TW200831517A - Chemical compounds - Google Patents

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TW200831517A
TW200831517A TW096147437A TW96147437A TW200831517A TW 200831517 A TW200831517 A TW 200831517A TW 096147437 A TW096147437 A TW 096147437A TW 96147437 A TW96147437 A TW 96147437A TW 200831517 A TW200831517 A TW 200831517A
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1h
2h
group
intermediate
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TW096147437A
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Chinese (zh)
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Janelle Comita-Prevoir
Mark Cronin
Bolin Geng
Folkert Reck
Andrew Aydon Godfrey
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Astrazeneca Ab
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D513/00Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/02Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains two hetero rings
    • C07D513/04Ortho-condensed systems

Abstract

The present invention relates to compounds of Formula (I): Formula (I) or pharmaceutically acceptable salts thereof, to their use in the treatment of bacterial infections, and to their methods of preparation.

Description

200831517 IX. DESCRIPTION OF THE INVENTION: TECHNICAL FIELD OF THE INVENTION The present invention relates to novel hexahydropyridines, pharmaceutical compositions thereof, and methods of use. Furthermore, the invention relates to the treatment of bacterial infections. [Prior Art] “The international health care community continues to express serious concerns that the development of antibiotic resistance will result in strains that are currently not available for antibacterial agents. For example, Gram-positive pathogens are resistant to bacteria, such as Cyclooxyphenylpenicillin resistance to gold (4) (four) to mrSA), methicillin-resistant clotting enzyme-negative (four) genus (MRCNS), penicillin-resistant W-super-ball mill and multi-drug resistant granules are difficult It is difficult to eradicate. Therefore, in order to overcome the threat of a wide range of multi-drug resistant organisms, there is a need to develop novel antibiotics, especially those with novel mechanisms of action and/or containing new lances. In accordance with the present invention, Applicants have hereby discovered certain compounds which have the ability to act as antimicrobial agents. Accordingly, the present invention relates to compounds which exhibit antibacterial activity, processes for their preparation, and pharmaceuticals containing them as active ingredients. a composition, its use as a medicament, and its use in the manufacture of a medicament, the name of which is in a warm-blooded animal such as a human For the treatment of bacterial infections Accordingly, the invention provides a compound of formula ⑴: 127,286,200,831,517

Or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) is a cis (±) mixture of the palmo isomers, and the towels thereof are not contained, and the A group is selected from the group consisting of CH and N;

D is selected from the group consisting of C-R7 and n; wherein at least one of A and D is carbon; E is selected from the group consisting of 〇, nh and s, wherein: i) if R8 and R9 together form =0, then E is NH; ϋ) If R8 and R9 are each Η, then E is Ο or S; G is selected from 〇 and s; J is selected from C_R4 and Ν; R1 is selected from Η, halo, cyano, c!-6 a C2_6 alkenyl group and a c2_6 alkynyl group, ORla and "N(Rh)2, wherein the Cl_6 alkyl group, the c^6 alkenyl group and the c26 alkynyl group are optionally substituted by one or more R1 0;

Rla, in each presence, is independently selected from the group consisting of 11 and (: 1-6 alkyl, wherein the Cl 6 alkyl group is optionally substituted by one or more R 2 G; R 2 is selected from the group consisting of hydrazine, halo, cyano, C 6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, -OR 2a & -N(R 2a) 2 wherein the Cu alkyl group, C: 2-6 alkenyl group and (: 2-6 alkynyl group) Optionally substituted by one or more R20; 127286 200831517 R2a, in each presence, independently selected from the group consisting of hydrazine and Cu alkyl, wherein the Cu alkyl group is optionally substituted by one or more R20, R3 is selected From hydrazine, halo, cyano, Cu alkyl, c2-6 alkenyl and c2_6 alkynyl, • 0R3a and -N(R3a)2, wherein the Ci6 alkyl, c2_6 alkenyl and C2_6 alkynyl are optionally One or more r3〇 substituted; R3a' is independently selected from the group consisting of 11 and (: 1-6 alkyl, wherein the alkyl group is optionally substituted by one or more R3 ;; _r4 is selected from Η, halo, 〇) 2Η, cyano, Ch alkyl, c 2_6 alkenyl and C 2-6 alkynyl, wherein the Ci-6 alkyl, C 2-6 alkenyl and c 2-6 alkynyl are optionally One or more R40 substitutions; R is selected from the group consisting of a fluorine group, a C!-6 alkyl group, a C2-6 alkenyl group, a C2-6 fast group, and a 〇R6a, wherein the Ci-6 is burned. , C: 2-6 alkenyl and C 2_6 alkynyl are optionally substituted by one or more r 6 ;; R 6a, in each presence, is independently selected from 11 and (: 16 alkyl, wherein the alkyl group is optionally Substituted by one or more R6 0; _ R7 is selected from the group consisting of H, halo, cyano, alkyl, c26 alkenyl and Ch alkynyl, wherein the Ch, the c2-6, and the Ch alkynyl are optionally One or more R70 substitutions; R8 and R9 are each hydrogen, or 圮 and 圮 together form =〇; and the invention details ^乂'^^' (four) and ^' in each of the places 'each independently selected from the tooth base, search a base, an aryl group, a _C〇2H, a decyl group, a C2.6 alkenyl group, and a c2_6 alkynyl group. When used in a term such as Cx_y, it is indicated in the group, in the present specification, the prefix Q alkyl group, etc. (where X and y are integers) when 127286 200831517 carbon number range; for example, C1-4 alkyl includes Ci alkyl (methyl), c2 alkyl (ethyl), C3 alkyl (propyl and isopropyl) And c4 alkyl (butyl, μmethylpropyl, fluorenylmethylpropyl and tert-butyl). As used herein, the term "alkyl" refers to the saturation of linear and branched chains. Both hydrocarbon groups, with The number of carbon atoms specified. For individual alkyl groups such as "propyl", the reference is only for straight-chain variants, and for individual branched-chain alkyl groups such as "isopropyl", the term "only" refers to Branch chain modification. The term "alkenyl" refers to both straight-chain and branched-chain hydrocarbon groups having the specified number of carbon atoms and containing at least one carbon-carbon double bond. For example, C2_8 alkenyl, including but not limited to - some groups, such as c2 6 dilute, c2 4 dilute, ethyl, 2-propenyl, 2-methyl-2-propenyl, 3· Butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl and 2-methylstetonyl. The term alkynyl refers to both straight-chain and branched-chain hydrocarbon radicals having the specified number of fire atoms and 3 having at least one carbon-carbon bond. For example, "Cm alkynyl" includes, but is not limited to, a cleavage group, suspected ‘r 丞 丞 such as C2·6 alkynyl, c2-4 alkynyl, ethynyl,

2-propynyl, 2-methyl-2-propane, 1, butyl gamma, 3-butynyl, 4-pentynyl, 5-hexynyl, 2-heptynyl and 4- Methyl-5-heptynyl. The term "H halo" refers to a fluoro group, a sputum, and a bromo group. In one aspect, "." can mean a fluoro group. ^ Where the substituent is selected from a "_ or a plurality of " groups, it should be understood that this definition includes all substituents selected from one of the specified groups, or the substituents are selected from the specified groups. Two or more. The term "carbocyclyl" refers to a saturated, carbocyclic ring containing a ring atom and or an unsaturated, mono- or bicyclic ring, one or more of the -CH2_ groups may be 127286 200831517 A corresponding number of c(〇) 4 group substitutions. In one aspect, "carbocyclyl" 4 may be a one-ring ring containing 3 or 6 ring atoms or a double-shaped ring containing 9 or 1 atom.环. In another aspect, "carbocyclyl," can refer to a ring containing 5 or 6 atoms. Examples of carbocyclic groups include, but are not limited to, adamantyl group, propyl group, cyclobutyl group, cyclopentyl group, cyclopentenyl group, cyclohexyl group, cycloazinyl group, fluorenyl group, phenyl group, phenyl group. A tetrahydroindenyl group, a hydrohalyl group or a 1 keto group is a phenyl group, a specific example of a ###, &

襄 屑 refers to saturated, partially saturated or unsaturated, mono- or bicyclic, ring: contains '12 ring atoms, at least one ring atom nitrogen: sulfur and milk' and unless otherwise indicated Linked by carbon or nitrogen, wherein the CH2 group may be replaced by "(〇)_ as appropriate. The ring sulfur atom may optionally be oxidized to form an 8-oxide. The ring nitrogen atom may be oxidized as appropriate to form a conversion impurity & base word description, including but not limited to benzodioxanthene hexahydrohexyl, (tetra)yl (tetra), iso-linone Iso-indolyl L-based group, phoranyl, 2 • bismuth & tetrachloroindolyl, 2-keto-based 3'-oxazolidinyl, hexahydropyridinyl, hexahydropyridyl, piperidyl , 峨嗤基" than bite base, (tetra) base, tetrahydrogen base, dihydro (tetra) base, mouth: specific well, pyrazolyl, hydrazine, 4-pyridine, quinolinyl, tetragoniper , thiazolyl "sedadiazolyl" oxazolidinyl, thienyl, thiofolf ", thiophenyl" (tetra), called __n oxidant. In one aspect of the invention, - ', clothing It is said that it is saturated, partially saturated or unsaturated: a single ring containing 5 or 6 atoms, at least one of which is kk or oxygen, and may be linked by carbon or nitrogen unless otherwise specified. And the % nitrogen atom may be oxidized as appropriate to form an N-oxide. 127286 -10- 200831517 (4) "(±)" is intended to mean a racemic mixture; that is, the indicated compound (etc.) (-) an optically inactive mixture of oxime isomers. When a compound or mixture is referred to as "cis (soil) " or, trans (±)", it should be understood that (4) The cis or trans relationship is related to the relationship between the upper group and the -NH- group on the carbon "b". The presence of a particular R group in the compound of formula (I) occurs more than once. In the following, it is intended that each choice of the R group is independent at each occurrence. • ^ is not specifically described, otherwise the bonding atom of the _ group may be any suitable atom of the group; For example, the propyl group includes a propyl group and a propyl group. The word "be on the babe" is intended to mean that the specified system is less than ίο%, more specifically less than 5%, especially less than 2%. , more particularly below μ, especially below 0.5%, especially below 〇·2%. The term "optionally substituted" as used herein means substitution is optional and therefore specified The group may be either substituted or unsubstituted. _in the case of a substitution, any of the specified groups Hydrogen can be broken from the indicated substituent substitutions, provided that the normal valence bond of the atom on the particular substituent is not exceeded, and the substitution results in a stability compound that exhibits an antibacterial effect. The term "acceptable" means that such compounds, substances, compositions and/or dosage forms are within the scope of safe and reliable medical judgment and are suitable for use in contact with human and animal tissues without excessive toxicity or irritation. An allergic response or other problem or complication is accompanied by a reasonable benefit/risk ratio. 127286 200831517 As used herein, "effective amount" is used to significantly and positively alter the signs and/or symptoms of i slave treatment (for example, in a compound or composition).獒 For positive clinical response). The effective amount will be combined with the active ingredients of the beam composition / the specific symptoms of the treatment, the severity of the symptoms, the duration of the treatment, the nature of the simultaneous treatment ^ ^ The active ingredients, the particular Chinese gamma used, and the excipients/carriers of the above-mentioned texts, and similar factors in the knowledge and expertise of the physician are changed. ,

The definitions of the compounds and substituents of the present invention have been naming the ACD/Name called ACD/Labs® for naming. (d) The compound may form a pharmaceutically acceptable acid or salt, and in this case, the compound is suitably salted, and the pharmaceutically acceptable salt may be used in the art. Knowing the method of preparation 1 The compound of the present invention is suitably pharmaceutically acceptable: .. ^ ^ The salt of the fungus is, for example, an acid addition salt of a compound of the present invention which is sufficiently basic, such as an inorganic or organic acid. Salt formation, the acid such as hydrochloric acid, 4, sulphuric acid, sulphuric acid, difluoroacetic acid, citric acid or maleic acid. In addition, a suitably pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic, a salt of the formula 1, such as sodium or potassium phos, an alkaline earth metal salt such as calcium or magnesium Μ μ ^ ^ ^ ^ ^ It is asleep with an organic test salt that provides physiologically acceptable X% ions, for example, with methylamine, dimethylamine, trimethylamine, hexahydrodithiomethane, chlorhexidine or ethylamine. The compound of formula (I) is in the central hexahydropyridine ring. Furthermore, the compound may have a geometric center of isomerism (Ε-and Ζ-isomer). The present invention encompasses all such optical diastereoisomers and geometries, which have antibacterial activity 127286 -12-200831517 14 . The invention further relates to any and all tautomeric forms of the compounds of formula (i) having antibacterial activity. It should also be understood that certain compounds of formula (I) may exist in solvated as well as unsolvated forms, such as in hydrated form. It should be understood that the present invention encompasses all such solvated forms having antibacterial activity. Other embodiments of the invention are as follows. These other specific embodiments relate to the compound of formula (I) and pharmaceutically acceptable salts thereof. This particular substituent may be used in conjunction with any definition, claim or embodiment as defined above or below. Carbon "a" and carbon "b" In one aspect, the r6 group on carbon "a" and the group on carbon "b" can be in a cis (+) relationship with each other, wherein the compound of formula 1 is substantially Containing no cis (±) mixture of its palmomers; on the other hand, the r6 group on carbon "a" and the ΝΗ• group on carbon"b" In the cis (a) relationship, the compound of formula (I) is substantially free of its cis (±) mixture of the φ isomers; and on the other hand, the R6 group on carbon "a""b"上上-ΝΑ Groups can be in a trans (+) relationship with each other. In still another aspect, the R6 group on carbon, a" and the _ group on the carbon "b, can be in a trans (a) relationship with each other.

A On the one hand, A can be N. On the other hand, A can be CH. In yet another aspect, A can be selected from the group consisting of N and CH. 127286 -13· 200831517

D On the one hand, D can be N. In another aspect, D can be CH. In yet another aspect, D can be selected from the group consisting of N and CH.

A and D are in one aspect, A can be N; and D can be CH. In another aspect, A can be CH; and 10D can be N. E, Q R8 and R9 In one aspect, E and G can each be 0; and R8 and R9 can each be Η. In another aspect, Ε can be NH; G can be selected from Ο and S; and R8 and R9 can together form =0; on the other hand, Ε can be NH; G can be S; and R8 and R9 can be together Form = 0. On the other hand, Ε can be ΝΗ; G can be Ο; and R8 and R9 can form =0 together.

J On the one hand, J can be awkward. On the other hand, J can be CH. In another aspect, J can be selected from the group consisting of hydrazine and CH. In yet another aspect, J can be selected from the group consisting of ruthenium and C-R4; and R4 can be selected from the group consisting of ruthenium and alkyl. Further, in another aspect, j w is selected from the group consisting of N and C-R 4 ; and R 4 may be selected from the group consisting of hydrazine and methyl. A, D, G, E, R8 and R9

In one aspect, A, D, G fly RS, K and R and they are joined to form a group selected from: strip < % atom together

In one aspect, R1 can be Η. R2 In one aspect, R2 may be selected from cyano and _OR2a; and R2a may be Cb6 alkyl. In another aspect, R2 can be selected from the group consisting of cyano and methoxy. In yet another aspect, R2 can be a cyano group. In still another aspect, R2 can be -〇R2a; and R2a can be an alkyl group. R3 On the one hand, R3 can be Η. R6 In the aspect, R6 may be selected from a fluoro group and 〇R6a; and R6a may be selected from the group consisting of 11 and (:1_6 alkyl).

In another aspect, R6 can be selected from the group consisting of a fluoro group, a hydroxy group, and a methoxy group. Rl' R2, R3, R6, R8, R9, A, D, E, G and J 127286 -15- 200831517 In one aspect, the compound of formula (1) can be a compound of formula (Ia):

Or a pharmaceutically acceptable salt thereof, wherein ^, ^, ^, ^, 丄 and the sentence are as above = mixed and combined:. In one aspect of the compound of formula (la), G may be selected from ruthenium and s; J may be selected from N and CH; R1 may be ruthenium; R2 may be selected from cyano and -ORh; and R2a may be Ci-6 alkane R3 may be hydrazine; R6 may be selected from fluorenyl and 〇R6a; and R6a may be selected from hydrazine and Cu alkyl. In another aspect of the compound of formula (la), G may be selected from the group consisting of ruthenium and s; J may be selected from N and CH; R1 may be ruthenium; R2 may be selected from cyano and methoxy; 127286 -16 * 200831517 R3 It is Η; and 妒 can be selected from a fluorine group, a hydroxyl group, and a methoxy group. In another aspect of the compound of formula (la) or a pharmaceutically acceptable salt thereof, G may be selected from the group consisting of ruthenium and S; J may be selected from N and C-R4; R1 may be ruthenium; R2 may be selected from cyano and - 〇R2a; _ can be Cle6 alkyl; a can be Η; ¥ can be selected from 11 and (: 1-6 alkyl; R6 can be selected from fluoro and -OR6a; and R6a can be selected from 11 and (: 1-6 alkyl. In the compound of the formula (la) or a pharmaceutically acceptable salt thereof, G may be selected from the group consisting of ruthenium and S; J may be selected from N and C-R4; The cation may be selected from the group consisting of cyano and -R2a; R2a may be a fluorenyl group; $ may be H; Di 4 may be selected from fluorenyl and methyl; chemistry 6 may be selected from fluoro and -OR6a; and R6 a may be selected from hydrazine; And the methyl group. On the other hand, the compound of the formula (I) can be a compound of the formula (Ib)·· -17· 200831517

Eight, , ruler, 玟 and J are as above

The compound of formula (10) is substantially free of its mixture of palmier isomers (±). < In one aspect of the compound of formula (lb), J may be selected from N and CH; R1 may be Η; R2 may be selected from cyano and -OR2a; R2a may be Cu alkyl; R3 may be ruthenium; And R6a may be selected from the group consisting of ruthenium and (V6 alkyl. In another aspect of the compound of formula (lb), J may be selected from N and CH; may be ruthenium; R2 may be selected from cyano and And methoxy; 1Be 86 -18· 200831517 R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be (V6 alkyl; R3 may be Η; R6 may be selected from fluoro and -R6a; and R6a may In another aspect, J is selected from the group consisting of a compound of formula (lb) or a pharmaceutically acceptable salt thereof, J may be selected from N and CH; R1 may be hydrazine; and R2 may be selected from cyano and hydrazine. Alkyl; R3 may be hydrazine; and R6 may be selected from fluoro, hydroxy and methoxy. In yet another aspect, the compound of formula (I) may be a compound of (Ic):

Formula (Ic)

Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R6, R8, R9, A, D, E, G and J are as defined above, wherein the compound of formula (Ic) is substantially free of its palm A cis (±) mixture of isomers. Forming a group together with one of the compounds of the formula (Ic) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the ring atom to which they are attached are selected from the group consisting of: 127286 -19- 200831517

J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2"; R2a may be Cu alkyl; R3 may be hydrazine; _ R4 may be selected from hydrazine and Cu alkyl; From the fluorine group to -〇R6a; and R6a may be selected from the group consisting of ruthenium and Cu alkyl. In another aspect of the compound of formula (Ic), or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9, together with the ring atoms to which they are attached, form a group selected from the group consisting of:

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be fluorenyl; R3 may be Η; R4 may be selected from fluorenyl and methyl; R6 may be selected from fluoro And -R6a; and 127286 -20-200831517 R6a may be selected from hydrazine and methyl. Further, the compound of the formula (1) may be a compound of the formula (10)

Or a pharmaceutically acceptable salt thereof, wherein r1, r2, r3, r6, r8, r9, a, d, eg are as defined above and wherein the compound of formula (10) is substantially free of cis to isomers (±) mixture. In one aspect of the compound of the formula (Id) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 together with the % atom to which the distal link is attached form a group selected from the group consisting of:

J can be selected from N and CR4

It may be Η; 1 (2 may be selected from cyano and -OR2a; R2a may be alkyl; R3 may be oxime; R4 may be selected from oxime and Cu alkyl; may be selected from fluoro and -OR6a; and R6a is optional From oxime to CV6 alkyl. 127286 200831517 In another aspect of the compound of formula (id) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the ring atom to which they are attached form a radical The group is selected from:

J may be selected from fluorene and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be fluorenyl; R3 may be hydrazine; R4 may be selected from fluorenyl and fluorenyl; -OR6a; and R6a may be selected from the group consisting of hydrazine and methyl. In a further aspect the compound of formula (I) may be a compound of formula (Ie):

Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R6, R8, R9, A, D, E, G are as defined above, and wherein the compound of formula (le) is substantially free of its A cis (±) mixture of constructs. 127286 -22· 200831517 In the aspect of the compound of the formula (Ie) or a pharmaceutically acceptable salt thereof, A, D, QE, R8 and R9 together with the ring atom to which they are attached form a group selected from the group consisting of:

J may be selected from N and CR4; R1 may be Η; 胪 may be selected from cyano and -OR2a; R2a may be cv6 alkyl; 鲈 may be Η; and R4 may be selected from 11 and (: 1-6 alkyl). In another aspect of the compound of formula (Ie), A, D, G, E, R4R> the ring atom to which they are attached - the forming group is selected from the group consisting of:

J may be selected from N and CR4; & 1 may be Η; ^ may be selected from cyano and formamidine; may be oxime; and 4 may be selected from ruthenium and methyl. In still a further aspect, the compound of formula (1) can be a compound of formula (10): 127286 200831517

Or a pharmaceutically acceptable salt thereof, wherein R1, R2, R3, R8, R9, A, D, E, Gj J are as defined above, wherein the fluoro group and the carbon in the carbon "a" The groups above are in cis relationship to each other, and wherein the compound of formula (If) is substantially free of its cis (±) mixture of palmier isomers. In one aspect of the compound of the formula (If) or a pharmaceutically acceptable salt thereof, the bird, £, 妒 and 妒 together with the ring atom to which they are attached form a group selected from the group consisting of: 〇

J may be selected from N and CR4; Di1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be Ci_6 alkyl; Di3 may be hydrazine; and Pol. 4 may be selected from hydrazine and CV6 alkyl. In another aspect of the compound of the formula (If), the ring atoms together form a group A, D, G, E, R8 and R9 and are attached thereto. 127286 -24- 200831517

R1 may be Η; r2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from fluorenyl and fluorenyl. In still further aspects, the compound of formula 1 can be a formula _ chelate R8

Or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (Ig) is substantially free of its cis (±) mixture of palmitic isomers as defined above. In the aspect of the compound of the formula (Ig) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 form a group together with the selected core of the sheath, selected from the group consisting of: 127286 -25 - 200831517

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be ruthenium; and _R4 may be selected from ruthenium and Cu alkyl. In another aspect of the compound of formula (Ig), A, D, G, E, R8 and R9, together with the ring atoms to which they are attached, form a group selected from the group consisting of:

J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be hydrazine; and R4 may be selected from hydrazine and methyl. In one aspect, the compound of formula (I) can be a compound of formula (Ih): 127286 -26- 200831517

J is as defined above, wherein the compound of formula (Ih) is substantially free of its cis (±) mixture of palmitic isomers. Or a pharmaceutically acceptable salt thereof, wherein Ri, R2, R3, R8, R9, A, D, Eg and one of the compounds of the formula (Ih) or a pharmaceutically acceptable salt thereof, are happed ^:^妒 and 妒 together with the ring atoms to which they are attached form a group selected from:

J may be selected from N and CR4; may be oxime; only 2 may be selected from cyano and -OR2a; R2a may be (^_6 alkyl; R3 may be oxime; and may be selected from 11 and 0:1_6 alkyl. In another aspect of the compound of formula (Ih), A, D, G, E, R4R9 and the enthalpy of the compound - (iv) are selected from the group consisting of: 12^286 200831517

J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from hydrazine and methyl. In another aspect, the invention provides a compound of formula (ΪΙ):

Or a pharmaceutically acceptable salt thereof, wherein R6 on carbon "a" is in trans relationship with each other on a carbon, -, and -NH- group, and wherein A is selected from CH And N; D is selected from C-R7 and N; wherein at least one of A and D is carbon; E is selected from 〇, nh and s, wherein: 1) if R8 and R9 together form = 〇, then E is NH; and ϋ) If R8 and R9 are each Η, then E is 〇 or S; G is selected from 〇 and s; 127286 -28- 200831517 J is selected from C-R4 and N; R1 is selected from lanthanum and halogen a cyano group, a cyano group, a c -6 alkyl group, a C 2-6 alkenyl group and a c26 alkynyl group, 〇Rla and -N(Rla) 2, wherein the C -6 alkyl group, the C 2 ·6 alkenyl group and the C 2 -6 alkynyl group Replaced by one or more R10 as appropriate;

Rla, in each presence, is independently selected from the group consisting of hydrazine and alkyl, wherein the 〇16 alkyl group is optionally substituted by one or more R 2 ;; R is selected from the group consisting of hydrazine, halo, cyano, C 〗 6 An alkyl group, a C2-6 fluorenyl 'c2-6 alkynyl group, a -R2a and -N(R2a)2, wherein the Cl_6 alkyl group, the C2_6 alkenyl group and the C2-6 alkynyl group are optionally one or more R20 Substituting; R2a, in each presence, independently selected from the group consisting of hydrazine and alkyl, wherein the Cl-6 alkyl group is optionally substituted with one or more R20; R is selected from the group consisting of hydrazine, halo, cyano, -6 An alkyl group, a C2-6 thin group and a c2-6 fast group, • OR3a&-N(R3a)2, wherein the Ci_6 alkyl group, the C2-6 alkenyl group, and the (2-6 alkynyl group) are optionally treated as one or a plurality of R 3 0 substituted; R 3a ' is independently selected from the group consisting of hydrazine and C! 6 alkyl, wherein the alkyl group is optionally substituted by one or more R 3 0 ; R 4 is selected from the group consisting of hydrazine, a halogen group, -C02H, cyano, CV6 alkyl, C2-6 alkenyl and C2-6 alkynyl, wherein the (^-6 alkyl, C2-6 alkenyl and C2-6 alkynyl groups are optionally one or more R40 Substituted; R6 is selected from the group consisting of a fluoro group, a Ch alkyl group, a C2-6 alkenyl group, a c2_6 alkynyl group, a -R6a group, wherein the Ci_6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group Optionally substituted by one or more R60; R6a' is independently selected from the group consisting of hydrazine and C!-6 alkyl, wherein the alkyl group is optionally substituted by one or more R6 ;; 127286 -29- 200831517 R7 is selected from the group consisting of _ 氡, 氡, 虱, 虱 Cl Cl_6 alkyl, C 2-6 alkenyl and c 2 _ alkynyl, wherein the Ch county, C 2.6 county is 6 acetylene based on the situation - or more R7G is substituted; R9 is each hydrogen, or R8 and R9 together form =〇; and R3〇, R-, R6〇aR7〇' are in each of the respective positions, each independently selected from the group L group, cyano group, -C02H 'Ch alkyl, c2 6 alkenyl and CH block. In one of the compounds of formula (II) or a pharmaceutically acceptable salt thereof,

Eight, ", 〇, £, 妒 and 妒 together with the ring atoms to which they are attached form a group, selected from:

J may be selected from N and CR4; may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be Η; R4 may be selected from 11 and (: 1-6 alkyl; It is selected from the group consisting of a fluoro group and a hydrazine R6a; and R6a may be selected from only a heart-alkyl group. On the other hand, a compound of the formula (II) or a pharmaceutically acceptable salt thereof, human, 〇, £, 妒 and ^ and The ring atoms to which they are attached together form a group, selected from: -30- 127 of 86 200831517

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be methyl; R3 may be Η; Φ R4 may be selected from ruthenium and methyl; R6 may be selected from fluorene And -R6a; and R6a may be selected from fluorenyl and fluorenyl. In one aspect, the compound of formula (II) can be a compound of formula (Ila):

Formula (Ila)

Or a pharmaceutically acceptable salt thereof, wherein 圮, 妒, 圮, 妒, 妒, 尺 9, A, D, E, G and J are as defined above. In one aspect of the compound of the formula (Ila) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 together with the ring atom to which they are attached form a group selected from the group consisting of: 127286 -31 - 200831517

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be Cu alkyl; R3 may be Η; _R4 may be selected from fluorene and CV6 alkyl; From the fluorine group and -〇R6a; and R6a may be selected from the group consisting of ruthenium and (ν6 alkyl group. On the other hand, a compound of the formula (Ila) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and The ring atoms to which they are attached together form a group selected from:

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be methyl; R3 may be Η; R4 may be selected. Η and methyl; R6 may be selected from fluoro And - R6a; and 127286 - 32 - 200831517 R6a may be selected from the group consisting of hydrazine and methyl. In another aspect, the compound of formula (π) can be a compound of formula (IIb): R8

Wherein R1, R2, R3, R6, R8, R9, A, D, E, G and J are as defined above. In one aspect of the compound of formula (lib) or a pharmaceutically acceptable salt thereof, 怠1>, (^1: 舻 and 妒 together with the ring atom to which they are attached form a group

Selected from: J can be selected from N and CR4;

Di 1 may be oxime; may be selected from cyano and -OR2a; R2a may be C 6 alkyl; 妒 may be Η; may be selected from Η and Ch alkyl; R 6 may be selected from fluoro and -ORh; 3 may be selected from the group consisting of 11 and (6) alkyl. In one aspect, the group is formed from a compound of formula (lib) or a pharmaceutically acceptable salt thereof, A, D, G, E, R8 and R9 and the same The ring atom to be connected is 12 is 86 -33- 200831517 From:

J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and -OR2a; R2a may be methyl; R3 may be Η; R4 may be selected from fluorenyl and methyl; R6 may be selected from fluoro and -OR6a; and R6a may be selected from the group consisting of hydrazine and methyl. In yet another aspect, the compound of formula (II) can be a compound of formula (IIc)

Or a pharmaceutically acceptable salt thereof, wherein tR1, R2, R3, R8, R9, A, D, E, G& J are as defined above, and wherein the carbon group "a" is in the carbon "b" The upper _NH-groups are in a trans relationship with each other. In one aspect of the compound of the formula (lie) or a pharmaceutically acceptable salt thereof, ^, (^,:^ and the ring atoms to which they are attached are together Forming group, 127286 -34- 200831517 From:

J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -R2a; R2a may be Cb6 alkyl; R3 may be hydrazine; and R4 may be selected from fluorene and 〇ν6 alkyl. In another aspect of the compound of the formula (lie), the atoms together form a group A, D, G, E, R8 and R9 and the ring to which they are attached are selected from:

J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be hydrazine; and R4 may be selected from hydrazine and methyl. In yet another aspect, the compound of formula (II) can be a compound of formula (nd) · 127286 -35- 200831517

Or a pharmaceutically acceptable salt thereof, wherein R1, r2, R3, R8, R9, a, d, e, G&J are as defined above.

In the case of a compound of formula (lid) or one of its pharmaceutically acceptable salts, 'puppets, £, 妒 and # together with the ring atoms to which they are attached are optional

J may be selected from N and CR4; Di 1 may be Η;

W may be selected from cyano and -OR2a; R2a may be CV6 alkyl; 把 may be Η; and 4 may be selected from Η and CV6 alkyl. In another aspect of the compound of formula (lid), the groups A, D, G, E, R8 and the ring atom to which they are attached are selected from the group consisting of: 12:86 -36 - 200831517

N-y and y-/ κΡ. J may be selected from N and CR4; R1 may be H; R2 may be selected from cyano and decyloxy; may be hydrazine; and R4 may be selected from hydrazine and methyl. In a further aspect, the compound of formula (Π) can be a compound of formula (ne) R°

Or a pharmaceutically acceptable salt thereof, wherein r1, r2, r3, r8, r9, a, d, e, q J are as defined above. Selecting one of the compounds of the formula (lie) or a pharmaceutically acceptable salt thereof ^(^, and forming a group with the ring atom to which they are attached, r\

J may be selected from N and CR4; 12?286 200831517 R1 may be Η; R2 may be selected from cyano and -R2a; R2a may be CV6 alkyl; R3 may be hydrazine; and R4 may be selected from fluorene and CV6 alkyl . In another aspect of the compound of the formula (lie), ^(^,:^ and the ring atoms to which they are attached - (iv) a group

Selected from: J may be selected from N and CR4; R1 may be Η; R2 may be selected from cyano and methoxy; R3 may be Η;

R4 may be selected from hydrazine and methyl. In the case of further steps, the compound of the formula (IV) can be a compound of the formula (IV): Ο

Or a pharmaceutically acceptable salt thereof, wherein R 1 and I 八 K, R, 妒 and J are as defined above, the groups are to each other

And wherein the fluorine group on carbon "a" has a trans relationship with A ^ 7286 - 38 · 200831517 on carbon "b". In one aspect of the compound of Formula (Ilf) or a pharmaceutically acceptable salt thereof, J may be selected from N and CR4; may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be (V6 alkyl; R3 may be And _ R4 may be selected from the group consisting of hydrazine and Cu alkyl. In another aspect of the compound of formula (Ilf), J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; It may be Η; and R4 may be selected from fluorenyl and fluorenyl. In yet a further aspect, the compound of formula (II) may be a compound of formula (IIg):

R3 Formula (3⁄4) or a pharmaceutically acceptable salt thereof, wherein R^R'r3 and j are as defined above, and wherein the fluoro group on carbon "a" and the group on carbon "b" They are in a trans relationship with each other. In one aspect of the compound of the formula (IIg) or a pharmaceutically acceptable salt thereof, ^7286 -39 - 200831517 J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and -OR2a; R2a may be C ^6 alkyl; R3 may be H., and R4 may be selected from: ^ and heart. In another aspect of the compound of formula (Ilg): J may be selected from N and CR4; R1 may be hydrazine; R2 may be selected from cyano and methoxy; R3 may be H; and R4 may be selected from fluorenyl and fluorenyl. - Going to Gan-, ', and, by way of example, the parental line provides a further ^ ^ ^ independent aspect of the invention. Biological activity

The ability of the compounds of formula (I) to achieve antibacterial action by the compounds of formula (I) which are of interest in the art by virtue of their anti-(iv) action is described herein. Bacterial Infectivity Test Method 1 Ν π / generation snails, 96 wells; Ν, test for antimicrobial activity. The compound was dissolved in dimethyl hydrazine and tested in 10 doubling dilutions in an easy-to-reduced wood assay. The organism used for the test can be grown overnight in a suitable agar medium and then hanged in a liquid medium suitable for growth of the organism. This suspension can be adjusted to | 127286 200831517 at 0.5 McFarland ' and further 1 to 1 〇 dilution in the same liquid medium to prepare the final biological suspension in 100 μl. The plates can be incubated for 24 hours at 3 Tc under appropriate conditions prior to reading. The minimum inhibitory concentration (MIC) is determined by the lowest drug concentration that can reduce growth by up to 8% or more. The compounds were evaluated against a list of tests for Gram-positive species, including Staphylococcus aureus, Streptococcus pneumoniae, and Streptococcus pyogenes. _ In addition, 'compounds' were evaluated against a list of trials for Gram-negative species, including influenza bacterium, E. coli, M. catarrhalis. The present hair milling composition has an MJC of less than or equal to 8 micrograms per milliliter for one or more of the organisms referred to above. The compound of Example 2 had a 0.25 (milligram/liter) for Golden Charcoal and a MIC of 0.5 (mg/L) for the itching mill. Bacterial Infectivity Test Method 2 Compounds were tested for antimicrobial activity by a susceptibility test using the micro-culture dilution method recommended by CSLI. The compound can be dissolved in dimethyl sulfoxide and tested in a susceptibility test with a 1 doubling double dilution so that the final concentration of dimethyl hydrazine in the assay is 2 〇/〇 (v/v). The Jinbian Cijiao Ball Mill (San) 516 cells used in the assay can be grown overnight on a suitable agar medium and then suspended in the liquid susceptibility test medium recommended by NCCLS. The turbidity of each suspension can be adjusted to equal 0.5 McFarland standard and a further i to 2 〇〇 dilution can be performed in the same liquid medium to prepare the final biological suspension, and 100 microliters of this suspension is added to the containing The microtiter plates of the compound dissolved in 2 μl of dimethyl sulfoxide were each 127286 • 41- 200831517 well. Before reading, the plate can be cultured under the conditions of high oxygen pressure and temperature, and reduced by Ncm# π < When used in 矣1, the word "suppression" refers to the inhibition of gold by the compound of ^ τ, which is not the case number. #芑##硪磨516 cells 生夕石八 L / t肥Percentage of growth (compared to untreated samples). When tested in the above in vitro assay, the compounds of the example numbers listed below are tested at the indicated concentrations to provide the indicated inhibition. In most cases, the highest concentration of the test compound is 8 μg/ml. However, in some cases, the compound is tested at a concentration higher than 8 μg/μl, typically when the concentration is first //M metric, then converted to micrograms/ml. In the case where the compound is tested at a concentration greater than 8 μg/ml, the concentration closest to 8 μg/ml is provided below. Table 1 Examples No. Tested concentration (μg/ml) Inhibition (%) 1 8 100 2 8 100 3 8 99 4 8 100 5 1 8 100 6 8 99 7 8 100 8 8 99 9 8 100 10— ------ -----* 100 127286 -42- 200831517

Examples 11 to 20 11 8 100 12 8 100 13 8 100 14 8 100 15 8 97 16 8 97 17 8 99 18 8 95 19 8 100 20 8 100 Examples 21 to 30 21 8 100 22 8 100 23 8 100 24 8 100 25 8 98 26 8 98 27 8 87 28 8 98 29 8 84 30 8 98 Examples 31 to 40 31 8 87 32 8 98 33 13 96 34 12 91 35 14 100 36 12 90 37 13 100 127286 -43- 200831517 38 12 100 39 14 100 40 12 100 Examples 41-47 and 50 41 8 100 42 8 100 43 4 100* 44 8 100 45 8 97 46 8 100 47 8 100 50 14 100 51 9 100 52 13 100

* The inhibition of the compound of Example 43 at a concentration of 8 μg/ml was 12%, but the 12% number was generally considered to be erroneous. Thus, in one aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use as a medicament. In yet another aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as a human is provided. In yet another aspect, the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of one or more pathogenic organisms in a warm-blooded animal such as a human Caused by bacterial infections such as Acinetobacter bovis, hydrophilic gas-demanding bacteria, Bacillus anthracis, Bacteroides fragilis, B. pertussis, Burkholderia cepacia, Chlamydia pneumoniae, Citricus faecalis, Clostridium difficile, Enterobacter cloacae, fecal intestine 127286 -44- 200831517 cocci, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusarium oxysporum, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus serovar , oxytoca Klebsiella, Klebsiella pneumoniae, G. jejuni, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, gonorrhea Neisseria, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Common Proteobacteria, Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Fushishi Shiga Bacteria, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus haemolyticus, Staphylococcus aureus, Staphylococcus aureus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae S. Cocci. In a further aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of an infection, such as bronchitis, Clostridium difficile, in a warm-blooded animal such as a human. Colitis, cervicitis, endocarditis, gonococcal urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections And urinary tract infections. In still a further aspect, there is provided the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for the treatment of a bacterial infection in a warm-blooded animal such as a human, wherein the bacterium is a genus, selected Self-produced Agrobacterium, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydia, Citric Acid, Clostridium, Enterobacter, Enterococcus, Escherichia, Flavobacterium, Fusobacterium, Pseudomonas, Klebsiella, Legianella, Listeria, 127286 -45- 200831517, Morganella, Moraxella, Mycoplasma, Neisseria, Pasteurella, Digestococcus, Peptostococcus, Pftilida, Proteus, Salmonella, Pseudomonas Genus, Serratia, Shigella, Stenotrophomonas, Streptococcus anti-Staphylococcus. In another aspect, a method of treating a bacterial infection in a warm-blooded animal, such as a human, is provided, the method comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof. In another aspect, the invention provides a method for treating a bacterial infection caused by one or more pathogenic organisms in a warm-blooded animal such as a human, such as Acinetobacter baumannii, hydrophilic gas-demanding bacteria, Bacillus anthracis, Bacteroides fragilis, Bordetella pertussis, Burkholderia cepacia, Chlamydia pneumoniae, Citrobacter freundii, Clostridium difficile, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli , Neisseria gonorrhoeae, Haemophilus influenzae, Haemophilus parainfluenzae, Haemophilus sphaeroides, O. ytoca Klebsiella, Klebsiella pneumoniae, G. elegans, Monocyte proliferation Streptomyces, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, Neisseria meningitidis, Pasteurella multocida, Proteus mirabilis, Common proteobacteria , Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Shigella flexneri, Shigella dysenteriae, Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus aureus, type Staphylococcus, Staphylococcus aureus, Stenotrophomonas maltophila, Noococcus lactis, Streptococcus mutans, Pneumococcal I heat and chain honing, the method comprising administering to the animal an effective amount of a compound of formula (I) or pharmaceutically thereof Acceptable salt. 127286 -46- 200831517 In another aspect, the invention provides a method for treating bacterial infections in Wenjin animals such as humans, such as t, +, method, such as bronchitis, C. difficile colitis, sub-cerebral inflammation, intracardiac fire, Nine, dripping urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, bone test, raising, 1 > ulnar otitis, pharyngitis, pneumonia, prostatitis, septicemia, palace sputum, * ^ shell, and anti-skin In combination with a soft tissue infection and a urinary tract infection, the method comprises administering to the animal a compound of the formula (1) or a pharmaceutically acceptable salt thereof.

^面's method provides a method for treating and mulching wood in warm-blooded animals such as humans, wherein the bacterium is a genus, selected from the group consisting of the genus, the genus, the genus Bacillus, and the genus Bacteroides. , Bordetella, Bi^khcMena, Chlamydia, citric acid, Clostridium, Enterobacter, Escherichia, Flavobacterium, Fusobacterium, bloodthirsty Bacillus, Lactobacillus, Legianella, Listeria, Morgan, Moss, Mycoplasma, Neisseria, Pasteur Genus, Digestive genus 'Digestive Streptococcus, Pftilida, Proteobacter, Salmonella, Pseudomonas, Serratia, Shigella Ste ' Stenotwph Gmmas, Streptococcus A method of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the genus of the formula (I) or a pharmaceutically acceptable salt thereof Salt for the treatment of bacterial infections in warm-blooded animals such as humans. In another aspect, a compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in treating a bacterial infection caused by one or more pathogenic organisms in a warm-blooded animal such as a human, such as灭 149 179 127286 -47- 200831517 Hydrophilic gas, Bacillus anthracis, Bacteroides fragilis Clostridium, Enterobacter cloacae, Enterococcus faecalis, Enterococcus faecium, Enterobacter aerogenes, Escherichia coli, Fusarium oxysporum, Influenza bacterium, Parainfluenzae, Haemophilus haemophilus, Klebsiella oxytoca Klebsiella pneumoniae, G. elegans, Listeria monocytogenes, Moraxella catarrhalis, Morganella morganii, Mycoplasma pneumoniae, Neisseria gonorrhoeae, meningitis Neisseria, Pasteurella, Proteus, Common Proteobacteria, Pseudomonas aeruginosa, Salmonella typhimurium, Salmonella typhimurium, Serratia marcescens, Shigella flexneri, Shigella dysenteriae, golden yellow Portuguese Staphylococcus, Staphylococcus epidermidis, Staphylococcus aureus, Staphylococcus aureus, Staphylococcus aureus, Stenotrophomonas maltophila, Streptococcus agalactiae, Streptococcus mutans, Streptococcus pneumoniae, Streptococcus pyogenes. In yet another aspect, the compound of formula (I), or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of infections in warm blood, animals, such as humans, such as bronchitis, C. difficile colitis, cervicitis Endocarditis, gonococcal urethritis, inhalation of anthrax, intra-abdominal infection, meningitis, osteomyelitis, otitis media, pharyngitis, pneumonia, prostatitis, septicemia, sinusitis, skin and soft tissue infections and urinary tract infections. In still another aspect, there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, for use in the treatment of a bacterial infection in a warm-blooded animal such as a human, wherein U is a green scorpion and the sputum is a gas production list. Cyanobacteria, Acinetobacter, Bacillus, Bacteroides, Bordetella, Burkholderia, Chlamydia, Citric Acid, Clostridium, Enterobacter, Enterococcus, Escherichia 127286 -48- 200831517 Genus, Flavobacterium, Fusobacterium, Pedibacterium, Klebsiella, Legianella, Listeria, Morganella, Moraxella Genus, Mycoplasma, Neisseria, Pasteurella, Digestive, Digestive Streptococcus, Pftilida, Proteus, Salmonella, Pseudomonas, Sand Helicobacter, Shigella, Stenotrophomonas, Streptomyces and ##球磨广和门黑米亚属. In one aspect, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by 竑f yg 不磨#磨. On the other hand, the terms 'infection' and ''bacterial infection'' may refer to a bacterial infection caused by a fan. In yet another aspect, the term π-infected with π and "bacterial infection" may refer to a bacterial infection caused by blistering. On the other hand, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by a cure. In a further aspect, the terms π-infected with 'bacterial infection' may refer to a bacterial infection caused by 0 泞##武磨. In a further aspect, the term "infected π" and "bacterial infection" may refer to the bacterial infection caused by it. In yet further, the term "infection" and "bacterial infection" may refer to the cause of the injury. Bacterial infection. On the one hand, the term "fever" and "bacterial infection" may refer to bacterial infections caused by the 戌##鑀# grinding. On the other hand, the terms 'infection' and 'bacterial infection' may refer to The bacterial infection caused by Cai #礼磨. On the other hand, the term “π infection” and “bacterial infection” may refer to bacterial infection caused by 麿#靡# grinding. On the other hand, "infection" and "bacterial infection" terms may refer to bacterial infections caused by ball milling. In further aspects, the terms "infection" and "bacterial infection" may refer to a wide-body ball mill. Bacterial infection. In a further aspect, the terms "infection" and "bacterial infection" may refer to a bacterial infection caused by 127286 -49-200831517. In a further aspect, the term "infection" and "bacterial infection" can refer to bacterial infections caused by 乂 禅 禅 。. On the one hand, the term '1 infection' and 'bacterial infection' can refer to 禳 礼 礼# Bacterial infection caused by grinding. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by full-scale tamping. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by the annihilation of the camp. On the other hand, the term "infection" and "bacterial infection of π" may refer to a bacterial infection caused by a rug. In a further aspect, the term "infection" and "bacterial infection" may refer to -toca. A bacterial infection caused by Yumenbo. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by the sputum. In yet a further aspect, the term "infection" and π bacterial infection '' can refer to a bacterial infection caused by Capricorn / #冷拉磨. On the one hand, "infection" and "bacterial infection" terminology may refer to bacterial infections caused by meditation and martial arts. On the other hand, "infection" and "bacterial infection" The term may refer to a bacterial infection caused by #廯:# pulling into a mill. On the other hand, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by #沃#广戌磨. On the other hand, "infection" and "bacterial infection'' may refer to bacterial infections caused by 厣爻. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by a full-body rifle. In a further aspect, the term "infection 11" and "bacterial infection" may refer to a bacterial infection caused by the rot of Neisser. In yet further aspects, the terms '1 infection' and ''bacterial infection' may refer to On the one hand, the term "n infection" and "bacterial infection" π term can refer to 127286 -50-200831517 bacterial infection caused by singular deformation grinding. On the other hand, "infection "And, bacterial infection, the term can refer to bacterial infection caused by Pu Dao Deformation #. In another aspect, the term "infected" disk "bacterial infection" can refer to a bacterial infection caused by a miscellaneous (four) #.

On the other hand, infection, 'and' bacterial infection, the term can refer to bacterial infection caused by blasphemy, further aspects, "infection" and "bacterial infection" can refer to the cause of (four) material W (four) Bacterial infection. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by sputum sputum, which may be caused by sputum sputum. In terms of further steps, infection, and "bacterial infection" may be used. Refers to the bacterial infection caused by the cause. In terms of infection, "and"bacterial infection" term can refer to bacterial infection caused by dysentery, and on the other hand, infection ""Bacterialinfection" terminology may refer to a bacterial infection caused by the thorns of the gold stalk. On the other hand, the terms 'infection' and 'bacterial infection' may refer to the fineness caused by the smashing of the ball. infection. In yet another aspect, the infection, and, bacterial infection, the term may refer to a bacterial infection caused by a sputum. In a further aspect, the terms 'infected' and "bacterial infection" may refer to a bacterial infection caused by a sharpening of the body. In a further aspect, "infection" and "bacterial infection," the term can refer to a bacterial infection caused by Fangli Mill # ball mill. In still further aspects, the term & and the term ii infection may refer to the bacterial infection caused by it. On the one hand, "infection" and "bacterial infection," the term can be caused by a bacterial infection caused by Zhao. On the other hand, the terms π infection and "bacterial infection" may refer to bacterial infections caused by tampering of the wheat chain. On the other hand, "infection, and,, bacterial infection, the term can refer to bacterial infection caused by smashing of the scorpion chain. On the other hand,,, infection, with 127286 -51 - 200831517 The term 'bacterial infection' can refer to a bacterial infection caused by sputum sulphur. On the one hand '"infection" and "bacterial infection, the term may refer to a bacterial infection caused by bacteria that are edging by the peasant. On the other hand, the term "infection," and "bacterial infection" may refer to Bacterial infection caused by bacteria that do not smash the shoulders. On the other hand, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by the use of a fine ape. On the other hand, the terms "infection" and "bacterial infection" may refer to the bacterial sensation caused by the bacteria of the ## shoulder. In a further aspect, the "infection" and "bacterial infection" terms may Refers to the bacterial infection caused by the bacteria of ##戌尔边. In a further aspect, the terminology and the infection of the fine sputum may refer to the bacterial infection caused by the bacteria of η·α. "Infection" and "bacterial infection," the term can refer to a bacterial infection caused by bacteria in the clothing and the rim. In one aspect, "infect' and ' bacterial infection, the term may refer to a bacterial infection caused by a bacterium of the genus. On the other hand, "infection" and "bacterial infection" can only cause bacterial infections caused by fine-grained rituals. On the other hand, _ ''infection" and "bacterial infections "The term can refer to the bacterial infection caused by the bacteria of the wide axillary mill. On the other hand, "infection,, and,, bacterial infection, the term can be caused by the bacteria caused by the bacteria of the I ball." infection. Further in the 'infected' and ''inferior infections" terms may refer to the bacterial infection caused by the bacteria of the genus. In a further aspect, the infection "and, bacterial infection" can refer to a bacterial infection caused by the bacteria of the axe. In a further aspect, the terms "infection" and "bacterial infection" may refer to bacterial infections caused by bacteria of the genus. In one aspect, the term "infection" and "bacterial infection" may refer to营血# The bacterial infection caused by the bacteria of the shoulder. On the one hand, 127286 -52· 200831517 sensible wood / bacterial infections " terminology can refer to the bacteria of the gram 戌 戌 戌 = = = = = = = = = = = = = = = = =. On the other hand, "infection" and "bacterial infection, the term can be used to buckle the bacteria caused by the cold-grinding bacteria. On the other hand, the sense of wood and "bacterial infection," the term refers to Because of the suppression of life, it is the fineness of the genus. On the other hand, "infection" and, bacterial sensation can be deducted by the bacterial infection caused by the bacteria of the genus Jurassic. In the case of 乂, infection " &"bacterialinfection" The term may refer to the bacterial infection caused by the genus Moura mulberry. In a further aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by bacteria of the genus Fungus. In terms of re-entering V, infection, and the term "bacterial infection" may refer to bacterial infections caused by Neisseria genus and bacteria. In one aspect, the term "infection" and "bacterial infection" may refer to a bacterial infection caused by bacteria. In other respects, the term "infection" and "bacterial infection" may refer to In addition, the "infection" & "bacterial infection" term can refer to the bacterial infection caused by bacteria. On the other hand, the term "infection" and "bacterial infection" can refer to a bacterial infection caused by a bacterium of the genus Tira Mill. In a further aspect, the term "infection," and "bacterial infection" It can refer to the bacterial infection caused by the bacteria that have been honed. In a further aspect, the term "infection" and "bacterial infection" can refer to the bacterial infection caused by the bacteria of the ammonium. Another _ aspect of the second sense ^ f 'and ''bacterial infections' term can refer to a bacterial infection caused by the bacteria of the body 7# grinding shoulder. In a further aspect, "infection" and "bacterial infection" terms It may refer to a bacterial infection caused by a genus of the genus Mongolian genus. On the one hand, the term "infection" and "bacterial infection" may refer to bacterial infections caused by bacteria belonging to the genus genus genus 127286 • 53- 200831517 On the other hand, the term "nn Q 木兴细_感染" can be caused by bacterial infections caused by bacteria. On the other hand, the term 'infection•' and "bacterial infections can refer to _ bacterial bacterial infection. In another aspect, "infection" and, bacterial infections " know- may refer to bacterial infections caused by bacteria.

In contrast, "infection" and "bacterial infection" terms can refer to gynecological infections. In another aspect, "infection" and, bacterial infection" terminology can refer to a respiratory infectionist. In yet another aspect, the infection "and"bacterial infection" term can refer to a sexually transmitted disease. On the other hand, "infection" and "bacterial infection" terms may refer to urinary tract infections. In terms of 'steps', 'infections' and 'bacterial infections' can refer to acute exacerbations of chronic bronchitis (ACEB). In yet further, the term "infection" and "bacterial infection" can refer to acute Otitis media. On the one hand, "infection" and "bacterial infection" terms may refer to acute sinusitis. In another aspect, "infection"盥, "bacterial infection" terminology may be caused by drug-resistant bacteria Infection, on the other hand, infection "and"fine g infection" terminology can guide urinary catheter-related failures in another aspect, "infection" and "bacterial infection" can refer to soft boating. In terms of 'steps' and 'infections' and 'bacterial infections', it is meant that Chlamydia is a progressive aspect, and "infections" and "bacterial infections" can refer to group acquired pneumonia (CAP). "Infection" and "bacterial infection" terms may refer to concomitant skin and skin structure infections. On the -, "sense half" and "bacterial infection" terms can refer to non-concurrent skin and skin structure infections. In other senses * and "bacterial infections" terms can refer to heart, endometritis. The term "wood and bacterial infection" can refer to fever neutropenia. In addition, the '"infection" and "bacterial infection" term can be 127286 -54- 200831517 refers to gonococcal cervicitis. ;隹^Bei people in the step-by-step,,, infection, and, bacterial infections, the term can refer to gonococcal urethritis. In addition, face, "infection" and "bacterial infection" terms can refer to hospitals Pneumonia (HAP). On the other hand, "infection,, and "bacterial infection" terms can refer to osteomyelitis. In a further aspect, the term "infection" can refer to septicemia. In still further aspects, the term "infected sputum" and "bacterial infection" may refer to syphilis. In an advanced aspect, a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient is provided. In still a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (lc), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. In still a further aspect, there is provided a pharmaceutical composition comprising a compound of formula (Id), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. In one aspect, the invention provides a pharmaceutical composition comprising a compound of formula (Ie), or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier, diluent or excipient. The compositions of the present invention may be suitably used orally (for example, as tablets, troches, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example, Creams, ointments, gels or aqueous or oily solutions or suspensions), by inhalation (for example as a finely divided powder or liquid aerosol), by insufflation (for example as a finely divided powder) or parenterally (for example as sterile) The aqueous or oily solution is administered intravenously, 127286-55-200831517, intramuscularly or intramuscularly, or as a suppository for rectal administration. The compositions of the present invention can be obtained by conventional procedures using conventional pharmaceutical excipients as are known in the art. Thus, compositions intended for oral use may contain, for example, one or more coloring, sweetening, flavoring and/or preservatives. Suitable pharmaceutically acceptable excipients for tablet formulation, including, for example, inert diluents such as lactose, sodium carbonate, calcium phosphate or calcium carbonate, granulation and disintegrating agents, such as corn starch or alginic acid; binders For example, starch; lubricants such as magnesium stearate, stearic acid or talc; preservatives such as ethyl or propyl p-hydroxybenzoate; and antioxidants such as ascorbic acid. The tablet formulation may be uncoated or coated, whether to alter its disintegration, and subsequent absorption of the active ingredient in the gastrointestinal tract, or to improve its stability and/or appearance, in either case, Conventional coating agents and procedures are known in the art. The composition for oral use can be in the form of a hard gelatin capsule, wherein the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or as a soft gelatin capsule, wherein the active ingredient is water or oil such as peanut oil, Mix with liquid paraffin or olive oil. The aqueous suspension usually contains the active ingredient in the form of a fine powder or in the form of nano or micronized particles, accompanied by one or more suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose. , sodium alginate, polyvinyl tetrahydrogen t, the gums and gum arabic; dispersing or wetting agents, such as lecithin, or condensation products of alkylene oxides with fatty acids (such as polyethylene oxide stearic acid) Ester), or a condensation product of ethylene bromide with a long-bond aliphatic alcohol, such as cetyl vinyl ether cetyl alcohol, or an ester of ethylene oxide with a derivative derived from fat 127286 -56·200831517 acid and hexitol a condensation product of the class, such as a polyoxyethylene monooleate, or a condensation product of ethylene oxide with a long-chain aliphatic alcohol, such as cetyl vinyl ether cetyl alcohol, or an ethylene oxide derived from a fatty acid a condensation product of a partial ester with a hexitol such as polyoxyethylene monooleate S- or a mixture of Ethylene Ethylene and a partial ester derived from a fatty acid and a hexitol anhydride For example, polyethylene monooleate ester. The aqueous suspension may also contain one or more preservatives, for example ethyl or propyl p-hydroxybenzoate; an antioxidant such as ascorbic acid; a coloring agent; a flavoring agent; and/or a sweetening agent such as sucrose, saccharin or day. Methyl phenylalanine. The oily suspensions can be formulated by suspending the active ingredient in a vegetable oil, such as peanut oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may also contain a thickening agent, such as beeswax, hard wax or cetyl alcohol. Sweetening agents, such as those set forth above, with flavoring agents may be added to provide a savoury oral preparation. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid. Dispersible powders and granules suitable for use in the preparation of aqueous suspensions by the addition of water contain the active ingredient with dispersion or wetting agents, suspending agents and one or more preservatives. Examples of suitable dispersing or wetting agents and suspending agents are those already mentioned above. Other excipients, such as scent, scent and coloring agents, may also be present. The pharmaceutical composition of the present invention may also be in the form of an oil in the form of an aqueous emulsion. The oil phase is a vegetable oil such as olive oil or peanut oil, or mineral oil, such as liquid stone soil, or a mixture of any of these. Suitable emulsifiers may be, for example, natural gelatin such as gum arabic or scutellaria gum, naturally occurring phosphorus 127286 -57 - 200831517 曰, such as ugly, lecithin, derived from fatty acids and hexitols The product of a sputum or a sputum (for example, a monoolein monooleate) and a condensation product of the partial ester with the % lactobion, such as a polyoxyethylene monooleate. The emulsion may also contain sweetening, flavoring and preservatives. The syrup/widiness agent may be formulated with a sweetener such as glycerin, propylene glycol or saponin; I methyl propylamine or sucrose, and may also contain a emollient, a preservative, a flavor and/or a coloring agent. The surface may be in the form of a sputum-injectable aqueous or oily suspension which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents as mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example, a solution in 1,3-butanediol. The compositions for administration by inhalation may be in the form of conventional pressurized aerosols which are arranged to dispense the active ingredient, either as an aerosol containing finely divided solids or liquid droplets. Conventional aerosol propellants, such as volatile fluorinated hydrocarbons or hydrocarbons, may be used, and the aerosol device may conveniently be arranged to dispense the metered amount of active ingredient. / For further information on the formula, the reader can refer to Chapter 25 of the Comprehensive Medical Chemistry (Corwin Hansch; Chairman of the Editorial Board), and Perg_n Press. The amount of active ingredient combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host to be treated and the particular route of administration. For example, a formulation intended for oral administration to humans will typically contain, for example, from 5 mg to 4 g of active agent, in admixture with suitable and suitable amounts of excipients, which may be from about 5 parts by weight of the total composition. Change to about 98%. Dosage unit forms will generally contain from about 127286 • 58 to 200831517 1 gram to about 500 mg of active ingredient. For further information on the route of administration and dosage regimen, the reader is referred to Chapter 25.3 of the Journal of Integrated Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergam〇n Press 199〇. In addition to the compounds of the present invention, the pharmaceutical compositions of the present invention may also contain or co-administer (simultaneously, sequentially or individually) one or more known drugs, selected from the group's available antibacterial agents (eg, Macrolides, 4-linoleones, linoleamides or aminoglycosides) and/or other anti-infective agents (such as antifungal tri-wound or amphotericin). These may include carbapenems such as mer〇penem or imipenem to broaden the therapeutic effectiveness. The compounds of the present invention may also contain or co-administer a finely divided g/increased permeability protein f (Βρι) product or a jet pumping inhibitor to improve the activity against Gram-negative bacteria and bacteria resistant to antimicrobial agents. As described above, the dose size required to treat or prevent a particular disease state must be changed depending on the host to be treated, the route of administration, and the severity of the disease being treated. Preferably, (four) mg/kg r color is used. The daily dosage will therefore be determined by the practitioner who is treating any particular patient. The compound of formula (I) and its pharmaceutically acceptable salts, in addition to its use in therapeutic medicine, may also Development of in vitro and in vivo test systems and use as a pharmacological tool in quasi-chemotherapy to assess antibacterial effects in laboratory animals such as Jewish, Dog, Rabbit, Monkey, Rat and Mouse, as a novel treatment for search Any of the alternative embodiments of the compounds of the invention described herein in any of the above-mentioned pharmaceutical compositions, processes, methods, 127286-59-200831517 uses, agents and manufacturing characteristics of the invention The example also applies. If the method is not commercially available, the necessary starting materials for such procedures, such as those described herein, may be Is made, which is selected from standard organic chemical techniques, techniques similar to the synthesis of known similarly to the structure of the compound, or a similar technique or the application instance of the program.

It should be noted that many of the starting materials for the synthetic methods as described herein are commercially available and/or widely reported in the scientific literature, or may be modified using methods reported in the scientific literature, t. Available compounds are available. Read 乂 ί 考 荨 Organic Chemistry 5th Edition, by March and Michael Smith' by J〇hn Wiley & Sons, published in 2002, general guidelines on reaction conditions and reagents. It should also be understood that in some of the reactions mentioned herein, it may be necessary/want to protect any sensitive groups in the compound. Where the protection is necessary or desirable, it is known to those skilled in the art and is a method of such shame. Conventional protecting groups can be used according to standard practice (for a description, see T.W. Thus, Protective Groups for Organic Synthesis, published by John Wiley & Sons, 1991). With regard to the appropriate protecting group of the thiol group, for example, an acid group, such as burning

The base ', for example, an ethyl group, an a, a group thereof, for example, a benzyl group, a decyl group, for example, a trimethyl decyl group, or an arylmethyl group such as a benzyl group. With regard to the removal protection conditions of the above protecting groups, it will have to be changed with the choice of the test basis. Thus, for example, a fluorenyl group, such as an alkanoyl group or an aryl group I group, can be removed by hydrolysis, for example, with a suitable base such as 127286 200831517, a metal hydroxide such as a hydroxide clock or sodium. , such as trimethyl sulphide, such as trimethyl sulphide, may be removed, for example, by vaporization or by aqueous acid, or aryl groups, such as in the presence of a catalyst, by nitrogen Turn into: remove the base. Suitable protecting groups for the amine group are, for example, anthracenyl groups, such as, for example, a fluorenyl group, such as an ethyl group, a oxycarbonyl group, such as a methoxy group, an ethoxy group or a third group, a aryl group, an aryl group. A few groups, such as an oxycarbonyl group, or an aryl fluorenyl group, such as a benzyl group. The removal protection conditions for the above protecting groups must be changed with the choice of the protecting group. Thus, for example, a sulfhydryl group, such as a (iv) group or a oxy-oxygen group or an aryl group, can be removed, for example, by hydrolysis, such as a metal oxychloride, such as lithium ruthenate or sodium. Alternatively, a mercapto group, such as a second-butoxycarbonyl group, can be removed, for example, by treatment with a suitable acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trifluoroacetic acid, and a mercaptomethoxy group, such as an anthracene group. For example, on a contact such as Ιε/carbon, it is removed by hydrogenation or by treatment with a Lewis acid such as fluoro(trifluoroacetate) boron. A suitable alternative protecting group for the primary amide group is, for example, anthraquinone, which can be removed via treatment with an alkylamine such as dimethylaminopropylamine or 2. ethylamine or with a monthly well. Another suitable protecting group for the amine is, for example, a cyclical mystery, such as a four-nitrogen bite, which is removed by treatment with a suitable acid such as trifluoroacetic acid. The sulphate can be removed at any convenient stage in the synthesis using conventional techniques known in the art, or it can be removed at a later reaction step or treatment. In one aspect, the present invention provides a process for the preparation of a compound of formula (I) or a formula or a method thereof which is acceptable for the day and summer, comprising the compound of formula (ΑΑ): 127286 -61 - 200831517

Re

Compound with formula (AB): formula (AB)

The reaction is carried out in the presence of a suitable reducing agent, and then, if necessary: 0 to convert a compound of formula (1) to another compound of formula (I); remove any protecting groups; and/or m) form a pharmaceutically acceptable salt. The compound of formula (AA) can be reacted with a compound of formula (AB) under typical reductive amination conditions. The first step of the reaction, the formation of the imine, typically in the presence of a dehydrating agent such as the molecule _S3A, is carried out, except that the reaction is generally carried out without a suitable bath as a mixture of methanol or methanol/chloroform. The imine intermediate is typically not per detached; rather, the reducing agent is typically added to the reaction mixture after the imine is formed. Regarding the second (reduction) step of the method, the reduction of the ruthenium includes a boron reducing agent, such as NaB (〇AchH or n 〇玛〇 in another aspect, the invention provides a preparation of the formula (I) or (II) A compound, wherein R is F' or a pharmaceutically acceptable salt thereof, the process comprising the compound of formula (AC): 127286 - 62 · 200831517

With the compound of formula (AB):

Formula (AB) φ is reacted in the presence of a suitable reducing agent, and then, if necessary: 0 to convert a compound of formula (I) or (II) to another compound of formula 1 or (II); U) removing any protecting groups; And/or Hi) form a pharmaceutically acceptable salt. The reaction conditions for the reaction of the compound of the formula (AC) with the compound of the formula (AB) are as described above for the reaction of the compound of the formula (AA) with the compound of the formula (AB). • In yet another aspect, the invention provides a process for the preparation of a compound of formula (I) or (II), or a pharmaceutically acceptable salt thereof, which comprises reacting a compound of formula (BI): R8

Reacting with a suitable reducing agent, then, if necessary: 127286 200831517 i) converting a compound of formula (I) or (9) to another formula (1) or (9) character; 〇ϋ) removing any protecting groups; and/or &;) Form a pharmaceutically acceptable salt. Suitable reducing agents for the reduction of the compound of formula (BI) include rotten reducing agents such as NaB(OAc)3H or NaB^CN. Appropriate solvent A 帀 斗 斗 ', (1) Hungarian alcohol or methanol / gas imitation mixture. The compound of the formula (ΑΑ) can be produced as shown in Scheme 1.囷式1

Removal protection R6

A reaction of a compound of the formula (AD) with a compound of the formula (ΑΕ) in the presence of a base such as sodium hydride can be used to obtain a compound of the formula (AF). Removal of the protection system provides a compound of the formula (ΑΑ). Suitable exfoliating groups include exfoliating groups such as methanesulfonate, chloro, bromo and iodo. Suitable protecting groups include alkoxycarbonyl groups, such as a third butoxycarbonyl group, which can be removed using an acid such as HCl. Another method which can be used to prepare the compound of formula (AA) is shown in Scheme 2. Figure 2

Re

^ (AG) removal protection

If R6

The reaction of a compound of the formula (AD) with a compound of the formula (AG) under Mitsunobu conditions can be used to obtain a compound of the formula (AF). Removal of the protecting system provides a compound of formula (AA). Suitable protecting groups include alkoxycarbonyl groups, such as a third-butoxycarbonyl group, which can be removed using an acid such as HCl. Scheme 3 depicts another method for preparing a compound of formula (AA). 127286 65- 200831517 Figure 3

PG type (Al) reducing agent

Re

Removal protection

Re

The compound of the formula (AF) can be reacted with a base such as NaH, followed by reaction with bromine or chlorohydrin or > odor or gas path or with a protected derivative thereof (in the case of an alcohol derivative, Subsequent removal of protection and oxidation) provides a compound of formula (AH). The compound of formula (AH) can be reacted with a compound of formula (AI) under typical reductive amination conditions. As described above with respect to the reaction of the compound of the formula (AA) with the compound of the formula (AB), the imine formation is typically carried out in the presence of a dehydrating agent such as a molecular sieve (MS 3 person), but the reaction is generally carried out without using a dehydrating agent. A suitable solvent is tetrahydrofuran, di-methane or a gas/methanol mixture. The imine intermediate is typically not isolated; instead, the reducing agent is typically added to the reaction mixture after the imine is formed. Suitable reducing agents for the second step of the reaction (reduction) include boron reducing agents such as NaB(OAc)3H or NaBH3CN. The removal protection of the compound of formula (AF) provides a compound of formula (AA). With respect to suitable protecting groups for the amine substituents on the hexahydropyridine ring of the compound of formula (AI), including alkoxycarbonyl 127286-66-200831517 groups, such as a third-butoxycarbonyl group, which may be removed using an acid such as HCl; With an azide, it can be converted to an amine in a reducing manner, whether using triphenylphosphine (Staudinger reaction) or by hydrogenation. A compound of the formula (AL) which is a compound of the formula (AE) wherein the leaving group is a methanesulfonate cleavage group can be produced according to the formula 4. Figure 4

Formula (AG) Formula (AG) Compounds of formula (AG) can be prepared by reacting a compound of formula (AI) with bromoethanol or a derivative thereof in the presence of a base such as triethylamine to provide a compound of formula (AG). The compound of the formula (AG) can be reacted with a gasified decanesulfonium sulfonate in the presence of an alkali hydrazine such as a trialkylamine or an immobilized modification thereof on a resin to provide a compound of the formula (AL) φ. The compound of formula (AL) is potentially unstable and may be present in part of a mixture of the corresponding chloride (derived from the attack of chloride on methanesulfonyl), so new conditions must be prepared under carefully controlled conditions. . A compound of the formula (AO) which is a compound of the formula (AD) wherein J is CH can be prepared according to Scheme 5. 127286 -67- 200831517

Formula (AM) Figure 5

Formula (AN) Outline: The formula of the formula (Formula 5) can be obtained from the municipality.

° The reaction is carried out with chlorinated cinnabarin in the presence of a suitable base such as 2 6-dimethyl hydrazine, followed by cyclization with trichlorin. In a similar manner, chlorinated cinnabarin can be replaced by Ε ethoxylated propylene chloride, and the cyclization of the hydrazine-ethoxy propylene decyl amide is achieved by replacing the aluminum chloride with sulfuric acid. (Ε. Baston et al., European Journal of Medicinal Chemistry (2〇〇〇) 931). Asymmetrically substituted anilines generally result in regioisomeric quinoline-2(1H)-one derivatives which may be difficult to separate by chromatography due to limited solubility. Such a mixture may be isolated by crystallization or may be converted to its corresponding 2-chlorojunlin derivative (for example, phosphorus oxychloride, which may be separated by chromatography or via crystallization, and then The reflux hydrochloride acid hydrolyzes back to a single regioisomer of the compound of formula (AO). The compound of formula (AO) can also be prepared according to Scheme 6. 127286 68· 200831517

Ethyl acrylate Ρ (3·catalyst)

0, Me 2. uv light ΙΖη

Ο

The compound of formula (AO) can be prepared from a compound of the formula ( ΑΡ) by forming a carbon-carbon bond followed by intermolecular guanamine linkage formation of a suitably installed cis-unsaturated system. The isomerization of the trans double bond can be carried out thermally or photochemically under UV light. Alternatively, carbon-carbon bond formation can be carried out as a coupling of Sonogashira to an alkyne intermediate which can be partially hydrogenated to a cis double bond under Lindlar conditions. The compound of the formula (AO) can also be produced according to the formula 7. 127286 69- 200831517 Figure 7

The compound of formula (AO) can be prepared from a compound of formula (BE) by protonation with an alkali such as sodium ethoxide followed by reaction with diethyl oxalate to form a compound of formula (BF). This intermediate can then be reduced with a suitable reducing agent such as sodium borohydride to provide a compound of formula (BG). After reduction of the nitro group with a suitable reducing agent such as iron in acetic acid or tin dichloride, the compound of formula (BG) can be subsequently cyclized to a compound of formula (BH). Finally, the removal of a base such as DBU provides the compound of formula (AO). A compound of the formula (AU) which is a compound of the formula (AD) wherein J is N, can be prepared according to Scheme 8. Figure 8

The regioisomeric mixture of the ethyl glyoxylate (ΑΤ) formula (AU) can be isolated by the method described above with respect to Scheme 5. 127286 -70- 200831517 Figure 9 is a depiction of the preparation formula (AU) Another method of compound

Ri Figure 9 rTVn〇2 (AW)

Formula (AY)

> The compound of the formula can be obtained by oxidation of a compound of the formula (ΑΧ) with an oxidizing agent such as peroxidation. The compound of the formula (10)) can be obtained by reacting a compound of the formula (AV) with methylene acetate 8 or with B (IV) B, followed by reduction of nitro group, and cyclization from %. Suitable reducing agents include Pd/c and H2, iron in acetic acid, and tin chloride. A compound of the formula (AZ) which is a compound of the formula (AG) wherein the protecting group is a third-butoxycarbonyl group can be produced according to the formula 1 . 127286 •71 - 200831517

Schematic

Formula (BC)

1) H2, Pd(OH)2 2) Di-tertiary-butyl phthalate removal protection

The compound of formula (BD) can be reacted with a compound of formula (BB) in the presence of a base to provide a compound of formula (BC). Examples of bases are CS2 C〇3, NaH, & c〇3 or Ν&2 c〇3. Suitable leaving groups for this reaction include methane sulfonates and halo groups such as chloro and bromo groups. Suitable protecting groups for this reaction include a decyl protecting group such as a third butyl-dimethyl decyl group. The protecting group of the compound of formula (BC) can

Removal with tri-butylammonium fluoride provides the compound of formula (BD). The compound of the formula (bd) can be removed by hydrogenation. Examples of suitable catalysts for such reactions include Pd(OH)2, platinum black and Pt〇2' followed by reaction with dibutyl succinic acid to provide a compound of formula (AZ). When an optically active form of a compound of the invention is desired, it can be carried out by using the above procedure, using the pure palmomerate as the starting material f or using standard procedures, by the final product or the pair of palmitic intermediates. Obtained by analysis of a palmomer or a mixture of diastereomers. The analysis of the palm isomer can be achieved by chromatography on the palm stationary phase, such as the Chiralpak column. Must be 127286 -72· 200831517 : Quantity: resolution and resolution. Alternatively, the resolution can be obtained by the preparation and selective crystallization of a palmitic intermediate or a diastereomeric salt of a palmitic acid such as camphorsulfonic acid as a 1 TF. Alternatively, a stereoselective method can be employed. For example, where appropriate, in the reaction sequence, a parasitic variant, a palmitic catalyst or a palmitic reagent can be utilized. • A single technique can also be used to prepare optically active compounds and/or intermediates. Similarly, when a pure regioisomer of a compound of the invention is desired, it may be: by performing the above procedure, using a pure regioisomer as a starting material or using 'sequence' by a regioisomer or Obtained by analysis of a mixture of intermediates. The Ice Organic Chemist will be able to (4) revise the information contained in the reference (4) above, along with examples of the present, as well as examples of this article, to obtain the necessary starting materials and products. [Embodiment] Example

The invention will now be described by way of example only, but not limited thereto, wherein the treatment procedure is followed by (the evaporation is carried out by vacuum evaporation in a vacuum to remove residual solids. (8) The temperature is measured by C. · p 〆 at room temperature τ, which is typically within the range of -26C, without excluding air, unless the skilled person otherwise works in an inert atmosphere; :) use, chromatography (by a flash procedure) to purify the compound, which is carried out on 哟 (Item 5), unless otherwise stated; 127286 -73- 200831517 (iv) In general, the reaction process is by TLC, HPLC or LC/MS tracking, and the reaction time is only a description; the yield is only an indication, not necessarily the maximum achievable; (v) The structure of the final product of the invention is generally by NMR and mass spectrometry confirm. Proton magnetic resonance spectroscopy is generally measured in DMSO-d6, unless otherwise stated, using a Brnker DRX-300 spectrometer or a 31111^010^400 spectrometer with individual field strengths of 300 MHz or 400 MHz. In the case where the NMR spectrum is complicated, only the diagnostic signal is reported. The chemical shift is reported in parts per million of the low magnetic field of tetramethyl decane as the internal standard ((5 scale), and the absorption peak multiplicity is shown as: s, single peak; d, double ♦ ; dd, the doublet of the doublet; dt, the doublet of the triplet; dm, the doublet of the multiplet; t, the triplet; m, the multiplet; br, broad. Fast atomic impact (FAB) mass spectrometry data Obtained using a platform spectrometer (provided by Micromass), operated by electrospray, and, where appropriate, collected either positive ion data or negative ion data, or using an Agilent 1100 Series LC/MSD, equipped with Sedex 75ELSD, and where appropriate Underneath, collect either positive ion data or negative ion data. The lowest mass primary ion is reported for molecules where isotopic splitting causes multiple mass spectral absorption peaks (eg when chlorine is present). Reverse phase HPLC uses YMC component ODS-AQ (within 100x20 mm) Diameter, S-5//particle size, 12 nm pore size) was performed on an Agilent instrument; (vi) each intermediate was purified to the required standard for subsequent stages, with sufficient detail It is characterized by the fact that the specified structure is correct; the purity is evaluated by HPLC, TLC or NMR, and its identity is determined by infrared spectroscopy 127286 -74 - 200831517 (IR), mass spectroscopy or NMR spectroscopy The following abbreviations can be used; and (vii) the following abbreviations can be used: TLC is thin layer chromatography; HPLC is high pressure liquid chromatography; MPLC is medium pressure liquid chromatography; NMR is nuclear magnetic resonance spectroscopy; AZ; CDC13 is deuterated chloroform; MeOD is deuterated methanol, meaning D3 COD; MS is mass spectrometry; ESP (or ES) is electrospray; El is electron collision; APCI is atmospheric pressure chemical ionization; Is tetrafurfuran; DCM is dichloromethane; MeOH is methanol; DMF is dimethylformamide; EtOAc is ethyl acetate; LC/MS is liquid chromatography/mass spectrometry; h is hour; Min; d is day; MTBD is N-methyl-1,5,7-triazabicyclo[4.4.0]non-5-ene; TFA is trifluoroacetic acid; v/v is volume/volume ratio; Boc represents a third-butoxycarbonyl group; Cbz represents a benzyloxycarbonyl group; Bz represents a benzamidine group; atm represents atmospheric pressure, rt is not room temperature, and mg is not a house gram, g Table is not gram, / L table does not rise slightly; mL means milliliter; L means liter; / / M means micromolar concentration; mM means millimolar concentration; Μ means molar concentration; N means equivalent concentration; Intermediate 1. Intermediate 1 1-{2-[(3ΙΙ,48)·4·amino-3-hydroxyhexaazin-1-yl]ethyl}-2-keto·1,2-dihydroquinoquinone Lin-7-carbonitrile and intermediate 2 l-{2-[(3S,4R)-4-amino-3-hydroxyhexafluoropyridin-1-yl]ethyl}_2·keto-1,2_ Nitrogen sulphate -7-A gambling 1-[2-cis(±)(4-azido-3-light hexahydrop-p-pred-l-yl)ethyl]-2-keto 127286 -75- 200831517 -1,2-dihydroquinolin-7-carbonitrile (Intermediate 3) (〇·545 g, L61 mmol) and triphenylphosphine (0.507 g, 1.93 mmol) in acetonitrile The mixture in /water (9: hydrazine, 5 mL) was stirred at room temperature for 6 days. The reaction mixture was concentrated to dryness under reduced pressure. Chromatography on dichloromethane/methanol (6::, containing 〇·2% ammonium hydroxide) afforded the racemic mixture of intermediates 1 and 2 as colorless rigid foam, 452·452 g ( 90%). MS (ESP): 313 (MH+),,,,,,,,,,, 2·72 (m, 1H); 3·44 (m, 1H); 4·35 (dd, 2H); 6.78 (d, 1H); 7·64 (d, 1H); 7.90 (d, 1H); 8·00 (d,1H) ; 8·08 (d,1H)· (OH and NH2 protons exchanged with methanol). The racemic mixture was applied to a Chiralpak AD column (250 x 20 mm, i〇 micron) Separated with 6% hexane containing 0.1% diethylamine and 4% ethanol/decyl alcohol (1:1). Intermediate 2 was first eluted, [a] D = +45·5, followed by intermediate 1, [Q]d = -45.9 (in sterol / chloroform, 1: i, 〇 = 1). Intermediate 3 cis (±) (4·azido-3-hydroxyhexahydroP to m)ethyl]_2-keto·1,2_dihydroquinolin-7-indolecarbonitrile 1-[2- Cis (4-azido-3-{[tert-butyl(dimethyl)oxalyl]oxy}hexahydropyridine·1·yl)ethyl]-2-keto-1, a solution of 2-dihydroquinone-7-carbonitrile (Intermediate 4) (0.724 g '1.66 mol) in THF (5 mL) at room temperature with tetrabutylammonium fluoride The solution in THF (1 Torr, 2.2 mL) was applied dropwise. After one hour, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added and the THF was removed under reduced pressure. It was extracted with dichloromethane/ether (1:1 to 2 mL). 127286 -76- 200831517 Separate the organic phase containing some insoluble products, test & 4 ^ ah and, the aqueous phase is dioxane

(100 ml) reverse extraction, and the combined organic, #广A' machine phase was concentrated to dryness under reduced pressure

Dry, and dry under high vacuum to give the product, </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 4-NMR _6) d : L56 (m,1H) ; U1 (m,1Η) ; 2 25 2 says (m, 6H) ; 3.67 (m, 2H) ; 4.35 (dd, 2H) ; 5.06 (m , 1H); 6&gt;78 (d&gt;m); 64 (10), 1H); 7.90 (d, 1H); 8.00 (d, 1H); 8.08 (brs, 1H). Intermediate 4 arguing (1) ( 4-N-nitrogen group_3_{[Third-butyl(dimethyl>weiki)oxy}hexahydropyridin-1-yl)ethyl]_2·keto group·1,2·dihydrojun A A suspension of 2-keto-1,2-dihydroquinolin-7-carbonitrile (Intermediate 5) (〇·51 g, 3 〇 mmol) in DMF (15 mL) Treated with sodium hydride (60% in oil, 132 mg). Stir it for 2 hours, then add cis-sulfonate 2-cis (4-azido-3) via injection 1 § [third_ Butyl (dimethyl) oxalate]oxy}/, 虱ρ ratio -1-yl) B1 (Intermediate 6) (3 mM) solution in DMp (7 φ mL) The cooling was removed, and it was stirred at room temperature overnight. DMF was removed under reduced pressure and the residue was dissolved in dichloromethane (~~~~~~~~~~~~~~~~~~~~ The solution will adjust ΡΗ to pHIO). The aqueous phase was back-extracted twice with dichloromethane (2×1 mL), and the combined organic phases were dried with sodium sulfate and evaporated to hexane/acetone (4:1). For rigid foam, 724·724 g (53%) MS (ESP): 453 (ΜΗ+) vs. C23H32N602Si 'H-NMR (DMSO-d6): 0.00 ^ 0.03 (2xs, 6H); 0.80 (s, 9H) 1.59 (m, _ ; 1.70 (m, m); 2.30-2.65 (m, 6H); 3.69 (m, 1H); 3.80 (m, 1H); 127286-77· 200831517 4.29 (m, 1H); 4·42 (m,1H) ; 6·77 (d,1H) ; 7·63 (d,1H) ; 7·90 (d,1H); 7.99 (d5 1H) ; 8.08 (s, 1H). 5 2-keto-1,2-dihydrop-quino-n-lin_7-carbonitrile 7·bromoquinolinium (IK)-ketone (intermediate 46) (9·21 g, 41 mmol) With copper (I) cyanide (4.05 g) in N-methyltetrahydropyrhenone (5 mL), heated under 16 hours, allowed to cool to room temperature, and added aqueous solution of ethylenediaminetetraacetate (2M, pH 8.3, 1 mL) and mix the mixture at room temperature and open to air for 5 days. After 〇·45 micron film, the genus was collected by filtration, washed with water and ethyl acetate, and recrystallized from DMF/water to obtain the product as a brown solid, 90% purity, 4.72 g (60%) ), used without further purification.

MS (ESP): 171 (ΜΗ+) vs. C10H6N2O 'H-NMR (DMSO-d6) ά : 6.66 (d5 1Η); 7.55 (d5 1H); 7.61 (s5 1H); 7·85 (d, 1H); 7.99 (d,1H); 12.01 (s,1H)· An alternative procedure for the synthesis of intermediate 5 is 3-methyl-2-keto-1,2,3,4·tetrahydroquinoline; carbonitrile (Intermediate 66, 15 51 g, 82.42 mmol) and a mixture of W-azabicyclo[5A〇]11·7-ene (DBu) in acetonitrile (155 ml), heated at 751 2 5 hour. The reaction mixture was cooled to EtOAc EtOAc (EtOAc m. . Melting point &gt;25(Τ(:

MS (ESP): 171 (MHLC10H6N2O 127286 -78 - 200831517 iH-NMR (DMSO-d6) 5 : ppm 6.67 (d,1H); 7.48-7.68 (m,2H); 7.85 (d, 1H); 7_98 (d ,1H) ; 12.01 (s,1H)· Intermediate 6 combidic acid 2-(cis (soil))-(4-azido-3·{[T-butyl (dimethyl)) fever 2-(cis)-(4-azido-3-{[t-butyl(dimethyl)-stone)-oxyl a mixture of hexahydropyridine 4·yl)ethanol (intermediate 7,1,8 g, 6 mmol) in anhydrous dichloromethane (20 mL) and triethylamine (1.18 mL, 8.4 mmol) , at 〇 ° C, treated with gasified methane sulfonate (0.556 ml, 7.2 mmol). After 9 minutes, 'by TLC (chloroform / methanol 6 : 1, rf ~ 〇 · 9), the reaction has Complete. Add potassium phosphate buffer (pH 7, 1 Μ, 15 ml), remove the methylene chloride under reduced pressure and extract it with ice-cold ether (100 liters). The water phase is scaled (5 〇 ml) The mixture was back-extracted once and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue dissolved in DMF (1 mL) The crude methanesulfonate was used in the next step without delay. MS (ESP): 379 (MH+) to C! 4 H3 6 N4 04 SSi Intermediate 7 2-(cis (±)) -(4_N-nitrogen group {[T-butyl(dimethyl)decyl)oxy}hexahydropyridin-1yl)ethanol (cis)-4-azido-3-{ [Third-butyl (dimethyl) oxalate]oxy} hexahydropurine (Intermediate 8) (1.625 g, 6.34 mmol), n,N-diisopropylethylamine (1.65 Zhaisheng '9.5 house Moh) and 2-glycolethanol (〇·584 ml, 8.25 mmol) were mixed in anhydrous acetonitrile (17 ml) and heated in a microwave at 7 ° C for two hours. The solvent was removed under reduced pressure and the residue was purified ethyljjjjjjjjjjjjjjjjjjjjj (100 ml) was back-extracted once, and the combined organic phases were dried with sodium sulfate, and then purified eluting with methylene chloride/methanol (2 〇: 丨) to give 1.80 g (95%) of product as colorless. Oil. MS (ESP): 301 (MH+MiC13H28N4O2Si !Η- ΜΚ (DMSO-d6) δ · 0.08 (s5 6H) ; 0.87 (s5 9H); 1.65 (m, 2H); 2.18 (m? 1H); 2.25-2.60 (m? 5H); 3.44 (m? 2H); 3.73 (m5 1H) ; 3.91 (m3 1H) ; 4.35 (m, 1H). ® Intermediate 8 (cis (±))-4·azido-3-{[T-butyl (dimethyl)发 】 】 氧基 氧基 六 六 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺 顺A solution of the third-butyl carboxylic acid (Intermediate 9) (2.3 g, 6.45 mmol) in di-methane (50 mL). Underarm, treated with trifluoroacetic acid (5 mL). After 3 hours, the mixture was concentrated under reduced pressure and the residue was twice distilled twice with dichloro </ br> methane. The residue was dissolved in dichloromethane (1 mL) and washed with saturated aqueous sodium hydrogen carbonate (3 mL). The aqueous phase was back-extracted once with chlorohydrin (100 mL) and the combined organic phases were dried <RTI ID=0.0></RTI> to <RTI ID=0.0> iH-NMR (DMSO-d6) (5: 〇·〇7 and 0.09 (2xs, 6H); 0.88 (s5 9H); 1.49-1.73 (m, 2H); 2·45 (m, 1Η); 2.56-2.69 (m5 3H) ; 3·65 (m,1H) ; 3·79 (m,1H)· Intermediate 9 (cis (±))-4-manazyl·3-{[Third-butyl ( Dimethyl)alkyl]oxy}hexahydropyridine small carboxylic acid tert-butyl ester 127286 -80 - 200831517

(cis)-4-azido-3-hydroxyhexahydropyridine-1.carboxylic acid tert-butyl ester (Intermediate 10) (1.76 g, 7-25 mmol) and imidazole (0.74 g, hydrazine) A mixture of 9 mmoles in DMF (7 mL) was treated with tributyl butyl chloride (1.3 g, 8.7 Torr). The cooling was removed and the mixture was scrambled at room temperature. It was allowed to cool to 〇 ° C and the reaction was quenched with sulphate buffer (iM, pH 7 &lt After 15 minutes, the mixture was diluted with ethyl acetate (1 mL) and brine and evaporated. Chromatography on EtOAc/EtOAc (EtOAc:EtOAc) 'H-NMR (DMSO-d6) 5 : 0.10 (s? 6H); 0.87 (s? 9H); 1.37 (s? 9H); 1.56^1.80 (m? 2H); 3.09-3.30 (m, 2H); 3.46 (m5 2H) ; 3.62 (m, 1H) ; 3.88 (m, 1H). Intermediate 10 (cis (±))-4·azido-3-hydroxyhexahydropyridine-i-carboxylic acid third - butyl ester in (cis)_4-@nitrogen hexahydrop ratio lean _3_alcohol (made according to the procedure described in 2005/066176 for yttrium) (2.1 g, 14.8 mmol) And a mixture of potassium hydroxide (2.5 g, 44 mmol) in isopropanol (2 ml) and dichloromethane (ml), at 〇 ° C, adding di-dicarbonate A solution of the ester (3·9 g, 17.7 mmol) in dichloromethane (10 mL). The cooling was removed and it was stirred at room temperature for 2 hours. The reaction was quenched with water (5 mL) and isopropyl alcohol and dichloromethane were removed under reduced pressure. It was neutralized with potassium phosphate buffer (1 Torr, 7, 100 ml), extracted twice with ethyl acetate (2 χ 3 mL), and the combined organic phases were dried over sodium sulfate. The solvent was removed under reduced pressure and the residue was purified from methylene chloride (~ 20 ml) to afford -6 % of product as 127286 - 81 - 200831517. The mother liquor was chromatographed with hexane / ethyl acetate (5:1) to afford 353 g of product (35%). MS (ESP): 265·2 (MNa+) vs q οΗ! 8N403 ^-NMRODMSO-d^ 5 : 1.39 (s,9H); 1.58 (m5 1H) ; L74 (m, 1H); 3.20-3.40 (m, 4H) ; 3·69 (m, 2H) ; 5·40 (d, 1H)· Intermediate 11 l-{2-[(3R,4S)-4·Amino-3-hydroxyhexahydropyridine-1· Ethyl}-7-methoxyquinoxaline-2(1H)-one and intermediate 12 l-{2_[(3S,4R)-4·amino-3-hydroxyhexahydropyridine-1· Ethyl]ethyl}-7_decyloxyquinoxalinone 1-[2-{(cis-)-(4-indole-nitro-3-ylhexachloro-p-but-1-yl)}B Benzyl-7-methoxyporphyrin-2(1H)-one (Intermediate 13) (0.507 g, 1.47 mmol) with triphenylphosphine (0.463 g, 1.77 mmol) in acetonitrile/water ( The mixture in 9: 1, 20 ml) was stirred at room temperature for 5 days. The reaction mixture was concentrated to dryness under reduced pressure. The residue was dissolved in di-methane (5 mL) and chromatographed eluted eluted eluted eluted It is a colorless rigid foam (0.422 g, 90%). MS (ESP): 319 (MH+) vs. C16H22N403, iH-NMR (DMSO-d6) (5 ·· 1.48 (m, 2H); 1·89 (m, 1H); 2·28 (m, 1H); 2.37 ( Dd5 1H) ; 2.54-2.62 (m5 3H) ; 2.71 (m, 1H) ; 3.45 (m5 1H) ; 3.91 (s5 3H); 4.30 (dd, 2H) ; 6.96-7.00 (m, 2H) ; 7.73 (d , 1H); 8.03 (s, 1H)· (OH and NH2 protons exchanged with methanol). 127286 -82 - 200831517 The racemic mixture was applied to a Chiralpak AD column (250 x 20 mm, 10 μm) to contain 0.1% diethylamine in ethanol/methanol: U separated. Intermediate 12 was first dissolved out, [a] D = +45.5, followed by intermediate u, [a] D = · 44.7 (in methanol/chloroform 1:1) , c = l). Intermediate 13 cis (±))-(4-azido-hydroxypyrohydropyridin-1yl)}ethyl-7-methoxyquinoxaline-2 (1H) -ketone _ 1-[2-(cis) ice azide-3-{[t-butyl(diindenyl) oxalate]oxy}hexahydro b--1-yl) a solution of 7-methoxy-p-quineline-2(1H)-one (intermediate 14, 0.721 g, 1.57 mmol) in THF (5 mL) at room temperature A solution of tetrabutylammonium fluoride in THF (1 M, 2.2 mL) was applied dropwise. After one hour, a saturated aqueous solution of sodium hydrogencarbonate (1 mL) was added, and THF was removed under reduced pressure. It was extracted with dichloromethane/ether (1:1 to 2 mL). The aqueous phase was back-extracted with dichloromethane (1 mL) and the combined organic phases dried over sodium sulfate. Chromatography on hexane/acetone (1:1) afforded the product as a colorless ss. foam, 0.507 g (94%). MS (ESP): 345 (MH+) vs. Ci6h2gN603^-NMR (DMSO-d6) 5: 1.58 (m? 1H); 1.70 (m5 1H); 2.25-2.65 (m? 6H); 3.67 (m, 2H); 3.90 (s,3H); 4.31 (dd,2H) ; 5.11 (m,1H) ; 6.97-7.00 (m,2H) ; 7.73 (d,1H) ; 8.03 (s,1H). Intermediate 14 1-12 -(cis(±))-4-azido-3-{[tert-butyl(dimethyl)]alkyl]oxy}hexahydropyridin-1-yl)ethyl]-7- Methoxyquinoxaline-2(1H)-one using a procedure similar to that described for the synthesis of intermediate 4, 7-methoxyindole 127286 -83 - 200831517 -2(m)-one (intermediate 15 , 0.528 g, 3.00 mmol) with sodium hydride (60% in oil, 132 mg) and 2-cis of methanesulfonate (4-azido_3_{[Third-butyl C- Methyl)cracking]oxy}hexachlorop-pyridin-1-yl)acetic acid (intermediate 6,3 mmol) treatment to obtain the product as a rigid foam, 〇·721 g (52%) . MS (ESP): 459 (MH+) vs. C2 2 H3 4 N6 03 Si 1H-NMR (DMSO-d6) 5 : 0.03 and 0·05 (2xs, 6H); 0.82 (s, 9H); 1.65 (m, 2H) ; 2.25-2.70 (m,6H) ; 3·70 (m,1H) ; 3·90 (s,3H) ; 3·83 (m,1H); 4.24 (m,1H) ; 4.39 (m,1H ; 6.96-7.00 (m, 2H); 7.73 (m, 1H); 8.02 (s, 1H). Intermediate 15 7 · methoxy porphyrin-2 (1H)-one in 8% aqueous sodium hydroxide solution (1·32 liters), 7-methoxy_3,4-dihydroporphyrin-2(1H)-one (intermediate 16,100 g) was added, followed by 3 wt% hydrogen peroxide in water Solution (L17 liters). The reaction mixture was slowly heated to 8 Torr and maintained at this temperature for 4 hours. The heat source was then removed and vinegar acid (150 mL) was added dropwise. The suspension was stirred at room temperature overnight, and the solid which crystallised was collected by filtration to give the product as a tan solid (9 g). MS (ESP): 177 (MH+) vs. C9H8N202^-NMR (DMSO-d6) δ: 3.83 (s? 3Η); 6.76 (d, 1H); 6.90 (dd, 1H); 7.67 (d, 1H); (s? 1H); 12.32 (brs, 1H). Intermediate 16 7-Methoxy-3,4-dihydroquinoxaline-2 (1H&gt; ketone in 18 liter Parr apparatus, [[4- a suspension of methoxy-2-nitrophenyl)imido]acetate (intermediate 17) at 55 psi at 20 weights ❶/〇Pd/C (100 127286 •84-200831517 grams, containing Hydrogenation in the presence of ~50% by weight of water) until no hydrogen is consumed (Note) The reaction is strongly exothermic and the temperature should be controlled by a cooling system to be controlled at about 6 Torr. The reaction mixture was discharged, filtered over EtOAc EtOAc (EtOAc)EtOAc. MS (ESP): 179 (MH+) vs. C9H1 gN2 〇 2 'H-NMR (DMSO-d6) ά : 3.61 (m? 5H); 5.57 (m5 1H); 6.35-6.40 (m? 2H); 6.60 (m , 1H); 10.13 (brs, 1H) · An alternative procedure for intermediate 16 to make N-(4-decyloxy- Ethyl 2-nitrophenyl)glycine (intermediate 18, ι 5 · 8 g of crude material) was dissolved in 200 ml of 1: methanol/acetic acid, treated with 1% palladium on carbon (g) After stirring overnight under a hydrogen atmosphere, the reaction mixture was filtered over EtOAc EtOAc (EtOAc m.). ) for C9Hl 〇Ν2〇2 Intermediate 17 [(4-Methoxy-2-nitrophenyl)imido]Acetylacetate for 4-methoxy-2-nitroaniline (1 kg, 5 95 Mohr) with glyoxylic acid vinegar _ml '50% by weight in toluene, 595 mol) in toluene (1 liter), refluxed in a Dean-Stark apparatus for 8 hours, and under reduced pressure Evaporation gave the crude product as a dark brown oil which was used without further purification. Intermediate 18 Ν-(4·methoxy-2-nitrophenyl)glycolic acid ethyl ester 127286 -85- 200831517 4-methoxy-2-nitroaniline (25·0 g, 0·15 A mixture of ethyl bromoacetate (200 ml, 1.8 mol) and potassium carbonate (3 U g, 〇 23 mol) was heated at 150 ° C for 4.5 hours. After cooling to room temperature, an aqueous sodium hydroxide solution (1M, 600 mL) was added. The mixture was extracted with ethyl acetate (2 x 500 mL). The combined organic phases were dried over magnesium sulfate and concentrated to dryness. Chromatography on 25-30% acetone in hexane gave a crude product of 22.1 g as a red solid. 1H NMR showed the presence of ~20% dialkylation product. This material was used without further purification. XH NMR (DMSO-d6) δ : 1.18-1.23 (t5 3H) ; 3.74 (s5 3H) ; 4.12-4.18 (q5 2H), 4.23-4.25 (d, 2H), 6.90-6.93 (d, 1H); 7.25 -7.29 (dd,1H); 7·51-7.52 (d5 1H) ; 8.23-8.27 (t? 1H). Intermediate 19 cis (±)1_[2-(4_Amino-3-fluoroyl-6 Hydropyridine small) ethyl] fluorenyl 4,2-dihydroquinoline-7-carbonitrile cis (±) {1-[2-(7-cyano-2-ketoporphyrin-; (2Η)-yl)ethyl]-3-fluorohexafluoropyridin-4-yl}amino carboxylic acid tert-butyl ester (intermediate 20,397 mg, 0.95 «m) in chloroform (8 ml) The solution is at 0. Underarm, treated with 3 % trifluoroacetic acid (5 mL) in chloroform. After 5 hours at room temperature, the solvent was removed under reduced pressure to give the product trifluoroacetate which was taken to the next step without further purification. MS (ESP): 315 (MH+) vs. C17H19FN4 〇 intermediate 20 cis (±) {1-丨2-(7-cyano-2-ylquinolinyl)ethyl]fluorohexahydropyridine- 3-Hydryl}aminocarbamic acid tert-butyl ester 127286 -86 - 200831517 2-keto·ι,2-dihydroquinoline-7-indenecarbonitrile (intermediate 5,0) as described for intermediate 4 · 3 g, L7 Halo) suspension in DMF (1 mL) at room temperature with sodium hydride and methanesulfonate cis [(t-butoxycarbonyl)amino]-3- Treatment with fluoropiperidine-l-yl}ethyl ester (intermediate 21, ~17 mmol). Chromatography on hexane/ethyl acetate (2:3) gave the product as a solid, 397 mg (73%). MS (ESP): 415 (ΜΗ+) vs. C22H27FN4 〇3^-NMR (DMSO-d6) δ: 1.37 (s, 9Η); 1.48 (m, 1H); 1.67 (m5 1H); 2.27 (m, 2H) ; 2.56 (m, 2H); 2.96 (m, 1H); 3.15 (m, 1H); 3.46 (m, 1H); 4.34 (m, 2H); 4·60 (m, 1H); 6.77 (m, 1H) 6.91 (m,1H); 7·64 (m,1H); 7·90 (m,1H); 7.99 (m,1H) ; 8.07 (s,1H)· Intermediate 21 A burnt acid cis (±) 2-{4_[(Thr-Butoxycarbonyl)amino]-3·fluoropyridinium-1-yl}ethyl was synthesized using a procedure similar to that described for the synthesis of intermediate 6, in triethylamine The presence of φ under '' cis (±) [3_fluoro-small (2-hydroxyethyl) hexahydropyridin-4-yl]carbamic acid tert-butyl ester (intermediate 22,314 mg, 1.2 Millol) reacts with methane chloride. The crude methanesulfonate was used in the next step without delay. Intermediate 22 cis (±) [3-fluoro-based small (2. hydroxyethyl) hexahydropyridinyl] tert-butyl carbazate in cis (±) [1-(2-{[third -butyl (dimethyl) oxalyl]oxy}ethyl) each gas hexahydropyridine · 4 yl] carbamic acid tert-butyl ester (intermediate 23, 530 mg ' 1.4 millimoles ) in a solution of tetrahydrofuran (1 mL) in hydrazine. Under the armpit, tetrabutylammonium fluoride (1 Torr in THF, 2.8 mL) was added. After 30 minutes, 127286 - 87 - 200831517 was quenched with saturated NaHCO3 and EtOAc (EtOAc) The product was obtained as a colorless solid, 314 mg (85%). ^-NMR (CDCI3-d) ά : 1.43 (s3 9H) ; 1.81 (m? 2H) ; 2.30 (m5 1H); 2.36 (m, 1H); 2.59 (m5 2H); 2·75 (m, 1H) ; 2·95 (m,1H); 3·24 (m,1H); 3.61 (m,2H) ; 3·71 (m,1H) ; 4·68 (m,1H) ; 4·85 (m, 1H)· Intermediate 23 _cis (MHM [t-butyl(dimethyl)-alkyl)oxy}ethyl)-3-fluoro hexahydroindole biting ice base] amino decanoic acid third - Butyl ester cis(1) 1-(2][t-butyl(dimethyl)oxalyl]oxy}ethyl)-3-fluoropyrohydropyridine-4-amine Intermediate 24, 2.8 g, 10.4 mmoles, combined with di-tert-butyl dicarbonate (3.4 g, 15.6 mmol) in tetrahydrofuran (50 mL). After 90 minutes, the reaction mixture was concentrated under reduced pressure. Chromatography with hexane/ethyl acetate (3:2) gave the product as a colorless oil, 3-2 g (82%). _ ^-NMR (CDCl3-d) δ : 0.03 (s5 6H) ; 0.86 (s5 9H) ; 1.43 (s5 9H) ; 1.77 (m5 2H) ; 2·25 (m, 1H) ; 2·37 (m, 1H); 2.58 (m, 2H); 2.95 (m, 1H); 3.26 (m, 1H); 3·62 (m, 1H); 3.74 (m, 2H); 4·65 (m, 1H); 4.83 (m, 1H). Intermediate 24 cis (±) l-(2-{[T-butyl(dimethyl)alkyl)oxy}ethyl)fluorohexahydropyridyl-4 _Amine makes cis (±) benzyl [1-(2-{[tri-butyl(dimethyl))-yl)oxy}ethyl)-3-fluorohexahydropyridine-4- Benzyl carbamic acid ester (intermediate 25, 5.2 g, 1 〇 4 mmol) in anhydrous methanol (15 ml) in palladium hydroxide 20% by weight / 127286 -88 - 200831517 carbon (31 mg) The mixture was hydrogenated for 24 hours, then filtered over Celite, and concentrated under reduced pressure to give the product as a colorless oil, 2.8 g. Intermediate 25 will be cis (±) aryl [1_(2·{丨T-butyl(dimethyl)c-alkyl]oxyanthracene))fluorohexahydropyridin-4-yl]amine Benzyl carbamate will be cis (±) y (3-formyl hexahydropyridin-4-yl) guanidine carboxylic acid hydrazine hydrochloride (intermediate 26 '4.3 g, 6.1 mmol) , (2-bromoethoxy)-tris-butyl dimethyl ketone (9·8 ml, 45.7 mmol) and cesium carbonate (9.9 g, 30.4 mmol) in acetonitrile (150 The mixture in ml) was heated at 60 ° C overnight. Filtration, reaction mixture' and concentration under reduced pressure. The product was obtained as a colorless oil, 5.2 g (yield: 91%). MS (ESP): 501 (MH+) on C28H41FN2〇3Si intermediate 26 cis (±) benzyl (3-fluorohexahydropyridin-4-yl) carbazate in cis (±) 4 _ benzyl Base [(benzyloxy)carbonyl]amino}_3_fluoropyrohydropyridin-1-φcarboxylic acid tert-butyl ester (intermediate 27, 6 g, 13.5 mmol) in di-methane ( In the solution of 50 liters, add HCi (6 8 house liters) in dioxane in the solution at 〇 °C. The reaction mixture was stirred at room temperature overnight. The product was obtained as a colourless solid, 4.4 g (86%). MS (ESP) : 343 (ΜΗ+ ) to c2 0H2 3 FN2 02 Intermediate 27 cis (±) 4_{爷基丨(Ethylene oxy-based) Aminodi 3_Fluorohexahydropyridinecarboxylic acid Di-S-S are intended for cis(±)4-(;amino)_3· yl hexahydro ττ than 唆-1-teric acid third butyl ester (in 127286 -89- 200831517) 28,1· 1 g, 3.6 mmol.) In a mixture of dioxane (20 ml) and saturated sodium carbonate (10 ml), add chloroformic acid (〇.76 ml, 5.4 m) dropwise. Mohr), and the reaction mixture was stirred at 〇 °c for an hour. Add ethyl acetate (~20 ml) and brine (~20 ml), and separate the liquid layer. The aqueous phase was extracted once with ethyl acetate. The combined organic phases were dried over MgSO4 and evaporated and evaporated tolulujjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj H3! FN2 04 ^-NMR (CDCl3-d) δ : IA6 (s, 9H) ; L46 (m? 1H) ; 2.00 (m, IH); 2.91 (m5 2H) ; 4.33 (m5 4H) ; 4.86 (m5 2H) ; 5.16 (m? 2H) ; 7.28 (m5 10H). Intermediate 28 cis (±) 4-(benzylamino)-3- Fluorylhexahydropyridine small carboxylic acid tert-butyl ester 3-fluoro-4-ketohexahydropyridine-1-carboxylic acid tert-butyl ester (intermediate 29, 8.1 g, 37.3 mmol), a mixture of benzylamine (4.5 ml, 41 mmol) and 3A molecular sieves in dichloromethane (150 mL) at 〇 ° C with triethyl ethoxy hydride • sodium hydride (11.8 g, 56 mmol) The reaction mixture was stirred at room temperature for 30 minutes, then filtered. A saturated aqueous solution of sodium hydrogencarbonate was added and the layers were separated. The aqueous layer was extracted once with dichloromethane. Dehydration and drying, and concentrating under reduced pressure. EtOAc/EtOAc (EtOAc (EtOAc) C17H25FN202 Intermediate 29 Fluoro-4-ketohexahydroacridine·1-Resinic acid tert-butyl ester 4-[(Trimethyldecyl)oxy]-3,6-dihydroabipyridine·1 (2Η)-carboxylic acid third · Ding 127286 -90- 200831517 ester (intermediate 30, 14 g '51 mmol) solution in acetonitrile (2 ml), under Ot: 'with SELECTFLUORTM qo grams, 57 millimoles) deal with. The reaction mixture was triturated at 0 C for 30 min then diluted with EtOAc EtOAc. The product was obtained as a colorless oil (yield: hexane/ethyl acetate (3·2). !Η-ΝΜΚ (CDCI3-d) 5-1.48 (s, 9H) ; 2.56 (m? 2H) ; 3.22 (m5 2H); 4·18 (m, 1H) ; 4-45 (m5 1H) ; 72 (m5 1H)· Intermediate 30 4_[(Trimethyldecyl)oxy]_3,6-dihydropyridinyl-叩T-butyl tartrate 4-keto·1_hexahydropyridinium carboxylate a mixture of acid tert-butyl ester (ng, 55 mmol) and triethylamine (18.5 ml, 132 mmol) in DMF (40 mL), chloro dimethyl sulphate at 0 C Xishou (8.4 ml, 66 mmol) was treated dropwise. The reaction mixture was heated at 80 ° C overnight and then cooled to room temperature. Saturated sodium bicarbonate was added and the product was extracted twice with hexane. The combined organic extracts were dried with EtOAc EtOAc (EtOAc) ^-NMR (CDC13) δ : 0.18 (s5 9H) ; 1.45 (s, 9H) ; 2.09 (m5 2H) ; 3.51 (m, 2H) ; 3·86 (m, 2H) ; 4·78 (m, 1H) ·· Intermediate 31 l-{2-[(3S,4R)-4-Aminomethoxyhexahydropyridine small group] ethyl b 7• methoxy quinoxaline-2(1H)-one will be { (3S,4R)_3_methoxy-!·[2_(7_methoxy·2_keto-p-quinonin-cardioin)·yl) ethyl]hexahydropyridyl]aminocarbamic acid • A solution of butyl ester (intermediate 32, 42 mg, 〇·97 mmol) in dichloromethane (5 mL) was treated with trifluoroacetic acid 127286-91 - 200831517 (1 liters). After 1 hour, the reaction was concentrated to dryness. The residue was dissolved in 15% methanol (3 g mL) in chloroform and washed with saturated sodium hydrogen carbonate. The aqueous layer was re-extracted with 15% methanol / EtOAc (4 EtOAc). The combined organic phases were dried with EtOAc EtOAc (EtOAc) MS (ESP) : 333 (MH+)ff C17H24N403 Intermediate 32 10{(3S,4R) 3 methoxymethoxy ketone, 奎 淋 _ ιιιιιιιιιιι Amino-based carboxylic acid tert-butyl ester gives 7-methoxyporphyrin-2(1H)-one (intermediate 15,320 mg, ι·79 mmol) in anhydrous DMF (10 mL) The solution was cooled in an ice bath under nitrogen and treated with sodium hydride (60%, EtOAc, EtOAc. The reaction was stirred at room temperature for ~9 min. The reaction was cooled once more in an ice bath and methanesulfonic acid 2-{(3S,4R)-4-[(T-butoxycarbonyl)aminomethoxyhexahydropyridyl-l-yl} Ethyl ester was treated in anhydrous DMF (intermediate 33, _ 耄mole / house liter, 1.97 faint). The reaction was stirred at room temperature and then concentrated to dryness under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were dried over magnesium sulfate. Chromatography on 15-30% acetone in hexanes afforded 420 mg (55%) of product as colorless solid. MS (ESP): 433 (ΜΗ+) vs. C22H32N4 〇5 W NMR (DMSO-d6) 5 : 1.38 (s, 9H); 1.43-1.51 (m, lH); 1.57-1.72 (m, 1H); 2.20-2.40 (m,2H); 2.55-2.66 (m,2H); 2·67-2·78(ηι,1H); 2.80-2.93 127286 •92· 200831517 (m,1H) ; 3·18 (s,3H) 3.29 (s,1H) ; 3.51-3.65 (m,1H) ; 3.92 (s,3H); 4.24-4.43 (m5 2H) ; 6.40 (d5 1H) ; 6.96-7.05 (m9 2H) ; 7.75 (d5 1H ; 8.04 (s5 1H). Intermediate 33 methanesulfonic acid 2_{(3S,4R)-4-[(tris-butoxycarbonyl)amino] methoxy hexahydropyridine small ethyl ester ethyl ester [ (3S,4R)-l-(2-hydroxyethyl) methoxy hexahydropyridin-4-yl]amino decanoic acid tert-butyl ester (intermediate 34,540 mg, 1.97 mmol) A solution of anhydrous methylene chloride (20 mL) was obtained from triethylamine (yield: 38 ml, 2.76 mmol) at 〇 ° C, followed by chlorobenzene (0·18 ml, 2.36 m). Moore) processing. After 15 minutes, TLC showed that the starting material was completely disappeared. The reaction was quenched with a phosphate buffer (1 Torr, pH 7). The aqueous phase was re-extracted with methylene chloride (1 Torr). Ethyl acetate was added to the combined organic phase. The methylene chloride was removed under reduced pressure, leaving the product in ethyl acetate. This organic phase is washed with water to remove any residual salts. The aqueous phase was re-extracted with ethyl acetate (1 Torr). The combined organic phases were dried over sodium sulfate and filtered. Anhydrous DMp (1 mL) was added to the filtrate. The ethyl acetate was removed under reduced pressure to leave the product in DMF which was used directly in the next step without further purification. Intermediate 34 [(3S,4R)-l-(2-ethyl)_3·methoxyhexahydropyp ratio bite_4_yl]carbamic acid tert-butyl ester makes 2-[(3S,4R) -4·(dibenzylamino)-3-methoxyhexahydropyridinium+yl]ethanol (intermediate 35,940 mg, 2.66 mmol) and di-tert-butyl ester dicarbonate • 67 ml, 2.92 mmol) solution in decyl alcohol (1 mL) was hydrogenated over 2 〇 0 / 〇 hydrogen 127286 - 93 - 200831517 palladium oxide / carbon (240 gram) overnight. The reaction mixture was filtered through celite and concentrated to dryness under reduced pressure. Chromatography on 2% hydrazine in chloroform to give 540 mg (yield: 74%) of product as colorless oil. 4 NMR (DMSO-d6) 6 : 1.38 (s, 9H); L43-1.50 (m, lH); 1.58-1.73 (m, 1H) ' 2.15 (d, 2H), 2.37 (t, 2H); 5.4·2·64 (m,1H) 1H); 6.35 (d,1H)· Intermediate 35 2-[(3S,4R)-4-(dibenzylamino)methoxymethoxypyroquinone+yl]ethanol and intermediate 36 2-[ (3R,4S)_4-(dibenzylamino)·3_methoxyhexahydropyridine small group] Ethanol similar to the intermediate 7 described, cis (soil) ν, Ν-dibenzyl each Oxy hexahydropyridin-4-amine (1.7 g, 5.5 mmol) (WO 2005/068461), bromoethanol (〇·5 耄 '7·1 house Moule) and Ν, Ν·diisopropyl The reaction of the ethylamine (1.4 ml, 8.3 mmol) was heated for one hour at 70 C. On a crushed gel, 5% methanol in a gas chromatograph of S. 0.25 was used to obtain 13 g (68%) of the cis-racemic product as a colorless solid. MS (ESP) ··355 (ΜΗ+) vs. C22H3()N202 'H NMR (DMSO-d6): 1.44-1.58 (m, 1H); 1.64 (d5 1H); 1.79-2.08 (m? 2H); (t? 2H); 2.36-2.45 (m? 1H); 2.88 (d5 1H); 3.13 (d? 1H); 3.30 (s, 3H); 3.40-3.49 (m, 2H); 3.56 (s, 1H) ; 3.59-3.87 (m5 4H); 4.34 (s? m); 7.11-7.24 (m, 2H); 7.24-7.40 (m, 8H). , 10 micro-palm isomers in the palm of the OJ tube Columns (250 x 20 mm 127286 - 94 - 200831517 m) were separated by palm chromatography, eluted with 1:j methanol/ethanol and hydrazine 1% diethylamine at a flow rate of ίο ml/min. (·) The isomer (intermediate 36) is first eluted, followed by (1) isomer (intermediate 35) ^ intermediate 37 1- {2-[(3R, 4S) amylamine methoxy six Hydropyridyl]ethylmethoxyquinoxaline-2(1H)-one is similar to the procedure described for the synthesis of intermediates, such that {(3R 4S)_3_methyl oxime is small [2-(7-曱) Oxybutanyl quinoxaline-1(2H)-yl)ethyl]hexahydropyridine hydrazino} methic acid tert-butyl ester (intermediate 38, 1 mg, 〇 23 mmol) Reaction with trifluoroacetic acid gave 70 mg (91%) of crude material. MS (ESP): 333 (MH+)fiC17H24N403 Intermediate 38 {(3R,4S)-3·decyloxy-i_[2_(7-methoxy-2-keto-p-quinone)-ethyl] Hexahydrogen 1: Digestive-4-yl}aminocarbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 7-methoxy p-quino-u Ruolin_2(1H)__ ( Intermediate 15,530 mg, 3.00 mmol, decanesulfonic acid 2-{(3R,4S)-4-[(T-butoxycarbonyl)amino]_3_methoxyhexahydropyridine small group}B Vinegar (intermediate 39, ~〇·33 mmol/ml, 3·30 mmol) and sodium hydride (60% in oil, 140 mg, 3.60 mmol). The crude product was purified by flash chromatography eluting with EtOAc EtOAc MS (ESP): 433 (ΜΗ+) pair (:221132 pneumatic 〇5 1H NMR (DMSO-d6) (5: 1.38 (s59H); 1.42-1.50 (m5 1H); 1.57-1.72 (m, 1H); 2.20- 2.38 (m5 2H) ; 2.60 (t, 2H) ; 2.68-2.78 (m5 1H) ; 2.79-2.93 (m5 127286 -95· 200831517 1H) ; 3.18 (s? 3H) ; 3.25-3.31 (m3 1H) ; 3.50 -3.67 (m, 1H); 3.92 (s? 3H); 4.23-4.42 (m, 2H); 6.41 (d, 1H); 6.96-7.07 (m, 2H); 7·75 (d, 1H); 8.04 (s, 1H). Intermediate 39 methanesulfonic acid 2-{(3R,4S)-4-indole (t-butoxycarbonyl)amino]-3-methoxyhexahydropyridin-1-yl } 乙为为[(3R,4S)4-(2-Hydroxyethyl]3-methoxyhexahydropyridin-4-yl]carbamic acid tri-butyl as described for intermediate 33 The ester (intermediate 4 〇, 0.91 g, 3.3 mmol), triethylamine (0.64 mL, 4.62 mmol) and decanesulfonium chloride (0.31 mL ' 3.99 </ br> Used directly in the next step without further purification. Intermediate 40 [(3R,4S)-l-(2_ethyl)-3-methoxyhexamidine-4-yl]carbamic acid Tri-butyl ester is used analogously to the synthesis intermediate 34 Order, 2-[(3R,4S)-4-肇(---ylamino)-3-methoxyhexahydroindole-1-yl]ethanol (intermediate 36,3·2 g' 9.0 house The reaction was obtained as a colorless oil. NMR (DMSO-d6) 5: 1.38 (s, 9H); 1.42-1.50 (m, 1H); 1.58-1.73 (m) 1H), 2·11-2.21 (m, 2H); 2.38 (t, 2H); 2.55-2.66 (m, 1H); 2.77-2.89 (m, 1H), 3.23 (s, 3H); 3.28-3.33 (m5 1H) ; 3.41-3.59 (m5 3H) ; 4.38 (s, 1H); 6.36 (d,1H)· Intermediate 41 l_{2_[(3S,4R)-4-Amino-3-methoxy Hexahydro!i ratio bite-i-based j ethyl b 2 keto-oxime, 2 · dihydroporphyrin_7-carbonitrile 127286 -96- 200831517 using a procedure similar to that described for the synthesis of intermediate 31, {(3s,4R) marriage (7-cyano-2.keto group such as linyl) ethyl]_3•methoxy hexazone bite _4_ carbazyl formate third-butyl ester (middle The product was reacted with trifluoroacetic acid in methylene chloride to give 3 mg (yield) of crude product as an oil. MS (ESP): 327 (MH+) vs. q 8 Η 22 Ν 402 Intermediate 42 {(3S,4R)-l-[2-(7-Cyano-2-keto)-1(2H)-yl)ethyl] 3-methoxy hexahydropyridine _4-yl} carbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 2-keto-i,2-dihydroquinoline Nitrile (intermediate 5,370 mg, 2.20 mmol), methanesulfonic acid 2-{(3S,4R)-4-[(dioxa-butoxy)amino]-3·methoxyhexahydro? Ethyl ester (intermediate 33, ~ 〇 24 mmol/ml, 2.40 mmol) and sodium hydride (60% 'in oil, 11 〇 mg, 2.60 mmol) were reacted. Chromatography on 25-30% acetone in hexane afforded 370 mg (39%) of product as a white solid. MS (ESP): 427 (ΜΗ+) vs. C23H3GN404 1H NMR (DMSO-d6) 5 : 1.38 (s, 9H); 1.42-1.51 (m,1H); 1.57-1.71 (m, 1H); 2.18-2.40 ( m, 2H); 2.56 (t, 2H); 2.65-2.76 (m, 1H); 2.78-2.90 (m5 1H); 3.18 (s53H); 3.27 (s51H); 3.58 (s5 1H); 4.30-4.46 (m 2H) ; 6.37 (d,1H) ; 6.78 (d,1H) ; 7.66 (dd,1H) ; 7·91 (d,1H) ; 8·01 (d,1H) ; 8.09 (s,1H)_ Intermediate 43 l-{2-[(3R,4S)-4.Aminomethylmethoxyhexahydropyridin-1-yl]ethylid-2-keto-1,2-127286-97- 200831517 Dihydrogen Quinoline-7-carbonitrile The procedure described for the synthesis of intermediate 31 was used to give {(3R,4S)-l-[2-(7-cyano-2-ketoporphyrin-1 (2H&gt; Ethyl]-3-methoxyhexahydropyridine 4-yl}aminocarboxylic acid tert-butyl ester (intermediate 44, 320 mg, 〇·75 mmol) was reacted with trifluoroacetic acid to obtain 250 mg (Quantitative) crude product as an oil. MS (ESP): 327 (MH+) to C18H22N4 〇2 Intermediate 44 {(3R,4S)-l-[2-(7-Cyano-2-ketoquinequine Porphyrin·1(2Η)-yl)ethyl] each methoxy hexahydropyridine _4_yl} carbamic acid tert-butyl ester makes {(3R,4S)-l-[2-(7- Tert-butanyl ketolin-1(2Η)-yl)ethyl]-3-methoxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (intermediate 45, 46 〇 mg , 〇·98 mM) degassed with a mixture of potassium cyanide (96 mg, 1.5 mmol) in acetonitrile (1 mL) and purged with nitrogen (3 times). Add vaporized tributyltin ( 14 μl/ml in heptane, 0. 90 μl, 0.003 mmol, 4,5-bis(diphenylphosphino)-9,9-dimethyldibenzopyran (3 Mg (0.005 mmol) and a solution of bis(diphenyl-methyleneacetone)dipalladium (〇) (5 mg, 〇·〇〇 5 mmol). The mixture was degassed for 3 Torr and allowed to stand at room temperature. Stir for 30 minutes. The mixture was again degassed and then heated to 80 ° C overnight. LC/MS showed incomplete conversion to product. Add more tributyltin chloride (14 μL/ml, in hexane, 0.90 s.升,〇.〇〇3 mM), 4,5-bis(diphenylphosphino)-9,9-dimercaptodibenzopyran (3 mg, 0.005 mmol) and ginseng Benzomethyleneacetone) two (9) (5 mg, 〇〇〇 5 mmol). The reaction was stirred once more overnight, resulting in complete conversion to the product. The reaction was diluted with dichloromethane. The organic phase is washed with water. The aqueous phase was re-extracted 4x with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated 127286 - 98 - 200831517. Chromatography on 25-55% acetone in hexane afforded 320 mg (76%) of product as a yellow solid. MS (ESP): 427 (MH+), i.sup..sup..sup..sup..sup..sup..sup..sup.. -2.41 (m? 2H) ; 2.57 (t? 2H) ; 2.64-2.76 (m? 1H) ; 2.78-2.91 (m,1H) ; 3.13-3.22 (m,3H) ; 3.25-3.30 (m,1H) ; 3.52-3.66 (m, 1H); 4,29-4.44 (m5 2H); 6.38 (d? 1H); 6,79 (d5 1H); 7,65 (dd? 1H); 7.92 (d5 1H); 8.01 (d,1H) ; 8.09 (d,1H). Intermediate 45 {(3R,4S)-l-[2_(7-Alkyl: keto, quinolate-1(2h)-yl)ethyl] 3-methoxyhexafluoropyridin-4-yl}carbamic acid tert-butyl ester using a procedure similar to that described for the synthesis of intermediate 32 to give 7-bromoporphyrin-2(1H)-one (middle 46,450 mg, 2.00 mmol, methanesulfonic acid 2-{(3R,4SH-[(t-butoxycarbonyl)amino]_3_methoxyhexahydropyridyl) ethyl ester 39, ~0.23 mmol/ml, 2.30 mmol, and sodium hydride (60% in oil, 100 mg, 2.61 mmol). The crude product was purified by flash chromatography. 15-30% acetone was dissolved in a gradient of hexane to obtain 460 mg (48%) of product as a white solid. MS (ESP): 480/482 (ΜΗ+) vs. C2 2 Η3 〇BrN3 〇4 1H NMR (DMSO-d6) 5 : 1.36-1.41 (m,9H); 1.43-1.52 (m,1H); 59-1·75 (m? 1H) ; 2.20-2.38 (m5 2H) ; 2.54 (t5 2H) ; 2.63-2.75 (m5 1H) ; 2.77-2.89 (m,1H) ; 3.16-3.23 (m,3H) ; 3·26-3·32 (m,1H) ; 3.52-3.68 (m,1H) ; 4·33 (t,2H); 6·40 (d,1H); 6·64 (d,1H); 7.44 (dd,1H); 7.68 (d,1H); 7.73-7.78 (m,1H); 7.91 (d,1H). 127286 -99- 200831517 Intermediate 46 7 ·Bromoquinoline·2(1Η&gt; ketone (2Ε)-Ν_(3^,phenyl)_3_phenylpropenylamine (intermediate 47, 16 g, 53 moles) with aluminum trichloride (31.8 g, 238 mmol) in chlorobenzene (1 〇〇 ml) Medium 'heat at 90 ° bath temperature for one hour. The reaction mixture was allowed to cool to room temperature and poured on ice. Stir it until the ice has completely melted, and the mixture is filtered and washed with water and ethyl acetate to give a crude product as a slightly brown solid, with less product 5-bromopyridinium (111)- '8.8 g (70%) in a mixture of ketones (~3:2). This mixture cannot be separated. The mixture was heated in a gasified phosphorus (50 ml) at 65 ° C for one hour. The reaction mixture was allowed to cool to room temperature and poured on ice. It was carefully neutralized with sodium carbonate at 〇 ° C, extracted with ethyl acetate (300 ml), washed with brine, dehydrated with sodium sulfate and dried, and obtained 7-methanol-2. A crude mixture of gas p-lin and 5-xiyl-2-chlorop-quine. The mixture was dissolved in dichloromethane (1 mL), filtered with EtOAc (~2 g) and filtered. The filtrate was combined with the washing solution and concentrated. The residue was crystallized from toluene / hexanes (~ 70 mL, 1:1) to afford purified crystals. ^-NMR (DMSO-d6) δ : 7.63 (d? J 8.4 Hz? 1H); 7.81 (dd, J 8.4, 1.6 Hz5 1H); 8,03 (d5 J 8.4 Hz5 1H); 8.18 (d5 J 1.6 Hz5 1H); 8.48 (d, J 8.4 Hz? 1H).

MS (ESP): 242/244/246 (MH+), C.sub.2H.sub.2BrClN. It was cooled, filtered, and washed with EtOAcjjjjjjjj Hey.

MS (ESP): 224.13/226.13 (MH+e+C9H6Bi*NO 127286-100-200831517^-NMR (DMSO-d6) &lt;5: 6.51 (d, J 9.6 Hz, 1H); 7.32 (dd, J 8.6 , 1.6 Hz, 1H); 7.46 (d, J 1.6 Hz, 1H); 7.61 (d, J 8.6 Hz, 1H); 7.88 (d, J 9.6 Hz, 1H); 11.80 (brs, 1H). Intermediate 47 (2Ε)·Ν-(3·Bromophenyl)·3·Phenylpropionylamine in 3-bromoaniline (13.1 ml, 120 mmol) in dichloromethane (1 mL) with 2 In a solution of 6-lutidine (21 ml, 180 mmol), chlorinated cinnabarin (20 g, 120 mmol) in dichloromethane (5 mL) was added dropwise under 叱_ The reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction was quenched with potassium sulphate buffer (100 mL, 1 M, pH 7) and spoiled for 15 kn. The gas was burned and extracted with ethyl acetate. The organic phase was washed with a phosphate buffer (similar to the above, 200 ml), dried over sodium sulfate, and concentrated to dryness. The product was obtained as a colorless solid (33.4 g, 92%) MS (ESP): 302/304 (M H+) vs q 5 2 BrNO _ H-NMR (DMSO-d6) δ · 6.79 (d? 1H); 7.23-7.70 (m5 9H); 8.07 (s? 1H); 10.38 (s, 1H). 48 l-{2-[(3S,4S)-4-Amino-3-methoxyhexahydropyridine·1-yl]ethyl b-7-methoxy, quinoxaline-2(1H)-one According to the intermediate 31, {(3S,4S)-3-methoxy-μ[2-(7-methoxy-2-indenyl)-quinoquinone-1(2Η)·yl) Ethyl]hexachloropyptotridyl-4-yl}aminocarbamic acid tert-butyl ester, ruthenium trans-isomer (intermediate 49,190 mg, 〇.44 mmol) reacted with trifluoroacetic acid Obtained 140 mg (93%) of crude material as oil. 127286 - 101 - 200831517 MS (ESP): 333 (MH+) to C17H24N403 Intermediate 49 {(3S,4S)-3·methoxy-1· [2-(7-methoxy-2-ketoquinoxalin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}carbamic acid tert-butyl ester, (a) trans-pair Isomers and intermediates 50 {(3R,4R)-3-methoxy-1-indol-2-(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl] Hexa-butyl hexahydrocarbylaminocarbamic acid, (7) trans-palphasomer isomers using a procedure similar to that described for the synthesis of intermediate 32 to make 7-methoxy 4 喏琳-2(1H)-ketone (intermediate 15,430 mg, 2.45 mmol), carbofuric acid 2-{trans (±)-4_[(di-butoxy-yl)amine Base]·3_methoxyhexanitrogen p is more than bite_1_base} Intermediate (51'~0.27 millimoles/ml, 2.70 millimoles) and sodium hydride (60% in oil, 11 〇mg, 2.70 mmol) reaction. The crude product was purified by flash chromatography eluting eluting elut elut MS (ESP): 433 (ΜΗ+) vs. C22H32N405 4 NMR (DMSO-d6) δ: 1.21-1.33 (m, lH); L37 (s, 9H); 1.63-1.74 (m, 1H); 1.78 (t5 1H ); 2.01 (t? 1H); 2.62 (t5 2H); 2.80-2.90 (m? 1H); 2.96-3.06 (m, 1H); 3.07-3.18 (m, 1H); 3·22-3·29 ( m,4H) ; 3·93 (s,3H) ; 4·27-4·43 (m,2H) ; 6·78 (d,1H) ; 6·96·7·06 (m,2H) ; ·75 (d,1H) ; 8·05 (s,1H). Separate the mixture of palmomerisomers on a Chiralpak AD_H column (250 x 21 mm '5 μm) by supercritical fluid chromatography to 2 A constant composition gradient of 〇% isopropanol/〇1% dimethylethylamine was dissolved at a flow rate of 60 ml/min. This gave 190 mg of {(3S,4S)-3-methoxyl[2-(7-fluorenyloxy-ylhydrazone 127286-102-200831517 porphyrinyl)ethyl]hexahydropyridinyl}amino group Formic acid tert-butyl ester (intermediate 49) (first dissolved compound (a) trans-palomerisomer) and carrying milligram {(3R,4R) 3 methoxy_1·[2·(7-A) Oxy-2,yl 4,if u(2H)-yl)ethyl]hexahydropyridyl}aminoglycolic acid tert-butyl ester (intermediate continent) (second dissolved compound (+) trans For palm isomers). Intermediate 51 methanesulfonic acid 2-{trans (±)·4_[(t-butoxycarbonyl)amino] net methoxy hexahydro-external b-l-yl} ethyl brewing similar to synthetic intermediates The procedure described in 33 gives [trans (earth) small (2-hydroxyethyl) methoxy hexahydropyridyl] methic acid tert-butyl ester (intermediate 52, 0.74 g '2.7 耄 mol ), triethylamine (〇 毫升 ml, 3.78 mmol) and decane sulfonium chloride (0·25 ml, 3·24 mmol). This crude product was used directly in the next step without further purification. Intermediate 52 [trans (±)_1_(2_hydroxyethyl)_3·methoxyhexahydropyridyl) Amino carboxylic acid tert-butyl ester was prepared using a procedure similar to that described for the synthesis of intermediate 7 Trans (soil) methoxy hexahydropyridine sulfhydryl] amino decanoic acid tert-butyl ester (intermediate phantom, u grams, 4.8 millimoles), 2-bromoethanol (0.44 ml, 6 • 2 mM) and ethyl (diisopropyl)amine (1.25 mL, 7.2 mmol) were obtained as a colourless oil. ^HNMRiDMSO.d,) 5 : 1.24-1.34 (m? 1H); 1.38 (s, 9H); 1.62-1.77 (m5 2H); 1.82-1.97 (m? 1H); 2.38 (t5 2H); 2.73 (d3 1H) ; 2.98-3.18 (m5 3H); 3·27 (s,3H) ; 3.46 (q,2H) ; 4.39 (t,1H) ; 6·78 (d,1H) 127286 -103 - 200831517 Intermediate 53 [trans (±) each methoxy hexahydropyridin-4 yl] methamic acid tert-butyl ester to give trans (±) -4-[(third-butoxy)amino]·3 -methoxy hexahydro ρ than benzyl-1-carboxylate (intermediate 54, 0.98 g, 2.69 mmol) in methanol (50 mL) over 10% Pd / C (400 mg) Hydrogenation under normal pressure. After 1 hour, the reaction mixture was filtered through celite. The filtrate was concentrated to dryness to give 0.61 g (98%). 1H NMR (DMSO-d6) 5 : 1.14-1.29 (m, lH); L34-L42 (m, 9H); 1.68 (d5 1Η); 2.11 (dd5 1H); 2.26-2.38 (m5 1H); -2.82 (m? 1H) ; 2.86-2.98 (m,1H) ; 3.14-3.21 (m,3H) ; 3.26 (s,3H) ; 6·75-6·86 (m,1H)· Intermediate 54 Formula (±&gt;4_[(t-butoxycarbonyl)amino) benzyl hexahydropyridine small carboxylic acid cis ester (±&gt;4·[(T-butoxycarbonyl)amino group) ]_3·Sodium hexahydropyridine small carboxylic acid (intermediate 55, L0 g, 2.86 mmol) was suspended in 1 mL of toluene _, and a 50% by weight solution (6 mL) of aqueous sodium hydroxide solution, It was then treated with dimethyl sulfate (0.33 mL, 3.43 mmol) and benzyltriethylammonium hydride (catalyzed K). The reaction was stirred vigorously for one hour. The reaction was quenched with ice. The aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness. EtOAc EtOAc EtOAc The product is a colorless oil. MS (ESP): 365 (MH+)f^c19H28N205 NMR (DMS〇-d6) δ: 0.55-0. 68 (m5 10H) ; 1.04-1.19 (m5 1H); 2.17-2.46 (m5 2H) ; 2.55-2.64 (m5 2H) ; 2.67-2.80 (m5 1H) ; 2.85-3.07 (m5 127286 •104- 200831517 1H) ; 3·1〇'3·31 (m,1H) ; 4.09 (s,3H) ; 4.32 (s5 2H) ; 6.45-6.61 (m, 5H)· Intermediate 55 Trans (±)-4-[( Third-butoxycarbonyl)amino]benzyl perhexyl hexahydropyridine carboxylic acid benzyl trans-(±)-glyamyl-3-hydroxyhexahydropyridine-1-carboxylate (WO 2005/066176, 3.0 g, 12.0 mmol, di-tert-butyl dicarbonate (2-9 g, 13.2 mol) and sodium bicarbonate (3 g, 36.0 mmol) in ethyl acetate/water (1 The mixture of 1 '100 ml) was stirred vigorously overnight. The two phases were separated and the aqueous phase was re-extracted with ethyl acetate. The combined organic phases were dried over sodium sulfate and concentrated to dryness to yield 4.2 g. The product was obtained as a colorless solid. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; -2.79 (m, 1H); 2.82-2.98 (m, 1H); 3.15-3.29 (m5 2H); 3.74-3.86 (m, 1H); 3.88-3.98 (m,1H); 5.00 (d,1H); 5.04-5.08 (m,2H); 6.73 (d,1H); 7.25-7.42 (m,5H). Intermediate 56 φ W2·^31^ , 4% 4 · Amino-3 methoxy hexahydropyridine · 1-yl] ethyl b 7-methoxyquinoxaline · 2 (1 fluorene) ketone using a procedure similar to that described for the synthesis of intermediate 31 ,{(3r,4r)_3_decyloxy-l-[2-(7-methoxy-2-keto 喏 喏 林 - - -1(Η)-yl)ethyl]hexahydropyridine _4 · } 胺 胺 胺 第三 , , , , , 胺 胺 胺 胺 胺 胺 胺 胺 ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( ( The crude product is an oil. MS (ESP): 333 (ΜΗ+) vs. C17H24N403 Intermediate 57 127286 -105- 200831517 1·{2-丨(4-Amino·3·Pyridinylhexazinium-1-yl]ethyl}^ 7. methoxy p-quinone 1 * if p-lin-2 (m)-ketone, trans-palphasomer isomer a as described in relation to intermediate 31, such that {(3-pyrase is small [2-(7-) Methoxy-2-ketopyl porphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}carbamic acid tert-butyl ester, trans-p-isomer A (intermediate 58 , 130 mg (0.31 mmol) were reacted with trifluoro acid to give 78 mg (yield: 79%) of crude product as an oil. MS (ESP): 319 (MH+) to C16H22N403 Intermediate 58 {3- 1-[2-(7.Methoxy-2-ketoquinoxalinium·ι(2Η)-yl)ethyl]hexahydropyridylsyl)-amino carbamic acid tert-butyl ester, trans-pair Structure a and · Intermediate 59

{3 aryl Η 2-(7-methoxy-2-ketoquinoxaline-1(2H)-yl)ethyl]hexahydropyridine 4 yl} carbamic acid tert-butyl ester, trans-pair Palmeromer B will be {trans (±)-3-{[Third-butyl(dimethyl)-indolyl]oxy} small [2_(7-methyl•yl 1 ketoquinazoline) Phenanthroline, ethyl)ethyl]hexahydropyridinyl}aminocarbamic acid first-butan (intermediate 60,0·60 g, 1.9 mmol) in THF (20 ml) The solution was treated with a solution of tetrabutylammonium fluoride in THF (1 Μ, 2·2, liter) under EtOAc. The reaction was stirred at room temperature for 2 hr then concentrated to dryness under reduced pressure. The crude residue was dissolved in ethyl acetate. Wash the t phase with water. The aqueous phase was re-extracted 3 times with (tetra)ethyl ester. The combined organic phases were dried over 1 min, and concentrated. On the Shixi gum, the mixture was chromatographed in a gas-fired gas to obtain 0. 27 g of the desired product and 0.12 g of the hydrazine-acetamidine by-product. This by-product was dissolved in methanol and treated with a catalytic amount of potassium carbonate. 127286 -106- 200831517 It was disturbed at room temperature for one hour, resulting in complete conversion to alcohol. The reaction mixture was concentrated to dryness. The residue was partitioned between potassium phosphate aqueous solution buffer (pH = 7) and ethyl acetate. The aqueous phase was extracted twice with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness eluting MS (ESP): 419 (MH+)^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ 1.97 (t5 1H) ; 2.54-2.64 (m? 2H); 2.80-2.93 (m5 1H); 2.96-3.09 (m, 2H); 3.23 (dd, 1H); 3.92 (s, 3H); 4.32 ( t,2H); 4.67 (d,1H); 6.62 (d,1H) ; 6·94-7·06 (m,2H) ; 7.69-7.79 (m,1H) ; 8.04 (s,1H)· A mixture of palmomers was separated by supercritical fluid chromatography on a Chimlpak AD-H column (250 x 21 mm '5 μm) with a constant composition gradient of 25% isopropanol/〇1% monoethylethylamine. The solution was dissolved at a flow rate of 60 ml/min. This gave 130 mg of {3-hydroxy-1-[2-(7-methoxybutanylquinoxalin-1(2Η)-yl)ethyl] Hexa-butyl hexahydropyridine 4-yl}aminocarbamate, trans-p-isomer A (intermediate 58, the first dissolving para-isomer) with 130 mg {(3-carbyl) -1·[2·(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino decanoic acid tert-butyl ester, Trans-palphasomer b (intermediate 59, second dissolving para-isomer). Intermediate 60 {trans (±)-3-{丨T-butyl(dimethyl)alkyl]oxybumethoxy: ketoquinoxalinyl)ethyl]hexahydropyridin-4-yl} The third-butyl carbamic acid ester was used in a procedure similar to that described for the synthesis of intermediate 32 to give 7-decyloxyguanidine-2(1Η)-one (intermediate 15,430 mg, 2.43 mmol), Methanesulfonic acid 127286 -107- 200831517 2-(trans (±)-4·[(T-butoxycarbonyl)amino]-3-{[T-butyl(dimethyl)-toluene ]oxy}hexahydropyridin-1-yl)ethyl ester (intermediate 61, ~0·27 mmol/ml, 2.70 mmol) and sodium hydride (60% in oil, 110 mg, 2.70 mmol. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut (ΜΗ+) vs. C27H44N405Si 1H NMR (DMSO-d6) δ : 0.00 (s? 6H); 0.79 (s, 9H); L33 (s? 9H); 1.37-L47 (m, 1H); 1.49-1.59 (m9 1H) ; 1.87 (t5 1H) ; 1.95-2.07 (m5 1H); 2.55-2.66 (m5 2H) ; 2.77-2.89 (m5 1H) ; 2.92-3.02 (m5 1H) ; 3.11 (s5 1H); 3.30-3.40 (m,1H); 3.89 (s,3H); 4.17-4.41 (m,2H); 6.57 (d,1H); 6.91-7.04 (m,2H); 7.72 (d,1H) ; 01 (s, 1H). Intermediate 61 methanesulfonic acid 2 · (trans (±) · 4 _ [(t-butoxycarbonyl) amine group] {[T-butyl (dimethyl)) Ethyl oxy] hexahydro p is a small base. Ethyl vinegar is similar to the procedure described for the synthesis of intermediate 33, so that [trans (soil) each • {[T. butyl (didecyl) decyl) ]oxy Η·(2·hydroxyethyl)hexahydropyridin-4-yl]amino decanoic acid tert-butyl ester (intermediate 62, 1 gram, 27 mmol), triethylamine (0.52 ml) ' 3.74 mmoles and chloromethanesulfonate (〇 25 ml, 321 mmol). This crude product was used directly in the next step without further purification. Intermediate 62 [trans (±) each {[Third butyl (dimethylhydropyridin-4-yl) carbamic acid tertyl) calcinyl] oxy hydroxyethyl) hexa-butyl ester The procedure described for the synthesis of intermediate 7 is such that (trans (±)-3-{[12728-108-200831517 a &quot;butyl (monomethyl) decyl] oxy} hexachloropyrene -4-yl) carbamic acid tert. butyl ester (intermediate 63, 1.3 g, 3.9 mmol), 2-bromoethanol (0.36 ml, 5.2 m mole) and ethyl (two Reaction of isopropyl)amine (1. mM, 5.9 mmol) gave 1.0 g (67%) of desired product. ^ NMR (DMSO-d6) δ : 0.00 (s5 6H) ; 0.79 (s3 9H) ; 1.33 (s? 9H); 1·39 (dd, 1H); 1.46-1.58 (m, 1H); 1.71-L82 ( m,1H); 1.82-1.93 (m,1H); 2·33 (t,2H); 2J2 (d,1H); 2.80-2.90 (m,1H); 2,99-3-16 (m,1H) 3.32-3.47 (m,3H) ; 4.36 (t,1H) ; 6.56 (d,1H). Intermediate 63 (trans (:t)-3-{[T-butyl(dimethyl))矽alkyl]oxy}hexahydropyridin-4-yl) methamic acid tert-butyl ester to trans(±)-4-[(tris-butoxycarbonyl)amino]-3-{[third - butyl (diindenyl) decyl]oxy} hexahydropyridine carboxylic acid benzyl ester (intermediate 64, 1.8 g, 3.9 mmol) in methanol (50 mL) at 10% palladium on carbon ( ~400 mg), hydrogenated at atmospheric pressure for one hour. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give &lt 1H NMR (DMSO-d6) (5: 0·00 (s, 6H); 0.80 (s, 9H); L20-1.30 (m, 1H); 1.33 (s, 9H); 1.53 (d, 1Η); (dd,1H) ; 2·23-2·39 (m,1H) ; 2.74 (d 1H) ; 2.88 (dd5 1H) ; 3.20-3.30 (m,2H) ; 4.08 (s,1H) ; 6·58 (d,1H)· Intermediate 64 trans (±)-4-[(Thr-Butoxycarbonyl)amino]-3-{[T-butyl(dimethyl)oxime]oxy } Benzylpyridin-1_carboxylic acid benzyl ester trans (±)-4-[(tris-butoxycarbonyl)amino group &gt; 3-hydroxy hexahydropyridine | benzylic acid benzyl ester (intermediate 55, 2 · 0 g, 5.7 mmol, imidazole (0 · 58 g, 8.6 127 286 - 109 - 200831517 Mo) and third - butyl (chloro) dimethyl decane (1 · gram, 6.9 mmol) The mixture was stirred at room temperature under nitrogen overnight. Water (50 mL) was added to the mixture and the mixture was extracted with ether. And concentrating to dryness. Chromatography on 10% toluene in hexanes eluted EtOAc (EtOAc: EtOAc: 0.80 (s? 9H); 1.27-1.41 (m5 _ l〇H); 1.61-1.72 (m,1H); 2.59-3.05 (m,2H); 3.30-3.40 (m,2H); 3.69-3.95 (m,2H) ; 4.92-5.14 (m, 2H); 6.68 (d5 1H) ; 7.24-7.40 (m, 5H). Intermediate 65

Amino-hydroxy hexahydropyridin-1-yl]ethyl 7-decyloxyquinoxaline-2(1H)-one, trans-p-isomer B using procedures similar to those described for the synthesis of intermediate 31 To make {3-carbyloxy-2-ketoquinoxaline-1(211)-yl)ethyl]hexahydropyridylsyl-aminocarbamic acid tert-butyl ester, trans-pair Compound B (intermediate 59, 13 〇 mg, _ 〇 · 31 mmol) was reacted with three of acetic acid to give 84 mg (85%) of crude material as pale white foam. MS (ESP): 319 (ΜΗ+) on C16H22N403 Intermediate 66 3-Terino-2·keto-1,2,3,4·tetrahydro 4 _7-carbonitrile 3-(4-Galy Ethyl 2-nitrophenyl)-2-ketopropanoate (6.5 kg, 24.8 mol) was stirred with acetonitrile (21 L) at 22 °C. Sodium borohydride (〇·3 〇 kg, 7.9 mol) was added in portions, and then the mixture was stirred at 24 ° C for 1 hour. Acetic acid (65 liters) was added to the solution and the internal temperature was raised to still it. Iron (3 3 127286 • 110 - 200831517 kg) was added to the solution (6 χ 0.5 kg) in portions for 1 hour. After an additional 1 hour, the product was isolated by filtration, washed sequentially with water (3.times.25 liters) and ethanol (29 liters) and dried under reduced pressure to give the product as a beige solid, 3 〇 7 kg (66%) .

Melting point &gt; 250 ° C MS (ESP): 189 (MH+) vs. C 〇H8 N2 02 ^-NMR (DMSO-d6) δ ppm : 2.90-3.20 (m5 2H); 4.10-4.20 (m, 1H); 5·65 (d,1H) 7.15 (s,1H) 7.35-7.45 (m,2H) ; 1〇·38 (s,1H). Intermediate 67

1_{2·[·4-Amino-3-carbylhexafluoroindole-1_yl]ethyl b-indenyl-1,2-dihydrop-quinion-7-carbonitrile, trans-pair Palmomerium A in {l-[2_(7-cyano-2-ketoquinolin-1(2H)-yl)ethyl]-3-fluorohexahydropyridyl)aminocarbamic acid Tri-butyl ester, trans-p-isomer a ( intermediate 68, 0.30 g '0.72 mmol) in dichlorohydrin (20 mL), trifluoroacetic acid (4 mL) Cool in an ice bath. The reaction mixture was allowed to warm to room temperature. The TLC system was not pure after ~30 minutes but was not completely converted (15% methanol/di-methane containing 0.5% ammonium hydroxide as the eliminator). An additional 4 ml of trifluoroacetic acid was added. After 30 minutes, the reaction was concentrated to dryness. The crude residue was partitioned between 15% methanol/diqi methane and saturated sodium bicarbonate. The aqueous phase was adjusted to a pH of ~10 with a saturated sodium carbonate solution. Separate the liquid layer. The aqueous phase was re-extracted 2x with 15% methanol / di-methane. The combined organic phases were dried over sodium sulfate, dried and evaporated to dryness. MS (ESP): 315 (MH+) vs. C17H19FN4〇5 127286 -111- 200831517 Intermediate 68

{1-丨2-(7-Cyano-2-ketoporphyrin-1(2H)-yl)ethyl]·3·fluoropyrohydropyridinyl}-tert-butyl carbamic acid Formulation of 2-keto-1,2-dihydroquinolin-7-carbonitrile (intermediate 5,500 mg, 2.94 mmol) in anhydrous DMF (10 mL) The solution was treated with sodium hydride (60% in oil, 153 mg, 3.82 mmol) at EtOAc. Cooling was removed and the reaction was stirred at room temperature for 90 min. The reaction was allowed to cool once again in an ice bath, and methanesulfonic acid 2-{(3R,4R) s[(tris-butoxycarbonyl)amino]_3_fluorohexahydropyridine-l-yl} Ethyl ester, trans-p-isomer A (intermediate 69, ~0.38 mmol/ml, 3.82 mmol) was treated in dry DMF and the reaction was stirred at room temperature overnight. The reaction was quenched with water (1 mL) andEtOAc. The organic layer was washed with brine, dried over sodium sulfate sulfate Chromatography on a silica gel eluting EtOAc EtOAc (EtOAc) φ ^ NMR (DMS〇-d6) δ ppm : 1.25-1.43 (m5 11H) ; 1.67-1.78 (m, 1H); 2.04-2.17 (m? 2H); 2.57-2.68 (m5 2H) ; 2.80-2.89 ( M5 1H) ; 3.25-332 (m5 1H) ; 4.27-4.47 (m, 2H) ; 4·30 (m, 1H) ; 6.78 (d, 1H); 6.99 (d, 1H); 7.66 (dd, 1H) 7.91 (d,1H) ; 8·01 (d,1H) ; 8.09 (s,1H)· MS (ESP) : 415 (MH+) vs. C22H27FN403 Intermediate 69

Methyl benzoate 2-{4_[(T-butoxycarbonyl)amino]·3_fluoropyrohydropyridyl} ethyl ester, trans-p-isomer A under 〇C will [3 -fluoro-1-(2·ethyl)hexanitrogen p butyl-4-yl]carbamic acid 127286 -112- 200831517 second-butyl ester, trans-p-isomer A (intermediate 70, 2.0 g, 7_62 mmol, in anhydrous dichloromethane (5 mL), triethylamine (15 mL, 10.7 mmol), followed by chloromethanesulfonate (〇·71 mL, 915 mM Mohr) processing. After 15 minutes, the reaction was quenched with potassium phosphate buffer (1 Μ, ρ Η 7). The aqueous phase was extracted once with methyl chloride. Ethyl acetate was added to the combined organic phases. The dichloromethane was removed under reduced pressure to leave the product in ethyl acetate. This organic phase is washed with water to remove any residual salts. The aqueous phase was re-extracted (1x) with ethyl acetate. The combined organic phases were dried over sodium sulfate and filtered. Anhydrous DMF (20 mL) was added to the filtrate. The ethyl acetate was removed under reduced pressure to leave a product in DMF which was used in the next step without further purification without further purification. Intermediate 70

[3-Fluoro-1(2-hydroxyethyl)hexahydropyridyl] Aminobutyric acid tert-butyl ester, trans-p-isomer A in thiol [3-fluoro-based small (2- Hydroxyethyl) hexahydropyridine _4_yl] amino decanoate, φ trans-palphasomer A (intermediate 71, 5.6 g, 14.5 mmol) in ethanol (1 〇〇耄In the solution of liter), 20% palladium hydroxide/carbon (1.5 g) was added. The reaction was stirred overnight under a hydrogen atmosphere. TLC showed complete disappearance of starting material (15% methanol/dichloromethane containing 0.5% ammonium hydroxide as solvent). Then, the reaction mixture was treated with di-tert-butyl dicarbonate (4 mL, 14.7 mmol) and stirred for 1 hour under nitrogen. TLC showed the starting material completely disappeared. The reaction mixture was filtered through celite. The filtrate was concentrated to dryness and subjected to chromatography on silica gel eluting with a gradient of 5% hexanes / methylene chloride, followed by a constant composition of 5% methanol / dioxane containing 0.25% ammonium hydroxide. Gradient 127286 • 113- 200831517 Liquid &gt; Valley Separation' obtained 2.86 g (75%) of product as a yellow oil. ^ NMR (DMSO-d6) δ ppm : 1.29-1.45 (m5 11H) ; 1.65-1.79 (m? 1H); 1.93-2.08 (m, 2H); 2.38-2.46 (m, 2H); 2.69-2.79 (m ,1H) ; 3.10-3.21 (m, 1H) ; 3.47 (q5 2H) ; 4.26 (m? 1H) 4.44 (t5 1H) ; 6.99 (d, 1H). Intermediate 71

Benzyl-[3-fluoro-1-(2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid decyl ester, trans-p-isomer A and intermediate 72

Benzyl-indole-3-fluoro-1-(2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid benzyl ester, trans-p-isomer B. tetrabutylammonium fluoride in tetrahydrofuran The solution (1M, 21.3 ml, 21.3 mmol) was added to the trans (±) base in tetrahydrofuran (20 mL) at 0 ° C [1-(2_{[di-butyl] Methyl) 石 烧 ] 氧基 氧基 氧基 氧基 氧基 氧基 。 。 。 。 。 ] ] ] ] ] ] 。 。 。 中间 中间 。 。 中间 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 _ Warm the solution to room temperature and stir for one hour. Then, the mixture was cooled to 〇 ° C, and the reaction was quenched with water. The mixture was extracted with ethyl acetate and washed with brine. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. Chromatography on 40% acetone in hexanes eluted elute δ ppm : 1.55 (m5 1H) ; m,2H) ; 3·43 (m,2H); 3.93 (m,1H) ; 4·40 (t,2H) ; 4.50 (m,1H) ; 5.06 (m,2H); 7.15 (m,ljj) · 7.20-7.31 (m,8H); 7.36 (m,1H)· 127286 -114· 200831517 MS (ESP): 387.25 (MH+)fiC22H27FN2〇3 racemic mixture KChiralpak (5〇〇x 2〇) Millimeter, job m) separated by 3 with 0 J / ° - ethylamine ethanol / methanol (1: 丨). The trans-p-isomer A (intermediate 71) is first eluted, followed by the trans-p-isomer B (intermediate 72). Regarding the two palmar isomers, the palm purity (analytical method using the above-mentioned preparation method) was determined to be &gt;98% a. Intermediate 73 φ trans (±) benzyl (2 喟 tri-butyl (dimethyl) carbonyl) oxy} ethyl) each fluorohexaphos p 唆 _ 4 _ group] amine Formic acid is a trans-(±)-based (3-fluorohexahydropyridyl) carbazate hydrochloride (intermediate 74, 7.78 g, 2 U mmol), (2-bromo) A mixture of ethoxy)-t-butyl decyl decane (6.85 g, 27.5 mmol) and carbonated (17. 9 g, 55.0 house Mo) in acetonitrile (60 mL) was heated to 6 〇. 〇c, after twelve days t. The reaction mixture was allowed to cool to room temperature and concentrated under reduced pressure to dryness. The residue was diluted with ethyl acetate and washed with water and brine. The φ machine phase was dehydrated and dried over sodium sulfate, and concentrated under reduced pressure. The product was obtained as an oil (8·9 g, 84%). 1H NMR (gas-d3) ά ppm : 0.04-0.07 (s,6Η); 0.77-0.88 (s,9Η); 1.58-L74(m,2H); 2.05-2.20 (m,2H); 2.44-2.58 (m, 2H); 2.69-2.84 (m, 1H); 3·24 (m, 1H); 3·65 (s, 2H); 4.44-4.59 (m, 3H); 5.11 (s, 2H); 7.13 -7.28 (m,9H) ; 7.34 (m,2H). MS(ESP): 501·28(ΜΗ+) for C28H41FN203Si intermediate 74 trans(±) mercapto (3-fluorohexahydropyridine_4_ Benzyl carbamic acid benzyl ester hydrochloride 127286 -115- 200831517 in trans (±) 4-{ aryl [(yloxy) benzyl] aminyl 3 fluoro hexahydropyridine small carboxylic acid third - Butyl ester (intermediate 75, 12·5 g, 28.2 mmol) in a solution of methylene chloride (50 ml), then added cesium chloride (1 Μ in diethyl ether, 56.5 ml) , 56.5 millimoles). The solution was stirred for one hour. The solid was filtered and the filter cake was washed with a riddle to give the monohydrochloride salt of the product (1 〇 1 g, 95%) NMR (DMS 〇.d6) 6 ppm : 1.68 (m? 1H); 2.00-2J5 (m5 1H) ; 3.08 (m,1H); 3.18 (m,1H); 3·34 (m,2H); 3·50 (m,1H); 4·34-4·49 (m,2H); 4.65 ( m,1H) ; 5.02 (s,1H) ; 5.14 (d,J = 19.40 Hz, 2H) ; 7·15-7·30 (m, 8H) ; 7·32 (m, 2H)· MS (ESP) : 343.19 (MH+) to C2gH23FN202 Intermediate 75 trans (±) ice {Yuyl [(;oxy) aryl] amine} each fluorohexahydropyridine small carboxylic acid tert-butyl ester in trans (± (4-Y-Amino)-3-ylhexahydropyridine···carboxylic acid tert-butyl ester (intermediate 76, 1〇_3 g, 33.4 mmol) in ι,4-diox In 圜〇〇〇ml), add benzyl chloroformate (5.89 ml, dropwise) at 0 °C with sodium carbonate (5.31 g, 5 (U mmol) in water (2 mL). 41.8 mmol). / / Compound 1 was allowed to warm to room temperature ' and stirred for two hours. Then, the reaction mixture was concentrated to near dryness and diluted with ethyl acetate. The organic phase was washed with water and brine. Sodium dehydration The product was obtained as a solid (12.5 g, 94%) eluting with EtOAc EtOAc EtOAc (EtOAc: EtOAc) 〇4 1H NMR (gas-d3) 5 ppm ·· ι·45 (s,9Η); 1.67 (d, J = 8·67 Ηζ, 2Η); 127286 •116- 200831517 1.84 (m,1H); 2.59 -2.75 (m, 2H) ; 3·91-4·07 (m, 2H) ; 4·48 (d, J = 16 Hz, 2H); 4.63 (d, J = 16 Hz, 1H); 5.18 (s , 2H) ; 7·20-7·34 (m, 10H) · Intermediate 76 trans (± ) (4- arylamino) each fluoro hexahydropyridine-1 carboxylic acid tert-butyl ester title compound Made by Monique B. van Neil et al., J. Med. Chem., 1999, 42, 2〇87_21〇4, and references therein. !H NMR (DMSO-d6) δ ppm : 132 (m5 1H) ; 1.39 (s5 9H) ; 1.79 (m5 1H); 2.38 (m, 1H); 2.73 (m, 1H); 3·18 (m, 1H); 3.31 (m, 1H); 3.46 (m , 1H) ; 3.60-3.80 (m5 3H) ; 4.39 (m, 1H) ; 7.20-7.38 (m5 5H). Intermediate 77

L-{2-[4-Amino-3·fluorohexahydropyridin-1-yl]ethyl b 7·methoxylated guanidine--2(1H)-one, trans-p-isomer A Using a procedure similar to that described for the synthesis of intermediate 67, {3-fluoroyl-1·[2·(7-methoxy-2-ketoporphyrin-1(2H)-yl)ethyl]hexa Hydrogen pyridinyl}amino decanoic acid, third butyl ester, trans-p-isomer A (intermediate 78, 0.30 g, φ 0·71 mmol) was reacted with trifluoroacetic acid to obtain 〇·25 g. The crude product was an oil. MS (ESP) ·· 321 (ΜΗ+) to C16H21FN402 Intermediate 78 {3-Alkyl-1·[2·(7-Methoxy-2-ketoquinoxaline-i(2H&gt;yl)ethyl </RTI> hexahydropyridinyl}-amino carbamic acid tert-butyl ester, trans-p-isomer a, using a procedure similar to that described for the synthesis of intermediate 68, to give methoxy quinoxaline-2(1H)- Ketone (intermediate 15, 0.52 g, 2.95 mmol), 2-{4-[(T-butoxycarbonyl)amino]-3-fluoropyridinyl} , trans 127286 •117- 200831517 to the isomer A (intermediate 69, ~0.38 mmol/ml, 3 82 mmol) and sodium hydride (60% in oil, 153 mg, 3.82 mmol) The reaction was carried out on a silica gel eluting with a gradient of 10-50% acetone in hexane to give the product (67%) as an off-white solid. NMR (DMSO-d6) δ ppm : 1.23- 1.45 (m5 11H) ; 1.64-1.80 (m? 1H); 2.04-2.19 (m, 2H) ; 2.61-2.71 (m, 2H); 2.84 (d, 1H); 3.25-3.33 (m, 1H); 3.92 (s, 3H); 4.27-4.43 (m5 2H); 4.28 (m? 1H); 16,94-7.05 (m5 3H); 7.75 (d,1H); 8.04 (s,1H)· MS (ESP): 421 (MH+) to C2 H2 9 FN4 04 Intermediate 79

1-{2-[4-Amino-3-fluorohexahydropyridinyl]ethyl}_2,yl^•dihydroquinolin-7-carbonitrile, trans-p-isomer B The procedure described in the synthesis of intermediate 67 is such that {i_[2_(7-cyano-2-oxoquinolin-1(2H&gt;yl)ethyl]-3-fluoropyrohydropyridyl)aminocarbamic acid Di-Di-S-, trans-extracted isomer B (intermediate 8 〇, 〇% gram, ο·% mM) and trifluoroacetic acid to obtain 〇·25 g of crude product as oil MS (ESP): 315 (ΜΗ+) vs. C17H19FN40 Intermediate 80

{1-[2-(7-Cyano-2-indenyl, quinolin-1(2H)-yl)ethyl b-3-fluorohexahydropyridinyl}-amino carboxylic acid tert-butyl ester, anti The formula for the palmomeromer B was similar to that described for the synthesis of intermediate 68 to give 2-keto-; 1,2-dihydrotetralin-7-carbonitrile (intermediate 5,0.50 g, 2.94). Mol), methane-reductive acid 2-{4-[(second-butoxycarbonyl)amino]-3-fluoropyrohydropyridinyl ethyl ester, trans-palomerisomer Β (intermediate 81, ~〇·38 mmol/ml, 3.82 mmol) 127286 •118- 200831517 and sodium hydride (60% in oil, 153 mg, 3.82 mmol). Chromatograph on 10% to 50% of EtOAc in EtOAc (EtOAc) MS (ESP): 415 (MH+) vs. C22H27FN403 NMR (DMSO-d6) δ ppm : 1.25-1.43 (m5 11H); 1.67-1.78 (m? 1H); 2.04-2.17 (m, 2H); 2.57-2.68 (m, 2H); 2·80-2·89 (m, 1H); 3.25-3.32 (m, 1H); 4.27-4, 47 (m? 2H); 430 (m3 1H); 6.78 (d? 1H 6.99 (d5 1H); 7.66 (dd,1H) ; 7.91 (d,1H) ; 8.01 (d,1H) ; 8·09 (s,1H). *Intermediate 81

2-{4-[(Thrs. Butoxycarbonyl)amino]-3-fluorohexahydropyridyl) ethyl ester, trans-p-isomer B is similar to that used in the synthesis of intermediates 69 The procedure described is such that [3-1 ketone stem ethyl) hexaqip is more than ter-4-yl] carbamic acid tert-butyl vinegar, trans-palphaliomer B (intermediate 82, 2.0 g) , 7.62 millimolar), triethylamine (1.5 ml, 1〇7 house Moule) and a continuous reaction of methylamine (0.71 ml, 9.15 mmol). This crude product was used directly in the next step without further purification. Intermediate 82 [3-Fluorosuccinyl (2-hydroxyethyl)hexahydropyridin-4-yl]carbamic acid tert-butyl ester, trans-p-isomer hydrazine using similar to synthetic intermediate 70 The procedure is to make the base gas base small (2-3⁄4 ethyl) hexahydro ρ than the bite _4_ yl] carbamic acid for the purpose of the trans, the palm to the isomer B (intermediate 72, 5. 6 grams , 4.4 mmol, 20% palladium hydroxide/carbon (〇5 g) and di-tert-butyl dicarbonate (3.5 g, 15.8 mmol). Chromatography on silica gel, eluting with 10% methanol (0.1% ammonium hydroxide) in ethyl acetate afforded y. XH NMR (CDCI3) δ ppm 1.36-L55 (m, 1〇Η); 2.02-2.31 (m, 3H); 2.52-2.64 (m5 2H); 2.72-2.82 (m, 2H) ; 3.09-3.20 (m5 1H ; 3.60 (t, 3H); 4.31 (m, 1H); 4.80 (d, 1H) Intermediate 83

L-{2-[4-Amino-3-fluorohexahydropyridine·1_yl]ethyl decyloxyquinoxaline-2(1H)-one, trans-p-isomer B The procedure described in the synthesis of intermediate 67 is such that {3-fluoro-indenyl 2 (7-methoxy-2-ketoquinoxaline·1(2Η)·yl)ethyl]hexahydropyridine The third-butyl carboxylic acid, trans-palladium isomer Β (intermediate 84, 0. 33 g, 〇 · 78 mmol) was reacted with trifluoroacetic acid to obtain 〇·27 g of crude product as an oil. MS 0 (ESP): 321 (ΜΗ+) to C! 6Η2! FN402 Intermediate 84 {3-Fluoro-l-[2-(7-methoxy-2-keto 4 喏 _1 _1 (211 _ yl) ethyl] hexahydropyridinyl carbyl} methic acid tert-butyl ester, trans-palphaliomer β using a procedure similar to that described in the synthesis of intermediate 68 to make 7-methoxy若若淋·2(1Η)-ketone (intermediate 15, 0.52 g, 2.95 mmol), formazanic acid [(di-butoxy-yl)amino]_3·san hexahydropy ratio Bite _1_ base} B, the trans-isomer isomer Β (intermediate 81, ~0.38 mmol/ml, 3.82 mmol) and sodium hydride (60% in oil, 153 mg, 3.82) Millions of reactions. Chromatography on 10-5% acetone in hexane afforded EtOAc (EtOAc) MS (ESP): 421 (ΜΗ+) vs. C21H29FN4〇4 127286 • 120- 200831517 XH NMR (DMSO-d6) δ ppm : L23-1.45 (m5 11H) ; L64-1.80 (m, 1H); 2.04-2.19 ( m? 2H) ; 2.61.2.71 (m5 2H) ; 2.84 (d5 1H) ; 3.25-3.33 (m? 1H); 3.92 (s, 3H) ; 4.27-4.43 (m, 2H) ; 4.28 (m, 1H) ; 16·94-7·05 (m,3H); 7.75 (d,1H) ; 8.04 (s,1H). Intermediate 85 l-{2-[(3R,4R)-4-Amino·3· Methoxy hexahydropyridyl]ethyl b 2-keto-1,2-dihydroporphyrin-7-carbonitrile will be {(3R,4R)-H2-(7-cyano-2-ketoindole) L-(2H)-yl)ethyl]-3-decyloxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (intermediate 86, 280 mg, 0.66 mmol) in dichloro The solution in methane (30 mL) was taken in trifluoroacetic acid (10 mL). After 1 hour, the reaction was concentrated to dryness. The residue was dissolved in 15% MeOH (30 mL)EtOAc. The aqueous layer was adjusted to pH ~1 EtOAc and then extracted with 15% methanol / chloroform (3 X 30 mL). The combined organic phases were dried with sodium sulfate <RTI ID=0.0> MS (ESP): 327 (MH+) to C18H22N402 Intermediate 86 {(3R,4R)-l-[2-(7-Cyano-2. ketoquinoline_i(2H)-yl)ethyl]- 3. Methoxyhexahydropyridine-each yl}-amino carboxylic acid tri-butyl ester and intermediate 87 {(3S,4S)-l-[2-(7-cyano-2-ketoquinoline_1 (211)-yl)ethyl]-3-methoxyhexahydropyridine ice-based} tert-butyl carbazate [trans (±)-3-methoxyhexahydrop to butyl-4-yl Amino carboxylic acid tert-butyl ester 127286 -121 - 200831517 (intermediate - gram '2.7 mM) and 2 keto phenone ketoethyl like dihydroquinolinium carbonitrile (intermediate 88, 〇·57 g, 2·7 mmoles) A mixture of ι: ι anhydrous methanol/chloroform (30 ml) was heated to hydrazine over 2 hours. The reaction was allowed to cool to rt and was taken &lt;RTI ID=0.0&gt;&gt; The reaction was filtered through celite, and the filtrate was concentrated in vacuo. The crude residue was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The liquid layer was separated and the water phase was extracted once more with ethyl acetate. The combined organic phases were dried over sodium sulfate, filtered, and concentrated in vacuo. Chromatography on 25-50% hexane in hexane afforded a racemic mixture of y 74 g (62%). MS (ESP): 427 (ΜΗ+) vs. C23H3GN4 〇4H NMR (DMSO-d6) δ ppm: 1.19-133 (m, 1H); 1.37 (s, 9H); 1.64-1.73 (m,1H), 1.77 (m,1H); 1.99 (m,1H); 2.59 (m5 2H); 2.79-2.87 (m,1H); 2.93-3.04 (m5 1H); 3.05-3.15 (m5 1H) ; 3.23-3.30 (m5 1H ; 3.28 (s? 3H); 4.30-4.47 (m, 2H); 6.79 (d, 2H); 7.66 (dd, 1H); 7.91 (d, 1H); 8.01 (d, _ 1H); 8·09 (s, 1H)· The mixture of palmomers is attached to a Chiralpak AD column (20 x 250 mm, 10 μm) by HPLC with 80% hexane, 20% 1:1 ethanol/methanol, hydrazine A constant gradient of ι〇/0 monoethylamine was separated at a flow rate of 20 ml/min. This gave 0·28 g of {(3R,4R) small [2-(7-cyano-2-ketoquinoline-1(2Η&gt;yl)ethyl]&gt;3-methoxyhexahydropyridine-4- Aminobutyric acid tri-butyl ester (intermediate 86, second dissolved peak (ten) isomer) and 0.32 g {(3S,4S&gt;l-[2-(7•cyano-2-one) Porphyrin-1(2H)-yl)ethyl]-3-methoxyhexahydropyridin-4-yl}carbamic acid tert-butyl ester (Intermediate 87, first dissolving peak (I) isomer) 127286 -122- 200831517 Intermediate 88 2-keto-1-(2-ketoethyl)_1,2-dihydroporphyrin·7·carbonitrile in 1-(2,2-ethoxylated Base)-2-Tenyl·1,2·Dichloro ρ 淋 _7·carbonitrile (intermediate 89, 21·5 g, 75.1 mmol) in acetonitrile (230 ml), add concentrated Hydrochloric acid (2 eq., 12.5 mL). After 1 hr, the formed precipitate was collected by filtration. After drying, this afforded 16 g (100%) of product as a colourless solid. (ESP): 213 (ΜΗ+) vs. C12H8N202^ NMR (DMSO-d6) δ ppm: 5.25-5.38 (m? 2H); 6.82 (d5 1H); 7.67 (d? 1H); 7.95 (d, 1H); 8.02-8.14 (m, 2H) ; 9.64-9.74 (m, 1H) · Intermediate 89 l-(2,2·Ethoxyethyl) 2 fluorenyl-1,2_diazo ____carbonitrile 2-keto-1,2-dihydroquinoline- 7-carbonitrile (intermediate 5,35·〇g, 2〇1 mmol), 2-Mo,-1,1-ethoxy bethane (44.1 liters, 281 mmol) and cesium carbonate (78.5 g of '241 mmol) mixture in anhydrous hydrazine (2 (8) mL) was stirred at _ 70 C overnight. The reaction mixture was diluted with water (350 mL) and vinegar

Extraction of butyl vinegar (2 x 350 ml). The combined organic phases were filtered through celite and washed with water (1× 175 mL). The butyl acetate solution was concentrated to 14 mL and diluted with 525 mL of isohexane. Use the filter to separate the Shen Temple and wash it with 70 liters of isohexane. After drying, this gave 34 g (6 %) of product as a colorless solids. &lt;EMI ID=9.1&&&&&&&&&&&&&&&&&&&&&& : 0.96 (t5 6H); 334-3.47 (m? 2H); 3.56-3.73 (m, 2H); 4.39 (d, 2H); 4.72 (t, 1H); 6.80 (d, 1H); 7·62 ( d,1H) ; 7·89 127286 -123 - 200831517 (d5 1H) ; 8.02 (d, 1H) ; 8.13-8.22 (m, 1H). Intermediate 90, l-{2-[(3S,4S)- 4_Amino-3-methoxyhexahydropyridine-i-yl]ethyl keto-l,2-dihydroquinoline-7-carbonitrile was prepared using a procedure similar to that described for the synthesis of intermediate 85. 3S,4S)4-|&gt; (7-Cyano-2·ketoquinoline-i(2H)·yl)ethyl]-3-decyloxyhexahydropyridyl yl) Butyl ester (intermediate 87, (U2 g, 0.75 mmol) was reacted with trifluoroacetic acid to give 0.24 g of crude product as an oil. MS (ESP): 327 (MH+) vs. q 8 Η 22 Ν 402 Intermediate 91 Cis (±) 1·[2-(4·amino·3_fluorohexahydropyridyl) ethyl]methoxy p-quephetine-2(111)-one, trifluoroacetate in cis Formula (±){3·Fluoro group small [2-(7-methoxy-2-keto) - Illustrated - yl) ethyl] hexahydropyridine hydrazino} carbamic acid tert-butyl ester (intermediate 92, 222 mg, 0·53 mmol) in chloroform (1 mL), under The title compound was obtained in the next step without purification. The form of bis-trifluoroacetate is present. MS (ESP) ·· 321 (ΜΗ+) vs. q 6Η21FN4〇 intermediate 92 (IV) _H2_(7-methoxy-2, oxime q(tetra)yl)ethyl]hexahydropyridine- 4-Base} Amino Butyrate Tri-Butyl Ester Using a procedure similar to that described for the synthesis of Intermediate 20, 7-methoxy-4-carboline-2(1Η)-one (intermediate 15,181 mg,! Lean 7 Maosi Moer) and methanesulfonic acid cis 127286 -124- 200831517 Formula (±) 2-{4-[(T-Butoxycarbonyl)amino]-3-fluoropyrazine small base} B The ester (intermediate 21, 〜1 mmol) was purified by chromatography eluting EtOAc EtOAc EtOAc MS (ESP): 421 (MH+) vs. C21H29FN404^-NMR (CDCI3-d) 5: 1.44 (s, 9H); 1.86 (m? 2H); 2.40 (m? 2H); 2·80 (m, 2H) 3.15 (m, 1H); 3·41 (m, 1H); 3.70 (m, 1H); 3.94 (s, 3H); 4.42 (m5 2H); 4.70 (m5 2H); 6.93 (m? 2H); 7.77 (m5 1H) ; 8.11 (s? 1H). Intermediate 93 l-{2-[(3R,4S)-4-Amino-3-methoxyhexahydropyridinyl]ethyl η-曱Base 2-keto-1,2-dihydro, quinolin-7-carbonitrile, trifluoroacetate using a procedure similar to that described for the synthesis of intermediate 91 to give {(3r,4S)-1-[2 -(7-Cyano-4-methyl-2-keto porphyrin-l(2H).yl)ethyl]_3_methoxyhexahydropyridyl]-amino carboxylic acid tert-butyl ester (middle Reaction 94, 36 mg, 〇 81 mmol (m. The title compound can exist as a ditrifluoroacetate salt. MS (ESP): 341 (MH+)ff C19H24N4〇2 Intermediate 94 {(3R,4S)-l-[2-(7-Cyano-4-methyl-2-ketoporphyrin 4(2H)• Ethyl]ethyl]_3•methoxy hexahydropp ratio bite_4_yl}amino carboxylic acid third _ butyl in 4-methyl-2-keto-1,2-dihydroquinoline _7_ Nitrile (ν· N. (5) takes s b. KuMmi and BD Tilak, shirts are allowed to shoot y, now, win 773 (i977)) (10) mg, 2 millimoles) in anhydrous DMF (2 liters) In the solution, add 020 mg of sodium chloride, · 'in oil, 3 mmol. The mixture was stirred at room temperature for 1 hour. Next, methanesulfonic acid 2_{(3R,4s&gt;4_[(Third 127286-125-200831517 Butoxycarbonyl)amino]-3-methoxyhexahydropyridine small ethyl ester) was added under the armpit. a solution of 39, 〜2 mmol of the mixture in DMF. The reaction mixture was stirred at room temperature overnight, then diluted with water and extracted with dichloromethane three times. Concentration. Chromatography with hexane/ethyl acetate (3:2) afforded 360 mg of the title compound as a 3:1 mixture of the hydrazine-alkylation product MS (ESP): 441 (MH+) to C24H32N404 Intermediate 95 cis (±) 1-[2-(4-Amino-3-fluorohexahydrop-indenyl)ethyl]-4-methyl-2-indolyl-1,2-dihydroporphyrin -7-carbonitrile, trifluoroacetate using a procedure similar to that described for the synthesis of intermediate 91 to give cis(±){1-[2-(7-cyano-4-methyl-2-ketohydrazide) Porphyrin-i(2H)-yl)ethyl]-3-dylhexahydroindole-4-yl}amino-carbamic acid tert-butyl ester (intermediate %, 269 mg, 〇 毫 莫) and trifluoro The acetic acid is reacted to give the crude product (2 mg). φ MS (ESP): 329 (MH+)#C18H21FN4〇Intermediate 96 cis (±){1-丨2-(7-cyano-4-methyl-2.ketoquinolinyl)ethyl Each of the fluoro-piperidine 4 yl} carbamic acid _ _ _ _ 4-methyl keto group 1, 2 - dihydroquinoline carbonitrile (ν · N · G〇gte, Μ. Kulkami and BD · Tilak, Life Degree, Yunwen, 15Β, 769·773 (1977)) (35〇 mg, 1_9耄莫耳) Add sodium hydride (9) mg, 60% in a mixture of anhydrous dmf (2 liters) %, in oil, 2 · 2 millimoles). The mixture was stirred at room temperature for 1 λ ΙΊ followed by the addition of methanesulfonic acid cis (1) 2 points [(third 127286 • 126·200831517 -butoxycarbonyl)amino] 3-fluorohexahydropyridine small group } Ethyl ester (intermediate 21, ~) 9 millimolar) solution in DMF. The reaction mixture was allowed to stand overnight at room temperature, then diluted with water and extracted thrice with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. Chromatography with hexanes / ethyl acetate (1: EtOAc, 269 mg (33%) ield: s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s s , 4R)-4_Amino_3·Fluorohexahydrop-biti-1-yl)ethyl)·2__yl-7-2-dihydroporphyrin carbonitrile, trifluoroacetate is similar to synthetic intermediates The procedure described in 91 is such that (3S,4R)-l-(2-C7-cyano-2.keto-P-quinion-1(2H)-yl)ethyl)-3-ylhexahydropyrene Bite _4_ carbamic acid tert-butyl ester (intermediate 98, 0.5 g, 1.21 mmol) was reacted with trifluoroacetic acid. The crude product was obtained in quantitative yield and used directly in the next step. The title compound can exist as a bis-trifluoroacetate salt. MS (ESP): 315 (ΜΗ+) vs. C17H19FN40 Intermediate 98 (3S,4R)-1-(2-(7-Cyano- 2-ketoquinolinyl)ethyl)-fluorohexahydropyridine- 4-tert-aminocarbamic acid tert-butyl ester 2-keto-i,2-dihydroquinoline-7-indolecarbonitrile (intermediate 5, 〇_5 g, 2.94 mmol) and mineral oil A mixture of 60% by weight of sodium hydride (0.176 g, 4.41 mmol) in DMF (5 mL) was stirred at room temperature under nitrogen for 1 hour. The solution was cooled to 0 ° C and 2-((3S,4R)-4-(tris-butoxycarbonylamino)-3-fluorohexahydropyridinyl)ethyl methanesulfonate was added (intermediate) 99, 1 g, 2.94 mmol) solution in DMF (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with water 127286 - 127 - 200831517 and extracted twice with dichloromethane. The combined organic extracts were dehydrated and dried with sulfuric acid, filtered, and evaporated. The title compound was obtained as a yellow-brown solid 0.55* (45% p[a]D=+0.063 (c = 0.25 DMSO)··················· MS(ESP): 415(1^) for C22H27FN4〇3 Intermediate 99 A calcination acid 2-((3S,4R)-4_(tris-butoxycarbonylamino)fluorohexanitropyridine The ethyl ester title compound was prepared using a procedure similar to that described for the synthesis of intermediate 21 from intermediate 24 from (3S,4RH-(2-(T-butyl-dimethyl decyloxy)ethyl)- 3-fluorohexahydropyridin-4-amine (Intermediate 100) MS (ESP): 341 (MH+) vs. q 3 H2 5 FN2 05 S Intermediate 100 (3S,4R)-l-(2-third · Butyl dimethyl decyloxy) ethyl)-3-fluoro hexahydro butyl-4-amine to give (3S,4R)-:K2-(tris-butyldimethyl decyloxy Ethyl) fluorinated hexahydropyridin-4-ylaminocarbazide (intermediate 101, 8 g, 19.48 mmol) solution in ethanol (100 ml) in palladium on carbon (10%) Activated, 1.037 g), hydrogenated overnight at ambient pressure and room temperature. The reaction mixture was filtered through EtOAc EtOAc (EtOAc) MS (ESP): 277 (MH+) vs. C13H29FN2OSi^-NMR (CDCl3-d) δ: 0.04 (s, 6 Η); 0.87 (s? 9H); L75 (m5 4H); 2.35 (m5 2H); 2.56 (m5) 2H) ; 2.81 (m? 2H) ; 3.15 (m, 1H) ; 3.74 (m, 2H); 127286 -128- 200831517 4.57 (m, 1H). Intermediate 101 ceramic buckle although third-butyl dimethyl Fenyloxy)ethyl)_3fluorohexafluoropyridin-4-ylaminocarbamic acid hydrazine vinegar in (3 S,4R)-3-fluorohexahydropyridinyl guanidinoate oxime hydrochloride (102, 5·9 g, 20.43 mmol) and carbonated planer (33·3 g, 1〇217 mmol) in a stirred mixture of acetonitrile (300 ml) at room temperature (2_ Bromoethoxy) (t-butyl) dimethyl decane (21.92 ml, 1 〇 217 mmol). The reaction was stirred at 60 ° C overnight. The reaction mixture was filtered through a sintered funnel and concentrated. The title compound was obtained as a yellow oil (yield: EtOAc/EtOAc). MS (ESP): 411 (MH+)^c21H35FN203Si Intermediate 102 (3S,4R)-3-fluorohexahydropyridin-4-ylaminocarbamate, hydrochloride (3S,4R)-4-( Octyl oxy-amino)-3-fluoro hexahydro-P is a solution of hydrazine carboxylic acid tert-butyl ester (intermediate 103, 8 g, 22.7 mmol) in dichloromethane (200 mL) , (TC, add 4M hydrogen chloride in dioxane (11.35 ml, 45·4 mmol). Allow the reaction mixture to warm to room temperature and stir the instrument. Add another equivalent of dioxane. The title compound (5·9 g, 90%) was obtained from the title compound (5·9 g, 90%). 253 (ΜΗ+) to q 3呒7FN202 intermediate 103 (3S,4R)-4-(octyloxycarbonylamino)-3·fluoropyrohydropyridine small carboxylic acid tert-butyl ester 127286 -129- 200831517 (3S,4R)-4.Amino-fluoro-hexahydropyridine small carboxylic acid tert-butyl ester (made using the procedure described in PCT Publication No. WO 2006087543 and WO 2007071965) (5_1 g, 23.37 mmol) Ear) in dioxane (150 ml) and saturated In a mixture of sodium (50 ml), decyl chloroformate (5 〇〇 ml, 35.05 mmol) was added at 〇 ° C. After 15 minutes, the reaction mixture was diluted with ethyl acetate and saturated sodium chloride. The layers were separated and dried (MgSO4) eluted eluted elut elut elut elut elut克(97%) MS (ESP): 353 (MH+) to C 8 H2 5 FN2 04 XH-NMR (CDCl3-d) 5 : 1.44 (m5 9H) ; L73 (m5 2H) ; 2.80 (m5 2H) 3.60 (m,1H); 4.30 (m,2H); 4.65 (m,1H); 5.06 (m,1H); 5.09 (s,2H); 7·34 (m,5H)· Intermediate 104 l- {2-[(3S,4R)-4-Amino-3_methoxyhexahydropyridyl)-ethyl}methylenemethyl-1,2-dihydroquinone-7- Tris-carbamate uses a procedure similar to that described for the synthesis of intermediate 91 to give {(3j§,4r)_;^[2(7-cyano-4-methyl-2-ketoquinolin-1) 2H)·yl)ethylmethoxyhexahydroindole-4-yl}amino decanoic acid second-butyl vinegar (intermediate 1〇5,191 mg, 〇43 mmol) with trifluoroacetic acid Should, obtained in quantitative yield crude title compound which was used directly in the next step. The title compound can exist as a bis-trifluoroacetate salt. MS (ESP): 341 Intermediate 105 {(3S,4R)-l-[2-(7-Cyano-4·methyl-2-ketoquineline-i(2H)-yl)ethyl μ3_ Methoxy 127286 -130- 200831517 hexahydropyridinyl-based methic acid tert-butyl ester in 4-methyl-2-keto 4,2-dihydroquinoline-7-carbonitrile (v. N·G 〇gte, sB

Kulkami and BD·Tilak, Yan Yan Optics, 15B, 769-773 (1977)) (435 mg, 2.36 mmol) in a solution of anhydrous DMF (2 mL), sodium hydride (142 mg, 60% in oil, 3.54 millimoles). The mixture was stirred at room temperature for 1 hour. Then Yu Yu. Adding methanesulfonic acid 2-{(3S,4R)-4-[(second-butoxycarbonyl)amino]-3-methoxyhexahydrop to hydrazinyl}ethyl ester (intermediate 33, ~2·8 millimoles) solution in DMF. The reaction mixture was stirred at room temperature and then diluted with water and extracted three times with dichloromethane. The organic extract was dried over magnesium sulfate and concentrated. The title compound was obtained as a pale yellow solid (191 mg, 18%) EtOAc (ESP): 441 (ΜΗ+) vs. C24H32N404 Intermediate 106 l- After EtOAc/EtOAc/EtOAc. (2-((3R,4S)4-Amino-3.sodium hexahydroacridinyl)ethyl)n-ketonedihydroquinolin-7-indolenitriletrifluoroacetate The title compound is similar The procedure for the sequence of the racemic material (intermediate 19) is prepared from (3R,4S&gt;4-(;amino)_3_fluorohexahydropyridine small carboxylic acid tert-butyl ester (WO2007071965 and WO2006087543) Except for the following modifications in the final step: the crude trifluoroacetate salt of the title compound was dissolved in chloroform (100 liters) and washed once with saturated sodium bicarbonate (2 mL). The mixture was adjusted to EtOAc = EtOAc (EtOAc (EtOAc) Grayish white 127286 •131- 200831517 solid, 352 mg (81%). MS (ESP): 315 (MH+)^C17H19FN4〇Example 1 H2-{(m,4s )-4-[(2,3·^ Hydrogen μ,4]: Oxalo-ene ρ,3·φ-pyridin-7-ylmethyl) Amino] each hexahydropyridinium+yl)ethyl Keto group 4,2-dihydroporphyrin carbonitrile, dihydrochloride salt 1-{2-[(3R,4S)-4-amino-3-hydroxyhexahydropyridin-1-yl]ethyl}· 2-keto-1,2-dihydroporphyrin as a nitrile (intermediate i, 74 mg, 0.24 mmol) and 2,3-dihydro[1,4]dioxolene [2,3 A mixture of -φ pyridine carboxaldehyde (WO 2〇〇4/〇58144) (39 mg, 0·24 mmol) was heated on a just-activated 3A molecular sieve at 70 ° C for 3 hours. The reaction mixture was allowed to cool to room temperature and sodium triacetoxyborohydride (15 mg, 0.75 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes, then filtered through a 〇·45 μm film and concentrated to dryness under reduced pressure. Chromatography on dichloromethane/methanol (8:1 to 4:1). The fractions containing the product were pooled and concentrated to dryness. The residue was dissolved in dichloromethane/diethyl ether (1:2, 10 mL), and EtOAc (2 EtOAc, EtOAc) The mixture was concentrated to dryness under reduced pressure to dryness &lt;RTI ID=0.0&gt;&&&&&&&&&&&&&&&&&gt;21〇. Hey. MS (ESP): 462 (MH+) vs. C2 5 H27N5 〇4^H-NMR (DMSO-d6) 5 : 2.18 (m, 2H); 3.15 (m5 1H); 3.25-3.36 (m5 4H) ; 3.69 (m , 2H) ; 4.10-4.49 (m,7H) ; 4.61 (dd,2H) ; 6·64 (bi*s,1H); 6.83 (d, 1H); 7.30 (s, 1H) ; 7.72 (d5 1H) ; 7.97 (d5 1H) ; 8.08 (d3 1H); 8.22 (m, 2H) ; 9.45 (brs, 2H) ; 10.00 (brs, 1H)· 127286 -132· 200831517 Example 2 H2-((3R,4S)- 3-hydroxy-4-{[(3-keto-3,4-dihydrogen such as _pyridinopyrene 3,2 ton 14] 噚 -6-6-yl)methyl]amino}}hexahydropyridine small group) Ethyl]_2-ketodihydroquinoline-7-carbonitrile, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give 3-keto-3,4-dihydro-2H-pyridinium [ 3,2-b][l,4] morphine-6-carboxaldehyde (w〇2〇〇4/〇58144) was reacted with Intermediate 1 to provide the title composition. 4 NMR (D20) 5 : (D20) 2.28 (m, 2H); 3.15 (ddd, 1H); 3.26 (m, 1H); 3.40- 3.72 (m, 4H); 3·91 (m, 1H); ·28 (s,2H) ; 4·52 (m,1H) ; 4.61 (m, 1H) ; 4.71 (s,2H) ; 4.80 (m,1H) ; 6.65 (d,1H) ; 7.08 (d,1H 7.35 (d, 1H); 7.66 (d, 1H); 7·87 (d, 1H); 7.96 (s, 1H); 8.02 (d, 1H)· ES (MH)+ : 475 Example 3 1- [2_((3R,4S)_3-radio-4-{[(3-keto-3,4-dihydro-2H_p ratio bite|3,2-b][l,4]^ 耕-6 -yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile, bis-hydrochloride using similar synthetic examples The procedure described for the 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-carboxaldehyde (WO 2004/058144) and intermediate Reagent 1 was reacted to provide the title composition. NMR (D20) δ : (D2 0) 2.31 (m, 2H); 3.20 (ddd5 1H); 3.31 (m? 1H); 3.40- 3.80 (m? 4H); 3.55 (s? 2H); 3.95 (m? 1H) ; 4.34 (s5 2H) ; 4.55-4.70 (m, 2H) ; 4.82 (m, 1H) ; 6.84 (d, 1H); 7.11 (d, 1H); 7.66 (d, 1H); 7.80 (d, 1H) ; 7·87 (d,1H) ; 7.96 (s5 1H) ; 8·03 (d,1H)· ES (MH)+ : 491 127286 -133- 200831517 Example 4 1-(2-{(38,卿4-[1] argon [1,4] dioxo-alkenes and [2 3_small than winter ^ amine] hydroxy hexahydropyridine small oxime ethyl) · 2_ 鲷基山 2_ dihydroanthracene Porphyrin_7 carbonitrile, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give 2,3-dihydro[indenyl(4)dioxoamphet[2,3-c]pyridine-7-carboxyindole The aldehyde is reacted with the intermediate 2 to provide the title compound. NMR (DMSO-d6) δ: 2.17 (m? 2H); 3.14 (m5 1H); 3.25-3.38 (m? 4H); 3.69 (m, 2H); -4.49 (m, 7H); "61 (dd, 2H); 6 62 (brs, m); 6.83 (d, 1H); 7.25 (s, 1H); 7·72 (d, 1H); 7.97 (d ,ih) ; 8.06 (d,1H); 8.20 (m,2H) ; 9.39 (brs,2H) ; 9.93 (brs,1H) ES (MH)+ : 462 Example 5 l-[2-((3S,4R )-3- Base_4-{[(3·keto-3,4-dihydropyridinium[3,2 mailing-6-yl)methyl]amino}hexahydropyridine small) ethyl b-2-one Dihydroquinoline-7-carbonitrile, dihydrochloride salt was used to make 3-keto-3,4-dihydro-2H-p ratio bite [3,2- using a procedure similar to that described in Synthesis Example 1. b][l,4]Recombinant -6-decanoic acid was reacted with Intermediate 2 to provide the title composition. XH NMR (DMSO-d6) δ: 2.20 (m? 2Η); 3.19 (m? IH); , 25-3.48 (m? 4H); 3.71 (m, 2H); 4.19 (m, 2H); 4.55-4.65 (m, 3H); 4.69 (s, 2H); 6.63 (brs, IH); (d, IH); 7.26 (d, IH); 7·44 (d, IH); 7.73 (d, IH); 7.97 (d, IH); 8.07 (d, IH); 8.24 (brs5 IH) 9.28 (m5 IH); 9.58 (m5 IH); 10.07 (m, IH); 11.40 (m, IH). 127286 -134- 200831517 ES (MH)+ : 475 Example 6 l-[2-((3S, 4-linked-radio--4·{[(3-keto-3,4chydro-piperidine[3 2_called Guan Geng-6·yl)methyl]amino}hexahydropyridine+yl)ethyl] _2-keto-l-dihydroquinoline-7-carbonitrile, dihydrochloride salt was similarly used in the procedure described in Synthesis Example 1 to give 3-keto-3,4-dihydro-2H-pyrido[3 ,2-b][l,4]pyrimidine Each carbaldehyde and Intermediate 2 response, providing the title composition. NMR (DMSO-d6) δ : 2.21 (m5 2H) ; 3.20 (m? 1H) ; 3.30-3.76 (m? 6H) ; 3.60 (s, 2H) ; 4.24 (m, 2H) ; 4.57-4.67 (m5 3H 6.62 (d,1H); 6.83 (d,1H); 7.27 (d,1H); 7.73 (d,1H); 7.89 (d,1H); 7.98 (d,1H); 8_07 (d,1H) ; 8.24 (m,1H); 9·34 (m,1H); 9.61 (m,1H); 10.04 (m,1H); 11.08 (s,1H). ES (MH)+ : 491 Example 7 φ 1_( 2-{(3民48)-4-[(2,3-Dihydro[1,4]dioxolynene[2,3_decapyridin-7-ylfluorenyl)amino]-3 Hydroxyhexahydropyridine-l-yl}ethyl)-7-methoxyquinoxaline-2(1H)-one, dihydrochloride salt using a procedure similar to that described in Synthesis Example 1, 2,3- Dihydro[1,4]dioxantim[2,3-c]pyridine-7-carboxaldehyde was reacted with Intermediate 11 to provide the title composition. XH NMR (ρ20) δ : 2.28 (m, 2Η); 3.20 (ddd? 1H); 3.31 (m, 1H); 3.45-3.76 (m? 4H); 3.92 (s? 3H) ; 3.99 (m? 1H) 4.29-4.62 (m? 8H); 4.83 (m, 1H); 6.93 (m, 1H); 7·12 (m, 1H); 7·22 (d, 1H); 7.81 (dd, 1H); 127286 -135- 200831517 8.06 (d,1H) ; 8.19 (d,1H). ES (MH)+ : 468 Example 8 6-[({(3R,4S)_3·经基-l-[2-(7_ Methoxy·2·ketoquinoxaline-1(2H^yl)ethyl] hexahydroindole-4-yl}amino)methyl b 211-pyrido[3,2-13][1, 4] 噚耕-3(411)-ketone, dihydrochloride using a procedure similar to that described in Synthesis Example 1, to give 3-keto-3,4-dihydro 2H·acridine [3,2-b [[,4] No.6-carboxaldehyde is reacted with the intermediate u to provide the target composition. ^ NMR (DMSO-d6) δ: 2.19 (m? 2H); 3.19 (m? 1H); 3.30 -3.48 (m? 4H); 3.62-3.83 (m, 2H): 3.96 (s, 3H); 4.18 (m, 2H); 4.54-4.76 (m, 3H); 4.69 (s, 2H); 6.54 (m ,1H) ; 7.04 (dd,1H) ; 7.21 (d,1H) ; 7.26 (d,1H); 7·44 (d,1H) ; 7_79 (d,1H) ; 8.09 (s,1H) ; 9.28 ( m,1H) ; 9·61 (m,1H); 10.26 (m,1H) ; 11.41 (s 1H). ES (MH)+ : 481 $ Example 9 6-[({(3R,4S)_3_ 经基-1·[2·(7·methoxy keto porphyrin _i(2H)_ Ethyl)ethyl hexahydropyridin-4-yl}amino)methyl]_211_pyridine hydrazine 3,2-1&gt;][1,4]pyrimyl-_3(411)-one, use of dihydrochloride Similar to the procedure described in Synthesis Example 1, 3-keto- 3,4-dihydro-2H-pyrido[3,2-b][l,4]thratic-6-carboxaldehyde and intermediate u Reaction, providing the title composition. XH NMR (DMSO-d6) δ: 2.19 (m5 2Η); 3.17 (m5 1H); 3.25-3.70 (m? 6H); 3·59 (s, 2H); 3.96 (s, 3H) ; 4.23 (m, 2H) ; 4.55-4.67 (m, 3H) ; 6.53 127286 -136- 200831517 (d,1H) ; 7.04 (dd,1H) ; 7.20 (d,1HV 7 n) ^ /-27 (d5 1H) ; 7.79 (d5 1H) ; 7.90 (d, 1H) ; 8.09 (s, 1H) ; 9.30 (m lm · 0 heart / , , iH ) , 9 · 60 (m, 1H) ; 10.21 (m , 1H); 11·08 (s, 1H)· ES (MH)+ : 497 Example 10 Noisy (4) Duo-like dihydro (10) dioxerem and then amine-based 3--3-yl hexamidine Small base} B &amp; K_methoxy 嗔 _ __• 嗣, bis-hydrochloride using a procedure similar to that described for the synthesis of m, 2,3_ dihydro[Μ]diox Won dilute and [2,3_e] f between M • continued fiscal acid 12 was reacted to provide the title composition. lH NMR (DMS〇'd6) &quot; : 2·18 2H) ; 3.16 (m5 1H) ; 3.26-3.40 (m, 4H), 3·65_3·74 (m, 2H), 3.96 (s, 3H); 4·26·4·43 (m,7H); 4·62 (dd,2H); 6.55 (m,1H) ' 7.04 (dd,1H), 7.19 (d,1H); 7.36 (s,1H) ; 7.79 (d,1H); 8.08 (s,1H), 8.26 (s,1H),9.51 (m,2H); 10.18 (m,1H)· ES (MH)+ : 468 Example 11 6-[( {(38,41〇 Each ketone-1-[2_(7-methoxyl-ketoquinoquinoxaline 1(211)))ethyl]hexahydropyridin-4-yl}amino)methyl]- 211-pyrido[3,2-7][1,4]indole-3(411)-one, dihydrochloride salt was used in a procedure similar to that described in Synthesis Example 1, to give keto-3,4-dihydrogen -2H·bite and [3,2-b][l,4]$ till -6-carboxaldehyde was reacted with intermediate 12 to provide the title composition. XH NMR (D20) δ: 2.28 (m5 2 Η); (ddd5 1H) ; 3.27 (m5 1H); 127286 -137- 200831517 3.51-3.75 (m? 4H) ; 3.91 (s5 3H) ; 3.99 (m5 1H) ; 4.28 (m? 2H) ; 4.50-4.62 (m, 2H); 4.71 (s5 2H); 4.80 (m, 1H); 6·90 (d, 1H); 7.08 (d, 1H); 7·11 (dd, 1H); 7·34 (d, 1H); 7.79 (d, 1H); 8.05 (s, 1H). ES (MH)+: 481 Example 12 1-(2-{(38,4)-4-[(2,3-Dihydro[1,4]dioxo-area[2,3-indole]pyridine -7-ylmethyl)amino]-3-formyl hexafluorene-l-yl}ethyl)-2-indenyl-1,2.diazop-quineline-7-carbonitrile, monoacetic acid Salts and Examples 13 l-(2-{(3R,4S)-4-[(2,3-Dihydro[1,4]dioxolynene[2,3-c]acridin-7-yl) Methyl)amino]-3-fluorohexafluoropterin small base}ethyl)_2-keto 4,2-dihydrop-quinone_7-carbonitrile, monoacetate

Cis (±) 1-[2-(4-Amino-3-fluorohexahydropyridine+yl)ethyl]_2-keto-U-dihydroporphyrin-7·carbonitrile (Intermediate 19 , 〇95 mmol, suspended in chloroform / methanol (1:1, 20 mL), and free alkalized by dropwise addition of N,N-diisopropylethylamine until all the material was dissolved. Next, using a procedure similar to that described in Synthesis Example 1, it was accepted to accept 2,3-dihydro[M]dioxanthine and [2,3-indole ratio -7-staple (10) gram, 〇 Reductive amination of 95 mmoles with triethyloxyborohydride (_mg, 2.8 mmol). The residue obtained after filtration was dissolved in methylene chloride and saturated sodium hydrogencarbonate. The aqueous phase tpH was adjusted to a positive value by dechlorination of sodium oxide solution. The aqueous phase was reversely extracted with methylene chloride. The combined organic phases were dried over sodium sulfate and concentrated. The product was obtained by reverse phase chromatography of water / acetonitrile / acetic acid to afford a yellow brown bead 127286 -138 - 200831517, 276 mg (62%). ^-NMR (CDCl3-d) δ: 1.86 (m, 2H); 2.34 (m5 3H); 2.71 (m5 2H); 2.82 (m, 1H); 3.03 (m? 1H); 3.30 (m5 1H); (m5 2H) ; 4.30 (m5 4H); 4·42 (m, 2H) ; 4·90 (m, 1H); 6.80 (d, 1H); 6.90 (s5 1H) ; 7·45 (d, 1H) 7.65 (m,2H) ; 7.78 (s,1H) ; 8.09 (s,1H). MS (ESP): 464 (MH+) to C2 5 H2 6 FN5 03 The racemic mixture is attached to Chiralpak _AD, 250 x 20 Millimeter, 10 μ column (50% methanol, 50% ethanol, 〇·1% diethylamine) was separated. Example 12 was first dissolved in 10, [a] D = +14.3 (c = 0.3, methanol) (89 mg), followed by Example 13, [a] D = -11.6 (c = 〇·328, methanol) (80) Mg). Example 14 1-(2-{(38,411)-4-[(2,3-Dihydro[1,4]dioxolynene oxime 2,3^]pyridin-7-ylmethyl)amino] -3-methoxyhexahydropyridine-i-yl}ethyl)-7-methoxyquinoxaline-2(1Η)_one, bis-hydrochloride salt l_{2_[(3S,4R)-4 -amino-3-methoxyhexahydropurine -1 -yl]ethyl oxime _ ke p Kui Lin -2 (1H)-ketone (intermediate 31, 160 mg crude, 〇 · 48 mmol Ear) with 2,3-dihydro[I,4]dioxantemene[2,3-c]pyridine; carboxaldehyde (8 mg, 〇·48 mmol) in anhydrous methanol/chloroform (i : 〗 〖, 1 〇 ml), under nitrogen, on a 3A molecular sieve, heated at 7 (rc) for one hour. The reaction was cooled to room temperature and sodium triethyl sulfonate hydride (31 〇) was added. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> 15% methanol / chloroform was extracted twice more. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. On the silica gel, 127286 • 139 - 200831517 Chromatography of 0.25% ammonium hydroxide in 2-5% methanol in di-methane to afford 160 mg (yield: 70%) of the title compound as free oil as an oil. Treated with diethyl ether (1:1,5 mL) and treated with 2 〇M HCl (~2 eq.) in ether. The precipitate formed was collected by filtration, reconstituted in water, and lyophilized to give 148 mg of title combination. XH NMR φ2〇) δ : 2.04-2.33 (m5 2H); 3.05-3.25 (m? 2H); 3.44 (s, 3H); 3,50-3,71 (m5 3H) ; 3- 87 (s5 3H) ; 4.04 (s5 1H) ; 4.21 (d5 3H) ; 4.26-4.32 (m,3H) ; 4.33-4.40 (m,2H) ; 4.45-4.58 (m,1H) ; 4.74-4.87 (m ,1H); 6·82-6·92 (m,1H) ; 7 02-7.12 (m,2H) ; 7.75 (d,1H) ; 8.01 (s,1H) ; 8.09 (s,lH)· MS ( ESP): 482 (MH+) to C2 5 H3 i N5 05 Example 15 6-[({(3S,4R)-3-methoxy-l-[2_(7-methoxy-2-ketoquinazoquinone) Oleone_1(2H)-yl)ethyl]hexahydropyridine_4_yl}amino)methyl]-2H-pyrido[3,2_b][l,4]噚耕·3(4Η)_ ketone According to Example 14 (except for the preparation of the hydrochloride salt), l-{2-[(3S,4R)-4-amino-3-oxo Hexahydro-p-buty-1 -yl]ethyl}-7-methoxy ρ quinoxaline-2(1H)-one (intermediate 31, 160 mg crude, 0.48 mmol), 3-keto -3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carboxaldehyde (WO 2004/ 058144) (85 mg, 0·48 mmol) and three Reaction with sodium acetoxyborohydride (310 mg, 1.44 mmol) afforded 139 mg (58%) of the title compound. ^NMRCDMSO-de) δ : 1364.53 (m? 1H); 1.59-1.77 (m, 1H); 2.24-2.37 (m, 1H); 2.40-2.46 (m, 1H); 2.60 (t, 2H); 2.65- 2.84 (m, 2H) ; 3.14-3.21 (m, 3H) ; 3.30-3.34 (m, 2H) ; 3·67 (q, 2H) ; 3·92 (s, 3H) ; 4·22-4·45 (m, 127286 -140- 200831517 2H); 4.61 (s, 2H); 6.92-7.10 (m, 3H); 7.30 (d, 1H); 7.75 (d, 1H); 8.04 (s, 1H); 11.15- 11.27 (m? 1H). MS (ESP): 495 (MH+) vs. C2 5 H3 〇N6 05 Example 16 l-(2-{(3R,4S)_4-[(2,3-Dihydro[1,4 Dioxanedecene and P,3-c]pyridinylmethyl)amino]-3-decyloxyhexahydropyridine-l-yl}ethyl)-7-methoxyporphyrin·2 (1Η) ketone, bis-hydrochloride salt as described in Example 14, l-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl] -7-7-methoxyquinoxaline-2(1Η)-one (intermediate 37, 37 mg, 0·11 mmol), 2,3-dihydro[1,4]dioxene terpene And [2,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (18 mg, 0·11 mmol) and sodium triethoxysulfonate (70 mg, 0.33 mmol) , obtained 29 mg of the title composition, which is colorless and solid . ^ NMR (〇2〇) δ : 2.17-2.30 (m? 2H); 3.12-3.24 (m5 2H); 3.49 (s, 3H); 3·56-3·75 (m, 3H) ; 3.92 (s, 3H) ; 4·09 (s, 1H) ; 4.25 (d5 2H) ; 4.34 (dd, 2H); 4.41 (dd? 2H); 4.52-4.70 (m5 2H); 4.79-4.93 (m5 2H); 6.93 ( D5 1H); 7.08-7.16 (m? 2H) ; 7.82 (d5 1H) ; 8.07 (s, 1H) ; 8.13 (s, 1H). MS (ESP) ·· 482 (MH+) vs C2 5 H3 i N5 05 Example 17 6_[({(3R,4S)-3-methoxy-1·[2·(7-methoxy-2-keto-p-p-quinone- _i(2H)-yl)ethyl) Hydropyridine-4-yl}amino)methyl]_2Η-acridino[3,2-b][1,4]indole-3(4H)-one as described in Example 14 (but its hydrochloride) Except for the preparation), l-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridinyl]ethyl b 7-methoxyporphyrin-2 (1H) -ketone (intermediate 37, 37 mg crude, ail millimolar), 3_127286-141 - 200831517 keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]唠耕-6-carboxaldehyde (WO 2004/ 058144) (20 mg, 〇·11 mmol) and sodium triethoxy borohydride (7 〇 mg, 0.33 mmol) to obtain 34 mg (63 %) title composition^NMRCDMSO-^) (5: 1.39-1.53 (m? 1H); 1.59-1.77 (m5 1H); 2.29 (d, 1Η); 2.38-2.47 (m, 1Η); 2.60 (t, 2H); 2.65- 2.85 (m,3H) ; 3.13-3.22 (m5 3H) ; 3.30-3.34 (m5 2H) ; 3.58-3.78 (m5 2H) ; 3.92 (s5 3H) ; 4.24-4.44 (m5 2H) ; 4.61 (s? 2H ;;93.30 (d5 1H) 〇N6 05 Example 18 6-[({(3R,4S)-3·曱oxy·1-[2·(7-methoxy-2-ketoquinoxalin-1(2H)-yl)) Hexylpyridylsylamino}amino)methyl]-2H-pyrido[3,2-b][l,4]^_-3(4H)-one, bis-hydrochloride The procedure described in Example 14 gave 1-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl}_7-methoxyquinoxaline- 2(1H)-ketone (intermediate 37, 70 mg crude, 〇·21 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l, 4] Pyridine-6·carboxyformaldehyde (WO 2004/058144) (40 mg, 0.21 mmol) and sodium triethoxysulfonate (130 mg, 0.63 mmol) to obtain 73 mg of the title combination , XH NMR φ20) δ : 2.13-2.28 (m5 2H); 3.03-3.21 (m5 2H); 3.41-3.46 (m, 3H); 3.50 (s5 2H); 3.52-3.72 (m, 4H); 3.86 (s5 3H); 4.08 (s5 1H); 4.19-4.35 (m, 3H); 4.44-4.59 (m, 1H); 4.74-4.88 (m, 1H); 6.86 (d, 1H); 7.01 -7.10 (m, 2H); 7.70-7.79 (m, 2H); 8.01 (s, 1H).

MS (ESP): 511 (MH+) vs. C25H30N6O4S 127286 - 142 - 200831517 Example 19 l-(2-{(3S,4R)-4_[(2,3-Dihydro[1,4]dioxene) [2,3-c]pyridin-7-ylmethyl) lie-based]-3-methoxy hexaploid-i-yl}ethyl)_2_mercapto-i,2_diaza T? p-Linonitrile, bis-hydrochloride using a procedure similar to that described in Synthesis Example 14 to give 1-{2-[(3S,4R)-4-amino-3-yloxyhexahydrop-pyrene 1_yl]ethyl}_2-keto-1,2-dihydro-p-quinolin-7-carbonitrile (intermediate 41,93 mg, 0.29 mmol), 2,3-dihydro[1,4 Dioxordecene and P,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (47 mg, 0.29 mmol) and sodium triethoxysulfonate (180 mg, 0.86 mmol) Reaction of the ear gave 95 mg of the title compound as a colourless solid. NMR (D20) δ : 2.14-2.33 (m5 2H); 3.12-3.27 (m, 2H); 3.42-3.49 (m? 3H); 3.54-3.62 (m, 2H); 3.63-3.76 (m, 2H); 4.09 (s,1H) ; 4.25 (d,1H); 4.32-4.39 (m, 4H) ; 4.43-4.50 (m5 2H) ; 4.50-4.65 (m5 1H) ; 4.83 (d? 1H); 6.80 (d, 1H) ; 7.29 (s,1H) ; 7.61 (dd,1H) ; 7.82 (d,1H) ; 7.91 (s,1H); 7.97 (d, 1H) ; 8.22 (s5 1H). MS (ESP) : 476 (MH+) vs. C26H29N5 04 Example 20 l-[2-((3S,4R)-3-Methoxy·4-{[(3·keto-3,4-dihydro-2H-pyrido[3, 2-b]丨1,4J 噚耕-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]·2·keto-1,2-dihydrotetralin-7- The nitrile was used in a procedure similar to that described in the synthesis of Example 14 (except for the preparation of the hydrochloride salt) to give l-{2-[(3S,4R)-4.amino-indoleoxyhexahydropyridinyl]ethyl ketone Base-1,2-dihydroquinolin-7-carbonitrile (intermediate 41,93 mg, 0.29 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2- b][l,4]噚耕-6-carboxaldehyde 127286 -143- 200831517 2004/058144) (51 mg, 0.29 mmol) and sodium triethoxysulfonate (180 mg, 0.86 mmol) reaction, 80 mg (57%) of the title compound was obtained as a white solid. 4 NMR (DMSO-d6) 6 : 1.36-1.51 (m, 1H); L59-1.75 (m, 1H); 2.23-2.37 (m? 1Η); 2.56 (t? 2H); 2.60-2.80 (m? 3H) 3.17 (s? 3H); 3.26-3.32 (m? 2H); 3.68 (q, 2H); 4·25-4·45 (m, 2H); 4.61 (s, 2H); 6.78 (d, 1H) 6.99 (d,1H) ; 7·29 (d,1H) ; 7·65 (dd,1H) ; 7,91 (d5 1H) ; 8.00 (d5 1H) ; 8.10 (s,1H) ; 11.20 ( s,1H). MS (ESP): 489 (MH+) to C26H28N604 Example 21 1-[2_((3S,4R)_3-methoxy-4-{[(3-keto-3,4·dihydro) _2H-p ratio bite [3,2-b][l,4] 喽耕-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-2-keto- 1 , 2_dihydroquinoline-7-carbonitrile, bis-hydrochloride using a procedure similar to that described in Synthesis Example 14, l-{2-[(3S,4R)-4-amino-3-methyl Oxy hexahydropyridine small group] ethyl}-2-keto-1,2-dihydroquinolin-7·carbonitrile (intermediate 41,93 mg, 0.29 mmol), 3-keto-3 ,4-dihydro-2H-pyrido[3,2_b][l,4]pyrazine-6-carboxycarboxaldehyde (WO 2004/058144) (55 mg, 0.29 mmol) and triethoxyhydroxyborohydride Sodium (180 mg, 0.86 mmol) was reacted to obtain a 68 mg heading combination As a yellow solid. NMR (D20) (5: 2.14-2.27 (m5 2H); 3.00-3.15 (m? 2H); 3.44 (s5 3H); 3.47-3.53 (m? 4H); 3.57-3.70 (m5 2H); 4.05 (s5 1H) ; 4.12-4.21 (m3 1H); 4·27 (d, 2H); 4.47-4.64 (m, 1H); 4.72-4.86 (m, 1H); 6.80 (d, 1H) ; 7·05 (d , 1H); 7·61 (dd, 1H); 7.75 (d, 1H); 7·82 (d, 1H); 7·91 (s, 1H); 7.97 (d, 1H). 127286 -144- 200831517

MS (ESP): 505 (MH+:^C26H28N6〇3S Example 22 1-(2-{(311,48)-4-[(2,3-Dihydro[1,4] Dioxererene and [2] , 3 is better than biting 7-ylmethyl) Amino]·3-methoxy hexazone bite small base} ethyl)_2-keto-mouth-dihydro-quinoline_7_carbonitrile, double- The hydrochloride salt was similar to that described in Synthesis Example 14 to give i-{2-[(3R,4S)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl b-2- g with the same base _i, 2_ dihydroquinolin-7-methyl nitrile (intermediate 43, 80 mg, 0.25 mmol), 2 &gt; dihydro[1,4]dioxane hydrazin [2, 3-c] mouth ratio bite-7-weilic acid (WO 2004/058144) (41 mg, 〇·25 mmol) and triethyl decyloxydisodium (160 mg, 〇·74 mmol) Obtained 69 mg of the title compound as an off-white solid. NMR (D20) δ: 2.14-2.30 (m5 2H); 3.12-3.25 (m, 2H); 3.41-3.48 (m5 3H); 3.54-3.62 (m? 2H); 3.63-3.74 (m? 2H); 4.08 (s5 1H); 4.26 (s5 1H); 4.30-4.38 (m, 4H); 4.40-4.47 (m? 2H); 4.53-4.66 (m5 1H); 4.75-4.90 (m5 1H) ; 6.80 (d,1H) ; 7.24 (s,1H) ; 7.62 (dd,1H) ; 7.83 (d,1H) ; 7.92 (s, 1H) ; 7.98 (d, 1H) ; 8·19 (s, 1H)·

W MS (ESP): 476 (MH+) vs. C2 6 H2 9 N5 04 Example 23 l-[2-((3R,4S)-3·曱oxy·4_{[(3_keto·3,4· Dihydro-: 2H-pyridine and [3,2-b][l,4] 3 p-well-6-yl)methyl]amino}hexazone quinone-1-yl)ethyl]-2· Mercapto-1,2-diazepine-7-methasin was used similarly to the procedure described in Synthesis Example 14 except for the preparation of the hydrochloride salt, such that l-{2-[(3R,4S)-4 -amino-3-indolyl hexahydropyridine small group] ethyl}_2_ keto·1,2-dihydroporphyrin-7-indoleonitrile (intermediate 43, 80 mg, 0.25 mmol), 127286 -145- 200831517 3-keto-3,4-dihydro-2H-p is more than [3,2-b][l,4]p p well-6-carboxymethyl (w〇2004/058144 (45 mg, 0.25 mmol) and sodium triethoxysulfonyl borohydride (160 mg, 0. 74 mmol) gave 62 mg (55% yield) of !H NMR (DMSO-d6) (5: 1.36-1.51 (m5 1H); 1.6M.74 (m? 1H); 2.23-2.36 (m9 1H); 2.58 (t5 2H); 2.61-2.85 (m5 3H) 3.13-3.21 (m? 3H); 3.26-3.32 (m5 2H); 3,58-3.78 (m5 2H); 4.30-4.45 (m5 2H); 4.61 (s? 2H); 6.78 (d? 1H); 7 00 (d,1H) ; 7.30 (d,1H) ; 7.65 (dd,1H) ; 7.91 (d,1H) ; 8.00 (d, 1H) ; 8·07·8·13 (m,1H) ; 1L21 (s,1H). MS (ESP): 489 (MH+) vs. C2 6 H2 8 N6 04 Example 24 H2-((3R,4S)-3·曱oxy-4-{[(3-keto-3) ,4-dihydro·2Η·pyrido[3,2-b]丨1,4] 喽耕-6-yl) fluorenyl]amino}hexahydropyridine small) ethyl]·2-keto- 1,2-dihydroquinoline-7-indoleonitrile, bis-hydrochloride as described in Example 14, l-{2-[(3R,4S)-4-amino-3-methoxy-6 Hydropyridine-1_yl]ethyl}-2-keto-1,2-dihydroquinolin-7·carbonitrile (intermediate 43, 80 mg, 0.25 mmol), 3-keto-3, 4·Dihydro 2Η·pyrido[3,2-b][l,4]pyrazine-6-carboxaldehyde (WO 2004/058144) (48 mg, 0·25 mmol) and triethylene oxide Sodium borohydride (160 mg, 0.74 mmol) was reacted to obtain 56 mg The composition is an off-white solid. NMR (D20) δ: 2.10-2.24 (m, 2H); 2.89-3.13 (m? 2H); 3.38-3.46 (m, 5H); 3.48-3.52 (m, 2H); 3.53-3.68 (m, 2H); 4·04 (s5 1H); 4.11 (d, 1H); 4.27 (d? 2H); 4.49-4.62 (m5 1H); 4.73-4.84 (m5 1H); 6.79 (d 1H) ; 7.05 (d,1H) ; 7.61 (dd,1H) ; 7.75 (d,1H) ; 7.82 (d,1H) ; 7_91 (s,1H) ; 7.97 127286 -146· 200831517 (d,1H) MS (ESP): 505 (MH+) vs. C26H28N6〇3S Example 25 l_(2-{(3S,4S)-4-[(2,3·二氲[1,4] Dioxetene] [2 , 3_φ ratio bit i methyl) Amino]-3-methoxyhexahydropyridine-1-yl}ethyl)-7-methoxyquinoxaline-2 (1H^one, bis-hydrochloride Using a procedure similar to that described in Synthesis Example 14, i_{2_[(3s,4S)-4-amino-3-indolylhexahydrop-pyridin-1-yl]ethyl b-7-methoxy p奎喏淋·2(ιη)·ketone _ (intermediate 48, 70 mg, 〇·21 mmol), 2,3-dihydro[Μ]dioxolene [2,3-c] p is more than 唆-7-Wei ( (WO 2004/058144) (35 mg, 0.21 mmol) and sodium triethoxy borohydride (130 mg, 〇 · 63 mmol) 61 mg of the title composition is obtained, as yellow solid. ^NMR^O) δ : 1.83-2.02 (m5 1H); 2.37-2.50 (m5 1H); 2.90-3.06 (m? 1H); 3.08-3.23 (m5 1H); 3.33-3.48 (m5 4H) ; 3.55- 3.70 (m5 3H) ; 3.73-3.81 (m,1H) ; 3.87 (s,3H) ; 4.16-4.26 (m,1H) ; 4.32-4.39 (m,4H) ; 4.43-4.51 馨 (m,2H); 4.60-4.80 (m, 2H); 6.87 (d, 1H); 7·07 (dd, 1H); 7·27 (s, 1H); 7.76 (d, 1H); 8·01 (s, 1H); 8.20 (s,1H)· MS (ESP): 482 (MH+) vs. C25H3 &quot;505 Example 26 6-[({(3S,4S)-3_methoxy_1-[2_(7·methoxy) -2_ketoquinoxaline-1(2H)-yl)ethyl]hexahydropyridine ice-based}amino)methyl]_2H_pyrido[3,2-b][1,4] 3(4H)-one as described in Example 14 (except for the preparation of the hydrochloride salt), l-{2-[(3S,4S)-4-amino group methoxy hexahydropyridine small group] ethyl }-7-methoxyquinoxaline-2(1H)-one (intermediate 48, 70 mg, 0·21 mmol), 3-keto-3,4-127286-147-200831517 Dihydro- 2H-pyrido-p,2-b][l,4]indole-6-carboxaldehyde (WO 2(10)4/058144) (37 mg, 0.21 mmol) and sodium triethoxysulfonate (13 mg) , 0.63 millimoles) reaction . The crude product was purified by flash chromatography eluting elut elut elut elut elut elut elut elut elut elut ). ^NMRCDMSO-^) δ : 1.04-1.23 (m? 1H); 1.76 (t, 1H); L81-L9I (m5 1H); 1.93-2.07 (m3 1H); 2,18-242 (m5 1H); (t5 2H); 2.79-2.99 (m? 2H); 3.20-3.30 (m, 4H); 3.54-3.75 (m, 2H); 3.91 (s? 3H); 4.25-4.43 (m? 2H); 59 (s, 2H); 6.90-7.06 (m, 3H); 7.27 (d, 1H); 7·74 (d, 1H); 8.02-8.06 (m, 1H); 1L18 (s, 1H). MS ( ESP): 495 (MH+) vs. C2 5 H3 0N6 05 Example 27 l-(2_{(3R,4R)-4-[(2,3-Dihydro[1,4] Dioxetidene[2, 3-c]pyridin-7-ylmethyl)amino]-3·methoxyhexahydropyridine small group}ethyl)-7-methoxyindoline-2(111)-one, double-salt Acid salt as described in Example 14 to give 1-{2-[(3R,4R)-4-amino-3-methoxyhexahydropyridin-1-yl]ethyl}-7-methoxyanthracene Porphyrin-2(1Η)-one (intermediate 56, 75 mg, 〇·23 mmol), 2,3-dihydro[1,4]dioxolynene[2,3-c]pyridine -7. Carboxaldehyde (WO 2004/058144) (37 mg, 0.23 mmol) and sodium triethoxysulfonium borohydride (150 mg, 0·69 mmol) gave the title compound (63 mg) , a yellow solid. 1H NMR (D20) 5 : 1·81-2·02 (m,1H); 2.34-2.52 (m,1H); 2.92-3.05 (m, 1H); 3.10-3.23 (m, 1H); 337-3.49 (m5 4H) ; 3.54-3.72 (m, 3H) ; 3.73 &lt;3.82 (m,1H) ; 3.85-3.90 (m,3H) ; 4.22 (d,1H) ; 4.29-4.41 (m,4H) ; 4.43 -4.51 127286 -148· 200831517 (m,2H); 4.60-4.80 (m,2H) ; 6.83-6.91 (m,1H); 7.07 (dd,1H) ; 7·26-7·31 (m,1H) 7·74 (d,1H) ; 7.97-8.03 (m,1H) ; 8·17_8·26 (m,1H). MS (ESP) : 482 (MH+) vs. C25H3 Example 28 6-[({(3R) , 4R)-3-methoxy-l-[2-(7-methoxy-2-ketoquinoxalin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino )methyl]-2H-pyrido[3,2-b][1,4],#, well-3 (4H&gt; ketone as described in Example 14 (except for the preparation of the hydrochloride), l-{ 2-[(3R,4R)-4-amino-3-methoxyhexahydropyridine small group]ethyl}·7-methoxyindoline-2(1Η)-one (intermediate 56,75 Mg, 0.23 mmol, 3-keto-3,4-dihydro-2Η-pyrido p,2-b][l,4]indole-6-carboxaldehyde (WO 2004/058144) (40 Mg, 0.23 mM) and sodium triethoxy borohydride (150 mg, 〇·69 The reaction was carried out to give the title compound (d,j,j,j,jjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj (t,lH); 1.834.93 (m, 1H); 2.00 (m? 1H); 2.22-2.35 (m5 1H); 2.62 (t? 2H); 2.81-3.00 (m5 2H); 3.20-3.30 (m , 4H) ; 3.56-3.78 (m5 2H) ; 3.92 (s? 3H) ; 4.26-4.44 (m, 2H); 4.61 (s, 2H); 6.92-7.08 (m, 3H); 7.29 (d, 1H) 7.75 (d,1H); 8·05 (s,1H); 11.21 (s5 1H). MS (ESP): 495 (MH+) vs. C25H3〇N605 Example 29 l-(2-{4-丨(2, 3-Dihydro[1,4]dioxolynene[2,3-c]pyridin-7-ylmethyl)amino]-3-peryl hexanitropurine than bite-l-yl}ethyl - 7-methoxy p-couver, trans-p-isomer A, dihydrochloride as described in Example 14, 1-{2-[4-amino-3-hydroxyhexahydro Pyridin-1-yl] 127286 -149- 200831517 ethyl}-7-methoxyporphyrin-2(1H)-one, trans-palomeris a (intermediate 57, 39 house, 〇_ 12 millimolar), 2,3-dihydro[1,4]dioxolynene[2,3-c]pyridine-7-carboxaldehyde (WO 2004/058144) (20 mg, 0 J 2 mmol) And triethyl decyloxy Sodium hydride (76 mg, 0.36 mmol) to give the title composition as a yellow solid (39 mg). NMR (D20) (5: 1.82-2.00 (m? 1H); 2.48 (dd5 1H); 3.01 (t5 1H); 3.08-3.21 (m5 1H); 3.30-3.44 (m? 1H); 3.58 (t? 2H) ;79.95 (d,2H); ,1H) ; 7·28 (s,1H) ; 7.76 (d,1H) ; 8.01 (s,1H) ; 8.20 (s,1H). MS (ESP) : 468 (MH+) vs. C24H29N505 Example 30

H({3-hydroxy-l-[2-(7-methoxy-2-keto porphyrin-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino)methyl 】-; 2H-pyrido[3,2_b][l,4] 哼3_4(4H)·one, trans-palphasomer A as described in Example 14 (except for the preparation of the hydrochloride), I-{2-[4-Amino-3·!^-ylhexahydro-p-diyl-1-yl]ethyl}_7_fluorenyl p-quino-p-lin-2(1H)-one, trans Pair of palm isomer A (intermediate 57, 39 mg, 0.12 mmol), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4] Carboxycarboxaldehyde (WO 2004/058144) (21 mg, 0.12 mmol) and sodium triethoxysulfonylborohydride (76 mg, 0.36 mmol) afforded 49 mg (84%) XH NMR (DMSO-d6) δ: 1.09-1.26 (m, 1H); 1.94 (t, 2H); 2.04 (t? 1H); 2.20-2.35 (m, 1H); 2.64 (t, 2H); 88·3·10 (m,2H) ; 3.18-3.32 (m,1H); 3.63-3.87 (m,2H); 3.98 (s,3H); 4·39 (t,2H); 4.67 (s,2H 4.90 (d,1H); 6.99-7.11 (m,3H); 7·36 (d,1H); 7.81 (d,1H); 8.10 (s,1H); 11.27 (s,lH). 127286 • 150-200831517 MS (ESP): 481 (MH+) vs. c24H28N605 Example 31 l-(2-{4-[(2,3-Dihydroindole-1,4)dioxanthene and p,3-c]pyridine -7-ylmethyl)amino]-3·hydroxyhexahydropyridine small group}ethyl)-7-methoxy porphyrinone, trans-p-isomer B, bis-hydrochloride according to examples 14, let 1-{2-[4-amino-3-hydroxyhexahydropyridinyl]ethyl}-7-methoxyquinoxaline_2(m)-one, trans-pair Structure (intermediate 65, 42 mg, 0.13 mmol), 2,3-dihydro[1,4]dioxantho[2,3-c]pyridin-7-carboxaldehyde (WO 2004) </RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; </RTI> <RTIgt; 1H NMR (D20) 5 : L82-1.99 (m, 1H); 2.42-2.53 (m5 1H); 3.01 (t5 1H); 3·08·3·20 (m, 1H); 3.32-3.44 (m5 1H); 3.58 (t, 2H); 3.80-3.95 (m, 5H); 3.96-4.09 (m5 1H); 4.32-4.50 (m, 6H); 4.65 (t5 2H); 6.87 (d5 1H) ; 7.07 (dd, 1H) ; 7.29 (s,1H) ; 7·76 (d,1H) ; 8.00 (s,1H) ; 8·21 (s,1H)· MS (ESP) : 467 (MH+) vs C24H29N505 Example 32

6-[({3_经基·1_[2_(7_methoxy-2-keto)porphyrin-1(2H)-yl)ethyl]hexahydropyridinyl}amino)methyl 】 _2H-pyrido[3,2-|&gt;][1,4]噚_-3(4H)-one, trans-palphasomer B as described in Example 14 (except for the preparation of the hydrochloride salt) ,{{2-[4-Amino-3-hydroxyhexahydropyridine small group; jethyl}_7_decyloxyporphyrin-2(m)-one, trans-palphaliomer (Intermediate 65, 42 mg, 0·13 mmol), 3·keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]唠耕-6-carboxyl Formaldehyde (W02004/058144) (24 127286 -151 - 200831517 g, 0.13 mmol) and sodium triethoxy borohydride (83 mg, 〇 _ 39 mmol) to obtain 42 mg (68% yield) Rate) Title compound. 1H NMR (DMSO-d6) 5 : 1.02-1.21 (m, 1H); 1.88 (t, 2H); 1.98 (t, 1H); 2·15-2·31 (m, 1H); 2.59 (t, 2H) ; 2.84-3.03 (m, 2H); 3.13-3.25 (m, 1H); 3.58-3.80 (m, 2H); 3·92 (s, 3H); 4·32 (t, 2H); 4.61 (s5 2H); 4·84 (d,1H); 6.94-7.05 (m,3H); 7·30 (d,1H); 7.68-7.79 (m,1H); 8.04 (s,1H); 11.16-1L29 ( M5 1H). MS (ESP): 481 (MH+) vs. C24H28N605 β Example 33 H2-{4_[(2,3-Dihydro[1,4] Dioxetan[2,3_e]pyridine·7_ Methyl)amino]-3-fluoropyrohydropyristyl}ethyl)_2·ketodihydropyrazine_7-carbonitrile, trans-p-isomer A, bis-hydrochloride 1-{2-[4-Amino-3-fluorohexahydropyridine-μ-yl]ethyl b 2,yl-indole, 2-dihydrotetralin-7-carbonitrile, trans-pair A (intermediate 67, crude, 15 〇 gram '0.48 mmol) and 2,3-dihydro[1,4]dioxene deceno[2,3-c]pyridine-7-φ A mixture of carboxymethyl jun (W 〇 2004/058144) (80 mg, 0.48 mmol) in anhydrous methanol / chloroform (1:1, 20 mL), heated at 70 C on a 3A molecular sieve under nitrogen. One hour. The reaction was allowed to cool to room temperature and a solution of sodium succinate (3 mg, 1.43 mmol) was added. The reaction was stirred overnight to / pho. The reaction mixture was filtered through celite. The filtrate was concentrated to dry/solid. The crude product was dissolved in 15 mL / methanol / pets and washed with saturated aqueous sodium chloride. The aqueous phase was extracted once more with 15% methanol / chloroform. The combined organic phases were dried over sodium sulfate, filtered and evaporated. Chromatography on a mixture of 0-5% methanol in dichloromethane afforded 127286 - 152 - </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; This was dissolved in 1 · 1 methylene chloride / diethyl ether (5 ml) and treated with 10M EtOAc (~2 eq. This mixture was concentrated to dryness. The resulting solid was reconstituted in water and lyophilized to give 66 mg of the title compound. ^NMR^O) δ ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m? 1H); 3.13-3.26 (m? 1H); 3.32-3.42 (m5 1H); 3.42-3.50 (m5 1H) 3.53 (t? 2H) ; 3.57-3.66 (m5 1H) ; 3,79-3,93 (m? 1H) ; 4.11-4.27 (m5 2H) ; 4.38-4.43 (m5 2H); 4.50-4.56 (m , 2H); 4·62_4·75 (m, 1H); 4.80-4.88 (m, 1H); 4.85 (m, 1H) 6.85 (d, 1H); 7·25 (s, 1H); 7.68 (dd, 1H); 7.89 (d,1H); 7.98 (s,1H); 8.03 (d, 1H); 8.20 (s5 1H). MS (ESP) ·· 464 (MH+) vs. C25H26FN503 Example 34

L-[2-((3-fluoro)-4_{[(3-keto-3,4-dihydro-2H-pyrido[3,2-7][1,4]噚耕-6-yl) Methyl 1 amino}}hexahydropyridin-1-yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile, trans-p-isomer A (except for the preparation of hydrochloride), l-{2-[4-amino-3-fluorohexahydropyridinyl]ethyl}-2-keto-1,2-dihydroquinoline-7 -carbonitrile, trans-p-isomer A (intermediate 67, 150 mg, 0.48 mmol), 3-keto-3,4-dihydro-2Η-pyrido[3,2-b][ l,4] 唠耕-6·carboxycarboxaldehyde (WO 2004/058144) (85 mg, 0·48 mmol) and sodium triethoxy borohydride (300 mg, 1.43 mmol) to obtain 70 </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> <RTIgt; 2.04-2.21 (m, 2H); 2.30-2.41 (m, 1H); 2.57-2.67 (m, 2H); 2.78-2.87 (m, 1H); 127286-153-200831517 3.18-3.29 (m, 1H); 3.73 (s3 2H) ; 4.29 (m5 1H) ; 4.29-4.46 (m? 2H) ; 4.61 (s, 2H) ; 6.78 (d, 1H) ; 7·01 (d, 1H) ; 7.30 (d, 1H) ; 7·66 (dd, 1H); 7.91 (d,1H) ; 8.01 (d,1H) ; 8.11 (s,1H) ; 1U9 (s,1H)· MS (ESP) : 477 (MH+) vs. C2 5 H2 5 FN6 03 Let Examples 3S to 4 Waters XBridge C-18 column was purified by reverse phase HPLC and eluted with 5-50% water/acetonitrile with ammonium acetate buffer (pH == 8). Example 35 1_(2-{4-[(2,3) -Dihydro[indenyl]dioxanthene and p,3-c]pyridin-7-ylmethyl)amino]-3-1ylhexahydropyridine small group}ethyl)-7-methoxyquin Porphyrin-2(1H)-one, trans-palladium isomer, dihydrochloride using 2,3-dihydro[1,4]dioxene terpene using procedures similar to those described in Synthesis Example 33 And [2,3-c]pyridine-7-carboxaldehyde and 1-{2-[4-amino-3-fluorohexahydropyridin-1-yl]ethyl}_7_methoxy -2(1H)-one, trans-reaction to palmoisomer A (intermediate 77) provides the title composition. 1H NMR (D20) δ ppm: 1.81-1.97 (m5 1H); 2.32-2.45 (m? 1H); 3.20-3.32 (m, 1H); 3.35-3.44 (m, 1H); 3.52-3.72 (m, 4H) 3.91 (s,3H) ; 3.85-3.95 (m,1H) ; 4·13·4·28 (m,2H) ; 4.37-4.43 (m,2H) ; 4.51-4.56 (m,2H); 4.57- 4.73 (m,2H) ; 4·94 (m,1H) ; 6.90 (d,1H) ; 7.10 (dd,1H) ; 7.30 (s, 1H) ; 7·78 (d,1H) ; 8.03 (s, 1H) ; 8.22 (s,1H)· ES (MH)+ 470 Example 36

6-[({3·Fluoro-l-[2-(7-methoxy-2-indenyl)- quinone-1(2H)-yl)ethyl]hexahydro,pyridin-4-yl} Amino)methyl]-2H·pyrido[3,2-b]indole 1,4], cultivating-3(4H)-one, trans-palphasomer isomer A 127286 -154- 200831517 The procedure described in Synthesis Example 33 (except for the preparation of the hydrochloride salt) was such that 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6- Carboxaldehyde and 1-{2-[4-amino-3-yl-based squirrel ρ-diyl-1-yl]ethyl]-7-methoxy-suppressed p-lin-2(1H)-one The reaction is carried out on the palm of the isomer A (Intermediate 77) to afford the title compound. NMR (DMSO-d6) δ ppm : 1.14-1.29 (m? 1H) ; 1.82-1.95 (m5 1H); 2,04-2,20 (m5 2H) ; 2.52-2.61 (m5 1H) ; 2.60-2.70 ( M5 2H) ; 2.78-2.89 (m? 1H); 3.16-3.27 (m? 1H); 3.67-3.80 (m? 2H); 3.88-3.96 (m, 3H); 4.29-4.43 (m, 2H); 4.30 (m,1H) ; 4·61 (s,2H) ; 6.96-7.06 (m,3H) ; 7.30 (d,1H); 7.75 (d,1H) ; 8.00-8.09 (m,1H) ; 11.19 (s , 1H)·ES (MH)+483 Example 37 l_(2-{4-[(2,3-Dihydro[1,4]dioxolynene[2,3-c]pyridin-7-yl) Methyl)amino]-3·fluorohexahydroindole than biting-l-yl}ethyl)-2·keto-1,2·dihydroττ quinine-7-carbonitrile, trans-pair The construct, bis-hydrochloride, was similar to the procedure described in Synthesis Example 33 to give 2,3-dihydro[1,4]dioxantim[2,3-c]pyridine-7-carboxylate. Formaldehyde with 1-{2-[4-amino-3-fluorohexahydropyridin-1-yl]ethyl}-2-keto-1,2-dihydroquinolin-7-carbonitrile, trans Reaction of palmate isomer B (Intermediate 79) provides the title composition. ΐΗΝΜΚ(°2〇) δ ppm: 1.81-1.94 (m, 1H); 2.30-2.43 (m5 1H); 3.13-3.26 (m? 1H); 3.32-3.42 (m5 1H) ; 3.42-3.50 (m5 1H) 3.53 (t, 2H) ; 3.57-3.66 (m? 1H) ; 3.79-3.93 (m5 1H) ; 4.11-4.27 (m, 2H) ; 438-4.43 (m? 2H); 4.50-4.56 (m, 2H) ; 4·62_4·75 (m,1H) ; 4.80_4,88 (m,1H) ; 4.85 (m,1H) 6.85 (d,1H) ; 7·25 (s,1H) ; 7.68 (dd,1H 7.89 (d,1H) ; 7·98 (s,1H); 127286 -155- 200831517 8.03 (d5 1H) ; 8.20 (s5 1H) ES (MH)+464 Example 38

• Fluoro group _4·{[(3-keto- 3,4·dihydro-2H-峨 bite and [3,2-b]丨l,4] 兮i i base) methyl]amino}6 Hydrogen p is more specific than the salt described in the synthesis of Example 33 (only the salt thereof). Except for the preparation of acid salt, 3-keto-3,4-dihydro-2H·pyrido[3,2-7][1,4] 噚 鲮 鲮 与 与 与 and 1-{2-[4-amine Benzyl-3-ylhexahydrop-p-but-1-yl]ethyl}-2-S synthyl-1,2-dihydro-hydroxyquinoline-7-carbonitrile, trans-p-isomer B ( Intermediate 79) was reacted to provide the title compound. 1H NMR (DMSO-d6) 5 ppm: 1.21 (m, 1H) 1.84-1.95 (m, 1H); 2.04-2.21 (m5 2H); 2.30-2.41 (m, 1H); 2·57·2·67 (m , 2H) ; 2.78-2.87 (m,1H); 318-3.29 (m,1H) ; 3.73 (s,2H); 4.29 (m,1H) 4·29_4·46 (m,2H) ; 4.61 (s, 2H) ; 6.78 (d,1H) ; 7.01 (d,1H) ; 7.30 (d,1H) ; 7.66 (dd,1H) ; 7.91 (d, 1H) ; 8·01 (d,1H) ; 8.11 (s ,1H); 11.19 (s,1H) ES (MH)+477 [a]D= +19.8 (methanol, c = 0.46) Example 39 l-(2-{4-[(2,3-dihydro[1] , 4] dioxo-encyclo[6,3-c]pyridin-7-ylmethyl)amino]-3-decylhexahydropyridine-1-yl}ethyl)-7-methoxyquinidine Porphyrin·2(1Η)·one, trans-p-isomer, bis-hydrochloride, using a procedure similar to that described in Synthesis Example 33, to 2,3-dihydro[1,4]dioxane Alkeno[2,3-c]pyridine-7-indolecarboxaldehyde and μ{2_[4.amino-3-fluorohexahydropyridin-1-yl]ethyl}-7-methoxy porphyrin_ 2(m)-ketone, trans-p-isomer Β 127286 - 156 - 200831517 (Intermediate 83) was reacted to provide the title composition. !H NMR (D20) δ ppm: 1.81-1.97 (m? 1H); 2.32-2.45 (m? IH); 3.20-3.32 (m,1H); 3.35-3.44 (m,1H) ; 3.52-3.72 (m , 4H); 3_91 (s, 3H); 3.85-3.95 (m, 1Ή); 4.13-4.28 (m, 2H); 4.37-4.43 (m, 2H); 4.51-4.56 (m, 2H); 4.57-4.73 (m,2H) ; 4_94 (m,1H) ; 6.90 (d,1H) ; 7·10 (dd,1H) ; 7.30 (s, IH) ; 7·78 (d,IH) ; 8·03 (s , IH) ; 8·22 (s, 1H). ES (MH)+470 Example 40

6-[({3-Fluoro-l-[2-(7-methoxy-2-keto)p-quineline-1(2H)-yl)ethyl]hexahydrop-pyridin-4-yl }Amino)methyl]-2H-pyrido[3,2-b][l,4]indole-3(4H)-one, trans-p-isomer B was used as described in Synthesis Example 33. Procedure (except for the preparation of hydrochloride), 3-keto-3,4-dihydro-2H-pyrido[3,2-b][l,4]indole-6-carboxaldehyde and 1- {2-[4-Amino-3-fluorohexahydroindole-1-yl]ethyl b-7-methoxy ρ ϋ ϋ 琳 -2-2(1Η)-one, trans-pair The title compound (Intermediate 83) was reacted to provide the title compound. NMR (DMSO-d6) δ ppm : L14-L29 (m5 IH) ; 1.82-1.95 (m, IH); 2.04-2.20 (m, 2H); 2.52-2.61 (m, IH); 2.60-2.70 (m, 2H) ; 2.78-2.89 (m, IH); 3.16-3.27 (m5 IH); 3.67-3.80 (m5 2H); 3.88-3.96 (m? 3H); 4.29-4.43 (m, 2H); 4.30 (m, 4.H (3,3H); )) +483 Example 41 l-(2-{(3R,4R)-4-[(2,3-Dihydro[1,4]dioxoalthene and p,3-c]pyridine-7-yl) 127286 -157- 200831517 yl) hydrazinyl methoxy hexahydro _ small group} ethyl) 2, yl · w. diammonium • 7-carbonitrile, dihydrochloride ^ 1-{2. (3R,4R&gt;4^^ -3.f ^ ^ ^ ^ ,k ^ ^ ^ ^ -U-Dihydrojun #-7-甲月奋 (Intermediate 85,1〇5mg crude, 〇·32 Milliole m 2,3-dihydrodioxyterpenem and a mixture of 2 fields compared to a few jun Talk (5) milligrams (4) in a dry methanol/chloroform (1) (7) ml Under nitrogen atmosphere, add _ heat for 3 hours on the molecular sieve. Allow the reaction to cool to room temperature and add triethyl sulphate sodium chloride (205 mil. , 〇·97耄莫耳). The reaction was stirred at room temperature overnight, then filtered through celite. The filtrate was concentrated to dryness, dissolved in 15% methanol in chloroform, and saturated sodium bicarbonate solution The aqueous phase was extracted twice with 15% methanol/chloroform. The combined organic phases were dried over magnesium sulfate and concentrated under reduced pressure. Chromatography of the sterol in dichloromethane gave 61 mg (4%) of the title compound as free oil as an oil, which was dissolved in 1: chloroform / _ _ ( The mixture was treated with 1% hydrazine HC1 (~2 eq.) in ether. The precipitate formed by filtration was collected and reconstituted in water, and dried to give 63 mg of the title compound as a solid. MS (ESP): 476 (ΜΗ+) vs. C26H29N504 rH NMR (D20) δ ppm: 1.84-2.00 (m? 1H); 2.37-2.49 (m? 1H); 2.93-3.06 (m5 1H); 3.10-3, 23 (m? 1H); 3.33-3.44 (m5 4H); 3, 53-3.80 (m5 4H); 4.19 (d, 1H); 4.27-4.40 (m, 4H); 4.40-4.48 (m, 2H); 4.62-4.76 (m, 2H); 6.79 (d, 1H) ; 7·22 (s 1H) ; 7.62 (dd,1H) ; 7·83 (d,1H) ; 7.91 (s,1H) ; 7.97 (4 1H) ; 8·14-8·20 (m,1H). 127286 -158- 200831517 Example 42 1- [2_((3R,4R)_3_methoxy_4_{丨(3-keto-3,4·dihydro-2H-pyrido[3,2-b][l,4] 噚Plung-6-yl)methyl]amino}hexahydropyridine-1·yl)ethyl]-2-keto-1,2-dihydroquinolin-7-carbonitrile was used in a similar manner as described in Synthesis Example 41. The procedure (except for the preparation of the hydrochloride salt) is such that the ratio of 1-{2-[(3R,4R)-4-amino-3-methoxyhexahydro-P. Ding-1-yl]ethyl ketone dihydrogen -7- gambling (intermediate 85,105 mg, 0.32 mmol), 3-keto-3,4-diindole-2Η-峨唆[3,2-b][l,4]4 ρ Well-6-Weicarboxylic acid (WO 2004/ 058144) (57 mg, 0.32 mmol) and sodium triethoxy borohydride (2 〇 5 mg, 0.97 millimoles) reaction. Chromatography on EtOAc (EtOAc) elute MS (ESP): 489 (MH+) vs. C2 6 H2 8 N6 04 lH NMR (DMSO-d6) δ ppm · 1.00-1.15 (m5 1H) ; 1.76 (m5 1H) ; 1.87 (d,1H) ; 1.99 (m , 1H); 2·22-2·34 (m, 1H); 2·59 (m, 2H); 2.78-2.96 (m, 2H); 3.25-3.33 (m5 2H); 3.30 (s? 3H); 3.55-3.77 (m? 2H); 4.30-4.50 (m, 2H); 4·61 (s, 2H); 6·79 (d, 1H); 6.97 (d, 1H); 7.28 (d, 1H); 7,66 (dd, 1H) ; 7·91 (d,1H) ; 8.01 (d,1H) ; 8.12 (s,1H) ; 11.21 (s,1H). Example 43 l-(2-{(3S, 4S)-4-[(2,3-Dihydro[1,4]dioxolysine and [2,3-c]p ratio -7-ylmethyl)amino]methoxy hexazone p Than-l-yl}ethyl)_2_fluorenyl-1,2-diazap-kulin-7-carbonitrile, dihydrochloride using a procedure similar to that described in Synthesis Example 41, i_{2- [(3S,4S)-4-amino-3-methoxyhexaazepine-_1-yl]ethyl}-2-yl-1,2-dichloro-Jun--7-A 127286-159 - 200831517 Nitrile (intermediate 90, 120 mg, 〇 · 37 mmol), 2,3-dihydro[1,4]dioxanthene [2,3·φ than pyridine·7-carboxaldehyde ( WO 2004/058144) (61 mg, 〇·37 mmol) and triethoxynitride boron Sodium (234 mg, 1.1 mmol 1〇) to provide the title composition (54 mg). MS (ESP): 476 (ΜΗ+) vs. C26H29N504 1H NMR (D20) 5 ppm 1.84-2.00 (m,1H); 2.37-2.49 (m,1H); 2.93-3.06 (m? 1H); 3.10-3.23 ( M5 1H) ; 3.33-3.44 (m? 4H) ; 3.53-3.80 (m? 4H) ; 4.19 (d? 1H) ; 4.27-4.40 (m? 4H) ; 4.40-4.48 (m5 2H) ; 4.62-4.76 ( M5 2H) ; 6.79 (d,1H) ; 7·22 (s,1H) ; 7·62 (dd,1H) ; 7.83 (d,1H) ; 7.91 (s,1H) ; 7.97 (d5 1H) ; 8.14 -8.20 (m5 1H). Example 44 l-[2-((3S,4S)-3_ 曱oxy-4_{[(3·keto-3,4-dihydro-2H·pyro[3, 2-b][l,4] 噚 _6_yl)methyl]amino}hexahydroacridine·1_yl)ethyl]·2-keto-1,2-dihydroquinoline-7 -carbonitrile using a procedure similar to that described in Example 41 (except for the preparation of the hydrochloride salt) to give H2-[(3S,4SH-amino-3.nonyloxyhexahydropyridine small group;]ethyl}-2_ Ketopropyl-1,2-dihydroquinolin-7-indenecarbonitrile (intermediate 90, Π0 mg, 0.37 mmol), 3-keto-3,4-dihydro-2H-P 唆弁[3 , 2-b][l,4]p well-6·retarded formic acid (WO 2004/ 058144) (61 mg, 0·37 mmol) and sodium triethoxy borohydride (234 mg, L10 mil Moore) reaction MS (ESP): 489 (ΜΗ+) vs. C26H28N604 1H NMR (DMSO-d6) 5 ppm 1.00-1.15 (m, 1H); 1.76 (m5 1H); 1.87 (d, 1H); M5 1H); 2.22-2.34 (m,1H); 2.59 (m,2H); 2.78-2.96 (m5 2H); 3.25-3.33 (m5 2H) ; 3.30 (s5 3H) ; 3.55-3.77 (m, 2H) 4.30-4.50 (m, 2H); 127286 -160- 200831517 4.61 (s, 2H) ; 6·79 (d, 1H); 6·97 (d, 1H); 7.28 (d, 1H); 7·66 (dd,1H); 7·91 (d,1H) ; 8.01 (d,1H) ; 8·12 (s,1H) ; 11.21 (s,1H)· Example 45 6-[({(3S,4R) 3-fluoroyl·1-[2_(7-methoxy-2-ketophenyl)ethyl]hexahydropyridyl]amino)methyl]-2Η-pyridoindole 3,2 Seven py] 噚耕-3(4H)·one, bis-hydrochloride and Example 46 6-[({(3R,4S)-3-fluoroyl[2-(7-methoxy-2.keto) Quinoxaline-1(2H)-yl)ethyl]hexahydropyridin-4-yl}amino)methyl]·2Η_pyridine[3,2_b][1,4]噚 〜~3(4H) - Ketone, dihydrochloride salt cis (:!:) 1-[2-(4-Amino-3-fluorohexahydropyridin-1-yl)ethyl]methoxyquinoxaline-2 ( 1Η)-ketone, trifluoroacetate (intermediate 91, ~〇·53 mmol) in two In the ethane / methanol (1 mL, 20 ··) solution ν, Ν- diisopropylethylamine neutralization. Add 3-keto-3,4-dihydro-2-indole-[3,2-b][l,4]indolylcarboxaldehyde (WO 2004/058144) (113 mg, 〇·63 mmol) The reaction was stirred overnight on a 3 person molecular sieve under reflux. The reaction mixture was cooled to 〇c &lt;c, and sodium cyanoborohydride (40 mg, EtOAc &lt; The reaction mixture was stirred at room temperature for 2 hr then filtered over EtOAc EtOAc. The residue was dissolved in ethyl acetate and washed with saturated sodium bicarbonate then brine. The organic extract was dried over magnesium sulfate and concentrated. Reverse phase chromatography with water/methanol/difluoroacetic acid gave the product as trifluoroacetate. This salt was dissolved in water and chloroform and basified with saturated sodium carbonate. The liquid layer was separated, and the aqueous solution was extracted with chloroform. The organic extract was dehydrated to dryness with MgSO.sub.sub.sub.sub.sub.sub. MS (ESP): 483 (MH+) vs. C24H27FN604^-NMR (CDC!3-d) δ: 1.70 (m5 4 Η); 2.35 (m5 2H); 2.64 (m? IH); 2.73 (m? 2H); (m? 1H) ; 3.31 (m5 1H) ; 3.86 (s5 2H) ; 3.92 (s5 3H); 4.35 (m, 2H) ; 4.63 (s, 2H) ; 4.83 (m, 1H) ; 6.86 (m, 1H 6·92 (m, IH); 6.98 (m5 1H); 7.21 (m5 1H); 7.77 (m5 IH); 8.11 (s5 1H). The racemic mixture is by palm chromatography (HPLC, Chimlcel) OJ, 250 x 20 mm, 10 // mobile phase: 50% hexane, 25% ethanol, 25% decyl alcohol, 0.1% diethylamine). The free base of Example 45 was first eluted, followed by the free base of Example 46. The hydrochloride salt was prepared by dissolving a free base in dichloromethane (2 ml) and adding 2.2 equivalents of 4 HCl in dioxane. The colorless precipitate formed was collected by filtration, and 48 and 46 mg of Examples 45 and 46 were separately produced. Example 47 l-[2-((3R,4S)-3-曱-oxy-4-{[(3-keto-3,4-dihydro-2Η·ρ ratio bite [3,2_b][l , 4] 噚耕-6-yl)methyl]amino}hexahydropyridine-1_yl)ethyl hydrazine-methyl-2-keto-1,2-dihydroquinoline _7-carbonitrile, Bis-hydrochloride salt l-{2-[(3R,4S)-4-amino-3-pyridyloxyhexahydrop to butyl-1-yl]ethylmethyl-2-keto-1, 2-Dihydro-p-quinoline-7-carbonitrile (intermediate 93, ~0·81 mmol) was suspended in chloroform/methanol (1:1, 20 ml), and hydrazine, hydrazine-diiso was added dropwise. Propylethylamine until the solid dissolves. Add 3-keto-3,4-dihydro-2Η_ρ to bite P,2-b][l,4]哼h-6-carboxaldehyde (WO 2004/058144) (210 mg, 1.2 mmol) The reaction was refluxed on a 3A molecular sieve for 5 hours. Under it, add three 127286 -162- 200831517 sodium acetoxyborohydride (340 mg, 16 mmol). The reaction mixture was stirred at room temperature for 2 hours, then filtered through a EtOAc EtOAc EtOAc. The residue was dissolved in dichloromethane and saturated sodium bicarbonate. The pH value of the aqueous phase was adjusted to pH 〜10 with 1 NaOH solution. The aqueous phase was back-extracted with dichloromethane and the combined organic phases dried over sodium sulfate and concentrated. The free-form base of the title composition was obtained as a tan-yellow foam of 144 mg (36%). Its bis-hydrochloride salt was prepared using a procedure similar to that described in Synthesis Example 45. MS (ESP): 503 (MH+) tj- C27H3 〇N604^-NMR (DMSO-d6) δ: 1.41 (m, 1H); 1.75 (m? 2H); 2.28 (m5 1H); 2_44 (s, 3H) ; 2·53 (m, 2H) ; 2.70 (m, 2H); 3.16 (s, 3H); 3.31 (m, 2H); 3.64 (m5 2H); 4.35 (m, 2H); 4·59 (s, 2H) ; 6·68 (s,1H) ; 6·97 (d,1H); 7.27 (d,1H) ; 7·66 (d,1H) ; 7.92 (d,1H) ; 8.08 (s,1H) ; 8.31 (s, 1H); 11.19 (s? 1H). Example 48 l-[2_((3S,4R)-3_Fluoro-4-{[(3-keto-3,4·dihydro) 2H-pyrido[3,2-b][l,4]indole-6-yl)methyl]amino}hexahydropyridin-1-yl)ethyl]-4-methyl-2-keto- 1,2-Dihydroquinoline-7-carbonitrile, dihydrochloride and Example 49 l-[2_((3R,4S)-3-fluoro-4-{[(3-keto-3,4) -Dihydro-2H-pyridoindole 3,2-7][1,4]哼啼-6·yl)methyl]amino}hexahydropyridin-1-yl)hexyl]methanol-2-keto -1,2-dihydroporphyrin-7-carbonitrile, dihydrochloride using a procedure similar to that described in Synthesis Example 47 to give cis (±) 1-[2-(4-127286-163-200831517 amine 3-fluorohexahydropyridin-1yl)ethyl]-4-methyl-2-keto-1,2-dihydroinden-7-carbonitrile 95,200 mg, 0.63 mmol, 3·keto-3,4-dihydro-m-pyrido[3,2-b][l,4]噚_carboxaldehyde (WO 2004/058144) (170 mg, 〇·94 mmol) and sodium triethoxysulfonate hydride (26 mg, 126 mmol), eluted with water / acetonitrile / TFA to afford the title compound The mixture was a dry film, 80 mg. The racemic mixture was isolated by palm chromatography (SFC, Chiralpak AD-H, 250 X 21 mm, 5; 5 % methanol, 〇.ι〇/0 dimercaptoethylamine). The free base of Example 48 was first eluted, followed by the free base of Example 49. The bis-hydrochloride salt was prepared using a procedure similar to that described for the synthesis of Example 45 to afford the title compound as a colorless solid (6 mg and 4 mg each). MS (ESP): 491 (MH+) vs. C26H27FN6 〇3^-NMR (DMSO-d6) δ: 1.60 (m, 2 Η); 2.12 (m? 4H); 2.44 (s? 3H); 2.54 (m, 2H) 2.91 (m,1H); 3.12 (m,1H); 3.71 (m,2H); 4.34 (m,2H); 4·59 (s,2H) ; 4.70 (m,1H) ; 6.68 (s,1H ; 7.01 (d,1H) ; 7.28 (d,1H); 7.66 (m,1H) ; 7.92 (d,1H) ; 8.07 (s,1H) ; iL18 (s,1H). Example 50 H2-(( 3s, 4r)-3-fluoroyl_4_{[(3·嗣基·3,4-dihydropyridinium hydrazide 3, 哜6_yl)methyl]amino}hexahydropyridine small group) Ethyl 2 ketohydroquinoline 'carbonitrile, dihydrochloride salt l-{2-[(3S,4R&gt;4_amino-3-fluorohexahydropyridine q•yl]ethyl}_2 - Ketopropyl 1,2-monohydroporphyrin-7-oxime difluoroacetate (intermediate 97, millimolar) suspended in chloroform / methanol (1: 2, 30 mL) and added dropwise Ν,Ν·Ιisopropylethylamine was neutralized. Add 3-_yl_3,4_dihydro-2Η_pyridine and [3&gt;b][1,4] 127286 -164- 200831517 噚耕-6 Carboxyfurfural (WO 2004/058144) (258 mg, 1.45 mmol), and refluxing the reaction on a 3A molecular sieve for 5 hours. Add triethoxycarbonyl under 〇〇c Sodium hydride (512 mg, 2.42 mmol). The reaction mixture was stirred at room temperature for 30 min then filtered over a sifting funnel and concentrated. The sodium and the saturated sodium chloride were washed. The organic phase was dried over magnesium sulfate and concentrated, and then purified with water/acetonitrile / ammonium acetate reverse phase chromatography 'after drying' to obtain the product as an off-white solid. The lyophilized product was dissolved in dichloromethane (5 mL) and EtOAc (EtOAc m. MS (ESP): 477 (ΜΗ+) vs. C25H25FN603 ^-NMR (DMSO-d6) 5 : 1.61 (m, 2H); 2.20 (m5 2H); 2.52 (m? 4H); 3.04 (m, 2H) 3.72 (s,2H) ; 4·34 (m,2H) ; 4.59 (s,2H) ; 4.82 (m,1H); 6.67 (d,1H) ; 7·01 (d,1H) ; 7.28 (d ,1H) ; 7.64 (d,1H) ; 7.89 (d,1H); 8.00 (d,1H) ; 8.09 (s,1H) ; 11.19 (s,1H)· Example 51 1-[2_((3S,4R )·3-methoxy_4_{[(3_keto_3,4_dihydro-2h_p ratio bite [3,2-b][l,4] 唠哜-6-yl) Amino]hexahydropyridin-1-yl)ethyl]-4-methyl-2-keto-j,2-dihydroquinoline-7-carbonitrile, bis-trifluoroacetate makes l-{2 -[(3S,4R) piperidinyl·3·decyloxyhexahydropyridine-μ-yl]ethylmethyl-2·keto-1,2-dihydroρ-quinion-7-indene nitrile, trifluoro The succinate (intermediate 1〇4, ~0.52 mmol) was suspended in chloroform/methanol (1:2, 15 mL) and neutralized by dropwise addition of hydrazine, hydrazine-diisopropylethylamine. . Add 3-keto-3,4-dihydro-2-indole-pyrido P,2-b][l,4]indole-6-carboxaldehyde (WO 2004/058144) (93 mg, 0.52 127286 -165 - 200831517 millimolar) and the reaction was refluxed over 3A molecular sieves overnight. Add sodium triethylsulfonylborohydride (138 mg, 0.65 mmol) to TC. The reaction mixture was stirred at room temperature for 5 hr then filtered over a fritted funnel and concentrated. The mixture was washed with saturated sodium hydrogencarbonate and saturated sodium sulfate. The organic phase was dried over magnesium sulfate and concentrated. After lyophilization, the mixture was subjected to water/acetonitrile/trifluoroacetic acid reverse phase chromatography to obtain the title combination. , as a white solid, 108 mg (34%). MS (ESI): 503 (MH+), s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, s, 2H); 3.48 (s,3H) ; 3.64 (m,4H) ; 4.18 (m,4H); 4·70 (m,6H) ; 6·75 (s,1H); 7·06 (d,1H) 7.35 (d,1H); 7.69 (m,1H); 7.94 (s,1H); 8.01 (d,1H). Example 52 1-P-((3R,4S)_3-fluoroketone-based, 4_Dihydro-2H•pyridyl[3,2-7]Craft No.5-yl)methyl]amino}hexahydropyridinium+yl)ethyl]_2-ketoquinonequinoline-7- The carbonitrile and the dihydrochloride salt l-{2-[(3R,4SH-amino-fluorohexahydropyridinyl)ethyl}_2-keto-1,2-dihydroporphyrin-7·A Nitrile (intermediate 106, 352 Mg, 1.12 mmol, suspended in chloroform/methanol (1:1,30 mL). Add 3·keto-3,4-dihydro-2H·pyrido[3,2-b][l,4 ] 噚 -6-6-carboxaldehyde (WO 2004/058144) (299 mg, 1.68 mmol), and the reaction was refluxed overnight on 3A molecular sieves. Sodium triethoxy borohydride was added at 〇 ° C ( The residue was dissolved in dioxethane and washed with saturated sodium bicarbonate and brine. The organic phase was dried over MgSO4, EtOAc (EtOAc m.) A solution of the acetate in dichloromethane (5 ml) was prepared by adding 2.2 eq. of 4 ΝΗα in dioxane, filtered, and dried under vacuum to give the desired compound as a colorless solid. 154 mg (26%) 〇MS (ESP): 477 (ΜΗ+) vs C2 5 H2 5 FN6 03

^-NMR (DMSO-d6) δ: 1.57 (m5 2Η); 2.37 (m5 2H); 2.58 (m? 4H); 2.91 (m5 2H); 3.71 (s? 2H); 4.34 (m5 2H); 4.59 ( s? 2H) ; 4.70 (m5 1H); 6.76 (d, 1H) ; 7·00 (d, 1H); 7·28 (d, 1H); 7.63 (d, 1H); 7·89 (d, 1H) ); 7.98 (d, 1H); 8.08 (s, 1H).

127286 -167·

Claims (1)

  1. 200831517 X. Patent application scope: h - compound of formula (I):
    Or a pharmaceutically acceptable salt thereof, wherein the carbon &quot;a&quot; and carbon"b&quot; are in a cis (ten) relationship, a cis (a) relationship, a trans (ten) or a trans (_) relationship with each other, wherein the formula (I) The compound is substantially free of its cis (±) mixture of palmar isomers, and wherein the A is selected from the group consisting of CH and N; the D is selected from the group consisting of C-R7 and N; wherein at least one of A and D is carbon. , E is selected from 〇, NH and s, wherein: 1) If R8 and R9 together form =〇, then E is NH; and U) If R8 and R9 are each Η, then E is Ο or S; G system It is selected from the group consisting of hydrazine and S; the J series is selected from the group consisting of C-R4 and hydrazine; and the R1 is selected from the group consisting of anthracene, halo, cyano, Ci-6 alkyl, c26 alkenyl and C2_6 alkynyl, OR1 & and -N (Ri %, Wherein the Ci-alkyl, C2 6 alkenyl and c2_6 alkynyl groups are optionally substituted by one or more R1 ;; Rla, in each presence, is independently selected from hydrazine and (^_6 alkyl, wherein the 127286 200831517 Entertainment: The base is optionally substituted by one or more R20; R2 is selected from the group consisting of halo, cyano, Cu alkyl, C2-6 alkenyl, C2_6 alkynyl, -OR2a and -N(R2a)2, wherein The Cp6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group are optionally substituted by one or more R2 0 R2a, in each presence, is independently selected from the group consisting of only the alkyl group, wherein the C!-6 alkyl group is optionally substituted with one or more R20; R3 is selected from the group consisting of hydrazine, halo, cyano, Cb6 alkyl, C2-6 alkenyl and C2-6 alkynyl, -OR3a and -N(R3a)2, wherein the C 6 alkyl group, the C 2_6 alkenyl group and the C 2-6 alkynyl group are optionally treated as one or a plurality of R30 substituted; R3a, in each presence, independently selected from 11 and <21-6 alkyl, wherein the Cle6 alkyl is optionally substituted with one or more R30; R4 is selected from the group consisting of hydrazine and halo a cyano group, a -C02H, a CV6 alkyl group, a C2_6 alkenyl group, and a C2-6 alkynyl group, wherein the (^-6 alkyl group, the C2-6 alkenyl group, and the C2_6 alkynyl group are optionally substituted by one or more R40; R6 is selected from the group consisting of a fluorine group, a C!-6 alkyl group, a C2_6 alkenyl group, (: 2-6 alkynyl group, -〇R6a, ^ wherein the q-6 alkyl group, the C2_6 alkenyl group and the C2_6 alkynyl group are optionally Or a plurality of R60 substitutions; R6a, in each presence, independently selected from the group consisting of hydrazine and Cu alkyl, wherein the C1-6 alkyl group is optionally substituted with one or more R60; R7 is selected from the group consisting of hydrazine, halo, a cyano group, a Cl 6 alkyl group, a C 2_6 alkenyl group, and a C 2-6 alkynyl group, wherein the heart 6 alkyl group, the C 2_6 alkenyl group, and the C 2_6 alkyne group Depending on the situation, it is replaced by one or more R7 0; R8 and R9 are each hydrogen, or R8 and R9 together form =〇; and Rl〇, R2❹, 妒〇, 圮0, 妒〇 and furnace exist in each Each is independently selected from the group consisting of 127286 • 2 - 200831517 halo, hydroxy, cyano, -C02H, (V6 alkyl, c2_6 alkenyl and c2_alkynyl).
    127286 200831517 VII. Designation of representative drawings: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention:
    127286
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