is separated from one of the carbonyl carbon atoms by a mono-substituted or unsubstituted alpha-carbon atom. Preferred are hydrophobic residues such as mono-or di-alkyl or aryl amino acids, cycloalkyl amino acids, and the like. These residues contribute to cell permeability by increasing the partition coefficient of the parent drug. Typically, this residue does not contain a mercapto or guanidino substituent.
Natural amino acid residues are residues found naturally in plants, animals or microorganisms, in particular proteins thereof. Polypeptides typically consist essentially of such naturally occurring amino acid residues. These amino acids are glycine, alanine, valine, leucine, isoleucine, serine, threonine, cysteine, methionine, glutamic acid, aspartic acid, lysine, hydroxylysine, arginine, histidine, phenylalanine, tyrosine, tryptophan, proline, asparagine, glutamine and hydroxyproline.
When R is6bAnd R6cWhen a single amino acid residue or polypeptide, it is usually at R3，W6，W1And/or W2Upper substitution, but preferably only W1Or W2And (4) substituted. These conjugates are formed by coupling the carboxyl group of the amino acid (or, for example, the carbon-terminal amino acid of the polypeptide) with W2Form amide bond therebetween. Similarly, W may be used1And forms a conjugate with an amino acid or an amino group of a polypeptide. Typically, only one position in the parent molecule is amidated with an amino acid as described herein, however, it is within the scope of the invention to introduce an amino acid at more than one positionInside the enclosure. Usually W1The carboxyl group of (a) is amidated with an amino acid. Typically, the α -amino or α -carbonyl group of such an amino acid or the terminal amino or carboxyl group of the polypeptide is attached to a functional group of the parent compound, i.e., the carboxyl or amino group on the side chain of the amino acid is not typically used to form an amide bond with the parent compound (although these groups may need to be protected during conjugate synthesis, as described below).
With respect to the carboxyl-containing side chain of an amino acid or polypeptide, it is understood that the carboxyl group may be optionally protected, for example, with R6aWith R5By esterification, or with R6cAnd (4) amidation. Similarly, the amino side chain R16Can be arbitrarily used as R6bProtection or by R5And (4) substitution.
These ester or amide bonds with the side chain amino or carboxyl groups, like the ester or amide bonds with the parent molecule, can be hydrolyzed under acidic (pH < 3) or basic (pH > 10) conditions, optionally in vivo or in vitro. In addition, they are substantially stable in the human gastrointestinal tract, but are enzymatically hydrolyzed in the blood or intracellular environment. These esters or amino acids or polypeptide amides may also be used as intermediates in the preparation of parent molecules containing free amino or carboxyl groups. The free acid or base of the parent compound can be readily prepared from the ester or amino acid or polypeptide conjugates of the present invention via conventional hydrolysis.
When the amino acid residue contains one or more chiral centers, any D, L, meso, threo or erythro (if appropriate) racemate, crystalline isomers (scalemates) or mixtures thereof may be used. In general, the D isomer is useful if it is desired to non-enzymatically hydrolyze the intermediate (e.g., using the amide as a chemical intermediate for the free acid or free amine). On the other hand, the L isomer is more versatile because it can be hydrolyzed enzymatically or non-enzymatically and is more efficiently transferred in the gastrointestinal tract by amino acid or dipeptide transfer systems.
Suitable amino acids (residues thereof are represented by R)6bAnd R6cRepresentative) examples include the following:
glycine;
aminopolycarboxylic acids, for example, aspartic acid, β -hydroxyaspartic acid, glutamic acid, β -hydroxyglutamic acid, β -methylaspartic acid, β -methylglutaric acid, β, β -dimethylaspartic acid, γ -hydroxyglutamic acid, β, γ -dihydroxyglutamic acid, β -phenylglutamic acid, γ -methyleneglutamic acid, 3-aminoadipic acid, 2-aminopimelic acid, 2-aminosuberic acid and 2-aminosebacic acid;
amino acid amides, such as glutamine and asparagine;
polyamino-or polycarboxylic acids, such as arginine, lysine, β -alanine, γ -aminobutamin, ornithine, citrulline, homoarginine, homocitrulline, hydroxylysine, allohydroxylysine and diaminobutyric acid;
other basic amino acid residues, such as histidine;
diaminodicarboxylic acids, such as, for example, α, α '-diaminosuccinic acid, α, α' -diaminoglutaric acid, α, α '-diaminoadipic acid, α, α' -diaminopimelic acid, α, α '-diamino- β -hydroxypimelic acid, α, α' -diaminosuberic acid, α, α '-diaminoazelaic acid, and α, α' -diaminosebacic acid;
Imino acids such as proline, hydroxyproline, allohydroxyproline, γ -methylproline, piperidine-2-carboxylic acid, 5-hydroxypiperidine-2-carboxylic acid, and azetidine-2-carboxylic acid;
mono-or dialkyl (preferably C)1-C8Branched or straight chain) amino acids, such as alanine, valine, leucine, allylglycine, butyline, norvaline, norleucine, heptylamine (heptanyline), α -methylserine, α -amino- α 0-methyl- γ -hydroxypentanoic acid, α 1-amino- α 2-methyl- δ -hydroxypentanoic acid, α 3-amino- α 4-methyl- ε -hydroxycaproic acid, isovaline, α 5-methylglutamic acid, α 6-aminoisobutyric acid, α 7-aminodiethylacetic acid, α -aminodiisopropylacetic acid, α -aminodi-n-propylacetic acid, α -aminodiisobutylalcetic acid, α -aminodi-n-butylacetic acid, α -aminoethylisopropylacetic acid, α -aminodi-isobutylacetic acid, α -aminodi-n-butylacetic acid-amino n-propylacetic acid, α -aminodiisopentylacetic acid, α -methylaspartic acid, α -methylglutamic acid, 1-aminocyclopropane-1-carboxylic acid, isoleucine, alloisoleucine, tert-leucine, β -methyltryptophan, and α -amino- β -ethyl- β -phenylpropionic acid;
β -phenylserinyl;
aliphatic alpha-amino-beta-hydroxy acids, such as serine, beta-hydroxy leucine, beta-hydroxy norleucine, beta-hydroxy norvaline, and alpha-amino-beta-hydroxystearic acid;
α -amino, α -, γ -, δ -or ε -hydroxy acids, such as homoserine, γ -hydroxy norvaline, δ -hydroxy norvaline, and ε -hydroxy norleucine residues; canavanine and paracanavaline; gamma-hydroxyornithine;
2-hexonine, such as D-glucamine or D-galactamine;
alpha-amino-beta-thiols, such as penicillamine, beta-thiol norvaline or beta-thiol butyl alcohol;
other sulfur-containing amino acid residues include cysteine; homocystine, beta-phenylmethionine, methionine, S-allyl-L-cysteine sulfoxide, 2-thiol histidine, cystathionine, and thiol ethers of cysteine or homocysteine;
phenylalanine, tryptophan and ring-substituted α -amino acids, e.g., phenyl-or cyclohexyl amino acids, α -aminophenylacetic acid, α -aminocyclohexylacetic acid and α -amino- β -cyclohexylpropionic acid; phenylalanine analogs and derivatives containing aryl, lower alkyl, hydroxy, guanidino, oxyalkyl ether, nitro, sulfur or halogen substituted phenyl (e.g., tyrosine, methyltyrosine and o-, p-, 3, 4-dichloro-, o-, m-or p-methyl-, 2, 4, 6-trimethyl, 2-ethoxy-5-nitro-, 2-hydroxy-5-nitro-and p-nitro-phenylalanine); furyl-, thienyl-, pyridyl-, pyrimidinyl-, purinyl-or naphthyl-alanine; and tryptophan analogs and derivatives, including kynurenine, 3-hydroxykynurenine, 2-hydroxytryptophan and 4-carboxytryptophan;
Alpha-amino substituted amino acids including sarcosine (N-methylglycine), N-benzylglycine, N-methylalanine, N-benzylalanine, N-methylphenylalanine, N-benzylphenylalanine, N-methylvaline and N-benzylvaline;
alpha-hydroxy and substituted alpha-hydroxy amino acids include serine, threonine, allothreonine, phosphoserine, and phosphothreonine.
The polypeptide is a polymer of amino acids, wherein the carboxyl group of one amino acid monomer and the amino or imino group of another amino acid monomer are bonded together with an amide bond. The polypeptides include dipeptides, low molecular weight polypeptides (about 1500-. The protein may optionally comprise 3, 5, 10, 50, 75, 100 or more residues and preferably has a substantially similar sequence to a human, animal, plant or microbial protein. It includes enzymes (e.g., hydroperoxides) as well as immunogens (e.g., KLH), or antibodies, or any type of protein that is immunoreactive with an antagonist. The nature and identifying characteristics of these polypeptides may vary widely.
The polypeptide amides may be used as immunogens to generate antibodies against the polypeptide (if not immunogenic in the animal to which it is administered) or against epitopes on the remainder of the compounds of the invention.
Antibodies that can bind to a parent compound that is not peptidyl can be used to isolate the parent compound from the mixture, for example, in diagnostics or in the preparation of the parent compound. Conjugates of a parent compound with a polypeptide will generally be more immunogenic in animals of the same class than the polypeptide, thus rendering the polypeptide more immunogenic and facilitating the production of antibodies against it. Thus, the polypeptide or protein may not necessarily be immunogenic in the animals normally used to produce antibodies (e.g., rabbits, mice, horses, and rats), provided that the final conjugate product is immunogenic in at least one such animal. The polypeptide optionally comprises a cleavage site for a peptolytic enzyme at the peptide bond between the first and second residues adjacent to the acidic heteroatom. This cleavage site is laterally attacked by enzyme recognition structures, e.g., specific residue sequences recognized by peptidases.
Peptidases useful for cleaving the polypeptide conjugates of the invention are well known and include, inter alia, carboxypeptidases. Carboxypeptidases break down polypeptides by removing carbon-terminal residues and, in many instances, are specific for a particular carbon-terminal sequence. Such enzymes and their matrix requirements are generally known. For example, a dipeptide (having a particular pair of residues and a free carboxyl end group) is covalently bound with its alpha-amino group to a phosphorus or carbon atom of a compound herein. At W 1In the case of phosphonates, it is expected that the peptide will be cleaved by an appropriate peptiase leaving the carboxyl group of the proximal (proximal) amino acid residue to autocatalytically cleave the phosphine amide bond.
Suitable dipeptidyl radicals (in their single letter code) are 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, NQ, NG, NH, NI, NL, NK, NE, NF, NP, NS, NT, NW, NY, NV, DA, DR, DN, DD, DC, DE, DQ, DI, DL, DH, DM, DF, DP, DS, DT, DW, DY, DV, CA, CR, CN, CD, CC, CE, CQ, CG, CI, CL, CK, CF, CP, CS, CW, EA, CW, EC, EE, EC, EE, 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, HW, HY, HV, IA, IR, IN, ID, IC, IE, IQ, IG, LM, II, IL, IK, IM, IF, IP, IS, IT, IW, IY, IV, LA, LR, LN, LD, LC, LGLE, LQ, LG, LI, LM, LS, LP, KL, KM, K, 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, TD, TC, TE, TQ, TG, TH, TI, TL, TK, TM, TF, SI, TS, TT, TW, TY, TV, WA, WR, WD, WC, WE, WG, WO, WH, WI, WL, WM, YK, YW, YWT, YW, YWT, YF, YY, YW, Y, YY, YV, VA, VR, VN, VD, VC, VE, VQ, VG, VH, VI, VL, VK, VM, VF, VP, VS, VT, VW, VY and VV.
Tripeptide residues may also be used as R6bOr R6c. When W is1In the case of phosphonates, the sequence-X4-pro-X5- (where X4 is any amino acid residue and X5 is an amino acid residue, a carboxyl ester of proline, or hydrogen) is cleaved by luminal (luminal) carboxypeptidase to X4, which carries a free carboxyl group and which is expected to autocatalytically cleave a phosphine amide bond. The carboxyl group of X5 is optionally esterified with a benzyl group.
The choice of dipeptide or tripeptide may be based on known translocation properties and/or sensitivity to peptidases, which may affect translocation to the intestinal mucosa or other cellular morphology. Dipeptides or tripeptides lacking the alpha-amino group are the transfer substrates for peptide transferors found in brush border membranes of intestinal mucosal cells (Bai, J.P.F., "Pharm Res." 9: 969-978 (1992)). Peptides suitable for transfer can be used to enhance the bioavailability of the amide compound. Dipeptides or tripeptides having one or more amino acids in the D configuration are also suitable for peptide transfer and may be used in the present amide compounds. The D configuration of amino acids may also be used to reduce the likelihood of hydrolysis of di-or tripeptides by proteases which are common in brush boundaries, such as aminopeptidase N (EC 3.4.11.2). In addition, the choice may be based on the relative resistance of the di-or tripeptides to hydrolysis by proteases found in the intestinal lumen. For example, tripeptides or polypeptides lacking asp and/or glu are poor substrates for aminopeptidase a (EC 3.4.11.7); dipeptides or tripeptides lacking amino acid residues on the nitrogen terminal side of hydrophobic amino acids (leu, tyr, phe, val, trp) are poor substrates for endophthalic enzyme 24.11(EC 3.4.24.11); peptides lacking a pro residue in the penultimate position of the free carboxy terminus are poor substrates for carboxypeptidase P (EC 3.4.17). Similar considerations may also be applied to select peptides that are less or more easily hydrolyzed by cytosolic, renal, hepatic, serum or other peptidases. Such non-cleavable polypeptide amides are immunogens or may be used to bind to proteins to make immunogens.
Another embodiment of the invention relates to a composition of formula (VII) or (VIII):
wherein E1，G1，T1，U1，J1，J1a，J2And J2aAs defined above, but with the difference:
T1is-NR1W3Heterocyclic ring, or with G1Together form a group having the structure
X1Is a bond, -O-, -N (H) -, -N (R)5) -, -S-, -SO-, or-SO2-; provided however that U is not included1Is H or-CH2CH(OH)CH2(OH) compounds;
and salts, solvates, resolved enantiomers and purified diastereomers thereof.
Typical or general embodiments of formulae (I) - (VI) detailed above are also typical embodiments of formulae (VI) and (VIII).
A plurality of compounds of formulae (IVV) and (VII) (wherein U1Is H or-CH2CH(OH)CH2(OH) Synthesis is described in Nishimura, Y, et al;J.Antibiotics，1993，46(2)，300；46(12) 1883; andNat.Prod.Lett.1992,1(1),39. Will be invented U1The method of attaching the groups is as described herein.
Stereoisomers
The compounds of the invention are enriched in (enriched) or resolved optical isomers at any or all of the asymmetric atoms. For example, the chiral centers as apparent in the description are chiral isomers or racemic mixtures. Racemic mixtures or diastereomeric mixtures, as well as the individual optical isomers isolated or synthesized (substantially free of their enantiomers or diastereomers), are within the scope of the invention. The racemic mixture is separated into the substantially optically pure individual isomers by known techniques, for example, diastereomeric salts with optically active auxiliaries (e.g., acids or bases) are separated and converted back into the optically active substance. In most cases, the desired optical isomer is synthesized in a stereospecific reaction, starting with the appropriate stereoisomer of the desired starting material.
Stereochemical examples of the compounds of the present invention are shown in table C below.
Watch C
Formula (I)
Formula (I)
| E1 | J1a | J1b | J2 | U1 | T1 | G1 |
| - | α | β | α | β | α | α |
| - | β | α | α | β | α | α |
| - | α | β | β | α | α | α |
| - | α | β | α | β | β | α |
| - | α | β | α | β | α | β |
| - | β | α | β | α | α | α |
| - | β | α | α | β | β | α |
| - | β | α | α | β | α | β |
| - | α | β | β | α | β | α |
| - | α | β | β | α | α | β |
| - | α | β | α | β | β | β |
| - | β | α | β | α | β | α |
| - | β | α | β | β | α | β |
| - | β | α | α | β | β | β |
| - | α | β | β | α | β | β |
| - | β | α | β | α | β | β |
The compounds of the invention may also be present as tautomers in certain instances. For example, imidazole, guanidine, amidine and tetrazole systems can be in ene-amine tautomers, and all possible tautomers are within the scope of the invention.
Illustrative Compounds
Examples of compounds, by way of example and not limitation, are listed in tabular form (table 6). Typically, each compound is represented by a substituted nucleus (nucleus is in capital letters) and each substituent is in turn represented by a lower case letter or number. Tables 1a and 1b are tables of the respective cores, which are mainly different in the site of unsaturation on the ring and the nature of the substituents on the ring of the respective cores. Each core is given an alphabetic code in tables 1a and 1b, and this code is the 1 st word of each compound name. Similarly, tables 2a-av, 3a-b, 4a-c and 5a-d list selected Q' s1，Q2，Q3，Q4Substituents, likewise, are numbered with a letter or number. Thus, each compound named will be represented as: one capital letter represents the nucleus in tables 1a-1b, followed by Q1Number of substituents, representing Q4Lower case letter of substituent, representing Q3Number of substituents, representing Q 4Lower case letters for substituents. Structure 8 in reaction scheme 1 is denoted as a.49.a.4. i. It is understood that Q1-Q4And are not groups or atoms, but are merely related representations.
TABLE 1a
TABLE 1b
TABLE 2a
TABLE 2b
TABLE 2c
TABLE 2d
TABLE 2e
TABLE 2f
TABLE 2g
TABLE 2h
TABLE 2i
TABLE 2j
TABLE 2k
TABLE 2l
TABLE 2m
TABLE 2n
TABLE 2o
TABLE 2p
TABLE 2q
TABLE 2r
TABLE 2s
TABLE 2t
TABLE 2u
TABLE 2v
TABLE 2w
TABLE 2x
TABLE 2y
TABLE 2z
TABLE 2aa
TABLE 2ab
TABLE 2ac
TABLE 2ad
TABLE 2ae
TABLE 2af
TABLE 2ag
TABLE 2ah
TABLE 2ai
TABLE 3a
TABLE 3b
TABLE 4a
TABLE 4b
TABLE 4c
TABLE 5a
TABLE 5b
TABLE 5c
TABLE 6 exemplary Compounds
A.17.a.4.i；A.17.a.4.v；A.17.a.6.i；A.17.a.6.v；A.17.a.11.i；A.17.a.11.v；A.17.a.14.i；
A.17.a.14.v；A.17.a.15.i；A.17.a.15.v；A.17.a.18.i；A.17.a.18.v；A.17.a.25.i；
A.17.a.25.v；A.17.e.4.i；A.17.e.4.v；A.17.e.6.i；A.17.e.6.v；A.17.e.11.i；A.17.e.11.v；
A.17.e.14.i；A.17.e.14.v；A.17.e.15.i；A.17.e.15.v；A.17.e.18.i；A.17.e.18.v；
A.17.e.25.i；A.17.e.25.v；A.17.g.4.i；A.17.g.4.v；A.17.g.6.i；A.17.g.6.v；A.17.g.11.i；
A.17.g.11.v；A.17.g.14.i；A.17.g.14.v；A.17.g.15.i；A.17.g.15.v；A.17.g.18.i；
A.17.g.18.v；A.17.g.25.i；A.17.g.25.v；A.17.l.4.i；A.17.l.4.v；A.17.l.6.i；A.17.l.6.v；
A.17.l.11.i；A.17.l.11.v；A.17.l.14.i；A.17.l.14.v；A.17.l.15.i；A.17.l.15.v；A.17.l.18.i；
A.17.l.18.v；A.17.l.25.i；A.17.l.25.v；A.17.m.4.i；A.17.m.4.v；A.17.m.6.i；
A.17.m.6.v；A.17.m.11.i；A.17.m.11.v；A.17.m.14.i；A.17.m.14.v；A.17.m.15.i；
A.17.m.15.v；A.17.m.18.i；A.17.m.18.v；A.17.m.25.i；A.17.m.25.v；A.17.o.4.i；
A.17.o.4.v；A.17.o.6.i；A.17.o.6.v；A.17.o.11.i；A.17.o.11.v；A.17.o.14.i；
A.17.o.14.v；A.17.o.15.i；A.17.o.15.v；A.17.o.18.i；A.17.o.18.v；A.17.o.25.i；
A.17.o.25.v；A.33.a.4.i；A.33.a.4.v；A.33.a.6.i；A.33.a.6.v；A.33.a.11.i；A.33.a.11.v；
A.33.a.14.i；A.33.a.14.v；A.33.a.15.i；A.33.a.15.v；A.33.a.18.i；A.33.a.18.v；
A.33.a.25.i；A.33.a.25.v；A.33.e.4.i；A.33.e.4.v；A.33.e.6.i；A.33.e.6.v；A.33.e.11.i；
A.33.e.11.v；A.33.e.14.i；A.33.e.14.v；A.33.e.15.i；A.33.e.15.v；A.33.e.18.i；
A.33.e.18.v；A.33.e.25.i；A.33.e.25.v；A.33.g.4.i；A.33.g.4.v；A.33.g.6.i；A.33.g.6.v；
A.33.g.11.i；A.33.g.11.v；A.33.g.14.i；A.33.g.14.v；A.33.g.15.i；A.33.g.15.v；
A.33.g.18.i；A.33.g.18.v；A.33.g.25.i；A.33.g.25.v；A.33.l.4.i；A.33.l.4.v；A.33.l.6.i；
A.33.l.6.v；A.33.l.11.i；A.33.l.11.v；A.33.l.14.i；A.33.l.14.v；A.33.l.15.i；A.33.l.15.v；
A.33.l.18.i；A.33.l.18.v；A.33.l.25.i；A.33.l.25.v；A.33.m.4.i；A.33.m.4.v；
A.33.m.6.i；A.33.m.6.v；A.33.m.11.i；A.33.m.11.v；A.33.m.14.i；A.33.m.14.v；
A.33.m.15.i；A.33.m.15.v；A.33.m.18.i；A.33.m.18.v；A.33.m.25.i；A.33.m.25.v；
A.33.o.4.i；A.33.o.4.v；A.33.o.6.i；A.33.o.6.v；A.33.o.11.i；A.33.o.11.v；A.33.o.14.i；
A.33.o.14.v；A.33.o.15.i；A.33.o.15.v；A.33.o.18.i；A.33.o.18.v；A.33.o.25.i；
A.33.o.25.v；A.49.a.4.i；A.49.a.4.v；A.49.a.6.i；A.49.a.6.v；A.49.a.11.i；A.49.a.11.v；
A.49.a.14.i；A.49.a.14.v；A.49.a.15.i；A.49.a.15.v；A.49.a.18.i；A.49.a.18.v；
A.49.a.25.i；A.49.a.25.v；A.49.e.4.i；A.49.e.4.v；A.49.e.6.i；A.49.e.6.v；A.49.e.11.i；
A.49.e.11.v；A.49.e.14.i；A.49.e.14.v；A.49.e.15.i；A.49.e.15.v；A.49.e.18.i；
A.49.e.18.v；A.49.e.25.i；A.49.e.25.v；A.49.g.4.i；A.49.g.4.v；A.49.g.6.i；A.49.g.6.v；
A.49.g.11.i；A.49.g.11.v；A.49.g.14.i；A.49.g.14.v；A.49.g.15.i；A.49.g.15.v；
A.49.g.18.i；A.49.g.18.v；A.49.g.25.i；A.49.g.25.v；A.49.l.4.i；A.49.l.4.v；A.49.l.6.i；
A.49.l.6.v；A.49.l.11.i；A.49.l.11.v；A.49.l.14.i；A.49.l.14.v；A.49.l.15.i；A.49.l.15.v；
A.49.l.18.i；A.49.l.18.v；A.49.l.25.i；A.49.l.25.v；A.49.m.4.i；A.49.m.4.v；
A.49.m.6.i；A.49.m.6.v；A.49.m.11.i；A.49.m.11.v；A.49.m.14.i；A.49.m.14.v；
A.49.m.15.i；A.49.m.15.v；A.49.m.18.i；A.49.m.18.v；A.49.m.25.i；A.49.m.25.v；
A.49.o.4.i；A.49.o.4.v；A.49.o.6.i；A.49.o.6.v；A.49.o.11.i；A.49.o.11.v；A.49.o.14.i；
A.49.o.14.v；A.49.o.15.i；A.49.o.15.v；A.49.o.18.i；A.49.o.18.v；A.49.o.25.i；
A.49.o.25.v；B.17.a.4.i；B.17.a.4.v；B.17.a.6.i；B.17.a.6.v；B.17.a.11.i；B.17.a.11.v；
B.17.a.14.i；B.17.a.14.v；B.17.a.15.i；B.17.a.15.v；B.17.a.18.i；B.17.a.18.v；B.17.a.25.i；
B.17.a.25.v；B.17.e.4.i；B.17.e.4.v；B.17.e.6.i；B.17.e.6.v；B.17.e.11.i；B.17.e.11.v；
B.17.e.14.i；B.17.e.14.v；B.17.e.15.i；B.17.e.15.v；B.17.e.18.i；B.17.e.18.v；B.17.e.25.i；
B.17.e.25.v；B.17.g.4.i；B.17.g.4.v；B.17.g.6.i；B.17.g.6.v；B.17.g.11.i；B.17.g.11.v；
B.17.g.14.i；B.17.g.14.v；B.17.g.15.i；B.17.g.15.v；B.17.g.18.i；B.17.g.18.v；B.17.g.25.i；
B.17.g.25.v；B.17.l.4.i；B.17.l.4.v；B.17.l.6.i；B.17.l.6.v；B.17.l.11.i；B.17.l.11.v；
B.17.l.14.i；B.17.1.14.v；B.17.l.15.i；B.17.l.15.v；B.17.1.18.i；B.17.l.18.v；B.17.l.25.i；
B.17.l.25.v；B.17.m.4.i；B.17.m.4.v；B.17.m.6.i；B.17.m.6.v；B.17.m.11.i；
B.17.m.11.v；B.17.m.14.i；B.17.m.14.v；B.17.m.15.i；B.17.m.15.v；B.17.m.18.i；
B.17.m.18.v；B.17.m.25.i；B.17.m.25.v；B.17.o.4.i；B.17.o.4.v；B.17.o.6.i；B.17.o.6.v；
B.17.o.11.i；B.17.o.11.v；B.17.o.14.i；B.17.o.14.v；B.17.o.15.i；B.17.o.15.v；
B.17.o.18.i；B.17.o.18.v；B.17.o.25.i；B.17.o.25.v；B.33.a.4.i；B.33.a.4.v；B.33.a.6.i；
B.33.a.6.v；B.33.a.11.i；B.33.a.11.v；B.33.a.14.i；B.33.a.14.v；B.33.a.15.i；B.33.a.15.v；
B.33.a.18.i；B.33.a.18.v；B.33.a.25.i；B.33.a.25.v；B.33.e.4.i；B.33.e.4.v；B.33.e.6.i；
B.33.e.6.v；B.33.e.11.i；B.33.e.11.v；B.33.e.14.i；B.33.e.14.v；B.33.e.15.i；B.33.e.15.v；
B.33.e.18.i；B.33.e.18.v；B.33.e.25.i；B.33.e.25.v；B.33.g.4.i；B.33.g.4.v；B.33.g.6.i；
B.33.g.6.v；B.33.g.11.i；B.33.g.11.v；B.33.g.14.i；B.33.g.14.v；B.33.g.15.i；B.33.g.15.v；
B.33.g.18.i；B.33.g.18.v；B.33.g.25.i；B.33.g.25.v；B.33.l.4.i；B.33.l.4.v；B.33.l.6.i；
B.33.l.6.v；B.33.l.11.i；B.33.l.11.v；B.33.l.14.i；B.33.l.14.v；B.33.l.15.i；B.33.l.15.v；
B.33.l.18.i；B.33.l.18.v；B.33.l.25.i；B.33.l.25.v；B.33.m.4.i；B.33.m.4.v；B.33.m.6.i；
B.33.m.6.v；B.33.m.11.i；B.33.m.11.v；B.33.m.14.i；B.33.m.14.v；B.33.m.15.i；
B.33.m.15.v；B.33.m.18.i；B.33.m.18.v；B.33.m.25.i；B.33.m.25.v；B.33.o.4.i；
B.33.o.4.v；B.33.o.6.i；B.33.o.6.v；B.33.o.11.i；B.33.o.11.v；B.33.o.14.i；B.33.o.14.v；
B.33.o.15.i；B.33.o.15.v；B.33.o.18.i；B.33.o.18.v；B.33.o.25.i；B.33.o.25.v；B.49.a.4.i；
B.49.a.4.v；B.49.a.6.i；B.49.a.6.v；B.49.a.11.i；B.49.a.11.v；B.49.a.14.i；B.49.a.14.v；
B.49.a.15.i；B.49.a.15.v；B.49.a.18.i；B.49.a.18.v；B.49.a.25.i；B.49.a.25.v；B.49.e.4.i；
B.49.e.4.v；B.49.e.6.i；B.49.e.6.v；B.49.e.11.i；B.49.e.11.v；B.49.e.14.i；B.49.e.14.v；
B.49.e.15.i；B.49.e.15.v；B.49.e.18.i；B.49.e.18.v；B.49.e.25.i；B.49.e.25.v；B.49.g.4.i；
B.49.g.4.v；B.49.g.6.i；B.49.g.6.v；B.49.g.11.i；B.49.g.11.v；B.49.g.14.i；B.49.g.14.v；
B.49.g.15.i；B.49.g.15.v；B.49.g.18.i；B.49.g.18.v；B.49.g.25.i；B.49.g.25.v；B.49.l.4.i；
B.49.l.4.v；B.49.l.6.i；B.49.l.6.v；B.49.l.11.i；B.49.l.11.v；B.49.l.14.i；B.49.l.14.v；
B.49.l.15.i；B.49.l.15.v；B.49.l.18.i；B.49.l.18.v；B.49.l.25.i；B.49.l.25.v；B.49.m.4.i；
B.49.m.4.v；B.49.m.6.i；B.49.m.6.v；B.49.m.11.i；B.49.m.11.v；B.49.m.14.i；
B.49.m.14.v；B.49.m.15.i；B.49.m.15.v；B.49.m.18.i；B.49.m.18.v；B.49.m.25.i；
B.49.m.25.v；B.49.o.4.i；B.49.o.4.v；B.49.o.6.i；B.49.o.6.v；B.49.o.11.i；B.49.o.11.v；
B.49.o.14.i；B.49.o.14.v；B.49.o.15.i；B.49.o.15.v；B.49.o.18.i；B.49.o.18.v；
B.49.o.25.i；B.49.o.25.v；E.17.a.4.i；E.17.a.4.v；E.17.a.6.i；E.17.a.6.v；E.17.a.11.i；
E.17.a.11.v；E.17.a.14.i；E.17.a.14.v；E.17.a.15.i；E.17.a.15.v；E.17.a.18.i；E.17.a.18.v；
E.17.a.25.i；E.17.a.25.v；E.17.e.4.i；E.17.e.4.v；E.17.e.6.i；E.17.e.6.v；E.17.e.11.i；
E.17.e.11.v；E.17.e.14.i；E.17.e.14.v；E.17.e.15.i；E.17.e.15.v；E.17.e.18.i；E.17.e.18.v；
E.17.e.25.i；E.17.e.25.v；E.17.g.4.i；E.17.g.4.v；E.17.g.6.i；E.17.g.6.v；E.17.g.11.i；
E.17.g.11.v；E.17.g.14.i；E.17.g.14.v；E.17.g.15.i；E.17.g.15.v；E.17.g.18.i；E.17.g.18.v；
E.17.g.25.i；E.17.g.25.v；E.17.l.4.i；E.17.l.4.v；E.17.l.6.i；E.17.l.6.v；E.17.l.11.i；
E.17.l.11.v；E.17.l.14.i；E.17.l.14.v；E.17.l.15.i；E.17.l.15.v；E.17.l.18.i；E.17.l.18.v；
E.17.l.25.i；E.17.l.25.v；E.17.m.4.i；E.17.m.4.v；E.17.m.6.i；E.17.m.6.v；E.17.m.11.i；
E.17.m.11.v；E.17.m.14.i；E.17.m.14.v；E.17.m.15.i；E.17.m.15.v；E.17.m.18.i；
E.17.m.18.v；E.17.m.25.i；E.17.m.25.v；E.17.o.4.i；E.17.o.4.v；E.17.o.6.i；E.17.o.6.v；
E.17.o.11.i；E.17.o.11.v；E.17.o.14.i；E.17.o.14.v；E.17.o.15.i；E.17.o.15.v；E.17.o.18.i；
E.17.o.18.v；E.17.o.25.i；E.17.o.25.v；E.33.a.4.i；E.33.a.4.v；E.33.a.6.i；E.33.a.6.v；
E.33.a.11.i；E.33.a.11.v；E.33.a.14.i；E.33.a.14.v；E.33.a.15.i；E.33.a.15.v；E.33.a.18.i；
E.33.a.18.v；E.33.a.25.i；E.33.a.25.v；E.33.e.4.i；E.33.e.4.v；E.33.e.6.i；E.33.e.6.v；
E.33.e.11.i；E.33.e.11.v；E.33.e.14.i；E.33.e.14.v；E.33.e.15.i；E.33.e.15.v；E.33.e.18.i；
E.33.e.18.v；E.33.e.25.i；E.33.e.25.v；E.33.g.4.i；E.33.g.4.v；E.33.g.6.i；E.33.g.6.v；
E.33.g.11.i；E.33.g.11.v；E.33.g.14.i；E.33.g.14.v；E.33.g.15.i；E.33.g.15.v；E.33.g.18.i；
E.33.g.18.v；E.33.g.25.i；E.33.g.25.v；E.33.l.4.i；E.33.l.4.v；E.33.l.6.i；E.33.l.6.v；
E.33.l.11.i；E.33.l.11.v；E.33.l.14.i；E.33.l.14.v；E.33.l.15.i；E.33.l.15.v；E.33.l.18.i；
E.33.l.18.v；E.33.l.25.i；E.33.l.25.v；E.33.m.4.i；E.33.m.4.v；E.33.m.6.i；E.33.m.6.v；
E.33.m.11.i；E.33.m.11.v；E.33.m.14.i；E.33.m.14.v；E.33.m.15.i；E.33.m.15.v；
E.33.m.18.i；E.33.m.18.v；E.33.m.25.i；E.33.m.25.v；E.33.o.4.i；E.33.o.4.v；E.33.o.6.i；
E.33.o.6.v；E.33.o.11.i；E.33.o.11.v；E.33.o.14.i；E.33.o.14.v；E.33.o.15.i；E.33.o.15.v；
E.33.o.18.i；E.33.o.18.v；E.33.o.25.i；E.33.o.25.v；E.49.a.4.i；E.49.a.4.v；E.49.a.6.i；
E.49.a.6.v；E.49.a.11.i；E.49.a.11.v；E.49.a.14.i；E.49.a.14.v；E.49.a.15.i；E.49.a.15.v；
E.49.a.18.i；E.49.a.18.v；E.49.a.25.i；E.49.a.25.v；E.49.e.4.i；E.49.e.4.v；E.49.e.6.i；
E.49.e.6.v；E.49.e.11.i；E.49.e.11.v；E.49.e.14.i；E.49.e.14.v；E.49.e.15.i；E.49.e.15.v；
E.49.e.18.i；E.49.e.18.v；E.49.e.25.i；E.49.e.25.v；E.49.g.4.i；E.49.g.4.v；E.49.g.6.i；
E.49.g.6.v；E.49.g.11.i；E.49.g.11.v；E.49.g.14.i；E.49.g.14.v；E.49.g.15.i；E.49.g.15.v；
E.49.g.18.i；E.49.g.18.v；E.49.g.25.i；E.49.g.25.v；E.49.l.4.i；E.49.l.4.v；E.49.l.6.i；
E.49.l.6.v；E.49.l.11.i；E.49.l.11.v；E.49.l.14.i；E.49.l.14.v；E.49.l.15.i；E.49.l.15.v；
E.49.l.18.i；E.49.l.18.v；E.49.l.25.i；E.49.l.25.v；E.49.m.4.i；E.49.m.4.v；E.49.m.6.i；
E.49.m.6.v；E.49.m.11.i；E.49.m.11.v；E.49.m.14.i；E.49.m.14.v；E.49.m.15.i；
E.49.m.15.v；E.49.m.18.i；E.49.m.18.v；E.49.m.25.i；E.49.m.25.v；E.49.o.4.i；
E.49.o.4.v；E.49.o.6.i；E.49.o.6.v；E.49.o.11.i；E.49.o.11.v；E.49.o.14.i；E.49.o.14.v；
E.49.o.15.i；E.49.o.15.v；E.49.o.18.i；E.49.o.18.v；E.49.o.25.i；E.49.o.25.v；H.17.a.4.i；
H.17.a.4.v；H.17.a.6.i；H.17.a.6.v；H.17.a.11.i；H.17.a.11.v；H.17.a.14.i；H.17.a.14.v；
H.17.a.15.i；H.17.a.15.v；H.17.a.18.i；H.17.a.18.v；H.17.a.25.i；H.17.a.25.v；
H.17.e.4.i；H.17.e.4.v；H.17.e.6.i；H.17.e.6.v；H.17.e.11.i；H.17.e.11.v；H.17.e.14.i；
H.17.e.14.v；H.17.e.15.i；H.17.e.15.v；H.17.e.18.i；H.17.e.18.v；H.17.e.25.i；
H.17.e.25.v；H.17.g.4.i；H.17.g.4.v；H.17.g.6.i；H.17.g.6.v；H.17.g.11.i；H.17.g.11.v；
H.17.g.14.i；H.17.g.14.v；H.17.g.15.i；H.17.g.15.v；H.17.g.18.i；H.17.g.18.v；
H.17.g.25.i；H.17.g.25.v；H.17.l.4.i；H.17.l.4.v；H.17.l.6.i；H.17.l.6.v；H.17.l.11.i；
H.17.l.11.v；H.17.l.14.i；H.17.l.14.v；H.17.l.15.i；H.17.l.15.v；H.17.l.18.i；H.17.l.18.v；
H.17.l.25.i；H.17.l.25.v；H.17.m.4.i；H.17.m.4.v；H.17.m.6.i；H.17.m.6.v；
H.17.m.11.i；H.17.m.11.v；H.17.m.14.i；H.17.m.14.v；H.17.m.15.i；H.17.m.15.v；
H.17.m.18.i；H.17.m.18.v；H.17.m.25.i；H.17.m.25.v；H.17.o.4.i；H.17.o.4.v；
H.17.o.6.i；H.17.o.6.v；H.17.o.11.i；H.17.o.11.v；H.17.o.14.i；H.17.o.14.v；
H.17.o.15.i；H.17.o.15.v；H.17.o.18.i；H.17.o.18.v；H.17.o.25.i；H.17.o.25.v；
H.33.a.4.i；H.33.a.4.v；H.33.a.6.i；H.33.a.6.v；H.33.a.11.i；H.33.a.11.v；H.33.a.14.i；
H.33.a.14.v；H.33.a.15.i；H.33.a.15.v；H.33.a.18.i；H.33.a.18.v；H.33.a.25.i；
H.33.a.25.v；H.33.e.4.i；H.33.e.4.v；H.33.e.6.i；H.33.e.6.v；H.33.e.11.i；H.33.e.11.v；
H.33.e.14.i；H.33.e.14.v；H.33.e.15.i；H.33.e.15.v；H.33.e.18.i；H.33.e.18.v；
H.33.e.25.i；H.33.e.25.v；H.33.g.4.i；H.33.g.4.v；H.33.g.6.i；H.33.g.6.v；H.33.g.11.i；
H.33.g.11.v；H.33.g.14.i；H.33.g.14.v；H.33.g.15.i；H.33.g.15.v；H.33.g.18.i；
H.33.g.18.v；H.33.g.25.i；H.33.g.25.v；H.33.l.4.i；H.33.l.4.v；H.33.l.6.i；H.33.l.6.v；
H.33.l.11.i；H.33.l.11.v；H.33.l.14.i；H.33.l.14.v；H.33.l.15.i；H.33.l.15.v；H.33.l.18.i；
H.33.l.18.v；H.33.l.25.i；H.33.l.25.v；H.33.m.4.i；H.33.m.4.v；H.33.m.6.i；
H.33.m.6.v；H.33.m.11.i；H.33.m.11.v；H.33.m.14.i；H.33.m.14.v；H.33.m.15.i；
H.33.m.15.v；H.33.m.18.i；H.33.m.18.v；H.33.m.25.i；H.33.m.25.v；H.33.o.4.i；
H.33.o.4.v；H.33.o.6.i；H.33.o.6.v；H.33.o.11.i；H.33.o.11.v；H.33.o.14.i；
H.33.o.14.v；H.33.o.15.i；H.33.o.15.v；H.33.o.18.i；H.33.o.18.v；H.33.o.25.i；
H.33.o.25.v；H.49.a.4.i；H.49.a.4.v；H.49.a.6.i；H.49.a.6.v；H.49.a.11.i；H.49.a.11.v；
H.49.a.14.i；H.49.a.14.v；H.49.a.15.i；H.49.a.15.v；H.49.a.18.i；H.49.a.18.v；
H.49.a.25.i；H.49.a.25.v；H.49.e.4.i；H.49.e.4.v；H.49.e.6.i；H.49.e.6.v；H.49.e.11.i；
H.49.e.11.v；H.49.e.14.i；H.49.e.14.v；H.49.e.15.i；H.49.e.15.v；H.49.e.18.i；
H.49.e.18.v；H.49.e.25.i；H.49.e.25.v；H.49.g.4.i；H.49.g.4.v；H.49.g.6.i；H.49.g.6.v；
H.49.g.11.i；H.49.g.11.v；H.49.g.14.i；H.49.g.14.v；H.49.g.15.i；H.49.g.15.v；
H.49.g.18.i；H.49.g.18.v；H.49.g.25.i；H.49.g.25.v；H.49.l.4.i；H.49.l.4.v；H.49.l.6.i；
H.49.l.6.v；H.49.l.11.i；H.49.l.11.v；H.49.l.14.i；H.49.l.14.v；H.49.l.15.i；H.49.l.15.v；
H.49.l.18.i；H.49.l.18.v；H.49.l.25.i；H.49.l.25.v；H.49.m.4.i；H.49.m.4.v；
H.49.m.6.i；H.49.m.6.v；H.49.m.11.i；H.49.m.11.v；H.49.m.14.i；H.49.m.14.v；
H.49.m.15.i；H.49.m.15.v；H.49.m.18.i；H.49.m.18.v；H.49.m.25.i；H.49.m.25.v；
H.49.o.4.i；H.49.o.4.v；H.49.o.6.i；H.49.o.6.v；H.49.o.11.i；H.49.o.11.v；H.49.o.14.i；
H.49.o.14.v；H.49.o.15.i；H.49.o.15.v；H.49.o.18.i；H.49.o.18.v；H.49.o.25.i；
H.49.o.25.v；I.17.a.4.i；I.17.a.4.v；I.17.a.6.i；I.17.a.6.v；I.17.a.11.i；I.17.a.11.v；
I.17.a.14.i；I.17.a.14.v；I.17.a.15.i；I.17.a.15.v；I.17.a.18.i；I.17.a.18.v；I.17.a.25.i；
I.17.a.25.v；I.17.e.4.i；I.17.e.4.v；I.17.e.6.i；I.17.e.6.v；I.17.e.11.i；I.17.e.11.v；
I.17.e.14.i；I.17.e.14.v；I.17.e.15.i；I.17.e.15.v；I.17.e.18.i；I.17.e.18.v；I.17.e.25.i；
I.17.e.25.v；I.17.g.4.i；I.17.g.4.v；I.17.g.6.i；I.17.g.6.v；I.17.g.11.i；I.17.g.11.v；
I.17.g.14.i；I.17.g.14.v；I.17.g.15.i；I.17.g.15.v；I.17.g.18.i；I.17.g.18.v；I.17.g.25.i；
I.17.g.25.v；I.17.l.4.i；I.17.l.4.v；I.17.l.6.i；I.17.l.6.v；I.17.l.11.i；I.17.l.11.v；I.17.l.14.i；
I.17.l.14.v；I.17.l.15.i；I.17.l.15.v；I.17.l.18.i；I.17.l.18.v；I.17.l.25.i；I.17.l.25.v；
I.17.m.4.i；I.17.m.4.v；I.17.m.6.i；I.17.m.6.v；I.17.m.11.i；I.17.m.11.v；I.17.m.14.i；
I.17.m.14.v；I.17.m.15.i；I.17.m.15.v；I.17.m.18.i；I.17.m.18.v；I.17.m.25.i；
I.17.m.25.v；I.17.o.4.i；I.17.o.4.v；I.17.o.6.i；I.17.o.6.v；I.17.o.11.i；I.17.o.11.v；
I.17.o.14.i；I.17.o.14.v；I.17.o.15.i；I.17.o.15.v；I.17.o.18.i；I.17.o.18.v；I.17.o.25.i；
I.17.o.25.v；I.33.a.4.i；I.33.a.4.v；I.33.a.6.i；I.33.a.6.v；I.33.a.11.i；I.33.a.11.v；
I.33.a.14.i；I.33.a.14.v；I.33.a.15.i；I.33.a.15.v；I.33.a.18.i；I.33.a.18.v；I.33.a.25.i；
I.33.a.25.v；I.33.e.4.i；I.33.e.4.v；I.33.e.6.i；I.33.e.6.v；I.33.e.11.i；I.33.e.11.v；
I.33.e.14.i；I.33.e.14.v；I.33.e.15.i；I.33.e.15.v；I.33.e.18.i；I.33.e.18.v；I.33.e.25.i；
I.33.e.25.v；I.33.g.4.i；I.33.g.4.v；I.33.g.6.i；I.33.g.6.v；I.33.g.11.i；I.33.g.11.v；
I.33.g.14.i；I.33.g.14.v；I.33.g.15.i；I.33.g.15.v；I.33.g.18.i；I.33.g.18.v；I.33.g.25.i；
I.33.g.25.v；I.33.l.4.i；I.33.l.4.v；I.33.l.6.i；I.33.l.6.v；I.33.l.11.i；I.33.l.11.v；I.33.l.14.i；
I.33.l.14.v；I.33.l.15.i；I.33.l.15.v；I.33.l.18.i；I.33.l.18.v；I.33.l.25.i；I.33.l.25.v；
I.33.m.4.i；I.33.m.4.v；I.33.m.6.i；I.33.m.6.v；I.33.m.11.i；I.33.m.11.v；I.33.m.14.i；
I.33.m.14.v；I.33.m.15.i；I.33.m.15.v；I.33.m.18.i；I.33.m.18.v；I.33.m.25.i；
I.33.m.25.v；I.33.o.4.i；I.33.o.4.v；I.33.o.6.i；I.33.o.6.v；I.33.o.11.i；I.33.o.11.v；
I.33.o.14.i；I.33.o.14.v；I.33.o.15.i；I.33.o.15.v；I.33.o.18.i；I.33.o.18.v；I.33.o.25.i；
I.33.o.25.v；I.49.a.4.i；I.49.a.4.v；I.49.a.6.i；I.49.a.6.v；I.49.a.11.i；I.49.a.11.v；
I.49.a.14.i；I.49.a.14.v；I.49.a.15.i；I.49.a.15.v；I.49.a.18.i；I.49.a.18.v；I.49.a.25.i；
I.49.a.25.v；I.49.e.4.i；I.49.e.4.v；I.49.e.6.i；I.49.e.6.v；I.49.e.11.i；I.49.e.11.v；
I.49.e.14.i；I.49.e.14.v；I.49.e.15.i；I.49.e.15.v；I.49.e.18.i；I.49.e.18.v；I.49.e.25.i；
I.49.e.25.v；I.49.g.4.i；I.49.g.4.v；I.49.g.6.i；I.49.g.6.v；I.49.g.11.i；I.49.g.11.v；
I.49.g.14.i；I.49.g.14.v；I.49.g.15.i；I.49.g.15.v；I.49.g.18.i；I.49.g.18.v；I.49.g.25.i；
I.49.g.25.v；I.49.l.4.i；I.49.l.4.v；I.49.l.6.i；I.49.l.6.v；I.49.l.11.i；I.49.l.11.v；I.49.l.14.i；
I.49.l.14.v；I.49.l.15.i；I.49.l.15.v；I.49.l.18.i；I.49.l.18.v；I.49.l.25.i；I.49.l.25.v；
I.49.m.4.i；I.49.m.4.v；I.49.m.6.i；I.49.m.6.v；I.49.m.11.i；I.49.m.11.v；I.49.m.14.i；
I.49.m.14.v；I.49.m.15.i；I.49.m.15.v；I.49.m.18.i；I.49.m.18.v；I.49.m.25.i；
I.49.m.25.v；I.49.o.4.i；I.49.o.4.v；I.49.o.6.i；I.49.o.6.v；I.49.o.11.i；I.49.o.11.v；
I.49.o.14.i；I.49.o.14.v；I.49.o.15.i；I.49.o.15.v；I.49.o.18.i；I.49.o.18.v；I.49.o.25.i；
I.49.o.25.v；L.17.a.4.i；L.17.a.4.v；L.17.a.6.i；L.17.a.6.v；L.17.a.11.i；L.17.a.11.v；
L.17.a.14.i；L.17.a.14.v；L.17.a.15.i；L.17.a.15.v；L.17.a.18.i；L.17.a.18.v；L.17.a.25.i；
L.17.a.25.v；L.17.e.4.i；L.17.e.4.v；L.17.e.6.i；L.17.e.6.v；L.17.e.11.i；L.17.e.11.v；
L.17.e.14.i；L.17.e.14.v；L.17.e.15.i；L.17.e.15.v；L.17.e.18.i；L.17.e.18.v；L.17.e.25.i；
L.17.e.25.v；L.17.g.4.i；L.17.g.4.v；L.17.g.6.i；L.17.g.6.v；L.17.g.11.i；L.17.g.11.v；
L.17.g.14.i；L.17.g.14.v；L.17.g.15.i；L.17.g.15.v；L.17.g.18.i；L.17.g.18.v；L.17.g.25.i；
L.17.g.25.v；L.17.l.4.i；L.17.l.4.v；L.17.l.6.i；L.17.l.6.v；L.17.l.11.i；L.17.l.11.v；
L.17.l.14.i；L.17.l.14.v；L.17.l.15.i；L.17.l.15.v；L.17.l.18.i；L.17.l.18.v；L.17.l.25.i；
L.17.l.25.v；L.17.m.4.i；L.17.m.4.v；L.17.m.6.i；L.17.m.6.v；L.17.m.11.i；
L.17.m.11.v；L.17.m.14.i；L.17.m.14.v；L.17.m.15.i；L.17.m.15.v；L.17.m.18.i；
L.17.m.18.v；L.17.m.25.i；L.17.m.25.v；L.17.o.4.i；L.17.o.4.v；L.17.o.6.i；L.17.o.6.v；
L.17.o.11.i；L.17.o.11.v；L.17.o.14.i；L.17.o.14.v；L.17.o.15.i；L.17.o.15.v；L.17.o.18.i；
L.17.o.18.v；L.17.o.25.i；L.17.o.25.v；L.33.a.4.i；L.33.a.4.v；L.33.a.6.i；L.33.a.6.v；
L.33.a.11.i；L.33.a.11.v；L.33.a.14.i；L.33.a.14.v；L.33.a.15.i；L.33.a.15.v；L.33.a.18.i；
L.33.a.18.v；L.33.a.25.i；L.33.a.25.v；L.33.e.4.i；L.33.e.4.v；L.33.e.6.i；L.33.e.6.v；
L.33.e.11.i；L.33.e.11.v；L.33.e.14.i；L.33.e.14.v；L.33.e.15.i；L.33.e.15.v；L.33.e.18.i；
L.33.e.18.v；L.33.e.25.i；L.33.e.25.v；L.33.g.4.i；L.33.g.4.v；L.33.g.6.i；L.33.g.6.v；
L.33.g.11.i；L.33.g.11.v；L.33.g.14.i；L.33.g.14.v；L.33.g.15.i；L.33.g.15.v；L.33.g.18.i；
L.33.g.18.v；L.33.g.25.i；L.33.g.25.v；L.33.l.4.i；L.33.l.4.v；L.33.l.6.i；L.33.l.6.v；
L.33.l.11.i；L.33.l.11.v；L.33.l.14.i；L.33.l.14.v；L.33.l.15.i；L.33.l.15.v；L.33.l.18.i；
L.33.l.18.v；L.33.l.25.i；L.33.l.25.v；L.33.m.4.i；L.33.m.4.v；L.33.m.6.i；L.33.m.6.v；
L.33.m.11.i；L.33.m.11.v；L.33.m.14.i；L.33.m.14.v；L.33.m.15.i；L.33.m.15.v；
L.33.m.18.i；L.33.m.18.v；L.33.m.25.i；L.33.m.25.v；L.33.o.4.i；L.33.o.4.v；L.33.o.6.i；
L.33.o.6.v；L.33.o.11.i；L.33.o.11.v；L.33.o.14.i；L.33.o.14.v；L.33.o.15.i；L.33.o.15.v；
L.33.o.18.i；L.33.o.18.v；L.33.o.25.i；L.33.o.25.v；L.49.a.4.i；L.49.a.4.v；L.49.a.6.i；
L.49.a.6.v；L.49.a.11.i；L.49.a.11.v；L.49.a.14.i；L.49.a.14.v；L.49.a.15.i；L.49.a.15.v；
L.49.a.18.i；L.49.a.18.v；L.49.a.25.i；L.49.a.25.v；L.49.e.4.i；L.49.e.4.v；L.49.e.6.i；
L.49.e.6.v；L.49.e.11.i；L.49.e.11.v；L.49.e.14.i；L.49.e.14.v；L.49.e.15.i；L.49.e.15.v；
L.49.e.18.i；L.49.e.18.v；L.49.e.25.i；L.49.e.25.v；L.49.g.4.i；L.49.g.4.v；L.49.g.6.i；
L.49.g.6.v；L.49.g.11.i；L.49.g.11.v；L.49.g.14.i；L.49.g.14.v；L.49.g.15.i；L.49.g.15.v；
L.49.g.18.i；L.49.g.18.v；L.49.g.25.i；L.49.g.25.v；L.49.l.4.i；L.49.l.4.v；L.49.l.6.i；
L.49.l.6.v；L.49.l.11.i；L.49.l.11.v；L.49.l.14.i；L.49.l.14.v；L.49.l.15.i；L.49.l.15.v；
L.49.l.18.i；L.49.l.18.v；L.49.l.25.i；L.49.l.25.v；L.49.m.4.i；L.49.m.4.v；L.49.m.6.i；
L.49.m.6.v；L.49.m.11.i；L.49.m.11.v；L.49.m.14.i；L.49.m.14.v；L.49.m.15.i；
L.49.m.15.v；L.49.m.18.i；L.49.m.18.v；L.49.m.25.i；L.49.m.25.v；L.49.o.4.i；
L.49.o.4.v；L.49.o.6.i；L.49.o.6.v；L.49.o.11.i；L.49.o.11.v；L.49.o.14.i；L.49.o.14.v；
L.49.o.15.i；L.49.o.15.v；L.49.o.18.i；L.49.o.18.v；L.49.o.25.i；L.49.o.25.v；B.93.a.4.i；
B.93.a.4.v；B.93.a.6.i；B.93.a.6.v；B.93.a.11.i；B.93.a.11.v；B.93.a.14.i；B.93.a.14.v；
B.93.a.15.i；B.93.a.15.v；B.93.a.18.i；B.93.a.18.v；B.93.a.25.i；B.93.a.25.v；B.93.e.4.i；
B.93.e.4.v；B.93.e.6.i；B.93.e.6.v；B.93.e.11.i；B.93.e.11.v；B.93.e.14.i；B.93.e.14.v；
B.93.e.15.i；B.93.e.15.v；B.93.e.18.i；B.93.e.18.v；B.93.e.25.i；B.93.e.25.v；B.93.g.4.i；
B.93.g.4.v；B.93.g.6.i；B.93.g.6.v；B.93.g.11.i；B.93.g.11.v；B.93.g.14.i；B.93.g.14.v；
B.93.g.15.i；B.93.g.15.v；B.93.g.18.i；B.93.g.18.v；B.93.g.25.i；B.93.g.25.v；B.93.l.4.i；
B.93.l.4.v；B.93.l.6.i；B.93.l.6.v；B.93.l.11.i；B.93.l.11.v；B.93.l.14.i；B.93.l.14.v；
B.93.l.15.i；B.93.l.15.v；B.93.l.18.i；B.93.l.18.v；B.93.l.25.i；B.93.l.25.v；B.93.m.4.i；
B.93.m.4.v；B.93.m.6.i；B.93.m.6.v；B.93.m.11.i；B.93.m.11.v；B.93.m.14.i；
B.93.m.14.v；B.93.m.15.i；B.93.m.15.v；B.93.m.18.i；B.93.m.18.v；B.93.m.25.i；
B.93.m.25.v；B.93.o.4.i；B.93.o.4.v；B.93.o.6.i；B.93.o.6.v；B.93.o.11.i；B.93.o.11.v；
B.93.o.14.i；B.93.o.14.v；B.93.o.15.i；B.93.o.15.v；B.93.o.18.i；B.93.o.18.v；
B.93.o.25.i；B.93.o.25.v；B.94.a.4.i；B.94.a.4.v；B.94.a.6.i；B.94.a.6.v；B.94.a.11.i；
B.94.a.11.v；B.94.a.14.i；B.94.a.14.v；B.94.a.15.i；B.94.a.15.v；B.94.a.18.i；B.94.a.18.v；
B.94.a.25.i；B.94.a.25.v；B.94.e.4.i；B.94.e.4.v；B.94.e.6.i；B.94.e.6.v；B.94.e.11.i；
B.94.e.11.v；B.94.e.14.i；B.94.e.14.v；B.94.e.15.i；B.94.e.15.v；B.94.e.18.i；B.94.e.18.v；
B.94.e.25.i；B.94.e.25.v；B.94.g.4.i；B.94.g.4.v；B.94.g.6.i；B.94.g.6.v；B.94.g.11.i；
B.94.g.11.v；B.94.g.14.i；B.94.g.14.v；B.94.g.15.i；B.94.g.15.v；B.94.g.18.i；B.94.g.18.v；
B.94.g.25.i；B.94.g.25.v；B.94.l.4.i；B.94.l.4.v；B.94.l.6.i；B.94.l.6.v；B.94.l.11.i；
B.94.l.11.v；B.94.l.14.i；B.94.l.14.v；B.94.l.15.i；B.94.l.15.v；B.94.l.18.i；B.94.l.18.v；
B.94.l.25.i；B.94.l.25.v；B.94.m.4.i；B.94.m.4.v；B.94.m.6.i；B.94.m.6.v；B.94.m.11.i；
B.94.m.11.v；B.94.m.14.i；B.94.m.14.v；B.94.m.15.i；B.94.m.15.v；B.94.m.18.i；
B.94.m.18.v；B.94.m.25.i；B.94.m.25.v；B.94.o.4.i；B.94.o.4.v；B.94.o.6.i；B.94.o.6.v；
B.94.o.11.i；B.94.o.11.v；B.94.o.14.i；B.94.o.14.v；B.94.o.15.i；B.94.o.15.v；
B.94.o.18.i；B.94.o.18.v；B.94.o.25.i；B.94.o.25.v；E.93.a.4.i；E.93.a.4.v；E.93.a.6.i；
E.93.a.6.v；E.93.a.11.i；E.93.a.11.v；E.93.a.14.i；E.93.a.14.v；E.93.a.15.i；E.93.a.15.v；
E.93.a.18.i；E.93.a.18.v；E.93.a.25.i；E.93.a.25.v；E.93.e.4.i；E.93.e.4.v；E.93.e.6.i；
E.93.e.6.v；E.93.e.11.i；E.93.e.11.v；E.93.e.14.i；E.93.e.14.v；E.93.e.15.i；E.93.e.15.v；
E.93.e.18.i；E.93.e.18.v；E.93.e.25.i；E.93.e.25.v；E.93.g.4.i；E.93.g.4.v；E.93.g.6.i；
E.93.g.6.v；E.93.g.11.i；E.93.g.11.v；E.93.g.14.i；E.93.g.14.v；E.93.g.15.i；E.93.g.15.v；
E.93.g.18.i；E.93.g.18.v；E.93.g.25.i；E.93.g.25.v；E.93.l.4.i；E.93.l.4.v；E.93.l.6.i；
E.93.l.6.v；E.93.l.11.i；E.93.l.11.v；E.93.l.14.i；E.93.l.14.v；E.93.l.15.i；E.93.l.15.v；
E.93.l.18.i；E.93.l.18.v；E.93.l.25.i；E.93.l.25.v；E.93.m.4.i；E.93.m.4.v；E.93.m.6.i；
E.93.m.6.v；E.93.m.11.i；E.93.m.11.v；E.93.m.14.i；E.93.m.14.v；E.93.m.15.i；
E.93.m.15.v；E.93.m.18.i；E.93.m.18.v；E.93.m.25.i；E.93.m.25.v；E.93.o.4.i；
E.93.o.4.v；E.93.o.6.i；E.93.o.6.v；E.93.o.11.i；E.93.o.11.v；E.93.o.14.i；E.93.o.14.v；
E.93.o.15.i；E.93.o.15.v；E.93.o.18.i；E.93.o.18.v；E.93.o.25.i；E.93.o.25.v；E.94.a.4.i；
E.94.a.4.v；E.94.a.6.i；E.94.a.6.v；E.94.a.11.i；E.94.a.11.v；E.94.a.14.i；E.94.a.14.v；
E.94.a.15.i；E.94.a.15.v；E.94.a.18.i；E.94.a.18.v；E.94.a.25.i；E.94.a.25.v；E.94.e.4.i；
E.94.e.4.v；E.94.e.6.i；E.94.e.6.v；E.94.e.11.i；E.94.e.11.v；E.94.e.14.i；E.94.e.14.v；
E.94.e.15.i；E.94.e.15.v；E.94.e.18.i；E.94.e.18.v；E.94.e.25.i；E.94.e.25.v；E.94.g.4.i；
E.94.g.4.v；E.94.g.6.i；E.94.g.6.v；E.94.g.11.i；E.94.g.11.v；E.94.g.14.i；E.94.g.14.v；
E.94.g.15.i；E.94.g.15.v；E.94.g.18.i；E.94.g.18.v；E.94.g.25.i；E.94.g.25.v；E.94.l.4.i；
E.94.l.4.v；E.94.l.6.i；E.94.l.6.v；E.94.l.11.i；E.94.l.11.v；E.94.l.14.i；E.94.l.14.v；
E.94.l.15.i；E.94.l.15.v；E.94.l.18.i；E.94.l.18.v；E.94.l.25.i；E.94.l.25.v；E.94.m.4.i；
E.94.m.4.v；E.94.m.6.i；E.94.m.6.v；E.94.m.11.i；E.94.m.11.v；E.94.m.14.i；
E.94.m.14.v；E.94.m.15.i；E.94.m.15.v；E.94.m.18.i；E.94.m.18.v；E.94.m.25.i；
E.94.m.25.v；E.94.o.4.i；E.94.o.4.v；E.94.o.6.i；E.94.o.6.v；E.94.o.11.i；E.94.o.11.v；
E.94.o.14.i；E.94.o.14.v；E.94.o.15.i；E.94.o.15.v；E.94.o.18.i；E.94.o.18.v；E.94.o.25.i；
E.94.o.25.v；I.93.a.4.i；I.93.a.4.v；I.93.a.6.i；I.93.a.6.v；I.93.a.11.i；I.93.a.11.v；
I.93.a.14.i；I.93.a.14.v；I.93.a.15.i；I.93.a.15.v；I.93.a.18.i；I.93.a.18.v；I.93.a.25.i；
I.93.a.25.v；I.93.e.4.i；I.93.e.4.v；I.93.e.6.i；I.93.e.6.v；I.93.e.11.i；I.93.e.11.v；
I.93.e.14.i；I.93.e.14.v；I.93.e.15.i；I.93.e.15.v；I.93.e.18.i；I.93.e.18.v；I.93.e.25.i；
I.93.e.25.v；I.93.g.4.i；I.93.g.4.v；I.93.g.6.i；I.93.g.6.v；I.93.g.11.i；I.93.g.11.v；
I.93.g.14.i；I.93.g.14.v；I.93.g.15.i；I.93.g.15.v；I.93.g.18.i；I.93.g.18.v；I.93.g.25.i；
I.93.g.25.v；I.93.l.4.i；I.93.l.4.v；I.93.l.6.i；I.93.l.6.v；I.93.l.11.i；I.93.l.11.v；I.93.l.14.i；
I.93.l.14.v；I.93.l.15.i；I.93.l.15.v；I.93.l.18.i；I.93.l.18.v；I.93.l.25.i；I.93.l.25.v；
I.93.m.4.i；I.93.m.4.v；I.93.m.6.i；I.93.m.6.v；I.93.m.11.i；I.93.m.11.v；I.93.m.14.i；
I.93.m.14.v；I.93.m.15.i；I.93.m.15.v；I.93.m.18.i；I.93.m.18.v；I.93.m.25.i；
I.93.m.25.v；I.93.o.4.i；I.93.o.4.v；I.93.o.6.i；I.93.o.6.v；I.93.o.11.i；I.93.o.11.v；
I.93.o.14.i；I.93.o.14.v；I.93.o.15.i；I.93.o.15.v；I.93.o.18.i；I.93.o.18.v；I.93.o.25.i；
I.93.o.25.v；I.94.a.4.i；I.94.a.4.v；I.94.a.6.i；I.94.a.6.v；I.94.a.11.i；I.94.a.11.v；
I.94.a.14.i；I.94.a.14.v；I.94.a.15.i；I.94.a.15.v；I.94.a.18.i；I.94.a.18.v；I.94.a.25.i；
I.94.a.25.v；I.94.e.4.i；I.94.e.4.v；I.94.e.6.i；I.94.e.6.v；I.94.e.11.i；I.94.e.11.v；
I.94.e.14.i；I.94.e.14.v；I.94.e.15.i；I.94.e.15.v；I.94.e.18.i；I.94.e.18.v；I.94.e.25.i；
I.94.e.25.v；I.94.g.4.i；I.94.g.4.v；I.94.g.6.i；I.94.g.6.v；I.94.g.11.i；I.94.g.11.v；
I.94.g.14.i；I.94.g.14.v；I.94.g.15.i；I.94.g.15.v；I.94.g.18.i；I.94.g.18.v；I.94.g.25.i；
I.94.g.25.v；I.94.l.4.i；I.94.l.4.v；I.94.l.6.i；I.94.l.6.v；I.94.l.11.i；I.94.l.11.v；I.94.l.14.i；
I.94.l.14.v；I.94.l.15.i；I.94.l.15.v；I.94.l.18.i；I.94.l.18.v；I.94.l.25.i；I.94.l.25.v；
I.94.m.4.i；I.94.m.4.v；I.94.m.6.i；I.94.m.6.v；I.94.m.11.i；I.94.m.11.v；I.94.m.14.i；
I.94.m.14.v；I.94.m.15.i；I.94.m.15.v；I.94.m.18.i；I.94.m.18.v；I.94.m.25.i；
I.94.m.25.v；I.94.o.4.i；I.94.o.4.v；I.94.o.6.i；I.94.o.6.v；I.94.o.11.i；I.94.o.11.v；
I.94.o.14.i；I.94.o.14.v；I.94.o.15.i；I.94.o.15.v；I.94.o.18.i；I.94.o.18.v；I.94.o.25.i；
I.94.o.25.v；L.93.a.4.i；L.93.a.4.v；L.93.a.6.i；L.93.a.6.v；L.93.a.11.i；L.93.a.11.v；
L.93.a.14.i；L.93.a.14.v；L.93.a.15.i；L.93.a.15.v；L.93.a.18.i；L.93.a.18.v；L.93.a.25.i；
L.93.a.25.v；L.93.e.4.i；L.93.e.4.v；L.93.e.6.i；L.93.e.6.v；L.93.e.11.i；L.93.e.11.v；
L.93.e.14.i；L.93.e.14.v；L.93.e.15.i；L.93.e.15.v；L.93.e.18.i；L.93.e.18.v；L.93.e.25.i；
L.93.e.25.v；L.93.g.4.i；L.93.g.4.v；L.93.g.6.i；L.93.g.6.v；L.93.g.11.i；L.93.g.11.v；
L.93.g.14.i；L.93.g.14.v；L.93.g.15.i；L.93.g.15.v；L.93.g.18.i；L.93.g.18.v；L.93.g.25.i；
L.93.g.25.v；L.93.l.4.i；L.93.l.4.v；L.93.l.6.i；L.93.l.6.v；L.93.l.11.i；L.93.l.11.v；
L.93.l.14.i；L.93.l.14.v；L.93.l.15.i；L.93.l.15.v；L.93.l.18.i；L.93.l.18.v；L.93.l.25.i；
L.93.l.25.v；L.93.m.4.i；L.93.m.4.v；L.93.m.6.i；L.93.m.6.v；L.93.m.11.i；
L.93.m.11.v；L.93.m.14.i；L.93.m.14.v；L.93.m.15.i；L.93.m.15.v；L.93.m.18.i；
L.93.m.18.v；L.93.m.25.i；L.93.m.25.v；L.93.o.4.i；L.93.o.4.v；L.93.o.6.i；L.93.o.6.v；
L.93.o.11.i；L.93.o.11.v；L.93.o.14.i；L.93.o.14.v；L.93.o.15.i；L.93.o.15.v；L.93.o.18.i；
L.93.o.18.v；L.93.o.25.i；L.93.o.25.v；L.94.a.4.i；L.94.a.4.v；L.94.a.6.i；L.94.a.6.v；
L.94.a.11.i；L.94.a.11.v；L.94.a.14.i；L.94.a.14.v；L.94.a.15.i；L.94.a.15.v；L.94.a.18.i；
L.94.a.18.v；L.94.a.25.i；L.94.a.25.v；L.94.e.4.i；L.94.e.4.v；L.94.e.6.i；L.94.e.6.v；
L.94.e.11.i；L.94.e.11.v；L.94.e.14.i；L.94.e.14.v；L.94.e.15.i；L.94.e.15.v；L.94.e.18.i；
L.94.e.18.v；L.94.e.25.i；L.94.e.25.v；L.94.g.4.i；L.94.g.4.v；L.94.g.6.i；L.94.g.6.v；
L.94.g.11.i；L.94.g.11.v；L.94.g.14.i；L.94.g.14.v；L.94.g.15.i；L.94.g.15.v；L.94.g.18.i；
L.94.g.18.v；L.94.g.25.i；L.94.g.25.v；L.94.l.4.i；L.94.l.4.v；L.94.l.6.i；L.94.l.6.v；
L.94.l.11.i；L.94.l.11.v；L.94.l.14.i；L.94.l.14.v；L.94.l.15.i；L.94.l.15.v；L.94.l.18.i；
L.94.l.18.v；L.94.l.25.i；L.94.l.25.v；L.94.m.4.i；L.94.m.4.v；L.94.m.6.i；L.94.m.6.v；
L.94.m.11.i；L.94.m.11.v；L.94.m.14.i；L.94.m.14.v；L.94.m.15..；L.94.m.15.v；
L.94.m.18.i；L.94.m.18.v；L.94.m.25.i；L.94.m.25.v；L.94.o.4.i；L.94.o.4.v；L.94.o.6.i；
L.94.o.6.v；L.94.o.11.i；L.94.o.11.v；L.94.o.14.i；L.94.o.14.v；L.94.o.15.i；L.94.o.15.v；
L.94.o.18.i；L.94.o.18.v；L.94.o.25.i；L.94.o.25.v；O.93.a.4.i；O.93.a.4.v；O.93.a.6.i；
O.93.a.6.v；O.93.a.11.i；O.93.a.11.v；O.93.a.14.i；O.93.a.14.v；O.93.a.15.i；
O.93.a.15.v；O.93.a.18.i；O.93.a.18.v；O.93.a.25.i；O.93.a.25.v；O.93.e.4.i；O.93.e.4.v；
O.93.e.6.i；O.93.e.6.v；O.93.e.11.i；O.93.e.11.v；O.93.e.14.i；O.93.e.14.v；O.93.e.15.i；
O.93.e.15.v；O.93.e.18.i；O.93.e.18.v；O.93.e.25.i；O.93.e.25.v；O.93.g.4.i；O.93.g.4.v；
O.93.g.6.i；O.93.g.6.v；O.93.g.11.i；O.93.g.11.v；O.93.g.14.i；O.93.g.14.v；O.93.g.15.i；
O.93.g.15.v；O.93.g.18.i；O.93.g.18.v；O.93.g.25.i；O.93.g.25.v；O.93.l.4.i；O.93.l.4.v；
O.93.l.6.i；O.93.l.6.v；O.93.l.11.i；O.93.l.11.v；O.93.l.14.i；O.93.l.14.v；O.93.l.15.i；
O.93.l.15.v；O.93.l.18.i；O.93.l.18.v；O.93.l.25.i；O.93.l.25.v；O.93.m.4.i；O.93.m.4.v；
O.93.m.6.i；O.93.m.6.v；O.93.m.11.i；O.93.m.11.v；O.93.m.14.i；O.93.m.14.v；
O.93.m.15.i；O.93.m.15.v；O.93.m.18.i；O.93.m.18.v；O.93.m.25.i；O.93.m.25.v；
O.93.o.4.i；O.93.o.4.v；O.93.o.6.i；O.93.o.6.v；O.93.o.11.i；O.93.o.11.v；O.93.o.14.i；
O.93.o.14.v；O.93.o.15.i；O.93.o.15.v；O.93.o.18.i；O.93.o.18.v；O.93.o.25.i；
O.93.o.25.v；O.94.a.4.i；O.94.a.4.v；O.94.a.6.i；O.94.a.6.v；O.94.a.11.i；O.94.a.11.v；
O.94.a.14.i；O.94.a.14.v；O.94.a.15.i；O.94.a.15.v；O.94.a.18.i；O.94.a.18.v；
O.94.a.25.i；O.94.a.25.v；O.94.e.4.i；O.94.e.4.v；O.94.e.6.i；O.94.e.6.v；O.94.e.11.i；
O.94.e.11.v；O.94.e.14.i；O.94.e.14.v；O.94.e.15.i；O.94.e.15.v；O.94.e.18.i；
O.94.e.18.v；O.94.e.25.i；O.94.e.25.v；O.94.g.4.i；O.94.g.4.v；O.94.g.6.i；O.94.g.6.v；
O.94.g.11.i；O.94.g.11.v；O.94.g.14.i；O.94.g.14.v；O.94.g.15.i；O.94.g.15.v；
O.94.g.18.i；O.94.g.18.v；O.94.g.25.i；O.94.g.25.v；O.94.l.4.i；O.94.l.4.v；O.94.l.6.i；
O.94.l.6.v；O.94.l.11.i；O.94.l.11.v；O.94.l.14.i；O.94.l.14.v；O.94.l.15.i；O.94.l.15.v；
O.94.l.18.i；O.94.l.18.v；O.94.l.25.i；O.94.l.25.v；O.94.m.4.i；O.94.m.4.v；O.94.m.6.i；
O.94.m.6.v；O.94.m.11.i；O.94.m.11.v；O.94.m.14.i；O.94.m.14.v；O.94.m.15.i；
O.94.m.15.v；O.94.m.18.i；O.94.m.18.v；O.94.m.25.i；O.94.m.25.v；O.94.o.4.i；
O.94.o.4.v；O.94.o.6.i；O.94.o.6.v；O.94.o.11.i；O.94.o.11.v；O.94.o.14.i；O.94.o.14.v；
O.94.o.15.i；O.94.o.15.v；O.94.o.18.i；O.94.o.18.v；O.94.o.25.i；O.94.o.25.v；
P.93.a.4.i；P.93.a.4.v；P.93.a.6.i；P.93.a.6.v；P.93.a.11.i；P.93.a.11.v；P.93.a.14.i；
P.93.a.14.v；P.93.a.15.i；P.93.a.15.v；P.93.a.18.i；P.93.a.18.v；P.93.a.25.i；P.93.a.25.v；
P.93.e.4.i；P.93.e.4.v；P.93.e.6.i；P.93.e.6.v；P.93.e.11.i；P.93.e.11.v；P.93.e.14.i；
P.93.e.14.v；P.93.e.15.i；P.93.e.15.v；P.93.e.18.i；P.93.e.18.v；P.93.e.25.i；P.93.e.25.v；
P.93.g.4.i；P.93.g.4.v；P.93.g.6.i；P.93.g.6.v；P.93.g.11.i；P.93.g.11.v；P.93.g.14.i；
P.93.g.14.v；P.93.g.15.i；P.93.g.15.v；P.93.g.18.i；P.93.g.18.v；P.93.g.25.i；P.93.g.25.v；
P.93.l.4.i；P.93.l.4.v；P.93.l.6.i；P.93.l.6.v；P.93.l.11.i；P.93.l.11.v；P.93.l.14.i；
P.93.l.14.v；P.93.l.15.i；P.93.l.15.v；P.93.l.18.i；P.93.l.18.v；P.93.l.25.i；P.93.l.25.v；
P.93.m.4.i；P.93.m.4.v；P.93.m.6.i；P.93.m.6.v；P.93.m.11.i；P.93.m.11.v；
P.93.m.14.i；P.93.m.14.v；P.93.m.15.i；P.93.m.15.v；P.93.m.18.i；P.93.m.18.v；
P.93.m.25.i；P.93.m.25.v；P.93.o.4.i；P.93.o.4.v；P.93.o.6.i；P.93.o.6.v；P.93.o.11.i；
P.93.o.11.v；P.93.o.14.i；P.93.o.14.v；P.93.o.15.i；P.93.o.15.v；P.93.o.18.i；P.93.o.18.v；
P.93.o.25.i；P.93.o.25.v；P.94.a.4.i；P.94.a.4.v；P.94.a.6.i；P.94.a.6.v；P.94.a.11.i；
P.94.a.11.v；P.94.a.14.i；P.94.a.14.v；P.94.a.15.i；P.94.a.15.v；P.94.a.18.i；P.94.a.18.v；
P.94.a.25.i；P.94.a.25.v；P.94.e.4.i；P.94.e.4.v；P.94.e.6.i；P.94.e.6.v；P.94.e.11.i；
P.94.e.11.v；P.94.e.14.i；P.94.e.14.v；P.94.e.15.i；P.94.e.15.v；P.94.e.18.i；P.94.e.18.v；
P.94.e.25.i；P.94.e.25.v；P.94.g.4.i；P.94.g.4.v；P.94.g.6.i；P.94.g.6.v；P.94.g.11.i；
P.94.g.11.v；P.94.g.14.i；P.94.g.14.v；P.94.g.15.i；P.94.g.15.v；P.94.g.18.i；P.94.g.18.v；
P.94.g.25.i；P.94.g.25.v；P.94.l.4.i；P.94.l.4.v；P.94.l.6.i；P.94.l.6.v；P.94.l.11.i；
P.94.l.11.v；P.94.l.14.i；P.94.l.14.v；P.94.l.15.i；P.94.l.15.v；P.94.l.18.i；P.94.l.18.v；
P.94.l.25.i；P.94.l.25.v；P.94.m.4.i；P.94.m.4.v；P.94.m.6.i；P.94.m.6.v；P.94.m.11.i；
P.94.m.11.v；P.94.m.14.i；P.94.m.14.v；P.94.m.15.i；P.94.m.15.v；P.94.m.18.i；
P.94.m.18.v；P.94.m.25.i；P.94.m.25.v；P.94.o.4.i；P.94.o.4.v；P.94.o.6.i；P.94.o.6.v；
P.94.o.11.i；P.94.o.11.v；P.94.o.14.i；P.94.o.14.v；P.94.o.15.i；P.94.o.15.v；P.94.o.18.i；
P.94.o.18.v；P.94.o.25.i；P.94.o.25.v；A.2.a.4.o；A.2.a.4.bh；A.2.a.4.bi；A.2.a.4.bj；
A.2.a.4.bk；A.2.a.11.o；A.2.a.11.bh；A.2.a.11.bi；A.2.a.11.bj；A.2.a.11.bk；A.2.a.15.i；
A.2.a.15.o；A.2.a.15.bh；A.2.a.15.bi；A.2.a.15.bj；A.2.a.15.bk；A.2.a.37.i；A.2.a.37.o；
A.2.a.37.bh；A.2.a.37.bi；A.2.a.37.bj；A.2.a.37.bk；A.2.a.38.i；A.2.a.38.o；A.2.a.38.bh；
A.2.a.38.bi；A.2.a.38.bj；A.2.a.38.bk；A.2.a.39.i；A.2.a.39.o；A.2.a.39.bh；A.2.a.39.bi；
A.2.a.39.bj；A.2.a.39.bk；A.2.a.40.i；A.2.a.40.o；A.2.a.40.bh；A.2.a.40.bi；A.2.a.40.bj；
A.2.a.40.bk；A.2.a.41.i；A.2.a.41.o；A.2.a.41.bh；A.2.a.41.bi；A.2.a.41.bj；A.2.a.41.bk；
A.2.a.42.i；A.2.a.42.o；A.2.a.42.bh；A.2.a.42.bi；A.2.a.42.bj；A.2.a.42.bk；A.2.a.43.i；
A.2.a.43.o；A.2.a.43.bh；A.2.a.43.bi；A.2.a.43.bj；A.2.a.43.bk；
A.3.a.4.o；A.3.a.4.bh；A.3.a.4.bi；A.3.a.4.bj；A.3.a.4.bk；A.3.a.11.o；A.3.a.11.bh；
A.3.a.11.bi；A.3.a.11.bj；A.3.a.11.bk；A.3.a.15.i；A.3.a.15.o；A.3.a.15.bh；A.3.a.15.bi；
A.3.a.15.bj；A.3.a.15.bk；A.3.a.37.i；A.3.a.37.o；A.3.a.37.bh；A.3.a.37.bi；A.3.a.37.bj；
A.3.a.37.bk；A.3.a.38.i；A.3.a.38.o；A.3.a.38.bh；A.3.a.38.bi；A.3.a.38.bj；A.3.a.38.bk；
A.3.a.39.i；A.3.a.39.o；A.3.a.39.bh；A.3.a.39.bi；A.3.a.39.bj；A.3.a.39.bk；A.3.a.40.i；
A.3.a.40.o；A.3.a.40.bh；A.3.a.40.bi；A.3.a.40.bj；A.3.a.40.bk；A.3.a.41.i；A.3.a.41.o；
A.3.a.41.bh；A.3.a.41.bi；A.3.a.41.bj；A.3.a.41.bk；A.3.a.42.i；A.3.a.42.o；A.3.a.42.bh；
A.3.a.42.bi；A.3.a.42.bj；A.3.a.42.bk；A.3.a.43.i；A.3.a.43.o；A.3.a.43.bh；A.3.a.43.bi；
A.3.a.43.bj；A.3.a.43.bk；A.4.a.4.o；A.4.a.4.bh；A.4.a.4.bi；A.4.a.4.bj；A.4.a.4.bk；
A.4.a.11.o；A.4.a.11.bh；A.4.a.11.bi；A.4.a.11.bj；A.4.a.11.bk；A.4.a.15.i；A.4.a.15.o；
A.4.a.15.bh；A.4.a.15.bi；A.4.a.15.bj；A.4.a.15.bk；A.4.a.37.i；A.4.a.37.o；A.4.a.37.bh；
A.4.a.37.bi；A.4.a.37.bj；A.4.a.37.bk；A.4.a.38.i；A.4.a.38.o；A.4.a.38.bh；A.4.a.38.bi；
A.4.a.38.bj；A.4.a.38.bk；A.4.a.39.i；A.4.a.39.o；A.4.a.39.bh；A.4.a.39.bi；A.4.a.39.bj；
A.4.a.39.bk；A.4.a.40.i；A.4.a.40.o；A.4.a.40.bh；A.4.a.40.bi；A.4.a.40.bj；A.4.a.40.bk；
A.4.a.41.i；A.4.a.41.o；A.4.a.41.bh；A.4.a.41.bi；A.4.a.41.bj；A.4.a.41.bk；A.4.a.42.i；
A.4.a.42.o；A.4.a.42.bh；A.4.a.42.bi；A.4.a.42.bj；A.4.a.42.bk；A.4.a.43.i；A.4.a.43.o；
A.4.a.43.bh；A.4.a.43.bi；A.4.a.43.bj；A.4.a.43.bk；A.7.a.4.o；A.7.a.4.bh；A.7.a.4.bi；
A.7.a.4.bj；A.7.a.4.bk；A.7.a.11.o；A.7.a.11.bh；A.7.a.11.bi；A.7.a.11.bj；A.7.a.11.bk；
A.7.a.15.i；A.7.a.15.o；A.7.a.15.bh；A.7.a.15.bi；A.7.a.15.bj；A.7.a.15.bk；A.7.a.37.i；
A.7.a.37.o；A.7.a.37.bh；A.7.a.37.bi；A.7.a.37.bj；A.7.a.37.bk；A.7.a.38.i；A.7.a.38.o；
A.7.a.38.bh；A.7.a.38.bi；A.7.a.38.bj；A.7.a.38.bk；A.7.a.39.i；A.7.a.39.o；A.7.a.39.bh；
A.7.a.39.bi；A.7.a.39.bj；A.7.a.39.bk；A.7.a.40.i；A.7.a.40.o；A.7.a.40.bh；A.7.a.40.bi；
A.7.a.40.bj；A.7.a.40.bk；A.7.a.41.i；A.7.a.41.o；A.7.a.41.bh；A.7.a.41.bi；A.7.a.41.bj；
A.7.a.41.bk；A.7.a.42.i；A.7.a.42.o；A.7.a.42.bh；A.7.a.42.bi；A.7.a.42.bj；A.7.a.42.bk；
A.7.a.43.i；A.7.a.43.o；A.7.a.43.bh；A.7.a.43.bi；A.7.a.43.bj；A.7.a.43.bk；
A.17.a.4.i；A.17.a.4.o；A.17.a.4.bh；A.17.a.4.bi；A.17.a.4.bj；A.17.a.4.bk；A.17.a.11.i；
A.17.a.11.o；A.17.a.11.bh；A.17.a.11.bi；A.17.a.11.bj；A.17.a.11.bk；A.17.a.15.i；
A.17.a.15.o；A.17.a.15.bh；A.17.a.15.bi；A.17.a.15.bj；A.17.a.15.bk；A.17.a.37.i；
A.17.a.37.o；A.17.a.37.bh；A.17.a.37.bi；A.17.a.37.bj；A.17.a.37.bk；A.17.a.38.i；
A.17.a.38.o；A.17.a.38.bh；A.17.a.38.bi；A.17.a.38.bj；A.17.a.38.bk；A.17.a.39.i；
A.17.a.39.o；A.17.a.39.bh；A.17.a.39.bi；A.17.a.39.bj；A.17.a.39.bk；A.17.a.40.i；
A.17.a.40.o；A.17.a.40.bh；A.17.a.40.bi；A.17.a.40.bj；A.17.a.40.bk；A.17.a.41.i；
A.17.a.41.o；A.17.a.41.bh；A.17.a.41.bi；A.17.a.41.bj；A.17.a.41.bk；A.17.a.42.i；
A.17.a.42.o；A.17.a.42.bh；A.17.a.42.bi；A.17.a.42.bj；A.17.a.42.bk；A.17.a.43.i；
A.17.a.43.o；A.17.a.43.bh；A.17.a.43.bi；A.17.a.43.bj；A.17.a.43.bk；A.18.a.4.i；
A.18.a.4.o；A.18.a.4.bh；A.18.a.4.bi；A.18.a.4.bj；A.18.a.4.bk；A.18.a.11.i；
A.18.a.11.o；A.18.a.11.bh；A.18.a.11.bi；A.18.a.11.bj；A.18.a.11.bk；A.18.a.15.i；
A.18.a.15.o；A.18.a.15.bh；A.18.a.15.bi；A.18.a.15.bj；A.18.a.15.bk；A.18.a.37.i；
A.18.a.37.o；A.18.a.37.bh；A.18.a.37.bi；A.18.a.37.bj；A.18.a.37.bk；A.18.a.38.i；
A.18.a.38.o；A.18.a.38.bh；A.18.a.38.bi；A.18.a.38.bj；A.18.a.38.bk；A.18.a.39.i；
A.18.a.39.o；A.18.a.39.bh；A.18.a.39.bi；A.18.a.39.bj；A.18.a.39.bk；A.18.a.40.i；
A.18.a.40.o；A.18.a.40.bh；A.18.a.40.bi；A.18.a.40.bj；A.18.a.40.bk；A.18.a.41.i；
A.18.a.41.o；A.18.a.41.bh；A.18.a.41.bi；A.18.a.41.bj；A.18.a.41.bk；A.18.a.42.i；
A.18.a.42.o；A.18.a.42.bh；A.18.a.42.bi；A.18.a.42.bj；A.18.a.42.bk；A.18.a.43.i；
A.18.a.43.o；A.18.a.43.bh；A.18.a.43.bi；A.18.a.43.bj；A.18.a.43.bk；A.19.a.4.i；
A.19.a.4.o；A.19.a.4.bh；A.19.a.4.bi；A.19.a.4.bj；A.19.a.4.bk；A.19.a.11.i；
A.19.a.11.o；A.19.a.11.bh；A.19.a.11.bi；A.19.a.11.bj；A.19.a.11.bk；A.19.a.15.i；
A.19.a.15.o；A.19.a.15.bh；A.19.a.15.bi；A.19.a.15.bj；A.19.a.15.bk；A.19.a.37.i；
A.19.a.37.o；A.19.a.37.bh；A.19.a.37.bi；A.19.a.37.bj；A.19.a.37.bk；A.19.a.38.i；
A.19.a.38.o；A.19.a.38.bh；A.19.a.38.bi；A.19.a.38.bj；A.19.a.38.bk；A.19.a.39.i；
A.19.a.39.o；A.19.a.39.bh；A.19.a.39.bi；A.19.a.39.bj；A.19.a.39.bk；A.19.a.40.i；
A.19.a.40.o；A.19.a.40.bh；A.19.a.40.bi；A.19.a.40.bj；A.19.a.40.bk；A.19.a.41.i；
A.19.a.41.o；A.19.a.41.bh；A.19.a.41.bi；A.19.a.41.bj；A.19.a.41.bk；A.19.a.42.i；
A.19.a.42.o；A.19.a.42.bh；A.19.a.42.bi；A.19.a.42.bj；A.19.a.42.bk；A.19.a.43.i；
A.19.a.43.o；A.19.a.43.bh；A.19.a.43.bi；A.19.a.43.bj；A.19.a.43.bk；A.97.a.4.i；
A.97.a.4.o；A.97.a.4.bh；A.97.a.4.bi；A.97.a.4.bj；A.97.a.4.bk；A.97.a.11.i；
A.97.a.11.o；A.97.a.11.bh；A.97.a.11.bi；A.97.a.11.bj；A.97.a.11.bk；A.97.a.15.i；
A.97.a.15.o；A.97.a.15.bh；A.97.a.15.bi；A.97.a.15.bj；A.97.a.15.bk；A.97.a.37.i；
A.97.a.37.o；A.97.a.37.bh；A.97.a.37.bi；A.97.a.37.bj；A.97.a.37.bk；A.97.a.38.i；
A.97.a.38.o；A.97.a.38.bh；A.97.a.38.bi；A.97.a.38.bj；A.97.a.38.bk；A.97.a.39.i；
A.97.a.39.o；A.97.a.39.bh；A.97.a.39.bi；A.97.a.39.bj；A.97.a.39.bk；A.97.a.40.i；
A.97.a.40.o；A.97.a.40.bh；A.97.a.40.bi；A.97.a.40.bj；A.97.a.40.bk；A.97.a.41.i；
A.97.a.41.o；A.97.a.41.bh；A.97.a.41.bi；A.97.a.41.bj；A.97.a.41.bk；A.97.a.42.i；
A.97.a.42.o；A.97.a.42.bh；A.97.a.42.bi；A.97.a.42.bj；A.97.a.42.bk；A.97.a.43.i；
A.97.a.43.o；A.97.a.43.bh；A.97.a.43.bi；A.97.a.43.bj；A.97.a.43.bk；A.98.a.4.i；
A.98.a.4.o；A.98.a.4.bh；A.98.a.4.bi；A.98.a.4.bj；A.98.a.4.bk；A.98.a.11.i；
A.98.a.11.o；A.98.a.11.bh；A.98.a.11.bi；A.98.a.11.bj；A.98.a.11.bk；A.98.a.15.i；
A.98.a.15.o；A.98.a.15.bh；A.98.a.15.bi；A.98.a.15.bj；A.98.a.15.bk；A.98.a.37.i；
A.98.a.37.o；A.98.a.37.bh；A.98.a.37.bi；A.98.a.37.bj；A.98.a.37.bk；A.98.a.38.i；
A.98.a.38.o；A.98.a.38.bh；A.98.a.38.bi；A.98.a.38.bj；A.98.a.38.bk；A.98.a.39.i；
A.98.a.39.o；A.98.a.39.bh；A.98.a.39.bi；A.98.a.39.bj；A.98.a.39.bk；A.98.a.40.i；
A.98.a.40.o；A.98.a.40.bh；A.98.a.40.bi；A.98.a.40.bj；A.98.a.40.bk；A.98.a.41.i；
A.98.a.41.o；A.98.a.41.bh；A.98.a.41.bi；A.98.a.41.bj；A.98.a.41.bk；A.98.a.42.i；
A.98.a.42.o；A.98.a.42.bh；A.98.a.42.bi；A.98.a.42.bj；A.98.a.42.bk；A.98.a.43.i；
A.98.a.43.o；A.98.a.43.bh；A.98.a.43.bi；A.98.a.43.bj；A.98.a.43.bk；A.2.a.4.i；
A.3.a.4.i；A.4.a.4.i；A.5.a.4.i；A.6.a.4.i；A.7.a.4.i；A.9.a.4.i；A.10.a.4.i；A.15.a.4.i；
A.100.a.4.i；A.101.a.4.i；A.102.a.4.i；A.103.a.4.i；A.104.a.4.i；A.105.a.4.i；A.106.a.4.i；
A.107.a.4.i；A.108.a.4.i；A.109.a.4.i；A.110.a.4.i；A.111.a.4.i；A.112.a.4.i；A.113.a.4.i；
A.114.a.4.i；A.115.a.4.i；A.116.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.122.a.4.i；A.123.a.4.i；A.124.a.4.i；A.125.a.4.i；A.126.a.4.i；A.127.a.4.i；
A.128.a.4.i；A.129.a.4.i；A.130.a.4.i；A.131.a.4.i；A.132.a.4.i；A.133.a.4.i；A.134.a.4.i；
A.135.a.4.i；A.136.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.143.a.4.i；A.144.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.152.a.4.i；A.153.a.4.i；A.154.a.4.i；A.155.a.4.i；
A.156.a.4.i；A.157.a.4.i；A.158.a.4.i；A.159.a.4.i；A.160.a.4.i；A.161.a.4.i；A.162.a.4.i；
A.163.a.4.i；A.164.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.177.a.4.i；A.178.a.4.i；A.179.a.4.i；A.180.a.4.i；A.181.a.4.i；A.182.a.4.i；A.183.a.4.i；
A.184.a.4.i；A.185.a.4.i；A.186.a.4.i；A.187.a.4.i；A.188.a.4.i；A.189.a.4.i；A.190.a.4.i；
A.191.a.4.i；A.192.a.4.i；A.193.a.4.i；A.194.a.4.i；A.195.a.4.i；A.196.a.4.i；A.197.a.4.i；
A.198.a.4.i；A.199.a.4.i；A.200.a.4.i；A.201.a.4.i；A.202.a.4.i；A.203.a.4.i；A.204.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.214.a.4.i；A.215.a.4.i；A.216.a.4.i；A.217.a.4.i；A.218.a.4.i；
A.219.a.4.i；A.220.a.4.i；A.221.a.4.i；A.222.a.4.i；A.223.a.4.i；A.224.a.4.i；A.225.a.4.i；
A.226.a.4.i；A.227.a.4.i；A.228.a.4.i；A.229.a.4.i；A.230.a.4.i；A.231.a.4.i；A.232.a.4.i；
A.233.a.4.i；A.234.a.4.i；A.235.a.4.i；A.236.a.4.i；A.237.a.4.i；A.238.a.4.i；A.239.a.4.i；
A.240.a.4.i；A.241.a.4.i；A.242.a.4.i；A.243.a.4.i；A.244.a.4.i；A.245.a.4.i；A.246.a.4.i；
A.247.a.4.i；A.248.a.4.i；A.249.a.4.i；A.250.a.4.i；A.251.a.4.i；A.252.a.4.i；A.253.a.4.i；
A.254.a.4.i；A.255.a.4.i；A.256.a.4.i；A.257.a.4.i；A.258.a.4.i；A.259.a.4.i；A.260.a.4.i；
A.261.a.4.i；A.262.a.4.i；A.263.a.4.i；A.264.a.4.i；A.265.a.4.i；A.266.a.4.i；A.267.a.4.i；
A.268.a.4.i；A.269.a.4.i；A.270.a.4.i；A.271.a.4.i；A.272.a.4.i；A.273.a.4.i；A.274.a.4.i；
A.275.a.4.i；A.276.a.4.i；A.277.a.4.i；A.278.a.4.i；A.279.a.4.i；A.280.a.4.i；A.281.a.4.i；
A.282.a.4.i；A.283.a.4.i；A.284.a.4.i；A.285.a.4.i；A.286.a.4.i；A.287.a.4.i；A.288.a.4.i；
A.289.a.4.i；A.290.a.4.i；A.291.a.4.i；A.292.a.4.i；A.293.a.4.i；A.294.a.4.i；A.295.a.4.i；
A.296.a.4.i；A.297.a.4.i；A.298.a.4.i；A.299.a.4.i；A.300.a.4.i；A.301.a.4.i；A.302.a.4.i；
A.303.a.4.i；A.304.a.4.i；A.305.a.4.i；A.306.a.4.i；A.307.a.4.i；A.308.a.4.i；A.309.a.4.i；
A.310.a.4.i；A.311.a.4.i；A.312.a.4.i；A.313.a.4.i；A.314.a.4.i；A.315.a.4.i；A.316.a.4.i；
A.317.a.4.i；A.318.a.4.i；A.319.a.4.i；A.320.a.4.i；A.321.a.4.i；A.323.a.4.i；A.324.a.4.i；
A.325.a.4.i；A.326.a.4.i；A.327.a.4.i；A.328.a.4.i；A.329.a.4.i；A.330.a.4.i；A.331.a.4.i；
A.332.a.4.i；A.333.a.4.i；A.334.a.4.i；A.335.a.4.i；A.336.a.4.i；A.337.a.4.i；A.338.a.4.i；
A.339.a.4.i；A.340.a.4.i；A.341.a.4.i；A.342.a.4.i；A.343.a.4.i；A.344.a.4.i；A.345.a.4.i；
A.346.a.4.i；A.347.a.4.i；A.348.a.4.i；A.349.a.4.i；A.350.a.4.i；A.351.a.4.i；A.352.a.4.i；
A.353.a.4.i；A.354.a.4.i；A.355.a.4.i；A.356.a.4.i；A.357.a.4.i；A.358.a.4.i；A.359.a.4.i；
A.360.a.4.i；A.361.a.4.i；A.362.a.4.i；A.363.a.4.i；A.364.a.4.i；A.365.a.4.i；A.366.a.4.i；
A.367.a.4.i；A.368.a.4.i；A.369.a.4.i；A.370.a.4.i；A.371.a.4.i；A.372.a.4.i；A.373.a.4.i；
A.374.a.4.i；A.375.a.4.i；A.376.a.4.i；A.377.a.4.i；A.378.a.4.i；A.379.a.4.i；A.380.a.4.i；
A.381.a.4.i；A.382.a.4.i；A.383.a.4.i；A.384.a.4.i；A.385.a.4.i；A.386.a.4.i；A.387.a.4.i；
A.388.a.4.i；A.389.a.4.i；A.390.a.4.i；A.391.a.4.i；A.392.a.4.i；A.393.a.4.i；A.394.a.4.i；
A.395.a.4.i；A.396.a.4.i；A.397.a.4.i；A.398.a.4.i；A.399.a.4.i；A.400.a.4.i；A.401.a.4.i；
A.402.a.4.i；A.403.a.4.i；A.404.a.4.i；A.405.a.4.i；A.406.a.4.i；A.407.a.4.i；A.408.a.4.i；
A.409.a.4.i；A.410.a.4.i；A.411.a.4.i；A.412.a.4.i；A.413.a.4.i；A.414.a.4.i；A.415.a.4.i；
A.416.a.4.i；A.417.a.4.i；A.418.a.4.i；A.419.a.4.i；A.420.a.4.i；A.421.a.4.i；A.422.a.4.i；
A.423.a.4.i；A.424.a.4.i；A.425.a.4.i；A.426.a.4.i；A.427.a.4.i；A.428.a.4.i；A.429.a.4.i；
A.430.a.4.i；A.431.a.4.i；A.432.a.4.i；A.433.a.4.i；A.434.a.4.i；A.435.a.4.i；A.436.a.4.i；
A.437.a.4.i；A.438.a.4.i；A.439.a.4.i；A.440.a.4.i；A.441.a.4.i；A.442.a.4.i；A.443.a.4.i；
A.444.a.4.i；A.445.a.4.i；A.446.a.4.i；A.447.a.4.i；A.448.a.4.i；A.449.a.4.i；A.450.a.4.i；
A.451.a.4.i；A.452.a.4.i；A.453.a.4.i；A.454.a.4.i；A.455.a.4.i；A.456.a.4.i；A.457.a.4.i；
A.458.a.4.i；A.459.a.4.i；A.460.a.4.i；A.461.a.4.i；A.462.a.4.i；A.463.a.4.i；A.464.a.4.i；
A.465.a.4.i；A.466.a.4.i；A.467.a.4.i；A.468.a.4.i；A.469.a.4.i；A.470.a.4.i；A.471.a.4.i；
A.472.a.4.i；A.473.a.4.i；A.474.a.4.i；A.475.a.4.i；A.476.a.4.i；A.477.a.4.i；A.478.a.4.i；
A.479.a.4.i；A.480.a.4.i；A.481.a.4.i；A.482.a.4.i；A.483.a.4.i；A.484.a.4.i；A.485.a.4.i；
A.486.a.4.i；A.487.a.4.i；A.488.a.4.i；A.489.a.4.i；A.490.a.4.i；A.491.a.4.i；A.492.a.4.i；
A.493.a.4.i；A.494.a.4.i；A.495.a.4.i；A.496.a.4.i；A.497.a.4.i；A.498.a.4.i；A.499.a.4.i；
A.500.a.4.i；A.501.a.4.i；A.502.a.4.i；A.503.a.4.i；A.504.a.4.i；A.505.a.4.i；A.506.a.4.i；
A.507.a.4.i；A.508.a.4.i；A.509.a.4.i；A.510.a.4.i；A.511.a.4.i；A.512.a.4.i；A.512.a.4.i；
A.513.a.4.i；A.514.a.4.i；A.515.a.4.i；A.516.a.4.i；A.517.a.4.i；A.518.a.4.i；A.519.a.4.i；
A.520.a.4.i；A.521.a.4.i；A.522.a.4.i；A.523.a.4.i；A.524.a.4.i；A.525.a.4.i；A.526.a.4.i；
A.527.a.4.i；A.528.a.4.i；A.529.a.4.i；A.530.a.4.i；A.531.a.4.i；A.532.a.4.i；A.533.a.4.i；
A.534.a.4.i；A.535.a.4.i；A.536.a.4.i；A.537.a.4.i；A.538.a.4.i；A.539.a.4.i；A.540.a.4.i；
A.541.a.4.i；A.542.a.4.i；A.543.a.4.i；A.544.a.4.i；A.545.a.4.i；A.546.a.4.i；A.547.a.4.i；
A.548.a.4.i；A.549.a.4.i；A.550.a.4.i；A.551.a.4.i；A.552.a.4.i；A.553.a.4.i；A.554.a.4.i；
A.555.a.4.i；A.556.a.4.i；A.557.a.4.i；A.558.a.4.i；A.559.a.4.i；A.560.a.4.i；A.561.a.4.i；
A.562.a.4.i；A.563.a.4.i；A.564.a.4.i；A.565.a.4.i；A.566.a.4.i；A.567.a.4.i；A.568.a.4.i；
A.569.a.4.i；A.570.a.4.i；A.571.a.4.i；A.572.a.4.i；A.573.a.4.i；A.574.a.4.i；A.575.a.4.i；
A.576.a.4.i；A.577.a.4.i；A.578.a.4.i；A.579.a.4.i；A.580.a.4.i；A.581.a.4.i；A.582.a.4.i；
A.583.a.4.i；A.584.a.4.i；A.585.a.4.i；A.586.a.4.i；A.587.a.4.i；A.588.a.4.i；A.589.a.4.i；
A.590.a.4.i；A.591.a.4.i；A.592.a.4.i；A.593.a.4.i；A.594.a.4.i；A.595.a.4.i；A.596.a.4.i；
A.597.a.4.i；A.598.a.4.i；A.599.a.4.i；A.600.a.4.i；A.601.a.4.i；A.602.a.4.i；A.603.a.4.i；
A.604.a.4.i；A.605.a.4.i；A.606.a.4.i；A.607.a.4.i；A.608.a.4.i；A.609.a.4.i；A.610.a.4.i；
A.611.a.4.i；A.612.a.4.i；A.613.a.4.i；A.614.a.4.i；A.615.a.4.i；A.616.a.4.i；A.617.a.4.i；
A.618.a.4.i；A.619.a.4.i；A.620.a.4.i；A.621.a.4.i；A.622.a.4.i；A.623.a.4.i；A.624.a.4.i；
A.625.a.4.i；A.626.a.4.i；A.627.a.4.i；A.628.a.4.i；A.629.a.4.i；A.630.a.4.i；A.631.a.4.i；
A.632.a.4.i；A.633.a.4.i；A.634.a.4.i；A.635.a.4.i；A.636.a.4.i；A.637.a.4.i；A.638.a.4.i；
A.639.a.4.i；A.640.a.4.i；A.641.a.4.i；A.642.a.4.i；A.643.a.4.i；A.644.a.4.i；A.645.a.4.i；
A.646.a.4.i；A.647.a.4.i；A.648.a.4.i；A.649.a.4.i；A.650.a.4.i；A.651.a.4.i；A.652.a.4.i；
A.653.a.4.i；A.654.a.4.i；A.655.a.4.i；A.656.a.4.i；A.657.a.4.i；A.658.a.4.i；A.659.a.4.i；
A.660.a.4.i；A.2.a.11.i；A.3.a.11.i；A.4.a.11.i；A.5.a.11.i；A.6.a.11.i；A.7.a.11.i；
A.9.a.11.i；A.10.a.11.i；A.15.a.11.i；A.100.a.11.i；A.101.a.11.i；A.102.a.11.i；
A.103.a.11.i；A.104.a.11.i；A.105.a.11.i；A.106.a.11.i；A.107.a.11.i；A.108.a.11.i；
A.109.a.11.i；A.110.a.11.i；A.111.a.11.i；A.112.a.11.i；A.113.a.11.i；A.114.a.11.i；
A.115.a.11.i；A.116.a.11.i；A.117.a.11.i；A.118.a.11.i；A.119.a.11.i；A.120.a.11.i；
A.121.a.11.i；A.122.a.11.i；A.123.a.11.i；A.124.a.11.i；A.125.a.11.i；A.126.a.11.i；
A.127.a.11.i；A.128.a.11.i；A.129.a.11.i；A.130.a.11.i；A.131.a.11.i；A.132.a.11.i；
A.133.a.11.i；A.134.a.11.i；A.135.a.11.i；A.136.a.11.i；A.137.a.11.i；A.138.a.11.i；
A.139.a.11.i；A.140.a.11.i；A.141.a.11.i；A.142.a.11.i；A.143.a.11.i；A.144.a.11.i；
A.145.a.11.i；A.146.a.11.i；A.147.a.11.i；A.148.a.11.i；A.149.a.11.i；A.150.a.11.i；
A.151.a.11.i；A.152.a.11.i；A.153.a.11.i；A.154.a.11.i；A.155.a.11.i；A.156.a.11.i；
A.157.a.11.i；A.158.a.11.i；A.159.a.11.i；A.160.a.11.i；A.161.a.11.i；A.162.a.11.i；
A.163.a.11.i；A.164.a.11.i；A.165.a.11.i；A.166.a.11.i；A.167.a.11.i；A.168.a.11.i；
A.169.a.11.i；A.170.a.11.i；A.171.a.11.i；A.172.a.11.i；A.173.a.11.i；A.174.a.11.i；
A.175.a.11.i；A.176.a.11.i；A.177.a.11.i；A.178.a.11.i；A.179.a.11.i；A.180.a.11.i；
A.181.a.11.i；A.182.a.11.i；A.183.a.11.i；A.184.a.11.i；A.185.a.11.i；A.186.a.11.i；
A.187.a.11.i；A.188.a.11.i；A.189.a.11.i；A.190.a.11.i；A.191.a.11.i；A.192.a.11.i；
A.193.a.11.i；A.194.a.11.i；A.195.a.11.i；A.196.a.11.i；A.197.a.11.i；A.198.a.11.i；
A.199.a.11.i；A.200.a.11.i；A.201.a.11.i；A.202.a.11.i；A.203.a.11.i；A.204.a.11.i；
A.205.a.11.i；A.206.a.11.i；A.207.a.11.i；A.208.a.11.i；A.209.a.11.i；A.210.a.11.i；
A.211.a.11.i；A.212.a.11.i；A.213.a.11.i；A.214.a.11.i；A.215.a.11.i；A.216.a.11.i；
A.217.a.11.i；A.218.a.11.i；A.219.a.11.i；A.220.a.11.i；A.221.a.11.i；A.222.a.11.i；
A.223.a.11.i；A.224.a.11.i；A.225.a.11.i；A.226.a.11.i；A.227.a.11.i；A.228.a.11.i；
A.229.a.11.i；A.230.a.11.i；A.231.a.11.i；A.232.a.11.i；A.233.a.11.i；A.234.a.11.i；
A.235.a.11.i；A.236.a.11.i；A.237.a.11.i；A.238.a.11.i；A.239.a.11.i；A.240.a.11.i；
A.241.a.11.i；A.242.a.11.i；A.243.a.11.i；A.244.a.11.i；A.245.a.11.i；A.246.a.11.i；
A.247.a.11.i；A.248.a.11.i；A.249.a.11.i；A.250.a.11.i；A.251.a.11.i；A.252.a.11.i；
A.253.a.11.i；A.254.a.11.i；A.255.a.11.i；A.256.a.11.i；A.257.a.11.i；A.258.a.11.i；
A.259.a.11.i；A.260.a.11.i；A.261.a.11.i；A.262.a.11.i；A.263.a.11.i；A.264.a.11.i；
A.265.a.11.i；A.266.a.11.i；A.267.a.11.i；A.268.a.11.i；A.269.a.11.i；A.270.a.11.i；
A.271.a.11.i；A.272.a.11.i；A.273.a.11.i；A.274.a.11.i；A.275.a.11.i；A.276.a.11.i；
A.277.a.11.i；A.278.a.11.i；A.279.a.11.i；A.280.a.11.i；A.281.a.11.i；A.282.a.11.i；
A.283.a.11.i；A.284.a.11.i；A.285.a.11.i；A.286.a.11.i；A.287.a.11.i；A.288.a.11.i；
A.289.a.11.i；A.290.a.11.i；A.291.a.11.i；A.292.a.11.i；A.293.a.11.i；A.294.a.11.i；
A.295.a.11.i；A.296.a.11.i；A.297.a.11.i；A.298.a.11.i；A.299.a.11.i；A.300.a.11.i；
A.301.a.11.i；A.302.a.11.i；A.303.a.11.i；A.304.a.11.i；A.305.a.11.i；A.306.a.11.i；
A.307.a.11.i；A.308.a.11.i；A.309.a.11.i；A.310.a.11.i；A.311.a.11.i；A.312.a.11.i；
A.313.a.11.i；A.314.a.11.i；A.315.a.11.i；A.316.a.11.i；A.317.a.11.i；A.318.a.11.i；
A.319.a.11.i；A.320.a.11.i；A.321.a.11.i；A.323.a.11.i；A.324.a.11.i；A.325.a.11.i；
A.326.a.11.i；A.327.a.11.i；A.328.a.11.i；A.329.a.11.i；A.330.a.11.i；A.331.a.11.i；
A.332.a.11.i；A.333.a.11.i；A.334.a.11.i；A.335.a.11.i；A.336.a.11.i；A.337.a.11.i；
A.338.a.11.i；A.339.a.11.i；A.340.a.11.i；A.341.a.11.i；A.342.a.11.i；A.343.a.11.i；
A.344.a.11.i；A.345.a.11.i；A.346.a.11.i；A.347.a.11.i；A.348.a.11.i；A.349.a.11.i；
A.350.a.11.i；A.351.a.11.i；A.352.a.11.i；A.353.a.11.i；A.354.a.11.i；A.355.a.11.i；
A.356.a.11.i；A.357.a.11.i；A.358.a.11.i；A.359.a.11.i；A.360.a.11.i；A.361.a.11.i；
A.362.a.11.i；A.363.a.11.i；A.364.a.11.i；A.365.a.11.i；A.366.a.11.i；A.367.a.11.i；
A.368.a.11.i；A.369.a.11.i；A.370.a.11.i；A.371.a.11.i；A.372.a.11.i；A.373.a.11.i；
A.374.a.11.i；A.375.a.11.i；A.376.a.11.i；A.377.a.11.i；A.378.a.11.i；A.379.a.11.i；
A.380.a.11.i；A.381.a.11.i；A.382.a.11.i；A.383.a.11.i；A.384.a.11.i；A.385.a.11.i；
A.386.a.11.i；A.387.a.11.i；A.388.a.11.i；A.389.a.11.i；A.390.a.11.i；A.391.a.11.i；
A.392.a.11.i；A.393.a.11.i；A.394.a.11.i；A.395.a.11.i；A.396.a.11.i；A.397.a.11.i；
A.398.a.11.i；A.399.a.11.i；A.400.a.11.i；A.401.a.11.i；A.402.a.11.i；A.403.a.11.i；
A.404.a.11.i；A.405.a.11.i；A.406.a.11.i；A.407.a.11.i；A.408.a.11.i；A.409.a.11.i；
A.410.a.11.i；A.411.a.11.i；A.412.a.11.i；A.413.a.11.i；A.414.a.11.i；A.415.a.11.i；
A.416.a.11.i；A.417.a.11.i；A.418.a.11.i；A.419.a.11.i；A.420.a.11.i；A.421.a.11.i；
A.422.a.11.i；A.423.a.11.i；A.424.a.11.i；A.425.a.11.i；A.426.a.11.i；A.427.a.11.i；
A.428.a.11.i；A.429.a.11.i；A.430.a.11.i；A.431.a.11.i；A.432.a.11.i；A.433.a.11.i；
A.434.a.11.i；A.435.a.11.i；A.436.a.11.i；A.437.a.11.i；A.438.a.11.i；A.439.a.11.i；
A.440.a.11.i；A.441.a.11.i；A.442.a.11.i；A.443.a.11.i；A.444.a.11.i；A.445.a.11.i；
A.446.a.11.i；A.447.a.11.i；A.448.a.11.i；A.449.a.11.i；A.450.a.11.i；A.451.a.11.i；
A.452.a.11.i；A.453.a.11.i；A.454.a.11.i；A.455.a.11.i；A.456.a.11.i；A.457.a.11.i；
A.458.a.11.i；A.459.a.11.i；A.460.a.11.i；A.461.a.11.i；A.462.a.11.i；A.463.a.11.i；
A.464.a.11.i；A.465.a.11.i；A.466.a.11.i；A.467.a.11.i；A.468.a.11.i；A.469.a.11.i；
A.470.a.11.i；A.471.a.11.i；A.472.a.11.i；A.473.a.11.i；A.474.a.11.i；A.475.a.11.i；
A.476.a.11.i；A.477.a.11.i；A.478.a.11.i；A.479.a.11.i；A.480.a.11.i；A.481.a.11.i；
A.482.a.11.i；A.483.a.11.i；A.484.a.11.i；A.485.a.11.i；A.486.a.11.i；A.487.a.11.i；
A.488.a.11.i；A.489.a.11.i；A.490.a.11.i；A.491.a.11.i；A.492.a.11.i；A.493.a.11.i；
A.494.a.11.i；A.495.a.11.i；A.496.a.11.i；A.497.a.11.i；A.498.a.11.i；A.499.a.11.i；
A.500.a.11.i；A.501.a.11.i；A.502.a.11.i；A.503.a.11.i；A.504.a.11.i；A.505.a.11.i；
A.506.a.11.i；A.507.a.11.i；A.508.a.11.i；A.509.a.11.i；A.510.a.11.i；A.511.a.11.i；
A.512.a.11.i；A.512.a.11.i；A.513.a.11.i；A.514.a.11.i；A.515.a.11.i；A.516.a.11.i；
A.517.a.11.i；A.518.a.11.i；A.519.a.11.i；A.520.a.11.i；A.521.a.11.i；A.522.a.11.i；
A.523.a.11.i；A.524.a.11.i；A.525.a.11.i；A.526.a.11.i；A.527.a.11.i；A.528.a.11.i；
A.529.a.11.i；A.530.a.11.i；A.531.a.11.i；A.532.a.11.i；A.533.a.11.i；A.534.a.11.i；
A.535.a.11.i；A.536.a.11.i；A.537.a.11.i；A.538.a.11.i；A.539.a.11.i；A.540.a.11.i；
A.541.a.11.i；A.542.a.11.i；A.543.a.11.i；A.544.a.11.i；A.545.a.11.i；A.546.a.11.i；
A.547.a.11.i；A.548.a.11.i；A.549.a.11.i；A.550.a.11.i；A.551.a.11.i；A.552.a.11.i；
A.553.a.11.i；A.554.a.11.i；A.555.a.11.i；A.556.a.11.i；A.557.a.11.i；A.558.a.11.i；
A.559.a.11.i；A.560.a.11.i；A.561.a.11.i；A.562.a.11.i；A.563.a.11.i；A.564.a.11.i；
A.565.a.11.i；A.566.a.11.i；A.567.a.11.i；A.568.a.11.i；A.569.a.11.i；A.570.a.11.i；
A.571.a.11.i；A.572.a.11.i；A.573.a.11.i；A.574.a.11.i；A.575.a.11.i；A.576.a.11.i；
A.577.a.11.i；A.578.a.11.i；A.579.a.11.i；A.580.a.11.i；A.581.a.11.i；A.582.a.11.i；
A.583.a.11.i；A.584.a.11.i；A.585.a.11.i；A.586.a.11.i；A.587.a.11.i；A.588.a.11.i；
A.589.a.11.i；A.590.a.11.i；A.591.a.11.i；A.592.a.11.i；A.593.a.11.i；A.594.a.11.i；
A.595.a.11.i；A.596.a.11.i；A.597.a.11.i；A.598.a.11.i；A.599.a.11.i；A.600.a.11.i；
A.601.a.11.i；A.602.a.11.i；A.603.a.11.i；A.604.a.11.i；A.605.a.11.i；A.606.a.11.i；
A.607.a.11.i；A.608.a.11.i；A.609.a.11.i；A.610.a.11.i；A.611.a.11.i；A.612.a.11.i；
A.613.a.11.i；A.614.a.11.i；A.615.a.11.i；A.616.a.11.i；A.617.a.11.i；A.618.a.11.i；
A.619.a.11.i；A.620.a.11.i；A.621.a.11.i；A.622.a.11.i；A.623.a.11.i；A.624.a.11.i；
A.625.a.11.i；A.626.a.11.i；A.627.a.11.i；A.628.a.11.i；A.629.a.11.i；A.630.a.11.i；
A.631.a.11.i；A.632.a.11.i；A.633.a.11.i；A.634.a.11.i；A.635.a.11.i；A.636.a.11.i；
A.637.a.11.i；A.638.a.11.i；A.639.a.11.i；A.640.a.11.i；A.641.a.11.i；A.642.a.11.i；
A.643.a.11.i；A.644.a.11.i；A.645.a.11.i；A.646.a.11.i；A.647.a.11.i；A.648.a.11.i；
A.649.a.11.i；A.650.a.11.i；A.651.a.11.i；A.652.a.11.i；A.653.a.11.i；A.654.a.11.i；
A.655.a.11.i；A.656.a.11.i；A.657.a.11.i；A.658.a.11.i；A.659.a.11.i；A.660.a.11.i；
A.2.b.4.i；A.3.b.4.i；A.4.b.4.i；A.5.b.4.i；A.6.b.4.i；A.7.b.4.i；A.9.b.4.i；A.10.b.4.i；
A.15.b.4.i；A.100.b.4.i；A.101.b.4.i；A.102.b.4.i；A.103.b.4.i；A.104.b.4.i；A.105.b.4.i；
A.106.b.4.i；A.107.b.4.i；A.108.b.4.i；A.109.b.4.i；A.110.b.4.i；A.111.b.4.i；A.112.b.4.i；
A.113.b.4.i；A.114.b.4.i；A.115.b.4.i；A.116.b.4.i；A.117.b.4.i；A.118.b.4.i；A.119.b.4.i；
A.120.b.4.i；A.121.b.4.i；A.122.b.4.i；A.123.b.4.i；A.124.b.4.i；A.125.b.4.i；A.126.b.4.i；
A.127.b.4.i；A.128.b.4.i；A.129.b.4.i；A.130.b.4.i；A.131.b.4.i；A.132.b.4.i；A.133.b.4.i；
A.134.b.4.i；A.135.b.4.i；A.136.b.4.i；A.137.b.4.i；A.138.b.4.i；A.139.b.4.i；A.140.b.4.i；
A.141.b.4.i；A.142.b.4.i；A.143.b.4.i；A.144.b.4.i；A.145.b.4.i；A.146.b.4.i；A.147.b.4.i；
A.148.b.4.i；A.149.b.4.i；A.150.b.4.i；A.151.b.4.i；A.152.b.4.i；A.153.b.4.i；A.154.b.4.i；
A.155.b.4.i；A.156.b.4.i；A.157.b.4.i；A.158.b.4.i；A.159.b.4.i；A.160.b.4.i；A.161.b.4.i；
A.162.b.4.i；A.163.b.4.i；A.164.b.4.i；A.165.b.4.i；A.166.b.4.i；A.167.b.4.i；A.168.b.4.i；
A.169.b.4.i；A.170.b.4.i；A.171.b.4.i；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.177.b.4.i；A.178.b.4.i；A.179.b.4.i；A.180.b.4.i；A.181.b.4.i；A.182.b.4.i；
A.183.b.4.i；A.184.b.4.i；A.185.b.4.i；A.186.b.4.i；A.187.b.4.i；A.188.b.4.i；A.189.b.4.i；
A.190.b.4.i；A.191.b.4.i；A.192.b.4.i；A.193.b.4.i；A.194.b.4.i；A.195.b.4.i；A.196.b.4.i；
A.197.b.4.i；A.198.b.4.i；A.199.b.4.i；A.200.b.4.i；A.201.b.4.i；A.202.b.4.i；A.203.b.4.i；
A.204.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.214.b.4.i；A.215.b.4.i；A.216.b.4.i；A.217.b.4.i；
A.218.b.4.i；A.219.b.4.i；A.220.b.4.i；A.221.b.4.i；A.222.b.4.i；A.223.b.4.i；A.224.b.4.i；
A.225.b.4.i；A.226.b.4.i；A.227.b.4.i；A.228.b.4.i；A.229.b.4.i；A.230.b.4.i；A.231.b.4.i；
A.232.b.4.i；A.233.b.4.i；A.234.b.4.i；A.235.b.4.i；A.236.b.4.i；A.237.b.4.i；A.238.b.4.i；
A.239.b.4.i；A.240.b.4.i；A.241.b.4.i；A.242.b.4.i；A.243.b.4.i；A.244.b.4.i；A.245.b.4.i；
A.246.b.4.i；A.247.b.4.i；A.248.b.4.i；A.249.b.4.i；A.250.b.4.i；A.251.b.4.i；A.252.b.4.i；
A.253.b.4.i；A.254.b.4.i；A.255.b.4.i；A.256.b.4.i；A.257.b.4.i；A.258.b.4.i；A.259.b.4.i；
A.260.b.4.i；A.261.b.4.i；A.262.b.4.i；A.263.b.4.i；A.264.b.4.i；A.265.b.4.i；A.266.b.4.i；
A.267.b.4.i；A.268.b.4.i；A.269.b.4.i；A.270.b.4.i；A.271.b.4.i；A.272.b.4.i；A.273.b.4.i；
A.274.b.4.i；A.275.b.4.i；A.276.b.4.i；A.277.b.4.i；A.278.b.4.i；A.279.b.4.i；A.280.b.4.i；
A.281.b.4.i；A.282.b.4.i；A.283.b.4.i；A.284.b.4.i；A.285.b.4.i；A.286.b.4.i；A.287.b.4.i；
A.288.b.4.i；A.289.b.4.i；A.290.b.4.i；A.291.b.4.i；A.292.b.4.i；A.293.b.4.i；A.294.b.4.i；
A.295.b.4.i；A.296.b.4.i；A.297.b.4.i；A.298.b.4.i；A.299.b.4.i；A.300.b.4.i；A.301.b.4.i；
A.302.b.4.i；A.303.b.4.i；A.304.b.4.i；A.305.b.4.i；A.306.b.4.i；A.307.b.4.i；A.308.b.4.i；
A.309.b.4.i；A.310.b.4.i；A.311.b.4.i；A.312.b.4.i；A.313.b.4.i；A.314.b.4.i；A.315.b.4.i；
A.316.b.4.i；A.317.b.4.i；A.318.b.4.i；A.319.b.4.i；A.320.b.4.i；A.321.b.4.i；A.323.b.4.i；
A.324.b.4.i；A.325.b.4.i；A.326.b.4.i；A.327.b.4.i；A.328.b.4.i；A.329.b.4.i；A.330.b.4.i；
A.331.b.4.i；A.332.b.4.i；A.333.b.4.i；A.334.b.4.i；A.335.b.4.i；A.336.b.4.i；A.337.b.4.i；
A.338.b.4.i；A.339.b.4.i；A.340.b.4.i；A.341.b.4.i；A.342.b.4.i；A.343.b.4.i；A.344.b.4.i；
A.345.b.4.i；A.346.b.4.i；A.347.b.4.i；A.348.b.4.i；A.349.b.4.i；A.350.b.4.i；A.351.b.4.i；
A.352.b.4.i；A.353.b.4.i；A.354.b.4.i；A.355.b.4.i；A.356.b.4.i；A.357.b.4.i；A.358.b.4.i；
A.359.b.4.i；A.360.b.4.i；A.361.b.4.i；A.362.b.4.i；A.363.b.4.i；A.364.b.4.i；A.365.b.4.i；
A.366.b.4.i；A.367.b.4.i；A.368.b.4.i；A.369.b.4.i；A.370.b.4.i；A.371.b.4.i；A.372.b.4.i；
A.373.b.4.i；A.374.b.4.i；A.375.b.4.i；A.376.b.4.i；A.377.b.4.i；A.378.b.4.i；A.379.b.4.i；
A.380.b.4.i；A.381.b.4.i；A.382.b.4.i；A.383.b.4.i；A.384.b.4.i；A.385.b.4.i；A.386.b.4.i；
A.387.b.4.i；A.388.b.4.i；A.389.b.4.i；A.390.b.4.i；A.391.b.4.i；A.392.b.4.i；A.393.b.4.i；
A.394.b.4.i；A.395.b.4.i；A.396.b.4.i；A.397.b.4.i；A.398.b.4.i；A.399.b.4.i；A.400.b.4.i；
A.401.b.4.i；A.402.b.4.i；A.403.b.4.i；A.404.b.4.i；A.405.b.4.i；A.406.b.4.i；A.407.b.4.i；
A.408.b.4.i；A.409.b.4.i；A.410.b.4.i；A.411.b.4.i；A.412.b.4.i；A.413.b.4.i；A.414.b.4.i；
A.415.b.4.i；A.416.b.4.i；A.417.b.4.i；A.418.b.4.i；A.419.b.4.i；A.420.b.4.i；A.421.b.4.i；
A.422.b.4.i；A.423.b.4.i；A.424.b.4.i；A.425.b.4.i；A.426.b.4.i；A.427.b.4.i；A.428.b.4.i；
A.429.b.4.i；A.430.b.4.i；A.431.b.4.i；A.432.b.4.i；A.433.b.4.i；A.434.b.4.i；A.435.b.4.i；
A.436.b.4.i；A.437.b.4.i；A.438.b.4.i；A.439.b.4.i；A.440.b.4.i；A.441.b.4.i；A.442.b.4.i；
A.443.b.4.i；A.444.b.4.i；A.445.b.4.i；A.446.b.4.i；A.447.b.4.i；A.448.b.4.i；A.449.b.4.i；
A.450.b.4.i；A.451.b.4.i；A.452.b.4.i；A.453.b.4.i；A.454.b.4.i；A.455.b.4.i；A.456.b.4.i；
A.457.b.4.i；A.458.b.4.i；A.459.b.4.i；A.460.b.4.i；A.461.b.4.i；A.462.b.4.i；A.463.b.4.i；
A.464.b.4.i；A.465.b.4.i；A.466.b.4.i；A.467.b.4.i；A.468.b.4.i；A.469.b.4.i；A.470.b.4.i；
A.471.b.4.i；A.472.b.4.i；A.473.b.4.i；A.474.b.4.i；A.475.b.4.i；A.476.b.4.i；A.477.b.4.i；
A.478.b.4.i；A.479.b.4.i；A.480.b.4.i；A.481.b.4.i；A.482.b.4.i；A.483.b.4.i；A.484.b.4.i；
A.485.b.4.i；A.486.b.4.i；A.487.b.4.i；A.488.b.4.i；A.489.b.4.i；A.490.b.4.i；A.491.b.4.i；
A.492.b.4.i；A.493.b.4.i；A.494.b.4.i；A.495.b.4.i；A.496.b.4.i；A.497.b.4.i；A.498.b.4.i；
A.499.b.4.i；A.500.b.4.i；A.501.b.4.i；A.502.b.4.i；A.503.b.4.i；A.504.b.4.i；A.505.b.4.i；
A.506.b.4.i；A.507.b.4.i；A.508.b.4.i；A.509.b.4.i；A.510.b.4.i；A.511.b.4.i；A.512.b.4.i；
A.512.b.4.i；A.513.b.4.i；A.514.b.4.i；A.515.b.4.i；A.516.b.4.i；A.517.b.4.i；A.518.b.4.i；
A.519.b.4.i；A.520.b.4.i；A.521.b.4.i；A.522.b.4.i；A.523.b.4.i；A.524.b.4.i；A.525.b.4.i；
A.526.b.4.i；A.527.b.4.i；A.528.b.4.i；A.529.b.4.i；A.530.b.4.i；A.531.b.4.i；A.532.b.4.i；
A.533.b.4.i；A.534.b.4.i；A.535.b.4.i；A.536.b.4.i；A.537.b.4.i；A.538.b.4.i；A.539.b.4.i；
A.540.b.4.i；A.541.b.4.i；A.542.b.4.i；A.543.b.4.i；A.544.b.4.i；A.545.b.4.i；A.546.b.4.i；
A.547.b.4.i；A.548.b.4.i；A.549.b.4.i；A.550.b.4.i；A.551.b.4.i；A.552.b.4.i；A.553.b.4.i；
A.554.b.4.i；A.555.b.4.i；A.556.b.4.i；A.557.b.4.i；A.558.b.4.i；A.559.b.4.i；A.560.b.4.i；
A.561.b.4.i；A.562.b.4.i；A.563.b.4.i；A.564.b.4.i；A.565.b.4.i；A.566.b.4.i；A.567.b.4.i；
A.568.b.4.i；A.569.b.4.i；A.570.b.4.i；A.571.b.4.i；A.572.b.4.i；A.573.b.4.i；A.574.b.4.i；
A.575.b.4.i；A.576.b.4.i；A.577.b.4.i；A.578.b.4.i；A.579.b.4.i；A.580.b.4.i；A.581.b.4.i；
A.582.b.4.i；A.583.b.4.i；A.584.b.4.i；A.585.b.4.i；A.586.b.4.i；A.587.b.4.i；A.588.b.4.i；
A.589.b.4.i；A.590.b.4.i；A.591.b.4.i；A.592.b.4.i；A.593.b.4.i；A.594.b.4.i；A.595.b.4.i；
A.596.b.4.i；A.597.b.4.i；A.598.b.4.i；A.599.b.4.i；A.600.b.4.i；A.601.b.4.i；A.602.b.4.i；
A.603.b.4.i；A.604.b.4.i；A.605.b.4.i；A.606.b.4.i；A.607.b.4.i；A.608.b.4.i；A.609.b.4.i；
A.610.b.4.i；A.611.b.4.i；A.612.b.4.i；A.613.b.4.i；A.614.b.4.i；A.615.b.4.i；A.616.b.4.i；
A.617.b.4.i；A.618.b.4.i；A.619.b.4.i；A.620.b.4.i；A.621.b.4.i；A.622.b.4.i；A.623.b.4.i；
A.624.b.4.i；A.625.b.4.i；A.626.b.4.i；A.627.b.4.i；A.628.b.4.i；A.629.b.4.i；A.630.b.4.i；
A.631.b.4.i；A.632.b.4.i；A.633.b.4.i；A.634.b.4.i；A.635.b.4.i；A.636.b.4.i；A.637.b.4.i；
A.638.b.4.i；A.639.b.4.i；A.640.b.4.i；A.641.b.4.i；A.642.b.4.i；A.643.b.4.i；A.644.b.4.i；
A.645.b.4.i；A.646.b.4.i；A.647.b.4.i；A.648.b.4.i；A.649.b.4.i；A.650.b.4.i；A.651.b.4.i；
A.652.b.4.i；A.653.b.4.i；A.654.b.4.i；A.655.b.4.i；A.656.b.4.i；A.657.b.4.i；A.658.b.4.i；
A.659.b.4.i；A.660.b.4.i；A.2.b.11.i；A.3.b.11.i；A.4.b.11.i；A.5.b.11.i；A.6.b.11.i；
A.7.b.11.i；A.9.b.11.i；A.10.b.11.i；A.15.b.11.i；A.100.b.11.i；A.101.b.11.i；
A.102.b.11.i；A.103.b.11.i；A.104.b.11.i；A.105.b.11.i；A.106.b.11.i；A.107.b.11.i；
A.108.b.11.i；A.109.b.11.i；A.110.b.11.i；A.111.b.11.i；A.112.b.11.i；A.113.b.11.i；
A.114.b.11.i；A.115.b.11.i；A.116.b.11.i；A.117.b.11.i；A.118.b.11.i；A.119.b.11.i；
A.120.b.11.i；A.121.b.11.i；A.122.b.11.i；A.123.b.11.i；A.124.b.11.i；A.125.b.11.i；
A.126.b.11.i；A.127.b.11.i；A.128.b.11.i；A.129.b.11.i；A.130.b.11.i；A.131.b.11.i；
A.132.b.11.i；A.133.b.11.i；A.134.b.11.i；A.135.b.11.i；A.136.b.11.i；A.137.b.11.i；
A.138.b.11.i；A.139.b.11.i；A.140.b.11.i；A.141.b.11.i；A.142.b.11.i；A.143.b.11.i；
A.144.b.11.i；A.145.b.11.i；A.146.b.11.i；A.147.b.11.i；A.148.b.11.i；A.149.b.11.i；
A.150.b.11.i；A.151.b.11.i；A.152.b.11.i；A.153.b.11.i；A.154.b.11.i；A.155.b.11.i；
A.156.b.11.i；A.157.b.11.i；A.158.b.11.i；A.159.b.11.i；A.160.b.11.i；A.161.b.11.i；
A.162.b.11.i；A.163.b.11.i；A.164.b.11.i；A.165.b.11.i；A.166.b.11.i；A.167.b.11.i；
A.168.b.11.i；A.169.b.11.i；A.170.b.11.i；A.171.b.11.i；A.172.b.11.i；A.173.b.11.i；
A.174.b.11.i；A.175.b.11.i；A.176.b.11.i；A.177.b.11.i；A.178.b.11.i；A.179.b.11.i；
A.180.b.11.i；A.181.b.11.i；A.182.b.11.i；A.183.b.11.i；A.184.b.11.i；A.185.b.11.i；
A.186.b.11.i；A.187.b.11.i；A.188.b.11.i；A.189.b.11.i；A.190.b.11.i；A.191.b.11.i；
A.192.b.11.i；A.193.b.11.i；A.194.b.11.i；A.195.b.11.i；A.196.b.11.i；A.197.b.11.i；
A.198.b.11.i；A.199.b.11.i；A.200.b.11.i；A.201.b.11.i；A.202.b.11.i；A.203.b.11.i；
A.204.b.11.i；A.205.b.11.i；A.206.b.11.i；A.207.b.11.i；A.208.b.11.i；A.209.b.11.i；
A.210.b.11.i；A.211.b.11.i；A.212.b.11.i；A.213.b.11.i；A.214.b.11.i；A.215.b.11.i；
A.216.b.11.i；A.217.b.11.i；A.218.b.11.i；A.219.b.11.i；A.220.b.11.i；A.221.b.11.i；
A.222.b.11.i；A.223.b.11.i；A.224.b.11.i；A.225.b.11.i；A.226.b.11.i；A.227.b.11.i；
A.228.b.11.i；A.229.b.11.i；A.230.b.11.i；A.231.b.11.i；A.232.b.11.i；A.233.b.11.i；
A.234.b.11.i；A.235.b.11.i；A.236.b.11.i；A.237.b.11.i；A.238.b.11.i；A.239.b.11.i；
A.240.b.11.i；A.241.b.11.i；A.242.b.11.i；A.243.b.11.i；A.244.b.11.i；A.245.b.11.i；
A.246.b.11.i；A.247.b.11.i；A.248.b.11.i；A.249.b.11.i；A.250.b.11.i；A.251.b.11.i；
A.252.b.11.i；A.253.b.11.i；A.254.b.11.i；A.255.b.11.i；A.256.b.11.i；A.257.b.11.i；
A.258.b.11.i；A.259.b.11.i；A.260.b.11.i；A.261.b.11.i；A.262.b.11.i；A.263.b.11.i；
A.264.b.11.i；A.265.b.11.i；A.266.b.11.i；A.267.b.11.i；A.268.b.11.i；A.269.b.11.i；
A.270.b.11.i；A.271.b.11.i；A.272.b.11.i；A.273.b.11.i；A.274.b.11.i；A.275.b.11.i；
A.276.b.11.i；A.277.b.11.i；A.278.b.11.i；A.279.b.11.i；A.280.b.11.i；A.281.b.11.i；
A.282.b.11.i；A.283.b.11.i；A.284.b.11.i；A.285.b.11.i；A.286.b.11.i；A.287.b.11.i；
A.288.b.11.i；A.289.b.11.i；A.290.b.11.i；A.291.b.11.i；A.292.b.11.i；A.293.b.11.i；
A.294.b.11.i；A.295.b.11.i；A.296.b.11.i；A.297.b.11.i；A.298.b.11.i；A.299.b.11.i；
A.300.b.11.i；A.301.b.11.i；A.302.b.11.i；A.303.b.11.i；A.304.b.11.i；A.305.b.11.i；
A.306.b.11.i；A.307.b.11.i；A.308.b.11.i；A.309.b.11.i；A.310.b.11.i；A.311.b.11.i；
A.312.b.11.i；A.313.b.11.i；A.314.b.11.i；A.315.b.11.i；A.316.b.11.i；A.317.b.11.i；
A.318.b.11.i；A.319.b.11.i；A.320.b.11.i；A.321.b.11.i；A.323.b.11.i；A.324.b.11.i；
A.325.b.11.i；A.326.b.11.i；A.327.b.11.i；A.328.b.11.i；A.329.b.11.i；A.330.b.11.i；
A.331.b.11.i；A.332.b.11.i；A.333.b.11.i；A.334.b.11.i；A.335.b.11.i；A.336.b.11.i；
A.337.b.11.i；A.338.b.11.i；A.339.b.11.i；A.340.b.11.i；A.341.b.11.i；A.342.b.11.i；
A.343.b.11.i；A.344.b.11.i；A.345.b.11.i；A.346.b.11.i；A.347.b.11.i；A.348.b.11.i；
A.349.b.11.i；A.350.b.11.i；A.351.b.11.i；A.352.b.11.i；A.353.b.11.i；A.354.b.11.i；
A.355.b.11.i；A.356.b.11.i；A.357.b.11.i；A.358.b.11.i；A.359.b.11.i；A.360.b.11.i；
A.361.b.11.i；A.362.b.11.i；A.363.b.11.i；A.364.b.11.i；A.365.b.11.i；A.366.b.11.i；
A.367.b.11.i；A.368.b.11.i；A.369.b.11.i；A.370.b.11.i；A.371.b.11.i；A.372.b.11.i；
A.373.b.11.i；A.374.b.11.i；A.375.b.11.i；A.376.b.11.i；A.377.b.11.i；A.378.b.11.i；
A.379.b.11.i；A.380.b.11.i；A.381.b.11.i；A.382.b.11.i；A.383.b.11.i；A.384.b.11.i；
A.385.b.11.i；A.386.b.11.i；A.387.b.11.i；A.388.b.11.i；A.389.b.11.i；A.390.b.11.i；
A.391.b.11.i；A.392.b.11.i；A.393.b.11.i；A.394.b.11.i；A.395.b.11.i；A.396.b.11.i；
A.397.b.11.i；A.398.b.11.i；A.399.b.11.i；A.400.b.11.i；A.401.b.11.i；A.402.b.11.i；
A.403.b.11.i；A.404.b.11.i；A.405.b.11.i；A.406.b.11.i；A.407.b.11.i；A.408.b.11.i；
A.409.b.11.i；A.410.b.11.i；A.411.b.11.i；A.412.b.11.i；A.413.b.11.i；A.414.b.11.i；
A.415.b.11.i；A.416.b.11.i；A.417.b.11.i；A.418.b.11.i；A.419.b.11.i；A.420.b.11.i；
A.421.b.11.i；A.422.b.11.i；A.423.b.11.i；A.424.b.11.i；A.425.b.11.i；A.426.b.11.i；
A.427.b.11.i；A.428.b.11.i；A.429.b.11.i；A.430.b.11.i；A.431.b.11.i；A.432.b.11.i；
A.433.b.11.i；A.434.b.11.i；A.435.b.11.i；A.436.b.11.i；A.437.b.11.i；A.438.b.11.i；
A.439.b.11.i；A.440.b.11.i；A.441.b.11.i；A.442.b.11.i；A.443.b.11.i；A.444.b.11.i；
A.445.b.11.i；A.446.b.11.i；A.447.b.11.i；A.448.b.11.i；A.449.b.11.i；A.450.b.11.i；
A.451.b.11.i；A.452.b.11.i；A.453.b.11.i；A.454.b.11.i；A.455.b.11.i；A.456.b.11.i；
A.457.b.11.i；A.458.b.11.i；A.459.b.11.i；A.460.b.11.i；A.461.b.11.i；A.462.b.11.i；
A.463.b.11.i；A.464.b.11.i；A.465.b.11.i；A.466.b.11.i；A.467.b.11.i；A.468.b.11.i；
A.469.b.11.i；A.470.b.11.i；A.471.b.11.i；A.472.b.11.i；A.473.b.11.i；A.474.b.11.i；
A.475.b.11.i；A.476.b.11.i；A.477.b.11.i；A.478.b.11.i；A.479.b.11.i；A.480.b.11.i；
A.481.b.11.i；A.482.b.11.i；A.483.b.11.i；A.484.b.11.i；A.485.b.11.i；A.486.b.11.i；
A.487.b.11.i；A.488.b.11.i；A.489.b.11.i；A.490.b.11.i；A.491.b.11.i；A.492.b.11.i；
A.493.b.11.i；A.494.b.11.i；A.495.b.11.i；A.496.b.11.i；A.497.b.11.i；A.498.b.11.i；
A.499.b.11.i；A.500.b.11.i；A.501.b.11.i；A.502.b.11.i；A.503.b.11.i；A.504.b.11.i；
A.505.b.11.i；A.506.b.11.i；A.507.b.11.i；A.508.b.11.i；A.509.b.11.i；A.510.b.11.i；
A.511.b.11.i；A.512.b.11.i；A.512.b.11.i；A.513.b.11.i；A.514.b.11.i；A.515.b.11.i；
A.516.b.11.i；A.517.b.11.i；A.518.b.11.i；A.519.b.11.i；A.520.b.11.i；A.521.b.11.i；
A.522.b.11.i；A.523.b.11.i；A.524.b.11.i；A.525.b.11.i；A.526.b.11.i；A.527.b.11.i；
A.528.b.11.i；A.529.b.11.i；A.530.b.11.i；A.531.b.11.i；A.532.b.11.i；A.533.b.11.i；
A.534.b.11.i；A.535.b.11.i；A.536.b.11.i；A.537.b.11.i；A.538.b.11.i；A.539.b.11.i；
A.540.b.11.i；A.541.b.11.i；A.542.b.11.i；A.543.b.11.i；A.544.b.11.i；A.545.b.11.i；
A.546.b.11.i；A.547.b.11.i；A.548.b.11.i；A.549.b.11.i；A.550.b.11.i；A.551.b.11.i；
A.552.b.11.i；A.553.b.11.i；A.554.b.11.i；A.555.b.11.i；A.556.b.11.i；A.557.b.11.i；
A.558.b.11.i；A.559.b.11.i；A.560.b.11.i；A.561.b.11.i；A.562.b.11.i；A.563.b.11.i；
A.564.b.11.i；A.565.b.11.i；A.566.b.11.i；A.567.b.11.i；A.568.b.11.i；A.569.b.11.i；
A.570.b.11.i；A.571.b.11.i；A.572.b.11.i；A.573.b.11.i；A.574.b.11.i；A.575.b.11.i；
A.576.b.11.i；A.577.b.11.i；A.578.b.11.i；A.579.b.11.i；A.580.b.11.i；A.581.b.11.i；
A.582.b.11.i；A.583.b.11.i；A.584.b.11.i；A.585.b.11.i；A.586.b.11.i；A.587.b.11.i；
A.588.b.11.i；A.589.b.11.i；A.590.b.11.i；A.591.b.11.i；A.592.b.11.i；A.593.b.11.i；
A.594.b.11.i；A.595.b.11.i；A.596.b.11.i；A.597.b.11.i；A.598.b.11.i；A.599.b.11.i；
A.600.b.11.i；A.601.b.11.i；A.602.b.11.i；A.603.b.11.i；A.604.b.11.i；A.605.b.11.i；
A.606.b.11.i；A.607.b.11.i；A.608.b.11.i；A.609.b.11.i；A.610.b.11.i；A.611.b.11.i；
A.612.b.11.i；A.613.b.11.i；A.614.b.11.i；A.615.b.11.i；A.616.b.11.i；A.617.b.11.i；
A.618.b.11.i；A.619.b.11.i；A.620.b.11.i；A.621.b.11.i；A.622.b.11.i；A.623.b.11.i；
A.624.b.11.i；A.625.b.11.i；A.626.b.11.i；A.627.b.11.i；A.628.b.11.i；A.629.b.11.i；
A.630.b.11.i；A.631.b.11.i；A.632.b.11.i；A.633.b.11.i；A.634.b.11.i；A.635.b.11.i；
A.636.b.11.i；A.637.b.11.i；A.638.b.11.i；A.639.b.11.i；A.640.b.11.i；A.641.b.11.i；
A.642.b.11.i；A.643.b.11.i；A.644.b.11.i；A.645.b.11.i；A.646.b.11.i；A.647.b.11.i；
A.648.b.11.i；A.649.b.11.i；A.650.b.11.i；A.651.b.11.i；A.652.b.11.i；A.653.b.11.i；
A.654.b.11.i；A.655.b.11.i；A.656.b.11.i；A.657.b.11.i；A.658.b.11.i；A.659.b.11.i；
A.660.b.11.i；A.2.x.4.i；A.3.x.4.i；A.4.x.4.i；A.5.x.4.i；A.6.x.4.i；A.7.x.4.i；A.9.x.4.i；
A.10.x.4.i；A.15.x.4.i；A.100.x.4.i；A.101.x.4.i；A.102.x.4.i；A.103.x.4.i；A.104.x.4.i；
A.105.x.4.i；A.106.x.4.i；A.107.x.4.i；A.108.x.4.i；A.109.x.4.i；A.110.x.4.i；A.111.x.4.i；
A.112.x.4.i；A.113.x.4.i；A.114.x.4.i；A.115.x.4.i；A.116.x.4.i；A.117.x.4.i；A.118.x.4.i；
A.119.x.4.i；A.120.x.4.i；A.121.x.4.i；A.122.x.4.i；A.123.x.4.i；A.124.x.4.i；A.125.x.4.i；
A.126.x.4.i；A.127.x.4.i；A.128.x.4.i；A.129.x.4.i；A.130.x.4.i；A.131.x.4.i；A.132.x.4.i；
A.133.x.4.i；A.134.x.4.i；A.135.x.4.i；A.136.x.4.i；A.137.x.4.i；A.138.x.4.i；A.139.x.4.i；
A.140.x.4.i；A.141.x.4.i；A.142.x.4.i；A.143.x.4.i；A.144.x.4.i；A.145.x.4.i；A.146.x.4.i；
A.147.x.4.i；A.148.x.4.i；A.149.x.4.i；A.150.x.4.i；A.151.x.4.i；A.152.x.4.i；A.153.x.4.i；
A.154.x.4.i；A.155.x.4.i；A.156.x.4.i；A.157.x.4.i；A.158.x.4.i；A.159.x.4.i；A.160.x.4.i；
A.161.x.4.i；A.162.x.4.i；A.163.x.4.i；A.164.x.4.i；A.165.x.4.i；A.166.x.4.i；A.167.x.4.i；
A.168.x.4.i；A.169.x.4.i；A.170.x.4.i；A.171.x.4.i；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.177.x.4.i；A.178.x.4.i；A.179.x.4.i；A.180.x.4.i；A.181.x.4.i；
A.182.x.4.i；A.183.x.4.i；A.184.x.4.i；A.185.x.4.i；A.186.x.4.i；A.187.x.4.i；A.188.x.4.i；
A.189.x.4.i；A.190.x.4.i；A.191.x.4.i；A.192.x.4.i；A.193.x.4.i；A.194.x.4.i；A.195.x.4.i；
A.196.x.4.i；A.197.x.4.i；A.198.x.4.i；A.199.x.4.i；A.200.x.4.i；A.201.x.4.i；A.202.x.4.i；
A.203.x.4.i；A.204.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.214.x.4.i；A.215.x.4.i；A.216.x.4.i；
A.217.x.4.i；A.218.x.4.i；A.219.x.4.i；A.220.x.4.i；A.221.x.4.i；A.222.x.4.i；A.223.x.4.i；
A.224.x.4.i；A.225.x.4.i；A.226.x.4.i；A.227.x.4.i；A.228.x.4.i；A.229.x.4.i；A.230.x.4.i；
A.231.x.4.i；A.232.x.4.i；A.233.x.4.i；A.234.x.4.i；A.235.x.4.i；A.236.x.4.i；A.237.x.4.i；
A.238.x.4.i；A.239.x.4.i；A.240.x.4.i；A.241.x.4.i；A.242.x.4.i；A.243.x.4.i；A.244.x.4.i；
A.245.x.4.i；A.246.x.4.i；A.247.x.4.i；A.248.x.4.i；A.249.x.4.i；A.250.x.4.i；A.251.x.4.i；
A.252.x.4.i；A.253.x.4.i；A.254.x.4.i；A.255.x.4.i；A.256.x.4.i；A.257.x.4.i；A.258.x.4.i；
A.259.x.4.i；A.260.x.4.i；A.261.x.4.i；A.262.x.4.i；A.263.x.4.i；A.264.x.4.i；A.265.x.4.i；
A.266.x.4.i；A.267.x.4.i；A.268.x.4.i；A.269.x.4.i；A.270.x.4.i；A.271.x.4.i；A.272.x.4.i；
A.273.x.4.i；A.274.x.4.i；A.275.x.4.i；A.276.x.4.i；A.277.x.4.i；A.278.x.4.i；A.279.x.4.i；
A.280.x.4.i；A.281.x.4.i；A.282.x.4.i；A.283.x.4.i；A.284.x.4.i；A.285.x.4.i；A.286.x.4.i；
A.287.x.4.i；A.288.x.4.i；A.289.x.4.i；A.290.x.4.i；A.291.x.4.i；A.292.x.4.i；A.293.x.4.i；
A.294.x.4.i；A.295.x.4.i；A.296.x.4.i；A.297.x.4.i；A.298.x.4.i；A.299.x.4.i；A.300.x.4.i；
A.301.x.4.i；A.302.x.4.i；A.303.x.4.i；A.304.x.4.i；A.305.x.4.i；A.306.x.4.i；A.307.x.4.i；
A.308.x.4.i；A.309.x.4.i；A.310.x.4.i；A.311.x.4.i；A.312.x.4.i；A.313.x.4.i；A.314.x.4.i；
A.315.x.4.i；A.316.x.4.i；A.317.x.4.i；A.318.x.4.i；A.319.x.4.i；A.320.x.4.i；A.321.x.4.i；
A.323.x.4.i；A.324.x.4.i；A.325.x.4.i；A.326.x.4.i；A.327.x.4.i；A.328.x.4.i；A.329.x.4.i；
A.330.x.4.i；A.331.x.4.i；A.332.x.4.i；A.333.x.4.i；A.334.x.4.i；A.335.x.4.i；A.336.x.4.i；
A.337.x.4.i；A.338.x.4.i；A.339.x.4.i；A.340.x.4.i；A.341.x.4.i；A.342.x.4.i；A.343.x.4.i；
A.344.x.4.i；A.345.x.4.i；A.346.x.4.i；A.347.x.4.i；A.348.x.4.i；A.349.x.4.i；A.350.x.4.i；
A.351.x.4.i；A.352.x.4.i；A.353.x.4.i；A.354.x.4.i；A.355.x.4.i；A.356.x.4.i；A.357.x.4.i；
A.358.x.4.i；A.359.x.4.i；A.360.x.4.i；A.361.x.4.i；A.362.x.4.i；A.363.x.4.i；A.364.x.4.i；
A.365.x.4.i；A.366.x.4.i；A.367.x.4.i；A.368.x.4.i；A.369.x.4.i；A.370.x.4.i；A.371.x.4.i；
A.372.x.4.i；A.373.x.4.i；A.374.x.4.i；A.375.x.4.i；A.376.x.4.i；A.377.x.4.i；A.378.x.4.i；
A.379.x.4.i；A.380.x.4.i；A.381.x.4.i；A.382.x.4.i；A.383.x.4.i；A.384.x.4.i；A.385.x.4.i；
A.386.x.4.i；A.387.x.4.i；A.388.x.4.i；A.389.x.4.i；A.390.x.4.i；A.391.x.4.i；A.392.x.4.i；
A.393.x.4.i；A.394.x.4.i；A.395.x.4.i；A.396.x.4.i；A.397.x.4.i；A.398.x.4.i；A.399.x.4.i；
A.400.x.4.i；A.401.x.4.i；A.402.x.4.i；A.403.x.4.i；A.404.x.4.i；A.405.x.4.i；A.406.x.4.i；
A.407.x.4.i；A.408.x.4.i；A.409.x.4.i；A.410.x.4.i；A.411.x.4.i；A.412.x.4.i；A.413.x.4.i；
A.414.x.4.i；A.415.x.4.i；A.416.x.4.i；A.417.x.4.i；A.418.x.4.i；A.419.x.4.i；A.420.x.4.i；
A.421.x.4.i；A.422.x.4.i；A.423.x.4.i；A.424.x.4.i；A.425.x.4.i；A.426.x.4.i；A.427.x.4.i；
A.428.x.4.i；A.429.x.4.i；A.430.x.4.i；A.431.x.4.i；A.432.x.4.i；A.433.x.4.i；A.434.x.4.i；
A.435.x.4.i；A.436.x.4.i；A.437.x.4.i；A.438.x.4.i；A.439.x.4.i；A.440.x.4.i；A.441.x.4.i；
A.442.x.4.i；A.443.x.4.i；A.444.x.4.i；A.445.x.4.i；A.446.x.4.i；A.447.x.4.i；A.448.x.4.i；
A.449.x.4.i；A.450.x.4.i；A.451.x.4.i；A.452.x.4.i；A.453.x.4.i；A.454.x.4.i；A.455.x.4.i；
A.456.x.4.i；A.457.x.4.i；A.458.x.4.i；A.459.x.4.i；A.460.x.4.i；A.461.x.4.i；A.462.x.4.i；
A.463.x.4.i；A.464.x.4.i；A.465.x.4.i；A.466.x.4.i；A.467.x.4.i；A.468.x.4.i；A.469.x.4.i；
A.470.x.4.i；A.471.x.4.i；A.472.x.4.i；A.473.x.4.i；A.474.x.4.i；A.475.x.4.i；A.476.x.4.i；
A.477.x.4.i；A.478.x.4.i；A.479.x.4.i；A.480.x.4.i；A.481.x.4.i；A.482.x.4.i；A.483.x.4.i；
A.484.x.4.i；A.485.x.4.i；A.486.x.4.i；A.487.x.4.i；A.488.x.4.i；A.489.x.4.i；A.490.x.4.i；
A.491.x.4.i；A.492.x.4.i；A.493.x.4.i；A.494.x.4.i；A.495.x.4.i；A.496.x.4.i；A.497.x.4.i；
A.498.x.4.i；A.499.x.4.i；A.500.x.4.i；A.501.x.4.i；A.502.x.4.i；A.503.x.4.i；A.504.x.4.i；
A.505.x.4.i；A.506.x.4.i；A.507.x.4.i；A.508.x.4.i；A.509.x.4.i；A.510.x.4.i；A.511.x.4.i；
A.512.x.4.i；A.512.x.4.i；A.513.x.4.i；A.514.x.4.i；A.515.x.4.i；A.516.x.4.i；A.517.x.4.i；
A.518.x.4.i；A.519.x.4.i；A.520.x.4.i；A.521.x.4.i；A.522.x.4.i；A.523.x.4.i；A.524.x.4.i；
A.525.x.4.i；A.526.x.4.i；A.527.x.4.i；A.528.x.4.i；A.529.x.4.i；A.530.x.4.i；A.531.x.4.i；
A.532.x.4.i；A.533.x.4.i；A.534.x.4.i；A.535.x.4.i；A.536.x.4.i；A.537.x.4.i；A.538.x.4.i；
A.539.x.4.i；A.540.x.4.i；A.541.x.4.i；A.542.x.4.i；A.543.x.4.i；A.544.x.4.i；A.545.x.4.i；
A.546.x.4.i；A.547.x.4.i；A.548.x.4.i；A.549.x.4.i；A.550.x.4.i；A.551.x.4.i；A.552.x.4.i；
A.553.x.4.i；A.554.x.4.i；A.555.x.4.i；A.556.x.4.i；A.557.x.4.i；A.558.x.4.i；A.559.x.4.i；
A.560.x.4.i；A.561.x.4.i；A.562.x.4.i；A.563.x.4.i；A.564.x.4.i；A.565.x.4.i；A.566.x.4.i；
A.567.x.4.i；A.568.x.4.i；A.569.x.4.i；A.570.x.4.i；A.571.x.4.i；A.572.x.4.i；A.573.x.4.i；
A.574.x.4.i；A.575.x.4.i；A.576.x.4.i；A.577.x.4.i；A.578.x.4.i；A.579.x.4.i；A.580.x.4.i；
A.581.x.4.i；A.582.x.4.i；A.583.x.4.i；A.584.x.4.i；A.585.x.4.i；A.586.x.4.i；A.587.x.4.i；
A.588.x.4.i；A.589.x.4.i；A.590.x.4.i；A.591.x.4.i；A.592.x.4.i；A.593.x.4.i；A.594.x.4.i；
A.595.x.4.i；A.596.x.4.i；A.597.x.4.i；A.598.x.4.i；A.599.x.4.i；A.600.x.4.i；A.601.x.4.i；
A.602.x.4.i；A.603.x.4.i；A.604.x.4.i；A.605.x.4.i；A.606.x.4.i；A.607.x.4.i；A.608.x.4.i；
A.609.x.4.i；A.610.x.4.i；A.611.x.4.i；A.612.x.4.i；A.613.x.4.i；A.614.x.4.i；A.615.x.4.i；
A.616.x.4.i；A.617.x.4.i；A.618.x.4.i；A.619.x.4.i；A.620.x.4.i；A.621.x.4.i；A.622.x.4.i；
A.623.x.4.i；A.624.x.4.i；A.625.x.4.i；A.626.x.4.i；A.627.x.4.i；A.628.x.4.i；A.629.x.4.i；
A.630.x.4.i；A.631.x.4.i；A.632.x.4.i；A.633.x.4.i；A.634.x.4.i；A.635.x.4.i；A.636.x.4.i；
A.637.x.4.i；A.638.x.4.i；A.639.x.4.i；A.640.x.4.i；A.641.x.4.i；A.642.x.4.i；A.643.x.4.i；
A.644.x.4.i；A.645.x.4.i；A.646.x.4.i；A.647.x.4.i；A.648.x.4.i；A.649.x.4.i；A.650.x.4.i；
A.651.x.4.i；A.652.x.4.i；A.653.x.4.i；A.654.x.4.i；A.655.x.4.i；A.656.x.4.i；A.657.x.4.i；
A.658.x.4.i；A.659.x.4.i；A.660.x.4.i；A.2.x.11.i；A.3.x.11.i；A.4.x.11.i；A.5.x.11.i；
A.6.x.11.i；A.7.x.11.i；A.9.x.11.i；A.10.x.11.i；A.15.x.11.i；A.100.x.11.i；A.101.x.11.i；
A.102.x.11.i；A.103.x.11.i；A.104.x.11.i；A.105.x.11.i；A.106.x.11.i；A.107.x.11.i；
A.108.x.11.i；A.109.x.11.i；A.110.x.11.i；A.111.x.11.i；A.112.x.11.i；A.113.x.11.i；
A.114.x.11.i；A.115.x.11.i；A.116.x.11.i；A.117.x.11.i；A.118.x.11.i；A.119.x.11.i；
A.120.x.11.i；A.121.x.11.i；A.122.x.11.i；A.123.x.11.i；A.124.x.11.i；A.125.x.11.i；
A.126.x.11.i；A.127.x.11.i；A.128.x.11.i；A.129.x.11.i；A.130.x.11.i；A.131.x.11.i；
A.132.x.11.i；A.133.x.11.i；A.134.x.11.i；A.135.x.11.i；A.136.x.11.i；A.137.x.11.i；
A.138.x.11.i；A.139.x.11.i；A.140.x.11.i；A.141.x.11.i；A.142.x.11.i；A.143.x.11.i；
A.144.x.11.i；A.145.x.11.i；A.146.x.11.i；A.147.x.11.i；A.148.x.11.i；A.149.x.11.i；
A.150.x.11.i；A.151.x.11.i；A.152.x.11.i；A.153.x.11.i；A.154.x.11.i；A.155.x.11.i；
A.156.x.11.i；A.157.x.11.i；A.158.x.11.i；A.159.x.11.i；A.160.x.11.i；A.161.x.11.i；
A.162.x.11.i；A.163.x.11.i；A.164.x.11.i；A.165.x.11.i；A.166.x.11.i；A.167.x.11.i；
A.168.x.11.i；A.169.x.11.i；A.170.x.11.i；A.171.x.11.i；A.172.x.11.i；A.173.x.11.i；
A.174.x.11.i；A.175.x.11.i；A.176.x.11.i；A.177.x.11.i；A.178.x.11.i；A.179.x.11.i；
A.180.x.11.i；A.181.x.11.i；A.182.x.11.i；A.183.x.11.i；A.184.x.11.i；A.185.x.11.i；
A.186.x.11.i；A.187.x.11.i；A.188.x.11.i；A.189.x.11.i；A.190.x.11.i；A.191.x.11.i；
A.192.x.11.i；A.193.x.11.i；A.194.x.11.i；A.195.x.11.i；A.196.x.11.i；A.197.x.11.i；
A.198.x.11.i；A.199.x.11.i；A.200.x.11.i；A.201.x.11.i；A.202.x.11.i；A.203.x.11.i；
A.204.x.11.i；A.205.x.11.i；A.206.x.11.i；A.207.x.11.i；A.208.x.11.i；A.209.x.11.i；
A.210.x.11.i；A.211.x.11.i；A.212.x.11.i；A.213.x.11.i；A.214.x.11.i；A.215.x.11.i；
A.216.x.11.i；A.217.x.11.i；A.218.x.11.i；A.219.x.11.i；A.220.x.11.i；A.221.x.11.i；
A.222.x.11.i；A.223.x.11.i；A.224.x.11.i；A.225.x.11.i；A.226.x.11.i；A.227.x.11.i；
A.228.x.11.i；A.229.x.11.i；A.230.x.11.i；A.231.x.11.i；A.232.x.11.i；A.233.x.11.i；
A.234.x.11.i；A.235.x.11.i；A.236.x.11.i；A.237.x.11.i；A.238.x.11.i；A.239.x.11.i；
A.240.x.11.i；A.241.x.11.i；A.242.x.11.i；A.243.x.11.i；A.244.x.11.i；A.245.x.11.i；
A.246.x.11.i；A.247.x.11.i；A.248.x.11.i；A.249.x.11.i；A.250.x.11.i；A.251.x.11.i；
A.252.x.11.i；A.253.x.11.i；A.254.x.11.i；A.255.x.11.i；A.256.x.11.i；A.257.x.11.i；
A.258.x.11.i；A.259.x.11.i；A.260.x.11.i；A.261.x.11.i；A.262.x.11.i；A.263.x.11.i；
A.264.x.11.i；A.265.x.11.i；A.266.x.11.i；A.267.x.11.i；A.268.x.11.i；A.269.x.11.i；
A.270.x.11.i；A.271.x.11.i；A.272.x.11.i；A.273.x.11.i；A.274.x.11.i；A.275.x.11.i；
A.276.x.11.i；A.277.x.11.i；A.278.x.11.i；A.279.x.11.i；A.280.x.11.i；A.281.x.11.i；
A.282.x.11.i；A.283.x.11.i；A.284.x.11.i；A.285.x.11.i；A.286.x.11.i；A.287.x.11.i；
A.288.x.11.i；A.289.x.11.i；A.290.x.11.i；A.291.x.11.i；A.292.x.11.i；A.293.x.11.i；
A.294.x.11.i；A.295.x.11.i；A.296.x.11.i；A.297.x.11.i；A.298.x.11.i；A.299.x.11.i；
A.300.x.11.i；A.301.x.11.i；A.302.x.11.i；A.303.x.11.i；A.304.x.11.i；A.305.x.11.i；
A.306.x.11.i；A.307.x.11.i；A.308.x.11.i；A.309.x.11.i；A.310.x.11.i；A.311.x.11.i；
A.312.x.11.i；A.313.x.11.i；A.314.x.11.i；A.315.x.11.i；A.316.x.11.i；A.317.x.11.i；
A.318.x.11.i；A.319.x.11.i；A.320.x.11.i；A.321.x.11.i；A.323.x.11.i；A.324.x.11.i；
A.325.x.11.i；A.326.x.11.i；A.327.x.11.i；A.328.x.11.i；A.329.x.11.i；A.330.x.11.i；
A.331.x.11.i；A.332.x.11.i；A.333.x.11.i；A.334.x.11.i；A.335.x.11.i；A.336.x.11.i；
A.337.x.11.i；A.338.x.11.i；A.339.x.11.i；A.340.x.11.i；A.341.x.11.i；A.342.x.11.i；
A.343.x.11.i；A.344.x.11.i；A.345.x.11.i；A.346.x.11.i；A.347.x.11.i；A.348.x.11.i；
A.349.x.11.i；A.350.x.11.i；A.351.x.11.i；A.352.x.11.i；A.353.x.11.i；A.354.x.11.i；
A.355.x.11.i；A.356.x.11.i；A.357.x.11.i；A.358.x.11.i；A.359.x.11.i；A.360.x.11.i；
A.361.x.11.i；A.362.x.11.i；A.363.x.11.i；A.364.x.11.i；A.365.x.11.i；A.366.x.11.i；
A.367.x.11.i；A.368.x.11.i；A.369.x.11.i；A.370.x.11.i；A.371.x.11.i；A.372.x.11.i；
A.373.x.11.i；A.374.x.11.i；A.375.x.11.i；A.376.x.11.i；A.377.x.11.i；A.378.x.11.i；
A.379.x.11.i；A.380.x.11.i；A.381.x.11.i；A.382.x.11.i；A.383.x.11.i；A.384.x.11.i；
A.385.x.11.i；A.386.x.11.i；A.387.x.11.i；A.388.x.11.i；A.389.x.11.i；A.390.x.11.i；
A.391.x.11.i；A.392.x.11.i；A.393.x.11.i；A.394.x.11.i；A.395.x.11.i；A.396.x.11.i；
A.397.x.11.i；A.398.x.11.i；A.399.x.11.i；A.400.x.11.i；A.401.x.11.i；A.402.x.11.i；
A.403.x.11.i；A.404.x.11.i；A.405.x.11.i；A.406.x.11.i；A.407.x.11.i；A.408.x.11.i；
A.409.x.11.i；A.410.x.11.i；A.411.x.11.i；A.412.x.11.i；A.413.x.11.i；A.414.x.11.i；
A.415.x.11.i；A.416.x.11.i；A.417.x.11.i；A.418.x.11.i；A.419.x.11.i；A.420.x.11.i；
A.421.x.11.i；A.422.x.11.i；A.423.x.11.i；A.424.x.11.i；A.425.x.11.i；A.426.x.11.i；
A.427.x.11.i；A.428.x.11.i；A.429.x.11.i；A.430.x.11.i；A.431.x.11.i；A.432.x.11.i；
A.433.x.11.i；A.434.x.11.i；A.435.x.11.i；A.436.x.11.i；A.437.x.11.i；A.438.x.11.i；
A.439.x.11.i；A.440.x.11.i；A.441.x.11.i；A.442.x.11.i；A.443.x.11.i；A.444.x.11.i；
A.445.x.11.i；A.446.x.11.i；A.447.x.11.i；A.448.x.11.i；A.449.x.11.i；A.450.x.11.i；
A.451.x.11.i；A.452.x.11.i；A.453.x.11.i；A.454.x.11.i；A.455.x.11.i；A.456.x.11.i；
A.457.x.11.i；A.458.x.11.i；A.459.x.11.i；A.460.x.11.i；A.461.x.11.i；A.462.x.11.i；
A.463.x.11.i；A.464.x.11.i；A.465.x.11.i；A.466.x.11.i；A.467.x.11.i；A.468.x.11.i；
A.469.x.11.i；A.470.x.11.i；A.471.x.11.i；A.472.x.11.i；A.473.x.11.i；A.474.x.11.i；
A.475.x.11.i；A.476.x.11.i；A.477.x.11.i；A.478.x.11.i；A.479.x.11.i；A.480.x.11.i；
A.481.x.11.i；A.482.x.11.i；A.483.x.11.i；A.484.x.11.i；A.485.x.11.i；A.486.x.11.i；
A.487.x.11.i；A.488.x.11.i；A.489.x.11.i；A.490.x.11.i；A.491.x.11.i；A.492.x.11.i；
A.493.x.11.i；A.494.x.11.i；A.495.x.11.i；A.496.x.11.i；A.497.x.11.i；A.498.x.11.i；
A.499.x.11.i；A.500.x.11.i；A.501.x.11.i；A.502.x.11.i；A.503.x.11.i；A.504.x.11.i；
A.505.x.11.i；A.506.x.11.i；A.507.x.11.i；A.508.x.11.i；A.509.x.11.i；A.510.x.11.i；
A.511.x.11.i；A.512.x.11.i；A.512.x.11.i；A.513.x.11.i；A.514.x.11.i；A.515.x.11.i；
A.516.x.11.i；A.517.x.11.i；A.518.x.11.i；A.519.x.11.i；A.520.x.11.i；A.521.x.11.i；
A.522.x.11.i；A.523.x.11.i；A.524.x.11.i；A.525.x.11.i；A.526.x.11.i；A.527.x.11.i；
A.528.x.11.i；A.529.x.11.i；A.530.x.11.i；A.531.x.11.i；A.532.x.11.i；A.533.x.11.i；
A.534.x.11.i；A.535.x.11.i；A.536.x.11.i；A.537.x.11.i；A.538.x.11.i；A.539.x.11.i；
A.540.x.11.i；A.541.x.11.i；A.542.x.11.i；A.543.x.11.i；A.544.x.11.i；A.545.x.11.i；
A.546.x.11.i；A.547.x.11.i；A.548.x.11.i；A.549.x.11.i；A.550.x.11.i；A.551.x.11.i；
A.552.x.11.i；A.553.x.11.i；A.554.x.11.i；A.555.x.11.i；A.556.x.11.i；A.557.x.11.i；
A.558.x.11.i；A.559.x.11.i；A.560.x.11.i；A.561.x.11.i；A.562.x.11.i；A.563.x.11.i；
A.564.x.11.i；A.565.x.11.i；A.566.x.11.i；A.567.x.11.i；A.568.x.11.i；A.569.x.11.i；
A.570.x.11.i；A.571.x.11.i；A.572.x.11.i；A.573.x.11.i；A.574.x.11.i；A.575.x.11.i；
A.576.x.11.i；A.577.x.11.i；A.578.x.11.i；A.579.x.11.i；A.580.x.11.i；A.581.x.11.i；
A.582.x.11.i；A.583.x.11.i；A.584.x.11.i；A.585.x.11.i；A.586.x.11.i；A.587.x.11.i；
A.588.x.11.i；A.589.x.11.i；A.590.x.11.i；A.591.x.11.i；A.592.x.11.i；A.593.x.11.i；
A.594.x.11.i；A.595.x.11.i；A.596.x.11.i；A.597.x.11.i；A.598.x.11.i；A.599.x.11.i；
A.600.x.11.i；A.601.x.11.i；A.602.x.11.i；A.603.x.11.i；A.604.x.11.i；A.605.x.11.i；
A.606.x.11.i；A.607.x.11.i；A.608.x.11.i；A.609.x.11.i；A.610.x.11.i；A.611.x.11.i；
A.612.x.11.i；A.613.x.11.i；A.614.x.11.i；A.615.x.11.i；A.616.x.11.i；A.617.x.11.i；
A.618.x.11.i；A.619.x.11.i；A.620.x.11.i；A.621.x.11.i；A.622.x.11.i；A.623.x.11.i；
A.624.x.11.i；A.625.x.11.i；A.626.x.11.i；A.627.x.11.i；A.628.x.11.i；A.629.x.11.i；
A.630.x.11.i；A.631.x.11.i；A.632.x.11.i；A.633.x.11.i；A.634.x.11.i；A.635.x.11.i；
A.636.x.11.i；A.637.x.11.i；A.638.x.11.i；A.639.x.11.i；A.640.x.11.i；A.641.x.11.i；
A.642.x.11.i；A.643.x.11.i；A.644.x.11.i；A.645.x.11.i；A.646.x.11.i；A.647.x.11.i；
A.648.x.11.i；A.649.x.11.i；A.650.x.11.i；A.651.x.11.i；A.652.x.11.i；A.653.x.11.i；
A.654.x.11.i；A.655.x.11.i；A.656.x.11.i；A.657.x.11.i；A.658.x.11.i；A.659.x.11.i；
A.660.x.11.i；A.2.y.4.i；A.3.y.4.i；A.4.y.4.i；A.5.y.4.i；A.6.y.4.i；A.7.y.4.i；A.9.y.4.i；
A.10.y.4.i；A.15.y.4.i；A.100.y.4.i；A.101.y.4.i；A.102.y.4.i；A.103.y.4.i；A.104.y.4.i；
A.105.y.4.i；A.106.y.4.i；A.107.y.4.i；A.108.y.4.i；A.109.y.4.i；A.110.y.4.i；A.111.y.4.i；
A.112.y.4.i；A.113.y.4.i；A.114.y.4.i；A.115.y.4.i；A.116.y.4.i；A.117.y.4.i；A.118.y.4.i；
A.119.y.4.i；A.120.y.4.i；A.121.y.4.i；A.122.y.4.i；A.123.y.4.i；A.124.y.4.i；A.125.y.4.i；
A.126.y.4.i；A.127.y.4.i；A.128.y.4.i；A.129.y.4.i；A.130.y.4.i；A.131.y.4.i；A.132.y.4.i；
A.133.y.4.i；A.134.y.4.i；A.135.y.4.i；A.136.y.4.i；A.137.y.4.i；A.138.y.4.i；A.139.y.4.i；
A.140.y.4.i；A.141.y.4.i；A.142.y.4.i；A.143.y.4.i；A.144.y.4.i；A.145.y.4.i；A.146.y.4.i；
A.147.y.4.i；A.148.y.4.i；A.149.y.4.i；A.150.y.4.i；A.151.y.4.i；A.152.y.4.i；A.153.y.4.i；
A.154.y.4.i；A.155.y.4.i；A.156.y.4.i；A.157.y.4.i；A.158.y.4.i；A.159.y.4.i；A.160.y.4.i；
A.161.y.4.i；A.162.y.4.i；A.163.y.4.i；A.164.y.4.i；A.165.y.4.i；A.166.y.4.i；A.167.y.4.i；
A.168.y.4.i；A.169.y.4.i；A.170.y.4.i；A.171.y.4.i；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.177.y.4.i；A.178.y.4.i；A.179.y.4.i；A.180.y.4.i；A.181.y.4.i；
A.182.y.4.i；A.183.y.4.i；A.184.y.4.i；A.185.y.4.i；A.186.y.4.i；A.187.y.4.i；A.188.y.4.i；
A.189.y.4.i；A.190.y.4.i；A.191.y.4.i；A.192.y.4.i；A.193.y.4.i；A.194.y.4.i；A.195.y.4.i；
A.196.y.4.i；A.197.y.4.i；A.198.y.4.i；A.199.y.4.i；A.200.y.4.i；A.201.y.4.i；A.202.y.4.i；
A.203.y.4.i；A.204.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.214.y.4.i；A.215.y.4.i；A.216.y.4.i；
A.217.y.4.i；A.218.y.4.i；A.219.y.4.i；A.220.y.4.i；A.221.y.4.i；A.222.y.4.i；A.223.y.4.i；
A.224.y.4.i；A.225.y.4.i；A.226.y.4.i；A.227.y.4.i；A.228.y.4.i；A.229.y.4.i；A.230.y.4.i；
A.231.y.4.i；A.232.y.4.i；A.233.y.4.i；A.234.y.4.i；A.235.y.4.i；A.236.y.4.i；A.237.y.4.i；
A.238.y.4.i；A.239.y.4.i；A.240.y.4.i；A.241.y.4.i；A.242.y.4.i；A.243.y.4.i；A.244.y.4.i；
A.245.y.4.i；A.246.y.4.i；A.247.y.4.i；A.248.y.4.i；A.249.y.4.i；A.250.y.4.i；A.251.y.4.i；
A.252.y.4.i；A.253.y.4.i；A.254.y.4.i；A.255.y.4.i；A.256.y.4.i；A.257.y.4.i；A.258.y.4.i；
A.259.y.4.i；A.260.y.4.i；A.261.y.4.i；A.262.y.4.i；A.263.y.4.i；A.264.y.4.i；A.265.y.4.i；
A.266.y.4.i；A.267.y.4.i；A.268.y.4.i；A.269.y.4.i；A.270.y.4.i；A.271.y.4.i；A.272.y.4.i；
A.273.y.4.i；A.274.y.4.i；A.275.y.4.i；A.276.y.4.i；A.277.y.4.i；A.278.y.4.i；A.279.y.4.i；
A.280.y.4.i；A.281.y.4.i；A.282.y.4.i；A.283.y.4.i；A.284.y.4.i；A.285.y.4.i；A.286.y.4.i；
A.287.y.4.i；A.288.y.4.i；A.289.y.4.i；A.290.y.4.i；A.291.y.4.i；A.292.y.4.i；A.293.y.4.i；
A.294.y.4.i；A.295.y.4.i；A.296.y.4.i；A.297.y.4.i；A.298.y.4.i；A.299.y.4.i；A.300.y.4.i；
A.301.y.4.i；A.302.y.4.i；A.303.y.4.i；A.304.y.4.i；A.305.y.4.i；A.306.y.4.i；A.307.y.4.i；
A.308.y.4.i；A.309.y.4.i；A.310.y.4.i；A.311.y.4.i；A.312.y.4.i；A.313.y.4.i；A.314.y.4.i；
A.315.y.4.i；A.316.y.4.i；A.317.y.4.i；A.318.y.4.i；A.319.y.4.i；A.320.y.4.i；A.321.y.4.i；
A.323.y.4.i；A.324.y.4.i；A.325.y.4.i；A.326.y.4.i；A.327.y.4.i；A.328.y.4.i；A.329.y.4.i；
A.330.y.4.i；A.331.y.4.i；A.332.y.4.i；A.333.y.4.i；A.334.y.4.i；A.335.y.4.i；A.336.y.4.i；
A.337.y.4.i；A.338.y.4.i；A.339.y.4.i；A.340.y.4.i；A.341.y.4.i；A.342.y.4.i；A.343.y.4.i；
A.344.y.4.i；A.345.y.4.i；A.346.y.4.i；A.347.y.4.i；A.348.y.4.i；A.349.y.4.i；A.350.y.4.i；
A.351.y.4.i；A.352.y.4.i；A.353.y.4.i；A.354.y.4.i；A.355.y.4.i；A.356.y.4.i；A.357.y.4.i；
A.358.y.4.i；A.359.y.4.i；A.360.y.4.i；A.361.y.4.i；A.362.y.4.i；A.363.y.4.i；A.364.y.4.i；
A.365.y.4.i；A.366.y.4.i；A.367.y.4.i；A.368.y.4.i；A.369.y.4.i；A.370.y.4.i；A.371.y.4.i；
A.372.y.4.i；A.373.y.4.i；A.374.y.4.i；A.375.y.4.i；A.376.y.4.i；A.377.y.4.i；A.378.y.4.i；
A.379.y.4.i；A.380.y.4.i；A.381.y.4.i；A.382.y.4.i；A.383.y.4.i；A.384.y.4.i；A.385.y.4.i；
A.386.y.4.i；A.387.y.4.i；A.388.y.4.i；A.389.y.4.i；A.390.y.4.i；A.391.y.4.i；A.392.y.4.i；
A.393.y.4.i；A.394.y.4.i；A.395.y.4.i；A.396.y.4.i；A.397.y.4.i；A.398.y.4.i；A.399.y.4.i；
A.400.y.4.i；A.401.y.4.i；A.402.y.4.i；A.403.y.4.i；A.404.y.4.i；A.405.y.4.i；A.406.y.4.i；
A.407.y.4.i；A.408.y.4.i；A.409.y.4.i；A.410.y.4.i；A.411.y.4.i；A.412.y.4.i；A.413.y.4.i；
A.414.y.4.i；A.415.y.4.i；A.416.y.4.i；A.417.y.4.i；A.418.y.4.i；A.419.y.4.i；A.420.y.4.i；
A.421.y.4.i；A.422.y.4.i；A.423.y.4.i；A.424.y.4.i；A.425.y.4.i；A.426.y.4.i；A.427.y.4.i；
A.428.y.4.i；A.429.y.4.i；A.430.y.4.i；A.431.y.4.i；A.432.y.4.i；A.433.y.4.i；A.434.y.4.i；
A.435.y.4.i；A.436.y.4.i；A.437.y.4.i；A.438.y.4.i；A.439.y.4.i；A.440.y.4.i；A.441.y.4.i；
A.442.y.4.i；A.443.y.4.i；A.444.y.4.i；A.445.y.4.i；A.446.y.4.i；A.447.y.4.i；A.448.y.4.i；
A.449.y.4.i；A.450.y.4.i；A.451.y.4.i；A.452.y.4.i；A.453.y.4.i；A.454.y.4.i；A.455.y.4.i；
A.456.y.4.i；A.457.y.4.i；A.458.y.4.i；A.459.y.4.i；A.460.y.4.i；A.461.y.4.i；A.462.y.4.i；
A.463.y.4.i；A.464.y.4.i；A.465.y.4.i；A.466.y.4.i；A.467.y.4.i；A.468.y.4.i；A.469.y.4.i；
A.470.y.4.i；A.471.y.4.i；A.472.y.4.i；A.473.y.4.i；A.474.y.4.i；A.475.y.4.i；A.476.y.4.i；
A.477.y.4.i；A.478.y.4.i；A.479.y.4.i；A.480.y.4.i；A.481.y.4.i；A.482.y.4.i；A.483.y.4.i；
A.484.y.4.i；A.485.y.4.i；A.486.y.4.i；A.487.y.4.i；A.488.y.4.i；A.489.y.4.i；A.490.y.4.i；
A.491.y.4.i；A.492.y.4.i；A.493.y.4.i；A.494.y.4.i；A.495.y.4.i；A.496.y.4.i；A.497.y.4.i；
A.498.y.4.i；A.499.y.4.i；A.500.y.4.i；A.501.y.4.i；A.502.y.4.i；A.503.y.4.i；A.504.y.4.i；
A.505.y.4.i；A.506.y.4.i；A.507.y.4.i；A.508.y.4.i；A.509.y.4.i；A.510.y.4.i；A.511.y.4.i；
A.512.y.4.i；A.512.y.4.i；A.513.y.4.i；A.514.y.4.i；A.515.y.4.i；A.516.y.4.i；A.517.y.4.i；
A.518.y.4.i；A.519.y.4.i；A.520.y.4.i；A.521.y.4.i；A.522.y.4.i；A.523.y.4.i；A.524.y.4.i；
A.525.y.4.i；A.526.y.4.i；A.527.y.4.i；A.528.y.4.i；A.529.y.4.i；A.530.y.4.i；A.531.y.4.i；
A.532.y.4.i；A.533.y.4.i；A.534.y.4.i；A.535.y.4.i；A.536.y.4.i；A.537.y.4.i；A.538.y.4.i；
A.539.y.4.i；A.540.y.4.i；A.541.y.4.i；A.542.y.4.i；A.543.y.4.i；A.544.y.4.i；A.545.y.4.i；
A.546.y.4.i；A.547.y.4.i；A.548.y.4.i；A.549.y.4.i；A.550.y.4.i；A.551.y.4.i；A.552.y.4.i；
A.553.y.4.i；A.554.y.4.i；A.555.y.4.i；A.556.y.4.i；A.557.y.4.i；A.558.y.4.i；A.559.y.4.i；
A.560.y.4.i；A.561.y.4.i；A.562.y.4.i；A.563.y.4.i；A.564.y.4.i；A.565.y.4.i；A.566.y.4.i；
A.567.y.4.i；A.568.y.4.i；A.569.y.4.i；A.570.y.4.i；A.571.y.4.i；A.572.y.4.i；A.573.y.4.i；
A.574.y.4.i；A.575.y.4.i；A.576.y.4.i；A.577.y.4.i；A.578.y.4.i；A.579.y.4.i；A.580.y.4.i；
A.581.y.4.i；A.582.y.4.i；A.583.y.4.i；A.584.y.4.i；A.585.y.4.i；A.586.y.4.i；A.587.y.4.i；
A.588.y.4.i；A.589.y.4.i；A.590.y.4.i；A.591.y.4.i；A.592.y.4.i；A.593.y.4.i；A.594.y.4.i；
A.595.y.4.i；A.596.y.4.i；A.597.y.4.i；A.598.y.4.i；A.599.y.4.i；A.600.y.4.i；A.601.y.4.i；
A.602.y.4.i；A.603.y.4.i；A.604.y.4.i；A.605.y.4.i；A.606.y.4.i；A.607.y.4.i；A.608.y.4.i；
A.609.y.4.i；A.610.y.4.i；A.611.y.4.i；A.612.y.4.i；A.613.y.4.i；A.614.y.4.i；A.615.y.4.i；
A.616.y.4.i；A.617.y.4.i；A.618.y.4.i；A.619.y.4.i；A.620.y.4.i；A.621.y.4.i；A.622.y.4.i；
A.623.y.4.i；A.624.y.4.i；A.625.y.4.i；A.626.y.4.i；A.627.y.4.i；A.628.y.4.i；A.629.y.4.i；
A.630.y.4.i；A.631.y.4.i；A.632.y.4.i；A.633.y.4.i；A.634.y.4.i；A.635.y.4.i；A.636.y.4.i；
A.637.y.4.i；A.638.y.4.i；A.639.y.4.i；A.640.y.4.i；A.641.y.4.i；A.642.y.4.i；A.643.y.4.i；
A.644.y.4.i；A.645.y.4.i；A.646.y.4.i；A.647.y.4.i；A.648.y.4.i；A.649.y.4.i；A.650.y.4.i；
A.651.y.4.i；A.652.y.4.i；A.653.y.4.i；A.654.y.4.i；A.655.y.4.i；A.656.y.4.i；A.657.y.4.i；
A.658.y.4.i；A.659.y.4.i；A.660.y.4.i；A.2.y.11.i；A.3.y.11.i；A.4.y.11.i；A.5.y.11.i；
A.6.y.11.i；A.7.y.11.i；A.9.y.11.i；A.10.y.11.i；A.15.y.11.i；A.100.y.11.i；A.101.y.11.i；
A.102.y.11.i；A.103.y.11.i；A.104.y.11.i；A.105.y.11.i；A.106.y.11.i；A.107.y.11.i；
A.108.y.11.i；A.109.y.11.i；A.110.y.11.i；A.111.y.11.i；A.112.y.11.i；A.113.y.11.i；
A.114.y.11.i；A.115.y.11.i；A.116.y.11.i；A.117.y.11.i；A.118.y.11.i；A.119.y.11.i；
A.120.y.11.i；A.121.y.11.i；A.122.y.11.i；A.123.y.11.i；A.124.y.11.i；A.125.y.11.i；
A.126.y.11.i；A.127.y.11.i；A.128.y.11.i；A.129.y.11.i；A.130.y.11.i；A.131.y.11.i；
A.132.y.11.i；A.133.y.11.i；A.134.y.11.i；A.135.y.11.i；A.136.y.11.i；A.137.y.11.i；
A.138.y.11.i；A.139.y.11.i；A.140.y.11.i；A.141.y.11.i；A.142.y.11.i；A.143.y.11.i；
A.144.y.11.i；A.145.y.11.i；A.146.y.11.i；A.147.y.11.i；A.148.y.11.i；A.149.y.11.i；
A.150.y.11.i；A.151.y.11.i；A.152.y.11.i；A.153.y.11.i；A.154.y.11.i；A.155.y.11.i；
A.156.y.11.i；A.157.y.11.i；A.158.y.11.i；A.159.y.11.i；A.160.y.11.i；A.161.y.11.i；
A.162.y.11.i；A.163.y.11.i；A.164.y.11.i；A.165.y.11.i；A.166.y.11.i；A.167.y.11.i；
A.168.y.11.i；A.169.y.11.i；A.170.y.11.i；A.171.y.11.i；A.172.y.11.i；A.173.y.11.i；
A.174.y.11.i；A.175.y.11.i；A.176.y.11.i；A.177.y.11.i；A.178.y.11.i；A.179.y.11.i；
A.180.y.11.i；A.181.y.11.i；A.182.y.11.i；A.183.y.11.i；A.184.y.11.i；A.185.y.11.i；
A.186.y.11.i；A.187.y.11.i；A.188.y.11.i；A.189.y.11.i；A.190.y.11.i；A.191.y.11.i；
A.192.y.11.i；A.193.y.11.i；A.194.y.11.i；A.195.y.11.i；A.196.y.11.i；A.197.y.11.i；
A.198.y.11.i；A.199.y.11.i；A.200.y.11.i；A.201.y.11.i；A.202.y.11.i；A.203.y.11.i；
A.204.y.11.i；A.205.y.11.i；A.206.y.11.i；A.207.y.11.i；A.208.y.11.i；A.209.y.11.i；
A.210.y.11.i；A.211.y.11.i；A.212.y.11.i；A.213.y.11.i；A.214.y.11.i；A.215.y.11.i；
A.216.y.11.i；A.217.y.11.i；A.218.y.11.i；A.219.y.11.i；A.220.y.11.i；A.221.y.11.i；
A.222.y.11.i；A.223.y.11.i；A.224.y.11.i；A.225.y.11.i；A.226.y.11.i；A.227.y.11.i；
A.228.y.11.i；A.229.y.11.i；A.230.y.11.i；A.231.y.11.i；A.232.y.11.i；A.233.y.11.i；
A.234.y.11.i；A.235.y.11.i；A.236.y.11.i；A.237.y.11.i；A.238.y.11.i；A.239.y.11.i；
A.240.y.11.i；A.241.y.11.i；A.242.y.11.i；A.243.y.11.i；A.244.y.11.i；A.245.y.11.i；
A.246.y.11.i；A.247.y.11.i；A.248.y.11.i；A.249.y.11.i；A.250.y.11.i；A.251.y.11.i；
A.252.y.11.i；A.253.y.11.i；A.254.y.11.i；A.255.y.11.i；A.256.y.11.i；A.257.y.11.i；
A.258.y.11.i；A.259.y.11.i；A.260.y.11.i；A.261.y.11.i；A.262.y.11.i；A.263.y.11.i；
A.264.y.11.i；A.265.y.11.i；A.266.y.11.i；A.267.y.11.i；A.268.y.11.i；A.269.y.11.i；
A.270.y.11.i；A.271.y.11.i；A.272.y.11.i；A.273.y.11.i；A.274.y.11.i；A.275.y.11.i；
A.276.y.11.i；A.277.y.11.i；A.278.y.11.i；A.279.y.11.i；A.280.y.11.i；A.281.y.11.i；
A.282.y.11.i；A.283.y.11.i；A.284.y.11.i；A.285.y.11.i；A.286.y.11.i；A.287.y.11.i；
A.288.y.11.i；A.289.y.11.i；A.290.y.11.i；A.291.y.11.i；A.292.y.11.i；A.293.y.11.i；
A.294.y.11.i；A.295.y.11.i；A.296.y.11.i；A.297.y.11.i；A.298.y.11.i；A.299.y.11.i；
A.300.y.11.i；A.301.y.11.i；A.302.y.11.i；A.303.y.11.i；A.304.y.11.i；A.305.y.11.i；
A.306.y.11.i；A.307.y.11.i；A.308.y.11.i；A.309.y.11.i；A.310.y.11.i；A.311.y.11.i；
A.312.y.11.i；A.313.y.11.i；A.314.y.11.i；A.315.y.11.i；A.316.y.11.i；A.317.y.11.i；
A.318.y.11.i；A.319.y.11.i；A.320.y.11.i；A.321.y.11.i；A.323.y.11.i；A.324.y.11.i；
A.325.y.11.i；A.326.y.11.i；A.327.y.11.i；A.328.y.11.i；A.329.y.11.i；A.330.y.11.i；
A.331.y.11.i；A.332.y.11.i；A.333.y.11.i；A.334.y.11.i；A.335.y.11.i；A.336.y.11.i；
A.337.y.11.i；A.338.y.11.i；A.339.y.11.i；A.340.y.11.i；A.341.y.11.i；A.342.y.11.i；
A.343.y.11.i；A.344.y.11.i；A.345.y.11.i；A.346.y.11.i；A.347.y.11.i；A.348.y.11.i；
A.349.y.11.i；A.350.y.11.i；A.351.y.11.i；A.352.y.11.i；A.353.y.11.i；A.354.y.11.i；
A.355.y.11.i；A.356.y.11.i；A.357.y.11.i；A.358.y.11.i；A.359.y.11.i；A.360.y.11.i；
A.361.y.11.i；A.362.y.11.i；A.363.y.11.i；A.364.y.11.i；A.365.y.11.i；A.366.y.11.i；
A.367.y.11.i；A.368.y.11.i；A.369.y.11.i；A.370.y.11.i；A.371.y.11.i；A.372.y.11.i；
A.373.y.11.i；A.374.y.11.i；A.375.y.11.i；A.376.y.11.i；A.377.y.11.i；A.378.y.11.i；
A.379.y.11.i；A.380.y.11.i；A.381.y.11.i；A.382.y.11.i；A.383.y.11.i；A.384.y.11.i；
A.385.y.11.i；A.386.y.11.i；A.387.y.11.i；A.388.y.11.i；A.389.y.11.i；A.390.y.11.i；
A.391.y.11.i；A.392.y.11.i；A.393.y.11.i；A.394.y.11.i；A.395.y.11.i；A.396.y.11.i；
A.397.y.11.i；A.398.y.11.i；A.399.y.11.i；A.400.y.11.i；A.401.y.11.i；A.402.y.11.i；
A.403.y.11.i；A.404.y.11.i；A.405.y.11.i；A.406.y.11.i；A.407.y.11.i；A.408.y.11.i；
A.409.y.11.i；A.410.y.11.i；A.411.y.11.i；A.412.y.11.i；A.413.y.11.i；A.414.y.11.i；
A.415.y.11.i；A.416.y.11.i；A.417.y.11.i；A.418.y.11.i；A.419.y.11.i；A.420.y.11.i；
A.421.y.11.i；A.422.y.11.i；A.423.y.11.i；A.424.y.11.i；A.425.y.11.i；A.426.y.11.i；
A.427.y.11.i；A.428.y.11.i；A.429.y.11.i；A.430.y.11.i；A.431.y.11.i；A.432.y.11.i；
A.433.y.11.i；A.434.y.11.i；A.435.y.11.i；A.436.y.11.i；A.437.y.11.i；A.438.y.11.i；
A.439.y.11.i；A.440.y.11.i；A.441.y.11.i；A.442.y.11.i；A.443.y.11.i；A.444.y.11.i；
A.445.y.11.i；A.446.y.11.i；A.447.y.11.i；A.448.y.11.i；A.449.y.11.i；A.450.y.11.i；
A.451.y.11.i；A.452.y.11.i；A.453.y.11.i；A.454.y.11.i；A.455.y.11.i；A.456.y.11.i；
A.457.y.11.i；A.458.y.11.i；A.459.y.11.i；A.460.y.11.i；A.461.y.11.i；A.462.y.11.i；
A.463.y.11.i；A.464.y.11.i；A.465.y.11.i；A.466.y.11.i；A.467.y.11.i；A.468.y.11.i；
A.469.y.11.i；A.470.y.11.i；A.471.y.11.i；A.472.y.11.i；A.473.y.11.i；A.474.y.11.i；
A.475.y.11.i；A.476.y.11.i；A.477.y.11.i；A.478.y.11.i；A.479.y.11.i；A.480.y.11.i；
A.481.y.11.i；A.482.y.11.i；A.483.y.11.i；A.484.y.11.i；A.485.y.11.i；A.486.y.11.i；
A.487.y.11.i；A.488.y.11.i；A.489.y.11.i；A.490.y.11.i；A.491.y.11.i；A.492.y.11.i；
A.493.y.11.i；A.494.y.11.i；A.495.y.11.i；A.496.y.11.i；A.497.y.11.i；A.498.y.11.i；
A.499.y.11.i；A.500.y.11.i；A.501.y.11.i；A.502.y.11.i；A.503.y.11.i；A.504.y.11.i；
A.505.y.11.i；A.506.y.11.i；A.507.y.11.i；A.508.y.11.i；A.509.y.11.i；A.510.y.11.i；
A.511.y.11.i；A.512.y.11.i；A.512.y.11.i；A.513.y.11.i；A.514.y.11.i；A.515.y.11.i；
A.516.y.11.i；A.517.y.11.i；A.518.y.11.i；A.519.y.11.i；A.520.y.11.i；A.521.y.11.i；
A.522.y.11.i；A.523.y.11.i；A.524.y.11.i；A.525.y.11.i；A.526.y.11.i；A.527.y.11.i；
A.528.y.11.i；A.529.y.11.i；A.530.y.11.i；A.531.y.11.i；A.532.y.11.i；A.533.y.11.i；
A.534.y.11.i；A.535.y.11.i；A.536.y.11.i；A.537.y.11.i；A.538.y.11.i；A.539.y.11.i；
A.540.y.11.i；A.541.y.11.i；A.542.y.11.i；A.543.y.11.i；A.544.y.11.i；A.545.y.11.i；
A.546.y.11.i；A.547.y.11.i；A.548.y.11.i；A.549.y.11.i；A.550.y.11.i；A.551.y.11.i；
A.552.y.11.i；A.553.y.11.i；A.554.y.11.i；A.555.y.11.i；A.556.y.11.i；A.557.y.11.i；
A.558.y.11.i；A.559.y.11.i；A.560.y.11.i；A.561.y.11.i；A.562.y.11.i；A.563.y.11.i；
A.564.y.11.i；A.565.y.11.i；A.566.y.11.i；A.567.y.11.i；A.568.y.11.i；A.569.y.11.i；
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A.138.z.11.i；A.139.z.11.i；A.140.z.11.i；A.141.z.11.i；A.142.z.11.i；A.143.z.11.i；
A.144.z.11.i；A.145.z.11.i；A.146.z.11.i；A.147.z.11.i；A.148.z.11.i；A.149.z.11.i；
A.150.z.11.i；A.151.z.11.i；A.152.z.11.i；A.153.z.11.i；A.154.z.11.i；A.155.z.11.i；
A.156.z.11.i；A.157.z.11.i；A.158.z.11.i；A.159.z.11.i；A.160.z.11.i；A.161.z.11.i；
A.162.z.11.i；A.163.z.11.i；A.164.z.11.i；A.165.z.11.i；A.166.z.11.i；A.167.z.11.i；
A.168.z.11.i；A.169.z.11.i；A.170.z.11.i；A.171.z.11.i；A.172.z.11.i；A.173.z.11.i；
A.174.z.11.i；A.175.z.11.i；A.176.z.11.i；A.177.z.11.i；A.178.z.11.i；A.179.z.11.i；
A.180.z.11.i；A.181.z.11.i；A.182.z.11.i；A.183.z.11.i；A.184.z.11.i；A.185.z.11.i；
A.186.z.11.i；A.187.z.11.i；A.188.z.11.i；A.189.z.11.i；A.190.z.11.i；A.191.z.11.i；
A.192.z.11.i；A.193.z.11.i；A.194.z.11.i；A.195.z.11.i；A.196.z.11.i；A.197.z.11.i；
A.198.z.11.i；A.199.z.11.i；A.200.z.11.i；A.201.z.11.i；A.202.z.11.i；A.203.z.11.i；
A.204.z.11.i；A.205.z.11.i；A.206.z.11.i；A.207.z.11.i；A.208.z.11.i；A.209.z.11.i；
A.210.z.11.i；A.211.z.11.i；A.212.z.11.i；A.213.z.11.i；A.214.z.11.i；A.215.z.11.i；
A.216.z.11.i；A.217.z.11.i；A.218.z.11.i；A.219.z.11.i；A.220.z.11.i；A.221.z.11.i；
A.222.z.11.i；A.223.z.11.i；A.224.z.11.i；A.225.z.11.i；A.226.z.11.i；A.227.z.11.i；
A.228.z.11.i；A.229.z.11.i；A.230.z.11.i；A.231.z.11.i；A.232.z.11.i；A.233.z.11.i；
A.234.z.11.i；A.235.z.11.i；A.236.z.11.i；A.237.z.11.i；A.238.z.11.i；A.239.z.11.i；
A.240.z.11.i；A.241.z.11.i；A.242.z.11.i；A.243.z.11.i；A.244.z.11.i；A.245.z.11.i；
A.246.z.11.i；A.247.z.11.i；A.248.z.11.i；A.249.z.11.i；A.250.z.11.i；A.251.z.11.i；
A.252.z.11.i；A.253.z.11.i；A.254.z.11.i；A.255.z.11.i；A.256.z.11.i；A.257.z.11.i；
A.258.z.11.i；A.259.z.11.i；A.260.z.11.i；A.261.z.11.i；A.262.z.11.i；A.263.z.11.i；
A.264.z.11.i；A.265.z.11.i；A.266.z.11.i；A.267.z.11.i；A.268.z.11.i；A.269.z.11.i；
A.270.z.11.i；A.271.z.11.i；A.272.z.11.i；A.273.z.11.i；A.274.z.11.i；A.275.z.11.i；
A.276.z.11.i；A.277.z.11.i；A.278.z.11.i；A.279.z.11.i；A.280.z.11.i；A.281.z.11.i；
A.282.z.11.i；A.283.z.11.i；A.284.z.11.i；A.285.z.11.i；A.286.z.11.i；A.287.z.11.i；
A.288.z.11.i；A.289.z.11.i；A.290.z.11.i；A.291.z.11.i；A.292.z.11.i；A.293.z.11.i；
A.294.z.11.i；A.295.z.11.i；A.296.z.11.i；A.297.z.11.i；A.298.z.11.i；A.299.z.11.i；
A.300.z.11.i；A.301.z.11.i；A.302.z.11.i；A.303.z.11.i；A.304.z.11.i；A.305.z.11.i；
A.306.z.11.i；A.307.z.11.i；A.308.z.11.i；A.309.z.11.i；A.310.z.11.i；A.311.z.11.i；
A.312.z.11.i；A.313.z.11.i；A.314.z.11.i；A.315.z.11.i；A.316.z.11.i；A.317.z.11.i；
A.318.z.11.i；A.319.z.11.i；A.320.z.11.i；A.321.z.11.i；A.323.z.11.i；A.324.z.11.i；
A.325.z.11.i；A.326.z.11.i；A.327.z.11.i；A.328.z.11.i；A.329.z.11.i；A.330.z.11.i；
A.331.z.11.i；A.332.z.11.i；A.333.z.11.i；A.334.z.11.i；A.335.z.11.i；A.336.z.11.i；
A.337.z.11.i；A.338.z.11.i；A.339.z.11.i；A.340.z.11.i；A.341.z.11.i；A.342.z.11.i；
A.343.z.11.i；A.344.z.11.i；A.345.z.11.i；A.346.z.11.i；A.347.z.11.i；A.348.z.11.i；
A.349.z.11.i；A.350.z.11.i；A.351.z.11.i；A.352.z.11.i；A.353.z.11.i；A.354.z.11.i；
A.355.z.11.i；A.356.z.11.i；A.357.z.11.i；A.358.z.11.i；A.359.z.11.i；A.360.z.11.i；
A.361.z.11.i；A.362.z.11.i；A.363.z.11.i；A.364.z.11.i；A.365.z.11.i；A.366.z.11.i；
A.367.z.11.i；A.368.z.11.i；A.369.z.11.i；A.370.z.11.i；A.371.z.11.i；A.372.z.11.i；
A.373.z.11.i；A.374.z.11.i；A.375.z.11.i；A.376.z.11.i；A.377.z.11.i；A.378.z.11.i；
A.379.z.11.i；A.380.z.11.i；A.381.z.11.i；A.382.z.11.i；A.383.z.11.i；A.384.z.11.i；
A.385.z.11.i；A.386.z.11.i；A.387.z.11.i；A.388.z.11.i；A.389.z.11.i；A.390.z.11.i；
A.391.z.11.i；A.392.z.11.i；A.393.z.11.i；A.394.z.11.i；A.395.z.11.i；A.396.z.11.i；
A.397.z.11.i；A.398.z.11.i；A.399.z.11.i；A.400.z.11.i；A.401.z.11.i；A.402.z.11.i；
A.403.z.11.i；A.404.z.11.i；A.405.z.11.i；A.406.z.11.i；A.407.z.11.i；A.408.z.11.i；
A.409.z.11.i；A.410.z.11.i；A.411.z.11.i；A.412.z.11.i；A.413.z.11.i；A.414.z.11.i；
A.415.z.11.i；A.416.z.11.i；A.417.z.11.i；A.418.z.11.i；A.419.z.11.i；A.420.z.11.i；
A.421.z.11.i；A.422.z.11.i；A.423.z.11.i；A.424.z.11.i；A.425.z.11.i；A.426.z.11.i；
A.427.z.11.i；A.428.z.11.i；A.429.z.11.i；A.430.z.11.i；A.431.z.11.i；A.432.z.11.i；
A.433.z.11.i；A.434.z.11.i；A.435.z.11.i；A.436.z.11.i；A.437.z.11.i；A.438.z.11.i；
A.439.z.11.i；A.440.z.11.i；A.441.z.11.i；A.442.z.11.i；A.443.z.11.i；A.444.z.11.i；
A.445.z.11.i；A.446.z.11.i；A.447.z.11.i；A.448.z.11.i；A.449.z.11.i；A.450.z.11.i；
A.451.z.11.i；A.452.z.11.i；A.453.z.11.i；A.454.z.11.i；A.455.z.11.i；A.456.z.11.i；
A.457.z.11.i；A.458.z.11.i；A.459.z.11.i；A.460.z.11.i；A.461.z.11.i；A.462.z.11.i；
A.463.z.11.i；A.464.z.11.i；A.465.z.11.i；A.466.z.11.i；A.467.z.11.i；A.468.z.11.i；
A.469.z.11.i；A.470.z.11.i；A.471.z.11.i；A.472.z.11.i；A.473.z.11.i；A.474.z.11.i；
A.475.z.11.i；A.476.z.11.i；A.477.z.11.i；A.478.z.11.i；A.479.z.11.i；A.480.z.11.i；
A.481.z.11.i；A.482.z.11.i；A.483.z.11.i；A.484.z.11.i；A.485.z.11.i；A.486.z.11.i；
A.487.z.11.i；A.488.z.11.i；A.489.z.11.i；A.490.z.11.i；A.491.z.11.i；A.492.z.11.i；
A.493.z.11.i；A.494.z.11.i；A.495.z.11.i；A.496.z.11.i；A.497.z.11.i；A.498.z.11.i；
A.499.z.11.i；A.500.z.11.i；A.501.z.11.i；A.502.z.11.i；A.503.z.11.i；A.504.z.11.i；
A.505.z.11.i；A.506.z.11.i；A.507.z.11.i；A.508.z.11.i；A.509.z.11.i；A.510.z.11.i；
A.511.z.11.i；A.512.z.11.i；A.512.z.11.i；A.513.z.11.i；A.514.z.11.i；A.515.z.11.i；
A.516.z.11.i；A.517.z.11.i；A.518.z.11.i；A.519.z.11.i；A.520.z.11.i；A.521.z.11.i；
A.522.z.11.i；A.523.z.11.i；A.524.z.11.i；A.525.z.11.i；A.526.z.11.i；A.527.z.11.i；
A.528.z.11.i；A.529.z.11.i；A.530.z.11.i；A.531.z.11.i；A.532.z.11.i；A.533.z.11.i；
A.534.z.11.i；A.535.z.11.i；A.536.z.11.i；A.537.z.11.i；A.538.z.11.i；A.539.z.11.i；
A.540.z.11.i；A.541.z.11.i；A.542.z.11.i；A.543.z.11.i；A.544.z.11.i；A.545.z.11.i；
A.546.z.11.i；A.547.z.11.i；A.548.z.11.i；A.549.z.11.i；A.550.z.11.i；A.551.z.11.i；
A.552.z.11.i；A.553.z.11.i；A.554.z.11.i；A.555.z.11.i；A.556.z.11.i；A.557.z.11.i；
A.558.z.11.i；A.559.z.11.i；A.560.z.11.i；A.561.z.11.i；A.562.z.11.i；A.563.z.11.i；
A.564.z.11.i；A.565.z.11.i；A.566.z.11.i；A.567.z.11.i；A.568.z.11.i；A.569.z.11.i；
A.570.z.11.i；A.571.z.11.i；A.572.z.11.i；A.573.z.11.i；A.574.z.11.i；A.575.z.11.i；
A.576.z.11.i；A.577.z.11.i；A.578.z.11.i；A.579.z.11.i；A.580.z.11.i；A.581.z.11.i；
A.582.z.11.i；A.583.z.11.i；A.584.z.11.i；A.585.z.11.i；A.586.z.11.i；A.587.z.11.i；
A.588.z.11.i；A.589.z.11.i；A.590.z.11.i；A.591.z.11.i；A.592.z.11.i；A.593.z.11.i；
A.594.z.11.i；A.595.z.11.i；A.596.z.11.i；A.597.z.11.i；A.598.z.11.i；A.599.z.11.i；
A.600.z.11.i；A.601.z.11.i；A.602.z.11.i；A.603.z.11.i；A.604.z.11.i；A.605.z.11.i；
A.606.z.11.i；A.607.z.11.i；A.608.z.11.i；A.609.z.11.i；A.610.z.11.i；A.611.z.11.i；
A.612.z.11.i；A.613.z.11.i；A.614.z.11.i；A.615.z.11.i；A.616.z.11.i；A.617.z.11.i；
A.618.z.11.i；A.619.z.11.i；A.620.z.11.i；A.621.z.11.i；A.622.z.11.i；A.623.z.11.i；
A.624.z.11.i；A.625.z.11.i；A.626.z.11.i；A.627.z.11.i；A.628.z.11.i；A.629.z.11.i；
A.630.z.11.i；A.631.z.11.i；A.632.z.11.i；A.633.z.11.i；A.634.z.11.i；A.635.z.11.i；
A.636.z.11.i；A.637.z.11.i；A.638.z.11.i；A.639.z.11.i；A.640.z.11.i；A.641.z.11.i；
A.642.z.11.i；A.643.z.11.i；A.644.z.11.i；A.645.z.11.i；A.646.z.11.i；A.647.z.11.i；
A.648.z.11.i；A.649.z.11.i；A.650.z.11.i；A.651.z.11.i；A.652.z.11.i；A.653.z.11.i；
A.654.z.11.i；A.655.z.11.i；A.656.z.11.i；A.657.z.11.i；A.658.z.11.i；A.659.z.11.i；
A.660.z.11.i；A.2.A.4.i；A.3.A.4.i；A.4.A.4.i；A.5.A.4.i；A.6.A.4.i；A.7.A.4.i；
A.9.A.4.i；A.10.A.4.i；A.15.A.4.i；A.100.A.4.i；A.101.A.4.i；A.102.A.4.i；
A.103.A.4.i；A.104.A.4.i；A.105.A.4.i；A.106.A.4.i；A.107.A.4.i；A.108.A.4.i；
A.109.A.4.i；A.110.A.4.i；A.111.A.4.i；A.112.A.4.i；A.113.A.4.i；A.114.A.4.i；
A.115.A.4.i；A.116.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.122.A.4.i；A.123.A.4.i；A.124.A.4.i；A.125.A.4.i；A.126.A.4.i；
A.127.A.4.i；A.128.A.4.i；A.129.A.4.i；A.130.A.4.i；A.131.A.4.i；A.132.A.4.i；
A.133.A.4.i；A.134.A.4.i；A.135.A.4.i；A.136.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.143.A.4.i；A.144.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.152.A.4.i；A.153.A.4.i；A.154.A.4.i；A.155.A.4.i；A.156.A.4.i；
A.157.A.4.i；A.158.A.4.i；A.159.A.4.i；A.160.A.4.i；A.161.A.4.i；A.162.A.4.i；
A.163.A.4.i；A.164.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.177.A.4.i；A.178.A.4.i；A.179.A.4.i；A.180.A.4.i；
A.181.A.4.i；A.182.A.4.i；A.183.A.4.i；A.184.A.4.i；A.185.A.4.i；A.186.A.4.i；
A.187.A.4.i；A.188.A.4.i；A.189.A.4.i；A.190.A.4.i；A.191.A.4.i；A.192.A.4.i；
A.193.A.4.i；A.194.A.4.i；A.195.A.4.i；A.196.A.4.i；A.197.A.4.i；A.198.A.4.i；
A.199.A.4.i；A.200.A.4.i；A.201.A.4.i；A.202.A.4.i；A.203.A.4.i；A.204.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.214.A.4.i；A.215.A.4.i；A.216.A.4.i；
A.217.A.4.i；A.218.A.4.i；A.219.A.4.i；A.220.A.4.i；A.221.A.4.i；A.222.A.4.i；
A.223.A.4.i；A.224.A.4.i；A.225.A.4.i；A.226.A.4.i；A.227.A.4.i；A.228.A.4.i；
A.229.A.4.i；A.230.A.4.i；A.231.A.4.i；A.232.A.4.i；A.233.A.4.i；A.234.A.4.i；
A.235.A.4.i；A.236.A.4.i；A.237.A.4.i；A.238.A.4.i；A.239.A.4.i；A.240.A.4.i；
A.241.A.4.i；A.242.A.4.i；A.243.A.4.i；A.244.A.4.i；A.245.A.4.i；A.246.A.4.i；
A.247.A.4.i；A.248.A.4.i；A.249.A.4.i；A.250.A.4.i；A.251.A.4.i；A.252.A.4.i；
A.253.A.4.i；A.254.A.4.i；A.255.A.4.i；A.256.A.4.i；A.257.A.4.i；A.258.A.4.i；
A.259.A.4.i；A.260.A.4.i；A.261.A.4.i；A.262.A.4.i；A.263.A.4.i；A.264.A.4.i；
A.265.A.4.i；A.266.A.4.i；A.267.A.4.i；A.268.A.4.i；A.269.A.4.i；A.270.A.4.i；
A.271.A.4.i；A.272.A.4.i；A.273.A.4.i；A.274.A.4.i；A.275.A.4.i；A.276.A.4.i；
A.277.A.4.i；A.278.A.4.i；A.279.A.4.i；A.280.A.4.i；A.281.A.4.i；A.282.A.4.i；
A.283.A.4.i；A.284.A.4.i；A.285.A.4.i；A.286.A.4.i；A.287.A.4.i；A.288.A.4.i；
A.289.A.4.i；A.290.A.4.i；A.291.A.4.i；A.292.A.4.i；A.293.A.4.i；A.294.A.4.i；
A.295.A.4.i；A.296.A.4.i；A.297.A.4.i；A.298.A.4.i；A.299.A.4.i；A.300.A.4.i；
A.301.A.4.i；A.302.A.4.i；A.303.A.4.i；A.304.A.4.i；A.305.A.4.i；A.306.A.4.i；
A.307.A.4.i；A.308.A.4.i；A.309.A.4.i；A.310.A.4.i；A.311.A.4.i；A.312.A.4.i；
A.313.A.4.i；A.314.A.4.i；A.315.A.4.i；A.316.A.4.i；A.317.A.4.i；A.318.A.4.i；
A.319.A.4.i；A.320.A.4.i；A.321.A.4.i；A.323.A.4.i；A.324.A.4.i；A.325.A.4.i；
A.326.A.4.i；A.327.A.4.i；A.328.A.4.i；A.329.A.4.i；A.330.A.4.i；A.331.A.4.i；
A.332.A.4.i；A.333.A.4.i；A.334.A.4.i；A.335.A.4.i；A.336.A.4.i；A.337.A.4.i；
A.338.A.4.i；A.339.A.4.i；A.340.A.4.i；A.341.A.4.i；A.342.A.4.i；A.343.A.4.i；
A.344.A.4.i；A.345.A.4.i；A.346.A.4.i；A.347.A.4.i；A.348.A.4.i；A.349.A.4.i；
A.350.A.4.i；A.351.A.4.i；A.352.A.4.i；A.353.A.4.i；A.354.A.4.i；A.355.A.4.i；
A.356.A.4.i；A.357.A.4.i；A.358.A.4.i；A.359.A.4.i；A.360.A.4.i；A.361.A.4.i；
A.362.A.4.i；A.363.A.4.i；A.364.A.4.i；A.365.A.4.i；A.366.A.4.i；A.367.A.4.i；
A.368.A.4.i；A.369.A.4.i；A.370.A.4.i；A.371.A.4.i；A.372.A.4.i；A.373.A.4.i；
A.374.A.4.i；A.375.A.4.i；A.376.A.4.i；A.377.A.4.i；A.378.A.4.i；A.379.A.4.i；
A.380.A.4.i；A.381.A.4.i；A.382.A.4.i；A.383.A.4.i；A.384.A.4.i；A.385.A.4.i；
A.386.A.4.i；A.387.A.4.i；A.388.A.4.i；A.389.A.4.i；A.390.A.4.i；A.391.A.4.i；
A.392.A.4.i；A.393.A.4.i；A.394.A.4.i；A.395.A.4.i；A.396.A.4.i；A.397.A.4.i；
A.398.A.4.i；A.399.A.4.i；A.400.A.4.i；A.401.A.4.i；A.402.A.4.i；A.403.A.4.i；
A.404.A.4.i；A.405.A.4.i；A.406.A.4.i；A.407.A.4.i；A.408.A.4.i；A.409.A.4.i；
A.410.A.4.i；A.411.A.4.i；A.412.A.4.i；A.413.A.4.i；A.414.A.4.i；A.415.A.4.i；
A.416.A.4.i；A.417.A.4.i；A.418.A.4.i；A.419.A.4.i；A.420.A.4.i；A.421.A.4.i；
A.422.A.4.i；A.423.A.4.i；A.424.A.4.i；A.425.A.4.i；A.426.A.4.i；A.427.A.4.i；
A.428.A.4.i；A.429.A.4.i；A.430.A.4.i；A.431.A.4.i；A.432.A.4.i；A.433.A.4.i；
A.434.A.4.i；A.435.A.4.i；A.436.A.4.i；A.437.A.4.i；A.438.A.4.i；A.439.A.4.i；
A.440.A.4.i；A.441.A.4.i；A.442.A.4.i；A.443.A.4.i；A.444.A.4.i；A.445.A.4.i；
A.446.A.4.i；A.447.A.4.i；A.448.A.4.i；A.449.A.4.i；A.450.A.4.i；A.451.A.4.i；
A.452.A.4.i；A.453.A.4.i；A.454.A.4.i；A.455.A.4.i；A.456.A.4.i；A.457.A.4.i；
A.458.A.4.i；A.459.A.4.i；A.460.A.4.i；A.461.A.4.i；A.462.A.4.i；A.463.A.4.i；
A.464.A.4.i；A.465.A.4.i；A.466.A.4.i；A.467.A.4.i；A.468.A.4.i；A.469.A.4.i；
A.470.A.4.i；A.471.A.4.i；A.472.A.4.i；A.473.A.4.i；A.474.A.4.i；A.475.A.4.i；
A.476.A.4.i；A.477.A.4.i；A.478.A.4.i；A.479.A.4.i；A.480.A.4.i；A.481.A.4.i；
A.482.A.4.i；A.483.A.4.i；A.484.A.4.i；A.485.A.4.i；A.486.A.4.i；A.487.A.4.i；
A.488.A.4.i；A.489.A.4.i；A.490.A.4.i；A.491.A.4.i；A.492.A.4.i；A.493.A.4.i；
A.494.A.4.i；A.495.A.4.i；A.496.A.4.i；A.497.A.4.i；A.498.A.4.i；A.499.A.4.i；
A.500.A.4.i；A.501.A.4.i；A.502.A.4.i；A.503.A.4.i；A.504.A.4.i；A.505.A.4.i；
A.506.A.4.i；A.507.A.4.i；A.508.A.4.i；A.509.A.4.i；A.510.A.4.i；A.511.A.4.i；
A.512.A.4.i；A.512.A.4.i；A.513.A.4.i；A.514.A.4.i；A.515.A.4.i；A.516.A.4.i；
A.517.A.4.i；A.518.A.4.i；A.519.A.4.i；A.520.A.4.i；A.521.A.4.i；A.522.A.4.i；
A.523.A.4.i；A.524.A.4.i；A.525.A.4.i；A.526.A.4.i；A.527.A.4.i；A.528.A.4.i；
A.529.A.4.i；A.530.A.4.i；A.531.A.4.i；A.532.A.4.i；A.533.A.4.i；A.534.A.4.i；
A.535.A.4.i；A.536.A.4.i；A.537.A.4.i；A.538.A.4.i；A.539.A.4.i；A.540.A.4.i；
A.541.A.4.i；A.542.A.4.i；A.543.A.4.i；A.544.A.4.i；A.545.A.4.i；A.546.A.4.i；
A.547.A.4.i；A.548.A.4.i；A.549.A.4.i；A.550.A.4.i；A.551.A.4.i；A.552.A.4.i；
A.553.A.4.i；A.554.A.4.i；A.555.A.4.i；A.556.A.4.i；A.557.A.4.i；A.558.A.4.i；
A.559.A.4.i；A.560.A.4.i；A.561.A.4.i；A.562.A.4.i；A.563.A.4.i；A.564.A.4.i；
A.565.A.4.i；A.566.A.4.i；A.567.A.4.i；A.568.A.4.i；A.569.A.4.i；A.570.A.4.i；
A.571.A.4.i；A.572.A.4.i；A.573.A.4.i；A.574.A.4.i；A.575.A.4.i；A.576.A.4.i；
A.577.A.4.i；A.578.A.4.i；A.579.A.4.i；A.580.A.4.i；A.581.A.4.i；A.582.A.4.i；
A.583.A.4.i；A.584.A.4.i；A.585.A.4.i；A.586.A.4.i；A.587.A.4.i；A.588.A.4.i；
A.589.A.4.i；A.590.A.4.i；A.591.A.4.i；A.592.A.4.i；A.593.A.4.i；A.594.A.4.i；
A.595.A.4.i；A.596.A.4.i；A.597.A.4.i；A.598.A.4.i；A.599.A.4.i；A.600.A.4.i；
A.601.A.4.i；A.602.A.4.i；A.603.A.4.i；A.604.A.4.i；A.605.A.4.i；A.606.A.4.i；
A.607.A.4.i；A.608.A.4.i；A.609.A.4.i；A.610.A.4.i；A.611.A.4.i；A.612.A.4.i；
A.613.A.4.i；A.614.A.4.i；A.615.A.4.i；A.616.A.4.i；A.617.A.4.i；A.618.A.4.i；
A.619.A.4.i；A.620.A.4.i；A.621.A.4.i；A.622.A.4.i；A.623.A.4.i；A.624.A.4.i；
A.625.A.4.i；A.626.A.4.i；A.627.A.4.i；A.628.A.4.i；A.629.A.4.i；A.630.A.4.i；
A.631.A.4.i；A.632.A.4.i；A.633.A.4.i；A.634.A.4.i；A.635.A.4.i；A.636.A.4.i；
A.637.A.4.i；A.638.A.4.i；A.639.A.4.i；A.640.A.4.i；A.641.A.4.i；A.642.A.4.i；
A.643.A.4.i；A.644.A.4.i；A.645.A.4.i；A.646.A.4.i；A.647.A.4.i；A.648.A.4.i；
A.649.A.4.i；A.650.A.4.i；A.651.A.4.i；A.652.A.4.i；A.653.A.4.i；A.654.A.4.i；
A.655.A.4.i；A.656.A.4.i；A.657.A.4.i；A.658.A.4.i；A.659.A.4.i；A.660.A.4.i；
A.2.A.11.i；A.3.A.11.i；A.4.A.11.i；A.5.A.11.i；A.6.A.11.i；A.7.A.11.i；A.9.A.11.i；
A.10.A.11.i；A.15.A.11.i；A.100.A.11.i；A.101.A.11.i；A.102.A.11.i；A.103.A.11.i；
A.104.A.11.i；A.105.A.11.i；A.106.A.11.i；A.107.A.11.i；A.108.A.11.i；A.109.A.11.i；
A.110.A.11.i；A.111.A.11.i；A.112.A.11.i；A.113.A.11.i；A.114.A.11.i；A.115.A.11.i；
A.116.A.11.i；A.117.A.11.i；A.118.A.11.i；A.119.A.11.i；A.120.A.11.i；A.121.A.11.i；
A.122.A.11.i；A.123.A.11.i；A.124.A.11.i；A.125.A.11.i；A.126.A.11.i；A.127.A.11.i；
A.128.A.11.i；A.129.A.11.i；A.130.A.11.i；A.131.A.11.i；A.132.A.11.i；A.133.A.11.i；
A.134.A.11.i；A.135.A.11.i；A.136.A.11.i；A.137.A.11.i；A.138.A.11.i；A.139.A.11.i；
A.140.A.11.i；A.141.A.11.i；A.142.A.11.i；A.143.A.11.i；A.144.A.11.i；A.145.A.11.i；
A.146.A.11.i；A.147.A.11.i；A.148.A.11.i；A.149.A.11.i；A.150.A.11.i；A.151.A.11.i；
A.152.A.11.i；A.153.A.11.i；A.154.A.11.i；A.155.A.11.i；A.156.A.11.i；A.157.A.11.i；
A.158.A.11.i；A.159.A.11.i；A.160.A.11.i；A.161.A.11.i；A.162.A.11.i；A.163.A.11.i；
A.164.A.11.i；A.165.A.11.i；A.166.A.11.i；A.167.A.11.i；A.168.A.11.i；A.169.A.11.i；
A.170.A.11.i；A.171.A.11.i；A.172.A.11.i；A.173.A.11.i；A.174.A.11.i；A.175.A.11.i；
A.176.A.11.i；A.177.A.11.i；A.178.A.11.i；A.179.A.11.i；A.180.A.11.i；A.181.A.11.i；
A.182.A.11.i；A.183.A.11.i；A.184.A.11.i；A.185.A.11.i；A.186.A.11.i；A.187.A.11.i；
A.188.A.11.i；A.189.A.11.i；A.190.A.11.i；A.191.A.11.i；A.192.A.11.i；A.193.A.11.i；
A.194.A.11.i；A.195.A.11.i；A.196.A.11.i；A.197.A.11.i；A.198.A.11.i；A.199.A.11.i；
A.200.A.11.i；A.201.A.11.i；A.202.A.11.i；A.203.A.11.i；A.204.A.11.i；A.205.A.11.i；
A.206.A.11.i；A.207.A.11.i；A.208.A.11.i；A.209.A.11.i；A.210.A.11.i；A.211.A.11.i；
A.212.A.11.i；A.213.A.11.i；A.214.A.11.i；A.215.A.11.i；A.216.A.11.i；A.217.A.11.i；
A.218.A.11.i；A.219.A.11.i；A.220.A.11.i；A.221.A.11.i；A.222.A.11.i；A.223.A.11.i；
A.224.A.11.i；A.225.A.11.i；A.226.A.11.i；A.227.A.11.i；A.228.A.11.i；A.229.A.11.i；
A.230.A.11.i；A.231.A.11.i；A.232.A.11.i；A.233.A.11.i；A.234.A.11.i；A.235.A.11.i；
A.236.A.11.i；A.237.A.11.i；A.238.A.11.i；A.239.A.11.i；A.240.A.11.i；A.241.A.11.i；
A.242.A.11.i；A.243.A.11.i；A.244.A.11.i；A.245.A.11.i；A.246.A.11.i；A.247.A.11.i；
A.248.A.11.i；A.249.A.11.i；A.250.A.11.i；A.251.A.11.i；A.252.A.11.i；A.253.A.11.i；
A.254.A.11.i；A.255.A.11.i；A.256.A.11.i；A.257.A.11.i；A.258.A.11.i；A.259.A.11.i；
A.260.A.11.i；A.261.A.11.i；A.262.A.11.i；A.263.A.11.i；A.264.A.11.i；A.265.A.11.i；
A.266.A.11.i；A.267.A.11.i；A.268.A.11.i；A.269.A.11.i；A.270.A.11.i；A.271.A.11.i；
A.272.A.11.i；A.273.A.11.i；A.274.A.11.i；A.275.A.11.i；A.276.A.11.i；A.277.A.11.i；
A.278.A.11.i；A.279.A.11.i；A.280.A.11.i；A.281.A.11.i；A.282.A.11.i；A.283.A.11.i；
A.284.A.11.i；A.285.A.11.i；A.286.A.11.i；A.287.A.11.i；A.288.A.11.i；A.289.A.11.i；
A.290.A.11.i；A.291.A.11.i；A.292.A.11.i；A.293.A.11.i；A.294.A.11.i；A.295.A.11.i；
A.296.A.11.i；A.297.A.11.i；A.298.A.11.i；A.299.A.11.i；A.300.A.11.i；A.301.A.11.i；
A.302.A.11.i；A.303.A.11.i；A.304.A.11.i；A.305.A.11.i；A.306.A.11.i；A.307.A.11.i；
A.308.A.11.i；A.309.A.11.i；A.310.A.11.i；A.311.A.11.i；A.312.A.11.i；A.313.A.11.i；
A.314.A.11.i；A.315.A.11.i；A.316.A.11.i；A.317.A.11.i；A.318.A.11.i；A.319.A.11.i；
A.320.A.11.i；A.321.A.11.i；A.323.A.11.i；A.324.A.11.i；A.325.A.11.i；A.326.A.11.i；
A.327.A.11.i；A.328.A.11.i；A.329.A.11.i；A.330.A.11.i；A.331.A.11.i；A.332.A.11.i；
A.333.A.11.i；A.334.A.11.i；A.335.A.11.i；A.336.A.11.i；A.337.A.11.i；A.338.A.11.i；
A.339.A.11.i；A.340.A.11.i；A.341.A.11.i；A.342.A.11.i；A.343.A.11.i；A.344.A.11.i；
A.345.A.11.i；A.346.A.11.i；A.347.A.11.i；A.348.A.11.i；A.349.A.11.i；A.350.A.11.i；
A.351.A.11.i；A.352.A.11.i；A.353.A.11.i；A.354.A.11.i；A.355.A.11.i；A.356.A.11.i；
A.357.A.11.i；A.358.A.11.i；A.359.A.11.i；A.360.A.11.i；A.361.A.11.i；A.362.A.11.i；
A.363.A.11.i；A.364.A.11.i；A.365.A.11.i；A.366.A.11.i；A.367.A.11.i；A.368.A.11.i；
A.369.A.11.i；A.370.A.11.i；A.371.A.11.i；A.372.A.11.i；A.373.A.11.i；A.374.A.11.i；
A.375.A.11.i；A.376.A.11.i；A.377.A.11.i；A.378.A.11.i；A.379.A.11.i；A.380.A.11.i；
A.381.A.11.i；A.382.A.11.i；A.383.A.11.i；A.384.A.11.i；A.385.A.11.i；A.386.A.11.i；
A.387.A.11.i；A.388.A.11.i；A.389.A.11.i；A.390.A.11.i；A.391.A.11.i；A.392.A.11.i；
A.393.A.11.i；A.394.A.11.i；A.395.A.11.i；A.396.A.11.i；A.397.A.11.i；A.398.A.11.i；
A.399.A.11.i；A.400.A.11.i；A.401.A.11.i；A.402.A.11.i；A.403.A.11.i；A.404.A.11.i；
A.405.A.11.i；A.406.A.11.i；A.407.A.11.i；A.408.A.11.i；A.409.A.11.i；A.410.A.11.i；
A.411.A.11.i；A.412.A.11.i；A.413.A.11.i；A.414.A.11.i；A.415.A.11.i；A.416.A.11.i；
A.417.A.11.i；A.418.A.11.i；A.419.A.11.i；A.420.A.11.i；A.421.A.11.i；A.422.A.11.i；
A.423.A.11.i；A.424.A.11.i；A.425.A.11.i；A.426.A.11.i；A.427.A.11.i；A.428.A.11.i；
A.429.A.11.i；A.430.A.11.i；A.431.A.11.i；A.432.A.11.i；A.433.A.11.i；A.434.A.11.i；
A.435.A.11.i；A.436.A.11.i；A.437.A.11.i；A.438.A.11.i；A.439.A.11.i；A.440.A.11.i；
A.441.A.11.i；A.442.A.11.i；A.443.A.11.i；A.444.A.11.i；A.445.A.11.i；A.446.A.11.i；
A.447.A.11.i；A.448.A.11.i；A.449.A.11.i；A.450.A.11.i；A.451.A.11.i；A.452.A.11.i；
A.453.A.11.i；A.454.A.11.i；A.455.A.11.i；A.456.A.11.i；A.457.A.11.i；A.458.A.11.i；
A.459.A.11.i；A.460.A.11.i；A.461.A.11.i；A.462.A.11.i；A.463.A.11.i；A.464.A.11.i；
A.465.A.11.i；A.466.A.11.i；A.467.A.11.i；A.468.A.11.i；A.469.A.11.i；A.470.A.11.i；
A.471.A.11.i；A.472.A.11.i；A.473.A.11.i；A.474.A.11.i；A.475.A.11.i；A.476.A.11.i；
A.477.A.11.i；A.478.A.11.i；A.479.A.11.i；A.480.A.11.i；A.481.A.11.i；A.482.A.11.i；
A.483.A.11.i；A.484.A.11.i；A.485.A.11.i；A.486.A.11.i；A.487.A.11.i；A.488.A.11.i；
A.489.A.11.i；A.490.A.11.i；A.491.A.11.i；A.492.A.11.i；A.493.A.11.i；A.494.A.11.i；
A.495.A.11.i；A.496.A.11.i；A.497.A.11.i；A.498.A.11.i；A.499.A.11.i；A.500.A.11.i；
A.501.A.11.i；A.502.A.11.i；A.503.A.11.i；A.504.A.11.i；A.505.A.11.i；A.506.A.11.i；
A.507.A.11.i；A.508.A.11.i；A.509.A.11.i；A.510.A.11.i；A.511.A.11.i；A.512.A.11.i；
A.512.A.11.i；A.513.A.11.i；A.514.A.11.i；A.515.A.11.i；A.516.A.11.i；A.517.A.11.i；
A.518.A.11.i；A.519.A.11.i；A.520.A.11.i；A.521.A.11.i；A.522.A.11.i；A.523.A.11.i；
A.524.A.11.i；A.525.A.11.i；A.526.A.11.i；A.527.A.11.i；A.528.A.11.i；A.529.A.11.i；
A.530.A.11.i；A.531.A.11.i；A.532.A.11.i；A.533.A.11.i；A.534.A.11.i；A.535.A.11.i；
A.536.A.11.i；A.537.A.11.i；A.538.A.11.i；A.539.A.11.i；A.540.A.11.i；A.541.A.11.i；
A.542.A.11.i；A.543.A.11.i；A.544.A.11.i；A.545.A.11.i；A.546.A.11.i；A.547.A.11.i；
A.548.A.11.i；A.549.A.11.i；A.550.A.11.i；A.551.A.11.i；A.552.A.11.i；A.553.A.11.i；
A.554.A.11.i；A.555.A.11.i；A.556.A.11.i；A.557.A.11.i；A.558.A.11.i；A.559.A.11.i；
A.560.A.11.i；A.561.A.11.i；A.562.A.11.i；A.563.A.11.i；A.564.A.11.i；A.565.A.11.i；
A.566.A.11.i；A.567.A.11.i；A.568.A.11.i；A.569.A.11.i；A.570.A.11.i；A.571.A.11.i；
A.572.A.11.i；A.573.A.11.i；A.574.A.11.i；A.575.A.11.i；A.576.A.11.i；A.577.A.11.i；
A.578.A.11.i；A.579.A.11.i；A.580.A.11.i；A.581.A.11.i；A.582.A.11.i；A.583.A.11.i；
A.584.A.11.i；A.585.A.11.i；A.586.A.11.i；A.587.A.11.i；A.588.A.11.i；A.589.A.11.i；
A.590.A.11.i；A.591.A.11.i；A.592.A.11.i；A.593.A.11.i；A.594.A.11.i；A.595.A.11.i；
A.596.A.11.i；A.597.A.11.i；A.598.A.11.i；A.599.A.11.i；A.600.A.11.i；A.601.A.11.i；
A.602.A.11.i；A.603.A.11.i；A.604.A.11.i；A.605.A.11.i；A.606.A.11.i；A.607.A.11.i；
A.608.A.11.i；A.609.A.11.i；A.610.A.11.i；A.611.A.11.i；A.612.A.11.i；A.613.A.11.i；
A.614.A.11.i；A.615.A.11.i；A.616.A.11.i；A.617.A.11.i；A.618.A.11.i；A.619.A.11.i；
A.620.A.11.i；A.621.A.11.i；A.622.A.11.i；A.623.A.11.i；A.624.A.11.i；A.625.A.11.i；
A.626.A.11.i；A.627.A.11.i；A.628.A.11.i；A.629.A.11.i；A.630.A.11.i；A.631.A.11.i；
A.632.A.11.i；A.633.A.11.i；A.634.A.11.i；A.635.A.11.i；A.636.A.11.i；A.637.A.11.i；
A.638.A.11.i；A.639.A.11.i；A.640.A.11.i；A.641.A.11.i；A.642.A.11.i；A.643.A.11.i；
A.644.A.11.i；A.645.A.11.i；A.646.A.11.i；A.647.A.11.i；A.648.A.11.i；A.649.A.11.i；
A.650.A.11.i；A.651.A.11.i；A.652.A.11.i；A.653.A.11.i；A.654.A.11.i；A.655.A.11.i；
A.656.A.11.i；A.657.A.11.i；A.658.A.11.i；A.659.A.11.i；A.660.A.11.i；A.2.B.4.i；
A.3.B.4.i；A.4.B.4.i；A.5.B.4.i；A.6.B.4.i；A.7.B.4.i；A.9.B.4.i；A.10.B.4.i；A.15.B.4.i；
A.100.B.4.i；A.101.B.4.i；A.102.B.4.i；A.103.B.4.i；A.104.B.4.i；A.105.B.4.i；
A.106.B.4.i；A.107.B.4.i；A.108.B.4.i；A.109.B.4.i；A.110.B.4.i；A.111.B.4.i；
A.112.B.4.i；A.113.B.4.i；A.114.B.4.i；A.115.B.4.i；A.116.B.4.i；A.117.B.4.i；
A.118.B.4.i；A.119.B.4.i；A.120.B.4.i；A.121.B.4.i；A.122.B.4.i；A.123.B.4.i；
A.124.B.4.i；A.125.B.4.i；A.126.B.4.i；A.127.B.4.i；A.128.B.4.i；A.129.B.4.i；
A.130.B.4.i；A.131.B.4.i；A.132.B.4.i；A.133.B.4.i；A.134.B.4.i；A.135.B.4.i；
A.136.B.4.i；A.137.B.4.i；A.138.B.4.i；A.139.B.4.i；A.140.B.4.i；A.141.B.4.i；
A.142.B.4.i；A.143.B.4.i；A.144.B.4.i；A.145.B.4.i；A.146.B.4.i；A.147.B.4.i；
A.148.B.4.i；A.149.B.4.i；A.150.B.4.i；A.151.B.4.i；A.152.B.4.i；A.153.B.4.i；
A.154.B.4.i；A.155.B.4.i；A.156.B.4.i；A.157.B.4.i；A.158.B.4.i；A.159.B.4.i；
A.160.B.4.i；A.161.B.4.i；A.162.B.4.i；A.163.B.4.i；A.164.B.4.i；A.165.B.4.i；
A.166.B.4.i；A.167.B.4.i；A.168.B.4.i；A.169.B.4.i；A.170.B.4.i；A.171.B.4.i；
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.177.B.4.i；
A.178.B.4.i；A.179.B.4.i；A.180.B.4.i；A.181.B.4.i；A.182.B.4.i；A.183.B.4.i；
A.184.B.4.i；A.185.B.4.i；A.186.B.4.i；A.187.B.4.i；A.188.B.4.i；A.189.B.4.i；
A.190.B.4.i；A.191.B.4.i；A.192.B.4.i；A.193.B.4.i；A.194.B.4.i；A.195.B.4.i；
A.196.B.4.i；A.197.B.4.i；A.198.B.4.i；A.199.B.4.i；A.200.B.4.i；A.201.B.4.i；
A.202.B.4.i；A.203.B.4.i；A.204.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.214.B.4.i；A.215.B.4.i；A.216.B.4.i；A.217.B.4.i；A.218.B.4.i；A.219.B.4.i；
A.220.B.4.i；A.221.B.4.i；A.222.B.4.i；A.223.B.4.i；A.224.B.4.i；A.225.B.4.i；
A.226.B.4.i；A.227.B.4.i；A.228.B.4.i；A.229.B.4.i；A.230.B.4.i；A.231.B.4.i；
A.232.B.4.i；A.233.B.4.i；A.234.B.4.i；A.235.B.4.i；A.236.B.4.i；A.237.B.4.i；
A.238.B.4.i；A.239.B.4.i；A.240.B.4.i；A.241.B.4.i；A.242.B.4.i；A.243.B.4.i；
A.244.B.4.i；A.245.B.4.i；A.246.B.4.i；A.247.B.4.i；A.248.B.4.i；A.249.B.4.i；
A.250.B.4.i；A.251.B.4.i；A.252.B.4.i；A.253.B.4.i；A.254.B.4.i；A.255.B.4.i；
A.256.B.4.i；A.257.B.4.i；A.258.B.4.i；A.259.B.4.i；A.260.B.4.i；A.261.B.4.i；
A.262.B.4.i；A.263.B.4.i；A.264.B.4.i；A.265.B.4.i；A.266.B.4.i；A.267.B.4.i；
A.268.B.4.i；A.269.B.4.i；A.270.B.4.i；A.271.B.4.i；A.272.B.4.i；A.273.B.4.i；
A.274.B.4.i；A.275.B.4.i；A.276.B.4.i；A.277.B.4.i；A.278.B.4.i；A.279.B.4.i；
A.280.B.4.i；A.281.B.4.i；A.282.B.4.i；A.283.B.4.i；A.284.B.4.i；A.285.B.4.i；
A.286.B.4.i；A.287.B.4.i；A.288.B.4.i；A.289.B.4.i；A.290.B.4.i；A.291.B.4.i；
A.292.B.4.i；A.293.B.4.i；A.294.B.4.i；A.295.B.4.i；A.296.B.4.i；A.297.B.4.i；
A.298.B.4.i；A.299.B.4.i；A.300.B.4.i；A.301.B.4.i；A.302.B.4.i；A.303.B.4.i；
A.304.B.4.i；A.305.B.4.i；A.306.B.4.i；A.307.B.4.i；A.308.B.4.i；A.309.B.4.i；
A.310.B.4.i；A.311.B.4.i；A.312.B.4.i；A.313.B.4.i；A.314.B.4.i；A.315.B.4.i；
A.316.B.4.i；A.317.B.4.i；A.318.B.4.i；A.319.B.4.i；A.320.B.4.i；A.321.B.4.i；
A.323.B.4.i；A.324.B.4.i；A.325.B.4.i；A.326.B.4.i；A.327.B.4.i；A.328.B.4.i；
A.329.B.4.i；A.330.B.4.i；A.331.B.4.i；A.332.B.4.i；A.333.B.4.i；A.334.B.4.i；
A.335.B.4.i；A.336.B.4.i；A.337.B.4.i；A.338.B.4.i；A.339.B.4.i；A.340.B.4.i；
A.341.B.4.i；A.342.B.4.i；A.343.B.4.i；A.344.B.4.i；A.345.B.4.i；A.346.B.4.i；
A.347.B.4.i；A.348.B.4.i；A.349.B.4.i；A.350.B.4.i；A.351.B.4.i；A.352.B.4.i；
A.353.B.4.i；A.354.B.4.i；A.355.B.4.i；A.356.B.4.i；A.357.B.4.i；A.358.B.4.i；
A.359.B.4.i；A.360.B.4.i；A.361.B.4.i；A.362.B.4.i；A.363.B.4.i；A.364.B.4.i；
A.365.B.4.i；A.366.B.4.i；A.367.B.4.i；A.368.B.4.i；A.369.B.4.i；A.370.B.4.i；
A.371.B.4.i；A.372.B.4.i；A.373.B.4.i；A.374.B.4.i；A.375.B.4.i；A.376.B.4.i；
A.377.B.4.i；A.378.B.4.i；A.379.B.4.i；A.380.B.4.i；A.381.B.4.i；A.382.B.4.i；
A.383.B.4.i；A.384.B.4.i；A.385.B.4.i；A.386.B.4.i；A.387.B.4.i；A.388.B.4.i；
A.389.B.4.i；A.390.B.4.i；A.391.B.4.i；A.392.B.4.i；A.393.B.4.i；A.394.B.4.i；
A.395.B.4.i；A.396.B.4.i；A.397.B.4.i；A.398.B.4.i；A.399.B.4.i；A.400.B.4.i；
A.401.B.4.i；A.402.B.4.i；A.403.B.4.i；A.404.B.4.i；A.405.B.4.i；A.406.B.4.i；
A.407.B.4.i；A.408.B.4.i；A.409.B.4.i；A.410.B.4.i；A.411.B.4.i；A.412.B.4.i；
A.413.B.4.i；A.414.B.4.i；A.415.B.4.i；A.416.B.4.i；A.417.B.4.i；A.418.B.4.i；
A.419.B.4.i；A.420.B.4.i；A.421.B.4.i；A.422.B.4.i；A.423.B.4.i；A.424.B.4.i；
A.425.B.4.i；A.426.B.4.i；A.427.B.4.i；A.428.B.4.i；A.429.B.4.i；A.430.B.4.i；
A.431.B.4.i；A.432.B.4.i；A.433.B.4.i；A.434.B.4.i；A.435.B.4.i；A.436.B.4.i；
A.437.B.4.i；A.438.B.4.i；A.439.B.4.i；A.440.B.4.i；A.441.B.4.i；A.442.B.4.i；
A.443.B.4.i；A.444.B.4.i；A.445.B.4.i；A.446.B.4.i；A.447.B.4.i；A.448.B.4.i；
A.449.B.4.i；A.450.B.4.i；A.451.B.4.i；A.452.B.4.i；A.453.B.4.i；A.454.B.4.i；
A.455.B.4.i；A.456.B.4.i；A.457.B.4.i；A.458.B.4.i；A.459.B.4.i；A.460.B.4.i；
A.461.B.4.i；A.462.B.4.i；A.463.B.4.i；A.464.B.4.i；A.465.B.4.i；A.466.B.4.i；
A.467.B.4.i；A.468.B.4.i；A.469.B.4.i；A.470.B.4.i；A.471.B.4.i；A.472.B.4.i；
A.473.B.4.i；A.474.B.4.i；A.475.B.4.i；A.476.B.4.i；A.477.B.4.i；A.478.B.4.i；
A.479.B.4.i；A.480.B.4.i；A.481.B.4.i；A.482.B.4.i；A.483.B.4.i；A.484.B.4.i；
A.485.B.4.i；A.486.B.4.i；A.487.B.4.i；A.488.B.4.i；A.489.B.4.i；A.490.B.4.i；
A.491.B.4.i；A.492.B.4.i；A.493.B.4.i；A.494.B.4.i；A.495.B.4.i；A.496.B.4.i；
A.497.B.4.i；A.498.B.4.i；A.499.B.4.i；A.500.B.4.i；A.501.B.4.i；A.502.B.4.i；
A.503.B.4.i；A.504.B.4.i；A.505.B.4.i；A.506.B.4.i；A.507.B.4.i；A.508.B.4.i；
A.509.B.4.i；A.510.B.4.i；A.511.B.4.i；A.512.B.4.i；A.512.B.4.i；A.513.B.4.i；
A.514.B.4.i；A.515.B.4.i；A.516.B.4.i；A.517.B.4.i；A.518.B.4.i；A.519.B.4.i；
A.520.B.4.i；A.521.B.4.i；A.522.B.4.i；A.523.B.4.i；A.524.B.4.i；A.525.B.4.i；
A.526.B.4.i；A.527.B.4.i；A.528.B.4.i；A.529.B.4.i；A.530.B.4.i；A.531.B.4.i；
A.532.B.4.i；A.533.B.4.i；A.534.B.4.i；A.535.B.4.i；A.536.B.4.i；A.537.B.4.i；
A.538.B.4.i；A.539.B.4.i；A.540.B.4.i；A.541.B.4.i；A.542.B.4.i；A.543.B.4.i；
A.544.B.4.i；A.545.B.4.i；A.546.B.4.i；A.547.B.4.i；A.548.B.4.i；A.549.B.4.i；
A.550.B.4.i；A.551.B.4.i；A.552.B.4.i；A.553.B.4.i；A.554.B.4.i；A.555.B.4.i；
A.556.B.4.i；A.557.B.4.i；A.558.B.4.i；A.559.B.4.i；A.560.B.4.i；A.561.B.4.i；
A.562.B.4.i；A.563.B.4.i；A.564.B.4.i；A.565.B.4.i；A.566.B.4.i；A.567.B.4.i；
A.568.B.4.i；A.569.B.4.i；A.570.B.4.i；A.571.B.4.i；A.572.B.4.i；A.573.B.4.i；
A.574.B.4.i；A.575.B.4.i；A.576.B.4.i；A.577.B.4.i；A.578.B.4.i；A.579.B.4.i；
A.580.B.4.i；A.581.B.4.i；A.582.B.4.i；A.583.B.4.i；A.584.B.4.i；A.585.B.4.i；
A.586.B.4.i；A.587.B.4.i；A.588.B.4.i；A.589.B.4.i；A.590.B.4.i；A.591.B.4.i；
A.592.B.4.i；A.593.B.4.i；A.594.B.4.i；A.595.B.4.i；A.596.B.4.i；A.597.B.4.i；
A.598.B.4.i；A.599.B.4.i；A.600.B.4.i；A.601.B.4.i；A.602.B.4.i；A.603.B.4.i；
A.604.B.4.i；A.605.B.4.i；A.606.B.4.i；A.607.B.4.i；A.608.B.4.i；A.609.B.4.i；
A.610.B.4.i；A.611.B.4.i；A.612.B.4.i；A.613.B.4.i；A.614.B.4.i；A.615.B.4.i；
A.616.B.4.i；A.617.B.4.i；A.618.B.4.i；A.619.B.4.i；A.620.B.4.i；A.621.B.4.i；
A.622.B.4.i；A.623.B.4.i；A.624.B.4.i；A.625.B.4.i；A.626.B.4.i；A.627.B.4.i；
A.628.B.4.i；A.629.B.4.i；A.630.B.4.i；A.631.B.4.i；A.632.B.4.i；A.633.B.4.i；
A.634.B.4.i；A.635.B.4.i；A.636.B.4.i；A.637.B.4.i；A.638.B.4.i；A.639.B.4.i；
A.640.B.4.i；A.641.B.4.i；A.642.B.4.i；A.643.B.4.i；A.644.B.4.i；A.645.B.4.i；
A.646.B.4.i；A.647.B.4.i；A.648.B.4.i；A.649.B.4.i；A.650.B.4.i；A.651.B.4.i；
A.652.B.4.i；A.653.B.4.i；A.654.B.4.i；A.655.B.4.i；A.656.B.4.i；A.657.B.4.i；
A.658.B.4.i；A.659.B.4.i；A.660.B.4.i；A.2.B.11.i；A.3.B.11.i；A.4.B.11.i；A.5.B.11.i；
A.6.B.11.i；A.7.B.11.i；A.9.B.11.i；A.10.B.11.i；A.15.B.11.i；A.100.B.11.i；
A.101.B.11.i；A.102.B.11.i；A.103.B.11.i；A.104.B.11.i；A.105.B.11.i；A.106.B.11.i；
A.107.B.11.i；A.108.B.11.i；A.109.B.11.i；A.110.B.11.i；A.111.B.11.i；A.112.B.11.i；
A.113.B.11.i；A.114.B.11.i；A.115.B.11.i；A.116.B.11.i；A.117.B.11.i；A.118.B.11.i；
A.119.B.11.i；A.120.B.11.i；A.121.B.11.i；A.122.B.11.i；A.123.B.11.i；A.124.B.11.i；
A.125.B.11.i；A.126.B.11.i；A.127.B.11.i；A.128.B.11.i；A.129.B.11.i；A.130.B.11.i；
A.131.B.11.i；A.132.B.11.i；A.133.B.11.i；A.134.B.11.i；A.135.B.11.i；A.136.B.11.i；
A.137.B.11.i；A.138.B.11.i；A.139.B.11.i；A.140.B.11.i；A.141.B.11.i；A.142.B.11.i；
A.143.B.11.i；A.144.B.11.i；A.145.B.11.i；A.146.B.11.i；A.147.B.11.i；A.148.B.11.i；
A.149.B.11.i；A.150.B.11.i；A.151.B.11.i；A.152.B.11.i；A.153.B.11.i；A.154.B.11.i；
A.155.B.11.i；A.156.B.11.i；A.157.B.11.i；A.158.B.11.i；A.159.B.11.i；A.160.B.11.i；
A.161.B.11.i；A.162.B.11.i；A.163.B.11.i；A.164.B.11.i；A.165.B.11.i；A.166.B.11.i；
A.167.B.11.i；A.168.B.11.i；A.169.B.11.i；A.170.B.11.i；A.171.B.11.i；A.172.B.11.i；
A.173.B.11.i；A.174.B.11.i；A.175.B.11.i；A.176.B.11.i；A.177.B.11.i；A.178.B.11.i；
A.179.B.11.i；A.180.B.11.i；A.181.B.11.i；A.182.B.11.i；A.183.B.11.i；A.184.B.11.i；
A.185.B.11.i；A.186.B.11.i；A.187.B.11.i；A.188.B.11.i；A.189.B.11.i；A.190.B.11.i；
A.191.B.11.i；A.192.B.11.i；A.193.B.11.i；A.194.B.11.i；A.195.B.11.i；A.196.B.11.i；
A.197.B.11.i；A.198.B.11.i；A.199.B.11.i；A.200.B.11.i；A.201.B.11.i；A.202.B.11.i；
A.203.B.11.i；A.204.B.11.i；A.205.B.11.i；A.206.B.11.i；A.207.B.11.i；A.208.B.11.i；
A.209.B.11.i；A.210.B.11.i；A.211.B.11.i；A.212.B.11.i；A.213.B.11.i；A.214.B.11.i；
A.215.B.11.i；A.216.B.11.i；A.217.B.11.i；A.218.B.11.i；A.219.B.11.i；A.220.B.11.i；
A.221.B.11.i；A.222.B.11.i；A.223.B.11.i；A.224.B.11.i；A.225.B.11.i；A.226.B.11.i；
A.227.B.11.i；A.228.B.11.i；A.229.B.11.i；A.230.B.11.i；A.231.B.11.i；A.232.B.11.i；
A.233.B.11.i；A.234.B.11.i；A.235.B.11.i；A.236.B.11.i；A.237.B.11.i；A.238.B.11.i；
A.239.B.11.i；A.240.B.11.i；A.241.B.11.i；A.242.B.11.i；A.243.B.11.i；A.244.B.11.i；
A.245.B.11.i；A.246.B.11.i；A.247.B.11.i；A.248.B.11.i；A.249.B.11.i；A.250.B.11.i；
A.251.B.11.i；A.252.B.11.i；A.253.B.11.i；A.254.B.11.i；A.255.B.11.i；A.256.B.11.i；
A.257.B.11.i；A.258.B.11.i；A.259.B.11.i；A.260.B.11.i；A.261.B.11.i；A.262.B.11.i；
A.263.B.11.i；A.264.B.11.i；A.265.B.11.i；A.266.B.11.i；A.267.B.11.i；A.268.B.11.i；
A.269.B.11.i；A.270.B.11.i；A.271.B.11.i；A.272.B.11.i；A.273.B.11.i；A.274.B.11.i；
A.275.B.11.i；A.276.B.11.i；A.277.B.11.i；A.278.B.11.i；A.279.B.11.i；A.280.B.11.i；
A.281.B.11.i；A.282.B.11.i；A.283.B.11.i；A.284.B.11.i；A.285.B.11.i；A.286.B.11.i；
A.287.B.11.i；A.288.B.11.i；A.289.B.11.i；A.290.B.11.i；A.291.B.11.i；A.292.B.11.i；
A.293.B.11.i；A.294.B.11.i；A.295.B.11.i；A.296.B.11.i；A.297.B.11.i；A.298.B.11.i；
A.299.B.11.i；A.300.B.11.i；A.301.B.11.i；A.302.B.11.i；A.303.B.11.i；A.304.B.11.i；
A.305.B.11.i；A.306.B.11.i；A.307.B.11.i；A.308.B.11.i；A.309.B.11.i；A.310.B.11.i；
A.311.B.11.i；A.312.B.11.i；A.313.B.11.i；A.314.B.11.i；A.315.B.11.i；A.316.B.11.i；
A.317.B.11.i；A.318.B.11.i；A.319.B.11.i；A.320.B.11.i；A.321.B.11.i；A.323.B.11.i；
A.324.B.11.i；A.325.B.11.i；A.326.B.11.i；A.327.B.11.i；A.328.B.11.i；A.329.B.11.i；
A.330.B.11.i；A.331.B.11.i；A.332.B.11.i；A.333.B.11.i；A.334.B.11.i；A.335.B.11.i；
A.336.B.11.i；A.337.B.11.i；A.338.B.11.i；A.339.B.11.i；A.340.B.11.i；A.341.B.11.i；
A.342.B.11.i；A.343.B.11.i；A.344.B.11.i；A.345.B.11.i；A.346.B.11.i；A.347.B.11.i；
A.348.B.11.i；A.349.B.11.i；A.350.B.11.i；A.351.B.11.i；A.352.B.11.i；A.353.B.11.i；
A.354.B.11.i；A.355.B.11.i；A.356.B.11.i；A.357.B.11.i；A.358.B.11.i；A.359.B.11.i；
A.360.B.11.i；A.361.B.11.i；A.362.B.11.i；A.363.B.11.i；A.364.B.11.i；A.365.B.11.i；
A.366.B.11.i；A.367.B.11.i；A.368.B.11.i；A.369.B.11.i；A.370.B.11.i；A.371.B.11.i；
A.372.B.11.i；A.373.B.11.i；A.374.B.11.i；A.375.B.11.i；A.376.B.11.i；A.377.B.11.i；
A.378.B.11.i；A.379.B.11.i；A.380.B.11.i；A.381.B.11.i；A.382.B.11.i；A.383.B.11.i；
A.384.B.11.i；A.385.B.11.i；A.386.B.11.i；A.387.B.11.i；A.388.B.11.i；A.389.B.11.i；
A.390.B.11.i；A.391.B.11.i；A.392.B.11.i；A.393.B.11.i；A.394.B.11.i；A.395.B.11.i；
A.396.B.11.i；A.397.B.11.i；A.398.B.11.i；A.399.B.11.i；A.400.B.11.i；A.401.B.11.i；
A.402.B.11.i；A.403.B.11.i；A.404.B.11.i；A.405.B.11.i；A.406.B.11.i；A.407.B.11.i；
A.408.B.11.i；A.409.B.11.i；A.410.B.11.i；A.411.B.11.i；A.412.B.11.i；A.413.B.11.i；
A.414.B.11.i；A.415.B.11.i；A.416.B.11.i；A.417.B.11.i；A.418.B.11.i；A.419.B.11.i；
A.420.B.11.i；A.421.B.11.i；A.422.B.11.i；A.423.B.11.i；A.424.B.11.i；A.425.B.11.i；
A.426.B.11.i；A.427.B.11.i；A.428.B.11.i；A.429.B.11.i；A.430.B.11.i；A.431.B.11.i；
A.432.B.11.i；A.433.B.11.i；A.434.B.11.i；A.435.B.11.i；A.436.B.11.i；A.437.B.11.i；
A.438.B.11.i；A.439.B.11.i；A.440.B.11.i；A.441.B.11.i；A.442.B.11.i；A.443.B.11.i；
A.444.B.11.i；A.445.B.11.i；A.446.B.11.i；A.447.B.11.i；A.448.B.11.i；A.449.B.11.i；
A.450.B.11.i；A.451.B.11.i；A.452.B.11.i；A.453.B.11.i；A.454.B.11.i；A.455.B.11.i；
A.456.B.11.i；A.457.B.11.i；A.458.B.11.i；A.459.B.11.i；A.460.B.11.i；A.461.B.11.i；
A.462.B.11.i；A.463.B.11.i；A.464.B.11.i；A.465.B.11.i；A.466.B.11.i；A.467.B.11.i；
A.468.B.11.i；A.469.B.11.i；A.470.B.11.i；A.471.B.11.i；A.472.B.11.i；A.473.B.11.i；
A.474.B.11.i；A.475.B.11.i；A.476.B.11.i；A.477.B.11.i；A.478.B.11.i；A.479.B.11.i；
A.480.B.11.i；A.481.B.11.i；A.482.B.11.i；A.483.B.11.i；A.484.B.11.i；A.485.B.11.i；
A.486.B.11.i；A.487.B.11.i；A.488.B.11.i；A.489.B.11.i；A.490.B.11.i；A.491.B.11.i；
A.492.B.11.i；A.493.B.11.i；A.494.B.11.i；A.495.B.11.i；A.496.B.11.i；A.497.B.11.i；
A.498.B.11.i；A.499.B.11.i；A.500.B.11.i；A.501.B.11.i；A.502.B.11.i；A.503.B.11.i；
A.504.B.11.i；A.505.B.11.i；A.506.B.11.i；A.507.B.11.i；A.508.B.11.i；A.509.B.11.i；
A.510.B.11.i；A.511.B.11.i；A.512.B.11.i；A.512.B.11.i；A.513.B.11.i；A.514.B.11.i；
A.515.B.11.i；A.516.B.11.i；A.517.B.11.i；A.518.B.11.i；A.519.B.11.i；A.520.B.11.i；
A.521.B.11.i；A.522.B.11.i；A.523.B.11.i；A.524.B.11.i；A.525.B.11.i；A.526.B.11.i；
A.527.B.11.i；A.528.B.11.i；A.529.B.11.i；A.530.B.11.i；A.531.B.11.i；A.532.B.11.i；
A.533.B.11.i；A.534.B.11.i；A.535.B.11.i；A.536.B.11.i；A.537.B.11.i；A.538.B.11.i；
A.539.B.11.i；A.540.B.11.i；A.541.B.11.i；A.542.B.11.i；A.543.B.11.i；A.544.B.11.i；
A.545.B.11.i；A.546.B.11.i；A.547.B.11.i；A.548.B.11.i；A.549.B.11.i；A.550.B.11.i；
A.551.B.11.i；A.552.B.11.i；A.553.B.11.i；A.554.B.11.i；A.555.B.11.i；A.556.B.11.i；
A.557.B.11.i；A.558.B.11.i；A.559.B.11.i；A.560.B.11.i；A.561.B.11.i；A.562.B.11.i；
A.563.B.11.i；A.564.B.11.i；A.565.B.11.i；A.566.B.11.i；A.567.B.11.i；A.568.B.11.i；
A.569.B.11.i；A.570.B.11.i；A.571.B.11.i；A.572.B.11.i；A.573.B.11.i；A.574.B.11.i；
A.575.B.11.i；A.576.B.11.i；A.577.B.11.i；A.578.B.11.i；A.579.B.11.i；A.580.B.11.i；
A.581.B.11.i；A.582.B.11.i；A.583.B.11.i；A.584.B.11.i；A.585.B.11.i；A.586.B.11.i；
A.587.B.11.i；A.588.B.11.i；A.589.B.11.i；A.590.B.11.i；A.591.B.11.i；A.592.B.11.i；
A.593.B.11.i；A.594.B.11.i；A.595.B.11.i；A.596.B.11.i；A.597.B.11.i；A.598.B.11.i；
A.599.B.11.i；A.600.B.11.i；A.601.B.11.i；A.602.B.11.i；A.603.B.11.i；A.604.B.11.i；
A.605.B.11.i；A.606.B.11.i；A.607.B.11.i；A.608.B.11.i；A.609.B.11.i；A.610.B.11.i；
A.611.B.11.i；A.612.B.11.i；A.613.B.11.i；A.614.B.11.i；A.615.B.11.i；A.616.B.11.i；
A.617.B.11.i；A.618.B.11.i；A.619.B.11.i；A.620.B.11.i；A.621.B.11.i；A.622.B.11.i；
A.623.B.11.i；A.624.B.11.i；A.625.B.11.i；A.626.B.11.i；A.627.B.11.i；A.628.B.11.i；
A.629.B.11.i；A.630.B.11.i；A.631.B.11.i；A.632.B.11.i；A.633.B.11.i；A.634.B.11.i；
A.635.B.11.i；A.636.B.11.i；A.637.B.11.i；A.638.B.11.i；A.639.B.11.i；A.640.B.11.i；
A.641.B.11.i；A.642.B.11.i；A.643.B.11.i；A.644.B.11.i；A.645.B.11.i；A.646.B.11.i；
A.647.B.11.i；A.648.B.11.i；A.649.B.11.i；A.650.B.11.i；A.651.B.11.i；A.652.B.11.i；
A.653.B.11.i；A.654.B.11.i；A.655.B.11.i；A.656.B.11.i；A.657.B.11.i；A.658.B.11.i；
A.659.B.11.i；A.660.B.11.i；A.2.C.4.i；A.3.C.4.i；A.4.C.4.i；A.5.C.4.i；A.6.C.4.i；
A.7.C.4.i；A.9.C.4.i；A.10.C.4.i；A.15.C.4.i；A.100.C.4.i；A.101.C.4.i；A.102.C.4.i；
A.103.C.4.i；A.104.C.4.i；A.105.C.4.i；A.106.C.4.i；A.107.C.4.i；A.108.C.4.i；
A.109.C.4.i；A.110.C.4.i；A.111.C.4.i；A.112.C.4.i；A.113.C.4.i；A.114.C.4.i；
A.115.C.4.i；A.116.C.4.i；A.117.C.4.i；A.118.C.4.i；A.119.C.4.i；A.120.C.4.i；
A.121.C.4.i；A.122.C.4.i；A.123.C.4.i；A.124.C.4.i；A.125.C.4.i；A.126.C.4.i；
A.127.C.4.i；A.128.C.4.i；A.129.C.4.i；A.130.C.4.i；A.131.C.4.i；A.132.C.4.i；
A.133.C.4.i；A.134.C.4.i；A.135.C.4.i；A.136.C.4.i；A.137.C.4.i；A.138.C.4.i；
A.139.C.4.i；A.140.C.4.i；A.141.C.4.i；A.142.C.4.i；A.143.C.4.i；A.144.C.4.i；
A.145.C.4.i；A.146.C.4.i；A.147.C.4.i；A.148.C.4.i；A.149.C.4.i；A.150.C.4.i；
A.151.C.4.i；A.152.C.4.i；A.153.C.4.i；A.154.C.4.i；A.155.C.4.i；A.156.C.4.i；
A.157.C.4.i；A.158.C.4.i；A.159.C.4.i；A.160.C.4.i；A.161.C.4.i；A.162.C.4.i；
A.163.C.4.i；A.164.C.4.i；A.165.C.4.i；A.166.C.4.i；A.167.C.4.i；A.168.C.4.i；
A.169.C.4.i；A.170.C.4.i；A.171.C.4.i；A.172.C.4.i；A.173.C.4.i；A.174.C.4.i；
A.175.C.4.i；A.176.C.4.i；A.177.C.4.i；A.178.C.4.i；A.179.C.4.i；A.180.C.4.i；
A.181.C.4.i；A.182.C.4.i；A.183.C.4.i；A.184.C.4.i；A.185.C.4.i；A.186.C.4.i；
A.187.C.4.i；A.188.C.4.i；A.189.C.4.i；A.190.C.4.i；A.191.C.4.i；A.192.C.4.i；
A.193.C.4.i；A.194.C.4.i；A.195.C.4.i；A.196.C.4.i；A.197.C.4.i；A.198.C.4.i；
A.199.C.4.i；A.200.C.4.i；A.201.C.4.i；A.202.C.4.i；A.203.C.4.i；A.204.C.4.i；
A.205.C.4.i；A.206.C.4.i；A.207.C.4.i；A.208.C.4.i；A.209.C.4.i；A.210.C.4.i；
A.211.C.4.i；A.212.C.4.i；A.213.C.4.i；A.214.C.4.i；A.215.C.4.i；A.216.C.4.i；
A.217.C.4.i；A.218.C.4.i；A.219.C.4.i；A.220.C.4.i；A.221.C.4.i；A.222.C.4.i；
A.223.C.4.i；A.224.C.4.i；A.225.C.4.i；A.226.C.4.i；A.227.C.4.i；A.228.C.4.i；
A.229.C.4.i；A.230.C.4.i；A.231.C.4.i；A.232.C.4.i；A.233.C.4.i；A.234.C.4.i；
A.235.C.4.i；A.236.C.4.i；A.237.C.4.i；A.238.C.4.i；A.239.C.4.i；A.240.C.4.i；
A.241.C.4.i；A.242.C.4.i；A.243.C.4.i；A.244.C.4.i；A.245.C.4.i；A.246.C.4.i；
A.247.C.4.i；A.248.C.4.i；A.249.C.4.i；A.250.C.4.i；A.251.C.4.i；A.252.C.4.i；
A.253.C.4.i；A.254.C.4.i；A.255.C.4.i；A.256.C.4.i；A.257.C.4.i；A.258.C.4.i；
A.259.C.4.i；A.260.C.4.i；A.261.C.4.i；A.262.C.4.i；A.263.C.4.i；A.264.C.4.i；
A.265.C.4.i；A.266.C.4.i；A.267.C.4.i；A.268.C.4.i；A.269.C.4.i；A.270.C.4.i；
A.271.C.4.i；A.272.C.4.i；A.273.C.4.i；A.274.C.4.i；A.275.C.4.i；A.276.C.4.i；
A.277.C.4.i；A.278.C.4.i；A.279.C.4.i；A.280.C.4.i；A.281.C.4.i；A.282.C.4.i；
A.283.C.4.i；A.284.C.4.i；A.285.C.4.i；A.286.C.4.i；A.287.C.4.i；A.288.C.4.i；
A.289.C.4.i；A.290.C.4.i；A.291.C.4.i；A.292.C.4.i；A.293.C.4.i；A.294.C.4.i；
A.295.C.4.i；A.296.C.4.i；A.297.C.4.i；A.298.C.4.i；A.299.C.4.i；A.300.C.4.i；
A.301.C.4.i；A.302.C.4.i；A.303.C.4.i；A.304.C.4.i；A.305.C.4.i；A.306.C.4.i；
A.307.C.4.i；A.308.C.4.i；A.309.C.4.i；A.310.C.4.i；A.311.C.4.i；A.312.C.4.i；
A.313.C.4.i；A.314.C.4.i；A.315.C.4.i；A.316.C.4.i；A.317.C.4.i；A.318.C.4.i；
A.319.C.4.i；A.320.C.4.i；A.321.C.4.i；A.323.C.4.i；A.324.C.4.i；A.325.C.4.i；
A.326.C.4.i；A.327.C.4.i；A.328.C.4.i；A.329.C.4.i；A.330.C.4.i；A.331.C.4.i；
A.332.C.4.i；A.333.C.4.i；A.334.C.4.i；A.335.C.4.i；A.336.C.4.i；A.337.C.4.i；
A.338.C.4.i；A.339.C.4.i；A.340.C.4.i；A.341.C.4.i；A.342.C.4.i；A.343.C.4.i；
A.344.C.4.i；A.345.C.4.i；A.346.C.4.i；A.347.C.4.i；A.348.C.4.i；A.349.C.4.i；
A.350.C.4.i；A.351.C.4.i；A.352.C.4.i；A.353.C.4.i；A.354.C.4.i；A.355.C.4.i；
A.356.C.4.i；A.357.C.4.i；A.358.C.4.i；A.359.C.4.i；A.360.C.4.i；A.361.C.4.i；
A.362.C.4.i；A.363.C.4.i；A.364.C.4.i；A.365.C.4.i；A.366.C.4.i；A.367.C.4.i；
A.368.C.4.i；A.369.C.4.i；A.370.C.4.i；A.371.C.4.i；A.372.C.4.i；A.373.C.4.i；
A.374.C.4.i；A.375.C.4.i；A.376.C.4.i；A.377.C.4.i；A.378.C.4.i；A.379.C.4.i；
A.380.C.4.i；A.381.C.4.i；A.382.C.4.i；A.383.C.4.i；A.384.C.4.i；A.385.C.4.i；
A.386.C.4.i；A.387.C.4.i；A.388.C.4.i；A.389.C.4.i；A.390.C.4.i；A.391.C.4.i；
A.392.C.4.i；A.393.C.4.i；A.394.C.4.i；A.395.C.4.i；A.396.C.4.i；A.397.C.4.i；
A.398.C.4.i；A.399.C.4.i；A.400.C.4.i；A.401.C.4.i；A.402.C.4.i；A.403.C.4.i；
A.404.C.4.i；A.405.C.4.i；A.406.C.4.i；A.407.C.4.i；A.408.C.4.i；A.409.C.4.i；
A.410.C.4.i；A.411.C.4.i；A.412.C.4.i；A.413.C.4.i；A.414.C.4.i；A.415.C.4.i；
A.416.C.4.i；A.417.C.4.i；A.418.C.4.i；A.419.C.4.i；A.420.C.4.i；A.421.C.4.i；
A.422.C.4.i；A.423.C.4.i；A.424.C.4.i；A.425.C.4.i；A.426.C.4.i；A.427.C.4.i；
A.428.C.4.i；A.429.C.4.i；A.430.C.4.i；A.431.C.4.i；A.432.C.4.i；A.433.C.4.i；
A.434.C.4.i；A.435.C.4.i；A.436.C.4.i；A.437.C.4.i；A.438.C.4.i；A.439.C.4.i；
A.440.C.4.i；A.441.C.4.i；A.442.C.4.i；A.443.C.4.i；A.444.C.4.i；A.445.C.4.i；
A.446.C.4.i；A.447.C.4.i；A.448.C.4.i；A.449.C.4.i；A.450.C.4.i；A.451.C.4.i；
A.452.C.4.i；A.453.C.4.i；A.454.C.4.i；A.455.C.4.i；A.456.C.4.i；A.457.C.4.i；
A.458.C.4.i；A.459.C.4.i；A.460.C.4.i；A.461.C.4.i；A.462.C.4.i；A.463.C.4.i；
A.464.C.4.i；A.465.C.4.i；A.466.C.4.i；A.467.C.4.i；A.468.C.4.i；A.469.C.4.i；
A.470.C.4.i；A.471.C.4.i；A.472.C.4.i；A.473.C.4.i；A.474.C.4.i；A.475.C.4.i；
A.476.C.4.i；A.477.C.4.i；A.478.C.4.i；A.479.C.4.i；A.480.C.4.i；A.481.C.4.i；
A.482.C.4.i；A.483.C.4.i；A.484.C.4.i；A.485.C.4.i；A.486.C.4.i；A.487.C.4.i；
A.488.C.4.i；A.489.C.4.i；A.490.C.4.i；A.491.C.4.i；A.492.C.4.i；A.493.C.4.i；
A.494.C.4.i；A.495.C.4.i；A.496.C.4.i；A.497.C.4.i；A.498.C.4.i；A.499.C.4.i；
A.500.C.4.i；A.501.C.4.i；A.502.C.4.i；A.503.C.4.i；A.504.C.4.i；A.505.C.4.i；
A.506.C.4.i；A.507.C.4.i；A.508.C.4.i；A.509.C.4.i；A.510.C.4.i；A.511.C.4.i；
A.512.C.4.i；A.512.C.4.i；A.513.C.4.i；A.514.C.4.i；A.515.C.4.i；A.516.C.4.i；
A.517.C.4.i；A.518.C.4.i；A.519.C.4.i；A.520.C.4.i；A.521.C.4.i；A.522.C.4.i；
A.523.C.4.i；A.524.C.4.i；A.525.C.4.i；A.526.C.4.i；A.527.C.4.i；A.528.C.4.i；
A.529.C.4.i；A.530.C.4.i；A.531.C.4.i；A.532.C.4.i；A.533.C.4.i；A.534.C.4.i；
A.535.C.4.i；A.536.C.4.i；A.537.C.4.i；A.538.C.4.i；A.539.C.4.i；A.540.C.4.i；
A.541.C.4.i；A.542.C.4.i；A.543.C.4.i；A.544.C.4.i；A.545.C.4.i；A.546.C.4.i；
A.547.C.4.i；A.548.C.4.i；A.549.C.4.i；A.550.C.4.i；A.551.C.4.i；A.552.C.4.i；
A.553.C.4.i；A.554.C.4.i；A.555.C.4.i；A.556.C.4.i；A.557.C.4.i；A.558.C.4.i；
A.559.C.4.i；A.560.C.4.i；A.561.C.4.i；A.562.C.4.i；A.563.C.4.i；A.564.C.4.i；
A.565.C.4.i；A.566.C.4.i；A.567.C.4.i；A.568.C.4.i；A.569.C.4.i；A.570.C.4.i；
A.571.C.4.i；A.572.C.4.i；A.573.C.4.i；A.574.C.4.i；A.575.C.4.i；A.576.C.4.i；
A.577.C.4.i；A.578.C.4.i；A.579.C.4.i；A.580.C.4.i；A.581.C.4.i；A.582.C.4.i；
A.583.C.4.i；A.584.C.4.i；A.585.C.4.i；A.586.C.4.i；A.587.C.4.i；A.588.C.4.i；
A.589.C.4.i；A.590.C.4.i；A.591.C.4.i；A.592.C.4.i；A.593.C.4.i；A.594.C.4.i；
A.595.C.4.i；A.596.C.4.i；A.597.C.4.i；A.598.C.4.i；A.599.C.4.i；A.600.C.4.i；
A.601.C.4.i；A.602.C.4.i；A.603.C.4.i；A.604.C.4.i；A.605.C.4.i；A.606.C.4.i；
A.607.C.4.i；A.608.C.4.i；A.609.C.4.i；A.610.C.4.i；A.611.C.4.i；A.612.C.4.i；
A.613.C.4.i；A.614.C.4.i；A.615.C.4.i；A.616.C.4.i；A.617.C.4.i；A.618.C.4.i；
A.619.C.4.i；A.620.C.4.i；A.621.C.4.i；A.622.C.4.i；A.623.C.4.i；A.624.C.4.i；
A.625.C.4.i；A.626.C.4.i；A.627.C.4.i；A.628.C.4.i；A.629.C.4.i；A.630.C.4.i；
A.631.C.4.i；A.632.C.4.i；A.633.C.4.i；A.634.C.4.i；A.635.C.4.i；A.636.C.4.i；
A.637.C.4.i；A.638.C.4.i；A.639.C.4.i；A.640.C.4.i；A.641.C.4.i；A.642.C.4.i；
A.643.C.4.i；A.644.C.4.i；A.645.C.4.i；A.646.C.4.i；A.647.C.4.i；A.648.C.4.i；
A.649.C.4.i；A.650.C.4.i；A.651.C.4.i；A.652.C.4.i；A.653.C.4.i；A.654.C.4.i；
A.655.C.4.i；A.656.C.4.i；A.657.C.4.i；A.658.C.4.i；A.659.C.4.i；A.660.C.4.i；
A.2.C.11.i；A.3.C.11.i；A.4.C.11.i；A.5.C.11.i；A.6.C.11.i；A.7.C.11.i；A.9.C.11.i；
A.10.C.11.i；A.15.C.11.i；A.100.C.11.i；A.101.C.11.i；A.102.C.11.i；A.103.C.11.i；
A.104.C.11.i；A.105.C.11.i；A.106.C.11.i；A.107.C.11.i；A.108.C.11.i；A.109.C.11.i；
A.110.C.11.i；A.111.C.11.i；A.112.C.11.i；A.113.C.11.i；A.114.C.11.i；A.115.C.11.i；
A.116.C.11.i；A.117.C.11.i；A.118.C.11.i；A.119.C.11.i；A.120.C.11.i；A.121.C.11.i；
A.122.C.11.i；A.123.C.11.i；A.124.C.11.i；A.125.C.11.i；A.126.C.11.i；A.127.C.11.i；
A.128.C.11.i；A.129.C.11.i；A.130.C.11.i；A.131.C.11.i；A.132.C.11.i；A.133.C.11.i；
A.134.C.11.i；A.135.C.11.i；A.136.C.11.i；A.137.C.11.i；A.138.C.11.i；A.139.C.11.i；
A.140.C.11.i；A.141.C.11.i；A.142.C.11.i；A.143.C.11.i；A.144.C.11.i；A.145.C.11.i；
A.146.C.11.i；A.147.C.11.i；A.148.C.11.i；A.149.C.11.i；A.150.C.11.i；A.151.C.11.i；
A.152.C.11.i；A.153.C.11.i；A.154.C.11.i；A.155.C.11.i；A.156.C.11.i；A.157.C.11.i；
A.158.C.11.i；A.159.C.11.i；A.160.C.11.i；A.161.C.11.i；A.162.C.11.i；A.163.C.11.i；
A.164.C.11.i；A.165.C.11.i；A.166.C.11.i；A.167.C.11.i；A.168.C.11.i；A.169.C.11.i；
A.170.C.11.i；A.171.C.11.i；A.172.C.11.i；A.173.C.11.i；A.174.C.11.i；A.175.C.11.i；
A.176.C.11.i；A.177.C.11.i；A.178.C.11.i；A.179.C.11.i；A.180.C.11.i；A.181.C.11.i；
A.182.C.11.i；A.183.C.11.i；A.184.C.11.i；A.185.C.11.i；A.186.C.11.i；A.187.C.11.i；
A.188.C.11.i；A.189.C.11.i；A.190.C.11.i；A.191.C.11.i；A.192.C.11.i；A.193.C.11.i；
A.194.C.11.i；A.195.C.11.i；A.196.C.11.i；A.197.C.11.i；A.198.C.11.i；A.199.C.11.i；
A.200.C.11.i；A.201.C.11.i；A.202.C.11.i；A.203.C.11.i；A.204.C.11.i；A.205.C.11.i；
A.206.C.11.i；A.207.C.11.i；A.208.C.11.i；A.209.C.11.i；A.210.C.11.i；A.211.C.11.i；
A.212.C.11.i；A.213.C.11.i；A.214.C.11.i；A.215.C.11.i；A.216.C.11.i；A.217.C.11.i；
A.218.C.11.i；A.219.C.11.i；A.220.C.11.i；A.221.C.11.i；A.222.C.11.i；A.223.C.11.i；
A.224.C.11.i；A.225.C.11.i；A.226.C.11.i；A.227.C.11.i；A.228.C.11.i；A.229.C.11.i；
A.230.C.11.i；A.231.C.11.i；A.232.C.11.i；A.233.C.11.i；A.234.C.11.i；A.235.C.11.i；
A.236.C.11.i；A.237.C.11.i；A.238.C.11.i；A.239.C.11.i；A.240.C.11.i；A.241.C.11.i；
A.242.C.11.i；A.243.C.11.i；A.244.C.11.i；A.245.C.11.i；A.246.C.11.i；A.247.C.11.i；
A.248.C.11.i；A.249.C.11.i；A.250.C.11.i；A.251.C.11.i；A.252.C.11.i；A.253.C.11.i；
A.254.C.11.i；A.255.C.11.i；A.256.C.11.i；A.257.C.11.i；A.258.C.11.i；A.259.C.11.i；
A.260.C.11.i；A.261.C.11.i；A.262.C.11.i；A.263.C.11.i；A.264.C.11.i；A.265.C.11.i；
A.266.C.11.i；A.267.C.11.i；A.268.C.11.i；A.269.C.11.i；A.270.C.11.i；A.271.C.11.i；
A.272.C.11.i；A.273.C.11.i；A.274.C.11.i；A.275.C.11.i；A.276.C.11.i；A.277.C.11.i；
A.278.C.11.i；A.279.C.11.i；A.280.C.11.i；A.281.C.11.i；A.282.C.11.i；A.283.C.11.i；
A.284.C.11.i；A.285.C.11.i；A.286.C.11.i；A.287.C.11.i；A.288.C.11.i；A.289.C.11.i；
A.290.C.11.i；A.291.C.11.i；A.292.C.11.i；A.293.C.11.i；A.294.C.11.i；A.295.C.11.i；
A.296.C.11.i；A.297.C.11.i；A.298.C.11.i；A.299.C.11.i；A.300.C.11.i；A.301.C.11.i；
A.302.C.11.i；A.303.C.11.i；A.304.C.11.i；A.305.C.11.i；A.306.C.11.i；A.307.C.11.i；
A.308.C.11.i；A.309.C.11.i；A.310.C.11.i；A.311.C.11.i；A.312.C.11.i；A.313.C.11.i；
A.314.C.11.i；A.315.C.11.i；A.316.C.11.i；A.317.C.11.i；A.318.C.11.i；A.319.C.11.i；
A.320.C.11.i；A.321.C.11.i；A.323.C.11.i；A.324.C.11.i；A.325.C.11.i；A.326.C.11.i；
A.327.C.11.i；A.328.C.11.i；A.329.C.11.i；A.330.C.11.i；A.331.C.11.i；A.332.C.11.i；
A.333.C.11.i；A.334.C.11.i；A.335.C.11.i；A.336.C.11.i；A.337.C.11.i；A.338.C.11.i；
A.339.C.11.i；A.340.C.11.i；A.341.C.11.i；A.342.C.11.i；A.343.C.11.i；A.344.C.11.i；
A.345.C.11.i；A.346.C.11.i；A.347.C.11.i；A.348.C.11.i；A.349.C.11.i；A.350.C.11.i；
A.351.C.11.i；A.352.C.11.i；A.353.C.11.i；A.354.C.11.i；A.355.C.11.i；A.356.C.11.i；
A.357.C.11.i；A.358.C.11.i；A.359.C.11.i；A.360.C.11.i；A.361.C.11.i；A.362.C.11.i；
A.363.C.11.i；A.364.C.11.i；A.365.C.11.i；A.366.C.11.i；A.367.C.11.i；A.368.C.11.i；
A.369.C.11.i；A.370.C.11.i；A.371.C.11.i；A.372.C.11.i；A.373.C.11.i；A.374.C.11.i；
A.375.C.11.i；A.376.C.11.i；A.377.C.11.i；A.378.C.11.i；A.379.C.11.i；A.380.C.11.i；
A.381.C.11.i；A.382.C.11.i；A.383.C.11.i；A.384.C.11.i；A.385.C.11.i；A.386.C.11.i；
A.387.C.11.i；A.388.C.11.i；A.389.C.11.i；A.390.C.11.i；A.391.C.11.i；A.392.C.11.i；
A.393.C.11.i；A.394.C.11.i；A.395.C.11.i；A.396.C.11.i；A.397.C.11.i；A.398.C.11.i；
A.399.C.11.i；A.400.C.11.i；A.401.C.11.i；A.402.C.11.i；A.403.C.11.i；A.404.C.11.i；
A.405.C.11.i；A.406.C.11.i；A.407.C.11.i；A.408.C.11.i；A.409.C.11.i；A.410.C.11.i；
A.411.C.11.i；A.412.C.11.i；A.413.C.11.i；A.414.C.11.i；A.415.C.11.i；A.416.C.11.i；
A.417.C.11.i；A.418.C.11.i；A.419.C.11.i；A.420.C.11.i；A.421.C.11.i；A.422.C.11.i；
A.423.C.11.i；A.424.C.11.i；A.425.C.11.i；A.426.C.11.i；A.427.C.11.i；A.428.C.11.i；
A.429.C.11.i；A.430.C.11.i；A.431.C.11.i；A.432.C.11.i；A.433.C.11.i；A.434.C.11.i；
A.435.C.11.i；A.436.C.11.i；A.437.C.11.i；A.438.C.11.i；A.439.C.11.i；A.440.C.11.i；
A.441.C.11.i；A.442.C.11.i；A.443.C.11.i；A.444.C.11.i；A.445.C.11.i；A.446.C.11.i；
A.447.C.11.i；A.448.C.11.i；A.449.C.11.i；A.450.C.11.i；A.451.C.11.i；A.452.C.11.i；
A.453.C.11.i；A.454.C.11.i；A.455.C.11.i；A.456.C.11.i；A.457.C.11.i；A.458.C.11.i；
A.459.C.11.i；A.460.C.11.i；A.461.C.11.i；A.462.C.11.i；A.463.C.11.i；A.464.C.11.i；
A.465.C.11.i；A.466.C.11.i；A.467.C.11.i；A.468.C.11.i；A.469.C.11.i；A.470.C.11.i；
A.471.C.11.i；A.472.C.11.i；A.473.C.11.i；A.474.C.11.i；A.475.C.11.i；A.476.C.11.i；
A.477.C.11.i；A.478.C.11.i；A.479.C.11.i；A.480.C.11.i；A.481.C.11.i；A.482.C.11.i；
A.483.C.11.i；A.484.C.11.i；A.485.C.11.i；A.486.C.11.i；A.487.C.11.i；A.488.C.11.i；
A.489.C.11.i；A.490.C.11.i；A.491.C.11.i；A.492.C.11.i；A.493.C.11.i；A.494.C.11.i；
A.495.C.11.i；A.496.C.11.i；A.497.C.11.i；A.498.C.11.i；A.499.C.11.i；A.500.C.11.i；
A.501.C.11.i；A.502.C.11.i；A.503.C.11.i；A.504.C.11.i；A.505.C.11.i；A.506.C.11.i；
A.507.C.11.i；A.508.C.11.i；A.509.C.11.i；A.510.C.11.i；A.511.C.11.i；A.512.C.11.i；
A.512.C.11.i；A.513.C.11.i；A.514.C.11.i；A.515.C.11.i；A.516.C.11.i；A.517.C.11.i；
A.518.C.11.i；A.519.C.11.i；A.520.C.11.i；A.521.C.11.i；A.522.C.11.i；A.523.C.11.i；
A.524.C.11.i；A.525.C.11.i；A.526.C.11.i；A.527.C.11.i；A.528.C.11.i；A.529.C.11.i；
A.530.C.11.i；A.531.C.11.i；A.532.C.11.i；A.533.C.11.i；A.534.C.11.i；A.535.C.11.i；
A.536.C.11.i；A.537.C.11.i；A.538.C.11.i；A.539.C.11.i；A.540.C.11.i；A.541.C.11.i；
A.542.C.11.i；A.543.C.11.i；A.544.C.11.i；A.545.C.11.i；A.546.C.11.i；A.547.C.11.i；
A.548.C.11.i；A.549.C.11.i；A.550.C.11.i；A.551.C.11.i；A.552.C.11.i；A.553.C.11.i；
A.554.C.11.i；A.555.C.11.i；A.556.C.11.i；A.557.C.11.i；A.558.C.11.i；A.559.C.11.i；
A.560.C.11.i；A.561.C.11.i；A.562.C.11.i；A.563.C.11.i；A.564.C.11.i；A.565.C.11.i；
A.566.C.11.i；A.567.C.11.i；A.568.C.11.i；A.569.C.11.i；A.570.C.11.i；A.571.C.11.i；
A.572.C.11.i；A.573.C.11.i；A.574.C.11.i；A.575.C.11.i；A.576.C.11.i；A.577.C.11.i；
A.578.C.11.i；A.579.C.11.i；A.580.C.11.i；A.581.C.11.i；A.582.C.11.i；A.583.C.11.i；
A.584.C.11.i；A.585.C.11.i；A.586.C.11.i；A.587.C.11.i；A.588.C.11.i；A.589.C.11.i；
A.590.C.11.i；A.591.C.11.i；A.592.C.11.i；A.593.C.11.i；A.594.C.11.i；A.595.C.11.i；
A.596.C.11.i；A.597.C.11.i；A.598.C.11.i；A.599.C.11.i；A.600.C.11.i；A.601.C.11.i；
A.602.C.11.i；A.603.C.11.i；A.604.C.11.i；A.605.C.11.i；A.606.C.11.i；A.607.C.11.i；
A.608.C.11.i；A.609.C.11.i；A.610.C.11.i；A.611.C.11.i；A.612.C.11.i；A.613.C.11.i；
A.614.C.11.i；A.615.C.11.i；A.616.C.11.i；A.617.C.11.i；A.618.C.11.i；A.619.C.11.i；
A.620.C.11.i；A.621.C.11.i；A.622.C.11.i；A.623.C.11.i；A.624.C.11.i；A.625.C.11.i；
A.626.C.11.i；A.627.C.11.i；A.628.C.11.i；A.629.C.11.i；A.630.C.11.i；A.631.C.11.i；
A.632.C.11.i；A.633.C.11.i；A.634.C.11.i；A.635.C.11.i；A.636.C.11.i；A.637.C.11.i；
A.638.C.11.i；A.639.C.11.i；A.640.C.11.i；A.641.C.11.i；A.642.C.11.i；A.643.C.11.i；
A.644.C.11.i；A.645.C.11.i；A.646.C.11.i；A.647.C.11.i；A.648.C.11.i；A.649.C.11.i；
A.650.C.11.i；A.651.C.11.i；A.652.C.11.i；A.653.C.11.i；A.654.C.11.i；A.655.C.11.i；
A.656.C.11.i；A.657.C.11.i；A.658.C.11.i；A.659.C.11.i；A.660.C.11.i；A.2.D.4.i；
A.3.D.4.i；A.4.D.4.i；A.5.D.4.i；A.6.D.4.i；A.7.D.4.i；A.9.D.4.i；A.10.D.4.i；A.15.D.4.i；
A.100.D.4.i；A.101.D.4.i；A.102.D.4.i；A.103.D.4.i；A.104.D.4.i；A.105.D.4.i；
A.106.D.4.i；A.107.D.4.i；A.108.D.4.i；A.109.D.4.i；A.110.D.4.i；A.111.D.4.i；
A.112.D.4.i；A.113.D.4.i；A.114.D.4.i；A.115.D.4.i；A.116.D.4.i；A.117.D.4.i；
A.118.D.4.i；A.119.D.4.i；A.120.D.4.i；A.121.D.4.i；A.122.D.4.i；A.123.D.4.i；
A.124.D.4.i；A.125.D.4.i；A.126.D.4.i；A.127.D.4.i；A.128.D.4.i；A.129.D.4.i；
A.130.D.4.i；A.131.D.4.i；A.132.D.4.i；A.133.D.4.i；A.134.D.4.i；A.135.D.4.i；
A.136.D.4.i；A.137.D.4.i；A.138.D.4.i；A.139.D.4.i；A.140.D.4.i；A.141.D.4.i；
A.142.D.4.i；A.143.D.4.i；A.144.D.4.i；A.145.D.4.i；A.146.D.4.i；A.147.D.4.i；
A.148.D.4.i；A.149.D.4.i；A.150.D.4.i；A.151.D.4.i；A.152.D.4.i；A.153.D.4.i；
A.154.D.4.i；A.155.D.4.i；A.156.D.4.i；A.157.D.4.i；A.158.D.4.i；A.159.D.4.i；
A.160.D.4.i；A.161.D.4.i；A.162.D.4.i；A.163.D.4.i；A.164.D.4.i；A.165.D.4.i；
A.166.D.4.i；A.167.D.4.i；A.168.D.4.i；A.169.D.4.i；A.170.D.4.i；A.171.D.4.i；
A.172.D.4.i；A.173.D.4.i；A.174.D.4.i；A.175.D.4.i；A.176.D.4.i；A.177.D.4.i；
A.178.D.4.i；A.179.D.4.i；A.180.D.4.i；A.181.D.4.i；A.182.D.4.i；A.183.D.4.i；
A.184.D.4.i；A.185.D.4.i；A.186.D.4.i；A.187.D.4.i；A.188.D.4.i；A.189.D.4.i；
A.190.D.4.i；A.191.D.4.i；A.192.D.4.i；A.193.D.4.i；A.194.D.4.i；A.195.D.4.i；
A.196.D.4.i；A.197.D.4.i；A.198.D.4.i；A.199.D.4.i；A.200.D.4.i；A.201.D.4.i；
A.202.D.4.i；A.203.D.4.i；A.204.D.4.i；A.205.D.4.i；A.206.D.4.i；A.207.D.4.i；
A.208.D.4.i；A.209.D.4.i；A.210.D.4.i；A.211.D.4.i；A.212.D.4.i；A.213.D.4.i；
A.214.D.4.i；A.215.D.4.i；A.216.D.4.i；A.217.D.4.i；A.218.D.4.i；A.219.D.4.i；
A.220.D.4.i；A.221.D.4.i；A.222.D.4.i；A.223.D.4.i；A.224.D.4.i；A.225.D.4.i；
A.226.D.4.i；A.227.D.4.i；A.228.D.4.i；A.229.D.4.i；A.230.D.4.i；A.231.D.4.i；
A.232.D.4.i；A.233.D.4.i；A.234.D.4.i；A.235.D.4.i；A.236.D.4.i；A.237.D.4.i；
A.238.D.4.i；A.239.D.4.i；A.240.D.4.i；A.241.D.4.i；A.242.D.4.i；A.243.D.4.i；
A.244.D.4.i；A.245.D.4.i；A.246.D.4.i；A.247.D.4.i；A.248.D.4.i；A.249.D.4.i；
A.250.D.4.i；A.251.D.4.i；A.252.D.4.i；A.253.D.4.i；A.254.D.4.i；A.255.D.4.i；
A.256.D.4.i；A.257.D.4.i；A.258.D.4.i；A.259.D.4.i；A.260.D.4.i；A.261.D.4.i；
A.262.D.4.i；A.263.D.4.i；A.264.D.4.i；A.265.D.4.i；A.266.D.4.i；A.267.D.4.i；
A.268.D.4.i；A.269.D.4.i；A.270.D.4.i；A.271.D.4.i；A.272.D.4.i；A.273.D.4.i；
A.274.D.4.i；A.275.D.4.i；A.276.D.4.i；A.277.D.4.i；A.278.D.4.i；A.279.D.4.i；
A.280.D.4.i；A.281.D.4.i；A.282.D.4.i；A.283.D.4.i；A.284.D.4.i；A.285.D.4.i；
A.286.D.4.i；A.287.D.4.i；A.288.D.4.i；A.289.D.4.i；A.290.D.4.i；A.291.D.4.i；
A.292.D.4.i；A.293.D.4.i；A.294.D.4.i；A.295.D.4.i；A.296.D.4.i；A.297.D.4.i；
A.298.D.4.i；A.299.D.4.i；A.300.D.4.i；A.301.D.4.i；A.302.D.4.i；A.303.D.4.i；
A.304.D.4.i；A.305.D.4.i；A.306.D.4.i；A.307.D.4.i；A.308.D.4.i；A.309.D.4.i；
A.310.D.4.i；A.311.D.4.i；A.312.D.4.i；A.313.D.4.i；A.314.D.4.i；A.315.D.4.i；
A.316.D.4.i；A.317.D.4.i；A.318.D.4.i；A.319.D.4.i；A.320.D.4.i；A.321.D.4.i；
A.323.D.4.i；A.324.D.4.i；A.325.D.4.i；A.326.D.4.i；A.327.D.4.i；A.328.D.4.i；
A.329.D.4.i；A.330.D.4.i；A.331.D.4.i；A.332.D.4.i；A.333.D.4.i；A.334.D.4.i；
A.335.D.4.i；A.336.D.4.i；A.337.D.4.i；A.338.D.4.i；A.339.D.4.i；A.340.D.4.i；
A.341.D.4.i；A.342.D.4.i；A.343.D.4.i；A.344.D.4.i；A.345.D.4.i；A.346.D.4.i；
A.347.D.4.i；A.348.D.4.i；A.349.D.4.i；A.350.D.4.i；A.351.D.4.i；A.352.D.4.i；
A.353.D.4.i；A.354.D.4.i；A.355.D.4.i；A.356.D.4.i；A.357.D.4.i；A.358.D.4.i；
A.359.D.4.i；A.360.D.4.i；A.361.D.4.i；A.362.D.4.i；A.363.D.4.i；A.364.D.4.i；
A.365.D.4.i；A.366.D.4.i；A.367.D.4.i；A.368.D.4.i；A.369.D.4.i；A.370.D.4.i；
A.371.D.4.i；A.372.D.4.i；A.373.D.4.i；A.374.D.4.i；A.375.D.4.i；A.376.D.4.i；
A.377.D.4.i；A.378.D.4.i；A.379.D.4.i；A.380.D.4.i；A.381.D.4.i；A.382.D.4.i；
A.383.D.4.i；A.384.D.4.i；A.385.D.4.i；A.386.D.4.i；A.387.D.4.i；A.388.D.4.i；
A.389.D.4.i；A.390.D.4.i；A.391.D.4.i；A.392.D.4.i；A.393.D.4.i；A.394.D.4.i；
A.395.D.4.i；A.396.D.4.i；A.397.D.4.i；A.398.D.4.i；A.399.D.4.i；A.400.D.4.i；
A.401.D.4.i；A.402.D.4.i；A.403.D.4.i；A.404.D.4.i；A.405.D.4.i；A.406.D.4.i；
A.407.D.4.i；A.408.D.4.i；A.409.D.4.i；A.410.D.4.i；A.411.D.4.i；A.412.D.4.i；
A.413.D.4.i；A.414.D.4.i；A.415.D.4.i；A.416.D.4.i；A.417.D.4.i；A.418.D.4.i；
A.419.D.4.i；A.420.D.4.i；A.421.D.4.i；A.422.D.4.i；A.423.D.4.i；A.424.D.4.i；
A.425.D.4.i；A.426.D.4.i；A.427.D.4.i；A.428.D.4.i；A.429.D.4.i；A.430.D.4.i；
A.431.D.4.i；A.432.D.4.i；A.433.D.4.i；A.434.D.4.i；A.435.D.4.i；A.436.D.4.i；
A.437.D.4.i；A.438.D.4.i；A.439.D.4.i；A.440.D.4.i；A.441.D.4.i；A.442.D.4.i；
A.443.D.4.i；A.444.D.4.i；A.445.D.4.i；A.446.D.4.i；A.447.D.4.i；A.448.D.4.i；
A.449.D.4.i；A.450.D.4.i；A.451.D.4.i；A.452.D.4.i；A.453.D.4.i；A.454.D.4.i；
A.455.D.4.i；A.456.D.4.i；A.457.D.4.i；A.458.D.4.i；A.459.D.4.i；A.460.D.4.i；
A.461.D.4.i；A.462.D.4.i；A.463.D.4.i；A.464.D.4.i；A.465.D.4.i；A.466.D.4.i；
A.467.D.4.i；A.468.D.4.i；A.469.D.4.i；A.470.D.4.i；A.471.D.4.i；A.472.D.4.i；
A.473.D.4.i；A.474.D.4.i；A.475.D.4.i；A.476.D.4.i；A.477.D.4.i；A.478.D.4.i；
A.479.D.4.i；A.480.D.4.i；A.481.D.4.i；A.482.D.4.i；A.483.D.4.i；A.484.D.4.i；
A.485.D.4.i；A.486.D.4.i；A.487.D.4.i；A.488.D.4.i；A.489.D.4.i；A.490.D.4.i；
A.491.D.4.i；A.492.D.4.i；A.493.D.4.i；A.494.D.4.i；A.495.D.4.i；A.496.D.4.i；
A.497.D.4.i；A.498.D.4.i；A.499.D.4.i；A.500.D.4.i；A.501.D.4.i；A.502.D.4.i；
A.503.D.4.i；A.504.D.4.i；A.505.D.4.i；A.506.D.4.i；A.507.D.4.i；A.508.D.4.i；
A.509.D.4.i；A.510.D.4.i；A.511.D.4.i；A.512.D.4.i；A.512.D.4.i；A.513.D.4.i；
A.514.D.4.i；A.515.D.4.i；A.516.D.4.i；A.517.D.4.i；A.518.D.4.i；A.519.D.4.i；
A.520.D.4.i；A.521.D.4.i；A.522.D.4.i；A.523.D.4.i；A.524.D.4.i；A.525.D.4.i；
A.526.D.4.i；A.527.D.4.i；A.528.D.4.i；A.529.D.4.i；A.530.D.4.i；A.531.D.4.i；
A.532.D.4.i；A.533.D.4.i；A.534.D.4.i；A.535.D.4.i；A.536.D.4.i；A.537.D.4.i；
A.538.D.4.i；A.539.D.4.i；A.540.D.4.i；A.541.D.4.i；A.542.D.4.i；A.543.D.4.i；
A.544.D.4.i；A.545.D.4.i；A.546.D.4.i；A.547.D.4.i；A.548.D.4.i；A.549.D.4.i；
A.550.D.4.i；A.551.D.4.i；A.552.D.4.i；A.553.D.4.i；A.554.D.4.i；A.555.D.4.i；
A.556.D.4.i；A.557.D.4.i；A.558.D.4.i；A.559.D.4.i；A.560.D.4.i；A.561.D.4.i；
A.562.D.4.i；A.563.D.4.i；A.564.D.4.i；A.565.D.4.i；A.566.D.4.i；A.567.D.4.i；
A.568.D.4.i；A.569.D.4.i；A.570.D.4.i；A.571.D.4.i；A.572.D.4.i；A.573.D.4.i；
A.574.D.4.i；A.575.D.4.i；A.576.D.4.i；A.577.D.4.i；A.578.D.4.i；A.579.D.4.i；
A.580.D.4.i；A.581.D.4.i；A.582.D.4.i；A.583.D.4.i；A.584.D.4.i；A.585.D.4.i；
A.586.D.4.i；A.587.D.4.i；A.588.D.4.i；A.589.D.4.i；A.590.D.4.i；A.591.D.4.i；
A.592.D.4.i；A.593.D.4.i；A.594.D.4.i；A.595.D.4.i；A.596.D.4.i；A.597.D.4.i；
A.598.D.4.i；A.599.D.4.i；A.600.D.4.i；A.601.D.4.i；A.602.D.4.i；A.603.D.4.i；
A.604.D.4.i；A.605.D.4.i；A.606.D.4.i；A.607.D.4.i；A.608.D.4.i；A.609.D.4.i；
A.610.D.4.i；A.611.D.4.i；A.612.D.4.i；A.613.D.4.i；A.614.D.4.i；A.615.D.4.i；
A.616.D.4.i；A.617.D.4.i；A.618.D.4.i；A.619.D.4.i；A.620.D.4.i；A.621.D.4.i；
A.622.D.4.i；A.623.D.4.i；A.624.D.4.i；A.625.D.4.i；A.626.D.4.i；A.627.D.4.i；
A.628.D.4.i；A.629.D.4.i；A.630.D.4.i；A.631.D.4.i；A.632.D.4.i；A.633.D.4.i；
A.634.D.4.i；A.635.D.4.i；A.636.D.4.i；A.637.D.4.i；A.638.D.4.i；A.639.D.4.i；
A.640.D.4.i；A.641.D.4.i；A.642.D.4.i；A.643.D.4.i；A.644.D.4.i；A.645.D.4.i；
A.646.D.4.i；A.647.D.4.i；A.648.D.4.i；A.649.D.4.i；A.650.D.4.i；A.651.D.4.i；
A.652.D.4.i；A.653.D.4.i；A.654.D.4.i；A.655.D.4.i；A.656.D.4.i；A.657.D.4.i；
A.658.D.4.i；A.659.D.4.i；A.660.D.4.i；A.2.D.11.i；A.3.D.11.i；A.4.D.11.i；A.5.D.11.i；
A.6.D.11.i；A.7.D.11.i；A.9.D.11.i；A.10.D.11.i；A.15.D.11.i；A.100.D.11.i；
A.101.D.11.i；A.102.D.11.i；A.103.D.11.i；A.104.D.11.i；A.105.D.11.i；A.106.D.11.i；
A.107.D.11.i；A.108.D.11.i；A.109.D.11.i；A.110.D.11.i；A.111.D.11.i；A.112.D.11.i；
A.113.D.11.i；A.114.D.11.i；A.115.D.11.i；A.116.D.11.i；A.117.D.11.i；A.118.D.11.i；
A.119.D.11.i；A.120.D.11.i；A.121.D.11.i；A.122.D.11.i；A.123.D.11.i；A.124.D.11.i；
A.125.D.11.i；A.126.D.11.i；A.127.D.11.i；A.128.D.11.i；A.129.D.11.i；A.130.D.11.i；
A.131.D.11.i；A.132.D.11.i；A.133.D.11.i；A.134.D.11.i；A.135.D.11.i；A.136.D.11.i；
A.137.D.11.i；A.138.D.11.i；A.139.D.11.i；A.140.D.11.i；A.141.D.11.i；A.142.D.11.i；
A.143.D.11.i；A.144.D.11.i；A.145.D.11.i；A.146.D.11.i；A.147.D.11.i；A.148.D.11.i；
A.149.D.11.i；A.150.D.11.i；A.151.D.11.i；A.152.D.11.i；A.153.D.11.i；A.154.D.11.i；
A.155.D.11.i；A.156.D.11.i；A.157.D.11.i；A.158.D.11.i；A.159.D.11.i；A.160.D.11.i；
A.161.D.11.i；A.162.D.11.i；A.163.D.11.i；A.164.D.11.i；A.165.D.11.i；A.166.D.11.i；
A.167.D.11.i；A.168.D.11.i；A.169.D.11.i；A.170.D.11.i；A.171.D.11.i；A.172.D.11.i；
A.173.D.11.i；A.174.D.11.i；A.175.D.11.i；A.176.D.11.i；A.177.D.11.i；A.178.D.11.i；
A.179.D.11.i；A.180.D.11.i；A.181.D.11.i；A.182.D.11.i；A.183.D.11.i；A.184.D.11.i；
A.185.D.11.i；A.186.D.11.i；A.187.D.11.i；A.188.D.11.i；A.189.D.11.i；A.190.D.11.i；
A.191.D.11.i；A.192.D.11.i；A.193.D.11.i；A.194.D.11.i；A.195.D.11.i；A.196.D.11.i；
A.197.D.11.i；A.198.D.11.i；A.199.D.11.i；A.200.D.11.i；A.201.D.11.i；A.202.D.11.i；
A.203.D.11.i；A.204.D.11.i；A.205.D.11.i；A.206.D.11.i；A.207.D.11.i；A.208.D.11.i；
A.209.D.11.i；A.210.D.11.i；A.211.D.11.i；A.212.D.11.i；A.213.D.11.i；A.214.D.11.i；
A.215.D.11.i；A.216.D.11.i；A.217.D.11.i；A.218.D.11.i；A.219.D.11.i；A.220.D.11.i；
A.221.D.11.i；A.222.D.11.i；A.223.D.11.i；A.224.D.11.i；A.225.D.11.i；A.226.D.11.i；
A.227.D.11.i；A.228.D.11.i；A.229.D.11.i；A.230.D.11.i；A.231.D.11.i；A.232.D.11.i；
A.233.D.11.i；A.234.D.11.i；A.235.D.11.i；A.236.D.11.i；A.237.D.11.i；A.238.D.11.i；
A.239.D.11.i；A.240.D.11.i；A.241.D.11.i；A.242.D.11.i；A.243.D.11.i；A.244.D.11.i；
A.245.D.11.i；A.246.D.11.i；A.247.D.11.i；A.248.D.11.i；A.249.D.11.i；A.250.D.11.i；
A.251.D.11.i；A.252.D.11.i；A.253.D.11.i；A.254.D.11.i；A.255.D.11.i；A.256.D.11.i；
A.257.D.11.i；A.258.D.11.i；A.259.D.11.i；A.260.D.11.i；A.261.D.11.i；A.262.D.11.i；
A.263.D.11.i；A.264.D.11.i；A.265.D.11.i；A.266.D.11.i；A.267.D.11.i；A.268.D.11.i；
A.269.D.11.i；A.270.D.11.i；A.271.D.11.i；A.272.D.11.i；A.273.D.11.i；A.274.D.11.i；
A.275.D.11.i；A.276.D.11.i；A.277.D.11.i；A.278.D.11.i；A.279.D.11.i；A.280.D.11.i；
A.281.D.11.i；A.282.D.11.i；A.283.D.11.i；A.284.D.11.i；A.285.D.11.i；A.286.D.11.i；
A.287.D.11.i；A.288.D.11.i；A.289.D.11.i；A.290.D.11.i；A.291.D.11.i；A.292.D.11.i；
A.293.D.11.i；A.294.D.11.i；A.295.D.11.i；A.296.D.11.i；A.297.D.11.i；A.298.D.11.i；
A.299.D.11.i；A.300.D.11.i；A.301.D.11.i；A.302.D.11.i；A.303.D.11.i；A.304.D.11.i；
A.305.D.11.i；A.306.D.11.i；A.307.D.11.i；A.308.D.11.i；A.309.D.11.i；A.310.D.11.i；
A.311.D.11.i；A.312.D.11.i；A.313.D.11.i；A.314.D.11.i；A.315.D.11.i；A.316.D.11.i；
A.317.D.11.i；A.318.D.11.i；A.319.D.11.i；A.320.D.11.i；A.321.D.11.i；A.323.D.11.i；
A.324.D.11.i；A.325.D.11.i；A.326.D.11.i；A.327.D.11.i；A.328.D.11.i；A.329.D.11.i；
A.330.D.11.i；A.331.D.11.i；A.332.D.11.i；A.333.D.11.i；A.334.D.11.i；A.335.D.11.i；
A.336.D.11.i；A.337.D.11.i；A.338.D.11.i；A.339.D.11.i；A.340.D.11.i；A.341.D.11.i；
A.342.D.11.i；A.343.D.11.i；A.344.D.11.i；A.345.D.11.i；A.346.D.11.i；A.347.D.11.i；
A.348.D.11.i；A.349.D.11.i；A.350.D.11.i；A.351.D.11.i；A.352.D.11.i；A.353.D.11.i；
A.354.D.11.i；A.355.D.11.i；A.356.D.11.i；A.357.D.11.i；A.358.D.11.i；A.359.D.11.i；
A.360.D.11.i；A.361.D.11.i；A.362.D.11.i；A.363.D.11.i；A.364.D.11.i；A.365.D.11.i；
A.366.D.11.i；A.367.D.11.i；A.368.D.11.i；A.369.D.11.i；A.370.D.11.i；A.371.D.11.i；
A.372.D.11.i；A.373.D.11.i；A.374.D.11.i；A.375.D.11.i；A.376.D.11.i；A.377.D.11.i；
A.378.D.11.i；A.379.D.11.i；A.380.D.11.i；A.381.D.11.i；A.382.D.11.i；A.383.D.11.i；
A.384.D.11.i；A.385.D.11.i；A.386.D.11.i；A.387.D.11.i；A.388.D.11.i；A.389.D.11.i；
A.390.D.11.i；A.391.D.11.i；A.392.D.11.i；A.393.D.11.i；A.394.D.11.i；A.395.D.11.i；
A.396.D.11.i；A.397.D.11.i；A.398.D.11.i；A.399.D.11.i；A.400.D.11.i；A.401.D.11.i；
A.402.D.11.i；A.403.D.11.i；A.404.D.11.i；A.405.D.11.i；A.406.D.11.i；A.407.D.11.i；
A.408.D.11.i；A.409.D.11.i；A.410.D.11.i；A.411.D.11.i；A.412.D.11.i；A.413.D.11.i；
A.414.D.11.i；A.415.D.11.i；A.416.D.11.i；A.417.D.11.i；A.418.D.11.i；A.419.D.11.i；
A.420.D.11.i；A.421.D.11.i；A.422.D.11.i；A.423.D.11.i；A.424.D.11.i；A.425.D.11.i；
A.426.D.11.i；A.427.D.11.i；A.428.D.11.i；A.429.D.11.i；A.430.D.11.i；A.431.D.11.i；
A.432.D.11.i；A.433.D.11.i；A.434.D.11.i；A.435.D.11.i；A.436.D.11.i；A.437.D.11.i；
A.438.D.11.i；A.439.D.11.i；A.440.D.11.i；A.441.D.11.i；A.442.D.11.i；A.443.D.11.i；
A.444.D.11.i；A.445.D.11.i；A.446.D.11.i；A.447.D.11.i；A.448.D.11.i；A.449.D.11.i；
A.450.D.11.i；A.451.D.11.i；A.452.D.11.i；A.453.D.11.i；A.454.D.11.i；A.455.D.11.i；
A.456.D.11.i；A.457.D.11.i；A.458.D.11.i；A.459.D.11.i；A.460.D.11.i；A.461.D.11.i；
A.462.D.11.i；A.463.D.11.i；A.464.D.11.i；A.465.D.11.i；A.466.D.11.i；A.467.D.11.i；
A.468.D.11.i；A.469.D.11.i；A.470.D.11.i；A.471.D.11.i；A.472.D.11.i；A.473.D.11.i；
A.474.D.11.i；A.475.D.11.i；A.476.D.11.i；A.477.D.11.i；A.478.D.11.i；A.479.D.11.i；
A.480.D.11.i；A.481.D.11.i；A.482.D.11.i；A.483.D.11.i；A.484.D.11.i；A.485.D.11.i；
A.486.D.11.i；A.487.D.11.i；A.488.D.11.i；A.489.D.11.i；A.490.D.11.i；A.491.D.11.i；
A.492.D.11.i；A.493.D.11.i；A.494.D.11.i；A.495.D.11.i；A.496.D.11.i；A.497.D.11.i；
A.498.D.11.i；A.499.D.11.i；A.500.D.11.i；A.501.D.11.i；A.502.D.11.i；A.503.D.11.i；
A.504.D.11.i；A.505.D.11.i；A.506.D.11.i；A.507.D.11.i；A.508.D.11.i；A.509.D.11.i；
A.510.D.11.i；A.511.D.11.i；A.512.D.11.i；A.512.D.11.i；A.513.D.11.i；A.514.D.11.i；
A.515.D.11.i；A.516.D.11.i；A.517.D.11.i；A.518.D.11.i；A.519.D.11.i；A.520.D.11.i；
A.521.D.11.i；A.522.D.11.i；A.523.D.11.i；A.524.D.11.i；A.525.D.11.i；A.526.D.11.i；
A.527.D.11.i；A.528.D.11.i；A.529.D.11.i；A.530.D.11.i；A.531.D.11.i；A.532.D.11.i；
A.533.D.11.i；A.534.D.11.i；A.535.D.11.i；A.536.D.11.i；A.537.D.11.i；A.538.D.11.i；
A.539.D.11.i；A.540.D.11.i；A.541.D.11.i；A.542.D.11.i；A.543.D.11.i；A.544.D.11.i；
A.545.D.11.i；A.546.D.11.i；A.547.D.11.i；A.548.D.11.i；A.549.D.11.i；A.550.D.11.i；
A.551.D.11.i；A.552.D.11.i；A.553.D.11.i；A.554.D.11.i；A.555.D.11.i；A.556.D.11.i；
A.557.D.11.i；A.558.D.11.i；A.559.D.11.i；A.560.D.11.i；A.561.D.11.i；A.562.D.11.i；
A.563.D.11.i；A.564.D.11.i；A.565.D.11.i；A.566.D.11.i；A.567.D.11.i；A.568.D.11.i；
A.569.D.11.i；A.570.D.11.i；A.571.D.11.i；A.572.D.11.i；A.573.D.11.i；A.574.D.11.i；
A.575.D.11.i；A.576.D.11.i；A.577.D.11.i；A.578.D.11.i；A.579.D.11.i；A.580.D.11.i；
A.581.D.11.i；A.582.D.11.i；A.583.D.11.i；A.584.D.11.i；A.585.D.11.i；A.586.D.11.i；
A.587.D.11.i；A.588.D.11.i；A.589.D.11.i；A.590.D.11.i；A.591.D.11.i；A.592.D.11.i；
A.593.D.11.i；A.594.D.11.i；A.595.D.11.i；A.596.D.11.i；A.597.D.11.i；A.598.D.11.i；
A.599.D.11.i；A.600.D.11.i；A.601.D.11.i；A.602.D.11.i；A.603.D.11.i；A.604.D.11.i；
A.605.D.11.i；A.606.D.11.i；A.607.D.11.i；A.608.D.11.i；A.609.D.11.i；A.610.D.11.i；
A.611.D.11.i；A.612.D.11.i；A.613.D.11.i；A.614.D.11.i；A.615.D.11.i；A.616.D.11.i；
A.617.D.11.i；A.618.D.11.i；A.619.D.11.i；A.620.D.11.i；A.621.D.11.i；A.622.D.11.i；
A.623.D.11.i；A.624.D.11.i；A.625.D.11.i；A.626.D.11.i；A.627.D.11.i；A.628.D.11.i；
A.629.D.11.i；A.630.D.11.i；A.631.D.11.i；A.632.D.11.i；A.633.D.11.i；A.634.D.11.i；
A.635.D.11.i；A.636.D.11.i；A.637.D.11.i；A.638.D.11.i；A.639.D.11.i；A.640.D.11.i；
A.641.D.11.i；A.642.D.11.i；A.643.D.11.i；A.644.D.11.i；A.645.D.11.i；A.646.D.11.i；
A.647.D.11.i；A.648.D.11.i；A.649.D.11.i；A.650.D.11.i；A.651.D.11.i；A.652.D.11.i；
A.653.D.11.i；A.654.D.11.i；A.655.D.11.i；A.656.D.11.i；A.657.D.11.i；A.658.D.11.i；
A.659.D.11.i；A.660.D.11.i；A.2.E.4.i；A.3.E.4.i；A.4.E.4.i；A.5.E.4.i；A.6.E.4.i；
A.7.E.4.i；A.9.E.4.i；A.10.E.4.i；A.15.E.4.i；A.100.E.4.i；A.101.E.4.i；A.102.E.4.i；
A.103.E.4.i；A.104.E.4.i；A.105.E.4.i；A.106.E.4.i；A.107.E.4.i；A.108.E.4.i；
A.109.E.4.i；A.110.E.4.i；A.111.E.4.i；A.112.E.4.i；A.113.E.4.i；A.114.E.4.i；
A.115.E.4.i；A.116.E.4.i；A.117.E.4.i；A.118.E.4.i；A.119.E.4.i；A.120.E.4.i；
A.121.E.4.i；A.122.E.4.i；A.123.E.4.i；A.124.E.4.i；A.125.E.4.i；A.126.E.4.i；
A.127.E.4.i；A.128.E.4.i；A.129.E.4.i；A.130.E.4.i；A.131.E.4.i；A.132.E.4.i；
A.133.E.4.i；A.134.E.4.i；A.135.E.4.i；A.136.E.4.i；A.137.E.4.i；A.138.E.4.i；
A.139.E.4.i；A.140.E.4.i；A.141.E.4.i；A.142.E.4.i；A.143.E.4.i；A.144.E.4.i；
A.145.E.4.i；A.146.E.4.i；A.147.E.4.i；A.148.E.4.i；A.149.E.4.i；A.150.E.4.i；
A.151.E.4.i；A.152.E.4.i；A.153.E.4.i；A.154.E.4.i；A.155.E.4.i；A.156.E.4.i；
A.157.E.4.i；A.158.E.4.i；A.159.E.4.i；A.160.E.4.i；A.161.E.4.i；A.162.E.4.i；
A.163.E.4.i；A.164.E.4.i；A.165.E.4.i；A.166.E.4.i；A.167.E.4.i；A.168.E.4.i；
A.169.E.4.i；A.170.E.4.i；A.171.E.4.i；A.172.E.4.i；A.173.E.4.i；A.174.E.4.i；
A.175.E.4.i；A.176.E.4.i；A.177.E.4.i；A.178.E.4.i；A.179.E.4.i；A.180.E.4.i；
A.181.E.4.i；A.182.E.4.i；A.183.E.4.i；A.184.E.4.i；A.185.E.4.i；A.186.E.4.i；
A.187.E.4.i；A.188.E.4.i；A.189.E.4.i；A.190.E.4.i；A.191.E.4.i；A.192.E.4.i；
A.193.E.4.i；A.194.E.4.i；A.195.E.4.i；A.196.E.4.i；A.197.E.4.i；A.198.E.4.i；
A.199.E.4.i；A.200.E.4.i；A.201.E.4.i；A.202.E.4.i；A.203.E.4.i；A.204.E.4.i；
A.205.E.4.i；A.206.E.4.i；A.207.E.4.i；A.208.E.4.i；A.209.E.4.i；A.210.E.4.i；
A.211.E.4.i；A.212.E.4.i；A.213.E.4.i；A.214.E.4.i；A.215.E.4.i；A.216.E.4.i；
A.217.E.4.i；A.218.E.4.i；A.219.E.4.i；A.220.E.4.i；A.221.E.4.i；A.222.E.4.i；
A.223.E.4.i；A.224.E.4.i；A.225.E.4.i；A.226.E.4.i；A.227.E.4.i；A.228.E.4.i；
A.229.E.4.i；A.230.E.4.i；A.231.E.4.i；A.232.E.4.i；A.233.E.4.i；A.234.E.4.i；
A.235.E.4.i；A.236.E.4.i；A.237.E.4.i；A.238.E.4.i；A.239.E.4.i；A.240.E.4.i；
A.241.E.4.i；A.242.E.4.i；A.243.E.4.i；A.244.E.4.i；A.245.E.4.i；A.246.E.4.i；
A.247.E.4.i；A.248.E.4.i；A.249.E.4.i；A.250.E.4.i；A.251.E.4.i；A.252.E.4.i；
A.253.E.4.i；A.254.E.4.i；A.255.E.4.i；A.256.E.4.i；A.257.E.4.i；A.258.E.4.i；
A.259.E.4.i；A.260.E.4.i；A.261.E.4.i；A.262.E.4.i；A.263.E.4.i；A.264.E.4.i；
A.265.E.4.i；A.266.E.4.i；A.267.E.4.i；A.268.E.4.i；A.269.E.4.i；A.270.E.4.i；
A.271.E.4.i；A.272.E.4.i；A.273.E.4.i；A.274.E.4.i；A.275.E.4.i；A.276.E.4.i；
A.277.E.4.i；A.278.E.4.i；A.279.E.4.i；A.280.E.4.i；A.281.E.4.i；A.282.E.4.i；
A.283.E.4.i；A.284.E.4.i；A.285.E.4.i；A.286.E.4.i；A.287.E.4.i；A.288.E.4.i；
A.289.E.4.i；A.290.E.4.i；A.291.E.4.i；A.292.E.4.i；A.293.E.4.i；A.294.E.4.i；
A.295.E.4.i；A.296.E.4.i；A.297.E.4.i；A.298.E.4.i；A.299.E.4.i；A.300.E.4.i；
A.301.E.4.i；A.302.E.4.i；A.303.E.4.i；A.304.E.4.i；A.305.E.4.i；A.306.E.4.i；
A.307.E.4.i；A.308.E.4.i；A.309.E.4.i；A.310.E.4.i；A.311.E.4.i；A.312.E.4.i；
A.313.E.4.i；A.314.E.4.i；A.315.E.4.i；A.316.E.4.i；A.317.E.4.i；A.318.E.4.i；
A.319.E.4.i；A.320.E.4.i；A.321.E.4.i；A.323.E.4.i；A.324.E.4.i；A.325.E.4.i；
A.326.E.4.i；A.327.E.4.i；A.328.E.4.i；A.329.E.4.i；A.330.E.4.i；A.331.E.4.i；
A.332.E.4.i；A.333.E.4.i；A.334.E.4.i；A.335.E.4.i；A.336.E.4.i；A.337.E.4.i；
A.338.E.4.i；A.339.E.4.i；A.340.E.4.i；A.341.E.4.i；A.342.E.4.i；A.343.E.4.i；
A.344.E.4.i；A.345.E.4.i；A.346.E.4.i；A.347.E.4.i；A.348.E.4.i；A.349.E.4.i；
A.350.E.4.i；A.351.E.4.i；A.352.E.4.i；A.353.E.4.i；A.354.E.4.i；A.355.E.4.i；
A.356.E.4.i；A.357.E.4.i；A.358.E.4.i；A.359.E.4.i；A.360.E.4.i；A.361.E.4.i；
A.362.E.4.i；A.363.E.4.i；A.364.E.4.i；A.365.E.4.i；A.366.E.4.i；A.367.E.4.i；
A.368.E.4.i；A.369.E.4.i；A.370.E.4.i；A.371.E.4.i；A.372.E.4.i；A.373.E.4.i；
A.374.E.4.i；A.375.E.4.i；A.376.E.4.i；A.377.E.4.i；A.378.E.4.i；A.379.E.4.i；
A.380.E.4.i；A.381.E.4.i；A.382.E.4.i；A.383.E.4.i；A.384.E.4.i；A.385.E.4.i；
A.386.E.4.i；A.387.E.4.i；A.388.E.4.i；A.389.E.4.i；A.390.E.4.i；A.391.E.4.i；
A.392.E.4.i；A.393.E.4.i；A.394.E.4.i；A.395.E.4.i；A.396.E.4.i；A.397.E.4.i；
A.398.E.4.i；A.399.E.4.i；A.400.E.4.i；A.401.E.4.i；A.402.E.4.i；A.403.E.4.i；
A.404.E.4.i；A.405.E.4.i；A.406.E.4.i；A.407.E.4.i；A.408.E.4.i；A.409.E.4.i；
A.410.E.4.i；A.411.E.4.i；A.412.E.4.i；A.413.E.4.i；A.414.E.4.i；A.415.E.4.i；
A.416.E.4.i；A.417.E.4.i；A.418.E.4.i；A.419.E.4.i；A.420.E.4.i；A.421.E.4.i；
A.422.E.4.i；A.423.E.4.i；A.424.E.4.i；A.425.E.4.i；A.426.E.4.i；A.427.E.4.i；
A.428.E.4.i；A.429.E.4.i；A.430.E.4.i；A.431.E.4.i；A.432.E.4.i；A.433.E.4.i；
A.434.E.4.i；A.435.E.4.i；A.436.E.4.i；A.437.E.4.i；A.438.E.4.i；A.439.E.4.i；
A.440.E.4.i；A.441.E.4.i；A.442.E.4.i；A.443.E.4.i；A.444.E.4.i；A.445.E.4.i；
A.446.E.4.i；A.447.E.4.i；A.448.E.4.i；A.449.E.4.i；A.450.E.4.i；A.451.E.4.i；
A.452.E.4.i；A.453.E.4.i；A.454.E.4.i；A.455.E.4.i；A.456.E.4.i；A.457.E.4.i；
A.458.E.4.i；A.459.E.4.i；A.460.E.4.i；A.461.E.4.i；A.462.E.4.i；A.463.E.4.i；
A.464.E.4.i；A.465.E.4.i；A.466.E.4.i；A.467.E.4.i；A.468.E.4.i；A.469.E.4.i；
A.470.E.4.i；A.471.E.4.i；A.472.E.4.i；A.473.E.4.i；A.474.E.4.i；A.475.E.4.i；
A.476.E.4.i；A.477.E.4.i；A.478.E.4.i；A.479.E.4.i；A.480.E.4.i；A.481.E.4.i；
A.482.E.4.i；A.483.E.4.i；A.484.E.4.i；A.485.E.4.i；A.486.E.4.i；A.487.E.4.i；
A.488.E.4.i；A.489.E.4.i；A.490.E.4.i；A.491.E.4.i；A.492.E.4.i；A.493.E.4.i；
A.494.E.4.i；A.495.E.4.i；A.496.E.4.i；A.497.E.4.i；A.498.E.4.i；A.499.E.4.i；
A.500.E.4.i；A.501.E.4.i；A.502.E.4.i；A.503.E.4.i；A.504.E.4.i；A.505.E.4.i；
A.506.E.4.i；A.507.E.4.i；A.508.E.4.i；A.509.E.4.i；A.510.E.4.i；A.511.E.4.i；
A.512.E.4.i；A.512.E.4.i；A.513.E.4.i；A.514.E.4.i；A.515.E.4.i；A.516.E.4.i；
A.517.E.4.i；A.518.E.4.i；A.519.E.4.i；A.520.E.4.i；A.521.E.4.i；A.522.E.4.i；
A.523.E.4.i；A.524.E.4.i；A.525.E.4.i；A.526.E.4.i；A.527.E.4.i；A.528.E.4.i；
A.529.E.4.i；A.530.E.4.i；A.531.E.4.i；A.532.E.4.i；A.533.E.4.i；A.534.E.4.i；
A.535.E.4.i；A.536.E.4.i；A.537.E.4.i；A.538.E.4.i；A.539.E.4.i；A.540.E.4.i；
A.541.E.4.i；A.542.E.4.i；A.543.E.4.i；A.544.E.4.i；A.545.E.4.i；A.546.E.4.i；
A.547.E.4.i；A.548.E.4.i；A.549.E.4.i；A.550.E.4.i；A.551.E.4.i；A.552.E.4.i；
A.553.E.4.i；A.554.E.4.i；A.555.E.4.i；A.556.E.4.i；A.557.E.4.i；A.558.E.4.i；
A.559.E.4.i；A.560.E.4.i；A.561.E.4.i；A.562.E.4.i；A.563.E.4.i；A.564.E.4.i；
A.565.E.4.i；A.566.E.4.i；A.567.E.4.i；A.568.E.4.i；A.569.E.4.i；A.570.E.4.i；
A.571.E.4.i；A.572.E.4.i；A.573.E.4.i；A.574.E.4.i；A.575.E.4.i；A.576.E.4.i；
A.577.E.4.i；A.578.E.4.i；A.579.E.4.i；A.580.E.4.i；A.581.E.4.i；A.582.E.4.i；
A.583.E.4.i；A.584.E.4.i；A.585.E.4.i；A.586.E.4.i；A.587.E.4.i；A.588.E.4.i；
A.589.E.4.i；A.590.E.4.i；A.591.E.4.i；A.592.E.4.i；A.593.E.4.i；A.594.E.4.i；
A.595.E.4.i；A.596.E.4.i；A.597.E.4.i；A.598.E.4.i；A.599.E.4.i；A.600.E.4.i；
A.601.E.4.i；A.602.E.4.i；A.603.E.4.i；A.604.E.4.i；A.605.E.4.i；A.606.E.4.i；
A.607.E.4.i；A.608.E.4.i；A.609.E.4.i；A.610.E.4.i；A.611.E.4.i；A.612.E.4.i；
A.613.E.4.i；A.614.E.4.i；A.615.E.4.i；A.616.E.4.i；A.617.E.4.i；A.618.E.4.i；
A.619.E.4.i；A.620.E.4.i；A.621.E.4.i；A.622.E.4.i；A.623.E.4.i；A.624.E.4.i；
A.625.E.4.i；A.626.E.4.i；A.627.E.4.i；A.628.E.4.i；A.629.E.4.i；A.630.E.4.i；
A.631.E.4.i；A.632.E.4.i；A.633.E.4.i；A.634.E.4.i；A.635.E.4.i；A.636.E.4.i；
A.637.E.4.i；A.638.E.4.i；A.639.E.4.i；A.640.E.4.i；A.641.E.4.i；A.642.E.4.i；
A.643.E.4.i；A.644.E.4.i；A.645.E.4.i；A.646.E.4.i；A.647.E.4.i；A.648.E.4.i；
A.649.E.4.i；A.650.E.4.i；A.651.E.4.i；A.652.E.4.i；A.653.E.4.i；A.654.E.4.i；
A.655.E.4.i；A.656.E.4.i；A.657.E.4.i；A.658.E.4.i；A.659.E.4.i；A.660.E.4.i；A.2.E.11.i；
A.3.E.11.i；A.4.E.11.i；A.5.E.11.i；A.6.E.11.i；A.7.E.11.i；A.9.E.11.i；A.10.E.11.i；
A.15.E.11.i；A.100.E.11.i；A.101.E.11.i；A.102.E.11.i；A.103.E.11.i；A.104.E.11.i；
A.105.E.11.i；A.106.E.11.i；A.107.E.11.i；A.108.E.11.i；A.109.E.11.i；A.110.E.11.i；
A.111.E.11.i；A.112.E.11.i；A.113.E.11.i；A.114.E.11.i；A.115.E.11.i；A.116.E.11.i；
A.117.E.11.i；A.118.E.11.i；A.119.E.11.i；A.120.E.11.i；A.121.E.11.i；A.122.E.11.i；
A.123.E.11.i；A.124.E.11.i；A.125.E.11.i；A.126.E.11.i；A.127.E.11.i；A.128.E.11.i；
A.129.E.11.i；A.130.E.11.i；A.131.E.11.i；A.132.E.11.i；A.133.E.11.i；A.134.E.11.i；
A.135.E.11.i；A.136.E.11.i；A.137.E.11.i；A.138.E.11.i；A.139.E.11.i；A.140.E.11.i；
A.141.E.11.i；A.142.E.11.i；A.143.E.11.i；A.144.E.11.i；A.145.E.11.i；A.146.E.11.i；
A.147.E.11.i；A.148.E.11.i；A.149.E.11.i；A.150.E.11.i；A.151.E.11.i；A.152.E.11.i；
A.153.E.11.i；A.154.E.11.i；A.155.E.11.i；A.156.E.11.i；A.157.E.11.i；A.158.E.11.i；
A.159.E.11.i；A.160.E.11.i；A.161.E.11.i；A.162.E.11.i；A.163.E.11.i；A.164.E.11.i；
A.165.E.11.i；A.166.E.11.i；A.167.E.11.i；A.168.E.11.i；A.169.E.11.i；A.170.E.11.i；
A.171.E.11.i；A.172.E.11.i；A.173.E.11.i；A.174.E.11.i；A.175.E.11.i；A.176.E.11.i；
A.177.E.11.i；A.178.E.11.i；A.179.E.11.i；A.180.E.11.i；A.181.E.11.i；A.182.E.11.i；
A.183.E.11.i；A.184.E.11.i；A.185.E.11.i；A.186.E.11.i；A.187.E.11.i；A.188.E.11.i；
A.189.E.11.i；A.190.E.11.i；A.191.E.11.i；A.192.E.11.i；A.193.E.11.i；A.194.E.11.i；
A.195.E.11.i；A.196.E.11.i；A.197.E.11.i；A.198.E.11.i；A.199.E.11.i；A.200.E.11.i；
A.201.E.11.i；A.202.E.11.i；A.203.E.11.i；A.204.E.11.i；A.205.E.11.i；A.206.E.11.i；
A.207.E.11.i；A.208.E.11.i；A.209.E.11.i；A.210.E.11.i；A.211.E.11.i；A.212.E.11.i；
A.213.E.11.i；A.214.E.11.i；A.215.E.11.i；A.216.E.11.i；A.217.E.11.i；A.218.E.11.i；
A.219.E.11.i；A.220.E.11.i；A.221.E.11.i；A.222.E.11.i；A.223.E.11.i；A.224.E.11.i；
A.225.E.11.i；A.226.E.11.i；A.227.E.11.i；A.228.E.11.i；A.229.E.11.i；A.230.E.11.i；
A.231.E.11.i；A.232.E.11.i；A.233.E.11.i；A.234.E.11.i；A.235.E.11.i；A.236.E.11.i；
A.237.E.11.i；A.238.E.11.i；A.239.E.11.i；A.240.E.11.i；A.241.E.11.i；A.242.E.11.i；
A.243.E.11.i；A.244.E.11.i；A.245.E.11.i；A.246.E.11.i；A.247.E.11.i；A.248.E.11.i；
A.249.E.11.i；A.250.E.11.i；A.251.E.11.i；A.252.E.11.i；A.253.E.11.i；A.254.E.11.i；
A.255.E.11.i；A.256.E.11.i；A.257.E.11.i；A.258.E.11.i；A.259.E.11.i；A.260.E.11.i；
A.261.E.11.i；A.262.E.11.i；A.263.E.11.i；A.264.E.11.i；A.265.E.11.i；A.266.E.11.i；
A.267.E.11.i；A.268.E.11.i；A.269.E.11.i；A.270.E.11.i；A.271.E.11.i；A.272.E.11.i；
A.273.E.11.i；A.274.E.11.i；A.275.E.11.i；A.276.E.11.i；A.277.E.11.i；A.278.E.11.i；
A.279.E.11.i；A.280.E.11.i；A.281.E.11.i；A.282.E.11.i；A.283.E.11.i；A.284.E.11.i；
A.285.E.11.i；A.286.E.11.i；A.287.E.11.i；A.288.E.11.i；A.289.E.11.i；A.290.E.11.i；
A.291.E.11.i；A.292.E.11.i；A.293.E.11.i；A.294.E.11.i；A.295.E.11.i；A.296.E.11.i；
A.297.E.11.i；A.298.E.11.i；A.299.E.11.i；A.300.E.11.i；A.301.E.11.i；A.302.E.11.i；
A.303.E.11.i；A.304.E.11.i；A.305.E.11.i；A.306.E.11.i；A.307.E.11.i；A.308.E.11.i；
A.309.E.11.i；A.310.E.11.i；A.311.E.11.i；A.312.E.11.i；A.313.E.11.i；A.314.E.11.i；
A.315.E.11.i；A.316.E.11.i；A.317.E.11.i；A.318.E.11.i；A.319.E.11.i；A.320.E.11.i；
A.321.E.11.i；A.323.E.11.i；A.324.E.11.i；A.325.E.11.i；A.326.E.11.i；A.327.E.11.i；
A.328.E.11.i；A.329.E.11.i；A.330.E.11.i；A.331.E.11.i；A.332.E.11.i；A.333.E.11.i；
A.334.E.11.i；A.335.E.11.i；A.336.E.11.i；A.337.E.11.i；A.338.E.11.i；A.339.E.11.i；
A.340.E.11.i；A.341.E.11.i；A.342.E.11.i；A.343.E.11.i；A.344.E.11.i；A.345.E.11.i；
A.346.E.11.i；A.347.E.11.i；A.348.E.11.i；A.349.E.11.i；A.350.E.11.i；A.351.E.11.i；
A.352.E.11.i；A.353.E.11.i；A.354.E.11.i；A.355.E.11.i；A.356.E.11.i；A.357.E.11.i；
A.358.E.11.i；A.359.E.11.i；A.360.E.11.i；A.361.E.11.i；A.362.E.11.i；A.363.E.11.i；
A.364.E.11.i；A.365.E.11.i；A.366.E.11.i；A.367.E.11.i；A.368.E.11.i；A.369.E.11.i；
A.370.E.11.i；A.371.E.11.i；A.372.E.11.i；A.373.E.11.i；A.374.E.11.i；A.375.E.11.i；
A.376.E.11.i；A.377.E.11.i；A.378.E.11.i；A.379.E.11.i；A.380.E.11.i；A.381.E.11.i；
A.382.E.11.i；A.383.E.11.i；A.384.E.11.i；A.385.E.11.i；A.386.E.11.i；A.387.E.11.i；
A.388.E.11.i；A.389.E.11.i；A.390.E.11.i；A.391.E.11.i；A.392.E.11.i；A.393.E.11.i；
A.394.E.11.i；A.395.E.11.i；A.396.E.11.i；A.397.E.11.i；A.398.E.11.i；A.399.E.11.i；
A.400.E.11.i；A.401.E.11.i；A.402.E.11.i；A.403.E.11.i；A.404.E.11.i；A.405.E.11.i；
A.406.E.11.i；A.407.E.11.i；A.408.E.11.i；A.409.E.11.i；A.410.E.11.i；A.411.E.11.i；
A.412.E.11.i；A.413.E.11.i；A.414.E.11.i；A.415.E.11.i；A.416.E.11.i；A.417.E.11.i；
A.418.E.11.i；A.419.E.11.i；A.420.E.11.i；A.421.E.11.i；A.422.E.11.i；A.423.E.11.i；
A.424.E.11.i；A.425.E.11.i；A.426.E.11.i；A.427.E.11.i；A.428.E.11.i；A.429.E.11.i；
A.430.E.11.i；A.431.E.11.i；A.432.E.11.i；A.433.E.11.i；A.434.E.11.i；A.435.E.11.i；
A.436.E.11.i；A.437.E.11.i；A.438.E.11.i；A.439.E.11.i；A.440.E.11.i；A.441.E.11.i；
A.442.E.11.i；A.443.E.11.i；A.444.E.11.i；A.445.E.11.i；A.446.E.11.i；A.447.E.11.i；
A.448.E.11.i；A.449.E.11.i；A.450.E.11.i；A.451.E.11.i；A.452.E.11.i；A.453.E.11.i；
A.454.E.11.i；A.455.E.11.i；A.456.E.11.i；A.457.E.11.i；A.458.E.11.i；A.459.E.11.i；
A.460.E.11.i；A.461.E.11.i；A.462.E.11.i；A.463.E.11.i；A.464.E.11.i；A.465.E.11.i；
A.466.E.11.i；A.467.E.11.i；A.468.E.11.i；A.469.E.11.i；A.470.E.11.i；A.471.E.11.i；
A.472.E.11.i；A.473.E.11.i；A.474.E.11.i；A.475.E.11.i；A.476.E.11.i；A.477.E.11.i；
A.478.E.11.i；A.479.E.11.i；A.480.E.11.i；A.481.E.11.i；A.482.E.11.i；A.483.E.11.i；
A.484.E.11.i；A.485.E.11.i；A.486.E.11.i；A.487.E.11.i；A.488.E.11.i；A.489.E.11.i；
A.490.E.11.i；A.491.E.11.i；A.492.E.11.i；A.493.E.11.i；A.494.E.11.i；A.495.E.11.i；
A.496.E.11.i；A.497.E.11.i；A.498.E.11.i；A.499.E.11.i；A.500.E.11.i；A.501.E.11.i；
A.502.E.11.i；A.503.E.11.i；A.504.E.11.i；A.505.E.11.i；A.506.E.11.i；A.507.E.11.i；
A.508.E.11.i；A.509.E.11.i；A.510.E.11.i；A.511.E.11.i；A.512.E.11.i；A.512.E.11.i；
A.513.E.11.i；A.514.E.11.i；A.515.E.11.i；A.516.E.11.i；A.517.E.11.i；A.518.E.11.i；
A.519.E.11.i；A.520.E.11.i；A.521.E.11.i；A.522.E.11.i；A.523.E.11.i；A.524.E.11.i；
A.525.E.11.i；A.526.E.11.i；A.527.E.11.i；A.528.E.11.i；A.529.E.11.i；A.530.E.11.i；
A.531.E.11.i；A.532.E.11.i；A.533.E.11.i；A.534.E.11.i；A.535.E.11.i；A.536.E.11.i；
A.537.E.11.i；A.538.E.11.i；A.539.E.11.i；A.540.E.11.i；A.541.E.11.i；A.542.E.11.i；
A.543.E.11.i；A.544.E.11.i；A.545.E.11.i；A.546.E.11.i；A.547.E.11.i；A.548.E.11.i；
A.549.E.11.i；A.550.E.11.i；A.551.E.11.i；A.552.E.11.i；A.553.E.11.i；A.554.E.11.i；
A.555.E.11.i；A.556.E.11.i；A.557.E.11.i；A.558.E.11.i；A.559.E.11.i；A.560.E.11.i；
A.561.E.11.i；A.562.E.11.i；A.563.E.11.i；A.564.E.11.i；A.565.E.11.i；A.566.E.11.i；
A.567.E.11.i；A.568.E.11.i；A.569.E.11.i；A.570.E.11.i；A.571.E.11.i；A.572.E.11.i；
A.573.E.11.i；A.574.E.11.i；A.575.E.11.i；A.576.E.11.i；A.577.E.11.i；A.578.E.11.i；
A.579.E.11.i；A.580.E.11.i；A.581.E.11.i；A.582.E.11.i；A.583.E.11.i；A.584.E.11.i；
A.585.E.11.i；A.586.E.11.i；A.587.E.11.i；A.588.E.11.i；A.589.E.11.i；A.590.E.11.i；
A.591.E.11.i；A.592.E.11.i；A.593.E.11.i；A.594.E.11.i；A.595.E.11.i；A.596.E.11.i；
A.597.E.11.i；A.598.E.11.i；A.599.E.11.i；A.600.E.11.i；A.601.E.11.i；A.602.E.11.i；
A.603.E.11.i；A.604.E.11.i；A.605.E.11.i；A.606.E.11.i；A.607.E.11.i；A.608.E.11.i；
A.609.E.11.i；A.610.E.11.i；A.611.E.11.i；A.612.E.11.i；A.613.E.11.i；A.614.E.11.i；
A.615.E.11.i；A.616.E.11.i；A.617.E.11.i；A.618.E.11.i；A.619.E.11.i；A.620.E.11.i；
A.621.E.11.i；A.622.E.11.i；A.623.E.11.i；A.624.E.11.i；A.625.E.11.i；A.626.E.11.i；
A.627.E.11.i；A.628.E.11.i；A.629.E.11.i；A.630.E.11.i；A.631.E.11.i；A.632.E.11.i；
A.633.E.11.i；A.634.E.11.i；A.635.E.11.i；A.636.E.11.i；A.637.E.11.i；A.638.E.11.i；
A.639.E.11.i；A.640.E.11.i；A.641.E.11.i；A.642.E.11.i；A.643.E.11.i；A.644.E.11.i；
A.645.E.11.i；A.646.E.11.i；A.647.E.11.i；A.648.E.11.i；A.649.E.11.i；A.650.E.11.i；
A.651.E.11.i；A.652.E.11.i；A.653.E.11.i；A.654.E.11.i；A.655.E.11.i；A.656.E.11.i；
A.657.E.11.i；A.658.E.11.i；A.659.E.11.i；A.660.E.11.i；A.2.F.4.i；A.3.F.4.i；A.4.F.4.i；
A.5.F.4.i；A.6.F.4.i；A.7.F.4.i；A.9.F.4.i；A.10.F.4.i；A.15.F.4.i；A.100.F.4.i；
A.101.F.4.i；A.102.F.4.i；A.103.F.4.i；A.104.F.4.i；A.105.F.4.i；A.106.F.4.i；
A.107.F.4.i；A.108.F.4.i；A.109.F.4.i；A.110.F.4.i；A.111.F.4.i；A.112.F.4.i；
A.113.F.4.i；A.114.F.4.i；A.115.F.4.i；A.116.F.4.i；A.117.F.4.i；A.118.F.4.i；
A.119.F.4.i；A.120.F.4.i；A.121.F.4.i；A.122.F.4.i；A.123.F.4.i；A.124.F.4.i；
A.125.F.4.i；A.126.F.4.i；A.127.F.4.i；A.128.F.4.i；A.129.F.4.i；A.130.F.4.i；
A.131.F.4.i；A.132.F.4.i；A.133.F.4.i；A.134.F.4.i；A.135.F.4.i；A.136.F.4.i；
A.137.F.4.i；A.138.F.4.i；A.139.F.4.i；A.140.F.4.i；A.141.F.4.i；A.142.F.4.i；
A.143.F.4.i；A.144.F.4.i；A.145.F.4.i；A.146.F.4.i；A.147.F.4.i；A.148.F.4.i；
A.149.F.4.i；A.150.F.4.i；A.151.F.4.i；A.152.F.4.i；A.153.F.4.i；A.154.F.4.i；
A.155.F.4.i；A.156.F.4.i；A.157.F.4.i；A.158.F.4.i；A.159.F.4.i；A.160.F.4.i；
A.161.F.4.i；A.162.F.4.i；A.163.F.4.i；A.164.F.4.i；A.165.F.4.i；A.166.F.4.i；
A.167.F.4.i；A.168.F.4.i；A.169.F.4.i；A.170.F.4.i；A.171.F.4.i；A.172.F.4.i；
A.173.F.4.i；A.174.F.4.i；A.175.F.4.i；A.176.F.4.i；A.177.F.4.i；A.178.F.4.i；
A.179.F.4.i；A.180.F.4.i；A.181.F.4.i；A.182.F.4.i；A.183.F.4.i；A.184.F.4.i；
A.185.F.4.i；A.186.F.4.i；A.187.F.4.i；A.188.F.4.i；A.189.F.4.i；A.190.F.4.i；
A.191.F.4.i；A.192.F.4.i；A.193.F.4.i；A.194.F.4.i；A.195.F.4.i；A.196.F.4.i；
A.197.F.4.i；A.198.F.4.i；A.199.F.4.i；A.200.F.4.i；A.201.F.4.i；A.202.F.4.i；
A.203.F.4.i；A.204.F.4.i；A.205.F.4.i；A.206.F.4.i；A.207.F.4.i；A.208.F.4.i；
A.209.F.4.i；A.210.F.4.i；A.211.F.4.i；A.212.F.4.i；A.213.F.4.i；A.214.F.4.i；
A.215.F.4.i；A.216.F.4.i；A.217.F.4.i；A.218.F.4.i；A.219.F.4.i；A.220.F.4.i；
A.221.F.4.i；A.222.F.4.i；A.223.F.4.i；A.224.F.4.i；A.225.F.4.i；A.226.F.4.i；
A.227.F.4.i；A.228.F.4.i；A.229.F.4.i；A.230.F.4.i；A.231.F.4.i；A.232.F.4.i；
A.233.F.4.i；A.234.F.4.i；A.235.F.4.i；A.236.F.4.i；A.237.F.4.i；A.238.F.4.i；
A.239.F.4.i；A.240.F.4.i；A.241.F.4.i；A.242.F.4.i；A.243.F.4.i；A.244.F.4.i；
A.245.F.4.i；A.246.F.4.i；A.247.F.4.i；A.248.F.4.i；A.249.F.4.i；A.250.F.4.i；
A.251.F.4.i；A.252.F.4.i；A.253.F.4.i；A.254.F.4.i；A.255.F.4.i；A.256.F.4.i；
A.257.F.4.i；A.258.F.4.i；A.259.F.4.i；A.260.F.4.i；A.261.F.4.i；A.262.F.4.i；
A.263.F.4.i；A.264.F.4.i；A.265.F.4.i；A.266.F.4.i；A.267.F.4.i；A.268.F.4.i；
A.269.F.4.i；A.270.F.4.i；A.271.F.4.i；A.272.F.4.i；A.273.F.4.i；A.274.F.4.i；
A.275.F.4.i；A.276.F.4.i；A.277.F.4.i；A.278.F.4.i；A.279.F.4.i；A.280.F.4.i；
A.281.F.4.i；A.282.F.4.i；A.283.F.4.i；A.284.F.4.i；A.285.F.4.i；A.286.F.4.i；
A.287.F.4.i；A.288.F.4.i；A.289.F.4.i；A.290.F.4.i；A.291.F.4.i；A.292.F.4.i；
A.293.F.4.i；A.294.F.4.i；A.295.F.4.i；A.296.F.4.i；A.297.F.4.i；A.298.F.4.i；
A.299.F.4.i；A.300.F.4.i；A.301.F.4.i；A.302.F.4.i；A.303.F.4.i；A.304.F.4.i；
A.305.F.4.i；A.306.F.4.i；A.307.F.4.i；A.308.F.4.i；A.309.F.4.i；A.310.F.4.i；
A.311.F.4.i；A.312.F.4.i；A.313.F.4.i；A.314.F.4.i；A.315.F.4.i；A.316.F.4.i；
A.317.F.4.i；A.318.F.4.i；A.319.F.4.i；A.320.F.4.i；A.321.F.4.i；A.323.F.4.i；
A.324.F.4.i；A.325.F.4.i；A.326.F.4.i；A.327.F.4.i；A.328.F.4.i；A.329.F.4.i；
A.330.F.4.i；A.331.F.4.i；A.332.F.4.i；A.333.F.4.i；A.334.F.4.i；A.335.F.4.i；
A.336.F.4.i；A.337.F.4.i；A.338.F.4.i；A.339.F.4.i；A.340.F.4.i；A.341.F.4.i；
A.342.F.4.i；A.343.F.4.i；A.344.F.4.i；A.345.F.4.i；A.346.F.4.i；A.347.F.4.i；
A.348.F.4.i；A.349.F.4.i；A.350.F.4.i；A.351.F.4.i；A.352.F.4.i；A.353.F.4.i；
A.354.F.4.i；A.355.F.4.i；A.356.F.4.i；A.357.F.4.i；A.358.F.4.i；A.359.F.4.i；
A.360.F.4.i；A.361.F.4.i；A.362.F.4.i；A.363.F.4.i；A.364.F.4.i；A.365.F.4.i；
A.366.F.4.i；A.367.F.4.i；A.368.F.4.i；A.369.F.4.i；A.370.F.4.i；A.371.F.4.i；
A.372.F.4.i；A.373.F.4.i；A.374.F.4.i；A.375.F.4.i；A.376.F.4.i；A.377.F.4.i；
A.378.F.4.i；A.379.F.4.i；A.380.F.4.i；A.381.F.4.i；A.382.F.4.i；A.383.F.4.i；
A.384.F.4.i；A.385.F.4.i；A.386.F.4.i；A.387.F.4.i；A.388.F.4.i；A.389.F.4.i；
A.390.F.4.i；A.391.F.4.i；A.392.F.4.i；A.393.F.4.i；A.394.F.4.i；A.395.F.4.i；
A.396.F.4.i；A.397.F.4.i；A.398.F.4.i；A.399.F.4.i；A.400.F.4.i；A.401.F.4.i；
A.402.F.4.i；A.403.F.4.i；A.404.F.4.i；A.405.F.4.i；A.406.F.4.i；A.407.F.4.i；
A.408.F.4.i；A.409.F.4.i；A.410.F.4.i；A.411.F.4.i；A.412.F.4.i；A.413.F.4.i；
A.414.F.4.i；A.415.F.4.i；A.416.F.4.i；A.417.F.4.i；A.418.F.4.i；A.419.F.4.i；
A.420.F.4.i；A.421.F.4.i；A.422.F.4.i；A.423.F.4.i；A.424.F.4.i；A.425.F.4.i；
A.426.F.4.i；A.427.F.4.i；A.428.F.4.i；A.429.F.4.i；A.430.F.4.i；A.431.F.4.i；
A.432.F.4.i；A.433.F.4.i；A.434.F.4.i；A.435.F.4.i；A.436.F.4.i；A.437.F.4.i；
A.438.F.4.i；A.439.F.4.i；A.440.F.4.i；A.441.F.4.i；A.442.F.4.i；A.443.F.4.i；
A.444.F.4.i；A.445.F.4.i；A.446.F.4.i；A.447.F.4.i；A.448.F.4.i；A.449.F.4.i；
A.450.F.4.i；A.451.F.4.i；A.452.F.4.i；A.453.F.4.i；A.454.F.4.i；A.455.F.4.i；
A.456.F.4.i；A.457.F.4.i；A.458.F.4.i；A.459.F.4.i；A.460.F.4.i；A.461.F.4.i；
A.462.F.4.i；A.463.F.4.i；A.464.F.4.i；A.465.F.4.i；A.466.F.4.i；A.467.F.4.i；
A.468.F.4.i；A.469.F.4.i；A.470.F.4.i；A.471.F.4.i；A.472.F.4.i；A.473.F.4.i；
A.474.F.4.i；A.475.F.4.i；A.476.F.4.i；A.477.F.4.i；A.478.F.4.i；A.479.F.4.i；
A.480.F.4.i；A.481.F.4.i；A.482.F.4.i；A.483.F.4.i；A.484.F.4.i；A.485.F.4.i；
A.486.F.4.i；A.487.F.4.i；A.488.F.4.i；A.489.F.4.i；A.490.F.4.i；A.491.F.4.i；
A.492.F.4.i；A.493.F.4.i；A.494.F.4.i；A.495.F.4.i；A.496.F.4.i；A.497.F.4.i；
A.498.F.4.i；A.499.F.4.i；A.500.F.4.i；A.501.F.4.i；A.502.F.4.i；A.503.F.4.i；
A.504.F.4.i；A.505.F.4.i；A.506.F.4.i；A.507.F.4.i；A.508.F.4.i；A.509.F.4.i；
A.510.F.4.i；A.511.F.4.i；A.512.F.4.i；A.512.F.4.i；A.513.F.4.i；A.514.F.4.i；
A.515.F.4.i；A.516.F.4.i；A.517.F.4.i；A.518.F.4.i；A.519.F.4.i；A.520.F.4.i；
A.521.F.4.i；A.522.F.4.i；A.523.F.4.i；A.524.F.4.i；A.525.F.4.i；A.526.F.4.i；
A.527.F.4.i；A.528.F.4.i；A.529.F.4.i；A.530.F.4.i；A.531.F.4.i；A.532.F.4.i；
A.533.F.4.i；A.534.F.4.i；A.535.F.4.i；A.536.F.4.i；A.537.F.4.i；A.538.F.4.i；
A.539.F.4.i；A.540.F.4.i；A.541.F.4.i；A.542.F.4.i；A.543.F.4.i；A.544.F.4.i；
A.545.F.4.i；A.546.F.4.i；A.547.F.4.i；A.548.F.4.i；A.549.F.4.i；A.550.F.4.i；
A.551.F.4.i；A.552.F.4.i；A.553.F.4.i；A.554.F.4.i；A.555.F.4.i；A.556.F.4.i；
A.557.F.4.i；A.558.F.4.i；A.559.F.4.i；A.560.F.4.i；A.561.F.4.i；A.562.F.4.i；
A.563.F.4.i；A.564.F.4.i；A.565.F.4.i；A.566.F.4.i；A.567.F.4.i；A.568.F.4.i；
A.569.F.4.i；A.570.F.4.i；A.571.F.4.i；A.572.F.4.i；A.573.F.4.i；A.574.F.4.i；
A.575.F.4.i；A.576.F.4.i；A.577.F.4.i；A.578.F.4.i；A.579.F.4.i；A.580.F.4.i；
A.581.F.4.i；A.582.F.4.i；A.583.F.4.i；A.584.F.4.i；A.585.F.4.i；A.586.F.4.i；
A.587.F.4.i；A.588.F.4.i；A.589.F.4.i；A.590.F.4.i；A.591.F.4.i；A.592.F.4.i；
A.593.F.4.i；A.594.F.4.i；A.595.F.4.i；A.596.F.4.i；A.597.F.4.i；A.598.F.4.i；
A.599.F.4.i；A.600.F.4.i；A.601.F.4.i；A.602.F.4.i；A.603.F.4.i；A.604.F.4.i；
A.605.F.4.i；A.606.F.4.i；A.607.F.4.i；A.608.F.4.i；A.609.F.4.i；A.610.F.4.i；
A.611.F.4.i；A.612.F.4.i；A.613.F.4.i；A.614.F.4.i；A.615.F.4.i；A.616.F.4.i；
A.617.F.4.i；A.618.F.4.i；A.619.F.4.i；A.620.F.4.i；A.621.F.4.i；A.622.F.4.i；
A.623.F.4.i；A.624.F.4.i；A.625.F.4.i；A.626.F.4.i；A.627.F.4.i；A.628.F.4.i；
A.629.F.4.i；A.630.F.4.i；A.631.F.4.i；A.632.F.4.i；A.633.F.4.i；A.634.F.4.i；
A.635.F.4.i；A.636.F.4.i；A.637.F.4.i；A.638.F.4.i；A.639.F.4.i；A.640.F.4.i；
A.641.F.4.i；A.642.F.4.i；A.643.F.4.i；A.644.F.4.i；A.645.F.4.i；A.646.F.4.i；
A.647.F.4.i；A.648.F.4.i；A.649.F.4.i；A.650.F.4.i；A.651.F.4.i；A.652.F.4.i；
A.653.F.4.i；A.654.F.4.i；A.655.F.4.i；A.656.F.4.i；A.657.F.4.i；A.658.F.4.i；
A.659.F.4.i；A.660.F.4.i；A.2.F.11.i；A.3.F.11.i；A.4.F.11.i；A.5.F.11.i；A.6.F.11.i；
A.7.F.11.i；A.9.F.11.i；A.10.F.11.i；A.15.F.11.i；A.100.F.11.i；A.101.F.11.i；
A.102.F.11.i；A.103.F.11.i；A.104.F.11.i；A.105.F.11.i；A.106.F.11.i；A.107.F.11.i；
A.108.F.11.i；A.109.F.11.i；A.110.F.11.i；A.111.F.11.i；A.112.F.11.i；A.113.F.11.i；
A.114.F.11.i；A.115.F.11.i；A.116.F.11.i；A.117.F.11.i；A.118.F.11.i；A.119.F.11.i；
A.120.F.11.i；A.121.F.11.i；A.122.F.11.i；A.123.F.11.i；A.124.F.11.i；A.125.F.11.i；
A.126.F.11.i；A.127.F.11.i；A.128.F.11.i；A.129.F.11.i；A.130.F.11.i；A.131.F.11.i；
A.132.F.11.i；A.133.F.11.i；A.134.F.11.i；A.135.F.11.i；A.136.F.11.i；A.137.F.11.i；
A.138.F.11.i；A.139.F.11.i；A.140.F.11.i；A.141.F.11.i；A.142.F.11.i；A.143.F.11.i；
A.144.F.11.i；A.145.F.11.i；A.146.F.11.i；A.147.F.11.i；A.148.F.11.i；A.149.F.11.i；
A.150.F.11.i；A.151.F.11.i；A.152.F.11.i；A.153.F.11.i；A.154.F.11.i；A.155.F.11.i；
A.156.F.11.i；A.157.F.11.i；A.158.F.11.i；A.159.F.11.i；A.160.F.11.i；A.161.F.11.i；
A.162.F.11.i；A.163.F.11.i；A.164.F.11.i；A.165.F.11.i；A.166.F.11.i；A.167.F.11.i；
A.168.F.11.i；A.169.F.11.i；A.170.F.11.i；A.171.F.11.i；A.172.F.11.i；A.173.F.11.i；
A.174.F.11.i；A.175.F.11.i；A.176.F.11.i；A.177.F.11.i；A.178.F.11.i；A.179.F.11.i；
A.180.F.11.i；A.181.F.11.i；A.182.F.11.i；A.183.F.11.i；A.184.F.11.i；A.185.F.11.i；
A.186.F.11.i；A.187.F.11.i；A.188.F.11.i；A.189.F.11.i；A.190.F.11.i；A.191.F.11.i；
A.192.F.11.i；A.193.F.11.i；A.194.F.11.i；A.195.F.11.i；A.196.F.11.i；A.197.F.11.i；
A.198.F.11.i；A.199.F.11.i；A.200.F.11.i；A.201.F.11.i；A.202.F.11.i；A.203.F.11.i；
A.204.F.11.i；A.205.F.11.i；A.206.F.11.i；A.207.F.11.i；A.208.F.11.i；A.209.F.11.i；
A.210.F.11.i；A.211.F.11.i；A.212.F.11.i；A.213.F.11.i；A.214.F.11.i；A.215.F.11.i；
A.216.F.11.i；A.217.F.11.i；A.218.F.11.i；A.219.F.11.i；A.220.F.11.i；A.221.F.11.i；
A.222.F.11.i；A.223.F.11.i；A.224.F.11.i；A.225.F.11.i；A.226.F.11.i；A.227.F.11.i；
A.228.F.11.i；A.229.F.11.i；A.230.F.11.i；A.231.F.11.i；A.232.F.11.i；A.233.F.11.i；
A.234.F.11.i；A.235.F.11.i；A.236.F.11.i；A.237.F.11.i；A.238.F.11.i；A.239.F.11.i；
A.240.F.11.i；A.241.F.11.i；A.242.F.11.i；A.243.F.11.i；A.244.F.11.i；A.245.F.11.i；
A.246.F.11.i；A.247.F.11.i；A.248.F.11.i；A.249.F.11.i；A.250.F.11.i；A.251.F.11.i；
A.252.F.11.i；A.253.F.11.i；A.254.F.11.i；A.255.F.11.i；A.256.F.11.i；A.257.F.11.i；
A.258.F.11.i；A.259.F.11.i；A.260.F.11.i；A.261.F.11.i；A.262.F.11.i；A.263.F.11.i；
A.264.F.11.i；A.265.F.11.i；A.266.F.11.i；A.267.F.11.i；A.268.F.11.i；A.269.F.11.i；
A.270.F.11.i；A.271.F.11.i；A.272.F.11.i；A.273.F.11.i；A.274.F.11.i；A.275.F.11.i；
A.276.F.11.i；A.277.F.11.i；A.278.F.11.i；A.279.F.11.i；A.280.F.11.i；A.281.F.11.i；
A.282.F.11.i；A.283.F.11.i；A.284.F.11.i；A.285.F.11.i；A.286.F.11.i；A.287.F.11.i；
A.288.F.11.i；A.289.F.11.i；A.290.F.11.i；A.291.F.11.i；A.292.F.11.i；A.293.F.11.i；
A.294.F.11.i；A.295.F.11.i；A.296.F.11.i；A.297.F.11.i；A.298.F.11.i；A.299.F.11.i；
A.300.F.11.i；A.301.F.11.i；A.302.F.11.i；A.303.F.11.i；A.304.F.11.i；A.305.F.11.i；
A.306.F.11.i；A.307.F.11.i；A.308.F.11.i；A.309.F.11.i；A.310.F.11.i；A.311.F.11.i；
A.312.F.11.i；A.313.F.11.i；A.314.F.11.i；A.315.F.11.i；A.316.F.11.i；A.317.F.11.i；
A.318.F.11.i；A.319.F.11.i；A.320.F.11.i；A.321.F.11.i；A.323.F.11.i；A.324.F.11.i；
A.325.F.11.i；A.326.F.11.i；A.327.F.11.i；A.328.F.11.i；A.329.F.11.i；A.330.F.11.i；
A.331.F.11.i；A.332.F.11.i；A.333.F.11.i；A.334.F.11.i；A.335.F.11.i；A.336.F.11.i；
A.337.F.11.i；A.338.F.11.i；A.339.F.11.i；A.340.F.11.i；A.341.F.11.i；A.342.F.11.i；
A.343.F.11.i；A.344.F.11.i；A.345.F.11.i；A.346.F.11.i；A.347.F.11.i；A.348.F.11.i；
A.349.F.11.i；A.350.F.11.i；A.351.F.11.i；A.352.F.11.i；A.353.F.11.i；A.354.F.11.i；
A.355.F.11.i；A.356.F.11.i；A.357.F.11.i；A.358.F.11.i；A.359.F.11.i；A.360.F.11.i；
A.361.F.11.i；A.362.F.11.i；A.363.F.11.i；A.364.F.11.i；A.365.F.11.i；A.366.F.11.i；
A.367.F.11.i；A.368.F.11.i；A.369.F.11.i；A.370.F.11.i；A.371.F.11.i；A.372.F.11.i；
A.373.F.11.i；A.374.F.11.i；A.375.F.11.i；A.376.F.11.i；A.377.F.11.i；A.378.F.11.i；
A.379.F.11.i；A.380.F.11.i；A.381.F.11.i；A.382.F.11.i；A.383.F.11.i；A.384.F.11.i；
A.385.F.11.i；A.386.F.11.i；A.387.F.11.i；A.388.F.11.i；A.389.F.11.i；A.390.F.11.i；
A.391.F.11.i；A.392.F.11.i；A.393.F.11.i；A.394.F.11.i；A.395.F.11.i；A.396.F.11.i；
A.397.F.11.i；A.398.F.11.i；A.399.F.11.i；A.400.F.11.i；A.401.F.11.i；A.402.F.11.i；
A.403.F.11.i；A.404.F.11.i；A.405.F.11.i；A.406.F.11.i；A.407.F.11.i；A.408.F.11.i；
A.409.F.11.i；A.410.F.11.i；A.411.F.11.i；A.412.F.11.i；A.413.F.11.i；A.414.F.11.i；
A.415.F.11.i；A.416.F.11.i；A.417.F.11.i；A.418.F.11.i；A.419.F.11.i；A.420.F.11.i；
A.421.F.11.i；A.422.F.11.i；A.423.F.11.i；A.424.F.11.i；A.425.F.11.i；A.426.F.11.i；
A.427.F.11.i；A.428.F.11.i；A.429.F.11.i；A.430.F.11.i；A.431.F.11.i；A.432.F.11.i；
A.433.F.11.i；A.434.F.11.i；A.435.F.11.i；A.436.F.11.i；A.437.F.11.i；A.438.F.11.i；
A.439.F.11.i；A.440.F.11.i；A.441.F.11.i；A.442.F.11.i；A.443.F.11.i；A.444.F.11.i；
A.445.F.11.i；A.446.F.11.i；A.447.F.11.i；A.448.F.11.i；A.449.F.11.i；A.450.F.11.i；
A.451.F.11.i；A.452.F.11.i；A.453.F.11.i；A.454.F.11.i；A.455.F.11.i；A.456.F.11.i；
A.457.F.11.i；A.458.F.11.i；A.459.F.11.i；A.460.F.11.i；A.461.F.11.i；A.462.F.11.i；
A.463.F.11.i；A.464.F.11.i；A.465.F.11.i；A.466.F.11.i；A.467.F.11.i；A.468.F.11.i；
A.469.F.11.i；A.470.F.11.i；A.471.F.11.i；A.472.F.11.i；A.473.F.11.i；A.474.F.11.i；
A.475.F.11.i；A.476.F.11.i；A.477.F.11.i；A.478.F.11.i；A.479.F.11.i；A.480.F.11.i；
A.481.F.11.i；A.482.F.11.i；A.483.F.11.i；A.484.F.11.i；A.485.F.11.i；A.486.F.11.i；
A.487.F.11.i；A.488.F.11.i；A.489.F.11.i；A.490.F.11.i；A.491.F.11.i；A.492.F.11.i；
A.493.F.11.i；A.494.F.11.i；A.495.F.11.i；A.496.F.11.i；A.497.F.11.i；A.498.F.11.i；
A.499.F.11.i；A.500.F.11.i；A.501.F.11.i；A.502.F.11.i；A.503.F.11.i；A.504.F.11.i；
A.505.F.11.i；A.506.F.11.i；A.507.F.11.i；A.508.F.11.i；A.509.F.11.i；A.510.F.11.i；
A.511.F.11.i；A.512.F.11.i；A.512.F.11.i；A.513.F.11.i；A.514.F.11.i；A.515.F.11.i；
A.516.F.11.i；A.517.F.11.i；A.518.F.11.i；A.519.F.11.i；A.520.F.11.i；A.521.F.11.i；
A.522.F.11.i；A.523.F.11.i；A.524.F.11.i；A.525.F.11.i；A.526.F.11.i；A.527.F.11.i；
A.528.F.11.i；A.529.F.11.i；A.530.F.11.i；A.531.F.11.i；A.532.F.11.i；A.533.F.11.i；
A.534.F.11.i；A.535.F.11.i；A.536.F.11.i；A.537.F.11.i；A.538.F.11.i；A.539.F.11.i；
A.540.F.11.i；A.541.F.11.i；A.542.F.11.i；A.543.F.11.i；A.544.F.11.i；A.545.F.11.i；
A.546.F.11.i；A.547.F.11.i；A.548.F.11.i；A.549.F.11.i；A.550.F.11.i；A.551.F.11.i；
A.552.F.11.i；A.553.F.11.i；A.554.F.11.i；A.555.F.11.i；A.556.F.11.i；A.557.F.11.i；
A.558.F.11.i；A.559.F.11.i；A.560.F.11.i；A.561.F.11.i；A.562.F.11.i；A.563.F.11.i；
A.564.F.11.i；A.565.F.11.i；A.566.F.11.i；A.567.F.11.i；A.568.F.11.i；A.569.F.11.i；
A.570.F.11.i；A.571.F.11.i；A.572.F.11.i；A.573.F.11.i；A.574.F.11.i；A.575.F.11.i；
A.576.F.11.i；A.577.F.11.i；A.578.F.11.i；A.579.F.11.i；A.580.F.11.i；A.581.F.11.i；
A.582.F.11.i；A.583.F.11.i；A.584.F.11.i；A.585.F.11.i；A.586.F.11.i；A.587.F.11.i；
A.588.F.11.i；A.589.F.11.i；A.590.F.11.i；A.591.F.11.i；A.592.F.11.i；A.593.F.11.i；
A.594.F.11.i；A.595.F.11.i；A.596.F.11.i；A.597.F.11.i；A.598.F.11.i；A.599.F.11.i；
A.600.F.11.i；A.601.F.11.i；A.602.F.11.i；A.603.F.11.i；A.604.F.11.i；A.605.F.11.i；
A.606.F.11.i；A.607.F.11.i；A.608.F.11.i；A.609.F.11.i；A.610.F.11.i；A.611.F.11.i；
A.612.F.11.i；A.613.F.11.i；A.614.F.11.i；A.615.F.11.i；A.616.F.11.i；A.617.F.11.i；
A.618.F.11.i；A.619.F.11.i；A.620.F.11.i；A.621.F.11.i；A.622.F.11.i；A.623.F.11.i；
A.624.F.11.i；A.625.F.11.i；A.626.F.11.i；A.627.F.11.i；A.628.F.11.i；A.629.F.11.i；
A.630.F.11.i；A.631.F.11.i；A.632.F.11.i；A.633.F.11.i；A.634.F.11.i；A.635.F.11.i；
A.636.F.11.i；A.637.F.11.i；A.638.F.11.i；A.639.F.11.i；A.640.F.11.i；A.641.F.11.i；
A.642.F.11.i；A.643.F.11.i；A.644.F.11.i；A.645.F.11.i；A.646.F.11.i；A.647.F.11.i；
A.648.F.11.i；A.649.F.11.i；A.650.F.11.i；A.651.F.11.i；A.652.F.11.i；A.653.F.11.i；
A.654.F.11.i；A.655.F.11.i；A.656.F.11.i；A.657.F.11.i；A.658.F.11.i；A.659.F.11.i；
A.660.F.11.i；A.2.a.44.i；A.3.a.44.i；A.4.a.44.i；A.5.a.44.i；A.9.a.44.i；A.100.a.44.i；
A.101.a.44.i；A.102.a.44.i；A.103.a.44.i；A.104.a.44.i；A.105.a.44.i；A.106.a.44.i；
A.107.a.44.i；A.108.a.44.i；A.109.a.44.i；A.110.a.44.i；A.111.a.44.i；A.112.a.44.i；
A.113.a.44.i；A.114.a.44.i；A.115.a.44.i；A.116.a.44.i；A.117.a.44.i；A.118.a.44.i；
A.119.a.44.i；A.120.a.44.i；A.121.a.44.i；A.122.a.44.i；A.123.a.44.i；A.124.a.44.i；
A.125.a.44.i；A.126.a.44.i；A.127.a.44.i；A.128.a.44.i；A.129.a.44.i；A.130.a.44.i；
A.131.a.44.i；A.132.a.44.i；A.133.a.44.i；A.134.a.44.i；A.135.a.44.i；A.136.a.44.i；
A.137.a.44.i；A.138.a.44.i；A.139.a.44.i；A.140.a.44.i；A.141.a.44.i；A.142.a.44.i；
A.143.a.44.i；A.144.a.44.i；A.145.a.44.i；A.146.a.44.i；A.147.a.44.i；A.148.a.44.i；
A.149.a.44.i；A.150.a.44.i；A.151.a.44.i；A.152.a.44.i；A.153.a.44.i；A.154.a.44.i；
A.155.a.44.i；A.156.a.44.i；A.157.a.44.i；A.158.a.44.i；A.159.a.44.i；A.160.a.44.i；
A.161.a.44.i；A.162.a.44.i；A.163.a.44.i；A.164.a.44.i；A.165.a.44.i；A.166.a.44.i；
A.167.a.44.i；A.168.a.44.i；A.169.a.44.i；A.170.a.44.i；A.171.a.44.i；A.172.a.44.i；
A.173.a.44.i；A.174.a.44.i；A.175.a.44.i；A.176.a.44.i；A.177.a.44.i；A.178.a.44.i；
A.179.a.44.i；A.180.a.44.i；A.181.a.44.i；A.182.a.44.i；A.183.a.44.i；A.184.a.44.i；
A.185.a.44.i；A.186.a.44.i；A.187.a.44.i；A.188.a.44.i；A.189.a.44.i；A.190.a.44.i；
A.191.a.44.i；A.192.a.44.i；A.193.a.44.i；A.194.a.44.i；A.195.a.44.i；A.196.a.44.i；
A.197.a.44.i；A.198.a.44.i；A.199.a.44.i；A.200.a.44.i；A.201.a.44.i；A.202.a.44.i；
A.203.a.44.i；A.204.a.44.i；A.205.a.44.i；A.206.a.44.i；A.207.a.44.i；A.208.a.44.i；
A.209.a.44.i；A.210.a.44.i；A.211.a.44.i；A.212.a.44.i；A.213.a.44.i；A.214.a.44.i；
A.215.a.44.i；A.216.a.44.i；A.217.a.44.i；A.218.a.44.i；A.219.a.44.i；A.220.a.44.i；
A.221.a.44.i；A.222.a.44.i；A.223.a.44.i；A.224.a.44.i；A.225.a.44.i；A.226.a.44.i；
A.227.a.44.i；A.228.a.44.i；A.229.a.44.i；A.230.a.44.i；A.231.a.44.i；A.232.a.44.i；
A.233.a.44.i；A.234.a.44.i；A.235.a.44.i；A.236.a.44.i；A.237.a.44.i；A.238.a.44.i；
A.239.a.44.i；A.240.a.44.i；A.241.a.44.i；A.242.a.44.i；A.243.a.44.i；A.244.a.44.i；
A.245.a.44.i；A.246.a.44.i；A.247.a.44.i；A.248.a.44.i；A.249.a.44.i；A.250.a.44.i；
A.251.a.44.i；A.252.a.44.i；A.253.a.44.i；A.254.a.44.i；A.255.a.44.i；A.256.a.44.i；
A.257.a.44.i；A.258.a.44.i；A.259.a.44.i；A.260.a.44.i；A.261.a.44.i；A.262.a.44.i；
A.263.a.44.i；A.264.a.44.i；A.265.a.44.i；A.266.a.44.i；A.267.a.44.i；A.268.a.44.i；
A.269.a.44.i；A.270.a.44.i；A.271.a.44.i；A.272.a.44.i；A.273.a.44.i；A.274.a.44.i；
A.275.a.44.i；A.276.a.44.i；A.277.a.44.i；A.278.a.44.i；A.279.a.44.i；A.280.a.44.i；
A.281.a.44.i；A.282.a.44.i；A.283.a.44.i；A.284.a.44.i；A.285.a.44.i；A.286.a.44.i；
A.287.a.44.i；A.288.a.44.i；A.289.a.44.i；A.290.a.44.i；A.291.a.44.i；A.292.a.44.i；
A.293.a.44.i；A.294.a.44.i；A.295.a.44.i；A.296.a.44.i；A.297.a.44.i；A.298.a.44.i；
A.299.a.44.i；A.300.a.44.i；A.301.a.44.i；A.302.a.44.i；A.303.a.44.i；A.304.a.44.i；
A.305.a.44.i；A.306.a.44.i；A.307.a.44.i；A.308.a.44.i；A.309.a.44.i；A.310.a.44.i；
A.311.a.44.i；A.312.a.44.i；A.313.a.44.i；A.314.a.44.i；A.315.a.44.i；A.316.a.44.i；
A.317.a.44.i；A.318.a.44.i；A.319.a.44.i；A.320.a.44.i；A.321.a.44.i；A.322.a.44.i；
A.323.a.44.i；A.324.a.44.i；A.325.a.44.i；A.326.a.44.i；A.327.a.44.i；A.328.a.44.i；
A.329.a.44.i；A.330.a.44.i；A.331.a.44.i；A.332.a.44.i；A.333.a.44.i；A.334.a.44.i；
A.335.a.44.i；A.336.a.44.i；A.337.a.44.i；A.338.a.44.i；A.339.a.44.i；A.340.a.44.i；
A.341.a.44.i；A.342.a.44.i；A.343.a.44.i；A.344.a.44.i；A.345.a.44.i；A.346.a.44.i；
A.347.a.44.i；A.348.a.44.i；A.349.a.44.i；A.350.a.44.i；A.351.a.44.i；A.352.a.44.i；
A.353.a.44.i；A.354.a.44.i；A.355.a.44.i；A.356.a.44.i；A.357.a.44.i；A.358.a.44.i；
B.2.a.44.i；B.3.a.44.i；B.4.a.44.i；B.5.a.44.i；B.9.a.44.i；B.100.a.44.i；B.101.a.44.i；
B.102.a.44.i；B.103.a.44.i；B.104.a.44.i；B.105.a.44.i；B.106.a.44.i；B.107.a.44.i；
B.108.a.44.i；B.109.a.44.i；B.110.a.44.i；B.111.a.44.i；B.112.a.44.i；B.113.a.44.i；
B.114.a.44.i；B.115.a.44.i；B.116.a.44.i；B.117.a.44.i；B.118.a.44.i；B.119.a.44.i；
B.120.a.44.i；B.121.a.44.i；B.122.a.44.i；B.123.a.44.i；B.124.a.44.i；B.125.a.44.i；
B.126.a.44.i；B.127.a.44.i；B.128.a.44.i；B.129.a.44.i；B.130.a.44.i；B.131.a.44.i；
B.132.a.44.i；B.133.a.44.i；B.134.a.44.i；B.135.a.44.i；B.136.a.44.i；B.137.a.44.i；
B.138.a.44.i；B.139.a.44.i；B.140.a.44.i；B.141.a.44.i；B.142.a.44.i；B.143.a.44.i；
B.144.a.44.i；B.145.a.44.i；B.146.a.44.i；B.147.a.44.i；B.148.a.44.i；B.149.a.44.i；
B.150.a.44.i；B.151.a.44.i；B.152.a.44.i；B.153.a.44.i；B.154.a.44.i；B.155.a.44.i；
B.156.a.44.i；B.157.a.44.i；B.158.a.44.i；B.159.a.44.i；B.160.a.44.i；B.161.a.44.i；
B.162.a.44.i；B.163.a.44.i；B.164.a.44.i；B.165.a.44.i；B.166.a.44.i；B.167.a.44.i；
B.168.a.44.i；B.169.a.44.i；B.170.a.44.i；B.171.a.44.i；B.172.a.44.i；B.173.a.44.i；
B.174.a.44.i；B.175.a.44.i；B.176.a.44.i；B.177.a.44.i；B.178.a.44.i；B.179.a.44.i；
B.180.a.44.i；B.181.a.44.i；B.182.a.44.i；B.183.a.44.i；B.184.a.44.i；B.185.a.44.i；
B.186.a.44.i；B.187.a.44.i；B.188.a.44.i；B.189.a.44.i；B.190.a.44.i；B.191.a.44.i；
B.192.a.44.i；B.193.a.44.i；B.194.a.44.i；B.195.a.44.i；B.196.a.44.i；B.197.a.44.i；
B.198.a.44.i；B.199.a.44.i；B.200.a.44.i；B.201.a.44.i；B.202.a.44.i；B.203.a.44.i；
B.204.a.44.i；B.205.a.44.i；B.206.a.44.i；B.207.a.44.i；B.208.a.44.i；B.209.a.44.i；
B.210.a.44.i；B.211.a.44.i；B.212.a.44.i；B.213.a.44.i；B.214.a.44.i；B.215.a.44.i；
B.216.a.44.i；B.217.a.44.i；B.218.a.44.i；B.219.a.44.i；B.220.a.44.i；B.221.a.44.i；
B.222.a.44.i；B.223.a.44.i；B.224.a.44.i；B.225.a.44.i；B.226.a.44.i；B.227.a.44.i；
B.228.a.44.i；B.229.a.44.i；B.230.a.44.i；B.231.a.44.i；B.232.a.44.i；B.233.a.44.i；
B.234.a.44.i；B.235.a.44.i；B.236.a.44.i；B.237.a.44.i；B.238.a.44.i；B.239.a.44.i；
B.240.a.44.i；B.241.a.44.i；B.242.a.44.i；B.243.a.44.i；B.244.a.44.i；B.245.a.44.i；
B.246.a.44.i；B.247.a.44.i；B.248.a.44.i；B.249.a.44.i；B.250.a.44.i；B.251.a.44.i；
B.252.a.44.i；B.253.a.44.i；B.254.a.44.i；B.255.a.44.i；B.256.a.44.i；B.257.a.44.i；
B.258.a.44.i；B.259.a.44.i；B.260.a.44.i；B.261.a.44.i；B.262.a.44.i；B.263.a.44.i；
B.264.a.44.i；B.265.a.44.i；B.266.a.44.i；B.267.a.44.i；B.268.a.44.i；B.269.a.44.i；
B.270.a.44.i；B.271.a.44.i；B.272.a.44.i；B.273.a.44.i；B.274.a.44.i；B.275.a.44.i；
B.276.a.44.i；B.277.a.44.i；B.278.a.44.i；B.279.a.44.i；B.280.a.44.i；B.281.a.44.i；
B.282.a.44.i；B.283.a.44.i；B.284.a.44.i；B.285.a.44.i；B.286.a.44.i；B.287.a.44.i；
B.288.a.44.i；B.289.a.44.i；B.290.a.44.i；B.291.a.44.i；B.292.a.44.i；B.293.a.44.i；
B.294.a.44.i；B.295.a.44.i；B.296.a.44.i；B.297.a.44.i；B.298.a.44.i；B.299.a.44.i；
B.300.a.44.i；B.301.a.44.i；B.302.a.44.i；B.303.a.44.i；B.304.a.44.i；B.305.a.44.i；
B.306.a.44.i；B.307.a.44.i；B.308.a.44.i；B.309.a.44.i；B.310.a.44.i；B.311.a.44.i；
B.312.a.44.i；B.313.a.44.i；B.314.a.44.i；B.315.a.44.i；B.316.a.44.i；B.317.a.44.i；
B.318.a.44.i；B.319.a.44.i；B.320.a.44.i；B.321.a.44.i；B.322.a.44.i；B.323.a.44.i；
B.324.a.44.i；B.325.a.44.i；B.326.a.44.i；B.327.a.44.i；B.328.a.44.i；B.329.a.44.i；
B.330.a.44.i；B.331.a.44.i；B.332.a.44.i；B.333.a.44.i；B.334.a.44.i；B.335.a.44.i；
B.336.a.44.i；B.337.a.44.i；B.338.a.44.i；B.339.a.44.i；B.340.a.44.i；B.341.a.44.i；
B.342.a.44.i；B.343.a.44.i；B.344.a.44.i；B.345.a.44.i；B.346.a.44.i；B.347.a.44.i；
B.348.a.44.i；B.349.a.44.i；B.350.a.44.i；B.351.a.44.i；B.352.a.44.i；B.353.a.44.i；
B.354.a.44.i；B.355.a.44.i；B.356.a.44.i；B.357.a.44.i；B.358.a.44.i；E.2.a.44.i；E.3.a.44.i；
E.4.a.44.i；E.5.a.44.i；E.9.a.44.i；E.100.a.44.i；E.101.a.44.i；E.102.a.44.i；E.103.a.44.i；
E.104.a.44.i；E.105.a.44.i；E.106.a.44.i；E.107.a.44.i；E.108.a.44.i；E.109.a.44.i；
E.110.a.44.i；E.111.a.44.i；E.112.a.44.i；E.113.a.44.i；E.114.a.44.i；E.115.a.44.i；
E.116.a.44.i；E.117.a.44.i；E.118.a.44.i；E.119.a.44.i；E.120.a.44.i；E.121.a.44.i；
E.122.a.44.i；E.123.a.44.i；E.124.a.44.i；E.125.a.44.i；E.126.a.44.i；E.127.a.44.i；
E.128.a.44.i；E.129.a.44.i；E.130.a.44.i；E.131.a.44.i；E.132.a.44.i；E.133.a.44.i；
E.134.a.44.i；E.135.a.44.i；E.136.a.44.i；E.137.a.44.i；E.138.a.44.i；E.139.a.44.i；
E.140.a.44.i；E.141.a.44.i；E.142.a.44.i；E.143.a.44.i；E.144.a.44.i；E.145.a.44.i；
E.146.a.44.i；E.147.a.44.i；E.148.a.44.i；E.149.a.44.i；E.150.a.44.i；E.151.a.44.i；
E.152.a.44.i；E.153.a.44.i；E.154.a.44.i；E.155.a.44.i；E.156.a.44.i；E.157.a.44.i；
E.158.a.44.i；E.159.a.44.i；E.160.a.44.i；E.161.a.44.i；E.162.a.44.i；E.163.a.44.i；
E.164.a.44.i；E.165.a.44.i；E.166.a.44.i；E.167.a.44.i；E.168.a.44.i；E.169.a.44.i；
E.170.a.44.i；E.171.a.44.i；E.172.a.44.i；E.173.a.44.i；E.174.a.44.i；E.175.a.44.i；
E.176.a.44.i；E.177.a.44.i；E.178.a.44.i；E.179.a.44.i；E.180.a.44.i；E.181.a.44.i；
E.182.a.44.i；E.183.a.44.i；E.184.a.44.i；E.185.a.44.i；E.186.a.44.i；E.187.a.44.i；
E.188.a.44.i；E.189.a.44.i；E.190.a.44.i；E.191.a.44.i；E.192.a.44.i；E.193.a.44.i；
E.194.a.44.i；E.195.a.44.i；E.196.a.44.i；E.197.a.44.i；E.198.a.44.i；E.199.a.44.i；
E.200.a.44.i；E.201.a.44.i；E.202.a.44.i；E.203.a.44.i；E.204.a.44.i；E.205.a.44.i；
E.206.a.44.i；E.207.a.44.i；E.208.a.44.i；E.209.a.44.i；E.210.a.44.i；E.211.a.44.i；
E.212.a.44.i；E.213.a.44.i；E.214.a.44.i；E.215.a.44.i；E.216.a.44.i；E.217.a.44.i；
E.218.a.44.i；E.219.a.44.i；E.220.a.44.i；E.221.a.44.i；E.222.a.44.i；E.223.a.44.i；
E.224.a.44.i；E.225.a.44.i；E.226.a.44.i；E.227.a.44.i；E.228.a.44.i；E.229.a.44.i；
E.230.a.44.i；E.231.a.44.i；E.232.a.44.i；E.233.a.44.i；E.234.a.44.i；E.235.a.44.i；
E.236.a.44.i；E.237.a.44.i；E.238.a.44.i；E.239.a.44.i；E.240.a.44.i；E.241.a.44.i；
E.242.a.44.i；E.243.a.44.i；E.244.a.44.i；E.245.a.44.i；E.246.a.44.i；E.247.a.44.i；
E.248.a.44.i；E.249.a.44.i；E.250.a.44.i；E.251.a.44.i；E.252.a.44.i；E.253.a.44.i；
E.254.a.44.i；E.255.a.44.i；E.256.a.44.i；E.257.a.44.i；E.258.a.44.i；E.259.a.44.i；
E.260.a.44.i；E.261.a.44.i；E.262.a.44.i；E.263.a.44.i；E.264.a.44.i；E.265.a.44.i；
E.266.a.44.i；E.267.a.44.i；E.268.a.44.i；E.269.a.44.i；E.270.a.44.i；E.271.a.44.i；
E.272.a.44.i；E.273.a.44.i；E.274.a.44.i；E.275.a.44.i；E.276.a.44.i；E.277.a.44.i；
E.278.a.44.i；E.279.a.44.i；E.280.a.44.i；E.281.a.44.i；E.282.a.44.i；E.283.a.44.i；
E.284.a.44.i；E.285.a.44.i；E.286.a.44.i；E.287.a.44.i；E.288.a.44.i；E.289.a.44.i；
E.290.a.44.i；E.291.a.44.i；E.292.a.44.i；E.293.a.44.i；E.294.a.44.i；E.295.a.44.i；
E.296.a.44.i；E.297.a.44.i；E.298.a.44.i；E.299.a.44.i；E.300.a.44.i；E.301.a.44.i；
E.302.a.44.i；E.303.a.44.i；E.304.a.44.i；E.305.a.44.i；E.306.a.44.i；E.307.a.44.i；
E.308.a.44.i；E.309.a.44.i；E.310.a.44.i；E.311.a.44.i；E.312.a.44.i；E.313.a.44.i；
E.314.a.44.i；E.315.a.44.i；E.316.a.44.i；E.317.a.44.i；E.318.a.44.i；E.319.a.44.i；
E.320.a.44.i；E.321.a.44.i；E.322.a.44.i；E.323.a.44.i；E.324.a.44.i；E.325.a.44.i；
E.326.a.44.i；E.327.a.44.i；E.328.a.44.i；E.329.a.44.i；E.330.a.44.i；E.331.a.44.i；
E.332.a.44.i；E.333.a.44.i；E.334.a.44.i；E.335.a.44.i；E.336.a.44.i；E.337.a.44.i；
E.338.a.44.i；E.339.a.44.i；E.340.a.44.i；E.341.a.44.i；E.342.a.44.i；E.343.a.44.i；
E.344.a.44.i；E.345.a.44.i；E.346.a.44.i；E.347.a.44.i；E.348.a.44.i；E.349.a.44.i；
E.350.a.44.i；E.351.a.44.i；E.352.a.44.i；E.353.a.44.i；E.354.a.44.i；E.355.a.44.i；
E.356.a.44.i；E.357.a.44.i；E.358.a.44.i；B.2.a.4.i；B.3.a.4.i；B.4.a.4.i；B.5.a.4.i；B.9.a.4.i；
B.100.a.4.i；B.101.a.4.i；B.102.a.4.i；B.103.a.4.i；B.104.a.4.i；B.105.a.4.i；B.106.a.4.i；
B.107.a.4.i；B.108.a.4.i；B.109.a.4.i；B.110.a.4.i；B.111.a.4.i；B.112.a.4.i；B.113.a.4.i；
B.114.a.4.i；B.115.a.4.i；B.116.a.4.i；B.117.a.4.i；B.118.a.4.i；B.119.a.4.i；B.120.a.4.i；
B.121.a.4.i；B.122.a.4.i；B.123.a.4.i；B.124.a.4.i；B.125.a.4.i；B.126.a.4.i；B.127.a.4.i；
B.128.a.4.i；B.129.a.4.i；B.130.a.4.i；B.131.a.4.i；B.132.a.4.i；B.133.a.4.i；B.134.a.4.i；
B.135.a.4.i；B.136.a.4.i；B.137.a.4.i；B.138.a.4.i；B.139.a.4.i；B.140.a.4.i；B.141.a.4.i；
B.142.a.4.i；B.143.a.4.i；B.144.a.4.i；B.145.a.4.i；B.146.a.4.i；B.147.a.4.i；B.148.a.4.i；
B.149.a.4.i；B.150.a.4.i；B.151.a.4.i；B.152.a.4.i；B.153.a.4.i；B.154.a.4.i；B.155.a.4.i；
B.156.a.4.i；B.157.a.4.i；B.158.a.4.i；B.159.a.4.i；B.160.a.4.i；B.161.a.4.i；B.162.a.4.i；
B.163.a.4.i；B.164.a.4.i；B.165.a.4.i；B.166.a.4.i；B.167.a.4.i；B.168.a.4.i；B.169.a.4.i；
B.170.a.4.i；B.171.a.4.i；B.172.a.4.i；B.173.a.4.i；B.174.a.4.i；B.175.a.4.i；B.176.a.4.i；
B.177.a.4.i；B.178.a.4.i；B.179.a.4.i；B.180.a.4.i；B.181.a.4.i；B.182.a.4.i；B.183.a.4.i；
B.184.a.4.i；B.185.a.4.i；B.186.a.4.i；B.187.a.4.i；B.188.a.4.i；B.189.a.4.i；B.190.a.4.i；
B.191.a.4.i；B.192.a.4.i；B.193.a.4.i；B.194.a.4.i；B.195.a.4.i；B.196.a.4.i；B.197.a.4.i；
B.198.a.4.i；B.199.a.4.i；B.200.a.4.i；B.201.a.4.i；B.202.a.4.i；B.203.a.4.i；B.204.a.4.i；
B.205.a.4.i；B.206.a.4.i；B.207.a.4.i；B.208.a.4.i；B.209.a.4.i；B.210.a.4.i；B.211.a.4.i；
B.212.a.4.i；B.213.a.4.i；B.214.a.4.i；B.215.a.4.i；B.216.a.4.i；B.217.a.4.i；B.218.a.4.i；
B.219.a.4.i；B.220.a.4.i；B.221.a.4.i；B.222.a.4.i；B.223.a.4.i；B.224.a.4.i；B.225.a.4.i；
B.226.a.4.i；B.227.a.4.i；B.228.a.4.i；B.229.a.4.i；B.230.a.4.i；B.231.a.4.i；B.232.a.4.i；
B.233.a.4.i；B.234.a.4.i；B.235.a.4.i；B.236.a.4.i；B.237.a.4.i；B.238.a.4.i；B.239.a.4.i；
B.240.a.4.i；B.241.a.4.i；B.242.a.4.i；B.243.a.4.i；B.244.a.4.i；B.245.a.4.i；B.246.a.4.i；
B.247.a.4.i；B.248.a.4.i；B.249.a.4.i；B.250.a.4.i；B.251.a.4.i；B.252.a.4.i；B.253.a.4.i；
B.254.a.4.i；B.255.a.4.i；B.256.a.4.i；B.257.a.4.i；B.258.a.4.i；B.259.a.4.i；B.260.a.4.i；
B.261.a.4.i；B.262.a.4.i；B.263.a.4.i；B.264.a.4.i；B.265.a.4.i；B.266.a.4.i；B.267.a.4.i；
B.268.a.4.i；B.269.a.4.i；B.270.a.4.i；B.271.a.4.i；B.272.a.4.i；B.273.a.4.i；B.274.a.4.i；
B.275.a.4.i；B.276.a.4.i；B.277.a.4.i；B.278.a.4.i；B.279.a.4.i；B.280.a.4.i；B.281.a.4.i；
B.282.a.4.i；B.283.a.4.i；B.284.a.4.i；B.285.a.4.i；B.286.a.4.i；B.287.a.4.i；B.288.a.4.i；
B.289.a.4.i；B.290.a.4.i；B.291.a.4.i；B.292.a.4.i；B.293.a.4.i；B.294.a.4.i；B.295.a.4.i；
B.296.a.4.i；B.297.a.4.i；B.298.a.4.i；B.299.a.4.i；B.300.a.4.i；B.301.a.4.i；B.302.a.4.i；
B.303.a.4.i；B.304.a.4.i；B.305.a.4.i；B.306.a.4.i；B.307.a.4.i；B.308.a.4.i；B.309.a.4.i；
B.310.a.4.i；B.311.a.4.i；B.312.a.4.i；B.313.a.4.i；B.314.a.4.i；B.315.a.4.i；B.316.a.4.i；
B.317.a.4.i；B.318.a.4.i；B.319.a.4.i；B.320.a.4.i；B.321.a.4.i；B.322.a.4.i；B.323.a.4.i；
B.324.a.4.i；B.325.a.4.i；B.326.a.4.i；B.327.a.4.i；B.328.a.4.i；B.329.a.4.i；B.330.a.4.i；
B.331.a.4.i；B.332.a.4.i；B.333.a.4.i；B.334.a.4.i；B.335.a.4.i；B.336.a.4.i；B.337.a.4.i；
B.338.a.4.i；B.339.a.4.i；B.340.a.4.i；B.341.a.4.i；B.342.a.4.i；B.343.a.4.i；B.344.a.4.i；
B.345.a.4.i；B.346.a.4.i；B.347.a.4.i；B.348.a.4.i；B.349.a.4.i；B.350.a.4.i；B.351.a.4.i；
B.352.a.4.i；B.353.a.4.i；B.354.a.4.i；B.355.a.4.i；B.356.a.4.i；B.357.a.4.i；B.358.a.4.i；
E.2.a.4.i；E.3.a.4.i；E.4.a.4.i；E.5.a.4.i；E.9.a.4.i；E.100.a.4.i；E.101.a.4.i；E.102.a.4.i；
E.103.a.4.i；E.104.a.4.i；E.105.a.4.i；E.106.a.4.i；E.107.a.4.i；E.108.a.4.i；E.109.a.4.i；
E.110.a.4.i；E.111.a.4.i；E.112.a.4.i；E.113.a.4.i；E.114.a.4.i；E.115.a.4.i；E.116.a.4.i；
E.117.a.4.i；E.118.a.4.i；E.119.a.4.i；E.120.a.4.i；E.121.a.4.i；E.122.a.4.i；E.123.a.4.i；
E.124.a.4.i；E.125.a.4.i；E.126.a.4.i；E.127.a.4.i；E.128.a.4.i；E.129.a.4.i；E.130.a.4.i；
E.131.a.4.i；E.132.a.4.i；E.133.a.4.i；E.134.a.4.i；E.135.a.4.i；E.136.a.4.i；E.137.a.4.i；
E.138.a.4.i；E.139.a.4.i；E.140.a.4.i；E.141.a.4.i；E.142.a.4.i；E.143.a.4.i；E.144.a.4.i；
E.145.a.4.i；E.146.a.4.i；E.147.a.4.i；E.148.a.4.i；E.149.a.4.i；E.150.a.4.i；E.151.a.4.i；
E.152.a.4.i；E.153.a.4.i；E.154.a.4.i；E.155.a.4.i；E.156.a.4.i；E.157.a.4.i；E.158.a.4.i；
E.159.a.4.i；E.160.a.4.i；E.161.a.4.i；E.162.a.4.i；E.163.a.4.i；E.164.a.4.i；E.165.a.4.i；
E.166.a.4.i；E.167.a.4.i；E.168.a.4.i；E.169.a.4.i；E.170.a.4.i；E.171.a.4.i；E.172.a.4.i；
E.173.a.4.i；E.174.a.4.i；E.175.a.4.i；E.176.a.4.i；E.177.a.4.i；E.178.a.4.i；E.179.a.4.i；
E.180.a.4.i；E.181.a.4.i；E.182.a.4.i；E.183.a.4.i；E.184.a.4.i；E.185.a.4.i；E.186.a.4.i；
E.187.a.4.i；E.188.a.4.i；E.189.a.4.i；E.190.a.4.i；E.191.a.4.i；E.192.a.4.i；E.193.a.4.i；
E.194.a.4.i；E.195.a.4.i；E.196.a.4.i；E.197.a.4.i；E.198.a.4.i；E.199.a.4.i；E.200.a.4.i；
E.201.a.4.i；E.202.a.4.i；E.203.a.4.i；E.204.a.4.i；E.205.a.4.i；E.206.a.4.i；E.207.a.4.i；
E.208.a.4.i；E.209.a.4.i；E.210.a.4.i；E.211.a.4.i；E.212.a.4.i；E.213.a.4.i；E.214.a.4.i；
E.215.a.4.i；E.216.a.4.i；E.217.a.4.i；E.218.a.4.i；E.219.a.4.i；E.220.a.4.i；E.221.a.4.i；
E.222.a.4.i；E.223.a.4.i；E.224.a.4.i；E.225.a.4.i；E.226.a.4.i；E.227.a.4.i；E.228.a.4.i；
E.229.a.4.i；E.230.a.4.i；E.231.a.4.i；E.232.a.4.i；E.233.a.4.i；E.234.a.4.i；E.235.a.4.i；
E.236.a.4.i；E.237.a.4.i；E.238.a.4.i；E.239.a.4.i；E.240.a.4.i；E.241.a.4.i；E.242.a.4.i；
E.243.a.4.i；E.244.a.4.i；E.245.a.4.i；E.246.a.4.i；E.247.a.4.i；E.248.a.4.i；E.249.a.4.i；
E.250.a.4.i；E.251.a.4.i；E.252.a.4.i；E.253.a.4.i；E.254.a.4.i；E.255.a.4.i；E.256.a.4.i；
E.257.a.4.i；E.258.a.4.i；E.259.a.4.i；E.260.a.4.i；E.261.a.4.i；E.262.a.4.i；E.263.a.4.i；
E.264.a.4.i；E.265.a.4.i；E.266.a.4.i；E.267.a.4.i；E.268.a.4.i；E.269.a.4.i；E.270.a.4.i；
E.271.a.4.i；E.272.a.4.i；E.273.a.4.i；E.274.a.4.i；E.275.a.4.i；E.276.a.4.i；E.277.a.4.i；
E.278.a.4.i；E.279.a.4.i；E.280.a.4.i；E.281.a.4.i；E.282.a.4.i；E.283.a.4.i；E.284.a.4.i；
E.285.a.4.i；E.286.a.4.i；E.287.a.4.i；E.288.a.4.i；E.289.a.4.i；E.290.a.4.i；E.291.a.4.i；
E.292.a.4.i；E.293.a.4.i；E.294.a.4.i；E.295.a.4.i；E.296.a.4.i；E.297.a.4.i；E.298.a.4.i；
E.299.a.4.i；E.300.a.4.i；E.301.a.4.i；E.302.a.4.i；E.303.a.4.i；E.304.a.4.i；E.305.a.4.i；
E.306.a.4.i；E.307.a.4.i；E.308.a.4.i；E.309.a.4.i；E.310.a.4.i；E.311.a.4.i；E.312.a.4.i；
E.313.a.4.i；E.314.a.4.i；E.315.a.4.i；E.316.a.4.i；E.317.a.4.i；E.318.a.4.i；E.319.a.4.i；
E.320.a.4.i；E.321.a.4.i；E.322.a.4.i；E.323.a.4.i；E.324.a.4.i；E.325.a.4.i；E.326.a.4.i；
E.327.a.4.i；E.328.a.4.i；E.329.a.4.i；E.330.a.4.i；E.331.a.4.i；E.332.a.4.i；E.333.a.4.i；
E.334.a.4.i；E.335.a.4.i；E.336.a.4.i；E.337.a.4.i；E.338.a.4.i；E.339.a.4.i；E.340.a.4.i；
E.341.a.4.i；E.342.a.4.i；E.343.a.4.i；E.344.a.4.i；E.345.a.4.i；E.346.a.4.i；E.347.a.4.i；
E.348.a.4.i；E.349.a.4.i；E.350.a.4.i；E.351.a.4.i；E.352.a.4.i；E.353.a.4.i；E.354.a.4.i；
E.355.a.4.i；E.356.a.4.i；E.357.a.4.i；E.358.a.4.i；B.2.a.11.i；B.3.a.11.i；B.4.a.11.i；
B.5.a.11.i；B.9.a.11.i；B.100.a.11.i；B.101.a.11.i；B.102.a.11.i；B.103.a.11.i；
B.104.a.11.i；B.105.a.11.i；B.106.a.11.i；B.107.a.11.i；B.108.a.11.i；B.109.a.11.i；
B.110.a.11.i；B.111.a.11.i；B.112.a.11.i；B.113.a.11.i；B.114.a.11.i；B.115.a.11.i；
B.116.a.11.i；B.117.a.11.i；B.118.a.11.i；B.119.a.11.i；B.120.a.11.i；B.121.a.11.i；
B.122.a.11.i；B.123.a.11.i；B.124.a.11.i；B.125.a.11.i；B.126.a.11.i；B.127.a.11.i；
B.128.a.11.i；B.129.a.11.i；B.130.a.11.i；B.131.a.11.i；B.132.a.11.i；B.133.a.11.i；
B.134.a.11.i；B.135.a.11.i；B.136.a.11.i；B.137.a.11.i；B.138.a.11.i；B.139.a.11.i；
B.140.a.11.i；B.141.a.11.i；B.142.a.11.i；B.143.a.11.i；B.144.a.11.i；B.145.a.11.i；
B.146.a.11.i；B.147.a.11.i；B.148.a.11.i；B.149.a.11.i；B.150.a.11.i；B.151.a.11.i；
B.152.a.11.i；B.153.a.11.i；B.154.a.11.i；B.155.a.11.i；B.156.a.11.i；B.157.a.11.i；
B.158.a.11.i；B.159.a.11.i；B.160.a.11.i；B.161.a.11.i；B.162.a.11.i；B.163.a.11.i；
B.164.a.11.i；B.165.a.11.i；B.166.a.11.i；B.167.a.11.i；B.168.a.11.i；B.169.a.11.i；
B.170.a.11.i；B.171.a.11.i；B.172.a.11.i；B.173.a.11.i；B.174.a.11.i；B.175.a.11.i；
B.176.a.11.i；B.177.a.11.i；B.178.a.11.i；B.179.a.11.i；B.180.a.11.i；B.181.a.11.i；
B.182.a.11.i；B.183.a.11.i；B.184.a.11.i；B.185.a.11.i；B.186.a.11.i；B.187.a.11.i；
B.188.a.11.i；B.189.a.11.i；B.190.a.11.i；B.191.a.11.i；B.192.a.11.i；B.193.a.11.i；
B.194.a.11.i；B.195.a.11.i；B.196.a.11.i；B.197.a.11.i；B.198.a.11.i；B.199.a.11.i；
B.200.a.11.i；B.201.a.11.i；B.202.a.11.i；B.203.a.11.i；B.204.a.11.i；B.205.a.11.i；
B.206.a.11.i；B.207.a.11.i；B.208.a.11.i；B.209.a.11.i；B.210.a.11.i；B.211.a.11.i；
B.212.a.11.i；B.213.a.11.i；B.214.a.11.i；B.215.a.11.i；B.216.a.11.i；B.217.a.11.i；
B.218.a.11.i；B.219.a.11.i；B.220.a.11.i；B.221.a.11.i；B.222.a.11.i；B.223.a.11.i；
B.224.a.11.i；B.225.a.11.i；B.226.a.11.i；B.227.a.11.i；B.228.a.11.i；B.229.a.11.i；
B.230.a.11.i；B.231.a.11.i；B.232.a.11.i；B.233.a.11.i；B.234.a.11.i；B.235.a.11.i；
B.236.a.11.i；B.237.a.11.i；B.238.a.11.i；B.239.a.11.i；B.240.a.11.i；B.241.a.11.i；
B.242.a.11.i；B.243.a.11.i；B.244.a.11.i；B.245.a.11.i；B.246.a.11.i；B.247.a.11.i；
B.248.a.11.i；B.249.a.11.i；B.250.a.11.i；B.251.a.11.i；B.252.a.11.i；B.253.a.11.i；
B.254.a.11.i；B.255.a.11.i；B.256.a.11.i；B.257.a.11.i；B.258.a.11.i；B.259.a.11.i；
B.260.a.11.i；B.261.a.11.i；B.262.a.11.i；B.263.a.11.i；B.264.a.11.i；B.265.a.11.i；
B.266.a.11.i；B.267.a.11.i；B.268.a.11.i；B.269.a.11.i；B.270.a.11.i；B.271.a.11.i；
B.272.a.11.i；B.273.a.11.i；B.274.a.11.i；B.275.a.11.i；B.276.a.11.i；B.277.a.11.i；
B.278.a.11.i；B.279.a.11.i；B.280.a.11.i；B.281.a.11.i；B.282.a.11.i；B.283.a.11.i；
B.284.a.11.i；B.285.a.11.i；B.286.a.11.i；B.287.a.11.i；B.288.a.11.i；B.289.a.11.i；
B.290.a.11.i；B.291.a.11.i；B.292.a.11.i；B.293.a.11.i；B.294.a.11.i；B.295.a.11.i；
B.296.a.11.i；B.297.a.11.i；B.298.a.11.i；B.299.a.11.i；B.300.a.11.i；B.301.a.11.i；
B.302.a.11.i；B.303.a.11.i；B.304.a.11.i；B.305.a.11.i；B.306.a.11.i；B.307.a.11.i；
B.308.a.11.i；B.309.a.11.i；B.310.a.11.i；B.311.a.11.i；B.312.a.11.i；B.313.a.11.i；
B.314.a.11.i；B.315.a.11.i；B.316.a.11.i；B.317.a.11.i；B.318.a.11.i；B.319.a.11.i；
B.320.a.11.i；B.321.a.11.i；B.322.a.11.i；B.323.a.11.i；B.324.a.11.i；B.325.a.11.i；
B.326.a.11.i；B.327.a.11.i；B.328.a.11.i；B.329.a.11.i；B.330.a.11.i；B.331.a.11.i；
B.332.a.11.i；B.333.a.11.i；B.334.a.11.i；B.335.a.11.i；B.336.a.11.i；B.337.a.11.i；
B.338.a.11.i；B.339.a.11.i；B.340.a.11.i；B.341.a.11.i；B.342.a.11.i；B.343.a.11.i；
B.344.a.11.i；B.345.a.11.i；B.346.a.11.i；B.347.a.11.i；B.348.a.11.i；B.349.a.11.i；
B.350.a.11.i；B.351.a.11.i；B.352.a.11.i；B.353.a.11.i；B.354.a.11.i；B.355.a.11.i；
B.356.a.11.i；B.357.a.11.i；B.358.a.11.i；E.2.a.11.i；E.3.a.11.i；E.4.a.11.i；E.5.a.11.i；
E.9.a.11.i；E.100.a.11.i；E.101.a.11.i；E.102.a.11.i；E.103.a.11.i；E.104.a.11.i；
E.105.a.11.i；E.106.a.11.i；E.107.a.11.i；E.108.a.11.i；E.109.a.11.i；E.110.a.11.i；
E.111.a.11.i；E.112.a.11.i；E.113.a.11.i；E.114.a.11.i；E.115.a.11.i；E.116.a.11.i；
E.117.a.11.i；E.118.a.11.i；E.119.a.11.i；E.120.a.11.i；E.121.a.11.i；E.122.a.11.i；
E.123.a.11.i；E.124.a.11.i；E.125.a.11.i；E.126.a.11.i；E.127.a.11.i；E.128.a.11.i；
E.129.a.11.i；E.130.a.11.i；E.131.a.11.i；E.132.a.11.i；E.133.a.11.i；E.134.a.11.i；
E.135.a.11.i；E.136.a.11.i；E.137.a.11.i；E.138.a.11.i；E.139.a.11.i；E.140.a.11.i；
E.141.a.11.i；E.142.a.11.i；E.143.a.11.i；E.144.a.11.i；E.145.a.11.i；E.146.a.11.i；
E.147.a.11.i；E.148.a.11.i；E.149.a.11.i；E.150.a.11.i；E.151.a.11.i；E.152.a.11.i；
E.153.a.11.i；E.154.a.11.i；E.155.a.11.i；E.156.a.11.i；E.157.a.11.i；E.158.a.11.i；
E.159.a.11.i；E.160.a.11.i；E.161.a.11.i；E.162.a.11.i；E.163.a.11.i；E.164.a.11.i；
E.165.a.11.i；E.166.a.11.i；E.167.a.11.i；E.168.a.11.i；E.169.a.11.i；E.170.a.11.i；
E.171.a.11.i；E.172.a.11.i；E.173.a.11.i；E.174.a.11.i；E.175.a.11.i；E.176.a.11.i；
E.177.a.11.i；E.178.a.11.i；E.179.a.11.i；E.180.a.11.i；E.181.a.11.i；E.182.a.11.i；
E.183.a.11.i；E.184.a.11.i；E.185.a.11.i；E.186.a.11.i；E.187.a.11.i；E.188.a.11.i；
E.189.a.11.i；E.190.a.11.i；E.191.a.11.i；E.192.a.11.i；E.193.a.11.i；E.194.a.11.i；
E.195.a.11.i；E.196.a.11.i；E.197.a.11.i；E.198.a.11.i；E.199.a.11.i；E.200.a.11.i；
E.201.a.11.i；E.202.a.11.i；E.203.a.11.i；E.204.a.11.i；E.205.a.11.i；E.206.a.11.i；
E.207.a.11.i；E.208.a.11.i；E.209.a.11.i；E.210.a.11.i；E.211.a.11.i；E.212.a.11.i；
E.213.a.11.i；E.214.a.11.i；E.215.a.11.i；E.216.a.11.i；E.217.a.11.i；E.218.a.11.i；
E.219.a.11.i；E.220.a.11.i；E.221.a.11.i；E.222.a.11.i；E.223.a.11.i；E.224.a.11.i；
E.225.a.11.i；E.226.a.11.i；E.227.a.11.i；E.228.a.11.i；E.229.a.11.i；E.230.a.11.i；
E.231.a.11.i；E.232.a.11.i；E.233.a.11.i；E.234.a.11.i；E.235.a.11.i；E.236.a.11.i；
E.237.a.11.i；E.238.a.11.i；E.239.a.11.i；E.240.a.11.i；E.241.a.11.i；E.242.a.11.i；
E.243.a.11.i；E.244.a.11.i；E.245.a.11.i；E.246.a.11.i；E.247.a.11.i；E.248.a.11.i；
E.249.a.11.i；E.250.a.11.i；E.251.a.11.i；E.252.a.11.i；E.253.a.11.i；E.254.a.11.i；
E.255.a.11.i；E.256.a.11.i；E.257.a.11.i；E.258.a.11.i；E.259.a.11.i；E.260.a.11.i；
E.261.a.11.i；E.262.a.11.i；E.263.a.11.i；E.264.a.11.i；E.265.a.11.i；E.266.a.11.i；
E.267.a.11.i；E.268.a.11.i；E.269.a.11.i；E.270.a.11.i；E.271.a.11.i；E.272.a.11.i；
E.273.a.11.i；E.274.a.11.i；E.275.a.11.i；E.276.a.11.i；E.277.a.11.i；E.278.a.11.i；
E.279.a.11.i；E.280.a.11.i；E.281.a.11.i；E.282.a.11.i；E.283.a.11.i；E.284.a.11.i；
E.285.a.11.i；E.286.a.11.i；E.287.a.11.i；E.288.a.11.i；E.289.a.11.i；E.290.a.11.i；
E.291.a.11.i；E.292.a.11.i；E.293.a.11.i；E.294.a.11.i；E.295.a.11.i；E.296.a.11.i；
E.297.a.11.i；E.298.a.11.i；E.299.a.11.i；E.300.a.11.i；E.301.a.11.i；E.302.a.11.i；
E.303.a.11.i；E.304.a.11.i；E.305.a.11.i；E.306.a.11.i；E.307.a.11.i；E.308.a.11.i；
E.309.a.11.i；E.310.a.11.i；E.311.a.11.i；E.312.a.11.i；E.313.a.11.i；E.314.a.11.i；
E.315.a.11.i；E.316.a.11.i；E.317.a.11.i；E.318.a.11.i；E.319.a.11.i；E.320.a.11.i；
E.321.a.11.i；E.322.a.11.i；E.323.a.11.i；E.324.a.11.i；E.325.a.11.i；E.326.a.11.i；
E.327.a.11.i；E.328.a.11.i；E.329.a.11.i；E.330.a.11.i；E.331.a.11.i；E.332.a.11.i；
E.333.a.11.i；E.334.a.11.i；E.335.a.11.i；E.336.a.11.i；E.337.a.11.i；E.338.a.11.i；
E.339.a.11.i；E.340.a.11.i；E.341.a.11.i；E.342.a.11.i；E.343.a.11.i；E.344.a.11.i；
E.345.a.11.i；E.346.a.11.i；E.347.a.11.i；E.348.a.11.i；E.349.a.11.i；E.350.a.11.i；
E.351.a.11.i；E.352.a.11.i；E.353.a.11.i；E.354.a.11.i；E.355.a.11.i；E.356.a.11.i；
E.357.a.11.i；E.358.a.11.i；A.661.a.4.i；A.662.a.4.i；A.663.a.4.i；A.664.a.4.i；
A.665.a.4.i；B.661.a.4.i；B.662.a.4.i；B.663.a.4.i；B.664.a.4.i；B.665.a.4.i；C.661.a.4.i；
C.662.a.4.i；C.663.a.4.i；C.664.a.4.i；C.665.a.4.i；A.661.a.11.i；A.662.a.11.i；
A.663.a.11.i；A.664.a.11.i；A.665.a.11.i；B.661.a.11.i；B.662.a.11.i；B.663.a.11.i；
B.664.a.11.i；B.665.a.11.i；C.661.a.11.i；C.662.a.11.i；C.663.a.11.i；C.664.a.11.i；
C.665.a.11.i；A.661.a.44.i；A.662.a.44.i；A.663.a.44.i；A.664.a.44.i；A.665.a.44.i；
B.661.a.44.i；B.662.a.44.i；B.663.a.44.i；B.664.a.44.i；B.665.a.44.i；C.661.a.44.i；
C.662.a.44.i；C.663.a.44.i；C.664.a.44.i；C.665.a.44.i；A.666.a.4.i；A.666.a.11.i；
A.666.a.44.i；A.666.b.4.i；A.666.b.11.i；A.666.b.44.i；A.666.x.4.i；A.666.x.11.i；
A.666.x.44.i；A.666.y.4.i；A.666.y.11.i；A.666.y.44.i；A.666.z.4.i；A.666.z.11.i；
A.666.z.44.i；A.666.A.4.i；A.666.A.11.i；A.666.A.44.i；A.666.B.4.i；A.666.B.11.i；
A.666.B.44.i；A.666.C.4.i；A.666.C.11.i；A.666.C.44.i；A.666.D.4.i；A.666.D.11.i；
A.666.D.44.i；A.666.E.4.i；A.666.E.11.i；A.666.E.44.i；A.666.F.4.i；A.666.F.11.i；
A.666.F.44.i；B.666.a.4.i；B.666.a.11.i；B.666.a.44.i；B.666.b.4.i；B.666.b.11.i；
B.666.b.44.i；B.666.x.4.i；B.666.x.11.i；B.666.x.44.i；B.666.y.4.i；B.666.y.11.i；
B.666.y.44.i；B.666.z.4.i；B.666.z.11.i；B.666.z.44.i；B.666.B.4.i；B.666.B.11.i；
B.666.B.44.i；B.666.B.4.i；B.666.B.11.i；B.666.B.44.i；B.666.C.4.i；B.666.C.11.i；
B.666.C.44.i；B.666.D.4.i；B.666.D.11.i；B.666.D.44.i；B.666.E.4.i；B.666.E.11.i；
B.666.E.44.i；B.666.F.4.i；B.666.F.11.i；B.666.F.44.i；E.666.a.4.i；E.666.a.11.i；
E.666.a.44.i；E.666.b.4.i；E.666.b.11.i；E.666.b.44.i；E.666.x.4.i；E.666.x.11.i；
E.666.x.44.i；E.666.y.4.i；E.666.y.11.i；E.666.y.44.i；E.666.z.4.i；E.666.z.11.i；
E.666.z.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.B.4.i；E.666.B.11.i；
E.666.B.44.i；E.666.C.4.i；E.666.C.11.i；E.666.C.44.i；E.666.D.4.i；E.666.D.11.i；
E.666.D.44.i；E.666.E.4.i；E.666.E.11.i；E.666.E.44.i；E.666.F.4.i；E.666.F.11.i；
E.666.F.44.i；
A.2.a.46.i；A.3.a.46.i；A.4.a.46.i；A.5.a.46.i；A.7.a.46.i；A.9.a.46.i；A.100.a.46.i；
A.101.a.46.i；A.102.a.46.i；A.103.a.46.i；A.104.a.46.i；A.105.a.46.i；A.106.a.46.i；
A.107.a.46.i；A.108.a.46.i；A.109.a.46.i；A.110.a.46.i；A.111.a.46.i；A.112.a.46.i；
A.113.a.46.i；A.114.a.46.i；A.115.a.46.i；A.116.a.46.i；A.117.a.46.i；A.118.a.46.i；
A.119.a.46.i；A.120.a.46.i；A.121.a.46.i；A.122.a.46.i；A.123.a.46.i；A.124.a.46.i；
A.125.a.46.i；A.126.a.46.i；A.127.a.46.i；A.128.a.46.i；A.129.a.46.i；A.130.a.46.i；
A.131.a.46.i；A.132.a.46.i；A.133.a.46.i；A.134.a.46.i；A.135.a.46.i；A.136.a.46.i；
A.137.a.46.i；A.138.a.46.i；A.139.a.46.i；A.140.a.46.i；A.141.a.46.i；A.2.a.47.i；
A.3.a.47.i；A.4.a.47.i；A.5.a.47.i；A.7.a.47.i；A.9.a.47.i；A.100.a.47.i；A.101.a.47.i；
A.102.a.47.i；A.103.a.47.i；A.104.a.47.i；A.105.a.47.i；A.106.a.47.i；A.107.a.47.i；
A.108.a.47.i；A.109.a.47.i；A.110.a.47.i；A.111.a.47.i；A.112.a.47.i；A.113.a.47.i；
A.114.a.47.i；A.115.a.47.i；A.116.a.47.i；A.117.a.47.i；A.118.a.47.i；A.119.a.47.i；
A.120.a.47.i；A.121.a.47.i；A.122.a.47.i；A.123.a.47.i；A.124.a.47.i；A.125.a.47.i；
A.126.a.47.i；A.127.a.47.i；A.128.a.47.i；A.129.a.47.i；A.130.a.47.i；A.131.a.47.i；
A.132.a.47.i；A.133.a.47.i；A.134.a.47.i；A.135.a.47.i；A.136.a.47.i；A.137.a.47.i；
A.138.a.47.i；A.139.a.47.i；A.140.a.47.i；A.141.a.47.i；A.2.a.48.i；A.3.a.48.i；
A.4.a.48.i；A.5.a.48.i；A.7.a.48.i；A.9.a.48.i；A.100.a.48.i；A.101.a.48.i；A.102.a.48.i；
A.103.a.48.i；A.104.a.48.i；A.105.a.48.i；A.106.a.48.i；A.107.a.48.i；A.108.a.48.i；
A.109.a.48.i；A.110.a.48.i；A.111.a.48.i；A.112.a.48.i；A.113.a.48.i；A.114.a.48.i；
A.115.a.48.i；A.116.a.48.i；A.117.a.48.i；A.118.a.48.i；A.119.a.48.i；A.120.a.48.i；
A.121.a.48.i；A.122.a.48.i；A.123.a.48.i；A.124.a.48.i；A.125.a.48.i；A.126.a.48.i；
A.127.a.48.i；A.128.a.48.i；A.129.a.48.i；A.130.a.48.i；A.131.a.48.i；A.132.a.48.i；
A.133.a.48.i；A.134.a.48.i；A.135.a.48.i；A.136.a.48.i；A.137.a.48.i；A.138.a.48.i；
A.139.a.48.i；A.140.a.48.i；A.141.a.48.i；A.2.a.49.i；A.3.a.49.i；A.4.a.49.i；A.5.a.49.i；
A.7.a.49.i；A.9.a.49.i；A.100.a.49.i；A.101.a.49.i；A.102.a.49.i；A.103.a.49.i；
A.104.a.49.i；A.105.a.49.i；A.106.a.49.i；A.107.a.49.i；A.108.a.49.i；A.109.a.49.i；
A.110.a.49.i；A.111.a.49.i；A.112.a.49.i；A.113.a.49.i；A.114.a.49.i；A.115.a.49.i；
A.116.a.49.i；A.117.a.49.i；A.118.a.49.i；A.119.a.49.i；A.120.a.49.i；A.121.a.49.i；
A.122.a.49.i；A.123.a.49.i；A.124.a.49.i；A.125.a.49.i；A.126.a.49.i；A.127.a.49.i；
A.128.a.49.i；A.129.a.49.i；A.130.a.49.i；A.131.a.49.i；A.132.a.49.i；A.133.a.49.i；
A.134.a.49.i；A.135.a.49.i；A.136.a.49.i；A.137.a.49.i；A.138.a.49.i；A.139.a.49.i；
A.140.a.49.i；A.141.a.49.i；A.2.a.50.i；A.3.a.50.i；A.4.a.50.i；A.5.a.50.i；A.7.a.50.i；
A.9.a.50.i；A.100.a.50.i；A.101.a.50.i；A.102.a.50.i；A.103.a.50.i；A.104.a.50.i；
A.105.a.50.i；A.106.a.50.i；A.107.a.50.i；A.108.a.50.i；A.109.a.50.i；A.110.a.50.i；
A.111.a.50.i；A.112.a.50.i；A.113.a.50.i；A.114.a.50.i；A.115.a.50.i；A.116.a.50.i；
A.117.a.50.i；A.118.a.50.i；A.119.a.50.i；A.120.a.50.i；A.121.a.50.i；A.122.a.50.i；
A.123.a.50.i；A.124.a.50.i；A.125.a.50.i；A.126.a.50.i；A.127.a.50.i；A.128.a.50.i；
A.129.a.50.i；A.130.a.50.i；A.131.a.50.i；A.132.a.50.i；A.133.a.50.i；A.134.a.50.i；
A.135.a.50.i；A.136.a.50.i；A.137.a.50.i；A.138.a.50.i；A.139.a.50.i；A.140.a.50.i；
A.141.a.50.i；A.2.a.51.i；A.3.a.51.i；A.4.a.51.i；A.5.a.51.i；A.7.a.51.i；A.9.a.51.i；
A.100.a.51.i；A.101.a.51.i；A.102.a.51.i；A.103.a.51.i；A.104.a.51.i；A.105.a.51.i；
A.106.a.51.i；A.107.a.51.i；A.108.a.51.i；A.109.a.51.i；A.110.a.51.i；A.111.a.51.i；
A.112.a.51.i；A.113.a.51.i；A.114.a.51.i；A.115.a.51.i；A.116.a.51.i；A.117.a.51.i；
A.118.a.51.i；A.119.a.51.i；A.120.a.51.i；A.121.a.51.i；A.122.a.51.i；A.123.a.51.i；
A.124.a.51.i；A.125.a.51.i；A.126.a.51.i；A.127.a.51.i；A.128.a.51.i；A.129.a.51.i；
A.130.a.51.i；A.131.a.51.i；A.132.a.51.i；A.133.a.51.i；A.134.a.51.i；A.135.a.51.i；
A.136.a.51.i；A.137.a.51.i；A.138.a.51.i；A.139.a.51.i；A.140.a.51.i；A.141.a.51.i；
A.2.b.46.i；A.3.b.46.i；A.4.b.46.i；A.5.b.46.i；A.7.b.46.i；A.9.b.46.i；A.100.b.46.i；
A.101.b.46.i；A.102.b.46.i；A.103.b.46.i；A.104.b.46.i；A.105.b.46.i；A.106.b.46.i；
A.107.b.46.i；A.108.b.46.i；A.109.b.46.i；A.110.b.46.i；A.111.b.46.i；A.112.b.46.i；
A.113.b.46.i；A.114.b.46.i；A.115.b.46.i；A.116.b.46.i；A.117.b.46.i；A.118.b.46.i；
A.119.b.46.i；A.120.b.46.i；A.121.b.46.i；A.122.b.46.i；A.123.b.46.i；A.124.b.46.i；
A.125.b.46.i；A.126.b.46.i；A.127.b.46.i；A.128.b.46.i；A.129.b.46.i；A.130.b.46.i；
A.131.b.46.i；A.132.b.46.i；A.133.b.46.i；A.134.b.46.i；A.135.b.46.i；A.136.b.46.i；
A.137.b.46.i；A.138.b.46.i；A.139.b.46.i；A.140.b.46.i；A.141.b.46.i；A.2.b.47.i；
A.3.b.47.i；A.4.b.47.i；A.5.b.47.i；A.7.b.47.i；A.9.b.47.i；A.100.b.47.i；A.101.b.47.i；
A.102.b.47.i；A.103.b.47.i；A.104.b.47.i；A.105.b.47.i；A.106.b.47.i；A.107.b.47.i；
A.108.b.47.i；A.109.b.47.i；A.110.b.47.i；A.111.b.47.i；A.112.b.47.i；A.113.b.47.i；
A.114.b.47.i；A.115.b.47.i；A.116.b.47.i；A.117.b.47.i；A.118.b.47.i；A.119.b.47.i；
A.120.b.47.i；A.121.b.47.i；A.122.b.47.i；A.123.b.47.i；A.124.b.47.i；A.125.b.47.i；
A.126.b.47.i；A.127.b.47.i；A.128.b.47.i；A.129.b.47.i；A.130.b.47.i；A.131.b.47.i；
A.132.b.47.i；A.133.b.47.i；A.134.b.47.i；A.135.b.47.i；A.136.b.47.i；A.137.b.47.i；
A.138.b.47.i；A.139.b.47.i；A.140.b.47.i；A.141.b.47.i；A.2.b.48.i；A.3.b.48.i；
A.4.b.48.i；A.5.b.48.i；A.7.b.48.i；A.9.b.48.i；A.100.b.48.i；A.101.b.48.i；A.102.b.48.i；
A.103.b.48.i；A.104.b.48.i；A.105.b.48.i；A.106.b.48.i；A.107.b.48.i；A.108.b.48.i；
A.109.b.48.i；A.110.b.48.i；A.111.b.48.i；A.112.b.48.i；A.113.b.48.i；A.114.b.48.i；
A.115.b.48.i；A.116.b.48.i；A.117.b.48.i；A.118.b.48.i；A.119.b.48.i；A.120.b.48.i；
A.121.b.48.i；A.122.b.48.i；A.123.b.48.i；A.124.b.48.i；A.125.b.48.i；A.126.b.48.i；
A.127.b.48.i；A.128.b.48.i；A.129.b.48.i；A.130.b.48.i；A.131.b.48.i；A.132.b.48.i；
A.133.b.48.i；A.134.b.48.i；A.135.b.48.i；A.136.b.48.i；A.137.b.48.i；A.138.b.48.i；
A.139.b.48.i；A.140.b.48.i；A.141.b.48.i；A.2.b.49.i；A.3.b.49.i；A.4.b.49.i；A.5.b.49.i；
A.7.b.49.i；A.9.b.49.i；A.100.b.49.i；A.101.b.49.i；A.102.b.49.i；A.103.b.49.i；
A.104.b.49.i；A.105.b.49.i；A.106.b.49.i；A.107.b.49.i；A.108.b.49.i；A.109.b.49.i；
A.110.b.49.i；A.111.b.49.i；A.112.b.49.i；A.113.b.49.i；A.114.b.49.i；A.115.b.49.i；
A.116.b.49.i；A.117.b.49.i；A.118.b.49.i；A.119.b.49.i；A.120.b.49.i；A.121.b.49.i；
A.122.b.49.i；A.123.b.49.i；A.124.b.49.i；A.125.b.49.i；A.126.b.49.i；A.127.b.49.i；
A.128.b.49.i；A.129.b.49.i；A.130.b.49.i；A.131.b.49.i；A.132.b.49.i；A.133.b.49.i；
A.134.b.49.i；A.135.b.49.i；A.136.b.49.i；A.137.b.49.i；A.138.b.49.i；A.139.b.49.i；
A.140.b.49.i；A.141.b.49.i；A.2.b.50.i；A.3.b.50.i；A.4.b.50.i；A.5.b.50.i；A.7.b.50.i；
A.9.b.50.i；A.100.b.50.i；A.101.b.50.i；A.102.b.50.i；A.103.b.50.i；A.104.b.50.i；
A.105.b.50.i；A.106.b.50.i；A.107.b.50.i；A.108.b.50.i；A.109.b.50.i；A.110.b.50.i；
A.111.b.50.i；A.112.b.50.i；A.113.b.50.i；A.114.b.50.i；A.115.b.50.i；A.116.b.50.i；
A.117.b.50.i；A.118.b.50.i；A.119.b.50.i；A.120.b.50.i；A.121.b.50.i；A.122.b.50.i；
A.123.b.50.i；A.124.b.50.i；A.125.b.50.i；A.126.b.50.i；A.127.b.50.i；A.128.b.50.i；
A.129.b.50.i；A.130.b.50.i；A.131.b.50.i；A.132.b.50.i；A.133.b.50.i；A.134.b.50.i；
A.135.b.50.i；A.136.b.50.i；A.137.b.50.i；A.138.b.50.i；A.139.b.50.i；A.140.b.50.i；
A.141.b.50.i；A.2.b.51.i；A.3.b.51.i；A.4.b.51.i；A.5.b.51.i；A.7.b.51.i；A.9.b.51.i；
A.100.b.51.i；A.101.b.51.i；A.102.b.51.i；A.103.b.51.i；A.104.b.51.i；A.105.b.51.i；
A.106.b.51.i；A.107.b.51.i；A.108.b.51.i；A.109.b.51.i；A.110.b.51.i；A.111.b.51.i；
A.112.b.51.i；A.113.b.51.i；A.114.b.51.i；A.115.b.51.i；A.116.b.51.i；A.117.b.51.i；
A.118.b.51.i；A.119.b.51.i；A.120.b.51.i；A.121.b.51.i；A.122.b.51.i；A.123.b.51.i；
A.124.b.51.i；A.125.b.51.i；A.126.b.51.i；A.127.b.51.i；A.128.b.51.i；A.129.b.51.i；
A.130.b.51.i；A.131.b.51.i；A.132.b.51.i；A.133.b.51.i；A.134.b.51.i；A.135.b.51.i；
A.136.b.51.i；A.137.b.51.i；A.138.b.51.i；A.139.b.51.i；A.140.b.51.i；A.141.b.51.i；
A.2.x.46.i；A.3.x.46.i；A.4.x.46.i；A.5.x.46.i；A.7.x.46.i；A.9.x.46.i；A.100.x.46.i；
A.101.x.46.i；A.102.x.46.i；A.103.x.46.i；A.104.x.46.i；A.105.x.46.i；A.106.x.46.i；
A.107.x.46.i；A.108.x.46.i；A.109.x.46.i；A.110.x.46.i；A.111.x.46.i；A.112.x.46.i；
A.113.x.46.i；A.114.x.46.i；A.115.x.46.i；A.116.x.46.i；A.117.x.46.i；A.118.x.46.i；
A.119.x.46.i；A.120.x.46.i；A.121.x.46.i；A.122.x.46.i；A.123.x.46.i；A.124.x.46.i；
A.125.x.46.i；A.126.x.46.i；A.127.x.46.i；A.128.x.46.i；A.129.x.46.i；A.130.x.46.i；
A.131.x.46.i；A.132.x.46.i；A.133.x.46.i；A.134.x.46.i；A.135.x.46.i；A.136.x.46.i；
A.137.x.46.i；A.138.x.46.i；A.139.x.46.i；A.140.x.46.i；A.141.x.46.i；A.2.x.47.i；
A.3.x.47.i；A.4.x.47.i；A.5.x.47.i；A.7.x.47.i；A.9.x.47.i；A.100.x.47.i；A.101.x.47.i；
A.102.x.47.i；A.103.x.47.i；A.104.x.47.i；A.105.x.47.i；A.106.x.47.i；A.107.x.47.i；
A.108.x.47.i；A.109.x.47.i；A.110.x.47.i；A.111.x.47.i；A.112.x.47.i；A.113.x.47.i；
A.114.x.47.i；A.115.x.47.i；A.116.x.47.i；A.117.x.47.i；A.118.x.47.i；A.119.x.47.i；
A.120.x.47.i；A.121.x.47.i；A.122.x.47.i；A.123.x.47.i；A.124.x.47.i；A.125.x.47.i；
A.126.x.47.i；A.127.x.47.i；A.128.x.47.i；A.129.x.47.i；A.130.x.47.i；A.131.x.47.i；
A.132.x.47.i；A.133.x.47.i；A.134.x.47.i；A.135.x.47.i；A.136.x.47.i；A.137.x.47.i；
A.138.x.47.i；A.139.x.47.i；A.140.x.47.i；A.141.x.47.i；A.2.x.48.i；A.3.x.48.i；
A.4.x.48.i；A.5.x.48.i；A.7.x.48.i；A.9.x.48.i；A.100.x.48.i；A.101.x.48.i；A.102.x.48.i；
A.103.x.48.i；A.104.x.48.i；A.105.x.48.i；A.106.x.48.i；A.107.x.48.i；A.108.x.48.i；
A.109.x.48.i；A.110.x.48.i；A.111.x.48.i；A.112.x.48.i；A.113.x.48.i；A.114.x.48.i；
A.115.x.48.i；A.116.x.48.i；A.117.x.48.i；A.118.x.48.i；A.119.x.48.i；A.120.x.48.i；
A.121.x.48.i；A.122.x.48.i；A.123.x.48.i；A.124.x.48.i；A.125.x.48.i；A.126.x.48.i；
A.127.x.48.i；A.128.x.48.i；A.129.x.48.i；A.130.x.48.i；A.131.x.48.i；A.132.x.48.i；
A.133.x.48.i；A.134.x.48.i；A.135.x.48.i；A.136.x.48.i；A.137.x.48.i；A.138.x.48.i；
A.139.x.48.i；A.140.x.48.i；A.141.x.48.i；A.2.x.49.i；A.3.x.49.i；A.4.x.49.i；A.5.x.49.i；
A.7.x.49.i；A.9.x.49.i；A.100.x.49.i；A.101.x.49.i；A.102.x.49.i；A.103.x.49.i；
A.104.x.49.i；A.105.x.49.i；A.106.x.49.i；A.107.x.49.i；A.108.x.49.i；A.109.x.49.i；
A.110.x.49.i；A.111.x.49.i；A.112.x.49.i；A.113.x.49.i；A.114.x.49.i；A.115.x.49.i；
A.116.x.49.i；A.117.x.49.i；A.118.x.49.i；A.119.x.49.i；A.120.x.49.i；A.121.x.49.i；
A.122.x.49.i；A.123.x.49.i；A.124.x.49.i；A.125.x.49.i；A.126.x.49.i；A.127.x.49.i；
A.128.x.49.i；A.129.x.49.i；A.130.x.49.i；A.131.x.49.i；A.132.x.49.i；A.133.x.49.i；
A.134.x.49.i；A.135.x.49.i；A.136.x.49.i；A.137.x.49.i；A.138.x.49.i；A.139.x.49.i；
A.140.x.49.i；A.141.x.49.i；A.2.x.50.i；A.3.x.50.i；A.4.x.50.i；A.5.x.50.i；A.7.x.50.i；
A.9.x.50.i；A.100.x.50.i；A.101.x.50.i；A.102.x.50.i；A.103.x.50.i；A.104.x.50.i；
A.105.x.50.i；A.106.x.50.i；A.107.x.50.i；A.108.x.50.i；A.109.x.50.i；A.110.x.50.i；
A.111.x.50.i；A.112.x.50.i；A.113.x.50.i；A.114.x.50.i；A.115.x.50.i；A.116.x.50.i；
A.117.x.50.i；A.118.x.50.i；A.119.x.50.i；A.120.x.50.i；A.121.x.50.i；A.122.x.50.i；
A.123.x.50.i；A.124.x.50.i；A.125.x.50.i；A.126.x.50.i；A.127.x.50.i；A.128.x.50.i；
A.129.x.50.i；A.130.x.50.i；A.131.x.50.i；A.132.x.50.i；A.133.x.50.i；A.134.x.50.i；
A.135.x.50.i；A.136.x.50.i；A.137.x.50.i；A.138.x.50.i；A.139.x.50.i；A.140.x.50.i；
A.141.x.50.i；A.2.x.51.i；A.3.x.51.i；A.4.x.51.i；A.5.x.51.i；A.7.x.51.i；A.9.x.51.i；
A.100.x.51.i；A.101.x.51.i；A.102.x.51.i；A.103.x.51.i；A.104.x.51.i；A.105.x.51.i；
A.106.x.51.i；A.107.x.51.i；A.108.x.51.i；A.109.x.51.i；A.110.x.51.i；A.111.x.51.i；
A.112.x.51.i；A.113.x.51.i；A.114.x.51.i；A.115.x.51.i；A.116.x.51.i；A.117.x.51.i；
A.118.x.51.i；A.119.x.51.i；A.120.x.51.i；A.121.x.51.i；A.122.x.51.i；A.123.x.51.i；
A.124.x.51.i；A.125.x.51.i；A.126.x.51.i；A.127.x.51.i；A.128.x.51.i；A.129.x.51.i；
A.130.x.51.i；A.131.x.51.i；A.132.x.51.i；A.133.x.51.i；A.134.x.51.i；A.135.x.51.i；
A.136.x.51.i；A.137.x.51.i；A.138.x.51.i；A.139.x.51.i；A.140.x.51.i；A.141.x.51.i；
A.2.y.46.i；A.3.y.46.i；A.4.y.46.i；A.5.y.46.i；A.7.y.46.i；A.9.y.46.i；A.100.y.46.i；
A.101.y.46.i；A.102.y.46.i；A.103.y.46.i；A.104.y.46.i；A.105.y.46.i；A.106.y.46.i；
A.107.y.46.i；A.108.y.46.i；A.109.y.46.i；A.110.y.46.i；A.111.y.46.i；A.112.y.46.i；
A.113.y.46.i；A.114.y.46.i；A.115.y.46.i；A.116.y.46.i；A.117.y.46.i；A.118.y.46.i；
A.119.y.46.i；A.120.y.46.i；A.121.y.46.i；A.122.y.46.i；A.123.y.46.i；A.124.y.46.i；
A.125.y.46.i；A.126.y.46.i；A.127.y.46.i；A.128.y.46.i；A.129.y.46.i；A.130.y.46.i；
A.131.y.46.i；A.132.y.46.i；A.133.y.46.i；A.134.y.46.i；A.135.y.46.i；A.136.y.46.i；
A.137.y.46.i；A.138.y.46.i；A.139.y.46.i；A.140.y.46.i；A.141.y.46.i；A.2.y.47.i；
A.3.y.47.i；A.4.y.47.i；A.5.y.47.i；A.7.y.47.i；A.9.y.47.i；A.100.y.47.i；A.101.y.47.i；
A.102.y.47.i；A.103.y.47.i；A.104.y.47.i；A.105.y.47.i；A.106.y.47.i；A.107.y.47.i；
A.108.y.47.i；A.109.y.47.i；A.110.y.47.i；A.111.y.47.i；A.112.y.47.i；A.113.y.47.i；
A.114.y.47.i；A.115.y.47.i；A.116.y.47.i；A.117.y.47.i；A.118.y.47.i；A.119.y.47.i；
A.120.y.47.i；A.121.y.47.i；A.122.y.47.i；A.123.y.47.i；A.124.y.47.i；A.125.y.47.i；
A.126.y.47.i；A.127.y.47.i；A.128.y.47.i；A.129.y.47.i；A.130.y.47.i；A.131.y.47.i；
A.132.y.47.i；A.133.y.47.i；A.134.y.47.i；A.135.y.47.i；A.136.y.47.i；A.137.y.47.i；
A.138.y.47.i；A.139.y.47.i；A.140.y.47.i；A.141.y.47.i；A.2.y.48.i；A.3.y.48.i；
A.4.y.48.i；A.5.y.48.i；A.7.y.48.i；A.9.y.48.i；A.100.y.48.i；A.101.y.48.i；A.102.y.48.i；
A.103.y.48.i；A.104.y.48.i；A.105.y.48.i；A.106.y.48.i；A.107.y.48.i；A.108.y.48.i；
A.109.y.48.i；A.110.y.48.i；A.111.y.48.i；A.112.y.48.i；A.113.y.48.i；A.114.y.48.i；
A.115.y.48.i；A.116.y.48.i；A.117.y.48.i；A.118.y.48.i；A.119.y.48.i；A.120.y.48.i；
A.121.y.48.i；A.122.y.48.i；A.123.y.48.i；A.124.y.48.i；A.125.y.48.i；A.126.y.48.i；
A.127.y.48.i；A.128.y.48.i；A.129.y.48.i；A.130.y.48.i；A.131.y.48.i；A.132.y.48.i；
A.133.y.48.i；A.134.y.48.i；A.135.y.48.i；A.136.y.48.i；A.137.y.48.i；A.138.y.48.i；
A.139.y.48.i；A.140.y.48.i；A.141.y.48.i；A.2.y.49.i；A.3.y.49.i；A.4.y.49.i；A.5.y.49.i；
A.7.y.49.i；A.9.y.49.i；A.100.y.49.i；A.101.y.49.i；A.102.y.49.i；A.103.y.49.i；
A.104.y.49.i；A.105.y.49.i；A.106.y.49.i；A.107.y.49.i；A.108.y.49.i；A.109.y.49.i；
A.110.y.49.i；A.111.y.49.i；A.112.y.49.i；A.113.y.49.i；A.114.y.49.i；A.115.y.49.i；
A.116.y.49.i；A.117.y.49.i；A.118.y.49.i；A.119.y.49.i；A.120.y.49.i；A.121.y.49.i；
A.122.y.49.i；A.123.y.49.i；A.124.y.49.i；A.125.y.49.i；A.126.y.49.i；A.127.y.49.i；
A.128.y.49.i；A.129.y.49.i；A.130.y.49.i；A.131.y.49.i；A.132.y.49.i；A.133.y.49.i；
A.134.y.49.i；A.135.y.49.i；A.136.y.49.i；A.137.y.49.i；A.138.y.49.i；A.139.y.49.i；
A.140.y.49.i；A.141.y.49.i；A.2.y.50.i；A.3.y.50.i；A.4.y.50.i；A.5.y.50.i；A.7.y.50.i；
A.9.y.50.i；A.100.y.50.i；A.101.y.50.i；A.102.y.50.i；A.103.y.50.i；A.104.y.50.i；
A.105.y.50.i；A.106.y.50.i；A.107.y.50.i；A.108.y.50.i；A.109.y.50.i；A.110.y.50.i；
A.111.y.50.i；A.112.y.50.i；A.113.y.50.i；A.114.y.50.i；A.115.y.50.i；A.116.y.50.i；
A.117.y.50.i；A.118.y.50.i；A.119.y.50.i；A.120.y.50.i；A.121.y.50.i；A.122.y.50.i；
A.123.y.50.i；A.124.y.50.i；A.125.y.50.i；A.126.y.50.i；A.127.y.50.i；A.128.y.50.i；
A.129.y.50.i；A.130.y.50.i；A.131.y.50.i；A.132.y.50.i；A.133.y.50.i；A.134.y.50.i；
A.135.y.50.i；A.136.y.50.i；A.137.y.50.i；A.138.y.50.i；A.139.y.50.i；A.140.y.50.i；
A.141.y.50.i；A.2.y.51.i；A.3.y.51.i；A.4.y.51.i；A.5.y.51.i；A.7.y.51.i；A.9.y.51.i；
A.100.y.51.i；A.101.y.51.i；A.102.y.51.i；A.103.y.51.i；A.104.y.51.i；A.105.y.51.i；
A.106.y.51.i；A.107.y.51.i；A.108.y.51.i；A.109.y.51.i；A.110.y.51.i；A.111.y.51.i；
A.112.y.51.i；A.113.y.51.i；A.114.y.51.i；A.115.y.51.i；A.116.y.51.i；A.117.y.51.i；
A.118.y.51.i；A.119.y.51.i；A.120.y.51.i；A.121.y.51.i；A.122.y.51.i；A.123.y.51.i；
A.124.y.51.i；A.125.y.51.i；A.126.y.51.i；A.127.y.51.i；A.128.y.51.i；A.129.y.51.i；
A.130.y.51.i；A.131.y.51.i；A.132.y.51.i；A.133.y.51.i；A.134.y.51.i；A.135.y.51.i；
A.136.y.51.i；A.137.y.51.i；A.138.y.51.i；A.139.y.51.i；A.140.y.51.i；A.141.y.51.i；
A.2.z.46.i；A.3.z.46.i；A.4.z.46.i；A.5.z.46.i；A.7.z.46.i；A.9.z.46.i；A.100.z.46.i；
A.101.z.46.i；A.102.z.46.i；A.103.z.46.i；A.104.z.46.i；A.105.z.46.i；A.106.z.46.i；
A.107.z.46.i；A.108.z.46.i；A.109.z.46.i；A.110.z.46.i；A.111.z.46.i；A.112.z.46.i；
A.113.z.46.i；A.114.z.46.i；A.115.z.46.i；A.116.z.46.i；A.117.z.46.i；A.118.z.46.i；
A.119.z.46.i；A.120.z.46.i；A.121.z.46.i；A.122.z.46.i；A.123.z.46.i；A.124.z.46.i；
A.125.z.46.i；A.126.z.46.i；A.127.z.46.i；A.128.z.46.i；A.129.z.46.i；A.130.z.46.i；
A.131.z.46.i；A.132.z.46.i；A.133.z.46.i；A.134.z.46.i；A.135.z.46.i；A.136.z.46.i；
A.137.z.46.i；A.138.z.46.i；A.139.z.46.i；A.140.z.46.i；A.141.z.46.i；A.2.z.47.i；
A.3.z.47.i；A.4.z.47.i；A.5.z.47.i；A.7.z.47.i；A.9.z.47.i；A.100.z.47.i；A.101.z.47.i；
A.102.z.47.i；A.103.z.47.i；A.104.z.47.i；A.105.z.47.i；A.106.z.47.i；A.107.z.47.i；
A.108.z.47.i；A.109.z.47.i；A.110.z.47.i；A.111.z.47.i；A.112.z.47.i；A.113.z.47.i；
A.114.z.47.i；A.115.z.47.i；A.116.z.47.i；A.117.z.47.i；A.118.z.47.i；A.119.z.47.i；
A.120.z.47.i；A.121.z.47.i；A.122.z.47.i；A.123.z.47.i；A.124.z.47.i；A.125.z.47.i；
A.126.z.47.i；A.127.z.47.i；A.128.z.47.i；A.129.z.47.i；A.130.z.47.i；A.131.z.47.i；
A.132.z.47.i；A.133.z.47.i；A.134.z.47.i；A.135.z.47.i；A.136.z.47.i；A.137.z.47.i；
A.138.z.47.i；A.139.z.47.i；A.140.z.47.i；A.141.z.47.i；A.2.z.48.i；A.3.z.48.i；
A.4.z.48.i；A.5.z.48.i；A.7.z.48.i；A.9.z.48.i；A.100.z.48.i；A.101.z.48.i；A.102.z.48.i；
A.103.z.48.i；A.104.z.48.i；A.105.z.48.i；A.106.z.48.i；A.107.z.48.i；A.108.z.48.i；
A.109.z.48.i；A.110.z.48.i；A.111.z.48.i；A.112.z.48.i；A.113.z.48.i；A.114.z.48.i；
A.115.z.48.i；A.116.z.48.i；A.117.z.48.i；A.118.z.48.i；A.119.z.48.i；A.120.z.48.i；
A.121.z.48.i；A.122.z.48.i；A.123.z.48.i；A.124.z.48.i；A.125.z.48.i；A.126.z.48.i；
A.127.z.48.i；A.128.z.48.i；A.129.z.48.i；A.130.z.48.i；A.131.z.48.i；A.132.z.48.i；
A.133.z.48.i；A.134.z.48.i；A.135.z.48.i；A.136.z.48.i；A.137.z.48.i；A.138.z.48.i；
A.139.z.48.i；A.140.z.48.i；A.141.z.48.i；A.2.z.49.i；A.3.z.49.i；A.4.z.49.i；A.5.z.49.i；
A.7.z.49.i；A.9.z.49.i；A.100.z.49.i；A.101.z.49.i；A.102.z.49.i；A.103.z.49.i；
A.104.z.49.i；A.105.z.49.i；A.106.z.49.i；A.107.z.49.i；A.108.z.49.i；A.109.z.49.i；
A.110.z.49.i；A.111.z.49.i；A.112.z.49.i；A.113.z.49.i；A.114.z.49.i；A.115.z.49.i；
A.116.z.49.i；A.117.z.49.i；A.118.z.49.i；A.119.z.49.i；A.120.z.49.i；A.121.z.49.i；
A.122.z.49.i；A.123.z.49.i；A.124.z.49.i；A.125.z.49.i；A.126.z.49.i；A.127.z.49.i；
A.128.z.49.i；A.129.z.49.i；A.130.z.49.i；A.131.z.49.i；A.132.z.49.i；A.133.z.49.i；
A.134.z.49.i；A.135.z.49.i；A.136.z.49.i；A.137.z.49.i；A.138.z.49.i；A.139.z.49.i；
A.140.z.49.i；A.141.z.49.i；A.2.z.50.i；A.3.z.50.i；A.4.z.50.i；A.5.z.50.i；A.7.z.50.i；
A.9.z.50.i；A.100.z.50.i；A.101.z.50.i；A.102.z.50.i；A.103.z.50.i；A.104.z.50.i；
A.105.z.50.i；A.106.z.50.i；A.107.z.50.i；A.108.z.50.i；A.109.z.50.i；A.110.z.50.i；
A.111.z.50.i；A.112.z.50.i；A.113.z.50.i；A.114.z.50.i；A.115.z.50.i；A.116.z.50.i；
A.117.z.50.i；A.118.z.50.i；A.119.z.50.i；A.120.z.50.i；A.121.z.50.i；A.122.z.50.i；
A.123.z.50.i；A.124.z.50.i；A.125.z.50.i；A.126.z.50.i；A.127.z.50.i；A.128.z.50.i；
A.129.z.50.i；A.130.z.50.i；A.131.z.50.i；A.132.z.50.i；A.133.z.50.i；A.134.z.50.i；
A.135.z.50.i；A.136.z.50.i；A.137.z.50.i；A.138.z.50.i；A.139.z.50.i；A.140.z.50.i；
A.141.z.50.i；A.2.z.51.i；A.3.z.51.i；A.4.z.51.i；A.5.z.51.i；A.7.z.51.i；A.9.z.51.i；
A.100.z.51.i；A.101.z.51.i；A.102.z.51.i；A.103.z.51.i；A.104.z.51.i；A.105.z.51.i；
A.106.z.51.i；A.107.z.51.i；A.108.z.51.i；A.109.z.51.i；A.110.z.51.i；A.111.z.51.i；
A.112.z.51.i；A.113.z.51.i；A.114.z.51.i；A.115.z.51.i；A.116.z.51.i；A.117.z.51.i；
A.118.z.51.i；A.119.z.51.i；A.120.z.51.i；A.121.z.51.i；A.122.z.51.i；A.123.z.51.i；
A.124.z.51.i；A.125.z.51.i；A.126.z.51.i；A.127.z.51.i；A.128.z.51.i；A.129.z.51.i；
A.130.z.51.i；A.131.z.51.i；A.132.z.51.i；A.133.z.51.i；A.134.z.51.i；A.135.z.51.i；
A.136.z.51.i；A.137.z.51.i；A.138.z.51.i；A.139.z.51.i；A.140.z.51.i；A.141.z.51.i；
A.2.A.46.i；A.3.A.46.i；A.4.A.46.i；A.5.A.46.i；A.7.A.46.i；A.9.A.46.i；A.100.A.46.i；
A.101.A.46.i；A.102.A.46.i；A.103.A.46.i；A.104.A.46.i；A.105.A.46.i；A.106.A.46.i；
A.107.A.46.i；A.108.A.46.i；A.109.A.46.i；A.110.A.46.i；A.111.A.46.i；A.112.A.46.i；
A.113.A.46.i；A.114.A.46.i；A.115.A.46.i；A.116.A.46.i；A.117.A.46.i；A.118.A.46.i；
A.119.A.46.i；A.120.A.46.i；A.121.A.46.i；A.122.A.46.i；A.123.A.46.i；A.124.A.46.i；
A.125.A.46.i；A.126.A.46.i；A.127.A.46.i；A.128.A.46.i；A.129.A.46.i；A.130.A.46.i；
A.131.A.46.i；A.132.A.46.i；A.133.A.46.i；A.134.A.46.i；A.135.A.46.i；A.136.A.46.i；
A.137.A.46.i；A.138.A.46.i；A.139.A.46.i；A.140.A.46.i；A.141.A.46.i；A.2.A.47.i；
A.3.A.47.i；A.4.A.47.i；A.5.A.47.i；A.7.A.47.i；A.9.A.47.i；A.100.A.47.i；
A.101.A.47.i；A.102.A.47.i；A.103.A.47.i；A.104.A.47.i；A.105.A.47.i；A.106.A.47.i；
A.107.A.47.i；A.108.A.47.i；A.109.A.47.i；A.110.A.47.i；A.111.A.47.i；A.112.A.47.i；
A.113.A.47.i；A.114.A.47.i；A.115.A.47.i；A.116.A.47.i；A.117.A.47.i；A.118.A.47.i；
A.119.A.47.i；A.120.A.47.i；A.121.A.47.i；A.122.A.47.i；A.123.A.47.i；A.124.A.47.i；
A.125.A.47.i；A.126.A.47.i；A.127.A.47.i；A.128.A.47.i；A.129.A.47.i；A.130.A.47.i；
A.131.A.47.i；A.132.A.47.i；A.133.A.47.i；A.134.A.47.i；A.135.A.47.i；A.136.A.47.i；
A.137.A.47.i；A.138.A.47.i；A.139.A.47.i；A.140.A.47.i；A.141.A.47.i；A.2.A.48.i；
A.3.A.48.i；A.4.A.48.i；A.5.A.48.i；A.7.A.48.i；A.9.A.48.i；A.100.A.48.i；
A.101.A.48.i；A.102.A.48.i；A.103.A.48.i；A.104.A.48.i；A.105.A.48.i；A.106.A.48.i；
A.107.A.48.i；A.108.A.48.i；A.109.A.48.i；A.110.A.48.i；A.111.A.48.i；A.112.A.48.i；
A.113.A.48.i；A.114.A.48.i；A.115.A.48.i；A.116.A.48.i；A.117.A.48.i；A.118.A.48.i；
A.119.A.48.i；A.120.A.48.i；A.121.A.48.i；A.122.A.48.i；A.123.A.48.i；A.124.A.48.i；
A.125.A.48.i；A.126.A.48.i；A.127.A.48.i；A.128.A.48.i；A.129.A.48.i；A.130.A.48.i；
A.131.A.48.i；A.132.A.48.i；A.133.A.48.i；A.134.A.48.i；A.135.A.48.i；A.136.A.48.i；
A.137.A.48.i；A.138.A.48.i；A.139.A.48.i；A.140.A.48.i；A.141.A.48.i；A.2.A.49.i；
A.3.A.49.i；A.4.A.49.i；A.5.A.49.i；A.7.A.49.i；A.9.A.49.i；A.100.A.49.i；
A.101.A.49.i；A.102.A.49.i；A.103.A.49.i；A.104.A.49.i；A.105.A.49.i；A.106.A.49.i；
A.107.A.49.i；A.108.A.49.i；A.109.A.49.i；A.110.A.49.i；A.111.A.49.i；A.112.A.49.i；
A.113.A.49.i；A.114.A.49.i；A.115.A.49.i；A.116.A.49.i；A.117.A.49.i；A.118.A.49.i；
A.119.A.49.i；A.120.A.49.i；A.121.A.49.i；A.122.A.49.i；A.123.A.49.i；A.124.A.49.i；
A.125.A.49.i；A.126.A.49.i；A.127.A.49.i；A.128.A.49.i；A.129.A.49.i；A.130.A.49.i；
A.131.A.49.i；A.132.A.49.i；A.133.A.49.i；A.134.A.49.i；A.135.A.49.i；A.136.A.49.i；
A.137.A.49.i；A.138.A.49.i；A.139.A.49.i；A.140.A.49.i；A.141.A.49.i；A.2.A.50.i；
A.3.A.50.i；A.4.A.50.i；A.5.A.50.i；A.7.A.50.i；A.9.A.50.i；A.100.A.50.i；
A.101.A.50.i；A.102.A.50.i；A.103.A.50.i；A.104.A.50.i；A.105.A.50.i；A.106.A.50.i；
A.107.A.50.i；A.108.A.50.i；A.109.A.50.i；A.110.A.50.i；A.111.A.50.i；A.112.A.50.i；
A.113.A.50.i；A.114.A.50.i；A.115.A.50.i；A.116.A.50.i；A.117.A.50.i；A.118.A.50.i；
A.119.A.50.i；A.120.A.50.i；A.121.A.50.i；A.122.A.50.i；A.123.A.50.i；A.124.A.50.i；
A.125.A.50.i；A.126.A.50.i；A.127.A.50.i；A.128.A.50.i；A.129.A.50.i；A.130.A.50.i；
A.131.A.50.i；A.132.A.50.i；A.133.A.50.i；A.134.A.50.i；A.135.A.50.i；A.136.A.50.i；
A.137.A.50.i；A.138.A.50.i；A.139.A.50.i；A.140.A.50.i；A.141.A.50.i；A.2.A.51.i；
A.3.A.51.i；A.4.A.51.i；A.5.A.51.i；A.7.A.51.i；A.9.A.51.i；A.100.A.51.i；
A.101.A.51.i；A.102.A.51.i；A.103.A.51.i；A.104.A.51.i；A.105.A.51.i；A.106.A.51.i；
A.107.A.51.i；A.108.A.51.i；A.109.A.51.i；A.110.A.51.i；A.111.A.51.i；A.112.A.51.i；
A.113.A.51.i；A.114.A.51.i；A.115.A.51.i；A.116.A.51.i；A.117.A.51.i；A.118.A.51.i；
A.119.A.51.i；A.120.A.51.i；A.121.A.51.i；A.122.A.51.i；A.123.A.51.i；A.124.A.51.i；
A.125.A.51.i；A.126.A.51.i；A.127.A.51.i；A.128.A.51.i；A.129.A.51.i；A.130.A.51.i；
A.131.A.51.i；A.132.A.51.i；A.133.A.51.i；A.134.A.51.i；A.135.A.51.i；A.136.A.51.i；
A.137.A.51.i；A.138.A.51.i；A.139.A.51.i；A.140.A.51.i；A.141.A.51.i；A.2.B.46.i；
A.3.B.46.i；A.4.B.46.i；A.5.B.46.i；A.7.B.46.i；A.9.B.46.i；A.100.B.46.i；A.101.B.46.i；
A.102.B.46.i；A.103.B.46.i；A.104.B.46.i；A.105.B.46.i；A.106.B.46.i；A.107.B.46.i；
A.108.B.46.i；A.109.B.46.i；A.110.B.46.i；A.111.B.46.i；A.112.B.46.i；A.113.B.46.i；
A.114.B.46.i；A.115.B.46.i；A.116.B.46.i；A.117.B.46.i；A.118.B.46.i；A.119.B.46.i；
A.120.B.46.i；A.121.B.46.i；A.122.B.46.i；A.123.B.46.i；A.124.B.46.i；A.125.B.46.i；
A.126.B.46.i；A.127.B.46.i；A.128.B.46.i；A.129.B.46.i；A.130.B.46.i；A.131.B.46.i；
A.132.B.46.i；A.133.B.46.i；A.134.B.46.i；A.135.B.46.i；A.136.B.46.i；A.137.B.46.i；
A.138.B.46.i；A.139.B.46.i；A.140.B.46.i；A.141.B.46.i；A.2.B.47.i；A.3.B.47.i；
A.4.B.47.i；A.5.B.47.i；A.7.B.47.i；A.9.B.47.i；A.100.B.47.i；A.101.B.47.i；
A.102.B.47.i；A.103.B.47.i；A.104.B.47.i；A.105.B.47.i；A.106.B.47.i；A.107.B.47.i；
A.108.B.47.i；A.109.B.47.i；A.110.B.47.i；A.111.B.47.i；A.112.B.47.i；A.113.B.47.i；
A.114.B.47.i；A.115.B.47.i；A.116.B.47.i；A.117.B.47.i；A.118.B.47.i；A.119.B.47.i；
A.120.B.47.i；A.121.B.47.i；A.122.B.47.i；A.123.B.47.i；A.124.B.47.i；A.125.B.47.i；
A.126.B.47.i；A.127.B.47.i；A.128.B.47.i；A.129.B.47.i；A.130.B.47.i；A.131.B.47.i；
A.132.B.47.i；A.133.B.47.i；A.134.B.47.i；A.135.B.47.i；A.136.B.47.i；A.137.B.47.i；
A.138.B.47.i；A.139.B.47.i；A.140.B.47.i；A.141.B.47.i；A.2.B.48.i；A.3.B.48.i；
A.4.B.48.i；A.5.B.48.i；A.7.B.48.i；A.9.B.48.i；A.100.B.48.i；A.101.B.48.i；
A.102.B.48.i；A.103.B.48.i；A.104.B.48.i；A.105.B.48.i；A.106.B.48.i；A.107.B.48.i；
A.108.B.48.i；A.109.B.48.i；A.110.B.48.i；A.111.B.48.i；A.112.B.48.i；A.113.B.48.i；
A.114.B.48.i；A.115.B.48.i；A.116.B.48.i；A.117.B.48.i；A.118.B.48.i；A.119.B.48.i；
A.120.B.48.i；A.121.B.48.i；A.122.B.48.i；A.123.B.48.i；A.124.B.48.i；A.125.B.48.i；
A.126.B.48.i；A.127.B.48.i；A.128.B.48.i；A.129.B.48.i；A.130.B.48.i；A.131.B.48.i；
A.132.B.48.i；A.133.B.48.i；A.134.B.48.i；A.135.B.48.i；A.136.B.48.i；A.137.B.48.i；
A.138.B.48.i；A.139.B.48.i；A.140.B.48.i；A.141.B.48.i；A.2.B.49.i；A.3.B.49.i；
A.4.B.49.i；A.5.B.49.i；A.7.B.49.i；A.9.B.49.i；A.100.B.49.i；A.101.B.49.i；
A.102.B.49.i；A.103.B.49.i；A.104.B.49.i；A.105.B.49.i；A.106.B.49.i；A.107.B.49.i；
A.108.B.49.i；A.109.B.49.i；A.110.B.49.i；A.111.B.49.i；A.112.B.49.i；A.113.B.49.i；
A.114.B.49.i；A.115.B.49.i；A.116.B.49.i；A.117.B.49.i；A.118.B.49.i；A.119.B.49.i；
A.120.B.49.i；A.121.B.49.i；A.122.B.49.i；A.123.B.49.i；A.124.B.49.i；A.125.B.49.i；
A.126.B.49.i；A.127.B.49.i；A.128.B.49.i；A.129.B.49.i；A.130.B.49.i；A.131.B.49.i；
A.132.B.49.i；A.133.B.49.i；A.134.B.49.i；A.135.B.49.i；A.136.B.49.i；A.137.B.49.i；
A.138.B.49.i；A.139.B.49.i；A.140.B.49.i；A.141.B.49.i；A.2.B.50.i；A.3.B.50.i；
A.4.B.50.i；A.5.B.50.i；A.7.B.50.i；A.9.B.50.i；A.100.B.50.i；A.101.B.50.i；
A.102.B.50.i；A.103.B.50.i；A.104.B.50.i；A.105.B.50.i；A.106.B.50.i；A.107.B.50.i；
A.108.B.50.i；A.109.B.50.i；A.110.B.50.i；A.111.B.50.i；A.112.B.50.i；A.113.B.50.i；
A.114.B.50.i；A.115.B.50.i；A.116.B.50.i；A.117.B.50.i；A.118.B.50.i；A.119.B.50.i；
A.120.B.50.i；A.121.B.50.i；A.122.B.50.i；A.123.B.50.i；A.124.B.50.i；A.125.B.50.i；
A.126.B.50.i；A.127.B.50.i；A.128.B.50.i；A.129.B.50.i；A.130.B.50.i；A.131.B.50.i；
A.132.B.50.i；A.133.B.50.i；A.134.B.50.i；A.135.B.50.i；A.136.B.50.i；A.137.B.50.i；
A.138.B.50.i；A.139.B.50.i；A.140.B.50.i；A.141.B.50.i；A.2.B.51.i；A.3.B.51.i；
A.4.B.51.i；A.5.B.51.i；A.7.B.51.i；A.9.B.51.i；A.100.B.51.i；A.101.B.51.i；
A.102.B.51.i；A.103.B.51.i；A.104.B.51.i；A.105.B.51.i；A.106.B.51.i；A.107.B.51.i；
A.108.B.51.i；A.109.B.51.i；A.110.B.51.i；A.111.B.51.i；A.112.B.51.i；A.113.B.51.i；
A.114.B.51.i；A.115.B.51.i；A.116.B.51.i；A.117.B.51.i；A.118.B.51.i；A.119.B.51.i；
A.120.B.51.i；A.121.B.51.i；A.122.B.51.i；A.123.B.51.i；A.124.B.51.i；A.125.B.51.i；
A.126.B.51.i；A.127.B.51.i；A.128.B.51.i；A.129.B.51.i；A.130.B.51.i；A.131.B.51.i；
A.132.B.51.i；A.133.B.51.i；A.134.B.51.i；A.135.B.51.i；A.136.B.51.i；A.137.B.51.i；
A.138.B.51.i；A.139.B.51.i；A.140.B.51.i；A.141.B.51.i；A.2.C.46.i；A.3.C.46.i；
A.4.C.46.i；A.5.C.46.i；A.7.C.46.i；A.9.C.46.i；A.100.C.46.i；A.101.C.46.i；
A.102.C.46.i；A.103.C.46.i；A.104.C.46.i；A.105.C.46.i；A.106.C.46.i；A.107.C.46.i；
A.108.C.46.i；A.109.C.46.i；A.110.C.46.i；A.111.C.46.i；A.112.C.46.i；A.113.C.46.i；
A.114.C.46.i；A.115.C.46.i；A.116.C.46.i；A.117.C.46.i；A.118.C.46.i；A.119.C.46.i；
A.120.C.46.i；A.121.C.46.i；A.122.C.46.i；A.123.C.46.i；A.124.C.46.i；A.125.C.46.i；
A.126.C.46.i；A.127.C.46.i；A.128.C.46.i；A.129.C.46.i；A.130.C.46.i；A.131.C.46.i；
A.132.C.46.i；A.133.C.46.i；A.134.C.46.i；A.135.C.46.i；A.136.C.46.i；A.137.C.46.i；
A.138.C.46.i；A.139.C.46.i；A.140.C.46.i；A.141.C.46.i；A.2.C.47.i；A.3.C.47.i；
A.4.C.47.i；A.5.C.47.i；A.7.C.47.i；A.9.C.47.i；A.100.C.47.i；A.101.C.47.i；
A.102.C.47.i；A.103.C.47.i；A.104.C.47.i；A.105.C.47.i；A.106.C.47.i；A.107.C.47.i；
A.108.C.47.i；A.109.C.47.i；A.110.C.47.i；A.111.C.47.i；A.112.C.47.i；A.113.C.47.i；
A.114.C.47.i；A.115.C.47.i；A.116.C.47.i；A.117.C.47.i；A.118.C.47.i；A.119.C.47.i；
A.120.C.47.i；A.121.C.47.i；A.122.C.47.i；A.123.C.47.i；A.124.C.47.i；A.125.C.47.i；
A.126.C.47.i；A.127.C.47.i；A.128.C.47.i；A.129.C.47.i；A.130.C.47.i；A.131.C.47.i；
A.132.C.47.i；A.133.C.47.i；A.134.C.47.i；A.135.C.47.i；A.136.C.47.i；A.137.C.47.i；
A.138.C.47.i；A.139.C.47.i；A.140.C.47.i；A.141.C.47.i；A.2.C.48.i；A.3.C.48.i；
A.4.C.48.i；A.5.C.48.i；A.7.C.48.i；A.9.C.48.i；A.100.C.48.i；A.101.C.48.i；
A.102.C.48.i；A.103.C.48.i；A.104.C.48.i；A.105.C.48.i；A.106.C.48.i；A.107.C.48.i；
A.108.C.48.i；A.109.C.48.i；A.110.C.48.i；A.111.C.48.i；A.112.C.48.i；A.113.C.48.i；
A.114.C.48.i；A.115.C.48.i；A.116.C.48.i；A.117.C.48.i；A.118.C.48.i；A.119.C.48.i；
A.120.C.48.i；A.121.C.48.i；A.122.C.48.i；A.123.C.48.i；A.124.C.48.i；A.125.C.48.i；
A.126.C.48.i；A.127.C.48.i；A.128.C.48.i；A.129.C.48.i；A.130.C.48.i；A.131.C.48.i；
A.132.C.48.i；A.133.C.48.i；A.134.C.48.i；A.135.C.48.i；A.136.C.48.i；A.137.C.48.i；
A.138.C.48.i；A.139.C.48.i；A.140.C.48.i；A.141.C.48.i；A.2.C.49.i；A.3.C.49.i；
A.4.C.49.i；A.5.C.49.i；A.7.C.49.i；A.9.C.49.i；A.100.C.49.i；A.101.C.49.i；
A.102.C.49.i；A.103.C.49.i；A.104.C.49.i；A.105.C.49.i；A.106.C.49.i；A.107.C.49.i；
A.108.C.49.i；A.109.C.49.i；A.110.C.49.i；A.111.C.49.i；A.112.C.49.i；A.113.C.49.i；
A.114.C.49.i；A.115.C.49.i；A.116.C.49.i；A.117.C.49.i；A.118.C.49.i；A.119.C.49.i；
A.120.C.49.i；A.121.C.49.i；A.122.C.49.i；A.123.C.49.i；A.124.C.49.i；A.125.C.49.i；
A.126.C.49.i；A.127.C.49.i；A.128.C.49.i；A.129.C.49.i；A.130.C.49.i；A.131.C.49.i；
A.132.C.49.i；A.133.C.49.i；A.134.C.49.i；A.135.C.49.i；A.136.C.49.i；A.137.C.49.i；
A.138.C.49.i；A.139.C.49.i；A.140.C.49.i；A.141.C.49.i；A.2.C.50.i；A.3.C.50.i；
A.4.C.50.i；A.5.C.50.i；A.7.C.50.i；A.9.C.50.i；A.100.C.50.i；A.101.C.50.i；
A.102.C.50.i；A.103.C.50.i；A.104.C.50.i；A.105.C.50.i；A.106.C.50.i；A.107.C.50.i；
A.108.C.50.i；A.109.C.50.i；A.110.C.50.i；A.111.C.50.i；A.112.C.50.i；A.113.C.50.i；
A.114.C.50.i；A.115.C.50.i；A.116.C.50.i；A.117.C.50.i；A.118.C.50.i；A.119.C.50.i；
A.120.C.50.i；A.121.C.50.i；A.122.C.50.i；A.123.C.50.i；A.124.C.50.i；A.125.C.50.i；
A.126.C.50.i；A.127.C.50.i；A.128.C.50.i；A.129.C.50.i；A.130.C.50.i；A.131.C.50.i；
A.132.C.50.i；A.133.C.50.i；A.134.C.50.i；A.135.C.50.i；A.136.C.50.i；A.137.C.50.i；
A.138.C.50.i；A.139.C.50.i；A.140.C.50.i；A.141.C.50.i；A.2.C.51.i；A.3.C.51.i；
A.4.C.51.i；A.5.C.51.i；A.7.C.51.i；A.9.C.51.i；A.100.C.51.i；A.101.C.51.i；
A.102.C.51.i；A.103.C.51.i；A.104.C.51.i；A.105.C.51.i；A.106.C.51.i；A.107.C.51.i；
A.108.C.51.i；A.109.C.51.i；A.110.C.51.i；A.111.C.51.i；A.112.C.51.i；A.113.C.51.i；
A.114.C.51.i；A.115.C.51.i；A.116.C.51.i；A.117.C.51.i；A.118.C.51.i；A.119.C.51.i；
A.120.C.51.i；A.121.C.51.i；A.122.C.51.i；A.123.C.51.i；A.124.C.51.i；A.125.C.51.i；
A.126.C.51.i；A.127.C.51.i；A.128.C.51.i；A.129.C.51.i；A.130.C.51.i；A.131.C.51.i；
A.132.C.51.i；A.133.C.51.i；A.134.C.51.i；A.135.C.51.i；A.136.C.51.i；A.137.C.51.i；
A.138.C.51.i；A.139.C.51.i；A.140.C.51.i；A.141.C.51.i；A.2.D.46.i；A.3.D.46.i；
A.4.D.46.i；A.5.D.46.i；A.7.D.46.i；A.9.D.46.i；A.100.D.46.i；A.101.D.46.i；
A.102.D.46.i；A.103.D.46.i；A.104.D.46.i；A.105.D.46.i；A.106.D.46.i；A.107.D.46.i；
A.108.D.46.i；A.109.D.46.i；A.110.D.46.i；A.111.D.46.i；A.112.D.46.i；A.113.D.46.i；
A.114.D.46.i；A.115.D.46.i；A.116.D.46.i；A.117.D.46.i；A.118.D.46.i；A.119.D.46.i；
A.120.D.46.i；A.121.D.46.i；A.122.D.46.i；A.123.D.46.i；A.124.D.46.i；A.125.D.46.i；
A.126.D.46.i；A.127.D.46.i；A.128.D.46.i；A.129.D.46.i；A.130.D.46.i；A.131.D.46.i；
A.132.D.46.i；A.133.D.46.i；A.134.D.46.i；A.135.D.46.i；A.136.D.46.i；A.137.D.46.i；
A.138.D.46.i；A.139.D.46.i；A.140.D.46.i；A.141.D.46.i；A.2.D.47.i；A.3.D.47.i；
A.4.D.47.i；A.5.D.47.i；A.7.D.47.i；A.9.D.47.i；A.100.D.47.i；A.101.D.47.i；
A.102.D.47.i；A.103.D.47.i；A.104.D.47.i；A.105.D.47.i；A.106.D.47.i；A.107.D.47.i；
A.108.D.47.i；A.109.D.47.i；A.110.D.47.i；A.111.D.47.i；A.112.D.47.i；A.113.D.47.i；
A.114.D.47.i；A.115.D.47.i；A.116.D.47.i；A.117.D.47.i；A.118.D.47.i；A.119.D.47.i；
A.120.D.47.i；A.121.D.47.i；A.122.D.47.i；A.123.D.47.i；A.124.D.47.i；A.125.D.47.i；
A.126.D.47.i；A.127.D.47.i；A.128.D.47.i；A.129.D.47.i；A.130.D.47.i；A.131.D.47.i；
A.132.D.47.i；A.133.D.47.i；A.134.D.47.i；A.135.D.47.i；A.136.D.47.i；A.137.D.47.i；
A.138.D.47.i；A.139.D.47.i；A.140.D.47.i；A.141.D.47.i；A.2.D.48.i；A.3.D.48.i；
A.4.D.48.i；A.5.D.48.i；A.7.D.48.i；A.9.D.48.i；A.100.D.48.i；A.101.D.48.i；
A.102.D.48.i；A.103.D.48.i；A.104.D.48.i；A.105.D.48.i；A.106.D.48.i；A.107.D.48.i；
A.108.D.48.i；A.109.D.48.i；A.110.D.48.i；A.111.D.48.i；A.112.D.48.i；A.113.D.48.i；
A.114.D.48.i；A.115.D.48.i；A.116.D.48.i；A.117.D.48.i；A.118.D.48.i；A.119.D.48.i；
A.120.D.48.i；A.121.D.48.i；A.122.D.48.i；A.123.D.48.i；A.124.D.48.i；A.125.D.48.i；
A.126.D.48.i；A.127.D.48.i；A.128.D.48.i；A.129.D.48.i；A.130.D.48.i；A.131.D.48.i；
A.132.D.48.i；A.133.D.48.i；A.134.D.48.i；A.135.D.48.i；A.136.D.48.i；A.137.D.48.i；
A.138.D.48.i；A.139.D.48.i；A.140.D.48.i；A.141.D.48.i；A.2.D.49.i；A.3.D.49.i；
A.4.D.49.i；A.5.D.49.i；A.7.D.49.i；A.9.D.49.i；A.100.D.49.i；A.101.D.49.i；
A.102.D.49.i；A.103.D.49.i；A.104.D.49.i；A.105.D.49.i；A.106.D.49.i；A.107.D.49.i；
A.108.D.49.i；A.109.D.49.i；A.110.D.49.i；A.111.D.49.i；A.112.D.49.i；A.113.D.49.i；
A.114.D.49.i；A.115.D.49.i；A.116.D.49.i；A.117.D.49.i；A.118.D.49.i；A.119.D.49.i；
A.120.D.49.i；A.121.D.49.i；A.122.D.49.i；A.123.D.49.i；A.124.D.49.i；A.125.D.49.i；
A.126.D.49.i；A.127.D.49.i；A.128.D.49.i；A.129.D.49.i；A.130.D.49.i；A.131.D.49.i；
A.132.D.49.i；A.133.D.49.i；A.134.D.49.i；A.135.D.49.i；A.136.D.49.i；A.137.D.49.i；
A.138.D.49.i；A.139.D.49.i；A.140.D.49.i；A.141.D.49.i；A.2.D.50.i；A.3.D.50.i；
A.4.D.50.i；A.5.D.50.i；A.7.D.50.i；A.9.D.50.i；A.100.D.50.i；A.101.D.50.i；
A.102.D.50.i；A.103.D.50.i；A.104.D.50.i；A.105.D.50.i；A.106.D.50.i；A.107.D.50.i；
A.108.D.50.i；A.109.D.50.i；A.110.D.50.i；A.111.D.50.i；A.112.D.50.i；A.113.D.50.i；
A.114.D.50.i；A.115.D.50.i；A.116.D.50.i；A.117.D.50.i；A.118.D.50.i；A.119.D.50.i；
A.120.D.50.i；A.121.D.50.i；A.122.D.50.i；A.123.D.50.i；A.124.D.50.i；A.125.D.50.i；
A.126.D.50.i；A.127.D.50.i；A.128.D.50.i；A.129.D.50.i；A.130.D.50.i；A.131.D.50.i；
A.132.D.50.i；A.133.D.50.i；A.134.D.50.i；A.135.D.50.i；A.136.D.50.i；A.137.D.50.i；
A.138.D.50.i；A.139.D.50.i；A.140.D.50.i；A.141.D.50.i；A.2.D.51.i；A.3.D.51.i；
A.4.D.51.i；A.5.D.51.i；A.7.D.51.i；A.9.D.51.i；A.100.D.51.i；A.101.D.51.i；
A.102.D.51.i；A.103.D.51.i；A.104.D.51.i；A.105.D.51.i；A.106.D.51.i；A.107.D.51.i；
A.108.D.51.i；A.109.D.51.i；A.110.D.51.i；A.111.D.51.i；A.112.D.51.i；A.113.D.51.i；
A.114.D.51.i；A.115.D.51.i；A.116.D.51.i；A.117.D.51.i；A.118.D.51.i；A.119.D.51.i；
A.120.D.51.i；A.121.D.51.i；A.122.D.51.i；A.123.D.51.i；A.124.D.51.i；A.125.D.51.i；
A.126.D.51.i；A.127.D.51.i；A.128.D.51.i；A.129.D.51.i；A.130.D.51.i；A.131.D.51.i；
A.132.D.51.i；A.133.D.51.i；A.134.D.51.i；A.135.D.51.i；A.136.D.51.i；A.137.D.51.i；
A.138.D.51.i；A.139.D.51.i；A.140.D.51.i；A.141.D.51.i；A.2.E.46.i；A.3.E.46.i；
A.4.E.46.i；A.5.E.46.i；A.7.E.46.i；A.9.E.46.i；A.100.E.46.i；A.101.E.46.i；A.102.E.46.i；
A.103.E.46.i；A.104.E.46.i；A.105.E.46.i；A.106.E.46.i；A.107.E.46.i；A.108.E.46.i；
A.109.E.46.i；A.110.E.46.i；A.111.E.46.i；A.112.E.46.i；A.113.E.46.i；A.114.E.46.i；
A.115.E.46.i；A.116.E.46.i；A.117.E.46.i；A.118.E.46.i；A.119.E.46.i；A.120.E.46.i；
A.121.E.46.i；A.122.E.46.i；A.123.E.46.i；A.124.E.46.i；A.125.E.46.i；A.126.E.46.i；
A.127.E.46.i；A.128.E.46.i；A.129.E.46.i；A.130.E.46.i；A.131.E.46.i；A.132.E.46.i；
A.133.E.46.i；A.134.E.46.i；A.135.E.46.i；A.136.E.46.i；A.137.E.46.i；A.138.E.46.i；
A.139.E.46.i；A.140.E.46.i；A.141.E.46.i；A.2.E.47.i；A.3.E.47.i；A.4.E.47.i；A.5.E.47.i；
A.7.E.47.i；A.9.E.47.i；A.100.E.47.i；A.101.E.47.i；A.102.E.47.i；A.103.E.47.i；
A.104.E.47.i；A.105.E.47.i；A.106.E.47.i；A.107.E.47.i；A.108.E.47.i；A.109.E.47.i；
A.110.E.47.i；A.111.E.47.i；A.112.E.47.i；A.113.E.47.i；A.114.E.47.i；A.115.E.47.i；
A.116.E.47.i；A.117.E.47.i；A.118.E.47.i；A.119.E.47.i；A.120.E.47.i；A.121.E.47.i；
A.122.E.47.i；A.123.E.47.i；A.124.E.47.i；A.125.E.47.i；A.126.E.47.i；A.127.E.47.i；
A.128.E.47.i；A.129.E.47.i；A.130.E.47.i；A.131.E.47.i；A.132.E.47.i；A.133.E.47.i；
A.134.E.47.i；A.135.E.47.i；A.136.E.47.i；A.137.E.47.i；A.138.E.47.i；A.139.E.47.i；
A.140.E.47.i；A.141.E.47.i；A.2.E.48.i；A.3.E.48.i；A.4.E.48.i；A.5.E.48.i；A.7.E.48.i；
A.9.E.48.i；A.100.E.48.i；A.101.E.48.i；A.102.E.48.i；A.103.E.48.i；A.104.E.48.i；
A.105.E.48.i；A.106.E.48.i；A.107.E.48.i；A.108.E.48.i；A.109.E.48.i；A.110.E.48.i；
A.111.E.48.i；A.112.E.48.i；A.113.E.48.i；A.114.E.48.i；A.115.E.48.i；A.116.E.48.i；
A.117.E.48.i；A.118.E.48.i；A.119.E.48.i；A.120.E.48.i；A.121.E.48.i；A.122.E.48.i；
A.123.E.48.i；A.124.E.48.i；A.125.E.48.i；A.126.E.48.i；A.127.E.48.i；A.128.E.48.i；
A.129.E.48.i；A.130.E.48.i；A.131.E.48.i；A.132.E.48.i；A.133.E.48.i；A.134.E.48.i；
A.135.E.48.i；A.136.E.48.i；A.137.E.48.i；A.138.E.48.i；A.139.E.48.i；A.140.E.48.i；
A.141.E.48.i；A.2.E.49.i；A.3.E.49.i；A.4.E.49.i；A.5.E.49.i；A.7.E.49.i；A.9.E.49.i；
A.100.E.49.i；A.101.E.49.i；A.102.E.49.i；A.103.E.49.i；A.104.E.49.i；A.105.E.49.i；
A.106.E.49.i；A.107.E.49.i；A.108.E.49.i；A.109.E.49.i；A.110.E.49.i；A.111.E.49.i；
A.112.E.49.i；A.113.E.49.i；A.114.E.49.i；A.115.E.49.i；A.116.E.49.i；A.117.E.49.i；
A.118.E.49.i；A.119.E.49.i；A.120.E.49.i；A.121.E.49.i；A.122.E.49.i；A.123.E.49.i；
A.124.E.49.i；A.125.E.49.i；A.126.E.49.i；A.127.E.49.i；A.128.E.49.i；A.129.E.49.i；
A.130.E.49.i；A.131.E.49.i；A.132.E.49.i；A.133.E.49.i；A.134.E.49.i；A.135.E.49.i；
A.136.E.49.i；A.137.E.49.i；A.138.E.49.i；A.139.E.49.i；A.140.E.49.i；A.141.E.49.i；
A.2.E.50.i；A.3.E.50.i；A.4.E.50.i；A.5.E.50.i；A.7.E.50.i；A.9.E.50.i；A.100.E.50.i；
A.101.E.50.i；A.102.E.50.i；A.103.E.50.i；A.104.E.50.i；A.105.E.50.i；A.106.E.50.i；
A.107.E.50.i；A.108.E.50.i；A.109.E.50.i；A.110.E.50.i；A.111.E.50.i；A.112.E.50.i；
A.113.E.50.i；A.114.E.50.i；A.115.E.50.i；A.116.E.50.i；A.117.E.50.i；A.118.E.50.i；
A.119.E.50.i；A.120.E.50.i；A.121.E.50.i；A.122.E.50.i；A.123.E.50.i；A.124.E.50.i；
A.125.E.50.i；A.126.E.50.i；A.127.E.50.i；A.128.E.50.i；A.129.E.50.i；A.130.E.50.i；
A.131.E.50.i；A.132.E.50.i；A.133.E.50.i；A.134.E.50.i；A.135.E.50.i；A.136.E.50.i；
A.137.E.50.i；A.138.E.50.i；A.139.E.50.i；A.140.E.50.i；A.141.E.50.i；A.2.E.51.i；
A.3.E.51.i；A.4.E.51.i；A.5.E.51.i；A.7.E.51.i；A.9.E.51.i；A.100.E.51.i；A.101.E.51.i；
A.102.E.51.i；A.103.E.51.i；A.104.E.51.i；A.105.E.51.i；A.106.E.51.i；A.107.E.51.i；
A.108.E.51.i；A.109.E.51.i；A.110.E.51.i；A.111.E.51.i；A.112.E.51.i；A.113.E.51.i；
A.114.E.51.i；A.115.E.51.i；A.116.E.51.i；A.117.E.51.i；A.118.E.51.i；A.119.E.51.i；
A.120.E.51.i；A.121.E.51.i；A.122.E.51.i；A.123.E.51.i；A.124.E.51.i；A.125.E.51.i；
A.126.E.51.i；A.127.E.51.i；A.128.E.51.i；A.129.E.51.i；A.130.E.51.i；A.131.E.51.i；
A.132.E.51.i；A.133.E.51.i；A.134.E.51.i；A.135.E.51.i；A.136.E.51.i；A.137.E.51.i；
A.138.E.51.i；A.139.E.51.i；A.140.E.51.i；A.141.E.51.i；A.2.F.46.i；A.3.F.46.i；
A.4.F.46.i；A.5.F.46.i；A.7.F.46.i；A.9.F.46.i；A.100.F.46.i；A.101.F.46.i；A.102.F.46.i；
A.103.F.46.i；A.104.F.46.i；A.105.F.46.i；A.106.F.46.i；A.107.F.46.i；A.108.F.46.i；
A.109.F.46.i；A.110.F.46.i；A.111.F.46.i；A.112.F.46.i；A.113.F.46.i；A.114.F.46.i；
A.115.F.46.i；A.116.F.46.i；A.117.F.46.i；A.118.F.46.i；A.119.F.46.i；A.120.F.46.i；
A.121.F.46.i；A.122.F.46.i；A.123.F.46.i；A.124.F.46.i；A.125.F.46.i；A.126.F.46.i；
A.127.F.46.i；A.128.F.46.i；A.129.F.46.i；A.130.F.46.i；A.131.F.46.i；A.132.F.46.i；
A.133.F.46.i；A.134.F.46.i；A.135.F.46.i；A.136.F.46.i；A.137.F.46.i；A.138.F.46.i；
A.139.F.46.i；A.140.F.46.i；A.141.F.46.i；A.2.F.47.i；A.3.F.47.i；A.4.F.47.i；A.5.F.47.i；
A.7.F.47.i；A.9.F.47.i；A.100.F.47.i；A.101.F.47.i；A.102.F.47.i；A.103.F.47.i；
A.104.F.47.i；A.105.F.47.i；A.106.F.47.i；A.107.F.47.i；A.108.F.47.i；A.109.F.47.i；
A.110.F.47.i；A.111.F.47.i；A.112.F.47.i；A.113.F.47.i；A.114.F.47.i；A.115.F.47.i；
A.116.F.47.i；A.117.F.47.i；A.118.F.47.i；A.119.F.47.i；A.120.F.47.i；A.121.F.47.i；
A.122.F.47.i；A.123.F.47.i；A.124.F.47.i；A.125.F.47.i；A.126.F.47.i；A.127.F.47.i；
A.128.F.47.i；A.129.F.47.i；A.130.F.47.i；A.131.F.47.i；A.132.F.47.i；A.133.F.47.i；
A.134.F.47.i；A.135.F.47.i；A.136.F.47.i；A.137.F.47.i；A.138.F.47.i；A.139.F.47.i；
A.140.F.47.i；A.141.F.47.i；A.2.F.48.i；A.3.F.48.i；A.4.F.48.i；A.5.F.48.i；A.7.F.48.i；
A.9.F.48.i；A.100.F.48.i；A.101.F.48.i；A.102.F.48.i；A.103.F.48.i；A.104.F.48.i；
A.105.F.48.i；A.106.F.48.i；A.107.F.48.i；A.108.F.48.i；A.109.F.48.i；A.110.F.48.i；
A.111.F.48.i；A.112.F.48.i；A.113.F.48.i；A.114.F.48.i；A.115.F.48.i；A.116.F.48.i；
A.117.F.48.i；A.118.F.48.i；A.119.F.48.i；A.120.F.48.i；A.121.F.48.i；A.122.F.48.i；
A.123.F.48.i；A.124.F.48.i；A.125.F.48.i；A.126.F.48.i；A.127.F.48.i；A.128.F.48.i；
A.129.F.48.i；A.130.F.48.i；A.131.F.48.i；A.132.F.48.i；A.133.F.48.i；A.134.F.48.i；
A.135.F.48.i；A.136.F.48.i；A.137.F.48.i；A.138.F.48.i；A.139.F.48.i；A.140.F.48.i；
A.141.F.48.i；A.2.F.49.i；A.3.F.49.i；A.4.F.49.i；A.5.F.49.i；A.7.F.49.i；A.9.F.49.i；
A.100.F.49.i；A.101.F.49.i；A.102.F.49.i；A.103.F.49.i；A.104.F.49.i；A.105.F.49.i；
A.106.F.49.i；A.107.F.49.i；A.108.F.49.i；A.109.F.49.i；A.110.F.49.i；A.111.F.49.i；
A.112.F.49.i；A.113.F.49.i；A.114.F.49.i；A.115.F.49.i；A.116.F.49.i；A.117.F.49.i；
A.118.F.49.i；A.119.F.49.i；A.120.F.49.i；A.121.F.49.i；A.122.F.49.i；A.123.F.49.i；
A.124.F.49.i；A.125.F.49.i；A.126.F.49.i；A.127.F.49.i；A.128.F.49.i；A.129.F.49.i；
A.130.F.49.i；A.131.F.49.i；A.132.F.49.i；A.133.F.49.i；A.134.F.49.i；A.135.F.49.i；
A.136.F.49.i；A.137.F.49.i；A.138.F.49.i；A.139.F.49.i；A.140.F.49.i；A.141.F.49.i；
A.2.F.50.i；A.3.F.50.i；A.4.F.50.i；A.5.F.50.i；A.7.F.50.i；A.9.F.50.i；A.100.F.50.i；
A.101.F.50.i；A.102.F.50.i；A.103.F.50.i；A.104.F.50.i；A.105.F.50.i；A.106.F.50.i；
A.107.F.50.i；A.108.F.50.i；A.109.F.50.i；A.110.F.50.i；A.111.F.50.i；A.112.F.50.i；
A.113.F.50.i；A.114.F.50.i；A.115.F.50.i；A.116.F.50.i；A.117.F.50.i；A.118.F.50.i；
A.119.F.50.i；A.120.F.50.i；A.121.F.50.i；A.122.F.50.i；A.123.F.50.i；A.124.F.50.i；
A.125.F.50.i；A.126.F.50.i；A.127.F.50.i；A.128.F.50.i；A.129.F.50.i；A.130.F.50.i；
A.131.F.50.i；A.132.F.50.i；A.133.F.50.i；A.134.F.50.i；A.135.F.50.i；A.136.F.50.i；
A.137.F.50.i；A.138.F.50.i；A.139.F.50.i；A.140.F.50.i；A.141.F.50.i；A.2.F.51.i；
A.3.F.51.i；A.4.F.51.i；A.5.F.51.i；A.7.F.51.i；A.9.F.51.i；A.100.F.51.i；A.101.F.51.i；
A.102.F.51.i；A.103.F.51.i；A.104.F.51.i；A.105.F.51.i；A.106.F.51.i；A.107.F.51.i；
A.108.F.51.i；A.109.F.51.i；A.110.F.51.i；A.111.F.51.i；A.112.F.51.i；A.113.F.51.i；
A.114.F.51.i；A.115.F.51.i；A.116.F.51.i；A.117.F.51.i；A.118.F.51.i；A.119.F.51.i；
A.120.F.51.i；A.121.F.51.i；A.122.F.51.i；A.123.F.51.i；A.124.F.51.i；A.125.F.51.i；
A.126.F.51.i；A.127.F.51.i；A.128.F.51.i；A.129.F.51.i；A.130.F.51.i；A.131.F.51.i；
A.132.F.51.i；A.133.F.51.i；A.134.F.51.i；A.135.F.51.i；A.136.F.51.i；A.137.F.51.i；
A.138.F.51.i；A.139.F.51.i；A.140.F.51.i；A.141.F.51.i；
Salts and hydrates
The compositions of the invention optionally contain a salt of a compound herein, particularly a pharmaceutically acceptable non-toxic salt containing, for example, Na+，Li+，K+，Ca++With Mg++. Such salts may also include those derived from a combination of an appropriate cation (such as an alkali metal ion, alkaline earth metal ion or ammonium ion with a quaternary amino ion) and an acid anion moiety (typically W)1Carboxylic acid). If expected to be water-solubleThe salt is preferably a monovalent salt.
Typically, metal salts are prepared by reacting a metal hydroxide with a compound of the invention. Examples of metal salts prepared in this way are those containing Li+，Na+And K+A salt. The addition of an appropriate metal compound from a solution of a more soluble salt precipitates the less soluble metal salt.
In addition, it is also possible to add an acid to the basic center (preferably G)1Amines) or to acidic groups (e.g. E)1) To form salts, e.g., certain organic and inorganic acids (e.g., HCl, HBr, H)2SO4) Or an organic sulfonic acid. Finally, it is to be understood that the compositions herein include the compounds of the present invention in undissociated, or zwitterionic form, or in the case of hydrates, mixed with stoichiometric amounts of water.
Also included within the scope of the invention are salts of the parent compounds with one or more amino acids. Any of the above amino acids is suitable, particularly naturally occurring amino acids as protein components, but the amino acid is preferably an amino acid having a side chain containing a basic or acidic group, such as lysine, arginine or glutamic acid, or an amino acid having a neutral group, such as glycine, serine, threonine, alanine, isoleucine or leucine.
Method for inhibiting neuraminidase
Another aspect of the present invention relates to a method for inhibiting neuraminidase activity which comprises the step of treating a sample which may contain neuraminidase with a compound of the invention.
The composition of the invention is used as an inhibitor of neuraminidase, an intermediate of the inhibitor or has the following application. The inhibitor binds to a site on the surface of neuraminidase or in a cavity (the site having a structure unique to neuraminidase only). The binding of the composition to neuraminidase is reversible to varying degrees. Those compounds which bind substantially irreversibly are desirable materials for use in the methods of the invention. Once labeled, the substantially irreversibly bound composition can be used as a probe for detecting neuraminidase. Accordingly, the present invention relates to a method for detecting neuraminidase in a sample which may contain neuraminidase, comprising the steps of: treating a sample, which may contain neuraminidase, with a composition containing a compound of the invention bound to a label (label); the efficacy of the test sample on the activity of the marker was observed. Suitable labels are well known in the diagnostic arts and include stable free radicals, fluorophores, radioisotopes, enzymes, chemiluminescent groups and chromophores. The compounds herein are labeled with functional groups (e.g., hydroxyl or amino) in a conventional manner.
In the present invention, the sample which may contain neuraminidase includes natural or artificial materials such as a living body; tissue or cell culture; biological samples, such as biomass samples (blood, serum, urine, cerebrospinal fluid, tears, sputum, saliva, tissue samples, etc.); a laboratory sample; food, water or air samples; biological samples, such as cell extracts, particularly recombinant cells (which synthesize the desired glycoprotein), and the like. Typically, the possible samples will contain organisms that produce neuraminidase, usually pathogenic organisms, such as viruses. The sample may be contained in any medium containing water and an organic solvent/water mixture. The sample comprises a living organism, such as a human or an artificial substance, such as a cell culture.
The treatment step of the present invention comprises adding the composition of the present invention to the sample, or adding a precursor of the composition to the sample. This addition step includes any of the above-described methods of application.
If desired, the activity of neuraminidase after administration of the composition can be observed by any method, including direct and indirect neuraminidase assays. Quantitative, qualitative and semi-quantitative neuraminidase activity assays are available. Typically, any of the above screening methods is used, but any other method may be used, for example, observation of a physiological property of a living body.
Neuraminidase-containing organisms include bacteria (Vibrio cholerae, Clostridium perfringens, Streptococcus pneumoniae and Arthrobacter sialophilus) and viruses (particularly orthomyxoviruses or paramyxoviruses such as influenza A and B, parainfluenza, mumps, Newcastle disease, fowl plague, and sendai). Inhibition of neuraminidase activity occurring or found in these organisms is within the scope of the present invention. Virology for influenza viruses is described in "Fundamental Virology" (Raven Press, New York, 1986), chapter 24. The compounds of the invention are useful for treating or preventing such infections in animals or humans, such as ducks, rodents or pigs.
However, when screening compounds that inhibit influenza virus, it should be kept in mind that the results of the enzyme assay do not necessarily correspond to the results of the cell culture assay, as in Chandler et al,same as aboveTable 1 below. Therefore, a spot reduction analysis (plaque reduction assay) should be used as a main screening method.
Screening of neuraminidase inhibitors
The inhibitory activity of the compositions of the present invention against neuraminidase is screened by any technique conventionally used to assess enzyme activity. In this context, compositions are typically screened for inhibition of neuraminidase in vitro, compositions with inhibitory activity are screened for in vivo activity. Ki (inhibition constant) of less than about 5X 10 in vitro -6M, preferably less than about 1X 10-7M, more preferably less than about 5X 10-8The compositions of M, are preferred for in vivo use.
Useful in vitro screens have been described in detail and are not described in detail herein.
Itzstein, m.von et al; "Nature", 363 (6428): 418-423(1933), especially from column 2, column 3, page 420, to column 2, column 1, page 421, which describes Potier m. et al; "analyt. biochem.", 94: 287-296(1979), Chong, A.K.J., et al; "biochem. biophysis. acta", 1077: 65-71(1991), and further, WO 92/06691(int. App. No. PCT/AU90/00501, published 1992, 4/30) by Colman, P.M. et al, page 34, line 13 to page 35, line 16, illustrates another useful in vitro screening method.
In vivo screening methods have also been detailed, see Itzstein, m.von et al; as mentioned above, especially page 421, column 2, full 1, to page 423, column 2, paragraph 1, and Colman, p.m. et al; page 36, lines 1-38, which illustrate suitable in vitro screening methods, as described above.
Pharmaceutical formulations and routes of administration
The compounds of the invention are formulated with conventional carriers and excipients selected in accordance with common practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form and, if intended for non-oral use, are generally isotonic. All formulations optionally contained Excipients such as those described in "Handbook of Pharmaceutical Excipients" (1986). Excipients include ascorbic acid and other antioxidants, such as chelating agents like ED-TA, carbohydrates, such as dextrin, hydroxyalkyl cellulose, hydroxyalkyl methyl cellulose, stearic acid, and the like. The pH of these formulations is about 3 to 11, but is typically about 7 to 10.
One or more compounds of the present invention (referred to herein as the active ingredient) are administered by a route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. There are different preferred routes depending on the condition of the recipient. The advantage of the compounds of the invention is their oral bioavailability and can therefore be administered orally, without having to go via the intrapulmonary or intranasal route. Surprisingly, the anti-influenza compounds of WO 91/16320, WO 92/06691 and us 5360817 can be successfully administered orally or intraperitoneally. See example 161, infra.
Although the active ingredient may be used alone, it is preferably used in a pharmaceutical formulation. The formulations of the invention, for veterinary or human use, comprise at least one active ingredient as defined above, together with one or more acceptable carriers and any other therapeutic ingredients. The carrier must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
Formulations include those suitable for the foregoing routes of administration, preferably in unit dosage form, which may be prepared by any of the methods well known in the pharmaceutical arts. These techniques and formulations are generally known from Remington's pharmaceutical-cal Sciences (Mack Publishing co., Easton, PA). These methods include the step of bringing into association the active ingredient with the carrier (which constitutes one or more accessory ingredients). The formulations are generally prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.
Formulations of the present invention suitable for oral administration are presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; a powder or granules; solutions or suspensions (in aqueous or non-aqueous liquids); an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may be in the form of a bolus, electuary or paste.
Tablets are made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets were made as follows: the active ingredient (e.g., powder or granules) is compacted in a free-flowing form in a suitable machine, optionally mixed with a binder, lubricant, inert diluent, preservative, surfactant or dispersant. Molded tablets are prepared by molding, in a suitable machine, a mixture of the active ingredient which is powdered and moistened with an inert liquid diluent. These tablets may optionally be coated or scored and optionally formulated so as to provide slow or controlled release of the active ingredient therein.
For infections of the eye or other external tissues (e.g. mouth or skin), it is preferably used as a topical ointment or cream containing, for example, 0.075 to 20% W/W of active ingredient (including 0.1% to 20% active ingredient in increments of 0.1% W/W, such as 0.6% W/W, 0.7% W/W, etc.), preferably 0.2 to 15% W/W, most preferably 0.5 to 10% W/W. When formulated into an ointment, the active ingredient may be used in combination with either a paraffin or water-miscible ointment base. In addition, the active ingredient can be formulated with an oil-in-water cream base to form a cream.
If desired, the aqueous phase of the cream base may comprise, for example, at least 30% W/W of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups, for example, propylene glycol, butane-1, 3-diol, mannitol, sorbitol, glycerol and polyethylene glycols (including PEG 400) and mixtures thereof. The topical formulations preferably contain compounds that enhance the absorption or penetration of the active ingredient through the skin or other damaged areas. Examples of such transdermal penetration enhancers include dimethyl sulfoxide and related analogs.
The oil phase of the emulsions of the invention may be composed of known ingredients in known manner. Although this phase may comprise only emulsifiers, it is preferred to comprise a mixture of at least one emulsifier with a fat or oil (or both a fat and an oil). Preferably, a hydrophilic emulsifier is used in combination with a lipophilic emulsifier (as a stabilizer). It is also preferred to include both oils and fats. Emulsifiers, with or without stabilizers, constitute the so-called emulsifying waxes, while waxes with oils and fats constitute the so-called emulsifying ointment base, which forms the oily dispersed phase of the cream.
Emulsifiers and emulsion stabilizers suitable for use in the formulations of the present invention includeCetostearyl alcohol, benzyl alcohol, myristyl alcohol, glycerol monostearate and sodium lauryl sulfate.
The oils or fats to which the formulation is applied are selected according to the desired cosmetic properties. Creams are preferably non-greasy, non-staining and washable products with a suitable consistency without leaking out of tubes or other containers. Straight or branched chain, mono-or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or mixtures of branched chain esters (such as Crodamol CAP) may be used, the latter three being preferred esters. Depending on the desired properties, they may be used individually or in combination. In addition, high melting point grease such as white soft paraffin and/or liquid paraffin or other mineral oil can be used.
Formulations suitable for topical application to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent thereof. The concentration of the active ingredient is preferably from 0.5 to 20% w/w, more preferably from 0.5 to 10%, most preferably about 1.5%.
Formulations suitable for topical use in the mouth include: lozenges comprising the active ingredient in a flavoured base, usually sucrose, acacia and tragacanth; pastilles comprising the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.
Rectal formulations may be in the form of suppositories with which suitable bases include, for example, cocoa butter or a salicylate.
The intrapulmonary or nasal formulation has a particle size of, for example, 0.1 to 500 microns (including particle sizes in the range of 0.1 to 500 microns, in increasing combinations, e.g., 0.5, 1, 30 microns, 35 microns, etc.), which is rapidly inhaled through the nasal passages or inhaled through the mouth to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for administration as aerosols or dry powders may be formulated according to conventional methods and may be administered with other therapeutic agents, such as the compounds previously described for the treatment or prevention of influenza a or B infection.
Formulations for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray compositions containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffering substances, bacteriostatic substances and solutes which render the formulation isotonic with the blood of the recipient; aqueous and non-aqueous sterile suspensions which may contain suspending agents and thickening agents.
These formulations are presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials, and may be stored in a freeze-dried condition requiring only the addition of the sterile liquid carrier, for example, water for injections, prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules or tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit of daily sub-doses (as hereinbefore described) or an appropriate sub-amount thereof of the active ingredient.
It will be appreciated that in addition to the ingredients particularly mentioned above, the formulations of the present invention may contain other agents commonly used in formulations having regard to the type of formulation in question, for example, oral formulations may contain flavouring agents.
The invention also provides a veterinary composition comprising at least one of the above active ingredients and a veterinary carrier.
Veterinary carriers are substances used for administering the composition, and may be solid, liquid or gaseous substances, inert or veterinarily acceptable, and compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by other desired routes.
The compounds of the present invention are useful for providing controlled release pharmaceutical formulations (controlled release formulations) containing one or more compounds of the present invention as active ingredients, wherein the release of the active ingredient is controlled and regulated without frequent administration or to modify the pharmacokinetic or toxicity properties of the active ingredient.
The effective dose of the active ingredient depends at least on the following factors: the nature of the condition to be treated, the toxicity, whether the compound is used prophylactically (at lower doses) or therapeutically active influenza infection, the method of administration, and the pharmaceutical formulation, which can be determined by the physician in accordance with routine dose modification studies. It is contemplated that the dosage will be about 0.0001 to 100mg/kg body weight/day, preferably about 0.01 to 10mg/kg body weight/day, more preferably about 0.01 to 5mg/kg body weight/day, and most preferably about 0.05 to 0.5mg/kg body weight/day. For example, an adult weighing about 70kg in one body, when administered by inhalation, has a daily dose of 1mg to 1000mg, preferably 5mg to 500mg, and can be administered in single or multiple doses.
The active ingredients of the present invention may also be used in combination with other active ingredients. The combination will depend on the condition to be treated, the cross-reactivity between the ingredients and the pharmacological properties of the combination. For example, when used to treat viral infections of the respiratory system, particularly influenza infections, the compositions of the present invention may be used in combination with antiviral agents (e.g., amantadine, rimantadine, and ribavirin), mucolytic agents, expectorants, bronchodilators, antibiotics, antipyretics, or analgesics. Generally, antibiotics, antipyretics and analgesics are administered in conjunction with the compounds of the present invention.
Metabolites of the compounds of the invention
In vivo metabolites of the compounds herein are also within the scope of the present invention, provided such products are novel and unobvious to the prior art. Such products can result from, for example, oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic processes. The present invention thus includes novel and unobvious compounds made by the following process: the metabolites of the compounds of the present invention can be produced by contacting the compounds with a mammal for a period of time. Typically, by first preparing a radiolabel (e.g., C)14Or H3) The compounds of the invention are administered parenterally to an animal (e.g., rat, mouse, guinea pig, monkey) or human at detectable doses (e.g., generally greater than about 0.5mg/kg) and after a sufficient period of metabolism has occurred (typically about 30 seconds to 30 hours), their conversion products are isolated from urine, blood or other biological samples. These products are easily separated because they are labeled (others use antibodies that bind to epitopes remaining in the metabolitesBut separated out). The structure of the metabolites is determined in a conventional manner, e.g., by MS or NMR analysis. Typically, analysis of metabolites is performed in a conventional manner of drug metabolism studies well known in the art. The conversion product, if not found elsewhere in the body, even if not itself having neuraminidase inhibitory activity, can be used in diagnostic assays for the treatment of the compounds of the invention.
Further uses of the compounds of the invention
The compounds of the invention, or their biologically active substances produced by in vivo hydrolysis or metabolism, can be used as immunogens or for conjugation to proteins, i.e., as components of immunogenic compositions to produce antibodies that specifically bind to the protein, the compound or its metabolites that retain the immunogenically recognized epitope (antibody binding site). The immunogenic composition is therefore useful as an intermediate in the preparation of the antibody (for use in methods or assays such as diagnostics, quality control, etc. of the compound or novel metabolite thereof). The compounds can be used to generate antibodies against other non-immunogenic polypeptides, at which time the compounds act as hapten sites, stimulating an immune response that cross-reacts with the unmodified conjugated protein.
Preferred hydrolysates include the products of hydrolysis of the protected acidic and basic groups described above. As noted above, acidic or basic amides containing immunogenic polypeptides (e.g., albumin, keyhole limpet-immobilized hemocyanin) are commonly used as immunogens. The above metabolites may retain a significant degree of immunological cross-reactivity with the compounds of the present invention. The antibodies of the invention can bind to unprotected compounds of the invention and not to protected compounds; in addition, in the presence of metabolites, the antibody may bind to the protected compound and/or metabolite, but not to the protected compound of the invention, or may specifically bind to one or all three thereof. The antibody is expected to be substantially non-cross-reactive with the native material. Substantial cross-reactivity refers to reactivity under specific analytical conditions for a specific analyte sufficient to interfere with the analytical results.
Immunogens of the present invention include compounds of the present invention that provide an epitope, to which an immunogenic substance is conjugated. As used herein, binding means covalent binding to form an immunogenic conjugate (where appropriate) or a mixture of non-covalently bound substances, or a combination thereof. Immunogenic substances include auxiliary substances, such as Freund's auxiliary substance, immunogenic proteins, such as viruses, bacteria, yeast, plant and animal polypeptides, in particular hemocyanin fixed in keyhole limpet, serum albumin, bovine thyroglobulin or soybean trypsin inhibitor and immunogenic polysaccharides. Typically, compounds having the desired epitope structure are covalently conjugated to the immunogenic polypeptide or polysaccharide by means of a multifunctional (usually difunctional) cross-linking agent. The process of preparing hapten immunogens is common per se and any process previously used to conjugate haptens to immunogenic polypeptides and the like is also suitable for this, taking into account the functional groups on the parent or hydrolysate which can be used for cross-linking and the possibility of producing antibodies specific for the epitope (as opposed to the immunogenic material).
Typically, the polypeptide is conjugated to a position of the compound of the invention remote from the epitope to be recognized.
The conjugate is prepared by a conventional method. For example, the conjugates of the invention may be prepared using a crosslinking agent such as N-hydroxysuccinimide, succinic anhydride or alkyl-N ═ C ═ N-alkyl. The conjugate comprises a compound of the invention having a bond or C1-C100(preferably, C)1-C25Preferably, C1-C10) The linker is attached to the immunogenic agent. The conjugate is separated from the starting material and by-products by chromatography, etc., and then sterile filtered, bottled and stored.
The compounds of the invention are crosslinked by any one or more of the following groups, for example, U1Hydroxy group of (E)1Carboxyl group of (5), U1，E1，G1Or T1Carbon atom (substituted H) of (a); g1The amine group of (1). This classThe compounds also include amides of the polypeptides which act as R as described above6cOr R6bA group.
Typically, the animal is immunized against the immunogenic conjugate or derivative and an antiserum or monoclonal antibody prepared in a conventional manner.
The compounds of the invention are useful for maintaining the structural integrity of glycoproteins in recombinant cell culture, i.e., they are added to fermentations with glycoprotein production to inhibit neuraminidase-catalyzed cleavage of the desired glycoprotein. This is particularly useful for protein recombination in heterologous host cells, which degrade the carbohydrate portion of the synthesized protein.
The compounds of the present invention are multifunctional. It can be used as a special monomer in polymer synthesis. By way of example, and not limitation, polymers made from the compounds of the present invention include polyamides and polyesters.
The compounds of the present invention are useful as monomers to make polymers with unique pendant functional groups, which can be used in homopolymers, or as comonomers that are copolymerized with monomers not within the scope of the present invention. The homopolymer formed by the compound of the invention has the following application: as cation exchangers (polyesters or polyamides) in the preparation of molecular sieves (polyamides), fabrics, fibers, membranes, moldings, etc., in which the acid function E is1Quilt U1In (b) is esterified, thus the side chain basic group G1Can be combined with an acidic functional group, for example, an acidic functional group in the polypeptide to be purified. The polyamide is composed of E1And G1Is cross-linked to form and U1The moiety adjacent to the ring may be free as a hydrophilic or hydrophobic group (depending on the choice of U)1And thus) are used. The process for preparing polymers from the compounds according to the invention is known per se.
The compounds of the present invention also serve as a unique class of multifunctional surfactants. Especially when U is1When the compound does not contain a hydrophilic substituent and is, for example, an alkyl group or an alkoxy group, the compound has the property of a bifunctional surfactant. They are originally It has useful interfacial activity, surface coating, emulsion modification, rheology modification and surface wetting properties.
When having a specific structure with both polar and non-polar moieties, the compounds of the present invention can serve as a unique class of phase transfer agents. By way of example, and not limitation, the compounds of the present invention may be used in phase transfer catalysis and liquid/liquid ion extraction (LIX).
Compounds of the invention in the group U1，E1，G1And T1Optionally containing asymmetric carbon atoms, in which case it may be a unique class of chiral auxiliary agents used in the synthesis or resolution of other optically active substances. For example, a racemic mixture of carboxylic acids can be resolved into its enantiomers by the following method: 1) with a compound of the invention (wherein U1Asymmetric hydroxyalkyl or aminoalkyl) to form a mixture of diastereomeric esters or amides; 2) separating the diastereomers; 3) the ester structure is hydrolyzed. Racemic alcohols are then substituted by E1The acid group of (a) is isolated as an ester. In addition, this method is also used to resolve the compounds of the invention themselves if the optically active acid or alcohol is used instead of the racemic starting material.
The compounds of the invention may be used as linkers or spacers in the preparation of affinity matrices, immobilized enzymes for process control, or immunoassay reagents. The compounds herein contain multiple functional groups as sites for crosslinking the desired species. For example, it is customary to bond affinity agents, such as hormones, peptides, antibodies, drugs, etc., to insoluble substrates. The insoluble reagent is then used in a known manner to absorb the binding partner of the affinity reagent from the preparation, diagnostic sample or other impure mixture. Similarly, immobilized enzymes are used for catalytic conversion and the enzymes can be easily recovered. In preparing diagnostic reagents, bifunctional compounds are typically used to attach an analyte to a detectable group.
Many functional groups in the compounds of the present invention may be used for crosslinking. E.g. E1The carboxylic or phosphonic acid groups of (a) can form esters or amides, respectively, with the alcohol or amine of the agent to be crosslinked. Suitable positions are via OH, NHR1，SH，Azido (which may be reduced to amino groups before crosslinking if desired), CN, NO2G substituted by amino, guanidino, halogen, etc1Location. To prevent the bifunctional compound of the present invention from polymerizing when reacted with a crosslinking agent, the reactive group may be appropriately protected. Typically the compounds herein are bound via a carboxylic or phosphonic acid to a hydroxy or amino group on a first binding partner followed by T1Or G1Covalently bound to other binding partners. For example, a first binding partner (e.g., a steroid hormone) is esterified with a carboxylic acid of a compound of the invention, and the conjugate is then conjugated with G1The hydroxyl group was crosslinked to Sepharose (trade name of Sepharose) activated with cyanogen bromide, thus obtaining an immobilized steroid. Other conjugation chemistries are known. Reference is made, for example, to Maggio, "Enzyme-Immunoas-say" (CRC, 1988, pages 71-135) and to the references cited therein.
As indicated above, the therapeutically useful compounds of the present invention (wherein W1Or G1Hydroxy, carboxy or amino protected) can be made into oral or sustained release dosage forms. In these applications, the protection is based on the removal (e.g., hydrolysis or oxidation) in vivo to produce free carboxyl, amino or hydroxyl groups. Esters or amides suitable for this purpose depend on the matrix specificity of the esterase and/or carboxypeptidase enzymes that are expected to be found in cells in which precursor hydrolysis is carried out. If the specificity of the enzyme is unknown, a number of compounds of the invention can be screened until the desired substrate specificity is found. This can be seen from the appearance or antiviral activity of the free compound. The amides or esters of the compounds of the invention are generally selected according to the following two principles: (i) not hydrolyzed or slowly hydrolyzed in the upper intestinal tract, (ii) intestinal and cell permeability, and (iii) hydrolysis in the cytosol and/or systemic circulation. Cells from a particular tissue (susceptible to influenza infection), such as the lung bronchial mucosa, are preferably used in the screening assay. Assays known in the art can be used to determine in vivo bioavailability, including gut lumen stability, cell permeability, liver homogenate stability and plasma stability assays. However, even if the ester, amide or other protected derivative is not converted in vivo to a free carboxyl, amino or hydroxyl group, it is still a useful chemical intermediate.
Exemplary methods of making the Compounds of the invention
The invention also relates to a process for making the composition of the invention. The composition is made by any suitable technique of organic synthesis. Many such techniques are known in the art, many of which are detailed in: "Complex of Organic Synthetic Methods" (John Wiley & Sons, New York), Vol.1, Ian T.Harrison and Shuyen Harri-son, 1971; vol 2, Ina t.harrison and Shuyen Harrison, 1974; vol.3, Louis S.Hegedus and Leroy Wade, 1977; vol.4, leroyg.wade, jr., 1980; vol.5, Leroy g.wade, jr., 1984; andVol.6 Michael B.Smith; and March, J., "Advanced Organic chemistry, Third Edition," (John Wiley & Sons, New York, 1985), "Comprehensive organic.Synthesis.Selectivity, Strategy & Efficiency in model Organic chemistry.In 9 Volumes", BarryM.Trost, Edition-in-Chief (Pergamon Press, New York, 1993).
Exemplary methods of preparing the compositions of the present invention are set forth below for the purpose of illustrating the nature of these preparations and not for the purpose of limiting same.
Generally, reaction conditions such as temperature, reaction time, solvents, processing steps, and the like are well known in the art for the particular reaction to be carried out. The cited references, including those cited therein, contain a detailed description of these conditions. Typically, the temperature is from-100 ℃ to 200 ℃, the solvent is an aprotic or protic solvent, and the reaction time is from 10 seconds to 10 days. The treatment mainly comprises the following steps: any unreacted reagents are discontinued and then distributed in a water/organic layer system (extraction) and the product-containing layer is separated.
The oxidation and reduction reactions are typically carried out at temperatures near room temperature (about 20℃.), however, when reducing with metal hydrides, the temperature is typically lowered to 0℃ to-100℃, the reducing solvent is mostly aprotic, and the oxidation can be protic or aprotic. The reaction time was adjusted to achieve the desired conversion.
The condensation reaction is typically carried out at temperatures close to room temperature, however for non-equilibrium, kinetically controlled condensation, reduced temperatures (0 ℃ to-100 ℃) are typically useful. The solvent may be protic (as is common in equilibrium reactions) or aprotic (as is common in kinetic control reactions).
Standard synthetic techniques, such as azeotropic removal of reaction by-products and the use of anhydrous reaction conditions (e.g., inert gas environment) are common in the art and may be used where applicable.
An exemplary method for preparing the compounds of the present invention is shown in scheme 1 below. The details of which are described in the "experiment" section below.
Reaction scheme 1
Modified variations of reaction scheme 1 to form additional embodiments are shown in reaction schemes 2-4.
Reaction scheme 2
Reaction scheme 2
By Utimoto and co-workers, "Tetrahedron letter", 31: 6379(1990) procedure aziridine 5 in Yb (CN) 3Catalytic addition of TMSCN to the aminonitrile 9.
Conversion of nitrile 9 to the corresponding amidine 10 was accomplished using a standard three-step procedure: i) h2S，ii)CH3I，iii)NH4And OAc. In "j.med.chem.", 36: 1811(1993) a typical transformation can be found.
Nitrile 9 can be reduced to aminomethyl compound 11 by any of the methods described in "Modern Synthetic Reactions", second edition, H.O.House, Benjamin/Cummings Publishing Co., 1972.
Aminomethyl compound 11 was purified via N, N' -di-Boc-1H-pyrazole-1-carboxyformamidine as described by "Tetrahedron lett," 36: 299(1995) to convert to di-Boc protected guanidino compound 12.
Reaction scheme 3
Reaction scheme 3
Opening of aziridine 5 with tert-butyl α -cyanoacetate gave 13. This type of aziridine ring opening reaction is referred to as "Tetrahedron lett", 23: 5021(1982). The tert-butyl ester is selectively partially hydrolyzed under acidic conditions, followed by decarboxylation, to give the nitrile 14.
The reduction of 14 to the aminoethyl derivative 15 is accomplished in the same manner as the conversion of 9 to 11. Amine 15 was then reacted with N, N' -di-Boc-1H-pyrazole-1-carboxyformamidine as described by "Tetrahedron lett.", 36: 299(1995) to guanidino derivatives 16.
The nitrile 14 is converted to the corresponding amidine 17 in the same procedure as described above for the conversion of 9 to 10.
Reaction scheme 4
Reaction scheme 4
Epoxy alcohol 1 is protected (PG ═ protecting group), for example with MOMCl. Exemplary conditions can be found in "Protective Groups in Organic Synthesis" second edition, T.W.Greene and P.G.M.Wuts, John Wiley & Sons, New York, NY, 1991.
Epoxide 19 was prepared according to Sharpless and co-workers "J.org.chem.", 50: 1557(1985) step with NaN3/NH4The Cl is ring opened to amino alcohol 20.
The reduction of 20 to N-acetyl aziridine 21 is accomplished in three steps as follows: 1) MsCl/triethylamine; 2) h2Pd; 3) AcCl/pyridine. Such transformations may be referred to "angelw.chem.int.ed.engl.", 35: 599(1994).
Aziridine 21 in DMF at 65 ℃ with NaN3/NH4Cl is converted to the azidoamide 22 by ring opening as described in "J.chem.Soc.Perkin Trans I", 801 (1976).
The MOM protecting group of 22 was removed by the method described in "Protective Groups in Organic Synthesis" second edition, T.W.Greene and P.G.M.Wuts, John Wiley & Sons, New York, NY, 1991. The resulting alcohol is directly converted to aziridine 24 in pyridine with TsCl. Such transformations may be found in "Angew. chem. int. Ed. En-gl.", 33: 599(1994).
Then reacting aziridine 24 with ROH, RNH2RSH or organometallic (metal-R) reactions give the corresponding ring-opened derivatives 25, 26, 27 and 27.1, respectively. Such aziridine ring opening is described in reference to "Tetrahedron lett.", 23: 5021(1982) and "angelw.chem.int.ed.engl.", 33: 599(1994).
Reaction scheme 5
Another class of compounds of the present invention is prepared by the methods of reaction schemes 5a and 5 b. In the case of shing.T.K.M. et al, "Tetrahedron", 47 (26): 4571(1991) converts cinchona acid to 28. In TEA/CH2Cl2Mesylation with MsCl gave 29, 29 in DMF and NaN3The reaction gave 30. 30 in CH2Cl2Reaction with TFA gave 31, 31 in TEA/CH2Cl2Mesylation with MsCl gave 32. With triphenylphosphine in waterReaction gives 33, which in turn applies 1) CH in pyridine3C (O) Cl; 2) NaN in DMF3(ii) a And 3) conversion to 35 by treatment with NaH in THF. Alkylation of 35 with various nucleophiles known in the art yields a number of compounds such as 36. Methods for converting a compound according to 36 into other embodiments of the invention are described above.
Reaction scheme 5a
Reaction scheme 5b
Reaction scheme 6
Reaction scheme 6
Another class of compounds of the present invention is prepared by the method of reaction scheme 6. Protected alcohol 22(PG ═ methoxy methyl ether) is described in e.g. "Protective Groups in Organic Synthesis" second edition, T.W.Greene and P.G.M.Wuts, John Wiley&Sons, New York, NY, 1991Standard conditions were left unprotected. Alcohol 51 was converted to acetate 52 using acetic anhydride and pyridine under standard conditions. Acetate 52 with TMSOTf or BF 3·OEt2Treatment gave oxazoline 53. Such transformations may be referred to as "Liebigs Ann. chem." 129(1991) and "Carbohydrate Research", 181(1993), respectively. Alternatively, alcohol 51 can be converted to oxazoline 53 as follows: first converted to the corresponding mesylate or tosylate 23, followed by cyclization to the oxazoline under standard conditions, such as "j.org.chem.", 50: 1126(1985) and "J.chem.Soc.", 1385 (1970). Oxazoline 53 with ROH, RR 'NH or RSH (wherein R and R' are as defined above for W)6Consistent with the definition of) gives the corresponding ring-opened derivatives 54, 55 and 56, respectively. Such transformations may be referred to as "j.org.chem.", 49: 4889(1984) and "chem.rev.", 71: 483(1971).
Reaction schemes 7-35
Other exemplary methods for preparing the compounds of the present invention are shown in reaction schemes 7-35 below. Details of these methods are described in the "experimental" section below.
Reaction scheme 7a
Reaction scheme 7b
Reaction scheme 7c
Reaction scheme 8
Reaction scheme 9
Reaction scheme 10
Reaction scheme 11
Reaction scheme 12
Reaction scheme 13
Reaction scheme 14
Reaction scheme 15a
Reaction scheme 15b
Reaction scheme 16
Reaction scheme 17
Reaction scheme 18
Reaction scheme 19
Reaction scheme 20
Reaction scheme 21
Reaction scheme 22
Reaction scheme 23
Reaction scheme 24
Reaction scheme 25
Reaction scheme 26
Reaction scheme 27
Reaction scheme 28
Reaction scheme 29
Reaction scheme 30
Reaction scheme 31
Reaction scheme 32
Reaction scheme 33
Reaction scheme 34
Reaction scheme 35
Reaction scheme 36
Reaction scheme 37
Reaction scheme 38
Reaction scheme 39
Reaction scheme 40
Reaction scheme 40.1
Additional embodiments for making and using the compositions of the present invention are shown in reaction schemes 36-40.1. One aspect of the present invention pertains to a process for preparing a compound of the present invention comprising method A, B, C, D, E, F, G, H, I, J, K.L, M.N, O, P, Q, R, S, T, U, V or W (alone or in combination with each other) of reaction scheme 36-40.1. Table 27 shows specific examples of the exemplary methods A to W. Each specific example is a single method using the unit methods A to W (alone or in combination). In Table 27, each method is given by a semicolon "; "separate. A single letter corresponds to one of methods a-W if the embodiment is a single letter, or to each method and in the order shown if there is more than one letter.
In another aspect, the invention relates to a method for preparing compound 270 using shikimic acid (as shown in a in scheme 36), a method for preparing compound 271 using compound 270 (as shown in B in scheme 36), a method for preparing compound 272 using compound 271 (as shown in C in scheme 36), a method for preparing compound 273 using compound 272 (as shown in D in scheme 36), a method for preparing compound 274 using quinic acid (as shown in E in scheme 37), a method for preparing compound 275 using compound 274 (as shown in F in scheme 37), a method for preparing compound 276 using compound 275 (as shown in G in scheme 37), a method for preparing compound 272 using compound 276 (as shown in H in scheme 37), a method for preparing compound 277 using compound 273 (as shown in I in scheme 38), a method for preparing compound 278 using compound 277 (as shown by J in reaction scheme 38), a method for preparing compound 279 using compound 278 (as shown by K in reaction scheme 38), a method for preparing compound 280 using compound 279 (as shown by L in reaction scheme 38), a method for preparing compound 281 using compound 280 (as shown by M in reaction scheme 38), a method for preparing compound 282 using compound 281 (as shown by N in reaction scheme 39), a method for preparing compound 283 using compound 282 (as shown by O in reaction scheme 39), a method for preparing compound 284 using compound 283 (as shown by P in reaction scheme 39), a method for preparing compound 285 using compound 283 (as shown by Q in reaction scheme 40), a method for preparing compound 286 using compound 285 (as shown by R in reaction scheme 40), a method for preparing compound 288 using compound 287 (as shown by S in reaction scheme 40.1), a method for preparing compound 289 using compound 288 (as shown by T in scheme 40.1), a method for preparing compound 290 using compound 289 (as shown by U in scheme 40.1), a method for preparing compound 291 using compound 290 (as shown by V in scheme 40.1), a method for preparing compound 292 using compound 291 ((as shown by W in scheme 40.1)).
The general contents of these exemplary methods are described below in the examples. The products of the processes described below are optionally separated, isolated and/or purified before being used in the next process.
The term "treating" refers to contacting, mixing, reacting, contacting, and other terms commonly used in the art to denote the conversion of one or more chemical entities into one or more other chemical entities by treatment. Thus "treating compound 1 with compound 2" is synonymous with: "reacting compound 1 with compound 2", "compound 1 in contact with compound 2", "compound 1 reacted with compound 2" and other organic syntheses are used generically to indicate that compound 1 is "treated" with compound 2 or "reacted" with compound 2.
"treating" means a reasonable and general way of reacting organic chemicals. Unless otherwise specified, normal concentrations (0.01M to 10M, preferably 0.1M to 1M), temperatures (-100 ℃ to 250 ℃, preferably-78 ℃ to 150 ℃, more preferably-78 ℃ to 100 ℃, most preferably 0 ℃ to 100 ℃), reaction vessels (preferably glass, plastic, metal), solvents, pressures, atmospheres (preferably air when not sensitive to oxygen and water, and nitrogen or argon when sensitive to oxygen and water), and the like are referred to. Knowledge of similar reactions known in the art of organic synthesis can be used to select the conditions and equipment used for "processing" in a given process. In particular, the person generally familiar with organic synthesis techniques selects, based on knowledge known in the art, the conditions and apparatuses which are expected to allow the chemical reactions of the process to be carried out successfully.
Method A, reaction scheme 36
Compound 270 is prepared from shikimic acid in the following manner.
The cis-4, 5-diol function of shikimic acid can be made different from the carboxylic acid group on carbon 1 by selectively protecting both. Typically, the cis-4, 5-diol functional group is protected with a cyclic ketal and the carboxylic acid group is protected with an ester.
R501, 2-diol protecting groups which are susceptible to acid decomposition, such as those described in the Greene's work cited above, are typically cyclic ketals or acetals, more preferably ketals of cyclohexanone or acetone. R51Are acid-stable carboxylic acid protecting groups, such as those described in Gereene, cited below, typically linear, branched or cyclic C1-C12Alkyl, alkenyl or alkynyl groups, such as the groups 2-7, 9-10, 15 or 100-660 as shown in Table 2, preferably linear or branched C1-C8Alkyl, as in the groups 2-5, 9 or 100-358 shown in Table 2, is preferably linear or branched C1-C6Alkyl, as in the group 2-5, 9 or 100-141 shown in Table 2, however better R51Is methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, or tert-butyl.
Reacting shikimic acid to its carboxylic acid-protected group R51Protecting cis-4, 5-diols by the group R50And (4) protecting. Typically, shikimic acid is treated with an alcohol (such as methanol, ethanol, n-propanol or isopropanol) with an acid catalyst (such as a mineral acid or a sulphonic acid, such as methanesulphonic acid, benzenesulphonic acid or toluenesulphonic acid) followed by protection with a dialkyl ketal or acetal of a ketone or aldehyde, such as 2, 2-dimethoxypropane or 1, 1-dimethoxycyclohexane, and in the presence of the corresponding ketone or aldehyde (such as acetone or cyclohexanone). Optionally, the alcohol is separated, isolated and/or purified from the acid catalyst treated product prior to treatment with the dialkyl ketal or ketal. In addition, shikimic acid uses CH 2N2And (6) processing.
Typically, the process comprises treatment of shikimic acid with an alkanol or sulfonic acid followed by treatment with a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane with an alkanone or cycloalkanone to yield compound 270. More typically, the method comprises treating shikimic acid with alkanol and sulphonic acid; evaporating the excess alkanol to obtain a residue; the residue is treated with a gem-dialkoxyalkane or gem-dialkoxycycloalkane and an alkanone or cycloalkanone to form compound 270. More typically comprises treating shikimic acid with methanol and p-toluene sulphonic acid; evaporation of excess methanol gave a residue which was treated with 2, 2-dimethoxypropane and acetone to give compound 270.
An exemplary embodiment of this method is embodiment 35.
Method B, reaction scheme 36
Compound 271 was prepared from compound 270 in the following manner.
The hydroxyl group at position 3 is activated, typically by a metathesis reaction, more typically by a metathesis of an alcohol at position 4 to form an epoxy ring.
R52Is an alcohol activating group, typically a metathesis activating group, more typically, an activating group that is metathesized with a position 4 alcohol to form an epoxy reaction. Such groups include those typically used in the art, such as sulfonates, more preferably methanesulfonate, benzenesulfonate, or tosylate. In one embodiment, R 52Combined with O (i.e. -OR)52) Are commonly used in the art as leaving groups.
Typically, the method comprises treating compound 270 with an acid halide to form compound 271. More typically, the method comprises treating compound 270 with a sulfonyl halide in a suitable solvent to form compound 271. More typically, the process comprises treating compound 270 with a sulfonyl halide in a suitable solvent, such as an amine, and optionally in the presence of a co-solvent (e.g., an alkyl halide) to form compound 271. Preferably, the process comprises treating compound 270 with methanesulfonyl chloride in triethylamine/dichloromethane to form compound 271.
An exemplary embodiment of this method is illustrated in example 56 below.
Method C, reaction scheme 36
Compound 271 was used in the following manner to prepare compound 272.
Acid-cleavable protecting groups (R) for removal of the hydroxyl groups at positions 4 and 550). Typically, R is removed50Without substantial removal of the base-decomposable carboxylic acid protecting group (e.g., R)51) Or hydroxy activating groups (e.g., R)52). More typically, R50And the cleavage is carried out under acidic conditions.
Typically, the process comprises treating compound 271 with a protic solvent, more typically in the presence of an acid catalyst as described above. Preferably, the method comprises treating compound 271 with an alkanol and acid catalyst as described above. Preferably, the process comprises treating compound 271 with methanol and p-toluenesulfonic acid to produce compound 272.
An exemplary embodiment of this method is shown in example 57 below.
Method D, reaction scheme 36
Compound 272 was used to prepare compound 273 in the following manner.
The activated hydroxyl group at position 3 of compound 272 is replaced with a hydroxyl group at position 4 of compound 272 to form epoxide 273. Typically, this displacement reaction is catalyzed by a suitable base, preferably an amine base such as DBU or DBN.
Typically, the method comprises treating compound 272 with a base catalyst (optionally in the presence of a suitable solvent). More typically, compound 272 is treated with an amine base in a polar, aprotic solvent (e.g., diethyl ether or THF). More typically, the method comprises treating compound 272 with DBU in THF to make compound 273.
An exemplary embodiment of this method is shown in example 58 below.
Method E, reaction scheme 37
Cinchona acid was used to make compound 274 in the following manner.
The cis-4, 5-diol function of cinchona-acid is distinguished from the carboxylic acid on carbon 1 by selective protection. Typically, the cis-4, 5-diol functionality is protected with a cyclic ketal and the carboxylic acid functionality is protected with a hydroxyl group at position 3 to form a lactone.
R50As described above.
Typically, the process comprises treating cinchona acid with a geminal-dialkoxyalkane or geminal-dialkoxycycloalkane (as described above) and an alkanone or cycloalkanone (as described above), optionally in the presence of an acid catalyst (as described above), to form compound 274. More typically, the process comprises treating cinchona-acid with a geminal-dialkoxy alkane or geminal-dialkoxy cycloalkane, alkanone or cycloalkanone, acid catalyst to form compound 274. More typically, the process comprises treating cinchona-acid with 2, 2-dimethoxypropane, acetone and p-toluenesulfonic acid to form compound 274.
An exemplary embodiment of this method is shown in example 101 below.
Method F, reaction scheme 37
Compound 274 was used to prepare compound 275 in the following manner.
The lactone is ring opened to compound 275. Typically, the lactone is ring opened to form a protected carboxylic acid at position 1 and a free hydroxyl group at position 3. More typically, the lactone ring opening formation position 1 is R under basic conditions51The protected carboxylic acid, position 3 is the free hydroxyl group.
R51As described above.
Typically, compound 274 is treated with a suitable base in a suitable protic solvent. More typically, compound 274 is treated with a metal alkoxide base (e.g., sodium, potassium, lithium alkoxide) in an alkanol (as described above). More typically, compound 274 is treated with NaOMe in MeOH to form compound 275.
An exemplary embodiment of this method is shown in example 102 below.
Method G, reaction scheme 37
Compound 275 was used to prepare compound 276 in the following manner.
The hydroxyl group at position 3 is activated, typically by a metathesis reaction, more typically by a metathesis of an alcohol at position 4 to form an epoxy ring.
R52Is an alcohol activating group, typically an activating group of a metathesis reaction, more typically an activating group of an epoxy ring reaction formed by the metathesis of the alcohol at position 4. Such groups include those typically used in the art, such as sulfonates, more preferably methanesulfonate, benzenesulfonate, or tosylate. In one embodiment, R 52Combined with O (i.e., -OR)52) Are commonly used in the art as leaving groups.
Typically, the process comprises treating compound 275 with an acid halide to produce compound 276. More typically, the method comprises treating compound 275 with a sulfonyl halide in a suitable solvent to form compound 276. More typically, the process comprises treating compound 275 with a sulfonyl halide in a suitable solvent, such as an amine, and optionally in the presence of a co-solvent (e.g., an alkyl halide) to form compound 276. Preferably, the process comprises treating compound 275 with p-toluenesulfonyl chloride in pyridine/dichloromethane to form compound 276.
An exemplary embodiment of this method is shown in example 103 below.
Method H, reaction scheme 37
Compound 276 was used to prepare compound 272 in the following manner.
The hydroxyl group at position 1 is eliminated to remove the cis-4, 5-diol protecting group. Elimination of the hydroxyl group at position 1 results in the formation of an olefinic bond between positions 1 and 6, and removal of the cis-4, 5-diol protecting group regenerates the cis-4, 5-diol.
Typically, the process involves the use of a suitable dehydrating agent, such as a mineral acid (HCl, H)2SO4) Or SO2Cl2Compound 276 is treated. More typically, compound 276 is treated with SO2Cl2The treatment, followed by treatment with a alkanol, optionally in the presence of an acid catalyst. More typically, compound 276 is treated with CH in a suitable polar aprotic solvent (e.g., an amine) 2Cl2Treating to form an olefin; the alkene is treated with an alkanol (as described above) and an acid catalyst (as described above) to form compound 272. More typically, compound 276 is in pyridine/SO2Cl2In the presence of SO at a temperature of-100 deg.C to 0 deg.C (preferably-100 deg.C to-10 deg.C, more preferably-78 deg.C)2Cl2Treating to form an olefin; the olefin is treated with methanol and p-toluenesulfonic acid to form compound 272.
An exemplary embodiment of this method is shown in example 104 below.
Method I, reaction scheme 38
Compound 273 was used in the following manner to prepare compound 277.
The hydroxyl group at position 5 is protected. Typically, this protecting group is an acid-cleavable hydroxyl protecting group. More typically, this protecting group is not transferred to an adjacent hydroxyl group.
R53To acid-decompose the hydroxyl protecting group, such as those described in the Greene cited above. More typically, R53Is an acid-cleavable ether, preferably R53Is methoxymethyl (MOM, CH)3-O-CH2-)。
Typically, this method involves treating compound 273 with a hydroxyl protecting group reagent (as described by Greene). More typically, the process comprises reacting compound 273 with a substituted or unsubstituted alkyl or alkenyl halide (e.g., methoxymethyl chloride (MOM chloride, CH) in a suitable solvent (e.g., polar aprotic solvent) 3-O-CH2Cl) treatment. More typically, the process includes treating compound 273 with MOM chloride in an amine solvent. More typically, this process involves treating compound 273 with MOM chloride in diisopropylethylamine.
An exemplary embodiment of this method is shown in example 59 below.
Method J, reaction scheme 38
Compound 277 is used to prepare compound 278 in the following manner.
The epoxy groups at positions 3 and 4 are opened to form azides. More typically, the epoxy groups at positions 3 and 4 are ring opened to form the 3-azido-4-hydroxy compound 278.
Typically, this method involves treating compound 277 with an azide salt in a suitable solvent. More typically, the method comprises treating compound 277 with sodium azide in a polar protic solvent (such as an alkanol or water) with a mild base (such as ammonium halide). Typically, this process involves treating compound 277 with sodium azide and ammonium chloride in water/methanol solution to compound 278.
An exemplary embodiment of this method is shown in example 60 below.
Method K, reaction scheme 38
Compound 278 was used to prepare compound 279 using the following procedure.
The hydroxyl group at the 4 position of compound 278 is substituted with a 3-azido group to form aziridine compound 279.
Typically, this method involves treating compound 278 with a hydroxyl activating group (as described above), an organophosphine, and a base. More typically, the method includes treating compound 278 with a sulfonyl halide (as described above) to form an activated hydroxyl compound, treating the activated hydroxyl compound with a trialkyl phosphine or triaryl phosphine (e.g., triphenylphosphine) to form a phosphonium salt, and treating the phosphonium salt with a base (e.g., an amine) to form compound 279. More typically, the method comprises treating compound 278 with methanesulfonyl chloride to form an activated hydroxyl compound, treating the activated hydroxyl compound with triphenylphosphine to form a phosphonium salt, and treating the phosphonium salt with triethylamine and water to form compound 279.
Exemplary embodiments of this method are shown in examples 61 and 62 below.
Method L, reaction scheme 38
Compound 279 was used in the following manner to prepare compound 280.
Aziridine compound 279 is ring opened with azide to azidoamine 280.
Typically, this method involves treating compound 279 with an azide salt in a suitable solvent. More typically, the method comprises treating compound 279 with sodium azide in a polar aprotic solvent (e.g., ether, amine, amide) with a mild base (e.g., ammonium halide). More typically, the process comprises treating compound 279 with sodium azide and ammonium chloride in DMF to afford compound 280.
An exemplary embodiment of this method is shown in example 63 below.
Method M, reaction scheme 38
Compound 280 was used to prepare compound 281 in the following manner.
The protected hydroxyl at position 5 is replaced with an amine at position 4 to form aziridine 281. Typically, aziridine 281 is substituted with an acid-cleavable group, more preferably an aziridine activating group.
R54Are acid-cleavable groups, typically acid-cleavable amine protecting groups (such as those described in Greene, supra). More typically, R54As the aziridine activating group, a group which can activate aziridine for acid-catalyzed ring opening is more preferable. Typically, the group R54Including, by way of example and not limitation, linear or branched C1-C121-oxo-alk-1-yl, wherein the alkyl moiety is C1-C11Linear or branched alkyl (e.g. C)H3(CH2)zC (O) -, z is an integer of 0 to 10, i.e., acetyl (CH)3C (O) -), substituted methyl (e.g., trityl (Ph)3C-), or simply Tr), or a carbamate, such as BOC or Cbz, or a sulfonate (e.g., an alkyl sulfonate (e.g., methyl sulfonate)). More typically, R54The radicals including trityl and C1-C81-oxo-alk-1-yl, preferably having 1, 2, 3, 4, 5 or 6 carbon atoms, most preferably having 2 or 3 carbon atoms.
Typically, the method includes treating compound 280 with a deprotecting agent to remove group R53，R54Generation reagents (as described by Greene, R)54Halides, e.g. acetyl chloride or Tr-Cl, or R54-O-R54E.g., acetic anhydride) and hydroxyl activating groups (e.g., those described in method B, reaction scheme 36). More typically, the process comprises treating compound 280 with a polar protic solvent, optionally in the presence of an acid catalyst as described above, to form a first intermediate; treating the first intermediate with Tr-Cl in a polar aprotic solvent (e.g., an amine) to form a second intermediate; this second intermediate is treated with a sulfonyl halide (e.g., methanesulfonyl chloride or p-toluenesulfonyl chloride) in a polar aprotic solvent (e.g., an amine) to afford compound 281. More typically, the process comprises treating compound 280 with methanol and HCl to form a first intermediate, treating the first intermediate with Tr-Cl and triethylamine to form a second intermediate, and treating the second intermediate with methanesulfonyl chloride and triethylamine to form compound 281.
An exemplary embodiment of this method is shown in example 64 below.
Method N, reaction scheme 39
Compound 281 was used to prepare compound 282 in the following manner.
After opening of the aziridine 281, the resulting amine is reacted with R 55Substitution of the group forms compound 282. Typically, aziridine 281 is ring-opened by an acid-catalyzed ring-opening reaction, while the resulting amine is acylated.
R55Is the above-mentioned W3. Typically, R55is-C (O) R5. More typically, R55is-C (O) R1More preferably R55is-C (O) CH3。
R56Is the above U1. Typically, R56Is W6-O-，W6-S-, or W6-N (H) -. More typically, R56Is R5-O-，R5-S-or R5-N (H) -, preferably, R56Is R5-O-, preferably R56Is R1-O-。
Typically, the process comprises reacting compound 281 with an acid catalyst and a compound of formula W6-X1Treatment of compounds of the formula-H (in which X1As defined above) to form an amine intermediate; the formula W3-X1-W3，W3-X10Treatment of a compound of (wherein X)10Is a leaving group) to form compound 282. The acid catalyst is preferably a Lewis acid commonly used in the art, such as BF3·Et2O，TiCl3，TMSOTf，SmI2(THF)2，LiClO4，Mg(ClO4)2，Ln(OTf)3(where Ln ═ Yb, Gd, Nd), Ti (Oi-Pr)4，AlCl3，AlBr3，BeCl2，CdCl2，ZnCl2，BF3，BCl3，BBr3，GaCl3，GaBr3，TiCl4，TiBr4，ZrCl4，SnCl4，SnBr4，Sb-Cl5，SbCl3，BiCl3，FeCl3，UCl4，ScCl3，YCl3，LaCl3，CeCl3，PrCl3，Nd-Cl3，SmCl3，EuCl3，GdCl3，TbCl3，LuCl3，DyCl3，HoCl3，ErCl3，Tm-Cl3，YbCl3，ZnI2，Al(OPri)3，Al(acac)3，ZnBr2Or SnCl4. Typically, X1is-O-, -S-, or-N (H) -. X10Typically a halogen, e.g., Cl, Br or I. More typically, the method comprises using R5-OH，R5-SH or R5-NH2Compound of (5) and BF3·Et2O treatment of compound 281 forms an intermediate, which is then treated with alkanoic acid anhydride to form compound 282. More typically, the method comprises using R5-OH compound with BF3·Et2Compound 281 is treated with O to form an intermediate, which is treated with substituted or unsubstituted acetic anhydride to form compound 282. R 5Examples of-OH compounds include 2-7, 9-10, 15 and 660 in Table 2 (wherein Q is1to-OH), additional examples are those shown in table 25 below (including its CAS registry) and those shown in table 26 below (including its CAS registry and Aldrich chemical company product number). More typically R5Examples of-OH compounds are 2-5, 9 and 100-141 in Table 2 (wherein Q is1are-OH).
Process N, in another embodiment of reaction scheme 39, R55Is H.
Typically, the process involves reacting R with an acid catalyst56-X1-H compound (wherein X1As defined above) to form an amine intermediate to form compound 282. Acid catalyst and X1As defined above. More typically, the method comprises using R5-OH，R5-SH or R5-NH2Compound and BF3·Et2Compound 281 is treated to form compound 282. More typically, the method comprises using R5-OH compound with BF3·Et2Compound 281 is treated to form compound 282. R5Examples of-OH compounds are mentioned above.
Exemplary embodiments of this method are shown in examples 65, 86, 92 and 95 below.
Method O, reaction scheme 39
Compound 282 was used to prepare compound 283 in the following manner.
Azide 282 is reduced to amino compound 283.
Typically, the method includes treating compound 282 with a reducing agent to form compound 283. More typically, the process involves treating compound 282 with hydrogen gas and a catalyst (e.g., Pt/C, or Lindlar catalyst) or a reducing agent (e.g., a trialkyl phosphine or triaryl phosphine as described above). More typically, the method comprises treating compound 282 with triphenylphosphine in water/THF to form compound 283.
Exemplary embodiments of this method are shown in examples 87, 93 and 96 below.
Method P, reaction scheme 39
Compound 283 was used in the following manner to prepare compound 284.
Removing the carboxylic acid protecting group.
Typically, this method includes treating compound 283 with a base. More typically, the method includes treating compound 283 with a metal hydroxide in a suitable solvent (e.g., an aprotic polar solvent). More typically, the method comprises treating compound 283 with aqueous potassium hydroxide in THF to produce compound 284.
Exemplary embodiments of this method are shown in examples 88, 94 and 97 below.
Method O, reaction scheme 40
Compound 283 was used in the following manner to prepare compound 285.
The amine is converted to a protected guanidine.
R57Are guanidine protecting groups commonly used in the art, such as BOC or Me.
Typically, this method involves treating compound 283 with a guanylating agent (such as those commonly used in the art). Examples of guanylating agents include di-BOC thiourea aminoiminomethylSulfonic acids (Kim et al; "Tet.Lett." 29 (26): 3183-3186 (1988)) and 1-amidinopyrazoles (Bernatowicz et al; "Tet.Lett." 34 (21): 3389-3392(1993)) more typically, the method comprises treating the compound 283 with di-BOC thiouric acid, more typically, the method comprises treating the compound with di-BOC thiouric acid and HgCl 2Compound 283 is treated to form compound 285.
An exemplary embodiment of this method is shown in example 67 below.
Method R, reaction scheme 40
Compound 285 compound 286 was prepared as follows.
Removing the carboxylic acid protecting group and the guanidine protecting group.
Typically, this process involves treating compound 285 with a base, followed by treatment with an acid as described above. More typically, the method includes treating compound 285 with a metal hydroxide base (as described above) to form an intermediate, followed by treatment with an acid to form compound 286. More typically, this compound comprises intermediate formation by treatment of compound 285 with aqueous potassium hydroxide and THF, followed by treatment of this intermediate with TFA to form compound 286.
Method S, reaction scheme 40.1
Compound 287 is used to prepare compound 288 in the following manner.
E of Compounds 287 and 2881，J1And J2As described above. Typically, E1is-CO2R51(as described above), J1H, F or methyl, preferably H. Typically, J1Is H or linear or branched C1-C6Alkyl, more preferably H, methyl, ethyl, n-propyl or isopropyl, more preferably H.
R60And R61Is reactable to form R in compound 28863(as defined below) a substituted aziridine ring. Typically, R60And R61One of them being a primary or secondary amine, or Are groups that can be converted to primary or secondary amines. R60And R61Such groups of (A) include, by way of example and not limitation, -NH2，-N(H)(R6b)，-N(R6b)2，-NH(R1)，-N(R1)(R6b) and-N3。R60And R61Is preferably substituted with a primary OR secondary amine to form an aziridine, including, by way of example and not limitation, -OH, -OR6aBr, Cl and I. Typically, R60And R61In the trans configuration. More typically, R60Is a primary or secondary amine, or a group convertible into a primary or secondary amine, R61Being a group which can be replaced by a primary or secondary amine to form an aziridine, preferably R60Is beta-azido or beta-NH2，R61Is alpha-OH, alpha-O-methylsulfonyl, or alpha-O-p-toluenesulfonyl.
R61Illustrated below in method U, reaction scheme 40.1.
The method comprises treating compound 287 to form compound 288. Which is typically prepared by treating compound 287 to render R60Substitution of R61And is completed. More typically, compound 287 is treated to activate R61To be R by60And (4) replacement. More typically, compound 287 is treated to cause R61Is activated and then is activated by R60By substitution of R60Is activated into replaceable R61. If R is60And R61Both of which are activated, either simultaneously or sequentially. If performed sequentially, this can be done in any order, typically R61In R60Before activation of (3).
Typically, let R61To R60The displacement activation of (3) is performed by treating compound 287 with a hydroxyl activating reagent such as methanesulfonyl chloride or toluenesulfonyl chloride. Make R 60For substitution of R61Activation is typically accomplished as follows: treatment of compound 287 forms a primary or secondary amine, which is then treated with a base. By way of example and not limitation, compound 287 is treated with a reducing agent that reduces the azide to an amine and a base.
In one embodiment of this method, compound 287 is substituted with R61Activating reagent and R60The activating reagent is treated to compound 288. In another embodiment, R for compound 28761Activating reagent and R60The activating reagent is treated in a suitable solvent to form compound 288. In another embodiment, R for compound 28761Activating reagent, R60The activating reagent and base treatment provide compound 288. In another embodiment, compound 287 is prepared with R in a suitable solvent61Activating reagent, R60The activating reagent and base treatment provide compound 288. In another embodiment, compound 287 (wherein R is60Is azide) with R61Treatment of the activating reagent with an azide reducing reagent produces compound 288. In another embodiment, compound 287 (wherein R is60Is azide) in a suitable solvent with R61Treatment with an activating reagent and an azide reducing reagent produces compound 288. In another embodiment, compound 287 (wherein R is60Is azide) with R61Activating reagent, azide reducing reagent and base treatment to produce compound 288. In another embodiment, compound 287 (wherein R is 60Is azide) in a suitable solvent with R61Compound 288 is prepared by treatment of the activating reagent with an azide reducing reagent and a base. In another embodiment, compound 287 (wherein R is60Is azide, R61Is a hydroxyl group) is treated with a hydroxyl activating reagent, an azide reducing reagent to form compound 288. In another embodiment, compound 287 (wherein R is60Is azide, R61Is a hydroxyl group) in a suitable solvent with a hydroxyl activating reagent, an azide reducing reagent to form compound 288. In another embodiment, compound 287 (wherein R is60Is azide, R61Is a hydroxyl group) is treated with a hydroxyl activating reagent, an azide reducing reagent and a base to form compound 288. In another embodiment, compound 287 (wherein R is60Is azide, R61Is a hydroxyl group) in a suitable solvent with a hydroxyl activator, azide reducing agent and base to form compound 288.
Exemplary embodiments of this process are illustrated above in process K, reaction scheme 38.
Method T, reaction scheme 40.1
Compound 288 is used to prepare compound 289 in the following manner.
R64Typically H, R6bOr may be converted into H or R6bA group of (1). More typically, R64Is H. R65Typically G1Or may be converted to G1A group of (2), preferably R 65is-N3-CN or- (CR)1R2)m1W2Most preferably R65is-N3，-NH2，-N(H)(R6b)，-N(R6b)2，-CH2N3or-CH2CN。
Typically, compound 288 is treated as amine 289. More typically, compound 288 is treated with a nucleophile (preferably a nitrogen nucleophile, such as R)65，R65A cationic salt of (A), or R65By way of example and not limitation, e.g. NH3Azide salt (NaN)3，KN3Etc.), HCN, cyanide salts (e.g., NaCN, KCN, etc.) or cyanoalkyl salts (e.g., (CH)2CN) -, e.g. NaCH2CN，KCH2CN, etc.)). More typically, compound 288 is treated with an azide salt. Optionally, a base (preferably a mild base, e.g., ammonium halide) and a solvent (preferably a polar aprotic solvent (e.g., an ether, amine or amide) may be used.
In one embodiment, compound 288 is treated with a nucleophile. In another embodiment, compound 288 is treated with a nucleophile in a suitable solvent to afford compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base to form compound 289. In another embodiment, compound 288 is treated with a nucleophile and a base in a suitable solvent to form compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile to form compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile in a suitable solvent to form compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base to form compound 289. In another embodiment, compound 288 is treated with a nitrogen nucleophile and a base in a suitable solvent to form compound 289. In another embodiment, compound 288 is treated with an azide salt to form compound 289. In another embodiment, compound 288 is treated with an azide salt in a suitable solvent to form compound 289. In another embodiment, compound 288 is treated with an azide salt and a base to form compound 289. In another embodiment, compound 288 is treated with an azide salt and a base in a suitable solvent to form compound 289.
An exemplary embodiment of this process is shown above in process L, reaction scheme 38.
Method U, reaction scheme 40.1
Compound 289 was used to make compound 290 in the following manner.
R62Is available for reaction with an amine to form R in compound 29066(as defined below) a substituted aziridine ring. Typically, R62Is a group that can be displaced by a primary or secondary amine to form an aziridine. Such groups include, by way of example and not limitation, -OR53，-OH，-OR6aBr, Cl and I. Typically, R62In trans configuration with the nitrogen at position 4. Preferably, R62is-OR53。
R64Is H or R6bTypically an acid-cleavable protecting group, such as R54。
R66Is H, R6bOr R54。
The method includes treating compound 289 to form compound 290. Typically, this is done by treating compound 289 to make it R62By replacement with an amine in position 4. More typically, the treatment compound 289 activates the amine at position 4 to displace R62. More preferably, compound 289 is treated to activate the amine at position 4 to replace R62And R is62Is activated and displaced by the amine at position 4. If R is62And the amine in position 4 are activated, either simultaneously or sequentially. If activation is carried out sequentially, it can be carried out in any order, preferably R62Prior to the activation of the amine at position 4.
Make R62The displacement activation of the amine at position 4 is typically performed by treating compound 289 with a hydroxy activator (such as those described in method B, reaction scheme 36). Optionally make R 62Deprotection is carried out prior to activation. By replacement of R by an amine pair in position 462Activation is generally carried out by treating compound 289 to form a primary or secondary amine and then treating the amine with an acid catalyst (such as those described in method N, scheme 39).
Typically, when R is62is-OR53And R is66Is R56When this method involves treating compound 289 with a deprotecting reagent to remove R53，R54Generation reagents such as those described by Greene (R)54Halides, e.g. acetyl chloride or Tr-Cl, or R54-O-R54E.g., acetic anhydride) and hydroxyl activating groups (e.g., those described in method B, reaction scheme 36). More typically, the process comprises treating compound 289 with a polar protic solvent, optionally in the presence of an acid catalyst as described above, to form a first intermediate; treating the first intermediate with Tr-Cl in a polar aprotic solvent (e.g., an amine) to form a second intermediate; this second intermediate is then treated with a sulfonyl halide (e.g., methanesulfonyl chloride or p-toluoyl sulfonyl chloride) in a polar aprotic solvent (e.g., an amine) to afford compound 290. More typically, the process comprises treating compound 289 with methanol and HCl to form a first intermediate, treating with Tr-Cl and triethylamine to form a second intermediate, and treating with methanesulfonyl chloride and triethylamine to form compound 290.
In one embodiment, compound 289 is treated with an acidic catalyst to form compound 290. In another embodiment, compound 289 is treated with an acidic catalyst in a suitable solvent to form compound 290. In another embodiment, compound 289 is treated with a hydroxyl activating reagent and an acid catalyst to form compound 290. In another embodiment, compound 289 is treated with a hydroxyl activating reagent and an acid catalyst in a suitable solvent to form compound 290. In another embodiment, compound 289 is treated with a hydroxyl deprotecting reagent, a hydroxyl activating reagent and an acid catalyst to form compound 290. In another embodiment, compound 289 is treated with a hydroxyl deprotecting reagent, a hydroxyl activating reagent and an acid catalyst in a suitable solvent to form compound 290.
Specific examples of this process are shown above in Process M, reaction scheme 38.
Method V, reaction scheme 40.1
Compound 290 was used to prepare compound 291 in the following manner.
Aziridine 290 is treated to form compound 291. Typically, aziridine 290 is ring-opened by an acid-catalyzed ring-opening reaction, and the resulting amine is acylated.
R68Independently is H, R6b，R1Or R55(as described above). Typically, R55is-C (O) R5. Typically one R68Is H or R6bAnd the other is W3。
R67Is U 1(as described above). Typically, R67Is W6-O-，W6-S-, or W6-N (H) -, preferably R67Is R5-O-，R5-S-or R5-N(H)-。
Typically, the process comprises contacting W with an acid catalyst6-X1-H compound (wherein X1As defined above) to process compound 290 to form an amine intermediate; then W3-X1-W3Or W3-X10Compound (wherein X10Is a leaving group) to form compound 291. W6-X1Treatment of the-H compound with an acid catalyst may be with W3-X1-W3Or W3-X10The treatment of the compound is carried out simultaneously or before it. The acid catalyst is typically Process N, one of which is described in reaction scheme 39And (4) seed preparation. More typically, the method comprises using R5-OH，R5-SH, or R5-NH2Compound and acid catalyst treatment compound 290; the intermediate is then treated with an alkanoic acid anhydride to form compound 291.
One embodiment includes using W6-X1Compound 290 is treated with an acid catalyst to form compound 291. Another embodiment is the use of W in a suitable solvent6-X1Compound 291 is prepared by treating compound 290 with an acid catalyst. In another embodiment, W is used6-X1-H compound, acid catalyst and W3-X1-W3Or W3-X10Compound treatment compound 290 is prepared as compound 291. Another embodiment is the use of W in a suitable solvent6-X1-H compound, acid catalyst and W3-X1-W3Or W3-W10Compound 290 is processed to form compound 291.
Specific examples of this method are method N, scheme 39, above.
Method W, reaction scheme 40.1
Compound 291 was used to prepare compound 292 in the following manner.
Compound 291 is treated as compound 292. Typically R65Is converted into G1。U1Is R67An embodiment of (1), T1is-N (R)68)2An embodiment of (1). Prepared as above for method V, reaction scheme 40.1.
In one embodiment, R65By deprotection, alkylation, guanidation, oxidation or reduction to G1. Any of the above processes may be performed in any order or simultaneously. By way of example, and not limitation, when R65Specific examples of the method include methods O, OQ, OQR and OP when the azide group is used. Typically, alkylating agents are conventional in the art and include, by way of example and not limitation, alkyl halides (e.g., methyl iodide, methyl bromide, ethyl iodide,ethyl bromide, n-propyl iodide, n-propyl bromide, isopropyl iodide, isopropyl bromide) and olefin oxides (e.g., ethylene oxide or propylene oxide). The base catalyst described herein may be optionally used in the alkylation step.
One embodiment includes reacting compound 291 (wherein R is65Azido) is treated with a reducing agent to form compound 292. Another embodiment includes reacting compound 291 (wherein R is 65Is azido) in a suitable solvent with a reducing agent to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Amino) is treated with an alkylating agent to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Amino) in a suitable solvent with an alkylating agent to compound 292. Another embodiment includes reacting compound 291 (wherein R is65Is azido) is treated with a reducing agent and an alkylating agent to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Is azido) is treated with a reducing agent and an alkylating agent in a suitable solvent to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Is an amino group) is treated with an alkylating agent and a base catalyst to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Is an amino group) in a suitable solvent with an alkylating agent and a base catalyst to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Azido) is treated with a reducing agent, an alkylating agent, and a base catalyst to form compound 292. Another embodiment includes reacting compound 291 (wherein R is65Azido) in a suitable solvent with a reducing agent, an alkylating agent, and a base catalyst to form compound 292.
An exemplary embodiment of the method is given as method O of scheme 39 above.
Exemplary embodiments of this method are described in examples 68 and 69 below.
TABLE 25 formula R5Exemplary Compounds of-OH (CAS No.)
C4 fluoroalcohol
(R*，R*) - (+ -) -3-fluoro-2-butanol (139755-61-6)
1-fluoro-2-butanol (124536-12-5)
(R) -3-fluoro-1-butanol (120406-57-7)
3-fluoro-1-butanol (19808-95-8)
4-fluoro-2-butanol (18804-31-4)
(R*，S*) -3-fluoro-2-butanol (6228-94-0)
(R*，R*) -3-fluoro-2-butanol (6133-82-0)
2-fluoro-1-butanol (4459-24-9)
2-fluoro-2-methyl-1-propanol (3109-99-7)
3-fluoro-2-butanol (1813-13-4)
4-fluoro-1-butanol (372-93-0)
1-fluoro-2-methyl-2-propanol (353-80-0)
C5 fluoroalcohol
2-fluoro-1-pentanol (123650-81-7)
(R) -2-fluoro-3-methyl-1-butanol (113943-11-6)
(S) -2-fluoro-3-methyl-1-butanol (113942-98-6)
4-fluoro-3-methyl-1-butanol (104715-25-5)
1-fluoro-3-pentanol (30390-84-2)
4-fluoro-2-pentanol (19808-94-7)
5-fluoro-2-pentanol (18804-35-8)
3-fluoro-2-methyl-2-butanol (7284-96-0)
2-fluoro-2-methyl-1-butanol (4456-02-4)
3-fluoro-3-methyl-2-butanol (1998-77-2)
5-fluoro-1-pentanol (592-80-3)
C6 fluoroalcohol
(R-(R*，S*) 2-fluoro-3-methyl-1-pentanol (168749-88-0)
1-fluoro-2, 3-dimethyl-2-butanol (161082-90-2)
2-fluoro-2, 3-dimethyl-1-butanol (161082-89-9)
(R) -2-fluoro-4-methyl-1-pentanol (157988-30-2)
(S-(R*，R*) 2-fluoro-3-methyl-1-pentanol (151717-18-9)
(R*，S*) -2-fluoro-3-methyl-1-pentanol (151657-14-6)
(S) -2-fluoro-3, 3-dimethyl-1-butanol (141022-94-8)
(M) -2-fluoro-2-methyl-1-pentanol (137505-57-8)
(S) -2-fluoro-1-hexanol (127608-47-3)
3-fluoro-3-methyl-1-pentanol (112754-22-0)
3-fluoro-2-methyl-2-pentanol (69429-54-5)
2-fluoro-2-methyl-3-pentanol (69429-53-4)
1-fluoro-3-hexanol (30390-85-3)
5-fluoro-2-methyl-2-pentanol (21871-78-3)
5-fluoro-3-hexanol (19808-92-5)
4-fluoro-3-methyl-2-pentanol (19808-90-3)
4-fluoro-4-methyl-2-pentanol (19031-69-7)
1-fluoro-3, 3-dimethyl-2-butanol (4604-66-4)
2-fluoro-2-methyl-1-pentanol (4456-03-5)
2-fluoro-4-methyl-1-pentanol (4455-95-2)
2-fluoro-1-hexanol (1786-48-7)
3-fluoro-2, 3-dimethyl-2-butanol (661-63-2)
6-fluoro-1-hexanol (373-32-0)
C7 fluoroalcohol
5-fluoro-5-methyl-1-hexanol (168268-63-1)
(R) -1-fluoro-2-methyl-2-hexanol (153683-63-7)
(S) -3-fluoro-1-heptanol (141716-56-5)
(S) -2-fluoro-2-methyl-1-hexanol (132354-09-7)
(R) -3-fluoro-1-heptanol (120406-54-4)
(S) -2-fluoro-1-heptanol (110500-31-7)
1-fluoro-3-heptanol (30390-86-4)
7-fluoro-2-heptanol (18804-38-1)
2-Ethyl-2- (fluoromethyl) -1-butanol (14800-35-2)
2- (fluoromethyl) -2-methyl-1-pentanol (13674-80-1)
2-fluoro-5-methyl-1-hexanol (4455-97-4)
2-fluoro-1-heptanol (1786-49-8)
7-fluoro-1-heptanol (408-16-2)
C8 fluoroalcohol
(M) -2-fluoro-2-methyl-1-heptanol (137505-55-6)
6-fluoro-6-methyl-1-heptanol (135124-57-1)
1-fluoro-2-octanol (127296-11-1)
(R) -2-fluoro-1-octanol (118205-91-7)
(±) -2-fluoro-2-methyl-1-heptanol (117169-40-1)
(S) -2-fluoro-1-octanol (110500-32-8)
(S) -1-fluoro-2-octanol (110270-44-5)
(R) -1-fluoro-2-octanol (110270-42-3)
(±) -1-fluoro-2-octanol (110229-70-4)
2-fluoro-4-methyl-3-heptanol (87777-41-1)
2-fluoro-6-methyl-1-heptanol (4455-99-6)
2-fluoro-1-octanol (4455-93-0)
8-fluoro-1-octanol (408-27-5)
C9 fluoroalcohol
6-fluoro-2, 6-dimethyl-2-heptanol (160981-64-6)
(S) -3-fluoro-1-nonanol (160706-24-1)
(R-(R*，R*) -3-fluoro-2-nonanol (137909-46-7)
(R-(R*，S*) -3-fluoro-2-nonanol (137909-45-6)
3-fluoro-2-nonanol (137639-20-4)
(S-(R*，R*) -3-fluoro-2-nonanol (137639-19-1)
(S-(R*，S*) -3-fluoro-2-nonanol (137639-18-0)
(±) -3-fluoro-1-nonanol (134056-76-1)
2-fluoro-1-nonanol (123650-79-3)
2-fluoro-2-methyl-1-octanol (120400-89-7)
(R) -2-fluoro-1-nonanol (118243-18-8)
(S) -1-fluoro-2-nonanol (111423-41-7)
(S) -2-fluoro-1-nonanol (110500-33-9)
1-fluoro-3-nonanol (30390-87-5)
2-fluoro-2, 6-dimethyl-3-heptanol (684-74-2)
9-fluoro-1-nonanol (463-24-1)
C10 fluoroalcohol
4-fluoro-1-decanol (167686-45-5)
(P) -10-fluoro-3-decanol (145438-91-1)
(R-(R*，R*) -3-fluoro-5-methyl-1-nonanol (144088-79-9)
(P) -10-fluoro-2-decanol (139750-57-5)
1-fluoro-2-decanol (130876-22-1)
(S) -2-fluoro-1-decanol (127608-48-4)
(R) -1-fluoro-2-decanol (119105-16-7)
(S) -1-fluoro-2-decanol (119105-15-6)
2-fluoro-1-decanol (110500-35-1)
1-fluoro-5-decanol (106533-31-7)
4-fluoro-2, 2, 5, 5-tetramethyl-3-hexanol (24212-87-1)
10-fluoro-1-decanol (334-64-5)
C11 fluoroalcohol
10-fluoro-2-methyl-1-decanol (139750-53-1)
2-fluoro-1-undecanol (110500-34-0)
8-fluoro-5, 8-dimethyl-5-nonanol (110318-90-6)
11-fluoro-2-undecanol (101803-63-8)
11-fluoro-1-undecanol (463-36-5)
C12 fluoroalcohol
11-fluoro-2-methyl-1-undecanol (139750-52-0)
1-fluoro-dodecanol (132547-33-2)
(R*，S*) -7-fluoro-6-dodecanol (130888-52-7)
(R*，R*) -7-fluoro-6-dodecanol (130876-18-5)
(S) -2-fluoro-1-dodecanol (127608-49-5)
12-fluoro-2-pentyl-heptanol (120400-91-1)
(R*，S*) - (+ -) -7-fluoro-6-dodecanol (119174-39-9)
(R*，R*) - (+ -) -7-fluoro-6-dodecanol (119174-38-8)
2-fluoro-1-dodecanol (110500-36-2)
11-fluoro-2-methyl-2-dodecanol (101803-67-2)
1-fluoro-1-dodecanol (100278-87-3)
12-fluoro-1-dodecanol (353-31-1)
C4 nitroalcohols
(R) -4-Nitro-2-butanol (129520-34-9)
(S) -4-Nitro-2-butanol (120293-74-5)
4-Nitro-1-butanolic acid ion radical (1-) (83051-13-2)
(R*，S*) -3-nitro-2-butanol (82978-02-7)
(R*，R*) -3-nitro-2-butanol (82978-01-6)
4-Nitro-1-butanol (75694-90-5)
(±) -4-nitro-2-butanol (72959-86-5)
4-nitro-2-butanol (55265-82-2),
1-acid-nitro-2-butanol (22916-75-2)
3-acid-nitro-2-butanol (22916-74-1)
2-methyl-3-nitro-1-propanol (21527-52-6)
3-Nitro-2-butanol (6270-16-2)
2-methyl-1-nitro-2-propanol (5447-98-3)
2-acid-nitro-1-butanol (4167-97-9)
1-Nitro-2-butanol (3156-74-9)
2-Nitro-1-butanol (609-31-4)
2-methyl-2-nitro-1-propanol (76-39-1)
C5 nitroalcohols
(R) -3-methyl-3-nitro-2-butanol (154278-27-0)
3-methyl-1-nitro-1-butanol (153977-20-9)
(±) -1-nitro-3-pentanol (144179-64-6)
(S) -1-nitro-3-pentanol (144139-35-5)
(R) -1-nitro-3-pentanol (144139-34-4)
(R) -3-methyl-1-nitro-2-butanol (141434-98-2)
(±) -3-methyl-1-nitro-2-butanol (141377-55-1)
(R*，R*) -3-nitro-2-pentanol (138751-72-1)
(R*，S*) -3-nitro group-2-pentanol (138751-71-0)
(R*，R*) -2-nitro-3-pentanol (138668-26-5)
(R*，S*) -2-nitro-3-pentanol (138668-19-6)
3-Nitro-1-pentanol (135462-98-5)
(R) -5-nitro-2-pentanol (129520-35-0)
(S) -5-Nitro-2-pentanol (120293-75-6)
4-Nitro-1-pentanol (116435-64-4)
(±) -3-methyl-3-nitro-2-butanol (114613-30-8)
(S) -3-methyl-3-nitro-2-butanol (109849-50-5)
3-methyl-4-nitro-2-butanol (96597-30-7)
(±) -5-nitro-2-pentanol (78174-81-9)
2-methyl-2-nitro-1-butanol (77392-55-3)
3-methyl-2-nitro-1-butanol (77392-54-2)
3-methyl-4-nitro-1-butanol (75694-89-2)
2-methyl-4-nitro-2-butanol (72183-50-7)
3-methyl-3-nitro-1-butanol (65102-50-3)
5-Nitro-2-pentanol (54045-33-9)
2-methyl-3-acid-nitro-2-butanol (22916-79-6)
2-methyl-1-acid-nitro-2-butanol (22916-78-5)
2-methyl-3-nitro-2-butanol (22916-77-4)
2-methyl-1-nitro-2-butanol (22916-76-3)
5-Nitro-1-pentanol (21823-27-8)
2-methyl-3-nitro-1-butanol (21527-53-7)
2-nitro-3-pentanol (20575-40-0)
3-methyl-3-nitro-2-butanol (20575-38-6)
3-Nitro-2-pentanol (5447-99-4)
2-nitro-1-pentanol (2899-90-3)
3-methyl-1-nitro-2-butanol (2224-38-6)
1-nitro-2-pentanol (2224-37-5)
C6 nitroalcohols
(-) -4-methyl-1-nitro-2-pentanol (158072-33-4)
3- (nitromethyl) -3-pentanol (156544-56-8)
(R*，R*) -3-methyl-2-nitro-3-pentanol (148319-17-9)
(R*，S*) -3-methyl-2-nitro-3-pentanol (148319-16-8)
6-Nitro-2-hexanol (146353-95-9)
(±) -6-nitro-3-hexanol (144179-63-5)
(S) -6-nitro-3-hexanol (144139-33-3)
(R) -6-nitro-3-hexanol (144139-32-2)
3-Nitro-2-hexanol (127143-52-6)
5-Nitro-2-hexanol (110364-37-9)
4-methyl-1-nitro-2-pentanol (102014-44-8)
(R*，S*) -2-methyl-4-nitro-3-pentanol (82945-29-7)
(R*，R*) -2-methyl-4-nitro-3-pentanol (82945-20-8))
2-methyl-5-nitro-2-pentanol (79928-61-3)
2, 3-dimethyl-1-nitro-2-butanol (68454-59-1)
2-methyl-3-nitro-2-pentanol (59906-62-6)
3, 3-dimethyl-1-nitro-2-butanol (58054-88-9)
2, 3-dimethyl-3-nitro-2-butanol (51483-61-5)
2-methyl-1-nitro-2-pentanol (49746-26-1)
3, 3-dimethyl-2-nitro-1-butanol (37477-66-0)
6-Nitro-1-hexanol (31968-54-4)
2-methyl-3-nitro-1-pentanol (21527-55-9)
2, 3-dimethyl-3-nitro-1-butanol (21527-54-8)
2-methyl-4-nitro-3-pentanol (20570-70-1)
2-methyl-2-nitro-3-pentanol (20570-67-6)
2-Nitro-3-hexanol (5448-00-0)
4-Nitro-3-hexanol (5342-71-2)
4-methyl-4-nitro-1-pentanol (5215-92-9)
1-nitro-2-hexanol (2224-40-0)
C7 nitroalcohols
1-nitro-4-heptanol (167696-66-4)
(R) -1-Nitro-4-heptanol (146608-19-7)
7-Nitro-1-heptanol (133088-94-5)
(R*，S*) -3-nitro-2-heptanol (127143-73-1)
(R*，R*) -3-nitro-2-heptanol (127143-72-0)
(R*，S*) -2-nitro-3-heptanol (127143-71-9)
(R*，R*) -2-nitro-3-heptanol (127143-70-8)
(R*，S*) -2-methyl-5-nitro-3-hexanol (103077-95-8)
(R*，R*) -2-methyl-5-nitro-3-hexanol (103077-87-8)
3-Ethyl-4-nitro-1-pentanol (92454-38-1)
3-Ethyl-2-nitro-3-pentanol (77922-54-4)
2-Nitro-3-pentanol (61097-77-6)
2-methyl-1-nitro-3-hexanol (35469-17-1)
2-methyl-4-nitro-3-hexanol (20570-71-2)
2-methyl-2-nitro-3-hexanol (20570-69-8)
5-methyl-5-nitro-2-hexanol (7251-87-8)
1-nitro-2-heptanol (6302-74-5)
3-Nitro-4-heptanol (5462-04-4)
4-nitro-3-heptanol (5342-70-1)
C8 nitroalcohols
(±) -1-nitro-3-octanol (141956-93-6)
1-Nitro-4-octanol (167642-45-7)
(S) -1-Nitro-4-octanol (167642-18-4)
6-methyl-6-nitro-2-heptanol (142991-77-3)
(R*，S*) -2-nitro-3-octanol (135764-74-8)
(R*，R*) -2-nitro-3-octanol (135764-73-7)
5-Nitro-4-octanol (132272-46-9)
(R*，R*) -3-nitro-4-octanol (130711-79-4)
(R*，S*) -3-nitro-4-octanol (130711-78-3)
4-Ethyl-2-nitro-3-hexanol (126939-74-0)
2-Nitro-3-octanol (126939-73-9)
1-Nitro-3-octanol (126495-48-5)
(R*，R*) - (+ -) -3-nitro-4-octanol (118869-22-0)
(R*，S*) - (+ -) -3-nitro-4-octanol (118869-21-9)
3-Nitro-2-octanol (127143-53-7)
(R*，S*) -2-methyl-5-nitro-3-heptanol (103078-03-1)
(R*，R*) -2-methyl-5-nitro-3-heptanol (103077-90-3)
8-Nitro-1-octanol (101972-90-1)
(±) -2-nitro-1-octanol (96039-95-1)
3, 4-dimethyl-1-nitro-2-hexanol (64592-02-5)
3- (nitromethyl) -4-heptanol (35469-20-6)
2, 5-dimethyl-1-nitro-3-hexanol (35469-19-3)
2-methyl-1-nitro-3-heptanol (35469-18-2)
2, 4-trimethyl-1-nitro-2-pentanol (35223-67-7)
2, 5-dimethyl-4-nitro-3-hexanol (22482-65-1)
2-Nitro-1-octanol (2882-67-9)
1-nitro-2-octanol (2224-39-7)
C9 nitroalcohols
4-Nitro-3-nonanol (160487-89-8)
(R*，R*) -3-ethyl-2-nitro-3-heptanol (148319-18-0)
2, 6-dimethyl-6-nitro-2-heptanol (117030-50-9)
(R*，S*) -2-nitro-4-nonanol (103077-93-6)
(R*，R*) -2-nitro-4-nonanol (103077-85-6)
2-nitro-3-nonanol (99706-65-7)
9-Nitro-1-nonanol (81541-84-6)
2-methyl-1-nitro-3-octanol (53711-06-1)
4-nitro-5-nonanol (34566-13-7)
2-methyl-3- (nitromethyl) -3-heptanol (5582-88-7)
1-nitro-2-nonanol (4013-87-0)
C10 nitroalcohols
2-nitro-4-decanol (141956-94-7)
(R*，S*) -3-nitro-4-decanol (135764-76-0)
(R*，R*) -3-nitro-4-decanol (135764-75-9)
5, 5-dimethyl-4- (2-nitroethyl) -1-hexanol (133088-96-7)
(R*，R*) - (+ -) -3-nitro-4-decanol (118869-20-8)
(R*，S*) - (+ -) -3-nitro-4-decanol (118869-19-5)
5-Nitro-2-decanol (112882-29-8)
3-nitro-4-decanol (93297-82-6)
4, 6, 6-trimethyl-1-nitro-2-heptanol (85996-72-1)
2-methyl-2-nitro-3-nonanol (80379-17-5)
1-nitro-2-decanol (65299-35-6)
2, 2, 4, 4-tetramethyl-3- (nitromethyl) -3-pentanol (58293-26-8)
C11 nitroalcohols
11-Nitro-5-undecanol (167696-69-7)
(R*，R*) -2-nitro-3-undecanol (144434-56-0)
(R*，S*) -2-nitro-3-undecanol (144434-55-9)
2-nitro-3-undecanol (143464-92-0)
2, 2-dimethyl-4-nitro-3-nonanol (126939-76-2)
4, 8-dimethyl-2-nitro-1-nonanol (118304-30-6)
11-Nitro-1-undecanol (81541-83-5)
C12 nitroalcohols
2-methyl-2-nitro-3-undecanol (126939-75-1)
2-nitro-1-dodecanol (62322-32-1)
1-nitro-2-dodecanol (62322-31-0)
2-nitro-3-dodecanol (82981-40-6)
12-nitro-1-dodecanol (81541-78-8)
TABLE 26 formula R5Illustrative Compounds of OH (CAS number/Aldrich No.)
3-bromo-1-propanol 627189167169
1, 3-dichloro-2-propanol 96231184489
3-chloro-2, 2-dimethyl-1-propanol 13401564189316
2, 2-bis (chloromethyl) -1-propanol 5355544207691
1, 3-difluoro-2-propanol 453134176923
2- (methylthio) ethanol 5271385226424
2- (dibutylamino) ethanol 102818168491
2- (diisopropylamino) ethanol 96800168726
3-methyl-3-buten-1-ol 763326129402
2-methyl-3-buten-2-ol 115184136816
3-methyl-2-buten-1-ol 556821162353
4-Hexen-1-ol 928927237604
5-Hexen-1-ol 821410230324
Cis-2-hexen-1-ol 928949224707
Trans-3-hexen-1-ol 928972224715
Trans-2-hexen-1-ol 928950132667
(+/-) -6-methyl-5-hepten-2-ol 4630062195871
Dihydrogeranenol 18479588196428
Trans, trans-2, 4-hexadien-1-ol 17102646183059
2, 4-dimethyl-2, 6-heptadien-1-ol 80192569238767
Geraniol 106241163333
3-butyn-1-ol 927742130850
3-pentyn-1-ol 10229104208698
Isethionic acid, sodium salt 1562001220078
(4- (2-hydroxyethyl) -1-piperazinyl 16052065163740
Propane sulfonic acid)
HEPES, sodium salt 75277393233889
1-methylcyclopropanemethanol 2746147236594
2-methylcyclopropanemethanol 6077721233811
(+/-) -chrysanthenol 18383590194654
Cyclobutanemethanol 4415821187917
3-cyclopentyl-1-propanol 767055187275
1-ethynylcyclopentanol 17356193130869
3-methylcyclohexanol 591231139734
3, 3, 5, 5-Tetramethylcyclohexanol 2650400190624
4-cyclohexyl-1-butanol 4441570197408
Dihydrocarveol 619012218421
(1S, 2R, 5S) - (+) -menthol 15356704224464
(1S, 2S, 5R) - (+) -Neomenthol 2216526235180
(1S, 2R, 5S) - (+) -Isomenthol 23283978242195
(+/-) -3-cyclohexene-1-menthol 72581329162167
(+)-P--1-en-9-ol 13835308 183741
(S) - (-) -perilla alcohol 536594218391
Terpinen-4-ol 562743218383
Alpha-terpineol 98555218375
(+/-) -trans-P--6-ene-32226643247774
2, 8-diols
Cycloheptane methanol 4448753138657
Tetrahydrofurfuryl alcohol 97994185396
(S) - (+) -2-pyrrolidinemethanol 23356969186511
1-methyl-2-pyrrolidineethanol 67004642139513
1-Ethyl-4-hydroxypiperidine 3518830224634
3-Hydroxypiperidine hydrochloride 64051792174416
(+/-) -2-piperidinemethanol 3433372155225
3-Piperidinemethanol 4606659155233
1-methyl-2-piperidinemethanol 20845345155241
1-methyl-3-piperidinemethanol 7583531146145
2-Piperidinoethanol 1484840131520
4-Hydroxypiperidine 5382161128775
4-methyl-1-piperazinepropanol 5317339238716
Exo-norborneol 497370179590
Endo-norborneol 497369186457
5-norbornene-2-methanol 95125248533
(+/-) -3-methyl-2-norbornanemethanol 6968758130575
(1S) -inner- (-) -borneol 464459139114
(1R) -endo- (+) -fenchyl alcohol 2217029196444
9-Ethylbicyclo (3.3.1) nonan-9-ol 21951333193895
(+/-) -isopinocampheol 51152115183229
(S) -cis-verbenol 18881044247065
(1R, 2R, 3R, 5S) - (-) -isopinocampheol 25465650221902
(1R) - (-) -myrtenol 515004188417
1-adamantanol 768956130346
3, 5-dimethyl-1-adamantanol 707379231290
2-adamantanol 700572153826
1-adamantanemethanol 770718184209
1-Adamantadine ethanol 6240115188115
3-Furanomethanol 4412913196398
Furfuryl alcohol 98000185930
2- (3-thienyl) EtOH 13781674228796
4-methyl-5-imidazolemethanol hydrochloride 38585625227420
2-methyl-5-nitro-1-imidazolylethanol 443481226742
4- (hydroxymethyl) imidazole hydrochloride 32673419219908
4-methyl-5-thiazoleethanol 137008190675
2- (2-hydroxyethyl) pyridine 103742128643
2-hydroxy-6-methylpyridine 3279763128740
4-Pyridylcarbinol 586958151629
3-Pyridylcarbinol N-oxide 6968725184446
1-benzyl-4-hydroxypiperidine 4727724152986
1- (4-chlorophenyl) -1-cyclopentanemethanol 80866791188697
(4S, 5S) - (-) -2-methyl-5-phenyl-
2-oxazoline-4-methanol 53732415187666
6- (4-chlorophenyl) -4, 5-dihydro-2-
(2-hydroxybutyl) -3(2H) -pyridazinone 38958826243728
N- (2-hydroxyethyl) phthalimide 3891074138339
2-Naphthalenethanol 1485070188107
1-Naphthalenethanol 773999183458
2-Isopropyl phenol 88697129526
4-chloro-alpha, alpha-dimethyl phenethyl alcohol 5468973130559
4-fluoro-alpha-methylbenzyl alcohol 403418132705
3-phenyl-1-propanol 122974140856
3- (4-methoxyphenyl) -1-propanol 5406188142328
4-Fluorophenethyl alcohol 7589277154172
4-Methoxyphenylethanol 702238154180
Trans-2-methyl-3-phenyl-2-propen-1-ol 1504558155888
2-anilinoethanol 122985156876
3-fluorobenzyl alcohol 456473162507
2-fluorobenzyl alcohol 446515162515
2-methyl-1-phenyl-2-propanol 100867170275
Alpha- (chloromethyl) -2, 4-dichlorobenzyl alcohol 13692143178403
2-phenyl-1-propanol 1123859179817
4-Chlorobenzeneethanol 1875883183423
4-Bromophenylethanol 4654391183431
4-Nitrophenyl EtOH 100276183466
2-Nitrophenyl EtOH 15121843183474
Beta-ethylphenylethanol 2035941183482
4-phenyl-1-butanol 3360416184756
2-Methoxyphenylethanol 7417187187925
3-Methoxyphenylethanol 5020417187933
3-phenyl-1-butanol 2722363187976
2-Methylphenylethanol 19819988188123
3-Methylphenylethanol 1875894188131
4-Methylphenylethanol 699025188158
5-phenyl-1-pentanol 10521912188220
4- (4-methoxyphenyl) -1-butanol 22135508188239
4- (4-Nitrophenyl) -1-Butanol 79524202188751
3, 3-Diphenyl-1-propanol 20017678188972
1-phenyl-2-propanol 14898874189235
(+/-) -alpha-ethylphenylethanol 701702190136
1, 1-Diphenyl-2-propanol 29338496190756
3-Chlorobenzeneethanol 5182445193518
2-Chlorobenzeneethanol 19819955193844
(+/-) -1-phenyl-2-pentanol 705737195286
2, 2-Diphenylethanol 1883325196568
4-ethoxy-3-methoxyphenylethanol 77891293197599
3, 4-Dimethoxybenzene ethanol 7417212197653
3- (3, 4-dimethoxyphenyl) -1-propanol 3929473197688
2- (4-bromophenoxy) ethanol 34743889198765
2-Fluorophenethyl alcohol 50919067228788
3- (trifluoromethyl) phenethyl alcohol 455016230359
2- (Phenylthio) ethanol 699127232777
1- (2-methoxyphenyl) -2-propanol 15541261233773
TABLE 27 method specific examples of methods A-R
A；B；C；D；I；J；K；L；M；N；O；P；Q；R；E；F；G；H；AB；BC；CD；DI；IJ；JK；KL；LM；MN；NO；OP；OQ；QR；EF；FG；GH；HI；ABC；BCD；CDI；DIJ；IJK；JKL；KLM；LMN；MNO；NOP；NOQ；OQR；EFG；FGH；GHI；HIJ；ABDC；BCDI；CDIJ；DIJK；IJKL；JKLM；KLMN；LMNO；MNOP；MNOQ；NOQR；EFHG；FGHI；GHIJ；HIJK；ABCDI；BCDIJ；CDIJK；DIJKL；IJKLM；JKLMN；KLMNO；LMNOP；LMNOQ；MNOQR；EFGHI；FGHIJ；GHIJK；HIJKL；ABCDIJ；BCDIJK；CDIJKL；DIJKLM；IJKLMN；JKLMNO；KLMNOP；KLMNOQ；LMNOQR；EFGHIJ；FGHIJK；GHIJKL；HIJKLM；ABCDIJK；BCDIJKL；CDIJKLM；DIJKLMN；IJKLMNO；JKLMNOP；JKLMNOQ；KLMNOQR；EFGHIJK；FGHIJKL；GHIJKLM；HIJKLMN；ABCDIJKL；BCDIJKLM；CDIJKLMN；DIJKLMNO；IJKLMNOP；IJKLMNOQ；JKLMNOQR；EFGHIJKL；FGHIJKLM；GHIJKLMN；HIJKLMNO；ABCDIJKLM；BCDIJKLMN；CDIJKLMNO；DIJKLMNOP；DIJKLMNOQ；IJKLMNOQR；EFGHIJKLM；FGHIJKLMN；GHIJKLMNO；HIJKLMNOP；HIJKLMNOQ；ABCDIJKLMN；BCDIJKLMNO；CDIJKLMNOP；CDIJKLMNOQ；DIJKLMNOQR；EFGHIJKLMN；FGHIJKLMNO；GHIJKLMNOP；GHIJKLMNOQ；HIJKLMNOQR；ABCDIJKLMNO；BCDIJKLMNOP；BCDIJKLMNOQ；CDIJKLMNOQR；EFGHIJKLMNO；FGHIJKLMNOP；FGHIJKLMNOQ；GHIJKLMNOQR；ABCDIJKLMNOP；ABCDIJKLMNOQ；BCDIJKLMNOQR；EFGHIJKLMNOP；EFGHIJKLMNOQ；FGHIJKLMNOQR；ABCDIJKLMNOQR；EFGHIJKLMNOQR；S；T；U；V；W；ST；TU；UV；VW；STU；TUV；UVW；STUV；TUVW；STUVW.
Reaction scheme 41
Reaction scheme 41
Treatment of amine 300 with Boc anhydride (intermediate from example 52, optionally purified before use) gave mono-Boc protected amine 301. This transformation can be referred to Greene, T.W. "Protective Groups in Organic Synthesis" 2nd Ed. (John Wiley & Sons, New York, 1991) page 327, 328.
Methyl ester 301 is reduced to the corresponding primary allyl alcohol 302 with DIBAL at low temperature. This conversion is as described in Garner, p. and Park, j.m., and "j.org.chem., 52-2361 (1987).
The primary alcohol 302 is protected under basic conditions by treatment with 4-methoxybenzyl chloride to the p-methoxybenzyl ether derivative 303. Such a transformation is described by Horita, k, et al, "Tetrahedron", 42: 3021 (1986).
303 MOM with Boc protecting group by TFA/CH2Cl2Treated to remove and yield amino alcohol 304. Such a transformation is described in Greene, T.W. "Protective Groups in organic Synthesis", 2nd.Ed. (John Wiley) &Sons, New York, 1991).
The conversion of 304 to the corresponding trityl protected aziridine 305 is accomplished in a two-step procedure as follows: 1) TrCl/TEA, 2) MsCl/TEA. This conversion is as described above.
Aziridine 305 is then converted to the corresponding Boc-protected derivative 307 as follows: removal of the trityl group with HCl/acetone gives 306 a transformation as described in Hanson, r.w. and Law, h.d. "j.chem.soc." 7285(1965) and conversion of aziridine 306 to the corresponding Boc derivative 307 by treatment with Boc anhydride, a transformation as described in Fitre-mann, j. et al, "Tetrahedron lett", 35: 1201 (1994).
Allylaziridine 307 transport as a carbon nucleophile (via a high valent organocuprate) at BF3·Et2The ring-opened adduct 308 is obtained by selective ring-opening at an allyl position in the presence of O at a low temperature. This open loop is described in Hudlicky, T. et al, "Synlett." 1125 (1995).
The method comprises the following steps: 1) TFA/CH2Cl2；2)Ac2The O/pyridine converts the Boc protected amine 308 to an N-acetyl derivative 309. This transformation can be referred to Greene, T.W. "Protective Groups in Organic Synthesis″，2nd.Ed.(JohnWiley &Sons, New York, 1991) at pages 327 and 351 and 352.
The benzyl ether 309 is deprotected with DDQ at room temperature to give primary allyl alcohol 310. Such a transformation is described in Horita, K. et al, "Tetrahedron" 42: 3021 (1986).
Alcohol 310 is oxidized and converted to methyl ester 311 in a one pot reaction using MnO2A-cOH/MeOH/NaCN by Corey oxidation. This transformation is as described by Corey, e.j. et al, "j.am.chem.soc., 90: 5616 (1968).
Azido ester 311 in a two-step reaction procedure: 1) ph3P/H2O/THF: 2) KOH/THF was converted to amino acid 312. This transformation is as described above.
Reaction scheme 42
Reaction scheme 42
The known fluoroacetate 320(Sutherland, j.k. et al, "j.chem.soc.chem.commun." 464(1993)) was deprotected to the free alcohol and then converted to the corresponding mesylate 321 in a two step process: 1) NaOMe; 2) MsCl/TEA. This transformation is described in Greene, T.W., "Protective Groups in Organic Synthesis", second edition (John Wiley & Sons, New York, 1991).
Deprotection of 321 under acidic conditions gives diol 322, which cyclizes to epoxy alcohol 323 under basic conditions. This transformation is as described previously. 323 to the N-trityl protected aziridine 324 is accomplished in the following order: 1) MOMCl/TEA; 2) NaN3/NH4Cl；3)MsCl/TEA；4) PPh3/TEA/H2O；5)NaN3/NH4Cl; 6) HCl/MeOH; 7) i) TrCl, ii) MsCl/TEA. This sequence is as described above.
The aziridine 324 is then ring-opened with a suitable alcohol under Lewis acid conditions, followed by Ac2O/pyridine treatment gave an acetylated product 325. This transformation is as described above.
Ester 325 is converted to the corresponding amino acid 326 via the following two-step procedure: 1) PPh3/H2O/THF; 2) KOH/THF. This transformation is as described above.
U.S. Pat. No. 5214165, particularly "Descriptions and EXAMPLES" from column 9, line 61 to column 18, line 26, describes the preparation of 6 α and 6 β fluoroshikimic acids. These fluoro compounds are suitable as starting materials in the preparation of the compounds of the invention using shikimic acid.
Recipe 43
Reaction scheme 43
Unsaturated ester 330 (prepared from acetonide alcohol by standard acetylation procedures, as described by Campbell, M.M. et al, "Synthesis", 179 (1993)) was reacted with a suitable organocuprate salt, where R' is the ligand transferred from the organocuprate salt to the compound, and the resulting intermediate was captured with PhSeCl to give 331, followed by 30% H2O2The treatment gives the α, β -unsaturated ester 332. This conversion can be found in Hayashi, y, et al, "j.org.chem." 47: 3428(1982).
Then, with a two-step procedure: 1) NaO Me/MeOH; 2) MsCl/TEA converted acetate 332 to the corresponding mesylate 333. This transformation is as described above and can be referred to Greene, T.W. "Protective Groups in Organic Synthesis", second edition (John Wiley & Sons, New York, 1991).
Then, with a two-step procedure: 1) p-TsOH/MeOH/Δ; 2) DBU/THF converts acetonide 333 to epoxy alcohol 334. This transformation is as described above.
Epoxide 334 is converted to N-trityl aziridine 335 by the following procedure: 1) MOMCl/TEA; 2) NaN3/NH4Cl；3)MsCl/TEA；4)PPh3/TEA/H2O；5)NaN3/NH4Cl; 6) HCl/MeOH; 7) i) TrCl, ii) MsCl/TEA. Such a procedure is as described above.
The aziridine 335 is then ring-opened with a suitable alcohol under Lewis acid conditions, followed by Ac2O/pyridine treatment gave 336 acetylated product. This transformation is as described above.
Azido ester 336 is converted to the corresponding amino acid 337 via the following two-step procedure: 1) PPh3/H2O/THF; 2) KOH/THF. This transformation is as described above.
Reference is made to reaction schemes 44 and 45 in the examples.
Reaction scheme 44
Varying the starting materials of the examples to form different E1Groups have been described in detail and are not described in detail herein. See Fleet, G.W.J. et al, "J.chem.Soc.Perkin Trans.I", 905-908(1984), Fleet, G.W.J. et al; "J.chem.Soc., chem.Com-mu.", 849-850(1983), Yee, Ying K.et al; "j.med.chem.", 33: 2437-2451 (1990); olson, r.e. et al: "Bioorganic" compound&Medici-nal Chemistry Letters ", 4 (18): 2229-; santella, j.b.iii et al; bioorganic &Medicinal Chemistry Letters ", 4 (18): 2235-; judd, d.b. et al; "j.med.chem.", 37: 3108 3120(1994) and Lombaert,de et al; bioorganic& Medici-nal Chemistry Letters″，5(2)：151-154(1994)。
E of the Carboxylic acid Compound of the present invention1The sulfur analogs are prepared by any standard technique, by way of example and not limitation, by reducing the carboxylic acid to an alcohol by standard methods, converting the alcohol to a halide or sulfonate by standard methods, and reacting the resulting compound with NaSH to the sulfide product. Such reactions are described in Patai, "The Chemistry of The thio Group" (John Wiley, New York, 1974), pt.2, especially page 721-.
Modifications of the above reaction schemes can yield various analogs of the above specific exemplary compounds. The works described above for suitable organic synthesis methods can be applied to these improvements.
In each of the above reaction schemes, it is preferred to separate the reaction products from each other and/or from the starting materials. The desired product of each step or series of steps is isolated and/or purified (hereinafter collectively referred to as isolation) to the desired degree of homogeneity by techniques commonly used in the art. Typically, this separation involves heterogeneous extraction, crystallization from a solvent or solvent mixture, distillation, sublimation, or chromatographic separation. Chromatographic separations can be performed by a variety of methods, for example, size exclusion or ion exchange chromatography, high, medium, low pressure liquid chromatography, small scale and preparative thin or thick layer chromatography, and small scale thin layer and flash chromatography.
Another type of separation involves treating the mixture with a reagent selected to bind to or allow separation of the desired product, unreacted starting materials, reaction by-products, and the like. Such agents include adsorbents or absorbents such as activated carbon, molecular sieves, ion exchange media, and the like. Further, in the case of an alkaline substance, the reagent may be an acid, and in the case of an acidic substance, it may be a base, or it may be a binding agent such as an antibody, a binding protein, a selective chelating agent such as a crown ether, a liquid/liquid ion extraction agent (LIX), or the like.
The choice of a suitable separation method depends on the nature of the participating substances. For example, boiling point and molecular weight for distillation and sublimation, presence or absence of polar functional groups for chromatographic separation, stability of the material in acidic or basic media for heterogeneous extraction, and the like. The person skilled in the art will be able to apply the best skills to achieve the desired separation results.
All documents and patents mentioned above are incorporated herein by reference. The paragraphs or pages specifically recited in the above work are expressly referenced to that which is described. The invention has been described in detail so that those skilled in the art can make and use the subject matter of the claims that follow. It is to be clearly understood that certain modifications of the methods and compositions of the following claims are within the scope and spirit of the invention.
Examples
General rule
The following examples refer to reaction schemes.
Some of these are performed several times, and in repeated implementations, the reaction conditions (e.g., time, temperature, concentration, etc.) and yields are within normal experimental error. If the experiment is repeated with significant improvement, those with significantly different results are indicated. If the examples use different starting materials, this is also indicated. When the "corresponding" analog of the compound, e.g., "corresponding ethyl ester", is used in the examples that are repeated, it means that another group (typically methyl ester in this example) is changed to the indicated group. For example, "corresponding ethyl ester of Compound 1" means
Example 1
Epoxy alcohol 1: from shikimic acid, the reaction product of McGowan with berchtodold, "j.org.chem.", 46: 2381 (1981).
Example 2
Epoxy allyl ether 2: thallium (I) ethoxide (1.01mL) was added to a solution of epoxy alcohol 1(2.37g, 14.08mmol) in dry benzene (50mL) in one portion. After 2 hours the reaction mixture was concentrated in vacuo and the residue was dissolved in acetonitrile. Allyl iodide (3.0mL) was added and the mixture was stirred in the dark for 16 h. The solid was filtered off through a pad of celite and washed with chloroform. After concentration in vacuo, flash chromatography (40% EtOAc in hexane) afforded 1.24g (42%) of 2 as a light, viscous oil.
1H NMR(300MHz，CDCl3)：δ
6.75(1H，m)
6.10-5.90(1H, m, -CH ═ allyl);
5.40-5.15(2H，m，＝CH2allyl); 4.47-4.43(1H, m);
4.30-4.15(2H，m，-CH2-, allyl); 3.73(3H, s);
3.55-3.50(1H，m)；
3.45-3.40(1H，m)；
3.15-3.00(1H，dm，J＝19.5Hz)；
2.50-2.35(1H，dm，J＝2.7，19.5Hz)。
example 3
Azido alcohol 3: epoxide 2(1.17g, 5.57mmol), sodium azide (1.82g) and ammonium chloride (658mg) in MeOH/H2O (8: 1) (35mL) for 18 h. The reaction mixture was then concentrated in vacuo and the residue was partitioned between ether and water. The organic layer was washed with brine and dried. Concentration in vacuo afforded 3 as a light oil, 1.3g (92%), which was used without purification.
1H NMR(300MHz，CDCl3)：δ
6.95-6.85(1H，m)；
6.00-5.85(1H, m, -CH ═ allyl);
5.35-5.25(2H，m，＝CH2allyl);
4.25-4.10(2H，m，-CH2-, allyl);
4.12(1H，bt，J＝4.2Hz)；3.95-3.75(2H，m)，
3.77(3H，s)；2.85(1H，dd，J＝5.3，18.3Hz)；2.71(1H，bs)；
2.26(1H，dd，J＝7.2，18,3Hz)。
example 4
Aziridine 4: add alcohol 3(637mg, 2.52mmol) to CH2Cl2To a solution (20mL) and cooled to 0 deg.C was added DMAP (several crystals) and triethylamine (442. mu.L). Then, MsCl (287. mu.L) was further added thereto, and the reaction was stirred at 0 ℃ for 2 hours. The volatiles were removed and the residue was partitioned between ether and water. The organic layer was washed with saturated bicarbonate, brine and water and dried. Concentration in vacuo gave 881mg of crude mesylate.
1H NMR(300MHz，CDCl3)：δ
6.87-6.84(1H，s)；
6.00-5.85(1H，m，-CH2Allyl);
5.40-5.25(2H，m，＝CH2allyl);
4.72(1H，dd，J＝3.9，8.5Hz)；
4.32(1H，bt，J＝3.9Hz)；
4.30-4.15(2H，m，-CH2-, allyl);
3.77(3H，s)；3.14(3H，s)；
2.95(1H，dd，J＝5.7，18.6Hz)；
2.38(1H，dd，J＝6.7，18.6Hz)。
this crude mesylate was dissolved in anhydrous THF (20mL) and Ph was used3P (727 mg). After stirring at room temperature for 3 hours, water (15mL) and solid NaH-CO were added 3(1.35g), and the mixture was further stirred at room temperature overnight. The reaction mixture was then concentrated in vacuo and the residue partitioned between EtOAc, saturated bicarbonate and brine. The organic layer was separated and MgSO4And (5) drying. After concentration in vacuo, the residue is flash chromatographed to give aziridine 4, 170mg (33%) as a pale yellow oil.
1H NMR(300MHz，CDCl3)：δ
6.82-6.80(1H，m)；
6.04-5.85(1H, m, -CH ═ allyl);
5.35-5.20(2H，m，＝CH2allyl);
4.39(1H，bd，J＝2.4Hz)；
4.20-4.05(2H，m，-CH2-, allyl);
3.73(3H，s)；
2.90-2.80(1H，bd，J＝18.9Hz)；2.65-2.40(2H，m)。
example 5
N-acetyl aziridine 5: aziridine 4(170mg, 0.814mmol) was dissolved in CH2Cl2(2ml) in pyridine (4ml) and cooled to 0 ℃. Acetyl chloride (87. mu.l) was then added and stirred at 0 ℃ for 1 hour. The volatiles were removed in vacuo and the residue was partitioned between ethyl acetate, saturated bicarbonate and brine. The organic layer was separated and MgSO4And (5) drying. Concentration gave crude 5, 196mg (96%) which was used without further purification.
1H NMR(300MHz，CDCl3)：δ
6.88-6.86(1H，m)；
6.00-5.85(1H, m, -CH ═ allyl);
5.40-5.20(2H，m，＝CH2allyl);
4.45-4.40(1H，m)；
4.16(2H，d，J＝6.0Hz，-CH2-, allyl); 3.76(3H, s)
3.00-2.95(2H，m)；
2.65(1H，bd，J＝18.5HZ)；
2.14(3H，s)。
Example 6
Azidoallyl ether 6: aziridine 5(219mg, 0.873mmol), sodium azide (426mg) and ammonium chloride (444mg) were heated in anhydrous DMF (7mL) under nitrogen at 65 ℃ overnight. The reaction mixture was poured into saturated bicarbonate/brine and extracted several times with ether. The ether layers were combined, washed with brine and dried. Concentration followed by flash chromatography (EtOAc only) gave 77mg (35%) of azidoamine, which was dissolved in CH 2Cl2(1mL) and pyridine (1mL) and cooled to 0 ℃. Acetyl chloride (38 μ L) was added and after 45 minutes solid NaHCO was added3Volatiles were removed in vacuo. The residue was partitioned between EtOAc and brine. The organic layer was MgSO4After drying, the mixture was concentrated in vacuo. Flash chromatography (EtOAc only) afforded 90mg of 6 (99%).
1H NMR(500MHZ，CDCl3)；δ
6.86(1H，bt，J＝2.2HZ)；
5.95-5.82(1H, m, CH ═ allyl);
5.68(1H，bd，J＝7.3HZ)；
5.35-5.20(2H，m，＝CH2allyl);
4.58-4.52(1H，m)；
4.22-4.10(2H，m)；
4.04(1H，dd，J＝5.9，12.5HZ)；3.77(3H，s)；
3.54-3.52(1H，m)；
2.89(1H，dd，J＝5.9，17.6HZ)；2.32-2.22(1H，m)；
2.06(3H，s)。
example 7
Azido diol 7: to a solution of olefin 6(90mg, 0.306mmol) in acetone (3mL) and water (258 μ L) was added N-methylmorpholine-N-oxide (39mg) and OsO4(73. mu.L, 2.5% w/w t-butanol solution). The reaction mixture was then stirred at room temperature for 3 days. Solid sodium bisulfite was added, stirred for 20 minutes and then filtered through a pad of celite. Washed with sufficient acetone. After concentration in vacuo, flash chromatography (10% MeOH/CH)2Cl2) Yield diol 7, 50mg (50%).
1H NMR(300MHZ，CD3CN)：δ
6.80-6.70(1H，m)；
4.20-4.15(1H，bm)；
3.95-3.80(1H，m)；
3.80-3.25(6H，m)；
3.70(3H，s)；3.10(1H，bs)；
2.85(1H，bs)；
2.85-2.75(1H，m)；
2.30-2.15(1H，m)；
2.16(1H，bs)；1.92(3H，s)。
Example 8
Amino acid diol 8: a solution of diol 7(23mg, 0.07mmol) in THF (1mL) was treated with aqueous KOH (223 μ L, 0.40M) at room temperature. After stirring for 1.5 hours, the reaction mixture was acidified to pH 4 with Amberlite IR-120 (cationic) ion exchange resin. The resin was filtered off and washed with MeOH. Concentration in vacuo gave the crude carboxylic acid, which was dissolved in ethanol (1.5 mL). To this solution was added Lindlar catalyst (20mg), and the mixture was stirred under hydrogen atmosphere (1atm, via a balloon) for 20 hours. The reaction mixture was filtered through a pad of celite, washed with hot ethanol and water. Ethanol was removed under vacuum and the resulting aqueous layer was freeze dried to give a mixture of the expected amino acid 8 and the starting azide 7 as a white powder. Compound 8:
1H NMR(500MHZ，D2O)：δ
6.5(1H，s)；
4.24-4.30(2H，m)；
4.25-4.18(1H，m)；
3.90-3.55(5H, compound m);
2.96-2.90(1H，m)；
2.58-2.50(1H, composite m);
2.12(3H，s)。
example 9
Compound 62: a suspension of cinchona-acid (60g), cycloethanone (160mL) and toluene sulfonic acid (600mg) in benzene (450mL) was refluxed with a Dean-Stark apparatus for 14 hours. After the reaction mixture was cooled to room temperature, saturated NaHCO was poured in3Solution (150 mL). CH for aqueous layer2Cl2The extraction was performed 3 times. Combine the organic layers, wash with water (2 times), brine (1 time), Na2SO4Concentration after drying gave a white solid which was recrystallized from ether (75g, 95%);
1H NMR(CDCl3)δ
4.73(dd，J＝6.1，2.5HZ，1H)；
4.47(ddd，J＝7.0，7.0，3.0HZ，1H)；
4.30(ddd，J＝5.4，2.6，1.4HZ，1H)，
2.96(s，1H)，
2.66(d，J＝11.7HZ，1H)，
2.40-2.15(m，3H)，
1.72-1.40(m，10H)。
example 10
Compound 63: add sodium methoxide (2.7g, 500mmol) once to a solution of lactone 62(12.7g, 50mmol) in methanol (300 mL). The mixture was stirred at room temperature for 3 hours, and after discontinuation of the reaction with acetic acid (3mL), the mixture was stirred for another 10 minutes. The reaction mixture was poured into saturated NH4In Cl solution (300mL), with CH2Cl2Extraction was carried out three times. The organic layers were combined, washed once with brine, MgSO4And (5) drying. Purification by flash column chromatography (hexanes/EtOAc ═ 1/1 to 1/2) gave the diol (11.5g, 80%) and starting material (1.2g, 10%);
1H NMR(CDCl3)δ
4.47(ddd，J＝7.4，5.8，3.5HZ，1H)，4.11(m，1H)，
3.98(m，1H)，3.81(s，3H)，
3.45(s，1H)，
2.47(d，J＝3.3HZ，1H)，
2.27(m，2H)，
2.10(dd，J＝11.8，4.3HZ，1H)，1.92-1.26(m，10H)。
example 11
Compound 64: PCC (3.3g, 15.6mmol) was added in one portion to diol 63(1.100g, 3.9mmol), molecular sieve (3A, 2.2g) and pyridine (1.1g) in CH2Cl2(15 mL). The mixture was stirred at room temperature for 26 hours and then diluted with ether (30 mL). The suspension was filtered through a pad of celite and washed with ether (2X 20 mL). The ether layers were combined, washed with brine (2X) and MgSO 4And (5) drying. Concentration followed by purification by flash column chromatography (hexanes/EtOAc ═ 3/1) gave the ketone (0.690g, 67%);
1H NMR(CDCl3)δ
6.84(d，J＝2.8HZ，1H)，
4.69(ddd，J＝6.4，4.9，1.6HZ，1H)，
4.30(d，J＝5.0HZ，1H)，
3.86(s，3H)，
3.45(d，J＝22.3HZ，1H)，
2.86(m，1H)，
1.69-1.34(m，10H)。
example 12
Compound 28: NaBH is added at 0 ℃ over 30 minutes4Ketone 64(0.630g, 2.4-mmol) in MeOH (12mL) was added. The mixture was stirred at 0 ℃ for a further 1.5 h, 15mL of saturated NH4The reaction was interrupted by a Cl solution. CH for this solution2Cl2Extracting three times, combining organic extracts, and reacting with MgSO4And (5) drying. Purification by flash column chromatography (hexanes/EtOAc ═ 2/1) gave the alcohol (0.614g, 97%):
1H NMR(CDCl3)δ
6.94(d，J＝0.5Hz，1H)，
4.64(ddd，J＝9.8，6.7，3.2Hz，1H)，
4.55(dd，J＝7.1，4.2Hz，1H)，
4.06(m，1H)，3.77(s，3H)，
3.04(dd，J＝16.5，2.1Hz，1H)，
2.73(d，J＝10.2Hz，1H)，
1.94(m，1H)，
1.65-1.29(m，10H)。
example 13
Compound 66: alcohol 28(2.93g, 10.9mmol) and toluene sulfonic acid (1.5g) were dissolved in acetone (75mL) and the mixture was stirred at room temperature for 15 h. The reaction was stopped with water (30mL) and concentrated NH3-H2Basified to pH 9. Removing acetone under reduced pressure, and using CH for water phase2Cl2The extraction was performed 3 times. The organic extracts were combined, washed once with brine, Na2SO4And (5) drying. Concentration gave the expected product:
1H NMR(CDCl3)δ
7.01(m，1H)，4.73(m，1H)，
4.42(m，1H)，3.97(m，1H)，
3.76(s，3H)，
2.71-2.27(m，2H)，
2.02(s，3H)，1.98(s，3H)。
example 14
Compound 67: pyridine (4.4mL, 54.5mmol) was added to the CH of alcohol 66(10.9mmol) at 0 deg.C2Cl2(60mL) followed by the addition of trimethylacetyl chloride (2.7mL, 21.8 mmol). The mixture was warmed to room temperature and stirred for 14 hours, then CH was added2Cl2Diluting, washing twice with water, washing once with brine, and reacting with MgSO 4And (5) drying. Flash column chromatography (hexanes/EtOAc ═ 9/1) gave the diester (2.320g, 68%):
1H NMR(CDCl3)δ
6.72(m，1H)，5.04(m，1H)，
4.76(m，1H)，4.40(m，1H)，
3.77(s，3H)，
2.72-2.49(m，2H)，
1.37(s，3H)，1.35(s，3H)，
1.23(s，9H)。
example 15
Compound 68: diester 67(2.32g, 2.3mmol) was dissolved in acetone/water (1/1, 100mL) and heated at 55 ℃ for 16 h. The solvent was removed, water (2X 50mL) was added and evaporated. Concentration with toluene (2 × 50mL) gave the diol, which was used without further purification:
1H NMR(CDCl3)δ
6.83(m，1H)，5.06(m，1H)，
4.42(m，1H)，4.09(m，1H)，
3.77(s，3H)，
2.68-2.41(m，2H)，
1.22(s，9H)。
example 16
Compound 69: triethylamine (0.83mL, 6.0mmol) was added to a solution of diol 68(0.410g, 1.5mmol) in THF (8mL) at 0 deg.C, followed by slow addition of thionyl chloride (0.33mL, 4.5 mmol). The mixture was warmed to room temperature and stirred for 3 hours. With CHCl3After dilution, the mixture was washed three times with water, once with brine, and MgSO4And (5) drying. Flash column chromatography (hexanes/EtOAc ═ 5/1) afforded an external/internal mixture (0.430g, 90%);
1H NMR(CDCl3)δ
6.89-6.85(m，1H)，
5.48-4.84(m，3H)，
3.80，3.78(s，3H)，
2.90-2.60(m，2H)，
1.25，1.19(s，9H)。
example 17
Compound 70: a mixture of sulfone 69(0.400g, 1.3mmol) and sodium azide (0.410g, 6.29mmol) in DMF (10mL) was stirred for 20 h. The reaction mixture was then diluted with ethyl acetate and saturated NH4Cl solution, water and brine, MgSO4And (5) drying. Concentration gave the azide (0.338g, 90%);
1H NMR(CDCl3)δ
6.78(m，1H)，5.32(m，1H)，
4.20(m，1H)，3.89(m，1H)，
3.78(s，3H)，
3.00-2.60(m，2H)，
1.21(s，9H)。
example 18
Compound 71: triethylamine (0.4mL, 2.9mmol) was added to the CH solution of alcohol 70(0.338g, 1.1mmol) at 0 deg.C 2Cl2(11mL) followed by slow addition of methanesulfonyl chloride (0.18mL, 2.3 mmol). The mixture was stirred at 0 ℃ for 30 minutes with CH2Cl2Diluting, washing the organic layer twice with water, then with brine, MgSO4And (5) drying. Flash column chromatography (Hexane/EtOAc 3/1)Purification gave the expected compound (0.380g, 82%);
1H NMR(CDCl3)δ
6.82(m，1H)，5.44(m，1H)，
4.76(dd，J＝7.3，1.4Hz，1H)，
4.48(m，1H)，3.80(s，3H)，
3.11(s，3H)，
2.82-2.61(m，2H)，
1.21(s，9H)。
example 19
Compound 72: a mixture of azide 71(0.380g, 0.94mmol) and triphenylphosphine (0.271g, 1.04mmol) in THF (19mL) was stirred for 2 h. The reaction was quenched with water (1.9mL) and triethylamine (0.39mL, 2.82mmol) and stirred for an additional 14 hours. The solvent was removed under reduced pressure and the mixture was used directly in the next step. Pyridine (0.68mL, 8.4mmol) was added to the mixture in CH at 0 deg.C2Cl2(20mL), followed by the slow addition of the acid chloride (0.30mL, 4.2 mmol). The mixture was stirred at 0 ℃ for 5 minutes and diluted with ethyl acetate. The mixture was washed twice with water, once with brine, and once with MgSO4And (5) drying. Flash column chromatography (hexanes/EtOAc ═ 3/1) gave aziridine (0.205g, 83%):
1H NMR(CDCl3)δ
7.19(m，1H)，5.58(m，1H)，
3.77(s，3H)，3.14(m，2H)，
2.85(dd，J＝7.0，1.6Hz，1H)，
2.34(m，1H)，2.16(s，3H)，
1.14(s，9H)。
example 20
Compound 73: a mixture of aziridine 72(0.200g, 0.68mmol), sodium azide (0.221g, 3.4mmol) and ammonium chloride (0.146g, 2.7mmol) in DMF (10mL) was stirred at room temperature for 14 h. The mixture was then diluted with ethyl acetate, washed five times with water, once with brine and then with MgSO 4And (5) drying. Flash column chromatography (hexane/E-thoac ═ 2/1) gave the expected product after purification with deacetylated amine (0.139 g). This mixture was dissolved in acetic anhydride (2mL) and stirred for 2 hours. Excess anhydride was removed under reduced pressure to give the expected product (149 mg):
1H NMR(CDCl3)δ
6.76(m，1H)，
5.53(d，J＝8.5Hz，1H)，
5.05(m，1H)，4.31(m，1H)，
4.08(m，1H)，3.79(s，3H)，
2.91(m，1H)，2.51(m，1H)，
1.99(s，3H)，1.20(s，9H)。
example 21
Compound 74: adding MeOH/H of KOH2Solution O (0.5M, 4.4mL, 2.2mmol) was added to ester 73(149mg, 0.44mmol), the mixture was stirred at room temperature for 3 hours, then cooled to 0 ℃ and acidified with Amberlite (acidic) to pH 3-4. The mixture was filtered, washed with MeOH and concentrated to give the carboxylic acid as a white solid (73mg, 69%):
1H NMR(CD3OD)δ
6.62(m，1H)，4.15(m，1H)，
3.95-3.72(m，2H)，2.84(dd，J＝6.7，1.4Hz，1H)，2.23(m，1H)，1.99(s，3H)。
example 22
Compound 75: a mixture of azide 74(8mg) and Pd-C (Lindlar) (15mg) in ethanol (2mL)) was stirred under hydrogen for 16 h. The mixture was filtered through celite and hot MeOH-H2O (1/1) washing. Concentration gave a solid. This solid was dissolved in water, passed through a short C-8 column, washed with water and concentrated to give a white solid (6 mg):
1H NMR(D2O)δ
6.28(m，1H)，
4.06-3.85(m，3H)，
2.83(dd，J＝17.7，5.4Hz，1H)，2.35(m，1H)，2.06(s，3H)。
example 23
Compound 76: carboxylic acid 74(68mg, 0.28mmol) and diphenyldiazomethane (61mg, 0.31mmol) were dissolved in ethanol (12mL) and stirred for 16 h. The reaction was interrupted with acetic acid (0.5mL) and stirred for a further 10 minutes. The solvent was removed under reduced pressure and flash column chromatography (E-tOAc) purified to give the ester (56mg, 50%);
1H NMR(CD3OD)δ
7.36-7.23(m，10H)，
6.88(s，1H)，6.76(s，1H)，
4.21(m，1H)，
3.93-3.79(m，2H)，
2.89(dd，J＝17.7，5.0Hz，1H)，2.34(m，1H)，
2.00(s，3H)。
Example 24
Compound 77: pyridine (40. mu.L, 0.5mmol) was added to alcohol 76(20mg, 0.05mmol) in CH2Cl2(1mL) followed by acetic anhydride (24. mu.L, 0.25 mmol). Mixing the mixtureAfter stirring for 24 hours, the solvent and reagents were removed under reduced pressure. Flash column chromatography (hexanes/EtOAc ═ 1/2) gave the diester (20mg, 91%):
1H NMR(CDCl3)δ
7.40-7.27(m，10H)，
6.95(s，1H)，6.87(m，1H)，
5.60(m，1H)，
5.12(ddd，J＝16.4，10.2，5.9Hz，1H)，
4.28(dd，J＝20.0，9.4Hz，1H)，4.15(m，1H)，
2.93(dd，J＝17.8，5.2Hz，1H)，2.57(m，1H)，
2.09(s，3H)，2.01(s，3H)。
example 25
Compound 78: diester 77(20mg, 0.045mmol), anisole (50. mu.L, 0.45mmol) and TFA (1mL) in CH2Cl2The mixture in (1mL) was stirred for 20 minutes. The solvent and reagents were removed under reduced pressure. Purification by flash column chromatography (EtOAc to EtOAc/AcOH ═ 100/1) gave the carboxylic acid (6 mg):
1H NMR(CDCl3)δ
6.85(m，1H)，5.54(m，1H)，
5.12(m，1H)，
4.31-4.03(m，2H)，
2.89(m，1H)，
2.60-2.41(m，1H)，2.11(s，3H)，2.03(s，3H)。
example 26
Compound 79: azide 78(6mg, 0.02mmol) was reacted with Pd-C (Lindlar) (15mg) in EtOH/H2Mixing in O (2.2mL, 10/1)The material was stirred under hydrogen for 3 hours. The mixture was filtered through a pad of celite and hot MeOH/H2O (1/1) washing. Evaporation gave a white solid which was dissolved in water and passed through a C-8 column. Evaporation of water gave a white powder (3 mg):
1H NMR(D2O)δ
6.32(m，1H)，5.06(m，1H)，
4.06(t，J＝10.4Hz，1H)，
3.84(m，1H)，2.83(m，1H)，
2.42(m，1H)，2.06(s，3H)，
2.00(s，3H)。
example 27
Compound 80: DCC (35mg, 0.172mmol) was added to alcohol 76(35mg, 0.086mmol), Boc-glycine (30mg, 0.172mmol) with a catalytic amount of DMAP in CH2Cl2(1 mL). The mixture was stirred for 30 minutes, filtered and washed with CHCl 3And (6) washing. Obtained CHCl3The solution was washed twice with water. Concentration gave a white solid. Flash column chromatography (hexanes/EtOAc ═ 1/2) purified the product (30 mg):
1H NMR(CDCl3)δ
7.39-7.26(m，10H)，
6.95(s，1H)，6.86(m，1H)，
5.77(m，1H)，5.27(m，1H)，
4.99(m，1H)，
4.18-4.01(m，2H)，
3.94-3.84(m，2H)，
2.96(dd，J＝7.8，5.9Hz，1H)，
2.57(m，1H)，2.02(s，3H)，
1.45(s，9H)。
example 28
Compound 81: diester 80(30mg, 0.05mmol), anisole (150. mu.L) and TFA (1mL) in CH2Cl2The mixture in (1mL) was stirred for 3 hours. The solvent and reagents were evaporated. This mixture was dissolved in water and washed with CHCl3Washed three times. Evaporation of the aqueous phase gave a white solid (15 mg):
1H NMR(CD3OD)δ
6.73(m，1H)，
5.25-5.15(m，1H)，
4.35(m，1H)，4.17(m，1H)，
3.82(m，2H)，
2.93(dd，J＝17.7，5.6Hz，1H)，2.42(m，1H)，1.97(s，3H)。
example 29
Compound 82: azide 81(15mg, 0.05mmol) was reacted with Pd-C (Lindlar) (30mg) in EtOH/H2The mixture in O (4mL, 1/1) was stirred under hydrogen for 3 hours. The reaction mixture was filtered through a pad of celite and hot MeOH/H2O (1/1) washing. Concentration gave a glassy solid which was dissolved in water and passed through a C-8 column. The amino acid is obtained after water is evaporated:
1H NMR(D2O)δ
6.68(m，1H)，5.28(m，1H)，
4.29(m，1H)，
4.08-3.79(m，3H)，
2.85(m，1H)，2.41(m，1H)，
2.04(s，3H)。
example 30
di-Boc guanidinomethyl ester 92: such as Kim and Qian, "tetrahedron lett", 34: 7677 (1993). Mercury chloride (46mg, 0.170mmol) was added in one portion to a 0 deg.C solution of amine 91(42mg, 0.154mmol), di-Boc thiourea (43mg, 0.155mmol) and triethylamine (72. mu.L) in dry DMF (310. mu.L). After 30 minutes, the reaction mixture was warmed to room temperature and stirred for an additional 2.5 hours. The reaction mixture was filtered through a pad of celite, concentrated, and purified by flash column chromatography (100% ethyl acetate) to give 70mg (89%) 92 as a colorless foam.
1H NMR(CDCl3，300MHz)：δ
11.37(s，1H)；
8.60(d，1H，J＝7.8Hz)；
6.83(t，1H，J＝2.1Hz)；
6.63(d，1H，J＝8.4Hz)；
4.76(d，1H，J＝7.0Hz)；
4.71(d，1H，J＝7.0Hz)；
4.45-4.10 (composite m, 2H);
3.76(s，3H)；3.39(s，3H)；
2.84(dd，1H，J＝5.4，17.4Hz)；2.45-2.30(m，1H)；
1.92(s，3H)；1.49(s，18H)。
example 31
di-Boc guanidino carboxylic acid 93: add aqueous KOH (350. mu.L, 0.476M) to a solution of ester 92(70mg, 0.136mmol) in THF (3mL) (cooled to 0 ℃). The reaction mixture was then warmed to room temperature and stirred for 2 hours, and acidified to pH 4.5 with Amberlite IR-120 (n) acidic resin. The resin was filtered off and washed with ethanol and water. Concentration in vacuo gave 66mg (97%) of carboxylic acid 93 as a white solid.
1H NMR(CDCl3，300MHz)：δ
11.40(br s，1H)；
8.67(d，1H，J＝7.8Hz)；
6.89(s，1H)；
6.69(br d，1H，J＝8.4Hz)；
4.77(d，1H，J＝7.2Hz)；
4.70(d，1H，J＝7.2Hz)；
4.40-4.15(m，2H)；
3.39(s，3H)；
2.84(dd，1H，J＝4.8，17.1Hz)；
2.45-2.30(m，1H)；
1.95(s，3H)；1.49(s，9H)；
1.48(s，9H)。
Example 32
Guanidinecarboxylic acid TFA salt 94: add di-Boc guanidinocarboxylic acid 93(23mg, 0.046mmol) to CH2Cl2To a solution (cooled to 0 ℃ C.) (1mL) was added neat trifluoroacetic acid (500. mu.L). After 30 minutes the reaction mixture was warmed to room temperature and stirred for an additional 1.25 hours. The volatiles were removed in vacuo and the residue was taken up in H2Co-evaporation of O several times gave a pale orange solid. By inverting C18Chromatography by H2O as eluent, the residue was purified, the fractions containing the expected product were combined and lyophilized to give 15mg 93 as a white powder.
1H NMR(D2O，500MHz)：δ
6.82(t，1H，J＝2.0Hz)；
4.51-4.47(m，1H)；
3.93(dd, 1H, J ═ 9.0, 11.2 Hz); 3.87-3.80 (apparent ddd, 1H);
2.88(m，1H)；
2.48-2.45 (composite m);
2.07(s，3H)。
13C NMR(D2O)：δ
176.1；170.0；157.1；139.2；129.5；69.4；56.2；50.9；30.3；22.2。
example 33
102, synthesis: a solution of azidoallyl ether 6(24mg, 0.082mmol) in ethanol (1mL) was treated with hydrogen (1atm) over Lindlar catalyst (30mg) for 1.5 hours. The reaction mixture was filtered through a pad of celite, washing with hot ethanol. Concentration in vacuo gave a pale solid which was dissolved in THF (1.5mL), treated with aqueous KOH (246. mu.L, 0.50M), stirred at room temperature for 2 hours, acidified to pH 4.0 with Amberlite IR-120 (n) acidic resin, filtered and washed with ethanol and H 2And O washing. Concentrated in vacuo to give an orange solid which was taken up with C18Column chromatography (H)2O elution) purification. The product containing fractions were combined and lyophilized to give a 2: 1 mixture of 102 and fully saturated compound 103 as a white powder. Of Compound 1021H NMR data:
1H NMR(D2O，500MHz)：δ
7.85(s，1H)；
4.29(br d，1H，J＝9.2Hz)；
4.16(dd，1H，J＝11.6，11.6Hz)；3.78-3.72(m，2H)；
3.62 (apparent ddd, 1H);
2.95 (apparent dd, 1H);
2.58-2.52(m，1H)；
2.11(s，3H)；
1.58(q，2H，J＝7.3Hz)；
0.91(t，3H，J＝7.3Hz)。
example 34
115 synthesis: a solution of amino acid 114(10.7mg, 0.038mmol) in water (1.3mL) was cooled to 0 ℃, adjusted to pH 9.0 with 1.0M NaOH, then benzylformamide hydrochloride (formimidate) was added in one portion (26mg, 0.153mmol), and the reaction mixture was stirred at 0-5 ℃ for 3 hours while maintaining pH 8.5 to 9.0 with 1.0M NaOH. The reaction mixture was then concentrated in vacuo and the residue was taken up in C18The column was eluted with water. The product containing fractions were combined and lyophilized to give formamidinecarboxylic acid 115(10mg) as a white powder.
1H NMR(D2O, 300MHz, isomer mixture): δ 7.83(s, 1H); [ 6.46 (s')&6.43(s); a total of 1H ]; 4.83(d, 1H, J ═ 7.3 Hz); 4.73(d, 1H, J ═ 7.3 Hz);
4.50-4.35(m，1H)；
4.10-4.05(m，1H)；
[ 4.04-3.95(m) & 3.80-3.65(m), total 1H ]; 3.39(s, 3H);
2.90-2.75(m，1H)；
2.55-2.30(m，1H)；
[ 2.03(s) & 2.01(s), total 3H ].
Example 35
Compound 123: tosyl chloride (4.3g, 22.6mmol) was added to a solution of alcohol 63(5.842g, 20.5mmol) and DMAP (200mg) in pyridine (40 mL). The mixture was stirred at room temperature for 40 hours and the pyridine was removed under reduced pressure. The reaction was quenched with water and extracted three times with E-tOAc. The combined organic extracts were washed with water, brine, MgSO 4After drying, purification by flash column chromatography (hexane/EtOAc ═ 2/1) gaveP-toluenesulfonate (8.04g, 89%):
1H NMR(CDCl3)δ
7.84(d，J＝8.3Hz，2H)，
7.33(d，J＝8.1Hz，2H)
4.78(m，1H)，4.43(m，1H)，
4.06(m，1H)，3.79(s，3H)，
2.44(s，3H)，
2.43-1.92(m，4H)，
1.61-1.22(m，10H)。
example 36
Compound 124: adding POCl3(100. mu.L, 1.1mmol) was added to a solution of alcohol 123(440mg, 1.0mmol) in pyridine (3 mL). The mixture was stirred at room temperature for 12 hours with saturated NH4The reaction was interrupted by a Cl solution. The aqueous phase was extracted three times with diethyl ether, the diethyl ether layers were combined, washed twice with water, twice with 2N HCl solution, washed with brine and then MgSO4And (5) drying. Flash column chromatography (hexanes/EtOAc ═ 2/1) gave the expected product 124 as a mixture with some impurities (350mg, 83%, 2/1).
Example 37
Compound 1: methanesulfonyl chloride (330 μ L, 4.23mmol) was added to a-10 ℃ solution of acetonide of known methyl shikimate (877mg, 3.85mmol, "Tetrahedron Lett.", 26: 21(1985)) in dichloromethane (15mL), followed by dropwise addition of triethylamine (640 μ L, 4.62 mmol). The solution was stirred at-10 ℃ for 1 hour and then at 0 ℃ for 2 hours, at which time methanesulfonyl chloride (30. mu.L), triethylamine (64. mu.L) were added. After 1 hour, cold water was added, the organic phase was separated, washed with water and dried (MgSO)4) And then evaporated. The crude product was chromatographed on silica gel (1/1 hexanes/ethyl acetate) to give the mesylate 130 as an oil (1.1g, 93%). Mesylate 130(990mg, 3) 2mmol) was dissolved in tetrahydrofuran (5. mu.L) and treated with 1M HCl (5 mL). The solution was stirred at room temperature for 19 hours, diluted with 5mL of water and stirred for a further 7 hours. The organic solvent was distilled off to leave an oily residue, which was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried (MgSO)4) And then evaporated. Adding CH2Cl2To the crude residue, the white solid which separated out was filtered off and washed with CH2Cl2After washing diol 131(323mg, 38%) was obtained. A partial suspension of this diol 131(260mg, 0.98mmol) in THF (5mL) was cooled to 0 deg.C, DBU (154. mu.L, 1.03mmol) was added, and the solution was stirred at 0 deg.C for 3 hours, then warmed to room temperature and stirred for 5 hours. The solvent was evaporated and the crude residue partitioned between ethyl acetate (40mL) and 5% citric acid (20 mL). The organic phase was washed with brine, the aqueous phase was back-extracted with ethyl acetate (15mL), the organic extracts were combined and dried (MgSO)4) Post evaporation gave epoxide (117mg, 70%) as a white solid, which was1The H NMR spectrum is consistent with structure 1 prepared by literature methods.
Example 38
Alcohol 51: trifluoroacetic acid (8mL) was added to 0 ℃ CH of a protected alcohol (PG ═ methoxymethyl) (342mg, 1.15mmol)2Cl2(10mL) in solution. After 5 minutes at 0 ℃, the solution was stirred at room temperature for 1 hour and evaporated. The crude product was purified on silica gel (ethyl acetate) to give the alcohol 51 as an oil (237mg, 82%):
1H NMR(300MHz，CDCl3)δ
2.11(s，3H)，2.45(m，1H)，
2.97(dd，1H，J＝3.8，18.8)，
3.66(m，2H)，3.78(s，3H)，
4.40(br s，1H)，
5.22(br s，1H)，
6.19(br s，1H)，
6.82(m，1H)。
Example 39
Methyl ether 150: NaH (60% dispersion in mineral oil, 8mg, 0.20mmol) was added to a solution of alcohol 51(46mg, 0.18mmol) and methyl iodide (56. mu.L, 0.90mmol) in THF (0.7mL), and after stirring at 0 ℃ for 2.5 hours, a second portion of NaH (2mg) was added. Stir at rt for 1h, rt for 4 h, cool to 0 ℃ and add 5% citric acid (0.5 mL). The mixture was extracted with ethyl acetate (4X 2mL), and the organic extracts were combined and dried (MgSO4) And then evaporating. The crude residue was purified on silica gel (ethyl acetate) to give methyl ether 150(12mg, 25%) as a solid:
1H NMR(300MHz，CDCl3)δ
2.07(s，3H)，
2.23-2.34(m，1H)，
2.89 (apparent ddd, 1H),
3.43(s，3H)，3.58(m，1H)，
3.78(s，3H)，4.13(m，1H)，
4.40(m，1H)，
5.73(d，1H，J＝7.6)，
6.89(m，1H)。
example 40
Amino acid 151: ph loaded by polymer3P (75mg, 3mmol P/g resin) was added to methyl ether 150(12mg, 0.45mmol) in THF (1mL)/H2O (100. mu.L) solution. The mixture was stirred at room temperature for 19 hours. The resin was filtered off, washed several times with THF, the filtrate combined with washings and evaporated to give 8mg of a crude residue which was dissolved in THF (0.5mL) and 0.5M KOH (132. mu.L)/water (250. mu.L) added. The solution was stirred at room temperature for 1.25 h, the pH was adjusted to 3-4 with IR 120 ion exchange resin, the resin was filtered off and reacted with 1M HThe Cl was stirred together and filtered, and the resin was treated with 1M HCl in the same way until the acidic washings were free of amine (as detected by ninhydrin). The resin washes were combined and the residue after evaporation was purified on C-18 reverse phase silica gel (eluting with water) and freeze dried to give amino acid 151(1.8mg, 15%) as a white solid:
1H NMR(300MHz，D2O)δ
2.09(S，3H)，
2.48 to 2.59 (apparent qt, 1H),
2.94(dd，1H，J＝5.7，17.4)，
3.61(m，1H)，
4.14-4.26(m，2H)，
6.86(br s，1H)。
EXAMPLE 41
Amino acid allyl ether 153: polystyrene-supported PPh3(50mg) to azide 6(16mg, 0.054mmol) in THF (0.5mL)/H2O (35. mu.L) solution. The reaction mixture was stirred at room temperature for 24 hours, filtered through a sintered glass funnel and washed with hot methanol. Concentration in vacuo gave the crude amino ester, which was dissolved in THF (1.0mL) and treated with aqueous KOH (220. mu.L, 0.5M). After stirring at room temperature for 2 hours, Amber-lite IR-120 (n) -acidic resin was added until the solution pH was 4.5. Filtering the resin, reacting with ethanol and H2And O washing. Vacuum concentrating to give a pale orange solid, and adding reverse phase C18Chromatography (H)2O elution) purification. Fractions containing the expected product were combined and lyophilized to give the amino acid as a white powder.1H
NMR(D2O，300MHz)：δ
6.51(br t，1H)；
6.05-5.80(m, 1H, -CH ═ allyl); 5.36-5.24(m, 2H, ═ CH2Allyl); 4.35-4.25(m, 1H);
4.25-4.05(m，2H，-CH2-, allyl); 4.02-3.95(m, 1H);
3.81-3.70(m，1H)；
2.86-2.77 (apparent dd, 1H);
2.35-2.24 (composite m, 1H);
2.09(s，3H)。
example 42
Epoxide 161: MCPBA (690mg) was added to a 0 deg.C solution of alkene 160(532mg, 1.61mmol, prepared in example 14, crude mesylate filtered through silica gel with 30% EtOAc in hexanes) in dichloromethane (15mL) before use. The mixture was allowed to warm to room temperature and stirred overnight. The solvent was removed under vacuum and diluted with ethyl acetate. The organic layer was washed with aqueous sodium bisulfite, saturated sodium bicarbonate, brine, MgSO 4Drying, concentration in vacuo and subsequent purification of the residue by flash column chromatography (30% hexane/ethyl acetate) gave 161(437mg, 78%) as a light-coloured oil.
1H NMR(CDCl3，300MHz)：
[ 1: 1 diastereomer mixture ] δ [ 4.75(dd, J ═ 3.9, 8.2Hz) & 4.71(dd, J ═ 3.9, 8.4Hz), total 1H ];
4.37(m，1H)；
4.25-4.00(m，2H)；
3.78(s，3H)；
〔3.68(dd，J＝5.7，11.7Hz)&
3.51(dd, J ═ 6.6, 11.7Hz), for a total of 1H ];
[ 3.17(s) & 3.16(s), total 3H ];
[ 2.99(m) & 2.93(m), total 1H ];
[ 2.83(t, J ═ 4.1Hz) and
2.82(t, J ═ 4.5Hz), total number 1H ];
2.70-2.60(m，1H)；
2.45-2.30(m，1H)。
example 43
Diol 162: epoxide 161(437mg, 1.23mmol) in 5 drops of 70% HClO4THF (20mL)/H of (1)2O (10mL) was warmed and refluxed for 1 hour. Adding solid NaHCO3The mixture was concentrated in vacuo. The residue was dissolved in EtOAc, washed with brine and dried. Concentration in vacuo gave crude diol 162 as a light oil (quantitative yield). Used directly in the next reaction without purification.
Example 44
An aldehyde 163: oxidation of diol 162 was carried out as described by Vo-Quang et al, "Synthesis", 68 (1988). NaIO is introduced4(4.4mL, 0.65M aqueous solution) was added to a slurry of silica gel (4.3g) in dichloromethane (30 mL). Further EtOAc (5mL)/CH in crude diol 162(520mg) was added 2Cl2(15mL) of the solution. After 1 hour the solid was filtered off and washed with 20% hexane/EtOAc. Concentrate to an oily residue, dissolve in EtOAc and use MgSO4And (5) drying. Concentration in vacuo gave the aldehyde 163 as a light oil which was used directly in the next reaction.
1H NMR(CDCl3，300MHz)：δ
9.69(s，1H)；6.98(m，1H)；
4.72(dd，1H，J＝3.7，9.1Hz)；
4.53(d，1H，J＝18.3Hz)；
4.45(d，1H，J＝18.3Hz)；
4.31(m，1H)；
4.26-4.18(m，1H)；
3.79(s，3H)；3.19(s，3H)；
3.05(dd，1H，J＝5.7，18.6Hz)；2.20-2.45(m，1H)。
Example 45
Alcohol 164: crude aldehyde 163 was purified by Borch co-workers, "j.amer.chem.soc.", 93: 2897(1971) to the procedure of NaCNBH3Work-up, flash chromatography (40% hexanes/EtOAc) gave 269mg (65%) of alcohol 164:
1H NMR(CDCl3，300MHz)：δ
6.91(m，1H)；
4.75(dd，1H，J＝3.9，8.7Hz)；
4.34(br t，1H，J＝4.1Hz)；
4.25-4.15(m，1H)；
3.85-3.70(m，4H)；
3.77(s，3H)；3.16(s，3H)；
2.95(dd，1H，J＝5.7，18.6Hz)；
2.37(dd，1H，J＝7.1，18.6Hz)；
2.26(br s，1H)。
example 46
Aziridine 165: alcohol 164(208mg, 0.62mmol) was acetylated using conventional methods (AcCl, pyridine, dichloromethane, DMAP catalyst) to give the acetate (241mg, 100%). The crude acetate (202mg, 0.54mmol) was taken up Ph in THF (12mL) at room temperature3P (155mg) for 2 hours. Then H is added2O (1.1mL) and triethylamine (224. mu.L) were added and the solution was stirred overnight. The reaction mixture was concentrated and the residue partitioned between ethyl acetate and saturated bicarbonate/brine. Drying the organic layer, vacuum concentrating, and purifying by flash chromatographyConversion (10% MeOH/EtOAc) gave aziridine 165 as a white solid (125mg, 90%).
1H NMR(CDCl3，300MHz)：δ
6.80(m，1H)；4.44(br s，1H)；4.23(t，2H，J＝4.8Hz)；
3.82-3.65(m，2H)；
3.74(s，3H)；
2.85(br d，1H，J＝19.2Hz)；
2.65-2.40(m，3H)；
2.09(s，3H)；
1.25(br s，1H)。
Example 47
N-Boc aziridine 166: boc anhydride (113mg, 0.52mmol) was added to a solution of aziridine 165(125mg, 0.49mmol), triethylamine (70. mu.L), DMAP (catalytic amount) in dichloromethane (7 mL). After 1 h, it was concentrated and the residue was purified by flash chromatography (40% EtOAc/hexanes) to yield 154mg (88%) of N-Boc aziridine 166 as a light oil.
1H NMR(CDCl3，300MHz)：δ
6.82(m，1H)；
4.47(brm，1H)；
4.23(t，2H，J＝4.7Hz)；
3.81(t，2H，J＝4.7Hz)；
3.75(s，3H)；
3.00(brd，1H，J＝18.0Hz)；
2.90-2.85(m，2H)；
2.65-2.55(m，1H)；
2.10(s，3H)；1.44(s，9H)。
Example 48
Azido ester 167: aziridine 166(154mg, 0.43mmol), sodium azide (216mg) and ammonium chloride (223mg) were heated in DMF (5mL) at 100 ℃ for 18 h. After the reaction mixture was cooled, it was partitioned between ether and brine. The ether layer was washed with water and brine and dried (MgSO)4). Concentration gave a crude residue which was in CH at room temperature2Cl2Treated with 40% TFA. After 2 h, concentrate in vacuo to give a pale oil which is passed through a short column of silica gel (eluting with EtOAc). The acylation product was isolated by flash chromatography (5% MeOH in chloroform) in the conventional manner (AcCl, pyridine, dichloromethane, DMAP catalyst) to give azido ester 167 as a pale yellow oil, 16mg (11% over three steps).
1H NMR(CDCl3，300MHz)：δ
6.85(m，1H)；
5.80(brd，1H，J＝7.8Hz)；
4.55(m，1H)；
4.25-4.10(m，3H)；
3.90-3.85(m，2H)；
3.78(s，3H)；3.55(m，1H)；
2.90(dd，1H，J＝5.4，17.0Hz)；2.45-2.25(m，1H)；
2.10(s，3H)；2.05(s，3H)。
Example 49
Amino acid 168: aqueous KOH (208. mu.L, 0.0476M) was added to a 0 ℃ solution of ester 167(16mg, 0.047mmol) in THF (1 mL). The reaction mixture was then warmed to room temperature and stirred for 2 hours, and acidified to pH 4.0 with Amberlite IR-120 (n) acidic resin. Filtering the resin, reacting with ethanol and H2And O washing. Concentration in vacuo afforded 14mg (100%) of azidocarboxylic acid as a white solid, which was dissolved in ethanol (2 mL)) According to the procedure described by Corey and co-workers, "Synthesis", 590(1975), on Lindlar catalyst (15mg) with hydrogen (1atm) for 16 hours. The reaction mixture was filtered through a pad of celite, washed with hot ethanol and water. After concentration in vacuo, a pale orange solid is obtained, which is washed with C 18Column chromatography (H)2O elution) and the product containing fractions were combined and lyophilized to give 9.8mg of white powder 168.
1H NMR(D2O，500MHz)：δ
6.53(br s，1H)；
4.28(br m，1H)；
4.08(dd, 1H, J ═ 11.0, 11.0 Hz); 3.80-3.65 (composite m, 4H);
3.44(m，1H)；
2.84 (apparent dd, 1H);
2.46-2.39 (composite m, 1H);
2.08(s，3H)。
example 50
Epoxy MOM ether 19(PG ═ methoxymethyl): according to Mordini and co-workers, "j.org.chem.", 59: 4784(1994) from epoxy alcohol 1 (74%).
1H NMR(CDCl3，300MHz)：δ
6.73(m，1H)；4.87(s，2H)；
4.59(t，1H，J＝2.4Hz)；
3.76(s，3H)；3.57(m，1H)；
3.50-3.40(m，1H)；
3.48(s，3H)；
3.10(d，J＝19.5Hz)；
2.45(m，1H)。
Example 51
Aziridine 170: prepared according to the general procedure described in examples 3 and 4 from epoxide 19(PG ═ methoxymethyl) (total yield 77%).
1H NMR(CDCl3，300MHz)：δ
6.85(m，1H)；4.78(s，2H)；
4.54(m，1H)；3.73(s，3H)；
3.41(s，3H)；
2.87(d，1H，J＝18.9Hz)；
2.70-2.45(m，3H)。
Example 52
Azido ester 22(PG ═ methoxymethyl): aziridine 170(329mg, 1.54mmol), NaN3(446mg) with NH4Cl (151mg) was heated in DMF (20mL) at 65 ℃ for 18 h. After the reaction mixture was cooled, it was partitioned between ether and brine. The ether layer was washed with water, brine and dried (MgSO)4). Concentration in vacuo gave crude azidoamine as a pale oil which was dissolved in CH2Cl2In (15mL), pyridine (4mL) was treated with AcCl (150. mu.L). Flash chromatography of the residue afforded 350mg (76%) of azido ester 22(PG ═ methoxymethyl) as a light oil.
1H NMR(CDCl3，300MHz)：δ
6.78(s，1H)；
6.39(br d，1H，J＝7.8Hz)；
4.72(d，1H，J＝6.9Hz)；
4.66(d，1H，J＝6.9Hz)；
4.53(br d，1H，J＝8.4Hz)；
4.00-3.90(m，1H)；
3.80-3.65(m，1H)；
3.75(s，3H)；3.37(s，3H)；
2.85(dd，1H，J＝5.4，17.7Hz)；
2.35-2.20(m，1H)；
2.04(s，3H)。
Example 53
Amino acid 114: azide 22(PG ═ methoxymethyl) (39mg, 0.131mmol) was treated with hydrogen (1atm) over Lindlar catalyst (39mg) in ethanol for 2.5 hours as per Corey co-workers, "Synthesis", 590 (1975). The reaction mixture was filtered through a pad of celite, washed with hot ethanol and concentrated to give crude amine as a light foam, 33mg (92%). This amine was treated with aqueous KOH (380 μ L, 0.476M) in THF (1mL) and acidified to pH 4.0 after 1 hour with Amberlite IR-120 (n) acidic resin. Then filtering out the resin, washing with water and concentrating to obtain a light-colored solid, and then filtering out the solid C 18Column chromatography (H)2O elution) and the product containing fractions were collected and lyophilized to give 20mg of white powder 114.
1H NMR(D2O，300MHz)：δ
6.65(s，1H)；
4.87(d，1H，J＝7.5Hz)；
4.76(d，1H，J＝7.5Hz)；
4.47(br d，1H，J＝8.7Hz)；
4.16(dd，1H，J＝11.4，11.4Hz)；
3.70-3.55(m，1H)；
3.43(s，3H)；
2.95(dd，1H，J＝5.7，17.4Hz)；
2.60-2.45(m，1H)；
2.11(s，3H)。
Example 54
Amino acid 171: the mixture was washed with 40% TFA/CH2Cl2(1mL, cooled to 0 ℃ C. before addition) was added to solid amino acid 114(4mg, 0.015 mmol). The reaction mixture was stirred at room temperature for 1.5 hours and concentrated to give a white foam. And H2O was co-evaporated several times and lyophilized to give 5.5mg of white solid 117 as TFA salt.
1H NMR(D2O，300MHz)：δ
6.85(m，1H)；4.45(m，1H)；
4.05(dd，1H，J＝11.4，11.4Hz)；
3.65-3.55(m，1H)；
3.00-2.90(m，1H)；
2.60-2.45(m，1H)；
2.09(s，3H)。
Example 55
Acetonide 180: p-toluenesulfonic acid (274mg, 1.44mmol, 1 mol%) was added to a suspension of shikimic acid (25g, 144mmol, Aldrich) in methanol (300mL) and the mixture was heated at reflux for 2 h. More p-toluenesulfonic acid (1 mol%) was added and evaporated after 26 hours of reflux. The crude methyl ester (28.17g) was suspended in acetone, treated with dimethoxypropane (35mL, 288mmol), stirred at room temperature for 6 hours and evaporated. The crude product was dissolved in ethyl acetate (400mL) and saturated NaHCO was used3(3X 125mL) was washed with saturated NaCl. Organic phase drying (MgSO)4) Filtered and evaporated to give crude acetonide 180 (-29.4 g), which was used as such:
1H NMR(CDCl3)：δ
6.91(t，1H，J＝1.1)，
4.74(t，1H，J＝4.8)，
4.11(t，1H，J＝6.9)，
3.90(m，1H)；
2.79(dd，1H，J＝4.5，17.4)，
2.25(m，2H)，1.44(s，3H)，
1.40(s，3H)。
example 56
Mesylate 130: triethylamine (29.5mL, 212mmol) was added to 0 deg.C acetone compound 180(29.4, 141mmol) in CH 2Cl2(250mL) followed by addition of methanesulfonyl chloride (13.6mL, 176mmol) over 10 minutes. The reaction mixture was stirred at 0 ℃ for 1 hour, ice-cold water (250mL) was added, and after transfer to a separatory funnel, the organic phase was washed with water, 5% citric acid (300mL), saturated NaHCO3Washed (300mL) and dried (MgSO)4) Filtered and evaporated. The crude product was filtered (eluting with ethyl acetate) through a sintered glass funnel (packed with a small piece of silica gel). Evaporation of the filtrate gave mesylate 130(39.5g, 91%) as a viscous oil and was used directly in the next step:
1H NMR(CDCl3)：δ
6.96(m，1H)，4.80(m，2H)，
4.28(dd，1H，J＝6.6，7.5)，
3.90(s，3H)，3.12(s，3H，)，
3.01(dd，1H，J＝5，17.7)，
2.56-2.46(m，1H)。
example 57
Diol 131: p-toluenesulfonic acid (1.11g, 5.85mmol, 5 mol%) was added to a solution of mesylate 130(35.85g, 117mmol) in methanol (500mL)The solution was refluxed for 1.5 hours and evaporated. The residue was redissolved in methanol (500mL) and refluxed for 4 hours. The solvent was evaporated and the crude oil was triturated with ether (250 mL). After crystallization at 0 ℃ overnight, the solid was filtered off, washed with cold ether and dried to give diol 131(24.76g) as a white solid. After evaporation of the filtrate, the residue was crystallized from methanol/ether to give a further 1.55 g. A total of 26.3g (85%) of diol 131:1H NMR(CD3OD)：δ
6.83(m，1H)，4.86(m，1H)，
4.37(t，1H，J＝4.2)，
3.87(dd，1H，J＝4.2，8.4)，
3.75(s，3H)，3.13(s，3H)，
2.98-2.90(m，1H)，
2.53-2.43(m，1H)。
example 58
Epoxy alcohol 1: a suspension of diol 131(20.78g, 78mmol) in tetrahydrofuran (400mL) was treated with 1, 8-diazabicyclo [ 5.4.0 ] undec-7-ene (11.7mL, 78mmol) at 0 deg.C and stirred at room temperature for 9 hours to complete the reaction. After evaporation the crude residue was dissolved in CH 2Cl2(200mL) and washed with saturated NaCl (300 mL). Using CH as the aqueous phase2Cl2Extraction (2X 200 mL). The combined organic extracts were dried (MgSO)4) Filtered and evaporated. The crude product was purified on silica gel (ethyl acetate) to give 1(12g, 90%) of solid epoxy alcohol as a white solid, which was purified1H NMR spectrum is consistent with literature reports:
McGowan，D.A.；Berchtold，G.A.，″J.Org.Chem.″，46：2381(1981)。
example 59
Methoxymethyl ether 22(PG ═ methoxymethyl): n, N' -diisopropylethylamine (12.3mL, 70.5mmol) was added to the CH of epoxyalcohol 1(4g, 23.5mmol)2Cl2(100mL) was added followed by chloromethyl methyl ether (3.6mL, 47mmol, from technical distillation). After refluxing the solution for 3.5 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate (200mL) and water (200 mL). The aqueous phase was extracted with ethyl acetate (100mL), and the combined organic extracts were washed with saturated NaCl (100mL) and dried (MgSO)4) After filtration, evaporation gives 4.9g of a solid residue, the purity of which is suitable for direct use in the following step: mp62-65 deg.C (crude); mp64-66 deg.C (diethyl ether/hexane);
1H NMR(CDCl3)：δ
6.73(m，1H)，4.87(s，2H)，
4.59(m，1H)，3.75(s，3H)，
3.57(m，1H)，
3.48 (s, 4H with m superimposed),
3.07(dd，1H，J＝1.2，19.8)，
2.47(dq，1H，J＝2.7，19.5)。
ethyl ester congener of compound 22:
diisopropylethylamine (34.0mL, 0.13mmol) was added to the corresponding ethyl ester of Compound 1 (12.0g, 0.065mol) in CH at room temperature2Cl2(277mL) followed by chloromethyl methyl ether (10.0mL, 0.19 mol). The reaction mixture was gently refluxed for 2 hours, cooled and concentrated in vacuo, and redistributed in EtOAc and water. The organic layer was separated, washed sequentially with dilute HCl, saturated bicarbonate, brine, MgSO 4After drying, evaporation is carried out in vacuo. Flash chromatography (silica gel, 50% hexane/EtOAc) afforded 13.3g (90%) of the corresponding ethyl ester of compound 22 as a colorless liquid,
1H NMR(300MHz，CDCl3)：δ
6.73-6.71(m，1H)；
4.87(s，2H)；
4.61-4.57(m，1H)；
4.21(q，2H，J＝7.2Hz)；
3.60-3.55(m，1H)；
3.50-3.45(m，1H)；
3.48(s，3H)；
3.12-3.05(m，1H)；
2.52-2.42(m，1H)；
1.29(t，3H，J＝7.2Hz)。
example 60
Alcohol 181: sodium azide (7.44g, 114.5mmol) and ammonium chloride (2.69g, 50.4mmol) were added to methoxymethyl ether 22(PG ═ methoxymethyl) (4.9g, 22.9mmol) in 8/1-MeOH/H2O (175mL, v/v) solution and the mixture was refluxed for 15 hours. The precipitated salt was dissolved by dilution with water (75mL), and the solution was concentrated to remove methanol. The resulting aqueous phase containing the oily residue which separated out was diluted to 200mL with water and extracted with ethyl acetate (3X 100 mL). The combined organic extracts were washed with saturated NaCl (100mL) and dried (MgSO)4) After filtration and evaporation. The crude was purified on silica gel (1/1-hexane/ethyl acetate) to give alcohol 181(5.09g, 86%) as a pale yellow oil. The alcohol 181 can be used directly in the next step without further purification for subsequent preparation.
1H NMR(CDCl3)：δ
6.86(m，1H)，4.79(s，2H)，
4.31(brt，1H，J＝4.2)，
3.90-3.75, 3.77 (s, 5H with m superimposed), 3.43(s, 1H),
2.92(d，1H，J＝6.6)，
2.87(dd，1H，J＝5.4，18.6)，
2.21-2.30(m，1H)。
example 61
Mesylate 184: triethylamine (4.4mL, 31.5mmol) and methanesulfonyl chloride (2.14mL, 27.7mmol) were added sequentially to CH in alcohol 181(6.47g, 25.2mmol) at 0 deg.C2Cl2(100mL) in solution. The reaction mixture was stirred at 0 ℃ for 5 minutes, then warmed to room temperature and stirred for 15 minutes. After evaporation, the residue was partitioned between ethyl acetate (200mL) and water (100mL) and the organic phase was washed with water (100mL), saturated NaHCO 3(100mL), washed with saturated NaCl (100 mL). The water eluate was extracted once with ethyl acetate and the same NaH-CO was used3The ethyl acetate was washed with NaCl solution. The combined organic extracts were dried (MgSO)4) Filtered and evaporated. The purity of the crude product is suitable for direct use in the following step: 1H NMR (CDCl)3)δ
6.85(m，1H)，
4.82(d，1H，J＝6.9)，
4.73(d，1H，J＝6.9)，
4.67(dd，1H，J＝3.9，9.0)，
4.53(brt，1H，J＝4.2)，
3.78(s，3H)，3.41(s，3H)，
3.15(s，3H)，
2.98(dd，1H，J＝6.0，18.6)，
2.37(m，1H)；
13C NMR(CDCl3)δ165.6，134.3，129.6，96.5，78.4，69.6，55.8，55.7，52.1，38.2，29.1。
Example 62
Aziridine 170: ph is reduced at 0 DEG C3P (8.2g, 31mmol) was added to a solution of mesylate 184(8.56g, 25mmol) in THF (150mL), initially with an 1/3 amount added on cooling, and after removal of the ice bath the remainder was taken over 10-15 minutesPh of3And adding P. Ph3After the addition of P was complete, stirring was carried out at room temperature for 3 hours during which a white precipitate formed. To this suspension was added triethylamine (5.2mL, 37.5mmol) and water (10mL), and the mixture was stirred at room temperature for 12 hours. Concentrated to remove THF and the residue partitioned in CH2Cl2(200mL) with saturated NaCl2(200 mL). Using CH as the aqueous phase2Cl2Extracting for several times, combining organic extracts, and drying (MgSO)4) Filtration and evaporation gave the crude product, which was purified on silica gel (10% MeOH/EtOAc) to give aziridine 170 as an oil (4.18g, 78%) which typically contained trace amounts of triphenylphosphine oxide impurities:
1H NMR(CDCl3)δ
6.81(m，1H)，4.78(s，2H)，
4.54(m，1H)，3.73(s，3H)，
3.41(s，3H)，
2.87 (apparent dd, 1H),
2.64(brs，1H)，
2.56-2.47(m，2H)，
the NH signal is not significant;
13C NMR(CDCl3)δ166.9，132.5，128.0，95.9，69.5，55.2，51.6，31.1，27.7，24.1。
example 63
Amine 182: a solution of aziridine 170(3.2g, 15mmol) in DMF (30mL) was degassed by applying vacuum on a rotary evaporator (40 ℃ C.) for several minutes. Then sodium azide (4.9g, 75mmol) and ammonium chloride (1.6g, 30mmol) were added and the mixture was heated at 65-70 ℃ for 21 hours. After cooling to room temperature, it was diluted with ethyl acetate (. about.100 mL) and filtered. The filtrate was evaporated and the residue partitioned between ether (100mL) and saturated NaCl (100 mL). The organic phase was washed once more with saturated NaCl (100mL) and dried (MgSO) 4) Filtration ofAnd then evaporating. The water-washed solution was extracted with ethyl acetate and treated as above to obtain additional crude product. The crude product was purified on silica gel (5% MeOH/CH)2Cl2) Purification gave amine 182(2.95g) as an oil containing a small amount of the triphenylphosphine oxide impurity from the previous step:
1H NMR(CDCl3)δ
6.82(t，1H，J＝2.3)，
4.81(d，1H，J＝7.2)，
4.77(d，1H，J＝6.9)，
4.09-4.04(m，1H)，
3.76(s，3H)，
3.47 and 3.44 (s, 4H with m superimposed),
2.94-2.86(m，2H)，
2.36-2.24(m，1H)，
13C NMR(CDCl3)δ165.9，137.3，128.2，96.5，79.3，61.5，55.7，55.6，51.9，29.5。
example 64
N-trityl aziridine 183: amine 182(2.59g, 10.2mmol) was dissolved in 5% HCl/MeOH (30mL) and the solution was stirred at room temperature for 3 hours. 5% HCl/MeOH (10mL) was added and stirred for 1 h, the solvent was evaporated off and 2.52g of HCl salt was obtained as a brown solid after high vacuum. To this solution at 0 ℃ in the form of the HCl salt CH2Cl2To the suspension (50mL) was added triethylamine (3.55mL, 25.5mmol) followed by a single addition of solid trityl chloride (5.55g, 12.8 mmol). The mixture was stirred at 0 ℃ for 1 hour, warmed to room temperature more than once and stirred for 2 hours, cooled to 0 ℃ again, triethylamine (3.6mL, 25.5mmol) was added, methanesulfonyl chloride (0.97mL, 12.5mmol) was added, and the resulting mixture was stirred at 0 ℃ for 1 hour and at room temperature for 22 hours. After evaporation, the residue was partitioned between ether (200mL) and water (200 mL). Water for organic phaseWashed (200mL), the aqueous phases were combined and extracted with ether (200 mL). The combined organic extracts were washed with water (100mL) and saturated NaCl (200mL) and dried (MgSO) 4) Filtered and evaporated. The crude product was purified on silica gel (1/1 hexane/CH)2Cl2) Purification gave N-trityl aziridine 183 as a white foam (3.84g, 86%).
1H NMR(CDCl3)δ
7.4-7.23(m，16H)，
4.32(m，1H)，3.81(s，3H)，
3.06(dt，1H，J＝1.8，17.1)，
2.94-2.86(m，1H)，
2.12(m，1H)，
1.85(t，1H，J＝5.0)。
Example 65
Compound 190: a solution of N-trityl aziridine 183(100mg, 0.23mmol), cyclohexanol (2mL) and boron trifluoride-diethyl ether (42. mu.L, 0.35mmol) was heated at 70 ℃ for 1.25 hours, then evaporated. The residue was dissolved in pyridine (2mL) and treated with acetic anhydride (100. mu.L, 1.15mmol) and a catalytic amount of DMAP. After stirring at room temperature for 3 hours, the residue was evaporated and partitioned between ethyl acetate and 5% citric acid. The aqueous phase is extracted with ethyl acetate, the organic extracts are combined and saturated NaHCO is used3Washed with saturated NaCl. Organic phase drying (MgSO)4) Filtered and evaporated. The crude product was purified on silica gel (1/1-hexane/ethyl acetate) to give compound 190 as a solid (53mg, 69%): mp105-107 deg.C (ethyl acetate/hexane);
1H NMR(CDCl3)δ
6.78(m，1H)，
6.11(dd，1H，J＝7.4)，
4.61(m，1H)，
4.32-4.23(m，1H)，
3.76(s，3H)，
3.44-3.28(m，2H)，
2.85(dd，1H，J＝5.7，17.6)，
2.28-2.17(m，1H)，
2.04(s，3H)，
1.88-1.19(m，10H)。
example 66
Compound 191: triphenylphosphine (57mg, 0.22mmol) and water (270. mu.L) were added to a solution of compound 190(49mg, 0.15mmol) in THF, and the solution was heated at 50 ℃ for 10 hours. After evaporation the residue was dissolved in ethyl acetate and dried (Na)2SO4) Filtered and evaporated. The crude product was purified on silica gel (1/1-MeOH/EtOAc) to afford the amine as a pale yellow solid (46 mg). A1.039N KOH solution (217. mu.L) and water (200. mu.L) were added to a solution of this amine in THF (1.5mL), stirred at room temperature for 1 hour, cooled to 0 ℃ and acidified to pH6-6.5 with IR120 ion exchange resin. The resin was filtered off, washed with methanol and the filtrate was evaporated. The solid residue was dissolved in water and passed through a C-18 reverse phase silica gel column (4X 1cm) eluting with water and then 2.5% acetonitrile/water. The product fractions were combined, evaporated, the residue dissolved in water and lyophilized to give amino acid 191(28mg) as a white solid: 1HNMR(D2O)δ
6.47(brs，1H)，
4.80(brd，1H)，
4.00(dd，1H，J＝8.9，11.6)，
3.59-3.50(m，2H)，
2.87(dd，1H，J＝5.5，17.2)，
2.06(s，3H)，
1.90-1.15 (series m, 10H);
C15H24N2O4·H2calculated value of O element analysis:
C，57.31；H，8.34；N，8.91。
measured value: c, 57.38; h, 8.09; n, 8.77.
Example 67
di-Boc guanidino ester 201: the method was performed as described by Kim and Qian, "Tetrahedron lett.", 34: 7677 (1993). Adding HgCl2(593mg, 2.18mmol) amine 200(529mg, 1.97 mmol; from example 109), di-Boc thiourea (561mg, 2.02mmol) and Et at 0 ℃ were added in one portion3N (930. mu.L) in dry DMF (5.0 mL). The heterogeneous reaction mixture was stirred at 0 ℃ for 45 min, then at room temperature for 15 min, then diluted with EtOAc and filtered through a pad of celite. After concentration in vacuo, the residue was flash chromatographed on silica gel (10% hexane/ethyl acetate) to give 904mg (90%) of 201 as a light oil.
1H NMR(CDCl3，300MHz)δ
11.39(s，1H)；
8.63(d，1H，J＝7.8Hz)；
6.89(t，1H，J＝2.4Hz)；
6.46(d，1H，J＝8.7Hz)；
4.43-4.32(m，1H)；
4.27-4.17(m，1H)；
4.13-4.06(m，1H)；
3.77(s，3H)；
3.67-3.59(m，1H)；
2.83(dd，1H，J＝5.1，17.7Hz)；
2.45-2.33(m，1H)；
1.95(s，3H)；
1.65-1.50(m，2H)；
1.45(s，18H)；
0.90(t，3H，J＝7.5Hz)。
Example 68
Carboxylic acid 202: aqueous KOH (3.45mL, 1.039N) was added to a solution of methyl ester 201(904mg, 1.77mmol) in THF (10 mL). The reaction mixture was stirred at room temperature for 17 hours, cooled to 0 ℃ and washed with Amberlite IR-120 (H)+) The acidic resin was acidified to pH 4.0. The resin was filtered off, washed with water and methanol, and concentrated in vacuo to give the free acid as a pale foam, which was used directly in the next reaction without purification.
Example 69
Guanidine carboxylic acid 203: pure trifluoroacetic acid (25mL) was added to the CH of di-Boc guanylic acid 202 (crude product from previous reaction) at 0 deg.C 2Cl2(40mL), the reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 2 hours. Vacuum concentrating to give light orange solid, adding C18Purification by reverse phase chromatography (elution with water). The fractions containing the expected product were collected and lyophilized to yield 495mg (68%, 2 steps) of the trifluoroacetate salt of guanidinecarboxylic acid 203.
1H NMR(D2O，300MHz)：δ
6.66(s，1H)；
4.29(bd，1H，J＝9.0Hz)；
4.01(dd，1H，J＝10.8，10.8Hz)；
3.87-3.79(m，1H)；
3.76-3.67(m，1H)；
3.60-3.50(m，1H)；
2.83(dd，1H，J＝5.1，17.4Hz)；
2.47-2.36(m，1H)，
2.06(s，3H)；
1.65-1.50(m，2H)；
0.90(t，3H，J＝7.2Hz)。
C15H23O6N4F3Calculated values of elemental analysis:
C，43.69；H，5.62；N，13.59。
measured value: c, 43.29; h, 5.90; n, 13.78.
Example 70
Formamidine carboxylic acid 204: a solution of amino acid 102(25mg, 0.10mmol, prepared by the method of example 110) in water (500. mu.L) was adjusted to pH 8.5 with 0.1N NaOH at 0-5 ℃. Benzylcarbamide hydrochloride (45mg, 0.26mmol) was added in one portion and the reaction mixture was stirred at 0-5 ℃ for 3 hours while maintaining the pH 8.5-9.0 (with 1.0N NaOH). Then concentrated in vacuo C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product, followed by lyophilization gave 4.0mg (13%) of formamidinecarboxylic acid 204.
1H NMR(D2O，300MHz)：δ
7.85(s，1H)；
6.53(bd，1H，J＝7.8Hz)；
4.32-4.25(bm，1H)；
4.10-3.97(m，1H)；
3.76-3.67(m，2H)；
3.57-3.49(m，1H)；
2.86-2.81(m，1H)；
2.55-2.40(m，1H)；
2.04(s，1H)；
1.65-1.50(m，2H)；
0.90(t，3H，J＝7.4Hz)。
Example 71
Amino acid 206: aqueous KOH (481. mu.L, 1.039N) was added to a solution of aminomethyl ester 205(84mg, 0.331mmol, prepared from example 107) in THF (1.0 mL). The reaction mixture was stirred at room temperature for 2.5 hours and acidified to pH6.5 with Amberlite IR-120(H +) acid resin. The resin was filtered off, washed with water and methanol and concentrated in vacuo to give the amino acid as a white solid which was passed through C 18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product, followed by lyophilization gave 59mg (74%) of amino acid 206.
1H NMR(CD3OD，300MHz)：δ
6.60(bd，1H，J＝1.8Hz)；
4.01-3.95(m，1H)；
3.71-3.60(m，2H)；
3.50-3.42(m，1H)；
3.05-2.85(m，2H)；
2.39-2.28(m，1H)；
1.70-1.55(m，2H)；
0.95(t，3H，J＝7.5Hz)。
Example 72
Trifluoroacetamide 207: add Et under argon after degassing to a solution of amino acid 206(59mg, 0.246mmol) in dry methanol (1.0mL)3N (35. mu.L), methyl trifluoroacetate (35. mu.L) was added, stirred at room temperature for 1 week and concentrated. Analysis by 1H NMR showed the reaction to be 40% complete. The crude reaction product was redissolved in dry methanol (1.0mL), methyl trifluoroacetate (1.0mL) and Et3In N (0.5mL)And stirred at room temperature for 5 days. Then concentrated in vacuo and redissolved in 50% THF/H2In O (2.0mL), using Amberlite IR-120 (H)+) The acidic resin was acidified to pH4, filtered and concentrated to give crude trifluoroacetamide carboxylic acid which was used directly in the next reaction without purification.
Example 73
Amino acid 208: a solution of azide 207 (crude from the previous reaction) in THF (2.0mL) and water (160. mu.L) was treated with triphenylphosphine (225mg) supported on the polymer at room temperature, after stirring for 20 h, the polymer was filtered off and washed with methanol. Concentrating under vacuum to give a pale solid, and adding C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 6.5mg (9%) of trifluoroacetamide amino acid 208.
1H NMR(D2O，300MHz)：δ
6.59(bs，1H)；
4.40-4.30(m，1H)；
4.26(t，1H，J＝10.1Hz)；
3.80-3.66(m，2H)；
3.56-3.47(m，1H)；
2.96(bdd，1H，J＝5.4，17.7Hz)；
2.58-2.45(m，1H)；
1.62-1.50(m，2H)；
0.89(t，3H，J＝7.5Hz)。
Example 74
Methanesulfonamide methyl ester 209: methanesulfonyl chloride (19. mu.L) was added to 0 ℃ amine 205(58mg, 0.23mmol, prepared from example 107), Et3N (97. mu.L) in CH with catalytic amount of DMAP (several crystals)2Cl2(1.0 mL). After 30 minutes the reaction mixture was warmed to room temperatureWarm and stirring for an additional 1 h, concentrate in vacuo, and flash chromatograph the residue on silica gel (50% hexane/ethyl acetate) to yield 61mg (79%) of sulfonamide 209.
1H NMR(CDCl3，300MHz)：δ
6.87(t，1H，J＝2.3Hz)；
5.08(d，1H，J＝7.5Hz)；
4.03-3.90(m，1H)；
3.78(s，3H)；
3.75-3.45(m，4H)；
3.14(s，3H)；
2.95(dd，1H，J＝5.2，17.3Hz)；
2.42-2.30(m，1H)；
1.75-1.55(m，2H)；
0.95(t，3H，J＝7.5Hz)。
Example 75
Amino ester 210: a solution of azide 209(61mg, 0.183mmol) in THF (2.0mL) and water (118. mu.L) was treated with triphenylphosphine (170mg) supported on polymer at room temperature, and after stirring for 17.5 h the polymer was filtered off and washed with methanol. After concentration in vacuo, the residue is flash chromatographed on a short silica gel column (100% methanol) to give 45mg (80%) of the amino ester 210 as a pale foam.
1H NMR(CDCl3，300MHz)：δ
6.85(s，1H)；
3.94(bd，1H，J＝7.8Hz)；
3.77(s，3H)；
3.74-3.60(m，2H)；
3.55-3.45(m，1H)；
3.25-3.15(m，1H)；
3.11(s，3H)；
2.94-2.85(m，1H)；
2.85(bs，2H)；
2.22-2.10(m，1H)；
1.70-1.56(m，2H)；
0.94(t，3H，J＝7.5Hz)。
Example 76
Amino acid 211: a solution of methyl ester 210(21mg, 0.069mmol) in THF (200. mu.L) was treated with aqueous KOH (135. mu.L, 1.039N), the reaction mixture was stirred at room temperature for 40 minutes, and Amberlite IR-120 (H)+) Neutralizing with acidic resin to pH7.0, filtering off resin, washing with water and methanol, vacuum concentrating to obtain light-colored solid amino acid, and adding C 18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product, followed by lyophilization gave 3.5mg (17%) of amino acid 211.
1H NMR(D2O，300MHz)：δ
6.60(d，1H，J＝1.8Hz)；
4.30-4.20(m，1H)；
3.84-3.75(m，1H)；
3.68-3.58(m，1H)；
3.60-3.40(m，2H)；
3.20(s，3H)；
2.96-2.88(m，1H)；
2.55-2.45(m，1H)；
1.72-1.59(m，2H)；
0.93(t，3H，J＝7.4Hz)。
Example 77
di-Boc guanidino ester 212: the samples were prepared as described by Kim and Qian, "Tetrahedron lett." 34: 7677 (1993). Adding HgCl2(30mg, 0.11mmol) amine 210(31mg, 0.101mmol), di-Boc thiourea (28.5mg, 0.103mmol) and Et were added in one portion at 0 deg.C3N (47. mu.L) in dry DMF (203. mu.L). The heterogeneous reaction mixture was stirred at 0 ℃ for 30 min, at room temperature for a further 30 min, then diluted with EtOAc and filtered through a pad of celite. Concentration in vacuo and flash chromatography of the residue on silica gel (40% hexanes/ethyl acetate) gave 49mg (89%) of 212 as a light oil.
1H NMR(CDCl3，300MHz)：δ
11.47(s，1H)；
8.66(d，1H，J＝8.4Hz)；
6.87(s，1H)；6.01(bs，1H)；
4.50-4.35(m，1H)；
4.04(bd，1H，J＝8.4Hz)；
3.76(s，3H)；
3.70-3.60(m，1H)；
3.53-3.45(m，2H)；
3.02(s，3H)；
2.85(dd，1H，J＝5.3，17.3Hz)；
2.42-2.30(m，1H)；
1.66-1.55(m，2H)；
1.49(s，9H)；1.48(s，9H)；
0.93(t，3H，J＝7.3Hz)。
Example 78
Carboxylic acid 213: KOH aqueous solution (260. mu.L, 1.039)N) was added to a solution of methyl ester 212(49mg, 0.090mmol) in THF (1.0 mL). The reaction mixture was stirred at room temperature for 16H, cooled to 0 ℃ and washed with Amberlite IR-120 (H)+) The acidic resin is acidified to pH 4.0. The resin was filtered off and washed with water and methanol. Concentration in vacuo gave the free acid as a pale foam which was used directly in the next reaction without purification.
Example 79
Guanidine carboxylic acid 214: pure trifluoroacetic acid (2.0mL) was added to the CH of di-Boc guanylic acid 213 (crude from the previous reaction) at 0 deg.C 2Cl2(2.0mL) in solution. The reaction mixture was stirred at 0 ℃ for 1 hour and then at room temperature for 1 hour. Vacuum concentrating to give light orange solid, adding C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 10mg (25%, 2 steps) of guanidinecarboxylic acid 214.
1H NMR(D2O，300MHz)：δ
6.60(bs，1H)；
4.22(bd，1H，J＝9.0Hz)；
3.82-3.66(m，2H)；
3.65-3.54(m，1H)；
3.43(bt，1H，J＝9.9Hz)；
3.15(s，3H)；
2.82(dd，1H，J＝5.0，17.5Hz)；
2.48-2.30(m，1H)；
1.71-1.58(m，2H)；
0.93(t，3H，J＝7.3Hz)。
Example 80
Propionamide methyl ester 215: propionyl chloride (96. mu.L, 1.1mmol) was added to 0 ℃ amine 205(178mg, 0.70mmol, prepared from example 107)CH with pyridine (1.5mL)2Cl2(2.0mL) of the solution, after 30 minutes at 0 ℃ the reaction mixture was concentrated and partitioned between ethyl acetate and brine. The organic layer was separated, washed successively with saturated sodium bicarbonate, brine and dried (MgSO)4) Then concentrated in vacuo and the residue flash chromatographed on silica gel (40% hexanes/EtOAc) to give 186mg (86%) of propionamide methyl ester 215 as a pale yellow solid.
1H NMR(CDCl3，300MHz)：δ
6.86(t，1H，J＝2.3Hz)；
5.72(bd，1H，J＝7.8Hz)；
4.52-4.49(m，1H)；
4.25-4.15(m，1H)；
3.77(s，3H)；
3.65-3.38 (composite m, 3H);
2.87(dd，1H，J＝5.7，17.7Hz)；
2.28(q，2H，J＝7.5Hz)；
2.25-2.20(m，1H)；
1.65-1.50(m，2H)；
1.19(t，3H，J＝7.5Hz)。
0.92(t，3H，J＝7.5Hz)。
example 81
Amino methyl ester 216: a solution of azide 215(186mg, 0.60mmol) in THF (5.0mL) and water (400. mu.L) was treated with triphenylphosphine (560 mg) supported on the polymer at room temperature, after stirring for 21 h, the polymer was filtered off and washed with methanol. Concentration in vacuo afforded the crude amino ester 216, which was used directly in the next reaction without purification.
Example 82
Amino acid 217: a solution of methyl ester 216 (crude from the previous reaction) in THF (500. mu.L) was treated with aqueous KOH (866. mu.L, 1.039N), and after stirring the reaction mixture at room temperature for 3 hours, it was treated with Amberlite IR-120 (H)+) The acidic resin was neutralized to pH 7.0. The resin was filtered off and washed with water and methanol. Vacuum concentrating to obtain light solid amino acid, and adding C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 49mg (31%, 2 steps) of amino acid 217.
1H NMR(D2O，300MHz)：δ
6.54(s，1H)；
4.25(bd，1H，J＝8.7Hz)；
4.13(dd，1H，J＝9.0，11.3Hz)；
3.74-3.60(m，1H)；
3.61-3.40(m，2H)；
2.85(dd，1H，J＝5.9，17.1Hz)；
2.55-2.40(m，1H)；
2.35(q，2H，J＝7.5Hz)；
1.65-1.45(m，2H)；
1.13(t，3H，J＝7.5Hz)；
0.88(t，3H，J＝7.5Hz)。
Example 83
(mono-methyl) di-Boc guanidino ester 218: 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (38mg) was reacted with Et at room temperature3N (56. mu.L) was added to a solution of amine 200(51mg, 0.19mmol) and monomethyl-di-Boc thiourea (36mg, 0.19mmol) in anhydrous DMF (1.0mL) and HgCl was added after 1.5 h at room temperature2(about 75mg, excess) was added in one portion. The heterogeneous reaction mixture was stirred for 45 minutes, diluted with ethyl acetate and filtered through a pad of celite. FiltrateDiluted with additional ethyl acetate, washed with dilute HCl, saturated sodium bicarbonate, brine, and dried (MgSO 4)4) And (4) concentrating in vacuum. Flash chromatography of the residue on silica gel (10% MeOH/EtOAc) afforded 13mg (16%) of (monomethyl) di-Boc guanidino ester 218 as a colorless foam.
1H NMR(CDCl3，300MHz)：δ
6.84(s，1H)；
6.20(bd，1H，J＝5.1Hz)；
5.45(bs，1H)；
4.25-4.40(bm，1H)；
4.20-4.05(bm，2H)；
3.76(s，3H)；
3.60-3.50(m，1H)；
3.43-3.30(m，1H)；
2.90(dd，1H，J＝5.4，17.7Hz)；
2.77(d，3H，J＝4.8Hz)；
2.35-2.25(m，1H)；
1.96(s，3H)；
1.60-1.50(m，2H)；
1.47(s，9H)；
0.91(t，3H，J＝7.2Hz)。
Example 84
(mono-methyl) di-Boc guanylic acid 219: aqueous KOH (60. mu.L, 1.039N) was added to a solution of methyl ester 218(13mg, 0.031mmol) in THF (500. mu.L), the reaction mixture was stirred at room temperature for 1 hour, then refluxed gently for 1 hour, cooled to 0 ℃ and then quenched with Amberlite IR-120 (H)+) The acidic resin was acidified to pH 6.0. The resin was filtered off and washed with water and methanol. Concentration in vacuo afforded the free acid 219, which was freeThe product is used directly in the next reaction.
Example 85
(mono-methyl) guanidino amino acid 220: pure trifluoroacetic acid (1.0mL) was added to the CH of (monomethyl) di-Boc guanylic acid 219 (crude from the previous reaction) at 0 deg.C2Cl2(1.0mL) in solution. The reaction mixture was stirred at 0 ℃ for 1 hour, then at room temperature for 1 hour. Concentrating under vacuum to give a pale solid, and adding C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 4.4mg (33%, 2 steps) of guanidinecarboxylic acid 220.
1H NMR(D2O，300MHz)：δ
6.52(bs，1H)；
4.27(bd，1H，J＝8.4Hz)；
4.01(dd，1H，J＝9.2，10.3Hz)；
3.86-3.75(m，1H)；
3.75-3.67(m，1H)；
3.60-3.49(m，1H)；
2.85(s，3H)；
2.80(dd，1H，J＝5.1，17.7Hz)；
2.47-2.37(m，1H)；
2.04(s，3H)；
1.64-1.50(m，2H)；
0.90(t，3H，J＝7.2Hz)。
Example 86
(R) -methylpropyl ester 221: stirring the mixture under argon at room temperature to obtain BF3·Et2O (63. mu.L, 0.51mmol) was added to a solution of N-trityl aziridine 183(150mg, 0.341mmol) in (R) - (-) -2-butanol (1.2 mL). To make thisThe light colored solution was heated at 70 ℃ for 2 hours and concentrated in vacuo to give a brown residue which was dissolved in anhydrous pyridine (2.0mL), treated with acetic anhydride (225. mu.L) and catalytic amount of DMAP (several crystals) at 0 ℃ and the reaction mixture warmed to room temperature and stirred for 2 hours, concentrated in vacuo and partitioned between ethyl acetate and brine. The organic layer was separated, washed successively with dilute HCl, saturated sodium bicarbonate, brine, and dried (MgSO) 4) Then concentrated in vacuo. Flash chromatography of the residue on silica gel (50% hexanes/ethyl acetate) gave 75mg (72%) of (R) -methylpropyl ester 221 as a light-colored solid.
1H NMR(CDCl3，300MHz)：δ
6.79(t，1H，J＝2.2Hz)；
6.14(d，1H，J＝7.3Hz)；
4.55(bd，1H，J＝8.7Hz)；
4.33-4.23(m，1H)；
3.77(s，3H)
3.56-3.45(m，1H)；
3.40-3.27(m，1H)；
2.85(dd，1H，J＝5.5，17.5Hz)；
2.30-2.15(m，1H)；
2.04(s，3H)；
1.59-1.40(m，2H)；
1.10(d，3H，J＝6.0Hz)
0.91(t，3H，J＝7.4Hz)。
Example 87
(R) -methylpropylamino ester 222: ph is3P (95mg, 0.36mmol) was added in one portion to a solution of azide 221(75mg, 0.24mmol) and water (432. mu.L) in THF (3.0 mL). Heating the light yellow solution at 50 deg.C for 10 hr, cooling, and vacuum concentrating to obtain light yellow solutionA colored solid. Flash chromatography on silica gel (50% MeOH/EtOAc) afforded 66mg (97%) of the amino ester 222 as a light-colored solid.
Example 88
Amino acid 223: a solution of methyl ester 222(34mg, 0.12mmol) in THF (1.0mL) was treated with aqueous KOH (175. mu.L, 1.039N). After the reaction mixture was stirred at room temperature for 3 hours, Amberlite IR-120 (H) was used+) Acidifying the acidic resin to pH6.0, filtering off the resin, washing with water and methanol, concentrating in vacuo to give amino acid as a pale solid, and concentrating with C18Purification by reverse phase chromatography (elution with water). Fractions containing the expected product were collected and lyophilized yielding 11.5mg (36%) of amino acid 223.
1H NMR(D2O，300MHz)：δ
6.52(bs，1H)；
4.28(bd，1H，J＝8.7Hz)；
4.04(dd，1H，J＝8.8，11.5Hz)；
3.74-3.65(m，1H)；
3.50-3.60(m，1H)；
2.90(dd，1H，J＝5.5，17.2Hz)；
2.50-2.40(m，1H)；
2.10(s，3H)；
1.60-1.45(m，2H)；
1.14(d，3H，J＝6.2Hz)；
0.91(t，3H，J＝7.4Hz)。
Example 89
di-Boc guanidino ester 224: the samples were prepared as described by Kim and Qian, "Tetrahedron Lett.", 34: 7677 (1993). Adding HgCl2(34mg, 0.125mmol) amine 222(32mg, 0.113mmol), di-Boc thiourea (32mg, 0.115 m) was added in one portion at 0 deg.C mol) with Et3N (53. mu.L) in dry DMF (350. mu.L). The heterogeneous reaction mixture was stirred at 0 ℃ for 45 min and at room temperature for 1 h, then diluted with EtOAc and filtered through a pad of celite. Concentration in vacuo and flash chromatography of the residue on silica gel (20% hexane/ethyl acetate) gave 57mg (96%) of 224 as a colorless foam.
1H NMR(CDCl3，300MHz)：δ
11.40(s，1H)；
8.65(d，1H，J＝7.8hz)；
6.82(s，1H)；
6.36(d，1H，J＝8.7Hz)；
4.46-4.34(m，1H)；
4.20-4.10(m，1H)；
4.10-3.95(m，1H)；
3.76(s，3H)；
2.79(dd，1H，J＝5.4，17.7Hz)；
2.47-2.35(m，1H)；
1.93(s，3H)；
1.60-1.45(m，2H)；
1.49(s，18H)；
1.13(d，3H，J＝6.0Hz)；
0.91(t，3H，J＝7.5Hz)。
Example 90
Carboxylic acid 225: aqueous KOH (212. mu.L, 1.039N) was added to a solution of methyl ester 224(57mg, 0.11mmol) in THF (1.5 mL). The reaction mixture was stirred at room temperature for 16H, cooled to 0 ℃ and washed with Amberlite IR-120 (H)+) The acidic resin is acidified to pH 4.0. The resin was filtered off and washed with water and methanol. Vacuum concentrating to obtain light colorThe free acid, which was in the form of a foam, was used directly in the next reaction without purification.
Example 91
Guanidine carboxylic acid 226: pure trifluoroacetic acid (4.0mL) was added to the CH of di-Boc guanylic acid 225 (crude from the previous reaction) at 0 deg.C2Cl2(4.0mL) in solution. The reaction mixture was stirred at 0 ℃ for 1 hour and then at room temperature for 2 hours; vacuum concentrating to give light orange solid, adding C18Purification by reverse phase chromatography (eluting with water) and collection of the fractions containing the expected product, followed by lyophilization gave 18.4mg (40%, 2 steps) of guanidinecarboxylic acid 226.
1H NMR(D2O，300MHz)：δ
6.47(s，1H)；
4.28(bd，1H，J＝8.4Hz)；
3.93-3.74(m，2H)；
3.72-3.63(m，1H)；
2.78(dd，1H，J＝4.8，17.4Hz)；
2.43-2.32(m，1H)；
1.58-1.45(m，2H)；
1.13(d，3H，J＝6.0Hz)；
0.90(t，3H，J＝7.4Hz)。
Example 92
(diethyl) methyl ether ester 227: BF is stirred under argon at room temperature3·Et2O (6.27mL, 51mmol) was added to a solution of N-tritylaziridine 183(15g, 34mmol) in 3-pentanol (230 mL). The light colored solution was heated at 70-75 deg.C for 1.75 h and concentrated in vacuo to give a brown residue which was redissolved in anhydrous pyridine (2.0mL) and treated with acetic anhydride (16mL, 170mmol) and a catalytic amount of DMAP (200 mg). The reaction mixture was stirred at room temperature for 18 hours, concentrated in vacuo andpartitioned between ethyl acetate and 1M HCl. The organic layer was separated, washed successively with saturated sodium bicarbonate, brine and dried (MgSO)4) Then concentrated in vacuo. Flash chromatography of the residue on silica gel (50% hexane/ethyl acetate) gave 7.66g of (diethyl) methyl ether ester, and recrystallization from ethyl acetate/hexane gave 227(7.25g, 66%) as colorless needles.
1H NMR(CDCl3，300MHz)：δ
6.79(t，1H，J＝2.1Hz)；
5.92(d，1H，J＝7.5Hz)；
4.58(bd，1H，J＝8.7Hz)；
4.35-4.2(m，1H)；
3.77(s，3H)；
3.36-3.25(m，2H)；
2.85(dd，1H，J＝5.7，17.4Hz)；
2.29-2.18(m，1H)；
2.04(s，3H)；
1.60-1.45(m，4H)；
0.91(t，3H，J＝3.7Hz)；
0.90(t，3H，J＝7.3Hz)。
Example 93
(diethyl) methyl ether amino ester 228: ph is3P (1.21g, 4.6mmol) was added in one portion to a solution of azide 227(1g, 3.1mmol) and water (5.6mL) in THF (30 mL). The pale yellow solution was then heated at 50 ℃ for 10 hours, cooled and concentrated in vacuo. The aqueous oily residue was partitioned between EtOAc and saturated NaCl. Organic phase drying (Mg-SO) 4) Filtered and evaporated. Flash chromatography on silica gel (50% methanol/ethyl acetate) afforded 830mg (90%) of the amino ester 228 as a pale white solid.
1H NMR(CDCl3，300MHz)：δ
6.78(t，1H，J＝2.1Hz)；
5.68(bd，1H，J＝7.8Hz)；
4.21-4.18(m，1H)；
3.75(s，3H)；
3.54-3.45(m，1H)；
3.37-3.15(m，2H)；
2.74(dd，1H，J＝5.1，17.7Hz)；
2.20-2.07(m，1H)；
2.03(s，3H)；
1.69(bs，2H，-NH2)；
1.57-1.44(m，4H)；
0.90(t，3H，J＝7.5Hz)；
0.89(t，3H，J＝7.5Hz)。
Example 94
Amino acid 229: a solution of methyl ester 228(830mg, 2.8mmol) in THF (15mL) was treated with aqueous KOH (4mL, 1.039N). The reaction mixture was stirred at room temperature for 40 minutes and acidified to pH5.5-6.0 with Dowex 50WX8 acid resin. The resin was filtered off and washed with water and methanol. Vacuum concentrating to obtain light solid amino acid, and adding C18Reverse phase chromatography (with water followed by 5% CH)3CN/water elution) and fractions containing the expected product were collected and lyophilized yielding 600mg (75%) of amino acid 229.
1H NMR(D2，300MHz)：δ
6.50(t，1H，J＝2.1Hz)；
4.30-4.26(m，1H)；
4.03(dd，1H，J＝9.0，11.7Hz)；
3.58-3.48(m，2H)；
2.88(dd，1H，J＝5.4，16.8Hz)；
2.53-2.41(m，1H)；
1.62-1.40(m，4H)；
0.90(t，3H，J＝7.5Hz)；
0.85(t，3H，J＝7.5Hz)。
Example 95
Tert-amyl ether ester 230: BF is stirred under argon at room temperature3·Et2O (43. mu.L, 0.35mmol) was added to a solution of N-tritylaziridine 183(104mg, 0.24mmol) in t-amyl alcohol (2.5 mL). The light colored solution was heated at 75 ℃ for 3 hours and concentrated in vacuo to give a brown residue which was dissolved in anhydrous pyridine (2.0mL) and treated with acetic anhydride (250. mu.L) and catalytic amount of DMAP (several crystals). The reaction mixture was stirred at room temperature for 1.5 hours, concentrated in vacuo and partitioned between ethyl acetate and brine. The organic layer was separated, washed successively with dilute HCl, saturated sodium bicarbonate, brine, and dried (MgSO) 4) Then concentrated in vacuo. Flash chromatography of the residue on silica gel (50% hexane/ethyl acetate) afforded 27mg (35%) of tert-amyl ether ester 230 as a light orange oil.
1H NMR(CDCl3，300MHz)：δ
6.72(t，1H，J＝2.1Hz)；
5.83(d，1H，J＝7.2Hz)；
4.71(bd，1H，J＝8.1Hz)；
4.45-4.35(m，1H)；
3.75(s，3H)；
3.27-3.17(m，1H)；
2.84(dd，1H，J＝5.7，17.4Hz)；
2.27-2.15(m，1H)；
2.05(s，3H)；
1.57-1.47(m，2H)；
1.19(s，3H)；1.15(s，3H)；
0.90(t，3H，J＝7.5Hz)。
Example 96
Tert-amyl ether amino ester 231: ph is3P (35mg, 0.133mmol) was added once to a solution of azide 230(27mg, 0.083mmol) and water (160. mu.L) in THF (1.5 mL). The pale orange solution was heated at 50 ℃ for 10 hours, cooled and concentrated in vacuo to give a pale solid. Flash chromatography on silica gel (50% MeOH/EtOAc) afforded 20mg (82%) of the amino ester 231 as a light oil.
Example 97
Amino acid 232: a solution of methyl ester 231(20mg, 0.068mmol) in THF (1.0mL) was treated with aqueous KOH (131. mu.L, 1.039N). The reaction mixture was stirred at room temperature for 2.5 hours and then Amberlite IR-120 (H)+) The acidic resin was acidified to pH 5.0. The resin was filtered off and washed with water and methanol. Vacuum concentration gives the amino acid as a pale solid which is treated with C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 8.6mg (45%) of amino acid 232.
1H NMR(D2O，300MHz)：δ
6.47(bs，1H)；
4.42(bd，1H，J＝8.1Hz)；
3.97(dd，1H，J＝8.4，11.4Hz)；
3.65-3.54(m，1H)；
2.88(dd，1H，J＝5.5，17.3Hz)；
2.51-2.39(m，1H)；
2.08(s，3H)；
1.61-1.46(m，2H)；
1.23(s，3H)；1.18(s，3H)；
0.86(t，3H，J＝7.5Hz)。
Example 98
N-propyl thioether ester 233: BF is stirred under argon at room temperature3·Et2O (130. mu.L, 1.06mmol) was added to a solution of N-trityl aziridine 183(300mg, 0.68mmol) in 1-propanethiol (8.0 mL). The light colored solution was heated at 65 ℃ for 45 minutes, concentrated and partitioned between ethyl acetate and brine. The organic layer was separated, washed with saturated sodium bicarbonate, brine and dried (MgSO) 4) Then concentrated in vacuo. Flash chromatography of the residue on silica gel (30% hexane/ethyl acetate) gave 134mg (73%) of n-propyl thioether ester 233 as a light oil.
1H NMR(CDCl3，300MHz)：δ
6.87(t，1H，J＝2.4Hz)。
3.77(s，3H)；
3.48-3.38(m，1H)；
3.22-3.18(m，1H)；
2.93(dd，1H，J＝5.4，17.4Hz)；
2.80(t，1H，J＝9.9Hz)。
2.51(t，2H，J＝7.2Hz)。
2.32-2.20(m，1H)；
1.96(bs，2H，-NH2)；
1.69-1.56(m，2H)；
1.00(t，3H，J＝7.2Hz)。
Example 99
N-propyl thioether azido ester 234: pure acetyl chloride (60 μ L, 0.84mmol) was added to a 0 ℃ solution of amine 233(134mg, 0.50mmol) in pyridine (1.5 mL). The reaction mixture was stirred for 1 hour, then warmed to room temperature and stirred for another 15 minutes. The reaction mixture was concentrated and partitioned between ethyl acetate and brine, washed sequentially with dilute HCl, water, saturated sodium bicarbonate, brine, and dried (MgSO)4) Then concentrated in vacuo. Flash chromatography of the residue on silica gel (30% hexane/ethyl acetate) gave 162mg (100%) of n-propyl thioether azido ester 234 as a pale yellow solid.
1H NMR(CDCl3，300MHz)：δ
6.90(t，1H，J＝2.7Hz)；
5.87(bd，1H，J＝7.8Hz)；
4.07-3.98(m，1H)；
3.77(s，3H)；
3.65-3.55(m，1H)；
2.95-2.85(m，1H)；
2.60-2.45(m，2H)；
2.30-2.18(m，1H)；
2.08(s，3H)；
1.65-1.53(m，2H)；
0.98(t，3H，J＝7.2Hz)。
Example 100
N-propyl thioether amino ester 235: a solution of azide 234(130mg, 0.416mmol) in ethyl acetate (10mL) was hydrogenated over Lindlar catalyst (150mg) (1atm) at room temperature for 18 h. The catalyst was then filtered off over a pad of celite, washed with hot ethyl acetate and methanol, concentrated in vacuo and the orange residue isolated by flash chromatography to give 62mg (53%) of n-propyl thioetheramide 235.
1H NMR(CDCl3，300MHz)：δ
6.88(t，1H，J＝2.7Hz)；
5.67(bd，1H，J＝8.7Hz)；
3.76(s，3H)；
3.75-3.65(m，1H)；
3.45-3.35(bm，1H)；
3.05-2.95(m，1H)；
2.87-2.78(m，1H)；
2.56-2.40(m，2H)；
2.18-2.05(m，1H)；
2.09(s，3H)；
1.65-1.50(m，2H)；
1.53(bs，2H，-NH2)；
0.98(t，3H，J＝7.2Hz)。
Example 101
Compound 240: a suspension of cinchona acid (103g), 2, 2-dimethoxypropane (200mL) and toluene sulfonic acid (850mg) in acetone (700mL) was stirred at room temperature for 4 days. The solvent and excess reagent were removed under reduced pressure. Flash column chromatography (hexanes/EtOAc-2/1-1.5/1) gave lactone 240(84g, 73%): 1H NMR(CDCl3)δ
4.72(dd，J＝2.4，6.1Hz，1H)，
4.50(m，1H)，4.31(m，1H)，
2.67(m，2H)，
2.4-2.2(m，3H)；
1.52(s, 3H), 1.33(s, 3H). If the reaction was refluxed for 4 hours, the crude product after purification by water treatment (partitioning in ethyl acetate/water) was recrystallized from ethyl acetate/hexane to give lactone 240 (71% yield).
Example 102
Compound 241: sodium methoxide (4.37M, 46.5mL, 203mmol) was added once to a solution of lactone 240(43.5g, 203mmol) in methanol (1200 mL). The mixture was stirred at room temperature for 3 hours, and the reaction was quenched with acetic acid (11.62 mL). Methanol was removed under reduced pressure. The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed once with water, once with brine and dried (MgSO)4). Flash column chromatography (hexanes/EtOAc ═ 1/1 to 1/4) purified to afford the diol (43.4g, 87%):
1H NMR(CDCl3)δ
4.48(m，1H)，4.13(m，1H)，
3.99(t，J＝6.4Hz，1H)；
3.82(s，3H)，3.34(s，1H)，
2.26(d，J＝3.8Hz，2H)，
2.08(m，1H)，1.91(m，1H)，
1.54(s，3H)，1.38(s，3H)。
alternatively, if lactone 240 is treated with a catalytic amount of sodium ethoxide (1 mol%) in ethanol, the crude product recrystallizes from ethyl acetate/hexane to give the corresponding ethyl ester (67%). The residue from the mother liquor (consisting of starting material and product) is treated again under the same reaction conditions and after recrystallization gives additional product. The overall yield was 83%.
Example 103
Compound 242: p-toluenesulfonyl chloride (27.7g, 145mmol) was added to a solution of diol 241(29.8g, 121mmol) and 4- (N, N-dimethylamino) pyridine (500mg) in pyridine (230 mL). The mixture was stirred at room temperature for 3 days and pyridine was removed under reduced pressure. By using The mixture was diluted with water and extracted three times with EtOAc. The combined organic phases were washed twice with water, once with brine and dried (MgSO)4) And then concentrated. Purification by flash column chromatography (hexanes/EtOAc-2/1-1/1) gave p-toluenesulfonate 242(44.6g, 92%).
1H NMR(CDCl3)δ
7.84(d，J＝8.4Hz，2H)
7.33(d，J＝8.1Hz，2H)
4.76(m，1H)，4.42(m，1H)，
4.05(dd，J＝5.5，7.5Hz，1H)，
3.80(s，3H)，2.44(s，3H)，
2.35(m，1H)，2.24(m，2H)，
1.96(m，1H)，1.26(s，3H)，
1.14(s，3H)。
Corresponding ethyl ester of compound 241 at 0 ℃ in CH2Cl2Then the intermediate is treated by methanesulfonyl chloride and triethylamine, and the mesylate derivative is obtained after water treatment (quantitative yield). The mesylate was used without further purification.
Example 104
Compound 243: to p-toluenesulfonate 242(44.6g, 111.5mmol) in CH2Cl2(450mL) solution pyridine (89mL) was added at-78 deg.C followed by slow SO addition2Cl2(26.7mL, 335 mmol). After stirring the mixture at-78 ℃ for 5 hours, methanol (45mL) was added dropwise, and the mixture was warmed to room temperature and stirred for another 12 hours. After addition of ether, the mixture was washed three times with water, once with brine and dried (MgSO)4) After concentration, an oily intermediate (44.8g) was obtained. TsOH (1.06g, 5.6mmol) was added to a solution of this intermediate (44.8g, 111.5mmol) in MeOH (500mL) and refluxed for 4 h. After the reaction mixture was cooled to room temperature, methanol was removed under reduced pressure.Fresh methanol (500mL) was added and the mixture was refluxed for an additional 4 hours, cooled to room temperature and the methanol was removed under reduced pressure. Flash column chromatography (hexanes/EtOAc-3/1-1/3) gave a mixture of two isomers (26.8 g). Recrystallization from EtOAc/hexanes gave pure expected product 243(20.5g, 54%):
1H NMR(CDCl3)δ
7.82(d，J＝8.3Hz，2H)
7.37(d，J＝8.3Hz，2H)
6.84(m，1H)，
4.82(dd，J＝5.8，7.4Hz，1H)，
4.50(m，1H)，
3.90(dd，J＝4.4，8.2Hz，1H)，
3.74(s，3H)，
2.79(dd，J＝5.5，18.2Hz，1H)，
2.42(dd，J＝6.6，18.2Hz，1H)。
The corresponding mesylate-ethyl ester derivative of compound 242 was treated as described. The acetonide protecting group was removed by treatment with acetic acid in refluxing ethanol and the diol was directly precipitated from the crude reaction mixture with diethyl ether (39% yield).
Example 105
Compound 1: DBU (8.75mL, 58.5mmol) was added to a solution of diol 243(20.0g, 58.5mmol) in THF (300mL) at 0 deg.C. The reaction mixture was warmed to room temperature and stirred for 12 hours. The solvent (THF) was removed under reduced pressure. Flash column chromatography (hexane/E-thoac ═ 1/3) purified to give epoxide 1(9.72g, 100%):
1H NMR(CDCl3)δ
6.72(m，1H)，
4.56(td，J＝2.6，10.7Hz，1H)，
3.76(s，3H)，
3.56(m，2H)，
3.0(d，J＝21Hz，1H)，
2.50(d，J＝20Hz，1H)，
2.11(d，10.9Hz，1H)。
the corresponding mesylate-ethyl ester derivative of compound 243 was treated identically as described to give the epoxide in almost quantitative yield.
Example 106
Aziridine 244: a solution of allyl ether 4(223mg, 1.07mmol) and Lindlar catalyst (200mg) in absolute ethanol (8.0mL) was treated with hydrogen (1atm) at room temperature for 50 minutes. The catalyst was then filtered off over a pad of celite and washed with hot methanol. Concentration in vacuo gave about 230mg of a pale yellow oil 244, which was used in the next reaction without further purification.
Example 107
Azidoamine 205: a solution of crude aziridine 244(230mg), sodium azide (309mg, 4.75mmol) and ammonium chloride (105mg, 1.96mmol) in anhydrous DMF (10mL) was heated at 70 ℃ for 16 h under argon. After cooling, the solid was removed by filtration on a sintered glass funnel and then partitioned between ethyl acetate and brine. Separating the organic layer with MgSO 4And (5) drying. Concentration in vacuo and flash chromatography of the residue on silica gel (10% hexane/ethyl acetate) afforded 154mg (57%, 2 steps) of 205 as a yellow viscous oil pure enough to be used directly in the next reaction.
Example 108
N-acetyl azide 245: acetyl chloride (70. mu.L, 0.98mmol) was added to 0 ℃ CH of amine 205(154mg, 0.61mmol) and pyridine (1.3mL)2Cl2(4.0mL) in solution. 1.5 hours at 0 DEG CAfter time, the reaction mixture was concentrated and partitioned between ethyl acetate and brine. The organic layer was separated, washed successively with saturated sodium bicarbonate, brine, and MgSO4After drying, concentration in vacuo and flash chromatography of the residue on silica gel (ethyl acetate) gave 167mg (93%) of a pale yellow solid 245.
Example 109
Amino ester 200: triphenylphosphine (1.7g, 6.48mmol) was added in portions to a solution of 245(1.78g, 6.01mmol) in THF (40mL) and water (1.5mL), and the reaction mixture was stirred at room temperature for 42.5 h. Volatiles were removed in vacuo and the crude solid was adsorbed on silica gel and purified by flash chromatography on silica gel (100% ethyl acetate followed by 100% methanol) to give 1.24g (77%) of a light colored solid 200.
Example 110
Amino acid 102: aqueous NaOH (1.37mL, 1.0N) was added to a 0 ℃ solution of methyl ester 200(368mg, 1.37mmol) in THF (4.0mL), the reaction mixture was stirred at 0 ℃ for 10 minutes, at room temperature for 1.5 hours, and then acidified to pH7.0-7.5 with Amberlite IR-120(H +) acidic resin. The resin was filtered off and washed with water and methanol. Vacuum concentrating to obtain white solid amino acid, and adding C 18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 290mg (83%) of amino acid 102.
Example 111
Amine hydrochloride 250: amine 228(15.6mg, 0.05mmol) was treated with 0.1N HCl and evaporated. Dissolving the residue in water, and adding a short C18And (4) filtering by using a reverse phase silica gel column. Lyophilization afforded hydrochloride salt 250(12mg) as a solid:
1H NMR(D2O)δ
6.86(s，1H)，
4.35(br d，J＝9.0)，
4.06(dd，1H，J＝9.0，11.6)，
3.79(s，3H)
3.65-352(m，2H)，
2.97(dd，1H，J＝5.5，17.2)，
2.58-2.47(m，1H)，
2.08(s，3H)，
1.61-1.41(m，4H)，
0.88(t，3H，J＝7.4)，
0.84(t，3H，J＝7.4)。
example 112
di-Boc-guanidine 251: adding HgCl2(125mg, 0.46mmol) was added to a solution of amine 228(126mg, 0.42mmol), N, N' -di-tert-butoxycarbonylthiourea (127mg, 0.46mmol) and triethylamine (123. mu.L, 0.88mmol) in DMF (4mL) at 0 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at room temperature for 1.5 hours. Diluted with ethyl acetate and filtered through celite. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl and dried (MgSO)4) After filtration, the solvent was evaporated. This crude product was purified on silica gel (2/1, 1/1-hexane/ethyl acetate) to afford di-Boc-guanidine 251(155mg, 69%) as a solid.
1H NMR(CDCl3)δ
11.40(s，1H)，
8.66(d，1H，J＝7.9)，
6.8(s，1H)，
6.22(d，1H，J＝8.9)，
4.43-4.34(m，1H)，
4.19-4.08(m，1H)，
4.03(m，1H)，3.76(s，3H)，
3.35(m，1H)，
2.79(dd，1H，J＝5.4，17.7)，
2.47-2.36(m，1H)，
1.92(s，3H)，1.50，1.49(2s，18H)，
0.89(m，6H)。
Example 113
Guanylic acid 252: to a solution of di-Boc guanidine 251(150mg, 0.28mmol) in THF (3mL) was added 1.039N KOH solution (337. mu.L) and water (674. mu.L). The mixture was stirred for 3 hours, then 1.039N KOH solution (67 μ L) was added and stirred for an additional 2 hours. The reaction mixture was filtered to remove a small amount of dark precipitate. The filtrate was cooled to 0 ℃ and acidified to pH4.5-5.0 using IR-120 ion exchange resin. The resin was filtered off and washed with methanol. The filtrate was evaporated and the residue was dissolved in CH 2Cl2(3mL) and cooled to 0 ℃ and treated with trifluoroacetic acid (3mL), stirred at 0 ℃ for 10 minutes and then at room temperature for 2.5 hours. The solvent was evaporated and the residue was taken up in water and chromatographed using a short column of C-18 reverse phase silica gel (3X 1.5cm) (first with water and then with 5% acetonitrile/water). The product containing fractions were combined, evaporated, and the residue dissolved in water and lyophilized to give guanylic acid 252 as a white solid (97mg, 79%).
Example 114
Azido acid 260: aqueous KOH (1.60mL, 1.039N) was added to a solution of methyl ester 227(268mg, 0.83mmol) in THF (7.0mL) at room temperature. Stirred at room temperature for 19 hours with Amberlite IR-120 (H)+) The acidic resin was acidified to pH4.0, the resin was filtered, washed with water and ethanol, and concentrated in vacuo to give crude azido acid 260 as a light orange foam, which was used in the next reaction without further purification.
Example 115
Azido ethyl ester 261: DCC (172mg, 0.83mmol) was added to carboxylic acid 260 (hexane) once at room temperatureCrude from the previous reaction, assumed to be 0.83mmol, ethanol (150. mu.L) with catalytic amount of DMAP in CH2Cl2(6.0mL) in solution. After a few minutes a precipitate formed, which was stirred for a further 1 hour, filtered and washed with CH2Cl2And (6) washing. Concentration in vacuo gave a pale solid which, after flash chromatography on silica gel (50% hexane/ethyl acetate), gave 272mg (96% with a small amount of DCU as impurity) 261 as a white solid. The yield of 261 was 93% when DCC was changed to diisopropylcarbodiimide, but there was chromatographic purification to remove the urea impurity present when DCC was used.
Example 116
Aminoethyl ester 262: triphenylphosphine (342mg, 1.30mmol) was added in one portion to a solution of 261(272g, 0.80mmol) in THF (17 mL)/water (1.6 mL). The reaction mixture was then heated at 50 ℃ for 10 hours, cooled and concentrated in vacuo to give an off-white solid. The crude solid was purified by flash chromatography on silica gel (50% methanol/ethyl acetate) to yield 242mg (96%) of light colored solid aminoethyl ester 262. Dissolving in 3N HCl, and freeze drying to obtain corresponding water-soluble HCl salt.
1H NMR(D2O，300MHz)：δ
6.84(s，1H)；
4.36-4.30(br m，1H)；
4.24(q，2H，J＝7.2Hz)；
4.05(dd，1H，J＝9.0，11.7Hz)；
3.63-3.50(m，2H)；
2.95(dd，1H，J＝5.7，17.1Hz)；
2.57-2.45(m，1H)；
1.60-1.39(m，4H)；
1.27(t，3H，J＝7.2Hz)；
0.89-0.80(m，6H)。
Example 117
di-Boc guanidinoethyl ester 263: the results were obtained as described by Kim and Qian, "Tetrahedron Lett." 34: 7677 (1993). Adding HgCl2(69mg, 0.25mmol) amine 262(72mg, 0.23mmol), di-Boc thiourea (66mg, 0.24mmol) and Et at 0 deg.C in one portion3N (108. mu.L) in anhydrous DMF (600. mu.L). The heterogeneous reaction mixture was stirred at 0 ℃ for 1 hour and at room temperature for 15 minutes, then diluted with EtOAc and filtered through a pad of celite. After concentration in vacuo, the residue is flash chromatographed on silica gel (20% hexane/ethyl acetate) to give 113mg (89%) of 263 as a colorless foam.
1H NMR(CDCl3，300MHz)：δ
11.41(s，1H)；
8.65(d，1H，J＝8.1Hz)；
6.83(s，1H)；
6.22(d，1H，J＝9.0Hz)；
4.46-4.34(m，1H)；
4.21(q，2H，J＝6.9Hz)；
4.22-4.10(m，1H)；
4.04-4.00(m，1H)；
3.36 (quintuple, 1H, J ═ 5.7 Hz);
2.78(dd，1H，J＝5.4，17.7Hz)；2.46-2.35(m，1H)；
1.94(s，3H)；
1.60-1.40(m，4H)；
1.49(s，9H)；1.50(s，9H)；
1.30(t，3H，J＝6.9Hz)；
0.93-0.84(m，6H)。
example 118
Guanidyl ethyl ester 264: di-Boc guanidinoethyl ester 263(113mg, 0.20mmol) in CH 2Cl2After the solution (5.0mL) was cooled to 0 deg.C, neat trifluoroacetic acid (5.0mL) was added and the reaction mixture was stirred at 0 deg.C for 30 minutes and at room temperature for 1.5 hours. Vacuum concentrating to give light orange solid, adding C18Purification by reverse phase chromatography (eluting with water) and collection of fractions containing the expected product followed by lyophilization gave 63mg (66%) guanidinoethyl ester 264 as a white solid.
1H NMR(D2O，300MHz)：δ
6.82(s，1H)；
4.35-4.31(m，1H)；
4.24(q，2H，J＝7.1Hz)；
3.95-3.87(m，1H)；
3.85-3.76(m，1H)；
3.57-3.49(m，1H)；
2.87(dd，1H，J＝5.1，17.7Hz)；2.46-2.34(m，1H)；
2.20(s，3H)；
1.60-1.38(m，4H)；
1.28(t，3H，J＝7.1Hz)；
0.90-0.80(m，6H)。
Example 119
Enzyme inhibition: using the in vitro activity screening method described above, the following activities (+ 10-100. mu.m, +1-10 μm, + + + < 1.0. mu.m) were measured.
| Compound (I) | IC50 |
| 102/103(2∶1) | +++ |
| 8 | ++ |
| A.17.a.4.i | ++ |
| 114 | ++ |
| A.1.a.4.i | ++ |
| 79 | + |
| 82/75(1.2∶1) | + |
| 94 | +++ |
| A.100.a.11.i | +++ |
| A.101.a.11.i | +++ |
| A.113.a.4.i | +++ |
Example 120
Compounds a.113.b.4.i and a.113.x.4.i were incubated in enzyme assay buffer and assayed for activity as described in example 119, respectively. Both activities were > 100 μm. When each compound was incubated in rat plasma before testing as in example 119, the activity of both compounds was similar to that of compound a.113.a.4. i.
Example 121
Studies were conducted under the supervision of dr. robert Sidwell, Institute for anti viral Research at Utah State University to compare the anti-influenza a activity of compound 203 (example 69), GG167 with ribavirin in mice (administered by the i.p. or p.o. route). GG167 and ribavirin are known compounds against influenza virus.
Mice: male 13-15g non-specific pathogen BALB/c mice were obtained from Simonsen laboratories (Gilroy, Calif.). Quarantining 24 hours before use, and placing in Wayne LabBlox and tap water environment. Once infected, drinking water contains 0.006% oxytetracycline (Pfizer, New York, NY) to control possible secondary bacterial infections.
Virus: influenza virus A/NWS/33(H1N1) was obtained from K.W. Cochran, University of Michigan (Ann Arbor, MI). After infection of fused monolayers of Madin Darby canine kidney cells (MDCK cells), 5% CO was added at 37 deg.C2Culturing for 3-5 days, and collecting cells to obtain virus library when virus cytopathic effect reaches 90-100%. It was sealed and stored at-80 ℃ until ready for use.
A compound: compounds 203 and GG167 were dissolved in sterile saline for study.
Arterial oxygen saturation(SaO2) And (3) determination: SaO was measured with an Ohmeda Biox 3740 pulse oximeter (Ohmeda, Lonisville, OH)2. Using an ear probe, the probe was placed on the thigh of the animal and a slow assay was selected. Each animal was read after a 30 second stabilization period. The instrument was used to determine the effect of influenza virus on arterial saturation as determined by Sid-well et al, antimicrob. 473 and 476 (1992).
Experimental design for oral study: groups of 11 mice were allowed to infect approximately 95% lethal doses of virus intranasally and received various doses of test compound. 203 and 167 were dosed at 50, 10, 2 and 0.5 mg/kg/day. The 4 hour virus pre-infection was followed by i.p treatment (two times/day) for 5 days. 8 infected mice treated with each dose and 16 infected saline-treated control groups were taken from day 3 to day 10 and analyzed for SaO2Values, the number of deaths of these animals was recorded daily for 21 days. The remaining 3 animals in each group and 6 saline-treated controls were sacrificed on day 6, lungs removed and weighed to give a score to the extent of dark purple (plum) (0 ═ normal, 4 ═ 100% lung affected). No toxicity control was performed in this study because no toxicity was observed at the dose of 203, 300 mg/kg/day, and the literature reports showed that neither GG167 was toxic.
Experimental design for intraperitoneal administration study: a group of 11 mice was infected intranasally with approximately 95% lethal doses of virus and treated with ribavirin at a dose of 250, 50 or 10 mg/kg/day 203 or GG167 or at a dose of 100, 32 or 10 mg/kg/day. 4 hours the virus was first infected and then treated by oral gavage (p.o.) for 5 days (two times/day). 8 animals in each group were left alone for 21 days, and the number of deaths was recorded daily, and SaO was measured from day 3 to day 10 2The value is obtained. The remaining 3 infected mice in each group were sacrificed on day 6, lungs removed and weighed to give a score of dark purple lung (0 ═ normal, 4 ═ 100% lung affected). 15 infected mice were treated with saline only, left for 21 days and tested for SaO as described above2Another 6 infected mice were also taken and treated with saline, and killed on day 6A lung analysis was performed. The 3 normal control groups were left for 21 days and SaO was performed as described above2Assay, 3 additional normal animals were sacrificed on day 6, lungs were weighed and scored.
Experimental design for low dose oral study: one group of 8 mice was infected intranasally with approximately 90% lethal doses of virus and received various doses of test compound. The dose of each compound was 10, 1 and 0.1 mg/kg/day. The 4 hour pre-infection of the virus was followed by p.o. (two/day) treatment for 5 days. On days 3-11, 8 infected and dose-treated mice and 16 infected and saline-treated control groups were analyzed for SaO2Values, the number of deaths of these animals was recorded daily for 21 days.
And (3) statistical evaluation: at x degree2Analysis and Yates correction assessed an increase in survival number. Mean increase in survival time and SaO by t-test 2Poor, lung weight and pneumovirus titer. The difference in lung scores was assessed by rank sum analysis (rank sum analysis). In all cases, the difference between drug treatment and saline treated control groups was studied.
The results of the i.p. dosing experiments are summarized in table I and figures 1 and 2. In this model, both compounds were significantly inhibited at high doses, and 203 was also significantly survived at a dose of 10 mg/kg/day. Two compounds significantly inhibited SaO at 50 mg/kg/day dose2And GG167 at a dose of 10 mg/kg/day, even 2 mg/kg/day, could inhibit the above-mentioned decrease. The lung score data showed the same trend, with GG167 being effective at multiple doses. Some variability in lung weight was seen, with lungs from mice receiving the highest dose of GG167 having a higher average weight than the saline treated control group.
The results of the p.o dosing experiment are summarized in Table II, SaO daily2The values are shown in FIGS. 3-5. In this model, oral treatment with three drugs significantly inhibited influenza virus infection, prevented mortality, reduced lung score and lung weight associated with infection, and inhibited SaO2And decreases.
The results of the p.o. low dose study are summarized in Table III and FIGS. 6-8. In this experiment, the infection caused 14 deaths out of 16 saline treated animals, with an average survival time of 9.6 days in this group. All three compounds had some degree of inhibitory effect on viral infection, 262 (the ethyl ester prodrug) was most effective at each dose, which prevented SaO by the number of survivors, the average survival time 2The reduction is verified.
Table III shows the average SaO over all analysis times2% of the total weight of the composition. The daily values for each compound are graphically represented in figures 6 to 8. FIG. 6 shows SaO at the highest concentration of each compound2Data; FIG. 7 shows the values at a medium dose of each compound, and FIG. 8 compares the SaO at a low dose of each compound2The value is obtained.
Table III and FIGS. 6-8 show that the three compounds, when administered orally, were active in experimentally inducing influenza A (H1N1) virus infection, with 262 being most effective. It cannot be determined whether the improved antiviral ability of 262 is not accompanied by higher animal toxicity, but high animal toxicity will not likely occur because it is presumed that its higher efficacy is a result of higher oral bioavailability.
Tables I.203 and GG167 i.paComparison of Effect of administration to influenza A (H1N1) Virus infected mice
Infection, treatment
TABLE II.203 GG167 oral administration with ribavirinaComparison of the Effect on influenza A (H1N1) Virus infection in mice
Infection, treatment
TABLE III.260, 262 and GG167 oral administrationaComparison of the Effect on influenza A (H1N1) Virus infection in mice
Footnotes of tables I-III
a 4 hours Virus initial infection followed by 5 days
b animals that died on or before day 21
c mean values determined on days 3-10
d measurement on day 6
Relative to saline treated control group*p＜0.05，**p＜0.01，***p＜0.001
Surprisingly, it was shown above that oral or i.p. administration of GG167 at practical therapeutic doses was effective in reducing mortality in influenza infected mice in this model, although this is in contrast to the conclusion of Ryan et al (anti. agents chemi, 38 (10): 2270-. These observations are consistent with those of WO 91/16320, WO 92/06691 and US 5360817 to Von Izstein et al, which covers or is specifically directed to the GG167 study. These patent documents do not teach or suggest administering GG167 in a manner other than intranasally. However, in some cases intranasal administration is neither convenient nor inexpensive. It would be advantageous if there were a more feasible route to the administration of GG167 and its related compounds (as shown in WO 91/16320, WO 92/06691 and U.S. Pat. No. 3, 5360817).
Thus, one embodiment of the present invention relates to a method of treating or preventing influenza viral infection in a host, comprising administering to the host via a route other than topical administration to the respiratory system, a therapeutically effective amount of an antivirally active compound of formula (X) or (Y)
Wherein
In the general formula (X), A is oxygen, carbon or sulfur, and in the general formula (Y), A is nitrogen or carbon;
R1is COOH, P (O) (OH)2，NO2，SOOH，SO3H, tetrazole, CH2CHO, CHO or CH (CHO)2，
R2Is H, OR6，F，Cl，Br，CN，NHR6，SR6Or CH2X, wherein X is NHR6Halogen OR OR6And are and
R6is hydrogen; c1-C4An acyl group; linear or cyclic C1-C6Alkyl or halogen-substituted congener thereof; an allyl group; unsubstituted aryl or aryl substituted with: halogen, OH group, NO2Radical, NH2A group or a COOH group;
R3and R3' identically or mutually independently are hydrogen, CN, NHR6，N3，SR6，＝N-OR6，OR6A guanidine group,
R4is NHR6，SR6，OR6，COOR6，NO2，C(R6)3，CH2COOR6，CH2NO2Or CH2NHR6And an
R5Is CH2YR6，CHYR6CH2YR6Or CHYR6CHYR6CH2YR6Wherein Y is O, S, NH or H, and R5The Y moieties in the group are the same or different from each other,
and pharmaceutically acceptable salts or derivatives thereof,
provided that in the general formula (X)
(i) When R is3Or R3' is OR6Or hydrogen, and A is oxygen or sulfur, the compound cannot simultaneously have (a) R as hydrogen2And (b) R as NH-acyl4And are and
(ii) when Y is hydrogen, R6Is a covalent bond, and in the formula (y)
(i) When R is3Or R3' is OR6Or hydrogen, and A is nitrogen, the compound cannot simultaneously have (a) R as hydrogen2And (b) R as NH-acyl4And are and
(ii) when Y is hydrogen, R6Is a covalent bond.
The compounds of formulae (X) and (Y) are described in more detail on page 3, line 23 to page 7, line 1 of WO 91/16320, WO 92/06691 and U.S. Pat. No. 5360819, in which (X) and (Y) are denoted as I and Ia, respectively.
For the purposes of this document, the route via "non-topical administration to the respiratory tract" does not exclude buccal or sublingual administration and does not exclude oral, buccal or sublingual administration with occasional esophageal absorption, as long as the clip, oral, sublingual or esophageal absorption is not intended for pulmonary administration or inhalation through the nasal cavity and the like. Typically, the compounds are administered as a form, slurry or solution.
In a typical embodiment of the invention, the compound is GG167, the host is a non-murine animal (e.g., ferret or human), the route of administration is oral, and the purpose of treatment and prevention is to reduce mortality. Prodrugs of compounds of formula (X) or (Y) are optionally used, but as indicated above, are not required to achieve oral antiviral efficacy. As prodrugs of GG167 and its related disclosed compounds, any of the esters, amides, or other prodrugs of the compounds of the invention described herein may be used in combination with an analog (e.g., a carboxylic ester or amide) of a compound of formula (X) or (Y).
When GG167 and related compounds are administered orally or via other non-nasal routes, a therapeutically effective dose may be determined by a physician in accordance with the instructions for administration of the compounds of the invention. The most important considerations are the route of administration and the host species. Generally, dosages from intravenous to subcutaneous to oral will be escalating and may be applied on a routine pharmacologic scale-up basis if administered to larger animals. Determination of a therapeutically active dose is within the ordinary skill in the art, but generally the dose will be about the same as that used for the compounds of the invention.
Example 122
Each reaction shown in Table 50 was carried out in accordance with reaction scheme 50, and the reactions which had been carried out are represented by "√" as a means. Unless otherwise indicated in Table 50, steps AA, AB and AC were performed as in examples 92, 93 and 94, respectively, and step AD was performed as in the combination of examples 112 and 113.
Reaction scheme 50
Watch 50
Watch 50 (continuation)
Watch 50 (Note)
a) Ester hydrolysis prior to azide reduction
b) By Ph3P Azide reduction at room temperature
c) Ester hydrolysis with aqueous KOH/MeOH
d) Ph supported by polymer3P Azide reduction at room temperature
e) Separation into the HCl salt
f) By Ph3MeOH/THF/H of P2O Azide reduction
g) Diastereomer mixture, main diastereomer being indicated
h) With Me3P for azide reduction
i) Opening of aziridine at 55 deg.C
j) Separating off the C-alkylated product
Example 123
Trifluoroacetamide 340: pyridine (41. mu.L, 0.51mmol) and trifluoroacetic anhydride (TFAA) (52. mu.L, 0.37mmol) were added to 0 ℃ CH of amine 228(100mg, 34mmol)2Cl2(3.5mL) of the solution, and this solution was stirred for 45 minutesAdditional TFAA (0.5 equiv.) was added during this time. After 15 min, evaporation under reduced pressure and the residue partitioned between ethyl acetate and 1 MHCl. The organic phase was saturated NaHCO3Washed with saturated NaCl and dried (MgSO)4) Filtered and evaporated. The residue was chromatographed on silica gel (2/1-hexane/ethyl acetate) to give trifluoroacetamide 340(105mg, 78%):
1H NMR(CDCl3)δ
8.64(d，1H，J＝7.7)，
6.81(s，1H)，
6.48(d，1H，J＝8.2)，
4.25-4.07(m，3H)，
3.75(s，3H)，3.37(m，1H)，
2.76(dd，1H，J＝4.5，18.7)，
2.54(m，1H)，1.93(s，3H)，
1.48(m，4H)，0.86(m，6H)。
example 124
N-methyltrifluoroacetamide 341: sodium hydride (10mg, 60% dispersion in mineral oil, 0.25mmol) was added to a solution of trifluoroacetamide 340(90mg, 0.23mmol) in DMF (2mL) at 0 ℃. After 15 min at 0 ℃ methyl iodide 71 μ L, 1.15mmol) was added and stirred at 0 ℃ for 2 h and at room temperature for 1 h. Acetic acid (28. mu.L) was added and the solution was evaporated. The residue was partitioned between ethyl acetate and water. The organic phase was washed with saturated NaCl and dried (MgSO)4) Filtered and evaporated. The residue was chromatographed on silica gel (1/1-hexane/ethyl acetate) to give N-methyltrifluoroacetamide 341(81mg, 87%) as a colorless glass:
1H NMR(CDCl3)δ
6.80(s，1H)，
6.26(d，1H，J＝9.9)，
4.67(m，1H)，4.32(m，1H)，
4.11(m，1H)，3.78(s，3H)，
3.32(m，1H)，
3.07(br s，3H)，
2.60(m，2H)，1.91(s，3H)，
1.48(m，4H)，0.87(m，6H)。
Example 125
N-methylamine 342: 1.04N KOH (48. mu.L, 0.50mmol) was added to a solution of N-methyltrifluoroacetamide 341(81mg, 0.20mmol) in THF (3mL), the mixture was stirred at room temperature for 14 h and acidified to pH about 4 with IR-120 ion exchange resin. The resin was filtered off, washed with THF and the filtrate was evaporated. The residue was dissolved in 10% TFA/water (5mL) and evaporated, and the residue was eluted with water through a C-18 reverse phase silica gel column (1.5X 2.5 cm). The product fractions were collected and lyophilized to give N-methylamine 342(46mg, 56%) as a white solid:
1H NMR(D2O)δ
6.80(s，1H)，
4.31(br d，1H，J＝8.8)，
4.09(dd，1H，J＝8.9，11.6)，
3.53(m，2H)，
2.98(dd，1H，J＝5.4，16.9)，
2.73(s，3H)，
2.52-2.41(m，1H)，
2.07(s，3H)，
1.61-1.39(m，4H)，
0.84(m，6H)。
example 126
Compound 346: to epoxide 345(13.32g, 58.4mmol) in 8/1-MeOH/H2To a solution of O (440mL, v/v) was added sodium azide (19.0g, 292.0mmol) and ammonium chloride (2.69g, 129.3mmol), and the mixture was refluxed for 15 hours. After cooling, concentrate under reduced pressure and partition in EtOAc and water. The organic layer was washed sequentially with saturated bicarbonate, brine. Drying (MgSO)4) Then concentrated in vacuo. Flash chromatography on silica gel (30% EtOAc/hexanes) afforded 11.81g (75%) of viscous oleyl azido alcohol 346.
1H NMR(300MHz，CDCl3)δ
6.90-6.86(m，1H)；
4.80(s，2H)；
4.32(bt，1H，J＝4.2Hz)；
4.22(q，2H，J＝7.2Hz)；
3.90-3.74 (overlap m, 2H);
3.44(s，3H)；
2.90(d，1H；J＝6.9Hz)；
2.94-2.82(m，1H)；
2.35-2.21(m，1H)；
1.30(t，3H，J＝7.2Hz)。
example 127
Compound 437: DIBAL (5.1ml, 1.0M in toluene) was added dropwise via syringe to a solution of ethyl ester 346(420mg, 1,55mmol) in dry THF (8.0ml) (cooled to-78 ℃). The bright yellow reaction mixture was stirred at-78 ℃ for 1.25 h, then MeOH (1.2ml) was added slowly and hydrolyzed slowly. The volatiles were removed under reduced pressure and the residue was partitioned between EtOAc and cold dilute HCl. The organic layer was separated and the aqueous layer was back-extracted with EtOAc. The organic layers were combined and washed successively with saturated bicarbonate, brine, MgSO 4And (5) drying. TrueConcentrated in vacuo, then flash chromatographed on silica gel (20% hexanes/EtOAc) to give 127mg (36%) of diol 347 as a colorless viscous oil.
1H NMR(300MHz，CDCl3) δ 5.83-5.82(m, 1H); 4.78(s, 2H); 4.21(bt, 1H, J ═ 4.4 Hz); 4.06(bs, 2H); 3.85-3.65 (overlap m, 2H); 3.43(s, 3H); 3.18(d, 1H, J ═ 8.1 Hz); 2.51(dd, 1H, J ═ 5.5, 17.7 Hz); 2.07-1.90(m, 1H); 1.92(bs, 1H).
The following claims are directed to specific embodiments of the invention and are to be construed to cover many variations thereof.
Claims (9)
1. A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein,
E1is-CO2H，-CO2R5；
G1is-N (R)11)2or-N (R)11)C(N(R11))(N(R11)2)；
T1is-NH (C (O) CH3)，-NH(C(O)CH2F)，-NH(C(O)CHF2) or-NH (C (O) CF)3)；
U1is-OR4；
R4Is an alkyl group of 1 to 12 carbon atoms;
R5is an alkyl group of 1 to 12 carbon atoms; and is
R11Is H or R4。
2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
G1is-NH2，-N(H)C(N(H))(NH2)，-NHCH3，-NHCH2CH3，-N(CH3)2，-N(CH2CH3)2or-N (CH)3)(CH2CH3) (ii) a And is
R4Is an alkyl group of 1 to 8 carbon atoms.
3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
R4is an alkyl group of 1 to 12 carbon atoms, and R11Is R4。
4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
R4is an alkyl group of 1 to 8 carbon atoms, and R11Is R4。
5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
R4is an alkyl group of 1 to 6 carbon atoms, and R11Is R4。
6. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
R4is an alkyl group of 1 to 6 carbon atoms, and each R11Is H.
7. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein,
E1is C (O) OCH2CH3；G1Is NH2；T1Is NH (C (O) CH3) (ii) a And U1Is OCH (CH)2CH3)2。
8. A compound having the formula, or a pharmaceutically acceptable salt thereof,
9. a compound having the formula, or a pharmaceutically acceptable salt thereof,
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US39524595A | 1995-02-27 | 1995-02-27 | |
| US08/395,245 | 1995-02-27 | ||
| US08/476,946 | 1995-06-06 | ||
| US08/476,946 US5866601A (en) | 1995-02-27 | 1995-06-06 | Carbocyclic compounds |
| US58056795A | 1995-12-29 | 1995-12-29 | |
| US08/580,567 | 1995-12-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| HK1120494A1 HK1120494A1 (en) | 2009-04-03 |
| HK1120494B true HK1120494B (en) | 2013-08-16 |
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