WO2006103449A2 - Saminopyrimidine derivates with tie2 inhibiting activity - Google Patents

Saminopyrimidine derivates with tie2 inhibiting activity Download PDF

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WO2006103449A2
WO2006103449A2 PCT/GB2006/001175 GB2006001175W WO2006103449A2 WO 2006103449 A2 WO2006103449 A2 WO 2006103449A2 GB 2006001175 W GB2006001175 W GB 2006001175W WO 2006103449 A2 WO2006103449 A2 WO 2006103449A2
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alkyl
alkoxy
formula
group
amino
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PCT/GB2006/001175
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French (fr)
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WO2006103449A3 (en
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Clifford David Jones
Richard William Arthur Luke
William Mccoull
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Astrazeneca Ab
Astrazeneca Uk Limited
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Priority claimed from GB0506467A external-priority patent/GB0506467D0/en
Priority claimed from GB0512615A external-priority patent/GB0512615D0/en
Priority claimed from GB0512611A external-priority patent/GB0512611D0/en
Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Priority to EP06726581A priority Critical patent/EP1893605A2/en
Priority to US11/910,071 priority patent/US20080194552A1/en
Priority to JP2008503593A priority patent/JP2008534565A/en
Publication of WO2006103449A2 publication Critical patent/WO2006103449A2/en
Publication of WO2006103449A3 publication Critical patent/WO2006103449A3/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • This invention relates to compounds, or pharmaceutically acceptable salts thereof, which possess anti-angiogenic activity and are accordingly useful in methods of treatment of disease states associated with angiogenesis in the animal or human body.
  • the invention also concerns processes for the preparation of the compounds, pharmaceutical compositions containing the compounds as active ingredient, and methods for the use of the compounds in the manufacture of medicaments for use in the production of anti- angiogenic effects in warm-blooded animals such as humans.
  • the Tie2 receptor tyrosine kinase also known as TEK
  • TEK Tie2 receptor tyrosine kinase
  • Angiogenesis is a fundamental process defined as the generation of new blood vessels from existing vasculature. It is a vital yet complex biological process required for the formation and physiological functions of virtually all the organs. Normally it is transient in nature and is controlled by the local balance of angiogenic and angiostatic factors in a multi-step process involving vessel sprouting, branching and tubule formation by endothelial cells (involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
  • endothelial cells involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
  • angiogenesis plays an important role in a variety of processes and is under stringent control. In the adult, physiological angiogenesis is largely confined to wound healing and several components of female reproductive function and embryonic development. In undesirable or pathological angiogenesis, the local balance between angiogenic and angiostatic factors is dysregulated leading to inappropriate and/or structurally abnormal blood vessel formation. Pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacology. Science. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31).
  • VEGF vascular endothelial growth factor
  • polypeptide moieties interact with their respective receptors (transmembrane tyrosine kinases which are predominantly endothelial cell specific) and induce cellular responses via ligand mediated signal transduction. It has been speculated that VEGF and the angiopoietins co-operate to regulate various aspects of the angiogenic process during both normal and pathological angiogenesis via signalling through their respective receptors.
  • Receptor tyrosine kinases are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified.
  • fms-like tyrosine kinase receptor Fit or Fltl
  • KDR kinase insert domain-containing receptor
  • Flt4 Flt4
  • Two of these related RTKs, Fit and KDR have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
  • Tie receptors and their ligands co-operate closely with VEGF during both normal and pathological angiogenesis.
  • the transmembrane receptors Tiel and Tie2 constitute a family of endothelial cell specific tyrosine kinase receptors involved in maintenance of blood vessel integrity and which are involved in angiogenic outgrowth and vessel remodelling. Structurally Tiel and Tie2 share a number of features (e.g.
  • the intracellular domains of both these receptors each contain a tyrosine kinase domain interrupted by a kinase insert region) and thus constitute a distinct RTK subfamily.
  • Overall sequence identity between Tiel and Tie2 receptors at the amino acid level is 44% while their intracellular domains exhibit 76% homology.
  • Targeted disruption of the Tiel gene results in a lethal phenotype characterised by extensive haemorrhage and poor microvessel integrity (Puri, M. et al. 1995 EMBO Journal: 14:5884-5891).
  • Transgenic mice deficient in Tie2 display defects in vessel sprouting and remodelling and display a lethal phenotype in mid gestation (E9.5- 10.5) caused by severe defects in embryonic vasculature (Sato, T. et al. 1995 Nature 370: 70-74).
  • Tiel is believed to influence Tie2 signalling via heterodimerisation with the Tie2 receptor, hence potentially modulating the ability of Tie2 to autophosphorylate (Matron, M. et al. 2000 Journal of Biological Chemistry: 275, 39741-39746) and recent chimaeric Tiel receptor studies have indicated that Tie-1 may inhibit apoptosis via the PI 3 kinase/Akt signal transduction pathway (Kontos, CD., et al., 2002 Molecular and Cellular Biology: 22, 1704-1713).
  • angiopoietins a number of ligands, designated the angiopoietins have been identified for Tie2 of which Angiopoietin 1 (Angl) is the best characterised. Binding of Angl induces tyrosine phosphorylation of the Tie2 receptor via autophosphorylation and subsequently activation of its signalling pathways via signal transduction. Ang2 has been reported to antagonise these effects in endothelial cells (Maisonpierre, P. et al. 1997 Science: 277, 55-60). The knock-out and transgenic manipulation of Tie2 and its ligands suggest that stringent spatial and temporal control of Tie2 signalling is imperative for the correct development of new vasculature.
  • Activation of the Tie2 receptor by Angl inhibits apoptosis (Papapetropoulos, A., et al., 2000 Journal of Biological Chemistry: 275 9102-9105), promotes sprouting in vascular endothelial cells (Witzenbicher, B., et al., 1998 Journal of Biological Chemistry: 273, 18514-18521) and in vivo promotes blood vessel maturation during angiogenesis and reduces the permeability and consequent leakage from adult microvessels (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463).
  • Tie2 receptor is reported to be involved in the branching, sprouting and outgrowth of new vessels and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and overall appears to be consistent with promoting microvessel stability. Absence of Tie2 activation or inhibition of Tie2 auto phosphorylation may lead to a loss of vascular structure and matrix/cell contacts (Thurston, G., Cell Tissue Res (2003), 314: 61-69) and in turn may trigger endothelial cell death, especially in the absence of survival or growth stimuli.
  • Tie2 kinase activity may provide an anti-angiogenic effect and thus have application in the therapy of disease states associated with pathological angiogenesis.
  • Tie2 expression has been shown to be up- regulated in the neovasculature of a variety of tumours (e.g. Peters, K.G. et al, (British Journal of Cancer, 1998; 77,51-56) suggesting that inhibiting Tie2 kinase activity will result in anti-angiogenic activity.
  • studies with soluble Tie2 receptor extracellular domain
  • VM venous malformation
  • VM's are commonly found in the skin or mucosal membranes but can affect any organ.
  • lesions appear as spongy, blue to purple vascular masses composed of numerous dilated vascular channels lined by endothelial cells.
  • Tie2 kinase mutation C2545T in the Tie2 coding sequence (Calvert, J.T., et al., 1999 Human Molecular genetics: 8, 1279-1289), which produces a R849W amino acid substitution in the kinase domain.
  • Analysis of this Tie2 mutant indicates that it is constitutively activated even in the absence of ligand (Vikkula, M., et al., 1996 Cell: 87, 1181-1190).
  • Upregulation of Tie2 expression has also been found within the vascular synovial pannus of arthritic joints in humans, which is consistent with the role of inappropriate neovascularisation.
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R 1 and R 2 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy
  • R 3 and R 4 are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, (1 -6C)alkoxy wherein the (1 -6C)alkyl and the (1 -6C)alkoxy groups are optionally substituted by one or more groups independently selected from: fluoro, hydroxy, (1- 6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,mono(l- 6C)alkylamino, di(l-6C)alkylamino, carbamoyl, mono(l ⁇ 6C)alkylcarbamoyl or di-[(l- 6C)alkyl] carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (
  • A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
  • R 5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
  • n 0, 1, 2 or 3;
  • L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -, -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y - or -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein Z is a direct bond, -O- or -N(R 8 )- wherein x and y
  • B represents a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group,or a 5 or 6 membered heteroaryl ring,ring; or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic;
  • B is a (3-7C)cycloalkyl ring orring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group, the rings and the bicyclic group optionally bear 1 or 2 oxo or thioxo substituents;
  • R 6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(O) p -(l-6C)alkyl wherein p is 0, 1 or 2, -N(R c )C(O)(l-6C)alkylring and -N(R°)C(O)(l-6C)alkyl in which R c is hydrogen or (1-
  • R 6 is selected from (l-6C)alkyl or (l-6C)alkoxy, (l-6C)alkyl, -S(O) p -(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l- ⁇ C)alkyl, -S(O) p -(l-6C)alkyl and the (l-6C)alkoxy(l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy,(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated
  • L cannot be -C(R a )(R b )C(O)N(R 9 )-, -N(R 8 )C(O)C(R a )(R b )-, -N(R 8 )C(O)O- or -N(R 8 )C(O)N(R 8 )-.
  • L is selected from N(R 8 )C(O)-, N(R 8 )C(O)-(CR a R b ) 2 , -C(O)N(R 9 ), -C(O)N(R 9 )-CR a R b ), -C(R a )(R b )-N(R 8 )C(O)- or -C(R a )(R b )-C(O)N(R 9 )-(CR a R b )-.
  • R 3 and R 4 are other than a group NR 1 R 2 .
  • R y is a group NR 1 R 2 where R 1 and R 2 are as defined above.
  • the invention provides a compound of formula (IA):
  • R 1 , R 2 , R 5 , A, L, B, m and n are as defined above, R 3a and R 4a are groups R 3 and R 4 as defined above, and
  • R 6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring and -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-6C)alkyl; or R 6 is selected from (l-6C)alkyl, -S(O) p -(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(O) p -(l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di(l-6C)alkylamino, a (3-7C)cycloalkyl ring
  • n there is provided a compound of the Formula IA as defined above wherein:
  • R 1 , R 2 , A, B, L, R 5 , R 6 , m and n are as defined above in relation to formula (IA) and R 3a and R 4a are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or
  • R 3b are R 4b are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l- 6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are
  • R 3b and R 4b are other than NR 1 R 2 .
  • the compounds of the Formula IB is a compound of the Formula IBi:
  • R 1 , R 2 , R 4b , R 5 , R 6 , A, L, B, m and n are as defined above in relation to formula (IB) and R 10 and R 11 are independently selected from hydrogen or (l-6C)alkyl; and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof. with the proviso that:
  • L cannot be -C(R a )(R b )C(O)N(R 9 )-, -N(R 8 )C(O)C(R a )(R b )-, -N(R 8 )C(O)O- or
  • alkyl includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl.
  • references to individual alkyl groups such as "propyl” are specific for the straight-chain version only
  • references to individual branched-chain alkyl groups such as "isopropyl” are specific for the branched-chain version only.
  • (l- ⁇ C)alkoxy includes methoxy, ethoxy and isopropoxy
  • (l-6C)alkylamino includes methylamino, isopropylamino and ethylamino
  • di-[(l-6Calkyl] amino includes dimethylamino, diethylamino and N-methyl-N-isoproylamino
  • aryl refers to phenyl or naphthyl, particularly phenyl.
  • the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity.
  • the synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form.
  • the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. Suitable values for the generic radicals referred to above include those set out below.
  • Suitable 5 or 6 membered heteroaryl rings include, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 1,4,5-triazinyl or pyrazinyl.
  • Particular 5 or 6 membered heteroaryl rings include imidazolyl, pyridyl, thiazolyl, thiadiazolyl, pyrimidinyl, isoxazolyl, isothiazolyl and pyrazolyl.
  • Suitable saturated or partially saturated 3 to 7 membered heterocyclic rings include, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3- thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3 -azabicyclo [3.1.1 ]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-l,4-thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-
  • a suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2- thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5- dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl.
  • the saturated or partially saturated 3 to 7 membered heterocyclic rings are optionally substituted by one or more (C 1-6) alkyl groups and/or by one or more hydroxy.
  • this definition includes tautomers of hydroxy substituted ring systems where the hydroxy tautomerizes to an oxo group.
  • Suitable 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, imidazolo[2, 1 -bjthiazolyl, dihydrocyclopentathiazolyl, tetrahydrocyclopenta[c]pyrazolyl, furo[3,2-b]furanyl, pyrrolopyrrole, thienopyrazolyl, thieno[2,3-b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxal
  • Particular 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[bjfuranyl, benzo[b]thiophenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl.
  • the bicyclic groups are optionally substituted by one or more groups R 6 as hereinbefore defined.
  • the group A may particularly be attached to the ethynyl group via a carbon atom in the aryl group or in the 5 or 6 membered heteroaryl ring.
  • the group B may particularly be attached to the group L via a carbon atom.
  • Suitable values for any of the the substituents herein, for example the 'R' groups (R 1 to R 6 ) or for various groups within a A, B or L group include for halo fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l- ⁇ C)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl- N
  • (l-3C)alkyl group refers to alkyl groups containing up to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl.
  • (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)alkanoyl is adopted.
  • the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
  • a suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.
  • an acid-addition salt of a compound of the formula I for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid
  • a salt of a compound of the formula I which is sufficiently acidic
  • pro-drugs of compounds of the invention as herein before or herein after defined.
  • Compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I).
  • pro-drugs include in-vivo hydrolysable esters of a compound of the Formula (I).
  • pro-drugs are known in the art.
  • An in-vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol.
  • Suitable pharmaceutically-acceptable esters for carboxy include C ⁇ ealkoxymethyl esters for example methoxymethyl, C ⁇ - ⁇ alkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters,
  • Cs-gcycloalkoxycarbonyloxyCi-ealkyl esters for example 1-cyclohexylcarbonyloxy ethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-niethyl-l,3-dioxolen-2-onylmethyl; and C ⁇ ⁇ alkoxycarbonyloxyethyl esters.
  • An in-vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and ⁇ -acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s.
  • ⁇ -acyloxyalkyl ethers include acetoxymethoxy and
  • a selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-allcylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
  • Particular novel compounds of the invention include, for example, compounds of the formula I, or salts, particularly pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , A, B, L, m and n has any of the meanings defined hereinbefore or in paragraphs (a) to (Hill) hereinafter: -
  • (b) L is -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen ); (b 5 ) L is -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) r wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 8 are independently selected from hydrogen and (1 -6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (b' ") L is -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein x and y are as defined above, and Z is -O- or -N(H)-, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • L is -N(R s )C(O)-(CR a R b ) x -O-(CR a R b ) y - wherein x and y are as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a ,
  • R b and R 8 are all hydrogen );
  • (c') L is -C(O)N(R 9 )-(CR a R b ) x -O-(CR a R b ) y - wherein x and y are as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (c") L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -O-(CR a R b ) y - wherein x and y are as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (C'") L is -C(R a )(R b )-C(O)N(R 9
  • L is -N(R 8 )C(O)-(CR a R b ) x -N(R 8 )-(CR a R b ) r wherein R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (d') L is -C(O)N(R 9 )-(CR a R b ) ⁇ -N(R 8 )-(CR a R b ) y - wherein R a , R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (d' ') L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -N(R 8 )-(CR a R b ) y - wherein R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (d' ") L is -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -N(R 8 )-(CR a R b ) r wherein R a , R b , R 8 and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b , R 8 and R 9 are all hydrogen );
  • L is -N(R 8 )C(O)-(CR a R b ) x -O- wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • L is -C(O)N(R 9 )-(CR a R b ) x -O- wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (e" ') L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -O- wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and
  • R 8 are all hydrogen ); (e" ") L is -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -O- wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and
  • R 9 are all hydrogen );
  • (f) L is -N(R 8 )C(O)-(CR a R b ) x -N(H)- wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 8 are all hydrogen );
  • (f ) L is -C(O)N(R 9 )-(CR a R b ) x -N(H)- wherein x is as defined above, and R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (f ') L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -N(H)- wherein x is as defined above, and R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b ,
  • R 8 and R 9 are all hydrogen );
  • (f ) L is -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -N(H)- wherein x is as defined above, and R a ,
  • R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen ); (g) L is -N(R 8 )C(O)-(CR a R b ) x - wherein x is as defined above (particularly x is 1 or 2) and wherein R a , R b and R 8 are independently selected from hydrogen and (l-6C)alkyl
  • (g') L is -C(O)N(R 9 )-(CR a R b ) x - wherein x is as defined above (particularly x is 1 or 2) and wherein R a , R b and R 9 are independently selected from hydrogen and (l- ⁇ C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (g") L is -C(R a )(R b )-N(R 8 )C(O)-(CR a R b ) x -, wherein x is as defined above (particularly x is 1 or 2) and wherein R a , R b and R 8 are independently selected from hydrogen and (1-
  • (g' ") L is -C(R a )(R b )-C(O)N(R 9 )-(CR a R b ) x -, particularly -CH 2 -C(O)N(R 9 )- wherein x is as defined above (particularly x is 1 or 2) and wherein R a , R b and R 9 are independently selected from hydrogen and (l-6C)alkyl (particularly R a , R b and R 9 are all hydrogen );
  • (S"") L is -C(O)-N(H)-, -N(H)-C(O)-, -C(O)-N(H)-CH 2 -, -CH 2 -N(H)-C(O)-,
  • (S"") L is -C(O)N(H)CH 2 -.
  • (S""") L is -N(H)C(O)CH 2 CH 2 -.
  • (S'"""") L is CH 2 -C(O)-N(H)-CH 2 -, (h) R a and R b each represent hydrogen;
  • R a and R b independently represent hydrogen or (1 -6C)alkyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring;
  • R a and R b independently represent hydrogen or ( 1 -6C)alkyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or a saturated or partially saturated 5 to 6 membererd heterocyclic ring;
  • R a and R b independently represent hydrogen, methyl or ethyl, wherein a (l-6C)alkyl group in R a and R b is optionally substituted by hydroxy or pyrrolin-1-yl;
  • A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl;
  • A is selected from phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl;
  • (j) A is phenyl or pyridyl
  • (k) A is phenyl or pyridyl, wherein the nitrogen in the pyridyl ring is in the 3 -position relateive to the alkyne bond.
  • A is thienyl or thiazolyl
  • (V) A is phenyl, pyridyl, thienyl or thiazolyl
  • A is phenyl
  • A is phenyl or pyridyl and n is 0;
  • (n') A is phenyl or thiazolyl and n is 0;
  • A is phenyl and n is 0 or n is 1 and R 5 is (l-4C)aUcyl;
  • (p) A is pyridyl and n is 0 or n is 1 and R 5 is (l-4C)alkyl;
  • (p') A is thiazolyl and n is 0 or n is 1 and R 5 is (l-4C)alkyl;
  • (p) A is thienyl and n is 0 or n is 1 and R 5 is (l-4C)alkyl;
  • (q) A is selected from phenyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidyl.
  • B When B is a (3-7C)cycloalkyl ring then B is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (s) When B is a saturated or partially saturated 3 to 7 membered heterocyclic ring then B is selected from oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, , morpholinyl, 1,3- dioxolanyl, tetrahydrofuranyl, piperidyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, homopiperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, tetrahydropyridinyl, 1,2,4-oxadiazolyl and dihydrothiopyranyl;
  • B is a 5 or 6 membered heteroaryl ring then B is selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl; (u) When B is an 8, 9 or 10 membered bicyclic group which optionally contains 1,2,3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic then B is selected from 2,3-dihydro-lH-indenyl, benzodioxinyl, 1 ,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydropentalene,
  • W is a 5-7 membered ring (including the bridging atoms), said W ring comprising carbon atoms or optionally further heteroatoms independently selected from oxygen, nitrogen and sulphur, wherein said bicyclic ring contains no more that 4 heteroatoms in total.
  • Such rings include: pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5- cjpyrimidinyl, pyrazolo[ 1 ,5-a] [ 1 ,3,5]triazinyl, 4,5-dihydropyrazolo[ 1 ,5-a]pyridinyl, 4H-pyrazolo[5, 1 -c] [ 1 ,4]thiazinyl, 4H-pyrazolo[5, 1 -c] [ 1 ,4]oxazinyl, 1 ,2-benzisoxazolyl, isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-d]pyrimidinyl, 4H-thiopyrano[3,4-d]isoxazolyl, 4H-pyrano[3,4-d]isoxazolyl, 7aH-indolyl, 7aH-pyrrolo[2,3
  • (v) B is aryl, particularly phenyl;
  • (w) B is a saturated or partially saturated 3 to 7 (particularly 4 to 6) membered heterocyclic ring that contains one or two heteroatoms (particularly one heteroatom) selected from oxygen and nitrogen;
  • (x) B is a a 5 or 6 membered heteroaryl ring;
  • 5 (y) B is a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2 or 3 (particularly 1 or 2) heteroatoms independently selected from N and O and which is saturated, partially saturated or aromatic;
  • (z) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, o thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic; s (aa) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group or a 5 or 6 member
  • 1,4-dioxanyl 1,4-dioxanyl, morpholinyl, furyl, pyrrolidinyl, piperidinyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
  • (dd' ') B is selected from cyclohexyl, phenyl, tetrahydopyranyl, tetrahydrofuranyl, 5 morpholinyl, thiomo ⁇ holinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl;
  • (dd' ) B is selected from phenyl, imidazolyl, thienyl, and isoxazolyl;
  • (dd") B is selected from phenyl, isoxazolyl or tetrahydopyranyl.
  • (dd' " ' ") B is selected from isoxazolyl, pyrazolyl, tetrahydopyranyl, phenyl and benzodioxolyl I 0 (ee) B is selected from phenyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiornorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydr
  • B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl.
  • 2o (ff) B is selected from piperidinyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyr
  • (gg) B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • (hh) Bis selected from isoxazolyl, thiadiazolyl and pyrazolyl;
  • R 1 and R 2 are independently selected from hydrogen, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3- 30 6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, (1 -6C)alkoxy(l -6C)alkoxy, (1 -6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l)
  • (l-6C)alkoxy are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l -6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R 1 and/or R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l- 4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH 2 ) Z Y wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R 1 and/or R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R 1 and/or R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (pp) R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, I 5 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)
  • R is hydrogen and R is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
  • R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)aIkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and
  • R 1 and R 2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or T), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 1 and/or R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)allcylsulfonyl, phenyl(CH 2 ) u - wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1-
  • R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH 2 ) v - in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); (xx) R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkanoyl, (l- ⁇ C)alkyl or a 5 or
  • R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
  • R 1 is hydrogen and R 2 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkoxy, amino, mono(l-3C)alkylamino, di(l-3C)alkylamino, carbamoyl or-N(R d )C(O)(l-3C)alkyl in which R d is hydrogen or (l-3C)alkyl, or a saturated 5 or 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-4C)alkoxy and (l-4C)alkoxy(l-4C)alkoxy and the (1- 3C)alkyl groups of
  • R 1 is hydrogen and R 2 is selected from hydrogen and (l-6C)alkyl (particularly (l-3C)alkyl); wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or X), which may be the same or different, as hereinbefore defined in (zz);
  • R 1 is hydrogen and R 2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R 2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); (ccc') R 1 and R 2 are both hydrogen or R 1 is hydrogen and R 2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by amino, mono(l-6C)alkylamino or di(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring;
  • R 1 and R 2 are both hydrogen or R 1 is hydrogen and R 2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by di(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring;
  • (ccc")R ! and R 2 are both hydrogen or R 1 is hydrogen and R 2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by a saturated 3 to 7 membered heterocyclic ring;
  • R 1 is hydrogen and R 2 is selected from hydrogen, and 3-morpholin-4- ylpropyl;
  • R 1 is hydrogen and R 2 is selected from hydrogen, 3-(dimethylamino)propyl and 3-piperidin-l-ylpropyl;
  • R 1 is hydrogen and R 2 is selected from hydrogen, 3-(dimethylamino)propyl and 3-piperidin-l-ylpropyl;
  • (ddd) NR 1 R 2 is amino.
  • (ddd') R 1 and R 2 are both hydrogen or R 1 is hydrogen or (l-6C)alkyl and R 2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by hydroxy, amino, mono(l-6C)alkylamino or di(l-6C)alkylamino, carbamoyl, (l- ⁇ C)alkoxy,
  • R 1 and R 2 are independently selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 3-(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-ylpropylpropy
  • R 1 is hydrogen and R 2 is selected from R 2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is substituted by a saturated 5 or 6 membered heterocyclic ring;
  • R 1 is hydrogen and R 2 is selected from 2-morpholino-4-yl-ethyl or 3-morpholinyl- 4-ylpropyl;
  • R 2 is hydrogen or methyl and R 3 is selected from hydrogen, methyl, 2- hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-(2-hydroxyethoxy)ethyl, 2- methoxyethoxymethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-
  • R 1 is hydrogen and R 2 is selected from 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 4-methyl-piperazin-l-ylpropyl and 3-pyrrolidin-l-ylpropyl;
  • R 1 is hydrogen and R 2 is selected from 2-morpholin-4-ylethyl, 3 -morpholin-4-ylpropyl, 3 -piperidin- 1 -ylpropyl, 2-piperidin- 1 -ylethyl, 2-pyrrolidin- 1 - ylethyl, 3-pyrrolidin-l-ylpropyl and 4-methyl-piperazin-l-yl;
  • R 1 and R 2 are both (l-6C)alkyl (particularly (l-3C)alkyl); (111) R 1 is hydrogen and R 2 is methyl;
  • (mmm) R 1 and R 2 are both hydrogen;
  • (mmm) R 3 (including R 3a or R 3b ) is selected from hydrogen, (l-3C)alkyl or (l-3C)alkoxy, wherein the (l-3C)alkyl and the (l-3C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l- 6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more
  • R 3 , R 3a or R 3b is selected from hydrogen and a group -NR 1 R 2 as defined above (particularly
  • R 3 , R 3a or R 3b is hydrogen
  • R 3 , R 3a or R 3b is a group -NR 1 R 2 as defined above (particularly -NH 2 );
  • R 3 , R 3a or R 3b is selected from hydrogen or a group -NR 1 R 2 as defined above (particularly -NH 2 );
  • (qqq' ') R 3 , R 3a or R 3b is selected from hydrogen or -NH 2 .
  • (rrr) R 4 is independently selected from hydrogen and (l-6C)alkyl (particularly (l-3C)alkyl);
  • R 3 and R 4 , R 3a and R 4a s or R 3b and R 4b are both hydrogen;
  • R 3 , R 3a or R 3b is a group -NR 1 R 2 as defined above (particularly -NH 2 ) and R 4 , R 4a or R 4b is hydrogen;
  • (uuu') R 5 is selected from (l-6C)alkyl and (l-6C)alkoxy; (uuu' ') R 5 is selected from (l-4C)alkyl and (l-4C)alkoxy; (uuu'") R 5 is selected from methyl and methoxy; (wv) n is 0, 1 or 2 (particularly 0 or 1, more particularly 0); (wv') n is O or l;
  • R 5 is independently selected from halo, (l-6C)alkoxy and (1- 6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fluoro;
  • n is 1 or 2 and R 5 is independently selected from cyano, halo, (l-6C)alkoxy and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fluoro;
  • (yyy) n is 0 or 1 and when n is 1, R 5 is (l-4C)alkyl (particularly methyl); (zzz) n is 1 or 2 and R 5 is independently selected from cyclopropyl and (l-6C)alkyl, wherein the (l-6C)alkyl groups are optionally substituted by cyano or one or more fluoro;
  • (aaaa) n is 1 and R 5 is (l-6C)alkyl, particularly (l-3C)alkyl; (bbbb) n is O (cccc) n is i;
  • R 6 is independently selected from (l-6C)alkyl or (l- ⁇ C)alkoxy, (l-6C)alkyl,
  • -S(0)p-(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(0) p -(l-6C)alkyl and the (l-6C)alkoxy(l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy,(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl;
  • R 6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-6C)alkyl; or R 6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l- 6C)alkyl] amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; (eeee) R 6 is independently selected from halo,
  • R 6 is selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • R 6 is selected from fluoro, chloro, acetylamino, methyl, propyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy and morpholin-4-yl; (iiii) R 6 is independently selected from halo or (l-6C)alkyl wherein (l-6C)alkyl is optionally substituted by 1 to 3 halo, particularly fluoro,
  • R 6 is independently selected from halo, (l-6C)alkyl, (l-6C)alkoxy, and a saturated
  • R 6 is independently selected from (l-6C)alkyl, (l-6C)alkoxy or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl or piperidin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by hydroxy(l-2C)alkyl;
  • R 6 is independently selected from hydroxy, halo (particularly chloro or fluoro), (l-6C)alkyl, (l-6C)alkoxy, di-(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl, piperidin-1-yl or piperazin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by (1- 2C)alkyl or hydroxy(l -2C)alkyl;
  • R 6 is independently selected from (l-6C)alkyl (optionally substituted 1 to 3 groups independently selected from halo, particularly fluoro), halo or (l-6C)alkoxy; (jjjj) R 6 is independently selected from methyl, t-butyl, fluoro and trifluoromethyl;
  • GJJJ') R 6 is independently selected from methyl, t-butyl, 1-cyanoethyl, methoxy, isopropoxy, fluoro, trifluoromethyl, morpholin-4-yl and 4-methylpiperazin-l-ylmethyl;
  • GJJJ ' ') R 6 is independently selected from methyl, trifluoromethyl, morpholin-4-yl or piperidin- 1 -yl, 4-hydroxymethylpiperidin- 1 -yl;
  • R 6 is independently selected from methyl, methoxy, di-methylamino, hydroxy, oxo, chloro, fluoro, trifluoromethyl, morpholin-4-yl or piperidin- 1-yl,
  • R 6 is independently selected from chloro, fluoro, trifluoromethyl, methyl or methoxy;
  • R 6 is independently selected from halo, trifluoromethyl, methyl, tert-butyl, methoxy, acetylamino or morpholino.
  • R 6 is independently selected from halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(R°)C(O)(l-6C)alkyl wherein R° is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or (l-6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro).
  • R 6 is independently selected from hydroxy, halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(R c )C(O)(l-6C)alkyl wherein R c is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by a saturated 3 to 7 membered heterocyclic ring or up to three groups independently selected from halo, particularly fluoro), (l- ⁇ C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or di-(l-6C)alkylamino;.
  • R 6 is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, methoxy, acetylamino, oxo, cyclopropyl, morpholin- 4-yl, piperidin- 1 -yl, 4-(hydroxymethyl)piperidin- 1 -yl and 4-methyl-piperazin- 1 -yl.
  • R 6 is independently selected from hydroxy, halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, 1-cyanoethyl, methoxy, isopropoxy, di-methylamino, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-l-yl, 4-methyl-piperazin-l-yl and 4-methylpiperazin-l- ylmethyl
  • R 6 is independently selected from halo (such as chloro), trifluoromethyl, methoxy, dimethylamino, mo ⁇ holin-4-yl or piperidin-l-yl.
  • At least one R 6 group is selected from amino, mono(C 1-6 alkyl)amino, (U-(C 1-6 - alkyl)amino such as dimethylamino.
  • (qqqq) Ring B-R 6 where m is 1 or 2, is selected from: 2-fluoro-5-trifluoromethylphenyl,
  • Ring B-R 6 where m is 1 or 2, is selected from: phenyl, 3-methoxyphenyl,
  • 3-isopropoxyphenyl 4-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-(l-cyanoethyl)phenyl, 2-morpholin-4-ylphenyl, 3-mo ⁇ holin-4-ylphenyl, 4-methyl- pi ⁇ erazin-1-ylmethylphenyl, 5-t-butylisozazol-3-yl, l-methyl-3-tert-butylpyrazol-5-yl.
  • Ring B-R 6 where m is 1 or 2, is selected from: 2-(trifluoromethyl)phenyl,
  • Ring B-R 6 where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3,6-di-fluorophenyl, 2-(trifluoromethyl)phenyl, 3- (trifluoromethyl)phenyl, 2-chloro-thien-5-yl, l-methylimidazol-4-yl, 3-methoxyphenyl and
  • Ring B-R 6 where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,6-di-fluorophenyl, 2- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-chloro-thien-5-yl, 1-methylimidazol- 4-yl, 3-methoxyphenyl and 3,5-dimethyl-isoxazol-4-yl;
  • Ring B-R 6 where m is 1 or 2, is selected from
  • 2-oxopyrrolidin-l-yl 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 5 2,2-dimethyltetrahydropyran-4-yl, 5-methyl-furan-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-t-butyl-l,3,4-thiadiazol-2-yl, 5-triflluoromethyl-l,3,4-thiadiazol-2-yl, 5-cyclopropyl- 1 ,3,4-thiadiazol-2-yl, 5-ethyl- 1 ,3 ,4-thiadiazol-2-yl,
  • Ring B-R 6 where m is 1 or 2, is selected from
  • (ssss) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
  • L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -, -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, -C(R a )(R b )N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y - or -C(R a )(R b )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein Z is -O- or -N(R 8 )- or L represents -C(O)N(R 9
  • R 8 , R 9 , R a and R b independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y ⁇ 3, (tttt) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
  • L is attached meta or para on ring A with respect to the point of attachment of 5 the ethynyl group and represents -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -,
  • R 8 , R 9 , R a and R b independently represent hydrogen or (l-6C)alkyl (particularly o hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y ⁇ 3, (uuuu) A is phenyl; n is 0; and
  • B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic s ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially o saturated or aromatic; (vwv) A is phenyl; n is 0; and
  • B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • (wwww)A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, 5 imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
  • L is attached meta or para on ring A with respect to the point of attachment of o the ethynyl group and represents -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -,
  • R 8 , R 9 , R a and R b independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1 , or 2, with the proviso that x+y > 0 and x+y ⁇ 3,
  • B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
  • L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y -, -C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y -, -C(R a )(R b )N(R 8 )C(O)-(CR a R b ) x -Z-(CR a R b ) y - or -C(R a )(R b )C(O)N(R 9 )-(CR a R b ) x -Z-(CR a R b ) y - wherein Z is -O- or -N(R 8 )- or L represents -C(O)N(R 9
  • R 8 , R 9 , R a and R b independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y ⁇ 3, B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
  • (yyyy) m is 0, I or 2 (particularly 1 or 2);
  • (zzzz) B is selected from cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-l,4-benzodioxinyl and l,3-benzodioxol-5-yl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (aaaaa) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
  • R 6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(R c )C(O)(l-6C)alkyl in which R c is hydrogen or (l-6C)alkyl; or R 6 is selected from (l- ⁇ C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fiuoro);
  • (bbbbb) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (ccccc) B is phenyl; m is 1 or 2;
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
  • (ddddd) B is phenyl; m is 1 or 2;
  • R 6 is independently selected from fluoro and trifluoromethyl; (eeeee) B is isoxazolyl; m is 1 or 2; and
  • R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy;
  • (fffff) B is isoxazolyl; m is 1 or 2;
  • R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl);
  • (ggggg) B is pyrazolyl; m is 1 or 2; and R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy;
  • (hhhhh) B is pyrazolyl; m is 1 or 2; and
  • R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (iiiii) B is thiadiazolyl; m is 1 or 2; and R 6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy and butoxy; Ojjj) B is thiadiazolyl; m is 1 or 2; and R 6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (cccc)
  • R 1 and R 2 are both hydrogen, R 3 and R 4 are both hydrogen, n is 0, L is -C(O)NH- or -NHC(O)- and ring B-R 6 , where m is 1 or 2, is selected from 3-acetylaminophenyl, 2-(trifluoromethyl)phenyl, 3 -(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl,, 3,4-dichloro-phenyl, 2-morpholin-4-ylphenyl, 5-tert-butyl- 1.3 ,4-thiadiazol-2-yL 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-tert-butylisoxazol-3-yl, l-methyl-3-tert-butyl-pyrazol-5-yl, l--
  • a particular embodiment of the compounds of the Formula I is a compound of the Formula IA(i):
  • Formula IA(ii) ⁇ 4 , ⁇ R> 5 ⁇ % d R>4 D , R 0 , L, B, n and m are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
  • Another particular embodiment of the compounds of the Formula I is a compound of the Formula IA(iii):
  • Another particular embodiment of the compounds of the Formula I is a compound of the Formula IA(iv):
  • a particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(i):
  • Another particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(ii):
  • Another particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(iii):
  • Another particular embodiment of the compounds of the Formula I is a compound of the Formula IB(iv):
  • a compound of the Formula I, or a pharmaceutically-acceptable salt thereof may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
  • a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof (wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 11 L , ring A and ring B, n and m are, unless otherwise specified, as defined in formula I) as described schematically below.
  • Process Ta For compounds of the formula I wherein L is
  • W is -C(R a R b )- or a direct bond and R x , R y , R z , R 5 , R 8 , R a , R b , n, p and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a heterocycle of the formula III:
  • Lg 1 is a suitable displaceable group for example hydroxy, halogeno (such as fluoro, chloro or bromo), R X -C(O)-O- or R x -O- (wherein R x is a suitable alkyl or aryl group) and R 6 , R a , R b , m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
  • Lg 2 is a suitable displaceable group as described above for Lg 1
  • W is - C(R a R b )- or a direct bond
  • R x , R y , R z , , R 5 , R a , R b , n, p and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula V:
  • Vl wherein J is selected from -N(R 8 )C(O)-, -C(O)N(R 9 )-, -C(R a )(R b )-N(R 8 )C(O)- or -C(R a )(R b )-C(O)N(R 9 )- and Z R x , R y , R z , R 5 , R 8 , R 9 , R a , R b , x, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary and when Z is -O- then x>0, with a compound of formula VII,
  • Lg 3 is a suitable displaceable group, for example halogeno (such as fluoro, chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy and R a , R b , R 6 , y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
  • halogeno such as fluoro, chloro, bromo
  • Lg 4 is a suitable displaceable group, for example halogeno (such as chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy
  • J is selected from -N(R 8 )C(O)-, -C(O)N(R 9 )-, -C(R a )(R b )-N(R 8 )C(0)- or -C(R a )(R b )-C(O)N(R 9 )- and R x , R y , R 2 , R 5 , R 8 , R 9 , R a , R b , n, and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary and x is 1, 2 or 3, with a compound of formula IX,
  • Lg 5 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methyl sulfonyl, methylthio, methylsulphoxide or aryloxy (such as phenoxy) and R 3 , R 4 , R 5 , R 6 , n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 1 R 2 , wherein R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or for the preparation of a compound of formula (IB), the reaction of a compound of the formula X':
  • Lg 3 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methyl sulfonyl, methylthio or aryloxy (such as phenoxy) and R 3 , R 4 , R 5 , R 6 , n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 1 R 2 , wherein R 1 and R 2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (f) The reaction of a compound of the formula XI:
  • Lg 6 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and R 5 , R 6 , n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alkyne of the formula XII:
  • Lg 7 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and R x , R y and R z have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate.
  • halogeno such as chloro, bromo or iodo
  • a sulfonyloxy group such as trifluoromethylsulfonyloxy
  • a suitable coupling agent is, for example, a suitable peptide coupling agent, for example O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or a suitable carbodiimide such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole (CDI), optionally in the presence of a catalyst such as dimethylaminopyridine or hydroxybenzotriazole.
  • the reaction of process (a) may conveniently be carried out in the presence of a suitable base.
  • a suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene.
  • Another suitable base is, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate.
  • reaction of process (a) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide.
  • a suitable inert solvent or diluent for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a di
  • reaction of process (b) is conveniently carried out under the conditions as described above for process (a).
  • a suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
  • reaction of process (c) is conveniently carried out in the presence of a suitable solvent or diluent, for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide.
  • a suitable solvent or diluent for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide.
  • the reaction is conveniently carried out at a temperature in the range, for example, from about ambient temperature to about 100 0 C, and under atmospheric pressure.
  • reaction of process (d) is conveniently carried out under the conditions as described above for process (c).
  • reaction of process (e) is conveniently carried out in the presence of a catalytic amount of a suitable acid.
  • a suitable acid is, for example, hydrogen chloride.
  • reaction of process (e) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent.
  • a suitable inert solvent or diluent when used, is for example an alcohol such as ethanol, isopropanol or butanol or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
  • N-methylpyrrolidin-2-one or dimethylsulfoxide is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 120°C, preferably from about 8O 0 C to about 9O 0 C.
  • Process (f) The reaction of process (f) is conveniently carried out in the presence of a suitable palladium catalyst, optionally in combination with a suitable copper catalyst.
  • a suitable palladium catalyst is, for example, bis(triphenylphosphine)palladium dichloride, [1,1'- bis(diphenylphosphino)ferrocene] palladium dichloride or tetrakis(triphenylphosphine)palladium(0).
  • a suitable copper catalyst is, for example, copper (I) iodide.
  • a suitable base is, for example, an organic amine base, such as trialkylamine (for example triethylamine) or tetramethylguanidine.
  • reaction of process (f) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as
  • reaction is conveniently carried out at a temperature in the range, for example, from about -20 0 C to about 100 0 C.
  • Reaction Scheme 1 wherein Lg 8 is a suitable displaceable group as described above and R x R y , R z , R 5 , R 8 , n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • the reaction of Reaction Scheme 1 is conveniently carried out under the conditions as described above for process (f).
  • compounds of the formula II may be obtained by reaction of a pyrimidine of the formula XVII with a protected alkyne of the formula XVIII and then with an amine of the formula XIX as illustrated in Reaction Scheme 2:
  • Lg 9 and Lg 10 are each a suitable displaceable group
  • Pg is a suitable protecting group, for example a trialkylsilyl group, such as trimethylsilyl or tert-butyldimethylsilyl or Me 2 (OH)C-
  • R x , R y , R z , R 5 , R 8 , n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
  • Step (i) of Reaction Scheme 2 is the coupling of a protected alkyne of the formula XVIII to a pyrimidine of the formula XVII. Step (i) is carried out under conditions as described above for process (f).
  • Step (ii) of Reaction Scheme 2 is the deprotection of the alkyne under basic or acidic conditions to provide an unprotected alkyne. A person skilled in the art would readily be able to select the appropriate conditions for deprotection in step (ii).
  • Step (iii) of Reaction Scheme 2 is the coupling of the alkyne to an amine of the formula XIX. Step (iii) of Reaction Scheme 2 is carried out under conditions as described above for process (f).
  • compounds of the formula II where R y is a group NR 1 R 2 may be obtained by reaction of a compound of the formula XX, wherein Lg 11 is a suitable displaceable group and R 3a , R 4a , R 5 , R 8 , n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 1 R 2 using reaction conditions as described above for process (e).
  • compounds of the formula II where R x is NR 1 R 2 may be obtained by reaction of a compound of the formula XX', wherein Lg 3 is a suitable displaceable group as described above and R 3b , R 4b , R 5 , R 8 , n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR 1 R 2 using reaction conditions as described above for process (g).
  • the starting materials of the formulae XV, XVI, XVIII and XIX and the amine HNR 1 R 2 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • the starting material of the formula XX can be prepared by standard processes known in the art or by a method analogous to Reaction Scheme 2 as described above.
  • Amines of the formula HNR 1 R 2 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
  • Alkynes of the formula XII are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials.
  • compounds of the formula XII may conveniently be obtained by reaction of a pyrimidine of the formula XXI:
  • Examples of the types of conversion reactions that may be used include introduction of a substituent by means of an aromatic substitution reaction or of a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • nucleophilic substitution reactions include the introduction of an alkoxy group or of a monoalkylamino group, a dialkyamino group or a N-containing heterocycle using standard conditions.
  • reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating.
  • An example of a suitable conversion reaction is the conversion of a compound of the formula I wherein R 2 , R 3 , R 4 , R 5 , R 6 , n, m, A, B and L are as defined in claim 1 and R 1 and/or R 2 is hydrogen to a compound of the formula I wherein R 1 and/or R 2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group.
  • R 1 and/or R 2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group.
  • Such a conversion may be achieved using standard procedures, for example by substitution of one or both of the hydrogen atoms R 1 and/or R 2 for a desired, optionally substituted (l-6C)alkoxycarbonyl group.
  • Certain compounds of Formula I are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula I and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
  • Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation.
  • Enantiomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques (e.g. chiral High Performance Liquid Chromatography (HPLC)).
  • HPLC High Performance Liquid Chromatography
  • the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.
  • the compounds of the invention may be isolated from their reaction mixtures using conventional techniques. It will be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
  • protecting groups are given below for the sake of convenience, in which "lower”, as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention. It will also be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention.
  • Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents.
  • the reagents and reaction conditions for such procedures are well known in the chemical art.
  • aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group.
  • modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfmyl or alkylsulfonyl.
  • the following assay can be used to measure the effects of the compounds of the present invention as inhibitors of Tie2 autophosphorylation in whole cells.
  • This assay is based on measuring the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which normally leads to the production of "activated" receptor that in turn initiates the particular signal transduction pathways associated with the receptor function.
  • Autophosphorylation can be achieved by a number of means. It is known that expression of recombinant kinase domains in baculoviral systems can lead to the production of phosphorylated and activated receptor. It is also reported that over expression of receptors in recombinant cell lines can itself lead to receptor autophosphorylation in the absence of the ligand (Heldin C-H. 1995 Cell : 80, 213-223; Blume-J. P, Hunter T. 2001 Nature: 411, 355-65).
  • chimaeric receptors have been constructed.
  • the natural, external cell surface domain of the receptor has been replaced with that of a domain which is known to be readily dimerised via the addition of the appropriate ligand (e.g. TrkA-Tie2/NGF ligand (Matron, M.B., et al., 2000 Journal of Biological Chemistry : 275:39741-39746) or C-fms-Tie-1/CSF-l ligand (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713).
  • TrkA-Tie2/NGF ligand e.g. TrkA-Tie2/NGF ligand
  • C-fms-Tie-1/CSF-l ligand Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713.
  • ligand Naturally if the ligand is available one can use natural cell lines or primary cells which are known to express the receptor of choice and simply stimulate with ligand to achieve ligand induced phosphorylation.
  • the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which is expressed for example in EA.hy926/B3 cells (supplied by J. McLean/ B. Tuchi, Univ.of N. Carolina at Chapel Hill, CB- 4100, 300 Bynum Hall, Chapel Hill, N.C. 27599-41000, USA) or primary HUVEC (human umbilical vein endothelial cells - available from various commercial sources), can measured by this assay.
  • Natural Angl ligand can be isolated using standard purification technology from either tumour cell supernatants or alternatively the Angl gene can be cloned and expressed recombinantly using stand molecular biology techniques and expression systems. In this case one can either attempt to produce the ligand either in its native state or as recombinant protein which for example may have been genetically engineered to contain additional of purification tags (eg. polyhistidine peptides, antibody Fc domains) to facilitate the process.
  • purification tags eg. polyhistidine peptides, antibody Fc domains
  • EA.hy926/B3 or HUVEC cellular Tie2 receptor a Angl ligand stimulated cellular receptor phosphorylation assay can be constructed which can be used to analyse to determine the potential of compounds to inhibit this process.
  • EA.hy926/B3 cells were grown in the appropriate tissue culture media plus 10% foetal calf serum (FCS) for two days in 6 well plates starting with an initial seeding density of 5xlO 5 cells/well. On the third day the cells were serum starved for a total of 2 hours by replacing the previous media with media containing only 1% FCS.
  • FCS foetal calf serum
  • the ligand plus orthovandiate was added to stimulate autophosphorylation of the cellular Tie2 receptor (ligand can be added either as purified material diluted in serum starvation media or non-purified cell supernatant containing ligand e.g. when recombinantly expressed mammalian cells).
  • the cells were cooled on ice washed with approximately 5mls with cold PBS containing 1 mM orthovanadate, after which 1 ml of ice cold lysis buffer ((20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1 % SDS, 1% NP40, 0.5 % DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 ⁇ l / ml Aprotinin, 10 ⁇ g/ml Pepstatin, 10 ⁇ g/ml Leupeptin) was added the cells and left on ice for 10- 20 minutes.
  • ice cold lysis buffer ((20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1 % SDS, 1% NP40, 0.5 % DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 ⁇ l / ml
  • the lysate was removed and transferred to a 1.5 ml Eppendorf tube and centrifuged for 3 minutes at 13000 rpm at 4 °C. 800 ⁇ l of each lysate was transferred to fresh 2 ml Eppendorf tubes for the immuno-precipitation.
  • 3 mg 15 ⁇ l of anti-phospho- tyrosine antibody (Santa Cruz PY99 -sc-7020) was added to the lysates and left to incubate for 2 hours at 4 °C. 600 ⁇ l washed MagnaBind beads (goat anti-mouse IgG, Pierce 21354) were added to the lysates and the tubes left to rotate over night at 4 °C.
  • the beads were removed by exposing the tubes for 1 minutes in the magnet, and the total liquid separated from the beads from each immuno-precipitate loaded onto Polyacrylamide/SDS protein gels (pre-cast 4-12 % BisTris NuPAGE / MOPS 12 well gels from Novex). Protein gels were run at 200 V and then blotted onto NC membrane for
  • the antibody was left on for 1 hour at room temperature before subsequently washing the blots with PBS-Tween.
  • the western blots of the various immuno-precipitated samples were developed the blots with LumiGLO (NEB 7003). And transferred to an X-Ray cassette and films exposed for 15 sec / 30 sec and 60 sec.
  • the relative strength of the protein band which pertains to the phosphorylated Tie2 receptor was evaluated using a FluorS BioRad image analyser system. The percentage phosphorylation for each test compound dilution series was determined from which IC 50 values were calculated by standard methods using the appropriate control samples as reference.
  • Table A illustrates the activity of representative compounds according to the invention showing IC 50 data for the inhibition of autophosphorylation of Tie2 receptor tyrosine kinase.
  • references to a compound of formula I refer also to other sub-groups of the invention as described above, for example would also apply, amongst other sub-groups of the invention, to compounds of formula Ia, Ib, Ic and Id.
  • a pharmaceutical composition which comprises a compound of the Formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
  • compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing).
  • the compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art.
  • compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and
  • a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
  • the size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine.
  • a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses.
  • a parenteral route is employed.
  • a dose in the range for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used.
  • a dose in the range for example, 0.05 mg/kg to 25 mg/kg body weight will be used.
  • Oral administration is however preferred, particularly in tablet form.
  • unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
  • the compounds according to the present invention as defined herein are of interest for, amongst other things, their antiangiogenic effect.
  • the compounds of the invention are expected to be useful in the treatment or prophylaxis of a wide range of disease states associated with undesirable or pathological angiogenesis, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma.
  • compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
  • the compounds of the present invention are expected be useful to produce a Tie2 inhibitory effect in a warm-blooded animal in need of such treatment.
  • the compounds of the present invention may be used to produce an antiangiogenic effect mediated alone or in part by the inhibition of Tie2 receptor tyrosine kinase.
  • the compounds of the invention are expected to inhibit any form of cancer associated with Tie2. For example, the growth of those primary and recurrent solid tumours which are associated with Tie2, especially those tumours which are significantly dependent on Tie2 receptor tyrosine kinase for their growth and spread.
  • a compound of the formula I or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
  • a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid and skin cancer in a warm-blooded animal such as man.
  • a method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
  • a method of treating cancers in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the formula
  • a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer.
  • a compound of the present invention will possess activity against other diseases mediated by undesirable or pathological angiogenesis including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • undesirable or pathological angiogenesis including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
  • the anti-angiogenic activity defined herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments.
  • Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment.
  • the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy.
  • Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
  • anti-invasion agents for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function
  • antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as (2S)-2- ⁇ o-fluoro-rj-[N- ⁇ 2,7-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-ylmethyl)-
  • alkylating agents for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan
  • antitumour antibiotics for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin
  • antimitotic agents for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere
  • topoisomerase inhibitors for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin
  • cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5 ⁇ -reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitor
  • antiangiogenic agents that work by different mechanisms to those defined hereinbefore, such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inhibitors of integrin ⁇ v ⁇ 3 function and angiostatin);
  • biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequest receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g.
  • antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense
  • gene therapy approaches including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy
  • immunotherapy approaches including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dend
  • a pharmaceutical product comprising a compound of the Formula I as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer.
  • the compounds of Formula I and their pharmaceutically acceptable salts are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
  • Examples of compounds of the invention include:
  • temperatures are given in degrees Celsius ( 0 C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0 C;
  • chromatography means flash chromatography on silica gel; thin layer chromatography
  • NMR data when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-d ⁇ ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
  • PdCl 2 dppf (146 mg) was added to a solution of 2-amino-5-iodopyrimidine (221 mg), trimethylsilylacetylene (491 mg), CuI (57 mg) and DIPEA (259 mg) in EtOAc (5 mL) at -20 0 C under an inert atmosphere. The reaction was allowed to warm to ambient temperature and stirred for 6 hours. The reaction mixture was diluted with water (10 mL). The organic layer was separated, dried (MgSO 4 ), filtered and concentrated.
  • Triethylamine 300 mg was added to a mixture of 2-[(2-aminopyrimidin-5-yl)ethynyl]- l,3-thiazole-4-carboxylic acid (Intermediate 7) (197 mg) and O-benzotriazol-1-yl- N,N,N ⁇ N'-tetramethyluronium hexafluorophosphate (606 mg) in DMF (5 mL) and stirred for 10 min. Aniline (149 mg) was added and stirred for 60 hours at ambient temperature. The mixture was concentrated then partitioned between EtOAc and aqueous sodium bicarbonate. The solid formed was filtered off, the EtOAc extract was washed with water, dried and concentrated in vacuo.
  • Triethylamine (10 mL) was added to a stirred mixture of 2-amino-5-ethynylpyrimidine (Intermediate 2) (1.19 g), ethyl 2-bromo-l,3-thiazole-4-carboxylate (2.36 g), dichlorobis(triphenylphosphine)palladium(II) (140 mg), and copper (I) iodide (70 mg) in dry THF (100 mL). The mixture was degassed with nitrogen and heated at 6O 0 C for 3 hours. The mixture was cooled, diluted with water, and concentrated. The solid formed was filtered off, washed with water then dried at 60°C in vacuo.
  • Intermediate 2 2-amino-5-ethynylpyrimidine
  • ethyl 2-bromo-l,3-thiazole-4-carboxylate (2.36 g)
  • Triethylamine (7 mL) followed by DPPA (10.9 mL) was added to a solution of 5- bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction heated at reflux under an inert atmosphere for 1.5 hours.
  • the reaction mixture was diluted with EtOAc (100 mL) and water (100 mL).
  • the organic layer was separated, washed with NaHCO 3 (3 x 50 mL), dried (MgSO 4 ), filtered and concentrated in vacuo.
  • PdCl 2 dppf (907 mg) was added to a degassed solution of tert-butyl (5-iodopyridin-3- yl)carbamate (Intermediate 9) (7.94 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (3.7 g), CuI (94 mg) and Et 3 N (63 mL) in DMF (250 mL). The reaction was allowed to stir at ambient temperature under an inert atmosphere for 24 hours. Silica was added to the reaction mixture and then solvent was evaporated in vacuo.
  • the preabsorbed product was purified by flash chromatography on silica using 0-10% MeOH in DCM as the eluent followed by an aqueous wash and then dried in vacuo to give the title compound as a beige solid (5.3 g, 69%);
  • Example 7 The following Example was prepared in a similar manner to Example 7 by using Intermediate 11 with the appropriate acid.
  • the aqueous solution was acidified with a 2N aqueous solution of hydrochloric acid. On acidification to pH 4, a brown solid precipitated from the solution. The solid was collected by filtration then dried under vacuum for 20 hours, to give the title compound (2.40 g, 92%).
  • the aqueous solution was acidified with a 2N aqueous solution of hydrochloric acid. On acidification to pH 3, a yellow solid precipitated from the solution. The solid was collected by filtration and washed with water (2 x 50 mL) then dried under vacuum for 20 hours, to give the title compound (4.27 g, 96%).
  • Example 32 The following example was made in a similar way to Example 7 using intermediate 17 and the appropriate acid.
  • Example 32 The following example was made in a similar way to Example 7 using intermediate 17 and the appropriate acid.
  • Example 27 The following example was made in a similar way to Example 27 using the appropriate amine intermediate and the appropriate acid and using RP-HPLC for purification.
  • the aqueous was washed with another portion of diethyl ether (150 mL), the ether layers were combined and re-extracted with aqueous citric acid (500 mL), the combined aqueous layer was then basified with potassium carbonate, extracted with diethyl ether (3 x 500 mL), dried (MgSO 4 ) and the solvent removed in vacuo to yield a black viscous oil.
  • the oil was dissolved in 80% diethyl ether/iso-hexane and passed down a 4 inch plug of silica eluting with 80% diethyl ether/iso-hexane. On removal of the solvent an orange oil was obtained which solidified overrnight (87g); MS nVe MH + IPO.
  • DIPEA 3-[(5-aminopyridin-3-yl)ethynyl]pyrimidin-2- amine (Intermediate 11) (211 mg), 3-morpholin-4-ylbenzoic acid (414 mg) and HBTU (642 mg) in DMF (3 mL) and stirred for 65 hours at ambient temperature.
  • the mixture was purified by RPHPLC. Product fractions were made basic with aqueous ammonia and concentrated to low volume. The solid formed was filtered off and dried to give the product (179 mg, 44%).
  • DIPEA 129 mg was added to a mixture of 3-[(2-aminopyrimidin-5-yl)ethynyl]benzoic acid (Intermediate 16) (119 mg), 3-amino-l-isopropylpyrazole (Intermediate 37) (63 mg) and HATU (379 mg) in DMF (1.5 mL) and stirred for 17 hours at ambient temperature.
  • the mixture was diluted with IM aqueous sodium hydroxide and extracted with EtOAc. The extract was washed with brine, dried, and the solvent evaporated. Purification of the residue by RPHPLC gave the product as a solid (11 mg, 6%). MS nVe MH+ 347.
  • Example 36 The following example was made in a similar way to Example 36 using intermediate 16 and the appropriate amine.
  • Example 7 The following examples were made in a similar way to Example 7 using the appropriate amines and acids.
  • the ether layer was re-extracted with aqueous citric acid (100 ml), the aqueous layers were combined and basified with potassium carbonate until pH12, this was then extracted with diethyl ether (3 x 300 ml), dried (MgSO4) and solvent removed invacuo to yield viscous black oil. This was then used in the next step without any purification.

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Abstract

The invention relates to a compound of the Formula I or salt thereof wherein Rx, Ry, Rx, R5, R6, A, B, L, n and m are as defined in the description. The invention also relates to pharmaceutical compositions of said compounds, the use of said compounds as medicaments and in the production of an anti-angiogenic effect in a warm blooded animal. The invention also relates to processes for the preparation of said compounds.

Description

Compounds
This invention relates to compounds, or pharmaceutically acceptable salts thereof, which possess anti-angiogenic activity and are accordingly useful in methods of treatment of disease states associated with angiogenesis in the animal or human body. The invention also concerns processes for the preparation of the compounds, pharmaceutical compositions containing the compounds as active ingredient, and methods for the use of the compounds in the manufacture of medicaments for use in the production of anti- angiogenic effects in warm-blooded animals such as humans. The Tie2 receptor tyrosine kinase (also known as TEK) is expressed predominantly in endothelial and haematopoietic cells and is essential for vessel formation and maintenance (Jones, N. et al. Nature Reviews Molecular Cell Biology. 2001: 2, 257-67).
Angiogenesis is a fundamental process defined as the generation of new blood vessels from existing vasculature. It is a vital yet complex biological process required for the formation and physiological functions of virtually all the organs. Normally it is transient in nature and is controlled by the local balance of angiogenic and angiostatic factors in a multi-step process involving vessel sprouting, branching and tubule formation by endothelial cells (involving processes such as activation of endothelial cells (ECs), vessel destabilisation, synthesis and release of degradative enzymes, EC migration, EC proliferation, EC organisation and differentiation and vessel maturation).
Normal angiogenesis plays an important role in a variety of processes and is under stringent control. In the adult, physiological angiogenesis is largely confined to wound healing and several components of female reproductive function and embryonic development. In undesirable or pathological angiogenesis, the local balance between angiogenic and angiostatic factors is dysregulated leading to inappropriate and/or structurally abnormal blood vessel formation. Pathological angiogenesis has been associated with disease states including diabetic retinopathy, psoriasis, cancer, rheumatoid arthritis, atheroma, Kaposi's sarcoma and haemangioma (Fan et al, 1995, Trends Pharmacology. Science. 16: 57-66; Folkman, 1995, Nature Medicine 1: 27-31). In cancer, growth of primary and secondary tumours beyond 1-2 mm3 requires angiogenesis (Folkman, J. New England Journal of Medicine 1995; 33, 1757-1763). In diseases such as cancer in which progression is dependant on aberrant angiogenesis, blocking the process can lead to prevention of disease advancement (Folkman, J. 1995, Nature Medicine. 1: 27-31). Many factors are described in the scientific literature that are believed to play important critical roles in the regulation of angiogenesis. Two major classes of angiogenic factors are the vascular endothelial growth factor (VEGF) and the angiopoietins. These polypeptide moieties interact with their respective receptors (transmembrane tyrosine kinases which are predominantly endothelial cell specific) and induce cellular responses via ligand mediated signal transduction. It has been speculated that VEGF and the angiopoietins co-operate to regulate various aspects of the angiogenic process during both normal and pathological angiogenesis via signalling through their respective receptors.
Receptor tyrosine kinases (RTKs) are important in the transmission of biochemical signals across the plasma membrane of cells. These transmembrane molecules characteristically consist of an extracellular ligand-binding domain connected through a segment in the plasma membrane to an intracellular tyrosine kinase domain. Binding of ligand to the receptor results in stimulation of the receptor-associated tyrosine kinase activity that leads to phosphorylation of tyrosine residues on both the receptor and other intracellular molecules. These changes in tyrosine phosphorylation initiate a signalling cascade leading to a variety of cellular responses. To date, at least nineteen distinct RTK subfamilies, defined by amino acid sequence homology, have been identified. One of these subfamilies is presently comprised by the fms-like tyrosine kinase receptor, Fit or Fltl, the kinase insert domain-containing receptor, KDR (also referred to as FIk-I), and another fms-like tyrosine kinase receptor, Flt4. Two of these related RTKs, Fit and KDR, have been shown to bind VEGF with high affinity (De Vries et al, 1992, Science 255: 989-991; Terman et al, 1992, Biochem. Biophys. Res. Comm. 1992, 187: 1579-1586). Binding of VEGF to these receptors expressed in heterologous cells has been associated with changes in the tyrosine phosphorylation status of cellular proteins and calcium fluxes.
Recently a second family of predominantly endothelial cell specific receptors that regulate vessel destabilisation and maturation have been identified. The Tie receptors and their ligands, the angiopoietins, co-operate closely with VEGF during both normal and pathological angiogenesis. The transmembrane receptors Tiel and Tie2, constitute a family of endothelial cell specific tyrosine kinase receptors involved in maintenance of blood vessel integrity and which are involved in angiogenic outgrowth and vessel remodelling. Structurally Tiel and Tie2 share a number of features (e.g. the intracellular domains of both these receptors each contain a tyrosine kinase domain interrupted by a kinase insert region) and thus constitute a distinct RTK subfamily. Overall sequence identity between Tiel and Tie2 receptors at the amino acid level is 44% while their intracellular domains exhibit 76% homology. Targeted disruption of the Tiel gene results in a lethal phenotype characterised by extensive haemorrhage and poor microvessel integrity (Puri, M. et al. 1995 EMBO Journal: 14:5884-5891). Transgenic mice deficient in Tie2 display defects in vessel sprouting and remodelling and display a lethal phenotype in mid gestation (E9.5- 10.5) caused by severe defects in embryonic vasculature (Sato, T. et al. 1995 Nature 370: 70-74).
To date no ligands have been identified for Tiel and little is known regarding its signalling abilities. However, Tiel is believed to influence Tie2 signalling via heterodimerisation with the Tie2 receptor, hence potentially modulating the ability of Tie2 to autophosphorylate (Matron, M. et al. 2000 Journal of Biological Chemistry: 275, 39741-39746) and recent chimaeric Tiel receptor studies have indicated that Tie-1 may inhibit apoptosis via the PI 3 kinase/Akt signal transduction pathway (Kontos, CD., et al., 2002 Molecular and Cellular Biology: 22, 1704-1713). In contrast, a number of ligands, designated the angiopoietins have been identified for Tie2 of which Angiopoietin 1 (Angl) is the best characterised. Binding of Angl induces tyrosine phosphorylation of the Tie2 receptor via autophosphorylation and subsequently activation of its signalling pathways via signal transduction. Ang2 has been reported to antagonise these effects in endothelial cells (Maisonpierre, P. et al. 1997 Science: 277, 55-60). The knock-out and transgenic manipulation of Tie2 and its ligands suggest that stringent spatial and temporal control of Tie2 signalling is imperative for the correct development of new vasculature. There are also reports of at least another two ligands (Ang3 and Ang4) as well as the possibility of heterodimerisation between the angiopoietin ligands that has the potential to modify their activity (agonistic/antagonistic) on association with the receptor. Activation of the Tie2 receptor by Angl inhibits apoptosis (Papapetropoulos, A., et al., 2000 Journal of Biological Chemistry: 275 9102-9105), promotes sprouting in vascular endothelial cells (Witzenbicher, B., et al., 1998 Journal of Biological Chemistry: 273, 18514-18521) and in vivo promotes blood vessel maturation during angiogenesis and reduces the permeability and consequent leakage from adult microvessels (Thurston, G. et al., 2000 Nature Medicine: 6, 460-463). Thus activated Tie2 receptor is reported to be involved in the branching, sprouting and outgrowth of new vessels and recruitment and interaction of periendothelial support cells important in maintaining vessel integrity and overall appears to be consistent with promoting microvessel stability. Absence of Tie2 activation or inhibition of Tie2 auto phosphorylation may lead to a loss of vascular structure and matrix/cell contacts (Thurston, G., Cell Tissue Res (2003), 314: 61-69) and in turn may trigger endothelial cell death, especially in the absence of survival or growth stimuli. On the basis of the above reported effects due to Tie2 kinase activity, inhibiting Tie2 kinase may provide an anti-angiogenic effect and thus have application in the therapy of disease states associated with pathological angiogenesis. Tie2 expression has been shown to be up- regulated in the neovasculature of a variety of tumours (e.g. Peters, K.G. et al, (British Journal of Cancer, 1998; 77,51-56) suggesting that inhibiting Tie2 kinase activity will result in anti-angiogenic activity. In support of this hypothesis, studies with soluble Tie2 receptor (extracellular domain) (Pengnian, L. et al., 1997, Journal of Clinical Investigation 1997: 100, 2072-2078 and Pengnian, L. et al., 1998, Proceedings of the National Academy of Sciences 1998: 95, 8829-8834) have shown anti-tumour activity in in vivo tumour models. In addition these experiments also indicate that disruption of the Tie2 signalling pathways in a normal healthy individual may be well tolerated as no adverse toxicities were observed in these studies.
Examination of human primary breast cancer samples and human and murine breast cancer cell lines (Stratmann, A., et al., 2001, International Journal of Cancer: 91, 273-282) indicate that Tie2 dependant pathways of tumour angiogenesis may exist alongside KDR dependant pathways and, in fact, may operate both independently (Siemeister G., et al., 1999 Cancer Research: 59, 3185-3191) as well as in concert with each other (e.g. VEGF A and Angl reported to collaborate to induce angiogenesis and produce non-leaky mature vessels Thurston, G, et al., 1999 Science: 286, 2511-2514). It is quite possible that a mix of such angiogenic processes even exist within a single tumour. Tie2 has also been shown to play a role in the vascular abnormality called venous malformation (VM) (Mulliken, J.B. & Young, A.E. 1998, Vascular Birthmarks: W. B. Saunders, Philadelphia). Such defects can either be inherited or can arise sporadically. VM's are commonly found in the skin or mucosal membranes but can affect any organ. Typically lesions appear as spongy, blue to purple vascular masses composed of numerous dilated vascular channels lined by endothelial cells. Among the inherited forms of this disease the most common defect appears to be a Tie2 kinase mutation C2545T in the Tie2 coding sequence (Calvert, J.T., et al., 1999 Human Molecular genetics: 8, 1279-1289), which produces a R849W amino acid substitution in the kinase domain. Analysis of this Tie2 mutant indicates that it is constitutively activated even in the absence of ligand (Vikkula, M., et al., 1996 Cell: 87, 1181-1190).
Upregulation of Tie2 expression has also been found within the vascular synovial pannus of arthritic joints in humans, which is consistent with the role of inappropriate neovascularisation.
Such examples provide further indications that inhibition of Tie2 phosphorylation and subsequent signal transduction will be useful in treating disorders and other occurrences of inappropriate neovascularisation. To date only a few inhibitors of Tie2 are known in the art. For example, Internation Application No: WO 04/013141 describes a group of condensed pyridines and pyrimidines and International Application No: WO 04/058776 describes a group of pryidine and pyrimidine compounds. There is thus a need to identify additional Tie2 inhibitors that could exploit the full therapeutic potential of inhibiting/ modulating the Tie2 signalling pathways.
We have found that certain compounds possess inhibitory activity for the Tie2 receptor tyrosine kinase and accordingly have value in the treatment of disease states associated with pathological angiogenesis such as cancer, rheumatoid arthritis, and other diseases where active angiogenesis is undesirable.
According to the present invention there is provided a compound of Formula I:
Figure imgf000006_0001
Formula I wherein one of Rx or Ry is a group NR1R2, and the other is a group R3 or R4, and Rz is a group R3 or R4, R1 and R2 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R1 and R2 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-όC)alkyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl] amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or -N(Rd)C(O)(l-6C)alkyl, -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy and
(l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl] amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more hydroxy groups; wherein the phenyl is optionally substituted by one or more groups independently selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, wherein a (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino;di-(l-6C)alkylamino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more of the following: (l-4C)alkyl, (1- 4C)alkoxy,(l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l- 6C)alkylamino or di-[(l-6C)alkyl]amino,mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZY wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (1-
4C)alkoxy,(l-4C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy;
R3 and R4 are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, (1 -6C)alkoxy wherein the (1 -6C)alkyl and the (1 -6C)alkoxy groups are optionally substituted by one or more groups independently selected from: fluoro, hydroxy, (1- 6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,mono(l- 6C)alkylamino, di(l-6C)alkylamino, carbamoyl, mono(l~6C)alkylcarbamoyl or di-[(l- 6C)alkyl] carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]aminodi(l- 6C)alkylamino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or one of R3 and R4 is as defined above and the other represents a group -NR1R2 as defined above;
A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl;
R5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
n is 0, 1, 2 or 3;
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is a direct bond, -O- or -N(R8)- wherein x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4, wherein R8 and R9 independently represent hydrogen or (l-6C)alkyl, wherein Ra and Rb independently represent hydrogen or (l-όC)alkyl or Ra and Rb together with the carbon atom to which they are attached represent (3-6C)cycloalkyl; and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halo, cyano, hydroxy or a saturated or partially saturated 3 to 7 membered heterocyclic ring;
B represents a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group,or a 5 or 6 membered heteroaryl ring,ring; or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic;
and when B is a (3-7C)cycloalkyl ring orring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group, the rings and the bicyclic group optionally bear 1 or 2 oxo or thioxo substituents;
R6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(O)p-(l-6C)alkyl wherein p is 0, 1 or 2, -N(Rc)C(O)(l-6C)alkylring and -N(R°)C(O)(l-6C)alkyl in which Rc is hydrogen or (1-
6C)alkyl; or
R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, (l-6C)alkyl, -S(O)p-(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-βC)alkyl, -S(O)p-(l-6C)alkyl and the (l-6C)alkoxy(l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy,(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl or hydroxy(l-6C)alkyl; and m is O, 1, 2 or 3;
and salts or solvates thereof. with the proviso that:
(i) L cannot be -C(Ra)(Rb)C(O)N(R9)-, -N(R8)C(O)C(Ra)(Rb)-, -N(R8)C(O)O- or -N(R8)C(O)N(R8)-.
In particular, L is selected from N(R8)C(O)-, N(R8)C(O)-(CRaRb)2, -C(O)N(R9), -C(O)N(R9)-CRaRb), -C(Ra)(Rb)-N(R8)C(O)- or -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)-. Suitably, R3 and R4 are other than a group NR1R2. Suitably Ry is a group NR1R2 where R1 and R2 are as defined above.
Thus, in a particular aspect, the invention provides a compound of formula (IA):
Figure imgf000010_0001
Formula IA wherein:
R1, R2, R5, A, L, B, m and n are as defined above, R3a and R4a are groups R3 and R4 as defined above, and
R6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring and -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl, -S(O)p-(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(O)p-(l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl; and salts or solvates thereof.
In a particular embodiment, n there is provided a compound of the Formula IA as defined above wherein:
R1, R2, A, B, L, R5, R6, m and n are as defined above in relation to formula (IA) and R3a and R4a are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring. In a further embodiment, Rx is a group NR1R2 where R1 and R2 are as defined above.
Thus according to a further aspect of the present invention there is provided a compound of the Formula IB:
Figure imgf000011_0001
Formula IB wherein:
R .1 , R r>2 , τ R>5 , n R6 , A, L, B, m and n are as defined above in relation to formula (I) R3b are R4b are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l- 6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or one of R3b and R4b is as defined above and the other represents a group -NR1R2 as defined above.
In a particular embodiment, R3b and R4b are other than NR1 R2.
In another particular embodiment, the compounds of the Formula IB is a compound of the Formula IBi:
Figure imgf000012_0001
Formula IBi wherein:
R1, R2, R4b, R5, R6, A, L, B, m and n are as defined above in relation to formula (IB) and R10 and R11 are independently selected from hydrogen or (l-6C)alkyl; and salts or solvates thereof, particularly pharmaceutically acceptable salts thereof. with the proviso that:
L cannot be -C(Ra)(Rb)C(O)N(R9)-, -N(R8)C(O)C(Ra)(Rb)-, -N(R8)C(O)O- or
-N(R8)C(O)N(R8)-. In this specification the generic term "alkyl" includes both straight-chain and branched-chain alkyl groups such as propyl, isopropyl and tert-butyl. However references to individual alkyl groups such as "propyl" are specific for the straight-chain version only, references to individual branched-chain alkyl groups such as "isopropyl" are specific for the branched-chain version only. An analogous convention applies to other generic terms, for example (l-βC)alkoxy includes methoxy, ethoxy and isopropoxy, (l-6C)alkylamino includes methylamino, isopropylamino and ethylamino, and di-[(l-6Calkyl] amino includes dimethylamino, diethylamino and N-methyl-N-isoproylamino. The generic term aryl refers to phenyl or naphthyl, particularly phenyl.
It is to be understood that, insofar as certain of the compounds of Formula I defined above may exist in optically active or racemic forms by virtue of one or more asymmetric carbon atoms, the invention includes in its definition any such optically active or racemic form which possesses the above-mentioned activity. The synthesis of optically active forms may be carried out by standard techniques of organic chemistry well known in the art, for example by synthesis from optically active starting materials or by resolution of a racemic form. Similarly, the above-mentioned activity may be evaluated using the standard laboratory techniques referred to hereinafter. Suitable values for the generic radicals referred to above include those set out below. Suitable 5 or 6 membered heteroaryl rings include, for example furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, 1,4,5-triazinyl or pyrazinyl. Particular 5 or 6 membered heteroaryl rings include imidazolyl, pyridyl, thiazolyl, thiadiazolyl, pyrimidinyl, isoxazolyl, isothiazolyl and pyrazolyl. Suitable saturated or partially saturated 3 to 7 membered heterocyclic rings include, for example oxiranyl, oxetanyl, tetrahydrofuranyl, tetrahydropyranyl, 2,3-dihydro-l,3- thiazolyl, 1,3-thiazolidinyl, 1,3-oxazolidinyl, oxepanyl, pyrrolinyl, pyrrolidinyl, morpholinyl, thiamorpholinyl (perhydro-l,4-thiazinyl), (8-oxa-3-azabicyclo[3.2.1]octyl), (7-oxa-3 -azabicyclo [3.1.1 ]heptyl), perhydroazepinyl, perhydrooxazepinyl, tetrahydro-l,4-thiazinyl, 1-oxotetrahydrothienyl, l,l-dioxotetrahydro-l,4-thiazinyl, piperidinyl, homopiperidinyl, piperazinyl, homopiperazinyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl or tetrahydropyrimidinyl, preferably tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, l,l-dioxotetrahydro-4H- 1,4-thiazinyl, piperidinyl or piperazinyl, more preferably tetrahydrofuran-3-yl, tetrahy dropyran-4-yl, pyrrolidin-3 -yl, morpholino, 1 , 1 -dioxotetrahydro-4H- 1 ,4-thiazin-4- yl, piperidino, piperidin-4-yl or piρerazin-1-yl. A suitable value for such a group which bears 1 or 2 oxo or thioxo substituents is, for example, 2-oxopyrrolidinyl, 2- thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5- dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6-dioxopiperidinyl. The saturated or partially saturated 3 to 7 membered heterocyclic rings are optionally substituted by one or more (C 1-6) alkyl groups and/or by one or more hydroxy. For avoidance of doubt it will be understood that this definition includes tautomers of hydroxy substituted ring systems where the hydroxy tautomerizes to an oxo group.
Suitable 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, imidazolo[2, 1 -bjthiazolyl, dihydrocyclopentathiazolyl, tetrahydrocyclopenta[c]pyrazolyl, furo[3,2-b]furanyl, pyrrolopyrrole, thienopyrazolyl, thieno[2,3-b]thiophenyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[b]furanyl, benzo[b]thiophenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4- benzodioxinyl, l,3-benzodioxol-5-yl, decalin and norbornane. Particular 8, 9 or 10 membered bicyclic groups include thieno[2,3-b]furanyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolin-yl, benzo[bjfuranyl, benzo[b]thiophenyl, IH-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, chromanyl, isochromanyl, indenyl, naphthalenyl, 2,3-dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl.
The bicyclic groups are optionally substituted by one or more groups R6 as hereinbefore defined.
The group A may particularly be attached to the ethynyl group via a carbon atom in the aryl group or in the 5 or 6 membered heteroaryl ring. The group B may particularly be attached to the group L via a carbon atom.
Suitable values for any of the the substituents herein, for example the 'R' groups (R1 to R6) or for various groups within a A, B or L group include for halo fluoro, chloro, bromo and iodo; for (l-6C)alkyl: methyl, ethyl, propyl, isopropyl and tert-butyl; for (l-6C)alkoxy: methoxy, ethoxy, propoxy, isopropoxy and butoxy; for (l-βC)alkylsulfonyl: methylsulfonyl and ethylsulfonyl; for (l-6C)alkylamino: methylamino, ethylamino, propylamino, isopropylamino and butylamino; for di-[(l-6C)alkyl]amino: dimethylamino, diethylamino, N-ethyl- N-methylamino and diisopropylamino; 5 for (l-6C)allcoxycarbonyl: methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and tert-butoxycarbonyl; for (l-6C)alkanoyl: formyl, acetyl and propionyl; for (l-6C)alkoxycarbonyl methoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl; io for hydroxy(l-6C)alkyl: hydroxymethyl, 2-hydroxyethyl, 1-hydroxyethyl and 3-hydroxypropyl; for (l-6C)alkoxy(l-6C)alkyl: methoxymethyl, ethoxymethyl, 1-methoxy ethyl, 2-methoxyethyl, 2-ethoxyethyl and 3- methoxypropyl; is for (3-7C)cycloalkyl: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; for (l-6C)alkoxy(l-6C)alkoxy: methoxymethoxy, methoxyethoxy, methoxypropoxy, methoxybutoxy, methoxyhexoxy, ethoxyethoxy, ethoxypropoxy,
20 ethoxybutoxy, propoxypropoxy and propoxybutoxy; for (l-6C)alkoxy(l-6C)alkoxy(l-' 6C)alkoxy: methoxymethoxymethoxy, methoxyethoxyethoxy, methoxypropoxymethoxy, methoxybutoxyethoxy, methoxyhexoxymethoxy,
25 ethoxyethoxyethoxy, ethoxypropoxyethoxy, ethoxybutoxymethoxy, propoxypropoxymethoxy and propoxybutoxymethoxy; for mono(l-6C)alkylcarbamoyl: N-methylcarbamoyl, N-ethylcarbamoyl and N-propylcarbamoyl; and
30 for di-[(l-6C)alkyl]carbamoyl: N,N-dimethylcarbamoyl, N-ethyl- N-methylcarbamoyl and N,N-diethylcarbamoyl. When in this specification reference is made to a (l-4C)alkyl group it is to be understood that such groups refer to alkyl groups containing up to 4 carbon atoms. A skilled person will realise that representative examples of such groups are those listed above under (l-4C)alkyl that contain up to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. Similarly, reference to a (l-3C)alkyl group refers to alkyl groups containing up to 3 carbon atoms such as methyl, ethyl, propyl and isopropyl. A similar convention is adopted for the other groups listed above such as (l-4C)alkoxy, (2-4C)alkenyl, (2-4C)alkynyl and (l-4C)alkanoyl.
It is to be understood that certain compounds of the formula I may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
It is also to be understood that certain compounds of the formula I may exhibit polymorphism, and that the invention encompasses all such forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
It is also to be understood that the invention relates to all tautomeric forms of the compounds of the formula I forms which exhibit an inhibitory effect on a Tie2 receptor tyrosine kinase.
Whilst pharmaceutically-acceptable salts of compounds of the invention are preferred, other non-pharmaceutically-acceptable salts of compounds of the invention may also be useful, for example in the preparation of pharmaceutically-acceptable salts of compounds of the invention.
A suitable pharmaceutically acceptable salt of a compound of the formula I is, for example, an acid-addition salt of a compound of the formula I, for example an acid-addition salt with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, trifluoroacetic, citric or maleic acid; or, for example, a salt of a compound of the formula I which is sufficiently acidic, for example an alkali or alkaline earth metal salt such as a calcium or magnesium salt, or an ammonium salt, or a salt with an organic base such as methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine. Also provided as a further aspect of the invention are pro-drugs of compounds of the invention as herein before or herein after defined. Compounds of the invention may be administered in the form of a pro-drug which is broken down in the human or animal body to give a compound of the Formula (I). Examples of pro-drugs include in-vivo hydrolysable esters of a compound of the Formula (I).
Various forms of pro-drugs are known in the art. For examples of such pro-drug derivatives, see: a) Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) A Textbook of Drug Design and Development, edited by Rrogsgaard-Larsen and H. Bundgaard, Chapter 5 "Design and Application of Prodrugs", by H. Bundgaard p. 113-191 (1991); c) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); d) H. Bundgaard, et al, Journal of Pharmaceutical Sciences, 77, 285 (1988); and e) N. Kakeya, et al, Chem Pharm Bull, 32, 692 (1984).
An in-vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group is, for example, a pharmaceutically-acceptable ester which is hydrolysed in the human or animal body to produce the parent acid or alcohol. Suitable pharmaceutically-acceptable esters for carboxy include C^ealkoxymethyl esters for example methoxymethyl, Cϊ-όalkanoyloxymethyl esters for example pivaloyloxymethyl, phthalidyl esters,
Cs-gcycloalkoxycarbonyloxyCi-ealkyl esters for example 1-cyclohexylcarbonyloxy ethyl; l,3-dioxolen-2-onylmethyl esters, for example 5-niethyl-l,3-dioxolen-2-onylmethyl; and Cμδalkoxycarbonyloxyethyl esters.
An in-vivo hydrolysable ester of a compound of the Formula (I) containing a hydroxy group includes inorganic esters such as phosphate esters (including phosphoramidic cyclic esters) and α-acyloxyalkyl ethers and related compounds which as a result of the in-vivo hydrolysis of the ester breakdown to give the parent hydroxy group/s. Examples of α-acyloxyalkyl ethers include acetoxymethoxy and
2,2-dimethylpropionyloxy-methoxy. A selection of in-vivo hydrolysable ester forming groups for hydroxy include alkanoyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl, alkoxycarbonyl (to give alkyl carbonate esters), dialkylcarbamoyl and N- (dialkylaminoethyl)-N-allcylcarbamoyl (to give carbamates), dialkylaminoacetyl and carboxyacetyl.
Particular novel compounds of the invention include, for example, compounds of the formula I, or salts, particularly pharmaceutically acceptable salts thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, R5, R6, A, B, L, m and n has any of the meanings defined hereinbefore or in paragraphs (a) to (Hill) hereinafter: -
(a) L is attached meta on ring A with respect to the point of attachment of the ethynyl group; (a') L is attached para on ring A with respect to the point of attachment of the ethynyl group;
(b) L is -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen ); (b5) L is -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(b") L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R8 are independently selected from hydrogen and (1 -6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(b' ") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein x and y are as defined above, and Z is -O- or -N(H)-, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(c) L is -N(Rs)C(O)-(CRaRb)x-O-(CRaRb)y- wherein x and y are as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra,
Rb and R8 are all hydrogen );
(c') L is -C(O)N(R9)-(CRaRb)x-O-(CRaRb)y- wherein x and y are as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen ); (c") L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-O-(CRaRb)y- wherein x and y are as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen ); (C'") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-O-(CRaRb)y- wherein x and y are as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(d) L is -N(R8)C(O)-(CRaRb)x-N(R8)-(CRaRb)r wherein Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(d') L is -C(O)N(R9)-(CRaRb)χ-N(R8)-(CRaRb)y- wherein Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen ); (d' ') L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-N(R8)-(CRaRb)y- wherein Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(d' ") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-N(R8)-(CRaRb)r wherein Ra, Rb, R8 and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb, R8 and R9 are all hydrogen );
(e) L is -N(R8)C(O)-(CRaRb)x-O- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen );
(e') L is -C(O)N(R9)-(CRaRb)x-O- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(e" ') L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-O- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and
R8 are all hydrogen ); (e" ") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-O- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and
R9 are all hydrogen );
(f) L is -N(R8)C(O)-(CRaRb)x-N(H)- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R8 are all hydrogen ); (f ) L is -C(O)N(R9)-(CRaRb)x-N(H)- wherein x is as defined above, and Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(f ') L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-N(H)- wherein x is as defined above, and Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb,
R8 and R9 are all hydrogen );
(f ") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-N(H)- wherein x is as defined above, and Ra,
Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen ); (g) L is -N(R8)C(O)-(CRaRb)x- wherein x is as defined above (particularly x is 1 or 2) and wherein Ra, Rb and R8 are independently selected from hydrogen and (l-6C)alkyl
(particularly Ra, Rb and R8 are all hydrogen );
(g') L is -C(O)N(R9)-(CRaRb)x- wherein x is as defined above (particularly x is 1 or 2) and wherein Ra, Rb and R9 are independently selected from hydrogen and (l-όC)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(g") L is -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-, wherein x is as defined above (particularly x is 1 or 2) and wherein Ra, Rb and R8 are independently selected from hydrogen and (1-
6C)alkyl (particularly Ra, Rb and R8 are all hydrogen);
(g' ") L is -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-, particularly -CH2-C(O)N(R9)- wherein x is as defined above (particularly x is 1 or 2) and wherein Ra, Rb and R9 are independently selected from hydrogen and (l-6C)alkyl (particularly Ra, Rb and R9 are all hydrogen );
(g"") L is -C(O)-N(H)-.
(S"") L is -C(O)-N(H)-, -N(H)-C(O)-, -C(O)-N(H)-CH2-, -CH2-N(H)-C(O)-,
-N(H)-C(O)-(CH2)2 or -CH2-C(O)-N(H)-CH2-, (s""f) L is -N(H)C(O)-.
(S""") L is -C(O)N(H)CH2-.
(S1""") L iS - CH2N(H)C(O)-.
(S"""") L is -N(H)C(O)CH2CH2-.
(S'"""") L is CH2-C(O)-N(H)-CH2-, (h) Ra and Rb each represent hydrogen;
(h') Ra and Rb independently represent hydrogen or (1 -6C)alkyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or a saturated or partially saturated 3 to 7 membererd heterocyclic ring; (h") Ra and Rb independently represent hydrogen or ( 1 -6C)alkyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or a saturated or partially saturated 5 to 6 membererd heterocyclic ring; (h" ') Ra and Rb independently represent hydrogen, methyl or ethyl, wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by hydroxy or pyrrolin-1-yl;
(i) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl;
(i') A is selected from phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl;
(j) A is phenyl or pyridyl
(k) A is phenyl or pyridyl, wherein the nitrogen in the pyridyl ring is in the 3 -position relateive to the alkyne bond.
(1) A is thienyl or thiazolyl;
(V) A is phenyl, pyridyl, thienyl or thiazolyl;
(1") A is phenyl;
(m) A is pyridyl; (m') A is thiazolyl;
(n) A is phenyl or pyridyl and n is 0;
(n') A is phenyl or thiazolyl and n is 0;
(o) A is phenyl and n is 0 or n is 1 and R5 is (l-4C)aUcyl;
(p) A is pyridyl and n is 0 or n is 1 and R5 is (l-4C)alkyl; (p') A is thiazolyl and n is 0 or n is 1 and R5 is (l-4C)alkyl;
(p") A is thienyl and n is 0 or n is 1 and R5 is (l-4C)alkyl;
(q) A is selected from phenyl, oxazolyl, imidazolyl, pyrrolyl, pyrazolyl, thienyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrazinyl and pyrimidyl. (r) When B is a (3-7C)cycloalkyl ring then B is selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; (s) When B is a saturated or partially saturated 3 to 7 membered heterocyclic ring then B is selected from oxetanyl, azetidinyl, thietanyl, pyrrolidinyl, , morpholinyl, 1,3- dioxolanyl, tetrahydrofuranyl, piperidyl, piperazinyl, thiomorpholinyl, tetrahydropyranyl, homopiperazinyl, pyrrolinyl, imidazolinyl, pyrazolinyl, pyranyl, tetrahydropyridinyl, 1,2,4-oxadiazolyl and dihydrothiopyranyl;
(t) When B is a 5 or 6 membered heteroaryl ring then B is selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl; (u) When B is an 8, 9 or 10 membered bicyclic group which optionally contains 1,2,3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic then B is selected from 2,3-dihydro-lH-indenyl, benzodioxinyl, 1 ,2,3,4-tetrahydronaphthalenyl, 1,2,3,4-tetrahydropentalene, benzofuranyl, 2,3-dihydrobenzofuranyl, benzimidazolyl, benzthienyl, benzthiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, pyridoimidazolyl, pyrimidoimidazolyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, phthalazinyl, cinnolinyl, indolyl, and naphthyridinyl. or B is a group of the formula:
Figure imgf000022_0001
wherein W is a 5-7 membered ring (including the bridging atoms), said W ring comprising carbon atoms or optionally further heteroatoms independently selected from oxygen, nitrogen and sulphur, wherein said bicyclic ring contains no more that 4 heteroatoms in total. Examples of such rings include: pyrazolo[l,5-a]pyridinyl, pyrazolo[l,5- cjpyrimidinyl, pyrazolo[ 1 ,5-a] [ 1 ,3,5]triazinyl, 4,5-dihydropyrazolo[ 1 ,5-a]pyridinyl, 4H-pyrazolo[5, 1 -c] [ 1 ,4]thiazinyl, 4H-pyrazolo[5, 1 -c] [ 1 ,4]oxazinyl, 1 ,2-benzisoxazolyl, isoxazolo[5,4-b]pyridinyl, isoxazolo[5,4-d]pyrimidinyl, 4H-thiopyrano[3,4-d]isoxazolyl, 4H-pyrano[3,4-d]isoxazolyl, 7aH-indolyl, 7aH-pyrrolo[2,3-b]pyridinyl, 7aH-pyrrolo[2,3-b]pyrimidinyl, 4,7a-dihydrothiopyrano[4,3-b]pyrrolyl and 4,7a-dihydropyrano[4,3-b]pyrrolyl. (v) B is aryl, particularly phenyl; (w) B is a saturated or partially saturated 3 to 7 (particularly 4 to 6) membered heterocyclic ring that contains one or two heteroatoms (particularly one heteroatom) selected from oxygen and nitrogen; (x) B is a a 5 or 6 membered heteroaryl ring;
5 (y) B is a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2 or 3 (particularly 1 or 2) heteroatoms independently selected from N and O and which is saturated, partially saturated or aromatic;
(z) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, o thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl, or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic; s (aa) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl; o (bb) B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl; (cc) B is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, 5 piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, 1,4-dioxanyl, morpholinyl, pyrrolidinyl, piperidinyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-l,4-benzodioxinyl and 1,3- benzodioxol-5-yl; o (dd) B is selected from phenyl, tetrahydopyranyl, tetrahydrofuranyl, morpholinyl, thiomorpholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl; (dd5) B is selected from phenyl, cyclobutyl, tetrahydopyranyl, tetrahydrofuranyl,
1,4-dioxanyl, morpholinyl, furyl, pyrrolidinyl, piperidinyl, pyrazolyl, isothiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl;
(dd' ') B is selected from cyclohexyl, phenyl, tetrahydopyranyl, tetrahydrofuranyl, 5 morpholinyl, thiomoφholinyl, furyl, pyrrolidinyl, pyridyl and pyrimidinyl;
(dd' ") B is selected from phenyl, imidazolyl, thienyl, and isoxazolyl;
(dd"") B is selected from phenyl, isoxazolyl or tetrahydopyranyl.
(dd' " ' ") B is selected from isoxazolyl, pyrazolyl, tetrahydopyranyl, phenyl and benzodioxolyl I0 (ee) B is selected from phenyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiornorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl. is (ee') B is selected from phenyl, cyclohexyl, cyclobutyl, 2,3-di-hydro-indenyl, tetrahydopyranyl, tetrahydrofuranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, pyrrolidinyl, piperidinyl, furyl, imidazolyl, thienyl, pyrazolyl, isothiazolyl, thiadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzodioxinyl, benzodioxolyl or tetrahydropyranyl. 2o (ff) B is selected from piperidinyl, phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl;
(gg) B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
(hh) Bis selected from isoxazolyl, thiadiazolyl and pyrazolyl;
(ii) Bis selected from isoxazolyl and pyrazolyl; 25 (jj) B is phenyl;
(fck) B is isoxazolyl;
(11) B is pyrazolyl;
(mm) R1 and R2 are independently selected from hydrogen, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3- 30 6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, (1 -6C)alkoxy(l -6C)alkoxy, (1 -6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or-N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl] amino, wherein the (l-6C)alkyl or
(l-6C)alkoxy are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l -6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l- 4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZY wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy;
(nn) R1 and R2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
(oo) R1 and R2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (pp) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, I5 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1- 6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (l-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
(qq) R is hydrogen and R is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm);
(rr) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl or a
5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (mm); (ss) R1 and R2 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)aIkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or
6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or-N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkly]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from halo, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino, wherein the (l-6C)alkyl or (1- 6C)alkoxy are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, amino, mono(l-6C)alkylamino or di- [(l-6C)alkyl]amino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l~4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l- 4C)alkyl, hydroxy, amino, mono(l-6C)alkylarnino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)2Y wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l-
6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy; (tt) R1 and R2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl or (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(uu) R1 and R2 are independently selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or T), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(w) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)allcylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (1-
6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-βC)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); wherein the phenyl is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(ww) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); (xx) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkanoyl, (l-βC)alkyl or a 5 or 6 membered heteroaryl ring; wherein the (l-δC)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(yy) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl; wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (ss);
(zz) R1 is hydrogen and R2 is selected from hydrogen, (l-6C)alkanoyl and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from hydroxy, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkoxy, amino, mono(l-3C)alkylamino, di(l-3C)alkylamino, carbamoyl or-N(Rd)C(O)(l-3C)alkyl in which Rd is hydrogen or (l-3C)alkyl, or a saturated 5 or 6 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring, wherein the (l-4C)alkoxy and (l-4C)alkoxy(l-4C)alkoxy and the (1- 3C)alkyl groups of the mono(l-3C)alkylamino, di-[(l-3C)alkyl]amino and/or -N(R )C(O)(l-6C)alkyl groups are optionally substituted by one or more (for example 1 or 2) hydroxy groups; and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l-3C)alkylamino or di-[(l-3C)alkyl]amino, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZY wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (l-4C)alkoxy, amino, mono(l- 6C)alkylamino, di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (1 C)alkanoyl is not substituted by fluoro or hydroxy; (aaa) R1 is hydrogen and R2 is selected from hydrogen, (l-3C)alkanoyl and (l-3C)alkyl; wherein the (l-3C)alkyl and the (l-3C)alkanoyl groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz);
(bbb) R1 is hydrogen and R2 is selected from hydrogen and (l-6C)alkyl (particularly (l-3C)alkyl); wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or X), which may be the same or different, as hereinbefore defined in (zz);
(ccc) R1 is hydrogen and R2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); and wherein any heterocyclic and heteroaryl rings within R2 are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, as hereinbefore defined in (zz); (ccc') R1 and R2 are both hydrogen or R1 is hydrogen and R2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by amino, mono(l-6C)alkylamino or di(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring;
(ccc") R1 and R2 are both hydrogen or R1 is hydrogen and R2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by di(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring; (ccc")R! and R2 are both hydrogen or R1 is hydrogen and R2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by a saturated 3 to 7 membered heterocyclic ring;
(ccc'"") R1 is hydrogen and R2 is selected from hydrogen, and 3-morpholin-4- ylpropyl; (ccc""") R1 is hydrogen and R2 is selected from hydrogen, 3-(dimethylamino)propyl and 3-piperidin-l-ylpropyl;
(ccc'""") R1 is hydrogen and R2 is selected from hydrogen, 3-(dimethylamino)propyl and 3-piperidin-l-ylpropyl; (ddd) NR1R2 is amino. (ddd') R1 and R2 are both hydrogen or R1 is hydrogen or (l-6C)alkyl and R2 is (l-6C)alkyl wherein (l-6Calkyl) is optionally substituted by hydroxy, amino, mono(l-6C)alkylamino or di(l-6C)alkylamino, carbamoyl, (l-βC)alkoxy,
(l-6C)alkoxy(l-6C)alkoxy, -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or
(l-6C)alkyl, aryl (particularly phenyl), a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkoxy, mono(l-6C)alkylamino and -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by hydroxy; wherein an aryl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring is optionally substituted by (l-4C)alkyl, (l-4C)alkoxy or -C(O)CH2Y wherein Y is selected from hydroxy or di(l-6C)alkylamino.
(eee) R1 and R2 are independently selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxyethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 3-(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-(lH-imidazol-4-yl)ethyl, 2- pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5-tert-butylisoxazol-3-yl: (fff) R1 is hydrogen and R2 is selected from hydrogen, methyl, ethyl, propyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-methoxy ethyl, 3-methoxypropyl, 2-aminoethyl, 3-aminopropyl, 2-(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2- (dimethylamino)ethyl, 3-(dimethylamino)propyl, carbamoylmethyl, 2-carbamoylethyl, 3- carbamoylpropyl, 2-(2-methoxyethoxy)acetyl, 2-morpholin-4-ylethyl, 3-morpholin-4- ylpropyl, 2-pyrrolidin-l-ylethyl, 3-pyrrolidin-l-ylpropyl, 3~(4-methylpiperazin-l- yl)propyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-(lH-imidazol-4-yl)ethyl, 2- pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 2-pyridin-4-ylethyl, 2,4-dimethoxybenzyl and 5 -tert-butylisoxazol-3 -yl; (ggg) R1 is hydrogen and R2 is selected from hydrogen, methyl, ethyl, propyl, 3 -(isopropylamino)propyl, 2-pyrrolidin- 1 -ylethyl, 5 -tert-butylisoxazol-3 -yl, 3 -piperidin- 1 -ylpropyl, 2-morpholino-4-yl-ethyl, 2-pyrrolidin- 1 -ylethyl, 3-(dimethylamino)propyl, 2-hydroxyethyl and 2-piperidin-l-ylethyl;
(ggg') R1 is hydrogen and R2 is selected from R2 is (l-6C)alkyl (particularly (l-3C)alkyl), wherein the (l-6C)alkyl (particularly (l-3C)alkyl) group is substituted by a saturated 5 or 6 membered heterocyclic ring;
(ggg") R1 is hydrogen and R2 is selected from 2-morpholino-4-yl-ethyl or 3-morpholinyl- 4-ylpropyl;
(hhh) R2 is hydrogen or methyl and R3 is selected from hydrogen, methyl, 2- hydroxy ethyl, 2-methoxy ethyl, 3-methoxypropyl, 2-(2-hydroxyethoxy)ethyl, 2- methoxyethoxymethyl, 2-aminoethyl, 3-aminopropyl, 4-aminobutyl, 2-
(isopropylamino)ethyl, 3-(isopropylamino)propyl, 2-(dimethylamino)ethyl, 3-
(dimethylamino)propyl, 4-(dimethylamino)butyl, 2-(dimethylamino)- 1 -methylethyl, carbamoylmethyl, 2-carbamoylethyl, 2-(2-methoxyethoxy)acetyl, 2-(2-hydroxyacetamido)ethyl, 3-[N-(2-hydroxyethyl)amino]propyl, 2-moφholin-4-ylethyl,
3 -morpholin-4-ylpropyl, 2-[( 1 -methyl-2-moφholin-4-ylethyl), 2-pyrrolidin- 1 -ylethyl,
3 -pyrrolidin- 1 -ylpropyl, 1 -glycoloylpyrrolidin-2-yl)methyl,
1 -(N,N-dimethylglycyl)pyrrolidin-2-yl, 2-piperazin- 1 -ylethyl, 3-piperazin- 1 -ylpropyl,
3 -(4-methylpiperazin- 1 -yl)propyl, 3 -piperidin- 1 -ylpropyl, 2-( 1 H-imidazol-4-yl)ethyl, 2-pyridin-2-ylethyl, 3-(lH-imidazol-l-yl)propyl, 5-t-butyl-isoxazol-3-yl, 2-pyridin-4- ylethyl and 2,4-dimethoxybenzyl; (iii) R1 is hydrogen and R2 is selected from 2-morpholin-4-ylethyl, 3-morpholin-4-ylpropyl, 3-piperidin-l-ylpropyl, 2-piperidin-l-ylethyl, 2-pyrrolidin-l- ylethyl, 4-methyl-piperazin-l-ylpropyl and 3-pyrrolidin-l-ylpropyl;
(jjj) R1 is hydrogen and R2 is selected from 2-morpholin-4-ylethyl, 3 -morpholin-4-ylpropyl, 3 -piperidin- 1 -ylpropyl, 2-piperidin- 1 -ylethyl, 2-pyrrolidin- 1 - ylethyl, 3-pyrrolidin-l-ylpropyl and 4-methyl-piperazin-l-yl;
(kkk) R1 and R2 are both (l-6C)alkyl (particularly (l-3C)alkyl); (111) R1 is hydrogen and R2 is methyl;
(mmm) R1 and R2 are both hydrogen; (mmm) R3 (including R3a or R3b) is selected from hydrogen, (l-3C)alkyl or (l-3C)alkoxy, wherein the (l-3C)alkyl and the (l-3C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l- 6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R3, R3a or R3b represents a group -NR1R2 as defined above; (rmn) R3, R3a or R3b is selected from hydrogen or (1 -6C)alkyl, wherein the (l-6C)alkyl group is optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l- 6C)alkyl] amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or R3, R3a or R3b represents a group -NR1R2 as defined above;
(ooo) R3, R3a or R3b is selected from hydrogen and a group -NR1R2 as defined above (particularly
-NH2); (ppp) R3, R3a or R3b is hydrogen;
(qqq) R3, R3a or R3b is a group -NR1R2 as defined above (particularly -NH2);
(qqq') R3, R3a or R3b is selected from hydrogen or a group -NR1R2 as defined above (particularly -NH2);
(qqq' ') R3, R3a or R3b is selected from hydrogen or -NH2. (rrr) R4 is independently selected from hydrogen and (l-6C)alkyl (particularly (l-3C)alkyl);
(sss) R4, R4a or R4b is hydrogen;
(ttt) R3 and R4, R3a and R4a s or R3b and R4b are both hydrogen;
(uuu) R3, R3a or R3b is a group -NR1R2 as defined above (particularly -NH2) and R4, R4a or R4b is hydrogen;
(uuu') R5 is selected from (l-6C)alkyl and (l-6C)alkoxy; (uuu' ') R5 is selected from (l-4C)alkyl and (l-4C)alkoxy; (uuu'") R5 is selected from methyl and methoxy; (wv) n is 0, 1 or 2 (particularly 0 or 1, more particularly 0); (wv') n is O or l;
(www) n is 1 or 2 and R5 is independently selected from halo, (l-6C)alkoxy and (1- 6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fluoro;
(xxx) n is 1 or 2 and R5 is independently selected from cyano, halo, (l-6C)alkoxy and (l-6C)alkyl, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or one or more fluoro;
(yyy) n is 0 or 1 and when n is 1, R5 is (l-4C)alkyl (particularly methyl); (zzz) n is 1 or 2 and R5 is independently selected from cyclopropyl and (l-6C)alkyl, wherein the (l-6C)alkyl groups are optionally substituted by cyano or one or more fluoro;
(aaaa) n is 1 and R5 is (l-6C)alkyl, particularly (l-3C)alkyl; (bbbb) n is O (cccc) n is i;
(dddd) R6 is independently selected from (l-6C)alkyl or (l-βC)alkoxy, (l-6C)alkyl,
-S(0)p-(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(0)p-(l-6C)alkyl and the (l-6C)alkoxy(l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, hydroxy, (l-6C)alkoxy,(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected from (l-6C)alkyl;
(dddd') R6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy, (l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l- 6C)alkyl] amino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; (eeee) R6 is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or an -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1-or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro); (ffff) R is independently selected from halo, cyano, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-3C)alkyl; or R6 is selected from (l-4C)alkyl or (l-4C)alkoxy, wherein the (l-4C)alkyl and the (l-4C)alkoxy groups are optionally substituted by one or more groups (for example
1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fluoro); (ggg) R6 is selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(hhhh) R6 is selected from fluoro, chloro, acetylamino, methyl, propyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy and morpholin-4-yl; (iiii) R6 is independently selected from halo or (l-6C)alkyl wherein (l-6C)alkyl is optionally substituted by 1 to 3 halo, particularly fluoro,
(iiii') R6 is independently selected from halo, (l-6C)alkyl, (l-6C)alkoxy, and a saturated
3 to 7 membered heterocyclic ring (particularly morpholin-4-yl) wherein (l-6C)alkyl is optionally substituted by cyano, a saturated 3 to 7 membered heterocyclic ring or 1 to 3 halo, particularly fluoro, and wherein any saturated 3 to 7 membered heterocyclic ring within R6 is optionally substituted by (l-6C)alkyl
(iiii") R6 is independently selected from (l-6C)alkyl, (l-6C)alkoxy or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl or piperidin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by hydroxy(l-2C)alkyl;
(iiii'") R6 is independently selected from hydroxy, halo (particularly chloro or fluoro), (l-6C)alkyl, (l-6C)alkoxy, di-(l-6C)alkylamino or a saturated 3 to 7 membered heterocyclic ring (particularly morpholin-4-yl, piperidin-1-yl or piperazin-1-yl), wherein (l-6C)alkyl and (l-6C)alkoxy are optionally substituted by 1 to 3 halo, particularly fluoro, wherein a saturated 3-7 membered heterocyclic ring is optionally substituted by (1- 2C)alkyl or hydroxy(l -2C)alkyl;
(iiii"") R6 is independently selected from (l-6C)alkyl (optionally substituted 1 to 3 groups independently selected from halo, particularly fluoro), halo or (l-6C)alkoxy; (jjjj) R6 is independently selected from methyl, t-butyl, fluoro and trifluoromethyl;
GJJJ') R6 is independently selected from methyl, t-butyl, 1-cyanoethyl, methoxy, isopropoxy, fluoro, trifluoromethyl, morpholin-4-yl and 4-methylpiperazin-l-ylmethyl; GJJJ ' ') R6 is independently selected from methyl, trifluoromethyl, morpholin-4-yl or piperidin- 1 -yl, 4-hydroxymethylpiperidin- 1 -yl;
(jjjj"') R6 is independently selected from methyl, methoxy, di-methylamino, hydroxy, oxo, chloro, fluoro, trifluoromethyl, morpholin-4-yl or piperidin- 1-yl,
4-hydroxymethylpiperidin- 1 -yl, 4-methylpiperzin- 1 -yl; Ojjj " ") R6 is independently selected from chloro, fluoro, trifluoromethyl, methyl or methoxy;
(kkkk) R6 is independently selected from halo, trifluoromethyl, methyl, tert-butyl, methoxy, acetylamino or morpholino. (1111) R6 is independently selected from halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(R°)C(O)(l-6C)alkyl wherein R° is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or (l-6C)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro). (IHl') R6 is independently selected from hydroxy, halo, cyano, oxo, (3-7C)cycloalkyl, a saturated 3 to 7 membered heterocyclic ring (optionally substituted by (l-4C)alkyl or hydroxy(l-4C)alkyl), -N(Rc)C(O)(l-6C)alkyl wherein Rc is hydrogen or (l-6C)alkyl (particularly (l-4C)alkyl), (l-6C)alkyl (optionally substituted by a saturated 3 to 7 membered heterocyclic ring or up to three groups independently selected from halo, particularly fluoro), (l-όC)alkoxy (optionally substituted by up to three groups independently selected from halo, particularly fluoro) or di-(l-6C)alkylamino;. (mmmm) R6 is independently selected from halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, methoxy, acetylamino, oxo, cyclopropyl, morpholin- 4-yl, piperidin- 1 -yl, 4-(hydroxymethyl)piperidin- 1 -yl and 4-methyl-piperazin- 1 -yl. (mmmm') R6 is independently selected from hydroxy, halo, trifluoromethyl, trifluoromethoxy, cyano, methyl, isopropyl, tert-butyl, 1-cyanoethyl, methoxy, isopropoxy, di-methylamino, acetylamino, oxo, cyclopropyl, morpholin-4-yl, piperidin-1-yl, 4-(hydroxymethyl)piperidin-l-yl, 4-methyl-piperazin-l-yl and 4-methylpiperazin-l- ylmethyl
(nαmmm") R6 is independently selected from halo (such as chloro), trifluoromethyl, methoxy, dimethylamino, moφholin-4-yl or piperidin-l-yl.
(mmmm'") at least one R6 group is selected from amino, mono(C1-6alkyl)amino, (U-(C1-6- alkyl)amino such as dimethylamino.
(nnnn) m is 1 or 2 (oooo) m is l; (pppp) m is 2;
(qqqq) Ring B-R6, where m is 1 or 2, is selected from: 2-fluoro-5-trifluoromethylphenyl,
5-t-butylisozazol-3-yl and 2,2-dimethyltetrahydro-2H-pyran-4-yl;
(qqqq') Ring B-R6, where m is 1 or 2, is selected from: phenyl, 3-methoxyphenyl,
3-isopropoxyphenyl, 4-trifluorophenyl, 2-fluoro-5-trifluoromethylphenyl, 3-(l-cyanoethyl)phenyl, 2-morpholin-4-ylphenyl, 3-moφholin-4-ylphenyl, 4-methyl- piρerazin-1-ylmethylphenyl, 5-t-butylisozazol-3-yl, l-methyl-3-tert-butylpyrazol-5-yl.
2,2-dimethyltetrahydro-2H-pyran-4-yl and benzodioxolyl;
(qqqq") Ring B-R6, where m is 1 or 2, is selected from: 2-(trifluoromethyl)phenyl,
2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1 -yl, 2-morpholin-4-ylphenyl, 2-(piperidin-l-yl)phenyl, 2-[4-(hydroxymethyl)piperidin-l-yl)]phenyl, 5-methyl-furan-2-yl and 4-morpholin-4-ylpyrimidin-5-yl; (qqqq'") Ring B-R6, where m is 1 or 2, is selected from: 2-hydroxycyclohexyl,
2-methylphenyl, 2-methoxyphenyl, 2-chlorophenyl, 3-chlorophenyl, 2-
(dimethylamine)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 2-oxopyrrolidin- 1-yl, 2-moφholin-4-ylphenyl, 3-moφholin-4-ylρhenyl, moφhorin-4-yl-5- fluorophenyl, 2-(piperidin- 1 -yl)phenyl, 2- [4-(hydroxymethyl)piperidin- 1 -yl)]phenyl,
5-methyl-furan-2-yl, 2-(4-methylpiperzin-l-yl)phenyl and 4-moφholin-4-ylρyrimidin-5-yl;
(qqqq' " ') Ring B-R6, where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3,6-di-fluorophenyl, 2-(trifluoromethyl)phenyl, 3- (trifluoromethyl)phenyl, 2-chloro-thien-5-yl, l-methylimidazol-4-yl, 3-methoxyphenyl and
3,5-dimethyl-isoxazol-4-yl; (qqqq' " ") Ring B-R6, where m is 1 or 2, is selected from 2-chloro-phenyl, 2,3- dichorophenyl, 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 3,6-di-fluorophenyl, 2- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 2-chloro-thien-5-yl, 1-methylimidazol- 4-yl, 3-methoxyphenyl and 3,5-dimethyl-isoxazol-4-yl;
5 (rrrr) Ring B-R6, where m is 1 or 2, is selected from
2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro-phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4- methoxyphenyl, 3-cyano-phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, o 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 3-acetylaminophenyl, 2-moφholin-4-ylphenyl, 3-fluoro-5-(4-methylpiperazin-l-yl)phenyl, 2-moφholin-4-ylphenyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylpiperidin- 1 -yl)phenyl,
2-oxopyrrolidin-l-yl, 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 5 2,2-dimethyltetrahydropyran-4-yl, 5-methyl-furan-2-yl, 5-methyl-l,3,4-thiadiazol-2-yl, 5-t-butyl-l,3,4-thiadiazol-2-yl, 5-triflluoromethyl-l,3,4-thiadiazol-2-yl, 5-cyclopropyl- 1 ,3,4-thiadiazol-2-yl, 5-ethyl- 1 ,3 ,4-thiadiazol-2-yl,
5-isopropyl-l,3,4-thiadiazol-2-yl, 5-ethylthio-l,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methyl-isoxazol-3-yl, 5-methylisoxazol-3-yl, 5-t-butyl-isoxazol-3-yl, o 3,5-dimethylisoxazol-4-yl,4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl,
4-methyl-isothiazol-2-yl, 1 -methyl- 1 H-imidazol-4-yl,2-chloro-thien-5-yll -methyl-3-t-butyl -pyrazol-5-yl, l-methyl-3-cyclopropyl-pyrazol-5-yl, l-methyl-3-isopropyl-pyrazol-5-yl, 1 -t-butyl-pyrazol-4-yl, 1 -t-butyl-3-cyclopropyl-pyrazol-5-yl, 1 -ethyl-pyrazol-3-yl, l-isopropyl-pyrazol-3-yl, 5-isopropyl-l,3,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 5 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;5-methylpyrazin-2-yl and 4-morpholin-4-ylpyrimidin-5-yl;
(rrrr) Ring B-R6, where m is 1 or 2, is selected from
2-hydroxycyclohexyl,phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluorophenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, o 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- isopropoxyphenyl, 3-cyano-phenyl, 3-(l-cyanoethyl)phenyl, 2-(trifluoromethyl)plienyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-(dimethylamine)phenyl, 3-acetylaminophenyl, 2-moφholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 2-moφholin-4-yl-5-fluorophenyl, 2-(4- methylpiperazin-l-yl)phenyl, 3-fluoro-5-(4-methylpiperazin-l-yl)phenyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylpiperidin- 1 -yl)phenyl, 2-oxopyrrolidin-l-yl, 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 4-methyl-piperazin- 1 -ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl,
5-methyl-furan-2-yl, 5-methyl- 1 ,3 ,4-thiadiazol-2-yl, 5-t-butyl- 1 ,3,4-thiadiazol-2-yl, 5-triflluoromethyl- 1 ,3 ,4-thiadiazol-2-yl, 5-cyclopropyl- 1 ,3 ,4-thiadiazol-2-yl, 5-ethyl- 1 ,3 ,4-thiadiazol-2-yl, 5-isopropyl- 1 ,3,4-thiadiazol-2-yl, 5-ethylthio-l,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methyl-isoxazol-3-yl, 5 -methylisoxazol-3 -y 1, 5-t-butyl-isoxazol-3 -yl, 3 , 5 -dimethylisoxazol-4- yl,4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl, 1 -methyl- 1 H-imidazol-4-yl,2-chloro-thien-5-yll -methyl-3-t-butyl -pyrazol-5-yl, l-methyl-S-cyclopropyl-pyrazol-S-yl, l-methyl-3-isopropyl-pyrazol-5-yl, l-t-butyl-pyrazol-4-yl, l-t-butyl-S-cyclopropyl-pyrazol-S-yl, l-ethyl-pyrazol-3-yl, l-isopropyl-pyrazol-3-yl, 5-isopropyl-l ,3,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;5-methylpyrazin-2-yl and 4-moφholin-4-ylpyrimidin-5-yl;benzodioxolyl;
(rrrr") Ring B-R6, where m is 1 or 2, is selected from
2-hydroxycyclohexyl, phenyl, 2-methylphenyl, 2-fluoro-phenyl, 3-fluoro-phenyl, 4-fluoro- phenyl, 2-chloro-phenyl, 3-chloro-phenyl, 2,3-dichloro-phenyl, 3,4-dichloro-phenyl, 2,5-difluoro-phenyl, 3,4-difluoro-phenyl, 4,5-difluoro-phenyl, 3,6-di-fluorophenyl, 2- methylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3- isopropoxyphenyl, 3-cyano-phenyl, 3-(l-cyanoethyl)phenyl, 2-(trifluoromethyl)phenyl, 2-(trifluoromethoxy)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-(dimethylamine)phenyl, 3-acetylaminophenyl, 2-moφholin-4-ylphenyl, 3-moφholin-4-ylphenyl, 2-moφholin-4-yl-5-fluorophenyl, 2-(4- methylpiperazin-l-yl)phenyl, 3-fluoro-5-(4-methylpiperazin-l-yl)phenyl, 2-(piperidin- 1 -yl)phenyl, 2-(4-hydroxymethylpiperidin- 1 -yl)phenyl, 2-oxopyrrolidin-l-yl, 2-oxo-piperidin-3-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 4-methyl-piperazin- 1 -ylmethylphenyl, 2,2-dimethyltetrahydropyran-4-yl,
5-methyl-furan-2-yl, 5-methyl- 1 ,3 ,4-thiadiazol-2-yl, 5-t-butyl- 1 ,3 ,4-thiadiazol-2-yl, 5-triflluoromethyl-l,3,4-thiadiazol-2-yl, 5-cyclopropyl-l,3,4-thiadiazol-2-yl, 5-ethyl- 1 ,3 ,4-thiadiazol-2-yl, 5-isopropyl- 1 ,3,4-thiadiazol-2-yl,
5-ethylthio-l,3,4-thiadiazol-2-yl, 3-methylisoxazol-5-yl, 4-methyl-isoxazol-3-yl, 5-methylisoxazol-3-yl, 5-t-butyl-isoxazol-3-yl, 3,5-dimethylisoxazol-4-yl,
4-t-butyl-thiazol-2-yl, 3-methyl-isothiazol-5-yl, 4-methyl-isothiazol-2-yl,
1 -methyl- lH-imidazol-4-yl, 2-chloro-thien-5-yl, l-methyl-3-t-butyl-pyrazol-5-yl, 1 -methyl-S-cyclopropyl-pyrazol-S-yl, 1 -methyl-S-isopropyl-pyrazol-S-yl, l-t-butyl-pyrazol-4-yl, l-t-butyl-3-cyclopropyl-pyrazol-5-yl, l-ethyl-pyrazol-3-yl, l-isopropyl-pyrazol-3-yl, 5-isopropyl-l,3,4-oxadiazol-2-yl, 4-trifluoro-pyrid-2-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;
5-methylpyrazin-2-yl, 4-moipholin-4-ylpyrimidin-5-yl; benzodioxolyl, and 2- (dimethylamino)phenyl;
(ssss) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(Ra)(Rb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is -O- or -N(R8)- or L represents -C(O)N(R9)-CH2- or L represents -C(O)N(R9)- or -N(R8)C(O)-;
R8, R9, Ra and Rb independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y < 3, (tttt) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0; and
L is attached meta or para on ring A with respect to the point of attachment of 5 the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-,
-C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or ~C(Ra)(Rb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is -O- or -N(R8)- or L represents -C(O)N(R9)-CH2- or L represents -C(O)N(R9)- or -N(R8)C(0)-;
R8, R9, Ra and Rb independently represent hydrogen or (l-6C)alkyl (particularly o hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y < 3, (uuuu) A is phenyl; n is 0; and
B is selected from a saturated or partially saturated 4 to 6 membered heterocyclic s ring, an aryl group, a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5- triazinyl or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially o saturated or aromatic; (vwv) A is phenyl; n is 0; and
B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl; (wwww)A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, 5 imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
L is attached meta or para on ring A with respect to the point of attachment of o the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-,
-C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or ~C(Ra)(Rb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is -O- or -N(R8)- or L represents -C(O)N(R9)-CH2- or L represents -C(O)N(R9)- or -N(R8)C(0)-;
R8, R9, Ra and Rb independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1 , or 2, with the proviso that x+y > 0 and x+y < 3,
B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl; (xxxx) A is selected from phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl and 1,3,5-triazinyl (particularly phenyl, thiazolyl, thiadiazolyl, pyridyl and pyrimidinyl); n is 0;
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(Ra)(Rb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is -O- or -N(R8)- or L represents -C(O)N(R9)-CH2- or L represents -C(O)N(R9)- or -N(R8)C(0)-;
R8, R9, Ra and Rb independently represent hydrogen or (l-6C)alkyl (particularly hydrogen or (l-3C)alkyl, more particularly hydrogen); x and y are independently 0, 1, or 2, with the proviso that x+y > 0 and x+y < 3, B is selected from phenyl, pyrazolyl, thiadiazolyl and isoxazolyl;
(yyyy) m is 0, I or 2 (particularly 1 or 2);
(zzzz) B is selected from cyclopentyl, cyclohexyl, piperidinyl, tetrahydropyranyl, phenyl, furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 2,3-dihydro-l,4-benzodioxinyl and l,3-benzodioxol-5-yl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl;
(aaaaa) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
R6 is independently selected from halo, cyano, a (3-4C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or -N(Rc)C(O)(l-6C)alkyl in which Rc is hydrogen or (l-6C)alkyl; or R6 is selected from (l-βC)alkyl or (l-6C)alkoxy, wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups (for example 1 or 2), which may be the same or different, selected from cyano, fluoro, hydroxy and amino (particularly fiuoro);
(bbbbb) B is selected from phenyl, isoxazolyl, isothiazolyl, thiadiazolyl, pyrazolyl and pyridyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl; (ccccc) B is phenyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy, butoxy and morpholin-4-yl; (ddddd) B is phenyl; m is 1 or 2; and
R6 is independently selected from fluoro and trifluoromethyl; (eeeee) B is isoxazolyl; m is 1 or 2; and
R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy; (fffff) B is isoxazolyl; m is 1 or 2; and
R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (ggggg) B is pyrazolyl; m is 1 or 2; and R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclopropylmethyl, methoxy, ethoxy, propoxy and butoxy; (hhhhh) B is pyrazolyl; m is 1 or 2; and
R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (iiiii) B is thiadiazolyl; m is 1 or 2; and R6 is independently selected from fluoro, chloro, cyano, acetylamino, methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, trifluoromethyl, cyclopropyl, methoxy, ethoxy, propoxy and butoxy; Ojjjj) B is thiadiazolyl; m is 1 or 2; and R6 is independently selected from methyl, ethyl, propyl, isopropyl, butyl, tert- butyl (particularly methyl and tert-butyl, more particularly tert-butyl); (cccc) Ring B-R6 wherein m is O3 1 or 2 is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, phenyl, 2-fluorophenyl, 3 -fluorophenyl, 4- fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2- (trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5- (trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl, 3- methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2- acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 5-tert-butyl-l,3,4-thiadizol-2-yl, 5-methyl-l,3,4-thiadizol-2-yl, 5-cyclopropyl-l,3,4-thiadizol-2-yl, l-methyl-3-cyclopropyl- pyrazol-5-yl, l-tert-butyl-3-cyclopropyl-pyrazol-5-yl, 3-methylisothiazol-5-yl, 3- methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 4- (trifluoromethyl)pyridin-2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 2,3-dihydro-l,4-benzodioxinyl, l,3-benzodioxol-5-yl, 2-morpholin-4-ylphenyl, 3- moφholin-4-ylphenyl, 4-morpholin-4-ylphenyl, l-methylpiperidin-4-yl, 1-ethylpiperidin- 4-yl and l-propylpiperidin-4-yl; and (kkkkk) Ring B-R6 wherein m is 1 or 2 is selected from 2-fluorophenyl, 3 -fluorophenyl, 4-fluorophenyl, 2,5-difluorophenyl, 3,4-difluorophenyl, 3,5-difluorophenyl, 2-(trifluoromethyl)phenyl, 3-(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-fluoro-5-(trifluoromethyl)phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,5-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-methoxyphenyl,
3-methoxyphenyl, 4-methoxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenyl, 2-acetamidophenyl, 3-acetamidophenyl, 4-acetamidophenyl, 5-tert-butyl- 1 ,3 ,4-thiadizol-2- yl, 5-methyl-l,3,4-thiadizol-2-yl, 5-cyclopropyl-l,3,4-thiadizol-2-yl, 3-cyclopropyl- pyrazol-5-yl, l-tert-butyl-S-cyclopropyl-pyrazol-S-yl, 3-methylisothiazol-5-yl, 3- methylisoxazol-5-yl, 5-methylisoxazol-3-yl, 5-tert-butylisoxazol-3-yl, 4-
(trifluoromethyl)pyridin-2-yl, 2-oxopiperidin-3-yl, 2,2-dimethyltetrahydro-2H-pyran-4-yl, 2-morpholin-4-ylphenyl, 3-morpholin-4-ylphenyl, 4-moφholin-4-ylphenyl, 1- methylpiperidin-4-yl, l-ethylpiperidin-4-yl and l-propylpiperidin-4-yl.
(11111) R1 and R2 are both hydrogen, R3 and R4 are both hydrogen, n is 0, L is -C(O)NH- or -NHC(O)- and ring B-R6, where m is 1 or 2, is selected from 3-acetylaminophenyl, 2-(trifluoromethyl)phenyl, 3 -(trifluoromethyl)phenyl, 4-(trifluoromethyl)phenyl, 2-methoxyphenyl, 3-methoxyphenyl, 2-fluoro-5-(trifluoromethyl)phenyl,, 3,4-dichloro-phenyl, 2-morpholin-4-ylphenyl, 5-tert-butyl- 1.3 ,4-thiadiazol-2-yL 3-methylisothiazol-5-yl, 3-methylisoxazol-5-yl, 5-tert-butylisoxazol-3-yl, l-methyl-3-tert-butyl-pyrazol-5-yl, l-methylpiperidin-4-yl, l-propylpiperidin-4-yl, 4-(trifluoromethyl)pyrid-3-yl and 4-(trifluoromethyl)pyrid-2-yl;
A particular embodiment of the compounds of the Formula I is a compound of the Formula IA(i):
Figure imgf000047_0001
Formula IA(i) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof. Another particular embodiment of the compounds of the Formula I is a compound of the Formula IA(ii):
Figure imgf000048_0001
Formula IA(ii) τ 4, τ R> 5 τ% d
Figure imgf000048_0002
R>4 D, R0, L, B, n and m are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
Another particular embodiment of the compounds of the Formula I is a compound of the Formula IA(iii):
Figure imgf000048_0003
Formula IA(iii) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
Another particular embodiment of the compounds of the Formula I is a compound of the Formula IA(iv):
Figure imgf000048_0004
Formula IA(iv) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularly pharmaceutically acceptable salts thereof.
A particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(i):
Figure imgf000049_0001
Formula IB(i) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularily pharmaceutically acceptable salts thereof.
Another particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(ii):
Figure imgf000049_0002
Formula IB(ii) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularily pharmaceutically acceptable salts thereof.
Another particular embodiment of the compounds of the Formula IB is a compound of the Formula IB(iii):
Figure imgf000049_0003
Formula IB(iii) wherein: wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularily pharmaceutically acceptable salts thereof.
Another particular embodiment of the compounds of the Formula I is a compound of the Formula IB(iv):
Figure imgf000050_0001
Formula IB(iv) wherein R1, R2, R3, R4, R5, R6, L, B, n and m are as defined above and salts thereof, particularily pharmaceutically acceptable salts thereof.
A compound of the Formula I, or a pharmaceutically-acceptable salt thereof, may be prepared by any process known to be applicable to the preparation of chemically-related compounds. Such processes, when used to prepare a compound of the Formula I are provided as a further feature of the invention and are illustrated by the following representative process variants. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.
According to a further aspect of the present invention provides a process for preparing a compound of formula I or a pharmaceutically acceptable salt thereof (wherein R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11 L , ring A and ring B, n and m are, unless otherwise specified, as defined in formula I) as described schematically below. Process Ta) For compounds of the formula I wherein L is
-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(RaRb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula II:
Figure imgf000050_0002
wherein W is -C(RaRb)- or a direct bond and Rx, Ry, Rz, R5, R8, Ra, Rb, n, p and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a heterocycle of the formula III:
Figure imgf000051_0001
wherein Lg1 is a suitable displaceable group for example hydroxy, halogeno (such as fluoro, chloro or bromo), RX-C(O)-O- or Rx-O- (wherein Rx is a suitable alkyl or aryl group) and R6, Ra, Rb, m, x, y and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (b) For compounds of the formula I wherein L is
-C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- or -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula IV:
Figure imgf000051_0002
wherein Lg2 is a suitable displaceable group as described above for Lg1, W is - C(RaRb)- or a direct bond and Rx, Ry, Rz, , R5, Ra, Rb, n, p and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula V:
Figure imgf000052_0001
V wherein R6, R9, Ra, Rb, m, x, y, B and Z have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (c) For compounds of formula I wherein Z is -O- or -N(Ra)- and when Z is -O- then x>0, the reaction of a compound of formula VI
Figure imgf000052_0002
Vl wherein J is selected from -N(R8)C(O)-, -C(O)N(R9)-, -C(Ra)(Rb)-N(R8)C(O)- or -C(Ra)(Rb)-C(O)N(R9)- and Z Rx, Ry, Rz, R5, R8, R9, Ra, Rb, x, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary and when Z is -O- then x>0, with a compound of formula VII,
Figure imgf000052_0003
VII wherein Lg3 is a suitable displaceable group, for example halogeno (such as fluoro, chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy and Ra, Rb, R6, y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary;
Process (d) For compounds of formula I wherein Z is -O- or -N(Ra)- and x>0, the reaction of a compound of formula VIII
Figure imgf000053_0001
VIII wherein Lg4 is a suitable displaceable group, for example halogeno (such as chloro, bromo), O-tosyl, O-mesyl or trifluorosulphonyloxy, J is selected from -N(R8)C(O)-, -C(O)N(R9)-, -C(Ra)(Rb)-N(R8)C(0)- or -C(Ra)(Rb)-C(O)N(R9)- and Rx, Ry, R2, R5, R8, R9, Ra, Rb, n, and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary and x is 1, 2 or 3, with a compound of formula IX,
Figure imgf000053_0002
IX wherein Z, Ra, Rb, R6, y, m and B have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
Process (o) For the preparation of a compound of formula IA, the reaction of a compound of the formula X:
Figure imgf000053_0003
X wherein Lg5 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methyl sulfonyl, methylthio, methylsulphoxide or aryloxy (such as phenoxy) and R3, R4, R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR1R2, wherein R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or for the preparation of a compound of formula (IB), the reaction of a compound of the formula X':
Figure imgf000054_0001
wherein Lg3 is a suitable displaceable group for example halogeno (such as fluoro, chloro, bromo or iodo), methyl sulfonyl, methylthio or aryloxy (such as phenoxy) and R3, R4, R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR1R2, wherein R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (f) The reaction of a compound of the formula XI:
Figure imgf000054_0002
Xl wherein Lg6 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an alkyne of the formula XII:
Figure imgf000054_0003
XII wherein Rx, Ry, and Rz have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or Process (g) The reaction of a compound of the formula XIII:
Figure imgf000055_0001
XiIi wherein R5, R6, n, m, A, B and L have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with a pyrimidine of the formula XIV:
Figure imgf000055_0002
XIV wherein Lg7 is a suitable displaceable group for example halogeno (such as chloro, bromo or iodo) or a sulfonyloxy group (such as trifluoromethylsulfonyloxy) and Rx, Ry and Rz have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate. Reaction Conditions for Process (a) When Lg1 is hydroxy, the reaction of process (a) is conveniently carried out in the presence of a suitable coupling agent. A suitable coupling agent is, for example, a suitable peptide coupling agent, for example O-(7-azabenzotriazol-l-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (HATU) or a suitable carbodiimide such as dicyclohexylcarbodiimide (DCC) or carbonyldiimidazole (CDI), optionally in the presence of a catalyst such as dimethylaminopyridine or hydroxybenzotriazole.
When Lg1 is any suitable displaceable group as described above, the reaction of process (a) may conveniently be carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, diisopropylethylamine, N-methylmorpholine or diazabicyclo[5.4.0]undec-7-ene. Another suitable base is, for example, an alkali or alkaline earth metal carbonate, for example sodium carbonate, potassium carbonate, caesium carbonate or calcium carbonate. The reaction of process (a) is conveniently carried out in the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, a halogenated solvent such as dichloromethane, chloroform or carbon tetrachloride, an ether such as tetrahydrofuran or 1,4-dioxane, an aromatic solvent such as toluene or a dipolar aprotic solvent such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from about 0°C to about 120°C, preferably at or near ambient temperature. Reaction Conditions for Process (b)
The reaction of process (b) is conveniently carried out under the conditions as described above for process (a). Reaction Conditions for Process Tc)
The reaction of process (c) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base such as pyridine or a trialkylamine (such as triethylamine or diisopropylethylamine) or, for example, an alkali or alkaline earth metal carbonate such as sodium carbonate or potassium carbonate.
The reaction of process (c) is conveniently carried out in the presence of a suitable solvent or diluent, for example tetrahydrofuran, 1,4-dioxane or a dipolar aprotic solvent such as dimethylformamide or dimethylacetamide. The reaction is conveniently carried out at a temperature in the range, for example, from about ambient temperature to about 1000C, and under atmospheric pressure. Reaction Conditions for Process (d)
The reaction of process (d) is conveniently carried out under the conditions as described above for process (c).
Reaction Conditions for Process (e) The reaction of process (e) is conveniently carried out in the presence of a catalytic amount of a suitable acid. A suitable acid is, for example, hydrogen chloride.
The reaction of process (e) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent. A suitable inert solvent or diluent, when used, is for example an alcohol such as ethanol, isopropanol or butanol or a dipolar aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from ambient temperature to about 120°C, preferably from about 8O0C to about 9O0C.
Reaction Conditions for Process (f) The reaction of process (f) is conveniently carried out in the presence of a suitable palladium catalyst, optionally in combination with a suitable copper catalyst. A suitable palladium catalyst is, for example, bis(triphenylphosphine)palladium dichloride, [1,1'- bis(diphenylphosphino)ferrocene] palladium dichloride or tetrakis(triphenylphosphine)palladium(0). A suitable copper catalyst is, for example, copper (I) iodide.
The reaction of process (f) is conveniently carried out in the presence of a suitable base. A suitable base is, for example, an organic amine base, such as trialkylamine (for example triethylamine) or tetramethylguanidine.
The reaction of process (f) may conveniently be carried out in the absence or the presence of a suitable inert solvent or diluent, for example an ester such as ethyl acetate, an ether such as tetrahydrofuran or 1,4-dioxane or a dipolar aprotic solvent such as
N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one or dimethylsulfoxide. The reaction is conveniently carried out at a temperature in the range, for example, from about -200C to about 1000C. Reaction Conditions for Process Tg)
The reaction of process (g) is conveniently carried out under the conditions as described above for process (f). Starting Materials for Process fa)
Compounds of the formula II may be obtained by conventional procedures. For example, compounds of the formula II may be obtained by reaction of a pyrimidine of the formula XV with an alkyne of the formula XVI as illustrated in Reaction Scheme 1:
Figure imgf000058_0001
Reaction Scheme 1 wherein Lg8 is a suitable displaceable group as described above and Rx Ry, Rz, R5, R8, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary. The reaction of Reaction Scheme 1 is conveniently carried out under the conditions as described above for process (f).
Alternatively, compounds of the formula II may be obtained by reaction of a pyrimidine of the formula XVII with a protected alkyne of the formula XVIII and then with an amine of the formula XIX as illustrated in Reaction Scheme 2:
Figure imgf000059_0001
Reaction Scheme 2 wherein Lg9 and Lg10 are each a suitable displaceable group, Pg is a suitable protecting group, for example a trialkylsilyl group, such as trimethylsilyl or tert-butyldimethylsilyl or Me2(OH)C- and Rx, Ry, Rz, R5, R8, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary.
Step (i) of Reaction Scheme 2 is the coupling of a protected alkyne of the formula XVIII to a pyrimidine of the formula XVII. Step (i) is carried out under conditions as described above for process (f). Step (ii) of Reaction Scheme 2 is the deprotection of the alkyne under basic or acidic conditions to provide an unprotected alkyne. A person skilled in the art would readily be able to select the appropriate conditions for deprotection in step (ii). Step (iii) of Reaction Scheme 2 is the coupling of the alkyne to an amine of the formula XIX. Step (iii) of Reaction Scheme 2 is carried out under conditions as described above for process (f). Alternatively, compounds of the formula II where Ry is a group NR1R2 may be obtained by reaction of a compound of the formula XX, wherein Lg11 is a suitable displaceable group and R3a, R4a, R5, R8, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR1R2 using reaction conditions as described above for process (e).
Figure imgf000059_0002
XX Alternatively, compounds of the formula II where Rx is NR1R2 may be obtained by reaction of a compound of the formula XX', wherein Lg3 is a suitable displaceable group as described above and R3b, R4b, R5, R8, n and A have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with an amine of the formula HNR1R2 using reaction conditions as described above for process (g).
Figure imgf000060_0001
XX'
The starting materials of the formulae XV, XVI, XVIII and XIX and the amine HNR1R2 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. The starting material of the formula XX can be prepared by standard processes known in the art or by a method analogous to Reaction Scheme 2 as described above.
Compounds of the formula III may be obtained by conventional procedures.. Starting Materials for Process (b) Compounds of the formula IV may be obtained by analogous processes to those for the preparation of compounds of Formula II in 'Starting Materials for Process (a)' above.
Amines of the formula V are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (c) Compounds of the formula VI may be obtained by conventional procedures analogous to the procedures for the preparation of compounds of formula II in 'Starting Materials for Process (a)' above.
Compounds of formula VII are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art. Starting Materials for Process (d)
Compounds of the formula VIII may be obtained by conventional procedures analogous to the procedures for the preparation of compounds of formula II in 'Starting
Materials for Process (a)' above. Compounds of formula XV are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Starting Materials for Process (e)
As the skilled person would appreciate, compounds of the formula X can be prepared using similar processes to those described above using the appropriate starting materials, for example wherein the starting materials carry an, optionally protected, group
Lg3 in place of the -NR1R2 group.
Amines of the formula HNR1R2 are commercially available or they are known in the literature, or they can be prepared by standard processes known in the art.
Starting Materials for Process (f) Compounds of formula XI are commercially available or they are known in the literature, or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials using processes analogous to process a) above.
Alkynes of the formula XII are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials. For example, compounds of the formula XII may conveniently be obtained by reaction of a pyrimidine of the formula XXI:
Figure imgf000061_0001
XXI wherein Lg4 is a suitable displaceable group and R1, R2, R3 and R4 have any of the meanings defined hereinbefore except that any functional group is protected if necessary, with trimethylsilylacetylene or 2-methyl-3-butyn-2-ol conveniently under the conditions as described above in Reaction Scheme (2), followed by the removal of the protecting group using standard procedures known in the art. Starting Materials for Process (g)
Compounds of the formula XIII can be prepared using procedures analogous to processes (a) - (b) above.
Compounds of the formula XIVa are commercially available or as the skilled person would appreciate they can be prepared using similar processes to those described above using the appropriate starting materials.
Compounds of the formula I can be converted into further compounds of the formula I using standard procedures conventional in the art.
Examples of the types of conversion reactions that may be used include introduction of a substituent by means of an aromatic substitution reaction or of a nucleophilic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art.
Particular examples of aromatic substitution reactions include the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of nucleophilic substitution reactions include the introduction of an alkoxy group or of a monoalkylamino group, a dialkyamino group or a N-containing heterocycle using standard conditions. Particular examples of reduction reactions include the reduction of a carbonyl group to a hydroxy group with sodium borohydride or of a nitro group to an amino group by catalytic hydrogenation with a nickel catalyst or by treatment with iron in the presence of hydrochloric acid with heating. An example of a suitable conversion reaction is the conversion of a compound of the formula I wherein R2, R3, R4, R5, R6, n, m, A, B and L are as defined in claim 1 and R1 and/or R2 is hydrogen to a compound of the formula I wherein R1 and/or R2 is, for example, an optionally substituted (l-6C)alkoxycarbonyl group. Such a conversion may be achieved using standard procedures, for example by substitution of one or both of the hydrogen atoms R1 and/or R2 for a desired, optionally substituted (l-6C)alkoxycarbonyl group.
Certain compounds of Formula I are capable of existing in stereoisomeric forms. It will be understood that the invention encompasses all geometric and optical isomers of the compounds of formula I and mixtures thereof including racemates. Tautomers and mixtures thereof also form an aspect of the present invention.
Isomers may be resolved or separated by conventional techniques, e.g. chromatography or fractional crystallisation. Enantiomers may be isolated by separation of a racemic or other mixture of the compounds using conventional techniques (e.g. chiral High Performance Liquid Chromatography (HPLC)). Alternatively the desired optical isomers may be made by reaction of the appropriate optically active starting materials under conditions which will not cause racemisation, or by derivatisation, for example with a homochiral acid followed by separation of the diastereomeric derivatives by conventional means (e.g. HPLC, chromatography over silica) or may be made with achiral starting materials and chiral reagents. All stereoisomers are included within the scope of the invention.
The compounds of the invention may be isolated from their reaction mixtures using conventional techniques. It will be appreciated that in some of the reactions mentioned herein it may be necessary/desirable to protect any sensitive groups in the compounds. The instances where protection is necessary or desirable and suitable methods for protection are known to those skilled in the art. Conventional protecting groups may be used in accordance with standard practice (for illustration see T.W. Green, Protective Groups in Organic Synthesis, John Wiley and Sons, 1991). Thus, if reactants include groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein. Protecting groups may be removed by any convenient method as described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with minimum disturbance of groups elsewhere in the molecule.
Specific examples of protecting groups are given below for the sake of convenience, in which "lower", as in, for example, lower alkyl, signifies that the group to which it is applied preferably has 1-4 carbon atoms. It will be understood that these examples are not exhaustive. Where specific examples of methods for the removal of protecting groups are given below these are similarly not exhaustive. The use of protecting groups and methods of deprotection not specifically mentioned are, of course, within the scope of the invention. It will also be appreciated that certain of the various ring substituents in the compounds of the present invention may be introduced by standard aromatic substitution reactions or generated by conventional functional group modifications either prior to or immediately following the processes mentioned above, and as such are included in the process aspect of the invention. Such reactions and modifications include, for example, introduction of a substituent by means of an aromatic substitution reaction, reduction of substituents, alkylation of substituents and oxidation of substituents. The reagents and reaction conditions for such procedures are well known in the chemical art. Particular examples of aromatic substitution reactions include the introduction of a nitro group using concentrated nitric acid, the introduction of an acyl group using, for example, an acyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; the introduction of an alkyl group using an alkyl halide and Lewis acid (such as aluminium trichloride) under Friedel Crafts conditions; and the introduction of a halogeno group. Particular examples of modifications include the reduction of a nitro group to an amino group by for example, catalytic hydrogenation with a nickel catalyst or treatment with iron in the presence of hydrochloric acid with heating; oxidation of alkylthio to alkylsulfmyl or alkylsulfonyl.
It is believed that certain intermediate compounds of Formulae II, IV, VI, VIII, X and XX are novel and are herein claimed as another aspect of the present invention.
Biological Assays
The following assay can be used to measure the effects of the compounds of the present invention as inhibitors of Tie2 autophosphorylation in whole cells.
Cellular Tie2 autophosphorylation assay
This assay is based on measuring the ability of compounds to inhibit autophosphorylation of the Tie2 receptor which normally leads to the production of "activated" receptor that in turn initiates the particular signal transduction pathways associated with the receptor function. Autophosphorylation can be achieved by a number of means. It is known that expression of recombinant kinase domains in baculoviral systems can lead to the production of phosphorylated and activated receptor. It is also reported that over expression of receptors in recombinant cell lines can itself lead to receptor autophosphorylation in the absence of the ligand (Heldin C-H. 1995 Cell : 80, 213-223; Blume-J. P, Hunter T. 2001 Nature: 411, 355-65). Furthermore, there are numerous literature examples in which chimaeric receptors have been constructed. In these cases the natural, external cell surface domain of the receptor has been replaced with that of a domain which is known to be readily dimerised via the addition of the appropriate ligand (e.g. TrkA-Tie2/NGF ligand (Matron, M.B., et al., 2000 Journal of Biological Chemistry : 275:39741-39746) or C-fms-Tie-1/CSF-l ligand (Kontos, CD., et al., 2002 Molecular and Cellular Biology : 22, 1704-1713). Thus when the chimaeric receptor expressed in a host cell line and the respective ligand is added, this induces autophosphorylation of the chimeric receptor's kinase domain. This approach has the advantage of often allowing a known (and often easily obtained) ligand to be used instead of having to identify and isolate the natural ligand for each receptor of interest.
Naturally if the ligand is available one can use natural cell lines or primary cells which are known to express the receptor of choice and simply stimulate with ligand to achieve ligand induced phosphorylation. The ability of compounds to inhibit autophosphorylation of the Tie2 receptor, which is expressed for example in EA.hy926/B3 cells (supplied by J. McLean/ B. Tuchi, Univ.of N. Carolina at Chapel Hill, CB- 4100, 300 Bynum Hall, Chapel Hill, N.C. 27599-41000, USA) or primary HUVEC (human umbilical vein endothelial cells - available from various commercial sources), can measured by this assay.
Natural Angl ligand can be isolated using standard purification technology from either tumour cell supernatants or alternatively the Angl gene can be cloned and expressed recombinantly using stand molecular biology techniques and expression systems. In this case one can either attempt to produce the ligand either in its native state or as recombinant protein which for example may have been genetically engineered to contain additional of purification tags (eg. polyhistidine peptides, antibody Fc domains) to facilitate the process. Using the ligand stimulation of either EA.hy926/B3 or HUVEC cellular Tie2 receptor as the example, a Angl ligand stimulated cellular receptor phosphorylation assay can be constructed which can be used to analyse to determine the potential of compounds to inhibit this process. For example EA.hy926/B3 cells were grown in the appropriate tissue culture media plus 10% foetal calf serum (FCS) for two days in 6 well plates starting with an initial seeding density of 5xlO5 cells/well. On the third day the cells were serum starved for a total of 2 hours by replacing the previous media with media containing only 1% FCS. After 1 hour 40 minutes of serum starvation the media was removed and replace with 1 ml of the test compound dilutions (compound dilutions made in serum starvation media yet keeping the DMSO concentration below 0.8%). After 1.5 hours of serum starvation orthovanidate was added to a final concentration of 0.1 mM for the final 10 minutes of serum starvation.
Following a total of 2 hours of serum starvation, the ligand plus orthovandiate was added to stimulate autophosphorylation of the cellular Tie2 receptor (ligand can be added either as purified material diluted in serum starvation media or non-purified cell supernatant containing ligand e.g. when recombinantly expressed mammalian cells). After 10 minutes incubation at 37 0C with the ligand, the cells were cooled on ice washed with approximately 5mls with cold PBS containing 1 mM orthovanadate, after which 1 ml of ice cold lysis buffer ((20 mM Tris pH 7.6, 150 mM NaCl, 50 mM NaF, 0.1 % SDS, 1% NP40, 0.5 % DOC, 1 mM orthovanadate, 1 mM EDTA, 1 mM PMSF, 30 μl / ml Aprotinin, 10 μg/ml Pepstatin, 10 μg/ml Leupeptin) was added the cells and left on ice for 10- 20 minutes. The lysate was removed and transferred to a 1.5 ml Eppendorf tube and centrifuged for 3 minutes at 13000 rpm at 4 °C. 800 μl of each lysate was transferred to fresh 2 ml Eppendorf tubes for the immuno-precipitation. 3 mg = 15 μl of anti-phospho- tyrosine antibody (Santa Cruz PY99 -sc-7020) was added to the lysates and left to incubate for 2 hours at 4 °C. 600 μl washed MagnaBind beads (goat anti-mouse IgG, Pierce 21354) were added to the lysates and the tubes left to rotate over night at 4 °C.
Samples were treated for 1 minute in the magnet before carefully removing the lysis supernatant. 1 ml of lysis buffer was then added to the beads and this step repeated twice more. The beads were suspended in 25 μl of 94 0C hot 2 D Laemmli loading buffer plus beta-mercaptoethanol and left to stand for 15 minutes at room temperature.
The beads were removed by exposing the tubes for 1 minutes in the magnet, and the total liquid separated from the beads from each immuno-precipitate loaded onto Polyacrylamide/SDS protein gels (pre-cast 4-12 % BisTris NuPAGE / MOPS 12 well gels from Novex). Protein gels were run at 200 V and then blotted onto NC membrane for
Ihours30 minutes at 50 V / 250 mA. All blots were treated with 5% Marvel in PBS-Tween forl hour at room temperature to reduce non-specific binding of the detection antibody. A rabbit anti-Tie2 (Santa Cruz sc-324) was added in a 1:500 dilution in 0.5 % Marvel / PBS- Tween and left to incubate overnight at 4 0C. The blots were rigorously washed with PBS- Tween before adding the goat anti rabbit -POD conjugate (Dako P0448) at a 1:5000 dilution in 0.5 % Marvel / PBS-Tween. The antibody was left on for 1 hour at room temperature before subsequently washing the blots with PBS-Tween. The western blots of the various immuno-precipitated samples were developed the blots with LumiGLO (NEB 7003). And transferred to an X-Ray cassette and films exposed for 15 sec / 30 sec and 60 sec. The relative strength of the protein band which pertains to the phosphorylated Tie2 receptor was evaluated using a FluorS BioRad image analyser system. The percentage phosphorylation for each test compound dilution series was determined from which IC50 values were calculated by standard methods using the appropriate control samples as reference.
Although the pharmacological properties of the compounds of the Formula I vary with structural change as expected, in general activity possessed by compounds of the Formula I, is in the range of IC5O of < 50μM in the above test- By way of example, Table A illustrates the activity of representative compounds according to the invention showing IC50 data for the inhibition of autophosphorylation of Tie2 receptor tyrosine kinase. Table A
Figure imgf000067_0001
In the following section references to a compound of formula I, refer also to other sub-groups of the invention as described above, for example would also apply, amongst other sub-groups of the invention, to compounds of formula Ia, Ib, Ic and Id.
According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the Formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in association with a pharmaceutically-acceptable diluent or carrier.
The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular dosing or as a suppository for rectal dosing). The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and/or preservative agents.
The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 0.5 g of active agent (more suitably from 0.5 to 100 mg, for example from 1 to 30 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.
The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well known principles of medicine. In using a compound of the Formula I for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg/kg to 75 mg/kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous administration, a dose in the range, for example, 0.1 mg/kg to 30 mg/kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg/kg to 25 mg/kg body weight will be used. Oral administration is however preferred, particularly in tablet form. Typically, unit dosage forms will contain about 0.5 mg to 0.5 g of a compound of this invention.
The compounds according to the present invention as defined herein are of interest for, amongst other things, their antiangiogenic effect. The compounds of the invention are expected to be useful in the treatment or prophylaxis of a wide range of disease states associated with undesirable or pathological angiogenesis, including cancer, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation. Cancer may affect any tissue and includes leukaemia, multiple myeloma and lymphoma. In particular such compounds of the invention are expected to slow advantageously the growth of primary and recurrent solid tumours of, for example, the colon, breast, prostate, lungs and skin.
We believe that the antiangiogenic properties of the compounds according to the present invention arise from their Tie2 receptor tyrosine kinase inhibitory properties.
Accordingly, the compounds of the present invention are expected be useful to produce a Tie2 inhibitory effect in a warm-blooded animal in need of such treatment. Thus the compounds of the present invention may be used to produce an antiangiogenic effect mediated alone or in part by the inhibition of Tie2 receptor tyrosine kinase. More particularly the compounds of the invention are expected to inhibit any form of cancer associated with Tie2. For example, the growth of those primary and recurrent solid tumours which are associated with Tie2, especially those tumours which are significantly dependent on Tie2 receptor tyrosine kinase for their growth and spread.
According to a further aspect of the invention there is provided a compound of the Formula I, or a pharmaceutically-acceptable salt thereof, as defined hereinbefore, for use as a medicament.
According to another aspect of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal such as man.
According to another aspect of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an anti- angiogenic effect in a warm-blooded animal such as man.
According to another aspect of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancers in a warm-blooded animal such as man.
According to another aspect of the invention, there is provided the use of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid and skin cancer in a warm-blooded animal such as man.
According to another aspect of the invention there is provided a method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a method of treating cancers in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula
I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a method of treating a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer, in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore.
According to another aspect of the invention there is provided a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man.
According to an another aspect of the invention there is provided a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in producing an anti-angiogenic effect in a warm-blooded animal, such as man.
According to another aspect of the invention there is provided a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of cancer.
According to another aspect of the invention there is provided a compound of the formula I, or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer selected from leukaemia, breast, lung, colon, rectal, stomach, prostate, bladder, pancreas, ovarian, lymphoma, testicular, neuroblastoma, hepatic, bile duct, renal cell, uterine, thyroid or skin cancer.
As hereinbefore mentioned it is further expected that a compound of the present invention will possess activity against other diseases mediated by undesirable or pathological angiogenesis including psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, lymphoedema, acute and chronic nephropathies, atheroma, arterial restenosis, autoimmune diseases, acute inflammation, excessive scar formation and adhesions, endometriosis, dysfunctional uterine bleeding and ocular diseases with retinal vessel proliferation.
The anti-angiogenic activity defined herein may be applied as a sole therapy or may involve, in addition to a compound of the invention, one or more other substances and/or treatments. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate administration of the individual components of the treatment. In the field of medical oncology it is normal practice to use a combination of different forms of treatment to treat each patient with cancer. In medical oncology the other component(s) of such conjoint treatment in addition to the cell cycle inhibitory treatment defined hereinbefore may be: surgery, radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents: (i) anti-invasion agents (for example metalloproteinase inhibitors like marimastat and inhibitors of urokinase plasminogen activator receptor function);
(ii) antiproliferative/antineoplastic drugs and combinations thereof, as used in medical oncology, such as alkylating agents (for example cis-platin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan and nitrosoureas); antimetabolites (for example antifolates such as fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside and hydroxyurea, or, for example, one of the preferred antimetabolites disclosed in European Patent Application No. 562734 such as (2S)-2- {o-fluoro-rj-[N- {2,7-dimethyl-4-oxo-3 ,4-dihydroquinazolin-6-ylmethyl)-
N-(prop-2-ynyl)amino]benzamido}-4-(tetrazol-5-yl)butyric acid); antitumour antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
(iii) cytostatic agents such as antioestrogens (for example tamoxifen, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrazole, vorazole and exemestane) and inhibitors of 5α-reductase such as finasteride; (iv) inhibitors of growth factor function, for example such inhibitors include growth factor antibodies, growth factor receptor antibodies, farnesyl transferase inhibitors, tyrosine kinase inhibitors and serine/threonine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example the EGFR tyrosine kinase inhibitors N-(3- chloro-4-fluorophenyl)-7-methoxy- 6-(3-morpholinopropoxy)quinazolin-4-amine (ZDl 839), N-(3-ethynylphenyl)- 6,7-bis(2-methoxyethoxy)quinazolin-4-amine (CP 358774) and 6-acrylamido-N-(3-chloro- 4-fluorophenyl)-7-(3-moφholinopropoxy)quinazolin-4-amine (CI 1033)), for example inhibitors of the platelet-derived growth factor family and for example inhibitors of the hepatocyte growth factor family;
(v) antiangiogenic agents that work by different mechanisms to those defined hereinbefore, such as those which inhibit vascular endothelial growth factor such as the compounds disclosed in International Patent Applications WO 97/22596, WO 97/30035, WO 97/32856 and WO 98/13354 and those that work by other mechanisms (for example linomide, inhibitors of integrin αvβ3 function and angiostatin); (vi) biotherapeutic therapeutic approaches for example those which use peptides or proteins (such as antibodies or soluble external receptor domain constructions) which either sequest receptor ligands, block ligand binding to receptor or decrease receptor signalling (e.g. due to enhanced receptor degradation or lowered expression levels) (vii) antisense therapies, for example those which are directed to the targets listed above, such as ISIS 2503, an anti-ras antisense; (viii) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCAl or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and (ix) immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies. Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.
According to this aspect of the invention there is provided a pharmaceutical product comprising a compound of the Formula I as defined hereinbefore and an additional anti-tumour substance as defined hereinbefore for the conjoint treatment of cancer. In addition to their use in therapeutic medicine, the compounds of Formula I and their pharmaceutically acceptable salts, are also useful as pharmacological tools in the development and standardisation of in vitro and in vivo test systems for the evaluation of the effects of inhibitors of cell cycle activity in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents. Examples of compounds of the invention include:
5-[(4-Aminopyrimidin-5-yl)ethynyl]-N-[2-fluoro-5-(trifluoromethyl)phenyl]thiophene-2- carboxamide;
4-[(4-Aminoprimidin-5-yl)ethynyl]-N-[2-fluoro-5-(trifluoromethyl)phenyl]thiophene-2- carboxamide;
5-[(4-Aminopyrimidin-5-yl)ethynyl]-N-(5-tert-butylisoxazol-3-yl)thiophene-2- carboxamide;
2-[(4-Aminopyrimidin-5-yl)ethynyl]-N-phenyl-l,3-thiazole-4-carboxamide;
2-[(4-Aminopyrimidin-5-yl)ethynyl]-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-l,3- thiazole-4-carboxamide;
2-[(4-Aminopyrimidin-5-yl)ethynyl]-N-(5-tert-butylisoxazol-3-yl)-l,3-thiazole-4- carboxamide; and salts thereof, as well as the compounds listed in the following examples.
The invention will now be illustrated by the following non-limiting examples in which, unless stated otherwise:
(i) temperatures are given in degrees Celsius (0C); operations were carried out at room or ambient temperature, that is, at a temperature in the range of 18-25 0C;
(ii) organic solutions were dried over anhydrous magnesium sulfate; evaporation of solvent was carried out using a rotary evaporator under reduced pressure (600-4000 Pascals; 4.5-30 mmHg) with a bath temperature of up to 60 0C;
(iii) chromatography means flash chromatography on silica gel; thin layer chromatography
(TLC) was carried out on silica gel plates;
(iv) in general, the course of reactions was followed by TLC and / or analytical LC-MS, and reaction times are given for illustration only; (v) final products had satisfactory proton nuclear magnetic resonance (NMR) spectra and/or mass spectral data; (vi) yields are given for illustration only and are not necessarily those which can be obtained by diligent process development; preparations were repeated if more material was required;
(vii) when given, NMR data is in the form of delta values for major diagnostic protons, given in parts per million (ppm) relative to tetramethylsilane (TMS) as an internal standard, determined at 300 MHz using perdeuterio dimethyl sulphoxide (DMSO-dβ) as solvent unless otherwise indicated; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; b, broad;
(viii) chemical symbols have their usual meanings; SI units and symbols are used; (ix) solvent ratios are given in volume:volume (v/v) terms; and
(x) mass spectra (MS) were run with an electron energy of 70 electron volts in the chemical ionization (CI) mode using a direct exposure probe; where indicated ionization was effected by electron impact (EI), fast atom bombardment (FAB) or electrospray (ESP); values for m/z are given; generally, only ions which indicate the parent mass are reported; and unless otherwise stated, the mass ion quoted is MH+;
(xi) unless stated otherwise compounds containing an asymmetrically substituted carbon and/or sulphur atom have not been resolved;
(xii) where a synthesis is described as being analogous to that described in a previous example the amounts used are the millimolar ratio equivalents to those used in the previous example;
(xvi) the following abbreviations have been used:
AcOH Acetic acid
AIBN 2,2'-Azobisisobutyronitrile
DCM Dichloromethane
DIPEA Diisopropylethylamine
DMA N,N-Dimethylacetamide
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
DMTMM 4-(4,6-Dimethoxy- 133,5-triazin-2-yl)-4-methyhnorpholin-4-ium chloride
dppf 1 , 1 ' -Bis(diphenylphosphino)ferrocene EtOAc Ethylacetate
HATU O-(7-Azabenzotriazol- 1 -yl)-N,N,N' ,N' -tetramethyluronium hexafluorophosphate
1PrMgCl Isopropylmagnesium chloride
LDA Lithium diisopropylamide
LHMDS Lithium bis(trimethylsilyl) amide
7M-CPBA metø-Chloroperbenzoic acid
MeOH Methanol
MeCN Acetonitrile
MCX Mixed cation exchange resin
MTBE Methyl tert-buty\ ether
LCMS Liquid Chromatograpy - Mass Spectrometry
NMP 1 -Methyl-2-pyrrolidinone
POCl3 Phosphorus oxychloride
RPHPLC Reversed phase high peformance liquid chromatography
TFA Trifluoroacetic acid
THF Tetrahydrofuran
xvii) where a synthesis is described as leading to an acid addition salt (e.g. HCl salt), no comment is made on the stoichiometry of this salt. Unless otherwise stated, all NMR data is reported on free-base material, with isolated salts converted to the free-base form prior to characterisation.
Example 1
5-[(2-Aminopyrimidin-5-yl)ethynyI]-N-[2-fluoro-5-
(trifluoromethyl)phenyl]thiophene-2-carboxamide
Figure imgf000077_0001
A mixture of 2-amino-5-ethynylpyrimidine (Intermediate 2) (119 mg), 5-bromo-N-[2- fluoro-5-(trifluoromethyl)phenyl]thiophene-2-carboxamide (Intermediate 3) (368 mg), copper (I) iodide (5 mg) and tetrakis(triphenylphosphine)palladium(0) (58 mg) in dry DMF (1.5 mL) was stirred and degassed with nitrogen. 1,1,3,3-Tetramethylguanidine (138 mg) in DMF (0.5 mL) was added and the mixture heated at 6O0C for 3 hours. The mixture was cooled, stirred, and diluted with water (20 mL). The solid formed was filtered off and dried at 60°C in vacuo. Purification by flash chromatography on silica using 0-50% MeOH in DCM as eluent, then trituration with DCM gave the title compound as a solid (212 mg, 52%); 1H ΝMR (DMSO-d6) 7.23 (s, 2H), 7.42 (d, IH), 7.55 (m, IH)5 7.67 (m, IH), 7.99 (d, IH), 8.04 (m, IH), 8.45 (s, 2H), 10.48 (bs, IH); MS m/e MH+ + MeCN 448.
Intermediate 1 5-[(TrimethyIsiIyl)ethynyl]pyrimidin~2-amine
Figure imgf000077_0002
PdCl2dppf (146 mg) was added to a solution of 2-amino-5-iodopyrimidine (221 mg), trimethylsilylacetylene (491 mg), CuI (57 mg) and DIPEA (259 mg) in EtOAc (5 mL) at -200C under an inert atmosphere. The reaction was allowed to warm to ambient temperature and stirred for 6 hours. The reaction mixture was diluted with water (10 mL). The organic layer was separated, dried (MgSO4), filtered and concentrated. The crude product was used directly without further purification (191 mg, 100%); 1R NMR (CDCl3) 0.26 (s, 9H), 5.19 (bs, 2H), 8.39 (s, 2H); MS m/e MH+HhMeCN 233.
Intermediate 2 5-Ethynylpyrimidin-2~amine
Figure imgf000078_0001
Potassium carbonate (276 mg) was added to a solution of 5- [(trimethylsilyl)ethynyl]pyrimidin-2-amine (Intermediate 1) (191 mg) in MeOH (40 mL)/water (20 mL). The reaction mixture was stirred at ambient temperature under an inert atmosphere for 24 hours then neutralised with IM HCl. The reaction mixture was then concentrated and the resultant residue dissolved in DCM (30 mL). The DCM phase was washed with water (15 mL), brine (15 mL), dried (MgSO4), filtered and concentrated. The crude product was used directly without further purification (119 mg, 100%); 1R NMR (CDCl3) 3.19 (s, IH), 5.26 (bs, 2H), 8.41 (s, 2H); MS m/e MH+H-MeCN 161.
Intermediate 3
5-Bromo-7V-[2-fluoro-5-(trifluoromethyl)phenyl]thiophene-2-carboxamide
Figure imgf000078_0002
5-Bromothiophene-2-carbonyl chloride (1.12 g) in dry DCM (5 mL) was added dropwise to a solution of 2-fluoro-5-(trifluoromethyl)aniline (0.90 g) and triethylamine (3 mL) in DCM and stirred for 60 hours at ambient temperature. The solvent was removed by evaporation and the residue was stirred with 40% aqueous sodium hydroxide (1.0 mL) in MeOH (10 mL) for 17 hours. The mixture was concentrated then partitioned between DCM and water. The organic phase was washed with 2M hydrochloric acid then aqueous sodium bicarbonate, dried, and filtered through a short silica column. Concentration, then crystallization from isohexane gave the product (0.51 g, 27%);
1K NMR (DMSOd6) 7.39 (d, IH), 7.58 (m, IH), 7.69 (m, IH), 7.89 (d, IH), 8.05 (m, IH),
10.45 (s, IH);
MS m/e MH++ CH3CN 411, 409 (1 x Br).
o Example 2
4-[(2-Aminopyrimidin-5-yl)ethynyl]-N-[2-fluoro-5- (trifluoromethyl)phenyl]thiophene-2-carboxamide
Figure imgf000079_0001
s The title compound was prepared in a similar manner to Example 1.
SM: 2-amino-5-ethynylpyrimidine (Intermediate 2), 4-bromo-N-[2-fluoro-5-
(trifluoromethyl)phenyl]thiophene-2-carboxamide (Intermediate 4)
1R ΝMR (DMSO-de) 7.13 (s, 2H), 7.57 (m, IH), 7.67 (m, IH), 8.06 (m, IH), 8.12 (d, 2H),
8.41 (s, 2H), 10.41 (bs, IH); o MS m/e MH+ + CH3CN 448.
Intermediate 4 4-bromo-iV-[2-fluoro-5-(trifluoromethyl)phenyl]thiophene-2-carboxamide
Figure imgf000079_0002
The title compound was prepared in a similar manner to Intermediate 3 except the product was isolated by trituration with isohexane.
SM: 4-bromothiophene-2-carbonyl chloride, 2-fluoro-5-(trifluoromethyl)aniline. 1H NMR (DMSO-d6) 7.58 (m, IH), 7.68 (m, IH), 8.08 (m, 3H), 10.47 (s, IH); MS m/e MH++ CH3CN 411, 409 (1 x Br).
Example 3
5-[(2-Aminopyrimidin-5-yI)ethynyl]-N-(5-tert-butylisoxazol-3-yl)thiophene-2- carboxamide
Figure imgf000080_0001
The title compound was prepared in a similar manner to Example 1. SM: 2-amino-5-ethynylpyrimidine (Intermediate 2), 5-bromo-N-(5-fert-butylisoxazol-3- yl)thiophene-2-carboxamide (Intermediate 5)
1H ΝMR (DMSO-d6) 1.30 (s, 9H), 6.67 (s, IH), 7.23 (s, 2H), 7.39 (d, IH), 8.09 (d, IH), 8.44 (s, 2H), 11.52 (bs, IH); MS m/e (M-H)- 366.
Intermediate 5
5-Bromo-iV-(5-te^-butyIisoxazol-3-yl)thiophene-2-carboxamide
Figure imgf000080_0002
The title compound was prepared in a similar manner to Intermediate 3. SM: 5-bromothiophene-2-carbonyl chloride, 5-fert-butylisoxazol-3-amine 1H NMR (DMSO-d6) 1.32 (s, 9H), 6.67 (s, IH), 7.37 (d, IH), 7.99 (d, IH), 11.51 (s, IH); MS m/e MH+ 331, 329 (1 x Br). Example 4 2-[(2-Aminopyrimidin-5-yl)ethynyl]-N-phenyl-l,3-thiazole-4-carboxamide
Figure imgf000081_0001
Triethylamine (300 mg) was added to a mixture of 2-[(2-aminopyrimidin-5-yl)ethynyl]- l,3-thiazole-4-carboxylic acid (Intermediate 7) (197 mg) and O-benzotriazol-1-yl- N,N,N\N'-tetramethyluronium hexafluorophosphate (606 mg) in DMF (5 mL) and stirred for 10 min. Aniline (149 mg) was added and stirred for 60 hours at ambient temperature. The mixture was concentrated then partitioned between EtOAc and aqueous sodium bicarbonate. The solid formed was filtered off, the EtOAc extract was washed with water, dried and concentrated in vacuo. The combined solids were triturated with 1 : 1 DCM - MeOH to give the title compound (126 mg, 46%); 1H NMR (DMSO-de) 7.11 (m, IH), 7.38 (m, 4H), 7.85 (m, 2H), 8.55 (m, 3H), 10.35 (s, IH);
MS m/e MH+ 322.
Intermediate 6
Ethyl 2-[(2-aminopyrimidin-5-yl)ethynyl]-l,3-thiazole-4-carboxylate
Figure imgf000081_0002
Triethylamine (10 mL) was added to a stirred mixture of 2-amino-5-ethynylpyrimidine (Intermediate 2) (1.19 g), ethyl 2-bromo-l,3-thiazole-4-carboxylate (2.36 g), dichlorobis(triphenylphosphine)palladium(II) (140 mg), and copper (I) iodide (70 mg) in dry THF (100 mL). The mixture was degassed with nitrogen and heated at 6O0C for 3 hours. The mixture was cooled, diluted with water, and concentrated. The solid formed was filtered off, washed with water then dried at 60°C in vacuo. Purification by flash chromatography on silica using 0-10% MeOH in DCM as eluent, then trituration with DCM / isohexane gave the title compound as a solid (1.5 g, 54%); 1H NMR (DMSO-de) 1.30 (t, 3H), 4.31 (q, 2H), 7.37 (s, 2H), 8.52 (s, 2H), 8.58 (s, IH); MS m/e MH+ 275.
Intermediate 7 2-[(2-Aminopyrimidin-5-yl)ethynyl]-l,3-thiazole-4-carboxylic acid
Figure imgf000082_0001
Ethyl 2-[(2-aminopyrimidin-5-yl)ethynyl]-l,3-thiazole-4-carboxylate (Intermediate 6) (1.2 g) was added to a stirred solution of sodium hydroxide (0.8 g) in water (40 mL) and heated at 70°C for 3 hours. The mixture was acidified with glacial AcOH, stirred and cooled. The solid formed was filtered off, washed with water and dried at 6O0C in vacuo to give the product (1.0 g, 92%);
1H NMR (DMSO-de) 7.37 (s, 2H), 8.50 (m, 3H); MS m/e MH+ 247.
Example 5 2-[(2-Aminopyrimidin-5-yl)ethynyl]-N-(2,2-dimethyltetrahydro-2H-pyran-4-yl)-l,3- thiazole-4-carboxamide
Figure imgf000082_0002
The title compound was prepared in a similar manner to Example 4. SM: 2-[(2-aminopyrimidin-5-yl)ethynyl]-l,3-thiazole-4-carboxylic acid (Intermediate 7), 4-amino-2,2-dimethyltetrahydropyran 1H NMR (DMSO-de) 1.14 (s, 3H), 1.20 (s, 3H), 1.43 - 1.72 (m, 4H), 3.65 (m, 2H), 4.18 (m, IH), 7.39 (s, 2H), 8.30 (d, IH), 8.36 (s, 2H).
Example 6 2-[(2-Aminopyrimidin-5-yl)ethynyl]-N-(5-tert-butylisoxazol-3-yI)-l,3-thiazoIe-4- carboxamide
Figure imgf000083_0001
The title compound was prepared in a similar manner to Example 4. SM: 2-[(2-aminopyrimidin-5-yl)ethynyl]-l,3-thiazole-4-carboxylic acid (Intermediate 7), 5-fert-butylisoxazol-3-amine.
1H NMR (DMSO-de) 1.33 (s, 9H), 6.66 (s, IH), 7.40 (s, 2H), 8.55 (s, 2H), 8.61 (s, IH), 11.02 (s, IH); MS m/e MH+ 369.
s Example 7
N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-3-tert-butyl-l-methyl-lH- pyrazole-5-carboxamide
Figure imgf000083_0002
Q DIPEA (387 mg) was added to a mixture of 5-[(5-ammopyridm-3-yl)ethynyl]pyrimidin-2- amine (Intermediate 11) (211 mg), 3-tert-butyl-l -methyl- lH-pyrazole-5-carboxylic acid (364 mg) and HBTU (642 mg) in DMF (3 mL) and stirred for 65 hours at ambient temperature. The mixture was added dropwise to stirred IM aqueous sodium hydroxide
(100 mL). The solid formed was filtered off, and purified by RPHPLC to give the title compound (121 mg, 32%);
1H NMR (DMSO-d6) 1.28 (s, 9H), 4.02 (s, 3H), 6.97 (s, IH), 7.19 (s, 2H) 8.32 (t, IH), 8.42
(d, IH), 8.47 (s, 2H), 8.79 (d, IH) 10.39 (br s, IH);
MS m/e MH+ 376.
Intermediate 8 tert-butyl (5-bromopyridin-3-yl)carbamate
Figure imgf000084_0001
Triethylamine (7 mL) followed by DPPA (10.9 mL) was added to a solution of 5- bromonicotinic acid (10.1 g) and t-BuOH (7.1 mL) in toluene (100 mL) and the reaction heated at reflux under an inert atmosphere for 1.5 hours. The reaction mixture was diluted with EtOAc (100 mL) and water (100 mL). The organic layer was separated, washed with NaHCO3 (3 x 50 mL), dried (MgSO4), filtered and concentrated in vacuo. The product was purified by flash chromatography on silica using 0-4% EtOAc in DCM as the eluent to give the title compound as a beige solid (9.82 g, 72%); 1H NMR (DMSO-dδ) 1.50 (s, 9H), 8.19 (t, IH), 8.30 (d, IH), 8.57 (d, IH), 9.80 (s, IH);
MS m/e MH+ 273/275.
Intermediate 9 tert-Butyl (5-iodopyridin-3-yl)carbamate
Figure imgf000084_0002
tert-Butyl (5-bromopyridin-3-yl)carbamate (Intermediate 8) (14.9 g), CuI (520 mg), NaI (16.35 g) and N,N-dimethylethylenediamine (481 mg) in dioxane (300 mL) were heated at
110°C under an inert atmosphere for 24 hours. The reaction mixture was concentrated in vacuo to approx 100 mL and then water (400 mL) was added. The resultant solid was filtered, dissolved in DCM, dried (MgSO4), filtered and concentrated to afford the title compound as a beige solid (15.18 g, 87%); MS nVe MH+ 321.
Intermediate 10 {5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yI}carbamate
Figure imgf000085_0001
PdCl2dppf (907 mg) was added to a degassed solution of tert-butyl (5-iodopyridin-3- yl)carbamate (Intermediate 9) (7.94 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (3.7 g), CuI (94 mg) and Et3N (63 mL) in DMF (250 mL). The reaction was allowed to stir at ambient temperature under an inert atmosphere for 24 hours. Silica was added to the reaction mixture and then solvent was evaporated in vacuo. The preabsorbed product was purified by flash chromatography on silica using 0-10% MeOH in DCM as the eluent followed by an aqueous wash and then dried in vacuo to give the title compound as a beige solid (5.3 g, 69%);
1H NMR (DMSO-d6) 1.51 (s, 9H), 7.20 (s, 2H)5 8.05 (s, IH)3 8.31 (s, IH), 8.48 (s, 2H), 8.57 (s, IH), 9.74 (s, IH);
MS m/e (M-H+)- 310.
Intermediate 11 5~[(5-aminopyridin-3-yl)ethynyl]pyrimidin~2~amine
Figure imgf000085_0002
TFA (25 mL) was added to a solution of tert-bntyl {5-[(2-aminopyrimidin-5- yl)ethynyl]pyridin-3-yl} carbamate (Intermediate 10) (2.92 g) in DCM (150 mL) under an inert atmosphere. The reaction was allowed to stir at ambient temperature for 3 hours. It was then diluted with water (100 mL) and the DCM removed in vacuo. The aqueous solution was neutralised with NaHCO3 and the resultant precipitate was filtered, washed with water and then dried in vacuo to give the title compound (2.00 g, 66%); 1H NMR (DMSO-de) 5.49 (s, 2H), 7.00 (s, IH), 7.88 (s, 2H), 8.44 (s, 2H); MS nVe MH+ 212.
The following Example was prepared in a similar manner to Example 7 by using Intermediate 11 with the appropriate acid.
Example 8 N-{5-[(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl}-3-(l-cyanoethyl)benzamide
Figure imgf000086_0001
SM: 5-[(5-aminopyridin-3-yl)ethynyl]pyrimidin-2-amine (Intermediate 11) and 3-(l- cyanoethyl)benzoic acid.
1H NMR (DMSO-de) 1-60 (d, 3H), 4.42 (q, IH), 7.19 (s, 2H) 7.63 (m, 2H), 7.96 (m 2H), 8.35 (t, IH), 8.44 (d, IH), 8.47 (s, 2H), 8.87 (d, IH) 10.59 (br s, IH); MS m/e MH+ 369.
Example 9
3-morpholin-4-yl-iV-[3-({2-[(3-morpholin-4-ylpropyl)amino]pyrimidin-5- yl}ethynyl)phenyl] benzamide
Figure imgf000087_0001
5- [(3 -aminophenyl)ethynyl] -N-(3 -morpholin-4-ylpropyl)pyrimidin-2-amine (Intermediate 13) (337 mg), 3-morpholin-4-ylbenzoic acid (248 mg) and HBTU (455 mg) were stirred in DMF (5 mL). DIPEA (0.42 niL) was added and the resultant mixture stirred for 16 hours. The reaction was poured into water (20 mL) and extracted with DCM (20 mL). The organics were evaporated and the residue purified by reverse phase HPLC to afford the title compound as a pale yellow solid (126 mg, 24%).
1H NMR (DMSO-d6) 10.2 (s, IH), 8.46 (s, 2H), 7.97 (s, IH), 7.75 (d, IH), 7.68 (t, IH), 7.44 (s, IH), 7.30-7.40 (m, 3H), 7.22 (d, IH), 7.14-7.19 (m, IH), 3.76 (t, 4H), 3.56 (t, 4H), 3.29-3.34 (m, 4H under water), 3.19 (t, 4H), 2.39 (t, 4H), 1.64-1.73 (m, 2H); MS m/e MH+ 527.
Intermediate 12 {3-[(2-chloropyrimidin-5-yl)ethynyl]phenyl}amine
Figure imgf000087_0002
Palladium (10 wt.%) on activated carbon (1.5 g) was added to a stirred solution of 5- bromo-2-chloropyrimidine (12.76 g) and 3-ethynyl aniline (9.28 g) in DIPEA (120 mL) under an inert atmosphere. The reaction mixture was stirred at 80°C for 4 hours. The reaction mixture was filtered through diatomaceous earth and washed with DCM. The filtrate was purified by flash chromatography on silica using 0-30% EtOAc in DCM as eluent. The resultant solid was triturated with ether to give the title compound as a cream solid (4.28 g, 28%); 1H NMR (DMSOd6) 5.31 (s, 2H), 6.64 (dd, IH), 6.69-6.76 (m, 2H), 7.08 (dd, IH), 8.94 (s, 2H); MS m/e (MH+ MeCN)+ 271.
Intermediate 13 5-[(3-aminophenyl)ethynyl]-iV-(3-morpholin-4-ylpropyl)pyrimidin-2-amine
Figure imgf000088_0001
{3-[(2-chloropyrimidin-5-yl)ethynyl]phenyl}amine (Intermediate 12) (0.7 g) and l-(3- aminopropyl)morpholine (2.22 g) and IM HCl in diethyl ether were heated at reflux in EtOH (50 mL) for 16 hours. The reaction mixture was concentrated in vacuo and purified by flash chromatography on silica using 0-10% MeOH in DCM as eluent. The product was obtained as a yellow solid (0.35 g);
1H NMR (DMSO-d6) 1.67 (m, 2H), 2.28-2.36 (m, 6H), 3.27-3.35 (m, 2H+H2O), 3.53-3.58
(m, 4H), 5.19 (s, 2H), 6.54-6.58 (m, IH), 6.60 (d, IH), 6.66 (s, IH), 7.01 (t, IH), 7.62 (t, IH), 8.66 (s, 2H);
MS m/e MH+ 338.
The following examples were made in a similar way to Example 7 using Intermediate 14 and the appropriate acid: Example 10
N-{3-[(2-aminopyrimidin~5~yl)ethynyl]phenyl}~2-fluoro-5- (trifluoromethyl)benzamide
Figure imgf000089_0001
SM: Intermediate 14, 2-fluoro-5-(trifluoromethyl)benzoic acid
1H NMR (DMSO-de) 7.12 (s, 2H), 7.23-7.27 (m, IH), 7.40 (t, IH), 7.57-7.62 (m, 2H), 7.95 (s, IH), 7.96-8.00 (m, IH), 8.05-8.09 (m, IH), 8.43 (s, 2H), 10.67 (br s, IH);
MS m/e MH+ 401.
Example 11
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyI}-3-methoxybenzamide
Figure imgf000089_0002
SM: Intermediate 14, 3-methoxybenzoic acid
1HNMR (DMSO-d6) 3.83 (s, 3H), 7.12 (s, 2H), 7.13-7.16 (m, IH), 7.17-7.19 (m, IH),
3.35-7.55 (m, 4H), 7.72-7.77 (m, IH), 7.97-8.00 (m, IH), 8.43 (s, 2H), 10.27 (br s, IH);
MS m/e MH+ 345. Example 12 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyI}-3-isopropoxybenzamide
Figure imgf000090_0001
SM: Intermediate 14, 3-isopropoxybenzoic acid
1HNMR (DMSO-d6) 1.29 (d, 6H), 4.65-4.77 (m, IH), 7.12 (s, 2H), 7.14-7.16 (m, IH),
7.21-7.24 (m, IH), 7.35-7.51 (m, 4H), 7.73-7.76 (m, IH), 7.99 (s, IH), 8.43 (s, 2H), 10.24
(br s, lH);
MS m/e MH+ 373.
Example 13
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-3-morphoIin-4-ylbenzamide
Figure imgf000090_0002
SM: Intermediate 14, 3-morpholin-4-ylbenzoic acid
1HNMR (DMSO-d6) 3.15-3.20 (m, 4H), 3.73-3.78 (m, 4H), 7.12 (s, 2H), 7.13-7.17 (m, IH), 7.20-7.23 (m, IH), 7.35-7.56 (m, 4H), 7.72-7.77 (m, IH), 7.96-7.98 (m, IH), 8.43 (s, 2H), 10.21 (br s, IH);
MS m/e MH+ 400. Example 14 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-3-(l-cyanoethyl)benzamide
Figure imgf000091_0001
SM: Intermediate 14, 3-(l-cyanoethyl)benzoic acid
1H NMR (DMSO-d6) 1.60 (d, 3H), 4.42 (q, IH), 7.12 (s, 2H), 7.21-7.26 (m, IH), 7.37-7.43 (m, IH), 7.57-7.64 (m, 2H), 7.72-7.77 (m, IH), 7.92-7.98 (m, 3H), 8.43 (s, 2H), 10.37 (br s, IH);
MS m/e MH+ 368.
Example 15 N-IS-ICl-aminopyrimidin-S-yOethynyllphenylJ-ljS-benzodioxoIe-S-carboxamide
Figure imgf000091_0002
SM: Intermediate 14, piperonylic acid
1H NMR (DMSOd6) 6.13 (s, 2H), 7.03-7.14 (m, 3H), 7.17-7.22 (m, IH), 7.33-7.39 (m,
IH), 7.49-7.58 (m, 2H), 7.70-7.73 (m, IH), 7.98 (s, IH), 8.42 (s, 2H), 10.12 (br s, IH);
MS m/e MH+ 359. Example 16
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-4-[(4-methylpiperazin-l- yl)methyl] benzamide
Figure imgf000092_0001
SM: Intermediate 14, 4-(N-methylpiperazinyl)methylbenzoic acid
1H NMR (DMSO-d6) 2.18 (s, 3H), 2.33-2.37 (m, 4H), 2.41-2.45 (m, 4H), 3.56 (s, 2H), 6.72 (br s, 2H), 7.21-7.24 (m, IH), 7.36 (t, IH), 7.43 (d, 2H), 7.73-7.77 (m, IH), 7.92 (d, 2H), 7.97-7.99 (m, IH), 8.42 (s, 2H), 9.98 (br s, IH);
MS nVe MH+ 427.
10
Example 17
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-3-tert-butyl-l-methyl-lH-pyrazole-5- carboxamide
Figure imgf000092_0002
I5 SM: Intermediate 14, 3-te^butyl-l-methylpyrazole-5-carboxylic acid
1H NMR (DMSO-ds) 1.28 (s, 9H), 4.03 (s, 3H), 6.72 (br s, 2H), 6.91 (s, IH), 7.22-7.25 (m,
IH), 7.36 (t, IH), 7.68-7.71 (m, IH), 7.90-7.92 (m, IH), 8.41 (s, 2H), 9.91 (br s, IH);
MS m/e MH+ 375.
20 Example 18
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-2,2-dimethyltetrahydro-2H-pyran-4- carboxamide
Figure imgf000093_0001
SM: Intermediate 14, 2,2-dimethyl-tetrahydro-2H-pyrane-4-carboxylic acid 1H NMR (DMSO-d6) 1.17 (s, 3H), 1.22 (s, 3H), 1.47-1.70 (m, 4H), 2.72-2.80 (m, IH), 3.58-3.71 (m, 2H), 6.71 (br s, 2H), 7.14-7.17 (m, IH), 7.30 (t, IH), 7.51-7.54 (m, IH), 7.79-7.81 (m, IH), 8.39 (s, 2H), 9.58 (br s, IH); MS nVe MH+ 351.
Intermediate 14 5-[(3-aminophenyI)ethynyl]pyrimidin-2-amine
2-Amino-5-iodopyrimidine (2.21 g), bis(triphenylphosphine)palladium dichloride (350 mg) and copper(I) iodide (40 mg) were stirred in DMF (100 mL)-triethylamine (20 niL) and degassed with nitrogen for 10 min. 3-Ethynyl aniline (1.29 g) was added and the mixture heated to 95°C for 2 hours. The solvent was evaporated and the residue was purified by trituration with DCM (20 mL) to give the title compound as a brown solid (1.25 g, 60%);
1H NMR (DMSO-d6) 5.21 (bs, 2H), 6.58-6.70 (m, 3H), 7.03-7.07 (m, 3H), 8.40 (s, 2H); MS HVe MH+ 211.
The following examples were made in a similar way to Example 7 by using Intermediate 15 and the appropriate amine: Example 19
2-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N-[2-fluoro-5- (trifluor omethyl)benzyl] acetamide
Figure imgf000094_0001
SM: Intermediate 15, 2-fluoro-5-(trifluoromethyl)benzylamine
1H NMR (DMSO-d6) 3.53 (s, 2H), 4.40 (d, 2H), 6.71 (br s, 2H), 7.27-7.39 (m, 4H), 7.41-
7.43 (m, IH), 7.60-7.67 (m, 2H), 8.32 (br s, IH), 8.38 (s, 2H);
MS m/e MH+ 429.
Example 20
2-{3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}-N-(2-morpholin-4-ylbenzyl)acetamide
Figure imgf000094_0002
SM: Intermediate 15, (2-morpholin-4-ylbenzyl)amine
1R NMR (DMSO-de) 2.81-2.85 (m, 4H), 3.52 (s, 2H), 3.69-3.73 (m, 4H), 4.40 (d, 2H), 6.71 (br s, 2H), 7.02-7.06 (m, IH), 7.10-7.13 (m, IH), 7.20-7.25 (m, 2H), 7.28-7.37 (m, 3H), 7.44 (s, IH), 7.98 (br s, IH), 8.38 (s, 2H); MS m/e MH+ 428. Inter mediate 15 {3-[(2-aminopyrimidin-5-yl)ethynyl]phenyl}acetic acid
Figure imgf000095_0001
A mixture of 5-ethynylpyrimidin-2-amine (intermediate 2) (1.04 g), 3-iodophenylacetic acid (2.29 g), copper iodide (83 mg) and triethylamine (2.7 rnL) in DMF (27 mL) was stirred and degassed with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (615 mg) was added and the mixture heated at 60°C for 3 hours. The mixture was cooled to room temperature, then diluted with a 2N aqueous solution of sodium hydroxide (110 mL) and washed with ethyl acetate (70 mL). The aqueous solution was acidified with a 2N aqueous solution of hydrochloric acid. On acidification to pH 4, a brown solid precipitated from the solution. The solid was collected by filtration then dried under vacuum for 20 hours, to give the title compound (2.40 g, 92%).
1H NMR (DMSO-de) 3.59 (s, 2H), 7.11 (br s, 2H), 7.25-7.39 (m, 4H), 8.41 (s, 2H), 12.31 (br s, lH);
MS m/e MH+ 254.
The following examples were made in a similar way to Example 7 by using Intermediate 16 and the appropriate amine: Example 21
S-ICI-aminopyrimidin-S-ylJethynyll-N-CIjZ-dimethyltetrahydro^H-pyran^- yl)benzamide
Figure imgf000096_0001
SM: Intermediate 16, 4-amino-2,2-dimethyltetrahydropyran
1H NMR (DMSOd6) 1.18 (s, 3H), 1.23 (s, 3H), 1.40-1.55 (m, 2H), 1.75-1.82 (m, 2H), 3.61-3.72 (m, 2H), 4.13-4.22 (m, IH), 6.74 (br s, 2H), 7.44-7.49 (m, IH), 7.59-7.62 (m, IH), 7.80-7.83 (m, IH), 7.95-8.00 (m, 2H), 8.42 (s, 2H);
Figure imgf000096_0002
Example 22
3- [(2-aminopyrimidin-5-yI)ethynyl] -N- [2-fluoro-5-(trifluoromethyl)benzyl] benzamide
Figure imgf000096_0003
SM: Intermediate 16, 2-fluoro-5-(trifluoromethyl)benzylamine 1R NMR (DMSO-d6) 4.40 (d, 2H), 6.74 (br s, 2H), 7.36-7.42 (m, IH), 7.48-7.52 (m, IH), 7.62-7.65 (m, IH), 7.66-7.70 (m, IH), 7.75-7.78 (m, IH), 7.85-7.88 (m, IH), 7.99-8.01 (m, IH), 8.41 (s, 2H), 8.85-8.90 (m, IH); MS nVe MH+ 415. Example 23
3-[(2-aminopyrimidin-5-yl)ethynyl]-N-(3-tert-butyI-l-methyl-lH-pyrazol-5- yl)benzamide
Figure imgf000097_0001
5 SM: Intermediate 16, 3-ter^-butyl-l-methyl-lH-pyrazol-5-amine
1H NMR (DMSO-d6) 1.27 (s, 9H), 3.64 (s, 3H), 6.09 (s, IH), 6.77 (br s, 2H), 7.53-7.57 (m,
IH), 7.68-7.71 (m, IH), 7.92-7.95 (m, IH), 8.06-8.08 (m, IH), 8.43 (s, 2H), 10.01 (br s,
IH);
Figure imgf000097_0002
0
Example 24 3-[(2-aminopyrimidin-5-yI)ethynyl]-N-(2-morpholin-4-ylbenzyI)benzamide
Figure imgf000097_0003
SM: Intermediate 16, (2-morphorin-4-ylben2yl)amine s 1H NMR (DMSO-de) 2.87-2.91 (m, 4H), 3.75-3.79 (m, 4H), 4.63 (d, 2H), 6.74 (br s, 2H), 7.05-7.10 (m, IH), 7.14-7.17 (m, IH), 7.22-7.27 (m, IH), 7.31-7.34 (m, IH), 7.47-7.51 (m, IH), 7.61-7.64 (m, IH), 7.86-7.90 (m, IH), 8.01-8.03 (m, IH), 8.42 (s, 2H), 8.63 (m, IH);
MS m/e MH+ 414.
o Intermediate 16 3-[(2-aminopyrimidin-5-yl)ethynyl]benzoic acid
Figure imgf000098_0001
A mixture of 5-ethynylpyrimidin-2-amine (intermediate 2) (2.00 g), 3-iodobenzoic acid (4.16 g), copper iodide (80 mg) and triethylamine (5.2 mL) in DMF (50 mL) was stirred and degassed with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (590 mg) was added and the mixture heated at 6O0C for 2 hours. The mixture was concentrated, then the residue dissolved in a IN aqueous solution of sodium hydroxide (350 mL) and washed with ethyl acetate (200 mL). The aqueous solution was acidified with a 2N aqueous solution of hydrochloric acid. On acidification to pH 3, a yellow solid precipitated from the solution. The solid was collected by filtration and washed with water (2 x 50 mL) then dried under vacuum for 20 hours, to give the title compound (4.27 g, 96%).
1H NMR (DMSOd6) 7.14 (br s, 2H), 7.53 (t, IH), 7.71 (d, IH), 7.91 (d, IH), 8.00 (s, IH), 8.45 (s, 2H), 13.12 (br s, IH); MS HVe MH+ 240.
The following examples were made in a similar way to Example 7 by using Intermediate 17 and the appropriate acid: Example 25 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]benzyl}benzamide
Figure imgf000099_0001
SM: Intermediate 17, benzoic acid 1H NMR (DMSO-d6) 4.51 (d, 2H), 6.70 (br s, 2H), 7.34-7.38 (m, 3H), 7.43-7.52 (m, 4H), 7.87-7.91 (m, 2H), 8.39 (s, 2H), 8.69 (m, IH); MS m/e MH+ 329.
Example 26 N-{3-[(2-aminopyrimidin-5-yl)ethynyl]benzyl}-3-tert-butyl-l-methyl-lH-pyrazole-5- carboxamide
Figure imgf000099_0002
SM: Intermediate 17, S-tert-butyl-l-methyl-lH-pyrazole-S-carboxylic acid 1R NMR (DMSO-de) 1.27 (s, 9Η), 4.00 (s, 3H), 4.43 (d, 2H), 5.65 (s, IH), 6.70 (br s, 2H), 7.32-7.39 (m, 3H), 7.45 (s, IH), 8.39 (s, 2H), 8.56-8.81 (m, IH); MS m/e MH+ 389. Intermediate 17
5-{ [3-(aminomethyl)phenyl] ethynyl}pyrimidin-2-amine
Figure imgf000100_0001
A mixture of 5-ethynylpyrimidin-2-amine (intermediate 2) (2.40 g), 3-iodoben2ylamine (4.89 g), copper iodide (96 mg) and triethylamine (3.4 mL) in DMF (50 niL) was stirred and degassed with nitrogen. Dichlorobis(triphenylphosphine)palladium(II) (705 mg) was added and the mixture heated at 60°C for 2 hours. The mixture was concentrated in vacuo, then water (100 mL) was added, and the mixture slurried for 10 min, then the solid was collected by filtration. Purification by flash chromatography on silica using 5-10% 2N NH3MeOH in DCM as eluent afforded the title compound as a yellow solid (2.48 g, 55%);
1H NMR (DMSO-d6) 1.83 (br s, 2H), 3.72 (s, 2H), 7.09 (br s, 2H), 7.31-7.33 (m, 3H), 7.47 (s, IH), 8.40 (s, 2H);
MS m/e MH+ 225.
Example 27
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-4-methoxyphenyl}-3-[4-(trifluoromethyl) phenyl] propanamide
Figure imgf000100_0002
5-(5-Amino-2-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 19) (0.17 g), 3- [4-(trifluoromethyl)phenyl]propionic acid (0.17 g), HATU (0.32 g) and DIPEA (0.25 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5- 5.0% MeOH in DCM as eluent gave the title compound as a white solid (119 mg, 39%);
1H NMR (300.132 MHz, DMSO) D 9.85 (s, IH), 8.39 (s, 2H), 7.72 (s, IH), 7.65 (d, 2H), 7.50 - 7.43 (m, 3H), 7.10 (s, 2H), 7.01 (d, IH), 3.81 (s, 3H), 3.01 (t, 2H), 2.65 (t, 2H); s MS nVe MH+ 441.
Intermediate 18 »
5-(2-Methoxy-5-nitro-phenylethynyl)-pyrimidin-2-yIamine
Figure imgf000101_0001
10 A mixture of 4-iodo-2-nitroanisole (5.0 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (2.3 g), copper (I) iodide (27 mg) and bis(triphenylphosphine)palladium (II) chloride (176 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 6O0C for 3 hours. The reaction was filtered and the DMF was removed in vacuo to give a black gum/solid. DCM (100 mL) was added and the orange
I5 solid was filtered and dried (3.2 g, 67%);
1H NMR (300.074 MHz, dmso) D 8.43 (s, 2H), 8.25 - 8.22 (m, 2H), 7.29 (d, IH), 7.18 (s, 2H), 3.99 (s, 3H); MS m/e MH+ 271.
Intermediate 19 20 5-(5-Amino-2-methoxy-phenylethynyl)-pyrimidin-2-yIamine
Figure imgf000101_0002
A mixture of 5-(2-Methoxy-5-nitro-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 18) (3.2 g), indium powder (5.4 g) and cone HCl (1.8 mL) was stirred in THF/water (75 mL / 225 niL) overnight. The reaction was basified with aqueous potassium carbonate and the slurry was filtered through a pad of diatomaceous earth, the filtrate was extracted with EtOAc (3 x 200 mL), dried (MgSO4) and the solvent removed in vacuo to yield a black solid. Purification by flash chromatography on silica using 0-2.5% MeOH in DCM as s eluent gave the title compound as a white solid (1.2 g, 42%);
1H NMR (300.074 MHz, dmso) D 8.34 (s, 2H), 7.04 (s, 2H), 6.77 (d, IH), 6.66 (s, IH), 6.58 (d, IH), 4.78 (s, 2H), 3.70 (s, 3H); MS nVe MH+ 241.
o Example 28
N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-6-methylpyridin-3-yl}-3-[4-(trifluoro methyl)phenyl]propanamide
Figure imgf000102_0001
s 5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 21) (0.17 g), 3-[4-(trifluoromethyl)phenyl]propionic acid (0.22 g), HATU (0.38 g) and DIPEA (0.27 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-5.0% MeOH in DCM as eluent gave the title compound as a white solid (182 0 mg, 56%);
1HNMR (300.132 MHz, DMSO) D 10.17 (s, IH), 8.48 (s, 3H), 8.15 (s, IH), 7.66 (d, 2H), 7.49 (d, 2H), 7.19 (s, 2H), 3.02 (t, 2H), 2.71 (t, 2H), 2.57 (s, 3H); MS m/e MH+ 426.
5 Intermediate 20 5-(2-Methyl-5-nitro-pyridin-3-yIethynyl)-pyrimidin-2-ylamine
Figure imgf000103_0001
A mixture of 3-nitro-5-bromo-6-methylpyridine (5.0 g), 5-ethynylpyrimidin-2-amine
(Intermediate 2) (3.0 g), copper (I) iodide (18 mg) and bis(triphenyl phosphine)palladium
(II) chloride (226 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 6O0C for 3 hours. The reaction was cooled and filtered (3.2 g, 54%);
1U NMR (300.074 MHz, dmso) D 9.18 (s, IH), 8.56 (s, IH), 8.52 (s, 2H), 7.28 (s, 2H),
2.76 (s, 3H);
MS m/e MH+ 256.
Intermediate 21 5-(5-Amino-2-methyI-pyridin-3-ylethynyl)-pyrimidin-2-ylamine
Figure imgf000103_0002
5-(2-Methyl-5-nitro-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 20) (3.2 g) and iron powder (2.1 g) were added to glacial acetic acid (90 mL) and heated at 6O0C for 3 hours. The reaction was filtered and the solvent removed in vacuo to give a black, viscous oil. Acetone (100 mL) and water (100 mL) were added to the viscous oil, this was then basified with potassium carbonate, a portion of hot EtOAc (200 mL) was added and the residue was passed through a plug of diatomaceous earth. The filtrate was extracted with hot EtOAc (3 x 200 mL), dried (MgSO4) and the solvent removed in vacuo to yield a off white solid (1.2 g, 43%); 1HNMR (300.074 MHz, dmso) D 8.41 (s, 2H), 7.81 (s, IH), 7.12 (s, 2H), 6.96 (s, IH), 5.19 (s, 2H), 2.42 (s, 3H);
MS nVe MH+ 226.
Example 29
N-{3-[(2-aminopyrimidin-5-yl)ethynyl]-2-methoxyphenyl}-3-[4-(trifluoromethyl )phenyl]propanamide
Figure imgf000104_0001
5-(5-Amino-6-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 23) (0.17 g), 3- [4-(trifluoromethyl)phenyl]propionic acid (0.20 g), HATU (0.35 g) and DIPEA (0.33 niL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5-5.0% MeOH in DCM as eluent gave the title compound as a white solid (123 mg,
1H NMR (300.132 MHz, DMSO) D 9.36 (s, IH), 8.44 (s, 2H), 7.99 (d, IH), 7.66 (d, 2H), 7.51 (d, 2H), 7.20 (d, IH), 7.15 (s, 2H)3 7.07 (t, IH), 3.84 (s, 3H), 3.02 (t, 2H), 2.81 (t, 2H); MS nVe MH+ 441.
Intermediate 22 5-(6-Methoxy-5-nitro-phenylethynyl)-pyrimidin-2-yIamine
Figure imgf000105_0001
A mixture of l-iodo-2-methoxy-3-nitro-benzene (5.0 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (2.1 g), copper (I) iodide (27 mg) and bis(triphenylphosphine) palladium (II) chloride (176 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 6O0C for five hours. The DMF was removed in vacuo to yield a black gum/solid. DCM (100 mL) was added and the solid was filtered and dried (3.2 g, 65%); 0 1H NMR (300.074 MHz, dmso) D 8.47 (s, 2H), 7.87 (d, IH), 7.79 (d, IH), 7.33 (t, IH), 7.23 (s, 2H), 4.05 (s, 3H); MS m/e MH+ 271.
Intermediate 23 5 5~(5-Amino-6-methoxy-phenylethynyl)-pyrimidin-2-ylamine
Figure imgf000105_0002
A mixture of 5-(6-methoxy-5-nitro-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 22) (3.2 g) and iron powder (2.0 g) was stirred at 6O0C for 7 hours in glacial acetic acid (50 mL). The reaction was filtered and the solvent removed in vacuo to yield a black tar. o Water (70 mL) and 10% MeOH / EtOAc (100 mL) were added then basified with potassium carbonate, extracted with hot 10% MeOH / EtOAc (3 x 200 mL), dried (MgSO4) and the solvent removed in vacuo to yield a yellow solid (2.2 g, 76%); 1HNMR (300.074 MHz, dmso) D 8.38 (s, 2H), 7.08 (s, 2H), 6.80 (t, IH), 6.69 (d, IH), 6.61 (d, IH), 5.02 (s, 2H), 3.80 (s, 3H);
MS nVe MH+ 241.
Example 30
N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-2-methylpyridin-3-yl}-3-[4-(trifluoro methyl)phenyl]propanamide
Figure imgf000106_0001
5-(5-Amino-6-methyl-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 27) (0.17 g), 3-[4-(trifluoromethyl)phenyl]propionic acid (0.22 g), HATU (0.38 g) and DIPEA (0.27 niL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. The solid was added to 50% MeOH / DCM and sonicated for 20 minutes, the title compound was filtered and dried (129 mg, 40%); 1HNMR (300.132 MHz, DMSO) D 9.50 (s, IH), 8.45 (s, 2H), 8.36 (s, IH), 7.94 (s, IH), 7.67 (d, 2H), 7.51 (d, 2H), 7.17 (s, 2H), 3.03 (t, 2H), 2.77 (t, 2H), 2.35 (s, 3H);
MS m/e MH+ 426.
Intermediate 24 2-(5-Bromo-3-nitro-pyridin-2-yl)-maIonic acid diethyl ester
Figure imgf000107_0001
Sodium hydride (4.0 g) was dissolved in DMF (60 mL) to this was slowly added diethylmalonate (12.7 g) under an inert atmosphere. Once the addition was complete the reaction was stirred for 10 minutes. 5-Bromo-2-chloro-3-nitro-pyridine (10 g) in DMF (20 mL) was slowly added to the anion, the reaction was maintained at approximately 4O0C for 1 hour before being quenched with water (100 mL), extracted with diethyl ether (3 x 250 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow oil (12.6 g, 86%); 1H NMR (300.072 MHz, cdcl3) D 8.87 (s, IH), 8.62 (s, IH), 5.46 (s, IH), 4.30 (q, 4H), 1.29 (t, 6H); MS m/e MH+ 352.
Intermediate 25 5-Bromo-2-methyl-3-nitro-pyridine
Figure imgf000107_0002
2-(5-Bromo-3-nitro-pyridin-2-yl)-malonic acid diethyl ester (Intermediate 24) (12.6 g) was added to 7.0 N HCl (100 mL) and heated to reflux for 5 hours, the reaction was cooled, extracted with diethyl ether (3 x 250 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow oil. Purification by flash chromatography on silica using 20% diethylether in iso-hexane as eluent gave the title compound as a yellow waxy solid (7.5 g, 96%); 1H NMR (300.072 MHz, cdcl3) D 8.79 (s, IH), 8.43 (s, IH), 2.83 (s, 3H). Intermediate 26 5-(6-Methyl-5-nitro-pyridin-3-ylethynyl)-pyrimidin-2-ylamine
Figure imgf000108_0001
A mixture of 5-bromo-2-methyl-3-nitro-pyridine (Intermediate 25) (5.0 g), 5- ethynylpyrimidin-2-amine (Intermediate 2) (3.0 g), copper (I) iodide (34 mg) and bis(triphenyl phosphine)palladium (II) chloride (225 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 6O0C for three hours. The reaction was allowed to cool and filtered, the filtrate was removed in vacuo to yield a black solid, DCM (100 mL) was added and the slurry filtered to yield a brown solid (6.7 g), impure sample;
1H NMR (300.074 MHz, dmso) D 8.86 (s, IH), 8.49 - 8.47 (m, 3H), 7.25 (s, 2H), 2.77 (s, 3H); MS m/e MH+ 256.
Intermediate 27 5-(5-Amino-6-methyI-pyridin-3-ylethynyI)-pyrimidin-2-ylamine
Figure imgf000108_0002
5-(6-Methyl-5-nitro-pyridin-3-ylethynyl)-pyrimidin-2-ylamine (Intermediate 26) (6.7 g) and iron powder (2.6 g) were added to glacial acetic acid (90 mL) and heated at 6O0C for 1 hour. The reaction was filtered and the solvent removed in vacuo to yield a viscous oil. Acetone (100 mL), water (100 mL) and methanol (30 mL) were added to the viscous oil, this was then basified with potassium carbonate, extracted with hot 10% MeOH / EtOAc (3 x 200 mL), dried (MgSO4) and solvent removed in vacuo to yield a brown solid (2.6 g, 50% over two steps); 1H NMR (300.074 MHz, dmso) D 8.39 (s, 2H), 7.78 (s, IH), 7.10 (s, 2H), 6.98 (s, IH), 5.20 (s, 2H), 2.27 (s, 3H);
MS m/e MH+ 226.
Example 31
N-{5-[(2-aminopyrimidin-5-yl)ethynyl]-2-methoxyphenyI}-3-[4-(trifluoro methyl)phenyl]propanamide
Figure imgf000109_0001
5-(5-Amino-4-methoxy-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 29) (0.17 g), 3- [4-(trifluoromethyl)phenyl]propionic acid (0.19 g), HATU (0.35 g) and DIPEA (0.33 mL) were added to DMF (6 mL) and stirred at room temperature for 1 hour. Water (10 mL) was added and the solid was filtered. Purification by flash chromatography on silica using 2.5- 10% MeOH in DCM as eluent gave the title compound as a white solid (159 mg, 51%); 1U NMR (300.132 MHz, DMSO) D 9.22 (s, IH), 8.41 (s, 2H), 8.12 (s, IH), 7.64 (d, 2H), 7.51 (d, 2H), 7.21 (s, IH), 7.06 (s, 3H), 3.85 (s, 3H), 3.06-2.94 (m, 2H), 2.85-2.71 (m, 2H); MS m/e MH+ 441.
Intermediate 28 5-(4-Methoxy-5-nitro-phenylethynyl)-pyrimidin-2-ylamine
Figure imgf000109_0002
A mixture of l-bromo-4-methoxy-3-nitro-benzene (5.0 g), 5-ethynylpyrimidin-2-amine (Intermediate 2) (2.8 g), copper (I) iodide (33 mg) and bis(triphenylphosphine) palladium (II) chloride (212 mg) in DMF (90 mL) was stirred under an inert atmosphere. TEA (18 mL) was added and the reaction was stirred at 6O0C for 16 hours. The DMF was removed in vacuo to give a black solid. DCM (100 mL) was added and the solid was filtered and dried (10 g, impure); MS m/e MH+ 271.
Intermediate 29 5-(5-Amino-4-methoxy-phenylethynyl)-pyrimidin-2-ylamine
Figure imgf000110_0001
A mixture of 5-(4-methoxy-5-nitro-phenylethynyl)-pyrimidin-2-ylamine (Intermediate 28) (10 g) and iron powder (4.7 g) was stirred at 6O0C for five hours in glacial acetic acid (50 mL). The reaction was filtered and the filtrate was removed in vacuo to yield a yellow solid. Purification by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent gave the title compound as a yellow solid (2.5 g, 48% over two steps);
1H NMR (300.074 MHz, dmso) 68.35 (s, 2H), 7.00 (s, 2H), 6.79 (d, IH), 6.74 (s, IH), 6.69 (d, IH), 4.86 (brs, 2H), 3.77 (s, 3H);
MS m/e MH+ 241.
The following example was made in a similar way to Example 7 using intermediate 17 and the appropriate acid. Example 32
N-[[3-[2-(2-aminopyrimidin-5-yl)ethynyl]phenyl]methyl]-3~
(trifluoromethyl)benzamide
Figure imgf000111_0001
SM: Intermediate 17, 3-(trifluoromethyl)benzoic acid
1H NMR (DMSO-de) Q4.53 (d, 2H), 6.71 (br s, 2H), 7.40 - 7.35 (m, 3H), 7.49 (s, IH), 7.71 (t, IH), 7.86 (d, IH), 8.22 - 8.17 (m, 2H), 8.39 (s, 2H), 8.99 (br s, IH); MS m/e MH+ 397.
The following example was made in a similar way to example 9 using Intermediate 31 and the appropriate acid.
Example 33
3-(l-cyanoethyl)-N-[6-methyl-5-[2-[2-(2-morpholin-4-ylethylamino)pyrimidin-5- yl]ethynyI]pyridine-3-yl]-benzamide
Figure imgf000111_0002
SM: [5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-moφholin-4-yl- ethyl)-amine (Intermediate 31) and 3-(l-cyanoethyl)benzoic acid. 1H NMR (DMSO-de) 10.5 (s, IH), 8.75 (s, IH), 8.5 (s, 2H), 8.3 (s, IH), 8.0 (m, 2H), 7.6 (m, 3H), 4.45 (m, IH), 3.6 (m, 4H), 3.45(m, 2H), 2.6 (s, 3H), 2.4 (m, 4H), 1.6 (d, 3H). MS m/e MH+ 496.
Intermediate 31
[5-(5-Amino-2-methyl-pyridin-3-ylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yI-ethyI)- amine
Figure imgf000112_0001
(5-Bromo-pyrimidin-2-yl)-(2-morpholin-4-yl-ethyl)-amine (Intermediate 32) (7.0 g), PdCl2(PPh3);! (0.17 g), triphenylphosphine (0.2 g) and 5-ethynyl-6-methyl-pyridin-3- ylamine (Intermediate 41- see below) (3.54 g) were added to piperidine (70 mL) and heated at reflux for 2 hours. The piperidine was then removed in vacuo to yield a yellow gum. This was dissolved in water (200 mL), extracted with DCM (2 x 250 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow gum. The gum was dissolved in hot DCM, trituration with diethyl ether precipitated a yellow solid. Purification of the remaining liquor was achieved by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent gave the title compound as a yellow solid (6.5 g, 78%); 1H NMR (300.132 MHz, CDC13) δ 8.41 (s, 2H), 7.00 (d, IH), 6.81 (s, IH), 6.59 (d, IH), 5.84 (brs, IH), 3.72 (t, 4H), 3.56 - 3.50 (m, 4H), 2.60 (t, 2H), 2.49 (t, 4H), 2.36 (s, 3H); MS m/e MH+ 339. Intermediate 32 (5-Bromo-pyrimidin-2-yl)-(2-morphoIin-4-yl-ethyl)-amine
Figure imgf000113_0001
2-Chloro-5-bromopyrimidine (100 g) was added to propan-2-ol (700 mL), DIPEA (184 niL) and aminoethylmorpholine (80.8 g), then heated at 8O0C for 7 hours. The reaction was allowed to cool and the solvent removed in vacuo to yield an orange gum, this was quenched with water (200 mL), extracted with diethyl ether (3 x 600 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow viscous oil. Trituration with diethyl ether (100 mL) gave a solid, which was stirred in iso-hexane (200 mL) for 20 mins before being filtered and dried. White solid obtained (118g, 79%);
1H NMR (300.072 MHz, cdcl3) δ 8.28 (s, 2H), 5.73 (s, IH), 3.72 (t, 4H), 3.46 (q, 2H), 2.59 (t, 2H), 2.49 (t, 4H); MS m/e MH+ 288.
The following example was made in a similar way to Example 27 using the appropriate amine intermediate and the appropriate acid and using RP-HPLC for purification.
Example 34
N-[4-methyl-3-[2-[2-(3-morpholin-4-ylpropylamino)pyrimidin-5-yl]ethynyl]phenyl]-3- (trifluoromethyl)benzamide
Figure imgf000113_0002
SM: 5-[2-(5-amino-2-methyl-phenyl)ethynyl]-N-(3-moφholin-4-ylpropyl)pyrimidin-2- amine (Intermediate 36, 3-(trifluoromethyl)benzoic acid
1H NMR (DMSO-d6) δlθ.45 (s, IH), 8.49 (s, 2H), 8.31 (s, IH), 8.27 (d, IH), 7.98 (d, IH), 7.95 (s, IH), 7.80 (t, IH)3 7.70 (t, IH), 7.66 (d, IH), 7.31 (d, IH), 3.57 (t, 4H), 3.35 (q, 2H), 2.43 (s, 3H), 2.36 - 2.32 (m, 6H), 1.70 (quintet, 2H) MS m/e MH+ 524.
Intermediate 33 (5-Bromo-pyrimidin-2-yl)-(3-morpholin-4-yl-propyl)-amine
Figure imgf000114_0001
2-Chloro-5-bromopyrimidine (50 g) was added to propan-2-ol (300 niL), DIPEA (92 mL) and aminopropylmorpholine (46 mL) and the reaction was heated at 8O0C for 3 hours. The reaction was allowed to cool and the solvent removed in vacuo to yield an orange gum, this was quenched with water (200 mL), extracted with diethyl ether (3 x 600 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow viscous oil. Diethyl ether (100 mL) was rapidly added to the gum with scratching until a solid crashed out, this was filtered. Process repeated on the filtered mother liquor until no solid crashed out. The obtained solids were combined and stirred in iso-hexane (200 mL) for 20 mins before being filtered and dried. White solid obtained (67g, 86%); 1H NMR (CDCl3) δ 8.25 (s, 2H), 6.02 (s, IH), 3.73 (t, 4H), 3.45 (q, 2H), 2.49 - 2.44 (m, 6H), 1.78 (quintet, 2H); MS m/e MH+ 302. Intermediate 34 4-(5-Amino-2-methyl-phenyl)-2-methyl-but-3-yn-2-oI
Figure imgf000115_0001
3-Iodo-4-methylaniline (100 g), bis(triphenylphosphine)palladium (II) chloride (6.0 g), triphenylphosphine (112 g) and 2-methyl-but-3-yn-2-ol (83 mL) were added to piperidine (600 mL) and stirred at reflux under an inert atmosphere for 4 hours. The piperidine was removed in vacuo to afford a viscous black sludge. The slurry was stirred in diethyl ether (300 mL) before being acidified with aqueous citric acid (500 mL). The aqueous was washed with another portion of diethyl ether (150 mL), the ether layers were combined and re-extracted with aqueous citric acid (500 mL), the combined aqueous layer was then basified with potassium carbonate, extracted with diethyl ether (3 x 500 mL), dried (MgSO4) and the solvent removed in vacuo to yield a black viscous oil. The oil was dissolved in 80% diethyl ether/iso-hexane and passed down a 4 inch plug of silica eluting with 80% diethyl ether/iso-hexane. On removal of the solvent an orange oil was obtained which solidified overrnight (87g); MS nVe MH+ IPO.
Intermediate 35 3-Ethynyl-4-methyI-phenyIamine
Figure imgf000115_0002
4-(5-Amino-2-methyl-phenyl)-2-methyl-but-3-yn-2-ol (Intermediate 34) (81 g) was added to toluene, then powdered NaOH (25.8 g) and the reaction was heated at reflux for 6 hours. The toluene was removed in vacuo, aqueous NaHCO3 (300 mL) added, extracted with diethyl ether (3 x 400 mL), dried (MgSO4) and the solvent removed in vacuo to yield a black oil. Compound purified via bulb-to-bulb distillation at 0.30 mbar @ 12O0C. Slightly yellow oil obtained (47g, 84% over two steps); 1H NMR (300.072 MHz, cdcl3) δ 6.97 (d, IH), 6.80 (s, IH), 6.60 (d, IH), 3.53 (bra, IH), 3.20 (s, IH), 2.33 (s, 3H).
Intermediate 36 5-[2-(5-amino-2-methyl-phenyl)ethynyl]-N-(3-morpholin-4-ylpropyl)pyrimidin-2- amine
Figure imgf000116_0001
Intermediate 33 (15g, 49.8 mmol), PdCl2(PPh3)2 (0.35g, 0.50mmol), PPh3 (1.3g, 4.98 mmol) and 3-ethynyl-4-methyl-phenylamine (intermediate 35) (6.8 g, 52.3 mmol) were added to piperidine (150 ml) and heated at reflux for 2 hours. The piperidine was then removed in vacuo to yield a yellow solid. This solid was dissolved in water (200 ml) and the aqueous was extracted with DCM (3 x 250 ML), dried (MgSO4) and solvent removed in vacuo to yield a yellow solid. This solid was recrystalised from DCM/ether to give a solid. The remaining solvate was purified by flash chromatography on silica eluting with DCM, 2.5% MeOH/DCM, 5% MeOH/DCM and finally 10% MeOH/DCM. Both solids were combined to give the title compound as a yellow solid (14.6g);
1H NMR (CDCB) D 8.40 (s, 2H), 7.00 (d, IH), 6.81 (s, IH), 6.59 (d, IH), 6.14 (t, IH), 3.74 (t, 4H), 3.61 - 3.49 (m, 4H), 2.50 - 2.45 (m, 6H), 2.36 (s, 3H), 1.80 (quintet, 2H); MS m/e MH+ 352. Example 35 N-[5-[2-(2-aminopyrimidin-5-yl)ethynyl]pyridin-3-yl]-3-morpholin-4-yl-benzamide
DIPEA (387 mg) was added to a mixture of 5-[(5-aminopyridin-3-yl)ethynyl]pyrimidin-2- amine (Intermediate 11) (211 mg), 3-morpholin-4-ylbenzoic acid (414 mg) and HBTU (642 mg) in DMF (3 mL) and stirred for 65 hours at ambient temperature. The mixture was purified by RPHPLC. Product fractions were made basic with aqueous ammonia and concentrated to low volume. The solid formed was filtered off and dried to give the product (179 mg, 44%).
1H NMR (DMSO-de) 3.20 (m, 4H), 3.76 (m, 4H), 7.18 (m, 3H), 7.39 (m, 2H), 7.46 (m, IH), 8.33 (m, IH), 8.42 (m, IH), 8.49 (s, 2H), 8.87 (m, IH), 10.42 (s, IH); MS m/e MH+ 401.
Example 36 3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-(l-propan-2-ylpyrazol-3-yl)-benzamide
Figure imgf000117_0002
DIPEA (129 mg) was added to a mixture of 3-[(2-aminopyrimidin-5-yl)ethynyl]benzoic acid (Intermediate 16) (119 mg), 3-amino-l-isopropylpyrazole (Intermediate 37) (63 mg) and HATU (379 mg) in DMF (1.5 mL) and stirred for 17 hours at ambient temperature. The mixture was diluted with IM aqueous sodium hydroxide and extracted with EtOAc. The extract was washed with brine, dried, and the solvent evaporated. Purification of the residue by RPHPLC gave the product as a solid (11 mg, 6%). MS nVe MH+ 347.
Intermediate 37
3-Amino-l-isopropylpyrazoIe
Figure imgf000118_0001
Isopropylhydrazine hydrochloride (743 mg) was stirred with potassium carbonate (2.76 g) in water (15 mL) and 2-chloroacrylonitrile (870 mg) was added. The mixture was heated at 50 0C for 1 hour and then extracted with EtOAc. The extract was washed with brine, dried and the solvent evaporated to give crude product as a brown oil (630 mg, 74%) which was used in subsequent procedures without further purification; 1H NMR (DMSO-d6) 1.32 (d, 6H), 4.17 (m, IH), 4.51 (s, br, 2H), 5.34 (d, IH), 7.30 (d, IH).
The following example was made in a similar way to Example 36 using intermediate 16 and the appropriate amine.
Example 37
3-[2-(2-aminopyrimidin-5-yl)ethynyl]-N-(5-cyclopropyl-2-methyl-pyrazol-3-yI)- benzamide
Figure imgf000119_0001
SM: Intermediate 16, 5-cyclopropyl-2-methyl-pyrazole-3-amine. MS m/e MH+ 359.
The following examples were made in a similar way to Example 7 using the appropriate amines and acids.
Example 38
2-methyl-N-[3-[2-[4-(3-morpholin-4-ylpropylamino)phenyl]ethynyl]phenyl]-5-tert- butyl-pyrazole-3-carboxamide
Figure imgf000119_0002
SM: 5-[(3-aminophenyl)ethynyl]-N-(3-morpholin-4-ylpropyl)pyrimidin-2-amine (Intermediate 13), 2-methyl-5-tert-butyl pyrazole-3-carboxylic acid. 1H NMR (DMSO-d6) 1.27 (s, 9H), 1.61-1.76 (m, 2H), 2.27-2.38 (m, 6H), 3.23-3.39 (m, 2H under water peak), 3.55 (t, 4H), 4.02 (s, 3H), 6.95 (s, IH), 7.22 (d, IH), 7.38 (t, IH), 7.67 (d, 2H), 7.95 (s, IH), 8.39-8.52 (br s, 2H), 10.20 (s, IH); MS nVe MH+ 502.
Example 39
3-(l-cyanoethyl)-N-[3-[2-[2-(3-morpholin-4-yIpropylamino)pyrimidin-5- yl]ethynyl]phenyl]-benzamide
Figure imgf000120_0001
0
SM: 5-[(3-aminophenyl)ethynyl]-N-(3-moφholin-4-ylpropyl)pyrimidm-2-amine
(Intermediate 13), 3-(l-cyanoethyl)benzoic acid..
1H NMR (DMSOd6) 1.60 (d, 3H), 1.63-1.75 (m, 2H), 1.18-2.39 (m, 6H), 3.24-3.37 (m, 4H S under water peak), 3.56 (t, 2H), 4.42 (q, IH), 7.24 (d, IH), 7.39 (t, IH), 7.54-7.78 (m, 4H), 7.93 (d, 2H), 7.97 (s, IH), 8.40-8.53 (br s, 2H), 10.36 (s, IH); MS nVe MH+ 495.
Example 40 o N-[4-methyI-3-[2-[2-(2-morpholin-4-ylethylamino)pyrimidin-5-yl]ethynyI]phenyl]-3- morpholin-4-yl-benzamide
Figure imgf000120_0002
SM: [5-(5-Amino-2-methyl-phenylethynyl)-pyrimidin-2-yl]-(2-moφliolin-4-yl-ethyl)- amine (Intermediate 40), 3-moφholin-4-ylbenzoic acid.
1R NMR (DMSO-d6) 2.40 (t, 6H), 3.19 (t, 4H), 3.28 (s, 3H under water), 3.43 (q, 2H), 3.56 (t, 4H), 3.76 (t, 4H), 7.11-7.19 (m, IH), 7.26 (d, IH), 7.34-7.39 (m, 2H), 7.44 (s, IH), 7.49 (t, IH), 7.64 (d, IH), 7.91 (d, IH), 8.44-8.51 (br s, 2H), 10.11 (s, IH); MS nVe MH+ 527.
Intermediate 40
[5-(5-Amino-2-methyl-phenylethynyl)-pyrimidin-2-yl]-(2-morpholin-4-yl-ethyl)- amine
Figure imgf000121_0001
(5-Bromo-pyrimidin-2-yl)-(2-morpholm-4-yl-ethyl)-amine (Intermediate 32) (15 g), PdC12(PPh3)2 (0.37 g), triphenylphosphine (0.7 g) and 3-ethynyl-4-methyl-phenyl amine (Intermediate 23) (8.2 mL) were added to piperidine (150 mL) and heated at reflux for 2 hours. The piperidine was then removed in vacuo to yield a yellow solid. Water (200 mL) was added, this was extracted with DCM (2 x 250 mL), dried (MgSO4) and solvent removed in vacuo to yield a yellow solid. The solid was dissolved in a minimum amount of hot DCM, and then diethyl ether added to precipitate a solid, cooling gave a yellow solid. Purification of the remaining liquor was achieved by flash chromatography on silica using 2.5-10% MeOH in DCM as eluent to give the title compound as a white solid (13.5 g,
IH NMR (300.132 MHz, CDC13): 8.41 (s, 2H), 7.00 (d, IH), 6.82 (s, IH), 6.60 (d, IH), 5.85 (brs, IH), 3.72 (t, 4H), 3.60 - 3.50 (m, 4H), 2.61 (t, 2H), 2.50 (t, 4H), 2.36 (s, 3H); MS m/e MH+ 338. Intermediate 41
5-Ethynyl-6-methyl-pyridin-3-ylamine
Figure imgf000122_0001
4-(5-Amino-2-methyl-pyridin-3-yl)-2-methyl-but-3-yn-2-ol (Intermediate 42) (assume quantitative yield from next step) was dissolved in toluene (300 ml), to this was added NaOH (5.6g, 0.14 mol), the reaction was then refluxed for 5 hours after which the reaction was cooled and the solvent removed invacuo to yield a black tar. This was added to aqueous NaHCO3 (300 ml), extracted with diethyl ether (3 x 300 ml), dried (MgSO4) and solvent removed in vacuo to yield a brown solid. The residue was purified by column chromatography on silica eluting with 70-100% diethyl ether in iso-hexane to give the title compound as a off white solid (9.8 g, 80% over two steps); 1H NMR (300 MHz, cdcl3) D 7.97 (s, IH), 7.05 (s, IH), 3.59 (bra, 2H), 3.32 (s, IH), 2.56 (s, 3H); MH+ 133
Intermediate 42
4-(5-Amino-2-methyl-pyridin-3-yl)-2-methyl-but-3-yn-2-ol
Figure imgf000122_0002
5-Iodo-6-methyl-pyridin-3-ylamine (Intermediate 43) (22g, 93.6 mmol), PdC12(PPh3)2 (0.7g, 0.93 mmol), PPh3 (24g, 93.6 mmol) and acetylenepropan-2-ol (17 ml, 0.18 mol) were added to piperidine (180 ml) and heated at reflux for 4 hours. The piperidine was removed in vacuo and the remaining residue was acidified with aqueous citric acid (300 ml) and extracted with diethyl ether (300 ml). The ether layer was re-extracted with aqueous citric acid (100 ml), the aqueous layers were combined and basified with potassium carbonate until pH12, this was then extracted with diethyl ether (3 x 300 ml), dried (MgSO4) and solvent removed invacuo to yield viscous black oil. This was then used in the next step without any purification.
Intermediate 43 5-Iodo-6-methyl-pyridin-3-ylamine
Figure imgf000123_0001
3-Iodo-2-methyl-5-nitro-pyridine (Intermediate 44) (33g, 0.125 mol) and iron (21g, 0,38 mol) were added to acetic acid (200 ml), the reaction was heated to 60 degrees for 2 hours. The acetic acid was removed in vacuo to yield a black sludge; this was treated with potassium carbonate in water (250 ml), until basic. The reaction was then extracted with diethyl ether (3 x 300 ml), dried (MgSO4) and solvent removed invacuo to yield a brown solid. Purification on silica eluting with 80-100% diethyl ether in iso-hexane gave the title compound as a white solid (25 g, 86%); 1H NMR (300MHz, cdcl3) D 7.96 (s, IH), 7.43 (s, IH), 3.59 (brs, 2H), 2.62 (s, 3H).
Intermeditate 44
3-Iodo-2-methyl-5-nitro-pyridine
Figure imgf000123_0002
2-(3-Iodo-5-nitro-pyridin-2-yl)-malonic acid diethyl ester (Intermediate 45) (100 g) was added to 7.0N HCl (300 ml) and refluxed for 4 hours; the reaction was cooled and extracted with diethyl ether (3 x 200 ml). The aqueous was basifϊed to pHIO with ION NaOH, this was then re-extracted with diethyl ether (3 x 200 ml), dried (MgSO4) and solvent removed in vacuo to yield a black oil which solidified on standing. The solid was slurried in hot 30% ether/iso-hexane, the organic phase was then loaded onto a silica column, and the process was repeated until the entire solid had dissolved, the column was then eluted with 30% ether/iso-hexane to yield an orange solid. Recrystallisation from hot 50% ether/iso-hexane gave the title compound as a yellow solid. The process repeated until no solid crashed out (33g, 60% over two steps); 1H NMR (300 MHz, cdcl3) D 9.26 (s, IH), 8.82 (s, IH), 2.87 (s, 3H); MS+H 265.
Intermediate 45
2-(3-Iodo-5-nitro-pyridin-2-yl)-malonic acid diethyl ester
Figure imgf000124_0001
Sodium hydride (13.4g, 0.28 mol) was added to DMF (500 ML), to this was slowly added diethylmalonate (45ml, 0.28 mol), the reaction was stirred for 20 minutes before being cooled to OoC, once cooled 2-chloro-3-iodo-5-nitropyridine (61g, 0.21mol ) was slowly added. The reaction was stirred for 1 hour before being quenched with 2.0N HCl (300 ml), extracted with diethyl ether (3 x 300 ml), dried and solvent removed in vacuo to yield dark oil. This was used without any further purification.

Claims

1. A compound of the Formula I:
Figure imgf000125_0001
Formula I wherein one of Rx or Ry is a group NR1R2, and the other is a group R3 or R4, and Rz is a group R3 or R4,
R1 and R2 are independently selected from hydrogen, (l-6C)alkylsulfonyl, phenyl(CH2)u- wherein u is 0, 1, 2, 3, 4, 5 or 6, (l-6C)alkanoyl, (l-6C)alkyl, (l-6C)alkoxycarbonyl, (3-6C)cycloalkyl(CH2)v- in which v is 0, 1, 2, 3, 4, 5 or 6 , or a 5 or 6 membered heteroaryl ring, or R1 and R2 together with the nitrogen atom to which they are attached represent a saturated or partially saturated 3 to 7 membered heterocyclic ring optionally containing another heteroatom selected from N or O; wherein a (l-6C)alkyl, the (l-6C)alkoxy, the (l-6C)alkanoyl and the (3-6C)cycloalkyl groups are optionally substituted by one or more groups independently selected from fluoro, hydroxy, (l-6C)alkyl, (l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy, (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, carbamoyl, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl or -N(Rd)C(O)(l-6C)alkyl, -N(Rd)C(O)(l-6C)alkyl in which Rd is hydrogen or (1- 6C)alkyl, or a saturated or partially saturated 3 to 7 membered heterocyclic ring, or a 5 or 6 membered heteroaryl ring; wherein the (l-6C)alkyl, (l-6C)alkoxy3 (l-6C)alkoxy(l-6C)alkoxy and (l-6C)alkoxy(l-6C)alkoxy(l-6C)alkoxy groups and the (l-6C)alkyl groups of the mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, mono(l-6C)alkylcarbamoyl, di-[(l-6C)alkyl]carbamoyl and/or -N(Rd)C(O)(l-6C)alkyl groups are optionally substituted by one or more hydroxy groups; wherein the phenyl is optionally substituted by one or more groups independently selected from halo, (l-βC)alkyl, (l-6C)alkoxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino,di(l-6C)alkylamino, wherein a (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]amino;di-(l-6C)alkylamino; and wherein any heterocyclic and heteroaryl rings within R1 and/or R2 are optionally independently substituted by one or more of the following: (l-4C)alkyl, (1- 4C)alkoxy, (l-4C)alkoxy(l-4C)alkyl, hydroxy, amino, mono(l-6C)alkylamino or di-
[(l-6C)alkyl]amino,mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino, a saturated or partially saturated 3 to 7 membered heterocyclic ring, or -C(O)(CH2)ZY wherein z is 0, 1, 2 or 3 and Y is selected from hydrogen, hydroxy, (l-4C)alkoxy,(l-4C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl] amino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and provided that when R1 and/or R2 is a (lC)alkanoyl group, then the (lC)alkanoyl is not substituted by fluoro or hydroxy;
R3 and R4 are independently selected from hydrogen, (l-6C)alkyl or (l-6C)alkoxy, (1- 6C)alkoxy wherein the (l-6C)alkyl and the (l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: fluoro, hydroxy, (l-6C)alkyl, (1- 6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)alkyl]amino,mono(l-6C)alkylamino, di(l-6C)alkylamino, carbamoyl, mono(l-6C)alkylcarbamoyl or di-[(l-6C)alkyl]carbamoyl, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a 5 or 6 membered heteroaryl ring, wherein said heterocyclic and heteroaryl rings are optionally independently substituted by one or more of the following: (l-4C)alkyl, (l-4C)alkoxy, hydroxy, amino, mono(l-6C)alkylamino or di-[(l-6C)alkyl]aminodi(l-6C)alkylamino or a saturated or partially saturated 3 to 7 membered heterocyclic ring; or one of R3 and R4 is as defined above and the other represents a group -NR1R2 as defined above.
A represents an aryl group or a 5 or 6 membered heteroaryl ring selected from furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl; R5 is selected from cyclopropyl, cyano, halo, (l-6C)alkoxy or (l-6C)alkyl, wherein the (l-βC)alkyl and the (l-6C)alkoxy groups are optionally substituted by cyano or by one or more fluoro;
n is 0, 1, 2 or 3;
L is attached meta or para on ring A with respect to the point of attachment of the ethynyl group and represents -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, -C(Ra)(Rb)-N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(Ra)(Rb)-C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y- wherein Z is a direct bond, -O- or -N(R8)- wherein x and y are independently 0, 1, 2 or 3, with the proviso that x+y < 4, wherein R8 and R9 independently represent hydrogen or (l-6C)alkyl, wherein Ra and Rb independently represent hydrogen or (l-6C)alkyl or Ra and Rb together with the carbon atom to which they are attached represent (3-6C)cycloalkyl; and wherein a (l-6C)alkyl group in Ra and Rb is optionally substituted by halo, cyano, hydroxy or a saturated or partially saturated 3 to 7 membered heterocyclic ring;
B represents a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, an aryl group,or a 5 or 6 membered heteroaryl ring,ring; or a 8, 9 or 10 membered bicyclic group which optionally contains 1, 2, 3 or 4 heteroatoms independently selected from N, O and S and which is saturated, partially saturated or aromatic;
and when B is a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring or a saturated or partially saturated 8, 9 or 10 membered bicyclic group, the rings and the bicyclic group optionally bear 1 or 2 oxo or thioxo substituents;
R6 is selected from halo, cyano, oxo, a (3-7C)cycloalkyl ring, a saturated or partially saturated 3 to 7 membered heterocyclic ring, -S(O)p-(l-6C)alkyl wherein p is 0, 1 or 2, -N(RC)C(O)(1 -6C)alkylring and -N(RC)C(O)(1 -6C)alkyl in which Rc is hydrogen or (1 - 6C)alkyl; or R6 is selected from (l-6C)alkyl or (l-6C)alkoxy, (l-6C)alkyl, -S(0)p-(l-6C)alkyl wherein p is 0, 1 or 2, or (l-6C)alkoxy, wherein the (l-6C)alkyl, -S(0)p-(l-6C)alkyl and the (l-6C)alkoxy(l-6C)alkoxy groups are optionally substituted by one or more groups independently selected from: cyano, fluoro, 5 hydroxy, (l-6C)alkoxy,(l-6C)alkoxy, amino, mono(l-6C)alkylamino, di-[(l-6C)aUfyl]amino,di(l-6C)alkylamino, a (3-7C)cycloalkyl ring or a saturated or partially saturated 3 to 7 membered heterocyclic ring; and wherein the (3-7C)cycloalkyl ring and saturated or partially saturated 3 to 7 membered heterocyclic ring are optionally independently substituted by one or more groups selected i o from ( 1 -6C)alkyl or hydroxy ( 1 -6C)alkyl; and
m is 0, 1, 2 or 3;
or a salt or solvate thereof. is with the proviso that:
(ii) L cannot be -C(Ra)(Rb)C(O)N(R9)-, -N(R8)C(O)C(Ra)(Rb)-, -N(R8)C(O)O- or -N(R8)C(O)N(R8)-.
2. A compound according to claim 1 wherein L is selected from N(R8)C(O)-, 20 N(R8)C(O)-(CRaRb)2, -C(O)N(R9), -C(O)N(R9)-CRaRb), -C(Ra)(Rb)-N(R8)C(O)- or
-C(Ra)(Rb)-C(O)N(R9)-(CRaRb)-.
3. A compound according to claim 1 or claim 2 wherein R3 and R4 are other than a group NR1R2.
25
4. A compound according to any one of the preceding claims wherein Ry is a group NR1R2 where R1 and R2 are as defined in claim 1.
5. A compound according to any one of claims 1 to 3 wherein Rx is a group NR1R2 30 where R1 and R2 are as defined in claim 1.
6. A compound according to claim 5 of the Formula IBi:
Figure imgf000129_0001
Formula IBi wherein: R1, R2, R4, R5, R6, A, L, B, m and n are as defined above in claim 1 and
R10 and R11 are independently selected from hydrogen or (l-6C)alkyl; or a salt or solvate thereof.
7. A compound according to any one of the preceding claims wherein A is phenyl, o pyridyl, thienyl or thiazolyl.
8. A compound according to any one of the preceding claims wherein B is isoxazolyl, pyrazolyl, tetrahydopyranyl, phenyl or benzodioxolyl.
s
9. A process for preparing a compound of formula I as defined in claim 1 or a salt or solvate thereof, which process comprises:
(a) for compounds of the formula I wherein L is -N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y- or -C(RaRb)N(R8)C(O)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula II:
Figure imgf000129_0002
wherein W is -C(RaRb)- or a direct bond and Rx, Ry, Rz, R5, R8, Ra, Rb, n, p and A have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a heterocycle of the formula IE:
Figure imgf000130_0001
wherein Lg1 is a displaceable group, and Z, R6, Ra, Rb, m, x, y and B have any of the meanings defined in claim 1 except that any functional group is protected if necessary; or or
(b) for compounds of the formula I wherein L is
-C(RaRb)C(O)N(R9)-(CRaRb)x-Z-(CRaRb)r or -C(O)N(R9)-(CRaRb)x-Z-(CRaRb)y-, the reaction of a compound of the formula IV:
Figure imgf000130_0002
wherein Lg2 is a displaceable group, W is -C(RaRb)- or a direct bond and Rx, Ry, Rz, R5, Ra, Rb, n and A have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an amine of the formula V:
Figure imgf000130_0003
V wherein R6, R9, Ra, Rb, m, x, y, B and Z have any of the meanings defined in claim
1 except that any functional group is protected if necessary; or
(c) for compounds of formula I wherein Z is -O- or -N(Ra)- and when Z is -O- then x>0, the reaction of a compound of formula VI
Figure imgf000131_0001
Vl wherein J is selected from -N(R8)C(O)-, -C(O)N(R9)-, -C(Ra)(Rb)-N(R8)C(O)- or -C(Ra)(Rb)-C(O)N(R9)- and Rx, Ry, Rz, R5, R8, R9, Ra, Rb, x, n and A are as defined in claim 1 except that any functional group is protected if necessary and when Z is -O- then x>0, with a compound of formula VII,
Figure imgf000131_0002
VII wherein Lg3 is a suitable displaceable group, and Ra, Rb, R6, y, m and B are as defined in claim 1 except that any functional group is protected if necessary;
(d) for compounds of formula I wherein Z is -O- or -N(Ra)- and x>0, the reaction of a compound of formula VIII
Figure imgf000131_0003
VIII wherein Lg4 is a suitable displaceable group, J is selected from -N(R8)C(O)-, -C(O)N(R9)-, -C(Ra)(Rb)-N(R8)C(O)- or -C(Ra)(Rb)-C(O)N(R9)- and Rx, Ry, Rz, R5, R8, R9, Ra, Rb, n, and A are as defined in claim 1 except that any functional group is protected if necessary and x is 1 , 2 or 3, with a compound of formula IX, H-Z- (CRaRb)y-/ B J
IX wherein Z, Ra, Rb, R6, y, m and B are as defined in claim 1 except that any functional group is protected if necessary; or (e) for the preparation of a compound of formula IA, the reaction of a compound of the formula X:
Figure imgf000132_0001
X wherein Lg5 is a suitable displaceable group and R3, R4, R5, R6, n, m, A, B and L have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an amine of the formula HNR1R2, wherein R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or for the preparation of a compound of formula (IB), the reaction of a compound of the formula X':
Figure imgf000132_0002
wherein Lg3 is a suitable displaceable group for example halogeno and R3, R4, R5, R6, n, m, A, B and L have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with an amine of the formula HNR1R2, wherein R1 and R2 have any of the meanings defined hereinbefore except that any functional group is protected if necessary; or
(D the reaction of a compound of the formula XI:
Figure imgf000133_0001
Xl wherein Lg6 is a suitable displaceable group and R5, R6, n, m, A5 B and L are as defined in claim 1 except that any functional group is protected if necessary, with an alkyne of the formula XII:
Figure imgf000133_0002
XII wherein Rx, Ry, and Rz are as defined in claiml except that any functional group is protected if necessary; or (g) reaction of a compound of the formula XIII:
Figure imgf000133_0003
XIII wherein R5, R6, n, m, A, B and L have any of the meanings defined in claim 1 except that any functional group is protected if necessary, with a pyrimidine of the formula XIV:
Figure imgf000134_0001
XIV wherein Lg7 is a suitable displaceable group and Rx, Ry and Rz have any of the meanings defined in claim 1 except that any functional group is protected if necessary; or and thereafter if necessary: i) converting a compound of the Formula (I) into another compound of the Formula (I); ii) removing any protecting groups; iii) forming a salt or solvate.
10. A pharmaceutical composition which comprises a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically-acceptable diluent or carrier.
11. A compound according to any one of claims 1 to 8 or a pharmaceutically- acceptable salt thereof, for use as a medicament.
12. The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use as a Tie2 receptor tyrosine kinase inhibitor in a warm-blooded animal.
13. The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the production of an anti-angiogenic effect in a warm-blooded animal.
14. The use of a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of cancers in a warm-blooded animal.
15. A method of inhibiting Tie2 receptor tyrosine kinase in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
16. A method for producing an anti-angiogenic effect in a warm-blooded animal, such as man, in need of such treatment, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
17. A method of treating cancers in a warm-blooded animal, in need of such treatment, which comprises administering to said animal an effective amount of a compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof.
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