TW200407121A - Pyridyl substituted heterocycles useful for treating or preventing HCV infection - Google Patents

Abstract

The present invention relates to pyridyl substituted heterocycles and hydro isomers thereof and pharmaceutical compositions thereof that inhibit replication and/or proliferation of HCV virus. The present invention also relates to the use of the pyridyl heterocycles and hydro isomers thereof and/or pharmaceutical compositions comprising the compounds to treat or prevent HCV infections.

Description

200407121 (1) 说明 Description of the invention [Technical field to which the invention belongs] This case is filed under 35 USC §119 (e) for application No. 6 0/4 05,467, filed on August 23, 2002, October 11, 2002 The rights of Application No. 60/4 17,837 and Application No. 60/47 1,3 7 3 filed on May 15, 2003, the contents of which are incorporated herein by reference. The present invention relates to a pyridine-substituted heterocyclic ring and its composition, which can be used for treating or preventing hepatitis C (HCV) infection. In particular, the present invention relates to a pyridyl-substituted heterocyclic ring and a corresponding hydrogenated isomer, a composition thereof, and the compound and composition in humans and animals as a treatment route for the treatment and / or prevention of HCV infection in order to inhibit Application of HCV replication and / or proliferation. [Previous technology] Hepatitis C (HCV) infection is a global human health problem, and the United States alone has 15,000 newly notified cases each year. HCV is a single-stranded RNA virus that has been identified as the cause of most non-A, non-B transfusion and post-transplant hepatitis, and is the general etiology of acute sporadic hepatitis (Cho et al., 244: 359, 1989; Kuo et al., Science 244: 362, 1 9 8 9; and Alter et al., Current Perspective in Hepatology, p. 8 3 1 98 9) 〇 It is estimated that 50% of patients infected with HCV become chronic infection, and 20% of them develop cirrhosis within 20 years (Devis et al., JVew J. Med. 3 2 1: 1 5 0 1, 1 9 8 9; Alter et al., Current Perspective in

Hepatology, ρ · 83, 1989; Alter et al., IVew £ * 7? Public /. J. Med. (2) (2) 200 407 121 321: 1899, 1992; and Dienst ag G astroe η erolo gy 8 5: 4 3 0, 1 9 8 3). Moreover, the only treatment that can be used for HCV is interferon-a (INTRON® A, PEG-INTRON® A, Schering-Plough; ROFERON-A 'Roche). However, most patients did not respond, and patients who responded had a very high relapse rate within 6 to 12 months after stopping treatment (Liang et al., Med. F //, 〇 / · 40:69, 1 993). Ribavirin-a guanine nucleoside with broad-spectrum activity against many RNA and DNA viruses-has been shown in clinical trials to combat chronic HCV infection when used in combination with interferon-α (see, for example, P〇ynard et al., / 7 cei 352: 1426-1432, 1998; Reich ard et al., Zawa / 3 5 1: 8 3-8 7, 1 99 8), this type of combined treatment has been approved (REBETRON, Schering -Plough). However, the response rate is still well below 50%. Therefore, other compounds are needed for the treatment and prevention of HCV infection. [Summary of the Invention] One aspect of the present invention is to provide a pyridine-substituted heterocyclic ring, which is a potent inhibitor of hepatitis C virus ("HCV") replication and / or proliferation. In one embodiment, the compound is a pyridyl-substituted heterocyclic ring having the structural formula (I) and its B-ring hydrogenated isomer, which has the following "ring core" and numbering rules: -6- (3) 200407121

Wherein the B ring system is an aromatic or non-aromatic ring, which includes one to four heteroatoms. χ, γ, and Z are individually selected from C, CH, N, NR16, NR] 8, S, or 0, and U and T are individually selected from C, C, or N ', the prerequisite is that X and γ cannot be both. . One of the "A" or "C" rings is a ring ring, and the other ring is a benzene ring or a pyridine ring. When "A" and / or "C" are pyridyl, the ring may be connected to the "B" ring shown via any valid carbon atom. Therefore, the "A" and / or "C" ring may be pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl.

The "A" ring system includes substituents which are adjacent to the attachment point (and optionally include 1 to 4 additional substituents. The nature of the base can be greatly changed. It can be used to replace the typical "A" ring Substitution systems include halo, chloro, hydrocarbyl, hydrocarbylthio, hydrocarbyloxy, hydrocarbyloxy, arylhydrocarbyloxycarbonyl, and aromatic carbonyls, each of which is a hydrocarbyl group, each hydrocarbyl group, and aminoformyl haloalkyl , Dihydrocarbylamine or aminosulfonyl group, ammonium group, amyl group, and its adopted form. In the eighth example on the right, the "Α" ring is substituted at 2, h and 6-positions, and all positions are Without replacement.

The delta C "C" ring is at the meta ((0) RI2 substituent (where Ru is a substituted hydrocarbon group, halohydrocarbyl group 3 or 5 "). The general formula is hydrogen, hydrocarbyl or methyl. Group, dichloromethyl'Nr] 1C and R12'cyclohetero-7-(4) (4) 200407121 hydrocarbyl or substituted with cycloheterohydrocarbyl). In one embodiment, R12 is halohydrocarbyl Dichloromethyl. The "C" ring may optionally be substituted at one or more of the 2 "-, 4"-, 5 "-, and / or 6"-positions with the same or different halo groups. As recognized by those skilled in the art, the actual electron distribution or double bond pattern of the "B" ring depends on the groups of the substituents X, Y, Z, T, and / or U. As mentioned above, the structural formula (I) includes at least the following six structures:

-8 (5) (5) 200407121

Among them, 6, 0, £, 0,: [, 1 <:, 1 ^, river, 11] 1 and 1 ^ 2 are as defined below. As mentioned above, the structural formula (I) includes at least in particular the following B-ring hydrogenated isomers: 200407121

-10- (7) (7) 200407121 and R 1 8 are as defined below. In another aspect, the present invention provides a composition comprising a compound of the present invention. The composition typically comprises a pyridyl-substituted heterocyclic or hydroisomer of the present invention (as discussed in the overall specification) or a salt, hydrate, solvate, or N-oxide thereof, and an appropriate excipient, carrier, or Thinner. The composition can be formulated for veterinary use or for human use. The compounds of the present invention are potent inhibitors of HC V replication and / or proliferation. Therefore, another aspect of the present invention provides a method for inhibiting HCV replication and / or proliferation, which comprises contacting a hepatitis C virus with an amount of a compound or composition of the present invention effective to inhibit η C V replication and / or proliferation. This method can be performed at a cable office or at a cable oven, and can be used as a treatment to treat and / or prevent HCV infection. The present invention finally provides a method for treating and / or preventing HC V infection. The method generally involves administering to a patient at risk of developing HCV infection or at risk of developing HCV infection, an amount of a compound or composition of the invention that is effective to treat or prevent HCV infection. This method can be performed in animals within the veterinary scope or in humans. [Embodiment] 6.1 Definitions The following terms used in the present invention have the following meanings: "Hydrocarbyl" itself or as part of other substituents means a single carbon atom through a self-hydrophilic hydrocarbon, olefin or alkyne Removal of a hydrogen atom results in a saturated or unsaturated, branched, linear or cyclic monovalent hydrocarbon radical of -11-(8) (8) 200407121. Typical hydrocarbyl systems include (but are not limited to) methyl; ethyls such as ethane, vinyl, and ethynyl; propyls such as propane-butyl, propane-2-yl, cyclopropanyl, propane-1- Alkenyl, prop-2-enyl, prop-2-enyl (allyl), cycloprop-1-en-butyl; cycloprop-2-en-1-yl, prop-1-yn-butyl Group, prop-2-yn-1-yl group, etc .; butyl such as butane-1-yl, butane-2-yl, 2-methyl-propanyl group, 2-methyl-propanyl-2 -Yl, cyclobutan-1-yl, butyl-butan-1-yl, butyl-butan-2-yl, 2-methyl-propan-1-yl-1-yl, butan-2-yl-1 -Yl, but-2--2-en-2-yl, but-1,3-diene-butyl, but-1,3-dienyl, cyclobutanyl- 1-yl, cyclobut-1- Alken-3-yl, cyclobut-1,3-diene- 丨 -yl, but- ^ yne] -yl, but-1- fast-3-yl, but-3-3- fast-1-yl%; and Its kind. The term "hydrocarbyl" includes, in particular, groups having a degree or degree of saturation, that is, groups having only carbon-carbon single bonds, groups having one or more carbon-carbon double bonds, having one or more carbon-carbon double bonds, Carbon-carbon reference bonds and groups having single, double, and mixtures of bonds. When specific saturation is required, the terms "alkyl", "alkenyl" and "alkynyl" are used. The hydrocarbon group preferably includes 1 to 15 atoms (C] -C] 5 hydrocarbon group), more preferably 1 to 10 carbon atoms (hydrocarbon group), and more preferably 1 to 6 carbon atoms (C) -C6 Hydrocarbyl or low hydrocarbyl). "Alkyl" itself or as part of another substituent means a saturated branched, linear or cyclic hydrocarbon radical derived from the removal of a hydrogen atom from a single carbon atom of a parent alkane. Typical alkyls include, but are not limited to, methyl, ethane, propane such as propane-1-yl, propane-2-yl (isopropyl), cyclopropane-butyl, etc., butane such as butane Base, butane-2-yl (second butan-12- (9) 200407121), 2-methyl-propane-1-yl (isobutyl), 2-methyl-propane-2-yl (p. Tributyl), cyclobutane-1-yl, and the like.

"Alkenyl" itself and as part of other substituents means an unsaturated branched chain, straight chain or cyclic ring having at least one carbon or carbon double bond derived from the removal of a hydrogen atom from a single carbon atom of a parent olefin Alkyl. This group may be in cis or trans configuration with respect to the beta double bond. Typical alkenyl systems include, but are not limited to, ethenyl; propenyl such as propyl- ^ ene-] _ yl, propyl- 丨 _ene_2__, propyl 2-ene-1 -yl (allyl) , 2-propenyl 2-cycloyl, cyclopropene-butene_; cyclopropene-1-yl; butenyl, such as but-butenyl, butyl-K-2--2-yl, 2-methyl_1 -Propenyl, buten-2-enyl, butenyl, buten-2-enyl, 2-yl, butan-1,3-diene-butenyl, butylene q,% dienyl, cyclobutenyl Alkenes, 1-based, far-butene_3-butenyl, cyclobutene, 3_diene-butenyl, etc. and their reliance.

"Alkynyl" itself or as part of other substituents means an unsaturated branched, straight or cyclic hydrocarbon group having at least one -carbon father bond derived from the removal of a hydrogen atom from a single carbon atom of a parent alkyne. Typical alkynyl systems include, but are not limited to, ethynyl; propynyl such as propynyl-phenyl, phenyl, 2-alkyn-1-yl, and the like; butynyl such as butyl-acetylene-butyl, butyl- Bulkynyl, but_3_alkyn-; [-radicals, etc .; and the like. "Hydoxy" itself or as part of another substituent means a group having the general formula -OR3 ^ where R30 is a hydrocarbon group or a b hydrocarbon group as defined herein. Representative examples of alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, tertiary butoxy, cyclopropoxy, cyclopentyloxy, cyclohexyloxy, etc. . -13- (10) (10) 200407121 "Hydroxycarbonyl" itself or as part of other substituents represents a group of the formula -C (O) -alkoxy, where the alkoxy is as defined herein. ", Kk group" itself or as part of other substituents is a group of the general formula SR where R31 is a hydrocarbon or cyclic hydrocarbon group as defined herein. Representative examples include (but are not limited to) methylthio, ethylthio , Propylthio, isopropylthio, butylthioqi, diyi + JI didibutylthio, cyclopropylthio, cyclopentylthio, cyclohexylthio and the like. "Square group" itself or as part of other substituents means a monofluorene-based hydrocarbon group derived from the removal of a hydrogen atom from a single carbon atom in a parental family system (as defined herein). Typical aryl systems include (but are not limited to) 3 im n phenanthrene 'M', benzene, cave, halobenzene, fluorene M, manganese, = province, hexabenzene, hexene, indene, s-savings, hydrogen Indene, indene, π 芊, eight-benzene, benzene, benzene, pent-2 5 4 -diene, pentene, pentamidine, pentabenzene, phenanthrene, phenalene, phenanthrene, pinene, fluorene, Pine, jade red province, triphenylene, trinaphthalene and the like. The aryl group preferably contains 6 to 20 carbon atoms (C ^ Cn aryl), more preferably 6 to 15 carbon atoms (c6_c] 5 aryl), and 6 to 10 carbon atoms (aryl). Better. "Arylhydrocarbyl" itself or as part of other substituents means an acyclic hydrocarbon group in which a hydrogen atom (typically a terminal or sp carbon atom) bonded to a carbon atom is replaced by an aryl group as previously defined. Typical aryl hydrocarbyl systems include (but are not limited to) benzyl, phenylphenylethane, 2-phenylethen-1-yl, naphthyl, 2-naphthylethane, and 2-naphthylethylene. Burke, -14- (11) 200407121

Naphthobenzyl, 2-naphthophenylethane_buyl, and the like. When a specific nicotyl moiety is required, the names of square radical, arylalkenyl and / or arylalkynyl are used. Preferably, the aryl hydrocarbon group is a (C0-C3G) aryl hydrocarbon group, for example, the alkyl, alkenyl or alkynyl portion of the arylnicotinyl group is a (c "Ci.) Hydrocarbon group, and the aryl portion is (G -Cm) aryl group, more preferably aryl hydrocarbon group is (C6_C20) aryl hydrocarbon group, for example, the fluorene and fluorenyl moieties of the aryl hydrocarbon group are (C) -C8) hydrocarbon *, and the aryl moieties are C6_c] 2) an aryl group, and more preferably an aryl hydrocarbon group is a (C6-Ci5) aryl hydrocarbon group, for example, the aryl hydrocarbon group is a (C6-Ci) aryl group, and The aryl moiety is (c6-c1 ()) aryl. "Aryloxy" itself or as other substituents-part is a group of the general formula -0-Square, where the Square is as defined herein . "Square alkoxy" itself or as part of other substituents represents a group of the general formula arylalkyl, wherein arylalkyl is as defined herein.

"Aryloxy group" herein or as part of other substituents refers to a group of the general formula -C (0) -0-aryl, where aryl is as defined herein. "Aminomethylamino" itself or as part of other substituents is a group represented by the general formula-C (O) NR32R33, wherein R32 and R33 are each independently selected from hydrogen, nicotinyl and cyclonicotinyl as defined herein, or R3 2 and R3 3 together with the nitrogen atom to which they are bonded form a heterocyclic hydrocarbon ring as defined herein. "Compounds of the invention" means compounds covered by the descriptions and formulae disclosed herein. The compounds of the present invention can be identified by their chemical structure and / or chemical name. When the chemical structure does not match the chemical name, confirm the compound by the chemical -15- (12) (12) 200407121 structure. The compounds of the present invention may contain one or more palmar centers and / or double bonds, so stereoisomers such as double bond isomers (ie geometric isomers), rotational isomers, and mirror isomers Or non-mirromeric isomers. Therefore, when the stereochemistry of the palmar centers is not specified, the chemical structure shown in the present invention covers all possible configurations of the palmar centers, including those with stereoisomeric purity (such as geometrically isomeric purity, Mirror-isomer purity or non-mirro-isomer purity) and mirror-isomer and stereoisomer mixtures. Enantiomeric and stereoisomeric mixtures can be separated into their constituent enantiomers or stereoisomers using separation techniques well-known to those skilled in the art or homogeneous synthesis techniques. The compounds of the present invention may also exist in several tautomeric forms, including alcohol-burning forms, ketone forms, and mixtures thereof. It is for this reason that the chemical structure shown in the present invention covers all possible tautomeric forms of the illustrated compounds. The compounds of the present invention may also include isotopically labeled compounds in which one or more atoms have an atomic weight different from that found in traditional nature. Examples of isotopes that can be incorporated in the compounds of the present invention include, but are not limited to, 2H, 3H, I3C, MC, 5N, 80, 17O, 31p, 32p, 35S, 8F, and 3 6 C 1. The compounds of the present invention may be in unfused and fused forms, including hydrated forms and N-oxides. Generally, the hydrated, fused and N_oxide forms are encompassed within the scope of the invention. Specific compounds of the invention may have multiple crystalline or amorphous forms. In general, all physical forms have the same effect on the application of the present invention and are included in the scope of the present invention. "Cycloalkyl" as such or as part of another substituent means a saturated or unsaturated cyclic hydrocarbon, as defined herein. When a specific degree of saturation is required, 'the name "cycloalkyl" or "cycloalkenyl" is used. Typical cyclic hydrocarbon groups include -16- (13) 200407121 including (but not limited to) groups derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like. The cyclic hydrocarbon group preferably includes 3 to 10 ring atoms (C3-c10 ring nicotyl), and more preferably 3 to 7 ring atoms (C 3-c 7 ring nicotyl).

"Cyclo nicotinyl" itself or as part of other substituents means a saturated or unsaturated cyclic alkyl group, in which one or more carbon atoms (and optionally any hydrogen atom combined) are individually the same or different Replaced by heteroatoms. Typical heteroatom systems used to replace carbon atoms include, but are not limited to, N, P, 0, S, Si, and the like. When specific saturation is required, use the name "cycloheteroalkyl" or "cycloheteroalkenyl". Typical cycloheterohydrocarbyl systems include, but are not limited to, self-epoxy, azacyclopropane, thiacyclopropane, imidazolidine, morpholine, piperidine, piperidine, pyrazolidine, pyrrolidone, feedpyridine, and the like By. The cyclic heteroalkyl group is preferably 3 J to 10 ring atoms (3 to 10-membered ring heteroalkyl), and more preferably 3 to 7 members (3 to 7-membered ring heteroalkyl).

"Dihydrocarbylamino" itself or as part of other substituents represents a group of general formula R, where R34 and R35 are each selected from hydrocarbon and cyclic hydrocarbon groups, as defined herein. : Representative examples of hydrocarbon amines include (but are not limited to) dimethylamino, methylethylamino, bis (h methylethyl) amino, (cyclohexyl) (methyl) amine, (cyclo Hexyl) (ethyl) limb, (cyclohexyl) (propyl) amine and the like. "Halogen" or "halo" itself or as part of other substituents-means fluorine, chlorine, bromine and / or iodo. "Choketenyl" itself or as part of other substituents means a hydrocarbon a 'as defined herein in which-or more hydrogen atoms are replaced by a dentate. -17- (14) 200407121 "Haloalkyl" includes monohalo, dihalo, trihalo, etc. to perhalo. The halo groups of the substituted haloalkyl group may be the same or different. For example, "(Ci-G) haloalkyl" includes 1-fluoromethyl, 1-fluoro-2-chloroethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, difluoroethyl, 1,2-difluoroethyl, 1,1,1-trifluoroethyl, perfluoroethyl and the like.

"Heteroaryl" itself or as part of another substituent means a monovalent heteroaromatic group derived from the removal of a hydrogen atom from a parent heteroaromatic ring system as defined herein. Typical heteroaryl systems include, but are not limited to, groups derived from the following: ^ [alpha] pyridine, arsenic miscellaneous, D card, D seat, / 3 -yteolin, chroman, chromene, perylene, furan, imidazole , Indazole, indole, indolin, indole, isobenzofuran, isochromene, isoindole, isoindole, isoquinoline, isothiazole, isoDfazole, naphthyridine, Df diazole, Hexazole, oxidine, phenanthridine, phenanthroline, phenanthrene, phthalocyanine, pteridine, purine, pyran, pyran, pyridazole, pyridin, pyrimidine, pyrimidine, roar, roar, roar, D Quinazoline, hexoline, D quinoline, quinhumline, tetrazole, thiadiazole, thiazole, thiophene, triazole, gutton, and the like. The heteroaryl group preferably contains 5 to 20 ring atoms (5 to 20 member heteroaryl groups), and more preferably 5 to 10 ring atoms (5 to 10 member heteroaryl groups). Preferred heteroaryls are derived from thiophene, pyrrole, benzothiophene, benzofuran, indole, pyridine, quinoline, imidazole, oxazole and pyracin. "Heterocycle" means a compound covered by the definition of ^ B-ring "shown herein. The compound can be aromatic or non-aromatic (hydroisomer). The B-ring has the following general formula:

-18- (15) 200407121 CH, or fluorenyl, hydrocarbyl, low-substituted oxyoxy, monohydrocarbyl, hydrocarbyl, oxoyl, methyl, methyl, `` L_,

Yi encompasses one to four heteroatoms, where X, Y, and Z are each C, N, NR16, NR18, S, or 0; and U and T are each G, CH J. R1 6 and R18 are each selected from hydrogen, lower hydrocarbon, substituted lower hydrocarbon lower heteroalkyl, substituted lower heterocarbon, cyclic hydrocarbon, substituted ring, cycloheterocarbon, substituted cycloheterocarbon, low halogen hydrocarbon , Monohalomethyl monohalomethyl, trihalomethyl, trifluoromethyl, low hydrocarbon thio, substituted hydrocarbon thio, low alkoxy, substituted low alkoxy, methoxy, Oxy, low heteroalkoxy, substituted low heteroalkoxy, ring smoke, substituted cycloalkoxy, cycloheteroalkoxy, substituted cycloheterocarbon, low halogen alkoxy, monohalo Methoxy, dihalomethoxy, trihalomethoxytrifluoromethoxy, oligo- or monohydrocarbylamino, substituted oligo-orylamino, aryl, substituted aryl, aromatic Oxy, substituted arylbenzyloxy, substituted benzyloxy, arylhydrocarbyl, substituted aryl, square alkoxy, substituted arylhydrocarbyl, benzyl, benzyloxy ^^ Masonry-substituted heterosquaryl, heteroaryloxy, substituted heteroaryl-squaryl k-group, substituted heteroarylalkyl, heteroarylhydrocarbyl ^ substituted squarylalkoxy, carboxyl ,low Oxycarbonyl, substituted k-carbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylhydrocarbyloxy-substituted arylhydrocarbyloxycarbonyl, carbamate, substituted amine: 2. Substituted aminomethyl amidino group, aminosulfonyl substituted amino group and other groups. The group "wherein" is a linking group, and r 1 7 γ-1 — is a cyclic hydrocarbon group, a substituted cyclic hydrocarbon group, or a substituted cerium group. The linker can be any suitable

-19- (16) 200407121 In the atomic group that connects the R 17 moiety to a nitrogen atom. Suitable linking systems include, but are not limited to, selected from-(CH2) 1-6-, S, -C (0)-, -S02-, -NH-, -C (0) -S02NH-, and combinations thereof The part of things.

Suitable heterocyclic systems include, for example, isoxazole, pyrazole, oxadiazole, humidazole, thiazole, imidazole, triazole, thiadiazole, and their hydrogenated isomers. Suitable hydrogenated isomers of the aforementioned heterocyclic compounds include, for example, dihydroisomers and tetrahydroisomers. The hydrogenated isomer system includes, for example, 2-isoxazoline, 3-isoxazoline, 4-isoDfazoline, isoxazoline, 1,2-pyrazoline, 1,2-pyrazolidine, (3H) -dihydro-dihydro-1,2,4-fluorene f-diazole, (511) -dihydro-i, 2,4-oxadiazole, humazoline, oxazolidine, (3 Η) -Dihydrothiazole, (5 Η) -dihydrothiazole, thiazolidine (tetrahydrothiazole), (3 Η) -dihydrotriazole, (5 Η) -dihydrotriazole, triazolidine (tetrahydrotriazole ), Dihydro-Df two-seat sitting, tetrahydroming diamidine sitting, (3 Η) -dihydro-1,2,4-thiadiazole, (5 Η) -dihydro-1,2,4-thia Diazole, 1,2,4-thiadiazolidine (tetrahydrothiadiazole), (3Η) -dihydroimidazole, (5Η) -dihydroimidazole and tetrahydroimidazole.

"Parent aromatic ring system" means an unsaturated cyclic or polycyclic system having a conjugated π-electron system. "Parent aromatic ring systems" specifically include fused ring systems in which one or more soil systems are square, and one or more ring systems are saturated or unsaturated, such as manganese, hydrogen indene, indene, Benlin and others. Typical parent aromatic family 1 ring systems include (but are not limited to) vinegar, onion, phenanthrene, anthracene, methane, benzene, pyrene, halobenzene, fluoranthene, pyrene, hexaphenylene, hexabenzene, hexene, as -indene, s -indene, hydroindene, indene, naphthalene, octyl, octaphenidene, ovene, penta-2,4-dioxin, pentaene, pentaene, pentabenzene, pyrene, benzene Lin (phenalene), phenanthrene, pinene, pyrene, anthracene, jade red province, Sanya-20- (17) (17) 200407121 benzene, Sancai and the like. "Parent heteroaromatic ring system" means a parent aromatic ring system in which one or more carbon atoms (and optionally any hydrogen atoms combined) are individually replaced by the same or different heteroatoms. Typical heteroatoms used to replace the carbon atom include, but are not limited to, N, P, 0, S, Si, and the like. "Parent heteroaromatic ring systems" specifically include fused ring systems in which one or more ring systems are aromatic rings and one or more ring systems are saturated or unsaturated, such as, for example, arsenin, benzo Dioxane, benzofuran, chroman, chromene, indole, indolin, and so on. Typical parent heteroaromatic ring systems include (but are not limited to) arsenic heterocycles, carbazides, / 3-yteolin, chroman, chroman, phosphine, sulfan, imidazole, indazole, indole, indole Porphyrin, indole, isobenzofuran, isochromene, n-isophthalene, iso-isophthalene, iso-isoquinine, isothiazine, isoisocyanate DD sitting, Df I] sitting, 卩 white 定 ding, phenanthrene [] ding, phenanthroline, phenoxine, oxox, butterfly ?, purhaji, roar, roar, roar, roar, Dwell, Dtt定 ding, pyridine, pyrrole, pyrroline, quinazoline, D-quinoline, zanolinline, D-quinoline, tetra-Wa, thiadiazole, thiazole, thiophene, triazole, gluten, and the like . "Pharmaceutically acceptable salt" means that the compound of the present invention is a salt prepared by using a counter ion generally acceptable for medical purposes, and has the required pharmacological activity of the parent compound. The salt system includes: (1) an acid addition salt formed using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or an organic acid such as acetic acid, propionic acid, hexanoic acid, and cyclopentane Propionic acid, glycolic acid, pyruvate, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzyl acid, 3 4 _hydroxy; 醯) benzyl acid , Cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1, 2 _ Yiyuan_ -21-(18) (18) 200407121 *-δ flavonic acid, 2-acetyl acetic acid, benzenesulfonic acid, 4-Chlorobenzoic acid, 2-naphthoic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2 Buxin-2_fuel_formic acid, glucoheptonic acid, 3-benzene Formed from propionic acid, trimethylacetic acid, third butylacetic acid, laurylsulfuric acid, gluconic acid, glutaric acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or ( 2) A salt formed when the acidic proton contained in the compound of the present invention is replaced by a metal ion (such as an alkali metal ion, an alkaline earth metal ion, or an aluminum ion); or an organic base such as ethanolamine, Alcohol amines, triethanolamine, Ν - methyl-glucosamine, morpholine Fu morpholine, piperidine, dimethylamine, diethylamine and the person class of ligands thereof. Also included are salts of amino acids such as arginine and the like, and organic acids such as glucurmic acid or galacturonic acid and the like (see, for example, Berge et al., 1 9 77 , J. P / zwi Sc, 66: 1 -1 9). "Pharmaceutically acceptable adjuvant" means a diluent, adjuvant, excipient, or carrier administered concurrently with a compound of the invention. "Protective group" means an atomic group that masks, reduces, or prevents the reactivity of a functional group when attached to a reactive functional group in a molecule. Protecting groups can generally be selectively removed during synthesis. Examples of protecting groups can be found in Greene and Wuts, Protective Groups in Organic Chemistry, 3rd Ed., 1 999, John Wiley & Sons, NY and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8, 1 97 1 -1 996, John Wiley & S ο ns, NY. Representative amine protecting groups include, but are not limited to, methylamyl, ethylamyl, trifluoroacetamyl, benzyl, benzyloxycarbonyl ("CBZ"), third butoxycarbonyl ("Boc"), Trimethylsilyl ("TMS"), 2-trimethylsilyl-ethanesulfonyl (19) (19) 200407121 ("SES"), diphenylmethyl, allyloxycarbonyl, 9_ Fluorenylmethoxycarbonyl ('FMOC), nitro-quinoa ("NVOC") and the like. Representative radical protecting groups include (but are not limited to) those in which the radical is halogenated (for example, methyl and ethyl acetate, acetate or propionate or glycol ester) or nicotinated, such as And dibenzyl methyl ethers, and hydrocarbyl ethers, tetrahydropyrans, dimeryl methyl ether; Ibr; base acids (such as TMS or Tipps groups) and propyl ether. "Then drive music" thinks about the active compound derivative that is transformed under the conditions of use (such as in the body) to release the active drug. Prodrugs are often (but not necessarily) medically inert when they are converted into active animals. Prodrugs are generally prepared by using a precursor group (defined below) to mask the functional groups required to believe part of the activity of the drug to form a precursor moiety that undergoes transformation (such as ablation) under specific conditions of use, In order to release the functional group, the active drug is released. The excision of the precursor portion can be performed spontaneously (such as by a hydrolysis reaction), or it can be catalyzed or induced by other reagents (such as enzymes, light, acids, or changes or exposure to physical or environmental factors, such as temperature changes). The reagent may be endogenous to the conditions of use, such as enzymes present in the cells to which the prodrug is administered or acidic conditions of the stomach, or it may be provided from the outside. In a particular embodiment, the term prodrug includes a hydrogenated isomer of a compound of the invention. The hydrogenated isomers covered by the present invention can be oxidized to corresponding aromatic ring systems under physiological conditions. Various precursor groups (and precursor moieties formed) suitable for masking functional groups in active compounds to produce prodrugs are well known in the art. For example, a hydroxy-functional group can be masked to become a sulfonate, ester, or carbonate precursor. Its 23- (20) (20) 200407121 can be hydrolyzed to generate a hydroxyl group. The amine functional group can be masked as a sulfonium, imine, phosphine, phosphonium, phosphonium or sulfenyl precursor moiety, which can be hydrolyzed to produce an amine group. Carboxyl groups can be masked into esters (including silyl esters and thioesters), amidines, or amidine precursors, which can be hydrolyzed to produce carboxyl groups. Other specific examples of suitable precursor groups and their individual precursor portions are known to those skilled in the art. "Precursor group" means a protective group that forms a precursor when masking a functional group in an active drug and converts the drug into a prodrug. Protecting groups are typically attached to the functional group of the drug via a bond that can be cleaved under specific conditions of use. Therefore, prodrugs are prodrugs that excise and release functional bases under specific conditions of use. A specific example of the general formula -NH-C (O) CH3 contains a precursor group -C (O) CH3. "Silyl ether" refers to a protective group that converts a drug into a prodrug when it is used to mask a hydroxyl group in an active drug to form a precursor. Silyl ethers are known in the art and represent a removable gas that prevents the radical from participating in the reaction that takes place on the molecule. These groups are discussed by TW Greene in Protective Groups in Organic Synthesis, John Wiley and Sons, New York, Chapters 2 and 7 of 1981, and Protective Groups in Organic Synthesis by JW Barton Order, JF W McOmie, ed ., Plenum press, New York, 1 973 Chapter 2 discusses' The entire text is incorporated herein by reference. The silyl ether system includes, for example, trimethylsilyl, triethylsilyl, third butyldimethylsilyl, and methyldiisopropylsilyl. "Substituted" when used to modify a specific group or atomic group means that one or more hydrogen atoms of a given group or atomic group are individually replaced by the same or different substituents. Typical substituent systems include (but are not limited to) -M, -R40, -〇 ·, = 0, -OR40, -SR40, -S- ,, = S, -NR40R41, = NR40, -CM3 ,, CF3,- CN, -OCN, -SCN, -NO, -N02, = N2, -N3, -S (0) 2〇-, -S (0) 2〇H, -s (o) 2r40, -os (o) 2〇-, -os (o) 2R40, -P (〇) (CT) 2,

-P (O) (OR40) (〇 ·), -〇P (〇) (〇R40) (〇R4]), -c (o) R40,, C (S) R40, -C (〇) OR40, -c (o) nr40r41, -c (o) cr, -C (S) OR40, -NR42C (O) NR40R4], -NR42C (S) NR40R4], -NR42C (NR43) NR4 () R4] and -C (NR42) NR4 () R41 where M is each halogen; R4G, R41, R42, R43 and R44 are each selected from hydrogen, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted hydrocarbyl, cyclic hydrocarbyl, Substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl,

-NR45R46, -C (0) R45, and -S (0) 2R45, or R4. And R4] and / or R45 and R46 together with the nitrogen atom to which they are bonded may form a cycloheteroalkyl group or a substituted cycloheteroalkyl group ring as defined herein. "Aminosulfonyl" itself or as part of other substituents represents a group of the general formula -S (〇) 2NR36R37, where R36 and r37 are each hydrogen, nicotinyl or cyclonicotinyl, Or R36 and R37 together with the nitrogen atom to which they are bonded form a cycloheteroalkyl or substituted cycloheteroalkyl ring as defined herein. 7 · Compounds In the conventional examples, the compounds of the present invention are the structured formula (I) -25- (22) 200407121 pyridyl-substituted heterocycles and cyclohydroisomers: R7

Or a pharmaceutically acceptable salt, hydrate, solvate, or N-oxide thereof, wherein: the B ring system is an aromatic or non-aromatic ring including one to four heteroatoms, of which X, Y, and Z glj Selected from C, CH, N, NR16, NRI8, S or 0, the prerequisite is that X and Y are not 0 at the same time; U and T are individually selected from C, CH or N; Z is N or -C Η-;

A is N or -CR2-; B is N or -CR3-; D is N or -CR4-; E is N or -CR5-; G is N or -CR6-; J is N or -CR14-; K is N or -CR8-; L is N or -CR9-; M is N or -CR 1G; R2 and R6 are each selected from hydrogen, halo, fluorine, chlorine, hydrocarbon, methyl , -26- (23) 200407121 Substituted hydrocarbyl, isopropoxycarbonyl, aryl, substituted aminomethylamidoaminosulfonyl group conditions are R2 $ R3 and P group, hydrocarbylthio, hydrocarbyloxy The carbonyl aryl hydrocarbyl group, fluorenyl group and halocarbon R4 are selected from substituted alkoxy groups, and the aryloxycarbonyl moonylsulfonyl sulfonyl group f is R8, R9 R1 ] Is R12 system, dichloromethyl 'hydrocarbylthio, substituted hydrocarbylthio, hydrocarbyloxy, sulfonyl, substituted hydrocarbyloxy, oxymolybdenyl, substituted Furnace-based oxyalkoxy, substituted arylhydrocarbyl, reedyl; aryloxyfluorenyl, cycloheteroalkyl, substituted cycloheterodi, substituted aminocarbyl, haloalkyl, triphenyl Fluoromethyl,, substituted amine fluorenyl and methyl fluorenyl-, their prerequisites [one of R6 is not hydrogen; [individually selected from , Halo, aerosyl radical, hydrocarbyl, substituted hydrocarbon, substituted nicotylthio, substituted oxyoxy group of flue gas, substituted hydrocarbyloxy group, aryl hydrocarbyloxycarbonyl group, Taken oxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheterocyclic cycloheteroalkyl, aminoformyl, substituted aminomethyl, aminosulfonyl and substituted aminosulfonyl Fluorenyl; self-hydrogen, halo, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, thio, fe: methylformyl, substituted aminoformyl, hydrocarbyl nicotinyloxy, nicotinyloxy , Substituted hydrocarbyl, base, substituted squenyl oxynitride, aramid, substituted, dihydrocarbyl, substituted dihydrocarbyl, halocarbyl, and substituted Aminosulfonyl; -NR ^ C (0) R12;, R1G and R14 are each selected from hydrogen, halo and fluorine; f hydrogen, hydrocarbyl or methyl; and i substituted hydrocarbyl, halohydrocarbyl, halomethyl , Dihalomethyl, cycloheteroalkyl or substituted cycloheteroalkyl;

-27- (24) (24) 200407121 R 16 and R 18 are each selected from hydrogen, lower hydrocarbon, substituted lower hydrocarbon, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, ring Heterohydrocarbyl, substituted cycloheterohydrocarbyl, low-halogenated hydrocarbon, monohalomethyl, dihalomethyl, trihalomethyl, trifluoromethyl, low-hydrocarbon sulfur, substituted low-hydrocarbon sulfur, low-hydrocarbon oxygen Radical, substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, ring Heteroalkoxy, substituted cycloheteroalkoxy, low-haloalkoxy, mono-methoxy, dihalomethoxy, trihalomethoxy, trifluoromethoxy, lower di- or monohydrocarbyl Amino, substituted lower di- or monohydrocarbylamino, aryl, substituted aryl, aryloxy, substituted aryloxy, phenoxy, substituted phenoxy, arylhydrocarbyl, Substituted arylhydrocarbyl, arylalkoxy, substituted arylalkoxy, benzyl, benzyloxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryl oxygen , Heteroaryl hydrocarbyl, substituted heteroaryl hydrocarbyl, heteroaryl hydrocarbyloxy, substituted heteroaryl hydrocarbyloxy, carboxyl, low hydrocarbyloxy, substituted low hydrocarbyloxy, aryloxycarbonyl, Substituted aryloxycarbonyl, aryl hydrocarbon oxycarbonyl, substituted aryl hydrocarbon oxycarbonyl, carbamate, substituted carbamate, aminoformyl, substituted carbamate Group, aminosulfonyl group, substituted aminosulfonyl group and groups of the general formula -L-R17, where ^ "is a linking group, and R17 is a cyclic hydrocarbon group, a substituted cyclic hydrocarbon group, a cyclic group Heteroalkyl or substituted cycloheteroalkyl. Its prerequisites are: (i) at least one of A, B, D, E, G, J, K, L or M is N; -28- (25) 200407121 (ii) six, eight, zero, £ Or no more than one is 1 ^; and no more than one of K, L, or M is N.

(ill; J In another embodiment, the compound of the present invention is a substituted or substituted B-cyclochlorinated isomer of structural formula (π):

N J ~ <

') _X / / K

SM = L or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, of which eight, eight, zero, £, 0,], 1 ^, 1 ^, ^ 4 and 117 are as before The general formula (I) is defined and has the same prerequisites and --... represents an aromatic or non-aromatic (hydroisomer) heterocyclic ring. In one embodiment of the compound of formula (I), Z is -CH_, so that the compound is iso-Dfazole or pyrazole. In another embodiment of the compound of formula (I), Z is N, so that the compound is Ilf = azole or azole. In another embodiment, the compound of structural formula (I) is an isomeric |] sitting group. In a specific embodiment of the isoxazoles, X is N and Y is 0. In another embodiment, the compound of structural formula (I) is a humidazole. In one embodiment of the compounds of structural formulae (I) and (π), A, B, D, E or G is N, and one of J, K, L or M is n. In another embodiment, one of A, b, D, E, or G is N, and j, k, L, or M is not N. In another embodiment, none of A, B, D, E, or G is N, and one of -29- (26) 200407121 J, K, L, or M is N. In any of the foregoing embodiments of the general formula (I) and / or (II), r7 is -NRl lc (0) R12, where R11 is hydrogen or methyl, and R12 is _CHC12.

In another embodiment of the compounds of structural formulae (I) and (Π), 'A is -CR2-, G is -CR6-, and R7 is -NR ^ C (0) R12', wherein R11 is hydrogen or Methyl, and R12 is _CHCl2. In a more specific embodiment, B is -CR3-, D is N, E is -CR5-, J is -CR14-, K is -CR8-, L is -CR9-, and M is- CR1G-, and R3, R5, R9, R1G and R14 are each hydrogen. In another more specific embodiment, B is -CR3-, D is -CR4-, E is -CR5-, J is -CR14-, K is -CR8-, and L is -CR9-, M is N, and R3, R4, R5, R8, R9, and R14 are each hydrogen. In another more specific embodiment, B is -CRl, D is-CR4-, E is-CR5-, J is-CR14-, K is -CR8-, L is N, and M is -CR1G-, and R3, R4, R5, R8, R] () and R14 are each hydrogen. In the foregoing embodiment, R2 and R6 are each independently selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, N-morpholinyl and N-morpholinamine. Sulfosulfenyl is preferred. R2 and R6 are each preferably selected from chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. In another embodiment, R2 and R6 are each the same or different halo group. In the foregoing embodiment, X is preferably N, Y is 0, and Z is -C Η-. In another embodiment of the compounds of structural formulae (I) and (Π), A is -CR2-, G is -CR6- and R7 is -NRMC (0) R12, wherein R11 is hydrogen or methyl, And R12 is -CH2I. R2 and R6 are each independently selected from the group consisting of chloro, fluoro, methyl, trifluoromethyl, thiomethyl, methoxy, and isopropyloxy. 30- (27) 200407121 group, N-morpholinyl and N-morpho Phenolinamine fluorenyl is preferred. r 2 and r 6 are each preferably selected from chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. In another embodiment, R2 and R6 are each the same or different halo group. In the foregoing embodiment, X is preferably N, Y is 0, and Z is -C Η-.

In another embodiment of the compounds of structural formulae (I) and (11), A is -CR2-, B is -CR3-, and R7 is -NRuC (〇) R12, wherein R 1 1 is hydrogen or formaldehyde. And R] 2 is -CHC 12. In a more specific embodiment, D is -CR4-, G is -CR6-, E is -CR5-, J is -CR] 4, K is -CR8-, and L is -CR9-, M is N, and R4, R5, R6, R8, R9 and r14 are each ammonia. In a more specific embodiment, D is -CR4-, G is -CR6-, E is -CR5-, J is -CR14-, K is -CR8-, L is N-, and M is -CR] G-, and each of R4, R5, R6, R8, R1 (), and R14 is hydrogen. R2 and R6 are each selected from the group consisting of chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, N-morpholinyl and N-morpholinaminosulfonyl groups as good. R2 and R6 are each preferably selected from chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropoxy. In another embodiment, R2 and R6 are each the same or different halo group. In the foregoing embodiment, X is preferably N, Y is 0, and Z is preferably -CH-.

In another embodiment of the compounds of the formulae (I) and (Π), A is -CR2-, G is -CR6-, and R2 and R6 are each the same. The prerequisite is that they are not hydrogen. In another embodiment, A is -CR2-, B is -CR3-, and R2 and R3 are each the same. The prerequisite is that it is not hydrogen. In another embodiment, B is -CR3-, E is -CR5-, and R3 and R5 are each the same. The prerequisite is that they are not hydrogen. In another embodiment, B is -CR3-, D -31-(28) 200407121 is-CR4-, E is-CR5-, j is-CR14-, K is-CR8-, and R3 , R4, R5, R8 and R14 are each hydrogen. In another embodiment, D is -CR4-, E is -CR5-, G is CR6, J is -CR14-, K is-CR8-, and R4, R5, R6, R8, and R14 are each For hydrogen. In another embodiment, the compound of structural formula (I) and its B-ring hydrogenated isomer system include a C ring, which is a Dtt D-A-3 group.

In another embodiment, the compound of formula (I) and its B ring hydrogenated isomer system include a C ring, which is pyridin-4-yl. In another embodiment, the compound of structural formula (I) is an isoxazole compound of structural formula (la), (lb), (Ic), (Id), or (Ie):

-32- (29) (29) 200407121

Or a pharmaceutically acceptable salt, hydrate or solvate thereof, wherein X, Y, R2, R6, Rn, and R12 are as defined above for the structural formula (I), and--represents an unsaturated bond of the B ring (Aromatic heterocycles) or saturated bonds (non-aromatic heterocycles, such as hydrogenated isomers). In one embodiment, the compounds of structural formula (la), (lb), (Ic), (Id), or (Ie) each have one or more characteristics selected from the following: X is 0 and Y is N; X Is N and Y is 0; R 1] is hydrogen; R 1 2 is dichloromethyl; R 2 and R 6 are each selected from methyl, halo, fluorine, chlorine, trifluoromethyl, and methoxy And R2 and R6 are each selected from halo, fluorine and chlorine. -33- (30) 200407121 In another aspect of the present invention, X is N, Υ is 0, Z is m CH, and D and U are C '(骞 humazole ring)' A is-CR: 2- 9 G system 舄, CR6 1-〇 In another example of the present invention, X is N, Υ is 〇, Z is CH, D and U are C (iso-Dfazole ring), and A is-CR : 1-1 G CRe, where R6 is erphine or Jing Jing and replaced by plowing. Appropriately taken # Pipeline systems include for example

N-Boc

In another aspect of the present invention, X system is N, Y system is 0, Z system is CH2, T and u system are C (isoimidazole ring), A system is-CR2-, and G system is -C-0H. 'Let R6 form an ester, ether or silyl ether. Suitable r6 groups to form vinegar, methyl or silyl ether include, for example, hydrocarbyl, methyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbyloxy, methoxy, isopropyloxy , Substituted hydrocarbyloxy, hydrocarbyloxy, substituted nicotinyl, aryl hydrocarbyloxy, substituted aryl hydrocarbyloxy, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheteroalkyl, Substituted cycloheteroalkyl, aminoformyl, substituted aminoformyl, haloalkyl, trifluoromethyl and silyl ether. Exemplified compounds of the invention are shown in Figures 丨 and Tables. Those skilled in the art will appreciate that the compounds described in this invention may include functional groups that can be masked with precursor groups to produce a prodrug. The prodrug is usually (but not necessarily) medically inert before being converted into its active drug form. In the prodrug of the present invention, any effective functional group moiety can be masked with a precursor group to generate a prodrug. Many precursor groups suitable for masking this functional group to produce a precursor moiety that can be excised under the desired conditions of use are known in the art.

7.1 Synthesis method The compound of the present invention can be prepared by the synthesis method illustrated in Figs. 2 to 7. It should be understood that in Figures 2 to 7, A, B, D, E "G, J, K, L, M and R7 are as defined in the foregoing structural formula (I) and have the same proviso. They can be used in the preparation of the present invention The starting materials of the compounds and their intermediates are commercially available or can be prepared by well-known synthetic methods (see, for example, Harrison et al., "Compendium of Synthetic Organic Methods", Vo 1 s. 1-8, John Wiley and Sons, 1971 -1996; "Beilstein

Handbook of Organic Chemistry, `` B ei 1 stein Institute of Organic Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for Organic Synthesis," Volumes 1-17, Wiley Interscience; Trost et al., "Comprehensive Organic Synthesis," Perga m on Press, 1991; “Theilheimer's

Synthetic Methods of Organic Chemistry, "Volumes 1-45, Karger, 19 9 1; March," Advanced Organic Chemistry, "Wiley Interscience, 1991; La rock" Comprehensive Organic Transformations, "VCH Publishers, 1 9 8 9; Paquette,-- 35- (32) (32) 200407121 "Encyclopedia of Reagents for Organic Synthesis," John Wiley & Sons, 1995). Other methods and / or starting materials used to synthesize the compounds described herein are described in the technology Those who are familiar with this technology are known to those skilled in the art. The reagents and / or protective base alternatives illustrated in Figures 2 to 7 can refer to the aforementioned references and other outlines known to those skilled in the art. Choose the appropriate one Guiding principles of protecting groups can be referred to, for example, Greene & Wuts, "Protective Groups in Organic Synthesis", Wiley Inter science, 1999. Therefore, the synthesis methods and strategies presented in this article are for illustration, not limitation. One kind of synthesis The method of the substituted isomorphone D structure (Z-CH-) of structural formula (I) is shown in FIG. 2A. Referring to FIG. 2A, methyl ketone 201 and benzaldehyde 203 are Condensation of aldol under normal conditions, followed by dehydration at the chen site, to produce α-/ 3 unsaturated dilute ketones 2 05, which can be easily converted to isoxazole 207 by reduction of 20 7 to produce amines Ji Yi Yin _ 209, which can be converted into the stomach by various methods familiar to those skilled in the art, and finally ^ Niu 2 11. The special example of the synthetic method in Figure 2a is used to illustrate the isomorphazole 9 in Figure 2b. Preparation. Another method for synthesizing substituted isonf D structures of structural formula (I) (where Z is -CH-) is shown in Fig. 3A. Clay of methyl ketone 201 and vinegar 223 under alkaline conditions (C 1 aise η) condensation; 1,3 _ dione 2 2 9, which can be converted to a mixture of isoxazole 207 and 231 by hydroxylamine treatment). Taurogen produces amine isomers 209, li: can be transformed into isomers by well-known synthetic methods _ 2 1 1. It should be noted that omas η 2 3 1 can be interspersed with the synthesis path and converted into different affinities卩 Sitting in the 2 1 1 area, the structure-36 > (33) 200407121 (regioisomer). A special example of the synthetic method of FIG. 3A is used to illustrate the preparation of isoDf D 9 in FIG. 3B. In another embodiment of the pathway illustrated in Figure 3A, the condensation of the ester 2 2 5 system with the methyl ketone 2 2 7 produces 1,3 dione 2 2 9 which is then taken through the rest of the aforementioned synthetic pathways.

Another method for synthesizing substituted isoDfazoles of structural formula (I) (Z is -CΗ-) is shown in Fig. 4A. The nucleophilic addition of hydroxylamine to benzophenone 2 4 5 produces an intermediate oxime, which is treated by N-chlorosuccinimide (NCS) to convert to α-chlorooxime 2 4 7. The dehydrohalogenation of α-chlorooxime 2 4 7 produces a transition alkyne, which undergoes a 1,3-dipolar cycloaddition with acetylene 20 to produce the desired iso-Dfazole 2 1 1. Acetylene M9 can be prepared from commercially available precursors by well-known synthetic methods. The specific example of the synthetic method in Fig. 4A is used to illustrate the preparation of isoxazole 9 in Fig. 4B. Figure 4C illustrates the preparation of Figure 4B acetylene 2 5 5. The same method can be used to prepare other pyridylacetylene compounds.

Another method for synthesizing substituted isohumazole of structural formula (I) (Z is -C) is shown in FIG. 5A. The nucleophilic addition of hydroxylamine to benzaldehyde 24 5 produces an intermediate oxime, which can be directly converted to alkynide 2 5 7 using Na 0 C 1. The 1,3-dipolar cycloaddition of acetylide 2 5 7 to methyl ketone 2 5 9 produces the desired isoxazole 211. Methyl ketone 259 can be easily prepared from commercially available compounds by well-known synthetic methods. The specific example of the synthetic method in Figure 5A illustrates the preparation of isoxazole 9 in Figure 5B. The methods described in the foregoing Figs. 2 to 5 can be easily used to synthesize pyrazoles by replacing hydroxyamine with hydrazine in the reaction sequence. In addition, those skilled in the art have already known -37- (34) (34) 200407121 that it is known that the isoxazole regioisomers illustrated in the foregoing Figures 2 to 5 can be replaced by the reactive functionality of only two different aromatic rings While synthesized. An example of this research is shown in Figure 4D, which is "reverse" isoxazole 262. As shown in FIG. 4D, the exchange of chloroxime and alkyne functionality of two different aromatic rings (ie, A and C rings) yields regioisoisoxazole 2 62 (compare 2 5 3 and 2 5 5 and 254 and 2 5 6). In addition, specific synthetic schemes can directly provide isomerizole regional isomers (eg, Figures 3A and 3B), which can be separated from each other using standard techniques. A method for synthesizing the structural formula (I) substituted Df and D (z is-) is shown in Fig. 6A. Referring to FIG. 6A, the nucleophilic addition of hydroxylamine to phenylcyanide 265 produces α-amino oxime 26 7, which can be condensed with fluorenyl chloride 269 after dehydration and reduction. 2D sitting 2 7 1. Amino group 2 0 2 7 1 can be converted into the final product by various methods known to those skilled in the art. -38- (35) (35) 200407121 Thiazole can be modified by routine of Figures 2 to 7 or by other well-known Technical preparation. 7.2 Assay for the regulation of H C V The compounds of the present invention are potent inhibitors of H C V replication and / or proliferation. The activity of the compound of the present invention is confirmed by a concentration test which is suitable for measuring the inhibition of virus or retrovirus replication or proliferation. This test is well known in the technical world. Specific examples of replicon assays suitable for confirming the activity of specific compounds are shown in the Examples section. Alternatively, the activity of the compound can be determined using quantitative Western (W e s t e r η) printing assays using labeled antibodies directed against the H C V protein. Another test that can be used to confirm the anti-HCV properties of various compounds of the present invention is described by Fournier, 1 998; Gen. Virol. 7 9 (1 0): 23 6 7 -2 3 74, which is disclosed as This article is incorporated by reference. According to this method, hepatocytes can be tested in this method to determine the absence of a specific test compound and the IC50 of the compound. In general, the active compound is an IC50 that has a range of about 1 mM or less in a particular assay (e.g., a compound concentration that reduces replication by 50% or reduces the measured H C V protein mass by 50%). I C 50 (for example) compounds of about 100 μM, 10 μM, 1 μM, 100 μM, 10 μM, 1 nM, or even lower ranges are particularly useful as therapeutic or preventive agents for treating or preventing H CV infection. Or the active compound is LD50 (the concentration of the compound that kills 50% of the virus) in the range of about 1 mM or less. Compounds with a lower LD50, such as about 100 μM, 10 μM, 1 μM, 100 nM, 10 nM, 1 nM, or even lower ranges are particularly useful as a therapeutic or-39-(36) (36) 200407121 A therapeutic or preventive agent to prevent HCV infection. 7.3 Application and administration The compound of the present invention and / or its composition can be used in various situations because of its ability to inhibit H c v replication and / or proliferation. For example, the compound of the present invention can be used as a control group in the cable test to confirm other stronger or less effective anti-HCV compounds. In another embodiment, the compound of the present invention and / or its composition can be used as a preservative or disinfectant for clinical equipment to prevent medical equipment and stocks from being contaminated by HCV virus. When used in such a case, the compound of the present invention and / or its composition can be applied to the sterilization at a concentration several times as high as that measured by the compound (eg, IX, 2 ×, 3 ×, 4 ×, 5 × or higher). Of the instrument. The compounds of the present invention and / or their compositions are particularly useful for treating and / or preventing HCV infection in animals and humans. In this case, the compound can be administered in the form of a cream, but is generally formulated as a pharmaceutical composition for administration. The actual composition required depends in particular on the method of administration and is known to those skilled in the art. Various suitable pharmaceutical compositions are described in, for example, 7? / 77 gf 0 77] Pharmaceutical Sciences, 17th ed., 1 9 8 9 o Formulations suitable for oral administration may be (a) liquid solutions such as effective An amount of the active compound is suspended in a diluent such as water, silane or PE (3400); (b) capsules, sachets or lozenges, each containing a predetermined amount of the active ingredient in the form of a liquid, solid, granule or gelatin; (C) a suspension in a suitable liquid; and (d) a suitable emulsion. Lozenge dosage forms may include lactose, sucrose, mannitol, sorbitol, calcium phosphate, corn flour, horse bell -40- (37 ) (37) 200407121 Potato flour, microcrystalline cellulose, gelatin, colloidal silica, talc, magnesium stearate, stearic acid and other excipients, colorants, additives, binders, diluents, buffers One or more of a pharmaceutical agent, a wetting agent, a preservative, a flavoring agent, a dye, a disintegrant, and a pharmaceutically compatible carrier. The medicinal tablet type may contain the active ingredient in a flavoring agent such as sucrose, and the tablet type Is contained in an inert matrix (such as gelatin with glycerol or sucrose with In addition to the active ingredients, the active ingredients in the Laber emulsion, gel and the like also contain carriers known in the technical field. The selected compound (alone or in combination with other appropriate ingredients) can be formulated into an aerosol. Aerosol formulations can be placed in high-pressure acceptable propellants such as dichlorodifluoromethane, propane, nitrogen, and the like. Suitable for rectal administration Formulations include, for example, suppositories, which consist of a packaged nucleic acid and a suppository base. Suitable suppository bases include natural or synthetic triglycerides or paraffin hydrocarbons. Alternatively, gelatin rectal capsules may be used. The selected compound and matrix (including, for example, liquid triglycerides, polyethylene glycols, and paraffin hydrocarbons). Suitable for parenteral (such as, for example, intra-articular (in joint), intravenous, intramuscular, intradermal) , Intraperitoneal, and subcutaneous routes) formulations for administration include aqueous and non-aqueous, isotonic sterile injection solutions, which contain antioxidants, buffers, bacteriostatic agents, and formulations that enable the formulation The isotonic solutes of the recipient, as well as aqueous and non-aqueous sterile suspensions, may contain suspending agents, solubilizers, thickeners, stabilizers, and preservatives. In carrying out the present invention, the composition may be, for example, borrowed Administration by intravenous infusion, oral, topical, intraperitoneal, intravesical -41-(38) 200407121 or intrathecally. Parenteral administration, oral administration, and intravenous administration are the preferred methods of administration. Compound formulation The material can be placed in single-dose or multi-dose sealed containers (such as ampoules and vials). Injectable solutions and suspensions can be prepared from the aforementioned types of sterile powders, granules, and lozenges.

The pharmaceutical preparation is preferably in a single dosage form. This form of preparation can be subdivided into unit dosage forms containing appropriate amounts of the active ingredient. The unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Moreover, the unit dosage form can be a capsule, dragee, sachet, or tablet itself, or it can be any suitable number of the foregoing in a packaged form. The composition may (if necessary) also contain other compatible therapeutic agents.

When used for treating HCV infection, the compound used in the medical method of the present invention can be administered to a patient diagnosed with HCV infection at a dosage level suitable for achieving a therapeutic effect. The therapeutic effect means that the administration of the compound produces a therapeutic effect in a patient's body over time. For example, when the number or content of HCV titers in a patient decreases or stops increasing, the therapeutic effect is achieved. If the administration of the compound slows down or completely stops the beginning of organ damage or other negative symptoms (usually accompanied by HCV infection), the therapeutic effect is also achieved, regardless of the HCV titration or content of the patient's body. The compound of the present invention and / or its composition can also be administered preventively to patients who are at risk of developing HCV infection or have been exposed to HCV to prevent the development of HCV infection. For example, the compound of the present invention and / or its composition can be administered to a hospital staff member who is accidentally injured by a needle while treating HCV patients to reduce or completely avoid the risk of developing HCV infection. -42-(39) (39) 200407121 The starting dose suitable for administration to humans can be determined by cable tests or animal models. For example, the starting dose can be adjusted to achieve a blood radon concentration including the specific compound to be administered when measured with a cable test. Or human starting doses can be based on doses found to be effective in animal models of HCV infection, as is well known in the art. Examples of suitable model systems are described in Muchm ore? 2 0 0 1, I mmum ο 1. Rev. 183: 86-93 and La n ford & Biggei ·, 2002, Virology 293 (i): 1-9 And its references, the disclosure of which is incorporated herein by reference. In one embodiment, the starting dose may be in the range of about 0.001 mg / kg to about 1000 mg / kg per day. A dosage range of about 0.01 mg / kg to about 500 mg / kg may also be used, or about 0.1 mg / kg to about 200 mg / kg, or about 1 mg / kg to about 100 mg / kg, or about 10 Mg / kg to about 50 mg / kg. However, the dosage may depend on the needs of the patient, the severity of the symptoms to be treated, and the compound to be used. The size of the dose is also determined by the presence, nature, and extent of any side effects when a particular compound is administered in a particular patient. The determination of a dosage suitable for a particular situation is within the skill of the practitioner. Generally, treatment is initiated with a lower dose (below the optimal dose of the compound). Thereafter, increase the dose in low radon increments to achieve the best results in this case. It is convenient to divide the total daily dose into several portions and administer them in divided portions throughout the day (if required). 7.4 Combination therapy In certain embodiments of the present invention, the compound of the present invention and / or its composition can be used in combination therapy with at least one other therapeutic agent. The compound of the present invention and / -43- (40) (40) 200407121 or a composition thereof can act additively or (more preferably) synergistically with the therapeutic agent. In a preferred embodiment, the compound of the present invention and / or its composition is administered simultaneously with another therapeutic agent. In another embodiment, the compound of the present invention and / or its composition is administered before or after the administration of another therapeutic agent. Formula < In the examples, the compound of the present invention and / or its composition can be used in combination therapy with other antiviral agents. In one embodiment, the compound of the present invention and / or its composition can be used in combination therapy with interferon-α. In another embodiment, the compound of the present invention and / or its composition can be used in combination therapy with ribavirin. In another embodiment, the compound of the present invention and / or its composition can be used in combination therapy with ribavirin and interferon-α. 8 · Examples The following examples are for illustration only, and not for limitation. Those skilled in the art are aware of a variety of unimportant parameters that can be easily changed or modified and produce essentially the same results. 8.1. Exemplary compounds of the present invention that inhibit translation or replication of HCV The inhibitory activity of specific exemplary compounds of the present invention was confirmed using the H C V replicon assay. The HCV replicon may include characteristics such as HCV IRES, the HCV 3 'untranslated region, a specific HCV gene encoding a HCV polypeptide, a specific marker, and a communication gene such as luciferase GFP, and the like. In the assay, cells that were actively differentiated and contained 5-2 LUC replicons were seeded on 96-well culture plates at a density of approximately 5,000 and 7,500 cells / well-holes (each well had approximately 90 microliters of cells) , Incubate 24 small (41) (41) 200 407 121 inches at 37 ° C and 5% C02. After that, 'the test compound of various concentrations (approximately 10 microliters) was added to each well' and the cells were incubated for an additional 24 hours before the luciferase assay. Collect cells and detect hcv replication or translation via a communication gene test, such as a luciferase communication gene test. The culture medium was aspirated from each well and a Bright-G10 (Pharmacia, Peapack, NJ) luciferase assay reagent was added to each well according to the manufacturer's instructions. In this assay, the amount of a test compound that produces a 50% reduction in luciferase luminescence (IC50) is determined. Quantitative Western blot analysis is also used to determine the ability of specific exemplified compounds of the invention to inhibit HCV replication against antibodies against specific H C V proteins. In this assay, it was determined that the test compound reduced the amount of a specific H C V protein by 50% (I C 50) compared to a control sample. The results of the replicon and Western blot tests are shown in Table 1 below. The structure of the compound shown is provided in FIG. In Table 1, “+” means that the IC50 in a specific test is 10 μM or lower; “-” means that the IC5G in a specific test is greater than 10 μM. Several compounds have IC5Q in the replicon assays in the nanomolar range. -45- 200407121 Table 1 χ / \ / = ν \ .1 ^ -Λ \ / 〆Μ—L ι Τ D \ 〆6 R7 ^^ MRnC (0) R12 CHC12 CHC12 CHC12 CHC12 I CHC12 CHC12 ffi X z ίζ 〇 〇 o one X u δ XV CH CH ffi uuuuuo > uuouuu > -5 ffi o ffi u X u ffi uwu ffi u ο u COMe CC1 CC1 CC1 ffi u ffi u X o K ooo Q ffi u ffi uoo ffi u W ffi ouooou < CC1 ccf3 ptH o CC1 CC1 CC1 > oooooo X Replicon Sprinkler + $ + $ + / + Compound 1 R909850 3 R909794 5 R911427 7 R911418 9 R909921 Π 1 1 R909833 -46- 200407121

Table 1 χ / \ / = ν \ ϊΓ ^ Η— / d \ e, g R7 is NRnC (0) R12% CHC12 CHC12 CHC12 CHC12 CHC12 CHC12% ffi su D: U u OU ffi U s ffi uwuuuu > ouuuuuwo X u K osu X o ο u COMe cch3 cch3 uuw ffi u. 〇o ffi u ffi u ffi o QX o ffi uo ffi uu CH s L) uuu CC1 < CC1 U cch3 cch3 Ph u CC1 oooo 〇o X Replicon Sprinkle + + / + + + / + + Compound 13 R909845 17 R911424 19 R909851 21 R909846 27 R911422 29 R911423-47- 200407121

Table 1. uuuu »-5 X uoouuo 0 1 o CC1 u COMe CC1 w ffi uuu X u M uo P uu X o E u X usououu ffi u < ccf3 cch3 CC1 ccf3 Ph u CC1 > < o 〇〇〇ooz Replicon Sprinkler + + 1 1 1 1 Compound 31 R909864 33 R904855 35 R904800 37 R909793 39 R911427 43 R909873 -48- 200407121 i

0 \ / 0 iooIllIM— ^% CHC12 CHC12 CHC12 CHC12 CHC12 CHC12 ffi ffi o 2 ffi S uz CH ffi us ffi U ffi uso ffi U wu K os W u > uouu name u ►-5 ffi u ffi uussuo CCOOEt 0 〇 == (0 = 〇1 υ COMe CC1 9 0 1 o COMe woku X o ffi us. K u Q uuu X uss W uo K uusu < o ccf3 CC1 CC1 ccf3 oooooo X%% Replica Sprinkler 1 + $ + $ $ Compound 45 R909878 47 R909884 49 R905952 51 R909909 53 R905954 57 R905948

-49- 200407121

Table 1, Υ \ / = \ ι Τ d \ 〆R7 is NRnC (0) R12 CHC12 CHC12 CHC12 1 CHC12 CHC12 X sss ffi o K usss U ffi o >% ffisss X ooo 9 0 1 〇0 = ( 0 1 o (0 I CCl uwss Su CH Q CH δ. S oums δ s CJ ffi u ccf3 CCl CCl CCl ccf3 o 〇ooo X% Replicon Sprinkle + + 1 + Compound 61 R905961 63 R905962 65 R904857 67 R905451- 50- 200407121 Table 1 χ / \ guang \ r ^ H_ / D \ e, G R7 is NRUC (〇) R12 CHC12 CHC12 CHC12 1 CHC12 CHC12 CHC12 X ffi s CH U CH X u K u X uuu > uua > -5 s ffi o ffi u ffi o CH ffi uo 9 0 1 O CN N-Boc w X 1 o COSi (Me) 2-tBu COH j CO (CO) NHEt iwsu ffi u U os P s X uuus U w CH X au ffi o K ou < CC1 CCl CCl CCl CCl CCl > < o 〇oooo X ϊζ Replicon Sprinkler + + + + + + Compound 69 R905949 71 R905965 73 R905966 75 R905967 77 R905968 79 R905969 -51-200407121 Table 1 d \ e, g R7 is NRuC (0) R12 P < CHC12 CHC12 CHC12 CHC12 CHC12 CHC12 ffi KS W u ffi oo K uu CH s K uu K u ffi us > u € uuuos ffi uuwu ffi uuo X 0 = K 0 1 o COSi (Me) 2-tBu CO (CO) NHCH2CH2CH3 soooo C〇H CN ( CH3) 2 s ffi uo ffi uu P suuuuo «s ffi uou K uu < CC1 CC1 CC1 CC1 CC1 CC1 kH ooo 〇oo X Replicon Sprinkler + + + + + + Compound 81 R905970 83 R905971 85 R905973 87 R905982 89 R905983 91 R905984 -52- (49) 200407121

-53- (50) (50) 200407121 Use a counting balance (co n u t e s s c e e η) to confirm a non-specific inhibitor of the communication gene. In this counting sieve, a cell line having a structure such as a worm luciferase gene driven by CMV was used to confirm a compound that inhibits the communication gene instead of HCV. Many compounds have an IC50 of greater than 10 μM in the sieve luciferase inhibition assay. Standard cell proliferation assays are used to determine the cytotoxicity of the compounds of the invention. LD50 measured for many compounds was greater than 10 μM, and it was determined that this result reflected a decrease in virus production, not cell death. The TaqMan RT-PCR assay (Roche Molecular Systems, Pleasanton, CA) was used to analyze the number of HCV RN A replications to determine that the HCV viral genome was not replicated. Actively differentiated 9 to 13 replicon cells were seeded into a 24 well plate at a density of 3 × 104 cells / well at a volume of 1 ml / well. The cells were then incubated at 37 ° C and 5% C02 for 24 hours. Twenty-four hours after seeding the cells, compounds of various concentrations (10 microliters in volume) were added to each well. The cells were incubated with the compound for another 24 hours, and the medium was aspirated to prepare RNA samples from each well. TaqMan single-stage RT-PCR was performed using a previously prepared RNA sample according to the manufacturer's instruction manual. The ratio of HCV RNA to cellular GAPDH RNA is used to indicate the specificity of HCV inhibition and to confirm that the viral genome is not replicated. 8.2 The compound is not toxic in cell and animal models 8.2.1 Cytotoxic Compounds 1, 3, 7, 9, 11, 13, 17, 19, 21, 27, 29, -54- (51) 200407121

3 1, 3 3, 35, 37, 39, 47, 49, 51, 5 7 and 6 9 Hepatocytes (5-2 Luc cells, 9-13 cells or Hiih- 7 cells). In this assay, the cell line was seeded on a 96-well plate (approximately 7,500 cells / well in a 90 microliter volume) and cultured at 37 ° C for 24 hours. On the second day, test compounds of various concentrations (in a volume of 10 microliters) were added to the wells, and the cells were cultured at 37 ° C for another 48 hours. On the 4th day, the ATP-dependent R-luciferase assay (cell titer Glo assay) was performed to determine the number of viable cells. With the exception of compounds 1, 3, 19 and 57, all compounds tested had an IC50 of greater than or equal to 10 / M, confirming that the compound was non-toxic. Among the remaining compounds, all compounds except Compound 13 (whose ICm is 3 // M) have IC50 greater than 5 // M, which proves that these compounds are well tolerated. Synthesis of 8.3 compounds 8.3 '' compounds 3 (R909794) and 9 (R909921)

Step A Referring to FIG. 4C, compound 2 3 0 (25 g, 98.1 mmol) was added below 96% H2SO4 (50 ml), followed by 96% HNO3 ( 1 7.5 ml), and the resulting mixture was heated at 130T for 3 hours. The reaction mixture was cooled, poured into ice, and sodium carbonate was added to form a precipitate (PH > 7). The product was collected by filtration, washed with water, and dried to give 232 (17.0 g, 79%) as a yellow solid. -55- (52) 200407121

Step B Compound 2 3 2 (17 g, 78 mmol) was added to CHC 1 3 (2000 ml). PBr3 (7.4 ml) was added, and the mixture was refluxed for 1 hour or TLC showed that the reaction was complete. The reaction was cooled, most of the solvent was removed under reduced pressure, and the residue was poured onto ice to give a yellow solid. The product was collected by filtration to give 2 3 4 (14 · 5 g, 92%).

Step C 234 (6 g, 0.029 mol), PdCl2 (Ph3) 2 (62 0 mg '3 mol%)' Cul (3 38 mg, 6 mol%) in a nitrogen atmosphere and add diisopropyl Ethylamine (100 ml). The resulting mixture was stirred at ambient temperature for several minutes, after which TMS acetylene (6.3 mL, 1.5 equivalents) was introduced. The contents were heated at 60 ° C for 24 hours. The solvent was removed under reduced pressure, and the crude material was filtered through a silica gel column (hexane: EtQAe 10: 1) to give 236 as a yellow solid, 4.9 g (76%).

Step D A mixture of compound 2 3 6 (1.4 g), Fe powder (3.55 g, 10 angstroms), concentrated HC1 (1 ml) and methanol (100 ml) was refluxed for 3 hours. After cooling, the reaction mixture was filtered, the solution was concentrated, the residual% & NaHC03 was diluted, and extracted with EtOAc (several times). The combined EtOAc extract was dried, filtered, and concentrated to give a mixture of the crude product (ι · 〇g) 238 and the desilylated product 240. The oily mixture was dissolved in methanol (100 ml) It was treated with Kπ03 (about 2 equivalents). Fang-56- (53) 200407121 After stirring at room temperature for 1 hour, the reaction was concentrated in vacuo. The residue was dissolved in EtOAc, washed with water, dried, filtered and Concentrated in vacuo to give the product 2400 (5 1 3 mg) as a dark purple oil.

Step E Compound 240 (513 mg) was dissolved in anhydrous dichloromethane (50 mL), and Et3N (0.7 8 6 mL, 1.3 equivalents) was added under nitrogen. The mixture was cooled in an ice bath, and a solution of dichloroacetamide (0.483 ml, 1.1 equivalents) in anhydrous dichloromethane (5 ml) was added dropwise. The reaction was warmed to room temperature over 6 hours, diluted with EtOAc, washed with saturated sodium bicarbonate solution, dried, filtered and concentrated in vacuo. The crude material was passed through a silica gel plug and dissolved with 1: 1 hexane / EtO Ac. The eluate fraction was concentrated to give a purple oil, which solidified under high vacuum to give compound 255 (658 mg).

Step F

Chlorooxime (654 mg, 1.1 equivalents) of 2-fluoro-6-trifluoromethylbenzaldehyde and compound 2 5 5 (6 58 mg) were dissolved in anhydrous THF (30 ml), and Et3N (0.521 ml, 1.3 equivalent). The mixture was stirred at room temperature for 1 hour and then refluxed for 5 hours until the reaction was complete. The solvent was removed under vacuum and the residue was dissolved in EtO Ac, washed with water, washed with saturated sodium chloride, dried, filtered and concentrated. The crude was purified by chromatography (3: 2 hexane: EtO Ac) to give compound 3 (800 mg). Compound 9 was prepared in the same manner from 2,6-dichlorobenzaldehyde chloroxime and 2 5 5. -57- (54) (54) 200407121 8.3 · 2 Synthesis of Compound μ (R90 5 9 5 2) 3- (2-methoxy-6-trifluoromethylphenyl) -5- (4-aminopyridine Of N-Hydroxy) isohumidazole N-Hydroxy- (2-methoxy-6-trifluoromethylbenzene) carboxyimine sulfonium chloride (1 g, 3.94 mmol) and 4-amino-2-ethynylpyridine (310 mg, 2.63 mmol) to a solution in THF was added triethylamine (550 ml, 3.94 mmol). The reaction mixture was stirred at room temperature for one hour and then refluxed for three hours. The mixture was cooled to room temperature, and ethyl acetate and water were added. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated in vacuo to give a crude product. The final product was purified by flash chromatography using hexane: ethyl acetate (4: 1) to obtain 3- (2-methoxy-6-trifluoromethylphenyl) -5- (4-aminopyridyl) iso-Uqin Π Seated (609 mg). MW = 3 3 5.2 8 confirmed by LC = MS, tr = 8. 3 8 mi η. (Method Υ) M + = 3 3 5.2 8 NMR (300MHz, CDCl3): 8.24 (m, iH), 7.48 (m, 1Η) 5 7 · 4 (ιή, 1H), 7.26 (m, 1H), 7.2 (m, 1H)? 7.0 (s? 1H) 5 6.6 (m? 1H), 4.8 (bs, 2H), 3.8 (s, 3H). Preparation of 2,2-dichloro-1 ^-[2- [3- (2-methoxy-6-trifluoromethylphenyl) _5_isoxazole]-(4-pyridyl) acetamide -(2-methoxy-6-trifluoromethylphenyl) aminopyridyl) isoimidazole (609 mg, 1.82 mmol) and triethylamine (1.8 ml, 1 2.9 mmol) in dichloro The mixture in methane was cooled in an ice bath. Dichloroacetamidine (1.3 ml, 12.9 mmol) was added dropwise to a solution of Dichloromethane -58- (55) 200407121. After stirring for another hour, water and ethyl acetate were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered, and concentrated in vacuo. The final product was 2,2-dichloro-N- [2- [3- (2-methoxy-6-trifluoromethylphenyl) by hexane: ethyl acetate (4 ··) flash chromatography purification. -5-isoxazole]-(4-pyridyl) acetamidamine (300 mg). MW = 44 6.2 1 Confirmed by LC-MS, t r = 9.8 4 m i η · (Method Υ) MΗ + = 447.2 1.

NMR (300MHz, CDC13): 9.84 (s, 1 H) 5 8.63 (m, 1H), 7.9 (m5 1H), 7.62 (m, 1H), 7.41 (m5 1H), 7.22 (m5 1H) 5 5.64 (s , 1H), 3.8 (s, 3H). (Replicon Activity ++) Synthesis of Compound 57 · 3 · 3 (R90 5 948)

Preparation of 3- (2,2-dichloroacetamidinyl) -5-ethynylpyridine 3-amino-5-ethynylpyridine (2.73 g, 23.1 mmol) and triethylamine (3.54 ml, 25.42 A mixture of millimoles) in dichloromethane was cooled in an ice bath. A solution of dichloroacetamidine (2.57 ml, 25.42 mmol) in dichloromethane was added dropwise. After stirring for another hour, water and ethyl acetate were added. The organic layer was separated, washed with saturated sodium bicarbonate, dried over sodium sulfate, filtered and concentrated in vacuo to give 3- (2,2-dichloroacetamidino) -5-ethynylpyridine (3.5 g). MW = 22 9.3 1 Confirmed by LC-MS, tr = 9.76min. (Method Y) MH + = 23 0.3. NMR (300MHz, CDC13): 8.7 (s? 1H)? 8.52 (s? 1H)? 8.2 (m? -59- (56) 200407121 2H), 6.08 (s, 1H), 3.21 (s, 1H). Preparation of 2,2-dichloro-] ^ [3- [3- (2-methoxy-6-trifluoromethylphenyl) -5-isobutrazol]-(5-pyridyl) acetamidin

N-Hydroxy- (2-methoxy-6-trifluoromethylbenzene) carboxyimine ammonium chloride (111 mg, 0.44 mmol) and 3- (2,2-dichloroacetamido) -5- To a solution of ethynylpyridine (100 mg, 0.44 mmol) in THF was added triethylamine (0.9 1 ml, 0.65 mmol). The reaction mixture was stirred at room temperature for one hour and then refluxed for three hours. The mixture was cooled to room temperature, and ethyl acetate and water were added. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude product. Purification by flash chromatography using hexane: ethyl acetate (4: 1) to obtain the final product 2,2-dichloro-N- [3- [3- (2-methoxy-6-trifluoromethylphenyl)- 5-Isocroconazole]-(5-pyridyl) acetamidamine. MW = 446.3 1 Confirmed by LC-MS, t r = 1 3 · 4 5 m i η. (Method Υ) ΜΗ + = 447 · 3 1.

NMR (3 00MHz, CDC13): 9.4 (bs, 1 Η) 5 9.0 (s 5 1 Η), 8.9 (s, 2H), 7.58 (m, 1H), 7.4 (m, 1H) 5 7.24 (m , 1H), 6.8 (s, 1H), 6.2 (s, 1H), 3.8 (s, 3H). 8. 3.4 General synthetic method of the compound of the present invention In addition, the compound of the present invention can be prepared by the method shown in Figs. 8 to 63. Those who are familiar with this technology can base on this article and Figures 1 to 6 3, the reference materials shown in the figure, and the US provisional application filed on May 2, 2003 6 0/46 7, 6 5 0 (agent file number P-7 1 84 7 -2) (the contents of which are taught-60- (57) (57) 200407121 are incorporated herein by reference) provide instructions to easily prepare the compounds within the scope of the present invention. For example, for general synthesis of non-nitrogen-containing "^" ring isomers, refer to sections 5.3 and 6.1 below. A pyridin-2-yl, pyridin-3-yl, or pyridyl group can be used in the "C" ring to replace the non-heteroaromatic ring shown therein. In addition, it should be known that in Figs. 1 to 63, the "c" ring position isomer is simply used. It should be understood that the pyridine ring may be pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl. In addition, it should be noted that many of the "A" ring systems prepared are 2,6-dichlorophenyl. This is for illustration, not limitation. The starting materials that can be used to prepare the compounds of the present invention and their intermediates are commercially available or can be prepared by well-known synthetic methods (see, for example, Harrison et al./'Compendium of Synthetic Organic Methods ,,, Vols. 1-8 (J o li n Wiley and Sons, 1971-1996); "Beilstein Handbook 〇f O rga η ic C hemistry," B ei 1 stei η I nstituteof 0 rganic

Chemistry, Frankfurt, Germany; Feiser et al., "Reagents for

Organic Synthesis, "Volumes 1-21, Wiley I η ter science;

Trost et al./Comprehensive Organic Synthesis ,, Perga m on Press, 1991; "Theilheimer's Synthetic Methods of Organic Chemistry," Volumes 1-45, Karger, 1991; March, "Advanced Organic Chemistry," Wiley I liter science, 1991; Larock "Comprehensive Organic Transformations," VCH Publishers, 1989; Paquette, "Encyclopedia of Reagents for Organic Synthesis," 3d Edition, John Wiley & Sons, 1 99 5). Other methods of synthesizing the compounds and / or starting materials thereof according to the present invention are described in the technical field, or will be apparent to those skilled in the art -61-(58) (58) 200407121. The reagents and / or protective group alternatives shown in Figs. 1 to 63 can be referred to in reference materials and outlines familiar to those skilled in the art. Guiding principles for selecting an appropriate protecting group can be found in, for example, Greene & Wuts,

Protective Groups in Organic Synthesis 'Wiley illtei' SCienCe, 1 999. For this reason, the synthetic methods and strategies shown in this article are provided for illustration, not limitation. In particular, the method for synthesizing substituted diphenylisoxazole (z- is -CH-) of structural formula (I) is shown in Figs. 2A to 7b and 12C to 12E. The Examples section discusses Figures 4C, 4D and 15 to 18 to describe the preparation of acetylene compounds. It should be known that in Figs. 1 to 63 and many parts of the description, the rc "ring meta isomer is for illustration only. The method for preparing "C" ring ortho, meta or para position isomers can be selected by those skilled in the art. Therefore, when the "C" ring meta isomer is specified, the same synthetic method can be used to prepare the ortho or para "C" ring isomer. This meta isomer was simply and consistently selected from Figures 1 to 63 to illustrate the ability to prepare the compound in question. In Figures 1 to 63, the substituents R2, R3, R4 ,, r6 ,, R9, R1, and R14 may include reactive functional groups, which need to be protected during synthesis. The selection of the appropriate protecting group depends on the type of functional group and the synthesis method used, and it will be apparent to those skilled in the art. Guiding principles for selecting the appropriate protecting group can be described as W r e en e & W u t s, and various other references listed therein. Other guidelines for 1,3-dipolar cycloaddition reactions (also known as L 3 -dipole addition, [3 + 2] cyclization, or [3 + 2] cycloaddition) can be found in -62 -(59) (59) 200407121 " Cycloaddition Reactions in Organic Synthesis '', (Kobayashi, S. and Jorgensen, KA 5 Editors), 2002, Wiley-VCH Publishers, pp. 1-332, (more specifically, [3 + 2] Cyclic additions are in Chapters 6 and 7, and 1,3-dipole additions are in pages 21 1 to 24 8 and 249 to 300); "l, 3-Dipolar Cycloaddition", Chemistry of Heterocyclic Compounds, Vol. 59, (Padwa, A. and Pearson, W., Editors), 2002, John Wiley, New York, p. 1 -940; " Nitrile Oxides, Nitrones, Nitronates in Organic Synthesis: Novel Strategies in Synthesis Torssel, KBG, 1988, VCH Publishers, New York, pp. 1-332;

Barnes & Spriggs, 1945, J.Am. Che m S o c. 6 7: 1 3 4; A nj an eyu 1 u ^., 1 9 9 5, Indian J. Chem., Sect. 5 3 4 ( 1 1): 933-938); and T.L.Gilchrist, Pitman Publishing Ltd, 1985 ISBNO-273-02237-7; Strategies for Organic Drug

Synthesis and Design, Led nicer, D. 5 John Wiley and Sons, 1 99 8 ° For other guidelines for the synthesis of isoxazole and its hydrogenated isomers, see M. Sutharchanadevi, R. Muragan in Comprehensive Heterocyclic Chemistry // , AR Katritzky, CW Rees, EFV Scriven, Eds; Pergamon Press, Oxford, Vol. 3, p. 221; R. Grunager, P? In Heterocyclic Compounds, Vol 49, Isoxazoles} Part one,

John Wiley and Sons? New York, 1991; KBG Torssell, Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis, VCH Publishers, New York, 1988; YY. Κυ5 T. Grieme, P. Sharma, Y.-M. Pu? P. Raje? H. Morton, S. King Organic Letters, 2001, 35 4185; VG -63- (60) 200407121

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DEMINA, LA; et al .; Zh Org Kliim (ZORKAE) 1979, 15, 735. CHEM ABSTRA (CHABA8), 91 (74512). ARCHIBALD, AT; Nielsen, TG; Tetrahedron Lett (TELEAY) 1968? 3375. KOHLER, EP; Barrett, GR; J Am Chem Soc (JACSAT) 1924, 46, 2105. DEMINA, LA ·; Khismutdinov, GK; Tkachev, SV; Fainzilberg, AA ·; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15, 654. BAAVA, LN ·; Demina, LA ·; Trusova, TV; Furin, GG; Khisamutdinov, GK; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15? 2179. CARAMELLA, P .; Cellerino, G .; Houk? KN; Albini5 FM; Santiago, C .; J Org Chem (JOCEAH) 1978, 435 3007. CARAMELLA, P .; Cellerino, G .; Houk, K .; Albini, FM ,; Santiago, C · ; J Org Chem (JOCEAH) 1978, 43, 3006. SAUTER, F ·; Buyuk, G .; Monatsh Chem (MOCMB7) 1974, 105, 254. ELKASABY, MA ·; Salem, MAI ·; Indian J Chm (IJOCAP) 1980, 19, 571 · BAEVA, LN ·; Demina, LA ·; Trusova, TV; Furin, GG; Khisamutdinov, GK; J Org Chem USSR (Engl Transl) (JOCYA9) 1979, 15, 2179. MAKSOUD, AA; Hosnig, G .; Hassan, 0 .; Shafik, S .; Rev Roum Chim (RRCHAX) 1978, 235 1541. FUKUNAGA, K .; Synthesis (SYNTBF) 1978, 55. FARAGHER, R .; Gilchrist, TL; J Chem Soc5 Perkin Trans 1 (JGPRB4) 1977, 1196. BIANCHI, G .; De Micheli, C .; Gandolfi, R .; J Chem Soc, Perkin Trans 1 (JCPRB4) 1976, 1518. LO VECCHIO, G .; Atti Accad Peloritana Periocolanti, Cl Sci Fis, Mat Nat (AAPFAO) 1972? 52? 207. JTJRD, L .; Chem Ind (London) (CHINAG) 1970, 2? 624. BELTRAME, PL; Cattania, MG; Redaelli, V .; Zecchi , G ·; J Chem Soc, Perkin Trans 2 (JCPKBH) 1977, 706. PARK, CA; Beam, CF; Kaiser, EM; Hauser, CR; et al .; J Heterocyol Chem (JHTCAD) 1976, 13, 449. LO VECCHIO, G ·; Atti Accad Peloritana Pericolanti, Cl Sci Fis? Mat Nat (AAPFAO) 19725 52? 217. BORKHADE, KT;

Marathey5 MG; Indian J Chem (IJOCAP) 19705 85 796. WAKEFIELD, BJ; Wright, DJ; J Chem Soc C (JSOOAX) 19703 1165. UNTERHALT, B .; Pham Zentralhalle (PHZEBE) 1968, 107, 356. NIELSEN, AT Archibald, TG ·; Tetrahedron Lett (TELEAY) 1968, 3375. KIRTZ, DW; Shechter, H .; J Chem Soc? Chem Commun (JCCCAT) 1965, 689. JOSHI, KC ·; Jauhar, AK; J Indian Chem Soc (JICSAH) 1965, 42, 733 · NIELSEN, Α · Τ; Archibald, TG ·; J Org Chem (JOCEAH) 1969, 34, 984. BATTAGLIA, A .; Dondoni, A ·; Rio Sci (RISCAZ) 1968, 38, 201 · MONIORTE, F ·; Lo Vecchio, G .; Atti Accad Peloritana Periocolanti, Cl Sci Fis, Mat Nat (AAPFAO) 1966, 49, 169. ARBASINO, M .; Finzi, PV; Rio Sci (RISCAZ) 1966 , 36, 1339. ROTH5 HJ; Schwartz, M .; Arch Pharm Ber Dtsch Pharm Ges (APBDAJ) 1961, 294, 769. ROTH, HJ; Schwarz, M .; Arch Pharm Ber Dtsch Pharm Ges (APBDAJ) 1961, 294, 761. GRUNANGER? P .; Gandini, C .; Quilico, A .; Rend-1st Lomb Accad Sci Lett, A: Sci Mat, -67- (64) 200407121

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Org Lett (ORLEF7) 2000, 2 (15), 2331-2333 · BALASUNDARAM, B .; Veluchamy, T.P .;

Velmurugan, D .; Perumal, PT; Indian J Chem5 Sect B (IJSBDB) 1995, 34 (5), 367-371. CHAN, KS; Yeung, M 丄 ·; Chan, W ·; Wang, R.-J · Mak, TCW; J Org Chem (JOCEAH) 1995, 60 (6), 1741-1747. CHIACCHIO, U .; Casuscelli, F ·; Liguori, A ·; Rescifina, A ·;

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Other guidelines for the synthesis of pyrazole can be found in J. Elguero Comprehensive Heterocyclic Chemistry II, AR Katritzky, C. W. Reees, E. F. V. Scriven ·, Eds .; Perga m on Press, Oxford, 1996; Vol · 3, pl 〇 For guidance on the synthesis of the compounds shown in Figures 8A and 8B, please refer to -68- (65) 200407121 LHOTAK, P; Kurfuerst, A; Collect Czech Chem Commun [CCCCAK] 1993, 58 ( 11)? 2720-2728. BRAIN, CT; Paul, JM; Synlett [SYNLES] 1999? (10)? 1642-1644. VARMA? RS; Kumar, D .; J Heterocycl Chem [JHTCAD] 1998, 35 (6) , 1533-1534.

FEDYUNYAEVA, IA ·; Yushko, EG; Bondarenko, VE; Khim Geterotsikl Soedin [KGSSAQ] 1996 (3), 333-337. DOROSHENKO, AO; Patsenker, LD; Baumer, VN ·; Chepeleva, LV; Vankevich, AV; Shilo , OP; Yarmolenko, SN; Shershukov, VM; Mitina, VG; Ponomarev, OA; Zh Obshch Khim [ZOKHA4] 1994? 64 (4)? 646-652. FEDYUNYAEVA, IA; Shershukov, VM; Khim Geterotsikl Soedin [KGSSAQ] 1993 (2)? 234-237. KLEIN, RFX; Horak, V .; Baker, GAS; Collect Czech Chem Commun [CCCCAK] 1993, 58 (7)? 1631-1635. KERR, VN; Hayes, FN; Ott5 DG Lier5 R .; Hansbury, E ·, J Org Chem (JOCEAH) 1959, 24, 1864. NISHIO, T ·; Ori, M ·; Helv Chim

Acta [HCACAV] 2001, 84 (8), 2347-2354. LHOTAK, P ·; KurfUerst, A ·; Collect Czech Chem Commun [CCCCAK] 1993, 58 (11) 5 2720-2728. SIEGREST, A.E .; Helv Chim

Acta [HCACAV] 1967, 50, 906; and GABRIEL, S ·; Chem Ber [CHBEAM] 1910, 43, 134.

Guidance for the synthesis of the compounds described in Figures 9A and 9B can be found in ZHANG, P.-F .; Chen? Z.-C .; Synthesis (SYNTBF) 2001, (14), 2075-2077. BUTLER, RN; Cloonan, MO; McMahon, JM; Burke, LA; J Chem Soc5 Perkin Trans 1 (JCPRB4) 1999? (12)? 1709 ^ 1712. NAKAWISHI, S .; Otsuji, Y .; Nantaku5 J .; Chem Lett (CMLTAG) 1983, 341. POCAR, D .; Stradi, R .; Tetrahedron Lett (TELEAY) 1976, 1839. POPILIN, ON; Tishchenko, VG; Khim Geterotsikl Soedin (KGSSAQ) 1972? 1264; and KUNCKELL, F ·; Chem Ber ( CHBEAM) 1901, 34, 637. Guiding principles for the synthesis of the compounds described in Figures 10A and 10B can be found in y \ w -69- (66) (66) 200407121 VARLAMOV, AV; Turchin, KF; Chernyshev, AI; Zubkov, FI; Borisova, TN ·; Chem Heterocycl Compd (NY) [CHCCAL] 2000, 36 (5), 621-622. CASUSCELLI, F .; Chiacchio, U ·; Rescifma, A ·; Romeo, R. Romeo, G .; Tommasini, S .; Uccella, N .; Tetrahedron (TETRAB) 1995, 51 (10), 2979-2990. CHIACCHIO, U .; Casuscelli, F .; Corsaro, A .; Rescifina, A. ; Romeo, G .; Uccella, N .; Tetrahedron ( TETRAB) 1994, 50 (22), 6671-6680. MUKAI, C ·; Kim, IJ; Cho, WJ ·; Kido, M .; Hanaoka, M ·; J Chem Soc5 Perkin Trans 1 (JCPRB4) 1993 (20) , 2495-2503. MINAMI, T .; Isonaka, T .; Okada, Y .; Ichikawa, J ·; J Org Chem (JOCEAH) 1993, 58 (25), 7009-7015 · TANAKA, K .; Mori, T Mitsuhashi, K .; Bull Chem Soc Jpn (BCSJA8) 1993, 66 (1), 263-268 · HUISGEN, R ·; et al ·; Tetrahedron Lett (TELEAY) 1960, 12, 5 · CHEM BER (CHBEAM) 1968 , 101, 2043. CHEM BER (CHBEAM) 1968, 101, 2568 · CHEM BER (CHBEAM) 1969, 102, 117. SASAKI, T .; Bull Soc Chim Fr (BSCFAS) 1968, 41? 2960; R SASAKI, T. Bull Chem Soc Jpn (BCSJA8) 1968, 41, 2964, the guidelines for synthesizing the compounds described in Figures 1 A and 1 1 B can be found in j \ \\ KATRIZKY, AR; Qi? M .; Feng, D .; Zhang, G .; Griffith, MC; Watson, K .; Org Lett (ORLEF7) 1999, 1 (8), 1189-1191 · FRANCIS, JE; Cash, WD ·; Barbaz, BS ·; Bernard, PS Lovell, RA; Mazzenga, GC ·; Friedmann, RC ·; Hyun, J 丄 ·; Braunwalder, AF ·; Loo, PS ·; Bennett, D .A .; J Med Chem (JMCMAR) 1991, 34 (1), 281-290. POTTS, KT; J Chem Soc (JCSOA9) 1954? 3461. EINHORN, A .; Justus Liebigs Ann Chem (JLACBF) 1905? 3435 207. SHIBA, SA; El-Khamry? AA; Shaban? ME; Atia? KS; Pharmazie (PHARAT) 1997, 52 (3), 189-194; and MOLINA, P .; Tarranga, A .; Espinosa, A. Lidon, MJ; Synthesis (SYNTBF) 1987 (2) 3 128. The guidelines for synthesizing the compounds described in Figures 12A and 12B can be found in ASCHWANDEN? P .; Frantz, DE; Carreira, EM; Org Lett (ORLEF7) 20003 2 (15), 2331-2333. BALASUNDARAM? B .; Veluchamy, TP; Velmurugan, D .; Perumal, P · T; Indian J Chem, Sect B (IJSBDB) 1995, 34 (5), 367-371 CHAN, KS ·; Yeung, ML ·; Chan5 W .; Wang, R.-J .; Mak? TCW; J Org Chem (JOCEAH) 19953 60 (6)? 1741-1747. ALBEROLA, A .; Gonzalez, AM ·; Laguna, MA; Pulido, FJ ·; Synthesis (SYNTBF) 1982, 1067; and JACOB, KC; Jadhar, GV ·; Vakharia, MN; Pesticides (PSTDAN) 1972, 6, 94. -70- (67) (67) 200407121 The following compounds are representative compounds of the present invention. The compounds identified below are prepared by the method shown in the present invention. Melting point method Melting point was measured on an Electrothermal IA9 1 00 series digital melting point device. All melting points are uncorrected. Elemental analysis was performed by Desert Analytics, Tucson, AZ.

NMR method A N M R spectrum was measured on a 300 MW zV a r i a η M e r c u r y system. LC-MS method General method LC-MS was performed on a Waters Micromass ZQ device with electrospray ionization. The HPLC module is a Waters 2 690 separation module connected to a Waters 9 96 photodiode array detector.

Method W This method uses a 2.1 X 2 50 mm 5 μ MC-1 8 A 11 ima reverse phase column (Alltech) with a flow rate of 0.25 ml / min and a gradient of 5 to 85% acetonitrile and water (containing 0.1 %Trifluoroacetate). The gradient jumped to 100% acetonitrile at 0.5 minutes for 100% acetonitrile over 3.5 minutes.

Method X This method uses 2.1 x 2500 mm 5 μM C-18 Altima reverse-phase column -71-(68) 200407121 (Alltech) with a flow rate of 0.25 ml / min and a gradient of 5 to 85% acetonitrile and water (containing 0 · 1% trifluoroacetic acid). The gradient jumped to 100 ° / in 0.5 minutes. Acetonitrile for 100% acetonitrile over 25 minutes.

Method Y This method uses a 2.1 X 1 50 mm A gi 1 ent Z 〇rba X 5 μ MC-18 reverse phase column with a flow rate of 0.3 ml / min and a gradient of 10 to 100% acetonitrile in 16 minutes. With water (containing 0.1% trifluoroacetic acid) for 100% acetonitrile over 2 minutes.

Method Z This method uses a 2.1x150 mm Agilent Zorbax 5 μM C-18 reverse-phase column with a flow rate of 0.5 ml / min and a gradient of 5 to 100% acetonitrile and water (containing 0.1% trifluoroacetic acid) for 8 minutes for 1 minute 〇 ％ acetonitrile over 2 minutes.

Compound 1 · (R909850) 2,2-dichloro-1 ^-[2- [3- (2-chloro-6-fluorophenyl) _ · 5-isoimidazole] _ (4-pyridyl)] ethyl Amidine MW = 401, confirmed by LC-MS, tr = 3 2.6 3 minutes (method W) MH + di 3 9 9-403 compound 3 · (R909794) 2, 2-dichloro-N-[2-[3 -(2 -Fluoro-6-trifluoromethylphenyl 5-isocrocodazole]-(4-pyridyl)] acetamido MW = 43 4, confirmed by LC-MS, tr = 34.01 minutes (method W) MH + = 43 2-43 6 Compound 5. (R9 1 1 427) 2,2-dichloro-N-[2-[3-(2 -fluoro-6- -72- (69) 200407121 methoxyphenyl ) -5-Isotriazole]-(4-pyridyl)] acetamidamine MW = 3 9 6 confirmed by LC-MS = 3 1.28 minutes (method W) MH + = 3 94-3 9 8 Compound 7 · (R911418) 2,2-dichloro-1 ^-[5- [3- (2,6-dichlorophenyl) -5 -isonimazole]-(3-pyridyl)] acetamidin MW = 4 1 7, confirmed by LC-MS, tr = 33 · 10 minutes (method W) MH + = 415-419

Compound 9 · (R90 992 1) 2,2-dichloro-1 ^-[2- [3- (2,6-dichlorophenyl) -5 -isonimazole]-(4-pyridyl)] ethyl Amidine MW = 417, confirmed by LC-MS, tr = 3 4.2 5 minutes (method W) MH + = 415-419

Melting point = 1 8 7-1 8 8 ° C Compound 11 Azole] phenyl) acetamide

MW = 417, confirmed by LC-MS, tr = 34.13 minutes (method W) Μ Η + = 4 1 5-419 compound 13 · (R909 84 5) 2, 2-dichloro-N-[5-[3- (2 -Chloro-6-fluorophenyl) -5-isonimazole]-(3-pyridyl)] acetamidamine MW = 401, confirmed by LC-MS, tr = 3 2.5 5 minutes (method W) MH + = 3 9 9-403 Compound 17 · (R9 1 1 424) 2,2-Dichloro-N- [5-[3-(2 -Fluoro-6-methoxyphenyl) -5-Isotriazole] -(3-pyridyl)] acetamido MW = 3 96, confirmed by LC-MS, tr = 3 0.4 7 minutes (method W) MH + = 3 94-3 9 8 -73- (70) 200407121 compound 19 · (R9 0 9 8 5 1) 2,2-dichloro-N-[2-[3-(2,6-dimethylphenyl) -5-isohumidazole]-(4-pyridyl)] Acetamide MW = 3 7 6 confirmed by LC-MS, tr = 3 4.6 3 minutes (method W) MH + di 3 7 4-3 7 8 compound 21. (R909 8 4 6) 2, 2-dichloro -N-[5-[3-(2,6-dimethylphenyl) -5 -isoxazole]-(3-pyridyl)] acetamidin

MW = 3 7 6, confirmed by LC-MS, tr = 29.6 9 minutes (method W) MH + = 3 74- 3 7 8 compound 27 · (R9 1 1 4 2 2) 2 5 2 -dichloro-N · [5-[3-(2,6-Difluorophenyl) -5 -isopyrfazole]-(3-pyridyl)] acetamido MW = 3 8 4 confirmed by LC-MS, tr = 3 1.64 minutes (Method W) ΜΗ + = 3 8 2-3 8 6 Compound 29 · (R9 1 1 4 2 3) 2 5 2 -Dichloro-N · [5-[3-(2, 3-2 Chlorophenyl) -5 -isoimidazole]-(3-pyridyl)] acetamidamine

MW = 417, confirmed by LC-MS, tr = 3 4.9 9 minutes (method W) MH + = 4 1 5-4 1 9 compound 31. (R909 8 64) 2, 2-dichloro-N-[2- [3-(2 -morpholinyl-6-trifluoromethylphenyl) -5-isoxazole]-(4-pyridyl)] acetamidamine MW = 501, confirmed by LC-MS, tr = 6.97 minutes (Method Z) MH + = 499- 5 03 Compound 33 · (R904 8 5 5) 2, 2-dichloro-N-[3-[3-(3 -methyl-2-pyridyl) -5 -Isotriazole] -phenyl] acetamide MW = 3 62, confirmed by LC-MS, tr = 3 0.8 9 minutes (method W) MH + = 3 6 0-3 64 -74- (71) (71 200407121 Compound 35 · (R904 8 0 0) 2,2-dichloro-N-[6-[3-(2,6-dichlorophenyl) -5 -isoDfazole]-(2-pyridyl) ] Acetylamine MW = 417, confirmed by LC-MS, tr = 20.74 minutes (method X) MH + = 4 1 5-4 1 9 compound 37 · (R9097 93) 2,2-dichloro-N-[5 · [3-(2 -Fluoro-6-trifluoromethylphenyl) -5 -isonimazole]-(3-pyridyl)] acetamido MW = 43 4, confirmed by LC-MS, tr = 3 2.7 9 minutes (Method W) MH + = 43 2-4 3 6 Compound 43 · (R904 8 7 3) 2, 2 -dichloro-N-[2- [3-(2,6-dichlorophenyl) -5 -isoDfazole]-[4-(1 -oxypyridyl)] acetamidamine MW = 433, confirmed by LC-MS, tr = 6.44 minutes (Method Z) Μ Η + = 4 3 1-4 3 5 Compound 45 · (R9 0 9 8 7 8) 2 5 2 -dichloro-N-[3-[3-[(3 -ethoxycarbonyl)- 2-pyridyl] -5-isonimazole] -phenyl] acetamidamine MW = 420, confirmed by LC-MS, tr = 6.65 minutes (method Z) MH + = 418-422 compound 47. (R909 8 84 ) 2,2-dichloro-N-[2-[3-(2-fluoro-6-morpholinolaminesulfonylphenyl) -5-isohumidazole]-(4-pyridyl)] ethyl Amidine MW = 515, confirmed by LC-MS, t, 6.32 minutes (Method Z) MH + = 5 1 3-5 1 7 Compound 49 · (R905 952) 2,2-dichloro-1 [2- [3 -(2-methoxy-6-trifluoromethylphenyl) -5-isoimidazole]-(4-pyridyl)] acetamido MW = 446, confirmed by LC-MS, tr = 14.41 minutes (method Y) (72) 200407121 MH + = 444-448 Compound 5 1 · (R90 990 9) 2,2-dichloro_ N-[2-[3-(2,6-dichlorophenyl) -5-iso Oxazole]-(4-pyridyl)]-N-methylacetamidamine MW = 431, confirmed by LC-MS, tr = 14.99 minutes (method Y) M H + = 42 9-4 3 3 Compound 53 · (R90 5 9 5 4) 2, 2-dichloro-N-[2-[3-(2 -chloro-6-

[4-(N-2-Mouth Ratio Dingji) 丨 send out base] Benji) -5-Isobaric sitting and sitting]-(4-Mouth Ratio) acetamidine MW = 5 44, borrow LC-MS confirmed that tr = l 1.8 .1 1 minute (Method Y) MH + = 542 ~ 546 Compound 57 · (R905 948) 2,2-dichloro-1 ^ [5- [3- (2-methoxy -6-trifluoromethylphenyl) -5-isoxazole]-(3-pyridyl)] acetamidamine • MW = 446, confirmed by LC-MS, tr = 13.45 minutes (Method Y) MH +- 444-448 Compound 61 (R905961) 2,2-dichloro-. [5- [3- (2-chloro-6-

[4- (N-Ethyl) piperyl] phenyl) -5-isoDfazole (3-pyridyl)] acetamidamine MW = 5 0 9, confirmed by LC-MS, tr = 12. 1 1 minute (Method Y) Μ Η + two 5 0 7-5 1 1 Compound 63 · (R90 5 962) 2,2-dichloro-N-[5-[3-(2 -chloro-6- [4 -(N-ethyl) piperazinyl] phenyl) -5-isohumidazole]-(3-pyridyl)] acetamidamine MW = 49 5, confirmed by LC-MS, tr = 9.48 minutes (Method Y ) MH + = 4 93 -4 97 -76- (73) 200407121 Compound 65. (R9 04 8 5 7) 2,2-dichloro- > 1- [5- [3- (2,6-dichloro Phenyl) -5 -isoxazole]-(2-pyridyl)] acetamidamine MW = 417, confirmed by LC-MS, tr = 35.19 minutes (method W) MH + = 4 1 5-4 1 9 compound 67 · (R905451) 2,2-Dichloro-. [5- [3- (2-trifluoromethylphenyl) -5_isonimazole] ... (3-pyridyl) acetamidamine

MW = 4 16, confirmed by LC-MS, tr = 13.81 minutes (method Y) MH + = 4 1 4-4 1 8 compound 69 · (R9 05 949) 2,2-dichloro-1 [5- [3 -[2-Chloro-6- [4 — (N _ 2 -pyridinyl) piperazinyl] phenyl])-5 -isonimazole]-(3-pyridyl)] acetamidamine MW = 544, Confirmed by LC-MS, tf = 11.29 minutes (Method Y) MH + = 542-546 Compound 71 · (R9 0 5 9 6 5) 2 5 2 -Dichloro-N-[5-[3-[2 -Chlorine -6-

[4- (N-Third-butoxycarbonyl) piperidinyl] phenyl])-5-Isoimidazole]-(3-carbamyl)] acetamido MW = 5 6 7 confirmed by LC-MS , Tr = 15.91 minutes (method Y) MH + = 5 6 5-5 6 9 compound 73 · (R90 5 966) 2,2-dichloro-N-[5-[3-(2 · chloro-6-piper Phenylphenyl) -5 -isonimazole]-(3-pyridyl)] acetamidamine MW = 467, confirmed by LC-MS, tr = 9.51 minutes (method Y) MH + = 465 -469 compound 75 · (R90 5 967) 2,2-dichloro-N-[5-[3-(2 -chloro-6- tert-butyldimethylsilyloxyphenyl) -5 -isohumidazole]-(3 -Pyridyl)] -77- (74) 200407121 Acetylamine MW = 513, confirmed by LC-MS, tr = 17.49 minutes (Method Y) ΜΗ + = 5 1 1 -5 1 5 Compound 77 · (R9 0 5 9 6 8) 2,2-dichloro-1 [5- [3- (2-chloro-6-hydroxyphenyl) -5-isohumidazole]-(3-pyridyl)] acetamide MW = 3 9 9, confirmed by LC-MS, tr = 12.5 1 minute (method Y) MH + = 3 97-40]

Compound 79 · (R90 5 9 69) 2,2-dichloro-N-[5-[3-(2-chloro-6- N-ethylaminomethylmethoxyphenyl) -5-isocrocodazole] -(3-pyridyl)] acetamido MW = 47 0, confirmed by LC-MS, tr = 12.85 minutes (Method Y) MH + = 468 -472 compound 81 · (R905970) 2,2-dichloro-N -[5- [3- (2-Chloro-6- [4- (N-ethylcarboxyamido) piperazinyl] phenyl) -5-isoimidazole]-(3-carbamyl)] Acetamide

MW = 5 3 8, confirmed by LC-MS, tr = 12.77 minutes (method Y) MH + = 5 3 6- 5 4 0 Compound 83 · (R90 5 9 7 1) 2, 2-dichloro-N-[ 2-[3-(2 -Chloro-6- tert-butyldimethylsilyloxyphenyl) -5 -isonimazole]-(4-pyridyl)] acetamide MW = 513, by LC- MS confirmed that tr 2 17.96 minutes (Method Y) MH + = 5 1 1 -5 1 5 Compound 85 · (R9 0 5 9 7 3) 2 5 2 -Dichloro-N-[2 _ [3-(2- Chloro-6-N-propylaminomethylmethoxyphenyl) -5-isoxazole]-(4-pyridyl)] acetamidine-78- (75) 200407121 Amine MW = 484, confirmed by LC-MS , Tr = 13.36 minutes (method Y) MH + = 4 8 2-4 8 6 compound 87 · (R90 5 9 82) 2,2-dichloro-N-[2-[3-(2 -chloro-6- N -methoxymethoxyphenyl) -5 -isoxazole]-(4-pyridyl)] acetamidamine MW = 443, confirmed by LC-MS, tr = 14.65 minutes (method Y) MH + = 44 1 -445

Compound 89. (R 9 0 5 9 8 3) 2 5 2 -dichloro-N-[2-[3-(2 -chloro-6-hydroxyphenyl) -5-isoamidine fazole]-(4- Pyridyl)] acetamido MW = 399, confirmed by LC-MS, tr = 13.53 minutes (method Y) MH + = 3 9 7-40 1 compound 91 · (R 905984) 2,2-dichloro_N- [3- [3-[(4-chloro · 2-dimethylamino) -3-pyridyl] · 5-isohumidazole] phenyl] acetamidamine MW = 42 6, confirmed by LC-MS, tr = 13.33 minutes (Method Y) MH + = 424-4 28

Compound 93 · (R905 9 8 5) 2,2-Dichloro-N-[3-[3-[(2,4-Dichloro) -3-pyridylisoimidazole] phenyl] acetamidamine MW = 417, confirmed by LC-MS, tr = 15.37 minutes (method γ) MH + = 4 1 5-4 1 9 compound 95 · (R90 5 9 8 7) 2,2 · dichloro-N- [3- [3 -[(2-Chloro- 4-morpholinyl) -3-pyridyl] -5-isoDfazole] phenyl] acetamidamine MW = 468, confirmed by LC-MS, tr = 13.73 minutes (Method γ ) ΜΗ + = 466-470 compound 97 · (R909 8 74) 2,2-dichloro-N-[3-[3-[(6- -79- (76) (76) 200407121 bromo) -2-pyridine [Iso] -5-isoxazole] (4-pyridyl)] acetamidamine MW = 42 7, confirmed by LC-MS, tr = 3 6.0 3 minutes (method W) MH + = 42 5 -42 9 (R 9 0 4 8 7 1) 2,2-dichloro-N- [2- [3- [(2,6-dichlorophenyl) -5-

Isoxazole] _ (4-pyridyl)] acetamidine hydrochloride MW = 453 melting point = 24 0-2 4 1 ° C Elemental analysis: C] 6H1 () C15N2 02 Requirements: C, 42.3 7;;, 2.22;

Cl, 39.09; N? 9.27; Experiment 値: C, 42.51; H, 2.18; C1, 39.06; N, 9.05. (R909919) 2,2-dichloro-N- [2- [3- (2,6-dichlorophenyl) -5_isohumazole (4-pyridyl)] acetamidomethanesulfonate MW = 589 Melting point = 246-247 t: Elemental analysis: C23H] 7C14N3 0 5 S Requirements: C, 46.8 8; H, 2.91; N, 7.13; S, 5.44; Experiment 値: C, 47.05; Η, 3.06; Ν, 7 · 00; S, 5.30. (R909920) 2,2-dichloro-N- [2- [3- (2,6-dichlorophenyl) -5-

Isopropazole] (4-pyridyl)] acetamidoethane sulfonate MW = 527 Melting point = 2 10-2 1 1 ° C Elemental analysis: C] 8H15C14N 3 0 5 S Requirements: C, 41.01; H, 2.87 Ν57 · 97; S, 6.08; Experiment 値: C, 41.00; Η, 2.77; Ν, 7.72; S, 5.80. -80- (77) (77) 200407121 (R9 0 9 92 3) 2,2_-chloro 4- [2- [3- (2,6-dichlorophenyl) -5-

Iso-Dfazole] (4-pyridyl)] acetamidinium mononitrate MW = 480 melting point = 1 7 5-1 7 6 ° C Elemental analysis: C16H1GCl4N4 05 Requirements: c, 4 03; h, 2.10; Ν, 11.67; Experiment 値 · C, 40.3 3; Η5 1.94; Ν, 11.25. The following are additional experiments that can be used to synthesize other compounds of the invention. Method F (refer to Figure 15) #I 7 · Acetylene cross-coupling reaction is suitable for substituted o-bromonitrobenzene or substituted o-iodonitrobenzene dissolved in a suitable solvent (such as p-diDfane Or THF), followed by treatment with at least five equivalents of a suitable amine base (which may be triethylamine, diethylamine, or diisopropylethylamine). Alternatively, the amine base may be used alone as a solvent. Subsequently, an argon m stream was bubbled through the solution for several minutes, after which dichlorobis (triphenylphosphine) mesh (II) (3 to 4 mole percentage), CuI (6 to 8 mole percentage) and finally Trimethylsilylacetylene (1.2 to 1.5 Molar equivalents). The reaction mixture is heated at 50 to 8 (rc until the reaction is complete (detected by TLC or LC-MS). When more reactive substituted o-iodonitrobenzene is used, acetylene cross coupling can be performed at room temperature Reaction. If the reaction is slow, add other trimethylsilylacetylene. This general method is in the literature _ is S 〇n 〇gashira coupling (K · S ο η 〇gashira et al., -81- (78) (78) 200407121

Tetrahedron Lett., 1 97 5, 4467). The reaction mixture was then diluted with ethyl acetate and the solution was washed several times with brine. Or the crude reaction mixture was filtered through a pad of calcium ore, followed by dilution with ethyl acetate and washing with brine. The obtained organic layer was dried over anhydrous sodium sulfate, filtered 'and concentrated to dryness under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and ethyl acetate to produce the desired substituted o- (dimethylformylethynyl) nitrobenzene. #Media 2 • Reduction of nitro to amine The substituted o- (trimethylsilylethynyl) nitrobenzene prepared in step 1 is dissolved in a concentrated hydrochloric acid methanol solution of 10 to 15 volume percent. After that, iron powder (A 1 d r i c h c h e mi c a 1 C 0 ·) (5-10 mol equivalent) was added, and the mixture was heated at 70 to 80 ° C for 3 to 4 hours. This reaction is exothermic in large scale. After cooling to room temperature, the reaction mixture was filtered through calcium ore, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and carefully washed with an aqueous solution of sodium hydroxide or sodium bicarbonate. The aqueous layer was discarded, and the organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure. If necessary, the crude product is purified by column chromatography on silica gel and eluted with a mixture of hexane and ethyl acetate to produce the desired substituted o- (trimethylsilylethynyl) aniline. # J · Removing trimethylsilyl from acetylene The substituted o- (trimethylsilylethynyl) aniline prepared in step 2 is dissolved in methanol containing 2 to 5% water. If the solubility of aniline in -82- (79) (79) 200407121 is poor, use an appropriate amount of tetrahydrofuran (THF) as a co-solvent. Anhydrous potassium carbonate (1 mole equivalent) was added and the mixture was stirred at room temperature for 1 to 24 hours until TLC confirmed that the reaction was complete. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The substituted o-aminophenylacetylene can be purified by column chromatography on silica gel, and then dissolved in hexane and ethyl acetate (if necessary). #Media 4 · Introduction of a haloacetamidine or dihaloacetamide side chain The substituted o-v-aminophenylacetylene prepared in step 3 is dissolved in dichloromethane. Triethylamine (1.3 mole equivalents) was added and the solution was cooled in an ice bath under nitrogen. Thereafter, a solution of p-acetylacetamidine or dihaloacetamidine (1.0 mole equivalent) in methylene chloride was added dropwise. After the addition was complete, the reaction was stirred at 0 ° C for 0.5 to 1 hour and then allowed to warm to room temperature. After a total reaction time of 1 to 4 hours, the reaction mixture was diluted with water. The organic layer was separated and washed with saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give substituted 2-halo- or 2,2-dihalo-N- (2-ethynylphenyl) acetamidamine. Or the substituted o-aminophenylacetylene starting material is dissolved in dichloromethane, and 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride ( 1 mole. Equivalent), halo- or dihaloacetic acid (1 mole equivalent) and finally triethylamine (1 mole equivalent). The reaction mixture was stirred at room temperature until the substituted o-aminophenylacetylene starting material was consumed as determined by TLC analysis. The mixture was washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and -83- (80) (80) 200407121 was concentrated to dryness under reduced pressure to give a substituted 2-halo- or 2,2-dihalo-N -(2-ethynylphenyl) acetamide. Method G (refer to Figure 5) A suitably substituted ortho-iodoaniline or ortho-bromoaniline starting material is coupled to trimethylsilylacetylene as described in step F of method F. The formed substituted ortho- (trimethylsilylethynyl) aniline is then deprotected using the method described in Step 3 of Method F to produce a substituted ortho-aminophenylacetylene which is subsequently converted to the desired 2-halo- or 2,2-dihalo-N- (2-ethynylphenyl) acetamide, as described in step 4 of method F. General method and method for preparing 2 -dentyl- or 2,2 -fluorenyl-N- (4. acetyl radical) acetamide 醯 Introduction of haloacetamidine or dihaloacetamide side chains The p-aminophenylacetylene purchased from A1d1.ichChemica1C0 was dissolved in dichloromethane. Triethylamine (1.3 mole equivalents) 'solution was added and cooled in an ice bath under nitrogen. A solution of haloacetamidine or dihaloacetamidine (1.0 mole equivalent) in dichloromethane was added dropwise. After the addition was complete, the reaction was stirred at 0 ° C. for 0.5 to 5 hours, and then allowed to warm to room temperature. After a total reaction time of 1 to 4 hours, the reaction mixture was diluted with water. The organic layer was separated and washed with a saturated aqueous sodium hydrogen carbonate solution and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give substituted 2-halo- or 2,2-dihalo-N- (cardiethynylphenyl) acetamide. Or the substituted -84- (81) (81) 200407121 p-aminophenylacetylene starting material is dissolved in dichloromethane, and 1- (3-dimethylaminopropyl) -3 -ethyl Carbodiamidate hydrochloride (1 mole equivalent), halo- or dihaloacetic acid (1 mole equivalent) and finally triethylamine (1 mole equivalent). The reaction mixture was stirred at room temperature until the substituted p-aminophenylacetylene starting material was consumed by TLC analysis. The mixture was washed with water, the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated to dryness under reduced pressure to give substituted 2-halo- or 2,2-dihalo-N- (2-ethynylphenyl) ethene. Lamine. All publications, patents, and patent applications listed in this invention are incorporated herein by reference as if each individual publication, patent, and patent application was explicitly and individually incorporated. Although the present invention has been described in more detail by way of illustration and examples, those skilled in the art of the present invention will understand that specific changes and modifications can be made without departing from the spirit or scope of the present invention. [Brief Description of the Drawings] Fig. 1 provides an exemplary compound of the present invention; and Figs. 2 to 63 provide an exemplary synthetic flow chart for synthesizing the compound of the present invention. -85-

Claims (1)

200407121 Scope of patent application 1. A compound having the structural formula (I) or (II): Or a pharmaceutically acceptable salt, hydrate, solvate or N-oxide thereof, wherein: the B ring system is an aromatic or non-aromatic ring including one to four heteroatoms, of which X, Y, and Z are S1J Selected from C, CH, N, NR16, NR18, S or 0, the prerequisite is that X and Y are not 0 at the same time; U and T are individually selected from C, CH or N; Z is N or -CH-; A Is N or -CR2-; B is N or -CR3-; D is N or -CR4-; E is N or -CR5-; (2) (2) 200407121 G is N or -CR 6 _; J is N or -CR1; K is N or -CRL; L is N or -CR9-; M is N or -CRU; R2 and R6 are each selected from hydrogen, halo, fluorine, Chlorine, hydrocarbyl, methyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, hydrocarbyloxy, methoxy, isopropoxy, substituted hydrocarbyloxy, hydrocarbyloxy, substituted hydrocarbyl Hydrocarbyloxy, arylhydrocarbyl carbonyl, substituted arylhydrocarbyl carbonyl, aryloxyfluorenyl, substituted aryloxycarbonyl, cycloheteroalkyl, substituted cycloheteroalkyl, aminoformyl, Substituted aminomethyl amidino, haloalkyl, trifluoromethyl, amino fluorenyl, substituted amino sulfonyl and Silyl ether, the prerequisite is that one of R2 and R6 is not hydrogen; and R5 is each selected from hydrogen, halo, chlorine, hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted hydrocarbylthio, smoke Oxy, substituted hydrocarbyloxy, hydrocarbyloxy, substituted hydrocarbyloxycarbonyl, aryl hydrocarbyloxycarbonyl, substituted cubic nicotyloxycarbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, cycloheterocyclic Hydrocarbyl, substituted cycloheteroalkyl, aminoformyl, substituted aminoformyl, halohydrocarbyl, aminosulfonyl and substituted aminosulfonyl; R4 is selected from hydrogen and halo , Hydrocarbyl, substituted hydrocarbyl, hydrocarbylthio, substituted nicotinyl, aminoformamyl, substituted aminoformyl, hydrocarbyl, substituted hydrocarbyl, hydrocarbyloxy, substituted Oxynitrate, aryl oxynitrate, substituted aryl hydrocarbon oxycarbonyl, aryloxycarbonyl, substituted cubic oxygen radical, one hydrocarbon base, substituted dihydrocarbyl amine, halohydrocarbyl, -87- (3) (3) 200407121 aminosulfonyl and substituted aminosulfonyl; R7 is -NRMC (〇) R12; R8, R9, feet 10 and R] 4 are each selected from hydrogen, halo and fluorine; R11 is hydrogen, hydrocarbyl or methyl; and R12 is substituted hydrocarbyl, halohydrocarbyl, halomethyl, dihalomethyl, dichloromethyl, cycloheterohydrocarbyl Or substituted cycloheteroalkyl; R16 and R18 are each selected from hydrogen, lower alkyl, substituted lower hydrocarbon, lower heteroalkyl, substituted lower heteroalkyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, Substituted cycloheterohydrocarbyl, low-halohydrocarbyl, monohalomethyl, di-methyl, trihalomethyl, trifluoromethyl, low-hydrocarbon thio, substituted low-hydrocarbon thio, low-hydroxyl, Substituted lower alkoxy, methoxy, substituted methoxy, lower heteroalkoxy, substituted lower heteroalkoxy, cycloalkoxy, substituted cycloalkoxy, cycloheteroalkoxy Group, substituted cycloheteroalkoxy group, low alkoxy group, monohalomethoxy group, dihalomethoxy group, trihalomethoxy group, trigasmethoxy group, lower di- or monohydrocarbylamino group , Substituted lower difluorenyl or mononicotyl group, aryl group, substituted square group, square oxy group, substituted aryloxy group, phenoxy group, substituted phenoxy group, aryl hydrocarbon group Substituted aromatic radicals, arylhydrocarbyloxy, substituted arylhydrocarbyloxy, benzyl, π ^ Guangguang & fluorenyloxy, heteroside, substituted heteroaryl, heteroaryloxy Base, substituted heteroaryloxy, heteroarylhydrocarbyl, substituted heteroarylhydrocarbyl, heteroarylnicotinyl, facet substituted heteroarylhydrocarbyloxy, carboxyl, low-hydrocarbyloxycarbonyl, ^^ 1-Gas carbonyl, aryloxycarbonyl, substituted aryloxycarbonyl, arylqi #carbon group, substituted aryl hydrocarbon oxycarbonyl, carbamate, and substituted amine group Acid ester, aminomethylsulfonyl, substituted aminomethylsulfanylsulfonyl-88- (4) (4) 200407121 group, substituted aminosulfonylsulfonyl group and group of general formula -L-R17 Where ^ L ″ is a linking group, and R17 is a cyclic hydrocarbon group, a substituted cyclic hydrocarbon group, a cyclic heteroalkyl group or a substituted cyclic heteroalkyl group, and its prerequisites are: (i) A, B, D, E, At least one of G, J, K, L or M is N; (ii) not more than one of A, B, D, E or G is N; and (iii) J, K, L or M No more than one of them is N. 2. As for the compound in the scope of patent application, one of A, B, D, E or G is N, and one of J, K, L or M is N. 3. For the compound in the scope of application for item 1, where A, B, D, E or G is N, and J, K, L or M are not N. 4. For the compound in the scope of application for item 1, wherein A, B, D, E or G is not N, and one of J, K, L or M is N. 5. The compound according to item 1 of the scope of patent application, wherein the B-ring system is oxazole or a hydrogenated isomer thereof. 6. The compound according to item 1 of the scope of patent application, wherein the B ring system is thiazole or its hydrogenated isomer. 7. The compound according to item 1 of the application, wherein the B ring system is imidazole or a hydrogenated isomer thereof. 8. The compound according to item 1 of the scope of patent application, wherein the B ring system is a tri-π or its hydrogenated isomer. 9. The compound according to item 1 of the scope of patent application, in which the B ring system -89- (5) (5) 200407121 is the hydrogenated isomer of beer dioxin. 10. The compound according to item 1 of the scope of patent application, wherein the ring B system is isoxazole or a hydrogenated isomer thereof. 11 The compound according to item 1 of the application, wherein the ring b is pyrazole or a hydrogenated isomer thereof. 12. The compound according to item 1 of the scope of application, wherein the B ring system is a thiadi D group or a hydrogenated isomer thereof. 1 3 'A compound according to any one of claims 1 to 12 in the scope of patent application, wherein R7 is -NRnc (〇) r12, wherein r11 is hydrogen or methyl, and R 1 2 is _ c HC 12 . 14 For example, the compounds in Table 13 of the scope of the patent application, where X is N, Y is 0, and z is -CH-. ^ J For example, the compound of any one of items 1 to 12 of the 13th patent, where A is -CR2-, G is -CR6-, and R7 is -NR1 1 C (0) Ri2 , Where R11 is hydrogen or methyl, and is _CHCl2. 16. For the compound in the 15th scope of the patent application, where B is -CR3-, D is N, E is -CR5-, J is -CR14-, K is -CR8-, and L is Is -CR9-, M is -CR10-, and R3, R5, R9, R10, and R14 are each hydrogen. 17. The compound according to item 16 of the scope of patent application, wherein R8 is fluorine. 18. The compound according to item 15 of the scope of patent application, wherein B is -CR3-, D is -CR4-, E is -CR5-, J is -CR14- 'K is -CR8-, System B is -CR9-, System M is N, and R, R, R, R, -90- (6) (6) 200407121 R9 and R14 are each hydrogen. 19. If the compound in the 15th scope of the patent application, 8 is -CR3-, D is -CR4-, E is -CR5-, J is -CR14-, and K is -CR8-, 'L is N, M is -CR 1' ϋ_, and R3, R4, R5, R8, R1 (), and R14 are each hydrogen. 20. The compound according to any one of the items 1 to 12 of the scope of patent application, wherein R2 and R6 are each selected from chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, and isopropoxy Group, N-morpholinyl and N-morpholinylaminosulfonyl. 2 1. The compound according to any one of claims 1 to 12, wherein R2 and R6 are each selected from chlorine, fluorine, methyl, trifluoromethyl, methoxy or isopropoxy. 22 'A compound as claimed in any one of claims 1 to 12 in which R2 and R6 are each the same or different halo group. 23. The compound according to any one of claims 1 to 12, in which X is N, Y is 0 and Z is -CH-. 24. For the compound in the first item of the patent application, where A is -CR2-, G is -CR6- and R7 is -NR1 () R12, where Rn is hydrogen or methyl, and R12 is -CH2I. 25. For example, the compound in the 24th scope of the patent application, wherein R2 and R6 are each selected from chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, and N-morpholine And N-morpholine aminosulfonyl. 26. For example, the compound in the 24th scope of the patent application, in which R2 and R6 are individually selected from chlorine, fluorine, methyl, trifluoromethyl, methoxy and isopropyl-91-(7) (7) 200407121oxy . 27. The compound as claimed in claim 24, wherein R2 and r6 are each the same or different halo group. 2 8. If the compound in the 24th scope of the patent application, X is N, Y is 0, and z is _CH ... 2 9. In the scope of the patent application! A compound of the above item, wherein A is _Cr2-, B is -CR3-, R7 is -NRHCCO) R] 2, wherein R11 is hydrogen or methyl, and R12 is -CHC12. 30. For the compound in the 29th scope of the patent application, where D is -CR4-, G is -CR, E is -CR5-, J is -CR14-, and K is -CR8-, L The system is -CR9-, the M system is N, and each of R4, R5, R6, R8, R9, and RM is hydrogen. 3 1. As for the compound of item 29 in the scope of patent application, where D is -CR4-, G is -CR6-, E is -CR5 ·, J is -CR14, and K is-CR8-, L is N-, M is -CR10-, and R4, R5, R, R8, R1 (), and R14 are each hydrogen. 3 2 'A compound according to any one of claims 29 to 31, wherein R2 is chlorine, fluorine, methyl, trifluoromethyl, thiomethyl, methoxy, isopropoxy, N-morpholinyl or N-morpholinolinaminosulfonyl 'and R3 is chlorine, fluorine, methyl, trifluoromethyl or methoxy. 3 3. The compound according to any one of claims 29 to 31, wherein R2 is chlorine, fluorine, methyl, trifluoromethyl or methoxy, and R3 is chlorine, fluorine or tris Fluoromethyl. 3 4. The compound of any one of items 29 to 31 in the scope of patent application -92- (8) 200407121, in which R2 and R3 are each the same or different halo group. 3 5. The compound according to any one of the scope of patent application from item 29 to 31, wherein X is N, Y is 0 and z is _CH ... 3 6. The compound according to the scope of application patent 1 , Where a is -CR2-, G is -CR6-, and r6 are the same, and the prerequisite is that R2 and R6 are not hydrogen. 37. The compound according to item 1 of the scope of patent application, in which A is -CR2-, B is -CR3-, and V and r3 are each the same. The prerequisite is that R2 and R3 are not hydrogen. 38. If the compound in the first item of the patent application scope, where B is ― CR3-, E is -CR5 ... and R3 and R5 are each the same, the prerequisite is that R3 and R5 are not hydrogen. 39. The compound according to item 1 of the scope of patent application, wherein B is -CR3-, D is -CR4-, E is -CR5-, J is -CR14-, and K is -CR8-, and R3, R4, R5, R8, and R14 are each hydrogen. 40. The compound according to item 1 of the scope of patent application, wherein D is -CR4-, E is -CR5-, G is CR6, J is -CR14-, K is -CR8-, and R4, R5 , R6, R8, and R] 4 are each hydrogen. 4 1. The compound according to item 1 of the scope of patent application, which has the structural formula (la), (lb), (Ic), (Id) or (Ie): -93- 200407121 〇) Or a pharmaceutically acceptable salt, hydrate or solvate thereof, in which X, Y, R2, R6, R 1 1 and R 12 are as defined in the first scope of the previously applied patents and are -... means a single bond or Double bond. -94- 200407121 (ίο) 42. For example, the compound in the scope of patent application No. 4〗, where R]] is ammonia 'Rl2 is dichloromethyl, R2 and R6 are each selected from halo, chlorine, chlorine, fluorene Fluoromethyl and methoxy. 4 J 'As in the scope of patent application, the compound has the structural formula (If): Or a pharmaceutically acceptable salt, hydrate, or solvate thereof, in which R2, H3, R4 '' r6, r8, r9, r11, r12, and r14 are as defined in the first patent application and have the same prerequisites -... means single or double bond. 4 4. A compound selected from the compound group shown in FIG. 1, which inhibits HCV replication and / or proliferation and its I c 5 〇 is at a concentration of 100 μM or less when measured. 4 5 A compound such as the 44th in the scope of patent application, which has a 1C50 of 10 μM or less. 46. A pharmaceutical composition for inhibiting the replication or proliferation of hepatitis C ("HC") virion particles, which contains an effective inhibitor of Hc The amount of virus particles replicated or increased by the application of any one of the scope of patents 1 to 12, and a pharmaceutically acceptable adjuvant. 口 -95- (11) (11) 200407121 47, a A pharmaceutical composition for treating or preventing HCV infection, comprising a compound according to any one of claims 1 to 12 in an amount effective for treating or preventing HCV infection, and a pharmaceutically acceptable adjuvant. 4 8. The composition according to item 4 of the patent application scope, wherein the compound is administered at a dose of 0.1 mg / kg to 200 mg / kg. 4 9. The composition according to item 47 of the patent application scope, wherein the compound From 10 mg / kg to 100 mg / kg 50. The composition according to item 47 of the patent application, wherein the compound is administered orally. 51. The composition according to item 47, wherein the compound is administered by injection. 52. The composition according to item 4 of the scope of the patent application, wherein the compound is selected from the compound group shown in FIG. 1 and inhibits HCV complex exchange ^ / or proliferation and its IC50 is stored in concentration / min. Fold measurement is about 10 μ μ or less -96-