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  • C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
  • C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
  • C07C257/18—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of six-membered aromatic rings
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  • A61P17/00—Drugs for dermatological disorders
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  • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
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  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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  • C07C311/00—Amides of sulfonic acids, i.e. compounds having singly-bound oxygen atoms of sulfo groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
  • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
  • C07C311/19—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/56—Amides
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  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D213/81—Amides; Imides
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  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
  • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
  • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
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  • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
  • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
  • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D233/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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  • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
  • C07D275/02—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings
  • C07D275/03—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
  • C07D295/26—Sulfur atoms
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  • C07C2601/00—Systems containing only non-condensed rings
  • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

• This invention relates to compounds that are PAR2 receptor antagonists, to compositions containing them, to processes for their preparation, and to their use in medicine, in particular for the treatment of conditions which respond to antagonism of the PAR2 receptor, such as inflammation including intestinal inflammation, ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome, fibrosis, arthritis and inflammatory skin diseases including psoriasis, atopic dermatitis and itch, pain and cancer.
• inflammation including intestinal inflammation, ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome, fibrosis, arthritis and inflammatory skin diseases including psoriasis, atopic dermatitis and itch, pain and cancer.
• Protease activated receptors are a family of seven transmembrane domain G- protein-coupled receptors that are activated by cleavage of their extracellular N-terminal domain by proteolytic enzymes. The newly exposed N-terminal sequence acts as a tethered ligand that binds to the extracellular face of the receptor and activates it.
• PARs Four PARs have been described that are selectively cleaved by different enzymes; PARI , PAR3 and PAR4 are cleaved by thrombin, PAR2 and PAR4 predominantly by trypsin and tryptase and PAR4 also cleaved by cathepsin G.
• the GI tract and pancreas are particularly exposed to a large array of proteases which can activate PAR2 receptors. Trypsin is released into the lumen of the pancreatic duct and the upper GI tract, for physiological digestive purposes. Other proteases abundant in the GI tract include those derived from enteric bacteria and those generated during disease processes. On mucosal surfaces, a balance between proteolytic activity and the presence of protease inhibitors such as pancreatic secretory trypsin inhibitor (PSTI) is constantly present. PAR2 receptors are expressed throughout the GI tract specifically on mast cells, smooth muscle cells, myenteric neurons and endothelial cells, and on both the apical and basolateral sides of enterocytes (Kong et al., 1997). Since trypsin present in the GI lumen could activate PAR2 on apical surfaces, this receptor may provide a means by which the epithelium "senses" luminal processes.
• PSTI pancreatic secretory trypsin inhibitor
• APC00482WO In the gut, motility and secretion are regulated by neurons of the submucosal and myenteric plexi of the gastrointestinal tract. These neurones express PARI, PAR2 and PAR4. PAR2 is expressed by secretomotor neurons in the submucosal plexus of the small intestine, where brief activation of PAR2 by agonists such as SLIGRL-NH 2 or trypsin results in a prolonged depolarisation that is often accompanied by increased excitability. Tryptase also induces a transient depolarization and a sustained increase in neuronal excitability (Linden et al., 2001). These observations indicate that PAR2 excites a proportion of myenteric neurons, which may contribute to dysmotility during intestinal inflammation.
• PAR2 activation is important in the establishment, maintenance, and progression of intestinal inflammation and of fibrosis.
• APC00482WO by the identification of the receptor on the terminals of sensory nerve fibres which transduce the itch sensation (Steinhoff et al, 2000).
• tissue trypsins are secreted which can activate PAR2 receptors, as can other proteases including tryptase, Factor X, Factor Vila and Tissue Factor (Bunnett, 2006).
• PAR-2 has also been strongly implicated as a major cause of itch (Steinhoff et al., 2003).
• Psoriasis is a common skin condition which typically develops as patches ('plaques') of red, scaly skin. People with psoriasis have a faster turnover of skin cells associated with changes in the blood supply of the skin (redness) which causes local inflammation. Psoriasis is not due to an infection and is not infectious, nor is it cancerous.
• a PAR2 antagonist will be effective in the treatment of inflammatory skin diseases including psoriasis and itch
• topical or systemic administration of a PAR2 antagonist would reduce the itch caused by local inflammation in psoriasis, and therefore would constitute a targeted treatment for this unchallenged symptom of psoriasis.
• a PAR2 antagonist will be effective in the treatment of arthritis due to inflammation in or around the joint.
• APC00482WO The transmission of pain and/or unpleasant sensation is also enhanced by activation of PAR2 receptors as application of activating peptide excites C fibres and sensitises them to heat (Ding-Pfenmgdorf et al., 2004). Cancer
• PAR-2 has been implicated in cellular proliferation, invasion and metastasis. There is increasing evidence that PAR2 is an important mediator of tumour progression, with trypsin levels being elevated in gastric, colon, ovarian and lung tumours (Ducroc et al., 2002). In addition PAR-2 is expressed in cancers of the lungs, liver, prostate, thyroid, breast, gastrium, colon, pancreas, gallbladder, melanoma and glioblastoma (see Jahan et al., 2007 and references therein).
• Tissue factor is a primary component of the clotting cascade which with Factor Vila or Factor Xa can initiate clotting. Cancer patients are frequently in a pro- thrombotic state, apparently partly due to the release of TF containing microparticles (small membranous fragments perhaps released on apoptosis). TF is expressed at high levels in vessel wall fibroblasts but may also be expressed on endothelial and smooth muscle cells (Kasthuri et al., 2009). TF is also heavily implicated in cancer, its expression generally increasing with cancer stage (Kakkar et al., 1995; Kasthuri et al., 2009) and appears to be involved in metastasis (Belting et al., 2005).
• TF may play a role in forming the fibrinous clot around metastatic cells which serves to protect them from K cells and to maintain them in the vasculature (Palumbo et al., 2005, 2007).
• TF Factor Vila Factor Xa complexes stimulate breast carcinoma cell migration and invasion through activation of PAR2 (Hjortoe et al., 2004; Morris et al., 2006).
• activated PAR2 stimulates EGFR activity and thus cellular proliferation (Caruso et al., 2006); Darmoul et al., 2004).
• APC00482WO breast, colon, gastrium, pancreas, lungs, prostate, melanoma and glioblastoma see Jahan et al., 2007).
• PAR2 receptor activation has been shown to be important in inflammatory disorders. Based on in vivo studies in models of inflammatory disorders (Kelso et al, JPET, 2006, 316, 1017-1024, Sevigny, PNAS, 2011, 108, 20, 8491-8496 and Cenac et al, JDR, 2010, 89, 10, 1123-1128) it is expected that antagonism of the PAR2 receptor will be effective in the treatment of inflammatory disorders.
• Pancreatitis is an inflammatory condition understood to be the result of undesirable trypsin activity within the pancreas.
• the biological effects of trypsin in the pancreas have been shown to act through PAR2, which is strongly expressed on the luminal surface of acinar and ductal cells (Ceppa et al., 2011).
• Antagonism of the effects of trypsin at PAR2, within the pancreas, can be expected to be an effective treatment for pancreatitis. '
• the PAR2 receptor is regarded as a target for intervention in the treatment of the conditions referred to above.
• This invention makes available a class of compounds having surprisingly high antagonist activity at the PAR2 receptor, and their use in indications which respond to the antagonism of the PAR2 receptor such as those mentioned above.
• the present invention makes available a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof
• a disease or condition selected from inflammation, intestinal inflammation, ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome, fibrosis, arthntis and inflammatory skin diseases including psoriasis, atopic dermatitis and itch, pain and cancer
• ring P is a monocyclic aryl or heteroaryl ring having 5 or 6 ring atoms, which aryl or heteroaryl ring is optionally substituted with one or more R 1 groups
• ring Q is a monocyclic aryl or heteroaryl ring having 5 or 6 ring atoms, which aryl or heteroaryl ring is optionally substituted with one or more R 2 groups
• X is -(CH 2 )- n; n is 1, 2, 3, or 4;
• Y is -C(O)- or -S(0) 2 -;
• R 1 is one or more optional substituents selected from: hydrogen, halo, hydroxyl, oxo, cyano, d -4 -alkyl, fluoro-Ci -4 -alkyl, C ⁇ -alkoxy, -S0 2 R 4 , -NR 5 R 6 , -NR 7 S0 2 R 4 , - C(0)NR 5 R 6 , - R 7 C(0)OR 5 , - R 7 C(0)R 5 , -NR 7 C(0)NR 5 R 6 , -C(0)R 5 , -C(0)OR 5 , - NR 7 S(0) 2 R 5 , and wherein any Ci -4 -alkyl or Ci -4 -alkoxy residue is optionally substituted with one or more substituents selected from halogen, cyano, hydroxyl, NR 5 R 6 , Ci -4 - alkoxy, fluoro-Ci -4 -alkoxy, -S0 2 R 4 , -NR 7 S0
• R 2 is one or more optional substituents selected from: hydrogen, halo, hydroxyl, oxo, cyano, C M -alkyl, fluoro-Ci -4 -alkyl, C M -alkoxy, -S0 2 R 4 , -NR 5 R 6 , -NR 7 S0 2 R 4 , - C(0)NR 5 R 6 , - R 7 C(0)OR 5 , - R 7 C(0)R 5 , -NR 7 C(0)NR 5 R 6 , -C(0)R 5 , -C(0)OR 5 , - NR 7 S(0) 2 R 5 , and wherein any Ci -4 -alkyl or Ci -4 -alkoxy residue is optionally substituted
• R 3 is one or more optional substituents selected from hydrogen, halogen, Ci-4-alkyl, fluoro-Ci-4-alkyl, C3-6-cycloalkyl, C3-6-cycloalkyl-Ci-4-alkyl;
• R 4 is independently selected from hydrogen, NR 5 R 6 , Ci-4-alkyl, fluoro-Ci-4-alkyl, C3-6- cycloalkyl or C3.6-cycloalkyl-Ci-4-alkyl;
• R 5 and R 6 are independently selected from hydrogen, Ci-4-alkyl, fluoroCi-4-alkyl, C3-6- cycloalkyl or C3-6-cycloalkyl-Ci-4-alkyl, or hydroxyCi-4-alkyl; or
• R 5 and R 6 together with the nitrogen atom to which they are attached join together to form a 5 or 6-membered heterocyclic ring, the heterocyclic ring optionally further comprising a further heteroatom selected from nitrogen, oxygen or sulphur wherein the heterocyclic ring is optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, cyano, Ci-4-alkyl, and fluoro-Ci.4- alkoxy;
• R 7 is hydrogen, d-4-alkyl, C3_6-cycloalkyl, or C3.6-cycloalkyl-C 1 .4- alkyl;
• R 10 , R 11 , and R 12 are independently selected from hydrogen, Ci-4-alkyl, fluoro-Ci.4-alkyl, C3-6-cycloalkyl, or C3-6-cycloalkyl-Ci-4-alkyl.
• the applicant makes available a compound of formula (I) or a pharmaceutically acceptable salt, solvate or hydrate thereof wherein P, Q, X, Y, R 1 , R 2 , R 3 , Rio, Rn, and R i2 are as defined above, with the proviso that R 2 is not oxo, hydroxyl or -NR 5 R 6
• APC00482WO formula (I) includes salts, N-oxides, hydrates, solvates and polymorphs of such compounds;
• the compounds of the invention are antagonists of the PAR2 receptor. Therefore, in another broad aspect the invention provides the use of a compound of the invention in the treatment of, or in the preparation of a composition for treatment of, diseases or conditions responsive to the reduction of PAR2 mediated activity.
• diseases or conditions which are responsive to the reduction of PAR2 mediated activity include inflammation including intestinal inflammation (such as ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome), fibrosis, arthritis and inflammatory skin diseases (such as psoriasis, atopic dermatitis and itch), pain and cancers including cancers of the breast, colon, gastrium, pancreas, lungs, prostate, melanoma and glioblastoma.
• the compounds with which the invention is concerned may be used for the reduction of PAR2 mediated activity, ex vivo or in vivo.
• the compounds of the invention may be used in the preparation of a composition for the treatment of diseases or conditions selected from inflammation including intestinal inflammation (such as ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome), fibrosis, arthritis and inflammatory skin diseases (such as psoriasis, atopic dermatitis and itch), pain and cancers including cancers of the breast, colon, gastrium, pancreas, lungs, prostate, melanoma and glioblastoma.
• intestinal inflammation such as ulcerative colitis, Chrohn's disease, inflammatory bowel disease and irritable bowel syndrome
• fibrosis fibrosis
• arthritis inflammatory skin diseases
• pain and cancers including cancers of the breast, colon, gastrium, pancreas, lungs, prostate, melanoma and glioblastoma.
• the invention provides a method for the treatment of the foregoing disease types, which comprises administering to a subject suffering such disease an effective amount of a compound of the invention.
• APC00482WO According to the invention there is also provided a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the invention together with one or more pharmaceutically acceptable carriers and/or excipients.
• the compounds of the invention may be administered in a variety of dosage forms. Thus, they can be administered orally, for example as tablets, capsules, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules.
• the compounds can be administered in a sublingual formulation, for example a buccal formulation.
• the compounds of the invention may also be administered parenterally, whether subcutaneously, intravenously, intramuscularly, intrasternally, transdermally, by inhalation, intranasally, or by infusion techniques.
• the compounds may also be administered as suppositories.
• the compounds may also be administered topically.
• the compounds of the invention are administered orally, or by inhalation, topically, or intranasally.
• the compounds of the invention are administered orally and more preferably, the compounds of the invention are administered as a tablet or capsule.
• administration of the compounds in a hard gelatine capsule form, or in one of the many sustained release formulations known in the art will often be preferred.
• the compounds of the invention are administered as a topical treatment.
• the present invention further provides a pharmaceutical composition containing a compound of the invention or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier.
• the compounds of the invention are typically formulated for administration with a pharmaceutically acceptable carrier or diluent.
• solid oral forms may contain, together with the active compound, diluents, e.g. lactose, dextrose, saccharose, cellulose, corn starch or potato starch; lubricants, e.g. silica, talc, stearic acid, magnesium or calcium stearate, and/or polyethylene glycols; binding agents; e.g.
• starches arabic gums, gelatin, methylcellulose, carboxymethylcellulose or polyvinyl pyrrolidone; disaggregating agents, e.g. starch, algmic acid, alginates or sodium starch glycolate; effervescing mixtures; dyestuffs; sweeteners; wetting agents, such as lecithin, polysorbates, laurylsulphates; and, in general, non toxic and pharmacologically inactive substances used in pharmaceutical formulations.
• disaggregating agents e.g. starch, algmic acid, alginates or sodium starch glycolate
• dyestuffs effervescing mixtures
• sweeteners effervescing mixtures
• wetting agents such as lecithin, polysorbates, laurylsulphates
• non toxic and pharmacologically inactive substances used in pharmaceutical formulations may
• APC00482WO be manufactured in known manner, for example, by means of mixing, granulating, tableting, sugar coating, or film coating processes.
• Liquid dispersions for oral administration may be syrups, emulsions and suspensions.
• the syrups may contain as carriers, for example, saccharose or saccharose with glycerine and/or mannitol and/or sorbitol.
• Suspensions and emulsions may contain as carrier, for example a natural gum, agar, sodium alginate, pectin, methylcellulose, carboxymethylcellulose, or polyvinyl alcohol.
• the suspension or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g. sterile water, olive oil, ethyl oleate, glycols, e.g. propylene glycol, and if desired, a suitable amount of lidocaine hydrochloride.
• the present invention further provides a pharmaceutical composition containing a compound of the invention or a pharmaceutically acceptable salt thereof, as defined above, and a pharmaceutically acceptable carrier in the form of a capsule or tablet.
• the compounds of the invention are preferable administered topically.
• the compounds may be formulated in any form suitable for topical administration including semi-solid, spray, medicated powders, solution, and medicated adhesive systems.
• the compounds of the invention may be administered as external topicals that are spread, sprayed, or otherwise dispersed on to cutaneous tissues to cover the affected area. Topical drug delivery is especially effective in the fields of psoriasis, itch, and pain management.
• Solutions for injection or infusion may contain as carrier, for example, sterile water or preferably they may be in the form of sterile, aqueous, isotonic saline solutions.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing treatment. Optimum dose levels and frequency of dosing will be determined by clinical trial, as is required in the art. However, it is expected that a typical dose will be in the range from about 0.001 to 50 mg per kg of body weight.
• halo means -F, -CI, -Br, or -I.
• halo includes -F, -CI, -Br.
• hydroxyl means -OH.
• cyano means -CN.
• C a-b -alkyl wherein a and b are integers denotes a straight or branched alkyl group having from a to b carbon atoms.
• Ci-4-alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, /so-butyl, sec-butyl and tert-b tyl and "Ci-6-alkyl” includes the foregoing and straight- and branched-chain pentyl and hexyl.
• fluoro-C a-t ,-alkyl wherein a and b are integers denotes a straight or branched C a-b -alkyl group substituted by one or more fluorine atoms.
• fluoro-Ci-4- alkyl includes fluoromethyl, trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl.
• hydroxyl-C a _ b -alkyl wherein a and b are integers denotes a straight or branched C a-b -alkyl group substituted by one or more hydroxyl groups.
• hydroxyl-Ci-4-alkyl includes 1 -hydroxyl ethyl (-CH 2 CH 2 OH) and 1 -hydroxypropyl (- CH 2 CH 2 CH 2 OH).
• C a-b -alkoxy wherein a and b are integers refers to a straight or branched C a - b - alkyl group which is attached to the remainder of the molecule through an oxygen atom.
• a and b are integers refers to a straight or branched C a - b - alkyl group which is attached to the remainder of the molecule through an oxygen atom.
• oxygen atom for example includes methoxy, ethoxy, «-propoxy, wo-propoxy, «-butoxy, wo-butoxy, seobutoxy and feri-butoxy.
• fluoro-C a-b -alkoxy wherein a and b are integers denotes a fluoro-C a-b -alkyl group which is attached to the remainder of the molecule through an oxygen atom.
• fluoro-Ci-4-alkoxy groups include trifluoromethoxy and 2,2,2-trifluoroethoxy.
• Ca- b -alkoxy-Cc-d-alkyl wherein a, b, c and d are integers denotes a straight or branched alkoxy group having from a to b carbon atoms connected to a straight or branched alkyl group having from c to d carbon atoms.
• Ci-4-alkoxy-Ci.4- alkyl includes methoxymethyl, methoxyethyl, ethoxyethyl, ⁇ -propoxyethyl, n- butoxy ethyl and tert-butoxy ethyl.
• fluoro-C a-b -alkoxy-C c- d-alkyl wherein a, b, c and d are integers denotes a C a-b - alkoxy-C c- d-alkyl group substituted by one or more fluorine atoms.
• fluoro- Ci_4-alkoxy-Ci-4-alkyl includes trifluoromethoxymethyl and trifluoromethoxyethyl.
• C a-b -cycloalkyl wherein a and b are integers denotes a saturated monocyclic hydrocarbon ring having from a to b carbon atoms.
• C3-5-cycloalkyl includes cyclopropyl, cyclobutyl and cyclopentyl.
• C a-b -cycloalkyl-C c -d-alkyl wherein a, b, c and d are integers denotes a saturated monocyclic hydrocarbon ring having from a to b carbon atoms connected to a straight or branched alkyl group having from c to d carbon atoms.
• C3-5- cycloalkyl-Ci-4-alkyl includes cyclopropylmethyl and cyclobutylmethyl.
• carbocyclic refers to a mono-, bi- or tricyclic radical having up to 16 ring atoms, all of which are carbon, and includes aryl and cycloalkyl.
• heterocyclyl or “heterocyclic ring” denotes a saturated, monocyclic ring having from 4 to 7 ring atoms with at least one heteroatom such as O, N, or S, and the remaining ring atoms are carbon.
• heterocyclic rings include piperidinyl, tetrahydropyranyl, tetrahydrofuranyl, oxetanyl, azetidmyl, pyrrolidinyl, morpholmyl, thiomorpholmyl, dioxanyl, piperazmyl and homopiperazinyl.
• exemplary heterocyclic groups containing sulfur in oxidized form are 1,1-dioxido- thiomorpholinyl and 1,1-dioxido-isothiazolidinyl.
• heterocyclyl-C a- -alkyl wherein a and b are integers denotes a heterocyclic ring as defined above that is directly attached to a straight or branched C a- b-alkyl group via a carbon or nitrogen atom of said ring.
• heterocyclyl-Ci-4-alkyl groups include piperidin-l -ylmethyl, piperidin-4-ylmethyl and morpholin-4-ylmethyl.
• heteroaryl denotes a monocyclic or fused bicyclic heteroaromatic ring system comprising 5 to 10 ring atoms in which one or more of the ring atoms are other than carbon, such as nitrogen, sulphur or oxygen. Only one ring need be aromatic and said heteroaryl moiety can be linked to the remainder of the molecule via a carbon or nitrogen atom in any ring.
• heteroaryl groups include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyridinyl, pyrimidinyl, tetrazolyl, quinazolinyl, indolyl, indolinyl, isoindolyl, isoindolinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinolinyl, quinoxalinyl, oxadiazolyl, thiadiazolyl, benzofuranyl, 2,3-dihydrobenzofuranyl, 1,3-benzodioxolyl, 1 ,4- benzodioxmyl, benzothiazolyl, benzimidazolyl, azabenzimidazole, benzotriazolyl and chromanyl.
• C a- b-aryl wherein a and b are integers denotes a monocyclic or fused bicyclic hydrocarbon ring system comprising a to b ring atoms and wherein at least one ring is an aromatic ring.
• C6-io-aryl groups include phenyl, indenyl, 2,3-dihydroindenyl (indanyl), 1-naphthyl, 2-naphthyl or 1,2,3,4- tetrahydronaphthyl.
• C a- b-aryl-C c- d-alkyl wherein a, b, c and d are integers refers to a C a _b-aryl group that is directly linked to a straight or branched C c _d_ alkyl group.
• C6-io-aryl-Ci-4-alkyl groups include phenylmethyl (i.e. , benzyl) and phenylethyl.
• heteroaryl-C a- b-alkyl wherein a and b are integers denotes a heteroaryl ring as defined above that is directly linked to a straight or branched C a- b-alkyl group via a carbon or nitrogen atom of said ring.
• heteroaryl-Ci.4-alkyl groups include 2-(pyridin-2-yl)-ethyl and l ,2,4-oxadiazol-5- ylmethyl.
• substituted as applied to any moiety herein means substituted with up to four compatible substituents, each of which independently may be, for example, (Ci-Ce)alkyl, (Ci-C6)alkoxy, hydroxy, hydroxy(Ci-C6)alkyl, mercapto, mercapto(Ci-C6)alkyl, (Ci-C6)alkylthio, phenyl, halo (including fluoro, bromo and chloro), trifluoromethyl, trifluoromethoxy, nitro, nitnle (-CN), oxo, -COOH, -COOR A , -COR A , -S0 2 R A ,
• R A and R B are independently a (Ci-Ce)alkyl, (C3-C6) cycloalkyl , phenyl or monocyclic heteroaryl having 5 or 6 ring atoms, or R A and R B when attached to the same nitrogen atom form a cyclic amino group(for example morpholino, piperidinyl, piperazinyl, or tetrahydropyrrolyl).
• An "optional substituent" may be one of the foregoing substituent groups.
• Compounds of the invention may exist in one or more geometrical, optical, enantiomeric, diastereomeric and tautomeric forms, including but not limited to cis- and trans -ioims, E- and Z-forms, R-, S- and w3 ⁇ 4ero-forms, keto-, and enol-forms. Unless otherwise stated a reference to a particular compound includes all such isomeric forms, including racemic and other mixtures thereof. Where appropriate such isomers can be separated from their mixtures by the application or adaptation of known methods (e.g. chromatographic techniques and recrystallisation techniques). Where appropriate such isomers may be prepared by the application of adaptation of known methods (e.g. asymmetric synthesis).
• salt includes base addition, acid addition and ammonium salts.
• compounds of the invention which are acidic can form salts, including pharmaceutically acceptable salts, with bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine, dibenzylamine and the like.
• bases such as alkali metal hydroxides, e.g. sodium and potassium hydroxides; alkaline earth metal hydroxides e.g. calcium, barium and magnesium hydroxides; with organic bases e.g. N-methyl-D-glucamine, choline tris(hydroxymethyl)amino-methane, L-arginine, L-lysine, N-ethyl piperidine,
• APC00482WO hydrohalic acids such as hydrochloric or hydrobromic acids, sulphuric acid, nitric acid or phosphoric acid and the like, and with organic acids e.g. with acetic, trifluoroacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p- toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
• organic acids e.g. with acetic, trifluoroacetic, tartaric, succinic, fumaric, maleic, malic, salicylic, citric, methanesulphonic, p- toluenesulphonic, benzoic, benzenesulfonic, glutamic, lactic, and mandelic acids and the like.
• Those compounds (I) which have a basic nitrogen can also form quaternary ammonium salts with a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene- bis sulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.
• a pharmaceutically acceptable counter-ion such as chloride, bromide, acetate, formate, p-toluenesulfonate, succinate, hemi-succinate, naphthalene- bis sulfonate, methanesulfonate, trifluoroacetate, xinafoate, and the like.
• Some compounds of the invention having a nitrogen atom in an aromatic ring, may form N-oxides, and the invention includes compounds of the invention in their N-oxide form.
• the Ring P
• ring P is a monocyclic aryl or heteroaryl ring having 5 or 6 ring atoms, which aryl or heteroaryl ring is optionally substituted with one or more R 1 groups. Any such monocyclic aryl or heteroaryl ring is contemplated. In an embodiment the ring P is selected from
• ring P is optionally substituted with one or more R 1 groups.
• the ring P may be connected to ring Q via any P ring atom.
• ring P is a 5-membered monocyclic heteroaryl ring optionally substituted with one or more R 1 groups as defined in claims 1.
• ring P is phenyl or pyridyl ring optionally substituted with one or more R 1 groups.
• Ring Q is a monocyclic aryl or heteroaryl ring having 5 or 6 ring atoms, optionally substituted with one or more R 2 groups. Any such monocyclic aryl or heteroaryl ring is contemplated herein.
• ring Q is connected to X via a Q ring carbon atom.
• ring Q is a monocyclic aryl or heteroaryl ring having 6 ring atoms selected from:
• Q is a monocyclic heteroaryl ring having 5 ring atoms selected from:
• ring Q is optionally substituted with one or more R 2 groups.
• ring Q is phenylene or pyridmylene either of which is optionally substituted with one or more R 2 groups.
• bonds connecting ring P and X to ring Q are ortho to one another
• the ring Q atoms connecting ring Q to X and ring Q to P are adjacent.
• ring Q is substituted in the 1 -position by a direct bond to P and in the 2-position by a direct bond to X.
• bonds connecting ring P and X to ring Q are meta to one another.
• the ring Q atoms connecting ring Q to X and P are separated by one intermediate ring Q atom.
• ring Q is substituted in the 1 -position by a direct bond to P and in the 3 -position by a direct bond to X.
• X is -(CH 2 )-n, wherein n is 1, 2, 3, or 4.
• Examples of X include straight chain methylene, ethylene, propylene, or butylene.
• n 1.
• R 1 is one or more optional substituents selected from: halogen such as fluoro, chloro, and bromo, hydroxyl, oxo, cyano (-CN), Ci-4-alkyl such as methyl, ethyl, propyl, butyl, iso- propyl, sec-butyl, and tert-butyl, fluoro-Ci-4-alkyl such as trifluoromethyl or trifluoroethyl, Ci-4-alkoxy such as methoxy, ethoxy, isopropoxy, -SO 2 R 4 such as - S0 2 NH 2 , and -S0 2 CH 3 , -NR 5 R 6 such as -NH 2 , -NHC3 ⁇ 4 and N(CH 3 ) 2 , -NR 7 S0 2 R 4 such as -NHSO 2 NH 2 , -NHSO 2 CH3, -NHSOi'propyl, -C(0)NR 5 R 6 such as -C(0)
• R 1 is selected from hydrogen, Ci-4-alkyl such as methyl or isopropyl, fluoro-Ci-4-alkyl such as trifluoromethyl, Ci-4-alkoxy such as methoxy, halo such as fluoro or chloro, cyano, -S0 2 R 4 such as -S0 2 H 2 , S0 2 N(CH 3 ) 2 , , S0 2 NHC3 ⁇ 4 , S0 2 NHCH(CH 3 ) 2 , and -S0 2 CH 3 , -NHS0 2 R 4 such as -NHS0 2 NH 2 , -NHS0 2 N(CH 3 ) 2 ,- NHS0 2 NHCH 3 , -NHS0 2 NHCH(CH 3 ) 2 , and -NHS0 2 CH 3 , -C(0)NR 5 R 6 such as - C(0)NH 2 , -C(0)NHCH 2 -cyclopropyl, and -C(0)NHCH 2
• R 2 is one or more optional substituents selected from: halogen such as fluoro, chloro, and bromo, hydroxyl, oxo, cyano (-CN), Ci-4-alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl, fluoro-Ci -4 -alkyl such as trifluoromethyl or trifluoroethyl, Ci-4-alkoxy such as methoxy, ethoxy, isopropoxy, -S0 2 R 4 such as -S0 2 NH 2 , and -S0 2 CH 3 , -NR 5 R 6 such as -NH 2 , -NHCH 3 and N(CH 3 ) 2 , -NR 7 S0 2 R 4 such as -NHS0 2 NH 2 , -NHS0 2 CH 3 , - NHSOj'propyl
• Ci-4-alkyl such as
• R 2 is one or more optional substituents selected from: halogen such as fluoro, chloro, and bromo, cyano (- CN), Ci-4-alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl,
• APC00482WO fluoro-Ci-4-alkyl such as trifluoromethyl or trifluoroethyl, Ci -4 -alkoxy such as methoxy, ethoxy, isopropoxy, -S0 2 R 4 such as -S0 2 NH 2 , and -S0 2 C3 ⁇ 4, -NR 7 S0 2 R 4 such as - NHS0 2 H 2 , -NHS0 2 CH 3 , -NHSCVpropy -C(0)NR 5 R 6 such as -C(0)NH 2 , - C(0)NHCH2-cyclopropyl, and -C(0)NHCH2-cyclohexyl, -NR 7 C(0)OR 5 , -NR 7 C(0)R 5 , -NR 7 C(0)NR 5 R 6 , -C(0)R 5 , -C(0)OR 5 , -NR 7 S(0) 2 R 5 , and wherein any Ci -4 -alkyl or C M - alkoxy residue is optionally substitute
• R 2 is selected from hydrogen, halo such as chloro or fluoro, Ci-4-alkyl such as methyl or isopropyl, Ci -4 -alkoxy such as methoxy, cyano, or -C(0)NR 5 R 6 such as such as -C(0)NH 2 , -C(0)NHCH 2 -cyclopropyl, and -C(0)NHCH 2 -cyclohexyl, and Ci-4-alkyl substituted with -C(0)NR 5 R 6 such as -CH 2 C(0)NH 2 , -CH 2 C(0)NHCH 2 -cyclopropyl, and -CH 2 C(0) HCH 2 -cyclohexyl, and d -4 -alkyl substituted with -NR 7 C(0)R 5 such as -CH 2 R 7 C(0)R 5 .
• Ci-4-alkyl such as methyl or isopropyl
• Ci -4 -alkoxy such as methoxy, cyano
• R 3 is one or more optional substituents selected from hydrogen, halogen such as fluoro, chloro, and bromo, Ci -4 -alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl, fluoro-Ci -4 -alkyl, C3_6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or C3.6-cycloalkyl-Ci -4 -alkyl such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethy and cyclohexylmethyl, R 4 is independently selected from hydrogen, NR 5 R 6 , Ci -4 -alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl,
• R 5 and R 6 are independently selected from hydrogen, Ci -4 -alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl, fluoro-Ci -4 -alkyl such at trifluoromethyl or trifluoroethyl, C3-6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or C3.6-cycloalkyl-Ci -4 -alkyl such as cyclopropylmethyl,
• R 5 and R 6 together with the nitrogen atom to which they are attached join together to form a 5 or 6-membered heterocyclic ring such as piperidine, the heterocyclic ring optionally further comprising a further heteroatom selected from nitrogen, oxygen or sulphur to form a ring such as morpholine, or piperazine wherein the heterocyclic ring is optionally substituted with one or more substituents selected from halo, hydroxyl, oxo, cyano, Ci-4-alkyl such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert- butyl, and Ci-4-alkoxy such as methoxy or ethoxy, and such as trifluoromethyl, fluoro-Ci-4-alkoxy such as trifluoromethoxy;
• R 7 is hydrogen, such as methyl, ethyl, propyl, butyl, iso-propyl, sec-butyl, and tert-butyl, fluoro-Ci-4-alkyl such as trifluoromethyl, C3_6-cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl or such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethy and cyclohexylmethyl,.
• R 10 , R 11 , and R 12 are independently selected from hydrogen, Ci-4-alkyl, fluoro-Ci-4-alkyl, C3-6-cycloalkyl, or In an embodiment R 10 , R 11 , and R 12 are independently selected from hydrogen, methyl, isopropyl and cyclopropyl. In an embodiment R 10 , R 11 , and R 12 are hydrogen.
• Y is -C(O)-.
• the compounds of formula (I) above may be prepared by, or in analogy with, conventional methods.
• the preparation of intermediates and compounds according to the Examples of the present invention may in particular be illustrated by, but not limited to, the following Schemes. Definitions of variables in the structures in Schemes herein are commensurate with those of corresponding positions in the formulas delineated herein.
• APC00482WO Compounds of general formula (I) can easily be prepared from compounds of general formula II by aminolysis (for example by treatment with HC1 then ammonia, or by treatment with hydroxylamine then acetic anhydride and subsequent hydrogenation).
• Compounds of general formula (II) can be easily prepared from compounds of general formula (III) by amide coupling with compounds of general formula (IV) and subsequent Suzuki coupling, or by reversing these two steps.
• compounds of general formula (I) can be prepared from compounds of general formula (V) by amide coupling with compounds of general formula (VI).
• a compound of formula (I) can also be transformed into another compound of formula (I) in one or more synthetic steps. All of these alternatives are exemplified in the experimental section below.
• R is as defined in formula (I);
• Compounds of general formula (IV) can be easily prepared from benzoic acids of general formula (IVa) by reduction of the carboxylic acid and cyanide displacement of the bromo group to give alcohols of general formula (IVb).
• Compounds of general formula (IVb) can be easily converted into compounds of general formula (IV), for example by bromo-dehydroxylation and aminolysis (for example with B0C 2 NH and subsequent Boc deprotection).
• Analytical FIPLC was performed on an Agilent 1100 system using a Phenomenex Synergi, RP-Hydro, 150 x 4.6mm, 4um column with a flow rate of 1.5mL per min at 30°C (200-3 OOnm) and a gradient of 5-100% MeCN (+0.085% TFA) in water (+0.1% TFA) over 7mm.
• Mass directed HPLC was performed on a Waters system using a Phenomenex Gemini, CI 8, 100 x 21mm, 5um column with a flow rate of 20mL per min over 14.5min.
• Flash chromatography was performed on either a CombiFlash Companion system equipped with RediSep silica columns or a Flash Master Personal system equipped with Strata SI- 1 silica gigatubes or in a glass column under gravity.
• Reverse Phase HPLC was performed on a Gilson system (Gilson 322 pump with Gilson 321 equilibration pump and Gilson 21 autosampler) equipped with Phenomenex Synergi Hydro RP 150 x 10mm, or YMC ODS-A 100/1 0 x 20mm columns.
• Microwave irradiations were carried out using a Biotage microwave. Hydrogenations were performed using a Thales H-cube Nano. Reactions were performed at room temperature unless otherwise stated. The
• APC00482WO compounds were automatically named using ACD 6.0. All compounds were dried in a vacuum oven overnight. Where yields are not included, the intermediates were used crude. Reactions were monitored by TLC, LCMS or HPLC. INTERMEDIATE 1
• APC00482WO 4-Chlorobenzenesulfonyl chloride 150mg, 0.71mmol
• isopropylamine (0.18mL, 2.13mmol)
• DIPEA 0.13mL, 0.78mmol
• the reaction mixture was concentrated in vacuo and purified by column chromatography.
• 2-carboxybenzeneboronic acid 210mg, 1.42mmol
• Pd(PPh 3 ) 4 70.0mg, 0.06mmol
• Na 2 C0 3 130mg, 1.24mmol
• ntermediate 7 was prepared similarly to Intermediate 5, using morpholine instead of isopropylamine, to give the crude title compound (432mg) as a white solid.
• APC00482WO reaction mixture was cooled to -78°C.
• n-Butyllithium (3.5mL, 1.6M in hexanes, 5.61mmol) was added drop-wise over 30min and the reaction mixture was stirred at - 78°C for 30min.
• the reaction mixture was warmed to 0°C and a solution of zinc (II) chloride (2.22g, 16.3mmol) in ether (16.3mL) was added drop-wise over lOmin.
• the reaction mixture was stirred at 0°C for lh and at room temperature for 30min.
• Benzamide (l.OOg, 8.25mmol) was dissolved in dioxane (20mL), chlorocarbonylsulfenyl chloride (0.70mL, 8.25mmol) was added and the reaction mixture was heated under reflux at 101°C for 6h. The reaction mixture was concentrated in vacuo and the residue was dissolved in m-xylene (30mL). Methyl propiolate (0.84mL, 14.0mmol) was added and the reaction mixture was heated under reflux at 139° C for 24h. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM (50mL) and water (30mL).
• Example 56 was prepared similarly to Reference Example 55, using Intermediate 10 instead of Intermediate 88, to give the title compound (65.7mg, 8%) as a white solid.
• the PAR2 receptor couples through the Gq signaling pathway and results in activation of calcium mobilization.
• the functional activity of test compounds was routinely tested by measuring the ability of compounds to antagonize PAR2 (trypsin challenge) activity in a dose dependent manner, in Wild type HEK-293 cells, 1321N1 cells transfected with the rat PAR2 receptor and 1321N1 cells transfected with the mouse PAR2 receptor, using a calcium flux Fluorescent Imaging Plate Reader FLIPR assay.
• the selectivity of compounds for PAR2 versus the PARI and PAR4 receptors was evaluated using the native 1321N1 cell line.
• a series of serine protease assays was developed to measure the activity of in-house compounds on enzyme activity.
• test compounds were dissolved in DMSO to a concentration of 50mM and stored in matrix screenmate racks. The required amount of compound was transferred to 96-well compound plates on the day of assay and dose-response measurements were assayed by making 1 :3.16 serial dilutions to produce 10 point curves. Compounds were then diluted in assay buffer to the required final concentration before being transferred to 384-well assay plates ready for use. Top concentrations were adjusted depending on the potency of the compounds with a typical concentration range of 200 uM to 6.3 nM being used.
• the assay buffer used was HBSS buffer supplemented with 20 mM HEPES, 2.5 mM Probenicid, adjusted to pH7.4. The loading/wash buffers were the same as the assay buffer.
• Wild type HEK-293 cells were cultured in MEM AQmedia containing Glutamine, supplemented with 10% FBS, 1% (5 ml) Penicillin/Streptomycin and 1% Non Essential Amino Acids.
• Rat or Mouse PAR2 transfected 1321N1 cells were cultured in Dulbecco's modified Eagles medium (DMEM) supplemented with 10% dialyzed FBS, 1% Penicillin/Streptomycin, 378.5 ug/ml Geneticin G418 sulphate and maintained at 37 °C in a humidified, 5% C02 controlled atmosphere. Sub-cultivations were performed every 2-3 d.
• DMEM Dulbecco's modified Eagles medium
• the cells were lifted using 0.25% Trypsin (IX), spun at 1000 rpm for 3 min and re-suspended in medium at 3.3 x 10 5 cells/mL, transferred (30 ⁇ /well) to 384-well black/clear BD plates (SLS # 56663BD) and incubated at 37 °C in a 5% C02/95% air humidified incubator for 16 h.
• the cells were washed with assay buffer at 37 °C using the Biotek ELx 405, washing 3 times, leaving 20 ul buffer in the well.
• the cells were loaded with Fluo-4 AM dye (Molecular probes) at 2 uM containing 0.48 ug/mL pluronic acid for 60 min at 37 °C under 5% C02. Following the incubation, cells were washed in assay buffer at 37 °C using the Biotek ELx 405, washing 3 times, leaving 40 ⁇ in each well and incubated for 10 min at 37 °C before use.
• Fluo-4 AM dye Molecular probes
• a combined agonist/antagonist protocol was used to measure changes in intracellular calcium concentration.
• Compound (antagonist) was added to the cell plate using a Fluorometric Imaging Plate Reader (FLIPR) (Molecular Devices, Sunnyvale, CA, USA). Basal fluorescence was recorded every second for 10 sec prior to compound addition (10 uL) and fluorescence recorded every second for 1 min then every 6 sec for a further 1 min. Trypsin (EC 50 concentration) was then added using the FLIPR and fluorescense recorded as described above. Curve-fitting and parameter estimation were carried out using GraphPad Prism 4.0 (GraphPad Software Inc., San Diego, CA). Trypsin enzyme inhibition
• the commercially available protease assay kit from Calbiochem (Cat # 539125) was used to determine inhibition of trypsin activity.
• the kit quantifies trypsin activity by measuring the cleaved product of FTC-casein.
• To measure enzyme inhibition activity compounds were pre-incubated with trypsin before the addition of substrate.
• Compound IC50 was determined as percentage inhibition of trypsin.
• the Examples have significantly higher antagonist activity at the PAR2 receptor than the corresponding Reference Examples.
• the surprisingly improved activity arises by virtue of the Examples having n>0. (See Tables 7A, 7B, and 7C).
• PAR2 antagonist activity is assessed in rat 1321N1 cell line

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