TW201039826A - Anti-viral compounds, compositions, and methods of use - Google Patents

Abstract

Disclosed are compounds of Formula (I), pharmaceutically acceptable salts thereof, compositions thereof, and methods for their preparation and uses for treating viral infections mediated at least in part by a virus in the Flaviviridae family of viruses.

Description

201039826 VI. Description of the invention: [Technical field to which the invention pertains] The present invention relates to the field of the pharmaceutical industry. Provided herein are compounds and compositions, methods for their preparation and their use in treating a viral infection by at least a portion of a virus in a virus. [Prior Art] The following publications are quoted in the above references: 1. Szabo, E. et al., corpse βί/ιο/. /? Looking for 2003, 9: 215-221. 2. Hoofnagle J.H., 1997, 26: 15S-20S. 〇 3. Thomson B.J. and Finch R.G., C/m MicraZn'a/ /n/eci. 2005, 11 : 86-94. 4. Moriishi K. and Matsuura Y., C/ie/n. Plant 2003, 14: 285-297. 5. Fried, M. W. et al., EngZ. J Md. 2002, 347: 975-982. 6. Ni, Z. J. and Wagman, A. S. Cm/t; ppiw. /> ton Z) kc <9v. Z) eve/. 2004, 7, 446-459. 〇 7. Beaulieu, P. L. M- Tsantrizos, Y. S. Curr. Opin. Investig. Drugs 2004, 5, 838-850. 8. Griffith, R. C. et al., Αη«· Λπ· Afeil Ozem. 39, 223-237, 2004. 9. Watashi, K. et al., Molecular Plus, J9, 111-122, 2005 10. Horsmans, Υ· et al, // epato/og};, 42, 724-731, 2005 Chronic infection of HCV It is a major health problem associated with cirrhosis, hepatocellular carcinoma and liver failure. There are an estimated 170 million chronically intact 145833 201039826 people in the world at risk of developing liver disease. I'2 alone in the United States, 2.7 million are chronically infected with HCV, and the number of deaths in HCVja in 2000 is estimated to be between 8,000 and 10,000, which is expected to be significant over the next few years. Increase the number. Infected by HCV infection in a high proportion of chronic infection (and infectious) with the original, it may not experience clinical signs for many years. Cirrhosis can eventually lead to liver failure. Liver failure due to chronic HCV infection is currently considered to be a major cause of liver transplantation. HCV is a member of the plague that affects both animals and humans. The genome is RNAt single-~9.6_千千基基键, and contains an "open translation" selling month*' which will be tf at the 5' and 3' ends of the untranslated region (5, _ and tUTR) Then, the amino acid of the amino acid is encoded. This multi-egg/white system is important for at least the replication and assembly of progeny virions. Structure and non-structure in HCV polyprotein ^ ^ ^ f ^ ^ ^ T : C-El-E2-P7-NS2-NS3-NS4a-NS4b-NS5a- NS5b φ replication in HCV does not involve any Xie Ba Intermediate, and this virus has not been integrated into the host genome, so the occupational infection can be cured in theory. Although the pathology of CV infection mainly affects the liver, the virus is found in other cell types of the body t, including peripheral blood. Currently, the standard treatment for chronic HCV is interference ^ (winning, and using three nucleus Taste, and this requires at least six (6) months of treatment. Sheng α belongs to the group of naturally occurring small proteins, which has characteristic biological effects, such as “toxicity, immune regulation and anti-tumor activity”, which are Hei cells produce and secrete 'hearts should be several diseases, especially viral infections. 145833 201039826 IFN-α is an important regulator that affects cell growth and immunology (4). The treatment of HCV with interferon is often accompanied by disadvantages. Side effects such as fatigue, fever, chills, headache, myalgia, joint pain, mild filling, psychiatric effects and associated disorders, autoimmune phenomena and related

Joint illness, as well as thyroid dysfunction. Three (four) #, muscle #5, _ single Wei salt dehydrogenase (IMPDH) inhibitor, will strengthen the efficacy of hcv treatment. Despite the introduction of the triazole nucleus: y: ' However, more than 5% of patients do not rule out the virus using the current standard of intervention for interferon-a (IFN) and three-degree nucleoside. At this point, standard therapy for chronic hepatitis C has been altered to a combination of pEGylated Να plus triazole nucleoside. However, many patients still have significant side effects, and the main sputum is associated with diazoloside. The triazole nucleoside system causes significant hemolysis in 10-20% of the patients treated at the currently recommended dose, and the drug forms teratogenicity and embryotoxicity. Even with recent improvements, the actual number of patients did not continue to respond to viral load5, and there is a clear need for more effective antiviral therapy for Hcv infection. The Xuxi route is being implemented to eliminate the virus. This includes, for example, the use of antisense oligonucleotides or ribozymes to inhibit HCV replication. Furthermore, low molecular weight compounds that directly inhibit HCV protein and interfere with viral replication are an attractive strategy to control HCV infection. Among the viral targets, NS3/4a protease/helicase and NS5b RNA-dependent RNA polymerase are considered to be the most promising viral targets for novel drugs. 6-8 In addition to using viral genes and their transcription and translation products as targets, antiviral activity can also be achieved by targeting host cell proteins necessary for viral replication. For example, Watashi et al. 9 shows how antiviral activity 145833 201039826 is achieved by inhibiting the injured host cell cyclophilin. Alternatively, effective TLR7 agonists have been shown to reduce HCV plasma levels in humans. 1 〇 / The worldwide epidemic layer of HCV and other #病# members of the disease virus 2, and further given the limited treatment options, there is a strong demand for the treatment of novel and effective drugs for infections caused by such viruses. SUMMARY OF THE INVENTION Provided by the compound of formula (I): R2

Or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrazine or F; and R2 is selected from the group consisting of hydrazine, Ci (6 alkyl and hydrazine or one to three _ groups substituted by <^- (:6 alkyl;

Y is selected from the group consisting of c2_c oxy, substituted Cl_Q alkoxy, aryl, heteroaryl and heteroaryl substituted by 1 to 2 R6; R4 is CF3 or CN; R5 Independently selected from the group consisting of: _ group, cyano group and cyclopropyl group; 145833 £ 201039826 R6 is a group independently selected from the group consisting of dentyl, q & alkyl, && alkoxy And RaRbN-, wherein ^ and the oxime are independently H or Ci_C5 alkyl; and R7 is selected from the group consisting of: a methoxy group, a thiol group, a aryl group, an aryl group, and an RCRdN_, wherein the heart is independent or Cl-c3 alkyl. A pharmaceutical composition is also provided which comprises a pharmaceutically acceptable carrier, and a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof.

Also provided are methods of preparing a compound of formula (I), or a pharmaceutically acceptable salt thereof, and compositions thereof, and therapeutic uses thereof. In a specific embodiment, a method of treating at least a portion of a virus transmitted by a virus in a virus of a cockroach (IV) virus in a patient is provided, which comprises administering to the patient a compound comprising Formula 1 or a pharmaceutically acceptable compound thereof Accept the composition of the salt. In some embodiments, the viral infection is mediated by a hepatitis C virus. These and other specific embodiments are further described in the following text. DETAILED DESCRIPTION OF THE INVENTION Definitions Throughout this specification, reference is made to various specific embodiments of the compounds, compositions, and methods. The different specific embodiments are intended to provide a multi-monthly example and should not be construed as a substitute for the species. Rather, the description of the various embodiments provided herein may have overlapping ranges. The specific embodiments discussed herein are merely illustrative and are intended to limit the scope of the invention. It is to be understood that the terminology of the invention is not intended to limit the scope of the invention. In the specification of the patent 145833 201039826 and in the claims below, reference will be made to a number of terms which will be defined to have the following meanings: alkyl refers to a monovalent saturated aliphatic hydrocarbon group having from one to one carbon atom, but In some embodiments, it is 丨 to 6 carbon atoms. "Cx y alkyl, means an alkyl group having from X to y carbon atoms. By way of example, the term includes both linear and branched hydrocarbon radicals such as methyl (CHp), ethyl (CH3CH2), n-propyl (CH3CH2CH2-), isopropyl ((CH3)2CH-), n-butyl. (ch3CH2CH2CH2-), isobutyl cleavage, small second-butyl (6) is called (four) is called yuppe-tert-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2) and neopentyl ((CH3)3CCH2 -) "Alkoxy" refers to a group - 〇-hospital group, wherein the leuco group is defined herein. § 'Alkoxy includes methoxy, ethoxy, n-propoxy, Isopropoxy group, n-butoxy, tert-butoxy, second-butoxy and n-pentyloxy. Square or "Ar" means an aromatic group of 6 to 14 carbon atoms a group having no ring = atom ' and having a single ring (eg, phenyl) or multiple condensation (fused) ring (eg, or a dibasic ρ for a multiple ring system, including those having no ring heteroatoms) The fused, bridged and spiro ring system of the aromatic ring, m, Ar" ^ # is suitable for the attachment point when it is attached to an aromatic carbon atom (for example, the 5,6,7,8 four-gas group is the aryl gene and its linkage Point is in the position of the aromatic benzene ring 2) "Alkyl group or f-nitrile" refers to the group _CN. or "_" is a fluoro group, a gas group, a bromo group and an iodine group. The L-hetero group is intended to have 1 to 14 carbon atoms and 1 An unsubstituted aromatic group of up to 3 heteroatoms, "Hail heteroatoms selected from the group consisting of oxygen, nitrogen and sulfur, and including a single ring (you | » . (eg imidazolyl) and polycyclic System (eg benzimidazole_2-based 145833 201039826

Sitting on the 6-base with Benkai. The term heteroaryl as used herein does not have an aromatic group of the f-phase (tetra) hetero atom. For a condensed, bridged, and spiro ring system of a multi-family, ^2=family and non-family ring, if there are , , , :: solid-ring heteroatoms, and the point of attachment is on the atom of the aromatic ring, then Heteroaryl 2 is suitable (for example, 12,34•tetrahydro 4 4 _6• group and 5,6,7 fine hydrogen forest soil 3 in a specific example, heteroaryl.../or sulfur ring atomic pass = = providing N-oxide (tetra)), fluorenyl or hydrazine groups. More specifically, heteroaryl-terms include, but are not limited to, hydrazine. determinate/mercapto, fluorenyl, oxazolyl, imidazolyl , pyrrolyl, pyrimidine oxime, ^ open bite 7 base, tetrahydrobenzopyranyl, isobenzopyrene 9 base m sitting soil, material base, iso-based, benzo-xylene base, material base, four gas a base, a hetero-base, a 1 ή phase, a benzometh) or a benzo 4 phenyl group. As used herein, "a compound" and "the compound" refers to a compound encompassed by the general formula disclosed herein. Any subgenus of such general chemical formula, and any form of a compound within the general and subgeneric formula: including one or more compounds of racemates, stereoisomers and tautomeric racemates &q Uot; refers to a mixture of palmomers. Stereoisomers, or "stereoisomers" refers to compounds that differ in palmarity in one or more stereopsis. Stereoisomers include para-isomers and diastereomers. "Supplyable salt" means a pharmaceutically acceptable salt derived from a variety of organic and inorganic counterions well known in the art, and by way of example only, sodium, potassium, calcium, magnesium , ammonium and tetraalkyl money, and when the molecule contains 145833 201039826 an organic functional group, it is a salt of an organic or inorganic acid, such as a monoacid salt, a tartrate salt, an alkane sulfonate, an acetic acid, a smooth, stinky: = Salt is included in RHei峨stahlcamllleGW_th (edited " ~ ί± quality, selection and use manual; Congzhong said: Second-line hf ritual animals, including humans and non-human mammals. Disease =: disease, · To treat, or, to treat a disease, to prevent a disease from occurring in a patient who is susceptible or has not yet shown the disease; 2) to inhibit the disease or to curb its development; or 3) to ameliorate or cause the disease Degradation. : Unless otherwise indicated, the nomenclature of substituents not specifically defined herein is achieved by referring to the terminal portion of the functional group followed by the adjacent g energy group towards the point of attachment. For example, 'substituted alkoxy group' refers to the group alkyl-hydrazine-. It should be understood that 'in all of the substituted groups defined above, by definition the substituent has a further substituent for itself (eg A substituted aryl group having a substituted aryl group as a substituent and a substituted aryl group substituted by a substituted group, the latter being further substituted by a substituted aryl group, etc.) is not intended to be included Herein, in this case, the maximum number of such substituents is three. For example, the substituted aryl group is restricted to the -substituted aryl group by the sequence substitution of two other substituted aryl groups ( Substituted aryl)-substituted aryl. Likewise, it should be understood that the above definitions are not intended to include unacceptable substitution patterns (e.g., sulfhydryl groups substituted with 5 fluoro groups). It is known to skilled artisans to replace the plastic type. Therefore, the compound provided is the compound of formula (I): 145833 -10- 201039826

Or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrazine or F; and R2 is selected from the group consisting of hydrazine, Ci-C6 alkyl group and Ci-C6 alkyl group substituted by R7 or one to two halogen groups. ; L is

Ο Y is a group selected from the group consisting of CyQ alkoxy, Ci_C6 alkoxy substituted by 1 to 3 R5, aryl, heteroaryl and heteroaryl substituted by 1 to 2 R6; Ο R4 Is CF3 or CN; R is independently selected from the group consisting of: cyano, cyano and cyclopropyl; R is independently selected from the group consisting of halo, Ci_c3 alkyl, Ci_c5 alkoxy and RaRbN_, wherein Ra and Rb are independently H or ^&alkyl; and are selected from the group consisting of methoxy, thiol, thiol, cyano & RcRdN-, wherein RC is independent of Rd Is η or Ci_C3 alkyl. In some embodiments, a compound of formula 1 having the formula 145833 201039826 is provided.

A pharmaceutically acceptable salt thereof, wherein the γ is selected from the group consisting of unbranched alkoxy groups of the following composition, such as ethoxy, n-propoxy, n-butyl; pentyloxy and n- Hexyloxy; and ^^ are as defined for: (1). In some embodiments, R2 is deuterium. R 〇1

Or a pharmaceutically acceptable salt thereof, in the specific embodiments, provides a compound of the formula (1) having the formula: (1), in a specific embodiment, the guanidine 4 CP is supplied to a compound of the formula 1 having the formula

X.L. is as defined in formula (1) or a pharmaceutically acceptable salt thereof, and wherein /, hydrazine is substituted by 1 to 3 R5

Cj Cg is an oxy group, and R] β5 θ τ + Λι j* κ, R and L· are all as defined in the formula (1). In some embodiments, the Y master - / Y is a Ci _Q alkoxy substituted by two F. In some embodiments, y is substituted by a cyano group (IV). In some embodiments, γ is a cH alkoxy group substituted by a cyclopropyl group. In some embodiments, the compound of formula (I) having the formula: 145833 -J2· 201039826

Or a grammatically acceptable salt thereof, wherein the γ is selected from the group consisting of aryl, heteroaryl and heteroaryl substituted by 1 to 2 R6; and R, R6 and L are both As defined in Formula 1. In some embodiments, the gamma is selected from the group consisting of phenyl, pyrrolyl, phenyl, and pyridyl. Ο

Or a pharmaceutically acceptable salt thereof, wherein R1, MY are as defined in Formula 1. In some embodiments, the gamma is selected from the group consisting of unbranched alkoxy groups, such as ethoxy, n-, oxy, n-butoxy, n-decyloxy, and n-hexyloxy base.各种 Various features relating to the specific embodiments above are shown below. These features, when referring to different substituents or variables, may be combined with each other or with any other specific embodiment described herein. In one embodiment, the compound of the formula 1 having one or more of the following features is provided. In some embodiments, R1 is Η. In one embodiment of the 1st county, the R1 is F. τ In some embodiments, L is 0-Ν In some embodiments, L A compound selected from Table 1 or a pharmaceutically acceptable salt thereof is also provided as 145833 - 13 to 201039826. Table 1 Compound # Structure name 1 5-[3-(4-Cyclopropyl decyloxy-2-trifluoro Mercapto-phenyl)-isoxazol-5-ylindenyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]indole 2 FF 2-( 2-fluorophenyl)-5-{1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-yl]-ethyl}-5H-imidazole [4,5-d] 嗒耕3 FF ^^cr〇^F 2-(2,3-difluoro-phenyl)-5-{3-[2-曱-lacyl-4-(2,2, 2-difluoro-ethoxy)-phenyl]-isoxazole-5-ylmethyl}-5-imidazol[4,5-d] 嗒耕 4 FF 2-(2,3-二乱- Stupid)-5-{1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-yl]-ethyl}-5H-imidazo[4, 5-d]嗒耕5 ^^^-cr〇^F 2-(2,3-di-r-phenyl)-5-{3-[4-(4,4,4-trifluoro-butoxy -2_trifluoromethyl-phenyl]-isoxazole-5-ylindoleyl 5H-imidazo[4,5-d] 嗒耕6 cro>"bF 2-(2,3- two chaos -phenyl) -5-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-ylmethyl]-5H-imidazo[4,5-d] 嗒 7 7 FF 2-(2-Fluorophenyl)-5-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-ylindenyl]-5H-imidazo[4 ,5-d]嗒耕8 F , <^r〇:vb 5-[3-(4-ethoxy-2-trifluoromethyl-phenyl)-isoxazole-5-ylmethyl] -2-(2-fluorophenyl)-5H-imidazo[4,5-d]嗒耕145833 -14- 201039826 9 F 2-(2,3-Difluoro-phenyl)-5-[3- (4-ethoxy-2-trifluorodecyl-phenyl)-isoxazol-5-ylindenyl]-5H-imidazo[4,5-d]indole 10 2-(2,3- Difluoro-phenyl)-5-{(R)-l-[3-(4-propoxy-2-trifluoromethyl-phenyl)-iso-oxazole-5-yl]-ethyl} -511-imidazo[4,5-d] 嗒 11 11 2-(2,3-digas-phenyl)-5_ {(S)-l-[3-(4-propoxy-2-tris) Fluorinyl-phenyl)-isoindole^spin-5-yl]-ethyl}-511-imidazo[4,5-d] 嗒耕12 FF '^cr〇:vbF 2-(2,3- Dioxo-phenyl)-5-{3-[4-(3-fluoro-propoxy)-phenyl]-isoxazole-5-ylmethyl}-5H-imidazo[4,5-d ]嗒耕13 FF 2-(2,3-Difluoro-phenyl)-5-[3-(4-trifluoromethoxy-2-trifluoromethyl-phenyl)-isoxazole-5- Methyl]-5H-imidazo[4,5-d] 14 /CN f 2-{3-[2-(2-fluorophenyl)-cafe and [4,5-d]嗒井-5-ylmethyl]-isoxazole-5-yl}- 5-trifluoromethyl-benzonitrile 15 FF crc〇~y 2-(2,3-disorder-phenyl)-5-[5-(4-propoxy-2-trimethyl-benzene-benzene -isoxazole-3-ylindenyl]-5H-imidazo[4,5-d]嗒耕16 ~^y^° 2-{3-[2-(2,3-diphenyl) -isoxazo[4,5-d]indole-5-ylindenyl]-isoxazol-5-yl}-5-propoxy-benzonitrile 17 FF "^cr〇>^F 2-(2,3-dimur-phenyl)-5-[3-(4-isopropoxy-2-disorganinyl-phenyl)-isoxazole-5-ylindenyl]-5H -Imidazo[4,5-d] 嗒耕145833 -15- 201039826 18 2-(2,3-di-phenyl-phenyl)-5-[3-(4-isobutyllacyl-2-dimethoxy) Phenyl-phenyl)-isoxazol-5-ylmethyl]-5H-imidazo[4,5-d] 嗒耕 19 2-(2,3-disorder-phenyl)-5-{3- [4-((S)-2-Methyl-butoxy)-2-trifluoromethyl-phenyl]-isoxazol-5-ylindenyl}-5H-imidazo[4,5-d嗒耕20 2-(2,3-Disorder-phenyl)-5-{ 3_ [4-(3-indolyl-butoxy)-2-trifluoromethyl-phenyl]-iso 11 Zyrid-5-ylmethyl}-5-imidazo[4,5-d]indole 21 5-[3-(4-butoxy-2-trifluoromethyl-phenyl)-isoxazole- 5-ylmethyl]-2-(2,3-difluoro- ))-5H-imidazo[4,5-d] 嗒耕 22 FF ; c^Vo^f 2-(2,3-difluoro-phenyl)-5-{3-[4-(2,4 -Dimethyl-pyrazol-5-yl)-2-trimethylmethyl-phenyl]-isoxazole-5-ylindenyl}-5H-imidazo[4,5-d]嗒啩23 H 〇^crcc>^ 2-(2,3-dioxa-phenyl)-5-{ 3-[4-(1Η-pyrrol-3-yl)-2-trifluoromethyl-phenyl]-isoindole Zyrid-5-ylmethyl}-5& imidazo[4,5-d] 嗒 24 24 o^crco^ 2-(2,3-difluoro-phenyl)-5-[3-(4-pyridyl) Bite-4-yl-2-difluoroindolyl-phenyl)-isoxazole-5-ylmethyl]-5H-imidazo[4,5-d] 嗒耕 25 2-(2,3-. Mouse-bens)_5-[3-(4-mouth ratio σ-but-3-yl-2-trifluoromethyl-phenyl)-isoxazol-5-ylindenyl]-5Η-imidazo[4 ,5-d]嗒耕26 o^crco^ 2-(2,3-difluoro-phenyl)-5-[3-(3-trifluoromethyl-biphenyl-4-yl)-isoxazole -5-ylmethyl]-5H-imidazo[4,5-d] 嗒耕145833 -16- 201039826

2-(2,3-Difluoro-phenyl)-5-[3-(4->^ phen-2-yl-2-tris-methyl-phenyl)-isoxazole-5-ylindole ]]-5Η-imidazo[4,5-d] 嗒 well 2-(2,3-difluoro-phenyl)-5-[3-(4-峨 -2--2-yl-2-trisole Benzyl-phenyl)-iso 11 oxazol-5-ylmethyl]-5H-imidazo[4,5-d] oxime In some embodiments, a pharmaceutical composition comprising a pharmaceutical oxime 2- (3_[2-(2,3-Difluoro-phenyl)-imidazo[4,5-d]indole-5-ylmethyl]-isoxazole-5-yl}-5-trifluoromethyl 2-benzonitrile-(2-(2,3-difluoro-phenyl)-5-{1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-iso-sigma- 5-yl]-propyl}-511-»myzolo[4,5-d] 嗒耕(4-{5-[2-(2,3-difluoro-phenyl)- oxazolo[4 ,5-d]嗒耕-5-ylmethyl]_iso 1> oxazol-3-yl}-3-trifluoromethyl _ 4 oxy)-ethyl hydrazine An effective amount of a compound described herein or one of the ', a sub-acceptable salt, or one or more such compounds, accepts a mixture of salts. Dry #, in some specific implementations, provides at least a treatment in a patient份被: Yan #抒 virus (such as Hcv) virus-borne side of the virus> 'This method includes the pair has been A pharmaceutical composition is administered to a patient suffering from or at risk of developing the viral infection, 1 comprising a drug 5 = a diluent and a therapeutically effective amount of one of the compounds described herein, or one or a mixture of a plurality of such compounds or a pharmaceutically acceptable H salt. In some embodiments, there is currently provided a use of a pharmaceutically acceptable salt or a pharmaceutically acceptable salt for the preparation of a medicament, the drug 145833 • 17- 201039826 The treatment or prevention of the infection D is in humans in some embodiments. In some embodiments, a method of treating or preventing a viral infection in a patient is provided, and the therapeutically effective amount is one or more resistant. The active agent against HCV includes an anti-HCV active agent including nucleus #, leveverin ae poly _, vera (vir), thymosin w, _ lysin protease inhibitor and muscle # monophosphate Inhibitor of dehydrogenase, interferon-UEG-interferon, alone or in combination with trisalpin or verapamil (10) amidine). In one example, the other agent that is resistant to hcv activity is an interferon or a pegylated interferon, either alone or in combination with a tri-saliva or a viramidine n-acting agent active agent. [Embodiment] General Synthetic Method The compound which is not disclosed in the present invention can be produced by following the general & order and examples set forth below. It should be understood that other treatment conditions may be used in the case of giving typical or preferred processing conditions (i.e., reaction temperature, time, molar ratio of reactants, solvent, pressure, etc.) unless otherwise stated. The optimum reaction conditions may vary with the particular reactants or solvents employed, but such conditions may be determined by routine experimentation by those skilled in the art. Moreover, as is well known to those skilled in the art, conventional protecting groups may be necessary to prevent certain functional groups from undergoing unwanted reactions. Suitable protecting groups for different functional groups, as well as suitable conditions for protecting and removing specific functional groups, are those of the art which are omitted by n y, $. For example, 'many protection systems are described in τ. w. 145833 • 18- 201039826 with RGM, Wms, only the heart of the heart (four)

New York, 1999, and its references, f Β, 1 edition, Wiley, referenced in the sub-reference. The compound or pharmaceutically acceptable salt described in the right of the present invention contains the center of the palm of the hand, and the compound can be used as a pure stereoisomer, or as an individual. Isomer or diastereomer, or a mixture of rich 3 stereoisomers. All such stereoisomers (and enriched in: s) are included within the scope of the invention unless otherwise indicated. The pure stereoisomers (or mixtures enriched) can be prepared using, for example, the active starting materials or stereoselective reagents known in the art. Alternatively, the racemic mixture of such a compound can be isolated using, for example, a palmar column chromatography, a palmarity resolving agent, or the like. General Procedure A The synthesis of compound 1-13 will be 2-aryl--salt [4 field answer (〇1〇 millimolar), aryl-iso compound chloro-based thiol- or 曱院真酸甲酷(1 eq.) and the test metal carbonate Q recorded 20 mM) The solution in qing (3 ml) was heated under microwave irradiation for 10 minutes at 60-12 CTC. The reaction was passed through a helium and purified by reverse phase HpLc to give the desired product. The product was converted to the HCl salt by the addition of 1 Η Ηα prior to concentration. The synthesis of the chloromethylaryl isoxazole compound from the aryl disk is as follows. In a solution of the carboxylic acid (13 mmol) in EtOH (26 mL), NH2 〇H (2.6 mL, 39.1 mmol, 3 equivalents, 5 % aqueous solution), and the mixture was stirred at 50 C overnight. Then, the reaction mixture was concentrated to give a hydrazine. Under 〇 °C, 'DCE (100 ml) in 肟 (13 mmol) with gas 145833 -19· 201039826 acetylene-propanol (1.9 ml '26 mmol, 2 equivalents'' followed by Na Na〇 a (i3 ml) treatment 1 two-phase mixture is given under the armpit for 2 minutes, then heating c to 1], then, the reaction mixture is cooled, and the reaction is quenched with saturated NaHC〇3 X /liquid mixture' Dispensing treatment. The aqueous phase was extracted (2X) on (3) and the combined organic phases were washed with brine (IX), dried over Na 2 S s 4 , filtered, and concentrated to give chloro aryl aryl iso-p-azole. An alternative synthesis of substituted isoxazole is as follows: under Ar, at 60T: at aryl hydrazine (3.6 mmol) with pyridine (26 μL, 〇36 mmol) in THF (8 mL) NCS (〇.53 g, 4 〇 mmol) was added to the solution. The solution developed yellow and was stirred at 6 (TC for 45 min. then triethylamine (0.61 mL, 4.4 mmol) and propargyl alcohol (22 ml, 3 8 m). The mixture was stirred overnight at 60 C. The reaction mixture was partitioned between Et EtOAc and EtOAc (EtOAc) Addition of triethylamine (〇) to a solution of aryl-isoxazolyl methanol (2 2 mmol) in DCM (20 mL). • 5 ml, 2 eq.) with methanesulfonyl chloride (1.5 eq., 0.26 ml) and allowed to mix at room temperature for an hour. Then the reaction was quenched with water (10 ml) and the organic material was partitioned. Liquid treatment, and concentration, to give the product aryl sulfonate aryl-isosazolyl- decyl ester. Example 1 5 · [; 3- (4-cyclopropyl methoxy-2-trifluoromethyl- Phenyl)isoxazol-5-ylindenyl^-^difluoro-phenyl"imidazole and smear out of the sorghum (a) sulphate" according to the general procedure A, obtained from 5-gas thiol-3- (4-cyclopropylmethoxy) Base 2_ 145833 -20- 201039826 Trifluoromethyl-phenyl)-isoxazole with 2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d] sorghum. MS (M+H+): 510.3; tf-NMR (DMSO-d6): d (ppm) 10.03 (s, 1H), 9.35 (s, 1H), 7.86-7.82 (m, 1H), 7.39-7.31 (m, 1H), 7.24 (d, 1H), 7.14-6.98 (m, 3H), 6.61 (s, 1H), 5.97 (s, 2H), 3.64 (d, 2H), 0.95-0.87 (m, 1H), 0.29 -0.23 (m, 2H), 0.05-0.02 (m, 2H). Example 2 2-(2·fluorophenyl)·5-{1_[3-(4·propoxy-2-trifluoromethylbenzene) ))-isoxazole _5·yl]_ethyl}-5Η·imiphthene[4,5-d] Tower ρ well (Compound 2) 〇According to General Procedure A, obtained from 2-(2-fluorobenzene) -5Η-imidazo[4,5-d] plowing and 1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazole_5_• base of methanesulfonate ]-ethyl ester. MS: 512.2 (M+H+); i^NMR (DMSO-d6): ά (ppm) 10.78 (s, 1H), 9.88 (s, 1H), 8.33-8.43 (m, 1H), 7.71-7.83 (m, 1H), 7.47-7.62 (m, 3H), 7.30-7.39 (m, 2H), 7.02 (s, 1H), 6.88-7.00 (m, 1H), 4.07 (t, 2H), 2.13 (d, 3H), 1.67-1.83 (m, 2H), 0.98 (t, 3H). Example 3 q 2-(2,3-dioxazophenyl)-5_{3-[2-indolyl-4-(2,2,2-trifluoroethoxy)phenyl]-isoindole Zyrid-5-ylmethyl}-5Η·imidazo[4,5-d]indole (Compound 3) According to the general procedure A 'from 2-(2,3-difluoro-phenyl)-5H-imidazole And [4,5-d] . 嗒 与 and 5-fluoromethyl-3-[4-(4,4,4-trifluoro-butoxy)-2-trifluoromethyl-phenyl]- Isoxazole. MS 556.0 (M+H+); I^NMR (DMSO-d6): 5 (ppm) 10.52 (s, 1H), 9.74 (s, 1H), 8.15-8.10 (m, 1H), 7.74-7.64 (m, 1H), 7.60-7.57 (d, 1H), 7.52-7.50 (d, 1H), 7.45-7.39 (m, 2H), 6.93 (s, 1H), 6.35 (s, 2H), 4.97-4.88 (qrt· 2H). Example 4 145833 -21- 201039826 2-(2,3··-gas-phenyl)·5·{1-[3-(4-propoxy-2-.tris-methyl-phenyl)-iso嗤-5-yl]-ethyl}-5Η-imidazo[4,5-d] 嗒 (Compound 4) According to the general procedure A, from 2-(2,3-difluoro-phenyl)-5H -Imidazo[4,5-d] hydrazine and decanesulfonic acid l-[3-(4-propoxy-2-trifluoromethyl-phenyl)-iso-p-azole-5-yl]- Ethyl ester. MS : 530.1 (M+H+); Hi NMR (DMSO-d6): (5 (ppm) 10.57 (s, 1H), 9.79 (s, 1H), 8.13-8.22 (m, 1H), 7.67-7.80 (m, 1H), 7.58 (d, 1H), 7.42-7.52 (m, 1H), 7.30-7.40 (m, 2H), 6.99 (s, 1H), 6.70-6.82 (m, 1H), 4.07 (t, 2H) , 2.12 (d, 3H), 1.67-1.83 (m, 2H), 0.99 (t, 3H). Example 5 2-(2,3-difluoro-phenyl)·5-{3-[4-(4 , 4,4-trifluorobutoxy)-2-trifluoromethyl phenyl]. Isoxazole-5-ylmethyl}-5Η-isoxazo[4,5-d] Compound 5) is obtained according to the general procedure A from 5-oxylmercapto-3-[4-(4,4,4-trifluoro-butoxy)-2-trifluoromethyl-phenyl]-isoindole Oxazole and 2-(2,3-difluoro-phenyl)-1 Η-imidazo[4,5-d] 嗒. MS 584.2 (M+H+); i^NMR (DMSO-d6): δ (ppm ) 10.44 (s, 1H), 9.70 (s, 1H), 8.14-8.09 (m, 1H), 7.70-7.63 (q, 1H), 7.55-7.52 (d, 1H), 7.44-7.28 (m, 3H) , 6.90 (s, 1H), 6.30 (s, 2H), 4.15-4.10 (t, 2H), 2.44-2.34 (m, 2H), 1.95-1.88 (m, 2H). Example 6 1-Xi-4 · Propoxy-2-trimethylbenzene was introduced in each of three different 20 ml vials to introduce 2-bromo-5-fluorotrimethylated toluene (5 ml, 8.3 g '34 mmol) With 1-propanol (15 ML). When NaH (about 2.0 g, 60% in mineral oil) was added in portions, each solution was magnetically stirred at room temperature. After the addition, the reaction mixture became viscous and turbid with a yellow dye. The vial was sealed and heated by microwave irradiation to 145833 -22·201039826 145 ° C for 15 minutes. The reaction mixture was partitioned between water and diethyl ether (each approximately 丄〇〇 ml). The organic layer was washed with water and brine, then combined and dried over sodium sulfate. The solvent was removed and the residue was evaporated in vacuo to give the product as a colorless liquid (70-80 ° C, at 4 mm Hg). Yield: 25.0 g, 86%. 4·propoxy-2·trifluoromethyl·benzaldehyde in a flask, filled with diethyl ether (70 ml), and cooled at room temperature in a dry ice-acetone bath with magnetic Stir. In the reaction vessel, nBuLi (3〇5 ml '2.5M' in hexane, 78 mmol) was charged, and then 1-bromo-1,4-propoxy in hydrazine (30 ml) was added dropwise via a syringe. -2-Trifluoromethyl-benzene (2 〇. gram, 71 mmol). The reaction system develops a white sink. After μ minutes in a cold bath, DMF (6.1 mL, 83 mmol) was added dropwise. The cold bath was removed after 5 minutes and the reaction was allowed to warm to room temperature over 1 hour. Upon addition of DMF, the reactants first became a clear solution, followed by development of a white precipitate upon removal of the cold bath, and then, once further warmed to room temperature, again became a clear solution. The reaction was quenched with Η? SO# (about 1 mL, in) and vigorously stirred for 15 minutes. The liquid layer was separated and the organic layer was washed with water and brine, dried over sodium sulfate and concentrated. The product was purified by flash chromatography eluting with EtOAc EtOAc EtOAc Yield: 15.6 grams, 95%. 5-Alkylmethyl-3-(4-propoxy-2-tris-phenyl)-iso-p-salt 4-propyloxy-2-trifluoroindolyl-benzaldehyde (12 g , 51.7 mmol, dissolved in EtOH (46 mL, 1%) and treated with nh 2 〇H (6 mL, 50% in water, 98 mM). After 2 hours at room temperature, the reaction mixture was concentrated and EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc EtOAc The recovered hydrazine was dissolved in 90 mL of DCM and treated with chloropropanepropane (4.1 mL, &lt;RTI ID=0.0&gt;&gt; The reaction mixture was allowed to reflux for a small time&apos; and at this point LCMS showed complete consumption of ribs. The reaction mixture was left to stand at room temperature overnight. The organic layer was washed with brine, dried over sodium sulfate, evaporated, evaporated, and evaporated to give the product as oil (UO-MSt: </ RTI> </ RTI> </ RTI> <RTIgt; Yield: 9.2 g, 56%. 2-(2,3-Difluoro-phenyl)-5-[3-(4-propoxy-2-trifluoromethyl.phenyl)-isoindole·5_ylmethyl]-5Η-an嗤[4,5-d>荅" well (compound 6)

According to the general procedure A 'from 5-methylmethyl (4-propoxy-2-tris-yl-phenyl)-isoxazole and 2-(2,3-difluoro-phenyl)- iH-imidazo[4,5-d] morphine. MS 516.0 (M+H+); H1 NMR (DMSO-d6): (5 (ppm) 10.09 (s, 1H), 9.49 (s, 1H) 8.15 (m, 1H), 7.54 (m, 2H), 7.33 ( m, 3H), 6.90 (m, 1H), 6.18 (s, 2H), 4 06 (t, 2H), 1_75 (m, 2H), 0.98 (t, 3H). Example 7 2-(2·Fluorobenzene Base)-5-[3_(4·propoxy-2-.trifluoromethyl)phenyl)-iso-p-azole·5-ylmethyl]-5Η-flavored [4,5-d&gt;荅Well (Compound 7) According to the general procedure A, it is obtained from 5-chloroindolyl-3-(4-propoxy-2-tris-yl-phenyl)-iso 1*°° and 2-(2) -Fluorophenyl)-1Η-imiphthene[4,5-(3⁄4^荅p well. MS 498.0 (M+H+); WNMR (DMSO-d6): (ppm) 10.4 (s, 1H), 9.7 (s,1H), 8.34 (m, 1H), 7.7-7.3 (m, 6H), 6.90 (m, 1H), 6.33 (s, 2H), 4.06 (t, 2H), 1.75 (m, 2H), 0.97 (t, 3H). Example 8 5-[3-(4-Ethoxy-2·trifluoromethyl]phenyl)-iso-a sal _5·ylmethyl]·2_(2-fluorobenzene 145833 -24- 201039826 yl)-5H-imidazo[4,5-d] sorghum (Compound 8) According to the general procedure A, from 2-(2-fluorophenyl)-5H-imidazo[4,5 -d] 嗒, well with 5-oxyl fluorenyl-3-(4-ethoxy-2-trimethyl)-iso-indole. MS 484.7 (M+H+); H!NMR (DMSO-d6): (ppm) 10.56 (s, 1H), 9.80 (s, 1H), 8.39-8.33 (t, 1H), 7.77-7.67 (m, 1H), 7.57-7.46 (m, 3H), 7.36-7.30 (m, 2H), 6.96 (m, 1H), 6.4 (s, 2H), 4.19-4.12 (q, 2H), 1.36-1.32 (t, 3H). Example 9 2-(2,3-difluorophenyl)- 5-[3-(4-ethoxy-2-trimethylmethyl-phenyl)·iso-t»Jun_5_ylmethyl]-5H-imidazo[4,5-d] 9) According to the general procedure A 'from 2-(2,3-difluoro-1-phenyl)-511-flavored β and [4,5-d] sorghum and 5-chloromercapto-3-( 4-Ethoxy-2-trifluoromethyl phenyl)-isoxazole. MS 502.7 (M+H+); HJNMR (DMSO-d6): δ (ppm) 10.59 (s, 1H), 9.80 (s, 1H), 8.19-8.15 (m, 1H), 7.78 (q, 1H), 7.56 (d, 1H), 7.47 (t, 1H), 7.35-7.29 (m, 2H), 6.95 (s, 1H), 6.39 (s, 2H), 4.18-4.11 (q, 2H), 1.35-1.31 (t , 3H). Example 10 2-(2,3-di-phenyl-phenyl)-5-{(R)-l-[3-(4-propoxy-2-.trifluoromethyl-phenyl)-iso-p-azole -5_yl]-ethyl}-5Η·imidazo[4,5-d]嗒 (Compound 1〇) According to the general procedure A, obtained from decanesulfonic acid (S)-l-[3-(4 -propoxy-2-trifluoromethyl phenyl)-isoxazol-5-yl]-ethyl ester with 2-(2,3-difluoro-phenyl)-1Η-imidazo[4,5 -d] 嗒耕. MS: 530.1 (M+H+); I^NMI^DMSO-de): 5 (ppm) 10.57 (s, 1H), 9.79 (s, 1H), 8.13-8.22 (m, 1H), 7.67-7.80 (m , 1H), 7.58 (d, 1H), 7.42-7.52 (m, 1H), 7.30-7.40 (m, 2H), 6.99 (s, 1H), 6.70-6.82 (m, 1H), 4.07 (t, 2H) ), 2.12 (d, 3H), 1.67-1.83 (m, 2H), 0.99 (t, 3H). Example 11 145833 -25· 201039826 2-(2,3-Difluoro-phenyl)-5-you)-1-[3-(4·propoxy-2-trifluoromethylphenyl)-isoindole Azul-5-yl]•ethyl}-5Η·isoxazol[4,5-d] 嗒 (Compound 11) According to General Procedure A, obtained from methanesulfonic acid (R)-l-[3-(4 -propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-yl]-ethyl ester with 2-(2,3-difluoro-phenyl)-1Η-imidazo[4,5 -d] 嗒耕. MS: 530.1 (M+H+); tfNMI^DMSO-^): &lt;5 (ppm) 10.57 (s, 1Η), 9.79 (s, 1H), 8.13-8.22 (m, 1H), 7.67-7.80 (m , 1H), 7.58 (d, 1H), 7.42-7.52 (m, 1H), 7.30-7.40 (m, 2H), 6.99 (s, 1H), 6.70-6.82 (m, 1H), 4.07 (t, 2H) ), 2.12 (d, 3H), 1.67-1.83 (m, 2H), 0.99 (t, 3H). Example 12 2-(2,3-Difluoro-phenyl)-5-{3-[4-(3-fluoro-propoxy)-phenyl]-iso-p-indole-5-ylindenyl} 5Η_味唑[4,5-d]嗒 (Compound 12) According to the general procedure A, from 2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d] Sorghum and 5-methylmethyl-3-[4-(3-fluoro-propoxy)-phenyl]-isoxazole. MS: 534.2 (M+H+); H^MR (DMSO-d6): δ (ppm) 10.38 (s, 1H), 9.70 (s, 1H), 8.12-8.21 (m, 1H), 7.56-7.76 (m , 2H), 7.34-7.49 (m, 3H), 6.95 (s, 1H), 6.31 (s, 2H), 4.70 (t, 1H), 4.54 (t, 1H), 4.22 (t, 2H), 2.04- 2.25 (m, 2H). Example 13 4_Trifluoromethoxy-2-trifluoromethyl-benzaldehyde 1-nitro-4-trifluorodecyloxy-2-trifluoromethyl-benzene (0.95 g) was dissolved in methanol (90) In milliliters), and spray the solution in μ. Add Pd/C (1%, about 5 gram) and add a gas cylinder filled with hydrogen. The reaction was stirred at room temperature for 1 hour then filtered through Celite. The solvent was removed at 80 mm Hg and was at or below 35. (: heating down. The product was distilled under an 80 mm Hg spherical bottle to obtain 4-trifluoromethoxy-2-trifluoromethylanilide as a colorless liquid (063 145833 -26-201039826 g). 4-Trifluoromethoxy-2-trifluoromethyl-aniline (6 〇 7 mg, 25 mmol) was suspended in water (2.6 mL) and concentrated sulfuric acid (1 mL) was added. To the boiling point, and stir quickly, then allow to cool to room temperature, and continue to stir. When adding sodium nitrite solution (19 mg, in L2 ml of water) dropwise, the resulting suspension was placed in an ice bath. Stir. After stirring for 2 minutes in an ice bath, add a solution of potassium iodide (0.83 g in ι·ml of water) to a steady stream. Add a trace of bronze' and heat the reaction briefly to the boiling point. After 1 hour, the product was extracted into the mystery, washed with sodium sulphite and brine, dried over sodium sulfate, and concentrated to diatomaceous earth. _Iodo-4-trifluoromethoxy -Trifluoromethyl-benzene was isolated by flash chromatography on silica gel, using EtOAc (0-10%) from EtOAc. Mg). 1_Mercaptodifluoromethoxy-2-dimethyl-benzene (530 mg, 1.5 mmol, in 1. mL of anhydrous ether) under Ar, and in dry ice-acetone bath 'In a solution of anhydrous ether (1.5 ml) and nBuLi (0.65 ml, 2.5 Μ, 1.6 mmol) was added dropwise via a syringe. After 5 minutes, DMF (0.13 mL, 1.7 mmol) was added and The reaction was allowed to warm to room temperature over 30 min. The reaction was quenched with sulfuric acid (5 mL, 1 N) for 5 min and then the layer was separated. The organic layer was washed with water and brine. To the algae soil. 4_Trifluoromethoxy-2-trifluoromethyl-benzoquinone was subjected to flash chromatography on a mixture of EtOAc (0-5%). Liquid (186 mg). 2·(2,3·Difluorophenyl)·5·[3·(4·Trifluoromethoxy-2-trifluoromethyl-phenyl)-isoxazole-5- Methyl]-5Η-imidazo[4,5-d] 嗒 (Compound 13) According to the general procedure A 'from 2-(2,3-difluoro-phenyl)-5H-imidazo[4, 5-d]. morphine and 5-methylmethyl_3_(4-trifluoromethoxy-2-trifluoromethyl-phenyl)-isoindole 145833 - 27· 201039826 Wow. MS : 542.2 (M+H+” HMMR (DMSO-d6) ·· δ (ppm) 10.48 (s,1H), 9.75 (s, 1H), 8.13-8.22 (m, 1H), 7.97 ( s, 1H), 7.65-7.91 (m, 3H), 7.40-7.50 (m' 1H), 7.06 (s, 1H), 6.38 (s, 2H). General Procedure B Synthesis of compound 14_16 will be phenyl isocyanate (2.2 eq, n g), 2-(2-nitro-ethoxy)-tetrahydro-pyran (1 eq, 875 mg) and aryl A mixture of acetylene (1 eq., 5 mmol) in benzene (20 liters) was treated with DIEA (20 drops, excess) and then heated to 75 ° C overnight in a sealed small glass. The mixture was allowed to cool, the solution was decanted, concentrated, and purified on silica gel to afford &lt;RTIgt;&lt;/RTI&gt;&gt;&lt;/RTI&gt;&gt; (tetrahydro-P-pyrano-2-yloxyindenyl)-aryl-isoxazole. The solution of 3-(tetrahydro-indol-2-yloxyindenyl)-5-aryl-isoxazole in HOAc : HaO : THF (4:2:1) was heated to 75 ° C for 5 hour. The mixture was allowed to cool to room temperature and concentrated to give the product: 5- <RTI ID=0.0>#</RTI> </RTI> <RTIgt; Add 3-ethylamine (0.5 ml, 2 eq.) to methanesulfonyl chloride in a solution of 5-aryl-isoxazole-3-yl-methanol (22 mmol) in DCM (2 mL) (1.5 equivalents, 0.26 ml)' and stirred at room temperature for a few hours. Next, the reaction was quenched with water (10 ml), and the organic material was subjected to liquid separation and concentrated to give the crude product decanesulfonic acid 5-aryl-iso-p-azolamide methyl ester. Then, according to the general procedure A, the decanesulfonyl esters were coupled. Example 14 2-ethynyl-5-trifluoromethyl-benzonitrile 2-bromo-5-trifluoromethyl-benzonitrile (1 gram, 〇4 〇mol) was dissolved in triethylamine (600 ml), and spray the solution for 2 minutes. Add CuI (d (μg, 0.013 mol), Pd(PPh3)4 (450 mg, 0.38 mmol) and TMS_: 145833 -28· 201039826 alkyne (50 g '0.51 mol) and place the reaction in 8 (1 hour stirring at rc. A small amount of precipitate was developed and additional CuI(I) (1 g), Pd(PPh3)4 (1.5 g) and TMS-acetylene (15 ml) were added. The reaction was taken at 8 Torr. The mixture was further stirred for 3 hours at ° C. The reaction mixture was diluted with 1.5 liters of hexane and filtered over celite. The solvent was removed to give a yellow-brown crystal. The crystals were dissolved in methanol (250 ml) Potassium (1 g). The mixture was stirred at room temperature for 2 hours. Then, the reaction mixture was partitioned between ether (500 ml) and water (150 ml). The pH layer was no longer alkaline (about 10 times). The organic layer was washed with brine, dried over sodium sulfate, and concentrated, and then purified by silica gel chromatography using EtOAc (2-10% The 2-ethynyl-5-trifluoromethyl-benzonitrile was collected as a tan solid (62.5 g). H1 NMR (CDC13): δ (ppm) 7.9 3-7.92 (m, 1H), 7.84-7.80 (m, 1H), 7.76-7.74 (d, 1H), 3.64 (s, 1H). 2-{3·[2-(2·fluorophenyl)- Imidazo[4,5-d]indole-5-ylindenyl]isoxazole-5-yl}_5_ trimethyl-benzonitrile (Compound 14) ❹ According to the general procedure B, obtained from 2- (2-fluorophenyl)-5H-imidazo[4,5-d] morphine and oleic acid 5-(2-cyano-4-trifluoromethyl-phenyl)-iso-t»唆-3-based vinegar. MS: 465.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 10.60 (s, 1H), 9.80 (s, 1H), • 8.59 (s, 1H) , 8.33-8.42 (m, 1H), 8.23-8.28 (m, 2H), 7.69-7.80 (m, 1H), 7.45- 7.60 (m, 3H), 6.36 (s, 2H). Example 15 1 ·ethynyl 4-propoxy-2-trifluorodecylbenzene 4-propyloxy-2-trifluoromethyl-benzofural (795 mg, 3.43 mmol), (1_diazo-2-) --propyl)- bisphosphonate (790 mg, 4.11 mmol) and carbon 145833 -29- 201039826 acid clock (1.4 g ' 10.28 mmol) in methanol (i 〇 ml) Stir at ambient temperature overnight. The reaction was filtered and concentrated. Distilled water was added to the residue' and the mixture was extracted with ethyl acetate (3 x 15 mL). The organic layer was combined and dried by anhydrous sulphuric acid and filtered. The solvent is removed and the residue is purified by chromatography eluting to afford desired product. Example 15 2-(2,3-Difluoro-phenyl)-5.[5-(4-propoxy-2-trifluoromethyl)phenyl]isoxazole_3_ylmethyl]-5H -Imidazo[4,5-d] oxime (Compound 15) was obtained from methanesulfonic acid 5-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazole according to the general procedure B' 3-Gate oxime and 2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d] ta p well. MS . 516.1 (M+H+), I^NMR (DMSO-d6): d (ppm) 10.60 (s, 1H) 9.81 (s, 1H), 8.14-8.23 (m, 1H), 7.70-7.83 (m, 2H), 7.33-7.55 (m, 3H), 6.95 (s, 1H), 6.28 (s, 2H), 4.08 (t, 2H), 1.67-1.83 (m, 2H), 0.98 (t, 3H). Example 16 2-{3-[2-(2,3-difluorophenyl)·imidazo[4,5-d]*荅耕·5·ylmethyl]·isosaponi·5_ base}· 5. Propoxy-benzonitrile (Compound 16) According to the general procedure, it is obtained from 2-(2,3-difluoro-phenyl)-5Η-imidazo[4,5-d] Acid 5-(2-cyano-4-propoxy-phenyl)-isoxazol-3-ylmethyl ester. MS 472.6 (M+H+); HI NMR (DMSO-d6): δ (ppm) 10.43 (s, 1H), 9.69 (s, 1H), 8.17-8.13 (t, 1H), 7.93-7.90 (d, 1H ), 7.74-7.65 (m, 1H), 7.61 (d, 1H), 7.47- 7.39 (m, 2H), 7.22 (s, 1H), 6.22 (s, 2H), 4.08-4.04 (t, 2H), 1.76-1.67 (m, 2H), 0.98-0.93 (t, 3H). General Procedure C Synthesis of Compound 17_21 145833 -30- 201039826 In a solution of phenol (0.055 mmol) in DMF (1 mL), an alkyl halide (0.28 mmol, 5 eq.) and K2C 〇3 ( 23 mg, 0.17 mmol, 3 equivalents). The reaction mixture was heated to i 〇〇 °c under microwave irradiation for 45 minutes. The mixture was then filtered and purified by HPLC. Example 17 2_(2,3·Difluoro-phenyl)·5·[3-(4·isopropoxy-2-trifluoromethylphenyl)-isoxazol-5-ylindenyl]- 5Η·Imidazo[4,5-d] 嗒 (Compound 17) According to the general procedure C, from 4-{5-[2-(2,3-difluoro-phenyl)-imidazo[4,5 -d] °荅耕-5-ylmethyl]-isoazani-3-yl}-3-trifluoromethyl-disparate with 2-bromopropane. MS 516.1 (M+H+); H1 NMR (DMSO-d6): 5 (ppm) 10.28 (s,1H), 9.65 (s,1H), 8.23-8.18 (m, 1H), 7.69-7.60 (m, 2H ), 7.48-7.36 (m, 3H), 6.96 (s, 1H), 6.30 (s, 2H), 4.85 (seven peaks, J = 5.9, 1H), 1.34 (d, J = 5.9, 6H). Example 18 2-(2,3·-Gasylphenyl)-5-[3-(4-isobutoxy-2-tris-methyl-phenyl)-iso-I) 嗤-5· 曱]]-5Η-imidazo[4,5-d] 嗒 (Compound 18) According to the general procedure C, from 4-{5-[2-(2,3-difluoro-phenyl)-imidazo[ 4,5-d] 嗒耕-5-ylmercapto]-isoxazol-3-yl}-3-trifluoromethyl-- and 1-bromo-2-methylpropane oxime MS (M+H+ ) : 530.2 ; tf-NMR (DMSO-d6): (ppm) 10.24 (s, 1H), 9.59 (s, 1H), 8.18-8.13 (m, 1H), 7.63-7.55 (m, 2H), 7.42 -7.30 (m, 3H), 6.91 (s, 1H), 6.24 (s, 2H), 3.90-3.86 (m, 2H), 2.10-1.90 (m, 1H), 0.97 (d, 6H) 〇Example 19 2 -(2,3-difluorophenyl)-5.{3-[4-((S)-2-methyl-butoxy)-2-trifluoromethylphenyl]-isoxazole·5 -ylmethyl}·5Η-isoxazo[4,5-d] 嗒耕(化合物19) 145833 •31 · 201039826 According to the general procedure C 'from 4-{5-[2-(2,3- two Fluoro-phenyl)-imidazo[4,5-d] indole-5-ylmethyl]-isoxazole-3-ylbu-3-trifluoromethyl-phenol and (R)-l-bromo -2-methyl-butane. MS (M+H+): 544.2; Hi-NMR (DMSO-d6): 5 (ppm) 10.44 (s, 1H), 9.73 (s, 1H), 8.18 (m, 1H), 7.75-7.65 (m, 1H) ), 7.57-7.55 (m, 1H), 7.48-7.41 (m, 1H), 7.37-7.31 (m, 2H), 6.93 (s, 1H), 6.33 (s, 2H), 3.99-3.86 (m, 2H) ), 1.85-1.74 (m, 1H), 1.56-1.46 (m, 1H), 1.28-1.16 (m, 1H), 0.96 (d, 3H), 0.89 (t, 3H). Example 20 2-(2,3-Difluoro-phenyl)-5-{3-[4-(3-methyl.butoxy)-2-trifluoromethyl-phenyl]-isof" 哼Zyrid-5-ylmethyl}·5Η-isoxazo[4,5-d] 嗒 (Compound 20) According to the general procedure C 'from 4-{5-[2-(2,3-difluoro- Phenyl)-imidazo[4,5-d] indole-5-ylindenyl]-isosoxazol-3-yl}-3-trifluoromethyl-- and 1-bromo-3-methyl Butane. MS (M+H+): 544.2; HlNMR (DMSO-d6): 5 (PPm) 10.09 (s, 1H), 9.48 (s, 1H), 8.18-8.13 (m, 1H), 7.58-7.53 (m, 2H) ), 7.37-7.30 (m, 3H), 6.89 (s, 1H), 6.18 (s, 2H), 4.12 (t, 2H), 1.84-1.72 (m, 1H), 1.68-1.58 (m, 2H), 0.93 (s, 3H), 0.91 (s, 3H).

Example 21 U 5-[3-(4-Butoxy-2-trifluoromethyl-phenyl)-isoxazole-5-ylindenyl]-2-(2,3-difluoro-phenyl) -5H_imidazo[4,5-d] hydrazine (Compound 21) was obtained from 4-{5-[2-(2,3-difluoro-phenyl)-imidazo[4, according to General Procedure C. 5-d] Indole-5-ylmethyl]-isoxazol-3-yl}-3-trifluoromethyl-pan with 1-bromo-butane. MS (M+H+): 530.8; H1-NMR (DMSO-d6): 5 (ppm) 10.29 (s, 1H), 9.61 (s, 1H), 8.18-8.13 (m, 1H), 7.67-7.54 (m , 2,,,,, ), 0.91 (t, 145833 32· 201039826 3H). General Procedure D The synthesis of compounds 22-26 will be aryl bromide (0.2 mmol), aryl-dihydroxyborane (〇, 4 mmol, 2 equivalents) and Pd(PPh3) 4 ( 23 mg, 〇. 〇 2 mmol, 0.1 eq.) A solution of 1,4-dioxane (3 mL) and 1M aqueous K3P04 (1 mL) was heated to 120 with microwave. (: 'After 20 minutes. Then, concentrate the mixture' and purify by preparative HPLC to give the desired product. Example 22 2-(2,3-difluoro-phenyl)·5-{3-[4· (2,4-Dimethyl 4-propazol-5(yl)-2-trifluoromethyl-phenyl]-isoxazole-5-ylmethyl}-5Η·isoxazolo[4,5-d嗒耕(Compound 22) According to the general procedure D 'from 5-[3-(4-bromo-2-trifluoromethyl-phenyl)-isoindole-5-ylindenyl]-2-( 2,3-Difluoro-phenyl)-5H-mimicon[4,5-d]. Plutonic acid and 2,4-dimercapto-thiazole-5-dihydroxyborane oxime ester. MS 569.1 (M+H+); H1 NMR (DMSO-d6): δ (ppm) 10.52 (s, 1H), 9.80 (s, 1H), 8.24-8.19 (m, 1H), 7.93-7.90 (m, 2H), 7.80-7.22 (m, 2H), 7.51 (td, J = 8.2, 3.5, 1H), 7.10 (s, 1H), 6.43 (s, 2H), 2.70 (s, 3H), 2.47 (s, 3H). Example 23 2-(2,3-one gas)-phenyl)-5-{3-[2-trifluoromethyl-4-(1-triisopropylmethanepyrylene-3-yl)-benzene Isoazol _5·ylmethyl}-5Η-carbazolo[4,5-d] oxime spray according to the general procedure D, obtained from 5-[3-(4-bromo-2-trifluoromethyl) Phenyl-phenyl)-isoxazol-5-ylindenyl]-2-(2,3-difluoro-phenyl)-5Η·imidazo[4,5-d]嗒 与 and l (triisopropyl sulphate) 1 Η-ρ piroxi-3-dipyridyl. MS 679.0 (M+H+). 2-(2,3-difluoro-phenyl)-5 -{3-[4-(lH-sorol-3-yl)-2·trifluoromethyl]phenyl]•isoindole 145833 -33- 201039826 succinylmethyl}-5Η·imidazo[4,5 - plowing (Compound 23) in 2-(2,3·difluoro-phenyl)-5-{3-[2-trifluoromethyl-4-(1-triisopropyldecyl-alkyl-1H- Pyrrol-3-yl)-phenyl]-isoxazole-5-ylindoleyl 5H-imidazo[4,5-d] Tartrate in DCM (5 ml), TFA (1 ml) The reaction mixture was stirred at room temperature overnight, then filtered and purified by HPLC to give the desired product. MS 523.0 (M+H+); HWMR (DMSO-d6): (5 (ppm) 10.33 (s, 1H), 9.45 (s, 1H), 8.13-8.08 (m, 1H), 7.92 (s, 1H), 7.87-7.84 (d, 1H), 7.6-7.35 (m, 5H), 6.91 (s, 1H) , 6.81-6.79 (m, 1H), 6.54-6.53 (m, 1H), 6.26 (s, 2H) 〇 Example 24 2·(2,3-digas-phenyl)-5·[3·(4- ρ 比 bit-4_yl-2-trifluoromethyl·phenyl)_isomeric 嗤·5_ylmethyl]-5Η-imidazo[4,5-d] 嗒 (compound 24) according to the general procedure D 'from -[3-(4-bromo-2-trifluoromethyl-phenyl) _Isooxazol-5-ylmethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d] oxime and 4-pyridine dihydroxyborane. MS (M+H+): 535.2; HlNMR (DMSO-d6): 5 (ppm) 10.46 (br s, 1H), 9.72 (br s, 1H), 9.00-8.92 (m, 2H), 8.46-8.34 (m , 4H), 8.20-8.14 (m, 1H), 7.88 (d, 1H), 7.76-7.64 (m, 1H), 7.50-7.40 (m, 1H), 7.08 (s, 1H), 6.38 (s, 2H) ). Example 25 2-(2,3-Difluoro-phenyl)-5-[3_(4-p-pyridin-3-yl-2-trifluoromethyl-phenyl)-iso-spinning _ heart base ]]-5H-imidazo[4,5.d] 嗒 ( (Compound 25) According to the general procedure D 'from 5-[3-(4-bromo-2-trifluoromethyl-phenyl) Goxazol-5-ylindenyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]indole and 3-pyridinedihydroxyborane. MS (M+H+): 535.1 ; HLNMR (DMSO-d6): 5 (ppm) 145833 •34- 201039826 10.62 (s, 1H), 9.83 (s, 1H), 9.35 (s, 1H), 8.91 (d, 1H), 8.80 (d, 1H), 8.41 (s, 1H), 8.32-8.29 (m, 1H), 8.24-8.21 (m, 1H), 8.02-7.98 (m, 1H), 7.89 (d, 1H) , 7.82-7.73 (m, 1H), 7.55-7.49 (m, 1H), 7.14 (s, 1H), 6.47 (s, 2H). Example 26 2-(2,3-Difluoro-phenyl)-5-[3-(3-trifluoromethyl-biphenyl-4-yl)-isoxazole-5-ylmethyl]·5Η- Imidazo[4,5-d]indole (Compound 26) was obtained from 5-[3-(4-bromo-2-trifluoromethyl-phenyl)-isoxazole-5- according to General Procedure D. Methyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]indole and phenyldihydroxyborane. MS (M+H+): 534.1; HkNMR (DMSO-d6): d (ppm) 10.30 (s, 1H), 9.65 (s, 1H), 8.19-8.07 (m, 3H), 7.82-7.74 (m, 3H) ), 7.66-7.41 (m, 5H), 7.03 (s, 1H), 6.31 (s, 2H). General Procedure E Synthesis of Compound 27-31 aryl bromide (0.2 mmol), aryl or THF in THF (0.22 mmol) and Pd(PPh3)4 (23 mg) A solution of 毫2 mmol, 〇·1 equivalent) was sprayed with Ar. Then, the reaction mixture was heated to 130 ° C with microwave irradiation for 20 minutes, followed by cooling, and the reaction was quenched with MeOH. The mixture is then concentrated and purified on a celite (2% to 1% Me 〇H in CH/l2) and/or purified by preparative HPLC to give the desired product. Example 27 2-(2,3-Difluoro-phenyl)_5_[3_(4·,secen-2-yl-2·trifluoromethylphenyl)-isoxazole_5_ylmethyl]·5Η · Imidazo[4,5-d] sorghum (Compound 27) was obtained from 5-[3-(4-bromo-2-trifluoromethyl-phenyl)-isoindole-5 according to the general procedure E ' - fluorenyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d] hydrazine and 2-porphin 145833-35- 201039826 zinc bromide. MS 540.1 (M+H+); H1 NMR (DMSO-d6): 5 (ppm) 10.61 (s, 1H), 9.84 (s, 1H), 8.25-8.21 (m, 1H), 8.15 (s, 1H), 8.10 (dd, J = 8.2, 1.8, 1H), 7.86-7.73 (m, 4H), 7.52 (td, J = 8.2, 3.2, 1H), 7.30 (dd, J = 5.3, 3.8, 1H), 7.09 ( s, 1H), 6.46 (s, 2H). Example 28 2-(2,3-Difluorophenyl)-5-[3·(4·ρ ratio -2-yl-2,trifluoromethyl-phenyl)·isoindole _5_ylmethyl -5H-imidazo[4,5-d] morphine (Compound 28) was obtained from 5-[3-(4-bromo-2-trifluoromethyl-phenyl)-isoindole according to General Procedure E β-Sodium-5-ylindenyl]-2-(2,3-difluoro-indolyl)-5Η-β-miso-[4,5-d]°荅p well and 2-ρ ratio bromine Zinc. MS 535.1 (M+H+); I^NMR (DMSO-d6): δ (ppm) 10.75 (s, 1H), 9.92 (s, 1H), 8.81 (d, J = 4.1, 1H), 8.67 (s, 1H), 8.54 (d, J = 8.2, 1H), 8.30-8.22 (m, 2H), 8.09 (td, J = 7.6, 1.5, 1H), 7.87-7.79 (m, 2H), 7.60- 7.52 (m , 2H), 7.15 (s, 1H), 6.53 (s, 2H). 2-{3-[2-(2,3-difluorophenyl)-isoxazo[4,5_d]indole·5-ylmethyl]isoxazole &amp; base}-5-trifluoromethyl -benzonitrile (Compound 29) In a flask containing 2 ethynyl-5-trifluorodecyl-benzophenone (12 g) in toluene (24 mL) under Ar, add 2_(2) Nitroethoxy) tetrachloropyran (19 ml), diisopropylethylamine (35 ml) and phenylacetic acid isocyanate (14 ml). The reaction was stirred under machine for 5 hours and a white sink was developed. The mashed reaction was filtered through celite and washed. The combined organic material was purified on silica gel and dissolved in hexane (1 〇 5 〇%). Next, the product was treated with (10 mL) of acetic acid, TM (12 mL) and water (6 mL) and heated to the pits (1), 145833 &gt; 36-201039826. The cooled reaction mixture was subjected to a liquid separation between Et0Ac and water. The organic layer was washed several times with water and saturated sodium bicarbonate until the aqueous layer was neutral, washed with water and brine. The organic layer was dried over sodium sulfate, concentrated to EtOAc (EtOAc) (EtOAc) The product was collected as a yellow solid which was shown to be implied by NMR. The product was triturated with 3:1 hexanes:EtOAc. The solid matter was collected by filtration. Yield: 9.0 g of an off-white solid. The solid leaven (6 6 g, 24 5 mmol) was dissolved in dcm (75 mL) and EtOAc (EtOAc) The reaction was allowed to warm and stirred at ar for 1 h without heating. Then, the solvent was removed, and the residue was dissolved in DMF (60 mL), and then, with potassium carbonate (7 g) and 2-(2,3-difluoro-phenyl)-1 Η-imidazo[4,5 -d] 嗒 (5.7 grams) processing. The reaction was heated to 93. (:, after 3 hours. The reaction mixture was poured into ice water' and sonicated for 3 minutes. The mixture was filtered, triturated with ethanol and filtered. The ethanol solution was purified on silica gel to give the desired product (1.4 g). The self-developed insoluble material was purified on silica gel and dissolved in the methanol (0-10%) in methane methane to give more product as an off-white solid (4.7 g). MS: 483.9 (M+H+); i^NMR (DMSO-d6): 5 (ppm) 10.48 (s, 1H), 9.73 (s, 1H), 8.59 (s, 1H), 8.25 (d, 2H), 8.13-8.21 (m, 1H), 7.65-, 7.78 (m, 1H), 7.55 (s, 1H), 7.40-7.52 (m, 1H), 6.29 (s, 2H). Example 30 2-(2,3-difluoro-phenyl)-5 -{1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazole.5_yl]-propyl}-5H-imidazo[4,5-d] (Compound 30) 4-propoxy-2-trifluoromethyl-benzoic acid (〇.9 g, 3.6 mmol) and p-pyridyl (26 μL, 0.36 mmol) in Ar Dissolve in THF (8 ml), stir the 145S33 -37-201039826 solution at 60 C, and develop a yellow solution with a portion of NCS (〇53 g, 4 〇 mmol) solution. At 6 (rc) After stirring for 45 minutes, then diethylamine (0.61 liter, 4.4 mmol) and propargyl alcohol (22 ml, 38 mmol) were added. The reaction was stirred at 60 rt overnight. The organic layer was washed with water, 1 Ν 、α, water and brine, and dried over sodium sulfate. The organic layer was concentrated to celite, and the product was purified on silica gel. The Et 〇Ac (1 〇 _5 〇 %) in hexane was dissolved. The yield was 0.83 g. The alcohol (301 mg) was dissolved in DCM (7 mL) under Ar, and Dess-Martin periodinane (450) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with dichloromethane (5 mL) and washed with saturated aqueous sodium hydrogen sulfate/sodium sulfate The sodium was dehydrated and dried. The organic material was concentrated to EtOAc (EtOAc) eluted eluted elute Dissolved in THF (2.5 ml), and the solution was stirred in an ice bath under argon. Yl magnesium (1.5 ml, i.om, in THF) and the reaction was allowed to warm to room temperature over 1 h. To Syrian chloride aqueous reaction was quenched and the product was extracted in EtOAc. The organic layer was concentrated with EtOAc EtOAc (EtOAc) According to the general procedure A, the alcohol is converted to the decane sulfonate and coupled to 2-(2,3-difluoro-phenyl)-1 Η-imidazo[4,5-d]. MS 544.0 (M+H+) ; H^MR (DMS0-d6) : δ (ppm) 10.56 (s, 1H), 9.78 (s, 1H), 8.18-8.13 (t, 1H), 7.76-7.67 (qrt, 1H), 7.58-7.55 (d, 1H), 7.50-7.42 (m, 1H), 7.36-7.31 (m, 2H), 7.00 (s, 1H), 6.57-6.51 (t, 1H), 4.08-4.03 ( t, 2H), 2.60-2.50 (m, 2H), 1.78-1.68 (qnt. 2H), 1.00-0.88 (m, 6H). 145833 -38- 201039826 Example 31 (4-{5-[2·(2,3-Difluoro-phenyl)imidazo[4,5-d]indole-5-ylmethyl]-isoxazole 3_yl}-3-trifluoromethyl-phenoxyacetonitrile (compound 31)

G 4-{5-[2-(2,3-Difluoro-phenyl)-imidazo[4,5-d]indole-5, fluorenyl]-iso-sigma-3-yl} -3-trifluoromethyl-hydrazine (140 mg, 〇·3 〇 millimolar), 2-bromoacetonitrile (59 μl '0.85 mmol) and potassium carbonate Q22.4 mg, 0.89 mmol The solution in DMF (2.5 ml) was heated under microwave irradiation for 12 minutes. The reaction was filtered and purified by silica gel chromatography to give the desired product. MS: 513.2 (M+H+); H^NMR (DMSO-d6): 5 (ppm) 10.16 (s, 1H), 9.55 (s, 1H), 8.13-8.21 (m, 1H), 7.70 (d, 1H) ), 7.52-7.66 (m, 2H), 7.45-7.53 (m, 1H)' 7.32-7.43 (m, 1H), 6.96 (s, 1H), 6.23 (s, 2H), 5.37 (s, 2H). Administration and pharmaceutical compositions Also provided are compounds having antiviral activity, including the susceptibility virus, such as the hepatitis C virus. The compounds or pharmaceutically acceptable salts described herein inhibit viral replication by inhibiting enzymes involved in replication, including RNA-dependent polyphosphate synthase. It also inhibits other enzymes that are utilized in the activity or proliferation of the virus. In general, the compounds or pharmaceutically acceptable salts described herein are administered in a therapeutically effective amount by any of the accepted modes of administration as a drug of similar utility. The compound or pharmaceutically acceptable salt described herein, that is, the active ingredient, is actually determined by a number of factors, such as the severity of the condition to be treated, the age and relative health of the patient: The efficacy of the compound, the route and form of administration, and others. This kind of music can be given more than one time, such as - day - time or twice. 145833 -39- 201039826 The therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein may be in the range of from about (10) to about milligrams per day, per kilogram of body weight, such as about 0.01 to 25 mg per day. Kg/day, for example, about 1 to 1,000 mg/kg/day. Thus, in some embodiments, for administration of % yt, the dosage range is about 7-7 mg per day. The invention is not limited to any particular composition or pharmaceutical carrier, which may itself vary. In general, the compounds described herein or the pharmaceutically acceptable dishes are administered in a pharmaceutical composition by any of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository) or non-menstrual Administration of the intestine (eg, intramuscular, intravenous or subcutaneous). In some embodiments, the mode of administration is oral, and a suitable dosage regimen per dose can be used, which can be adjusted depending on the degree of suffering. The composition may be in the form of a silk tablet, pill, capsule, semi-solid, powder 'continuous release of sputum, solution, suspension, elixirs, aerosol or any other suitable plant. Another way of administering the compounds described herein is ~ "The choice of formulation depends on various factors, such as the mode of drug administration and the bioavailability of the drug. For inhalation, the compound can be formulated with a liquid solution, Suspension, aerosol propellant or dry powder, and filled to fit: There are several types of dosing dispensers. (4) Inhalation device like tank inhalation, K quantity 1 inhalation barrier) and dry atomization tank 2 will produce π speed The air flow 'causes the therapeutic agent (which is formulated into a liquid form) to be sprayed into a mist and is taken to the patient's beer suction channel. The blood type 2 is packaged in a gas-reducing formula. By venting a measured amount of therapeutic agent by a pressure dimer, thus providing a reliable method of administering a dose of sputum. The DPI is dispensed in the form of a free-flowing powder Ϊ45833 -40- 201039826 Treatment ^ 'It can be borrowed During the breathing of the device, it is dispersed in the patient's inhalation μ to achieve a free-flowing powder, and the therapeutic agent is formulated with an excipient such as lactose. The girl's sore m, - 'working degree ϊ: number set Therapeutic agent is stored It is in the form of a capsule and is dispensed with each priming. Recently, two pharmaceutical formulas have been developed, especially for drugs that show poor bioavailability, which can be handled by increasing the surface area by reducing the particle size. Based on the principle of s force, for example, U.S. Patent No. 4,1,7,288 describes a pharmaceutical formulation having particles in the range of (7) to (3) (8) nanometers, and the active substance in the sputum is carried on the macromolecule. The manufacture of a pharmaceutical formulation is described in U.S. Patent No. 5,145,684, the entire disclosure of which is incorporated herein by reference in its entirety in the the the the the the the A pharmaceutical formulation that exhibits a very high bioavailability. These groups generally comprise a compound or a pharmaceutically acceptable salt described herein, together with at least one pharmaceutically acceptable excipient. Excipients are non-toxic, help to administer the drug, and do not adversely affect the therapeutic benefit of the compound. The excipient can be any solid or liquid. In the case of an aerosol composition, or in the case of an aerosol composition, it is a gaseous form which is generally available to those skilled in the art. Solid pharmaceutical excipients include starch, cellulose, talc, glucose 'lactose, sucrose, Gelatin, malt, rice, flour, white peony, Shixi gum, magnesium stearate, hard larna 1 stearic acid glycerin s |, sodium gasification, dry canolaced cattle: special. Liquid and semi-solid excipients Selected from glycerin, propylene glycol, water, ethanol and various oils, including petroleum, animal, plant or synthetic sources, 145833 -41 - 201039826 such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carrier, especially for For injection solutions, water, saline, aqueous dextrose, and glycols are included. Compressed gases can be used to disperse the compounds described herein or the pharmaceutically acceptable salts in aerosol form. Suitable inert gases for this project are nitrogen, carbon dioxide and the like. Other suitable pharmaceutical excipients and their formulations are described in Remington's Medical Sciences, edited by EW Martin (Mack Publishing Company, 18th ed., 1990). The amount of bismuth compound in the formulation can be used by all those skilled in the art. Change within the scope. Typically, the formulation will comprise from about 0.01% to about 99.99% by weight of the compound or pharmaceutically acceptable salt described herein on a weight percent (% by weight) basis, based on the total formulation, with the remainder being one or A variety of suitable pharmaceutical excipients. In some embodiments, the compound is present at a level of from about 1% to about 80% by weight. Representative pharmaceutical formulations are described in the formulation examples below. Also provided is a pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt described herein in combination with a therapeutically effective amount of another RNA-resistant RNA virus, particularly against HCV Agent. Agents resistant to HCV activity include, but are not limited to, triazole nucleoside, levovirin, viramidine, thymosin alpha-1, inhibitor of HCV NS3 serine protease or inosine mono Inhibitor of phosphate dehydrogenase, interferon-α, PEGylated interferon-a (PEG interferon-α), combination of interferon-α and trisial nucleus, PEG interferon-α and three 1 A combination of nuclear assays, a combination of interferon-&lt;2 and levovirin, and a combination of PEG interferon-alpha and Levvir 145833-42-201039826 levovirin. Interferon-α includes, but is not limited to, recombinant interferon-〇2a (such as ROFERON interferon, available from Hoffman-LaRoche, Nutley, NJ), interferon- (such as Intron-A interferon, available) From Schering, Kenilworth, New Jersey, USA), the same interferon and purified interferon-alpha product. For a discussion of triazole nucleosides and their activity against HCV, see JO Saunders and SA Raybuck, "Eyes singular constitutional salt dehydrogenase: considerations of structure, kinetics and therapeutic potential", A. / to /. CAem., 35: 201-210 (2000).

Agents that are resistant to hepatitis C virus activity also include inhibition of HCV protease, HCV polymerase, HCV helicase, HCV NS4B protein, HCV entry, HCV assembly, HCV efflux, HCV NS5A protein and muscle: y: 5匕A phosphate dehydrogenase agent. Other agents include nucleoside analogs for the treatment of HCV infection. Still other compounds are included in WO 2004/014313 and WO 2004/014852, and the disclosures of which are incorporated herein by reference. The patent application WO 2004/014313 and WO 2004/014852 are hereby incorporated by reference in their entirety. Specific antiviral agents include 0IFN (Biomedical Corporation), BILN-2061 (Boehringer Ingelheim), Summetrel (Endo Pharmaceuticals Holdings), Roferon A (F. Hoffman-La Roche), and Pegasys (F. Hoffman-La Roche), Pegasys/Ribaravin (F. Hoffman-La Roche), CellCept (F. Hoffman-La Roche), Wellfell (GlaxoSmithKline) ), Abu Febon-α (Human Genome Sciences), Lev〇virin (ICN Medicine), IDN-6556 (Idun Medicine), IP-501 (Indevus Medicine), Jotim (Actimmune) (InterMune 145833 -43- 201039826 company), Interferon (Infergen) A (InterMune company), ISIS 14803 (ISIS Pharmaceutical Company), JTK-003 (Japan Tobacco Company), Pegasus (Pegasys) / Xipu Ceplene (Maxim Medicine), Ceplene (Maxim Medicine), Civacir (Nabi Biomedical Company), Intron A/Zadaxin (RegeneRx) ), Levovirin (Ribapharm), Vera pain (Vir) Amidine) (Ribapharm), Heptazyme (Ribozyme), Intron A (Schering-Plough), PEG-Intron (Schering-Plough), Rebetron (Schering) -Plough), Schering-Plough, PEG-Intron/Schering-Plough, Zadazim (SciClone), Rebif (Serono), IFN - yS/EMZ701 (Transition Therapeutics), T67 (Tularik), VX-497 (Vertex Pharmaceuticals), VX-950/LY-570310 (Vertex Pharmaceuticals), Omniferon (Viragen), XTL -002 (XTL Biomedical), SCH 503034 (Schering-Plough), isatoribine and its prodrugs ANA971 and ANA975 (Anadys), R1479 (Roche Biotechnology), Vibitabin (Valopicitabine) ( Idenix), NIM811 (Novartis) and Actilon (Coley Medicine). In some embodiments, the compositions and methods described herein comprise a compound described herein or a pharmaceutically acceptable salt, and an interferon. In some embodiments, the interferon is selected from the group consisting of interferon alpha 2 Β, PEGylated interferon alpha, consensus interferon, interferon alpha 2 Α, and lymphoblastoid interferon tau. In other specific embodiments, the compositions and methods described herein comprise a compound or a pharmaceutically acceptable salt described herein, and the compound having anti-HCV activity is selected from the group consisting of: Interleukocytokinin 145833 201039826 2. Interleukin-1, interleukin 12, enhances type 1 helper Τ Cell response to development of compounds, interfering RNA, antisense RNA, Imiquimod, triazole Nucleus, inosine 5'-monophosphate dehydrogenase inhibitor, amantadine and amantadine ethylamine. In some embodiments, the compound having anti-HCV activity is an inhibitor of triazole nucleus, levovirin, viraraidine, thymosin alpha-1, NS3 serine protease Inhibitor with inosine monophosphate dehydrogenase, interferon-α or PEGylated interferon-〇; alone or in combination with triazole core or vera. Viramidine. In some embodiments, the compound having anti-HCV activity is the agent having anti-HCV activity, which is interferon-〇: or PEGylated interferon-α, alone or in combination with triterpene or vera. Bite (viramidine). Biological Examples Biological Examples 1. Anti-C Hepatitis Activity Compounds can exhibit anti-C hepatitis activity by inhibiting the virus and the host cell target required in the _ replication cycle. A variety of tests have been published to assess these activities. Of U.S. Patent No. 5,738,985, issued to A.S. Pat. • In vitro testing has been reported in Ferrari et al. J. 〇/Vk, 73: 1649-1654, 1999; Ishii et al., //epfltotog};, 29: 1227-1235, 1999; Lohmann et al. 〇/历0. CTim” 274: 10807-10815, 1999; and Yamashita et al., /〇/Bio. C/iem., 273: 15479-15486, 1998. Replicon detection using cell line ET (Huh-lucubineo) - ET) to screen for the compound 145833 -45-201039826 or a pharmaceutically acceptable salt described herein for inhibition of HCV RNA-dependent RNA polymerase. The ET cell line is stably transfected with hidden I3 89luc-ubi-neo RNA transcript of /NS3-37ET; replicon with firefly luciferase-ubiquitin-neomycin phosphotransferase fusion protein, and EMCV-IRES containing cell culture-adapted mutant (E1202G; T1280I; K1846T) Driving NS3-5B polyprotein (Krieger et al., 2001 and unpublished). ET cells were grown in DMEM supplemented with 10% fetal bovine serum, 2 mM branamine, penicillin (100 IU/ml)/chain Mycin (100 μg/ml), lx non-essential amino acid and 250 μg/ml G418 thiol factor"). All of this is available through Life Technologies (Bethesda, MD). The cells were plated in 96 well plates at 0.5-1.0 X 104 cells/well and cultured for 24 hours, and then the test compound was added. The compound is then added to the cells to achieve a final concentration of 5 or 50 /zM. Insect luciferase activity was added 48 to 72 hours later by addition of lysis buffer and substrate (Catalog No. Glo-lysis buffer E2661 and Bright-Glo luciferase system E2620 Promega, Madison, WI) metrics. Cells should not be too confluent during the test. The percent inhibition of replication was plotted against the no compound control group. Under the same conditions, the cytotoxicity of the compounds was determined using the cell proliferation reagent WST-1 (Roche, Germany). Compounds showing antiviral activity but no significant cytotoxicity were selected to determine EC5〇 and TC5〇, which are the effective and toxic concentrations found at 50% of the highest inhibition. For these assays, 6 dilutions of each compound were used. Typically, the compound is diluted 3 fold to span a concentration range of 250 times. EC5〇 and similarly the TC5 depreciation is calculated by fitting the % inhibition at each concentration to the following equation: % inhibition = 100% / [(EC5〇 / [I]) b + 1] 145833 • 46- 201039826 Where b is the Hill's coefficient. It has been found that the compounds of formula (I) are active in the treatment of at least a portion of the viral infections mediated by the virus in the sputum venom virus, as shown by the data below. It has further been discovered that 'the compounds of formula (I), such as those in Tables 2a, 3a, 4a, 5a, 6a, 7a, 8a and 9a, are surprisingly more active 'compared to compounds of similar structure'. In Tables 2b, 3b, 4b, 5b, 6b, 7b and 8b, which are previously disclosed in U.S. Patent Application Serial No. 12/216,920. ❹ Table 2a Compound # Structure EC50 (μΜ) 29 0.0067 14 0.07681 Table 2b Structure EC50 (μΜ) 0.1309 1.1405 N 50 Ο 145833 -47- 201039826 Table 3a Compound #Structure EC50 (μΜ) 6 0.0014 15 FF 0.003327 9 F 0.005951 8 F 0.009622 7 FF 0.005206 21 a 0.004027 Table 3b

145833 • 48- 201039826 Ο xo-cr〇:vb 0.095 0.029065 ^-o-crcc&gt;^ 0.100672 0.019 &lt;ro^F 0.038875 0.050828 bixoyb 23.5 0.024675 0.055 o~cr〇yb 0.2508 145833 -49- 201039826 Table 4a Compound # Structure EC50 (μΜ) 31 FF 0.01977 13 FF 0.0261 3 FF 0.004953 5 FF ^r^^cr〇^bF 0.02177 12 FF 0.002566 1 0.006703 Table 4b Structure EC50 (μΜ) 0.2475 “i〇cra>^ 0.0425 145833 -50- 201039826 Ο 0.10085 0.0454 0.21235 Table 5a Compound #Structure EC50 (μΜ) 23 Ht^^CTCC&gt;^ 0.02678 27 FF 0.006176 28 FF 0.02391 26 o^crco^ 0.009441 25 a^crco^ 0.02323 24 ^^crcc&gt;^ 0.01547 145833 -51 - 201039826

Table 6a

Structure EC50 (μΜ) 0.1309 ^^r〇:R) 1.1405 N Wrcc^F 50 145833 -52- 201039826 Table 7a Compound # Structure EC50 (μΜ) 17 F F 0.02142 20 0.07396 18 &gt;v^crco^ 0.01132 19 0.01343

Table 7b

145833 -53- 201039826 Table 8a Compound #Structure EC50 (μΜ) 4 FF 0.007 2 FF 0.04359 30 0.02044 11 0.01646 10 0.009749 Table 8b Structure EC50 (μΜ) 0.082566 FFF^€^x〇::vbF 1.52 Formulation Example The following is a formula (I) A representative drug of the compound or pharmaceutically acceptable salt 145833 • 54- 201039826 formulation. Recipe example 1

Tablet Formulation The following ingredients are intimately mixed and compressed into a single dicing tablet. Ingredients Amount per tablet, mg Compound 400 Cornstarch 50 Cross-linked carboxymethylcellulose sodium 25 Lactose 120 Magnesium stearate 5 Formulation Example 2 Capsule Formulation The following ingredients are intimately mixed and filled into hard-shell gelatin capsules. Ingredients Per capsule amount, mg Compound 200 Spray dried lactose 148 Magnesium stearate 2 Formulation Example 3 Suspension formulation The following ingredients were mixed to form an oral pharmaceutical suspension. Ingredient amount compound 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methylparaben 0.15 g propylparaben 0.05 g granulated sugar 25.0 g 145833 -55- 201039826 Resveratrol (70% solution 13.00 g Veegum K (Vanderbilt) 1.0 g flavoring agent 0.035 ml coloring agent 0.5 mg distilled water sufficient (sufficient amount) to 100 ml Formulation Example 4 Injectable Formulation The following ingredients are mixed to form an injectable formulation. Ingredient amount Compound 0.2 mg-20 mg Sodium acetate buffer solution, 0.4 Μ 2.0 ml HCl (1 Ν) or NaOH (1 Ν) sufficient amount to the appropriate pH water (distilled, sterile) sufficient amount to 20 ml Formulation Example 5 Suppository formula total weight A 2.5 gram suppository is prepared by mixing the compound with Witepsol® H-15 (triglyceride of saturated vegetable fatty acids; Riches-Nelson, New York) and has the following composition; Component Quantity Compound 500 mg Witepsol® H- 15 Balance 145833 56-

Claims (1)

201039826 VII. Patent application scope: 1. A compound of formula (I) (I) or a pharmaceutically acceptable salt thereof, wherein: R1 is hydrazine or F; 〇 R2 is selected from the group consisting of hydrazine. —(^alkyl and Ci-Q alkyl substituted by R7 or one to one halogen; L is 0-N or Or R4 Y is selected from the group consisting of an alkoxy group, a Q-C6 alkoxy group which is deuterated to three R5-substituted oximes, an aryl group, a heteroaryl group, and a heteroaryl group substituted by 1 to 2 R6 groups. R4 is CF3 or CN; R: is independently selected from the group consisting of halo, cyano and cyclopropyl; R is independently selected from the group consisting of halo, QQ, Q-C5 Alkoxy and RaRbN-, wherein Ra and Rb are independently 11 or (:1_(:5 alkyl; and R7 is selected from the group consisting of alkoxy, thiol, ruthenium, aryl, and RcRdN - which is a compound which is independent of Η or Ci_c3 alkyl. 2', as in claim 1, which has the formula 145833 201039826 Or a pharmaceutically acceptable salt thereof, wherein: γ is selected from the group consisting of ethoxy, n-propoxy, n-butoxy, n-pentyloxy and n-hexyloxy; and R1, R2 and L are previously defined. The compound of claim 1 or 2, wherein R2 is H. The compound of claim 1, which has the formula 3. 4. or a pharmaceutically acceptable salt thereof, wherein ^ and 匕 are previously determined _ Or a pharmaceutically acceptable salt thereof, wherein: hydrazine is a Ci-Q alkoxy group substituted by 1 to 3 R5; and R1, R5 and L are as previously defined. 6. A compound according to claim 5, wherein Y is c]-C: 6 alkoxy substituted by three F. 7. The compound of claim 5, wherein γ is a &amp; _c6 alkoxy substituted by a cyano group. 8. The compound of claim 5, wherein γ is a Cl% alkoxy group 145833 -2- 201039826* group substituted by a cyclopropyl group. 9. The compound of claim 1 which has the formula Or a pharmaceutically acceptable salt thereof, wherein: the lanthanide is selected from the group consisting of aryl, heteroaryl and substituted heteroaryl; and 〇 R1, R6 and L are as previously defined. The compound of claim 9, wherein Y is selected from the group consisting of phenyl, pyrrolyl, thiophenyl and pyridyl. u. The compound of claim i, which has the formula Or a pharmaceutically acceptable salt thereof, wherein: ❹ Rl'L and Y are as previously defined. The compounds are exemplified by 〇, wherein γ is selected from the group consisting of: decyl-n-propoxy, n-butoxy, n-pentyloxy and n-hexyloxy. 13. The compound of any of items 1, 2, and 4 to 12, wherein Ri is H. The compound of any one of claims 1, 2, and 4 to 12, wherein Ri is F. The compound of any one of items 1, 2 and 4 to 12, wherein L is 0-Ν.如. For example, the compound of any one of items 1 '2 and 4 to 12, wherein l is 145833 201039826 N-0 17. A compound or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: Compound # Structure name 1 5-[3-(4-cyclopropylmethoxy-2-tris) Fluorinyl-phenyl)-isoxazol-5-ylindenyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]indole 2 FF 2- (2-fluorophenyl)-5-{1-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazole-5-yl]-ethyl}-5H-imidazole And [4,5-d] 嗒耕3 FF 2-(2,3-disorder-phenyl)-5-{3-[2_ 曱oxy-4-(2,2,2-trifluoro-B Oxy)-phenyl]-isoxazol-5-ylmethyl}-5沁imidazo[4,5-d]嗒耕4 FFC^〇&gt;^F 2-(2,3-diphenyl -5-{1-[3-(4-propoxy-2-trifluoromethyl-styl)-iso 17-deficient 1Ί5-yl]-ethyl}-5-imidazolium [4,5-d ] 嗒 5 FF 2-(2,3-difluoro-phenylindole 3-[4-(4,4,4-trifluoro-butoxy)-2-trifluoromethyl-phenyl]- Drink oxazol-5-ylindenyl}-5Η-imidazo[4,5-d] 嗒耕6^^cr〇C&gt;-bF 2-(2,3-disorder-phenyl)-5-[3 -(4-propoxy-2-trifluoromethyl-phenyl)-isoxazol-5-ylindenyl]-5H-imidazo[4,5-d]indole 7 FF 2-(2- Fluorophenyl)-5-[3-(4-propoxy-2-trifluoromethyl-phenyl)-isoxazole-5-ylfluorenyl ]-5H-imidazo[4,5-d] indole 8 F 5-[3-(4-ethoxy-2-trifluoromethyl-phenyl)-isoxazol-5-ylindenyl] -2-(2-fluorophenyl)-5H-imidazo[4,5-d]嗒耕145833 201039826 ❹ F9 F 2-(2,3-Difluoro-phenyl)-5-[3-( 4-ethoxy-2-trifluoromethyl-phenyl)-isoxazole-5-ylindenyl]-5H-imidazo[4,5-d]indole 10 FF 2-(2,3- Dioxo-phenyl)-5-{(R)-l-[3-(4-propoxy-2-trifluoromethyl-phenyl)-iso 11 oxazol-5-yl]-ethyl} -511-imidazo[4,5-d] morphine 11 2-(2,3-difluoro-phenylindole-indole (S)-l-[3-(4-propoxy-2-trifluoro Methyl-phenyl)-isoxazol-5-yl]-ethyl bromide 5H-imidazo[4,5-d]indole 12 FF 2-(2,3-digas-phenylhydrazine-ί 3 -[4-(3-fluoro-propoxy)-phenyl]-isoxazole-5-ylindenyl}-5Η-imidazo[4,5-d]嗒耕13 FF ^^crcc^F 2 -(2,3-difluoro-phenyl)-5-[3-(4-trifluoromethoxy-2-trifluoromethyl-phenyl)-isoxazole-5-ylindenyl]-5H -Imidazo[4,5-d] 嗒耕 14 /CN F ^~cr〇^ 2-{3-[2-(2-fluorophenyl)-°Mizozolo[4,5-d]嗒p Well-5-ylmethyl]-isoxazole-5-yl}-5-trifluoromethyl-benzoquinone 15 FF 2-(2,3-diphenyl)-5-[5-(4- Propoxy-2-trifluoromethyl- -isoxazole-3-ylindenyl]-5H-imidazo[4,5-d] 嗒耕16 Vp^o:^ 2-{3-[2-(2,3-difluoro-benzene Base)-isoxazo[4,5-d]indole-5-ylmethyl]-iso. N-azole-5-yl}-5-propoxy-benzonitrile 17 FF 2-(2,3-diphenyl)-5-[3-(4-isopropoxy-2-trifluoromethyl) -phenyl)-isoxazol-5-ylindenyl]-5H-imidazo[4,5-d]嗒耕145833 201039826 18 2-(2,3-di-l-phenyl)-5-[3 -(4-isobutoxy-2-trifluoromethyl-phenyl)-isoxazol-5-ylindenyl]-5H-imidazo[4,5-d]indole 19 2-(2, 3-difluoro-phenyl)-5-{3-[4-((S)-2-indolyl-butoxy)-2-trifluoromethyl-phenyl]-isoindole-5-yl曱基}-5H-imidazo[4,5-d] 嗒耕20 2-(2,3-difluoro-phenyl)-5-{3-[4-(3-indolyl-butoxy) -2-trifluoromethyl-phenyl]-isoxazole-5-ylmethyl}-5H-imidazo[4,5-d]嗒啩21 5-[3-(4-butoxy-2 -trifluoromethyl-phenyl)-isoxazol-5-ylmethyl]-2-(2,3-difluoro-phenyl)-5H-imidazo[4,5-d]嗒耕22 FF 2-(2,3-Difluoro-phenyl)-5-{3-[4-(2,4-dimethyl-o-azol-5-yl)-2-trifluoromethyl-phenyl]- Isoxazole-5-ylmethyl}-5H-imidazo[4'5-d]嗒口23 2-(2,3-Difluoro-phenyl)-5-{ 3-[4-(1Η -pyrrol-3-yl)-2-trifluoromethyl-phenyl]-isoxazole-5-ylmethyl}-5&amp; imidazo[4,5- 嗒 嗒 24 o^cro^ 2-( 2,3-difluoro-phenyl)-5-[3-(4- Pyridyl-4-yl-2-trifluoromethyl-phenyl)-isoxazole-5-ylmethyl]-5H-imidazo[4,5-d] 嗒耕 25 2-(2,3- Difluoro-phenyl)-5-[3-(4-pyridyl-3-yl-2-trifluoromethyl-phenyl)-iso 11-azol-5-ylindenyl]-5H-imidazo[ 4,5-d]嗒耕26 2-(2,3-Difluoro-phenyl)-5-[3-(3-trifluoromethyl-biphenyl-4-yl)-isoxazole-5- Methyl]-5H-imidazo[4,5-d] 嗒耕145833 201039826 2-(2,3-Difluoro-phenyl)-5-[3-(4-喽phen-2-yl-2-trifluoromethyl-phenyl)-isoazol-5-ylindenyl] -5Η-imidazo[4,5-d] indole 2-(2,3-difluoro-phenyl)-5-[3-(4-tonate-2-yl-2-trifluoromethyl- Phenyl)-iso" 嗤_5-yl fluorenyl]-5H-imidazo[4,5-d] 嗒耕2-{3-[2-(2,3-difluoro-phenyl)- Imidazo[4,5-d]indole-5-ylindenyl]-isoxazol-5-yl}-5-trifluoromethyl-benzonitrile 2-(2,3-difluoro-phenyl -5-U-[3-(4-propoxy-2-trifluoromethyl-stupyl)-different. -5-[5-[2-(2,3-difluoro-phenyl)-[4,5] -d]嗒耕-5-ylmethyl]-iso-indole-3-yl}-3-trifluorodecyl-phenoxy)-acetonitrile Ο G species such as: monthly 丄 to 1717 Use of a compound according to the invention for the preparation of a medicament for use in treating a virus which is at least partially infected by a virus in a virus. 19. The use of the method of claim 18 The infection is a vector infection of hepatitis C. 20. The use of claim 19, wherein the agent is used in combination with a therapeutically effective amount or a plurality of agents that are resistant to hepatitis C virus activity. 2L. Among the agents having anti-hepatitis C virus activity are HCV protease, HCV polymerase, Hcv helicase, hcvn pure protein, HCV entry, HCV assembly, HCV efflux, h (: vns5a protein or muscle: y: 5'- Inhibitor of monophosphate dehydrogenase. 22. The use of claim 2G, wherein the agent 145833 201039826 which is resistant to (IV) hepatitis virus activity is an interferon. 23. In claims 1, 2, 4 to 12 and 17, Any one a compound, which is used in a patient to treat at least a portion of a viral infection mediated by a virus in the genus #科病毒. 24. A pharmaceutical composition that is used in a patient to treat at least a portion of the disease A virus-mediated infection by a virus in a viral virus, the composition comprising a compound according to any one of claims 1 to 17. 25. The pharmaceutical composition according to claim 24, wherein the viral infection is a medium of hepatitis C 26. The pharmaceutical composition of claim 25, further comprising a therapeutically effective amount of one or more agents that are resistant to hepatitis C virus activity. 27_A pharmaceutical composition according to claim 26, wherein Agents that are resistant to hepatitis C virus activity are inhibitors of HCV protease, polymerase, HCV helicase, (10) protein, HCVmv assembly, hcvm, milk enteroprotein or tendon 5'-monophosphate dehydrogenase. For example, the pharmaceutical composition of the manuscript, which is resistant to e-type drugs, is interferon. 145833 201039826 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The component symbol of the representative figure Brief description: 5. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: R2—.CH 3/ T-2! 145833