[go: up one dir, main page]

CA2528626A1 - Indoles useful in the treatment of inflammation - Google Patents

Indoles useful in the treatment of inflammation Download PDF

Info

Publication number
CA2528626A1
CA2528626A1 CA002528626A CA2528626A CA2528626A1 CA 2528626 A1 CA2528626 A1 CA 2528626A1 CA 002528626 A CA002528626 A CA 002528626A CA 2528626 A CA2528626 A CA 2528626A CA 2528626 A1 CA2528626 A1 CA 2528626A1
Authority
CA
Canada
Prior art keywords
compound
optionally substituted
group
substituents selected
carboxylic acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
CA002528626A
Other languages
French (fr)
Inventor
Kristofer Olofsson
Edgars Suna
Benjamin Pelcman
Vita Ozola
Martins Katkevics
Ivars Kalvins
Wesley Schaal
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Biolipox AB
Original Assignee
Individual
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE0302035A external-priority patent/SE0302035D0/en
Application filed by Individual filed Critical Individual
Publication of CA2528626A1 publication Critical patent/CA2528626A1/en
Abandoned legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/08—Antiseborrheics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/42—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Immunology (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Diabetes (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Communicable Diseases (AREA)
  • Neurology (AREA)
  • Oncology (AREA)
  • Biomedical Technology (AREA)
  • Neurosurgery (AREA)
  • Reproductive Health (AREA)
  • Endocrinology (AREA)
  • Urology & Nephrology (AREA)
  • Emergency Medicine (AREA)
  • Obesity (AREA)
  • Cardiology (AREA)
  • Hematology (AREA)
  • Virology (AREA)
  • Vascular Medicine (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pregnancy & Childbirth (AREA)
  • Heart & Thoracic Surgery (AREA)

Abstract

There is provided a compound of formula (I), wherein X, Y, Z, R1, R2, R3, R4 and R5 have meanings given in the description, and pharmaceutically-acceptable salts thereof, which compounds are useful in the treatment of diseases in which inhibition of the activity of microsomal prostaglandin E synthase-1 is desired and/or required, and particularly in the treatment of inflammation.

Description

INDOLES USEFUL IN THE TREATMENT OF INFLAMMATION
Field of the Invention This invention relates to.novel pharmaceutically-useful compounds, which compounds are useful as inhibitors of microsomal prostaglandin E synthase-1 (mPGES-1). The compounds are of potential utility in the treatment of inflammatory diseases. The invention also relates to the use of such compounds as medicaments, to pharmaceutical compositions containing 1 o them, and to synthetic routes for their production.
Background of the Invention There are many diseases/disorders that are inflammatory in their nature.
Is One of the major problems associated with existing treatments of inflammatory conditions is a lacy of efficacy and/or the prevalence of side effects (real or perceived).
Inflammatory diseases that affect the population include asthma, 2o inflammatory bowel disease, rheumatoid arthritis, osteoarthritis, rhinitis, conjunctivitis and dermatitis.
Inflammation is also a common cause of pain. Inflammatory pain may arise for numerous reasons, such as infection, surgery or other trauma.
25 Moreover, several malignancies are known to have inflammatory components adding to the symptomatology of the patients.
The cyclooxygenase (COX) enzyme exists in two forms, one that is constitutively expressed in many cells and tissues (COX-1), and one that is induced by pro-inflammatory stimuli, such as cytokines during an inflammatory response (COX-2).
COXs metabolise arachidonic acid to the unstable intermediate s prostaglandin HZ (PGH2). PGH2 is further metabolised to other prostaglandins including PGEZ, PGF2a, PGD2, prostacyclin and tllromboxane A2. These arachidonic acid metabolites are known to have pronounced physiological and pathophysiological activity including pro-inflammatory effects.
PGE2 in particular is known to be a strong pro-inflammatory mediator, and is also known to induce fever and pain. Consequently, numerous drugs have been developed with a view to inhibiting the formation of PGE2, including "NSAIDs" (non-steroidal antiinflammatory drugs) and "coxibs"
1s (selective COX-2 inhibitors). These drugs act predominantly by inhibition of COX-1 and/or COX-2, thereby reducing the formation of PGE2.
However, the inhibition of COXs has the disadvantage that it results in the reduction of the formation of all metabolites of arachidonic acid, some of 2o which are known to have beneficial properties. In view of this, drugs which act by inhibition of COXs are therefore known/suspected to cause adverse biological effects. For example, the non-selective inhibition of COXs by NSAIDs may give rise to gastrointestinal side-effects and affect platelet and renal function. Even the selective inhibition of COX-2 by coxibs, whilst 2s reducing such gastrointestinal side-effects, is believed to give rise to cardiovascular problems.
An alternative treatment of inflammatory diseases that does not give rise to the above-mentioned side effects would thus be of real benefit in the clinic.
In particular, a drug that inhibits (preferably selectively) the transformation of PGH2 to the pro-inflammatory mediator PGE2 might be expected to reduce the inflammatory response in the absence of a corresponding reduction of the formation of other, beneficial arachidonic acid metabolites.
s Such inhibition would accordingly be expected to alleviate the undesirable side-effects mentioned above.
PGH2 may be transformed to PGE2 by prostaglandin E synthases (PGES).
Two microsomal prostaglandin E synthases (mPGES-1 and mPGES-2), and one cytosolic prostaglandin E synthase (cPGES) have been described.
mPGES-1 belongs to the membrane-associated proteins in the eicosanoi~d and glutathione metabolism (MAPEG) family. Other members of this family include the 5-Iipoxygenase-activating protein (FLAP), leukotriene C4 Is synthase and microsomal glutathione S-transferases (MGSTI, MGST2 and MGST3).
Thus, agents that are capable of inhibiting the action of mPGESs and, in particular, InPGES-l, and thus reducing the formation of the specific 2o arachidonic acid metabolite PGE2, are likely to be of benefit in the treatment of inflammation.
Pri~r Art 2s Various indoles, and derivatives thereof, have been disclosed in international patent applications WO 01/30343, WO 96/03377 and WO
99/33800, US patents Nos. S,I89,054 and 6,25,083 and European patent application EP 483 881. However, none of these documents disclose or suggest the use of the compounds disclosed therein in the treatment of 3o inflammation.
Structurally related indoles have been disclosed for potential use in the treatment of inflammation in international patent application WO 99105104 and European patent application EP 985 666. However these documents do s not disclose or suggest indoles that are substituted in the 1-position.
Other related indoles have been disclosed for potential use in the treatment of inflammation in international patent application WO 94/13662, US patent No. 5,081,145 and European patent application EF 535 924. However, 1o none of these documents disclose or suggest indoles that are directly substituted at the benzenoid moiety of the indole ring with an aryl or heteroaryl group.
US patent No. 5,081,138 and European patent application EP 166 591 Is disclose indoles for potential use in the treatment of inflammation.
However, neither of these documents disclose or suggest indoles that are directly substituted at the 2-position of the indole ring with a carboxylic acid group or a derivative thereof.
2o International patent applications WO 99/07351 and WO 99/07678 disclose indoles for potential use in the treatment of inflammation but do not disclose or suggest indoles that are substituted in the indolic 3-position by an aryl, a heteroaryl or an amide group.
2s International patent applications WO 00/46198, WO 00/46197, WO
00/46195, WO 00/46199, WO 94/14434, WO 96/18393 and WO 02/30895 describe indole compounds for potential use in the treatment of inflammation. However, there is no specific disclosure in any of these documents of substitution at the benzenoid moiety of the indole ring with an 3o aryl or heteroaryl group.
Tnternational patent applications WO 98/08818 and WO 99/43672 also disclose indoles for potential use in the treatment of inflammation.
However, there is no specific disclosure in either of these documents of s indoles substituted in the 3-position by an aryl or heteroaryl group, or a nitrogen derivative, such as an amine, amide or sulfonamide group attached to the indole ring through the nitrogen atom.
Finally, international patent applications WO 99/43654 and WO 99/43651 1o describe indole compounds for potential use in the treatment of inflammation. These documents do not specifically disclose indoles substituted in the 3-position by an aryl or heteroaryl group, or a nitrogen derivative, such as an amine, amide or sulfonamide group attached to the indole ring through the nitrogen atom, and which are further substituted at 1s the ben~enoid moiety of the indole ring with an aryl or heteroaryl group.
1)iscIosure ~f the invention According to the invention there is provided a compound of formula I, R2 )( \ ~ 1 Ra ~ N

wherein X represents:
i) an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A; or ii) -N(R6)-E-R';
s E,represents a single bond, -C(O)- or -S(O)ri ;
Y represents -CH20H, -C(O)N(H)R8, -C(O)N(H)OR8 or -C(O)OR8;
Z represents a Cl_s all~ylene or a C2_8 heteroalkylene chain, both of which:
to (i) optionally contain one or more unsaturations (for example double or triple bonds);
(ii) are optionally substituted by one or more substituents selected from halo, -R8, -N(Rg)(R9), -ORg and =O; and/or (iii) may form part of an additional 3- to 8-membered ring formed Is between any one or more (e.g. one or two) members of the C1_g alkylene or C2_8 heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms , and/or 1 to 3 unsaturations (for example double or triple bonds) and which ring is itself optionally substituted by one or more substituents selected from halo, -R8, hI(Rg)(R9), -OR8 and =O;
R1 represents an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A;
one of the groups R~, R3, R4 and R5 represents an aryl group or a heteroaryl 2s group (both of which are optionally substituted by one or more substituents selected from A) and:
a) the other groups are independently selected from hydrogen, Gl, an aryl group, a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A), C1_6 alkyl, C3_l~
(e.g. C3_g) cycloalkyl, C2_6 alkenyl, C~_6 alkynyl or C3_8 heterocycloall~yl (which latter f ve groups are optionally substituted by one or more substituents selected from Gl and/or Q1); and/or b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, a 5- to 6-membered ring, optionally containing 1 or more (e.g. 1 to 3) heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;
1o A represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) a C~_6 alkyl, C3_to (e.g. C3_8) cycloalkyl, C~_6 alkenyl, C2_6 alkynyl or C3_8 heterocycloalkyl group, all of which are optionally substituted by one is or more substituents selected from Gl and/or Q1; or III) a Gl group; or IV) two adjacent A substituents may be linked together to form, along with the essential atoms of the aryl or heteroaryl group to which the two A
substituents are attached, a further 5- to 6-membercd ring, optionally 2o containing 1 or more (e.g. 1 to 3) heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -ORg and =O;
2s Gl represents, on each occasion when mentioned above, halo, cyano, -N3, NO2, -ONOa or Al-Rlo;
wherein AI represents a single bond or a spacer group selected from -C(QZ)A2-, -S(O)nA3-, -N(Rll)A4-, -OA5- and -S-, in which:
A~ represents A6 or -S-;
3o A3 represents A6;
A4 represents A', -C(Q2)N(Rm)C(Qa)N(Rn)-, -C(Q2)N(Rm)C(Qa)O-, -C(QZ)N(R11)S(0)nN(R11)-~ -C(QZ)S-~ -S(O)nN(Rn)C(Q2)N.(R11)--S(O)nN(R.l~)L,(Qz)~-~ -S(O)nN(Rll)S(O)nN(R11)- or -S(O)n0-;
AS represents A' or -S(O)n0-;
s A6 represents a single bond, -N(Rl1)- or -O-;
A' represents a single bond, -C(QZ)-, -C(QZ)N(Rll)-, -C(Q2)O-, -S(O)n or -S(O)nN(Rn)~
Q1 and QZ independently represent, on each occasion when mentioned above, =O, =S, NRl°, NN(Rl°)(Rli), NORI°, NS(O)2N(Rz°)(Rll), NCN, =C(H)N02 or =C(R~°)(R1)?
R6 and R' independently represent, on each occasion when mentioned above:
is I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; or III) a C1_6 alkyl, C3_lo (e.g. C3_g) cycloalkyl, CZ_6 alkenyl, C2_6 alkynyl or C3_8 heterocycloalkyl group, all of which groups are optionally substituted 2o by one or more substituents selected from G2 and/or Q3; or R6 and R~ may be linked together to form along with the N atom and E- group to which R6 and R7 are respectively attached, a 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is optionally substituted by 2s one or more substituents selected from GZ and/or Q3;
B represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2 and/or wherein any 3o two adjacent atoms of the aryl or heteroaryl group may be linked together to form a further 5- to 6-membered ring, optionally containing 1 or more (e.g.
1 to 3) heteroatoms and/or 1 to 3 unsaturations (for example double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;
s II) a C1_6 alkyl, C3_lo (e.g. C;_s) cycloalkyl, C2_6 alkenyl, C2_6 alkynyl or C3_g heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G2 and/or Q3; or III) a GZ group; or I~ two adjacent B substituents may be linked together to form, along to with the essential atoms of the aryl or heteroaryl group to which the two B
substituents are attached, a further 5- to 6-membered ring, optionally containing 1 or more (e.g. 1 to 3) heteroatoms and/or 1 to 3 unsaturations (e.g. double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -ORg and =O;
1s G2 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONOZ or Ag_y2 wherein A8 represents a single bond or a spacer group selected from -C(Q4)A9-, -S(C)nAlo-' -N(Rl3)Al l-' _OA12- and -S-, in which:
2o A9 represents Al3 or -S-;
Al° represents Als;
All represents A14, -C(Q4)N(R13)C(Q4)N(Rl3)-~ -C(Q4)N(R13)C(Q4)~-, -C(Q4)N(R13)s(~)nN(Rl3)-~ -~'(Q4)'-~'-a -,f (~)nN(RI3)C(Q4)N(R13)-' -S(~)nN(Rl3)C(Q4)~-~ -s(o)nN(Rl3)~(~)nN(Rl3)- pr -s(O)n~-2s Ala represents Al4 or -S(O)n0-;
Al3 represents a single bond, -N(Rl3)- or -O-;
Al4 represents a single bond, -C(Q4)-, -C(Q4)N(Rl3)-, -C(Q4)O-, -S(O)ri or -S(O)nN~l3)~

Q3 and Q4 independently represent, on each occasion when mentioned above, =O, =S, NR12, NN(RiZ)(Rm)? NORtl, NS(O)2N(R'l)(Rl''), NCN, =C(H)N02 or =C(R~2)(RI3);
s Rg, R9, Rr°, Rn, R12 and RI3 are independently selected from:
i) hydrogen;
ii) an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G3 and/or wherein any two adjacent atoms of the aryl or heteroaryl group may be linked together to Io form a further 5- to 6-membered ring, optionally containing 1 or more (e.g.
1 to 3) heteroatoms, which ring is itself optionally substituted by one or more substituents selected from halo, -R14, -ORI4 and =O; or iii) a CI_6 alkyl, C3_lo (e.g. C3_8) cycloalkyl, C2_6 alkenyl, C2_6 alkynyl or C3_8 heterocycloalkyl group, all of which are optionally substituted by one Is or more substituents selected from G3 and/or Wl; or any pair of Rg, R9, Rl°, Rli, R~2 and R13 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms, a further 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example 2o double or triple bonds), which ring is itself optionally substituted by one or more substituents selected from G3 and/or Wl;
G3 represents, on each occasion when mentioned above, halo, cyano, -N3, -N02, -ON02 or AI5-R15;
2s wherein Als represents a single bond or a spacer group selected from -C(,WZ)Ai6-, -S(O)nAm-, -N(Ri6)Ais-, -OAIg- and -S-, in which:
A16 represents A2° or -S-;
Al' represents AZO;

AIg represents A21, -C(W2)N(RI6)C(W2)N(R16)-, -C(WZ)N(R16)C(Wz)O--C(W2)N(R16)S(~)nN(Ri6)-~ -C(Wa)S-~ -S(O)nN(RI6)C(Wa)N(Rls)--S(O)nN(R16)C(Wz)O-~ -S(O)nN(RI6)S(O)nN(RI6)- or -S(O)n~-;
AI9 represents AZI or -S(O)nO-;
s A2° represents a single bond, -N(RI6)- or -O-;
A21 represents a single bond, -C(W2)-, -C(WZ)N(RI6)-, -C(WZ)O-, -S(O)ri or -S(O)nN(R~6)~
WI and W2 independently represent, on each occasion when mentioned to above, =O, =S, KRIS, NN(Rls)(R16), NORIS, I~TS(O)~N(Rls)(Rl6)~
NCN, =C(H)NO2 or =C(Rls)(R16);
Rla~ RIS ~d Rls ~.e independently selected from:
i) hydrogen;
is ii) an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G4, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy; or iii) a CI_6 alkyl, C3_lo (e.g. C3_g) cycloalkyl, Ca_6 alkenyl, CZ_6 alkynyl or C3_s heterocycloalkyl group, aI1 of which are optionally substituted by one 20 or more substituents selected fxom G4 and/or J; or any pair of RI4, RIS and RI6 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms, a further 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations (for example double or triple 2s bonds), which ring is itself optionally substituted by one or more substituents selected from G4 and J;
G4 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONOZ or A22-RI~;

wherein AZ2 represents a single bond or a spacer group selected from -C(O)A23-, -S(O)nA24-' -N(Ria)Aas-~ _OA26- and -S-, in which:
A23 represents AZ' or -S-;
A24 represents A27;
s AZS represents A2g, -C(O)N(R~g)C(O)N(Rl$)-, -C(O)N(R1s)C(O)O-, -C(O)N(Rls)S(O)"N(R~s)-, _C(O)S_, -S(O)nN(Rlg)C(O)N(Ri8)-, -S(O)nN(Rls)C(O)O-~ -S(O)nN(Rl8)S(O)nN(R1s)- or -S(O)n0-A26 represents A2g or -S(O)nO-;
AZ~ represents a single bond, -N(Rl8)- or -O-;
to A2s represents a single bond, -C(O)-, -C(O)N(Rlg)-, -C(O)O-, -S(O)ri or -S(~)nN(RIg)~
J represents, on each occasion when mentioned above, =O, =S, =NRl', NN(R17)(Rls), =NORM, =NS(O)2N(Rl~)(Rlg), ~TCN, =C(I-i)N02 or is =C(Rl')(Rl8);
Rl~ and Rl8 are independently selected from hydrogen and C~_6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, -NH2, -N(H)Me, -N(H)Et, -N(H)i-Pr, -NMe2, -N(Me)Et, 20 -N(Me)i-Pr, -NEt2, -OH, -OMe, -OEt, -Oi-Pr and =O; and n represents, on each occasion when mentioned above, 1 or 2, or a pharmaceutically-acceptable salt thereof, as which compounds and salts are referred to hereinafter as "the compounds of the invention".
Pharmaceutically-acceptable salts include acid addition salts and base addition salts. Such salts may be foi~rned by conventional means, for example by reaction of a free acid or a free base form of a compound of the invention with one or more equivalents of an appropriate acid or base, optionally in a solvent, or in a medium in which the salt is insoluble, followed by removal of said solvent, or said medium, using standard s techniques (e.g. ifz vacu~, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of the invention in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
Io Compounds of the invention may contain double bonds and may thus exist as E (entgegen) and Z (zuranzn2erz) geometric isomers about each individual double bond. All such isomers and mixtures thereof are included within the scope of the invention.
Is Compounds of the invention may also exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention.
Compounds of the invention may also contain one or more asymmetric carbon atoms and may therefore exhibit optical and/or diastereoisomerism.
2o hiastereoisomers may be separated using conventional techniques, e.g.
chromatography or fractional crystallisation. The various stereoisomers may be isolated by separation of a racemic or other mixture of the compounds using conventional, e.g. fractional crystallisation or HPLC, techniques. Alternatively the desired optical isomers may be made by 2s reaction of the appropriate optically active starting materials under conditions which will not cause racemisation or epimerisation (i.e, a 'chiral pool' method), by reaction of the appropriate starting material with a 'chiral auxiliary' which can subsequently be removed at a suitable stage, by derivatisation (i.e. a resolution, including a dynamic resolution), for 3o example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means such as HPLC or chromatography over silica, or by reaction with an appropriate chiral reagent or chiral catalyst all under conditions known to the skilled person.
All stereoisomers and mixtures thereof are included within the scope of the s invention.
Unless otherwise specified, Cr_q alkyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain.
to C1_6 alkyl groups that may be mentioned include methyl, ethyl, n-propyl, isopropyl, ~-butyl, ,rec-butyl, isobutyl, tent-butyl, n-pentyl, isopentyl, jZ-hexyl, and isohexyl.
CI_q alkylene chains (where q is the upper limit of the range) defined herein is are straight-chain alkyl groups, which groups are attached at each terminal end.
CV_q heteroalkylene chains (where v is the lower limit and q is the upper limit of the range) defined herein are C~_q alkylene chains, wherein one or 2o more (e.g. 1 to q-1) carbon atoms have been replaced with a heteroatom.
C2_9 alkenyl groups (where q is the upper Limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched-chain. Such alkenyl groups may 2s contain one or more double bonds. C2_6 alkenyl groups that may be mentioned include ethenyl (i.e, vinyl), 1-propenyl, 2-propenyl (i.e. allyl), propadienyl, 1-butenyl, 2-butenyl, 3-butenyl, I,3-butadienyl, 1-pentenyl, 2-pentenyl, 4-pentenyl, and 5-hexenyl.

IS
C2_q alkynyl groups (where q is the upper limit of the range) defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be branched-chain. Such alkynyl groups may contain one or more triple bonds. CZ_6 alkynyl groups that may be s mentioned include ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, and 5-hexynyl.
C3_q cycloalkyl groups (where q is the upper limit of the range) that may be 1o mentioned include monocyclic or bicyclic alkyl groups or fused ring systems such as three fused cycloalkyl groups. Such cycloalkyl groups may be saturated or unsaturated containing one or more double or triple bond (forming for example a C3_q cycloalkenyl or a C3_q cycloalkynyl group).
C3_q (e.g. C3_In) cycloalkyl groups that may be mentioned include I~ adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclooctynyl, bicycloheptyl, bicyclooctyl, and bicyclooctenyl. Substituents may be attached at any point on the cycloalkyl group. Further in the case where the substituent is another cyclic compound, then the cyclic 2o substituent may be attached through a single atom on the cycloalkyl group, forming a so-called "spiro"-compound.
C3_q heterocycloalkyl groups (where q is the upper limit of the range) that may be mentioned include monocyclic or bicyclic alkyl groups in which at 2s Ieast one (e.g. one to four) of the atoms in the ring system is other than carbon (i.e. a hetereoatom). Further, such heterocycloalkyl groups may be saturated or unsaturated containing one or more double and/or triple bonds, forming for example a C3_q heterocycloalkenyl or a C3_q heterocycloalkynyl group. C3_q heterocycloalkyl groups that may be mentioned include 3o aziridinyl, azetidinyl, dihydropyranyl, dihydropyridyl, dihydropyrrolyl (including 2,5-dihydropyrrolyl), dioxolanyl (including 1,3-dioxolanyl), dioxanyl (including 1,3-dioxanyl and 1,4-dioxanyl), dithianyl (including 1,4-dithianyl), dithiolanyl (including 1,3-dithiolanyl), imida~olidinyl, imidazolinyl, morpholinyl, oxetanyl, oxiranyl, piperazinyl, piperidinyl, s pyranyl, pyrazolidinyl, pyrrolidinonyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, sulfolanyl, 3-sulfolenyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydropyridyl, thietanyl, thiiranyl, thiolanyl, thiomorpholinyl, trithianyl (including 1,3,5-trithianyl), tropanyl and the like. Substituents on the heterocycloalkyl groups may, where appropriate, be located on any atom in to the ring system including a heteroatom. Further in the case where the substituent is another cyclic compound, then the cyclic substituent may be attached through a single atom on the heterocycloalkyl group, forming a so-called "spiro"-compound. The point of attachment of a heterocycloalkyl group may be via any atom in the ring system including (where appropriate) 1s a heteroatom, or an atom on any fused carbocyclic ring that may be present as part of the ring system. Heterocycloalkyl groups may also be in the N or S- oxidised form.
The term "halo", when used herein, includes fluoro, chloro, bromo and iodo.
~lry1 groups that may be mentioned include C6_i3 aryl (e.g. C6_lo) groups.
Such groups may be monocyclic, bicyclic or tricylic and have between 6 and 13 ring carbon atoms, in which at least one ring is aromatic. C6_13 aryl groups include phenyl, naphthyl and the like, such as 1,2,3,4-tetrahydro-2s naphthyl, indanyl, indenyl and fluorenyl. The point of attachment of aryl groups may be via any atom of the ring system.
Heteroaryl groups that may be mentioned include those which have between 5 and 10 members. Such groups may be monocyclic, bicyclic or tricyclic, 3o in which at least one of the rings is aromatic and wherein at least one (e.g.

one to four) of the atoms in the ring system is other than carbon (i.e. a heteroatom). Heteroaryl groups that may be mentioned include acridinyl, benzimidazolyl, benzodioxanyl, benzodioxepinyl, benzodioxolyl (including I,3-benzodioxolyl), benzofuranyl, benzofurazanyl, benzothiazolyl s (including 2,1,3-benzothiazolyl), benzoxadiazolyl (including 2,1,3-benzoxadiazolyl), benzoxazinyl (including 3,4-dihydro-21~ 1,4-benzoxazinyl), benzoxazolyl, benzimidazolyl, benzomorpholinyl, benzoselenadiazolyl (including 2,1,3-benzoselenadiazolyl), benzothienyl, carbazolyl, chromanyl, cinnolinyl, furanyl, imidazolyl, imidazo[1,2-Io a]pyridyl, indazolyl, indolinyl, indolyl, isobenzofuranyl, isochromanyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl, isoxazolyl, naphthyridinyl (including 1,5-naphthyridinyl and 1,8-naphthyridinyl), oxadiazolyl (including 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl and 1,3,4-oxadiazolyl), oxazolyl, phenazinyl, phenothiazinyl, phthalazinyl, Is pteridinyl, purinyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolinyl, quinolizinyl, quinoxalinyl, tetrahydroiso-quinolinyl (including 1,2,3,4-tetrahydroisoquinolinyl and 5,6,7,~-tetrahydroisoquinolinyl), tetrahydroquinolinyl (including 1,2,3,4-tetrahydroquinolinyl and 5,6,7,x-tetrahydroquinolinyl), tetrazolyl, 2o thiadiazolyl (including 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl and 1,3,4-thiadiazolyl), thiazolyl, thiochromanyl, thienyl, triazolyl (including 1,2,3-triazolyl, 1,2,4-triazolyl and 1,3,4-triazolyl) and the line. The point of attachment of heteroaryl groups may be via any atom in the ring system including (Where appropriate) a heteroatom (such as a nitrogen atom), or an 2s atom on any fused carbocyclic ring that may be present as part of the ring system. Heteroalyl groups may also be in the N or S'- oxidised form.
Heteroatoms that may be mentioned include oxygen, nitrogen, sulphur and selenium.

For the avoidance of doubt, optionally substituted methylenedioxy groups, when attached to a ring system, are formed between any two adjacent atoms of the ring system.
s For the avoidance of doubt, in cases in which the identity of two or more substituents in a compound of the invention may be the same, the actual identities of the respective substituents are not in any way interdependent.
For example, in the situation in which Rl and R3 are both aryl groups substituted by one or more C1_6 alkyl groups, the alkyl groups in question to may be the same or different. Similarly, when groups are substituted by more than one substituent as defined herein, the identities of those individual substituents are not to be regarded as being interdependent. For example, when ~ and/or Rl represents e.g. an aryl group substituted by G1 in addition to, for example, Cl_6 alkyl, which latter group is substituted by is Gl, the identities of the two Gl groups are not to be regarded as being interdependent.
Compounds that may be mentioned include those in which:
E represents -C(O)-;
20 ~ when any two adjacent R2, R3, R4 or R5 groups, adjacent A substituents, adjacent B substituents, and/or, when B represents aryl or heteroaryl, adjacent atoms of those aryl or heteroaryl groups are linked to form a 5- to 6-membered ring, then that ring is fully saturated.
25 Preferred compounds of the invention include those in which:
Y represents -CH20H or, more preferably, -C(O)N(H)Rg, -C(O)N(H)OR8 or -C(O)ORg;
Ag represents a single bond, -C(Q4)A9-, -S(O)nAl°-, -N(R13)All- or -OA12-;
A9 represents A13;
All represents A~4;

Q' represents =O, =NN(R12)(R13), =N~Ri2, NS(O)2N(R12)(Rl'), =NCN or =C(H)NO2;
Q4 represents =O;
A15 represents a single bond, -C(W2)A16-, -S(O)nAl~-, -N(R16)AIg- or s -OA19-:
Al6 represents A2o;
Al8 represents A21;
WI represents =O, NN(Rls)(Rl6), =NORls, =NS(O)aN(Rls)(Rl~), NCN or =C(H)NOZ;
to WZ represents =O;
when any pair of Rl~, Rls and R16 is linked together to form a further optionally substituted 5- to 7-membered ring, then that ring optionally contains only 1 unsaturation;
A22 represents a single bond, -C(O)A23-, -S(O)nA24-, -N(Rl8)A''5- or 15 -~A2~-;
A23 represents Az~;
A'S represents AZ&; and/or J represents =O, 1VN(Rl')(Rig), I~TOR17, l~S(O)2N(Ri7)(RIa), NCN, or -C(H)NO2;
More preferred compounds of the invention include those in which:
Y represents -CHZOH or, more preferably, -C(O)N(H)R8 or -C(O)ORg;
when any two members of the Cl_g alkylene or C2_8 heteroalkylene chain that Z may represent form part of an additional optionally substituted 3- to 2s ~-membered ring, then that ring optionally contains 1 to 2 heteroatoms andlor 1 unsaturation;
A1 represents -S- or, more preferably, a single bond, -C(Q2)A~-, -S(O)nA3-, -N(Rii)A4- or _OAS-:
Aa represents A6;
A4 represents A~;

QI represents =O, =NORI°, NS(O)ZN(Rl°)(Rn), -NCN or =C(H)N02;
Q 2 represents =O;
when two adjacent atoms of the optionally substituted aryl or heteroaryl group that B may represent are linked together to form a further optionally 5 substituted ring, then the linking divalent substituent that forms part of that ring is selected from methylenedioxy, difluoromethylenedioxy and dimethylmethylenedioxy;
Q3 represents =O, NORl2, NS(O)ZN(Rl')(Rl3), =NCN or =C(H)NO2;
when R~ and R' are linked to form an optionally substituted 5- to 1o membered ring, then that ring optionally contains only 1 unsaturation;
when two adjacent atoms of the optionally substituted aryl or heteroaryl group that R8, R9, Rl°, Rll, Ri2 and/or R13 may represent are linked together to form a further optionally substituted ring, then the linking divalent substituent that forms part of that ring is selected from methylenedioxy, is difluoromethylenedioxy and dimethylmethylenedioxy;
Wl represents =O, =NORIS, NS(~)2N(R15)(R~6), -NCN or =C(H)N02;
and/or RI4, Rls and R16 independently represent an aryl or heteroaryl group, both of which groups are optionally substituted by one or more substituents selected 2o from halo, -NH2, -N(H)Me, -N(H)Et, -N(H)i-Pr, -NMe2, -N(Me)Et, -N(Me)i-Pr, -NEt2, -OH, -OMe, -OEt, -Oi-Pr and =O or, R14, RIS and R16 are, more preferably, hydrogen or C1_6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, -NH2, -N(H)Me, -N(H)Et, -N(H)i-Pr, -NMe2, -N(Me)Et, -N(Me)i-Pr, -NEt2, -OH, -OMe, 2s -OEt, -Oi-Pr and =O;
More preferred compounds include those in which:
~ represents -CHZOH, -C(O)NHRg or, more preferably, -C(O)ORB;
when any one or more members of the C1_g alkylene or C2_8 heteroalkylene 3o chain that Z may represent form part of an additional ring, then that ring is a cyclopropyl group formed together with the same or adjacent carbon atoms of that C1_8 alkylene or C2_s heteroalkylene chain;
when any adjacent pair of R2, R3, R4 or RS is linlced, to form an optionally substituted ring, then the linking divalent substituent that forms part of that s ring is a methylenedioxy, difluoromethylenedioxy or dimethylmethylene dioxy group;
when any two adjacent A substituents are linked to form an optionally substituted ring, then the linking divalent substituent that forms part of that ring is selected from methylenedioxy, difluoromethylenedioxy and to dimethylmethylenedioxy;
when any two adjacent B substituents axe linked to form an optionally substituted ring, then the linking divalent substituent that forms part of that ring is selected from methylenedioxy, difluoromethylenedioxy and dimethylmethylenedioxy;
is when R6 and R' are linked to form an optionally substituted ring, then that ring is a 5- to 6-membered ring;
when any pair of R8, R9, Rl°, Rll, R12 and R13 is linked to form a further optionally substituted ring, then that ring optionally contains only 1 unsaturation; and/or 2o n represents 2;
Preferred compounds of the invention include those in which Rl, and (when they represent an aryl or a heteroaryl group) X, R2, R3, R4 and/or RS
represent an optionally substituted fluorenyl, phenyl, naphthyl, pyrrolyl, 2s furanyl, thienyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl (e.g. 2-pyridyl, 3-pyridyl or 4-pyridyl), indazolyl, indolyl, indolinyl, isoindolinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl, isoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl, quinolizinyl, benzofuranyl, isobenzofuranyl, chromanyl, benzothienyl, pyridazinyl, pyrimidinyl, pyrazinyl, indazolyl, benzimidazolyl, quinazolinyl, quinoxalinyl, 1,3-benzodioxolyl, benzothiazolyl, and/or benzodioxanyl, group Preferred values of Rl include optionally substituted fluorenyl (e.g. 2-s fluorenyl) or pyridyl and, especially, optionally substituted phenyl.
Preferred values of X, when X represents an optionally substituted aryl or heteroaryl group include optionally substituted phenyl, thienyl (e.g. 2-thienyl), pyridyl (e.g. 3-pyridyl and 4-pyridyl), pyrazolyl, pyrazinyl or 1 o quinolinyl.
Preferred values of R2, R3, R4 and R5, when they represent an optionally substituted aryl or heteroaryl group, include optionally substituted phenyl, pyridyl (e.g. 3-pyridyl) or naphthyl (e.g. 1-naphthyl).
Is Further preferred compound of the invention include those in which:
~ represents C1_6 alkylene, such as methylene, propylene or hexylene, in which one of the carbon atoms in the chain may be replaced with a heteroatom (e.g. oxygen) so forming, for example, an oxypentylene group;
2o R2 represents hydrogen or Gl;
R3 represents hydrogen, phenyl or pyridyl (e.g. 3-pyridyl), which latter two groups are optionally substituted by one or more substituents selected from A;
R4 represents hydrogen, phenyl or naphthyl, which Latter two groups are 2s optionally substituted by one or more substituents selected from A;
R5 represents hydrogen or phenyl, which latter group is optionally substituted by one or more substituents selected from A or is preferably unsubstituted;
when R2, R3, R4 or RS represents an optionally substituted phenyl, pyridyl or 3o naphthyl group, then the other substituents on the essential benzene ring of the indole of formula I, (i.e. R2, R3, R4 or R4 (as appropriate)) represent hydrogen or Gl;
A represents Gl or any two adjacent A substituents may be linked to form a further ring, wherein the linking divalent substituent that forms part of that s ring is preferably methylenedioxy, which group is preferably unsubstituted;
G1 represents halo (such as chloro or fluoro), cyano, -N02 or Al-Rlo;
A2 represents A6;
A3 represents a single bond;
A4 represents A~;
AS represents A~ and, preferably, a single bond;
A~ represents a single bond, -C(Q2)- or -S(O)z-;
QZ represents =O;
R6 represents hydrogen or C1_3 alkyl group (such as methyl or ethyl), which Iatter group is optionally substituted by G2;
Is R' represents an aryl group (such as phenyl) or a heteroaryl group (such as pyridyl), which latter two groups are optionally substituted by one or more substituents selected from B, or R' represents CI_4 alkyl (such as methyl, ethyl, propyl, butyl (e.g. n-butyl or t-butyl)), C2.4 alkenyl (such as ethenyl) or CS_1o cycloallcyl (such as cyclohexyl or adamantyl), which latter three 2o groups are optionally substituted by one or more substituents selected from G2; or R6 and R~ are optionally linked to form a 5- to 6-membered ring optionally substituted by =0;
B represents GZ;
2s G~ represents halo (such as chloro or fluoro), cyano, -N~2 or Ag-R12;
Ag represents a single bond, -N(R13)An- or -OA12-;
AI I and A12 independently represent A14;
Al4 represents a single bond;
R8 represents C1_3 alkyl (such as ethyl) or, preferably, hydrogen;

R1° represents hydrogen, aryl (such as phenyl), heteroaryl (such as tetrazolyl), C1_4 alkyl (such as methyl, ethyl, isopropyl or butyl (e.g. n-butyl or t-butyl)), C2_4 alkenyl (such as ethenyl or butenyl (e.g. but-3-enyl)) or CS_6 cycloalkyl (such as cyclohexyl), which latter five groups are optionally s substituted by one or more substituents selected from G3;
Rll represents hydrogen or C2_4 all~enyl (such as propenyl (e.g. propen-2-yl, i.e. allyl));
R12 represents hydrogen, an aryl group (such as a phenyl group), a heteroaryl group (such as a pyrrolyl group), C1_4 alkyl (such as methyl, to isopropyl or butyl (e.g. n-butyl or t-butyl)) or CS_1° cycloalkyl (such as cyclohexyl or adamantyl) which latter four groups are optionally substituted by one or more substituents selected from G3;
R13 represents hydrogen or C1_3 alkyl (such as methyl);
G3 represents halo (such as fluoro) or p,ls-Ris;
Is Als represents a single bond or-~A19-;
Alg represents a single bond;
Rls represents hydrogen, C1_3 alkyl (such as C1_2 alkyl (e.g. methyl)) or aryl (such as phenyl).
20 (referred optional substituents on Rl, R6, R~ and (when they represent an aryl or heteroaryl group) X, R~, R3, R4 and Rs groups are selected from:
halo (e.g. chloro, fluoro or bromo);
-NGz~
cyano;
2s methylenedioxy;
C1-s alkyl, which all~yl group may be linear or branched (e.g. C1_4 alkyl (including methyl, ethyl, o-propyl, isopropyl, n-butyl, s-butyl, isobutyl or t~
butyl), ja-pentyl, isopentyl, 3Z-hexyl or isohexyl), and which alkyl groups are optionally substituted by one or more substituents selected from a halo (e.g.

fluoro) group (so forming, for example, -CH2F, -CHF2 or -CF3), an aryl group (such as phenyl) and OR19;
C2_6 alkenyl (e.g. ethenyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1-pentenyl, 2-pentenyl, 4-pentenyl or 5-hexenyl);
s C;_1° (e.g. C3_g) cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cyclooctyl), optionally substituted with C1_6 alkyl (such as methyl);
phenyl, optionally substituted with one or more substituents selected from halo (e.g. fluoro or, especially, chloro) and ~R19;
1o a heteroaryl group selected from tetrazolyl and pyrrolyl, optionally substituted by one or more C1_g alkyl group (such as methyl);
methylthio, methylsulfinyl, methylsulfonyl;
_~R19>
Zs -hT(Rl~)R2°;
-C(~)~R19;
-c(~)R19;
-C(~)~(R19)R20;
-~,(~)2~(RI9)R20; and/or 20 -N(R19)S(0)2R21;
wherein R19 and R2° independently represent, on each occasion when used above, hydrogen, phenyl, C1_4 alkenyl (such as propenyl (e.g. propen-2-yl, i.e. allyl) or butenyl (e.g. but-3-enyl)), C1_6 alkyl (such as methyl, ethyl, f2-propyl, isopropyl, h-butyl or t-butyl) which alkyl group is optionally 2s substituted by one or more fluoro atoms or a phenyl group;
R21 represents phenyl or C1_6 alkyl (such as methyl, ethyl, f~-propyl, isopropyl, fz-butyl or t-butyl), which allcyl group is optionally substituted by one or more fluoro atoms.

When X represents an aryl or a heteroaryl group, then the substituents on such groups are preferably selected from carboxy, acetyl, methoxy, -N02, fluoro, methyl, chloro, hydroxymethyl, ethyl, isopropoxy, trifluoromethoxy and methylthio.
s Preferred optional substituents on Rl groups include phenoxy, trifluoromethyl, vitro, fluoro, chloro, cyano, carbamoyl, trifluoromethoxy, tetrazolyl (e.g. 2H tetrazol-5-yl) and methyl.
1o When they represent an aryl or heteroaryl group, preferred optional substituents on R2, R3, R4 or RS groups include t-butyl, methylenedioxy, benzyloxy, vitro, methoxy, acetyl, chloro, fluoro, N allyl-N
methanesulfonyl, cyano, trifluoromethyl, 2,2-dimethylpropionylamino, lnethanesulfonylamino, amino, but-3-enylamino, isopropoxy, methylthio, 1s methylsulfonyl, ethenyl (i.e. vinyl), trifluoromethoxy, cyclohexyl, n-butyl, carboxy and hydroxymethyl.
Preferred optional substituents on Rg (when R6 does not represent hydrogen and is not linlced to form a ring with R') include an optionally substituted 2o phenyl group. Optional substituents on such phenyl groups include halo (especially fluoro) and Cl_3 alkoxy (such as methoxy), which substituents are preferably in the 4-position of the phenyl ring.
Preferred optionally substituents on R' (when R' is not linked to form a ring 2s with R6) include chloro, methoxy, amino, methyl, dimethylamino, phenyl, 4-methoxyphenyl, adamantyl, cyclohexyl, 3,3,5,5-tetramethylcyclohexyl, isopropoxy, trifluororriethyl, t-butyl, ~-butyl, isopropyl, trifluoromethoxy, cyano, pyrrole (e.g. 2,5-dimethylpyrrole) and vitro.

Particularly preferred compounds of the invention include those of the examples described hereinafter.
Compounds of the invention may be made in accordance with techniques s that are well known to those skilled in the art, for example as described hereinafter.
According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I, which process comprises:
(i) reaction of a compound of formula II, R~

R~
Is wherein ~, Y, RZ, R3, R4 and RS are as hereinbefore defined, with a compound of formula III, RrZLI III
2o wherein L1 represents a suitable leaving group, such as halo (e.g. chloro, . bromo or iodo), a carboxylate group, a sulfonylate group (e.g. -OS(O}2CF3, -OS(O)2CH3, -OS(O)ZPhMe or nonaflates), or an N imidazolyl group and Rl and Z are as hereinbefore defined, for example at around 0°C to room temperature, or at above room temperature (e.g. up to 40-180°C) in the 2s presence of a suitable base (e.g. sodium hydride, sodium bicarbonate, potassium carbonate, pyrrolidinopyridine, pyridine, triethylamine, tributylamine, trimethylamine, dimethylaminopyridine, diisopropylamine, I,8-diazabicyclo[5.4.0]undec-7-ene, sodium hydroxide, potassium hydroxide, N ethyl-diisopropylamine, N (methylpolystyrene)-4-(methylamino)pyridine, lithiumdiisopropylamide or mixtures thereof) and s an appropriate solvent (e.g. tetrahydrofuran, pyridine, toluene, dichloromethane, chloroform, dimethylformamide, trifluoromethylbenzene, dimethylsulfoxide or triethylamine). Preferred base/solvent systems include sodium hydride/dimethylformamide, dimethylaminopyridine/pyridine, sodium hydroxide/dichloromethane (optionally in the presence of a phase 1 o transfer catalyst (e.g. tetrabutylammonium hydrogensulfate)), lithiumdiisopropylamide/tetrahydrofuran, potassium hydroxide/dimethyl-sulfoxide. Other systems that may be mentioned include sodium/ammonia.
(ii) reaction of a compound of formula IV, X
~z-~s \ ~ m ~a ~~R~
wherein L4 represents L2 or L3, in which L2 represents a leaving group such as halo (e.g. chloro, bromo or iodo), a sulfonylate group (e.g.
-OS(O)2CF3, -OS(O)ZCH3, -OS{O)2PhMe or nonaflates) or B(OH)~, L3 represents a leaving group such as B(OH)2, -4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl, -Sn~u3, or a similar group known to the skilled person, Lø is attached to one or more of the carbon atoms of the benzenoid ring of the indole, and the remaining positions of the benzenoid ring are substituted with 1 to 3 (depending on the number of L4 substituents) substituents R~ to RS as appropriate, and Z, X, Y, R~, R2, R3, R4 and RS are as hereinbefore defined, with a compound of formula V, Ra2Ls V
wherein R22 represents R2, R3, R4 or Rs (as appropriate), and Ls represents s La (when L4 is L3) or L3 (when L4 is L2) as hereinbefore defined. The skilled person will appreciate that L2 and L3 must be mutually compatible.
This reaction may be performed, for example in the presence of a suitable catalyst system, e.g. a metal (or a salt or complex thereof) such as CuI, Pd/C, Pd(OAc)2, Pd(Ph;P)2C12, Pd(Ph3P)4, Pd2(dba)3 or NiCl2 and a ligand to such as t-Bu3P, (C6H~1)3P, Ph3P, P(o-Tol)3, 1,2-bis(diphenylphosphino)-ethane, 2,2'-bis(di-tef°t-butylphosphino)-l,I'-biphenyl, 2,2'-bis(diphenyl-phosphino)-l,l'-binaphthyl, 1,1'-bis(diphenylphosphinoferrocene), 1,3-bis(diphenylphosphino)propane or xantphos, together with a suitable base, such as NazC03, K;P04, CszCO;, NaOH, KZC03, CsF, Et3N, (i-Pr)2NEt or 1s t-BuOK (or mixtures thereof) in a suitable solvent, such as dioxane, toluene, ethanol, dimethylformamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N methylpyrrolidinone or mixtures thereof. The reaction may also be carried out for example at room temperature or above (e.g, at a high temperature such as the reflux 2o temperature of the solvent system) or using microwave irradiation;
(iii) for compounds of formula I, wherein X represents an optionally substituted aryl or heteroaryl group, reaction of a compound of formula VI, R~ L2 VI
R~ / N
25 R5 ~~R1 wherein Z, Y, L2, R1, R2, R3, R4 and R5 are as hereinbefore def ned, with a.
compound of formula VII, XaL3 VII

wherein Xa represents an aryl or heteroaryl group, optionally substituted as hereinbefore defined, and L3 is as hereinbefore defined, for example under reaction conditions such as those hereinbefore described hereinbefore in respect of process step (ii);
(iv) for compounds of formula I wherein X represents -N(R6)-E-R', reaction of a compound of formula VI as hereinbefore defined, with a compound of formula VIII, is I~T(R6)-E-R' VIII
wherein E, R6 and R~ are as hereinbefore defined for example optionally in the presence of an appropriate metal catalyst (or a salt or complex thereof) such as Cu, Cu(~.l~c)2, CuI (or CuIldiamine complex), Pd(~Ac)2, Pd2(dba)3 or NiCh and an optional additive such as Ph3F, 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl or xantphos, in the presence of an appropriate base such as Et3N, pyridine, N,N-dimethylethylenediamine, Na2C03, I~3PO4, Cs2C0~ or t-BuOK (or mixtures thereof), in a suitable solvent (e.g. dichloromethane, dioxane, toluene, ethanol, 2s dimethylfonnamide, ethylene glycol dimethyl ether, water, dimethylsulfoxide, acetonitrile, dimethylacetamide, N methylpyrrolidinone or mixtures thereof) or in the absence of an additional solvent when- the reagent may itself act as a solvent (e.g. when Rl represents phenyl and L1 represents bromo, i.e. bromobenzene). This reaction may be carried out at 3o room temperature or above (e.g. at a high temperature, such as the reflux temperature of the solvent system that is employed) or using microwave irradiati on;
(v) for compounds of formula I wherein X represents -N(R6)-E-R~, reaction s of a compound of formula IX, R2 \NH

N

wherein ~, Y, R1, R2, R3, R4, R$ and R6 are as hereinbefore defined, with a compound of formula X, R~_E_L1 X
wherein E, R~ and L1 are as hereinbefore defined, for example under is reaction conditions such as those hereinbefore described in respect of process step (i); or (vi) for compounds of formula I wherein E represents a single bond and R~
is a C1_6 alkyl group, C3_6 alkenyl or a C3_6 alkynyl group, reduction of a 2o compound of formula I, wherein X represents -C(O)- and R~ represents H, a CI_5 alkyl group, a C2_5 alkenyl or a CZ_5 alkynyl group, in the presence of a suitable reducing agent. A suitable reducing agent may be an appropriate reagent that reduces the amide group to the amine group in the presence of other functional groups (for example an ester or a carboxylic acid). Suitable 2s reducing agents include borane and other reagents known to the skilled person, under reaction conditions known to the skilled person.

Compounds of formula II may be prepared by:
(a) reaction of a compound of formula X.I, X
~a_R5 \ ~ xi N
H
wherein X, Y, L4, R2, R3, R4 and R5 are as hereinbefore defined with a compound of formula V for example under conditions such as to those described hereinbefore in respect of process step (ii);
(b) for compounds of formula II wherein X represents an optionally substituted aryl or heteroaryl group, reaction of a compound of formula XII, zs ~3 \ ~ x~l wherein Y, L2, R2, R3, R4 and RS are as hereinbefore defined, with a compound of formula VII as hereinbefore defined, for example under 2o conditions such as those described hereinbefore in respect of process step (iii);
(c) for compounds of formula II, wherein X represents N(R6)-E-R7, reaction of a compound of formula XII as hereinbefore defined, with a compound of formula VIII for example under conditions .such as those described hereinbefore in respect of process step (iv);
(d) for compounds of formula II, wherein X represents N(R6)-E-R', s reaction of a compound of formula XIII, R2 \NH

\ ~ VIII
R~ / H

wherein ~.', RZ, R3, R4, Rs and R6 are as hereinbefore defined with a 1o compound of formula X for example under conditions such as those described hereinbefore in respect of process step (v);
Compounds of formula IV may be prepared by reaction of a compound of formula XI as hereinbefore defined, with a compound of formula III as Is hereinbefore defined for example under conditions such as those described hereinbefore in respect of process step (i).
Compounds of formula IV in which L4 represents L3 may be prepared by reaction of a compound of formula IV in which L4 represents L2, with an 2o appropriate reagent for the conversion of the LZ group to the L3 group.
This conversion may be performed by methods blown to those skilled in the art, for example, compounds of formula IV, in which L3 is 4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl may be prepared by reaction of the reagent bis(pinacolato)diboron with a compound of formula IV in which L4 2s represents L~', for example under reaction conditions such as those described hereinbefore in respect of process route (ii) above.

Compounds of formula VI may be prepared by:
(a) reaction of a compound of formula XII as hereinbefore defined with s a compound of formula III as hereinbefore defined for example under conditions such as those described hereinbefore in respect of process step (i);
(b) for compounds of formula VI wherein L2 represents a sulfonylate 1o group, reaction of a compound of formula XIV, \ ~ ~I~/
~5 ~ ~ R1 wherein Y, ~, Rl, I~2, R3, R4 and Ids are as hereinbefore defined, with 1s an appropriate reagent for the conversion of the hydroxyl group to the sulfonylate group (e.g. tosyl chloride, mesyl chloride, triflic anhydride and the like) under conditions known to those skilled in the art.
2o Compounds of formula I~ may be prepared for example by reaction of a compound of formula XITI as hereinbefore def ned with a compound of formula III as hereinbefore defined for example under conditions such as those described hereinbefore in respect ofprocess step (i).
2s Compounds of formula XII may be prepared by standard techniques. For example:

(a) Compounds of formula XIT, wherein L2 represents halo may be prepared by reaction of a compound of formula X~1, \ ~ xv wherein R2, R3, R4, RS and Y are as hereinbefore defined, with a reagent, or mixture of reagents known to be a source of halide ions.
For example, for bromide ions, N bromosuccinimide may be 1o employed, for iodide ions, iodine or a mixture of NaI and N
chlorosuccinimide may be employed, for chloride ions, N
chlorosuccinimide may be employed and for fluoride ions, 1-(chloromethyl)-4-fluoro-1,4-diazoniabicyelo[2.2.2]octane bis(tetra-fluoroborate) may be employed. This reaction may be carried out in 15 a suitable solvent (e.g. acetone or benzene) under conditions known to the skilled person.
(b) by reaction of a compound of formula XVT, R~_Rs \ y ?C1/I
L~. N
a,o wherein Y, LZ, L4, Rz, R3, R4 and R5 are as hereinbefore defined with a compound of formula V as hereinbefore defined, for example under reaction conditions such as those described hereinbefore in respect of process route (ii) above; or (c) for compounds of formula XII wherein Ll represents a sulfonylate s group, reaction of a compound of formula XVII, R4 /' H

wherein Y, R2, R3, R4 and RS are as hereinbefore defined, with an to appropriate reagent for the conversion of the hydroxyl group to a sulfonylate group as described hereinbefore.
Compounds of formula XIII may be prepared by reaction of a compound of formula XII as hareinbefore defined with a compound of formula XVIII, Ha~TR6 XVIII
wherein R6 is as hereinbefore defined, for example under reaction conditions such as those described in respect of process step (iv).
Compounds of formula XIII wherein R6 represents hydrogen may be prepared by an aromatic nitration reaction carried out on a compound of formula XV, as hereinbefore defined, followed by reduction of the nitro group of the resultant intermediate to an amino group. both reactions may 2s be performed under conditions known to the skilled person.

Compounds of formulae III, V, VII, VIII, X, XVIII axe either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting s materials using appropriate reagents and reaction conditions.
Indoles of formulae II, IV, VI, Ice, XI, XII, VIII, XIV, XV, XVI and XVTI
may also be prepared with reference to a standard heterocyclic chemistry textbook (e.g. "Heterocyclic Chemistry" by J. A. Joule, K. Mills and G. F.
1o Smith, 3rd edition, published by Chapman ~ Hall) and/or made according to the following general procedures.
For example compounds of formulae II, ~I, XIII and XV may be prepared by reaction of a compound of formula SIX, is sU~ i xl~
H..H
H
wherein SUB represents the substitution pattern that is present in the compound of formula II, XT, XIII or XV to be formed, (G) represents either 2o X (as required for formation of compounds of formulae II and XI), a N(R6)H group (as required for formation of compounds of formula XIII) or the (G) substituent is absent (as required for formation of compounds of formula XV) and Y is as hereinbefore defined, under Fischer indole synthesis conditions known to the person spilled in the art.
?s Compounds of fornula XV may alternatively be prepared by reaction of a compound of formula XX, R
~H

R~
wherein R2, R3, R4 and Rs are as hereinbefore defined with a compound of s formula ~I, wherein Y is as hereinbefore defined, and preferably does not represent -COON, under conditions known to the person skilled in the art (i.e.
conditions to induce a condensation reaction, followed by a thermally induced cyclisation).
Compounds of formulae ~V and XVIT may be prepared by reaction of a zs compound of formula III, Rs O~RX
X?CI i N.~l R5 Ry wherein R" represents a C1_6 alkyl group, Ry represents either -Z-R1 as 2o hereinbefore defined (as required for formation of compounds of formula XIV), hydrogen (as required for formation of compounds of formula XVII) or a nitrogen-protected derivative thereof, and Y, R', R3, R4 and Rs are as hereinbefore defined, under standard cyclisation conditions known to those spilled in the art.
Compounds of formulae IX and XIII, wherein R6 represents H, may be s prepared by reaction of a compound of formula XXIII, R3 ~ CN
~Cfii R4 / N /y R ~ Rv wherein Y, R2, R3, R~, RS and Rv are as hereinbefore defined, for example 1o under intramolecular cyclisation conditions known to those skilled in the art.
Compounds of formula II and ~I, wherein ~ represents aryl or heteroaryl, may alternatively be prepared by reaction of a compound of formula HIV, ~CI~/
SIJ~
NH
I
wherein Q represents either -C(O)- or -CHZ-, ~ represents aryl or heteroaryl, and SLTB and Y are as hereinbefore defined. When Q represents -C(O)-, the intramolecular cyclisation may be induced by a reducing agent such as TiCl3/CBK, TiCl4/Zn or SmI2 under conditions known to the skilled person, for example, at room temperature in the presence of a polar aprotic solvent (such as THF).. When Q represents -CH2-, the reaction may be performed in the presence of base under intramolecular condensation reaction conditions known to the skilled person.
s Compounds of formula XIX may be prepared by:
(a) reaction of a compound of formula XXV, S U S ?C~V
N~NHz H
to wherein SLT~ is as hereinbefore defined with a compound of formula XXVI, ( \/I
is wherein (G) and Y are as hereinbefore defined under condensation conditions known to the skilled person; or (b) reaction of a compound of formula ~~XVII, \ X?C1/I
SUS
N+
z wherein SUB is as hereinbefore defined with a compound of formula XXVIII, (G) Rm wherein Rm represents OH, O-C1_6 alkyl, C1_6 alkyl and (G) and Y are as hereinbefore defined, for example under Japp-I~lingemann conditions known to the skilled person.
to Compounds of formulae XX, XXI, XXII, XXIII, XIV, XV, XVI, XVH and XVIII are either commercially available, are known in the literature, or may be obtained either by analogy with the processes described herein, or by conventional synthetic procedures, in accordance with standard techniques, from available starting materials using appropriate reagents and reaction is conditions.
The substituents X, Y, ~, Rl, Ra, R3, R4 and RS in final compounds of the invention or relevant intermediates may be modified one or more times, after or during the processes described above by way of methods that are 2o well known to those skilled in the art. Examples of such methods include substitutions, reductions, oxidations, alkylations, hydrolyses, esterifications, and etherifications. The precursor groups can be changed to a different such group, or to the groups defined in formula I, at any time during the reaction sequence. For example, in cases where Y represent a carboxylic 2s acid ester functional group, the skilled person will appreciate that at any stage during the synthesis (e.g. the final step), the relevant substituent may be hydrolysed so forming for example a carboxylic acid functional group.

Tn cases where Y represents a carboxylic acid or carboxylic acid ester functional group, the relevant substituent may be reduced, under suitable conditions known to the skilled person (for example in the presence of other potentially reducible functional groups), at any stage during the synthesis s (e.g. the final step), so forming for example a hydroxymethyl substituent.
Compounds of the invention may be isolated from their reaction mixtures using conventional techniques.
to It will be appreciated by those skilled in the art that, in the processes described above and hereinafter, the functional groups of intermediate compounds may need to be protected by protecting groups.
The protection and deprotection of functional groups may take place before 15 or after a reaction in the above-mentioned schemes.
Protecting groups may be removed in accordance with techniques that are well known to those skilled in the art and as described hereinafter. For example, protected compounds/intermediates described herein may be 2o converted chemically to unprotected compounds using standard deprotection techniques.
The type of chemistry involved will dictate the need, and type, of protecting groups as well as the sequence for accomplishing the synthesis.
The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by J W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis", 3rd edition, T.W. Greene ~
P.G.M. Wutz, Wiley-Interscience (1999).

Medical and Pharmaceutical Uses Compounds of the invention are indicated as pharmaceuticals. According to a further aspect of the invention there is provided a compound of the s invention for use as a pharmaceutical.
Although compounds of the invention may possess pharmacological activity as such, certain pharmaceutically-acceptable (e.g. "protected") derivatives of compounds of the invention may exist or be prepared which may not 1o possess such activity, but may be administered parenterally or orally and thereafter be metabolised in the body to form compounds of the invention.
Such compounds (which may possess some pharmacological activity, provided that such activity is appreciably lower than that of the "active"
compounds to which they are metabolised) may therefore be described as 15 "prodrugs" of compounds of the invention.
~y "prodrug of a compound of the invention", we include compounds that form a compound of the invention, in an experimentally-detectable amount, within a predetermined time (e.g. about 1 hour), following oral or parenteral 2o administration. All prodrugs of the compounds of the invention are included within the scope of the invention.
Furthermore, certain compounds of the invention (including, but not limited to, compounds of formula I in which Y is -C(O)ORS and Rg is other than 2s hydrogen) may possess no or minimal pharmacological activity as such, but may be administered parenterally or orally, and thereafter be metabolised in the body to form compounds of the invention that possess pharmacological activity as such (including, but not limited to, corresponding compounds of formula I in which Y represents -COOH). Such compounds (which also 3o includes compounds that may possess some pharmacological activity, but that activity is appreciably lower than that of the "active" compounds of the invention to which they are metabolised), may also be described as "prodrugs".
s Thus, the compounds of the invention are useful because they possess pharmacological activity, and/or are metabolised in the body following oral or parenteral administration to form compounds which possess pharmacological activity.
1o Compounds of the invention are particularly useful because they may inhibit (for example selectively) the activity of prostaglandin E synthases (mPGESs) and particularly the activity of microsomal prostaglandin E
synthase-1 (ml'GES-1), i.e. they prevent the action of lnPGES-1 or a complex of which the mPGES-1 enzyme forms a part, and/or may elicit a 15 mPGES-1 modulating effect, for example as may be demonstrated in the test described below. Compounds of the invention may thus be useful in the treatment of those conditions in which inhibition of a PGES, and particularly mPGES-1, is required.
2o Compounds of the invention are thus expected to be useful in the treatment of inflammation.
The term "inflammation" will be understood by those skilled in the art to include any condition characterised by a localised or a systemic protective 2s response, which may be elicited by physical trauma, infection, chronic diseases, such as those mentioned hereinbefore, and/or chemical and/or physiological reactions to external stimuli (e.g. as part of an allergic response). Any such response, which may serve to destroy, dilute or sequester both the injurious agent and the injured tissue, may be manifest 3o by, for example, heat, swelling, pain, redness, dilation of blood vessels and/or increased blood flow, invasion of the affected area by white blood cells, loss of function and/or any other symptoms known to be associated with inflammatory conditions.
s The term "inflammation" will thus also be understood to include any inflammatory disease, disorder or condition pe~° se, any condition that has an inflammatory component associated with it, and/or any condition characterised by inflammation as a symptom, including if2te~ alia acute, chronic, ulcerative, specific, allergic and necrotic inflammation, and other 1 o forms of inflammation known to those skilled in the art. The term thus also includes, for the purposes of this invention, inflammatory pain, pain generally andlor fever.
Accordingly, compounds of the invention may be useful in the treatment of 15 inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, fibromyalgia, myofascial disorders, viral infections (e.g~.
influenza, common cold, herpes zoster, and AIIaS), bacterial infections, fungal infections, dysmenorrhea, burns, surgical or dental procedures, malignancies (e.~. breast cancer, colon cancer, and prostate cancer), 2o atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, systemic Iupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes , (e.g. diabetes mellitus), neurodegenerative disorders such as 2s Alzheimer's disease and multiple sclerosis, autoimmune diseases, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, allergic disorders, rhinitis, ulcers, coronary heart disease, sarcoidosis and any other disease with an inflarrunatory component.

Compounds of the invention are indicated both in the therapeutic and/or prophylactic treatment of the above-mentioned conditions.
According to a further aspect of the present invention, there is provided a s method of treatment of a disease which is associated with, and/or which can be modulated by inhibition of, a PGES (such as a mPGES, e.g. mPGES-I), and/or a method of treatment of a disease in which inhibition of the activity of a FGES, and particularly mFGES-I, is desired and/or required (e.g.
inflammation), which method comprises administration of a therapeutically 1o effective amount of a compound of the invention, as hereinbefore defined, to a patient suffering from, or susceptible to, such a condition.
"Patients" include mammalian (including human) patients.
15 The term "effective amount" refers to an amount of a compound, which confers a therapeutic effect on the treated patient. The effect may be objective (i.e. measurable by some test or marker) or subjective (i.e. the subj ect gives an indication of or feels an effect).
2o Compounds of the invention will normally be administered orally, intravenously, subcutaneously, buccally, rectally, dermally, nasally, tracheally, bronchially, sublingually, intraperitoneally, topically (e.g.
ocularly), intramuscularly, intraspinally, epidurally, transdermally, by any other parenteral route or via inhalation, in a pharmaceutically acceptable 2s dosage form.
Compounds of the invention may be administered alone, but are preferably administered by way of known pharmaceutical formulations, including tablets, capsules or elixirs fox oral, administration, suppositories for rectal administration, sterile solutions or suspensions for parenteral or intramuscular administration, and the like.
Such formulations may be prepared in accordance with standard and/or s accepted pharmaceutical practice.
According to a further aspect of the invention there is thus provided a pharmaceutical formulation including a compound of the invention, as hereinbefore~ defined, in admixture with a pharmaceutically acceptable 1o adjuvant, diluent or carrier.
Compounds of the invention may also be combined with other therapeutic agents that are useful in the treatment of inflammation (e.g. NSAII~s and coxibs).
According to a further aspect of the invention, there is provided a combination product comprising: t (A) a compound of the invention, as hereinbefore defined; and (B) another therapeutic agent that is useful in the treatment of 2o inflammation, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
Such combination products provide for the administration of a compound of the invention in conjunction with the other therapeutic agent, and may thus be presented either as separate formulations, wherein at least one of those formulations comprises a compound of the invention, and at least one comprises the other therapeutic agent, or may be presented (i.e. formulated) as a combined preparation (i.e. presented as a single formulation including a 3o compound of the invention and the other therapeutic agent).

Thus, there is further provided:
(1) a pharmaceutical formulation including a compound of the invention, as s hereinbefore defined, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier; and (2) a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound of the invention, as hereinbefore defined, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admi~rture with a 1s pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
Compounds of the invention may be administered at varying doses. oral 2o dosages may range from between about 0.01 mg/kg of body weight per day (mg/kg/day) to about 100 mg/kg/day, preferably about 0.01 to about IO
mg/kg/day, and more preferably about 0.1 to about 5.0 mg/kg/day. For oral administration, the compositions typically contain between about 0.01 mg to about 500 mg, and preferably between about 1 mg to about 100 mg, of 2s the active ingredient. Intravenously, the most preferred doses will range from about 0.001 to about 10 mg/kg/hour during constant rate infusion.
Advantageously, compounds may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three or four times daily.

In any event, the physician, or the skilled person, will be able to determine the actual dosage which will be most suitable for an individual patient, which is likely to vary with the route of administration, the type and severity of the condition that is to be treated, as well as the species, age, s weight, sex, renal function, hepatic function and response of the particular patient to be treated. The above-mentioned dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited, and such are within the scope of this invention.
to Compounds of the invention may have the advantage that they are effective, and preferably selective, inhibitors of prostaglandin E synthases (PGES) and particularly microsomal prostaglandin E synthase-I (mPGES-1). The compounds of the invention may reduce the formation of the specific 1s arachidonic acid metabolite PGEZ without reducing the formation of other arachidonic acid metabolites, and thus may not give rise to the associated side-effects mentioned hereinbefore.
Compounds of the invention may also have the advantage that they may be 2o more efficacious than, be less toxic than, be longer acting than, be more potent than, produce fewer side effects than, be more easily absorbed than, and/or have a better pharmacokinetic profile (e.g. higher oral bioavailability and/or lower clearance) than, and/or have other useful pharmacological, physical, or chemical properties over, compounds known in the prior art, 2s whether for use in the above-stated indications or otherwise.
Biological Test In the assay mPGES-1 catalyses the reaction where the substrate PGH2 is 3o converted to PGE2, mPGES-1 is expressed in E. coli and the membrane fraction is dissolved in 20mM NaPi-buffer pH 8.0 and stored at -80 °C.
In the assay lnPGES-1 is dissolved in O.1M KPi-buffer pH 7.35 with 2.SmM
glutathione. The stop solution consists of H2O / MeCN (7/3), containing FeClz (25 mM) and HCl (0.15 M). The assay is performed at room s temperature in 96-well plates. Analysis of the amount of PGE2 is performed with reversed phase HPLC (Waters 2795 equipped with a 3.9 x 150 mm C18 column). The mobile phase consists of H2O / MeCN (7/3), containing TFA (0.056%), and absorbance is measured at 195 nm with a Waters 2487 LTV-detector.
to The following is added chronologically to each well:
1. 100 ~,L mPGES-1 in I~Pi-buffer with glutathione. Total protein concentration: 0.02 mg/mL.
2. 1 ~L inhibitor in DMSO. Incubation of the plate at room temperature for 25 minutes.
15 3. 4 uL of a 0.25mM PGH2 solution. Incubation of the plate at room temperature for 60 seconds.
4. 100 ~I, stop solution.
I80 ~,L, per sample is analysed with HPLC.
2o Examples The invention is illustrated by way of the following examples, in which the following abbreviations may be employed:
BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 2s dba dibenzylideneacetone DMAP 4,4-dimethylaminopyridine DME ethylene glycol dimethyl ether DMF dimethylformamide DMSO dimethylsulfoxide 3o EtOAc ethyl acetate HPLC High Pressure Liquid Chromatography MeCN acetonitrile NBS N bromosuccinimide NCS N chlorosuccinimide s NMR nuclear magnetic resonance TFA trifluoroacetic acid THF tetrahydrofuran TLC thin Layer chromatography to Starting materials and chemical reagents specified in the syntheses described below are commercially available from, e.g. Sigma-Aldrich Fine Chemicals.
Example 1 is 6-(4-tee°t-~u lphen~)-1-(3-phenoxybenwl)-3-phenylindole-2-carbox lic acid (a) 6-(4-te~°t-~utylphen~l)indole-2-carboxylic acid ethyl ester A mixture of 6-bromoindole-2-carboxylic acid ethyl ester (400 mg, 1.5 2o mmol), 4-tee°t-butylphenylboronic acid (400 mg, 2.25 mmol), I~3P04 (950 mg, 1.5 mmol), Pd(OAc)2 (18 mg, 0.075 mmol), 2,2'-bis(di-tef°t-butylphosphino)-l,l'-biphenyl (45 mg, 0.15 mmol), and toluene (9 mL) were stirred in an argon atmosphere for 30 min at room temperature, and at 100 °C for 40 min using microwave irradiation. The mixture was cooled to 25 room temperature and poured into NaHC03 (aq., sat.). The mixture was extracted with EtOAc and the combined extracts were washed with water, brine and dried over Na2SO4. The organic phase was then concentrated and the product purified by chromatography to give the sub-title compound (392 mg, ~l%).

s2 (b) 6-(4-te~°t-But~phenyll-3-iodoindole-2-carboxylic acid ethyl ester The reaction was performed with the exclusion of light. A solution of NaI
(300 mg, 2.0 mmol) in acetone (15 mL) was added dropwise to a stirred solution of NCS (270 mg, 2.0 mmol) in acetone (4 mL), followed after 15 s min by the dropwise addition of 6-(4-ter°t-butylphenyl)indole-2-carboxylic acid ethyl ester (650 mg, 2.0 mmol; see step (a) above) in acetone (20 mL).
After 30 min at room temperature the mixture was poured into an aqueous solution of Na2S203 (aq., 10%) and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. The organic to phase was then concentrated and then purified by chromatography to give the sub-title compound (743 mg, 82%).
(c) 6 ~4-tef~t-Buiylpheny~-3-iodo-1-(3-phenox~n~I)-indole-2-carboxylic acid ethyl ester is A solution of 6-(4-ter°t-butylphenyl)-3-iodoindole-2-carboxylic acid ethyl ester (743 rng, 1.66 mmol; see step (b) above) in DMF (10 mL) was added carefully to a stirred suspension of NaH (41 mg, 1.69 mmol) in DMF (4 mL) at 0 °C. The mixture was stirred at room temperature for 25 min. A
solution of 3-phenoxyber~yl chloride (37~ mg, 1.69 mmol) in DMF (6 mL) 2o was then added in portions and the mixture was stirred at room temperature for a further 24 h, then poured into water and extracted with t-BuOMe. The combined extracts were washed with water, brine and dried over Na2SO4.
The organic phase was concentrated and the product purified by chromatography and then crystallisation from EtOH to give the sub-title 25 compound (766 mg, 73 %).
(d) 6-~4-tef~t-Butylphenyl)-I-(3-phenoxYbenz~-3-phenylindole-2-carboxy-lic acid eth 1 A mixture of 6-(4-tent-butylphenyl)-3-iodo-I-(3-phenoxybenzyl)-indole-2-3o carboxylic acid ethyl ester (200 mg, 0.32 mmol; see step (c) above), phenylboronic acid (59 mg, 0.48 mmol), I~3P04 (238 mg, 1.12 mmol), Pd(OAc)2 (3.6 mg, 0.016 mmol) and toluene (3 mL) was stirred for 20 min at room temperature and then for 4 h at 80 °C. The mixture was poured into NaHCO3 (aq., sat.) and extracted with EtOAc. The combined extracts were s washed with water, brine and dried over Na2S04. The organic phase was then concentrated and the product purified by column chromatography to give the sub-title compound (163 mg, 88%).
6 ~4-ter°t-B ut~phenyl ~ l -(3 -phenoxyben~phenylin dol e-2-carb oxylic to acid A mixture of 6-(4-te~°t-butylphenyl)-1-(3-phenoxybenzyl)-3-phenylindole-2-carboxylic acid ethyl ester (163 mg, 0.281 nunol; see step (d)), aqueous NaOH ( 1 M, 10 mL) and MeCN (40 mL) was heated at reflux for 4 h. The mixture was then allowed to cool, acidified witl2 HCl (1M) to pH 2 and 1s extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2SO4. The combined extracts were concentrated and the product was purified by chromatography and recrystallisation firstly from EtOH and then from MeCN to give the title compound (95 mg, 61°f°).
1H NMIZ (DMSO-d6, 200 MHz): ~ 7.6I-7.37 (12H, m), 7.29-7.17 (3H, m), 20 7.09-7.00 (1H, m), 6.97-6.90 (2H, m), 6.85 (1H, d, J=2.0 Hz), 6.83-6.77 (2H, m), 5.86 (2H, s), 1.37 (9H, s).
Examt~le 2 6-(4-tee°t-But~phenyl)-1-(3- hp enoxybenzyl)-3-(2-thienyl)indole-2-carboxylic 25 acid (a) 6 ~4-tee°t-Butylphenyl -~1-(3-phenoxybenzyl)-3-(2-thienyl~indole-2-carb-oxylic acid eth h~ester 2-(Tributylstannyl)thiophene (72 mg, 0.20 mmol) was added to a stirred so mixture of 6-(4-tent-butylphenyl)-3-iodo-1-(3-phenoxybenzyl)-indole-2-s4 carboxylic acid ethyl ester (150 mg, 0.24 mmol; see Example 1(d)), CuI (25 mg, 0.13 rmnol), Pd(PPh3)2C12 (18 mg, 0.026 mmol) and DMF (3 mL).
After 10 min at room temperature and 1 h at 90°C another portion of 2-(tributylstannyl)thiophene (72 mg, 0.20 mmol) was added and the heating s was continued for 3 h. The mixture was filtered through Celite~ and the solids were washed with EtOAc. Concentration and purification by chromatography gave the sub-title compound (125 mg, 90%).
(b) 6-(4-ter°t-Butyllahenyl~3-phenoxybenzyl)-3-(2-thienyl)indole-2-carb-oxylic acid ethyl ester A mixture of 6-(4-t~~°t-butylphenyl)-1-(3-phenoxybenzyl)-3-phenylindole-2-carboxylic acid ethyl ester (125 mg, 0.213 mmol; see step (a)), aqueous KOH (2M, 2 mL) and MeCN (6 mL) was heated for 30 min at 130°C
using microwave irradiation. The mixture was acidified with HCl (1M) to pH 2 is and exrtracted with EtOAc. The combined extracts were washed with water, brine and dried over Na2S~~. Concentration and purification by chromatography gave the title compound (91 mg, 77%). 1H I~1MR (DMS~-d6, 200 MHz): b 7.75 (1H, d, ,I 8.4 Hz), 7.56-7.45 (6H, m), 7.44 (1H, dd, J=4.0, 1.4 Hz), 7.30-7.15 (SH, m), 7.09-7.03 (1H, m), 6.98-6.90 (2H, m), 6.86-6.79 (3H, m), 5.86 (2H, s), 1.37 (9H, s).
Example 3 5-(3~4-Methylenedioxyphenyl)-3-phenyl-1-(3-phen~prola~)indole-2-carb-oxy_lic acid (a) N (2-Benzoyl-4-chlorolahen~)oxalamic acid eth liter A mixture of 2-amino-5-chlorobenzophenone (I 1.6 g, 50 mmol), ethyl oxalyl-chloride (6.8 g, 50 mmol) and toluene (70 mL) was heated at reflux for 1.5 h.
On cooling a yellow precipitate formed. EtOAc (250 mL) was added and the solution was washed with NaHC03 (aq., 5%), H3P04 (aq., 5%), brine and dried over Na2S0~. Concentration gave the sub-title compound (IS.Sg, 94%).
(b) S-Chloro-3-phenylindole-2-carboxylic acid ethyl ester s TiCl4 in THF (0.25 M, 19.5 mL, 54.9 mmol) was added slowly to a stirred mixture of N (2-benzoyl-4-chlorophenyl)oxalamic acid ethyl ester (8.88 g, 26.8 mmol; see step (a)), Zn (7.19 g, 110 mmol) and THF (60 mL) at room temperature. After 2 h, silica gel was added and then after a further 30 min the mixture was filtered through a pad of silica gel which was washed with 1o EtOAc. The combined filtrates were washed with NaHC03 (aq., 5°/~), water, brine and dried over Na2S04. Concentration and crystallisation of the residue from CH2C12/petroleum ether gave the title compound (3.13g, 39°/~).
(c) 5-Chloro-3-phenyl-I ~3-phenylpropYl)indole-2-carboxylic acid ethyl ester 1s NaH (60 % dispersion in mineral oil, 0.25 g, 6.2 mmol) was washed with hexane (2x1 1nL) and Et2~ (1 mL) and suspended in I~MF (1 mL). A
solution of S-chloro-3-phenylindole-2-carboxylic acid ethyl ester (1.55 g, 5.17 mmol; see step (b)) in I~MF (10 mL) was added carefully at 0°C and the mixture was stirred for 20 min. A. solution of (3-bromopropyl)-benzene 20 (1.54 g, 7.75 mmol) in I~MF (3mL) was added carefully at 0°C. The cooling bath was removed and the mixture was stirred at room temperature for 16 h, poured into water, and extracted with EtOAc. The extract was washed with water, brine and dried over Na2S~4. Concentration and chromatography gave the title compound (1.66 g, 77%).
(d) S-(3,4-Meth~enedioxYphenyl)-3-phen 1-~1-(3-phenylpropyl~indole-2-car-boxylic acid The title compound was prepared in accordance with the procedure in Example 1(a) from 5-chloro-3-phenyl-1-(3-phenylpropyl)indole-2 3o carboxylic acid ethyl ester (see step (c)) and 3,4 methylenedioxyphenylboronic acid, followed by hydrolysis in accordance with the procedure described in Example 2(b).
1H NMR (CI~CI3, 200 MHz): 8 7.61-7.38 (8H, m), 7.36-7.I5 (SH, m), 7.04 (1H, s), 7.02 (1H, dd, J--8.5, 1.8 Hz), 6.85 (1H, d, J--8.5 Hz), 5.98 (2H, s), s 4.67-4.55 (2H, m), 2.75 (2H, t, J--7.6 Hz), 2.31-2.12 (2H, m).
Example 4 3-Phenyl-1 ~3-phenylpropyl)-5-(3-pyridyl)indole-2-carboxylic acid to (a) 3-Phenyl-1-(3-phenylpropyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yllindole-2-carbox ~lic acid ethyl ester A 0.01 M stock solution of a Pd/(C6Hlr)3P was prepared from Pd2(dba)3, (0.457 g, 0.5 rnmol), tricyclohexylphosphine (0.841 g, 3 mmol) and dioxane (100 mL). An aliquot of this stock solution (12.5 mL, O.I25 mmol Pd), 5-1s chloro-3-phenyl-1-(3-phenylpropyl)indole-2-carboxylic acid ethyl ester (1.05 g, 2.5 mmol; see Example 3(c)), bis(pinacolato)diboron (0.762 g, 3.0 mmol), I~OAc (0.44 g, 4.5 mmol), and dioxane (25 mL) were heated at 80°C
for 16 h.
Another aliquot of the Pd/(C6H11);P reagent (2.5 mL, 0.025 lnmol Pd) was added and the mixture was heated at 100°C for 24 h. The mixture was f ltered 2o through Celite~, and the filtrate was concentrated and purified by chromatography to give the sub-title compound (0.47 g, 37 %) together with 0.5 5 g recovered starting material.
(b) 3-Phenyl-1-(3-phen~propyl)-5-(3-p~yl)indole-2-carboxylic acid ethyl 25 ester 3-Phenyl-1-(3 -phenylpropyl)-5-(4, 4, 5, 5 -tetramethyl-1, 3 , 2-di oxab orolan-2-yl)indole-2-carboxylic acid ethyl ester (0.40 g, 91 mmol; see step (a)), 3-iodopyridine (0.28 g, 1.37 mmol), aqueous Na2C03 (2M, 0.46 mL, 0.9I
mmol), Pd(PPh3)4 (53 mg, 46 ~mol), toluene (7.3 mL), and EtOH (I.8 mL) so were heated at 80°C for I6 h. More 3-iodopyridine (0.19 g, 0.91 mrnol), aqueous Na2CO3 (2M, 1.4 mL, 2.73 mmol), and Pd(PPh3)4 (23 mg, 20 ~.mol) were added and the mixture was heated for a further 8 h. EtOAc (30 mL) and brine (30 mL) were added. The layers were separated and the aqueous phase was washed with EtOAc. The combined organic phases s were dried with brine and Na2S04. Concentration and chromatography gave the sub-title compound (0.32 g, 76%).
(c) 3-Phenyl~l-(3-phenylpropyl)-5-(3-pyridyl)indole-2-carboxylic aeid The title compound was prepared from 3-phenyl-1-(3-phenylpropyl)-5 lo (3-pyridyl)indole-2-carboxylic acid ethyl ester (see step (b)) in accordance with the procedure in Example 2(b).
1H NMR (CI~C13, 200 MHz): ~ 8.78 (1H, s), 8.52 (1H, d, ,I 4.2 Hz), 7.92 (1H, d, J 8.0 Hz)), 7.65-7.71 (1H, m), 7.59-7.13 (13H, m), 4.71-4.58 (2H, m), 2.75 (2H, t, J 7.6 Hz), 2.32-2.17 (2H, m).
Is Example 5 6-(4-Benzyloxypheny,-3-(3-carbox~yl)-1-(3-nitrobenzyl)indole-2-carboxylic acid The title compound was prepared in accordance with Example 1 from 20 4-benzyloxyphenylboronic acid, 3-nitrobenzylbromide and 3-carboxyphenyl-boronic acid.
~H NMR (DMSO-d6, 200 MHz): d 13.02 (2H, s), 8.13-7.94 (5H, m), 7.75 ( 1 H, ddd, .I--7. 6, 1. 5, 1. 5 Hz), 7. 63 ( 1 H, dd, J 7.6, 2.0 Hz), 7. 5 9-7 .27 ( 12H, m), 7.04-6.97 (1H, m), 6.12 (2H, s), 5.18 (2H, s).
as Exam,~le 6 3-(3-Carboxyphenyl)-4-phenyl-1-[3-(trifluorometh 1)benzyllindole-2-carboxylic acid The title compound was prepared in accordance with Example 1 from s 4-bromoindole-2-carboxylic acid ethyl ester, phenylboronic acid, 3-(trifluoromethyl)benzylbromide and 3-carboxyphenylboronic acid.
'H NMR (CI~Cl3, 200 MHz): ~ 7.79 (1H, dd, J 1.5, 1.5 Hz), 7.70 (1H, ddd, J 7.7, 1.5, 1.5 Hz), 7.57-7.50 (2H, m), 7.47-7.34 (3H, m), 7.25-7.20 (1H, m), 7.06 (1H, dd, J 6.2, 1.8 Hz), 7.06-6.85 (7H, m), 5.93 (2H, s).
Example 7 6-(4-B enzyl oxyphenyl)-1-(3 -nitrob enzyl)-3 -(2-oxopyrroli din-1-~1~ indole-carbo~lic acid Is (a) 6-(4-Eenzyloxy~henyl)-1-(3-nitrobenzyl)-3-(2-oxopyrrolidin-1-yl)indole-2-carboxylic acid eth ly ester A stock suspension of a CuI/MeNHCH2CH~NHMe complex was prepared by heating CuI (95.2 mg, 0.5 lnmol), MeNHCH2CH2NHMe (213 ~,L, 2.0 mmol), and dioxane (5 mL) at 100°C for 5 min using microwave irradiation. 1.5 mL
of this solution was added to 6-(4-benzyloxyphenyl)-3-iodo-1-(3-nitrobenzyl)indole-2-carboxylic acid ethyl ester (630 mg, 1.0 mmol, prepared in accordance with Example 1 from 6-bromoindole-2-carboxylic acid ethyl ester, 4-benzyloxyphenylboronic acid, and 3-nitrobenzylbromide), I~3PO4 (530 mg, 2.5 mmol), and dioxane (5 mL). Pyrrolidinone (390 mg, 5.0 mmol) 2s was added and the mixture was stirred at 95°C for 24 h, cooled to room temperature, poured into aqueous HCl (O.1M) and extracted with EtOAc. The combined extracts were dried with brine and NaZS04. Concentration and chromatography gave the sub-title compound (538 mg, 91%).

(b) 6-(4-Benzyloxyphenyl~I-(3-nitrobenzyl)-3-(2-oxopyrrolidin-1-yl)indole-2-carboxylic acid 6-(4-Benzyloxyphenyl)-1-(3-nitrobenzyl)-3-(2-oxopyrrolidin-1-yl)indole-2 carboxylic acid ethyl ester (see step (a)) was hydrolyzed in accordance with s Example 2(b), using dioxane as the solvent, to give the title compound.
1H NMR (DMSO, 200 MHz): ~ 13.37 (1H, s), 8.10-8.06 (2H, m), 7.96 (lI~, s), 7.66-7.26 (12H, m), 7.00 (1H, d, J 7.8 Hz), 6.06 (2H, s), 5.17 (2H, s), 3.81-3.74 (2H, m), 2.46-2.38 (2H, m), 2.24-2.06 (2H, m).
1 o Example 8 3-(2-Oxop~olidin-1 yI)-I~3-phenox~enzyl)-5-phen~lindole-2-carbox lic acid The title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, phenylboronic acid, Is 3-phenoxybenzylchloride and pyrrolidinone.
_ _ _ 1H NMR (CDCl3, 200 MHz): ~ 7.69-7.65 (1H, m), 7.63-7.52 (3H, m), 7.50-7.15 (7H, m), 7.13-7.01 (1H, m), 7.00-6.91 (2H, m), 6.88-6.79 (3H, m), 5.74 (2H, s), 3.98 (2H, t, ,J 7.0 Hz), 2.72 (2H, t, .I 8.0 Hz), 2.41-2.34 (2H, m).
2o Example 9 I-(3 5-Difluorobenz~l)-4-methoxy-3-(2-oxopyrrolidin-1-~)-7-phenyl-indole-2-carboxylic acid (a) 2-Azido-3-(4-methoxybiphenyl-3-yacrylic acid ethyl ester 2s A solution of 4-methoxybiphenyl-3-carboxaldehyde (1.8 g, 8.48 mmol) and azidoacetic acid ethyl ester (5.62 g, 44 mmol) in EtOH ( 15 mL) was added dropwise to a solution of NaOEt (3.13 g, 46 nnnol) in EtOH (3 5 mL) at -25°C. The mixture was stirred at that temperature for 10 min, kept in the freezer (-18°C) for 24 h and then poured whilst stirring vigorously to a cooled (0°C) solution of NH~CI (aq., sat.). The mixture was extracted with EtOAc and the combined extracts were washed with brine and dried over Na2S04.
Concentration and crystallisation from EtOH gave the title compound (1.~0 g, 66%).
s (b) 4-Methoxy-7-t~henylindole-2-carboxylic acid ethyl ester A solution of 2-azido-3-(4-methoxybiphenyl-3-yl)aclylic acid ethyl ester ( 1.75 g, 5.40 mmol; see step (a)) in o-xylene (25 mL) was added dropwise to boiling o-xylene (25 mL). The heating was continued for S min, then the solution was allowed to cool to room temperature and lcept in the freezer 10 (-18°C) for 16 h. The precipitate was isolated by filtration, washed with petroleum ether and dried in vacuo to afford the sub-title compound (1.20 g, 74%).
(c) 1-(3 5-I~ifluoroben~,y1)-4-methox~3-(2-oxopyrrolidin-1-~)-7-phen~l-Is indole-2-carboxylic acid The title compound was prepared from 4-methoxy-7-phenylindole-2-carboxylic acid ethyl ester (see step (b)) in accordance with Example 7.
1H NMR (L~MSO-d6, 200 MHz): S 7.34-7.21 (3H, m), 7.10-7.06 (2H, m), 7.01-6.91 (1H, m), 6.94 (1H, d, J 7.~ Hz), 6.67 (1H, d, ..T 8.1 Hz), 5.92-zo 5.89 (2H, m), 5.51-5.28 (2H, m), 3.~9 (3H, s), 3.77-3.67 (2H, m), 2.37-2.17 (2H, m), 2.14-2.10 (2H, m).
Example 10 6-(3,4-Meth~lenedioxyphen~)-1-[3,5-bis(trifluoromethyl)benzyll-3-(4-zs chlorobenzo l~ aminolindole-2-carboxylic acid The title compound was prepared according in accordance with Example 7 from 6-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy-phenylboronic acid, 3,5-bis(trifluoromethyl)benzylchloride and 4-chloro-benzamide.

1H NMR (DMSO-d6, 200 MHz): 8 10.35 (1H, s), 8.09-8.03 (2H, m), 8.01-7.99 (1H, m), 7.95-7.94 (1H, m), 7.81 (2H, s), 7.73 (1H, d, .I--8.6 Hz), 7.66-7 . 5 9 (2H, m), 7.44 ( I H, dd, J 8 .6, 1.2 Hz), 7. 34 ( 1 H, d, J 1. 8 Hz), 7.22 ( 1 H, dd, ,I 8.2, 1.8 Hz), 6.99 (1H, d, J 8.2 Hz), 6.08 (2H, s), 6.05 (2H, s).
Example 11 3- 3 5-Dimethox b~ylamino)-5-(4-nitrophenyl)-1-(3-phenoxy-benzyl~indole-2-carboxylic acid The title compound was prepared from 5-(4-nitrophenyl)indole-2-carboxylic to acid ethyl ester (prepared from 5-(4,4,5,5-tetramethyl-I,3,2-dioxaborolan-2-yl)indole-2-carboxylic acid ethyl ester (prepared from 5-bromoindole-2-carboxylic acid ethyl ester) and 4-nitrobromobenzene), 3-phenoxy-benzylchloride and 3,5-dimethoxybenzamide in accordance with Example 7.
1H NMl~ (DMSO-d6, 200 MHz): ~ 10.37 (1H, s), 8.32-8.24 (2H, m), 8.15 is (1H,~ s), B.OI-7.91 (2H, m), 7.76 (2H, s), 7.41-7.16 (~H, m), 7.15-7.05 (IH, m), 6.99-6.90 (2H, m), 6.84-6.69 (4H, m), 5.90 (2H, s), 3.81 (6H, s).
Example 12 3-(3-Amino-4-methylbenzoylamino)-5-(4-tee~t-butylphenyl)-1-(3-c111oro-2o benzyl)indole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, 4-tent-butylphenylboronic acid, 3-chlorobenzylchloride and 3-amino-4-methylbenzamide.
1H NMR (DMS~-d~, 200 MHz): 8 10.09 (1H, s), 8.00 (IH, s), 7.69-7.40 (6H, 2s m), 7.36-7.3I (3H, m), 7.19-6.94 (3H, m), 5.86 (2H, s), 4.3 (IH, br s), 3.3 (IH, br s), 2.11 (3H, s), 1.29 (9H, s).

Example 13 5-(4-tee°t-Butylphen l~)-1-(3-chlorobenzyl)-3-[(pyridine-3-carbonYl)amino]-indole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from s 5-bromoindole-2-carboxylic acid ethyl ester, 4-tee°t-butylphenylboronic aeid, 3-chlorobenzylchloride and nicotinamide.
1H NMR (l~MSO-d6, 200 MHz): ~ 10.50 (1H, s), 9.20 (1H, s), 8.80-8.71 (1H, m), 8.42-8.31 (1H, m), 7.91 (1H, s), 7.32-7.~2 (SH, m), 7.48-7.40 (2H, m), 7.34-7.27 (2H, m), 7.14 (1H, s), 7.06-6.97 (1H, m), 5.89 (2H, s), 1.29 (9H, s).
Example 14 3-~4-(I~imethylamino)but~rylamino]-6-(3,4-meth~lenedioxyphenyl)-1-(3-phenoxybenz~)indole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from ~s 6-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy-phenylboronic acid, 3-phenoxybenzylchloride and 4-(dimethylamino)-butyrylamide.
1H NMI~ (DMSO-d6, 200 MHz): b 12.3-11.2 (1H, br s), 8.22 (1H, d, J--8.6 Hz), 7.54 (1H, s), 7.37-7.05 (7H, m), 7.00-6.84 (SH, m), 6.71 (1H, dd, 2o J--8.2, 2.3 Hz), 6.14 (2H, s), 6.07 (2H, s), 2.81 (2H, t, J 7.5 Hz), 2.54 (6H, s), 2.46 (2H, t, J 7.3 Hz), 1.94 (2H, dt, J 7.5, 7.3 Hz).
Example 15 1-(3-Cyanobenz,~l)-6-(3,4-methylenedioxyphenYl)-3-(3-phenylacrylo T~l-2s amino)indole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from 6-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy-phenylboronic acid, 3-cyanobenzylchloride and cinnamamide.
1H NMR (DMSO-d6, 200 MHz): 8 11.95 (1H, br s), 8.28 (1H, d, J 8.6 Hz), 30 7.70-7.59 (6H, m), 7.54-7.37 (6H, m), 7.28-7.23 (2H, m), 7.15 (1H, dd, .I--8.2, 1. 8 Hz), 6.96 ( 1 H, d, J--8.2 Hz), 6. 8 8 ( 1H, d, J--1 S . 8 Hz), 6.16 (2H, s), 6.03 (2H, s).
Example 16 s 1-(3-Carbamo l~benzyl)-6-(3 4-methYlenedioxyphenYl)-3-(3-phenylacryloyl-aminolindole-2-carboxylic acid The title compound was isolated in the last synthetic step (the hydrolysis) in the preparation of the title compound of Example 1 S.
1H NMR (DMSO-d6, 200 MHz): 8 11.58 (1H, br s), 8.17 (1H, d, .I 8.6 Hz), l0 7.89 (IH, s), 7.74-7.55 (6H, m), 7.48-7.37 (3H, m), 7.34-7.23 (4H, m), 7.I6-7.0 8 (2H, m), 6.95 ( 1 H, d, .I 8.2 Hz), 6.91 ( 1 H, d, J--15 .6 Hz), 6.13 (2H, s), 6.03 (2H, s).
Example 17 15 3-Acetylamino-S-(3 4-methylenedioxyphenyll-I-(S-phenoxypentyllindole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy-phenylboronic acid, (5-bromopentyloxy)benzene, and acetamide.
20 1H NMR (DMSO-d6, 200 MHz): ~ 9.60 (1H, s), 7.71 (1H, s), 7.65-7.49 (2H, m), 7.30-7.15 (3H, m), 7.09 (1H, dd, J 8.1, 1.4 Hz), 6.77 (IH, d, ~ 8.I Hz), 6.93-6.82 (3H, m), 6.04 (2H, s), 4.60-4.46 (2H, m), 3.90 (2H, t, .~=6.3 Hz), 2.09 (3H, s), 1.81-1.61 (4H, m), 1.48-1.32 (2H, m).
2s Exam~Ie 18 S-(3,4-Methylenedioxxphenyl~ 3-(2-oxot~iperidin-1-yl)-1T(S-phenoxy-pentyl~indole-2-carboxylic acid The title compound was prepared in accordance with Example 7 from 5-bromoindole-2-carboxylic acid ethyl ester, 3,4-methylenedioxy-3o phenylboronic acid, (5-bromopentyloxy)benzene, and 2-piperidone.

1H NMR (DMSO-d6, 200 MHz): 8 7.66-7.49 (3H, m), 7.30-7.18 (3H, m), 7.I3 (IH, dd, J--8.1, 1.8 Hz), 6.97 (IH, d, J--8.1 Hz), 6.92-6.83 (3H, m), 6.04 (2H, s), 4.65-4.50 (2H, m), 3.9I (2H, t, .J 6.4 Hz), 3.64-3.55 (2H, m), 2.44-2.28 (2H, m), 1.98-I.64 (8H, m), 1.52-1.33 (2H, m).
Example 19 3-(3-Acet~l~henyl)-5-(4-methoxyphenYl)-I-[3-(trifluorometh~l)ben~ll-indole-2-carboxylic acid to (a) 5-(4-Methoxyphenyllindole-2-carboxylic acid eth l A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (268 mg, 1.0 mmol), 4-methoxyphenylboronic acid (243 mg, 1.6 mmol), Pd(OAc)2 ( 11.2 mg, 50 nmol), 2-(di-t-butylphosphino)biphenyl (60 mg, 200 nmol), K3PO4 (425 mg, 2 mmol) and toluene (2 mL) was heated at 170°C for 10 min using 1s microwave irradiation. The mixture was extracted with EOAc, and the combined extracts washed with water, dried with Na2SO4, and concentrated.
The residue was crystallised from EtOH to yield the sub-title compound (50%).
20 (b) 3-Iodo-5-(4-methoxyphenyl)indole-2-carboxylic acid ethyl ester Na,I (566 mg, 3.8 mmol) in acetone ( 18 mL) was added dropwise to a solution of NCS (458.5 mg, 3.4 mmol) in acetone (6 mL) at room temperature. After 15 min, 5-(4-methoxyphenyl)indole-2-carboxylic acid ethyl ester (1.01 g, 3.4 m~nol; see step (a)) in acetone (48 rnL) was added.
2s After 60 min Na2S203 (aq., I O%) was added and the mixture was extracted with EtOAc, and the combined extracts washed with water, dried with Na2SO4, and concentrated. The residue was crystallised from EtOAc/heptane to yield the sub-title compound (958 mg, 66%) (c) 3-Iodo-5-~4-methoxy~hen~l)-1-[3-(trifluoromethyl)benzyllindole-2-carboxylic acid ethyl ester A mixture of 3-iodo-5-(4-methoxyphenyl)indole-2-carboxylic acid ethyl ester (200 mg, 475 nmol; see step (b)), 1-(bromomethyl)-3-s (trifluoromethyl)benzene (182 ~L, 1.2 mmol), NaH (48 mg, 2 mmol) and DMF (2.5 mL) was heated at 170°C for 2 min using microwave irradiation.
The mixture was extracted with EOAc. The combined extracts were washed with water, dried with Na2SO4 and concentrated. The residue was crystallised from EtOH to yield the sub-title compound (several batches to were combined and employed in subsequent steps).
(d) 3-(3-Acetylpheny?)-5-(4-methoxyphenyl)-1-(3-(trifluorometh 1)ben~~l1-indole-2-carboxylic acid ethyl ester A mixture of 3-iodo-5-(4-methoxyphenyl)-1-[3-(trifluoromethyl)benzyl]-1s indole-2-carboxylic acid ethyl ester (100 mg, 173 ntnol; see step (c)), 3-acetylphenylboronic acid (42.5 mg, 259 rimol), Na~C~; (27 mg, 259 nmol), Pd(PPh;)2C12 (6.1 mg, 9 nmol) and DME/HZO/EtOH 7:3:2 (1 xnL) was heated at 160°C for .10 minutes using microwave irradiation. The reaction mixture was filtered through Celite° and the filter cake was washed with 2o Et2O. The combined filtrates were poured into NaHCO3 (aq., sat.) and extracted with Et20. The combined extracts were dried over Na2S04 and concentrated. Purification by chromatography yielded the sub-title compound (74 mg, 71 %).
2s (e) 3-(3-Acetylphenyl)-5-(4-methoxyphen~)-1-f3-(trifluoromethyl)benzyl]-indole-2-carbox ly is acid A mixture of 3-(3-acetylphenyl)-5-(4-methoxyphenyl)-1-[3-(trifluoro-methyl)benzyl]indole-2-carboxylic acid ethyl ester (59 mg, 103 rimol; see step (d)), NaOH (2 M, 500 ~.L) and MeCN (2 mL) was heated at 120°C for 30 10 min using microwave irradiation. The mixture was acidified with HCl (2IVI) and extracted with EOAc. The combined extracts were dried and concentrated. Purification by chromatography yielded the title compound.
IH NMR (200 MHz, CDC13): 8 8.10 (m, 1H), 7.99 (m, 1H), 7.7I (m, 1H), 7.63-7.54 (m, 3H), 7.53-7.47 (m, 3H), 7.46 (m, 1H), 7.40 (m, 1H), 7.35 (d, s J 8 Hz, 1H), 7.18 (d, J 8 Hz, 1H), 6.94 (m, 2H), 5.88 (s, 2H), 3.83 (s, 3H), 2.61 (s, 3H).
Example 20 5-(4-Methoxyt~hen l~)-3-phenyl-1-L3-(trifluoromethyl)benzyllindole-2-to carboxylic acid (a) 5 ~-Methoxyphen,~)-3-phenyl-1-j3-(trifluoromethyl)benzyllindole-2-carboxylic acid eth ly ester A mixture of 3-iodo-5-(4-methoxyphenyl)-1-[3-(trifluoromethyl)benzyl]-is indole-2-carboxylic acid ethyl ester (12.9 mg, 22 nmol; see Example 19(c)), phenylboronic acid (4.1 mg, 33 nmol), I~3PO4 (17 mg, 78 rimol), Pd(~Ac)2 (0.25 mg, 1.0 nmol) and toluene (500 ~.L) was heated at 170°C for 5 minutes using microwave irradiation. The mixture was filtered through Celite n and the filter cake was washed with Et2~. The combined filtrates 2o were poured into NaHC43 (aq., sat.) and extracted with Et20. The combined extracts were dried over Na2S04 and concentrated. Purification by chromatography yielded the sub-title compound (60%).
(b) 5-(4-Methoxyphen 1~)-3-phenyl-1-[3-(trifluoromethyl)benzyllindole-2-2s carboxylic acid The title compound was prepared from 5-(4-methoxyphenyl)-3-phenyl-1-[3-(trifluoromethyl)benzyl]indole-2-carboxylic acid ethyl ester (see step (a)) in accordance with Example I9(e).

Example 21 3,5-Bis(4-methoxyphen l~)-1-~3-(trifluoromethyl)ber~yllindole-2-carboxylic acid The title compound was prepared in accordance with Example 20 using s 4-methoxyphenylboronic acid instead of phenylboronic acid.
1H NMR (200 MHz, CI~Cl3): 8 7.68 (m, 1H), 7.59 (dd, J 9, 2 Hz, IH), 7.52-7.46 (m, SH), 7.45 (m, 1H), 7.40-7.34 (m, 2H), 7.19 (d, .I--7 Hz, 1H), 7.02 (m, 2H), 6.95 (m, 2H), 5.87 (s, 2H), 3.89 (s, 3H), 3.84 (s, 3H).
to Example 22 5-(4-Methoxyphenyl)-3-(3-nitrophenylLl -f 3-(trifluoromethyl)benzyll-indole-2-carboxylic acid The title compound was prepared in accordance with Example 19 using 3-nitrophenylboronic acid and 2.5 mol% Pd(PPh;)ZCh.
is 1H NMR (200 MHz, CI~Cl3): d 8.39 (m, 1H), 8.26 (m, 1H), 7.83 (m, 1H), 7.65 (m, 1H), 7.62 (m, 1H), 7.58 (m, 1H), 7.54-7.34 (m, 6H), 7.19 (d, .I 7 Hz, IH), 6.95 (m, 2H), 5.89 (s, 2H), 3.83 (s, 3H).
Example 23 20 5-(4-Methoxyphe~l~-3-(~yridin-3-yl)-1-[3-(trifluorometh 1)~,benzyllindole-2-carboxylic acid The title compound was prepared in accordance with Example 19 using pyridin-3-ylboronic acid and 5 mol% Pd(PPh;)2Cla.
1H NMR (200 MHz, DMS~-d6): b 8.76 (s, 1H), 8.50 (d, .I--4 Hz, IH), 8,00 2s (d, J--8 Hz, 1H), 7.72 (s, IH), 7.63-7.37 (m, 9H), 6.98 (m, 2H), 5.95 (s, 2H), 3.77 (s, 3H).

Example 24 3-(4-Fluoro-3-methylphenyl)-5-(4-methox phenyl)-1-[3 ~trifluoromethyll benzyllindole-2-carboxylic acid The title compound was prepared in accordance with Example 19 using 4-fluoro-3-methylphenylboronic acid and 5 mol% Pd(PPh;)2C12.
1H NMR (200 MHz, DMSO-d6): 8 7.69-7.50 (m, SH), 7.42 (m, IH), 7.37-7.28 (rn, 2H), 7.24-7.17 (m, 1H), 6.98 (m, 2H), 5.94 (s, 2H), 3.76 (s, 3H), 2.29 (d, J--2. Hz, 3H).
to Example 25 3-(3, 5-Dichlorophenyl)-5-(4-methoxyphenyl)-1-[3-(trifluoromethyl)-benzyl~indole-2-carboxylic acid The title compound was prepared in accordance with Example 19 using 3,5-dichlorophenylboronic acid and 3.5 mol°f° Pd(PPh;)2CI2.
Is 1H NMR (200 MHz, CI~Cl,): 8 7.63-7.5~ (m, 2H), 7.53-7.44 (m, 4H), 7.40-7.34 (m, SH), 7.14 (d, J'--8 Hz, 1H), 6.97 (m, 2H), 5.~2 (s, 2H), 3.54 (s, 3H).
Example 26 5-(2-Methoxyphenyl)-3-(3-nitrophen l~)-1-[3-(trifluoromethyl)benzyll-2o indole-2-carboxylic acid (a) 5-(2-Methoxyphenyl)indole-2-carboxylic acid eth 1 ester A mixture of 5-bromoindole-2-carboxylic acid ethyl ester (26~ mg, 1 mtnol), 2-methoxyphenylboronic acid (304 mg, 2 mmol), Pd(PPh3)2C12 (35 2s mg, 50 nmol), Na2CO3 (159 mg, 1.5 rnmol),and DMElH20/EtOH 7:3:2 (3 mL) was heated at 160°C for 8 minutes using microwave irradiation. The mixture was poured into water and extracted with EOAc. The combined extracts were dried over Na2S0~ and concentrated. The residue was crystallised from EtOH/HZO to yield the sub-title compound (37%).

(b) 5-(2-Methoxyphenyl)-3-(3-nitrophenyl)-1-[3-(trifluoromethyl)benzyll-indole-2-carbox Tli~ c acid The title compound was prepared in accordance with Example I9(b), 19(c) and 19(d) using 3-nitrophenylboronic acid and 2.5 mol% Pd(PPh3)2Clz.
s 1H NMR (200 MHz, DMSO-d6): b 13.31 (br s, 1H), 8.32 (m, 1H), 8.23 (m, IH), 7.98 (d, .I--8 Hz, 1H), 7.80-7.49 (m, 7H), 7.32-7.26 (m, 3H), 7.07 (d, ~I 8 Hz, 1H), 6.98 (t, J 8 Hz, IH), 6.01 (s, 2H), 3.72 (s, 3H).
Exam lp a 27 5-(2-Methoxyphenyl)-3-(4-methoxy~henyl~ 1-[3-(trifluoromethyl)benzyll-indole-2-carboxylic acid The title compound was prepared in accordance with Example 26 using 4-methoxyphenylboronic acid and 2.5 mol% Pd(PPh3)2C12.
1H NMR (200 MHz, DMSO-d6): 8 12.98 (br s, 1H), 7.66-7.60 (m, 3H), 1s 7.55 (t, J 8 Hz, 1H), 7.50-7.38 (m, 4H), 7.34-7.24 (m, 3H), 7.06 (d, .I--8 Hz, IH), 7.04-6.95 (m, 3H), 5.95 (s, 2H), 3.81 (s, 3H), 3.7I (s, 3H).
Example 28 3-(3,5-Dichlorophenyl)-5-(2-methoxyphen~)-1-j3 ~trifluoromethyl)-2o benzyl)indole-2-carboxylic acid The title compound was prepared in accordance with Example 26 using 3,5-dichlorophenylboronic acid and 2.5 mol°f° Pd(PPh3)ZCl2.
IH NMR (200 MHz, DMSO-d6): 8 7.72 (s, 1H), 7.65-7.56 (m, SH), 7.54-7.51 (m, 2H), 7.46 (m, 1H), 7.35-7.27 (m, 3H), 7.10 (m, 1H), 6.99 (m, 1H), 2s 5.96 (s, 2H), 3.73 (s, 3H).

Example 29 5-~3-Acetylphenyl~ 3-(4-methoxyphen~)-1-(3-(trifluoromethyl)benzyll-indole-2-carbox~Iic acid 5 (a) 5-(3-Acetylphenyl)indole-2-carboxylic acid ethyl ester The sub-title compound was prepared in accordance with Example 26(a) using 3-acetylphenylboronic acid and 2.5 mol% Pd(PPh3)2CI2 and heating at 160°C for 10 min.
10 (b) 5-(3-Acetylphen~)-3-~-methoxyphen~)-1-(3-(trifluoromethyl)benzyll-indole-2-carboxylic acid The title compound was prepared in accordance with Example 26(b) using 4-methoxyphenylboronic acid and 2.5 mol% Pd(PPh;)2C12.
IH I~IMR (200 MHz, DMSO-d6): ~ 13.06 (br s, 1H), 8.10 (s, 1H), 7.89 (m, Is 2H), 7.80-7.67 (m, 3H), 7.65-7.54 (m, 4H), 7.44 (m, 2H), 7.28 (d, J 8 Hz, 1H), 7.03 (m, 2H), 5.98 (s, 2H), 3.82 (s, 3H), 2.63 (s, 3H).
Example 30 ~,S-Bis~3-acetylphen~l)-1-~3-(trifluorometh~l)benzyllindole-2-carboxylic 2o acid The title compound was prepared in accordance with Example 29 using 3-acetylphenylboronic acid and 2.5 mol% Pd(PPh3)2Clz ~H NMR (200 MHz, DMSO-d6): b 13.21 (br s, 1H), 8.10 (m, 2H), 7.98 (m, 1H), 7.89 (m, 2H), 7.84-7.78 (m, 2H), 7.74 (m, 1H), 7.70 (m, 1H), 7.67-2s 7.52 (m, SH), 7.30 (d, J 8 Hz, 1H), 6.02 (s, 2H), 2.64 (s, 3H), 2.62 (s, 3H).

Example 31 5-(3-Acetylphenyl)-3-phen~ j3-(trifluoromethyl)benzy~indole-2-carboxylic acid The title compound was prepared in accordance with Example 29 using s phenylboronic acid and 2.5 mol% Pd(PPh3)2Ch.
1H NMR (200 MHz, DMSO-d6): ~ 13.14 (br s, 1H), 8.I0 (m, 1H), 7.89 (m, 2H), 7.82-7.67 (m, 3H), 7.65-7.44 (m, 8H), 7.38 (m, 1H), 7.30 (d, J--Hz, 1H), 5.99 (s, 2H), 2.62 (s, 3H).
to Exam lp a 32 5~3-Acetylbhenyl)-3-(4-p~ridyl)-I-[3-(trifluoromethyl)benzyl~indole-2-carboxylic acid The title compound was prepared in accordance with Example 29 using 4-pyridylboronic acid and 2.5 mol% Pd(PPh;)2C12.
1s 1H (200 MHz, DMS~-d6): ~ 8.65 (m, 2H), 8.13 (m, 1H), 7.91 (m, 2H), 7.85-7.80 (m, 1H), 7.77-7.73 (m, 2H), 7.66-7.51 (m, 6H), 7.30 (d, ..I--8 Hz, 1H), 6.01 (s, 2H), 2.63 (s, 3H).
Example 33 20 5-(3-Acetylphenyl)-3-(4-chlorophenyl)-I-[3-(trifluoromethyl)benzy~indole-2-carbox lic acid The title compound was prepared in accordance with Example 29 using chlorophenylboronic acid and 2.5 moI% Pd(PPh3)2C12.
1H NMR (200 MHz, DMSO-d6): ~ 13.22 (br s, 1H), 8.I2 (m, 1H), 7.90 (m, 2s 2H), 7.83-7.67 (m, 3H), 7.65-7.50 (m, 8H), 7.29 (d, J 8 Hz, 1H), 6.00 (s, 2H), 2.63 (s, 3H).

Example 34 ~4-Chlorophenyl)-3-(3-p~rid~)-1-[3-(trifluorometh 1)benzyllindole-2-carbox ly is acid s (a) 5-(4-ChlorophenYl)indole-2-carboxylic acid eth 1 ester The sub-title compound was prepared in accordance with Example 26(a) using 4-chlorophenylboronic acid and 4.0 mol% Pd(PPh3)ZCI2 and heating at 160°C for 10 min.
ro (b) 1-(3-(Trifluoromethyl)benzyl)-5-(4-chlorophen~)-3-(3-pyridyl)-1-[3-(trifluoromethyl)benzz~Ilindole-2-carboxylic acid The title compound was prepared in accordance with Example 26(b) using 3-pyridylboronic acid and 2.5 mol% Pd(PPh3)2C12.
is Example 35 5-(4-Chlorot~henyl)-3 -(4-(hydroxym eth~)phen~l)-1-[3 -(trifluoromethyl)-benzyl]indole-2-carboxylic acid The title compound was prepared in accordance with Example 34 using 4-(hydroxymethyl)phenylboronic acid and 5 mol% Pd(PPh;)?C12.
20 ~H NMR (200 MHz, DIMS~-d6): ~ 7.74 (m, 2H), 7.66-7.58 (m, 4H), 7.55-7.26 (m, 9H), 5.95 (s, 2H), 5.29 (br s, 1H), 4.57 (s, 2H).
Example 36 5-(4-Chlorophenyl)-3-(4-fluoro-3-meth~phenyl)-1-j3-(trifluoromethyl)-2s benzyl]indole-2-carboxylic acid The title compound was prepared in accordance with Example 34.using 4-fluoro-3-methylphenylboronic acid and 5 mol% Pd(PPh;)aCl2.

Example 37 5-(4-Chlorophenyl)-3-(4-ethylphenyl)-1-[3-(trifluoromethyl benz~]indole-2-carboxylic acid The title compound was prepared in accordance with Example 34 using s 4-ethylphenylboronic acid and 5 moI% Pd(PPhs)2C12.
1H NMIt (200 MHz, DMSO-d6): 8 7.76-7.70 (m, IH), 7.66-7.5~ (m, 5H), 7.57-7.50 (m, 2H), 7.4~-7.40 (m, 4H), 7.33-7.30 (m, 3H), 5.94 (s, 2H), 2.6~
(q, ~_~ Hz, 2H), 1.25 (t, .~ 8 Hz, 3H).
1 o Exam 1~ a 3 $
6-(3-Aminophenyl)-3-phenyl-1-((3-(trifluoromethoxy)benz~]indole-2-carboxylic acid hydrochloride (a) 6-(3-Aminophenyl)-3-~henyl-1-[(3-_ (trifluoromethox )benzyl~indole-2-1s carboxylic acid ethyl ester hydrochloride 6-(3 -Nitrophenyl)-3 -phenyl-1-[(3 -(trifluoromethoxy)b errlzylJ-indole-2-carboxylic acid ethyl ester, prepared in accordance with the procedure in Example 1 (a)-(d) from 6-bromoindole-2-carboxylic acid ethyl ester, 3-nitro-phenylboronic acid and 3-(trifluoromethoxy)benzyl chloride (1.55 g, 2.76 2o mmol), in Et~Ac (35 mL) was hydrogenated at ambient temperature and pressure over Pd-C (10%, 440 mg) until all starting material was consumed as judged by TLC. The mixture was filtered through Celite~ and the filtxate concentrated. The residue was purified by chromatography, dissolved in anhydrous EtzO, whereafter the sub-title compound was precipitated by the 2s addition of an excess of HCl (4M) in dioxane. Yield: 955 mg (73%).
(b) 6~3-A~.ninophenyl)-3-phenyl-1-f(3-(trifluoromethoxy)benzyl]indole-2-carboxylic acid hydrochloride The title compound was prepared by hydrolysis of 6-(3-aminophenyl)-3-3o phenyl-1-[(3-(trifluoromethoxy)benzylJ-indole-2-carboxylic acid ethyl ester in accordance with the procedure described in Example 2(b) (2M KOH
(aq.), dioxane, 100°C, 1 h), followed by precipitation from an ethereal solution by addition of HCl (4M) in dioxane as described above.
1H NMR (200 MHz, DMSO-dg): 8 11.5-9.6 (3H, br s), 7.94 (1H, s), 7.67-s 7.05 (15H, zn), 5.99 (2H, s), 4.5-3.0 (1H, br s).
Example 39 6-(3-(2,2-Dimethylpropion lamino)phenyl]-3-phenyl-1_[3-(trifluorometh-ox ~benzy~indole-2-carboxylic acid (a) 6-[3-(2 2-Dimeth~propion Iamino~ahenyl]-3-phen~-1-j3-(trifluoro methoxy)benzyl]indole-2-carboxylic acid ethyl ester Pivaloyl chloride ( 156 ~,L, 1.27 mmol) was added over 5 min to a stirred solution of 6-(3-arninophenyl)-3-phenyl-1-[3-(trifluoromethoxy)ben~yl]-Is indole-2-carboxylic acid ethyl ester hydrochloride (600 mg, 1.06 mmol; see Example 38(a)), DMAP (65 mg, 0.53 mznol), Et3N (530 ~I,, 3.8 mmol), and dry CH~Cl2 (10 mL). The mixture was stirred at room temperature overnight whereafter another portion of pivaloyl chloride (0.156 ~L, 1.27 znmol) and Et3N (530, ~,L, 3.8 mznol) was added. ~-l.fter 2 h at room temperature, the 2o mixture was diluted with CH2Ch and washed with HCl (aq., 1M), NaHCO3 (aq., sat.) and brine, and concentrated. The residue was treated with pentane to give the title compound as a white solid (480 mg, 74%).
(b) 6-[3-(2 2-Dimeth lpro,~ionylamino~henyl~-3-phenyl-1-[3 (trifluoro 2s methoxY)benzyl]indole-2-carboxylic acid The title compound was prepared by hydrolysis of 6-[3-(2,2-dimethyl-propionylamino)phenyl]-3-phenyl-1-[3-(trifluoromethoxy)benzyl]indole-2-carboxylic acid ethyl ester in accordance with the procedure described in Example 1 (e) (2M KOH (aq.), dioxane, 120 °C, 2 h).

7s 1H NMR (200 MHO, I?MSO-d6): 8 13.0 (IH, s), 9.29 (1H, s), 7.98-7.96 (1H, m), 7.90 (1H, s), 7.72-7.66 (1H, m), 7.59-7.36 (IOH, m), 7.26-7.19 (2H, m), 7.11-7.07 (1H, m), 6.00 (2H, s), 1.24 (9H, s).
s Example 40 6-(3-(Methanesulfonylamino)phenyl)-3-phenyl-I-[3-(trifluoromethoxy) benz~,l]indole-2-carboxylic acid The title compound was prepared in accordance with the procedure in Example 39 using methanesulfonyl chloride instead ofpivaloyl chloride.
to iH NMR (200 MI3z, DMSO-d6): 8 13.2-12.9 (1H, br s), 9.80 (IH, s), 7.88-7.86 (1H, m), 7.56-7.35 (11H, m), 7.24-7.15 (3H, m), 7.10-7.05 (1H, m), 5.97 (2H, s), 3.00 (3H, s).
Example 41 Is 6-(3-hut-3-enylaminophenyl)-3-phenyl-1-[(3-(trifluoromethoxY ben~l~-indole-2-carboxylic acid (a) 6-(3-Eut-3-enylaminophenyl)-3-phenyl-1 j(3-(trifluoromethoxy)ben-~,yl]'ir~dole-2-carboxylic acid eth, l ester 20 4-Bromo-1-butene (143 mg, 1.06 mmol) was added to a mixture of 6-(3-aminophenyl)-3-phenyl-1-[3-(trifluoromethoxy)benzyl]indole-2-carboxylic acid ethyl ester hydrochloride (400 mg, 0.71 mmol; see Example 38(a)), NaI (3I7 mg, 2.12 mmol), I~2C03 (390 mg, 2.84 mmol), and dry DMF (3 ~nL). The mixture was heated at 100°C for I2 h, allowed to cool and poured 2s into water. The mixture was extracted with EtOAc and the combined extracts were washed with water, brine, dried over Na2CO3 and concentrated. The residue was purified by chromatography to give the title compound (173 mg, 42%).

(b) 6-(3-l3ut-3-enylaminophenyl~phenyl-1-f (3-(triftuoromethoxY)ben_ zyl]indole-2-carboxylic acid The title compound was prepared by hydrolysis of 6-(3-but-3-enylamino-phenyl)-3-phenyl-1-[(3-(trifluoromethoxy)benzyl]indole-2-carboxylic acid s ethyl ester in accordance with the procedure described in Example 1 (e) (NaOH (aq., 40%), DMF, room temperature, 2 h).
IH NMR (200 MHz, DMSO-d6): 8 7.79 (1H, s), 7.51-7.31 (8H, m), 7.24-7.06 (4H, m), 6.84-6.80 (2H, m), 6.57-6.52 (IH, m), 5.97 (2H, s), 5.88 (IH, ddt, .I--17.2, 10.3, 6.7 Hz), 5.15-4.98 (2H, m), 3.I1 (2H, t, J'--7.2 Hz) 2.30 to (2H, q, J 6.9 Hz).
Exam lt~ a 42 6-f3-(Allylmetllanesulfonylamino~phen ly_1-3-phenyl-1_C3-trifluoromethoxy benzyl)indole-2-carboxylic acid is Allyl iodide (54 ~.L, 0.59 mmol) was added to a mixture of 6-[3-(methane-sulfonylamino)phenyl]-3 -phenyl-1-(3 -trifluoromethoxy-b enzyl) indole-2-carboxylic acid ethyl ester (178 mg, 0.29 mmol; see Example 40), Cs2CO3 (333 mg, I.02 nnnol), and dry DIvlF (2.5 mL). The mixture was heated at 85°C for 30 min using microwave irradiation, allowed to cool and poured 2o into water. The mixture was extracted with EtOAc and the combined extracts were washed with brine, dried over Na2CO3 and concentrated. The residue was hydrolyzed in accordance with the procedure described in Example 2(b) (2M I~OH (aq.), dioxane, l I0 °C, 55 min) to give the title compound (140 mg, 78%).
2s 1H NMR (200 MHz, DMSO-d6): 8 13.08 (1H, s), 7.94 (1H, s), 7.68-7.63 (2H, m), 7.58-7.34 (lOH, m), 7.25-7.20 (2H, m), 7.12-7.07 (1H, m), 6.OI
(2H, s), 5.79 (1H, ddt, J--17.1, 10.2, 5.9 Hz), S.I9 (1H, dd, J--17.1, 1.5 Hz), 5.07 (1H, dd, J I0.2, 1.5 Hz), 4.35 (2H, d, J=5.9 Hz), 3.05 (3H, s).

Example 43 I-(3-Chlorobenzyl)-6-(3 5-difluorophenyl~[3-(4-methoxyphen propion lamino]indole-2-carboxylic acid s (a) 3-Arnino-1-(3-chlorobenzyl)-6~3 5-difluorophenyl)indole-2-carboxylic acid ethyi ester A mixture of 3-amino-6-bromo-1-(3-chlorobenzyl)indole-2-carboxylic acid ethyl ester (1.04 g, 2.25 mmol, see Example 54(b)) Pd(OAc)Z (31 mg, O.I4 mmol), tri-o-tolylphosphine (84 mg, 0.28 mmol), K2C03 (I.33 g, 9.b4 to mmol) and toluene (30 mL) was stirred under argon at room temperature for min whereafter 3,5-dimethoxyphenylboronic acid (0.78 g, 4.13 mmol) and EtOH (10 mL) was added. The mixture was heated at reflux for 2.5 h allowed to cool and filtered through Celite~'. The filter cake was washed with EtOAc and the combined filtrates were washed with NaHCO~ (aq., zs sat.). The aqueous phase u~as extracted with EtOAc and the combined organic phases were washed with water, brine and dried over NaZCO3.
Concentration and purification by chromatography gave the title compound (1.28 g, 98%).
(b) 1-(3-Chlorobenzyl)-6-(3 5-difluorophenyl)-3-[~4-methox phen propion lad]indole-2-carboxylic acid ethyl ester DMAP (22.3 mg, 0.18 mmol) and Et3N (154 ~,L, l.I mmol) were added at room temperature to a stirred mixture of 3-amino-1-(3-chlorobenzyl)-6-(3,5-difluorophenyl)indole-2-carboxylic acid ethyl ester (150 mg, 0.37 2s mmol), 3-(4-methoxyphenyl)propionyl chloride (I09 mg, 0.55 mmol) and MeCN (3.5 mL). The mixture was stirred at room temperature overnight, poured into HCl (aq., IM) and extracted with EtOAc. The combined extracts were washed with NaHC03 (aq., sat.), dried over Na2C03 and concentrated. The sub-title compound was obtained by crystallisation of the 3o residue from EtOAc/benzene (I08 mg, 50 %).

(c) 1-(3-Chloroben~yl~6-(3 5-difluorophenyl)-3-(3-(4-methoxyt~henyl)-~ropionylaminolindole-2-carboxylic acid The title compound was prepared by hydrolysis of 1-(3-chlorobenzyl)-6-(3,5-difluorophenyl)-3-[3-(4-methoxyphenyl)-propionylamino]indole-2-carboxylic acid ethyl ester (108 mg, 0.18 mmol) according to the procedure described in Example 2(b) (KOH (aq., 2M), dioxane, 60 °C 50 min then °C 30 min). 'Yield 75 mg (73 %).
1H NMR (200 MHz, I~MSO-d6): 8 13.6-13.2 (1H, br s), 9.73 (1H, s), 8.09-l0 8.03 (1H, m), 7.57-6.86 (13H, m), 5.94 (2H, s), 3.73 (3H, s), 2.95-2.86 (2H, m), 2.73-2.64 (2H, m).
The following Examples 44 to 53 were made in accordance With the procedure in Example 43 using the appropriate acid chloride or sulfonyl 1s chloride.
Example 44 1-(3-Chlorobenzyl)-6-(3 5-difluorophenyl)-3-((3,5-dimethyladamantane-1-carbonyl)aminolindole-2-carboxylic acid 20 1H NMR (200 MHz, I~MS~-d6): ~ 13.8-13.2 (1H, br s), 9.52 (1H, s), 8.04 (1H, s), 7.81 (1H, d, J 8.6 Hz), 7.60-7.48 (3H, m), 7.34-7.16 (3H, m), 7.11-7.10 (1H, m), 6.98-6.90 (1H, m), 5.94 (2H, s), 2.16-2.11 (1H, m), 1.81-1.80 (2H, m), 1.68-1.53 (4H, m), 1.45-1.30 (4H, m), 1.23-1.14 (2H, m), 0.87 (6H, s).
Example 45 3-(2-Adamant-1-ylacetylamino~-1-(3-chlorobenzyl)-6-(3,5-difluorophenyl)-indole-2-carboxylic acid 1H NMR (200 MHz, IJMSO-d6): 8 13.5-13.2 (1H, br s), 9.56 (1H, s), 8.04 (1H, s), 7.70 (1H, d, J 8.6 Hz), 7.59-7.49 (3H, m), 7.33-7.07 (4H, m), 6.94-6.89 (1H, m), 5.90 (2H, s), 2.14 (2H, s), 1.96-1.92 (3H, m), 1.69-1.63 (12H, m).
Example 46 s 1-(3-Chlorobenzyl)-6-(3,~-difluoro~hen~l)-3-(toluene-4-sulfonylamino)-indole-2-carboxylic acid 1H NMI~ (200 MHz, l~MSO-d6): S 13.8-12.8 (1H, br s), 9.33 (1H, s), 8.02 (1H, s), 7.78 (1H, d, ,J 8.6 Hz), 7.58-7.52 (3H, m), 7.44-7.38 (2H, m), 7.34-7.I7 (4H, m), 6.99 (2H, s), 6.79-6.73 (1H, m), 5.84 (2H, s), 2.33 (3H, to s).
Example 47 1-(3-Chlorobenz~l~ 3-(2-c~clohexylideneacetylamino)-6-(3,5-difluorophen-yl)indole-2-carbox~ic acid is 1H NMR (200 MHz, DMSO-d6): ~ 13.7-12.8 (1H, br s), 9.62 (1H, s), 8.03 {1H, s), 7.74 (1H, d, .I 8.6 Hz), 7.58-7.48 (3H, m), 7.33-7.23 (2H, m), 7.18 (1H, ddd, J=9.3, 2.3, 2.3 Hz), 7.09-7.07 (1H, m), 6.97-6.89 {1H, m), 5.94 (1H, s), 5.91 (2H, s), 2.89-2.83 (2H, m), 2.21-2.16 (2H, m), 1.65-1.52 (6H, m).
Example 48 1;~3-Chlorobenzy~-6~3 5-difluorophenyl)-3-[2-(3 3,5 5-tetramethylcyclo-hexylidene)acetylamino~indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.6-13.1 (1H, br s), 9.67 (1H, s), 8.06 2s (1H, s), 7.74 (1H, d, J--8.6 Hz), 7.61-7.51 (3H, m), 7.35-7.1b (3H, m), 7.11-7.09 (1H, m), 6.99-6.91 {1H, m), 6.07 (1H, s), 5.94 (2H, s), 2.70 (2H, s), 1.99 (2H, s), 1.33 (2H, s), 0.97-0.96 (12H, m).

Example 49 1-(3-Chlorobenzyl)-6-(3 5-difluorophen~L~r2-~3 3 5 5-tetramethylcyclo-hexylidene)acetylamino]indole-2-carboxylic acid sodium salt 1H NMR (200 MHz, DMSO-d6): 8 12.13 (1H, s), 8.38 (1H, d, J= 8.6 Hz), s 7.76 (1H, s), 7.48-7.42 (2H, m), 7.36-7.29 (1H, m), 7.25-7.15 (3H, m), 7.11 7.04 (2H, m), 6.17 (2H, s), 5.85 (1H, s), 2.74 (2H, s), 1.97 (2H, s), 1.31 (2H, s), 0.97-0.92 (12H, rn).
Example 50 l0 1-(3-Chlorobenzyl)-6-(3,5-difluorophenyl)-~4-isopropox benzoylamino) indole-2-carbox Iic acid 1H NMR (200 MHz, DMSO=d~): 8 13.6-13.2 (1H, br s), 10.13 (1H, s), 8.08 (1H, s), 8.03-7.96 (2H, m), 7.83 (1H, d, J=8.6 Hz), 7.62-7.51 (3H, m), 7.35-7.12 (4H, m), 7.08-7.0I (2H, m), 6.99-6.93 (1H, m), 5.96 (2H, s), 4.74 (1H, is septet, J=6.1 Hz), 1.29 (6H, d, J--6.I Hz).
Example 51 1-(3-Chlorobenzyl)-6-(3 5-difluorophen~)-3-~4-iso~ropoxybenzo lamino) indole-2-carboxylic acid sodium salt 20 1H NMF~ (200 MHz, DMSO-d6): ~ 13.14 (IH, br s), 8.49 (1H, d, ..T--g.4 Hz), 7.98-7.91 (2H, m), 7.81 (1H, s), 7.51-7.44 (2H, m), 7.40-7.33 (1H, m), 7.25-7.17 (3H, m), 7.16-6.99 (4H, m), 6.19 (2H, s), 4.72 (1H, septet, ,I--6.0 Hz), 1.28 (6H, d, J 6.0 Hz).
2s Example 52 1-(3-Chlorobenzyl)-6-(3,5-difluorophenyl)-3~4-(trifluoromethyl)benzoyl amino]indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.7-13.1 (1H, br s), 10.49 (1H, s), 8.23 (2H, m), 8.11 (1H, s), 7.93 (2H, m), 7.77 (1H, d, J 8.6 Hz), 7.59-7.53 (3H, 3o m), 7.35-7.09 (4H, m), 6.99-6.94 (1H, m), 5.97 (2H, s).

Example 53 1-(3-Chlorobenzyl)-3-[(6-chloropyridine-3-carbonyl)aminol-6-(3,5-di-fluorophenyl)indole-2-carboxylic acid s 1H NMR (200 Ml-Iz, DMSO-d6): d 14.21-14.16 (IH, br s), 8.99 (IH, d, J 2 .2 Hz), 8 . 5 6 ( 1 H, d, J--8 . 6 Hz), 8 . 3 7 ( 1 H, dd, J--8 .4, 2 . 6 Hz), 7 . 8 3 -7 . 82 (1H, m), 7.74 (1H, d, J 8.2 Hz), 7.51-7.36 (3H, m), 7.30-7.06 (5H, m), 6.21 (2H, s).
to Example 54 3-(4-Chlorobenzo ly amino-1-(3-chlorobenzyl)-6-~4-(methylsulfonyl)-phenylaindole-2-carboxylic acid (a) 6-Bromo-1-(3-chlorobenzy~-3-nitroindole-2-carboxylic acid ethyl ester Is Cu(NO;)2 X2.5 HZO (2.26 g, 9.74 mmol) was added to Ac~O (10 mL) at °C. The mixture was stirred until a homogenous solution was formed whereafter a solution 6-bromo-1-(3-chlorobenzyl)indole-2-carboxylic acid ethyl ester, prepay ed from 6-bromoindole-2-carboxylic acid ethyl ester and 3-chlorobenzyl chloride in accordance with the procedure in Example 1 (c), 20 (4.72 g, 12.02 mmol), in Ac2O (20 mL) was added dropwise. The mixture was allowed to come to room temperature and was stirred for I.5 h and filtered. The filtrate was poured onto ice and was left to stir overnight. The precipitate was collected and dried to give the sub-title compound (4.82 g, 92%).
(b) 3-Amino-6-bromo-1-(3-chlorobenz~l)indole-2-carboxylic acid ethyl ester A mixture of 6-bromo-1-(3-chlorobenzyl)-3-nitroindole-2-carboxylic acid ethyl ester (4.82 g, 1I.01 mmol), Fe-powder (3.15 g, 56.3 mmol), NH4Cl (aq., sat., 75 mL) and isopropanol (160 mL) was heated at reflux for 2 h, whereafter additional portions of Fe-powder (3.15 g, 56.3 mmol) and NHøCl (aq., sat., 75 mL) were added. The mixture was heated for an additional 2 h, allowed to cool and filtered through Celite~. The filter cake was washed with EtOAc and the combined filtrates were extracted with s EtOAc. The combined extracts were washed with water, brine and dried over NaZC03. Concentration and purif cation by chromatography gave the title compound (3.99 g, 89%).
(c) 6-Bromo-3-(4-chlorobenzo~lamino)-1-(3-chlorobenzyl)indole-2-carbox-ylic acid ethyl ester A mixture of 3-amino-6-bromo-1-(3-chlorobenzyl)indole-2-carboxylic acid ethyl ester (2.00 g, 4.91 mmol), 4-chlorobenzoyl chloride (1.72 g, 9.82 mmol), DMAP (300 mg, 2.46 mmol), Et3N (1.38 mL, 9.82 mmol) and MeCN (50 mL) was stirred at room temperature for 24 h. The mixture was 1s poured into water and extracted with EtOAc. The combined extracts were washed with water, brine and dried over Na~C03. Concentration, crystallisation from EtOH/EtOAc ( 1:1 ) and chromatography gave the title compound.
20 (d) 3-~4-Chlorobenzoylamino)-1-(3-chlorobenzyl)-6-f4-(methylsulfonyl)-phen~lindole-2-carboxylic acid eth ly__ester A mixture of 6-bromo-3-(4-chlorobenzoylamino)-1-(3-chloroben~yl)indole-2-carboxylic acid ethyl ester (160 mg, 0.29 mmol), 4-(methanesulfonyl)-phenylboronic acid (87.9 mg, 0.44 mmol), Pd(OAc)2 (3.4 mg, 0.015 mmol), 2s tri-o-tolylphosphine (8.8 mg, 0.029 mmol), K3PO4 (215 mg, 1.02 mmol), toluene (3 mL) and EtOH (0.5 mL) was stirred at room temperature for 20 min and heated at 90 °C for 3h. The mixture was allowed to cool, poured into NaHC03 (aq., sat.) and extracted with EtOAc. The combined extracts were washed brine and dried over Na2C0;. Concentration and purification 3o by chromatography gave the title compound (120 mg, 67%).

(e) 3-(4-Chlorobenzoylamino)-1-(3-chloroben~l)-6-f4 ~methylsulfonyl)-phenyl]indole-2-carboxylic acid The title compound was prepared by hydrolysis of 3-(4-chlorobenzoyl-s amino)-I-(3-chlorobenzyl)-6-[4-(methylsulfonyl)phenyl]indole-2-carboxyl-ic acid ethyl ester (120 mg, 0.19 mmol) according to the procedure described in Example 1 (e). Yield 84 mg (74%).
1H hIMR (200 MHz, DMSO-d6): b 13.6-13.4 (IH, br s), 10.36 (1H, s), 8.12-7.97 (7H, m), 7.83 (1H, d, J 8.4 Hz), 7.69-7.61 (2H, m), 7.57 (1H, d, .~=8.7 1o Hz), 7.38-7.25 (2H, m), 7.17-7.13 (1H, m), 7.03-6.96 (1H, m), 6.00 (2H, s), 3.26 (3H, s).
The following Examples 55 to 64 were made in accordance with the procedure in Example 54 using the appropriately substituted phenylboronic 1s acids.
Exam Ip a 55 3-(4-Chlorobenzoylamino)-1-(3-chlorobenzyl)-6Tf4-(methylthio)phenyll indole-2-carboxylic acid 20 1H MVII~ (200 MHz, DMSO-d~): d 13.7-13.1 (1H, br s), 10.35 (IH, s), 8.12-8.04 (2H, m), 7.93 (IH, s), 7.77 (1H, d, .I--8.5 Hz), 7.74-7.61 (4H, m), 7.47 (1H, d, J--8.5 Hz), 7.39-7.25 (4H, m), 7.16-7.12 (1H, m), 7.04-6.97 (IH, m), 5.97 (2H, s), 2.51 (3H, s).
2s Exam lp a 56 3-(4-Chlorobenzoylamino)-I-(3-chlorobenzyl~6~'4-viny_lphenyl)indole 2 carboxylic acid IH NMR (200 M~-Iz, DMSO-d6): d 13.6-13.2 (1H, br s), 10.35 (1H, s), 8.12-8.04 (2H, m), 7.97 (1H, s), 7.78 (1H, d, J 8.4 Hz), 7.78-7.72 (2H, m), 7.69-30 7.62 (2H, m), 7.61-7.54 (2H, m), 7.51 (IH, d, J--8.6 Hz), 7.38-7.25 (2H, m), 7.18-7.13 (1H, m), 7.05-6.98 (1H, m), 6.79 (H, dd, J--17.8, 11.0 Hz), 5.98 (2H, s), 5.90 (1H, d, .l 17.8 Hz), 5.29 (1H, d, 11.0 Hz).
Example 57 s 3-(4-Chlorobenzoylamino~-1-(3-chlorobenzyl)-6-(4-isopropoxyphenyl)-indole-2-carboxylic acid 1H .NMR (200 MHz, I~IvISO-d6): 8 13.5-13.3 (1H, br s), 10.35 (1H, s), 8.12-8.03 (2H, m), 7.85 (1H, s), 7.75 (1H, d, J 8.5 Hz), 7.70-7.61 (4H, m), 7.43 (1H, d, ,I 8.7 Hz), 7.38-7.25 (2H, m), 7.15-7.11 (1H, m), 7.05-6.96 (3H, m), 5.96 (2H, s), 4.67 (1H, septet, J 6.0 Hz), 1.28 (6H, d, J 6.0 Hz).
Example 58 6-(4-te~°t-Butylphenyl)-3-(4-chlorobenzoylamino)-1-(3-chlorobenzyl)indole-2-caxbox~ic acid Is 1H NMR (200 MHz, I~MS(~-d6): 8 13.5-13.3 (1H, br s), 10.34 (1H, s), 8.12-8.03 (2H, m), 7.88 (1H, s), 7.76 (1H, d, J=8.4 Hz), 7.70-7.60 (4H, m), 7.52-7.42 (3H, m), 7.38-7.25 (2H, m), 7.17-7.13 (1H, m), 7.05-6.98 (1H, m), 5.96 (2H, s), 1.31 (9H, s).
2o Example 59 3-(4-Chlorobenzoylamino,-1-(3-chlorobenzyl)-6-f 4-(trifluoromethyl)-phenyl~indole-2-carboxylic acid 1H NMR (200 MHz, I3MS~-d6): ~ 13.6-13.3 (1H, br s), 10.43 (1H, s), 8.12 8.04 (3H, m), 8.03-7.95 (2H, m), 7.87-7.78 (3H, m), 7.69-7.61 (2H, m), 2s 7.54 (1H, dd, J 8.5, 1.0 Hz), 7.38-7.25 (2H, m), 7.16-7.12 (1H, m), 7.03 6.96 (1H, m), 6.00 (2H, s).

8s Example 60 3-(4-Chlorobenzoylamino)-1 ~3-chlorobenzyl)-6-f4-(trifluoromethoxy)-phenyllindole-2-carboxylic acid 1H NMR (200 MHz, I~MS~-d6): 8 13.6-13.2 (1H, br s), I0.39 (1H, s), 8.10 s 8.02 (2H, m), 7.97 (1H, s), 7.89-7.82 (2H, m), 7.79 (IH, d, ,I--8.5 Hz), 7.67 7.59 (2H, m), 7.50-7.41 (3H, m), 7.36-7.23 (2H, m), 7.14-7.10 (1H, m), 7.02-6.95 (1H, m), 5.96 (2H, s).
Example 61 l0 3-(4-Chlorobenzo~lamino)-1-L-chlorobenzyl)-6-(4-cyclohexylphenyl)-indole-2-carboxylic acid 1H NMI~ (200 MHz, acetone-d6): d 11.9-11.5 (1H, br s), 8.61-8.52 (1H, m), 8.24-8.15 (2H, m), 7.71 (1H, s), 7.66-7.58 (2H, m), 7.58-7.49 (2H, m), 7.45 7.37 (1H, m), 7.34-7.12 (6H, m), 6.16 (2H, s), 2.64-2.47 (1H, m), 1.93-1.68 is (SH, m), 1.60-1.22 (SH, m).
Example 62 6-(4-l3utylphenyl)-3-(4-chlorobenzoylamino~3-chlorobenzyl)indole-2-carboxylic acid 20 1H MvII~ (200 MHz, I)MS~-d6): ~ 13.5-13.2 (1H, br s), 8.49 (IH, d, J--8.6 Hz), 8.12-8.00 (2H, m), 7.70-7.59 (4H, m), 7.57 (IH, s), 7.37-7.17 (6H, m), 7.16-7.08 (1H, m), 6.20 (2H, s), 2.61 (2H, t, J 7.4 Hz), 1.67-1.49 (2H, m), I.42-I.22 (2H, m), 0.91 (3H, t, J 7.2 Hz).
2s Example 63 3-(4-Chlorobenzoylamino)-1-(3-chlorobenz~l)-6-(4-cyanophenyl)indole-2-carboxylic acid IH NMR (200 MHz, DMSO-d6): S I3.3-13.1 (1H, br s), 8.52 (1H, d, J 8.6 Hz), 8.I0-8.01 (2H, m), 7.98-7.84 (SH, m), 7.68-7.60 (2H, m), 7.43 (1H, dd, 3o J 8.6, 0.9 Hz), 7.34-7.I8 (3H, m), 7.14-7.07 (1H, m), 6.2I (2H, s).

Example 64 3-(4-Chlorobenzo~amino~ 1-(3-chlorobenzyl)-6-(4-chlorophenyl)indole-2-carboxylic acid s 1H NMR (200 MHz, DMSO-d6): b 13.8-13.2 (1H, br s), 11.8-11.4 (1H, br s), 8.14-8.02 (3H, m), 7.87 (IH, s), 7.81-7.73 (2H, m), 7.68-7.60 (2H, m), 7.56-7.48 {2H, m), 7.42 {1H, dd, J=8.7, 1.1 Hz), 7.36-7.22 (2H, m), 7.19-7.14 (1H, m), 7.08-7.00 (1H, m), 6.07 (2H, s).
to The following Examples 65 to 109 were prepared by analogous techniques to those described herein.
Example 65 1-(3-Chlorobenzyl)-6-~3 5-difluorophenyl)-3-(4-methoxybenzoylamino)-is indole-2-carboxylic acid 1H MVIR (200 MHz, DMSO-d6): b 10.19 (1H, s), 8.14-8.02 (3H, m), 7.86 (1H, d, J 8.6 Hz), 7.64-7.53 (3H, m), 7.39-7.07 {6H, m), 7.03-6.96 (1H, m), 6.00 (2H, s), 3.87 (3H, s).
2o Example 66 1-(3-Chlorobenz~)-3-~4-methoxybenzoylamino)-6-naphth-1-ylindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): b 10.21 (1H, s), 8.09-7.91 (4H, m), 7.86 {1H, d, J=8.4 Hz), 7.66-7.69 {2H, m), 7.62-7.51 (2H, m), 7.48 (1H, d, J 1.2 2s Hz), 7.46-7.29 (3H, m), 7.23 (1H, dd, J 8.4, 1.2 Hz), 7.17-7.14 (1H, m), 7.13-7.OS (2H, rn), 7.04-6.97 (1H, m) 5.91 (2H, s), 3.84 (3H, s).

Example 67 6-Benzo~l 3~dioxol-5-yl-1-~3-cyanobenz~)-3-(3-phen~propionylamino)-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): & 9.7 (1H, s), 7.79 (1H, s), 7.70-7.64 (1H, s m), 7.56-7.14 (12H, m), 6.97 (1H, d, .I 8.1 Hz), 6.03 (2H, s), 5.92 (2H, s), 3.00-2.90 (2H, m), 2.75-2.64 (2H, m).
Example 68 I-(3-Chlorobenzy~-6~naphth-1-~-3-pentanoylaminoindole-2-carboxylic to acid 1H ,NMR (200 MHz, DMSO-d6): ~ 13.37 (1H, s), 9.67 (IH, s), 8.02-7.91 (2H, m), 7.74-7.65 (3H, m), 7.61-7.25 (6H, m), 7.22 (1H, dd, J--8.4, 0.9 Hz), 7.12-7.09 ( 1H, m), 7.02-6.93 ( 1H, m), 5.86 (2H, s), 2.41 (2H, t, J 7.2 Hz), 1.72-1.56 (2H, m), 1.49-I.29 (2H, m) , 0.93 (3H, t, ,I 7.3 Hz).
is Example 69 1-(3-Chlorobenzyl)-6-(3,5-difluorophenyl)-3-pentanoylaminoindole-2-carboxylic acid 1H NMI~ (200 MHz, DMS~-d6): ~ 13.4 (1H, br s), 9.67 (IH, s), 8.08 (1H, 2o s), 7.71 (1H, d, J 8.5 Hz), 7.62-7.51 (3H, m), 7.37-7.I8 (3H, m), 7.13-7.09 (IH, m), 7.00-6.92 (1H, m), 5.95 (2H, s), 2.42 (2H, t, J 7.3 Hz), 1.73-1.58 (2H, m), 1.49-1.31 (2H, m), 0.95 (3H, t, J 7.3 Hz).
Example 70 2s 3-[(Biphenyl-4-carbonyl)amino]-1~- 3-chlorobenzyl)-6-(3,5-difluorophenyl)-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): b 13.6-12.4 (1H, br s), 10.70 (1H, s), 8.21-8.06 (3H, m), 7.96 (1H, d, J 8.6 Hz), 7.92-7.85 (2H, zn), 7.84-7.77 (2H, m), 7.63-7.17 (lOH, m), 7.06-6.99 (IH, m), 6.04 (2H, s).

Example 71 1 ~'3-Chlorobenzyl)-6-(3 5-difluorophenyl)-3-[2 (4 methox henyl)acetyl aminolindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 9.81 (1H, s), 8.03 (1H, s), 7.63 (1H, d, s J=8.6 Hz), 7.59-7.45 (3H, m), 7.35-7.13 (5H, m), 7.09-7.05 (1H, m), 6.95-6.84 (3H, m), 5.91 (2H, s), 3.73 (3H, s), 3.66 (2H, s).
Examt~ie 72 1-(3-Chlorobenzyl)-6-(3 5-difluorophenyl)-3-phenylindole-2-carbox. lic 1o acid iH NM1Z (200 MHz, DMSO-d6): ~ 13.10 (1H, s), 8.11 (1H, s), 7.60-7.43 (8H, m), 7.42-7.14 (5H, m), 7.03-6.95 (1H, m), 5.96 (2H, s).
Example 73 Is 6-Benzof 1,31dioxol-5-yl-1-(3-cyanobenz~)-3l4-(dimethylamino)butyryl aminolindole-2-carboxylic acid hydrochloride IH NMR (200 MHz, DMSO-d6): S 13.8-12.8 (1H, br s), 9.89 (1H, s), 7.87-7.84 (1H, m), 7.75-7.67 (2H, m), 7.54 (IH, d, .~ 8.1 Hz), 7.51-7.39 (2H, rn), 7.36 (1H, d, J--I.7 Hz), 7.34-7.28 (1H, m), 7.23 (1H, dd, J 8.2, 1.7 Hz), 20 7.02 .(1H, d, J--8.I Hz), 6.08 (2H, s), 5.97 (2H, s), 3.19-3.08 (2H, m), 2.79 (6H, s), 2.58-2.48 (2H, m, overlapped With DMSO signal), 2.11-1.94 (2H, m).
Example 74 as 6-Benzof 1 3ldioxol-5-yl-3-(3-phenylacrylo Iamino)-1-~3-(2H tetrazol 5 yI)benzyllindole-2-carboxylic acid 1H NMI~ (200 MHz, DMSO-d6): 8 9.95 (1H, s), 7.89-7.82 (3H, m), 7.71 (1H, d, J--8.6 Hz), 7.68-7.35 (8H, m), 7.33 (1H, d, J 1.7 Hz), 7.23-7.14 (2H, m), 7.06 (1H, d, J 15.7 Hz), 6.97 (1H, d, .J=8.2 Hz), 6.03 (2H, s), 6.01 so (2H, s).' Example 7S
1-(3-Chlorobenzyl -S-(4-c~nophenyl)-3-(3,S-dimethoxybenzoylamino)-indole-2-carboxylic acid s 1H NMR (200 MHz, DMS~-d6): S 13.8-13.1 (1H, br s), 10.23 (1H, s), 8.08 (1H, s), 7.88 (4H, s), 7.75 (2H, s), 7.38-7.26 (2H, m), 7.24-7.17 (2H, m), 7.16-7.11 (1H, m), 7.05-6.95 (1H, m), 6.76-6.69 (1H, m), 5.90 (2H, s), 3.81 (6H, s).
to Example 76 1-(3-Chlorobenz~)-3-~entanoylamino-6-[4-(trifluoromethyl)phenyll-indole-2-carboxylic acid ~H NMR (200 MHz, DMS~-d6): ~ 9.83 (1H, s), 7.96-7.73 (6H, m), 7.47 (1H, d, J 8.7 Hz), 7.33-7.21 (2H, m), 7.10-7.07 (1H, m), 6.97-6.92 (1H, m), 5.93 (2H, s), 2.38 (2H, t, J 7.2 Hz), 1.69-1.55 (2H, m), 1.46-1.28 (2H, m), 0.91 (3H, t, J=7.3 Hz).
Example 77 1-(3-Chlorobenzyl)-3-j~3 3 S,S-tetrameth ~~lcyclohexanecarbonyl)aminol-6-20 ~4-(trifluoromethyl)phenyl)-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): d 13.5-13.2 (1H, br s), 9.68 (1H, s), 8.03-8.00 (1H, m), 7.99-7.94 (2H, m), 7.84-7.80 (2H, m), 7.70 (1H, d, ..T--8.S Hz), 7.51 (1H, d, J 8.S Hz), 7.35-7.25 (2H, m), 7.09 (1H, s), 7.01-6.94 (1H, m), 5.93 (2H, s), 2.85 (1H, t, J 12.4 Hz) 1.63 (2H, d, J 12.4 Hz), 1.34-1.21 2s (3H, m), 1.12-1.09 (1H, m), 1.06 (6H, s), 0.94 (6H, s).

Example 78 3-Benzoylamino-1-(3-chlorobenzyl)-5-(4-c~phenyl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 10.33 (1H, s), 8.13-8.01 (3H, m), 7.88 s (4H, s), 7.77-7.73 (2H, m), 7.64-7.49 (3H, m), 7.3 8-7.26 (2H, m), 7. I 7-7.12 (1H, m), 7.04-6.96 (1H, m), 5.90 (2H, s).
Example 79 5~(3-Chlorophenyl)-3-~hen~[(3-(trifluoromethoxY)benz~]indole-2-1o carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.2-13.0 (1H, br s), 7.78-7.70 (1H, m), 7.69-7.62 (3H, m), 7.60-7.30 (9H, m), 7.28-7.14 (2H, m), 7.10-7.02 (1H, m), 5.92 (2H, s).
is Example 80 5-(~-Chlorophen~)-3-phenyl-1-[(3-~trifluoromethoxylbenzyllindole-2-carbox~lic acid IH NMR (200 MHz, DMSO-d6): 8 13.2-13.0 (1H, br s), 7.75-7.67 (1H, m), 7.56-7.19 (14H, m), 7.15-7.07 (1H, m), 5.93 (2H, s).
Example 81 5-(4-Chlorophenyl~~hen~[(3-(trifluoromethoxy)benzyl]indole-2-carboxylic acid 1H NMR (200 MHz, I7MS0-d6): 8 13.2-13.0 (1H, br s), 7.77-7.56 (SH, m), 2s 7.54-7.30 (8H, m), 7.27-7.13 (2H, m), 7.I0-7.02 (IH, m), 5.92 (2H, s).

Example 82 S-(2-Chlorophenyl)-3-pentanoylamino-1-[(3-(trifluoromethox )~benzyl~-indole-2-carboxylic acid 1H NMR (200 MHz, I7MS0-d6): F~ 13.5-13.2 (1H, br s), 9.63 (1H, s), 7.69 s 7.58 (2H, m), 7.58-7.50 (1H, m), 7.48-7.31 (SH, m), 7.27-7.17 (IH, m), 7.13 (1H, s), 7.03 (1H, d, J--7.7 Hz), 5.87 (2H, s), 2.36 (2H, t, J--7.3 Hz), 1.67-1.47 (2H, m), 1.44-1.23 (2H, m), 0.88 (3H, t, J 7.2 Hz).
Example 83 l0 5-(3-Chlorophenyl)-3-pentanoylamino-1-[(3-(trifluoromethox )Y ben zYI]-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 13.4-13.2 (1H, br s) 9.67 (1H, s) 7.86 (1H, s) 7.74-7.55 (4H, m) 7.53-7.33 (3H, m) 7.27-7.16 (1H, m) 7.09 (1H, s) 6.98 (1H, d, J=7.8 Hz) 5.87 (2H, s) 2.40 (2H, t, J=7.3 Hz) 1.72-1.50 (2H, is m) 1.48-1.27 (2H, m) 0.91 (3H, t, J 7.2 Hz).
Example 84 5-(4-Chlorophenyl)-3-pentanoylamino-1-[(3-(trifluoromethox )y benzyl]-indole-2-carboxylic acid 20 1H I~~MR (200 MHz, l~MSO-d6): b 13.4-13.1 (1H, br s), 9.65 (1H, s), 7.83 (1H, s), 7.72-7.56 (4H, m), 7.55-7.45 (2H, m), 7.40 (1H, dd, J--8.0 and 8.0 Hz), 7.25-7.16 (1H, m), 7.09 (1H, s), 6.97 (1H, d, J 8.0 Hz), S.S6 (2H, s), 2.40 (2H, t, .I 7.2 Hz), 1.70-1.50 (2H, m), 1.48-1.28 (2H, m), 0.91 (3H, t, J=7.2 Hz).
Example 85 I-(3-Chlorobenzyl)-5-(4-chlorophenYl~phenylindole-2-carboxylic acid IH NMR (200 MHz, DMSO-d6): b 13.2-13.0 (1H, br s), 7.77-7.57 (SH, m), 7.54-7.29 (9H, m), 7.22 (1H, s), 7.05-6.97 (1H, m), 5.87 (2H, s).

Example 86 5-(4-Chlorophenyl)-1-(3 5-dimeth lbenz~l -3-phenylindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 13.I-13.0 (IH, br s), 7.73-7.57 (SH, m), s 7.53-7.30 (7H, m), 6.85 (1H, s), 6.74 (2H, s), 5.77 (2H, s), 2.17 (6H, s).
Exam lp a 87 5-(4-Chlorophenyl)-1-(3 5-difluorobenz~l)-3-phenylindole-2-carboxylic acid ro 1H NMR (200 MHz, DMSO-d6): ~ 13.2-13.0 (1H, br s), 7.76-7.58 (5H, m), 7.55-7.31 (17H, m), 7.12 (IH, t, J--9.4, 2,5 Hz), 6.86-6.73 (2H, m), 5.89 (2H, s).
Example 88 1s 6->3enzof 1 3ldioxol-5-yl-3-pentanoylamino-I-(3-~henoxybenz5yl)indole 2 carboxylic acid 1H NMR (200 MHz, DMSO-d6): S 13.3 (1H, br s), 9.73 (IH, br s), 7.78 {1H, s), 7.66 (1H, d, J--8.4 Hz), 7.42-7.I7 (6H, m), 7.16-7.07 (1H, m), 7.01 (1H, d, J=8.2 Hz), 6.99-6.91 (2H, m), 6.84-6.76 (3H, m), 6.09 (2H, s), 5.93 (2H, 2o s), 2.41 (2H, t, J--7.0 Hz), 1.73-1.56 (2H, m), 1.50-1.30 (2H, m), 0.95 (3H, t, .,T--7.2 Hz).
Exam lp a 89 6-Benzo~I,3ldioxol-5-yl-1-(9H fluoren-2-ylmeth~)-3-~entanoylamino 2s indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.2 (IH, br s), 10.16 (IH, br s), 7.85-7.75 (4H, m), 7.53 (1H, d, J--7.4 Hz), 7.40-7.26 (5H, m), 7.25-7.13 (2H, m), 7.00 (1H, d, J 8.4 Hz), 6.06 (2H, s), 6.04 (2H, s), 3.83 (2H, s), 2.41 (2H, t, J--7.4 Hz), 1.75-1.58 (2H, m), 1.51-1.30 (2H, m), 0.95 (3H, t, J--7.2 Hz).

Example 90 1-(3-Chlorobenz~l)-6 ~3,5-difluorophenyl)-3-(3-phenylacryloylamino)-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 13.52 (1H, br s), 10.1 (1H, s), 8.1.1 (1H, s s), 7.79 (1H, d, J 8.5 Hz), 7.74-7.38 (9H, m), 7.36-7.18 (3H, m), 7.16-7.03 (2H, m), 7.01-6.94 (1H, m), 5.98 (2H, s).
Example 91 1-(3-Chlorobenzyl)-6-(3,5-difluorophenyl)-3-(2,2-dimethylpropion ~~l-1o amino~indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 I3.8-I3.2 (IH, s), 9.51 (IH, s), 8.06 (1H, s), 7.81 (1H, d, .I--8.6 Hz), 7.63-7.51 (3H, m), 7.37-7.13 (4H, m), 7.01-6.93 (1H, m), 5.96 (2H, s), 1.31 (9H, s).
Is Exam,~le 92 3~4-Chlorobenzoylamino)-1-(3-chlorobenz~)-6-(3,5-difluorophenyl)-indole-2-carboxylic acid 1H NNIR (200 MHz, DMSO-d6): ~ 10.3 (1H, s), 8.12~8.06 (3H, m), 7.80 (1H, d, J 8.6 Hz), 7.67-7.55 (5H, m), 7.37-7.14 (4H, m), 7.01-6.96 (1H, m), 20 5.99 (2H, s).
Example 93 I-(3-Chlorobenz~l)-6-(2~isopropoxylahen l~pentanoylaminoindole-2-carboxylic acid zs IH NMR (200 MHz, DMSO-d6): ~ I3.2-13.5 (IH, br s) 10.4 (IH, br s) 7.85 (1H, d, J--8.5 Hz) 7.56 (1H, s) 7.38-7.24 (4H, m) 7.21 (1H, d, J=8.4 Hz) 7.12-6.96 (4H, m) 5.93 (2H, s) 4.51 (1H, septet, J 6.1 Hz) 2.41 (2H, t, J=7.3 Hz) 1.76-1.5 8 (2H, m) I .5 I -1.3 I (2H, m), 1. 05 (6H, d, J 6.1 Hz), 0.95 (3H, t, J 7.5 Hz).

Example 94 1-(3-Chlorobenz~)-6 ~2-isopropoxyphenYl)-3-phenylindole-2-carbox~ic acid 1H NMR (200 MHz, DMS~-d6): 8 12.99 (1H, br s), 7.71 (1H, s), 7.56-7.26 s (11H, m), 7.24-7.20 (1H, m), 7.13-6.97 (3H, m), 5.89 (2H, s), 4.54 (1H, septet, J 6.0 Hz), 1.07 (6H, d, .I 6.0 Hz).
Example 95 3-((Biphenyl-4-carbon)amino]-1-(3-chlorobenzyl)-6-(2-isopropox hen-lo y~indole-2-carboxylic acid 1H NMR (200 MHz, DMS~-d6): b l I.0-11.3 (IH, br s), 8.22-8.14 (2H, m), 7.97 (1H, d, ,I 8.4 Hz), 7.93-7.86 (2H, m), 7.84-7.78 (2H, m), 7.65 (1H, s), 7.60-7.44 (3H, m), 7.42-7.24 (SH, m), 7.16-6.98 (4H, m), 5.97 (2H, s), 4.53 (IH, septet, J 6.0 Hz), 1.07 (6H, d, J=6.0 Hz).
Example 96 1-(3-Chlorobenzyl)-6-~4-isopropoxyphen~l)-3-pentanoylaminoindole-2-carboxylic acid 1H NMI~ (200 MHz, DMS~-d6): S 13.3 (1H, br s), 9.65 (IH, s), 7.81 (IH, 2o s), 7.70-7.92 (3H, m), 7.42 (1H, dd, J 8.5, 1.1 Hz), 7.37-7.25 (2H, m), 7.12 6.94 (4H, m), 5.92 (2H, s), 4.68 (1H, septet, .I--6.0 Hz), 2.42 (2H, t, J--7.4 Hz), 1.74-1.56 (2H, m), 1.51-1.29 (2H, m), 1.26 (6H, d, .I--6.0 Hz), 0.95 (3H, t, J--7.2 Hz).
Example 97 1-(3-Chlorobenzyl)-6-(4-isopropoxyphenyl~phenylindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 12.98 (1H, br s), 7.88 (1H, s), 7.70-7.61 (2H, m), 7.56-7.27 (9H, m), 7.26-7.22 (1H, m), 7.08-6.97 (3H, m), 5.97 (2H, s), 4.68 (1H, septet, J--6.0 Hz), 1.30 (6H, d, 6.0 Hz).

Example 98 I-(3-Chlorobenzyl~-3,6-bis-(4-isopropoxyphenyl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 12.95 (1H, br s), 7.85 (1H, s), 7.69-7.60 s (2H, m), 7.54 (1H, d, J 8.6 Hz), 7.47-7.27 (SH, m), 7.24-7.20 (1H, m), 7.06-6.96 (SH, m), S.9S (2H, s), 4.69 (1H, septet, .I 6.0 Hz), 4.68 (1H, septet, J--6.0 Hz), 1.34 (6H, d, ~I--6.0 Hz) 1.30 (6H, d, .I--6.0 Hz).
Example 99 1o I-(3-Chlorobenz 1~)-6-~3-isopropoxyphen~)-3-phenylindole-2-carbox~lC
acid 1H NMR (200 MHz, DMSO-d6): 8 13.08 (1H, br s), 7.94 (1H, s), 7.58-7.31 (IOH, m), 7.30-7.21 (3H, m), 7.08-7.02 (IH, m), 6.97-6.89 (1H, m), 5.99 (2H, s), 4.73 (1H, septet, ,I--6.0 Hz), I.31 (6H, d, J 6.0 Hz).
is Example 100 I-(3-Chlorobenzyl)-3-(3-isopropoxyphenyll-6-(4-isopropoxyphenyl)indole-2-carboxylic acid 1H Mv» (200 IVI~Iz, DMSO-d6): ~ 7.81 (IH, s), 7.64-7.57 (2H, m), 7.5I
20 ( 1 H, d, J=8. S Hz), 7 .44-7.3 8 ( 1 H, m), 7.3 4 ( 1 H, dd, J--8 .0, 2. 0 Hz), 7. 3 0 7.24 (2H, m), 7.22-7.19 (1H, m), 7.05-6.93 (SH, m), 6.88 (1H, dd, ,l--8.0, 2.1 Hz), 5.89 (2H, s), 4.63 (1H, septet, .I--6.0 Hz), 4.61 (IH, septet, .I--6.0 Hz), 1.28 (6H, d, J 6.0 Hz), 1.26 (6H, d, J--6.0 Hz).
2s Example I01 1-(3-Chlorobenz~l)-6-(3-isopropoxyphenYl)-3-t~entanoylaminoindole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ I3.S-I3.1-(IH, br s), 9.64 (1H, br s), 7.84 (1H, s), 7.64 (1H, d, J 8.5 Hz), 7.41 (1H, d, .I--8.5 Hz), 7.36 (1H, d, 3o J--7.8 Hz), 7.31-7.17 (4H, m), 7.I2-7.08 (1H, m), 6.95-6.85 (2H, m), 5.91 (2H, s), 4.70 (1H, septet, J 6.0 Hz), 2.38 (2H, t, J--7.3 Hz), 1.70-1.53 (2H, m), 1.47-I.27 (2H, m), 1.27 (6H, d, J--6.0 Hz), 0.91 (3H, t, J 7.2 Hz).
Example 102 s 1-(3-Chlorobenzyl)-6-(4-isopropoxyphen~I)-3-~2-isopropoxy henyl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 12.67 (1H, br s), 7.81 (1H, s), 7.67-7.59 (2H, m), 7.43-7.26 (6H, m), 7.19-7.15 (1H, m), 7.13-6.97 (5H, m), 5.96 (2H, s), 4.67 (1H, septet, J 6.0 Hz), 4.46 (1H, septet, J 6.0 Hz), I.30 (6H, d, ,I 6.0 Hz), I.I3 (6H, d, J--6.0 Hz).
Exam lp a 103 1-(3 -Chl orob enzyl)- 3 -» entanoylamino-S-[4-(trifluoromethyl)pheny~ indole-2-carboxylic acid Is 'H NMR (200 MHz, DMS~-d6): ~ I3.5-I3.3 (IH, br s), 9.7 (1H, br s), 8.93 (IH, s), 7.90-7.75 (4H, m), 7.73-7.63 (2H, m), 7.35-7.24 (2H, m), 7.I3-6.04 (1H, m), 7.00-6.92 (IH, m), 5.84 (2H, s), 2.40 (2H, t, ~ 7.5 Hz), 1.7I-1.51 (2H, m), 1.47-1.26 (2H, m), 0.9I (3H, t, ~ 7.2 Hz).
2o Example 104 1-(3-Chlorobenzyl)-5-[4~methylthio)phenyll-3-~entanoylaminoindole-2 carboxylic acid ~H NMR (200 MHz, DMS~-d6): 8 10.9-10.7 (IH, br s), 8.21 (IH, s), 7.59-7.44 (4H, rn), 7.36-7.20 (4H, m), 7.12 (1H, s), 7.06-6.97 (1H, m), 5.96 (2H, 2s s), 2.48 (3H, s, overlapped With DMSO), 2.37 (2H, t, J 7.4 Hz), 1.71-1.51 (2H, m), 1.46-1.24 (2H, m), 0.90 (3H, t, J 7.2 Hz).

Example 105 1-(3-Chlorobenzyl)-3-(4-methoxybenzoylamino)-5~~~4-meth lthio)phenyll indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 12.0-1 I.8 (1H, br s), 8.47 (1H, s), 8.07-s 7.96 (2H, m), 7.63-7.47 (4H, m), 7.36-7.22 (4H, m), 7.17 (1H, s), 7.I2-7.00 (3H, m), 6.03 (2H, s), 3.80 (3H, s), 2.48 (3H, s, overlapped with DMS~).
Example 106 3-((Biphenyl-4-carbonyl)aminol-5-(4-t~f°t-butylphenyl)-1-(3-chlorobenzvll to indole-2-carboxylic acid 1H NM~ (200 MHz, DMSO-d6): 8 10.4-10.3 (1H, br s), 8.19-8.09 (2H, m), 7.93 (1H, s), 7.89-7.8I (2H, m), 7.80-7.61 (4H, m), 7.62-7.35 (7H, m), 7.34-7.25 (2H, m), 7.18-7.13 (1H, m), 7.05-6.97 (IH, m), 5.88 (2H, s), 1.28 (9H, s).
Exam lp a I07 ~3-Amino-4-methylbenzoylalnino)-1-(3-chlorobenzyl)-5-[4-~methylsul fon~l)pheny~indole-2-carboxylic acid 1H (200 MHz, DMSO-d6): ~ 10.2-I0.1 (1H, br s), 8.16 (1H, s), 8.01-7.86 (4H, m), 7.75-7.72 (2H, m), 7.37-7.24 (3H, m), 7.16-7.11 (2H, m), 7.09-6.93 (2H, m), 5.58 (2H, s), 3.22 (3H, s), 2.I 1 {3H, s).
Example 108 5-(4-te~°t-Butylphenyl)-1-(3-chlorobenzYl)-~4-isopropoxyphenyl)indole 2 2s carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 7.64 (IH, s), 7.60-7.34 (8H, m), 7.33-7.22 (3H, m), 7.16-7.06 (1H, m), 6.99-6.89 {2H, m), 5.80 (2H, s), 4.62 (IH, septet, J--6.0 Hz), 1.28 (6H, d, .J 6.0 Hz), 1.27 (9H, s).

Example I09 1-(3-Chlorobenz~)-6-(4-isopropoxyphenyl)-3-(4-methoxybenzoylamino)-indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 I3.5-13.3 (IH, br s), 10.16 (IH, s), 8.09 s 8.00 (2H, m), 7.86-7.77 (2H, m), 7.70-7.62 (2H, m), 7.42 (IH, d, J--8.5 Hz), 7.38-7.24 (2H, m), 7.16-7.10 (2H, m), 7.07 (1H, s), 7.04-6.96 (3H, m), 5.95 (2H, s), 4.67 (1H, septet, J 6.1 Hz), 3.86 (3H, s), 1.28 (6H, d, J--6.1 Hz).
Example 110 1o N [1-(3-Chlorobenzyl)-2-hydroxymethyl-6-(4-isopropoxyphenyl)indol-3-Y1Z 4-methoxybenzamide LiAIH4 (6.4 mg, 0.17 mmol) was added to a solution of 1-(3-chlorobenzyl)-6-(4-isopropoxyphenyl)-3-(4-methoxybenzoylamino)indole-2-carboxylic acid ethyl ester, prepared in accordance with the procedure described in Is Example 7(a), (100 mg, 0.17 mmol) in THF (5 mL) at 0°C. After stirring for 1 h another portion of LiAlH4 (6.4 mg, 0.17 mmol) was added and the stirring was continued at room temperature for 1 h. The mixture was acidified to pH 2 with HCl (aq., 4M), diluted with water and extracted with EtOAc. The combined extracts were washed with water, brine, and dried 20 over NazSO~ and concentrated. Purification of the residue by chromato-graphy gave the title compound (59 mg, 64%).
1H NMR (200 MHz, DMSO-d6): ~ 9.85 (1H, s), 8.08-7.99 (2H, m), 7.59 (1H, s), 7.57-7.50 (2H, m), 7.44 (1H, d, .I 8.4 Hz), 7.38-7.23 (3H, m), 7.21-7.16 (1H, m), 7.14-7.02 (3H, m), 6.99-6.90 (2H, m), 5.63 (2H, s), 5.20 (1H, 2s t, J--5.1 Hz), 4.62 (1H, septet, J--6.0 Hz), 4.54 (2H, d, ,I--5.1 Hz), 3.83 (3H, s), 1.25 (6H, d, J 6.0 Hz).
The following Examples I 11 to I30 were prepared by analogous techniques to those described herein.

Exam Ip a 1 I 1 5-(4-te~°t-Butylphenyl)-1-(3-chlorobenzyl)-3-[4 ~trifluoromethoxy)phenyll indole-2-carboxylic acid ~H NMK (200 MHz, CDCl3): ~ 7.69-7.60 (2H, m), 7.58-7.30 (9H, m), 7.25-s 7.12 (3H, m), 7.03-6.94 (1H, m), 5.83 (2H, s), 1.34 (9H, s).
Example 112 3-(4-Chlorobenzoylamino)-1-(3-ehloroben~l)-5~4 ~trifluoromethyl)-phenyllindole-2-carboxylic acid l0 1H NMR (200 MHz, I~MSO-d6): 8 I2.4-I2.2 (1H, br s), 8.53 (IH, s), 8.10-7.99 (2H, m), 7.92-7.72 (4H, m), 7.64-7.~6 (4H, m), 7.34-7.I5 {3H, m), 7.10-7.01 (1H, m), 6.04 {2H, s).
Example 113 ~s 5-(4-tei°t-Butylphenyl)-1-(3-chlorobenzyl)-3-[4-(methylthio)phenyl)indole 2-carbox lic acid 1H NMP~ (200 MHz, CDCl;): ~ 7.73-7.69 (1H, m), 7.67-7.58 (1H, m),. 7.54-7.30 (9H, m), 7.25-7.13 (3H, m), 7.02-6.94 (1H, m), 5.81 (2H, s), 2.56 (3H, s), 1.35 (9H, s).
Example 124 1-(3-Chlorobenzyl)-6-(3 5-difluoro~henyl)-3 j4-(dimethylamino)benzo~
aminolindole-2-carboxXlic acid 1H NMR (200 MHz, DMSO-d6): ~ I3.6-13.4 (1H, br s), 10.08 (1H, br s), as 8.05 (1H, s), 7.95-7.87 (3H, m), 7.59-7.48 (3H, m), 7.3I-7.I1 {4H, m), 6.97-6.91 (1H, m), 6.82-6.74 (2H, m), 5.96 (2H, br s), 3.00 (6H, s).

Example 1 I S
3-(4-te~°t-Butylbenzoylamino)-1-(3-chlorobenzyl)-6-(3,S-difluorophenyl) indole-2-carboxylic acid 1H NMR (200 MHz, DMS~-d6): ~ 13.6-13.4 (1H, br s), 10.24 (1H, s), 8.11 s (1H, s), 8.03-7.96 (2H, m), 7.84 (1H, d, J 8.6 Hz), 7.62-7.54 (SH, m), 7.37-7.13 (4H, m), 7.00-6.95 (1H, m), 5.99 (2H, s), 1.34 (9H, s).
Example I16 1-(3-Chlorobenzyl)-6-(3,S-difluorophen ly_)-3-(3 5-dimethoxybenzoyl to amino)indole-2-carbox, lic acid 1H NMR (200 MHz, DMSO-d6): 8 13.6-13.3 (IH, br s), 10.26 (1H, s), 8.09 (1H, s), 7.82 (IH, d, ~=8.6 Hz), 7.60-7.49 (3H, m), 7.31-7.10 (6H, m), 7.00-6.93 (1H, m), 6.73-6.69 (IH, m), 5.97 (2H, s), 3.81 (6H, s).
1 s Example 117 1-(3-Chlorobenzyl)-6-(3 S-difluorophenylL~[2-(3 3 S S-tetramethylcyclo hex 1)acetylamino]-indole-2-carboxylic acid 1H NMR. (200 MHz, DMSO-d6): b 13.4-I3.3 (1H, br s), 9.68 (1H, s), 8.04 (1H, s), 7.67 (1H, d, J 8.5 Hz), 7.59-7.50 (3H, m), 7.30-7.14 (3H, rn), 7.I0 20 7.OS (1H, m), 6.96-6.89 (1H, m), 5.91 (2H, s), 2.25-2.19 (2H, m), 1.SS-1.45 (2H, m), 1.25-0.75 (SH, m), 0.99 (6H, s), 0.86 (6H, s).
Exam Ip a I I 8 1-C3-Chlorobenzyl)-6-(3 S-difluorophenyl)-3-[~3,3 S,S-tetramethylcyclo 2s hexyl)acetylaminolindole-2-carboxylic acid sodium salt ~H NMR (200 MHz, DMSO-d6): ~ 12.09 (1H, s) 7.35 (1H, d, J--8.S Hz) 7.78 (1H, s) 7.51-7.43 (2H, m) 7.34 (1H, d, ,I--8.S Hz) 7.27-7.16 (3H, m) 7. I S-7.07 (2H, m) 6. I7 (2H, s) 2.22-2. I 6 (2H, m) 1.54-1.44 (2H, m) 1.27-1.18 (1H, m) I.06-0.73 (4H, m) 1.00 (6H, s), 0.87 (6H, s).

Example 119 1-(3-Chlorobenzyl)-3-(3-cyclohexylpropionylamino)-6-(3,5-difluorophen-yl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 13.4-13.3 (1H, br s), 9.63 (1H, s), 8.04 s (1H, s), 7.66 (1H, d, J=8.6 Hz), 7.58-7.48 (3H, m), 7.30-7.14 (3H, m), 7.08 7.05 (IH, m), 6.95-6.89 (IH, m), 5.91 (2H, s), 2.43-2.34 (2H, m), 1.79-1.48 (7H, m), 1.30-1.10 (4H, m), 0.98-0.81 (2H, m).
Example I20 Io 3-(4-Butylbenzoylamino~l-(3-chlorobenzyl)-6-(3,5-difluorophenyl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.6-I3.3 (1H, br s), 10.21 (1H, s), 8.09 (1H, s), 7.98-7.92 (2H, m), 7.82 (1H, d, .J--8.~ Hz), 7.61-7.51 (3H, m), 7.38-7.33 (2H, m), 7.31-7.11 (4H, m), 6.98-6.93 (1H, m), 5.96 (2H, s), 2.69-2.62 Is (2H, m), I.66-1.51 (2H, m), 1.40-1.22 (2H, m), 0.89 (3 H, t, ~=7.2 Hz).
Example 121 1-(3-Chlorobenz l,~)-6-~3 5-difluorophenyl)-3-(4-isopropylbenzoylamino)-indole-2-carboxylic acid 20 1H NMR (200 MHz, DMSO-d6): d 13.6-13.3 (1H, br s), 10.26 (1H, br s), 8.08 (1H, m), 8.00-7.94 (2H, m), 7.83 (1H, d, .I--8.6 Hz), 7.60-7.50 (3H, m), 7.43-7.37 (2H, m), 7.32-7.11 (4H, m), 7.00-6.93 (IH, m), 5.97 (2H, s), 2.98 (1H, septet, J--7.4 Hz), 1.24 (6H, d, J 7.4 Hz).
2s Example 122 3-f ( 1-Adamantylcarbonyl)amino]- I-(3-chlorobenzyl)-6-(3,5-difluoro-t~henyl)indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): 8 I3.8-13.2 (1H, br s), 9.45 (1H, s), 8.03 (IH, s), 7.79 (1H, d, .~=8.6 Hz), 7.58-7.46 (3H, m), 7.32-7.08 (4H, m), 6.96-6.88 (1H, m), 5.92 (2H, s), 2.04-2.00 (3H, m), 1.96-1.95 (6H, m), 1.72-1.69 (6H, m).
Examlale I23 s 3-f(1-Adamantylcarbon~)amino]-I ~3-chlorobenzyl)-6 ~3 5-difluoro-phen~)indole-2-carboxylic acid sodium salt 1H NMR (200 MHz, DMSO-d6): S 12.34 (1H, s), 8.37 (1H, d, .I--8.6 Hz), 7.74 (IH, s), 7.48-7.41 (2H, m), 7.3I-7.16 (4H, m), 7.14-7.04 (2H, m), 6.16 (2H, s), 2.05-1.99 (3H, m), 1.96-1.91 (6H, m), 1.73-1.68 (6H, m).
Io Examlale I24 1-(3-Chlorobenzyl)-6-(3 5-difluoro~hen~)-3-[4-(trifluoromethoxY)benzoyl amino]indole-2-carboxylic acid 1H Nl~~ (200 MHz, DMSO-d6): 8 13.6-I3.3 (1H, br s), 10.38 (1H, s), 8.19-Is 8.09 (3H, m), 7.78 (1H, d, .I--8.6 Hz), 7.58-7.52 (5H, m), 7.32-7.11 (4H, m), 6.99-6.94 (1H, m), 5.97 (2H, s).
Exam lp a 12 5 1-(3-Chlorobenzyl)-3-(4-cyanobenzo lamino)-6-(3 5-difluorophen~l)-2o indole-2-carboxylic acid 1H NMR (200 MHz, DMSO-d6): ~ I3.5-13.3 (1H, br s), 10.50 (1H, s), 8.22-B.IS (2H, m), 8.12-8.0I (3H, m), 7.77 (IH, d, J 8.6 Hz), 7.60-7.51 (3H, m), 7.35-7.I0 (4H, m), 7.00-6.94 (1H, m), 5.97 (2H, s).
2s Examlale 126 6-(4-Butylphenyl)-1-(3-chlorobenzyl)-3-[(3 5-dimethyladamant-1-ylcarbonyl)amino]indole-2-carbox lic acid 1H NMR (200 MHz, DMSO-d6): ~ 13.5-13.4 (IH, br s), 9.51 (1H, s), 7.81 (1H, s), 7.77 (1H, d, ,T--8.8 Hz), 7.66-7.58 (2H, m), 7.42-7.36 (1H, m), 7.29-30 7.23 (4H, m), 7.10-7.09 (1H, m), 6.96-6.91 (1H, m), 5.90 (2H, s), 2.60 (2H, t, J 7.2 Hz), 2.15-2.08 (IH, m), 1.81-1.78 (2H, m), 1.62-1.48 (6H, m), 1.40-1.24 (6H, m), 1.19-1.16 (2H, m) 0.89 (3H, t, J 7.2 Hz), 0.85 (6H, s).
Example 127 s 6~- 4-Butylphenyl -~-(3-chlorobenz~)-3-[(3,5-dimethyladamant-1-ylcarbonyl)amin~indole-2-carbox~ic acid sodium salt 1H NMR (200 MHz, DMSO-d6): ~ 12.30 (1H, s), 8.30 (1H, d, J--8.5 Hz), 7.57-7.50 (3H, m), 7.26-7.15 (6H, m), 7.11-7.05 (IH, m), 6.13 (2H, s), 2.57 (2H, t, .l 7.2 Hz), 2.15-2.08 (IH, m), 1.79-1.74 (2H, m), 1.59-1.47 (6H, m), Io 1.39-1.25 (6H, m), 1.I9-1.15 (2H, m) 0.88 (3H, t, J--7.2 Hz), 0.85 (6H, s).
Example 128 6-( _4-~utvlphenvl)-1-(3-chl~robenzyl)-3-(4-(2,5-dimethylpyrrol-1-yI)benz-oylaminolindole-2-carboxylic acid Is IH NMR (200 MHz, DMSO-d6): b 13.4-13.2 (1H, br s), 10.48 (1H, br s), 8.20-8.12 (2H, m), 7.88 (1H, s), 7.81 (1H, d, J 8.5 Hz), 7.69-7.6I (2H, m), 7.48-7.42 (3H, m), 7.3 2-7.24 (4H, m), 7.16-7.13 ( 1 H, m), 7.04-6.9 8 ( 1 H, m), 5.96 (2H, br s), 5.83 (2H, s), 2.60 (2H t, J=7.2 Hz), 2.01 (6H, s), 1.63-1.49 (2H, m), 1.39-1.22 (2H, m), 0.89 (3H, t, J 7.2 Hz).
Exam lp a 129 6-(4-Bu lphenyl)-1-(3-chlorobenzyl)-3-[4-(trifluoromethoxy)benzoyl-amino]indole-2-carboxylic acid 1H IvIMR (200 MHz, DMSO-d6): 8 13.5-13.3 (1H, br s), 10.37 (1H, s), 8.20 2s 8.14 (2H, m), 7.88 (1H, s), 7.76 (1H, d, J 7.6 Hz), 7.66-7.60 (2H, m), 7.59 7.53 (2H, m), 7.47-7.41 (1H, m), 7.32-7.23 (4H, m), 7.15-7.11 (1H, m), 7.02-6.96 (1H, m), 5.95 (2H, s), 2.60 (2H, t, J 7.2 Hz), 1.63-1.49 (2H, m), 1.39-1.21 (2H, m), 0.89 (3H, t, J--7.2 Hz).

Example 130 6 (4-But~lphenyl)-I-(3-chlorobenzyl~3-f4-(trifluoromethoxy)benzoyl-aminolindole-2-carbox~ic acid sodium salt 'H NMR (200 MHz, DMS~-d6): S 13.67 (1H, s), 8.51 (1H, d, J 7.6 Hz), s 8.18-8.12 (2H, rn), 7.61-7.51 (5H, m), 7.31-7.I8 (6H, m), 7.14-7.08 (1H, m), 6.19 (2H, s), 2.57 (2H, t, J 7.2 Hz), 1.62-1.47 (2H, m), 1.35-1.21 (2H, m), 0.88 (3H, t, J 7.2 Hz).
Example 131 6 (4-Butylt~henyl)-1-(3-chlorobenz~)-3-(4-isopropoxybenzoylamino)-indole-2-carboxylic acid (a) 6-(4-B~utylphen~)-1-(3-chlorobenz~)-3-(4-isopropoxybenzoylamino)-indole-2-carboxylic acid ethyl ester Is A mixture of 3-amino-6-(4-butylphenyl)-1-(3-chlorobenzyl)indole-2-carboxylic acid ethyl ester (250 mg, 540 nmol), 4-isopropoxybenzoyl chloride (I62 mg, 810 nmol), DMAh (33 mg, 270 mnol), triethylamine (229 ~,L, 1.63 mmol) and dry MeCN (2 mL) was stirred at room temperature under argon for 18h and then heated at 80°C for IO min, at I00°C
for 5 min 2o and finally at 120°C for IO min using microwave irradiation. The mixture was poured into HCl (1M) and extracted with EOAc. The combined extracts were washed with NaHCO3, dried with NazSO4 and concentrated.
The residue was crystallised from EOAclbenzene to yield the title compound (150 mg, 44%).
2s (b) 6-(4-ButylphenYl)-1-(3-chlorobenzyl)-3-(4-isopropoxybenzoylamino)-indole-2-carboxylic acid The title compound (45 mg, 32%) was prepared by hydrolysis of 6-(4-butylphenyl)-1-(3-chlorobenzyl)-3-(4-isopropoxybenzoylamino)indole-2-lOs carboxylic acid ethyl ester (see Example 131(a)) under conditions as hereinbefore described, for example at 90°C for 10 min in 1,4-dioxane.
1H NMR (200 MHz, DMSO-d6): d 13.5-13.3 (1H, br s), 10.14 (1H, s), 8.03 7.95 (2H, m), 7.86 (1H, s), 7.80 (1H, d, J 7.6 Hz), 7.67-7.60 (2H, m), 7.46 s 7.3 9 ( 1 H, m), 7.31-7 .23 (4H, m), 7.14-7.11 ( I H, m), 7.0 8-7 . 04 (2H, m), 7.01-6.95 (1H, m), 5.94 (2H, s), 4.74 (1H, septet, J--6.0 Hz), 2.60 (2H, t, J--7.2 Hz), 1.64-1.49 (2H, m), I.36-1.25 (2H, m), 1.30 (6H, d, J 6.0 Hz), 0.89 (3H, t, J=7.2 Hz).
to Example 132 6-(4-Butylphenyl)-1-(3-chlorobenz~l)-3-(3-isopropoxybenzoylamino~
indole-2-carboxylic acid The title compound was prepared in accordance with the procedures described herein.
is 1H NMR (200 MHz, DMSO-d6): 8 13.5-I3.3 (1H, br s), I0.25 (1H, s), 7.87 (1H, s), 7.75 (1H, d, .I--8.5 Hz), 7.67-7.54 (4H, m), 7.47-7.37 (2H, m), 7.34-7.22 (4H, m), 7.16-7.10 (2H, m), 7.02-6.95 (1H, m), 5.94 (2H, s), 4.71 (1H, septet, J=6.0 Hz), 2.60 (2H, t, J 7.2 Hz), 2.15-2.08 (2H, m), 1.36-1.21 (2H, m), 1.29 (6H, d, J--6.0 Hz), 0.88 (3H, t, ,J=7.2 Hz).
Example 133 6-(4-Butylphenyl)-1-(3-chlorobenzyl)-3-(3-isopropox~jbenz~lamino)-indole-2-carboxylic acid sodium salt The title compound was prepared in accordance with the procedures 2s described herein.
~H NME~ (200 MHz, DMSQ-d6): b 13.58 (1H, s) 8.52 (1H, d, J=8.6 Hz) 7.60-7.51 (5H, m) 7.46-7.3 8 ( 1H, m) 7.29-7.17 (6H, m) 7.14-7.07 (2H, m) 6.18 (2H, s) 4.69 (1H, septet, J--6.0 Hz) 2.58 (2H, t, J--7.2 Hz) 1.63-1.49 (2H, m) 1.35-1.24 (2H, m) 1.30 (6H, d, ,.T--6.0 Hz), 0.88 (3H, t, J--7.2 Hz).
~o Example 134 6-(4-Carboxyphenyl)-3-(4-chlorobenzo~amino)-1-(3-chlorobenzyl)indole-2-carboxylic acid The title compound was prepared in accordance with the procedures s described herein.
1HNMR (200 MHz, I)MSO-d6): b 13.6-12.8 (2H, br s), 10.37 (1H, s), 8.13-7.99 (SH, m), 7.94-7.86 (2H, m), 7.82 (1H, d, J 8.6 Hz), 7.68-7.61 (2H, m), 7.5 9-7.51 ( 1 H, m), 7.3 8-7.24 (2H, m), 7.17-7.11 ( 1 H, m), 7.04-6.95 ( 1 H, m), 5.99 (2H, s).
Example 13 5 3-(4-Chlorobenzoylamino~-1-(3-chlorobenzyl)-6-(4-hydroxymethylphenyl)-indole-2-carboxylic acid I5 (a) 3-(4-Chlorobenzoylamino)-1-(3-chlorobenzyl)-6-(4-hydroxymethyl-phenyl)indole-2-carboxylic acid ethyl ester 1M BH3xTHF (1M, 200~,L, 0.20 mmol) was added to a stirred solution of 6-(4-carboxyphenyl)-3-(4-chlorobenzoylamino)-1-(3-chlorobenzyl)indole-2-carboxylic acid ethyl ester, prepared by analogous techniques to those 2o described hereinbefore, (120 mg, 0.20 mtnol) in THF (5 mL) at -5 °C.
The temperature of the mixture was allowed to reach room temperature and stirring was continued for 12 h whereafter another portion of 1M BH;xTHF
(1M, 200~,L, 0.20 mmol) was added. The mixture was stirred for 8 h at room temperature and poured into AcOH (aq., 50%, 20 mL) and stirred for 2s 1 h. The mixture was extracted with EtOAc and the combined extracts were washed with H2O and brine, dried over Na2S04 and concentrated.
Purification of the residue by chromatography gave the sub-title compound (90 mg, 78 %).

(b) 3-(4-Chlorobenzoylamino)-I-(3-chlorobenz~)-6-(4-h droxymethyl-phen~)indole-2-carbox ly is acid The title compound was prepared by hydrolysis of 3-(4-chlorobenzoyl-amino)-1-(3-chlorobenzyl)-6-(4-hydroxymethylphenyl)indole-2-carboxylic s acid ethyl ester in accordance with the procedure in Example 2(b) (NaOH
(1M), MeCN, 80 °C, 20 min).
1H NMR (200 MHz, I)MSO-d6): 8 13.5-13.2 (1H, br s), 10.35 (1H, s), 8.13 8.04 (2H, m), 7.92 (1H, s), 7.79 (IH, d, J 8.4 Hz), 7.70-7.57 (4H, m), 7.51 7.25 (SH, m), 7.17-7.12 (1H, m), 7.04-6.96 (1H, m), 5.98 (2H, s), 5.14-5.34 to (1H, m), 4.62-4.54 (2H, m).
Exam lp a 13 6 6-(4-Butylphenyl)-1-(3-chlorobenzyl)-3-[3 ~2 5-dimeth~~ rry ol-I-yl benz-o lamino]indole-2-carboxylic acid (a) 6-(4-Butylphenyl)-I-(3-chlorobenzyl)-3-(3-nitrobenzamido~indole-2-carboxylic acid eth Iy ester The sub-title compound was prepared in accordance with Example I31 (a) using 3-nitrobenzoyl chloride (room temperature overnight, and then 90°C
2o for IO min, 110°C for 10 min and finally 130°C for 20 min).
(b) 3-(3-Aminobenzamido)-6-(4-buty~henyl)-1-(3-chlorobenz~ indole-2-carboxylic acid ethyl ester 6-(4-B utylphenyl)-1-(3 -chlorob enzyl)-3 -(3 -nitrob enzamido)indol e-2-carb-2s oxylic acid ethyl ester (23S mg, 0.39 mmol; see Example 136(a)) was hydrogenated at ambient pressure and temperature using palladium on charcoal (10%, 62 rng) in EtOAc for 6 h, then filtered through Celite°.
The filtrate was concentrated and the residue was crystallised from EtOAc/benzene to yield the sub-title compound (140 mg, 62%).

(c) 6-(4-Butylphenyl)-1-(3-chlorobenz~)-3-(~2 5-dimethylpyrrol-1-yl)-benzamido)indole-2-carboxylic acid ethyl ester A mixture of 3-(3-aminobenzamido)-6-(4-butylphenyl)-I-(3-chlorobenzyl)-indole-2-carboxylic acid ethyl ester ( 140 mg, 240 nmol; see Example s 136(b)), hexane-2,5-dione (I89 ~.L, 1.2I mmol), p-toluenesulfonic acid (50 ng, 0.24 nmol) and toluene ( 1 mL) was stirred at room temperature for 1 h and then heated at 70°C for 20 min using microwave irradiation. The mixture was diluted with EOAc, washed with NaZC03 (aq., sat.), dried over Na2SO4, and concentrated. The residue was crystallised from petroleum to ether/benzene to yield the sub-title compound (97 mg, 61%).
(d) 6~4-Butylphenyl)-1-(3-chlorobenzyl)-3-[3-(2 5-dimethylpyrrol-1-yl)-benzoylamino~Iindole-2-carboxylic acid The title compound was prepared by hydrolysis of 6-(4-butylphenyl)-I-(3-1s chlorobenzyl)-3-[3-(2,5-dimethylpyrrol-1-yl)benzoylamino]indole-2-carboxylic acid ethyl ester (see Example 136(c)) in accordance with the procedure described in Example 2(b) (2M T~CaH, dioxane, 70 °C, IO min, then 80 °C 20 min and finally 90 °C 10 min).
~H IVTV~ (200 MHz, DMS~-d6): b I3.5-I3.3 (IH, br s), 10.8-10.4 (1H, br 2o s), 8.14-8.08 (1H, m), 7.93-7.80 (3H, m), 7.73-7.69 (1H, m), 7.66-7.60 (2H, m), 7.55-7.49 (1H, m), 7.43 (1H, d, J 8.5 Hz), 7.31-7.23 (4H, m), 7.13-7.I 1 (1H, m), 7.02-6.96 (1H, m), 5.96 (2H, s), 5.83 (2H, s), 2.59 (2H, t, J--7.2 Hz), 2.00 (6H, s), 1.63-1.49 (2H, m), 1.39-1.21 (2H, m), 0.88 (3H, t, J--7.2 Hz).
Example 13 7 6-(4-Butylphenyl)-1-(3-chlorobenzyl)-3-[3-(2,5-dimeth~~yrrol-1-~l)benz-o lamino]indole-2-carboxylic acid sodium salt The title compound was prepared in accordance with the procedures so described herein.

~H NMR (200 MHz, DMSO-d6): b 13.91 (IH, br s), 8.57 (1H, d, J--8.5 Hz), 8.11-8.07 (1H, m), 7.83-7.81 (1H, m), 7.74-7.66 (1H, m), 7.61-7.54 (3H, m), 7.52-7.76 (1H, m), 7.31-7.19 (6H, m), 7.14-7.09 (1H, m), 6.19 (2H, s), 5.84 (2H, s), 2.59 (2H, t, J--7.2 Hz), 2.03 (6H, s), 1.64-1.49 (2H, m), 1.38 s 1.22 (2H, m), 0.89 (3H, t, J 7.2 Hz).
Ex_ amt~le 138 3-(4-Chlorobenzoylamino)-1-(4-chlorobenzyl)-5-[4-(trifluoromethyl)-phenyll indole-2-carboxylic acid to The title compound was prepared in accordance with the procedures described herein.
1H NMR (200 MHz, DMSO-d6): b 13.5-13.1 (1H, br s), 10.6-10.4 (1H, br s), 8.12-8.00 (3H, m), 7.93-7.84 (2H, m), 7.82-7.68 (4H, m), 7.68-7.57 (2H, m), 7.41-7.30 (2H, m), 7.13-7.03 (2H, m), 5.89 (2H, m). . , Is Example 139 3 -(Acetyl-(4-methoxyb enzyl) amino]-1-~3 -chlorobenz~I)-5~4-is oprop oxy-phenyl)indole-2-carbox~Iic acid 20 (a) 3-E~romo-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester A solution of NBS (0.904 5.082 mmol) in acetone (10 mL) was added dropwise to a solution of 5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester, prepared in accordance with Example 1 (a) from 5-bromoindole-carboxylic acid ethyl ester and 4-isopropoxyphenylboronic acid, (1.5 g, 4.62 zs mmol) in acetone (35 mL) at room temperature. After 2.5 h an additional portion of NBS (164 mg, 0.92 rnmol) was added and temperature of the mixture was increased to 45 °C. After 1.5 h the mixture was cooled to room temperature, poured into Na2S20~ (aq., 10%) and extracted with EtOAc.
The extract was washed with Na2S203 (aq., 10%), NaHCO; (aq., sat) and brine, dried over Na2S04 and concentrated. The residue was crystallised from EtOH to give the sub-title compound (1.63 g, 88 %).
(b) 1-(3-Chlorobenzyl)-5-(4-isopropoxyphenyl~indole-2-carboxylic acid s ethyl ester The sub-title compound was prepared in accordance with Example 1 (c) from 3-bromo-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (1.0 g, 2.5 mmol, see step (a) above) and 3-chlorobenzylchloride (0.604 g, 3.75 mmol). Yield 0.784 g (60 ~/o).
to (c) 1-(3-Chloroben~,yll-5-(4-isopropoxyphenyl)-3-f(4-methoxybenzyl)-amino]indole-2-carboxylic acid ethyl ester 4-lVlethoxyben~ylamine (60 ~.L, 0.46 mmol) was added to a mixture of 1-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl is ester (200 mg, 0.38 mmol), Pd2(dba); (17.4 mg, 0.019 mmol), EINAP (35.5 mg, 0.057 m~nol), Cs~C03 (173 mg, 0.53 mmol) and anhydrous toluene (10 mL). The mixture was stirred at 120°C for 24 h, cooled to room temperature and diluted with Et20. The mixture was filtered through Celite~ and the filter calve washed with Et20. The combined filtrates were concentrated and 2o the residue purified by chromatography to yield the sub-title compound (0.213 g, 96 %).
(d) 3-~Acetyl-(4-methoxybenzyl)aminol-1-(3-chlorobenzyl)-5-(4-isoprop-oxyphenyl)indole-2-carboxylic acid ethyl ester 25 Acetyl chloride (24 ~.L, 0.34 mmol) was added at room temperature to a solution of 1-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)-3-[(4-methoxybenz-yl)amino]indole-2-carboxylic acid ethyl ester (200 mg, 0.34 mmol) in dry toluene (2mL). The mixture was stirred at 70 °C for 1 h, allowed to cool to room temperature, diluted with EtOAc and washed with NaHCO; (aq., sat.), brine and finally dried over Na2S04. Concentration and purification by chromatography gave the sub-title compound (O.I36 g, 64 %).
(e) 3-(Acetyl-(4-methoxybenzyt)aminol-1-(3-chlorobenzyl)-5-(4-isoprop~
s oxyphenyl)indole-2-carboxylic acid The title compound ivas prepared by hydrolysis of 3-[acetyl-(4-methoxybenzyl)amino]-1-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester (136 mg, 0.217 mmol; see step (d) above), in accordance with the procedure in Example 1(e) (NaOH (aq.), dioxane, l0 80°C, I h). Yield: 93 mg (72 %).
1H NMI~ (200 MHz, DMSO-d6): 8 13.7-I3.3 (1H, br s), 7.55-7.40 (2H, m), 7.35-7.24 (4H, m), 7.15-7.06 (2H, m), 7.02-6.84 (SH, m), 6.80-6.71 (2H, m), 5.86 (2H, s), 5.34 (1H, d, .I--14.0 Hz), 4.61 (1H, septet J=6.0 Hz), 4.21 (1H, d, .I--14.0 Hz), 3.64 (3H, s), 1.72 (3H, s), 1.26 (6H, d, ,I--6.0 Hz).
is Example 140 1-(3-Chlorobenzyl)-3-; (4-chlorobutyryl)-[2-(4-fluoro~henyl)ethyllamino~-5-(4-isopropoxyphenyl)indole-2-carboxylic acid The title compound was prepared in accordance with the procedure in 2o Example 139(c)-(e) from 1-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)indole-2-carboxylic acid ethyl ester, 2-(4-fluorophenyl)ethylamine and 4-chloro-butyryl chloride.
'H NMR (200 MHz, DMS~-d6): b 7.54-7.36 (SH, m), 7.34-6.87 (lOH, m), 6.05 (1H, d, J--16.0 Hz), 5.87 (IH, d, J--16.0 Hz), 4.60 (1H, septet, J 6.0 2s Hz), 4.19-3.96 (1H, m), 3.82-3.61 (1H, m), 3.22 (2H, t, .T--6.4 Hz); 2.85-2.70 (2H, m), 2.37-2.10 (1H, m), 2.07-1.85 (1H, m), 1.67-1.44(2H, m), 1.25 (6H, d, J--6.0 Hz).

Example 141 1-(3-Chlorobenzyl)-3-; (6-chloro~yridine-3-carbonyl)-f2-(4-fluorophenyl)-ethyliamino~-5-(4-isopropoxyphenyl)indole-2-carboxylic acid The title compound was prepared in accordance with the procedure in Example 139(c)-(e) from 1-(3-chlorobenzyl)-5-(4-isopropoxyphenyl)indole 2-carboxylic acid ethyl ester, 2-(4-fluorophenyl)ethylamine and 6-chloro nicotinoyl chloride.
1H NMR (200 MHz, I~MSO-d6): 8 8.31 (1H, d, J--1.9 Hz), 7.82 (1H, s), 7.75 (1H, dd, J 8.2, 1.9 Hz), 7.66-7.43 (4H, m), 7.30 (1H, d, .I--8.2 Hz), l0 7.21-6.91 (9H, m), 6.38-6.29 (1H, m), 6.06 (1H, d, ,J 16.6 Hz), 5.60 (1H, d, J--16.6 Hz), 4.63 (1H, septet, J 6.1 Hz), 4.11-3.93 (2H, m), 3.09-2.75 (2H, m), 1.27 (6H, d, J 6.1 Hz).
Example 142 Title compounds of the invention were tested in the biological test described above and were found to exhibit 50% inhibition of mPGES-1 at a concentration of 10M or below. For example the inhibition of mPGES-1 is exemplified by the following compounds of the examples, as listed in the following table:
2o Example 1: 96% inhibition at 1 OM
Example 2: 100% inhibition at lOM
Example 3: 85% inhibition at lOM
Example 4: 81 % inhibition at l OM
Example 5: 93% inhibition at lOM
Example 6: 100% inhibition at lOM

Claims (39)

1. A compound of formula I, wherein X represents an optionally substituted aryl or heteroaryl group or an optionally substituted amide, amine or sulfonamide group, which latter three groups are connected to the indole ring through their nitrogen atom;
Y represents a carboxylic acid, a carboxylic acid ester, a carboxylic acid amide, a hydroxamic acid, a hydroxamic acid ester or hydroxymethyl;
Z represents a spacer group;
R1 represents an optionally substituted aryl or heteroaryl group;
one of the groups R2, R3, R4 and R5 represents an optionally substituted aryl or heteroaryl group.
2. A compound as claimed in Claim 1; wherein:
X represents:
i) an aryl group or a heteroaryl group, both of which groups are optionally substituted by one or more substituents selected from A; or ii) -N(R6)-E-R7;

E represents a single bond, -C(O)- or -S(O)n-;
Y represents -CH2OH, -C(O)N(H)R8, -C(O)N(H)OR8 or -C(O)OR8;
Z represents a C1-8 alkylene or a C2-8 heteroalkylene chain, both of which:
(i) optionally contain one or more unsaturations;
(ii) are optionally substituted by one or more substituents selected from halo, -R8, -N(R8)(R9), -OR8 and =O; and/or (iii) may form part of an additional 3- to 8-membered ring formed between any one or more members of the C1-8 alkylene or C2-8 heteroalkylene chain, which ring optionally contains 1 to 3 heteroatoms and/or 1 to 3 unsaturations and which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -N(R8)(R9), -OR8 and =O;
R1 represents an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from A;
one of the groups R2, R3, R4 and R5 represents an aryl group or a heteroaryl group (both of which are optionally substituted by one or more substituents selected from A) and:
a) the other groups are independently selected from hydrogen, G1, an aryl group, a heteroaryl group (which latter two groups are optionally substituted by one or more substituents selected from A), C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C3-8 heterocycloalkyl (which latter five groups are optionally substituted by one or more substituents selected from G1 and/or Q1); and/or b) any two other groups which are adjacent to each other are optionally linked to form, along with two atoms of the essential benzene ring in the compound of formula I, a 5- to 6-membered ring, optionally containing 1 or more heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;
A represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B;
II) a C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C3-8 heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G1 and/or Q1; or III) a G2 group; or IV) two adjacent A substituents may be linked together to form, along with the essential atoms of the aryl or heteroaryl group to which the two A
substituents are attached, a further 5- to 6-membered ring, optionally containing 1 or more heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;
G1 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or A1-R10;
wherein A1 represents a single bond or a spacer group selected from -C(Q2)A2-, -S(O)n A3-, -N(R11)A4-, -OA5- and -S-, in which:
A2 represents A6 or -S-;
A3 represents A6;
A4 represents A7, -C(Q2)N(R11)C(Q2)N(R11)-, -C(Q2)N(R11)C(Q2)O-, -C(Q2)N(R11)S(O)n N(R11)-, -C(Q2)S-, -S(O)n N(R11)C(Q2)N(R11)-, -S(O)n N(R11)C(Q2)O-, -S(O)n N(R11)S(O)n N(R11)- or -S(O)nO-;
A5 represents A7 or -S(O)nO-;
A6 represents a single bond, -N(R11)- or -O-;

A7 represents a single bond, -C(Q2)-, -C(Q2)N(R11)-, -C(Q2)O-, -S(O)n- or -S(O)n N(R11);
Q1 and Q2 independently represent, on each occasion when mentioned above, =O, =S, NR10, =NN(R10)(R11), =NOR10, -NS(O)2N(R10)(R11), =NCN, =C(H)NO2 or =C(R10)(R11);
R6 and R7 independently represent, on each occasion when mentioned above:
I) hydrogen;
II) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from B; or III) a C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C3-8 heterocycloalkyl group, all of which groups are optionally substituted by one or more substituents selected from G2 and/or Q3; or R6 and R7 may be linked together to form along with the N atom and E- group to which R6 and R7 are respectively attached, a 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations, which ring is optionally substituted by one or more substituents selected from G2 and/or Q3;
B represents, on each occasion when mentioned above:
I) an aryl group or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G2 and/or wherein any two adjacent atoms of the aryl or heteroaryl group may be linked together to form a further 5- to 6-membered ring, optionally containing 1 or more heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;

II) a C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C3-8 heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G2 and/or Q3; or III) a G2 group; or IV) two adjacent B substituents may be linked together to form, along with the essential atoms of the aryl or heteroaryl group to which the two B
substituents are attached, a further 5- to 6-membered ring, optionally containing 1 or more heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from halo, -R8, -OR8 and =O;
G2 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or A8-R12;
wherein A8 represents a single bond or a spacer group selected from -C(Q4)A9-, -S(O)n A10-, -N(R13)A11-, -OA12- and -S-, in which:
A9 represents A13 or -S-;
A10 represents A13;
A11 represents A14, -C(Q4)N(R13)C(Q4)N(R13)-, -C(Q4)N(R13)C(Q4)O-, -C(Q4)N(R13)S(O)n N(R13)-, -C(Q4)S-, -S(O)n N(R13)C(Q4)N(R13)-, -S(O)n N(R13)C(Q4)O-, -S(O)n N(R13)S(O)n N(R13)- or -S(O)n O-;
A12 represents A14 or -S(O)n O-;
A13 represents a single bond, -N(R13)- or -O-;
A14 represents a single bond, -C(Q4)-, -C(Q4)N(R13)-, -C(Q4)O-, -S(O)n- or -S(O)n N(R13);
Q3 and Q4 independently represent, on each occasion when mentioned above, =O, =S, =NR12, =NN(R12)(R13), =NOR12, NS(O)2N(R12)(R13), =NCN, =C(H)NO2 or =C(R12)(R13);
R8, R9, R10, R11, R12 and R13 are independently selected from:

i) hydrogen;
ii) an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G3 and/or wherein any two adjacent atoms of the aryl or heteroaryl group may be linked together to form a further 5- to 6-membered ring, optionally containing 1 or more heteroatoms, which ring is itself optionally substituted by one or more substituents selected from halo, -R14, -OR14 and =O; or iii) a C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C~_8 heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G3 and/or W1; or any pair of R8, R9, R10, R11, R12 and R13 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms, a further 5- to 8-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from G3 and/or W1;
G3 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or A15-R15;
wherein A15 represents a single bond or a spacer group selected from -C(W2)A16-, -S(o)n A17-, -N(R16)A18-, -OA19- and-S-, in which:
A16 represents A20 or -S-;
A17 represents A20;
A18 represents A21, -C(W2)N(R16)C(W2)N(R16)-, -C(W2)N(R16)C(W2)O-, -C(W2)N(R16)S(O)n N(R16)-, -C(W2)S-, -S(O)n N(R16)C(W2)N(R16)-, -S(O)n N(R16)C(W2)O-, -S(O)n N(R16)S(O)n N(R16)- or -s(O)n O-;
A19 represents A21 or -S(O)n O-;
A20 represents a single bond, -N(R16)- or -O-;
A21 represents a single bond, -C(W2)-, -C(W2)N(R16)-, -C(W2)O-, -S(O)n- or -S(O)n N(R16);

W1 and W2 independently represent, on each occasion when mentioned above, =O, =S, NR15, =NN(R15)(R16), =NOR15, =NS(O)2N(R15)(R16), =NCN, =C(H)NO2 or =C(R15)(R16);
R14, R15 and R16 are independently selected from:
i) hydrogen;
ii) an aryl or a heteroaryl group, both of which are optionally substituted by one or more substituents selected from G4, methylenedioxy, difluoromethylenedioxy and/or dimethylmethylenedioxy; or iii) a C1-6 alkyl, C3-10 cycloalkyl, C2-6 alkenyl, C2-6 alkynyl or C3-8 heterocycloalkyl group, all of which are optionally substituted by one or more substituents selected from G4 and/or J; or any pair of R14, R15 and R16 may, for example when present on the same or on adjacent atoms, be linked together to form with those, or other relevant, atoms, a further 5- to 7-membered ring, optionally containing 1 to 3 heteroatoms and/or 1 to 3 unsaturations, which ring is itself optionally substituted by one or more substituents selected from G4 and J;
G4 represents, on each occasion when mentioned above, halo, cyano, -N3, -NO2, -ONO2 or A22-R17;
wherein A22 represents a single bond or a spacer group selected from -C(O)A23-, -S(O)n A24-, -N(R18)A25-, -OA26- and -S-, in which:
A23 represents A27 or -S-;
A24 represents A27;
A25 represents A28, -C(O)N(R18)C(O)N(R18)-, -C(O)N(R18)C(O)O-, -C(O)N(R18)S(O)n N(R18)-, -C(O)S-, -S(O)n N(R18)C(O)N(R18)-, -S(O)n N(R18)C(O)O-, -S(O)n N(R18)S(O)n N(R18)- or -S(O)n O-;
A26 represents A28 or -S(O)n O-;
A27 represents a single bond, -N(R18)- or -O-;

A28 represents a single bond, -C(O)-, -C(O)N(R18)-, -C(O)O-, -S(O)n- or -S(O)n N(R18);
J represents, on each occasion when mentioned above, =O, =S, =NR17, =NN(R17)(R18), =NOR17, NS(O)2N(R17)(R18), =NCN, =C(H)NO2 or =C(R17)(R18);
R17 and R18 are independently selected from hydrogen and C1-6 alkyl, which latter group is optionally substituted by one or more substituents selected from halo, -NH2, -N(H)Me, -N(H)Et, -N(H)i-Pr, -NMe2, -N(Me)Et, -N(Me)i-Pr, -NEt2, -OH, -OMe, -OEt, -Oi-Pr and =O; and n represents, on each occasion when mentioned above, 1 or 2, or a pharmaceutically-acceptable salt thereof.
3. A compound as claimed in Claim 2, wherein n represents 2.
4. A compound as claimed in Claim 2 or Claim 3, wherein A represents G1 or any two adjacent A substituents may be linked by a methylenedioxy group.
5. A compound as claimed in any one of Claims 2 to 4, wherein G1 represents halo, cyano, -NO2 or A1-R10.
6. A compound as claimed in any one of Claims 2 to 5, wherein A2 represents A6.
7. A compound as claimed in any one of Claims 2 to 6, wherein A3 and A5 independently represent a single bond.
8. A compound as claimed in any one of Claims 2 to 7, wherein A4 represents a single bond, -C(Q2)- or -S(O)2-.
9. A compound as claimed in any one of Claims 2 to 8, wherein Q2 represents =O.
10. A compound as claimed in any one of Claims 2 to 9, wherein B
represents G2.
11. A compound as claimed in any one of Claims 2 to 10, wherein G2 represents halo, cyano, -NO2 or A8-R12.
12. A compound as claimed in any one of Claims 2 to 11, wherein A8 represents a single bond, -N(R13)A11- or -OA12-.
13. A compound as claimed in any one of Claims 2 to 12, wherein All and A12 independently represent a single bond.
14. A compound as claimed in any one of the preceding claims, wherein Z represents C1-6 alkylene, in which one of the carbon atoms in the chain may be replaced with oxygen.
15. A compound as claimed in any one of the preceding claims, wherein Y represents -CH2OH, -C(O)NHR8 or -C(O)OR8.
16. A compound as claimed in any one of the preceding claims, wherein R1 represents optionally substituted fluorenyl, phenyl or pyridyl.
17. A compound as claimed in any one of the preceding claims, wherein (when X represents an optionally substituted aryl or heteroaryl group) X
represents an optionally substituted phenyl, thienyl, pyridyl, pyrazolyl, pyrazinyl or quinolinyl group.
18. A compound as claimed in any one of the preceding claims, wherein (when they represent an optionally substituted aryl or heteroaryl group) R2, R3, R4 and R5 represent optionally substituted phenyl, pyridyl or naphthyl.
19. A compound as claimed in Claim 18, wherein the other substituents on the benzene ring of the indole represent hydrogen or G1.
20. A compound as claimed in any one of Claims 2 to 19, wherein R6 represents hydrogen or C1-3 alkyl group (which latter group is optionally substituted by G2).
21. A compound as claimed in any one of Claims 2 to 20, wherein R7 represents phenyl or pyridyl (which groups are optionally substituted by one or more substituents selected from B), or C1-4 alkyl, C2-4 alkenyl or C5-10 cycloalkyl (which latter three groups are optionally substituted by one or more substituents selected from G2).
22. A compound as claimed in any one of Claims 2 to 19, wherein R6 and R7 are linked to form a 5- to 6-membered ring optionally substituted by =O.
23. A compound as claimed in any one of Claims 2 to 22, wherein R8 and R13 independently represent C1-3 alkyl or hydrogen.
24. A compound as claimed in any one of Claims 2 to 23, wherein R10 represents hydrogen, phenyl, tetrazolyl, C1-4 alkyl, C2-4 alkenyl or C5-6 cycloalkyl, which latter five groups are optionally substituted by one or more substituents selected from G3.
25. A compound as claimed in any one of Claims 2 to 24, wherein R12 represents hydrogen, phenyl, pyrrolyl, C1-4 alkyl or C5-10 cycloalkyl, which latter four groups are optionally substituted by one or more substituents selected from G3.
26. A compound as claimed in any one of Claims 2 to 25, wherein R11 represents hydrogen or C2-4 alkenyl.
27. A compound as claimed in any one of Claims 2 to 26, wherein G3 represents halo, -R15 or -OR15.
28. A compound as claimed in any one of Claims 2 to 27, wherein R15 represents hydrogen, C1-3 alkyl or phenyl.
29. A compound as claimed in any one of Claim 16 to 21, wherein the optional substituents are selected from halo, -NO2, cyano, methylenedioxy, C1-6 alkyl (which alkyl group is optionally substituted by one or more substituents selected from a halo group, a phenyl group and OR19), C2-6 alkenyl, C3-10 cycloalkyl (which cycloalkyl group is optionally substituted with C1-6 alkyl), phenyl (which group is optionally substituted with one or more substituents selected from halo and OR19), a heteroaryl group selected from tetrazolyl and pyrrolyl (which groups are optionally substituted by one or more C1-6 alkyl groups), methylthio, methylsulfinyl, methylsulfonyl, =O, -OR19, -N(R19)R20, -C(O)OR19, -C(O)R19, -C(O)N(R19)R20, -S(O)2N(R19)R20 and/or -N(R19)S(O)2R21, wherein R19 and R20 independently represent hydrogen, phenyl, C1-4 alkenyl, C1-6 alkyl (which alkyl group is optionally substituted by one or more fluoro atoms) or a phenyl group and R21 represents phenyl or C1-6 alkyl (which alkyl group is optionally substituted by one or more fluoro atoms).
30. A compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, for use as a pharmaceutical.
31. A pharmaceutical formulation including a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
32. The use of a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, for the manufacture of a medicament for the treatment of a disease in which inhibition of the activity of microsomal prostaglandin E synthase-1 is desired and/or required.
33. A use as claimed in Claim 32, wherein the disease is inflammation.
34. A use as claimed in Claim 33 wherein the disease is inflammatory bowel disease, irritable bowel syndrome, migraine, headache, low back pain, fibromyalgia, a myofascial disorder, a viral infection, a bacterial infection, a fungal infection, dysmenorrhea, a burn, a surgical or dental procedure, a malignancy, atherosclerosis, gout, arthritis, osteoarthritis, juvenile arthritis, rheumatoid arthritis, rheumatic fever, ankylosing spondylitis, systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, iritis, scleritis, uveitis, wound healing, dermatitis, eczema, psoriasis, stroke, diabetes, a neurodegenerative disorder, an autoimmune disease, osteoporosis, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, an allergic disorder, rhinitis, an ulcer, coronary heart disease, sarcoidosis or any other disease with an inflammatory component.
35. A method of treatment of a disease in which inhibition of the activity of mPGES-1 is desired and/or required, which method comprises administration of a therapeutically effective amount of a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, to a patient suffering from, or susceptible to, such a condition.
36. A combination product comprising:
(A) a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof; and (B) another therapeutic agent that is useful in the treatment of inflammation, wherein each of components (A) and (E) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
37. A combination product as claimed in Claim 36 which comprises a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, another therapeutic agent that is useful in the treatment of inflammation, and a pharmaceutically-acceptable adjuvant, diluent or carrier.
38. A combination product as claimed in Claim 36 which comprises a kit of parts comprising components:
(a) a pharmaceutical formulation including a compound as defined in any one of Claims 1 to 29, or a pharmaceutically-acceptable salt thereof, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier; and (b) a pharmaceutical formulation including another therapeutic agent that is useful in the treatment of inflammation in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (a) and (b) are each provided in a form that is suitable for administration in conjunction with the other.
39. A process for the preparation of a compound as defined in Claim 2, which comprises:
(i) reaction of a compound of formula II, wherein X, Y, R2, R3, R4 and R5 are as defined in Claim 2, with a compound of formula III, wherein L1 represents a suitable leaving group and R1 and Z are as defined in Claim 2;
(ii) reaction of a compound of formula IV, wherein L4 represents L2 or L3, in which L2 and L3 represent appropriate leaving groups and L4 is attached to one or more of the carbon atoms of the benzenoid ring of the indole, and the remaining positions of the benzenoid ring are substituted with 1 to 3 (depending on the number of L4 substituents) substituents R2 to R5 as appropriate, and Z, X, Y, R1, R2, R3, R4 and R5 are as defined in Claim 2, with a compound of formula V, wherein R22 represents R2, R3, R4 or R5 (as appropriate), and L5 represents L2 (when L4 is L3) or L3 (when L4 is L2) as defined above;
(iii) for compounds of formula I in which X represents an optionally substituted aryl or heteroaryl group, reaction of a compound of formula VI, wherein L2 is as defined above and Z, Y, R1, R2, R3, R4 and R5 are as defined in Claim 2, with a compound of formula VII, X a L3 VII
wherein L3 is as defined above and X a represents an aryl or heteroaryl group, optionally substituted as defined in Claim 2;
(iv) for compounds of formula I in which X represents -N(R6)-E-R7, reaction of a compound of formula VI as defined above, with a compound of formula VIII, HN(R6)-E-R7 VIII
wherein E, R6 and R7 are as defined in Claim 2;
(v) for compounds of formula I in which X represents -N(R6)-E-R7, reaction of a compound of formula IX, wherein Z, Y, R1, R2, R3, R4, R5 and R6 are as defined in Claim 2, with a compound of formula X, wherein L1 is as defined above and E and R7 are as defined in Claim 2;
(vi) for compounds of formula I in which E represents a single bond and R7 is a C1-6 alkyl group, C3-6 alkenyl or a C3-6 alkynyl group, reduction of a compound of formula I, wherein X represents -C(O)- and R7 represents H, a C1-5 alkyl group, a C2-5 alkenyl or a C2-5 alkynyl group.
CA002528626A 2003-07-09 2004-07-09 Indoles useful in the treatment of inflammation Abandoned CA2528626A1 (en)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
US48539003P 2003-07-09 2003-07-09
US60/485,390 2003-07-09
SE0302035-1 2003-07-09
SE0302035A SE0302035D0 (en) 2003-07-09 2003-07-09 New compound
PCT/GB2004/002996 WO2005005415A1 (en) 2003-07-09 2004-07-09 Indoles useful in the treatment of inflammation

Publications (1)

Publication Number Publication Date
CA2528626A1 true CA2528626A1 (en) 2005-01-20

Family

ID=34067509

Family Applications (1)

Application Number Title Priority Date Filing Date
CA002528626A Abandoned CA2528626A1 (en) 2003-07-09 2004-07-09 Indoles useful in the treatment of inflammation

Country Status (4)

Country Link
EP (1) EP1646624A1 (en)
JP (1) JP2007516203A (en)
CA (1) CA2528626A1 (en)
WO (1) WO2005005415A1 (en)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2005254782A1 (en) 2004-06-18 2005-12-29 Biolipox Ab Indoles useful in the treatment of inflammation
NZ554493A (en) * 2004-10-12 2009-09-25 Decode Genetics Ehf Aryl sulfonamide peri-substituted bicyclics for occlusive artery disease
CA2593155A1 (en) 2005-01-19 2006-07-27 Biolipox Ab Indoles useful in the treatment of inflammation
JP2009511559A (en) * 2005-10-12 2009-03-19 バイオリポックス エービー Benzoxazoles useful for the treatment of inflammation
WO2007042817A1 (en) * 2005-10-13 2007-04-19 Biolipox Ab Naphthalene-disulfonamides useful for the treatment of inflammation
UA95788C2 (en) * 2005-12-15 2011-09-12 Ф. Хоффманн-Ля Рош Аг Fused pyrrole derivatives
US20100204282A1 (en) * 2007-02-05 2010-08-12 Hutchinson John H Reverse indoles as 5-lipoxygenase-activating protein (FLAP) inhibitors
MY162157A (en) * 2007-04-16 2017-05-31 Abbott Lab Substituted indole mcl-1 inhibitors
WO2008129276A1 (en) * 2007-04-19 2008-10-30 Boehringer Ingelheim International Gmbh Disulfonamides useful in the treatment of inflammation
CN101784274A (en) * 2007-06-15 2010-07-21 米申制药公司 Methods and compositions for inhibiting edema factor and adenylate cyclase
US20120029016A1 (en) 2008-12-30 2012-02-02 Biolipox Ab Indoles Useful in the Treatment of Inflammation
CN102395562A (en) * 2009-04-14 2012-03-28 阿费克蒂斯制药股份公司 Novel p2x7r antagonists and their use
GB201006846D0 (en) 2010-04-23 2010-06-09 Glaxo Group Ltd Novel compounds
WO2014026330A1 (en) * 2012-08-15 2014-02-20 Merck Sharp & Dohme Corp. 3-AMINOCYCLOALKYL COMPOUNDS AS RORgammaT INHIBITORS AND USES THEREOF
JP5474146B2 (en) * 2012-09-03 2014-04-16 アークレイ株式会社 Sampler for analyzer and analyzer
EP2903615B1 (en) * 2012-10-05 2021-04-07 Merck Sharp & Dohme Corp. 5-pyridin-3-yl-2,3-dihydro-1h-indole derivatives as aldosterone synthase (cyp11b2) inhibitors for the treatment of hypertension
KR102129842B1 (en) * 2013-10-02 2020-07-06 주식회사 대웅제약 Sulfonylindole derivatives and method for preparation thereof
TW202043198A (en) * 2019-01-17 2020-12-01 美商Ｉｆｍ Ｄｕｅ有限公司 Compounds and compositions for treating conditions associated with sting activity

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AP9801302A0 (en) * 1997-07-23 2000-01-23 Pfizer Indole compounds as anti-inflammatory/analgesic agents..
US6277878B1 (en) * 1998-09-07 2001-08-21 Pfizer Inc Substituted indole compounds as anti-inflammatory and analgesic agents
GB9902452D0 (en) * 1999-02-05 1999-03-24 Zeneca Ltd Chemical compounds

Also Published As

Publication number Publication date
EP1646624A1 (en) 2006-04-19
WO2005005415A1 (en) 2005-01-20
WO2005005415A8 (en) 2005-03-17
JP2007516203A (en) 2007-06-21

Similar Documents

Publication Publication Date Title
EP1841735B1 (en) Indoles useful in the treatment of inflammation
CA2528626A1 (en) Indoles useful in the treatment of inflammation
US20080249091A1 (en) Indoles Useful in the Treatment of Inflammation
US20090069384A1 (en) Thienopyrroles useful in the treatment of inflammation
WO2006077365A1 (en) Indoles useful in the treatment of inflammation
EP1778633B1 (en) Indoles useful in the treatment of inflammation
WO2008129276A1 (en) Disulfonamides useful in the treatment of inflammation
US7705023B2 (en) Indoles useful in the treatment of inflammation
WO2006077367A1 (en) Indoles useful in the treatment of inflamation
JP2012520275A (en) Bis aromatic compounds for use as LTC4 synthase inhibitors
US20060160879A1 (en) Indoles useful in the treatment of inflammation
EP1765775B1 (en) Indoles useful in the treatment of inflammation

Legal Events

Date Code Title Description
EEER Examination request
FZDE Dead