Classifications

• • 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
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
  • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
  • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
  • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
  • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
  • C07D295/182—Radicals derived from carboxylic acids
  • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• This invention relates to 2,4,5-substltuied pytimidines that inhibit vascular endothelial growth factor receptor s (VEGFR3), also known as Fms related tyrosine kinase 4 (FLT4), processes for their preparation or pharmaceutical agents or compositions containing such compounds.
• VEGFR3 vascular endothelial growth factor receptor s
• FLT4 Fms related tyrosine kinase 4
• Cancer remains a major cause of death In the 21 st century. Consequently, considerable drug research and development effort is currently placed on the discovery of therapeutics that may provide life extending or curative options to cancer sufferers.
• metastasis While there are many different varieties of cancer, each exhibiting a different array of genetic and growth properties, a common denominator among many solid cancer types is the ability to metastasise. Until the occurrence of metastasis, tu ors 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 8/os (Elite Ed). 2012; 4: 1888- 1897).
• lymphatic vessels differ from blood vessels In several ways. Large collecting ly phatic 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 !nter-endothe!a! 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.
• Iymphanglogenesis the formation of new lymphatic vessels
• the control of Iymphanglogenesis presents an attractive therapeutic strategy for preventing lymph node metastasis (J. Clin, Otic. 2007: 25: 4293-4307),
• the lymphatic system is comprised of capillaries and larger collecting vessels continuously lined by endothelial ceils which return extravasated fluid and macrornolecules from the Interstitial space back to the blood circulation .
• Metastasis to regional lymph nodes via lym hatic vessels Is a tu or 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 thai 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 lymphanglogenesls (8rit 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 lymphanglogenesls enabling lymphatic-mediated metastasis to regional lymph nodes.
• VEGFR3 is a transmembrane tyrosine kinase receptor that Is broadly expressed In endothelial cells during embryogenesls (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 GD34-r 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 3.5 (Biochem. J. 2011; 437: 169- 183).
• This observation demonstrates that VEGFR3 plays an essential role in the development of embryonic vasculature.
• VEGFR3 Is overexpressed In lymphatic sinuses in metastatic lymph nodes and In lymphangiomas.
• cancer cells themselves express VEGFR3.
• VEGFR3 expressing cancer ceils have been shown to be dependent on VEGFR3/VEGFC signalling for their proliferation J. Cane. 201 1: 47: 2353 -2363).
• thai Inhibition of 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 ceils that express VEGFR3,
• VEGFR3 plays an important role in the control of lymphangiogenesls. Accordingly, Inhibitors of VEGFR3 may have utility in the treatment of diseases other than cancer where control/Inhibition of lymphangiogenesls has a therapeutic benefit.
• the lymphatic system plays a major role in chronic inflammatory diseases and in transplant rejection. Inhibition of lymphanglogenesls through suppression of VEGFR3 function may provide a viable therapeutic strategy In these conditions.
• VEGFR3 In the cornea and ocular surface Is modified during corneal neovascularization 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 signif icant suppression of corneal graft rejection (Nat. Med 2004; 10: 813 ⁇ 815).
• CNV Choroidal neovascularization
• Treatments for AMD have been developed that target VEGFA, for example the anti-VEGFA antibodies ranlblzumab and bevaclzumab and the anthVEGF aptamer pegaptanlb, but to date no treatments have been clinically evaluated that mediate effects through modulation of VEGFC and Its cognate receptor VEGFR3.
• VEGFA for example the anti-VEGFA antibodies ranlblzumab and bevaclzumab and the anthVEGF aptamer pegaptanlb
• 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). Accordingly, compounds that Inhibit VEGFR3 may he useful for the prevention and/or treatment of skin inflammations, such as skin lesions In patients with psoriasis.
• Lymphanglogenesis has also been found to be associated with kidney transplant rejection. VEGFC producing macrophages induce formation of new lym hatics 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.
• the present Invention provides compounds of the following formula (i) or isomers, salts, solvates or prodrugs thereof:
• A is an optionally substituted 5-10 me bered 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 hi, O and S; and
• A may bear a single substituent R ,A which Is not alpha to the NH group, and may optionally further bear one, two or three substituents R' c , where R 1A Is selected from:
• R N Is selected from H, C,. 4 aiky!, C ; cycloalkyl and C( ⁇ 0)W!e;
• R m is selected from hi Ck 4 alkyL C 3 . 4 cycloalkyl and C(-"0)lvie:
• R m is selected from H, C ⁇ . alkyL C 3 ⁇ 4 . cycloalkyl and C ⁇ 0)We;
• R NS Is selected from H, C alkyl, C ; cycloalkyl and C( ⁇ 0)M&;
• R 10 is selected from H, d-4 alkyL cycloalkyl and C( ⁇ 0) e;
• R 11 Is selected from H. C alkyl, C 3 . 4 cycloalkyl and C( ⁇ 0)Me;
• R !5 Is selected from H, C,., ; alkyl C w cycloalkyl and C(-0; e; and where each R 1C Is independently selected from:
• R* Is selected from H, halo, C 1 alkyl, CF 3 , CF ⁇ H, CN and judicialhoxy;
• R s is selected from substituted phenyl and a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 heteroatoms, where
• R" bears a substituent R 4 either alpha or beta to the -C 2 H 4 - group, and may additionally bear further subst!iuents selected from F, methyl and CFy and
• the compounds of the first aspect of the present Invention are of formula (!) as defined above with the proviso that the compound Is not :
• the present invention provides compounds of the following formula (I I) or Isomers, salts, solvates or prodrugs thereof:
• A when A Is optionally substituted phenyl, A may bear a substituent R iA which is not alpha to the NH group and may optionally further bear one or two substituents R' i! which are not alpha to the NH group, where R 1A Is selected from:
• R ! Is selected from H, C alkyl, C 34 cycloalkyl and C( ⁇ 0)Me;
• R N3 ⁇ 4 Is selected from H, C,. 4 alkyl, cycloalkyl and C ⁇ -Q)Me
• R m Is selected from H, C ⁇ .. 4 alkyl, C 3 . 4 cycloalkyl and C ⁇ 0)Me:
• R m is selected from H, C,. 4 alkyl, C ; cycloalkyl and C( ⁇ 0)M&;
• R m is selected from H, Ck 4 alkyl, C 3 . 4 cycloalkyl and C(-"0)lvle:
• R w and are Independently selected from H and CH S ;
• R m Is selected from H, C M aiky!, C 34 cycloalkyl and C( ⁇ 0)Me;
• R N1C is selected from H, C ;. alkyl, C . 4 cycloalkyl and C( ⁇ 0) e;
• R m Is selected from H, C alkyl, C 34 cycloalkyl and C(-0) e;
• R " Si; Is selected from H, C ⁇ alkyl, C 3 cycloalkyl and C ⁇ 0)Me: and where each R lB Is independently selected from:
• R 2 is selected from H, halo, d. 4 alkyl, CF 3 , CF 2 H, CN and meihoxy;
• R" is selected from substituted phenyl and a substituted 6 membered heteroaryi group, where the heteroaryi ring system contains 1 or 2 N heteroatoms, where
• R s bears a subsi!!uent R '; either alpha or Seta to the -C 2 Hc group, and may additionally bear further subst!tuenis selected from F, methyl and CF S ; and
• R* is -CH 2 - €(0)N(R N!3 ⁇ Z 3 , where R m is selected from H and CH 3 ; and Z 3 is selected from H, CH 3 and OCH 3 .
• the compounds of the second aspect of the present Invention are of formula (II) or isomers, salts, solvates or prodrugs thereof as defined above with the proviso that the compound is not any of the following compounds:
• the compounds of the second aspect are of formula (11) as defined above with the proviso that:
• R iAS (R ;A7 ) (R !AS ) snci R ! is seiected from H, alkyl, and C( ⁇ 0)Me;
• R 2 is selected from H, alkyl, and C( ⁇ 0)Me;
• R m Is selected from H, C 1-a alkyl and C ⁇ 0)Me;
• R m is selected from H and CH 3 ;
• R m is selected from H, alkyl, and C( " 0) e;
• R ' and R m are Independently selected from H and CH 3 ;
• R' A is and Fr ! Is selected from H, C ; .. a alkyl, and C( ⁇ 0)W!e;
• R 2 Is selected from H, d. 3 aik l, and C( ⁇ 0)Me;
• R 2 Is not selected from CF S; halo, CF 2 H and CM.
• a third aspect of the Invention provides a process for the preparation of a compound of formula (i) or formula (II) or Isomers, salts, solvates or prodrugs thereof of either the first aspect or the second aspect, comprising reacting a compound of formula F1
• a fourth aspect of the invention provides a pharmaceutical agent comprising a compound of the formula (I) or formula (II) or Isomers, salts, solvates or prodrugs thereof of either the first aspect or the second aspect
• the pharmaceutical agent may be an anticancer agent, a lyphang!ogenesls inhibitor, an antimetatstasls agent or a VEGFR3 inhibitor.
• a fifth aspect of the present invention provides a composition
• a composition comprising a compound of formuia (I) or formula (II) or an isomer, sail, solvate or prodrug thereof of either the first aspect or the second aspec and a pharmaceutically acceptable carrier or diluent
• a sixth aspect of the Invention provides a compound of formuia (i) or formula (II) or an isomer, salt, solvate or prodrug thereof of either the first aspect or the second aspect, agent of the fourth aspect or composition or the fifth aspect for use in a method of therapy.
• a seventh aspect of the Invention provides for the use of a compound of formula (I) or formula (II) or an Isomer, salt, solvate or prodrug thereof, of either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect In the preparation of a medicament for treating a disease or condition ameliorated by the Inhibition of VEGFR3
• the seventh aspect of the Invention also provides a compound of formula (i) or (I I) of either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect for use in the method of treatment of a disease or condition ameliorated by the inhibition of VEGFR3.
• An eighth aspect of the Invention provides for the use of a compound of formula (I) or formula (II) or an Isomer, salt, solvate or prodrug thereof of either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect in the preparation of a medicament for treating cancer.
• the eighth aspect of the Invention aiso provides a compound of formula (! or formula (II) or an isomer, salt, solvate or prodrug thereof of either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect for use In the method of treatment of cancer.
• a further aspect of the Invention provides a compound of formula (i; or formula (II) or an isomer, salt, solvate or prodrug thereof of either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect for use in a method of treatment of the human or animal body, preferably In the form of a pharmaceutical 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 of formula (I) or formula (II) or an Isomer salt, solvate or prodrug thereof of either the first aspect or the second aspect agent of the fourth aspect or composition of the fifth aspect.
• a still further aspect of the Invention provides an anticancer tt&t&m&rA comprising a compound or formula (! or formula (I I) or an Isomer, salt, solvate or prodrug thereof or either the first aspect or the second aspect, agent of the fourth aspect or composition of the fifth aspect and an anti-tumour agent.
• A is unsubstltuted phenyl, It has the structure:
• a Is substituted phenyl, the R ! " group can either be rmta or para, and so A can have the structures:
• R ' s group cannot be alpha to the connection point to the rest of the compound (i.e., it cannot be In the asterixed positions).
• A When 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 beteroatoms selected from N « O and S, it Is a monovalent moiety obtained by removing a hydrogen atom from an aromatic ring atom of an heteroaromatlo compound (I.e. a compound having at ieast one heteroaro atic ring), which moiety has from 5 to 10 ring atoms.
• an heteroaromatlo compound I.e. a compound having at ieast one heteroaro atic ring
• each ring has from 5 to 7 ring atoms.
• Examples of monocyclic heteroaryi groups include, but are not limited to, those derived from: N ; : pyrrole (azote) (5-membered), pyridine (azine) (S-membered);
• N ; 0 ⁇ oxazole (5-membered;, Isoxszoie (5-membered), isoxszine (S-rnembered);
• heteroaryi groups which comprise fused rings, include, but are not limited to, those derived from:
• A is a 5 to 10 mernbered heteroaryi group, It may be selected from any of the groups listed above.
• A is a 5 or 6 mernbered heteroaryi group linked to the NH group through an aromatic ring carbon atom ,
• the heteroaryi ring system contains 1 or 2 heteroatoms selected from , O and S.
• the heteroatoms are N atoms.
• iiAise-membered heieroaryL the R !A group can either be m&ta or para to the NH group, if A is5--membered heieroaryl or a 7 to 10 membered heteroaiyl, the R ,A group is not alpha to the -NH- group.
• the R 1A group is beta io the - H- g oup
• R may have one of the following structures:
• R N1 is selected from H, C alkyl, C ; cycloalkyl and C( ⁇ 0)M&;
• R fts Is selected from H, C M alkyl, C 3 . 4 cycloalkyl and C ⁇ 0)Me:
• R m is seleded from H, C s!kyi. C 3 ⁇ 4 . cycloalkyl and C( ⁇ 0)Me;
• R Is selected from H and CH ;i ;
• R i Is selected from H, alkyl, C s . 4 cycloalkyl and C ⁇ -Q)Me
• R m is seleded from H, C ⁇ . 4 alkyl, C 3 . 4 cycloalkyl and C ⁇ 0)W®;
• R ; " 7 and R m are Independently selected from H and CH 3 ;
• R NS Is selected from H, C,. 4 alkyl, cycloalkyl and C ⁇ -Q)Me
• R 11 is selected from H. C ⁇ alkyl C ; cycloalkyl and C( ⁇ 0) e; and
• R N12 is selected from H, C,. a kyl, C M cycloalkyl and C(-0; e.
• R N R m , R i .. R*. R* 6 , R S , R* 10 , R m and R N 2 is independently selected from H. Ci.4 alkyl (I.e. methyl, ethyl, prop- 1 -yl, prap-2-yl, n-butyl, fso-butyl, sec-butyl, tert ⁇ buty ⁇ ), C w cycloalkyl (I.e. cyclopropyl, methylcydoprcpyl, cydobutyl) and C( ⁇ 0)Me.
• R m , R ( and R m is Independently selected from either H or methyl.
• Each of Z ! and Z' Is Independently selected from H, alkyl (i.e. methyl, ethyl, prop-1-y! and prop-2-yl) , optionally substituted by OH, C( ⁇ Q)QC Z alkyl (i.e. C(--0)0-methyl, C ⁇ 0 ⁇ 0- ethyl, C ⁇ 0)0-prop-1-y1 and C( ⁇ 0)0-prop-2-yi) and C(-0 ⁇ 8.
• alkyl i.e. methyl, ethyl, prop-1-y! and prop-2-yl
• C( ⁇ Q)QC Z alkyl i.e. C(--0)0-methyl, C ⁇ 0 ⁇ 0- ethyl, C ⁇ 0)0-prop-1-y1 and C( ⁇ 0)0-prop-2-yi
• Each R l B group may be d. s alkyl (i.e. methyl, ethyl, prop-1 -yl and prop-2-yi), CF ;; , F, CI, O- C;. 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 a/pfta to the NH group.
• Each R'° group may be C ; . 3 alky! (i.e.
• R' groups i.e. 1 , 2 or 3 depending on the nature of A, and In particular on the number of ring atoms and ring heteroaroms, as well as whether R' A is present.
• R is selected from H, halo (I.e. F, CI, Bp I), C-w alkyl (I.e. methyl, ethyl pr ⁇ p-1-yl and prop-2- yl, n-butyf, /sobutyL sec-butyl, feff-buiyi), CF 3 , CF 2 H, CN and metboxy.
• halo I.e. F, CI, Bp I
• C-w alkyl I.e. methyl, ethyl pr ⁇ p-1-yl and prop-2- yl, n-butyf, /sobutyL sec-butyl, feff-buiyi
• CF 3 CF 2 H
• CN metboxy
• the halo group I is either F or CI.
• R 3 is selected from substituted phenyl and a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 heteroaiorns.
• R ' ⁇ R ? and R 8 are Independently selected from H, F, methyl and CF S .
• One of 4A and R 48 is R ⁇ and the other Is selected from H, R methyl and CF 3
• R s Is a substituted 6 membered heteroaryl group, where the heteroaryl ring system contains 1 or 2 N heteroaioms, It may be selected from the any of the groups;
• R" is a substituted 6 membered heteroaryi group, it may have one of the following structures:
• R 6 , R ? and R s are Independently selected from H, F, methyl and CF 3 .
• R 4 * and R 4B are R 4 , and the other is selected from H, R methyl and CF 3 .
• R* is alpha to the -C 2 H 4 -group, it may also be described as being ho.
• R 4 Is beta to the -C 3 ⁇ 4 H 4 -group it may also be described as being eta.
• the further optional suDstltuen!s on R 3 are Independently selected from R methyl and CF 3 . These further groups may be at any available ring position on R", except that occupied by R ⁇ There may be upto 4 further optional substltuents groups (I.e. 1 , 2, 3 or 4 ⁇ depending on the nature of R s , and In particular on the number of ring heteroaroms.
• R* is -CH 2 - €(0)N(R N!3 ⁇ Z 3 .
• R is selected from H and CH 3 ; and Z 3 is seiected from H, CH 3 or OCH 3 .
• R 4 is selected from:
• R N1 Is selected from H, C ; . 3 aikyl end C( ⁇ 0)Me;
• R *£ is selected from H, C, -a aikyl, and C ⁇ 0)Me;
• R- j Is selected from H, C;. 3 alkyL and C( ⁇ 0) e:
• R 7 and R 1 * are independently selected from H and CH a ;
• R m is selected from H, C 1-3 aikyl, and C( " 0) e;
• R N'! Is selected from H, C ; . 3 aikyl, and C( ⁇ 0)Me;
• R *£ is selected from H, C, -a aikyl, and C ⁇ 0)Me;
• R 2 Is not selected from CF 3 , halo, GF 2 H and CN.
• a reference to carboxyllc acid (-COOH) aiso includes the anionic (csrboxy!ate) 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 ! R 2 ), a salt or solvate of me amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group.
• a reference to a hydroxy! group also Includes f he anionic form (-01, a salt or solvate thereof, as well as conventional protected for s of a hydroxy I grou .
• alpha and beta are used herein to Indicate the relative position of substltuent groups on rings. For the avoidance of doubt, their meaning is Illustrated with the structure below:
• bromo group Is alpha to the chioro group and the lodo group Is beta fo fhe chloro group. .Isomers, Salts, Solvates, Protected Forms, and Prodrugs
• Certain compounds may exist in one or more particular geometric, optical, enantiomeric, dlasterlomeric, epimerlc, stereoisomer ⁇ , tautomeric, conformational, or anomerlc forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t » , and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and Worms; (+) and (-) forms; koto--, end--, and enolafe-forms; syn- and anti-forms; synclinal- and anticlinal-forms; a- and ⁇ -forms; axis! and eguatoriai forms; boat-, chair-, twist-, envelope- , and halfchaln-forms; and combinations thereof, hereinafter collectively referred to as "isomers' 1 (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 fo a methoxy group, -OCH 3 Is not to be construed as a reference to Its structural Isomer, a hydroxymethy! group, -CH 3 ⁇ 4 OH.
• a reference to oftho-chlorophenyl is not to be construed as a reference to its structurai Isomer, eta- chlorophenyL
• a reference to a class of structures may well Include structurally
• Isomeric forms falling within that class e.g ., C ⁇ . ? alk l Includes n-propyl and /so- propyl; butyl includes n-, is -, see-, and ferf-butyl; methoxyphenyl includes ortho-, rneta-, and para- ethoxyphenyl).
• keto/enoi (illustrated below), imine/enamlne, amlde/lmlno a!coho!, amldlne/amldine, nltroso/oxlme,
• H may bs in any Isotopic form, Including ⁇ , ' ⁇ (D). and " ⁇ (T); C may be In any Isotopic form, including 12 C, W C and "*C; O may be in any Isotopic form, Including iS 0 and : 3 ⁇ 4 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 ad 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 pharmaceutlcaliy-accepiable salt.
• a pharmaceutlcaliy-accepiable salt examples of pharmaceutically acceptable salts are discussed In Berge et ai. J. Phar . 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 g 2* , and other cations such as A!* * .
• suitable organic cations include, but are not limited to, ammonium Ion (I.e., NrV) and substituted ammonium Ions (e.g., NH 3 Ft, NH 2 F , HR 3 ' ⁇ NR,,*).
• suitable substituted ammonium Ions are those derived from: ethylarnlne, diethylamine,
• dlethanolamlne piperazlne, benzylamlne, phenylbenzylamine. choline, meglumine, and tromethamlne, as weff as amino acids, such as lysine and arglnlne.
• An example of a co mon quaternary ammonium ion is (CH 3 ) ⁇ .
• 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, hydrobromio, 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, pa oic, tartaric, citric, gluconic, ascorbic, ma!e!c, hydroxymalelc, phenylaoetio, glutamic, aspartic, benzoic, cinnamlc, pyruvic, salloyclic, su!fan!!!c, 2- acetyoxybenzolc, fumarie, phenylsulfonlc, toluenesulfonlc, methanesulfonlc, ethanesu!fonic, ethane dlsulfonio, oxalic, pantothenic, Isethionio, valeric, lactogenic, and gluconic.
• suitable polymeric anions include, but are not limited to, those
• 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- ydrate, a i !-bydrate, etc.
• 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 ⁇ -GC( ⁇ 0 ⁇ R ⁇ , for example, as: a -bufyl eiher; a benzyl, benzhydry! (dlphenylmethyl), o trityl
• G-C( ::: 0)CH , -OAC acetai or keiaL respectively, In which the carbonyl group ⁇ >O0 ⁇ Is converted to a dieiher (>C(OR) ? ), by reaction with, for example, a primary alcohol.
• 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 (- HCO-Chk); a benzyioxy amide ⁇ -NHCO-OCH 2 CeH 5! -NH-- Cbz); as a t-batoxy amide (-NHCO-OC(CH 2 ⁇ 3 , -NH-Boc); a 2-blphenyl-2 ⁇ propoxy amide ( ⁇ HCO-OC ⁇ CH 3 )jC s H4C s H 5! -NH-Bpoc), as a S-fiuorenylmethoxy amide (-NH-Fmoc).
• a methyl amide a benzyioxy amide ⁇ -NHCO-OCH 2 CeH 5! -NH-- Cbz
• a t-batoxy amide -NHCO-OC(CH 2 ⁇ 3 , -NH-Boc)
• a carboxyllc acid group may be protected as an ester for exampie, as: an C ⁇ . 7 alkyl ester (e.g. a methyl ester; a i- utyl ester); a C i. 7 haloalkyl ester (e.g. , a C ⁇ . ? trihaloalkyl ester); a triCi.? alkylsllykCj . 7 alkyl ester: or a C M0 ar J-Ci . 7 alkyl ester (e.g. a benzyl ester; a nitrobenzyl ester): or as an amide, for example, as a ethyl amide.
• an C ⁇ . 7 alkyl ester e.g. a methyl ester; a i- utyl ester
• a C i. 7 haloalkyl ester e.g. , a C ⁇ . ? trihaloalky
• a thiol group may be protected as a thioetber (- SR), for example, as: a benzyl thioether: an acetamldomethyi ether C-S-CH 2 NHC(TM0)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 metaboiically labile ester). During metabolism, the ester group i-C( ⁇ 0)OR) is cleaved to yield the active drug.
• esters may be formed by esteriflcatlon, for example, of any of the carboxyllc acid groups (-C( ⁇ 0)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.
• metaboiically labile esters include those wherein R Is C1 -? alkyl (e.g. -fV!e, ⁇ Et); C ⁇ . 7 arnlnoaikyl (e.g. amlnoethyl; 2-(N !
• 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 or 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:
• A is an optionally s jstituted 6 membered beteroaryl group.
• 6 membered beteroaryl groups include, bs. are not limited to. pyndyl isoxazlnyi, pyridazlnyl, pyrlrnldlnyl, pyrazlnyl and tna snyl.
• R' A Is present R 1 is not an oxo ( ⁇ 0) grou
• R substl!uerns there are no R substl!uerns.
• A when A is pyridyl and there are no R'° groups, it may have the structures:
• a riA may be f urther preferred in some embodiments ot the tirst aspect, A is an optionally substituted 5 membered
• heteroaryi group 5 membered heteroaryi groups include, but are not limited to: pyrrolyl; turanyi; thlophenyl: oxazolyl; Isoxazolyl: oxadlazolyl; oxatriazolyl; thlazolyl: Isothiazolyl; imidazolyl; pyrazoiyl; tnazolyl and tefrazolyl.
• A is pyrazoiyl, which can have the structures:
• articularly preferred structures for A include:
• R A Is CH(R 0 i ⁇ NHZ ⁇ Z may be any one of.
• Z may be selected from H, CH 2 CH 2 OH and C( ⁇ G)Me.
• R A is selected from: CH 2 NH 2 ; CH(GH :5 )NH ;; : CH(C 2 H S )NH 2 ; CH 2 NHCH s CH 2 OH; CH(CH s )NHCH 2 CH a OH; and CH(C 2 H $ )NHCH S CH 2 QH.
• R ,A is CH(R C ! )NHZ ⁇ R C! may be selected from H and methyl.
• R A Is selected from: CH 2 NHZ' ; and CH(CH 3 )NHZ 1 .
• R ,A Is CH(R C S )NHZ : , Z i may be selected from H and
• R iA is selected from: CH 2 NH 2 ; CH 2 HCH 2 CH 2 OH: CH(CH 3 )NH 2 ; and CH(CH 5 )NHCH 2 CH 2 OH.
• R ,A Is XNHZ 2 , Z' may be any one of:
• R is X HZ'r Z 2 may be H.
• R' A has the structures:
• R 1A Is XNHZ 2 Z 2 may be C ⁇ 0)OMe.
• Z 2 may be C ⁇ 0)OMe.
• R ,A is X HZ 2
• X may be selected from CMe 3 ⁇ 4 , and
• R 1A has the structures:
• R 1A has
• R' A is: kA. (R 'A1 ), wherein R > is selected from H, C alky! (i.e. methyl, ethyl, prop-1 -y! and prop-2-yl, n-butyl, iso-butyl, sec-butyl, ferf-butyl), c3 ⁇ 4. 4 cycloalky! (i.e. cyclopropy!, methylcyclopropyl, cyc!obutyl) and C( ⁇ 0)M&. in some of these embodiments, it may be preferred that R M is C ⁇ 0)Me. In others of these embodiments, It may be preferred that R m Is H, methyl or ethyl.
• R ' Ai wherein R m is selected from H, C ;. 4 a!ky! (I.e. methyl, ethyl, prop-1 -y! and prop-2-yl, /j-butyi, /so- utyl, sec-butyl, fe/f-buty!), C 3 ., ⁇ cycloalkyi (i.e. cyclopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ 0)Me.
• R ';A is: wherein R is selected from H, C :. 4 alky! (i.e. methyl, ethyl, prop-1 -yl and prop-2-yl, n-buty!, /so-butyi, sec- butyl, ferf-buty!), G 3 . 4 cycloalkyl (i.e.
• R ° is C( ⁇ 0)Me.
• R** selected from H or methyl, in some of these embodiments, It may be preferred that R m Is R.
• R '!K Is
• R is selected from H, C aiky! (i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-buiyl,so-butyl, sec-butyl, fen-butyl), C s . cycloalkyl (i.e. cyciopropyl, methylcyclopropyl, cyclobutyl) and C( ⁇ 0)fV!e. in some of these embodiments, It may be preferred that R ⁇ 6 Is C( ⁇ 0)Wle. In others of these embodiments, it may be preferred that is H, methyl or ethyl, more preferably H or methyl.
• R 3 ⁇ 4i> Is:
• R Is selected from H. C w alkyl (I.e. methyl, ethyl, prop-1-yl and prop-2-yl, n-butyi, iso-butyl, sec-butyl, ierf-butyf), C 3 . ⁇ 8 cycloalkyl (I.e. cyciopropyl, methylcyclopropyl, cyclobutyl) and C(" : 0)lyle. in some of these embodiments, It may be preferred that R S Is C ⁇ -0)Me. In others of these embodiments, it may be preferred that R 8 is H, methyl or ethyl, more preferably H or methyl.
• R '!A Is
• R / and R m are both H or both niethyi. In some of these embodiments, It may be preferred that R N? and R m are both H.
• R ;A is:
• R 8 Is selected from H. C w alkyl (I.e. methyl, ethyl, prop-1-yi and prop-2-yl, n-butyi, /so- butyl sec-butyl, feri-buiyl), C w cycloalkyl (i.e. cyclopropyi, methyleyclopropyl, cyclobutyi) and Cf" : 0)lvle.
• R* 3 Is C(-0)Me.
• R m Is H, methyl or ethyl, mors preferably H or methyl.
• R ' 0 is selected from H, alkyl (I.e. methyl, ethyl, prop-1-yl and prop-2-yi, n-butyi, /so- butyl sec-butyi, ferf-buty!), C w cycloalkyl (i.e. cyclopropyi, methyicyclopropyl, cyclobutyi) and C(-0)M®.
• R N1 ° Is C(-0 ⁇ e.
• R N, ° is H, methyl or ethyl, more preferably H or methyl.
• R' A is:
• R is selected from H, alky! (I.e. methyl, ethyl, prop-1-y! and prop-2-yl, n-butyl, /so-butyi, sec-butyl, ferf-butyl), C :$ . « cycloalkyl (I.e. cyc!opropy!, methy!cyciopropy!, cyclobutyl) and C( ⁇ 0)Me, In some of these embodiments, It may be preferred that R ;1 Is C(-- : 0)lvle. in others of these embodiments, It may be preferred that R ! ' is H, methyl or ethyl, more preferably H or methyl.
• R 1A Is:
• R N12 is selected from H « C ⁇ . alkyl (I.e. methyl, ethyl, prop-1-y! and prop-2-yl, n-butyl, feo-butyl, sec-butyi, ierf-butyi).
• C 3 . 4 cycloalkyl (I.e. cyc!opropyi, methyicyclopropy!, cyclobutyl) and C( ⁇ 0)Me In some of these embodiments, It may be preferred that R ; ' ; Is C ⁇ 0 ⁇ Me. In others of these embodiments, It may be preferred that R 3 ⁇ 4 Is H, methyl or ethyl, more preferably H or methyl.
• R 1A Particularly preferred R 1A groups Include:
• R ,B is preferably alky! and more preferably methyl. in some embodiments, s single R' B substituent is present. It may be C h alky!;
• CF a F; CI; 0-(GK ⁇ a!k l): and CN.
• it is preferably F or alkyl and more preferably F or methyl.
• a single R C substituent is present. It may be C.. 3 alkyl
• I! Is preferably C ,.. S alkyl, and more preferably methyl.
• R' is H.
• R 2 Is halo i.e. F, CI, Br, I.
• the halo group is either F or CI.
• Fr Is C alkyl i.e. methyl, ethyl, prop-1-yl and prop-2-yl, n ⁇ butyi, iso- but i, sec-butyl, tert-buiy ⁇ .
• the C a!kyf group is methyl or ethyl, and methyl may be preferred.
• R 2 Is selected from CF 3 ⁇ 4 and CF 2 H.
• R : - is CF ;; .
• R 2 Is CN.
• R 2 is ethoxy. .R 5
• R° is substituted phenyl, and therefore it has the structure:
• R 8 , R' and R s are Independently selected from hi R methyi and CF 3 .
• the group of R 4A and R 48 that is not R 4 , and R s . R 7 and R 8 are all H.
• one of the group of R 4A and R S that Is not R 4 , R e , R ? and R ⁇ is not H, and therefore Is R methyl or CF ;
• the group that is not H may preferably be R K or R ⁇
• R 3 is substituted phenyl
• R 48 R s , R 7 and R 8 are all H
• R 'iA is R ' ⁇
• R 3 Is a substituted 6 membered heferoaryi group, where the heteroar l ring system contains 1 or 2 N heteroatoms.
• R 3 Is pyrldyl which can have the structures:
• R 3S (R 30 ) (R 3 ⁇ 4 ) (R 3e ) (R 3 y
• R s , R' and R s are Independently selected from H, R methyl and CF 3 ⁇ 4 .
• R 4A and R B (If present) is R ⁇ and the other is selected from H, R methyl and CF 3 .
• R 3 ⁇ 4 and R 3a may be preferred, in some of these embodiments, the group of R 4A and R 48 that Is not R 4 , and R s , R 7 and R 8 (If present) are all hi In others of these embodiments, one of the group of R 4A and R 4S that Is not R ' ⁇ R s , R 7 and R s (if present) Is not H, and therefore Is R methyl or CF 3 . In some embodiments. It may be preferred that a F substltuent is not alpha to a ring nitrogen atom.
• R 4 Is alpha to the -C 2 H group.
• R '! Is beta to the -C 2 H r group in some embodiments, R 1S Is H.
• R m is Me. in some embodiments, Z 3 is H.
• Z '5 is Me.
• Z 3 is Obie.
• the compounds of formula (i) are of formula (la) or isomers, salts, solvates, protected forms or prodrugs thereof wherein:
• A is an optionally substituted 5 or 6 embered heteroaryl group linked !o the NH group through an aromatic ring carbon atom ,
• the heteroaryl ring system contains 1 or 2 N atoms, and;
• A may bear a substituent R ,A which Is not alpha to the NH group and may optionally further bear a substituent R ; which are not alpha to the NH group, where R !A Is selected from:
• R 2 is selected from H and C M alkyl
• R 'c Is C 1-5 alkyl
• R' is selected from C-,. 4 alkyl and CF 3 :
• R z is substituted phenyl, where R J bears a substituent R 4 alpha to the -C 6 H. group, and may additionally bear a further substituent F;
• R* is GH r C(0; (R : ⁇ : :Z ⁇ where R ⁇ 13 is H; and Z Is H.
• the compounds of formula (I) are of formula (lb; or Isomers, salts, solvates, protected forms or prodrugs thereof wherein: A is an optionally substituted 5 or 6 membered heteroaryl group linked to the NH group through an aromatic ring carbon ato , In which the heteroaryl ring system contains 1 or 2 N atoms, and;
• A may bear a substltuent R 1A which Is not alpha to the NH group and may optionally further bear a substltuent R C which are not alpha to the NH group, where R iA is R 'iA2 :
• R** 2 is selected from H and C M alkyi
• R 2 Is selected from €,., ⁇ aikyl:
• R 3 is substituted phenyl, where R 3 bears a substltuent R 4 alpha to the ⁇ C 2 H ⁇ - group; and R" is -CH 2 - €(0)N(R N!3 ⁇ Z 3 , where R wa is H; and 2' Is H.
• the compounds of formula (I) are of formula (lc) or isomers, salts, solvates, protected forms or prodrugs thereof wherein;
• R ,A is selected from:
• R N1 is selected from H and Me:
• R" !2 IS selected from H and Me;
• R m is selected from H and Me
• R !5 Is selected from H and Me:
• R 2 is selected from H, methyl and CF 3 ;
• R ⁇ R s and R ? are Independently selected from H, F, methyl and CF S , and only one of them is not H;
• R 4 is -CH C(0)NH 2 .
• the compounds of formula (II) are of formula (I la; or Isomers, salts, solvates, protected forms or prodrugs thereof wherein:
• A may bear a substltuent R 1A which is not alpha to the NH group and may optionally further bear a substltuent R" 5 which Is not alpha to the NH group, where R ,A is selected from: (I) CH(R C 1 )NHZ ⁇ where R C1 is selected from H and d. 2 alkyl and Z' is selected from H,
• R N1 is H
• H m is selected from H and d- « aikyi;
• R 5 is H
• R 2 is selected from H, halo, 3 ⁇ 4 4 alkyf, CF-, and methoxy;
• R" is substituted phenyl, where R '! bears a substltuent R 4 alpha to the -C 2 H 4 - group, and may additionally bear a further substltuent selected from R methyl and CF-,; and
• R 4 Is ⁇ H C(0) (R i13 )Z 3 : where R' i13 Is H; and Z 2 is H.
• the compounds of formula (II) are of formula (l ib) or Isomers, salts, solvates, protected forms or prodrugs thereof wherein:
• A may bear a substltuent R 1A which is not alpha to the NH group and may optionally further bear a substltuent R" 5 which Is not alpha to the NH group, where R ,A is selected from: (i) CH(R C1 )NHZ ⁇ where R C1 is selected from H and -z alkyl and Z' is selected from H and C ⁇ .i alkyl optionally substituted by OH;
• R N1 is H
• H m is seiected from H and d. 4 aikyl
• R 5 is H
• R N i is H
• R 13 is H:
• R 3 ⁇ 4 is seiected from halo, Cn aikyl. CF 3 and rnethoxy;
• R '5 Is substituted phenyl, where R 3 bears a substituent R* aipha to the -C 2 H 4 - group, and may additionally bear a further substituent selected from methyl and CF S ;
• R" is -CH C(0)N(R Ni3 ⁇ Z 3 , where R wa is H; and 2' Is H.
• the compounds of formula (if) are of formula (l ie) or Isomers, salts, solvates, protected forms or prodrugs thereof wherein:
• A is:
• R A Is selected from:
• R ' is selected from H and Me
• R S Is selected from H and Me
• R N12 is selected from H and Me
• R i Is selected from H, methyl and CF 3 ;
• R 6 , R e and R ? are Independently selected from H, F. methyl and CF 3 . and only one of them Is not H;
• R" is -CH C(0)NH 2 .
• Embodiments of the Inventions are compounds of the examples, including compounds 1 to 41 .
• Embodiments of pedicular Interest include compounds 5, 6, 14, 16, 24, 28, 30 and 31 .
• 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 formula (II) or isomers, salts, solvates or prodrug thereof comprises reacting a compound of formula F1
• A, R 2 and R 3 are as defined in formula (I) or (II) above and L' and ⁇ are leaving groups.
• the leaving groups iJ and LT may be any suitable leaving groups, such as a halogen atom (F, CI, Br, I), -SR or -SQ ;; R where R is a C ;. straight chain or branched alkyl group.
• V and I 2 may be the same or different and may be selected from the group consisting of CI, Br, I , SMe, SC lv1e.
• Examples of commercially available amino compounds of the formula F2 include, but are not limited to those depicted in table 1 .
• nltro containing compounds are also commercially available including, but not limited to those depicted In table 2.
• Synthetic amino compounds of the Invention may be prepared v a 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 heteroaromatlc systems.
• tert-Buiyl 4- ⁇ 3-sminophenyl ⁇ plperazine-1-carboxyiate can be prepared by coupling of commercially available ferf-butyi piperazine-1 -carboxylate (G7) and compounds of the formula F4, where L" ⁇ I or Br, In a Buc waid type reaction to give fe/f-butyi 4-(3- nitrophenyl)piperazlne » 1 -carboxylste (G8), Reduction with hydrogen In the presence of a catalyst, for example palladium on charcoal, gives fe f-butyi 4-(3--am!nopheny!)p!perazine--1 - carboxylate (G9) .
• a catalyst for example palladium on charcoal
• the corresponding 4-piperidine analogues of G8 can be prepared by a sequence of reactions starting with the conversion of commercially available fe t-butyi 4- oxop!pend!ne- 1 - carboxylate (G10) to vinyl trifla!e G i l .
• Coupling of Gi l in a Suzuki type reaction with (4- n!trophenyhboron!c acid (G12) gives tetra ydropyridine G 13.
• the corresponding 4- ⁇ 3-aminophenyl ⁇ piperidine analogue of G9 can be prepared by a sequence of reactions starting with the conversion of commercially available fe/f-butyi 4- oxoplperldine-1 --carboxyiate (G 10) to vinyl trlflate Gi l Coupling of Gi l
• G 10 commercially available fe/f-butyi 4- oxoplperldine-1 --carboxyiate
• Gi l vinyl trlflate Gi l Coupling of Gi l
• S-nitrophenypboronic acid G 15
• tetrahydropyrldlne G 16 gives tetrahydropyrldlne G 16.
• a catalyst for example palladium on charcoal, gives fe/f-butyl 4-(3 ⁇ amlnophenyl)plperldlne-1-carbox late (G17).
• the 3- ⁇ 4-amlnophenyl)plperidlne regloisomers or G 14 can be prepared by reaction of commercially available compounds of the formula F5, where L° ⁇ I or Br, with pyridin-3- ylboronic acid (G18) In a Suzuki type reaction to form 3-(4--nltrophenyl)pyndlne (G19).
• the 2-(4-amlnophenyl)piperidine reglolsomer of G14 can be prepared by reaction of commercially available compounds of the formula F5, where L 3 » I or Br, with pyridin-2- ylboronlc acid (G22; In a Suzuki type reaction to form 2-(4-nltrophenyl)pyrldlne (G23). Reduction of G23 with hydrogen in the presence of a catalyst, for example platinum oxide, gives 4- ⁇ pipefidin-2-yr)aniiine (G24) which may be protected using Boc anhydride to give feff-buty! 2-(4-aminopheny!)plperldlne-1 -'Carboxylate (G25).
• a catalyst for example platinum oxide
• G26 Commercially available ferf-buiyl 3-oxopyrrolldine--1 -csrboxylate (G26) can be converted to a mixture of vinyl Inflates G27 and G28 In the presence of a irlfiamlde and a suitable base, for example NaHlvlDS. Coupling of the mixture with (4 ⁇ nitrophenyl)boronic acid (G 12) under Suzuki conditions gives dihydropyrroles G23 and G30. Reduction of this mixture using hydrogen In the presence of a catalyst, for example 10% palladium on charcoal gives tert- butyl 3-i4-amlnophenyl)pyrrolidlne ⁇ 1 -carboxylaie (G31).
• a catalyst for example 10% palladium on charcoal gives tert- butyl 3-i4-amlnophenyl)pyrrolidlne ⁇ 1 -carboxylaie (G31).
• fe i-Butyi (1 ⁇ 4-amir3 ⁇ 4ophenyl ⁇ plperidir3 ⁇ 4 ⁇ 4-yi)carbamate (G39) can be prepared by nucieopNiic aromatic substitution of commercially available tert-hutyl piperi in-4 ⁇ ylcarbama!e (G36) and l -fluoro-4-nltrobenzene (G37; under thermal conditions to give fe - butyl ( 1 -(4- nltrGphenyl)plperldln-4-yl)carPamate (G38).
• tert-Butyi 4"(4-anilnobenzyl)piperazlne-1- carboxylate (G49) can be prepared by the nucleophlllc displacement of commercially available 1- ⁇ &ramomethyl)-4-nitrobereerse (G4?) with teri-butyi piperazine-1 -cartoxylate (G7) to give fe/t-butyi 4-(4-nitrobenzyi)piperszine-1- carboxylate (G4S). Subsequent reduction with hydrogen in the presence of a catalyst, for example 10% palladium on charcoal, gives feri-butyi 4- ⁇ 4-aminobenzyl)piperazine-1 - carboxylate (G49) .
• a catalyst for example 10% palladium on charcoal
• a carboxyllc acid may be converted to a corresponding ester or amide as required and converseiy esters and amides can be hydroiysed to give carboxy!ie acids Halogenation, for example using W-bromosucclnimide, of compounds of the formula F10 gives compounds of the formula F11 , Compounds of the formula F11 may be reacted under Sonagashira type coupling conditions to give acetylenes of the formula F12 where P - T!VIS, TES or C ⁇ CH 3 ) 2 OH. R 3 ⁇ 4 may then be removed to generate compounds of the formula F13.
• R 9 JUS or TES potassium carbonate or teha-fi-buiyl ammonium fluoride may be employed to induce this transformation.
• R 8 C(CH 3 )?OH, sodium hydride In refluxlng toluene may be used.
• heteroaryl analogues of F t 3 may be prepared as outlined In Schemes R Q and R.
• 2,3-dl-chioropyrazine (G52) can be reacted with ethyl acetate in the presence of LiHWIDS to give ester G53.
• Coupling of ester G53 with IMS acetylene under Sonagashira conditions gives ethyl 2-(3-((tnmethylsllyl)ethynyl ⁇ pyra2ln » 2- yhacetate (G54).
• Removal of the trimethylsllyl group using TBAF gives ethyl 2-(3- etbyny!pyrszi!>2--y!acetate (G55).
• diethyl succinate (G56) and ethyi formate (G5?) can be condensed to give aldehyde G58 In the presence of sodium metal.
• Cycilsatlon using thiourea gives 4-oxo-2-thioxo-1 ,2.3,4-tetrahydropyrimidins (G59).
• Desulfur sation using Raney-nickel gives pyrimldone G60, which can be converted to 4-chloro pyrimidlne G61 using phosphorous oxychlorlde.
• 2-(pyrldin--3 ⁇ yl)acetonltrile (G64) can be oxidised to /V-Gxi e G65.
• Chlorination with phosphorous oxyohlorlde gives 2-c ioropyridine G88 which can be hydrolysed with sodium hydroxide to acetic acid G67.
• Ester formation using methanol gives 2-ch!oropyndlne ester G68.
• Pyrimldines of ihe formula F3 may be reacted with terminal acetylenes of the formula F13 to give acetylenes of the formula F14 In a Sonagashlra type coupling.
• the acetylene In compounds of the formula F14 may be reduced to an alkane of the formula F15 using hydrogen gas In the presence of a transition e!al catalyst.
• the exact choice of catalyst and conditions employed Is dependent on the nature of R 2 . For example, where R 2 ⁇ p, CFs, methyl or methoxy, 10% Pd/C may be used, where R 2 » CI, platinum oxide Is employed.
• heferoaromatic analogues of compounds of the formula F13 may be coupled in an analogous manner to that described in scheme S and then further elaborated to amides as described above.
• trlacetoxyborohydrlde to give N-M& analogues; by reductive alkylation with acetaldehyde in the presence of sodium trlacetoxyborohydrlde to give V-Et analogues or the /V-acety! analogues may be prepared by reaction with a suitable acylating agent, for example acetic anhydride.
• a suitable acylating agent for example acetic anhydride.
• Pyrimidlnes of the iormuia F 1 may be coupled to acetvienes of the formula F13 to give acetylenes of the formula F16 in a Sonagashlra type coupling. Depending on the nature of R 2 these couplings may either be regloselectlve, or where mixtures are obtained, regloisomers may be separated by chromatography.
• the acetylene In compounds of the formula F16 may be reduced to an aikane of the formula F17 using hydrogen gas In the presence of a transition metal catalyst. The exact choice of catalyst and conditions employed is dependent on the nature of Fc ⁇ For example, where R 2 - Me, 10% Pd/C may be used, where R 2 ⁇ CI, platinum oxide Is employed.
• the desired amide may already be present in compounds of the formula F 13, or alternatively an ester may be used and subsequently derlvatlsed as described above.
• Ketones of formula F18 where R 1 ' Is an a!ky! group or similar may be substituted with amines to form compounds of formula F 19.
• Q4 and GS may be the same such as H to form a primary amine or different such as NHiv e and may also be fused together to form a ring structure, for example but not limited to azetidine, pyrrolidine, plperazlne, morpholine and piperidine.
• the present Invention provides active compounds, specifically, active 2,4,5-substliuted pyrirnldlnes
• 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 ceil, 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 if) f?3 ⁇ 4 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 pad 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.
• Such a method may comprise administering to such a subject a therapeutloaliy-effectlve amount of an active compound, preferably In the form of a pharmaceutical composition.
• treatment refers 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 hait 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.
• Iherapeut!ca!!y-eifeci!ve a ount pertains to that amount of an active compound, or a materia!, 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 tor 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 iherapeut!ca!!y-effect!ve amount of an active compound, preferably in the form of a pharmaceutical composition.
• cancers include, but are not limited to, bone cancer, brain stern glioma, breast cancer, cancer of the adrenal gland, cancer of the ana! 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, haemeto!ogica!
• the cancer is melanoma, breast cancer or head and neck cancer. Any type of cell may be treated, including but not limited to, lung, gastrointestinal (including, e.g. , bowei, 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 iymphanglogenesis 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 metastasis.
• a compound of formula (i) or formula (I 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 formula (II) or an Isomer, salt, solvate or prodrug thereof for use in a method for preventing the spread of cancer or preventing of metastasis.
• an anti-cancer treatment comprising a compound of formula (I) or formula (I I) or an isomer, salt, solvate or prodrug thereof and an anti-tumour agent.
• the anil cancer treatment defined herein may be applied as a sole therapy or may Involve, In addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.
• Such chemotherapy may include one or more of the following categories of anti-tumour agenis:-
• alkylating agents for example clsplatln. oxaiiplatln, carboplatln, cyclophosphamide, nitrogen mustard, me!phaian, chlorambucil, busulphan, temozolamide and nitrosoureas
• antimetabolites for example gemcltabine and antifolates such as fluoropyrlmldlnes like 5 fluorouraoli and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea
• antltumour antibiotics for example anthracycllnes like adrlamycln, bleomycin, doxorubicin, daunomycln, eplrublcln, idarublcln, mlfomycl
• eplpodophyllotoxlns like etoposide and ariaposlde, amsacrlne, topotecan and cam tothecln);
• cytostatic agents such as antloestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxlfene and iodoxyfene), antlanorogens (for example
• LHRH antagonists or LHRH agonists for example goserelln, leaprorelln and buserelln
• progestogens for example megestrol acetate
• aromatase inhibitors for example ss anastrozole, letrozole, vorazoie and exeniestane
• inhibitors of 5* ⁇ - eductase such as finasteride
• anti-invasion agents for example c ⁇ Src kinase family inhibitors like 4-(6-c loro-2,3- met yienedioxyaniiino)-7 ⁇ [2-(4 ⁇ methyipiperazin-1 -yl ethoxy]-6 etra ydropyran--4- yioxyquinazo!ine (AZD0630; international Patent Application WO 01/94341), N-(2 ⁇ c ioro-e- methylphenyl)-2 6-[4-(2-hydroxyethyl ⁇ pip®razln-1 -yl
• anti-invasion agents for example c ⁇ Src kinase family inhibitors like 4-(6-c loro-2,3- met yienedioxyaniiino)-7 ⁇ [2-(4 ⁇
• inhibitors of growth factor function include growth factor antibodies and growth factor receptor antibodies (for example the antl erbB2 antibody trastu umab [HerceptlnT] ; the antl-EGFR antibody panliumumab, the anti erbBI antibody cetuximab [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et ai. Critical reviews In oncology/haematology 2005, Vol. 54, pol l -29); such inhibitors also Include tyrosine kinase Inhibitors, for example Inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase Inhibitors such as
• antianglogenlc and antilymphanglogenlc agents such as those which Inhibit the effects of vascular endothelial growth factor, [for example the antl vascular endothelial cell growth factor A (VEGPA) antibody bevaclzumab (AvastinT), the antl vascular endothelial cell growth factor A (VEGFA) antibody ranibKumab, the antlA/EGF aptamer pegaptanlb, the antl vascular endothelial growth factor receptor 3 (VEGFR3) antibody I C-3C5, the antl vascular endothelial ceil growth factor C (VEGFC) antibody VGX-100, the antl vascular endothelial cell growth factor D (yEGFD) antibody VGX-200, the soluble form of the vascular endothelial growth factor receptor 3 (VEGFR3) VGX-300 and VEGF receptor tyrosine kinase Inhibitors such as 4--(
• (vll) antisense therapies for example those which are directed to the targets listed above, such as ISIS 2503, an antnras antisense:
• (Ix) Immunotherapy approaches Including for example ex vivo and In vivo approaches to Increase fhe Immunogenlcity of patient tumour cells, such as transfectlon with cytokines such as inierleukin 2, Interleukln 4 or granulocyte macrophage colony stimulating factor, approaches to decrease T cell anergy, approaches using transfected Immune cells such as cytokine transfected dendritic cells, approaches using cytokine transfected tumour cell lines and approaches using antl Idiotypic antibodies
• lymphanglogenesls in one embodiment there is provided the use of a compound of formula (! or formula (I I) or an isomer, salt, solvate, protected form or prodrug thereof to inhibit, suppress or reduce lyniphanglogenesls.
• a compound of formula (I) or formula (II) or an isomer, salt, solvate, protected form or prodrug thereof for use in the method of Inhibiting, suppressing or reducing ly phangiogenesls.
• these diseases or conditions may include:
• the active compound or pharmaceutical composition comprising the active compound may be administered to a subject by any convenient route of administration, whether
• 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.
• feline e.g. a cat
• equine e.g. a horse
• a primate 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, chimpan
• composition 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.
• 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, exclplen!s, 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, exciplent, etc. must also be “acceptable” In the sense of being compatible with the other Ingredients of the formulation .
• Suitable carriers, exclpients, etc. can be found In standard pharmaceutical texts, for example, Remington's Pharmaceutical Sciences, 18th edition, Mack Publishing Company, Easton, Pa., 1 SS0.
• the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known In the ad 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 earners 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 oii-in-water liquid emulsion or a watenin-oll 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); tillers or diluents (e.g. lactose, rnlcroci ' ystalline cellulose, calcium hydrogen phosphate): lubricants (e.g. magnesium stearate, talc, silica); disintegrate (e.g.
• binders e.g. povidone, gelatin, acacia, sorbitol, tragacanth, hydroxypropylmethyl cellulose
• tillers or diluents e.g. lactose,
• 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 exciplents 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 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 nebulises 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 propelianf, such as
• dichiorodlfluoromethane trichlorofluoro etbsne : dlchoro-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-misclble ointment base Alternatively, the active compounds may be formulated in a cream with an ⁇ iMn-water cream base.
• the aqueous phase of the cream base may include, for example, at least about 30% w/w of a polyhydrlc alcohol, i.e., an alcohol having two or more hydroxy!
• topical formulations may desirably Include a compound which enhances absorption or penetration of the active compound through the skin or other affected areas.
• dermal penetration enhancers include dlmethylsulfoxlde 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 emulsifler with a fat or an oil or with both a fat and an oil.
• an emulsifier also known as an emulgent
• a bydrophillc 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 emulslfler(s) with or without stablllser(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, cetostearyi alcohol, myrlstyl alcohol, glyceryl onostearate and sodium iauryl sulphate.
• 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 si- Isoadipate, Isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myrlslate, decyl oleate, isopropyl paimitste, butyl stearate, 2-ethylhexyl palrnitate or a blend of branched chain esters Known as Crodamo! CAP may be used, the last three being preferred esters. These may be used alone or In combination depending on the properties required.
• alkyl esters such as si- Isoadipate, Isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myrlslate, decyl oleate, isopropyl paimitste, butyl stearate, 2-ethylhexyl palrnitate or a blend of branched chain esters
• 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 cutaneous, subcutaneous, Intramuscular, Intravenous and Intradermal
• parenteral administration e.g. by injection, including cutaneous, subcutaneous, Intramuscular, Intravenous and Intradermal
• aqueous and nonaqueous Isotonic, pyrogen-free, sterile Injection solutions which may contain antioxidants, buffers, preservatives, stabilisers, bacteriostats, and solutes which render the formulation isotonic with the blood of the Intended recipient
• aqueous and non-aqueous sterile suspensions which may Inciude 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.
• concentration of the active compound In the solution is from about 1 ng/ml to about 10 pg/mL, for example from about 10 ng/m! to about 1 pg/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-dned (lyophlllsed) 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.
• thai 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 ivo 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 pg to about 25G g per kilogram body weight of the subject per day.
• the active compound I 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.
• Solvent A Water 0.1 % Formic Acid
• Solvent 8 Acetonltnle 0.1 % Formic Acid
• Vaporizer temperature 200 °C
• Step size 0.1 sec
• Solvent A Water 0.1 % Formic Acid
• Solvent B Acetonitnle 0.1 % Formic Acid
• Solvent A Water 0.1 % Formic Acid
• Solvent B Acetonitrlle 0.1 % Formic Acid
• Ion Source Slngie-quadrupole
• Solvent A Water 0.1 % Formic Acid
• Solvent B Acetonitrlle 0.1 % Formic Acid
• Ion Source ion trap
• Analytical thin-layer chromatography was performed on Merck silica gel 60F2S4 aluminium- backed pistes which were visualised using fluorescence quenching under UV light or using an acidic anisa!dehyde or a basic potassium permanganate dip. Flash chromatography was performed using either a Te!edyne isco ComblFlash Rf purification system using standard RedlSep® cartridges or a Biotage Isolera purification system using either Grace, RediSep® or Biotage silica cartridges. Microwave irradiation was achieved using a CBM Explorer SP Microwave Reactor. All reactions carried out using microwave Irradiation were stirred..
• anhydrous solvents were prepared using a Braun purification system or purchased from Slgma-Aldhch.
• Ke intemwdfate 2 Beswyf 4 »
• nitrophenyhplperazlne hydrochloride (0.800 g, 3.28 mmol) and Et 3 N (1.14 ml, 8.21 mmol) in THF (20 ml) at 0 °C.
• the resulting mixture was stirred at 0 °C for 1 hour then at room temperature for 2 hours.
• DCM 40 n l was added and the organlcs were washed with saturated aHC0 3 (40 ml), water (40 nil.) then dried over WigSO .
• m-CPBA (70%; 174 mg, 1 .01 mmol; was added to a solution or methyl 2-(2-(2-(2- (rr5ethylthlo)pyrlmldln-4-yl)ethyl ⁇ phenyl)acetate (A2) (170 mg, 0.458 mmol) In DCIvl (50 ml) at 0 C C. The resulting mixture was stirred at 0 °C for 1 hour, then warmed to room temperature and stirred for a further 18 hours The temperature was reduced to 0 °C and additional m-CPBA (70%: 174 mg, 1.01 mmol) was added.
• ammonium carbonate (65 mg, 0.67 mmol) was added and stirring was continued at room temperature for 18 hours. The voiatlles were removed in vacuo and the residue was diluted with EtOAc (65 mL) and saturated NaHC0 3 (65 mL). The aqueous layer was extracted with EtOAc (2 * 50 mL) then the combined organic layers were washed with brine (50 ml) and dried over Na 2 S ⁇ 3 ⁇ 4.
• Example 3 S nt eses of 2-f2 « (2-f2-3 ⁇ 44-
• the resulting mixture was heated under microwave Irradiation at 120 °C for 20 minutes then adsorbed onto silica gei and purified by column chromatography (Biotage isolera, S!C1 ⁇ 2 cartridge, 0-100% EtOAc In petroleum benzine 40-60 °C) to yield a yellow solid.
• the solid was suspended In toluene and the resulting suspension sonicated for 10 minutes.
• HOBt (76 mg, 0.56 mmof) and EDCI.HC! (108 mg, 0.561 mmoi) were added to a solution of 2-(2-(2 2K ⁇ 4-(((fe/t-bu oxycarbonyl)amino)rnethyi)phenyl)amino)-5- (trlfluoromethyl)pynmldlh-4-yl)ethyl)pheny!acetlo acid (A 15) (251 mg, 0.468 mmoi) and D!PEA (326 pL, 1.87 mmol) in DMF (2 mL) and THF (10 mL).
• Formaldehyde (37% wt in H 2 0; 0.01 7 ml, 0.22 mmof) was scideci to a solution of 2-(2-(2-(5- methy1-2-((6 ⁇ iperk.in ⁇ yl)pyridin- ⁇ (4) (32 mg, 0.07 mmoi) in IvleOH (4 mL) under an atmosphere of nitrogen. The resulting solution was stirred for 15 minutes at room temperature then sodium triacetoxyborohydride (63 g, 0.30 rnrnoi) was added In one portion. After stirring at room temperature for 18 hours a further portion of formaldehyde (37 wt.
• Zinc(ll) chloride (1.0 M in Et 2 0; 2.00 ml, 2.00 mmoi) was added to a solution of 2,4-dichioro- 5-(trlfluoromethyl)pynmldine (0.399 g, 1 .84 mmoi) In 1 : 1 DCE/f-BuOH (15 ml) at 0 °C under a nitrogen atmosphere. The resulting mixture was stirred for 1 hour at 0 C C and then tert- butyl 4-(4-aminobenzoyi)piperazine-1-carb ⁇ xyiate (A21) (0 510 g, 1 67 mmol) in 1 : 1 DCE/fBuOH (15 ml) was added.
• HOB! (0.088 g, 0.50 mmol), EDCi .HCI (0.096 g, 0.50 mmol) and D!PEA (0.34 ml, 1.8 mmol) were added to a stirred soiution of fe/t-buty! 4- ⁇ 4-((4- ⁇ 2-(2 ⁇ methoxy ⁇ 2-oxoeth !)phes eth ⁇ -5- (trif!uoromethy pyrimidin-2-yl)amino)ben2oyl)piperazine-1 afboxylate (A25 (0.28 g, 0.39 mmol) In dry THF (6 mL) and dry DMF (1 ml) under an atmosphere of nitrogen.
• ammonium carbonate (0.19 g, 1 .9 mmol) was added In one portion and the resulting solution was stirred at room temperature for 17 hours. The volatlles were removed in vacuo and the residue was partitioned between EtOAc (65 mL) and saturated aqueous NaHC0 3 (65 mL). The aqueous layer was extracted with EtOAc (2 * 50 ml.) then the combined organic layers were washed with brine (50 mL) and dried over WlgSO*.
• Zinc(ll) chloride (1.0 M in Et 2 0; 1.08 ml, 1 .08 mmol) was added to a solution of 2,4-dichioro- 5-(trliluoro ethyl ⁇ pynmldlne (0.216 g, 0.994 m ol) in 1 : 1 DCE/f-BuOH (8 ml) at 0 °C under a nitrogen atmosphere.
• Example 8 Synthesis of 2- ⁇ 2 »
• HOB HOB
• (G.435 g, 3.22 rnnioi), EDGI.HCI (0.61? g. 3.22 rnmol) and DIPEA (1 .87 mL 1 7 mmol) were added to a stirred solution of 2-(2--bromo-5-phenyl)aceilc aold (0.500 g, 2.15 mmol) in dry THF (6 ml) and dry DMF (1 ml) under an atmosphere of nitrogen. After 10 minutes ammonium carbonate (1 .03 g, 10.7 mmoi) was added in one portion and the resulting mixture stirred at room iernperature or 16 hours.

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