TW200306975A - New mandelic acid derivatives and their use as thrombin inhibitors - Google Patents

Abstract

There is provided a compound of formula I, wherein Ra, R1, R2, Y and R3 have meanings given in the description and pharmaceutically-acceptable derivatives (including prodrugs) thereof, which compounds and derivatives are useful as, or are useful as prodrugs of, competitive inhibitors of trypsin-like proteases, such as thrombin, and thus, in particular, in the treatment of conditions where inhibition of thrombin is required (e.g. thrombosis) or as anticoagulants.

Description

200306975

W 玖 Description of the invention (The description of the invention should state: the technical field to which the invention belongs, the prior art, the content, the embodiments and the drawings). TECHNICAL FIELD The present invention relates to novel pharmaceutically usable compounds, especially trypsin-like Compounds of competitive inhibitors of serine proteases (especially thrombin), and / or compounds that will be metabolized to the compounds, their use as pharmaceuticals, containing their pharmaceutical compositions, and their synthetic synthesis way. Prior art background Blood coagulation is a key process that involves hemostasis (meaning preventing blood from being lost from an injured blood vessel) and thrombosis (meaning forming a blood clot in a blood vessel, sometimes resulting in blood vessel obstruction). Coagulation is the result of a series of complex enzyme reactions. One of the final steps in this series of reactions is proenzyme prothrombin / conversion to active enzyme thrombin. Thrombin is known to play a central role in coagulation. It activates platelets to cause platelet aggregation, converts fibrinogen into fibrin monomers, which naturally polymerizes into fibrin polymers, and activates factor XIII, which in turn causes the polymers to crosslink to form Insoluble fibrin. Furthermore, thrombin activates factor V and factor VIII, resulting in "positive feedback" of thrombin from prothrombin. By inhibiting platelet aggregation and fibrin formation and cross-linking, it is expected that an effective inhibitor of thrombin will exhibit antithrombotic activity. In addition, antithrombotic activity is expected to be enhanced by effective inhibition of a positive feedback mechanism. The early development of low molecular weight inhibitors of thrombin from previous techniques has been described by Claesson in Blood Coagul · Fibrinol · (1994) 5, 411 0 □ Continued (If the description page of the invention is insufficient, please note and use the continued page ) -6-200306975

Description of the invention

Blombdck et al. (In J. Clin Lab. Invest 24, Supplement 107, 59, (1969)) report thrombin inhibition based on the amino acid sequence located near the splitting site of fibrinogen Aα chain Agent. Among the amino acid sequences discussed, these authors point out that the tripeptide sequence (ρ9-ρ2-ρΐ, hereinafter referred to as the ρ3-ρ2 ρι sequence) is the most effective inhibitor. Thrombin inhibitors based on a dipeptidyl derivative having an α, amidoaminoalkylguanidine at the P1-position are known from U.S. Patent 4,346,078 and International Patent Application WO 93/11152. Similarly, structurally related dipeptidyl derivatives have also been reported. For example, 'International Patent Application No. WO 94/29336 discloses compounds having, for example, aminomethylbenzidines, cyclic aminoalkylfluorenes, and cyclic aminoguanidines at the ρΐ-position (International Patent application WO97 / 23499 discloses some of these compound precursors); European patent application 0648 780 discloses compounds having, for example, cyclic aminoalkylguanidines at the P1- position. Thrombin based on peptidyl derivatives and cyclic aminoalkylguanidines (eg, 3- or 4-aminomethyl-1-methylpyridylhexahydropyridine) at the P1-position Inhibitors are known from European patent applications 0468 231, 0559046 and 0 641 779. A thrombin inhibitor based on a tripeptidyl derivative having arginine aldehyde at the P1-position was first disclosed in European Patent Application 0 185 390. Recently, peptide-derived derivatives based on arginine aldehydes and modified at the P3-position have been reported. For example, the international patent application WO 93/18060 discloses hydroxy acids, the European patent application 0 526 877 is a deamino acid, and the European patent application 0 542 525 is a 0-methylmandelic acid at the P3_ position. Serine proteases based on electrophilic ketones at the P1-position (example 200306975

(3) Inhibitors such as thrombin are also known. For example, European patent application 0 195 212 discloses peptidyl ketone esters and amidines, European patent application 0 362 002 is fluoroalkylamidone, and European patent application 0364 344 is α, / 3, 5- Triketone-based compounds, and European patent application 0 530 167, are alpha-oxy ketone derivatives of arginine, in position.

Other structurally different trypsin-like serine protease inhibitors based on C-terminal dihydroxyborane derivatives of arginine and its isothiocyanate analogs are known from European patent application 0293 881. And recently, thrombin inhibitors based on peptidyl derivatives have been disclosed in European Patent Application 0669 317 and International Patent Applications WO 95/35309, WO 95/23609, WO 96/25426, WO 97 / 02284, WO 97/46577, WO 96/32110, WO 96/31504, WO 96/03374, WO 98/06740, WO 97/49404, WO 98/57932, WO 99/29664, WO 00/35869 and WO 00 / 42059.

In particular, WO 97/02284 and WO 00/42059 disclose thrombin inhibitors having substituted mandelic acid at the P3 position. However, there is still a need for effective inhibitors of trypsin-like serine proteases, such as thrombin. There is also a need for compounds that have favorable pharmacokinetic forms of action and are selective in inhibiting thrombin, outperforming other serine proteases, especially those involved in hemostasis. Compounds exhibiting a competitive inhibitory activity against thrombin are expected to be particularly useful as anticoagulants, and thus can be used for the treatment of thrombosis and related disorders. SUMMARY OF THE INVENTION According to the present invention, a compound of formula I is provided.

W 〇

among them

Ra represents -OH or -CH2 OH; R1 represents at least one selected halo substituent; R2 represents one or two C! _3 alkoxy substituents, the alkyl portion of this substituent itself is one or more Fluoro substituent substitution (meaning that R2 represents one or two fluoroalkoxy (< ^ 3) groups); Y represents -CH2- or-(CH2) 2-; and R3 represents formula I (i) Or a structural fragment of I⑼:

Wherein R4 represents fluorene or one or more fluoro substituents; and one or both of &, X2, X3, and X4 represent -N-, and the other represents -CH-, or a pharmaceutically acceptable derivative thereof Thing. The term "π pharmaceutically acceptable derivative" includes pharmaceutically acceptable salts (such as acid addition salts). 200306975

系列 Abbreviations are shown at the end of this patent specification. The segment of the equation j⑴ and I (ii) · The wavy line on the bond indicates the position of the segment's bond. _, ^ = ≪ halo, including fluoro, chloro, bromo and iodo. In order to avoid confusion, when representing at least one selected halogen group, r1 may be absent (so it is replaced by tritium, so that the rules of valence bonds are still adhered to) or may represent one or more _ radical atoms. Group: R Table: Structural fragment of formula I (i), in which r4 represents-or a plurality of fluorine groups are substituted at 7. "'Preferred compounds of formula I include wherein R4 represents a single fluoro substituent, or position, or two fluoro substituents on either the 2- and 孓 positions or more preferably the 2- and 6- positions (Where the position of the substituent is determined by the point of attachment of the formula ... to the rest of the molecule (meaning to the -NHCH2- group)). When representing a structural fragment of formula I (ii) 'Preferred compounds of formula I include any of the following: (a) one of Xl, X2, Feng, and χ4 represents -N-, and the other represents -CH-; or ⑼ Whether it is Xι and X3, or X2 and X4, both represent -N-, and the other two (in an appropriate manner) represent (Η ... · Preferred compounds of formula I include: R represents a single fluoro, chloro or Bromine substituent; & 2 represents Cl-2 alkoxy, substituted by one or more fluoro substituents, such as -〇CHF2-, -〇CF3, -OCH2CF3, -och2ch2f or -och (ch2f) 2 R3 represents a structural fragment of formula i (i); R4 represents Η. More preferred compounds of formula I include: -10- 200306975

(6)

Ra represents OH; R represents a mono-chloro-based substituent; r2 represents OCF3 'at the factory 1 is preferably -0CH2 CHf2, or more preferably -0CHF2 or -0CH2 CH2F. Preferred substitution points for R and R2 on an associated phenyl group of a compound of formula I include two meta positions at the point of attachment of the rest of the molecule of the phenyl pair (meaning,

Relative to a carbon atom where f has ... or hydroxy acid, at the 3- and / or 5-position (preferably 3,5-substitution). Identifiable compounds of formula I include: where R2 represents one or two Cl_2 alkoxy substituents, the alkyl portion of this substituent is itself substituted with one or more fluoro substituents; or R2 represents one or two A A alkoxy substituent, the alkyl portion of this substituent itself is substituted with / or multiple fluoro substituents. Compounds of formula I can be prepared according to techniques known to those skilled in the art, such as described below.

According to another aspect of the present invention, a method for preparing a compound of formula 丨 is provided, comprising: (i) a compound of formula II

Where Ra, R1 and R2 are as defined above, and are coupled with a compound of formula m, -11-200306975 ⑺

III

Where Y and R3 are as defined above, for example, in coupling agents (such as chloracetin, in DMF, EDC, DCC, HBTU, HATU, PyBOP, or TBTU), appropriate bases (such as pyridine, DMAP, TEA, 2, 4 , 6-trimethylpyridine or DIPEA) and a suitable organic solvent (such as dichloromethane, acetonitrile, EtOAc or DMF); compound of formula IV

Where Ra, R1, R2, and Y are as defined above, and are coupled to a compound of formula V, R3CH2NH2 V where R3 is as defined above, for example, under the conditions described in method (i) above; (iii) where For compounds of formula I in which R1 does not exist, it is as defined below ~ Corresponding compounds of formula la, where R5 represents OR6, where R5 and R6 are as defined and defined later, and its reducing effect, for example, by hydrogenation, In appropriate catalysts (such as supported metal catalysts, such as Pd / C (such as 10% (w / w) Pd / C)) and appropriate solvents (such as low-carbon (such as Q_6) alkyl alcohols, such as ethanol) In the presence, and -12-200306975

情况 as appropriate in the presence of a suitable acid (such as acetic acid) and / or as described in Synth. Comm. (1998) 4351; or (iv) a corresponding compound of formula XVIA or XVffi as defined below, with an appropriate source of ammonia (Such as ammonium acetate or ammonia), under conditions known to those skilled in the art, such as through the formation of ethyl imidate (formed by the reaction of a compound of formula XVIA or XVIB with HCl (g) in ethanol) and Ammonia is reacted in ethanol or under the conditions described in Tetrahedron Lett. 40, 7067 (1999), the disclosure of this document is hereby incorporated herein by reference (for example, where R3 represents formula I (ii) Structural fragment in which 乂 2 or χ4 represents N compounds of formula I are prepared by corresponding compounds of formula XV® and ammonium acetate (for example, 1 to 30 equivalents of ammonium acetate) in ethyl acetate cysteine (for example, 1 to 30 equivalents of N-acetamidine cysteine) and a suitable solvent (such as a low-carbon alkyl group (such as Ci-6) alcohol 'such as methanol). Compounds of formula II can be obtained using known and / or standard techniques. For example, a compound of formula π, where Ra represents OH, can be obtained via an acid of formula VI

Where R1 and R2 are as defined above, and are made by reacting with: ⑻ Compound VII of formula VII, R, CN νπ where R "represents Η or (CHshSi, for example, at room temperature or high temperature (for example, less than 100t) In the presence of a suitable organic solvent (such as chloroform or dichloromethane), and if -13 · 200306975

⑼ If necessary, appropriate tests (such as TEA) and / or appropriate catalyst systems (such as zinc chloride or zinc chloride, or the use of palm catalysts, such as in chem Rev., (1999) 99, 3649 (The)), and then hydrolyzed under conditions familiar to the artist (eg, as described later);

(b) NaCN or KCN, for example, in the presence of NaHS〇3 and water, followed by hydrolysis; (c) chloroform, for example, at high temperatures (e.g., above room temperature, but below 100 < ^) at In the presence of a suitable organic solvent (such as chloroform), and if necessary in the presence of a suitable catalyst system (such as phosphonium chloride), followed by hydrolysis; (d) a compound of formula VIII

VIII

Where M represents Mg or Li, and then undergo oxidative splitting (such as ozonolysis or osmium or ruthenium catalysis) under conditions familiar to the artist; Under conventional conditions, hydrolysis is followed by, for example, the presence of HgO and HBF4. Compounds of formula II, in which Ra represents -CH2OH, can be prepared by reduction of compounds of formula ιχ

-14- 200306975 Description of the invention (1〇) ~ ———— where R represents Ci-6 alkyl or Cu alkylphenyl, and R1 and R2 are as defined above, for example, at or below room temperature, at In the presence of a suitable reducing agent (such as sodium borohydride) and a suitable organic solvent (such as methanol, ethanol, THF, or mixtures thereof), followed by hydrolysis of the tropinate of the intermediate of formula IXA formed,

〇

Among them, R, R1, and R2 are as defined above. Under the conditions familiar to this artist, for example, as described later. The skilled person will understand the reduction and hydrolysis steps, which can be performed in a single pot procedure, for example as described later.

A compound of formula II, wherein Ra represents -OH, alternatively by a compound of formula IXB

IX 巳 or its derivatives are optionally protected at the secondary hydroxyl group, where R1 and R2 are as defined above, in a suitable oxidant (such as a suitable free radical oxidant (such as TEMPO) and a suitable hypochlorite (such as sodium hypochlorite) ()) In the presence of -15- 200306975 (11) Description of the invention Continued 'made by oxidation under conditions known to the artist, such as between -10 C and room temperature, in a suitable solvent ( For example, water, acetone, or a mixture thereof), a suitable salt (such as an alkali metal halide, such as potassium bromide), and a suitable base (such as a metal carbonate or bicarbonate, such as sodium bicarbonate) are present. Compounds of the formula II, in which Ra represents the isomeric form of _OH (that is, compounds having different configurations with respect to the C- atom of the α-position to the C02 fluorene group) can be obtained by Isolated on palm specific derivatization steps. This can be achieved by, for example, the enzyme method. Such enzyme methods include, for example, transesterification of the α_〇Η group between room temperature and reflux temperature (for example, between 45 and 65 °), appropriate enzymes (such as lipase PS Amano), appropriate esters (E.g. vinyl acetate) and a suitable agent (e.g. methyl tertiary-butyl acid). The derivatized isomers can then be separated from unreacted isomers by separation techniques such as chromatography. The groups added to the compound of formula II in this derivatization step can be removed either before any further reaction or at any later stage in the synthesis of the compound of formula I. Other groups can be removed using conventional techniques (e.g., for esters of α-ΟΗ groups, which are hydrolyzed under conditions known to those skilled in the art (e.g., between room temperature and reflux temperature, under a suitable base (e.g., Na (OH) in the presence of a suitable solvent (such as MeOH, water or a mixture thereof))). Compounds of formula II in which Ra represents the isomeric form of -CH2OH can be separated by isotropic chromatography techniques (e.g., isomeric HPLC). Compounds of formula III can be obtained via compounds of formula X 200306975

(12) wherein Y is as defined above and is prepared by coupling to a compound of formula V as defined above, for example under conditions similar to those described herein for the preparation of a compound of formula I. Compounds of formula IV can be prepared by coupling a compound of formula π as defined above to a compound of formula X as defined above, for example under conditions similar to those described herein for the preparation of compounds of formula I. Compounds of formula VI can be obtained using known and / or standard techniques. For example, it can be made by: metal substitution of the compound of Formula XI (where the metal can be, for example, an alkali metal such as Li, or preferably a divalent metal such as Mg),

Where Hal represents a fluorene atom, selected from C1, order and 1 ′, and ^ and ^ are as defined above, and then reacted with an appropriate fluorene total source (such as N, N-dimethylmethylamine), for example, Under the conditions described; 还原 reduction of compounds of formula XII '

In the presence of a suitable reducing agent (such as DIBAL-H) where R1 and R2 are as defined above 200306975 Description of the Invention _ pages (13)-below; or (iii) oxidation of compounds of formula XIII,

OH

XIII

Wherein R1 and R2 are as defined above, in the presence of a suitable oxidant (such as Mη02, pyridinium chlorochromate, a combination of DMSO and chloramphozone, or a S03 pyridine complex in DMSO).

Compounds of formula IX can be prepared from their corresponding phenyl acetate (which can be obtained, for example, from their corresponding acetophenone, as described in J. Am. Chem. Soc. 98, 6750 (1976), or from their corresponding Benzyl cyanide (by standard hydrolysis procedures), borrowing techniques such as those described in J. Org. Chem. 54, 3831 (1989), and / or as described later. Compounds of formula IXB can be prepared by dihydroxylation of the corresponding compounds of formula XIIIA

XIIIA, where R1 and R2 are as defined above, in the presence of a suitable dihydroxylation agent (for example, a reagent or a reagent mixture that will provide 0s04, such as AD-mix-α, or especially AD-mix- / 3), such as in Under the conditions known to the artist, such as between -10 ° C and room temperature, in a suitable solvent such as water, tertiary-butanol or -18-200306975 Description of the invention®® (14) L—- mixtures thereof ) Exist. When an asymmetric oxidant is used, such as AD-mixed-α or AD-mixed- / 5, this method can be used to prepare a compound of formula IXΒ, which has a group of two C-atoms connected to the primary and secondary hydroxyl groups. Specific configuration (meaning R or S).

Compounds of formula XIIIA can be prepared by reacting a corresponding compound of formula XI, as defined hereinbefore, with a suitable source of an ethyl anion (such as tributyl (ethyl) tin) under conditions known to those skilled in the art, such as under Between room temperature and reflux temperature (for example, 50 ° C), in the presence of a suitable solvent (such as toluene), a suitable coupling agent (such as a palladium-rhenium complex, such as palladium (triphenylphosphine) palladium (〇)), And, if appropriate, in the presence of a suitable catalyst (eg, 2,6-di-tertiary-butyl-4-methylphenol).

Compounds of formula V, VII, Vin, X, XI, XII and XIII are either commercially available, known in the literature, or can be obtained by methods similar to those described herein, or by borrowing synthetic procedures, Obtained from readily available starting materials using appropriate reagents and reaction conditions according to standard techniques. Compounds of formula la, XVIA and XVIB can be obtained by the method described later. In the compounds of formula I, II, III, IV, V, VI, IX, IXA, IXB, XI, XII, XIII and XIIIA, the substituents on the benzene ring can be obtained by using techniques known to those skilled in the art. Standard functional groups are converted into each other, and are introduced and / or converted into each other from readily available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, compounds of formulas I, II, IV, VI, IXA, XI, XII and XIII can be individually prepared from compounds of corresponding formulas XIVA, XIVB, XIVC, XIVD, XIVE, XIVF, XIVG and XIVH compounds -19- 200306975

(15)

XIVC XIVD XIVE 〇 \ / 〇Me .OH Hal ^ Γ

XIVF XIVG XIVH where Ra, R, R1, R3, Y, and Hal (as appropriate) are as defined above, for example: (a) via reaction with the corresponding halogenated halogen fluoride (such as chlorine fluoride), such as at room temperature Or above room temperature (eg under reflux) in the presence of a suitable base (eg potassium tert-butoxide, KOH or NaOH, for example in aqueous solution) and a suitable organic solvent (eg THF, chloroform or isopropanol) ; Or (b) via reaction with a compound of formula XIVJ,

RxS (0) 2 〇Ry XIVJ v-· * where Rx represents ¢: ^ 4 alkyl, Ci-4 perfluoroalkyl or phenyl (substituted by f group, nitro or halo group as appropriate), and silicon is ch2cf3, ch2chf2, ch2ch2f -20- 200306975

(16) or CH (CH2 F) 2, for example in the presence of a suitable test (such as K2 C03) and a suitable solvent (such as DMF), for example, in both cases as described below.

Those skilled in the art will understand that these functional group transformations can also be performed at an earlier stage in the overall synthesis of compounds of formula II, IV, VI, IXA, XI, XII, and XIII (meaning, individually in the formula XIVB, XIVC, XIVD , XIVE, XIVF, XIVG and XIVH compounds).

Compounds of formula XIVA, XIVB, XIVC, XIVD, XIVE, XIVF, XIVG, XIVH, and XIVJ are either commercially available, known in the literature, or can be obtained by methods similar to those described herein, or Borrowed from synthetic procedures, according to standard techniques, it is obtained from readily available starting materials using appropriate reagents and reaction conditions. For example, compounds of the formula XIVA, XIVB, XIVC, XIVD, XIVE, XIVF, XIVG and XIVH can be obtained through the corresponding protected phenols (where the protecting group can be, for example, methyl, allyl, benzyl or tertiary-butyl) The removal protection is obtained under standard conditions. Furthermore, compounds of formula XIVD, in which R1 is a single chloro substituent, can be obtained from di- or trihalo-substituted benzenes (such as 1-Br, 3-C1, 5-F-benzene, in the manner of methoxy Group to replace a fluorine atom (for example, in 1-methyl-2-tetrahydropyrrolidone / methanol at high temperature via reaction with NaOMe), and to replace the bromo group with a methyl group (for example, as previously described for the preparation of compounds of formula VI (Described above), and then demethylated (for example, using PhSH in the presence of 1-methyl-2-tetrahydroρ biha g, in the presence of K2CO3)). Compounds of formula I, in which R1 is absent, can also be prepared from the corresponding compound of formula I (or via its appropriate precursor), where R1 represents a halo group (such as chlorohydrazone), for example by hydrogenation, known to those skilled in the art Under conditions. -21-200306975 ⑼ Turn to i Continued The compound of formula I can be isolated from its reaction mixture using conventional techniques. According to the present invention, pharmaceutically acceptable derivatives of compounds of formula I also include "protected" derivatives and / or compounds that act as prodrugs of compounds of formula I. Identifiable compounds that can be used as prodrugs of compounds of formula I, including compounds of formula la

Where R3a represents a structural fragment of formula I (iii) or I (iv)

R4 l (iii) where R5 represents OR6 or C (0) 0R7; R6 represents fluorene, alkyl, Chalkylaryl, or (V3 alkoxyaryl (wherein the alkyl groups of the two groups described later are It is optionally inserted by one or more oxygen atoms, and the aryl part of the two groups described later is optionally substituted by one or more substituents, which are selected from the group consisting of dentyl, phenyl, methyl or methyl Oxy-22- 200306975 (18) Description of the invention continued, the three groups mentioned later are optionally substituted by one or more functional group substituents; R7 represents C!-I 〇 Po group (groups mentioned later are considered In some cases, it is inserted by one or more oxygen atoms), or Ci-3 alkylaryl or Ci-3 alkoxyaryl (wherein the alkyl portion of the two groups mentioned later is optionally one or more oxygen atoms Insertion, and the aryl part of the two groups described later are optionally substituted by one or more substituents, the substituents are selected from the group 'phenyl, methyl, or methoxy, and the three groups described later are also considered In this case, it is substituted by one or more halo substituents); and Ra, R1, R2, Y, R4, X !, X2, X3, and χ4 are as defined above, and their pharmaceutically acceptable derivatives. The term "pharmaceutically acceptable derivatives" of compounds la includes pharmaceutically acceptable drugs (such as acid addition salts). In the fragments of formulas I (iii) and I (iv), the The wavy line indicates the bonding position of the segment. The alkoxyaryl groups that R6 and R7 can represent include alkyl and aryl groups connected by an oxygen atom. Alkylaryl and alkoxyaryl groups By connecting the alkyl portion of such groups to the rest of the molecule, the alkyl portion can be a branched chain (if there are a sufficient number (meaning three) carbon atoms) of R. and R7 can be The aryl moiety of the alkaryl and alkoxyaryl groups represented or substituted by them includes carbocyclic and heterocyclic aromatic groups such as phenyl, fluorenyl, pyridyl, pyrazolyl, isopropyl Hexazolyl, thiadiazolyl, pyrrolidyl, benzocrotyl, etc. The alkyl groups that R6 and R7 can represent can be straight-chain, or when there are a sufficient number (meaning at least three) of carbon atoms' It is a branched chain and / or cyclic. Furthermore, when there are a sufficient number (meaning at least four) of carbon atoms, this alkyl group can also be partially cyclic / non-cyclic. It can also be saturated or when there are a sufficient number of carbon atoms (-23-200306975 (19) Inventory®® means at least two) carbon atoms, R6 and R7 can be substituted by halo groups. It is unsaturated. Including fluorine I, chloro, bromo, and iodine I include: groups, such as c4_6 cycloalkyl; as indicated above, when R5 represents C (〇) 〇R7, preferably R7 ⑻ linear, branched or Cyclic (: 3-6 alkane (b) Cb2 alkylaryl, such as fluorenyl, substituted. Preferred compounds of formula la, including those in which R5 represents OR6. When R5 represents OR6, preferred R6 groups include: (a) ；; ⑼ unsubstituted linear, branched, or cyclic Ci 8 (e.g., a alkynyl group such as a linear group & (Example # 61 'or especially methyl), branched & 8 alkyl group (Such as iso-propyl, iso-butyl, or 4. · heptyl) or cyclic Cl? Alkyl (meaning C4 -7 cyclopentyl 'such as cyclobutyl or cyclohexyl) · halogenated oxyphenyl ( For example, C2 alkoxyphenyl), the phenyl is optionally substituted by one or more substituents, as indicated above (for example, trifluoromethyl); (d) q -2 alkynylaryl (for example, methyl Aryl), The middle aryl group is benzidyl, indazolyl or isoxazolyl, in which the three groups mentioned below are respectfully replaced by one or more substituents, as noted above (for example, methoxy & Base, bromo and / or chloro). & Preferred compounds of formula la include those in which R5 represents OR6 and R6 represents linear branched (in an appropriate manner) or cyclic (in an appropriate manner) C ^ 6 (e.g., & alkyl, such as methyl, Ethyl, n-propyl, iso-propyl or cyclobutyl. -24-200306975 Description of the invention ⑽-A compound of formula la can be prepared by one or more of the following methods: 相应 The corresponding compound of formula II as defined above Reaction with a compound of formula XV

〇

Wherein Y and R3a are as defined above, for example, under conditions similar to those described above for the synthesis of compounds of formula I;

(b) the corresponding reaction of a compound of formula IV with a compound of formula XVI as defined previously R3aCH2NH2 XVI wherein R3a is as defined above, for example under conditions similar to those described above for the synthesis of a compound of formula I; (C) for a compound of formula la, Where R5 represents OH, via the corresponding compound of formula XVIA or XVIB.

XVIA

XVIB

-25- 200306975

(21) Of which 11% 111, & 2,114, Ah, 乂 1, 乂 2, 乂 3 and 乂 4 are as defined above and react with hydroxylamine, for example, under conditions known to those skilled in the art; (d) For compounds of formula la, where R5 represents OR6, is via a protected derivative of the corresponding compound of formula 1, which is, for example, a compound of formula XVII

Where R3b represents a structural fragment of formula I (v) or I (vi):

R4 N—C〇ORb NH2

N—C〇〇Rb f / NH2 l (vi) l (v) where Rb represents, for example, -CH2 CH2-Si (CH3) 3 or fluorenyl, or a tautomer thereof, and 1 ^, 111, 112, y , 114,: ^ 1,: ^ 2, 乂 3 and 乂 4 are as defined above, and the compound R6 〇ΝΗ2 χνιπ of the formula 乂 ¥ 111 wherein R6 is as defined above, or an acid addition salt reaction thereof, for example, at room temperature with Between reflux temperatures, in the presence of a suitable organic solvent (such as THF, CH; 3 CN, DMF, or DMSO), and then remove the -C (0) 〇Rb group. ) Description of the invention is carried out under contented conditions (such as via reaction with QF or TFA (such as described below)); ； For compounds of formula la, where R5 represents 0H, is via a compound of formula XVII as defined above, where Amidino is reacted with hydroxylamine or its acid addition salt, for example, under conditions known to those skilled in the art; ⑺ For compounds of formula la ', where R5 represents C00R7, via the corresponding compounds of formula I and formula XIX as defined above Reaction L1 COOR7 where L1 represents a suitable leaving group, such as halo or nitrophenyl (such as 4-nitrophenyl), and R 7 is as defined above, for example, at or about room temperature, in the presence of a suitable base (such as NaOH 'for example in an aqueous solution) and a suitable organic solvent (such as digas methane); or (g) for a compound of formula la, where R5 Represents 0CH3 or 0CH2 CH3, via the corresponding compound of formula la, where R5 represents OH, and individually reacts with dimethyl sulfate or diethyl sulfate, such as in a suitable base (such as an alkali metal hydroxide such as KOH (such as in 'At 50% by weight in aqueous solution)) and appropriate catalysts (such as quaternary ammonium halides) such as benzyltrimethylammonium chloride (for example in CH2 (¾ or THF solution at 10% by weight) ). In the fragments of formulas I (v) and I (vi), the wavy lines on the bonds represent the bonding positions of the fragments. The compounds of formula XVIA and XVIB can pass through the corresponding compounds of formula Π as defined above. Reacted with compounds of formula XIXA or XIXB to make -27- 200306975

Invention Description MM (23)-

X3 ~ X4 wherein R4, Y, Xi, X2, X3 and X4 are as defined above, for example under conditions similar to those described above for the synthesis of compounds of formula I. Compounds of formula XVIA and XVIB can alternatively be prepared by reacting corresponding compounds of formula IV as defined above with compounds of formula XIXC or XIXD

H2N

R4

XIXC

ΧΓχ4 wherein R4, Xi, X2, X3, and X4 are as defined above, for example, under conditions similar to those described above for the synthesis of compounds of formula I. A compound of formula XVII can be prepared by reacting a corresponding compound of formula II as defined above with a compound of formula XX

-28-

XX 200306975 Description of Invention Continued (24) ------ wherein Y and R3b are as defined above, for example, under conditions similar to those described above for the synthesis of compounds of formula I. Alternatively, a compound of formula XVII can be prepared by reacting a compound of formula I with a compound corresponding to compound of formula XIX. In the compound described below, R7 is substituted instead, and an Rb group exists, where Rb is as defined above, for example, above Under the conditions described for the preparation of compounds of formula la. Compounds of formula XV and XX can be prepared by reacting the corresponding compounds of formula X as defined above, individually with compounds of formula XVI as defined above, or compounds of formula XXI.

R3bCH2NH2 XXI wherein R3b is as defined above, for example under conditions similar to those described above for the synthesis of compounds of formula I. Compounds of formula XVI, XVIII, XIX, XIXA, XIXB, XIXC, XIXD and XXI are either commercially available, known in the literature, or can be used by methods similar to those described herein, or by borrowing Synthetic procedures are obtained from readily available starting materials using appropriate reagents and reaction conditions according to standard techniques. For example, compounds of formula XIXA and XIXB can be prepared by reacting the corresponding compound of formula XIXC or XIXD (as appropriate) with a compound of formula X, for example under conditions similar to those previously described. The compounds of formula I and la, as defined above, and any of the derivatives thereof are hereinafter referred to as "compounds of the present invention". Preferred compounds of the present invention therefore include compounds described in the examples below. In this regard, compounds of the invention which may be pointed out include:

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab; -29- 200306975

(25)

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl) (5-OCHF2 HR) CH (0H) C (0) -Aze-Pab (0Et);

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0nPr);

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0iPr);

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0cBu);

Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0H); Ph (3-Cl) (5-0CHF2)-(R) CH (0H) C (0) -Aze-Pab (C00c pentyl); Ph (3-Cl) (5-OCHF2)-(R) CH (OH) C (0) -Aze-Pab (Z);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Me); Ph (3-Cl) (5-0CF3HR) CH (0H) C (0) -Aze-Pab (0CH2-3- (5-Me-isoxazole :)); Ph (3-Cl) (5-0CF3HR) CH (0H) C (0) -Aze-Pab (0CH2-3-pyridine ); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0iBu);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Et);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn); Ph (3-Cl) (5-0CF3HR) CH (0H) C (0) -Aze-Pab (0c hexyl);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0cBu);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0CH2 CH2 OPh (3-CF3)); Ph (3-Cl) (5-OCF3)- (R) CH (0H) C (0) -Aze-Pab (0Bn (4-Cl)); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze- Pab (0Bn (3-Me0)); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (2-Br)); Ph (3- Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (4-Me)); Ph (3-Cl) (5-0CF3)-(R) CH (0H ) C (0) -Aze-Pab (0-4-heptyl); Ph (3-Cl) (5-OCHF2)-(S) CH (CH2 0H) C (0) -Aze-Pab; -30- 200306975 ⑻ L_Explanation

Ph (3-Cl) (5-OCF3)-(S) CH (CH2 0H) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCF3)-(S) CH (CH2 0H) C (0) -Aze-Pab (0Me);

Ph (3-OCHF2 HR) CH (OH) C (0) -Aze-Pab;

Ph (3-OCF3)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCH2 CF3)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCH2 CF3)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl) (5-OCH2 CHF2 HR) CH (OH) C (0) _Aze_Pab;

Ph (3-Cl) (5-OCH2 CHF2)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl) (5-OCH2 F)-(R) CH (OH) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCH2 F)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl) (5-OCH2 CH2 F)-(R) CH (OH) C (0) -Aze-Pab;

Ph (3-Cl) (5.0 CH2 CH2 F)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl) (5-OCH (CH2F) 2)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-Cl) (5-OCH (CH2 F) 2)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-F) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-F) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Br) (5-OCH2 FHR) CH (OH) C (0) -Aze-Pab;

Ph (3-Br) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab;

Ph (3-Br) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0Me);

Ph (3-Cl, 5-0CH2CHF2)-(R) CH (0H) C (0) -Aze-Pab (0H);

Ph (3-Cl, 5-0CH2CH2F)-(R) CH (0H) C (0) -Aze-Pab (0H);

Ph (3-Cl, 5-OCHF2) KR) CH (OH) C (0) -Pro-Pab;

Ph (3-Cl, 5-OCHF2)-(R) CH (OH) C (0) -Pro-Pab (OMe);

Ph (3-Cl, 5-0CHF2)-(R) CH (0H) C (0) -Aze-NH-CH2-((2-methylfluorenyl) -5-pyridyl); -31-200306975 Description of the invention Continued (27)-2 丨 丨 _.__-___ 丨 丨 丨 _ 丨 —

Ph (3-Cl, 5-0CHF2)-(R) CH (0H) C (0) -Aze-NH-CH2-((2-methoxymethylmethyl) -5-pyridyl);

Ph (3-Cl5 5-〇α ^ 2)-(ΙΙ) αί (ΟΗ) (: (0) -Αζ6-ΝΗ-αΗ2-((5-methylamino) -2-pyrimidinyl); ； 11 ( 3-(: 1,5-00 ^ 2)-(11) 0 «(011) (:( 0) -eight-2b> ^-012-((5-methoxymethylmethyl) -2-) Pyrimido);

Ph (3-Cl, 5-0CHF2HR) CH (0H) C (0) -Aze-Pab (3-F);

Ph (3-Cl, 5-0CHF2 > (R) CH (0H) C (0) -Aze-Pab (2,6-di-F);

Ph (3-Cl, 5-0CHF2: KR) CH (0H) C (0) -Aze-Pab (2,6-two F) (OMe);

Ph (3-Cl, 5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (2,5-di F);

Ph (3-Cl, 5-0CHF2) _ (R) CH (0H) C (0) -Aze-Pab (2,5-two F) (OMe); and Ph (3-Cl) (5-0CHF2HR) CH (0H) C (0)-(S) Aze-Pab (2,6-diF) (OH). The compounds of the present invention can exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. Specific tautomeric forms that may be indicated include those in compounds of formula la which are linked to the double bond position in the fluorene functional group and the R5 position of the substituent. The compounds of the present invention also contain two or more asymmetric carbon atoms, and thus can exhibit optical and / or diastereoisomeric phenomena. Diastereomers can be separated using conventional techniques such as chromatography. Various stereoisomers can be isolated by using compounds such as racemic or other mixtures to separate compounds using conventional HPLC techniques. Alternatively, the desired optical isomers can be reacted via suitable optically active starting materials under conditions that will not cause racemization or epimerization, or by derivatization, such as the use of homoparameric acids, It is then prepared by conventional separation of diastereomeric derivatives (such as HPLC chromatography on silica gel). All stereoisomers are included within the scope of the invention. -32- 200306975 Description of the Invention Continued (28) ————- The compound of the present invention, in which the following

The snippets are S-configured and are preferred. Preferred compounds of the present invention include the following structural fragments when Ra represents -OH.

Shows R-configuration, or when Ra represents -CH2OH, show S-configuration. g In the above two segments, the wavy line on the bond indicates the bond position of the segment. 1 The compounds of the present invention that can be pointed out include Ph (3-Cl) (5-0CHF2) -CH (0H) C (0) -Aze- ^

Pab (where, in this case, Aze represents the monoazatetra-2-carboxylic acid ester by a symbol (meaning in the (R)-and / or (S) -configuration), and equivalent compounds, where Instead of the hydrogen atom in the formazanyl unit in Pab, there is a group -OR6 (as defined above), where R6 represents a Ci-3 alkyl group (meaning? 11 (3-0: 1) (5-0 (: 1 ^ 2) -01 (0 print (:( 0) -Aze-Pab (OMe), Ph (3-Cl) (5-0CHF2) -CH (0H) C (0) -Aze-Pab (0Et ), Ph (3-Cl) (5-OCHF2) -CH (0H) C (0) -Aze-Pab (0nPr) or Ph (3-Cl) (5-0CHF2) -CH (0H) C (0) -Aze- -33-200306975 (29)

Pab (OiPi :)). The compounds of the present invention may be further pointed out, specific compounds identified in the sentence. Those skilled in the art should understand that the functional groups of the intermediate compounds mentioned above and below may have to be protected by a protecting group. Functional groups that are generally expected to be protected, including the appropriate protective groups for hydroxyl and amino groups, including Substituted and / or (such as methyl, allyl, fluorenyl, or tertiary-butyl), or a diarylalkylsilyl group (such as tertiary-butyldimethyl-butyldiphenylsilane or Appropriate protecting groups for trimethylsilyl) and tetrahydroacid, including Cu alkyl or fluorenyl ester fluorenyl, including tertiary-butoxycarbonyl, trimethylsilylethoxycarbonyl (Teoc) . Formamyl nitrogen may also be oxy-protected and may be protected either mono- or di-. The protection and removal of the functional group can be before the coupling or any other reaction in the scheme mentioned above, or the protecting group can be removed according to the techniques known to those skilled in the art. Those skilled in the art will understand that in order to obtain the compounds of the present invention in an alternative and in some field manners, as mentioned above, they can be performed in different orders, and / or individual reactions can be performed at different stages (meaning, The specific reactions mentioned above, the addition of substituents and / or the elimination of chemical groups for protective groups, or the need to carry out. The type of chemical substance involved, including the dominant protective group is not included in the aforementioned method , And carboxylic acid. P-hydroxy unsaturated alkyl trialkylsilyl silyl group, third piperanyl group. P-carboxyl. P-amino group and formamyloxycarbonyl or 2- by hydroxyl or alkane or after, Or later. Follow the more appropriate individual processing steps in the transfer described below (the different intermediates in the entire route are combined). This may take the requirements and types, -34- 200306975 (30) description of the invention and the order in which the synthesis is achieved. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry," edited by JWF McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd Edition, TW Greene & PGM. Wutz, Wiley-Interscience (1999). Protected derivatives of the compounds of the present invention can be chemically converted to the compounds of the present invention using standard removal protection techniques such as hydrogenation. Those skilled in the art will also understand that certain compounds of formula la may also be referred to as protected derivatives of compounds of formula I. "Medical and medicinal uses The compounds of the invention may themselves have pharmacological activity. The compounds of the invention may have such activity. Including, but not limited to, compounds of formula I. However, other compounds of the invention (including compounds of formula Ia) may not have such activity, but may be administered parenterally or orally, and may then be metabolized in the body to form Pharmacologically active compounds (including but not limited to the corresponding compounds of formula I). Such compounds (which also include compounds that may have a pharmacological activity of 10,000, but the activity is slightly lower than the `` activity '' they are metabolized to Compound), and thus can be described as a "prodrug of the active compound," which is' metabolized in the body due to its pharmacological activity 'and formed to show that the compound of the present invention is useful as a medicine and therefore' the compound of the present invention is useful and / Or a pharmacologically active compound after oral or parenteral administration. Therefore, in one aspect, the drug provides the present invention The compounds are thus used according to the invention for further medical pleasure. -35- 200306975 (31) Description of the invention Page M In particular, the compounds of the invention are effective inhibitors of thrombin, both by themselves and / or (For example, in the case of prodrugs), which are metabolized after administration to form an effective inhibitor of thrombin, which can be confirmed, for example, in the tests described below. The so-called "thrombin inhibitor prodrug", my It is added to it in an experimentally measurable amount and within a predetermined time (for example, about 1 hour) after oral or parenteral administration (see, for example, Test E below), or in the presence of liver microsomes Next, after incubation (see, for example, Test G below), compounds that form thrombin inhibitors are formed. _ Therefore, the compounds of the present invention are expected to be useful for symptoms in which thrombin inhibition is needed 'and / or symptoms in which anticoagulant treatment is needed, including the following: treatment and / or prevention of blood in animals (including humans) and / or Blood test formation in tissues and excessive blood coagulation. It is known that too high blood coagulability can lead to thrombotic plug disease. Mention may be made of symptoms associated with excessively high blood coagulation and thrombotic plug disease, including genetic or acquired protein C resistance 'such as factor V-mutation (factor V Leiden), and antithrombin 111, Genetic or acquired deficiency on protein C, protein S, heparin cofactor π. Other symptoms known to be associated with excessive blood coagulation and thromboembolic disease 'include circulating antiphospholipid antibodies (lupus anticoagulants), homocysteine, heparin-induced thrombocytopenia, and fibrils Defects in the action of proteolytic enzymes, as well as coagulation symptoms (such as disseminated intravascular aggregation (DIC)) and general vascular injury (such as due to surgery). Treatment of undesired excess of thrombin without signs of excessive blood coagulation, such as in neurodegenerative diseases such as Alzheimer's -36-200306975 (32) Description of the disease Specific disease states, including the treatment and / or prevention of venous thrombosis (such as DVT) and pulmonary vascular embolism, arterial thrombosis (such as stroke and peripheral arterial thrombosis based on myocardial infarction, restless colic, thrombosis), And systemic plugs, often from the anterior chamber during anterior atrial fibrillation (such as non-valvular anterior atrial fibrillation), or from the left ventricle after transmural myocardial infarction, or caused by congestive heart failure; prevent thrombolysis, Re-occlusion after percutaneous transluminal angioplasty (PTA) and coronary shunt surgery (meaning blood formation); prevention of thrombosis after general microsurgery and vascular surgery. Other indications include the treatment and / or prophylaxis of disseminated intravascular coagulation caused by bacteria, multiple trauma, poisoning, or any other mechanism; when blood and foreign body surfaces such as vascular grafts, vascular graft membranes, blood vessels Anti-amplification when contacting a catheter, mechanical and bioprosthetic valve or any other medical device is a blood agent 'and ▲ anticoagulant treatment when blood is in contact with a medical device outside the body, such as during cardiac and vascular surgery, use heart

Formation of atherosclerotic plaques, cerebral arterial disease, cerebral infarction, cerebral hemorrhage, colic (including aortic angioplasty (PTA) and thrombosis, cerebral plug, peripheral arterial disease, stable colic), Restenosis after perfusion injury and percutaneous coronary bypass surgery. -37- 200306975 (33) The invention shows that the compound of the present invention which can inhibit trypsin and / or thrombin can also be used in the treatment of pancreatitis. The compound of the present invention is therefore required in both the treatment and treatment of these symptoms. According to another aspect of the present invention, there is provided a method for treating a symptom in which it is necessary to inhibit blood enzymes, which method comprises administering a therapeutically effective amount of a compound of the present invention to a person suffering from or susceptible to such a symptom. The compounds of the present invention are generally administered orally, intravenously, subcutaneously, cheek, rectum, skin, nasally, tracheally, bronchally, by any other parenteral route or via inhalation to include whether It is a pharmaceutical preparation in the form of a free base or a pharmaceutically acceptable non-toxic organic or inorganic acid addition salt, and is administered in a pharmaceutically acceptable dosage form. The preferred route of administration of the compounds of the present invention is the oral cavity. Preferred pharmaceutical formulations include modified release pharmaceutical compositions containing a compound of the invention. The term "pharmaceutical composition", as amended, is well understood by those skilled in the art, including any where the drug (meaning the compound of the invention) expansion and / or release rate is changed by manipulation of Galen The composition, and therefore included in Jiang Tiexiangdian (USP XXII), has the definitions provided in pages xxΐί 序 and xiiv of the preface / preface, the disclosures associated with this document are hereby incorporated herein by reference. Therefore, a suitable modified release formula can be made by skilled personnel according to standard pharmaceutical techniques (see, for example, cadaver / zannacewtoc / i enteric waste, 6, 57 (1984); 别 炎 之 静 # 边 用, Volume II, edited by Langer and Wise (1984) -38- 200306975

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Bocaraton, Florida, pp. 1-34; # 桌 之 工 君 方 希, edited by Sandel, Swedish Medicine Press (1993) pp. 93-104;荸 ", pp. 191-211, edited by M. E. Aulton (1988) (Chui * chm Livingstone). Preferred modified release formulations therefore include those in which a suitable compound of the invention is embedded in a polymer matrix. In this regard, I prefer to provide a formulation containing the compound of the present invention for oral administration, in the form of a so-called "swelling" modified release system, or "gel matrix π modified release system, in which the compound of the present invention is present in an aqueous medium Swelling polymers (meaning π hydrophilic gelling ingredients '') are provided together. In particular, we prefer to formulate the compounds of the present invention together with the compounds containing carrageenan and one or more neutral gelling polymers. In a gelling matrix composition. Carrageenan is preferably present in such a preferred formulation at a content of more than 15% by weight. Preferred grades of r carrageenan, including pharmaceutical grade carrageenan (Available from FMC biopolymer), which has a viscosity of not less than 5 centipoise (cps), preferably in the range of 5-10 centipoise (for a 1.5% solution warmed to 82 ° C, Then at 75 ° C, measure viscosity with a Brookfield LV viscometer equipped with a # 1 spindle and operate at 30 rpm, and industrial grade carrageenan (available from Fluka Biochemica), which preferably has Viscosity of not less than 14 mPa.s 0.3% aqueous solution to 20 ° C, then use Haake-type falling ball viscometer, use with Lauda thermostat C3 and Hakke-Mess-System III, and use stainless steel balls coated with gold with a density of 7.8 g / cm³ to measure the viscosity The neutral gelled polymer can be a single or a mixture of more than one neutral corrosive polymer, which has gelling properties and has a pH value that is substantially independent of -39- 200306975 Invention Description Continued! .M ': · -: Ά㈣. (35)-Solubility. This neutral gelled polymer is preferably present in the formulation in an amount of more than 10%, but more than 20% by weight. Suitable neutral gelled polymers include polyethylene oxide ( PEO), derivatives and members of the PEO group (such as polyethylene glycol (PEG), preferably naturally occurring in a solid state, with appropriate molecular weight or viscosity). If used as a separate neutral gelling polymer, PEO is preferred The system has a MW ^ 4 million (4M), which corresponds to an aqueous solution with a viscosity range of 1650-5500 mPa.s (or 1650-5500 centipoise; for a 1% aqueous solution at 25 ° C, using a Brookfield RVF viscometer, using No. 2 Spindle, measured at 2 rpm Other suitable PEO examples include PEO with a MW of about 5 million (5M), which corresponds to an aqueous solution with a viscosity in the range of 5500-7500 mPa.s, or PEO with a MW of about 8 million (8M), which corresponds to an aqueous solution with a viscosity in the range of 10,000-15,000 mPa. .s. This range covers the typical solution viscosity values (expressed in centipoises) measured at 25 ° C as quoted in USP24 / NF 19,2000, pages 2285-2286. If PEG is used as the neutral gelling polymer alone, it preferably has a high molecular weight, such as about 20,000 MW, which corresponds to a viscosity range of 2700-3500 mPa.s (or 2700-3500 centipoise), using a 50% aqueous solution ( w / w), measured at 20 ° C using a capillary viscometer (Ubbelohde or equivalent). [Reference: European Pharmacopoeia 3rd edition, 2000, Supplement, pages 908-909. ] Other suitable gelling polymers include cellulose derivatives such as hydroxypropyl methylcellulose (HPMC) or hydroxyethyl cellulose (HEC), which have suitably high viscosity (for example, HPMC 10000 centipoise, ', f HPMC 15000 centipoise, f ,,, HECHH type "or nHEC type Η When used as a neutral polymer alone, hydroxypropyl methylcellulose polymer, such as nHPMC 10000 centipoise" and nHPMC 15000 centipoise π individually With apparent viscosity of 7500-14000 mPa.s (or 7500-14000 centipoise) and 11250-21000 -40- 200306975 Description of invention (36) -----

mPa.s (or 11250-21000 centipoise), which is measured at 20 ° C using a 2% (w / w) aqueous solution, with reference to dried material, and measured using a capillary viscometer (Ubbelohde or equivalent). A type of hydroxyethyl cellulose polymer, such as " Natrosol 250 Pharma, type HH ", available from Hercules (Aqualon), typically shows a Brookfield viscosity of about 20,000 mPa.s using a Brookfield Synchro-Lectric LVF instrument , At 1% solution concentration, No. 4 spindle, spindle speed 30 rpm, factor 200, 25 ° C (see Natrosol Booklet of Physical and Chemical Properties, 33 · 007-E6 (1993), page 21). The specific formulations indicated include those in which the compound of the present invention is formulated with (-carrageen and HPMC (10,000 centipoise)) at a ratio of 50 ... 50 (wt%), or at a ratio of 50:50 (wt%) Carrageen and PEO 4M—from the formulator. Preferred additional excipients in this formulation include lubricants such as sodium stearyl fumarate.

Depending on the condition and patient to be treated and the route of administration, these compositions may be administered in different doses. The compounds of the present invention may also be combined and / or co-administered with any antithrombotic agent with a different mechanism of action, such as one or more of the following antithrombotic agents · Platelet-destroying agents, ethsalic acid, ticlopidine And clopidogrel; Prostaglandin receptor and / or synthetase inhibitors; Fibrinogen receptor antagonists; Prostacyclin mimics; Phosphodiesterase inhibitors; ADP-receptors (P2T) antagonists; and inhibitors of carboxypeptidase U (CPU). The compounds of the invention may be further combined and / or co-administered with a thrombolytic agent, such as one or more tissue plasminogen activators (natural, -41-200306975).

(37) Recombination or denaturation), streptokinase, urokinase, prourokinase, p-methoxybenzylated plasminogen_streptokinase activator complex (APSAC), animal salivary gland plasmin Pro-activator I 'to treat thrombotic diseases, especially myocardial infarction. Therefore, according to another aspect of the present invention, there is provided a pharmaceutical formulation ' comprising a chemical compound of the present invention mixed with a pharmaceutically acceptable adjuvant, diluent or carrier. The oral dose is about 0.001 to 100 mg / kg body weight, and 0.001 to 50 mg / kg body weight, when administered orally parenterally.

In order to avoid confusion, "treatment" is used in this text. First, your AH system includes treatment and / or preventive treatment. Compared with compounds known in the prior art, the present invention > Λ & , Which can be more effective, lower toxicity, longer action, and two active ranges, more effective, produce fewer side effects, and "has a broader and tends to absorb and / or has a better pharmacokinetic action form (such as轺 *, oral bioavailability and / or lower clearance) and / or other Arita, 'use pharmacological, physical or chemical properties to outperform this known compound. This invention is based on the J 1 compound However, there is another advantage: 'It can be compared to the drug that is known in the art. Compounds are less commonly used in biological experiments

The following test procedures can be used. In this test, the measurement of the coagulation time of blood enzymes is described in 42-200306975 invention description; (38) 丨 one-one Incubate the inhibitor solution (25 microliters) with plasma (25 microliters) for three minutes. Then, add human thrombin (T 6769; Sigma Chemical Company or Hematology Technology) in buffer solution, pH 7.4 (25 μl, 4.0 NIH units / ml), and in an automatic device (KC 10; Amelung) Measure setting time. Thrombin clotting time (TT) is expressed in absolute values (seconds) and the ratio of TT (TT0) without inhibitor to TT (TTi) with inhibitor. Plot the ratio (range 1-0) to the concentration of the inhibitor (logarithmic conversion) and fit the S-shaped dose-response curve y = a / [l + (x / IC5〇) s] according to the following equation: a = maximum range, meaning 1; s = slope of the dose response curve; and IC50 = inhibitor concentration that doubles the clotting time. The calculated value is processed on a PC using the software program GraFit version 3. The equation is set to: start at 0, end of definition = 1 (Erithacus software, Robin Leatherbarrow, Imperial University of Technology, London, UK).

Test B. Chromogen detection and determination of thrombin inhibition by thrombin inhibitor. The chromogen acceptance method was used in Plato 3300 robotic micro processor (Rosys AG, CH-8634 Hombrechtikon, Switzerland). Well half volume microtiter plate (Costai :, Cambridge, MA, USA; catalog number 3690). A stock solution of the test substance in DMS0 (72 μl), 0.1-1 mmol / L, was continuously diluted with DMS0 at 1: 3 (24 + 48 μl) to obtain ten different concentrations. As a sample, analysis was performed during the test. Dilute 2 microliters of sample with 124 microliters of detection buffer, and add 12 microliters of chromogen receiving solution (S-2366, Chromogenix Molndal, Sweden) in the detection buffer -43- 200306975 39) -------------, and finally 12 microliters of alpha-thrombin solution (human alpha-thrombin, Sigma Chemical Co., or Hematology Technology Co., Ltd.) in detection buffer, and mix the samples. The final test concentrations were: test substance 0,00068-13.3 micromoles / liter, S-2366 0.30 millimolars / liter, α-thrombin 0.020NIHU / ml. The linear absorbance increase during 37 minutes at 37 ° C is used to calculate the percentage inhibition of the sample when compared to a blank test without inhibitors. The IC50-robot value corresponding to the inhibitor concentration that causes 50% inhibition of thrombin activity is calculated from the log concentration versus% inhibition curve.

C. Determination of human thrombin inhibition constant Kj_

The Ki-assay was performed using a chromogen receiving method at 37 ° C on a Cobas Bio centrifugal analyzer (Roche, Basel, Switzerland). Residual enzyme activity after human alpha-thrombin was cultured with test compounds at different concentrations was measured at three different substrate concentrations and was measured as a change in optical absorbance at 405 nm. The test compound solution (100 μl; usually in a buffer or saline containing 10 g / L of BSA) and a test buffer (0.5 mg / L Tris- HCl pH 7.4, ionic strength 0.15, adjusted with NaCl) 200 microliters of human alpha-thrombin (Sigma Chemical Co., Ltd.) were mixed and used as samples for analysis in Cobas Bio. A 60 microliter sample was added with 20 microliters of water to 320 microliters of substrate S-2238 (Chromogenix AB, Molndal, Sweden) in the detection buffer, and the change in absorbance (ΔΑ / min) was monitored. The final concentrations of S-2238 were 16, 24, and 50 micromoles / liter, while thrombin was 0.125 NIH U / ml. Use steady state reaction rates to construct Dixon patterns, meaning inhibitors are concentrated -44-200306975

For example, the graph of the degree of clearance versus 1 / (ΛΑ / minute). For data points with different substrate concentrations, X = -Kj °

In Test D, in the case of inverse dissociative inhibitors, the off-line and off-line systems form a straight line with an intercept at

Microliter of inhibitor solution (90 microliters of plasma) and incubate with Aρττ reagent for 3 minutes and 4 miles, then add 100 microliters of calcium gas solution (〇25 M), and use the coagulation analyzer KC10 (Amelung ), According to the instructions of the reagent manufacturer, the measurement of the APTT coagulation time is expressed in absolute values (seconds) and the ratio of ApTT (APTT) without inhibitor to APTT (APTTi) with inhibitor. Plot this later-mentioned ratio (range 1-0) against inhibitor concentration (logarithmic conversion), and fit the S-shaped dose-response curve y = a / [K (x / IC5〇) s] according to the following equation where A == maximum range, meaning 1; s = slope of the dose response curve; and ic50 = inhibitor concentration that doubles the clotting time. The calculated values are processed on a PC using the software program GraFit 3rd Edition. The equation is set to start at 0 and the definition ends = 1 (Erithacus software, Robin Leatherbarrow, Imperial College of Science and Technology, England). IC50 APTT is defined as the concentration in human plasma of an inhibitor that doubles the time of the activated partial thromboplastin.

Test E -45- 200306975 (41)

In vitro coagulation! After dissolving in oral solution or in a rat to obtain 1 part of a wooden tube from the carotid artery, blood deficiency was obtained. Dilute with formic acid at 100 μl at 4000 rpm. And use standard test F to estimate rfa plasma clearance in white gas. The samples were collected at a mol / kg interval, and centrifuged at 100 μl for 10 minutes under cooling. The 10 microliter standard curve measurement rule is used to estimate the serum enzyme time. The parenteral administration of the compound of the present invention in ethanol: SolutdK: water (5: 5: 90), the inhibition of thrombin is based on sensory test One or two & before the experiment, the system was fitted with a catheter for blood sampling. On the day of the experiment, the compound was poured into a sodium citrate solution (0.13 moles per liter) and 9 plastic parts of blood were taken at a fixed time. Centrifuge the tube to a small plate of plasma. Cold Bet 'precipitates a 50 microliter plasma sample. Hold the specimen for 10 minutes. 75 microliters of the supernatant was used to make microliters 0.2%, and a solution of 10 microliters in volume was formed, and the concentration of thrombin inhibitor was measured by lc-ms / Ms analysis of the standard curve.

The Uf removal rate was determined in male Sprague Dawley rats. The compound was dissolved in water, injected as a subcutaneous bolus, and administered at 4 microdoses. Continuous blood samples up to 5 hours after drug administration. Centrifuge blood samples and transfer plasma and blood cells to vials containing citrate (10% final concentration). Acetonitrile was used to precipitate a 50 microliter plasma sample. Allow the sample to stand at 4,000 rpm. 75 microliters of the supernatant was diluted with 75 microliters of 0.2% formic acid in a volume of the resulting solution, analyzed by LC-MS / MS, and the concentration of the thrombin inhibitor was determined. Use the area under the logarithmic / linear trapezoidal pulp concentration-time distribution pattern and extrapolate to -46-200306975 Invention Description $ 卖 Μ (42) ~~ --- unlimited time. Then, the plasma clearance (CL) of the compound was measured as follows

CL = Dose / AUC values are reported in ml / min / kg.

Test G Stability in vitro The liver microparticle system was prepared from Sporgo-Dory rats and human liver samples according to the internal SOP. The compound was incubated at 37 ° C at a total microsomal protein concentration of 3 mg / ml at 0.05 mol / L trimethylolamine methane.

The infusion was cultured at pH 7.4 in the presence of the cofactors NADH (2.5 mmol / L) and NADPH (0.8 mmol / L). The starting concentration of the compound was 5 or 10 micromoles / liter. 60 minutes after the start of the culture, samples were taken for analysis. The enzyme activity in the collected sample was immediately stopped by adding 20% myristic acid in a volume equivalent to 3.3% of the total volume of the sample. The residual compound concentration (FINAL CONC) in the 60-minute sample was measured by LCMS, and the sample collected at zero time was used as a reference (START CONC). The reduced% of thrombin inhibitor is calculated as follows: [START CONC]-[FINAL CONC] 100% x- [START CONC]

Test H Arterial Thrombosis Mode The topical application of ferric chloride (FeCl3) to the carotid artery causes vascular injury. Rats were anesthetized by intraperitoneal injection of sodium pentobarbital (80 mg / kg; Apoteksbolaget; Umea, Sweden), followed by continuous perfusion (12 mg / kg / hour) throughout the experiment. Throughout the experiment, the external heat method was used to make -47- 200306975

(43) The body temperature of rats was kept at 38 ° C. This experiment started with a 5-minute control period. Five minutes later, human 125I-fibrinogen (80 kBq; IM53; Amersham International, Buckinghamshire, UK) was administered intravenously and used as a marker for subsequent incorporation of fibrin (pro) into the thrombus. Place the basal end of the carotid segment in a longitudinally open plastic tube (6 mm; Silastic®; Dow Coming, MI, USA) containing FeCl3 (2 μl; 55% w / w; Merck, Darmstadt, immersed) Germany) filter paper (diameter 3 mm; IF; Munktell, Grycksbo, Sweden). The left carotid artery was exposed to FeCl3 for 10 minutes, then removed from the plastic tube and immersed in saline. After fifty minutes, the carotid artery was removed and rinsed in saline. Ten minutes after 125I-fibrinogen injection, and at the end of the experiment, a reference blood sample was also taken for blood 1 2 51-activity determination. The 125I-activity in reference blood samples and blood vessel fragments was measured on a T counter (1282 Compugamma; LKB Wallac Oy, Turku, Finland) on the same day that the experiment was performed. Thrombosis size was determined as the amount of 125I-activity (qpm / mg) related to 1 2 51-activity in the blood that was incorporated into the vascular segment. General experimental details TLC was performed on silicone. Palm HPLC analysis was performed using a 46 mm x 250 mm Chiralcel OD column with a 5 cm guard column. The column temperature was maintained at 35 ° C. A flow rate of 1.0 ml / min was used. A Gilson 115 UV detector at 228 nm was used. The mobile phase contains organic compounds, ethanol, and trifluoroacetic acid, and the appropriate proportions are listed for each compound. Typically, the product is dissolved in a minimum amount of ethanol and diluted in mobile phase. LC-MS / MS was performed using an HP-1100 instrument equipped with a CTC-PAL syringe and a 5 micron, 4x100 mm ThermoQuest, Hypersil BDS-C18 column. Using API-48-200306975 (44) Invention Description βΜ:: -ν 3000 (Sciex) MS Detector. The flow rate is 1.2 ml / min, and the mobile phase (gradient) contains 10-90% acetonitrile and 9 (M0% 4mM ammonium acetate aqueous solution, containing 0.2% formic acid. The 1H NMR spectrum uses tetramethylsilane as the Internal standards are recorded. 1 3 C NMR spectra are recorded using the deuterated solvents listed as internal standards. Embodiment Example 1

Phn-riVS-OCHFO-fR ^ CHrOmCfOVAze-PahrOnRii ^ (D3-Hydroxy-5-methoxybenzyl__ 鬼 _) 3,5-dichlorotoluene ether (74.0 g, 419 MM), added dropwise to rhenium metal (14.2 g, 585 mM, pre-washed with 0.5 N HC1) in THF (100 ml) at 25 ° C. After addition, dropwise Add ι, 2-dibromoethane (3.9 g, 20.8 mmol). The resulting dark brown mixture was heated at reflux for 3 hours. The mixture was cooled to 0 ° C and N, N-diamine was added in one portion. Methylformamide (60 mL). The mixture was separated with ether (3 X 400 mL) and 6N HC1 (500 mL). The combined organic extracts were washed with brine (300 mL), dried and dried. (Na2SO4), filtered and concentrated in vacuo to give an oil. Flash chromatography (2x) on silica gel, dissolving with hexane: EtoAc (4 ·· 1) to obtain the subtitled compound ( 38 · 9 g '54%) 'is a yellow oil. 1 H NMR (300 MHz, CDCI3) 6 9.90 (s, 1H), 7.53 (s, 1H), 7.38 (s, 1H), 7.15 (s, 1H) , 3.87 (s, 3H). (Ii) 3-f. A 5-hydroxy group 3. Chloro-5-methoxybenzaldehyde (22.8 g, 134 mmol; see -49-200306975 above, the solution in step (i)) in CH2C12 (250 ml) is cooled to 0 ° C. Boron tribromide (15.8 ml, 167 mmol) was added dropwise over a period of 15 minutes. After stirring, Η20 (50 ml) was slowly added to the reaction mixture over 2 hours. Then, Et20 (2 X 100 Ml). The solution was extracted. The organic layers were combined, dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel was performed with hexane: EtOAc (4: 1) to give the subtitled compound (5.2 G, 25%). 1 H NMR (300 MHz, CDC13) 5 9.85 (s, 1H), 7.35 (s, 1H), 7.20 (s, 1H) 3 7.10 (s, 1H)? 3.68 (s, 1H) (iii) 3-Chloro-5-difluoromethanebenzaldehyde. 3-Chloro-5-hydroxybenzaldehyde (7.5 g, 48 mmol; see step 骡 ⑼ above) in 2-propanol ( 250 ml) and 30% KOH (100 ml) was heated to reflux. While stirring, CHC1F2 was bubbled into the reaction mixture over 2 hours. The reaction mixture was cooled, acidified with IN HC1, and extracted with EtOAc ( 2 x 100 ml . The organic material was washed with brine (100 mL), dried (Na2S04), filtered, and concentrated in vacuo. Flash chromatography on silica gel and dissociation with hexane · EtOAc (4: 1) gave the sub-title compound (4.6 g, 46%). 1 H NMR (300 MHz, CDC13) 5 9.95 (s, 1H), 7.72 (s, 1H), 7.52 (s, 1H), 7.40 (s, 1H), 6.60 (t, JH-f = 71.1 Ηζ , 1 iv) (iv) PhG-ClXS-OCHF ^ WR set · Τ 观 Γκ [make 3-chloro-5-difluoromethoxybenzaldehyde (4.6 grams, 22.3 millimoles; see above) In step (iii)), the solution in CH2C12 (200 ml) was cooled to 0 ° C. Znl 2 · (1.8 g, 5.6 mmol) and trimethylsilyl cyanide (2.8 g, 27.9 mmol) were added, and the reaction mixture was allowed to warm to room temperature and stirred for 15 hours. The mixture was partially concentrated in vacuo to give the subtitled compound as a liquid, which was directly -50- 200306975

(46) Used in step (v) below without further purification or characterization β (ν) Phrg-nVS-OCHF ^ -m ^^ rHromcrNH ^ OEt

Add Ph (3-Cl) (5-OCHF2HR, S) CH (OTMS) CN (6.82 g, assuming 22.3 mmoles; see step (iv) above) dropwise to HCl / EtOH (500 ml) The reaction mixture was stirred for 15 hours and then partially concentrated in vacuo to produce; the subtitled compound was a liquid and was used in step (vi) without further purification or characterization. (vi) Phn-ciyiocim ^ vn ^ Aa ^ omacytOEt causes Ph (3-Cl) (5-OCHF2HR, S) CH (OH) C (NH) OEt (6.24 grams, assuming 22.3 millimoles; see above) Step 骡 (ν)) was dissolved in THF (250 ml), 0.5MH2SC> 4 (400 ml) was added, and the reaction was stirred at 40 ° C for 65 hours, cooled down, and then concentrated in the middle of the vacuum to remove Except for most THF. The reaction mixture was then extracted with Et20 (3 x 100 ml), dried (Na2S04), filtered, and concentrated in vacuo to give the subtitled compound as a solid, which was used in step (vll) ’

No further purification or characterization is required.

(vii) Phr3-nx5-〇CHF1vrR.s ^ CHromrro ^ 〇H Ph (3-Cl) (5-0CHF2HR, S) CH (0H) C (0) 0Et (6.25 g, assuming 22.3 mmol) Ear; see step (vi) above in 2-propanol (175 ml) and 20% KOH (350 ml), and stir at room temperature for 15 hours. The reaction was then partially concentrated in vacuo to remove most of the 2-propanol. The residual mixture was acidified with 1MH2S04, extracted with Et20 (3 X 100 ml), dried (NhSOJ, and concentrated in vacuo to obtain a solid. Flash chromatography on silica gel was performed with CHC13: MeOH: concentrated NH4OH (6: 3: 1) dissociation to obtain the ammonium salt of the subtitled compound. This ammonium salt is then dissolved in a mixture of EtOAc (75 ml) and Η20 (75 ml) -51 · 200306975 (47) And acidified with 2N HC1. The organic layer was separated, washed with brine (50 mL), dried (Na2S04), and concentrated in vacuo to give the subtitled compound (3.2 g, 57% from step (iv ) To (vii)). 1 H NMR (300 MHz, CD3 OD) 5 7.38 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 6.89 (t, JH_F = 71.1 Ηζ, 1Η) , 5.16 (s, lH) (viii) (a) Ph (3-Cl) (5-OCHF)

rs ^ CHroAc ^ cro ^ QH Ph (3-Cl) (5-0CHF2HR, S) CH (0H) C (0) 0H (3.2 g, 12.7 millimoles; see step (vii) above) and month purpose A mixture of lipase PS "Amanon (~ 2.0 g) in ethyl acetate (125 ml) and MTBE (125 ml) was heated at reflux for 48 hours. The reaction mixture was cooled, filtered through Celite®, and washed with EtOAc The filter cake. The filtrate was concentrated in vacuo and subjected to flash chromatography on silica gel and dissolved with CHC13: MeOH: concentrated NH4OH (6: 3: 1) to produce the ammonium salt of the subtitle compound ⑷ and (b) The salt of compound (a) was dissolved in H2O, acidified with 2N HC1, and extracted with EtOAc. The organic layer was washed with brine, dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (a ) (1.2 g, 37%). About the subtitle compound ⑷ 1 H NMR (300 MHz, CD3 OD) (5 7.38 (s, 1H), 7.22 (s, 1H), 7.15 (s, 1H), 6.89 (t , JH_ F = 7U Hz, 1 H), 5.17 (s, 1H) (ix) PTir3-C1V5-OCHF ^ VrR ^ CHr〇mcr〇VA7e-PahrTeo ^ in Ph (3-Cl) (5-0CHF2HR) CH ( 0H) C (0) 0H (1.1 grams, 4.4 millimoles; see step (viii above) )) With H-Aze-Pab (Teoc) (see International Patent Application WO 00/42059, 2.6 g, 5.7 mmol) in DMF (50 ml) at -52 at 0 ° C -200306975 Description of Invention Continued (48) --- ---, add PyBOP (2.8 g, 5.3 mmol) and trimethyl p-pyridine (1.3 g, 10.6 mmol). Place the reaction at 0 ° C Stir for 2 hours and then at room temperature for another 15 hours. The reaction mixture is concentrated in vacuo and flash-chromatographed on silica gel (3X), initially with CHC13: EtOH (9: 1), and then with EtOAc: EtOH (20: 1), and finally dissolved with CH2C12: CH3OH (95: 5) to give the subtitled compound (1.0 g, 37%) as a white solid. 1 H NMR (300 MHz, CD3 OD, rotational isomerism) Mixture of substances) 5 7.79-7.85 (d, J = 8.7 Hz, 2H), 7.15-7.48 (m, 5H), 6.89 and 6.91 (t, JH.F = 71 · 1 Hz, 1H), 5.12 and 5.20 (s, 1H), 4.75-4.85 (m, 1H), 3.97-4 · 55 (m, 6H), 2.10-2.75 (m, 2H), 1.051.15 (m, 2H), 0.09 (s, 9H) MS (m / z) 611 (M + 1) + (x) PhrS-nVS-OCHF ^ VrR ^ rHromcrOVAze.P ^ hrOcRu. T ^ πγΛ Make Ph (3-a) (5-OCHF2HR) CH (OH) C (O) -Aze-Pa b (Teoc) (0.051 g, 0.08 mmol; see step (ix) above) was dissolved in 3 ml of acetonitrile and 0.062 g (0.5 mmol) of o-cyclobutylhydroxylamine hydrochloride was added. The mixture was heated at 70 ° C for 4.5 hours. The solvent was evaporated and the residue was separated between water and ethyl acetate. The aqueous phase was re-extracted twice with ethyl acetate, and the combined organic phases were washed with water and brine, dried (Na2S04), filtered and evaporated. Yield: 0.054 g (95%) 〇1 H-NMR (400 MHz; CD3 0D): 5 8.66-8.50 (m, 1H), 7.45 (d, 2H), 7.29 (m, 3H), 7.15 (m , 2H), 6.88 (t, 1H main rotomer), 6.85 (t, 1H main rotomer), 5.18 (s, 1H main rotomer), 5.12 (s, 1H less isomer), 5.16 (m, 1H less isomer), 4.78 (m, 1H main isomer), 4.70 (m, 1H), 4.50- 4 · 30 (m, 3H), 4.19-3.93 (m, 3H), 2.71-2.44 (m, 1H), 2.34-53- 200306975 Invention_Monthly continued (49) L __-- 2 · 11 (m, 5H), 1.78 (m, 1H), 1.62 (m, 1H), 0.96 (m, 2H), 0.01 (s, 9H) (xi) PhfS-CiyS-OCHF ^ VrR ^ CHromr / OVAze-PabrOcRi ^ Ph (3-Cl) (5-OCHF2HR) CH (OH) C (O) _Aze-Pab (OcBu, Teoc) (0.054 g, 0.08 mmol; see step 上文 above) was dissolved in 0.5 ml of CH2C12 and 3 ml TFA. The reaction was allowed to proceed for 60 minutes. The TFA was evaporated and the residue was purified using preparative HPLC. Fractions of interest were pooled and lyophilized (2x) to yield 23 mg (54%) of the title compound. MS (m / z) 536 (Ml) ·; 538 (M + lf 1 H-NMR (400 MHz; CD3 OD): δ 7.56 (d, 2H), 7.33 (m, 3H), 7.15 (m5 2H), 6.89 (t, 1H main rotomer), 6.86 (t, 1H main rotomer), 5.18 (s, 1H main rotomer; less m, 1 Η rotomer ), 5.11 (s, 1H less rotational isomers), 4.77 (m, 1H major rotational isomers), 4.58 (m, 1H), 4.42 (m, 2H), 4.34 (m, 1H main rotomer), 4.15 (m, 1H main rotomer), 4.06 (m, 1H less rotomer), 3.97 (m, 1H rotomer), 2.66 (m, 1H less rotational isomers), 2.52 (m, 1H major rotational isomers), 2.33-2.25 (m, 3H), 2.01-2.20 (m, 2H), 1.75 (m , 1H), 1.59 (m, 1H) 13C-NMR (100MHz; CD30D) (carbonyl and / or fluorene, rotamer) (5 172.4, 172.3, 171.9, Π1.4, 152.3 Example 2

PhrB-CIVg-OCHF ^ VmCHromCrQVAze-P ^ hrom (i) Phn-nVg-OCHF ^^ R ^ CHrOH ^ CrOVAze-PahrOH ^ eoc ^ Make Ph (3-Cl) (5-OCHF2HR) CH (OH) C (O) ) -Aze-Pab (Teoc) (0.148 g, 0.24 mmol; see Example 1 (ix) above) was dissolved in 9 ml of acetonitrile and 0.101 g (1.45 mmol) of hydroxylamine hydrochloride was added. The mixture was heated at 70 ° C for 2.5 hours, after -54- 200306975 Description of the Invention (50)-:-

Celite® is filtered and evaporated. The crude product (0.145 g; 75% pure) was used directly in the next step without further purification. (ii) Phr ^ -rivs-ocHF ^ vrR ^ CHromrrovAze-EabiQE) Ph (3-Cl) (5-OCHF2HR) CH (OH) C (O) -Aze-Pab (OH, Teoc) (0.145 g, 0.23 MM; refer to the steps above; dissolve in 0.5 ml of CH2C12 and 9 ml of TFA. Allow the reaction to proceed for 60 minutes. Evaporate TFA and purify the residue using preparative HPLC. Pool the fractions of interest and freeze Dry (2x), yielding 72 mg (62% yield over two steps) of the title compound. MS (m / z) 482 (M-1) *; 484 (M + 1) + 1 H-NMR (400 MHz; CD3 0D): (5 7.58 (d, 2H), 7.33 (m, 3H), 7.15 (m, 2H), 6.89 (t, 1H main rotational isomer), 6.86 (t, 1H Less rotamers), 5.18 (s, 1H main rotamers; less rotamers with m, 1 Η), 5.12 (s, 1 Η less rotomers), 4.77 (m, 1H main rotomer), 4.42 (m, 2H), 4.34 (m, 1H main rotomer), 4.14 (m, 1H main rotomer), 4.06 ( m, 1H less rotomer), 3.95 (m, 1H less rotomer), 2.66 (m, 1H less rotomer), 2.50 (m 1H main rotational isomer), 2.27 (m, 1H main rotational isomer), 2.14 (m, 1H less rotational isomer) 13C-NMR (100MHz; CD30D): (carbonyl and / or amidine Carbon, rotamers) 5 172.4, 172.3, 172.0, 171.4, 152.3, 152.1 Example 3

Phr3 > C1X5 ^ QCHF1WR > iCHr〇mr / OVA7e.Pab makes Ph (3-a) (5-OCHF2)-(R) CH (OH) C (O) -Aze-Pab (Teoc) (0.045 g, 0.074 mmol) Mol (see Example 1 (ix) above) was dissolved in 3 ml of TFA and allowed to react for 1 hour. TFA was evaporated and the residue was lyophilized from water / acetonitrile to give 0.043 -55- 200306975 (51) Description of the invention The following titled compound was added as a TFA salt (100 mg). · IH-NMR (400 MHz; CD3OD) rotamer: 5 7.8-7.75 (m, 2H), 7.55-7.5 · (m, 2H), 7.35 (m, 1H, main rotamer), 7.31 (m, 1H, less rotomer), 7.19 (m, 1H, main rotomer), 7.15 (m, 1H), 7.12 (m, 1H, rotomer) ), 6.89 (t, 1H, major rotomer), 6.87 (t, 1H, minor rotomer), 5.22 (m, 1H, minor rotomer), 5.20 (s, 1H, major rotamer), 5.13 (s, 1H, minor rotamer), 4.80 (m, 1H, major rotomer), 4.6-4.4 ( m, 2H), 4 · 3 7 (m, 1H, main rotamer), 4.19 (m, 1H, main rotamer), 4.07 (m, 1H, less rotomer) , 3.98 (m, 1H, less rotomers), 2.70 (m, 1H, less rotomers), 2.55 (m, 1H, main rotomers), 2.29 (m, 1H , The main rotational isomers), 2.15 (m, 1H, less rotational isomers) 13ONMR (100MHz; CD3OD): (carbonyl and / or fluorene, carbon Isomers) (5 172.6, 172.5, 172.0, 171.7, 167.0 MS (m / z) 465 (Ml) ', 467 (M + l) + Example 4 £ h (3-ClV5-0CHF2 > (R) CH ( OmC (OVAze-Pab (C00c), and Ph (3-Cl) (5-0CHF2HR) CH (0H) C (0) -Aze-PabxTFA (74 mg, 0.13 mmol; see Example 3 above) and To a solution of cyclopentyl chloroformate (44 mg, 0.30 mole) in dichloromethane (5 ml) was added an aqueous NaOH solution (0.5 ml, 2 M, 1 mmol). The mixture was mixed. Stir off at room temperature and monitor the reaction with Ηρ] χ. After 2.5 hours, add water and separate the liquid phase. Extract the aqueous phase twice with dichloromethane. The combined organic phases are dehydrated and dried (MgS04) And purified on hair gel (originally dichloromethane, then EtOAc). After removing the solvent in vacuum -56-200306975 (52)---, the solid residue was dissolved in water / acetonitrile, And lyophilized to give the title compound as a white solid. Yield: 33 mg (44%) MS (m / z) 579 (M + 1) + 1 H NMR (400 MHz; CD3 OD): 5 7 · 79 ( d, 2H), 7.43-7.30 (m, 5H), 7.20-7.11 (m, 2H), 6.90 (t, 1H, main rotation Structure), 6.87 (t, 1H, less rotational isomers), 5.19 (dd, 1H, less rotational isomers), 5.18 (s, 1H, major rotation isomers), 5.13 ( m, 1H), 5.11 (s, 1H, less rotational isomers), 4.78 (dd, 1H, major rotational isomers), 4.45 (m, 2H), 4.35 (m, 1H, principal rotations) Isomers), 4.16 (s, 1H, major rotamer), 4.06 (s, 1H, minor rotamer), 3.97 (s, 1H, minor rotomer), 2.68 (m, 1H, less rotomer), 2.52 (s, 1H, main rotomer), 2.28 (s, 1H, main rotomer), 2.16 (s, 1H, less rotomer) Rotational isomers), 1.90 (m, 2H), 1.77 (m, 4H), 1.61 (m, 2H) 13 C NMR (carbonyl and / or hydrazone protons; 100 MHz): 5 173 · 6, 173.1 , 172.6, 170.3, 165.6 Example 5

Phr3> C1V5-OCHF ^ VrR ^ CHr0mcr0VA7e-Pab (; Z ^ The title compound was prepared according to the procedure described in Example 4 above, | Ph (3-Cl) (5-0CHF2)-(R ) CH (0H) C (0) -Aze-PabxTFA (73 mg, 0.13 mmol; see Example 3 above) starting with ethyl chloroformate (35 mg, 0.21 mmol). By reverse phase HPLC (0.1M Additional purification of ammonium acetate / MeCN40 / 60) was necessary. The appropriate fractions were concentrated in vacuo and extracted with EtOAc. Yield: 24 mg (32%). MS (m / z) 602 (M + 1) + 1 H NMR (400MHz; CD3 OD): 5 7.80 (d, 2H), 7.43-7.25 (m, 8H), 7.207.10 (m, 2H), -57- 200306975 6.90 (t, 1Η, main rotation difference Structure), 6.88 (t, 1Η, less rotomers), '5.18 (dd, 1H, less rotomers), 5.18 (s, 2H), 5.17 (s, 1H, rotomers Structure ·), 5.11 (s, 1H, rotamer), 4.78 (dd, 1H, main rotamer), 4.45 (m, 2H), 4.34 (m, 1H, main Rotoisomers), 4.15 (s, 1H, major rotamer), 4.06 (s, 1H, fewer rotomers), 3,97 (s, 1H, less rotomer) Rotational isomers), 2.66 (m, 1H, less rotational isomers), 2.51 (s, 1H, main rotation isomers), 2.27 (s, 1H, main rotation isomers), 2.15 (s, 1H, less rotational isomers) 13CNMR (carboxyl and / or amidine protons; 100MHz): (5 173.6, 173.1, 172.6, 170.5, 164.9 Example 6 £ hr3-Cl ¥ 5-OCF1VrR> iCHr〇mcr 〇VA7.e-Pah Y TFA (i) 2-nitro-5-trifluorofluorenylbenzoic acid in 3-trifluoromethoxybenzoic acid (49.0 g, 0.24 mole) in sulfuric acid (500 ml) To the solution, at below 0 ° C (ice-MeOH bath), a solution of potassium nitrate (31.3 g, 0.31 mol) in sulfuric acid (200 ml) was added over 20 minutes. The resulting solution was Stir for 2 hours at 0 ° C, then warm to room temperature and stir for 18 hours. Pour the reaction into ice and extract the resulting acidic solution with EtOAc (5x). H20 (1x), brine (2x), H20 (1x), and brine (1x). The combined organic materials were dried (Na2S04), filtered, and concentrated in vacuo to give the crude subtitled compound (65.7 g) as H.sub. Of Ac pollution solid. The crude sub-title compound was dissolved in EtOAc and toluene and concentrated in vacuo to give HOAc as a free state solid (58.4 g, 97%), which was used in the next step without further purification. -58- 200306975 (54) Description of the invention 1 H NMR (300 MHz, CDC13): 5 10 · 10 (br s, 1H), 8.02 (d, 1H, J = 8 Hz), 7.69 (d, 1H, J = 2 Hz), 7.54 (dd, 1H, J = 2 Hz, J = 8 Hz) (ii) 2-Amino-5-trifluoromethane is a formic acid in 2-nitro-5-trifluoromethyl Oxybenzoic acid (56.8 g, 0.23 mol; refer to the procedure above), add 10% pd / c (5.7 g) to the solution in EtOH (1000 ml). Rinse the solution with 2 The resulting solution was filtered through CeHte® over 5 hours and concentrated in vacuo to give the crude subtitled compound (497 g, 98%) as a solid, which was used in the next step without further purification. 1 H NMR (300 MHz, CD3 OD): δ 7.66 (m, 1H), 7.17 (d, 1H, J = 8 Hz), 6.77 (d, 1H, J = 8 Hz)氲 A Saijialing was slowly added to the solution of 2-amino-5-trifluoromethoxybenzoic acid (49.0 g, 0.22 mole; see step (ii) above) in HOAc (1200 ml). Sulfuric acid dichloride (41.8 g, 0.31 mole). Gas evolution was found. The heterogeneous mixture formed was stirred at room temperature for 1 hour. Add additional HOAc (300 mL) to help stir 'then add 5 mL portions of sulfur dichloride until the starting material is consumed, based on TLC analysis. The reaction was concentrated in vacuo To obtain a solid, which was washed on a rotary evaporator with EtOAc (2x), followed by Et20 (1x) to remove HOAc. The formed solid was further dried to obtain the crude HC1 salt of the subtitled compound ( 60.5 g, 94%), which was used in the next step without further purification. 1 H NMR (300 MHz, CD3 OD): 5 7.72 (s, 1H), 7.44 (s, 1H), 7.22 (s, may (Exchange) (iv) 3-Gas-5-trifluoromethylaeroyl jasmonamidine to 2-aminogato-5-trifluoromethoxybenzoic acid (60.5 g, assuming 0 · 22 -59- 200306975 Description of the invention continued; 1; (55) ____— Moore; see step (iii) above) In a solution in 1,4-dioxolane (looo ml), 6NHC1 (750 ml) was added. Part of the organic material was precipitated from the solution. The dioxolane solution was cooled to below 0 ° C (ice-MeOH bath) ^ sodium nitrite (18.2 g, 0.26 mol) was added via an addition funnel. In (250 ml) solution of H20, over 15 minutes. The resulting solution was stirred for 45 minutes. Phosphorous acid (221.5 ml, 50% by weight, in H20, 291.2 g, 2.20 mol) was added slowly through the addition funnel. The solution was stirred at 0 ° C for 1.5 hours, then warmed to room temperature (gas evolution was found) and dropped for 18 hours. The crude solution was transferred to a separatory funnel and extracted with Et20 (4x). The combined organics were extracted (3x) with aqueous NaHC03. The alkaline aqueous layer was carefully acidified with 6N HC1 and extracted with CH2C12 (3x). The CH2C12 extract was dried (Na2S04), filtered, and concentrated in vacuo to give the crude subtitled compound (26.5 g, 46% from 3-trifluoromethoxybenzoic acid) as a solid, which was Used in the next step without further purification. 1H NMR (300 MHz, CD3 OD): δ 7.98 (s, 1H), 7.83 (s, 1H), 7.58 (s, 1H) (v) 3-amino-5-trifluoromethyl 1 In a solution of 3-chloro-5-trifluoromethoxybenzoic acid (22.5 g, 93.5 mmol; see step (iv) above) in anhydrous THF (1200 ml), in the atmosphere At room temperature, a solution of the BΗ3 · THF complex (140 ml, 1 M in THF; 140.3 mmol) was added. The solution was refluxed for 2 hours, cooled to room temperature, and stirred for 18 hours. The reaction was carefully quenched with Η20 and concentrated in vacuo to remove most of the THF. The residue was diluted with EtOAc, and the organic material was washed with brine (3x), dried (Na2S04), filtered, and concentrated in vacuo to obtain the crude sub-title compound (21.2 g, 100%) as an oil, used No.-60-200306975 (56) Description of the invention _ page without further purification. H NMR (300 MHz, CDC13) · 5 7.33 (s, 1H), 7.17 (s, 1H), 7.14 (s, 1H), 4.72 (s 2H), 2.05 (br s? 1H) (vi) 3-chloro The solution of phenyl-5-trifluoroJ methoxybenzyl methoxide was used to cool a solution of DMSO (16.1 g, 205.9 mmol) in anhydrous CH2C12 (300 ml) to -78 ° C. Chloramprolium chloride (131 g, 103.0 mol) was slowly added via a syringe (gas evolution was found). The resulting solution was stirred for 15 minutes under 下 ye. Add a solution of 3_chloro_5_trifluoromethoxybenzyl alcohol (21.2 g '93.6 mol; see step (v) above) in ch2C12 (200 ml) via the addition funnel over 15 minutes period. The turbid solution was stirred at -78 ° C for 40 minutes, and DIPEA (60.5 g, 468.0 mmol) was added via an addition funnel over 10 minutes. The resulting homogeneous solution was stirred at -78 ° C for 1.5 hours, then warmed to room temperature 'and allowed to stir for 18 hours. The crude solution was concentrated in vacuo and the residue was diluted with EtOAc and washed with h20 (1x), 2N HCl (1x), brine (1x), aqueous NaHC03 solution (ΐχ) and brine (ΐχ). The organic material was dried (Na2S04), filtered and concentrated in vacuo to give the crude subtitled compound (199 g, 95%), which was used in the next step without further purification. 1 H NMR (300 MHz, CDC13): 5 10.00 (s, 1H), 7.83 (s, 1H), 7.66 (s, 1H), 7.51 (s, 1Η)

(vii) Ph (3-Cl) (^ QCF ^ fR ^ S ^ CHrOTMS ^ CN in 3-chloro-5-trifluoromethoxybenzaldehyde (19.9 g, 88.6 mmol); see step (vi )) In a solution in CH2C12 (600 ml), add Znl2 (1.4 g, 4.4 mmol) and trimethylsilyl cyanide (9.7 g, 97.5 mmol) at 0 ° C. After stirring for 1.5 hours at ° C and 2 hours at room temperature, TLC analysis showed 200306975 Description of the invention; (57) --------- Shows only the starting material. Add Znl2 in portions until the reaction proceeds (add a total of more than 30 · 0 g of Znl2). After stirring at room temperature for 18 hours, the reaction was quenched with water and the organic matter was separated. The organic matter was dried (Na2S04), filtered and concentrated in vacuo to obtain the crude subtitled compound (27.7 g , 96%), as a liquid, used without further purification. 1 H NMR (300 MHz, CDC13): 5 7.43 (s, 1H), 7.28 (s, 1H), 7.25 (s, 1H), 5.49 (s , 1H), 0.38 (s, 9H) (viii) PhrB-avs-ocF ^ vrR.s ^ CHromcro ^ oH Let Ph (3-Cl) (5-OCF3HR, S) CH (OTMS) CN (27.7 g, 85.6 Millimoles; see step (vii) above) in concentrated HC1 (300ml The suspension was refluxed for 3 hours. The resulting brown heterogeneous mixture was cooled to room temperature and extracted (2x) with Et20. The original organic material was extracted (2x) with 2NNaOH, then the basic layer was acidified with 2NHC1, and Extract with Et20. Dehydrate and dry Et20 (Na2S04), filter and concentrate in vacuo to obtain the crude subtitled compound (4.9 g, 21%). TLC analysis of the original organic material showed that the subtitled compound was still present, so 6NNaOH was used. Repeat the alkaline extraction / acidification to obtain another crude subtitled compound (2.8 g, 12%). The initial TLC analysis of the organic substance showed that the subtitled compound was still present, so the organic substance was dehydrated and dried (Na2S〇4) and Concentration in vacuo provided the sodium salt of the subtitled compound (18.3 g) as an oil. This salt was then redissolved in Et20 and the organic material was acidified with 2NHC1 and washed with brine. The formed organic The material was dried (Na2S04), treated with activated carbon, filtered through Celite®, and concentrated in vacuo to give the crude subtitled compound (14.3 g, 62%) as a solid It was used in the next step without further purification. -62- 200306975 Description of the Invention_Page (58) ---- 1 H NMR (300 MHz, CD3 OD): 5 7 · 53 (s, 1H), 7.38 ( s, 1H), 7.29 (s, 1H), 5.23 (s5 1H) (ix) Ehll'aM-OCF ^ VaOCHiOKOaCOOH ⑷ and PhOCl ^ -OCFiHSKHiOAcV CrO ^ QH (h) Put Ph (3-Cl) (5-OCF3HR , S) CH (OH) C (〇) OH (7.7 g, 28.5 mmol; see step (viii) above) and lipase PS "Amanon (3.8 g) in MTBE (100 ml) and The mixture in ethyl acetate (50 ml) was stirred at 60 ° C for 26 hours. The reaction was cooled and filtered through Celite® and the filter cake was washed with EtOAc. The combined organics were concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: MeOH: concentrated NH4OH (6: 3: 1) to obtain a mixture of the subtitle compound ⑷ and the subtitle compound ⑻ ammonium salt (6.7 g), and the subtitle compound ⑷ ammonium Pure sample of salt (1.2 g) with less than 95% ee. The individual fractions were dissolved in Et20 and washed with 2NHC1 (1x) and brine (1x), dried (Na2S04), filtered and concentrated to obtain the corresponding carboxylic acids (6.7g and 1.1g respectively). Then, these dissolved fractions were individually subjected to analytical conditions and re-purified as needed, and were subjected to chromatography on Shixi gum with CHCI3 · MeOH: concentrated NH4 OH (6: 3: 1 or 75: 20: 5 or 145: 45: 10) Dissolve as required. Prior to further use, the title compound, which has been purified, is acidified with aqueous HC1 or aqueous citric acid. With the ammonium salt of the title compound (b) this time, no characterization is required. About the subtitle compound ⑷ 1 H NMR (300 MHz, CD3 OD): 5 7 · 53 (s, 1H), 7.38 (s, 1H), 7.29 (s, 1H), 5.23 (s, 1H) 1 3 C NMR (75 MHz, CD3 OD): 5 174.9, 150.9, 145.4, 136.3, 126.8, 122.0, 120.6, -63- 200306975 Invention Note® Page (59) ---- 118.9, 72.9 MS (m / z) 269 (Ml) '(x) Phn-ClXS-OCF ^ -rR ^ CHromrrOVAze-PabrTeoc ^ make Ph (3-Cl) (5-OCF3HR) CH (OH) C (O) OH (0.73 g, 2.70 millimoles; Refer to the solution of step (ix)) in DMF (40 ml) above, and cool to 0 ° C under nitrogen atmosphere. To this solution, H-Aze-Pab (Teoc) (1.46 g, 3.24 mmol), trimethylpyridine (0.82 g, 6.75 mmol) and PyBOP (L83 g, 3.51 mmol) were added. The solution was stirred at 0 ° C for 2 hours, warmed to room temperature, and stirred for 18 hours. The reaction was quenched with water and concentrated in vacuo. The residue was diluted with EtOAc, washed with Θ H20 (lx), aqueous NaHC03 (lx), aqueous citric acid (lx), and brine (lx), dried (Na2S04), filtered, and concentrated in vacuo to obtain the crude product. Title compound. Flash chromatography on silica gel (2x), EtOAc: MeOH (30: 1), and then CH2C12: MeOH (93: 7) to give the subtitled compound (0.73 g, 43%) as crushable Foam. 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers: 5 7.78-7.82 (d, 2H, J = 8 Hz), 7.25-7.54 (m, 5H), 5.25 and 5.16 (s, 1H), 5.22 and 4.79 (111, 111), 3.92-4.58 (m, 6Η), 2.20-2.76 (m, 2Η), 1.04-1.13 (m, 2Η), 0.08 (s, 9Η) MS (m / z) 629 (M + 1) + (xi) Phr3-n ¥ 5-OCFLVrR ^ CHr〇mcr〇VAze-Pab Add trifluoroacetic acid (1.0 ml) to Php-ClXS-OCFsHPOCHCO ^ CCCO-Aze-pabCreoc) (101 mg; 160 micromolar; see step (x) above) in a stirred ice / water-cooled solution in dichloromethane (10 ml). After 1 hour, the cooling bath was removed. After 1.5 hours at room temperature, acetonitrile (30 ml) was added and the solvent was carefully removed under reduced pressure. The residue was dissolved in water and lyophilized, and -64- 200306975 Description of the Invention_page (60)---90 mg (92%) of the title compound was obtained as its TFA salt. MS (m / z) 483 (M-1)-; 485 (M + 1) + 1 H NMR (300 MHz; CD3 OD): (complex due to diastereomers / rotomers) : 5 7.70-7.80 (m, 2H), 7.45-7.58 (m, 3H), 7.24-7.38 (m, 2H), 5.26 (s, 1H), 5.17 (m, 1H, less rotational isomers) , 4.82 (m, 1H, main rotamer), 4.3 5-4.6 (m, 3H), 4.22 (m, lH, main rotamer), 3.92-4.12 (m, 2H, lesser Rotoisomers), 2.70 (m, 1H, less rotamers), 2.55 (m, 1H, major rotamers), 2.30 (m, 1H, major rotomers), 2.16 (m, 1H, less rotational isomers) 1 3 C NMR (100 MHz; CD3 OD): (carbonyl and / or amidine protons, rotational isomers): 5 173.7, 173.4, 173.0, 172.8, 168.1 Examples 7? H (3 ^ CA) (5 ^ 0C ¥ ^ VmCH (; OH ^ CiOVAze-Pab (; OMe ^ Add HATU (71 mg; 0.19 mmol) to Ph (3-Cl) (5-OCF3) -(R) CH- (0H) C (0) 0H (39 mg; 0.14 mmol; see Example 6 (ix) above) in a stirred ice / water-cooled solution in DMF (30 mL). 30 After minutes, H-Aze-Pab (OMe) x2HCl (69 mmol 0.21 millimolar; see International Patent Application WO 00/42059) and a solution of 2,4,6-trimethyl orbital (0.080 ml; 0.58 mmol) in DMF (1.5 ml). The mixture was left overnight and the temperature was allowed to slowly rise to ambient temperature. The solvent was removed in vacuo and the crude product (acetonitrile: 0.1M ammonium acetate aqueous solution) was purified using reverse-phase HPLC, and the title compound was obtained after lyophilizing the appropriate fraction (61 mg, 97%), colorless solid. MS (m / z) 513 (M-1) '515 (M + 1) + 1 H NMR (500 MHz; CD3 OD): 5 7.97 (bt, 1H), 7.53 (d, 2H), 7.27 (t, 1H), 7.22 -65- 200306975 Description of the invention _ stomach (61)-(d, 2H), 7.19 (t, 1H), 7.11 (t, 2H), 6.77 (s, 1H), 4.92 (s, 1H), 4.9 (bs, 3H), 4.81 (m, 2H), 4.40 (m, 2H), 4.09 (m, 1H), 3.87 (s, 3H), 2.58 (m, 1H), 2.37 (m, 1H) 13CNMR (125MHz; CD3OD): (carbonyl and / or tritium proton): 5 171.8, 169.9, 156.8 Example 8 Responses of alkane-based skin Synthesis This synthesis was performed in a 96-well Robbins plate. Add PhP-ClXS-OCFsHI ^ a ^ Oi ^ CXCO-Aze-PabCreoc to a well containing an appropriate amount of 0-substituted hydroxylamine (designated below; all of which are commercially available or made using known literature procedures) ) (10 mg; 17 micromoles; see Example 6) above) in acetonitrile (1.0 ml). The plate was sealed and the reaction mixture was spun in an oven at 60 ° C overnight. After cooling and filtering, the solid was washed with acetonitrile (3 X 0.3 ml). The combined liquids were separated and concentrated in a vacuum centrifuge. The residue was partitioned between water (0.4 ml) and ethyl acetate (0.4 ml). After the liquid-liquid extraction is complete, all materials are filtered through a HydromatrixTM column. After washing three times with ethyl acetate, the combined filtrates were concentrated in a vacuum centrifuge. Remove protection by adding dichloromethane (0.1 mL) and trifluoroacetic acid (0.3 mL). After stirring at room temperature for 3 hours', the solvent was removed in vacuo. The residue was partitioned between a saturated aqueous solution of sodium bicarbonate (0.5 ml) and ethyl acetate (0.5 ml). After extraction, filtration through HydromatrixTM, and concentration (see below), the residue was dissolved in isopropanol / water (7/3) (1 mL). Remove approximately 2% of this solution and dilute with isopropanol / water (7/3) (1 mL) for LOMS analysis. After removing the solvent in vacuo, the solid residue was transferred to a 96-well plate and acetonitrile and ethyl acetate were used to dissolve the compounds. -66- 200306975 Description of the invention (62) --- The solvent was evaporated in a vacuum centrifuge to obtain the following title compound:

Ph (3-a) (5-0CF3MR) CH (0H) C (0) -Aze-Pab (0CH2-3- (5-Me-isoxazole)) (obtained from 3-[(amineoxy) formaldehyde Group] -5-methylisoxazolium xHCl (18 mg; 0.11 mmol)). Yield: 3.64 milligrams (35%) (MS (m / z) 596 (M + l) +);

Ph (3-Cl) (5-〇CF3HR) CH (0H) C (0) -Aze-Pab (〇CH2-3-eridine) (obtained from 3-[(amineoxy) methyl] pyridine x 2HC1 (19 mg; 96 micromolar). Yield: 5.14 mg (50%) (MS (m / z) 592 (M + l) +);

Ph (3-Cl) (5-OCF3 HR) CH (0H) C (0) -Aze-Pab (0iBu) (from α-isobutylhydroxylamine x HCl (17 mg; 140 micromoles). Yield: 4.4 mg (45%). MS (m / z) 557 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (OH) C (0) -Aze-Pab (0Et) (obtained from 0-ethylhydroxylamine x HCl (14 mg; 140 micromoles). Yield: 4.04 mg (42%). MS (m / z) 529 (M + l) +);

Ph (3-C1) (5 ^ 0CF3 HR) CH (OH) C (0) -Aze-Pab (OBn) (obtained from 0-benzylhydroxylamine x HC1 (17 mg; 110 micromoles). Yield: 3 22 mg (29%). MS (m / z) 591 (M + l) +);

Ph (3-Cl) (5-0CF3)-(R) CH (〇H) C (0) -Aze «Pab (0chexyl) (from 0-cyclohexylhydroxylamine xHCl (15 mg; 99 μmol) . Yield: 2.9 mg (26%). MS (m / z) 583 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (OH) C (0) -Aze-Pab (OcBu) (obtained from 0-cyclobutylhydroxylamine x HCl (17 mg; 140 micromoles). Yield: 3.3 mg (30%). MS (m / z) 555 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (OH) C (0) -Aze-Pab (OCH2 CH2 OPh (3-CF3)) (from 0- [2-l > (trifluoro Methyl) phenoxy] ethyl] hydroxylamine x HCl (24 mg; 93 μ-67- 200306975

DESCRIPTION OF THE INVENTION MM (63) --- Mohr). Yield: 6.52 mg (46%). MS (m / z) 689 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (4-Cl)) (from 0- (4-chlorofluorenyl) hydroxylamine x HCl ( 16 mg; 82 micromolar). Yield: 3.47 mg (29%). MS (m / z) 625 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (3-Me0)) (from 0- (3-methoxyfluorenyl) light Amine xHCl (18 mg; 94 μmol). Yield: 4.33 mg (36%). MS (m / z) 621 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (2-Br)) (obtained from 0 (2-bromofluorenyl) hydroxylamine x HC1 (23 mg; 96 micromolar). Yield: 3.87 mg (30%). MS (m / z) 671 (M + l) +);

Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (4-Me)) (obtained from 0- (4-methylfluorenyl) hydroxylamine x HC1 (14 mg; 81 micromoles). Yield: 2.91 mg (25%). MS (m / z) 605 (M + 1) +); and Ph (3-Cl) (5-0CF3HR) CH ( OH) C (0) -Aze-Pab (0-4-heptyl) (obtained from 0- (4-heptyl) hydroxylamine x HCl (15 mg; 89 micromoles). Yield: 17 mg (100%). MS (m / z) 599 (M + l) +). Example 9

Ph (3-CDf5-OCHF ^)-(S) CH (CH1〇mcr0VA7fi.P ^ y HOAr (i) 3-Gaso-5-methoxybenzoic acid will be used for Grignard reaction with magnesium crumbs (Fluka pumrn) Pre-treatment in the following manner: Place the crumbs in a glass sintering funnel and pour 0.1 M hydrochloric acid thereon. Stir the crumbs with a glass rod for a few seconds, then use 3 parts of water to wash off the acid. Finally, The crumbs were washed with 2 parts of acetone and bottled. Tetrahydrofuran (100 ml, 99.95%) was dehydrated by adding RedAl (1 g, 70% by weight in toluene) -68- 200306975 (64) Description of the invention ® ;! Water-dried. Pre-treated magnesium dust (5 g, 200 mmol) was placed in a round bottom flask and flushed 3 times with nitrogen. Digas toluene ether (26 g, 146 mmol) Ear) was dissolved in THF (100 ml, RedAl-dried) and dibromoacetamidine (1 § g, millimoles) was added. The reaction mixture was flushed with nitrogen and then refluxed for 2 hours. Heating was interrupted and divided Add dry ice (10 g) over 2 minutes. When all dry ice is dissolved, pour the reaction mixture into ice containing hydrochloric acid (400 ml, 2 M). Extraction treatment (Ether, 300 ml) 11.2 g, 60.2 mmol (yield: 41%) of the title compound were obtained. 1 H-NMR (500 MHz; acetone-d6): 5 7.57 (m, 1H), 7.49 (m, 1H), 7.23 (m, 1H), 3,91 (s, 3H) chloro group via benzoic acid to alumina (1.65 g, 60 mmol) and iodine (21 g, 82 mmol) in toluene ( 200 ml) under reflux for 2 hours. Then, 3-chloro-5-methoxybenzoic acid (11.2 g, 60.2 mmol) was dissolved in toluene (50 ml); see step (0) above. ), Added together with tetrabutylammonium iodide (1.5 g, 4 mmol), and the mixture was refluxed for another 2 hours. After cooling to ambient temperature, the extraction treatment obtained 8.7 g '50 mmol (yield: 83%) of the title compound. 1 H-NMR (300 MHz; acetone-d6): 5 9.27 (s, 1Η), 7.48 (m, 1Η), 7.44 (m, 1Η), 7.11 (m, 1H) (iU) Flume gas itoformic acid transfers 3-amino-5-hydroxybenzoic acid (6.4 g, 37.2 Amor, dissolved in chloroform (200 ml); see step (ii) above) Into a 500 ml three-necked round bottom flask equipped with a dry ice condenser and a gas inlet tube. Add hydroxide Sodium (100 ml '5 M) and vigorously stirred. At ambient temperature, through the gas inlet tube, points -69- 200306975 (65) Description of the invention Continuation page Add chlorodifluoromethane (Freon 22; 25 g, 290 milligrams) Moore). After 2 hours, the reaction was complete. Extraction treatment gave 6.2 g, 28 millimoles (yield: 75%) of the title compound. 1 H-NMR (500 MHz; acetone-d6): 5 7.87 (m, 1H), 7.74 (m, 1H), 7.54 (m, 1H), 7.19 (t, 1H, JH_F73Hz) (iv) 3-chloro -5-; _ fluoromethylamino-N-methylamino-N-methyl jasmonate gfe makes 3-chloro-5-difluoromethoxybenzoic acid (1.8 g, 8 mmol; see above Step (iii)) is dissolved with vaporized grasshopper (1.5 g, 11.8 mmol) in dichloromethane (50 ml). DMF (2 drops) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. Then, N, 0-dimethylhydroxylamine (1 g, ι0.2 mmol) and triethylamine (3 g, 30 mmol) were added and stirred for another 10 minutes at ambient temperature. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ether (100 mL) and water (50 mL). After separation, the organic phase was washed with brine, dried over sodium sulfate, filtered and concentrated. This residue was chromatographed on silica gel (hexane / ethyl acetate 2.1) to obtain 2 g of the title compound, 7.5 μmol (93%). 1 H, NMR (400 MHz; CDC13): 5 7.54 (m, 1Η), 7.37 (m, 1Η), 7.27 (m, 1Η), 6.53 (t,

Jh.f73 Hz) (v) An acetophenone-based acetophenone makes 3-chloro-5-difluoromethoxys-methoxy-N-methylbenzamide (2 g, 7.5 millimoles; see step (iv) above) Dissolve in ether (100 liters) and cool to -70 ° C under nitrogen. Methyl lithium (7 ml, ηmmol ' 1.6 M in ether) was added dropwise via a syringe to the stirred reaction mixture over 1 minute. Remove the dry ice bath and allow the mixture to reach ambient temperature before quenching the reaction with ammonium chloride solution (50 ml, 5% Nh4C1 in water) -70- 200306975 (66). The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate 2: 1) to obtain L5 g, 6.8 mmol (yield: 90%) of the title compound. 1 H-NMR (600 MHz; CDC13): 5 7.77 (m, 1H), 7.59 (m, 1H), 7.35 (m, 1H), 6.56 (t,

1H, Jh.f73 Hz), 2.60 (s3 3H) (vi) 3-f. U-dione. Methylphenidyl acetate makes 3-chloro-5-difluoromethoxyacetophenone (1.5 G, 6.8 mmol; see step (v) above) dissolved in dichloromethane (200 ml). Added K-10 montmorillonite thallium (III) nitrate X 3Me0H (6 g, 10 mM (about 0.6 mM / g); see J. Am. Chem. Soc., 98, 6750 ( 1976)), and the mixture was stirred at ambient temperature for 20 hours. The mixture was filtered, and the filtrate was washed with sodium bicarbonate (100 ml, 0.5 M), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane / ethyl acetate 2: 1) to obtain 1 g, 4 mmol (yield: 56%) of the title compound. 1 H-NMR (500 MHz; CDC13) · 5 7.14 (m, 1H), 7.06 (m, 1H), 6.96 (m, 1H), 6.50 (t, 1H, JH-F 73 Hz), 3.72 (s , 3H), 3.60 (s, 1H) (vii) methyl ethyl methyl (3-gas-5-digasmethylbenzyl) methyl acetate makes 3-chloro-5-difluoromethoxyphenylacetic acid Methyl ester (1 g, 4 mmol; see step (vi) above) and methyl formate (1 g, 16 mmol) are dissolved in ether (100 mL) and placed in an ice bath (about 2 ° C). Then, finely cut sodium (180 mg '7.8 mol) and methanol (1 ml) were added, and the mixture was left in an ice bath' and stirred overnight. Water (100 ml) was carefully added and the liquid phases were separated. The aqueous phase was acidified with hydrochloric acid (2 M) to pH i and extracted with ether (2 X 100 ml). -71-200306975 Description of the invention®® (67) -—- The extract is dried over sodium sulfate 'filtered and concentrated under reduced pressure. The residue was chromatographed on silica gel (hexane: ethyl acetate (1: υ) to obtain 400 mg, 1.4 mmol (yield: 36%) of the title compound. 1 H-NMR (400 MHz): 5 12.10 (4 1Η), 7.32 (d, 1Η), 7.11 (m, 1Η), 7.07 (m, 1Η), 6.94 (m, 1Η), 6.51 (t, 1H, JF-H73) , 3.83 (s, 3H)

(viii) 3-amino-5-difluoro 1

Dissolve methyl a-formyl (3-chloro-5-difluoromethoxyphenyl) acetate (400 mg, μmmol; see step (vii) above) in THF: methanol (50 ml, 9 ·· 1). Add sodium borohydride and stir the mixture at ambient temperature for 30 minutes. Water was added and the mixture was concentrated to produce an aqueous suspension which was dissolved in ethyl acetate and water. The liquid phases were separated and the organic phase was washed with sodium chloride (15% in water), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (30 ml) and hydrolyzed with sodium hydroxide (1 ml, 10 m) at ambient temperature for minutes. Extraction treatment yielded 180 mg, 0.68 mmol (yield: 48%) of the title compound. 1 H-NMR (500 MHz; CDC13): 5 7.18 (m, 1H), 7.10 (m, 1H), 7.00 (m. 1H), 6.50 (t, 1H, JF.H73), 4.11 (m, 1H) , 3.90 (m, 1H), 3.84 (m, 1H) (ix)… h Y HOAc makes 3-chloro-5-difluoromethoxytropinic acid (180 mg '0.7 Memo Ear, see step (viii)) above, H-Aze-Pab (Teoc) X HC1 (450 mg, 1 mmol) and pyB0P (530 mg, 1 mmol) in DMF (10 ml), Then 1 ^ PEA (550 mg, 3.9 mmol) was added. The mixture was stirred at ambient temperature for 1 hour before being diluted with brine (20 ml, 15% NaC1) and extracted with ethyl acetate (40 ml). The extract was dried over sodium sulfate, filtered and evaporated to dry wine. Make -72- 200306975

㈣ The residue was dissolved in dichloromethane (5 ml) and trifluoroacetic acid (5 ml) was added. After 1 hour at ambient temperature, the diastereomeric mixture was evaporated to dryness and the residue was chromatographed on a reverse phase column (acetonitrile: water (30: 70), buffer: ammonium acetate, · 1 M). Lyophilization yielded 36 mg, 0.067 mmol (yield: 10.4%) of the title compound. MS (ES) 481 (Μ + 1) + 1 H-NMR (400 MHz; CDC13): δ 7.77 (d, 2Η), 7.57 (d, 2H), 7.30 (τη, 1H), 7.13 (m, 2H) , 6.87 (t, 1H, JF-H73 Hz), 4.76 (m, 1H), 4.55 (s, 2H), 4.37 (m, 1H), 4.03 (m, 2H), 3.82 (m, 1H), 3.72 ( m, 1H), 2.53 (m, 1H), 2.28 (m, 1H), 1.92 (s, 1, 5H) 1 3 ONMR (100 MHz; CD3OD): (carbonyl and / or europium proton) 5 172.3, 171.9, 167.2 Example 10

PhG-ClXS-OCF ^ rS ^ CHrCH ^ OmcrOVA ^ aP ^ Y (i) 3-Gas-5-trifluoromethoxyoctyl methanate salt at 3-Gas-5-trifluoromethoxy Benzyl alcohol (6.1 g, 26.9 mmol; see Example 6 (ν) above) in a solution of CH2C12 (250 ml) at 0 ° C and nitrogen atmosphere, add DIPEA (4.2 g, 32.3 mmol) Ear) and gasified methanesulfonium (3.4 g, 29.6 mmol). This solution was stirred at 0 ° C for 1.5 hours and the reaction was quenched with H20. The organic material was separated and washed with H20 (1x), 1NHCl (lx), H20 (1x), and NaHC03 aqueous solution (ΐχ); strips, followed by dehydration, drying, drying and concentration to obtain the subtitled compound (8 2 g, 99%) as an oil. 1 H NMR (300 MHz, CDC13): δ 7.37 (s, 1Η), 7.28 (s, 1H), 7.18 (s, 1H) 5.23 (s, 2H), 3.07 (s, 3H) 3-chloro-5-trifluoromethoxybenzyl methanoate (8.2 g, 26.8 mmol); -73 · 200306975 (69) Description of the invention Continuing the sheet, please refer to the above step in DMSO (50. To the solution in liters), sodium cyanide (2.6 grams, 53.6 pen moles) was added. The resulting heterogeneous sentence solution was warmed to 50 ° C and sonicated for 1 hour. The reaction was cooled, The solution was separated between% 0 and 0. The organic matter was washed with H20 (2x) and brine (2x). The combined aqueous phase was extracted with Ε20 (1x). The combined organic matter was dried and dried (N% s04), filtered, and concentrated under low heat and partial vacuum to give the subtitled compound (63 g, 100%) as a reddish volatile oil, which was used in the next step without further purification. 1 H NMR (300 MHz, CDC13) δ 7.32 (s, 1Η), 7.24 (s, 1H), 7.12 (s, 1H), 3.78 (s, 2H) (iii) 3-amino-5-trifluoromethoxybenzene Nongkuangyu cyanide 3-chloro-5-trifluoromethoxyfluorene (6.3 g, 26.7 mmol; see Step ii (ii)) To a solution in 2-propanol (100 ml), add water (200 ml) and hydroxide (7.5 g '133.5 mmol). Allow the solution to reflux for 1 hour and cool To room temperature 'and remove 2-propanol in true 2. Wash the aqueous phase with CH2Cl2 (2x) and discard the washing solution. Acidify the basic aqueous phase with 2N HC1 and extract with CH2Cl2 (3x). Make The CH2C12 extract was dried (Na2S04), filtered and concentrated in vacuo to give the title compound (5.2 g, 76%) as an oil, which was used in the next step without further purification. 1 H NMR ( 300 MHz, CDC13): (5 7.25 (s, 1H), 7.19 (s, 1H), 7.08 (s, 1H), 3.68 (s, 2H) (iv) 3-chloro-5-tristimulus, methyl chloride Phenylacetate in 3-chloro-5-trifluoromethoxyphenylacetic acid (5.2 g, 20.4 mmol; see step (iii) above) in EtOH (600 ml), Sulfuric acid (a few drops) was added. The solution was refluxed for 18 hours, cooled to room temperature, neutralized with solid NaHC03, and EtOH was removed in vacuo. The residue was diluted with EtOAc and then H20 (lx) -74- 200306975 Description of the invention Continued (70) -—-, NaH Wash with CO3 aqueous solution (1x) and brine (1x). The organic material was dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (5.5 g, 96%) as an oil, which was used in the next step without further pure 1 H NMR (300 MHz, CDC13) 6 7.24 (s, 1H), 7.16 (s, 1H), 7.07 (s, 1H), 4.13-4.22 (q, J = 8 Hz, 2H), 3.63 (s, 2H), 1.24 -1.32 (t, J = 8 Hz, 3H) (v) Phn-C1 ¥ 5-QCFLVrRTS ^ CH (; CH01Cr〇 ^ OEt in 3-chloro-5-trifluoromethoxyphenyl acetate (4.5 g , 15.9 millimoles; see step (iv) above) in a solution in anhydrous THF (400 ml), under a nitrogen atmosphere and below 0 ° C (ice-MeOH bath), add sodium ethoxide (4.5 g, 63.6 mmol). The cold solution was stirred for 40 minutes, and ethyl formate (8.1 g, 111.3 mmol) was added. This solution was stirred for 30 minutes, warmed to room temperature and stirred for 2 hours. Then, The THF was removed in vacuo. The residue was diluted with Et20 and extracted with Η20 (1x) and 0.5M NaOH (3x). The aqueous extract was acidified with 2NHC1 and extracted with CH2C12 (3x). The combined organic materials were dried and dried (Na2S04), filtered and concentrated in vacuo The crude sub-title compound (3.9 g) was obtained. It was subjected to flash chromatography on silica gel and dissolved with hexane: EtOAc (4: 1) to obtain the sub-title compound (3.0 g, 61%) as an oil. 1 H NMR (300 MHz, CDC13, mixture of isomers): 5 12.30 and 12.25 (s, 1H), 7.39 and 7.34 (s, 1H), 7.21 (s, 1H), 7.17 (s, 1H), 7.08 (s, 1H), 4.27-4.37 (q, J = 8 Hz, 2H), 1.28-1.38 (t, J = 8Hz, 3H) (vi) Phri-CIXS-OCF ^ VrR ^ S ^ CHiCH ^ OmcrO ^ OEt In a solution of Ph (3-Cl) (5-OCF3HR, S) CH (CHO) C (O) OEt (3.0 g, 9.66 mmol; see step (v) above) in MeOH (200 mL) , At -10 ° (: (ice- -75- 200306975 (,) continued;

MeOH bath), sodium borohydride (0.7 g, π ·% mmol) was added in portions over 5 minutes. This solution was stirred at -i (TC for 45 minutes, and additional sodium borohydride (0.4 g) was added. After another 15 minutes, the reaction was quenched with aqueous ammonium chloride solution to make it weakly acidic with 2N HC1 And the MeOH was removed in vacuo. The residue was diluted with EtOAc and washed with h20 (1x), aqueous NaHC03 (1x) and brine (1x). The organic material was dried (Na2S04), filtered and vacuumed. The mixture was concentrated in vacuo to give the crude subtitled compound. Flash chromatography on silica gel was performed with hexane: EtOAc (5: 1) to give the subtitled compound (2.0 g, 66%) as an oil. 1 H NMR (300 MHz, CDC13): 5 7.26 (s, 1H), 7.19 (s, 1H), 7.07 (s, 1H), 4.16-4.28 (m, 2H), 4.04-4.15 (m, 1H), 3 · 76_3 · 94 (m, 2H), 2.33 (t, J = 6 Hz, 1H), 1.18-1.30 (t, J = 8 Hz, 3H) (vii) PJi (3-Ciy5-OCFLVrR, S > > CHrCH1〇H > irrn ^ nN in Ph (3-Cl) (5-OCF3HR, S) CH (CH2OH) C (O) OEt (2.0 g, 6.24 mmoles; see step (vi) above) at 'Lithium hydroxide monohydrate (0.5 g, 12.48 mmol) was added to the solution in THF (50 ml) and H20 (25 ml). ). This solution was stirred at room temperature for 1 hour and the THF was removed in vacuo. The residue was diluted with η20, then washed with CHC13 (2χ), and the washing solution was discarded. The alkaline aqueous layer was acidified with 2N HC1 And extracted with CHC13 (4x). The CHC13 extract was dried (Na2S04) 'filtered and concentrated in vacuo to give the crude subtitled compound (1.5 g) as an oil. Flash chromatography on silica gel, CHC13: MeOH: concentrated NH4OH (gradient 7.0 ·· 2.5 ·· 0.5 to 6: 3 ·· 1) was dissolved to obtain the ammonium salt (U g) of the subtitle compound. The ammonium salt was prepared between IN HC1 and CHC13. Separation treatment. The organic material was dried (Na2S〇4), filtered and concentrated in vacuo to give -76- 200306975 Description of the Invention (72)-Sub-title compound (also known as 3-chloro-5-trifluoro Methoxytropine acid) as an oil (Ug, 62%). 1 H NMR (300 MHz, CD3 OD): ά 7.41 (s, 1H), 7.27 (s, 1H), 7.24 ( s, 1H), 4.03 (m, 1H), 3.75-3.87 (m, 2H) (viii) PhG-nX5-OCF3_VrS, CHiCH1〇H) C (0) -Aze-Pab (TeocUa) and Ph (3 -Cl) (5_ QCF ^ VrR ^ CHrCH ^ OmrrOVAze-PabrTeoc ^ (h ^ in Ph ( 3-Cl) (5-OCF3HR, S) CH (CH2OH) C (O) OH (0.65 g, 2.28 mmoles; see step (vii) above) in a solution in DMF, below 0 ° C (ice-MeOH bath), H-Aze-Pab (Teoc) (0.90 g, 2.39 mmol), trimethyl p-pyridine (0.71 g, 5.70 mmol) and PyBOP (1.31 g, 2.51 millimoles). The resulting solution was stirred at below 0 ° C for 1 hour, warmed to room temperature and stirred for 1 hour. Then, the DMF was removed in vacuo and the residue was diluted with EtOAc and washed with dilute aqueous HC1 (1x), brine (1x), aqueous NaHC03 (1x) and brine (ιχ). The organic material was dried (NadO4), filtered, and concentrated in vacuo to give the crude subtitled compound (2.1 g) as a diastereoisomeric leak. Flash chromatography (3x) on crushed gel, initially with EtOAc: MeOH (95: 5), then with CH2C12 ... MeOH (97: 3), and finally with CH2C12: MeOH (95: 5), The subtitled compound diastereomer ⑷ (0.51 g, 35%) and diastereoisomer ⑼ (0.45 g, 31%) were obtained as a crushable foam. About the subtitle compound diastereomers: 1 H NMR (300 MHz, CD3 OD, complex mixture of rotamers) 5 7 · 79_7.85 (d, J = 8Hz, 2H), 7.22-7.49 (m , 5H), 5.17-4.77 (m, lH), 4.53-4.18 (m, 4H), 3.5l 4.11 (m, 5H), 2.47-2.73 (m? 1H), 2.11-2.34 (m, 1H), 1.08 -1.12 (m, 2H), 0.07 (s, 9H) MS (m / z) 643 (M + 1) + -77- 200306975

(73)-(ix) PhrS-CIVS-OCF ^ Vr ^ CHrCH ^ OmrrOVAze-Pab X TFA makes Ph (3-Cl) (5-OCF3 HS) CH (CH2 OH) C (0) -Aze-Pab (Teoc ) (78 mg '0.121

Millimoles; see step (viii) -Diastereomers (i) above) dissolved in 5 ml of trifluoroacid. After 10 minutes, the reaction was complete and the solvent was evaporated. The residue was lyophilized from water and acetonitrile to give the desired product. Yield: 70 mg (94%). MS (m / z) 483 (M-1) '; 485 (M + 1) + 1H-NMR (400 MHz; D20) Rota isomer 1: 1: 5 8.83 (bt, 1Η), 7.79 (d, 1Η), 7.72 (d, 1H), 7.54 (d, 1H), 7.43 (d, 2H), 7.35 (m, 1H, rotomer), 7.28 (m, 1H, rotomer), 7.20 (m, 1H, rotomer), 7.05 (m, 1H, rotomer), 5.22 (m, 1H, rotomer), 4.83 (m, 1H, rotomer), 4.57 (m , 2H, rotomer), 4.38 (m, 2H, rotomer), 4.3-3.7 (m, 5H), 2.77 (m, 1H, rotomer), 2.55 (m, 1H, rotamer), 2.27 (m, 1H) 13C-NMR (100MHz; D20): (carbonyl and / or amidine proton, rotamer) 5

172.9, 172.2, 172.0, 171.8, 166.9 Example 11

Phr3-C1V5.〇rF ^ VrS ^ CHrCH1〇mC (; OVA7e-Pahr〇Me ^ (i) Phn-CIVS-OCF ^ VrS ^ CHrCH ^ mrrOVAze-PabrOMe. Teoc ^ i makes Ph (3-Cl) (5- CF3HS) CH (CH2OH) C (O) -Aze-Pab (Teoc) (100 mg, 0.155 mmol; see Example 10 (viii) above) was dissolved in 12 ml of tetrahydrofuran. 0-hydroxymethyl was added Amine hydrochloride (44 mg, 0.53 mmol) and the reaction was heated at 50 t overnight. The reaction mixture was evaporated and the residue was purified by preparative HPLC (CH3CN / 0.1MNH4OAc (70/30)). Evaporate the relevant fractions, and dissolve the residue in a small amount of acetonitrile and water, and freeze-dry. Repeat the freeze-drying once. Yield: 80 mg (76%) pure substance. -78- 200306975 /, Inventory page (74) _ 1 H-NMR (400 MHz; CD3 OD) rotational isomers: 7.5-7.4 (m, 3Η), 7.35-7.2 (m, 4H), 5.15 (m, 1H, less rotational isomers), 4 74 (m, 1H, major rotamer), 4.5-4.25 (m, 3H), 4.2-3.95 (m, 4H), 3.91 (b, 3H), 3.9-3.6 (m, 2H), 2 · 63 (m, 1H, fewer rotamers), 2.50 (m, 1H, main rotamers), 2.3-2.1 (m, 1H), 0.95 (m, 2H), 0.02 (s, 9H, major rotational isomers), o.oi (s, 9H, fewer rotational isomers) (ii) ^ hG-CiyS ^ OCFO ^ CHrCH ^ OmcrOVAze ^ Make Ph (3-Cl) (5-OCF3HS) CH (CH2OH) C (O) -Aze-Pab (OMe, Teoc) (80 mg, 0.12 mmol); see step 上文 above to dissolve in 1 ml of dichloromethane And cooled in an ice bath. 3 ml of trifluoroacetic acid was added, and the reaction flask was kept in the ice bath for two hours. The mixture was evaporated and dissolved in ethyl acetate, with NaHC03 (aqueous), and then with water. Washed three times with brine. The organic phase was dried (Na2S04), filtered and evaporated. The residue was lyophilized from a small amount of acetonitrile and water. Yield: 60 mg (95%) of the pure title product. MS (m / z) 528 (M) -1) &531; 531 (Μ + l) 4 * 1 H-NMR (500 MHz; CD3 0D) rotamer: 5 7.65-7.55 (m, 3H, rotamer), 7.45 (m , 1H, main rotamer), 7.4-7.2 (m, 4H), 5.15 (m, 1H, less rotomer), 4.74 (m, 1H, main rotomer) 4.5-4.3 (m, 3H), 4.05-3.95 (m, 2H), 3.85 (m, m), mainly rotational isomerism ), 182 (s, m, major rotomer), 3.81 (s, 3H, minor rotomer), 3.73 (m, 1H, major rotomer), 3.67 ( m, 1H, less rotomers), 3.62 (m, 1H, less rotomers), 2.63 (m, 1H, less rotomers), 2.50 (m, 1H , Main rotamer), 2.24 (m, 1H, main rotamer), 2.16 (m, 1H, less rotomer) -79- 200306975 Description of the invention (75) L- ---- 13C-NMR (125 MHz; CD3OD): (carbonyl and / or amidine protons, rotational isomers) 5 174.0, 173.2, 172.7, 172.6, 155.1 Example 12

PhrS-ClXS-OCHF ^ yrR ^ CHrOmrrOVAze-PabrOMe ^ (i) Phf3-ClX5-OCHF2_VrR > > CHr〇H > irr〇VAze-Pab (; OMeJ Teoc ^ i make Ph (3-Cl) (5-OCHF2HR) CH (OH) C (O) -Aze-Pab (Teoc) (0.40 g, 0.65 mol; see Example 1 (ix) above) was dissolved in 20 ml of acetonitrile, and 0.50 g (6.0 mmol) was added. -Hydroxymethylamine hydrochloride. Heat the mixture at 70 ° C for 2 hours. Evaporate the solvent and separate the residue between water and ethyl acetate. Re-extract the aqueous phase with ethyl acetate twice, The combined organic phases were washed with water, brine, dried (Na2S04), filtered and evaporated. Yield: 0.41 g (91%). 1 H-NMR (400 MHz; CDC13): ί 7.83 (bt, 1H ), 7.57 (bs, 1H), 7.47 (d, 2H), 7.30 (d, 2H), 7.20 (m, 1H), 7.14 (m, 1H), 7.01 (m, 1H), 6.53 (t, 1H) , 4.89 (s, 1H), 4.87 (m, 1H), 4.47 (m, 2H), 4.4-4.2 (b, 1H), 4.17-4.1 (m, 3H), 3.95 (s, 3H), 3.67 (m , 1H), 2.68 (m, 1H), 2.42 (m, 1H), 0.97 (m, 2H), 0.01 (s, 9H). (Ii) Phn ^ ClXS-OCHF ^ VrR ^ CHromcrOVAze ^ PabrOMe ^ make Ph (3-Cl) (5-OCHF2)-(R) CH (OH) C (O) -Aze-Pab (OMe, Teoc) (0.40 g, 0.62 mmol; see step (i) above) was dissolved in 5 ml of TFA and allowed to react for 30 minutes. The TFA was evaporated and The residue was separated between ethyl acetate and NaHC03 (aqueous solution). The aqueous phase was re-extracted twice with ethyl acetate, and the combined organic phases were washed with water and brine, dried (Na2S04), and filtered. And evaporated. The product was dried from water / acetonitrile. No purification was required. Yield: 0.28 g (85%). 1 H-NMR (600 MHz; CDC13): 5 7.89 (btlH), 7.57 (d, 2H), 7 · 28 (d, 2H), 7.18 (m, -80- 200306975 Description of the Invention Continuation Sheet (76) ~ ——- 1H), 7.13 (m, 1H), 6.99 (m, 1H), 6.51 (t, 1H ), 4.88 (s, 1H), 4.87 (m, 1H), 4.80 (bs, 2H), 4'48 (ddlH), 4.43 (ddlH), 4.10 (m, 1H), 3.89 (s, 3H), 3 68 (m, 1H), 2.68 (m, 1H), 2.40 (m, 1H) 13C-NMR (125MHz; CDC13): (carbonyl and / or fluorene, rotamer) δ 172.9, 170.8, 152.7 , 152.6 MS (m / z) 495 (Ml)-, 497 (M + l) + Example 13

Phn ^ OCHF ^ yrR ^ CHrOmcrOVAze-Pah X HOAr. Ph (3-Cl) (5-0CHF2HR) CH (0H) C (0) -AZe-Pab (0Me) (13 mg, 0.026 millimoles; see above) Example 12) Dissolved in absolute ethanol. Add ethanol (5 ml) and 30 mg of 10% Pd / C. Finally, acetic acid (5 µl) was added and the mixture was hydrogenated at atmospheric pressure for 20 hours. The mixture was filtered through Celite®, evaporated and purified by reverse-phase HPLC (0.1 M ammonium acetate / MeCN in water). An appropriate portion was lyophilized to obtain the title compound as a white solid · 8.5 mg (66%). 1 H-NMR (400 MHz; CD3 OD) rotamer: 5 7.73-7.78 (m, 2H), 7.55 (d, 2H), 7.19-7.43 (m, 3H), 7.06-7.13 (m, 1H) , 6.83 (t, 1H, JHF = 74Hz, main rotamer), 6.81 (t, 1H, main rotamer), 5.20 (s, m, main rotamer) ), 5.19 (m, 1H, less rotomers), 5.15 (s, 1H, less rotomers), 4.78 (m, 1H, main rotomers), 4.44. 6 (several absorptions ♦, 2Η), 4.35 (m, 1Η, major rotamer), 4.08 (m, 1Η), 3.99 (m, 1Η, less rotomer), 2.70 ( m, 1H, less rotomers), 2.52 (m, 1H, main · isomers), 2.30 (m, 1H, main rotomers), 2.15 (m, 1H, Fewer rotational isomers), 1.89 (s, 3H). 13C-NMR (100MHz; CD3OD): (carbonyl and / or fluorene carbon, rotational isomers) account for -81-200306975 Description of the invention; continued (77 )-173.7, 172.9, 168.3. MS (m / z) 433 (M + l) +; 431 (Ml) 'Example 14

Phn-OCF ^ WRICWOFnaOVAze-Pab x TFA makes Ph (3-Cl) (5-0CF3)-(R) CH (0H) C (0) -Aze-PabxTFA (34 mg, 0.057 mmol) from Example 6 ) Was dissolved in 5 ml of ethanol, and 20 mg of 10% Pd / C was added. The mixture was hydrogenated at atmospheric pressure overnight. The mixture was filtered through Celite®, evaporated and lyophilized from water / acetonitrile. 1 H-NMR (400 MHz; CD3 OD) rotational isomers · 5 7.8-7.7 (m, 2H), 7.55 (m, 2H), 7.5-7.2 (m, 4H), 5.24 (s, 1H, main Rotamers), 5.23 (m, 1H, less rotamers), 5.18 (s, 1H, less rotamers), 4.77 (m, 1H, main rotamers) , 4.6-4.45 (m, 2H), 4.36 (m, 1H, main rotamer), 4.08 (m, 1H), 3.99 (m, 1H, less rotamer), 2.70 (m, 1H, less rotational isomers), 2.52 (m, 1H, major rotational isomers), 2.30 (m, 1H, major rotational isomers), 2.15 (m, 1H, less rotational isomers) Structure). 1 3 C-NMR (100 MHz; CD3 OD): (carbonyl and / or carbon, rotational isomers); 174.1, 173.9, 173.5, 172.9, 168.2. 1 9 -F NMR (282 MHz; CD3 OD): -59.8 and -59.9 (3F, individual are less and major rotamers), -77.4 (3F) shows that the salt is TFA. MS (m / z) 451.3 (M + l) + Example 15

PhrS-ClXS-QCH ^ CF ^ -rR ^ CHromcrOVAze-Pab x TFA ω 3-chloro-5-trifluoroethoxy stearic acid under nitrogen in 3-chloro-5-hydroxybenzaldehyde (2.0 g, 12.8 millimoles; ref. -82- 200306975 (78) Description of the invention continued on page 1) and potassium carbonate (2.3 g, 16.6 millimoles) in a magnetically stirred solution in DMF (35 ml) At room temperature, p-toluene acid 2,2,2-trifluoroethyl (4.2 g, 16.6 mmol) was added. The mixture was heated to 10 °. 〇, after 7 hours, and then stirred at room temperature overnight. The reaction was cooled to zero, poured into ice-cold 2 N HC1 (100 mL), and extracted with EtOAc (2 X 75 mL). The combined organic extracts were washed with 0.5 N HCl (2 x 50 mL), dried (NazSO4), filtered and concentrated in vacuo. This brown oil was separated on silica gel and dissolved with hexane: EtOAc (6: 1) to give the subtitled compound (1.9 g, 61%) as a yellow oil. 1 H NMR (300 MHz, CDC13) 5 9.44 (s, 1H), 7.56) (s, 1H), 7.33 (s, 1H), 7.28 (s, 1H), 4.42 (q, J = 8 Hz, 2H)

(ii) Rh (3-Cl) (5-QCH9 CE ^ / RS ^ CHrOTMS ^ rN under nitrogen at 3-chloro-5-trifluoroethoxybenzaldehyde (5.2 g, 21.7 mmol) ; See step (i) above and a solution of zinc iodide (1.7 g, 5.4 mmol) in CH2C12 (200 ml) at 0 ° C, and add trimethyl cyanide dropwise via a syringe Silane (4.3 g, 43.3 mmol). The mixture was stirred at 0 ° C for 3 hours and then diluted with H20 (150 ml). The organic layer was separated, dried (Na2s〇4), filtered and vacuumed. It was concentrated under reduced pressure to give the subtitled compound (6.9 g, 95%) as a yellow oil, which was used without further purification. 1 H NMR (300 MHz, CDC13) 5 7.27 (s, 1H), 6.98 (s, 2H) , 5.44 (s, 1H), 4.38 (q, J = 8 Hz, 2H), 0 · 30 (s, 9H)

(iii) PhOCl milk-QCH9 CE2 > {RS) CH (Otir > a〇, OH) Concentrated hydrochloric acid (170 ml) was added to Ph (3-Cl) (5-OCH2CF3HR, S) CH (OTMS) CN (6.9 g , 20.4 millimoles; see step (ii)) above, and stir at -100 ° c -83-200306975 Description of the Invention Page β (79)-1 hour. After cooling to room temperature, The reaction was further cooled to 0 ° C and slowly basified with 3 N NaOH (300 mL). This mixture was washed with Et20 (2 X 100 mL) and the aqueous layer was acidified with 2 N HC1 (50 mL). The aqueous layer was then extracted with EtOAc (2 X 100 mL), dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (5.3 g, 92%) as a pale yellow oil, which was used without need Further purification: 1 H NMR (300 MHz, CD3 OD) 5 7.18 (s, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 5.13 (s, 1H), 4.58 (q, J = 8Hz, 2H) (iv) Phn-ClXS-OCF ^ CEiVODCHCOI ^ CCCOOH (a) and PhG-CDG-OCHiCFiV iS ^ CHfOAc ^ CrO ^ OH (b) Ph (3-Cl) (5-OCH2CF3)-(R, S ) CH (OH) C (O) OH (7.06 g, 24.8 mmol; see step (iii) above) with lipase PS nAmanoff (4.30 G) Solution in ethylene acetate (250 ml) and MTBE (250 ml), heated at 70 ° C under nitrogen for 40 hours. The reaction was cooled to room temperature, the enzyme was removed by filtration, and washed with EtOAc. The filtrate was concentrated in vacuo. Chromatography on silica gel and dissolution with CHC13: MeOH: Et3N (92: 6: 2) gave the tri-ethylamine salt (3.02 g) of the subtitle compound VII as a yellow oil. The subtitled compound ⑻ salt was dissolved in H20 (150 mL), acidified with 2 N HC1, and extracted with EtO Ac (2 X 75 mL). The combined organic extracts were dried (Na2S04), filtered and Concentration in vacuo gave the subtitled compound VII (2.18 g) as an off-white solid. In addition, the triethylamine salt (4.73 g) of the subtitled compound (b) was obtained from the column chromatography described above. About Data for Subtitled Compound ：:

Melting point: 98-103 ° C 1 H NMR (300 MHz, CD3 OD) 5 7.18 (s, 1H), 7.07 (s, 1H), 7.02 (s, 1H), 5.13 (s, 1H),- 84- 200306975 Description of the invention, continued (80)---4.58 (q, J = 8Hz, 2H). 1 3 CNMR (75 MHz, CD3 OD) 5 175.4, 159.6, 144.6, 136.2, 125.0 (q, J = 277 Hz), 121.8, 115.9, 113.1, 73.3, 67,0 (q, J = 35 Hz) HPLC analysis: 98.6%, > 99% ee, Chiralcel 〇D column (97: 3: 0.5 Jihu: EtOH • TFA mobile phase)

[a] 2 5 D = -81 · 50 (c = 1.0, MeOH) APCI-MS: (M-1) = 283 m / z (v) Phi3-Cl) (5-OCH2_CFLWR > > CH (; 〇 mC (; OVAze >Pahi; Teo ^ at Ph (3-a) (5-OCH2CF3)-(R) CH (OH) C (O) OH (0.50 g, 1.8 mmol) under nitrogen; see above ( Compound ii) Step (iv)) in a solution in DMF (20 ml), at 0 ° C, add H-Aze-Pab (Teoc) xHCl (1.03 g, 2.3 mmol)

, PyBOP (1.01 g, 1.9 mmol) and DIPEA (0.57 g, 4.4 mmol). The reaction was stirred at 0 ° C for 2 hours, and then at room temperature for 20 hours. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first eluting with CHC13: EtOH (10: 1) and then EtOAc: EtOH (10: 1) to obtain the subtitled compound (0.55 g, 48%), a crushable white foam.

Melting point: 90-95 ° C

Rf = 0.42 (10: 1 CHC13: EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) 5 7 · 78-7 · 81 (m, 2Η), 7.38-7.41 (m, 2Η ), 7.12-7.16 (m, 1Η), 7Ό0-7.06 (m, 2Η), 5.09-5.22 and 4.75-4.79 (m, 2H), 3.94-4.61 (m, 8H), 2.09-2.75 (m, 2H) , 1.04-1.11 (m, 2H), 0.70 (s, 9H) APCI-MS · (M + l) = 643 m / z

(vi) Phr ^ -CIXS-OCH ^ F ^ -mCHromcrOVAze-Pab x TFA makes Ph (3-Cl) (5-〇CH2 CF3)-(R) CH (OH) C (O) -Aze-Pab (Teoc ) (0.066 g, 0.13 -85- 200306975 ⑻ page millimoles; see step (v) above) was dissolved in 3 ml TFA and allowed to react for 30 minutes. TFA was evaporated and the residue was lyophilized from water / acetonitrile to give 0.060 g (94%) of the title compound as its TFA salt. 1 H-NMR (400 MHz; CD3 OD) rotational isomers: 6 7.8-7.7 (m, 2H), 7.6-7.5 (m, 2H), 7.2-7.0 (m, 3H), 5.21 (m, 1H, Fewer rotamers), 5.17 (s, 1H, major rotamers), 5.11 (s, 1H, fewer rotomers), 4.81 (m, 1H, major rotomers) Structure), 4.6-4.4 (m, 4H), 4.37 (m, 1H, main rotamer), 4.16 (m, 1H, main rotamer), 4.06 (m, 1H) , Less rotomers), 3.99 (m, 1H, less rotomers), 2.70 (m, 1H, less rotomers), 2.54 (m, 1H, mainly Rotational isomers), 2,29 (m, 1H, major rotational isomers), 2.15 (m, 1H, fewer rotational isomers) 1 3 C-NMR (100 MHz; CD3 OD) ·· (Carbonyl and / or fluorene, rotamer) 5 172.2, 171.8, 171.7, 167.0 · MS (m / z) 499.3 (M + l) + Example 16

Phn-ClV5> 〇rH ^ rF ^ VrR ^ rH (; 〇mC (OVAze-Pabr〇Me ^ under nitrogen, at Ph (3-Cl) (5-OCH2CF3HR) CH (OH) C (O) OH (0.48 G, 1.7 mmol; refer to the solution of Example 15 (Compound IX) (iv)) in DMF (20 ml) above, at 0 ° C, add H-Aze-Pab (OMe) x2HCl (0.74 g, 2.2 millimoles), PyBOP (0.97 grams, 1.9 millimoles) and DIPEA (0.55 grams, 4.2 millimoles). The reaction was stirred at 0 ° C for 2 hours and then at room temperature for 20 hours. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, the first time being dissolved with CHC13: EtOH (10: 1) and the second time with EtOAc: EtOH (10: 1) to obtain the title. Compound (0.62 g, 69%) is a crushable white bubble-86- 200306975 Description of the Invention, Continued; (82) ---- Mu Wu.

Melting point: 75-80 ° C

Rf = 0.43 (10: 1 CHC13 ·· EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) accounts for 7.517.60 (m, 2H), 7.32-7.36 (m, 2H), 7.13 -7.17 (m, 1H), 7.00-7.06 (m, 2H), 5.09-5.19 and 4.74- 4.80 (m, 2H), 3.93-4.62 (m, 6H), 3.81 (s, 3H), 2.10-2.73 ( m, 2H) APCI-MS: (M + 1) = 529 m / z Example 17

Phn-COrS-OCH ^ CHF ^ ymCHrOH ^ rOVAze-Pab x TFA (i) 2,2-difluoroethyl ester methanesulfonic acid under nitrogen in 2,2-difluoroethanol (1.52 g, 18.5 mmol) ) In a magnetically stirred solution in ch2C12 (20 ml), add triethylamine (5.6I g, 55.5 mmol) and methanesulfonium chloride (2.54 g, 22.2 mg) at 0 ° C. . The mixture was stirred at 0 ° C: dropped for 1.5 hours, diluted with CH2Cl2 (50 ml), and washed with 2NHC1 (50 ml). The aqueous layer was extracted with CH2C12 (30 mL), and the combined organic extracts were washed with brine (30 mL), dried (Na2S04), filtered, and concentrated in vacuo to give the subtitled compound (2.52 g, 85%). ), As a yellow oil, was used without further purification. 1 H NMR (300 MHz, CDC13) S 6.02 (tt, J = 3 Hz, J = 55 Hz, 1H) 5 4.39 (dt, J = 3 Hz, J = 13Hz, 2H), 3.13 (s, 3H) ( ii) 3-chloro-: 5-difluoroethoxybenzylamine-under nitrogen, at 3-chloro-5-hydroxybenzaldehyde (L50 g, 9.6 mmol; see Example 1 (ii above) )) With a solution of potassium carbonate (1.72 g, 12.5 mmol) in dmF (10 ml) at room temperature, add 2,2-difluoroethyl ester pyrochlore yellow -87- 200306975 (83) Description of the invention $ Sell; 1; Acid (2.0 g, 12.5 mmol; see step (i) above) in DMF (10 ml). The mixture was heated to 100 ° C for 6 hours and then stirred off at room temperature overnight. The reaction was cooled to 0 ° C, poured into ice-cold 2 N HC1 (100 liters), and extracted with EtOAc (2 X 75 mL). The combined organic extracts were washed with 0.5 N HC1 (2 X 50 ml), dried (Na2S04), filtered and concentrated in vacuo. This brown oil was chromatographed on silica gel and eluted with hexane · EtOAc (5: 1) to obtain the subtitled compound (1.35 g, 64%) as a yellow oil. 1 H NMR (300 MHz, CDC13) 5 9.92 (s, 1H), 7.52 (s, 1H), 7.31 (s, 1H), 7.22 (s, 1H), 6.12 (tt, J = 3 Hz, J = 55 Hz, 1H), 4.26 (dt, J = 3 Hz, J = 15 Hz, 2H)

(iii) Ph (; 3 ^ C1 ¥ 5 > OCH ^ CHF1V (; RTS) CH (; OTMS) CN in 3-chloro-5-difluoroethoxybenzaldehyde (1.35 g, 6.1 mmol) ; Refer to the above step ⑻) and a solution of zinc iodide (0.48 g, 1.5 mmol) in CH2C12 (50 ml) at 0 ° C and nitrogen, dropwise add trimethylsilyl cyanide ( 1.21 g, 12.2 mmol). The mixture was stirred at 0 ° C for 3 hours and then diluted with H20 (50 ml). The organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo to give the subtitle Compound (1.85 g, 95%) as a brown oil, used without further purification. 1 H NMR (300 MHz, CDC13) 5 7 · 13 (s, 1H), 6.94 (s, 2H), 6.10 (tt, J = 3 Hz, J = 55

Hz, 1H), 5.43 (s, 1H), 4.20 (dt, J = 3 Hz, J = 15 Hz, 2H), 0.28 (s, 9H)

(iv) Phr3-n ¥ 5-QCH1CHF1VrR.S > > CHr〇mcr〇 ^ nH Add concentrated hydrochloric acid (60 ml) to Ph (3-Cl) (5-OCH2CHF2)-(R, S) CH (OTMS ) CN (1.85 g, 5.8 millimoles; see step (iii)) above, and stir at 100 ° C for 1 hour. After cooling to room temperature, the reaction was further cooled to 0 ° C, slowly basified with 3 N NaOH (~ 180 ml), and washed with Et2 0 (2 X 75 ml) -88-200306975 Description of the invention $ Sell; Η (84) -----. The aqueous layer was acidified with 2 N HC1 (20 mL) and extracted with EtOAc (2 X 75 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (1.50 g, 97%) as a pale yellow solid which was used without further purification. 1 H NMR (300 MHz, CD3 0D) δ 7.15 (s? 1H), 7.05 (s3 1H) 5 6.98 (s, 1H)? 6.19 (tt, J = 4 Hz, J = 55 Hz, 1H), 5.12 ( s, 1H) 5 4.25 (dt5 J = 4 Hz, J = 17 Hz, 2H) (v) Phn-ClXS-OCH ^ CHEiHSKHCOAcKCCOOH (a) and PhG-ClXS-OO ^ CHFy- (R) C ¥ ((0H ) C (0) QH rb ^ Ph (3-Cl) (5-OCH2CHF2HR, S) CH (OH) C (O) OH (3.90 g, 14.6 millimoles; see step (iv) above) Solution with lipase PS '' Amano " (2.50 g) in vinyl acetate (140 ml) and MTBE (140 ml), heated at 70 ° C under nitrogen for 40 hours. The reaction was cooled to room temperature, the enzyme was removed by filtration, washed with EtoAc, and the filtrate was concentrated in vacuo. Chromatograph on silica gel and dissolve with CHC13: MeOH: Et3N (92: 6: 2) to obtain the subtitled compound VII triethylamine salt as a yellow oil. Further, a triethylamine salt (1.47 g) of the subtitled compound (b) was obtained, this salt was dissolved in H20 (100 ml), acidified with 2NHC1, and extracted with EtO Ac (2 X 75 ml). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound IX (1.00 g) as an off-white solid. Data on subtitled compound (b):

Melting point: 103-106 ° C

Rf = 0.39 (90: 8: 2CHC13: MeOH: Et3N) 1 H NMR (300 MHz, CD3 OD) 5 7.13 (s, 1H), 7.04 (s, 1H), 6.97 (s, 1H), 6.17 (tt, J = 4 Hz, J = 55 Hz, 1H), 5.12 (s, 1H), 4.24 (dt, J = 4 Hz, J = 8 Hz, 2H) · -89- 200306975 Invention description $ Sale page (85)- --- 1 3 CNMR (75 MHz, CD3〇D) 5 175.5, 160.3, 144.5, 136.1, 121.3, 115.7, 115.3, (t, J = 240 Hz), 112.9, 73.4, 68.6 (t, J = 29 Hz) HPLC analysis: 96.2%, > 95.0% ee, ChiralPakAD column (95: 5: 0.5 hexane: EtOH: TFA mobile phase) [α] 2 5 D = -84.0 ° (c = 0.85 MeOH) APCI-MS: (M- 1) = 265 m / z (vi) Phn-nVS.OCH ^ CHF ^ VrR ^ CHrOH ^ CrOVAze-PabrTeoc ^ under nitrogen at Ph (3-Cl) (5-OCH2CHF2HR) CH (OH) C (O) OH (0.35 g, 1.3 millimoles; see above (compound (b)) step (ν)) in DMF (18 ml) solution, at 0 ° C, add H-Aze- Pab (Teoc) xHCl (0.76 g, 1.7 mmol), PyBOP (0.75 g, 1.4 mmol) and DIPEA (0.43 g, 3.3 mmol). The reaction was stirred at 0 ° C for 2 hours and then at room temperature for 20 hours. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first eluting with CHC13: EtOH (10: 1), then EtOAc: EtOH (10: 1) to obtain the subtitled compound (0.69 g, 84%), which is a crushable white foam.

Melting point: 108-118 ° C

Rf = 0.48 (10: 1 CHC13: EtOH) iHNMRpOOMHz'DsOD, a complex mixture of rotamers) (5 7.78-7.81 (m, 2H), 7.40-7.43 (m, 2H), 7.09-7.12 (m, 1H ), 6.96-7.02 (m, 2H), 6.16 (t, J = 57 Hz, 1H), 5.09-5.20 and 4.75-4.80 (m, 2H), 3.95-4.55 (m, 8H), 2.10-2.75 (m , 2H), 1.04- 1.11 (m, 2H), 0.07 (s, 9H) APCI-MS: (M + l) = 625 m / z

(vii) PhrS-CIVS-OCH ^ CHF ^ -rR ^ CHromcrOVAze-Pah X TFA makes Ph (3-Cl) (5-OCH2CHF2HR) CH (OH) C (O) -Aze-Pab (Teoc) (0.086 g, 0.138 -90-200306975 / Description of the invention, continuation (86) _ millimoles; see step (vi) above) dissolve in 3 ml TFA and allow it to react for 1 hour. TFA was evaporated and the residue was lyophilized from water / acetonitrile to give 0 080 g (98%) of the title compound as its TFA salt. 1 H-NMR (300 MHz; CD3 OD) rotational isomers: 5 7.8-7.7 (m, 2H), 7 · 6-7 · 5 (m,

2H), 7.15-6.95 (m, 3H), 6.35-5.95 (m, 1H), 5.20 (m, 1H, less rotational isomers), 5.14 (s, 1H, main rotational isomers ), 5.10 (s, 1H, less rotational isomers), 4.80 (m, 1H, major rotational isomers), 4.6-4.0 (m, 6H), 2.70 (m, 1H, less Rota isomers), 2.53 (m, 1H, the main rotamer), 2.29 (m, 1H, the main rotamer), 2.15 (m, 1H, the less rotomer). 13 C-NMR (100 MHz; CD3 OD): (carbonyl and / or fluorene, rotamer) 5 174.0, 173.8, 173.4, 172.9, 168.2 MS (m / z) 481.2 (M + lf ^ Example 18

Ph (; 3 > C1X5-OCH1CHF1VfR > >CHr〇mrr〇VAze-Pahi; OMe ^

Under nitrogen, at Ph (3-Cl) (5-OCH2CHF2HR) CH (OH) C (O) OH (0.30 g, 1.7 millimoles; see Example 17 above (compound (b)) (ν)) In a solution in DMF (15 ml), H-Aze-Pab (OMe) x2HCl (0.49 g, 1.5 mmol), PyBOP (0.65 g, 1.2 mmol) and DIPEA ( 0.36 grams, 2.8 millimoles). The reaction was stirred at 0 ° C for 2 hours and then at room temperature for 20 hours. The mixture was concentrated in vacuo and the residue was chromatographed on silica three times, first with CHC13: EtOH (10: 1), then with EtOAc: EtOH (10: 1), and finally with CHC13: MeOH (20: 1) ) To give the title compound (0.47 g, 81%) as a crushable white foam.

Melting point: 65-75 ° C -91-200306975 Description of the invention, continued (87) -—-

Rf = 0.37 (10: 1 CHC13: Et〇H) iHNMRpOOMHz'DsOD, a complex mixture of rotamers) 5 7.58-7.60 (m, 2H), 7.32-7.35 (m, 2H), 7.09-7.12 (m, 1H), 6.96-7.02 (m, 2H), 6.16 (t, J = 55 Hz, 1H), 5.08-5.18 and 4.74-4.80 (m, 2H), 3.96-4.50 (m, 6H), 3.80 (s, 3H), 2.10-2.75 (m, 2H) APCI-MS: (M + 1) = 511 m / z. Example 19

Phr ^ -CIXS ^ OCH ^ FVrR ^ CHfOmcrOVAze-Pab X TFA ii ^ Ph (; 3 > C1 ¥ 5 > TMSOV (; R: SlCH (; OTMSlCN at 0 ° C, at 3-chloro-5-hydroxybenzene To a solution of formaldehyde (9.8 g, 62.6 mmol; see Example 1 (ii)) and ZηΙ2 (5.0 g, 15.7 mmol) in anhydrous CH2Cl2 (500 ml), add trimethyl cyanide Silane (13.7 g, 138 mmol). Warm the reaction mixture to room temperature and stir overnight. Add water (250 mL) and separate the layers. Extract the aqueous layer with CH2C12 (2 X 300 mL). Make The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (16.9 g, 83%) as a yellow oil, which was used without further purification.

Rf = 0.42 (3: 1 hex: EtOAc) 1 H NMR (300 MHz, CDC13) 5 7.06 (s, 1H), 6.86 (s, 2H), 5.40 (s, 1H), 0.30 (s, 9H) , · 0.24 (s, 9H)..

(W) Ph (; 3-C1 ¥ 5-OHVrRTS ^ CHr〇H ^ a〇 ^ OH) Ph (3-Cl) (5-〇TMSHR, S) CH (OTMS) CN (22.6 g, 68.8 mmol) ; Refer to the solution of step (i)) in concentrated HC1 (200 ml) above, reflux under nitrogen for 3 hours. Allow the reaction to cool to 0 ° C, and slowly alkalize with 2 NNaOH. Use Et20 -92- 200306975 Description of the invention (88) -—- (3 x 100 ml) The mixture was washed to remove organic impurities. The aqueous layer was acidified with 2 N HC1 and extracted with EtOAc (3 x 200 ml). The combined organic extracts were Dry (Na) S04) 'filtered and concentrated in vacuo to give the subtitled compound (9.3 g, 67%) as a brown oil, which was used without further purification.

Rf = 0.23 (6: 3: 1 CHC13: MeOH: concentrated NH4OH) 1 H NMR (300 MHz, CD3 OD) 5 7.05 (s, 1H), 6.94 (s, 1H), 6.73 (s, 1H), 5.03 (s, 1H). (Iii) Ph (; 3-C1 ¥ 5 ^ 0HV (; RS ^ CH (; OHX〇 ^ OEt in Ph (3-Cl) (5-〇HMR, S) CH (0H) C (0) 0H (9.3 g, 46.0 mmol; see step (ii) above) in a solution of anhydrous EtOH (200 mL), add concentrated sulfuric acid (0, 25 mL), and expose the reaction to nitrogen Under reflux for 4 hours. The reaction was cooled to 0 ° C, and solid NaHC03 (0.2 g) was added. The reaction was concentrated in vacuo and saturated with NaHC03 (100 mL) and Et2 0 (3 X 50 mL). Liquid separation was performed. The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the sub-title compound (6.9 g, 65%) as a yellow oil, which was used without further purification.

Rf = 0.62 (6: 3: 1 CHC13 · MeOH: concentrated NH4OH) · 1 H NMR (300 MHz, CDC13) 5 6.99 (s, 1H), 6.81 (s, 2H), 5.07 (s, 1H), 4.16- 4.32 (m, 2H), 1.23 (t, J = 7Hz, 3H) · (iv) Phi ^ -nVS-OCH ^ FVrR.S ^ CHromcrOlORt in Ph (3-Cl) (5-〇H)-(R, S) CH (〇H) C (〇) OEt (6.1 g, 26.8 mmol; see step (iii) above) in a solution of DMF (100 ml) in a sealed flask under nitrogen and At 0 ° C, cesium carbonate (13.1 g, 40.2 mmol) was added. The reaction mixture was stirred at 0 ° C for 15 minutes, and then potassium iodide (0.5 g, 2.7 mmol) was added. The reaction was cooled to -78 ° C and chlorofluoromethane (18.4 g, -93- 200306975 (89) invention description n] 268 mmol) was bubbled into the container. Then, the sealed flask was warmed to room temperature 'and stirred; dropped for 18 hours. The reaction mixture was cooled to 0 ° C, carefully vented to remove any excess chlorofluoromethane, and separated with H20 (20 mL) and Et20 (3 X 50 mL). The combined organics were washed with brine (2 X 50 mL), dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissolution with hexane: EtOAc (gradient 9: 1 to 3: 1) gave the subtitled compound (2.4 g, 35%) as a pale yellow oil. Note: This compound is faintly visible on TLC. It can be seen by staining TLC with bromocresol green.

Rf = 0.46 (2: 1 hexane, alkane: EtOAc) 1 H NMR (300 MHz, CDC13) 5 7 · 21 (s, 1H), 7.08 (s, 1H), 7.05 (s, 1H), 5.70 (d, JH.F = 54 Hz, 2H), 5.12 (d, J = 5 Hz, 1H)? 3.80-4.35 (m? 2H)? 3.50 (d? J = 5 Hz, 1H)? 1.26 (t, J = 7 Hz, 3H).

(v) Phn-nvs-ocH ^ -fR.siCHromcroiQH at 0 ° C and nitrogen at Ph (3-Cl) (5-OCH2F)-(R, S) CH (〇H) C (〇) 〇Et (1.8 g, 6.8 mmol; see step (iv) above) In a solution of H 2 0: THF (30 ml, 1: 2), lithium hydroxide monohydrate (0.40 g '10 · 3 millimoles). The mixture was stirred at 0 ° C for 2 hours. The reaction mixture was concentrated in vacuo and separated with H2 0 (5 ml) and Et2 0 (2 X 20 ml). At 0-, the aqueous layer was carefully acidified with 0.2 N HC1 and extracted with EtOAc (3 X 30 · mL). The combined organic materials were dried (Na2S04) 'filtered and concentrated in vacuo to give the subtitled compound (1.4 g, 87%)' as a colorless oil 'which solidified to a white solid upon standing.

Rf = 0.43 (6: 2: 1 CHC13: MeOH: Et3 N) -94- 200306975 1 H NMR (300 MHz, CD3 OD) 5 7.24 (s, 1H), 7.17 (s, 1H), 7.07 (s, 1H), 5.78 (d,

Jh-F = 54 Hz, 2H), 5.13 (s, 1H). (Vi) Ph (3-aX.5-OCH9 FMRXHiOKnaOlOHfa) and Ph (3-Cl) (5-OCH9 FV (S) CH-rOAc ^ CrO ^ OH (h) Ph (3-Cl) (5-0CH2FHR, S) CH (0H) C (0) 0H (3.2 g, 13.9 mmol; see step (v) above) and lipase A mixture of PS '' Amano "(1.9 g) in vinyl acetate (150 ml) and MTBE (150 ml) was heated at 70 ° C under a nitrogen atmosphere for 3 days. The reaction mixture was cooled, filtered through Celite®, and The filter cake was washed with EtOAc. The filtrate was concentrated in vacuo and subjected to flash chromatography on silica gel and dissolved in CHC13: MeOH: Et3N (15: 1: 0.5) to give the subtitled compound III Ethylamine salt (0.50 g, 21%), used without neutralization. In addition, triethylamine salt (0.46 g, 20%) of the subtitled compound (b) was obtained. Data on the subtitled compound (a):

Rf = 0.19 (15: 1: 0.5CHC13: MeOH: Et3N) 1 H NMR (300 MHz, CD3 OD) 5 7.26 (s, 1H), 7.18 (s, 1H), 6.97 (s, 1H), 5.74 (d , JH_F = 54 Hz, 2H), 4.81 (s, 1H), 3.17 (q, J = 7 Hz, 6H), 1.28 (t, J = 7 Hz, 9H) · Data on the subtitle compound (b) Rf = 0.33 (15: 1: 0.5 CHC13: MeOH: Et3N)

1 HNMR (300 MHz, CD3 OD) 5 7 · 28 (s, 1H), 7.19 (s, 1H), 7.09 (s, 1H), 5.76 (dJH.F = 54 Hz, 2H) 5 5.75 (s? 1H), 3.17 (q, J = 7 Hz, 6H), 2.16 (s? 3H), 1.28 (t? J = 7 Hz, 9H). (Vii) PhiB-ClVS-OCH ^ FVrR ^ CHromcrOVAze-PahrTeoc ^ Triethylamine salt (0.50 g, 1.50 mmol) Mol; see step (vi) above and a solution of HAze-Pab (Teoc) · HC1 (0.87 g, 1.90 mmol) in anhydrous DMF (15 ml), -95- 200306975 Description of the invention ϋΜ (91 ) -—- Add PyBOP (0.85 g, 2.60 mmol) and DIPEA (0.48 g, 3.70 mmol). The reaction was allowed to warm to room temperature and was stirred off overnight. The reaction mixture was concentrated in vacuo and flash-chromatographed twice on silica gel, first with CHC13: EtOH (9: 1) and second with EtOAc: EtOH (20: 1) to obtain Subtitled compound (0.23 g, 26%) as a crushable white foam. Melting point: 88-92 ^

Rf = 0.61 (9: 1 CHC13: EtOH) 1 H NMR (300 MHz, CD3 0D, complex mixture of rotational isomers) 5 7.81 (d, J = 8 Hz, 2H), 7.40-7.42 (m, 2H) , 7.06-7.23 (m, 3H), 5.76 (d, JH_F = 51 Hz, 2H), 5.10-5.16 and 4.77-4.83 (m, 2H), 3.80-4.49 (m, 6H), 2.30-2.53 (m, 2H), 1.08 (t, J = 7 Hz, 2H), 0.08 (s, 9H). APCI-MS (M + 1) = 593 m / z

(viii) PhrS-aVS-OCH ^ ymCHromcrOVAze-Pab X TFA makes Ph (3-Cl) (5-OCH2FHR) CH (OH) C (〇) -Aze-Pab (Teoc) (0.051 g, 0.086 millimoles; See step (vii) above) Dissolve in 3 ml TFA and allow to react for 20 minutes. TFA was evaporated and the residue was lyophilized from water / acetonitrile. The product was 95% pure with 5% defluoromethylated species. With the preparation of RPLC, CH3 CN: 0.1MNH4OAc was used to try to make it fail to purify, so this part of acetate was dissolved in 5 ml of TFA, evaporated and lyophilized to obtain 26 mg (51%) of the title compound. , Its TFA salt. Purity: 95%. 1 H-NMR (600 MHz; CD3 0D) rotational isomers: δ 7.8-7.7 (m, 2H), 7.6-7.5 (m, 2H), 7.21 (s, 1H, main rotational isomer), 7 17 (s, 1H, less rotomers), 7.13 (s, 1H, less rotomers), 7.09 (s, 1H, less rotomers), 7.07 (m, 1H , The main rotamers), 7.04 (m, 1H, less rotamers -96- 200306975 invention description _ pages (92)---- substances), 5.73 (d, 2H), 5.18 (m, 1H, less isomers), 5.16 (s, 1H, less isomers), 5.09 (s, 1H, less isomers), 4.78 (m, 1H, less isomers) Isomers), 4.56 (d, 1H major rotomer), 4.50 (d, 1H less rotational isomer), 4.46 (d, 1H less rotational isomer), 4.45 (d, 1H main rotamer), 4.35 (m, 1H, main rotomer), 4.14 (m, 1H, main rotomer), 4.05 (m, 1H, less rotomer) ), 3.97 (m, 1H, less rotomers), 2.68 (m, 1H, less rotomers), 2.52 (m 1H, main rotamer), 2.28 (m, 1H, main rotamer), 2.19 (m, 1H, less rotamer). 13 C-NMR (150 MHz; CD3 OD) : (Carbonyl and / or fluorene, rotamer) 5 173.9, 173.3, 172.9, 168.2 · ESI-MS +: (M + 1) = 449 (m / z) Example 20

PhrS-CIVS-OCH ^ ymCHiOmcrOVAze-PabrOMe) Triethylamine salt in Ph (3-Cl) (5-OCH2FHR) CH (〇H) C (〇) OH (0.60 g, 1.80 mmol; see Example 19 ( vi)) and HAze-Pab (OMe) .2HCl (0.79 g, 2.30 mmol) in DMF (15 ml) under nitrogen and 01, add PyBOP (1.04 g, 1.90 mmol) and DIPEA (0.58 g, 4.50 mmol). The reaction was warmed to room temperature and stirred overnight. The reaction mixture was concentrated in vacuo and flash-chromatographed on silica gel three times, firstly with CHC13: EtOH (9 ·· 1) and then with EtOAc: EtOH (20: 1) twice to give the title compound (0.22 G, 26%), is a crushable white foam.

Melting point: 66-70 ° C

Rf = 0.45 (9: 1 CHC13: EtOH) -97- 200306975 Description of the invention Page H (93) --- 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) 5 7.59 (d, J = 8 Hz, 2H), 7.32 (d, J = 7 Hz, 2H), 7.06-7.23 (m, 3H), 5.75 (s, JH_F = 54 Hz, 1H), 5.10-5.16 and 4.78-4.84 (m, 2H ), 4.11-4.45 (m, 4H), 3.80 (s, 3H), 2.10-2.75 (m, 2H). 13 C-NMR (150 MHz; CD3 OD): (carbonyl and / or fluorene, rotation Isomers) 5 173.0, 170.8, 170.7, 152.5 · APCI-MS: (M + l) = 479 m / z Example 21

Phr3-Cl ¥ 5-OCH1CH ^ FVrR ^ CHr〇mC (D) ^ Aze-Pab _x TFA ⑴ (2-monofluoroethyl) methane sulfonate_ in 2-fluoroethanol (5.0 g '78.0 mmol Ear) in a magnetic stirring solution in CH2C12 (90 ml), under nitrogen and 0 ° C, add triethylamine (23.7 g, 234 mmol) and methylsulfonyl chloride (10.7 g, 93.7) Mol). The mixture was stirred at TC for 1.5 hours, diluted with CH2C12 (100 mL), and washed with 2NHC1 (100 mL). The aqueous layer was extracted with CH2C12 (50 mL), and the combined organic extracts were brine (75 mL) ) Washed, dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (9.7 g,) as a yellow oil, which was used without further purification. 1 H NMR (300 MHz, CDC13) 5 4.76 (t, J = 4 Hz, 1H), 4.64 (t, J = 4 Hz, 1H), 4.52 (t, J = 4 Hz, 1H), 4.43 (t, J = 4 Hz, 1H), 3.09 (s , 3H) · (in 3-amino-5-military gas ethoxy j ΐ_., Aldehyde in 3-chloro-5-merylbenzaldehyde (8 · 2 g '52 · 5 mmol); see The solution of Example l (ii) above with potassium carboxylate (9.4 g, 68.2 mmol) in DMF (10 ml) was added dropwise with mesonic acid (2-monofluoro group) under nitrogen at room temperature. Ethyl) (9.7 g, 68.2 mmol); refer to the -98-200306975 ⑻ solution in step (0) in DMF (120 ml) above. Heat the mixture to 100 ° C for 5 hours, It was then stirred overnight at room temperature. To 0 ° C, poured into ice-cold 2 N HC1 and extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2S04), filtered, and concentrated in vacuo. The brown oil was allowed to pass through silica gel. Chromatographed and dissolved in hexane: EtOAc (4: 1) to give the subtitled compound (7.6 g, 71%) as a yellow oil. 1 H NMR (300 MHz, CDC13) 5 9.92 (s, 1H), 7.48 (s, 1H), 7.32 (s, 1H), 7.21 (s, 1H), 4.87 (t, J = 4 Hz, 1H), 4.71 (t, J = 3 Hz, 1H), 4.33 (t , J = 3 Hz, 1H), 4.24 (t, J 2 3 Hz, 1H).

(iii) Phr3-C1V5 > 0CH1CH1FV (; RTS) CH (; QTMS >) CN in 3-chloro-5-monofluoroethoxybenzaldehyde (7.6 g, 37.5 mmol; see step ⑼ above) In a solution of zinc iodide (3.0 g, 9.38 mmol) in CH2C12 (310 ml), trimethylsilyl cyanide (7.4 g, 75.0) was added dropwise at 0 ° C under nitrogen. Mol). The mixture was stirred at 0 ° C for 3 hours and overnight at room temperature. The reaction was diluted with H20 (300 ml), the organic layer was separated, dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (10 · 6 g, 94%) as a brown oil. No further purification or characterization is required.

(iv) Phi3-nV ^ 〇r ^ rH1FV (; RS) CH (; 0H >) C (; 0) 0H Add concentrated hydrochloric acid (100 ml) to Ph (3-Cl) (5-〇CH2CH2FHR, S) CH (OTMS) CN (10.6 g, 5.8 millimoles; see step (Qiu) above, and stir the solution at 100 ° C for 3 hours. After cooling to room temperature, the reaction was further cooled to 0. ° C, slowly basified with 3NNaOH (~ 300 mL) and washed with Et20 (3 x 200 mL). The aqueous layer was acidified with 2 N HC1 (80 mL) and EtOAc (3 X 300 -99- 200306975 Description of the invention: M (95) ---- ml) extraction. The combined EtOAc extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (8.6 g, 98%) as a pale yellow solid It was used without further purification.

Rf- 0.28 (90: 8: 2 CHC13: MeOH: concentrated NH4OH) 1 H NMR (300 MHz, CD3 OD) 5 7.09 (s, 1H), 7.02 (s, 1H), 6.93 (s, 1H), 5 · 11 (s, 1H), 4.77- 4.81 (m, 1H), 4.62-4.65 (m, 1H), 4.25-4.28 (m, 1H), 4.15-4.18 (m, 1H). (V) gjia: QX_5 : 0CH9CH? FHS) CH (OAc) C (0) 0H (a) PhO-ClM-OCI ^ CH ^ F)-rR ^ CHromcro ^ OH γμ Will? 11 (3 ^) (5-〇 (: 112 €: 112 卩)-(1 ^) 01 (〇} 1) (:( 0) 011 (8.6g, 34.5mmol); see step (iv) above )) With lipase PS nAmanon (4.0 g) in vinyl acetate (250 ml) and MTBE (250 ml), heated at 70 ° C under nitrogen for 3 days. The reaction was cooled to room temperature and passed Celite®, the enzyme was removed by filtration. The filter cake was washed with EtOAc and the filtrate was concentrated in vacuo. Chromatographed on silica gel and dissolved with CHC13: MeOH: Et3N (90: 8: 2) to obtain the subtitle The triethylamine salt of compound VII is a yellow oil. In addition, the triethylamine salt (4.0 g) of the subtitled compound (b) is obtained. The salt of the subtitled compound (b) is dissolved in H20 (250 ml), Acidified with 2NHC1 and extracted with EtOAc (3 x 200 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated in vacuo to give the subtitled compound (b) (2.8 g, 32%). ), A yellow oil. Data on the subtitle compound ⑹:

Rf- 0.28 (90: 8: 2 CHC13 ·· MeOH: concentrated NH4OH) 1 H NMR (300 MHz, CD3 OD) 5 7.09 (s, 1H), 7.02 (s, 1H), 6.93 (s, 1H), 5 · 11 (s, 1H), 4.77- 4.81 (m, 1H), 4.62-4.65 (m, 1H), 4.25-4.28 (m, 1H), 4.15-4.18 (m, 1H). (Vi) PhrS-CIVS -OCH ^ rH ^ FVrR ^ CHrOH ^ CrOVAze-PabiTeoc) -100- 200306975 Description of the invention page M (96)-

In a solution of Ph (3-Cl) (5-OCH2CH2FHR) CH (OH) C (O) OH (940 mg, 3.78 mmol; see step (v) above) in DMF (30 ml), in Under nitrogen and 0 ° C, HAze-Pab (Teoc) · HC1 (2.21 g, 4.91 mmol), PyBOP (2.16 g, 4.15 mmol), and DIPEA (1.22 g, 9.45 mmol) were added. The reaction was stirred at 0 ° C for 2 hours and then at room temperature for 4 hours. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first with CHC13: EtOH (15: 1) and second with EtOAc: EtOH (20: 1) to obtain the subtitle. Compound (450 mg, 20%) is a crushable white foam.

Melting point: 80-88 ° C

Rf = 0.60 (10: 1CHC13: EtOH) 1HNMR (300MHz, CD3OD, complex mixture of rotamers) (57.79 (d, J = 8 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 7.05 -7.08 (m, 1H), 6.93-6,99 (m, 2H), 5.08-5.13 (m, 1H), 4.75-4.80 (m, 2H), 4.60-4.68 (m, 1H), 3.95-4.55 ( m, 8H), 2.10-2.75 (m, 2H), 1.05-1.11 (m, 2H), 0.08 (s, 9H).

APCI-MS: (M + 1) = 607 m / z.

(vii) PhrS-CIXS-OCH ^ CH ^ VrR ^ CHromcrOVAze-Pab x TFA makes Ph (3, Cl) (5-OCH2CH2FHR) CH (〇H) C (〇) -Aze-Pab (Teoc) (0.357 g, 0.589 mmol; see step (vi) above) dissolved in 10 ml TFA and allowed to react for 40 minutes. TFA was evaporated and the residue was lyophilized from water / acetonitrile to give 0.33 g (93%) of the title compound as its TFA salt. 1 H-NMR (600 MHz; CD3 OD) rotational isomers: 5 7.8-7.7 (m, 2H), 7.54 (d, 2H), 7.08 (s, 1H, main rotational isomer), 7.04 (s , 1H, fewer rotomers), 6.99 (s, 1H, major rotomers), 6.95 (s, 1H), 6.92 (s, 1H, fewer rotomers), 5.18 ( m, 1H, less rotational isomers), 5.14 (s, 1H, main rotation-101-200306975 invention description _ page (97)---isomers), 5.08 (s, 1H, more Fewer rotamers), 4.80 (m, 1H, major rotamers), 4.73 (m, 1H), 4.65 (m, 1H), 4.6-4.4 (m, 2H), 4.35 (m , 1H, main rotamer), 4.21 (doublet, double line, doublet multiplet 2H), 4.12 (m, 1H, main rotamer), 4.06 (m, 1H, Fewer rotamers), 3.99 (m, 1H, fewer rotomers), 2.69 (m, 1H, fewer rotomers), 2.53 (m, 1H, main rotomers) Compounds), 2.29 (m, 1H, major rotamer), 2.14 (m, 1H, minor rotamers). 1 3 C-NMR (150 MHz; CD 3 OD): (carbonyl and / or fluorene) 5 172.8, 172.1, 167.4 · ESI-MS +: (M + 1) = 463 (m / z) Example 22

Phn-CIXS-OCH ^ CH ^ FVrR ^ CHromcrOVAze-PabrOMe ^ at Ph (3-Cl) (5-〇CH2CH2FHR) CH (0H) C (0) 0H (818 mg, 3.29 mmol; see Example 21 above) v)) In a solution in DMF (30 ml), under nitrogen and 0 ° C, add HAze-Pab (OMe) .2HCl (1.43 g, 4.27 mmol), PyBOP (1.89 g, 3.68 mmol) ) And DIPEA (1.06 g, 8.23 mmol). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first with CHC13: EtOH (15: 1) and second with EtOAc: EtOH (20: 1) to obtain The title compound (880 mg, 54%) is a crushable white foam.

Melting point 65-72 ° C

Rf-0.60 (10: 1 CHC13: EtOH) 1 H NMR (300 MHz, CD3 0D, complex mixture of rotational isomers) 5 7.58-7.60 (d, J = 8 Hz, 2H), 7.34 (d, J = 7 Hz, 2H), 7.05-7.08 (m, 2H), 6.95-6.99 (m? 1H), 5.08-5.13 (m, 1H), 4.77-4.82 (m, 1H), 4.60-4.68 (m, 1H) , 3.99-4.51 (m, 7H), 3.82 (s, 3H), -102- 200306975 (98) Description of the invention_page 2.10-2.75 (m, 2H) · 1 3 C-NMR (150 MHz; CD3 OD): (Carbonyl and / or fluorene) 5 173.3, 170.8, 152.5. APCI-MS · (M + 1) = 493 m / z. Example 23 (i) 1,3-difluoroisopropyl methanesulfonate at 1, 3-Difluoro-2-propanol (7.0 g, 72.8 mmol) in a magnetically stirred solution of CH2C12 (100 ml) under nitrogen and zero. (Next, triethylamine (22.1 g, 219 mmol) and methanesulfonium chloride (10.0 g, 87.4 mmol) were added. The mixture was stirred at 0 ° C for 3 hours. 2NHC1 ( 150 ml), the mixture was washed, and the layers were separated. The aqueous layer was extracted with ch2 α2 (200 ml), and the combined organic extracts were washed with brine (100 ml), dried (Na 2 S04), filtered and concentrated in vacuo The title compound (11.5 g, 91%) was obtained as a yellow oil and used without further purification. 1 H NMR (300 MHz, CDC13) 5 4.97-5.08 (m, 1H) 5 4.75-4.77 (m5 2H) ? 4.59-4.61 (m? 2H), 3.12 (s, 3H) ·

(ii) Phn-CIVS-OCHrCH ^ FMCHO in 3-chloro-5-merbenzaldehyde (8.0 g, 50.7 mmol; see Example 1 (ii) above) and potassium carbonate (9.1 g, 66.0 mmol) ) In a solution in DMF (75 ml), add dropwise I, 3-difluoroisopropyl methanesulfonate (11.5 g, 66.0 mmol) under nitrogen at room temperature; see the steps above in DMF (75 ml). The mixture was heated to no ° C. over 18 hours. The reaction was cooled to 0. 0, poured into ice-cold 2 N HC1 (200 ml) and washed with EtOAc (3 X 250 ml). ) Extraction. The combined organic extracts are dried (Na 2 s0 4), filtered and concentrated in vacuo -103- 200306975. Description of the Invention, Continued (99)----. The brown oil is chromatographed on silica gel. Dissolve in hexane: EtOAc (4: 1) to obtain the subtitled compound (4.4 g, 37%) as a yellow oil. 1 H NMR (300 MHz, CDC13) 5 9.92 (s, 1H), 7.51 (s , 1H), 7.36 (s, 1H), 7.26 (s, 1H), 4.70-4.89 (m, 3Η), 4.63-4.68 (m, 2Η).

(iii) PhrB-ClVS-OCHrCH ^ F ^ VrR.S ^ CHrOTMSlCN in Ph (3-Cl) (5-〇CH (CH2F) 2) CHO (4.4 g, 18.7 mmol; see step ⑼ above) and In a solution of zinc iodide (1.5 g, 4.67 mmol) in CH2C12 (200 ml), trimethylsilyl cyanide (3.7 g, 37.3 mmol) was added dropwise at 0 ° C and nitrogen. The mixture was stirred at 0 ° C for 3 hours and overnight at room temperature, then diluted with Η200 (200 ml). The organic layer was separated, dried (Na2S04), filtered, and concentrated in vacuo to give the subtitled compound (5.5 g, 87%) as a brown oil, which was used without further purification. 1 H NMR (300 MHz, CDC13) 5 7 · 12 (s, 1H), 7.00 (s, 2H), 5.42 (s, 1H), 4.70-4.80 (m, 3H), 4.59-4.64 (m, 2H) , 0.26 (s, 9H).

(iv) Phf3 > ClX5 > OCHrCH1F ^ VrR.S ^ CH (; OH > iCr〇 ^ OH Add concentrated hydrochloric acid (50 ml) to Ph (3-Cl) (5-〇CH (CH2F) 2HR, S) CH (〇TMS) CN (5.5 g, 16.3 mmol; see step (iii)) above, stir this solution for 1.5 hours at 100 ° C. After cooling to room temperature, the reaction is further cooled to 0 ° C, slowly basified with 3NNaOH (~ 200 ml) and washed with Et20 (3 x 200 ml). The aqueous layer was acidified with 2 N HC1 (75 ml) and extracted with EtOAc (3 x 200 ml). The combined EtoAc extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (4.6 g, 100%) as a brown oil, which was used without further purification. 1 H NMR (300 MHz, CD3 OD) 5 7.14 (s, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 5.12 (s, 1H), -104- 200306975

Description of the invention MM (100)-4.70-4.90 (m, 3H), 4.52-4.67 (m, 2H). (V) PhG-CDb-OCHiCi ^ EiiMSICHiOAc ^ aCOOH (a) and Ph (3-Cl ) (5-QCHCH.F ^ VmCHromcrO ^ QH (b) Ph (3-Cl) (5-〇CH (CH2F) 2HR, S) CH (0H) C (0) 0H (4.6 g, 16.4 mmol Moore; see step (iv) above and the lipid anti-enzyme PS nAmano "(3.0 g) in ethyl acetate (150 ml) and MTBE (150 ml) at 70 ° C under nitrogen Heat for 2.5 days. Allow the reaction to cool to room temperature, remove the enzyme by filtration through Celite®. Wash the filter cake with EtOAc, and concentrate the filtrate in vacuo. Chromatograph on Shixi gel and use CHC13 : MeOH: Et3N (90: 8: 2) was dissolved to obtain the triethylamine salt of the subtitle compound ⑻ as a yellow oil. In addition, the triethylamine salt (2.2g) of the subtitle compound (b) was obtained, and The salt was dissolved in H20 (100 mL), acidified with 2 N HC1, and extracted with EtOAc (3 X 200 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to obtain the subtitle Compound VIII (1.4 g, 29%) as a yellow oil. Regarding the subtitle of compound (b) According to: 1 H NMR (300 MHz, CD3 OD) 5 7.14 (s, 1H), 7.08 (s, 1H), 7.02 (s, 1H), 5.12 (s, 1H), 4.704.90 (m, 3Η ), 4.52-4.67 (m, 2Η) · (vi) Phn-CIVg-OCHrCH ^ F ^ VrR ^ CHromCrOVAze-PabrTeoc) in Ph (3-Cl) (5-0CH (CH2F) 2HR) CH (0H) C ( 0) 0H (824 mg, 2.94 mmol; see step (v) above) in a solution of DMF (30 ml) under nitrogen and 0. (:, add HAze-Pab (Teoc) · HC1 ( 1.71 g, 3.81 mmoles), PyBOP (1.68 g, 3.23 mmoles) and DIPEA (949 mg, 7.34 mmoles). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo, and the residue was chromatographed twice on Shi Xi Gum, the first time as CHCI3: -105- 200306975 Description of the invention _ stomach (101)-

EtOH (15: 1), and a second dissolution with EtOAc: EtOH (20: 1) gave the subtitled compound (720 mg, 38%) as a crushable white foam.

Melting point: 78-84 ° C

Rf-0.62 (10: 1 CHC13: EtOH) 1 H NMR (300 MHz, CD3OD, complex mixture of rotational isomers) 5 7.79 (d, J = 8 Hz, 2H), 7.42 (d, J = 8 Hz, 2H), 7.00-7.12 (m, 3H), 5.08-5.20 (m, 1H), 3.97-4.80 (m, 12H), 2.10-2.75 (m, 2H), 1.05-1.11 (m, 2H), 0.08 (s, 9H) · APCI-MS: (M + 1) = 639 m / z.

(vii) Phn-CIVS-OCHrCH ^ F ^ VrR ^ CHromcrOVAze-Pab X TFA makes Ph (3-Cl) (5-〇CH (CH2F) 2)-(R) CH (OH) C (〇) -Aze- Pab (Teoc) (0.129 g, 0.202 mmol; see step (vi) above) was dissolved in 3 ml TFA and allowed to react for 20 minutes. TFA was evaporated and the residue was lyophilized from water / acetonitrile to give 0.123 g (100%) of the title compound as its TFA salt. 1 H-NMR (400 MHz; CD3 0D) rotational isomers: 5 7.8-7.7 (m, 2H), 7.55 (d, 2H), 7.2-7.0 (m, 3H), 5.18 (m, 1H, less Rotoisomers), 5.15 (s, 1H, major rotamer), 5.08 (s, 1H, less rotomers), 4.80 (m, 1H, major rotomers, part Are blocked by the absorption peak of CD3 OH), 4.75-4.4 (m, 7H), 4.38 (m, 1H, the major rotamer), 4.15 (m, 1H, the major rotamer), 4.1-3.9 ( m, 2H, 2 signals from less rotomers), 2.70 (m, 1H, less rotomers), 2.53 (m, 1H, main rotomers), 2.30 (m, 1H, main rotamer), 2.15 (m, 1H, less rotamer). 1 3 C-NMR (100 MHz; CD3 OD): (carbonyl and / or fluorene, rotamer ) 5 172.9, 172.6, 172.2, 171.7, 167.1. ESI-MS +: (M + 1) = 495 (m / z) -106- 200306975 Description of the invention (102) _: _ Example 24

Ph (; 3-C1V5-OCH (; CH ^ F ^ VrR ^ CH (; 〇ma〇VAze-Pahr〇Me ^

In Ph (3-CI) (5-OCH (CH2F) 2MR) CH (OH) C (〇) 〇H (513 mg, 1.83 mmol; see Example 23 (v) above) in DMF (30 ml) In the solution, under nitrogen and 0 ° C, HAze-Pab (OMe) · 2HC1 (797 mg, 2.38 mmol), PyBOP (1.04 g, 2_01 mmol) and DIPEA (591 mg, 4.57) Mol). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first with CHC13: EtOH (15: 1) and second time with EtOAc: EtOH (20: 1). To obtain the title compound (370 Aike, 39%) as a dusty white foam.

Melting point: 58-63 ° C

Rf = 0.66 (10: 1CHC13: Et〇H) iHNMRpOOME ^ CDsOD, a complex mixture of rotational isomers) 5 7.58-7.60

(d, J = 8Hz, 2H), 7.34 (d, J = 8Hz, 2H), 7.00-7.12 (m, 3H), 5.08-5.20 (m, lH), 4.65-4.82 (m, 3H), 4.28- 4.65 (m, 5H), 3.92-4.18 (m, 2H), 3.82 (s, 3H), 2.10-2.75 (m, 2H) · 1 3C-NMR (150 MHz; CD3 OD): (carbonyl and / or fluorene Carbon) 5 173.2, 170.8, 152.5. APCI-MS: (M + 1) = 525 m / z. Example 25

Phn-FYS-OCHF ^ -mCHromcrOVAze-Pab X TFA ⑴1-Bromo-3-fluoro-5-fluorenylbenzyl sodium hydride (60% dispersion in oil, 2 g 0 g, 0.48 mole) Add to a stirred solution of anhydrous methanol (64.5 g, 0.60 mol) in THF (1.0 liter) in portions. After the mixture was stirred for 1 hour, a solution of 1-bromo-3,5-difluorobenzene (76.8 g, 0.40 mmol) in THF (100 ml) was added dropwise over 1 -107- 200306975 (103 ) Description of the invention continues during the hour. The reaction was stirred at room temperature for 2 days. Water (400 mL) was added and THF was removed in vacuo. The aqueous layer was extracted with hexane (3x 150 ml). The combined organic extracts were washed with 2 N NaOH (2 X 1 mL), then dried (NadCU), filtered and concentrated in vacuo to give the subtitled compound (ι07 g, 98%) as a pale yellow Oil, used without further purification. R 0.47 (hexane) 1 H NMR (300 MHz, CDC13) 5 7.36-7.41 (m, 5Η), 6.94 (bs, 1Η), 6.87 (d, JH F = 8

Hz, 1H), 6.63 (d, JH_F = 10 Hz, 1H), 5.03 (s, 2H). (Ii) 3- > Sulfuryl-5-fluoro is divided into 1-molyl-3- Fluoro-5-neoxybenzene (110.0 g, 0.39 mole; see step (1) above) with N, N-xylylamine (474.0 g, 3.92 mole) in anhydrous ch2C12 (1.0 liter) In the bath, chlorinated | g (156.0 g, 1.17 mol) was added at 0 C. After 10 minutes, the ice bath was removed and stirring was continued for 2 hours. The reaction was quenched by careful addition of 3 N HC1 (1 liter). The layers were separated and the aqueous layer was extracted with ch2Cl2 (2 x 150 mL). The combined organic extracts were washed with 2 N HC1 (250 mL) and H20 (3 X 250 mL). 15% KOH (500 ml) was added to the organic layer, and the liquid layer was separated. The organic layer was further extracted with 2N KOH (2 X 70 mL). The combined aqueous layers were washed with CH2Cl2 (3 X 100 ml) and then acidified with 4 N HC1. The aqueous layer was extracted with Et0 (3 x 125 ml), then the combined Et2O extracts were dehydrated and dried to afford O4SO4), filtered and concentrated in vacuo to give the subtitled compound (69.0 g, 92%) as brown Oil, used without further purification. Melting point: 33-35 ° C Rf = 0.25 (CHC13) 1 H NMR (300 MHz, DMSO-d6) (5 10.38 (s, 1H), 6.90 (dd, JH_F = 11 Hz, J = 2 Hz, 200306975

Description of the invention MM (104) --- lH), 6.81 (s, lH), 6.59 (dt, JH-F = llHz, J-2H2 :, lH) · APCI-MS: (Μ-1) = 189 m / z (iii) 1-bromo-3-fluoroyl dioxo-benzenebenzene 3-bromo-5-fluorophenol (6.1 g '31.0 mmol; see step ⑼ above) and chloro A mixture of difluoromethane (13.0 g, 15.0 mmol) in i-PrOH (100 ml) and 30% KOH (80 ml), heated in a sealed flask at 80-85 ° C 18 hours. The reaction mixture was allowed to cool to room temperature and the layers were separated. The organic layer was concentrated in vacuo 'to give a colorless oil. The aqueous layer was extracted with Et20 (3 X 30 mL). The crude oil and the combined organic extracts were washed with 2 N NaOH (3 X 30 mL) and H20 (3 X 30 mL). Then, the organic substance was dehydrated and dried (Na2S04), filtered through a small silica packed column, and concentrated in vacuo to obtain the subtitled compound (6.1 g, 79%) as a colorless oil, which was used without further purification of 1 H NMR (300 MHz, CDC13) ά 7.11-7.14 (m, 2H), 6.84 (dt, J = 9 Hz, J = 2 Hz, 1H), 6.50 (t, Jh_f = 72Hz, 1H). (Iv) 1- Fluoro-3-difluoromethoxy-5-vinylhydrazone Under nitrogen and 65 ° C, add tri (butyl) vinylstannane (7.0 g, 22.2 mmol) to 1-bromo- 3-Fluoro-5-difluoromethoxybenzene (4.9 g, 20.2 mmol; see step (iii) above), dichlorobis (triphenylphosphine) free (Π) (1.42 g, 2.02 Mmol) and a suspension of anhydrous lithium chloride (0.90 g, 20.2 mmol) in THF (40 ml), and the mixture was stirred for 5 hours. The reaction mixture was allowed to cool to zero. 〇 and 1 N NaOH (90 ml) was added. The two-phase mixture was stirred vigorously for 1 hour, and then the layers were separated. The aqueous layer was extracted with Et20 (3 X 70 mL). The combined organic layers were washed with 2NNaOH (2x40 ml) and H20 (40 ml), then dried with -109- 200306975 (105) water-dried (Na2 S04), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissociation with hexane gave the subtitled compound (2.2 g, 57%) 'as a colorless oil.

Rf = 0.47 (hex) 1 H NMR (300 MHz, CDC13) (5 6.93-6.99 (m, 2H), 6.73-6.78 (m, 1H), 6.67 (dd, J = 18 Hz, J = 11 Hz, 1H ), 6.51 (t, JH-F = 73 Hz, 1H), 5.77 (d, J = 18 Hz, 1H), 5.36 (d, J = 11 Hz, 1H) ·

(v) Phn-FVS ^ OCHF ^ -rR ^ CHiOHYCH ^ OH Combine 2-methyl-2-propanol (140 ml), H20 (140 ml) with AD-Mix-Recall (39.2 g), and Cool to 0 ° C. Immediately add 1-amino-3-difluoromethoxy-5-ethenylbenzene (5.0 g, 26.4 Emole; dissolved in a small amount of 2-methyl-2-propanol; see steps above ( iv)), and the heterogeneous slurry was stirred vigorously at 0 ° C until TLC showed that the starting material was absent. The reaction was quenched by adding sodium sulfite (42.0 g) at 0 ° C, then allowed to warm to room temperature and stirred for 60 minutes. The reaction mixture was extracted with Et20 (3 X 120 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: EtOAc (3.2) gave the subtitled compound (5.8 g, 98%) as a colorless oil.

Rf = 0.41 (3: 2 CHC13 ·· EtOAc) 1 H NMR (300 MHz, CDC13) 5 6.96-6.99 (m, 2H), 6.77-6.82 (m, 1H), 6.51 (t, JH-F = 73 Hz , 1H), 4.79-4.85 (m, 1H), 3.76-3.84 (m, 1H), 3.58-3.66 (m, 1H), 2.66 (d, J = 3 Hz, 1H), 2.00 (t, J = 6 Hz, 1H) ·

HPLC analysis: 89.2%, > 99% ee, ChiralPak AD column (95: 5 hexane: EtOH mobile phase). -110- 200306975 Description of the Invention®:!; (106)

Phn-FV.S-OCHF ^ VrR ^ CHrOHlCHo ^ OTBS makes Ph (3-F) (5-OCHF2)-(R) CH (OH) CH2OH (5.5 g, 24.7 mmol); see step (v) above ), 4- (dimethylamino) pyridine (121 mg, 1.0 mmol) and triethylamine (3.0 g, 29.6 mmol) in anhydrous CH2C12 (100 mL) were cooled to 0 ° C . A 1.0 M solution of tertiary-butyldimethylsilane in CH2C12 (26.0 ml, 26.0 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and stirred overnight. A saturated ammonium chloride solution (60 ml) was added and the layers were separated. The organic layer was washed with a saturated ammonium chloride solution (60 ml) and H20 (2 X 35 ml), then dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: hexane (3: 1) gave the sub-title compound (7.9 g, 85%) as a yellow oil.

Rf = 0.47 (3: 1 CHC13 * hexane) 1 H NMR (300 MHz, CDC13) 5 6.95-6.98 (m, 2H), 6.76-6.79 (m, 1H), 6.51 (t, JH_F = 73 Hz, 1H ), 4.71-4.74 (m, 1H), 3.75-3.80 (m, 1H), 3.48-3.54 (m, 1H), 2.99 (bs, 1H), 0.91 (s, 9H), 0.05 (s, 3H), 0 · 00 (s, 3H) ·

(vii) Phri-FV ^ OCHF ^ VrR ^ CHfOMEMlCH ^ OTBS in Ph (3-F) (5-〇CHF2HR) CH (OH) CH2OTBS (7.9 g, 0.51 mmol; see step (vi) above) and In a solution of DIPEA (4.9 g, 48.1 mmol) in anhydrous ch2C12 (50 ml), 2-o-methoxyethoxyformamidine chloride (6.6 g) was added dropwise at 0 ° C under nitrogen. '48.1 millimoles). The mixture was stirred for 24 hours. Saturated chlorinated solution (70 ml) was added and the layers were separated. The organic layer was washed with a saturated ammonium chloride solution (70 ml) and A0 (3 x 60 ml); strips were then dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound ( 8.8 g, 99%), as a yellow oil, was used without further purification. 200306975 Invention description (107)-

Rf = 0.41 (4: 1 CHC13: EtOAc) 1 H NMR (300 MHz, CDC13) 5 7.20 (s, 1H), 7.06 (s, 1H), 7.02 (s, 1H), 6.50 (t, JH_F = 73 Hz , 1H), 4.79-4.81 (m, 1H), 4.66-4.68 (m, 2H), 3.47-3.82 (m, 6H), 3.36 (s, 3H), 0.85 (s, 9H), 0.01 (s, 3H )? 0.00 (s? 3H).

(viii) PhrS-FXS-OCHF ^ -iR ^ CHrOMEMlCH ^ OH

In a solution of Ph (3-F) (5-〇CHF2HR) CH (〇MEM) CH2OTBS (9.3 g, 21.9 mmol; see step (vii) above) in THF (60 ml) at room temperature A 1.0 M solution of tetrabutylammonium fluoride in THF (70.0 ml, 70.0 mmol) was added, and the mixture was stirred under nitrogen overnight. The reaction was concentrated in vacuo. The yellow residue was dissolved in Et20 (100 ml) and hexane (100 ml) and washed successively with a saturated ammonium chloride solution (2 X 150 ml) and H20 (3 X 70 ml). The organic layer was dried (Na2SO4), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissociation with hexane: EtOAc (1: 1) gave the subtitled compound (4.2 g, 62%) as a yellow oil.

Rf = 0.42 (1: 1 hexane: EtOAc)

1 H NMR (300 MHz, CDC13) 5 6.91-6.95 (m, 2H), 6.75-6.81 (m, 1H)? 6.51 (t, JH.F = 73 Hz, 1H), 4.80-4.82 (m, 1H) , 4.70-4.74 (m, 2H), 3.88-3.93 (m, 1H), 3.67-3.71 (m, 3H), 3.53-3.56 (m, 2H), 3.39 (s, 3H), 2.96-2.99 (m, 1H).

(ix) Ph (; 3-Fy5 ^ QCHF ^ VmCH (; 0MEM ^ Q; 010H) Ph (3-F) (5-〇CHF2)-(R) CH (OMEM) CH2OH (4.2 g, 13.4 mmol) ; Refer to the solution of step (viii)) in acetone (100 ml) above, and add to 5% NaHC03 aqueous solution (35 ml). Allow the magnetically stirred heterogeneous mixture to cool to 0 ° C, and add bromine Potassium (159 mg, 1.3 mmol) with 2,2,6,6-tetramethyl-1-hexahydropyridyloxy radical (2.2 g, 14.1 mmol). Then, dropwise add- 112- 200306975

Description of the Invention MM (108)-

Sodium hypochlorite (5.25%, 30 ml) was added and the mixture was stirred vigorously and maintained at 0 ° C over a period of 20 minutes. After 1 hour, additional sodium hypochlorite (30 ml) and 5% NaHC03 solution (35 ml) were added, and stirring was continued at 0 ° C for 2 hours. The acetone was removed in vacuo. The aqueous layer was washed with Et20 (4 X 40 mL). The aqueous layer was acidified to pH 3.5 with 10% citric acid and extracted with EtOAc (4 X 50 mL). The combined EtOAc extracts were washed successively with Η20 (4 X 30 ml) and brine (60 ml), then dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (4.3 g, 98%) as a colorless oil, which was used without further purification.

Rf = 0.74 (8.0: 1.5: 0.5 CHC13: Me〇H: Et3 N) 1 H NMR (300 MHz, acetone-d6) 5 7.16-7.18 (m, 2H), 7.16 (t, JH.F = 89 Ηζ, 1Η), 7.00-7O3 (m, 1H), 5.30 (s, 1H), 4.88 (d, J = 7Hz, 1H), 4.80 (d, J = 7Hz, 1H), 3.54-3.75 (m, 2H), 3.46-3.49 (m, 2H), 3.28 (s, 3H) · (x) Phr3-F ¥ 5-OCHF1VrR) CHr〇MEM) C (; OVAze ^ PabiTeoc)

In a solution of Ph (3-F) (5-〇CHF2HR) CH (〇MEM) C (0) 0H (1.1 g, 3.4 mmol; see step (ix) above) in DMF (20 ml) Under nitrogen and 0 ° C, HAze-Pab (Teoc) .HCl (2.0 g, 4.4 mmol), PyB0P (1.9 g, 3.7 mmol) and DIPEA (1.1 g, 8.4 mmol) were added. The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first with CHC13: EtOH (15: 1) and second time with EtOAc: EtOH (20: 1). To obtain the subtitled compound (1.3 g, 56%) as a crushable white foam.

Rf = 0.65 (15: 1 CHC13: EtOH) iHNMRpOOfvffl ^ CDsOD, a complex mixture of rotational isomers) 5 7.80-7.84 -113- 200306975 Description of the invention Page H (109)-(m, 2Η), 7.40-7.46 (m , 2Η), 6.95-7.16 (m, 3Η), 6.92 and 6.88 (t, JH_F = 73 Hz, 1H), 5.28 and 5.08 (s, 1H), 5.18-5.22 and 4.70-4.78 (m, 1H), 4.50 -4.75 (m, 1H), 4.30-4.49 (m, 2H), 4.21-4.26 (m, 3H), 3.97-4.08 (m, 1H), 3.35-3.72 (m, 6H), 3.30 (s, 3H) , 2.10-2.75 (m, 2H), 1.05-L11 (m, 2H), 0.08 (s, 9H). (Xi) Phn-FXS-OCHF ^ VrR ^ CHromcrOVAze-PabrTeoc)

Make Ph (3-F) (5-〇CHF2)-(R) CH (OMEM) C (O) -Aze-Pab (Teoc) (590 mg, 0.87 mmole; see step (X) above )) And a mixture of carbon tetrabromide (287 mg, 0.87 mmol) in 2-propanol (20 ml) was refluxed for 1.5 hours. The mixture was concentrated in vacuo and then partitioned between Η20 (50 ml) and EtOAc (3 x 50 ml). The aqueous layer was extracted with additional EtOAc (2 X 10 mL). The combined organic extracts were washed with brine (30 mL), then dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: EtOH (15: 1) gave the subtitled compound (60 mg, 12%) as a crushable white foam.

Rf = 0.46 (15: 1 CHC13: EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) 5 7.74 (d, J = 8 Hz, 2H), 7.35-7.37 (m, 2H) , 6.97-7.07 (m, 2H), 6.80-6.84 (m, 1H), 6.82 and 6.80 (t, Jh.f = 73Hz, 1H), 5.10 and 5.06 (s, 1H), 4.68-4.70 (m, 1H) ), 3.974.60 (m, 6H), 2.10-2.75 (m, 2H), 1.05-U1 (m, 2H), 0.08 (s, 9H) · APCI-MS: (M + 1) = 595 m / z

(xii) PhG-FVS-OCHF ^ Vn ^ CWOmaOVAze-Pab x TFA makes Ph (3-F) (5-〇CHF2)-(R) CH (OH) C (O) -Aze-Pab (Teoc) (0.053 G, 0.089 mmol; see step (xi) above) Dissolved in 3 ml TFA and allowed to react for 80 minutes while cooling on an ice bath. TFA was evaporated and the residue was lyophilized from water / ethyl-114-200306975. Description of the invention M (110)-nitrile to give 0.042 g (80%) of the title compound as its TFA salt. 1 H-NMR (300 MHz; CD3 OD) rotational isomers: 5 7.7-7.6 (m, 2H), 7.5-7.4 (m,

2H), 7.1-6.6 (m, 4H), 5.2-5.0 (m, 1H, 1H plus fewer rotomers), about 4.8 (the main rotomers that were blocked by the CD3 OH signal from the previous signal) , 4.6-4.3 (m, 2H), 4.26 (m, 1H, main rotamer), 4.10 (m, 1H, main rotamer), 3.96 (m, 1H, less rotomer) ), 3.89 (m, 1H, less rotomer), 2.60 (m, 1H, less rotomer), 2.44 (m, 1H, main rotomer), 2.19 (m , 1H, main rotamer), 2.05 (m, 1H, less rotamer). 1 3 C-NMR (100 MHz; CD3 OD) ·· (carbonyl and / or fluorene) 5 172.8 , 172.0, 167.0. ESI-MS +: (M + 1) = 451 (m / z) Example 26

Phr. ^-FyS ^ OCHF ^ Vm ^ CHiOmcrOVAze-PabrOMe) (i) Phn-FVg-OCHF ^ ViR ^ CHrOMEMlCrOVAze-PabrOMe)

In Ph (3-F) (5-〇CHF2)-(R) CH (〇MEM) C (〇) 〇H (1.0 g, 3.1 mmol; see Example 25 (ix) above) in DMF (30 ml ), Under nitrogen and 0 ° C, add HAze-Pab (〇Me). 2HCl (1.4 g, 4.1 mmol), PyBOP (1.8 g, 3.4 mmol) and DIPEA (1.0 g, 7,8 millimoles). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed twice on silica gel, first with CHC13: EtOH (15: 1) and second with EtOAc to give the subtitled compound (1.5 g, 79% ) Is a crushable white foam.

Rf- 0.24 (EtOAc) 1 H NMR (300 MHz, CD30D, complex mixture of rotational isomers) (5 7.58-7.62 -115- 200306975 Description of the Invention __ (m), 2H), 7.32- 7.38 (m, 2H), 7.03-7.16 (m, 3H), 6.92 and 6.88 (d, JH_F = 73 Hz, 1H), 5.27 and 5.08 (s, 1H), 5.22-5.15 and 4.75-4.80 (m, 1H) ), 4.38-4.65 (m, 5H), 3.92-4.27 (m, 1H), 3.82 (s, 3H), 3.43-3.68 (m, 4H), 3.29 (s, 3H), 2.28-2.85 (m (2H) · (ii) Phn-FVS-OCHF ^ VmCHromCfOVAze-PabrOMe) Ph (3-F) (5-〇CHF2)-(R) CH (OMEM) C (〇) -Aze-Pab (OMe) ( 828 mg, 2.33 mmol; see step (i) above and carbon tetrabromide (525 mg, 2.33 mmol) in 2-propanol (20 ml) at reflux for 8 hours, then in the chamber Stir overnight at warm temperature. The mixture was concentrated in vacuo, and the residue was partitioned between H20 (70 mL) and EtOAc (50 mL). The aqueous layer was extracted with EtOAc (2 X 25 mL). The combined organic extracts were washed with brine (35 mL), then dried (Na2SO4), filtered and concentrated in vacuo. It was subjected to rapid delamination on silica gel and dissolved with CHC13: EtOH (15: 1) to obtain the title compound (520 mg, 74%) as a crushable foam.

Melting point: 73-81 ° C

Rf = 0.43 (15: 1 CHC13 ·· EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) (5 7.59 (d, J = 8 Hz, 2H), 7.32-7.37 (m, 2H), 7.05_7 · 14 (m, 2H), 6.87-6.92 (m, 1H), 6.90 and 6.86 (t, JH_F = 73 Hz, 1H), 5.13-5.18 and 4.75-4.85 (m, 2H) , 4.15-4.45 (m, 4H), 3.81 (s, 3H), 2.10-2.75 (m, 2H). 13 C-NMR (100 MHz; CD3 OD): (carbonyl and / or fluorene) 5 172 · 0 , 171.4, 153.9. APCI-MS: (M + 1) -481 m / z Example 27

Phr.l-BrVS-OCH ^ FVrRlCHrOHlCrOVAze-Pab x TFA (i) 1,3-di > Steryl-5_fluorenyl-benzene-116- 200306975 (112) Description of the invention S stomach at room temperature and nitrogen atmosphere , Hydrogenated steel (9.9 g, 0.414 mol, 95% anhydrous) was added to the alcohol solution (41.0 g, 0.394 mol) in thF (1.0 liter) in portions and stirred; and stirred; 1 hour. To this solution was added dropwise 1,3-dibromo-5-fluorobenzene (100.0 g, 0.394 mol). After stirring overnight, the mixture was separated with EtOAc (600 mL) and EtoAc (4 X 600 mL). The combined organic extracts were dried (NaSO4), filtered, and concentrated in vacuo. Flash chromatography on silica gel and dissociation with hexane gave the subtitled compound (101.3 g, 75%) as a yellow oil. 1 H NMR (300 MHz, CDC13) δ 7.30-7.48 (m? 5Η)? 7.18 (s5 1Η)? 7.06 (s, 2Η), 4.99 (s, 2Η). (Ii) 3,5-dibromophenol at Aluminium chloride (11.7 g, 87.6 mmol) was added to 1,3-di > styrol-5-etooxybenzene (10.0 g, 29.2 mmol) at room temperature and under nitrogen; see also The above step was combined with a solution of N, N-dimethyltoluidine (35.4 g, 292 mmol) in Ch2C12 (100 ml). After 30 minutes, the mixture was mixed with 1 N HC1 (300 ml) and EtOAc (5 X 150 ml) for liquid separation. The combined organic extracts were washed with saturated NaHCO3 (150 ml) and brine (150 ml), then dried (Na2S04), filtered and concentrated in vacuo. The layer was flashed on silicone Analyze and dissolve with hexane · EtOAc (9 ·· 1) to obtain the subtitled compound (6.1 g, 82%) as a white solid. 1 H NMR (300 MHz, CDC13) δ 7.21 (s? 1H)? 6.97 (s, 2H), 5.88 (bs, 1H). (iii) 1,3-dibromo-5-monofluoromethyl is a certain gas containing 3,5-dibromophenol (10.0 g, 39.7 mmol) ; See step (U) above) with Cs2C03 (20.7 g, 63.5 mmol) in DMF (150 ml 200306975 (113) of the suspension in a tared, sealed 350 ml round-bottomed pressure flask, and the bottom was bubbled for 5 minutes through the septum, and chlorofluoromethane was added. Replace the Teflon stopper in the middle After that, the flask was sealed and allowed to warm to room temperature, at which point the flask was weighed and measured to contain 9.0 g (131 mmol) of chlorofluoromethane. This solution was set at 7 ( Heat overnight in an oil bath of TC. Allow the flask to cool to room temperature, carefully release the pressure, and dilute the contents with water (100 mL). Extract the aqueous layer with Et20 (3 x 200 mL) and allow the combined organic material to Dehydrated and dried (N ^ SO1 2 3 4 5 6) 'Extinction and concentration in vacuo. Flash chromatography on silica gel to separate from it' to give the title compound (7.9 g, 71%), As a white solid 0

-118- 1 H NMR (300 MHz, CDC13) (5 7.40 (s, 1H) 5 7.18 (s? 2H)? 5.67 (d? JH-f = 53 Hz, 2H). 2 (iv) 1- 澳 _ Tris-monofluoro-methoxy-5-vinylhydrazone under nitrogen, tris (butyl) ethenyltin (10.0 g, 31.4 mmol) was added dropwise to 1,3-dibromo-5 -Monofluoro fluorenyloxybenzene (8.5 g, 29.9 mmol; see step (iii) above), tris (triphenylphosphine) palladium hydrazone (690 mg, 0.599 mmol) and 2,6-di- A solution of tri-butyl-4-methylphenol (the amount of a spatula tip) in toluene (100 ml). The mixture was stirred at 70 ° C for 8 hours. The mixture was cooled to 0 ° C, 3 and 1 N NaOH (70 mL) was added. After 1 hour, the mixture was extracted with CH2Cl2 (3 X 300 mL), then the combined organics were dried (Na2S04), filtered through 4 and concentrated in vacuo. Flash chromatography on silica gel dissociated with hexane to obtain the subtitled compound (4.3 g, 57%) as a colorless oil. 5 1 H NMR (300 MHz, CDC13) 5 7.30 (s, 1H), 7.16 (s, 1H), 7.01 (s, 1H), 6.60 (dd, J = 6

Hz, J = 11 Hz, 1H), 5.74 (d, J = 16 Hz, 1H), 5.67 (d, JH-F = 53 Hz, 2H), 5.32 (d, 200306975 Description of the invention (114) J = 8Hz, 1H).

(v) EhQzBi ^ orj ^ KHrOHKHiOH Mix 2-methyl-2-propanol (100 ml), H 2 0 (100 ml) and mix with AD- / 5

(27.5 g) combined and cooled to 0 ° C. Immediately add 1-bromo-3-monofluoromethoxy-5-vinylbenzene (4.3 g, 17.3 mmol; see step (iv) above) and stir the heterogeneous slurry vigorously at 0 ° C Until TLC shows that the starting material is absent. Below, the reaction was quenched by adding saturated sodium sulfite (200 mL), then warmed to room temperature and stirred for 60 minutes. The reaction mixture was extracted with EtoAc (3 x 150 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (4.9 g, 100%) as a colorless oil, which was used without further purification. 1 H NMR (300 MHz, CD3 OD) 5 7.30 (s, 1H), 7.15 (s, 1H), 7.11 (s, 1H), 5.70 (d, JH_F = 53 Hz, 2H), 4.62-4.70 (m, 1H), 3.52-3.70 (m, 2H).

HPLC analysis: 92.1%, 96.9% ee, ChiralPakAD column (95: 5 hexane: EtOH mobile phase).

(vi) Phn-BrVS-OCH ^ FVm ^ CHrOMFM ^ rH ^ OTBS? 11 (341:) (5-00 «2?)-(11) (^ (01 * 1) 0« 2011 (4.9 g, 18.6 mmol; see step (v) above), 4- (dimethylamine Base) p-pyridine (453 mg, 3.71 mmol) and DIpEA (8.9 g, 93.0 mmol) in a solution of anhydrous CH2C12 (200 ml), and the tertiary-butyl chloride was added dropwise. 1OM solution of dimethyl silane in CH2% (22.3 ml, 22.3 mmol). The reaction mixture was allowed to stand at room temperature for one hour. In the mixture, DIPEA (8.9 g, 93.0 mmol) was added dropwise. Ear) with 2-methoxyethoxymethane chloride (13.9 g, 111 mmol). After 16 hours, additional gasified 2-methoxyethoxymethyl (2.2 g) was added and the reaction彳 Sense off -119- 200306975 Instruction sheet H (115)-Overnight. Dilute the mixture with Η20 (100 ml) and separate the layers. Extract the aqueous layer with CH2C12 (3 X 200 ml), then combine the organic layers Dry (Na2S04), filter, and concentrate in vacuo. Flash chromatography on silica gel and dissociation with hexane: EtOAc (5: 1) to give the sub-title compound (4.8 g, 55%) as a colorless oil. 1 H NMR (300 MHz, CDC13) 5 7 .29 (s, 1H), 7.22 (s, 1H), 7.05 (s, 1H), 5.74 (d, JH · F = 53 Hz, 2H), 4.84 (d, J = 7 Hz, 1H), 4.70- 4.74 (m, 2H), 3.50-3.91 (m, 6H), 3.42 (s, 3H), 0.90 (s, 9H), 0.05 (s, 3H), 0.01 (s, 3H).

(vii) PhrB-BrVS-OCH ^ FViR ^ CHrOMEM ^ CH ^ OH in Ph (3-Br) (5-OCH2FHR) CH (OMEM) CH20TBS (4.7 g, 10.1 mmol); see step (vi) above )) In a solution in THF (100 ml), a 1.0 M solution of tetrabutylammonium fluoride in THF (13.1 ml, 13.1 mmol) was added at room temperature, and the mixture was stirred for 1 hour. The mixture was partitioned between Η20 (100 mL) and EtOAc (3 X 100 mL), and the combined organic materials were dried (Na2S04), filtered, and concentrated in vacuo to give the subtitled compound (3.3 G, 92%), is a colorless oil that was used without further purification. 1 H NMR (300 MHz, CD3 〇D) 5 7.22 (s, 1H), 7.14 (s, 1H), 7.03 (s, 1H), 5.71 (d, JH.F- 53 Hz, 2H), 4.80-4.82 (m? 1H)? 4.58-4.66 (m, 2H), 3.71-3.77 (m, 1H), 3.39-3.65 (m, 5H), 3.27 (s, 3H) ·

(viii) Phn ^ BrVS ^ OCH ^ FViRlCHrOMEMiaOlOH Ph (3-Br) (5-〇CH2FHR) CH (〇MEM) CH2OH (2.1 g, 6.0 mmol; see step (vii) above) in acetone (40 ml ) And added to a 5% NaHC03 aqueous solution (15 ml). The magnetically stirred heterogeneous mixture was cooled to 0 ° C, and potassium bromide (70 mg, 0.60 mmol) and 2,2,6,6-tetramethyl-1-hexa-120- 200306975 ( 116) Invention Description Continued

Hydropyridyloxy radical (976 mg, 5.8 mmol). Then, sodium hypoxymite (5.25% ' 15 liters) was added dropwise, while the mixture was vigorously stirred and kept at 0 ° C over a period of 10 minutes. After 1 hour, additional sodium chlorate (10 mL) and NaHC0 3 solution (20 mL) were added, and stirring was continued for 4 hours at (TC). The acetone was removed on a rotary evaporator. The aqueous layer was mixed with 10 % NaHC〇3 solution (30 ml) was diluted and the bars were washed with Et20 (3 x 20 ml). The aqueous layer was acidified to pH 3.5 with 10% citric acid and extracted with EtOAc (3 x 40 ml). The combined The EtOAc extract was washed with 0% (3 X 50 mL) and brine (50 mL), then dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (1.7 g, 78%) as Colorless oil, used without further purification. 1 H NMR (300 MHz, CD3 OD) 5 7.38 (s, 1H), 7.25 (s, 1H), 7.18 (s, 1H), 5.76 (4 JH _ F = 53 Hz, 2H), 5.21 (s, 1H), 4.83 (d, J = 7 Hz, 1H), 4.75 (d, J = 7 Hz, 1H), 3.62-3.78 (m, 2H), 3.48-3.52 (m, 2H), 3.32 (s, 3H). (Ix) PhiS-BrVS-OCH ^ FVrR ^ CHrOMKM ^ rrOVAze-PahrTeop)

In Ph (3-Br) (5-OCH2F)-(R) CH (OMEM) C (O) OH (1.0 g, 2.72 mmol; see step (viii) above) in DMF (20 ml) Inside the solution, under nitrogen and 0. (: Next, Tim Zekou HAze-Pab (Teoc) .HCl (1.6 g, 3.5 mmol), PyBOM1.6 g, 3.0 mmol) and DIPEA (880 mg, 6.81 mmol) . The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in true 2 and the residue was chromatographed twice on silica gel, first with ^^: EtOH (15: 1), and second time with EtOAc: EtOH (20: 1), The sub-title compound (1.2 g, 62%) was obtained as a crushable white foam. 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) (5 7.80-7-84 (m, 2H), 7.40-7.46 (m, 2H), 7.13-7.32 (m, 3H), 5.84 -5.87 (m, 1H), 5.67-5.69 (m, 1H), -121-200306975 Description of the Invention_Page (117)-5.25 and 5.07 (s, 1H), 5.18-5.23 and 4.80-4.88 (m, 1H) , 3.97-4 · 79 (m, 8H), 3.60-3.71 (m, 2H), 3.40-3.53 (m, 2H), 3.32 (s, 3H), 2.10-2.75 (m, 2H), 1.05- 1.11 (m, 2H), 0.08 (s, 9H). (X) Phn-BrXS-OCH ^ FVm ^ CHromcrOVAze-PabrTeoc ^ Make Ph (3-Br) (5-OCH2FHR) CH (〇MEM) C (0) -Aze-Pab (Teoc) (347 mg, 0.478 mmol; see step (ix) above) and reflux with a mixture of carbon tetrabromide (159 mg, 0.478 mmol) in 2-propanol (10 mL) 1.5 hours. The mixture was concentrated in vacuo and then separated with H2O (20 mL) and EtoAc (3x30 mL). The combined organics were dried (Na2S04), filtered, and concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: EtOH (15: 1) gave the subtitled compound (59 mg, 19%) as a crushable white foam.

Melting point: 81-87 ° C

Rf = 0.58 (9: 1 CHC13: ΕΐΟΗ) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) 5 7.84 (d, J = 8 Hz, 2H), 7.40-7.48 (m, 2Η) 7.18-7.30 (m, 3H), 5.80 (d, JH_F = 53 Hz, 2H), 5.21 and 5.15 (s, 1H), 5.18-5.24 and 4.80-4.88 (m, 1H), 3.98-4.54 (m , 6H), 2.10-2.70 (m, 2H), 1.05-1.11 (m, 2H), 0.08 (s, 9H). APCI-MS: (M + 1) = 637 m / z

(xi) Phn-BrVS-QCH ^ FVrR ^ CHromcrOVAze-Pab x TFA causes Ph (3-Br) (5-〇CH2FHR) CH (〇H) C (〇) -Aze-Pab (Teoc) (0.073 g, 0.11 Millimoles; see step ii above) Dissolve in 5 ml TFA and allow to react for 90 minutes while cooling on an ice bath. TFA was evaporated and the residue was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (30:70). Steam the relevant dissolve -122- 200306975

(118), and lyophilized from water / acetonitrile to give 49 mg (77%) of the title compound as its acetate. 1 H-NMR (300 MHz; CD3 OD) rotatory isomers 5 7.8-7.7 (m, 2H), 7.54 (m, 2H), 7.37 (s, 1H main rotomer), 7. 33 (s, 1H less rotational isomers), 7.25-7.1 (m, 2H), 5.75 (d, 2H) 5 5.22 (m, 1H less rotational isomers), 518 (s, m major Rotoisomers), 5.11 (s, 1H less rotoisomers), 480 (m, 1H major rotamers), 4.6-4.4 (m, 2H), 4.37 (m, 1H Major rotamers), 4.16 (m, 1H major rotamers), 4.1-3.9 (m, 2H, two signals from less rotomers), 2.70 (m, 1H less Rota isomers), 2 52 (m, 1H main rotamer), 2.30 (m, 1H main rotamer), 215 (m, m less rotomer), 1.89 ( s ， 3H). ESI-MS +: (M + 1) = 493/495 (m / z) Example 28 PM3-BrV5 ~ OCHF1VrR ^ CHr〇mr / OVA7, e--Pab x TFA (i) 1,3- Dibromo-5-difluoromethane will contain 3,5-dibromophenol (10.0 g, 39.7 mmol; see Example 27 (ii) above) in 2-propanol (100 ml) and Soluble in 30% κ〇Η (80 ml) The liquid was tared and sealed in a 350 ml round bottom pressure flask at -78. (3 times, after 15 minutes of bubbling in the septum, add chlorodifluoromethane. Replace the septum with a Teflon stopper and then seal the flask and allow it to warm to room temperature. At this time, weigh the flask and measure It contained 12.0 g (138 mmol) of chlorodifluoromethane. The solution was refluxed overnight in an oil bath set at 80 ° C. The flask was cooled to room temperature, carefully released the pressure, and 200 ml). The contents were diluted. The aqueous layer was extracted with CHC13 (2 X 150 ml), and the combined organic matter was dehydrated and dried. -123- 200306975 Invention Description_0 (119) --- (Na2 S〇4), filtered and Concentrated in vacuo. The residue was purified by diatomaceous earth distillation at 80 ° C and 0.2 Hg to obtain the sub-title compound (9.6 g, 80%) as a transparent liquid. 1 H NMR (300 MHz, CDC13) (5 7.55 (s, 1H), 7.26 (s, 2H), 6.52 (t, JH. F = 68 Hz, 1H). (Ii) Sinyl-3-dioxymethoxy-5-ethyl green Under nitrogen, tris (butyl) vinyltin (10.5 g, 33.1 mmol) was added dropwise to 1,3-dibromo-5-difluoromethoxybenzene (9.1 g, 30.1 mmol) Mol; see above (I)), (triphenylphosphine) palladium osmium (700 mg, 0.60 mmol) and 2,6-di-tertiary-butylaspartyl (with a spatula tip amount) in toluene (125 ml) In the solution. The mixture was stirred at 50 ° C overnight. The mixture was cooled to 0 ° C and 1 N NaOH (70 ml) was added. After 1 hour, the mixture was extracted with CH2Cl2 (3 X 300 ml), and then The combined organic material was dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel, dissociation with hexane, afforded the subtitled compound (5.1 g '68%) as a colorless oil. 1 H NMR (300 MHz, CDC13) 5 7.53 (s, 1H), 7.18 (s, 1H), 7.08 (s, 1H), 6.60 (dd, J = 6 Hz, J = 11 Hz, 1H), 6.57 (t, JH _F = 68 Hz, 1H), 5_77 (d, J = 11 Hz, 1H), 5.36 (d, J = 8 Hz, 1H).

(iii) Ehi3-Br ¥ 5--OCHF1VrR> iCHr〇mrHLnN combines 2-methyl-2-propanol (150 ml), H 2 0 (150 ml) and AD-Mix- / 3 (27.8 g) And cooled to 0 ° C. Immediately add 1-bromo-3-difluoromethoxy-5-ethylfluorenylbenzene (4.6 g, 18.6 mmol; see step ⑼ above) and stir the heterogeneous slurry vigorously at 0 ° C until TLC showed no starting material was present, then the solution was allowed to warm to room temperature and stirred overnight. At 〇. < 3, 200306975 Description of the Invention _ Stomach (120)-The reaction was quenched by adding saturated sodium sulfite (300 ml), then warmed to room temperature and stirred for 60 minutes. The reaction mixture was extracted with EtOAc (3 X 200 mL). The combined organic extracts were dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (5.0 g, 95%) as a colorless oil, which was used without further purification. 1 H NMR (300 MHz, CD3 0D) 5 7.43 (s, 1H), 7.23 (s, 1H), 7.16 (s, 1H), 6.86 (t, JH_ 75 Hz, 1H), 4.64-4.67 (m, 1H ), 3.54-3.59 (m, 2H).

HPLC analysis: 88.6%, 96.3% ee, ChiralPak AD column (95: 5 hexane: EtOH mobile phase).

(iv) Phn-BrVS-OCHF ^ VmCHrOMRM ^ CH ^ OTBS in Ph (3-Br) (5-OCHF2HR) CH (OH) CH2OH (4.9 g, 17.3 millimoles; see step (iii) above), 4- To a solution of (dimethylamino) pyridine (420 mg, 3.5 mmol) and DIPEA (11.2 g, 86.3 mmol) in anhydrous CH2C12 (250 ml), tertiary-butyl chloride was added dropwise. A 1.0 M solution of dimethylsilane in CH2C12 (20.7 ml, 20.7 mmol). The reaction mixture was stirred at room temperature overnight. To the mixture, DIPEA (11.2 g, 86.3 mmol) and 2-methoxyethoxymethane chloride (12.9 g, 104 mmol) were added dropwise. After 3 days, additional 2-methoxyethoxymethane chloride (3.3 g) was added and the reaction was stirred overnight. The mixture was diluted with water (250 ml) and the layers were separated. The aqueous layer was extracted with CH2C12 (2 X 250 mL), then the combined organics were dried (Na2SO4), filtered, and concentrated in vacuo. Flash chromatography on silica gel and dissociation with hexane · EtOAc (4: 1) gave the title compound (4.3 g, 51%) as a colorless oil. 1 H NMR (300 MHz, CDC13) 5 7.40 (s, 1H), 7.25 (s, 1H), 7.08 (s, 1H), 6.58 (t, JH _ -125- 200306975 Description of the invention $ 卖 stomach (121)- F = 75 Hz, 1H), 4.84 (d, J = 7 Hz, 1H), 4.70-4.74 (m, 2H), 3.50-3.91 (m, 6H), 3.42 (s, 3H), 0.90 (s, 9H ), 0.12 (s, 3H), 0.05 (s, 3H) ·

(v) PhiS-Br ^ iS-OCHF ^ VrR ^ CHrOMKM ^ CH ^ OH at room temperature in Ph (3-Br) (5-OCHF2)-(R) CH (OMEM) CH2OTBS (3.3 g, 6.9 mmol) Mol; see step (iv) above). To a solution in THF (60 ml), add a 1.0 M solution of tetrabutylammonium fluoride in THF (9.0 ml, 9.0 mmol). The reaction was stirred for 45 minutes, and the mixture was partitioned between water (150 mL) and EtOAc (2 X 120 mL). The combined organic materials were dried (Na2SO4), filtered and concentrated in vacuo to give the subtitled compound (2.5 g, 98%) as a yellow oil, which was used without further purification. 1HNMR (300 MHz, CD3OD) 5 7.35 (s, 1H), 7.21 (s, 1H), 7.08 (s, 1H), 6.83 (Uh_F = 73 Hz, 1H), 4.73 (d, J = 7 Hz , 1H), 4.59-4.68 (m, 2H), 3.40-380 (m, 6H), 3.26 (s, 3H).

(vi) PhO-BryS-OCHF ^ VmCHrOMFM ^ r / O ^ OW Ph (3-Br) (5-OCHF2HR) CH (OMEM) CH2OH (3.0 g, 8.1 mmol; see step (v) above) in A solution in acetone (60 mL) was added to a 5% NaHC03 aqueous solution (25 mL). The magnetically stirred heterogeneous mixture was cooled to 0 ° C, and potassium bromide (100 mg, 0.81 mmol) was added with 2,2,6,6-tetramethyl-1-hexahydropyridyloxy Free radicals (1.3 g, 8.5 mmol). Next, sodium hypochlorite (5.25%, 19 ml) was added dropwise over a period of 10 minutes while the mixture was vigorously stirred and kept at 0 ° C. After 1 hour, additional sodium chlorate (17 ml) and NaHC03 solution (34 ml) were added, and the mixture was stirred at room temperature. The stirring was continued for another 4 hours. Remove the acetone on a rotary evaporator. The aqueous layer was diluted with 10% NaHC03 solution (30 ml) and washed with Et20 (3 x 20 ml). The aqueous layer was acidified to pH 3.5 with 10% citric acid -126- 200306975 Description of the Invention and extracted with EtOAc (3 x 40 mL). The combined EtoAc layers were washed with Η20 (3 X 50 ml) and brine (50 ml), then dried (Na2S04), filtered and concentrated in vacuo to give the subtitled compound (2.1 g, 66%) As a colorless oil, it is used without further purification.

1 H NMR (300 MHz, CD3 OD) 5 7.51 (s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 6.88 (t, Jh_f = 73Hz, 1Η), 5.21 (s, lH ), 4.84 (d, J = 7Hz, 1H), 4.76 (d, J = 7Hz, 1Η), 3.62- 3.80 (m, 2H), 3.48-3.52 (m, 2H), 3.32 (s, 3H) (vii) Phr ^ -RryS-OCHF ^ -rR ^ CHrOMEM ^ r / OVAze-PabrTeocl

In a solution of Ph (3-Br) (5-OCHF2HR) CH (〇MEM) C (〇) 〇H (1.0 g, 2.62 mmol; see step (vi) above) in DMF (50 ml), Under nitrogen and 0 ° C, 1 ^ -64 & 13 (^ 〇 (^ 11 (: 1 (1.5 g, 3.38 mmol),? 78 (1.5 g, 2.9 mmol) and DIPEA ( 840 mg, 6.50 mmol). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel with CHC13: EtOH ( 15: 1) dissociation to obtain the subtitled compound (U g, 59%), which is a crushable white foam. 1 H NMR (300 MHz, CD3 0D, complex mixture of rotational isomers) 5 7.79-7.83 (m, 2H), 7.26-7.52 (m, 5H), 6.94 and 6.91 (t, JH 4 = 73 Hz, 1H), 5.27 and 5.07 (s, 1H), 5.20-5.23 and 4.80-4.88 (m, 1Η ), 4.01-4.79 (m, 8H), 3.60-3.71 (m, 2H), 3.40-3.53 (m, 2H), 3.32 (s, 3H), 2.10-2.75 (m, 2H), 1.05-1.11 (m (2H), 0.08 (s, 9H). (Viii) Phn-BrVS-OCHFO-rR ^ CHromcrOVAze-PabrTeoc ^ Make Ph (3-Br) (5-OCHF2HR) CH (OMEM) C (0) -Aze-Pab (Teoc) (369 mg 0.496 mmol; see step (vii) above and refluxing a mixture of carbon tetrabromide (165 mg, 0.496 mmol) in 2-propanol (10 ml) for 12 hours. Allow the mixture to be at -127- 200306975 ( 123) Concentrated in vacuo, then separated with H2 0 (15 mL) and EtOAc (5 X 20 mL). The combined organics were dried (Na 2 S04), filtered and concentrated in vacuo. Flash on silica gel Chromatography and dissolution with CHC13: EtOH (15: 1) to obtain the subtitled compound (134 g, 41%) as a crushable white foam.

Melting point: 92-98 ° C

Rf = 0.37 (9: 1 CHC13 · EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotamers) 5 7.80-7.86 (m, 2H), 7.40-7.48 (m, 2H) 7.10-7.33 (m, 3H), 6.92 and 6.88 (t, JH_F = 73 Hz, 1H), 5.18 and 5.11 (s, 1H), 5.18-5.24 and 4.76-4.80 (m, 1H), 3.98-4.54 (m, 6H) , 2.10-2.70 (m, 2H), 1.05-1.11 (m, 2H), 0.08 (s, 9H). APCI-MS: (M + 1) = 655 m / z

(ix) Phn-BrXS-OCHF ^ -rR ^ iCHrOmcrOVAze-Pah Y TFA makes Ph (3-Br) (5-〇CHF2HR) CH (〇H) C (0) -Aze-Pab (Teoc) (0.081 g, 0.124 millimoles; see step (viii) above) Dissolve in 5 ml TFA and allow to react for 80 minutes while cooling on an ice bath. TFA was evaporated and the residue was purified by preparative RPLC using CH3CN: 0.1MNH4OAc (30:70). The relevant fractions were evaporated and lyophilized from water / acetonitrile to give 59 mg (83%) of the title compound as its acetate. 1 H-NMR (300 MHz; CD3 OD) rotational isomers: 5 7.8-7.7 (m, 2H), 7.6-7.4 (m, 3H), 7.3-7.2 (m, 2H), 6.89 (t, 1H main rotomer), 6.87 (t, 1H less rotomer), 5.23 (m, 1H less rotomer), 5.21 (s, 1H main rotomer), 5.13 (s, 1H less rotational isomers), 4.80 (m, 1H principal rotational isomers), 4.6-4.4 (m, 2H), 4.38 (m, 1H principal rotational isomers), 4 20 (m, -128- 200306975 Description of the invention (124)-1Ηmain rotamer), 4.1-3.9 (m, 2Η two signals from less rotomers), 2.70 (m, 1H Less rotamer), 2.54 (m, 1H main rotamer), 2.29 (m, 1H main rotomer), 2.15 (m, 1H less rotomer), 1.89 ( s, 3H).

1 3 C-NMR (75 MHz; CD3 OD): (carbonyl and / or fluorene) accounted for 172.0, 171.7, 167.0 MS (m / z) 511/513 (M + l) + Example 29

PhrS-BryS-QCHF ^ -mCHromcroVA ^ e-PabrOMe) (i) Ph (3-BrX5-OCHF2 > (TOCH (OMEMXy〇VA7e-Pab (; OMe,

In Ph (3-Br) (5-OCHF2)-(R) CH (OMEM) C (〇) OH (957 mg, 2.48 mmol; see Example 28 (vi) above) in DMF (30 ml) In the solution, under nitrogen and 0 ° C, HAze-Pab (〇Me) .2HCl (11 g, 3.2 mmol), PyB0P (1.4 g, 2.7 mmol) and DIPEA (804 mg, 6.2) were added. Mol). The reaction was stirred at 0 ° C for 2 hours and then at room temperature overnight. The mixture was concentrated in vacuo and the residue was chromatographed on silica gel twice, first with CHC13: EtOH (9: 1) and second with EtOAc: EtOH (15: 1) to give The title compound (1.1 g, 72%) was a crushable white foam. 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) 5 7.59-7.65 (m, 2H), 7.20-7.55 (m, 5H), 6.95 and 6.91 (t, JH_F = 73 Hz, 1H) , 5.27 and 5.07 (s, 1H), 5.18-5.23 and 4.75-4.84 (m, 1H), 3.87-4.89 (m, 6H), 3.84 (s, 3H), 3.60-3.71 (m, 2H), 3.40- 3.53 (m, 2H), 3.32 (s, 3H), 2.10-2.75 (m, 2H). (Ii) Phn-RryS ^ OCHF ^ yrR ^ CHromcrOVAze-PabrOMe ^ Make Ph (3-Br) (5-OCHF2HR) CH (〇MEM) C (〇) -Aze-Pab (〇Me) (11 g, 1.8 mmol; see step (i) above) with carbon tetrabromide (583 mg, 1.8 mmol) at -129 -200306975 Description of the invention _ Stomach (125) --- The mixture in 2-propanol (30 ml) was refluxed for 2.5 days. During this period, additional carbon tetrabromide (5 portions of 50 mg each, at intervals, to provide an additional 0.90 mmol) was added to ensure completion of the reaction. The mixture was concentrated in vacuo and then partitioned between H20 (50 mL) and EtOAc (5 X 25 mL). The combined organics were dried (Na2S04), filtered and concentrated in vacuo. Flash chromatography on silica gel and dissolution with CHC13: EtOH (15: 1) gave the title compound (460 mg, 50%) as a crushable white foam. Melting point: 71-75 ° C Rf = 0.63 (9: 1 CHC13 ·· EtOH) 1 H NMR (300 MHz, CD3 OD, complex mixture of rotational isomers) (5 7 · 59 (d, J = 8 Hz, 2H), 7.20-7.54 (m, 5H), 6.90 and 6.87 (t, JH_F = 73 Hz, 1H), 5.18 and 5.11 (s, 1H), 4.76-4.80 (m, 1H), 3.98-4.54 (m, 4H), 3.82 (s, 3H), 2.10-2.70 (m, 2H). 1 3 C-NMR (100 MHz; CD3OD): (carbonyl and / or fluorene, rotamer) 5 172.5, 172.1 , 171.6, 154.1 · APCI-MS: (Μ + 1) = 542 m / z Example 30

PhG-ClXS-OCH ^ CHF ^ VrR ^ CHromcrOVAze-Pahrom (i) PhG-CiyS-OCH ^ CHF ^^ R ^ CHromrrOVAze-Pabm makes Boc-Aze-Pab (Z) (see International Patent Application WO 97 / 〇2284 (92 mg, 0.197 mmol) was dissolved in 10 ml of EtOAc saturated with HC1 (gas) and allowed to react for 10 minutes. The solvent was evaporated and the residue was mixed with 1 ^ (3-(: 1) (5-〇CH2CHF2HR) CH (〇H) C (O) OH (50 mg, 0.188 mmol); see Example 17 (v) above), PyBOP (109 mg, 0.209 mmol) and finally mixed with 2 ml of diisopropylethylamine (96 mg, 0.75 mmol) in DMF. Mix -130- 200306975

DESCRIPTION OF THE INVENTION The MM (126)-substance was stirred for 2 hours, then poured into 50 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water, dried (Na2SO4) and evaporated. The crude product was flash-chromatographed on silica using EtOAc: MeOH (9: 1). Yield: 100 mg (87%). 1 H NMR (300 MHz, CD3 OD, mixture of rotamers) 5 7.85-7.75 (m, 2H),

7.45-7 · 25 (m, 7H), 7.11 (m, 1H main rotomer), 7.08 (m, 1H less rotomer), 7.05-6.9 (m, 2H) , 6.13 (bt, lH), 5.25-5.05 (m, 3H), 4.77 (m, lH are partially masked by the CD3 OH signal), 4.5-3.9 (m, 7H), 2.64 (m, 1H) Structure), 2.47 (m, 1H main rotomer), 2.25 (m, 1H main rotomer), 2.13 (m, 1H less rotomer) (ii) PhiB-CiyS- OCH ^ CHF ^ -rR ^ CHromr / OVAze ^ Pahrom Mix hydroxylamine hydrochloride (65 mg, 0.94 mmol) with triethylamine (0.319 g, 3.16 mmol) in 8 ml of THF and mix at 40 ° C for 1 hour. In Ph (3-a) (5-〇CH2CHF2)-(R) CH (OH) C (〇) -Aze-Pab (Z) (96 mg, 0.156 mmol)

Ear; see step (i)) above. Add 8 ml more THF and stir the mixture at 40 ° C for 4.5 days. The solvent was evaporated and the crude product was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (40 ... 60). Yield: 30 mg (38%). Purity: 99%. 1 H NMR (300 MHz, CD3 OD, mixture of rotational isomers) 5 7.6-7.55 (m, 2H), \ 7.357.3 (m, 2H), 7.12 (m, 1H main rotational isomer), 7.09 (m, m less rotation, isomers), 7.05-6.9 (m, 2H), 6.15 (multiple triplet, 1H), 5.15 (m, less 1H rotation isomer), 5.13 (s, 1H main rotomer), 5.08 (s, 1H main rotomer), 4.77 (m, 1H main rotomer), 4.5-4.2 (m, 5H), 4.08 ( m, 1H main rotomer), 3.97 (m, 1H rotomer), -131-200306975 Description of the invention Page M (127) ---- 2.66 (m, 1 ， rotomer) Structure), 2.50 (m, 1Ηmain rotamer), 2.27 (m, 1H main rotamer), 2.14 (m, 1H less rotomer). 1 3 C-NMR ( 100 MHz; CD3 OD): (carbonyl and / or fluorene, a mixture of rotamers) 5 172.8, 172.2, 171.4, 159.1, 158.9, 154.2 · APCI-MS: (M + 1) = 497/499 m / z Example 31

Phn-ays-ocH ^ CH ^ FvrR ^ cHromcrovAze-PahroH ^ (i) Phn-nVS-OCH ^ CH ^ FWRWHrOFncyOVAze-Pabd Boc-Aze-Pab (Z) (130 mg, 0.279 mmol) was dissolved in HC1 (gas) was saturated in 15 mL of EtOAc and allowed to react for 10 minutes. Evaporate the solvent and combine the residue with Ph (3-α) (5-0CH2CH2FHR) CH (0H) -C (0) 0H (63 mg, 0.188 mmol) in 3 ml DMF; see Example 21 (v) above ), PyBOP (147 mg, 0.279 mmol), and finally mixed with diisopropylethylamine (134 mg, 1.03 mmol). The mixture was stirred for 130 minutes, then poured into 75 ml of water and extracted three times with EtOAc. The combined organic phases were washed with water, dried (Na2S04) and evaporated. The crude product was subjected to flash chromatography on silica gel using EtOAc / MeOH = 95/5. Yield · 119 mg (79%). 1 H NMR (400 MHz, CDC13) 5 8.06 (bt, 1H), 7.67 (d, 2H), 7.45-7.25 (m, 5H), 7.18 (d, 2H), 6.89 (m, 1H), 6.84 (m , 1H), 6.76 (m, 1H), 5.16 (s, 2H), 4.84 (s, 1H), 4.79 (m, 1H), 4.66 (multiple peak doublet, 2H), 4.4_4.3 ( m, 2H), 4 · 10 (multiple peak doublet, 2H), 4.02 (m, 1H), 3.67 (m, 1H), 2.46 (m, 1H), 2.28 (m, 1H). (ii) PhA -riVtOCHiCHin-n ^ CHiOFnarn-Aze-PabiOm mix hydroxylamine hydrochloride (80 mg, 1.16 mmol) with triethylamine (0.392 g, 3.87 mmol) in 9 ml of THF and at 40 ° C Sound for 1 hour. On -132- 200306975 Invention Description_1 (128)-

Ph (3-Cl) (5-0CH2CH2F)-(R) CH (0H) C (0) -Aze-Pab (Z) (96 mg, 0.156 mmol; see step (i) above), add 9 Ml more THF. The mixture was stirred at 40 ° C for 48 hours and at room temperature for 3 days. The solvent was evaporated and the crude product was purified by preparative RPLC using CH3CN: 0.1MNH4OAc (30:70). Yield: 72 mg (78%). Purity: 100%. 1 H NMR (400 MHz, mixture of CD3OD rotational isomers) 5 7.6-7.55 (m, 2H), 7.35-7.25 (m, 4H), 7.07 (m, 1Η main rotational isomer), 7.04 (m, 1H less rotomer), 7.0-6.9 (m, 2H), 5.12 (m, 1H less rotomer), 5.08 (s, 1% less rotomer) ), 5.04 (s, 1Η), 4.78 (m, 1Η major rotational isomer), 4.68 (multiple peak doublet, 2H), 4.5 bucket 25 (m, 3H), 4.20 (multiple peak of two Heavy peak, 2H) 4.06 (m, 1H main rotomer), 3.97 (m, 1H less rotomer), 2.65 (m, 1H less rotomer), 2.48 (m, 1H main rotational isomer), 2.27 (m, 1H main rotational isomer), 2.14 (m, 1H less rotational isomer) 13 C-NMR (100 MHz; CD3 OD): (carbonyl and (Or carbon, a mixture of rotamers) 5 172.3, 171.5, 159.8, 154.3 APCI-MS: (M + 1) = 479/481 m / z Example 32

PhfB-ClYS-OCHF ^ VrR ^ CHrOHVCrOVPrQ-Pab (i) Boc-Pro-Pab (Teoc) makes BooPro-Pab (Z) (see International Patent Application WO 97/02284, 15.0 g, 0.0321 mol) dissolved in 150 In ml of ethanol, add 200 mg of 10% Pd / C (50% water). The mixture was stirred and hydrogenated under atmospheric pressure for 2 hours, filtered through Hyflo, and concentrated. This product was used without further purification. Taken 10-133- 200306975

Description of the invention MM (129)-

G (0.029 mole) of this product was dissolved in 300 ml of THF. Teoc-p-nitroprivate carbonate (10 g '0.035 mole) was added. Over 3 minutes, a solution of acid solution (5.2 g, 0.038 mol) in 50 ml of water was added, and the resulting solution was stirred for 3 days, concentrated, and the remaining portion was extracted three times with EtOAc. The combined organic layers were washed with water, dried (Na2S04) and evaporated. The crude product was subjected to flash chromatography on silica gel using dichloromethane: acetone (4 ·· 1). Yield: 9.8 g (69%) 〇 (ii) Phr ^ -nXS-OCHF ^ VmCHrOHVCrOVPro-PabrTeoc)

Boc-Pro-Pab (Teoc) (107 mg, 0.218 mmol; see step (i) above) was dissolved in 10 ml of EtOAc saturated with HC1 (gas) and allowed to react for 10 minutes. Evaporate the solvent and mix the residue with 3 ml of DMF? 11 (3-(: 1) (5-〇CHF2)-(R) CH (OH) C (〇) OH (50 mg, 0.198 mmol; see Example 1 (viii) above), PyBOP (115 mg, 0.218 mmol) and finally mixed with diisopropylethylamine (104 mg, 0.80 mmol). The mixture was stirred for 2 hours, then poured into 75 ml of water and extracted three times with EtOAc. The combined organic phases were It was washed with water, dried (Na2S04), and evaporated. The crude product was subjected to flash chromatography on silica gel using EtOAc: MeOH (95: 5). Yield: 89 mg (72%). 1 H NMR (400 MHz, CDC13) 5 7.54 (bt, 1H), 7.47 (d, 2H), 7.12 (m, 1H), 7.08 (d, 2H), 7.02 (m, 1H), 6.95 (m, 1H), 6.50 (t, 1H ), 5.21 (s, 1H), 4.42 (m, 1H), 4.35-4.15 (m, 3H), 3.59 (m, 1H), 2.94 (m, 1H), 2.1-1.7 (m, 4H), 1.06 ( m, 2H), 0.04 (s, 9H).

(iii) PhiS-ClVS-OCHF ^ VmCHrOHVrrOVPro-Pab x TFA makes Ph (3-Cl) (5-OCHF2HR) CH (OH) C (0) -ProPab (Teoc) (85 mg, 0.136 mmol; see above) Step (ii)) is dissolved in 1 ml of dichloromethane and placed in an ice bath-134- 200306975

DESCRIPTION OF THE INVENTION MM (130)-Upper cooling. TFA (4 mL) was added and the reaction was stirred for 90 minutes. TFA was evaporated and the residue was lyophilized from water and acetonitrile. Yield: 79 mg (92%). Purity: 94%. 1 H NMR (400 MHz, CD3 OD, mixture of rotamers) 5 7.85-7.7 (m, 2H), 7.58 (d, 2H main rotamers), 7.47 (d, 2H less rotomers Structure), 7.35 (m, 1H major rotomer), 7.27 (m, 1H less rotomer), 7.2.7.1 (m, 2H), 6.88 (t, 1H), 5.38 (s , 1H main rotomer), 5.22 (s, 1H less rotomer), 4.58 (d, 1H), 4.5-4.2 (m, 2H), 3.8-3.5 (m, 1H), 3.35 (m, 1H), 2.2-1.8 (m? 4H). 1 3 C-NMR (100 MHz; CD3OD): (carbonyl and / or pyrene carbon) δ 173.6, 171.1, 167.0. APCI-MS: (Μ + 1 ) = 481/483 m / z Example 33 PTin-nVS ^ OCHF ^ VrRlCHrOHVCrOVPro-PabrOMe) G, 0.109 mole; Nishiyama et al .; Chem. Lett. (1982) 1477) were dissolved in 500 ml of toluene and 200 ml of absolute ethanol. This solution was cooled to -10 ° C and HC1 (gas) was bubbled through until saturated. When most of the solvent has evaporated, the mixture is stored in the refrigerator for 2 days. Diethyl ether was added and decanted. The product was re-dissolved in a solution of 0-hydroxymethylamine (10.5 g, 0.125 mol) and triethylamine (56 ml) in 200 ml of methanol. The mixture was allowed to stand for 3 days, then methanol was evaporated and EtO Ac was added. The organic phase was washed with water, dilute HOAc and aqueous sodium bicarbonate solution, dried (Na2SO4), and diluted with more EtOAc to a total volume of 500 mL. The 25 ml sample was evaporated to dryness. The rest is 932 mg. Total yield: 18.6 grams (83%). -135- 200306975 Description of the Invention _ Stomach (131)-⑹4-Aminomethylmethoxy-benzidine in 4-azidomethylmethoxy-benzidine (11.3 g, 0.055 mole; see above) Step (i)) To a solution in 200 ml of ethanol, 200 mg of Pt02 was added. With constant foaming of hydrogen, the mixture was hydrogenated for 4 hours, then filtered through Celite®, and evaporated. Yield: 7.34 grams (74%). (iii) Boc-Pro-Pab (OMe) in Boc-Prc-OH (9.7 g, 0.045 mole), 4-aminomethyl-N-methoxy-benzidine (7.34 g, 0.041 mole) ; Refer to step (ii)) above and a suspension of dimethylaminopyridine (7.8 g, 0.064 mole) in 300 ml of acetonitrile, and add EDC base (11.7 ml, 0.068 mole). The mixture was stirred for 18 hours, concentrated, and separated between water and EtoAc. The organic layer was washed with water, an aqueous solution of steel bicarbonate, dried (MgS04), and evaporated. The crude product was flash chromatographed on silica using EtOAc. Yield: 9,73 grams (63%). (\ v) H-Pro-PabroMe) x 2 HC1 Boc-Pro-Pab (oMe) (9.7 g, 0.026 moles; see step (iii) above) was dissolved in 250 ml of EtoAc. This ice-cold solution was saturated with HC1 (gas) by bubbling for 5 minutes. The product precipitated immediately and 125 ml of absolute ethanol was added. The mixture is sonicated until most of the material has cured. Acetic acid (200 ml) was added and the suspension was filtered. A few uncured cakes were treated with absolute ethanol and ether again. The solid was allowed to dry. Yield: 7.57 g (86%). 1 H NMR (400 MHz, CD3 OD) δ 7.74 (d, 2H), 7.58 (d, 2H), 4.55 (s, 2H), 4.38 (m, 1H), 3.98 (s, 3H), 3.45-3.3 ( m, 2H), 2.50 (m, 1H), 2.15-2.0 (m, 3H) (v) Phr ^^ nVS-OCHF ^ Vm ^ CHrOHVCrOVPro-PabfOMe) -136- 200306975 Invention description m (132)-Make 卩 11 (3- €: 1) (5-〇 (: 1 ^ 2)-(11) (: 11 (〇11) <: (〇) 〇11 (50 mg, 0.198 mmol); see Example 1 above νώ)), H-Pn> Pab (OMe) (76 mg, 0.218 mmol) (see step (iv) above) and PyBOP (115 mg, 0.218 mmol) are dissolved in 2 ml of DMF. Diisopropyl Ethylamine (104 mg, 0.80 mmol), and the mixture was stirred for 2.5 hours. The mixture was poured into 50 ml of water and extracted three times with EtOAc, and the combined organic phases were washed with brine, dried (Na2S04) ) And evaporated. The residue was subjected to flash chromatography on silica gel using EtOAc: MeOH (95: 5). Yield: 37 mg (36%). Purity: 98%. 1 H NMR (400 MHz, CD3 OD, Mixture of rotamers) 5 7.60 (d, 2H main rotamer), 7.57 (d, 2H less rotomer), 7.4-7.1 (m 5H), 6.89 (t, 1H main rotomer), 6.87 (t, 1H main rotomer), 5.35 (s, 1H main rotomer), 5.21 (s, 1H rotomer) Rotamers), 4.72 (m, 1H less rotomers), 4.5-4.35 (m, 1H and 2H main rotomers), 4.3-4.25 (m, 2H less rotomers) Structure), 3.814 (s, 3H major rotational isomer), 3.807 (s, 3H minor rotational isomer), 3.75-3.5 (m, 1H), 3.35 (m, 1H), 2.2-1.8 (m5 4H) 13 C-NMR (100 MHz; CD3 OD) ·· (carbonyl and / or europium, mixture of rotamers) 5 173.3, 173.2, 171.3, 171.0, 153.9, 152.4 APCI-MS: (M +1) = 511/513 m / z Example 34 Formamyl) -5-pyridyl) -137- 200306975 Description of the Invention Continued (133)-

To a solution of omega 6-cyanonic acid nicotinic acid in nicotinic acid N-oxide (51 g, 0.37 mole) in 1.2 liters of DMF, NaCN (54 g, U mole) was added, followed by triethyl Amine (255 ml, 1.83 moles) and TMSC1 (I85 ml). The reaction mixture was stirred at 110 ° C for 10 hours, filtered, and the filtrate was concentrated. The residue was dissolved in 100 ml of 2 N HC1 and extracted with dichloromethane. The organic layers were combined, concentrated, and recrystallized from water to give 12 g (22%) of the product. (ii) 5- (Hydroxymethylpyridine)

Add Et3N (12.4 ml, 0.0892 mol) to a solution of 6-cyanonicotinic acid (12 g, 0.081 mol; see step (i) above) in THF at 0 ° C, then Ethyl chloroformate (8.53 ml, 0.0892 mol). The reaction mixture was stirred for 15 minutes' and NaBH * (6.14 g, 0.162 mol) was added. The mixture was then stirred at room temperature overnight, the reaction was quenched with water, and extracted with dichloromethane. The organic layer was concentrated and purified by tube chromatography to give 4 g (20%) of alcohol. (ϋί) Nitromethyl% > Bipyridin-2-methylpyridine 5- (Methylpyridine aspartonitrile (4 g, 0.003 mole; see above step)) '4 in 25 耄Liter of methyl chloride and cooled in an ice bath. Methyl chloride was added dropwise (2.32 ml, 0.0300 mol), followed by triethylamine (46 ml, 0.033 -138- 200306975). Instructions continued (134) __ Mol). After stirring the reaction mixture, the crude methanesulfonate was treated with NaN3 (7.35 g, 0.113 mol) in 20 ml DMF. The reaction mixture was at 40 ° C It was stirred for 2 hours, diluted with water, and extracted with ethyl acetate. The organic layer was concentrated to obtain 3.95 g (83%) of crude azide. (Iv) Tertiary-butoxycarbonylaminomethyl) Pyridine_2-methazolidine in 5- (azidomethyl) 1: pyridonitrile (3.95 g, 0.0248 moles; see step (iii) above) in 30 ml of THF and 10 ml of water Triphenylphosphine (7.8 g, 0.0298 mole) was added, and the resultant was stirred for 24 hours. Then, triethylamine (3.8 ml, 0.027 mole) was added, followed by Boc anhydride (5.4 g, 0.025 mole), and stirred for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was concentrated and purified by column chromatography to give 2.1 g (36%) of the title compound. 1 H NMR (300 MHz, CDC13) 5 8.6 (s, 1H), 8.0 (d, 1H), 8.9 (d, 1H), 4.1 (m, 2H), 1.4 (s, 9H) (v) 5- ( Aminomethyl H-Dipidine-2-methazine x 2 HC1 Make 5- (third-butoxycarbonylaminomethyl) guridin-2-carbonitrile (0.200 g, 0.86 mmol) See above steps ( iv)) Dissolved in 10 ml of EtOAc saturated with HC1 (gas) and stirred for 30 minutes. The solvent was evaporated and 0.175 g (99%) of the title compound was obtained as its dihydrochloride. 1HNMR (500MHz, D20) 5 8.79 (s, 1H), 8.17 (d, 1H), 8.05 (d, 1H), 4.38 (s, 2H) (vi) Boc-A7e-NH-CH1-5-Py (; 2-CN > ) In 5- (aminomethyl > pyridin-2-carbonitrile x 2HCl (0.175 g, 0.85 mmol); see step (v) above), Boc-Aze-OH (0.201 g, 1.00 mmol) And a mixture of TBTU (0.321 g, 1.00 mmol) in 5 ml of DMF, add dimethylamine-139-200306975 Description of Invention (135) -ylpyridine (0.367 g, 3.00 mmol). Stir the mixture Overnight, then poured into water and extracted three times with EtoAc. The combined organic phases were washed with aqueous sodium bicarbonate solution and dried (Na2S04) And evaporated. The crude product began to crystallize and was used as such in the next step. Yield: 0.23 g (73%). 1 H NMR (500 MHz, CDC13) 5 8.66 (s, 1H), 8.2-7.8 (broad , 1H), 7.79 (d, 1H), 7.67 (d, 1H), 4.73 (m, 1H), 4.65-4.5 (m, 2H), 3.94 (m, 1H), 3.81 (m, 1H), 2.6. 2.35 (m, 2H), 1.8 (broad, 1H), 1.45 (s, 9H) (vii) H-Aze-NH-CH ^ -5 ^ Pv (; 2-CN ^ x 2 ΗΠ makes Boc-Aze-NH -CH2 -5-Py (2-CN) (0.23 g, 0.73 mmol; see step (vi) above) dissolved in 10 ml EtOAc saturated with HC1 (gas) and stirred for 30 minutes. Evaporate the solvent, And 0.21 g (100%) of the title compound was obtained as its dihydrochloride. 1 H NMR (500 MHz, D2 0) 5 8.64 (s, 1H), 8.0-7.9 (m, 2H), 5.19 (m, 1H), 4.65-4.55 (m, 2H), 4.20 (m, 1H), 4.03 (m, 1H), 2.88 (m, 1H), 2.64 (m, 1H) (viii) Phf3-ClX5-OCHF1VrR > ) CHr〇HVrr〇VAze ~ NH-CH1-5-Pyi2-CN) in H-Aze-NH-CH2-5-Py (2-CN) x2HCl (0.206 g, 0.713 mmol); see the above step (vii )), Ph (3-Cl) (5-〇CHF2HR) CH (OH) C (〇) OH (0.180 g, 0.713 mmol) ; See above examples l (viii)) and PyBOP (0.408 g, 1410.784 mmol ear MO) in 5 ml of DMF the mixture was added dimethylaminopyridine (0.367 g 'love 3.00 mole). The mixture was stirred overnight, then poured into water and extracted three times with EtOAc. The combined organic phases were washed with aqueous sodium bicarbonate solution, dried (Na2S04) and evaporated. The crude product was flash-chromatographed on silica using EtOAc to obtain the pure product. Yield: 0.197 g (61%). 1 H NMR (500 MHz, CDC13) 5 8.63 (m, 1H), 8.22 (bt, 1H), 7.78 (m, 1H), 7.67 (m, -140- 200306975 Description of the invention (136) 1Η), 7 · 21 (m, 1Η), 7.16 (m, 1Η), 7.04 (m, 1Η), 6.56 (t, 1Η), 4.97 (bd, 1Η), 4.92 (m, 1H), 4.6 -4.5 (m, 2H), 4.40 (bd, 1H), 4.18 (m, 1H), 3.80 (m, 1H), 2.69 (m, 1H), 2.46 (m, 1H), 1.92 (s, 1H ) APCI-MS: (M + 1) = 451/453 m / z

(ix) Phn-nVS-OCHFiWITlCHlOHVaOVAze-NH-aHrriG-formyl) -5-Hydroxypyridyl) x H〇Ac Ph (3-a) (5-0CHF2HR) CH (0H) in 10 ml of methanol -C (0) -Aze-NH-CH2-5-Py (2-CN) (0.200 g, 0.444 mmol; see step (viii) above), ammonium acetate (1.00 g, 0.0130 mole) and N -Acetylcysteine (2.00 g, 0.0122 mol), heated vigorously at 50 ° C for 2 days. Prepare the RPLC with CH3CN: 0.1MNH4OAc (30: 79), and again use CH3CN: 0.1MNH4OAc (5: 95-40: 60) to flow the appropriate dissolving fraction. After lyophilizing from water and acetonitrile, 60 mg (26%) of the pure title compound was obtained as its acetate salt. Purity: 100%. 1 H NMR (500 MHz, D2 0, mixture of rotamers) 5 8.68 (s, 1H main rotamer), 8.62 (s, 1H less rotomer), 8.05-7.9 (m , 2H), 7.33 (m, 1H rotomer), 7.27 (m, 1H rotomer), 7.22 (m, 1H rotomer), 7.17 (m, 1H rotomer), 7. · 01 (m, 1H rotamer), 6.84 (t, 1H), 5.32 (s, 1H main rotamer), 5.20 (m, 1H less rotomer), 5.13 (s, 1H Fewer rotamers), 4.88 (m, 1H main rotamers), 4.65-4.55 (m, 2H main rotamers), 4 45_4 35 (m, 1H, rotomers plus 1H, less isomers), 4.31 (d, 1H less isomers), 4.2-4.05 (m, 1H plus 1H, isomers), 2.80 (m, Rotational isomer with less m2.61 (m, 1H predominant rotamer), 2 33㈣m predominant rotomer), 2.24 (m, less 1H rotomer), 93 (s , 3H) -141-200306975 Description of the invention _ Stomach (137) --- 13C-NMR (100MHz; D20): (carbonyl and / or fluorene A mixture of rotamers) (5 181.6, 173.3, 172.7, 172.6, 172.3, 162.6, 162.3 APCI-MS: (Μ + 1)-468/470 m / z Example 35 methoxymethylamidino)- 5-pyridine

Pyridyl) 〇

(1) Boc-NH-CH ^ m / amino (hydroxyimino) methyl))-5-pyridyl 1 5- (Third-butoxycarbonylaminomethyl) said pyridin-2-methyl Nitrile (1.00 g, 4.29 mmol; see Example 34 (iv) above) was dissolved in 10 ml of ethanol, and hydroxylamine hydrochloride (0.894 g, 0.0129 mole) and triethylamine (1.30 g, 0.0129) were added. Moore). The mixture was stirred at room temperature for 6 days. The mixture was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed with water, dried (Na2S04), and evaporated. Yield: 0.96 g (84%). 1 H NMR (400 MHz, acetone-d6) 5 9.01 (bs, 1H), 8.50 (bs, 1H), 7.87 (m, 1H), 7.70 (m, 1H), 6.58 (broad, 1H), 5.70 (Broad, 2H), 4.31 (d, 2H), 1.41 (s, 9H) (ii) Boc-Aze-NH-CH2 _- (2- (formamyl V5-pyridyl) xH〇Ac This reaction system Comm. (1998) 4351, according to the method described in Judkins et al., Boc-NH-CH2-[(2- (amino (hydroxyimino) methyl))-5-pyridyl] -142- 200306975 _ Description of the invention_Page (138) (0.910 g, 3.42 mol; see the above steps, acetate (0.35 liter, 3.7 mol) and 0.35 g of 10% Pd / C (50% water) suspension in 100 ml of cool acid, hydrogenated at a pressure of 5 atmospheres for 5 hours. The mixture was filtered through diatomaceous earth, and concentrated. The residue was made from water and acetonitrile; Donggan 'and This gave 0.97 g (92%) of the title compound. 1 H NMR (500 MHz, CD3 OD) 5 8.74 (s, 1H), 8.12 (d, 1H), 7.98 (d, 1H), 4.38 (s, 2H), 1.92 (s, 3H), 1.46 (s, 9H) (iii) Amine (trimethylsilyl, an ethylimine) methyl) -5-leafyl group) in Boc-NH-CH2- (2 -(Armor ) -5-pyridyl) xHOAc (0.96 g, 3.1 mmol; see step (ii) above) in a suspension of 75 ml of THF, potassium carbonate (1.07 g, 7.7 mmol) and carbonic acid Teoc p-nitrophenyl ester (1.14 g, 4.02 mmol) in 15 ml of water. The mixture was stirred overnight. An excess of glycine and potassium carbonate were added and the reaction was allowed to continue for 2 hours. The THF was evaporated and the remainder was extracted three times with EtoAc. The combined organic phases were washed with water, dried (Na2S04) and evaporated. This product was used without further purification. 1 H NMR (500 MHz, CDC13) 5 9.31 (broad, 1H), 8.52 (s, 1H), 8.41 (d, 1H), 8.35 (broad, 1H), 7.74 (d, 1H), 4.97 (broad , 1 imprint, 4.39 (111,211), 4.26 (111, 2 imprint, 1.46 (5,911), -1.14 (m, 2H), 0.07 (s, 9H), (lv) H2NzCH2 group (trimethylsilyl ethyl Alkylidene) methyl) -5-P than pyridyl) X 2 HC1 makes βοΝο-αν (2- (amino (trimethylsilylethylimide) methyl) specific) (0.23 G, 0.58 mmol; refer to the above steps (Qiu) dissolve in 25 ml of EtOAc saturated with hci (-143-200306975 (139) invention description, continuation gas) and stir for 30 minutes. Evaporate the solvent, and This product was used without further purification. Yield: 0.21 g (98%). 1 H NMR (500 MHz, D2 0) (5 8.89 (s, 1H), 8.25 (s, 2H), 4.55 (m, 2H), 4.42 (s, 2H), 1.20 (m, 2H), 0.09 (s, 9H) (v) Boc-Aze-NH-CH?-(2- (Amine (trimethylsilyl + ethylimine) ) Methyl acetonyl) in H2N-CH2_ (2- (amino (trimethylsilylethylimino) methyl) _5 · ρ than pyridyl) X 2 HC1 (0.21 g '0.57 m 旲Refer to the above step (iv)), BOOAze-OH (0.127 g, 0.631 mmol) and TBTU (233 mg, 0.726 mmol) in a solution of 5 ml DMF, add diamido Pyridine (269 mg, 2.20 mmol). The mixture was stirred overnight, poured into 100 ml of water, and extracted three times with EtOAc. The combined organic phases were washed with an aqueous solution of sodium bicarbonate and water, and dried (Na2S04). 'And evaporated. The crude product was subjected to flash chromatography on crushed gum using EtOAc to give 170 mg (56%) of the desired product. 1 H NMR (500 MHz, CDC13) 5 9.33 (broad, 1H), 8.54 ( s, 1H), 8.41 (d, 1H), 8.36 (broad, 1H), 7.75 (m, 1H), 4.72 (m, 1H), 4.56 (m, 2H), 4.26 (m, 2H), 3.93 (m , 1H), 3.80 (m, 1H), 2.6-2.4 (m, 2H), 1.42 (s, 9H), U4 (m, 2H), 0.07 (s, 9H) (vi) H-Aze-NH-Ciy (2- (Amino (trimethylsilylethylimino) methyl V5-pyridyl) X 2 HC1 · Make Boc-Aze-NH-CH2- (2- (amino (trimethylsilyl Ethylimino) methyl) -5-pyridinyl) (170 mg, 0.356 mmol; see step ii) above Has to HC1 is (gas) saturated 25 ml of EtOAc and stirred for 30 minutes. The solvent was evaporated and the product was used without further purification. Yield: 160 mg (100%). -144- 200306975 Description of the Invention (140)-1 H NMR (500 MHz, CD3 OD) (5 9.00 (m, 1H), 8.84 (m, 1H), 8.23 (d, 2H), 8.10 (m, 1H), 5.09 (m, 1H), 4.7-4.6 (m, 2H), 4.51 (m, 2H), 4.14 (m, 1H), 3.97 (m, 1H), 2.86 (m, 1H), 2.58 (m, 1H) , 1.22 (m, 2H), 0.11 (s, 9H) (vii) amine (trimethylsilylethylimino) methyl) -5-pyridyl) in H-Aze-NH-CH2- ( 2- (amino (trimethylsilylethylimino) methyl) -5-pyridyl) X 2 HC1 (160 mg, 0.462 mmol; see step (vi) above), Ph (3- a) (5-0CHF2)-(R) CH (〇H) C (0) 〇H (131 mg, 0.462 mmol; see Example 1 (viii) above) and PyBOP (263 mg, 0.505 mmol) Ear) To a solution in 5 ml of DMF was added diisopropylethylamine (0.30 ml, 1.71 mmol). The mixture was stirred overnight, poured into water, and extracted three times with EtOAc. The combined organic phases were washed with strips of water and water, dried (Na2S04), and evaporated. Flash chromatography of the crude product on silica gel using EtOAc: MeOH (95: 5) gave 148 mg (52%) of the desired product. (viii) (methoxyamino (trimethylsilylethylimino) methyl) -5-pyridyl) Ph (3-a) (5-〇CHF2HR) CH (OH) -C ( 〇) -Aze-NH-CH2- (2- (methoxyamino (trimethylsilylethylimide) methyl > 5-pyridyl) (148 mg, 0.242 mmol); see above Step (vii)) and a suspension of 0-hydroxymethylamine (202 mg, 2.42 mmol) in 10 ml of acetonitrile and heated at 70 ° C. for 3 hours. The mixture was separated between water and EtOAc. The aqueous layer was extracted twice with EtOAc, and the combined organic phases were washed with water, dried (Na2S04), and evaporated. The crude material was subjected to flash chromatography on silica gel using EtOAc: MeOH (95: 5) to obtain 44 mg (28%) pure substance. -145- 200306975 Description of the invention continued (141)-1 H NMR (500 MHz, CDC13) (5 8.55 (m, 1H), 8.05 (bt, 1H), 7.70 (m, 1H), 7.58 (s, 1H), 7.56 (d, 1H), 7.22 (m, 1H), 7.16 (m, 1H), 7.03 (m, 1H), 6.50 (t, 1H), 4.92 (s, 1H) ), 4.89 (m, 1H), 4.55-4.45 (m, 2H), 4.38 (broad, 1H), 4.24.1 (m, 3H), 4.00 (s, 3H), 3.73 (m, 1H), 2.69 (m, 1H), 2.44 (m, 1H), 0.97 (m, 2H), 0.02 (s, 9H) (ix) PTin-axs-ocHF ^ -nFOCTWomaovAze-NH-a ^ -g ^ Methoxymethoxymethyl) -5-

p specific symptomatic group) make Ph (3-Cl) (5-〇CHF2MR) CH (0H) C (0) -Aze-NH-CH2- (2- (methoxyamino (trimethylsilylethyl) Imino) methyl) -5-pyridyl) (44 mg, 0.069 mmol; see step (viii) above) was dissolved in 2 ml TFA and allowed to react for 1 hour. TFA was evaporated and the residue was partitioned between EtOAc and aqueous sodium bicarbonate solution. The aqueous layer was extracted with EtO Ac, and the combined organic phases were washed with water, dried (Na2SO4) and evaporated. Yield: 30 mg (88%). Purity:> 95%.

1 H NMR (500 MHz, CDC13) 5 8.44 (m, 1H), 8.03 (bt, 1H), 7.91 (m, 1H), 7.60 (m, 1H), 7.19 (m, 1H), 7.13 (m, 1H) ), 7.00 (m, 1H), 6.52 (t, 1H), 5.6-5.45 (broad, 2H), 4.90 (s, 1H), 4.89 (m, 1H), 4.55-4.4 (m, 2H), 4.27 ( Broad, 1H), 4.12 (m, 1HX 3.92 (s, 3H), 2.68 (m, 1H), 2.41 (m, 1H) 13 C-NMR (100 MHz; CDC13): (carbonyl and / or fluorene) 5 173.0, 170.9, 152.6 APCI-MS: (M + 1) = 498/500 m / z Example 36

Phn-aVS-OCHF ^ -n ^ ri ^ OFnaOVAze-NH-CHyKS-formamyl V2-pyrimidinyl) -146-200306975 Description of the invention _ stomach (142)

Acetic acid 2-amino-2-imine Acetate AcOH made N-Boc-aminoacetonitrile (40.2 g, 257.4 mmol) and N-acetic acid cysteine (42.0 g, 257.4 millimolar) was dissolved in methanol (300 ml) at 60 ° C and ammonia was passed for 18 hours. The solvent was removed in vacuo. After ion exchange chromatography (AmberliteIRA-400 (AcOH)) and recrystallization from acetone, 28.4 g (53%) of the title compound was obtained as a white solid. 1 H NMR (300 MHz, CD3 OD) 5 4.41 (t, J = 4.9 Ηζ, 1Η), 4.01 (s, 2Η), 2.91 (d, J = 5.0 Hz, 2H), 2.01 (s, 3H ), 1.46 (s, 9H) (ii) 1,3-bis (dimethylamino) -2-cyanotrimethylammonium perchlorate, 3-dimethylaminopropionitrile (25.0 g, 260.0 mmol) Ear) in chloroform (75 ml), and (chloromethylene) dimethyl ammonium chloride (50.0 g, 390.1 mmol) in chloroform (175 ml) was added dropwise at 0 ° C. Inside the solution. The reaction mixture was stirred at 0 ° C for another 2 hours' and then allowed to warm to room temperature overnight, followed by heating under reflux for 8 hours. The solvent was removed in vacuo. The residue was added to a mixture of sodium perchlorate (110 g, 0.898 mmol) in water (150 ml) and ethanol (300 ml). The mixture was heated under reflux for 5 minutes, then cooled and allowed to stand overnight in a refrigerator. The sunken objects were collected and recrystallized from ethanol to obtain 23.8 g (52%) of the title compound as colorless needles. -147- 200306975 Invention description (143)

Melting point: 140-141 ° C 1 H NMR (300 MHz, CDC13) 5 8.24 (s, 2H), 3.59 (s, 6H), 3.51 (s, 6H) (iii) ΒοοΝΗ-ΟΗ ^ -cyano V2-pyrimidine Combine 2-amino-2-iminoethylaminocarboxylic acid tertiary-butyric acid A (: 0Η (5.0 g '23.8 mmol; see step (i) above) and 1,3-bis (di Methylamino) -2-cyanotrimethylammonium perchlorate (6.0 g, 23.8 mmol; see above step (ii)) in a mixture of pyridine (300 ml) under nitrogen and 70-75 ° Stir at C for 16 hours, then heat at reflux for 6 hours. Allow the mixture to cool to room temperature and remove the solvent in vacuo. Extract the residue with a hot mixture of ethyl acetate and chloroform (1: 1), The crude product was filtered through silica gel pad and concentrated to obtain crude product. Flash chromatography on silica gel and dissociation with chloroform gave 4.0 g (71%) of the title compound as a colorless oil, which solidified upon standing.

Melting point: 86-87 ° C

Rf = 0 · 77 (silicone, 3: 2 ethyl acetate / chloroform) 1 H NMR (300 MHz, DMSO-d6) 5 9.25 (s, 2H)? 7.39 (bt, 1H)? 4.39 (d? J = 6 Hz, 2H), 1.38 (s, 9H). 13C NMR (750 MHz, DMS〇-d6) 5 170.4, 160.3, 155.8, 115.2, 106.9, 80.0, 46.3, 28.1 APCI-MS · (M + 1) = 235 m / z (iv) Boc-Aze-NH-CH ^ M-cyano) -2-pyrimidine (1) Make Boc-NH-CH2- (5-cyano) -2-pyrimidine (U4 g, 4.87 Millimoles; see step (iii) above) Dissolved in 50 ml EtOAc saturated with HC1 (gas) and allowed to react for 1 hour, and concentrated. The residue was dissolved in 20 ml of DMF and cooled in an ice bath. Add diisopropylethylamine (3.5 ml, 0.020 mole), -148-200306975 (144) Description of the invention

Boc-Aze-OH (1.08 g, 5.37 mmol) and HATU (2.8 g, 5.38 mmol), and the reaction mixture was stirred at room temperature overnight. The solvent was evaporated, and the product was purified by preparative RPLC using CH3CN..0.1MNH4OAc (40:60). The acetonitrile was evaporated and the aqueous layer was extracted three times with EtO Ac. The combined organic layers were dried (MgS04) and evaporated. Yield: 1.12 grams (72%). 1 H NMR (400 MHz, CDC13) ά 8.95 (s5 2Η), 4.82 (d? 2H) 5 4.74 (m, 1H), 3.95 (m, 1H), 3.84 (m, 1H), 2.6-2.4 (m, 2H), 1.47 (s, 9H) (v) Ba & -Aze-NH-CH9-((5-formamyl V2-pyrimidinyl) xH〇Ac will be BooAze-NH-CH2 _ ((5-cyano)- 2-u dense group) (0.83 g, 2.6 mmol; see step (iv) above), N-acetamidine cysteine (0.43 g, 2.6 mmol), and ammonium acetate (0.60 g, 7.8 mmol) in 10 ml of methanol and heated at 60 ° C under nitrogen for 2 days. The solvent was evaporated and the crude material was prepared from rplc using CH3CN: 0.1MNH4OAc (5: 95 to 100 ··· 0) in a gradient solution. The lyophilized fractions of interest were lyophilized to obtain 1.0 g (93%) of the desired substance. 1 H NMR (300 MHz, D2 0, signal was masked by HDCM signal) 5 9.17 (s , 2H), 4.1-3.9 (m, 2H), 2.60 (m, 1H), 2.29 (m, 1H), 1.93 (s, 3H), 1.44 (s, 9H) (vi) £ Shen-eight 26-shun -(^ 9-"(5- (Amine (trimethylsilylethylimino) methyl))-2_ Oral sphingosyl 1 in BooAze-NH-CH2-((5-formamyl) -2-pyrimidinyl) xHOAc (0.95 g, 2.41 mmol 'mo Ear; see step (v) above) In a suspension in 50 ml of THF, add Teoc-p-nitrophenyl carbonate (0.85 g, 3.0 mmol) and potassium carbonate (1.0 g, 7.2 Φ) Mol) in 10 ml of water. The mixture was stirred for 24 hours, concentrated, and separated between water and dichloromethane. The organic layer was washed with saturated sodium hydrogen hydride, and stripped twice; dehydrated Dry (Na04S04) and evaporate. -149- 200306975 Inventive_page (145)-Flash chromatography of the crude product on silica gel using heptane: EtOAc (1: 1). Yield: 1.04 g (90 %). 1 H NMR (300 MHz, CDC13) 5 9.16 (s, 2H), 4.80 (d, 2H), 4.73 (m, 1H), 4.26 (m, 2H), 4.0-3.8 (m, 2H ), 2.6-2.4 (m, 2H), 1.47 (s, 9H), 1.12 (m, 2H), 0.07 (s, 9H) (vii)% gate-gate ¥ 5-0 (^^ 1;)-( 10 (: 〇 出 (^ 〇 \ 八 26call: "-(^ 2 /" (5- (amino (trimethylsilylethylimine) methyl) V2-pyrimidinyl 1 makes Boc- Aze-NH-CH2-[(5- (amino (trimethylsilylethylimino) methyl))-2-pyrimidinyl] (0.209 g, 0.437 mmol; see step (vi) above )) HC1 is to have to (gas) saturated 25 ml of EtOAc and allowed to react for 15 minutes. The solvent was evaporated and the remainder was dissolved in 4 ml of DMF. Add Ph (3-Cl) (5-〇CHF2HR) CH (0H) C (0) 0H (0.100 g, 0.396 mmol); see Example 1 (viii) above, PyBOP (0.231 g, 0.444 mmol) And diisopropylethylamine (0.208 g, 1.61 mmol), and the mixture was stirred for 80 minutes. The reaction mixture was poured into 100 ml of water and extracted three times with EtOAc. The combined organic layers were washed with brine, dried (Na2SO4) and evaporated. The crude product was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (1: 1). Yield: 63 mg (26%). 1 H NMR (400 MHz, CDC13, mixture of rotamers) 5 9.3 (broad, 1H), 9.03 (s, 2H less isomers), 9.00 (s, 2H main isomers) , 8.25 (m, 1H major rotamer), 7.9 (broad, 1H), 7.80 (m, 1H less rotomer), 7.2-6.9 (m, 3H), 6.50 (t, 1H) , 5.14 (s, 1H less rotational isomers), 5.08 (m, 1H less rotational isomers), 4.94 (s, 1H main rotational isomers), 4.80 (m, 1H main rotational isomers) Isomers), 4.7-4.4 (m, 2H), 4.3-3.9 (m, 3H), 3.74 (m, 1H main rotational isomers), 2.7-2.1 (m, 2H), 1.03 (m, 2H) ), 0.01 (s, 9H) -150- 200306975 Description of the invention # 卖 Ｍ (146)-

(viii) Phn-aYS-OCHFiUR ^ HiOfnaOVAze-NH-CH ^ aS-formyl) -2-pyrimidinyl) X TFA? 11 (3-(: 1) (5-〇0 ^^)-(11) (: 11 (011) (:( 0) -eight 2 € to 11-012-[(5- (amino -Silylethylimino) methyl))-2-pyrimidinyl] (21 mg, 0.034 mmol; see step (vii) above) dissolved in 0.5 ml of dichloromethane and placed in an ice bath Cool. TFA (2 ml) was added and the mixture was stirred for 60 minutes and then concentrated. The product was lyophilized from water with acetonitrile. Yield: 20 mg (100%). Purity: 100%. 1 H NMR (400 MHz, CD3 OD, a mixture of rotamers, the signal is obscured by HDO signals) 5 9.08 (s, 2H), 7.4-7.1 (m, 3H), 6.88 (t, 1H main rotomer), 6.85 (t, 1H Less rotamers), 5.30 (m, less 1H rotamers), 5.22 (s, less 1H rotomers), 5.20 (s, 1H main rotomers), 4.73 (m, 1H main isomer), 4.34 (m, 1H rotomer), 4.21 (m, 1H rotomer), 4.15-3.95 (m, 2H rotomer), 2.73 ( m, 1H rotomer), 2.57 (m, 1H rotomer), 2.45-2.25 (m, 2H rotomer) 13 C-NMR (10 0 MHz; CD3 OD): (carbonyl and / or carbon, mixture of rotamers) 5 173.0, 172.6, 172.1, 171.0, 163.4 · APCI-MS: (M + 1) = 469/471 m / z Example 37 methoxymethylfluorenyl) -2-pyrimidyl) -151-200306975 (147)

hovA

Description of the invention title page N—〇Me

OCHR (i) methoxyamino (trimethylsilylethylimino) methyl))-2-pyrimidinyl 1 Ph (3-Cl) (5-OCHF2HR) CH (〇H) C ( 〇) -Aze-NH-CH2-[(5- (Amino (trimethylsilylethylimino) methyl))-2-pyrimidinyl] (40 mg, 0.065 mmol; see examples above 36 (vii)) and a suspension of 0-hydroxymethylamine (33 mg, 0.40 mmol) in 3 ml of acetonitrile and heated at 70 ° C for 3 hours. The mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtoAc, and the combined organic phases were washed with water, dried (Na2SO4), and evaporated. Yield: 33 mg (79%). 1 H NMR (400 MHz, CDC13, mixture of rotamers) 5 8.76 (s, 2H main isomers), 8.70 (s, 2H rotomers), 8.18 (111, 111), 7.62 ( 3,1 print, 7.4-6.9 (m, 4H), 6.50 (bt, 1H), 5.3-4.5 (m, 4H), 4.2-4.05 (m, 3H), 3.96 (s, 3H), 3.68 (m, 1H), 2.8-2.2 (m, 2H), 2.1 (broad, 1H), 0.96 (m, 2H), 0.01 (s, 9H) (ii) methoxymethylamidino) Amine group) Make Ph (3-Cl) (5-〇CHF2HR) CH (0H) C (0) -Aze-NH-CH2-[(5- (methoxyamino- (trimethylsilylethylidene) Amine) methyl))-2-pyrimidinyl] (33 mg, 0.052 mmol; see step (i) above) was dissolved in 0.5 ml of dichloromethane and cooled in an ice bath. TFA (2 ml) was added, and the mixture was stirred for 2 hours, then -152- 200306975 (148) Description of the invention was concentrated! The product was lyophilized from water and acetonitrile. Yield: 31 mg (81%). Purity: 100%. 1 H NMR (400 MHz, CD3 OD, mixture of rotamers, signal is masked by HD0 signal) 5 8 · 96 (s, 2H rotomer), 8.94 (s, 2H rotomer), 7.4 _7.3 (m, 1Η), 7.2-7.1 (m, 2Η), 6.88 (t, 1Η rotomer), 6 85 (t, 1Η rotomer), 5.29 (m, 1Η iΗ) Transisomers), 5.24 (s, 1Ηrotomer), 5.20 (s, 1Ηrotomer), 4.75-4.55 (m, 2H), 4.33 (m, 1H rotomer), 4. · 19 (m, 1H rotomer), 4.15-3.95 (m, 2H rotomer), 3.88 (s, 3H rotomer), 3.86 (s, 3H rotomer), 2.72 ( m, 1H rotomer), 2.56 (m, 1H rotomer), 2.45-2.25 (m, 2H rotomer) 13C-NMR (100MHz; CD3OD): (carbonyl and / or fluorene, rotation Mixture of isomers) 5 172.8, 172.6, 172.1, 171.8, 167.8, 167.7, 155.1, 152.3, 152.1 APCI-MS: (Μ + 1) = 499/501 m / z Example 38

ω 2-Fluoro-4-vinyl, a methylpyrazine, 4-bromo-2 · fluorobenzonitrile (4.92 g '0.0246 mole), ethyl tributyltin (0.78 g, 0.246 mole), and unrefined Phenylphosphine (0.67 g, 0.58 mmol) at 250 -153- 200306975 (149) Description of the Invention_ A solution in gastric ml of toluene was refluxed overnight under nitrogen. The solvent was evaporated and the residue was subjected to flash chromatography on silica gel using heptane: CH2C12 (1: 1) to pure CH2C12. A crystalline colorless oil was obtained. Yield: 3.0 grams (82%). 1 H NMR (300 MHz, CDC13) 5 7.56 (m, 1H), 7.3-7.2 (m, 2H), 6.69 (m, 1H), 5.89 (d 1H), 5.51 (d, 1H) ⑹2-fluoro- 4-Hydroxymethyl jasmonitrile in 2-fluoro-4-vinylbenzonitrile (1.3 g, 8.8 mmol; refer to the steps above for a cooled solution in 40 ml of CH2 (¾ and 5 ml of methanol ( -78. Within (:), ozone (50 liters / hour, 29 grams / cubic meter) was bubbled for 30 minutes. Then argon was bubbled through to remove excess ozone. Sodium borohydride (0.67 grams, 0.1 〇18mol), and the ice bath was removed. The mixture was stirred and allowed to react for 1 hour. The mixture was evaporated and 2M HC1 was added. The mixture was extracted twice with ether and the combined was partially dehydrated and dried (Na2S 〇4), and evaporation. The crude product was crystallized. Yield: 1.1 g (81%). 1 H NMR (300 MHz, CDC13) 5 7.59 (m3 1H)? 7.3-7.2 (m5 2H)? 4.79 (d, 2H ), 2.26 (t, 1H) (iii) 4-Alkylsulfonic acid, 4-Alkyl, 1-Alkylsulfonium, 1-2-fluoro-4-hydroxymethylbenzonitrile (1.3 g, 8.6 mmol; see above Step (ii)) was dissolved in 50 ml of CH2Cl2 and cooled on an ice bath. Triethylamine (0.87 G, 8.6 mmoles) and methanesulfonium chloride (0.99 g, 8.7 mmoles). After stirring for 1.5 hours, the reaction mixture was washed with 1M HC1. The organic phase was dried (Na2S04) And evaporated. This product can be used without purification. Yield of colorless oil: 1.8 g (92%). 1 H NMR (400 MHz, CDC13) δ 7.66 (m, 1H), 7.35-7.3 (m, 2H) , 5.26 (s, 2H)? 3.07 -154- 200306975 Description of the invention _ page (150) L- (s, 3H) (iv) 4-azide, methylfluoro ... methylbenzonitrile in methanesulfonic acid 4- Cyanofluorofluoromethyl ester (1.8 g '7.9 millimoles; see step (iii)) above, add' sodium azide (0.80 g, 12 mol) to the ice-cold solution. Allow the mixture to stand overnight and pour Into 2 ml of water 'and extracted three times with ether. The combined ether phases were washed five times with water, dried (Na2S04) and evaporated. This crude colorless oil can be used without further purification. Yield: 1.2 g (87 %). 1 H NMR (300 MHz, CDC13) 5 7.64 (m, 1H), 7.25-7.18 (m, 2H), 4.47 (s, 2H) (V) Jiayue cream in stannous chloride with stirring Compound (0.45 g, 2.4 mmol) in 20 ml of acetonitrile within the suspension, was added thiophenol (1.07 g, 9.7 mmol) and triethylamine (0.726 g, 7.17 mmol). Then, a solution of 4-azidomethyl-2-fluorobenzonitrile (0.279 g, 1.58 mmol; see step (iv) above) in several milliliters of acetonitrile was added. After 1.5 hours, the azide was consumed and the solvent was evaporated. The residue was dissolved in dichloromethane and washed three times with 2M NaOH. The organic phase was extracted twice with 1M HC1. The combined acidic aqueous phases were washed with dichloromethane, then made basic with 2M NaOH, and extracted three times with dichloromethane. The organic phase was dried (Na2S04) and evaporated to give 0.172 g (72%) of the desired subtitled compound, which was used without purification. 1 H NMR (400 MHz, CDC13) 5 7.58 (m, 1H), 7.3-7, 2 (m, 2H), 3.98 (s, 2H), 1.55- 1.35 (broad, 2H) (vi) Boc ^ Aze ^ NHCH ^ Phr ^ -F. 4-CN) Cold-dissolved in Boc-Aze-OH (0.194 g, 0.96 mmol) in 5 ml DMF -155- 200306975 Description of the Invention β-Page (151)- To the solution, TBTU (0.50 g, 9.6 mmol) was added. After 30 minutes, another solution was added containing 4-aminomethyl-2-fluorobenzonitrile (0.17 g, 0.81 mmol) in 7 ml DMF and diisopropyl Ethylamine (0.326 g, 2.53 mmol). The resulting solution was stirred at room temperature overnight. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (50:50). Lyophilization gave 0.237 g (74%) of the desired subtitled compound. 1 H NMR (300 MHz, CD3 OD) 5 7.70 (m, 1H), 7.35-7.25 (m, 2H), 4.65-4.35 (m, 3H), 4.0-3.85 (m, 2H), 2.51 (m, 1H) ), 2.19 (m, 1H), 1.40 (s, 9H) (vii) Phn-CIYS-OCHF ^ ViR ^ CHrOmcrOVAze-NHCH ^ -PhrS-F, 4-CN ^ makes Boc-Aze-NHCH2-Ph (3- F, 4-CN) (0.118 g, 0.354 mmol; obtained from step (vi) above) was dissolved in 30 ml of EtOAc saturated with HC1 (gas). The reaction was stirred for 20 minutes and evaporated. The dihydrochloride formed was dissolved in 5 ml of DMF with HATU (0.152 g, 0.400 mmol). This solution was added with π SPh (3-C1) (5-OCHF2HR) CH (〇H) C (〇) OH (0.101 g, 0.400 mmol; see Example 1 (viii) above) in 5 ml of DMF. Inside an ice-cold solution. The reaction was stirred at ambient temperature overnight. The solvent was evaporated and the product was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (50:50). Lyophilization gave 0.130 g (77%) of the desired subtitled compound. iHNMRpOOMHz'DsOD mixture of rotamers) (5 7.7-7.6 (m, 1H), 7.35-7.1 (m, 5H), 6.88 (t, 1H rotomer), 6.86 (t, 1H rotomer ), 5.25-5.1 (m, 1H plus less rotational isomers from the following protons), 4.80 (m, 1H major rotational isomer), 4.6-4.4 (m, 2H), 4.36 (m, 1H main rotational isomers), 4.18 (m, 1H main rotational isomers), 4.07 (m, 1H less rotational isomers), -156- 200306975 Invention Description_Page (152) --- 3.98 (m, 1H less rotational isomers), 2.70 (m, 1H less rotational isomers), 2.53 (m, 1H main rotational isomers), 2.29 (m, 1H main rotational isomers) Structure), 2.16 (m, 1H less rotational isomer) (viii) Phr3> ClV5-OCHF ^ VrR ^ rHr〇mcr〇) -Aze-Pabi3.-El make Ph (3-Cl) (5- 0CHF2HR) CH (0H) C (0) -Aze-NHCH2-Ph (3-F, 4-CN) (0.130 g, 0.278 mmol; see step (vii) above) dissolved in HC1 (gas) Saturated in 80 ml of ethanol. The mixture was allowed to react at room temperature overnight. The solvent was evaporated and the residue was redissolved in 100 ml of ethanol saturated with NH3 (gas). The reaction was allowed to proceed slowly at room temperature for two days. The temperature was raised to 50X; and the reaction was continued for another 3 days. The starting material is consumed and the solvent is evaporated. The product was purified by preparative RPLC and lyophilized to give 17 mg (13%) of the title compound as its HO Ac salt. 1 H NMR (600 MHz, mixture of CD3O rotational isomers) 5 7.65-7.6 (m, 7.47 (3, m, 3H), 7.25-7.1 (m, 2H), 7.15-6, 7 ( m, 1H), 5.25-5.1 (m, 1H plus less isomers derived from the following protons), 4.8 (m, 1H is the major rotamer partially shaded by CD; OH), 4.6-3.95 (m, 4H), 2.69 (m, 1H less rotational isomers), 2.56 (m, 1H main rotational isomers), 2.28 (m, 1H main rotational isomers) 2.14 (m, 1H Fewer rotational isomers), 1.90 (s, 3H) 13 C-NMR (100 MHz; CD3 OD): (carbonyl and / or europium carbon, mixture of rotational isomers) 5 180.6, 173.4, 173.1, 172.9 , 164.5, 162.3, 159.8 APCI-MS: (M + 1) = 485/487 m / z Example 39 -157- 200306975 (153)

Description of the Invention Continued ⑴ Fluorine-44 (methyl sulfenyl) (methylthio) formazan under argon to make (methylsulfinyl) (methylthio) methane (7.26 g, 0.0584 mole) dissolved in 100 ml of anhydrous THF and cooled to -78X :. Add butyllithium (16 ml, L6M, 0.0256 mol) in hexanes dropwise and stir; stir. The mixture was stirred for 15 minutes. At the same time, a solution of 3,4,5-trifluorobenzonitrile (4.0 g, 025 mmol) in 100 ml of anhydrous THF was cooled to -78 under argon. 〇, and the solution was added to the solution to be described below through a cannula for 35 minutes. After 30 minutes, the cooling bath was removed, and when the reaction had reached room temperature, it was poured into 400 ml of water. Butane HF was evaporated and the remaining aqueous layer was extracted three times with ether. The combined ether phases were washed with water, dried (NQ304) and evaporated. Yield: 2.0 grams (30%). 1 H NMR ⑽ MHz, CDC13) 5 7 · 4-7.25 (m, Qiu, 5.01 (s, 1Η, diastereomer), 4.91 (s, 1Η, diastereomer) , 2.88 (s, 3Η, diastereomers), 2.52 & criminal, diastereomers), 2.49 (s, 3Η, diastereomers), 2.34 (s, 3Η, diastereomers), 丨 .72 (broad, 1Η) ⑼ 2 1 曱 醯 fluorenyl benzazine makes 2,6-difluoro-4-[(methylsulfinyl fluorenyl) (a Thio) methyl] benzonitrile (2 g, 7 g, 8.32 mmol; refer to the above steps, dissolve in 90 ml TPH and add "ml concentrated sulfuric acid. Leave the mixture at room temperature for 3 days, then Pour into 45 ° -158- 200306975 Description of the Invention_1 (154)-liter of water. Extract three times with EtOAc, then wash the combined ether phases twice with aqueous sodium bicarbonate solution and dry with brine (Na2s〇4) And evaporated. Yield: 1.36 g (98%). The position of the methyl group is established by 13 c NMR. The signal obtained from this carbon fluoride at 162.7 PPm shows the expected coupling pattern with two coupling constants individually Spectra at 260 Hz and 6.3 Hz, corresponding to those from fluorine atoms Adjacent and meta couplings. 1 H NMR (400 MHz, CDC13) 5 10.35 (s, 1H), 7.33 (m, 2H) (iii) M-dimethylhydrazine methylol benzyl ... , 6-Difluoro-4-methylfluorenylbenzonitrile (1.36 g, 8.13 mmol; see step (ii) above) was dissolved in 25 ml of methanol and cooled on an ice bath. Add in portions Sodium borohydride (0.307 g, 8.12 mmol) and stirred, and the reaction was left for 65 minutes. The solvent was evaporated and the residue was separated between ether and aqueous sodium bicarbonate solution. The ether-containing layer was treated with More aqueous sodium bicarbonate solution and brine were washed, dried (Na2S04), and evaporated. The crude product crystallized quickly and was used without further purification. Yield: 1.24 g (90%). 1 H NMR (400 MHz) , CDC13) 5 7.24 (m, 2H), 4.81 (s, 2H), 2.10 (broad, 1H) (iv) 4-cyano-2,6-difluorophosphonium methanesulfonate in 2,6-difluoro 4-Hydroxymethyl benzyl cream (1.24 g, 7.32 mmol; see step (iii) above) and ice-cold methanesulfonium chloride (0.93 g, 8.1 mmol) in 60 ml of dichloromethane To the solution, add triethylamine (0.81 g, 8.1 mmol) Ear) 'and stirred. After 0. (: After 3 hours, the mixture was washed twice with 1M HC1' and once with water, dried (Na2S04), and evaporated. This product was used without further purification. Yield · 1.61 g (89%). 1 H NMR (300 MHz, CDC13) (5 7.29 (m, 2H), 5.33 (s, 2H), 3.07 (s, 3H) -159- 200306975 (155) Description of the invention (V) t azide 2.6-Difluorobenzonitrile 4-cyano-2,6-difluorofluorenyl methanesulfonate (1.61 g, 6.51 mmol; see step (iv) above) and sodium azide (0.72 g, 0.0111 mole) in a mixture of 10 ml of water and 20 ml of DMF, and stirred at room temperature overnight. Then, the resultant was poured into 200 ml of water and extracted three times with acetic acid. The combined ether phases were washed with water Five times, dehydrated and dried (Na2S04), and evaporated. A small sample was evaporated for NMR purposes and the product crystallized. Carefully evaporated the rest, but did not reach completely dry wine. NMR Based on analytical HPLC, the yield (theoretically 1.26 g) is almost quantitative. 1 H NMR (400 MHz, CDC13) 5 7.29 (m, 2H), 4.46 (s, 2H) (vi) 4-aminomethyl -2.6-Difluorobenzonitrile This reaction was performed according to the procedure described in J. Chem. Res. (Μ) (1992) 3128. At 520 mg of 10% Pd / C (50% water) in 20 ml of water Boron hydride A solution of sodium (0.834 g, 0.0221 mol) in 20 ml of water. Causes some gas to be released. Makes 4-azidomethyl-2,6-difluorobenzonitrile (1.26 g, 6.49 millimoles; see The above step (v)) was dissolved in 50 ml of THF and added to the aqueous mixture on an ice bath for 15 minutes. The mixture was stirred for 4 hours, then 20 ml of 2M HC1 was added, and the mixture was filtered through celite. Rinse the diatomaceous earth with more water, and wash the combined aqueous phases with EtOAc, and then make it sensible with 2M NaOH. Extract three times with dichloromethane and then combine the combined organic phases with water. Washed, dried (Na2S04), and evaporated. Yield: 0.87 g (80%). 1 H NMR (400 MHz, CDC13) 5 7.20 (m, 2H), 3.96 (s, 2H), 1.51 (broad, 2H) (vii) 2,6-difluoro-4-third-but-oxycarbonylaminomethylbenzonitrile-160- 200306975 Description of the invention I Selling page (156) _--

A solution of 4-aminomethyl-2,6-difluorobenzonitrile (0.876 g, 5.21 mmol; see step (vi) above) was dissolved in 50 ml of THF and 10 ml of THF was added. Di-tertiary-butyl carbonate (1.14 g, 5.22 mmol). The mixture was stirred for 3.5 hours. The THF was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed three times with 0.5 M HC1 and water, dried (Na2S04), and evaporated. This product 'can be used without further purification. Yield: 1.38 g (99%). 1 H NMR (300 MHz, CDC13) (5 7.21 (m, 2H), 4.95 (broad, 1H), 4.43 (broad, 2H), 1.52 (s, 9H) (viii) Boc-Pab (2,6-two F) (0H)

Add 2,6-difluoro-4-tert-butoxycarbonylaminomethylbenzonitrile (1.38 g, 5.16 mmol; see step (vii) above), hydroxylamine hydrochloride (1.08 g, 0.0155 mo Ear) and a mixture of triethylamine (1.57 g, 0.0155 mol) in 20 ml of ethanol and stirred at room temperature for 36 hours. The solvent was evaporated and the residue was separated between water and dichloromethane. The organic layer was washed with water, dried (Na2S04) and evaporated. This product can be used without further purification. Yield: 1.43 g (92%). 1 H NMR (500 MHz, CD3 0D) 5 7.14 (m, 2H), 4.97 (broad, 1H), 4.84 (broad, 2H), 4.40 (broad, 2H), 1.43 (s, 9H) (ix) Boc- Pab (2,6-diF) x HAc This reaction was performed according to the procedure described in Judkins et al., Synth. Comm. (1998) 4351. Boc-Pab (2,6-diF) (OH) (1.32 g, 4.37 mmol; see step (viii) above) in 100 ml of acetic acid, acetic anhydride (0.477 g, 4.68 mmol) and 442 mg of 10% Pd / C (50% water), hydrogenated at 5 atmospheres for 3.5 hours. -161-200306975 Description of the invention (157) ------ The mixture was filtered through diatomaceous earth, rinsed with ethanol, and evaporated. The residue was lyophilized from acetonitrile with water and a few drops of ethanol. This title product was used without further purification. Yield: 49 g (99%). 1 H NMR (400 MHz, CD3 OD) 5 7.45 (m, 2H), 4.34 (s, 2H), 1.90 (s, 3H), 1.40 (s, 9H) (x) Boc-Pab (2,6-di FXTeoc) To a solution of Boc-Pab (2,6-diF) xHOAc (1.56 g, 5.49 mmol; see step (ix) above) in 100 ml of THF and 1 ml of water, add 2- (trimethyl carbonate) Silyl) ethyl p-nitrophenyl ester (1.67 g, 5.89 mmol). A solution of potassium carbonate (1.57 g, 0.0114 mol) in 20 ml of water was added dropwise over 5 minutes. The mixture was stirred overnight. The THF was evaporated and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed twice with an aqueous solution of hydrogen carbonate # 3, dried (Na2S04), and evaporated. Flash chromatography on silica gel using heptane / EtoAc = 2 / l gave 1.71 g (73%) of pure compound. 1 H NMR (400 MHz, CDC13) 5 7.43 (m, 2H), 4.97 (broad, 1H), 4.41 (broad, 2H), 4.24 (m, 2H), 1.41 (s, 9H), 1.11 (m, 2H ), 0.06 (s, 9H) (xi) Boc-Aze-Pab (2,6-di F) (Teoc) Boc-Pab (2,6-di F) (Teoc) (1.009 g, 2.35 mmol) ; See step ii above) Dissolved in 50 ml EtOAc saturated with HC1 (gas). The mixture was left for 10 minutes, evaporated, and dissolved in 18 ml of DMF, and then cooled on an ice bath. Tim Li Boc-Aze-〇H (0.450 g, 2.24 mmol), PyBOP (1.24 g, 2.35 mmol) and finally diisopropylethylamine (1.158 g, 8.96 mmol). The reaction mixture was stirred for 2 hours, then poured into 350 ml of water and extracted with EtOAc -162- 200306975 Description of Invention It M (158)-taken three times. The combined organic phases were washed with brine, dried (Na2SO4) and evaporated. Flash chromatography on silica gel gave 1.097 g (96%) of the desired compound with heptane: EtOAc (1: 3). 1 H NMR (500 MHz, CDC13) (5 7.46 (m, 2H)? 4.65-4.5 (m, 3H), 4.23 (m, 2H), 3.87 (m, 1H), 3.74 (m, 1H), 2.45- 2.3 (m, 2H), 1.40 (s, 9H), 1.10 (m, 2H), 0.05 (s, 9H) (xii) Phn-nV5-OCHF1MR) CH (〇H) a〇) _Aze-Pab (2, 6-: F) (Teoc) Dissolve Boc-Aze-Pab (2,6-diF) (Teoc) (0.256 g, 0.500 mmol; see step (xi) above) in a solution saturated with HC1 (gas) 20 ml of EtOAc. The mixture was left for 10 minutes, evaporated and dissolved in 5 ml of DMF.卩 11 (3-(: 1) (5-〇CHF2HR) CH (〇H) C (〇) 〇H (0.120 g, 0.475 mmol; see Example 1 (viii) above), PyBOP (0.263 g, 0.498 mmol) and finally diisopropylethylamine (0.245 g, 1.89 mmol). The reaction mixture was stirred for 2 hours, then poured into 350 ml of water and extracted three times with EtOAc. The combined organic phases were separated by Wash with brine, dry (Na2S04), and evaporate. Flash chromatography on silica gel using EtOAc to obtain 0.184 g (60%) of the desired subtitled compound. 1 H NMR (400 MHz, CD3 OD, rotamer) (Mixture) 5 7.55-7.45 (m, 2H), 7.32 (m, 1H main rotational isomers), 7.27 (m, 1H less rotational isomers), 7.2-7.1 (m, 2H) , 6.90 (t, 1H major rotational isomer), 6.86 (t, 1H major rotational isomer), 5.15 (s, 1H major rotational isomer), 5.12 (m, 1H minor rotational isomer) Isomers), 5.06 (s, 1H less rotational isomers), 4.72 (m, 1H main rotational isomers), 4.6-4.45 (m, 2H), 4.30 (m, 1H main Rotamers), 4.24 (m, 2H), 4.13 (m, 1H main rotomer), 4.04 (m, 1H less rotomer), 3.95 (m, 1H less rotomer), 2.62 (m, 1H rotomer) , 2.48 (m, 1H main rotational isomer), 2.22 (m, 1H main rotational isomer-163-200306975 Description of the invention m (159)-structure), 2.10 (m, 1H less rotational isomer) ), 1.07 (m, 2H), 0.07 (m, 9H) (xiii) Phi3-ClV5-OCHTYKROCHCOHQaOVAze-PabG ^ DiF) Ph (3-Cl) (5-〇CHF2)-(R) CH (〇H ) C (0) -Aze-Pab (2,6-diF) (Teoc) (81 mg, 0.127 mmol; see step (xii) above) was dissolved in 0.5 ml of dichloromethane and placed in an ice bath On cooling. TFA (3 mL) was added and the reaction was left for 75 minutes. TFA was evaporated and the residue was lyophilized from water and acetonitrile. The crude product was purified by preparative RPLC using CH3CN: 0.1MNH40Ac (35:65) to yield 39 mg (55%) of the title compound as its HOAc salt, purity: 99%. iHNMRMOOMI ^ CDsOD mixture of rotational isomers) 5 7.5-7.4 (m, 2H), 7.32 (m, 1H main rotational isomer), 7.28 (m, 1H less rotational isomer), 7.2-7.1 (m, 3H) 6.90 (t, 1H major rotational isomer), 6.86 (t, less rotational isomer), 5.15 (s, 1H principal rotational isomer), 5.14 (m, 1H comparative Less rotamers), 5.07 (s, less 1H rotamers), 4.72 (m, 1H main rotamers), 4.65-4.45 (m, 2H), 4.30 (m, 1H main rotomers) Rotational isomers), 4.16 (m, 1H major rotation isomers), 4.03 (m, 1H less rotational isomers), 3.95 (m, 1H less rotation isomers), 2.63 ( m, 1H less rotomer), 2.48 (m, 1H main rotomer), 2.21 (m, 1H main rotomer), 2.07 (m, 1H rotomer) ), 1.89 (s, 3H) 13 C-NMR (75 MHz; CD3 OD): (carbonyl and / or fluorene, a mixture of rotamers) 5 171.9, 171.2, 165.0, 162.8, 160.4 APCI-MS : (M + 1) = 503/505 m / z. Example 40 2F) (〇Me) -164- 200306975 (160)

O F

(i) Outer (; 3-0: ^ 5-00 ^ 1 ^ > (100-0 ~ 1 (0 print €: (0) -person 26-? & 1) (2,6-two F) (〇Me, Teoc) Ph (3-Cl) (5-0CHF2)-(R) CH (0H) C (0) -Aze-Pab (2,6-diF) (Teoc) (64 mg, 0.099 Millimoles; see Example 39 (xii) above and a mixture of 0-hydroxymethylamine hydrochloride (50 mg, 0.60 millimoles) in 4 ml of acetonitrile and heated at 70 ° C for 3 hours. Evaporate the solvent, The residue was separated between water and EtOAc. The aqueous layer was extracted twice with EtoAc, and the combined organic phases were washed with water, dried (Na2S04), and evaporated. This product can be used instead No further purification required. Yield: 58 mg (87%). 1 H NMR (400 MHz, CDC13) 5 7.90 (bt, 1H), 7.46 (m, 1H), 7.25-6.95 (m, 5H), 6.51, t, 1H), 4.88 (s, 1H), 4.83 (m, 1H), 4.6-4.5 (m, 2H), 4.4-3.9 (m, 4H), 3.95 (s, 3H), 3.63 (m, (1H), 2.67 (m, 1H), 2.38 (m, 1H), 1.87 (wide, 1H), 0.98 (m, 2H), 0.01, s, 9H) ) Make Ph (3-Cl) (5-〇CHF2)-(R) CH (〇H) C (0) -Aze-Pab (2,6- 二 F) (OMe, Teoc) (58 G, 0.086 mmol; see the above step (i)) was dissolved in 3 ml of TFA, cooled on an ice bath, and allowed to react for 2 hours. TFA was evaporated and the residue was dissolved in EtOAc. The organic layer was washed twice with an aqueous sodium carbonate solution and water, dried (Na2S04), and evaporated. The residue was lyophilized from water and acetonitrile to give 42 mg (92%) of the title compound. Purity: 94%. 1 H NMR (300 MHz, CDC13) (5 7.95 (bt, 1H), 7.2-7.1 (m, 4H), 6.99 (m, 1H), 6.52 (t3 -165- 200306975 invention description β page (161) 1Η) , 4.88 (s, 1Η), 4.85-4.75 (m, 3Η), 4.6-4.45 (m, 2Η), 4.29 (broad, 1Η), 4.09 (m, 1Η), 3.89 (s, 3H), 3.69 (m , 1H), 2.64 (m, 1H), 2.38 (m, 1H), 1.85 (broad, 1H) 13C-NMR (100MHz; CDC13) · · (carbonyl and / or fluorene) (5 172.1, 169.8, 151.9 APCI -MS: (Μ + 1) = 533/535 m / z Example 41

PhH-nV5-OCHF, MR) CH (0H) C (0VAze-Pab (2,5-two F)

ffl 2,5-Difluoromethylsulfinyl) (methylthio) methyl 1 benzonitrile to (methylsulfinyl) (methylthio) methane (3.16 g, 0.0255 moles) at Dissolve in 50 ml of anhydrous THF under argon and cool to -78 ° C. Add butyllithium in hexane (16 ml, 1.6 M, 0.0256 mol) dropwise and stir. The mixture was stirred for 15 minutes. At the same time, a solution of 2,4,5-trifluorobenzonitrile (2.0 g; 0.013 moles) in 50 ml of anhydrous THF was cooled to -78 ° C under argon, and the aforementioned solution was passed through a sleeve Add to the solution described below over a period of 3-5 minutes. After 30 minutes, the cooling bath was removed and when the reaction had reached room temperature, it was poured into 2 ml of water. The THF was evaporated and the remaining aqueous layer was extracted three times with ether. The combined ether phases were washed with water, dried (Na2S04) and evaporated. The crude product begins to crystallize and can be used as such in the next step. Yield: 2.8 g (84%). -166- 200306975 (162) Description of the invention continued iHNMR (500MHz, CDa3) 5 7.5U7 44 (m, 2H major diastereomer), 7.39 (dd, 1H less I diastereomer Structure), 500 (s, m less isomers), 4.92 (s, 1H Wang wants 4 diastereomers), 2.59 (s, 3H less diastereomers) Enantiomers), 2.56 (s, 1H Wang Yaozhi diastereomers), 2.46 (s, m less diastereomers), 2.40 (s, 1H main diastereomers Isomers) (Along the 2,5-difluoro-4-methylfluorenyl ^ wax, 2,5-difluoro-4 [(methylsulfinyl) (methylthio) methyl] benzonitrile (28 grams, 0.0107 moles; see above for dissolving in 100 ml of THF and adding 65 g of concentrated sulfuric acid. The mixture was left at room temperature for 6 days and then poured into 500 ml of water. It was extracted three times with ether, and the combined ether phases were washed several times with water (dehydrated to dryness) and evaporated. The crude product was subjected to flash chromatography on silica gel using heptane: EtOAc (8: 2). Yield: 1.2 g (67%). The position of formazanyl was established by nCNMR. From this carbon fluoride, 160.1 was individually obtained. The mosquito puppet under 158.4 is a doublet_ instead of a quartet ^. If the methyl group is already in the 2-position, it is already a doublet. 1 H NMR (300 MHz, CDC13) 5 10.36 (d, 1H), 7.72 (dd, 1H), 7.54 (dd, 1H) ⑽difluoro-4-hydroxymethyl 苽 y compensation for 2,5-difluoro-4-methylamidinobenzonitrile ( 3.60 g, 0.0215 mol; see step (ii) above) Dissolved in 50 ml of methanol and cooled on an ice bath. Sodium borohydride (0.815 g, 0.0215 mol) was added in portions and stirred, and The reaction was left for 45 minutes. Water (300 ml) was added, then 2M HC1 was carefully added until an acidic pH was obtained. The mixture was extracted three times with ether, and the combined ether phases were washed with water, dried (Na2S04), and evaporated. The crude product crystallized quickly and could be used without further purification. Yield: 3.1 g (85%). -167- 200306975 Description of the invention $ sales page (163)-1 H NMR (300 MHz, CDC13) 5 7.45 ( dd, 1H), 7.30 (dd, 1H), 4.85 (s, 2H), 2.10 (broad, 1H) (iv) $ 4-Cyano-2,5-difluorofluorenyl alkanesulfonate at 2,5- Difluoro-4-hydroxymethyl benzonitrile (3.10 g, 0.0183 Ear; see step (iii) above) in an ice-cold solution of methanesulfonium chloride (2.21 g, 0.0192 mole) in 60 ml of dichloromethane, add triethylamine (1.95 g, 0.0192 mole), and stir . After 1.5 hours at 0 ° C, the mixture was washed with water, dried (Na2SO4), and evaporated. This product was used without further purification. Yield: 4.5 g (99%). 1 H NMR (300 MHz, CDC13) (5 7.45-7.35 (m, 2H), 5.32 (s, 2H), 3.13 (s, 3H) (v) 4-azidomethyl-2,5- Dichlorobenzonitrile makes 4-cyano-2,5-difluorofluorenyl methanesulfonate (4.5 g, 0.0182 mole; see step (iv) above) with sodium azide (2.0 g, 0.031 mole) The mixture in 20 ml of water and 40 ml of DMF was stirred at room temperature for 2 hours. Then, it was poured into 300 ml of water and extracted three times with ether. The combined ether phases were washed several times with water and dried (dehydrated) Na2S04), and evaporated. Evaporate a small sample for NMR purposes and crystallize the product. Carefully evaporate the rest, but not until completely dry. Based on NMR and analytical HPLC, the yield (theoretically 3.5 g) was almost quantitative. 1 H NMR (500 MHz, CDC13) 5.38 (dd, 1H), 7.32 (dd, 1H), 4.54 (s, 2H) (vi) oxaminomethyl-2,5 -This reaction was performed according to the procedure described in J. Chem. Res. (M) (1992) 3128. 300 mg 10% Pd / C (50% water) in 20 ml To the suspension in water, add sodium borohydride (0.779 g, 0.0206 moles) In 20 ml of water. -168-200306975 made (164)

The invention illustrates that MM is released as some gas. Nitromethyl-2,5-difluorobenzonitrile (ΐ.00 g, 5-15 mmol; obtained from step (ν) above) was dissolved in 60 ml of THF and added to the water content on an ice bath In the mixture. The mixture was stirred for 15 hours, then 10 ml of 2M HC1 was added, and the mixture was filtered through celite. The diatomaceous earth was rinsed with more water, and the combined aqueous phases were washed with EtOAc, and then made testative with 2M NaOH. It was extracted three times with dichloromethane, then the combined organic phases were washed with water, dried (NaSO4) and evaporated. Yield: 0.47 g (54%). 1 H NMR (300 MHz, CDC13) 5 7.39 (dd, 1H), 7.29 (dd, 1H), 3.99 (s, 2H), 1.45 (broad, 2H) (νϋ) 2,5-difluoro-4 -Third, 4-aminomethyl-2,5-difluorobenzonitrile (0.46 g, 2.7 mmol; see step (vi)) above and two A solution of di-tertiary-butyl carbonate (0.60 g, 2.7 mol) in 10 ml of THF was stirred overnight. The THF was evaporated and the residue was partitioned between water and EtOAc. The organic layer was washed with water, dried (v% so4), and evaporated. This product can be used without further purification. Yield: 71 g (97%). 1 H NMR (300 MHz, CDC13) 5 7.35-7.2 (m, 2H), 5.11 (broad triplet, 1H), 4.38 (d, 2H), 1.45 (s, 9H)

(viii) Boc-Pab (2,5-diF) (OID 2,5-difluoropyridine third-butoxycarbonylaminomethylbenzonitrile (0.70 g, 2.6 mmoles; see above steps ( vii)), a mixture of hydroxylamine hydrochloride (0.54 g, 7.8 mmol) and triethylamine (0.79 g, 7.8 mmol) in ml of ethanol and stirred at room temperature for 6 days. Then, It was separated between water and dichloromethane. The aqueous layer was extracted with dichloromethane and the combined organic phases were washed with water-169- 200306975

DESCRIPTION OF THE INVENTION MM (165)-, dehydrated (Na2SO4), and evaporated. This product can be used without further purification in the factory. Yield: 0.72 g (92%). 1 H NMR (500 MHz, CD3 OD) 5 7.27 (dd, 1H), 7.12 (dd, 1H), 4.29 (s, 2H), 1.47 (s, 9H) (ix) Boc-Pab (2,5-two F) x HAc This reaction was performed according to the procedure described in Judkins et al., Synth. Comm. (1998) 4351. Boc-Pab (2,5-diF) (OH) (0.70 g, 2.3 mmol) in 70 ml of acetic acid; acetic anhydride (0.25 g, 2.4 mmol); 230 mg of 10% Pd / C (50% water) was hydrogenated at 5 atmospheres for 2.5 hours. The mixture was filtered through celite and evaporated. The residue was lyophilized from acetonitrile and water. The product can be used in the next step without further purification. Yield: 0.80 g (100%). 1 H NMR (500 MHz, CD3 OD) 5 7.49 (dd, 1H), 7.31 (dd, 1H), 4.33 (s, 2H), 1.91 (s, 3H), 1.46 (s, 9H) 〇〇Boc -Pab (2,5-DiF) (Teoc) in Boc-Pab (2,5-DiF) x HOAc (0.80 g, 2.3 mmol; see step (ix) above) in 50 ml of THF Then, 2- (trimethylsilyl) ethyl p-nitrophenyl carbonate (0.85 g, 3.0 mmol) was added. A solution of potassium carbonate (0.80 g, 5.8 mmol) in 10 ml of water was added dropwise. The mixture was stirred overnight. The excess Teoc reagent was decomposed by adding glycine (0.100 g) and potassium carbonate (0.75 g) to the solution and allowed to react for another 2 hours. The THF was evaporated and the residue was partitioned between water and dichloromethane. The aqueous layer was extracted with dichloromethane, and the combined organic phases were washed with water, dried (Na2SO4) and evaporated. Flash chromatography on silica gel using heptane: EtOAc (2: 1) to obtain -170- 200306975

Description of the invention, MM (166)-yields 0.72 g (72%) of pure compound. 1 H NMR (400 MHz, CDC13) 5 8.00 (dd, 1Η), 7.15 (dd, 1Η), 4.98 (broad, 1Η), 4.36 (bd, 2H), 4.24 (m, 2H), 1.45 (s, 9H ), 1.12 (m, 2H), 0.07 (s, 9H) (xi) H-Pab (2,5-DiF) (Teoc) x 2 HC1

Boc-Pab (2,5-di F) (Teoc) (0.38 g, 0.88 mmol; see step (x) above) was dissolved in 50 ml of EtOAc saturated with HC1 (gas). The mixture was left for 30 minutes and evaporated. 1 H NMR (500 MHz, CD3 0D) 5 7.75-7.6 (m, 2H), 4.46 (m, 2H), 4.3 (s, 2H), 1.15 (m, 2H), 0.07 (s, 9H) (xii) Boc-Aze-Pab (2,5-DiF) (Teoc) in Boc-Aze-OH (0.189 g, 0.94 mmol), H-Pab (2,5-DiF) (Teoc) x 2HC1 (0.36 G, 0.89 mmol; see step (xi) above and PyBOP (0.54 g, 1.03 mmol) in a stirred solution in 5 ml DMF, add diisopropylethylamine (0.49 g, 3.8 mmol) Ear), and the mixture was allowed to react overnight. Then, the resultant was poured into an aqueous sodium hydrogen carbonate solution, and extracted three times with EtO Ac. The combined organic phases were washed with water, dried (Na2SO4) and evaporated. Flash chromatography on silica gel using heptane: EtO Ac (3: 7) to obtain sufficiently pure compounds. Yield: 0.25 g (48%). 1 H NMR (500 MHz, CDC13) 5 7.98 (dd, 1H), 7.13 (dd5 1H), 4.69 (m, 1H)? 4.53 (m? 2H), 4.22 (m, 2H), 3.92 (m, 1H) , 3.79 (m, 1H), 2.55-2.35 (m, 2H), 1.44 (s, 9H), 1.11 (m, 2H), 0.06 (s, 9H) (xiii) H-Aze-Pab (2,5- Di (Foc) (Teoc) x 2HC1 Dissolve Boc-Aze-Pab (2,5-DiF) (Teoc) (0.25 g, 0.49 mmol; see step (xii) above) in HC1 (Gas ) Saturated in 50 ml of EtoAc. Mixture -171-200306975 Description of the invention $ Sale page (167) ---- Leave on for 30 minutes and evaporate. The product was used in the next step without further purification. Yield: 0.23 g (97%). 1 H NMR (400 MHz, CD3 OD) 5 7.59 (dd, 1H), 7.47 (dd, 1H), 5.14 (m, 1H), 4.54 (m, 2H), 4.48 (m, 2H), 4.15 (m , 1H), 3.96 (m, 1H), 2.87 (m, 1H), 2.56 (m, 1H), 1.17 (m, 2H), 0.05 (s, 9H) (xiv) Ph (3: C_l) (5- 〇CHF9 V (R) CH (0H) C (0) -Aze-Paba5-DiF) (Teoc) in Ph (3-Cl) (5-OCHF2)-(R) CH (OH) C (O) OH (0.12 grams, 0.47 millimoles; see Example 1 (viii) above), H-Aze-Pab (2,5-DiF) (Teoc) x2HCl (0.23 grams, 0.47 millimoles; see step (xiii above) )) And PyBOP (0.27 g, 0.52 mmol) in 10 ml of DMF, diisopropylethylamine (0.245 g, 1.90 mmol) was added and the mixture was stirred overnight. The resultant was poured into water and extracted three times with EtoAc. The combined organic phases were washed with water, dried (Na2S04) and evaporated. Flash chromatography on silica gel using EtOAc yielded 100 mg pure fractions and 30 mg 90% pure fractions. Total yield: 0.13 g (41%) 〇1 H NMR (400 MHz, CDC13) 5 9.80 (broad, 1H), 8.05 (bt, 1H), 7.94 (dd, 1H), 7.20 (m, 1H), 7.2- 7.1 (m, 2H), 7.02 (m, 1H), 6.54 (t, 1H), 4.93 (s, 1H), 4.91 (m, 1H), 4.51 (m, 2H), 4.28 (broad, 1H), 4.23 (m, 2H), 4.13 (m, 1H), 3.74 (m, 1H), 2.69 (m, 1H), 2.43 (m, 1H), 1,73 (broad, 1H), U1 (m , 2H), 1.11 (s, 9H) (xv) Phri-nVS-OCHT ^ VaOCHiOHOCiOVAze-PabO diF) Ph (3-Cl) (5-〇CHF2HR) CH (OH) C (O: l · Aze- Pab (2,5-DiF) (Teoc) (60 mg (0.093 mmol) from the pure solvent from step (xiv) above) was dissolved in 3 ml of TFA and left at room temperature for 1 hour. Evaporation TFA and lyophilize the residue from water and acetonitrile to produce 55 mg (96%) of the title compound as its TFA salt, purity -172- 200306975 Description of the invention (168): > 99% 〇1 H NMR (500 MHz, a mixture of CD3 OD rotomers) (5 7.55-7.3 (m, 3Η), 7.27.1 (m, 2H), 88 (t, m is the main rotomer), ό · 8ό ( t, ΙΡί less rotational isomers), 5.22 (m, 1 Rota isomers), 5.20 (s, 1Ηmain rotamer), 5.13 (s, 1H less rot isomer), 4.80 (m, 1H main rot isomer), 4.6-4.45 (m, 2H), 4.36 (m, 1H main rotamer), 4.19 (m, 1H main rotamer), 4.07 (m, 1H less rotomer), 3.98 (m, 1H less rotational isomers), 2.70 (m, 1H less rotational isomers), 2.54 (m, 1H main rotational isomers), 2.28 (m, 1H main rotational isomers), 2 · 14 (m, 1H less rotational isomers) 13C-NMR (75MHz; CD3OD): (carbonyl and / or europium, mixture of rotational isomers) (5 173.0, 172.6, 172.1, 172.0, 162.4 APCI-MS: (M + 1) = 503/505 m / z. Example 42

Ph (3.-CDa: QCHF9 V (R) CH (〇H) C (0) -Aze-Pab (2,5-Di FVOMe)

(i) Ph (3-ClX5-OCHF: >: KR) CH (OH) C (OVAze-Pab (2,5-: F) (OMe, Teoc) will be PI (3-α) (5-0 < : ΗΡ2ΗΐΙ) (: Η (0Η) α〇) _Αζ6P & ΐ3 (2,5, diF) (Teoc) (40 mg, 0.062 mmol; see Example 41 (xiv) above) and hydroxymethylamine salt Acid salt (58 -173- 200306975 (169) invention description, M pages mg, 0.70 mmol) in 5 ml of acetonitrile and heated at 70 ° C for 2 hours. The solvent was evaporated and the residue was dissolved in water and The layers were separated between EtOAc. The aqueous layer was extracted with EtoAc and the combined organic phases were washed with water, dried (NaSO4) 'and evaporated. This product was used without further purification. Yield: 35 Mg (84%).

1 H NMR (600 MHz, CDC13) ά 7.99 (bt, 1H), 7.72 (s, 1H), 7.20 (m, 1H) 7.15-7.1 (m, 1H), 7.07 (dd? 1H)? 7.01 (m, 1H)? 6.53 (t? 1H)? 4.90 (s, 1H)? 4.88 (m? 1H), 4.48 (m5 2H), 4.2-4.1 (m, 3H), 3.95 (s, 3H), 3.67 (m, 1H), 2.68 (m, 1H), 2.41 (m, 1H), 0.97 (m, 2H), 0.07 (s, 9H) (ii))-(R) CH (0H) C (0) -Aze-Pab (2,5-DiF) (0Me) make Ph (3-Cl) (5-〇CHF2HR) CH (0H) C (0) -Aze-Pab (2,5-DiF) (OMe, Teoc) (35 mg 0.052 millimoles; see step (i) above) Dissolve in 3 ml TFA and allow to react for 30 minutes. TFA was evaporated and the residue was lyophilized from water and acetonitrile to give 29 mg (99%) of the title compound. Purity: 97%.

1 H NMR (300 MHz, CDC13) 5 8.01 (bt, 1H), 7.45 (dd, 1H), 7.20 (m, 1H), 7.15 (m, 1H), 7.09 (dd, 1H), 7.02 (m, 1H ), 6.54 (t, 1H), 5.2-5.0 (m, 2H), 4.95-4.85 (m, 2H), 4.6-4.4 (m, 2H), 4,25 (broad, 1H), 4.13 (m, 1H) ), 3.90 (s, 3H), 3.71 (m, 1H), 2.69 (m, 1H), 2.43 (m, 1H) 13C-NMR (75MHz; CDC13): (carbonyl and / or fluorene) (5 173.0, 170.9, 152.6 APCI-MS: (Μ + 1) = 533/535 m / z. Example 43

PhG-CiyS-OCHF ^ VrR ^ CHromcrOVAze-PabfOEt) (i) PhG-nVlOCHF ^ Vn ^ CHiOFnaOVAze-PablOEt. Teod makes Ph (3-Cl) (5-OCHF2)-(R) CH (OH) C (0) -Aze-Pab (Teoc) (55 mg, 0.090 mmol-174-200306975) Description of the invention It M (170)-Moore; see Example 1 (ix) above and 0-ethylhydroxylamine hydrochloride (53 mg, 0.54 mmol) in 4 ml of THF. The mixture was stirred at 60 ° C for 5 hours. The solvent was evaporated. The residue was chromatographed on Shixi gel and dissolved in dichloromethane: methanol (95: 5) to give 55 mg (93%) of the title compound. 1 H-NMR (400 MHz; CDC13): 5 7.84 (bt, 1H), 7.59 (bs, 1H)? 7.47 (bd, 1H)? 7.29 (bd, 1H), 7.21 (m, 1H), 7.14 (m , 1H), 7.02 (m, 1H), 6.53 (t, 1H), 4.90 (s, 1H), 4.86 (m, 1H), 4.55-4.4 (m, 2H), 4.25-4.1 (m, 5H), 3.69 (m, 1H), 2.66 (m, 1H), 2.41 (m, 1H), 1.33 (t, 3H), 0.98 (m, 2H), 0.02 (s, 9H) (ii) Phn-civs-ocHF ^ vmcHromcrovAze-PabroF ^ in Ph (3-Cl) (5-〇CHF2HR) CH (OH) C (0) -Aze-Pab (〇Et, Teoc) (55 mg, 0.084 mmoles; see step (i) above) )) To an ice-cold solution in 0.5 ml of dichloromethane, 3 ml of TFA was added. The mixture was stirred (ice bath) for 160 minutes. This material was purified using preparative HPLC. The fractions of interest were pooled and lyophilized (2x) to yield 20 mg (47%) of the title compound. 1 H-NMR (400 MHz; CD3 OD) rotamer: 5 7.59 (bd, 2H), 7.35 (m, 1H), 7.32 (bd, 2H), 7.25-7.1 (m, 2H), 6.89 (t, 1H main rotomer), 6.86 (t, 1H main rotomer), 5.18 (s, 1H main rotomer), 5.18 (m, 1H rotomer) Compounds), 5.11 (s, 1H less rotational isomers), 4.77 (m, 1 ，), 4.5-4.3 (m, 3H), 4.2-3.9 (m, 3H), 2.67 (m, 1H compared with Less rotamer), 2.52 (m, 1H main rotamer), 2.28 (m, 1H main rotamer), 2.15 (m, 1H less rotomer), 1.28 ( t, 3H) 1 3 C-NMR (100 MHz; CD3 OD): (carbonyl and / or fluorene, rotamer) 〇 172.4, 171.9, 171.4, 153.8, 152.3 MS (m / z) 509 (Ml) ', 511 (M + 1) + -175- 200306975 Description of the Invention Continued (171)-Example 44

Phr ^ -ayg-OCHF ^ -rR ^ CHromrrOVAze-PabrOTiPr ^ (i) PhrS-CIVS-OCHF ^ Vm ^ CHromrrOVAze-PabrOnPr. Teoc ^) Make Ph (3-Cl) (5-〇CHF2HR) CH (〇H) C (0) -Aze-Pab (Teoc) (53 mg '0.087 mmol; see Example 1 (ix) above) dissolved with 58 mg (0.52 mmol) of 0-n-propylhydroxylamine hydrochloride In 4 ml of THF. The mixture was stirred at 60 ° C for 5 hours. The solvent was evaporated. The residue was chromatographed on Shixi gel and dissolved in dichloromethane: methanol (95: 5) to give 51 mg (88%) of the title compound. 1 H-NMR (400 MHz; CDC13): 5 7.84 (m, 1H), 7.59 (bs, 1H), 7.47 (bd, 2H), 7.28 (bd, 2H), 7.21 (m, 1H), 7.14 (m , 1H), 7.02 (m, 1H), 6.53 (t, 1H), 4.90 (s, 1H), 4.85 (m, 1H), 4.55-4.4 (m, 2H), 4.2-4.05 (m, 5H ), 3.69 (m, 1H), 2.65 (m, 1H), 2.41 (m, 1H), 1.74 (m, 2H), 1.05-0.95 (m, 5H), 0.03 (s, 9H) (ii) Phn ^ nys-ocHF ^ v ^ cHromcrovAze-PabronPr) in Ph (3-Cl) (5-OCHF2HR) CH (OH) C (0) -Aze-Pab (OnPi :, Teoc) (51 mg, 0.078 millimoles; see The above step (0) was added to 0.5 ml of an ice-cold solution in dichloromethane, and 3 ml of TFA was added. The mixture was stirred (ice bath) for 110 minutes. This material was purified using preparative HPLC. The fractions of interest were evaporated, And lyophilized to yield 20 mg (47%) of the title compound. 1 H-NMR (500 MHz; CD3 0D) rotamer: 5 7.61 (bd, 2H), 7.38 (m, 1H), 7.35 (bd, 2H) ), 7.22 (m, 1H major rotomer), 7.18 (m, 1H), 7.15 (m, 1H minor rotomer), 6.92 (t, 1H major rotomer), 6.89 (t, 1H less rotation Structure), 5.20 (s, 1H main rotomer), 5.20 (m, 1H main rotomer), 4.80 (m, 1H main rotomer), 4.5-4.4 (m, 2H contains less rotational isomers, corresponding to the major rotational isomers under 4.37), -176- 200306975 Invention description $ Selling stomach (172)-4.37 (m, 1H major rotational isomers), 4.18 ( m, 1H main rotomer), 4.09 (m, 1H less rotomer), 3.99 (m, 2H), 2.70 (m, 1H less rotomer), 2.54 (m, 1H main rotomer), 2.30 (m, 1H main rotomer), 2.18 (m, 1H less rotomer), 1.73 (m, 2H), 1.01 (t, 3H) 13 C-NMR (125MHz; CD3 OD): (carbonyl and / or fluorene, rotamer) 5 171.4, 153.8, 152.3 MS (m / z) 523 (M-1)-, 525 (M + 1) + Example 45

Phn-nV ^ OCHF ^ VrR ^ CHromrrOVAze ^ PabrOiP ^ (i) Phn-nV5-OC: HF1WR) n ^ Ofna〇VAze-Pab (OiPrTTecK ^ Make Ph (3-Cl) (5-OCHF2HR) CH (OH) C (O) -Aze-Pab (Teoc) (50 mg, 0.082 mmol; see Example 1 (ix) above) and 0-iso-propylhydroxylamine hydrochloride 55 mg (0.49 mmol) in 4 ml In THF. The mixture was stirred at 60 ° C for 5 hours. The solvent was evaporated. The residue was chromatographed on silica gel and dissolved in dichloromethane: methanol (95 ·· 5) to give 46 mg (84%) of the title Compound: 1 H-NMR (400 MHz; CDC13): δ 7.84 (m, 1H), 7.57 (bs, 1H), 7.48 (bd, 2H), 7.29 (bd, 2H), 7.21 (m, 1H), 7.14 (m, 1H), 7.02 (m, 1H), 6.53 (t, 1H), 4.91 (s, 1H), 4.87 (m, 1H), 4.55-4.45 (m, 2H), 4.42 (m, 1H) ), 4.2-4.1 (m, 3H), 3.69 (m, 1H), 2.66 (m, 1H), 2.42 (m, 1H), 1.30 (d, 6H), 0.98 (m, 2H), 0.02 (s, 9H) (ii) Phr ^ -nVg ^ OCHF ^ VrR ^ CHrOH ^ CrOVAze-PabiOiPr) at Ph (3-Cl) (5-〇CHF2HR) CH (〇H) C (0) -Aze-Pab (OiPr, Teoc ) (46 mg, 0.069 mmoles; see step (i) above) in ice-cold solution in 0.5 ml dichloromethane To the solution, 3 ml of TFA was added. The mixture was stirred (ice bath) for 150 minutes. This material was purified using preparative HPLC. Evaporate the fraction of interest -177- 200306975 Inventive__ (173) and lyophilize (2x) to give 22 mg (58%) of the title compound. 1 H-NMR (400 MHz; CD3 OD) rotational isomers: 5 7.59 (d, 2H), 7.35 (m, 1H), 7.32 (d, 2H), 7.19 (m, 1H main rotational isomers) , 7.15 (m, 1H), 7.12 (m, 1H less rotational isomers), 6.89 (t, 1H main rotational isomers), 6.86 (t, 1H less rotational isomers), 5.18 (s, 1H major rotomer), 5.18 (m, 1H minor rotomer), 5.12 (s, 1H minor rotomer), 4.78 (m, 1H major rotomer) ), 4.5-3.9 (m, 5H), 2.67 (m, 1H less rotational isomers), 2.52 (m, 1H main rotational isomers), 2.28 (m, 1H main rotational isomers) ), 2.15 (m, 1H less isomers), 1.26 (d, 6H) 13 C-NMR (100 MHz; CD3 OD): (carbonyl and / or fluorene, isomers) 5 171.9, 171.4, 153.6. MS (m / z) 523 (M-1)-, 525 (M + 1) + Example 46

PhG-nVS-OCHF ^ HIOCHCOHOaOVOAze-Paba ^ II F) (OH)

(i) Roc (II) F, 4-CN) Boc- (S) Aze-OH (1.14 g, 5.6 mmol) was dissolved in 45 ml of DMF. Add 4-aminomethyl-2,6-difluorobenzonitrile (1.00 g, 5.95 moles, see Example 39 (vi) above), PyBOP (3.10 g, 5.95 mmoles) and DIPEA (3.95 Ml, 22.7 -178- 200306975 description of the invention _ page (174)-millimoles), and the solution was stirred at room temperature for 2 hours. The solvent was evaporated and the residue was partitioned between Η20 and EtOAc (75 mL each). The aqueous phase was extracted with 2 × 50 mL of EtOAc, and the combined organic phases were washed with brine and dried over Na 2 SO 4. Flash chromatography (SiO2, EtOAc / heptane (3/1)) yielded the subtitled compound (1.52 g, 77%) as an oil, which crystallized in the refrigerator. 1 H-NMR (400 MHz; CD3 OD): 5 7.19 (m, 2H), 4.65-4.5 (m, 3H), 3.86 (m, 1H), 3.73 (m, 1H), 2.45-2.3 (m, 2H ), 1.39 (s, 9H) (ii) H-iSUze-NHCHpPhO di F, 4-CN) x HC1 makes Boc- (S) Aze-NHCH2-Ph (2,6-di F, 4-CN) (0.707 G, 2.01 mmol, refer to step (i) above) and dissolved in 60 ml of EtO Ac saturated with HC1 (gas). After stirring at room temperature for 15 minutes, the solvent was evaporated. The residue was dissolved in CH3CN / H2 0 (1/1) and lyophilized to obtain the subtitled compound (0.567 g, 98%) as an off-white amorphous powder. 1 H-NMR (400 MHz; CD3 0D): 5 7.49 (m, 2H), 4.99 (m, 1H), 4.58 (m, 2H), 4.12 (m, 1H), 3.94 (m, 1H), 2.80 ( m, 1H), 2.47 (m, 1H) MS (m / z) 252.0 (M + 1) + (iii) Phn-ClXS-OCRFiVn ^ nWOBnaOKSlAze-NHCHi-PhO diF, 4-CN) Make Ph (3- Cl) (5-〇CHF2HR) CH (OH) C (O) OH (0.40 g, 1.42 mmol, see Example 1 (viii) above) was dissolved in 10 ml of DMF and H- (S) Aze- NHCH2-Ph (2,6-diF, 4-CN) xHCl (0.43 g, 1.50 mmol, see step ⑻ above) and PyBOP (0.779 g, 1.50 mmol) followed by DIPEA (L0 ml , 5.7 millimoles). After stirring at room temperature for 2 hours, the solvent was evaporated. The residue was partitioned between H20 (200 mL) and EtOAc (75 mL). The aqueous phase was extracted with 2 X 75 milligrams of 200306975 (175) invention, and the combined organic phases were washed with brine and dried over NadO4. Flash chromatography (SiO2, EtOAc / heptane (4/1)) gave the 'human' compound (0.56 g '81%) as an oil.

H-NMR (400 MHz, CD3 OD) rotamers · (5 7.43 (m, 2H), 7.31 (m, 1H main rotomer), 7.26 (m, 1H less rotomer) ), 7.2-7.1 (m, 2H), 6.90 (t, 1H main rotomer), 6.86 (t, 1H main rotomer), 5.14 (s, 1H main rotomer) , 5.11 (m, 1H less rotational isomers), 5.04 (s, 1H less rotational isomers), 4.71 (m, 1H main rotational isomers),

4.6-4.45 (m, 2H), 4.30 (m, 1H main rotomer), 4.2-3.9 (m, 1H; less rot isomer with 1H), 2.62 (m, 1H less Rotational isomers), 2.48 (m, 1H main rotation isomers), 2.21 (m, 1H main rotation isomers), 2.09 (m, 1H less rotation isomers) 13C- NMR (100MHz; CD30D): (carbonyl carbon) 5171.9, 171.8 MS (m / z) 484.0, 485.9 (M-1) '486.0, 487.9 (M +1) + (iv) £ K3-: Cl) a-_Q £ HF7)-(R) CH (OH) C (〇V (S) Aze-Pab (2,6-: F) (〇En makes Ph (3-Cl) (5-OCHF2HR) CH (OH) C ( 〇HS) Aze-NHCH2-Ph (2,6-diF, 4-CN) (0.555 g, U4 mmol, obtained from the above step (Hi)) was dissolved in 10 ml of EtOH (95%). Here Hydroxylamine hydrochloride (0.238 g, 3.42 mmol) and Et3N (0.48 ml, 3.44 mmol) were added to the solution. After stirring at room temperature for 14 hours, the solvent was removed and the residue was dissolved in EtO Ac The organic phase was washed with brine and H2 0 and dehydrated and dried with Na2 S04. The crude product was purified by preparative RPLC, and CH3CN: 0.1 MNH40Ac was used as the eluent. After cold beam drying, the title compound was produced as an amorphous powder 0.429 g, 72%).

1 H-NMR (400 MHz; CD3 0D) rotamers: 5 7.35-7.1 (m, 5H), 6.90 (t, 1H -180- 200306975 (176) Description of the invention continued on the main rotational isomers), 6.85 (t, 1H less rotational isomer), 5.15 (s, 1H main rotational isomer), 5.12 (m, 1H less rotational isomer), 5.08 (s, m Fewer rotamers), 4.72 (m, 1H main rotomer), 4.6-44 (m, 2H), 4.30 (m, 1H main rotomer), 4.12 (m, 1H main rotomer) Rotomers), 4.04 (m, 1H less rotomers), 3.94 (m, 1H less rotomers), 2.62 (m, 1H less rotomers) , 2.48 (m, 1H main rotational isomer), 2.22 (m, 1H main rotational isomer), 2. 旋转 〇 (m, 1H less rotational isomer) 1 3 C-NMR (100 MHz; CD3 OD): (carbonyl and fluorene carbon, rotamer) 6 172.4, 171.9, 171.0, 152.3, 151.5 MS (m / z) 517.1, 519.0 (Μ · 1)-, 519.1, 521.0 (M ten 1 ) + Example 47 The title compounds of Examples 3, 6, 9, 10, 13 to 15, 17, 19, 21, 23, 25, 27, 28, 32, 34, 36, 38, 39 and 41, Α above experiment tested showing less than 3.5 / IC50TT value of zM. The compounds of Examples 3, 6, 9, 10, 13, 15, 17, 19, 21, 23, 27, 32, 34, and 39 were found to show values less than 0.02 "M; Examples 25 and 28 Compounds were below 0.03 μM, Example 14 was below 0.004 // M; and Examples 38 and 41 were below 0.15 // M. Example 48 Examples 3, 6, 13, 15, 17, 19, 21 The title compounds of, 23, 25, 27, 28, 32 and 34 were tested in Test D above and found to show IC50 APTT values below 1 "M. Example 49 The title compounds of Examples 1, 2, 4, 5, 7, 12, 16, 18, 20, 22, 24, 26, 29, 30, 33, and 43 to 45 were tested in Experiment E above and found It shows the oral and / or parenteral bioavailability in rats, such as its corresponding active inhibitor 200306975. Description of the invention _ page (177)---- (free state 脒). Example 50 The title compounds of Examples 1, 2, 7, 8, 11, 12, 16, 18, 20, 22, 24, 26, 29, 33, 37, 40, 43 and 45 were tested in Test G above. It was found that in liver microsomes obtained from humans and rats, it was converted into its corresponding inhibitor of activity (free state 脒). abbreviation

Ac = Ethyl

AcOH = Acetic acid APCI = Atmospheric pressure chemical ionization (associated with MS) API = Atmospheric pressure electrolysis (associated with MS) aq. = Aqueous solution AUC = Area under the curve

Aze = (S) · —Nitrotetrakinium-2-undanoate (unless otherwise specified)

AzeOH = monoazatetra-2-carboxylic acid

Bn = Grandpa

Boc = tertiary-butoxyyl BSA = bovine serum albumin

Bu = butyl

Bzl = hexyl group CI = chemical ionization (related to MS) d = day DCC = dicyclohexylcarbodiimide DIBAL-H = di-isobutylaluminum hydride -182- 200306975

Description of the invention MM (178)-DIPEA = diisopropylethylamine DMAP = 4- (N, N-dimethylaminopyridine) DMF = dimethylformamide DMSO = dimethylformamide DVT = deep vein thrombosis EDC = 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ee = para palm isomer excess

Et = ethyl 8¾ = acetic acid

EtOAc = ethyl acetate

EtOH = ethanol

Et2 〇 = acetic acid h = hour HATU = hexafluorophosphate 0- (nitrobenzotriazole small group) -N, N, NW-tetramethylphosphonium HBTU = [hexafluorophosphate N, N, N ', N'- Tetramethyl-〇- (benzotriazole small group) thre] HC1 = hydrochloric acid, hydrogen chloride gas or hydrochloride (depending on the context)

Hex — hexadecane HOAc = acetic acid HPLC = high performance liquid chromatography LC = liquid chromatography

Me = methyl MEM = methoxyethoxymethyl

MeOH = methanol min = minute -183- 200306975 Description of the invention _ stomach (179)-MS = mass spectrum MTBE = methyl tertiary-butyl acid NADH = nicotine amine adenine dinucleotide, reduced form NADPH = smoke Sodium amine adenine dinuclear acid phosphate, reduced form NIH = National Institutes of Health (USA) NIHU = National Institutes of Health Unit NMR-Nuclear Magnetic Resonance OAc = Acrylate

Pab = p-Marchylamine H-Pab = p-Marchylamine

Ph = phenyl

Pr = propyl

Pro = (S) -proline

PyBOP = Hexaphylic acid (benzotris. S--1-yloxy) di-p-biloxo-based scale QF = vaporized tetrabutyl

RedAl = bis (2-methoxyethoxy sodium hydride RPLC = reverse-phase high performance liquid chromatography rt / RT = room temperature SOP = standard operating procedure TBTU = [Ν, Ν, Ν ', Ν ^ 4 Methyl-0- (benzotriazol-1-yl) tetrafluoroborate] TEA = triethylamine

Teoc = 2- (trimethyllithium) ethoxyl TEMPO = 2,2,6,6-tetramethyl-1-hexahydropyridyloxy radical TFA = trifluoroacetic acid -184- 200306975 (180 ) Description of the invention THF ΤΡΡ TLC TMSC1 TMSCN uv z prefix. Prefix = tetrahydrofuran = tetrahydrofuranyl group = thin layer chromatography = trimethylsilyl chloride = trimethylated gasification = UV light = benzyloxycarbonyl n, s, i and t have their Common meanings: positive and c mean ring. Second, Third and Third -185-

Claims (1)

200306975 Scope of patent application Where Ra represents -OH or -CH2 OH; R1 represents one or more halogen substituents selected; R2 represents one or two C! _3 alkoxy substituents, the alkyl portion of the substituent itself is One or more fluoro substituents; Y represents -CH2- or-(CH2) 2-; and R3 represents a structural fragment of formula I (i) or I (ii): R4 丨 ⑴ l (ii) where R4 represents Η or one or more fluoro substituents; and one or both of Xi, X2, X3, and X4 represent -N-, and the other represent -CH-, or Its pharmaceutically acceptable derivative. 0 Continued pages (Please note and use the continuation pages when the patent application page is not enough.) 200306975 Patent application scope_page 2. Compounds according to item 1 of the patent application scope, where R1 represents a single fluoro, chloro or bromine Substituent. 3. The compound according to item 2 of the scope of patent application, wherein R1 represents a chloro group. 4. The compound according to any one of the above patent applications, wherein R2 represents -〇chf2, -ocf3, -och2 cf3, -〇ch2 chf2, -〇ch2 CH2 F or -och (ch2 f) 2 o 5. According to the application The fourth scope of the compound of the patent, wherein R2 represents -OCHF2, -och2chf2 or -〇ch2ch2f. 6. The compound according to any one of the above patent applications, wherein R3 represents a structural fragment of formula I (i). 7. The compound according to item 6 of the scope of patent application, wherein R4 represents Η. 8. The compound according to item 6 of the scope of patent application, wherein when R4 represents one or more fluoro group substituents, it means that a single fluoro group substitution is based on the 2- or 3-position, or two fluoro group substitutions are based on either 2- and 5-position or 2- and 6-position. 9. The compound according to item 8 of the scope of patent application, wherein R4 represents a single fluoro group substitution at the 2-position, or two fluoro group substitutions at the 2- and 6-position. 10. The compound according to any one of the aforementioned patent applications, wherein Ra represents 0Η. 11. The compound according to any one of the above patent applications, wherein the substitution point of R1 and R2 on the associated phenyl group of the compound of formula I is between two points relative to the connection point of the rest of the molecule of the phenyl pair One or both. 12. —A pharmaceutically acceptable derivative of the compound of formula I as defined in any one of claims 1 to 11 of the scope of patent application, the derivative compound is a compound of formula la Where R3a represents a structural fragment of formula I (iii) or I (iv): Where R5 represents OR6 or C (0) 0R7; R6 represents fluorene, CVio alkyl, Cu alkylaryl, or C 3 alkoxyaryl (wherein the alkyl portion of the two groups described later is optionally inserted by one or more oxygen atoms, and two of which are described later The aryl portion of the group is optionally substituted by one or more substituents, and the substituent is selected from halo, phenyl, methyl, or methoxy, of which the three groups described below are also optionally substituted by one or more halogens. Group substituents); R7 represents (: Bu alkyl group (hereinafter described groups are optionally inserted by one or more oxygen atoms) or alkylaryl or (^ _3 alkoxyaryl (two The alkyl portion of the group is optionally inserted by one or more oxygen atoms, and the aryl portion of the two groups described below is optionally taken by one or more substituents. -3- 200306975 Scope of Patent Application Continued Generation, the substituent is selected from halo, phenyl, methyl or methoxy, wherein the three groups mentioned below are optionally substituted by one or more halo substituents; and ^, 111, & 2, ya, 0, 1, 1, 乂 2, 乂 3, and 乂 4 are as defined in any of the items 1 to 11 of the patent application scope (as appropriate), or Pharmaceutically acceptable derivatives. 13. Compound according to claim 12 in which R5 represents OR6. 14. Compound according to claim 13 in which R6 represents pyrene, or an unsubstituted linear Dendritic or cyclic Q_8 alkyl. 15. Compound according to item 14 of the patent application, wherein R6 represents fluorene or C6 alkyl. 16. Compound according to item 14 of the patent application, where R6 represents linear q _3 alkyl, branched C3-8 alkyl, or cyclic C4-7 alkyl. 17. Compound according to item 15 or 16 of the scope of patent application, where R6 represents methyl, ethyl, n-propyl, iso -Propyl or butyl. 18. Compound according to claim 17 in the scope of application, wherein R6 represents methyl. 19. Compound according to any of claims 1 to 18, in which the fragment is S -configuration. 20. The compound according to any one of claims 1 to 19 of the scope of patent application, wherein the following fragment 200306975 patent application scope continuation page 〇 R1, R2 is R-configuration, or when Ra represents -CH2 OH When Ra represents -OH, the system assumes an S-configuration. 21. The compound according to item 1 of the scope of patent application, which is: Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Cl) (5-OCHF2)-(S) CH (CH2 0H) C (0) -Aze-Pab ; Ph (3-Cl) (5-OCF3)-(S) CH (CH2 0H) C (0) -Aze-Pab; Ph (3-OCHF2)-(R) CH (OH) -CO-Aze-Pab ; Ph (3-OCF3)-(R) CH (OH) -CO-Aze-Pab; Ph (3-Cl) (5-OCH2 CF3)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Cl) (5-OCH2 CHF2)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Cl) (5-OCH2 F)-(R) CH (OH) C (0) -Aze-Pab; Ph (3-Cl) (5-OCH2 CH2 F) -(R) CH (OH) C (0) -Aze-Pab; Ph (3-Cl) (5-OCH (CH2 F) 2)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-F) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Br) (5-OCH2 F)-(R) CH (OH) C ( 0) -Aze-Pab; Ph (3-Br) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab; Ph (3-Cl, 5-OCHF2)-(R) CH (OH) C (0) -Pro-Pab; Ph (3-Cl, 5-〇ΟίΡ2)-(ΙΙ) αί (ΟΗ) (:( 0) -Αζ & ΝΗ-αί2-((2-formamyl ) -5-pyridyl); -5- 200306975 Patent application scope_page? 11 (3-(: 1,5_00 ^ 2)-(11) 01 (011) (:( 0) '/ ^^ -> ^-€: ^ 12-((5-methylfluorenyl) -2-pyrimidinyl); Ph (3-Cl, 5-OCHF2)-(R) CH (0H) C (0) -Aze- Pab (3-F); Ph (3-Cl, 5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (2? 6- ^. F); Ph (3-Cl, 5 -〇CHF2HR) CH (OH) C (〇) -Aze-Pab (2,5-: F); Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze -Pab (0Me); Ph (3-Cl) (5-〇CHF2 HR) CH (OH) C (0) -Aze-Pab (〇Et); Ph (3-Cl) (5-OCHF2)-(R ) CH (0H) C (0) -Aze-Pab (0nPr); Ph (3-Cl) (5-OCHF2)-( R) CH (0H) C (0) -Aze-Pab (0iPr); Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0cBu); Ph (3-Cl) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0H); Ph (3-Cl) (5-0CHF2HR) CH (0H) C (0)- Aze-Pab (C00cpentyl); Ph (3-Cl) (5-OCHF2)-(R) CH (OH) C (0) -Aze-Pab (Z); Ph (3-Cl) (5-OCF3 )-(R) CH (0H) C (0) -Aze-Pab (0Me); 卩 11 (3-(: 1) (5-0 ^ 3)-(11) (: 11 (0 印 <: (0) -eight 26-? &Amp; 13 (00 «2-3- (5-^^-isoxazole)); Ph (3-Cl) (5-OCF3 HR) CH (0H) C (0) -Aze-Pab (0CH2 -3- batch of pyridine); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0iBu); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Et); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze -Pab (0Bn); 卩 11 (3-0: 1) (5-〇 €? 3)-(11) 01 (011) (:( 0) -eight 2 &? &Amp; 13 (0 (: hexyl)) ; Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0cBu); Ph (3-Cl) (5-OCF3)-(R) CH (0H ) C (0) -Aze-Pab (0CH2 CH2 OPh (3-CF3)); Ph (3-C1) (5,0CF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn ( 4-Cl)); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (3-Me0)); Ph (3-Cl) (5 -OCF3 HR) CH (0H) C (0) -Aze-Pab (0Bn (2-Br)); 200306975 Patent Application Continued Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab (0Bn (4-Me)); Ph (3-Cl) (5-OCF3)-(R) CH (0H) C (0) -Aze-Pab ( 0-4-heptyl); " Ph (3-Cl) (5-OCF3)-(S) CH (CH2 0H) C (0) -Aze-Pab (0Me) ;: Ph (3-Cl) ( 5-OCH2 CF3)-(R) CH (0H) C (0) -Aze-Pab (0Me); v Ph (3-Cl) (5-OCH2 CHF2)-(R) CH (OH) C (〇) -Aze-Pab (〇Me); Ph (3-Cl) (5-OCH2 F)-(R) CH (0H) C (0) -Aze-Pab (0Me); φ Ph (3-Cl) (5 -OCH2 CH2 F)-(R) CH (0H) C (0) -Aze-Pab (0Me); Ph (3-Cl) (5-OCH (CH2 F) 2)-(R) CH (0H) C (0) -Aze-Pab (0Me); Ph (3-F) (5-OCHF2)-(R) CH (0H) C (0) -Aze-Pab (0Me); Ph (3-Br) (5 -OCHF2 HR) CH (〇H) C (0) -Aze-Pab (OMe); Ph (3-Cl, 5 ^ 0CH2CHF2)-(R) CH (0H) C (0) -Aze-Pab (0H) ; Ph (3-Cl, 5-OCH2CH2F)-(R) CH (〇H) C (〇) -Aze-Pab (〇H); Ph (3-Cl? 5-OCHF2)-(R) CH (OH ) C (0) -Pro-Pab (OMe); Ph (3-Cl, 5-0CHF2HR) CH (〇H) C (0) -Aze-NH-CH2-((2-methoxy-formyl) )-5-External 1: Yodo); _ Ph (3-Cl, 5-0CHF2HR) CH (0H) C (0) -Aze-NH-CH2-((5-methoxy-formamyl)- , 2-pyrimidinyl); Λ η Ph (3-Cl? 5-0CHF2)-(R) CH (0H) C (0) -Aze-Pab (2,6-Ji F) (OMe); ^ Ph ( 3-Cl ， 5-0CHF2)-(R) CH (0H) C (0) -Aze-Pab (2,5-Di-F) ( OMe); or Ph (3-Cl, 5-0CHF2)-(R) CH (0H) C (0) -Aze-Pab (2,6-di-F) (OH). -22. A pharmaceutical formula comprising a compound as defined in any one of claims 1 to 21 of the scope of patent application, or a pharmaceutically acceptable derivative thereof, and a pharmaceutically acceptable adjuvant, diluent or Vehicle mixed. 23. Formulation according to item 22 of the scope of patent application, in which adjuvants, diluents and 200306975 patent application scope renewal pages and / or carriers will result in modified compounds being released. 24. The formula according to item 22 or 23 of the scope of patent application is suitable for oral administration. 25. The formula according to item 23 or 24 of the scope of patent application, which is in the form of a gelatinous matrix modified release system, comprising a hydrophilic gelling ingredient and an active ingredient. 26. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, which is used as a medicine. 27. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, for the treatment of a condition in which the inhibition of thrombin is required. 28. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, for the treatment of a condition in which anticoagulant treatment is required. 29. A compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, which is used for the treatment of thrombosis. 30. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable derivative thereof, which is used as an anticoagulant. 31. The use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable derivative thereof as an active ingredient in the manufacture of a medicament, the medicament is used for the treatment of those in need of inhibiting thrombin symptom. 32. The use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable derivative thereof as an active ingredient in the manufacture of a medicament for the treatment of an anticoagulant in which it is needed Treatment of symptoms. 33. Use according to item 31 or 32 of the scope of patent application, wherein the symptom is thrombosis. 200306975 Continuation of the scope of patent application 34. The application according to item 31 or 32 of the scope of patent application, wherein the symptom is excessive blood coagulation in blood and / or tissue. 35. Use of a compound according to any one of claims 1 to 21 or a pharmaceutically acceptable derivative thereof as an active ingredient in the manufacture of an anticoagulant. 36. A method for treating a symptom in which thrombin inhibition is required, which method comprises administering a therapeutically effective amount of any one of items 1 to 21 to a person suffering from or susceptible to such a symptom. Compound, or a pharmaceutically acceptable derivative thereof. 37. A method for treating a symptom in which anticoagulant treatment is needed, which method comprises administering a therapeutically effective amount of any one of the items according to claims 1 to 21 of the scope of the patent application to a person suffering from or susceptible to such symptoms. A compound of one item, or a pharmaceutically acceptable derivative thereof. 38. The method according to claim 36 or 37, wherein the symptom is thrombosis. 39. The method according to claim 36 or 37, wherein the symptom is excessive blood coagulation in blood and / or tissue. 40. A method for preparing a compound of formula I according to item 1 of the scope of patent application, which comprises: (i) a compound of formula II 0200306975 scope of patent application continued ^ where Ra, R1 and R2 are all the same as scope of patent application scope 1 As defined in the coupling with the compound of formula III, Wherein Y and R3 are as defined in item 1 of the scope of patent application; IV where Ra, R1, R2 and Y are as defined in item 1 of the scope of patent application, coupled with a compound of formula V, r3ch2nh2 V where R3 is as defined in item 1 of scope of patent application; (iii) For formula I Compounds, wherein R1 does not represent one or more halo groups, is to reduce the corresponding compound of formula la according to item 12 of the scope of the patent application, where R5 represents OR6, and R5 and R6 are as defined in the scope of patent application item 12; (iv) If the corresponding compound of formula XVIA or XVIB of the 48th scope of the patent application, the reaction with the ammonia source; -10- 200306975 Application scope of the patent continued (V) compound of the formula XIVA Among them, Ra, R1, R3 and Y are as defined in the first patent application scope, and react with the following compounds: (a) the corresponding fluorinated haloalkane; or (b) for the compound of formula I, wherein R2 represents -OCH2CF3, -OCH2CHF2, -och2ch2f or -〇ch (ch2f) 2, a compound of formula XIVJ Rx S (〇) 2 〇Ry XIVJ where Rx represents Ci_4 alkyl, Ci-4 perfluoroalkyl or phenyl (optionally methyl, Nitro or halo)), and Ry represents -CH2CF3, -CH2CHF2, -CH2CH2F or -CH (CH2F) 2 ;, (vi) for compounds of formula I, where R1 does not represent one or more halo groups, A ¥ where R1 represents the hydrogenation of one or more corresponding compounds of formula I; or (vii) the removal protection of a protected derivative of a compound as defined in item 1 of the scope of the patent application. — 41. A compound of formula II or a protected derivative thereof as defined in item 40 of the scope of the patent application. 42. The compound according to item 41 of the scope of patent application, wherein when Ra represents -OH, the compound has an R-configuration (about the carbon atom to which Ra is connected), or its Ra-11-200306975 patent application scope, continued When -CH2OH is indicated, it is in S-configuration. 43. A compound of formula IV or a protected derivative thereof as defined in item 40 of the scope of the patent application. 44. A compound of formula VIa, Wherein R1 represents a halogen group, and R2 is the same as defined in item 1 of the scope of patent application, or a protected derivative thereof. 45.-a compound of formula IXa, Where R represents a Cu alkyl group or (V3 alkylphenyl group, R1 represents an (S group), and R2 is as defined in item 1 of the scope of patent application, or a protected derivative thereof. 46. —A compound of formula IXAa— 12- 200306975 Scope of Patent Application Continued Wherein R is as defined in item 45 of the scope of patent application, R1 represents a halo group, and R2 is as defined in item 1 of the scope of patent application, or a protected derivative thereof. 47. — a compound of formula XIVBa, XIVBa Or a phenol O-protected derivative thereof, in which R1 represents a halogen group, and Ra is as defined in item 1 of the scope of patent application. 48. A method for preparing a compound of formula la according to item 12 of the scope of patent application, comprising: (a) reacting a compound of formula II according to item 40 of the scope of patent application with a compound of formula XV, ~ -xv -13 -200306975 Continuation of the scope of patent application, where Y is the definition in item 1 of the scope of patent application, and R3 a is the definition in item 12 of the scope of patent application; β (b) According to item 40 of the scope of patent application The reaction of a compound of formula IV with a compound of formula XVI *, R3aCH2NH2 XVI, where R3 ^ is as defined in item 12 of the patent application scope; (c) For a compound of formula la, where R5 represents OH, the corresponding formula XVIA or XVIB compound Wherein, and X4 are as defined in item 1 of the scope of patent application, and react with light amines; (d) For compounds of formula la, where R5 represents OR6, which makes the compound of formula XVII -14-200306975 patent application continuation page 〇 Where R3b represents a structural fragment of formula I (v) or I (vi): R4 l (v) N-C〇〇Rd // x = x〇lv 1 Ν-C〇〇Rb // nh2 Γ \\ // Λ χΓχ4 nh2 Kvi) where Rb represents -CH2CH2-Si (CH3) 3 or Benzyl, or tautomers thereof, and R ^ R ^ R2, and X4 are as the first item in the scope of patent application As defined in Formula XVIII, R6 ONH2 XVIII wherein R6 is as defined in item 12 of the patent application scope, or an acid addition salt thereof, followed by removal of the -C (0) 0Rb group; (e) for A compound of formula la, wherein R5 represents OH, is a compound of formula XVII as defined above, wherein Rb represents a fluorenyl group, and reacted with hydroxylamine or an acid addition salt thereof; (f) for a compound of formula la, wherein R5 represents COOR7, is According to the corresponding compound of formula I in item 1 of the scope of patent application, which reacts with the compound of formula XIX, L1 COOR7 XIX -15-200306975 Application for the scope of patent continuation page where L1 represents a leaving group, and R7 is as defined in item 12 of the scope of patent application Or (g) For a compound of formula la, wherein R5 represents OCH3 or OCH2CH3, the corresponding compound of formula la, wherein R5 represents OH, is individually reacted with dimethyl sulfate or diethyl sulfate. 49. A compound of the formula XVIA or XVIB or a protected derivative thereof as defined in item 48 of the scope of the patent application. 50. A compound of the formula XVII or a protected derivative thereof as defined in item 48 of the Chinese Patent Application. -16- 200306975 Lu, (1), the designated representative of the case is: Figure ___ (2), the representative symbols of the representative diagram are briefly explained: 柒 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: