TW200808694A - Chemical compounds - Google Patents

Abstract

The present invention relates to a compound that is a non-nucleoside reverse transcriptase inhibitor, and to processes for the preparation and use of the same. Specifically, the present invention includes methods of using such compound in the treatment of human immunodeficiency virus infection.

Description

200808694 IX. INSTRUCTIONS OF THE INVENTION: TECHNICAL FIELD The present invention relates to a compound which is a non-nucleoside reverse transcriptase inhibitor and relates to a preparation method and use thereof. In particular, the present invention discloses treatment of human immunodeficiency virus infections comprising administering a benzophenone derivative. [Prior Art] Human immunodeficiency virus (''HIV") is a pathogen of acquired immunodeficiency syndrome (''AIDS1') and its precursor AIDS-related syndrome ("ARC"), a characteristic of the AIDS system is the immune system. In particular, CD4+ T-cells are disrupted and associated with diseases that are susceptible to opportunistic infections. ARC is a syndrome characterized by symptoms such as persistent systemic lymphadenopathy, fever, and weight loss. HIV is a retrovirus; its RNA-to-DNA transformation is achieved by the action of an enzyme reverse transcriptase. Compounds that inhibit reverse transcriptase function inhibit the replication of HIV in infected cells. These compounds are used to prevent or treat HIV infection in humans. In addition to nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors (NNRTI) are also decisive in the treatment of HIV-1 infection. Thus, NNRTI interacts with a specific site of HIV-1 reverse transcriptase, which is closely related to, but different from, the NRTI binding site. However, it is well known that NNRTI rapidly induces resistance due to mutations in the amino acid surrounding the NNRTI-binding site (E. De Clercq, // Fam Coronation 54, 26-45, 1999). The lack of long-term efficacy of NNRTI is often associated with the emergence of anti-drug resistant strains (J. Balzarini, jP/zarmaco/o illus;; 58 119946.doc 200808694, 1-27, 1999). In addition, mutations that occur in reverse transcriptase enzymes generally result in reduced sensitivity to other reverse transcriptase inhibitors, which leads to cross-resistance. Since the antiviral use in the treatment and prevention of HIV infection continues, it is expected that the emergence of new resistant new strains will increase. Therefore, the industry is in need of new reverse transcriptase inhibitors that have different potency patterns against various mutants. Certain dibenzophenones which are non-nucleoside reverse transcriptase inhibitors are disclosed in WO 02/070470, WO 01/17982, and U.S. Patent No. 2006/0025480. It has now been found that the compounds of the invention are useful as inhibitors of both wild-type and mutant forms of HIV reverse transcriptase. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I)

Or a pharmaceutically acceptable derivative thereof. The invention also provides a compound of formula (IA)

(IA) 119946.doc 200808694 or its pharmaceutically acceptable derivative.

0 ό A feature of the invention provides a compound of formula (IB)

Or a pharmaceutically acceptable derivative thereof. (IB) The present invention features a pharmaceutical composition comprising a compound of the present invention. SUMMARY OF THE INVENTION The present invention provides a compound of the invention for use in the treatment of Western medicine, such as viral infections and related conditions, such as HIV salt smugglers and related conditions. The present invention is also characterized in that the compound of the present invention is used in the manufacture of a medicament for treating a disease-related sensation and related conditions (for example, s, treatment of V infection and related diseases/brothers). the use of. The present invention features a method of treating υΤΛ7, ^ _ regular wood and related conditions (e.g., HIV infection and related conditions). The method includes administration of the present invention. [Embodiment] The term "treatment" as used herein refers to alleviating the symptoms of a given condition, eliminating the symptoms, slowing or eliminating the development of the condition and preventing or delaying the two: Initially occurring, or first arrowed again. Type: 3⁄4 is not subject to party torture. Can become a condition again 119946.doc 200808694 "Pharmaceutically Acceptable Derivatives" 咅 l Initial "^ 曰 Direct investment and recipients can directly or

Intervening to provide a compound of the invention or A ^ ^ fly, inhibiting the active metabolite or residue of any of the compounds of the compound can be used to kill the ester, ester salts, ethers or other bamboo organisms . Derivatives and prodrugs, and other salts and salts thereof, when administered to a mammal, enhance the bioavailability of such compounds (eg, by oral administration) The outsider can only absorb the compound into the blood more easily, or can be green relative to the parent substance. #瓶视贝〃 The delivery of the i-strong parent compound to the biological chamber such as the 'brain or lymphatic system' . The term "effective amount" as used herein means, for example, the amount of a drug or agent that a researcher or clinician seeks to induce a biological or medical response to a tissue, system, animal or human. The biological or medical response can be considered to be prevention, response, response, or response. The term "therapeutically effective amount" means any amount that provides improved treatment, cure, prevention or amelioration of a disease condition or side effect, or a rate of progression of a disease or condition, as compared to a corresponding subject who does not receive the amount.兮 The term also includes within its scope an amount effective to enhance normal physiology. The present invention provides a compound of the formula (1)

Or a pharmaceutically acceptable derivative thereof. This compound has the name 2_({4, chloro 2_[(3-a-5-cyanophenyl)-dyl]phenyl}oxy)_, {4_[(2,3_2)3_曱Butyl)oxy]-3-fluoro-2-methylphenyl}acetamide. & 119946.doc 200808694 The invention also provides a compound of formula (IA)

Or a pharmaceutically acceptable derivative thereof. This compound has the name 2_({4_chloro-2-([3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)_#_(4_{[(25()_2,3•2 Hydroxy-3-mercaptobutyl]oxy}_3_fluoro-2-indolylphenyl)acetamide. The present invention further provides a compound of the formula (Ιβ).

(IB) or a pharmaceutically acceptable derivative thereof. This compound has the name 2_({4_chloro-2-([3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy{[(2^-2,3-di-amino-3-) Alkyl butyl]oxy}_3_fluoro-2-methylphenyl)acetamide. The compounds of the present invention can exist in both non-fused and fused forms (including hydrated forms) in both cold and non-fused forms. It is within the scope of the invention. The compounds of the invention may exist in various forms and/or mixtures of solvates or as a mixture of amorphous materials and one or more forms and/or solvates. In general, all physical forms are intended It is within the scope of the invention. The forms can be distinguished by various physical properties well known in the art, such as xenon ray diffraction patterns, solubility and melting point. 119946.doc 200808694 The compounds described herein contain one or more pairs of palm centers, oxygen In addition, it can exist in the form of a stereoisomer. The scope of the invention includes a mixture of abdomen and purified enantiomers or a mixture enriched in enantiomers/diastereomers. The scope of the present invention is the individual isomers of the person represented by the formula (1), And any wholly or partially balanced mixture thereof. 2 The invention also includes individual isomers of the compound represented by the above formula, a mixture of eleven or more pairs of #inverted isomers Other compounds of the present invention can be prepared by those skilled in the art from the teachings of the present specification and the use of reagents which are readily synthesized or commercially available in accordance with the teachings of the present invention. The vinegar of the compound of the present invention is independently selected from the group consisting of: (1) a few acid vinegars obtained by cooling a radical group, wherein the non-radical moiety of the carboxylic acid moiety of the ester group is selected from a linear or branched alkyl group (eg, ethyl fluorenyl, n-propyl, = three) a butyl or n-butyl group, an alkoxyalkyl group (for example, a methoxymethyl aralkyl group (for example, benzyl group), an aryloxyalkyl group (for example, a phenoxymethyl group = a group ( For example, a phenyl group substituted by, for example, a peptin, a Ci_4 alkyl group or a Ci4 alkane & oxy 2 amine group; (2) a sulfonate such as an alkyl- or aralkyl-based fluorenyl group (for example) , (A) amino acid ester (for example, L_net amine brewing group or diisoleucine fluorenyl (4) phosphonate and 5) mono-di- or tri-phosphate. The phosphates may be further acylated with, for example, Ci 2 Q alcohol or a reactive derivative thereof or by 2,3-(C 6 · 2 4 ) Si & In the above § § 'unless the special purpose' is present, any of the alkyl groups present preferably comprise from 1 to 18 carbon atoms, preferably from 6 carbon atoms, more preferably from 4 carbon atoms. Any of the cycloalkyl moieties of the self-contained towels preferably comprise 3 119946.doc -11 - 200808694 to 6 carbon atoms. Any aryl moiety present in the phenyl group, preferably 包括, ... Ethers of the inventive compounds include, but are not limited to, methyl, ethyl, butyl, and the like. The term "solvate" as used herein, amp amp 卜 “ 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 心 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 。 For the purpose, the solvents should not affect the biological activity of the solute. Suitable non-limiting examples of solvents include, but are not limited to, water, methanol, ethanol, and ethyl, which are pharmaceutically acceptable. Suitable non-limiting examples include: water, ethanol and acetic acid. Preferably, the solvent used is water. For treatment, a therapeutically effective amount of the compound of the present invention may be a chemical raw material: Further: 'The active ingredient may be in the form of a pharmaceutical composition. The present invention provides an effective amount of a compound of the present invention and a pharmaceutically acceptable carrier, diluent or a substance. The compound of the present invention is as herein described. Said that it is compatible with the formulation of the Straight Beam Group = compatible and harmless to the recipient of the pharmaceutical composition, its ingredient carrier, diluent or thief-shaped agent must be acceptable; .. 'This (etc.) according to this Invention another - Also provided is a method which comprises mixing a compound of the present invention with a carrier, diluent or domain-formulation agent. The therapeutically effective amount of the compound of the present invention which can be administered to the stomach drug will depend on a plurality of factors. The sound depends on the species, age and voxel of the recipient. For example, the severity, composition properties and cast:: the exact condition of the library and the whites should be considered. 119946.doc -12- 200808694 σΡ The effective amount of the therapeutic agent should be determined by the attending physician or veterinarian. The effective amount of the compound of the present invention used to treat a weak person should generally be between ο.1 and 100 mg/kg of the recipient (mammal) Between body weight/day. Usually, the effective amount should be between phlegm and (7) mg/kg body weight/day. The actual amount per day is usually 0.3 to 3, _mg. This amount can be single dose per day or more per day. One (e.g., 2, 3, 4, 5 or more) divided doses are administered such that the total daily dose is the same. The effective amount of a pharmaceutically acceptable derivative thereof can be determined in the form of an effective amount of the compound of the present invention. Should be suitable for treatment Other conditions as referred to herein. ^The pharmaceutical composition may be present in a unit dosage form containing a predetermined amount of active ingredient per unit dose. As a non-limiting example, the treatment of the condition, the route of administration, the age, weight and condition of the patient, The unit may comprise from 5 mg to 1 g of a compound of the invention. Preferred unit dose compositions are those which comprise a daily or divided dose, or a suitable fraction thereof, as described above. Any of the ingredients well known in the pharmaceutical industry. Pharmaceutical compositions may be by any suitable route, for example by oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual or It is suitable for administration by slow intravenous or dermal path. Compositions such as xiao can be prepared by a method known in the pharmaceutical industry, for example, by subjecting the active ingredient to a carrier or excipient... The pharmaceutical composition may be present in the form of, for example, a capsule or lozenge; a powder or granule; a solution or suspension, each having an aqueous or non-aqueous liquid; an edible foam or a puncturing body; Or 119946.doc -13- 200808694 Oil-in-water liquid emulsion or water-in-oil liquid emulsion. For example, in the case of oral administration, the active pharmaceutical ingredient may be combined with a toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. In general, powders are prepared by mixing the compound in a fine size and in a suitable pharmaceutical carrier such as an edible carbohydrate (e.g., powdered mannitol). Weft agents, preservatives, dispersing agents, and coloring agents may also be present. Capsules are made by preparing a powder, liquid or suspension mixture and encapsulating it with gelatin or some other suitable shell material. Sliding agents and lubricants (e.g., 'colloidal silica, talc, stearic acid, stearic acid, or solid polyethylene glycol) can be added to the mixture prior to encapsulation. It is also possible to add a disintegrating hydrazine or a bulking agent (for example, Qiongyue, calcium carbonate or sodium carbonate) to improve the utility of the medicinal agent when absorbing the capsule. Further, suitable binders, lubricants, disintegrants, and coloring agents may also be incorporated into the mixture when desired or desired. Examples of suitable binders include starch, gelatin, natural sugars (such as glucose or milk, '), rice sweeteners, natural and synthetic gums (such as acacia, gutta or sodium alginate), slow methylcellulose. , polyethylene glycol, ants, and the like; lubricants for such dosage forms include, for example, sodium oleate, sodium stearate, stearic acid, sodium benzoate, sodium acetate, sodium hydride, and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite gum, and the like. The μ, = agent can be formulated, for example, by preparing a powder mixture, a granulated money ingot, adding a / π J and a disintegrant, and pressing into a tablet. The powder mixture can be prepared by mixing a suitably ground compound with a diluent or a substrate as described above. 119946.doc •14-200808694. Optional ingredients include binders such as carboxymethyl cellulose, citric acid sleep, gelatin or polyethylene ratios; solution blockers such as stone soil; sputum under accelerators such as quaternary salts' and / or absorbent 'such as bentonite, kaolin or linalic acid. The powder mixture may be subjected to wet granulation using a binder (e.g., sugar poly, starch/a = acadia mucilage or a solution of cellulose or polymeric material) and forcing it through the trainer. As an alternative to granulation, the = mixture can be passed through the tablet machine and incomplete pieces formed, which are then pressed. The particles may be lubricated by the addition of stearic acid, stearate, talc or mineral oil to prevent sticking to the tablet forming a mold. The lean lubricating mixture is then compressed into a tablet. The compounds of the invention may also be combined with a free flowing inert carrier and compressed directly into a tablet without passing through a granulation or repeated bonding step. The present invention provides a clear or opaque protective coating from a shellac seal coat, a coating of sugar or polymeric material, and a soil. Dyes can be added to the specialty coating to distinguish between different unit doses. Oral fluids (e.g., solutions, syrups, and _) may be formulated to: provide a given amount of a compound in a given amount. The syrup W is prepared by dissolving in a suitably seasoned aqueous solution, and the granule is prepared by a == toxic alcohol vehicle. Suspensions can usually be formulated by chemically treating the compound with a non-toxic medium. Solubilizers and emulsifiers such as ethoxylated isostearic acid and polyoxyethylene sorbitol can also be added; anti-:: his scaly additives such as peppermint oil, or natural sweeteners, saccharin, or other artificial Sweeteners; and the like. The composition of the appropriate dosage unit administered to the mouth of the mouth can be microencapsulated. Thus, "the substance may also be prepared for extended or sustained release by, for example, coating or encapsulating the particulate material 119946.doc 200808694 with a polymer, hydrazine or the like. The compounds of the invention may also be lipids. The bulk delivery system is administered in the form of, for example, a single layer of oligolipids, a single layer of large vesicles, and a plurality of vesicles. The liposomes can be made from a variety of phospholipids, such as cholesteryl, stearylamine or phospholipid choline. The present granules can also be delivered by using a monoclonal antibody as a separate carrier, wherein the compound molecule binds to a separate carrier. The human compounds can also be dissolved as a targeted drug carrier. Polymers such as polymer knots can include polyvinylpyrrolidone (PVP), pyran co-esters, polypropylmethacrylamide-benzene, polyethylidene-aspartamide phenol Or polyethylene oxide polylysine substituted with a palmitoyl residue. In addition, the compounds can be used with a class of biodegradable nozzles for drug controlled release. For example, cross-linking or amphoteric block copolymerization of polylactic acid, poly-ε-caprolactone, polyhydroxybutyric acid, poly-s-sodium, polyacetal, polydihydropyran, polycyanoacrylate and hydrogel A pharmaceutical composition suitable for transdermal administration may be in the form of a discrete patch intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, active wounds can be as outlined in p/2arwacd (1986). The iontophoresis method (as it is incorporated herein by reference) is used to deliver the self-adhesive agent. The pharmaceutical composition for topical administration can be ointment, cream, suspension, lotion, powder. For the treatment of the eye or other external tissues (such as the mouth and skin), 119946.doc -16- 200808694 Application in the form of topical lean or creamy. When applied as an ointment, the active ingredient may be applied with a paraffin or water-miscible ointment base or I may be an oil-in-water cream base or a water-in-oil base. The ingredients are formulated into a cream. Pharmaceutical compositions suitable for topical administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent. The pharmaceutical composition for topical administration in a medium-sized mouth includes a diamond-shaped spinner, a fragrant key, and a mouthwash. Pharmaceutical compositions suitable for nasal administration with a carrier-based solid include a coarse powder having a particle size of, for example, between 20 and 5 G microns. The powder is administered in such a manner that the container is inhaled, i.e., by self-sealing the container containing the powder via the nose passage. Suitable media for the administration of the carrier liquid in the form of a nasal spray or in the form of a liquid include an aqueous solution or an oil solution of the active ingredient. • Appropriate: The pharmaceutical composition to be administered by inhalation includes finely divided powder or fine: medicinal Γ 1 assists various types of metered doses of pressure aerosol, nebulizer or formula 2 pharmaceutical composition for rectal administration can be (iv) sputum form or enema Formulation suitable for vaginal administration of pharmaceutical composition cream, gel, paste, f ^ (4) Vaginal plug, milk suitable for parenteral administration of pharmaceutical compositions including human liquid 'which may contain antioxidants, buffers, and second ..., water sterile injection of the isotonic solute of the intended recipient; and: 2: the formulation and 3 water and anhydrous sterile suspension 119946.doc -17- 200808694) Ij /, may include suspending agents and thickeners. The compositions may be in the form of unit doses or containers I (eg, sealed vials and vials) and may be stored under lyophilization (lyophilization) conditions and only require the addition of a sterile liquid carrier for injection prior to use. , such as water. Temporary preparations for injections and suspensions can be prepared from sterile powders, granules and lozenges. In addition to the above-described particular length 1 and ingredients, such compositions may also include other pharmaceutical agents customary in the art depending on the type of formulation. For example, compositions suitable for oral administration can include flavoring or coloring agents. In another embodiment of the invention, a compound of the invention for use in medical therapy, particularly for the treatment of viral infections, such as HIV infection, is provided. The compounds of the present invention have been shown to have anti-HIV infection activity, although such compounds may also have anti-HBV infection activity. The compounds of the invention are especially suitable for the treatment of HIV infection and related conditions. The treatments referred to herein extend to the treatment of established infections, symptoms and related clinical conditions such as AIDS-related syndrome (ARC), Kapsi's sarcoma (Kap〇si, s sarcoma) and AIDS dementia. The present invention provides a method of treating an HIV mutated virus exhibiting NNRTI resistance by administering a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable derivative thereof to a mammal, particularly a human. In particular, the compounds of the invention are useful for the treatment of wild-type Hivd as well as several drug-resistant mutations, such as K103N, L100I or Y181C. The invention provides a method of treating the symptoms or effects of a viral infection in an infected animal, such as a mammal, including a human, comprising treating the animal with a therapeutically effective amount of a compound of the invention. A specific embodiment of this aspect of the invention 119946.doc -18-200808694 'The virus infection is a retroviral HIV infection. The invention is another method of separating, basketing, or influencing.匕 — — 种 种 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗 治疗The compounds of the invention and any pharmaceutically acceptable are administered in combination with other therapeutic agents. This tobacco date may be administered alone or separately with the compound of the present invention and other pharmaceutically active stimuli, and when administered separately, may be administered simultaneously or sequentially in any order. The compounds of the invention and other pharmaceutically active agents = = administration timing should be selected to achieve the desired combination of therapeutic effects. The pharmaceutical combination can be administered by:: the following: a derivative of the received compound and the other treatment of the two compounds, the 筚 种 种 种 种 种 种 种 四 四 四 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或 或First, a therapeutic agent is administered and then administered in the order of "Hai Shun 庠 μ or vice versa, respectively, and can be separated by a shorter time or longer. The compound of the present invention can be accessed by #, Λ明化合物, disease And the condition, and the same as the hair, the sputum, etc. are used to treat or prevent other conditions or conditions of the other appropriate / / oral combination of drugs. /, . These compounds can be combined with any other medical orders The combination is used, wherein the western table combination is active and thus pre-regulates the chemical kinetin receptor W/〇 〇 及 and/or immunomodulatory disease. The present invention can be used in a green tenth eve < use. Examples of combinations of agents for preventing or treating HIV include examples of such agents: nuclear (four) recording enzyme inhibition swords such as zidovudine (10). - 119946.doc •19- 200808694 didanosine, lamivudine, zalcitabine, abacavir, stavidine, ade Adefovir, adefovir dipivoxil, fozivudine todoxil, emtricitabine, alovudine, and doxorubivir Amdoxovir), elvucitabine and similar agents; non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.) For example, nevirapine, delavirdine, efavirenz, loviride, euphoria, oltipraz, capravirine, TMC-278, TMC-125, etravirine and similar agents; protease inhibitors such as saquinavir, ritonavir, indinavir, nelfinavir ( Nelfinavir), amprenavir (amprenavir), fosanavir ( Fosamprenavir), brecanavir, atazanavir, tipranavir, palinavir, lasinavir and the like; invasion inhibitors , for example, Enfuweidi (61^11¥丨1^(16) (Ding-20), Ding-1249, PRO-542, PRO-140, TNX-355, BMS-806, 5-helix and similar agents; Integrase inhibitors, such as L-870, 180 and similar agents; budding inhibitors, such as PA-344 and PA-457 and similar agents; and other CXCR4 and/or CCR5 inhibitors, such as Wake Vivel 119946.doc -20 - 200808694 (vicriviroc) (Sch-C), Sch-D, TAK779, Maraviroc (UK 427, 857), TAK 449, and their disclosures in WO 02/74769, PCT/US Patent No. US 03/39644 No. PCT/US Patent No. US 03/39975, PCT/US Patent No. US 03/39619, PCT/US Patent No. US 03/39618, PCT/US Patent No. US 03/39740, and PCT/US Patent US 03/39732 and similar agents. The combination of the compound of the present invention and the HIV agent is not limited to the above, but includes, in principle, any combination with any pharmaceutical composition for treating HIV. As mentioned, the compounds of the invention may be administered separately or in combination with other HI V agents in such combinations. In addition, one agent can be administered before, at the same time as, or after the administration of other agents. The compounds of the invention can be prepared by a variety of methods including well known standard synthetic methods. Exemplary general synthetic methods are set forth below and subsequently in the working examples to prepare specific compounds of the invention. In all of the schemes described below, (if necessary) a protecting group of a sensitive or reactive group is used in accordance with the general principles of synthetic chemicals. The protecting group is controlled according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons, with reference to the protecting group incorporated herein by reference). Such groups are removed at suitable stages of compound synthesis using methods well known to those skilled in the art. The method and the selection of the reaction conditions and the order of their implementation should be consistent with the preparation of the compounds of the invention. Those skilled in the art will be aware of the presence or absence of a stereocenter in the compounds of the invention. Accordingly, the invention includes all possible stereoisomers and not only 119946.doc 21 - 200808694, but also includes the individual enantiomers. When a compound of the single enantiomer is desired, it can be obtained by stereoselective synthesis or by redissolving the final product or any suitable intermediate. The re-dissolution of the final product, medium (four) or starting material can be achieved by any suitable method known in the art. See, for example, E·L· Elieb S. η. Wilen and L. Ν· from (10)άα Stereochemistry 〇f 〇rganic c〇mp_ds(mUy_

Interscience,: [994] (incorporated by Stereochemistry). Abbreviations As used herein, the symbols and conventions used in such processes, protocols, and examples should be consistent with those used in the current scientific literature, for example,

Journal thef the American Chemical Society or Journal of 5z (9/og/ca/C/zem(4)〇;. Specifically, the following abbreviations can be used in the examples and throughout the specification: g (g); mg (mg); L ( Liters); mL (ml); pL (microliters); psi (pounds per square inch); Μ (molar); mM (mole); Hz (Hz); MHz (megahertz); M〇l (mole); mmol (mole); rt (room temperature); min (minutes); h (hours); mp (refining point); TLC (thin layer chromatography); CH2C12 ( Dichloromethane) TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); 119946.doc -22- 200808694 CDC13 (gas chloroform); CD3OD (deuterated methanol) Si〇2 (cerium oxide); DMSO (dimethyl hydrazine); EtOAc (ethyl acetate); atm (atmospheric pressure); HC1 (hydrochloric acid); CHC13 (chloroform); DMF (N, N-II) Methylformamide); Ac (ethylidene); Cs2C03 (barium sulphate); Me (methyl); Et (ethyl); EtOH (ethanol); MeOH (sterol); t-Bu (p. Tri-butyl); Et20 (diethyl ether); N2 (nitrogen); MsCl (decanesulfonate); sat'd (saturated); K2CO3 (potassium carbonate); DMAP (4_(dimethylamino)pyridine) DCE (1,2_di-ethane); Ps (polymer supported); EDCI (1-(3-didecylaminopropyl)-3-ethylcarbodiimide hydrochloride P-BEMP (polymer supported 2-tris-butylimido-2-diethylamino-1,3-didecylperhydro-diaza-triphosphorane); TsCl (toluenesulfonate); TES (triethyldecane); TBAF (tetrabutylammonium fluoride); CSA (camphorsulfonic acid); n_BuLi (n-butyllithium); TBDPSC1 (tris-butyldiphenyl) Formyl chloride; HOAc (acetic acid); AcCl (acetonitrile); DIBAL-Η (diisobutylaluminum hydride); 119946.doc -23 - 200808694 DBU (1,8-diazabicyclo[ 5.4.0] undec-7-ene);

MgS〇4 (magnesium magnesium sulphate);

NaHC〇3 (hydrogen hydride);

Pd/C (palladium on carbon); DCM (diqi methane);

Eq (equivalent); IPA (isopropanol);

Rt (retention time); SFC (supercritical fluid chromatography); N (standard); mCPBA (m-chloroperbenzoic acid); ACN (acetonitrile); DBU (l,8-diazabicyclo[5·4 ·0]undec-7-ene);

MgS04 (magnesium sulfate);

NaHC03 (sodium bicarbonate);

Pd/C (palladium on carbon); 'DCM (dichloromethane);

Eq (equivalent) IPA (isopropyl alcohol);

Rt (retention time); SFC (supercritical fluid chromatography); N (standard); mCPBA (m-chloroperbenzoic acid). All temperatures are expressed in ° C (degrees Celsius) unless otherwise stated. 119946.doc -24- 200808694 The reaction was carried out in an inert atmosphere at room temperature unless otherwise stated. Reagents which are used without synthetic details are either commercially available or can be prepared according to literature procedures. 0 The compounds of the invention can be prepared by the procedures set forth below. plan 1 :

Journal fuer Praktische Chemie (Leipzig), 328(5-6), 705-712; 1986

119946.doc 25- 200808694 Option 2:

Except for the intermediates prepared in accordance with WO2001017982 and shown in the schemes, the <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; Ready. In this aspect, intermediate A is reacted with at least one f-alkyl alkyl hydride reagent in the presence of a palladium catalyst and a ligand to form intermediate B. 119946.doc -26 - 200808694 Option 3:

Zn(CN)2; palladium catalyst in suitable ligands; hydrazine alkyl hydride reagent

CN

Wherein R1 is a halogen, R2 is a halogen, specifically chlorine, and m is 1. The following scheme, Scheme 4, represents an intermediate process in which the palladium catalyst is Pd2(dba)3 in DPPF and NMP is used as a solvent.

Option 4

R

Zn(CN)2 Pd2(dba)3/DPPF NMP methyl hydrazine hydride reagent

B wherein R1 is a halogen, R2 is a halogen, specifically, chlorine, and m is 1. The following scheme, Scheme 5, represents an intermediate process in which the palladium catalyst is Pd(OAc) 2 in DPPF and NMP is used as a solvent. Option 5 R1

NMP decyl hydride reagent

Zn(CN)2 Pd(OAc)2/DPPF

CN

Wherein R1 is a halogen, R2 is a halogen, specifically chlorine, and m is 1. The following scheme, Scheme 6, represents an intermediate process in which the palladium catalyst is Pd(Cl) 2 in DPPF and NMP is used as a solvent. Option 6: 119946.doc -27- 200808694

Zn(CN)2 PdCl2/DPPF

曱梦烧基hydride reagent

CN

Wherein R1 is a halogen, R2 is a halogen, specifically chlorine, and m is 1. Example 1: 2-({4-Gas2-[(3-a-5-cyanophenyl)carbonyl]phenyl}oxy (4-{[(25)·2,3-dihydroxy-3) -methylbutyl]oxy}-3-fluoromethylphenyl)acetamide

Procedure 1 Step A: 1,2-Difluoro-3-methyl-4-nitrobenzene (Intermediate 1)

(2,3-Difluoro-6-nitrophenyl)acetic acid (34.78 g, 160 mmol, European Patent No. EP470578 (A1), W02002028825 (A2)) and copper oxide in 500 ml of acetonitrile (I) (4.58 g, 32 mmol, 〇 2 equivalent) were combined and heated under reflux for 1 hour. The reaction mixture was transferred via celite and the filtrate was concentrated to a green oil. The residue was dissolved in the scales and filtered a second time via diatomaceous earth. The filtrate was concentrated to dryness and the title compound was crystalljjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjjj 119946.doc -28 - 200808694 (300 MHz, DMSO-d6) δ ppm 2.44 (d, J=2.7 Hz, 3 H), 7.57 (m, 1 H), 7.95 (ddd, /=9.3, 4.7, 2.1 Hz , 1 H). Step B. (45&gt;2,2-Dimethyl-4-{l-methyl_i_[(phenylmethyl)oxy]ethyl 1,3-dioxocyclopentane (Intermediate 2)

To sodium hydride (6% in mineral oil, 13.5 g, 336 mmol, equivalent) in 400 ml of dry THF at ambient temperature was added dropwise to 200 ml of dry THF in a stirred slurry. -[(4Q-2,2-dimethyl-[ 1,3-dioxolan-4-yl]-2-propanol (44.89 g, 280 mmol, eg / fuer Praktische Chemie (Leipzig), 328 (5-6), 705-712;

1986). The reaction mixture was allowed to stir at ambient temperature for 3 Torr after the addition. Tetrabutylammonium iodide (5 ι 8 g, 14 mmol, 〇. 〇 5 eq.) was added to the mixture at ambient temperature, followed by dropwise addition of benzylidene (3 ml) in dry THF. 47.9 grams, 280 millimoles, i equivalent). The reaction mixture was stirred at ambient temperature for 16 h, quenched with EtOAc EtOAc EtOAc. The combined organics were dried with EtOAc EtOAc EtOAc EtOAc. 1h NMR (400 MHz? DMSO-d6) δ ppm 1.16 (s5 3 Η)5 1.20 (s5 3 Η)5 1.26 (s93H)?1.33 (s5 3 Η), 3.81 (m5 ! Η), 3.93 (m? 1 Η)! 4.05 (m,1 Η), 4.47 (m,2 Η), 7·21-7·33 (m,5 Η). Step C: (25&gt; 3-methyl-3-[(phenylmethyl)oxybutyrenediol (middle 119946.doc -29- 200808694

Dissolved in 560 ml of 1N 11 (:1) in 56 ml of THF (45 &gt; 2,2_dimethyl_4_{1_methyl[(phenylindenyl)oxy] at %^μ Ethyl bromide was dissolved in dioxetane (7 g of crude product, intermediate 2) for 4 hours. The reaction mixture was concentrated to remove most of THF, diluted with water and extracted with diethyl ether. The 〇4 was dried, filtered, and the filtrate was evaporated to dryness crystals crystals crystalssssssssssssssssssssssssssss δ ppm 1.11 (s5 3 H)5 1.19 (Sj 3 H), 3.29 (m5 1 H)? 3.42 (m? 1 H), 3·65 (m, 1 H), 4.30 (dd, J=6.0, 5.4 Hz, 1 H), 4.4 (m, 2 H), 4.7 (d, J = 4.9 Hz, 1 H), 7.20-7.34 (m, 5 H) Step D: (25&gt;1-[(2- Fluoro-3-methyl-4-nitrophenyl)oxy]-3-methyl-3-[(benzyl)oxy]-2-butanol (Intermediate 4)

(25&gt; 3-methyl-3-[(phenylindenyl)oxy]butanediol (58·9 g of crude product 'Intermediate 3) and 1,2-difluoro-3-indolyl-4 -Nitrobenzene (42.6 g, 219 House Moer 'Intermediate 1) was combined in 730 ml of benzene and used 73 0 ml of 6 NaOH and benzyltriethyl hydrazine hydrate (2.5 gram, ^ mmol) , 〇〇5 equivalents) Treatment 'at the same time vigorous mechanical stirring at 60 ° C for 16 hours. Separate the phases and 119946.doc -30- 200808694 Extract the aqueous phase twice with EtOAc. Combine the organic phases and dry with MgS The filtrate was filtered and the filtrate was dried to dryness. The crude material was purified by flashing on EtOAc (EtOAc) The title compound (33. 9 g, 93.2* mol, 33% of 3 steps) was obtained as a crude oil. lH NMR (4 〇〇MHz? DMSO-d6) δ ppm 1.22 (s5 3 H)5 1.28 (s5 3 H)? 2.42 (d, /=2.6 Hz? 3 H)? 3.79 (t5 /=5.9 Hz5 1 H)5 4.10 (dd5 y=10.35 8.1 Hz, 1 H), 4.41 (dd, J=l 〇.3, 2.0 Hz, 1 H), 4.49 (m, 2 H), 5.38 (d, J = 6.0 Hz, 1 H), 7.20-7.33 (m, 6 h), 7·88 (dd J=9.2, 1.7 Hz5 1 H) 〇Step E: (2*S)-l-[(4-Amino-2-fluoro-3-indolylphenyl)oxy]_3_methyl· 2,3 -butanediol (intermediate 5)

The (2S)-1-[(2-fluoro-3-methyl-4-) dissolved in 200 liters of EtOH was treated with palladium hydroxide (3 g, 2% by weight on carbon) under a 60 psi hydrogen atmosphere. Nitrophenyl)oxy]-3-methyl-3-[(phenylmethyl)oxy]butanol (33.87 g, 93.2 mmol, Intermediate 4) with vigorous stirring for 3 days. The catalyst was filtered through celite, and the filtrate was concentrated to dryness to afford titled compound (20.39 g, 83.8 m. 4 NMR (400 MHz, DMSO-d6) δ ppm 1.02 (s, 3 Η), 1 · ΐ〇 (s, 3 H), 1.94 (d, J = 2.0 Hz, 3 H), 3.48 (ddd, /= 8.0, 5.7, 2.3 Hz, 1 H), 3·70 (dd, /=10.1, 8.1 Hz, 1 H), 4·07 (dd, J=l〇.〇, 2.3 Hz, 1 H), 4.31 119946 .doc 31· 200808694 (s,1 Η), 4.67 (s,2 H), 4.90 (d, /=5.7 Hz, 1 Η), 6.33 (dd, piece ·7, 1.6 Hz, 1 H), 6.70 (t, /=9.1 Hz, 1 H) 〇Step F: ({4-chlorochloro-5-cyanophenyl)carbonyl]phenyl}oxy)acetamidine chloride (Intermediate 6)

({4-Chloro-2-[(3-a-5-cyanophenyl)carbonyl]phenyl}oxy)acetic acid (74.85 g, 213.8 mmol) in 1 liter of DCM at ambient temperature , W02001017982) A catalytic amount of DMF (1 ml) was added to the suspension, followed by dropwise addition of 2 valerium chloride (214 ml, 428 mmol, 2 liters) in DCM while stirring. The reaction mixture was allowed to stir at ambient temperature for 1 hour after the addition, at which time no more carbon dioxide was observed. The reaction mixture was concentrated to dryness afforded EtOAc m. Step G: 2-({'Chloro-2-[(3_气_5_cyanophenyl)carbonyl]phenyl}oxy), (4-{[(2),3-diyl)acetamide Hydroxy-3-methylbutyl]oxybu 3-fluoro-2-methylbenzene

(2Phosin-1-[(4_Amino-2_fluoro_3_methylphenyl)oxy]_3_methyl_2,3 119946.doc -32- 200808694 diol (29·9 g) , 81·1 mmol, intermediate 5) with ({4-gas-2_[(3-chloro-5-cyanophenyl)carboxy]phenyl}oxy)ethonyl chloride (19.73 g, 81.1 m Moxies, 1 equivalent, intermediate 6) were combined in 300 mL of acetone containing sodium bicarbonate (3 4.06 g, 405 mmol, 5 eq.) and stirred at ambient temperature for 2 hr. The EtOAc was partitioned between EtOAc and EtOAc (EtOAc m. The title compound (35.83 g, 62.3 mmol, 77%) was obtained as a white crystalline solid. NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3 H), 1.12 (s, 3 H), 1.95 (d, J = 2.4 Hz, 3 H), 3.53 (ddd, J = 8.0, 5.9, 2.1 Hz, 1 H), 3.85 (dd, *7=10.1, 8.1 Hz, 1 H), 4.23 (dd J=l〇.l, 2.0 Hz, 1 H), 4.41 (s, 1 H), 4.73 (s, 2 H), 5.03 (d, J = 5.7 Hz, 1 H), 6.98 (m, 2 H) ,7·22 (d, J=9.2 Hz, 1 H), 7.53 (d, J=2.6 Hz, 1 H), 7.68 (dd, /=9.0, 2.7 Hz, 1 H), 8.06 (m, 1 H) ), 8.13 (t, J=1.5 Hz, 1 H), 8.30 (m, 1 H), 9.29 (s, 1 H) 〇LCMS (ES·) m/z 573.06, 575.01 (MH), LCMS (ES+) m/z 597.07, 599.07 (M+Na). ee=96.4% (chiral SFC, 25% CH3OH in C02, 2000 pSi, 30 ° C, 2 ml/min, on 4.6 x 250 mm Diacel OJ-H column; Rt = 6 · 3 minutes, the first elution peak of the racemic mixture.) Example 2: 2·({4·Gas-2_[(3-Ga-5-cyanophenyl)carbonyl]phenyl} Oxy (4-{[(2i〇-2,3-dihydroxy-3-methylbutyl)oxybu 3-fluoro-2-methylphenyl)acetamide 119946.doc -33 - 200808694

Procedure 2: Example 2 was prepared by the method of Procedure 1, except for the following: 2-[(4Λ)-2,2-^-indenyl-1,3-dioxanthene-cardoyl] was used in Step B -2_propanol replaces 2-[(4$)-2,2-monomethyl-1,3-dioxolan-4-yl]-2-propanol. And 2_[(4i?)-2,2-monomethyl-1,3-monoxanthene]-2-propanol is based on SchroUer k (Journal fuer praktische Chemie (Leipzig), 328 (5-6) , 705-712; 1986) Method from (4 and) 2,2-dimercapto-1,3-dioxocyclopentane-4-carboxylic acid methyl ester instead of (4S)-2,2-dimethyl -1,3-dioxolone _4_ decanoic acid for the preparation. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3 Η), 1.12 (s, 3 Η), 1.95 (d, /=2.4 Ηζ, 3 Η), 3.53 (ddd, /=8) ·0, 5.9, 2·1 Ηζ,1 Η),3·85 (dd,/=1〇·1,8.1 Ηζ,1 Η),4·23 (dd,/=10·1,2·0 Ηζ ,1 Η),4·41 (s,1 Η),4·73 (s,2 Η),5.03 (d,J=5.7 Ηζ,1 Η),6·98 (m,2 Η), 7.22 ( d, J=9.2 Ηζ,1 Η), 7.53 (d, J=2.6 Ηζ,1 Η), 7.68 (dd, J=9.0, 2.7 Ηζ, 1 Η), 8·06 (m5 1 Η), 8.13 (t, J=1.5 Ηζ,1 Η), 8·30 (m,1 Η), 9.29 (s? 1 Η) 〇LCMS (ES&quot;) m/z 573.26 (Μ-Η), LCMS (ES+) m/z 597.28 (M+Na). Ee=97.4% (chiral SFC, 25% CH3OH in C02, 2000 psi, 30 ° C, 2 mL/min on a 4.6 x 250 mm Diacel OJ-H column; Rt = 7.4 min, racemic mixture Second eluting peak). 119946.doc -34- 200808694 Example 3: 2-({4-gas_2-[(3-a-5-cyanophenyl)carbonyl]phenyl}oxy)_#_ {4-[(2 , 3-dihydroxy-3-methylbutyl)oxy]_3_fluoro-2-methylphenyl}acetamide

Procedure 3: Step A · 2-Fluoro-3-indolyl-4-nitrophenol (Intermediate 7)

To hydrazine dissolved in anhydrous DMF (15 ml), 2_difluoro_3_methyl_4•nitrobenzene (1.0 g '5·7 halo, sodium acetate (2.4 g) , 28.93⁄4 mol) and the solution was heated to 12 Torr for 24 hours. The reaction was diluted with ethyl acetate and washed with water then brine and dried with &lt;RTI ID=0.0&gt; Chromatography was carried out on a 30% EtOAc EtOAc EtOAc (EtOAc) -d6) δ ppm 2.40 (d, J=2.6 Hz, 3 Η), 6.93 (t, J=9.1 Hz,

1 H), 7.81 (d, J = 9.2 Hz, 1 H), 11.26 (br s, i H). LCMS (ES-) m/z 170.12 (M_H). Step B: 2-Fluoro-3-methyl-l-[(3-methyl-2-butene-i•yl)oxy]_'nitrobenzene (Intermediate 8) 119946.doc •35- 200808694 〇

2•Fluorine-3-methyl-4-nitrophenol (311 mg, U mmol, intermediate 7) and potassium carbonate (5 mg, 36 mmol) dissolved in anhydrous DMF (5 mL) To the solution was added H3·methylbutene (315 μL, 27 mmol). The solution was stirred at ambient temperature for 2 hours. The reaction was partitioned between an equal volume of EtOAc and water. The organic layer was washed with brine and dried with MgSO 4 and concentrated. The crude product was chromatographed on a hair gel eluted with 40% Et0Ac in hexane. The title compound (400 mg, 17 mmol, 93%) was obtained as a pale yellow solid. 4 NMR (400 MHz, DMSO-d6) 6 ppm !.73 (d, J=11.〇Hz?, H)? 2.41 (d, J=2.6 Hz, 3 H), 4.72 (d, J=6.6 Hz , 2 H), 5.44 (t! J-6.6 Hz, 1 H), 7.23 (t, J=8.8 Hz, 1 H), 7.93 (d, J=9.2 Hz 1H) 〇, step c: l-[( 2-Fluoromethylmethyl_4_nitrophenyl)oxy]_3_methyl_2,3-butane V, diol (intermediate 9) 〇

2-Hydroxy-3-methyl-[[3-methyl-2-butene-i-yl)oxy]_4_nitrobenzene (4) in anhydrous dichloromethane (20 mL) 〇〇mg, 17 mmol, intermediate 8) Add mCPBA (75 mg, 3.4 mmol, 77%) to the solution and 119946.doc -36- 200808694

The reaction was allowed to stir at ambient temperature for 2 hours. The reaction was diluted with di-methane and washed with aliquots of aqueous sodium thiosulfate, saturated sodium bicarbonate (2 s) and brine, dried with &lt;RTIgt; The residue was dissolved in THF (12 mL) and diluted with water &lt;RTI ID=0.0&gt;&gt; . The solution was partitioned between EtOAc and water. The organic layer was washed with saturated aqueous sodium bicarbonate and then brine and dried and evaporated. The crude product was purified with EtOAc EtOAcjjjjjjj 4 NMR (400 MHz, DMSO-d6) δ ppm 1.22 (s, 3 H), 1.28 (s, 3 H), 2.43 (d, J = 2.6 Hz, 3 H), 3.54-3.59 (m, 1 H) , 3.99-4.04 (m, 1 H), 4.39 (d, J = 10.3 Hz, 1 H), 4.49 (s, 1 H), 5.15 (d, J = 5.9 Hz, 1 H), 7.26 (t, Bu 8.8 Hz, 1 H), 7.92 (d, J = 9.1 Hz, 1 H). Step D: l-[(4-Amino-2-fluoromethylphenyl)oxymethyl.2,3_τdiol (Intermediate 10)

1-[(2-Fluoro-3-methyl-4-nitrophenyl)oxy]-3-indenyl 2,3-butanediol (〇) dissolved in ethanol (1 ml) 369 mg, 1.4 mmol, intermediate 9) 10% carbon on palladium (40 mg) was added to the solution and stirred under a 60 psi hydrogen atmosphere with stirring at % temperature for 2 hours, thereby filtering through the algae The title compound was obtained as a white solid (296 119946.doc -37 - 200808694 mg, 1-2 mmol, 90%). 4 NMR (400 MHz, DMSO-d6) δ ppm 1·02 (s, 3 Η), 1·1 〇 (s, 3 Η), 1.94 (d, J=2.0 Ηζ, 3 Η), 3.48 (ddd, Household 8.0, 5.7, 2·3 Ηζ, 1 Η), 3·70 (dd, J=10.1, 8·1 Ηζ, 1 Η), 4·07 (dd, “7=10.0, 2·3 Ηζ, 1 Η), 4·31 (s, 1 Η), 4.67 (s, 2 Η), 4.90 (d, J=5.7 Ηζ, 1 Η), 6.33 (dd, J=8.7, 1·6 Ηζ, 1 Η) , 6.70 (t, J = 9.1 Ηζ, 1 Η). Step Ε : 2-({4-Chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)-| {4-[(2,3-diyl-3) -methylbutyl)oxy]-3-fluoro-2-methylphenyl}acetamide

({4-Chloro-2-[(3-)-5-cyanophenyl)carbonyl]phenyl}oxy)acetic acid (6 mg, 0.17 mmol, W02001017982), 1-[(4- Amino 2-fluoro-3-indolylphenyl)oxy]-3-methyl-2,3-butanediol (50 mg, 〇·2 mmol, intermediate 10), 1-hydroxybenzo Triazole hydrate (6 mg) and ι_[3_(dimethylamino)propyl]-3-ethylcarbodiimide hydrogenate (38 mg, 〇·2 mmol) and anhydrous dichloride Methane (1.5 ml) was combined and stirred at ambient temperature. The reaction mixture was purified on a silica gel eluted with 50 to 100% EtOAc in hexane. The appropriate fractions were taken with EtOAc EtOAc (EtOAc m. Mohr, 79%). iH (full MHz, DMSO-d6) δ ppm 1·〇5 (s, 3 h), 1.12 (s, 3 Η), 1.95 (d, J=2 4 119946.doc -38- 200808694

Hz, 3 H), 3.53 (ddd, J=8.0, 5.9, 2·1 Hz, 1 Η), 3·85 (dd, /=10.1, 8.1 Hz, 1 H), 4.23 (dd, J=10.1, 2·0 Hz, 1 H), 4.41 (s, 1 H), 4.73 (s, 2 H), 5.03 (d, /=5.7 Hz, 1 H), 6.98 (m, 2 H), 7.22 (d, J=9.2 Hz, 1 H), 7.53 (d, /=2.6 Hz, 1 H), 7.68 (dd, J=9.0, 2.7 Hz, 1 H), 8.06 (m, 1 H), 8.13 (t, J = 1.5 Hz, 1 H), 8.30 (m, 1 h), 9.29 (s, 1 H). LCMS (ES-) m/z 573.09 (M-H). Example 4: 2-({4_Gas-2_[(3-)-(cyanophenyl)carbonyl]phenyl}oxy)-indole_(4][(2 22,3-dihydroxymethyl butyl) 2]oxy}-3_fluoro-2-methylphenyl)acetamide type 2 27.0 g of 2-({4-chloro-2-[(3-a-5-cyanide) prepared according to Example 1] Phenyl)carbonyl]phenyl}oxy)_1(4_{[(2._2,3-dihydroxy-3-methylbutyl)oxy-3-tri-2-methylphenyl)acetamidine The amine was added to about 600 ml of refluxing ethanol, and the mixture was stirred at this temperature until completely dissolved. The solution was slowly cooled to 袠/m degree' and then stirred for 2 hours, at which time no crystals were observed. The mixture was allowed to stand in an ice bath. The mixture was cooled and stirred for a further 30 minutes. The reaction mixture was filtered and washed with EtOAc (EtOAc)EtOAc. The materials were characterized by 4 NMR and LC-MS to obtain results consistent with those obtained from the materials in Shell 1. The melting point was determined by differential scanning 2 heat I using an unsealed clamp aluminum disk. Determined by heating rate of 1 〇 (: / min. The melting point starting point is about 16 〇 r. Example S · 3-Gas-5_{[5_Gas-2-(indolyloxy)phenyl]carbonylbenzonitrile (intermediate vessel) 119946.doc -39- 200808694

The reactor was charged with (3-bromo-5-p-phenyl)[5-chloro-2-(methyloxy)phenyl]methyl ketone (1.0 wt, 1·〇 equivalent) under a nitrogen atmosphere. Cyanide (〇·2〇 weight, 0.60 equivalent) and 90% 1,2-dimethoxyethane/water (5 vol). The reactor contents were heated to about 80 ° C under nitrogen. 1,1-bis-(diphenylphosphino)ferrocene (DPPF, 0.01 weight, 0.0065 equivalent) and palladium acetate (.0031 by weight, .005) in DME (0.15 by volume) added in a single portion Equivalent) the slurry was washed into the reactor with additional DME (0.05 vol). PMHS (0.01 weight, 0.06 equivalent) in DME (0.1 volume) was added in a single portion. The reaction was allowed to stir at about 80 ° C for 2 hours. By adding 1,1 bis-(diphenylphosphino)ferrocene (DPPF, 0-01 wt., 0.0065 equivalent) and palladium acetate (.0031 wt.·〇〇5 equivalent) in DME (0.15 vol) The slurry was added to the second half of the catalyst, ligand and PMHS and washed into the reactor with additional DME (〇·05 volume). The PMHS (0.01 weight, 〇·〇6 equivalent) stored in dme (〇·1 volume) was added in a single portion. The reaction was allowed to heat for an additional 2 hours at about 8 (TC) while maintaining the remaining starting material &lt;1% by standard LC method. The mixture was cooled to 2 (rc and kept at an internal temperature below 30 C). The prepared solution was concentrated at a rate of 4 Torr (1 vol), saturated Nh4C1 (4 vol) aqueous solution and water (5 vol). After stirring for a few hours, the reaction mixture was filtered through a filter cloth and passed through a filter cake ( 2 volumes) rinse the reactor. The filter cake was then washed with additional water (4 X 2 volume) and suction dried. The resulting solid was returned to the reactor and dissolved in C-volume and 119946.doc • 40· 200808694 Warm to 5 (TC. Filter the contents through a diatomaceous earth pad and wash with acetone (〇1 volume). Keep the filtrate at 5 (rc and treat with water (〇·9 volumes) while remaining dissolved The reactor was cooled to 10 C over a period of 1 hour and held at 10 C for 1 to 2 hours. The solid was then filtered through a filter cloth and the filter cake was rinsed with cold 9:1 acetone·water (2 χ 1 volume). The solids were transferred to a drying oven and under vacuum at 5 Torr. Hour. iH NMR (4〇〇MHz, DMSO-d6) δ 8.31 (s,1Η) 8.02 (s,1Η) 7.94 (s, 1Η7.63 (d, j = 8.8Hz,1H) 7.45 (s,1H) 7.22 (d, j = 9.0 Hz, 1H) 3.65 (s, 3H). Example 6: Inhibition of bioactive viral replication I · H e L a cell analysis

HeLa Cell Analysis is based on the detection of replication-competent and pseudotyped human immunodeficiency virus with a sensitive cell line on the basis of activation of an integrated β-galactosidase gene, J.

A modified version of Wro/66: 2232-2239 (1992) in which HIV-1 infection is activated by the HIV-LTR-driven beta-galactosidase reporter gene integrated into the genome of the CD4+ HeLa cell line. Detection. Quantitative determination of β-galactosidase was achieved by measuring the activation of a chemiluminescent substrate (Applied Biosystems). The concentration of each compound required to inhibit 50% (ic5〇) HIV-1 induction of β-galactosidase signal was determined for each isogenic, recombinant virus relative to the untreated control. A · Materials 119946.doc -41 - 200808694

HeLa-CD4-LTR-p-gal cell line (AIDS Research and Reference Reagent Program, Division of AIDS, NIAID) DMEM (GibcoBRL No. 12430-047)

Trypsin-EDTA (GibcoBRL No. 25300-054) Heat inactivated fetal bovine serum (FBS) (Hyclone No. SH3 0070.03) Geneticin (GibcoBRL No. 1013 1-035) Hygromycin B (GibcoBRL No. 1687-010) 96-well Black, clear bottom, tissue culture treated plate (Costar No. 3 904) phosphate buffered saline (PBS) (GibcoBRL No. 14190-144) Dimethyl sulfoxide (DMSO) (ATCC No. 741625)

Gal-Screen Reporter Gene Analysis System (Applied Biosystems No. T1030) B. Growth and Preservation of CD4-HIV LTR-P-gal HeLa Cell Line HeLa-CD4-LTR-p-gal Cell Line Contains 10% Fetal Bovine Serum + 0.2 Reproduction in DMEM with mg/ml geneticin + 0.1 mg/ml hygromycin B. When 80% is confluent, the cells are lysed by standard trypsin digestion techniques (approximately every 2 to 3 days). C. Construction of the transcriptase (RT) mutant The DNA encoding HIV-1 reverse transcriptase was subcloned from the M13 phage subunit to the common shuttle vector PBCSK+ as a DNA fragment of about 1.65 kbp EcoRI/Hindlll. The HIV DNA insertion line of the resulting plasmid pRT2 was completely sequenced on both strands and then used in site-directed mutagenesis experiments. Specific amino acid substitutions were performed using Stratagene Quick Change reagent and mutagenic oligonucleotides from Oligos 119946.doc -42- 200808694. After mutagenesis, the entire mutant RT coding sequence was confirmed by sequence determination of two DNA strands. D. Construction of the isogenic HIV-1 RT mutant virus The mutant HIV-1 strain was analyzed by modified recombinant virus (Kellam P. and Larder B., Recombinant virus assay: a rapid, phenotypic assay for assessment of drug susceptibility The separation was performed by human immunodeficiency virus type 1 isolates, Antimicrobial Agents and 38: 23-30, 1994). 1 X 107 MT4 t cells (preserved in RPMI containing 10% fetal bovine serum, lysed every 5 to 6 days) in the presence of DMRIE-C transfection agent (Gibco) were digested with EcoRI/Hindlll according to the supplier's recommended protocol. The mutant RT plasmid and Bst EII digested HIV-1 hxb^rt DNA were co-transfected. Each mutant RT coding sequence was hybridized into the RT-deleted HIV_1 viral DNA backbone by homologous recombination in vivo. The transfected cell culture was developed and monitored until the syncytia formation &amp; CPE was extremely broad. The disease was harvested by clarifying the spin of the culture supernatant and frozen at -80 ° C as the initial stock solution. Sequence analysis was performed on the progeny virus in the RT region to determine the mutant genotype. The virus stock is further expanded, harvested by cell infection and stored as a frozen aliquot. The stock titer was determined for analysis in HeLa MAGI cells. E. Viral stock titer The HIV-1 virus stock titer was determined in the HeLa_CD4-LTR-p-gal assay system to determine the appropriate infectious dose. The endpoint of this analysis was Relative Light & RLU and the titer was recorded as RLU/ml. Dilute the virus stock (with 119946.doc -43 - 200808694 1:2) into DMEM containing 10% FBS plus 25 μg/ml DEAE-dextran and do not use as described in the ''Experimental Protocol'' section below Test compounds were analyzed. The "infection rate" (MOI) defined as the infectious unit/cell is usually not calculated but it is usually 1.0. The relationship between RLU/ml and other infection metrics (eg HeLa PFU/ml or MT4 TCID50/ml) in batches and batches Between the materials or between the strain and the strain may be inconsistent, but should be determined for each batch. F. Experimental protocol Day 1 1. Use 96-well plate (Costar No. 3904) with HeLa-CD4-LTR-P- Gal was inoculated with 3 &gt;&lt; 103 cells/well in 100 μl of 0^^ containing 10%? 38. Incubate overnight at 37 ° C, 5% CO 2 . Day 2 1. Bring the virus stock in a water bath Thaw (diluted at room temperature) and dilute to DMEM + 10% FBS + 25 μg / ml DEAE-dextran to an infection dose of approximately 10 million RLU / ml. Virus dilution will vary depending on the titer of the stock (see above) "The titer of the virus stock solution π." 2. Remove all media from each well with an 8 or 12-channel manifold aspirator. Work on one plate at a time to prevent HeLa-CD4-LTR-p-gal single The layers were dried. Add 35 μl (a total of about 350,000 RLUs) to each well and dilute the virus. Incubate for 2 hours at 37 ° C, 5% CO 2 . During the addition phase, compound titration plates were prepared at a final concentration of 1.35 times. In general, the titration test was reduced from 2.7 uM (final 2 uM) to 0·01 nM (final 0.008 nM) in a four-fold stepwise manner in an automated manner. 119946.doc -44- 200808694 Compound. This protocol allows 8 test compounds/96_well plate and 1 dilution point and 2 control samples/compound (η=丨). Titrate the test compound to DMEM+IO0/.FBS + 0.135 % DMSO (final 〇·1%). The final volume of the titrated compound in each well should be at least 15 μL and the DMSO including the control containing no compound should be 0.135% (final 0.1%) 4. Remove 1 〇〇 microliter of titrated compound from each well of the titration plate prepared in step 3 above and add to the virus adsorption plate (step 2 above). 5. At 3 7 ° C, 5% Incubate for 72 hours under C02. Day 5. 1. Reduce the supernatant to 50 μl and add 50 μl of Gal-Screen reconstituted according to the manufacturer's recommended protocol. 2 • Mix the plates vigorously on the platform shaker 3. Read the plate in 1 minute/hole in the Topcount photometer (Packard). G·Data analysis will be original by the following formula Percentage converted to control: (original signal in each well / two syllabic #initial signals in the same column without a compound) *100. Use the Robsage or Robofit program (GSK) to compare Percentage is plotted against compound concentration. The default model is Y=vt A * κ(χΛη/ (ΚΛη+χΛη)), however, any other model that gives IC5〇(where κ,,) is reasonably evaluated + ten can be used. 119946.doc • 45- 200808694 Table 1. Antiviral activity against wild-type and clinically relevant HIV. IC5G(nM) Example No. K103N K103N/ G190A V106A V106I/ Y181C WTRVA Y181C 1 aaabaa 2 ababaa 3 a ND a ND aa 10 + abbbaa 251 * b ND b ND ab 105 * bcccbb 106* bcccbb 252* bbbbbb 1001** b ND b ND ab 1018** c ND c ND bc

a &lt; InM b 1-10 nM c &gt; 10 nM + compound 40, example number 10 from WO 02/070470 * Example number obtained from WO 01/1 7982 ** from US Patent No. 2006/0025480A1 Example number ND = not determined

-46- 119946.doc

Claims (1)

200808694 X. Patent application scope: 2. - Compound of formula (IA): 4. A compound which is 2-({4-chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)-#-(4-{[(2 magic- 2,3-Dihydroxy-3-methylbutyl]oxy}-3-fluoro-2-methylphenyl)acetamidamine 5. A compound which is 2_({4_chloro-5-cyanide) Phenyl)carbonyl]phenyl}oxy)-, (4-{[(25&gt;2,3-dihydroxy-3-methylbutyl)oxybu 3_fluoro-2-methylphenyl) Indoleamine type 2. 6. A pharmaceutical composition comprising a compound of 119946.doc 200808694 as claimed in any one of claims 1 to 5 and a pharmaceutically acceptable carrier. A compound according to any one of the preceding claims, wherein the compound of any one of claims 1 to 5 is for use in the treatment of a viral infection and a related condition. Wherein the viral infection is HIV infection. 10. The use of a compound according to any one of claims 1 to 5 for the manufacture of a medicament for the treatment of a viral infection and a related condition. The virus infection is HIV infection. 12 - A method for treating HIV infection, including A composition according to any one of claims 1 to 5, wherein the composition of claim 6 wherein the composition comprises at least one additional therapeutic agent selected from the group consisting of nucleoside reverse transcriptase inhibitors, For example, zidovudine, didanosine, lamivudine, zalcitabine, abacavir, stavidine, ar Adefovir, adefovir dipivoxil, fozivudine todoxil, emtricitabine, alovudine, and doxorubivir Amdoxovir), elvucitabine and similar agents; non-nucleoside reverse transcriptase inhibitors (including agents with anti-oxidative activity, such as immunocal, oltipraz, etc.) For example, nevirapine, delavirdine, efavirenz, loviride, euphoria, oltipraz, capravirine, TMC-278, TMC-125, etravirine and similar agents; eggs Enzyme inhibitors such as Sabinavir 119946.doc 200808694 (saquinavir), ritonavir, indinavir, nelfinavir, amprenavir, blessing Fosamprenavir, brecanavir, palinavir, lasinavir, atazanavir, tipranavir and the like; Invasion inhibitors such as enfuvirtide (T-20), T-1249, PRO-542, PRO-140, TNX-355, BMS-806, helix 5- and similar agents; integrase inhibitors, For example, L-870, 180 and similar agents; budding inhibitors such as PA_344 and PA-457 and similar agents; and CXCR4 and/or CCR5 inhibitors, such as vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427, 857), TAK449; and similar agents. 119946.doc 200808694 VII. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbol of the symbol of the representative figure is simple: 8. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula: 119946.doc