WO2015123722A1 - Inhibiteurs - Google Patents

Inhibiteurs Download PDF

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Publication number
WO2015123722A1
WO2015123722A1 PCT/AU2015/000089 AU2015000089W WO2015123722A1 WO 2015123722 A1 WO2015123722 A1 WO 2015123722A1 AU 2015000089 W AU2015000089 W AU 2015000089W WO 2015123722 A1 WO2015123722 A1 WO 2015123722A1
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WIPO (PCT)
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alkyl
group
substituted
compound
cancer
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PCT/AU2015/000089
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English (en)
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Andrew John Harvey
Justin Anthony Ripper
Belinda Cheryl HUFF
Dharam Paul
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Bionomics Limited
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Priority claimed from AU2014900536A external-priority patent/AU2014900536A0/en
Application filed by Bionomics Limited filed Critical Bionomics Limited
Publication of WO2015123722A1 publication Critical patent/WO2015123722A1/fr

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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
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings

Definitions

  • This invention relates to 2,4,5-substituted pyrimidines that inhibit vascular endothelial growth factor receptor 3 (VEGFR3), also known as Fms related tyrosine kinase 4 (FLT4), processes for their preparation and pharmaceutical agents or compositions containing such
  • VEGFR3 vascular endothelial growth factor receptor 3
  • FLT4 Fms related tyrosine kinase 4
  • This invention also relates to a method of using such compounds for the treatment of proliferative diseases, such as cancer, as well as the treatment of diseases ameliorated by the control and/or inhibition of lymphangiogenesis.
  • This invention relates to 2,4,5-substituted pyrimidines that inhibit focal adhesion kinase (FAK), processes for their preparation or pharmaceutical agents or compositions containing such compounds.
  • This invention also relates to a method of using such compounds for the treatment of proliferative diseases, such as cancer.
  • Cancer remains a major cause of death in the 21 st century. Consequently, considerable drug research and development effort is currently placed on the discovery of therapeutics that may provide life extending or curative options to cancer sufferers.
  • metastasis While there are many different varieties of cancer, each exhibiting a different array of genetic and growth properties, a common denominator among many solid cancer types is the ability to metastasise. Until the occurrence of metastasis, tumors are confined to one area of the body and may be controlled through surgical intervention and/or radiotherapy. However, metastasis causes cancer cells to spread to disparate parts of the body and while surgical intervention may remove the primary tumor lesion, removal of all metastatic lesions is very difficult to manage.
  • Tumor metastasis is a multistage process, involving the breakdown of extracellular matrix, invasion of local tissue parenchyma, intravasation into regional blood vessels and lymphatics, survival in the circulation and finally extravasation, survival and growth in secondary tissue sites ⁇ Front. Biosci. (Elite Ed). 2012; 4: 1888-1897).
  • lymphatic vessels differ from blood vessels in several ways. Large collecting lymphatic vessels contain vascular smooth muscle cells in their wall, as well as valves, which prevent the backflow of lymph.
  • lymphatic capillaries unlike typical blood capillaries, lack pericytes and continuous basal lamina and contain large inter-endothelial valve-like openings (J. Theor. Med. 2003; 5: 59-66). Due to their greater permeability, lymphatic capillaries are more effective than blood capillaries in allowing tumor cells to pass. Experimental evidence demonstrates that lymphangiogenesis (the formation of new lymphatic vessels) within a growing tumor lesion promotes metastasis through lymphatic vessels. The control of lymphangiogenesis presents an attractive therapeutic strategy for preventing lymph node metastasis (J. Clin. One. 2007; 25: 4298-4307).
  • the lymphatic system is comprised of capillaries and larger collecting vessels continuously lined by endothelial cells which return extravasated fluid and macromolecules from the interstitial space back to the blood circulation. Metastasis to regional lymph nodes via lymphatic vessels is a tumor progression process that is common to many cancer types. The extent of lymph node involvement is a major determinant for the staging of many types of cancer and is an important prognostic factor that is used as the basis for surgical and radiation treatment intervention of the affected lymph nodes.
  • VEGFC or VEGFD Molecular signalling through binding of the growth factors VEGFC or VEGFD to their membrane receptor VEGFR3 has been shown to play a central role in the process of lymphangiogenesis ⁇ Brit. J. Cancer 2006; 94: 1355-1360). Stimulation of the VEGFR3 receptor occurs through the phosphorylation of its intracellular region and triggers a downstream signalling cascade that drives lymphatic endothelial cell proliferation, migration and differentiation leading to formation of lymphatic vessels ⁇ Exp. Cell Res. 2006; 312: 575- 583). Increased expression of VEGFC or VEGFD has been shown to promote tumor associated lymphangiogenesis enabling lymphatic-mediated metastasis to regional lymph nodes. These observations have been reported for several different tumor types, including colorectal ⁇ Oncol.
  • VEGFR3 is a transmembrane tyrosine kinase receptor that is broadly expressed in endothelial cells during embryogenesis ⁇ Biochem. J. 2011; 437: 169-183). In the latter stages of development VEGFR3 expression becomes restricted to developing lymphatic vessels. In adults, VEGFR3 expression is primarily restricted to lymphatic endothelium and a subset of CD34+ hematopoietic cells. In addition, fenestrated capillaries and veins in certain endocrine organs, as well as monocytes, macrophages and some dendritic cells (DCs), continue to express VEGFR3 in adults.
  • DCs dendritic cells
  • VEGFR3 Disruption of the VEGFR3 gene in mouse embryos results in the failure of vascular network formation and death after embryonic day 9.5 ⁇ Biochem. J. 2011; 437: 169-183).
  • This observation demonstrates that VEGFR3 plays an essential role in the development of embryonic vasculature.
  • VEGFR3 is overexpressed in lymphatic sinuses in metastatic lymph nodes and in lymphangiomas.
  • cancer cells themselves express VEGFR3.
  • VEGFR3 expressing cancer cells have been shown to be dependent on VEGFR3A EGFC signalling for their proliferation ⁇ Eur. J. Cane. 2011; 47: 2353 -2363).
  • VEGFR3 signalling has strong potential as therapeutic strategy for mammalian subjects that have been diagnosed with a disease characterised by proliferation of endothelial cells that express this receptor.
  • targeting VEGFR3 is likely to result in therapeutic benefit through suppression of lymphatic metastasis and suppression of growth in cancer cells that express VEGFR3.
  • VEGFR3 compounds that selectively inhibit VEGFR3 would be useful for the treatment of proliferative diseases, such as cancer.
  • VEGFR3 plays an important role in the control of lymphangiogenesis. Accordingly, inhibitors of VEGFR3 may have utility in the treatment of diseases other than cancer where control/inhibition of lymphangiogenesis has a therapeutic benefit.
  • the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Inhibition of lymphangiogenesis through suppression of VEGFR3 function may provide a viable therapeutic strategy in these conditions.
  • VEGFR3 the expression of VEGFR3 in the cornea and ocular surface is modified during corneal neovascularisation and that VEGFR3 mediates corneal dendritic cell migration to lymph nodes and induction of immunity to corneal transplant.
  • High-risk corneal transplantation where grafting is performed on inflamed and highly vascularized host beds, has a very poor success rate, with rejection rates as high as 90% (J. Leukoc Biol. 2003; 74: 172-178).
  • treatment with a VEGFR3 antibody leads to significant suppression of corneal graft rejection ⁇ Nat. Med. 2004; 10: 813 - 815).
  • Choroidal neovascularization the creation of new blood vessels in the choroid layer of the eye, leads to chronic inflammation which is implicated in the pathogenesis of age related macular degeneration (AMD) and is driven by factors which include uncontrolled expression of the vascular endothelial growth factor (VEGF) family members VEGFA and VEGFC (J. Cell. Physiol. 2012; 227(1): 116-26).
  • VEGF vascular endothelial growth factor
  • VEGFA vascular endothelial growth factor family members
  • VEGFA and VEGFC J. Cell. Physiol. 2012; 227(1): 116-26.
  • Treatments for AMD have been developed that target VEGFA, for example the anti-VEGFA antibodies ranibizumab and bevacizumab and the anti-VEGF aptamer pegaptanib, but to date no treatments have been clinically evaluated that mediate effects through modulation of VEGFC and its cognate receptor VEGFR3.
  • compounds that inhibit VEGFR3 may be useful for the prevention and/or treatment of eye diseases, for example corneal graft rejection and age related macular degeneration.
  • eye diseases for example corneal graft rejection and age related macular degeneration.
  • lymphatic vessels have an active role in chronic inflammation of the skin. Lymphatic endothelial cell proliferation and lymphatic hyperplasia have been described in chronic skin inflammation in mice and have been reported for skin lesions in psoriasis patients ⁇ Blood 2004; 104: 1048-1057).
  • compounds that inhibit VEGFR3 may be useful for the prevention and/or treatment of skin inflammations, such as skin lesions in patients with psoriasis.
  • Lymphangiogenesis has also been found to be associated with kidney transplant rejection.
  • VEGFC producing macrophages induce formation of new lymphatics which induce and support the maintenance of an alloreactive immune response in renal transplants ⁇ Nat. Med. 2006; 12: 230-234).
  • compounds that inhibit VEGFR3 may be useful for the prevention and/or treatment of rejection in renal transplantation.
  • FAK is a 125 kDa ubiquitously expressed non-receptor tyrosine kinase that becomes phosphorylated upon integrin clustering at the cell surface. Phosphorylation renders FAK active and mediates downstream signalling events that influence a number of pathways including PI3K/Akt, ERK and JNK/MAPK leading to induction of gene transcription events that dictate cell movement, growth and survival under normal physiological circumstances but are also capable of driving tumor growth, resistance and metastasis in cancer pathological settings.
  • FAK is a key component of protein complexes involving well- recognized signaling pathways in cancer, more specifically a signaling complex containing oncogenic proteins, such as the epidermal growth factor receptor (EGFR), human epidermal growth factor receptor 2 (HER-2), MET (the hepatocyte growth factor receptor, encoded by c-Met ), and Src, and tumor suppressor proteins such as the transcription factor p53 and neurofibromin-1 (NF-1 ) places FAK at the center of cancer cell growth and regulation.
  • EGFR epidermal growth factor receptor
  • HER-2 human epidermal growth factor receptor 2
  • MET the hepatocyte growth factor receptor, encoded by c-Met
  • Src tumor suppressor proteins
  • tumor suppressor proteins such as the transcription factor p53 and neurofibromin-1 (NF-1 ) places FAK at the center of cancer cell growth and regulation.
  • FAK has been implicated in nearly every aspect of cancer: invasion, metastasis,
  • angiogenesis angiogenesis
  • epithelial mesenchymal transition EMT
  • maintenance of cancer stem cells and globally promoting tumor cell survival.
  • Dysregulation of FAK expression and function has been implicated in the development and propagation of several malignancies through its role in enhancing tumor angiogenesis, tumor cell invasion and metastasis.
  • Amplification of FAK expression has been described in a range of tumor types including Non-Small Cell Lung Cancer (NSCLC), pancreatic cancer, breast cancer, Head and Neck cancer, brain cancer, thyroid cancer, prostate cancer and acute myelogeneous leukemia. In these cases, high FAK expression was associated with a worse disease outcome.
  • NSCLC Non-Small Cell Lung Cancer
  • pancreatic cancer breast cancer
  • Head and Neck cancer brain cancer
  • thyroid cancer prostate cancer
  • acute myelogeneous leukemia acute myelogeneous leukemia
  • PF-562271 was the first inhibitor evaluated.
  • PF- 562271 displayed nonlinear pharmacokinetics profile suggesting underlying issues with CYP450 enzyme metabolism.
  • Attenuation of the p53 protein is one of the most common abnormalities in human tumours. Characterization of the FAK promoter demonstrated that p53 can bind and inhibit the FAK promoter activity in vitro. It was also demonstrated that p53 binds the FAK promoter-chromatin region in vivo and down-regulates FAK mRNA and protein levels. Furthermore many common p53 mutations blocked this transcriptional suppressor function of p53 against the FAK promoter. Finally a sample of primary breast and colon cancers were analysed for p53 mutations and FAK expression, and showed that FAK expression was increased in tumours containing mutations of p53 compared to tumours with wild type p53. In addition, tumour-derived missense mutations in the DNA-binding domain (R282, R249, and V173) also led to increased FAK promoter activity.
  • FAK inhibition appears to curtail tumor growth and progression, increasing overall survival in animal models when combined with docetaxel, gemcitabine, 5-fluorouracil, temozolomide, sunitinib, oxaliplatin, doxorubicin or radiotherapy.
  • Inflammatory cytokines including TN F-a and IL-1 ⁇ activate inflammatory gene expression via mitogen activated protein kinases (MAPKs) cascade and nuclear factor kappa B (N F-KB) activation. Inhibition of MAPK or N F- ⁇ pathway significantly reduces inflammatory gene expression.
  • MAPKs mitogen activated protein kinases
  • N F-KB nuclear factor kappa B
  • TN F-a activates MAPKs via FAK
  • FAK inhibition blocks inflammatory VCAM-1 expression.
  • N F- KB is a critical player in inflammation signaling network, FAK inhibition does not block N F-KB activation but still does block VCAM-1 expression. Additionally, active MAPK expression in KD FAK cells did not rescue VCAM-1 expression.
  • FAK inhibition via a small molecule FAK inhibitor or genetic KD FAK promotes turnover of GATA4 transcription factor required for VCAM-1 expression. This is mediated by nuclear FAK scaffold function through interaction with GATA4 and ubiquitin E3 ligase CHIP.
  • VEGFR3 inhibitors which are effective as VEGFR3 inhibitors. These compounds may exhibit selectivity for VEGFR3 over kinases such as VEGFR2. These compounds may exhibit FAK activity and accordingly improved in vivo efficacy for cancer. These compounds may exhibit improved selectivity for FAK over other kinases such as VEGFR2.
  • a first aspect provides compounds of the following formula (I) or isomers, salts, solvates or prodrugs thereof:
  • A is an optionally substituted 5 to 10 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;
  • A may optionally bear a substituent R 1A which is not alpha to the NH group, A may optionally bear one or two substituents R 1B which are alpha to the NH group, and A may optionally bear one or two further substituents R 1C which are not alpha to the NH group,
  • R 1A is selected from:
  • XNHZ 2 XNHZ 2 , where X is selected from CF 2 , CMe 2 , cyclopropylidene, cyclobutylidene, cyclopentylidene and oxetanylidine, and Z 2 is selected from H, alkyl and
  • each R 1B is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo and cyano, where the
  • C 1-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo, cyano and hydroxyl, where the C 1-2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ; R 4 is selected from:
  • the compounds of formula (I) or isomers, salts, solvates or prodrugs thereof as defined above with the proviso that the compound is not any of the following compounds or Boc-protected intermediates thereof:
  • a second aspect provides a compound of the formula (IC) or isomers, salts, solvates or prodrugs thereof:
  • A is an optionally substituted 5 or 6 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 or 2 N heteroatoms;
  • A bears a substituent R 1A which is not alpha to the NH group
  • A may optionally bear one or two substituents R 1 B which are alpha to the NH group
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group
  • R 1A is selected from
  • each R 1 B is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo and cyano, where the
  • Ci -2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3 -4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the group R 1B is absent.
  • the group A may optionally bear a substituent R 1A and may optionally bear one or two substituents R 1C .
  • a third aspect provides a compound of formula (IE) or isomers, salts, solvates, or prodrugs thereof:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • a fourth aspect provides a compound of formula (IG) or isomers, salts, solvates, or prodrugs thereof:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R N2 is independently selected from C 2-3 alkyl, C 3 alkenyl, and alkyl;
  • R N3 is d alkyl
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • a fifth aspect provides a compound of formula (IH) or isomers, salts, solvates, or prodrugs thereof:
  • the substituent R 1A is not al ha to the NH rou and is selected from:
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • a sixth aspect provides a process for the preparation of a compound of formula (I) or isomers, salts, solvates or prodrugs thereof, which comprises reacting a compound of formula F1
  • R 2 and R 3 are as defined in formula (I) above and L 1 and L 2 are leaving groups.
  • a seventh aspect provides a pharmaceutical agent comprising a compound of the formula (I) or isomers, salts, solvates or prodrugs thereof.
  • the pharmaceutical agent may be an anticancer agent, a lymphangiogenesis inhibitor, an antimetastasis agent or a VEGFR3 inhibitor.
  • the pharmaceutical agent may be an anticancer agent, an angiogenesis inhibitor, an antimetatstasis agent or a FAK inhibitor.
  • An eighth aspect provides a composition
  • a composition comprising a compound of formula (I) or an isomer, salt, solvate or prodrug thereof and a pharmaceutically acceptable carrier or diluent.
  • a ninth aspect provides a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect for use in a method of therapy.
  • a tenth aspect provides for the use of a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect in the preparation of a medicament for treating a disease or condition ameliorated by the inhibition of VEGFR3.
  • the tenth aspect of the invention also provides a compound of formula (I), agent of the seventh aspect or composition of the eighth aspect for use in the method of treatment of a disease or condition ameliorated by the inhibition of VEGFR3.
  • An eleventh aspect provides for the use of a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect in the preparation of a medicament for treating cancer.
  • the eleventh aspect of the invention also provides a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect for use in the method of treatment of cancer.
  • a twelfth aspect provides for the use of a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the eighth aspect or composition of the ninth aspect in the preparation of a medicament for inhibiting, suppressing or reducing lymphangiogenesis.
  • the thirteenth aspect of the invention also provides a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect for use in the method of inhibiting, supressing or reducing lymphangiogenesis.
  • a further aspect provides a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical composition.
  • Another aspect provides a method of inhibiting VEGFR3 in vitro or in vivo, comprising contacting a cell or cell lysates with an effective amount of a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect.
  • a still further aspect provides an anti-cancer treatment comprising a compound of formula (I) or an isomer, salt, solvate or prodrug thereof, agent of the seventh aspect or composition of the eighth aspect and an anti-tumour agent.
  • the present invention provides compounds of the formula (I) or isomers, salts, solvates or prodrugs thereof:
  • A is an optionally substituted 5 to 10 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;
  • A may optionally bear a substituent R 1A which is not alpha to the NH group,
  • A may optionally bear one or two substituents R 1 B which are alpha to the NH group, and
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group,
  • R 1A is selected from:
  • each R 1 B is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo and cyano, where the
  • C 1-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • A is a substituted 5 to 10 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;
  • A bears a substituent R 1A which is not alpha to the NH group
  • A may optionally bear one or two substituents R 1B which are alpha to the NH group
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group
  • each R 1B is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo and cyano, where the
  • C 1-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo, cyano and hydroxyl, where the C 1-2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • A is a substituted 5 to 10 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S;
  • A bears a substituent R 1A which is not alpha to the NH group
  • A may optionally bear one or two substituents R 1B which are alpha to the NH group
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group
  • R 1A is selected from:
  • each R 1B is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo and cyano, where the
  • C 1-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo, cyano and hydroxyl, where the C 1-2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • A is an optionally substituted 5- or 6-membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl ring system contains 1 to 4 heteroatoms selected from N, O and S;
  • A may optionally bear a substituent R 1A which is not alpha to the NH group, A may optionally bear one or two substituents R 1 B which are alpha to the NH group, and A may optionally bear one or two further substituents R 1C which are not alpha to the NH group,
  • R 1A is selected from:
  • each R 1 B is independently selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo and cyano, where the
  • Ci -2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • A is an optionally substituted 5- or 6-membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl ring system contains 1 to 4 heteroatoms selected from N, O and S;
  • A may optionally bear a substituent R 1A which is not alpha to the NH group, A may optionally bear one or two substituents R 1B which are alpha to the NH group, and A may optionally bear one or two further substituents R 1C which are not alpha to the NH group,
  • R 1A is selected from:
  • each R 1B is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo and cyano, where the
  • Ci-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3 -4 cycloalkyl, oxetanyl, C 3- 4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the compounds of the first aspect are of formula (I) as defined above wherein when A is substituted pyridinyl,
  • R 2 is CF 3 or CH 3 ,
  • R 3 is substituted phenyl and bears a substituent R 4 alpha to the -C 2 H 4 - group
  • R 4 is -CH 2 -C(0)-NH 2
  • R 1A selected from:
  • each of R N1 , R N3 , R N4 , R N5 , R N6 , R N9 , R N1 °, R>N N 1 1 1 1 and c R>N N 1 1 2 2 is independently selected f f.rom H, C 1-
  • each of R and R is independently selected from H and methyl.
  • the compounds of formula (IB) are as defined above wherein when A is substituted pyrazolyl,
  • R 2 is CF 3 or CH 3 ,
  • R 3 is substituted phenyl and bears a substituent R 4 alpha to the -C 2 H 4 - group
  • R 4 is -CH 2 -C(0)-NH 2
  • R 1A selected from:
  • each of R N7 and R N8 is independently selected from H and methyl.
  • IC formula (IC) or isomers, salts, solvates or prodrugs thereof:
  • A is an optionally substituted 5 or 6 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 or 2 N heteroatoms;
  • A bears a substituent R 1A which is not alpha to the NH group
  • A may optionally bear one or two substituents R 1B which are alpha to the NH group
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group
  • R 1A is selected from
  • each R 1B is independently selected from O-C1-2 alkyl, Ci -2 alkyl, halo and cyano, where the
  • C1-2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from O-C1-2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3 -4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • A is an optionally substituted 5 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl group contains 1 or 2 N heteroatoms;
  • A bears a substituent R 1A which is not alpha to the NH group,
  • A may optionally bear one or two substituents R 1B which are alpha to the NH group, and
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group,
  • R 1A is selected from
  • each R 1B is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo and cyano, where the
  • Ci -2 alkyl group may be substituted by one or more fluoro groups
  • each R 1C is independently selected from 0-Ci -2 alkyl, Ci -2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • IE formula (IE) or isomers, salts, solvates, or prodrugs thereof:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3 -4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R N2 is independently selected from C2-4 alkyl, C2-4 alkenyl, C2-4 alkynyl, Ci -4 alkylCN,
  • Ci -4 alkyl group may be substituted by one or more fluoro groups
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the substituent R is not alpha to the NH group, and is selected from:
  • R N3 is d alkyl
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 C 1-3 alkyl, cyano and OCH 2 -cyclopropyl where the C 1-3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R 2 is selected from H, halo, C 1-3 alkyl, 0-(C 1-3 alkyl), 0-(CH 2 )n-C 3-4 cycloalkyl, oxetanyl, C 3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the substituent R 1A is not alpha to the NH group, and is selected from:
  • R N2 is selected from C 3 alkyl and C 3 alkynyl
  • R 2 is selected from H, halo, Ci -3 alkyl, 0-(Ci -3 alkyl), 0-(CH 2 )n-C 3 -4 cycloalkyl, oxetanyl, C3-4 cycloalkyl, S0 2 Ci -3 alkyl, cyano and OCH 2 -cyclopropyl where the Ci -3 alkyl group may be substituted by one or more fluoro groups and the group n is 0 or 1 ;
  • R 3 is selected from substituted phenyl and a substituted 6-membered heteroaryl group, where the heteroaryl group contains 1 or 2 N heteroatoms, where R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further substituents selected from F, methyl and CF 3 ;
  • R 4 is selected from:
  • the following embodiments and preferences relate to the compounds of formula (I), (IA), (IA1 ), (IB), (1 B1 ), (IC), (ID), (IE), (IF), (IG), (IH) and (IJ), as defined in the first to fifth aspects, above.
  • Each of these embodiments and preferences may be combined with one another as appropriate.
  • A is a substituted 5 to 10 membered heteroaryl group.
  • the heteroaryl group is linked to the NH group through an aromatic ring carbon atom, and the heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S.
  • A is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an heteroaromatic compound (i.e. a compound having at least one heteroaromatic ring), which moiety has from 5 to 10 ring atoms.
  • an heteroaromatic compound i.e. a compound having at least one heteroaromatic ring
  • each ring has from 5 to 7 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, those derived from: pyrrole (azole) (5-membered), pyridine (azine) (6-membered), azepine (7-membered), azocine (8-membered);
  • furan (oxole) (5-membered); pyran (6-membered); oxepine (7-membered); oxocine (8- membered); oxonine (9-membered), oxecine (10-membered); Si: thiophene (thiole) (5-membered), thiopyran (6-membered), thiepine (7-membered), thiocine (8-membered);
  • ⁇ - ⁇ - ⁇ oxazole (5-membered), isoxazole (5-membered), isoxazine (6-membered);
  • N-iS-i thiazole (5-membered), isothiazole (5-membered);
  • N 2 imidazole (1 ,3-diazole) (5-membered), pyrazole (1 ,2-diazole) (5-membered), pyridazine (1 ,2-diazine) (6-membered), pyrimidine (1 ,3-diazine) (6-membered) (e.g., cytosine, thymine, uracil), pyrazine (1 ,4-diazine) (6-membered), diazepine (7-membered);
  • N 3 triazole (5-membered), triazine (6-membered); and,
  • heteroaryl groups which comprise fused rings include, but are not limited to, those derived from:
  • A when A is a 5 to 10 membered heteroaryl group, it may be selected from any of the groups listed above.
  • the 5 to 10 membered heteroaryl group contains 1 to 4 heteroatoms selected from N, O and S. In some embodiments the 5 to 10 membered heteroaryl ring system contains 1 or 2 heteroatoms selected from N, O and S. In some embodiments the heteroatoms are N atoms.
  • A is a 5 or 6 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom.
  • the 5 or 6 membered heteroaryl ring system contains 1 to 4 heteroatoms selected from N, O and S. In some embodiments the 5 or 6 membered heteroaryl ring system contains 1 or 2 heteroatoms selected from N, O and S. In other embodiments the heteroatoms are N atoms.
  • A is a 5 or 6 membered heteroaryl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl ring system contains 1 or 2 N heteroatoms.
  • A is selected from the group consisting of pyrrole, pyridine, imidazole, pyrazole, pyridazine, pyrimidine or pyrazine.
  • A when A is a 5 to 10 membered heteroaryl group, A is substituted.
  • A may be unsubstituted.
  • A may be substituted with a substituent R 1A , one or two substituents R 1B and one or two further substituents R 1C . It will be appreciated that A may be substituted with any combination of the substituents R 1A , R 1B ,
  • A when A is substituted pyridine, A may bear one or two substituents R 1B which are alpha to the NH group.
  • R 1B when present the R 1B group is ortho to the NH group, therefore, A has the structure:
  • the R 1B group cannot be beta or gamma to the connection point to the rest of the compound (i.e., it cannot be in the asterixed positions).
  • A may optionally bear a substituent R 1A which is not alpha to the NH group.
  • R 1A group can either be meta or para, and so A can, for example, have the structures:
  • R 1A group cannot be alpha to the connection point to the rest of the compound (i.e., it cannot be in the positions that are asterixed or occupied by R 1B ).
  • A may optionally bear one or two further substituents R 1C which are not alpha to the NH group.
  • R 1C group can either be meta or para, and so A can, for example, have the structures:
  • R 1C group cannot be alpha to the connection point to the rest of the compound (i.e., it cannot be in the positions that are asterixed or occupied by R 1B ).
  • the R 1A group is meta to the -NH- group.
  • the R 1A group is beta to the -NH- group.
  • A is substituted with a substituent R 1A , optionally one or two substituents R 1B , and R 1C is absent.
  • A bears a substituent R 1A .
  • R 1A is substituted with a substituent R 1A , and R 1B and R 1C are absent.
  • R 1A is selected from:
  • A is a 5 to 10 membered heteroaryl group and the substituent R 1A must be present when A is a 9 or 10 membered heteroaryl group.
  • R 1A may optionally be present.
  • R 1A may be absent.
  • R 1A is selected from:
  • R 1A is an optionally substituted 4 to 6 membered non-aromatic heterocycle containing 1 to 2 heteroatoms selected from N, O and S.
  • R 1A is selected from any one of the following structures:
  • the cycloalkyl group has one or two substituents.
  • R 1A when R 1A is a substituted 4 to 6 membered non-aromatic heterocycle containing 1 to 2 heteroatoms selected from N, O and S, the heterocycle may have one or two substituents.
  • R 1A is an optionally substituted 4 to 6 membered non-aromatic heterocycle containing 1 to 2 heteroatoms selected from N and O.
  • R 1A is an optionally substituted 4 to 6 membered non-aromatic heterocycle containing 1 to 2 N heteroatoms.
  • R 1A is an optionally substituted 4 to 6 membered non-aromatic heterocycle containing 1 to 2 O heteroatoms.
  • R is selected from any one of the following structures:
  • each of R N1 , R N2 , R N3 , R N4 , R N5 , R N6 , R N9 , R N1 °, R N11 and R N12 is independently selected from H, C1-4 alkyl (i.e. methyl, ethyl, prop-1-yl, prop-2-yl, n-butyl, / ' so-butyl, sec-butyl, ferf-butyl), C 2 -4 alkenyl (i.e.
  • C 1-4 alkyl(CN) i.e. -CH 2 CN, -CH(CN)CH 3 , -CH 2 CH 2 CN, -CH(CN)CH 2 CH 3 , -CH 2 CH(CN)CH 3 , -CH 2 CH 2 CH 2 CN, -CH(CN)CH 2 CH 2 CH 3 ,
  • C 3-4 cycloalkyi i.e. cyclopropyl, methylcyclopropyl, cyclobutyl
  • each of R N7 and R N8 is independently selected from either H or methyl.
  • R 1A is CH(R C1 )NHZ 1
  • R C1 is selected from H, Ci -3 alkyl, C 3-5 cycloalkyi and oxetanyl
  • Z 1 is selected from H, alkyl
  • R 1A is XNHZ 2
  • X is selected from CF 2 , CMe 2 , cyclopropylidene, cyclobutylidene, cyclopentylidene and oxetanylidine
  • R is selected from any one of the following structures:
  • R is present and is selected from any one of the following structures:
  • R N3 and R N5 are independently selected from H, Ci -4 alkyl, C 2- alkenyl, C 2-4 alkynyl, Ci -4 alkyl(CN), C3-4 cycloalkyl, cycloalkyl, where the alkyl group may be substituted by one or more fluoro groups.
  • R 1A is present and is selected from any one of the following structures:
  • R A is present and is selected from any one of the following structures:
  • R N2 is selected from C 2 -4 alkyl, C 2- 4 alkenyl, C2-4 alkynyl, Ci -4 alkylCN, C 3-4 cycloalkyl,
  • Ci -4 alkyl group may be substituted by one or more fluoro groups
  • R 1A is present and is selected from any one of the following structures:
  • R N2 is selected from C 2-3 alkyl, C 3 alkenyl, and alkyl
  • R N3 is Ci alkyl.
  • R is present and is selected from any one of the following structures:
  • R 1A is present and is selected from any one of the following structures:
  • R N2 is selected from C 3 alkyl and C 3 alkynyl.
  • A When A is a 5 to 10 membered heteroaryl group, A may optionally bear one or two substituents R 1B .
  • Each R 1B group may be selected from 0-C 1-2 alkyl (i.e. methoxy, ethoxy), C 1-2 alkyl (i.e. methyl or ethyl), halo (i.e. F, CI, Br, I) and CN.
  • the C 1-2 alkyl groups may be substituted by one or more fluoro groups (e.g. CF 3 , CF 2 CH 3 , CFH 2 , OCF 2 H, OCH 2 CF 3 ).
  • each R 1B is independently selected from 0-Ci -2 alkyl (i.e. methoxy, ethoxy), or Ci -2 alkyl (i.e. methyl or ethyl), where the Ci -2 alkyl group may be substituted by one or more fluoro groups (e.g. CF 3 , CF 2 CH 3 , CFH 2 , OCF 2 H, OCH 2 CF 3 ).
  • the R 1B groups are located at the ring position on A which is alpha to the NH group. There may be up to 2 R 1B groups (i.e. 1 or 2) depending on the nature of A, and in particular on the number of ring atoms and ring heteroaroms, as well as whether R 1A and/or R 1C are present.
  • each R 1B group may be selected from fluoro, methoxy, methyl and CF 3 .
  • R 1B is absent.
  • A may optionally bear one or two substituents R 1C .
  • Each R 1C group may be selected from 0-C 1-2 alkyl, C 1-2 alkyl, halo, cyano and hydroxyl, where the Ci -2 alkyl group may be substituted by one or more fluoro groups;
  • the R groups may be located at any available ring position on A, except that which is alpha to the NH group.
  • There may be up to 2 R 1B groups (i.e. 1 or 2) depending on the nature of A, and in particular on the number of ring atoms and ring heteroaroms, as well as whether R 1A and/or R 1B are present.
  • R 1C is absent.
  • R 2 is selected from H, halo (i.e. F, CI, Br, I), C 1-3 alkyl (i.e. methyl, ethyl, prop-1 -yl and prop-2- yl), 0-C 1-3 alkyl (i.e. methoxy, ethoxy, prop-1 -oxy and prop-2-oxy), 0-(CH 2 )n-C 3- 4 cycloalkyl, O-C3-4 cycloalkyl (i.e. cyclopropyloxy, cyclopropyl methoxy, cyclobutyloxy), oxetanyl, C 3-4 cycloalkyl (i.e. cyclopropyl, cyclopropylmethyl and cyclobutyl), S0 2 C 1-3 alkyl (i.e.
  • C 1-3 alkyl groups may be substituted by one or more fluoro groups (e.g. CF 3 , CF 2 CH 3 , CFH 2 , OCF 2 H, OCH 2 CF 3 ).
  • R 2 is CF 3 .
  • R 3 is selected from substituted phenyl and a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 N heteroatoms.
  • R 3 bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group and may bear further substituents selected from F, CH 3 and CF 3 .
  • R 3 When R 3 is substituted phenyl, it has the structure:
  • R 3a where R 6 , R 7 and R 8 are independently selected from H, F, methyl and CF 3 .
  • R 4A and R 4B is R 4 , and the other is selected from H, F, methyl and CF 3 .
  • R 3 is a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 N heteroatoms, it may be selected from the any of the groups:
  • pyrrolyl (azole) (5-membered), pyridyl (azine) (6-membered), imidazolyl (1 ,3-diazole) (5- membered), pyrazolyl (1 ,2-diazole) (5-membered), pyridazinyl (1 ,2-diazine) (6-membered), pyrimidinyl (1 ,3-diazine) (6-membered) (e.g., cytosine, thymine, uracil), pyrazine
  • R 3 is a substituted 6 membered heteroaryl group, it may have one of the following structures:
  • R 6 , R 7 and R 8 are independently selected from H, F, methyl and CF 3 .
  • R 4A and R 4B are R 4 , and the other is selected from H, F, methyl and CF 3 .
  • R 4 When R 4 is alpha to the -C 2 H 4 -group, it may also be described as being ortho. When R 4 is beta to the -C 2 H 4 -group, it may also be described as being meta.
  • R 4 is alpha to the -C 2 H 4 -group.
  • the further optional substituents on R 3 are independently selected from F, methyl and CF 3 . These further groups may be at any available ring position on R 3 , except that occupied by R 4 . There may be up to 4 further optional substituents groups (i.e. 1 , 2, 3 or 4) depending on the nature of R 3 , and in particular on the number of ring heteroaroms.
  • R 3 is phenyl and R 6 , R 7 and R 8 (if present) are H.
  • R 4 is selected from CH 2 -C(0)N(R N13 )Z 4 , NR N14 (S0 2 )R S1 and C(0)N(R N13 )Z 4 .
  • R 4 is -CH 2 -C(0)N(R N13 )Z 4
  • R N13 is selected from H and Ci -2 alkyl
  • Z 4 is selected from H, Ci -2 alkyl or OCH 3
  • R 4 is selected from:
  • R 4 is -NR N14 (S0 2 )R S1
  • R N14 is selected from H and C 1-3 alkyl
  • R S1 is selected from C 1-3 alkyl.
  • R 4 is selected from:
  • R 4 is -C(0)N(R N13 )Z 4
  • R N13 is selected from H and Ci -2 alkyl
  • Z 4 is selected from H, Ci -2 alkyl and OCH 3 .
  • R 4 is selected from:
  • R 4 is selected from CH 2 -C(0)N(R N13 )Z 4 and C(0)N(R N13 )Z 4 . In some embodiments, R 4 is -CH 2 -C(0)NH 2 .
  • R 4 is -NMe(S02)Me. In some embodiments, R 4 is -C(0)NHMe.
  • R 3 is substituted phenyl
  • R 4 is either alpha or beta to the -C 2 H 4 - group, and is -CH 2 -C(0)N(R N13 )Z 4 where R N13 is selected from H and CH 3 ; and Z 4 is selected from H, CH 3 and OCH 3 .
  • R 4 is alpha to the -C 2 H 4 - group.
  • Embodiments of the invention which are of particular interest include the following compounds or isomers, salts, solvates or prodrugs thereof:
  • the compound is selected from any one of compounds C1 to C18 of the Examples, or isomers, salts, solvates or prodrugs thereof.
  • the compound is selected from any one of the following compounds, or isomers, salts, solvates or prodrugs thereof:
  • the compound is selected from any one of the following compounds, or isomers, salts, solvates or prodrugs thereof:
  • the compound is selected from any one of the following compounds, or isomers, salts, solvates or prodrugs thereof:
  • the compound is selected from any one of the following compounds, or isomers, salts, solvates or prodrugs thereof:
  • a reference to carboxylic acid (-COOH) also includes the anionic (carboxylate) form (-COO " ), a salt or solvate thereof, as well as conventional protected forms.
  • a reference to an amino group includes the protonated form (-N + HR 1 R 2 ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
  • a reference to a hydroxyl group also includes the anionic form (-0 " ), a salt or solvate thereof, as well as conventional protected forms of a hydroxyl group.
  • alpha and beta are used herein to indicate the relative position of substituent groups on rings. For the avoidance of doubt, their meaning is illustrated with the structure below:
  • bromo group is alpha to the chloro group
  • iodo group is beta to the chloro group
  • Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and l-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers” (or "isomeric forms").
  • isomers are structural (or constitutional) isomers (i.e. isomers which differ in the connections between atoms rather than merely by the position of atoms in space).
  • a reference to a methoxy group, -OCH 3 is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH 2 OH.
  • a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta- chlorophenyl.
  • a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C 1-7 alkyl includes n-propyl and /so-propyl; butyl includes n-, iso-, sec-, and ferf-butyl; methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and /so-propyl
  • butyl includes n-, iso-, sec-, and ferf-butyl
  • methoxyphenyl includes ortho-, meta-, and para- methoxyphenyl
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime,
  • H may be in any isotopic form, including 1 H, 2 H (D), and 3 H (T); C may be in any isotopic form, including 12 C, 13 C and 14 C; O may be in any isotopic form, including 16 0 and 18 0; and the like.
  • a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof.
  • Methods for the preparation (e.g. asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting the methods taught herein, or known methods, in a known manner.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms of thereof, for example, as discussed below. It may be convenient or desirable to prepare, purify, and/or handle a corresponding salt of the active compound, for example, a pharmaceutically-acceptable salt. Examples of pharmaceutically acceptable salts are discussed in Berge et al. J. Pharm. Sci., 66, 1-19 (1977).
  • a salt may be formed with a suitable cation.
  • suitable inorganic cations include, but are not limited to, alkali metal ions such as Na + and K + , alkaline earth cations such as Ca 2+ and Mg 2+ , and other cations such as Al 3+ .
  • suitable organic cations include, but are not limited to, ammonium ion (i.e., NH 4 + ) and substituted ammonium ions (e.g., NH 3 R + , NH 2 R2 + , NHR 3 + , NR ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine,
  • diethanolamine piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as amino acids, such as lysine and arginine.
  • amino acids such as lysine and arginine.
  • An example of a common quaternary ammonium ion is N(CH 3 ) 4 + .
  • a salt may be formed with a suitable anion.
  • suitable inorganic anions include, but are not limited to, those derived from the following inorganic acids:
  • organic anions include, but are not limited to, those derived from the following organic acids: acetic, propionic, succinic, glycolic, stearic, palmitic, lactic, malic, pamoic, tartaric, citric, gluconic, ascorbic, maleic, hydroxymaleic, phenylacetic, glutamic, aspartic, benzoic, cinnamic, pyruvic, salicyclic, sulfanilic, 2- acetyoxybenzoic, fumaric, phenylsulfonic, toluenesulfonic, methanesulfonic, ethanesulfonic, ethane disulfonic, oxalic, pantothenic, isethionic, valeric, lactobionic, and gluc
  • solvate is used herein in the conventional sense to refer to a complex of solute (e.g. active compound, salt of active compound) and solvent. If the solvent is water, the solvate may be conveniently referred to as a hydrate, for example, a mono-hydrate, a di-hydrate, a tri-hydrate, etc. It may be convenient or desirable to prepare, purify, and/or handle the active compound in a chemically protected form.
  • chemically protected form pertains to a compound in which one or more reactive functional groups are protected from undesirable chemical reactions, that is, are in the form of a protected or protecting group (also known as a masked or masking group or a blocked or blocking group).
  • a protected or protecting group also known as a masked or masking group or a blocked or blocking group.
  • the aldehyde or ketone group is readily regenerated by hydrolysis using a large excess of water in the presence of acid.
  • an amine group may be protected, for example, as an amide or a urethane, for example, as: a methyl amide (-NHCO-CH 3 ); a benzyloxy amide (-NHCO-OCH 2 C 6 H 5 , -NH- Cbz); as a t-butoxy amide (-NHCO-OC(CH 3 ) 3 , -NH-Boc); a 2-biphenyl-2-propoxy amide (- NHCO-OC(CH 3 )2C 6 H 4 C 6 H5, -NH-Bpoc), as a 9-fluorenylmethoxy amide (-NH-Fmoc), as a 6- nitroveratryloxy amide (-NH-Nvoc), as a 2-trimethylsilylethyloxy amide (-NH-Teoc), as a 2,2,2-trichloroethyloxy amide (-NH-Troc), as an allyloxy amide (-NH-All) (
  • a carboxylic acid group may be protected as an ester for example, as: an C 1-7 alkyl ester (e.g. a methyl ester; a t-butyl ester); a C 1-7 haloalkyl ester (e.g., a C 1-7 trihaloalkyl ester); a triC 1-7 alkylsilyl-C 1-7 alkyl ester; or a C 5-2 o aryl-C ⁇ alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester); or as an amide, for example, as a methyl amide.
  • an C 1-7 alkyl ester e.g. a methyl ester; a t-butyl ester
  • a C 1-7 haloalkyl ester e.g., a C 1-7 trihaloalkyl ester
  • prodrug refers to a compound which, when metabolised (e.g. in vivo), yields the desired active compound.
  • the prodrug is inactive, or less active than the active compound, but may provide advantageous handling, administration, or metabolic properties.
  • Examples of such metabolically labile esters include those wherein R is C1-7 alkyl (e.g. -Me, -Et); C 1-7 aminoalkyl (e.g. aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy- Ci-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g.
  • pivaloyloxymethyl acetoxymethyl; 1 - acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl;
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound.
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • the compounds of formula (I) may exhibit improved selectivity for VEGFR3 over other kinases such as VEGFR2.
  • the selectivity of the compounds for inhibiting VEGFR3 over other kinases, such as VEGFR2 can be demonstrated by cellular assay results (see, for example, the VEGFR3 assay described below).
  • the compounds of formula (I) may exhibit improved VEGFR3 activity and accordingly improved in vivo efficacy for cancer.
  • the compounds of formula (I) may exhibit improved FAK activity and accordingly improved in vivo efficacy for cancer.
  • the compounds of formula (I) may exhibit improved pharmacokinetic and safety profiles. These compounds may have diminished activity on safety targets, such as hERG and/or CYP450S.
  • the compounds of the invention can be prepared by employing the following general methods and using procedures described in detail in the experimental section.
  • the reaction conditions referred to are illustrative and non-limiting.
  • the process for the preparation of a compound of formula (I) or isomers, salts, solvates or prodrug thereof comprises reacting a compound of formula F1
  • R 2 and R 3 are as defined in formula (I) above and L 1 and L 2 are leaving groups.
  • the leaving groups L 1 and L 2 may be any suitable leaving groups, such as a halogen atom (F, CI, Br, I), -SR or -S0 2 R where R is a Ci_ 4 straight chain or branched alkyl group.
  • L 1 and L 2 may be the same or different and may be selected from the group consisting of CI, Br, I, SMe, S0 2 Me.
  • Compounds of formula (I), as described above, can be prepared by synthetic strategies outlined below, wherein the definitions above apply:
  • 2,4-dichloro-5-(trifluoromethyl)pyrimidine (G1 ) can be selectively reacted with sodium thiomethoxide in the presence of zinc(ll) chloride to give 2-thiomethyl-4- chloro-5-(trifluoromethyl)pyrimidine (G2).
  • 2-Thiomethyl-4-chloro-5-(trifluoromethyl)pyrimidine (G2) can be further reacted, for example by conversion to 2-thiomethyl-4-iodo-5- (trifluoromethyl)pyrimidine (G3) under Finkelstein conditions and/or by oxidation with m- CPBA to give the corresponding sulfone if further differentiation of the 2 and 4-position is required or if additional activation is desirable.
  • Examples of commercially available amino compounds of the formula F2 include, but are not limited to those depicted in table 1.
  • Synthetic amino compounds of the invention may be prepared via a range of procedures. It will be appreciated that heterocyclic analogues may also be prepared by analogous methods to those outlined below via substitution of heteroaromatic ring-containing starting materials with suitable heteroaromatic systems.
  • Carbonyl compounds of the formula F6 can be reacted with 2-methylpropane-2-sulfinamide (G50) to give compounds of the formula F7.
  • Compounds of the formula F7 can be reacted with anions prepared from suitably protected amino compounds, for example ⁇ /-(4- bromophenyl)-1 ,1 ,1-trimethyl-/V-(trimethylsilyl)silanamine (G51 ) treated with n-butyllithium, to give compounds of the formula F8.
  • Hydrolysis of compounds of the formula F8 under acidic conditions, for example using aqueous hydrochloric acid gives compounds of the formula F9.
  • compounds of the formula F9 can be further protected to facilitate regiospecific reactivity.
  • Q 1 and Q 2 may be the same or different and may be fused together to form a ring structure, for example as in cyclobutanone - Substituents Q 1 and Q 2 form either R C1 or part of X in compounds of formula I. It will also be appreciated that anions of suitably protected amino heterocycles may be added to compounds of the formula F7 to give heterocyclic analogues of compounds of the formula F9. It will also be appreciated that the phenyl in F9 may be substituted with substituents R 1B and/or R 1C as described above.
  • R 3 is aryl or substituted aryl compounds of the formula F13 may be prepared as outlined in scheme O.
  • Halogenation, for example using /V-bromosuccinimide, of compounds of the formula F10 gives compounds of the formula F11 , Compounds of the formula F11 may be reacted under Sonagashira type coupling conditions to give acetylenes of the formula F12 where R 9 is TMS, TES or
  • R 9 may then be removed to generate compounds of the formula F13.
  • R 9 is TMS or TES
  • potassium carbonate or tetra-n-butyl ammonium fluoride may be employed to induce this transformation.
  • R 9 is C(CH 3 ) 2 OH
  • sodium hydride in refluxing toluene may be used.
  • heteroaryl analogues of F13 may be prepared as outlined in Schemes P, Q and R.
  • 2,3-di-chloropyrazine (G52) can be reacted with ethyl acetate in the presence of LiHMDS to give ester G53.
  • Coupling of ester G53 with TMS acetylene under Sonagashira conditions gives ethyl 2-(3-((trimethylsilyl)ethynyl)pyrazin-2- yl)acetate (G54).
  • Removal of the trimethylsilyl group using TBAF gives ethyl 2-(3- ethynylpyrazin-2-yl)acetate (G55).
  • diethyl succinate (G56) and ethyl formate (G57) can be condensed to give aldehyde G58 in the presence of sodium metal.
  • Cyclisation using thiourea gives 4-oxo-2-thioxo-1 ,2,3,4-tetrahydropyrimidine (G59).
  • Desulfurisation using Raney-nickel gives pyrimidone G60, which can be converted to 4-chloro pyrimidine G61 using phosphorous oxychloride.
  • 2-(pyridin-3-yl)acetonitrile (G64) can be oxidised to /V-oxide G65.
  • Chlorination with phosphorous oxychloride gives 2-chloropyridine G66 which can be hydrolysed with sodium hydroxide to acetic acid G67.
  • Ester formation using methanol gives 2-chloropyridine ester G68.
  • Coupling of ester G68 with TES-acetylene under Sonagashira conditions, followed by removal of the triethylsilyl group using TBAF gives methyl 2-(2- ethynylpyridin-3-yl)acetate (G70).
  • the other regioisomeric pyridine analogues can be prepared using an analogous sequence starting from other commercially available pyridyl acetates.
  • Pyrimidines of the formula F3 may be reacted with terminal acetylenes of the formula F13 to give acetylenes of the formula F14 in a Sonagashira type coupling.
  • the acetylene in compounds of the formula F14 may be reduced to an alkane of the formula F15 using hydrogen gas in the presence of a transition metal catalyst.
  • the exact choice of catalyst and conditions employed is dependent on the nature of R 2 . For example, where R 2 is selected from F, CF 3 , methyl and methoxy, 10% Pd/C may be used, where R 2 is CI, platinum oxide is employed.
  • Functional group manipulation may be carried out on compounds of the formula F15 if necessary.
  • esters compounds of the formula F15 where Q 3 is O-alkyl
  • carboxylic acids of the formula F15 where Q 3 is OH may then be deprotected to give carboxylic acids of the formula F15 where Q 3 is OH.
  • esters where Q 3 is OMe lithium hydroxide solutions may be employed.
  • Q 3 is Of- Bu acidic solutions, for example trifluoroacetic acid in dichloromethane may be used to facilitate hydrolysis. It will be appreciated that under acidic conditions Boc protecting groups in A will also be cleaved.
  • heteroaromatic analogues of compounds of the formula F13 may be coupled in an analogous manner to that described in scheme S and then further elaborated to amides as described above.
  • triacetoxyborohydride to give /V-Me analogues; by reductive alkylation with acetaldehyde in the presence of sodium triacetoxyborohydride to give N-Et analogues or the /V-acetyl analogues may be prepared by reaction with a suitable acylating agent, for example acetic anhydride.
  • a suitable acylating agent for example acetic anhydride.
  • Pyrimidines of the formula F1 may be coupled to acetylenes of the formula F13 to give acetylenes of the formula F16 in a Sonagashira type coupling. Depending on the nature of R 2 these couplings may either be regioselective, or where mixtures are obtained, regioisomers may be separated by chromatography.
  • the acetylene in compounds of the formula F16 may be reduced to an alkane of the formula F17 using hydrogen gas in the presence of a transition metal catalyst.
  • the exact choice of catalyst and conditions employed is dependent on the nature of R 2 . For example, where R 2 is Me, 10% Pd/C may be used, where R 2 is CI, platinum oxide is employed.
  • the desired amide may already be present in compounds of the formula F13, or an ester may be used and subsequently derivatised as described above.
  • R 9 is C(CH 3 ) 2 OH
  • sodium hydride in refluxing toluene may be used.
  • Compounds of the formula F20 may be reacted in an analogous manner to the routes described in Schemes S, T and U to give compounds of the formula F21.
  • Compounds of the formulae F22 and F23 are either commercially available or may be prepared synthetically.
  • compounds of the formula F22 may be halogenated using N-halsuccinimide to give compounds of the formula F23.
  • a substituted 2-iodobenzoic acid may be amidated to give compounds of formula F23.
  • Compounds of the formula F23 may be reacted under Sonagashira type coupling conditions to give acetylenes of the formula F24 where the protecting group, R 9 is TMS, TES or C(CH 3 ) 2 OH. In compounds of the formula F24, R 9 may then be removed to generate compounds of the formula F25.
  • Potassium carbonate or tetra-n-butyl ammonium fluoride can be used to remove the protecting group, when R 9 is TMS or TES.
  • R 9 is C(CH 3 ) 2 OH
  • sodium hydride in refluxing toluene may be used.
  • Compounds of the formula F20 may be reacted in an analogous manner to the routes described in Schemes S and T to give compounds of the formula F21.
  • the present invention provides active compounds, specifically, active 2,4,5-substituted pyrimidines .
  • active pertains to compounds which are capable of inhibiting VEGFR3 activity, and specifically includes both compounds with intrinsic activity (drugs) as well as prodrugs of such compounds, which prodrugs may themselves exhibit little or no intrinsic activity.
  • the present invention further provides a method of inhibiting VEGFR3 activity in a cell, comprising contacting said cell with an effective amount of an active compound, preferably in the form of a pharmaceutically acceptable composition. Such a method may be practised in vitro or in vivo.
  • the present invention further provides active compounds which inhibit VEGFR3 activity, as well as methods of inhibiting VEGFR3, comprising contacting a cell with an effective amount of an active compound, whether in vitro or in vivo.
  • Active compounds may also be used as part of an in vitro assay, for example, in order to determine whether a candidate host is likely to benefit from treatment with the compound in question.
  • the invention further provides active compounds for use in a method of treatment of the human or animal body.
  • a method may comprise administering to such a subject a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • treatment as used herein in the context of treating a condition, pertains generally to treatment and therapy, whether of a human or an animal (e.g. in veterinary applications), in which some desired therapeutic effect is achieved, for example, the inhibition of the progress of the condition, and includes a reduction in the rate of progress, a halt in the rate of progress, amelioration of the condition, and cure of the condition.
  • Treatment as a prophylactic measure i.e. prophylaxis
  • prophylaxis is also included.
  • terapéuticaally-effective amount refers to that amount of an active compound, or a material, composition or dosage from comprising an active compound, which is effective for producing some desired therapeutic effect, commensurate with a reasonable benefit/risk ratio.
  • active compounds which are anticancer agents.
  • One of ordinary skill in the art is readily able to determine whether or not a candidate compound treats a cancerous condition for any particular cell type, either alone or in combination.
  • the use of the active compounds for the treatment of cancer in the human or animal body there is provided the use of the active compounds for the treatment of cancer in the human or animal body.
  • active compounds for use in a method of treatment of cancer in the human or animal body may comprise administering to such a subject a therapeutically-effective amount of an active compound, preferably in the form of a pharmaceutical composition.
  • cancers include, but are not limited to, bone cancer, brain stem glioma, breast cancer, cancer of the adrenal gland, cancer of the anal region, cancer of the bladder, cancer of the endocrine system, cancer of the oesophagus, cancer of the brain, cancer of the head or neck, cancer of the kidney or ureter, cancer of the liver, cancer of the parathyroid gland, cancer of the penis, cancer of the small intestine, cancer of the thyroid gland, cancer of the urethra, carcinoma of the cervix, carcinoma of the endometrium, carcinoma of the fallopian tubes, carcinoma of the renal pelvis, carcinoma of the vagina, carcinoma of the vulva, chronic or acute leukemia, acute myelogenous leukemia, colon cancer, melanoma such as cutaneous or intraocular melanoma, haemetological malignancies, Hodgkin's disease, lung cancer, non-small cell lung cancer (NSCLC), mesothelioma, lymphocytic lymph
  • the cancer includes types and/or subtypes that display amplification of FAK expression. These include: hepatocellular carcinoma, non-small cell lung cancer, small cell lung carcinoma, breast cancer, pancreatic cancer, brain cancer, sarcoma, osteosarcoma, ovarian cancer, cervical cancer, colon cancer, neuroblastoma, thyroid cancer, prostate cancer, head and neck cancer, hematopoietic cancer and mesothelioma.
  • FAK inhibitor compounds will be used for the treatment of tumor types or subtypes that have inactivated NF2 gene, or mutated KRAS and CDKN2A genes or inactivated p53 gene.
  • Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g., bowel, colon), breast (mammary), ovarian, prostate, liver (hepatic), kidney (renal), bladder, pancreas, brain, skin, blood, endothelial or epithelial.
  • Compounds of the present invention may also be useful in inhibiting lymphangiogenesis and/or suppressing lymph node metastasis. Compounds of the present invention may also be useful in inhibiting tumor angiogenesis, tumor cell invasion and/or suppressing
  • Compounds of the present invention may also be useful in preventing the spread of cancer and in the prevention of metastasis.
  • Compounds of the present invention may also be useful in inhibiting several cancer properties, processes and cell configurations, including but not limited to, growth, survival, de-differentiation (epithelial-to-mesenchymal transition), invasion, metastasis, angiogenesis, lymphangiogenesis, cancer stem cells.
  • a compound of formula (I) or an isomer, salt, solvate, protected form or prodrug thereof to prevent the spread of cancer or prevent metastasis.
  • a compound of formula (I) or an isomer, salt, solvate or prodrug thereof for use in a method for preventing the spread of cancer or preventing of metastasis.
  • an anti-cancer treatment comprising a compound of formula (I) or an isomer, salt, solvate or prodrug thereof and an anti-tumour agent.
  • anti-cancer treatment may be applied as a sole therapy or may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
  • chemotherapy may include one or more of the following categories of anti-tumour agents:-
  • antiproliferative/antineoplastic drugs and combinations thereof as used in medical oncology, such as alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); 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
  • epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin);
  • cytostatic agents such as antioestrogens (for example tamoxifen, fulvestrant, 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, letrozole, vorazole and exemestane
  • inhibitors of 5 * -reductase such as finasteride
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1 -yl)ethoxy]-5-tetrahydropyran-4- yloxyquinazoline (AZD0530; International Patent Application WO 01/94341 ), N-(2-chloro-6- methylphenyl)-2- ⁇ 6-[4-(2-hydroxyethyl)piperazin-1 -yl]-2-methylpyrimidin-4-ylamino ⁇ thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med.
  • anti-invasion agents for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1 -yl)ethoxy]-5-tetrahydr
  • inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the anti erbB2 antibody trastuzumab [HerceptinT], the anti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. Critical reviews in oncology/haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as
  • N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6 ,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI 774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)- quinazolin-4-amine (CI 1033), erbB2 tyrosine kinase inhibitors such as lapatinib, inhibitors of the hepatocyte growth factor family, inhibitors of the platelet-derived growth factor family such as imatinib, inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafen
  • antiangiogenic and antilymphangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor A (VEG FA) antibody bevacizumab (AvastinT), the anti-vascular endothelial cell growth factor A (VEG FA) antibody ranibizumab, the anti-VEGF aptamer pegaptanib, the anti- vascular endothelial growth factor receptor 3 (VEGFR3) antibody IMC-3C5, the anti-vascular endothelial cell growth factor C (VEGFC) antibody VGX-100, the anti-vascular endothelial cell growth factor D (VEGFD) antibody VGX-200, the soluble form of the vascular endothelial growth factor receptor 3 (VEGFR3) VGX-300 and VEGF receptor tyrosine kinase inhibitors such as 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1
  • vascular damaging agents such as Combretastatin A4 and compounds disclosed in International Patent Applications WO 99/02166, WO 00/40529, WO 00/41669, WO
  • 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 BRCA1 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
  • 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
  • a combination of particular interest is with docetaxel.
  • Other possible combinations of interest include with paclitaxel, gemcitabine, cisplatin, carboplatin, oxaliplatin, 5-fluorouracil, doxorubicin, temozolomide, sunitinib, axitinib, sorafenib, pazopanib, cabozantinib, the camptothecin prodrug irinotecan and radiotherapy.
  • the present invention provides active compounds which are useful in preventing and/or treating diseases or conditions ameliorated by the control and/or inhibition of
  • a compound of formula (I) or an isomer, salt, solvate, protected form or prodrug thereof to inhibit, suppress or reduce lymphangiogenesis.
  • a compound of formula (I) or an isomer, salt, solvate, protected form or prodrug thereof for use in the method of inhibiting, suppressing or reducing
  • these diseases or conditions may include:
  • eye diseases for example corneal graft rejection and age related macular degeneration
  • the active compounds of formula (I) are useful in preventing and/or treating diseases or conditions ameliorated by the control and/or inhibition of angiogenesis or inflammation.
  • a compound of formula (I) or formula (II) or an isomer, salt, solvate, protected form or prodrug thereof to inhibit, suppress or reduce angiogenesis.
  • a compound of formula (I) or formula (II) or an isomer, salt, solvate, protected form or prodrug thereof for use in the method of inhibiting, suppressing or reducing angiogenesis.
  • These diseases or conditions may include:
  • eye diseases for example corneal graft rejection and age related macular degeneration
  • cardiovascular diseases such as atherosclerosis
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether
  • oral e.g. by ingestion
  • topical including e.g. transdermal, intranasal, ocular, buccal, and sublingual
  • pulmonary e.g. by inhalation or insufflation therapy using, e.g. an aerosol, e.g. through mouth or nose
  • rectal vaginal
  • parenteral for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal,
  • the subject may be a eukaryote, an animal, a vertebrate animal, a mammal, a rodent (e.g. a guinea pig, a hamster, a rat, a mouse), murine (e.g. a mouse), canine (e.g. a dog), feline (e.g. a cat), equine (e.g. a horse), a primate, simian (e.g. a monkey or ape), a monkey (e.g. marmoset, baboon), an ape (e.g. gorilla, chimpanzee, orang-utan, gibbon), or a human.
  • a rodent e.g. a guinea pig, a hamster, a rat, a mouse
  • murine e.g. a mouse
  • canine e.g. a dog
  • feline e.g. a cat
  • the active compound While it is possible for the active compound to be administered alone, it is preferable to present it as a pharmaceutical composition (e.g. formulation) comprising at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, adjuvants, excipients, diluents, fillers, buffers, stabilisers, preservatives, lubricants, or other materials well known to those skilled in the art and optionally other therapeutic or prophylactic agents.
  • a pharmaceutical composition e.g. formulation
  • the present invention further provides pharmaceutical compositions, as defined above, and methods of making a pharmaceutical composition comprising admixing at least one active compound, as defined above, together with one or more pharmaceutically acceptable carriers, excipients, buffers, adjuvants, stabilisers, or other materials, as described herein.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgement, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio.
  • a subject e.g. human
  • Each carrier, excipient, etc. must also be “acceptable” in the sense of being compatible with the other ingredients of the formulation.
  • Suitable carriers, excipients, etc. can be found in standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1990.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active compound with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active compound with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.
  • Formulations may be in the form of liquids, solutions, suspensions, emulsions, elixirs, syrups, tablets, losenges, granules, powders, capsules, cachets, pills, ampoules, suppositories, pessaries, ointments, gels, pastes, creams, sprays, mists, foams, lotions, oils, boluses, electuaries, or aerosols.
  • Formulations suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets, each containing a predetermined amount of the active compound; as a powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion; as a bolus; as an electuary; or as a paste.
  • a tablet may be made by conventional means, e.g., compression or moulding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared by compressing in a suitable machine the active compound in a free-flowing form such as a powder or granules, optionally mixed with one or more binders (e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose); fillers or diluents (e.g. lactose, microcrystalline cellulose, calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc, silica); disintegrants (e.g.
  • Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active compound therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.
  • Formulations suitable for topical administration may be formulated as an ointment, cream, suspension, lotion, powder, solution, past, gel, spray, aerosol, or oil.
  • a formulation may comprise a patch or a dressing such as a bandage or adhesive plaster impregnated with active compounds and optionally one or more excipients or diluents.
  • Formulations suitable for topical administration in the mouth include losenges comprising the active compound in a flavoured basis, usually sucrose and acacia or tragacanth; pastilles comprising the active compound in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active compound in a suitable liquid carrier.
  • Formulations suitable for topical administration to the eye also include eye drops wherein the active compound is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active compound.
  • Formulations suitable for nasal administration wherein the carrier is a solid, include a coarse powder having a particle size, for example, in the range of about 20 to about 500 microns which is administered in the manner in which snuff is taken, i.e. by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
  • Suitable formulations wherein the carrier is a liquid for administration as, for example, nasal spray, nasal drops, or by aerosol administration by nebuliser include aqueous or oily solutions of the active compound.
  • Formulations suitable for administration by inhalation include those presented as an aerosol spray from a pressurised pack, with the use of a suitable propellant, such as
  • dichlorodifluoromethane trichlorofluoromethane, dichoro-tetrafluoroethane, carbon dioxide, or other suitable gases.
  • Formulations suitable for topical administration via the skin include ointments, creams, and emulsions.
  • the active compound When formulated in an ointment, the active compound may optionally be employed with either a paraffinic or a water-miscible ointment base.
  • the active compounds may be formulated in a cream with an oil-in-water cream base.
  • the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydric alcohol, i.e., an alcohol having two or more hydroxyl groups such as propylene glycol, butane-1 ,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol and mixtures thereof.
  • the topical formulations may desirably include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethylsulfoxide and related analogues.
  • the oily phase may optionally comprise merely an emulsifier (otherwise known as an emulgent), or it may comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil.
  • an emulsifier otherwise known as an emulgent
  • a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabiliser. It is also preferred to include both an oil and a fat.
  • the emulsifier(s) with or without stabiliser(s) make up the so-called emulsifying wax
  • the wax together with the oil and/or fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.
  • Suitable emulgents and emulsion stabilisers include Tween 60, Span 80, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate and sodium lauryl sulphate.
  • the choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties, since the solubility of the active compound in most oils likely to be used in pharmaceutical emulsion formulations may be very low.
  • the cream should preferably be a non-greasy, non-staining and washable product with suitable consistency to avoid leakage from tubes or other containers.
  • Straight or branched chain, mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required.
  • mono- or dibasic alkyl esters such as di- isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may
  • high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils can be used.
  • Formulations suitable for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter or a salicylate.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active compound, such carriers as are known in the art to be appropriate.
  • Formulations suitable for parenteral administration include aqueous and nonaqueous isotonic, pyrogen-free, sterile injection solutions which may contain anti-oxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents, and liposomes or other microparticulate systems which are designed to target the compound to blood components or one or more organs.
  • Suitable isotonic vehicles for use in such formulations include Sodium Chloride Injection, Ringer's Solution, or Lactated Ringer's Injection.
  • concentration of the active compound in the solution is from about 1 ng/mL to about 10 ⁇ g mL, for example from about 10 ng/ml to about 1 ⁇ g/mL
  • the formulations may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
  • Formulations may be in the form of liposomes or other microparticulate systems which are designed to target the active compound to blood components or one or more organs.
  • appropriate dosages of the active compounds, and compositions comprising the active compounds can vary from patient to patient. Determining the optimal dosage will generally involve the balancing of the level of therapeutic benefit against any risk or deleterious side effects of the treatments of the present invention.
  • the selected dosage level will depend on a variety of factors including, but not limited to, the activity of the particular compound, the route of administration, the time of administration, the rate of excretion of the compound, the duration of the treatment, other drugs, compounds, and/or materials used in combination, and the age, sex, weight, condition, general health, and prior medical history of the patient.
  • the amount of compound and route of administration will ultimately be at the discretion of the physician, although generally the dosage will be to achieve local concentrations at the site of action which achieve the desired effect without causing substantial harmful or deleterious side-effects.
  • Administration in vivo can be effected in one dose, continuously or intermittently (e.g. in divided doses at appropriate intervals) throughout the course of treatment. Methods of determining the most effective means and dosage of administration are well known to those of skill in the art and will vary with the formulation used for therapy, the purpose of the therapy, the target cell being treated, and the subject being treated. Single or multiple administrations can be carried out with the dose level and pattern being selected by the treating physician.
  • a suitable dose of the active compound is in the range of about 100 ⁇ g to about 250 mg per kilogram body weight of the subject per day.
  • the active compound is a salt, an ester, prodrug, or the like
  • the amount administered is calculated on the basis of the parent compound and so the actual weight to be used is increased proportionately.
  • LCMS Agilent 1100 Series LC/MSD, column Luna 5 ⁇ C8, 150 x 4.6 mm, with mobile phase 80% ACN, 15% H20, 5% buffer (3:1 MeOH/H20, 315 mg HC02NH4, 1 mL AcOH) and MS detection (ESI method).
  • Analytical thin-layer chromatography was performed on Merck silica gel 60F254 aluminium- backed plates which were visualised using fluorescence quenching under UV light or using an acidic anisaldehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purification system using standard RediSep® cartridges. Microwave irradiation was achieved using a CEM Explorer 48 Microwave Reactor. All reactions carried out using microwave irradiation were stirred..
  • anhydrous solvents were prepared using a Glascontour purification system or purchased from Sigma-Aldrich.
  • Analytical thin-layer chromatography was performed on Merck silica gel 60F254 aluminium- backed plates which were visualised using fluorescence quenching under UV light or using an acidic anisaldehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Teledyne Isco CombiFlash Rf purification system using standard RediSep® cartridges. Microwave irradiation was achieved using a CEM Explorer 48 Microwave Reactor. All reactions carried out using microwave irradiation were stirred.
  • anhydrous solvents were prepared using a Glascontour purification system or purchased from Sigma-Aldrich.
  • Example C3 2-(2- ⁇ 2-[2- ⁇ [3,5-Dimethyl-1-(1-methylpiperidin-4-yl)-1H-pyrazol-4- yl]amino ⁇ -5-(trifluoromethyl)pyrimidin-4-yl]ethyl ⁇ phenyl)acetamide
  • Example C5 2-(2- ⁇ 2-[2- ⁇ [1 -(1 -ethylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino ⁇ -5- (trifluoromethyl)pyrimidin-4-yl]ethyl ⁇ phenyl)acetamide
  • Example C6 2-(2- ⁇ 2-[2-( ⁇ 1 -[1 -(propan-2-yl)piperidin-4-yl]-1 H-pyrazol-4-yl ⁇ amino)-5- (trifluoromethyl)pyrimidin-4-yl]ethyl ⁇ phenyl)acetamide
  • Example C7 2-(2- ⁇ 2-[2- ⁇ [1 -(1 -acetylpiperidin-4-yl)-1 H-pyrazol-4-yl]amino ⁇ -5- (trifluoromethyl)pyrimidin-4-yl]ethyl ⁇ phenyl)acetamide
  • Acetyl chloride (6 uL, 0.084 mmol) was added to a solution of D2 (20 mg, 0.042 mmol) and triethylamine (23 uL, 0.168 mmol) in DCM (2 mL) and the resulting reaction mixture was stirred at room temperature for 2 h. The solvent was removed and the residue filtered through a short plug of amino bonded silica eluting with methanol/chloroform (1/9). The solvent was removed from the filtrate and the residue purified by PTLC using methanol/chloroform (1/9) to give the titled product (16mg, 74%).
  • Example C13 2-(2-(2-(2-(1 -(1 -(prop-2-ynyl)piperidin-4-yl)-1 H-pyrazol-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide
  • Example C14 2-(2-(2-(2-(1 -(1 -ethylpiperidin-3-yl)-1 H-pyrazol-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide
  • Example C15 2-(2-(2-(2-(1 -(1 -isopropylpiperidin-3-yl)-1 H-pyrazol-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide
  • Example C16 2-(2-(2-(2-(1 -(1 -acetylpiperidin-3-yl)-1 H-pyrazol-4-ylamino)-5- (trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)acetamide
  • Acetyl chloride (12 uL, 0.170 mmol) was added to a solution of D4 (40 mg, 0.085 mmol) and triethylamine (47 uL, 0.340 mmol) in DCM (2 mL) and the resulting reaction mixture was stirred at room temperature for 18 h. The solvent was removed and the residue filtered through a short plug of amino bonded silica eluting with methanol/chloroform (1/9). The solvent was removed from the filtrate and the residue purified by PTLC using methanol/chloroform (1/9) to give the titled product (28 mg, 64%).
  • the activity of compounds of the invention can be profiled using the following assays.
  • the human Phospho-FAK (y397) DuoSet IC ELISA (R& D Systems ) is used to determine the inhibition of phosphorylation of FAK in MDA-MB-231 breast cancer cells after exposure to the FAK inhibitor compound of interest.
  • cells are exposed to a 9 point dilution series of FAK inhibitor for 1 hour in normal cellular conditions.
  • Cellular proteins are then lysed and collected in the presence of protease and phosphatase inhibitors and used for analysis.
  • a detection antibody specific to FAK phosphorylated at the Tyr397 position is used.
  • the presence of the secondary protein is then quantitated using a substrate specific to the Streptavidin-HRP tag associated with the antibody.
  • Compounds of the formula 1 including C3, C4, C5, C6, C7, C10 show activity against FAK in assay P1 with IC 50 ⁇ 5 ⁇ .
  • HMVEC-dLyAD Human dermal lymphatic microvascular endothelial cells
  • EGM-2MV Cat# CC-3202, Lonza
  • the media was replaced with EBM-2 (Cat # CC-3156, Lonza) + 0.1 % BSA (Cat# A8412, Sigma) and cells incubated for a further period (overnight at 37 °C and 5% C0 2 ).
  • the coating antibody was flicked out and the plates washed three times with Wash Buffer (Phosphate buffered saline (137 mM NaCI, 2.7 nM KCI, 8.1 nM Na 2 HP0 4 , 1 .5 mL KH 2 P0 4 , pH 7.2-7.4), 0.05% Tween 20).
  • 300 ⁇ _ of blocking buffer (5% v/v Tween 20, 5% w/v sucrose in PBS) was then added to wells and plate incubated for 2 hours at room temperature. Blocking solution is flicked out and plates washed three times and tapped dry.
  • Compound dilution series were prepared in EBM-2 (Cat # CC-3156, Lonza) + 0.1 % BSA (Cat# A8412, Sigma) with constant 0.1 % DMSO concentration. 439 ⁇ of sample or vehicle control was added to the cell monolayers. Cells are treated for 1 hour at 37 °C and 5% C0 2 . 250 ng/mL Recombinant human VEGFC (Cat # 2179-VC, R & D Systems) added to wells and plates incubated for an additional 10 minutes at 37 °C and 5% C0 2 .
  • Dulbecco's Phosphate Buffered Saline (Cat # 21600-044, Invitrogen). 130 ⁇ _ of Lysis buffer added to wells and cell lysate harvested and transferred to tubes and stored on ice.
  • Complete lysis buffer was prepared by adding 10 ⁇ _ Protease Inhibitor Cocktail (Cat # P8340, Sigma-Aldrich), 10 ⁇ _ PMSF (Phenylmethanesulfonyl fluoride, Cat # P7626, Sigma- Aldrich, prepared as 500mM DMSO stock), 5uL Phosphatase Inhibitor Cocktail (100x) (Cat # 5870 Cell Signaling) per 1 mL of PathScan Sandwich ELISA Lysis Buffer (1X) (Cat # 7018 Cell Signaling) .
  • the harvested samples were then diluted 1 :2 in IC Diluent #18 (5% Tween 20/PBS) and 100 ⁇ transferred to the Total and Phospho VEGFR3 coated, blocked and washed 96 well plates and incubated for 2 hours at room temperature. The plates were then washed three times in wash buffer as described above and tapped dry.
  • Total VEGFR3 100 ⁇ of Detection antibody (Total VEGFR3 Detection Antibody Part# 841888 in Total VEGFR3 kit) diluted in IC Diluent #1 (1 % w/v BSA (Cat # A7906, Sigma-Aldrich)/PBS) was added to wells and the plate incubated for 2 hours at room temperature. The plate was then washed three times in wash buffer and tapped dry.
  • VEGFR3 levels were quantified using a Multiskan Ascent plate reader and Ascent software fitted with 450 nm filter.
  • Detection antibody For detection of Phospho VEGFR3, 100 ⁇ _ of Detection antibody (Anti-Phospho-Tyrosine- HRP Detection Antibody, Part # 841403 in Phospho VEGFR3 kit) was diluted in IC Diluent #1 (1 % w/v BSA/PBS), added to the wells and the plate incubated for 2 hours at room temperature. The plate was then washed three times in wash buffer as described above and tapped dry.
  • Phospho VEGFR3 levels were quantified using a Multiscan ascent plate reader and ascent software fitted with 450 nm filter.
  • IC 50 values are determined by first calculating the level of phospho VEGFR3 relative to Total VEGFR3 according to the following formula:
  • SRP is the Sample Relative Phospho level
  • SP is Phospho VEGFR3 reading
  • ST is Total VEGFR3 reading.
  • Percent inhibition (%l) for each lysate relative to vehicle control (VEGFC stimulated) is then calculated according to the following formula:
  • SRP is the Sample Relative Phospho level as calculated above.
  • %l is plotted against compound concentration and data fitted using a Sigmoidal dose response with IC50 determined from curve.

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Abstract

La présente invention concerne des composés représentés par la formule (I) : L'invention porte également sur des procédés de préparation du composé représenté par la formule (I), des agents ou des compositions pharmaceutiques contenant le composé ou un procédé d'utilisation du composé pour le traitement de maladies prolifératives, telles que le cancer.
PCT/AU2015/000089 2014-02-19 2015-02-19 Inhibiteurs WO2015123722A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114258318A (zh) * 2019-06-17 2022-03-29 德西费拉制药有限责任公司 氨基嘧啶酰胺自噬抑制剂及其使用方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012022408A1 (fr) * 2010-08-18 2012-02-23 Merck Patent Gmbh Dérivés de pyrimidine en tant qu'inhibiteurs de fak
WO2014026243A1 (fr) * 2012-08-17 2014-02-20 Cancer Therapeutics Crc Pty Limited Inhibiteurs de vegfr3
WO2014026242A1 (fr) * 2012-08-17 2014-02-20 Cancer Therapeutics Crc Pty Limited Inhibiteurs de vegfr3

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012022408A1 (fr) * 2010-08-18 2012-02-23 Merck Patent Gmbh Dérivés de pyrimidine en tant qu'inhibiteurs de fak
WO2014026243A1 (fr) * 2012-08-17 2014-02-20 Cancer Therapeutics Crc Pty Limited Inhibiteurs de vegfr3
WO2014026242A1 (fr) * 2012-08-17 2014-02-20 Cancer Therapeutics Crc Pty Limited Inhibiteurs de vegfr3

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114258318A (zh) * 2019-06-17 2022-03-29 德西费拉制药有限责任公司 氨基嘧啶酰胺自噬抑制剂及其使用方法

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