CN101326160B

CN101326160B - Biphenyloxyacetic acid derivatives for the treatment of respiratory disease

Info

Publication number: CN101326160B
Application number: CN200680046141.0A
Authority: CN
Inventors: 蒂莫西·J·卢克; 鲁克萨纳·T·穆罕默德; 马克·迪金森; 斯蒂芬·汤姆
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2005-10-06
Filing date: 2006-10-05
Publication date: 2013-04-17
Anticipated expiration: 2026-10-05
Also published as: ZA200802948B; GB0520324D0; UA94915C2; CN101326160A

Abstract

The invention relates to substituted phenoxyacetic acids as useful pharmaceutical compounds for treating respiratory disorders, pharmaceutical compositions containing them, and processes for their preparation.

Description

The biphenylyloxy acetogenin that is used for the treatment of respiratory system disease

Technical field

The present invention relates to as useful medical compounds be used for the treatment of the replacement of respiratory system disease phenylium, comprise their pharmaceutical composition and prepare their method.

Background technology

WO2004089884 and WO2004089885 disclosed a series of with regard to the CRTh2 acceptor the activated phenylium of tool.It has been found that, some compound exhibits in WO2004089884 and the WO2004089885 scope goes out the quite high effectiveness to the CRTh2 acceptor, in animal species, has simultaneously outstanding pharmacokinetic property, therefore be supposed to be used for the treatment of various respiratory system diseases, comprise asthma and COPD, but in these two patents, do not disclose particularly.

Summary of the invention

Therefore, first aspect of the present invention provides formula (I) compound or pharmaceutically acceptable salt thereof:

Wherein

A and D independently are selected from hydrogen, halogen, cyano group, C _1-3Alkyl and C _1-3Alkoxyl group (described last 2 groups can be chosen wantonly by one or more halogen atoms and replace);

X is halogen or C _1-3Alkyl, described C _1-3Alkyl is optional to be replaced by one or more halogen atoms;

Y is chemical bond;

Z is aryl or heteroaryl, and described aryl or heteroaryl are selected from following group and replace by one or more: hydrogen, halogen, cyano group, C _1-6Alkyl, C _1-6Alkoxyl group, SO ₂C _1-6Alkyl and heteroaryl, described last four groups can be chosen wantonly by halogen atom, cyano group or SO ₂C _1-6Alkyl replaces;

R ¹And R ²Independent expression hydrogen atom or C _1-3Alkyl; Or

R ¹And R ²Can form together 3-8 unit ring, optional one or more O of being selected from, S and the NR of containing of described 3-8 unit's ring ³Atom, and itself is optional by one or more C ₁-C ₃Alkyl replaces; And

R ³Be hydrogen or C ₁-C ₆Alkyl.

In the context of the present specification, except as otherwise noted, alkyl or moieties in the substituting group can be straight or branched.

Aryl is defined as phenyl, naphthyl or biphenyl.

Heteroaryl is defined as 5-7 unit aromatic ring, maybe can be two rings that 6,6-or 6,5-condense, the optional heteroatoms that contains one or more N of being selected from, S and O of described heteroaryl.Described two rings can connect by carbon or nitrogen, can connect by 5 or 6 yuan of rings, and can be saturated wholly or in part.

Example includes but not limited to pyridine, pyrimidine, thiazole, oxazole, pyrazoles, imidazoles, furans, isoxazole, pyrroles, isothiazole, azulene (azulene), naphthyl, indenes, quinoline, isoquinoline 99.9, indoles, indolizine, benzo [b] furans, benzo [b] thiophene, 1H-indazole, benzoglyoxaline, benzothiazole, benzoxazole, purine, 4H-quinolizine, cinnolines, phthalazines, quinazoline, quinoxaline, 1,8-naphthyridine, pteridine, quinolone and 1,2-methylenedioxybenzenes.

Preferably, X is chlorine, fluorine or methyl.

Preferably, group SO ₂-Y-Z is positioned at 4 of phenyl ring:

More preferably, group SO ₂-Y-Z is positioned at 4 of phenyl ring, all becomes the ortho position with group A with group D:

Most preferably, group SO ₂-Y-Z is positioned at 4 of phenyl ring, and A becomes the ortho position with group, and with position between group D becomes:

Preferably, group A and D independently are hydrogen, halogen or C _1-3Alkyl (described last group is optional to be replaced by halogen atom); More preferably, A is hydrogen, halogen or CF ₃D is hydrogen, halogen or methyl; Most preferably, A and D independently are selected from hydrogen and halogen.

Preferably, R ¹And R ²Independent is hydrogen or C _1-3Alkyl, more preferably hydrogen or methyl.

Preferably, Y is chemical bond.

Preferably, Z is phenyl, and described phenyl is optional by halogen or C _1-6Alkoxyl group replaces; More preferably, Z is phenyl, and described phenyl is optional to be replaced by halogen; Most preferably, Z is phenyl, and described phenyl is optional to be replaced by fluorine.

Preferred compound of the present invention comprises:

{ [5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

{ [3 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

(2S)-and 2-{[3 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid;

({ 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid;

{ [2 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

{ [5-chloro-2 '-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

{ [5-fluoro-4 '-(phenyl sulfonyl)-3 '-(trifluoromethyl) biphenyl-2-yl] oxygen base } acetic acid;

(2S)-2-({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid;

({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid;

(2S)-2-({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid;

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid;

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid;

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(3-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid;

({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2 '-methyl diphenyl-2-yl } oxygen base) acetic acid;

(2S)-and 2-{[2 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid;

({ 3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid;

({ 5-chloro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid;

({ 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-yl } oxygen base) acetic acid;

(2S)-and 2-{[3 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid;

({ 4 '-[(3-chloro-phenyl-) alkylsulfonyl]-2 ', 5-DfBP-2-yl } oxygen base) acetic acid;

({ 2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid;

{ [3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

{ [5-chloro-3 ', 5 '-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

With its pharmacologically acceptable salt.

Some formula (I) compound can exist with stereoisomeric forms in any ratio.It should be understood that the present invention contains all geometrical isomers of formula (I) compound and optically active isomer and composition thereof, comprise racemic modification.Tautomer and its mixture also consist of one aspect of the present invention.

Can with changing into its pharmacologically acceptable salt or solvate with following formula (I) compound, be preferably base addition salt (such as sodium salt, sylvite, calcium salt, aluminium salt, lithium salts, magnesium salts, zinc salt, benzyl star (benzathine) salt, chloroprocaine salt, choline salt, diethanolamine salt, ethanolamine salt, quadrol (ethyldi amine) salt, tert-butylamine salt, meglumine salt, tromethamine salt or procaine salt) or acid salt (such as hydrochloride, hydrobromate, phosphoric acid salt, acetate, fumarate, maleate, tartrate, Citrate trianion, oxalate, mesylate or tosilate).

It will be understood by those skilled in the art that in the method for the invention, some functional group in initial reagent or the midbody compound may need to protect with protecting group.Thereby the preparation of formula (I) compound may be involved in the suitable stage and remove one or more protecting groups.Protection and the deprotection of functional group fully are documented in ' Protective Groups in Organic Chemistry ', edited by J.W.F.McOmie, Plenum Press (1973) and ' Protective Groups in Organic Synthesis ', 3rdedition, T.W.Greene﹠amp; P.G.M.Wuts is among the Wiley-Interscience (1999).

Formula (I) compound can prepare by hydrolyzing type (II) compound:

Wherein X, A, D, Y, Z, R ¹And R ²Such as in formula (I) definition, or be shielded deriveding group.R ⁴Be C ₁-C ₁₀Alkyl.Suitable radicals R ⁴Comprise methyl, ethyl or the tertiary butyl.Ester group R ⁴Hydrolysis can utilize ordinary method to carry out, for example methyl esters and ethyl ester are processed with aqueous sodium hydroxide solution, and the tert-butyl ester is processed with acid (such as trifluoroacetic acid).

Formula (II) compound can react to prepare by making formula (III) compound and formula (IV) compound:

Wherein X, A, D, Y, Z, R ¹And R ²Such as in formula (I) definition, or be shielded deriveding group.L is suitable leavings group, such as the alcohol radical of halogen or activation, is specially chlorine/bromine or methylsulfonic acid ester group.Reaction can be carried out under the following conditions: in suitable solvent (such as acetonitrile or DMF), utilize alkali (such as salt of wormwood etc.), carry out described reaction.L also can be hydroxyl, and triphenylphosphine and diethylazodicarboxylate carry out three letter reactions (Mitsunobureaction) to compound (II) thereby for example can utilize.Formula (II) compound is novel, and consists of another part of the present invention.

Formula (III) compound can prepare by formula (V) compound is carried out deprotection:

Wherein X, A, D, Y and Z such as in formula (I) definition, or be shielded deriveding group.R ⁵Be suitable protecting group, for example benzyl or C _1-6Alkyl (such as methyl).Protecting group R ⁵Can utilize and suitable take off the alkyl agent (such as BBr ₃) in suitable solvent (such as DCM etc.), remove.If R ⁵Be benzyl, the hydrogenation conditions of its usable criterion (such as palladium/carbon) is removed under hydrogen atmosphere in the container of sealing so.Formula (V) compound is novel, and consists of another part of the present invention.

Formula (III) compound and formula (V) compound can prepare by the following method: by Su Chuji linked reaction (Suzuki coupling reaction), make the reaction of formula (VI) compound or formula (VII) compound and formula (VIII) compound, next to R ⁵Carry out deprotection:

Wherein X, A, D, Y and Z such as in formula (I) definition, or be its shielded deriveding group, R ⁵As defining with regard to formula (V) compound.L ¹Be suitable leavings group, such as the alcohol radical of halogen or activation, suitable leavings group is bromine, iodine or trifluoromethanesulfonic acid ester group (triflate).Formula (VI) compound is purchased, or can be as before preparing summarizing among WO2004089884 and the WO2004089885.

Above step also can be put upside down and carry out.For example, formula (V) compound can prepare by the following method: utilize the Su Chuji linked reaction to make formula (VIa) compound and the reaction of formula (VIIIa) compound, next remove protecting group as above the general introduction.

Wherein X, A, D, Y and Z such as in formula (I) definition, or be its shielded deriveding group, L ¹, R ⁵And R ⁶Such as above general introduction.

Formula (VIII) compound can react to prepare by making formula (IX) compound and formula (X) compound:

Wherein A, D, Y and Z such as in formula (I) definition, or be its shielded deriveding group, L ¹Such as above general introduction.

Reaction can be in microwave be carried out in the temperature that raises, maybe can be by carrying out described reaction at temperature (such as reflux conditions) heating-type (IX) compound of rising and formula (X) compound in the mode of heat.Reaction utilizes Lewis acid (Lewis acid) catalyzer (such as iron(ic) chloride (III)) to carry out.

Formula (VIII) compound also can prepare as following the general introduction:

Wherein A, D and Z such as in formula (I) definition, or be its shielded deriveding group, L ¹For as the above suitable leavings group of summarizing.Dimerization reaction occurs in described mercaptan by the following method: described mercaptan and SULPHURYL CHLORIDE are reacted at low temperature (being preferably 0 ℃) in suitable organic solvent (such as methylene dichloride).Replacedly, dimerization reaction occurs in described mercaptan by the following method: described mercaptan and hexamethyldisilazane and DMSO are reacted in suitable organic solvent (such as acetonitrile).Then, the Ge Liya coupling condition of disulfide product utilization standard comes and aryl halide (being specially formula (XI) aryl iodide compound) reaction.Then, resulting thioether can utilize the known method for oxidation of those skilled in the art to come oxidation, and these method for oxidation are such as described thioether and mCPBA are reacted in methylene dichloride etc.

Replacedly, formula (VIII) compound also can prepare from described disulfide by the following method: utilize the diazotization condition, preferably utilize Isopentyl nitrite, in suitable solvent (such as acetonitrile etc.), temperature raising makes described disulfide and formula (VIV) aniline reaction.Resulting thioether comes oxidation as above the general introduction.

Wherein A, D and Z such as in formula (I) definition, or be its shielded deriveding group, L ¹For as the above suitable leavings group of summarizing.

Formula (VIV) compound is purchased, and maybe can utilize the known literature method of those skilled in the art easily to prepare.

In yet another aspect, the invention provides formula (I) compound or its prodrug, pharmacologically acceptable salt or the solvate purposes in treatment.

Formula (I) compound or pharmaceutically acceptable salt thereof has as medicine particularly as the activity of CRTh2 receptor activity modulators, and can be used for disposing (therapeutic or preventative) human and non-human animal owing to PGD ₂The condition/disease that produces with the excessive of its metabolite or imbalance and worsen or cause.

Compound or pharmaceutically acceptable salt thereof of the present invention can be used for treating following disease:

1. respiratory tract: airway obstructive disease, comprise asthma, comprise bronchial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, exercise-induced asthma, drug-induced property (comprising what acetylsalicylic acid and NSAID brought out) asthma and bringing out property of dust asthma, intermission asthma and persistent asthma, and the asthma of various severities, reach the airway hyperreactivity that other reason causes; Chronic obstructive pulmonary disease (COPD); Bronchitis comprises infectious bronchitis and acidophilia bronchitis; Pulmonary emphysema; Bronchiectasis; Cystic fibrosis; Sarcoidosis; Farmer lung and relative disease; Hypersensitivity pneumonitis; Pulmonary fibrosis comprises the concurrent fibrosis of CFA, idiopathic interstitial pneumonia, antineoplaston and chronic infection (comprising tuberculosis and aspergillosis and other fungi infestation); The complication of lung transplantation; Pulmonary vascular vasculitis and thrombotic disease and pulmonary hypertension; Antitussive activity comprises chronic cough and iatrogenic cough that treatment and airway inflammation are relevant with the secretion situation; Acute rhinitis and chronic rhinitis comprise medicamentous rhinitis and vasomotor rhinitis; Property (perennial) allergic rhinitis and seasonal allergic rhinitis comprise nervous rhinitis's (pollinosis) throughout the year; Nasal polyposis; Acute viral infection comprises common cold and the infection that is caused by respiratory syncytial virus, influenza, coronavirus (comprising SARS) and adenovirus;

2. bone and joint: relevant with osteoarthritis/osteoarthropathy or comprise and the sacroiliitis of osteoarthritis/osteoarthropathy comprise primary and post-traumatic arthritis, for example congenital hip dysplasia; Neck and lumbar spine inflammation and lumbago and backache and cervical pain; Rheumatoid arthritis and Still disease (Still ' s disease); Seronegative spondyloanthropathy comprises ankylosing spondylitis, arthritic psoriasis, reactive arthritis and does not break up SpA; Septic arthritis infects relevant joint disease and osteopathia with other, and tuberculosis for example comprises Pott's disease (Potts ' disease) and Poncet syndrome (Poncet ' s syndrome); Acute and the chronic synovitis that crystal brings out comprises urate deposition is sick, calcium pyrophosphate deposition disease is relevant with apatite calcium tendon, mucous bursa and synovial membrane inflammation; Behcet's disease (Behcet ' s disease); Primary and Secondary cases xerodermosteosis (Sjogren ' s syndrome); Sjogren's syndrome and local scleroderma; Systemic lupus erythematous, mixed connective tissue disease and undifferentiated connective tissue disease; Inflammatory myopathy comprises dermatomyositis and polymyositis; Polymyalgia rheumatica; Juvenile arthritis comprises the idiopathic inflammatory arthritis and related syndromes and rheumatic fever and the general complication thereof that are distributed in any joint; Vasculitis (vasculitis) comprises giant cell arteritis, aortic arch syndrome (Takayasu ' s arteritis), Qiu-Shi syndrome (Churg-Strauss syndrome), polyarteritis nodosa, microscope polyarteritis and the vasculitis relevant with virus infection, allergy, cryoglobulin and M-band; Lumbago and backache; Familial Mediterranean fever, Mu-Wei syndrome (Muckle-Wells syndrome) and familial Ireland heat (FamilialHibernian Fever), Kikuchi sick (Kikuchi disease); Drug-induced property arthrodynia, tendonitis and myopathy;

3. the musculoskeletal disease that the pain that is caused by damage (for example sport injury) or disease and reticular tissue reproduce: sacroiliitis (rheumatoid arthritis for example, osteoarthritis, gout or crystallographic joint disease), other joint disease (for example degeneration of intervertebral disc or temporomandibular joint (TMJ) sex change), bone remodelling disease (osteoporosis for example, Paget's disease (Paget ' s disease) or osteonecrosis), polychondritis, scleroderma, mixed connective tissue disease, spondyloarthropathy or periodontopathy (for example periodontitis);

4. skin: psoriasis, atopic dermatitis, contact dermatitis or other eczema dermatoses and delayed type hypersensitivity; Vegetalitas and solar dermatitis; Seborrheic dermatitis, dermatitis herpetiformis, lichen planus, atrophic sclerosis lichen, PG, cutaneous sarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema toxicum, skin eosinophilia, alopecia areata, male pattern alopecia, sweet's syndrome (Sweet ' ssyndrome), Wei-Ke syndrome (Weber-Christian syndrome), erythema multiforme; Cellulitis comprises infectivity and non-infectious cellulitis; Pimelitis; Lymphoma cutis, non-melanoma skin cancer and other dysplasia damage; Drug-induced disease comprises fixed drug eruption;

The eye: blepharitis; Conjunctivitis, comprise the perennial allergic conjunctivitis or spring anaphylaxis conjunctivitis; Iritis; Anterior uveitis and posterior uveitis; Choroiditis; Autoimmunization; Affect amphiblestroid sex change or inflammatory diseases; Ophthalmia comprises sympathetic ophthalmia; Sarcoidosis; Infect, comprise that virus, fungus and bacterium infect;

6. gi tract: glossitis, oulitis, periodontitis; Esophagitis comprises and backflowing; Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease (Crohn ' s disease), colitis comprise ulcerative colitis, rectitis, pruritus ani; Coeliac disease, irritable bowel syndrome, and have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect;

7. belly: hepatitis comprises autoimmunity, Alcoholic and viral hepatitis; Hepatic fibrosis and sclerosis; Cholecystitis; Pancreatitis comprises acute and chronic pancreatitis;

8. urogenital system: ephritis comprises interstitial nephritis and glomerulonephritis; Nephrotic syndrome; Urocystitis comprises acute and chronic (matter) urocystitis and hunner's ulcer (Hunner ' s ulcer); Acute and chronic urethritis, prostatitis, epididymitis, ovaritis and salpingitis; Vulvo-vaginitis; Perun alunite disease (Peyronie ' s disease); Erectile dysfunction (masculinity and femininity);

9. allograft rejection: the acute and chronic allograft rejection that after for example kidney, heart, liver, lungs, marrow, skin or corneal transplantation or in blood transfusion, occurs afterwards; Or chronic graft versus host disease;

10.CNS: degenerative brain disorder (Alzheimer ' s disease) and other dementia disease comprise CJD and nvCJD; Amyloidosis; Multiple sclerosis and other demyelination syndrome; Cerebral atherosclerosis and vasculitis; Temporal arteritis; Myasthenia gravis; Acute and chronic pain (acute, intermittence or rest pain, no matter be maincenter source property or outer perigene), comprise Encelialgia, headache, migraine, trigeminal neuralgia, atypical facial pain, joint and ostalgia, invade the pain, the neuropathic pain syndrome that cause by cancer and tumour and comprise the neuropathy relevant with HIV after diabetic, the bleb; The nervosa sarcoidosis; Maincenter and the peripheral nervous system complication of pernicious, infectivity or autoimmunity process;

11. other autoimmunity and allergic disorder comprise Hashimoto thyroiditis (Hashimoto ' s thyroiditis), Graves disease (Graves ' disease), bronzed disease (Addison ' sdisease), diabetes, idiopathic thrombocytopenic purpura, eosinophilic fasciitis, hyper-IgE syndrome, antiphospholipid syndrome;

12. other comprises acquired immune deficiency syndrome (AIDS) (AIDS), leprosy, Sezary syndrome (Sezary syndrome) and paraneoplastic syndrome with the disease of inflammatory or immunity composition;

13. cardiovascular: the atherosclerosis that affects coronary artery and peripheral circulation; Pericarditis; Myocarditis; Inflammatory and autoimmune cardiomyopathy comprise myocardial sarcoisosis; Ischemic damage and reperfusion damage; Endocarditis, cardiovalvulitis and aortitis comprise infectivity (for example syphilis); Vasculitis; The disease of near-end and peripheral vein comprises that phlebitis and thrombosis comprise venous thrombosis and cirsoid complication;

14. tumour: to the treatment of general cancer, comprise prostate gland, mammary gland, lung, ovary, pancreas, intestines and colon, stomach, skin and cerebral tumor and affect marrow (comprising leukemia) and the malignant tumour of lymphocytic hyperplasia system (for example He Jiejin (Hodgkin ' s) and non Hodgkin lymphoma); Comprise prevention and treatment to metastatic disease and tumor recurrence and paraneoplastic syndrome; With

15. gi tract: coeliac disease, rectitis, Eosinophilic Gastroenteritis, Mastocytosis, Crohn's disease, ulcerative colitis, microscope colitis, uncertain colitis, intestines stress disease, irritable bowel syndrome, non-inflammatory diarrhoea, have away from the relevant transformation reactions (for example migraine, rhinitis or eczema) of the food of intestines effect.

16. with PGD ₂Or the relevant disease of its metabolite level rising.

Thereby, the invention provides above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate, it is used for the treatment of.

Preferably, compound of the present invention is used for the treatment of the disease that Chemokine Receptors wherein belongs to CRTh2 acceptor subfamily.

The disease specific of available the compounds of this invention treatment is asthma, rhinitis and PGD wherein ₂Or the Other diseases of its metabolite level rising.Preferably, compound of the present invention is used for the treatment of asthma.

In yet another aspect, the invention provides defined formula (I) compound or pharmaceutically acceptable salt thereof above or solvate for the preparation of the purposes in the medicine for the treatment of.

In yet another aspect, the invention provides above defined formula (I) compound or pharmaceutically acceptable salt thereof or the purposes of solvate in the medicine that preparation is used for the treatment of with the medicine that is used for the treatment of asthma and rhinitis (such as sucking and oral steroid class, the beta 2 receptor agonist of suction and oral LTRA) coupling.

The invention still further relates to combination therapy, wherein compound or pharmaceutically acceptable salt thereof of the present invention comprise the pharmaceutical composition of the compounds of this invention or preparation and another kind of therapeutical agent or multiple therapeutical agent simultaneously or successively give, or give as combination preparation with another kind of therapeutical agent or multiple therapeutical agent, be used for the treatment of in the listed illness one or more.

Particularly, in order to treat inflammatory disease, such as (but being not limited to) rheumatoid arthritis, osteoarthritis, asthma, allergic rhinitis, chronic obstructive pulmonary disease (COPD), psoriasis and inflammatory bowel, can be with compound of the present invention and following listed drug regimen:

Nonsteroidal anti-inflammatory agent (being NSAID hereinafter) comprises the non-selective cyclooxygenase COX-1/COX-2 inhibitor that topical application no matter or whole body use (piroxicam for example; Diclofenac; Phenoxy propionic acid, for example Naproxen Base, flurbiprofen, fenoprofen, Ketoprofen and Ibuprofen BP/EP; Fragrant that acids, for example mefenamic acid, indomethacin, sulindac, Azapropazone (azapropazone); Pyrazolone, for example Phenylbutazone; Salicylate (ester), for example acetylsalicylic acid); Selective COX-2-2 inhibitor (for example meloxicam, celecoxib, rofecoxib, valdecoxib, Lu Makao former times (lumarocoxib), parecoxib and L-791456); The nitric oxide donors (CINODs) that suppresses cyclooxygenase; Glucocorticosteroid (no matter still coming administration by the intraarticular approach by local, oral, intramuscular, intravenous route); Methotrexate; Leflunomide; Oxychloroquine; The d-Trolovol; Auranofin or other are non-through intestines or New Oral Gold preparation; Anodyne; Diacerein (diacerein); Intraarticular therapeutical agent, for example derivatives of hyaluronic acids; And nutritional supplement, for example glucosamine.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the agonist of cytokine or cytokine function or antagonist (comprise the medicine that acts on the cytokine signaling conducting path, the conditioning agent of SOCS system for example), comprise α-, β-and gamma-interferon; I type rhIGF-1 (IGF-1); Interleukin (IL) comprises IL1 to 17 and interleukin antagonist or inhibitor (for example Kineret); Cachectin (TNF-α) inhibitor, for example anti-TNF monoclonal antibody (for example infliximab (infliximab), adalimumab (adalimumab) and CDP-870) and TNF receptor antagonist (comprising immunoglobulin molecules (for example etanercept) and low-molecular-weight drug (for example pentoxifylline (pentoxyfylline))).

In addition, the present invention relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: target is in the monoclonal antibody (for example CD20 (Rituximab (rituximab)), MRA-aIL16R) of bone-marrow-derived lymphocyte and target in the lymphocytic monoclonal antibody of T (CTLA4-Ig, HuMax Il-15).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: chemokine receptor function conditioning agent, for example antagonist of CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (C-C family); The antagonist of CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (C-X-C family); And CX ₃CR1 (C-X ₃-C family) antagonist.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the instant stromatin enzyme of matrix metalloproteinase (MMPs) (stromelysin), collagenase and gelatinase and proteoglycan enzyme (aggrecanase) (collagenase-1 (MMP-1) especially, collagenase-2 (MMP-8), collagenase-3 (MMP-13), molten stromatin enzyme-1 (MMP-3), molten stromatin enzyme-2 (MMP-10) and mmp-3 (MMP-11) and MMP-9 and MMP-12) inhibitor, comprise medicine, for example Vibravenos.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: inhibitors of leukotriene biosynthesis, 5-lipoxidase (5-LO) inhibitor or 5-lipoxidase activated protein (FLAP) antagonist, for example zileuton; ABT-761; Fenleuton; Tepoxalin; Abbott-79175; Abbott-85761; N-(5-replaces)-thiophene-2-alkyl sulfonamide; 2,6-, two-tert.-butyl phenol hydrazone; Methoxyl group tetrahydropyrans, for example Zeneca ZD-2138; Compound S B-210661; The 2-cyano group naphthalene compound that pyridyl replaces, L-739 for example, 010; 2-cyano quinolines compound, L-746 for example, 530; Or indoles or quinoline compound, for example MK-591, MK-886 and BAY * 1005.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the receptor antagonist of leukotriene (LT) B4, LTC4, LTD4 and LTE4 is selected from thiodiphenylamine-3-based compound, L-651 for example, 392; Amidino compounds, for example CGS-25019c; Ben Bing Evil amine (benzoxalamine), for example Ontazolast; Benzenyl amidine (benzenecarboximidamide), for example BIIL 284/260; And compound, for example Zafirlukast, Ro 23-3544, Singulair, pranlukast, verlukast (MK-679), RG-12525, Ro-245913, iralukast (CGP 45715A) and BAY * 7195.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: phosphodiesterase (PDE) inhibitor, for example methyl xanthine (methylxanthanine) comprises theophylline and aminophylline; Selectivity PDE isozyme inhibitor comprises PDE4 inhibitor, isoform PDE4D inhibitor or PDE5 inhibitor.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: histamine 1 receptor antagonist, for example cetirizine, Loratadine, Desloratadine, fexofenadine, acrivastine, terfenadine, astemizole, nitrogen

Si Ting, levocabastine, chlorphenamine, promethazine, cyclizine (eyclizine) or mizolastine; Oral, local or non-through enteral administration.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: proton pump inhibitor (for example omeprazole) or stomach protectiveness histamine 2 receptor antagonist.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: histamine 4 receptor antagonists.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: α 1/ α 2 adrenoceptor agonists, vasoconstrictor, sympathomimetic, for example propylhexedrine (propylhexedrine), phenylephrine, Phenylpropanolamine, ephedrine,d-pseudo-ephedrine, naphcon, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, tramazoline hydrochloride or ethylnorephinephrine hydrochloride.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: anticholinergic, comprise M-ChR (M1, M2 and M3) antagonist, for example coromegine, Scopolamine, GLYCOPYRRONIUM (glycopyrrrolate), ipratropium bromide (ipratropium bromide), tiotropium bromide (tiotropium bromide), oxitropium bromide (oxitropium bromide), pirenzepine (pirenzepine) or telenzepine (telenzepine).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: beta-2 adrenoceptor (comprising beta receptor hypotype 1-4) agonist, such as Racemic isoproterenol, salbutamol, formoterol, Salmeterol, terbutaline, Orciprenaline, bitolterol mesilate or pirbuterol or their chirality enantiomer.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: chromone, for example Sodium Cromoglicate or sodium nedocromil.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: glucocorticosteroid, for example flunisolide, Triamcinolone Acetonide, Beconase Nasal Syray, budesonide, fluticasone propionate, ciclesonide or furoic acid momisone.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the medicine of regulating nuclear hormone receptor (for example PPARs).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: immunoglobulin (Ig) (Ig) or Ig goods; Or antagonist or the antibody of adjusting Ig function, for example anti-IgE (for example omalizumab (omalizumab)).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the antiphlogiston of another kind of whole body or topical application, for example Thalidomide (thalidomide) or derivatives thereof, retinoid, Dithranol (dithranol) or calcipotriol (calcipotriol).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: the combination of aminosalicylate (ester) and sulfapyridine (for example sulfasalazine, mesalazine, Balsalazide and Olsalazine); And immunomodulator, for example thio-purine and reflunomide (for example budesonide).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: antimicrobial drug, for example penicillin derivative, tsiklomitsin, macrolide, beta-lactam, fluoroquinolone, metronidazole, imbedibility aminoglycoside; Antiviral drug comprises acyclovir, Famciclovir, valacyclovir, ganciclovir, cidofovir, amantadine, Rimantadine, ribavirin, zanamivir (zanamavir) and special quick clothes (oseltamavir); Proteinase inhibitor, for example Indinavir, viracept see nelfinaivr, ritonavir and Saquinavir; Nucleoside reverse transcriptase inhibitor, for example didanosine, lamivudine, stavudine (stavudine), zalcitabine or zidovudine; Or non-nucleoside reverse transcriptase inhibitor, for example nevirapine (nevirapine) or efavirenz (efavirenz).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: cardiovascular drug, for example calcium channel blocker, receptor,β blocker, angiotensin-converting enzyme (ACE) inhibitor, hypertensin 2 receptor antagonist; Lipid lowerers, for example special class of statin or shellfish; The blood cell morphology conditioning agent is for example joined the appropriate western film (pentoxyfylline); Thrombolytic Drugs or anticoagulation, for example anticoagulant.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: CNS medicine, for example thymoleptic (for example Sertraline), anti-Parkinson medicine (selegiline for example, L-3,4 dihydroxyphenylalanine, Ropinirole, pramipexole, MAOB inhibitor (for example selegiline and rasagiline), comP inhibitor (for example tolcapone (tasmar)), the A-2 inhibitor, the dopamine reuptake inhibitor, nmda antagonist, the Nicotine agonist, dopamine agonist or neuronal nitric oxide synthase inhibitor) or anti-Alzheimer medicine (E2020 (donepezil) for example, EXELON, tacrine, cox 2 inhibitor, propentofylline or Metrifonate).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: be used for the treatment of the medicine of acute or chronic pain, the anodyne (for example opioid or derivatives thereof), Carbamzepine, Phenytoin Sodium Salt, Sodium Valproate, amitriptyline (amitryptiline) or other thymoleptic, paracetamol or the nonsteroidal anti-inflammatory agent that for example play a role in maincenter or periphery.

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: non-through (the comprising suction) of intestines or topical application local anaesthetics, for example lignocaine or derivatives thereof.

Compound or pharmaceutically acceptable salt thereof of the present invention also can with following material coupling: anti-osteoporotic comprises hormonal medicaments (for example raloxifene (raloxifene)) or diphosphonate (for example alendronate (alendronate)).

The invention still further relates to the combination of the compounds of this invention or its pharmacologically acceptable salt and following material: (i) tryptase (tryptase) inhibitor; (ii) platelet activation factor (PAF) antagonist; (iii) interleukin converting enzyme (ICE) inhibitor; (iv) IMPDH inhibitor; (v) adhesion molecule inhibitor comprises the VLA-4 antagonist; (vi) kethepsin; (vii) kinase inhibitor, Tyrosylprotein kinase (for example Btk, Itk, Jak3 or MAP) inhibitor (for example Gefitinib (gefitinib) or imatinib mesylate (imatinib)), serine/threonine kinase inhibitor (map kinase (p38 for example for example for example, JNK, protein kinase A, B or C, or IKK) inhibitor) or the inhibitor of the kinases (for example cell cycle protein dependent kinase) that in Cycle Regulation, involves; (viii) glucose-6 monophosphate dehydrogenase inhibitor; (ix) kassinin kinin B ₁Acceptor or kassinin kinin B ₂Receptor antagonist; (x) antigout drug, for example colchicine; (xi) xanthine oxidase inhibitor, for example allopurinol; (xii) uricosuric, for example probenecid, sulfinpyrazone or benzbromarone; (xiii) growth hormone secretagogues; (xiv) transforming growth factor (TGF β); (xv) platelet-derived growth factor (PDGF); (xvi) fibroblast growth factor, for example basic fibroblast growth factor (bFGF); (xvii) rHuGM-CSF (GM-CSF); (xviii) capsicum vegetable oil (capsaicin cream); (xix) tachykinin NK-1 ₁Acceptor or tachykinin NK-1 ₃Receptor antagonist, for example NKP-608C, SB-233412 (Talnetant (talnetant)) or D-4418; (xx) elastatinal, for example UT-77 or ZD-0892; (xxi) TNF-α converting enzyme inhibitor (TACE); The nitricoxide synthase of (xxii) inducing (iNOS) inhibitor; The chemoattractant receptor homolog molecule of (xxiii) expressing on the TH2 cell (for example CRTH2 antagonist); (xxiv) inhibitor of P38; (xxv) medicine of adjusting Toll sample acceptor (TLR) function; (xxvi) medicine of adjusting purinergic receptor activity, for example P2X7; Or (xxvii) transcription factor activation inhibitor, for example NFkB, API or STATS.

Also compound or pharmaceutically acceptable salt thereof of the present invention and existing medicine coupling can be used for the treatment of cancer, suitable medicine for example comprises:

(i) antiproliferative/antitumour drug that in medical oncology, uses or its combination, for example alkylating agent (for example cis-platinum, carboplatin, endoxan, mustargen, melphalan, Chlorambucil, busulfan or nitrosourea); Antimetabolite (for example antifol, for example 5-FU sample 5 FU 5 fluorouracil or Tegafur, Raltitrexed, methotrexate, cytosine arabinoside, hydroxyurea, gemcitabine or taxol); Antitumor antibiotics (for example anthracycline antibiotics, for example Zorubicin, bleomycin, Dx, daunorubicin, epirubicin, idarubicin, ametycin, gengshengmeisu or Plicamycin); Antimitotic agent (for example catharanthus alkaloid, for example vincristine(VCR), vinealeucoblastine(VLB), vindesine or vinorelbine; Or Taxan, for example PTX (taxol) or taxotere (taxotere)); Or topological isozyme inhibitor (for example epipodophyllotoxin, for example Etoposide, teniposide, Amsacrine, Hycamtin or camptothecine);

(ii) cell growth inhibition medicine, for example antiestrogen (for example tamoxifen, toremifene, raloxifene, droloxifene or iodoxyfene); Adjust under the estrogen receptor (for example fulvestrant); Antiandrogen (for example bicalutamide, flutamide, Nilutamide or CPA); Lhrh antagonist or LHRH agonist (for example goserelin, Leuprolide or buserelin); Progestogen (for example acetic acid megestrol); Aromatization enzyme (aromatase) inhibitor (for example being Anastrozole, letrozole, vorozole (vorazole) or Exemestane); Or 5α-reductase inhibitor (for example finasteride);

(iii) medicine (for example inhibitors of metalloproteinase (for example Marimastat) or UPA function of receptors inhibitor) of anticancer intrusion;

(iv) somatomedin depressant of functions, for example: growth factor antibodies (for example anti-erb b2 antibody trastuzumab or anti-erb b1 antibody Cetuximab [C225]); Farnesyl transferase inhibitor; Tyrosine kinase inhibitor or serine/threonine kinase inhibitor; Epidermal growth factor family inhibitor (EGFR family tyrosine kinase inhibitor for example, N-(3-chloro-4-fluorophenyl)-7-methoxyl group-6-(3-morpholino propoxy-) quinazoline-4-amine (Gefitinib for example, AZD1839), N-(3-ethynyl phenyl)-6,7-two (2-methoxy ethoxy) quinazoline-4-amine (erlotinib (erlotinib), OSI-774) or 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholino propoxy-) quinazoline-4-amine (CI 1033)); Platelet-derived growth factor man group inhibitor; Or pHGF man group inhibitor;

(v) anti-angiogenic drugs for example suppresses the anti-angiogenic drugs (for example anti-vascular endothelial cell growth factor antibody rhuMAb-VEGF, the compound that discloses) of vascular endothelial growth factor effect in WO 97/22596, WO 97/30035, WO 97/32856 or WO 98/13354; Or the compound (for example linomide, beta 2 integrin alpha v β 3 depressant of functions or angiostatin) that plays a role by another kind of mechanism;

(vi) blood vessel injury agent, for example compound of combretastatin A4 or disclosure in WO 99/02166, WO 00/40529, WO 00/41669, WO 01/92224, WO 02/04434 or WO 02/08213;

(vii) medicine that in antisense therapy, uses, the antisense therapy medicine of one of listed target, for example ISIS 2503, anti-ras antisense thing more than for example pointing to;

(viii) medicine that in following gene therapy method for example, uses: the method for displacement aberrant gene (for example unusual p53 or unusual BRCA1 or BRCA2); The GDEPT enzyme prodrug of the gene mediated (treatment) method is for example used the GDEPT method of Isocytosine deaminase, thymidine kinase or bacterium nitroreductase; With the method that improves Chemotherapy in Patients or radiotherapy tolerance, for example multi-medicament opposing gene therapy; Or

(ix) medicine that in following immunotherapy method for example, uses: improve exsomatizing and at body method, for example using cytokine (for example interleukin-22, IL-4 or granulocyte-macrophage colony stimutaing factor) transfection of patient tumors cell immunogenicity; Reduce the method for T cell anergy; Use the method for the immunocyte (for example dendritic cell of cytokine transfection) of transfection; Use the method for the tumor cell line of cytokine transfection; With the method for using anti-id AB.

In yet another aspect, the invention provides defined formula (I) compound or pharmaceutically acceptable salt thereof above or the solvate purposes in the medicine that for the preparation for the treatment of to the adjusting of CRTh2 receptor active is useful human diseases or illness.

In the context of the present specification, term " treatment " also comprises " prevention ", unless opposite specifying arranged in addition.Term " treatment " and " treatment ground " also should correspondingly be explained.

The present invention also provides treatment PGD ₂Or the method for the disease that mediates of its metabolite (wherein prostanoid and its acceptor (especially CRTh2 acceptor) in conjunction with), described method comprise will the treatment significant quantity above defined formula (I) compound or pharmaceutically acceptable salt thereof, solvate or prodrug give the patient.

The present invention also provides treatment to suffer from inflammatory diseases (especially psoriasis) or faces the patient's of described disease danger the method for described disease, described method comprise will the treatment significant quantity above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate give described patient.

With regard to therepic use mentioned above, the dosage that gives changes with employed compound, mode of administration, desired treatment and the illness that shows certainly.

Formula (I) compound or its prodrug, pharmacologically acceptable salt and solvate can use separately, but the form with pharmaceutical composition gives usually, its Chinese style (I) compound/salt/solvate (activeconstituents) and pharmaceutically acceptable auxiliaries, diluent or carrier combination.Based on mode of administration, pharmaceutical composition can preferably include 0.05 to 99%w (weight percent) more preferably 0.05 to 80%w still more preferably 0.10 to 70%w even 0.10 to 50%w activeconstituents more preferably, and all wt per-cent all is based on total composition.

The present invention also provides pharmaceutical composition, and it comprises above defined formula (I) compound or pharmaceutically acceptable salt thereof or solvate and pharmaceutically acceptable auxiliaries, diluent or carrier.

Pharmaceutical composition can come topical (for example be administered into lung and/or air flue or be administered into skin) by following form: solution, suspensoid, Sevoflurane hydrocarbon aerosol and dry powder formulations; Or can for example come by the following method the whole body administration: the form with tablet, capsule, syrup, pulvis or granule is come oral administration, or come administered parenterally with the form of solution or suspensoid, or subcutaneous administration, or come rectal administration with the form of suppository, or percutaneous dosing.Preferably, compound of the present invention comes administration by oral.

The present invention is existing to be illustrated by following nonrestrictive embodiment, wherein, and except as otherwise noted:

(i) when providing, quote ¹H NMR data, its form for respect to as interior target tetramethylsilane (TMS) with the hundred δ values of counting very much the principal character proton that (ppm) provide;

(ii) mass spectrum (MS): generally only reported the ion of indication parent quality, except as otherwise noted;

(iii) title compound of embodiment and method utilizes ACD/Name and ACD/Name Batch (8.0 editions) (Advanced Chemical Development Inc, Canada) to name according to the IUPAC rule;

(iv) except as otherwise noted, reversed-phase HPLC utilizes Symmetry, and NovaPak or Ex-Terra reverse phase silica gel post carry out;

(v) solvent MgSO ₄Or Na ₂SO ₄Dry;

(vi) use following abbreviation:

The EtOAc ethyl acetate

The Ether ether

MgSO ₄Anhydrous magnesium sulfate

Na ₂SO ₄Anhydrous sodium sulphate

HCl hydrochloric acid

The DCM methylene dichloride

The DMSO dimethyl sulfoxide (DMSO)

H hour

MCPBA 3-chloroperoxybenzoic acid (Aldrich 77%max)

Min minute

NaHCO ₃Sodium bicarbonate

The TFA trifluoroacetic acid

Pd (dppf) Cl ₂[1,1 '-two (diphenylphosphino) ferrocene] palladium chloride (II)

Mixture with methylene dichloride

The THF tetrahydrofuran (THF)

NaOH sodium hydroxide

The RT room temperature

Embodiment 1

{ [5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

(i) 2 '-(benzyl oxygen base)-5 '-chlordiphenyl-4-base phenylsulfone

5-chloro-2-(phenyl methoxyl group) phenyl]-boric acid (method by WO2004089885A1 prepares) (0.5g) De diox (20ml) solution with 1-bromo-4-(phenyl sulfonyl) benzene (0.57g) (by in JACS (1952); employed method prepares among 74, the 394-7) process.Add yellow soda ash (0.40g) and palladium (diphenylphosphino ferrocene) dichloride (0.070g), then with mixture heating up to 80 ℃, kept 16 hours.The mixture dilute with water is used ethyl acetate extraction, drying, and then reduction vaporization obtains oily matter.Oily matter comes purifying by silica gel chromatography (with 2: 1 wash-outs of isohexane/ether), obtains subhead compound (0.9g), is white solid.

¹H?NMR?CDCl ₃：δ8.00-7.92(4H，m)，7.67-7.49(5H，m)，7.30-7.19(7H，m)7.02-6.95(1H，d)，5.08(2H，s)。

(ii) 5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

The product (0.9g) of embodiment 1 step (i) in anhydrous DCM (20ml) with DCM (3.10ml) solution-treated of 1.0M boron tribromide, stirring at room 1 hour.Mixture is cancellation in frozen water, with the DCM extraction, and dry (MgSO ₄), then concentrating under reduced pressure obtains subhead compound (0.9g).

MS：ESI(-ve)343(M-1)。

(iii) { [5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } tert.-butyl acetate

Flask is equipped with the product (0.9g) of bromo-acetic acid tert-butyl (0.42ml), dry DMF (20ml), salt of wormwood (0.36g) and embodiment 1 step (ii), then in stirred overnight at room temperature.Mixture is cancellation in water, uses extracted with diethyl ether, dry (MgSO ₄), then concentrating under reduced pressure obtains oily matter.Oily matter comes purifying by silica gel chromatography (with 2: 1 wash-outs of isohexane/ether), obtains subhead compound (0.6g), is colorless oil.

MS：ESI(+ve)476(M+NH ₄)。

(iv) { [5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

Title compound prepares from the product (0.6g) of step (iii), with the product of step (iii) TFA/DCM (1: 1, stir in 10ml) and spend the night.Mixture is carried out concentrating under reduced pressure, obtain oily matter.Resistates comes purifying by reversed-phase HPLC, and the amount of getting is 0.31g.

¹H?NMR：DMSO-d ₆：δ8.03-7.62(9H，m)，7.42-7.39(2H，m)，7.08-7.05(1H，d)，4.74(2H，s)。

MS：ESI(-ve)401(M-1)。

Embodiment 2

{ [3 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

(i) 4-bromo-2-fluoro-1-(phenyl sulfonyl) benzene

(35mg) in the pipe of sealing, utilize microwave with 200 watts of heating 15 seconds in 4-bromo-2-fluoro-benzene sulfonyl chloride (2g), benzene (1.3ml) and iron(ic) chloride (III).After the cooling, come purifying by flash column chromatography (eluent is the 20%EtOAc/ hexane), obtain subhead compound (1.8g), be solid.

¹H?NMR?DMSO-d ₆：δ8.03-7.95(3H，m)，7.84(1H，dd)，7.80-7.65(4H，m)。

(ii) 3 ', 5-difluoro-2-methoxyl-4 '-(phenyl sulfonyl) biphenyl

To the product (0.55g) of step (i) and 5-fluoro-2-methoxyl group-phenyl-boron dihydroxide (0.3g) at toluene (6ml), ethanol (4ml) and 2M Na ₂CO ₃Solution/suspension (3ml) is added tetrakis triphenylphosphine palladium (0.05g).With mixture heating up to 85 ℃, keep 3h, then concentrating under reduced pressure obtains thick material.Resistates is suspended in the water, uses ethyl acetate extraction, use the salt water washing, dry (MgSO ₄), concentrating under reduced pressure then.Utilize flash column chromatography (eluent is 10% ether/hexane) to come purifying, obtain subhead compound (0.39g).

¹H?NMR?DMSO-d ₆：δ8.08(1H，t)，8.00(2H，d)，7.81-7.55(5H，m)，7.28(2H，m)，7.17(1H，m)，3.77(3H，s)。

(iii) 3 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

The product (0.44g) of step (ii) with DCM (3.7ml) solution-treated of 1.0M boron tribromide, stirs 18h at 0 ℃ in DCM (10ml).Mixture is cancellation in frozen water, with the EtOAc extraction, and dry (MgSO ₄), then vacuum concentration obtains subhead compound (0.39g).

¹H?NMR?DMSO-d ₆：δ9.97(1H，s)，8.07(1H，t)，7.99(2H，d)，7.80-7.60(5H，m)，7.25(1H，m)，7.10(1H，m)，6.96(1H，m)。

(iv) { [3 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } tert.-butyl acetate

The subhead compound utilizes the product of step (iii) to prepare by the method for embodiment 1 step (iii).

¹H?NMR?DMSO-d ₆：δ8.09(1H，t)，8.00(2H，d)，7.80-7.65(5H，m)，7.34(1H，m)，7.25(1H，m)，7.07(1H，m)，4.71(2H，s)，1.37(9H，s)。

(v) { [3 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

Title compound utilizes the product of step (iv) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ13.08(1H，s)，8.08(1H，t)，8.00(2H，d)，7.80-7.66(5H，m)，7.33(1H，m)，7.24(1H，m)，7.09(1H，m)，4.75(2H，s)。

MS：APCI-ve?403(M-1)。

Embodiment 3

(2S)-and 2-{[3 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

(i) (2S)-and 2-{[3 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } the propionic acid tert-butyl ester

With diisopropyl azo-2-carboxylic acid (0.19ml) at 0 ℃ of tetrahydrofuran (THF) (10ml) solution that adds to product (250mg), (R)-(+)-lactic acid tert-butyl ester (141mg) and the triphenylphosphine (252mg) of embodiment 2 steps (iii).After 20 minutes ice bath is removed, then with reaction mixture in stirred overnight at room temperature.Then, reaction mixture is adsorbed onto on the silica gel, utilizes flash column chromatography (eluent is 10% ethyl acetate/hexane) to come purifying, obtain subhead compound (140mg), be oily matter.

¹H?NMR?DMSO-d ₆：δ8.09(1H，t)，8.00(2H，m)，7.81-7.66(5H，m)，7.34(1H，m)，7.24(1H，m)，7.02(1H，m)，4.91(1H，q)，1.40(3H，d)，1.34(9H，s)。

(ii) (2S)-and 2-{[3 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

Title compound utilizes the product of step (i) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ8.08(1H，t)，8.00(2H，d)，7.80-7.67(5H，m)，7.33(1H，m)，7.23(1H，m)，7.02(1H，m)，4.95(1H，q)，1.42(3H，d)。

MS：APCI-ve?417(M-1)。

Embodiment 4

({ 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid

I) 4-bromo-2-fluoro-1-[(4-fluorophenyl) alkylsulfonyl] benzene

The subhead compound utilizes 4-bromo-2-fluorobenzene SULPHURYL CHLORIDE and fluorobenzene to prepare by the method for embodiment 2 steps (i).

¹H?NMR?DMSO-d ₆：δ8.04(2H，m)，7.99(1H，t)，7.86(1H，d)，7.75(1H，dd)，7.51(2H，m)。

Ii) 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2-methoxyl biphenyl

The subhead compound utilizes the product of step (i) and 5-chloro-2-anisole ylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.1-8.05(3H，m)，7.65-7.44(6H，m)，7.19(1H，d)，3.78(3H，s)。

Iii) 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-alcohol

The subhead compound utilizes the product of step (ii) to prepare by the method for embodiment 2 steps (iii).

¹H?NMR?DMSO-d ₆：δ10.27(1H，s)，8.09-8.04(3H，m)，7.7(1H，dd)，7.63(1H，dd)，7.52(2H，m)，7.41(1H，d)，7.29(1H，dd)，6.99(1H，d)。

Iv) ({ 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) tert.-butyl acetate

¹H?NMR?DMSO-d ₆：δ8.11-8.05(3H，m)，7.73-7.66(2H，m)，7.56-7.43(4H，m)，7.09(1H，m)，4.74(2H，s)，1.38(9H，s)。

V) ({ 5-chloro-3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid

¹H?NMR?DMSO-d ₆：δ13.13(1H，s)，8.10-8.05(3H，m)，7.73(1H，s)，7.7(1H，dd)，7.53(2H，dt)，7.49(1H，d)，7.44(1H，dd)，7.11(1H，d)，4.78(2H，s)。

MS：APCI(-ve)436(M-1)。

Embodiment 5

{ [2 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

I) 1-bromo-2-fluoro-4-(phenyl sulfonyl) benzene

The subhead compound utilizes 4-bromo-3-fluorobenzene SULPHURYL CHLORIDE and benzene to prepare by the method for embodiment 2 steps (i).

¹H?NMR?DMSO-d ₆：δ8.04-7.97(4H，m)，7.74(2H，m)，7.65(2H，m)。

Ii) 2,5 '-two fluoro-2 '-methoxyl biphenyl-4-base phenylsulfone

The subhead compound utilizes the product of step (i) and 5-fluoro-2-anisole ylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.07(2H，m)，7.91(1H，dd)，7.85(1H，dd)，7.75(1H，m)，7.7-7.61(3H，m)，7.29(1H，m)，7.21(1H，dd)，7.15(1H，dd)，3.72(3H，s)。

Iii) 2 ', 5-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ9.77(1H，s)，8.06(2H，d)，7.89(1H，d)，7.83(1H，d)，7.78-7.63(4H，m)，7.12(2H，m)，6.93(1H，m)。

Iv) { [2 ', 5-, two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

Title compound utilizes the product of step (iii) to prepare by the method for embodiment 1 step (iii) and embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ12.97(1H，s)，8.07(2H，m)，7.91(1H，dd)，7.85(1H，dd)，7.77-7.64(4H，m)，7.29-7.21(2H，m)，7.05(1H，dd)，4.67(2H，s)。

MS：APCI(-ve)403(M-1)。

Embodiment 6

{ [5-chloro-2 '-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

I) 5 '-chloro-2-fluoro-, 2 '-methoxyl biphenyl-4-base phenylsulfone

The subhead compound utilizes the product of embodiment 5 steps (i) and 5-chloro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.08-8.05(2H，m)，7.91(1H，dd)，7.84(1H，dd)，7.75(1H，m)，7.7-7.62(3H，m)，7.50(1H，dd)，7.37(1H，d)，7.17(1H，d)，3.73(3H，s)。

Ii) 5-chloro-2 '-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

The subhead compound utilizes the product of step (i) to prepare by the method for embodiment 2 steps (iii).

¹H?NMR?DMSO-d ₆：δ10.09(1H，s)，8.08-8.05(2H，m)，7.89(1H，dd)，7.83(1H，dd)，7.77-7.72(1H，m)，7.69-7.64(3H，m)，7.32-7.27(2H，m)，6.96(1H，dd)。

Iii) { [5-chloro-2 '-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

Title compound utilizes the product of step (ii) to prepare by the method for embodiment 1 step (iii) and embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ13.02(1H，s)，8.09-8.06(2H，m)，7.92(1H，dd)，7.85(1H，dd)，7.77-7.65(4H，m)，7.46(1H，d)，7.39(1H，d)，7.06(1H，d)，4.7(2H，s)。

MS：APCI(-ve)419(M-1)。

Embodiment 7

{ [5-fluoro-4 '-(phenyl sulfonyl)-3 '-(trifluoromethyl) biphenyl-2-yl] oxygen base } acetic acid

I) 4-bromo-1-(phenyl sulfonyl)-2-(trifluoromethyl) benzene

The subhead compound utilizes 4-bromo-2-(trifluoromethyl) benzene sulfonyl chloride and benzene to prepare by the method for embodiment 2 steps (i).

¹H?NMR?DMSO-d ₆：δ8.35(1H，d)，8.25(1H，dd)，8.21(1H，d)，7.88(2H，d)，7.76-7.72(1H，m)，7.67-7.62(2H，m)。

Ii) 5 '-fluoro-2 '-methoxyl group-3-(trifluoromethyl) biphenyl-4-base phenylsulfone

The subhead compound utilizes the product of step (i) and 5-fluoro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.47(1H，d)，8.12(1H，dd)，8.09(1H，d)，7.92(2H，d)，7.77-7.64(3H，m)，7.40(1H，dd)，7.31(1H，td)，7.20(1H，dd)，3.78(3H，s)。

Iii) 5-fluoro-4 '-(phenyl sulfonyl)-3 '-(trifluoromethyl) biphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ10.06(1H，s)，8.47(1H，d)，8.21-8.15(2H，m)，7.91(2H，d)，7.77-7.62(3H，m)，7.35(1H，dd)，7.14(1H，m)，6.99(1H，dd)。

Iv) { [5-fluoro-4 '-(phenyl sulfonyl)-3 '-(trifluoromethyl) biphenyl-2-yl] oxygen base } tert.-butyl acetate

¹H?NMR?DMSO-d ₆：δ8.47(1H，s)，8.25(1H，d)，8.17(1H，m)，7.92(2H，d)，7.74(1H，m)，7.66(2H，m)，7.42(1H，m)，7.28(1H，m)，7.13(1H，m)，4.74(2H，s)，1.36(9H，s)。

V) { [5-fluoro-4 '-(phenyl sulfonyl)-3 '-(trifluoromethyl) biphenyl-2-yl] oxygen base } acetic acid

¹H?NMR?DMSO-d ₆：δ13.10(1H，s)，8.47(1H，d)，8.31(1H，d)，8.18(1H，dd)，7.92(2H，d)，7.74(1H，m)，7.66(2H，t)，7.42(1H，dd)，7.28(1H，td)，7.15(1H，dd)，4.78(2H，s)。

MS：APCI(-ve)453(M-1)。

Embodiment 8

(2S)-2-({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

I) 4-bromophenyl 4-fluorophenyl sulfone

The subhead compound utilizes 4-fluorobenzene SULPHURYL CHLORIDE and bromobenzene to prepare by the method for embodiment 2 steps (i).

¹H?NMR?DMSO-d ₆：δ8.1-8.02(2H，m)，7.94-7.82(4H，m)，7.53-7.44(2H，m)。

Ii) 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2-methoxyl biphenyl

The subhead compound utilizes the product of step (i) and 5-chloro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.13-8.06(2H，m)，8.00(2H，dt)，7.73(2H，dt)，7.54-7.38(4H，m)，7.17(1H，d)，3.76(3H，s)。

Iii) 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ10.14(1H，s)，8.14-8.07(2H，m)，8.01(2H，d)，7.81(2H，d)，7.54-7.46(2H，m)，7.36(1H，d)，7.29(1H，dd)，6.99(1H，d)。

Iv) (2S)-2-({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) the propionic acid tert-butyl ester

The subhead compound utilizes the product of step (iii) to prepare by the method for embodiment 3 steps (i).

¹H?NMR?DMSO-d ₆：δ8.15-8.10(2H，m)，8.03(2H，d)，7.88(2H，d)，7.54-7.42(4H，m)，7.03-6.99(1H，m)，4.95(1H，q)，1.41(3H，d)，1.36(9H，s)。

V) (2S)-2-({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

¹H?NMR?DMSO-d ₆：δ8.12-8.07(2H，m)，8.0(2H，d)，7.87(2H，d)，7.49(2H，t)，7.43-7.38(2H，m)，7.0(1H，d)，4.95(1H，q)，1.41(3H，d)。

MS：APCI(-ve)433(M-1)。

Embodiment 9

({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid

I) 1-bromo-2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl] benzene

Iron(ic) chloride (0.5g) is added to the mixture of 4-bromo-3-fluoro-benzene sulfonyl chloride (2.5g) and fluorobenzene (3ml), then return stirring is 18 hours.Flask is cooled to room temperature, then with resistates at NaHCO ₃Distribute between the aqueous solution and the DCM.The salt water washing of DCM layer, dry (MgSO ₄), reduction vaporization then.With resistates recrystallization in ethanol, obtain pale yellow crystals.

¹H?NMR?DMSO-d ₆：δ8.15-7.98(4H，m)，7.76(1H，dd)，7.56-7.46(2H，m)。

Ii) 5 '-chloro-2-fluoro-4-[(4-fluorophenyl) alkylsulfonyl]-2 '-methoxyl biphenyl

¹H?NMR?DMSO-d ₆：δ8.12(2H，dddd)，7.9(1H，dd)，7.82(1H，dd)，7.62(1H，t)，7.51-7.44(3H，m)，7.33(1H，d)，7.14(1H，d)，3.7(3H，s)。

Iii) 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ10.12(1H，s)，8.2-8.14(2H，m)，7.93(1H，dd)，7.86(1H，dd)，7.68(1H，t)，7.52(2H，t)，7.35-7.28(2H，m)，6.98(1H，d)。

Iv) ({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) tert.-butyl acetate

¹H?NMR?DMSO-d ₆：δ8.21-8.14(2H，m)，7.95(1H，dd)，7.89(1H，dd)，7.74-7.68(1H，m)，7.58-7.41(4H，m)，7.05(1H，d)，4.68(2H，s)，1.36(9H，s)。

¹H?NMR?DMSO-d ₆：δ8.18-8.13(2H，m)，7.94(1H，dd)，7.86(1H，dd)，7.74-7.69(1H，m)，7.54-7.48(2H，m)，7.46(1H，dd)，7.39(1H，d)，7.06(1H，d)，4.70(2H，s)。

MS：APCI(-ve)437(M-1)。

Embodiment 10

(2S)-2-({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

I) (2S)-2-({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid uncle fourth Ester

The subhead compound utilizes the product of embodiment 9 steps (iii) to prepare by the method for embodiment 3 steps (i).

¹H?NMR?DMSO-d ₆：δ8.21-8.14(2H，m)，7.96(1H，dd)，7.89(1H，dd)，7.78-7.73(1H，m)，7.56-7.46(3H，m)，7.42(1H，d)，7.0(1H，d)，4.88(1H，q)，1.36-1.33(12H，m)。

Ii) (2S)-2-({ 5-chloro-2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

Title compound utilizes the product of step (ii) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ8.18-8.12(2H，m)，7.93(1H，dd)，7.87-7.79(2H，m)，7.53-7.47(2H，m)，7.42(1H，dd)，7.37(1H，d)，6.97(1H，d)，4.78(1H，q)，1.31(3H，s)。

MS：APCI(-ve)451(M-1)。

Embodiment 11

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

I) 1,1 '-disulfide group two (2-fluorobenzene)

With SULPHURYL CHLORIDE (0.7ml) at 0 ℃ of DCM (20ml) solution that dropwise adds to 2-fluoro thiophenol (1.5ml).Reaction mixture was stirred 30 minutes, then concentrating under reduced pressure.Resistates comes purifying by silica gel chromatography (using the isohexane wash-out), obtains subhead compound (1.7g), is oily matter.

MS：APCI(+ve)254(M+H)。

Ii) 4-bromo-2-fluoro-1-[(2-fluorophenyl) sulfenyl] benzene

4-bromo-2-fluoro-1-iodobenzene (1.67g) is added to THF (8ml) solution of the isopropyl-magnesium chloride (2.79ml, the THF solution of 2M) that is cooled to 0 ℃, restir 2h.Then, mixture is added to THF (5ml) solution of the product of step (i).Make reaction mixture reach RT, spend the night, then stirred 1 hour at 40 ℃, 50 ℃ of restir 1 hour.Reaction mixture is cooled to RT, with the ammonium chloride dilution, then uses extracted with diethyl ether.The ether cut is carried out drying (MgSO ₄), reduction vaporization then, the amount of getting is 1.9g, it is not in the situation that be further purified directly and use.

MS：APCI(+ve)302(M+H)。

Iii) 4-bromo-2-fluoro-1-[(2-fluorophenyl) alkylsulfonyl] benzene

With MCPBA (2.58g) at 0 ℃ of DCM (25ml) solution that adds to the product (1.8g) of step (ii).Make reaction mixture reach RT, then stirred 23 hours.Reaction mixture metabisulfite solution and NaHCO ₃Solution washing, dry (MgSO ₄), reduction vaporization then.Resistates comes purifying by silica gel chromatography (use the isohexane wash-out, then use 4: 1 isohexane/eluent ethyl acetates), obtains subhead compound (0.71g), is white solid.

¹H?NMR?CDCl ₃：δ8.16(1H，t)，8.05(1H，t)，7.67-7.62(1H，m)，7.53(1H，d)，7.37(1H，d)，7.31(1H，d)，7.13(1H，t)。

Iv) 3 ', 5-two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl]-2-methoxyl biphenyl

The subhead compound utilizes the product of step (iii) and 5-fluoro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

V) 3 ', 5-two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl] biphenyl-2-alcohol

The subhead compound utilizes the product of step (iv) to prepare by the method for embodiment 2 steps (iii).

MS：APCI(-ve)363(M-H)。

Vi) (2R)-and the 2-{[(4-aminomethyl phenyl) alkylsulfonyl] the oxygen base } methyl propionate

Acetonitrile (33ml) solution of (R)-(+)-methyl lactate (6.66g) is cooled to 5 ℃, then adds triethylamine (9.8ml), next add trimethylamine hydrochloride (0.62g).Dropwise add acetonitrile (33ml) solution of extra Tosyl chloride (11.6g), last 20 minutes, simultaneously temperature is remained under 5 ℃.Reaction mixture is filtered, then concentrated.Add ether and water, organic fraction is carried out drying (MgSO ₄), then vacuum concentration obtains subhead compound (13.71g), is yellow oil.

¹H?NMR?CDCl ₃：δ7.82(2H，d)，7.35(2H，d)，4.95(1H，q)，3.67(3H，s)，2.45(3H，s)，1.51(3H，d)。

Vii) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) methyl propionate

The product (175mg) of step (v), the product (124mg) of step (vi) and acetonitrile (10ml) solution of salt of wormwood (133mg) are filled to flask, then spend the night 65 ℃ of stirrings.With the reaction mixture cooling, then water (20ml) dilution uses extracted with diethyl ether.The organic extract liquid salt water washing that merges, dry (MgSO ₄), concentrating under reduced pressure then.Resistates comes purifying by silica gel chromatography (use the isohexane wash-out, then use 4: 1 isohexane/eluent ethyl acetates), obtains subhead compound (121mg), is colorless oil.

MS：APCI(+ve)451(M+H)。

Viii) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(2-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

Product (121mg), 1M NaOH (0.4ml), THF (2ml) and the DCM (2ml) of step (vii) are filled to flask, stirred 3 hours, then concentrating under reduced pressure.Resistates is dissolved among the EtOAc, washs with 1MHCl.Organic phase is carried out dry MgSO ₄), then concentrating under reduced pressure obtains title compound (63mg), is white solid.

¹H?NMR?DMSO-d ₆：δ8.12(2H，q)，7.89-7.8(2H，m)，7.75(1H，dd)，7.56(1H，t)，7.47(1H，dd)，7.36(1H，dd)，7.24(1H，td)，7.03(1H，dd)，4.96(1H，q)，1.43(3H，d)。

MS：APCI(-ve)435(M-H)。

Embodiment 12

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

I) 4-bromo-2-fluoro-1-[(4-p-methoxy-phenyl) alkylsulfonyl] benzene

The subhead compound utilizes 4-bromo-2-fluorobenzene SULPHURYL CHLORIDE and phenylmethylether to prepare by the method for embodiment 9 steps (i).

¹H?NMR?DMSO-d ₆：δ7.94(1H，t)，7.89-7.85(2H，m)，7.8(1H，dd)，7.71-7.68(1H，m)，7.18-7.14(2H，m)，3.84(3H，s)。

Ii) 2-(benzyl oxygen base)-3 ', 5-two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl

The subhead compound utilizes the product of step (iii) and [2-(benzyl oxygen base)-5-fluorophenyl] boric acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.01(1H，t)，7.9(2H，d)，7.64(1H，dd)，7.58(1H，dd)，7.33-7.29(6H，m)，7.26-7.23(2H，m)，7.2-7.16(2H，m)，5.12(2H，s)，3.85(3H，s)。

Iii) 3 ', 5-two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-alcohol

The product (838mg) of step (ii) and acetic acid (30ml) suspension of 10%Pd/C (200mg) were stirred 30 minutes under the hydrogen of 2 bar pressures.Remove by filter catalyzer, then filtrate is evaporated, obtain subhead compound (630mg).

¹H?NMR?DMSO-d ₆：δ8.04-7.99(1H，m)，7.91(2H，dd)，7.68(1H，dd)，7.6(1H，dd)，7.23(1H，dd)，7.18(2H，dd)，7.09(1H，td)，6.95(1H，dd)，3.85(3H，s)。

Iv) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid The tert-butyl ester

¹H?NMR?DMSO-d ₆：δ8.08-8.02(1H，m)，7.93(2H，dd)，7.73(1H，dd)，7.68(1H，dd)，7.33(1H，dd)，7.28-7.15(3H，m)，7.02(1H，dd)，4.91(1H，q)，3.86(3H，s)，1.41(3H，d)，1.34(9H，s)。

V) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

¹H?NMR?DMSO-d ₆：δ8.01(1H，t)，7.92(2H，d)，7.86(1H，d)，7.78(1H，dd)，7.26(1H，dd)，7.20-7.12(3H，m)，6.96(1H，dd)，4.74(1H，q)，3.85(3H，s)，1.34(3H，d)。

MS：APCI(-ve)447(M-1)。

Embodiment 13

(2S)-2-({ 3 ', 5-, two fluoro-4 '-[(3-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

I) 1,1 '-disulfide group two (3-fluorobenzene)

The subhead compound utilizes the 3-fluoro thiophenol to prepare by the method for embodiment 11 steps (i).

¹H?NMR?CDCl ₃：δ7.3-7.21(6H，m)，6.92(2H，tt)。

Ii) 4-bromo-2-fluoro-1-[(3-fluorophenyl) alkylsulfonyl] benzene

With anhydrous acetonitrile (25ml) solution of the product (1.98g) of step (i) and Isopentyl nitrite (1.6ml) 50 ℃ of stirrings.Dropwise add 4-bromo-2-fluoroaniline (1.23g), reaction mixture is stirred 2h, then concentrating under reduced pressure at 60 ℃.Resistates (2.1g) is dissolved among the DCM (25ml), then dropwise adds MCPBA (6g) at 0 ℃.With reaction mixture in stirred overnight at room temperature.Reaction mixture metabisulfite solution and NaHCO ₃Solution washing, dry (MgSO ₄), reduction vaporization then.Resistates comes purifying by silica gel chromatography (with 9: 1 isohexane/eluent ethyl acetates), obtains subhead compound (0.67g), is white solid.

¹H?NMR?CDCl ₃：δ7.96(1H，td)，7.8(1H，dq)，7.7(1H，dq)，7.56-7.49(2H，m)，7.33(2H，dd)。

Iii) 3,5 '-two fluoro-2 '-methoxyl biphenyl-4-base 3-fluorophenyl sulfone

The subhead compound utilizes the product of step (ii) and 5-fluoro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?CDCl ₃：δ8.10(1H，t)，7.85(1H，d)，7.75(1H，d)，7.54(1H，td)，7.46(1H，dd)，7.36-7.3(2H，m)，7.07(1H，ddd)，7.01(1H，dd)，6.92(1H，dd)，3.79(3H，m)。

Iv) 3 ', 5-two fluoro-4 '-[(3-fluorophenyl) alkylsulfonyl] biphenyl-2-alcohol

The subhead compound utilizes the product of step (iii) to prepare by the method for embodiment 2 steps (iii).

MS：APCI(-ve)363(M-H)。

V) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(3-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) methyl propionate

The subhead compound utilizes the product of step (iv) and the product of embodiment 11 steps (vi) to prepare by the method for embodiment 11 steps (vii).

¹H?NMR?CDCl ₃：δ8.11(1H，t)，7.86(2H，d)，7.76(1H，d)，7.58-7.51(2H，m)，7.47(1H，dd)，7.33(1H，dd)，7.04-6.98(2H，m)，6.82-6.77(1H，m)，4.72(1H，q)，3.72(3H，s)，1.51(3H，d)。

Vi) (2S)-2-({ 3 ', 5-, two fluoro-4 '-[(3-fluorophenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) propionic acid

Title compound utilizes the product of step (v) to prepare by the method for embodiment 11 steps (viii).

¹H?NMR?DMSO-d ₆：δ8.1(1H，t)，7.87-7.736(5H，m)，7.67(1H，td)，7.33(1H，dd)，7.24(1H，td)，7.03(1H，dd)，4.96(1H，q)，1.43(3H，d)。

MS：APCI(-ve)435(M-H)。

Embodiment 14

({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2 '-methyl diphenyl-2-yl } oxygen base) acetic acid

I) 4-bromo-3-aminomethyl phenyl 4-fluorophenyl sulfone

The subhead compound utilizes 4-bromo-3-toluene sulfonyl chloride and fluorobenzene to prepare by the method for embodiment 9 steps (i).

¹H?NMR?CDCl ₃：δ7.97-7.92(2H，m)，7.77(1H，d)，7.67(1H，d)，7.59(1H，dd)，7.19(2H，t)，2.45(3H，s)。

Ii) 5 '-chloro-4-[(4-fluorophenyl) alkylsulfonyl]-2 '-methoxyl group-2-methyl diphenyl

MS：APCI(+ve)391(M+H)。

Iii) 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2 '-methyl diphenyl-2-alcohol

MS：APCI(-ve)375(M-H)。

Iv) ({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2 '-methyl diphenyl-2-yl } oxygen base) tert.-butyl acetate

MS：APCI(+ve)435(M-tBu)。

V) ({ 5-chloro-4 '-[(4-fluorophenyl) alkylsulfonyl]-2 '-methyl diphenyl-2-yl } oxygen base) acetic acid

¹H?NMR?DMSO-d ₆：δ8.10(2H，ddd)，7.89(1H，d)，7.8(1H，dd)，7.49(2H，tt)，7.43-7.39(2H，m)，7.20(1H，d)，6.99(1H，d)，4.66(2H，s)，2.2(3H，s)。

MS：APCI-ve?447(M-1)。

Embodiment 15

(2S)-and 2-{[2 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

I) 4-bromo-3-chlorophenyl phenyl sulfone

The subhead compound utilizes 4-bromo-3-chlorobenzene sulfonyl chloride and benzene to prepare by the method for embodiment 9 steps (i).

¹H?NMR?DMSO-d ₆：δ8.19(1H，d)，8.05-8.03(3H，m)，7.83(1H，dd)，7.74(1H，t)，7.65(2H，t)。

Ii) 2-chloro-5 '-fluoro-2 '-methoxyl biphenyl-4-base phenylsulfone

¹H?NMR?DMSO-d ₆：δ8.11-8.07(3H，m)，7.96(1H，dd)，7.78-7.73(1H，m)，7.68(2H，t)，7.59(1H，d)，7.28(1H，td)，7.16-7.11(2H，m)，3.69(3H，s)。

Iii) 2 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ9.68(1H，s)，8.09-8.06(3H，m)，7.94(1H，dd)，7.77-7.72(1H，m)，7.7-7.65(2H，m)，7.59(1H，d)，7.10(1H，td)，7.02(1H，dd)，6.92(1H，dd)。

Iv) (2S)-and 2-{[2 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } the propionic acid tert-butyl ester

¹H?NMR?DMSO-d ₆：δ8.12-8.06(3H，m)，8.019-7.95(1H，m)，7.79-7.72(1H，m)，7.67(3H，t)，7.25(1H，td)，7.17(1H，dd)，6.95(1H，dd)，4.77-4.68(1H，m)，1.32(9H，s)，1.26(3H，d)。

V) (2S)-and 2-{[2 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

¹H?NMR?DMSO-d ₆：δ8.12-8.07(3H，m)，7.97(1H，dd)，7.8-7.65(4H，m)，7.21(1H，td)，7.14(1H，dd)，6.96(1H，dd)，4.69-4.6(1H，m)，1.25(3H，d)。

MS：APCI-ve?433(M-1)。

Embodiment 16

({ 3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid

I) 3-fluoro-2 '-methoxyl group-5 '-methyl diphenyl-4-base 4-fluorophenyl sulfone

The subhead compound utilizes the product of embodiment 4 steps (i) and (2-methoxyl group-5-aminomethyl phenyl) boric acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.10-8.03(3H，m)，7.60(1H，dd)，7.55-7.50(3H，m)，7.23(1H，dd)，7.20(1H，d)，7.04(1H，d)，3.74(3H，s)，2.28(3H，s)。

Ii) 3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-alcohol

¹H?NMR?DMSO-d ₆：δ9.71(1H，s)，8.09-8.02(3H，m)，7.68(1H，dd)，7.59(1H，dd)，7.54-7.49(2H，m)，7.16(1H，d)，7.05(1H，dd)，6.86(1H，d)，2.23(3H，s)。

Iii) ({ 3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) tert.-butyl acetate

The subhead compound utilizes the product of step (ii) to prepare by the method for embodiment 1 step (iii).

¹H?NMR?DMSO-d ₆：δ8.09-8.04(3H，m)，7.69-7.63(2H，m)，7.55-7.49(2H，m)，7.24(1H，d)，7.19(1H，dd)，6.93(1H，d)，4.67(2H，s)，2.28(3H，s)，1.38(9H，s)。

Iv) ({ 3 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid

The subhead compound utilizes the product of step (iii) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ8.1-8.03(3H，m)，7.71-7.67(2H，m)，7.55-7.49(2H，m)，7.23(1H，d)，7.19(1H，dd)，6.95(1H，d)，4.71(2H，s)，2.27(3H，s)。

MS：APCI-ve?417(M-1)。

Embodiment 17

({ 5-chloro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid

I) 1-bromo-4-[(4-p-methoxy-phenyl) alkylsulfonyl] benzene

The subhead compound utilizes 4-bromobenzene sulfonyl chloride and phenylmethylether to prepare by the method for embodiment 9 steps (i).

¹H?NMR?DMSO-d ₆：δ7.91-7.87(2H，m)，7.86-7.80(4H，m)，7.16-7.12(2H，m)，3.83(3H，s)。

The subhead compound utilizes the product of step (i) and [2-(benzyl oxygen base)-5-chloro-phenyl-] boric acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ7.95-7.91(4H，m)，7.77-7.74(2H，m)，7.43(1H，dd)，7.40(1H，d)，7.31-7.29(5H，m)，7.23(1H，d)，7.16-7.13(2H，m)，5.14(2H，s)，3.83(3H，s)。

The subhead compound utilizes the product of step (ii) and the acetic acid solution of 10%Pd/C to prepare by the method for embodiment 12 steps (iii).

¹H?NMR?DMSO-d ₆：δ7.95-7.89(4H，m)，7.76(2H，dd)，7.32(1H，d)，7.25(1H，dd)，7.16-7.11(2H，m)，6.97(1H，d)，3.83(3H，d)。

Iv) ({ 5-chloro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) tert.-butyl acetate

The subhead compound utilizes product and the bromo-acetic acid tert-butyl of step (iii) to prepare by the method for embodiment 1 step (iii), and it is not in the situation that further characterize directly use in step (v).

V) ({ 5-chloro-4 '-[(4-p-methoxy-phenyl) alkylsulfonyl] biphenyl-2-yl } oxygen base) acetic acid

The subhead compound utilizes the product of step (iv) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ7.96-7.91(4H，m)，7.81-7.78(2H，m)，7.42-7.39(2H，m)，7.15(2H，dd)，7.06(1H，dd)，4.74(2H，s)，3.83(3H，s)。

Embodiment 18

({ 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-yl } oxygen base) acetic acid

I) 1,1 '-disulfide group two (2-chlorobenzene)

Hexamethyldisilazane (4.4ml) is added to the 2-chlorothio-phenol (2.0ml) of stirring and the anhydrous acetonitrile of DMSO (3.7ml) in room temperature.Behind the 2h white precipitate is filtered, then washing (cold acetonitrile) obtains subhead compound (2.27g), is white solid.

¹H?NMR?CDCl ₃：δ7.56(2H，dd)，7.36(2H，dd)，7.26-7.14(4H，m)。

Ii) 4-bromo-1-[(2-chloro-phenyl-) alkylsulfonyl]-the 2-fluorobenzene

The subhead compound utilizes the product of step (i) and 4-bromo-2-fluoroaniline to prepare by the method for embodiment 13 steps (ii).

¹H?NMR?CDCl ₃：δ8.38(1H，dt)，8.10(1H，dd)，7.60-7.51(3H，m)，7.45(1H，dd)，7.29(1H，dd)。

Iii) the 2-chloro-phenyl-3,5 '-two fluoro-2 '-methoxyl biphenyl-4-base sulfone

The subhead compound utilizes the product of step (ii) and 5-fluoro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii), and it is not in the situation that further characterize directly use in step (iv).

Iv) 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-alcohol

The subhead compound utilizes product and the boron tribromide of step (iii) to prepare by the method for embodiment 2 steps (iii).

MS：MM(-ve)379(M-H)。

V) ({ 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-yl } oxygen base) tert.-butyl acetate

The subhead compound utilizes the product of step (iv) to prepare by the method for embodiment 1 step (iii), and it is not in the situation that further characterize directly use in step (iv).

Vi) ({ 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-yl } oxygen base) acetic acid

Title compound utilizes the product of step (v) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ8.32(1H，d)，8.14(1H，t)，7.82-7.67(5H，m)，7.36(1H，dd)，7.24(1H，td)，7.09(1H，dd)，4.74(2H，s)。

MS：MM(-ve)437(M-H)。

Embodiment 19

(2S)-and 2-[{3 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

I) 4-bromo-2-chloro-1-(phenyl sulfonyl) benzene

The subhead compound utilizes 4-bromo-2-chlorobenzene sulfonyl chloride and benzene to prepare by the method for embodiment 9 steps (i).

MS：MM(-ve)331(M-H)。

Ii) 3 '-chloro-5-fluoro-2-methoxyl group-4 '-(phenyl sulfonyl) biphenyl

¹H?NMR?DMSO-d ₆：δ8.37(1H，dd)，8.00(2H，dd)，7.61(3H，dd)，7.53(2H，td)，7.07(1H，ddd)，7.02(1H，dd)，6.92(1H，dd)，3.79(3H，s)。

Iii) 3 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

MS：MM(-ve)361(M-H)。

Iv) (2S)-and 2-{[3 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } methyl propionate

The subhead compound utilizes the product of step (iii) and the product of embodiment 11 steps (vi) to prepare by the method for embodiment 11 steps (vii).

MS：MM(+ve)449(M+H)。

V) (2S)-and 2-{[3 '-chloro-5-fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] the oxygen base } propionic acid

Title compound utilizes the product of step (iv) to prepare by the method for embodiment 11 steps (viii).

¹H?NMR?DMSO-d ₆：δ8.32(1H，d)，7.98-7.96(3H，m)，7.93(1H，dd)，7.76(1H，tt)，7.67(2H，t)，7.35(1H，dd)，7.23(1H，td)，7.03(1H，dd)，4.95(1H，q)，1.42(3H，d)。

MS：MM(-ve)433(M-H)。

Embodiment 20

({ 4 '-[(3-chloro-phenyl-) alkylsulfonyl]-2 ', 5-DfBP-2-yl } oxygen base) acetic acid

I) 1,1 '-disulfide group two (3-chlorobenzene)

The subhead compound utilizes the 3-chlorothio-phenol to prepare by the method for embodiment 11 steps (i).

MS：MM(+ve)287(M+H)。

Ii) 1-bromo-4-[(3-chloro-phenyl-) alkylsulfonyl]-the 2-fluorobenzene

The subhead compound utilizes the product of step (i) and 4-bromo-3-fluoroaniline to prepare by the method for embodiment 13 steps (ii).

¹H?NMR?CDCl ₃：δ7.91(1H，t)，7.82(1H，dt)，7.74(1H，dd)，7.68(1H，dd)，7.61(1H，dd)，7.59-7.56(1H，m)，7.48(1H，t)。

Iii) the 3-chloro-phenyl-2,5 '-two fluoro-2 '-methoxyl biphenyl-4-base sulfone

MS：APCI(-ve)393(M-H)。

Iv) 4 '-[(3-chloro-phenyl-) alkylsulfonyl]-2 ', 5-DfBP-2-alcohol

MS：APCI(-ve)381(M-H)。

V) ({ 4 '-[(3-chloro-phenyl-) alkylsulfonyl]-2 ', 5-DfBP-2-yl } oxygen base) tert.-butyl acetate

The subhead compound utilizes the product of step (iv) to prepare by the method for embodiment 1 step (iii).

¹H?NMR?DMSO-d ₆：δ8.10(1H，t)，7.98(2H，dd)，7.55-7.49(3H，m)，7.45(1H，dd)，7.07-7.02(2H，m)，6.80(1H，dd)，4.48(2H，s)，1.44(9H，s)。

Vi) ({ 4 '-[(3-chloro-phenyl-) alkylsulfonyl]-2 ', 5-DfBP-2-yl } oxygen base) acetic acid

¹H?NMR?DMSO-d ₆：δ8.09(1H，t)，8.00(2H，t)，7.77-7.72(4H，m)，7.32(1H，dd)，7.24(1H，td)，7.09(1H，dd)，4.74(2H，s)。

MS：MM(-ve)437(M-H)。

Embodiment 21

({ 2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid

I) 2-fluoro-2 '-methoxyl group-5 '-methyl diphenyl-4-base 4-fluorophenyl sulfone

The subhead compound utilizes the product of embodiment 9 steps (i) and 5-methyl-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii).

¹H?NMR?DMSO-d ₆：δ8.00(2H，ddd)，7.73(1H，dd)，7.66(1H，dd)，7.49(1H，dd)，7.24-7.18(3H，m)，7.01(1H，d)，6.89(1H，d)，3.76(3H，s)，2.31(3H，s)。

Ii) 2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-alcohol

MS：MM(-ve)360(M-H)。

Iii) ({ 2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) tert.-butyl acetate

MS：MM(-ve)472(M-H)。

V) ({ 2 '-fluoro-4 '-[(4-fluorophenyl) alkylsulfonyl]-5-methyl diphenyl-2-yl } oxygen base) acetic acid

Title compound utilizes the product of step (iii) to prepare by the method for embodiment 1 step (iv).

¹H?NMR?DMSO-d ₆：δ8.14(2H，ddd)，7.90(1H，dd)，7.84(1H，dd)，7.68(1H，t)，7.50(2H，dd)，7.20(1H，dd)，7.09(1H，s)，6.90(1H，d)，4.62(2H，s)，2.22(3H，s)。

MS：MM(-ve)417(M-H)。

Embodiment 22

{ [3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

I) 3 '-fluoro-2-methoxyl group-5-methyl-4 '-(phenyl sulfonyl) biphenyl

The subhead compound utilizes the product of embodiment 2 steps (i) and (2-methoxyl group-5-aminomethyl phenyl) boric acid to prepare by the method for embodiment 2 steps (ii).

MS：ES+ve?357(M+1)。

Ii) 3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-alcohol

MS：APCI-ve?341(M-1)。

Iii) { [3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } tert.-butyl acetate

MS:APCI-ve 401 (the M-[tertiary butyl]).

Iv) { [3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

¹H?NMR?DMSO-d ₆：δ8.06(1H，t)，7.99(2H，d)，7.77(1H，tt)，7.70-7.66(4H，m)，7.23(1H，d)，7.18(1H，dd)，6.94(1H，d)，4.71(2H，s)，2.27(3H，s)。

MS：APCI-ve?399(M-1)。

Embodiment 23

{ [5-chloro-3 ', 5 '-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

I) the 4-bromo-2,6-difluorophenyl phenylsulfone

With anhydrous acetonitrile (20ml) solution of Diphenyl disulfide ether (1.26g) and Isopentyl nitrite (1.2ml) 50 ℃ of stirrings.Dropwise add 4-bromo-2,6-difluoroaniline (1.0g) stirs 2h, then concentrating under reduced pressure with reaction mixture at 60 ℃.Resistates (2.1g) is dissolved in the acetic acid (7.5ml), then adds hydrogen peroxide (0.7ml, the aqueous solution of 30% (w/w)), mixture is spent the night 100 ℃ of stirrings.Add ice, with mixture restir 30 minutes, then beige solid (0.76g) is filtered out, it is not in the situation that be further purified and be used for next step.

Ii) 5 '-chloro-3,5-two fluoro-2 '-methoxyl biphenyl-4-base phenylsulfone

The subhead compound utilizes the product of step (i) and 5-chloro-2-methoxyphenylboronic acid to prepare by the method for embodiment 2 steps (ii), and it is not in the situation that further characterize directly use in step (iv).

MS：MM(-ve)394(M-H)。

Iii) 4 '-[(2-chloro-phenyl-) alkylsulfonyl]-3 ', 5-DfBP-2-alcohol

The subhead compound utilizes product and the boron tribromide of step (ii) to prepare by the method for embodiment 2 steps (iii).

MS：MM(-ve)379(M-H)。

Iv) { [5-chloro-3 ', 5 '-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } tert.-butyl acetate

The subhead compound utilizes the product of step (iii) to prepare by the method for embodiment 1 step (iii), and it is not in the situation that be further purified directly use in step (iv).

MS：ES(+ve)495(M+H)。

V) { [5-chloro-3 ', 5 '-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid

¹H?NMR?DMSO-d ₆：δ8.04(2H，d)，7.81(1H，tt)，7.71(2H，t)，7.65(1H，s)，7.62(1H，s)，7.54(1H，d)，7.46(1H，dd)，7.12(1H，d)，4.80(2H，s)。

MS：MM(-ve)437(M-H)。

The rat pharmacokinetic data

IV and PO rat pharmacokinetic study

Test sample is mixed with 1mg/ml in suitable solvent, then gives Sprague Dawley rat through tail vein (IV, 1ml/kg) or per os (PO, 3ml/kg).Collect blood sample at a series of time points from tail vein (opposition side of IV administration), and place it on ice.Blood sample is carried out centrifugal, then collect blood plasma, be used for analyzing.Then, plasma sample utilizes MS/MS to analyze, and determines the concentration of parent compound from typical curve.Plasma concentration-temporal mapping utilization is purchased software WinNonLin 3.1 (Pharsight, Mountain View, CA) and analyzes.Determined pharmacokinetic parameter (such as clearance rate, distribution volume and transformation period).Formula (I) compound has＞transformation period of 2.5 hours.

Pharmacology data

Ligand binding is measured

[ ³H] PGD ₂Available from Perkin Elmer Life Sciences, its specific activity is 100-210Ci/mmol.All other chemical substances all are AG.

The HEK cell of expressing rhCRTh2/G α 16 is kept among the DMEM routinely, and described DMEM contains 10% foetal calf serum (HyClone), 1mg/ml Geneticin, 2mM L-glutaminate and 1% non-essential amino acid.In order to carry out film preparation, the HEK cell of the transfection of adhesion is cultivated in factory's (Fisher, catalog number (Cat.No.) are TKT-170-070E) in two layers of tissue grown to fusion.The highest level of expression of receptor was induced by adding the 500mM Sodium propanecarboxylate at last 18 hours that cultivate.The cell of adhesion phosphate buffered saline buffer (PBS, the 50ml/ cell factory) then washing once separates the cell of adhesion by add the ice-cold film homogenize damping fluid [20mM HEPES (pH 7.4), 0.1mM dithiothreitol (DTT), 1mMEDTA, 0.1mM phenyl methyl sulfonic acid fluoride and 100 μ g/ml bacitracins] of 50ml to each cell factory.Cell in the fresh film homogenize damping fluid of half initial volume, then utilizes the Polytron homogenizer to carry out fragmentation (2 * 20 seconds) its Eddy diffusion by depositing in centrifugal 10 minutes with 220 * g at 4 ℃, and test tube is remained in the ice.Broken cell by not removing with 220 * g at 4 ℃ in centrifugal 10 minutes, and then the film fraction by depositing with 90000 * g at 4 ℃ in centrifugal 30 minutes.With regard to each cell factory, final precipitation Eddy diffusion in the film homogenize damping fluid of 4ml, is then measured protein content.Film is stored in-80 ℃ of temperature with the form of suitable five equilibrium thing.

All mensuration are all carried out in hole NBS plate (Fisher) of the transparent white ends 96 of Corning.The HEK cytolemma that will contain CRTh2 before measuring is coated on the SPA PVT WGA pearl (Amersham).In order to apply, 4 ℃ of overnight incubation, constant speed stirs simultaneously with film and pearl (being generally 25 μ g membranin/mg pearls).The best concentration that applies depends on every batch of film.Pearl deposits by centrifugal (at 4 ℃ with centrifugal 7 minutes of 800 * g), with measuring damping fluid (50mM HEPES pH 7.4 contains the 5mM magnesium chloride) washing once, at last with its Eddy diffusion in measuring damping fluid, bead concentration is 10mg/ml.

Every part of mensuration all contains the 6.25nM[of 20 μ l ³H] PGD ₂, SPA pearl that 20 μ l films are saturated (the two is all in measuring damping fluid) and 10 μ l compound solution or 13,14-dihydro-15-ketone group PGD ₂(DK-PGD ₂, be used for determining non-specific binding, Cayman Chemical Company).

With compound and DK-PGD ₂Be dissolved among the DMSO, then in identical solvent, be diluted to 100 * required ultimate density.Add and measure damping fluid, the ultimate density that makes DMSO is 10% (compound is 10 * required ultimate density now), and this is the solution that adds to assay plate.With assay plate incubated at room 2 hours, then at Wallac Microbeta liquid scintillation counter counting (1 minute/hole).

Formula (I) compound has＞8.5 pIC ₅₀Value.

Particularly, the pIC of embodiment 7 ₅₀Value is the pIC of 8.5, embodiment 8 ₅₀Value is 8.8, and the pIC of embodiment 15 ₅₀Value is 8.8.

Claims

1. formula (I) compound or pharmaceutically acceptable salt thereof:

Wherein

A is hydrogen, halogen or CF ₃

D is hydrogen, halogen or methyl;

X is chlorine, fluorine or methyl;

Y is chemical bond;

Z is phenyl, and described phenyl is optional by halogen or C _1-6Alkoxyl group replaces;

R ¹And R ²Independent expression hydrogen or methyl.

2. the compound of claim 1, wherein A and D independently are selected from hydrogen and halogen.

3. the compound of claim 1, wherein Z is phenyl, described phenyl is optional to be replaced by halogen.

4. the compound of claim 1, wherein Z is phenyl, described phenyl is optional to be replaced by fluorine.

5. the formula of claim 1 (I) compound or pharmaceutically acceptable salt thereof, described compound is selected from:

{ [5-chloro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid;

{ [3 '-fluoro-5-methyl-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid; With

{ [5-chloro-3 ', 5 '-two fluoro-4 '-(phenyl sulfonyl) biphenyl-2-yl] oxygen base } acetic acid.

6. the compound or pharmaceutically acceptable salt thereof of claim 1, described compound is formula (IA):

7. the compound of claim 6, wherein said compound is free alkali form.

In the claim 1 to 7 each formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the treatment by the purposes in the medicine of prostaglandin mediated disease.

In the claim 1 to 7 each formula (I) compound or pharmaceutically acceptable salt thereof for the preparation for the treatment of by the purposes in the medicine of the disease of PGD2 mediation.

In the claim 1 to 7 each formula (I) compound or pharmaceutically acceptable salt thereof for the preparation of the treatment respiratory system disease medicine in purposes.

11. the purposes of claim 10, wherein said respiratory system disease are asthma or rhinitis.

12. formula (II) compound:

Wherein

A is hydrogen, halogen or CF ₃

D is hydrogen, halogen or methyl;

X is chlorine, fluorine or methyl;

Y is chemical bond;

R ¹And R ²Independent expression hydrogen or methyl;

R ⁴Be C ₁-C ₁₀Alkyl.