HK1090635B

HK1090635B - Substituted 3-sulfur indoles

Info

Publication number: HK1090635B
Application number: HK06111158.9A
Authority: HK
Inventors: Roger Bonnert; Rukhsana Rasul
Original assignee: 阿斯利康(瑞典)有限公司
Priority date: 2003-05-27
Filing date: 2004-05-25
Publication date: 2012-06-29

Description

Substituted 3-thioindoles

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

EPA1170594 discloses methods for identifying compounds useful in the treatment of diseases mediated by the orphan receptor CRTh2 ligand, prostaglandin D2. US5,486,525 discloses a series of indoles which are said to have PAF antagonist activity. It has now been unexpectedly found that certain indoleacetic acids are active at the CRTh2 receptor and are therefore expected to be potentially useful in the treatment of various respiratory diseases including asthma and COPD.

Thus in a first aspect the present invention provides compounds of formula (I) or pharmaceutically acceptable salts and solvates thereof:

wherein:

R¹is one or more substituents independently selected from NR⁴SO₂R⁵、NR⁴CO₂R⁶、NR⁴COR⁶、NR⁴SO₂NR⁵R⁶、NHSO₂R⁵、NHCO₂R⁶、NHCOR⁶、NHCONR⁴、NHSO₂NR⁵R⁶OR heteroaryl, the latter optionally being substituted by halogen, CN, OR⁷、C_1-3Alkyl (which may be optionally substituted with halogen atoms);

R²is hydrogen, halogen, CN, SO₂R⁴Or CONR⁵R⁶、CH₂OH、CH₂OR⁴Or C_1-7Alkyl, the latter optionally substituted by one OR more groups independently selected from halogen atoms, OR⁸And NR⁵R⁶S (O) wherein x is 0, 1 or 2_xR⁷Substituted by a substituent;

R³is aryl or heteroaryl, each optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, OH, SO₂R⁴、OR⁴、SR⁴、SOR⁴、SO₂NR⁵R⁶、CONR⁵R⁶、NR⁵R⁶、NHSO₂R⁴、NHCOR⁴、NHCO₂R⁴、NR⁷SO₂R⁴、NR⁷CO₂R⁴、 NR⁷COR⁴、C₂-C₆Alkenyl radical, C₂-C₆Alkynyl, C₁-₆Alkyl, the last three groups being optionally substituted by one OR more groups independently selected from halogen atoms, OR⁸And NR⁵R⁶S (O) wherein x is 0, 1 or 2_xR⁷Substituted by a substituent;

R⁴represents aryl, heteroaryl, or C_1-6Alkyl groups, each of which may be optionally substituted with one or more substituents independently selected from halogen atoms, alkyl groups, alkoxy,Aryl, heteroaryl, OR¹⁰、OH、NR¹¹R¹²、S(O)_xR¹³(wherein x is 0, 1 or 2), CONR¹⁴R¹⁵、NR¹⁴COR¹⁵、SO₂NR¹⁴R¹⁵、NR¹⁴SO₂R¹⁵CN, nitro;

R⁵and R⁶Independently represents a hydrogen atom, C_1-6Alkyl, OR aryl, OR heteroaryl, the last three groups may optionally be substituted by one OR more groups independently selected from halogen atoms, aryl, OR⁸And NR¹⁴R¹⁵、CONR¹⁴R¹⁵、NR¹⁴COR¹⁵、SO₂NR¹⁴R¹⁵、NR¹⁴SO₂R¹⁵(ii) a CN, nitro, C_1-3Alkyl (which may be optionally substituted with halogen atoms);

or

R⁵And R⁶Together with the nitrogen atom to which they are attached can form a 3-to 8-membered saturated heterocyclic ring optionally containing one or more S (O) s selected from O, x being 0, 1 or 2_x、NR¹⁶And the ring itself is optionally substituted by C_1-3Alkyl substitution;

R⁷and R¹³Independently represent C₁-C₆Alkyl, aryl or heteroaryl, all of which may be optionally substituted by halogen atoms;

R⁸represents a hydrogen atom, C (O) R⁹、C₁-C₆Alkyl (optionally substituted with halogen atoms or aryl), aryl or heteroaryl (optionally substituted with halogen);

R⁹、R¹⁰、R¹¹、R¹²、R¹⁴、R¹⁵each independently represents a hydrogen atom, C₁-C₆Alkyl, aryl or heteroaryl (all of which may be optionally substituted with halogen atoms); and

R¹⁶is hydrogen, C_1-4Alkyl, COC₁-C₄Alkyl or Y is O or NR⁷COYC of₁-C₄An alkyl group.

In the context of the present description, unless otherwise indicated, an alkyl or alkenyl group or an alkyl or alkenyl moiety in a substituent may be linear, branched or cyclic.

Aryl as defined in the specification may be phenyl or naphthyl.

Heteroaryl is defined as being a 5-7 membered aromatic ring or may be a 6, 6-or 6, 5-fused bicyclic ring containing one or more heteroatoms per ring selected from N, S and O. Examples include pyridine, pyrimidine, thiazole, oxazole, pyrazole, imidazole, furan, isoxazole, pyrrole, isothiazole and azulene, naphthyl, indene, quinoline, isoquinoline, indole, indolizine, benzo [ b ] furan, benzo [ b ] thiophene, 1H-indazole, benzimidazole, benzothiazole, benzoxazole, purine, 4H-quinolizine, cinnoline, phthalazine, quinazoline, quinoxaline, 1, 8-naphthyridine, pteridine, quinolone.

When R is⁵And R⁶When they may form a 3-to 8-membered saturated heterocyclic ring together with the nitrogen atom to which they are attached, examples include morpholine, thiomorpholine, azetidine, imidazolidine, pyrrolidine, piperidine and piperazine. Substituents can be present on the carbon or suitable nitrogen atoms of these rings.

Suitably R¹Is one or more substituents independently selected from NR⁴SO₂R⁵、NR⁴CO₂R⁶、NR⁴COR⁶、NR⁴SO₂NR⁵R⁶、NHSO₂R⁵、NHCO₂R⁶、NHCOR⁶、NHCONR⁴、NHSO₂NR⁵R⁶OR heteroaryl, the latter optionally being substituted by halogen, CN OR OR⁷And (4) substitution.

Suitably R¹Is one or more substituents independently selected from NR⁴SO₂R⁵、NR⁴CO₂R⁶、NR⁴COR⁶、NR⁴SO₂NR⁵R⁶、NHSO₂R⁵、NHCO₂R⁶、NHCOR⁶、NHSO₂NR⁵R⁶OR heteroaryl, the latter optionally being substituted by halogen, CN OR OR⁷And (4) substitution.

Preferably R¹Is NR⁴COR6⁴、NHSO₂R⁴、NHCOR⁶Or a heteroaryl group.

More preferably R¹Is NHSO₂Me or NR⁴COMe, NHCONH alkyl, NR⁴CO cyclopropyl, NHSO₂Heteroaryl, NHSO₂NMe₂、NHCONR⁴5-6 membered heteroaryl containing 1-2 heteroatoms. Most preferably R¹Is NHSO₂Me or NR⁴COMe, NHCONH alkyl, two methyl oxazole, pyrimidine or pyrazine. Even more preferably R¹Is nhcoome.

The R is¹The group can be present at any suitable position on the indole ring. Preferably the R¹Is in the 5-and/or 4-position.

Preferably R²Is C_1-6Alkyl or hydrogen, more preferably C_1-6Alkyl or hydrogen, still more preferably methyl or hydrogen. Most preferably R²Is methyl.

Preferably R³Is quinolinyl or phenyl, the latter being optionally substituted by halogen, alkoxy, SO₂R⁴More preferably the phenyl is substituted by chloro, methoxy, methyl sulfone or ethyl sulfone.

Substituents can be present in R³At any suitable position of the group. Preferably, if R is³Is phenyl, the substituents being in the 2, 3 and 4-positions. Most preferably a single substituent is present at the 4-position.

Preferred compounds of the invention include:

4- (acetylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -2-methyl-4- (5-pyrimidinyl) -1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -2-methyl-4-pyrazinyl-1H-indole-1-acetic acid

3- [ (2-chlorophenyl) thio ] -2-methyl-5- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (3-chlorophenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (3-methoxyphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (4-methoxyphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (2-trifluoromethylphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (8-quinolyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

3- [ (2- (methylethyl) phenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid

5- (acetylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

4- (Acetylethylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -4- [ cyclopropylcarbonyl) amino ] -2-methyl-1H-indole-1-acetic acid

4- (benzoylamino) -3- [ (4-chlorophenyl) thio ] - -2-methyl-1H-indole-1-acetic acid

4- (acetylamino) -3- [ (3-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -4- [ [ (dimethylamino) sulfonyl ] amino ] -2-methyl-1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -2-methyl-4- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl ] amino ] -1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -4- [ [ (dimethylamino) acetyl ] amino ] -2-methyl-1H-indole-1-acetic acid

4- (acetylamino) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

4- (acetylamino) -3- [ (2-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

4- (acetylamino) -2-methyl-3- [ [4- (ethylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

3- [ (4-chlorophenyl) thio ] -4- [ [ (ethylamino) carbonyl ] amino ] -2-methyl-1H-indole-1-acetic acid

3- [ [4- (methylsulfonyl) phenyl ] thio ] -4- (5-pyrimidinyl) -1H-indole-1-acetic acid

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -4- (2-thienyl) -1H-indole-1-acetic acid

4- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

4- (3-furyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

2-methyl-4- [ (methylsulfonyl) amino ] -3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

2-methyl-5- [ (methylsulfonyl) amino ] -3- [ [3- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

2-methyl-5- [ (methylsulfonyl) amino ] -3- [ [2- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (5-pyrimidinyl) -1H-indole-1-acetic acid

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (3-thienyl) -1H-indole-1-acetic acid

5- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (3-pyridyl) -1H-indole-1-acetic acid

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (1H-pyrazol-4-yl) -1H-indole-1-acetic acid

4- (acetylamino) -3- [ (4-cyanophenyl) thio ] -2-methyl-1H-indole-1-acetic acid

And pharmaceutically acceptable salts and solvates thereof.

Certain compounds of formula (I) can exist as stereoisomers. It is to be understood that the invention includes all geometric and optical isomers of the compounds of formula (I) and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the invention.

The compounds of formula (I) above may also be converted into pharmaceutically acceptable salts or solvates thereof, preferably base addition salts such as ammonium, sodium, potassium, calcium, aluminium, lithium, magnesium, zinc, benzathine (benzathine), chloroprocaine, choline, diethanolamine, ethanolamine, ethylenediamine, meglumine, tromethamine or procaine, or acid addition salts such as hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, oxalate, methanesulfonate or p-toluenesulfonate. Preferred salts include sodium and ammonium salts.

It will be appreciated by those skilled in the art that in the process of the present invention, certain functional groups in the starting materials or intermediate compounds may need to be protected with protecting groups. The preparation of the compounds of formula (I) may thus comprise the removal of one or more protecting groups at an appropriate stage. Protection and deprotection of functional Groups is well described in 'Protective Groups in organic Chemistry', Plenum Press (1973), edited by J.W.F.McOmie, and 'Protective Groups in organic Synthesis', third edition, Wiley-Interscience (1999), T.W.Greene and P.G.M.Wuts.

In another aspect of the invention there is provided a process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, which process comprises reacting a compound of formula (II):

wherein R is¹、R²And R³Is as defined for formula (I) or a protected derivative thereof,

with a compound of formula (IIA):

L-CH₂CO₂R¹⁷(IIA)

wherein R is¹⁷Is an alkyl group and L is a leaving group such as a halogen atom,

then optionally in any order as follows:

removal of the protecting group

An ester group R¹⁷Hydrolysis to the corresponding acid

Forming a pharmaceutically acceptable salt or solvate.

The reaction may be carried out in a suitable solvent such as THF using a base such as sodium hydride or the like. Suitable R¹⁷The radicals including C_1-6Alkyl groups such as methyl, ethyl or tert-butyl. Is suitable forL of (a) is a leaving group such as halogen, especially bromine. Preferably the compound of formula (IIA) is ethyl, methyl or tert-butyl bromoacetate.

Ester group R¹⁷The hydrolysis of (a) can be carried out by conventional procedures, for example by stirring with aqueous sodium hydroxide solution or trifluoroacetic acid.

It will be appreciated that certain functional groups may need to be protected with standard protecting groups. Protection and deprotection of functional Groups is illustrated, for example, in 'Protective Groups in organic chemistry' edited by J.W.F.Mc. Omie, Plenum Press (1973), and 'Protective Groups in organic Synthesis' of T.W.Greene and P.G M.Wuts, third edition, Wiley-Interscience (1999).

A compound of formula (II) wherein R¹Is NRSO₂R or NRC (O) R, obtainable by reacting a compound of formula (III) with an acylating agent such as acetyl chloride or sulfonyl chloride.

The compound of formula (III) can be prepared from the compound of formula (IV) by reaction with hydrogen and a suitable catalyst, preferably palladium or platinum on activated carbon in the presence of a polar solvent such as ethanol.

The compounds of formula (IV) can be prepared from compounds of formula (V) and formula (VI),

wherein R is¹、R²And R³Is as defined for formula (I).

Preferably the reaction is carried out using a chlorinating agent such as sulfonyl chloride or tert-butyl hypochlorite in a suitable solvent such as dichloromethane or THF.¹

The compounds of formulae (V) and (VI) are commercially available or can be prepared using standard chemical methods well known in the art.

Certain compounds of formula (I) can be prepared from compounds of formula (VII) wherein X ═ halogen, preferably bromine or iodine, by reaction with an organostannane (Stille coupling) or boronic acid (Suzuki coupling) using a palladium catalyst. Preferably the catalyst used is tetrakistriphenylphosphine palladium (0), or palladium (II) acetate in the presence of a phosphine ligand such as tri-o-tolylphosphine in a suitable solvent such as toluene or methanol at 80 ℃. Then R is¹⁷The groups were hydrolyzed as described previously.

The compound of formula (VII) is prepared from a compound of formula (II) and a compound of formula (IIA) according to the methods described previously:

a compound of formula (II) wherein X is halogen, is prepared by reacting a compound of formula (VIII) with a compound of formula (VI):

wherein R is¹、R²And R³Is as defined for formula (I).

The compounds of formula (II) can be prepared by reacting a compound of formula (IX) with a compound of formula (X), and then hydrolyzing the ester according to the methods previously described to synthesize a compound of formula (I):

wherein R is¹、R²And R³Or a protected derivative thereof, is as defined for formula (I). The reaction is carried out at room temperature in a suitable solvent in the presence of a halogen, preferably iodine, in a polar aprotic solvent such as DMF. The compounds of formula (IX) and formula (X) are commercially available or can be prepared by methods well known in the art.

The compounds of formula (I) have activity as pharmaceuticals, in particular as modulators of CRTh2 receptor activity, and can be used in the treatment (therapy or prophylaxis) of disorders due to PGD₂And conditions/diseases in human and non-human animals that are exacerbated or caused by excessive or irregular production of their metabolites.

The compounds of the present invention or pharmaceutically acceptable salts thereof may be used in the treatment of:

(1) (respiratory) -airway obstructive diseases include: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, intermittent and persistent and of all severity, and other causes of airway hyperreactivity; chronic Obstructive Pulmonary Disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung diseases and related diseases; allergic pneumonia; pulmonary fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonia, fibrosis complicated by antineoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitis and thrombotic disease of the pulmonary vasculature, and pulmonary hypertension; antitussive activity, including treatment of chronic and iatrogenic coughs with inflammation and airway secretosis; acute and chronic rhinitis including rhinitis medicamentosa and vasomotor rhinitis; allergic rhinitis, including rhinitis nervosa (pollinosis), has occurred for many years and in quarterly; nasal polyposis; acute viral infections include the common cold, and infections due to respiratory syncytial virus, influenza virus, coronavirus (including SARS) and adenovirus.

(2) Arthritis (bone and joint) with or including osteoarthritis/osteoarthrosis, primary and secondary to, for example, congenital hip dysplasia; cervical and lumbar spondylitis, lower back and neck pain; rheumatoid arthritis and still's disease; seronegative spondyloarthropathies including ankylosing spondylitis, psoriatic arthritis, reactive arthritis and undifferentiated spondyloarthropathy; pyoviral arthritis and other infection-related joint and bone diseases, such as tuberculosis, such as baud disease and bursitis syndrome; acute and chronic crystallization-induced synovitis including urate, calcium pyrophosphate deposition disease, and tendon, bursal and synovial inflammation associated with calcium apatite; behcet's disease; primary and secondary sjogren's syndrome; systemic sclerosis and topical scleroderma; systemic lupus erythematosus, mixed connective tissue disease, and undifferentiated connective tissue disease; inflammatory myopathies including dermatomyositis and polymyositis; polymalegia rheumatism; juvenile arthritis includes idiopathic inflammatory arthritis whether it is joint distribution and associated syndromes, or rheumatic fever and its systemic complications; vasculitis, including giant cell arteritis, takayasu arteritis, churg-strauss syndrome, polyarteritis nodosa, microscopic (microscopical) polyarteritis, and vasculitis associated with viral infections, hypersensitivity reactions, cryoglobulins, and pathological proteins; lower back pain; familial mediterranean fever, muckle-virs syndrome, and familial irish fever, Kikuchi disease; drug-induced arthalgias, tendonitis, and myopathy.

(3) (skin) psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed type hypersensitivity; vegetative and solar dermatitis; seborrheic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus, pyoderma gangrenosum, cutaneous sarcoidosis, discoid lupus erythematosus, pemphigus, pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, toxic erythema, cutaneous eosinophilia, alopecia areata, male pattern baldness, sjolt syndrome, Weeker-gram syndrome, erythema multiforme; cellulitis, infectious and non-infectious; panniculitis; cutaneous lymphomas, non-melanoma skin cancers and other dysplastic disorders; drug-induced disorders include fixed drug eruptions.

(4) (eye) blepharitis; conjunctivitis, including years of vernal allergic conjunctivitis; iritis; anterior and posterior uveitis; choroiditis; autoimmunity; degenerative and inflammatory diseases that infect the retina; ophthalmia, including sympathetic ophthalmia; sarcoidosis; infections, including viral, fungal, and bacterial infections.

(5) Glossitis, gingivitis, periodontitis (gastrointestinal tract); esophagitis, including reflux; eosinophilic gastroenteritis, mastocytosis, Crohn's disease, colitis including ulcerative colitis, proctitis, and pruritus ani; abdominal disorders, irritable bowel syndrome, and food-related allergies acting away from the bowel (e.g. migraine, rhinitis or eczema).

(6) (abdominal) hepatitis, including autoimmune, alcoholic and viral; liver fibrosis and cirrhosis; cholecystitis (cholecystitis); acute and chronic pancreatitis.

(7) (genitourinary) nephritis, including interstitial nephritis and glomerulonephritis; nephrotic syndrome; cystitis, including acute and chronic (interstitial) cystitis and henna ulcers; acute and chronic urethritis, prostatitis, epididymitis and salpingitis; vulvovaginitis; peyronie's disease; erectile dysfunction (both male and female).

(8) (allograft rejection) such as acute and chronic rejection by kidney, heart, liver, lung, bone marrow, skin or cornea transplants or blood transfusions; or chronic graft versus host disease;

(9) (CNS) alzheimer's disease and other dementing diseases including CJD and nvCJD; amyloidosis; multiple sclerosis and other demyelinating syndromes; cerebral atherosclerosis and vasculitis; temporal arteritis; myasthenia gravis; acute and chronic pain (acute, intermittent or persistent, whether of central or peripheral origin) including visceral pain, headache, flat headache, trigeminal neuralgia, joint and bone pain resulting from cancer and tumor invasion, neuropathic pain syndromes including diabetes, post-herpetic, and HIV-associated neuropathy; sarcoidosis neuroid; central and peripheral nervous system complications of malignancy, infectivity and autoimmune processes.

(10) Other autoimmune and allergic diseases include hashimoto's thyroiditis, graves ' addison ' disease, diabetes, idiopathic platelet purpura, hyper-IgE syndrome, antiphospholipid syndrome.

(11) Other diseases with inflammatory and immune components include acquired immunodeficiency syndrome (AIDS), leprosy, Securium syndrome, and neoplastic symptom syndrome.

(12) (cardiovascular); atherosclerosis, which affects the coronary and peripheral circulation; pericarditis; myocarditis, inflammatory and autoimmune heart diseases including myocardial sarcoidosis; ischemia (ischaemic) reperfusion injury; endocarditis, valvular inflammation, and aortic inflammation including infectious (e.g., syphilis); vasculitis; including phlebitis and thrombosis, including deep vein thrombosis and varicose complications.

(13) (oncology) the treatment of common cancers including prostate, breast, lung, ovarian, pancreatic, intestinal and colon, gastric, skin and brain tumors, and malignancies including those affecting the myelogenous (including leukemias) and lymphoproliferative systems such as hodgkin and non-hodgkin lymphomas; including the prevention and treatment of metastatic disease and tumor recurrence, as well as the symptomatic tumor syndrome.

(14) And PGD₂Or a disease associated with an elevated level of a metabolite thereof.

Accordingly, the present invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined for use in therapy.

Preferably the compounds of the invention are used for the treatment of diseases in which the chemokine receptors belong to the subfamily CRTh2 receptor.

Specific diseases to be treated with the compounds of the present invention are asthma, rhinitis and PGD₂Or other diseases in which the levels of metabolites thereof are elevated. Preferably, the compounds of the present invention are used for the treatment of asthma.

In a further aspect, the present invention provides the use of a compound of formula (I), as hereinbefore defined, and pharmaceutically acceptable salts or solvates thereof, in the manufacture of a medicament for use in the treatment, inter alia, of CRTh2 mediated diseases such as asthma and rhinitis.

The invention also relates to combination therapies wherein a compound of formula (I), or a pharmaceutically acceptable salt, solvate or in vivo hydrolysable ester thereof, or a pharmaceutical composition or formulation containing a compound of formula (I), is administered concurrently or sequentially with therapies and/or formulations for the treatment of any of the following diseases: asthma, allergic rhinitis, cancer, COPD, rheumatoid arthritis, psoriasis, inflammatory bowel disease, osteoarthritis or osteoporosis.

In particular, for the treatment of the inflammatory diseases rheumatoid arthritis, psoriasis, inflammatory bowelIn diseases, COPD, asthma and allergic rhinitis, the compounds of the present invention may be used in combination (combination) with agents such as TNF- α inhibitors such as anti-TNF monoclonal antibodies (e.g., Remicade, CDP-870 and D)₂E₇) And TNF receptor immunoglobulin molecules (such as enbrel. reg.), non-selective COX-1/COX-2 inhibitors (such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen, and ibuprofen, fenamic acids such as mefenamic acid, indomethacin, sulindac, apazone, phenylbutazone, such as phenylbutazone, salicylic acids such as aspirin), COX-2 inhibitors (such as meloxicam, celecoxib, rofecoxib, valdecoxib, and etoricoxib), low dose methotrexate, leflunomide; ciclesonide; hydroxychloroquine, d-penicillamine, auranofin or hydroxyzine or oral gold (oral gold).

The invention also relates to combinations of the compounds of the invention with the following agents (combination): leukotriene biosynthesis inhibitors, 5-lipoxygenase (5-LO) inhibitors or 5-lipoxygenase activating protein (FLAP) antagonists such as zileuton; ABT-761; fenleton (fenleuton); tibozaline; abbott-79175; abbott-85761; n- (5-substituted) -thiophen-2-alkylsulfonamide; 2, 6-di-tert-butylphenol hydrazone; methoxytetrahydropyrans such as ZenecaZD-2138; compound SB-210661; pyridyl-substituted 2-cyanonaphthalene compounds such as L-739,010; 2-cyanoquinoline compounds such as L-746,530; indole and quinoline compounds such as MK-591, MK-886, and BAYx 1005.

The invention also relates to the compounds of the invention and leukotriene LTB₄、LTC₄、LTD₄And LTE₄A combination of receptor antagonists selected from the group consisting of phenothiazin-3-ones such as L-651,392; amidino compounds such as CGS-25019 c; benzoxalamines such as ondansilast; benzathinamides such as BIIL 284/260; and compounds such as zafirlukast, arlukast, montelukast, pranlukast, vilelukast (MK-679), RG-12525, Ro-245913, ilakast (CGP45715A), and BAYx 7195.

The invention also relates to the combination of a compound of the invention and a PDE4 inhibitor, including an inhibitor of the isoform PDE 4D.

The invention also relates to the compounds of the invention and antihistamines H₁Combinations of receptor antagonists such as cetirizine, loratadine, desloratadine, fexofenadine, astemizole, azelastine, and chlorpheniramine.

The invention also relates to the compounds of the invention and to gastric protective H₂A combination of receptor antagonists.

The invention also relates to compounds of the invention and alpha₁-and α₂-a combination of adrenergic receptor agonists vasoconstrictor sympathomimetic agents such as propylhexedrine, phenylephrine, phenylpropanolamine, pseudoephedrine, naphazoline hydrochloride, oxymetazoline hydrochloride, tetrahydrozoline hydrochloride, xylometazoline hydrochloride, and ethylnorepinephrine hydrochloride.

The invention also relates to combinations of a compound of the invention with anticholinergic agents, such as ipratropium bromide; tiotropium bromide; oxitropibromoamine; pirenzepine; and telenzepine.

The invention also relates to compounds of the invention and beta₁-to beta₄-combinations of adrenergic receptor agonists such as isoproterenol, salbutamol, formoterol, salmeterol, terbutaline, metaproterenol, metamitron mesylate, and pirbuterol; or methylxanthines include theophylline and aminophylline; sodium cromoglycate; or muscarinic receptor (M1, M2, and M3) antagonists.

The invention also relates to a combination of a compound of the invention and insulin-like growth factor type I (IGF-1).

The present invention also relates to combinations of a compound of the present invention and inhaled glucocorticoids which reduce systemic side effects, such as prednisone, prednisolone, flunisolide, triamcinolone acetonide, beclomethasone dipropionate, budesonide, fluticasone propionate, and mometasone furoate.

The invention also relates to the combination of a compound of the invention and an inhibitor of Matrix Metalloproteinases (MMPs), i.e. stromelysin, collagenase and gelatinase, and aggrecanase; especially collagenase-1 (MMP-1), collagenase-2 (MMP-8), collagenase-3 (MMP-13), stromelysin-1 (MMP-3), stromelysin-2 (MMP-10), and stromelysin-3 (MMP-11) and MMP-12.

The invention also relates to the combination of a compound of the invention with other modulators of chemokine receptor function such as CCR1, CCR2, CCR2A, CCR2B, CCR3, CCR4, CCR5, CCR6, CCR7, CCR8, CCR9, CCR10 and CCR11 (for the C-C family); CXCR1, CXCR2, CXCR3, CXCR4 and CXCR5 (for the C-X-C family) and CX₃CR1 (for C-X)₃-group C).

The invention also relates to combinations of the compounds of the invention with antiviral agents such as nelfinavir, AZT, acyclovir and famciclovir and an anti-corrosive compound such as Valant.

The invention also relates to the combination of a compound of the invention with cardiovascular agents such as calcium channel blockers, lipid lowering agents such as statins, fibrates, beta-blockers, Ace inhibitors, angiotensin-2 receptor antagonists and inhibitors of platelet aggregation.

The invention also relates to the combination of a compound of the invention with CNS agents such as antidepressants (such as sertraline), anti-parkinson agents (such as risperidone, levodopa, ropinirole, parmesalamine, MAOB inhibitors such as selegiline and rasagiline, comP inhibitors such as tolcapone, a-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists, nicotinic agonists, dopamine agonists and neuronal nitric oxide synthase inhibitors), and anti-alzheimer agents such as donepezil, tacrine, COX-2 inhibitors, propentofylline or metryfonate.

The invention also relates to combinations of the compounds of the invention with the following agents: (i) tryptase inhibitors; (ii) platelet Activating Factor (PAF) antagonists; (iii) interleukin Converting Enzyme (ICE) inhibitors; (iv) an IMPDH inhibitor; (v) adhesion molecule inhibitors include VLA-4 antagonists; (vi) (ii) a cathepsin; (vii) MAP kinase inhibitors; (viii) glucose-6-phosphate dehydrogenase inhibitors; (ix) kinin-b.sub 1. and b.sub 2-receptor antagonists; (x) Anti-gout agents, such as colchicine; (xi) Xanthine oxidase inhibitors, such as allopurinol; (xii) Uricosuric agents, such as probenecid, sulindac, and benzbromarone; (xiii) A growth hormone secretagogue; (xiv) Transforming growth factor (TGF β); (xv) Platelet Derived Growth Factor (PDGF); (xvi) Fibroblast growth factors, such as basic fibroblast growth factor (bFGF); (xvii) Granulocyte macrophage colony stimulating factor (GM-CSF); (xviii) Capsaicin cream; (xix) Selected from NKP-608C; SB-233412 (talnetant); and D-4418 tachykinin NK₁And NK₃A receptor antagonist; (xx) An elastase inhibitor selected from UT-77 and ZD-0892; (xxi) TNF α converting enzyme inhibitors (TACE); (xxii) Inducible nitric oxide synthase Inhibitor (iNOS) or (xxiii) chemoattractant receptor-like molecules expressed on TH2 cells.

The compounds of the present invention may also be used in combination with an osteoporosis agent such as roloxifene, droloxifene, lasofoxifene or fosomax and an immunosuppressant such as FK-506, rapamycin, cyclosporine, azathioprine, and methotrexate.

The compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of osteoarthritis. Formulations suitable for combined use include standard non-steroidal anti-inflammatory agents (hereinafter NSAID's) such as piroxicam, diclofenac, propionic acids such as naproxen, flurbiprofen, fenoprofen, ketoprofen and ibuprofen, fenamic acids such as mefenamic acid, indomethacin, sulindac, apazone, phenylbutazone analogs such as phenylbutazone, salicylic acids such as aspirin, COX-2 inhibitors such as celecoxib, valdecoxib, and rofecoxib and etoricoxib, analgesics and intra-articular therapeutic agents such as corticosteroids and hyaluronic acids such as halerin and synvisc and P2X7 receptor antagonists.

The compounds of the present invention may also be used in combination with existing therapeutic agents for the treatment of cancer. Agents suitable for combined use include:

(i) antiproliferative/antineoplastic agents and combinations thereof for use in medical oncology, such as alkylating agents (e.g., cisplatin, carboplatin, cyclophosphamide, mechlorethamine, melphalan, chlorambucil, busulfan, and nitrosurea); antimetabolites (e.g. antifolates such as fluoropyrimidine-like 5-uracil and tegafur, raltitrexed, methotrexate, cytarabine, hydroxyurea, gemcitabine and paclitaxel (Taxol)) (ii) a Antitumor antibiotics (e.g., anthracycline-like doxorubicin, bleomycin, doxorubicin, daunorubicin, epirubicin, idarubicin, mitomycin-C, dactinomycin, and mithramycin); anticracking agents (e.g., vincristine, vinblastine, vindesine, and vinorelbine, which are vinca alkaloids-like, and taxol and taxotere, which are taxane-like); and topoisomerase inhibitors (e.g., etoposide and teniposide, amsacrine, topotecan, and camptothecin, which are etoposide-like);

(ii) cytostatics such as antiestrogens (e.g., tamoxifen, toremifene, raloxifene, droloxifene and iodoravine (iodoxyfene)), estrogen receptor negative modulators (e.g., fulvestrant), antiandrogens (e.g., bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (e.g., goserelin, leuprolide and buserelin), progestins (e.g., megestrol acetate), aromatase inhibitors (e.g., anastrozole, letrozole, vorazole and exemestane), and 5 α -reductase inhibitors such as finasteride;

(iii) agents that inhibit cancer cell invasion (e.g., metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);

(iv) growth ofInhibitors of factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies (e.g. anti-erbb 2 antibody trastuzumab [ Herceptin ]^TM]And anti-erbbl antibody cetuximab [ C225]) Farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, e.g. inhibitors of the epidermal growth factor family (e.g. inhibitors of the EGFR family of tyrosine kinases, such asN- (3-chloro-4-fluorophenyl) -7-methoxy-6- (3-morpholinopropoxy) quinazolin-4-amine (gefitinib, AZDl839),N- (3-ethynylphenyl) -6, 7-bis (2-methoxyethoxy) quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N- (3-chloro-4-fluorophenyl) -7- (3-morpholinopropoxy) quinazolin-4-amine (CI1033)), e.g. platelet derived growth factor family inhibitors and e.g. hepatocyte growth factor family inhibitors;

(v) anti-angiogenic agents such as those that inhibit the action of vascular endothelial growth factor (e.g., the anti-vascular endothelial growth factor antibody bevacizumab [ Avastin ]^TM]Such as those disclosed in international patent applications WO97/22596, WO97/30035, WO97/32856 and WO 98/13354) and compounds which act by other mechanisms (e.g., linamide, inhibitors of integrin α v β 3 function, and angiostatin);

(vi) vascular damaging agents such as combretastatin A4 and the compounds disclosed in International patent applications WO99/02166, WO00/40529, WO00/41669, WO01/92224, WO02/04434 and WO 02/08213;

(vii) antisense therapies, e.g., those directed to the above-mentioned targeting, such as ISIS2503, an anti-ras antisense;

(viii) gene therapy methods, including, for example, methods of replacing variant genes such as variant p53 and variant BRCA1 and BRCA2, GDEPT (gene-directed enzyme prodrug therapy) methods such as those using cytosine deaminase, thymidine kinase, or bacterial nitroreductase, and methods of increasing patient tolerance to chemotherapy or radiation therapy such as multidrug resistance gene therapy; and

(ix) immunotherapeutic approaches, including, for example, in vitro and in vivo approaches to increasing the immunogenicity of patient tumor cells, such as transfection with cytokines such as interleukin 2, interleukin 4 and granulocyte-macrophage colony stimulating factor, approaches to reducing T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumor cell lines and approaches using anti-idiotypic antibodies.

In another aspect, the present invention provides the use of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined in the manufacture of a medicament for the treatment of a disease or condition in a human in which modulation of CRTh2 receptor activity is beneficial.

In the context of this specification, the term "treatment" also includes "prevention", unless specifically stated to the contrary. The terms "therapeutic" and "therapeutically" should also be construed accordingly.

The present invention also provides a method of treating a PGD2 or a metabolite thereof mediated disease in which prostaglandins bind to their receptors, particularly CRTh2, which method comprises administering to a patient a therapeutically effective amount of a compound of formula (I) as hereinbefore defined, or a pharmaceutically acceptable salt or solvate thereof.

The invention also provides a method of treating an inflammatory disease, particularly psoriasis, in a patient suffering from, or at risk of, said disease, which comprises administering to the patient a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, as hereinbefore defined.

For the above-mentioned therapeutic applications, the dosage administered will, of course, vary with the compound employed, the mode of administration, the desired treatment and the condition to be treated.

The compounds of formula (I), prodrugs and pharmaceutically acceptable salts and solvates thereof may be used as such, but are generally administered as pharmaceutical compositions wherein the compound/salt/solvate of formula (I) (active ingredient) is in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. Depending on the mode of administration, the pharmaceutical composition preferably comprises 0.05 to 99% w (weight percent), more preferably 0.05 to 80% w, still more preferably 0.10 to 70% w, and most preferably 0.10 to 50% w of the active ingredient, all weight percent being based on the total composition.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

The present invention also provides a pharmaceutical composition comprising a compound of formula (I) as defined above, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable adjuvant, diluent or carrier.

The invention will now be illustrated by the following non-limiting examples in which, unless otherwise stated:

(i) the title and subtitle compounds in the examples and methods were named using the ACD lab/naming program (version 6.0) from advanced chemical Development Inc, Canada;

(ii) unless otherwise stated, reverse phase preparative HPLC was performed using Symmetry, NovaPak or Ex-Terra reverse phase silica gel columns;

(iii) flash column chromatography refers to normal phase silica gel chromatography

(iv) The solvent adopts MgSO₄Or Na₂SO₄Drying

(v) The evaporation is carried out using vacuum rotary evaporation and is carried out after removing solid residues such as drying agents by filtration;

(vi) unless otherwise stated, the operation is carried out at room temperature, i.e. 18-25 ℃, and under an inert atmosphere such as argon or nitrogen;

(vii) the yields are given for illustration only and are not necessarily the maximum achievable;

(viii) the structure of the final product of formula (1) was confirmed by nuclear (typically proton) magnetic resonance (NMR) and mass praseodymium techniques; proton magnetic resonance chemical shift values are measured on the delta scale and the multiplicity of peaks is expressed as follows: s, singlet; d, double peak; t, triplet; m, multiplet; br, broad peak; q, quartet, quin, quintet;

(ix) intermediates are generally incompletely characterized and purity determined using Thin Layer Chromatography (TLC), High Performance Liquid Chromatography (HPLC), Mass Spectrometry (MS), Infrared (IR) and NMR analysis;

(x) Mass Spectrum (MS): typically only ions that indicate the parent mass are reported, if given,¹HNMR data are plotted as the delta value for the main judged proton, given in parts per million (ppm) relative to Tetramethylsilane (TMS) as an internal standard;

(xi) The following abbreviations are used:

m.p. ═ melting point

THF ═ tetrahydrofuran

EtOAc ═ ethyl acetate

MCPBA ═ m-chloroperoxybenzoic acid

DMF ═ N, N-dimethylformamide

MgSO₄Magnesium sulfate ═ magnesium sulfate

Na₂SO₄Sodium ═ sulfate

NaHCO₃Sodium bicarbonate

Example 1

4- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indoleIndole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-2-methyl-4-nitro-1H-indoles

The stirred solution of 3-nitroaniline (8g) in THF (700ml) was cooled to-78 deg.C and tert-butyl hypochlorite (6.3g) was added dropwise thereto over 5 minutes. The reaction mixture was heated to-65 ℃ over 20 minutes before adding a solution of 1- [ 4-chlorophenyl ] thio ] -2-propanone (11.6g) in THF (20 ml). After 2 hours triethylamine (8.1ml) was added and the reaction mixture was warmed to room temperature. 2M HCl (aq) was added to the reaction mixture before concentration in vacuo. The residue was mixed with methanol with stirring and the precipitated solid was isolated by filtration to give the sub-title compound (5.8 g).

¹HNMR(DMSO-d6)δ12.55(s，1H)，7.76(dd，1H)，7.63(dd，1H)，7.31-7.22(m，3H)，6.91(dd，2H)，2.47(s，3H)。

ii)3- [ (4-chlorophenyl) thio]-2-methyl-4-nitro-1H-indole-acetic acid ethyl ester

To a stirred suspension of 60% sodium hydride (0.85g) in mineral oil in THF (100ml) was added a solution of the product of step (i) (5.6g) in THF (50 ml). After stirring at room temperature for 30 minutes, ethyl bromoacetate (2.3ml) was added dropwise over 10 minutes. After 2 hours the reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with water, brine and dried (MgSO)₄) And concentrated in vacuo. Recrystallization from ethanol gave the sub-title compound (5 g).

¹HNMR(DMSO-d6)δ7.97(dd，1H)，7.65(dd，1H)，7.35(t，1H)，7.26(dt，2H)，6.92(dt，2H)，5.40(s，2H)，4.19(q，2H)，2.45(s，3H)，1.22(t，3H)。

iii) 4-amino-3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-acetic acid ethyl ester

H at a pressure of 2bar in the presence of 5% Pt/C (0.5g)₂Next, a suspension of the product of step (ii) (2.25g) in ethanol (170ml) was stirred. After stirring overnight the catalyst was removed by filtration and the filtrate was concentrated in vacuo. Purification by flash column chromatography (14% EtOAc/hexanes as eluent) afforded the sub-title compound (1.4 g).

¹HNMR(DMSO-d6)δ7.30(dd，2H)，7.00(dt，2H)，6.85(t，1H)，6.68(dd，1H)，6.23(dd，1H)，5.33(s，2H)，5.09(s，2H)，4.16(q，2H)，2.33(s，3H)，1.21(t，3H)。

3- [ (4-chlorophenyl) thio]-4- (ethylamino) -2-methyl-1H-indole-1-acetic acid ethyl esterThe by-product of the reaction was also isolated (0.33 g).

¹HNMR(DMSO-d6)δ7.32(dd，2H)，7.01(dd，2H)，6.95(t，1H)，6.73(d，1H)，6.16(d，1H)，5.70(t，1H)，5.11(s，2H)，4.16(q，2H)，3.05(dt，2H)，2.34(s，3H)，1.21(t，3H)，1.02(t，3H)。

iv)4- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-acetic acid ethyl ester

To a solution of the product of step (iii) (0.5g) in dichloromethane (10ml) were added triethylamine (0.18ml) and acetyl chloride (0.1ml), and the reaction was stirred at room temperature for 30 minutes. The mixture was then adsorbed onto silica gel and purified by column chromatography (33% EtOAc/hexanes as eluent) to give the sub-title compound (0.52 g).

¹HNMR(DMSO-d6)δ9.51(s，1H)，7.46(d，1H)，7.34-7.27(m，3H)，7.11(t，1H)，6.97(d，2H)，5.24(s，2H)，4.18(q，2H)，2.39(s，3H)，1.86(s，3H)，1.21(t，3H)。

v)4- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-acetic acid

To a solution of the product of step (iv) (0.31g) in THF (10ml) was added a 1M NaOH solution (aqueous solution) (0.75 ml). The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated in vacuo and the residue was dissolved/suspended in water. The pH was adjusted to 2 with dilute HCl (aq) and the precipitated solid was isolated by filtration. Recrystallization from acetonitrile gave the title compound (0.16 g).

¹HNMR(DMSO-d6)δ13.21(s，1H)，9.51(s，1H)，7.46(d，1H)，7.33-7.27(m，3H)，7.11(t，1H)，6.98(d，2H)，5.12(s，2H)，2.39(s，3H)，1.85(s，3H)。

APCI+[M+H]389

M.p.dec＞266℃

Example 2

3- [ (4-chlorophenyl) thio]-2-methyl-4- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-2-methyl-4- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

To a solution of the product of step (iii) in example 1 (0.5g) in dichloromethane (10ml) were added triethylamine (0.18ml) and methanesulfonyl chloride (0.1ml), and the reaction mixture was stirred at room temperature for 2 hours before being heated under reflux overnight. Dichloromethane was removed in vacuo, acetonitrile (10ml) was added and the reaction mixture was heated to 60 ℃ for 5 hours. The mixture was adsorbed on silica gel and purified by column chromatography (33% EtOAc/hexanes as eluent) to give the sub-title compound (0.44 g).

¹HNMR(DMSO-d6)δ8.80(s，1H)，7.39(d，1H)，7.32(d，2H)，7.20-7.07(m，2H)，6.97(d，2H)，5.27(s，2H)，4.18(q，2H)，2.74(s，3H)，2.38(s，3H)，1.22(t，3H)。

ii)3- [ (4-chlorophenyl) thio]-2-methyl-4- [ (methylsulfonyl) aminoBase of]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (i).

¹HNMR(DMSO-d6)δ13.25(s，1H)，8.80(s，1H)，7.39(d，1H)，7.32(m，2H)，7.16(t，1H)，7.09(d，1H)，6.98(dt，2H)，5.15(s，2H)，2.73(s，3H)，2.38(s，3H)。

APCI-[M-H]423

M.p.dec＞243℃

Example 3

3- [ (4-chlorophenyl) thio]-2-methyl-4- (5-pyrimidinyl) -1H-indole-1-acetic acid

i) 4-bromo-3- [4 (-chlorophenyl) thio]-2-methyl-1H-indoles

3-bromophenylhydrazine hydrochloride (15.34g) aqueous (80ml) solution was added to 1- [ (4-chlorophenyl) thio group]Acetone (13.77g) was suspended in acetonitrile (200ml) and stirred at room temperature overnight, then concentrated in vacuo. The residue was partitioned between aqueous sodium bicarbonate and dichloromethane. The organic phase was washed with brine and dried (MgSO)₄) And concentrated in vacuo. The residual oil was treated with acetic acid (70ml) and heated at 80 ℃ overnight. The reaction mixture was poured into water, basified with aqueous sodium hydroxide and extracted with EtOAc (twice). The combined organics were washed (brine), dried (MgSO)₄) And concentrated in vacuo.

The mixture was purified by flash column chromatography (40% EtOAc/hexanes as eluent) to give the sub-title compound (4.43 g).

¹HNMR(DMSO-d6)δ7.31(s，1H)，7.30(d，2H)，7.13(dt，2H)，7.02(t，1H)，6.94(dt，2H)，2.52(s，3H)。

ii) 4-bromo-3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid, 1, 1-dimethylethyl ester

The subtitle compound was prepared by the method of example 1 step (ii) using the product of step (i) and tert-butyl bromoacetate. The product was purified by column chromatography (10% EtOAc/hexanes as eluent).

¹HNMR(CDCl₃：δ7.31(dd，1H)，7.21(dd，1H)，7.14-7.10(m，2H)，7.05(t，1H)，6.94-6.91(m，2H)，4.77(s，2H)，2.49(s，3H)，1.43(s，9H)。

iii)3- [ (4-chlorophenyl) thio]-2-methyl-4- (5-pyrimidinyl) -1H-indole-1-acetic acid, 1, 1-dimethylethyl ester

To a solution/suspension of the product of step (ii) (500mg) in toluene (4ml) was added ethanol (1ml), 5-pyrimidinyl-boronic acid (133mg), 2M sodium carbonate (1.5ml) and finally tetrakis (triphenylphosphine) palladium (0) (125 mg). The mixture was heated at 100 ℃ for 3 days. Purification by column chromatography (eluent 2: 1 hexanes: EtOAc) afforded the sub-title compound as an orange solid (140 mg).

¹HNMR(DMSO-d6)δ8.99(s，1H)，8.57(s，2H)，7.68(d，1H)，7.10(dd，2H)，6.99(d，1H)，7.30(dt，1H)，6.46(dd，2H)，5.21(s，2H)，2.42(s，3H)，1.45(s，9H)。

iii)3- [ (4-chlorophenyl) thio]-2-methyl-4- (5-pyrimidinyl) -1H-indole-1-acetic acid

The title compound was prepared from the product of step (iii) by the method of example 1 step (v) using reverse phase hplc (MeCN/NH)₃(aqueous solution) as eluent).

¹HNMR(DMSO-d6)δ8.99(s，1H)，8.57(s，2H)，7.69(d，1H)，7.29(t，1H)，7.10(m，2H)，6.98(d，1H)，6.47(m，2H)，5.19(s，2H)，2.43(s，3H)。

Example 4

3- [ (4-chlorophenyl) thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid, 1, 1-dimethylethyl ester

To a solution of the product of step (ii) (0.4g) in example 3 in toluene (4ml) was added 2-tributylstannylpyrazine (0.32g) and tetrakis (triphenylphosphine) palladium (0) (0.1 g). The reaction mixture was heated to 80 ℃ for 18 hours. The mixture was adsorbed onto silica gel and purified by column chromatography (33% EtOAc/hexanes as eluent) to give the sub-title compound (160 mg).

¹HNMR(DMSO-d6)δ8.52(d，1H)，8.47(d，1H)，8.41(t，1H)，7.68(d，1H)，7.30(t，1H)，7.13-7.09(m，3H)，6.55(m，2H)，5.21(s，2H)，2.40(s，3H)，1.44(s，9H)。

ii)3- [ (4-chlorophenyl) thio]-2-methyl-4-pyrazinyl-1H-indole-1-acetic acid

The title compound was prepared as in example 1 step (v) using preparation hplc (MeCN/NH)₃(aqueous solution) as eluent).

¹HNMR(DMSO-d6)δ8.50(d，1H)，8.45(d，1H)，8.41(dd，1H)，7.56(dd，1H)， 7.22(dd，1H)，7.13-7.09(m，2H)，7.04(dd，1H)，6.58(dt，2H)，4.68(s，2H)，2.38(s，3H)。

APCI-[M-H]408

Example 5

3- [ (2-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i) 2-methyl-5-nitro-1H-indole-1-acetic acid ethyl ester

2-methyl-5-nitro-1H-indole (5.3g) was dissolved in dimethylformamide (20ml) and sodium hydride (1.2g) was added thereto to stir the mixture for 1 hour. Ethyl bromoacetate (6.8g) was added immediately and a precipitate started to form. The mixture was quenched with 1% aqueous acetic acid and the precipitate was collected by filtration and washed thoroughly with water, triturated with diethyl ether and dried under vacuum to give the pure sub-title product (6.2 g).

¹HNMR(DMSO-d6)δ8.45(d，1H)，7.96(dd，1H)，7.59(d，1H)，6.56(s，1H)，5.21(s，2H)，4.16(q，2H)，2.37(s，3H)，1.19(t，3H)。

APCI-[M-H]263

ii) 5-amino-2-methyl-1H-indole-1-acetic acid ethyl ester

A suspension of ethyl 2-methyl-5-nitro-1H-indole-1-acetate (6.2g) in ethanol (600ml) was stirred under a hydrogen atmosphere of 3bar for 4 hours in the presence of 10% palladium on charcoal (0.6 g). The mixture was filtered through Celite and the filtrate was evaporated to give the sub-title compound as a pink viscous oil (5.3 g).

APCI-[M-H]233

iii) 2-methyl-5- [ (methylsulfonyl) amino]-1H-indole-1-acetic acid ethyl ester

Methanesulfonyl chloride (1.15g) was added to a solution of ethyl 5-amino-2-methyl-1H-indole-1-acetate (2.3g) in triethylamine (1.7ml) and dichloromethane (20ml) at 0 ℃ to give a pink viscous oil and stirred at 20 ℃ for 1 hour. Water was added and the mixture was extracted with dichloromethaneDried (Na)₂SO₄) And evaporated to give a crude solid. It was purified by chromatography on silica gel (40: 1 dichloromethane/ethyl acetate as eluent) to give the sub-title compound as a pink solid (1.4 g).

¹HNMR(DMSO-d6)δ9.23(s，1H)，7.30(m，2H)，6.94(dd，1H)，6.23(s，1H)，5.03(s，2H)，4.14(q，2H)，2.85(s，3H)，2.31(s，3H)，1.19(t，3H)。

APCI-[M-H]311

iv)3- [ (2-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

Ethyl 2-methyl-5- [ (methylsulfonyl) amino ] -1H-indole-1-acetate (0.31g) and 2-chlorobenzenethiol (0.27g) were dissolved in dimethylformamide (3ml), after which iodine (0.30g) was added and the mixture was stirred at room temperature overnight. The mixture was poured into aqueous sodium thiosulfate (50ml) and the resulting white precipitate was collected by filtration and washed with water, dried under vacuum and recrystallized in ethanol. The crystals were collected and rinsed with isohexane and dried under vacuum to give the sub-title compound (0.20 g).

¹HNMR(DMSO-d6)δ9.34(s，1H)，7.55(d，1H)，7.45(m，H)，7.21(d，1H)，7.23-7.06(m，3H)，6.44(m，1H)，5.26(s，2H)，4.18(q，2H)，2.83(s，3H)，2.38(s，3H)，1.22(t，3H)。

APCI-[M-H]453/455

v)3- [ (2-chlorophenyl) thio]-2-methyl-4- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

The title compound (0.10g) was prepared by the method of example 1 step (v) except that recrystallization was not required.

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.33(s，1H)，7.54(d，1H)，7.45(dd，1H)，7.21(d，1H)，7.08(m，3H)，6.45(d，1H)，5.13(s，2H)，2.83(s，3H)，2.38(s，3H)。

APCI-[M-H]425/427

M.p.212℃

Example 6

3- [ (3-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (3-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) chloro group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 3-chlorobenzenethiol (0.34 g).

APCI-[M-H]453/455

ii)3- [ (3-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 5 step (v) using the product from example 6 step (i).

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.33(s，1H)，7.46(d，1H)，7.21(m，2H)，7.11(dd，1H)，7.07(dd，1H)，6.95(m，2H)，4.88(s，2H)，2.82(s，3H)，2.39(s，3H)。

APCI+[M+H]425/427

M.pt.224℃

Example 7

3-[(4-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 4-chlorobenzenethiol.

APCI-[M-H]453/455

ii)3- [ (4-chlorophenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 5 step (v) using the product from step (i).

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.37(s，1H)，7.57(d，1H)，7.23(d，2H)，7.22(d，1H)，7.07(dd，1H)，6.96(d，2H)，5.11(s，2H)，2.82(s，3H)，2.39(s，3H)。

APCI+[M+H]425/427

M.p.214℃

Example 8

3- [ (3-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (3-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 3-methoxyphenylthiol

APCI-[M-H]449

ii)3- [ (3-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.34(s，1H)，7.50(d，1H)，7.26(d，1H)，7.08(t，1H)，7.06(dd，1H)，6.64(dd，1H)，6.55(d，1H)，6.47(d，1H)，5.11(s，2H)，3.62(s，3H)，2.82(s，3H)，2.40(s，3H)。

APCI-[M-H]421

M.p.292℃

Example 9

3- [ (4-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (4-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The sub-title compound was prepared as in example 5 step (iv) using the product from example 5 step (iv) and 4-methoxyphenylthiol.

APCI-[M-H]449

ii)3- [ (4-methoxyphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.33(s，1H)，7.46(d，1H)，7.03(d，1H)，7.04(dd，1H)，7.00(d，2H)，6.81(d，2H)，5.07(s，2H)，3.67(s，3H)，2.83(s，3H)，2.42(s，3H)。

APCI+[M+H]421

M.p.215℃

Example 10

3- [ (2-trifluoromethylphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (2-trifluoromethylphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 2-trifluoromethylbenzenethiol.

APCI-[M-H]487

ii)3- [ (2-trifluoromethylphenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.35(s，1H)，7.72(d，1H)，7.54(d，1H)，7.36(t，1H)，7.24(t，1H)，7.22(s，1H)，7.11(dd，1H)，6.73(d，1H)，5.12(s，2H)，2.82(s，3H)，2.40(s，3H)。

APCI-[M-H]459

M.p.207℃

Example 11

3- [ (8-quinolyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (8-quinolyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 8-quinolinethiol.

APCI-[M-H]470

ii)3- [ (8-quinolyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.29(s，1H)，8.99(dd，1H)，8.38(d，1H)，7.65(m，2H)，7.54(d，1H)，7.30(t，1H)，7.20(s，1H)，7.11(dd，1H)，6.68(d，1H)，5.14(s，2H)，2.80(s，3H)，2.40(s，3H)。

APCI+[M+H]442

M.p.257℃

Example 12

3- [ (2- (methylethyl) phenyl) thio group]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

i)3- [ (2- (2-methylethyl) phenyl) thio]-2-methyl-5- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 5 step (iv) and 2- (2-methylethyl) benzenethiol.

APCI-[M-H]461

ii)3- [ (2- (2-methylethyl) phenyl) thio]-2-methyl-5- [ (methylsulfonyl) oxy group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.33(s，1H)，7.49(d，1H)，7.27(d，1H)，7.22(d，1H)，7.06(m，2H)，6.89(t，1H)，6.50(dd，1H)，5.10(s，2H)，3.50(m，1H)，2.81(s，3H)，2.39(s，3H)，1.33(s，3H)，1.31(s，3H)。

APCI+[M+H]433

M.p.160℃

Example 13

5- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

i)5- (acetylamino) -2-methyl-1H-indole-acetic acid ethyl ester

Acetyl chloride (0.10g) was added to a 0 ℃ solution of the product of step ii) example 5 (0.28g) in dichloromethane (10ml) and triethylamine (0.2ml) and stirred at 20 ℃ for 1 hour. Water was added and the mixture was extracted with dichloromethane and dried (Na)₂SO₄) And purified by column chromatography (eluting with 1: 1 iso-hexane/ethyl acetate) to give the sub-title compound as a pink powder (0.19 g).

¹HNMR(DMSO-d6)δ9.69(s，1H)，7.73(d，1H)，7.22(d，1H)，7.12(dd，1H)，6.18(s，1H)，5.00(s，2H)，4.13(q，2H)，2.30(s，3H)，2.02(s，3H)，1.20(t，3H)。

APCI-[M-H]275

ii)5- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-acetic acid ethyl ester

The subtitle compound was prepared as in example 5 step (iv) using the product from step (i) (0.19g) and 4-chlorobenzenethiol (0.20 g). The mixture was poured into aqueous sodium thiosulfate solution, extracted with ethyl acetate, washed with water, and dried (Na)₂SO₄) And evaporated. The residue was recrystallized from ethanol to give the sub-title compound as a pink solid (0.13 g).

¹HNMR(DMSO-d6)δ9.80(s，1H)，7.67(d，1H)，7.43(d，1H)，7.36(dd，1H)，7.27(d，2H)，6.94(d，2H)，5.20(s，2H)，4.16(q，2H)，2.39(s，3H)，1.98(s，3H)，1.21(t，3H)。

APCI-[M-H]417/419

iii)5- (acetylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-acetic acid

The title compound was prepared by the method of example 5 step (v) using the product from step (ii).

¹HNMR(DMSO-d6)δ13.25(s，1H)，9.79(s，1H)，7.67(d，1H)，7.42(d，1H)，7.34(dd，1H)，7.27(d，2H)，6.96(d，2H)，5.07(s，2H)，2.39(s，3H)，1.98(s，3H)。

APCI+[M+H]389/391

M.p.247℃

Example 14

4- (Acetyl ethyl)Phenylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-4- (ethylamino) -2-methyl-1H-indole-1-acetic acid ethyl ester.

The sub-title compound was prepared by the method of example 1 step (iv) using the by-product of example 1 step (iii).

¹HNMR(DMSO-d6)δ7.53(d，1H)，7.22-7.18(m，3H)，6.91-6.87(m，3H)，5.21(s，2H)，4.19(q，2H)，4.01(m，1H)，2.92-2.81(m，1H)，2.41(s，3H)，1.31(s，3H)，1.21(t，3H)，0.91(t，3H)。

ii)4- (Acetylethylamino) -3- [ (4-chlorophenyl) thio group]-2-methyl-1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) and the product of step (i).

¹HNMR(DMSO-d6)δ7.55(d，1H)，7.22(dt，2H)，7.18(t，1H)，6.89-6.86(m，3H)，4.99(s，2H)，2.77(m，1H)，4.02(m，1H)，2.39(s，3H)，1.28(s，3H)，0.91(t，3H)。

APCI+[M+H]417

Example 15

3- [ (4-chlorophenyl) thio]-4- [ cyclopropylcarbonyl) amino]-2-methyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-4- [ cyclopropylcarbonyl group]Amino group]-2-methyl-1H-indole-1-acetic acid ethyl ester.

The subtitle compound was prepared by the method of example 1 step (iv) using the product of example 1 step (iii) and cyclopropylcarbonyl chloride.

¹HNMR (DMSO-d6)δ9.74(s，1H)，7.49(d，1H)，7.43-7.26(m，3H)，7.10(t，1H)，6.98(m，2H)，5.24(s，2H)，4.18(q，2H)，2.40(s，3H)，1.53(m，1H)，1.18(t，3H)，0.64(m，4H)。

ii)3- [ (4-chlorophenyl) thio]-4- [ cyclopropylcarbonyl group]Amino group]-2-methyl-1H-indole-1-acetic acid

The subtitle compound was prepared by the method of example 1 step (v) and the product of step (i).

¹HNMR(DMSO-d6)δ9.58(s，1H)，7.60(d，1H)，7.28-7.22(m，3H)， 7.09(t，1H)，7.02(m，2H)，5.03(s，2H)，2.41(s，3H)，1.50(m，1H)，0.68(m，4H)。

APCI-[M-H]413

M.p.183-185℃

Example 16

4- (benzoylamino) -3- [ (4-chlorophenyl) thio]- - (2-methyl-1H) -indole-1-acetic acid

i)4- (benzoylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 1 step (iv) using the product from example 1 step (iii) and benzoyl chloride.

¹HNMR(DMSO-d6)δ10.25(s，1H)，7.84(d，1H)，7.75(m，2H)，7.59(m，1H)，7.50(m，2H)，7.40(d，1H)，7.21(m，3H)，6.88(m，2H)，5.28(s，2H)，4.19(q，2H)，2.40(s，3H)，1.17(t，3H)。

ii)4- (benzoylamino) -3- [ (4-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ10.26(s，1H)，7.86(d，1H)，7.75(dt，2H)，7.58(m，1H)，7.50(m，2H)，7.36(dd，1H)，7.21(dt，2H)，7.17(t，1H)，6.90(dt，2H)，5.03(s，2H)，2.40(s，3H)。

APCI-[M-H]449

M.pt213-215℃

Example 17

4- (acetylamino) -3- [ (3-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

i)4- (acetylamino) -2-methyl-1H-indole-1-acetic acid ethyl ester

Thiosalicylic acid was added to a solution of the product of step (iv) in example 1 (474mg) in trifluoroacetic acid (10ml), thiosalicylic acid (351mg) was added and the resulting suspension was heated to 60 ℃ for 4 hours. The mixture was concentrated in vacuo and the residue was dissolved in EtOAc and washed with NaHCO₃(aqueous), washed with brine and dried (MgSO)₄) And evaporated to give crude material. Purification by column chromatography (50% EtOAc/hexanes as eluent) afforded the sub-title compound (0.13 g).

¹HNMR(DMSO-d6)δ9.51(s，1H)，7.54(d，1H)，7.07(d，1H)，6.96(t，1H)，6.50(s，1H)，5.02(s，2H)，4.14(q，2H)，2.33(d，3H)，2.12(s，3H)，1.20(t，3H)。

ii)4- (acetylamino) -3- [ (3-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

The sub-title compound was prepared as in example 5 step (iv) using the product of step (i) (0.11g) and 3-chlorobenzenethiol (0.048g) and then prepared as preparation hplc (eluent MeCN/NH)₃(aqueous)) was purified to give the title compound (70 mg).

¹HNMR(DMSO-d6)δ9.49(s，1H)，7.43(d，1H)，7.29(d，1H)，7.24(t，1H)，7.14(dd，1H)，7.08(t，1H)，6.97-6.95(m，2H)，4.96(s，2H)，2.38(s，3H)，1.86(s，3H)。

APCI-[M-H]387

Example 18

3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) sulfonyl ] group]Amino group]-2-methyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) sulfonyl ] group]Amino group]-2-methyl-1H-indole-1-acetic acid ethyl ester

Triethylamine (55. mu.l) and dimethylsulfamoyl chloride (43. mu.l) were added to a solution of the product of step (iv) in example 1 (150mg) in acetonitrile (5 ml). The mixture was heated to reflux for 24 h, adsorbed onto silica gel and purified by column chromatography (33% EtOAc/hexanes as eluent) to give the sub-title compound (95 mg).

¹HNMR(DMSO-d6)δ.8.80(s，1H)，7.35-7.29(m，3H)，7.13(t，1H)，7.07(dd，1H)，6.99(dt，2H)，5.25(s，2H)，4.18(q，2H)，2.56(s，6H)，2.37(s，3H)，1.21(t，3H)。

ii)3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) sulfonyl ] group]Amino group]-2-methyl-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ.8.79(s，1H)，7.31(m，2H)，7.14(dd，1H)，7.04-6.99(m，4H)，4.51(s，2H)，2.54(s，6H)，2.34(s，3H)。

APCI-[M-H]452

Example 19

3- [ (4-chlorophenyl) thio]-2-methyl-4- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl]Amino group]-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-2-methyl-4- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl]Amino group]-1H-indole-1-acetic acid ethyl ester

Triethylamine (75. mu.l) and 1-methyl-1H-imidazole e-4-sulfonyl chloride (96mg) were added to a solution of the product of step (iii) example 1 (0.2g) in acetonitrile (20ml) and the mixture was heated at reflux overnight, cooled, adsorbed onto silica gel and purified by column chromatography (70% EtOAc/hexane as eluent) to give the sub-title compound as an oil (245 mg).

¹HNMR(DMSO-d6)δ9.17(s，1H)，7.73(d，1H)，7.63(d，1H)，7.32(dt，2H)，7.24(dd，1H)，7.08-7.02(m，2H)，6.98(dt，2H)，5.20(s，2H)，4.15(q，2H)，3.60(s，3H)，2.33(s，3H)，1.17(t，3H)。

ii)3- [ (4-chlorophenyl) thio]-2-methyl-4- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl]Amino group]-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ.9.16(s，1H)，7.73(d，1H)，7.62(d，1H)，7.31(dt，2H)，7.22(dd，1H)，7.08-7.02(m，2H)，6.99(dt，2H)，5.01(s，2H)，3.59(s，3H)，2.32(s，3H)。

APCI-[M-H]489

Example 20

3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) acetyl group]Amino group]-2-methyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) acetyl group]Amino group]-2-methyl-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 1 step (iv) using the product from example 1 step (iii) and (dimethylamino) -acetyl chloride hydrochloride. The product was purified by column chromatography (33% EtOAc/hexanes as eluent).

¹HNMR(DMSO-d6)δ10.77(s，1H)，8.15(d，1H)，7.35-7.27(m，3H)，7.13(t，1H)，6.97(d，2H)，5.25(s，2H)，4.17(q，2H)，2.94(s，2H)，2.38(s，3H)，2.10(s，6H)，1.21(t，3H)。

ii)3- [ (4-chlorophenyl) thio]-4- [ [ (dimethylamino) acetyl group]Amino group]-2-methyl-1H-indole-1-acetic acid.

¹HNMR(DMSO-d6)δ.10.76(s，1H)，8.10(d，1H)，7.30(dt，2H)，7.17(d，1H)，7.05(t，1H)，6.98(dd，2H)，4.66(s，2H)，2.93(s，2H)，2.35(s，3H)，2.09(s，6H)。

APCI-[M-H]430

Example 21

4- (acetylamino) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

i)4- (methylsulfonyl) benzenethiol

1-fluoro-4- (methylsulfonyl) benzene and sodium disulphide (10g) were heated in NMP (10ml) at 80 ℃ for 2 h. The mixture was poured into water, washed with EtOAc, acidified with concentrated hydrochloric acid and extracted with EtOAc. The organics were washed with water and dried (MgSO)₄) And evaporated to give the sub-title compound, which was used in the next step without identification.

ii)4- (acetylamino) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid ethyl ester.

The sub-title compound was prepared from the product of step (i) and the product of example 17 step (i) by the method of example 5 step (iv) and purified by chromatography (50% EtOAc/hexane up to 66% EtOAc/hexane as eluent) to give the sub-title compound.

¹HNMR(DMSO-d6)δ9.45(s，1H)，7.72(dt，2H)，7.38(d，1H)，7.32(d，1H)，7.16-7.11(m，3H)，5.27(s，2H)，4.19(q，2H)，3.14(s，3H)，2.38(s，3H)，1.82(s，3H)，1.22(t，3H)。

iv)4- (acetylamino) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) and the product of step (ii).

¹HNMR(DMSO-d6)δ9.44(s，1H)，7.72(dd，2H)，7.38(d，1H)，7.31(d，1H)，7.17-7.10(m，3H)，5.14(s，2H)，3.14(s，H)，2.38(s，3H)，1.82(s，3H)。

APCI-[M-H]431

Example 22

4- (acetylamino) -3- [ (2-chlorophenyl) thio]-2-methyl-1H-indole-1-acetic acid

The title compound was prepared by the method of example 5 step (iv) using the product from example 17 step (i) and 2-chlorothiophenol and purified by column chromatography (33% EtOAc/hexane as eluent). The resulting product was treated according to the procedure outlined in example 1 step (v) to give the title compound.

¹HNMR(DMSO-d6)δ9.43(s，1H)，7.46(dd，1H)，7.37(dd，2H)，7.14-7.05(m，3H)，6.42(dd，1H)，5.14(s，2H)，2.37(s，3H)，1.81(s，3H)

APCI+[M+H]389

Example 23

4- (acetylamino) -2-methyl-3- [ [4- (ethylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

i)4- (acetylamino) -2-methyl-3- [ [4- (ethylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

Use the factThe title compound was prepared by the method of example 5 step (iv) using the product of example 17 step (i) and 4- (ethylsulfonyl) benzenethiol. The product was purified to prepare hplc (eluent MeCN/NH)₃(aqueous solution)) was purified.

¹HNMR(DMSO-d6)δ9.41(s，1H)，7.66(d，2H)，7.30(d，2H)，7.17(d，2H)，7.08(t，1H)，4.85(s，2H)，3.20(q，2H)，2.37(s，3H)，1.78(s，3H)，1.05(t，3H)。

APCI-[M-H]445

Example 24

3- [ (4-chlorophenyl) thio]-4- [ [ (ethylamino) carbonyl group]Amino group]-2-methyl-1H-indole-1-acetic acid

i)3- [ (4-chlorophenyl) thio]-4- [ [ (ethylamino) carbonyl group]Amino group]-2-methyl-1H-indole-1-acetic acid ethyl ester

Ethyl isocyanate (32. mu.l) was added to a solution of the product of step (iii) in example 1 (150mg) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 4 days and then heated under reflux for 24 hours. The mixture was adsorbed onto silica gel and purified by column chromatography (33% EtOAc/hexanes to 50% EtOAc/hexanes as eluent) to give the sub-title compound (150 mg).

¹HNMR(DMSO-d6)δ8.37(s，1H)，7.57(d，1H)，7.28(dt，2H)，7.12(dd，1H)，7.06-6.98(m，3H)，6.81(t，1H)，5.19(s，2H)，4.17(q，2H)，2.98(dt，2H)，2.37(s，3H)，1.21(t，3H)，0.96(t，3H)。

ii)3- [ (4-chlorophenyl) thio]-4- [ [ (ethylamino) carbonyl group]Amino group]-2-methyl-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ8.39(s，1H)，7.53(dd，1H)，7.26(dt，2H)，7.04-6.94(m，4H)，6.76(t，1H)，4.56(s，2H)，2.98(dt，2H)，2.34(s，3H)，0.95(t，3H)。

APCI+[M+H]418

Example 25

3- [ [4- (methylsulfonyl) phenyl ] methyl ester]Thio group]-4- (5-pyrimidinyl) -1H-indole-1-acetic acid

i) 4-bromo-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indoles

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 21 step (i) (0.89g) and 4-bromoindole (0.96 g). The residue was purified by chromatography (50% EtOAc/hexanes as eluent) to give the sub-title compound (1.3 g).

¹HNMR(DMSO-d6)δ12.18(s，1H)，7.93(s，1H)，7.73(d，2H)，7.56(d，1H)，7.29(d，1H)，7.17(d，2H)，7.12(t，1H)，3.14(s，3H)。

ii) 4-bromo-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

Sodium tert-butoxide (1.37g) was added to a solution of the product of step (i) (2.4g) in DMF (20ml) and the mixture was stirred for 15 minutes. Ethyl bromoacetate (0.86ml) was added and the mixture was stirred for a further 30 minutes. 1M sodium hydroxide (10ml) was then added and the mixture was stirred for 2 hours. The mixture was diluted with water (200ml), washed with EtOAc (50ml), acidified with 2M hydrochloric acid and the resulting solid filtered and dried to give the sub-title compound (2.5 g).

¹HNMR(DMSO-d6)δ7.86(s，1H)，7.73(d，2H)，7.50(d，1H)，7.28(d，1H)，7.19(d，2H)，7.11(t，1H)，4.73(s，2H)，3.14(s，3H)。

iii)3- [ [4- (methylsulfonyl) phenyl]Thio group]-4- (5-pyrimidinyl) -1H-indole-1-acetic acid

The product of step (ii) (0.4g), phenylboronic acid (0.17g), tetrakis (triphenylphosphine) palladium (100mg) and 2M aqueous sodium bicarbonate solution (2ml) were dissolved in ethanol (10ml) and heated under reflux for 8 hours. The mixture was cooled to room temperature, diluted with EtOAc (100mL), washed with water and brine. The organic solution was dried (MgSO₄) Filtered and evaporated in vacuo and the residue purified by hplc to give the title compound (190 mg).

¹HNMR(DMSO-d6)δ8.93(s，1H)，8.58(s，1H)，7.93(s，1H)，7.70(d，1H)，7.52(d，2H)，7.37(t，1H)，7.03(d，1H)，6.70(d，2H)，5.15(s，2H)，3.12(s，3H)。

APCI-[M-H]438

Example 26

2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-4- (2-thienyl) -1H-indole-1-acetic acid

i)1- [ [4- (methylsulfonyl) phenyl ] methyl ester]Thio group]Acetone (II)

The product from step (i) example 21 (3.4g) was dissolved in acetone (100ml), potassium carbonate (3.0g) was added and chloroacetone (1.5ml) was added dropwise. The mixture was stirred at rt for 20 h, concentrated, partitioned between EtOAc and water, dried (MgSO)₄) And evaporated. The residue was purified by chromatography (50% EtOAc/hexanes as eluent) to give the sub-title compound (2.6 g).

¹HNMR(400MHz，CDCl₃)δ7.84(d，2H)，7.43(d，2H)，3.81(s，2H)，3.06(s，3H)，2.34(s，3H)。

APCI-[M-H]243

M.p.95-7℃。

ii) 4-bromo-2-methyl-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indoles

The sub-title compound was prepared by the method of example 3 step (i) using the product from step (i) (1.6g) and 3-bromophenylhydrazine hydrochloride (1.47 g). The product was purified by column chromatography (30% EtOAc/hexanes as eluent) to give the sub-title compound (0.5 g).

¹HNMR(CDCl₃)δ8.41(s，1H)，7.68(d，2H)，7.54(s，1H)，7.32(d，1H)，7.25(d，1H)，7.10(d，2H)，3.00(s，3H)，2.50(s，3H)。

APCI-[M-H]394

iii) 4-bromo-2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid, 1, 1-dimethylethyl ester

The subtitle compound was prepared by the method of example 1 step (ii) using the product from step (i) and tert-butyl bromoacetate. The product was purified by column chromatography (50% EtOAc/hexanes as eluent) to give the sub-title compound (0.5 g).

APCI+[M+H]510

iv) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-4- (2-thienyl) -1H-indole-1-acetic acid, 1, 1-dimethylethyl ester

A mixture of palladium acetate (24mg), tri-o-tolylphosphine (64mg) and methanol (6ml) was stirred under nitrogen for 10 minutes. (iii) A solution of the product of step (ii) in methanol (10ml) was added followed by sodium carbonate (1.12g) and thiophene-2-boronic acid (0.68 g). After stirring at 80 ℃ for 45 minutes, palladium acetate (24mg) was added) And a mixture of tri-o-tolylphosphine (64mg) and methanol (1ml), followed by addition of thiophene-2-boronic acid (0.2g) and toluene (5ml), and the reaction mixture was stirred at 80 ℃ for 1 hour. The reaction mixture was concentrated in vacuo, water was added and the mixture was extracted with dichloromethane. The organic layer was dried (MgSO₄) Then concentrated in vacuo. The residue was dissolved in methanol and treated with sodium hydroxide (5 ml). After one hour the reaction mixture was concentrated in vacuo and then purified by reverse phase HPLC to give the title compound (160 mg).

¹HNMR(DMSO-d6)δ7.58(m，3H)，7.38(d，1H)，7.18(t，1H)，6.99(d，1H)，6.87(m，3H)，6.78(s，1H)，4.98(s，2H)，3.11(s，3H)，2.38(s，3H)。

APCI-[M-H]456

Example 27

4- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

Prepared by the method of example 26 step (iv) using the product of example 26 step (ii) and 3, 5-dimethylisoxazolyl-4-boronic acid. The product was purified by reverse phase preparative column chromatography (eluent MeCN/NH)₃(aqueous)) was purified to give the title compound (6 mg).

¹HNMR(DMSO-d6)δ7.61(d，1H)，7.46(d，2H)，7.17(t，1H)，6.82(d，2H)，6.75(d，1H)，4.57(s，2H)，3.32(s，3H)，1.9(s，3H)，1.11(s，6H)。

APCI-[M-H]469

Example 28

4- (3-furyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

i)4- (3-furyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 26 step (iv) using the product from example 27 step (i) and furan-3-boronic acid. The product was not identified for use in step (ii).

ii)4- (3-furyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (i). The product was purified using hplc (eluent MeCN/NH)₃(aqueous)) was purified to give the title compound (60 mg).

¹HNMR(DMSO-d6)δ7.41-7.63(m，5H)，7.17(t，1H)，6.9-6.96(m，3H)，6.36(s，1H)，5.18(s，2H)，3.18(s，3H)，2.4(s，3H)。

APCI-[M-H]440

Example 29

2-methyl-4- [ (methylsulfonyl) amino group]-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

i) 2-methyl-4- [ (methylsulfonyl) amino group]-1H-indole-1-acetic acid

Thiosalicylic acid (0.35g) was added to a solution of the product of step (i) in example 2 (0.47g) in TFA (10 ml). Mixing the mixtureStirred at room temperature for 1 hour and then heated at 60 ℃ for 4 hours. TFA was evaporated and the residue was dissolved in EtOAc. The organics were washed with aqueous sodium bicarbonate and brine, dried (MgSO)₄) And evaporated. The residue was purified by column chromatography (50% EtOAc/hexanes as eluent) to give the sub-title compound (0.16 g).

¹HNMR(DMSO-d6)δ9.4(s，1H)，7.19(d，1H)，6.95-7.04(m，2H)，6.53(d，1H)，5.04(s，2H)，4.15(q，2H)，2.91(s，3H)，2.32(d，3H)，1.21(t，3H)。

ii) 2-methyl-4- [ (methylsulfonyl) amino]-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from step (i) and the product from example 21 step (i).

¹HNMR(DMSO-d6)δ8.76(s，1H)，7.74(dd，2H)，7.44(d，1H)，7.07-7.21(m，4H)，5.29(s，2H)，4.19(q，2H)，3.14(s，3H)，2.76(s，3H)，2.36(s，3H)，1.22(t，3H)。

iii) 2-methyl-4- [ (methylsulfonyl) amino]-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

The title compound was prepared from the product of step (ii) by the method of example 1 step (v) and recrystallised from ethanol to give the title compound as a pale pink solid (75 mg).

¹HNMR(DMSO-d6)δ8.78(s，1H)，7.74(d，2H)，7.44(d，1H)，7.13-7.2(m，3H)，7.08(d，1H)，5.15(s，2H)，3.14(s，3H)，2.76(s，3H)，2.36(s，3H)。

APCI+[M+H]469

Example 30

2-methyl-5- [ (methylsulfonyl) amino group]-3- [ [3- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

i) O- [3- (methylsulfonyl) phenyl]Thiocarbamic acid (carbamonothioic acid), dimethyl ester (dimethyl ester)

Sodium hydride (0.33g) was added to a DMF (10ml) solution of 3- (methylsulfonyl) phenol and stirred for 30 minutes. Dimethylcarbamoylchloride (1.1g) was added and the reaction mixture was heated at 80 ℃ for 4 hours. The mixture was poured into aqueous ammonium chloride, extracted with EtOAc, washed with water, and dried (MgSO)₄) And evaporated in vacuo. The residue was purified by column chromatography (30-50% ether/hexane as eluent) to give the sub-title compound (1.3 g).

¹HNMR(DMSO-d6)δ7.82(dd，1H)，7.69(t，1H)，7.59(t，1H)，7.39(dd，1H)，3.47(s，3H)，3.37(s，3H)，3.08(s，3H)。

APCI+[M+H]260

ii) S- [3- (methylsulfonyl) phenyl]Thiocarbamic acid, dimethyl ester

The product of step (i) (1.1g) was dissolved in N, N-dimethylaniline (3ml) and heated at 220 ℃ for 8 hours. The mixture was cooled, poured into 2M hydrochloric acid and extracted with EtOAc. The organics were washed with 2M hydrochloric acid and water, dried (MgSO)₄) And evaporated in vacuo. The oil residue was treated with diethyl ether to give the sub-title compound as a white solid (0.9 g).

¹HNMR(DMSO-d6)δ8.07(d，1H)，7.94(dd，1H)，7.79(dd，1H)，7.59(t，1H)，3.04-3.12(m，6H)，3.07(s，3H)。

APCI+[M+H]260

iii)3- (methylsulfonyl) benzenethiol

The product of step (ii) (0.9g) was suspended in 2M sodium hydroxide (70ml) and heated under reflux for 1.5h to give a brown solution. The solution was cooled, extracted with EtOAc and dried (MgSO₄) And evaporated to give the sub-title compound (0.45 g).

¹HNMR(DMSO-d6)δ7.84(m，1H)，7.7(m，1H)，7.52(m，1H)，7.44(t，1H)，3.67(s，1H)，3.06(s，3H)。

APCI-[M-H]187

iv) 2-methyl-5- [ (methylsulfonyl) amino]-3- [ [3- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product of step (iii) (0.22g) and the product of example 5 step (iii) and recrystallised from ethanol.

¹HNMR(DMSO-d6)δ7.58(m，2H)，7.34(m，2H)，7.18(t，2H)，6.28(s，1H)，4.89(s，2H)，4.25(q，2H)，3.06(s，3H)，2.96(s，3H)，2.49(s，3H)，1.28(t，3H)。

APCI+[M+NH₄]514

M.p.176-8℃。

v) 2-methyl-5- [ (methylsulfonyl) amino]-3- [ [3- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole Indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (iv). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried to give the title compound (0.19 g).

¹HNMR(DMSO-d6)δ9.35(s，1H)，7.61(m，1H)，7.57(d，1H)，7.53(d，1H)，7.46(t，1H)，7.24(d，1H)，7.18(m，1H)，7.08(dd，1H)，5.05(s，2H)，3.17(s，3H)，2.82(s，3H)，2.41(s，3H)。

APCI+[M+NH₄]469

M.p.233-6℃。

Example 31

2-methyl-5- [ (methylsulfonyl) amino group]-3- [ [2- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

i) 1-fluoro-2- (methylsulfonyl) benzene

A solution of oxone (17g) in water (85ml) was added to a solution of 2-fluorothioanisole in acetonitrile (85ml) and the mixture was stirred at room temperature for 20 h. The mixture was concentrated, extracted with EtOAc, washed with water, and dried (MgSO)₄) And evaporated to give the sub-title compound (5.9 g).

¹HNMR(DMSO-d6)δ7.98(t，1H)，7.66(m，1H)，7.35(t，1H)，7.26(t，1H)，3.23(s，3H)。

ii)2- (methylsulfonyl) benzenethiol

The subtitle compound was prepared by the method of example 26 step (i) using the product from step (i) (5.4 g).

¹HNMR(DMSO-d6)δ.8.05(d，1H)，7.46(m，2H)，7.35(m，1H)，4.84(s，1H)，3.21(s，3H)。

APCI-[M-H]187

iii) 2-methyl-5- [ (methylsulfonyl) amino]-3- [ [2- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from step (ii) (1.3g) and the product from example 5 step (iii) (0.6 g). The product was purified by column chromatography (50-67% EtOAc/hexanes as eluent) to give the sub-title compound (0.18 g).

¹HNMR(DMSO-d6)δ8.05(d，1H)，7.16-7.27(m，4H)，6.77(dd，1H)，6.33(s，1H)，4.9(s，2H)，4.26(q，2H)，3.44(s，3H)，2.88(s，3H)，2.5(s，3H)，1.21(t，3H)。

APCI+[M+NH₄]514

M.p.174-7℃。

v) 2-methyl-5- [ (methylsulfonyl) amino]-3- [ [2- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid

Prepared by the method of example 1, step (v) using the product of step (iii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried to give the title compound.

¹HNMR(DMSO-d6)δ9.38(s，1H)，7.92(dd，1H)，7.53(d，1H)，7.39(m，1H)，7.31(m，1H)，7.16(d，1H)，7.10(dd，1H)，6.75(dd，1H)，5.11(s，2H)，3.51(s，3H)，2.81(s，3H)，2.41(s，3H)。

APCI+[M+NH₄]486

M.p.227-30℃。

Example 32

2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (5-pyrimidinyl) -1H-indole-1-acetic acid

i) 5-bromo-2-methyl-3- [ [4- (methylsulfonyl) phenyl ] methyl ester]Thio group]-1H-indoles

The subtitle compound was prepared by the method of example 3 step (i) using the product from example 26 step (i) (2.5g) and 4-bromophenylhydrazine hydrochloride (2.3 g). The reaction mixture was evaporated to half volume and the resulting precipitate was filtered, washed with diethyl ether and dried to give the sub-title compound (2.2 g).

¹HNMR(DMSO-d6)δ12.04(s，1H)，7.73(d，2H)，7.4(m，2H)，7.27(dd，1H)，7.14(d，2H)，3.14(s，3H)，2.45(s，3H)。

APCI-[M-H]394

ii) 5-bromo-2-methyl-3- [ [4- (methylsulfonyl) phenyl ] methyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The sub-title compound was prepared from the product of step (i) by the method of example 1 step (ii) and the product was purified by column chromatography (33-50% EtOAc/hexanes as eluent).

¹HNMR(DMSO-d6)δ7.71(d，2H)，7.64(d，1H)，7.34(dd，1H)，7.16(d，1H)，7.1(d，2H)，4.88(s，2H)，4.24(q，2H)，3.0(s，3H)，2.47(s，3H)，1.29(t，3H)。

APCI+[M+H]482

iii) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (5-pyrimidinyl) -1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 3 step (iii) using the product of step (ii) and pyrimidine-5-boronic acid. (iv) applying to step (iii) without identification.

iv) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (5-pyrimidinyl) -1H-indole-1-acetic acid

The title compound was prepared as in example 1 step (v) using the product from step (iii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried to give the title compound (21 mg).

¹HNMR (DMSO-d6)δ9.38(s，1H)，9.09(s，2H)，7.71-7.79(m，4H)，7.64(dd，1H)，7.17(d，2H)，5.23(s，2H)，3.12(s，3H)，2.45(s，3H)。

APCI+[M+H]454

M.p.＞290℃。

Example 33

2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (2-thienyl) -1H-indole-1-acetic acid

i) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (3-thienyl) -1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 3 step (iii) using the product of step (ii) and thiophene-2-boronic acid. Used without further characterization.

ii) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (2-thienyl) -1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (ii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried, then recrystallized from acetonitrile to give the title compound.

¹HNMR(DMSO-d6)δ7.72(d，2H)，7.63(d，1H)，7.53(m，2H)，7.42(d，1H)，7.39(t，1H)，7.18(d，2H)，7.08(m，1H)，5.15(s，2H)，3.13(s，3H)，2.42(s，3H)。

APCI+[M+H]458

Example 34

5- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

i)5- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 3 step (iii) using the product of step (ii) and 3, 5-dimethylisoxazolyl-4-boronic acid. It was used in the next step without identification.

ii)5- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (ii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered, dried and recrystallized in cyclohexane/ethanol to give the title compound.

¹HNMR(DMSO-d6)δ7.73(d，2H)，7.66(d，1H)，7.24(d，1H)，7.19(m，3H)，5.19(s，2H)，3.13(s，3H)，2.44(s，3H)，2.31(s，3H)，2.13(s，3H)。

APCI+[M+H]471

Example 35

2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (3-pyridinyl) -1H-indole-1-acetic acid

i) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (3-pyridinyl) -1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 3 step (iii) using the product of step (ii) and pyridine-3-boronic acid.

¹HNMR(CDCl₃)δ8.85(s，1H)，8.54(s，1H)，7.87(m，1H)，7.73-7.69(m，3H)，7.49(d，1H)，7.39(d，1H)，7.33(t，1H)，7.14(d，2H)，4.95(s，2H)，4.26(q，2H)，2.98(s，3H)，2.51(s，3H)，1.29(t，3H)。

ii) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (3-pyridinyl) -1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (ii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried to give the title compound (20 mg).

¹HNMR(DMSO-d6)δ8.84(d，1H)，8.5(dd，1H)，8.1(m，1H)，7.73-7.69(d，3H)，7.63(d，1H)，7.53(dd，1H)，7.43(dd，1H)，7.18(d，2H)，5.22(s，2H)，3.12(s，3H)，2.44(s，3H)。

APCI+[M+H]453

Example 36

2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5- (1H-pyrazol-4-yl) -1H-indole-1-acetic acid

i) 2-methyl-3- [ [4- (methylsulfonyl) phenyl]Thio group]-5-(1]H-pyrazol-4-yl) -1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 3 step (iii) using the product from step (ii) and (1H-pyrazol-4-yl) -boronic acid and was used in the next step without identification.

ii) 2-methyl-3- [ [4- (methylsulfonyl) sulfonic acidAcyl) phenyl]Thio group]-5- (1H-pyrazol-4-yl) -1H-indole-1-acetic acid

The title compound was prepared by the method of example 1 step (v) using the product from step (ii). The basic solution was adjusted to pH5 with 0.5M hydrochloric acid and the resulting precipitate was filtered and dried to give the title compound.

¹HNMR(DMSO-d6)δ7.97(s，2H)，7.71(d，2H)，7.56(d，1H)，7.53(s，1H)，7.45(dd，1H)，7.16(d，2H)，5.14(s，2H)，3.12(s，3H)，2.4(s，3H)。

APCI+[M+H]442

Example 37

4- (acetylamino) -3- [ (4-cyanophenyl) thio]-2-methyl-1H-indole-1-acetic acid

i)4- (acetylamino) -3- [ (4-oxyphenyl) thio group]-2-methyl-1H-indole-1-acetic acid ethyl ester

The subtitle compound was prepared by the method of example 5 step (iv) using the product from example 13 step (i) (330mg) and 4-mercaptobenzonitrile (330 mg). Purification by column chromatography (3% EtOAc/dichloromethane as eluent) afforded the sub-title compound (300 mg).

¹HNMR(DMSO-d6)δ9.33(s，1H)，8.07(d，1H)，7.47(d，2H)，7.23(t，1H)，7.09(d，2H)，7.02(d，1H)，4.88(s，2H)，4.23(q，2H)，2.44(s，3H)，1.93(s，3H)，1.28(t，3H)。

APCI+[M+H]408

M.p.263-5℃。

ii)4- (acetylamino) -3- [ (4-cyanophenyl) thio]-2-methyl-1H-indole-1-acetic acid

¹HNMR(DMSO-d6)δ7.63(d，2H)，7.37(d，1H)，7.27(d，1H)，7.13(t，1H)，7.07(d，2H)，5.13(s，2H)，2.37(s，3H)，1.79(s，3H)。

APCI+[M+H]380

Pharmacological data

Ligand binding assays

[³H]PGD₂Purchased from Perkin Elmer Life Sciences, and having a specific activity of 100-210 Ci/mmol. All other chemical reagents were of analytical grade.

HEK cells expressing rhCRTh 2/G.alpha.16 were routinely maintained in DMEM containing 10% fetal bovine serum (HyClone), 1mg/ml geneticin, 2 mML-glutamine and 1% essential amino acids. To prepare membranes, the adhesion transfected HEK cells were grown in fusion in two layers of tissue culture vessels (factory) (Fisher, catalog number TKT-170-070E). The maximum level of receptor expression was induced by the addition of 500mM sodium butyrate for the last 18 hours of culture. The adherent cells were washed once with phosphate buffered saline (PBS, 50ml per cell dish) and isolated by adding 50ml per cell dish of ice-cold membrane homogenization buffer [20mM HEPES (pH7.4), 0.1mM dithiothreitol, 1mM EDTA, 0.1mM phenylmethylsulfonyl fluoride and 100. mu.g/ml bacitracin ]. Cells were pelleted at 220Xg for 10 min at 4 ℃, re-suspended in the original half volume of fresh membrane homogenization buffer and disrupted by bursting with a Polytron homogenizer for 2X20 seconds, keeping the tube in ice at all times. The undamaged cells were removed by centrifugation at 220Xg for 10 min at 4 ℃ and the membrane fraction was precipitated by centrifugation at 90000Xg for 30 min at 4 ℃. The final pellet was re-suspended in 4ml membrane homogenization buffer per cell vessel and the protein content was determined. The membrane was stored in suitable aliquots at-80 ℃.

All assays were performed in Corning Net bottom white 96-well NBS plates (Fisher). The CRTh 2-containing HEK cell membrane was coated onto SPA PVT WGA beads (Amersham) prior to assay. For coating, the membrane is incubated with the beads, typically 25. mu.g of membrane protein per mg of beads, with constant stirring overnight at 4 ℃. (the optimal coating concentration for each membrane batch was determined) the beads were pelleted by centrifugation (800 Xg7 min at 4 ℃), washed once with assay buffer (50 mM HEPES pH7.4 containing 5mM magnesium chloride) and finally re-suspended in assay buffer at a bead concentration of 10 mg/ml.

Each assay contained 20. mu.l of 6.25nM in assay buffer³H]PGD₂20. mu.l of membrane-saturated SPA strain granules, and 10. mu.l of a compound solution and 13, 14-dihydro-15-keto prostaglandin D₂(DK-PGD₂For non-specific binding assays, Cayman chemical reagents). Mixing the compound with DK-PGD₂Dissolved in DMSO and diluted with the same solvent to 100 times the desired final concentration. The assay buffer was added to give a final concentration of 10% DMSO (compound is now 10 times the desired final concentration) and this is the solution to be added to the assay plate. The assay plates were incubated at room temperature for 2 hours and counted on a WallacMicrobeta liquid scintillation counter (1 minute per well).

The compounds of formula (I) having IC₅₀The value is less than (<) 10. mu.M.

Specifically, pIC of example 14₅₀pIC of example 26 ═ 6.65₅₀8.35, and pIC of example 34₅₀＝9.4。

Claims

1. A compound of formula I:

wherein:

R¹is NR⁴COR⁶、NR⁴SO₂NR⁵R⁶、NHSO₂R⁵、NHCOR⁶Or a heteroaryl group selected from pyridine,pyrimidine, pyrazole, furan, isoxazole or pyrazine, said heteroaryl group optionally being substituted by C_1-3Alkyl substitution;

R²is hydrogen or C_1-7An alkyl group;

R³is quinolinyl or phenyl, each optionally substituted with one or more substituents independently selected from hydrogen, halogen, CN, SO₂R⁴、OR⁴And C_1-6Alkyl radical, said C_1-6Alkyl is optionally substituted with one or more substituents independently selected from halogen atoms;

R⁴represents C_1-6An alkyl group;

R⁵and R⁶Independently represents a hydrogen atom, C_1-6Alkyl, phenyl or as above for R¹The last three groups of heteroaryl, as defined, are optionally substituted by one or more groups independently selected from NR¹⁴R¹⁵And C_1-3Alkyl is substituted by a substituent;

R¹⁴and R¹⁵Each independently represents a hydrogen atom or C₁-C₆An alkyl group.

2. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R²Is C_1-6An alkyl group.

3. A compound according to claim 2, or a pharmaceutically acceptable salt thereof, wherein R³Is phenyl optionally substituted by halogen or methyl sulfone.

4. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

5. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

6. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -2-methyl-4- (5-pyrimidinyl) -1H-indole-1-acetic acid.

7. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -2-methyl-4-pyrazinyl-1H-indole-1-acetic acid.

8. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (2-chlorophenyl) thio ] -2-methyl-5- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

9. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (3-chlorophenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

10. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

11. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (3-methoxyphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

12. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-methoxyphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

13. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (2-trifluoromethylphenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

14. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (8-quinolyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

15. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (2- (methylethyl) phenyl) thio ] -2-methyl-4- [ (methylsulfonyl) amino ] -1H-indole-1-acetic acid.

16. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

5- (acetylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

17. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (Acetylethylamino) -3- [ (4-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

18. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (benzoylamino) -3- [ (4-chlorophenyl) thio ] - -2-methyl-1H-indole-1-acetic acid.

19. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -3- [ (3-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

20. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -4- [ [ (dimethylamino) sulfonyl ] amino ] -2-methyl-1H-indole-1-acetic acid.

21. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -2-methyl-4- [ [ (1-methyl-1H-imidazol-4-yl) sulfonyl ] amino ] -1H-indole-1-acetic acid.

22. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ (4-chlorophenyl) thio ] -4- [ [ (dimethylamino) acetyl ] amino ] -2-methyl-1H-indole-1-acetic acid.

23. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

24. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -3- [ (2-chlorophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

25. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -2-methyl-3- [ [4- (ethylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

26. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

3- [ [4- (methylsulfonyl) phenyl ] thio ] -4- (5-pyrimidinyl) -1H-indole-1-acetic acid.

27. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

28. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (3-furyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

29. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-4- [ (methylsulfonyl) amino ] -3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

30. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-5- [ (methylsulfonyl) amino ] -3- [ [3- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

31. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-5- [ (methylsulfonyl) amino ] -3- [ [2- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

32. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (5-pyrimidinyl) -1H-indole-1-acetic acid.

33. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

5- (3, 5-dimethyl-4-isoxazolyl) -2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -1H-indole-1-acetic acid.

34. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (3-pyridyl) -1H-indole-1-acetic acid.

35. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (1H-pyrazol-4-yl) -1H-indole-1-acetic acid.

36. A compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is

4- (acetylamino) -3- [ (4-cyanophenyl) thio ] -2-methyl-1H-indole-1-acetic acid.

37. A compound, or a pharmaceutically acceptable salt thereof, selected from:

3- [ (4-chlorophenyl) thio ] -4- [ (cyclopropylcarbonyl) amino ] -2-methyl-1H-indole-1-acetic acid;

3- [ (4-chlorophenyl) thio ] -4- [ [ (ethylamino) carbonyl ] amino ] -2-methyl-1H-indole-1-acetic acid;

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -4- (2-thienyl) -1H-indole-1-acetic acid; and

2-methyl-3- [ [4- (methylsulfonyl) phenyl ] thio ] -5- (3-thienyl) -1H-indole-1-acetic acid.

38. Use of a compound of any one of claims 1-37 or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating a prostaglandin D2 mediated disease.

39. Use according to claim 38, wherein the disease is asthma or rhinitis.

40. Use of a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of CRTh 2-mediated diseases.

41. The use according to claim 40, wherein the disease is asthma.

42. A process for preparing a compound of formula I according to claim 1, or a pharmaceutically acceptable salt thereof, which process comprises reacting a compound of formula II:

wherein R is¹、R²And R³Is as defined for formula I in claim 1 or a protected derivative thereof,

with a compound of formula IIA:

L-CH₂CO₂R¹⁷ IIA

wherein R is¹⁷Is an alkyl radical andl is a leaving group, and

an ester group R¹⁷Hydrolysis to the corresponding acid;

then optionally in any order as follows:

● removal of protecting groups

● to form a pharmaceutically acceptable salt.

43. The method of claim 42, wherein L in the compound of formula IIA is a halogen atom.

44. A compound of formula II as defined in claim 42.