TW200814993A - 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

[Technical Field] The present invention relates to a compound which is a non-nucleoside reverse transcriptase inhibitor, and relates to a preparation method, and a use for treating a human immunodeficiency virus infection. [Prior Art] v Human immunodeficiency virus ("HIV" is a pathogen of acquired immunodeficiency syndrome ("AIDS") and its precursor AIDS-related syndrome ("ARC", • A feature of the AIDS system For diseases in which the immune system, particularly CD4+ T-cells are disrupted, and 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. These NNRTIs interact with specific sites of HIV-reverse transcriptase, which are 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, J7 54, 26-45, 1999). The lack of long-term efficacy of NNRTI is often associated with the emergence of antiviral strains (J. Balzarini, vol. 58, 1-27, 1999). In addition, mutations found in the reverse transcriptase enzyme 119947.doc 200814993 generally result in reduced sensitivity to other reverse transcriptase inhibitors, which results in 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 RT inhibitors that have different performance modalities against various mutants.

Certain benzophenones as 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 mutants of HIV reverse transcriptase. SUMMARY OF THE INVENTION The present invention provides a compound of formula (I)

Cl Cl (I)

F 〇^V° or a pharmaceutically acceptable derivative thereof. A feature of the invention is a pharmaceutical composition comprising a compound of the invention. Features of the invention provide a compound of the invention for use in viral infections and medical treatment of related conditions (e.g., treatment of HIV infection and related conditions). It is also a feature of the present invention to provide a use of a compound of the present invention in the manufacture of a medicament for the treatment of viral infections and related conditions, for example, for the treatment of HIV infection and related conditions. Features of the invention provide a compound for the treatment of viral infections and related conditions (e.g., H9947.doc 200814993 for the treatment of HIV infection and related conditions). The method includes the administration of the present invention. [Embodiment] The term "treatment" as used herein refers to alleviating the development of a prescribed condition, a symptom of a condition, slowing or eliminating the development of the condition, and preventing or delaying; 〗 〖First to suffer from afflicting the subject again. "Pharmaceutically acceptable derivative" means that the compound of the invention or its inhibitory active metabolite can be provided directly or indirectly after administration to the recipient. Pharmaceutically acceptable vinegar, vinegar salt, test or ^ He Hesheng & You Jiahe organisms and prodrugs and their salts, when the compounds of the invention are administered to mammals, can enhance the bio-profit of such compounds The carrier of the parent compound to the biological chamber (eg, the 'brain or lymphatic system') can be enhanced by, for example, allowing the orally administered compound to be more readily absorbed into the blood or relative to the parent substance. The term, effective amount, as used herein. , means, for example, the amount of a drug or agent that is being sought by a researcher or clinician to induce a biological or medical response to a tissue, system, animal or human. The biological or medical response may be considered a preventive response or a therapeutic response. The term "therapeutically effective amount" means that an improved treatment, cure, rib or improvement of a disease, condition or side effect, or reduction, can be obtained as compared to a subject who does not receive the amount. Any disease or disorder an amount of development rate. The surgery. Also includes within its scope amounts effective to enhance normal physiological function. The present invention features provides a compound of formula (I) 119947.doc 200814993

—Λ^〇 (ι) or a pharmaceutically acceptable derivative thereof. This compound has the name 2_({4_chloro-2-([3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)_#_{3_Fluor_4_[(2_hydroxy_甲甲Propyl)oxy]_2-methylphenyl}acetamidamine. The two compounds of the present invention may exist in a non-fused form and a dissolved form). Both fused and non-fused forms are encompassed herein. The compounds of the invention may exist in a mixture of various forms and/or solvates or as a mixture of amorphous materials and forms or mixtures. In general, all physical forms are intended to fall within the scope of the invention. Such forms can be distinguished by various physical properties well known in the art, such as X-ray diffraction patterns, solubility, and melting point. Other compounds of the present invention can be readily synthesized or purchased by those skilled in the art in light of the teachings of the present specification without the use of industry knowledge.

The present invention is composed of the following groups: (1) by the 2 group of the radical group (4) the stagnation of the acid §, "the non-single base of the § of the zhizhi group is selected, from the straight chain Or a branched alkyl group (for example, an ethenyl group, a n-propyl group, a second-butyl group or a n-butyl group), an alkoxyalkyl group (for example, a methoxymethyl group), an aralkyl group (for example, a aryloxyalkyl group (eg, phenoxymethyl), an aryl group (eg, 'optionally, for example, halogen, CM alkyl or & alkoxy or hydroxy-based base) (2) a continuous acid vinegar, such as a decyl- or a aryl sulfhydryl group (for example, a sulfonyl sulfhydryl group); (3) an amino acid vinegar (for example, an L-sodium sulfhydryl group or I 119947.doc) 200814993^Eliminyl); (4) phosphonic acid s and (5) single, second or third. These sides can be passed: for example, c-alcohol or a reactive derivative thereof or esterified with 2,3-mono(C0-24)mercaptoglycerol. In these purposes, unless the special sentence day preferably contains up to 18 carbon houses, then there is any burning base part of the fire atom, preferably 1 to 6 carbon atoms, more preferably to # carbon The original ^ son. Any of the ring-based moieties present in the singularity preferably comprise from 3 to 6 stone anti-atoms. Present in the poor phenyl group. Preferably, any of the aryl moieties of the formula include ethers of the compounds of the invention including, but not limited to, methyl, ethyl, butyl, and the like. The term "," and "compound", means a variable stoichiometric complex formed by a solute (in the present invention, a compound). For the purpose of the present invention, non-limiting examples of such solvents include: water, methanol, ethanol, and B. The solvent is a pharmaceutically acceptable solvent. Non-limiting examples of suitable pharmaceutical agents include water, ethanol, and acetic acid. The solvent used is water. Treatment = a therapeutically effective amount of a compound of the invention may be a chemical material / eight. Further, the active ingredient may be in the form of a pharmaceutical composition. (iv) Further providing a pharmaceutical combination comprising an effective amount of a compound of the invention and one or an optional carrier, diluent or excipient: the compounds of the invention are as set forth herein. In the sense that it is compatible with the other ingredients of the formulation and is not deleterious to the recipient of the pharmaceutical composition, the carrier: the carrier, the dilute form, the dosage form is acceptable ι 119947.doc 200814993 According to another aspect of the invention Also provided is a method of preparing a pharmaceutical composition comprising admixing a compound of the invention with one or more pharmaceutically acceptable carriers, diluents or excipients. The therapeutically effective amount of the present compound will depend on a number of factors. For example: 'The species, age and weight of the recipient, the exact condition to be treated and its severity, the composition properties and the route of administration are all factors that should be considered. The therapeutically effective amount should ultimately be determined by the attending physician or veterinarian. In any event, the effective amount of a compound of the invention used to treat a debilitated person will generally be between 0.1 and 100 mg/kg of recipient (mammal) weight/day. Usually, the effective amount should be between 01 and 10 mg/kg body weight/day. The amount per day is usually 0.3 to 3, _ milligrams. The amount may be administered in a single dose per day or multiple (e.g., 2, 3, 4, 5 or more) divided doses such that the "dose is the same. An effective amount of a pharmaceutically acceptable derivative thereof may be the compound of the present invention itself. The effective amount ratio (4) formula is combined with the treatment of other conditions mentioned in this article. The heart-shaped i-suitable pharmaceutical composition may contain. ^ ^ , Pre-existing 1 active ingredient / unit dose of the unit dosage form of the tube exists as a non-limiting early The position and path, the age of the patient, the physical condition of the slave, the condition of the oral therapy, and the administration of 1 gram of the compound of the present invention. Compared with the 日3 0.5 gram, the daily dose or the amount of the substance as described above is included. The pharmaceutical composition can be prepared by _ 5 /, and some of the active ingredients are prepared by any method well known in the pharmaceutical industry. The two drug compositions can be made by any suitable path or sublingual, by rectal, and by the rectum. , , , (including ~, partial (including buccal, sublingual or 119947.doc 200814993 skin), vaginal or parenteral (including subcutaneous, intramuscular, intravenous or intradermal), and These compositions can be used in the pharmaceutical industry For example, by combining the active ingredient with a carrier or excipient. The pharmaceutical composition suitable for administration by π can be present in the form of discrete single ratios such as capsules or lozenges, powders or granules; solutions or Suspensions, each having an aqueous or non-aqueous liquid; an edible foam or an insecticide; or an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. For example, for oral administration in the form of a key or a capsule In contrast, the 'active pharmaceutical ingredient can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like. - Generally, the powder is prepared by grinding the compound into a suitable fine The size is prepared by mixing with a suitable pharmaceutical carrier such as an edible carbohydrate (for example, starch or mannitol). Flavoring agents, preservatives, dispersing agents, and coloring agents may also be present. Capsules are prepared by powders, liquids or The suspension mixture is prepared by encapsulation with gelatin or some other suitable shell material. Slip agents and lubricants (eg, tantalum dioxide, talc, magnesium stearate, etc.) may be applied prior to encapsulation. Addition of stearic acid or solid polyethylene glycol to the mixture. A disintegrant or a bulking agent (such as agar 'calcium carbonate or sodium carbonate) may also be added to improve the utility of the agent when the capsule is absorbed. If necessary, suitable binders, lubricants, disintegrants, and coloring agents may also be included in the mixture. Examples of suitable binders include powder killing, gelatin, natural sugars (such as glucose or lactose), and corn sweeteners. , natural and synthetic gums (such as gum arabic, silicone or sodium alginate), 1 methylcellulose, polyethylene glycol, waxes, and the like. Lubricants used in such formulations include, for example, sodium oleate, Heart _, hard 119947.doc -12- 200814993 magnesium citrate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, but are not limited to, starch, methyl cellulose, agar, bentonite , xanthan gum and the like.

Tablets can be formulated, for example, by preparing a powder mixture, granulating or tableting, adding a lubricant and a disintegrant, and compressing into a tablet. The powder mixture can be prepared by mixing a suitably ground compound with a diluent or a substrate as described above. Optional ingredients include binders such as carboxymethylcellulose, alginate, gelatin or polyvinylpyrrolidone; solution retarders such as paraffin; absorption enhancers such as quaternary salts, and/or absorbents such as bentonite , kaolin or calcium hydrogen phosphate. The powder mixture may be subjected to wet granulation using a binder such as mash, starch paste, acadia mucilage or a solution of cellulose or polymeric material and forcing it through a sieve. As an alternative to granulation, the powder can be passed through the tablet machine and the result unfortunately forms a tablet into pieces. 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 lubricated mixture is then compressed into a bonding agent. 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 tableting step. The present invention can provide a clear or opaque protective coating comprised of a shellac seal coat, a coating of sugar or polymeric material, and a bright coating of wax. Dyes can be added to the 5 Hai coating to distinguish between different unit doses. Oral fluids (e.g., solutions, syrups, and elixirs) can be prepared in dosage unit form such that a given amount comprises a predetermined amount of compound. The syrup can be prepared by (10), for example, dissolving the compound in a suitably seasoned aqueous solution, while the granule can be prepared by using a non-toxic alcohol vehicle. Suspensions can usually be formulated by dispersing 2 into 119947.doc •13-200814993 in a non-toxic vehicle. Alcoholic solvents and emulsifiers such as ethoxylated isostearic acid and polyoxyethylene sorbitol t preservatives; flavor additives such as peppermint oil or natural sweeteners, saccharin, or other artificial sweeteners may also be added. Agents; and the like. Months The appropriate dosage unit compositions administered orally can be microencapsulated. The formulation may also be prepared for extended or sustained release by, for example, coating or encapsulating the particulate material with a polymer, wax or the like.

The compounds of the invention may also be administered in the form of liposome delivery systems, such as a single layer of small vesicles, a single layer of large aliquots, and multiple layers of vesicles. Liposomes can be made from a variety of phospholipids, such as cholesteryl, stearylamine or phospholipid choline. The compounds of the invention may also be delivered by the use of monoclonal antibodies as separate carriers for the molecules of the compounds bound thereto. These compounds may also be combined with a soluble polymer which is applied to the drug. Such polymers may include polyglycol (4) (pvp), decyl copolymer, poly(tetra)methacrylamide, phenylhydrazine, polyethylidene, aspartic acid, or palmitoyl residues. Substituted polyepoxybutane poly(4). In addition, the compounds can be combined with biodegradable polymers that are used to achieve drug-controlled release; for example, polylactic acid, poly-ε-caprolactone, polyhydroxybutyrate, poly-original I-polyacetal, polydihydropyridyl Crosslinked or amphoteric block copolymers of succinyl, polycyanoacrylate and hydrogel. The pharmaceutical composition may be in the form of a discontinuous patch intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time. For example, the active ingredient can be incorporated herein by reference (1986) as outlined in Domestic Offices, 3 (6), 318 119947.doc • 14-200814993 (which is as described in relation to such delivery systems) The iontophoresis method is delivered from the patch. Formulation Suitable for topical administration of a pharmaceutical composition in the form of a soft f, milk mi lotion, powder, solution, paste, gel, spray, aerosol or oil

For the treatment of the eye or other external tissues, such as the mouth and skin, the compositions can be administered in the form of a topical ointment or cream. When formulated in the form of an ointment, the active ingredient can be applied together with a stone or a water-miscible ointment & Alternatively, the active ingredient may be formulated into a cream with an oil-in-water cream base or a water-in-oil base. 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 aqueous solvent. Pharmaceutical compositions suitable for topical administration in the mouth include rhomboid tablets, scented tablets and mouthwashes. Pharmaceutical compositions suitable for nasal administration with a carrier-borne solid include a powder having a particle size (for example) of between 20 and 500 microns. The powder is administered in such a manner that it is inhaled by the nose, i.e., by quickly sucking the container containing the powder through the nose passage into the nose. Suitably the carrier liquid is administered in the form of a nasal spray or in the form of a nasal drops. Suitable formulations include aqueous or oily solutions of the active ingredient. Pharmaceutical compositions suitable for administration by inhalation include finely divided powders or fine mists which can be produced by means of various types of metered dose pressure aerosols, nebulizers or insufflators. The pharmaceutical composition suitable for rectal administration may be in the form of a suppository or in the form of an enema form H9947.doc -15· 200814993. <Pharmaceutical compositions suitable for administration to the vaginal administration may be in the form of a vaginal suppository, a vaginal plug, a cream, a gel, a paste, a foam or a spray formulation. The pharmaceutical composition comprising IS, 5%, and 5% includes an aqueous and anhydrous sterile injection solution, which may contain an antioxidant, a buffer, a bacteriostatic agent, and a liquid for allowing the composition to be combined with an intended recipient. Soluble solute; and aqueous and anhydrous sterile suspensions which may include suspending agents and thickening agents. The compositions may be in unit or multi-dose containers (eg, sealed vials and vials) and may be stored in a cold-dried (dry) condition and only need to be added prior to use for the purpose of: A sterile liquid carrier such as water. Temporary preparations for injections and suspensions can be prepared from sterile powders, granules and lozenges. In addition to the ingredients specifically mentioned above, such compositions may also include other pharmaceutical agents customary in the art depending on the type of composition. 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 treating viral infections (e.g., 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 mentioned 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. According to a particular embodiment of the invention, there is provided a method of administering a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable derivative thereof to a mammal 119947.doc • 16-200814993 (specifically human) _The method of medicinal Ηιν mutant virus. In particular, the compounds of the invention can be used to treat wild-type HIV-1 as well as several drug-resistant mutations, such as ki〇3n, Lww Y181C. In another embodiment, the invention provides a method of treating a symptom or effect of a viral infection in an infected animal (eg, a lactating animal, including a human), the method comprising treating the animal with a therapeutically effective amount of a compound of the invention . According to a particular embodiment of this aspect of the invention, the viral infection is a retrograde viral signature, in particular an HIV infection. Another aspect of the invention includes a method of treating the symptoms or effects of an HBV infection. The compounds of the invention may also be used in the adjuvant treatment in the treatment of HIV infection or HIV related symptoms or effects (e.g., Kaposi's sarcoma). The compounds of the invention and any pharmaceutically acceptable derivatives thereof can be administered alone or in combination with other therapeutic agents. The compound of the present invention and other pharmaceutically active elixirs may be administered together or separately, and may be administered simultaneously or sequentially in any order, when the 糸 field knife is administered. The amount of the compound of the present invention and other pharmaceutically active agents and the relative administration timing should be selected and achieved in combination with the desired therapeutic effect. The combination of the yangming compound and any of its pharmaceutically acceptable derivatives and agents can be combined by administering a single 1 (four) squeaking of the sputum therapeutic compound: (1) an early medical composition comprising two substances; or (7) each comprising Separate pharmaceutical compositions of the above species. Or, cats, and 5 may be first administered with a therapeutic agent and then administered in another or vice versa. (d) or I, the compounds of the invention may be used to treat a variety of conditions, and the compounds of the invention are also useful in combination with a variety of other suitable therapeutic agents for the treatment or prevention of such conditions or conditions. Used in combination with any other pharmaceutical composition, wherein the combination therapy can be used to modulate chemical actin receptor activity and thereby prevent and treat inflammatory and/or immunomodulatory diseases. The invention may be used in combination with one or more of the following for the prevention or treatment of HI V The agents are used in combination. Examples of such agents include:

Nucleoside reverse transcriptase inhibitors, such as zidovudine, didanosine, lamivudine, zalcitabine, abacavir, s Stavidine, adefovir, adefovir dipivoxil, fozivudine todoxil, emtricitabine, alovudine ), amdoxovir, elvucitabine and similar agents; non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oloti) Oltipraz, etc., such as nevirapine, delavirdine, efavirenz, loviride, euphoria, oltipraz, carbamide ( Capravirine), TMC-278, TMC-125, etravirine and similar agents; protease inhibitors such as saquinavir, ritonavir, indinavir ), nelfinavir, aprenavir Amprenavir), fosamprenavir, brecanavir, atazanavir, tipranavir, palinavir, lasinavir And 119947.doc -18- 200814993 similar agents; invasive inhibitors, such as Enfuweidi 01^11¥丨46) (Ding-2〇), 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 vicriviroc (Sch-C), Sch-D, TAK779, maraviroc (UK 427, 857), TAK 449, and those disclosed in WO 02/74769, PCT/USA Patent No. US 03/39644, 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 No. and PCT/US Patent No. 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. Control groups are controlled according to standard methods of organic synthesis (T. W. Green and P. G. M. 119947.doc -19- 200814993

Wuts (1991) Protecting Groups in Organic Synthesis^ John Wiley & Sons, with protection groups incorporated herein by reference). Such groups are removed at a suitable stage in the synthesis of the compound using methods well known to those skilled in the art. The method and the choice of reaction conditions and their order of execution 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 includes not only racemic compounds but also individual enantiomers. When a compound of a single enantiomer is desired, it can be obtained by stereoselective synthesis or by redissolving the final product or any suitable intermediate. Re-dissolution of the final product, intermediate or starting material can be accomplished by any suitable method known in the art. See, for example, E. L. EHel, s· H· wilen, and L· Ν·

Interscience, 1994) (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 of the American Chemical Society Gas Journal of Price Wg—/ Specifically, the following abbreviations can be used in the examples and throughout the specification: g (g)·, mg (mg); L (liters); mL (ml); L); Psi (pounds per square inch); Μ (molar); mM (mole (touch); 119947.doc 200814993

Hz (Hz); MHz (megahertz); mol (mole); mmol (mole); rt (room temperature); min (minutes); h (hours); mp (melting point); TLC (thin layer) CH2C12 (dichloromethane); TEA (triethylamine); TFA (trifluoroacetic acid); TFAA (trifluoroacetic anhydride); THF (tetrahydrofuran); CDC13 (deuterated chloroform); CD3OD (deuterated methanol) ; Si〇2 (cerium oxide); DMSO (dimethyl sulphate); EtOAc (ethyl acetate); atm (atmospheric pressure); HC1 (hydrochloric acid); CHCI3 (chloroform); DMF (N, N-II) Methylformamide); Ac (ethylidene); Cs2C03 (carbonate); Me(methyl); Et (ethyl); EtOH (ethanol); MeOH (methanol); t-Bu (third Et20 (B scale); N2 (nitrogen); MsCl (methanesulfonate); K2CO3 (potassium bartate); sat'd (saturated); DMAP (4-(dimethylamino) DCE (1, 2-dichloroethane); pyridine); Ps (polymer supported); ^ EDCI (1-(3-didecylaminopropyl)_3_ethylcarbodiamine, salt); P -BEMP (Polymer loaded 2- Three - amino-2-butyl; dagger-yl 1,3-dimethyl-perhydro-limb-diaza _1,3,2- - three hetero fill benzene); 119947.doc -21- 200814993

TsCl (phenylsulfonium chloride); TES (triethyldecane); TBAF (tetrabutylammonium fluoride); CSA (camphorsulfonic acid); η-BuLi (n-butyllithium); TBDPSC1 (third-butyl) Diphenyl phenyl hydrazine chloride; HOAc (acetic acid); AcCl (acetamethylene); DIBAL-H (diisobutylaluminum hydride); DBU (1,8-diazabicyclo[5·4 ·0]undec-7-ene);

MgS04 (magnesium sulfate);

NaHC03 (sodium bicarbonate);

Pd/C (palladium on carbon); DCM (dichlorodecane);

Eq (equivalent) IPA (isopropanol);

Rt (retention time); SFC (supercritical fluid chromatography); N (standard); mCPBA (m-chloroperbenzoic acid); ACN (acetonitrile). All temperatures are expressed in ° C (degrees Celsius) unless otherwise stated. All reactions were carried out in an inert atmosphere at room temperature unless otherwise stated. Reactive reagents that are used without synthetic details are commercially available or can be prepared according to literature procedures. The compounds of the present invention can be prepared by the processes described below: 119947.doc • 22- 200814993 Scheme 1: ο- Λο咕: ΕΡ470578(Α1), W02002028825(A2)

119947.doc -23-200814993 In addition to the intermediates prepared in accordance with WO2001017982 and shown in Schemes 1 and 2, certain intermediates may also be disclosed in U.S. Provisional Application Serial No. 60/863,846, the disclosure of which is incorporated herein by reference. Prepared in Schemes 3-6 incorporated herein. In this aspect, intermediate A is reacted with at least one methionyl halide reagent to form intermediate B in the presence of a palladium catalyst and a ligand. Option 3:

R

Solvent

Zn(CN)2; suitable for the Is catalyst in g

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

Zn(CN)2 Pd2(dba)3/DPPF -► NMP 2 Hydrazine hydride reagent wherein R1 is a halogen, R2 is a halogen, 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

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

* CN NMP l y A decyl hydride reagent (R)m .0

B 119947.doc -24- 200814993 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

Zn(CN)2 PdCl2/DPPF

Mercapto alkyl hydride reagent

CN

Wherein R1 is halogen, and 112 is specifically chlorine, and 111 is 1. Example 1: 2·({4-Ga-2-[(3_气-5-cyanophenyl))yl}phenyl}oxy {3-fluoro-4-[(2-hydroxy-2-A) Propyl)oxy]-2-methylphenyl}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 (Ι) (4·58 g, 32 mmol, 〇·2 eq.) was combined and heated under reflux for 1 hour. The reaction mixture was passed through a pad of celite and the filtrate was concentrated to a green oil. The residue was dissolved in the sulphur and filtered a second time through the algae. The filtrate was concentrated to dryness and 119947.doc -25- 200814993

The title compound (28.0 g) was obtained as a pale yellow oil (yield: EtOAc). iH NMR (300 MHz, DMSO-d6) δ ppm 2.44 (d, J = 2.7 Hz, 3 H), 7·57 (m, 1 H), 7.95 (ddd, ·7=9·3, 4.7, 2.1 Hz , 1 H). Step B: 2-Methyl-l,2-propanediol (Intermediate 2)

Adding sodium hydride (16 gram, 423 mmol) to a solution of 2-hydroxy-2-methylpropionic acid methyl vinegar (5 gram, 423 mmol) dissolved in 600 ml of IPA and in the environment Stir at temperature for 16 hours. The reaction was quenched by the addition of 250 mL of methanol followed by 25 mL of 2M HCl in hexanes. The reaction mixture was filtered and concentrated to dryness. The crude product was purified by distillation (yield: <RTI ID=0.0>> 4 NMR (400 MHz, DMSO_36) δ ppm 1·02 (s, 6 H), 3.11 (s, 2 H), 4.08 (br s, 1 Η) 4·49 (m, 1 H). Step C : 1-[(2-Fluoro-3-methyl-4-nitrophenyl)oxy]-2-methyl-2-propanol (Intermediate 3)

1,2-difluoro-3-methyl-4-nitrobenzene (1 g, 57.8 mmol, intermediate 1) and 2·mercapto-1,2-propanediol (10·4 g, 115 Millol, 2 equivalents, intermediate 2) combined in 200 ml of benzene and treated with 200 ml of 6 NaOH and benzyltriethylammonium hydride (2.6 g '11.5 mmol, 〇 2 equivalent) while at 80 Vigorous mechanical stirring for 16 hours at °C. The reaction mixture was taken up in EtOAc EtOAc EtOAc EtOAc EtOAc. The organic phase was separated, washed twice with 3 mL of 10% EtOAc EtOAc EtOAc. The crude material was purified by flash chromatography on cerium chloride eluting with 1 Q + 80% EtOAc. Appropriate fractions were combined and concentrated to give the title compound (7.31 g, 3 〇 〇m, 52%). NMR (400 MHz, DMSO-d6) δ ppm 1.20 (s,6 Η), 2·44 (d, J=2.6 Hz, 3 Η), 3·91 (s, 2 Η), 4.73 (s, 1 Η ), 7·24 (t, J=8.9 Ηζ, 1 Η), 7·91 (dd, “7=9.2,1·7 Ηζ, 1 Η). Step D: 1-[(4-Amino-2-fluoro-3-indenylphenyl)oxy]-2-methyl-2-propanol (Intermediate 4)

Treatment of 1·[(2-fluoro-3-methyl-4-nitrophenyl)oxy] A in 12 mL of EtOH with 1% Pd/C (0.45 g) under a 60 psi hydrogen atmosphere Base 2-propanol (8.79 g '36.1 mmol, intermediate 3) while vigorously disturbing for 5 days. Filtering the catalyst through the diatomaceous earth and concentrating the filtrate to a dry state

To the title compound (7.70 g, 36.1 mmol, 100%). hNMRMOO MHz, DMSO-d6) δ ppm 1.16 (s,6 Η),1·95 (d, “7=1.8 Hz, 3 H), 3.57 (s, 2 H), 4·51 (s, 1 H) , 4·68 (s, 2 H), 6.32 (dd, J = 8.9, 1.0 Hz, 1 H), 6.67 (t, J = 9.2 Hz, 1 H). Step E: ({4-Chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)acetamidine Chloride (Intermediate 5) 119947.doc -27- 200814993

({4-Chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy)acetic acid (74.85 g, 213.8 mmol) in 1 liter of DCM at ambient temperature , 〇 〇 2001017982) Add a catalytic amount of 1:)]^17 (1 ml) to the suspension, then add 2M of chlorophyll chloride (214 ml, 428 mmol, 2 eq.) in DCM while stirring. . The reaction mixture was allowed to scramble for 1 hour at ambient temperature after addition, at which time no more carbon dioxide was observed. The reaction mixture was concentrated to dryness afforded title title title titled ^? · 2-({4-Ga-2-[(3-chloro-5-cyanophenyl)methyl]phenyl}oxy) {3-fluoro-4-[(2-hydroxy-2-methyl) Propyl)oxy]_2_mercaptophenyl}acetamide

M(4-Aminofluoro-3-indolylphenyl)oxy]_2-methyl-2-propanol (1.87 g, 8.8 mmol, 1; 1 equivalent, intermediate sentence and Acridine (1.95 ml, 24 mmol, 3 equivalents) in 45 ml of dry acetonitrile was combined and cooled to 0 ° C. To the mixture was added to 3 ml of dry acetonitrile with stirring (Η-gas - 2-[(3-Chloro-5-cyanophenyl)carbonyl]phenyl}oxy)acetamidine chloride (3·〇7 g, 8·〇 mmol, i equivalent, intermediate 5) and on ice Cooling in a bath. After stirring at ice 4 for 1 min, the reaction mixture was allowed to warm to ambient 119 947. doc -28 - 2008 14993 and stirred for 16 hr. The reaction mixture was concentrated to dryness and taken to EtOAc ( (200 ml) was partitioned between EtOAc (2 mL) and EtOAc (EtOAc) (EtOAcjjjjjjjjjj The title compound (2.84 g, 5.21 mmol, 65%). 4 NMR (400 MHz, DMSO-d6) s s s 1.18 (s, 6 Η), 1.95 (d, J = 2.2 Hz, 3 H), 3·73 (s, 2 H), 4.63 (s, 1 H),4·73 (s,2 H),6·96 (m, 2 Η), 7·22 (d, J=9.0 Hz, 1 h), 7·53 (d, J=2.6 Hz, 1 H), 7.68 (dd, J=9.0, 2.7 Hz, 1 H), 8.06 (t, J = 1.7 Hz, 1 H), 8.13 (t, 7 = 1.3 Hz, 1 H), 8·30 (m, 1 H), 9·29 (s, 1 H). Example 2: 3_gas_5-{[5-a-2-(fluorenyloxy)phenyl]carbonyl}benzonitrile (intermediate)

The reactor was charged with (3-bromo-5-chlorophenyl)[5-gas-2-(methyloxy)phenyl]methyl ketone (1·〇 weight, 1 〇 equivalent) under a nitrogen atmosphere. And zinc cyanide (〇·2〇 weight, 0.60 equivalent) and 90% i,2•dimethoxyethane/water (5 volumes). The reactor contents were heated to about 8 Torr under nitrogen. . . 1,1_bis-diphenylphosphino)ferrocene (DPPF, 0.01 weight, 0.0065 equivalent) and palladium acetate (〇〇31 weight, 〇〇) in DME (0.15 vol) 5 equivalents of the slurry was washed into the reactor with additional DME (〇·5 volumes). The pMHS (〇〇1 weight K, 0·06 equivalent) stored in DME (0.1 volume) was added in a single portion. The reaction was allowed to stir at about 8 ° C for 2 hours. It was added to DME (0.15 vol) by adding 119947.doc -29- 200814993: ^^bis(diphenylphosphino)ferrocene (DPPF '0.01 weight, 〇·0065 equivalent) and palladium acetate ( 〇〇31 weight, 〇〇5 equivalents) of the slurry and add the second half of the catalyst, ligand and PMIiS and use another dme

(〇·〇5 volumes) This was washed into the reactor. The PMHS (0.01 weight, 〇·06 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 80 ° C, at which time the remaining starting was maintained by standard lC method and the material was <1. /. . The mixture was cooled to 2 (rc and a concentrated solution of NH4〇H (1 volume), saturated NH4C1 (4 volume) solution and water (5 volumes) was added at a rate to keep the internal temperature below 30 °C. After stirring for 1 hour, the reaction mixture was filtered through a filter cloth and the reactor was rinsed with water (2 volumes) through a filter cake. The filter cake was then washed with additional water (4 X 2 volume) and subjected to suction drying. The resulting solids were returned to the reactor and dissolved in acetone (8 vol) while warming to 50 C. The contents were filtered through a pad of diatomaceous earth and washed with acetone (1 volume). Treated at 50 ° C with water (〇·9 volumes) while remaining in a dissolved state. The reactor was cooled to 1 (C) over a period of 丨 hours and maintained at 10 ° C for 1 to 2 hours. The solid was washed with cold 9:1 acetone: water (2 x 1 volume). The solid was transferred to dry oven and dried under vacuum at 50 ° C for 24 hours. 4 NMR (400 • MHz 5 DMSO-d6) δ 8.31 (s5 1H) 8.02 (s, 1H) 7.94 (s5 1H7.63 (d, j = 8.8Hz, 1H) 7.45 (s, 1H) 7.22 (d, j=9.0 Hz, 1H) 3.65 (s, 3H) Example 3: Biological activity Inhibition of viral replication I· HeLa cell analysis 119947.doc -30- 200814993

HeLa Cell Analysis is based on 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, «/. 66:2232-2239 ( A modified form of 1992) wherein HIV-1 infection is detected by activation of the β-galactosidase reporter gene driven by HIV-LTR integrated into the genome of the CD4+ HeLa cell line. 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% (IC50) HIV-1 induction of β-galactosidase signal was determined for each isogenic, recombinant virus relative to the untreated control. Α.Material

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. SH30070.03) Geneticin (GibcoBRL No. 1013 1 -03 5) Hygromycin B (GibcoBRL No. 1687-010) 96 - Well black, clear bottom, tissue culture treated plate (Costar No. 3904) Phosphate buffered saline (PBS) (GibcoBRL No. 14190-144) Dimethyl hydrazine (0^480) (into D (: (3) No. 741625)

Gal-Screen Reporter Gene Analysis System (Applied Biosystems No. 119947.doc •31-200814993 Ding 1030) Β·CD4_HIV LTR-p-gal HeLa Cell Line Growth and Preservation

The HeLa-CD4-LTR-P_gal cell line was propagated in DMEM containing 10% fetal calf serum + 0.2 mg/ml geneticin + 0.1 mg/ml hygromycin mash. When 80% is confluent, the cells are lysed by standard trypsin digestion techniques (approximately every 2 to 3 days). C. Construction of HIV-1 reverse 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. 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 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 Of human immunodeficiency virus type 1 isolates, Antimicrobial 38:23_30, 1994). 1 X 107MT4 T-cells (preserved in RPMI containing 10% fetal bovine serum, lysed 1:5 every 5 to 6 days) in the presence of DMRIE-C transfection agent (Gibco) according to the supplier's recommendations EcoRI/Hindlll digested mutant RT plasmid and Bst EII digested HIV-Ihxb2art DNA co-transfected. 119947.doc •32·200814993 Each mutant RT coding sequence was hybridized to the RT-deleted HIV-1 viral DNA scaffold by in vivo homologous recombination. The transfected cell culture is developed and monitored until the syncytium is formed and the CPE is extremely broad. The virus was harvested by clarifying spin of the culture supernatant and frozen at -80 ° C as an initial stock solution. Sequence assays were performed on recombinant progeny viruses in the RT region to determine mutant genotypes. The virus stock was further expanded, harvested and stored as cold by ‘infection with MT4 cells; aliquots were stored. The stock titer was determined in HeLa MAGI cells for analysis. φ 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 the analysis was relative light units (RLU) and the titer was recorded as RLU/ml. The virus stock was diluted (1:2 consecutive) into DMEM containing 10% FBS plus 25 μg/ml DEAE-dextran and analyzed without the use of test compounds as described in the "Experimental Protocol" section below. The infection rate defined as infectious unit/cell is usually not calculated as "(MOI), _ but it is usually 1.0. RLU/ml is related to other infection metrics (eg HeLa PFU/ml or MT4 TCID50/ml) in batch There may be inconsistencies between batches or strains and strains, but should be determined for each batch. F. Protocol Day 1 1. Use 96-well plates (Costar No. 3904) with HeLa-CD4_LTRj-gal 119947.doc -33-200814993 was taken in 100 μl of DMEM containing 10% FBS at 3 X 103 cells/well. Incubate overnight at 37 ° C, 5% CO 2 . Day 2 1 · Make disease sputum Thaw in a water bath (room temperature) and dilute to DMEM + 丨〇 % FBS + 25 μg / 3⁄4 liter DEAE · dextran to an infection dose of about 1 million RLU / ml. Virus dilution will look at the stock solution titer And change (see ''The titer of the virus stock' above). 2. Remove all medium from each well with an 8 or 12-channel manifold aspirator. Work was performed on one plate at a time to prevent the HeL-cD4-LTR_P-gal single layer from drying. Add 35 μl (total 35 〇, 〇〇 () RLU) to each well to dilute the virus. Incubate for 2 hours at 37 ° C, 5% CO 2 . 3. A compound titer plate was prepared at a final concentration of 135 times during the disease adsorption phase. In general, the test substance is titrated in a four-fold stepwise manner from 2·7 uM (final 2 b) to 〇·01 ηΜ (final 〇〇〇8 ηΜ) in an automated manner. This protocol allowed 8 test compounds/96-well plates and 1 dilution point and 2 control/compounds (η = 丨). Test compounds were titrated into DMEM + 10% FBS + 〇 · 135% DMS 〇 (final 〇 1%). The final volume of the titrated compound in each well should be at least 15 μL and the DMS〇 including the control containing no compound should be 〇135% (final 0. 1%) 〇4. From the above steps One microliter of the titrated compound was taken from each well of the titration plate prepared in 3 and added to the virus adsorption plate (step 2 above). 5. Incubate at 37 ° C, 5% C 〇 2 for 72 hours. Day 5 1. Reduce the supernatant to 50 μl and add 50 μl of Gal-Screen reconstituted according to the manufacturer's push 119947.doc •34- 200814993 recommended. 2. Mix the plates vigorously on the platform shaker. 3. Read the plate at 1 second/well in a Topcount photometer (Packard). G. Data Analysis The raw data was converted to a percentage of the control by the following formula: (the original signal in each well/the average original signal of two control samples in the same column without the compound) *1〇〇. The percentage of the control is plotted against the compound concentration using the Robsage or Robofit program (GSK). The default model is Y=Vmax* * 1-(χΛη/(ΚΛη+χΛη)), however, any other model that gives a reasonable estimate of IC5〇(式ΠΚ) can be used. Table 1. Anti-wild type And clinically relevant antiviral activity of HIV. IC5G(nM) Example No. K103N K103N/G190A V106A V106I/Y181C WTRVA Y181C 1 ababaa 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 < 1 nM b 1 - 10 nM

c > 1 0 nM + compound 40, example number 10 from WO 02/070470 * Example number I19947.doc-35-200814993 from WO 01/17982 ** Example from US Patent No. 2006/0025480 No. ND = not determined

-36- 119947.doc

Claims (1)

200814993 X. Patent application scope: 1. A compound of formula (I): 2. A 2-({4-chloro-2-[(3-chloro-5-cyanophenyl)carbonyl]phenyl}oxy{3-fluoro-4-[(2-hydroxy-2-methyl) Propyl)oxy]-2.methylphenyl}acetamide. 3. A pharmaceutical composition comprising a compound of claim 1 or 2 and a pharmaceutically acceptable carrier. 4. A compound according to claim 1 or 2 for use in medical treatment. 5. A compound according to claim 1 or 2 for use in the treatment of a viral infection and related conditions. 6. The compound of claim 5, wherein the viral infection is HIV infection. 7. Use of a compound according to claim 1 or 2 for the manufacture of a medicament for the treatment of a viral infection and a related condition. 8. The use of claim 7, wherein the viral infection is HIV infection. 9. A method of treating HIV infection comprising administering a compound as claimed in claim 1 or 2. 10. The composition of claim 3, wherein the composition comprises at least one additional therapeutic agent selected from the group consisting of nucleoside reverse transcriptase inhibitors, such as zidovudine, dardano New (didanosine), lamivudine, zalcitabine, abacavir, stavidine, adefovir 119947.doc 200814993 (adefovir), Adefovir dipivoxil, fozivudine todoxil, emtricitabine, alovudine, amdoxovir, erf Elvucitabine and similar agents; non-nucleoside reverse transcriptase inhibitors (including agents with antioxidant activity, such as immunocal, oltipraz, etc.), such as nevirapine, dila Delavirdine, efavirenz, loviride, euphoria, oltipraz, capravirine, TMC-278, TMC-125, yitra Etravirine and similar agents; eggs Enzyme inhibitors such as saquinavir, ritonavir, indinavir, nelifinavir, amprenavir, fosanavir ( Fosamprenavir), brecanavir, atazanavir, tipranavir, palinavir, lasinavir and similar agents; invasion inhibitors For example, enfuvirtide (T-20), T-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 CXCR4 and /, or CCR5 inhibitors, such as vicriviroc (Sch-C), Sch_D, TAK779, maraviroc (UK 427, 857), TAK449; and similar agents. 119947.doc 200814993 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: 119947.doc