US20150210722A1 - Kinase inhibitors - Google Patents

Kinase inhibitors Download PDF

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US20150210722A1
US20150210722A1 US14/424,967 US201314424967A US2015210722A1 US 20150210722 A1 US20150210722 A1 US 20150210722A1 US 201314424967 A US201314424967 A US 201314424967A US 2015210722 A1 US2015210722 A1 US 2015210722A1
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phenyl
oxy
pyrazol
naphthalen
dimethylphosphoryl
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Matthew Colin Thor Fyfe
Michael Knaggs
Premji Meghani
Stephen Malcolm Thom
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Respivert Ltd
TopiVert Pharma Ltd
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Respivert Ltd
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Priority claimed from GB201215370A external-priority patent/GB201215370D0/en
Priority claimed from GB201304780A external-priority patent/GB201304780D0/en
Application filed by Respivert Ltd filed Critical Respivert Ltd
Assigned to TOPIVERT PHARMA LIMITED, RESPIVERT LIMITED reassignment TOPIVERT PHARMA LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THOM, Stephen Malcolm, MEGHANI, PREMJI, KNAGGS, MICHAEL, FYFE, MATTHEW COLIN THOR
Publication of US20150210722A1 publication Critical patent/US20150210722A1/en
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6558—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system
    • C07F9/65583—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing at least two different or differently substituted hetero rings neither condensed among themselves nor condensed with a common carbocyclic ring or ring system each of the hetero rings containing nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • 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]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
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    • 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
    • C07D213/60—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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C07D231/14—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 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
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    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/082—
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
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    • C07F9/28—Phosphorus compounds with one or more P—C bonds
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/304—Aromatic acids (P-C aromatic linkage)
    • C—CHEMISTRY; METALLURGY
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
    • C07F9/6568—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms
    • C07F9/65685—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus atoms as the only ring hetero atoms the ring phosphorus atom being part of a phosphine oxide or thioxide
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    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/65031—Five-membered rings having the nitrogen atoms in the positions 1 and 2
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6509—Six-membered rings
    • C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3

Definitions

  • This invention relates, inter alia, to compounds which are antiinflammatory agents (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha kinase sub-type thereof; Syk kinase; and the Src family of tyrosine kinases).
  • p38 mitogen-activated protein kinase enzymes referred to herein as p38 mitogen-activated protein kinase enzymes (referred to herein as p38 MAP kinase inhibitors), for example the alpha kinase sub-type thereof; Syk kinase; and the Src family of tyrosine kinases).
  • the invention also relates to the use of such compounds in therapy, including in mono- and combination therapies, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease (COPD)), eye (such as uveitis) and gastrointestinal tract (such as Crohn's disease and ulcerative colitis).
  • inflammatory diseases including inflammatory diseases of the lung (such as asthma and chronic obstructive pulmonary disease (COPD)), eye (such as uveitis) and gastrointestinal tract (such as Crohn's disease and ulcerative colitis).
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • eye such as uveitis
  • gastrointestinal tract such as Crohn's disease and ulcerative colitis
  • p38 MAPK isoforms (alpha, beta, gamma and delta respectively) have been identified, each displaying different patterns of tissue expression.
  • the p38 MAPK alpha and beta isoforms are found ubiquitously throughout the body; are present in many different cell types and are inhibited by a number of previously described small molecular weight compounds. Early classes of inhibitors were highly toxic due to the broad tissue distribution of these isoforms which resulted in off-target effects of the compounds. Some of the more recently identified inhibitors show improved selectivity for p38 MAPK alpha and beta isoforms and have wider safety margins.
  • p38 MAP kinase is believed to play a pivotal role in many of the signalling pathways that are involved in initiating and maintaining chronic, persistent inflammation in human disease, for example, in severe asthma, COPD and inflammatory bowel disease (IBD).
  • IBD inflammatory bowel disease
  • p38 MAP kinase is activated by a range of pro-inflammatory cytokines and that its activation results in the recruitment and release of further pro-inflammatory cytokines.
  • data from some clinical studies demonstrate beneficial changes in disease activity in patients during treatment with p38 MAP kinase inhibitors. For instance Smith describes the inhibitory effect of p38 MAP kinase inhibitors on TNF ⁇ (but not IL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404).
  • COPD is a condition in which the underlying inflammation is reported to be substantially resistant to the anti-inflammatory effects of inhaled corticosteroids. Consequently, a superior strategy for treating COPD would be to develop an intervention which has both inherent anti-inflammatory effects and the ability to increase the sensitivity of the lung tissues of COPD patients to inhaled corticosteroids.
  • the recent publication of Mercado et al. (2007; American Thoracic Society Abstract A 56) demonstrates that silencing p38 MAPK gamma has the potential to restore sensitivity to corticosteroids. Thus, there may be a dual benefit for patients in the use of a p38 MAP kinase inhibitor for the treatment of COPD.
  • Certain p38 MAPK inhibitors have also been described as inhibitors of replication of respiratory syncytial virus (Cass L. et al., WO 2011/158039).
  • IBD The precise etiology of IBD is uncertain, but is believed to be governed by genetic and environmental factors that interact to promote an excessive and poorly controlled mucosal inflammatory response directed against components of the luminal microflora. This response is mediated through infiltration of inflammatory neutrophils, dendritic cells and T-cells from the periphery. Due to the ubiquitous expression of p38 in inflammatory cells it has become an obvious target for investigation in IBD models. Studies investigating the efficacy of p38 inhibitors in animal models of IBD and human biopsies from IBD patients indicated that p38 could be a target for the treatment of IBD (Hove, T. ten et al., Gut, 2002, 50:507-512, Docena, G.
  • T cells are known to play key role in mediating inflammation of the gastrointestinal tract.
  • SCID immunodeficient
  • mucosal membranes from IBD patients showed an upregulation of CD4+ cells which were either Th1 (IFN ⁇ /IL-2) or Th2 (IL5/TGF ⁇ ) biased depending on whether the patient had Crohn's disease or ulcerative colitis (Fuss I J. et al. J Immunol. 1996 157:1261-70.).
  • T cells are known to play a key role in inflammatory disorders of the eye with several studies reporting increased levels of T cell associated cytokines (IL-17 and IL-23) in sera of Behçets patients (Chi W. et al. Invest Ophthalmol Vis Sci. 2008 49:3058-64). In support, Direskeneli and colleagues demonstrated that Behçets patients have increased Th17 cells and decreased Treg cells in their peripheral blood (Direskeneli H. et al. J Allergy Clin Immunol. 2011 128:665-6).
  • Src family kinases are known to play a key role in this pathway, where Src family kinases, Fyn and Lck, are the first signalling molecules to be activated downstream of the T cell receptor (Barber E K. et al. PNAS 1989 86:3277-81). They initiate the tyrosine phosphorylation of the T cell receptor leading to the recruitment of the Syk family kinase, ZAP-70. Animal studies have shown that ZAP-70 knockout results in a SCID phenotype (Chan A C. et al. Science. 1994 10; 264(5165): 1599-601).
  • Syk kinase is widely expressed in cells of the hematopoietic system, most notably in B cells and mature T cells. Through interaction with immunoreceptor tyrosine-based activation (ITAM) motifs it plays an important role in regulating T cell and B cell expansion as well as mediating immune-receptor signalling in inflammatory cells.
  • ITAM immunoreceptor tyrosine-based activation
  • Syk activation leads to IL-6 and MMP release inflammatory mediators commonly found upregulated in inflammatory disorders including IBD and rheumatoid arthritis (Wang Y D. et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al. Cytokine. 2006 January 33:106-10).
  • kinase enzymes are now also recognised to regulate the activity of a range of cellular functions, including the maintenance of DNA integrity (Shilo, Y. Nature Reviews Cancer, 2003, 3: 155-168) and co-ordination of the complex processes of cell division. Indeed, certain kinase inhibitors (the so-called “Olaharsky kinases”) have been found to alter the frequency of micronucleus formation in vitro (Olaharsky, A. J. et al., PLoS Comput. Biol., 2009, 5(7)). Micronucleus formation is implicated in, or associated with, disruption of mitotic processes and is therefore undesirable.
  • GSK3 ⁇ glycogen synthase kinase 3 ⁇
  • urea derivatives are disclosed as having anti-inflammatory properties (see, for example, WO 01/36403, WO 01/4115, WO 02/092576, WO 2003/068228, WO 2003/072569, WO 2004/113352, WO 2007/053394 and Bioorg. Med. Chem. Lett. 2007, 17, 354-357).
  • a superior therapeutic index e.g. inhibitors that are at least equally efficacious and, in one or more respects, are less toxic at the relevant therapeutic dose than previous agents.
  • R 1 represents C 2-6 alkyl, Si(R 1a )(R 1b )(R 1c ), C 3-7 cycloalkyl, phenyl or a 5- or 6-membered heteroaryl group containing one or more heteroatoms selected from N, O and S, which alkyl, cycloalkyl, phenyl and heteroaryl groups are optionally substituted by one or more substituents selected from halo, C 1-4 alkyl, C 2-3 alkynyl, C 3-4 cycloalkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino and cyano; R 1a and R 1b independently represent C 1-4 alkyl or C 3-6 cycloalkyl, or R 1a and R 1b together combine to form C 2-6 alkylene; R 1c represents C 1-2 alkyl; X 1 and X 2 are both N, or X 1 is C and X 2 is either O or S; Ar is phenyl or phen
  • R 6g represents C 1-6 alkyl, C 3-6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from halo, hydroxy, C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl;
  • R 6h , R 6i , R 6j and R 6k independently represent C 1-4 alkyl optionally substituted by one or more halo atoms, or R 6h and R 6i independently represent H;
  • R 7a represents H or C 1-3 alkyl optionally substituted by one or more halo atoms;
  • R 7b represents C 1-4 alkoxy, S—C 1-4 alkyl, phenyl or Het 4 , which latter two groups are optionally substituted by one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloalkyl, C 1-4 alkoxy, hydroxy, amino and cyano;
  • R 8 represents, independently on each occurrence, halo, hydroxy, C 1-4 alkoxy, oxo, C 3-8 cycloalkyl, Het 3 or phenyl, which latter three groups are optionally substituted by one or more substituents selected from halo, C 1-4 alkyl, C 1-4 haloal
  • salts include acid addition salts and base addition salts.
  • Such salts may be formed by conventional means, for example by reaction of a free acid or a free base form of a compound of formula I 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 techniques (e.g. in vacuo, by freeze-drying or by filtration). Salts may also be prepared by exchanging a counter-ion of a compound of formula I in the form of a salt with another counter-ion, for example using a suitable ion exchange resin.
  • Examples of pharmaceutically acceptable salts include acid addition salts derived from mineral acids and organic acids, and salts derived from metals.
  • compounds of formula I may contain the stated atoms in any of their natural or non-natural isotopic forms.
  • embodiments of the invention that may be mentioned include those in which:
  • references herein to an “isotopic derivative” relate to the second of these two embodiments.
  • the compound of formula I is isotopically enriched or labelled (with respect to one or more atoms of the compound) with one or more stable isotopes.
  • the compounds of the invention that may be mentioned include, for example, compounds of formula I that are isotopically enriched or labelled with one or more atoms such as deuterium or the like.
  • alkyl groups and alkoxy groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of three) of carbon atoms, be branched.
  • Particular alkyl groups that may be mentioned include, for example, methyl, ethyl, n-propyl, iso-propyl, butyl, n-butyl and tert-butyl.
  • Particular alkoxy groups that may be mentioned include, for example, methoxy, ethoxy, propoxy, and butoxy.
  • cycloalkyl groups as defined herein may, when there is a sufficient number (i.e. a minimum of four) of carbon atoms, be part cyclic/acyclic.
  • alkylene groups as defined herein may be straight-chain or, when there is a sufficient number (i.e. a minimum of two) of carbon atoms, be branched.
  • alkylene refers to straight-chain alkylene.
  • aryl groups may be via any atom of the ring system. However, when aryl groups are bicyclic or tricyclic, they are linked to the rest of the molecule via an aromatic ring.
  • C 6-14 aryl groups include phenyl, naphthyl and the like. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.
  • Het a that may be mentioned include imidazolyl (e.g. imidazol-2-yl), isothiazolyl (e.g. isothiazol-3-yl), isoxazolyl (e.g. isoxazol-3-yl), 1,2,4-oxadiazolyl (e.g. 1,2,4-oxadiazol-3-yl or 1,2,4-oxadiazol-5-yl), 1,3,4-oxadiazolyl, oxazolyl (e.g. oxazol-2-yl), pyridinyl (e.g. pyridin-2-yl), pyrimidinyl (e.g.
  • 1,2,4-thiadiazolyl e.g. 1,2,4-thiadiazol-3-yl or 1,2,4-thiadiazol-5-yl
  • 1,3,4-thiadiazolyl thiazolyl (e.g. thiazol-2-yl)
  • 1,2,3-triazolyl e.g. 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl or 1,2,3-triazol-5-yl
  • 1,2,4-triazolyl e.g. 1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl or 1,2,4-triazol-5-yl.
  • halo includes references to fluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo, especially fluoro or chloro.
  • R 1 represents C 2-6 alkyl optionally substituted by halo or C 3-6 cycloalkyl optionally substituted by C 1-4 alkyl, C 1-4 haloalkyl or C 1-4 alkoxy, or R 1 represents Si(R 1a )(R 1b )(R 1c ); R 1a and R 1b independently represent C 1-4 alkyl (e.g. C 1-2 alkyl), or R 1a and R 1b together combine to form C 2-6 alkylene; R 1c represents C 1-2 alkyl; X 1 and X 2 are both N; Ar is phenyl or pyridyl; L is a direct bond or C 1-2 alkylene (e.g.
  • R 2 represents C 1-4 alkyl (e.g. C 1-2 alkyl);
  • R 3 represents C 1-4 alkyl (e.g. C 1-2 alkyl), C 1-4 alkoxy (e.g.
  • R 4 and R 5 are each independently C 1-3 alkyl, C 1-3 haloalkyl, cyano or halo, or, particularly, R 4 and R 5 , together with the C-atoms to which they are attached, form a fused phenyl ring, which ring is optionally substituted by one or more substituents selected from C 1-3 alkyl, C 1-3 haloalkyl, cyano or halo; either A represents N and A 1 represents CH, or both A and A 1 represent CH; E represents N(G 1 ) or S; G represents R 6a , C(O)R 6b , phenyl optionally substituted by one or more Y 1 or Het 2 optionally substituted by one or more Y 2 ; G 1 represents H or C 1-3 alkyl (e.g.
  • R 6a represents C 1-8 alkyl, wherein one or two non-adjacent C-atoms of the alkyl group, that are not linked directly to E, are optionally replaced by heteroatoms independently selected from O and N and/or wherein the alkyl group is substituted by one or more R 8 substituents;
  • R 6b represents C 1-8 alkyl, wherein one C-atom of the alkyl group is, or two non-adjacent C-atoms of the alkyl group are, optionally replaced by heteroatoms independently selected from O and N and/or wherein the alkyl group is substituted by one or more R 8 substituents;
  • each Y 1 is independently selected from the group consisting of halo, hydroxy, cyano
  • L is a direct bond or, particularly, —CH 2 —;
  • R 2 represents C 1-4 alkyl (e.g. C 1-2 alkyl), and
  • R 3 represents hydroxy or, particularly, C 1-4 alkyl (e.g. C 1-2 alkyl) or C 1-4 alkoxy (e.g. C 1-2 alkoxy).
  • R 1 to R 5 , A, A 1 , G, G 1 , X 1 , X 2 , Ar and L are as defined above in respect of compounds of formula I.
  • R 1 represents C 1-4 alkyl or Si(CH 3 ) 3 ;
  • R 2 and R 3 independently represent C 1-2 alkyl or C 1-2 alkoxy, or R 2 and R 3 together combine to form C 3-6 alkylene (e.g. C 4-5 alkylene, such C 4 alkylene);
  • X 1 and X 2 are both N;
  • Ar is pyrimidinyl, pyridinyl or, particularly, phenyl, which three groups are optionally substituted by one or more substituents selected from halo, C 1-3 alkyl and C 1-3 alkoxy;
  • L is a direct bond or —CH 2 —;
  • R 4 and R 5 are each independently cyano or halo, or R 4 and R 5 , together with the C-atoms to which they are attached, form a fused phenyl ring; either A represents N and A 1 represents CH, or both A and A 1 represent CH;
  • G represents
  • Z 1 and Z 2 represents H;
  • R 1 represents C 1-4 alkyl (e.g. C 3-4 alkyl) or Si(CH 3 ) 3 ;
  • R 2 and R 3 independently represent C 1-2 alkyl (e.g. methyl) or C 1-2 alkoxy (e.g. ethoxy); or R 2 and R 3 together combine to form C 3-6 alkylene (e.g.
  • L is a direct bond or, particularly, —CH 2 —;
  • A represents CH or N;
  • G 1 represents H or methyl;
  • a 2 and A 3 both represent C(R a ), or one of A 2 and A 3 represents N and the other represents C(R a );
  • R a , R b , R c and R d independently represent (or, particularly, one or two (e.g.
  • R a , R b , R c and R d represents) H, halo, hydroxy, or particularly, cyano, P(O)R 6c R 6d , SF 5 , —C ⁇ CH, —O—CH 2 CH 2 —N(R 6e )R 6f , —C(O)NHC 1-2 alkyl, —C(O)NHCH 2 CH 2 —N(R 6e )R 6f , —S(O) 2 R 6g , —O—[CH 2 CH 2 O] 2-7 —CH 3 , —S—C 1-4 alkyl, —S—C 2-4 hydroxyalkyl, C 1-4 hydroxyalkyl, C 1-4 alkyl or C 1-4 alkoxy, which latter two groups are optionally substituted by one or more halo atoms (e.g.
  • R a , R b , R c and R d independently represent H, halo, hydroxy, or particularly, P(O)R 6c R 6d , SF 5 , —C ⁇ CH, —O—CH 2 CH 2 —N(R 6e )R 6f , —C(O)NHC 1-2 alkyl, —C(O)NHCH 2 CH 2 —N(R 6e )R 6f , —S(O) 2 R 6g , —O—[CH 2 CH 2 O] 2-7 —CH 3 , —S—C 1-4 alkyl, —S—C 2-4 hydroxyalkyl, C 1-4 hydroxyalkyl, C 1-4 alkyl or C 1-4 alkoxy, which latter two groups are optionally substituted by one or more halo atoms); or R b and R c , together with the C-atoms to which they are attached, form a fused, 5- or 6-membered aromatic, heteroaromatic
  • R a to R d are all H
  • R a to R c are all H and R d is other than H; or R a and R b are both H and R c and R d are both other than H.
  • R 1 to R 3 , A, G 1 and R a to R d are as defined above in respect of compounds of formula Ib and A 3′ represents CH or N.
  • R a to R d are all H
  • R a to R c are all H and R d is other than H; or R a and R b are both H and R c and R d are both other than H.
  • G 1 and R a to R d are as defined above in respect of compounds of formula Ib or Ic.
  • R 1 to R 3 , A, A 3′ and G 1 are as defined above in respect of compounds of formula I, Ia, Ib or Ic;
  • R d1 is as defined above for R d in respect of compounds of formula Ib and Ic;
  • R a2 to R d2 are as defined above for R a to R d , respectively, in respect of compounds of formula Ib and Ic.
  • Embodiments of the invention that may be mentioned include those in which one or more of the following definitions apply to the compound of formula Id, Ie or If:
  • references herein to a compound of the invention are intended to include references to the compound and to all pharmaceutically acceptable salts, solvates and/or tautomers of said compound, unless the context specifically indicates otherwise.
  • solvates that may be mentioned include hydrates.
  • the compounds of the invention are p38 MAP kinase inhibitors (especially of the alpha subtype) and are therefore useful in medicine, in particular for the treatment of inflammatory diseases. Further aspects of the invention that may be mentioned therefore include the following.
  • diluents and carriers that may be mentioned include those suitable for parenteral, oral, topical, mucosal and rectal administration.
  • compositions and combination products of aspects (a) and (b) above may be prepared e.g. for parenteral, subcutaneous, intramuscular, intravenous, intra-articular, intravitreous, periocular, retrobulbar, subconjunctival, sub-Tenon, topical ocular or peri-articular administration, particularly in the form of liquid solutions, emulsions or suspensions; for oral administration, particularly in the form of tablets or capsules, and especially involving technologies aimed at furnishing colon-targeted drug release (Patel, M. M. Expert Opin. Drug Deliv. 2011, 8 (10), 1247-1258); for topical e.g.
  • pulmonary or intranasal administration particularly in the form of powders, nasal drops or aerosols and transdermal administration; for topical ocular administration, particularly in the form of solutions, emulsions, suspensions, ointments, implants/inserts, gels, jellies or liposomal microparticle formulations (Ghate, D.; Edelhauser, H. F. Expert Opin. Drug Deliv. 2006, 3 (2), 275-287); for ocular administration, particularly in the form of biodegradable and non-biodegradable implants, liposomes and nanoparticles (Thrimawithana, T. R. et al. Drug Discov. Today 2011, 16 (5/6), 270-277); for mucosal administration e.g. to buccal, sublingual or vaginal mucosa, and for rectal administration e.g. in the form of a suppository or enema.
  • mucosal administration e.g. to buccal, sublingual or vagina
  • compositions and combination products of aspects (a) and (b) above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., (1985).
  • Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered sprays.
  • excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • Pharmaceutical formulations and combination products suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
  • Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone; fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or poly-vinylpyrollidone
  • fillers such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine
  • lubricants such as magnesium stearate, talc,
  • Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
  • emulsifying agents such as lecithin, or acacia
  • vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
  • preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluen
  • Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
  • SEG soft elastic gelatin
  • a dry shell formulation typically comprises of about 40% to 60% w/w concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water. Other materials such as preservatives, dyes, opacifiers and flavours also may be present.
  • the liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
  • a compound of the invention may be administered topically (e.g. to the lung, eye or intestines).
  • topically e.g. to the lung, eye or intestines.
  • embodiments of aspects (a) and (b) above that may be mentioned include pharmaceutical formulations and combination products that are adapted for topical administration.
  • Such formulations include those in which the excipients (including any adjuvant, diluent and/or carrier) are topically acceptable.
  • Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • a suitable aerosol propellant such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC).
  • CFC propellants include trichloromonofluoromethane (propellant 11), dichlorotetrafluoromethane (propellant 114), and dichlorodifluoromethane (propellant 12).
  • Suitable HFC propellants include tetrafluoroethane (HFC-134a) and heptafluoropropane (HFC-227).
  • the propellant typically comprises 40% to 99.5% e.g.
  • the formulation may comprise excipients including co-solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Aerosol formulations are packaged in canisters and a suitable dose is delivered by means of a metering valve (e.g. as supplied by Bespak, Valois or 3M).
  • a metering valve e.g. as supplied by Bespak, Valois or 3M.
  • Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension. This may be administered by means of a nebuliser. Topical administration to the lung may also be achieved by use of a dry-powder formulation.
  • a dry powder formulation will contain the compound of the disclosure in finely divided form, typically with a mass mean aerodynamic diameter (MMAD) of 1-10 ⁇ m.
  • the formulation will typically contain a topically acceptable diluent such as lactose, usually of large particle size e.g. an MMAD of 100 ⁇ m or more. Examples of dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.
  • the compounds of the present invention may also be administered rectally, for example in the form of suppositories or enemas, which include aqueous or oily solutions as well as suspensions and emulsions.
  • suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides.
  • the drug is mixed with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the total amount of the inhibitor will be about 0.0001 to less than 4.0% (w/w).
  • compositions administered according to the present invention will be formulated as solutions, suspensions, emulsions and other dosage forms.
  • Aqueous solutions are generally preferred, based on ease of formulation, as well as a patient's ability to administer such compositions easily by means of instilling one to two drops of the solutions in the affected eyes.
  • the compositions may also be suspensions, viscous or semi-viscous gels, or other types of solid or semi-solid compositions. Suspensions may be preferred for compounds that are sparingly soluble in water.
  • compositions administered according to the present invention may also include various other ingredients, including, but not limited to, tonicity agents, buffers, surfactants, stabilizing polymer, preservatives, co-solvents and viscosity building agents.
  • Preferred pharmaceutical compositions of the present invention include the inhibitor with a tonicity agent and a buffer.
  • the pharmaceutical compositions of the present invention may further optionally include a surfactant and/or a palliative agent and/or a stabilizing polymer.
  • tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions.
  • sodium chloride, potassium chloride, magnesium chloride, calcium chloride, simple sugars such as dextrose, fructose, galactose, and/or simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates may be added to the composition to approximate physiological tonicity.
  • Such an amount of tonicity agent will vary, depending on the particular agent to be added.
  • compositions will have a tonicity agent in an amount sufficient to cause the final composition to have an ophthalmically acceptable osmolality (generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm).
  • ophthalmically acceptable osmolality generally about 150-450 mOsm, preferably 250-350 mOsm and most preferably at approximately 290 mOsm.
  • the tonicity agents of the invention will be present in the range of 2 to 4% w/w.
  • Preferred tonicity agents of the invention include the simple sugars or the sugar alcohols, such as D-mannitol.
  • An appropriate buffer system e.g., sodium phosphate, sodium acetate, sodium citrate, sodium borate or boric acid
  • the particular concentration will vary, depending on the agent employed.
  • the buffer will be chosen to maintain a target pH within the range of pH 5 to 8, and more preferably to a target pH of pH 5 to 7.
  • Surfactants may optionally be employed to deliver higher concentrations of inhibitor.
  • the surfactants function to solubilise the inhibitor and stabilise colloid dispersion, such as micellar solution, microemulsion, emulsion and suspension.
  • examples of surfactants which may optionally be used include polysorbate, poloxamer, polyosyl 40 stearate, polyoxyl castor oil, tyloxapol, triton, and sorbitan monolaurate.
  • Preferred surfactants to be employed in the invention have a hydrophile/lipophile/balance “HLB” in the range of 12.4 to 13.2 and are acceptable for ophthalmic use, such as TritonX114 and tyloxapol.
  • Additional agents that may be added to the ophthalmic compositions of the present invention are demulcents which function as a stabilising polymer.
  • the stabilizing polymer should be an ionic/charged example with precedence for topical ocular use, more specifically, a polymer that carries negative charge on its surface that can exhibit a zeta-potential of ( ⁇ )10-50 mV for physical stability and capable of making a dispersion in water (i.e. water soluble).
  • a preferred stabilising polymer of the invention would be polyelectrolyte, or polyelectrolytes if more than one, from the family of cross-linked polyacrylates, such as carbomers and Pemulen®, specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w/w.
  • viscosity enhancing agents include, but are not limited to: polysaccharides, such as hyaluronic acid and its salts, chondroitin sulfate and its salts, dextrans, various polymers of the cellulose family; vinyl polymers; and acrylic acid polymers.
  • Topical ophthalmic products are typically packaged in multidose form. Preservatives are thus required to prevent microbial contamination during use. Suitable preservatives include: benzalkonium chloride, chlorobutanol, benzododecinium bromide, methyl paraben, propyl paraben, phenylethyl alcohol, edentate disodium, sorbic acid, polyquaternium-1, or other agents known to those skilled in the art. Such preservatives are typically employed at a level of from 0.001 to 1.0% w/v. Unit dose compositions of the present invention will be sterile, but typically unpreserved. Such compositions, therefore, generally will not contain preservatives.
  • Embodiments of the invention that may be mentioned in connection with the combination products described at (b) above include those in which the other therapeutic agent is one or more therapeutic agents that are known by those skilled in the art to be suitable for treating inflammatory diseases (e.g. the specific diseases mentioned below).
  • the other therapeutic agent is one or more agents selected from the list comprising:
  • the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
  • the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
  • the compounds of the invention may be used as monotherapies for inflammatory diseases, or in combination therapies for such diseases.
  • embodiments of aspects (e) to (g) above include those in which the compound of formula I, Ia, Ib, Ic, Id, Ie or If (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is the sole pharmacologically active ingredient utilised in the treatment.
  • the compound of formula I, Ia, Ib, Ic, Id, Ie or If (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is administered to a subject who is also administered one or more other therapeutic agents (e.g. wherein the one or more other therapeutic agents are as defined above in connection with combination products).
  • inflammatory disease specifically includes references to any one or more of the following:
  • references herein to diseases having an inflammatory component include references to diseases that involve inflammation, whether or not there are other (non-inflammatory) symptoms or consequences of the disease.
  • E, L, Ar, X 1 , X 2 , R 1 to R 5 , A, A 1 , G and G 1 are as hereinbefore defined, for example under conditions known to those skilled in the art, for example at a temperature from ambient (e.g. 15 to 30° C.) to about 110° C. in the presence of a suitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or mixtures thereof); (b) reaction of a compound of formula IIa,
  • Z 1 is as defined above, with a suitable azide-forming agent (i.e. a suitable source of a leaving group and activated azide ion, such as diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30, 2151-2157) under conditions known to those skilled in the art, such as at sub-ambient to ambient temperature (e.g. from an initial reaction temperature of about ⁇ 5 to 5° C. to ambient temperature post-reaction) in the presence of an amine base (e.g. triethylamine or a sterically hindered base such as N,N-diisopropylethylamine) and a suitable organic solvent (e.g.
  • a suitable azide-forming agent i.e. a suitable source of a leaving group and activated azide ion, such as diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30, 2151-2157
  • a suitable azide-forming agent i.e. a suitable source
  • LG 1 represents a suitable leaving group (e.g. imidazolyl, chloro, or aryloxy) and Z 1 is as defined above, with a compound of formula III, as defined above, for example under conditions known to those skilled in the art, such as at ambient temperature (e.g. from 15 to 30° C.), optionally in the presence of an amine base (e.g. a sterically hindered base like N,N-diisopropylethylamine) and a suitable organic solvent (e.g. an aprotic solvent, such as dichloromethane); (d) reaction of a compound of formula VI,
  • amine base e.g. a sterically hindered base like N,N-diisopropylethylamine
  • a suitable organic solvent e.g. an aprotic solvent, such as dichloromethane
  • LG 2 represents a suitable leaving group (e.g. a halo group such as fluoro, chloro, bromo or methanesulfonyl) and L
  • Ar, X 1 , X 2 , R 1 to R 5 , A and A 1 are as hereinbefore defined with a compound of formula VII,
  • G and E are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. as described in J. Am. Chem. Soc. 2011, 133, 15686-15696), such as at elevated temperature (e.g. from 50 to 110° C.), in the presence of a suitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or a protic solvent, such as trifluoroethanol or ethanol, or mixtures thereof) and, optionally, an acidic catalyst (e.g.
  • a suitable organic solvent e.g. a polar aprotic solvent such as DMF, THF, 1,4-dioxane, or a protic solvent, such as trifluoroethanol or ethanol, or mixtures thereof
  • an acidic catalyst e.g.
  • a sulfonic acid such as para-toluenesulfonic acid, for example in the presence of approximately 0.5 to 1 equivalents of such an acid relative to the compound of formula VI or formula VII); or (e) deprotection of an protected derivative of a compound of formula I, under conditions known to those skilled in the art, wherein the protected derivative bears a protecting group on an O- or N-atom of the compound of formula I (and, for the avoidance of doubt, a protected derivative of one compound of formula I may or may not represent another compound of formula I).
  • Compounds of formula II may be prepared according to or by analogy with methods known to those skilled in the art, for example by reaction of a compound of formula IIa, as defined above, with an azide-forming agent, followed by rearrangement of the intermediate acyl azide (as described at (b) above; see, for example, Tetrahedron 1974, 30, 2151-2157).
  • LG 1 is as hereinbefore defined, with a compound of formula IX,
  • Z 1 is as hereinbefore defined, for example under conditions known to those skilled in the art.
  • Amines of formula IX may be prepared from carboxylic acids of formula IIa through the route described in (b) above, where the intermediate isocyanate II is hydrolysed with water to give a carbamic acid that loses carbon dioxide to furnish IX.
  • the intermediate isocyanate II can be reacted with an alcohol, such as t-butanol, to generate a protected version of IX.
  • pyrazole XII may be subjected to a copper (II)-mediated Chan-Lam reaction with a boronic acid of formula XV—where W represents chlorine, bromine or iodine, or a latent halogen that can be revealed after the coupling step (Scheme 2)—to furnish a compound of formula XVI.
  • W represents chlorine, bromine or iodine
  • Scheme 2 a latent halogen that can be revealed after the coupling step
  • a Pd(II) catalytic species such as Pd(II) acetate
  • a bidentate phosphine ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos); see, for example, WO 2009/143389) to furnish the phosphoryl-containing compounds XIV.
  • Saponification of esters XIV typically employing an alkali hydroxide, followed by acidification, furnishes the desired carboxylic acids of formula IIa, where Z 1 is a structural fragment of formula IV.
  • Certain amines of formula III, where Z 2 is a structural fragment of formula IV, in which both X 1 and X 2 are nitrogen and L is C 1 or C 2 alkylene, may be synthesised employing the route outlined in Scheme 3 below.
  • the compounds of formula XVIII, in which W 1 is a leaving group, such as chlorine, bromine or iodine may be combined with compounds XVII (as defined in Scheme 2), for example by heating in a polar aprotic solvent (e.g. DMF) in the presence of a palladium-containing catalyst (e.g.
  • a polar aprotic solvent e.g. DMF
  • a palladium-containing catalyst e.g.
  • a Pd(II) catalytic species such as Pd(II) acetate
  • a bidentate phosphine ligand such as 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos)
  • the compounds of formula XVIII are coupled, in an Arbuzov-type reaction (WO 2010/141406 ; Bioorg. Med. Chem. Lett. 2009, 19, 2053-2058), with compounds XIX.
  • the latter compounds are typically made in situ by reaction of the corresponding chlorophosphine (Cl—PR 2 R 3 ) with a C 1-4 alkyl alcohol in the presence or a base (e.g. diisopropylethylamine), or with an alkali metal salt of a C 1-4 alkyl alcohol.)
  • Arylamines of formula III in which Z 2 is a structural fragment of formula IV and X 1 and X 2 are N, as well as amines of formula XVIII, may be synthesised by adapting known strategies for preparing 1-aryl-5-aminopyrazoles.
  • arylhydrazine XX (in which W 2 is chloro, bromo or iodo, or a group that may be converted to C 1 alkylene-W 1 or C 2 alkylene-W 1 , such as C 1-2 alkylene-OH or C 0-1 alkylene-COOH) may be condensed with ⁇ -ketonitrile XXI to furnish aminopyrazole XXII bearing a substituted aryl group in the 1-position (WO 2011/124930; US 20070191336).
  • the desired amine III is then produced via a cross-coupling reaction—typically utilising a transition metal, such as palladium(II) (see, for example, Org. Lett. 2011, 13, 3270-3273 and WO 2009/143389) or nickel ( Bioorg. Med. Chem. Lett. 2009, 19, 2053-2058), catalyst—of XXII with phosphoryl compound XVII (as defined in Scheme 2) to generate the phosphoryl-aryl bond.
  • a transition metal such as palladium(II) (see, for example, Org. Lett. 2011, 13, 3270-3273 and WO 2009/143389) or nickel ( Bioorg. Med. Chem. Lett. 2009, 19, 2053-2058)
  • catalyst—of XXII with phosphoryl compound XVII as defined in Scheme 2 to generate the phosphoryl-aryl bond.
  • the W 2 group is converted to C 1 alkylene-W 1 or C 2 alkylene-W 1 , for example by reduction (e.g. using diborane or borane:THF) of C(O)OH or CH 2 C(O)OH to CH 2 OH or CH 2 CH 2 OH, respectively, followed by reaction of the resulting compound with a halogenating agent, such as thionyl chloride.
  • a halogenating agent such as thionyl chloride.
  • the appropriate C 1-2 alkylene-OH-containing hydrazines e.g., (3-hydrazinophenyl)methanol, are available from commercial sources.
  • Certain arylamines of formula III, in which Z 2 is a structural fragment of formula V, may be synthesised employing the route outlined in Scheme 5 (see, for example: WO 2003/072569; and WO 2008/046216), wherein R 4 , R 5 , A, A 1 , G and G 1 are as hereinbefore defined, LG 1 and LG 2 represent leaving groups, e.g., halogen or methanesulfonyl, and FG represents a real or latent NH 2 group, i.e., a group that is readily transformed into an NH 2 group, such as nitro or a protected variant NH—PG 2 , where PG 2 is a typical protecting group (see, for example: Greene, T.
  • the remaining halogen or methanesulfonyl substituents (LG 2 ) of the ether XXV is then displaced i) by an amine of formula VII in a second S N Ar reaction or (ii) via a Buchwald coupling (see, for example, WO 2009/017838) with an amine of formula VII to furnish the desired compound (when FG is NH 2 ), or XXVI (when FG is nitro or NH—PG 2 ).
  • the NH 2 group may be revealed by a reduction reaction, typically done through hydrogenation employing a suitable catalyst, e.g., palladium on carbon, or employing dissolving metal conditions, such as with iron in glacial acetic acid.
  • the NH 2 group may be revealed by a deprotection reaction. Although only depicted as taking place in the final step of the sequence, it should be noted that the unmasking of the latent NH 2 group represented by FG can take place at any stage in the synthetic route shown in Scheme 5.
  • compounds of formula VI may be synthesised by analogy with the compounds of formula I (see, for example, alternative processes (a) to (c) above).
  • compounds of formula VI can be prepared by reaction of a compound of formula IIx with a compound of formula IIIx, wherein the compounds of formulae IIx and IIIx take the same definitions as the compounds of formulae II and III, with the exception that one of Z 1 and Z 2 represents a structural fragment of formula IV, as hereinbefore defined, and the other of Z 1 and Z 2 represents a structural fragment of formula Va,
  • Novel intermediates as described herein form an aspect of the invention.
  • further aspects of the invention relate to:
  • the groups L, Ar, X 1 , X 2 , R 1 to R 5 , A, A 1 and LG 2 when present, take any of the definitions for those groups as hereinbefore defined.
  • Protected derivatives of the compound of formula IIa include esters (e.g. C 1-4 alkyl esters) thereof.
  • Protected derivatives of the compound of formula III include those in which the essential NH 2 group is protected.
  • such protected derivatives include amides or, particularly, carbamates of those compounds.
  • those protected derivatives include compounds in which a H-atom of the NH 2 group is replaced by:
  • the aspects of the invention described herein may have the advantage that, in the treatment of the conditions described herein, they may be more convenient for the physician and/or patient than, be more efficacious than, be less toxic than, have better selectivity over, have a broader range of activity than, be more potent than, produce fewer side effects than, have a better pharmacokinetic and/or pharmacodynamic profile than, have more suitable solid state morphology than, have better stability (e.g. long term stability) than, or may have other useful pharmacological properties over, similar compounds, combinations, methods (treatments) or uses known in the prior art for use in the treatment of those conditions or otherwise.
  • the compounds of the invention may additionally (or alternatively):
  • Analytical HPLC was carried out using an Agilent Zorbax Extend C18, Rapid Resolution HT 1.8 ⁇ m column eluting with a gradient of either 0.1% formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in 10 mM Ammonium Bicarbonate; a Waters Xselect CSH C18 3.5 ⁇ m eluting with a gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid. UV spectra of the eluted peaks were measured using either a diode array or variable wavelength detector on an Agilent 1100 system.
  • Analytical LCMS was carried out using an Agilent Zorbax Extend C18, Rapid Resolution HT 1.8 ⁇ m column eluting with a gradient of either 0.1% formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in 10 mM Ammonium Bicarbonate; a Waters Xselect CSH C18 3.5 ⁇ m eluting with a gradient of 0.1% formic acid in MeCN in 0.1% aqueous formic acid.
  • UV and mass spectra of the eluted peaks were measured using a variable wavelength detector on either an Agilent 1100 with or an Agilent Infinity 1260 LC with 6120 quadrupole mass spectrometer with positive and negative ion electrospray.
  • Preparative HPLC was carried out using an Agilent Prep-C18 5 ⁇ m Preparative Cartridge using either a gradient of either 0.1% formic acid in MeCN in 0.1% aqueous formic acid or a gradient of MeCN in 10 mM Ammonium Bicarbonate; or a Waters Xselect CSH C18 5 ⁇ m column using a gradient 0.1% MeCN in 0.1% aqueous formic acid. Fractions were collected following detection by UV at 254 nm.
  • 1 H NMR Spectroscopy 1 H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz. Either the central peaks of chloroform-d, dimethylsulfoxide-d 6 or an internal standard of tetramethylsilane were used as references.
  • p-TSA monohydrate (2.80 g, 14.72 mmol) was added to a stirred mixture of 4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-amine (see, for example, Cirillo, P. F. et al., WO 2002/92576, 21 Nov. 2000; 8 g, 29.4 mmol) and aniline (6.71 mL, 73.6 mmol) in THF (50 mL) at rt under N 2 . The mixture was heated under reflux for 2 h (reaction mixture solidified), a further 50 mL of THF was added and the mixture heated for a further 2 h.
  • reaction was duplicated then the reaction mixtures were quenched with acetic acid ( ⁇ 0.5 mL), combined and loaded onto SCX resin ( ⁇ 20 g), washing with methanol (4 CV) and then eluting with 1N NH 3 in MeOH (3 CV). Solvent removed under reduced pressure afforded 700 mg of a yellow oil.
  • the crude product was purified by chromatography on the Companion (40 g column, 0-10% MeOH in DCM) to afford the sub-title compound (300 mg) as a pale yellow foam.
  • the product was further purified by preparative HPLC (Waters acidic method: Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 30-60% MeCN in Water 0.1% Formic Acid) to afford the title compound (90 mg) as a white powder.
  • preparative HPLC Waters acidic method: Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 30-60% MeCN in Water 0.1% Formic Acid
  • CDI (198 mg, 1.221 mmol) was added to a stirred solution of the product from step (i) above (348 mg, 1.183 mmol) in DCM (5 mL) at rt under N 2 and the mixture stirred for 18 h.
  • CDI (270 mg, 1.666 mmol) was dissolved in DCM (5 mL) and the product from step (i) above (440 mg, 1.587 mmol) in DCM (5 mL) added in one portion and the reaction mixture stirred for 16 h.
  • 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see Example 1(i) above; 391 mg, 1.190 mmol) was added in one portion.
  • the product had precipitated from reaction mixture and was filtered off. The solid was washed with ice cold DCM (2 mL), dried to give the product (300 mg) as a colourless solid.
  • Liquors were purified by chromatography on the Companion (40 g column, DCM to 10% MeOH: DCM) to afford a second batch (220 mg). Batches were combined to afford the title compound (520 mg).
  • reaction was cooled to ambient temperature and filtered on Glass fibre pad (Whatmans GF/C), solvents evaporated and the residue was preadsorbed onto silica (ca. 4 g) and purified by chromatography on the Companion (12 g column, DCM to 10% MeOH:DCM) to afford the sub-title compound (250 mg) as a brown solid.
  • step (ii) above 250 mg, 0.686 mmol was dissolved in ethanol (2 mL), 2N NaOH (514 ⁇ L, 1.029 mmol) added and stirred for 72 h. Solvent evaporated and the residue partitioned between water (10 mL) and EtOAc (10 mL). Aqueous separated and acidified with 1N HCl. Product extracted with EtOAc (2 ⁇ 10 mL), organics bulked and washed with 20% w/w brine (10 mL). Organic layer separated, dried (MgSO 4 ) filtered and solvent evaporated to give the sub-title compound (220 mg) as a pale yellow solid.
  • DPPA (138 ⁇ L, 0.639 mmol) was added to a stirred solution of the product from step (iii) above (215 mg, 0.639 mmol) and Et 3 N (223 ⁇ L, 1.598 mmol) in DMF (7 mL) under N 2 at 0-5° C. After 30 min the mixture was warmed to rt and stirred for a further 1 h. 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see Example 1(i) above; 199 mg, 0.607 mmol) was added and the mixture heated at 100° C. for 1 h.
  • reaction was cooled to ambient temperature and filtered on Glass fibre pad (Whatmans GF/C), solvents removed under reduced pressure. Residue was preadsorbed onto silica (ca. 4 g) and purified by chromatography on the Companion 40 g column, 5% MeOH:DCM to 10% MeOH:DCM) to afford the sub-title compound (175 mg) as a beige foam.
  • CDI (26.8 mg, 0.165 mmol) was dissolved in DCM (1 mL) and the product from step (i) above (50 mg, 0.158 mmol) added in one portion. Stirred for 16 h, then 4-((4-aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see Example 1(i) above; 12.93 mg, 0.039 mmol) added and stirring continued for 2 h. Solvent was evaporated and the crude product was purified by chromatography on the Companion (4 g column, DCM to 10% MeOH:DCM) to afford a light tan solid (19 mg), which was purified by recrystallising from MeCN (1 mL) to give the title compound (10 mg).
  • CDI (237 mg, 1.459 mmol) was added to a stirred solution of (3-(5-amino-3-(tert-butyl)-1H-pyrazol-1-yl)phenyl)dimethylphosphine oxide (see Example 2(i) above; 425 mg, 1.459 mmol) in DCM (5 mL) at rt. The mixture was stirred for 18 h then a solution of 4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-amine (see, for example, Cirillo, P. F. et al., WO 2002/92576, 21 Nov.
  • the crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 25-70% MeCN in Water) and then purified on SCX (5 g, loading in MeOH/THF (2 mL)) washed with MeOH (15 mL) and eluted with 0.7 N ammonia in MeOH (10 mL) to afford the title compound (20 mg) as a pale yellow solid.
  • the solid was dissolved in 1:1 MeOH/THF and dry loaded onto silica then purified by chromatography on silica gel (12 g column, 0-10% MeOH in DCM) to afford a green solid.
  • the solid was dissolved in THF and isohexane added until the product precipitated. The solid was filtered, washed with isohexane and transferred to the vacuum oven overnight to afford the title compound (26 mg) as an off-white solid.
  • the crude product was purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 5-95% MeCN in Water) to afford a cream solid which was loaded onto a column of SCX (5 g) in MeOH. The column was washed with MeOH (15 mL) and then the product was eluted with 0.7 M ammonia in MeOH (15 mL). The resultant mixture was concentrated in vacuo to afford the title compound (60 mg) as a cream powder.
  • preparative HPLC Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 5-95% MeCN in Water
  • the crude product was purified by preparative HPLC (Varian, Acidic (0.1% Formic acid), Agilent Prep C-18, 5 ⁇ m, 21.2 ⁇ 50 mm column, 5-95% MeCN in Water) to afford a pink solid.
  • the solid was triturated with acetonitrile to yield the title compound (45 mg) as a pale pink solid.
  • step (i) above 500 mg, 1.424 mmol
  • Xantphos 82 mg, 0.142 mmol
  • palladium(II) acetate 15.98 mg, 0.071 mmol
  • K 3 PO 4 .H 2 O 332 mg, 1.424 mmol
  • Diethylphosphine oxide (181 mg, 1.708 mmol) was dissolved in degassed anhydrous DMF (40 mL), the reactants were combined under nitrogen and heated at 150° C. in a microwave (300 W) for 40 min.
  • step (ii) above (420 mg, 1.116 mmol) was dissolved in ethanol (5 mL) and NaOH, 2N (837 ⁇ L, 1.674 mmol) added. Stirred at rt for 16 h, then the solvent was evaporated and the residue partitioned between EtOAc (20 mL) and water (20 mL). Aqueous separated and acidified with conc. HCl to pH 1. Product was extracted with ethyl acetate (2 ⁇ 20 mL), organics combined, dried (MgSO 4 ) filtered and solvent evaporated to give the sub-title compound (372 mg) as a colourless solid.
  • DPPA (217 ⁇ L, 1.005 mmol) was added to a stirred solution of the product from step (iii) above (350 mg, 1.005 mmol) and Et 3 N (350 ⁇ L, 2.51 mmol) in DMF (4 mL) at 0-5° C. After 30 min the mixture was warmed to rt and stirred for a further 1 h. 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see Example 1(i) above; 313 mg, 0.954 mmol) was added and the mixture heated at 100° C. for 1 h, cooled and partitioned between EtOAc (100 mL) and water (50 mL).
  • the suspension was extracted with EtOAc (3 ⁇ 10 mL) and the combined organic phases were concentrated onto loose silica.
  • the silicate was purified by chromatography on the Companion (40 g column, 0-5% CH 3 OH:CH 2 Cl 2 ) to afford the sub-title compound (175 mg) as a colourless gum.
  • DPPA (90 ⁇ L, 0.419 mmol) was added to a stirred solution of the product from step (iv) above (140 mg, 0.419 mmol) and Et 3 N (146 ⁇ L, 1.047 mmol) in DMF (10 mL) under N 2 at 0-5° C. After 30 min the mixture was warmed to rt and stirred for a further 1 h. 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see Example 1(i) above; 137 mg, 0.419 mmol) was added and the mixture heated at 100° C. for 1 h.
  • the crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH) to afford a solid (143 mg) at 81% purity.
  • the solid was triturated with ether to afford the title compound (23 mg) as a light tan solid.
  • the mixture was diluted with water (10 mL) and the precipitate was collected by filtration.
  • the solid was triturated in acetonitrile and collected by filtration.
  • the solid was triturated two further times in methanol and collected by filtration to afford the title compound (75 mg, 0.113 mmol, 39.6% yield) as a solid.
  • 2-Morpholinoethanamine (0.911 mL, 6.94 mmol) was added to an ice cold suspension of T3P (2.76 mL, 4.63 mmol), 3-amino-5-bromobenzoic acid (1 g, 4.63 mmol) and TEA (1.936 mL, 13.89 mmol) in DCM (20 mL). Allowed to warm to room temperature and stirred overnight. More T3P (2.76 mL, 4.63 mmol) and 2-morpholinoethanamine (0.911 mL, 6.94 mmol) were added and stirred for a further 1 h.
  • Pd(PPh 3 ) 4 (176 mg, 0.152 mmol) was added to a degassed suspension of the product from step (i) above (500 mg, 1.523 mmol), copper(I) iodide (29.0 mg, 0.152 mmol), and ethynyltriisopropylsilane (0.513 mL, 2.285 mmol) in TEA (3 mL) and DMF (3 mL), heated at 80° C. (block temp.) for 1 h then cooled, filtered on Celite and solvents evaporated. The crude product was purified by chromatography on the Companion (12 g column, 5% MeOH:DCM to 10%) to afford the sub-title compound (600 mg) as a pale yellow gum.
  • step (ii) above 500 mg, 1.164 mmol was dissolved in THF (5 mL) and TBAF (1164 ⁇ L, 1.164 mmol) added and stirred for 1 h. TBAF (1164 ⁇ L, 1.164 mmol) added again and stirred for 30 min. Reaction partitioned between water (10 mL) and ethyl acetate (10 mL), organic layer separated and washed with 20% w/w NaCl solution. Organic layer separated, dried (MgSO 4 ) filtered and evaporated. The crude product was purified by chromatography on the Companion (12 g column, 2% MeOH:DCM to 5%) to afford the sub-title compound (260 mg) as a colourless gum.
  • the precipitate was collected by filtration and washed with water (15 mL) to yield a dark solid.
  • the crude product was purified by chromatography on the Companion (40 g column, DCM:MeOH:ammonia, 90:9:1) to afford a pink solid.
  • the solid was triturated in acetonitrile to afford the title compound (125 mg) as a pale pink solid.
  • step (i) above 165 mg, 0.425 mmol was dissolved in ethanol (2 mL) and 2 M NaOH (255 ⁇ L, 0.510 mmol) added and stirred for 4 h. Solvents were evaporated and the residue partitioned between water (5 mL) and EtOAc (5 mL), aqueous layer separated and acidified to pH 1 with conc. HCl. The product was extracted into EtOAc (5 mL). Organic layer separated, dried (MgSO 4 ) filtered and solvent evaporated to the sub-title compound (150 mg) as a colourless gum.
  • DPPA (90 ⁇ L, 0.416 mmol) was added to a solution of the product from step (ii) above (150 mg, 0.416 mmol) and TEA (145 ⁇ L, 1.041 mmol) in DMF (3 mL). Stirred at rt for 1 h before addition of 4-((4-aminonaphthalen-1-yl)oxy)-N-phenylpyridin-2-amine (see Example 41(i) above; 129 mg, 0.395 mmol). Heated at 100° C. for 2 h.
  • the brown oil was further purified by preparative HPLC (Waters, Acidic (0.1% Formic acid), Waters X-Select Prep-C18, 5 ⁇ m, 19 ⁇ 50 mm column, 25-70% MeCN in Water) to afford the title compound (41 mg) as a cream glass.
  • step (i) above 450 mg, 1.749 mmol was dissolved in ethanol (8 mL) and iron powder (977 mg, 17.49 mmol) added followed by a solution of ammonium chloride (936 mg, 17.49 mmol) in water (4 mL). Heated at 60° C. in a sonic bath for 1 h. Filtered on glass fibre pad (Whatman GF/A) and solvent evaporated until a thick beige precipitate formed which was filtered and washed with water. Oven dried to give the sub-title compound (337 mg) as a pale yellow solid.
  • DPPA (0.771 mL, 3.58 mmol) was added to a stirred solution of the product from step (ii) above (800 mg, 2.386 mmol) and triethylamine (0.998 mL, 7.16 mmol) in tert-butanol (10 mL) and heated to reflux for 18 h. The mixture was cooled, water (50 mL) added and extracted with ethyl acetate (3 ⁇ 50 mL). The combined organic phases were washed with saturated brine (25 mL), dried (MgSO 4 ) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (40 g column, EtOAc) to afford the sub-title compound (586 mg).
  • step (iii) above (580 mg, 1.356 mmol) was stirred in 5 M HCl solution in isopropanol (5 mL) at rt for 18 h. The volatiles were removed under reduced pressure and the residue was co-evaporated with acetonitrile ⁇ 3 to yield the sub-title compound (520 mg) as a white foam.
  • DPPA (78 ⁇ L, 0.360 mmol) was added to a stirred solution of 1-(3-((dimethylphosphoryl)methyl)phenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (see Example 37(iv) above; 105 mg, 0.327 mmol) and Et 3 N (114 ⁇ L, 0.818 mmol) in DMF (1.5 mL) at 0-5° under N 2 . The mixture was warmed to rt and stirred for 1 h. A solution of the product from step (i) above (210 mg, 0.327 mmol) in DMF (1 mL) was added and the mixture heated at 100° C.
  • DPPA (97 ⁇ L, 0.452 mmol) was added to a stirred solution of 1-(3-((dimethylphosphoryl)methyl)phenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid (see Example 37(iv) above; 132 mg, 0.411 mmol) and Et 3 N (143 ⁇ L, 1.028 mmol) in DMF (1.5 mL) at 0-5° under N 2 . The mixture was warmed to rt and stirred for 1 h. A solution of the product from step (i) above (200 mg, 0.411 mmol) in DMF (1 mL) was added and the mixture heated at 100° C.
  • step (i) above (363 mg, 1.099 mmol) was dissolved in ethanol (3 mL) and Pd-C, 10% (58.5 mg, 0.055 mmol) added. Stirred under hydrogen for 1 h then filtered and solvents evaporated to give the sub-title compound (300 mg) as a colourless oil.
  • DPPA 105 ⁇ L, 0.486 mmol
  • 1-(3-((dimethylphosphoryl)methyl)phenyl)-3-isopropyl-1H-pyrazole-5-carboxylic acid see Example 37(iv) above; 108 mg, 0.324 mmol
  • triethylamine 113 ⁇ L, 0.809 mmol
  • the mixture was allowed to warm to rt then stirred for 40 min.
  • the product from step (iv) above (276 mg, 0.486 mmol) was added and the mixture heated at 100° C. for 1 h.
  • the crude product was loaded onto a column of SAX (Discovery® DSC-SAX, a polymer-bound quaternary amine) in MeOH.
  • SAX Discovery® DSC-SAX, a polymer-bound quaternary amine
  • the column was washed with MeOH and then the product was eluted with 5% AcOH in MeOH.
  • the resultant mixture was concentrated in vacuo then loaded onto a column of SCX in MeOH.
  • the column was washed with MeOH and then the product was eluted with 0.7 M ammonia in MeOH.
  • the resultant mixture was concentrated in vacuo to afford the sub-title compound (450 mg) as a yellow powder.
  • the enzyme inhibitory activities of compounds disclosed herein are determined by FRET using synthetic peptides labelled with both donor and acceptor fluorophores (Z-LYTE, Invitrogen Ltd., Paisley, UK).
  • the following two assay variants can be used for determination of p38 MAPK ⁇ inhibition.
  • the inhibitory activities of test compounds against the p38 MAPK ⁇ isoform are evaluated indirectly by determining the level of activation/phosphorylation of the down-stream molecule, MAPKAP-K2.
  • the p38 MAPK ⁇ protein (80 ng/mL, 2.5 ⁇ L) is mixed with the test compound (2.5 ⁇ L of either 4 ⁇ g/mL, 0.4 ⁇ g/mL, 0.04 ⁇ g/mL or 0.004 ⁇ g/mL) for 2 hr at RT.
  • the mix solution (2.5 ⁇ L) of the p38 ⁇ inactive target MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 ⁇ M; a phosphorylation target for MAPKAP-K2) is then added and the kinase reaction is initiated by adding ATP (40 ⁇ M, 2.5 ⁇ L).
  • the mixture is incubated for 1 hr at RT.
  • Development reagent prote, 5 ⁇ L
  • This method follows the same steps as Method 1 above, but utilises a higher concentration of the p38 MAPK ⁇ protein (2.5 ⁇ L of 200 ng/mL protein instead of 2.5 ⁇ L of 80 ng/mL protein) for mixing with the test compound.
  • the inhibitory activities of compounds of the invention against p38MAPK ⁇ are evaluated in a similar fashion to that described hereinabove.
  • the enzyme (800 ng/mL, 2.5 ⁇ L) is incubated with the test compound (2.5 ⁇ L at either 4 ⁇ g/mL, 0.4 ⁇ g/mL, 0.04 ⁇ g/mL, or 0.004 ⁇ g/mL) for 2 hr at RT.
  • the FRET peptides (8 ⁇ M, 2.5 ⁇ L), and appropriate ATP solution (2.5 ⁇ L, 400 ⁇ M) is then added to the enzymes/compound mixtures and incubated for 1 hr.
  • Development reagent (protease, 5 ⁇ L) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, Thermo Scientific).
  • the inhibitory activities of compounds of the invention against c-Src and Syk enzymes are evaluated in a similar fashion to that described hereinabove.
  • the relevant enzyme (3000 ng/mL or 2000 ng/mL respectively, 2.5 ⁇ L) is incubated with the test compound (either 4 ⁇ g/mL, 0.4 ⁇ g/mL, 0.04 ⁇ g/mL, or 0.004 ⁇ g/mL, 2.5 ⁇ L each) for 2 hr at RT.
  • the FRET peptides (8 ⁇ M 2.5 ⁇ L), and appropriate ATP solutions (2.5 ⁇ L, 800 ⁇ M for c-Src, and 60 ⁇ M ATP for Syk) are then added to the enzymes/compound mixtures and incubated for 1 hr. Development reagent (protease, 5 ⁇ L) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific).
  • the following two assay variants can be used for determination of GSK 3 ⁇ inhibition.
  • Method 1 The inhibitory activities of compounds of the invention against the GSK 3 ⁇ enzyme isoform (Invitrogen), are evaluated by determining the level of activation/phosphorylation of the target peptide.
  • the GSK3- ⁇ protein 500 ng/mL, 2.5 ⁇ L
  • the test compound 2.5 ⁇ L at either 4 ⁇ g/mL, 0.4 ⁇ g/mL, 0.04 ⁇ g/mL, or 0.004 ⁇ g/mL
  • 2 hr at RT is a test compound for 2 hr at RT.
  • the FRET peptide (8 ⁇ M, 2.5 ⁇ L), which is a phosphorylation target for GSK3 ⁇ , and ATP (40 ⁇ M, 2.5 ⁇ L) are then added to the enzyme/compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 ⁇ L) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific).
  • the site-specific protease cleaves non-phosphorylated peptide only and eliminates the FRET signal.
  • Phosphorylation levels of each reaction are calculated using the ratio of coumarin emission (donor) over fluorescein emission (acceptor), for which high ratios indicate high phosphorylation and low ratios indicate low phosphorylation levels.
  • the percentage inhibition of each reaction is calculated relative to non-inhibited control and the 50% inhibitory concentration (IC 50 value) is then calculated from the concentration-response curve.
  • This method follows the same steps as Method 1 above, but utilises a shorter period of mixing of the test compound (105 minutes instead of 2 hours) with the GSK3- ⁇ protein.
  • the compounds of the invention were studied using one or more of the following assays.
  • U937 cells a human monocytic cell line
  • macrophage-type cells by incubation with phorbol myristate acetate (PMA; 100 ng/mL) for 48 to 72 hr.
  • PMA phorbol myristate acetate
  • Cells are pre-incubated with final concentrations of test compound for 2 hr and are then stimulated with 0.1 ⁇ g/mL of LPS (from E. Coli : O111:B4, Sigma) for 4 hr.
  • LPS from E. Coli : O111:B4, Sigma
  • the supernatant is collected for determination of TNF ⁇ and IL-8 concentrations by sandwich ELISA (Duo-set, R&D systems).
  • the inhibition of TNF ⁇ production is calculated as a percentage of that achieved by 10 ⁇ g/mL of BIRB796 at each concentration of test compound by comparison against vehicle control.
  • the relative 50% effective concentration (REC 50 ) is determined from the resultant concentration-response curve.
  • the inhibition of IL-8 production is calculated at each concentration of test compound by comparison with vehicle control.
  • the 50% inhibitory concentration (IC 50 ) is determined from the resultant concentration-response curve.
  • PBMCs Peripheral blood mononuclear cells
  • PBMCs Peripheral blood mononuclear cells
  • the PBMCs are seeded in 96 well plates and treated with compounds at the desired concentration for 2 hours before addition of 1 ng/mL LPS ( Escherichia Coli 0111:B4 from Sigma Aldrich) for 24 hours under normal tissue culture conditions (37° C., 5% CO 2 ).
  • LPS Escherichia Coli 0111:B4 from Sigma Aldrich
  • the supernatant is harvested for determination of IL-8 and TNF ⁇ concentrations by sandwich ELISA (Duo-set, R&D systems) and read on the fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific).
  • the concentration at 50% inhibition (IC 50 ) of IL-8 and TNF ⁇ production is calculated from the dose response curve.
  • PBMCs from healthy subjects are separated from whole blood using a density gradient (Lymphoprep, Axis-Shield Healthcare). Cells are added to a 96 well plate pre-coated with a mixture of CD3/CD38 monoclonal antibodies (0.3 ⁇ g/mL eBioscience and 3 ⁇ g/mL BD Pharmingen respectively). Compound at the desired concentration is then added to the wells and the plate left for 3 days under normal tissue culture conditions. Supernatants are harvested and IL-2 and IFN gamma release determined by Sandwich ELISA (Duo-set, R&D System). The IC 50 is determined from the dose response curve.
  • HT29 cells a human colon adenocarcinoma cell line
  • IL-1 ⁇ IL-1 ⁇
  • supernatants are harvested for IL-8 quantification by Sandwich ELISA (Duo-set, R&D System). The IC 50 is determined from the dose response curve.
  • PBMCs from healthy subjects are separated from whole blood using a density gradient (Lymphoprep, Axis-Shield Healthcare). Cells are incubated for 2 hrs and non-adherent cells removed by washing. To differentiate the cells to macrophages the cells are incubated with 5 ng/mL of GM-CSF (Peprotech) for 7 days under normal tissue culture conditions. Compounds are then added to the cells at the desired concentration for a 2 hour pre-treatment before stimulation with 10 ng/mL LPS for 24 hours. Supernatants are harvested and IL-8 and TNF ⁇ release determined by Sandwich ELISA (Duo-set, R&D System). The IC 50 is determined from the dose response curve.
  • Poly I:C is used in these studies as a simple, RNA virus mimic.
  • Poly I:C-Oligofectamine mixture (1 ⁇ g/mL Poly I:C, ⁇ 2% Oligofectamine, 25 ⁇ L; Invivogen Ltd., San Diego, Calif., and Invitrogen, Carlsbad, Calif., respectively) is transfected into BEAS2B cells (human bronchial epithelial cells, ATCC). Cells are pre-incubated with final concentrations of test compounds for 2 hr and the level of ICAM1 expression on the cell surface is determined by cell-based ELISA.
  • the cells are washed with PBS-Tween (3 ⁇ 200 ⁇ L) and incubated with the secondary antibody (100 ⁇ L; HRP-conjugated anti-rabbit IgG, Dako Ltd., Glostrup, Denmark). The cells are then incubated with of substrate (50 ⁇ L) for 2-20 min, followed by the addition of stop solution (50 ⁇ L, 1N H 2 SO 4 ).
  • the ICAM-1 signal is detected by reading the absorbance at 450 nm against a reference wavelength of 655 nm using a spectrophotometer.
  • the cells are then washed with PBS-Tween (3 ⁇ 200 ⁇ L) and total cell numbers in each well are determined by reading absorbance at 595 nm after Crystal Violet staining (50 ⁇ L of a 2% solution in PBS) and elution by 1% SDS solution (100 ⁇ L) in distilled water.
  • the measured OD 450-655 readings are corrected for cell number by dividing with the OD595 reading in each well.
  • the inhibition of ICAM-1 expression is calculated at each concentration of test compound by comparison with vehicle control.
  • the 50% inhibitory concentration (IC 50 ) is determined from the resultant concentration-response curve.
  • PBMCs Peripheral blood mononucleocytes from healthy subjects are separated from whole blood (Quintiles, London, UK) using a density gradient (Histopaque®-1077, Sigma-Aldrich, Poole, UK).
  • the PBMCs (3 million cells per sample) are subsequently treated with 2% PHA (phytohaemagglutinin, Sigma-Aldrich, Poole, UK) for 48 hr, followed by a 20 hr exposure to varying concentrations of test compounds.
  • PHA phytohaemagglutinin, Sigma-Aldrich, Poole, UK
  • demecolcine 0.1 ⁇ g/mL; Invitrogen, Paisley, UK
  • PBMCs are permeabilised and fixed by adding Intraprep (50 ⁇ L; Beckman Coulter, France), and stained with anti-phospho-histone 3 (0.26 ng/L; #9701; Cell Signalling, Danvers, Mass.) and propidium iodide (1 mg/mL; Sigma-Aldrich, Poole, UK) as previously described (Muehlbauer P. A. and Schuler M. J., Mutation Research , 2003, 537:117-130). Fluorescence is observed using an ATTUNE flow cytometer (Invitrogen, Paisley, UK), gating for lymphocytes. The percentage inhibition of mitosis is calculated for each treatment relative to vehicle (0.5% DMSO) treatment.
  • Human rhinovirus RV16 is obtained from the American Type Culture Collection (Manassas, Va.). Viral stocks are generated by infecting Hela cells with HRV until 80% of the cells are cytopathic.
  • BEAS2B cells are infected with HRV at an MOI of 5 and incubated for 2 hr at 33° C. with gentle shaking for to promote absorption. The cells are then washed with PBS, fresh media added and the cells are incubated for a further 72 hr. The supernatant is collected for assay of IL-8 concentrations using a Duoset ELISA development kit (R&D systems, Minneapolis, Minn.).
  • the level of ICAM1 expressing cell surface is determined by cell-based ELISA.
  • cells are fixed with 4% formaldehyde in PBS. After quenching endogenous peroxidase by adding 0.1% sodium azide and 1% hydrogen peroxide, wells are washed with wash-buffer (0.05% Tween in PBS: PBS-Tween). After blocking well with 5% milk in PBS-Tween for 1 hr, the cells are incubated with anti-human ICAM-1 antibody in 5% BSA PBS-Tween (1:500) overnight. Wells are washed with PBS-Tween and incubated with the secondary antibody (HRP-conjugated anti-rabbit IgG, Dako Ltd.).
  • the ICAM-1 signal is detected by adding substrate and reading at 450 nm with a reference wavelength of 655 nm using a spectrophotometer.
  • the wells are then washed with PBS-Tween and total cell numbers in each well are determined by reading absorbance at 595 nm after Crystal Violet staining and elution by 1% SDS solution.
  • the measured OD 450-655 readings are corrected for cell number by dividing with the OD 595 reading in each well.
  • Compounds are added 2 hr before HRV infection and 2 hr after infection when non-infected HRV is washed out.
  • MRC-5 cells are infected with HRV16 at an MOI of 1 in DMEM containing 5% FCS and 1.5 mM MgCl 2 , followed by incubation for 1 hr at 33° C. to promote adsorption. The supernatants are aspirated, and then fresh media added followed by incubation for 4 days. Where appropriate, cells are pre-incubated with compound or DMSO for 2 hr, and the compounds and DMSO added again after washout of the virus.
  • Supernatants are aspirated and incubated with methylene blue solution (100 ⁇ L, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2 hr at RT. After washing, 1% SDS in distilled water (100 ⁇ L) is added to each well, and the plates are shaken lightly for 1-2 hr prior to reading the absorbance at 660 nm. The percentage inhibition for each well is calculated. The IC 50 value is calculated from the concentration-response curve generated by the serial dilutions of the test compounds.
  • Normal human bronchial epithelial cells grown in 96 well plates are infected with RSV A2 (Strain A2, HPA, Salisbury, UK) at an MOI of 0.001 in the LHC8 Media:RPMI-1640 (50:50) containing 15 mM magnesium chloride and incubated for 1 hr at 37° C. for adsorption. The cells are then washed with PBS (3 ⁇ 200 ⁇ L), fresh media (200 ⁇ L) is added and incubation continued for 4 days. Where appropriate, cells are pre-incubated with the compound or DMSO for 2 hr, and then added again after washout of the virus.
  • the cells are fixed with 4% formaldehyde in PBS solution (50 ⁇ L) for 20 min, washed with WB (3 ⁇ 200 ⁇ L), (washing buffer, PBS including 0.5% BSA and 0.05% Tween-20) and incubated with blocking solution (5% condensed milk in PBS) for 1 hr. Cells are then washed with WB (3 ⁇ 200 ⁇ L) and incubated for 1 hr at RT with anti-RSV (2F7) F-fusion protein antibody (40 ⁇ L; mouse monoclonal, lot 798760, Cat. No. ab43812, Abcam) in 5% BSA in PBS-tween.

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