WO2014162126A1 - Urea derivatives useful as kinase inhibitors - Google Patents

Urea derivatives useful as kinase inhibitors Download PDF

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Publication number
WO2014162126A1
WO2014162126A1 PCT/GB2014/051022 GB2014051022W WO2014162126A1 WO 2014162126 A1 WO2014162126 A1 WO 2014162126A1 GB 2014051022 W GB2014051022 W GB 2014051022W WO 2014162126 A1 WO2014162126 A1 WO 2014162126A1
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WO
WIPO (PCT)
Prior art keywords
methoxy
ethoxy
oxy
tert
butyl
Prior art date
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PCT/GB2014/051022
Other languages
French (fr)
Inventor
Matthew Colin Thor Fyfe
Stephen Malcolm THOM
Thomas Matthew Baker
Gareth William Harbottle
Vedran Hasimbegovic
Premji Meghani
Aaron Rigby
Colin Sambrook-Smith
Original Assignee
Respivert Limited
Topivert Pharma Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Priority claimed from GB201305945A external-priority patent/GB201305945D0/en
Priority claimed from GBGB1322678.2A external-priority patent/GB201322678D0/en
Priority claimed from GB201402647A external-priority patent/GB201402647D0/en
Priority to ES14716378T priority Critical patent/ES2856902T3/en
Priority to CN201480031484.4A priority patent/CN105246884B/en
Priority to AU2014246870A priority patent/AU2014246870C1/en
Priority to MX2015013945A priority patent/MX363950B/en
Priority to CA2907663A priority patent/CA2907663A1/en
Application filed by Respivert Limited, Topivert Pharma Limited filed Critical Respivert Limited
Priority to BR112015024671A priority patent/BR112015024671A2/en
Priority to DK14716378.6T priority patent/DK2981535T3/en
Priority to EA201591906A priority patent/EA030483B1/en
Priority to KR1020157031287A priority patent/KR102283876B1/en
Priority to EP14716378.6A priority patent/EP2981535B8/en
Priority to JP2016505888A priority patent/JP6495238B2/en
Publication of WO2014162126A1 publication Critical patent/WO2014162126A1/en

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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
  • Smith describes the inhibitory effect of p38 MAP kinase inhibitors on TNFa (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 A56) demonstrates that silencing p38 MAPK ⁇ 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.
  • p38 MAPK inhibitors have also been described as inhibitors of replication of respiratory syncytial virus (Cass L. et al., WO 2011/158039).
  • 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.
  • p38 has become an obvious target for investigation in IBD models as a consequence of its ubiquitous expression in inflammatory cells.
  • T cells are known to play a 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 (IFNg/IL-2) or Th2 (IL5/ TGFb) biased depending on whether the patient had Crohn's disease or ulcerative colitis (Fuss IJ. 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 Bechets patients (Chi W. et al. Invest Ophthalmol Vis Sci. 2008 49:3058-64). In support of these observations, Direskeneli and colleagues demonstrated that Bechets patients have increased Th17 cells and decreased Treg cells in their peripheral blood (Direskeneli H. et al. J Allergy Clin Immunol. 201 1 128:665-6).
  • 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 EK. 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 AC. 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 motifs (ITAM), 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 motifs
  • Syk activation leads to IL-6 and MMP release - inflammatory mediators commonly found upregulated in inflammatory disorders including IBD and rheumatoid arthritis (Wang YD. et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al. Cytokine. 2006 Jan 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 “Olaharski kinases”) have been found to alter the frequency of micronucleus formation in vitro (Olaharski, A. J. et al., PLoS Comput. Biol., 2009, 5(7), e1000446; doi: 10.1371/journal.pcbi.1000446).
  • Micronucleus formation is implicated in, or associated with, disruption of mitotic processes and is therefore undesirable.
  • Inhibition of glycogen synthase kinase 3a was found to be a particularly significant factor that increases the likelihood of a kinase inhibitor promoting micronucleus formation.
  • inhibition of the kinase ⁇ 8 ⁇ 3 ⁇ with RNAi has been reported to promote micronucleus formation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34).
  • Examples of such compounds may be found in WO 99/23091 , WO 00/041698, WO 00/043384, WO 00/055139, WO 01/36403, WO 01/4115, WO 02/083628, WO 02/083642, WO 02/092576, WO 02/096876, WO 2003/005999, WO 2003/068223, WO 2003/068228, WO 2003/072569, WO 2004/014870, WO 2004/113352, WO 2005/005396, WO 2005/018624, WO 2005/023761 , WO 2005/044825, WO 2006/015775, WO 2006/043090, WO 2007/004749 and WO 2007/053394. Further examples may be found in articles published in:
  • R represents
  • Ci_6 alkyl C 2 _6 alkenyl, C 2 _6 alkynyl, d -6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, and Ci_ 2 alkoxy,
  • A represents O, S or N(R A2 ),
  • R represents H, Ci -4 alkyl or hydroxy
  • R A2 represents H or Ci -4 alkyl
  • R B represents H, halo, cyano, -Ci. 4 alkylene-CN, -Ci. 4 alkylene-OH, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR X2 S(0) 2 NR x R Y , -NR x P(0)R Y R Y2 , -NR x C(0)OR Y or Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
  • R x and R X independently represent H or Ci_ 6 alkyl, or R x and R X together represent C 3 . 6 n- alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-, or R X represents Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
  • R Y , R Y and R Y2 independently represent Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, benzyl, Het 1 or Het 2 , which latter six groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci. 2 alkoxy, NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH and C(0)0-(Ci-4 alkyl),
  • R Y represents H
  • R x and R Y together represent C 3 . 6 n-alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
  • each R X2 independently represents H or Ci_ 4 alkyl
  • R C and R E independently represent H, halo, cyano or methyl; provided that at least one of R A , R B , R C and R E is other than H;
  • R D represents trimethylsilyl, C 2 _ 7 alkyl, C 2 _ 7 alkenyl, C 2 _ 7 alkynyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter seven groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, cyano, hydroxy and Ci_ 2 alkoxy;
  • R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from Ci_ 3 alkyl, Ci_ 3 haloalkyl, cyano and halo,
  • R 2 and R 3 represents H, halo, cyano, Ci_ 3 alkyl or Ci_ 3 haloalkyl and the other independently represents halo, cyano, Ci_ 3 alkyl or Ci_ 3 haloalkyl,
  • R 2 and R 3 together combine to form C 3 . 5 alkylene or C 3 . 5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from Ci_ 3 alkyl, Ci- 3 haloalkyl, cyano and halo;
  • X 1 represents N or CH
  • L represents a direct bond or Ci_ 2 alkylene
  • X 2 and X 3 both represent CR Z or one of X 2 and X 3 represents N and the other represents CR Z ;
  • R z represents hydrogen, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
  • R 4 represents
  • R 4 may alternatively represent H, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
  • R 5 represents Ci_ 3 alkoxy or Ci_ 3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R 5 represents H, cyano, -C(0)NH 2 , hydroxy, halo or C 2 - 3 alkynyl;
  • R 6a represents OR 7a , N(R 7 )R 7c or C0 2 H;
  • R 6 represents Ci_ 8 alkyl, C 3 . 8 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxyl, Ci_ 3 alkyl and Ci- 3 alkoxy;
  • R 6c and R 6d independently represent H or methyl;
  • R 7a to R 7c independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R 7 and R 7c , together with the N-atom to which they are attached, form a 4- to 7- membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N , and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, Ci_ 4 alkyl and Ci_ 4 alkoxy;
  • Q and Q 2 independently represent C(0)NH, O or S(0) p ;
  • n and p independently represent 0, 1 or 2
  • Het 1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; Het 2 represents, independently upon each occurrence, a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or more heteroatoms selected from N , O and S; or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, which compounds may be referred to hereinafter as "the compounds of the invention”.
  • 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:
  • the compound of formula I is isotopically enriched or labelled with respect to one or more atoms of the compound.
  • 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. In particular embodiments of the invention, 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.
  • heterocyclic groups represented by N(R 7 )R 7c may be attached to any appropriate atoms in the heterocyclic ring including, where valencies allow, to C-, N- and/or S- atoms within the ring (thereby forming keto, N-oxide, S(O) and/or S(0) 2 groups).
  • Het 1 values include oxadiazolyl (e.g. 1 ,3,4-oxadiazol-2-yl), pyrimidinyl (e.g. pyrimidin-2-yl) and triazolyl (e.g. 1 ,2,3-triazol-4-yl).
  • oxadiazolyl e.g. 1 ,3,4-oxadiazol-2-yl
  • pyrimidinyl e.g. pyrimidin-2-yl
  • triazolyl e.g. 1 ,2,3-triazol-4-yl
  • Het 2 examples include morpholinyl (e.g. morpholin-4-yl), oxetanyl (e.g. 3-oxetanyl) and tetrahydropyranyl (e.g. 4-tetrahydropyranyl).
  • morpholinyl e.g. morpholin-4-yl
  • oxetanyl e.g. 3-oxetanyl
  • tetrahydropyranyl e.g. 4-tetrahydropyranyl
  • halo includes references to fluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo, especially fluoro or chloro.
  • Embodiments of the invention that may be mentioned include those in which the compound of formula I is a co
  • R A represents
  • Ci_6 alkyl C 2 _6 alkenyl, C 2 _6 alkynyl, Ci. 6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, and d -2 alkoxy,
  • R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR x P(0)R Y R Y2 or -NR x C(0)OR Y ;
  • R x and R X independently represent H or Ci_ 6 alkyl, or R x and R X together represent C 3 . 6 n- alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
  • R Y , R Y and R Y2 independently represent Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter five groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy and Ci_ 2 alkoxy,
  • R Y represents H
  • R x and R Y together represent C 3 . 6 n-alkylene or C 4 . 5 n-alkylene interrupted between C2 and C3 by -O- or -N(R X2 )-;
  • R X2 represents H or Ci_ 4 alkyl
  • R 4 represents
  • R 6a represents OR 7a or N(R 7t) )R 7c ;
  • Het 1 represents 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S.
  • R A and R B together represent m the following
  • A represents O, S or N(R A2 ),
  • R A represents H, Ci_ 4 alkyl or hydroxy
  • R A2 represents H or Ci_ 4 alkyl
  • R B represents -Ci_ 4 alkylene-CN, -Ci_ 4 alkylene-OH or, particularly, Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy, or -NR X2 S(0) 2 NR x R Y ;
  • R X represents Het 1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_ 2 alkyl and Ci_ 2 alkoxy;
  • R Y , R Y and/or R Y2 represents benzyl optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci_ 2 alkoxy, NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH and C(0)0-(d. 4 alkyl),
  • R Y , R Y and/or R Y2 represents Ci_ 6 alkyl, C 3 . 7 cycloalkyl, phenyl, Het 1 or Het 2 , which latter six groups are substituted by NH 2 , N(H)-Ci_ 4 alkyl, N(Ci_ 4 alkyl) 2 , C(0)OH or C(0)0-(Ci_ 4 alkyl) and optionally further substituted by one or more substituents selected from Ci_ 2 alkyl, halo, hydroxy, Ci.
  • R D represents C 2 _ 7 alkyl, C 2 _ 7 alkenyl, C 2 _ 7 alkynyl, C 3 . 7 cycloalkyl, phenyl, Het or Het 2 , which latter seven groups are substituted by cyano and optionally further substituted one or more substituents selected from Ci_ 2 alkyl, halo, cyano, hydroxy and Ci_ 2 alkoxy;
  • R z represents hydroxy
  • R 4 represents -Q 2 -C(R 6c )(R 6d )-[Ci. 5 alkylene]-R 6a , which Ci -5 alkylene group is substituted by oxo, or, particularly, R 4 represents -CH 2 OH, -COR 6 or -Q -[C(R 6c )(R 6d )-(CH 2 ) 0 - 1 CH 2 -O] 1 . 12 - CH 2 (CH 2 )o-iCH 2 -R 6a in which R 6c and/or R 6d represents methyl (e.g.
  • R 4 represents -COR 6 or -Q -[C(R 6c )(R 6d )-(CH 2 ) 0 - 1 CH 2 -0] 1 . 12 -CH 2 (CH 2 )o- 1 CH 2 -R 6a in which R 6c and/or R 6d represents methyl);
  • R B represents either -C(0)NR x R Y , in which R Y represents optionally substituted Het 1 or optionally substituted Het 2 , or -NR X2 S(0) 2 NR x R Y then R 4 may alternatively represent H, halo, cyano, hydroxy, Ci_ 3 alkyl or Ci_ 3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
  • R 5 represents -C(0)NH 2 or, particularly, hydroxy
  • R 6a represents C0 2 H.
  • R B represents -Ci_ 4 alkylene-CN or -Ci_ 4 alkylene-OH;
  • L represents Ci_ 2 alkylene
  • R 4 represents -CH 2 OH
  • R 5 represents -C(0)NH 2 .
  • Embodiments of the invention that may be mentioned include those in which the compound of formula I (or Ix) is
  • R to R E , R 2 to R 5 , L and X 1 to X 3 are as hereinbefore defined.
  • Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I (or Ix) and la:
  • R A and R B together represent a structural fragment selected from the following
  • R represents phenyl optionally substituted with one or more substituents selected from methyl and methoxy
  • R A represents H, halo, Ci_ 4 alkyl or Ci_ 4 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
  • R A represents H, Ci_ 2 alkyl or hydroxy
  • R B represents -CH 2 CN, -CH 2 OH or, particularly, R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y , -NR x C(0)OR Y , Het or -NR X2 S(0) 2 NR x R Y (e.g.
  • R B represents H, halo, cyano, -NR X R X , -C(0)OR x , -C(0)NR x R Y , -S(0) 2 NR x R Y , -NR x C(0)R Y , -NR x S(0) 2 R Y or -NR x C(0)OR Y );
  • R X represents Het 1 or, particularly, R x and R X independently represent H or Ci_ 4 alkyl, or R x and R X together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-;
  • R Y represents benzyl, Het 2 optionally substituted by one or more substituents selected from methyl, halo, hydroxy and methoxy or, particularly,
  • R Y and R Y independently represent Ci_ 4 alkyl, 0 3 . 6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from methyl, halo, hydroxy, methoxy, NH 2 , N(H)-Ci_ 2 alkyl, N(Ci_ 2 alkyl) 2 , C(0)OH and C(0)0-(Ci- 2 alkyl) (e.g. by one or more substituents selected from methyl, halo, hydroxy and methoxy),
  • R Y represents H
  • R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-;
  • R X2 represents H or Ci_ 2 alkyl
  • R C and R E independently represent H or halo
  • R D represents trimethylsilyl, C 3 _ 7 alkyl, C(Ci_ 2 alkyl) 2 -C ⁇ CH, C 3 . 5 cycloalkyl, phenyl or Het 2 , which latter three groups are optionally substituted by one or more substituents selected from Ci_ 2 alkyl, halo and Ci_ 2 alkoxy;
  • R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 independently represent halo or Ci_ 2 alkyl;
  • (k) L represents CH 2 or, particularly, a direct bond
  • X 2 and X 3 both represent CH or one of X 2 represents CH and X 3 represents N or CR Z ;
  • R z represents H or halo
  • R 4 represents
  • Ci_ 4 alkylene group is optionally substituted by oxo, -S(0) n R 6 ,
  • R 4 may alternatively represent H, (e.g. R 4 represents
  • R 5 represents H or, particularly, cyano, chloro, fluoro, C 2 -3 alkynyl, C 1 - 2 alkyl or Ci- 2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
  • R 6a represents C0 2 H or, particularly, OH, O-C 1 . 2 alkyl or N(R 7 )R 7c ;
  • R 6 represents Ci_ 5 alkyl or C 3 . 5 cycloalkyl
  • R 7 and R 7c independently represent H or Ci -2 alkyl (e.g. methyl), or R 7 and R 7c , together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more Ci_ 2 alkyl groups;
  • Q and Q 2 independently represent C(0)NH or O;
  • Het 1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
  • Het 2 represents a 4- to 6-membered (e.g. 5- or 6-membered) heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S.
  • R A to R E , R 2 to R 5 , X 1 and L are as hereinbefore defined.
  • Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la and lb:
  • R represents H or, particularly, fluoro, chloro, methyl or Ci_ 2 alkoxy (e.g. methoxy), which latter two groups are optionally substituted by one or more fluoro atoms;
  • R B represents H, cyano, -C(0)OR x or, particularly, fluoro, chloro, Het , -C(0)NR x R Y , -NR x S(0) 2 R Y or -N(H)S(0) 2 NR x R Y (e.g. H, cyano, -C(0)OR x or, particularly, fluoro, chloro, -C(0)NR x R Y or -NR x S(0) 2 R Y );
  • R x represents H or methyl
  • R Y represents H, Het 2 , Ci_ 3 alkyl or C 3 . 5 cycloalkyl, which latter two groups are optionally substituted by fluoro, hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 , and C(0)OCH 3 ,
  • R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(R X2 )-
  • R Y represents H or methyl
  • R X2 represents H or methyl
  • R Y represents Ci_ 4 alkyl, C 3 . 6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
  • R C and R E independently represent fluoro or, particularly, H
  • R D represents C 4 _ 6 alkyl, C(CH 3 ) 2 -C ⁇ CH, cyclopropyl or morpholinyl (e.g. morpholin-
  • R 2 and R 3 together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 both represent methyl or, particularly, chloro;
  • X 1 represents N or CH
  • L represents CH 2 or, particularly, a direct bond
  • R z represents chloro or, particularly, H
  • R 4 represents
  • Ci_ 3 alkylene group is optionally substituted by oxo
  • R 4 may alternatively represent H
  • R 4 represents
  • R 5 represents H or, particularly, C 2 . 3 alkynyl, Ci_ 2 alkyl or Ci_ 2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms (e.g. R 5 represents methyl, trifluoromethyl or, particularly, -C ⁇ CH or methoxy, which latter group is optionally substituted by one or more fluoro atoms);
  • R 6a represents OH or, particularly, C0 2 H, 0-CH 3 or N(R 7 )R 7c (e.g. 0-CH 3 or N(R 7 )R 7c) ;
  • R 6 represents C 3 . 5 cycloalkyl (e.g. cyclopropyl); (q) R and R both represent methyl, or R and R , together with the N-atom to which they are attached, form a 5- or 6-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more methyl groups;
  • R and R both represent methyl, or R and R , together with the N-atom to which they are attached, form a 5- or 6-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R 7 and R 7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more methyl groups;
  • Het represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
  • Het 2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N,
  • R A , R B and R D , R 2 to R 5 , X 1 , L and R z are as hereinbefore defined.
  • Embodiments of the invention include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la, lb and Ic:
  • R A represents H or, particularly, Ci_ 2 alkoxy (e.g. methoxy) optionally substituted by one or more fluoro atoms (e.g. R A represents methoxy);
  • R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, chloro, or, particularly, -C(0)N(H)R Y , -NHS(0) 2 CH 3 , -N(H)S(0) 2 NR x R Y or Het 1
  • R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, -C(0)NH 2 , -C(0)N(H)CH 3 or, particularly, -NHS(0) 2 CH 3
  • R B represents H, cyano, -C(0)OH, -C(0)N(CH 3 ) 2 , fluoro, -C(0)NH 2 , -C(0)N(H)CH 3 or, particularly, -NHS(0) 2 CH 3
  • R x represents H or methyl
  • R Y represents H, Het 2 , C 3 . 5 cycloalkyl or Ci_ 3 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 or C(0)OCH 3 (e.g. R Y represents H or methyl),
  • R x and R Y together represent C 4 . 5 n-alkylene optionally interrupted between C2 and C3 by -0-;
  • R D represents morpholinyl, cyclopropyl optionally substituted by methyl or, particularly, branched C 4 _ 6 alkyl (such as te/f-butyl) (e.g. R D represents morpholin-4- yl or, particularly, te/f-butyl); R 2 and R 3 , together with the C-atoms to which they are attached, form a fused phenyl ring, or R 2 and R 3 both represent chloro;
  • X 1 represents N or CH
  • L represents CH 2 or, particularly, a direct bond
  • R 4 represents
  • Ci-3 alkylene group is optionally substituted by oxo
  • R 4 may alternatively represent H
  • R 4 represents
  • R 5 represents H, -C ⁇ CH, or methoxy, which latter group is optionally substituted by one or more fluoro atoms (for example, R 5 represents -C ⁇ CH or, particularly, methoxy, which latter group is optionally substituted by one or more fluoro atoms (e.g. R 5 represents -C ⁇ CH or, particularly, OCH 3 or OCHF 2 ));
  • R 6a represents OH or, particularly, C0 2 H, 0-CH 3 or N(R 7 )R 7c (e.g. 0-CH 3 or N(R 7 )R 7c );
  • R 7 and R 7c both represent methyl, or R 7 and R 7c , together with the N-atom to which they are attached, form a piperazinyl group optionally substituted by methyl, a pyrrolidinyl group or a morpholinyl group (e.g. a piperazinyl group optionally substituted by methyl or, particularly, a morpholinyl group); and/or
  • Q represents O or, particularly, C(0)NH.
  • Het 1 represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N and O (e.g. Het 1 represents oxadiazolyl, such as 1 ,2,4-oxadiazolyl, or triazolyl, such as 1 ,2,3-triazolyl);
  • Het 2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S (e.g. Het 2 represents oxetanyl, such as 3-oxetanyl).
  • R A represents methoxy or ethoxy
  • R B represents Het 1 or, particularly, -C(0)N(H)R Y , -NHS(0) 2 CH 3 ;
  • R Y represents H, Het 2 , cyclopropyl, Ci alkyl, optionally substituted with C(0)OCH 3 , or C 2 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH 2 , N(H)CH 3 , N(CH 3 ) 2 or C(0)OCH 3 ,
  • R D represents te/f-butyl
  • X 1 represents N or CH (e.g. X 1 represents N or, particularly, CH);
  • L represents a direct bond;
  • Ci. 3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH 3 )CH 2 -R 6a , -C(0)NH-CH 2 C(CH 3 ) 2 -R 6a ,
  • R 4 may alternatively represent H
  • R B represents -C(0)N(H)-Het 2 and R 4 represents H
  • R 5 represents -C ⁇ CH or methoxy optionally substituted by one or more fluoro atoms (to give, for example, OCH 3 or OCHF 2 )
  • R 5 may alternatively represent H.
  • R 4 represents -C(0)NH-C(H)(R 6c )-[Ci. 3 alkylene]-R 6a , which Ci. 3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH 3 )CH 2 -R 6a ,
  • R 6a represents N(R 7 )R 7c ;
  • R 4 represents -Q -[C(H)(R 6c )CH 2 -0] 1 . 6 -CH 2 CH 2 -R 6a , then R 6a represents OH, C0 2 H or 0-CH 3 (e.g. 0-CH 3 ).
  • R B represents -NR X2 S(0) 2 NR x R Y or -C(0)NR x R Y , in which latter group R Y represents optionally substituted Het 1 or optionally substituted Het 2 ;
  • both R 4 and R 5 represent H.
  • Still further embodiments of the invention include those wherein, in the compound of formula I, Ix, la, lb and lc:
  • R 4 represents
  • R B represents either -C(0)NR x R Y , in which R Y represents optionally substituted Het 1 or optionally substituted Het 2 , or -NR X2 S(0) 2 NR x R Y , then R 4 may alternatively represent H, halo, cyano or Ci_ 3 alkyl, which latter group is optionally substituted by one or more halo atoms;
  • Q and Q 2 independently represent C(0)NH or S(0) p ; and n and p independently represent 1 or 2.
  • embodiments of the invention include those wherein, in the compound of formula I, Ix, la, lb and Ic:
  • Ci_3 alkoxy optionally substituted by one or more halo atoms
  • R 5 represents Ci_ 3 alkyl, which latter group is optionally substituted by one or more halo atoms, or R 5 represents H, cyano, -C(0)NH 2 , halo or C 2 -3 alkynyl.
  • R 4 represents:
  • Ci_ 5 alkylene group is optionally substituted by oxo.
  • salts of compounds of formula I, Ix, la, lb or lc include all pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HCI and HBr salts and addition salts of strong organic acids such as methanesulfonic acid.
  • 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.
  • a pharmaceutical formulation comprising compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
  • the combination product may be either a single
  • this aspect of the invention encompasses a pharmaceutical formulation including a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and another therapeutic agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation").
  • kit of parts comprising components: (i) a pharmaceutical formulation including a compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and
  • a pharmaceutical formulation including another therapeutic agent, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (i) and (ii) are each provided in a form that is suitable for administration in conjunction with the other.
  • component (i) of the kit of parts is thus component (A) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • component (ii) is component (B) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • a process for preparing the pharmaceutical formulation of aspect (a) above comprising the step of admixing the compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
  • Embodiments of this aspect of the invention include those in which the pharmaceutically acceptable adjuvant, diluent or carrier is a topically acceptable adjuvant, diluent or carrier (and/or wherein the process is for preparing a topical pharmaceutical formulation, i.e. a pharmaceutical formulation that is adapted for topical administration).
  • a method of treating or preventing an inflammatory disease comprising administering to a subject an effective amount of a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
  • Embodiments of this aspect of the invention include those in which the subject is one who has become refractory to the anti-inflammatory effects of a corticosteroid.
  • 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
  • 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);
  • ocular administration particularly in the form of biodegradable and non-biodegradable implants, liposomes and nanoparticles (Thrimawithana, T. R. et al. Drug Discov.
  • 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
  • Such two-piece hard shell capsules may be made from, for example, gelatin or hydroxylpropyl methylcellulose (HPMC).
  • 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 1 1), dichlorotetrafluoroethane (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).
  • excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine 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 or alternatively by Aptar, Coster or Vari).
  • Topical administration to the lung may also be achieved by use of a non-pressurised formulation such as an aqueous solution or suspension.
  • a non-pressurised formulation such as an aqueous solution or suspension.
  • This may be administered by means of a nebuliser e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable).
  • the formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents.
  • Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a D 50 of 0.5-10 ⁇ e.g. around 1-5 ⁇ .
  • Particle size distributions may be represented using Di 0 , D 50 and D 90 values.
  • the D 50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half.
  • the measurement derived from laser diffraction is more accurately described as a volume distribution, and consequently the D 50 value obtained using this procedure is more meaningfully referred to as a Dv 50 value (median for a volume distribution).
  • Dv values refer to particle size distributions measured using laser diffraction.
  • Di 0 and D 90 values used in the context of laser diffraction, are taken to mean Dvi 0 and Dv 90 values and refer to the particle size whereby 10% of the distribution lies below the Di 0 value, and 90% of the distribution lies below the D 90 value, respectively.
  • 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 ⁇ or a D 50 of 0.5-10 ⁇ e.g. around 1-5 ⁇ .
  • Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument).
  • the formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of large particle size e.g. an MMAD of 50 ⁇ or more, e.g. 100 ⁇ or more or a D 50 of 40-150 ⁇ .
  • lactose refers to a lactose-containing component, including a-lactose monohydrate, ⁇ -lactose monohydrate, a-lactose anhydrous, ⁇ -lactose anhydrous and amorphous lactose. Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying.
  • lactose in various forms are also encompassed, for example Lactohale ® (inhalation grade lactose; DFE Pharma), lnhal_ac ® 70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose ® (DFE Pharma) and Respitose ® (sieved inhalation grade lactose; DFE Pharma) products.
  • the lactose component is selected from the group consisting of a-lactose monohydrate, ⁇ -lactose anhydrous and amorphous lactose.
  • the lactose is a- lactose monohydrate.
  • Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate.
  • a dry powder formulation is typically delivered using a dry powder inhaler (DPI) device.
  • dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER.
  • Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
  • DPI dry powder inhaler
  • a compound of the present invention is provided in a micronized dry powder formulation, for example further comprising lactose of a suitable grade optionally together with magnesium stearate, filled into a single dose device such as AEROLISER or filled into a multi dose device such as DISKUS.
  • 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, e.g., Suppocire.
  • 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.
  • 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.
  • 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.
  • simple sugars such as dextrose, fructose, galactose
  • simply polyols such as the sugar alcohols mannitol, sorbitol, xylitol, lactitol, isomaltitol, maltitol, and hydrogenated starch hydrolysates
  • 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, polyoxyl 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, polycarbophil and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w/w.
  • Other compounds may also be added to the ophthalmic compositions of the present invention to increase the viscosity of the carrier.
  • 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.
  • the medical practitioner or other skilled person, will be able to determine a suitable dosage for the compounds of the invention, and hence the amount of the compound of the invention that should be included in any particular pharmaceutical formulation (whether in unit dosage form or otherwise).
  • 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:
  • steroids e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, fluticasone furoate; a further example is ciclesonide;
  • beta agonists particularly beta2 agonists (e.g. terbutaline, salbutamol, salmeterol, formoterol; further examples are vilanterol, olodaterol, reproterol and fenoterol); and xanthines (e.g. theophylline).
  • beta2 agonists e.g. terbutaline, salbutamol, salmeterol, formoterol; further examples are vilanterol, olodaterol, reproterol and fenoterol
  • xanthines e.g. theophylline
  • the other therapeutic agent is one or more agents selected from the list comprising:
  • muscarinic antagonists e.g. tiotropium, umeclidinium, glycopyrronium, aclidinium and daratropium, any of these for example as the bromide salt
  • the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
  • 5-aminosalicylic acid or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide);
  • corticosteroids e.g. prednisolone, methylprednisolone, or budesonide
  • immunosuppressants e.g. cyclosporin, tacrolimus, methotrexate, azathioprine or 6- mercaptopurine
  • anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol or golimumab
  • infliximab e.g., infliximab, adalimumab, certolizumab pegol or golimumab
  • - anti-IL12/IL23 antibodies e.g., ustekinumab
  • small molecule IL12/IL23 inhibitors e.g., apilimod
  • ⁇ - ⁇ 4 ⁇ 7 antibodies e.g., vedolizumab
  • MAdCAM-1 blockers e.g., PF-00547659
  • antibodies against the cell adhesion molecule a4-integrin e.g., natalizumab
  • IL2 receptor a subunit e.g., daclizumab or basiliximab
  • JAK3 inhibitors e.g., tofacitinib or R348
  • Syk inhibitors and prodrugs thereof e.g., fostamatinib and R-406;
  • Phosphodiesterase-4 inhibitors e.g., tetomilast
  • protein kinase C inhibitors e.g. AEB-071.
  • the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
  • corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
  • corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
  • glucocorticoid agonists e.g., mapracorat
  • immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
  • immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
  • anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
  • infliximab e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
  • anti-IL-17A antibodies e.g., secukinumab
  • mTOR inhibitors e.g., sirolimus
  • adenosine A3 receptor agonists e.g., CF-101
  • JAK3 inhibitors e.g., tofacitinib or R348.
  • protein kinase C inhibitors e.g. AEB-071.
  • the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
  • corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
  • corticosteroids e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide
  • immunosuppressants e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus
  • anti-TNFa antibodies e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab
  • anti-IL-17A antibodies e.g., secukinumab
  • mTOR inhibitors e.g., sirolimus
  • JAK3 inhibitors e.g., tofacitinib or R348.
  • protein kinase C inhibitors e.g. AEB-071.
  • 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, Ix, la, lb or Ic (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is the sole pharmacologically active ingredient utilised in the treatment.
  • the compound of formula I, Ix, la, lb or Ic (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:
  • lung diseases or disorders having an inflammatory component such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis or, particularly, COPD (including chronic bronchitis and emphysema), asthma or paediatric asthma;
  • an inflammatory component such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis or, particularly, COPD (including chronic bronchitis and emphysema), asthma or paediatric asthma;
  • nasal diseases or disorders having an inflammatory component such as allergic rhinitis, rhinitis or sinusitis;
  • eye diseases or disorders having an inflammatory component such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic retinopathy, macular oedema (including diabetic macular oedema), central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, or, particularly, keratoconjunctivitis sicca (dry eye), uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection; and
  • gastrointestinal diseases or disorders having an inflammatory component such as gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease or, particularly, Crohn's disease or ulcerative colitis.
  • 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.
  • a process for the preparation of a compound of formula I which process comprises: reaction of a compound of formula II,
  • R A to R E , R 2 to R 5 , L and X 1 to X 3 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); reaction of a compound of formula Ila,
  • a suitable organic solvent e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
  • 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 of a leaving group and activated azide ion, such as diphenyl phosphorazidate; see, for example, Tetrahedron 1974, 30, 2151-2157
  • an amine base e.g. triethylamine or a sterically hindered base such as A/,A/-diisopropylethylamine
  • a suitable organic solvent e.g.
  • a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
  • reaction is followed, without isolation, by thermal rearrangement (e.g. under heating) of the intermediate acyl azide (of formula Z -C(0)-N 3 ) e.g. at ambient temperature (such as from 15 to 30°C) to provide, in situ, a compound of formula II, which compound is then reacted with a compound of formula III, as defined above, to provide the compound of formula I; reaction of a compound of formula lib,
  • LG 1 represents a suitable leaving group (e.g. imidazolyl, chloro, or aryloxy, such as phenoxy) and Z 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 ambient to 80°C), optionally in the presence of an amine base (e.g. triethylamine or a sterically hindered base like A/./V-diisopropylethylamine) and a suitable organic solvent (e.g. an aprotic solvent, such as dichloromethane or an ester such as isopropyl acetate);
  • a suitable organic solvent e.g. an aprotic solvent, such as dichloromethane or an ester such as isopropyl acetate
  • LG 2 represents a suitable leaving group (e.g. a halo group such as chloro or bromo) and R A to R E , R 2 , R 3 and X 1 are as hereinbefore defined with a compound of formula VII,
  • R 4 , R 5 , L, X 2 and X 3 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 mixtures thereof) and, optionally, an acidic catalyst (e.g. a sulfonic acid such as para-toluenesulfonic acid); or
  • a suitable organic solvent e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof
  • an acidic catalyst e.g. a sulfonic acid such as para-toluenesulfonic acid
  • R 6a to R 6d are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. at 0 to 25°C in the presence of a suitable solvent (such as dichloromethane, methanol or a mixture thereof) and a peracid, such as meta- chloroperbenzoic acid);
  • a suitable solvent such as dichloromethane, methanol or a mixture thereof
  • a peracid such as meta- chloroperbenzoic acid
  • Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula Vila,
  • R 4' represents H or a Ci_ 3 alkyl group (e.g. methyl) and R A to R E , R 2 , R 3 , R 5 , L and X 1 to X 3 are as hereinbefore defined, with a compound of formula Vllb or Vile,
  • a trialkyl aluminium reagent such as trimethylaluminium
  • an aprotic organic solvent e.g. THF
  • R 4' represents H
  • reaction in the presence of a tertiary amine base e.g. a trialkylamine such as triethylamine or diisopropylethylamine or a cyclic amine such as N- methylpyrrolidine or N-methylmorpholine
  • a tertiary amine base e.g. a trialkylamine such as triethylamine or diisopropylethylamine or a cyclic amine such as N- methylpyrrolidine or N-methylmorpholine
  • an amide (peptide) coupling reagent e.g.
  • T3P T3P, HATU, CDI, BOP, PyBOP, HOAt, HOBt or a carbodiimide such as DCC or diisopropylcarbodiimide
  • an aprotic organic solvent e.g. a chlorinated solvent such as DCM, an ester such as ethyl acetate, an amide of dimethylamine such as DMF, or a mixture of any such solvents
  • R A , R C , R D , R E , R a , R , X 1 to X 3 , L, R 4 and R 5 are as hereinbefore defined and R x represents H or Ci_ 4 alkyl, with a compound of formula Vile, wherein R x and R Y are as hereinbefore defined, under conditions known to those skilled in the art, for example
  • R x represents H
  • a base e.g. triethylamine or A/./V-diisopropylethylamine
  • an amide (peptide) coupling reagent such as HATU, CDI, ⁇ /, ⁇ /'-dicyclohexylcarbodiimide, ⁇ /, ⁇ /'-diisopropylcarbodiimide BOP or PyB
  • R x represents H
  • conversion of the carboxylic acid to an acid halide e.g. by reaction with a halogenating agent such as thionyl chloride
  • reaction with the compound of formula (XI) in the presence of a suitable solvent and a base e.g. triethylamine or A/./V-diisopropylethylamine, or
  • R x represents Ci_ 4 alkyl (e.g. methyl)
  • a trialkylaluminium e.g. trimethylaluminium
  • an aprotic solvent e.g. THF
  • 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 lla, 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).
  • Amines of formula IX may be prepared from carboxylic acids of formula I la 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 f-butanol, to generate a protected version of IX.
  • Certain compounds of formula III in which Z 2 represents a structural fragment of formula V, or compounds of formula IX in which Z represents a structural fragment of formula V, may be synthesised employing the route outlined in Scheme 1 (see, for example: WO 2003/072569; and WO 2008/046216), wherein R 2 , R 3 and X 1 to X 3 are as hereinbefore defined, LG 3 and LG 4 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 substituent (LG 4 ) of the ether XII 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 XIII (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 1.
  • amines of formula IX in which Z represents a structural fragment of formula IV may be synthesised by conversion of a latent to a real NH 2 group in a compound of formula Xllla,
  • Ci-5 alkylene group is optionally substituted by oxo
  • 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 llx with a compound of formula Mix, wherein the compounds of formulae llx and Mix take the same definitions as the compounds of formulae II and III, with the exception that one of Z and Z 2 represents a structural fragment of formula IV, as hereinbefore defined, and the other of Z and Z 2 represents a structural fragm
  • FG 1 either represents FG or C(0)0-(Ci_ 6 alkyl)
  • FG, R 5 , X 2 and X 3 are as hereinbefore defined, with a compound of formula XVa or XVb
  • LG 5 represents a suitable leaving group such as halo, (perfluoro)alkane- sulfonate or arylsulfonate (e.g.
  • R 6a , R 6c and R 6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of an organic solvent and either a suitable base, followed by when FG represents NH-PG 2 , removal of the PG 2 protecting group, when FG 1 represents N0 2 , reduction of N0 2 to NH 2 or
  • R 6a , R 6c and R 6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. under Mitsunobu conditions, i.e. in the presence of using triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate), followed by
  • LG 5 -R' XVIII wherein LG 5 and R 6 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a suitable base and an organic solvent), followed by
  • FG 1 and R 5 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a peracid, such as mefa-chloroperbenzoic acid), followed by
  • LG6 represents a suitable leaving group such as halo trifluoromethanesulfonate
  • FG 1 , R 5 , X 2 and X 3 are as hereinbefore defined, with compound of formula XXI, H-S-R 6b XXI wherein R 6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a Pd(0) catalyst, Cu(l) iodide and a suitable base), followed by
  • x and y are integers from 0 to 1 1 , the sum of x and y being from 0 to 11 , and Q , LG 5 and R 6a are as hereinbefore defined, under conditions known to those skilled in the art (e.g. at ambient temperature in the presence of a base such as sodium hydride and a polar organic solvent such as DMF).
  • R' represents
  • Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula XXV,
  • M s+ is a metal cation
  • s is 1 or 2 (e.g. s is 1 and M is an alkali metal such as potassium or, particularly, sodium) and R 6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. at elevated temperature (e.g. 80 to 100°C) in the presence of: a suitable transition metal catalyst, such as Cu(l) iodide; an aprotic organic solvent, such as DMSO; a suitable base, such as an alkali metal hydroxide (e.g.
  • FG, LG 2 , R A and R C to R E are as hereinbefore defined, with a source of cyanide ion (e.g. NaCN), for example under conditions known to those skilled in the art, such as in the presence of a polar, aprotic organic solvent (e.g. DMSO).
  • a source of cyanide ion e.g. NaCN
  • a polar, aprotic organic solvent e.g. DMSO
  • R" represents -CH 2 -[Ci_ 5 alkylene]-OH, with a halogenating agent (e.g. a mixture of 2,4,6-trichloro, 1 ,3,5-triazine and dimethylformamide).
  • a halogenating agent e.g. a mixture of 2,4,6-trichloro, 1 ,3,5-triazine and dimethylformamide.
  • FG, R X , R A and R C to R E are as hereinbefore defined, for example under conditions known to those skilled in the art, such as by reaction with borohydride or aluminium hydride-based reducing agent (e.g. an alkali metal borohydride or aluminium hydride, such as lithium borohydride or lithium aluminium hydride) in the presence of a reaction-inert organic solvent.
  • borohydride or aluminium hydride-based reducing agent e.g. an alkali metal borohydride or aluminium hydride, such as lithium borohydride or lithium aluminium hydride
  • Z represents a structural fragment of formula IV, in which R A , R B , R C , R D and R E are as hereinbefore defined (e.g. in which R A , R B , R C , R D and R E take the combinations of definitions illustrated in respect of those groups in any of the compounds of the examples); and
  • LG 1 is as hereinbefore defined (e.g. LG 1 represents phenoxy).
  • 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 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):
  • GSK 3a not strongly inhibit GSK 3a (e.g. they may have an IC 50 against GSK 3a of 1 ,000 nM or greater; such as 1 ,500, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or greater);
  • a relatively high local drug concentration between doses e.g. a high local concentration relative to other previously disclosed p38 MAP kinase inhibitors such as, for example, BIRB796;
  • topical/local administration e.g. following topical/local administration, the generation of high target tissue concentrations but low plasma concentrations of the compounds of formula (I) and/or rapid clearance of the compounds of formula (I) from plasma, for example as a result of high renal or hepatic extraction;
  • reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 1 % NH 3 in MeOH.
  • Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
  • 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 a Waters Xselect CSH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 ⁇ , 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
  • UV and mass spectra of the eluted peaks were measured using a variable wavelength detector on either an Agilent 1200 or an Agilent Infinity 1260 LCMS with 6120 single quadrupole mass spectrometer with positive and negative ion electrospray.
  • Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 ⁇ , 19x50 mm column using either a gradient of either 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate or employing a Waters Xbridge BEH C18, 5 ⁇ , 19x50 mm column using a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate.
  • Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector on a Gilson 215 preparative HPLC or Varian PrepStar preparative HPLC or by mass and UV at a single wavelength measured by a ZQ single quadrupole mass spectrometer, with positive and negative ion electrospray, and a dual wavelength detector on a Waters FractionLynx LCMS.
  • H NMR Spectroscopy H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz. Either the central peaks of chloroform-d, dimethylsulfoxide-cfe or an internal standard of tetramethylsilane were used as references.
  • Phenyl chloroformate (0.5 mL, 3.99 mmol) was added to a stirred solution of N-(3-amino-5- (tert-butyl)-2-methoxyphenyl)methanesulfonamide (see, for example, Cirillo, P. F. et al., WO 2002/083628, 24 October 2002; 1 g, 3.67 mmol) and NaHC0 3 (620 mg, 7.38 mmol) in THF (10 mL) and DCM (10 mL). The mixture was stirred for 2 h, then water (20 mL) was added. The organic layer was separated, dried (MgS0 4 ), filtered and evaporated to furnish a brown foam, which was stirred in cyclohexane (20 mL) to afford the sub-title compound (1.4 g) as a colourless solid.
  • Triethylamine (5 ⁇ , 0.036 mmol) was added to a mixture of the product from step (vi) above (75 mg, 0.191 mmol) and the product from step (v) above (100 mg, 0.197 mmol) in isopropyl acetate (3 mL) and the mixture heated at 50°C (block temperature) for 6 h. The reaction was cooled to rt and left stirring for 72 h. The resulting solid was filtered and washed with isopropyl acetate (1 mL). The crude product was recrystallised from MeCN (3 mL), washed with MeCN (1 mL), filtered and dried to afford the title compound (100 mg) as a colourless solid.
  • the mixture was diluted with DCM (30 mL), was washed with water (30 mL) and filtered through a phase-separating cartridge. The filtrate was evaporated and the residue was purified on a 40 g redisep silica cartridge using a gradient of 0 to 50% of ethyl acetate in isohexane as eluent to afford the sub-title compound (1.565 g) as a pink solid.
  • the solid was washed with isopropyl acetate (2 x 2ml_) and digested with boiling acetonitrile (20 mL) for 20 mins. The suspension was allowed to cool then filtered. The solid washed with acetonitrile (2 x 4 mL) followed by ether (2 x 4 mL) and dried to afford the title compound (97 mg) as a buff solid.
  • 3-Amino-5-methoxybenzoic acid (1.0g, 5.98 mmol) was added to an ice cold suspension of 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (1.2 g, 7.35 mmol), 50% T3P in ethyl acetate (4.50 mL, 7.56 mmol) and TEA (2.5 mL, 17.94 mmol) in ethyl acetate (15 mL). The mixture was allowed to warm to rt and stir overnight. Saturated aq. NaHC0 3 solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL).
  • the solid was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 20-50% MeCN in Water) to afford a white solid which was redissolved in methanol (2 mL) loaded onto an SCX column. The column was washed with methanol (3 x 3 mL) then eluted with 1 % ammonia in methanol to yield the title compound (21 mg) as a white solid.
  • N 2 was bubbled through a stirred mixture of tert-butyl (4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 10 g, 26.9 mmol), 3-amino-5-methoxybenzoic acid (8.99 g, 53.8 mmol) and p-TSA monohydrate (1.02 g, 5.36 mmol) in THF (150 mL) for 10min. The mixture was heated under reflux for 20 h, cooled and filtered.
  • tert-butyl (4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 10 g, 26.9 mmol
  • step (ii) above (570 mg, 0.927 mmol) was suspended in DCM (10 mL) and TFA (1500 ⁇ , 19.47 mmol) added. The reaction mixture was stirred for 2 h. The solvents were evaporated and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was separated and basified with NaHC0 3 before extraction with DCM (3 x 20 mL). The organics were bulked, dried (MgS0 4 ), filtered and evaporated to give a brown solid. The crude product was purified by chromatography on silica gel (40 g column, 5% MeOH: DCM to 10%) to afford the sub-title compound (350 mg) as a colourless solid.
  • Et 3 N (6 ⁇ _, 0.043 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 76 mg, 0.194 mmol) and the product from step (iii) above (100 mg, 0.194 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 7 h. The reaction was diluted with DCM and MeOH then concentrated in vacuo onto silica gel.
  • the crude product was purified by chromatography on the Companion (12 g column, 1-10% MeOH DCM) to afford the product as a clear oil which was purified further by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 20-50% MeCN in Water) to afford the formate salt of the product as a white solid.
  • the material was dissolved in MeOH and loaded onto a pre-conditioned cartridge of SCX resin. The resin was washed with MeOH and the product released with 1 % NH 3 in MeOH. The NH 3 solution was concentrated in vacuo to afford the title compound (54 mg) as a white solid.
  • the temperature was increased to 85°C and the mixture was stirred for a further 3 h.
  • the mixture was diluted with water (10 mL) and saturated aq. NaHC0 3 solution (10 mL), then extracted with ethyl acetate (3 x 10 mL).
  • the combined organic phases were washed with 20% brine (2 x 10 mL), saturated brine (10 mL), dried (MgS0 4 ) and concentrated under reduced pressure.
  • the crude product was purified by chromatography on the Companion (40 g column, 0-100% THF/EtOAc) to afford a pale brown glass.
  • Phenyl chloroformate (1.40 mL, 11.16 mmol) was added to a stirred solution of 5-(tert-butyl)- 2-methoxyaniline (2.00 g, 1 1.16 mmol) and NaHC0 3 (1.90 g, 22.62 mmol) in THF (20 mL) and DCM (20 mL). The mixture was stirred overnight then diluted with water (40 mL) and DCM (20 mL) then passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (3.53 g) as a red-brown oil.
  • Phenyl chloroformate (300 ⁇ , 2.391 mmol) was added to a stirred solution of 3-amino-5- (tert-butyl)-2-methoxy-N-methylbenzamide (see, for example, Cirillo, P. F. et al., Bioorg. Med. Chem. Lett. 2009, 19, 2386-2391 ; 550 mg, 2.327 mmol) and NaHC0 3 (300 mg, 3.57 mmol) in THF (5 mL) and DCM (5 mL). The mixture was stirred for 2 h, filtered and the solvent evaporated to give a pale brown oil. Trituration with isohexane (10 mL) gave the sub-title compound (470 mg) as a colourless solid.
  • the catalyst solution was added to the main reaction mixture and the whole was heated to 90°C for 48 h.
  • Pd 2 (dba) 3 22 mg, 0.024 mmol
  • BINAP 30 mg, 0.048 mmol
  • Water was added (15 mL) and the mixture was extracted with EtOAc (3 x 15 mL).
  • the combined organic phases were washed with saturated brine (15 mL), dried (MgS0 4 ) and concentrated under reduced pressure.
  • the crude product was purified by chromatography on the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound (194 mg) as a sticky brown oil.
  • Phenyl chloroformate (300 ⁇ , 2.391 mmol) was added to a stirred solution of 2-methoxy-5- morpholinoaniline (500 mg, 2.401 mmol) and NaHC0 3 (400 mg, 4.76 mmol) in THF (5 mL) and DCM (5 mL) and the mixture was stirred overnight. The mixture was diluted with water (40 mL) and DCM (20 mL) then the mixture passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (789 mg) as a yellow oil which solidified on standing.
  • Triethylamine (6 ⁇ , 0.043 mmol) was added to a mixture of the product from step (i) above (58 mg, 0.177 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 100 mg, 0.192 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 4 days. The reaction was cooled to rt and diluted with MeOH. The solution was concentrated in vacuo onto silica gel.
  • the crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the product as an off-white solid.
  • the crude product was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 ⁇ , 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (51 mg) as an off-white solid.
  • Triethylamine (15 ⁇ _, 0.108 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2- methoxy-3-(methylcarbamoyl)phenyl)carbamate (see Example 9(i) above; 150 mg, 0.421 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 200 mg, 0.384 mmol) in THF (5 mL) and the mixture heated at 50°C (block temperature) for 24h.
  • Iron powder (5.90 g, 106 mmol) was added to a solution of the product from step (i) above (8.24 g, 20.43 mmol) and concentrated HCI (2 mL, 23.40 mmol) in EtOH (65 mL) and water (15 mL). The mixture was heat at 75 °C (block temperature) for 1 h. Then, the reaction was cooled to rt, before being diluted with water (30 mL), filtered and concentrated in vacuo. The residue was basified (NaHC0 3 ) then partitioned between EtOAc (350 mL) and water (275 mL).
  • the reaction was heated at 85 °C for 3 h, before beingcooled to rt and partitioned between EtOAc (250 mL) and brine (250 mL).
  • the aqueous phase was further extracted with EtOAc (250 mL), then the combined organic extracts were washed with water (3 x 200 mL) and brine (200 mL), before being dried (MgS0 4 ), filtered and concentrated in vacuo to afford a dark brown oil.
  • the crude product was purified by chromatography on silica gel (220 g column, 0-3% MeOH in DCM) to afford the sub-title compound (5.4 g) as an orange oil.
  • step (I) above (1 kg, 2.56mol) was dissolved in THF (3.5 L) and AcOH (500 mL) and hydrogenated at 3 MPa (30 bar) H 2 at up to 60°C with 5% Pt/C (30 g of JM type 18 MA, 55% water). Analysis after 5 hrs showed a 1 : 1 ratio of ArNHOH and ArNH 2 . The reaction reached completion after being left overnight, with H NMR analysis showing 3% des-bromo side product. The catalyst was filtered off, then the residue was diluted with ethyl acetate (3 L) and washed with 20% potassium carbonate solution (3.5 L).
  • step (IV) The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (IV), 22.24% the product of step (VI), 8.98% chloropyrimidine starting material and 64.08% the product of step (V). Further product from step (IV) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (IV), 30.23% the product of step (VI), 4.50% starting chloropyrimidine and 58.61 % the product of step (V).
  • step (VII) Under N 2 was charged the product of step (VII) (471 g, 2.099 mol), toluene (1880 mL) and pyridine (471 mL), then methanesulfonyl chloride (179 mL) was added dropwise over 1 h while maintaining the temperature below 35 °C. The reaction was stirred at 30-35 °C overnight, before being cooled to below 20 °C, then water (1880 mL) and 2 M HCI (1880 mL) were charged (pH 3 achieved). The layers were separated and the organic phase was washed with 2.5% brine (1880 mL). Heptane (3760 mL) was then charged to the organic layer over 0.5 h to isolate a precipitate.
  • step (IX) Under N 2 was charged the product of step (IX) above (167.0 g, 613 mmol), NaHC0 3 (77.3 g, 920 mmol), THF (870 mL) and DCM (1440 mL). Phenyl chloroformate (82.6 mL, 659 mmol) was added dropwise, while maintaining the temperature below 20°C, and the reaction was stirred at room temperature for 4 h. HPLC analysis of the reaction mixture indicated 98.6% product and 0.03% starting material. The reaction mixture was filtered and the cake was washed with THF (-50 mL). The filtrate was concentrated to -900 mL and cyclohexane (2400 mL) was added, then the mixture was left to stir overnight.
  • step (vi) Under N 2 was charged the product of step (vi) above (175.5g, 0.324mol), the product of step (X) above (145.0 g, 0.369 mmol) and / ' PrOAc (8800 mL). The resulting solution was heated to 60°C and NEt 3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60 °C overnight, following which HPLC analysis indicated 25.77% product of step (VI), 3.60% product of step (X) and 57.85% product of step (XI).
  • step (X) Further product of step (X) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60 °C overnight, whereupon HPLC analysis indicated 5.47% product of step (VI), 3.72% product of step (X) and 73.33% product of step (XI).
  • the reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with / ' PrOAc (2 x 500 mL). The pink solid obtained was dried, under vacuum, at 40 °C overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. H NMR conformed to structure.
  • Example 17 Example 17

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Abstract

There are provided compounds of formula I, wherein R1A to R1E, R2 to R5, L and X1 to X3 have meanings given in the description, which compounds have antiinflammatory activity (e.g. through inhibition of one or more of members of: the family of p38 mitogen-activated protein kinase enzymes; Syk kinase; and members of the Src family of tyrosine kinases) and have use in therapy, including in pharmaceutical combinations, especially in the treatment of inflammatory diseases, including inflammatory diseases of the lung, eye and intestines.

Description

UREA DERIVATIVES USEFUL AS KINASE INHIBITORS
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). 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).
The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Four 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). There is now an abundant literature which demonstrates that 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. Indeed, 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 TNFa (but not IL-8) release from human PBMCs (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404).
The use of inhibitors of p38 MAP kinase in the treatment of COPD and IBD has also been proposed. Small molecule inhibitors targeted to p38 ΜΑΡΚα/β have proved to be effective in reducing various parameters of inflammation in:
cells and tissues obtained from patients with COPD, who are generally corticosteroid insensitive (Smith, S. J., Br. J. Pharmacol., 2006, 149:393-404);
biopsies from IBD patients (Docena, G. et al., J. Trans. Immunol., 2010, 162: 108- 1 15); and
in vivo animal models (Underwood, D. C. et al., Am. J. Physiol., 2000, 279:L895-902; Nath, P. et ai, Eur. J. Pharmacol., 2006, 544: 160-167). Irusen and colleagues also suggested the possibility of involvement of p38 ΜΑΡΚα/β on corticosteroid insensitivity via the reduction of binding affinity of the glucocorticoid receptor (GR) in nuclei (Irusen, E. et al., J. Allergy Clin. Immunol., 2002, 109:649-657). Clinical investigations in inflammatory diseases with a range of p38 MAP kinase inhibitors, including AMG548, BIRB 796, VX702, SCI0469 and SCI0323, have been described (Lee, M. R. and Dominguez, C, Current Med. Chem., 2005, 12:2979-2994.). However, the major obstacle hindering the utility of p38 MAP kinase inhibitors in the treatment of human chronic inflammatory diseases has been the toxicity observed in patients. This has been sufficiently severe to result in the withdrawal from clinical development of many of the compounds progressed, including all those specifically mentioned above.
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 A56) demonstrates that silencing p38 MAPK γ 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.
Many patients diagnosed with asthma or with COPD continue to suffer from uncontrolled symptoms and from exacerbations of their medical condition that can result in hospitalisation. This occurs despite the use of the most advanced, currently available treatment regimens, comprising of combination products of an inhaled corticosteroid and a long acting β-agonist. Data accumulated over the last decade indicates that a failure to manage effectively the underlying inflammatory component of the disease in the lung is the most likely reason that exacerbations occur. Given the established efficacy of corticosteroids as anti-inflammatory agents and, in particular, of inhaled corticosteroids in the treatment of asthma, these findings have provoked intense investigation. Resulting studies have identified that some environmental insults invoke corticosteroid-insensitive inflammatory changes in patients' lungs. An example is the response arising from virally-mediated upper respiratory tract infections (URTI), which have particular significance in increasing morbidity associated with asthma and COPD. It has been disclosed previously that compounds that inhibit the activity of both the c-Src and Syk kinases are effective agents against rhinovirus replication (Charron, C.E. et al., WO 2011/158042) and that compounds that inhibit p59-HCK are effective against influenza virus replication (Charron, C.E. et al., WO 2011/070369). Taken together with inhibition of p38 MAPK, these are particularly attractive properties for compounds to possess that are intended to treat patients with chronic respiratory diseases.
Certain p38 MAPK inhibitors have also been described as inhibitors of replication of respiratory syncytial virus (Cass L. et al., WO 2011/158039). 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. p38 has become an obvious target for investigation in IBD models as a consequence of its ubiquitous expression in inflammatory cells. 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. et al., J. Trans. Immunol,. 2010, 162:108-115). However, these findings are not completely consistent with other groups reporting no effect with p38 inhibitors (Malamut G. et al., Dig. Dis. Sci, 2006, 51 : 1443-1453). A clinical study in Crohn's patients using the p38 alpha inhibitor BIRB796 demonstrated potential clinical benefit with an improvement in C-reactive protein levels. However this improvement was transient, returning to baseline by week 8 (Schreiber, S. et al., Clin. Gastro. Hepatology, 2006, 4:325-334). A small clinical study investigating the efficacy of CNI-1493, a p38 and Jnk inhibitor, in patients with severe Crohn's disease showed significant improvement in clinical score over 8 weeks (Hommes, D. et al. Gastroenterology. 2002 122:7-14).
T cells are known to play a key role in mediating inflammation of the gastrointestinal tract. Pioneering work by Powrie and colleagues demonstrated that transfer of naive CD4+ cells into severely compromised immunodeficient (SCID) animals results in the development of colitis which is dependent on the presence of commensal bacteria (Powrie F. et al. Int Immunol. 1993 5:1461-71). Furthermore, investigation of mucosal membranes from IBD patients showed an upregulation of CD4+ cells which were either Th1 (IFNg/IL-2) or Th2 (IL5/ TGFb) biased depending on whether the patient had Crohn's disease or ulcerative colitis (Fuss IJ. et al. J Immunol. 1996 157:1261-70.). Similarly, 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 Bechets patients (Chi W. et al. Invest Ophthalmol Vis Sci. 2008 49:3058-64). In support of these observations, Direskeneli and colleagues demonstrated that Bechets patients have increased Th17 cells and decreased Treg cells in their peripheral blood (Direskeneli H. et al. J Allergy Clin Immunol. 201 1 128:665-6).
One approach to inhibit T cell activation is to target kinases which are involved in activation of the T cell receptor signalling complex. Syk and 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 EK. 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 AC. et al. Science. 1994, 10;264(5165): 1599- 601).
A clinical trial in rheumatoid arthritis patients with the Syk inhibitor Fostamatinib demonstrated the potential of Syk as an anti-inflammatory target with patients showing improved clinical outcome and reduced serum levels of IL-6 and MMP-3 (Weinblatt ME. et al. Arthritis Rheum. 2008 58:3309-18). 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 motifs (ITAM), it plays an important role in regulating T cell and B cell expansion as well as mediating immune-receptor signalling in inflammatory cells. Syk activation leads to IL-6 and MMP release - inflammatory mediators commonly found upregulated in inflammatory disorders including IBD and rheumatoid arthritis (Wang YD. et al World J Gastroenterol 2007; 13: 5926-5932, Litinsky I et al. Cytokine. 2006 Jan 33: 106-10).
In addition to playing key roles in cell signalling events which control the activity of proinflammatory pathways, 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 "Olaharski kinases") have been found to alter the frequency of micronucleus formation in vitro (Olaharski, A. J. et al., PLoS Comput. Biol., 2009, 5(7), e1000446; doi: 10.1371/journal.pcbi.1000446). Micronucleus formation is implicated in, or associated with, disruption of mitotic processes and is therefore undesirable. Inhibition of glycogen synthase kinase 3a (GSK3a) was found to be a particularly significant factor that increases the likelihood of a kinase inhibitor promoting micronucleus formation. Also, inhibition of the kinase Θ8Κ3β with RNAi has been reported to promote micronucleus formation (Tighe, A. et al., BMC Cell Biology, 2007, 8:34).
Whilst it may be possible to attenuate the adverse effects of inhibition of Olaharski kinases such as GSK3a by optimisation of the dose and/or by changing the route of administration of a molecule, it would be advantageous to identify further therapeutically useful molecules with low or negligible inhibition of Olaharski kinases, such as GSK 3a and/or have low or negligible disruption of mitotic processes (e.g. as measured in a mitosis assay). Various compounds, including urea derivatives, are disclosed as inhibiting one or more kinases. Examples of such compounds may be found in WO 99/23091 , WO 00/041698, WO 00/043384, WO 00/055139, WO 01/36403, WO 01/4115, WO 02/083628, WO 02/083642, WO 02/092576, WO 02/096876, WO 2003/005999, WO 2003/068223, WO 2003/068228, WO 2003/072569, WO 2004/014870, WO 2004/113352, WO 2005/005396, WO 2005/018624, WO 2005/023761 , WO 2005/044825, WO 2006/015775, WO 2006/043090, WO 2007/004749 and WO 2007/053394. Further examples may be found in articles published in:
Curr. Opin. Drug Devel. (2004, 7(5), 600-616);
J. Med. Chem. (2007, 50, 4016-4026; 2009, 52, 3881-3891 ; and 2010, 53, 5639- 5655);
Bioorg. Med. Chem. Lett. (2007, 17, 354-357; 2008, 18, 3251-3255; 2009, 19, 2386-
2391 ; and 2010, 20, 4819-4824);
Curr. Top. Med. Chem. (2008, 8, 1452-1467);
Bioorg. Med. Chem. (2010, 18, 5738-5748); Eur. J. Pharmacol. (2010, 632, 93-102) and
J. Chem. Inf. Model. (2011 , 51, 115-129).
Nevertheless, there remains a need to identify and develop new kinase inhibitors, specifically alternative p38 MAP kinase inhibitors that are suitable for the treatment of inflammation. There is particularly a need for such inhibitors that have improved therapeutic potential over currently available treatments or, in particular, that exhibit 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).
We have now discovered, surprisingly, that certain aniline-substituted diarylureas inhibit one or more of p38 MAP kinase, Syk and Src family kinases and therefore possess good antiinflammatory properties.
Thus, according pound of formula I,
Figure imgf000007_0001
wherein
R represents
H, halo, cyano,
Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, d-6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, and Ci_2 alkoxy,
phenyl or Het , which latter two groups are optionally substituted with one or more substituents selected from Ci_2 alkyl and Ci_2 alkoxy,
or R A and R B together repres d from the following
Figure imgf000007_0002
wherein the wavy lines represent the points of attachment to the phenyl ring,
A represents O, S or N(RA2),
R represents H, Ci-4 alkyl or hydroxy,
RA2 represents H or Ci-4 alkyl; R B represents H, halo, cyano, -Ci.4 alkylene-CN, -Ci.4 alkylene-OH, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRxS(0)2RY , -NRX2S(0)2NRxRY, -NRxP(0)RY RY2, -NRxC(0)ORY or Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci_2 alkoxy;
Rx and RX independently represent H or Ci_6 alkyl, or Rx and RX together represent C3.6 n- alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -O- or -N(RX2)-, or RX represents Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci_2 alkoxy;
RY, RY and RY2 independently represent Ci_6 alkyl, C3.7 cycloalkyl, phenyl, benzyl, Het1 or Het2, which latter six groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, Ci.2 alkoxy, NH2, N(H)-Ci_4 alkyl, N(Ci_4 alkyl)2, C(0)OH and C(0)0-(Ci-4 alkyl),
or RY represents H,
or Rx and RY together represent C3.6 n-alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -O- or -N(RX2)-;
each RX2 independently represents H or Ci_4 alkyl;
R C and R E independently represent H, halo, cyano or methyl; provided that at least one of R A, R B, R C and R E is other than H;
R D represents trimethylsilyl, C2_7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3.7 cycloalkyl, phenyl, Het1 or Het2, which latter seven groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, cyano, hydroxy and Ci_2 alkoxy;
R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from Ci_3 alkyl, Ci_3 haloalkyl, cyano and halo,
or one of R2 and R3 represents H, halo, cyano, Ci_3 alkyl or Ci_3 haloalkyl and the other independently represents halo, cyano, Ci_3 alkyl or Ci_3 haloalkyl,
or R2 and R3 together combine to form C3.5 alkylene or C3.5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from Ci_3 alkyl, Ci-3 haloalkyl, cyano and halo;
X1 represents N or CH;
L represents a direct bond or Ci_2 alkylene; X2 and X3 both represent CRZ or one of X2 and X3 represents N and the other represents CRZ;
Rz represents hydrogen, halo, cyano, hydroxy, Ci_3 alkyl or Ci_3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms; R4 represents
-Q -[C(R6c)(R6d)-(CH2)o-i CH2-0]1.12-CH2(CH2)o-i CH2-R6a,
-Q2-C(R6c)(R6d)-[Ci-5 alkylene]-R6a, which Ci-5 alkylene group is optionally substituted by oxo,
-S(0)nR6 ,
-COR6 , or, when R B represents either -C(0)N RxRY, in which RY represents optionally substituted Het or optionally substituted Het2, or -N RX2S(0)2N RxRY then R4 may alternatively represent H, halo, cyano, hydroxy, Ci_3 alkyl or Ci_3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
R5 represents Ci_3 alkoxy or Ci_3 alkyl, which latter two groups are optionally substituted by one or more halo atoms, or R5 represents H, cyano, -C(0)NH2, hydroxy, halo or C2-3 alkynyl;
R6a represents OR7a, N(R7 )R7c or C02H;
R6 represents Ci_8 alkyl, C3.8 cycloalkyl, phenyl, Het1 or Het2, which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxyl, Ci_3 alkyl and Ci-3 alkoxy;
R6c and R6d independently represent H or methyl; R7a to R7c independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R7 and R7c, together with the N-atom to which they are attached, form a 4- to 7- membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R7 and R7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N , and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, Ci_4 alkyl and Ci_4 alkoxy;
Q and Q2 independently represent C(0)NH, O or S(0)p; and
n and p independently represent 0, 1 or 2,
Het1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; Het2 represents, independently upon each occurrence, a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or more heteroatoms selected from N , O and S; or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, which compounds may be referred to hereinafter as "the compounds of the invention".
Pharmaceutically acceptable salts that may be mentioned 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.
For the avoidance of doubt, compounds of formula I may contain the stated atoms in any of their natural or non-natural isotopic forms. In this respect, embodiments of the invention that may be mentioned include those in which:
(a) the compound of formula I is not isotopically enriched or labelled with respect to any atoms of the compound; and
(b) the compound of formula I is isotopically enriched or labelled with respect to one or more atoms of the compound.
References herein to an "isotopic derivative" relate to the second of these two embodiments. In particular embodiments of the invention, 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. Thus, 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.
Compounds of formula I may exhibit tautomerism. All tautomeric forms and mixtures thereof are included within the scope of the invention. For example, the structural fragment containing the substituent RA may exhibit keto-enol tautomerism when the group RA represents OH (giving the fragment -N=C(OH)-A-, which may tautomerise to provide the fragment -NH-C(=0)-A-).
Unless otherwise specified, 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.
Unless otherwise specified, 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. Unless otherwise specified, 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. In particular embodiments of the invention, alkylene refers to straight-chain alkylene.
Unless otherwise stated, the point of attachment of 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. C6-14 aryl groups include phenyl, naphthyl and the like. Embodiments of the invention that may be mentioned include those in which aryl is phenyl.
For the avoidance of doubt, oxo substituents that may be present on heterocyclic groups represented by N(R7 )R7c may be attached to any appropriate atoms in the heterocyclic ring including, where valencies allow, to C-, N- and/or S- atoms within the ring (thereby forming keto, N-oxide, S(O) and/or S(0)2 groups).
Values of Het1 that may be mentioned include oxadiazolyl (e.g. 1 ,3,4-oxadiazol-2-yl), pyrimidinyl (e.g. pyrimidin-2-yl) and triazolyl (e.g. 1 ,2,3-triazol-4-yl).
Values of Het2 that may be mentioned include morpholinyl (e.g. morpholin-4-yl), oxetanyl (e.g. 3-oxetanyl) and tetrahydropyranyl (e.g. 4-tetrahydropyranyl).
Unless otherwise specified, the term "halo" includes references to fluoro, chloro, bromo or iodo, in particular to fluoro, chloro or bromo, especially fluoro or chloro. Embodiments of the invention that may be mentioned include those in which the compound of formula I is a co
Figure imgf000011_0001
wherein:
R A represents
H, halo, cyano,
Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, Ci.6 alkoxy, which latter four groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, and d-2 alkoxy,
phenyl or Het1 , which latter two groups are optionally substituted with one or more substituents selected from Ci_2 alkyl and C^2 alkoxy; R B represents H, halo, cyano, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRxS(0)2RY , -NRxP(0)RY RY2 or -NRxC(0)ORY ;
Rx and RX independently represent H or Ci_6 alkyl, or Rx and RX together represent C3.6 n- alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -O- or -N(RX2)-;
RY, RY and RY2 independently represent Ci_6 alkyl, C3.7 cycloalkyl, phenyl, Het1 or Het2, which latter five groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy and Ci_2 alkoxy,
or RY represents H,
or Rx and RY together represent C3.6 n-alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -O- or -N(RX2)-;
RX2 represents H or Ci_4 alkyl;
R4 represents
-Q1-[CH2(CH2)o-iCH2-0]i-i2-CH2(CH2)o-iCH2-R'
-Q^CCR^CR^-fd-s alkylene]-R6a or
-S(0)nR6 ;
R6a represents OR7a or N(R7t))R7c; and/or
Het1 represents 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S.
Alternative embodiments of the invention that may be mentioned include those in which the compound is of formula I or Ix wherein:
R A and R B together represent m the following
Figure imgf000012_0001
wherein the wavy lines represent the points of attachment to the phenyl ring,
A represents O, S or N(RA2),
RA represents H, Ci_4 alkyl or hydroxy,
RA2 represents H or Ci_4 alkyl;
or R B represents -Ci_4 alkylene-CN, -Ci_4 alkylene-OH or, particularly, Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci_2 alkoxy, or -NRX2S(0)2NRxRY;
RX represents Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci_2 alkoxy;
RY, RY and/or RY2 represents benzyl optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, Ci_2 alkoxy, NH2, N(H)-Ci_4 alkyl, N(Ci_4 alkyl)2, C(0)OH and C(0)0-(d.4 alkyl),
or RY, RY and/or RY2 represents Ci_6 alkyl, C3.7 cycloalkyl, phenyl, Het1 or Het2, which latter six groups are substituted by NH2, N(H)-Ci_4 alkyl, N(Ci_4 alkyl)2, C(0)OH or C(0)0-(Ci_4 alkyl) and optionally further substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, Ci.2 alkoxy, NH2, N(H)-Ci_4 alkyl, N(Ci_4 alkyl)2, C(0)OH and C(0)0-(Ci_4 alkyl); R D represents C2_7 alkyl, C2_7 alkenyl, C2_7 alkynyl, C3.7 cycloalkyl, phenyl, Het or Het2, which latter seven groups are substituted by cyano and optionally further substituted one or more substituents selected from Ci_2 alkyl, halo, cyano, hydroxy and Ci_2 alkoxy;
Rz represents hydroxy;
R4 represents -Q2-C(R6c)(R6d)-[Ci.5 alkylene]-R6a, which Ci-5 alkylene group is substituted by oxo, or, particularly, R4 represents -CH2OH, -COR6 or -Q -[C(R6c)(R6d)-(CH2)0-1CH2-O]1.12- CH2(CH2)o-iCH2-R6a in which R6c and/or R6d represents methyl (e.g. R4 represents -COR6 or -Q -[C(R6c)(R6d)-(CH2)0-1CH2-0]1.12-CH2(CH2)o-1CH2-R6a in which R6c and/or R6d represents methyl);
or, when R B represents either -C(0)NRxRY, in which RY represents optionally substituted Het1 or optionally substituted Het2, or -NRX2S(0)2NRxRY then R4 may alternatively represent H, halo, cyano, hydroxy, Ci_3 alkyl or Ci_3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
R5 represents -C(0)NH2 or, particularly, hydroxy; and/or
R6a represents C02H.
Particular alternative embodiments of the invention that may be mentioned include compounds of formula I in which:
R B represents -Ci_4 alkylene-CN or -Ci_4 alkylene-OH;
L represents Ci_2 alkylene;
R4 represents -CH2OH; and/or
R5 represents -C(0)NH2.
Other alternative embodiments of the invention that may be mentioned include compounds of formula I in which R4 represents -Q2-C(R6c)(R6d)-[Ci.5 alkylene]-R6a, which Ci-5 alkylene group is substituted by oxo.
Embodiments of the invention that may be mentioned include those in which the compound of formula I (or Ix) is
Figure imgf000013_0001
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R to R E, R2 to R5, L and X1 to X3 are as hereinbefore defined.
Embodiments of the invention that may be mentioned include those in which one or more of the following definitions apply to the compounds of formula I (or Ix) and la:
(a) R A and R B together represent a structural fragment selected from the following
Figure imgf000014_0001
R represents phenyl optionally substituted with one or more substituents selected from methyl and methoxy,
or, particularly, R A represents H, halo, Ci_4 alkyl or Ci_4 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
(b) RA represents H, Ci_2 alkyl or hydroxy,
(c) R B represents -CH2CN, -CH2OH or, particularly, R B represents H, halo, cyano, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRxS(0)2RY , -NRxC(0)ORY , Het or -NRX2S(0)2NRxRY (e.g. R B represents H, halo, cyano, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRxS(0)2RY or -NRxC(0)ORY );
(d) RX represents Het1 or, particularly, Rx and RX independently represent H or Ci_4 alkyl, or Rx and RX together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(RX2)-;
(e) RY represents benzyl, Het2 optionally substituted by one or more substituents selected from methyl, halo, hydroxy and methoxy or, particularly,
RY and RY independently represent Ci_4 alkyl, 03.6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from methyl, halo, hydroxy, methoxy, NH2, N(H)-Ci_2 alkyl, N(Ci_2 alkyl)2, C(0)OH and C(0)0-(Ci-2 alkyl) (e.g. by one or more substituents selected from methyl, halo, hydroxy and methoxy),
or RY represents H,
or Rx and RY together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(RX2)-;
(f) RX2 represents H or Ci_2 alkyl;
(9) R C and R E independently represent H or halo;
(h) R D represents trimethylsilyl, C3_7 alkyl, C(Ci_2 alkyl)2-C≡CH, C3.5 cycloalkyl, phenyl or Het2, which latter three groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo and Ci_2 alkoxy;
(i) R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring, or R2 and R3 independently represent halo or Ci_2 alkyl;
(j) X1 represents N or CH;
(k) L represents CH2 or, particularly, a direct bond;
(I) X2 and X3 both represent CH or one of X2 represents CH and X3 represents N or CRZ;
Rz represents H or halo;
R4 represents
CH2OH or, particularly,
-Q -[C(R6c)(R6d)CH2-0]1.8-CH2CH2-R6a,
-Q2-C(R6c)(R6d)-[d.4 alkylene]-R6a (e.g.
Figure imgf000014_0002
alkylene]- or -Q2-C(R6c)(R6d)-[Ci.2 alkylene]-R6a), which Ci_4 alkylene group is optionally substituted by oxo, -S(0)nR6 ,
-COR6 ;
or, when R B represents either -C(0)NRxRY, in which RY represents optionally substituted Het2, or -NRX2S(0)2NRxRY, then R4 may alternatively represent H, (e.g. R4 represents
-Q -[CH2CH2-0]1.8-CH2CH2-R6a),
-Q2-CHr[Ci-2 alkylene]-R6a or
-S(0)nR6 );
(o) R5 represents H or, particularly, cyano, chloro, fluoro, C2-3 alkynyl, C1-2 alkyl or Ci-2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms;
(p) R6a represents C02H or, particularly, OH, O-C1.2 alkyl or N(R7 )R7c;
(q) R6 represents Ci_5 alkyl or C3.5 cycloalkyl;
(r) R7 and R7c independently represent H or Ci-2 alkyl (e.g. methyl), or R7 and R7c, together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R7 and R7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more Ci_2 alkyl groups;
(s) Q and Q2 independently represent C(0)NH or O;
(t) n represents 0 or 2;
(u) Het1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
(v) Het2 represents a 4- to 6-membered (e.g. 5- or 6-membered) heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S.
Further embodiments of the invention that may be mentioned include those in which the compound of formula I, Ix or la is a compound of formula lb,
Figure imgf000015_0001
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R A to R E, R2 to R5, X1 and L are as hereinbefore defined.
Embodiments of the invention that may be mentioned include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la and lb: R represents H or, particularly, fluoro, chloro, methyl or Ci_2 alkoxy (e.g. methoxy), which latter two groups are optionally substituted by one or more fluoro atoms;
R B represents H, cyano, -C(0)ORx or, particularly, fluoro, chloro, Het , -C(0)NRxRY, -NRxS(0)2RY or -N(H)S(0)2NRxRY (e.g. H, cyano, -C(0)ORx or, particularly, fluoro, chloro, -C(0)NRxRY or -NRxS(0)2RY );
Rx represents H or methyl;
RY represents H, Het2, Ci_3 alkyl or C3.5 cycloalkyl, which latter two groups are optionally substituted by fluoro, hydroxy, methoxy, NH2, N(H)CH3, N(CH3)2, and C(0)OCH3,
or Rx and RY together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(RX2)-
(e.g. RY represents H or methyl);
RX2 represents H or methyl;
RY represents Ci_4 alkyl, C3.6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from halo, methyl and methoxy;
R C and R E independently represent fluoro or, particularly, H;
R D represents C4_6 alkyl, C(CH3)2-C≡CH, cyclopropyl or morpholinyl (e.g. morpholin-
4-yl), which latter two groups are optionally substituted by methyl;
R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring, or R2 and R3 both represent methyl or, particularly, chloro;
X1 represents N or CH;
L represents CH2 or, particularly, a direct bond;
Rz represents chloro or, particularly, H;
R4 represents
-Q -[C(R6c)(R6d)CH2-0]1.6-CH2CH2-R6a,
-C(0)NH-C(R6c)(R6d)-[Ci_3 alkylene]-R6a (e.g. -C(0)NH-C(R6c)(R6d)-[d.2 alkylene]-R6a), which Ci_3 alkylene group is optionally substituted by oxo,
-S(0)2R6 ,
-COR6 ;
or, when R B represents either -C(0)NRxRY, in which RY represents Het2, or -N(H)S(0)2NRxRY, then R4 may alternatively represent H,
(e.g. R4 represents
-Q -[CH2CH2-0]1.7-CH2CH2-R6a,
-C^NH-CH fd-z alkylene]-R6a or
-S(0)2R6 );
R5 represents H or, particularly, C2.3 alkynyl, Ci_2 alkyl or Ci_2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms (e.g. R5 represents methyl, trifluoromethyl or, particularly, -C≡CH or methoxy, which latter group is optionally substituted by one or more fluoro atoms);
R6a represents OH or, particularly, C02H, 0-CH3 or N(R7 )R7c (e.g. 0-CH3 or N(R7 )R7c);
R6 represents C3.5 cycloalkyl (e.g. cyclopropyl); (q) R and R both represent methyl, or R and R , together with the N-atom to which they are attached, form a 5- or 6-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R7 and R7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more methyl groups;
(r) Q represents C(0)NH or O;
(s) Het represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N, O and S;
(t) Het2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N,
O and S.
Further embodiments of the invention that may be mentioned include those in which the compound of formul
Figure imgf000017_0001
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof, wherein R A, R B and R D, R2 to R5, X1, L and Rz are as hereinbefore defined.
Embodiments of the invention that may be mentioned include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la, lb and Ic:
(a) R A represents H or, particularly, Ci_2 alkoxy (e.g. methoxy) optionally substituted by one or more fluoro atoms (e.g. R A represents methoxy);
(b) R B represents H, cyano, -C(0)OH, -C(0)N(CH3)2, fluoro, chloro, or, particularly, -C(0)N(H)RY, -NHS(0)2CH3, -N(H)S(0)2NRxRY or Het1
(e.g. H, cyano, -C(0)OH, -C(0)N(CH3)2, fluoro, chloro, or, particularly, -C(0)NH2, -C(0)N(H)CH3 or -NHS(0)2CH3 (e.g. R B represents H, cyano, -C(0)OH, -C(0)N(CH3)2, fluoro, -C(0)NH2, -C(0)N(H)CH3 or, particularly, -NHS(0)2CH3));
(c) Rx represents H or methyl;
(d) RY represents H, Het2, C3.5 cycloalkyl or Ci_3 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH2, N(H)CH3, N(CH3)2 or C(0)OCH3 (e.g. RY represents H or methyl),
or Rx and RY together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -0-;
(e) R D represents morpholinyl, cyclopropyl optionally substituted by methyl or, particularly, branched C4_6 alkyl (such as te/f-butyl) (e.g. R D represents morpholin-4- yl or, particularly, te/f-butyl); R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring, or R2 and R3 both represent chloro;
X1 represents N or CH;
L represents CH2 or, particularly, a direct bond;
R4 represents
-Q -[C(H)(R6c)CH2-0]1.6-CH2CH2-R6a,
-C(0)NH-C(H)(R6c)-[d.3 alkylene]-R6a (e.g. -C(0)NH-C(H)(R6c)-[C1.2 alkylene]- R6a), which Ci-3 alkylene group is optionally substituted by oxo,
-S(0)2-cyclopropyl
or, when R B represents either -C(0)N(H)RY, in which RY represents Het2, or -N(H)S(0)2NRxRY, then R4 may alternatively represent H,
(e.g. R4 represents
-Q -[CH2CH2-0]2.6-CH2CH2-OCH3,
-C(0)NH-CH2-CH2-N(R7 )R7c or
-S(0)2-cyclopropyl;
R5 represents H, -C≡CH, or methoxy, which latter group is optionally substituted by one or more fluoro atoms (for example, R5 represents -C≡CH or, particularly, methoxy, which latter group is optionally substituted by one or more fluoro atoms (e.g. R5 represents -C≡CH or, particularly, OCH3 or OCHF2));
R6a represents OH or, particularly, C02H, 0-CH3 or N(R7 )R7c (e.g. 0-CH3 or N(R7 )R7c);
R7 and R7c both represent methyl, or R7 and R7c, together with the N-atom to which they are attached, form a piperazinyl group optionally substituted by methyl, a pyrrolidinyl group or a morpholinyl group (e.g. a piperazinyl group optionally substituted by methyl or, particularly, a morpholinyl group); and/or
Q represents O or, particularly, C(0)NH.
Het1 represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N and O (e.g. Het1 represents oxadiazolyl, such as 1 ,2,4-oxadiazolyl, or triazolyl, such as 1 ,2,3-triazolyl);
Het2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S (e.g. Het2 represents oxetanyl, such as 3-oxetanyl).
Particular embodiments of the invention that may be mentioned include those in which one or more of the following definitions apply to the compounds of formula I, Ix, la, lb and lc:
(a) R A represents methoxy or ethoxy;
(b) R B represents Het1 or, particularly, -C(0)N(H)RY, -NHS(0)2CH3;
(c) RY represents H, Het2, cyclopropyl, Ci alkyl, optionally substituted with C(0)OCH3, or C2 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH2, N(H)CH3, N(CH3)2 or C(0)OCH3,
(d) R D represents te/f-butyl;
(e) R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring;
(f) X1 represents N or CH (e.g. X1 represents N or, particularly, CH); (g) L represents a direct bond;
(h) R4 represents
-Q -[C(H)(R6c)CH2-0]1.6-CH2CH2-R6a,
-C(0)NH-C(H)(R6c)-[Ci-3 alkylene]-R6a, which Ci.3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH3)CH2-R6a, -C(0)NH-CH2C(CH3)2-R6a,
-C(0)NH-CH2CH2CH2-R6a, -C(0)NH-CH2C(0)-R6a or, particularly, -C(0)NH-CH2CH2- R6a)
or
-S(0)2-cyclopropyl
or, particularly, when R B represents -C(0)N(H)-Het2, in which RY represents Het2, then R4 may alternatively represent H,
(e.g. R B represents -C(0)N(H)-Het2 and R4 represents H);
(i) R5 represents -C≡CH or methoxy optionally substituted by one or more fluoro atoms (to give, for example, OCH3 or OCHF2)
or, particularly, when R B represents -C(0)N(H)-Het2, in which RY represents Het2, then R5 may alternatively represent H.
More particular embodiments of the inventon that may be mentioned include those wherein:
(i) when R4 represents -C(0)NH-C(H)(R6c)-[Ci.3 alkylene]-R6a, which Ci.3 alkylene group is optionally substituted by oxo (e.g. -C(0)NH-C(H)(CH3)CH2-R6a,
-C(0)NH-CH2C(CH3)2-R6a, -C(0)NH-CH2CH2CH2-R6a, -C(0)NH-CH2C(0)-R6a or -C(0)NH-CH2CH2-R6a), then R6a represents N(R7 )R7c; or
(ii) when R4 represents -Q -[C(H)(R6c)CH2-0]1.6-CH2CH2-R6a, then R6a represents OH, C02H or 0-CH3 (e.g. 0-CH3).
Other embodiments of the invention that may be mentioned include those in which:
R B represents -NRX2S(0)2NRxRY or -C(0)NRxRY, in which latter group RY represents optionally substituted Het1 or optionally substituted Het2; and
both R4 and R5 represent H.
Still further embodiments of the invention that may be mentioned include those wherein, in the compound of formula I, Ix, la, lb and lc:
R4 represents
-Q -[C(R6c)(R6d)-(CH2)0-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a,
-Q2-C(R6c)(R6d)-[Ci-5 alkylene]-R6a, which Ci-5 alkylene group is optionally substituted by oxo,
-S(0)nR6 ,
-COR6 ,
-CH2OH,
or, when R B represents either -C(0)NRxRY, in which RY represents optionally substituted Het1 or optionally substituted Het2, or -NRX2S(0)2NRxRY, then R4 may alternatively represent H, halo, cyano or Ci_3 alkyl, which latter group is optionally substituted by one or more halo atoms;
Q and Q2 independently represent C(0)NH or S(0)p; and n and p independently represent 1 or 2.
Alternatively, embodiments of the invention that may be mentioned include those wherein, in the compound of formula I, Ix, la, lb and Ic:
when R4 represents
-SR6 ,
hydroxy,
Ci_3 alkoxy optionally substituted by one or more halo atoms,
-Q -[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a, wherein Q represents O or S or
-Q2-C(R6c)(R6d)-[Ci-5 alkylene]-R6a, which Ci-5 alkylene group is optionally substituted by oxo, wherein Q2 represents O or S,
then R5 represents Ci_3 alkyl, which latter group is optionally substituted by one or more halo atoms, or R5 represents H, cyano, -C(0)NH2, halo or C2-3 alkynyl.
Particular compounds of the invention that may be mentioned include those wherein, in the compound of formula I, Ix, la, lb and Ic, R4 represents:
-C^NH-fCCR^CR^-CCHzViCHz^Mz-CHzCCHzViCHz-R63 or
-C(0)NH-C(R6c)(R6d)-[Ci-5 alkylene]-R6a, which Ci_5 alkylene group is optionally substituted by oxo.
Other compounds of formula I, Ix, la, lb or Ic that may be mentioned include the compounds of the examples described hereinafter. Thus, embodiments of the invention that may be mentioned include those in which the compound of formula I, Ix, la, lb or Ic is a compound selected from the list:
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
3-ethynyl-5-((4-((4-(3-(3-fluoro-5-morpholinophenyl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2- yl)amino)-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methane- sulfonamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(cyclopropylsulfonyl)-5-methoxyphenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 1-(5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide; N-(5-(tert-butyl)-3-(3-(2,3-dichloro-4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)ureido)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide; 1-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)-3-(2-methoxy-5-morpholinophenyl)urea;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
N-(3-(3-(4-((2-((3-(2,5,8, 1 1 , 14,17,20-heptaoxadocosan-22-yloxy)-5-methoxyphenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; N-(5-(tert-butyl)-3-(3-(4-((2-((3-(difluoromethoxy)-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pynmidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-morpholinoethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)- methanesulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N,N-dimethylbenzamide; 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid;
1-(5-(tert-butyl)-3-cyano-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-(tert-butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
N-(3-(tert-butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide; 1-(3-amino-5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)-propanoic acid;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
1-(5-(tert-butyl)-2-methoxy-3-(pyrimidin-2-ylamino)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea; 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic acid; 3-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-
1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)propanoic acid;
2- methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methyl-5-morpholinobenzamide;
5-(tert-butyl)-N-cyclopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-(2-hydroxyethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-methoxyethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;
methyl 2-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)acetate;
N-benzyl-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
3- ((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-N-(2,5,8, 11 ,14, 17,20-heptaoxadocosan-22-yl)-5-methoxy- benzamide;
5-(tert-butyl)-N-ethyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-isopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(2-methoxyethyl)benzamide; 2-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)acetic acid; N-(3-(3-(4-((2-((3-(2,5,8, 1 1 , 14,17,20-heptaoxadocosan-22-yloxy)-5-methoxyphenyl)- amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methane- sulfonamide;
5-(tert-butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide;
3-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-
2- yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3- ((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(cyclopropanecarbonyl)-5-methoxyphenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)-benzarriide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-methoxyethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzenesulfonarTiide;
(R)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2-yl)benzarriide;
(S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2-yl)benzarriide;
N-(5-(tert-butyl)-3-(3-(4-((2-((4-chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pynmidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide;
1-(5-(tert-butyl)-2-methoxy-3-(1 ,3,4-oxadiazol-2-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
(S)-5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
(R)-5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
3-((4-((4-(3-(3-(tert-butyl)-5-carbamoylphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)- 5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
1-(5-(tert-butyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
1-(5-(tert-butyl)-2-methylbenzo[d]oxazol-7-yl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2- yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide;
(S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2- yl)benzamide;
(R)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2- yl)benzamide; N-(5-(tert-butyl)-2-ethoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;
1-(5-(tert-butyl)-2-methoxy-3-(1 H-1 ,2,3-triazol-5-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-1 , 1 , 1-trifluoro- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)cyclohexane- sulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)piperidine-1- sulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)dimethylamino sulfonamide;
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide;
N-(4-(tert-butyl)-6-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-[1 ,1 '-biphenyl]-2-yl)methanesulfonamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)morpholine-4- sulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)benzamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-5-methoxyphenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide; 5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(piperidin-1-yl)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1- yl)ureido)phenyl)morpholine-4-sulfonamide;
N-(2-aminoethyl)-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-tert-butyl-2-methoxy-N-(oxetan-3-yl)-3-[[4-[[2-(2-pyridylmethylamino)-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]benzamide; 5-tert-butyl-2-methoxy-3-[[4-[[2-(3-methoxyanilino)-4-pyridyl]oxy]-1-naphthyl]- carbamoylamino]-N-(oxetan-3-yl)benzamide; 3-[[4-[(2-anilino-4-pyridyl)oxy]-2,3- difluorophenyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-(oxetan-3-yl)benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N- tetrahydropyran-4-yl-benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-(1- methyl-4-piperidyl)benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-[(3R)- tetrahydrofuran-3-yl]benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-[(3S)- tetrahydrofuran-3-yl]benzamide;
1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[[2-[3-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]-5-methoxy-anilino]-4-pyridyl]oxy]-1-naphthyl]urea;
1- [5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[[2-[3-(hydroxymethyl)-5- methoxyanilino]-4-pyridyl]oxy]-1-naphthyl]urea;
5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxybenzamide;
5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxy-N-methyl-benzamide;
3-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-morpholino-2-oxo-ethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]-oxy]-
2- pyridyl]amino]-5-ethynyl-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide;
3- [[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-ethynyl-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-ethynyl-N-(3-morpholinopropyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]-5-methoxy-N-[2-(4-methylpiperazin-1-yl)ethyl]benza^ 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]-5-methoxy-N-(3-morpholinopropyl)benzamide;
5-tert-butyl-3-[[4-[2-[3-ethynyl-5-(2-morpholinoethylcarbamoyl)anilino]pyrimidin-4-yl]oxy-1^ naphthyl]carbamoylamino]-2-methoxy-benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-methyl-2-morpholino-propyl)benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-thiomorpholinoethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(1-oxo-1 ,4-thiazinan-4-yl)ethyl]benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(1 , 1-dioxo-1 ,4-thiazinan-4-yl)ethyl]-5-methoxybenzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-5-methoxybenzami 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonam
naphthyl]oxy]-2-pyridyl]amino]-N-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-5-methoxybenzam 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl]-5-methoxy- benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(1 ,4-oxazepan-4-yl)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(4-methyl-1 ,4-diazepan-1-yl)ethyl]benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-piperazin-1-ylethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]-5-methoxybenzamide; 3-[[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzam 3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-N-(2-morpholinoethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(2-methoxyethoxy)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl]- benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-hydroxy-1-piperidyl)ethyl]-5-methoxybenzamide; 1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethylsulfinyl]anilino]pyridin-4-yl]oxy-1-naphthyl]urea;
1-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethylsulfonyl]anilino]pyridin-4-yl]oxy-1-naphthyl]urea;
5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1-naphthyl]- carbamoylamino]-2-methoxy-N-(oxetan-3-yl)benzamide;
3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-5-methoxy-N-[2-[2-(2-methoxyethoxy)ethoxy]- ethyl]benzamide;
3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-5-methoxy-N-(2-morpholinoethyl)benzam
1-[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]-3-[4-[[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;
3-[[4-[[4-[[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2- pyridyl]amino]-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2- pyridyl]amino]-5-ethynyl-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide;
5-tert-butyl-3-[[4-[[2-[3-ethynyl-5-(hydroxymethyl)anilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxybenzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylami naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(4-oxo-1-piperidyl)ethyl]benzamide;an 5-tert-butyl-3-[[4-[[2-[3-ethynyl-5-(hydroxymethyl)anilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylarnino]-2-methoxy-N-methyl-benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
In this respect, particular embodiments of the invention that may be mentioned include those in which the compound of formula I, Ix, la, lb or lc is a compound selected from the list:
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide; and
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. Other particular embodiments of the invention that may be mentioned include those in which the compound of formula I, Ix, la, lb or lc is not:
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methane- sulfonamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide; and/or
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. Other particular embodiments of the invention that may be mentioned include those in which the compound of formula I, Ix, la, lb or lc either is or is not 3-((4-((4-(3-(5-(tert-butyl)-2- methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5- ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
Examples of salts of compounds of formula I, Ix, la, lb or lc include all pharmaceutically acceptable salts, such as, without limitation, acid addition salts of strong mineral acids such as HCI and HBr salts and addition salts of strong organic acids such as methanesulfonic acid.
References herein to a compound of the invention (a compound of formula I, Ix, la, lb or lc) 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. In this respect, solvates that may be mentioned include hydrates.
The compounds of the invention (compounds of formula I, Ix, la, lb or lc) 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.
(a) A pharmaceutical formulation comprising compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
(b) A combination product comprising
(A) a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and
(B) another therapeutic agent,
wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier. In this aspect of the invention, the combination product may be either a single
(combination) pharmaceutical formulation or a kit-of-parts.
Thus, this aspect of the invention encompasses a pharmaceutical formulation including a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and another therapeutic agent, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier (which formulation is hereinafter referred to as a "combined preparation").
It also encompasses a kit of parts comprising components: (i) a pharmaceutical formulation including a compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier; and
(ii) a pharmaceutical formulation including another therapeutic agent, in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier, which components (i) and (ii) are each provided in a form that is suitable for administration in conjunction with the other.
Component (i) of the kit of parts is thus component (A) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. Similarly, component (ii) is component (B) above in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier.
A process for preparing the pharmaceutical formulation of aspect (a) above, said process comprising the step of admixing the compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, with a pharmaceutically acceptable adjuvant, diluent or carrier.
Embodiments of this aspect of the invention that may be mentioned include those in which the pharmaceutically acceptable adjuvant, diluent or carrier is a topically acceptable adjuvant, diluent or carrier (and/or wherein the process is for preparing a topical pharmaceutical formulation, i.e. a pharmaceutical formulation that is adapted for topical administration).
A compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for use in medicine (or for use as a medicament or as a pharmaceutical).
A compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical formulation or combination product as defined in connection with aspect (a) or (b) of the invention, for use in the treatment or prevention of an inflammatory disease.
The use of
a compound of formula I, Ix, la, lb or Ic, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
a pharmaceutical formulation or combination product as defined in connection with aspect (a) or (b) of the invention,
for the preparation of a medicament for the treatment or prevention of an inflammatory disease.
A method of treating or preventing an inflammatory disease, said method comprising administering to a subject an effective amount of a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
a pharmaceutical formulation or combination product as defined in connection with aspect (a) or (b) of the invention.
(h) A method of sensitizing a subject to the anti-inflammatory effects of a corticosteroid, said method comprising administering to the subject an effective amount of
a compound of formula I, Ix, la, lb or lc, as hereinbefore defined, or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
a pharmaceutical formulation or combination product as defined in connection with aspect (a) or (b) of the invention.
Embodiments of this aspect of the invention that may be mentioned include those in which the subject is one who has become refractory to the anti-inflammatory effects of a corticosteroid.
Formulations
In relation to aspects (a) and (b) above, diluents and carriers that may be mentioned include those suitable for parenteral, oral, topical, mucosal and rectal administration.
The pharmaceutical formulations 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.
The pharmaceutical formulations 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. For buccal administration, typical 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. 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). Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form.
Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. Such two-piece hard shell capsules may be made from, for example, gelatin or hydroxylpropyl methylcellulose (HPMC).
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). Thus, 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.
Topical administration to the lung may be achieved by use of an aerosol formulation. Aerosol formulations typically comprise the active ingredient suspended or dissolved in a suitable aerosol propellant, such as a chlorofluorocarbon (CFC) or a hydrofluorocarbon (HFC). Suitable CFC propellants include trichloromonofluoromethane (propellant 1 1), dichlorotetrafluoroethane (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. 40% to 90% by weight of the total inhalation composition. The formulation may comprise excipients including co- solvents (e.g. ethanol) and surfactants (e.g. lecithin, sorbitan trioleate and the like). Other possible excipients include polyethylene glycol, polyvinylpyrrolidone, glycerine 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 or alternatively by Aptar, Coster or Vari).
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 e.g. one that can be hand-held and portable or for home or hospital use (i.e. non-portable). The formulation may comprise excipients such as water, buffers, tonicity adjusting agents, pH adjusting agents, surfactants and co-solvents. Suspension liquid and aerosol formulations (whether pressurised or unpressurised) will typically contain the compound of the invention in finely divided form, for example with a D50 of 0.5-10 μηι e.g. around 1-5 μηι. Particle size distributions may be represented using Di0, D50 and D90 values. The D50 median value of particle size distributions is defined as the particle size in microns that divides the distribution in half. The measurement derived from laser diffraction is more accurately described as a volume distribution, and consequently the D50 value obtained using this procedure is more meaningfully referred to as a Dv50 value (median for a volume distribution). As used herein Dv values refer to particle size distributions measured using laser diffraction. Similarly, Di0 and D90 values, used in the context of laser diffraction, are taken to mean Dvi0 and Dv90 values and refer to the particle size whereby 10% of the distribution lies below the Di0 value, and 90% of the distribution lies below the D90 value, respectively.
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 μηι or a D50 of 0.5-10 μηι e.g. around 1-5 μηι. Powders of the compound of the invention in finely divided form may be prepared by a micronization process or similar size reduction process. Micronization may be performed using a jet mill such as those manufactured by Hosokawa Alpine. The resultant particle size distribution may be measured using laser diffraction (e.g. with a Malvern Mastersizer 2000S instrument). The formulation will typically contain a topically acceptable diluent such as lactose, glucose or mannitol (preferably lactose), usually of large particle size e.g. an MMAD of 50 μηι or more, e.g. 100 μηι or more or a D50 of 40-150 μηι. As used herein, the term "lactose" refers to a lactose-containing component, including a-lactose monohydrate, β-lactose monohydrate, a-lactose anhydrous, β-lactose anhydrous and amorphous lactose. Lactose components may be processed by micronization, sieving, milling, compression, agglomeration or spray drying. Commercially available forms of lactose in various forms are also encompassed, for example Lactohale® (inhalation grade lactose; DFE Pharma), lnhal_ac®70 (sieved lactose for dry powder inhaler; Meggle), Pharmatose® (DFE Pharma) and Respitose® (sieved inhalation grade lactose; DFE Pharma) products. In one embodiment, the lactose component is selected from the group consisting of a-lactose monohydrate, α-lactose anhydrous and amorphous lactose. Preferably, the lactose is a- lactose monohydrate.
Dry powder formulations may also contain other excipients such as sodium stearate, calcium stearate or magnesium stearate.
A dry powder formulation is typically delivered using a dry powder inhaler (DPI) device. Examples of dry powder delivery systems include SPINHALER, DISKHALER, TURBOHALER, DISKUS and CLICKHALER. Further examples of dry powder delivery systems include ECLIPSE, NEXT, ROTAHALER, HANDIHALER, AEROLISER, CYCLOHALER, BREEZHALER/NEOHALER, MONODOSE, FLOWCAPS, TWINCAPS, X- CAPS, TURBOSPIN, ELPENHALER, MIATHALER, TWISTHALER, NOVOLIZER, PRESSAIR, ELLIPTA, ORIEL dry powder inhaler, MICRODOSE, PULVINAL, EASYHALER, ULTRAHALER, TAIFUN, PULMOJET, OMNIHALER, GYROHALER, TAPER, CONIX, XCELOVAIR and PROHALER.
In one embodiment a compound of the present invention is provided in a micronized dry powder formulation, for example further comprising lactose of a suitable grade optionally together with magnesium stearate, filled into a single dose device such as AEROLISER or filled into a multi dose device such as DISKUS.
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. Such compositions are prepared following standard procedures, well known by those skilled in the art. For example, suppositories can be prepared by mixing the active ingredient with a conventional suppository base such as cocoa butter or other glycerides, e.g., Suppocire. In this case, 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. Such materials are cocoa butter and polyethylene glycols.
Generally, for compositions intended to be administered topically to the eye in the form of eye drops or eye ointments, the total amount of the inhibitor will be about 0.0001 to less than 4.0% (w/w).
Preferably, for topical ocular administration, the 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. However, 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. The 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.
Various tonicity agents may be employed to adjust the tonicity of the composition, preferably to that of natural tears for ophthalmic compositions. For example, 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. In general, however, the 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). In general, 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) may be added to the compositions to prevent pH drift under storage conditions. The particular concentration will vary, depending on the agent employed. Preferably however, 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, polyoxyl 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, polycarbophil and Pemulen(R), specifically Carbomer 974p (polyacrylic acid), at 0.1-0.5% w/w. Other compounds may also be added to the ophthalmic compositions of the present invention to increase the viscosity of the carrier. Examples of 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. The medical practitioner, or other skilled person, will be able to determine a suitable dosage for the compounds of the invention, and hence the amount of the compound of the invention that should be included in any particular pharmaceutical formulation (whether in unit dosage form or otherwise). 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). For example, for the treatment of respiratory disorders (such as COPD or asthma), the other therapeutic agent is one or more agents selected from the list comprising:
steroids (e.g. budesonide, beclomethasone dipropionate, fluticasone propionate, mometasone furoate, fluticasone furoate; a further example is ciclesonide);
beta agonists, particularly beta2 agonists (e.g. terbutaline, salbutamol, salmeterol, formoterol; further examples are vilanterol, olodaterol, reproterol and fenoterol); and xanthines (e.g. theophylline).
For example, for the treatment of respiratory disorders (such as COPD or asthma), the other therapeutic agent is one or more agents selected from the list comprising:
- muscarinic antagonists (e.g. tiotropium, umeclidinium, glycopyrronium, aclidinium and daratropium, any of these for example as the bromide salt); and
phosphodiesterase inhibitors.
Further, for the treatment of gastrointestinal disorders (such as Crohn's disease or ulcerative colitis), the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide);
corticosteroids (e.g. prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate, azathioprine or 6- mercaptopurine);
anti-TNFa antibodies (e.g., infliximab, adalimumab, certolizumab pegol or golimumab);
- anti-IL12/IL23 antibodies (e.g., ustekinumab) or small molecule IL12/IL23 inhibitors (e.g., apilimod);
Αηίί-α4β7 antibodies (e.g., vedolizumab);
MAdCAM-1 blockers (e.g., PF-00547659);
antibodies against the cell adhesion molecule a4-integrin (e.g., natalizumab);
- antibodies against the IL2 receptor a subunit (e.g., daclizumab or basiliximab);
JAK3 inhibitors (e.g., tofacitinib or R348);
Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406);
Phosphodiesterase-4 inhibitors (e.g., tetomilast);
HMPL-004;
- probiotics;
Dersalazine;
semapimod/CPSI-2364; and
protein kinase C inhibitors (e.g. AEB-071).
For the treatment of eye disorders (such as uveitis and keratoconjunctivitis sicca (dry eye)), the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide);
glucocorticoid agonists (e.g., mapracorat);
immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus);
anti-TNFa antibodies (e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab);
anti-IL-17A antibodies (e.g., secukinumab);
mTOR inhibitors (e.g., sirolimus);
VGX-1027;
adenosine A3 receptor agonists (e.g., CF-101);
lifitegrast;
JAK3 inhibitors (e.g., tofacitinib or R348); and
protein kinase C inhibitors (e.g. AEB-071).
In particular embodiments, for the treatment of eye disorders (such as uveitis and keratoconjunctivitis sicca (dry eye)), the other therapeutic agent may be, for example, one or more agents selected from the list comprising:
corticosteroids (e.g. dexamethasone, prednisolone, triamcinolone acetonide, difluprednate or fluocinolone acetonide);
immunosuppressants (e.g. cyclosporin, voclosporin, azathioprine, methotrexate, mycophenolate mofetil or tacrolimus); anti-TNFa antibodies (e.g., infliximab, adalimumab, certolizumab pegol, ESBA-105 or golimumab);
anti-IL-17A antibodies (e.g., secukinumab);
mTOR inhibitors (e.g., sirolimus);
- VGX-1027;
JAK3 inhibitors (e.g., tofacitinib or R348); and
protein kinase C inhibitors (e.g. AEB-071).
Medical Uses
The compounds of the invention may be used as monotherapies for inflammatory diseases, or in combination therapies for such diseases.
Thus, embodiments of aspects (e) to (g) above that may be mentioned include those in which the compound of formula I, Ix, la, lb or Ic (or pharmaceutically acceptable salt, solvate or isotopic derivative thereof) is the sole pharmacologically active ingredient utilised in the treatment.
However, in other embodiments of aspects (e) to (g) above, the compound of formula I, Ix, la, lb or Ic (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).
When used herein, the term "inflammatory disease" specifically includes references to any one or more of the following:
(i) lung diseases or disorders having an inflammatory component, such as cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis or, particularly, COPD (including chronic bronchitis and emphysema), asthma or paediatric asthma;
(ii) skin diseases or disorders having an inflammatory component, such as atopic dermatitis, allergic dermatitis, contact dermatitis or psoriasis;
(iii) nasal diseases or disorders having an inflammatory component, such as allergic rhinitis, rhinitis or sinusitis;
(iv) eye diseases or disorders having an inflammatory component, such as conjunctivitis, allergic conjunctivitis, glaucoma, diabetic retinopathy, macular oedema (including diabetic macular oedema), central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, or, particularly, keratoconjunctivitis sicca (dry eye), uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection; and
(v) gastrointestinal diseases or disorders having an inflammatory component, such as gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease or, particularly, Crohn's disease or ulcerative colitis. 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. According to a further aspect of the invention there is provided a process for the preparation of a compound of formula I which process comprises: reaction of a compound of formula II,
\.
N=C=0
with a compound of formula III,
Figure imgf000038_0001
wherein one of Z and Z2 is a structural fragment of formula IV
Figure imgf000038_0002
and the other of Z and Z2 is a structural fragment of formula V
Figure imgf000038_0003
where R A to R E, R2 to R5, L and X1 to X3 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); reaction of a compound of formula Ila,
Figure imgf000038_0004
wherein Z 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 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 A/,A/-diisopropylethylamine) and a suitable organic solvent (e.g. a polar aprotic solvent such as DMF, THF, 1 ,4-dioxane, or mixtures thereof), which reaction is followed, without isolation, by thermal rearrangement (e.g. under heating) of the intermediate acyl azide (of formula Z -C(0)-N3) e.g. at ambient temperature (such as from 15 to 30°C) to provide, in situ, a compound of formula II, which compound is then reacted with a compound of formula III, as defined above, to provide the compound of formula I; reaction of a compound of formula lib,
Figure imgf000039_0001
wherein LG1 represents a suitable leaving group (e.g. imidazolyl, chloro, or aryloxy, such as phenoxy) and Z 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 ambient to 80°C), optionally in the presence of an amine base (e.g. triethylamine or a sterically hindered base like A/./V-diisopropylethylamine) and a suitable organic solvent (e.g. an aprotic solvent, such as dichloromethane or an ester such as isopropyl acetate);
(d) reaction
Figure imgf000039_0002
wherein LG2 represents a suitable leaving group (e.g. a halo group such as chloro or bromo) and R A to R E, R2, R3 and X1 are as hereinbefore defined with a compound of formula VII,
Figure imgf000039_0003
wherein R4, R5, L, X2 and X3 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 mixtures thereof) and, optionally, an acidic catalyst (e.g. a sulfonic acid such as para-toluenesulfonic acid); or
(e) for compounds of formula I in which R4 represents
-S(0)1.2-[C(R6c)(R6d)-(CH2)o-1CH2-0]1.12-CH2(CH2)o-1CH2-R6a,
alkylene]-R6a,
Figure imgf000039_0004
oxidation of a corresponding compound of formula I in which, respectively, represents -S-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a,
-S-CCR^CR^-fd-s alkylene]-R6a,
-S-R6 ,
wherein R6a to R6d are as hereinbefore defined, for example under conditions known to those skilled in the art (e.g. at 0 to 25°C in the presence of a suitable solvent (such as dichloromethane, methanol or a mixture thereof) and a peracid, such as meta- chloroperbenzoic acid);
(f) for compounds of formula I in which R4 represents
-C^NH-fCiR^iR^-iCHzViCHz^Mz-CHziCHzViCHz-R63 or -CCC NH-CCR^XR^-fC!-s alkylene]-R6a,
which Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula Vila,
Figure imgf000040_0001
wherein R4' represents H or a Ci_3 alkyl group (e.g. methyl) and R A to R E, R2, R3, R5, L and X1 to X3 are as hereinbefore defined, with a compound of formula Vllb or Vile,
H2N-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a Vllb
Figure imgf000040_0002
or Vile which Ci-5 alkylene group is optionally substituted by oxo, wherein R and R are as hereinbefore defined, and R6a takes the same definition as R6a above, except that C02H is only present in protected form (e.g. as C(0)0-Ci_4 alkyl), for example under conditions known to those skilled in the art, such as (i) when R4' represents a Ci_3 alkyl group, reaction at ambient temperature in the presence of a suitable Lewis acidic catalyst (e.g. a trialkyl aluminium reagent such as trimethylaluminium) and an aprotic organic solvent (e.g. THF) or (ii) when R4' represents H, reaction in the presence of a tertiary amine base (e.g. a trialkylamine such as triethylamine or diisopropylethylamine or a cyclic amine such as N- methylpyrrolidine or N-methylmorpholine), an amide (peptide) coupling reagent (e.g. T3P, HATU, CDI, BOP, PyBOP, HOAt, HOBt or a carbodiimide such as DCC or diisopropylcarbodiimide) and an aprotic organic solvent (e.g. a chlorinated solvent such as DCM, an ester such as ethyl acetate, an amide of dimethylamine such as DMF, or a mixture of any such solvents), followed, if necessary, by deprotection of R6a when that group represents C(0)0-Ci_4 alkyl;
(g) for compounds of formula I in which R represents -C(0)NRxRY, reaction of compound of formula VI Id,
wherein R A, R C, R D, R E, Ra, R , X1 to X3, L, R4 and R5 are as hereinbefore defined and Rx represents H or Ci_4 alkyl, with a compound of formula Vile,
Figure imgf000041_0001
wherein Rx and RY are as hereinbefore defined, under conditions known to those skilled in the art, for example
when Rx represents H, reaction in the presence of a suitable solvent, a base (e.g. triethylamine or A/./V-diisopropylethylamine) and an amide (peptide) coupling reagent, such as HATU, CDI, Λ/,Λ/'-dicyclohexylcarbodiimide, Λ/,Λ/'-diisopropylcarbodiimide BOP or PyBOP, optionally in combination with an activated ester-forming agent such as HOBt or 1-hydroxy-7- azabenzotriazole,
when Rx represents H, conversion of the carboxylic acid to an acid halide (e.g. by reaction with a halogenating agent such as thionyl chloride), followed by reaction with the compound of formula (XI) in the presence of a suitable solvent and a base (e.g. triethylamine or A/./V-diisopropylethylamine), or
when Rx represents Ci_4 alkyl (e.g. methyl), reaction in the presence of a trialkylaluminium (e.g. trimethylaluminium) and an aprotic solvent (e.g. THF);
(h) 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 lla, 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).
Compounds of formula lib may be prepared reaction of a compound of formula VIII,
Figure imgf000041_0002
wherein LG is as hereinbefore defined, with a compound of formula IX, Z1^NH2 IX
wherein Z 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 I la 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. By the same token, the intermediate isocyanate II can be reacted with an alcohol, such as f-butanol, to generate a protected version of IX.
Certain compounds of formula III in which Z2 represents a structural fragment of formula V, or compounds of formula IX in which Z represents a structural fragment of formula V, may be synthesised employing the route outlined in Scheme 1 (see, for example: WO 2003/072569; and WO 2008/046216), wherein R2, R3 and X1 to X3 are as hereinbefore defined, LG3 and LG4 represent leaving groups, e.g., halogen or methanesulfonyl, and FG represents a real or latent NH2 group, i.e., a group that is readily transformed into an NH2 group, such as nitro or a protected variant NH-PG2, where PG2 is a typical protecting group (see, for example: Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wley, 4th revised edition, 2006; ISBN-10: 0471697540), e.g., a carbamate ester or carboxamide. The sequence starts with the base-mediated SNAr displacement of LG3 in XI by the aroxides formed when X is treated with base to generate ethers XII. The remaining halogen or methanesulfonyl substituent (LG4) of the ether XII is then displaced i) by an amine of formula VII in a second SNAr 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 NH2), or XIII (when FG is nitro or NH-PG2). When FG is nitro in XIII, the NH2 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. Alternatively, when FG is a protecting group, the NH2 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 NH2 group represented by FG can take place at any stage in the synthetic route shown in Scheme 1.
Scheme 1
Figure imgf000043_0001
In a similar manner, amines of formula IX in which Z represents a structural fragment of formula IV may be synthesised by conversion of a latent to a real NH2 group in a compound of formula Xllla,
Xllla
Figure imgf000043_0002
wherein FG' is as defined for FG above, except that it does not represent NH2, and R A to R E are as hereinbefore defined. Compounds of formula III in which Z2 represents a structural fragment of formula V, or compounds of formula IX in which Z represents a structural fragment of formula V, wherein, in the structural fragment of formula V, R4 represents
-C^NH-fCCR^CR^-CCHzViCHz^Mz-CHzCCHzViCHz-R63 or
Figure imgf000043_0003
alkylene]-R6a,
which Ci-5 alkylene group is optionally substituted by oxo, may be prepared by analogy with processes described herein for preparing compounds of formula I (see process (f) above) and other compounds of formula III (see, for example, Scheme 1 above), for example by reaction of a compound of Xllla
Figure imgf000044_0001
wherein FG, R2, R3, R4 , R5, L and X1 to X3 are as hereinbefore defined, with a compound of formula Vllb or Vile, as hereinbefore defined, under conditions known to those skilled in the art (for example the peptide coupling conditions described in respect of process (f) above), followed by conversion (if necessary) of FG to NH2, for example as described above in connection with Scheme 1.
Compounds of formula VI may be synthesised by analogy with the compounds of formula I (see, for example, alternative processes (a) to (c) above). For example, compounds of formula VI can be prepared by reaction of a compound of formula llx with a compound of formula Mix, wherein the compounds of formulae llx and Mix take the same definitions as the compounds of formulae II and III, with the exception that one of Z and Z2 represents a structural fragment of formula IV, as hereinbefore defined, and the other of Z and Z2 represents a structural fragm
Figure imgf000044_0002
Compounds of formula VII in which L represents a direct bond may be prepared according to or by analogy with procedures known to those skilled in the art, for example as described below.
(i) For compounds of formula VII in which R4 represents
-0-[C(R6c)(R6d)-(CH2)o.1CH2-0]1.12-CH2(CH2)o.1CH2
-O-C R^XR^Hd-s alkylene]-R6a,
reaction of a compound of
Figure imgf000044_0003
wherein FG1 either represents FG or C(0)0-(Ci_6 alkyl), and FG, R5, X2 and X3 are as hereinbefore defined, with a compound of formula XVa or XVb
LG5-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a XVa LG5-C(R6c)(R6d)-[Ci-5 alkylene]-R6a XVb wherein LG5 represents a suitable leaving group such as halo, (perfluoro)alkane- sulfonate or arylsulfonate (e.g. methanesulfonate or p-toluenesulfonate) and R6a , R6c and R6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of an organic solvent and either a suitable base, followed by when FG represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above) and/or by deprotection of R6a when that group represents C(0)0-Ci_4 alkyl.
For compounds of formula VII in which R4 represents
-0-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a or
-O-C R^XR^Hd-s alkylene]-R6a
reaction of a compound of formula XIV, as hereinbefore defined, with a compound of formula XVIa or XVIb
HO-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a XVIa
HO-C(R6c)(R6d)-[Ci-5 alkylene]-NR6a XVIb
wherein R6a , R6c and R6d are as hereinbefore defined, under conditions known to those skilled in the art (e.g. under Mitsunobu conditions, i.e. in the presence of using triphenylphosphine and an azodicarboxylate, such as diethyl azodicarboxylate or diisopropyl azodicarboxylate), followed by
when FG1 represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above) and/or by deprotection of R6a when that group represents C(0)0-Ci_4 alkyl.
For compounds of formula VII in which R4 represents
-S-[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a,
-S-C R^XR^HCLs alkylene]-R6a or
-S-R6 ,
reaction of a compound of
Figure imgf000045_0001
wherein FG1 , R5, X2 and X3 are as hereinbefore defined, with a compound of formula XVa or XVb, as hereinbefore defined, or a compound of formula XVIII
,6b
LG5-R' XVIII wherein LG5 and R6 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a suitable base and an organic solvent), followed by
when FG represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above).
For compounds of formula VII in which X2 and X3 both represent CRZ and R4 represents
-S(0)1.2-[C(R6c)(R6d)-(CH2)o-1CH2-0]1.12-CH2(CH2)o-1CH2-R6a,
-S O z-C R^XR^Md-s alkylene]-R6a or oxidati
Figure imgf000046_0001
wherein R represents
-[C(R6c)(R6d)-(CH2)0-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a,
-C R^XR^Hd-s alkylene]-R6a or
-R6b,
and FG1 and R5 are as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a peracid, such as mefa-chloroperbenzoic acid), followed by
when FG1 represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above).
For compounds of formula VII in which R4 represents -S-R6 , coupling of a compound of formula XX
Figure imgf000046_0002
wherein LG6 represents a suitable leaving group such as halo trifluoromethanesulfonate, FG1, R5, X2 and X3 are as hereinbefore defined, with compound of formula XXI, H-S-R6b XXI wherein R6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. in the presence of a Pd(0) catalyst, Cu(l) iodide and a suitable base), followed by
when FG represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above).
For compounds of formula VII in which R4 represents
-Q -[C(R6c)(R6d)-(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a
wherein Q and R6a are as hereinbefore defined, reaction of a compound of formula XXII
Figure imgf000047_0001
in which R4a represents
-Q -[C(R6c)(R6d)-(CH2)o-iCH2-0]x-CH2(CH2)o-iCH2-OH
with a compound of formula XXIII,
LG5-[CH2(CH2)o-iCH2-0]y-CH2(CH2)o-iCH2-R6a XXIII
wherein x and y are integers from 0 to 1 1 , the sum of x and y being from 0 to 11 , and Q , LG5 and R6a are as hereinbefore defined, under conditions known to those skilled in the art (e.g. at ambient temperature in the presence of a base such as sodium hydride and a polar organic solvent such as DMF).
For compounds of formula VII in which X2 and X3 both represent CRZ represents
-S-C R^XR^HCLs alkylene]-N(R7 )R'
reaction of a compound of
Figure imgf000047_0002
wherein R' represents
Figure imgf000047_0003
alkylene]-LG6
with a compound of formula HN(R7 )R7c, wherein FG1, R5, R6 , R6c, R7 , R7c, Rz and LG6 are as hereinbefore defined, under conditions known to those skilled in the art (for example in the presence of a suitable organic solvent (e.g. acetone) and, optionally, catalyst for nucleophilic displacement, such as an iodide sale (e.g. sodium iodide)), followed by when FG represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above).
For compounds of formula VII in which R4 represents
-C(0)NH-[CH2(CH2)o-iCH2-0]1.12-CH2(CH2)o-iCH2-R6a or
-C(0)NH-C(R6c)(R6d)-[Ci-5 alkylene]-R6a,
which Ci-5 alkylene group is optionally substituted by oxo, reaction of a compound of formula XXV,
Figure imgf000048_0001
wherein FG1, R4', R5, R6a, R6 and R6d, X2 and X3 are as hereinbefore defined, with a compound of formula Vllb or Vile, as hereinbefore defined, under conditions known to those skilled in the art (for example the peptide coupling conditions described in respect of process (f) above), followed by
when FG1 represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above). (ix) For compounds of formula VII in which R4 represents -S(0)2-R6 , coupling of a compound of formula XXVI
Figure imgf000048_0002
wherein R5, X2, X3, FG1 and LG6 are as hereinbefore defined, with a compound of formula XXVII,
(Ms+)(O-S(0)-R6 )s XXVII wherein Ms+ is a metal cation, s is 1 or 2 (e.g. s is 1 and M is an alkali metal such as potassium or, particularly, sodium) and R6 is as hereinbefore defined, under conditions known to those skilled in the art (e.g. at elevated temperature (e.g. 80 to 100°C) in the presence of: a suitable transition metal catalyst, such as Cu(l) iodide; an aprotic organic solvent, such as DMSO; a suitable base, such as an alkali metal hydroxide (e.g. NaOH); and, optionally, an organic ligand for Cu(l), such as L-proline), followed by when FG represents NH-PG2, removal of the PG2 protecting group, when FG1 represents N02, reduction of N02 to NH2 or
when FG1 represents C(0)0-(Ci.6 alkyl), saponification to provide the corresponding carboxylic acid and then reaction with a suitable azide-forming agent and thermal rearrangement of the resulting acyl azide (see, for example, process (b) above).
Compounds of formula VII in which L represents Ci_2 alkylene may be prepared by analogous procedures.
Similar interconversions of functional groups may also be employed to prepare compounds of formula Xllla. For example, compounds of formula XI Ma in which R B represents -CH2CN may be prepared by reaction of a compound of formula XXVI la,
Figure imgf000049_0001
wherein FG, LG2, R A and R C to R E are as hereinbefore defined, with a source of cyanide ion (e.g. NaCN), for example under conditions known to those skilled in the art, such as in the presence of a polar, aprotic organic solvent (e.g. DMSO).
Compounds of formula XXIV in which LG6 represents halo can be prepared according to or by analogy with procedures known to those skilled in the art, for example by reaction of a compound of formula XXVIII,
XXVIII
Figure imgf000049_0002
wherein R" represents -CH2-[Ci_5 alkylene]-OH, with a halogenating agent (e.g. a mixture of 2,4,6-trichloro, 1 ,3,5-triazine and dimethylformamide).
Compounds of formula XXVIIa may be prepared according to (or by analogy with) procedures know to those skilled in the art. For example, compounds of formula XXVIIa in which LG2 represents CI may be prepared by chlorination of a corresponding compound of formula XXVI lb,
Figure imgf000049_0003
wherein FG, R A and R C to R E are as hereinbefore defined, for example under conditions known to those skilled in the art, such as by reaction with thionyl chloride. Compounds of formula XXVI lb may, for example, be prepared by reduction of corresponding compounds of formula XXVI Ic,
Figure imgf000050_0001
wherein FG, RX, R A and R C to R E are as hereinbefore defined, for example under conditions known to those skilled in the art, such as by reaction with borohydride or aluminium hydride-based reducing agent (e.g. an alkali metal borohydride or aluminium hydride, such as lithium borohydride or lithium aluminium hydride) in the presence of a reaction-inert organic solvent.
It will be understood by persons skilled in the art that compounds represented by formulae II, llx and lib are generally reactive intermediates. These intermediates may be formed in situ and reacted directly, without isolation, with compounds of formula III to provide compounds of formula I. Furthermore, it will be understood by those skilled in the art that the use of appropriate protective groups may be required during the processes described above for any of the groups Z and Z2 which possess chemically-sensitive functional groups, for example, a hydroxyl group or an amino function.
Many of the compounds illustrated in the Schemes are either commercially available, or can be obtained using the cited procedures, or can be readily prepared by conventional methods by those skilled in the art. See for example Regan, J. et al.; J. Med. Chem. 2003, 46, 4676- 4686, WO 2000/043384, WO 2007/053346, WO 2007/087448, WO 2007/089512, WO 2009/117080 and WO 2014/027209. Novel intermediates as described herein form an aspect of the invention. In this respect, a further aspect of the invention relates to a compound of formula lib as hereinbefore defined (e.g. a compound of formula lib in which LG represents phenoxy). Particular compounds of formula lib that may be mentioned include those in which:
Z represents a structural fragment of formula IV, in which R A, R B, R C, R D and R E are as hereinbefore defined (e.g. in which R A, R B, R C, R D and R E take the combinations of definitions illustrated in respect of those groups in any of the compounds of the examples); and
LG1 is as hereinbefore defined (e.g. LG1 represents phenoxy).
The aspects of the invention described herein (e.g. the above-mentioned compounds, combinations, methods and uses) 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 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):
exhibit a long duration of action and/or persistence of action (e.g. in comparison to other previously disclosed p38 MAP kinase inhibitors such as, for example, BIRB796);
- not strongly inhibit GSK 3a (e.g. they may have an IC50 against GSK 3a of 1 ,000 nM or greater; such as 1 ,500, 2,000, 3,000, 4,000, 5,000, 6,000, 7,000, 8,000, 9,000 or 10,000 nM or greater);
target a smaller portion of the kinome, i.e., with improved selectivity, as illustrated by lowered KinomeScan Selectivity Scores;
- maintain a relatively high local drug concentration between doses (e.g. a high local concentration relative to other previously disclosed p38 MAP kinase inhibitors such as, for example, BIRB796);
exhibit properties that are particularly suited to topical/local administration (e.g. following topical/local administration, the generation of high target tissue concentrations but low plasma concentrations of the compounds of formula (I) and/or rapid clearance of the compounds of formula (I) from plasma, for example as a result of high renal or hepatic extraction);
exhibit little or no β-catenin induction and/or inhibition of mitosis in cells;
not produce increases in binucleated cells containing micronuclei in the human lymphocyte in vitro micronucleus test;
exhibit little or no time-dependent inhibition of members of the cytochrome P450 superfamily;
show improved chemical stability in the presence of water (e.g. stability to hydrolysis in aqueous mixtures at elevated temperatures) compared to previously disclosed p38 MAP kinase inhibitors such as, for example, BIRB796;
following administration to a patient, give rise to metabolites associated with little or no safety (e.g. toxicity) concerns;
exhibit good solubility and/or cellular permeability;
have a high degree of crystallinity; and/or
- exhibit little or no hygroscopicity in the solid state.
Experimental Methods
General Procedures
All starting materials and solvents were obtained either from commercial sources or prepared according to the literature citation. Unless otherwise stated all reactions were stirred. Organic solutions were routinely dried over anhydrous magnesium sulfate. Hydrogenations were performed on a Thales H-cube flow reactor under the conditions stated or under a balloon of hydrogen. Microwave reactions were performed in a CEM Discover and Smithcreator microwave reactor, heating to a constant temperature using variable power microwave irradiation. Normal phase column chromatography was routinely carried out on an automated flash chromatography system such as CombiFlash Companion or CombiFlash RF system using pre-packed silica (230-400 mesh, 40-63 μηι) cartridges. SCX was purchased from Supelco and treated with 1 M hydrochloric acid prior to use. Unless stated otherwise the reaction mixture to be purified was first diluted with MeOH and made acidic with a few drops of AcOH. This solution was loaded directly onto the SCX and washed with MeOH. The desired material was then eluted by washing with 1 % NH3 in MeOH.
Analytical Methods Analytical HPLC was carried out using a Waters Xselect CSH C18, 2.5 μηι, 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μηι, 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. 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 a Waters Xselect CSH C18, 2.5 μηι, 4.6x30 mm column eluting with a gradient of 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a Waters Xbridge BEH C18, 2.5 μηι, 4.6x30 mm column eluting with a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. UV and mass spectra of the eluted peaks were measured using a variable wavelength detector on either an Agilent 1200 or an Agilent Infinity 1260 LCMS with 6120 single quadrupole mass spectrometer with positive and negative ion electrospray.
Preparative HPLC was carried out using a Waters Xselect CSH C18, 5 μηι, 19x50 mm column using either a gradient of either 0.1 % Formic Acid in MeCN in 0.1 % aqueous Formic Acid or a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate or employing a Waters Xbridge BEH C18, 5 μηι, 19x50 mm column using a gradient of MeCN in aqueous 10 mM Ammonium Bicarbonate. Fractions were collected following detection by UV at a single wavelength measured by a variable wavelength detector on a Gilson 215 preparative HPLC or Varian PrepStar preparative HPLC or by mass and UV at a single wavelength measured by a ZQ single quadrupole mass spectrometer, with positive and negative ion electrospray, and a dual wavelength detector on a Waters FractionLynx LCMS.
1H NMR Spectroscopy: H NMR spectra were acquired on a Bruker Avance III spectrometer at 400 MHz. Either the central peaks of chloroform-d, dimethylsulfoxide-cfe or an internal standard of tetramethylsilane were used as references.
Preparation of Compounds of the Invention Example 1
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
Figure imgf000053_0001
(i) 3-Amino-5-bromo-N-(2-morpholinoethyl)benzamide
T3P (50% w/w in EtOAc, 56.2 mL, 94 mmol), was added carefully to a solution of 3-amino-5- bromobenzoic acid (13.6 g, 63.0 mmol), 2-morpholinoethanamine (16.52 mL, 126 mmol) and
Et3N (26.3 mL, 189 mmol) in DCM (200 mL). An ice bath was used sporadically to prevent temperature rising above 35°C. Reaction stirred at room temperature for 1 h. Partitioned with sat. aq. NaHC03 solution (250 mL). Aqueous separated and partitioned with fresh DCM
(250 mL). Organics separated, bulked and partitioned with 20%w/w NaCI solution (250 mL). The organic layer was separated, dried (MgS04), filtered and solvent evaporated. The crude product was dissolved in DCM (100 mL) and the sub-title compound (13 g) crystallised out on standing as a light tan crystalline solid.
H NMR (400 MHz, DMSO-d6) δ 8.29 (t, 1 H), 7.06 (t, 1 H), 6.98 (t, 1 H), 6.85 (t, 1 H), 5.59 (s, 2H), 3.57 (t, 4H), 3.41 - 3.26 (m, 2H), 2.48 - 2.33 (m, 6H).
LCMS m/z 328/330(M+H)+ (ES+)
(ii) 3-Amino-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethvnyl)benzamide
Pd(PPh3)4 (2.90 g, 2.51 mmol) was added to a degassed suspension of the compound from step (i) above (16.5 g, 50.3 mmol), Cul (0.479 g, 2.51 mmol), and ethynyltriisopropylsilane
(16.92 mL, 75 mmol) in Et3N (30 mL) and DMF (150 mL). Reaction heated at 85°C (block temp.) for 5h then cooled and filtered (Whatman glass fibre pad GF/C). Solvents evaporated and the residue partitioned between EtOAc (500 mL) and 20%w/w NaCI solution (500 mL).
Aqueous layer separated and washed with fresh EtOAc (500 mL). Organic layers bulked, washed with fresh 20%w/w NaCI solution (500 mL), dried (MgS04), filtered and solvent evaporated to a thick brown oil. The crude product was purified by chromatography on silica gel (220 g column, 2% MeOH:DCM to 10%) to afford the sub-title compound (18.5 g) as a pale yellow glass.
H NMR (400 MHz, DMSO-d6) δ 8.29 (t, 1 H), 7.04 (dd, 1 H), 7.02 (t, 1 H), 6.79 (dd, 1 H), 5.44 (s, 2H), 3.57 (t, 4H), 3.37 - 3.28 (m, 2H), 2.47 - 2.36 (m, 6H), 1.11 (s, 21 H).
LCMS m/z 430 (M+H)+ (ES+) (iii) 3-Amino-5-ethvnyl-N-(2-morpholinoethyl)benzamide
The compound from step (ii) above (18.5 g, 43.1 mmol) was dissolved in EtOAc (250 mL) and TBAF (1.0 M in THF, 43.1 mL, 43.1 mmol) added. The reaction was stirred for 1 h, then partitioned between water (500 mL) and ethyl acetate (200 mL). Organic layer was separated, washed with 20%w/w NaCI solution (400 mL), dried (MgS04), filtered and solvents evaporated. The crude product was slurried in Et20 (100 mL) for 30 minutes, filtered and washed with fresh Et20 (20 mL). The solid was oven dried at 45°C to afford the sub-title compound (9.2 g).
H NMR (400 MHz, DMSO-d6) δ 8.28 (t, 1 H), 7.12 - 6.97 (m, 2H), 6.76 (t, 1 H), 5.45 (s, 2H), 4.08 (s, 1 H), 3.57 (t, 4H), 3.41 - 3.25 (m, 2H), 2.48 - 2.32 (m, 6H).
LCMS m/z 274 (M+H)+ (ES+)
(iv) tert-Butyl (4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate
A solution of tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 6.46 g, 17.37 mmol), the compound from step (iii) above (7.12 g, 26.0 mmol) and p-TSA monohydrate (5.62 g, 29.5 mmol) in
DMF (60 mL) was heated at 55°C (internal temperature) for 7h. The mixture was cooled and added dropwise to sat. aq NaHC03 (1 L). Solid filtered and washed with water (50 mL) then isohexane (100 mL). The amorphous solid was stirred in MeOH (200 mL) and product crystallised. Slurried overnight, filtered and the solid washed with MeOH (20 mL) and dried to give the sub-title compound (9 g).
H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1 H), 9.32 (s, 1 H), 8.45 (d, 1 H), 8.41 - 8.33 (m, 1 H), 8.16 - 8.03 (m, 2H), 7.90 (t, 1 H), 7.85 - 7.78 (m, 1 H), 7.67 - 7.51 (m, 3H), 7.48 - 7.37 (m, 2H), 6.58 (d, 1 H), 4.16 (s, 1 H), 3.56 (t, 4H), 3.46 - 3.27 (m, 2H), 2.49 - 2.30 (m, 6H), 1.52 (s, 9H). LCMS m/z 609 (M+H)+ (ES+)
(v) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-morpholino ethvDbenzamide
TFA (22 mL, 286 mmol) was added dropwise to a stirred solution of the compound from step (iv) above (9 g, 14.05 mmol) in DCM (50 mL). The reaction was stirred at room temperature for 2 h. The mixture was added dropwise to stirred water (100 mL) and 1.0 M K2C03 solution (280 mL, 280 mmol) and stirring continued until effervescence ceased. The mixture was extracted with DCM (2 x 250 mL) then the combined organic phases were dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (120 g column, 2% MeOH:DCM to 6%) to afford the sub-title compound (6.7 g) as a pale brown foam.
H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1 H), 8.39 (t, 1 H), 8.36 (d, 1 H), 8.17 - 8.10 (m, 1 H), 8.06 (s, 1 H), 7.94 (dd, 1 H), 7.67 - 7.59 (m, 1 H), 7.49 - 7.38 (m, 3H), 7.15 (d, 1 H), 6.70 (d, 1 H), 6.37 (d, 1 H), 5.79 (s, 2H), 4.20 (s, 1 H), 3.56 (t, 4H), 3.41 - 3.30 (m, 2H), 2.48 - 2.34 (m, 6H).
LCMS m/z 509 (M+H)+ (ES+)
(vi) Phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate
Phenyl chloroformate (0.5 mL, 3.99 mmol) was added to a stirred solution of N-(3-amino-5- (tert-butyl)-2-methoxyphenyl)methanesulfonamide (see, for example, Cirillo, P. F. et al., WO 2002/083628, 24 October 2002; 1 g, 3.67 mmol) and NaHC03 (620 mg, 7.38 mmol) in THF (10 mL) and DCM (10 mL). The mixture was stirred for 2 h, then water (20 mL) was added. The organic layer was separated, dried (MgS04), filtered and evaporated to furnish a brown foam, which was stirred in cyclohexane (20 mL) to afford the sub-title compound (1.4 g) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1 H), 9.14 (s, 1 H), 7.56 (s, 1 H), 7.50 - 7.37 (m, 2H), 7.31 - 7.13 (m, 4H), 3.77 (s, 3H), 3.06 (s, 3H), 1.25 (s, 9H)
LCMS m/z 393 (M+H)+ (ES+); 391 (M-H)" (ES")
(vii) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
Triethylamine (5 μί, 0.036 mmol) was added to a mixture of the product from step (vi) above (75 mg, 0.191 mmol) and the product from step (v) above (100 mg, 0.197 mmol) in isopropyl acetate (3 mL) and the mixture heated at 50°C (block temperature) for 6 h. The reaction was cooled to rt and left stirring for 72 h. The resulting solid was filtered and washed with isopropyl acetate (1 mL). The crude product was recrystallised from MeCN (3 mL), washed with MeCN (1 mL), filtered and dried to afford the title compound (100 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1 H), 9.32 (s, 1 H), 9.13 (s, 1 H), 8.90 (s, 1 H), 8.44 (d, 1 H), 8.35 (t, 1 H), 8.27 (d, 1 H), 8.18 (d, 1 H), 8.13 - 8.02 (m, 2H), 7.92 - 7.80 (m, 2H), 7.72 - 7.64 (m, 1 H), 7.63 - 7.55 (m, 1 H), 7.50 - 7.37 (m, 2H), 7.03 (d, 1 H), 6.56 (d, 1 H), 4.12 (s, 1 H), 3.81 (s, 3H), 3.63 - 3.48 (m, 4H), 3.40 - 3.33 (m, 2H), 3.10 (s, 3H), 2.47 - 2.33 (m, 6H), 1.27 (s, 9H).
LCMS m/z 807 (M+H)+ (ES+)
Example 2
3-Ethvnyl-5-((4-((4-(3-(3-fluoro-5-morpholinophenyl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2- yl)amino)-N-(2-morpholinoethyl)benzamide
Figure imgf000055_0001
(i) Phenyl (3-fluoro-5-morpholinophenyl)carbamate
A stirred suspension of 3-fluoro-5-morpholinoaniline (1.00 g, 5.10 mmol) and sodium bicarbonate (0.878 g, 10.45 mmol) in DCM (10 mL) and THF (4 mL) was treated dropwise with phenyl chloroformate (0.7 mL, 5.57 mmol). After - 0.1 mL had been added the mixture became very thick and difficult to stir, so it was diluted with more DCM (5 mL) and THF (2 mL) and stirred overnight. The mixture was treated with more sodium bicarbonate (0.086 g, 1.019 mmol) and phenyl chloroformate (0.07 mL, 0.557 mmol) and stirred over the weekend. The mixture was diluted with DCM (30 mL), was washed with water (30 mL) and filtered through a phase-separating cartridge. The filtrate was evaporated and the residue was purified on a 40 g redisep silica cartridge using a gradient of 0 to 50% of ethyl acetate in isohexane as eluent to afford the sub-title compound (1.565 g) as a pink solid. H NMR (400MHz; DMSO-d6) δ 10.27 (s, 1 H), 7.45-7.40 (m, 2H), 7.29-7.20 (m, 3H), 6.90 (bs, 1 H), 6.82-6.79 (m, 1 H), 6.51-6.47 (m, 1 H), 3.73-3.70 (m, 4H), 3.10-3.08 (m, 4H). 90% purity
LCMS m/z 317 (M+H)+ (ES+)
(ii) tert-Butyl (4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate
tert-Butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 6.46 g, 17.37 mmol), 3-amino-5-ethynyl-/V-(2- morpholinoethyl)benzamide (see Example 1 (iii) above; 7.12 g, 26.0 mmol) and p-TSA monohydrate (5.62 g, 29.5 mmol) in DMF (60 ml_) was heated at 60°C (block temperature,
55°C internal temperature) for 7 h. The mixture was cooled and added dropwise to sat. aq
NaHC03 (1 L). The solid was filtered, washed with water (50 ml_) then isohexane (100 ml_).
The amorphous solid was stirred in MeOH (200 ml_) and product crystallised. Slurried overnight, then filtered and solid washed with MeOH (20 ml_) and dried to afford the sub-title compound (8 g).
H NMR (400 MHz, DMSO-d6) δ 9.76 (s, 1 H), 9.32 (s, 1 H), 8.45 (d, 1 H), 8.41 - 8.33 (m, 1 H), 8.16 - 8.03 (m, 2H), 7.90 (t, 1 H), 7.85 - 7.78 (m, 1 H), 7.67 - 7.51 (m, 3H), 7.48 - 7.37 (m, 2H), 6.58 (d, 1 H), 4.16 (s, 1 H), 3.56 (t, 4H), 3.46 - 3.27 (m, 2H), 2.49 - 2.30 (m, 6H), 1.52 (s, 9H). 10%w/w de-BOC compound.
LCMS m/z 609 (M+H)+ (ES+)
(iii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2- morpholinoethvDbenzamide
TFA (22 mL, 286 mmol) was added dropwise to a stirred solution of the product from step (ii) above (9 g, 14.05 mmol) in DCM (50 mL). The reaction was stirred at rt for 2 h, then added dropwise to stirred water (100 mL) and 1 M potassium carbonate solution (280 mL, 280 mmol) and stirring continued until effervescence ceased. The mixture was extracted with dichloromethane (2 x 250 mL) then the combined organic phases were dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (120 g column, 2% MeOH:DCM to 6%) to afford the sub-title compound (6.7 g) as a pale brown foam.
H NMR (400 MHz, DMSO-d6) δ 9.77 (s, 1 H), 8.39 (t, 1 H), 8.36 (d, 1 H), 8.17 - 8.10 (m, 1 H), 8.06 (s, 1 H), 7.94 (dd, 1 H), 7.67 - 7.59 (m, 1 H), 7.49 - 7.38 (m, 3H), 7.15 (d, 1 H), 6.70 (d, 1 H), 6.37 (d, 1 H), 5.79 (s, 2H), 4.20 (s, 1 H), 3.56 (t, 4H), 3.41 - 3.30 (m, 2H), 2.48 - 2.34 (m, 6H).
LCMS m/z 509 (M+H)+ (ES+)
(iv) 3-Ethvnyl-5-((4-((4-(3-(3-fluoro-5-morpholinophenyl)ureido)naphthalen-1-yl)oxy)- pyrimidin-2-yl)amino)-N-(2-morpholinoethyl)benzamide
A stirred suspension of the product from step (i) above (100 mg, 0.295 mmol) and the product from step (iii) above (150 mg, 0.295 mmol) in isopropyl acetate (6 mL) was treated with Et3N (10 μί, 0.072 mmol) and stirred at 50°C (bath) for 1 h (all dissolved) and then at 60°C for 4 h to give a thick suspension. The mixture was treated with more triethylamine (10 μΙ_, 0.072 mmol) and diluted with isopropyl acetate (6 mL) to aid stirring and stirred at 60°C overnight. The mixture was allowed to cool then filtered. The solid was washed with isopropyl acetate (2 x 2ml_) and digested with boiling acetonitrile (20 mL) for 20 mins. The suspension was allowed to cool then filtered. The solid washed with acetonitrile (2 x 4 mL) followed by ether (2 x 4 mL) and dried to afford the title compound (97 mg) as a buff solid. H NMR (400MHz; DMSO-d6) δ 9.76 (s, 1 H), 9.13 (s, 1 H), 8.82 (s, 1 H), 8.45 (d, 1 H), 8.35 (t, 1 H), 8.17 (d, 1 H), 8.06 (s, 1 H), 7.99 (d, 1 H), 7.86-7.84 (m, 2H), 7.69-7.65 (m, 1 H), 7.61-7.57 (m, 1 H), 7.45-7.43 (m, 2H), 6.93-6.90 (m, 1 H), 6.81 (s, 1 H), 6.57 (d, 1 H), 6.47-6.43 (m, 1 H), 4.12 (s, 1 H), 3.76-3.73 (m, 4H), 3.57-3.54 (m, 4H), 3.14-3.12 (m, 4H), 2.46-2.40 (m, 6H). 2H obscured by water.
LCMS m/z 366 (M+2H)2+ (ES+)
Example 3
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Figure imgf000057_0001
(i) 3-Amino-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
3-Amino-5-methoxybenzoic acid (1.0g, 5.98 mmol) was added to an ice cold suspension of 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (1.2 g, 7.35 mmol), 50% T3P in ethyl acetate (4.50 mL, 7.56 mmol) and TEA (2.5 mL, 17.94 mmol) in ethyl acetate (15 mL). The mixture was allowed to warm to rt and stir overnight. Saturated aq. NaHC03 solution (20 mL) was added and the mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with saturated brine (20 mL), dried (MgS04) and concentrated under reduced pressure to yield a yellow oil. The oil was purified by chromatography on the Companion (40 g column, 0-100% acetone/toluene) to afford a pale yellow oil. The oil was purified by chromatography on the Companion (40 g column, 0-100% THF/DCM) to afford the sub-title compound (843 mg) as a pale yellow oil.
LCMS m/z 313 (M+H)+ (ES+)
(ii) tert-Butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate
A mixture of 4-((2-chloropyridin-4-yl)oxy)naphthalen-1 -amine (see, for example, Ito, K. et al., WO 2010/112936, 07 Oct 2010; 1000 mg, 3.69 mmol) and di-tert-butyl dicarbonate (750 mg, 3.44 mmol) in t-BuOH (10 mL) was stirred at reflux for 18 h. The mixture was diluted with water (15 mL) and the solid collected by filtration. The solid was triturated in diethyl ether to yield the sub-title compound (1002 mg) as a pale grey solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.37 (s, 1 H), 8.28 (d, 1 H), 8.16 (d, 1 H), 8.82 (dd, 1 H), 7.66 (d, 1 H), 7.66-7.54 (m, 2H), 7.40 (d, 1 H), 7.03 (d, 1 H), 6.91 (dd, 1 H), 1.52 (s, 9H).
LCMS m/z 371 (M+H)+ (ES+); 369 (M-H)" (ES") (iii) tert-Butyl (4-((2-((3-methoxy-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
Pd2dba3 (22 mg, 0.024 mmol) and BINAP (30 mg, 0.048 mmol) were stirred in 1 ,4-dioxane (1 mL) for 10 minutes under N2. In a separate vessel, purged with N2, caesium carbonate (455 mg, 1.396 mmol), the product from step (i) above (291 mg, 0.930 mmol) and the product from step (ii) above (345 mg, 0.930 mmol) were stirred in 1 ,4-dioxane (5 mL). The catalyst solution was added to the main reaction mixture and the whole was heated to 90°C for 18 h. Upon cooling, the mixture was diluted with water (40 mL) and extracted with ethyl acetate (3 x 25 mL). The combined organic phases were washed with saturated brine (15 mL), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (40 g column, 0-50% acetone/ethyl acetate) to afford the sub-title compound (320 mg) as a sticky orange oil.
H NMR (DMSO-d6) 400 MHz, δ: 9.37 (s, 1 H), 9.09 (s, 1 H), 8.35 (t, 1 H), 8.17-8.05 (m, 2H), 7.83 (d, 1 H), 7.67-7.46 (m, 5H), 7.35 (d, 1 H), 6.88 (s, 1 H), 6.57 (dd, 1 H), 6.09 (d, 1 H), 3.74 (s, 3H), 3.58-3.44 (m, 8H), 3.44-3.34 (m, 4H), 3.20 (s, 3H), 1.52 (s, 9H).
LCMS m/z 647 (M+H)+ (ES+); 645 (M-H)" (ES")
(iv) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)benzamide
A solution of the product from step (iii) above (320 mg, 0.495 mmol) in DCM (1 mL) was treated with TFA (1000 μί, 12.98 mmol) and stirred at rt for 3 h. The mixture was diluted with water (10 mL) and DCM (10 mL). The mixture was neutralised with aq. NaHC03 solution and passed through a phase separation cartridge. The organic phase was dried (MgS04) and concentrated to give the sub-title compound (270 mg) as a brown gum.
H NMR (DMSO-d6) 400 MHz, δ: 9.00 (s, 1 H), 8.34 (dd, 1 H), 8.20-8.10 (m, 1 H), 8.05 (d, 1 H), 7.67-7.60 (m, 1 H), 7.59-7.55 (m, 1 H), 7.52-7.47 (m, 1 H), 7.47-7.41 (m, 2H), 7.10 (d, 1 H), 6.89-6.84 (m, 1 H), 6.71 (d, 1 H), 6.51 (dd, 1 H), 6.05 (d, 1 H), 5.83 (s, 2H), 3.73 (S, 3H), 3.58- 3.45 (m, 8H), 3.45-3.35 (m, 4H), 3.21 (s, 3H).
LCMS m/z 547 (M+H)+ (ES+)
(v) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)-ethyl)benzamide Et3N (5.33 μί, 0.038 mmol) was added to a stirred solution of phenyl (5-(tert-butyl)-2- methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 75 mg, 0.191 mmol) and the product from step (iv) above (110 mg, 0.201 mmol) in isopropyl acetate (5 mL) and heated to 50°C for 8 h. Et3N (5.33 μί, 0.038 mmol) was added and the mixture was heated to 60°C for a further 3 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on the Companion (40 g column, 0-50% acetone/EtOAc) to afford a an off-white solid which was recrystallised in acetonitrile (2 mL) to yield a white solid. The solid was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 20-50% MeCN in Water) to afford a white solid which was redissolved in methanol (2 mL) loaded onto an SCX column. The column was washed with methanol (3 x 3 mL) then eluted with 1 % ammonia in methanol to yield the title compound (21 mg) as a white solid. H NMR (DMSO-d6) 400 MHz, δ: 9.41 (s, 1 H), 9.17 (s, 1 H), 9.08 (s, 1 H), 8.94 (s, 1 H), 8.38 (dd, 1 H), 8.30 (d, 1 H), 8.19 (d, 1 H), 8.12 (d, 1 H), 8.11 (d, 1 H), 7.87 (d, 1 H), 7.74-7.67 (m, 1 H), 7.65-7.56 (m, 2H), 7.50 (dd, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.91-6.86 (m, 1 H), 6.58 (dd, 1 H), 6.12 (d, 1 H), 3.81 (s, 3H), 3.74 (s, 3H), 3.55-3.46 (m, 8H), 3.42-3.36 (m, 4H), 3.20 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 845 (M+H)+ (ES+); 843 (M-H)" (ES")
Example 4
N-(5-(tert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonami
Figure imgf000059_0001
(i) 3-Methoxy-5-nitrophenol
A mixture of KOH (29.0 g, 517 mmol) and 1-bromo-3-methoxy-5-nitrobenzene (30 g, 129 mmol) in water (70 mL) and dioxane (70 mL) was degassed for 5 minutes prior to the addition of di-tert-butyl(2',4',6'-triisopropyl-[1 , 1 '-biphenyl]-2-yl)phosphine (1.263 g, 2.97 mmol) and Pd2(dba)3 (1.184 g, 1.293 mmol). The resulting mixture was degassed for a further 2 minutes then heated under a nitrogen atmosphere at 100°C for 2 h. The mixture was cooled, then acidified with 5 M HCI to ~pH 1 and extracted with EtOAc (2 x 500 mL). The organic layer was washed with saturated brine (200 mL), dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified through a pad of silica eluting with 30% EtOAc/isohexane to afford the sub-title compound (20.76 g) as a yellow solid.
H NMR (400MHz; DMSO-d6) δ 10.46 (s, 1 H), 7.20 (s, 1 H), 7.19 (s, 1 H), 6.76 (s, 1 H), 3.82 (s, 3H).
LCMS m/z 168 (M-H)" (ES")
(ii) 1-Methoxy-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-5-nitrobenzene
To a stirred suspension of the product from step (i) above (8.14 g, 45.7 mmol) and K2C03 (12.64 g, 91 mmol) in acetone (150 mL) was added 1-bromo-2-(2-(2-methoxyethoxy)- ethoxy)ethane (8.85 mL, 48.0 mmol). The resulting mixture was refluxed overnight, cooled and filtered. The filtrate was evaporated under reduced pressure and the residue purified by chromatography on silica gel (220 g column, 0-60% EtOAc/isohexane) to afford the sub-title compound (13.41 g) as a yellow oil.
H NMR (DMSO-d6) 400 MHz, δ: 7.34-7.32 (m, 2H), 6.98 (t, 1 H), 4.22-4.20 (m, 2H), 3.85 (s, 3H), 3.77-3.74 (m, 2H), 3.60-3.57 (m, 2H), 3.54-3.50 (m, 4H), 3.44-3.40 (m, 2H), 3.23 (s, 3H).
LCMS m/z 316 (M+H)+ (ES+)
(iii) 3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline The product from step (ii) above (13.4 g, 42.5 mmol) was dissolved in ethanol (150 mL) and Fe powder (13 g, 233 mmol) was added followed by a solution of NH4CI (2.3 g, 43.0 mmol) in water (150 mL). The resulting suspension was heated at 80°C for 3 h. The reaction was cooled to room temperature and filtered through Celite. The filtrate was concentrated in vacuo then partitioned between water (250 mL) and EtOAc (400 mL). The organic layer was separated, dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-4% MeOH/DCM) to afford the sub-title compound (10.95 g) as an oil.
H NMR (400 MHz, DMSO-d6) δ 5.76 - 5.73 (m, 2H), 5.68 (t, 1 H), 5.07 (s, 2H), 3.98 - 3.89 (m, 2H), 3.72 - 3.65 (m, 2H), 3.63 (s, 3H), 3.60 - 3.48 (m, 6H), 3.47 - 3.40 (m, 2H), 3.24 (s, 3H)
LCMS m/z 286 (M+H)+ (ES+)
(iv) tert-Butyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
tert-Butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 1 g, 2.69 mmol), the product of step (iii) above (1.15 g, 4.03 mmol) and p-TSA monohydrate (0.100 g, 0.526 mmol) in DMF (10 mL) was heated at
55°C (internal temperature) for 14 h. The mixture was cooled and added dropwise to sat. aq. NaHC03 (100 mL) then partitioned with EtOAc (2 x 50 mL). Organics were bulked and washed with 20%w/w NaCI solution (50 mL), then dried (MgS04), filtered and solvent evaporated. The crude product was purified by chromatography on silica gel (40 g column) to afford the sub-title compound (1.14 g) as a clear brown oil.
H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1 H), 9.34 (s, 1 H), 8.42 (d, 1 H), 8.1 1 (d, 1 H), 7.86 - 7.76 (m, 1 H), 7.66 - 7.49 (m, 3H), 7.39 (d, 1 H), 6.85 (s, 2H), 6.56 (d, 1 H), 6.05 (t, 1 H), 3.88 (dd, 2H), 3.71 - 3.63 (m, 2H), 3.59 - 3.48 (m, 9H), 3.46 - 3.38 (m, 2H), 3.22 (s, 3H), 1.52 (s, 9H)
LCMS m/z 621 (M+H)+ (ES+) (v) 4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)pyrimidin-2-amine
TFA (2.8 mL, 36.3 mmol) was added dropwise to a stirred solution of the product of step (iv) above (1.1 g, 1.772 mmol) in DCM (5 mL). The reaction was stirred at room temperature for 2 h. The mixture was added dropwise to stirred water (10 mL) and 1 M K2C03 solution (35 mL, 35.0 mmol) and stirring continued until effervescence ceased. The mixture was extracted with DCM (2 x 25 mL) then the combined organic phases were dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 5%) to afford a brown gum. Recrystallised from iPrOAc (3 mL) afforded the sub-title compound (0.80 g) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1 H), 8.33 (d, 1 H), 8.22 - 8.03 (m, 1 H), 7.69 - 7.56 (m, 1 H), 7.51 - 7.35 (m, 2H), 7.1 1 (d, 1 H), 6.87 (d, 2H), 6.68 (d, 1 H), 6.35 (d, 1 H), 6.04 (t, 1 H), 5.79 (s, 2H), 3.94 - 3.78 (m, 2H), 3.74 - 3.64 (m, 2H), 3.60 - 3.47 (m, 9H), 3.46 - 3.38 (m, 2H), 3.22 (s, 3H)
LCMS m/z 521 (M+H)+ (ES+) (vi) N-(5-(tert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)meth
Et3N (7 μί, 0.050 mmol) was added to a stirred suspension of phenyl (5-(tert-butyl)-2- methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 1 14 mg, 0.282 mmol) and the product from step (v) above (150 mg, 0.282 mmol) in i-PrOAc (6 mL). The resulting mixture was heated at 70°C overnight. The reaction was cooled to rt and the solvent removed in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH in DCM) to afford an off-white solid at -90% purity. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Waters X-Bridge Prep-C18, 5 μητι, 19x50 mm column, 20-65% MeCN in Water) to afford a colourless glass, which was triturated with diethyl ether to afford the title compound (21 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.44 (s, 1 H), 9.35 (s, 1 H), 9.17 (s, 1 H), 8.93 (s, 1 H), 8.41 (d, 1 H), 8.27 (d, 1 H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.84 (d, 1 H), 7.69-7.65 (m, 1 H), 7.60-7.56 (m, 1 H), 7.41 (d, 1 H), 7.02 (d, 1 H), 6.83-6.77 (br m, 2H), 6.55 (d, 1 H), 6.03-6.02 (m, 1 H), 3.89-3.83 (m, 2H), 3.80 (s, 3H), 3.66-3.64 (m, 2H), 3.54-3.47 (m, 9H), 3.40-3.37 (m, 2H), 3.20 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 819 (M+H)+ (ES+); 817 (M-H)" (ES")
Example 5
N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(cvclopropylsulfonyl)-5-methoxyphenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide
Figure imgf000061_0001
(i) 1-(Cvclopropylsulfonyl)-3-methoxy-5-nitrobenzene
A mixture of 1-bromo-3-methoxy-5-nitrobenzene (9.05 g, 39.0 mmol), sodium cyclopropanesulfinate (6.5 g, 50.7 mmol), copper(l) iodide (0.743 g, 3.90 mmol), L-proline (0.908 g, 7.88 mmol) and NaOH (0.315 g, 7.88 mmol) in DMSO (50 mL) was heated at 90°C for 18h and 100°C for 12 h. The mixture was partitioned between EtOAc (500 mL) and water (300 mL), the organic layer separated, washed with brine (200 mL), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40% EtOAc/isohexane) to afford the sub-title compound (4.226 g) as a solid.
H NMR (400MHz; DMSO-d6) δ 8.31 (s, 1 H), 7.97 (s, 1 H), 7.73 (s, 1 H), 3.98 (s, 3H), 2.55- 2.49 (m, 1 H), 1.48-1.36 (m, 2H), 1.15-1.10 (m, 2H).
(ii) 3-(Cyclopropylsulfonyl)-5-methoxyaniline
A mixture of the product from step (i) above (4.22 g, 16.40 mmol), Fe powder (4.3 g, 77 mmol) and NH4CI (0.439 g, 8.20 mmol) in EtOH (40 mL) and water (20 mL) was heated under reflux for 1 h. The mixture was cooled, diluted with EtOH (50 mL) and filtered through Celite. The filtrate was evaporated, partitioned between EtOAc (300 mL) and brine (200 mL), the organic layer separated, dried (MgS04), filtered, and evaporated under reduced pressure. The residue was triturated with ether and filtered to afford the sub-title compound (3.308 g).
LCMS m/z 228 (M+H)+ (ES+)
(iii) tert-Butyl (4-((2-((3-(cvclopropylsulfonyl)-5-methoxyphenyl)amino)pyrimidin-4-yl)oxy)- naphthalen-1-yl)carbamate
A mixture of tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 2.92 g, 7.86 mmol), the product from step (ii) above (2.5 g, 11.00 mmol) and p-TSA monohydrate (0.3 g, 1.577 mmol) in THF (40 mL) was heated at 55°C for 4 h. The mixture was cooled, partitioned between EtOAc (150 mL) and water (100 mL), the organic layer separated, washed with brine (50 mL), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-50% EtOAc/isohexane) to give a solid which was recrystallised from ether to afford the sub-title compound (3.8 g) as a white solid. LCMS m/z 563 (M+H)+ (ES+)
(iv) 4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-(cvclopropylsulfonyl)-5-methoxyphenyl)-pyrimidin- 2-amine
A mixture of the product from step (iii) above (3.8 g, 6.75 mmol) and TFA (3 mL, 38.9 mmol) in DCM (50 mL) was stirred at room temperature for 18h. A further 5 mL of TFA was added and stirred for a further 2 h. The solvent was evaporated under reduced pressure and the residue partitioned between DCM (150 mL) and sat. aq. NaHC03 solution (150 mL). The organic layer was separated, washed with brine, dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-2% MeOH/DCM) to afford a foam which was recrystallised from DCM/ether to afford the sub-title compound (2.332 g) as a solid.
H NMR (400MHz; CDCI3) δ 8.29 (d, 1 H), 7.87-7.81 (m, 2H), 7.52-7.45 (m, 4H), 7.22 (s, 1 H), 7.11 (d, 1 H), 6.97 (s, 1 H), 6.78 (d, 1 H), 6.38 (d, 1 H), 4.18 (s, 2H), 3.68 (s, 3H), 2.42-2.36 (m, 1 H), 1.32-1.28 (m, 2H), 1.01-0.96 (m, 2H).
LCMS m/z 463 (M+H)+ (ES+); 461 (M-H)" (ES")
(v) N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(cvclopropylsulfonyl)-5-methoxyphenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide
Et3N (6 μί, 0.043 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 85 mg, 0.216 mmol) and the product from step (iv) above (100 mg, 0.216 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 7h. The reaction was diluted with DCM and MeOH then concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH DCM) to afford the title compound (94 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.85 (s, 1 H), 9.36 (s, 1 H), 9.14 (s, 1 H), 8.93 (s, 1 H), 8.48 (d, 1 H), 8.29 (d, 1 H), 8.18 (d, 1 H), 8.11 (d, 1 H), 7.85 (dd, 1 H), 7.74 (s, 1 H), 7.66-7.70 (m, 1 H), 7.57-7.61 (m, 1 H), 7.51 (s, 1 H), 7.43 (d, 1 H), 7.03 (d, 1 H), 6.86 (dd, 1 H), 6.65 (d, 1 H), 3.81 (s, 3H), 3.65 (s, 3H), 3.10 (s, 3H), 2.70-2.76 (m, 1 H), 1.27 (s, 9H), 0.99-1.09 (m, 4H). LCMS m/z 761 (M+H)+ (ES+) Example 6
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
Figure imgf000063_0001
(i) 3-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5- methoxybenzoic acid
N2 was bubbled through a stirred mixture of tert-butyl (4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 10 g, 26.9 mmol), 3-amino-5-methoxybenzoic acid (8.99 g, 53.8 mmol) and p-TSA monohydrate (1.02 g, 5.36 mmol) in THF (150 mL) for 10min. The mixture was heated under reflux for 20 h, cooled and filtered. The filtrate was evaporated, MeOH (300 mL) added and the solid filtered, washed with MeOH then ether to afford the sub-title compound (10.063 g). H NMR (400MHz; DMSO-d6) δ 12.83 (brs, 1 H), 9.68 (s, 1 H), 9.32 (s, 1 H), 8.44 (d, 1 H), 8.1 1 (d, 1 H), 8.13-8.10 (m, 2H), 7.61-7.51 (m, 4H), 7.41 (d, 1 H), 6.98 (s, 1 H), 6.58 (d, 1 H), 3.60 (s, 3H), 1.52 (s, 9H).
LCMS m/z 503 (M+H)+ (ES+)
(ii) tert-Butyl (4-((2-((3-methoxy-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)carbamate
T3P, 50%w/w in EtOAc (592 μί, 0.995 mmol) was added to a solution of the product from step (i) above (500 mg, 0.995 mmol), 2-morpholinoethanamine (150 μί, 1.143 mmol) and TEA (420 μί, 3.01 mmol) in DMF (10 mL). The mixture was stirred at rt for 1 h. The solvent was evaporated and the residue triturated with water (50 mL) to give the sub-title compound (540 mg).
H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1 H), 9.34 (s, 1 H), 8.42 (dd, 1 H), 8.32 - 8.17 (m, 1 H), 8.11 (d, 1 H), 7.82 (d, 1 H), 7.68 - 7.48 (m, 4H), 7.48 - 7.35 (m, 2H), 6.88 (d, 1 H), 6.62 - 6.47 (m, 1 H), 3.58 (s, 7H), 3.45 - 3.25 (m, 2H), 2.43 (s, 6H), 1.52 (s, 9H).
LCMS m/z 615 (M+H)+ (ES+) (iii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2- morpholinoethvDbenzamide
The product from step (ii) above (570 mg, 0.927 mmol) was suspended in DCM (10 mL) and TFA (1500 μί, 19.47 mmol) added. The reaction mixture was stirred for 2 h. The solvents were evaporated and the residue partitioned between water (20 mL) and DCM (20 mL). The aqueous layer was separated and basified with NaHC03 before extraction with DCM (3 x 20 mL). The organics were bulked, dried (MgS04), filtered and evaporated to give a brown solid. The crude product was purified by chromatography on silica gel (40 g column, 5% MeOH: DCM to 10%) to afford the sub-title compound (350 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.47 (d, 1 H), 8.33 (d, 1 H), 8.21 - 8.1 1 (m, 1 H), 8.07 (s, 1 H), 7.72 - 7.56 (m, 2H), 7.52 - 7.33 (m, 3H), 7.12 (d, 1 H), 6.94 - 6.80 (m, 1 H), 6.71 (d, 1 H), 6.33 (d, 1 H), 5.69 (s, 2H), 3.61 (s, 3H), 3.58 (t, 4H), 3.36 (q, 2H), 2.47 (t, 2H), 2.42 (t, 4H).
LCMS m/z 515 (M+H)+ (ES+) (iv) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
Et3N (6 μΙ_, 0.043 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 76 mg, 0.194 mmol) and the product from step (iii) above (100 mg, 0.194 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 7 h. The reaction was diluted with DCM and MeOH then concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-10% MeOH DCM) to afford the product as a clear oil which was purified further by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μητι, 19x50 mm column, 20-50% MeCN in Water) to afford the formate salt of the product as a white solid. The material was dissolved in MeOH and loaded onto a pre-conditioned cartridge of SCX resin. The resin was washed with MeOH and the product released with 1 % NH3 in MeOH. The NH3 solution was concentrated in vacuo to afford the title compound (54 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.61 (s, 1 H), 9.35 (s, 1 H), 9.14 (s, 1 H), 8.92 (s, 1 H), 8.41 (d, 1 H), 8.28 (d, 1 H), 8.19 (d, 2H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.56-7.61 (m, 2H), 7.43 (d, 1 H), 7.34 (s, 1 H), 7.03 (d, 1 H), 6.86 (s, 1 H), 6.55 (d, 1 H), 3.81 (s, 3H), 3.59 (s, 3H), 3.49-3.59 (m, 4H), 3.32-3.41 (m, 2H), 3.10 (s, 3H), 2.33-2.50 (m, 6H), 1.27 (s, 9H).
LCMS m/z 407 (M+2H)2+ (ES+) Example 7
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide
Figure imgf000064_0001
(i) N-(5-(tert-Butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2- methoxyphenvDmethanesulfonamide
In a 20 mL vial, a solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)- phenyl)carbamate (see Example 1 (vi) above; 0.5 g, 1.261 mmol) and 4-((2-chloropyrimidin-4- yl)oxy)naphthalen-1 -amine (see, for example, Cirillo, P. F. et al., WO 2002/92576, 21 Nov 2000; 0.361 g, 1.261 mmol) in isopropyl acetate (13 mL) was treated dropwise with Et3N (0.035 mL, 0.252 mmol). The resultant brown solution was heated at 70°C for 72 h and solvent removed in vacuo to afford a brown thick oil. The crude product was purified by chromatography on silica gel (120 g column, 0-60% EtOAc in Hexane) to afford the sub-title compound (0.1584 g) as a clear white solid.
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 9.13 (s, 1 H), 8.92 (s, 1 H), 8.66 (d, 1 H), 8.30 (d, 1 H), 8.17 (d, 1 H), 8.10 (d, 1 H), 7.81 (d, 1 H), 7.70 (ddd, 1 H), 7.64 - 7.55 (m, 1 H), 7.44 (d, 1 H), 7.27 (d, 1 H), 7.02 (d, 1 H), 3.80 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 570/572 (M+H)+ (ES+); 568/570 (M-H)" (ES")
(ii) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide The product from step (i) above (158 mg, 0.277 mmol), 3-amino-5-methoxy-N-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)benzamide (see Example 3(i) above; 100 mg, 0.320 mmol) and p-TSA monohydrate (13.18 mg, 0.069 mmol) were heated to 65°C in DMF (3 mL) for 1.5h. The temperature was increased to 85°C and the mixture was stirred for a further 3 h. The mixture was diluted with water (10 mL) and saturated aq. NaHC03 solution (10 mL), then extracted with ethyl acetate (3 x 10 mL). The combined organic phases were washed with 20% brine (2 x 10 mL), saturated brine (10 mL), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (40 g column, 0-100% THF/EtOAc) to afford a pale brown glass. The glass was triturated in diethyl ether to yield a white solid which was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 40% isocratic MeCN in Water) to afford the title compound (65 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.60 (s, 1 H), 9.36 (s, 1 H), 9.14 (br s, 1 H), 8.92 (s, 1 H), 8.41 (d, 1 H), 8.35-8.24 (m, 2H), 8.18 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.72-7.64 (m, 1 H), 7.63- 7.53 (m, 2H), 7.43 (d, 1 H), 7.37-7.32 (m, 1 H), 7.03 (d, 1 H), 6.91-6.86 (m, 1 H), 6.54 (d, 1 H), 3.81 (s, 3H), 3.59 (s, 3H), 3.55-3.45 (m, 8H), 3.42-3.35 (m, 4H), 3.20 (s, 3H),3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 846 (M+H)+ (ES+); 844 (M-H)" (ES")
Example 8
1-(5-(tert-Butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000065_0001
(i) Phenyl (5-(tert-butyl)-2-methoxyphenyl)carbamate
Phenyl chloroformate (1.40 mL, 11.16 mmol) was added to a stirred solution of 5-(tert-butyl)- 2-methoxyaniline (2.00 g, 1 1.16 mmol) and NaHC03 (1.90 g, 22.62 mmol) in THF (20 mL) and DCM (20 mL). The mixture was stirred overnight then diluted with water (40 mL) and DCM (20 mL) then passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (3.53 g) as a red-brown oil.
H NMR (DMSO-d6) 400 MHz, δ: 9.04 (s, 1 H), 7.68 (s, 1 H), 7.40-7.44 (m, 2H), 7.19-7.27 (m, 3H), 7.14 (dd, 1 H), 6.98 (d, 1 H), 3.82 (s, 3H), 1.25 (s, 9H).
(ii) 1-(5-(tert-Butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Et3N (6 μΙ_, 0.043 mmol) was added to a mixture of the product from step (i) above (58 mg,
0.194 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 100 mg, 0.192 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 7 days. The reaction was cooled to rt and diluted with MeOH. The solution was concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (56 mg) as a yellow solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.46 (s, 1 H), 9.32 (s, 1 H), 8.75 (s, 1 H), 8.42 (d, 1 H), 8.33 (s, 1 H), 8.29 (d, 1 H), 8.08 (d, 1 H), 7.84 (d, 1 H), 7.66 (t, 1 H), 7.58 (t, 1 H), 7.40 (d, 1 H), 6.95- 6.99 (m, 2H), 6.81 (d, 2H), 6.56 (d, 1 H), 6.04 (s, 1 H), 3.91 (s, 3H), 3.86-3.88 (m, 2H), 3.65- 3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 1.27 (s, 9H).
LCMS m/z 726 (M+H)+ (ES+)
Example 9
5-(tert-Butyl)-3-(3-(4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide
Figure imgf000066_0001
(i) Phenyl (5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)carbamate
Phenyl chloroformate (300 μί, 2.391 mmol) was added to a stirred solution of 3-amino-5- (tert-butyl)-2-methoxy-N-methylbenzamide (see, for example, Cirillo, P. F. et al., Bioorg. Med. Chem. Lett. 2009, 19, 2386-2391 ; 550 mg, 2.327 mmol) and NaHC03 (300 mg, 3.57 mmol) in THF (5 mL) and DCM (5 mL). The mixture was stirred for 2 h, filtered and the solvent evaporated to give a pale brown oil. Trituration with isohexane (10 mL) gave the sub-title compound (470 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.47 (s, 1 H), 8.19 (q, 1 H), 7.84 (s, 1 H), 7.54 - 7.36 (m, 2H), 7.33 - 7.14 (m, 4H), 3.75 (s, 3H), 2.80 (d, 3H), 1.27 (s, 9H).
LCMS m/z 357 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-3-(3-(4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide Et3N (5 μΙ_, 0.036 mmol) was added to a mixture of the product from step (i) above (70 mg, 0.196 mmol) and 3-((4-((4-aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2- morpholinoethyl)benzamide (see Example 2(iii) above; 100 mg, 0.197 mmol) in isopropyl acetate (3 ml_) and the mixture heated at 50°C (block temperature) for 16 h. The reaction mixture was cooled to rt and the solid filtered off. The residue was recrystallised from MeCN (3 ml_). The resultant solid was filtered, rinsing with MeCN, and dried in vacuo to afford a tan solid. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Waters X-Bridge Prep-C18, 5 μητι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (17 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.75 (s, 1 H), 9.40 (s, 1 H), 8.86 (s, 1 H), 8.50 - 8.38 (m, 2H), 8.34 (t, 1 H), 8.26 (d, 1 H), 8.17 (q, 1 H), 8.10 - 7.99 (m, 2H), 7.95 - 7.79 (m, 2H), 7.68 (ddd, 1 H), 7.59 (ddd, 1 H), 7.50 - 7.37 (m, 2H), 7.10 (d, 1 H), 6.55 (d, 1 H), 4.11 (s, 1 H), 3.79 (s, 3H), 3.54 (t, 4H), 3.38 - 3.32 (m, 2H), 2.82 (d, 3H), 2.47 - 2.33 (m, 6H), 1.28 (s, 9H).
LCMS m/z 771 (M+H)+ (ES+); 769 (M-H)" (ES")
Example 10
N-(5-(tert-Butyl)-3-(3-(2.3-dichloro-4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)ureido)-2-methoxyphenyl)- methanesulfonamide
Figure imgf000067_0001
(i) 2,3-Dichloro-4-((2-chloropyrimidin-4-yl)oxy)aniline
DBU (11.85 ml_, 79 mmol) was added over 5min to a stirred mixture of 4-amino-2,3- dichlorophenol (10 g, 56.2 mmol) in MeCN (150ml_) at 0-5°C. After stirring for 5min, 2,4- dichloropyrimidine (8.95 g, 60.1 mmol) was added portionwise over 5min then the mixture warmed to rt and stirred for 2h. The solvent was evaporated under reduced pressure and the residue partitioned between ether (200 ml_) and water (200 ml_). The aqueous layer was extracted with ether (200 ml_) then the combined organic layers washed with brine (200 ml_), dried (MgS04), filtered through a pad of silica and evaporated under reduced pressure. The residue was triturated with ether-isohexane, filtered and dried to afford the sub-title compound (14.403 g) as a light brown solid.
H NMR (CDCI3) 400 MHz, δ: 8.45 (d, 1 H), 6.96 (d, 1 H), 6.84 (d, 1 H), 6.73 (d, 1 H), 4.22 (s, 2H).
LCMS m/z 290/2/4 (M+H)+ (ES+)
(ii) N-(5-(tert-Butyl)-3-(3-(2.3-dichloro-4-((2-chloropyrimidin-4-yl)oxy)phenyl)ureido)-2- methoxyphenvDmethanesulfonamide
Et3N (1 1 μΙ_, 0.079 mmol) was added to a stirred solution of phenyl (5-(tert-butyl)-2-methoxy- 3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 200 mg, 0.504 mmol) and the product from step (i) above (154 mg, 0.504 mmol) in i-PrOAc (8 mL). The mixture was stirred at 70°C for 48 h. The reaction mixture was no longer solublised and the reaction had stalled. The solvent was removed in vacuo and DMF (5 mL) was added to the resulting residue. A fresh quantity of Et3N (1 1 μί, 0.079 mmol) was added and the reaction heated at 70°C for 3 h. A further quantity of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)- phenyl)carbamate (396 mg, 1.009 mmol) was added, followed by Et3N (35.2 μί, 0.252 mmol) and the reaction heated at 70°C overnight. The reaction was cooled to rt and partitioned between EtOAc (50 mL) and water (40 mL). The organic phase was washed with water (40 mL), brine (40 mL), dried (MgS04), filtered and concentrated in vacuo to afford a solid (514 mg). The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (106 mg) as an off-white semi-solid (85% purity).
H NMR (DMSO-d6) 400 MHz, δ: 9.22 (s, 1 H), 9.15 (s, 1 H), 9.12 (s, 1 H), 8.71 (d, 1 H), 8.22 (d, 1 H), 8.08 (d, 1 H), 7.46 (d, 1 H), 7.35 (d, 1 H), 7.04 (d, 1 H), 3.74 (s, 3H), 3.07 (s, 3H), 1.25 (s, 9H).
LCMS m/z 588/590 (M+H)+ (ES+); 586/588 (M-H)" (ES")
(iii) N-(5-(tert-Butyl)-3-(3-(2.3-dichloro-4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)ureido)-2-methoxyphenyl)- methanesulfonamide
To a stirred solution of the product from step (ii) above (100 mg, 0.144 mmol) and 3- methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline (see Example 4(iii) above; 64 mg, 0.218 mmol) in DMF (4 mL) was added p-TSA monohydrate (14 mg, 0.074 mmol). The resulting solution was stirred at 60°C for 48 h. The reaction was cooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHC03 (30 mL). The aqueous phase was back- extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford a sticky orange oil (150 mg). The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc in isohexane) to give a white semi-solid (57 mg), which was triturated with a diethylether-isohexane mix and filtered to afford an off-white solid (30 mg). The crude product was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 40-70% MeCN in Water) to afford the title compound (14 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.51 (s, 1 H), 9.24 (s, 1 H), 9.21-9.10 (br m, 2H), 8.42 (d, 1 H), 8.23 (d, 1 H), 8.08-8.06 (m, 1 H), 7.40 (d, 1 H), 7.04 (d, 1 H), 6.79 (br s, 1 H), 6.75 (br s, 1 H), 6.58 (d, 1 H), 6.07 (t, 1 H), 3.95-3.92 (m, 2H), 3.75 (s, 3H), 3.69-3.67 (m, 2H), 3.60 (s, 3H), 3.56-3.53 (m, 2H), 3.51-3.47 (m, 4H), 3.41-3.39 (m, 2H), 3.21 (s, 3H), 3.07 (s, 3H), 1.25 (s, 9H).
LCMS m/z 837/839 (M+H)+ (ES+); 835/837 (M-H)" (ES")
Example 11
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-methanesulfonamide
Figure imgf000069_0001
(i) tert-Butyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)- pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
Pd2(dba)3 (22 mg, 0.024 mmol) and BINAP (30 mg, 0.048 mmol) were stirred in 1 ,4-dioxane (1 mL) for 10 minutes under N2. In a separate vessel, purged with N2, Cs2C03 (455 mg, 1.396 mmol), 3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline (see Example 4(iii) above; 265 mg, 0.930 mmol) and tert-butyl (4-((2-chloropyridin-4-yl)oxy)-naphthalen-1- yl)carbamate (see Example 3(H) above; 345 mg, 0.930 mmol) were stirred in 1 ,4-dioxane (5 mL). The catalyst solution was added to the main reaction mixture and the whole was heated to 90°C for 48 h. Pd2(dba)3 (22 mg, 0.024 mmol) and BINAP (30 mg, 0.048 mmol) were added and the mixture was stirred for a further 18 h. Water was added (15 mL) and the mixture was extracted with EtOAc (3 x 15 mL). The combined organic phases were washed with saturated brine (15 mL), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound (194 mg) as a sticky brown oil.
H NMR (DMSO-d6) 400 MHz, δ: 9.35 (s, 1 H), 8.89 (s, 1 H), 8.18-8.08 (m, 2H), 7.84 (d, 1 H), 7.67-7.52 (m, 3H), 7.35 (d, 1 H), 6.91 (s, 1 H), 6.79 (s, 1 H), 6.58 (dd, 1 H), 6.07-6.02 (m, 2H), 4.01-3.95 (m, 2H), 3.74-6.67 (m, 2H), 3.65 (s, 3H), 3.60-3.48 (m, 6H), 3.46-3.39 (m, 2H), 3.23 (s, 3H), 1.52 (s, 9H).
LCMS m/z 620 (M+H)+ (ES+); 618 (M-H)" (ES")
(ii) 4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)pyridin-2-amine
A solution of the product from step (i) above (190 mg, 0.307 mmol) in DCM (0.5 mL) was treated with TFA (500 μί, 6.49 mmol) and stirred at rt for 3 h. The mixture was diluted with water (10 mL) and DCM (10 mL). The mixture was neutralised with sat. aq. NaHC03 and passed through a phase separation cartridge. The organic phase was dried (MgS04) and concentrated to give the sub-title compound (135 mg) as a brown gum.
H NMR (DMSO-d6) 400 MHz, δ: 8.08 (s, 1 H), 8.20-8.10 (m, 1 H), 8.05 (d, 1 H), 7.67-7.59 (m, 1 H), 7.49-7.39 (m, 2H), 7.09 (d, 1 H), 6.89 (s, 1 H), 6.76 (s, 1 H), 6.71 (d, 1 H), 6.52 (dd, 1 H), 6.06-5.55 (m, 2H), 5.83 (s, 2H), 4.00-3.90 (m, 2H), 3.74-3.66 (m, 2H), 3.64 (s, 3H), 3.60-3.47 (m, 6H), 3.46-3.38 (m, 2H), 3.23 (s, 3H).
LCMS m/z 520 (M+H)+ (ES+)
(iii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide Et3N (6 μί, 0.043 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 68.0 mg, 0.173 mmol) and the product from step (ii) above (90 mg, 0.173 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) overnight. The reaction was cooled to rt and diluted with EtOAc. The solution was concentrated in vacuo onto silica gel and purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the product as a pink solid. The solid was triturated with Et20 three times affording the title compound (73 mg) as a pale pink solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.38 (s, 1 H), 9.14 (s, 1 H), 8.91 (s, 1 H), 8.88 (bs, 1 H), 8.29 (d, 1 H), 8.19 (d, 1 H), 8.12 (d, 1 H), 8.10 (s, 1 H), 7.87 (d, 1 H), 7.69-7.72 (m, 1 H), 7.59-7.63 (m, 1 H), 7.39 (d, 1 H), 7.03 (d, 1 H), 6.90 (s, 1 H), 6.78 (s, 1 H), 6.59 (dd, 1 H), 6.09 (d, 1 H), 6.04 (t, 1 H), 3.97-3.99 (m, 2H), 3.81 (s, 3H), 3.69-3.72 (m, 2H), 3.65 (s, 3H), 3.56-3.58 (m, 2H), 3.50-3.54 (m, 4H), 3.43 (dd, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 818 (M+H)+ (ES+)
Example 12
1-(4-((2-((3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)-3-(2-methoxy-5-morpholinophenyl)urea
Figure imgf000070_0001
(i) Phenyl (2-methoxy-5-morpholinophenyl)carbamate
Phenyl chloroformate (300 μί, 2.391 mmol) was added to a stirred solution of 2-methoxy-5- morpholinoaniline (500 mg, 2.401 mmol) and NaHC03 (400 mg, 4.76 mmol) in THF (5 mL) and DCM (5 mL) and the mixture was stirred overnight. The mixture was diluted with water (40 mL) and DCM (20 mL) then the mixture passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo to afford the sub-title compound (789 mg) as a yellow oil which solidified on standing.
H NMR (DMSO-d6) 400 MHz, δ: 9.04-9.31 (m, 1 H), 7.23-7.44 (m, 1 H), 7.14-7.21 (m, 2H), 6.95-7.01 (m, 1 H), 6.69-6.81 (m, 4H), 3.78-3.85 (s, 3H), 3.68-3.73 (m, 4H), 2.96-3.00 (m, 4H).
LCMS m/z 329 (M+H)+ (ES+)
(ii) 1-(4-((2-((3-Methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)-3-(2-methoxy-5-morpholinophenyl)urea
Triethylamine (6 μί, 0.043 mmol) was added to a mixture of the product from step (i) above (58 mg, 0.177 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 100 mg, 0.192 mmol) in isopropyl acetate (3 mL) and the mixture heated at 70°C (block temperature) for 4 days. The reaction was cooled to rt and diluted with MeOH. The solution was concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the product as an off-white solid. The crude product was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μητι, 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (51 mg) as an off-white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.44 (s, 1 H), 9.41 (s, 1 H), 8.83 (s, 1 H), 8.42 (d, 1 H), 8.29 (d, 1 H), 8.08 (d, 1 H), 8.08 (bs, 1 H), 7.84 (d, 1 H), 7.67 (t, 1 H), 7.58 (t, 1 H), 7.40 (d, 1 H), 7.00 (d, 1 H), 6.81 (d, 2H), 6.68 (bs, 1 H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.90 (s, 3H), 3.85-3.87 (m, 2H), 3.78 (bs, 4H), 3.64-3.66 (m, 2H), 3.48-3.55 (m, 6H), 3.50 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 3.08 (bs, 4H).
LCMS m/z 378 (M+2H)2+ (ES+)
Example 13
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide
Figure imgf000071_0001
Triethylamine (15 μΙ_, 0.108 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2- methoxy-3-(methylcarbamoyl)phenyl)carbamate (see Example 9(i) above; 150 mg, 0.421 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)pyrimidin-2-amine (see Example 4(v) above; 200 mg, 0.384 mmol) in THF (5 mL) and the mixture heated at 50°C (block temperature) for 24h. The solvents were evaporated and the crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 5%) to afford a pale brown glass which was triturated with Et20 to afford the title compound (255 mg) as a tan solid.
H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 2H), 8.89 (s, 1 H), 8.45 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.17 (q, 1 H), 8.08 (d, 1 H), 7.89 - 7.81 (m, 1 H), 7.72 - 7.65 (m, 1 H), 7.64 - 7.56 (m, 1 H), 7.42 (d, 1 H), 7.11 (d, 1 H), 6.87 - 6.75 (m, 2H), 6.54 (d, 1 H), 6.04 (t, 1 H), 3.87 (t, 2H), 3.80 (s, 3H), 3.71 - 3.61 (m, 2H), 3.60 - 3.46 (m, 9H), 3.44 - 3.39 (m, 2H), 3.22 (s, 3H), 2.82 (d, 3H), 1.28 (s, 9H).
LCMS m/z 783 (M+H)+ (ES+); 781 (M-H)" (ES")
Example 14
N-(3-(3-(4-((2-((3-(2.5.8.1 1.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)- methanesulfonamide
Figure imgf000071_0002
(i) 22-(3-Methoxy-5-nitrophenoxy)-2,5,8, 1 1 , 14, 17,20-heptaoxadocosane DIAD (2.76 mL, 14.19 mmol) was added dropwise to a stirred solution of 3-methoxy-5- nitrophenol (2 g, 11.82 mmol), 2,5,8,1 1 , 14, 17,20-heptaoxadocosan-22-ol (4.03 g, 1 1.82 mmol) and PPh3 (3.72 g, 14.19 mmol) in THF (15 mL) at 0-5°C. The mixture was warmed to rt, stirred for 18h then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g) column, EtOAc then 0-10%EtOH/EtOAc) to afford the sub-title compound (3.905 g, 70% purity) as an oil.
H NMR (400MHz; CDCI3) δ 7.38 (s, 1 H), 7.36 (s, 1 H), 6.78 (s, 1 H), 4.19-4.17 (m, 2H), 3.89- 3.85 (m, 5H), 3.73-3.62 (m, 22H), 3.56-3.53 (m, 2H), 3.38 (s, 3H). (ii) 3-(2.5.8.11.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyaniline
The product from step (i) above (3.90 g, 5.55 mmol) was dissolved in EtOH (30 mL) and Fe powder (3.10 g, 55.5 mmol) was added followed by a solution of NH4CI (2.97 g, 55.5 mmol) in water (15 mL). The resulting suspension was heated at 80 °C for 1 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo, basified to pH 10 by the addition of sat. aq. NaHC03 (80 mL), then extracted with EtOAc (3 x 100 mL). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to afford an orange oil (3.7 g). The crude product was dissolved in the minimum of MeOH and loaded onto SCX. The column was eluted first with MeOH (3 column volumes) and then 1 % NH3 in MeOH (3 column volumes). The product containing fraction was concentrated in vacuo to afford the sub-title compound (2.54 g) as a brown oil.
H NMR (400 MHz, DMSO-d6) δ: 5.75-5.74 (m, 2H), 5.68 (t, 1 H), 5.04 (s, 2H), 3.95-3.93 (m, 2H), 3.69-3.67 (m, 2H), 3.62 (s, 3H), 3.58-3.49 (m, 22H), 3.43-3.41 (m, 2H), 3.23 (s, 3H). LCMS m/z 462 (M+H)+ (ES+) (iii) tert-Butyl (4-((2-((3-(2.5.8.11.14.17.20-heptaoxadocosan-22-yloxy)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
To a stirred solution of tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 289 mg, 0.701 mmol) and the product from step (ii) above (500 mg, 1.051 mmol) in DMF (20 mL) was added pTSA monohydrate (67 mg, 0.352 mmol). The resulting solution was heated at 60 °C for 48 h. The reaction was cooled to rt and partitioned between EtOAc (80 mL) and sat. aq. NaHC03 (50 mL). The aqueous phase was back-extracted with EtOAc (80 mL). The combined organic extracts were washed with water (3 x 50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford an orange oil. The crude product was purified by chromatography on silica gel (40 g column, 0-2% MeOH in EtOAc) to afford the sub-title compound (498 mg) as an orange oil.
H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1 H), 9.30 (s, 1 H), 8.41 (d, 1 H), 8.12-8.09 (m, 1 H), 7.82-7.80 (m, 1 H), 7.62-7.52 (m, 3H), 7.38 (d, 1 H), 6.85 (s, 2H), 6.54 (d, 1 H), 6.04 (t, 1 H), 3.90-3.84 (m, 2H), 3.69-3.63 (m, 2H), 3.58-3.48 (m, 25H), 3.42-3.40 (m, 2H), 3.22 (s, 3H), 1.52 (s, 9H).
(iv) N-(3-(2.5.8.1 1.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)-4-((4- aminonaphthalen-1-yl)oxy)pyrimidin-2-amine To a stirred solution of the product from step (iii) above (452 mg, 0.567 mmol) in DCM (10 ml_) was added TFA (2.2 ml_, 28.6 mmol). The resulting solution was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo, dissolved in the minimum of MeOH then loaded onto SCX. The column was eluted with MeOH (3 column volumes) then 1 % NH3 in MeOH (3 column volumes). The product containing fraction was concentrated in vacuo to afford the sub-title compound (258 mg) as a dark orange oil.
H NMR (400 MHz, DMSO-d6) δ: 9.30 (s, 1 H), 8.32 (d, 1 H), 8.14-8.10 (m, 1 H), 7.66-7.63 (m, 1 H), 7.45-7.39 (m, 2H), 7.10 (d, 1 H), 6.87 (s, 2H), 6.70 (d, 1 H), 6.34 (d, 1 H), 6.04 (t, 1 H), 5.68 (s, 2H), 3.89-3.87 (m, 2H), 3.69-3.67 (m, 2H), 3.60-3.47 (m, 25H), 3.45-3.41 (m, 2H), 3.23 (s, 3H).
LCMS m/z 349 (M+2H)2+ (ES+)
(v) N-(3-(3-(4-((2-((3-(2.5.8.1 1.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)-methane sulfonamide
A mixture of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 74 mg, 0.187 mmol), the product from step (iv) above (120 mg, 0.170 mmol) and triethylamine (5 μΙ_, 0.036 mmol) in i-PrOAc (2 ml_) was heated at 70 °C overnight. The reaction was cooled to rt and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-10% MeOH in EtOAc) to afford an oil. The oil was dissolved in MeCN and water (4 ml_, 1 : 1) and freeze-dried overnight to afford the title compound (118 mg) as a pale pink solid.
H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1 H), 9.34 (s, 1 H), 9.13 (s, 1 H), 8.91 (s, 1 H), 8.41 (d, 1 H), 8.27 (d, 1 H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.85-7.83 (m, 1 H), 7.69-7.65 (m, 1 H), 7.60- 7.56 (m, 1 H), 7.41 (d, 1 H), 7.02 (d, 1 H), 6.82-6.80 (m, 2H), 6.54 (d, 1 H), 6.03 (t, 1 H), 3.87- 3.85 (m, 2H), 3.80 (s, 3H), 3.67-3.64 (m, 2H), 3.55-3.47 (m, 25H), 3.41-3.39 (m, 2H), 3.22 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 995 (M+H)+ (ES+) Example 15
N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide
Figure imgf000073_0001
(i) 2-(2-(2-(3-Methoxy-5-nitrophenoxy)ethoxy)ethoxy)-N,N-dimethylethanamine
DIAD (480 μΙ_, 2.469 mmol) was added dropwise to a stirred solution of 3-methoxy-5- nitrophenol (350 mg, 2.069 mmol), 2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethanol (440 mg, 2.483 mmol) and PPh3 (651 mg, 2.483 mmol) in THF (15 ml_) at 0-5°C. The mixture was warmed to rt, stirred for 18h then the solvent evaporated under reduced pressure. The crude product was loaded onto a column of SCX in MeOH. The column was washed with MeOH and then the product was eluted with 7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g column, 0-10% MeOH/DCM) to afford the sub-title compound (428 mg) as a yellow oil.
H NMR (400MHz; CDCI3) δ 7.38-7.36 (m, 2H), 6.78 (s, 1 H), 4.19-4.17 (m, 2H), 3.89-3.86 (m, 5H), 3.57-3.58 (m, 6H), 2.51 (t, 2H), 2.26 (s, 6H).
LCMS m/z 329 (M+H)+ (ES+)
(ii) 3-(2-(2-(2-(Dimethylamino)ethoxy)ethoxy)ethoxy)-5-methoxyaniline
Pd/C, 10%w/w (50 mg) was added to a solution of the product from step (i) above (420 mg, 1.279 mmol) in EtOH (10 mL) and the mixture stirred under hydrogen (5 bar) for 2h. The mixture was filtered and the solvent evaporated to give the sub-title compound (380 mg) as a thick yellow oil.
H NMR (400 MHz, DMSO-d6) δ 5.79 - 5.72 (m, 2H), 5.68 (t, 1 H), 5.06 (s, 2H), 4.01 - 3.90 (m, 2H), 3.73 - 3.65 (m, 2H), 3.62 (s, 3H), 3.59 - 3.54 (m, 2H), 3.54 - 3.50 (m, 2H), 3.48 (t, 2H), 2.39 (t, 2H), 2.14 (s, 6H).
LCMS m/z 299 (M+H)+ (ES+)
(iii) N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide
A suspension of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- 2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 73.6 mg, 0.129 mmol), the product from step (ii) above (77 mg, 0.258 mmol) and pTSA monohydrate (54.0 mg, 0.284 mmol) in THF/DMF (6 mL, 1 :2) was heated at 60 °C for 24h. The reaction was cooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHC03 (30 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (2 x 50 mL) and brine (2 x 50 mL), then dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 4-10% MeOH) to afford the title compound (51 mg) as a pale pink solid.
H NMR (400MHz; DMSO-d6) δ: 9.43 (s, 1 H), 9.39 (s, 1 H), 9.15 (bs, 1 H), 8.94 (s, 1 H), 8.42 (d, 1 H), 8.29 (d, 1 H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.41 (d, 1 H), 7.03 (d, 1 H), 6.83 (s, 1 H), 6.81 (s, 1 H), 6.55 (d, 1 H), 6.03 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.68 (m, 2H), 3.49-3.60 (m, 6H), 3.51 (s, 3H), 3.10 (s, 3H), 2.51-2.55 (m, 2H), 2.25 (s, 6H), 1.27 (s, 9H).
LCMS m/z 832 (M+H)+ (ES+); 417 (M+2H)2+ (ES+)
Example 16
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Figure imgf000074_0001
METHOD 1
(i) 3-Bromo-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5-nitrobenzamide
T3P, 50 wt% in EtOAc (25 mL, 42.0 mmol) was slowly added to a solution of 3-bromo-5- nitrobenzoic acid (7.05 g, 28.7 mmol), 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (4 g, 24.25 mmol) and Et3N (12 mL, 86 mmol) in EtOAc (50 mL) whilst immersed in an ice-bath. Once the addition was complete, the ice bath was removed and the reaction allowed to stir at rt for 2 h. The mixture was partitioned between sat. aq NaHC03 solution (100 mL) and EtOAc (100 mL). The organic layer was washed with aq K2C03 solution (10 g in 100 mL) and brine (100 mL), before being dried (MgS04), filtered and concentrated in vacuo to afford the sub-title compound (8.23 g) as a brown oil.
H NMR (400 MHz, DMSO-d6) δ 9.02 (t, 1 H), 8.65-8.64 (m, 1 H), 8.53 (t, 1 H), 8.46 (t, 1 H), 3.57-3.43 (m, 10H), 3.41-3.38 (m, 2H), 3.21 (s, 3H).
LCMS m/z 391/393 (M+H)+ (ES+); 389/391 (M-H)" (ES")
(ii) 3-Amino-5-bromo-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Iron powder (5.90 g, 106 mmol) was added to a solution of the product from step (i) above (8.24 g, 20.43 mmol) and concentrated HCI (2 mL, 23.40 mmol) in EtOH (65 mL) and water (15 mL). The mixture was heat at 75 °C (block temperature) for 1 h. Then, the reaction was cooled to rt, before being diluted with water (30 mL), filtered and concentrated in vacuo. The residue was basified (NaHC03) then partitioned between EtOAc (350 mL) and water (275 mL). The organic layer was dried (MgS04), filtered and concentrated in vacuo to afford an orange oil that was purified by chromatography on silica gel (220 g column, 0-5% MeOH in DCM) to afford the sub-title compound (5.25 g) as an orange oil.
H NMR (400 MHz, DMSO-d6) δ: 8.36 (t, 1 H), 7.07 (t, 1 H), 7.00-6.99 (m, 1 H), 6.84 (t, 1 H), 5.57 (s, 2H), 3.52-3.48 (m, 8H), 3.42-3.39 (m, 2H), 3.35 (q, 2H), 3.22 (s, 3H).
LCMS m/z 361/363 (M+H)+ (ES+)
(iii) 3-Amino-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5-((triisopropylsilyl)ethvnyl)-benzamide To a degassed solution of the product from step (ii) above (5.06 g, 13.31 mmol), ethynyltriisopropylsilane (4.5 mL, 20.06 mmol), Cu(l)l (130 mg, 0.683 mmol) and Et3N (8 mL, 57.4 mmol) in DMF (45 mL) was added Pd(PPh3)4 (770 mg, 0.666 mmol). The reaction was heated at 85 °C for 3 h, before beingcooled to rt and partitioned between EtOAc (250 mL) and brine (250 mL). The aqueous phase was further extracted with EtOAc (250 mL), then the combined organic extracts were washed with water (3 x 200 mL) and brine (200 mL), before being dried (MgS04), filtered and concentrated in vacuo to afford a dark brown oil. The crude product was purified by chromatography on silica gel (220 g column, 0-3% MeOH in DCM) to afford the sub-title compound (5.4 g) as an orange oil.
H NMR (400 MHz, DMSO-d6) δ: 8.39 (t, 1 H), 7.06-7.03 (m, 2H), 6.79-6.78 (m, 1 H), 5.43 (s, 2H), 3.54-3.49 (m, 8H), 3.41-3.33 (m, 4H), 3.21 (s, 3H), 1.10 (s, 21 H).
LCMS m/z 463 (M+H)+ (ES+)
(iv) 3-Amino-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide To a stirred solution of the product from step (iii) above (5.33 g, 11.40 mmol) in EtOAc (75 mL) was added 1 M TBAF in THF (11.40 mL, 1 1.40 mmol). The reaction was stirred at rt for 1 h, before being partitioned between water (300 mL) and EtOAc (400 mL), the aqueous phase being further extracted with EtOAc (300 mL). The combined organic extracts were washed with brine (400 mL), before being dried (MgS04), filtered and concentrated to afford an orange oil. The crude product was dissolved in the minimum quantity of MeOH and loaded onto SCX. The column was eluted with MeOH (3 column volumes) followed by 1 % NH3 in MeOH (3 column volumes). The product containing fraction was concentrated in vacuo to afford the sub-title compound (3.27 g) as a brown oil.
H NMR (400 MHz, DMSO-d6) δ: 8.38 (t, 1 H), 7.06-7.04 (m, 2H), 6.75-6.74 (m, 1 H), 5.46 (s, 2H), 4.09 (s, 1 H), 3.53-3.48 (m, 8H), 3.41-3.39 (m, 2H), 3.37-3.33 (m, 2H), 3.21 (s, 3H). LCMS m/z 307 (M+H)+ (ES+)
(v) tert-Butyl (4-((2-((3-ethvnyl-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
To a stirred solution of the product from step (iv) above (1 g, 3.13 mmol) and tert-butyl (4-((2- chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 777 mg, 2.090 mmol) in DMF (60 mL) was added pTSA monohydrate (200 mg, 1.051 mmol). The resulting solution was stirred at 60 °C for 72 h. The reaction was cooled to rt then partitioned between EtOAc (150 mL) and sat. aq. NaHC03 (100 mL). The aqueous layer was further extracted with EtOAc (2 x 150 mL), then the combined organic extracts were washed with water (3 x 200 mL) and brine (200 mL), before being dried (MgS04), filtered and concentrated to afford an orange oil (1.17 g). The crude product was purified by chromatography on silica gel (80 g column, 0-5% MeOH in EtOAc) to afford the sub-title compound (552 mg) as a light brown foam.
H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1 H), 9.29 (s, 1 H), 8.46-8.43 (m, 2H), 8.1 1-8.09 (m, 2H), 7.92-7.88 (br m, 1 H), 7.83-7.80 (m, 1 H), 7.62-7.53 (m, 3H), 7.56-7.55 (m, 1 H), 7.42 (d, 1 H), 6.57 (d, 1 H), 4.14 (s, 1 H), 3.54-3.48 (m, 8H), 3.40-3.35 (m, 4H), 3.20 (s, 3H), 1.52 (s, 9H).
LCMS m/z 642 (M+H)+ (ES+)
(vi) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2- methoxyethoxy)ethoxy)ethyl)benzamide
To a stirred solution of the product from step (v) above (540 mg, 0.825 mmol) in DCM (8 mL) was added TFA (3.2 mL, 41.5 mmol). The reaction was stirred at rt for 1 h. The solution was concentrated in vacuo and the resulting oil dissolved in the minimum of MeOH and loaded onto SCX. The column was eluted with MeOH (3 column volumes), then 1 % NH3 in MeOH (3 column volumes). The product-containing portion was concentrated in vacuo to afford the sub-title compound (405 mg) as a light, brown foam.
H NMR (400 MHz, DMSO-d6) δ: 9.73 (s, 1 H), 8.45 (t, 1 H), 8.36 (d, 1 H), 8.14-8.10 (m, 1 H), 8.07-8.05 (br m, 1 H), 7.94-7.92 (br m, 1 H), 7.65-7.61 (m, 1 H), 7.47-7.40 (m, 3H), 7.15 (d, 1 H), 6.72 (d, 1 H), 6.37 (d, 1 H), 5.87 (br s, 2H), 4.17 (s, 1 H), 3.54-3.48 (m, 8H), 3.40-3.36 (m, 4H), 3.20 (s, 3H).
LCMS m/z 542 (M+H)+ (ES+) (vii) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonam
yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)-ethyl)benzam
A stirred mixture of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- carbamate (see Example 1 (vi) above; 95 mg, 0.239 mmol), the product from step (vi) above (120 mg, 0.217 mmol) and Et3N (6 μΙ_, 0.043 mmol) in i-PrOAc (3 ml_) was heated at 70 °C overnight. The reaction was cooled to rt and concentrated in vacuo. The remainder was purified by chromatography on silica gel (40 g column, 0-5% MeOH in EtOAc) to afford an oil, which was triturated with diethyl ether to afford a light beige solid. The crude product was purified by preparative HPLC (Varian, Basic (10 mM Ammonium Bicarbonate), Waters X- Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (69 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1 H), 9.32 (s, 1 H), 9.13 (s, 1 H), 8.89 (s, 1 H), 8.46- 8.43 (m, 2H), 8.26 (d, 1 H), 8.17 (d, 1 H), 8.09-8.07 (m, 2H), 7.87-7.83 (m, 2H), 7.69-7.65 (m, 1 H), 7.61-7.57 (m, 1 H), 7.45-7.43 (m, 2H), 7.02 (d, 1 H), 6.55 (d, 1 H), 4.11 (s, 1 H), 3.80 (s, 3H), 3.53-3.47 (m, 8H), 3.40-3.35 (m, 4H), 3.20 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 840 (M+H)+ (ES+); 838 (M-H)" (ES")
METHOD 2 (I) 3-Bromo-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5-nitrobenzamide
To a 10 L flask, equipped with a scrubber under nitrogen, was added 3-bromo-5-nitrobenzoic acid (2686 g, 10.91 mol) and thionyl chloride (5.37 L, 75.8 mol). The reaction was heated to 68°C [GAS EVOLUTION] and was then stirred at 60 °C overnight, after which LC analysis indicated complete reaction. The reaction was cooled to rt and concentrated in vacuo to furnish 3.2 kg of material, an amount that indicated the presence of thionyl chloride (100% yield = 2.88 kg). The mixture was concentrated from toluene (2 x 3 L) to remove all traces of thionyl chloride. A total of 3370 g of acid chloride was obtained, with toluene accounting for the excess yield.
To a 20 L flask under nitrogen was added 2-(2-(2-methoxyethoxy)ethoxy)ethanamine (890 g, 5.45 mol) and DCM (3.5 L). This was followed by the addition of 8% aq NaHC03 (9 L). The acid chloride (1373 g active, 4.89 mol) was then added to the mixture while maintaining the temperature below 25 °C [EXOTHERM and GAS EVOLUTION]. The mixture was stirred for 30 mins, after which LC indicated complete reaction. The organics were separated and washed with 1 M HCI (4.5 L) and 8% aq NaHC03 (4.5 L), before being dried, filtered and concentrated in vacuo to give a total of 1956 g of the sub-title compound (95% yield). Analysis by H NMR indicated a product purity of >95%.
(II) 3-Amino-5-bromo-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
The product from step (I) above (1 kg, 2.56mol) was dissolved in THF (3.5 L) and AcOH (500 mL) and hydrogenated at 3 MPa (30 bar) H2 at up to 60°C with 5% Pt/C (30 g of JM type 18 MA, 55% water). Analysis after 5 hrs showed a 1 : 1 ratio of ArNHOH and ArNH2. The reaction reached completion after being left overnight, with H NMR analysis showing 3% des-bromo side product. The catalyst was filtered off, then the residue was diluted with ethyl acetate (3 L) and washed with 20% potassium carbonate solution (3.5 L). The organics were then dried, filtered and concentrated in vacuo to provide a residue that was then slurried in 5 volumes of diethyl ether overnight to reduce the level of the des-bromo species (<2% after the slurry). The sub-title compound was obtained in 90% yield with a purity of 86% by LC. (III) 3-Amino-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-5-((triisopropylsilyl)ethvnyl)benzamide To a 10 L flask under nitrogen was added the product from step (II) above (700 g, 1.93 mol) and THF (5.59 L). This was followed by the addition of Cul (19.2 g, 0.1 mol), triethylamine (1.29 L, 9.27 mol) and ethynyltriisopropylsilane (389 g, 2.13 mol). The reaction was degassed and purged with nitrogen three times. Pd(PPh3)4 (125.5 g, 0.198 mol) was added and the reaction degassed and purged with nitrogen. The reaction was heated to 65 °C overnight, after which LC indicated 91 % product and <1 % starting material. The reaction mixture was concentrated in vacuo, then the residue was taken up in ethyl acetate (2 L) and put through a silica plug (2 kg), eluting with additional ethyl acetate (30 L). The product- containing fractions were concentrated in vacuo, then the crude product was dissolved in TBME (5 L) and extracted with 6 N HCI (5 L). The aqueous HCI phase was washed with TBME (2 x 5 L), before being basified with 6 N NaOH to pH 9-10. The product was then extracted with TBME (2 x 5 L), the organics were dried, filtered and concentrated in vacuo to give 635g of the sub-title compound with a purity of >95% by H NMR (excluding solvents). (IV) 3-Amino-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
To the product from step (III) above (1200 g, 2.59 mol) in MeCN (8.8 L) was added CsF (433.6 g, 2.85 mol). The reaction was stirred at RT overnight, after which HPLC analysis showed 1.7% product, 97.4% starting material. Additional CsF (420 g, 2.76 mol) was charged and the reaction stirred at RT overnight, whereupon HPLC analysis revealed 91.0% product, 4.4% starting material. The mixture was filtered and the filtrate concentrated in vacuo to give material which was 92.5% product, 0.7% starting material by HPLC. The residue was dissolved in DCM (3 L) and EtOAc (3 L), before being split into two equal portions. Each portion was passed through a silica pad (1.6 kg), eluting with EtOAc (50 L). The filtrates were combined and concentrated in vacuo. The crude material was washed with heptane (2 x 4 L) to remove silyl impurities. A total of 719 g of sub-title compound was isolated (83% assay by H NMR, 75% active yield, 597 g active).
(V) tert-Butyl (4-((2-((3-ethvnyl-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
Under N2 was charged the product from step (IV) above (301.2 g, 250.0 g active, 0.816 mol), tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 252.8 g, 0.680 mol), pTSA.H20 (24.7 g, 0.130 mol) and THF (7600 mL). The dark red solution was heated to reflux for 6 h then cooled to room temperature, after which HPLC analysis indicated 0.25% the product of step (IV), 22.24% the product of step (VI), 8.98% chloropyrimidine starting material and 64.08% the product of step (V). Further product from step (IV) above (27.1 g, 22.5 g active, 73.4 mmol) was charged and the reaction was heated back to reflux and stirred overnight, with HPLC analysis subsequently revealing 0.20% the product of step (IV), 30.23% the product of step (VI), 4.50% starting chloropyrimidine and 58.61 % the product of step (V). The reaction was cooled to room temperature and quenched with 20% K2C03 (735 mL), then the layers were separated, with the organic layer being washed with sat. brine (880 mL). The organic layer was dried over MgS04, filtered and concentrated to isolate a brown sticky solid. Yield = 491.2g (93.8%). HPLC revealed 30.59% the product of step (VI) and 59.50% the product of step (V), with H NMR conforming to structure.
(VI) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxy- ethoxy)ethoxy)ethyl)benzamide
Under N2 was charged the crude product mixture from step (V) above (491.2 g) and DCM (3700 mL). TFA (695 mL, 12.3 equivalents) was added dropwise, while maintaining the temperature below 20°C. The dark brown solution was stirred at room temperature overnight, following which HPLC analysis indicated 86.90% product of step (VI) and 0.94% product of step (V). The mixture was concentrated and the residue taken up in EtOAc (3700 mL), before being washed with sat. aq. NaHC03 (2 x 2000 mL) until a pH of 7-8 was achieved. The organic layer was dried over MgS04, filtered and concentrated to isolate a purple solid. Yield = 360.8g. HPLC purity 78.58%.
(VII) 5-tert-Butyl-2-methoxy-3-nitroaniline
Under N2 was charged 4-te/f-butyl-2,6-dinitroanisole (620 g, 2.439 mol), IMS (4774 mL) and 10% Pd/C (31.8g). The reaction mixture was heated to reflux (78°C) and 4-methyl-1- cyclohexene (500 mL, 4.159 mol) was added dropwise over 4.5 h. The reaction was stirred at reflux overnight, whereupon HPLC analysis indicated 72.13% product and 27.17% starting material. Further 4-methyl-1-cyclohexene (160 mL, 1.331 mol) was added dropwise over 3 h and the reaction was stirred at reflux for 72 h. HPLC analysis indicated 92.72% product and 0% starting material. The reaction was cooled to room temperature and the catalyst was removed via vacuum filtration and washed with IMS (500 mL). The solvents were concentrated to ca. 1200 mL to give a ratio of 1 : 4.45 product : ethanol (target 1 : 5). 2 M HCI (124 mL) was charged dropwise to the remainder while maintaining the temperature below 23°C. Water (3100 mL) was charged and the resulting suspension was stirred at room temperature for 1.5 h. The solid was collected via vacuum filtration and washed with water (2 x 1000 mL). The resulting orange needles were dried, under vacuum, at 40°C overnight. Yield = 475.2 g (86.9%). Purity >97% by H NMR. HPLC purity 98.8%. KF 0.36%.
(VIII) N-(5-tert-Butyl-2-methoxy-3-nitrophenyl)methanesulfonamide
Under N2 was charged the product of step (VII) (471 g, 2.099 mol), toluene (1880 mL) and pyridine (471 mL), then methanesulfonyl chloride (179 mL) was added dropwise over 1 h while maintaining the temperature below 35 °C. The reaction was stirred at 30-35 °C overnight, before being cooled to below 20 °C, then water (1880 mL) and 2 M HCI (1880 mL) were charged (pH 3 achieved). The layers were separated and the organic phase was washed with 2.5% brine (1880 mL). Heptane (3760 mL) was then charged to the organic layer over 0.5 h to isolate a precipitate. The mixture was cooled to 0 °C and stirred for 1 h. The solid was collected via vacuum filtration and washed with heptane (1880 mL), before being dried, under vacuum, at 40 °C overnight. Yield = 551 g (87%). HPLC purity 98.5%. Purity >97% by H NMR. (IX) N-(3-Arnino-5-tert-butyl-2-methoxyphenyl)methanesulfonamide
To a 5L hydrogenator was charged the product from step (VIII) above (209.4 g, 0.693 mol), methanol (1675 mL, 8 volumes) and 10% Pd/C (10.2 g). The vessel was purged with 3 x N2 and 3 x H2 and then stirred under 0.3447 MPa (50 psi) H2 until no further exotherm was observed, with HPLC indicating 96.35% product and 1.10% starting material. The reaction was diluted with THF (314 mL) and the catalyst was removed via vacuum filtration (Cuno filter), before being washed with THF (1000 mL). The solvents were concentrated to isolate a light brown solid, which was dried under vacuum at 40°C overnight. Yield = 167.0 g (88.5%). HPLC purity 96.7%. Purity >95% by H NMR.
(X) Phenyl N-r5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyllcarbamate
Under N2 was charged the product of step (IX) above (167.0 g, 613 mmol), NaHC03 (77.3 g, 920 mmol), THF (870 mL) and DCM (1440 mL). Phenyl chloroformate (82.6 mL, 659 mmol) was added dropwise, while maintaining the temperature below 20°C, and the reaction was stirred at room temperature for 4 h. HPLC analysis of the reaction mixture indicated 98.6% product and 0.03% starting material. The reaction mixture was filtered and the cake was washed with THF (-50 mL). The filtrate was concentrated to -900 mL and cyclohexane (2400 mL) was added, then the mixture was left to stir overnight. The resulting solid was collected via vacuum filtration and washed with cyclohexane (500 mL). The pale pink solid produced was dried, under vacuum, at 40°C for 4h. Yield = 232.6g (96.7%). HPLC purity 94.5%. H NMR purity >95%.
(XI) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Under N2 was charged the product of step (vi) above (175.5g, 0.324mol), the product of step (X) above (145.0 g, 0.369 mmol) and /'PrOAc (8800 mL). The resulting solution was heated to 60°C and NEt3 (9.3 mL) was charged in one portion, then the mixture was left to stir at 60 °C overnight, following which HPLC analysis indicated 25.77% product of step (VI), 3.60% product of step (X) and 57.85% product of step (XI). Further product of step (X) (36.0 g, 0.092 mol) was charged, then the reaction was left to stir at 60 °C overnight, whereupon HPLC analysis indicated 5.47% product of step (VI), 3.72% product of step (X) and 73.33% product of step (XI). The reaction mixture was cooled to room temperature, before being concentrated to isolate a dark purple solid (522.9 g). This solid was recrystallised from acetonitrile (2615 mL, 5 volumes), before being collected via vacuum filtration and washed with /'PrOAc (2 x 500 mL). The pink solid obtained was dried, under vacuum, at 40 °C overnight, yielding 181.1 g (66.5%) of the title compound with HPLC purity 99.27%. H NMR conformed to structure. Example 17
N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(difluoromethoxy)-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide
Figure imgf000081_0001
(i) 1-Bromo-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-5-nitrobenzene
A mixture of 3-bromo-5-nitrophenol (1.5 g, 6.88 mmol), 1-bromo-2-(2-(2-methoxyethoxy)- ethoxy)ethane (1.72 g, 7.57 mmol), sodium iodide (0.103 g, 0.688 mmol) and K2C03 (2.85 g, 20.64 mmol) in MeCN (30 mL) was heated at 60°C for 18h. The mixture was cooled and partitioned between EtOAc (150 mL) and water (150 mL). The organic layer was separated, dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-50% EtOAc/isohexane) to afford the sub-title compound (2.5 g) as an oil.
H NMR (400MHz; DMSO-d6) δ 7.97 (s, 1 H), 7.72 (s, 1 H), 7.41 (s, 1 H), 4.22-4.19 (m, 2H), 3.90-3.87 (m, 2H), 3.74-3.54 (m, 8H), 3.38 (s, 3H).
(ii) 3-(2-(2-(2-Methoxyethoxy)ethoxy)ethoxy)-5-nitrophenol
A mixture of KOH (1.54 g, 27.4 mmol) and the product from step (i) above (2.5 g, 5.83 mmol) in water (10 mL) and dioxane (10 mL) was degassed for 5 minutes prior to the addition of di- tert-butyl(2',4',6'-triisopropyl-[1 ,1 '-biphenyl]-2-yl)phosphine (0.067 g, 0.158 mmol) and Pd2(dba)3 (0.063 g, 0.069 mmol). The resulting mixture was degassed for a further 2 minutes and then heated under a nitrogen atmosphere at 100 °C for 2h. The mixture was cooled then partitioned between ether (100 mL) and water (100 mL). The aqueous layer was acidified with aq. 1 M HCI to ~pH 1 and extracted with ethyl acetate (2 x 200 mL). The organic layer was washed with saturated brine (200 mL), dried over MgS04, filtered, and concentrated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-80% EtOAc/isohexane) to afford an oil which was triturated with ether/isohexane to give a solid. The solid was filtered and dried to afford the sub-title compound (1.46 g). H NMR (400MHz; CDCI3) δ 7.61 (s, 1 H), 7.27 (s, 1 H), 7.19 (s, 1 H), 6.76 (s, 1 H), 4.13-4.1 1 (m, 2H), 3.85-3.83 (m, 2H), 3.76-3.67 (m, 6H), 3.61-3.59 (m, 2H), 3.39 (s, 3H).
LCMS m/z 302 (M+H)+ (ES+); 300 (M-H)" (ES") (iii) 1-(Difluoromethoxy)-3-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)-5-nitrobenzene
A mixture of the product from step (ii) above (1.4 g, 4.65 mmol), sodium 2-chloro-2,2- difluoroacetate (1.771 g, 11.62 mmol) and Cs2C03 (3.03 g, 9.29 mmol) in DMF (15 mL) was heated at 100°C for 1 h. The mixture was partitioned between EtOAc (100 mL) and water (100 mL), the organic layer washed with water (100 mL), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-80% EtOAc/isohexane) to afford the sub-title compound (900 mg) as an oil.
H NMR (400 MHz, CDCI3) δ 7.64 (s, 1 H), 7.59 (s, 1 H), 7.04 (s, 1 H), 6.58 (t, 1 H), 4.23-4.20 (m, 2H), 3.90-3.88 (m, 2H), 3.75-3.64 (m, 6H), 3.56-3.54 (m, 2H), 3.38 (s, 3H).
LCMS m/z 352 (M+H)+ (ES+) (iv) 3-(Difluoromethoxy)-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline
A mixture of the product from step (iii) above (890 mg, 2.53 mmol), Fe powder (890 mg, 15.94 mmol) and NH4CI (50 mg, 0.935 mmol) in EtOH (12 mL) and water (4 mL) was heated under reflux for 1 h. The mixture was cooled, filtered and the MeOH removed under reduced pressure. The residue was partitioned between EtOAc (100 mL) and aq sat NaHC03 soln (100mL), the organic layer washed with brine (100 mL), dried (MgS04), filtered and evaporated under reduced pressure to afford the sub-title compound (749 mg). H NMR (400 MHz, CDCI3) δ 6.45 (t, 1 H), 6.09 (s, 1 H), 6.08 (s, 1 H), 6.03 (s, 1 H), 4.07 (m, 2H), 3.83-3.81 (m, 2H), 3.77 (s, 2H), 3.74-3.71 (m, 2H), 3.69-3.64 (m, 4H), 3.56-3.54 (m, 2H), 3.38 (s, 3H).
LCMS m/z 322 (M+H)+ (ES+) (v) N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(difluoromethoxy)-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide
To a stirred solution of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1- yl)ureido)-2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 150 mg, 0.250 mmol) and the product from step (iv) above (104 mg, 0.317 mmol) in DMF (7 mL) was added pTSA monohydrate (24 mg, 0.126 mmol). The reaction was heated at 60 °C for 48 h. The reaction was cooled to rt then partitioned between EtOAc (40 mL) and sat aq. NaHC03 (40 mL). The aqueous phase was back-extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (3 x 50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford an oil (212 mg). The crude product was purified by chromatography on silica gel (40 g column, 100% EtOAc) to afford a foam, which was triturated with diethyl ether to afford the title compound (90 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1 H), 9.34 (s, 1 H), 9.13 (s, 1 H), 8.90 (s, 1 H), 8.44 (d, 1 H), 8.27 (d, 1 H), 8.18 (d, 1 H), 8.10 (d, 1 H), 7.85-7.83 (m, 1 H), 7.69-7.65 (m, 1 H), 7.60- 7.56 (m, 1 H), 7.42 (d, 1 H), 7.23-6.86 (m, 4H), 6.58 (d, 1 H), 6.28 (t, 1 H), 3.92-3.89 (m, 2H), 3.80 (s, 3H), 3.68-3.66 (m, 2H), 3.55-3.53 (m, 2H), 3.50-3.47 (m, 4H), 3.40-3.38 (m, 2H), 3.20 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 855 (M+H)+ (ES+) Example 18
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-morpholinoethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide
Figure imgf000082_0001
(i) 4-(2-(2-(2-(3-Methoxy-5-nitrophenoxy)ethoxy)ethoxy)ethyl)morpholine DIAD (530 μΙ_, 2.73 mmol) was added dropwise to a stirred solution of 3-methoxy-5- nitrophenol (386 mg, 2.280 mmol), 2-(2-(2-morpholinoethoxy)ethoxy)ethanol (600mg, 2.74 mmol) and PPh3 (718 mg, 2.74 mmol) in THF (15 mL) at 0-5°C. The mixture was warmed to rt , stirred for 18h then the solvent evaporated under reduced pressure. The crude product was loaded onto a column of SCX in MeOH. The column was washed with MeOH and then the product was eluted with 7 M ammonia in MeOH. The resultant mixture was concentrated in vacuo and purified by chromatography on silica gel (40 g column, 0-5% MeOH/DCM) to afford the sub-title compound (728 mg) as a yellow oil.
H NMR (400MHz; CDCI3) δ 7.40-7.36 (m, 2H), 6.78 (s, 1 H), 4.18 (t, 2H), 3.89-3.96 (m, 5H), 3.73-3.62 (m, 10H), 2.59 (t, 2H), 2.50 (br s , 4H).
LCMS m/z 371 (M+H)+ (ES+)
(ii) 3-Methoxy-5-(2-(2-(2-morpholinoethoxy)ethoxy)ethoxy)aniline
Pd/C, 10%w/w (100 mg) was added to a solution of the product from step (i) above (720 mg, 1.944 mmol) in EtOH (10 mL) and the mixture stirred under hydrogen (5 bar) for 2h. The mixture was filtered and the solvent evaporated to give the sub-title compound (650 mg) as a thick yellow oil.
H NMR (400 MHz, DMSO-d6) δ 5.79 - 5.71 (m, 2H), 5.68 (t, 1 H), 5.06 (s, 2H), 3.98 - 3.90 (m, 2H), 3.73 - 3.65 (m, 2H), 3.62 (s, 3H), 3.59 - 3.48 (m, 10H), 2.45 (t, 2H), 2.42 - 2.33 (m, 4H).
LCMS m/z 341 (M+H)+ (ES+)
(iii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-morpholinoethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methane- sulfonamide
A suspension of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- 2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 84 mg, 0.147 mmol), the product from step (ii) above (100 mg, 0.294 mmol) and pTSA monohydrate (62 mg, 0.326 mmol) in THF/DMF (6 mL, 1 :2) was heated at 60 °C for 24h. The reaction was cooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHC03 (30 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (2 x 50 mL), dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH) and the product triturated with Et20 to afford a pale pink solid. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Waters X-Bridge Prep- C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (52 mg) as a white solid.
H NMR (400MHz; DMSO-d6) δ: 9.43 (s, 1 H), 9.35 (s, 1 H), 9.13 (s, 1 H), 8.92 (s, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.03 (d, 1 H), 6.83 (s, 1 H), 6.80 (s, 1 H), 6.55 (s, 1 H), 6.03 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.49-3.58 (m, 10H), 3.52 (s, 3H), 3.10 (s, 3H), 2.30-2.46 (m, 6H), 1.27 (s, 9H).
LCMS m/z 438 (M+2H)2+ (ES+) Example 19
5-(tert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N,N-dimethylbenzamid
Figure imgf000084_0001
(i) Phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
Phenyl chloroformate (125 μί, 0.996 mmol) was added to a stirred solution of 4-((4- aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)pyrimidin-2-amine (see Example 4(v) above; 500 mg, 0.960 mmol) and NaHC03 (125 mg, 1.488 mmol) in THF (5 mL) and DCM (5 mL) and the mixture was stirred for 2h. The mixture was filtered and the solvent evaporated from the filtrate to give a pale brown oil which was stirred in isohexane (20 mL) overnight. The resultant solid was filtered off and dried to afford the sub-title compound (600 mg).
H NMR (400 MHz, CDCI3) δ 8.30 (d, 1 H), 8.12 (d, 1 H), 8.03 - 7.79 (m, 3H), 7.70 - 7.57 (m, 1 H), 7.57 - 7.48 (m, 1 H), 7.48 - 7.35 (m, 2H), 7.35 - 7.16 (m, 4H), 7.04 (s, 1 H), 6.69 - 6.54 (m, 1 H), 6.47 (d, 1 H), 6.41 (s, 1 H), 6.05 (t, 1 H), 3.79 - 3.70 (m, 6H), 3.70 - 3.65 (m, 4H), 3.63 (s, 3H), 3.60 - 3.52 (m, 2H), 3.35 (s, 3H).
LCMS m/z 641 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N,N-dimethylbenzamide TEA (10 μί, 0.072 mmol) was added to a solution of the product from step (i) above (100 mg, 0.156 mmol) and 3-amino-5-(tert-butyl)-2-methoxy-N,N-dimethylbenzamide (40 mg, 0.160 mmol) in THF (5 mL) and the reaction heated at 50°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 8%) to afford the title compound (124 mg) as a tan solid. H NMR (400 MHz, DMSO-d6) δ 9.41 (d, 2H), 8.89 (s, 1 H), 8.51 - 8.36 (m, 2H), 8.28 (d, 1 H), 8.08 (d, 1 H), 7.85 (d, 1 H), 7.74 - 7.63 (m, 1 H), 7.65 - 7.52 (m, 1 H), 7.42 (d, 1 H), 6.94 - 6.68 (m, 3H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.87 (t, 2H), 3.77 (s, 3H), 3.72 - 3.60 (m, 2H), 3.60 - 3.45 (m, 9H), 3.45 - 3.36 (m, 2H), 3.22 (s, 3H), 3.04 (s, 3H), 2.85 (s, 3H), 1.28 (s, 9H).
LCMS m/z 797 (M+H)+ (ES+); 795 (M-H)" (ES")
Example 20
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000084_0002
TEA (10 μΙ_, 0.072 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 100 mg, 0.156 mmol) and 3-amino-5-(tert-butyl)-2- methoxybenzamide (35 mg, 0.157 mmol) in THF (5 mL) and the reaction heated at 50°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 8%) to afford the title compound (1 10 mg) as a pale tan solid.
H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 2H), 8.92 (s, 1 H), 8.46 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.09 (d, 1 H), 7.85 (d, 1 H), 7.76 - 7.64 (m, 2H), 7.64 - 7.53 (m, 2H), 7.42 (d, 1 H), 7.22 (d, 1 H), 6.89 - 6.70 (m, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.87 (t, 2H), 3.83 (s, 3H), 3.73 - 3.62 (m, 2H), 3.61 - 3.44 (m, 9H), 3.44 - 3.37 (m, 2H), 3.22 (s, 3H), 1.29 (s, 9H).
LCMS m/z 769 (M+H)+ (ES+); 767 (M-H)" (ES")
Example 21
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid
Figure imgf000085_0001
(i) 3-Amino-5-(tert-butyl)-2-methoxybenzoic acid
5% Pd-C (50 mg) was added to a solution of 5-(tert-butyl)-2-methoxy-3-nitrobenzoic acid (450 mg, 1.777 mmol) in EtOH (3 mL) and acetic acid (2 drops). The reaction was stirred under hydrogen (5 bar) for 2h. The catalyst was filtered off and the solvent evaporated to give the sub-title compound (380 mg) as a dark brown foam.
LCMS m/z 224 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid
TEA (30 μί, 0.215 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 100 mg, 0.156 mmol) and the product from step (i) above (50 mg, 0.168 mmol) in THF (5 mL) and the reaction heated at 50°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 5% MeOH:DCM to 10%). This product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 25-55% MeCN in Water) to afford the title compound (25 mg) as a pale yellow solid. H NMR (400 MHz, DMSO-d6) δ 9.52 (s, 1 H), 9.42 (s, 1 H), 8.97 (s, 1 H), 8.48 (d, 1 H), 8.41 (d, 1 H), 8.30 (d, 1 H), 8.08 (d, 1 H), 7.85 (d, 1 H), 7.72 - 7.63 (m, 1 H), 7.63 - 7.51 (m, 1 H), 7.42 (d, 1 H), 7.26 (d, 1 H), 6.92 - 6.70 (m, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86 (s, 5H), 3.72 - 3.62 (m, 2H), 3.57 - 3.45 (m, 9H), 3.44 - 3.35 (m, 2H), 3.21 (s, 3H), 1.28 (s, 9H).
LCMS m/z 770 (M+H)+ (ES+) Example 22
1-(5-(tert-Butvn-3-cvano-2-methoxyphenvn-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000086_0001
TEA (10 μΙ_, 0.072 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 100 mg, 0.156 mmol) and 3-amino-5-(tert-butyl)-2- methoxybenzonitrile (35 mg, 0.171 mmol) in THF (5 mL) and the reaction heated at 50°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 8%). This product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Waters X- Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (40 mg) as a pale yellow solid. H NMR (400 MHz, DMSO-d6) δ 9.60 - 9.29 (m, 2H), 9.08 (s, 1 H), 8.71 (d, 1 H), 8.42 (d, 1 H), 8.27 (d, 1 H), 8.07 (d, 1 H), 7.86 (d, 1 H), 7.76 - 7.65 (m, 1 H), 7.65 - 7.52 (m, 1 H), 7.52 - 7.30 (m, 2H), 6.93 - 6.69 (m, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.03 (s, 3H), 3.94 - 3.79 (m, 2H), 3.78 - 3.60 (m, 2H), 3.60 - 3.45 (m, 9H), 3.45 - 3.37 (m, 2H), 3.22 (s, 3H), 1.29 (s, 9H).
LCMS m/z 751 (M+H)+ (ES+); 749 (M-H)" (ES")
Example 23
3-(tert-Butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide
Figure imgf000086_0002
(i) Methyl 3-((tert-butoxycarbonyl)amino)-5-(tert-butyl)benzoate
To a stirred solution of 3-(tert-butyl)-5-(methoxycarbonyl)benzoic acid (2.3 g, 9.73 mmol) and triethylamine (1.628 mL, 11.68 mmol) in dioxane (15 mL) and tBuOH (10 mL, 105 mmol) under N2 at 0°C was added DPPA (2.52 mL, 11.68 mmol). The mixture was stirred at rt for 10 minutes then heated to 80°C for 4h. The reaction was cooled to rt and diluted with EtOAc (100 mL). The organic phase was washed with 1 M HCI aq. (50 mL), water (50 mL), sat. NaHC03 aq. (50 mL) and brine (50 mL), then dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (80 g column, 0-25% EtOAc in hexane) to afford the sub-title compound (1.80 g) as a white solid. H NMR (DMSO-d6) 400 MHz, δ: 9.49 (s, 1 H), 8.03 (s, 1 H), 7.73 (t, 1 H), 7.58 (t, 1 H), 3.84 (s, 3H), 1.49 (s, 9H), 1.28 (s, 9H).
LCMS m/z 252 (M+H-tBu)+ (ES+) (ii) 3-((tert-Butoxycarbonyl)amino)-5-(tert-butyl)benzoic acid
To a stirred solution of the product from step (i) above (1.80 g, 5.09 mmol) in THF (50 mL) and MeOH (10 mL) was added NaOH (2.0 M aq.) (7.6 mL, 15.20 mmol) and the reaction stirred at rt overnight. Additional NaOH (4 mL) was added and stirring continued for 5h. The organic solvent was removed in vacuo and the resulting aqueous phase washed with Et20. The aqueous phase was acidified with 1 M HCI and extracted with EtOAc (2 x 50 mL). The combined organic phases were dried (MgS04), filtered and concentrated in vacuo affording a greasy, pale yellow solid. The solid was triturated with hexane and then collected by filtration, washing with more hexane to afford the sub-title compound (1.21 g) as a free-flowing white solid.
H NMR (400MHz; DMSO-d6) δ: 12.84 (s, 1 H), 9.44 (s, 1 H), 7.98 (s, 1 H), 7.72 (s, 1 H), 7.58 (s, 1 H), 1.49 (s, 9H), 1.28 (s, 9H).
LCMS m/z 238 (M+H-tBu)+ (ES+); 292 (M-H)" (ES")
(iii) tert-Butyl (3-(tert-butyl)-5-(methylcarbamoyl)phenyl)carbamate
To a stirred solution of methanamine (2.0M in THF) (520 μί, 1.040 mmol), the product from step (ii) above (300 mg, 1.023 mmol) and HATU (514 mg, 1.352 mmol) in DMF (5 mL) was added Hunig's base (725 μί, 4.16 mmol) and the reaction was stirred for 3h. The reaction was diluted with water (100 mL) and the aqueous phase extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with water (100 mL) and brine (50 mL) then dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 0-50% EtOAc in hexane) to afford the sub-title compound (220 mg) as a colourless oil.
H NMR (DMSO-d6) 400 MHz, δ: 9.35 (s, 1 H), 8.32 (q, 1 H), 7.78 (s, 1 H), 7.58 (s, 1 H), 7.43 (s, 1 H), 2.77 (d, 3H), 1.48 (s, 9H), 1.28 (s, 9H).
LCMS m/z 307 (M+H)+ (ES+); 251 (M+H-tBu)+ (ES+)
(iv) 3-Amino-5-(tert-butyl)-N-methylbenzamide
To a stirred solution of the product from step (iii) above (220 mg, 0.718 mmol) in DCM (15 mL) was added TFA (2 mL, 26.0 mmol) and the reaction stirred at rt for 3h. The reaction was concentrated in vacuo and the residue re-dissoved in MeOH (1 mL) and loaded onto a preconditioned cartridge of SCX resin. The resin was washed with MeOH then the product released in 1 % NH3 in MeOH. The NH3 solution was concentrated in vacuo affording the subtitle compound (1 10 mg) as an off-white foam.
LCMS m/z 207 (M+H)+ (ES+)
(v) 3-(tert-Butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide
Triethylamine (9.0 μί, 0.065 mmol) was added to a mixture of phenyl (4-((2-((3-methoxy-5- (2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)carbamate above (see Example 19(i) above; 64.4 mg, 0.312 mmol) and the product from step (iv) above (200 mg, 0.312 mmol) in isopropyl acetate (3 mL) and the mixture heated at 60°C (block temperature) for 1 h. The reaction was diluted with MeOH and concentrated in vacuo onto silica gel. The material was purified by column chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (97 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1 H), 9.17 (s, 1 H), 8.80 (s, 1 H), 8.39-8.42 (m, 2H), 8.20 (d, 1 H), 8.05 (d, 1 H), 7.85 (d, 1 H), 7.80 (s, 1 H), 7.66-7.70 (m, 2H), 7.59 (t, 1 H), 7.50 (s, 1 H), 7.42 (d, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 2.80 (d, 3H), 1.33 (s, 9H). LCMS m/z 377 (M+2H)2+ (ES+)
Example 24
N-(3-(tert-Butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide
Figure imgf000088_0001
(i) Di-tert-butyl (5-(tert-butyl)-1 ,3-phenylene)dicarbamate
To a stirred solution of 5-(tert-butyl)isophthalic acid (1.0 g, 4.50 mmol) and triethylamine (1.380 mL, 9.90 mmol) in dioxane (15 mL) and tBuOH (10 mL, 105 mmol) under N2 at 0°C was added DPPA (2.15 mL, 9.98 mmol). The mixture was stirred at rt for 10 min then heated to 80°C for 4h. The reaction was cooled to rt and diluted with EtOAc (100 mL). The organic phase was washed with 1 M HCI aq. (50 mL), water (50 mL), sat. NaHC03 aq. (50 mL) and brine (50 mL), then dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 0-15% EtOAc in hexane) to afford the sub-title compound (1.01 g) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.14 (s, 2H), 7.54 (s, 1 H), 7.08 (d, 2H), 1.47 (s, 18H), 1.21 (s, 9H).
LCMS m/z 253 (M+H- 2 x tBu)+ (ES+) (ii) 5-(tert-Butyl)benzene-1 ,3-diamine
To a stirred solution of the product from step (i) above (1.01 g, 2.217 mmol) in DCM (40 mL) was added TFA (5 mL, 64.9 mmol) and the reaction stirred at rt overnight. The reaction was concentrated in vacuo and the residue re-dissolved in MeOH (5 ml) and loaded onto a preconditioned cartridge of SCX resin. The resin was washed with MeOH then the product released in 1 % NH3 in MeOH. The NH3 solution was concentrated in vacuo affording the subtitle compound (269 mg) as an off-white foam.
H NMR (400 MHz, DMSO-d6) δ: 5.85 (d, 2H), 5.66 (t, 1 H), 4.62 (bs, 4H), 1.16 (s, 9H).
LCMS m/z 165 (M+H)+ (ES+) (iii) N-(3-Amino-5-(tert-butyl)phenyl)methanesulfonamide
Methanesulfonyl chloride (125 μΙ_, 1.604 mmol) was added dropwise to a stirred solution of the product from step (ii) above (269 mg, 1.638 mmol) and triethylamine (320 μΙ_, 2.293 mmol) in DCM (15 ml_) at 0-5°C. The mixture was stirred for 30 minutes, warmed to rt and stirred for an additional 20h. More triethylamine (0.1 ml_) and methanesulfonyl chloride (0.02 ml_) were added and stirring continued for 1 h. The mixture was washed with 10% brine (10 ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g column, 0-50% EtOAc in hexane) to afford the sub-title compound (258 mg) as a pale brown gum.
LCMS m/z 243 (M+H)+ (ES+)
(iv) N-(3-(tert-Butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide
Triethylamine (24 μΙ_, 0.172 mmol) was added to a mixture of the product from step (iii) above (258 mg, 0.852 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 545 mg, 0.851 mmol) in isopropyl acetate (6 ml_) and the mixture heated at 60°C (block temperature) for 1 h. The reaction was diluted with THF and concentrated in vacuo onto silica gel. The material was purified by column chromatography on the Companion (40 g column, 1-4% MeOH in DCM) to afford the title compound (372 mg) as a pale orange solid. H NMR (400 MHz, DMSO-d6) δ: 9.66 (s, 1 H), 9.42 (s, 1 H), 9.14 (s, 1 H), 8.75 (s, 1 H), 8.42 (d, 1 H), 8.19 (d, 1 H), 8.06 (d, 1 H), 7.85 (d, 1 H), 7.67 (t, 1 H), 7.59 (t, 1 H), 7.41 (d, 1 H), 7.37 (s, 1 H), 7.29 (s, 1 H), 6.90 (s, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.65-3.67 (m, 2H), 3.48-3.56 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 3.01 (s, 3H), 1.28 (s, 9H).
LCMS m/z 789 (M+H)+ (ES+); 395 (M+2H)2+ (ES+)
Example 25
1-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000089_0001
Triethylamine (25 μΙ_, 0.179 mmol) was added to a mixture of 5-(tert-butyl)-2- methoxybenzene-1 ,3-diamine (150 mg, 0.772 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2- (2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1- yl)carbamate (see Example 19(i) above; 495 mg, 0.772 mmol) in isopropyl acetate (6 ml_) and the mixture heated at 60°C (block temperature) for 1 h. The reaction was diluted with Et20 and stirred for 15 minutes resulting in the precipitation of a pale solid which was removed by filtration. The filtrate was concentrated in vacuo onto silica gel. The material was purified by column chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (220 mg) as a pink foam.
H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1 H), 9.32 (s, 1 H), 8.67 (s, 1 H), 8.41 (d, 1 H), 8.29 (d, 1 H), 8.08 (d, 1 H), 7.84 (d, 1 H), 7.67 (t, 1 H), 7.56-7.60 (m, 2H), 7.40 (d, 1 H), 6.82 (d, 2H), 6.54 (d, 1 H), 6.43 (d, 1 H), 6.04 (t, 1 H), 4.81 (s, 2H), 3.86-3.88 (m, 2H), 3.71 (s, 3H), 3.65- 3.67 (m, 2H), 3.48-3.56 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 1.22 (s, 9H).
LCMS m/z 371 (M+2H)2+ (ES+)
Example 26
3-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)-propanoic acid
Figure imgf000090_0001
(i) tert-Butyl 3-(2-(2-(3-amino-5-methoxybenzamido)ethoxy)ethoxy)propanoate
A stirred mixture of 3-amino-5-methoxybenzoic acid (178 mg, 1.066 mmol), tert-butyl 3-(2-(2- aminoethoxy)ethoxy)propanoate (500 mg, 2.132 mmol) and triethylamine (450 μΙ_, 3.23 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (950 μΙ_, 1.596 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was partitioned between sat. aq. NaHC03 (20 mL) and DCM (20 mL). The aqueous phase was back extracted with fresh DCM (20 mL). The combined organic extracts were washed with water (40 mL), brine (40 mL), dried (MgS04), filtered and concentrated in vacuo to afford an oil (496 mg). The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (295 mg) as an oil.
H NMR (400 MHz, DMSO-d6) δ: 8.19 (t, 1 H), 6.62 (t, 1 H), 6.53-6.52 (m, 1 H), 6.25 (t, 1 H), 5.22 (s, 2H), 3.69 (s, 3H), 3.58 (t, 2H), 3.53-3.47 (m, 6H), 3.34 (q, 2H), 2.40 (t, 2H), 1.39 (s, 9H).
LCMS m/z 383 (M+H)+ (ES+)
(ii) tert-Butyl 3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)- propanoate
To a stirred solution of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1- yl)ureido)-2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 200 mg, 0.333 mmol) and the product from step (i) above (191 mg, 0.500 mmol) in DMF (9 mL) was added pTSA (32 mg, 0.168 mmol). The resulting mixture was heated at 60 °C overnight. The reaction was cooled to rt and partitioned between sat. aq. NaHC03 (40 mL) and EtOAc (50 mL). A white solid crashed out in the aqueous layer. Water (50 mL) was added and the layers separated. The aqueous layer was back extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford an oil. The crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH in EtOAc) to afford the sub-title compound (185 mg) as an oil.
H NMR (400 MHz, DMSO-d6) δ: 9.59 (s, 1 H), 9.34 (s, 1 H), 9.12 (s, 1 H), 8.91 (s, 1 H), 8.41 (d, 1 H), 8.29-8.26 (m, 2H), 8.20-8.17 (m, 1 H), 8.09 (d, 1 H), 7.85-7.83 (m, 1 H), 7.69-7.65 (m, 1 H), 7.60-7.56 (m, 2H), 7.42 (d, 1 H), 7.34 (s, 1 H), 7.02 (d, 1 H), 6.88-6.87 (m, 1 H), 6.54-6.52 (m, 1 H), 3.80 (s, 3H), 3.60-3.54 (m, 5H), 3.53-3.46 (m, 6H), 3.38-3.33 (m, 2H), 3.09 (s, 3H), 2.38 (t, 2H), 1.36 (s, 9H), 1.26 (s, 9H).
LCMS m/z 459 (M+2H)2+ (ES+)
(Hi) 3-(2-(2-(3-((4-((4-(3-(5-(tert-Butvn-2-methoxy-3-(methylsulfonamido)phenvnureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)-propanoic acid
TFA (600 μΙ_, 7.79 mmol) was added to a stirred solution of the product from step (ii) above (179 mg, 0.156 mmol) in DCM (2 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the resulting oil dissolved in the minimum of MeOH and loaded onto a SCX column. The column was eluted with MeOH then 1 % NH3 in MeOH. The product containing fraction was concentrated in vacuo, then purified by chromatography on silica gel (40 g column, 0-10% MeOH in DCM) to afford a colourless glass. The glass was triturated with diethyl ether, filtered and dried to afford the title compound (31 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 12.13 (s, 1 H), 9.59 (s, 1 H), 9.35 (s, 1 H), 9.12 (s, 1 H), 8.91 (s, 1 H), 8.41 (d, 1 H), 8.31-8.26 (m, 2H), 8.18 (d, 1 H), 8.09 (d, 1 H), 7.84 (d, 1 H), 7.69-7.65 (m, 1 H), 7.60-7.56 (m, 2H), 7.42 (d, 1 H), 7.34 (s, 1 H), 7.02 (d, 1 H), 6.88 (s, 1 H), 6.53 (d, 1 H), 3.80 (s, 3H), 3.59-3.56 (m, 5H), 3.52-3.46 (m, 6H), 3.38-3.34 (m, 2H), 3.09 (s, 3H), 2.41 (t, 2H), 1.26 (s, 9H).
LCMS m/z 860 (M+H)+ (ES+); 858 (M-H)" (ES")
Example 27
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
Figure imgf000091_0001
(i) 3-Amino-5-methoxy-N-(2-morpholinoethyl)benzamide
To a stirred mixture of 3-amino-5-methoxybenzoic acid (5.20 g, 31.1 mmol), Et3N (4.50 mL, 32.3 mmol) and 2-morpholinoethanamine (4.23 mL, 32.3 mmol) in THF (150 mL) and DMF (4 mL) was added HATU (14.72 g, 38.7 mmol) and the reaction stirred at ambient temperature overnight. After this time the mixture was taken up in ethyl acetate (300 mL) and washed with sat NaHC03 (aq) (2 x100 mL). The aqueous was back extracted with further ethyl acetate (4 x 50 mL) and organics combined, dried over MgS04, filtered and concentrated under reduced pressure. Trituration with isohexanes (100 mL) afforded a pale orange gum (15 g). The crude product was purified by chromatography on the Companion (220 g column, 0-60% IPA in DCM). Fractions were combined as two separate batches to afford the sub-title compound as two separate batches (2.48 g and 2.87 g) as orange solids.
H NMR (400MHz; CDCI3) δ: 6.69-6.64 (m, 3H), 6.35 (t, 1 H), 3.81 (br.s, 2H), 3.81 (s, 3H), 3.73 (m, 4H), 3.53 (dd, 2H), 2.62-2.57 (m, 2H), 2.53-2.49 (m, 4H).
LCMS m/z 280 (M+H)+ (ES+)
The first batch (2.0 g) was recrystallised in acetonitrile (18 mL) to yield the sub-title compound (1.70 g) as a white solid which was used in the next step. (ii) tert-Butyl (4-((2-((3-methoxy-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)carbamate
Pd2dba3 (123 mg, 0.135 mmol) and BINAP (168 mg, 0.270 mmol) were stirred in 1 ,4-dioxane (5 mL) for 10 min under N2. In a separate vessel, purged with N2, caesium carbonate (1318 mg, 4.04 mmol), the product from step (i) above (753 mg, 2.70 mmol) and tert-butyl (4-((2- chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 1000 mg, 2.70 mmol) were stirred in 1 ,4-dioxane (10 mL). The catalyst solution was added to the main reaction mixture and the whole was heated to 90°C for 18 h. Upon cooling, the mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 75 mL). The combined organic phases were washed with saturated brine (75 mL), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (80 g column, 0-10%MeOH(10%NH3)/DCM) to afford the sub-title compound (750 mg) as a tan glass.
LCMS m/z 614 (M+H)+ (ES+); 612 (M-H)" (ES") (iii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2- morpholinoethvDbenzamide
A solution of the product from step (ii) above (750 mg, 1.222 mmol) in isopropanol (2 mL) was added to a 4 M HCI solution (10 mL) at rt and stirred for 1 h. The mixture was basified with saturated Na2C03 solution (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic phases were washed with saturated brine (50 mL), dried (MgS04) and concentrated under reduced pressure. The resulting brown oil was triturated in diethyl ether (25 mL) and collected by filtration to yield the sub-title compound (490 mg) as a cream solid. LCMS m/z 514 (M+H)+ (ES+) (iv) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
Triethylamine (5 μί, 0.036 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2-methoxy- 3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 75 mg, 0.191 mmol) and the product from step (iii) above (82 mg, 0.159 mmol) in isopropyl acetate (5 mL) and the mixture heated at 50°C (block temperature) for 48 h. The mixture was concentrated under reduced pressure onto loose silica gel. The silicate was purified by chromatography on silica gel (80 g column, EtOAc) to afford a colourless glass. The glass was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X-Select Prep-C18, 5 μητι, 19x50 mm column, 10-60% MeCN in Water) to afford a colourless glass. The glass was redissolved in EtOAc (40 mL) and washed with NaHC03 solution (40 mL), saturated brine (40 mL), dried (MgS04) and concentrated under reduced pressure to yield the title compound ( 55 mg) as a tan glass.
H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1 H), 9.14 (s, 1 H), 9.05 (s, 1 H), 8.91 (s, 1 H), 8.33- 8.27 (d, 1 H), 8.26-8.20 (m, 1 H), 8.19 (d, 1 H), 8.14-8.08 (m, 2H), 7.91-7.81 (m, 1 H), 7.74-7.67 (m, 1 H), 7.67-7.58 (m, 1 H), 7.56 (dd, 1 H), 7.51 (dd, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.85 (dd, 1 H), 6.58 (dd, 1 H), 6.13 (d, 1 H), 3.81 (s, 3H), 3.75 (s, 3H), 3.60-3.53 (m, 4H), 3.39-3.32 (m, 2H), 3.10 (s, 3H), 2.48-2.35 (m, 6H), 1.27 (s, 9H).
LCMS m/z 812 (M+H)+ (ES+); 810 (M-H)" (ES")
Example 28
1-(5-(tert-Butyl)-2-methoxy-3-(pyrimidin-2-ylamino)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000093_0001
A suspension of 1-(3-amino-5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea (see Example 25 above; 100 mg, 0.135 mmol), 2-chloropyrimidine (16 mg, 0.140 mmol) and p- TSA monohydrate (52 mg, 0.273 mmol) in THF/DMF (3 mL, 1 :2) was heated at 70°C for overnight, then at 60°C for 4 days. The reaction was cooled to rt and combined with a similar 50 mg reaction. The combined mixture was partitioned between EtOAc (40 mL) and sat. aq. NaHC03 (30 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (2 x 50 mL), dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 1-5% MeOH/DCM) to afford a pink solid. The crude product was further purified by chromatography on the silica gel (40 g column, 100% EtOAc) to afford the title compound (38 mg) as a pink solid.
H NMR (400MHz; DMSO-d6) δ: 9.43 (s, 1 H), 9.34 (s, 1 H), 8.89 (s, 1 H), 8.49 (s, 1 H), 8.46 (d, 2H), 8.42 (d, 1 H), 8.29 (d, 1 H), 8.1 1-8.13 (m, 2H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.57-7.61 (m, 2H), 7.42 (d, 1 H), 6.81-6.84 (m, 3H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.75 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.56 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.21 (s, 3H), 1.29 (s, 9H).
LCMS m/z 410 (M+2H)2+ (ES+)
Example 29
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide
Figure imgf000094_0001
Phenyl (5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)carbamate (see Example 9(i) above; 107 mg, 0.301 mmol), 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)pyridin-2-amine (see Example 11 (ii) above; 125 mg, 0.241 mmol) and Et3N (33.5 μΙ_, 0.241 mmol) were heated to 50°C in THF (5 mL) overnight. The mixture was concentrated under reduced pressure and purified by chromatography on the Companion (40 g column, 1-5% MeOH/DCM) to afford a white foam. The foam was further purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X- Select Prep-C18, 5 μηι, 19x50 mm column, 25-80 MeCN in Water). Fractions were combined, concentrated to remove acetonitrile, and diluted with saturated NaHC03 solution (50 mL). The product was extracted with ethyl acetate (3 x 50 mL) and the organic phases were washed with saturated brine (50 mL), dried (MgS04) and concentrated under reduced pressure to afford the title compound (100 mg) as a tan glass.
H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 8.89 (s, 2H), 8.44 (d, 1 H), 8.30 (d, 1 H), 8.18 (q, 1 H), 8.1 1 (d, 1 H), 8.09 (d, 1 H), 7.87 (d, 1 H), 7.71 (ddd, 1 H), 7.61 (ddd, 1 H), 7.39 (d, 1 H), 7.11 (d, 1 H), 6.91 (dd, 1 H), 6.79 (dd, 1 H), 6.57 (dd, 1 H), 6.09 (d, 1 H), 6.04 (dd, 1 H), 4.01- 3.94 (m, 2H), 3.80 (s, 3H), 3.74-3.68 (m, 2H), 3.66 (s, 3H), 3.60-3.55 (m, 2H), 3.55-3.48 (m, 4H), 3.45-3.39 (m, 2H), 3.23 (s, 3H), 2.82 (d, 3H), 1.29 (s, 9H).
LCMS m/z 782 (M+H)+ (ES+); 780 (M-H)" (ES")
Example 30
3-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphtha en-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic acid
Figure imgf000094_0002
(i) tert-Butyl 3-(2-(2-(3-Methoxy-5-nitrophenoxy)ethoxy)ethoxy)propanoate
DIAD (730 μί, 3.60 mmol) was added dropwise to a stirred solution of 3-methoxy-5- nitrophenol (510 mg, 2.99 mmol), tert-butyl 3-(2-(2-hydroxyethoxy)ethoxy)propanoate (700 mg, 2.99 mmol) and triphenylphosphine (950 mg, 3.59 mmol) in THF (4 mL) at 0-5 °C. The reaction was allowed to warm to rt and stirred at this temperature overnight. The reaction mixture was concentrated in vacuo. The crude product was purified by chromatography on silica gel (80 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (1.13 g) as a yellow oil, which solidified on standing. The product was used in the next without further purification.
H NMR (400 MHz, DMSO-d6) δ: 7.34-7.32 (m, 2H), 6.98 (t, 1 H), 4.21-4.19 (m, 2H), 3.85 (s, 3H), 3.76-3.74 (m, 2H), 3.60-3.56 (m, 4H), 3.52-3.50 (m, 2H), 2.40 (t, 2H), 1.38 (s, 9H). 42wt% Hydrazine by-product present (ii) tert-Butyl 3-(2-(2-(3-Methoxy-5-nitrophenoxy)ethoxy)ethoxy)propanoate
The product from step (i) above (1.10 g, 1.598 mmol) was dissolved in EtOH (15 mL) and Fe powder (895 mg, 16.03 mmol) was added, followed by a solution of NH4CI (855 mg, 15.98 mmol) in water (7 mL). The resulting suspension was heated at 80 °C for 1 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo, diluted with water (40 mL) then partitioned between sat. aq. NaHC03 (40 mL) and EtOAc (60 mL). The aqueous phase was back extracted with EtOAc (50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford an orange oil. The crude product was dissolved in the minimum of MeOH and loaded onto SCX. The column was eluted with MeOH (3 column volumes) followed by 1 % NH3 in MeOH (3 column volumes). The product containing portion was concentrated in vacuo to afford the sub-title compound (422 mg) as a brown oil.
H NMR (400 MHz, DMSO-d6) δ: 5.75-5.73 (m, 2H), 5.67 (t, 1 H), 5.04 (s, 2H), 3.94-3.91 (m, 2H), 3.68-3.66 (m, 2H), 3.62-3.58 (m, 5H), 3.57-3.54 (m, 2H), 3.52-3.49 (m, 2H), 2.42 (t, 2H), 1.39 (s, 9H).
LCMS m/z 356 (M+H)+ (ES+)
(iii) tert-Butyl 3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)- propanoate
To a stirred solution of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1- yl)ureido)-2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 204 mg, 0.340 mmol) and the product from step (ii) above (185 mg, 0.510 mmol) in DMF (9 mL) was added p-TSA monohydrate (32 mg, 0.168 mmol). The reaction mixture was stirred at 60 °C for 48 h. The reaction was cooled to rt, diluted with water (40 mL), then partitioned between sat. aq. NaHC03 (40 mL) and EtOAc (50 mL). The organic phase was washed with water (2 x 50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo to afford a foam. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc in isohexane) to afford the sub-title compound (180 mg) as a beige foam.
H NMR (400 MHz, DMSO-d6) δ: 9.41 (s, 1 H), 9.34 (s, 1 H), 9.13 (s, 1 H), 8.91 (s, 1 H), 8.41 (d, 1 H), 8.27 (d, 1 H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.85-7.83 (m, 1 H), 7.69-7.65 (m, 1 H), 7.60- 7.56 (m, 1 H), 7.41 (d, 1 H), 7.02 (d, 1 H), 6.83-6.78 (br m, 2H), 6.54 (d, 1 H), 6.02 (t, 1 H), 3.87- 3.84 (m, 2H), 3.80 (s, 3H), 3.66-3.64 (m, 2H), 3.56 (t, 2H), 3.54-3.45 (m, 7H), 3.09 (s, 3H), 2.39 (t, 2H), 1.36 (s, 9H), 1.26 (s, 9H).
(iv) 3-(2-(2-(3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic acid TFA (698 μί, 9.06 mmol) was added to a stirred solution of the product from step (iii) above (179 mg, 0.181 mmol) in DCM (2 mL). The reaction mixture was stirred at rt for 1 h. The solvent was removed in vacuo and the resulting oil dissolved in the minimum of MeOH and loaded onto an SCX column. The column was eluted with MeOH (3 column volumes), then 1 % NH3 in MeOH (3 column volumes). Formation of some of the methyl ester occurred. The crude product was dissolved in THF (5 mL) and water (1 mL), 2M NaOH (0.5mL) added and stirred for 4h. The mixture was acidified to pH 2 with 1 M HCI then extracted with EtOAc (40ml_). The organic layer was washed with water (10 ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (12 g column, 0-10% MeOH/DCM) to give a solid that was triturated with 5% MeOH/DCM (5 ml_), the solid filtered, washed with MeCN (5ml_) and DCM (5ml_) to afford the title compound (47 mg) as an off white solid.
H NMR (DMSO-d6) 400 MHz, δ: 12.08 (s, 1 H), 9.35 (s, 1 H), 9.28 (s, 1 H), 9.07 (brs, 1 H), 8.85 (s, 1 H), 8.34 (d, 1 H), 8.20 (d, 1 H), 8.1 1 (s, 1 H), 8.03 (d, 1 H), 7.77 (d, 1 H), 7.62-7.58 (m, 1 H), 7.53-7.50 (m, 1 H), 7.34 (d, 1 H), 6.96 (s, 1 H), 6.74 (s, 2H), 6.47 (d, 1 H), 5.96 (s, 1 H), 3.80-3.78 (m, 2H), 3.74 (s, 3H), 3.59-3.57 (m, 2H), 3.51 (t, 2H), 3.47-3.40 (m, 7H), 3.03 (s, 3H), 2.35 (t, 2H), 1.20 (s, 9H).
LCMS m/z 833 (M+H)+ (ES+); 831 (M-H)" (ES")
Example 31
3-(2-(3-((4-((4-(3-(5-(tert-Butvn-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen- 1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)propanoic acid
Figure imgf000096_0001
The title compound was prepared using the method of Example 30 above to afford the product (53mg) as an off white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.36 (s, 1 H), 9.29 (s, 1 H), 9.06 (s, 1 H), 8.85 (s, 1 H), 8.34 (d, 1 H), 8.21 (d, 1 H), 8.11 (s, 1 H), 8.03 (d, 1 H), 7.78 (d, 1 H), 7.62-7.58 (m, 1 H), 7.54-7.50 (m, 1 H), 7.34 (d, 1 H), 6.96 (s, 1 H), 6.74 (s, 2H), 6.48 (d, 1 H), 5.96 (s, 1 H), 3.80-3.77 (m, 2H), 3.74 (s, 3H), 3.58-3.55 (m, 4H), 3.44 (s, 3H), 3.03 (s, 3H), 2.37 (t, 2H), 1.20 (s, 9H).
LCMS m/z 789 (M+H)+ (ES+); 787 (M-H)" (ES")
Example 32
2-Methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methyl-5-morpholinobenzamide
Figure imgf000096_0002
(i) Methyl 2-methoxy-5-morpholino-3-nitrobenzoate
A degassed solution of Pd2(dba)3 (170 mg, 0.186 mmol) and BINAP (240 mg, 0.385 mmol) was added to a degassed suspension of methyl 5-bromo-2-methoxy-3-nitrobenzoate (1680 mg, 3.82 mmol), morpholine (500 μΙ_, 5.73 mmol) and Cs2C03 (1900 mg, 5.83 mmol) and heated to 90°C for 48 h. The mixture was diluted with water (100 ml_) and extracted with ethyl acetate (3 x 100 ml_). The combined organic phases were washed with saturated brine (100 mL), dried (MgS04) and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (80 g column, 0-50% EtOAc/isohexanes) to afford a waxy yellow solid. Diethyl ether (50 mL) was added and the resulting solid was removed by filtration. The filtrate was concentrated under reduced pressure to yield the sub- title compound (389 mg) as a yellow solid.
LCMS m/z 297 (M+H)+ (ES+)
(ii) 2-Methoxy-N-methyl-5-morpholino-3-nitrobenzamide
The product from step (i) above (340 mg, 1.148 mmol) and 40% aqueous methanamine solution (5 mL, 64.4 mmol) were heated to 50°C in ethanol in a sealed tube overnight. The mixture was co-evaporated with toluene (150 mL) and the residue was absorbed onto silica gel. The silicate was purified by chromatography on the Companion (4 g column, 0-50% EtOAc/isohexanes) to afford the sub-title compound ( 210 mg) as a yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 8.40-8.27 (m, 1 H), 7.44 (d, 1 H), 7.27 (d, 1 H), 3.75 (s, 3H), 3.75-3.67 (m, 4H), 3.21-3.13 (m, 4H), 2.78 (d, 3H).
LCMS m/z 296 (M+H)+ (ES+)
(iii) 3-Amino-2-methoxy-N-methyl-5-morpholinobenzamide
A suspension of the product from step (ii) above (100 mg, 0.339 mmol) and Pd/C (36.0 mg) in ethanol (2 mL) was stirred at rt under a balloon of hydrogen for 18 h. Repeated in duplicate. The combined reaction suspensions were filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (12 g column, 0-5% MeOH/DCM) to afford the sub-title compound (159 mg) as a brown oil.
LCMS m/z 266 (M+H)+ (ES+)
(iv) 2-Methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methyl-5-morpholinobenzamide
Triethylamine (10 μί, 0.072 mmol) was added to a mixture of the product from step (iii) above (70 mg, 0.264 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 125 mg, 0.195 mmol) in isopropyl acetate (3 mL) and the mixture heated at 60°C (block temperature) for 18h. The mixture was diluted with ethyl acetate (30 mL) and washed with water (10 mL), saturated NaHC03 solution (10 mL), saturated brine (10 mL), dried (MgS04) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 30-70 MeCN in Water) to afford the title compound ( 61 mg) as a tan glass. H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 9.45 (s, 1 H), 8.89 (s, 1 H), 8.41 (d, 1 H), 8.28 (d, 1 H), 8.17 (q, 1 H), 8.08 (d, 1 H), 8.07 (s, 1 H), 7.85 (d, 1 H), 7.68 (ddd, 1 H), 7.59 (ddd, 1 H), 7.42 (d, 1 H), 6.86-6.74 (m, 2H), 6.67 (d, 1 H), 6.54 (d, 1 H), 6.03 (dd, 1 H), 3.90-3.81 (m, 2H), 3.80-3.70 (m, 4H), 3.76 (s, 3H), 3.69-3.61 (m, 2H), 3.58-3.45 (m, 6H), 3.50 (s, 3H), 3.44- .3.38 (m, 2H), 3.22 (s, 3H), 3.09-2.99 (m, 4H), 2.81 (d, 3H).
LCMS m/z 812 (M+H)+ (ES+); 810 (M-H)" (ES") Example 33
5-(tert-Butvn-N-cvclopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-benzami
(i) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoate
Triethylamine (45 μί, 0.323 mmol) was added to a mixture of methyl 3-amino-5-(tert-butyl)-2- methoxybenzoate (370 mg, 1.561 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 1000 mg, 1.561 mmol) in isopropyl acetate (12 ml_) and the mixture heated at 60°C (block temperature) for 1 h. The reaction was concentrated in vacuo onto silica gel and the crude product purified by chromatography on the Companion (40 g column, 1-3% MeOH in DCM) to afford the sub-title compound (1.02 g) as a white foam. H NMR (400 MHz, DMSO-d6) δ: 9.45 (s, 1 H), 9.43 (s, 1 H), 8.98 (s, 1 H), 8.62 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.08 (d, 1 H), 7.86 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.43 (d, 1 H), 7.35 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.85-3.88 (m, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.21 (s, 3H), 1.29 (s, 9H). LCMS m/z 393 (M+2H)2+ (ES+)
(ii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid
To a stirred solution of the product from step (i) above (1.02 g, 1.301 mmol) in THF (40 ml_) and water (10 ml_) was added NaOH (2M aq.) (3.90 mL, 7.81 mmol) and the reaction vigorously stirred for 3h. MeOH (10 mL) was added and stirring continued over the weekend. The reaction was concentrated in vacuo affording a pale purple solid. The material was suspended in water and acidified with 1 M HCI causing a solid to precipitate. The solid was collected by filtration, washed with water and the solid dried at 40°C under vacuum affording the sub-title compound (877 mg) as a beige solid.
H NMR (400 MHz, DMSO-d6) δ: 9.54 (s, 1 H), 9.52 (s, 1 H), 9.02 (s, 1 H), 8.58 (d, 1 H), 8.42 (d, 1 H), 8.31 (d, 1 H), 8.08 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.35 (d, 1 H), 6.80 (d, 2H), 6.58 (d, 1 H), 6.05 (t, 1 H), 5.59 (bs, 1 H), 3.85-3.88 (m, 2H), 3.85 (s, 3H), 3.65-3.67 (m, 2H), 3.47-3.55 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.21 (s, 3H), 1.29 (s, 9H). LCMS m/z 385 (M+2H)2+ (ES+)
(iii) 5-(tert-Butyl)-N-cvclopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-benzamide
A stirred mixture of the product from step (ii) above (70 mg, 0.091 mmol), cyclopropanamine (13.0 μί, 0.188 mmol) and triethylamine (38.0 μί, 0.273 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (80 μί, 0.134 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-4% MeOH in DCM) to afford the title compound (51 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1 H), 9.42 (s, 1 H), 8.90 (s, 1 H), 8.44 (d, 1 H), 8.42 (d, 1 H), 8.29 (d, 1 H), 8.26 (s, 1 H), 8.08 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.02 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.03 (t, 1 H), 3.86-3.88 (m, 2H), 3.78 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.21 (s, 3H), 2.85-2.90 (m, 1 H), 1.28 (s, 9H), 0.70-0.75 (m, 2H), 0.55-0.59 (m, 2H).
LCMS m/z 405 (M+2H)2+ (ES+) Example 34
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000099_0001
(i) Phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyridin- 4-yl)oxy)naphthalen-1-yl)carbamate
Phenyl chloroformate (37 μί, 0.295 mmol) was added to a stirred solution of 4-((4- aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)pyridin-2-amine (see Example 19(i) above; 150 mg, 0.289 mmol) and NaHC03 (50 mg, 0.595 mmol) in THF (1.5 mL) and DCM (5 mL). The mixture was stirred over the weekend. The mixture was diluted with water (5 mL) and DCM (5 mL) and the mixture passed through a phase-sep cartridge. The resulting filtrate was concentrated in vacuo giving the product as a pink gum. The material was stirred vigorously in hexane for 1 h then concentrated in vacuo affording the sub-title compound (183 mg) as a pink solid.
LCMS m/z 640 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Triethylamine (7 μί, 0.050 mmol) was added to a mixture of 3-amino-5-(tert-butyl)-2- methoxybenzamide (51 mg, 0.229 mmol) and the product from step (i) above (183 mg, 0.229 mmol) in isopropyl acetate (3 mL) and the mixture heated at 60°C (block temperature) for 1 h. The reaction was concentrated in vacuo onto silica gel and the crude product purified by chromatography on the Companion (40 g column, 1-5% MeOH in DCM) to afford the product as a pink foam. The material was dissolved in MeOH and loaded onto a pre-conditioned cartridge of SCX resin. The resin was washed with MeOH then the product released with 1 % NH3 in MeOH. The ammonia solution was concentrated in vacuo and the residue purified further by prep-HPLC (Varian, XS Basic, 40-80% MeCN, 10 min) affording the title compound (24 mg) as a beige solid.
H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 8.93 (s, 1 H), 8.88 (s, 1 H), 8.46 (d, 1 H), 8.30 (d, 1 H), 8.12 (d, 1 H), 8.10 (d, 1 H), 7.87 (d, 1 H), 7.69-7.73 (m, 2H), 7.58-7.63 (m, 2H), 7.39 (d, 1 H), 7.22 (d, 1 H), 6.91 (t, 1 H), 6.78 (t, 1 H), 6.58 (dd, 1 H), 6.08 (d, 1 H), 6.04 (t, 1 H), 3.97- 3.99 (m, 2H), 3.83 (s, 3H), 3.69-3.72 (m, 2H), 3.65 (s, 3H), 3.50-3.58 (m, 6H), 3.42 (dd, 2H), 3.23 (s, 3H), 1.29 (s, 9H).
LCMS m/z 385 (M+2H)2+ (ES+)
Example 35
5-(tert-Butvn-N-(2-hvdroxyethvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-benzamide
Figure imgf000100_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 70 mg, 0.091 mmol), 2-aminoethanol (11 μΙ_, 0.182 mmol) and triethylamine (38.0 μΙ_, 0.273 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (80 μί, 0.134 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. A further equivalent of 2- aminoethanol was added and stirring was continued overnight. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1- 5% MeOH in DCM) to afford the title compound (26 mg) as a pale pink solid.
H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1 H), 9.42 (s, 1 H), 8.93 (s, 1 H), 8.47 (d, 1 H), 8.42 (d, 1 H), 8.24-8.29 (m, 2H), 8.09 (d, 1 H), 7.85 (d, 1 H), 7.69 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.21 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.80 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.59 (m, 8H), 3.51 (s, 3H), 3.36-3.41 (m, 4H), 3.21 (s, 3H), 1.29 (s, 9H).
LCMS m/z 407 (M+2H)2+ (ES+) Example 36
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-methoxyethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide
Figure imgf000101_0001
(i) 1-Methoxy-3-(2-(2-methoxyethoxy)ethoxy)-5-nitrobenzene
A mixture of 3-methoxy-5-nitrophenol (2g, 1 1.82 mmol), 1-bromo-2-(2-methoxyethoxy)- ethane (2.4 g, 13.11 mmol) and K2C03 (4.90 g, 35.5 mmol) in acetone (40ml_) was heated at reflux for 30h. The mixture was partitioned between EtOAc (200ml_) and water (100ml_), the organic layer separated, washed with brine (100ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-40%EtOAc/isohexane) to afford the sub-title compound (2.762 g) as an oil. H NMR (CDCI3) 400 MHz, δ: 7.39 (s, 1 H), 7.36 (s, 1 H), 6.78 (s, 1 H), 4.19 (t, 2H), 3.88 (t, 2H), 3.85 (s, 3H), 3.73-3.71 (m, 2H), 3.60-3.57 (m, 2H), 3.39 (s, 3H).
(ii) 3-Methoxy-5-(2-(2-methoxyethoxy)ethoxy)aniline
A mixture of the product from step (i) above (2.75 g, 10.14 mmol), 5% Pd-C (500 mg) in EtOH (30ml_) was hydrogenated at 4Bar for 18h. The mixture was filtered through Celite and the filtrate evaporated under reduced pressure to afford the sub-title compound (2.294 g) as a brown oil.
H NMR (CDCI3) 400 MHz, δ: 5.93 (t, 1 H), 5.88 (t, 1 H), 5.86 (t, 1 H), 4.08 (t, 2H), 3.82 (t, 2H), 3.73 (s, 3H), 3.72-3.69 (m, 2H), 3.64 (s, 2H), 3.58-3.55 (m, 2H), 3.39 (s, 3H).
LCMS m/z 242 (M+H)+ (ES+)
(iii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-methoxyethoxy)ethoxy) phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide
A mixture of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2- methoxyphenyl)methanesulfonamide (see Example 7(i) above; 150 mg, 0.263 mmol), the product from step (ii) above (127 mg, 0.526 mmol) and p-TSA monohydrate (15 mg, 0.079 mmol) in THF (6 ml_) was heated at 60°C for 18h. The mixture was partitioned between EtOAc (50ml_) and sat aq NaHC03 (50ml_), the organic layer separated, washed with brine (50ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-50%EtOAc/isohexane) to give a solid that was triturated with ether/EtOAc, then filtered and dried to afford the title compound (83 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.45 (s, 1 H), 9.36 (s, 1 H), 9.15 (s, 1 H), 8.93 (s, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.19 (s, 1 H), 8.11 (d, 1 H), 7.85 (d, 1 H), 7.70-7.66 (m, 1 H), 7.61-7.57 (m, 1 H), 7.42 (d, 1 H), 7.02 (s, 1 H), 6.81 (brd, 2H), 6.56 (d, 1 H), 6.04 (s, 1 H), 3.87-3.85 (m, 2H), 3.81 (s, 3H), 3.66-3.64 (m, 2H), 3.55-3.51 (m, 5H), 3.43-3.41 (m, 2H), 3.22 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 775 (M+H)+ (ES+); 773 (M-H)" (ES") Example 37
Methyl 2-(5-(tert-butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)-acetate
Figure imgf000102_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), methyl 2-aminoacetate, HCI (20 mg, 0.159 mmol) and triethylamine (35 μΙ_, 0.251 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.1 18 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (35 mg) as an off-white solid. H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1 H), 9.43 (s, 1 H), 8.94 (s, 1 H), 8.67 (t, 1 H), 8.51 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.09 (d, 1 H), 7.86 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.43 (d, 1 H), 7.25 (d, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.10 (d, 2H), 3.86-3.88 (m, 2H), 3.86 (s, 3H), 3.71 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 1.29 (s, 9H).
LCMS m/z 421 (M+2H)2+ (ES+)
Example 38
N-Benzyl-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000102_0002
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), phenylmethanamine (17 μί, 0.156 mmol) and triethylamine (35 μί, 0.251 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.118 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1- 5% MeOH in DCM) to afford the title compound (38 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1 H), 9.41 (s, 1 H), 8.93 (s, 1 H), 8.78 (t, 1 H), 8.47 (d, 1 H), 8.42 (d, 1 H), 8.27 (d, 1 H), 8.09 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.36- 7.43 (m, 5H), 7.26-7.30 (m, 1 H), 7.15 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.52 (d, 2H), 3.86-3.88 (m, 2H), 3.74 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.21 (s, 3H), 1.29 (s, 9H).
LCMS m/z 430 (M+2H)2+ (ES+) Example 39
5-(tert-Butyl)-3-(3-(4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)-pyridin-
4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide
Figure imgf000103_0001
(i) tert-Butyl (4-((2-((3-((2-morpholinoethyl)carbamoyl)-5-((triisopropylsilyl)ethvnyl)phenyl) amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
Pd2(dba)3 (0.125 g, 0.137 mmol) was added to a degassed suspension of tert-butyl (4-((2- chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 1 g, 2.70 mmol), 3-amino-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethynyl)benzamide (see Example 1 (H) above; 1.26 g, 2.93 mmol), BINAP (0.17 g, 0.273 mmol), and Cs2C03 (2.7 g, 8.29 mmol) in 1 ,4-dioxane (12ml_) under nitrogen. The mixture was stirred under nitrogen at 90°C (block temperature) for 18h. The reaction mixture was filtered and partitioned between water (20ml_) and EtOAc (20ml_). The aqueous was separated and washed again with EtOAc (20ml_). The organics were bulked, dried (MgS04), filtered and evaporated to a brown gum. The crude product was purified by chromatography on silica gel (80 g column, 2% MeOH:DCM to 8%) to afford the sub-title compound (1.8 g) as a tan solid.
H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1 H), 9.21 (s, 1 H), 8.41 (t, 1 H), 8.19 - 8.10 (m, 2H), 8.10 - 8.07 (m, 1 H), 7.96 - 7.89 (m, 1 H), 7.88 - 7.79 (m, 1 H), 7.68 - 7.53 (m, 3H), 7.42 - 7.32 (m, 2H), 6.61 (dd, 1 H), 6.10 (d, 1 H), 3.66 - 3.51 (m, 4H), 3.41 - 3.33 (m, 2H), 2.49 - 2.34 (m, 6H), 1.53 (s, 9H), 1.11 (s, 21 H).
LCMS m/z 764 (M+H)+ (ES+); 762 (M-H)" (ES")
(ii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-5- ((triisopropylsilvDethvnvDbenzamide
The product from step (i) above (1.8 g, 2.356 mmol) was dissolved in DCM (20 mL) and TFA (2 mL, 26.0 mmol) added. The reaction was stirred at rt for 16h. The solvents were evaporated and the residue partitioned between DCM (20 mL) and sat. NaHC03 soln (20 mL). The aqueous was separated and washed with fresh DCM (20 mL). The organics were separated, bulked, dried (MgS04), filtered and evaporated to give the sub-title compound (1.3 g) as a brown foam. H NMR (400 MHz, DMSO-d6) δ 9.1 1 (s, 1 H), 8.40 (t, 1 H), 8.23 - 8.11 (m, 1 H), 8.11 - 8.00 (m, 2H), 7.96 - 7.85 (m, 1 H), 7.70 - 7.56 (m, 1 H), 7.50 - 7.39 (m, 2H), 7.34 (t, 1 H), 7.10 (d, 1 H), 6.72 (d, 1 H), 6.55 (dd, 1 H), 6.05 (d, 1 H), 5.83 (s, 2H), 3.69 - 3.48 (m, 4H), 3.43 - 3.34 (m, 2H), 2.49 - 2.27 (m, 6H), 1.10 (s, 21 H).
LCMS m/z 664 (M+H)+ (ES+)
(Hi) 5-(tert-Butyl)-2-methoxy-N-methyl-3-(3-(4-((2-((3-((2-m^
((triisopropylsilyl)ethvnyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-b
Triethylamine (10 μΙ_, 0.072 mmol) was added to a solution of phenyl (5-(tert-butyl)-2- methoxy-3-(methylcarbamoyl)phenyl)carbamate (see Example 9(i) above; 64 mg, 0.180 mmol) and the product from step (ii) above (120 mg, 0.181 mmol) in THF (2 mL) and the reaction stirred at 50°C for 24h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 4% MeOH:DCM to 10%) to afford the sub-title compound (120 mg) as a pale pink solid.
LCMS m/z 927 (M+H)+ (ES+)
(iv) 5-(tert-Butyl)-3-(3-(4-((2-((3-ethvnyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)- pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide
The product from step (iii) above (120 mg, 0.130 mmol) was dissolved in THF (3 mL) and TBAF, 1 M in THF (150 μί, 0.150 mmol) added. The mixture was stirred for 1 h then partitioned between water (10 mL) and DCM (10 mL). The organic layer was separated and washed with 20%w/w NaCI soln. (10 mL). The organics were separated, dried (MgS04) filtered and solvents evaporated to give a tan solid. The crude product was purified by chromatography on silica gel (40 g column, 4% MeOH:DCM to 10%) to afford the title compound (60 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.48 (s, 1 H), 9.22 (s, 1 H), 8.89 (s, 1 H), 8.44 (d, 1 H), 8.38 (t, 1 H), 8.30 (d, 1 H), 8.21 - 8.12 (m, 2H), 8.12 - 8.03 (m, 2H), 7.93 (t, 1 H), 7.88 (d, 1 H), 7.77 - 7.67 (m, 1 H), 7.66 - 7.55 (m, 1 H), 7.47 - 7.34 (m, 2H), 7.12 (d, 1 H), 6.62 (dd, 1 H), 6.14 (d, 1 H), 4.19 (s, 1 H), 3.80 (s, 3H), 3.56 (t, 4H), 3.50 - 3.37 (m, 2H), 2.82 (d, 3H), 2.49 - 2.30 (m, 6H), 1.28 (s, 9H).
LCMS m/z 770 (M+H)+ (ES+); 768 (M-H)" (ES")
Example 40
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-N-(2,5,8, 11 ,14, 17,20-heptaoxadocosan-22-yl)-5-methoxy- benzamide
Figure imgf000104_0001
(i) tert-Butyl (4-((2-((3-(2.5.8.1 1.14.17.20-heptaoxadocosan-22-ylcarbamoyl)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate A stirred mixture of 3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyrimidin-2- yl)amino)-5-methoxybenzoic acid (see Example 6(i) above; 800 mg, 1.592 mmol), 2,5,8, 1 1 , 14, 17, 20-heptaoxadocosan-22-amine (513 mg, 1.512 mmol) and triethylamine (666 μΙ_, 4.78 mmol) in DCM (60 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (1422 μί, 2.388 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for overnight. The reaction mixture was partitioned between sat. aq. NaHC03 (100 mL) and DCM (100 mL). The aqueous phase was back extracted with fresh DCM (50 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (80 g column, 2-5% MeOH in DCM) to afford the sub-title compound (1.01 g) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.60 (s, 1 H), 9.33 (s, 1 H), 8.42 (d, 1 H), 8.32 (t, 1 H), 8.1 1 (d, 1 H), 7.82 (d, 1 H), 7.54-7.63 (m, 4H), 7.39-7.42 (m, 2H), 6.91 (s, 1 H), 6.55 (d, 1 H), 3.58 (s, 3H), 3.48-3.52 (m, 24H), 3.37-3.43 (m, 4H), 3.23 (s, 3H), 1.52 (s, 9H).
LCMS m/z 385 (M-tBu+2H)2+ (ES+)
(ii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-N-(2.5.8.1 1.14.17.20- heptaoxadocosan-22-yl)-5-methoxybenzamide
TFA (1.0 mL, 12.98 mmol) was added to a stirred solution of the product from step (i) above (1.01 g, 1.226 mmol) in DCM (50 mL) at rt then stirred overnight. More TFA (5 mL) was added and stirring continued for 4h. The reaction mixture was concentrated in vacuo then the residue partitioned between DCM and NaHC03 aq. solution. The organic phase was dried (MgS04), filtered and concentrated in vacuo affording the sub-title compound (816 mg) as a pale yellow gum.
LCMS m/z 363 (M+2H)2+ (ES+)
(iii) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-N-(2,5,8, 11 , 14,17,20-heptaoxadocosan-22-yl)-5- methoxybenzamide
Triethylamine (7.0 μί, 0.050 mmol) was added to a mixture of phenyl (5-(tert-butyl)-2- methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 100 mg, 0.255 mmol) and the product from step (ii) above (172 mg, 0.238 mmol) in isopropyl acetate (5 mL) and the mixture heated at 50°C (block temperature) for 65 h. The mixture was cooled to rt and concentrated in vacuo onto silica gel. The crude material was purified by chromatography on silica gel (12 g column, 1-5% MeOH in DCM) to afford a colourless glass. The material was dissolved in DCM and washed with 1 M HCI. The organic phase was dried (MgS04), filtered and concentrated in vacuo affording the title compound (131 mg) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 9.65 (s, 1 H), 9.42 (s, 1 H), 9.13 (s, 1 H), 8.96 (s, 1 H), 8.42 (d, 1 H), 8.29-8.33 (m, 2H), 8.19 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.67 (t, 1 H), 7.57-7.61 (m, 2H), 7.43 (d, 1 H), 7.34 (s, 1 H), 7.03 (d, 1 H), 6.90 (s, 1 H), 6.56 (d, 1 H), 3.81 (s, 3H), 3.60 (s, 3H), 3.47-3.51 (m, 24H), 3.35-3.42 (m, 4H), 3.23 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 512 (M+2H)2+ (ES+) Example 41
5-(tert-Butvn-N-ethyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000106_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), ethanamine (13 μΙ_, 0.161 mmol) and triethylamine (35 μΙ_, 0.251 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.118 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature overnight. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1- 5% MeOH in DCM) to afford the title compound (22 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 2H), 8.99 (s, 1 H), 8.45 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.23 (t, 1 H), 8.08 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.10 (d, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 365-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.28-3.55 (m, 2H under H20 peak), 3.22 (s, 3H), 1.29 (s, 9H), 1.16 (t, 3H).
LCMS m/z 797 (M+H)+ (ES+); 795 (M-H)" (ES")
Example 42
5-(tert-Butyl)-N-isopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000106_0002
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), propan-2-amine (14 μί, 0.163 mmol) and triethylamine (35 μί, 0.251 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.118 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature overnight. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1- 5% MeOH in DCM) to afford the title compound (21 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1 H), 9.41 (s, 1 H), 8.91 (s, 1 H), 8.44 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.08 (t, 2H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.07 (d, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.06-4.15 (m, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 1.29 (s, 9H), 1.20 (d, 6H).
LCMS m/z 811 (M+H)+ (ES+); 809 (M-H)" (ES") Example 43
5-(tert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(2-methoxyethyl)- benzamide
Figure imgf000107_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), 2-methoxyethanamine (14 μΙ_, 0.161 mmol) and triethylamine (33 μΙ_, 0.237 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.118 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (33 mg) as an off-white solid. H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 1 H), 9.41 (s, 1 H), 8.94 (s, 1 H), 8.47 (d, 1 H), 8.42 (d, 1 H), 8.27-8.30 (m, 2H), 8.09 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.57 (t, 1 H), 7.42 (d, 1 H), 7.20 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65- 3.67 (m, 2H), 3.47-3.55 (m, 10H), 3.51 (s, 3H), 3.40 (dd, 2H), 3.33 (s, 3H), 3.22 (s, 3H), 1.29 (s, 9H).
LCMS m/z 827 (M+H)+ (ES+); 414 (M+2H)2+ (ES+)
Example 44
2-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)acetic acid
Figure imgf000107_0002
To a stirred solution of methyl 2-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamido)acetate (see Example 37 above; 29 mg, 0.034 mmol) in THF (3 mL) and water (0.5 mL) was added NaOH (2M aq.) (100 μί, 0.200 mmol) and the reaction vigorously stirred for 4h. The THF was removed in vacuo affording a pale purple solution. The solution was acidified with 1 M HCI causing a solid to precipitate. This solid was solubilised in a 3: 1 mix of DCM/EtOAc and the organic phase dried by passage through a phase sep cartridge. The organic phase was concentrated in vacuo affording the title compound (23 mg) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 9.45 (s, 1 H), 9.44 (s, 1 H), 8.96 (s, 1 H), 8.57 (t, 1 H), 8.50 (d, 1 H), 8.42 (d, 1 H), 8.29 (d, 1 H), 8.09 (d, 1 H), 7.85 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.42 (d, 1 H), 7.29 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.02 (d, 2H), 3.85-3.88 (m, 2H), 3.85 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.21 (s, 3H), 1.29 (s, 9H).
LCMS m/z 827 (M+H)+ (ES+); 414 (M+2H)2+ (ES+)
Example 45
N-(3-(3-(4-((2-((3-(2.5.8.1 1.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)- amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methane- sulfonamide
Figure imgf000108_0001
(i) 22-Chloro-2.5.8.1 1.14.17.20-heptaoxadocosane
SOCI2 (900 μί, 12.33 mmol) was added over 5min to a solution of 2,5,8, 11 , 14,17,20- heptaoxadocosan-22-ol (3.2 g, 9.40 mmol) and pyridine (760 μΙ_, 9.40 mmol) in CHCI3 (20 mL) at rt. The mixture was heated under reflux for 3h, cooled and evaporated under reduced pressure. The residue was partitioned between EtOAc (200 mL) and water (100 mL), the organic layer washed with sat. aq NaHC03 (100 mL), dried (MgS04), filtered and evaporated under reduced pressure to afford the sub-title compound (1.616 g) as an oil.
H NMR (CDCI3) 400 MHz, δ: 3.77-3.74 (m, 2H), 3.68-3.62 (m, 24H), 3.56-3.54 (m, 2H), 3.38 (s, 3H).
(ii) 22-(3-Methoxy-5-nitrophenoxy)-2,5,8,1 1 , 14, 17,20-heptaoxadocosane
A mixture of 3-methoxy-5-nitrophenol (0.830 g, 4.90 mmol), the product from step (i) above (1.6 g, 4.46 mmol), Kl (0.370 g, 2.229 mmol) and K2C03 (1.3 g, 9.41 mmol) in MeCN (20 mL) was heated at 60°C for 30h. The mixture was partitioned between EtOAc (150 mL) and water (100 mL), the organic layer separated, dried (MgS04) and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (80 g column, 0- 5% MeOH/DCM) to afford the sub-title compound (1.958 g) as an oil. H NMR (CDCI3) 400 MHz, δ: 7.38 (t, 1 H), 7.37 (t, 1 H), 6.78 (t, 1 H), 4.19-4.17 (m, 2H), 3.89- 3.87 (m, 2H), 3.86 (s, 3H), 3.74-3.63 (m, 22H), 3.56-3.53 (m, 2H), 3.38 (s, 3H).
LCMS m/z 492 (M+H)+ (ES+) (iii) 3-(2,5,8, 11 , 14,17,20-Heptaoxadocosan-22-yloxy)-5-methoxyaniline
A mixture of the product from step (ii) above (1.95 g, 3.97 mmol) and 10% Pd/C (300mg) in EtOH (30 mL) was hydrogenated under a balloon of hydrogen for 5h then filtered through Celite. The filtrate was evaporated under reduced pressure to afford the sub-title compound (1.51 g) as an oil.
H NMR (CDCI3) 400 MHz, δ: 5.93 (t, 1 H), 5.88 (t, 1 H), 5.86 (t, 1 H), 4.08-4.05 (m, 2H), 3.83- 3.80 (m, 2H), 3.73 (s, 3H), 3.71-3.63 (m, 22H), 3.56-3.53 (m, 2H), 3.38 (s, 3H).
(iv) tert-Butyl (4-((2-((3-(2.5.8.1 1.14.17.20-heptaoxadocosan-22-yloxy)-5-methoxyphenyl) amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
N2 was bubbled through a mixture of the product from step (iii) above (1.5 g, 3.25 mmol), tert- butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 900 mg, 2.427 mmol), BINAP (0.079 g, 0.126 mmol), Pd2(dba)3 (0.058 g, 0.063 mmol) and Cs2C03 (1.2 g, 3.68 mmol) in dioxane (20 mL) for 5min then the mixture heated at 100°C for 20h. The mixture was cooled, partitioned between EtOAc (150mL) and water (100 mL), the organic layer washed with brine (100 mL), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (120 g column, 0-5%MeOH/DCM) to afford the sub-title compound (785 mg, 50% purity) as an oil. LCMS m/z 796 (M+H)+ (ES+); 794 (M-H)" (ES") (v) N-(3-(2.5.8.1 1.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)-4-((4- aminonaphthalen-1-yl)oxy)pyridin-2-amine
TFA (1 mL, 12.98 mmol) was added to a solution of the product from step (iv) above (780 mg, 0.490 mmol) in DCM (10mL) and the mixture stirred at rt for 6h. The solvent was evaporated and the residue partitioned between DCM (80mL) and aq NaHC03 (50mL). The organic phase was separated, washed with brine (50mL), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (80g column, 0-5% MeOH/DCM) to afford the sub-title compound (252 mg) as a brown oil.
H NMR (CDCI3) 400 MHz, δ: 7.98 (d, 1 H), 7.89 (d, 1 H), 7.81 (d, 1 H), 7.52-7.44 (m, 2H), 7.04 (d, 1 H), 6.75 (d, 1 H), 6.46 (d, 1 H), 6.36 (s, 1 H), 6.34 (s, 1 H), 6.26 (s, 1 H), 6.12 (s, 1 H), 3.84- 3.76 (m, 4H), 3.74-3.60 (m, 25H), 3.53-3.51 (m, 2H), 3.36 (s, 3H).
LCMS m/z 696 (M+H)+ (ES+)
(vi) N-(3-(3-(4-((2-((3-(2.5.8.11.14.17.20-Heptaoxadocosan-22-yloxy)-5-methoxyphenyl)- amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl) methane- sulfonamide
A mixture of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 176 mg, 0.448 mmol), the product from step (v) above (240 mg, 0.345 mmol) and Et3N (20 μί, 0.143 mmol) in iPrOAc (3mL) was heated at 60°C for 4h. The solvent was evaporated and the residue purified by chromatography on silica gel (40 g column, 0-5% MeOH/DCM) then purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), 20-80% MeCN in Water) to give a gum that was 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 give a red gum which was purified by chromatography on silica gel (12 g column, 0-20%MeCN/EtOAc) to afford the title compound (53 mg) as a pink foam.
H NMR (DMSO-d6) 400 MHz, δ: 9.39 (s, 1 H), 9.15 (s, 1 H), 8.92 (s, 1 H), 8.88 (s, 1 H), 8.30 (d, 1 H), 8.19 (d, 1 H), 8.12 (d, 1 H), 8.10 (s, 1 H), 7.87 (d, 1 H), 7.73-7.69 (m, 1 H), 7.63-7.59 (m, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.92 (s, 1 H), 7.78 (s, 1 H), 6.59-6.57 (m, 1 H), 6.08 (d, 1 H), 6.04 (s, 1 H), 3.99-3.97 (m, 2H), 3.81 (s, 3H), 3.72-3.70 (m, 2H), 3.65 (s, 3H), 3.59-3.46 (m, 22H), 3.42-3.40 (m, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 994 (M+H)+ (ES+); 992 (M-H)" (ES") Example 46
5-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide
Figure imgf000110_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), N1 ,N1-dimethylethane-1 ,2-diamine (17.03 μΙ_, 0.156 mmol) and triethylamine (32.6 μΙ_, 0.234 mmol) in DCM (4 mL) was cooled in an ice- bath. 50 wt% T3P in EtOAc (69.6 μί, 0.117 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred at this temperature for 2 h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 5-10% MeOH in DCM) to afford the product as a white solid. The crude product was purified by preparative HPLC (Gilson, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column) to afford the title compound (22 mg) as a pale brown solid.
H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1 H), 9.41 (s, 1 H), 8.99 (s, 1 H), 8.49 (d, 1 H), 8.42 (d, 1 H), 8.32 (t, 1 H), 8.8 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.42 (d, 1 H), 7.29 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.03 (t, 1 H), 3.85-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.51 (s, 3H), 3.39-3.41 (m, 4H), 3.31-3.34 (m, 2H), 3.21 (s, 3H), 2.27 (bs, 6H), 1.29 (s, 9H).
LCMS m/z 840 (M+H)+ (ES+); 420 (M+2H)2+ (ES+) Example 47
3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
(i) Phenyl (4-((2-((3-methoxy-5-((2-morpholinoethyl)carbamoyl)phenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)carbamate
To a stirred mixture of 3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N- (2-morpholinoethyl)benzamide (see Example 27(iii) above; 372 mg, 0.703 mmol) and NaHCOs (117 mg, 1.398 mmol) in DCM (1.4 mL) and THF (0.6 mL) was added phenyl chloroformate (93 μί, 0.734 mmol). The resulting mixture was stirred at rt overnight. The reaction mixture was partitioned between water (10 mL) and DCM (10 mL), then passed through a phase sep cartridge. The filtrate was concentrated in vacuo to afford a light beige foam which was triturated with a mixture of diethyl ether and isohexane, filtered and dried to afford the sub-title compound (272 mg, 77% purity) as a sand coloured solid.
LCMS m/z 634 (M+H)+ (ES+)
(ii) 3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide
Triethylamine (23 μί, 0.165 mmol) was added to a stirred mixture of 3-amino-5-(tert-butyl)-2- methoxybenzamide (75 mg, 0.334 mmol) and the product from step (i) above (275 mg, 0.334 mmol) in i-PrOAc (4.5 mL). The resulting mixture was heated at 60 °C for 1 h. DMF (2 mL) was added and stirring continued at 60 °C overnight. The reaction was cooled then partitioned between water (20 mL) and EtOAc (20 mL). The organic phase was washed with water (2 x 20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo to afford a brown residue. The crude product was purified by chromatography on silica gel (40 g column, 0-10% (1 % NH3 in MeOH) in DCM) to afford a glass, which was triturated with diethyl ether, filtered and dried to afford an off-white solid. The product was purified by chromatography on silica gel (12 g column, 0-10% MeOH in DCM) to afford the title compound (19 mg) as a white solid. .
H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 9.07 (s, 1 H), 8.92 (s, 1 H), 8.45 (d, 1 H), 8.30 (d, 1 H), 8.23 (t, 1 H), 8.11-8.08 (m, 2H), 7.87 (d, 1 H), 7.73-7.68 (m, 2H), 7.62-7.55 (m, 3H), 7.51-7.48 (m, 1 H), 7.38 (d, 1 H), 7.21 (d, 1 H), 6.87-6.84 (m, 1 H), 6.58-6.56 (m, 1 H), 6.13 (d, 1 H), 3,82 (s, 3H), 3.74 (s, 3H), 3.57-3.54 (m, 4H), 2H under H20 peak at 3.33 ppm, 2.45- 2.36 (m, 6H), 1.28 (s, 9H).
LCMS m/z 762 (M+H)+ (ES+); 760 (M-H)" (ES")
Example 48
3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
Figure imgf000112_0001
(i) Phenyl (5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)carbamate
Phenyl chloroformate (300 μΙ_, 2.391 mmol) was added to a stirred solution of 3-amino-5- (tert-butyl)-2-methoxybenzamide (390 mg, 1.755 mmol) and NaHC03 (450 mg, 5.36 mmol) in THF (10 mL) and DCM (10 mL). The mixture was stirred for 2h then filtered and the solvent evaporated from the filtrate to give a pale brown oil which was stirred in cyclohexane (20 mL) overnight. The resultant solid was filtered off and dried to give the sub-title compound (500 mg) as a tan crystalline solid.
H NMR (400 MHz, CDCI3) δ 8.40 (s, 1 H), 7.77 (d, 1 H), 7.51 (s, 1 H), 7.48 - 7.39 (m, 2H), 7.38 - 7.31 (m, 1 H), 7.31 - 7.24 (m, 1 H), 7.24 - 7.18 (m, 2H), 5.95 (s, 1 H), 3.90 (s, 3H), 1.32 (s, 9H).
LCMS m/z 343 (M+H)+ (ES+) (ii) 3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethvnyl)benzamide
TEA (10 μί, 0.072 mmol) was added to a solution of 3-((4-((4-aminonaphthalen-1-yl)oxy)- pyridin-2-yl)amino)-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethynyl)benzamide (see Example 39(ii) above; 260 mg, 0.392 mmol) and the product from step (i) above (150 mg, 0.438 mmol) in THF (2 mL). The reaction mixture was stirred at 60°C for 16h. The temperature was increased to 65°C and stirring continued for a further 24h. The solvents were evaporated and the crude product was purified by chromatography on silica gel (40 g column, 5% MeOH:DCM to 8%) to give a tan glass. This material was stirred in MeCN (8 mL) at 65°C for 1 h then cooled, filtered and washed with MeCN (2 mL) to afford the sub-title compound (168 mg) as a colourless solid.
LCMS m/z 913 (M+H)+ (ES+)
(iii) 3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
The product from step (ii) above (168 mg, 0.184 mmol) was dissolved in THF (2 mL) and TBAF, 1 M in THF (250 μί, 0.250 mmol) added. The reaction mixture was stirred at rt for 2h. The solvents were evaporated and the residue stirred in diethyl ether (8 mL) for 72h. The resulting precipitate was filtered off and washed with diethyl ether (3 mL) to give a colourless solid. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μητι, 19x50 mm column, 40% - 80% MeCN in Water) to afford the title compound (75 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.49 (s, 1 H), 9.23 (s, 1 H), 8.94 (s, 1 H), 8.46 (d, 1 H), 8.39 (t, 1 H), 8.31 (d, 1 H), 8.15 (d, 1 H), 8.13 - 8.07 (m, 2H), 7.93 (t, 1 H), 7.91 - 7.83 (m, 1 H), 7.80 - 7.67 (m, 2H), 7.67 - 7.53 (m, 2H), 7.47 - 7.32 (m, 2H), 7.22 (d, 1 H), 6.63 (dd, 1 H), 6.12 (d, 1 H), 4.21 (s, 1 H), 3.83 (s, 3H), 3.65 - 3.48 (m, 4H), 3.41 - 3.34 (m, 2H), 2.48 - 2.33 (m, 6H), 1.29 (s, 9H). LCMS m/z 756 (M+H)+ (ES+); 754 (M-H)" (ES") Example 49
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
Figure imgf000113_0001
TEA (10 μΙ_, 0.072 mmol) was added to a solution of 3-((4-((4-aminonaphthalen-1- yl)oxy)pyridin-2-yl)amino)-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethynyl)benzamide (see Example 39(H) above; 120 mg, 0.181 mmol) and phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 75 mg, 0.191 mmol) in iPrOAc. The reaction mixture was stirred at 60°C for 16h then the temperature was increased to 65°C and stirring continued for a further 24h. The solvents were evaporated and the crude product was purified by chromatography on silica gel (40 g column, 2% MeOH:DCM to 8%) to give a beige glass (143 mg) which was dissolved in THF (2ml_) and TBAF, 1 M in THF (200 μΙ_, 0.200 mmol) added. The reaction mixture was stirred at rt for 2h. The solvents were evaporated and the residue stirred in diethyl ether (8ml_) for 72h. The resulting precipitate was filtered off and washed with diethyl ether (3ml_) to give a colourless solid. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 40%-80% MeCN in Water) to afford the title compound (25 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 9.22 (s, 1 H), 9.14 (s, 1 H), 8.92 (s, 1 H), 8.39 (t, 1 H), 8.30 (d, 1 H), 8.22 - 8.06 (m, 4H), 7.97 - 7.90 (m, 1 H), 7.90 - 7.84 (m, 1 H), 7.75 - 7.67 (m, 1 H), 7.66 - 7.57 (m, 1 H), 7.46 - 7.32 (m, 2H), 7.02 (d, 1 H), 6.63 (dd, 1 H), 6.12 (d, 1 H), 4.20 (s, 1 H), 3.81 (s, 3H), 3.56 (t, 4H), 3.09 (s, 3H), 2.47 - 2.35 (m, 6H), 1.27 (s, 9H). 2H under the water peak at 3.32ppm.
LCMS m/z 806 (M+H)+ (ES+); 804 (M-H)" (ES")
Example 50
N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(cvclopropanecarbonyl)-5-methoxyphenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide
Figure imgf000113_0002
(i) (3-Amino-5-methoxyphenyl)(cyclopropyl)methanone
Cyclopropylmagnesium bromide (1 M in 2-Me THF, 20 mL, 20.00 mmol) was added to a mixture of 3-amino-5-methoxybenzonitrile (1 g, 6.75 mmol) and copper(l) bromide (20 mg, 0.139 mmol) in THF (10ml_) at rt under N2. The mixture was stirred for 1 h at rt then heated under reflux for 2h. The mixture was cooled and aq. 1 M HCI (20ml_) added and stirred for 1 h. The mixture was partitioned between EtOAc (100ml_) and aq NaHC03 (50mL), the organic layer separated, dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0- 40%EtOAc/isohexane) to afford the sub-title compound (71 mg) as an orange oil.
H NMR (CDCI3) 400 MHz, δ: 6.95-6.93 (m, 2H), 6.42 (t, 1 H), 3.82 (s, 3H), 3.80 (s, 2H), 2.62- 2.56 (m, 1 H), 1.23-1.19 (m, 2H), 1.03-0.99 (m, 2H).
LCMS m/z 192 (M+H)+ (ES+)
(ii) N-(5-(tert-Butyl)-3-(3-(4-((2-((3-(cvclopropanecarbonyl)-5-methoxyphenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide
A mixture of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2- methoxyphenyl)methanesulfonamide (see Example 7(i) above; 194 mg, 0.340 mmol), the product from step (i) above (65 mg, 0.340 mmol) and p-TSA monohydrate (20 mg, 0.105 mmol) in THF (3ml_) was heated at 60°C for 20h. The mixture was partitioned between EtOAc (50ml_) and sat aq NaHC03 (50ml_), the organic layer separated, washed with water, dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-5%MeOH/DCM) and the product triturated with MeCN to give a solid (1 10mg). The solid was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 50-95% MeCN in Water) to afford the title compound (5 mg) as a solid. H NMR (DMSO-d6) 400 MHz, δ: 9.68 (s, 1 H), 9.35 (s, 1 H), 9.13 (s, 1 H), 8.92 (s, 1 H), 8.45 (d, 1 H), 8.28 (d, 1 H), 8.18 (d, 1 H), 8.1 1 (d, 1 H), 7.87 - 7.83 (m, 2H), 7.70 - 7.66 (m, 1 H), 7.61 - 7.57 (m, 1 H), 7.50 (s, 1 H), 7.43 (d, 1 H), 7.11 - 6.96 (m, 2H), 6.60 (d, 1 H), 3.81 (s, 3H), 3.63 (s, 3H), 3.09 (s, 3H), 2.69 - 2.62 (m, 1 H), 1.27 (s, 9H), 0.98 (d, 4H).
LCMS m/z 725 (M+H)+ (ES+); 723 (M-H)" (ES")
Example 51
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)-benzamide
\ — o
^0^
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid (see Example 21 above; 60 mg, 0.078 mmol), oxetan-3-amine (10.85 μί, 0.156 mmol) and triethylamine (35 μί, 0.251 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (70 μί, 0.118 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred for 2h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (38 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.43 (s, 2H), 8.98 (d, 1 H), 8.91 (s, 1 H), 8.47 (d, 1 H), 8.42 (d, 1 H), 8.28 (d, 1 H), 8.09 (d, 1 H), 7.86 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.42 (d, 1 H), 7.07 (d, 1 H), 6.82 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.99-5.08 (m, 1 H), 4.81 (t, 2H), 4.60 (t, 2H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.56 (m, 6H), 3.51 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 1.29 (s, 9H).
LCMS m/z 825 (M+H)+ (ES+); 413 (M+2H)2+ (ES+) Example 52
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-methoxyethoxy)ethyl)benzamide
Figure imgf000115_0001
(i) 3-Amino-5-((triisopropylsilyl)ethvnyl)benzoic acid
Pd(PPh3)4 (9.36 g, 8.10 mmol) was added to a degassed suspension of 3-amino-5- bromobenzoic acid (50 g, 231 mmol), Cul (1.499 g, 7.87 mmol), and ethynyltriisopropylsilane (80 mL, 356 mmol) in Et3N (300 ml_) and DMF (300 ml_). The mixture was heated to 90°C for 2h. The mixture was cooled and carefully poured into ice-cold HCI (2.0M aq.) (1100 mL, 2200 mmol) and diluted with diethyl ether (500 mL). The biphasic mixture was filtered to remove palladium residues. The layers of the filtrate were separated and the aqueous phase was extracted with a further portion of diethyl ether (300 mL). The organic phases were combined and washed with 20% brine (2 x 300 mL), 40% brine (300 mL), dried (MgS04), filtered and concentrated in vacuo affording a pale orange solid. The solid was recrystallised in acetonitrile (250 mL) and collected by filtration, washing with fresh acetonitrile (2 x 30 mL) affording the product as a yellow solid. The solid was slurried in hexane (250 mL) for 5h then filtered, washing with more hexane to afford the sub-title compound (45.5 g) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 12.87 (bs, 1 H), 7.18 (t, 1 H), 7.10 (t, 1 H), 6.86 (t, 1 H), 5.54 (bs, 2H), 1.10 (s, 21 H).
LCMS m/z 318 (M+H)+ (ES+); 316 (M-H)" (ES")
(ii) 3-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5- ((triisopropylsilvDethvnvDbenzoic acid
N2 was bubbled through a mixture of tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1- yl)carbamate (see Example 3(H) above; 0.5 g, 1.348 mmol), the product from step (i) (0.490 g, 1.544 mmol), Cs2C03 (0.966 g, 2.97 mmol), BINAP (0.078 g, 0.125 mmol) and Pd2dba3 (0.056 g, 0.061 mmol) in dioxane (15mL) for 10min then heated at 90C for 4h. The mixture was partitioned between ether (100mL) and 1 M HCI (50mL), the organic layer separated, washed with water, dried (MgS04), filtered and evaporated under reduced pressure. The residue was triturated with ether/isohexane, filtered and dried to afford the crude sub-title compound (760mg).
(iii) 3-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5- ethynylbenzoic acid
1.0 M TBAF in THF (2.5 mL, 2.500 mmol) was added to a stirred solution of the crude product from step (ii) above (760 mg) in THF (15ml_). The mixture was stirred for 2h then water (10ml_) added and acidified to pH~4 with 1 M HCI. The mixture was partitioned between EtOAc (70ml_) and water (40ml_), the organic phase washed with sat brine (50ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-100%EtOAc/isohexane) to afford the sub-title compound (344 mg) as a foam.
H NMR (DMSO-d6) 400 MHz, δ: 13.07 (s, 1 H), 9.39 (s, 1 H), 9.29 (s, 1 H), 8.18-8.13 (m, 4H), 7.84 (d, 1 H), 7.66-7.56 (m, 3H), 7.44 (s, 1 H), 7.38 (d, 1 H), 6.66 (dd, 1 H), 6.07 (d, 1 H), 4.22 (s, 1 H), 1.53 (s, 9H).
LCMS m/z 496 (M+H)+ (ES+)
(iv) tert-Butyl (4-((2-((3-ethvnyl-5-((2-(2-methoxyethoxy)ethyl)carbamoyl)phenyl)amino)- pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
HATU (422 mg, 1.1 10 mmol) was added to a stirred solution of the product from step (iii) (500 mg, 1.009 mmol), 2-(2-methoxyethoxy)ethanamine (180 mg, 1.514 mmol) and Hunig's Base (529 μΙ_, 3.03 mmol) in DMF (10ml_) at rt. The mixture was stirred for 3h then partitioned between EtOAc (100ml_) and aq sat NaHC03 soln (50ml_). The organic layer was washed with brine (50ml_), dried (MgS04), filtered and evaporated under reduced pressure. The residue was purified by chromatography on silica gel (40 g column, 20- 100%EtOAc/isohexane) to afford the sub-title compound (530 mg) as a foam.
H NMR (CDCI3) 400 MHz, δ: 8.06 (d, 1 H), 7.96-7.93 (m, 2H), 7.80-7.76 (m, 2H), 7.70 (s, 1 H), 7.60-7.48 (m, 2H), 7.41 (s, 1 H), 7.18 (d, 1 H), 6.89 (s, 1 H), 6.83-6.76 (m, 2H), 6.42 (dd, 1 H), 6.20 (d, 1 H), 3.67-3.53 (m, 8H), 3.36 (s, 3H), 3.07 (s, 1 H), 1.57 (s, 9H).
LCMS m/z 597 (M+H)+ (ES+); 595 (M-H)" (ES")
(v) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-methoxy- ethoxy)ethyl)benzamide
TFA (1 mL, 12.98 mmol) was added dropwise to a stirred solution of the product from step (iv) above (520 mg, 0.871 mmol) in DCM (10 mL). The reaction was stirred at rt for 16 h. The solvents were evaporated and the residue partitioned between DCM (20mL) and sat. NaHC03 soln (20mL), the aqueous was separated and washed with DCM (20mL). The organics were bulked, dried, filtered and evaporated to afford the title compound (430 mg) as a brown glass.
H NMR (400 MHz, DMSO-d6) δ 9.14 (s, 1 H), 8.46 (t, 1 H), 8.23 - 8.13 (m, 1 H), 8.13 - 8.02 (m, 2H), 7.92 (t, 1 H), 7.69 - 7.57 (m, 1 H), 7.50 - 7.42 (m, 2H), 7.41 (t, 1 H), 7.11 (d, 1 H), 6.72 (d, 1 H), 6.57 (dd, 1 H), 6.06 (d, 1 H), 5.85 (s, 2H), 4.18 (s, 1 H), 3.58 - 3.47 (m, 4H), 3.47 - 3.42 (m, 2H), 3.40 - 3.35 (m, 2H), 3.23 (s, 3H).
LCMS m/z 497 (M+H)+ (ES+) (vi) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1^ yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-methoxyethoxy)ethyl)-benzarnide
Et3N (10 μί, 0.072 mmol) was added to a solution of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 100 mg, 0.252 mmol) and the product from step (v) above (100 mg, 0.201 mmol) in iPrOAc (3m L) at 60°C (block temperature) and the mixture stirred for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 1 % MeOH:DCM to 6%) to give 120mg as a brown glass The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (65 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 9.21 (s, 1 H), 9.14 (s, 1 H), 8.91 (s, 1 H), 8.47 (t, 1 H), 8.30 (d, 1 H), 8.18 (d, 1 H), 8.15 (d, 1 H), 8.13 - 8.09 (m, 2H), 7.93 (t, 1 H), 7.88 (d, 1 H), 7.78 - 7.67 (m, 1 H), 7.66 - 7.57 (m, 1 H), 7.42 (t, 1 H), 7.40 (d, 1 H), 7.03 (d, 1 H), 6.63 (dd, 1 H), 6.13 (d, 1 H), 4.19 (s, 1 H), 3.81 (s, 3H), 3.58 - 3.47 (m, 4H), 3.47 - 3.41 (m, 2H), 3.41 - 3.35 (m, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 795 (M+H)+ (ES+); 793 (M-H)" (ES")
Example 53
3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Figure imgf000117_0001
(i) tert-Butyl (4-((2-((3-ethvnyl-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)carbamoyl)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
HATU (500 mg, 1.315 mmol) was added to a stirred solution of 3-((4-((4-((tert- butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynylbenzoic acid (see Example 52(iii) above; 500 mg, 1.009 mmol), 2-(2-(2-methoxyethoxy)ethoxy)-ethanamine (277 mg, 1.695 mmol) and triethylamine (250 μΙ_, 1.796 mmol) in N,N-dimethylformamide (10 mL). The mixture was stirred at rt for 18 h. The mixture was diluted with EtOAc (50 mL) and washed with water (50 mL), 20% brine (3 x 50 mL) and saturated brine (50 mL). The organic phase was dried (MgS04), filtered 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 (580 mg) as a tan foam.
LCMS m/z 641 (M+H)+ (ES+); 639 (M-H)" (ES")
(ii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxy- ethoxy)ethoxy)ethyl)benzamide
TFA (1 mL, 12.98 mmol) was added to a solution of the product from step (i) above (580 mg, 0.905 mmol) in DCM (5 mL) at rt and stirred overnight. The volatiles were removed under reduced pressure and the residue was redissolved in DCM (20 mL). The organic phase was washed with saturated NaHC03 solution (20 mL), dried (MgS04) and concentrated under reduced pressure to yield the sub-title compound (475 mg).
LCMS m/z 541 (M+H)+ (ES+); 539 (M-H)" (ES") (iii) 3-((4-((4-(3-(5-(tert-Butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
To a stirred mixture of phenyl (5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)carbamate (see Example 48(i) above; 127 mg, 0.366 mmol) and the product from step (ii) above (200 mg, 0.366 mmol) in i-PrOAc (6 mL) was added Et3N (1 1 μί, 0.079 mmol). The reaction mixture was heated at 60 °C overnight. The solvent was removed in vacuo and the crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH in DCM) to afford a foam, which was triturated with diethyl ether, filtered and dried to afford the title compound (187 mg) as a light beige solid.
H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 9.21 (s, 1 H), 8.92 (s, 1 H), 8.48-8.44 (m, 2H), 8.30 (d, 1 H), 8.15 (d, 1 H), 8.1 1-8.09 (m, 2H), 7.93 (t, 1 H), 7.87 (d, 1 H), 7.73-7.69 (m, 2H), 7.63-7.59 (m, 1 H), 7.56 (s, 1 H), 7.42-7.38 (m, 2H), 7.22 (d, 1 H), 6.62 (dd, 1 H), 6.13 (d, 1 H), 4.18 (s, 1 H), 3.83 (s, 3H), 3.53-3.48 (m, 8H), 3.40-3.35 (m, 4H), 3.20 (s, 3H), 1.28 (s, 9H). LCMS m/z 789 (M+H)+ (ES+) Example 54
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Figure imgf000118_0001
To a stirred mixture of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)- phenyl)carbamate (see Example 1 (vi) above; 144 mg, 0.363 mmol) and 3-((4-((4- aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)- ethyl)benzamide (see Example 53(H) above; 198 mg, 0.363 mmol) in i-PrOAc (6 mL) was added Et3N (1 1 μί, 0.079 mmol). The reaction mixture was heated at 60 °C overnight. The solvent was removed in vacuo. The crude product was purified by chromatography on silica gel (40 g column, 0-5% MeOH in DCM) to afford an orange foam at -85% purity. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (89 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.40 (s, 1 H), 9.25 (s, 1 H), 9.13 (s, 1 H), 8.91 (s, 1 H), 8.47 (t, 1 H), 8.30 (d, 1 H), 8.18 (d, 1 H), 8.15-8.08 (m, 3H), 7.92 (t, 1 H), 7.88-7.86 (m, 1 H), 7,72-7.68 (m, 1 H), 7.63-7.59 (m, 1 H), 7.43 (s, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.63 (dd, 1 H), 6.13 (d, 1 H), 4.19 (s, 1 H), 3.80 (s, 3H), 3.52-3.48 (m, 8H), 3.40-3.37 (m, 4H), 3.20 (s, 3H), 3.09 (s, 3H), 1.26 (s, 9H).
LCMS m/z 839 (M+H)+ (ES+) Example 55
5-(tert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzenesulfonamide
Figure imgf000119_0001
(i) 5-(tert-Butyl)-2-methoxy-3-nitrobenzenesulfonamide
To an ice-cooled solution of 5-(tert-butyl)-2-methoxy-3-nitrobenzene-1-sulfonyl chloride (1.5 g, 4.87 mmol) in acetone (8 ml_) was added NH4OH (20 ml_, 502 mmol). The resulting mixture was stirred at rt for 1 h. The mixture was diluted with water (50 ml_) and concentrated under reduced pressure remove excess ammonia and acetone. The aqueous precipitate was collected by filtration to yield the sub-title compound (990 mg) as an off white solid.
H NMR (400 MHz, DMSO-d6) δ 8.15 (d, 1 H), 8.07 (d, 1 H), 7.61 (br s, 2H), 3.90 (s, 3H), 1.33 (s, 9H).
LCMS m/z 306 (M+NH4)+ (ES+); 287 (M-H)" (ES")
(ii) 3-Amino-5-(tert-butyl)-2-methoxybenzenesulfonamide
5% Platinum on carbon was added to a solution of the product from step (i) above (440 mg, 1.526 mmol) in ethanol (8 ml_) and ethyl acetate (2 ml_) and stirred under a balloon of hydrogen at rt for 2 h. Repeated in duplicate. The combined reactions were filtered to remove the catalyst and the filtrate was concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (12 g column, Et20) to afford the sub-title compound (870 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ 6.98 (s, 2H), 6.97 (d, 1 H), 6.95 (d, 1 H), 5.18 (br s, 2H), 3.73 (s, 3H), 1.23 (s, 9H).
LCMS m/z 259 (M+H)+ (ES+); 257 (M-H)" (ES")
(iii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzenesulfonamide
The product from step (ii) above (65.0 mg, 0.251 mmol), phenyl (4-((2-((3-methoxy-5-(2-(2- (2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl) carbamate (see Example 19(i) above; 100 mg, 0.156 mmol) and Et3N (5.00 μΙ_, 0.036 mmol) in iPrOAc were heated to 50°C (block temperature) overnight. The temperature was increased to 63°C and the mixture was stirred for a further 18 h. The mixture was concentrated under reduced pressure and the residue was purified by chromatography on the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the title compound (55 mg) as a white powder.
H NMR (400 MHz, DMSO-d6) δ 9.46-9.40 (m, 2H), 8.99 (s, 1 H), 8.55 (d, 1 H), 8.41 (d, 1 H), 8.27 (d, 1 H), 8.10 (d, 1 H), 7.86 (d, 1 H), 7.69 (ddd, 1 H), 7.60 (ddd, 1 H), 7.44 (s, 1 H), 7.43 (d, 1 H), 7.33 (s, 2H), 6.86-6.74 (m, 2H), 6.55 (d, 1 H), 6.04 (dd, 1 H), 3.92 (s, 3H), 3.90-3.82 (m, 2H), 3.70-3.63 (m, 2H), 3.58-3.45 (m, 6H), 3.51 (s, 3H), 3.43-3.38 (m, 2H), 3.22 (s, 3H), 1.30 (s, 9H). LCMS m/z 805 (M+H)+ (ES+); 803 (M-H)" (ES") Example 56
(R)-3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1-morpholinopropan-2-yl)-benzamide
Figure imgf000120_0001
(i) 3-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5- ((triisopropylsilvDethvnvDbenzoic acid
A suspension of tert-butyl (4-((2-chloropyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see, for example, Ito, K. et al., WO 2010/067130, 17 Jun 2010; 42.6 g, 115 mmol), 3-amino-5- ((triisopropylsilyl)ethynyl)benzoic acid (see Example 52(i) above; 40.00 g, 126 mmol), BINAP (6.42 g, 10.31 mmol) and caesium carbonate (74.6 g, 229 mmol) in 1 ,4-dioxane (500 ml_) was degassed with nitrogen for 10 minutes. Pd2(dba)3 (4.20 g, 4.58 mmol) was added and the mixture was heated to 90°C for 2.5h. The mixture was diluted with diethyl ether (600 ml_) then washed with water (600 ml_), followed by 0.5 M HCI solution (500 ml_) and saturated brine (500 ml_). The organic phase was dried (MgS04), filtered and concentrated in vacuo affording the sub-title compound (96 g) as a red foam which was used in the next step without further purification.
(ii) 3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5- ethynylbenzoic acid
The compound from step (i) above (96 g) was dissolved in THF (60 ml_) and diluted with MeCN (400 ml_). 1.0 M TBAF in THF (235 ml_, 235 mmol) was added and the reaction stirred at rt overnight. The reaction was diluted with MeCN (300 ml_) and water (600 ml_), then 1 M HCI solution (100 ml_, 1eq.) was added and stirring continued resulting in the precipitation of a pink solid which was collected by filtration. The pink solid was triturated in MeCN at 80°C, collected by filtration and dried at 40°C under vacuum for 2h. The solid was re-suspended in (9: 1) EtOAc/THF (400 ml_) and heated to 60°C for 90 mins then cooled to rt and stirred overnight. The suspended solid was collected by filtration, washing with EtOAc affording the sub-title compound (47 g) as a pale yellow/beige solid.
H NMR (400 MHz, DMSO-d6) δ: 13.12 (bs, 1 H), 9.83 (s, 1 H), 9.32 (s, 1 H), 8.46 (d, 1 H), 8.28 (s, 1 H), 8.10 (d, 1 H), 8.01 (s, 1 H), 7.82 (d, 1 H), 7.54-7.63 (m, 3H), 7.49 (s, 1 H), 7.42 (d, 1 H), 6.61 (d, 1 H), 4.17 (s, 1 H), 1.52 (s, 9H).
LCMS m/z 497 (M+H)+ (ES+); 495 (M-H)" (ES")
(iii) (R)-tert-Butyl (4-((2-((3-ethvnyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
To a stirred solution of (R)-1-morpholinopropan-2-amine, HCI (0.364 g, 2.014 mmol), the product from step (ii) above (1.0 g, 2.014 mmol) and HATU (0.996 g, 2.62 mmol) in DMF (15 ml_) was added Hunig's base (1.403 ml_, 8.06 mmol) and the reaction was stirred overnight. The reaction was diluted with water resulting in the precipitation of a beige solid. The suspension was stirred for an additional 20 minutes then the solid collected by filtration washing with water. The crude product was purified by chromatography on the Companion (80 g column, 1-5% MeOH in DCM) to afford the sub-title compound (752 mg) as a pale brown solid.
LCMS m/z 623 (M+H)+ (ES+); 312 (M+2H)2+ (ES+)
(iv) (R)-3-((4-((4-aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1- morpholinopropan-2-yl)benzamide
To a stirred solution of the product from step (iii) above (752 mg, 1.208 mmol) in DCM (80 ml_) was added TFA (2000 μΙ_, 26.0 mmol) and the reaction stirred at rt overnight. The mixture was concentrated in vacuo and the residue re-dissolved in DCM (100ml_). The solution was washed with sat. NaHC03 solution (100ml_) and the organic phase dried (MgS04), filtered and concentrated in vacuo affording the sub-title compound (667 mg) as a pale brown glassy solid.
H NMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1 H), 8.35 (d, 1 H), 8.12-8.15 (m, 2H), 8.05 (s, 1 H), 7.95 (s, 1 H), 7.62-7.64 (m, 1 H), 7.41-7.46 (m, 3H), 7.14 (d, 1 H), 6.70 (d, 1 H), 6.36 (d, 1 H), 5.76 (s, 2H), 4.13-4.20 (m, 1 H), 4.18 (s, 1 H), 3.54 (t, 4H), 2.39-2.45 (m, 5H), 2.26 (dd, 1 H), 1.13 (d, 3H).
LCMS m/z 523 (M+H)+ (ES+); 262 (M+2H)2+ (ES+)
(v) (R)-3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1-morpholinopropan-2-yl)-benzamide To a stirred solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- carbamate (see Example 1 (vi) above; 90 mg, 0.227 mmol) and the product from step (iv) above (100 mg, 0.191 mmol) in iPrOAc (3ml_) was added triethylamine (10 μΙ_, 0.072 mmol). The reaction was heated to 60 °C (block temperature) for 18h during which time a gel formed. The reaction was diluted with THF and concentrated in vacuo onto silica gel. The residue was purified by chromatography on the Companion (12 g column, 3% MeOH:DCM to 5%) affording an orange solid. The solid was triturated in iPrOAc and the solid collected by filtration, washing with further iPrOAc affording a cream-coloured solid. The solid was dissolved in MeOH and reconcentrated twice affording the title compound (72 mg) as a cream-coloured solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.75 (s, 1 H), 9.33 (s, 1 H), 9.14 (s, 1 H), 8.90 (s, 1 H), 8.44 (d, 1 H), 8.27 (d, 1 H), 8.18 (d, 1 H), 8.13 (d, 1 H), 8.09 (d, 1 H), 8.05 (d, 1 H), 7.89 (s, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.60 (t, 1 H), 7.44-7.46 (m, 2H), 7.03 (d, 1 H), 6.55 (d, 1 H), 4.12-4.20 (m, 1 H), 4.12 (s, 1 H), 3.81 (s, 3H), 3.53 (t, 4H), 3.10 (s, 3H), 2.34-2.44 (m, 5H), 2.26 (dd, 1 H), 1.27 (s, 9H), 1.12 (d, 3H).
LCMS m/z 821 (M+H)+ (ES+); 411 (M+2H)2+ (ES+)
Example 57
(S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1-morpholinopropan-2-yl)benzamide
Figure imgf000122_0001
(i) (S)-tert-Butyl (4-((2-((3-ethvnyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)arriino) pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate
To a stirred solution of (S)-1-morpholinopropan-2-amine, HCI (0.364 g, 2.014 mmol), 3-((4- ((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-benzoic acid (see Example 56(H) above; 1.0 g, 2.014 mmol) and HATU (0.996 g, 2.62 mmol) in DMF (15 ml_) was added Hunig's base (1.403 ml_, 8.06 mmol) and the reaction was stirred overnight. The reaction was diluted with water resulting in the precipitation of a beige solid. The suspension was stirred for an additional 20 minutes then the solid collected by filtration washing with water. The crude product was purified by chromatography on the Companion (80 g column, 1-5% MeOH in DCM) to afford the sub-title compound (920 mg) as a pale brown solid.
LCMS m/z 623 (M+H)+ (ES+); 312 (M+2H)2+ (ES+)
(ii) (S)-3-((4-((4-Aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1- morpholinopropan-2-yl)benzamide
To a stirred solution of the product from step (i) above (920 mg, 1.477 mmol) in DCM (80 ml_) was added TFA (2000 μΙ_, 26.0 mmol) and the reaction stirred at rt overnight. The mixture was concentrated in vacuo and the residue re-dissolved in DCM (100ml_). The solution was washed with sat. NaHC03 solution (100ml_) and the organic phase dried (MgS04), filtered and concentrated in vacuo affording the sub-title compound (728 mg) as a pale brown solid. H NMR (400 MHz, DMSO-d6) δ: 9.74 (s, 1 H), 8.35 (d, 1 H), 8.1 1-8.15 (m, 2H), 8.05 (s, 1 H), 7.95 (s, 1 H), 7.62-7.65 (m, 1 H), 7.41-7.47 (m, 3H), 7.14 (d, 1 H), 6.71 (d, 1 H), 6.36 (d, 1 H), 5.76 (s, 2H), 4.13-4.20 (m, 1 H), 4.18 (s, 1 H), 3.54 (t, 4H), 2.39-2.45 (m, 5H), 2.26 (dd, 1 H), 1.13 (d, 3H).
LCMS m/z 523 (M+H)+ (ES+); 262 (M+2H)2+ (ES+)
(Hi) (S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethvnyl-N-(1-morpholinopropan-2-yl)-benzamide To a stirred solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- carbamate (see Example 1 (vi) above; 91 mg, 0.230 mmol) and the product from step (ii) above (100 mg, 0.191 mmol) in iPrOAc (3ml_) was added triethylamine (10 μΙ_, 0.072 mmol). The reaction was heated to 60°C (block temperature) for 18h during which time a gel formed. The reaction was diluted with THF and concentrated in vacuo onto silica gel. The residue was purified by chromatography on the Companion (12 g column, 3% MeOH:DCM to 5%) affording an orange solid. The solid was triturated in iPrOAc and the solid collected by filtration, washing with further iPrOAc affording a cream coloured solid. The material was dissolved in MeOH and re-concentrated twice affording the title compound (64 mg) as a cream-coloured solid. H NMR (DMSO-d6) 400 MHz, δ: 9.75 (s, 1 H), 9.33 (s, 1 H), 9.13 (s, 1 H), 8.90 (s, 1 H), 8.44 (d, 1 H), 8.27 (d, 1 H), 8.18 (d, 1 H), 8.13 (d, 1 H), 8.09 (d, 1 H), 8.05 (d, 1 H), 7.89 (s, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.60 (t, 1 H), 7.44-7.46 (m, 2H), 7.03 (d, 1 H), 6.55 (d, 1 H), 4.12-4.20 (m, 1 H), 4.12 (s, 1 H), 3.81 (s, 3H), 3.53 (t, 4H), 3.10 (s, 3H), 2.34-2.44 (m, 5H), 2.26 (dd, 1 H), 1.27 (s, 9H), 1.12 (d, 3H).
LCMS m/z 821 (M+H)+ (ES+); 411 (M+2H)2+ (ES+)
Example 58
N-(5- ert-Butvn-3-(3-(4-((2-((4-chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide
Figure imgf000123_0001
(i) 5-Amino-2-chloro-3-methoxyphenol
BBr3 (1.1 mL, 11.64 mmol) was added dropwise to a solution of 4-chloro-3,5-dimethoxyaniline (2.19 g, 11.67 mmol) in DCM at rt. (ppte formed). The mixture was stirred for 18h then heated under reflux for 6h. A further 1 ml of BBr3 was added and the mixture stirred for 24h then quenched carefully with MeOH (10ml_). Water (100ml_) was added and the aqueous layer separated then basified with sat aq Na2C03 to pH 6. The mixture was extracted with DCM (2x100ml_), the organic layers combined, dried (MgS04), filtered and evaporated under reduced pressure. The residue was triturated with ether/isohexane to afford the sub-title compound (640 mg).
H NMR (400MHz; DMSO-d6) δ 9.44 (s, 1 H), 5.84 (s, 1 H), 5.82 (s, 1 H), 5.09 (s, 2H), 3.69 (s, 3H).
LCMS m/z 174/6 (M+H)+ (ES+)
(ii) 4-Chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)aniline
A mixture of 5-amino-2-chloro-3-methoxyphenol (630 mg, 3.23 mmol), 1-bromo-2-(2-(2- methoxyethoxy)ethoxy)ethane (907 mg, 3.99 mmol), sodium iodide (54 mg, 0.360 mmol) and K2C03 (1.5 g, 10.85 mmol) in MeCN (20ml_) was heated at 60°C for 18h. The mixture was cooled and partitioned between EtOAc (150ml_) and water (150ml_). The organic layer was separated, dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the sub-title compound (860 mg) as an oil.
H NMR (400MHz; CDCI3) δ 5.98 (s, 1 H), 5.96 (s, 1 H), 4.13 (t, 2H), 3.88 (t, 2H), 3.84 (s, 3H), 3.80-3.78 (m, 2H), 3.69-3.66 (m, 4H), 3.57-3.55 (m, 2H), 3.38 (s, 3H).
LCMS m/z 320/2 (M+H)+ (ES+) (Hi) N-(5- ert-Butvn-3-(3- -((2- 4-chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyph
methanesulfonamide
A suspension of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyrirnidin-4-yl)oxy)naphthalen-1-yl)ureido)- 2-methoxyphenyl)methanesulfonamide (see Example 7(i) above; 100 mg, 0.175 mmol), the product from step (ii) above (1 12 mg, 0.351 mmol) and p-TSA monohydrate (10 mg, 0.053 mmol) in THF/DMF (6 mL, 1 :2) was heated at 60 °C for 24h. The reaction was cooled to rt and partitioned between EtOAc (40 mL) and sat. aq. NaHC03 (30 mL). The aqueous layer was extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (2 x 50 mL), brine (2 x 50 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on silica gel (40 g column, 1- 3% MeOH) affording the title compound (53 mg) as an off-white solid.
H NMR (400MHz; DMSO-d6) δ: 9.15 (s, 1 H), 9.36 (s, 1 H), 9.14 (s, 1 H), 8.90 (s, 1 H), 8.46 (d, 1 H), 8.27 (d, 1 H), 8.19 (d, 1 H), 8.08 (d, 1 H), 7.86 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.42 (d, 1 H), 7.07 (d, 2H), 7.03 (d, 1 H), 6.64 (d, 1 H), 3.82 (s, 5H), 3.66-3.68 (m, 2H), 3.57 (dd, 2H), 3.46-3.50 (m, 7H), 3.39 (dd, 2H), 3.21 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 427 (M+2H)2+ (ES+)
Example 59
1-(5-(tert-Butyl)-2-methoxy-3-(1.3.4-oxadiazol-2-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000124_0001
(i) tert-Butyl 2-(5-(tert-butyl)-2-methoxy-3-nitrobenzoyl)hvdrazinecarboxylate
To a solution of 5-(tert-butyl)-2-methoxy-3-nitrobenzoic acid (500 mg, 1.974 mmol), tert-butyl hydrazinecarboxylate (313 mg, 2.369 mmol) and Hunig's Base (1034 μί, 5.92 mmol) in dry DMF (5mL) was added HATU (901 mg, 2.369 mmol) and the mixture stirred for 2 hours at rt. The reaction mixture was poured onto water (50 mL) and extracted into ethyl acetate (2x20 mL). The combined organic phase was dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography on the Companion (40 g column, 0-50% ethyl acetate: isohexane) to afford the sub-title compound (607 mg) as a colourless oil which turned yellow on standing and slowly began to crystallise.
H NMR (400 MHz, DMSO-d6) δ: 10.17 (s, 1 H), 9.06 (s, 1 H), 7.99 (d, 1 H), 7.62 (s, 1 H), 3.88 (s, 3H), 1.44 (s, 9H), 1.31 (s, 9H).
LCMS m/z 312 (M+H-tBu)+ (ES+); 366 (M-H)" (ES")
(ii) 5-(tert-Butyl)-2-methoxy-3-nitrobenzohydrazide
To a solution of the product from step (i) above (607 mg, 1.487 mmol) in DCM (15 mL) was added TFA (5728 μί, 74.3 mmol) and the mixture allowed to stand for 1 hour. The reaction was concentrated in vacuo and the residue was loaded onto a pre-conditioned cartridge of SCX resin. The resin was washed with MeOH and the product released with 1 % NH3 in MeOH affording the sub-title compound (302 mg) as a yellow oil.
H NMR (400 MHz, DMSO-d6) δ: 9.63 (s, 1 H), 7.92 (d, 1 H), 7.63 (d, 1 H), 4.58 (bs, 2H), 3.83 (s, 3H), 1.30 (s, 9H).
LCMS m/z 268 (M+H)+ (ES+)
(iii) 2-(5-(tert-Butyl)-2-methoxy-3-nitrophenyl)-1 ,3,4-oxadiazole
The product from step (ii) above (302 mg, 1.130 mmol) was dissolved in triethyl orthoformate (8.0 mL, 48.1 mmol) and p-TSA monohydrate (21.49 mg, 0.113 mmol) added. The mixture heated to 130 °C with stirring overnight then cooled to rt. The reaction was concentrated in vacuo and the crude product purified by chromatography on the Companion (12 g column, 1- 3% MeOH in DCM) to afford the sub-title compound (350 mg, 90% purity) as a yellow oil. H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 8.20 (d, 1 H), 8.19 (d, 1 H), 3.87 (s, 3H), 1.35 (s, 9H).
LCMS m/z 278 (M+H)+ (ES+)
(iv) 5-(tert-Butyl)-2-methoxy-3-(1 ,3,4-oxadiazol-2-yl)aniline
The product from step (iii) above (350 mg, 1.136 mmol) was dissolved in ethanol (7 mL) and Fe powder (630 mg, 1 1.28 mmol) was added followed by a solution of NH4CI (600 mg, 1 1.22 mmol) in water (3.5 mL). The resulting suspension was heated at 80 °C for 2 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo then partitioned between water (50 mL) and EtOAc (50 mL). The aqueous phase was extracted with EtOAc (25 mL). The combined organic extracts were washed with brine (30 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on silica gel (40 g column, 1-5% MeOH in DCM) to afford the sub-title compound (160 mg) as a colourless oil.
H NMR (DMSO-d6) 400 MHz, δ: 9.31 (s, 1 H), 7.04 (d, 1 H), 7.07 (d, 1 H), 5.20 (s, 2H), 3.68 (s, 3H), 1.26 (s, 9H).
LCMS m/z 248 (M+H)+ (ES+)
(v) 1-(5-(tert-Butyl)-2-methoxy-3-(1.3.4-oxadiazol-2-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2- (2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Triethylamine (8 μί, 0.057 mmol) was added to a mixture of the product from step (iv) above (80 mg, 0.259 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 166 mg, 0.259 mmol) in isopropyl acetate (3 mL) and the mixture heated at 60°C (block temperature) for 5h during which time reaction became turbid. The mixture was diluted with THF and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 1-5% MeOH in DCM) to afford the title compound (164 mg) as a pale pink solid.
H NMR (400 MHz, DMSO-d6) δ: 9.49 (s, 1 H), 9.45 (s, 1 H), 9.42 (s, 1 H), 9.10 (s, 1 H), 8.67 (d, 1 H), 8.43 (d, 1 H), 8.29 (d, 1 H), 8.10 (d, 1 H), 7.86 (d, 1 H), 7.70 (t, 1 H), 7.60 (t, 1 H), 7.53 (d, 1 H), 7.44 (d, 1 H), 6.81 (d, 2H), 6.56 (d, 1 H), 6.04 (t, 1 H), 3.86-3.91 (m, 2H), 3.86 (s, 3H), 3.65-3.67 (m, 2H), 3.47-3.54 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.21 (s, 3H), 1.33 (s, 9H). LCMS m/z 794 (M+H)+ (ES+), 398 (M+2H)2+ (ES+) Example 60
(S)-5-(tert-Butvn-3-(3-(4-((2-((3-ethvnyl-5-((1-morpholinopropan-2-vncarbamovn
phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide
Figure imgf000126_0001
To a stirred solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)- carbamate (see Example 9(i) above; 123 mg, 0.344 mmol) and (S)-3-((4-((4- aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2- yl)benzamide (see Example 57(ii) above; 150 mg, 0.287 mmol) in iPrOAc (3ml_) was added triethylamine (15 μΙ_, 0.108 mmol). The reaction was heated to 60 °C (block temperature) for 24h then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-10%EtOH/EtOAc) then triturated with EtOAc/ether to afford a solid that was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μητι, 19x50 mm column, 20-95% MeCN in Water). The fractions containing product were evaporated, partitioned between EtOAc (50ml_) and sat aq NaHC03 soln (20ml_), the organic layer was washed with water (20ml_), dried (MgS04), filtered and evaporated under reduced pressure. The solid was triturated with ether, then filtered to a give a solid that was dissolved in MeCN/DCM. The solvent was evaporated to afford the title compound (41 mg) as a solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.75 (s, 1 H), 9.44 (s, 1 H), 8.88 (s, 1 H), 8.45-8.43 (m, 2H), 8.28 (d, 1 H), 8.19-8.05 (m, 4H), 7.90 (s, 1 H), 7.86 (d, 1 H), 7.71-7.58 (m, 2H), 7.46-7.44 (m, 2H), 7.12 (s, 1 H), 6.56-6.53 (m, 1 H), 4.21-4.13 (m, 2H), 3.80 (s, 3H), 3.53 (s, 4H), 2.82 (d, 3H), 2.44-2.22 (m, 6H), 1.28 (s, 9H), 1.12 (d, 3H).
LCMS m/z 785 (M+H)+ (ES+); 783 (M-H)" (ES")
Example 61
(R)-5-(tert-Butyl)-3-(3-(4-((2-((3-ethvnyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl) amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide
Figure imgf000126_0002
To a stirred solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylcarbamoyl)phenyl)- carbamate (see Example 9(i) above; 123 mg, 0.344 mmol) and (R)-3-((4-((4- aminonaphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2- yl)benzamide (see Example 56(iv) above; 150 mg, 0.287 mmol) in iPrOAc (3ml_) was added triethylamine (15 μΙ_, 0.108 mmol). The reaction was heated to 60 °C (block temperature) for 24h then evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-10%EtOH/EtOAc) then triturated with EtOAc/ether to afford a solid that was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Waters X-Select Prep-C18, 5 μητι, 19x50 mm column, 20-95% MeCN in Water). The fractions containing product were evaporated, partitioned between EtOAc (50ml_) and sat aq NaHC03 soln (20ml_), the organic layer was washed with water (20ml_), dried (MgS04), filtered and evaporated under reduced pressure. The solid was triturated with ether, then filtered to a give a solid that was dissolved in MeCN/DCM. The solvent was evaporated to afford the title compound (47 mg).
H NMR (DMSO-d6) 400 MHz, δ: 9.75 (s, 1 H), 9.44 (s, 1 H), 8.89 (s, 1 H), 8.45-8.43 (m, 2H), 8.28 (d, 1 H), 8.19-8.05 (m, 4H), 7.90 (s, 1 H), 7.86 (d, 1 H), 7.71-7.58 (m, 2H), 7.46-7.44 (m, 2H), 7.12 (s, 1 H), 6.56-6.53 (m, 1 H), 4.22-4.13 (m, 2H), 3.80 (s, 3H), 3.53 (s, 4H), 2.82 (d, 3H), 2.44-2.23 (m, 6H), 1.28 (s, 9H), 1.12 (d, 3H).
LCMS m/z 785 (M+H)+ (ES+); 783 (M-H)" (ES")
Example 62
3-((4-((4-(3-(3-(tert-Butyl)-5-carbamoylphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)- 5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Figure imgf000127_0001
(i) Phenyl (3-(tert-butyl)-5-carbamoylphenyl)carbamate
Phenyl chloroformate (99 μΙ_, 0.779 mmol) was added to a stirred solution of 3-amino-5-(tert- butyl)benzamide (128 mg, 0.599 mmol) and NaHC03 (151 mg, 1.798 mmol) in THF (3 mL) and DCM (3 mL). The mixture was stirred at rt overnight. The mixture was diluted with water (15 mL) and DCM (15 mL) and passed through a phase sep cartridge. The organic layer was concentrated in vacuo to afford the sub-title compound (209 mg) as a sticky oil.
LCMS m/z 313 (M+H)+ (ES+), 75% purity
(ii) 3-((4-((4-(3-(3-(tert-Butyl)-5-carbamoylphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2- yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
To a stirred solution of the product from step (i) above (204 mg, 0.490 mmol) and 3-((4-((4- aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)- ethoxy)ethyl)benzamide (see Example 53(H) above; 188 mg, 0.344 mmol) in i-PrOAc (5 mL) was added Et3N (25 μί, 0.179 mmol). The resulting mixture was stirred at 60 °C overnight. The solvent was removed in vacuo to afford a brown oil. The crude product was purified by chromatography on silica gel (40 g column, 0-6% MeOH in EtOAc) to afford a glass, which was triturated with a diethyl ether/isohexane mix to afford a solid (137 mg). The crude product was purified by preparative HPLC (Gilson, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-70% MeCN in Water) to afford the title compound (98 mg) as a colourless solid. H NMR (400 MHz, DMSO-d6) δ 9.22 (s, 1 H), 9.18 (s, 1 H), 8.89 (s, 1 H), 8.47 (t, 1 H), 8.23 (d, 1 H), 8.15 (d, 1 H), 8.11 (dd, 1 H), 8.07 (d, 1 H), 7.98 (s, 1 H), 7.94 (t, 1 H), 7.88 (d, 1 H), 7.80 (t, 1 H), 7.75 - 7.67 (m, 2H), 7.66 - 7.58 (m, 1 H), 7.55 (t, 1 H), 7.42 (t, 1 H), 7.40 (d, 1 H), 7.31 (s, 1 H), 6.63 (dd, 1 H), 6.13 (d, 1 H), 4.19 (s, 1 H), 3.55 - 3.47 (m, 8H), 3.43 - 3.37 (m, 4H), 3.21 (s, 3H), 1.33 (s, 9H).
LCMS m/z 759 (M+H)+ (ES+); 757 (M-H)" (ES")
Example 63
1-(5-(tert-Butvn-2-oxo-2.3-dihvdrobenzordloxazol-7-vn-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000128_0001
(i) 2-Amino-4-(tert-butyl)-6-nitrophenol
10% Pd-C (J&M type 39 50%w/w H20, 1 g) was added to a solution of 4-(tert-butyl)-2,6- dinitrophenol (1 g, 4.16 mmol) and ammonium formate (1.5 g, 23.79 mmol) in MeCN (10ml_) and the mixture heated at reflux for 90 min then left stirring overnight. The mixture was filtered on glass fibre filter pad and the solid washed with EtOAc (10ml_) The filtrate was evaporated and the resulting solid filtered through silica (10g) eluting with DCM to afford the sub-title compound (300 mg) as a dark red crystalline solid.
H NMR (400 MHz, DMSO-d6) δ 7.1 1 (d, 1 H), 7.06 (d, 1 H), 1.24 (s, 9H).
LCMS m/z 211 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-7-nitrobenzordloxazol-2(3H)-one
Pyridine (200 μΙ_, 2.473 mmol) was added to a solution of 4-nitrophenyl carbonochloridate (200 mg, 0.992 mmol) and the product from step (i) above (210 mg, 0.999 mmol) in DCM (10ml_). The reaction mixture was stirred for 72h and then partitioned between DCM (10ml_) and sat. NaHC03 soln. (20ml_). The organics were separated, dried (MgS04), filtered and the solvent evaporated to a brown solid. The crude product was purified by chromatography on silica gel (40 g column, 10% EtOAc: isohexane to 60%) to afford the sub-title compound (150 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 12.24 (s, 1 H), 7.76 (d, 1 H), 7.48 (d, 1 H), 1.34 (s, 9H).
LCMS m/z 259 (M+Na)+ (ES+); 235 (M-H)" (ES")
(iii) 7-Amino-5-(tert-butyl)benzordloxazol-2(3H)-one
10% Pd-C (J&M type 39 50%w/w H20, 50 mg) was added to a solution of the product from step (ii) above (150 mg, 0.635 mmol) and cyclohexene (4 mL, 39.5 mmol) in EtOH (10mL) and the mixture heated at reflux for 3h. The reaction mixture was allowed to cool to rt and stirred overnight. The mixture was filtered (Whatmans glass fibre GF/A) and the solvent evaporated to give a brown gum, used crude in next step. H NMR (400 MHz, DMSO-d6) δ 1 1 .18 (s, 1 H), 6.53 - 6.39 (m, 1 H), 6.34 - 6.19 (m, 1 H), 5.21
(s, 2H), 1 .23 (s, 9H)
LCMS m/z 207 (M+H)+ (ES+) (iv) 1-(5-(tert-Butvn-2-oxo-2.3-dihvdrobenzo^
methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)o^
TEA (20 L, 0.143 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1 -yl)carbamate (see Example 19(i) above; 250 mg, 0.390 mmol) and the product from step (iii) above (90 mg, 0.436 mmol) in TH F (3m L) and the reaction heated at 60°C (block temperature) for 16h then stirred at rt for 48h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 50% EtOAc:isohexane to 100%) to afford the title compound (200 mg) as a colourless glass.
H NMR (400 MHz, DMSO-d6) δ 1 1.61 (s, 1 H), 9.44 (s, 1 H), 9.27 (s, 1 H), 9.14 (s, 1 H), 8.42 (d, 1 H), 8.24 (d, 1 H), 8.14 (d, 1 H), 8.00 (d, 1 H), 7.85 (d, 1 H), 7.74 - 7.63 (m, 1 H), 7.65 - 7.55 (m, 1 H), 7.42 (d, 1 H), 6.88 - 6.76 (m, 2H), 6.74 (d, 1 H), 6.56 (d, 1 H), 6.03 (t, 1 H), 3.86 (t, 2H), 3.73 - 3.60 (m, 2H), 3.58 - 3.45 (m, 9H), 3.44 - 3.37 (m, 2H), 3.21 (s, 3H), 1.30 (s, 9H).
LCMS m/z 753 (M+H)+ (ES+); 751 (M-H)" (ES") Example 64
1-(5-(tert-Butyl)-2-methylbenzord1oxazol-7-yl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000129_0001
(i) 5-(tert-Butyl)-2-methyl-7-nitrobenzordloxazole
2-Amino-4-(tert-butyl)-6-nitrophenol (200 mg, 0.951 mmol) was dissolved in triethyl orthoacetate (5 ml_, 27.3 mmol) and the reaction mixture heated at 100°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (12 g column, 10% EtOAc:isohexane to 40%) to afford the subtitle compound (150 mg) as a waxy yellow solid.
H NMR (400 MHz, DMSO-d6) δ 8.19 (d, 1 H), 8.10 (d, 1 H), 2.72 (s, 3H), 1.39 (s, 9H).
LCMS m/z 235 (M+H)+ (ES+)
(ii) 5-(tert-Butyl)-2-methylbenzordloxazol-7-amine
5% Pd-C (J &M type 87L 50% paste in H20, 30 mg) was added to a solution of the product from step (i) above (150 mg, 0.640 mmol) in ethanol (3mL) and the reaction stirred under hydrogen for 16h. The reaction was filtered through Celite and the solvent evaporated to afford the sub-title compound (125 mg).
H NMR (400 MHz, DMSO-d6) δ 6.80 (d, 1 H), 6.66 (d, 1 H), 5.32 (s, 2H), 2.54 (s, 3H), 1.27 (s, 9H).
LCMS m/z 205 (M+H)+ (ES+) (Hi) 1-(5-(tert-Butvn-2-methylbenzordloxazol-7-vn-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)o^
TEA (20 μΙ_, 0.143 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrirnidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 350 mg, 0.546 mmol) and the product from step (ii) above (125 mg, 0.612 mmol) in THF (3ml_) and the reaction heated at 60°C (block temperature) for 16h then stirred at rt for 48h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 50% EtOAc:isohexane to 100%) to afford the title compound (300 mg) as a pale yellow glass.
H NMR (400 MHz, DMSO-d6) δ 9.44 (s, 1 H), 9.40 (s, 1 H), 9.19 (s, 1 H), 8.42 (d, 1 H), 8.27 (d, 1 H), 8.18 (d, 1 H), 8.14 (d, 1 H), 7.86 (d, 1 H), 7.73 - 7.65 (m, 1 H), 7.65 - 7.57 (m, 1 H), 7.43 (d, 1 H), 7.30 (d, 1 H), 6.88 - 6.73 (m, 2H), 6.56 (d, 1 H), 6.04 (t, 1 H), 3.91 - 3.81 (m, 2H), 3.70 - 3.61 (m, 2H), 3.58 - 3.44 (m, 9H), 3.43 - 3.36 (m, 2H), 3.21 (s, 3H), 2.67 (s, 3H), 1.35 (s, 9H).
LCMS m/z 751 (M+H)+ (ES+)
Example 65
3-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)-pyridin- 2-yl)amino)-5-ethvnyl-N-(2-morpholinoethyl)benzamide
Figure imgf000130_0001
(i) Phenyl (3-(tert-butyl)-5-(methylsulfonamido)phenyl)carbamate
Phenyl chloroformate (45 μΙ_, 0.359 mmol) was added to a stirred solution of N-(3-amino-5- (tert-butyl)phenyl)methanesulfonamide (80 mg, 0.330 mmol) and NaHC03 (70 mg, 0.833 mmol) in THF (1 ml_) and DCM (1 ml_). The reaction mixture was stirred for 1 h then filtered and the filtrate evaporated to a brown gum which was stirred in cyclohexane for 16h. The liquid was decanted off to give the sub-title compound (63 mg).
LCMS m/z 363(M+H)+ (ES+); 361 (M-H)" (ES")
(ii) 3-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)- pyridin-2-yl)amino)-N-(2-morpholinoethyl)-5-((triisopropylsilyl)ethvnyl)benzamide
Et3N (10 μΙ_, 0.072 mmol) was added to a solution of the product from step (i) above (63 mg, 0.174 mmol) and 3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-N-(2-morpholino- ethyl)-5-((triisopropylsilyl)ethynyl)benzamide (see Example 39(H) above; 100 mg, 0.151 mmol) in iPrOAc (1 ml_) at 60°C (block temperature) and the mixture stirred for 16h. The solvent was evaporated and the residue was purified by chromatography on silica gel (12 g column, 2% MeOH:DCM to 8%) to give a brown gum. The crude product was purified by preparative HPLC (Gilson, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 50-95% MeCN in Water) to afford the sub-title compound (80 mg) as a colourless solid. H NMR (400 MHz, DMSO-d6) δ 9.66 (s, 1 H), 9.19 (s, 1 H), 9.15 (s, 1 H), 8.79 (s, 1 H), 8.41 (t, 1 H), 8.21 (d, 1 H), 8.12 (d, 1 H), 8.10 - 8.05 (m, 2H), 7.91 (dd, 1 H), 7.87 (d, 1 H), 7.76 - 7.66 (m, 1 H), 7.66 - 7.54 (m, 1 H), 7.39 (d, 1 H), 7.36 (dt, 2H), 7.29 (t, 1 H), 6.89 (t, 1 H), 6.61 (dd, 1 H), 6.12 (d, 1 H), 3.57 (t, 4H), 3.01 (s, 3H), 2.48 - 2.34 (m, 6H), 1.28 (s, 9H), 1.1 1 (s, 21 H). CH2 under water peak at 3.32 ppm.
(iii) 3-((4-((4-(3-(3-(tert-Butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)arnino)-5-ethvnyl-N-(2-rriorpholinoethyl)benzarTiide
The product from step (ii) above (80 mg, 0.086 mmol) was dissolved in THF (2ml_) and TBAF, 1 M in THF (100 μΙ_, 0.100 mmol) added. The reaction mixture was stirred at rt for 16h. The solvents were evaporated and the crude product was purified by preparative HPLC (Gilson, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 35-75% MeCN in Water) to afford the title compound (12 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.69 (s, 1 H), 9.30 (s, 1 H), 9.24 (s, 1 H), 8.95 (s, 1 H), 8.40 (t, 1 H), 8.23 (d, 1 H), 8.15 (d, 1 H), 8.09 (t, 1 H), 8.06 (d, 1 H), 7.93 (t, 1 H), 7.86 (d, 1 H), 7.74 - 7.65 (m, 1 H), 7.65 - 7.57 (m, 1 H), 7.42 - 7.38 (m, 2H), 7.36 (t, 1 H), 7.30 (t, 1 H), 6.88 (t, 1 H), 6.64 (dd, 1 H), 6.10 (d, 1 H), 4.21 (s, 1 H), 3.56 (t, 4H), 3.01 (s, 3H), 2.48 - 2.32 (m, 6H), 1.28 (s, 9H). CH2 under the water peak at 3.32 ppm.
LCMS m/z 776 (M+H)+ (ES+)
Example 66
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide
Figure imgf000131_0001
(i) 3-((4-((4-((tert-Butoxycarbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)amino)-5- methoxybenzoic acid
In a 100 ml_ flask, a suspension of tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1- yl)carbamate (see Example 3(H) above; 2.2673 g, 6.1 1 mmol), 3-amino-5-methoxybenzoic acid (1.226 g, 7.34 mmol), Cs2C03 (5.98 g, 18.34 mmol), 2,2'-bis(diphenylphosphino)-1 , T- binaphthalene (0.358 g, 0.575 mmol) and Pd2(dba)3 (0.258 g, 0.281 mmol) in dioxane (45 ml_) was de-gassed by bubbling N2 through for 10 min. The resultant brown suspension was heated at 90 °C for 15h. The mixture was partitioned between EtOAc (400ml_) and aq 1 M HCI (200ml_), the organic layer was washed with 10% brine soln (2x240ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (220 g column, 0.5-5% MeOH in DCM) to afford the sub-title compound (1.19 g) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ 12.86 (s, 1 H), 9.37 (s, 1 H), 9.14 (s, 1 H), 8.14 (m, 1 H), 8.13 (m, 1 H), 7.84 (m, 1 H), 7.74 (m, 1 H), 7.67 - 7.54 (m, 4H), 7.36 (d, 1 H), 6.96 (dd, 1 H), 6.61 (dd, 1 H), 6.09 (d, 1 H), 3.74 (s, 3H), 1.53 (s, 9H). LCMS m/z 502 (M+H)+ (ES+); 500 (M-H)" (ES")
(ii) tert-Butyl (4-((2-((3-methoxy-5-((3-morpholinopropyl)carbamoyl)phenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)carbamate
In a 20 mL vial, a solution of the product from step (i) above (84 mg, 0.151 mmol), 3- morpholinopropan-1-amine (32.6 mg, 0.226 mmol) and Hunig's Base (79 μΙ_, 0.452 mmol) in DMF (2.9 mL) was treated with HATU (63.0 mg, 0.166 mmol). The resultant yellow solution was stirred at rt for 3 h. The solution was then partitioned between 10% aq brine (50mL) and EtOAc (50mL). The organic layer was washed with sat aq NaHC03 soln (20 mL), 0.5M HCI (20 mL). Acidic aqueous phase was basified with NaHC03 soln (100 mL), extracted with EtOAc (3x 100 mL), the organic phase washed with 10% aq. brine (50mL), dried (Na2S04), filtered and evaporated under reduced pressure to afford the sub-title compound (69 mg, 80% purity) as pink solid.
LCMS m/z 314 (M+2H)2+ (ES+)
(iii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3- morpholinopropyDbenzamide
In a 20 mL vial, a solution of the product from step (ii) above (68 mg, 0.108 mmol) in DCM (1 mL) was treated dropwise with TFA (334 μί, 4.33 mmol). The resultant brown solution was stirred at rt for 3 h. The solution was diluted with toluene (200 mL) and concentrated in vacuo to afford a brown solid which was dissolved in EtOAc (100 mL). The EtOAc phase was washed with saturated NaHC03 solution (3 x 20 mL), water (3 x 20 mL) and brine (1 x 20 mL). The solvent was evaporated off in vacuo to afford the sub-title compound (47 mg) as a brown foam.
H NMR (400 MHz, DMSO-d6) δ 8.97 (s, 1 H), 8.30 (t, 1 H), 8.20 - 8.10 (m, 1 H), 8.05 (d, 1 H), 7.68 - 7.58 (m, 1 H), 7.53 (t, 1 H), 7.47 (t, 1 H), 7.46 - 7.41 (m, 2H), 7.09 (d, 1 H), 6.83 (dd, 1 H), 6.70 (d, 1 H), 6.51 (dd, 1 H), 6.05 (d, 1 H), 5.81 (s, 2H), 3.72 (s, 3H), 3.55 (t, 4H), 3.24 (m, 2H), 2.40 - 2.19 (m, 6H), 1.65 (m, 2H)
LCMS m/z 528 (M+H)+ (ES+)
(iv) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide
In a 20 mL vial, a solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)- phenyl)carbamate (see Example 1 (vi) above; 35.9 mg, 0.091 mmol), the product from step (iii) above (42 mg, 0.080 mmol) in isopropyl acetate (1.5 mL) was treated with triethylamine (4.6 μί, 0.033 mmol). The resultant brown solution was heated at 50 °C for 17 h then evaporated to dryness in vacuo. The crude product was purified by chromatography on silica gel (12 g column, 1-10% MeOH in 1 % MeOH in DCM) to give crude material that was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (9 mg) as a clear white solid.
H NMR (400 MHz, DMSO-d6) δ 9.37 (s, 1 H), 9.13 (s, 1 H), 9.04 (s, 1 H), 8.90 (s, 1 H), 8.36 - 8.24 (m, 2H), 8.18 (d, 1 H), 8.11 (s, 1 H), 8.09 (d, 1 H), 7.92 - 7.81 (m, 1 H), 7.76 - 7.66 (m, 1 H), 7.65 - 7.57 (m, 1 H), 7.55 (t, 1 H), 7.49 (t, 1 H), 7.38 (d, 1 H), 7.02 (d, 1 H), 6.85 (dd, 1 H), 6.57 (dd, 1 H), 6.13 (d, 1 H), 3.80 (s, 3H), 3.74 (s, 3H), 3.60 - 3.49 (m, 4H), 3.28 - 3.21 (m, 2H), 3.09 (s, 3H), 2.32 (d, 6H), 1.72 - 1.58 (m, 2H), 1.26 (s, 9H)
LCMS m/z 826 (M+H)+ (ES+); 824 (M-H)" (ES") Example 67
(S)-3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(1-(2-(2-methoxyethoxy)ethoxy)-propan-2- vDbenzamide
Figure imgf000133_0001
(i) (S)-N,N-Dibenzyl-1-(2-(2-methoxyethoxy)ethoxy)propan-2-amine
NaH (0.188 g, 4.70 mmol) was added to a stirred solution of (S)-2-(dibenzylamino)propan-1- ol (1 g, 3.92 mmol) in DMF (10ml_) at 0-5°C. The mixture was stirred for 20min then 1- bromo-2-(2-methoxyethoxy)ethane (0.860 g, 4.70 mmol) in DMF (2ml_) was added and the mixture warmed to rt. Tetrabutylammonium iodide (0.579 g, 1.566 mmol) was added and stirred for 4h. A further portion of NaH (0.188 g, 4.70 mmol) then 1-bromo-2-(2- methoxyethoxy)ethane (0.5 g) was added and stirred for 18h. The mixture was quenched with water (20ml_) and extracted with EtOAc (80ml_). The organic layer was washed with brine (20ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-20%EtOAc/isohexane) to afford the sub-title compound (695 mg) as an oil.
H NMR (CDCIs) 400 MHz, δ: 7.38 (d, 4H), 7.29-7.25 (m, 4H), 7.21-7.17 (m, 2H), 3.72 (d, 2H), 3.65-3.61 (m, 5H), 3.58 (d, 2H), 3.55-3.52 (m, 4H), 3.40 (dd, 1 H), 3.37 (s, 3H), 3.06-2.98 (m, 1 H), 1.07 (d, 3H).
LCMS m/z 358 (M+H)+ (ES+)
(ii) (S)-1-(2-(2-Methoxyethoxy)ethoxy)propan-2-amine
A mixture of the product from step (i) above (685 mg, 1.916 mmol) and 10% Pd/C (120 mg, JM type 39) in EtOH (15ml_) was hydrogenated under a balloon of hydrogen for 20h. The mixture was filtered through Celite, washing with EtOH (50ml_). The filtrate was evaporated and the crude product was 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 (305 mg) as a colourless oil.
H NMR (CDCI3) 400 MHz, δ: 3.68-3.54 (m, 8H), 3.43-3.40 (m, 1 H), 3.39 (s, 3H), 3.19-3.10 (m, 2H), 1.72 (s, 2H, under water), 1.03 (d, 3H).
(iii) (S)-tert-Butyl (4-((2-((3-ethvnyl-5-((1-(2-(2-methoxyethoxy)ethoxy)propan-2- yl)carbamoyl)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate HATU (422 mg, 1.110 mmol) was added to a stirred solution of 3-((4-((4-((tert-butoxy- carbonyl)amino)naphthalen-1-yl)oxy)pyridin-2-yl)arnino)-5-ethynylbenzoic acid (see Example 52(iii) above; 500 mg, 1.009 mmol), the product from step (ii) above (268 mg, 1.514 mmol) and Hunig's Base (530 μΙ_, 3.03 mmol) in DMF (10ml_) at rt. The mixture was stirred for 5h then partitioned between EtOAc (150ml_) and water (100ml_). The organic layer was washed with sat aq NaHC03 soln (100ml_), water (100ml_), dried (MgS04), filtered and evaporated under reduced pressure. The crude product was purified by chromatography on silica gel (40 g column, 0-100% EtOAc/isohexane) to afford the sub-title compound (536 mg) as a foam.
LCMS m/z 655 (M+H)+ (ES+)
(iv) (S)-3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(1-(2-(2- methoxyethoxy)ethoxy)propan-2-yl)benzamide
TFA (625 μΙ_, 8.11 mmol) was added to a stirred solution of the product from step (iii) above (531 mg, 0.811 mmol) in DCM (5 mL) and stirred at rt for 18 h. The mixture was concentrated under reduced pressure, the residue was redissolved in ethyl acetate (50 mL) and washed with saturated NaHC03 solution (50 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure to the sub-title compound (455 mg) as a brown foam. LCMS m/z 555 (M+H)+ (ES+); 599 (M+HC02)- (ES")
(v) (S)-3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen -1-yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(1-(2-(2-methoxyethoxy)ethoxy)-propan-2-yl) benzamide
A stirred solution of the product from step (iv) above (160 mg, 0.288 mmol), phenyl (5-(tert- butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 130 mg, 0.331 mmol) and Et3N (20 μί, 0.143 mmol) in isopropyl acetate (5 mL) was heated to 50°C (block temp) over a weekend. The mixture was concentrated under reduced pressure, the residue was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 20-95% MeCN in Water). Fractions were concentrated to remove acetonitrile, basifed with NaHC03 (150 mL) and extracted with ethyl acetate (100 mL). The organic phase was washed with saturated brine (100 mL), dried (MgS04) and concentrated under reduced pressure to afford a pink foam. The foam was triturated in diethyl ether (20 mL) to afford the title compound (107 mg) as a pink solid.
H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1 H), 9.21 (s, 1 H), 9.14 (br s, 1 H), 8.91 (s, 1 H), 8.30 (d, 1 H), 8.24-8.08 (m, 5H), 7.91-7.84 (m, 2H), 7.77-7.65 (ddd, 1 H), 7.65-7.57 (ddd, 1 H), 7.43 (dd, 1 H), 7.40 (d, 1 H), 7.02 (d, 1 H), 6.62 (dd, 1 H), 6.13 (d, 1 H), 4.19 (s, 1 H), 4.14 (ddq, 1 H), 3.81 (s, 3H), 3.57-3.33 (m, 10H), 3.20 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H), 1.11 (d, 3H).
LCMS m/z 853 (M+H)+ (ES+); 851 (M-H)" (ES") Example 68
(R)-3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(1-(2-(2-methoxyethoxy)ethoxy)-propan-2- vDbenzamide
Figure imgf000135_0001
The title compound was prepared using the method of Example 67 above to afford the product (1 12 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1 H), 9.21 (s, 1 H), 9.14 (br s, 1 H), 8.91 (s, 1 H), 8.30 (d, 1 H), 8.24-8.08 (m, 5H), 7.91-7.84 (m, 2H), 7.77-7.65 (ddd, 1 H), 7.65-7.57 (ddd, 1 H), 7.43 (dd, 1 H), 7.40 (d, 1 H), 7.02 (d, 1 H), 6.62 (dd, 1 H), 6.13 (d, 1 H), 4.19 (s, 1 H), 4.14 (ddq, 1 H), 3.81 (s, 3H), 3.57-3.33 (m, 10H), 3.20 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H), 1.11 (d, 3H).
LCMS m/z 853 (M+H)+ (ES+); 851 (M-H)" (ES")
Example 69
N-(5-(tert-butyl)-2-ethoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methane-sulfonamide
Figure imgf000135_0002
TEA (10 μΙ_, 0.072 mmol) was added to a solution of phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 170 mg, 0.265 mmol) and N-(3-amino-5-(tert-butyl)-2- ethoxyphenyl)methanesulfonamide (see, for example, Wagner, H. et al., WO 2010/026095, 1 1 Mar 2010; 80 mg, 0.279 mmol) in THF (3m L) and the reaction heated at 60°C (block temperature) for 16h. The solvent was evaporated and the crude product was purified by chromatography on silica gel (40 g column, 50% EtOAc:isohexane to 100%) to afford the title compound (183 mg) as a colourless glass.
H NMR (400 MHz, DMSO-d6) δ 9.43 (s, 1 H), 9.37 (s, 1 H), 9.03 (s, 1 H), 8.73 (s, 1 H), 8.41 (d, 1 H), 8.26 (d, 1 H), 8.12 (d, 1 H), 8.07 (d, 1 H), 7.85 (d, 1 H), 7.73 - 7.63 (m, 1 H), 7.63 - 7.52 (m, 1 H), 7.42 (d, 1 H), 7.02 (d, 1 H), 6.91 - 6.72 (m, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 4.02 (q, 2H), 3.93 - 3.78 (m, 2H), 3.73 - 3.59 (m, 2H), 3.59 - 3.45 (m, 9H), 3.45 - 3.37 (m, 2H), 3.21 (s, 3H), 3.10 (s, 3H), 1.43 (t, 3H), 1.27 (s, 9H)
LCMS m/z 833 (M+H)+ (ES+); 831 (M-H)" (ES") Example 70
1-(5-(tert-Butyl)-2-methoxy-3-(1 H-1 ,2,3-triazol-5-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Figure imgf000135_0003
(i) ((5-(tert-Butyl)-2-methoxy-3-nitrophenyl)ethvnyl)trimethylsilane
To a stirred solution of 1-bromo-5-(tert-butyl)-2-methoxy-3-nitrobenzene (500 mg, 1.735 mmol) and triethylamine (1200 μΙ_, 8.61 mmol) in dioxane (7 mL) was added ethynyltrimethylsilane (720 μΙ_, 5.21 mmol), PdCI2(PPh3)2 (180 mg, 0.256 mmol) and copper(l) iodide (100 mg, 0.525 mmol). The reaction was heated to 60°C (block temp) overnight. The reaction was cooled to rt and diluted with Et20 (20ml_). The mixture was filtered through Celite and the filtrate washed with 0.1 M HCI (20 mL) then NaHC03 solution (2 x 20 mL) and brine. The organic phase was dried (MgS04), filtered and concentrated in vacuo giving a brown semi-solid. The crude product was purified by chromatography on the Companion (40 g column, 20% DCM in hexane) to afford the sub-title compound (466 mg) as a yellow oil.
H NMR (400MHz; CDCI3) δ: 7.70 (d, 1 H), 7.63 (d, 1 H), 4.07 (s, 3H), 1.32 (s, 9H), 0.29 (s, 9H).
(ii) 5-(tert-Butyl)-1-ethvnyl-2-methoxy-3-nitrobenzene
A mixture of the product from step (i) above (400 mg, 1.310 mmol) and potassium carbonate (800 mg, 5.79 mmol) in MeOH (15mL) and water (6mL) was stirred at rt for 30 minutes. The mixture was diluted with EtOAc (100mL) and water (100mL). The aqueous phase was extracted with further EtOAc (2 x 50mL). Brine (20mL) was added to the aqueous phase and one further extraction in EtOAc (50 mL) performed. The combined organic phase was dried (MgS04), filtered and concentrated in vacuo affording a dark yellow/orange oil. The crude product was purified by chromatography on the Companion (12 g column, 0-10% EtOAc in hexane) to afford the sub-title compound (290 mg) as a pale yellow oil.
H NMR (CDCIs) 400 MHz, δ: 7.75 (d, 1 H), 7.68 (d, 1 H), 4.08 (s, 3H), 3.39 (s, 1 H), 1.33 (s, 9H).
LCMS m/z 234 (M+H)+ (ES+)
(iii) 5-(5-(tert-Butyl)-2-methoxy-3-nitrophenyl)-1 H-1.2.3-triazole
To a stirred solution of the product from step (ii) above (290 mg, 1.243 mmol) in a 9:1 solution of DMF/MeOH (3 mL) was added copper(l) iodide (12 mg, 0.063 mmol) and azidotrimethylsilane (250 μί, 1.884 mmol). The reaction was heated to 100°C and stirred for 7h. The reaction was cooled to rt and diluted with EtOAc (50 mL). The organic phase was washed with water (50 mL) and brine (2 x 30 mL), then dried (MgS04), filtered and concentrated in vacuo. The crude product was purified by chromatography on the Companion (12 g column, 10-30% EtOAc in hexane) to afford the sub-title compound (156 mg) as a pale yellow oil.
H NMR (DMSO-d6) 400 MHz, δ: 8.34 (s, 1 H), 8.26 (s, 1 H), 7.89 (d, 1 H), 3.72 (s, 3H), 1.34 (s, 9H).
LCMS m/z 277 (M+H)+ (ES+); 275 (M-H)" (ES")
(iv) 5-(tert-Butyl)-2-methoxy-3-(1 H-1.2.3-triazol-5-yl)aniline
The product from step (iii) above (156 mg, 0.565 mmol) was dissolved in ethanol (5 mL) and Fe powder (315 mg, 5.65 mmol) was added followed by a solution of NH4CI (300 mg, 5.61 mmol) in water (2 ml_). The resulting suspension was heated at 80 °C for 2 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo then partitioned between water (50 ml_) and EtOAc (50 ml_). The aqueous phase was extracted with EtOAc (25 ml_). The combined organic extracts were washed with brine (30 ml_), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on silica gel (12 g column, 1-10% MeOH in DCM) to afford the sub-title compound (8 mg) as a colourless oil.
LCMS m/z 247 (M+H)+ (ES+) (v) 1-(5-(tert-Butyl)-2-methoxy-3-(1 H-1.2.3-triazol-5-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2- (2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea
Triethylamine (1 μΙ_, 7.17 μηιοΙ) was added to a mixture of the product from step (iv) above (8 mg, 0.032 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 21 mg, 0.033 mmol) in isopropyl acetate (1.5 ml_) and the mixture heated at 60°C (block temperature) for 5h during which time reaction became turbid. Reaction left standing for 6 days during which time a suspension formed. The solid was collected by filtration, washing with further iPrOAc to afford the title compound (21 mg) as a pale pink solid.
H NMR (400 MHz, DMSO-d6) δ: 15.05-15.42 (bm, 1 H), 9.43 (s, 2H), 8.98 (bs, 1 H), 8.42 (d, 1 H), 8.30 (d, 1 H), 8.19-8.40 (bm, 2H), 8.11 (d, 1 H), 7.86 (d, 1 H), 7.69 (t, 1 H), 7.60 (t, 1 H), 7.44-7.84 (bm, 1 H), 7.43 (d, 1 H), 6.82 (d, 2H), 6.56 (d, 1 H), 6.04 (t, 1 H), 3.86-3.88 (m, 2H), 3.71 (s, 3H), 3.65-3.67 (m, 2H), 3.47-3.56 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.21 (s, 3H), 1.33 (s, 9H).
LCMS m/z 793 (M+H)2+ (ES+), 397 (M+2H)2+ (ES+)
Example 71
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-1 , 1 , 1-trifluoro- methanesulfonamide
Figure imgf000137_0001
(i) N-(5-(tert-Butyl)-2-methoxy-3-nitrophenyl)-1 ,1 , 1-trifluoromethanesulfonamide
To a stirred solution of 5-(tert-butyl)-2-methoxy-3-nitroaniline (100 mg, 0.441 mmol) in chloroform (2.5 ml_) at 0-5 °C, was added triethylamine (80 μΙ_, 0.574 mmol) then trifluoromethanesulfonic anhydride (75 μΙ_, 0.444 mmol). The mixture was heated at reflux for 2h. The reaction mixture was quenched with sat. aq. NaHC03 solution (10 ml_) and the layers separated. The aqueous layer was back-extracted with DCM (2 x 10 ml_). The combined organic extracts were dried (MgS04), filtered and concentrated in vacuo to afford a brown oil. The crude product was purified by chromatography on silica gel (12 g column, 1- 10% MeOH in DCM) to afford a dark yellow oil (70mg).
LCMS m/z 355 (M-H)" (ES") (ii) N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)-1 , 1 , 1-trifluoromethanesulfonamide
The product from step (i) above (70 mg, 0.196 mmol) was dissolved in ethanol (3 mL) and Fe powder (1 10 mg, 1.965 mmol) was added followed by a solution of NH4CI (105 mg, 1.965 mmol) in water (1 mL). The resulting suspension was heated at 80 °C for 2 h. The reaction was cooled to rt and filtered. The filtrate was concentrated in vacuo then partitioned between water (10 mL) and EtOAc (10 mL). The aqueous phase was extracted with EtOAc (10 mL). The combined organic extracts were washed with brine (15 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on silica gel (12 g column, 1-5% MeOH in DCM) to afford the sub-title compound (55 mg) as a white solid.
LCMS m/z 327 (M+H)+ (ES+); 325 (M-H)" (ES")
(iii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-1 , 1 , 1- trifluoromethanesulfonamide
Triethylamine (5 μί, 0.036 mmol) was added to a mixture of the product from step (ii) above (55 mg, 0.169 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 108 mg, 0.169 mmol) in isopropyl acetate (3 mL) and the mixture heated at 60°C (block temperature) for 5h. The reaction was cooled to rt and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (112 mg) as a pale pink solid. H NMR (400 MHz, DMSO-d6) δ: 11.51 (bs, 1 H), 9.43 (s, 1 H), 9.35 (s, 1 H), 9.00 (s, 1 H), 8.42 (d, 1 H), 8.36 (s, 1 H), 8.28 (d, 1 H), 8.11 (d, 1 H), 7.85 (d, 1 H), 7.68 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 6.91 (d, 1 H), 6.81 (d, 2H), 6.55 (d, 1 H), 6.04 (t, 1 H), 3.85-3.88 (m, 2H), 3.88 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 1.27 (s, 9H). LCMS m/z 873 (M+H)+ (ES+)
Example 72
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)cyclohexane- sulfonamide
Figure imgf000138_0001
(i) N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)cyclohexanesulfonamide To a stirred solution of 5-(tert-butyl)-2-methoxybenzene-1 ,3-diamine (100 mg, 0.515 mmol) in DCM (3 ml_) at 0-5 °C, was added pyridine (290 μΙ_, 3.59 mmol) then cyclohexanesulfonyl chloride (90 μΙ_, 0.618 mmol). The mixture was warmed to rt and stirred for 7 days. The reaction was concentrated in vacuo and the residue azeotroped with toluene (2 x 10 ml_). The residue was dissolved in a mixture of DCM and MeOH and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 5-40% EtOAc in hexane) to afford the sub-title compound (69 mg, 90% purity) as a sticky pink gum.
H NMR (400 MHz, DMSO-d6) δ: 8.61 (s, 1 H), 6.58 (d, 1 H), 6.56 (d, 1 H), 4.88 (s, 2H), 3.63 (s, 3H), 2.96-3.01 (m, 1 H), 2.09-2.12 (m, 2H), 1.78-1.81 (m, 2H), 1.60-1.63 (m, 1 H), 1.29- 1.37 (m, 2H), 1.13-1.29 (m, 3H), 1.19 (s, 9H).
(ii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)- cvclohexanesulfonamide
Triethylamine (5 μΙ_, 0.036 mmol) was added to a mixture of the product from step (i) above (69 mg, 0.182 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 120 mg, 0.187 mmol) in isopropyl acetate (3 ml_) and the mixture heated at 60°C (block temperature) for 4h. The reaction was cooled to rt and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-4% MeOH in DCM) to afford the product as a pale pink solid. The material was solubilised in DCM (10 ml_) and washed with 1 M HCI solution (10 ml_). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo affording the title compound (88 mg) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 9.50 (s, 1 H), 9.40 (s, 1 H), 9.04 (s, 1 H), 8.95 (s, 1 H), 8.42 (d, 1 H), 8.30 (d, 1 H), 8.16 (s, 1 H), 8.11 (d, 1 H), 7.85 (d, 1 H), 7.67 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.02 (d, 1 H), 6.80 (d, 2H), 6.57 (d, 1 H), 6.05 (t, 1 H), 3.86-3.88 (m, 2H), 3.81 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 3.02-3.08 (m, 1 H), 2.17 (bd, 2H), 1.84 (bd, 2H), 1.65 (bd, 1 H), 1.42-1.51 (m, 2H), 1.16-1.32 (m, 3H), 1.26 (s, 9H).
LCMS m/z 887 (M+H)+ (ES+)
Example 73
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)piperidine-1- sulfonamide
Figure imgf000139_0001
(i) N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)piperidine-1 -sulfonamide
To a stirred solution of 5-(tert-butyl)-2-methoxybenzene-1 ,3-diamine (150 mg, 0.772 mmol) in DCM (4 ml_) at 0-5 °C, was added pyridine (440 μΙ_, 5.44 mmol) then piperidine-1-sulfonyl chloride (108 μΙ_, 0.772 mmol). The mixture was warmed to rt and stirred for 6 days. The reaction was concentrated in vacuo and the residue azeotroped with toluene (2 x 10 ml_). The residue was dissolved in a mixture of DCM and MeOH and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 1-2% MeOH in DCM, detecting at 225 nm) to afford a yellow solid. The material was re-purified by chromatography on the Companion (12 g column, 1-5% THF in DCM, detecting at 225 nm) to afford the sub-title compound (135 mg) as a pale yellow solid.
LCMS m/z 342 (M+H)+ (ES+); 340 (M-H)" (ES")
(ii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)piperidine-1- sulfonamide
Triethylamine (5 μΙ_, 0.036 mmol) was added to a mixture of the product from step (i) above (60 mg, 0.176 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 1 15 mg, 0.179 mmol) in isopropyl acetate (3 ml_) and the mixture heated at 60°C (block temperature) overnight. The reaction was cooled to rt and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-4% MeOH in DCM) to afford a solid. The material was solubilised in DCM (10 ml_) and washed with 1 M HCI solution (10 ml_). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo affording the title compound (121 mg) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 9.55 (s, 1 H), 9.44 (s, 1 H), 9.13 (s, 1 H), 8.95 (s, 1 H), 8.42 (d, 1 H), 8.31 (d, 1 H), 8.1 1 (s, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.67 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.1 1 (d, 1 H), 6.79 (d, 2H), 6.58 (d, 1 H), 6.06 (t, 1 H), 3.86-3.88 (m, 2H), 3.80 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 3.16-3.17 (m, 4H), 1.45-1.57 (m, 6H), 1.26 (s, 9H).
LCMS m/z 888 (M+H)+ (ES+); 886 (M-H)" (ES")
Example 74
N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)dimethylamino- sulfonamide
Figure imgf000140_0001
(i) N-(3-Amino-5-(tert-butyl)-2-methoxyphenyl)dimethylamino-sulfonamide To a stirred solution of 5-(tert-butyl)-2-methoxybenzene-1 ,3-diamine (200 mg, 1.029 mmol) in DCM (4 ml_) at 0-5 °C, was added pyridine (580 μΙ_, 7.17 mmol) then dimethylsulfamoyl chloride (1 10 μΙ_, 1.024 mmol). The mixture was warmed to rt and stirred overnight. The reaction was concentrated in vacuo and the residue azeotroped with toluene (2 x 10 ml_). The residue was dissolved in a mixture of DCM and MeOH and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 1-2% MeOH in DCM, detecting at 225 nm) to afford a yellow solid. The material was re-purified by chromatography on the Companion (12 g column, 1-5% THF in DCM, detecting at 225 nm) to afford the sub-title compound (164 mg) as a pale yellow solid.
LCMS m/z 302 (M+H)+ (ES+); 300 (M-H)" (ES")
(ii) N-(5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-dimethylamino- sulfonamide
Triethylamine (5 μΙ_, 0.036 mmol) was added to a mixture of the product from step (i) above (55 mg, 0.182 mmol) and phenyl (4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 19(i) above; 117 mg, 0.182 mmol) in isopropyl acetate (3 ml_) and the mixture heated at 60°C (block temperature) overnight. The reaction was cooled to rt and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-4% MeOH in DCM) to a colourless solid. The material was solubilised in DCM (10 ml_) and washed with 1 M HCI solution (10 ml_). The organic phase was filtered through a hydrophobic frit and concentrated in vacuo affording the title compound (104 mg) as a pale yellow solid.
H NMR (400 MHz, DMSO-d6) δ: 9.58 (s, 1 H), 9.46 (s, 1 H), 9.10 (s, 1 H), 8.96 (s, 1 H), 8.42 (d, 1 H), 8.32 (d, 1 H), 8.13 (d, 1 H), 8.10 (d, 1 H), 7.85 (d, 1 H), 7.67 (t, 1 H), 7.59 (t, 1 H), 7.42 (d, 1 H), 7.08 (d, 1 H), 6.78 (d, 2H), 6.59 (d, 1 H), 6.06 (t, 1 H), 3.86-3.88 (m, 2H), 3.82 (s, 3H), 3.65-3.67 (m, 2H), 3.48-3.55 (m, 6H), 3.52 (s, 3H), 3.41 (dd, 2H), 3.22 (s, 3H), 2.78 (s, 6H), 1.26 (s, 9H).
LCMS m/z 848 (M+H)+ (ES+); 846 (M-H)" (ES")
Example 75
5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide
Figure imgf000141_0001
(i) tert-Butyl (4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
Nitrogen was bubbled through a mixture of aniline (1.1 g, 11.81 mmol), tert-butyl (4-((2- chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 4 g, 10.79 mmol), 2,2'-bis(diphenylphosphino)-1 , 1 '-binaphthalene (0.441 g, 0.709 mmol), Pd2dba3 (0.324 g, 0.354 mmol) and caesium carbonate (6.16 g, 18.90 mmol) in dioxane (50 ml_) for 5 min then the mixture heated at 100°C for 3h. The mixture was diluted with EtOAc (200 mL), filtered and the solvent evaporated under reduced pressure. Ether (20 mL) was added and the white solid filtered off, washed with ether (5 mL) and dried to afford the product (3.33 g) as a white solid. The filtrate was purified by chromatography on silica gel (220g column, 0- 50%EtOAc/isohexane) to give a solid that was triturated with ether, filtered and dried to afford additional product (608 mg) as a white solid. Materials were combined to afford the sub-title compound (3.938 g) as a white solid.
H NMR (400 MHz, CDCI3) δ: 8.02 (d, 1 H), 7.97 (dd, 2H), 7.87 (brd, 1 H), 7.63-7.51 (m, 2H), 7.21 (d, 1 H), 7.07-7.02 (m, 1 H), 6.86 (brs, 2H), 6.41 (d, 1 H), 6.34 (dd, 1 H), 1.59 (s, 9H). Peaks under CHCIs
LCMS m/z 428 (M+H)+ (ES+); 426 (M-H)" (ES")
(ii) 4-((4-Aminonaphthalen-1-yl)oxy)-N-phenylpyridin-2-amine
TFA (10 mL, 130 mmol) was added to a solution of the product from step (i) above (3.9 g, 9.12 mmol) in DCM (50 mL) and stirred at rt for 1 h. The volatiles were removed under reduced pressure and the residue was redissolved in DCM (75 mL). The solution was washed with saturated NaHC03 solution (50 mL) followed by saturated brine (50 mL) and dried (MgS04). The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure to yield a pale pink solid. The solid was recrystallised in iPrOAc (60 mL) to yield the sub-title compound (1.1 g) as a white solid. The filtrate was concentrated under reduced pressure and redissolved in refluxing iPrOAc (60 mL). Isohexane (60 mL) was added and the mixture was allowed to cool whilst stirring. The 2nd crop was collected by filtration to yield the sub-title compound (1.2 g) as a pale pink solid. Combined yield of 2.3g. H NMR (400 MHz, DMSO-d6) δ: 8.82 (s, 1 H), 8.20-8.1 1 (m, 1 H), 8.02 (d, 1 H), 7.69-7.61 (m, 1 H), 7.61-7.54 (m, 2H), 7.49-7.40 (m, 2H), 7.22-7.14 (m, 2H), 7.10 (d, 1 H), 6.82 (ddd, 1 H), 6.71 (d, 1 H), 6.49 (dd, 1 H), 6.02 (d, 1 H), 5.81 (br s, 2H).
LCMS m/z 328 (M+H)+ (ES+)
(iii) Methyl 5-(tert-butyl)-2-methoxy-3-((phenoxycarbonyl)amino)benzoate
Phenyl chloroformate (264 μί, 2.107 mmol) was added to a stirred mixture of methyl 3- amino-5-(tert-butyl)-2-methoxybenzoate (500 mg, 2.107 mmol) and NaHC03 (354 mg, 4.21 mmol) in DCM (20 mL) and THF (5 mL) at rt. The mixture was stirred overnight then partitioned between DCM (20 mL) and water (20 mL). The organic layer was separated and dried via a hydrophobic frit, affording the sub-title compound (812 mg) as a pale yellow oil which solidified on standing.
LCMS m/z 358 (M+H)+ (ES+)
(iv) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)-naphthalen-1- yl)ureido)benzoate
Triethylamine (48 μί, 0.344 mmol) was added to a mixture of the product from step (iii) above (610 mg, 1.707 mmol) and the product from step (ii) above (560 mg, 1.711 mmol) in iPrOAc (20 mL) and the mixture heated at 70°C (block temperature) overnight. The reaction mixture was diluted with THF and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 0.5-3% MeOH in DCM) to afford the sub-title compound (688 mg) as a light brown foam.
LCMS m/z 591 (M+H)+ (ES+); 589 (M-H)" (ES")
(v) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1-yl)- ureido)benzoic acid, HCI
To a stirred solution of the product from step (iv) above (688 mg, 1.165 mmol) in THF (25 mL) and water (5 mL) was added NaOH (2M aq.) (3500 μί, 7.00 mmol). MeOH (2 mL) was added and stirring continued for 48h. Additional NaOH was added (1 mL) and stirring continued over a weekend. The reaction was concentrated in vacuo affording a brown gum. The material was suspended in water and acidified with 1 M HCI causing a solid to precipitate. The solid was collected by filtration, washing with water and the solid dried at 40 °C under vacuum affording the sub-title compound (590 mg) as a pink solid.
LCMS m/z 577 (M+H)+ (ES+); 575 (M-H)" (ES") (vi) 5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide
A stirred mixture of the product from step (v) above (80 mg, 0.130 mmol), oxetan-3-amine (13.63 μί, 0.196 mmol) and Et3N (54.6 μί, 0.391 mmol) in DCM (4 mL) was cooled in an ice- bath. T3P (50 wt% in EtOAc) (78 μί, 0.130 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred overnight. Further portions of amine (10 μί), Et3N (25 μί) and T3P (20 μί) were added and stirring continued overnight. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-4% MeOH in DCM) to afford the title compound (63 mg) as a pink/brown solid. H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1 H), 8.98 (d, 1 H), 8.90 (s, 2H), 8.47 (d, 1 H), 8.30 (d, 1 H), 8.09 (d, 2H), 7.89 (d, 1 H), 7.72 (t, 1 H), 7.58-7.64 (m, 3H), 7.39 (d, 1 H), 7.20 (t, 2H), 7.08 (d, 1 H), 6.84 (t, 1 H), 6.55 (dd, 1 H), 6.1 1 (d, 1 H), 4.99-5.08 (m, 1 H), 4.81 (t, 2H), 4.60 (t, 2H), 3.82 (s, 3H), 1.29 (s, 9H).
LCMS m/z 632 (M+H)+ (ES+); 630 (M-H)- (ES")
Example 76
5-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide
Figure imgf000143_0001
(i) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoate Triethylamine (16.10 μΙ_, 0.1 15 mmol) was added to a mixture of methyl 5-(tert-butyl)-2- methoxy-3-((phenoxycarbonyl)amino)benzoate (see Example 75(iii) above; 206 mg, 0.577 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-(3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)pyridin-2-amine (see Example 11 (ii) above; 300 mg, 0.577 mmol) in iPrOAc (8 ml_) and the mixture heated at 70°C (block temperature) overnight. The reaction was cooled to rt and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (40 g column, 1-5% MeOH in DCM) to afford the sub-title compound (363 mg) as an off-white foam.
LCMS m/z 783 (M+H)+ (ES+)
(ii) 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid, HCI
To a stirred solution of the product from step (i) above (363 mg, 0.417 mmol) in THF (10 ml_) and water (2 ml_) was added NaOH (2M aq.) (1252 μΙ_, 2.504 mmol). MeOH (1 ml_) was added and stirring continued for 48h. The reaction was concentrated in vacuo affording a yellow/brown gum. The material was suspended in water and acidified with 1 M HCI causing a pale solid to precipitate. The solid was collected by filtration, washing with water and the solid dried at 40 °C under vacuum affording the sub-title compound (315 mg) as a pale pink solid.
LCMS m/z 769 (M+H)+ (ES+); 767 (M-H)" (ES")
(iii) 5-(tert-Butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide
A stirred mixture of the product from step (ii) above (100 mg, 0.124 mmol), N1 ,N1- dimethylethane-1 ,2-diamine (27 μΙ_, 0.247 mmol) and Et3N (69 μΙ_, 0.495 mmol) in DCM (4 ml_) was cooled in an ice-bath. T3P (50 wt% in EtOAc) (89 μΙ_, 0.149 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred over the weekend. The reaction mixture was partitioned between sat. aq. NaHC03 (10 ml_) and DCM (10 ml_). The aqueous phase was back extracted with fresh DCM (10 ml_). The combined organic extracts were washed with water (20 ml_), brine (20 ml_), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford a pale pink foam. The crude product was purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (44 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.47 (s, 1 H), 8.99 (s, 1 H), 8.89 (s, 1 H), 8.48 (d, 1 H), 8.35 (t, 1 H), 8.30 (d, 1 H), 8.10-8.12 (m, 2H), 7.87 (d, 1 H), 7.71 (t, 1 H), 7.61 (t, 1 H), 7.39 (d, 1 H), 7.28 (d, 1 H), 6.91 (s, 1 H), 6.78 (s, 1 H), 6.58 (dd, 1 H), 6.08 (d, 1 H), 6.04 (t, 1 H), 3.97-3.99 (m, 2H), 3.81 (s, 3H), 3.69-3.71 (m, 2H), 3.65 (s, 3H), 3.56-3.58 (m, 2H), 3.50-3.54 (m, 4H), 3.41- 3.45 (m, 4H), 3.22 (s, 3H), 2H under DMSO, 2.33 (bs, 6H), 1.29 (s, 9H).
LCMS m/z 839 (M+H)+ (ES+); 837 (M-H)- (ES") Example 77
5- ert-Butvn-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)benzamide
Figure imgf000145_0001
A stirred mixture of 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid, HCI (see Example 76(H) above; 137 mg, 0.170 mmol), oxetan-3-amine (24 μΙ_, 0.345 mmol) and triethylamine (100 μΙ_, 0.717 mmol) in DCM (5 ml_) was cooled in an ice-bath. 50 wt% T3P in EtOAc (150 μΙ_, 0.252 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred for 2h. The reaction mixture was partitioned between sat. aq. NaHC03 (10 ml_) and DCM (10 ml_). The aqueous phase was back extracted with fresh DCM (10 ml_). The combined organic extracts were washed with water (20 ml_), brine (20 ml_), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (117 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1 H), 8.98 (d, 1 H), 8.91 (s, 1 H), 8.88 (s, 1 H), 8.47 (d, 1 H), 8.30 (d, 1 H), 8.08-8.12 (m, 2H), 7.88 (d, 1 H), 7.72 (t, 1 H), 7.61 (t, 1 H), 7.39 (d, 1 H), 7.08 (d, 1 H), 6.91 (s, 1 H), 6.79 (s, 1 H), 6.58 (dd, 1 H), 6.10 (d, 1 H), 6.04 (t, 1 H), 4.99-5.08 (m, 1 H), 4.81 (t, 2H), 4.60 (t, 2H), 3.97-3.99 (m, 2H), 3.81 (s, 3H), 3.70-3.72 (m, 2H), 3.66 (s, 3H), 3.50-3.58 (m, 6H), 3.43 (dd, 2H), 3.23 (s, 3H), 1.29 (s, 9H).
LCMS m/z 824 (M+H)+ (ES+); 412 (M+2H)2+ (ES+)
Example 78
5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide
Figure imgf000145_0002
(i) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)naphthalen-1- yl)ureido)benzoate
Triethylamine (25 μΙ_, 0.179 mmol) was added to a mixture of methyl 5-(tert-butyl)-2- methoxy-3-((phenoxycarbonyl)amino)benzoate (see Example 75(iii) above; 320 mg, 0.895 mmol) and 4-((4-aminonaphthalen-1-yl)oxy)-N-phenylpyrimidin-2-amine (see, for example, Ito, K. et a/., WO 2013/050756, 294 mg, 0.895 mmol) in isopropyl acetate (10 ml_) and the mixture heated at 60°C (block temperature) overnight, during which time a solid precipitated from solution. The solid was collected by filtration, washing with additional iPrOAc afforded the sub-title compound (275 mg) as a white solid.
LCMS m/z 592 (M+H)+ (ES+) (ii) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyrim^
yl)ureido)benzoic acid
To a stirred solution of the product from step (i) above (275 mg, 0.465 mmol) in THF (10 mL) and water (2 mL) was added NaOH (2M aq.) (1000 μί, 2.000 mmol). MeOH (1 mL) was added and stirring continued overnight. Further portions of NaOH (0.5 mL), water (0.5 mL) and MeOH (0.5 mL) were added and stirring continued overnight. The reaction was concentrated in vacuo affording a pale pink solid. The material was suspended in water and acidified with 1 M HCI causing a solid to precipitate. The mixture was sonicated for 2 mins then the solid collected by filtration, washing with water. The solid was dried at 40°C under vacuum affording the sub-title compound (233 mg) as a yellow solid.
LCMS m/z 578 (M+H)+ (ES+); 576 (M-H)" (ES")
(iii) 5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)benzamide
A stirred mixture of the product from step (ii) above (60 mg, 0.104 mmol), oxetan-3-amine (11 μί, 0.158 mmol) and triethylamine (45 μί, 0.323 mmol) in DCM (4 mL) was cooled in an ice-bath. 50 wt% T3P in EtOAc (62 μί, 0.104 mmol) was added, the ice-bath was removed and the reaction mixture allowed to warm to rt and stirred over the weekend. The reaction mixture was partitioned between sat. aq. NaHC03 (10 mL) and DCM (10 mL). The aqueous phase was back extracted with fresh DCM (10 mL). The combined organic extracts were washed with water (20 mL), brine (20 mL), dried (MgS04), filtered and concentrated in vacuo onto silica gel. The crude product was purified by chromatography on the Companion (12 g column, 1-5% MeOH in DCM) to afford the title compound (41 mg) as a white solid.
H NMR (400 MHz, DMSO-d6) δ: 9.53 (s, 1 H), 9.49 (s, 1 H), 9.00 (d, 1 H), 8.90 (s, 1 H), 8.49 (d, 1 H), 8.41 (d, 1 H), 8.29 (d, 1 H), 8.06 (d, 1 H), 7.84 (d, 1 H), 7.69 (t, 1 H), 7.59 (t, 1 H), 7.43 (d, 1 H), 7.29 (bd, 2H), 7.07 (d, 1 H), 6.99 (t, 2H), 6.77 (t, 1 H), 6.60 (d, 1 H), 4.99-5.08 (m, 1 H), 4.81 (t, 2H), 4.60 (t, 2H), 3.82 (s, 3H), 1.29 (s, 9H).
LCMS m/z 633 (M+H)+ (ES+); 631 (M-H)" (ES") Example 79
3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide
Figure imgf000146_0001
(i) tert-Butyl (4-((2-((3-methoxy-5-((2-(4-methylpiperazin-1-yl)ethyl)carbamoyl)phenyl)amino) pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
In a 20 mL vial, a solution of 3-((4-((4-((tert-butoxycarbonyl)amino)naphthalen-1-yl)oxy)- pyridin-2-yl)amino)-5-methoxybenzoic acid (see Example 66(i) above; 250 mg, 0.476 mmol), 2-(4-methylpiperazin-1-yl)ethanamine (102 mg, 0.713 mmol) and Hunig's Base (249 μί, 1.427 mmol) in DMF (9 mL) was treated with HATU (199 mg, 0.523 mmol). The solution was then partitioned between 10% aq brine (150 mL) and EtOAc (150 mL). The organic layer was washed with sat aq NaHC03 soln (60 mL), 10% aq. brine (50 mL), dried (Na2S04), filtered and evaporated under reduced pressure to afford the sub-title compound (300 mg) as beige solid.
LCMS m/z 627 (M+H)+ (ES+); 625 (M-H)" (ES")
(ii) 3-((4-((4-Aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(4- methylpiperazin-1-yl)ethyl)benzamide
In a 20 mL vial, a solution of the product from step (i) above (300 mg, 0.479 mmol) in DCM (5 mL) was treated dropwise with TFA (1475 μί, 19.15 mmol). The resultant brown solution was stirred at RT for 3 h. The solution was diluted with toluene (400 mL) and concentrated in vacuo to afford a brown solid which was dissolved in EtOAc (300 mL). The EtOAc phase was washed with saturated NaHC03 solution (3 x 100 mL), water (3 x 100 mL) and brine (1 x 100 mL). The solvent was evaporated in vacuo to afford the sub-title compound (200 mg) as a brown foam.
LCMS m/z 527 (M+H)+ (ES+)
(iii) 3-((4-((4-(3-(5-(tert-Butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)-benzamide
In a 20 mL vial, a solution of phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)- phenyl)carbamate (see Example 1 (vi) above; 74.5 mg, 0.190 mmol), the product from step (ii) above (100 mg, 0.190 mmol) in isopropyl acetate was treated with TEA (5.29 μί, 0.038 mmol). The resultant brown suspension was heated at 60 °C for 18 h then evaporated to dryness in vacuo. The crude product was purified by preparative HPLC (Gilson, Acidic (0.1 % Formic acid), Acidic, Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 25-70% MeCN in Water). The residue was partitioned between 20 mL sat. NaHC03 and EtOAc (20 mL), organic phase was washed with brine (20 mL), dried over sodium sulfate and the solvent removed in vacuo to afford the title compound (48 mg) as an off-white solid.
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 9.16 (s, 1 H), 9.07 (s, 1 H), 8.93 (s, 1 H), 8.30 (d, 1 H), 8.22 (t, 1 H), 8.19 (d, 1 H), 8.13 (d, 1 H), 8.11 (s, 1 H), 7.90 - 7.84 (m, 1 H), 7.71 (m, 1 H), 7.61 (m, 1 H), 7.56 (t, 1 H), 7.50 (m, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.85 (m, 1 H), 6.58 (dd, 1 H), 6.13 (d, 1 H), 3.81 (s, 3H), 3.74 (s, 3H), 3.10 (s, 3H), 2.48 - 2.20 (m, 8H), 2.14 (s, 3H), 1.27 (s, 9H). (Four Protons overlapping the water peak)
LCMS m/z 825 (M+H)+ (ES+); 823 (M-H)" (ES") Example 80
5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-((pyridin-2-ylmethyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000147_0001
(i) tert-Butyl (4-((2-((pyridin-2-ylmethyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate
A mixture of tert-butyl (4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 1.0 g, 2.70 mmol), pyridin-2-ylmethanamine (0.350 g, 3.24 mmol), Pd2(dba)3 (0.150 g, 0.164 mmol), Cs2C03 (1.5 g, 4.60 mmol) and BINAP (0.200 g, 0.321 mmol) in 1 ,4- dioxane (15 mL) was purged with nitrogen for 10 minutes. The mixture was then heated to 90°C for 18 h then diluted with DCM (50 mL) and filtered. The filtrate was concentrated under reduced pressure and purified by chromatography on the Companion (80 g column, 50-100%EtOAc/isohexane) to afford the sub-title compound (390 mg) as an orange glass. LCMS m/z 443 (M+H)+ (ES+); 441 (M-H)" (ES")
(ii) 4-((4-Aminonaphthalen-1-yl)oxy)-N-(pyridin-2-ylmethyl)pyridin-2-amine
The product from step (i) above (390 mg, 0.749 mmol) and TFA (1.0 mL, 12.98 mmol) were stirred in DCM (5 mL) at rt for 1 h. The mixture was co-evaporated in toluene (40 mL) then redissolved in DCM (15 mL). The solution was washed with saturated NaHC03 solution (15 mL) then loaded directly onto the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound (235 mg) as a brown foam.
LCMS m/z 343 (M+H)+ (ES+); 341 (M-H)" (ES"). 90% purity
(iii) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((pyridin-2-ylmethyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzoate
Methyl 5-(tert-butyl)-2-methoxy-3-((phenoxycarbonyl)amino)benzoate (see Example 75(iii) above; 175 mg, 0.447 mmol), the product from step (ii) above (200 mg, 0.432 mmol) and Et3N (20 μί, 0.143 mmol) were heated to 70°C in isopropyl acetate (5 mL) for 18 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography on the Companion (40 g column, 0-5% MeOH/EtOAc) to afford the sub-title compound (200 mg) as a brown solid.
LCMS m/z 606 (M+H)+ (ES+)
(iv) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((pyridin-2-ylmethyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzoic acid
The product from step (iii) above (200mg, 0.330 mmol) and LiOH monohydrate (20 mg, 0.477 mmol) were stirred in water (1 mL), methanol (0.5 mL) and THF (1 mL) at rt for 18 h.
The mixture was diluted with water (10 mL) and washed with diethyl ether (10 mL). The aqueous layer was acidified with 1 M citric acid solution (1 mL) and extracted with ethyl acetate (10 mL). A solid formed in the separating funnel which was identified as product.
This was combined with the ethyl acetate layer and dissolved fully by adding methanol (10 mL). This combined solution was concentrated onto loose silica and the silicate was purified by chromatography on the Companion (12 g column, 0-20%MeOH(1 %NH3)/DCM) to afford the sub-title compound (130 mg) as a tan glass.
LCMS m/z 592 (M+H)+ (ES+); 590 (M-H)" (ES") (v) 5-(tert-Butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-((pyridin-2-ylmethyl)amino)-pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzamide
HATU (104 mg, 0.275 mmol) was added to a stirred solution of the product from step (iv) above (130 mg, 0.220 mmol), Et3N (50 μί, 0.359 mmol) and oxetan-3-amine (50 mg, 0.684 mmol) in DMF (3 mL). The mixture was stirred at rt over a weekend. The mixture was diluted with ethyl acetate (10 mL) then washed with water (10 mL), 20% brine (2 x 10 mL) and saturated brine (10 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure to yield a brown foam. The crude product was purified by chromatography on the Companion (12 g column, 0-5% MeOH/DCM) to afford the title compound (1 14 mg) as a beige solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.42 (s, 1 H), 8.96 (d, 1 H), 8.88 (s, 1 H), 8.45 (d, 1 H), 8.45- 8.42 (m, 1 H), 8.27 (d, 1 H), 8.04 (d, 1 H), 7.89-7.83 (m, 2H), 7.73-7.65 (m, 2H), 7.59 (ddd, 1 H), 7.30 (d, 1 H), 7.24 (d, 1 H), 7.20 (ddd, 1 H), 7.10 (dd, 1 H), 7.06 (d, 1 H), 6.24 (dd, 1 H), 5.93 (d, 1 H), 5.08-4.96 (m, 1 H), 4.80 (dd, 2H), 4.59 (dd, 2H), 4.49 (d, 2H), 3.80 (s, 3H), 1.28 (s, 9H).
LCMS m/z 647 (M+H)+ (ES+); 645 (M-H)" (ES")
Example 81
5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1- yl)ureido)-N-(oxetan-3-yl)benzamide
Figure imgf000149_0001
(i) tert-Butyl (4-((2-((3-methoxyphenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)carbamate Pd2(dba)3 (120 mg, 0.131 mmol) was added to a degassed suspension of tert-butyl (4-((2- chloropyridin-4-yl)oxy)naphthalen-1-yl)carbamate (see Example 3(H) above; 1 g, 2.70 mmol), 3-methoxyaniline (0.32 mL, 2.85 mmol), xantphos (150 mg, 0.259 mmol) and Cs2C03 (1.4 g, 4.30 mmol) in 1 ,4-dioxane (10 mL) and the reaction heated under nitrogen at 85°C for 4 h. The reaction mixture was diluted with DCM (100 mL) and filtered. The filtrate was washed with 1 M citric acid solution (100 mL), dried (MgS04) and the solvent evaporated. The crude product was purified by chromatography on silica gel (40 g column, 20-40% EtOAc/isohexane) to afford a pink foam. The foam was stirred in isopropyl acetate (20 mL) overnight and the solid removed by filtration. The filtrate was concentrated under reduced pressure to yield the sub-title compound (560 mg) as a pink gum.
LCMS m/z 458 (M+H)+ (ES+)
(ii) 4-((4-Aminonaphthalen-1-yl)oxy)-N-(3-methoxyphenyl)pyridin-2-amine
TFA (1.0 mL, 12.98 mmol) was added to a solution of the product from step (i) above (560 mg, 1.224 mmol) in DCM (3 mL) and the reaction left stirring overnight. The solvents were evaporated and the residue partitioned between sat NaHC03 soln. (10 mL) and DCM (10 mL). The organics were separated, dried (MgS04), filtered and the solvent evaporated to give a pink foam. The foam was purified by chromatography on the Companion (40 g column, 50-100% EtOAc/isohexane) to afford the sub-title compound (375 mg) as a purple solid.
H NMR (400 MHz, DMSO-d6) δ 8.90 (s, 1 H), 8.21 - 8.10 (m, 1 H), 8.03 (d, 1 H), 7.69 - 7.57 (m, 1 H), 7.52 - 7.39 (m, 2H), 7.35 - 7.28 (m, 1 H), 7.14 - 7.00 (m, 3H), 6.71 (d, 1 H), 6.53 (dd, 1 H), 6.43 (dt, 1 H), 6.02 (d, 1 H), 5.91 (s, 2H), 3.67 (s, 3H). LCMS m/z 358 (M+H)+ (ES+)
(iii) Methyl 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxyphenyl)arnino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzoate
Methyl 5-(tert-butyl)-2-methoxy-3-((phenoxycarbonyl)amino)benzoate (see Example 75(iii) above; 175 mg, 0.447 mmol), the product from step (ii) above (150 mg, 0.420 mmol) and Et3N (20 μΙ_, 0.143 mmol) were heated to 70°C in isopropyl acetate (5 mL) for 18 h. The volatiles were removed under reduced pressure and the residue was purified by chromatography on the Companion (40 g column, 20-80% EtOAc/isohexane) to afford the sub-title compound (130 mg) as a purple solid.
LCMS m/z 621 (M+H)+ (ES+), 85% purity
(iv) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxyphenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)benzoic acid
The product from step (iii) above (130 mg, 0.209 mmol) and LiOH monohydrate (12 mg, 0.286 mmol) were stirred in water (1 mL), methanol (0.5 mL) and THF (1 mL) at rt for 18 h. The mixture was diluted with water (10 mL) and washed with diethyl ether (10 mL). The aqueous layer was acidified with 1 M citric acid solution (1 mL) and extracted with ethyl acetate (10 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (12 g column, 0-20%MeOH(1 %NH3)/DCM) to afford the sub-title compound (90 mg) as a tan glass.
LCMS m/z 607 (M+H)+ (ES+); 605 (M-H)" (ES") (v) 5-(tert-Butyl)-2-methoxy-3-(3-(4-((2-((3-methoxyphenyl)amino)pyridin-4- yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)benzamide
HATU (70 mg, 0.184 mmol) was added to a stirred solution of the product from step (iv) above (90 mg, 0.148 mmol), Et3N (40 μί, 0.287 mmol) and oxetan-3-amine (30 mg, 0.410 mmol) in DMF (3 mL). The mixture was stirred at rt over a weekend. The mixture was diluted with ethyl acetate (10 mL) then washed with water (10 mL), 20% brine (2 x 10 mL) and saturated brine (10 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure to yield a brown foam. The crude product was purified by chromatography on the Companion (12 g column, 0-5% MeOH/DCM) to afford the title compound (74 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.46 (s, 1 H), 8.97 (d, 1 H), 8.93-8.87 (m. 2H), 8.46 (d, 1 H), 8.29 (d, 1 H), 8.10 (d, 1 H), 8.09 (d, 1 H), 7.88 (d, 1 H), 7.72 (ddd, 1 H), 7.62 (ddd, 1 H), 7.39 (d, 1 H), 7.36-7.31 (m, 1 H), 7.13-7.04 (m, 3H), 6.56 (dd, 1 H),6.47-6.39 (m, 1 H), 6.10 (d, 1 H), 5.09-4.97 (m, 1 H), 4.81 (dd, 2H), 4.60 (dd, 2H), 3.81 (s, 3H), 3.68 (s, 3H), 1.29 (s, 9H).
LCMS m/z 662 (M+H)+ (ES+); 660 (M-H)" (ES")
Example 82
5-(tert-Butyl)-3-(3-(2,3-difluoro-4-((2-(phenylamino)pyridin-4-yl)oxy)phenyl)ureido)-2- methoxy-N-(oxetan-3-yl)benzamide
Figure imgf000151_0001
(i) tert-Butyl (4-((2-chloropyridin-4-yl)oxy)-2,3-difluorophenyl)carbamate
4-((2-Chloropyridin-4-yl)oxy)-2,3-difluoroaniline (see, for example, Flynn, D. L, et al., WO 2013/036232, 4.33 g, 14.51 mmol) and di-tert-butyl dicarbonate (3.5 g, 16.04 mmol) were heated to reflux in tert-butanol (60 mL) for 18 h. Di-tert-butyl dicarbonate (3.5 g, 16.04 mmol) was added and the mixture was heated to reflux for a further 3 days. The mixture was diluted with ethyl acetate (300 mL) and washed with water (3 x 200 mL) followed by saturated brine (200 mL). The organic phase was dried (MgS04), filtered then concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (120 g column, 10-50% EtOAc/isohexane) then purified again on the Companion (80 g column, DCM) to afford the sub-title compound (3.1 1 g) as a yellow oil.
H NMR (400 MHz, CDCI3) δ 8.19 (d, 1 H), 7.89 (dd, 1 H), 6.88 (ddd, 1 H), 6.78-6.71 (m, 2H), 6.69-6.61 (m, 1 H), 1.48 (s, 9H).
LCMS m/z 357, 359 (M+H)+ (ES+)
(ii) tert-Butyl (2,3-difluoro-4-((2-(phenylamino)pyridin-4-yl)oxy)phenyl)carbamate
A mixture of BINAP (300 mg, 0.482 mmol), Pd2(dba)3 (210 mg, 0.229 mmol), the product from step (i) above (1.5 g, 4.20 mmol) and Cs2C03 (2.1 g, 6.45 mmol) in dioxane (25 mL) was degassed for 5min. Aniline (400 μί, 4.39 mmol) was added and the mixture heated at 70°C for 3 h then 85°C for 8 h. The mixture was diluted with DCM (150 mL) and filtered. The filtrate was concentrated under reduced pressure then purified by chromatography on the Companion (80 g column, 20-40% EtOAc/isohexane) to afford the sub-title compound (1.2 g) as an orange foam.
LCMS m/z 414 (M+H)+ (ES+); 412 (M-H)" (ES")
(iii) 4-(4-Amino-2,3-difluorophenoxy)-N-phenylpyridin-2-amine, 1.0TFA
TFA (4.0 ml, 51.9 mmol) was added to a solution of the product from step (ii) above (1.35 g, 3.27 mmol) in DCM (10 mL) and stirred at rt for 1 h. The mixture was concentrated under reduced pressure then co-evaporated with toluene (50 mL). The TFA salt was purified by chromatography on the Companion (40 g column, 30-70% EtOAc/isohexane) to afford the sub-title compound (1.36 g) as a tan solid.
LCMS m/z 314 (M+H)+ (ES+) (iv) Methyl 5-(tert-butyl)-3-(3-(2.3-difluoro-4-((2-(phenylamino)pyridin-4- yl)oxy)phenyl)ureido)-2-methoxybenzoate
The product from step (iii) above (200 mg, 0.468 mmol) was dissolved in isopropyl acetate (5 mL) and washed with NaHC03 solution (2 x 5 mL) followed by saturated brine (5 mL). The organic phase was dried (MgS04) then heated to 70°C with methyl 5-(tert-butyl)-2-methoxy- 3-((phenoxycarbonyl)amino)benzoate (see Example 75(iii) above; 175 mg, 0.447 mmol) and Et3N (20 μί, 0.143 mmol) for 48 h. Upon cooling, a solid was removed by filtration and the filtrate was concentrated under reduced pressure then purified by chromatography on the Companion (40 g column, 1-2% MeOH/DCM) to afford the sub-title compound (219 mg) as a light brown gum.
LCMS m/z 577 (M+H)+ (ES+)
(v) 5-(tert-Butyl)-3-(3-(2,3-difluoro-4-((2-(phenylamino)pyridin-4-yl)oxy)phenyl)ureido)-2- methoxybenzoic acid
The product from step (iv) above (220 mg, 0.382 mmol) and LiOH monohydrate (10 mg, 0.238 mmol) were stirred in water (1 mL), methanol (0.5 mL) and THF (1 mL) at rt for 18 h. The mixture was diluted with water (15 mL) and the resulting solid was removed by filtration. The filtrate was acidified with 1 M citric acid solution (1 mL) and extracted with ethyl acetate (20 mL). The organic phase was dried (MgS04), filtered and concentrated under reduced pressure. The crude product was purified by chromatography on the Companion (12 g column, 0-20%MeOH(1 %NH3)/DCM) to afford the sub-title compound (50 mg) as a tan glass. LCMS m/z 563 (M+H)+ (ES+); 561 (M-H)" (ES")
(vi) 5-(tert-Butyl)-3-(3-(2,3-difluoro-4-((2-(phenylamino)pyridin-4-yl)oxy)phenyl)ureido)-2- methoxy-N-(oxetan-3-yl)benzamide
HATU (50 mg, 0.131 mmol) was added to a stirred solution of the product from step (v) above (50 mg, 0.089 mmol), Et3N (30 μΙ, 0.215 mmol) and oxetan-3-amine (20 mg, 0.274 mmol) in DMF (3 mL). The mixture was stirred at rt over a weekend. Water (10 mL) was added dropwise and the resulting precipitate was collected by filtration. The solid was purified by chromatography on the Companion (12 g column, 0-5% MeOH/DCM) to afford the title compound (35 mg) as a white solid.
H NMR (DMSO-d6) 400 MHz, δ: 9.55 (s, 1 H), 9.00 (s, 1 H), 8.96 (d, 1 H), 8.93 (s, 1 H), 8.40 (d, 1 H), 8.14-8.06 (m, 2H), 7.67-7.60 (m, 2H), 7.28-7.18 (m, 3H), 7.08 (d, 1 H), 6.88 (ddd, 1 H), 6.50 (dd, 1 H), 6.25 (d, 1 H), 5.08-4.95 (m, 1 H), 4.80 (dd, 2H), 4.58 (dd, 2H), 3.76 (s, 3H), 1.29 (s, 9H).
LCMS m/z 618 (M+H)+ (ES+); 616 (M-H)" (ES")
Example 83
The following compounds were prepared by methods analogous to those described above. Where chemical shifts from H NMR spectra are reported, these were obtained at 400 MHz and ambient temperature, unless otherwise specified.
(a) N-(4-(tert-butyl)-6-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-[1 ,1 '-biphenyl]-2-yl)methane-sulfonamide
Figure imgf000153_0001
δ: 9.41 (s, 1H), 9.00 (s, 1H), 8.47 (s, 1H), 8.40 (d, 1H), 8.00 (d, 1H), 7.92 (s, 1H), 7.88 (d, 1H), 7.81 (d, 1H), 7.68 (s, 1H), 7.62-7.45 (m, 5H), 7.38-7.36 (m, 3H), 7.18 (s, 1H), 6.80 (brd, 2H), 6.53 (d, 1H), 6.04 (s, 1H), 3.88 (t, 2H), 3.66 (t, 2H), 3.56-3.49 (m, 9H), 3.42-3.40 (m, 2H), 3.22 (s, 3H), 2.60 (s, 3H), 1.33 (s, 9H).
LCMS m/z 865 (M+H)+ (ES+)
(b) N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)morpholine-4- sulfonamide
Figure imgf000153_0002
δ: 9.44 (s, 1H), 9.35 (s, 1H), 9.32 (s, 1H), 8.92 (s, 1H), 8.42 (d, 1H), 8.28 (d, 1H), 8.17 (d, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.68 (t, 1H), 7.59 (t, 1H), 7.42 (d, 1H), 7.10 (d, 1H), 6.81 (d, 2H), 6.55 (d, 1H), 6.04 (t, 1H), 3.86-3.88 (m, 2H), 3.82 (s, 3H), 3.65-3.67 (m, 2H), 3.60-3.63 (m, 4H), 3.48-3.54 (m, 6H), 3.51 (s, 3H), 3.40 (dd, 2H), 3.22 (s, 3H), 3.14-3.16 (m, 4H), 1.27 (s, 9H).
LCMS m/z 890 (M+H)+ (ES+)
(c) N-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-5-methoxyphenyl)- a phenyl)methanesulfonamide
Figure imgf000153_0003
δ: 9.44 (s, 1H), 9.36 (s, 1H), 9.16 (s, 1H), 8.93 (s, 1H), 8.42 (d, 1H), 8.27 (d, 1H), 8.19 (s, 1H), 8.11 (d, 1H), 7.85 (d, 1H), 7.68 (dd, 1H), 7.59 (dd, 1H), 7.42 (d, 1H), 7.02 (s, 1H), 6.81 (brs, 2H), 6.55 (d, 1H), 6.04 (s, 1H), 4.58 (t, 1H), 3.89-3.85 (m, 2H),3.81 (s, 3H), 3.68-3.64 (m, 2H), 3.55-3.45 (m, 9H), 3.42-3.37 (m, 2H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 805 (M+H)+ (ES+) (d) 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- in-1-yl)ethyl)benzamide
Figure imgf000154_0001
δ 9.39 (s, 1H), 9.11 (d, 2H), 8.92 (s, 1H), 8.39 - 8.23 (m, 2H), 8.18 (d, 1H), 8.14 - 8.06 (m, 2H), 7.91 - 7.80 (m, 1H), 7.69 (m, 1H), 7.60 (m, 1H), 7.56 (t, 1H), 7.49 (t, 1H), 7.38 (d, 1H), 7.01 (d, 1H), 6.86 (m, 1H), 6.57 (dd, 1H), 6.11 (d, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.09 (s, 3H), 2.65 - 2.52 (m, 4H), 1.67 (m, 4H), 1.26 (s, 9H). 4 Protons overlapping the water peak LCMS m/z 796 (M+H)+ (ES+) (e) 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- y -1-yl)ethyl)benzarnide
Figure imgf000154_0002
δ 9.40 (s, 1H), 9.16 (s, 1H), 9.07 (s, 1H), 8.93 (s, 1H), 8.30 (d, 1H), 8.26 - 8.17 (m, 2H), 8.12 (d, 1H), 8.11 (s, 1H), 7.91 - 7.84 (m, 1H), 7.71 (m, 1H), 7.61 (m, 1H), 7.56 (t, 1H), 7.50 (m, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.86 (m, 1H), 6.58 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.10 (s, 3H), 2.39 (s, 6H), 1.55 - 1.44 (m, 4H), 1.38 (s, 2H), 1.27 (s, 9H). 2 Protons overlapping the water peak
LCMS m/z 810 (M+H)+ (ES+) (f) N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1- mide
Figure imgf000154_0003
δ: 9.39 (s, 1H), 9.34 (s, 1H), 8.92 (d, 2H), 8.30 (d, 1H), 8.17 (d, 1H), 8.08-8.12 (m, 2H), 7.88 (d, 1H), 7.71 (t, 1H), 7.58-7.63 (m, 3H), 7.39 (d, 1H), 7.20 (t, 2H), 7.10 (d, 1H), 6.84 (t, 1H), 6.55 (dd, 1H), 6.09 (d, 1H), 3.82 (s, 3H), 3.60-3.62 (m, 4H), 3.13-3.15 (m, 4H), 1.27 (s, 9H). LCMS m/z 697 (M+H)+ (ES+)
(g) N-(2-aminoethyl)-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide
Figure imgf000155_0001
δ: 9.48 (s, 1H), 8.94 (s, 1H), 8.90 (s, 1H), 8.45 (d, 1H), 8.34 (t, 1H), 8.30 (d, 1H), 8.09-8.12 (m, 2H), 7.87 (d, 1H), 7.71 (t, 1H), 7.61 (t, 1H), 7.39 (d, 1H), 7.18 (d, 1H), 6.91 (s, 1H), 6.78 (s, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 3.97-3.99 (m, 2H), 3.81 (s, 3H), 3.69-3.71 (m, 2H), 3.65 (s, 3H), 3.56-3.58 (m, 2H), 3.50-3.54 (m, 4H), 3.42 (dd, 2H), 4H under H20, 3.23 (s, 3H), 2.78 (t, 2H), 1.29 (s, 9H).
LCMS m/z811 (M+H)+ (ES+)
Example 84
The following compounds were prepared by methods analogous to those described above. Where chemical shifts from H NMR spectra are reported, these were obtained at 400 MHz and ambient temperature, unless otherwise specified.
(a) 3-[[4-[(2-Anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-
Figure imgf000155_0002
H NMR (400 MHz, DMSO-d6) δ: 9.44 (s, 1H), 8.90 (d, 2H), 8.43 (d, 1H), 8.29 (d, 1H), 8.21 (d, 1H), 8.08 (d, 1H), 8.07 (s, 1H), 7.88 (d, 1H), 7.73 - 7.68 (m, 1H), 7.63 - 7.57 (m, 3H), 7.38 (d, 1H), 7.19 (dd, 2H), 7.06 (d, 1H), 6.85 - 6.82 (m, 1H), 6.55 (dd, 1H), 6.10 (d, 1H), 4.04 - 4.00 (m, 1 H), 3.89 - 3.87 (m, 2H), 3.80 (s, 3H)
LCMS m/z 660 (M+H)+ (ES+); 658 (M-H)" (ES")
(b) 3-[[4-[(2-Anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-(1-
Figure imgf000155_0003
H NMR (400 MHz, DMSO-d6) δ: 9.46 (s, 1H), 8.90 (d, 2H), 8.43 (d, 1H), 8.29 (d, 1H), 8.18 (d, 1H), 8.07 - 8.07 (m, 2H), 7.88 (d, 1H), 7.70 (t, 1H), 7.63 - 7.57 (m, 3H), 7.38 (d, 1H), 7.19 (t, 2H), 7.05 (d, 1H), 6.84 (t, 1H), 6.53 (dd, 1H), 6.10 (d, 1H), 3.82 - 3.79 (m, 4H), 2.91 - 2.87 (m, 2H), 2.33 (bs, 3H), 1.91 - 1.88 (m, 2H), 1.64- 1.60 (m, 2H), 1.28 (s, 9H).
LCMS m/z 673 (M+H)+ (ES+); 671 (M-H)" (ES") (c) 3-[[4-[(2-Anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N- [
Figure imgf000156_0001
H NMR (400 MHz, DMS0-d6) δ: 9.45 (s, 1H), 8.94 (bs, 1H), 8.91 (s, 1H), 8.44 - 8.42 (m, 2H), 8.29 (d, 1H), 8.09 - 8.07 (m, 2H), 7.88 (d, 1H), 7.69 (t, 1H), 7.61 - 7.57 (m, 3H), 7.38 (d, 1H), 7.20 (t, 2H), 7.06 (d, 1H), 6.85 (t, 1H), 6.55 (dd, 1H), 6.10 (s, 1H), 4.50 - 4.45 (m, 1H), 3.87-3.73 (m, 6H), 3.63 (dd, 1H), 2.20 - 2.15 (m, 1H), 1.93- 1.90 (m, 1H), 1.28 (s, 9H). LCMS m/z 646 (M+H)+ (ES+); 644 (M-H)" (ES")
(d) 3-[[4-[(2-Anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N- [(3S)-tetrahydrofuran-3-yl]benzamide
Figure imgf000156_0002
H NMR (400 MHz, DMS0-d6) δ: 9.44 (s, 1H), 8.90 (d, 2H), 8.44 - 8.42 (m, 2H), 8.29 (d, 1H), 8.09 (d, 1H), 8.07 (s, 1H), 7.88 (d, 1H), 7.71 (t, 1H), 7.63 - 7.57 (m, 3H), 7.38 (d, 1H), 7.19 (t, 2H), 7.06 (d, 1H), 6.84 (t, 1H), 6.55 (dd, 1H), 6.10 (d, 1H), 4.50 - 4.45 (m, 1H), 3.90 - 3.73 (m, 6H), 3.64 (dd, 1H), 2.22 - 2.13 (m, 1H), 1.95- 1.87 (m, 1H), 1.28 (s, 9H).
LCMS m/z 646 (M+H)+ (ES+); 644 (M-H)" (ES")
(e) 1-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]-3-[4-[[2-[3-[2-[2-(2- ino]-4-pyridyl]oxy]-1-naphthyl]urea
Figure imgf000156_0003
H NMR (400 MHz, DMS0-d6) δ 9.38 (s, 1H), 9.13 (s, 1H), 9.13 (s, 1H), 8.90 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.11 (dd, 2H), 7.87 (d, 1H), 7.75 - 7.66 (m, 1H), 7.67 - 7.56 (m, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.91 (t, 1H), 6.79 (t, 1H), 6.58 (dd, 1H), 6.08 (d, 1H), 6.04 (t, 1H), 4.57 (t, 1H), 4.03 - 3.92 (m, 2H), 3.81 (s, 3H), 3.77 - 3.69 (m, 2H), 3.66 (s, 3H), 3.63 - 3.52 (m, 4H), 3.52 - 3.45 (m, 2H), 3.45 - 3.39 (m, 2H), 3.09 (s, 3H), 1.27 (s, 9H).
LCMS m/z 804 (M+H)+ (ES+) (f) 1-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[[2-[3-(hydroxymeth
l]urea
Figure imgf000157_0001
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (s, 1H), 8.91 (s, 1H), 8.89 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.14 - 8.06 (m, 2H), 7.88 (d, 1H), 7.74 - 7.67 (m, 1H), 7.65 - 7.58 (m, 1H), 7.38 (d, 1H), 7.24 (t, 1H), 7.07 - 6.98 (m, 2H), 6.54 (dd, 1H), 6.43 - 6.38 (m, 1H), 6.12 (d, 1H), 5.10 (t, 1H), 4.38 (d, 2H), 3.81 (s, 3H), 3.67 (s, 3H), 3.09 (s, 3H), 1.27 (s, 9H).
LCMS m/z 686 (M+H)+ (ES+) (g) 5-tert-Butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- amide
Figure imgf000157_0002
H NMR (400 MHz, DMS0-d6) δ 9.47 (s, 1H), 8.93 (s, 1H), 8.89 (s, 1H), 8.46 (d, 1H), 8.30 (d, 1H), 8.16 - 8.05 (m, 2H), 7.88 (d, 1H), 7.77 - 7.67 (m, 2H), 7.66 - 7.59 (m, 1H), 7.57 (s, 1H), 7.38 (d, 1H), 7.24 (t, 1H), 7.22 (d, 1H), 7.07 - 6.97 (m, 1H), 6.54 (dd, 1H), 6.45 - 6.37 (m, 1H), 6.12 (d, 1H), 5.10 (s, 1H), 4.38 (s, 2H), 3.83 (s, 3H), 3.67 (s, 3H), 1.29 (s, 9H).
LCMS m/z 636 (M+H)+ (ES+)
(h) 5-tert-Butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- thyl-benzamide
Figure imgf000157_0003
H NMR (400 MHz, DMS0-d6) δ 9.48 (s, 1H), 8.89 (s, 2H), 8.44 (d, 1H), 8.30 (d, 1H), 8.18 (q, 1H), 8.10 (d, 1H), 8.08 (d, 1H), 7.88 (d, 1H), 7.78- 7.67 (m, 1H), 7.67- 7.56 (m, 1H), 7.38 (d, 1H), 7.24 (t, 1H), 7.11 (d, 1H), 7.08 - 6.96 (m, 1H), 6.54 (dd, 1H), 6.46 - 6.35 (m, 1H), 6.13 (d, 1H), 5.10 (s, 1H), 4.38 (s, 2H), 3.80 (s, 3H), 3.67 (s, 3H), 2.82 (d, 3H), 1.28 (s, 9H). LCMS m/z 650 (M+H)+ (ES+)
Example 85
Unless otherwise specified, the following compounds were prepared by methods analogous to those described above. Where chemical shifts from H NMR spectra are reported, these were obtained at 400 MHz and ambient temperature, unless otherwise specified. Example 85(a): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphe
carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-methoxy-N-(2-morpholino-2-oxo- ethvDbenzamide
Figure imgf000158_0001
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 9.13 (br s, 1 H), 9.09 (s, 1 H), 8.91 (s, 1 H), 8.37 (dd, 1 H), 8.30 (d, 1 H), 8.19 (d, 1 H), 8.13 (s, 1 H), 8.10 (d, 1 H), 7.88 (d, 1 H), 7.71 (ddd, 1 H), 7.63-7.60 (m, 1 H), 7.61 (ddd, 1 H), 7.54 (dd, 1 H), 7.39 (d, 1 H), 8.03 (d, 1 H), 6.92 (dd, 1 H), 6.58 (dd, 1 H), 6.14 (d, 1 H), 4.09 (d, 2H), 3.81 (s, 3H), 3.76 (s, 3H), 3.64-3.53 (m, 4H), 3.53- 3.40 (m, 4H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 826 (M+H)+ (ES+); 824 (M-H)" (ES")
Example 85(b): 3-[[4-[[4-[[5-tert-Butyl-3-(hvdroxymethyl)-2-methoxyphenyl1-carbamoylamino1- 1-naphthylloxyl-2-pyridyllaminol-5-ethvnyl-N-r2-r2-(2-methoxyethoxy)ethoxylethyllbenzamide
Figure imgf000158_0002
This compound was prepared by the following method.
(i) Phenyl (5-(tert-butyl)-3-(hvdroxymethyl)-2-methoxyphenyl)carbamate
Phenyl chloroformate (0.278 ml, 2.222 mmol) was added to a stirred mixture of (3-amino-5- (tert-butyl)-2-methoxyphenyl)methanol (Kaneko, H,, et al., WO 2011/040509, 0.5 g, 2.222 mmol) and NaHC03 (0.373 g, 4.44 mmol) in DCM (20 ml) and THF (2 mL) at rt. The reaction mixture was stirred for 17 hours then partitioned with DCM (2 mL) and water (10 mL). The aqueous layer was extracted with DCM (5 mL). The combined organic layers were dried over MgS04, filtered and concentrated in vacuo to afford the sub-title compound (895 mg, 74% purity).
LCMS m/z 312 (M+H-H20)+ (ES+)
(ii) 3-((4-((4-(3-(5-(tert-Butyl)-3-(hvdroxymethyl)-2-methoxyphenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethvnyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide
Triethylamine (2.60 μί, 0.019 mmol) was added to a mixture of the product from step (i) above (30.5 mg, 0.092 mmol) and 3-((4-((4-aminonaphthalen-1-yl)oxy)pyridin-2-yl)amino)-5- ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide (see Example 53(H) above; 50 mg, 0.092 mmol) in isopropyl acetate (4 mL) and the mixture heated at 70°C (block temperature) overnight (17 hours). A solution of the product from step (i) above (70 mg) in isopropyl acetate (1 mL) was added to the reaction mixture, and the reaction mixture was heated at 70°C overnight. The reaction mixture was diluted with THF and concentrated in vacuo to afford a pale pink gum. The crude product was purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μηι, 19x50 mm column, 25-70% MeCN in Water) to afford the title compound (10 mg) as a colourless solid. H NMR (400 MHz, DMSO-d6) δ: 9.42 (s, 1Η), 9.21 (s, 1Η), 8.80 (s, 1Η), 8.47 (t, 1Η), 8.30 (d, 1Η), 8.24 (d, 1Η), 8.14 (d, 1Η), 8.11 - 8.09 (m, 2Η), 7.92 (t, 1Η), 7.86 (d, 1Η), 7.72 - 7.68 (m, 1Η), 7.62 - 7.58 (m, 1Η), 7.41 - 7.38 (m, 2Η), 7.10 (d, 1Η), 6.61 (dd, 1Η), 6.12 (d, 1Η), 5.11 (t, 1Η), 4.56 (d, 2Η), 4.18 (s, 1Η), 3.77 (s, 3Η), 3.52 - 3.48 (m, 8Η), 3.40 - 3.38 (m, 4Η), 3.20 (s, 3Η), 1.28 (s, 9Η).
LCMS m/z 776 (M+H)+ (ES+) Example 85(c): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-ethvnyl-N-r2-(4-methylpiperazin-1- vDethyllbenzamide
Figure imgf000159_0001
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.21 (s, 1H), 9.14 (br s, 1H), 8.91 (s, 1H), 8.35 (dd, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.15 (d, 1H), 8.13 (d, 1H), 8.09 (dd, 1H), 7.93 (dd, 1H), 7.87 (d, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.42-7.37 (m, 2H), 7.02 (d, 1H), 6.62 (dd, 1H), 6.12 (d, 1H), 4.19 (s, 1H), 3.81 (s, 3H), 3.38-3.28 (m, 2H), 3.10 (s, 3H), 2.40-2.25 (m, 10H), 2.14 (s, 3H), 1.27 (s, 9H).
LCMS m/z 819 (M+H)+ (ES+); 817 (M-H)" (ES")
Example 85(d): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-ethvnyl-N-(3-morpholinopropyl)- benzamide
Figure imgf000159_0002
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 9.21 (s, 1H), 9.14 (br s, 1H), 8.91 (s, 1H), 8.46 (dd, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.15 (d, 1H), 8.12 (d, 1H), 8.09 (dd, 1H), 7.92 (dd, 1H), 7.87 (d, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.40 (d, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.62 (dd, 1H), 6.12 (d, 1H), 4.19 (s, 1H), 3.81 (s, 3H), 3.59-3.50 (m, 4H), 3.30-3.21 (m, 2H), 3.10 (s, 3H), 2.40-2.25 (m, 6H), 1.71-1.60 (m, 2H), 1.27 (s, 9H).
LCMS m/z 820 (M+H)+ (ES+); 818 (M-H)" (ES")
Example 85(e): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxylpyrimidin-2-yllaminol-5-methoxy-N-r2-(4-methylpiperazin-1- vDethyllbenzamide
Figure imgf000159_0003
H NMR (400 MHz, DMSO-d6) δ 9.61 (s, 1H), 9.36 (s, 1H), 9.14 (s, 1H), 8.93 (s, 1H), 8.42 (d, 1H), 8.28 (d, 1H), 8.19 (d, 1H), 8.17 (dd, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.68 (ddd, 1H), 7.59 (ddd, 1H), 7.56 (s, 1H), 7.43 (d, 1H), 7.36-7.30 (m, 1H), 7.02 (d, 1H), 6.85 (dd, 1H), 6.55 (d, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 3.37-3.26 (m, 4H), 3.10 (s, 3H), 2.47-2.19 (m, 8H), 2.14 (s, 3H), 1.27 (s, 9H).
LCMS m/z 826 (M+H)+ (ES+); 824 (M-H)" (ES")
Example 85(f): 3-rr4-rf4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxylpyrimidin-2-yllaminol-5-methoxy-N-(3-morpholinopropyl)- benzamide
Figure imgf000160_0001
H NMR (400 MHz, DMS0-d6) δ 9.60 (s, 1H), 9.36 (s, 1H), 9.14 (s, 1H), 8.93 (s, 1H), 8.41 (d, 1H), 8.34-8.24 (m, 2H), 8.19 (d, 1H), 8.10 (d, 1H), 7.85 (d, 1H), 7.68 (ddd, 1H), 7.59 (ddd, 1H), 7.56 (s, 1H), 7.43 (d, 1H), 7.36-7.30 (m, 1H), 7.02 (d, 1H), 6.86 (dd, 1H), 6.54 (d, 1H), 3.81 (s, 3H), 3.59 (s, 3H), 3.57-3.51 (m, 4H), 3.29-3.20 (m, 2H), 3.10 (s, 3H), 2.41-2.23 (m, 6H), 1.70-1.58 (m, 2H), 1.27 (s, 9H).
LCMS m/z 827 (M+H)+ (ES+); 825 (M-H)" (ES")
Example 85(g): 5-tert-Butyl-3-rr4-r2-r3-ethvnyl-5-(2-morpholinoethylcarbamoyl)anilinol- pyrimidin-4-yl1oxy-1-naphthyl1carbamoylamino1-2-methoxy-benzamide
Figure imgf000160_0002
H NMR (400 MHz, DMS0-d6) δ 9.76 (s, 1H), 9.43 (s, 1H), 8.92 (s, 1H), 8.49-8.41 (m, 2H), 8.36 (dd, 1H), 8.27 (d, 1H), 8.11-8.02 (m, 2H), 7.91-7.80 (m, 2H), 7.76-7.64 (m, 2H), 7.64- 7.51 (m, 2H), 7.49-7.40 (m, 2H), 7.22 (d, 1H), 6.56 (d, 1H), 4.13 (s, 1H), 3.83 (s, 3H), 3.62- 3.48 (m, 4H), 2 H underwater peak, 2.50-2.30 (m, 6H), 1.29 (s, 9H).
LCMS m/z 757 (M+H)+ (ES+); 755 (M-H)" (ES")
Example 85(h): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylamino1-1-naphthyl1oxy1-2-pyridyl1amino1-5-methoxy-N-(2-methyl-2- morpholinopropyDbenzamide
Figure imgf000160_0003
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (br s, 1H), 9.08 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.13-8.09 (m, 2H), 7.88 (d, 1H), 7.71 (ddd, 1H), 7.63-7.60 (m, 1H), 7.61 (ddd, 1H), 7.57 (dd, 1H), 7.51 (dd, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.82 (dd, 1H), 6.60 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.60-3.53 (m, 4H), 3.25 (d, 2H), 3.10 (s, 3H), 2.56-2.47 (m, 4H), 1.27 (s, 9H) 0.99 (s, 6H).
LCMS m/z 840 (M+H)+ (ES+); 838 (M-H)" (ES")
Example 85(i): 3-rr4-rr4-rf5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-methoxy-N-(2-thiomorpholinoethyl)- benzamide
Figure imgf000161_0001
H NMR (400 MHz, DMSO-d6) δ 9.38 (s, 1H), 9.14 (br s, 1H), 9.06 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.20 (dd, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.55 (dd, 1H), 7.51 (dd, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.85 (dd, 1H), 6.58 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.38-3.26 (m, 2H), 3.10 (s, 3H), 2.73-2.66 (m, 4H), 2.62-2.55 (m, 4H), 2.48 (t, 2H), 1.27 (s, 9H).
LCMS m/z 828 (M+H)+ (ES+); 826 (M-H)" (ES"). Example 85(i): 3-rr4-rf4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-methoxy-N-r2-(1-oxo-1,4-thiazinan-4- vDethyllbenzamide
Figure imgf000161_0002
H NMR (400 MHz, DMS0-d6) δ: 9.40 (s, 1H), 9.17 (s, 1H), 9.08 (s, 1H), 8.93 (s, 1H), 8.31- 8.25 (m, 2H), 8.19 (d, 1H), 8.12 (d, 1H), 8.11 (s, 1H), 7.87 (d, 1H), 7.73-7.69 (m, 1H), 7.63- 7.59 (m, 1H), 7.56 (s, 1H), 7.51 (s, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.86 (s, 1H), 6.58 (dd, 1H), 6.12 (d, 1H), 3.81 (s, 3H), 3.87 (s, 3H), 3.10 (s, 3H), 2.96-2.82 (m, 4H), 2.73-2.66 (m, 4H), 1.27 (s, 9H). (2xCH2 underwater and DMSO peaks)
LCMS m/z 844 (M+H)+ (ES+); 842 (M-H)" (ES").
Example 85(k): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-N-r2-(1,1-dioxo-1,4-thiazinan-4-yl)ethyll-5- methoxybenzamide
Figure imgf000162_0001
H NMR (400 MHz, DMSO-d6) δ: 9.38 (s, 1H), 9.13 (s, 1H), 9.05 (s, 1H), 8.90 (s, 1H), 8.29 (d, 1H), 8.24 (t, 1H), 8.18 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.87 (d, 1H), 7.72 - 7.68 (m, 1H), 7.60 - 7.58 (m, 1H), 7.54 (t, 1H), 7.50 (t, 1H), 7.38 (d, 1H), 7.02 (d, 1H), 6.85 - 6.84 (m, 1H), 6.57 (dd, 1H), 6.12 (d, 1H), 3.80 (s, 3H), 3.74 (s, 3H), 3.09 (s, 3H), 3.07 - 3.05 (m, 4H), 2.67 - 2.94 (m, 4H), 2.64 (t, 2H), 1.26 (s, 9H). (2 protons under the water signal)
LCMS m/z 430 (M+2H)2+ (ES+).
Example 85(l): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylamino1-1-naphthyl1oxy1-2-pyridyl1amino1-N^^
methoxybenzamide
Figure imgf000162_0002
H NMR (400 MHz, DMSO-d6) δ: 9.39 (s, 1H), 9.16 (s, 1H), 9.06 (s, 1H), 8.89 (s, 1H), 8.29 (d, 1H), 8.19 (d, 2H), 8.11 (d, 1H), 8.10 (d, 1H), 7.86 (d, 1H), 7.70 (dd, 1H), 7.59 (dd, 1H), 7.52 - 7.50 (m, 2H), 7.38 (d, 1H), 7.01 (d, 1H), 6.85 (t, 1H), 6.58 (dd, 1H), 6.11 (d, 1H), 3.80 (s, 3H), 3.73 (s, 3H), 3.58 (t, 2H), 3.23- 3.18 (m, 4H), 3.09 (s, 3H), 2.45 - 2.41 (m, 2H), 1.26 (s, 9H), 0.91 (s, 6H). (2H under the DMSO peak)
LCMS m/z 840 (M+H)+ (ES+); 838 (M-H)" (ES"). Example 85(m): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-N-r2-(2,2-dimethylmorpholin-4-yl)ethyll-5- methoxybenzamide
Figure imgf000162_0003
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (br s, 1H), 9.06 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.18 (d, 1H), 8.17 (dd, 1H), 8.12 (d, 1H), 8.10 (s, 1H), 7.87 (d, 1H), 7.71 (ddd, 1H), 7.61 (ddd, 1H), 7.55 (dd, 1H), 7.51 (dd, 1H), 7.39 (d, 1H), 7.02 (d, 1H), 6.84 (dd, 1H), 6.57 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.61-3.54 (m, 2H), 3.39-3.31 (m, 2H), 3.10 (s, 3H), 2.39 (t, 2H), 2.36-2.28 (m, 2H), 2.20 (s, 2H), 1.27 (s, 9H), 1.14 (s, 6H). LCMS m/z 840 (M+H)+ (ES+); 838 (M-H)" (ES").
Example 85(n): 3-rr4-rr4-rf5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-N-r2-r(2R,6S)-2,6-dimethylmorpholin-4- yllethyll-5-methoxybenzamide
Figure imgf000163_0001
H NMR (400 MHz, DMSO-d6) δ 9.42 (s, 1Η), 9.14 (br s, 1Η), 9.06 (s, 1Η), 8.93 (s, 1Η), 8.31 (d, 1Η), 8.22 (dd, 1Η), 8.18 (d, 1Η), 8.12 (s, 1Η), 8.10 (d, 1Η), 7.87 (d, 1Η), 7.70 (ddd, 1Η), 7.61 (ddd, 1Η), 7.56 (dd, 1Η), 7.50 (dd, 1Η), 7.39 (d, 1Η), 7.02 (d, 1Η), 6.85 (dd, 1Η), 6.58 (dd, 1Η), 6.13 (d, 1Η), 3.81 (s, 3Η), 3.74 (s, 3Η), 3.60-3.47 (m, 2Η), 3.39-3.31 (m, 2Η), 3.10 (s, 3Η), 2.77 (d, 2Η), 2.42 (t, 2Η), 1.64 (t, 2Η), 1.27 (s, 9Η), 1.03 (d, 6Η).
LCMS m/z 840 (M+H)+ (ES+); 838 (M-H)" (ES").
Example 85(o): 5-tert-Butvl-3-rr4-rr2-r3-ethvnvl-5-(hvdroxvmethvl)anilinol-4-pvridylloxvl-1- ide
Figure imgf000163_0002
H NMR (400 MHz, DMS0-d6) δ: 9.47 (s, 1Η), 9.02 (s, 1Η), 8.91 (s, 1Η), 8.45 (d, 1Η), 8.29 (d, 1Η), 8.12 (d, 1Η), 8.09 (d, 1Η), 7.87 (d, 1Η), 7.80 (t, 1Η), 7.73 - 7.69 (m, 2Η), 7.63 - 7.59 (m, 2Η), 7.45 (bs, 1Η), 7.39 (d, 1Η), 7.22 (d, 1Η), 6.89 (s, 1Η), 6.58 (dd, 1Η), 6.10 (d, 1Η), 5.18 (t, 1Η), 4.39 (d, 2Η), 4.05 (s, 1Η), 3.82 (s, 3Η), 1.28 (s, 9Η).
LCMS m/z 630 (M+H)+ (ES+); 628 (M-H)" (ES")
Example 85(p): 3-rr4-rf4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylamino1-1-naphthyl1oxy1-2-pyridyl1amino1-5-methoxy-N-[2-(4-methyl-1,4-diazepan-1- vDethyllbenzamide
Figure imgf000163_0003
H NMR (400 MHz, DMS0-d6) δ 9.45 (s, 1Η), 9.15 (br s, 1Η), 9.07 (s, 1Η), 8.94 (s, 1Η), 8.32 (d, 1Η), 8.20 (dd, 1Η), 8.18 (d, 1Η), 8.12 (s, 1Η), 8.10 (d, 1Η), 7.87 (d, 1Η), 7.70 (ddd, 1Η), 7.61 (ddd, 1Η), 7.55 (dd, 1Η), 7.52 (dd, 1Η), 7.38 (d, 1Η), 7.03 (d, 1Η), 6.86 (dd, 1Η), 6.60 (dd, 1Η), 6.13 (d, 1Η), 3.81 (s, 3Η), 3.75 (s, 3Η), 3.36-3.24 (m, 2Η), 3.10 (s, 3Η), 2.77-2.57 (d, 10Η), 2.34 (s, 3Η), 1.79-1.68 (m, 2Η), 1.27 (s, 9Η).
LCMS m/z 839 (M+H)+ (ES+); 837 (M-H)" (ES") Example 85(g): 3-rr4-rr4-rf5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllarriinol-5-methoxy-N-(2-piperaziri-1- ylethvDbenzamide
Figure imgf000164_0001
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.06 (s, 1H), 8.91 (s, 1H), 8.30 (d, 1H), 8.24 - 8.14 (m, 2H), 8.12 (s, 1H), 8.10 (d, 1H), 7.87 (d, 1H), 7.76-7.67 (m, 1H), 7.66-7.57 (m, 1H), 7.55 (t, 1H), 7.51 (t, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.86 (dd, 1H), 6.58 (dd, 1H), 6.13 (d, 1H), 3.81 (s, 3H), 3.74 (s, 3H), 3.09 (s, 3H), 2.69 (t, 4H), 2.41 (t, 2H), 2.38 - 2.26 (m, 4H), 1.27 (s, 9H). CH2 underwater peak 3.32ppm, one exchangeable proton not visible.
LCMS m/z 811 (M+H)+ (ES+); 809 (M-H)" (ES")
Example 85(r): 3-rr4-rf4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-N-r2-r2-(2-hvdroxyethoxy)ethoxyl-ethyll-5- methoxy-benzamide
Figure imgf000164_0002
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1H), 9.14 (s, 1H), 9.06 (s, 1H), 8.91 (s, 1H), 8.35 (t, 1H), 8.30 (d, 1H), 8.19 (d, 1H), 8.12 (s, 1H), 8.10 (d, 1H), 7.88 (d, 1H), 7.75 - 7.67 (m, 1H), 7.65 - 7.59 (m, 1H), 7.58 (t, 1H), 7.51 (t, 1H), 7.39 (d, 1H), 7.03 (d, 1H), 6.89 (dd, 1H), 6.57 (dd, 1H), 6.14 (d, 1H), 4.57 (t, 1H), 3.81 (s, 3H), 3.75 (s, 3H), 3.59 - 3.49 (m, 6H), 3.49 - 3.44 (m, 2H), 3.44 - 3.35 (m, 4H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 831 (M+H)+ (ES+); 829 (M-H)" (ES").
Example 85(s): 3-rrr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxylpyrimidin-2-yllaminolmethyll-N-r2-r2-(2- methoxyethoxy)ethoxylethyllbenzamide
Figure imgf000164_0003
H NMR (400 MHz, DMSO-d6, 100°C) δ: 9.08 (s, 1H), 6.82 (s, 1H), 8.55 (s, 1H), 8.23 (d, 1H), 8.18 (d, 1H), 8.10 (d, 1H), 7.96 - 7.94 (m, 2H), 7.85 (d, 1H), 7.71 (s, 1H), 7.63 - 7.60 (m, 2H), 7.55 - 7.53 (m, 1 H), 7.31 - 7.19 (m, 4H), 7.06 (d, 1 H), 6.22 (d, 1 H), 4.36 (d, 2H), 3.84 (s, 3H),
3.56 - 3.52 (m, 8H), 3.43 - 3.41 (m, 4H), 3.24 (s, 3H), 3.08 (s, 3H), 1.29 (s, 9H).
LCMS m/z 830 (M+H)+ 415 (M+2H)2+ (ES+); 828 (M-H)" (ES"). Example 85(t): 3-rrr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyph
carbamoylaminol-1-naphthylloxylpyrimidin-2-yllaminolmethyll-N-(2-mo
benzamide
Figure imgf000165_0001
The product was analysed by LCMS (Agilent, X-Select, Waters X-Select UPLC C18, 1.7 μηι, 2.1 x 30 mm, Basic (0.1 % Ammonium Bicarbonate) 4 min method, 5-95% MeCN/water): m/z 797 (M+H)+ (ES+); 795 (M-H)" (ES"), at 2.23 min, 99% purity @ 254 nm.
Example 85(u): 3-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl1- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-methoxy-N-r2-(2-methoxyethoxy)- ethyllbenzamide
Figure imgf000165_0002
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 9.14 (br s, 1 H), 9.06 (s, 1 H), 8.92 (s, 1 H), 8.34 (dd, 1 H), 8.30 (d, 1 H), 8.18 (d, 1 H), 8.12 (s, 1 H), 8.10 (d, 1 H), 7.87 (d, 1 H), 7.71 (ddd, 1 H), 7.61 (ddd, 1 H), 7.58 (dd, 1 H), 7.51 (dd, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.89 (dd, 1 H), 6.58 (dd, 1 H), 6.13 (d, 1 H), 3.81 (s, 3H), 3.75 (s, 3H), 3.56-3.47 (m, 4H), 3.46-3.42 (m, 2H), 3.41- 3.34 (m, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 801 (M+H)+ (ES+); 799 (M-H)" (ES").
Example 85(v): 3-rr4-rr4-rr5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-5-methoxy-N-r2-r2-r2-(2- methoxyethoxy)ethoxylethoxyl-ethyllbenzamide
Figure imgf000165_0003
H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1 H), 9.17 (s, 1 H), 9.08 (s, 1 H), 8.94 (s, 1 H), 8.37 (t, 1 H), 8.30 (d, 1 H), 8.19 (d, 1 H), 8.13 (d, 1 H), 8.1 1 (d, 1 H), 7.87 (d, 1 H), 7.75 - 7.67 (m, 1 H), 7.65 - 7.59 (m, 1 H), 7.58 (t, 1 H), 7.51 (t, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.89 (dd, 1 H), 6.58 (dd, 1 H), 6.13 (d, 1 H), 3.81 (s, 3H), 3.75 (s, 3H), 3.54 - 3.44 (m, 12H), 3.42 - 3.36 (m, 4H), 3.21 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 889 (M+H)+ (ES+).
Example 85(w): 3-rr4-rr4-rf5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll- carbamoylaminol-1-naphthylloxyl-2-pyridyllaminol-N-r2-(4-hvdroxy-1-piperidyl)ethyll-5- methoxybenzamide
Figure imgf000166_0001
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 9.14 (br s, 1 H), 9.06 (s, 1 H), 8.91 (s, 1 H), 8.30 (d, 1 H), 8.23-8.19 (m, 1 H), 8.19 (d, 1 H), 8.12 (s, 1 H), 8.10 (d, 1 H), 7.87 (d, 1 H), 7.71 (ddd, 1 H), 7.61 (ddd, 1 H), 7.55 (dd, 1 H), 7.51 (dd, 1 H), 7.39 (d, 1 H), 7.02 (d, 1 H), 6.85 (dd, 1 H), 6.57 (dd, 1 H), 6.13 (d, 1 H), 4.52 (d, 1 H), 3.81 (s, 3H), 3.74 (s, 3H), 3.48-3.36 (m, 1 H), 3.36- 3.26 (m, 2H), 3.10 (s, 3H), 2.79-2.66 (m, 2H), 2.42 (t, 2H), 2.06 (t, 2H), 1.75-1.63 (m, 2H), 1.44-1.31 (m, 2H), 1.27 (s, 9H).
LCMS m/z 826 (M+H)+ (ES+); 824 (M-H)" (ES")
Example 85(x): 1-r5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll-3-r4-r2-r3- methoxy-5-r2-r2-(2-methoxyethoxy)ethoxylethylsulfinyllanilinolpyridin-4-ylloxy-1- naphthyllurea
Figure imgf000166_0002
This compound was prepared by the following method.
(i) N-(5-(tert-Butvn-3-(3-(4-((2-chloropyridin-4-vnoxy)naphthalen-1-vnureido)-2- methoxyphenvDmethanesulfonamide
4-((2-Chloropyridin-4-yl)oxy)naphthalen-1 -amine (see, for example, Ito, K. et al., WO 2010/112936, 07 Oct 2010; 1.75 g, 6.46 mmol) was added to a solution of phenyl (5-(tert- butyl)-2-methoxy-3-(methylsulfonamido)phenyl)carbamate (see Example 1 (vi) above; 2.3 g, 5.86 mmol) and TEA (0.2 mL, 1.435 mmol) in 2-Me-THF (25 mL) and heated at 65°C (block temperature) for 20 h. Phenyl (5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)- carbamate (0.5 g, 1.274 mmol) and TEA (0.1 mL, 0.717 mmol) were added and heating continued for a further 5 h. Further quantities of phenyl (5-(tert-butyl)-2-methoxy-3- (methylsulfonamido)phenyl)carbamate (0.5 g, 1.274 mmol) and TEA (0.1 mL, 0.717 mmol) were added and heating continued for a further 16 h. The resultant solid was filtered off and washed with 2-Me-THF (5 mL) to afford the sub-title compound (2.5 g).
H NMR (400 MHz, DMSO-d6) δ 9.41 (s, 1 H), 9.13 (s, 1 H), 8.94 (s, 1 H), 8.32 (d, 1 H), 8.29 (d, 1 H), 8.18 (d, 1 H), 8.14 (d, 1 H), 7.85 (d, 1 H), 7.76 - 7.68 (m, 1 H), 7.66 - 7.59 (m, 1 H), 7.42 (d, 1 H), 7.06 - 7.01 (m, 2H), 6.94 (dd, 1 H), 3.81 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H).
LCMS m/z 569/571 (M+H)+ (ES+); 567/569 (M-H)" (ES")
(ii) 2-((3-Methoxy-5-nitrophenyl)thio)ethanol
1-Bromo-3-methoxy-5-nitrobenzene (2.36 g, 10.17 mmol), Pd2(dba)3 (0.4 g, 0.437 mmol) and xantphos (0.5 g, 0.864 mmol) were added to a degassed solution of DIPEA (5.5 mL, 31.5 mmol) and 2-mercaptoethanol (0.75 mL, 10.70 mmol) in 1 ,4-dioxane (20 mL). The mixture was heated under nitrogen at 100°C (block temperature) for 16 h then filtered through Celite and the solvents were evaporated. The residue was dissolved in DCM (-10 mL) and then isohexane added (-10 mL). The resultant solid was filtered off to give 1.5 g of the desired product. The filtrate was purified by chromatography on the Companion (80 g column, 10% EtOAc: isohexane to 30%) to afford 750 mg of the subtitle compound as a pale yellow solid. Combined yield of subtitle compound was 2.25 g.
H NMR (400 MHz, DMSO-d6) δ 7.69 (t, 1 H), 7.50 (t, 1 H), 7.33 (dd, 1 H), 5.05 (t, 1 H), 3.88 (s, 3H), 3.63 (q, 2H), 3.18 (t, 2H).
LCMS m/z 212 (M+H-H20)+ (ES+)
(iii) (3-Methoxy-5-nitrophenyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfane
The product from step (ii) above (1 g, 4.36 mmol) was dissolved in dry DMF (10 mL) under nitrogen and NaH (0.2 g, 5.00 mmol) added. Stirred for 10 minutes, then 1-bromo-2-(2- methoxyethoxy)ethane (0.75 ml, 5.57 mmol) and Nal (0.065 g, 0.436 mmol) added and stirred at rt for 2.5 h. The mixture was charged again with NaH (0.2 g, 5.00 mmol) and 1- bromo-2-(2-methoxyethoxy)ethane (0.75 ml, 5.57 mmol), stirred for a further 1 h then partitioned between NH4CI solution (200 mL) and ethyl acetate (100 mL). The organic layer was separated and washed with 20% NaCI soln. (200 mL). The organic layer was separated, dried (MgS04), filtered and solvent evaporated. The crude product was purified by chromatography on silica gel (80 g column, 30% EtOAc: isohexane to 50%) to afford the sub-title compound (1 g) as a clear yellow oil.
H NMR (400 MHz, CDCI3) δ 7.80 (t, 1 H), 7.53 (t, 1 H), 7.18 (dd, 1 H), 3.89 (s, 3H), 3.75 (t, 2H), 3.71 - 3.63 (m, 6H), 3.59 - 3.53 (m, 2H), 3.40 (s, 3H), 3.22 (t, 2H).
(iv) 1-Methoxy-3-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfinyl)-5-nitrobenzene
mCPBA (350 mg, 1.562 mmol) was added slowly to an ice cold solution of the product from step (iii) above (600 mg, 1.811 mmol) in ice cold DCM (5 mL). The reaction was stirred at 0°C for 1 h then mCPBA (35 mg, 0.156 mmol) added and stirring at 0°C continued for a further 10 minutes. The reaction mixture was filtered cold and the filtrate immediately partitioned with sodium bisulphite 20% w/w (20 mL). The organic layer was separated, washed with sat. NaHC03 soln. (20 mL), dried (MgS04), filtered and the solvent evaporated to a yellow oil. The crude product was purified by chromatography on silica gel (12 g column, 0% MeOH:EtOAc to 5%) to afford the sub-title compound (570 mg) as a yellow oil. H NMR (400 MHz, CDCI3) δ 8.04 (dd, 1 H), 7.83 (t, 1 H), 7.59 (dd, 1 H), 4.04 - 3.98 (m, 1 H), 3.98 (s, 3H), 3.83 (dt, 1 H), 3.73 - 3.61 (m, 6H), 3.61 - 3.53 (m, 2H), 3.40 (s, 3H), 3.20 - 3.09 (m, 1 H), 3.09 - 2.99 (m, 1 H).
LCMS m/z 348 (M+H)+ (ES+)
(v) 3-Methoxy-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfinyl)aniline
A suspension of the product from step (iv) above (570 mg, 1.641 mmol) and 5% palladium on carbon (50% paste with water) (100 mg, 0.023 mmol) in ethanol (5 mL) was stirred under hydrogen (5 bar) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to yield a pale yellow oil. The material was redissolved in EtOH (5ml) and 5% palladium on carbon (50% paste with water) (100 mg, 0.023 mmol) added and the reaction stirred under hydrogen (5 bar) for 72h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to give a yellow oil. The crude product was purified by chromatography on silica gel (12 g column, 2%MeOH:DCM to 8%) to afford the sub-title compound (250 mg) as a pale yellow oil.
H NMR (400 MHz, DMSO-d6) δ 6.45 (t, 1 H), 6.32 (dd, 1 H), 6.22 (t, 1 H), 5.50 (s, 2H), 3.77 (ddd, 1 H), 3.71 (s, 3H), 3.62 (dt, 1 H), 3.57 - 3.49 (m, 6H), 3.48 - 3.39 (m, 2H), 3.25 (s, 3H), 3.04 (ddd, 1 H), 2.89 (dt, 1 H).
LCMS m/z 318 (M+H)+ (ES+)
(vi) 1-r5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl1-3-r4-r2-r3-methoxy-5-r2-r2-(2- methoxyethoxy)ethoxylethylsulfinyllanilinolpyridin-4-ylloxy-1-naphthyllurea
A mixture of the product from step (i) above (100 mg, 0.176 mmol), the product from step (v) above (75 mg, 0.236 mmol), K2C03 (50 mg, 0.362 mmol), BrettPhos G1 precatalyst (5 mg, 6.26 μηιοΙ) and tBuBrettPhos (3 mg, 6.19 μηιοΙ) were degassed under vacuum, back filling with nitrogen 3 times. NMP (1 mL) was added and the suspension degassed under vacuum, back filling with nitrogen 3 times. The reaction was then heated under nitrogen at 75°C (block temperature) for 1 h. The reaction mixture was cooled and partitioned between 20% w/w NaCI soln. (20 mL) and DCM (10 mL), the organics were separated, dried (MgS04), filtered and the solvent evaporated to give a brown oil. The crude product was preabsorbed onto silica (4 g) and purified by chromatography on silica gel (12 g column, 2% MeOH:DCM to 8%) to give a brown gum which was further purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 25-80% MeCN in Water) to afford the title compound (70 mg) as a colourless solid.
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 9.22 (s, 1 H), 9.12 (s, 1 H), 8.91 (s, 1 H), 8.30 (d, 1 H), 8.18 (d, 1 H), 8.14 (d, 1 H), 8.12 (d, 1 H), 7.87 (d, 1 H), 7.76 - 7.67 (m, 1 H), 7.66 - 7.56 (m, 1 H), 7.52 - 7.47 (m, 1 H), 7.46 (t, 1 H), 7.39 (d, 1 H), 7.03 (d, 1 H), 6.70 (dd, 1 H), 6.62 (dd, 1 H), 6.13 (d, 1 H), 3.81 (s, 3H), 3.80 - 3.76 (m, 1 H), 3.76 (s, 3H), 3.62 (dt, 1 H), 3.56 - 3.47 (m, 6H), 3.45 - 3.39 (m, 2H), 3.23 (s, 3H), 3.10 (s, 3H), 3.09 - 3.03 (m, 1 H), 2.92 (dt, 1 H), 1.27 (s, 9H). LCMS m/z 425(M+2H)2+ (ES+) Example 85(v): 1-r5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyll-3-r4-r2-r3- methoxy-5-r2-r2-(2-methoxyethoxy)ethoxylethylsulfonyllanilinolpyridin-4-ylloxy-1- naphthyllurea
Figure imgf000169_0001
This compound was prepared by the following method.
(i) 1-Methoxy-3-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)-5-nitrobenzene
mCPBA (750 mg, 3.35 mmol) was added slowly to an ice cold solution of (3-methoxy-5- nitrophenyl)(2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfane (see Example 85(y)(iii) above; 450 mg, 1.358 mmol) in ice cold DCM (5 mL). The reaction was stirred at 0°C for 30 min then allowed to warm to rt and stirred for 1 h. The reaction mixture was filtered and the filtrate immediately partitioned with sodium bisulphite solution 20% w/w (20mL). The organic layer was separated, washed with sat. NaHC03 soln. (20 mL), dried (MgS04), filtered and the solvent evaporated to a yellow oil. The crude product was purified by chromatography on silica gel (12 g column, 50% EtOAc:isohexane to 100%) to afford the sub-title compound (470 mg)
H NMR (400 MHz, CDCI3) δ 8.37 (dd, 1 H), 7.98 (t, 1 H), 7.78 (dd, 1 H), 4.00 (s, 3H), 3.92 (t, 2H), 3.59 - 3.44 (m, 10H), 3.37 (s, 3H).
LCMS m/z 364 (M+H)+ (ES+)
(ii) 3-Methoxy-5-((2-(2-(2-methoxyethoxy)ethoxy)ethyl)sulfonyl)aniline
A suspension of the product from step (i) above (470 mg, 1.293 mmol) and 5% palladium on carbon (50% paste with water) (100 mg, 0.023 mmol) in ethanol (5 mL) was stirred under hydrogen (5 bar) for 2 h. The catalyst was removed by filtration and the filtrate was concentrated under reduced pressure to afford the sub-title compound (400 mg).
H NMR (400 MHz, DMSO-d6) δ 6.68 (t, 1 H), 6.52 (dd, 1 H), 6.39 (t, 1 H), 5.67 (s, 2H), 3.74 (s, 3H), 3.67 (t, 2H), 3.54 - 3.37 (m, 10H), 3.23 (s, 3H).
LCMS m/z 334 (M+H)+ (ES+) (iii) 1-r5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl1-3-r4-r2-r3-methoxy-5-r2-r2-(2- methoxyethoxy)ethoxylethylsulfonyllanilinolpyridin-4-ylloxy-1 -naphthyllurea
A mixture of N-(5-(tert-butyl)-3-(3-(4-((2-chloropyridin-4-yl)oxy)naphthalen-1-yl)ureido)-2- methoxyphenyl)methanesulfonamide (see Example 85(y)(i) above; 100 mg, 0.176 mmol), the product from step (ii) above (75 mg, 0.225 mmol), K2C03 (50 mg, 0.362 mmol), BrettPhos G1 precatalyst (5 mg, 6.26 μηιοΙ) and tBuBrettPhos (3 mg, 6.19 μηιοΙ) were degassed under vacuum, back filling with nitrogen 3 times. NMP (1 mL) was added and the suspension degassed under vacuum, back filling with nitrogen 3 times. The reaction was then heated under nitrogen at 75°C (block temperature) for 1 h. The reaction mixture was cooled and partitioned between 20%w/w NaCI soln. (20 mL) and DCM (10 mL), the organics were separated, dried (MgS04), filtered and the solvent evaporated to give a brown oil. The crude product was preabsorbed onto silica (4 g) and purified by chromatography on silica gel (12 g column, 2% MeOH:DCM to 10%) to give a brown gum which was further purified by preparative HPLC (Varian, Basic (0.1 % Ammonium Bicarbonate), Basic, Waters X-Bridge Prep-C18, 5 μηι, 19x50 mm column, 25-80% MeCN in Water) to afford the title compound (85 mg).
H NMR (400 MHz, DMSO-d6) δ 9.39 (s, 1 H), 9.33 (s, 1 H), 9.12 (s, 1 H), 8.91 (s, 1 H), 8.31 (d, 1 H), 8.18 (d, 1 H), 8.16 (d, 1 H), 8.12 (d, 1 H), 7.87 (d, 1 H), 7.78 - 7.67 (m, 3H), 7.67 - 7.55 (m, 1 H), 7.40 (d, 1 H), 7.03 (d, 1 H), 6.88 (t, 1 H), 6.65 (dd, 1 H), 6.13 (d, 1 H), 3.82 (s, 3H), 3.79 (s, 3H), 3.68 (t, 2H), 3.54 (t, 2H), 3.42 - 3.36 (m, 4H), 3.18 (s, 3H), 3.10 (s, 3H), 1.27 (s, 9H). 2 x CH2 obscured by H20 at 3.33 ppm.
LCMS m/z 433 (M+2H)2+ (ES+)
Example 86
The following compounds are prepared by methods analogous to those described above.
(a) 5-tert-Butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- yl)benzamide
Figure imgf000170_0001
(b) 3-[[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-5-methoxy-N-[2-[2-(2-methoxyethoxy)ethoxy]-
Figure imgf000170_0002
(c) 3-[[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxy-phenyl]carbamoylamino]-1- oxy-N-(2-morpholinoethyl)benzamide
Figure imgf000170_0003
(d) 1-[5-tert-Butyl-3-(cyanomethyl)-2-methoxy-phenyl]-3-[4-[[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]anilino]-4-pyridyl]oxy]-1-naphthyl]urea
Figure imgf000171_0001
(e) 3-[[4-[[4-[[5-tert-Butyl-3-(cyanomethyl)-2-methoxy-phenyl]carbamoylamino]-1- 2-morpholinoethyl)benzamicle
Figure imgf000171_0002
(f) 3-[[4-[[4-[[5-tert-Butyl-3-(cyanomethyl)-2-methoxy-phenyl]carbamoylamino]-1- [2-(2-methoxyethoxy)ethoxy]ethyl]-benzamide
Figure imgf000171_0003
(g) 3-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]-carbamoylamino]-1- 4-oxazepan-4-yl)ethyl]benzamide
Figure imgf000171_0004
(h) 3-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]-carbamoylarnino]-1- o-1-piperidyl)ethyl]-benzamide
Figure imgf000171_0005
(i) 5-tert-Butyl-3-[[4-[[2-[3-ethynyl-5-(hydroxymethyl)anilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxy-N-methyl-benzamide
Figure imgf000172_0001
Biological Testing: Experimental Methods Enzyme Binding Assays (Kinomescan)
Kinase enzyme binding activities of compounds disclosed herein may be determined using a proprietary assay which measures active site-directed competition binding to an immobilized ligand (Fabian, M.A. et al., Nature Biotechnol., 2005, 23:329-336). These assays may be conducted by DiscoverX (formerly Ambit; San Diego, CA). The percentage inhibition produced by incubation with a test compound may be calculated relative to the non-inhibited control.
Enzyme Inhibition Assays
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). p38 MAPKct Enzyme Inhibition
The following two assay variants can be used for determination of p38 MAPKa inhibition.
Method 1
The inhibitory activities of test compounds against the p38 MAPKa isoform (MAPK14: Invitrogen) are evaluated indirectly by determining the level of activation / phosphorylation of the down-stream molecule, MAPKAP-K2. The p38 MAPKa protein (80 ng/mL, 2.5 μί) is mixed with the test compound (2.5 of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL or 0.004 μg/mL) for 2 hr at RT. The mix solution (2.5 μί) of the p38a inactive target MAPKAP-K2 (Invitrogen, 600 ng/mL) and FRET peptide (8 μΜ; a phosphorylation target for MAPKAP-K2) is then added, then the kinase reaction is initiated by adding ATP (40 μΜ, 2.5μί). The mixture is incubated for 1 hr at RT. Development reagent (protease, 5 μί) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific). Method 2
This method follows the same steps as Method 1 above, but utilises a higher concentration of the p38 MAPKa protein (2.5 μί of 200 ng/mL protein instead of 2.5 μί of 80 ng/mL protein) for mixing with the test compound (tested at either 1 μg/mL, 0.1 μg/mL, 0.01 μg/mL or 0.001 μg/mL). p38 ΜΑΡΚγ Enzyme Inhibition
The inhibitory activities of compounds of the invention against ρ38ΜΑΡΚγ (MAPK12: Invitrogen), are evaluated in a similar fashion to that described hereinabove. The enzyme (800 ng/mL, 2.5 μΙ_) is incubated with the test compound (2.5 μΙ_ of either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRET peptides (8 μΜ, 2.5 μΙ_), and appropriate ATP solution (2.5 μΙ_, 400 μΜ) are then added to the enzymes / compound mixtures and the whole is incubated for 1 hr. Development reagent (protease, 5 μΙ_) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, Thermo Scientific). c-Src and Syk Enzyme Inhibition
The inhibitory activities of compounds of the invention against c-Src and Syk enzymes (Invitrogen), are evaluated in a similar fashion to that described hereinabove. The relevant enzyme (3000 ng/mL or 2000 ng/mL respectively, 2.5 μΙ_) is incubated with the test compound (either 1 μg/mL, 0.1 μg/mL, 0.01 μg/mL, or 0.001 μg/mL, 2.5 μΙ_ each) for 2 hr at RT. The FRET peptides (8 μΜ, 2.5 μΙ_), and appropriate ATP solutions (2.5 μΙ_, 800 μΜ for c-Src, and 60 μΜ ATP for Syk) are then added to the enzymes / compound mixtures and the mixture incubated for 1 hr. Development reagent (protease, 5 μΙ_) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific).
GSK 3a Enzyme Inhibition The following two assay variants can be used for determination of GSK 3a inhibition.
Method 1
The inhibitory activities of compounds of the invention against the GSK 3a enzyme isoform (Invitrogen), are evaluated by determining the level of activation / phosphorylation of the target peptide. The GSK3-a protein (500 ng/mL, 2.5 μΙ_) is mixed with the test compound (2.5 μΙ_ at either 4 μg/mL, 0.4 μg/mL, 0.04 μg/mL, or 0.004 μg/mL) for 2 hr at RT. The FRET peptide (8 μΜ, 2.5 μΙ_), which is a phosphorylation target for GSK3a, and ATP (40 μΜ, 2.5 μΙ_) are then added to the enzyme / compound mixture and the resulting mixture incubated for 1 hr. Development reagent (protease, 5 μΙ_ ) is added for 1 hr prior to detection in a fluorescence microplate reader (Varioskan® Flash, ThermoFisher Scientific).
In all cases, 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 (IC50 value) is then calculated from the concentration-response curve. Method 2
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-a protein. In addition, the concentrations of test compound employed are either 10 μg/mL, 1 μg/mL, 0.1 g/mL, or 0.01 μg/mL
Cellular Assays
The compounds of the invention were studied using one or more of the following assays.
(a) Inhibition of p38 MAPKct and Lck in Jurkat cells
Jurkat T cells were cultured in starve medium (RPMI 1640 + 5% FBS) for 24 h prior to the experiment. Cells were harvested and resuspended at 10x106 cells/mL in starve medium and then plated into round-bottomed 96 well plates at 1x106 ce//s/well. Serial dilutions of test compound were added (1 % final DMSO concentration) for 2 h prior to stimulation. Following pre-incubation with compound, cells were stimulated with H202 (0.05% final) for 5 min. The reaction was stopped by centrifugation at 2000 rpm (3 min, 4 °C), then the supernatant was removed and 100 μΙ_ of cold fix/perm solution (BD Fix/Perm kit #554714) added. Plates were incubated for 20 min at 4 °C before centrifugation and washing with supplied 1x wash medium (BD Fix/Perm kit #554714). Cells were stained for either phospho-p38a (T180/182), supplied by Cell Signalling Technology (9211 s), or phospho-Lck (Y394), supplied by R&D (MAB7500). Antibodies were diluted to 5 μg/mL (R&D) or 1 :200 (Cell Signalling Technology) in wash medium, before being incubated 1 h at 4 °C in the dark. Following 3 repeat washes with ice cold wash buffer, secondary antibody (anti-rabbit-FITC #F1362 or anti-mouse-FITC #F2883, both from Sigma) was added at a dilution of 1 : 1000 and incubated for 1 h at 4 °C in the dark. Cells were washed 3x times in cold wash buffer then, following a final wash in cold PBS, were resuspended in 150 μΙ_ cold PBS. Cells were analysed by flow cytometry using BD Accuri C6. (aa) LPS-induced TNFct /IL-8 release in d-U937 cells
U937 cells, a human monocytic cell line, are differentiated to macrophage-type cells by incubation with phorbol myristate acetate (PMA; 100 ng/mL) for 48 to 72 hr. Cells are pre- incubated with final concentrations of test compound for 2 hr and are then stimulated with 0.1 μg/mL of LPS (from E. Coli: 01 11 :B4, Sigma) for 4 hr. The supernatant is collected for determination of TNFa and IL-8 concentrations by sandwich ELISA (Duo-set, R&D systems). The inhibition of TNFa production is calculated as a percentage of that achieved by 10 μg/mL of BIRB796 at each concentration of test compound by comparison against vehicle control. The relative 50% effective concentration (REC50) 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 (IC50) is determined from the resultant concentration-response curve.
(b) LPS-induced TNFa /IL-8 release in PBMC cells Peripheral blood mononuclear cells (PBMCs) from healthy subjects are separated from whole blood using a density gradient (Lymphoprep, Axis-Shield Healthcare). 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%C02). The supernatant is harvested for determination of IL-8 and TNFa 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 (IC50) of IL-8 and TNFa production is calculated from the dose response curve.
(c) IL-2 and IFN gamma release in CD3/CD28 stimulated PBMC cells
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/CD28 monoclonal antibodies (0.3 μg/mL eBioscience and 3 μg/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 IC50 is determined from the dose response curve.
(d) IL-1B-induced IL-8 release in HT29 cells
HT29 cells, a human colon adenocarcinoma cell line, are plated in a 96 well plate (24 hr) and pre-treated with compounds at the desired concentration for 2 hours before addition of 5 ng/mL of IL-Ι β (Abeam) for 24 hours. Supernatants are harvested for IL-8 quantification by Sandwich ELISA (Duo-set, R&D System). The IC50 is determined from the dose response curve.
(e) LPS-induced IL-8 and TNFa release in primary macrophages
PBMCs from healthy subjects are separated from whole blood using a density gradient (Lymphoprep, Axis-Shield Healthcare). Cells are incubated for 2hrs and non-adherent cells removed by washing. To differentiate the cells to macrophages, they 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 TNFa release determined by Sandwich ELISA (Duo-set, R&D System). The IC50 is determined from the dose response curve.
(f) Poly l:C-induced ICAM-1 expression in BEAS2B cells
Poly l:C is used in these studies as a simple, RNA virus mimic. Poly l:C-Oligofectamine mixture (1 μg/mL Poly l:C, ± 2% Oligofectamine, 25 μί; Invivogen Ltd., San Diego, CA, and Invitrogen, Carlsbad, CA, 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. At a time point 18 hr after poly l:C transfection, cells are fixed with 4% formaldehyde in PBS and then endogenous peroxidase is quenched by the addition of washing buffer (100 μΙ_, 0.05% Tween in PBS: PBS-Tween) containing 0.1 % sodium azide and 1 % hydrogen peroxide. Cells are washed with wash-buffer (3 x 200 μΙ_) and after blocking the wells with 5% milk in PBS-Tween (100 μΙ_) for 1 hr, the cells are incubated with anti-human ICAM-1 antibody (50 μΙ_; Cell Signalling Technology, Danvers, MA) in 1 % BSA PBS overnight at 4°C.
The cells are washed with PBS-Tween (3 x 200 μΙ_) and incubated with the secondary antibody (100 μΙ_; HRP-conjugated anti-rabbit IgG, Dako Ltd., Glostrup, Denmark). The cells are then incubated with substrate (50 μΙ_) for 2-20min, followed by the addition of stop solution (50 μΙ_, 1 N H2S04). 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 x 200 μΙ_) and total cell numbers in each well are determined by reading absorbance at 595 nm after Crystal Violet staining (50 μΙ_ of a 2% solution in PBS) and elution by 1 % SDS solution (100 μΙ_) 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 (IC50) is determined from the resultant concentration-response curve.
(g) Cell mitosis assay
Peripheral blood mononucleocytes (PBMCs) 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. At 2 hr before collection, PBMCs are treated with demecolcine (0.1 μg/mL; Invitrogen, Paisley, UK) to arrest cells in metaphase. To observe mitotic cells, PBMCs are permeabilised and fixed by adding Intraprep (50 μί; Beckman Coulter, France), and stained with anti-phospho-histone 3 (0.26 ng/L; #9701 ; Cell Signalling, Danvers, MA) 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.
(h) Rhinovirus-induced IL-8 release and ICAM- 1 expression
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 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, MN). The level of ICAM-1 expressing cell surface is determined by cell-based ELISA. At 72 hr after infection, 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 with 1 % SDS solution. The measured OD450-655 readings are corrected for cell number by dividing with the OD595 reading in each well. Compounds are added 2 hr before HRV infection and 2 hr after infection when non-infected HRV is washed out. (i) Assessment of HRV 16 induced Cvtopathic Effect (CPE) in MRC5 cells
MRC5 cells are infected with HRV16 at an MOI of 1 in DMEM containing 5% FCS and 1.5 mM MgCI2, 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 μΙ_, 2% formaldehyde, 10% methanol and 0.175% Methylene Blue) for 2 hr at RT. After washing, 1 % SDS in distilled water (100 μΙ_) 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 IC50 value is calculated from the concentration-response curve generated by the serial dilutions of the test compounds.
(j) In vitro RSV virus load in primary bronchial epithelial cells
Normal human bronchial epithelial cells (NHBEC) grown in 96 well plates are infected with RSV A2 (Strain A2, HPA, Salisbury, UK) at a 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 washed with PBS (3 x 200 μΙ_), then fresh media (200 μΙ_) 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 μΙ_) for 20 min, washed with WB (3 x 200 μΙ_) (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 x 200 μΙ_) and incubated for 1 hr at RT with anti-RSV (2F7) F-fusion protein antibody (40 μΙ_; mouse monoclonal, lot 798760, Cat. No.ab43812, Abeam) in 5% BSA in PBS-tween. After washing, cells are incubated with an HRP-conjugated secondary antibody solution (50 μΙ_) in 5% BSA in PBS-Tween (lot 00053170, Cat. No. P0447, Dako) and then TMB substrate added (50 μΙ_; substrate reagent pack, lot 269472, Cat. No. DY999, R&D Systems, Inc.). This reaction is stopped by the addition of 2N H2S04 (50 μΙ_) and the resultant signal is determined colourimetrically (OD: 450 nm with a reference wavelength of 655 nm) in a microplate reader (Varioskan® Flash, ThermoFisher Scientific). Cells are then washed and a 2.5% crystal violet solution (50 μΙ_; lot 8656, Cat. No. PL7000, Pro-Lab Diagnostics) is applied for 30 min. After washing with WB, 1 % SDS in distilled water (100 μΙ_) is added to each well, and plates are shaken lightly on the shaker for 1 hr prior to reading the absorbance at 595 nm. The measured OD450.655 readings are corrected to the cell number by dividing the OD450.655 by the OD595 readings. The percentage inhibition for each well is calculated and the IC50 value is calculated from the concentration-response curve generated from the serial dilutions of compound.
(k) Cell viability assay: MTT assay
Differentiated U937 cells are pre-incubated with each test compound (final concentration 1 μg/mL or 10 μg/mL in 200 μΙ_ media indicated below) under two protocols: the first for 4 hr in 5% FCS RPMI 1640 media and the second in 10% FCS RPMI1640 media for 24 h. The supernatant is replaced with new media (200 μΙ_) and MTT stock solution (10 μΙ_, 5 mg/mL) is added to each well. After incubation for 1 hr the media are removed, DMSO (200 μΙ_) is added to each well and the plates are shaken lightly for 1 hr prior to reading the absorbance at 550 nm. The percentage loss of cell viability is calculated for each well relative to vehicle (0.5% DMSO) treatment. Consequently an apparent increase in cell viability for drug treatment relative to vehicle is tabulated as a negative percentage.
(I) Human biopsy assay
Intestinal mucosa biopsies are obtained from the inflamed regions of the colons of IBD patients. The biopsy material is cut into small pieces (2-3 mm) and placed on steel grids in an organ culture chamber at 37°C in a 5% C02/95% 02 atmosphere in serum-free media. DMSO control or test compounds at the desired concentration are added to the tissue and incubated for 24 hr in the organ culture chamber. The supernatant is harvested for determination of IL-6, IL-8, IL-1 β and TNFa levels by R&D ELISA. Percentage inhibition of cytokine release by the test compounds is calculated relative to the cytokine release determined for the DMSO control (100%).
(m) Accumulation of /3 catenin in d-U937 cells
U937 cells, a human monocytic cell line, are differentiated into macrophage-type cells by incubation with PMA (100 ng/mL) for between 48 to 72 hr. The cells are then incubated with either final concentrations of test compound or vehicle for 18 hr. The induction of β-catenin by the test compounds is stopped by replacing the media with 4% formaldehyde solution. Endogenous peroxide activity is neutralised by incubating with quenching buffer (100 μΙ_, 0.1 % sodium azide, 1 % H202 in PBS with 0.05% Tween-20) for 20 min. The cells are washed with washing buffer (200 μΙ_; PBS containing 0.05% Tween-20) and incubated with blocking solution (200 μΙ_; 5% milk in PBS) for 1 hr, re-washed with washing buffer (200 μΙ_) and then incubated overnight with anti^-catenin antibody solution (50 μΙ_) in 1 % BSA/PBS (BD, Oxford, UK). After washing with washing buffer (3 x 200 μΙ_; PBS containing 0.05% Tween-20), cells are incubated with a HRP-conjugated secondary antibody solution (100 μΙ_) in 1 % BSA/PBS (Dako, Cambridge, UK) and the resultant signal is determined colourimetrically (OD: 450 nm with a reference wavelength of 655 nm) using TMB substrate ( 50 μΙ_; R&D Systems, Abingdon, UK). This reaction is stopped by addition of 1 N H2S04 solution (50 μΙ_). Cells are then washed with washing buffer and 2% crystal violet solution (50 μΙ_) is applied for 30 min. After washing with washing buffer (3 x 200 μΙ_), 1 % SDS (100 μΙ_) is added to each well and the plates are shaken lightly for 1 hr prior to measuring the absorbance at 595 nm (Varioskan® Flash, Thermo-Fisher Scientific).
The measured OD450.655 readings are corrected for cell number by dividing the OD450.655 by the OD595 readings. The percentage induction for each well is calculated relative to vehicle, and the ratio of induction normalised in comparison with the induction produced by a standard control comprising the Reference compound A/-(4-(4-(3-(3-te/f-butyl-1-p-tolyl-1/-/- pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide (1 μg/mL), which is defined as unity.
(n) T cell proliferation
PBMCs from healthy subjects are separated from whole blood using a density gradient (Lymphoprep, Axis-Shield Healthcare). The lymphocyte fraction is first enriched for CD4+ T cells by negative magnetic cell sorting as per the manufacturer's instructions (Miltenyi Biotec 130-091-155). Naive CD4+ T cells are then separated using positive magnetic selection of CD45RA+ cells using microbeads as per the manufacturer's instructions (130-045-901). Cells are plated at 2x105 cells per well in 100 μΙ_ RPMI/10%FBS on 96 well flat bottomed plate (Corning Costar). 25 μΙ_ of test compound are diluted to the appropriate concentration (8x final concentration) in normal medium and added to duplicate wells on the plate to achieve a dose response range of 0.03 ng/mL - 250 ng/mL. DMSO is added as a negative control. Plates are allowed to pre-incubate for 2 hours before stimulation with 1 μg/mL anti- CD3 (OKT3; eBioscience). After 72 h, the medium in each well is replaced with 150 μΙ_ of fresh medium containing 10 μΜ BrdU (Roche). After 16 h, the supernatant is removed, the plate is dried and the cells fixed by adding 100 μΙ_ of fix/denature solution to each well for 20 min as per the manufacturer's instructions (Roche). Plates are washed once with PBS before addition of the anti-BrdU detection antibody and incubated for 90mins at room temperature. Plates are then washed gently 3x with the wash buffer supplied and developed by addition of 100 μΙ_ of substrate solution. The reaction is stopped by addition of 50 μΙ_ of 1 M H2S04 and read for absorbance at 450 nm on a plate reader (Varioskan® Flash, ThermoFisher Scientific). The IC50 is determined from the dose response curve. (o) IL-2 and IFNv release in CD3/CD28 stimulated LPMC cells from IBP patients
Lamina propria mononuclear cells (LPMCs) are isolated and purified from inflamed IBD mucosa of surgical specimens or from normal mucosa of surgical specimens as follows: The mucosa is removed from the deeper layers of the surgical specimens with a scalpel and cut in fragments of size 3-4mm. The epithelium is removed by washing the tissue fragments three times with 1 mM EDTA (Sigma-Aldrich, Poole, UK) in HBSS (Sigma-Aldrich) with agitation using a magnetic stirrer, discarding the supernatant after each wash. The sample is subsequently treated with type 1A collagenase (1 mg/mL; Sigma-Aldrich) for 1 h with stirring at 37°C. The resulting cell suspension is then filtered using a 100 μηι cell strainer, washed twice, resuspended in RPMI-1640 medium (Sigma-Aldrich) containing 10% fetal calf serum, 100 U/mL penicillin and 100 μg/mL streptomycin, and used for cell culture.
Freshly isolated LPMCs (2x105 cells/well) are stimulated with 1 μg/mL a-CD3/a-CD28 for 48 h in the presence of either DMSO control or appropriate concentrations of compound. After 48 h, the supernatant is removed and assayed for the presence of TNFa and IFNy by R&D ELISA. Percentage inhibition of cytokine release by the test compounds is calculated relative to the cytokine release determined for the DMSO control (100%).
(p) Inhibition of cytokine release from myofibroblasts isolated from IBP patients
Myofibroblasts from inflamed IBD mucosa are isolated as follows:
The mucosa is dissected and discarded and 1 mm-sized mucosal samples are cultured at 37°C in a humidified C02 incubator in Dulbecco's modified Eagle's medium (DMEM, Sigma- Aldrich) supplemented with 20% FBS, 1 % non-essential amino acids (Invitrogen, Paisley, UK), 100 U/mL penicillin, 100 μg/mL streptomycin, 50 μg/mL gentamycin, and 1 μg/mL amphotericin (Sigma-Aldrich). Established colonies of myofibroblasts are seeded into 25- cm2 culture flasks and cultured in DMEM supplemented with 20% FBS and antibiotics to at least passage 4 to provide a sufficient quantity for use in stimulation experiments.
Subconfluent monolayers of myofibroblasts, seeded in 12-well plates at 3x105 cells per well, are starved in serum-free medium for 24 h at 37°C, 5%C02, before being cultured for 24 h in the presence of either DMSO control or appropriate concentrations of compound. After 24 h, the supernatant is removed and assayed for the presence of IL-8 and IL-6 by R&D ELISA. Percentage inhibition of cytokine release by the test compounds is calculated relative to the cytokine release determined for the DMSO control (100%).
(q) Human neutrophil degranulation
Neutrophils are isolated from human peripheral blood as follows:
Blood is collected by venepuncture and anti-coagulated by addition of 1 : 1 EDTA:sterile phosphate buffered saline (PBS, no Ca+/Mg+). Dextran (3% w/v) is added (1 part dextran solution to 4 parts blood) and the blood allowed to stand for approximately 20 minutes at rt. The supernatant is carefully layered on a density gradient (Lymphoprep, Axis-Shield Healthcare) and centrifuged (15 mins, 2000rpm, no brake). The supernatant is aspirated off and the cell pellet is re-suspended in sterile saline (0.2%) for no longer than 60 seconds (to lyse contaminating red blood cells). 10 times volume of PBS is then added and the cells centrifuged (5 mins, 1200 rpm). Cells are re-suspended in HBSS+ (Hanks buffered salt solution (without phenol red) containing cytochalasin B (5 μg/mL) and 1 mM CaCI2) to achieve 5 x 106 cells/mL. 5 x 104 cells are added to each well of a V-bottom 96 well plate and are incubated (30 mins, 37°C) with the appropriate concentration of test compound (0.3 - 1000 ng/mL) or vehicle (DMSO, 0.5% final cone). Degranulation is stimulated by addition of fMLP (final concentration 1 μΜ). After a further incubation (30 mins, 37 °C), the cells are removed by centrifugation (5 mins, 1500 rpm) and the supernatants transferred to a flat bottom 96 well plate. An equal volume of tetramethylbenzidine (TMB) is added and, after 10 mins, the reaction terminated by addition of an equal volume of sulphuric acid (0.5 M) and absorbance read at 450 nm (background at 655nm subtracted). The 50% inhibitory concentration (IC50) is determined from the resultant concentration-response curve.
(r) Cell cytotoxicity assay
5 x 104 TK6 cells (lymphoblastic T cell line) are added to the appropriate number of wells of a 96 well plate in 195 μΙ_ of media (RPMI supplemented with 10% foetal bovine serum). 5 μΙ_ of DMSO control (final concentration 0.5% v/v) or test compound (final concentration either 5 or 1 μg/mL) is added to the wells and incubated at 37°C, 5% C02. After 24 hours, the plate is centrifuged at 1300 rpm for 3 minutes and the supernatant discarded. Cells are then resuspended in 7.5 μg/mL propidium iodide (PI) in PBS. After 15 minutes, cells are analysed by flow cytometry (BD accuri). The % viability is calculated as the % of cells that are PI negative in the test wells normalised to the DMSO control.
In Vivo Screening: Pharmacodynamics and Anti-inflammatory Activity
(i) LPS-induced neutrophil accumulation in mice
Non-fasted Balb/c mice are dosed by the intra tracheal route with either vehicle, or the test substance at the indicated times (within the range 2-8 hr) before stimulation of the inflammatory response by application of an LPS challenge. At T = 0, mice are placed into an exposure chamber and exposed to LPS (7.0 mL, 0.5 mg/mL solution in PBS) for 30 min. After a further 8 hr, the animals are anesthetized, their tracheas cannulated and BALF extracted by infusing and then withdrawing from their lungs 1.0 mL of PBS via the tracheal catheter. Total and differential white cell counts in the BALF samples are measured using a Neubaur haemocytometer. Cytospin smears of the BALF samples are prepared by centrifugation at 200 rpm for 5 min at RT and stained using a DiffQuik stain system (Dade Behring). Cells are counted using oil immersion microscopy. Data for neutrophil numbers in BAL are represented as mean ± S.E.M. (standard error of the mean). The percentage inhibition of neutrophil accumulation is calculated for each treatment relative to vehicle treatment.
(ii) Cigarette smoke model
A/J mice (males, 5 weeks old) are exposed to cigarette smoke (4% cigarette smoke, diluted with air) for 30 min/day for 11 days using a Tobacco Smoke Inhalation Experiment System for small animals (Model SIS-CS; Sibata Scientific Technology, Tokyo, Japan). Test substances are administered intra-nasally (35 μί of solution in 50% DMSO/PBS) once daily for 3 days after the final cigarette smoke exposure. At 12 hr after the last dosing, each of the animals is anesthetized, the trachea cannulated and bronchoalveolar lavage fluid (BALF) is collected. The numbers of alveolar macrophages and neutrophils are determined by FACS analysis (EPICS® ALTRA II, Beckman Coulter, Inc., Fullerton, CA, USA) using anti-mouse MOMA2 antibody (macrophage) or anti-mouse 7/4 antibody (neutrophil). (iii) DSS-induced colitis in mice
Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavage twice daily with either vehicle, reference item (5-ASA) or test compound one day before (Day -1) stimulation of the inflammatory response by treatment with dextran sodium sulphate (DSS). On Day 0 of the study, DSS (5% w/v) is administered in the drinking water followed by BID dosing of the vehicle (5 mL/kg), reference (100 mg/kg) or test compound (5 mg/kg) for 7 days. The drinking water with DSS is replenished every 3 days. During the study, animals are weighed every day and stool observations are made and recorded as a score, based on stool consistency. At the time of sacrifice on Day +6, the large intestine is removed and the length and weight are recorded. Sections of the colon are taken for either MPO analysis, to determine neutrophil infiltration, or for histopathology scoring to determine disease severity.
(iv) TNBS-induced colitis in mice
Non-fasted, 10-12 week old, male BDF1 mice are dosed by oral gavage twice daily with either vehicle (5 rnUkg), reference item (Budesonide 2.5 mg/kg) or test compound (1 or 5 mg/kg) one day before (Day -1) stimulation of the inflammatory response by treatment with 2,4,6-trinitrobenzenesulphonic acid (TNBS) (15 mg/mL in 50% ethanol / 50% saline). On Day 0 of the study TNBS (200 μΙ_) is administered intra-colonically via a plastic catheter with BID dosing of the vehicle, reference or test compound continuing for 2 or 4 days. During the study, animals are weighed every day and stool observations are made and recorded as a score, based on stool consistency. At the time of sacrifice on Day 2 (or Day 4), the large intestine is removed and the length and weight recorded. Sections of the colon are taken for histopathology scoring to determine disease severity.
(v) Adoptive transfer in mice
On Study day 0, female Balb/C mice are terminated and spleens obtained for CD45RBh'9h cell isolation (Using SCID IBD cell Separation protocol). Approximately 4X105 cells/mL CD45RBh'9h cells are then injected intraperitoneal ly (100 μυηιουεβ) into female SCID animals. On study day 14, mice are weighed and randomized into treatment groups based on body weight. On Day 14, compounds are administered BID, via oral gavage, in a peanut oil vehicle at the dose levels outlined below in Tables 6a and 6b and a dose volume of 5 rnUkg. Treatment continues until study day 42, at which point the animals are necropsied 4 hours after the morning administration. The colon length and weight are recorded and used as a secondary endpoint in the study as a measurement of colon oedema. The colon is then divided into six cross-sections, four of which are used for histopathology scoring (primary endpoint) and two are homogenised for cytokine analysis. Data shown is the % inhibition of the induction window between naive animals and vehicle animals, where higher inhibition implies closer to the non-diseased, naive, phenotype.
(vi) Endotoxin-induced uveitis in rats Male, Lewis rats (6-8 weeks old, Charles River UK Limited) are housed in cages of 3 at 19- 21 °C with a 12 h light/dark cycle (07:00/19:00) and fed a standard diet of rodent chow and water ad libitum. Non-fasted rats are weighed, individually identified on the tail with a permanent marker, and receive a single intravitreal administration into the right vitreous humor (5 dose volume) of 100 ng/animal of LPS (Escherichia coli 01 11 :B4 prepared in PBS, Sigma Aldrich, UK) using a 32-gauge needle. Untreated rats are injected with PBS. Test compound, dexamethasone (Dex) or vehicle (20% hydroxypropyl-/?-cyclodextrin, 0.1 % HPMC, 0.01 % Benzalkonium chloride, 0.05% EDTA, 0.7% NaCI in deionised water) are administered by the topical route onto the right eye (10 μί) of animals 30 minutes prior to LPS, at the time of LPS administration, and 1 , 2 and 4 hours post LPS administration. Before administration, the solution or suspension to be administered is agitated for 5 minutes to ensure a uniform suspension. 6 hours after LPS dosing, animals are euthanized by overdose with pentobarbitone (i.v.). Following euthanasia, the right eye of each animal is enucleated and dissected into front (anterior) and back (posterior) sections around the lens. Each section is weighed and homogenised in 500 of sterile phosphate buffered saline followed by 20 minutes centrifugation at 12000 rpm at 4°C. The resulting supernatant is divided into 3 aliquots and stored at -80°C until subsequent cytokine analysis by R&D DuoSet ELISA. Summary of In Vitro and In Vivo Screening Results
Test Compound Dissociation Constant (nM)
Example No. Lck p38 MAPKa Syk
Example 3 2.3 6.9 10
Example 4 3.0 19 14
Example 16 4.1 9 21
Example 27 4.3 29 27
Example 75 2.5 14 8.8
Table 1a: Dissociation constants for selected kinases determined by LeadHunter Discover Services (DiscoveRx Corporation, Fremont, CA), using the KINOMEscan™ technology. Studies conducted by LeadHunter Discover Services (DiscoveRx Corporation, Fremont, CA) using the KINOMEscan™ technology determined that compounds of Example 3, 4, 16, 27 and 75 did not have any significant effect on the binding of the kinases B-Raf and B-Raf (V600E) to their standard ligands. Moreover, these compounds showed substantially improved selectivities compared to the Reference Compound A/-(4-(4-(3-(3-te/f-butyl-1-p- tolyl-1 /-/-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide
(WO 2010/1 12936), as evidenced by lower selectivity scores (Table 1 b). KinomeScan Selectivity Scores / number of individual kinase hits
Figure imgf000184_0001
Table 1 b: KinomeScan Selectivity score data at 50 and 500 nM; S(35) = (number of non- mutant kinases with %Ctrl <35)/(number of non-mutant kinases tested); S(10) = (number of non-mutant kinases with %Ctrl <10)/(number of non-mutant kinases tested); S(1) = (number of non-mutant kinases with %Ctrl <1)/(number of non-mutant kinases tested)
Test Compound IC50 Values for Enz me Inhibition nM
Example No.
1
10
11
12
H
15
_16
!Z
8
9
20
21
22
24
Figure imgf000184_0002
Test Compound IC50 Values for Enzyme Inhibition (nM) Example No. p38 MAPKa c-Src Syk GSK3a5 — — — 18926 — — — 517 41 26 443 45028 — — — 32119 26 19 96 63210 — — — 1501 — — — 1352 — — — 6293 — 1 1 28 8284 25 19 85 93305 120 13 48 5976 69 16 67 20867 — 12 43 15158 — — — 106889 140 29 571 15960 — — — 3791 — — — 4462 — — — 7053 — — — 5204 — — — 80
145 39 455 21566 1 10 15 20 6367 92 15 169 15998 229 45 490 50339 258 56 1224 83550 — — — 137961 170 15 49 9772 277 100 1258 125803 132 46 1268 87844 140 42 1192 119195 157 22 131 23656 335 45 631 7637 286 48 706 11258 181 48 461 43459 132 28 128 9780 — — — 5391 — — — 3722 32 44 1318 106453 — — — 829
— — — 14575 326 85 1289 7396 Test Compound IC50 Values for Enz me Inhibition nM Example No.
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3(a
3(b
3(c;
3(d
3(e
3(f)
3(fl
4(a
4(b
4(c;
4(d
4(e
4(f)
4(g
4(h
5(a
5(b
5(c;
5(d
5(e
5(f)
5(g
5(h
Figure imgf000186_0001
Test Compound IC50 Values for Enz me Inhibition nM Example No.
85(1)
85(j)
85(k)
85i!i
85(m)
85(n)
85(o)
85(pl
85(q)
85(r)
85(s)
85(t
85(u)
85(v)
85(w)
85(x)
85(y)
Figure imgf000187_0001
Table 1c. Results from in vitro p38 MAPKa (Method 2), c-Src, Syk and GSK3a (Method 2) inhibition assays
IC50 Values (ng/mL)
Test Article
phospho-p38 MAPKa phospho-Lck
Example 16 20 6
Table 1 d. Data from phosphoflow assays evaluating cellular p38 MAPKa and Lck inhibition with the compound of Example 16.
ICso Val ues for Inhibition of Cytokine Release (nM)
Test Compound
dU937 cells PBMCs HT29 cells Example No.
IL-8 TNFa IL-8 TNFa IL-2 IFNy IL-8
1 — — 1.4 — 112.1 10.4 —
2 — — 142.0 — 1368.4 35.7 —
3 1.3 0.4 1.2 — 190.2 9.6 8.1
4 0.8 1.0 1.4 0.7 40.5 4.2 4.9
5 1.4 0.5 2.4 — 151.3 10.3 6.8
6 — — 0.8 — 89.9 9.3 —
7 — — 1.1 — — — —
8 — — 28.1 — — — —
9 — — 1.2 — — — —
10 0.8 0.3 2.3 — 9.0 4.4 4.6
11 1.4 1.2 2.6 — 73.6 17.7 9.3 IC5Q Values for Inhibition of Cytokine Release (nM) l est uompouna
dU937 cells PBMCs HT29 cells Example No.
IL-8 TNFa IL-8 TNFa IL-2 IFNy IL-8
12 — — 107.0 — — — 1324.8
13 — — 1.3 — 57.4 4.6 —
14 0.6 0.5 1.7 — 182.2 19.7 3.0
15 — — 0.9 — — — —
16 — — 1.5 — 74.0 7.3 8.0
17 1.4 1.8 — 65.6 8.2 5.1
18 — — 1.0 — — — —
19 — — 8.7 — — — —
20 — — 1.1 — 84.3 9.0 —
21 — — 34.4 — — — —
22 — — 16.9 — — — —
23 — — 2.6 — 17.1 9.1 4.7
24 — — 1.9 — 24.9 10.7 —
25 — — 7.0 — — — —
26 — — 21.7 — — — —
27 — — 1.9 — 46.3 1 1.0 8.3
28 — — 11.9 — — — —
29 — — 2.3 — 51.2 3.5 0.6
30 — — 5.7 — — — —
31 — — 7.2 — — — —
32 — — 7.7 — — — —
33 — — 4.2 — — — —
34 — — 3.0 — 62.5 7.6 2.1
35 — — 1.4 — 51.0 3.5 —
36 — — 1.8 — 65.3 5.7 0.8
37 — — 2.2 — — — —
38 — — 6.3 — — — —
39 — — 2.5 — 132.3 9.6 5.3
40 — — 3.1 — — — —
41 — — 4.5 — — — —
42 — — 6.6 — — — —
43 — — 2.0 — — — —
44 — — 86.8 — — — —
45 — — 1.4 — 182.2 7.8 2.1
46 — — 0.9 — — 2.0 —
47 — — 1.6 — 102.5 7.3 —
48 — — 3.4 — 144.5 17.2 10.2
49 — — 2.5 — 226.9 1 1.0 8.6
50 — — 12.1 — — — —
51 — — 1.6 — 46.3 1.8 1.7 IC5Q Values for Inhibition of Cytokine Release (nM) l est uompouna
dU937 cells PBMCs HT29 cells Example No.
IL-8 TNFa IL-8 TNFa IL-2 IFNy IL-8
52 — — 2.4 — 204.9 39.0 17.3
53 — — 1.6 — 181.0 14.9 6.4
54 — — 1.6 — 354.0 33.3 —
55 — — 2.2 — 35.2 12.0 4.5
56 — — 1.8 — 35.2 12.2 8.6
57 — — 3.6 — 140.3 74.5 21.2
58 — — 2.6 — 136.6 17.1 10.6
59 — — 3.3 — 58.6 7.6 —
60 — — 2.0 — — — —
61 — — 2.1 — — — —
62 — — 4.6 — 48.7 32.2 —
63 — — 17.3 — — — —
64 — — 10.5 — — — —
65 — — 4.0 — 130.8 34.4 145.4
66 — — 1.9 — 49.2 20.2 16.4
67 — — 2.7 — 200.2 39.5 —
68 — — 2.8 — 219.7 68.8 —
69 — — 1.6 — — 2.2 —
70 — — 4.9 — — 7.4 4.1
71 — — 114.3 — — — 1 145.6
72 — — 11.8 — — — 19.2
73 — — 19.0 — — — 31.6
74 — — 6.6 — — — 11.7
75 — — 5.0 — 56.8 14.9 —
76 — — 1.9 — — — —
77 — — 2.0 — — — —
78 — — 14.0 — — — —
79 — — 3.4 — 284.1 5.9 13.1
80 — — 4.3 — 1546.2 23.8 —
81 — — 2.7 — 98.8 4.0 —
82 — — 6.6 — — — —
83(a) — — 39.0 — — — 62.5
83(b) — — 3.7 — 109.2 — —
83(c) — — 1.8 — — — —
83(d) — — 12.1 — — — —
83(e) — — 8.0 — — — —
83(f) — — 13.1 — — — —
83(g) — — 7.3 — — — —
84(a) — — 12.4 — — — —
84(b) — — 9.1 — — — — IC50 Values for Inhibition of Cytokine Release (nM)
Test Compound
dU937 cells PBMCs HT29 cells Example No.
IL-8 TNFa IL-8 TNFa IL-2 IFNY IL-8
84(c) — — 21.8 - —
84(d) — — 11.5 —
84(e) — — 1.3 —
84(f) — — 13.5 - —
84(g) — — 0.7 - 43.5 1.3 —
84(h) — — 0.7 - 51.3 1.7 —
85(a) — — 0.8 - 53.8 1 1.8 —
85(b) — — 1.5 - 123.3 16.2 —
85(c) — — 4.6 - - —
85(d) — — 2.1 - 94.3 15.4 —
85(e) — — 1.7 —
85(f) — — 0.7 - - —
85(g) — — 1.0 —
85(h) — — 2.2 - 150.2 23.0 —
85(i) — — 1.5 - - —
850) — — 2.1 - - —
85(k) — — 1.7 - 57.1 9.3 —
85(11 — — 2.8 - - —
85(m) — — 1.8 - - —
85(n) — — 1.9 - - —
85(o) — — _ _ _ _ —
el — — 7.1 - - —
85(g) — — 6.1 - - —
85(r) — — 0.6 - - —
85(s) — — _ _ _ _ —
85φ — — _ _ _ _ —
85(u) — — 1.4 —
85(v) — — 0.4 - - —
85(w) — — 2.9 - - —
85(x) — — 0.9 - - —
85(y) — — 1.7 —
Table 2. Inhibition of cytokine release in stimulated cells (assays (aa), (b), (c) and (d) above).
As illustrated in Table 3 below, the compounds of Examples 4, 16 and 27 were also screened in cellular assay (I), i.e., the ex-vivo human biopsy model described above, where they demonstrated significant anti-inflammatory effects in biopsies from ulcerative colitis (UC) patients. In contrast to healthy volunteers, intestinal mucosal biopsies from UC patients have been shown to spontaneously release pro-inflammatory cytokines in vitro (Onken.J.E. et al., J Clin Immunol, 2008, 126(3): 345-352). Thus, the compounds of Examples 4, 16 and 27 significantly inhibited cytokine (I L-1 β, IL-6 and IL-8) release compared to the DMSO control when incubated, at 1 μg/mL, for 24 hours with biopsies from ulcerative colitis patients.
Treatment group Cytokine release from biopsies of UC patients
Figure imgf000191_0001
Table 3: Summary of results from assays using intestinal mucosa biopsies from the inflamed regions of the colon of various patients suffering from ulcerative colitis (a form of IBD).
As illustrated in Table 4a below, compounds of the examples of the present invention are, for the most part, markedly less active than the Reference Compound (A/-(4-(4-(3-(3-te/f-butyl-
1-p-tolyl-1/-/-pyrazol-5-yl)ureido)naphthalen-1-yloxy)pyridin-2-yl)-2-methoxyacetamide;
WO 2010/112936) in assay (g) above, which measures impact on cell division (mitosis) in
PBMCs.
Test compound % Inhibition of mitosis at 5 g/mL
Reference compound 87.8a
1 22.1
2 4.0
3 31.7
4 43.0
5 44.9
6 41.7
7 NT
8 NT
9 NT
10 70.2
11 33.5
12 NT
13 46.1
14 49.8
15 97.5
16 20.5
17 37.0
18 92.7
19 NT
20 44.3
21 NT
22 NT
23 25.4 Test compound % Inhibition of mitosis at 5 g/mL
24 22.5
25 NT
26 NT
27 49.8
28 NT
29 34.6
30 NT
31 NT
32 NT
33 NT
34 40.4
35 41.1
36 45.0
37 45.9
38 NT
39 34.7
40 NT
41 NT
42 NT
43 NT
44 NT
45 45.0
46 67.1
47 59.1
48 44.2
49 40.1
50 NT
51 44.3
52 31.0
53 30.3
54 37.8
55 54.3
56 46.4
57 42.1
58 41.7
59 55.3
60 NT
61 NT
62 NT
63 NT
64 NT
65 51.1 Test compound % Inhibition of mitosis at 5 g/mL
66 66.6
67 35.6
68 NT
69 NT
70 NT
71 NT
72 NT
73 NT
74 NT
75 42.6
76 91.3
77 NT
78 NT
79 54.4
80 70.4
81 58.1
82 NT
83(a) NT
83(b) NT
83(c) 57.1
83(d) NT
83(e) NT
83(f) NT
83(g) NT
84(a) NT
84(b) NT
84(c) NT
84(d) NT
84(e) NT
84(f) NT
84(g) 84.6
84(h) 87.0
85(a) 46.3
85(b) 25.3
85(c) NT
85(d) 33.2
85(e) NT
85(f) NT
85(g) NT
85(h) 27.5
85(i) NT
850 NT Test compound % Inhibition of mitosis at 5 g/mL
85(k) 41.0
85(1) NT
85(m) 26.4
85(n) 26.6
85(o) NT
85(p) NT
85(q) NT
85(r) NT
85(s) NT
85(t) NT
85(u) 38.4
85(v) NT
85(w) NT
85(x) NT
85(y) 20.1
Table 4a: Effect of compounds of the examples on cell division in PBMCs (NT = not tested) a See, for example, the value reported in WO 2013/050757.
As illustrated in Table 4b below, compounds of the examples of the present invention did not elicit any substantial β-catenin induction when studied in assay (m) above. Thus, the potential of those compounds tested to increase cellular concentrations of β-catenin was found to be negative in that their inductive effect at various test concentrations was substantially less than the effect produced by the Reference Compound at 1 μg/mL.
% β-catenin induction
Figure imgf000194_0001
% β-catenin induction
Test compound Concentration of test compound
Figure imgf000195_0001
% β-catenin induction
Test compound Concentration of test compound
Figure imgf000196_0001
% β-catenin induction
Test compound Concentration of test compound
Figure imgf000197_0001
Table 4b: Effect of compounds of the examples on β-catenin induction (NT = not tested)
As illustrated in Table 5 below, the compounds of Examples 3, 4, 16, 27, 34, 75 and 79 were also screened in in vivo assay (iv) above, as conducted over 2 days and employing a vehicle comprising a defined mixture of corn oil (32.5%), transcutol (20%), maisine (12.5%) and cremophor ELP (35%). Histopathology analysis revealed that the compounds of Examples 3, 4, 16, 27, 34, 75 and 79 displayed substantial activity in this in vivo model of colonic inflammation. In particular, these compounds, when dosed orally at 5 mg/kg, demonstrated marked improvements in ulcer grade and epithelial repair compared to the vehicle control. Furthermore, they produced a marked reduction in inflammatory cell infiltrate in the reticular and laminar propria zones.
Figure imgf000198_0001
Table 5: Effect of compounds of the examples on TNBS-induced colitis in mice.
As illustrated in Tables 6a and 6b below, the compounds of Examples 3, 4, 16 and 27 were also screened in the in vivo (adoptive transfer) assay (v) above. Analysis of the relative ratios of colon weight to length in naive, control and treated animals at the end of the study revealed that the compounds of Examples 3, 4, 16 and 27 displayed significant activity in this T cell driven in vivo model of colonic inflammation.
Figure imgf000198_0002
Table 6a: Summary of results from adoptive transfer mouse model. Treatment group n Colon weight:length
Non-diseased 4 0.021 ± 0.001
Vehicle control 12 0.047 ± 0.004
Example 3 (3 mg/kg) 12 0.039 ± 0.003
Example 16 (3 mg/kg) 12 0.034 ± 0.003
Example 16 (0.3 mg/kg) 12 0.041 ± 0.005
Example 16 (0.03 mg/kg) 12 0.033 ± 0.002
Example 27 (3 mg/kg) 12 0.034 ± 0.003
Example 27 (0.3 mg/kg) 12 0.038 ± 0.004
Example 27 (0.03 mg/kg) 12 0.047 ± 0.005
Table 6b: Summary of further results from an additional study in the adoptive transfer mouse model. As illustrated in Table 6c below, the compounds of Examples 4, 16 and 27 also significantly reduced levels of pro-inflammatory cytokines in samples of colon tissue from mice in the adoptive transfer model.
Figure imgf000199_0001
Table 6c: Summary of cytokine level measurements from adoptive transfer mouse model.
As illustrated in Tables 7a, 7b and 7c below, the compounds of Examples 4, 27, 29, 66 and 75 significantly reduced cytokine levels in both the anterior and posterior segments of the eyes of rats treated with intravitreal endotoxin LPS (see assay (vi) above).
Figure imgf000199_0002
Table 7a: Effect of compounds of the examples on cytokine levels in the eyes of LPS- stimulated rats.
Figure imgf000200_0001
Table 7b: Effect of compounds of the examples on cytokine levels in the eyes of LPS- stimulated rats.
Figure imgf000200_0002
Table 7c: Effect of compounds of the examples on cytokine levels and cell counts in the eyes of LPS-stimulated rats.
Summary of Additional Studies Determination of Pharmacokinetic Parameters
Studies were conducted by Sai Life Sciences (Hinjewadi, Pune, India) to investigate the plasma pharmacokinetics and total colon tissue distribution of compounds of the invention. In particular, pharmacokinetic studies were carried out in:
- male C57BL/6 mice, following a single oral administration; and
- male Wistar rats following a single intravenous or oral administration.
The data reveal that the compounds of the invention achieve substantial colonic concentrations, while plasma exposures are very low or negligible.
Time (h)
Example Vehicle 1 2 4 6 8 12 24
3 B 0.0 0.0 0.0 114 0.0 0.0 0.0
4 A 5.1 23.2 2.6 0.7 0.0 0.0 0.0
16 B 0.0 0.0 0.0 0.0 0.0 0.0 0.0
27 B 1.9 1.2 0.0 1.3 0.0 1.1 0.0
75 B 1.8 1.5 0.0 0.0 0.0 0.0 0.0 Table 8a: Median plasma concentrations (ng/mL) obtained following oral administration of compounds of the invention to mice at 5 mg/kg.
Key
Vehicle A = peanut oil
Vehicle B = corn oil:transcutol:maisine:cremophor ELP (32.5:20:12.5:35)
Time (h)
Example Vehicle 1 2 4 6 8 12 24
3 B 107 274 209 255 278 232 19.1
4 A 107 1718 2405 5242 2096 1188 1 18
16 B 0.0 10.4 420 3080 1951 126 23
27 B 7.0 52.0 250 438 246 1201 157
75 B 17.8 56.2 1338 5715 350 391 7.5
Table 8b: Median total colon concentrations (ng/g) obtained following oral administration of various Compound Examples to mice at 5 mg/kg (vehicles A and B are as in respect of Table
8a).
Co AUCiast AUCiNF Vss
Example Ti 2 (h) CI (mL/min/kg)
(ng/mL) (h*ng/mL) (h*ng/mL) (L/kg)
3 4379 820 821 0.2 5.1 0.1
4 3038 558 563 0.8 7.9 0.2
16 6536 869 871 0.1 4.8 0.03
27 3877 588 590 0.8 7.1 0.1
29 2505 293 295 0.7 14.2 0.3
75 3998 948 952 1.2 4.4 0.1
Table 9a: Pharmacokinetic data obtained following intravenous administration of various
Compound Examples to rats at 0.25 mg/kg in 5% DMSO-7.5% Solutol HS15-87.5% normal saline.
AUCiast AUCiNF
Example Vehicle Tmax (h) Cmax (ng/mL)
(h*ng/mL) (h*ng/mL) Fpo (%)
3 B NC[il NC[il NC[il NC[il 0.0
4 C 0.5 15.5 27.0 40.8 0.2
16 B NC[il NC[il NC[il NC[il 0.0
27 B NC[il NC[il NC[il NC[il 0.0
75 B 5.3 3.8 26.6 NC[il 0.1 Table 9b: Pharmacokinetic data obtained following oral administration of various Compound Examples to rats at 5 mg/kg.
Key
Vehicle B = as in respect of Table 8a.
Vehicle C = 2% hydroxypropyl methylcellulose and 0.5% Tween 80 in water.
[il Not calculated because no compound was detected in plasma. Time (h)
Example Vehicle 0.25 0.5 1 2 4 6 8 12 24
3 B NM[il 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
4 C NM[il 13.3 8.6 3.5 2.1 0.0 0.0 0.0 0.0
16 B 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
27 B 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0 0.0
75 B 0.0 0.0 0.0 1.2 3.1 2.0 3.2 2.3 0.0
Table 9c: Median plasma concentrations (ng/mL) obtained following oral administration of various Compound Examples to rats at 5 mg/kg
Key
Vehicles B and C are as in respect of Table 8a
[il Not measured.
Determination of ADME Parameters Assessment of certain in vitro ADME (absorption, distribution, metabolism, and excretion) parameters for certain compounds of the invention was conducted by BioFocus (Saffron Walden, UK). The results indicate that, in general, the compounds of the invention are cleared rapidly by human hepatocytes and that they have reduced liabilities for time- dependent cytochrome P450 inhibition.
Mean intrinsic clearance
Example Ti 2 (min) Mean hepatic extraction ratio
^IJmin/million cells)
3 36 39 0.85
4 48 29 0.81
16 34 41 0.85
27 96 15 0.68
75 >200 <7 <0.50
Table 10: Data from human hepatocyte stability tests for various Compound Examples
0 min preincubation 30 min preincubation
Example IC50 (μΜ) 15 μΜ %lnh IC50 (μΜ) 15 μΜ %lnh
Ref Cpd A >15 41 0.4 92
3 >15 22 >15 51
4 >5 g[†] 2.7 58[†l
5 >15 0 >15 27
16 >15 31 7.8 54
27 >15 19 8.9 57
75 >15 3 >15 42
Table 11 a: Summary of CYP3A4 inhibition studies for various Compound Examples (results reported are the arithmetic mean of two experiments).
Key Ref Cpd A: 1-(4-((2-((7-methyl-1 H-indazol-5-yl)amino)pyrimidin-4-yl)oxy)-naphthalen- 1-yl)-3-(3-(2-methylbut-3-yn-2-yl)-1-(p-tolyl)-1 H-pyrazol-5-yl)urea (Fyfe, M. C. T., et al. WO 2014/033447).
[†l Data at 15 μΜ variable, therefore not used. Inhibition at 5 μΜ reported instead.
0 min preincubation 30 min preincubation
Example ICso (μΜ) 15 μΜ %lnh ICso (μΜ) 15 μΜ %lnh
Ref Cpd A >5 31m 1.4 66[†l
4 >15 24 >15 41
16 >15 21 >15 37
27 >15 13 >13 55
75 >15 20 >15 36
Table 11 b: Summary of CYP2C9 inhibition studies for various Compound Examples (results reported are the arithmetic mean of two experiments).
Key
Ref Cpd A: as in respect of Table 1 1a.
[†l Precipitation observed at 15 μΜ, therefore inhibition at 5 μΜ reported instead. hERG Inhibition Studies
Compounds of the invention were tested for inhibition of the human ether a go-go (hERG) channel using lonWorks™ patch clamp electrophysiology at Essen Bioscience (Welwyn Garden City, England).
Example ICso (μΜ) % Inhibition at 3 μΜ
3 >3.0 -2 ± 2
4 >3.0 ^1 ± 2
16 >3.0 -12 ± 4
27 >3.0 -3 ± 5
75 >3.0 0 ± 6
Table 12: hERG inhibition data for compounds of the invention Analysis of Metabolites
Studies were conducted by BioFocus (Saffron Walden, UK) to determine the metabolic fate of the compound of Example 16 following incubation with rat, Cynomolgus macaque or human hepatocytes. Separate incubations (n=3) of the compound of Example 16 (10 μΜ initial concentration) or DMSO control, were performed with cryopreserved hepatocytes from each species (0.5 million cell/mL) at 37°C for 0, 60 and 90 minutes before termination of reactions and compound extraction with acetonitrile. Sample replicates were pooled prior to analysis. Potential metabolites were identified using time-of-flight (TOF) and triple quadruple (TQ) mass spectrometers. The results reveal that the Compound of Example 16 forms 9 metabolites in hepatocytes, 8 of which result from oxidation on the polyethylene glycol chain of the amide moiety. The other metabolite, seen principally in cynomolgus macaque hepatocytes, arises via oxidation on the 5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl fragment. Thus, no products were noted that could be connected to metabolism at the naphthalene moiety, a phenomenon that results in the hepatotoxicity associated with p38cr inhibitor BIRB796 (Iwano, S., et al., J. Appl. Toxicol. 2011 , 31, 671-677). All metabolites identified in human hepatocyte incubations were also detected in either rat or cynomolgus macaque hepatocyte incubations.
Mutagenicity Assessment (Bacterial Reverse Mutation Screen)
Studies were conducted by Sequani (Ledbury, Herefordshire, UK) to assess compounds of the invention for their ability to induce mutations in two histidine dependent auxotrophic mutants of Salmonella typhimurium, strains TA98 and TA100 in vitro.
The mutation screen was conducted using the plate incorporation method and was performed in both the presence and absence of S-9 mix (a liver post-mitochondrial fraction derived from the livers of Aroclor 1254 treated rats). The bacteria were exposed to test compounds dissolved in dimethylsulphoxide, which solvent was also used as the negative control. The dose levels used were 0.32, 1.6, 8, 40, 200, 1000 or 5000 g/plate.
Analysable treatment levels of test compounds were limited by insolubility to 1000 μg/plate, as heavy precipitation observed at 5000 μg/plate affected the scoring of the colonies. Precipitation was also noted in both strains at 1000 μg/plate in the presence and absence of S-9 mix.
The compounds of Examples 4, 16, 27 and 75 produced no dose-related or statistically significant increases in revertant colonies in either Salmonella typhimurium strain in the presence or absence of S-9 mix.
Hydrolvtic Stability Study Chemical stability of compounds of the invention was assessed in a mixture of DMSO and water (3: 1) at a test compound concentration of 1 mg/mL
General HPLC procedure
Agilent, Waters X-Select C18, 2.5 μητι, 4.6x30 mm column, 4 min method, 5-95% MeCN/water (0.1 % formic acid).
Flow rate 2.5 ml/min.
Column Oven Temperature 40°C.
Detection 254 nm. Sample preparation
A 1.0 mg sample of test compound was dissolved in 750 μΙ_ of DMSO. Water (250 μΙ_) was added slowly, ensuring no precipitation occurred.
Recording stability
A 50 μΙ_ aliquot of the test solution was removed and analysed in duplicate by 5 μΙ_ HPLC injections. The peak area for the test compound was recorded following manual integration of the corresponding UV trace.
The test solution was heated to 60°C, with stirring, and 50 μΙ_ aliquots removed for HPLC analysis at 5 and 24 h timepoints. In all cases, 5 μΙ_ injections were used and the samples analysed in duplicate.
The peak areas for the test compounds were recorded at both subsequent timepoints and the % decomposition calculated from the % change in peak area over time.
Reference Compound B (3-ethynyl-5-((4-((4-(3-(3-isopropyl-1-(p-tolyl)-1 /-/-pyrazol-5- yl)ureido)naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-/\/-(2-morpholinoethyl)benzamide) was included in each stability study as a control to validate the study. In contrast to the compounds of the present invention, this Reference Compound underwent substantial decomposition under the conditions of the experiment.
The results of the study are reported in the table below.
Test Compound Time (min) % Parent Remaining
Reference Compound B 0 100
300 82
1440 36
Example 4 0 100
300 103
1440 102
Example 16 0 100
300 100
1440 100
Example 27 0 100
300 102
1440 102
Example 75 0 100
300 101
1440 99 Abbreviations
AcOH glacial acetic acid
aq aqueous
5-ASA 5-aminosalicylic acid
ATP adenosine-5'-triphosphate
BALF bronchoalveolar lavage fluid
BID bis in die (twice-daily)
BINAP 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium
BOP
hexafluorophosphate
br broad
BrdU 5-bromo-2'-deoxyuridine
BSA bovine serum albumin
CatCart® catalytic cartridge
CDI 1 ,1-carbonyl-diimidazole
COPD chronic obstructive pulmonary disease
d doublet
dba dibenzylideneacetone
DBU 1 ,8-diazabicyclo[5.4.0]undec-7-ene
DCC dicyclohexylcarbodiimide
DCM dichloromethane
DIAD diisopropyl azodicarboxylate
DIPEA diisopropylethylamine
DMAP 4-dimethylaminopyridine
DMEM Dulbecco's modified eagle medium
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
DPPA diphenylphosphoryl azide
d-U937 cells PMA differentiated U-937 cells
EDTA ethylenediaminetetraacetic acid
ELISA enzyme-linked immunosorbent assay
(ES-) electrospray ionization, negative mode
(ES+) electrospray ionization, positive mode
Et ethyl
Et3N triethylamine
EtOAc ethyl acetate
EtOH ethanol
FACS fluorescence-activated cell sorting
FBS foetal bovine serum
FCS foetal calf serum
fMLP formyl-methionyl-leucyl-phenylalanine FRET fluorescence resonance energy transfer
GSK3a glycogen synthase kinase 3a
HBEC primary human bronchial epithelial cells
HBSS Hank's balanced salt solution
HPLC high performance liquid chromatography
HPMC hydroxypropylmethylcellulose
h or hr hour(s)
2-(1 H-7-azabenzotriazol-1-yl)-1 , 1 ,3,3-tetramethyl uronium hexafluorophosphate
HOAt 1 -hydroxy- 7-azabenzotriazole
HOBt hydroxybenzotriazole
HRP horseradish peroxidise
HRV human rhinovirus
ICAM-1 inter-cellular adhesion molecule 1
IFNy interferon-γ
IL interleukin
iPrOAc isopropyl acetate
JNK c-Jun N-terminal kinase
LC liquid chromatography
Lck lymphocyte-specific protein tyrosine kinase
LPS lipopolysaccharide
m multiplet
(M+H)+ protonated molecular ion
MAPK mitogen-activated protein kinase
MAPKAP-K2 mitogen-activated protein kinase-activated protein kinase-2 mCPBA mefa-chloroperbenzoic acid
Me methyl
MeCN acetonitrile
MeOH methanol
MHz megahertz
min or mins minute(s)
MMAD mass median aerodynamic diameter
MOI multiplicity of infection
MPO myeloperoxidase
MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide
MS mass spectrometry
m/z mass-to-charge ratio
NMP N-methyl pyrrolodinone
NMR nuclear magnetic resonance (spectroscopy)
OD optical density
PBMC peripheral blood mononuclear cell PBS phosphate buffered saline
Ph phenyl
PHA phytohaemagglutinin
PMA phorbol myristate acetate
pTSA 4-methylbenzenesulfonic acid (para-toluenesulfonic acid)
PyBOP (benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate q quartet
rt or RT room temperature
RP HPLC reverse phase high performance liquid chromatography
rpm revolutions per minute
RPMI Roswell Park Memorial Institute
RSV respiratory syncytical virus
s singlet
sat or satd saturated
SCID severe combined immunodeficiency
SCX solid supported cation exchange (resin)
SDS sodium dodecyl sulfate
SNAr nucleophilic aromatic substitution
Syk Spleen tyrosine kinase
t triplet
T3P 1-propanephosphonic acid cyclic anhydride
TBAF tetrabutylammonium fluoride
TBDMS te/f-butyldimethylsilyl
TCID50 50% tissue culture infectious dose
TEA triethylamine
THF tetrahydrofuran
TFA trifluoroacetic acid
TGFp transforming growth factor beta
TIPS triisopropylsilyl
TMB 3,3',5,5'-tetramethylbenzidine
TMS-CI trimethylsilyl chloride
TNFa tumor necrosis factor alpha
Prefixes n-, s-, /'-, t- and tert- have their usual meanings: normal, secondary, /'so, and tertiary.

Claims

Claims
Figure imgf000209_0001
R represents
Ci-6 alkoxy, Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, which latter four groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo, hydroxy, and Ci_2 alkoxy,
H, halo, cyano,
phenyl or Het1, which latter two groups are optionally substituted with one substituents selected from Ci_2 alkyl and Ci_2 alkoxy,
or R A and R B together repres d from the following
Figure imgf000209_0002
wherein the wavy lines represent the points of attachment to the phenyl ring,
A represents O, S or N(RA2),
RA represents H, d-4 alkyl or hydroxy,
RA2 represents H or Ci-4 alkyl;
R B represents -NRxS(0)2RY , H, halo, cyano, -d.4 alkylene-CN, -d.4 alkylene-OH, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRX2S(0)2NRxRY, -NRxP(0)RY RY2, -NRxC(0)ORY or Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci_2 alkoxy;
Rx and RX independently represent H or Ci_6 alkyl, or Rx and RX together represent 03.6 n- alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -O- or -N(RX2)-, or RX represents Het1 optionally substituted with one or more substituents selected from halo, hydroxy, Ci_2 alkyl and Ci.2 alkoxy;
RY, RY and RY2 independently represent Ci_6 alkyl, C3.7 cycloalkyl, phenyl, benzyl, Het1 or Het2, which latter six groups are optionally substituted by one or more substituents selected from C1-2 alkyl, halo, hydroxy, C1-2 alkoxy, NH2, N(H)-Ci-4 alkyl, N(Ci-4 alkyl)2, C(0)OH and C(0)0-(CH alkyl),
or RY represents H,
or Rx and RY together represent C3-6 n-alkylene or C4.5 n-alkylene interrupted between C2 and C3 by -0- or -N(RX2)-;
each RX2 independently represents H or C1-4 alkyl;
R1C and R1 E independently represent H, halo, cyano or methyl; provided that at least one of R1A, R B, R G and R1 E is other than H;
R D represents trimethylsilyl, C2-7 alkyl, C2-7 alkenyl, C2-7 alkynyl, C3-7 cycloalkyl, phenyl, Het1 or Het2, which latter seven groups are optionally substituted by one or more substituents selected from Ci-2 alkyl, halo, cyano, hydroxy and C1-2 alkoxy;
R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl or pyridyl ring, which latter two rings are optionally substituted by one or more substituents selected from C1-3 alkyl, C1.3 haloalkyl, cyano and halo,
or one of R2 and R3 represents H, halo, cyano, C1-3 alkyl or C1-3 haloalkyl and the other independently represents halo, cyano, C1-3 alkyl or C1-3 haloalkyl,
or R2 and R3 together combine to form C3-5 alkylene or C3-5 alkenylene, which latter two groups are optionally substituted by one or more substituents selected from C 1-3 alkyl, C1-3 haloalkyl, cyano and halo; X1 represents N or CH;
L represents a direct bond or C1-2 alkylene;
X2 and X3 both represent CRZ or one of X2 and X3 represents N and the other represents CRZ;
Rz represents hydrogen, halo, cyano, hydroxy, C1-3 alkyl or C1-3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms; R4 represents
-Q -[C(R6c)(R6d)-(CH2)o-iCH2-0]1-i2-CH2(CH2)o-iCH2-R6a,
-Q2-C(R6c)(R6d)-[Ci-5 alkylene]-R6a, which C1-5 alkylene group is optionally substituted by oxo,
-S(0)nR6 ,
-COR6b,
-CH2OH,
or, when R1 B represents either -C(0)NRxRY, in which RY represents optionally substituted Het1 or optionally substituted Het2, or -NRX S(0)2NRxRY then R4 may alternatively represent H, halo, cyano, hydroxy, Ci_3 alkyl or Ci_3 alkoxy, which latter two groups are optionally substituted by one or more halo atoms;
R5 represents C2-3 alkynyl, H, cyano, -C(0)NH2, hydroxy or halo, or R5 represents Ci_3 alkoxy or C1-3 alkyl, which latter two groups are optionally substituted by one or more halo atoms;
R6a represents OR7a, N(R7 )R7c or C02H;
R6 represents Ci_8 alkyl, C3.8 cycloalkyl, phenyl, Het or Het2, which latter five groups are optionally substituted by one or more substituents selected from halo, hydroxyl, Ci_3 alkyl and C1-3 alkoxy;
R6c and R6d independently represent H or methyl; R7a to R7c independently represent H or C1-4 alkyl optionally substituted by one or more halo atoms, or R7 and R7c, together with the N-atom to which they are attached, form a 4- to 7- membered heterocyclic group that is fully saturated, partially unsaturated or fully aromatic and which heterocyclic group contains one N atom (the atom to which R7 and R7c are attached) and, optionally, one or more further heteroatoms selected from O, S and N, and which heterocyclic group is optionally substituted by one or more substituents selected from halo, hydroxy, oxo, Ci_4 alkyl and Ci_4 alkoxy;
Q and Q2 independently represent C(0)NH, O or S(0)p; and
n and p independently represent 0, 1 or 2,
Het1 represents, independently upon each occurrence, a 5- or 6-membered heterocyclic group that is fully aromatic, which group contains one or more heteroatoms selected from N, O and S; Het2 represents, independently upon each occurrence, a 4- to 7-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or more heteroatoms selected from N, O and S; or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
2. A compound as claimed in Claim 1 that is a compound of formula la, lb or lc,
Figure imgf000212_0001
A compound as claimed in Claim 1 or Claim 2, wherein R A represents H, halo, Ci_4 alkyl or Ci_4 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms.
A compound as claimed in any preceding claim, wherein R B represents H, halo, cyano, -NRXRX , -C(0)ORx, -C(0)NRxRY, -S(0)2NRxRY, -NRxC(0)RY, -NRxS(0)2RY , -NRxC(0)ORY , Het , -NRX2S(0)2NRxRY, -CH2OH or -CH2CN.
A compound as claimed in any preceding claim, wherein RX represents Het1 or Rx and RX independently represent H or Ci_4 alkyl, or Rx and RX together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(RX2)-, wherein RX2 represents H or Ci_2 alkyl.
A compound as claimed in any preceding claim, wherein RY represents H, benzyl or Het2 optionally substituted by one or more substituents selected from methyl, halo, hydroxy and methoxy,
or RY and RY independently represent Ci_4 alkyl, C3.6 cycloalkyl or phenyl, which latter three groups are optionally substituted by one or more substituents selected from methyl, halo, hydroxy, methoxy, NH2, N(H)-Ci.2 alkyl, N(Ci.2 alkyl)2, C(0)OH and C(0)0-(Ci-2 alkyl),
or Rx and RY together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -O- or -N(RX2)-, wherein RX2 represents H or Ci_2 alkyl.
A compound of formula I, la or lb as claimed in any preceding claim, wherein R C and R E independently represent H or halo.
A compound as claimed in any preceding claim, wherein:
R D represents trimethylsilyl, C3_7 alkyl, C(Ci_2 alkyl)2-C≡CH, C3.5 cycloalkyl, phenyl or Het2, which latter three groups are optionally substituted by one or more substituents selected from Ci_2 alkyl, halo and Ci_2 alkoxy; and
Het2 represents a 5- or 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S.
A compound as claimed in any preceding claim, wherein:
R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring, or R2 and R3 independently represent halo or Ci_2 alkyl; and/or
L represents a direct bond or CH2.
A compound of formula I or la as claimed in any preceding claim, wherein X2 and X3 both represent CH or one of X2 represents CH and X3 represents N or CRZ, wherein Rz represents H or halo.
A compound as claimed in any preceding claim, wherein:
R4 represents
-Q -[C(R6c)(R6d)CH2-0]1.8-CH2CH2-R6a,
-Q2-C(R6c)(R6d)-[Ci.4 alkylene]-R6a, which Ci.4 alkylene group is optionally substituted by oxo,
-S(0)nR6 ,
-COR6 ,
CH2OH;
or, when R B represents either -C(0)NRxRY, in which RY represents optionally substituted Het2, or -NRX2S(0)2NRxRY, then R4 may alternatively represent H; and n represents 0 or 2.
A compound as claimed in any preceding claim, wherein R5 represents H, cyano, chloro, fluoro, C2.3 alkynyl, Ci_2 alkyl or Ci_2 alkoxy, which latter two groups are optionally substituted by one or more fluoro atoms. A compound as claimed in any preceding claim, wherein:
R6a represents C02H, OH, 0-d.2 alkyl or N(R7 )R7c; or
R6 represents Ci_5 alkyl or C3.5 cycloalkyl.
A compound as claimed in any preceding claim, wherein R and R independently represent H or methyl, or R7 and R7c, together with the N-atom to which they are attached, form a 4- to 7-membered heterocyclic group that is fully saturated, which heterocyclic group contains one N atom (the atom to which R7 and R7c are attached) and, optionally, one further heteroatom selected from O, S and N, and which heterocyclic group is optionally substituted by one or more Ci_2 alkyl groups.
A compound as claimed in any preceding claim, wherein Q and Q2 independently represent C(0)NH or O.
A compound as claimed in any preceding claim, wherein:
R A represents H or Ci_2 alkoxy optionally substituted by one or more fluoro atoms; R B represents H, cyano, -C(0)OH, -C(0)N(CH3)2, fluoro, chloro, or, particularly, -C(0)N(H)RY, -NHS(0)2CH3, -N(H)S(0)2NRxRY or Het1;
RY represents H, Het2, C3.5 cycloalkyl or Ci_3 alkyl, which latter group is optionally substituted by hydroxy, methoxy, NH2, N(H)CH3, N(CH3)2 or C(0)OCH3,
or Rx and RY together represent C4.5 n-alkylene optionally interrupted between C2 and C3 by -0-;
R D represents branched C4_6 alkyl, morpholinyl or cyclopropyl optionally substituted by methyl;
R2 and R3, together with the C-atoms to which they are attached, form a fused phenyl ring, or R2 and R3 both represent chloro;
R4 represents
-Q -[C(H)(R6C)CH2-0]1.6-CH2CH2-R6a,
-CCC N H-CHHCLZ alkylene]-R6a,
-S(0)2-cyclopropyl
or, when R B represents either -C(0)N(H)RY, in which RY represents Het2, or -N(H)S(0)2NRxRY, then R4 may alternatively represent H;
R5 represents H, -C≡CH or methoxy, which latter group is optionally substituted by one or more fluoro atoms;
R6a represents 0-CH3 or N(R7 )R7c;
R7 and R7c both represent methyl, or R7 and R7c, together with the N-atom to which they are attached, form a piperazinyl group optionally substituted by methyl, a pyrrolidinyl group or a morpholinyl group;
Q represents C(0)NH or O;
Het1 represents a 5-membered heterocyclic group that is fully aromatic, which group contains one to three heteroatoms selected from N and O; and/or Het2 represents a 4- to 6-membered heterocyclic group that is fully saturated or partially unsaturated, which group contains one or two heteroatoms selected from N, O and S. 17. A compound as claimed in any one of the preceding claims which is a compound selected from the list comprising:
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
3-ethynyl-5-((4-((4-(3-(3-fluoro-5-morpholinophenyl)ureido)naphthalen-1-yl)oxy)-pyrimidin-2- yl)amino)-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methane- sulfonamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(cyclopropylsulfonyl)-5-methoxyphenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 1-(5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((2-morpholinoethyl)carbamoyl)phenyl)amino) pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
N-(5-(tert-butyl)-3-(3-(2,3-dichloro-4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)phenyl)ureido)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide; 1-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)amino)-pyrimidin-4- yl)oxy)naphthalen-1-yl)-3-(2-methoxy-5-morpholinophenyl)urea;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
N-(3-(3-(4-((2-((3-(2,5,8, 1 1 , 14,17,20-heptaoxadocosan-22-yloxy)-5-methoxyphenyl)amino)- pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(2-(dimethylamino)ethoxy)ethoxy)ethoxy)-5- methoxyphenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide; N-(5-(tert-butyl)-3-(3-(4-((2-((3-(difluoromethoxy)-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pynmidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-morpholinoethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidiri-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)- methanesulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N,N-dimethylbenzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzarTiide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzoic acid;
1-(5-(tert-butyl)-3-cyano-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-(tert-butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzarriide;
N-(3-(tert-butyl)-5-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;
1-(3-amino-5-(tert-butyl)-2-methoxyphenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxybenzamido)ethoxy)ethoxy)-propanoic acid;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
1-(5-(tert-butyl)-2-methoxy-3-(pyrimidin-2-ylamino)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
3-(2-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)- naphthalen-1-yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)ethoxy)propanoic acid;
3-(2-(3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-
1- yl)oxy)pyrimidin-2-yl)amino)-5-methoxyphenoxy)ethoxy)propanoic acid;
2- methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methyl-5-morpholinobenzamide;
5-(tert-butyl)-N-cyclopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide; 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-(2-hydroxyethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-methoxyethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide; methyl 2-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)acetate^ N-benzyl-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((2-morpho^
yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-N-(2,5,8, 11 ,14, 17,20-heptaoxadocosan-22-yl)-5-methoxy- benzamide;
5-(tert-butyl)-N-ethyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-isopropyl-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(2-methoxyethyl)benzamide;
2- (5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzamido)acetic acid; N-(3-(3-(4-((2-((3-(2,5,8, 1 1 , 14,17,20-heptaoxadocosan-22-yloxy)-5-methoxyphenyl)- amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-5-(tert-butyl)-2-methoxyphenyl)methane- sulfonamide;
5-(tert-butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide;
3- ((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin- 2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-
2- yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
3- ((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(cyclopropanecarbonyl)-5-methoxyphenyl)amino)pyrimidin-4- yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)-benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-methoxyethoxy)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-3-carbamoyl-2-methoxyphenyl)ureido)naphthalen-1-yl)oxy)pyridin-
2- yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
3- ((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)benzenesulfonamide;
(R)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2-yl)benzamide; (S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(1-morpholinopropan-2-yl)benzarriide;
N-(5-(tert-butyl)-3-(3-(4-((2-((4-chloro-3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pynmidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)- methanesulfonamide;
1-(5-(tert-butyl)-2-methoxy-3-(1 ,3,4-oxadiazol-2-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
(S)-5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
(R)-5-(tert-butyl)-3-(3-(4-((2-((3-ethynyl-5-((1-morpholinopropan-2-yl)carbamoyl)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxy-N-methylbenzamide;
3-((4-((4-(3-(3-(tert-butyl)-5-carbamoylphenyl)ureido)naphthalen-1-yl)oxy)pyridin-2-yl)amino)- 5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide;
1-(5-(tert-butyl)-2-oxo-2,3-dihydrobenzo[d]oxazol-7-yl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
1-(5-(tert-butyl)-2-methylbenzo[d]oxazol-7-yl)-3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxy- ethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
3-((4-((4-(3-(3-(tert-butyl)-5-(methylsulfonamido)phenyl)ureido)naphthalen-1-yl)oxy)pyridin-2- yl)amino)-5-ethynyl-N-(2-morpholinoethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide;
(S)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2- yl)benzamide;
(R)-3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-ethynyl-N-(1-(2-(2-methoxyethoxy)ethoxy)propan-2- yl)benzamide;
N-(5-(tert-butyl)-2-ethoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)methanesulfonamide;
1-(5-(tert-butyl)-2-methoxy-3-(1 H-1 ,2,3-triazol-5-yl)phenyl)-3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)urea;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)-1 , 1 , 1-trifluoro- methanesulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)cyclohexane- sulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)piperidine-1- sulfonamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)dimethylamino- sulfonamide;
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide;
5-(tert-butyl)-N-(2-(dimethylamino)ethyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2- methoxyethoxy)ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)- benzamide;
N-(4-(tert-butyl)-6-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)phenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-[1 ,1 '-biphenyl]-2-yl)methanesulfonamide; N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)phenyl)morpholine-4- sulfonamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)ethoxy)- phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-(oxetan-3-yl)benzarTiide;
N-(5-(tert-butyl)-3-(3-(4-((2-((3-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)-5-methoxyphenyl)- amino)pyrimidin-4-yl)oxy)naphthalen-1-yl)ureido)-2-methoxyphenyl)methanesulfonamide; 5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyrimidin-4-yl)oxy)- naphthalen-1 -yl)ureido)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(pyrrolidin-1-yl)ethyl)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(piperidin-1-yl)ethyl)benzarriide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(4-methylpiperazin-1-yl)ethyl)benzamide;
N-(5-(tert-butyl)-2-methoxy-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)naphthalen-1- yl)ureido)phenyl)morpholine-4-sulfonamide;
N-(2-aminoethyl)-5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)- ethoxy)ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
5-tert-butyl-2-methoxy-N-(oxetan-3-yl)-3-[[4-[[2-(2-pyridylmethylamino)-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]benzamide;
5-tert-butyl-2-methoxy-3-[[4-[[2-(3-methoxyanilino)-4-pyridyl]oxy]-1-naphthyl]- carbamoylamino]-N-(oxetan-3-yl)benzamide; 3-[[4-[(2-anilino-4-pyridyl)oxy]-2,3- difluorophenyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-(oxetan-3-yl)benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N- tetrahydropyran-4-yl-benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-(1- methyl-4-piperidyl)benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-[(3R)- tetrahydrofuran-3-yl]benzamide;
3-[[4-[(2-anilino-4-pyridyl)oxy]-1-naphthyl]carbamoylamino]-5-tert-butyl-2-methoxy-N-[(3S)- tetrahydrofuran-3-yl]benzamide;
1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[[2-[3-[2-[2-(2- hydroxyethoxy)ethoxy]ethoxy]-5-methoxy-anilino]-4-pyridyl]oxy]-1-naphthyl]urea;
1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[[2-[3-(hydroxymethyl)-5- methoxyanilino]-4-pyridyl]oxy]-1-naphthyl]urea;
5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxybenzamide; 5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxy-N-methyl-benzamide;
3-[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-morpholino-2-oxo-ethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(hydroxymethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]-oxy]-
2- pyridyl]amino]-5-ethynyl-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide;
3- [[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-ethynyl-N-[2-(4-methylpiperazin-1-yl)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-ethynyl-N-(3-morpholinopropyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]-5-methoxy-N-[2-(4-methylpiperazin-1-yl)ethyl]benza^ 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]-5-methoxy-N-(3-morpholinopropyl)benzamide;
5-tert-butyl-3-[[4-[2-[3-ethynyl-5-(2-morpholin^
naphthyl]carbamoylamino]-2-methoxy-benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-methyl-2-morpholino-propyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-thiomorpholinoethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(1-oxo-1 ,4-thiazinan-4-yl)ethyl]benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(1 , 1-dioxo-1 ,4-thiazinan-4-yl)ethyl]-5-methoxybenzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(3,3-dimethylmorpholin-4-yl)ethyl]-5-methoxybenzami 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(2,2-dimethylmorpholin-4-yl)ethyl]-5-methoxybenzam 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-[(2R,6S)-2,6-dimethylmorpholin-4-yl]ethyl]-5-methox benzamide;
5-tert-butyl-3-[[4-[[2-[3-ethynyl-5-(hydroxymethyl)anilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxybenzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(4-methyl-1 ,4-diazepan-1-yl)ethyl]benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-(2-piperazin-1-ylethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-[2-(2-hydroxyethoxy)ethoxy]ethyl]-5-methoxybenzamide; 3-[[[4-[[4-[[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzam
3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-N-(2-morpholinoethyl)benzamide; 3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(2-methoxyethoxy)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethyl]- benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-N-[2-(4-hydroxy-1-piperidyl)ethyl]-5-methoxybenzamide;
1-[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethylsulfinyl]anilino]pyridin-4-yl]oxy-1-naphthyl]urea;
1-[5-tert-Butyl-3-(methanesulfonamido)-2-methoxyphenyl]-3-[4-[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethylsulfonyl]anilino]pyridin-4-yl]oxy-1-naphthyl]urea;
5-tert-butyl-3-[[4-[[2-[3-(hydroxymethyl)-5-methoxyanilino]-4-pyridyl]oxy]-1-naphthyl]- carbamoylamino]-2-methoxy-N-(oxetan-3-yl)benzamide;
3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-5-methoxy-N-[2-[2-(2-methoxyethoxy)ethoxy]- ethyl]benzamide;
3-[[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]pyrimidin-2-yl]amino]methyl]-5-methoxy-N-(2-morpholinoethyl)benzami
1-[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]-3-[4-[[2-[3-methoxy-5-[2-[2-(2- methoxyethoxy)ethoxy]ethoxy]anilino]-4-pyridyl]oxy]-1-naphthyl]urea;
3-[[4-[[4-[[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2- pyridyl]amino]-5-methoxy-N-(2-morpholinoethyl)benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(cyanomethyl)-2-methoxyphenyl]carbamoylamino]-1-naphthyl]oxy]-2- pyridyl]amino]-5-ethynyl-N-[2-[2-(2-methoxyethoxy)ethoxy]ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(1 ,4-oxazepan-4-yl)ethyl]benzamide;
3-[[4-[[4-[[5-tert-butyl-3-(methanesulfonamido)-2-methoxyphenyl]carbamoylamino]-1- naphthyl]oxy]-2-pyridyl]amino]-5-methoxy-N-[2-(4-oxo-1-piperidyl)ethyl]benzamide; and 5-tert-butyl-3-[[4-[[2-[3-ethynyl-5-(hydroxymethyl)anilino]-4-pyridyl]oxy]-1- naphthyl]carbamoylamino]-2-methoxy-N-methyl-benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
18. A compound as claimed in any one of the preceding claims which is a compound selected from the list comprising:
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide; 5-(tert-butyl)-2- methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide; and
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
19. A compound as claimed in any one of Claims 1 to 17, wherein the compound is not: 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)ethoxy)ethyl)-benzamide; 3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(2-morpholinoethyl)benzamide; 5-(tert-butyl)-2- methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy)- ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)-N-methylbenzamide;
5-(tert-butyl)-2-methoxy-3-(3-(4-((2-((3-methoxy-5-(2-(2-(2-methoxyethoxy)ethoxy) ethoxy)phenyl)amino)pyridin-4-yl)oxy)naphthalen-1-yl)ureido)benzamide;
3-((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)naphthalen-1- yl)oxy)pyridin-2-yl)amino)-5-methoxy-N-(3-morpholinopropyl)benzamide; and/or
5-(tert-butyl)-2-methoxy-N-(oxetan-3-yl)-3-(3-(4-((2-(phenylamino)pyridin-4-yl)oxy)- naphthalen-1-yl)ureido)benzamide,
or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
20. A compound as claimed in any one of Claims 1 to 17, wherein the compound is 3-((4- ((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen-1- yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)- ethoxy)ethyl)benzamide, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof. 21. A compound as claimed in any one of Claims 1 to 17, wherein the compound is not 3- ((4-((4-(3-(5-(tert-butyl)-2-methoxy-3-(methylsulfonamido)phenyl)ureido)-naphthalen- 1-yl)oxy)pyrimidin-2-yl)amino)-5-ethynyl-N-(2-(2-(2-methoxyethoxy)- ethoxy)ethyl)benzamide, or a pharmaceutically acceptable salt, solvate or isotopic derivative thereof.
22. A pharmaceutical formulation comprising a compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent or carrier. 23. A combination product comprising
(A) a compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, and
(B) another therapeutic agent, wherein each of components (A) and (B) is formulated in admixture with a pharmaceutically-acceptable adjuvant, diluent or carrier.
A compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, for use in medicine.
A compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical formulation as defined in Claim 22 or a combination product as defined Claim 23, for use in the treatment or prevention of an inflammatory disease.
A compound, formulation or combination product for use according to Claim 25, wherein the inflammatory disease is selected from the list comprising cystic fibrosis, pulmonary hypertension, lung sarcoidosis, idiopathic pulmonary fibrosis, COPD (including chronic bronchitis and emphysema), asthma, paediatric asthma, atopic dermatitis, allergic dermatitis, contact dermatitis or psoriasis, allergic rhinitis, rhinitis, sinusitis, conjunctivitis, allergic conjunctivitis, keratoconjunctivitis sicca (dry eye), glaucoma, diabetic retinopathy, macular oedema (including diabetic macular oedema), central retinal vein occlusion (CRVO), dry and/or wet age related macular degeneration (AMD), post-operative cataract inflammation, uveitis (including posterior, anterior and pan uveitis), corneal graft and limbal cell transplant rejection, gluten sensitive enteropathy (coeliac disease), eosinophilic esophagitis, intestinal graft versus host disease, Crohn's disease and ulcerative colitis.
A compound, formulation or combination product for use according to Claim 25 or Claim 26, wherein the inflammatory disease is uveitis, Crohn's disease or ulcerative colitis.
A compound, formulation or combination product for use according to Claim 25 or Claim 26, wherein the inflammatory disease is asthma or COPD.
The use of
a compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or
a pharmaceutical formulation as defined in Claim 22 or a combination product as defined Claim 23,
for the preparation of a medicament for the treatment or prevention of an inflammatory disease, as defined in any one of Claims 25 to 28.
A method of treating or preventing an inflammatory disease as defined in any one of Claims 25 to 28, said method comprising administering to a subject an effective amount of
a compound as defined in any one of Claims 1 to 21 , or pharmaceutically acceptable salt, solvate or isotopic derivative thereof, or a pharmaceutical formulation as defined in Claim 22, or a combination product as defined Claim 23.
A process for the preparation of a compound of formula I which process comprises: reaction of a compound o with a compound of formula III,
wherein one of Z and Z2 is a stru IV
Figure imgf000224_0001
and the other of Z and Z2 is a structural fragment of formula V
Figure imgf000224_0002
where R A to R E, R2 to R5, L and X1 to X3 are as defined in any one of Claims 1 to 21 ;
(b) reaction of a compound of formula Ila,
Figure imgf000224_0003
wherein Z is as defined above, with a suitable azide-forming agent,
which reaction is followed, without isolation, by thermal rearrangement of the intermediate acyl azide (of formula Z -C(0)-N3) to provide, in situ, a compound of formula II, which compound is then reacted with a compound of formula III as defined above;
(c) reaction of a compound of formula lib,
Figure imgf000224_0004
wherein LG1 represents a leaving group and Z is as defined above, with a compound of formula III, as defined above;
(d) reaction of a compound of formula VI,
Figure imgf000225_0001
wherein LG2 represents a leaving group and R A to R E, R2, R3 and X1 are as defined in any one of Claims 1 to 18, with a compound of formula VII,
Figure imgf000225_0002
wherein R4, R5, L, X2 and X3 are as defined in any one of Claims 1 to 21 ;
(e) for compounds of formula I in which R4 represents
-S(0)1.2-[C(R6c)(R6d)-(CH2)o.1CH2-0]1.12-CH2(CH2)o-1CH2-R6a,
alkylene]-R6a,
Figure imgf000225_0003
oxidation of a corresponding compound of formula I in which, respectively, represents
-S-[CH2(CH2)o-iCH2-0]i-i2-CH2(CH2)o-iCH2-R6a,
-S-CH2-[d.5 alkylene]-R6a,
-S-R6 ,
wherein R6a to R6d are as defined in any one of Claims 1 to 21 ;
(f) for compounds of formula I in which R4 represents
-C^NH-fCCR^CR^-CCH^o-iCH^Mz-CH^CH^o-iCHz-R63 or
-C^NH-CCR^XR^Md-s alkylene]-R6a,
reactio
Figure imgf000225_0004
wherein R4' represents H or a Ci-3 alkyl group and R A to R E, R2, R3, R5, L and X1 to X3 are as defined in any one of Claims 1 to 21 , with a compound of formula Vllb or Vllc,
H2N-[C(Rbc)(Rba)-(CH2)o.1CH2-0]1.12-CH2(CH2)o-1CH2-Rba Vllb H2N-C(Re°)(Red)-[Ci.5 alkylene]-R6a or Vllc wherein R6a, R6c and R6d are as defined in any one of Claims 1 to 21 ;
for compounds of formula I in which R represents -C(0)NRxRY, reaction compound of formula VI Id,
wherein R A, R C, R D, R E, Ra, R , X1 to X3, L, R4 and R5 are as defined in Claim 1 and Rx represents H or Ci_4 alkyl, with a compound of formula Vile,
Figure imgf000226_0001
wherein Rx and RY are as defined in Claim 1 ; or
(h) deprotection of an protected derivative of a compound of formula I, wherein the protected derivative bears a protecting group on an O- or N-atom of the compound of formula I.
PCT/GB2014/051022 2013-04-02 2014-04-01 Urea derivatives useful as kinase inhibitors WO2014162126A1 (en)

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