US20160009686A1 - Vegfr3 inhibitors - Google Patents

Vegfr3 inhibitors Download PDF

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US20160009686A1
US20160009686A1 US14/422,093 US201314422093A US2016009686A1 US 20160009686 A1 US20160009686 A1 US 20160009686A1 US 201314422093 A US201314422093 A US 201314422093A US 2016009686 A1 US2016009686 A1 US 2016009686A1
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phenyl
ethyl
group
pyrimidin
amino
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Richard Charles Foitzik
Benjamin Joseph Morrow
Catherine Fae Hemley
Gillian Elizabeth Lunniss
Michelle Ang Camerino
Danny Ganame
Paul Anthony Stupple
Romina Lessene
Wilhelmus Johannes Antonius Kersten
Andrew John Harvey
Ian Peter Holmes
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Cancer Therapeutics CRC Pty Ltd
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Cancer Therapeutics CRC Pty Ltd
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Assigned to CANCER THERAPEUTICS CRC PTY LTD reassignment CANCER THERAPEUTICS CRC PTY LTD ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BIONOMICS LTD, HARVEY, ANDREW JOHN
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—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
    • 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
    • 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
    • C07D403/14—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 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 compounds.
  • VEGFR3 vascular endothelial growth factor receptor 3
  • FLT4 Fms related tyrosine kinase 4
  • Cancer remains a major cause of death in the 21st 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. Onc. 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. Rep.
  • 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. In cancer, VEGFR3 is overexpressed in lymphatic sinuses in metastatic lymph nodes and in lymphangiomas. Furthermore, in many instances cancer cells themselves express VEGFR3. VEGFR3 expressing cancer cells have been shown to be dependent on VEGFR3/VEGFC signalling for their proliferation ( Eur. J. Canc. 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.
  • 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.
  • VEGFR3 inhibitors The present inventors have discovered a particular class of compounds which are effective as VEGFR3 inhibitors. These compounds may exhibit selectivity for VEGFR3 over kinases such as FAK and/or VEGFR2.
  • the present invention provides compounds of the following formula (I), isomers, salts, solvates, protected forms or prodrugs thereof:
  • A is selected from optionally substituted phenyl and an optionally substituted 5-10 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, and; when A is optionally substituted phenyl, A may bear a substituent R 1A which is not alpha to the NH group and may optionally further bear one or two substituents R 1B which are not alpha to the NH group, where R 1A is selected from:
  • R 2 is selected from H, halo, C 1-4 alkyl, CF 3 , CF 2 H, CN and O—(C 1-3 alkyl);
  • 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, 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 ; and
  • R 4 is —Y—C(O)N(R N13 )Z 4 , where Y is selected from —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, C 35 cycloalkylidene;
  • R N13 is selected from H and CH 3 ; and Z 4 is selected from H, CH 3 and OCH 3 .
  • the compounds of the first aspect of the present invention are of formula (I) as defined above with the proviso that the compound is not:
  • the compounds of the first aspect are of formula (I) as defined above with the proviso that:
  • R 3 is selected from:
  • R 4 is —CH(CH 3 )C(O)N(R N13 )Z 4 ;
  • A is either:
  • R 1A is selected from
  • R N1 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N2 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N3 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N4 is selected from H and CH 3
  • R N5 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N7 and R N8 are independently selected from H and CH 3
  • R N9 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N10 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me; or
  • R N1 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N2 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R 2 is not selected from CF 3 , halo, CF 2 H and CN.
  • the compounds of the first aspect are of formula (I) as defined above, wherein when A is phenyl, Y is selected from —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-5 cycloalkylidene.
  • a second aspect of the invention provides a process for the preparation of a compound of formula (I) or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, comprising:
  • a third aspect of the invention provides a pharmaceutical agent comprising a compound of the formula (I) or isomers, salts, solvates, protected forms or prodrugs thereof of the first aspect.
  • the pharmaceutical agent may be an anticancer agent, a lymphangiogenesis inhibitor, an antimetastasis agent or a VEGFR3 inhibitor.
  • a fourth aspect of the invention provides a composition comprising a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect and a pharmaceutically acceptable carrier or diluent.
  • a fifth aspect of the invention provides a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect for use in a method of therapy.
  • a sixth aspect of the invention provides for the use of a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect in the preparation of a medicament for treating a disease or condition ameliorated by the inhibition of VEGFR3.
  • the sixth aspect of the invention also provides a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect for use in a method of treatment of a disease or condition ameliorated by the inhibition of VEGFR3.
  • a seventh aspect of the invention provides for the use of a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect in the preparation of a medicament for the treatment of cancer.
  • the seventh aspect of the invention also provides a compound or an isomer, salt, solvate, protected form or prodrug thereof, an agent of the third aspect or a composition of the fourth aspect of the first aspect for use in a method for the treatment of cancer.
  • a further aspect of the invention provides a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect for use in a method of treatment of the human or animal body, preferably in the form of a pharmaceutical agent or composition.
  • Another aspect of the invention 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 or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect.
  • a still further aspect of the invention provides an anti-cancer treatment comprising a compound or an isomer, salt, solvate, protected form or prodrug thereof of the first aspect, an agent of the third aspect or a composition of the fourth aspect and an anti-tumour agent.
  • A is selected from optionally substituted phenyl and an optionally substituted 5-10 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 is unsubstituted phenyl, it has the structure:
  • R 1A group can either be meta or para, and so A can have the structures:
  • R 1B group cannot be alpha to the connection point to the rest of the compound (i.e., it cannot be in the asterixed positions).
  • A is a 5-10 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, it 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.
  • each ring has from 5 to 7 ring atoms.
  • monocyclic heteroaryl groups include, but are not limited to, those derived from:
  • N 1 pyrrole (azole) (5-membered), pyridine (azine) (6-membered); O 1 : furan (oxole) (5-membered); S 1 : thiophene (thiole) (5-membered); N 1 O 1 : oxazole (5-membered), isoxazole (5-membered), isoxazine (6-membered); N 2 O 1 : oxadiazole (furazan) (5-membered); N 3 O 1 : oxatriazole (5-membered); N 1 S 1 : 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
  • 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 R 1A group can either be meta or para to the NH group. If A is 5-membered heteroaryl or a 7 to 10 membered heteroaryl, the R 1A group is not alpha to the —NH— group. Thus, when A is 5-membered heteroaryl, the R 1A group is beta to the —NH— group.
  • R 1A may have one of the following structures:
  • R N1 , R N2 , R N3 , R N5 , R N6 , R N9 , R N10 , R N11 and R N12 is independently selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl, prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N4 , R N7 and R N8 is independently selected from either H or methyl.
  • Z 1 is independently selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl), optionally substituted by OH, C( ⁇ O)OC 1-4 alkyl (i.e. C( ⁇ O)O-methyl, C( ⁇ O)O-ethyl, C( ⁇ O)O-prop-1-yl, C( ⁇ O)O-prop-2-yl), C( ⁇ O)O-n-butyl, C( ⁇ O)O-iso-butyl, C( ⁇ O)O-sec-butyl, C( ⁇ O)O-tert-butyl) and C( ⁇ O)Me.
  • C 1-3 alkyl i.e. methyl, ethyl, prop-1-yl and prop-2-yl
  • C( ⁇ O)OC 1-4 alkyl i.e. C( ⁇ O)O-methyl, C( ⁇ O)O-ethyl, C( ⁇ O)O-prop
  • Z 2 is independently selected from H, C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl), optionally substituted by OH, C( ⁇ O)OC 1-3 alkyl (i.e. C( ⁇ O)O-methyl, C( ⁇ O)O-ethyl, C( ⁇ O)O-prop-1-yl and C( ⁇ O)O-prop-2-yl) and C( ⁇ O)Me.
  • C 1-3 alkyl i.e. methyl, ethyl, prop-1-yl and prop-2-yl
  • C( ⁇ O)OC 1-3 alkyl i.e. C( ⁇ O)O-methyl, C( ⁇ O)O-ethyl, C( ⁇ O)O-prop-1-yl and C( ⁇ O)O-prop-2-yl
  • C( ⁇ O)Me C( ⁇ O)Me
  • Z 3 is H, or Z 1 and Z 3 together with N form a 4-6 membered heterocycle containing at least one N and optionally one O.
  • suitable 4-6 membered heterocycle containing at least one N and optionally one O include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, and morpholinyl.
  • Each R 1B group may be C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl), CF 3 , F, Cl, O—C 1-3 alkyl (i.e. methoxy, ethoxy, prop-1-oxy and prop-2-oxy) or CN. These groups may be 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).
  • Each R 1C group may be C 1-3 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl) optionally substituted with one to three substituents selected from F, —OH, Cl, O—C 1-3 alkyl (i.e. methoxy, ethoxy, prop-1-oxy and prop-2-oxy), CN, ⁇ O or C( ⁇ O)Me.
  • Suitable optionally substituted C 1-3 alkyl groups include —CFH 2 , —CF 2 H, —CF 3 , —CH 2 CFH 2 , —CH 2 CF 2 H, —CH 2 CF 3 , —CFHCH 3 , —CF 2 CH 3 , —CH 2 CH 2 CFH 2 , —CH 2 CH 2 CF 2 H, —CH 2 CH 2 CF 3 , —CH 2 CFHCH 3 , —CH 2 CF 2 CH 3 , —CFHCH 2 CH 3 , —CF 2 CH 2 CH 3 , —CH 2 OH, —CH 2 OCH3, —CH(OH)CH 3 , CH(OCH 3 )CH 3 , —CH 2 CH 2 OH, —CH 2 CH 2 OCH 3 , —CH(OH)CH 2 CH 3 , CH(OCH 3 )CH 2 CH 3 , —CH 2 CH(OH)CH 3 , —CH 2 CH(OH)CH
  • R 1C groups may be substituted at any available ring position on A. There may be up to 3 R 1C groups (i.e. 1, 2 or 3) depending on the nature of A, and in particular on the number of ring atoms and ring heteroatoms, as well as whether R 1A is present.
  • R 2 is selected from H, halo (i.e. F, Cl, Br, I), C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), CF 3 , CF 2 H, CN and methoxy.
  • halo i.e. F, Cl, Br, I
  • C 1-4 alkyl i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl
  • CF 3 CF 2 H
  • CN methoxy
  • the halo group is either F or Cl.
  • 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 When R 3 is substituted phenyl, it has the structure:
  • 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: pyridyl; pyridazinyl (1,2-diazinyl); pyrimidinyl (1,3-diazinyl); and pyrazinyl (1,4-diazinyl).
  • 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.
  • 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 heteroatoms.
  • R 4 is selected from groups of the following formulae:
  • R N13 is selected from H and CH 3
  • Z 4 is selected from H, CH 3 or OCH 3 .
  • R 4 can be of the following formulae:
  • Y is selected from —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-5 cycloalkylidene.
  • compounds 12 and 155 of WO2012/110773 are disclaimed from the present application:
  • the compounds of the present invention do not include those disclosed in WO2012/110773, which is incorporated herein by reference.
  • R 3 is selected from:
  • R 4 is —CH(CH 3 )C(O)N(R N13 )Z 4 ;
  • A is either:
  • R 1A is selected from
  • R N1 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N2 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N3 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N4 is selected from H and CH 3
  • R N5 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N7 and R N8 are independently selected from H and CH 3
  • R N9 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N10 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me; or
  • R N1 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R N2 is selected from H, C 1-3 alkyl, and C( ⁇ O)Me
  • R 2 is not selected from CF 3 , halo, CF 2 H and CN.
  • the compounds of the first aspect are of formula (I), wherein when A is phenyl, Y is selected from —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-5 cycloalkylidene.
  • a reference to carboxylic acid 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 (—O ⁇ ), 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; B- and I-forms; (+) and ( ⁇ ) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; ⁇ - 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 iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).
  • C 1-7 alkyl includes n-propyl and iso-propyl
  • butyl includes n-, iso-, sec-, and tert-butyl
  • methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl
  • keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/amidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro.
  • 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 O and 18 O; 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.
  • a corresponding salt of the active compound for example, a pharmaceutically-acceptable salt.
  • a pharmaceutically-acceptable salt examples 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 R 2+ , NHR 3 + , NR 4 + ).
  • suitable substituted ammonium ions are those derived from: ethylamine, diethylamine, dicyclohexylamine, triethylamine, butylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine, benzylamine, phenylbenzylamine, choline, meglumine, and tromethamine, as well as 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: hydrochloric, hydrobromic, hydroiodic, sulphuric, sulphurous, nitric, nitrous, phosphoric, and phosphorous.
  • Suitable 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 gluconic.
  • suitable polymeric anions include, but are not limited to, those derived from the following polymeric acids: tannic acid, carboxymethyl cellulose.
  • 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.
  • a hydroxy group may be protected as an ether (—OR) or an ester (—OC( ⁇ O)R), for example, as: a t-butyl ether; a benzyl, benzhydryl (diphenylmethyl), or trityl (triphenylmethyl) ether; a trimethylsilyl or t-butyldimethylsilyl ether; or an acetyl ester (—OC( ⁇ O)CH 3 , —OAc).
  • 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 ) 2 C 6 H 4 C 6 H 5 , —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 5-20 aryl-C 1-7 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
  • a thiol group may be protected as a thioether (—SR), for example, as: a benzyl thioether; an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
  • SR thioether
  • benzyl thioether an acetamidomethyl ether (—S—CH 2 NHC( ⁇ O)CH 3 ).
  • 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.
  • some prodrugs are esters of the active compound (e.g. a physiologically acceptable metabolically labile ester). During metabolism, the ester group (—C( ⁇ O)OR) is cleaved to yield the active drug.
  • esters may be formed by esterification, for example, of any of the carboxylic acid groups (—C( ⁇ O)OH) in the parent compound, with, where appropriate, prior protection of any other reactive groups present in the parent compound, followed by deprotection if required.
  • 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-C 1-7 alkyl (e.g. acyloxymethyl; acyloxyethyl; e.g.
  • pivaloyloxymethyl acetoxymethyl; 1-acetoxyethyl; 1-(1-methoxy-1-methyl)ethyl-carbonxyloxyethyl; 1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl; 1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl; 1-cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl; 1-cyclohexyloxy-carbonyloxyethyl; (4-tetrahydropyranyloxy) carbonyloxymethyl; 1-(4-tetrahydropyranyloxyl)carbonyloxyethyl; (4-tetrahydropyranyl)carbonyloxymethyl; and 1-(4-tetrahydropyranyl)carbonyloxyethyl).
  • 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 selectivity of the compounds for inhibiting VEGFR3 over other kinases, such as FAK, and/or VEGFR2 can be demonstrated by cellular assay results (see, for example, the VEGFR3 and VEGFR2 assays described below).
  • A is optionally substituted phenyl and can have the structures:
  • R 1B group cannot be alpha the connection point to the rest of the compound.
  • R 1B substituents it may be preferred that either there are no R 1B substituents, or a single R 1B substituent. If there is a single R 1B substituent it is may be meta or para, so further preferred A groups include:
  • A is an optionally substituted 6 membered heteroaryl group.
  • 6 membered heteroaryl groups include, but are not limited to: pyridyl, isoxazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl.
  • A is pyridyl, which can have the structures:
  • R 1A is present R 1C is not an oxo ( ⁇ O) group.
  • R 1C is not an oxo ( ⁇ O) group.
  • a 6 may be further preferred.
  • R 1C substituents for pyridyl and there are no R 1C groups.
  • A when A is pyridyl and there are no R 1C groups, it may have the structures:
  • a 6A may be further preferred.
  • the pyridyl group may be unsubstituted, or it may have one of more R 1C groups.
  • the pyridyl group may have one of the following structures:
  • a 6A1 may be further preferred.
  • A is an optionally substituted 5 membered heteroaryl group.
  • 5 membered heteroaryl groups include, but are not limited to: pyrrolyl; furanyl; thiophenyl; oxazolyl; isoxazolyl; oxadiazolyl; oxatriazolyl; thiazolyl; isothiazolyl; imidazolyl; pyrazolyl; triazolyl and tetrazolyl.
  • A is pyrazolyl, which can have the structures:
  • R 1C is not an oxo ( ⁇ O) group.
  • a 16 and A 18 may be further preferred.
  • R 1C substituents for pyrazolyl and there are no R 1C groups.
  • A when A is pyrazolyl and there are no R 1C groups, it may have the structures:
  • a 19A may be further preferred.
  • the pyrazolyl group may be unsubstituted, or it may have one of more R 1C groups.
  • the pyrazolyl group may have one of the following structures:
  • a 19A1 may be further preferred.
  • R 1A is CH(R C1 )NZ 1 Z 3
  • R C1 is selected from H and C 1-2 alkyl
  • Z 1 may be any one of:
  • Z and Z 3 may be H, or Z 1 and Z 3 together with the N to which they are attached form a 4-6 membered heterocycle containing one N and optionally one O.
  • Z 1 may be selected from H and CH 2 CH 2 OH and Z 3 may be H.
  • R 1A is selected from: CH 2 NH 2 ; CH(CH 3 )NH 2 ; CH(C 2 H 5 )NH 2 ; CH 2 NHCH 2 CH 2 OH; CH(CH 3 )NHCH 2 CH 2 OH; and CH(C 2 H 5 )NHCH 2 CH 2 OH.
  • R 1A is CH(R C1 )NZ 1 Z 3
  • R C1 may be selected from H and methyl and Z 3 may be H.
  • R 1A is selected from: CH 2 NHZ 1 and CH(CH 3 )NHZ 1 .
  • R 1A is CH(R C1 )NHZ 1
  • Z 1 may be selected from H and CH 2 CH 2 OH
  • R C1 may be selected from H and methyl.
  • R 1A is selected from: CH 2 NH 2 ; CH 2 NHCH 2 CH 2 OH; CH(CH 3 )NH 2 ; and CH(CH 3 )NHCH 2 CH 2 OH.
  • R 1A is CH(R C1 )NZ 1 Z 3
  • Z 1 and Z 3 may together with the N to which they are attached form a 4-6 membered heterocycle containing one N and optionally one O.
  • R 1A is, for example, azetidinyl or morpholinyl.
  • Z 2 may be any one of:
  • R 1A is XNHZ 2
  • Z 2 may be H.
  • R 1A has the structures:
  • R 1A is XNHZ 2
  • Z 2 may be C( ⁇ O)OMe.
  • R 1A has the structures:
  • R 1A is XNHZ 2
  • X may be selected from CMe 2 , and cyclobutylidene.
  • R 1A has the structures:
  • R 1A is XNHZ 2
  • Z 2 may be selected from H and C( ⁇ O)OMe
  • X may be selected from CMe 2 , and cyclobutylidene.
  • R 1A has the structures:
  • R 1A is:
  • R N1 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N1 is C( ⁇ O)Me.
  • R N1 is H, methyl or ethyl.
  • R 1A is:
  • R N2 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N2 is C( ⁇ O)Me.
  • R N2 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N3 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N3 is C( ⁇ O)Me.
  • R N3 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N4 is selected from H or methyl. In some of these embodiments, it may be preferred that R N4 is H.
  • R 1A is:
  • R N5 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N5 is C( ⁇ O)Me.
  • R N5 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N6 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N6 is C( ⁇ O)Me.
  • R N6 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N7 and R N8 are both H or both methyl. In some of these embodiments, it may be preferred that R N7 and R N8 are both H.
  • R 1A is:
  • R N9 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N9 is C( ⁇ O)Me.
  • R N9 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N10 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R n10 is C( ⁇ O)Me.
  • R N10 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N11 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N11 is C( ⁇ O)Me.
  • R N11 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A is:
  • R N12 is selected from H, C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl), C 3-4 cycloalkyl (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ O)Me.
  • R N12 is C( ⁇ O)Me.
  • R N12 is H, methyl or ethyl, more preferably H or methyl.
  • R 1A groups include:
  • R 1A is selected from R 1A2 and R 1A6 :
  • R 1A is selected from R 1A2 and R 1A6 :
  • R 1B is preferably C 1-3 alkyl and more preferably methyl.
  • a single R 1B substituent is present. It may be C 1-3 alkyl; CF 3 ; F; Cl; O—(C 1-3 alkyl); and CN. In some of these embodiments, it is preferably C 1-3 alkyl, and more preferably methyl.
  • each R 1C substituent is independently selected from:
  • each R 1C substituent is independently selected from:
  • R 1C is preferably C 1-3 alkyl optionally substituted with one to three F atoms and more preferably methyl or CF 3 .
  • a single R 1C substituent is present. It may be C 1-3 alkyl; CF 3 ; F; Cl; O—(C 1-3 alkyl); CN; C( ⁇ O)Me; and ⁇ O. In some of these embodiments, it is preferably C 1-3 alkyl optionally substituted with one to three F substituents, and more preferably methyl or CF 3 .
  • R 2 is H.
  • R 2 is halo (i.e. F, Cl, Br, I). In some of these embodiments, the halo group is either F or Cl.
  • R 2 is C 1-4 alkyl (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyl, iso-butyl, sec-butyl, tert-butyl).
  • the C 1-4 alkyl group is methyl or ethyl, and methyl may be preferred.
  • R 2 is selected from CF 3 and CF 2 H. In some of these embodiments, R 2 is CF 3 .
  • R 2 is CN
  • R 2 is methoxy
  • R 2 is selected from CF 3 and Cl.
  • R 3 is substituted phenyl, and therefore it has the structure:
  • R 6 , R 7 and R 8 are independently selected from H, F, methyl and CF 3 .
  • One of R 4A and R 4B is R 4 , and the other is selected from H, F, methyl and CF 3 .
  • the group of R 4A and R 4B that is not R 4 , and R 6 , R 7 and R 8 are all H.
  • one of the group of R 4A and R 4B that is not R 4 , R 6 , R 7 and R 8 is not H, and therefore is F, methyl or CF 3 .
  • the group that is not H may preferably be R 6 or R 7 .
  • R 3 is substituted phenyl
  • R 4B , R 6 , R 7 and R 8 are all H
  • R 4A is R 4 .
  • R 3 is a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 N heteroatoms.
  • R 3 is pyridyl, which can have the structures:
  • R 6 , R 7 and R 8 are independently selected from H, F, methyl and CF 3 .
  • One of R 4A and R 4B (if present) is R 4 , and the other is selected from H, F, methyl and CF 3 .
  • R 3d and R 3e may be preferred.
  • the group of R 4A and R 4B that is not R 4 , and R 6 , R 7 and R 8 (if present) are all H.
  • one of the group of R 4A and R 4B that is not R 4 , R 6 , R 7 and R 8 (if present) is not H, and therefore is F, methyl or CF 3 .
  • it may be preferred that a F substituent is not alpha to a ring nitrogen atom.
  • R 4 is alpha to the —C 2 H 4 — group. In some embodiments R 4 is beta to the —C 2 H 4 — group.
  • the group R 4 is —Y—C(O)(R N13 )Z 4 .
  • R N13 is H.
  • R N13 is Me.
  • Z 4 is H.
  • Z 4 is Me.
  • Z 4 is OMe.
  • Y can be any of —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, C 3-5 cycloalkylidene.
  • Y is selected from CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-5 cycloalkylidene.
  • Y is selected from —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-5 cycloalkylidene.
  • Y is selected from Y a to Y e :
  • Y is selected from Y b , Y c , Y d and Y e .
  • Y is selected from Y a , Y b , Y c and Y e .
  • Y is selected from Y a , Y c , Y d and Y e .
  • R 4 is —Y′—C(O)NH 2 , where Y′ is selected from —C(CH 3 ) 2 —, —CH(CH 2 CH 3 )—, cyclopropylidene and cyclobutylidene.
  • R 4 is:
  • R 4 is:
  • R 4 is:
  • R 4 is:
  • the compounds are of formula (Ia) which is a compound of formula (I) of the first aspect or isomers, salts, solvates, protected forms or prodrugs thereof wherein:
  • A is selected from optionally substituted phenyl and 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 or 2 heteroatoms selected from N and O, and; when A is optionally substituted phenyl, A may bear a substituent R 1A which is not alpha to the NH group, where R 1A is selected from:
  • R 2 is selected from halo, CH 3 and CF 3 ;
  • R 3 is substituted phenyl, where R 3 bears a substituent R 4 either alpha or beta to the —C 2 H 4 — group, and may additionally bear a further substituent F; and
  • R 4 is —Y—C(O)N(R N13 )Z 4 , where Y is selected from —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-4 cycloalkylidene;
  • the compounds are of formula (Ib) which is a compound of formula (I) of the first aspect and formula (Ia) defined above or isomers, salts, solvates, protected forms or prodrugs thereof wherein:
  • A is selected from optionally substituted phenyl and 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 or 2 heteroatoms selected from N and O, and; when A is optionally substituted phenyl, A may bear a substituent R 1A which is not alpha to the NH group, where R 1A is selected from:
  • R 2 is selected from halo, CH 3 and CF 3 ;
  • R 3 is substituted phenyl, where R 3 bears a substituent R 4 either alpha or beta to the —C 2 H 4 — group, and may additionally bear a further substituent F; and
  • R 4 is —Y—C(O)N(R N13 )Z 4 , where Y is selected from —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and C 3-4 cycloalkylidene;
  • the compounds are of formula (Ic) which is a compound of formula (I) of the first aspect and formulae (Ia) and (Ib) defined above or isomers, salts, solvates, protected forms or prodrugs thereof wherein:
  • A is selected from substituted phenyl and 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 or 2 heteroatoms selected from N and O, and; when A is optionally substituted phenyl, A may bear a substituent R 1A which is not alpha to the NH group, where R 1A is selected from: (i) CH(R C1 )NZ 1 Z 3 , where R C1 is methyl, Z 1 is H and Z 3 is H; (iii) a group selected from:
  • R 2 is selected from halo and CF 3 ;
  • R 3 is substituted phenyl, where R 3 bears a substituent R 4 either alpha or beta to the —C 2 H 4 — group, and may additionally bear a further substituent F; and
  • R 4 is —Y—C(O)N(R N13 )Z 4 , where Y is selected from —CHCH 3 —, —CH(CH 2 CH 3 )—, —C(CH 3 ) 2 —, and cyclopropylidene;
  • R N13 is H; and Z 4 is H.
  • the compounds are of formula (Id) which is a compound of formula (I) of the first aspect and formulae (Ia) to (Ic) defined above or isomers, salts, solvates, protected forms or prodrugs thereof wherein:
  • A is selected from substituted phenyl and an optionally substituted pyrazolyl or pyridyl group linked to the NH group through an aromatic ring carbon atom, in which the heteroaryl ring system contains 1 or 2 heteroatoms selected from N and O, and; when A is optionally substituted phenyl, A may bear a substituent R 1A which is not alpha to the NH group, where R 1A is:
  • R 2 is selected from Cl and CF 3 ;
  • R 3 is substituted phenyl, where R 3 bears a substituent R 4 alpha to the —C 2 H 4 — group, and may additionally bear a further substituent F; and
  • R 4 is —Y—C(O)N(R N13 )Z 4 , where Y is selected from —CHCH 3 — and C 3 cycloalkylidene; R N13 is H; and Z 4 is H.
  • the compounds are of formula (Ie) or isomers, salts, solvates, protected forms or prodrugs thereof:
  • A is selected from: optionally substituted phenyl and optionally substituted pyridyl, wherein A may bear one substituent R 1A which is not alpha to the NH group, where R 1A is selected from R 1A2 and R 1A6 :
  • R 2 is Cl or CF 3 , then R 4 is not —CH(CH 3 )C(O)NH 2 .
  • the compounds are of formula (If) or isomers, salts, solvates, protected forms or prodrugs thereof:
  • A is selected from: optionally substituted phenyl and optionally substituted pyridyl, wherein A may bear one substituent R 1A which is not alpha to the NH group, where R 1A is selected from R 1A2 and R 1A6 :
  • the compounds are of formula (Ig) or isomers, salts, solvates, protected forms or prodrugs thereof:
  • A is selected from an optionally substituted 5 or 6 membered heteroaryl group which contains 1 or 2 heteroatoms selected from N and O, wherein A may bear one substituent R 1A which is not alpha to the NH group, where R 1A is selected from R 1A2 , R1A3 and R 1A6
  • A is selected from a 5 membered heteroaryl group which contains N such as optionally substituted pyrazolyl, a 5 membered heteroaryl group which contains N and O such as optionally substituted oxazolyl and a 6 membered heteroaryl group which contains N such as optionally substituted pyridinyl, optionally substituted pyrimidinyl and optionally substituted pyridazinyl, wherein A bears one substituent selected from R1A2, (R1A3) and R1A6 defined in formula (Ig) above and may optionally further bear one substituent R1C selected from CF3, C1-3alkyl, CH2CF3, CN, C( ⁇ O)Me, CH(CH3)NH2, CHCF2, OMe, CH(CH3)NHCH3, C1-3alkylOH and C1-3alkylOMe;
  • R2 is selected from Cl, Me and CF3;
  • R4 is CHCH3C( ⁇ O)NH2.
  • A is selected from a 5 membered heteroaryl group which contains N such as optionally substituted pyrazolyl wherein A bears one substituent selected from R 1A2 defined in formula (Ig) above;
  • R 2 is CF 3 ;
  • R 4 is CHCH 3 C( ⁇ O)NH 2 .
  • Embodiments of the inventions are compounds of the examples, including compounds 1 to 77.
  • Embodiments of particular interest include compounds 2, 3, 4, 5, 6, 7, 8, 13, 15, 19, 20, 33, 35, 45, 48, 49, 50, 56, 56-1A, 56-2A, 57, 57-1A, 57-2A, 68, and 70.
  • 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 an isomer, salt, solvate, protected form or prodrug thereof comprises reacting a compound of formula F1
  • the leaving groups L 1 and L 2 may be any suitable leaving groups, such as a halogen atom (F, Cl, Br, I), —SR or —S0 2 R where R is a C 1-4 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 Cl, Br, I, SMe, SO 2 Me.
  • suitable reaction conditions can be employed (choice of solvent, reaction temperature, addition of a Lewis acid, for example ZnCl 2 in Et 2 O) to allow L 1 to be selectively displaced over L 2 .
  • a Lewis acid for example ZnCl 2 in Et 2 O
  • 2,4-dichloro-5-(trifluoromethyl)pyrimidine (G1) can be selectively reacted with sodium thiomethoxide in the presence of zinc(II) 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 phenyl containing starting materials with suitable heteroaromatic systems.
  • a catalyst for example palladium on charcoal
  • the corresponding 4-piperidine analogues of G6 can be prepared by a sequence of reactions starting with the conversion of commercially available tert-butyl 4-oxopiperidine-1-carboxylate (G10) to vinyl triflate G11. Coupling of G11 in a Suzuki type reaction with (4-nitrophenyl)boronic acid (G12) gives tetrahydropyridine G13. Subsequent reduction via hydrogenation in the presence of a catalyst, for example palladium on charcoal, gives tert-butyl 4-(4-aminophenyl)piperidine-1-carboxylate (G14).
  • the corresponding 4-(3-aminophenyl)piperidine analogue of G9 can be prepared by a sequence of reactions starting with the conversion of commercially available tert-butyl 4-oxopiperidine-1-carboxylate (G10) to vinyl triflate G11. Coupling of G11 in a Suzuki type reaction with (3-nitrophenyl)boronic acid (G15) gives tetrahydropyridine G16. Subsequent reduction via hydrogenation in the presence of a catalyst, for example palladium on charcoal, gives tert-butyl 4-(3-aminophenyl)piperidine-1-carboxylate (G17).
  • a catalyst for example palladium on charcoal
  • G23 pyridin-2-ylboronic acid
  • G23 Reduction of G23 with hydrogen in the presence of a catalyst, for example platinum oxide, gives 4-(piperidin-2-yl)aniline (G24) which may be protected using Boc anhydride to give tert-butyl 2-(4-aminophenyl)piperidine-1-carboxylate (G25).
  • tert-butyl 3-oxopyrrolidine-1-carboxylate G26
  • a mixture of vinyl triflates G27 and G28 in the presence of a triflamide and a suitable base, for example NaHMDS.
  • Coupling of the mixture with (4-nitrophenyl)boronic acid (G12) under Suzuki conditions gives dihydropyrroles G29 and G30.
  • tert-Butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate can be prepared by nucleophilic aromatic substitution of commercially available tert-butyl piperidin-4-ylcarbamate (G36) and 1-fluoro-4-nitrobenzene (G37) under thermal conditions to give tert-butyl (1-(4-nitrophenyl)piperidin-4-yl)carbamate (G38). Reduction of G38 with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal gives tert-butyl (1-(4-aminophenyl)piperidin-4-yl)carbamate (G39).
  • tert-Butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G49) can be prepared by the nucleophilic displacement of commercially available 1-(bromomethyl)-4-nitrobenzene (G47) with tert-butyl piperazine-1-carboxylate (G7) to give tert-butyl 4-(4-nitrobenzyl)piperazine-1-carboxylate (G48). Subsequent reduction with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal, gives tert-butyl 4-(4-aminobenzyl)piperazine-1-carboxylate (G49).
  • a catalyst for example 10% palladium on charcoal
  • 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 N-(4-bromophenyl)-1,1,1-trimethyl-N-(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.
  • R 3 is aryl or substituted aryl compounds of the formula F14 may be prepared as outlined in scheme O.
  • Compounds of the formula F10 where Q 3 is an ester may be deprotonated using a suitable base, for example LDA and the resulting anion quenched with an alkylating agent, for example methyl iodide, to give compounds of the formula F11 where Y is a monoalkylated species.
  • a second deprotonation can then be carried out allowing the introduction of a second alkylating agent, which may be the same or different to the first alkylating agent employed, or to facilitate the cyclisation of a ring system where the first alkylating agent used was di-functional, for example 1,3-dibromopropane.
  • Halogenation of compounds of the formula F11 gives compounds of the formula F12, for example 1-phenyl-1-cyclopropanecarboxylic acid can be readily iodinated in the presence of Pd(OAc) 2 and (diacetoxyiodo)benzene to give 1-(2-iodophenyl)cyclopropanecarboxylic acid.
  • R 9 TMS or TES potassium carbonate or tetra-n-butyl ammonium fluoride may be employed to induce this transformation.
  • R 9 C(CH 3 ) 2 OH, sodium hydride in refluxing toluene may be used.
  • heteroaryl analogues of F14 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.
  • Deprotonation and alkylation as described above for aryl analogues, gives compounds of the formula F15.
  • Coupling of compounds of the formula F15 with TMS acetylene under Sonagashira conditions gives acetylenes of the formula F16.
  • Removal of the trimethylsilyl group using TBAF gives compounds of the formula F17.
  • diethyl succinate (G54) and ethyl formate (G55) can be condensed to give aldehyde G56 in the presence of sodium metal.
  • Cyclisation using thiourea gives 4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine (G57).
  • Desulfurisation using Raney-nickel gives pyrimidone G58, which can be converted to 4-chloro pyrimidine G59 using phosphorous oxychloride.
  • 2-(pyridin-3-yl)acetonitrile (G60) can be oxidised to N-oxide G61.
  • Chlorination with phosphorous oxychloride gives 2-chloropyridine G62 which can be hydrolysed with sodium hydroxide to acetic acid G63.
  • Ester formation using methanol gives 2-chloropyridine ester G64.
  • Coupling of compounds of the formula F21 with TES-acetylene under Sonagashira conditions, followed by removal of the triethylsilyl group using TBAF gives compounds of the formula F23.
  • 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 F14 to give acetylenes of the formula F24 in a Sonagashira type coupling.
  • the acetylene in compounds of the formula F24 may be reduced to an alkane of the formula F25 using hydrogen gas in the presence of a transition metal catalyst.
  • heteroaromatic analogues of compounds of the formula F14 may be coupled in an analogous manner to that described in scheme S and then further elaborated to amides as described above.
  • the amine functionality maybe further derivatised by reductive alkylation with formaldehyde in the presence of sodium triacetoxyborohydride to give N-Me analogues; by reductive alkylation with acetaldehyde in the presence of sodium triacetoxyborohydride to give N-Et analogues or the N-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 F14 to give acetylenes of the formula F26 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 F26 may be reduced to an alkane of the formula F27 using hydrogen gas in the presence of a transition metal catalyst.
  • the desired amide may already be present in compounds of the formula F14, or alternatively an ester may be used and subsequently derivatised as described above.
  • Aldehydes or ketones of formula F18 where R 11 is a hydrogen, an alkyl group or similar may be substituted with amines to form compounds of formula F19.
  • 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 activity, 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 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 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.
  • the present invention provides 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 invention provides the use of the active compounds for the treatment of cancer in the human or animal body.
  • the invention further provides active compounds for use in a method of treatment of cancer in the human or animal body.
  • Such a use or method 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 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, colon cancer, melanoma such as cutaneous or intraocular melanoma, haemetological malignancies, Hodgkin's disease, lung cancer, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), ovarian cancer, pancreatic cancer, pituitary ade
  • 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, and skin.
  • gastrointestinal including, e.g., bowel, colon
  • breast mammary
  • ovarian prostate
  • liver hepatic
  • kidney renal
  • bladder pancreas
  • brain and skin.
  • 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 preventing the spread of cancer and in the prevention of metastisis.
  • 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, protected form 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, protected form 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
  • 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.
  • 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 epidermal growth factor family
  • EGFR family tyrosine kinase inhibitors
  • a combination of particular interest is with docetaxel.
  • Other possible combinations of interest include with gemcitabine, cisplatin and the camptothecin prodrug irinotecan.
  • 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 lymphangiogenesis.
  • 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 lymphangiogenesis.
  • these diseases or conditions may include:
  • eye diseases for example corneal graft rejection and age related macular degeneration
  • skin inflammations such as skin lesions in patients with psoriasis
  • rejection in renal transplantation
  • the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether systemically/peripherally or at the site of desired action, including but not limited to, 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.
  • vaginal parenteral, for example, by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, intravitreal and intrasternal; by implant of a depot, for example, subcutaneously, intravitreal or intramuscularly.
  • 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.
  • simian e.g. a monkey or ape
  • a monkey e.g. marmoset, baboon
  • an ape e.g. gorilla, chimpanzee, orang-utan, gibbon
  • a human e.g. gorilla, chimpanzee, orang-utan, gibbon
  • 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.
  • 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-isoadipate 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
  • 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 non-aqueous 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.
  • LC/MS data was generated using either an Agilent 6100 Series Single Quad LC/MS (LCMS-A) or Waters ZQ 3100 system (LCMS-B) or Finnigan LCG Advantage Max (LCMS-C) or Agilent 1200 Infinity Series (LCMS-D).
  • LCMS-A Agilent 6100 Series Single Quad LC/MS
  • LCMS-B Waters ZQ 3100 system
  • LCMS-C Finnigan LCG Advantage Max
  • Agilent 1200 Infinity Series LCMS-D
  • Drying gas temp 300° C.
  • Vaporizer temperature 200° C.
  • Step size 0.1 sec Acquisition time: 10 min
  • Ion Source Single-quadrupole
  • Ion Source Ion trap Ion Mode: ES positive
  • Step size 0.1 sec Acquisition time: 5 min
  • Ion Source Single-quadrupole
  • 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 or a Biotage Isolera purification system using either Grace, RediSep® or Biotage silica cartridges. Microwave irradiation was achieved using a CEM Explorer SP Microwave Reactor.
  • anhydrous solvents were prepared using a Braun purification system or purchased from Sigma-Aldrich.
  • Lithium diisopropylamide solution (2.0 M in THF/heptane/ethylbenzene, 3.82 mL, 7.63 mmol) was added to dry THF (10 mL) under an atmosphere of nitrogen and cooled to 0° C.
  • a solution of 2-(2-iodophenyl)acetic acid 500 mg, 1.91 mmol
  • dry THF 15 mL
  • This solution was stirred for 40 minutes at 0° C. before the addition of iodoethane (0.92 mL, 11 mmol).
  • the solution was returned to room temperature and stirred for 4 hours.
  • 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (4.122 g, 19.00 mmol) was stirred in a 1:1 t-BuOH:DCE mixture (400 mL) at room temperature.
  • a 1.0 M ZnCl 2 solution in Et 2 O (21.71 mL, 21.71 mmol) was added cautiously and the resulting mixture was stirred for 10 minutes.
  • 1-Boc-4-(4-aminophenyl)piperidine (5.00 g, 18.1 mmol) was added followed by Et 3 N (6.052 mL, 43.42 mmol) and stirring continued at room temperature overnight. The volatiles were evaporated to dryness and the resulting residue was suspended in water (500 mL).
  • 1,2-Dibromoethane (0.146 mL, 1.69 mmol) was added to a vigorously stirred suspension of zinc dust (0.901 g, 13.8 mmol) in THF (3.5 mL) under a nitrogen atmosphere and the resulting suspension heated at 80° C. for 10 minutes.
  • Trimethylsilyl chloride (0.202 mL, 1.59 mmol) in THF (1.75 mL) was added at room temperature and after stirring for 4 minutes a solution of tert-butyl 3-iodoazetidine-1-carboxylate (3.00 g, 10.6 mmol) in THF (3.5 mL) was added dropwise over a period of 15 minutes.
  • Zinc chloride (1.0 M in Et 2 O) (4.83 mL, 4.83 mmol) was added to a solution of 2,4-dichloro-5-(trifluoromethyl)pyrimidine (0.769 g, 3.54 mmol) in 1:1 dichloroethane/tert-butanol (64 mL) at room temperature under nitrogen. After stirring for 10 minutes, tert-butyl 3-(4-aminophenyl)azetidine-1-carboxylate (I7) (0.800 g, 3.22 mmol) was added followed by Et 3 N (1.08 mL, 7.73 mmol). The resulting mixture was stirred at room temperature for 20 hours then the volatiles removed in vacuo.
  • the column was eluted with 5 column volumes of MeOH and then 5 column volumes of 5% v/v aqueous ammonia in MeOH to elute the amine product.
  • the ammoniacal filtrate was evaporated under reduced pressure and the residue was taken up in DCM ( ⁇ 2 mL). Cyclohexane ( ⁇ 10 mL) was added and the resulting suspension sonicated for 10 minutes.
  • ammonium carbonate (234 mg, 2.43 mmol) was added in one portion and the resulting solution was stirred at 40° C. for 72 hours. The volatiles were removed in vacuo and EtOAc (50 mL) and saturated NaHCO 3 (50 mL) were added to the residue. After separating the organic layer, the aqueous phase was extracted with EtOAc (2 ⁇ 50 mL). The organic extracts were combined, washed with brine and dried over MgSO 4 .
  • Formaldehyde (37 wt % in H 2 O; 8.8 ⁇ L, 0.12 mmol) was added to a solution of 1-(2-(2-(2-((4-(piperidin-4-yl)phenyl)amino)-5-(trifluoromethyl)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (2) (20 mg, 39 ⁇ mol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature then sodium triacetoxyborohydride (33 mg, 0.16 mmol) was added in one portion and stirring continued for 2.5 hours.
  • ammonium carbonate (280 mg, 2.91 mmol) was added in one portion and the resulting mixture was stirred at room temperature for 16 hours, then 40° C. for a further 24 hours.
  • the volatiles were removed in vacuo and EtOAc (20 mL) and saturated NaHCO 3 (20 mL) were added.
  • EtOAc (20 mL)
  • saturated NaHCO 3 (20 mL) were added.
  • the layers were separated then the aqueous phase extracted with EtOAc (2 ⁇ 20 mL). The organic extracts were combined, washed with brine, dried (MgSO 4 ) then evaporated to dryness.
  • PdCl 2 (PPh 3 ) 2 (16 mg, 0.023 mmol) was added to a stirred solution of 1-(2-ethynylphenyl)cyclopropanecarboxamide (K6) (0.420 g, 2.26 mmol), 2,4,5-trichloropyrimidine (0.338 mL, 2.94 mmol), Et 3 N (1.26 mL, 9.07 mmol) and copper(I) iodide (8.6 mg, 0.045 mmol) in 1,4-dioxane (4.5 mL). The resulting mixture was stirred at 60° C. for 2.5 hours under a nitrogen atmosphere before being diluted with petroleum benzine 40-60° C. (25 mL).
  • Formaldehyde (37 wt % in H 2 O; 14 ⁇ L, 0.19 mmol) was added to a solution of 1-(2-(2-(5-chloro-2-((4-(piperidin-4-yl)phenyl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide (7) (30 mg, 63 ⁇ mol) in MeOH (5.0 mL) under an atmosphere of nitrogen. The resulting mixture was stirred for 10 minutes at room temperature before the addition of sodium triacetoxyborohydride (53 mg, 0.25 mmol).
  • Xantphos (10.3 mg, 17.8 ⁇ mol) and Pd(OAc) 2 (2.00 mg, 8.92 ⁇ mol) were added and the resulting mixture was heated under microwave irradiation for 20 minutes at 120° C.
  • the resulting mixture was adsorbed onto silica gel and purified by column chromatography (Biotage Isolera, 40 g SiO 2 cartridge, 0-100% EtOAc in petroleum benzine 40-60° C. then 0-40% MeOH in EtOAc).
  • the purified solid was dissolved in acetone (0.2 mL) and petroleum benzene 40-60° C. (30 mL) added.
  • Formaldehyde (32.8 ⁇ L, 0.440 mmol, 37 wt % in H 2 O) was added to a suspension of 1-(2-(2-(5-chloro-2-((6-(piperidin-4-yl)pyridin-3-yl)amino)pyrimidin-4-yl)ethyl)phenyl)cyclopropanecarboxamide 15 (42.0 mg, 0.088 mmol) in MeOH (1.10 mL) under an atmosphere of nitrogen. Sodium triacetoxyborohydride (187 mg, 0.881 mmol) was then added in one portion and the mixture was stirred at room temperature overnight.
  • reaction mixture was adsorbed onto silica gel and purified by silica column chromatography (Combiflash Rf, 12 g SiO 2 Cartridge, 20-50% EtOAc in cyclohexane) to give the title product 23 as a light yellow foam (0.044 g, 46%).
  • LCMS-B rt 7.718 min; m/z 393 [M+H] + .

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