WO2010055304A2 - Pharmaceutical compounds - Google Patents

Pharmaceutical compounds Download PDF

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Publication number
WO2010055304A2
WO2010055304A2 PCT/GB2009/002662 GB2009002662W WO2010055304A2 WO 2010055304 A2 WO2010055304 A2 WO 2010055304A2 GB 2009002662 W GB2009002662 W GB 2009002662W WO 2010055304 A2 WO2010055304 A2 WO 2010055304A2
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optionally substituted
group
alkyl
compound
use according
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PCT/GB2009/002662
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French (fr)
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WO2010055304A3 (en
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John Charles Reader
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Sareum Limited
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Publication of WO2010055304A3 publication Critical patent/WO2010055304A3/en

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    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4168—1,3-Diazoles having a nitrogen attached in position 2, e.g. clonidine
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection

Definitions

  • This invention relates to compounds for use in the prophylaxis or treatment of automimmune diseases and in particular multiple sclerosis.
  • MS Multiple Sclerosis
  • myelin sheath a protective fatty layer that surrounds nerve fibres of the central nervous system.
  • the nerve fibres can no longer effectively conduct electrical signals and this gives rise to a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating, pain, and urinary and faecal incontinence.
  • MS will cause impaired mobility and disability.
  • MS is generally categorized as an autoimmune disease which results from attacks by an individual's immune system on the nervous system.
  • Multiple sclerosis can be categorised into three types, relapsing-remitting MS, secondary progressive MS and primary progressive MS.
  • MS starts off as a relapsing and remitting condition which means that there are periods of relapse, when symptoms flare up, often quite suddenly, and then periods of remission, when symptoms improve.
  • the periods between relapses can be highly unpredictable and often several years may pass between relapses.
  • the third type of MS primary progressive MS, afflicts about 10% of MS patients.
  • This type of MS there are no periods of remission and the disease gets gradually worse from the start. This causes increasing disability, and can reduce life expectancy.
  • Steroids are typically used to treat relapses but are not believed to alter the course of the disease. Largely because of the side effects, it is generally recommended not to use steroids for more than about three weeks at a time and for no more than about three courses per year.
  • Steroids are generally suitable for treating only about 10-20% of relapses.
  • Non-steroidal anti-inflammatory drugs have been used to alleviate or manage some of the symptoms of MS but, again, they have no effect on the course of the disease. Moreover, they have well known side effects such as gastric irritation and can cause gastric bleeding and stomach ulcers.
  • DCs Dendritic cells
  • Symadex-treated versus control animals for changes in several circulating biomarkers known to be relevant to autoimmune disease.
  • Symadex was found to bring elevated levels of monocyte- and macrophage-related biomarkers associated with disease back to normal.
  • MRI imaging showed that macrophage function was inhibited in areas of inflammation.
  • Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell (Hardie and Hanks (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA).
  • the kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (e.g., Hanks and Hunter, FASEB J., (1995) 9.
  • Protein kinases may be characterized by their regulation mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.
  • Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signalling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signalling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor.
  • Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
  • FMS-like tyrosine kinase 3 is a receptor tyrosine kinase involved in the proliferation, differentiation and apoptosis of hematopoietic and non-hematopoietic cells (Scheijen and Griffin, Oncogene (2002) 21, 3314-3333 and Reilly, British Journal of Haematology (2002) 116, 744-757).
  • the FLT3 receptor dimerises resulting in activation of its tyrosine kinase domain, receptor autophosphorylation and recruitment of downstream signalling molecules such as the p85 subunit of PI3K (phosphatidylinositol 3 kinase), PLC-gamma (Phospholipase-C gamma), STAT5a (signal transducer and activator of transcription 5a), and SRC family tyrosine kinases (Gilliland and Griffin, Blood (2002) 100(5), 1532-42; Drexler, Leukemia (1996) 10(4), 588-99 and Ravandi et al., CHn Cancer Res. (2003) 9(2), 535-50).
  • PI3K phosphatidylinositol 3 kinase
  • PLC-gamma Phospholipase-C gamma
  • STAT5a signal transducer and activator of transcription 5a
  • Ponomarev et a/., Zhurnal Fizicheskoi Khimii (1990) 64(10), 2723-9 (Chem Abs. 114:100938) describes the electronic absorption spectra of fused oxazole compounds. Amongst the compounds disclosed in the article is 2,5-diphenyl-oxazole-4-carboxylic acid amide.
  • Ozaki et a/., Chem. Pharm. Bull. (1983) 31(12), 4417-24 discloses a series of 2- substituted oxazole compounds as blood platelet aggregation inhibitors.
  • One of the compounds exemplified in the article is 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4- carboxylic acid amide.
  • JP 63-10767 and JP 86-155456 disclose diaryl imidazoles as analgesic and anti-inflammatory agents.
  • the compound 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H- imidazole-4-carboxylic acid amide is specifically disclosed.
  • WO 2006/095159 discloses imidazolyl-anilino-pyrimidines as cell proliferation inhibitors.
  • WO 02/00649 discloses substituted quinazolines as Aurora kinase inhibitors.
  • WO 2004/005283 discloses pyridyl and pyrimidinyl substituted oxazoles, thiazoles and imidazoles as protein kinase inhibitors.
  • WO 2007/043400 discloses aryl and heteroaryl pyrazole derivatives as xanthine oxidase inhibitors.
  • the compound 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide is specifically disclosed as a chemical intermediate.
  • WO 2005/040139 (AB Science et al.) and WO 2007/131953 (AB Science) disclose 2- phenylamino-oxazoles as inhibitors of various tyrosine kinases.
  • WO 2008/024980 discloses pyrrole, thiophene, furan, imidazole, oxazole and thiazole derivatives that have Hsp90 inhibiting activity and which are useful for treating a range of diseases including cancer.
  • Our earlier patent application PCT/GB2008/001612 discloses aryl- and heteroaryl-substituted oxazoles and imidazoles as inhibitors or various kinases, including FLT3 kinase.
  • the invention provides compounds of the type disclosed in our earlier application PCT/GB2008/001612 for use in the prophylaxis or treatment of autoimmune diseases and in particular multiple sclerosis.
  • the invention provides a compound for use in the treatment of an autoimmune disease, and in particular multiple sclerosis, the compound being a compound of the formula (1):
  • a is 0 or 1 ;
  • b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
  • T O or NH
  • Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S 1 and being optionally substituted by one or more substituents R 1 ; provided that, when b is 0, a carbon atom of Ar 2 is attached directly to the 5-membered ring containing the moiety T;
  • Ar 2 J s a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ;
  • R 1 is halogen; cyano; nitro; a group R a -R b ; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by one or more substituents R 3 ;
  • R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X ⁇ S, SO, SO 2 , NR 0 , SO 2 NR 0 or NR 0 SO 2 ;
  • R b is:
  • a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R°) 2 ; and 3 to 8-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms (e.g.
  • up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O 1 CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR 0 , SO 2 NR 0 or NR 0 SO 2 ;
  • R c is hydrogen or a C 1-4 hydrocarbon group
  • X 1 is O, S or NR 0 ;
  • R 2 is halogen; cyano; nitro; or a group R a -R d ;
  • R d is hydrogen; a C 1-4 alkyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms;
  • R 3 is X 2 ; halogen; cyano; nitro; a group R a -R e ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by a group R 4 ;
  • R e is:
  • - a C 1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°) 2 ; wherein one to three but not all of the carbon atoms of the C 1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ; or - a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1 .
  • Ci -4 alkoxy groups are each optionally substituted with one or more fluorine atoms; and R 4 is selected from halogen, cyano, nitro and a group R a -R d ; provided that when a is 0, Ar 1 is other than a 2-aminopyridin-4-y!
  • Ar 2 is other than a bicyclic group containing a pyrrole or pyrazole ring fused to a non-aromatic six-membered carbocyclic ring wherein the point of attachment of Ar 2 is a nitrogen atom of the pyrrole or pyrazole ring.
  • the compounds of formula (1) are as defined above provided that they are other than the compounds: 2,5-diphenyl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
  • the compound is an amide of the formula (1a):
  • a is 0 or 1 ;
  • b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
  • T is O or NH Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R 1 ;
  • Ar 2 J s a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 ; provided that, when b is O, a carbon atom of Ar 2 is attached directly to the 5-membered ring containing the moiety T;
  • R 1 is halogen; cyano; nitro; a group R a -R b ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ;
  • R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR 0 , SO 2 NR 0 or NR 0 SO 2 ;
  • R b is:
  • a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R°) 2 ; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 ; wherein one to three but not all of the carbon atoms of the C 1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X 1 C(X 2 ), C(X 2 )X ⁇ X 1 C(X 2 )X 1 , S, SO, SO 2 , NR 0 , SO 2 NR 0 or NR 0 SO 2 ;
  • R° is hydrogen or a Ci -4 hydrocarbon group
  • X 1 is O, S or NR 0 ;
  • R 2 is halogen; cyano; nitro; or a group R a -R d ;
  • R d is hydrogen or a Ci -4 alkyl group optionally substituted by one or more fluorine atoms
  • R 3 is X 2 ; halogen; cyano; nitro; a group R a -R e ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R 4 ;
  • R e is: - hydrogen
  • C- I-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°) 2 ; wherein one to three but not all of the carbon atoms of the C 1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR 0 , X 1 C(X 2 ), C(X 2 )X 1 or X 1 C(X 2 )X 1 ; and
  • R 4 is selected from halogen, cyano, nitro and a group R a -R d ; provided that when a is 0, Ar 1 is other than a 2-aminopyridin-4-yl or 2-amino- pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted; and that neither Ar 2 -(NH) b - nor Ar 1 -(NH) a - form an optionally substituted quinoxalin-4-ylamino group; but optionally excluding the compounds:
  • a and b are both 0 and therefore the compound is an amide of the formula (2):
  • one group of compounds consists of amides of the formula (2a):
  • Another group of compounds consists of amides of the formula (2b):
  • a further group of compounds for use in accordance with the invention consists of amides of the formula (2c):
  • a is 1 and b is 0 and therefore the compound is an amide of the formula (3):
  • one group of compounds consists of amides of the formula (3a):
  • a is 0 and b is 1 and therefore the compound is an amide of the formula (4):
  • one group of compounds for use in accordance with the invention consists of amides of the formula (4a):
  • references to formula (1) include not only formula (1) perse but also formulae (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) and sub-groups, examples or embodiments thereof, unless the context requires otherwise.
  • references to therapeutic uses, pharmaceutical formulations and processes for making compounds, where they refer to formula (1) are also to be taken as referring to formulae (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) and subgroups, examples or embodiments thereof.
  • modulation As used herein, the term “modulation”, as applied to the activity of FLT3 kinase, is intended to define a change in the level of biological activity of the kinase(s). Thus, modulation encompasses physiological changes which effect an increase or decrease in the relevant kinase activity. In the latter case, the modulation may be described as "inhibition”.
  • upregulation as used herein in relation to the kinase is defined as including elevated expression or over-expression of the kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of the kinase, including activation by mutations.
  • halogen refers to fluorine, chlorine, bromine and iodine and does not include astatine.
  • aryl refers to a carbocyclic ring or group having aromatic character and the term “heteroaryl” is used herein to denote a heterocyclic group having aromatic character.
  • aryl and heteroaryl e.g. as used in relation to the moieties Ar 1 and Ar 2
  • polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic.
  • the group may be attached to another moiety (e.g. the five membered ring containing N and T) by the aromatic ring, or by a non-aromatic ring.
  • heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members.
  • the heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings.
  • Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen.
  • the heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom.
  • the heteroaryl ring contains at least one ring nitrogen atom.
  • the nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen.
  • the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
  • Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups.
  • Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
  • a bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5-
  • bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).
  • imidazothiazole e.g. imidazo[2,1-b]thiazole
  • imidazoimidazole e.g. imidazo[1,2-a]imidazole
  • bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoiine, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g.
  • pyrazolo[1 ,5-a]pyrimidine benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups.
  • pyrazolopyridine groups e.g. pyrazolo[1,5-a]pyridine
  • a further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.
  • bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
  • polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring examples include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.
  • carbocyclic aryl groups examples include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.
  • references to "carbocyclic” and “heterocyclic” rings or groups as used herein shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems.
  • the term “carbocyclic and heterocyclic” includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.
  • the carbocyclic or heterocyclic rings or groups can be aryl or heteroaryl rings or groups as hereinbefore defined
  • non-aromatic group embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems.
  • fully saturated refers to rings where there are no multiple bonds between ring atoms.
  • Saturated carbocyclic groups include cycloalkyl groups as defined below.
  • Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl.
  • a further example of a cycloalkenyl group is cyclohexenyl.
  • non-aromatic heterocyclic groups include heterocyclic groups having from 3 to 7 ring members, typically 4 to 7 ring members, and more usually from 5 to 6 ring members. Such groups typically have 1 , 2, 3 or 4 heteroatom ring members selected from nitrogen, oxygen and sulphur.
  • non-aromatic heterocyclic rings include bridged bicyclic ring systems such as bicycloalkanes and azabicycloalkanes.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged ring systems include bicyclo[2.2.1]heptane, aza- bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, aza-bicyclo[2.2.2]octane (e.g.
  • quinuclidine quinuclidine
  • bicyclo[3.2.1]octane and aza-bicyclo[3.2.1]octane.
  • Particular examples of bridged bicyclic ring systems are quinuclidine and 8-methyl-8-aza-bicyclo[3.2.1]octane.
  • sulphur When sulphur is present, it may, where the nature of the adjacent atoms and groups permits, exist as -S-, -S(O)- or -S(O) 2 -.
  • the heterocyclic groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic amide moieties (e.g. as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ester moieties (e.g. as in butyrolactone), cyclic sulphones (e.g.
  • cyclic sulphoxides as in sulpholane and sulpholene
  • cyclic sulphonamides and combinations thereof e.g. morpholine and thiomorpholine and its S-oxide and S,S-dioxide
  • cyclic ureas e.g. as in imidazolidin-2-one
  • Examples of monocyclic non-aromatic heterocyclic groups include 4, 5, 6 and 7- membered monocyclic heterocyclic groups.
  • Particular examples include azetidine, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), piperidine (e.g.
  • Non-aromatic heterocyclic groups consists of saturated groups such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S 1 S- dioxide, piperazine, N-alkyl piperazines, and N-alkyl piperidines.
  • non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.
  • Preferred non-aromatic carbocyclic groups are saturated monocyclic rings. Typical examples are 3, 4, 5 and 6 membered saturated carbocyclic rings, e.g. optionally substituted cyclopentyl and cyclohexyl rings.
  • Non-aromatic carbocyclic groups includes monocyclic groups and particularly saturated monocyclic groups, e.g. cycloalkyl groups.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.
  • non-aromatic cyclic groups include bridged ring systems such as bicycloalkanes and azabicycloalkanes although such bridged ring systems are generally less preferred.
  • bridged ring systems is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 131-133, 1992.
  • bridged ring systems examples include bicyclo[2.2.1]heptane, aza-bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, aza- bicyclo[2.2.2]octane, bicyclo[3.2.1]octane and aza-bicyclo[3.2.1]octane.
  • a particular example of a bridged ring system is the 1-aza-bicyclo[2.2.2]octan-3-yl group.
  • hydrocarbon is used in its conventional sense to denote aliphatic, alicyclic and aromatic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated.
  • one or more of the carbon atoms making up the carbon backbone may be replaced by a specified atom or group of atoms.
  • hydrocarbon groups examples include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each of the hydrocarbon substituent groups or hydrocarbon-containing substituent groups referred to in the various definitions of substituents for compounds of the formula (1) unless the context indicates otherwise.
  • acyclic hydrocarbon group as used herein (e.g. in the phrase “Ci -I2 acyclic hydrocarbon group”) encompasses alkyl, alkenyl, alkynyl and mixed alkenyl-alkynyl groups.
  • Preferred non-aromatic hydrocarbon groups are saturated groups such as alkyl and cycloalkyl groups.
  • the hydrocarbon groups can have up to twelve carbon atoms, unless the context requires otherwise.
  • Subsets of hydrocarbon groups are C 1- S hydrocarbon groups, C 1-6 hydrocarbon groups, C 1-4 hydrocarbon groups, C 1-3 hydrocarbon groups and C 1-2 hydrocarbon groups, specific examples being any individual value or combination of values selected from Ci, C 2 , C 3 , C 4 , C 5 , C 6 , C 7 and C 8 hydrocarbon groups.
  • alkyl covers both straight chain and branched chain alkyl groups.
  • alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terf-butyl, n- pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers.
  • Subsets of alkyl groups are C 1-8 alkyl groups, C 1-6 alkyl groups, C 1-4 alkyl groups, C 1-3 alkyl groups and C 1-2 alkyl groups.
  • cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the sub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C 3-6 cycloalkyl groups.
  • alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2- propenyl (allyl), isopropenyl, butenyl, buta-1 ,4-dienyl, pentenyl, and hexenyl.
  • the alkenyl group may have 2 to 8 carbon atoms, particular examples being C 2-6 alkenyl groups, such as C 2-4 alkenyl groups.
  • cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the sub-set of cycloalkenyl groups, the cycloalkenyl groups may have from 3 to 8 carbon atoms, and particular examples are C 3-6 cycloalkenyl groups.
  • alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the sub-set of alkynyl groups the alkynyl groups may have 2 to 8 carbon atoms, particular examples being C 2-6 alkynyl groups and C 2-4 alkynyl groups.
  • carbocyclic aryl groups include substituted and unsubstituted phenyl groups.
  • cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.
  • 1 to 3 carbon atoms of a hydrocarbon group may optionally be replaced by O, S, SO, SO 2 , NR C , X 1 C(X 2 ), C(X 2 )X 1 orX 1 C(X 2 )X 1 (or a sub-group thereof) wherein X 1 and X 2 are as hereinbefore defined, provided that at least one carbon atom of the hydrocarbon group remains.
  • 1 , 2, 3 or 4 carbon atoms of the hydrocarbon group may be replaced by one of the atoms or groups listed, and the replacing atoms or groups may be the same or different.
  • the number of linear or backbone carbon atoms replaced will correspond to the number of linear or backbone atoms in the group replacing them.
  • Examples of groups in which one or more carbon atom of the hydrocarbon group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X 1 C(X 2 ) or C(X 2 )X 1 ), sulphones and sulphoxides (C replaced by SO or SO 2 ), amines (C replaced by NR 0 ). Further examples include ureas, carbonates and carbamates (C-C-C replaced by X 1 C(X 2 )X 1 ).
  • aza-cycloalkyl refers to a cycloalkyl group in which one of the carbon ring members has been replaced by a nitrogen atom.
  • examples of aza- cycloalkyl groups include piperidine and pyrrolidine.
  • oxa-cycloalkyl refers to a cycloalkyl group in which one of the carbon ring members has been replaced by an oxygen atom.
  • examples of oxa-cycloalkyl groups include tetrahydrofuran and tetrahydropyran.
  • diaza- cycloalkyl refers respectively to cycloalkyl groups in which two carbon ring members have been replaced by two nitrogen atoms, or by two oxygen atoms, or by one nitrogen atom and one oxygen atom.
  • R a -R b as used herein, either with regard to substituents present on a carbocyclic or heterocyclic moiety, or with regard to other substituents present at other locations on the compounds of the formula (1), includes inter alia compounds wherein R a is selected from a bond, O, CO, OC(O), SC(O), NR 0 C(O), OC(S), SC(S), NR 0 C(S), OC(NR 0 ), SC(NR C ), NR 0 C(NR 0 ), C(O)O, C(O)S, C(O)NR 0 , C(S)O, C(S)S, C(S) NR 0 , C(NR°)O, C(NR°)S, C(NR°)NR C , OC(O)O, SC(O)O, NR 0 C(O)O, OC(S)O, SC(O)O, NR 0 C(O)O, OC(S)O,
  • R b can be hydrogen or it can be a group selected from carbocyclic and heterocyclic groups having from 3 to 7 ring members (usually 4 to 7 and more usually 5 to 6), and a C 1-12 hydrocarbon group optionally substituted as defined. Examples of hydrocarbon, carbocyclic and heterocyclic groups are as set out above.
  • R a and R b together form a hydrocarboxy group.
  • Preferred hydrocarboxy groups include saturated hydrocarboxy such as alkoxy (e.g. Ci -6 alkoxy, more usually C 1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C 3 -e cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkylalkoxy (e.g. C 3-6 cycloalkyl-C 1-2 alkoxy such as cyclopropylmethoxy).
  • alkoxy e.g. Ci -6 alkoxy, more usually C 1-4 alkoxy such as ethoxy and methoxy, particularly methoxy
  • cycloalkoxy e.g. C 3 -e cycloalkoxy such as cyclopropyloxy, cyclobutyloxy
  • the hydrocarboxy groups can be substituted by various substituents as defined herein.
  • the alkoxy groups can be substituted by halogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C 1-2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C 1-2 alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. a cycloalkyl group or non-aromatic heterocyclic group as hereinbefore defined).
  • alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3-7 -cycloalkyl- piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C 1-4 alkoxy group, more typically a Ci -3 alkoxy group such as methoxy, ethoxy or n-propoxy.
  • the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C 1-4 -alkyl-piperazines, C 3-7 -cycloalkyl- piperazines, tetrahydropyran or tetrahydrofuran
  • the alkoxy group is a C 1-4 alkoxy group, more typically a Ci
  • Alkoxy groups substituted by a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N- C 1-4 acyl and N-C 1-4 alkoxycarbonyl.
  • a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N- C 1-4 acyl and N-C 1-4 alkoxycarbonyl.
  • Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.
  • hydrocarbon groups R a -R b are as hereinbefore defined.
  • the hydrocarbon groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl.
  • the hydrocarbon (e.g. alkyl) groups can be substituted by various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (particular examples including bromoethyl, chloroethyl and trifluoromethyl), or hydroxy (e.g.
  • Ci -8 acyloxy e.g. acetoxymethyl and benzyloxymethyl
  • amino and mono- and dialkylamino e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and terf-butylaminomethyl
  • alkoxy e.g. C 1-2 alkoxy such as methoxy - as in methoxyethyl
  • cyclic groups such as cycloalkyl groups, aryi groups, heteroaryl groups and non-aromatic heterocyclic groups as hereinbefore defined).
  • alkyl groups substituted by a cyclic group are those wherein the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, Ci -4 -alkyl-piperazines, C 3-7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a Ci -4 alkyl group, more typically a C 1-3 alkyl group such as methyl, ethyl or n-propyl.
  • a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, Ci -4 -alkyl-piperazines, C 3-7 -cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran
  • the alkyl group is a Ci -4 alkyl group, more typically a C 1-3 alkyl group such as methyl, eth
  • alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N- substituted forms thereof as defined herein.
  • alkyl groups substituted by aryl groups and heteroaryl groups include benzyl and pyridylmethyl groups.
  • R b can be, for example, hydrogen or an optionally substituted C 1-8 hydrocarbon group, or a carbocyclic or heterocyclic group.
  • R a -R b where R a is SO 2 NR 0 include aminosulphonyl, C 1-4 alkylaminosulphonyl and di-C- ⁇ -4 alkylaminosulphonyl groups, and sulphonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methyl piperazine.
  • R a -R b where R a is SO 2 examples include alkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups, particularly monocyclic aryl and heteroaryl sulphonyl groups. Particular examples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.
  • R b can be, for example, hydrogen or an optionally substituted C 1-8 hydrocarbon group, or a carbocyclic or heterocyclic group.
  • R a -R b where R a is NR 0 include amino, C 1-4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, terf-butylamino), di-C 1-4 alkylamino (e.g. dimethylamino and diethylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino).
  • C 1-4 alkylamino e.g. methylamino, ethylamino, propylamino, isopropylamino, terf-butylamino
  • di-C 1-4 alkylamino e.g. dimethylamino and
  • Ar 1 when T is N and a is 0, Ar 1 may be other than a pyrimidin-4- yl group bearing a substituent at the 2-position thereof.
  • Ar 1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 (more preferably up to 3, for example up to 2) heteroatoms selected from O, IM and S, and being optionally substituted by one or more substituents R 1 .
  • the 5- to 10-membered aryl or heteroaryl groups may be as set out above in the General Preferences and Definitions section.
  • Preferred aryl and heteroaryl groups are monocyclic 5- and 6-membered rings containing up to 2 and more preferably up to 1 heteroatom selected from O, N and S.
  • aryl and heteroaryl rings are optionally substituted phenyl, thiophene (e.g. 2- thienyl & 3-thienyl), furan (e.g. 2-furyl & 3-furyl), pyridine (e.g. 2-pyridyl, 3-pyridyl & 4- pyridyl), and pyrazole (e.g. 3-pyrazolyl & 4-pyrazolyl) rings.
  • thiophene e.g. 2- thienyl & 3-thienyl
  • furan e.g. 2-furyl & 3-furyl
  • pyridine e.g. 2-pyridyl, 3-pyridyl & 4- pyridyl
  • pyrazole e.g. 3-pyrazolyl & 4-pyrazolyl
  • aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl rings, each optionally substituted by one or more substituent groups R 1 .
  • the aryl or heteroaryl ring Ar 1 can be optionally substituted by one or more substituents R 1 .
  • each aryl or heteroaryl ring is substituted by 0, 1, 2 or 3 substituents R 1 .
  • each aryl or heteroaryl ring is substituted by 0, 1 or 2 substituents R 1 and more preferably by 0 or 1 substituents.
  • the aryl or heteroaryl ring is unsubstituted.
  • the aryl or heteroaryl ring is substituted by 1 substituent R 1 .
  • the aryl or heteroaryl ring is substituted by 2 substituents R 1 .
  • R 1 is halogen; cyano; nitro; a group R a -R b ; or a 3 to 8-membered (e.g. 3 to 7-membered) carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3 .
  • the definitions of halogen, R a -R b ; and 3 to 8-membered (e.g. 3 to 7-membered) carbocyclic or heterocyclic rings may be as set out above in the General Preferences and Definitions section.
  • R 1 is halogen; cyano; or a group R aa -R bb ;
  • R aa is a bond, O, CO, OC(O), C(O)O, NR CC C(O), C(O)NR CC , NR CO , OC(O)O, NR 00 C(O)O, OC(O)NR 00 , NR 00 C(O) NR C0 , S, SO, SO 2 , SO 2 NR 00 or NR 00 SO 2 wherein
  • R bb is:
  • a C 1-I2 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(R°°) 2 ; o 3 to 8-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g.
  • R 00 is hydrogen or a saturated C 1-4 hydrocarbon group;
  • R 3a is oxo; halogen; cyano; a group R aa -R ee ; or a 3 to 8-membered carbocyclic or heterocycl
  • R ee is:
  • benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C 1-4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms.
  • R 1 is halogen; cyano; or a group R aa -R bb' ;
  • R aa is a bond, O, CO, OC(O), C(O)O 1 NR 00 C(O), C(O)NR 00 , NR CC , OC(O)O, NR 00 C(O)O, OC(O)NR 00 , NR 00 C(O) NR 00 , S, SO, SO 2 , SO 2 NR 00 or NR 00 SO 2 wherein
  • R bb' is:
  • a C 1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(R CC ) 2 ; o 3 to 7-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 3a ; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g.
  • R 00 is hydrogen or a saturated C ⁇ hydrocarbon group
  • R 3a is oxo; halogen; cyano; a group R aa -R ee' ; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl or C 1-4 alkylsulphonyl;
  • R ee' is hydrogen; or a C 1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(R 00 ) 2 .
  • the C 1-12 acyclic hydrocarbon group may be unsubstituted or substituted. Where it is substituted, preferably it bears no more than 3 substituents, and preferably no more than one of the substituents is a cyclic group.
  • the 3 to 8-membered (e.g. 3 to 7-membered) non-aromatic carbocyclic or heterocyclic ring is preferably selected from azetidine, pyrrolidine, piperidine, piperazine, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine (and the S-oxide and the S,S-dioxides thereof) each optionally substituted by up to 2, and more preferably up to 1 substituents R 3a .
  • the 3 to 8-membered non-aromatic carbocyclic or heterocyclic ring (whether attached directly to R aa or via the C 1- - I2 acyclic hydrocarbon group) is a bridged bicyclic ring such as an aza-bicyclo[2.2.2]octane or aza- bicyclo[3.2.1]octane group, each optionally substituted by one or two C 1-4 alkyl (e.g. methyl) groups.
  • R 1 is selected from: halogen
  • C 1-4 alkoxy optionally substituted by hydroxy or Ci -2 alkoxy or one or more fluorine atoms; or a group Q, C(O)NHQ, HNC(O)Q, C(O)NH-AIk-Q, HNC(O)-AIk-Q, NH-AIk-Q, CH 2 Q,
  • AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH; and Q is selected from: a saturated or partially unsaturated 4 to 8 membered (e.g.
  • R 7 is hydrogen or C 1-4 alkyl
  • R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR 9 wherein the C 1-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C 1-4 alkylamino or phenyl;
  • AIk is as defined above and Q' is an optionally substituted saturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het 1 as hereinbefore defined or a group NR 7 R 8 ;
  • R 9 is C 1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C 1-4 alkyl, halogen, Ci -4 alkoxy or cyano.
  • R 1 is selected from: halogen
  • R 5a is C 1-6 alkyl; SO 2 R 5 ;
  • Ci -4 alkyl optionally substituted by hydroxy or C 1-2 alkoxy; C 1-4 alkoxy optionally substituted by hydroxy or Ci -2 alkoxy; or a group Q, CH 2 Q, S(O)Q, SO 2 Q, C(O)Q or O-Alk(OH) p -Q
  • AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH
  • NR 7 R 8 where R 7 is hydrogen or C 1-4 alkyl; and R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR 9 wherein the Ci -4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C 1-4 alkylamino or phenyl;
  • AIk is as defined above and Q' is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het 1 as hereinbefore defined or a group NR 7 R 8 ;
  • R 9 is C 1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C 1-4 alkyl, halogen, C 1-4 alkoxy or cyano.
  • R 1 is selected from: halogen
  • C 1-4 alkoxy optionally substituted by hydroxy or C 1-2 alkoxy; or a group Q, CH 2 Q, S(O)Q, SO 2 Q, C(O)Q or O-Alk-Q
  • AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms provided that there are at least 2 carbon atoms in line between O and Q
  • Q is selected from: a saturated 4 to 7 membered heterocyclic ring Het 1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het 1 is optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl; hydroxy;
  • R 7 is hydrogen or Ci -4 alkyl
  • R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR 9 ;
  • AIk is as defined above and Q' is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het 1 as hereinbefore defined or a group NR 7 R 8 ;
  • R 9 is C 1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryi groups are optionally substituted by C 1-4 alkyl, halogen, C 1-4 alkoxy or cyano.
  • the moiety AIk may typically be selected from CH 2 CH 2 , CH 2 CH 2 CH 2 , CH 2 CH(Me), CH 2 CMe 2 , CH 2 CH 2 CH(Me) and CH 2 CH 2 CMe 2 , and preferably is selected from CH 2 CH 2 and CH 2 CH 2 CH 2 .
  • the group Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C 1-4 alkyl, C 1-4 acyl, C 1-4 alkoxycarbonyl, C 1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C 1-4 alkylaminocarbonyl;
  • R 7 is hydrogen or C 1-4 alkyl
  • R 8 is hydrogen, C 1-4 alkyl, SO 2 R 9 or COR 9 ; where R 9 is as hereinbefore defined.
  • the group Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from Ci -4 alkyl, Ci -4 acyl, Ci -4 alkoxycarbonyl, Ci -4 alkylsulphonyl, aminocarbonyl, and mono- and di-Ci -4 alkylaminocarbonyl; hydroxy; and
  • R 7 is hydrogen or Ci -4 alkyl
  • R 8 is hydrogen, Ci -4 alkyl, SO 2 R 9 or COR 9 ; where R 9 is as hereinbefore defined.
  • R 1 One preferred group of substituents R 1 is represented by the formula:
  • Y is a bond, 0-AIk- (where AIk is as hereinbefore defined), or a C 1-3 alkylene group;
  • B is O, NH, CH 2 or a group NR 10 ;
  • R 10 is selected from Ci -4 alkyl, Ci -4 acyl, carbamoyl, mono- and di-Ci. 4 alkylcarbamoyl,
  • Ci -4 alkoxycarbonyl and Ci -4 alkylsulphonyl Ci -4 alkoxycarbonyl and Ci -4 alkylsulphonyl.
  • Ar 1 is a phenyl or other 6-membered aromatic ring such as pyridyl
  • a substituent R 1 is present at the para or 4-position of the ring. It is further preferred that only a single substituent R 1 is present and that the said single substituent is located at the para or 4-position of the ring.
  • R 1 are those found in the compounds set out below in the Examples section of this application.
  • Ar 2 Ar 2 J s a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 (more preferably up to 3, for example up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R 2 .
  • the 5- to 10-membered aryl or heteroaryl rings may be as set out above in the General Preferences and Definitions section.
  • Preferred aryl and heteroaryl rings are monocyclic 5- and 6-membered rings containing up to 3 and more preferably 1 or 2 heteroatoms selected from O, N and S, and bicyclic 6.5 fused rings containing up to 3 heteroatoms and more preferably 1 or 2 heteroatoms selected from O, N and S.
  • the aryl and heteroaryl rings are selected from phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine, pyrrolopyridine and pyrazole rings, each optionally substituted by one or more substituents R 2 .
  • the aryl and heteroaryl rings are selected from phenyl, thiophene, furan, indole, indazole, pyrrolopyridine, benzoimidazole, benzofuran, pyridine and pyrazole rings, each optionally substituted by one or more substituents R 2 .
  • the aryl and heteroaryl rings can be selected from phenyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6- indazolyl, benzimidazol-4-yl, 3-benzofuranyl, 4-benzofuranyl and pyrrolo[2,3-b]pyridine (e.g. pyrrolo[2,3-b]pyridin-4-yl) rings, each optionally substituted by one or more substituent groups R 2 .
  • pyrrolo[2,3-b]pyridine e.g. pyrrolo[2,3-b]pyridin-4-yl
  • the aryl and heteroaryl rings can be selected from phenyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3- indolyl, 4-indolyl, 3-indazolyl, 4-indazolyl, benzimidazol-4-yl, 3-benzofuranyl and A- benzofuranyl rings, each optionally substituted by one or more substituent groups R 2 .
  • the aryl and heteroaryl rings are optionally substituted phenyl, thiophene (e.g. 2-thienyl & 3-thienyl), furan (e.g. 2-furyl & 3-furyl), indole (e.g. 3-indolyl & 4-indolyl), benzofuran (e.g. 3-benzofuranyl & 4-benzofuranyl), pyridine (e.g. 2-pyridyl, 3- pyridyl & 4-pyridyl), and pyrazole (e.g. 3-pyrazolyl & 4-pyrazolyl) rings.
  • thiophene e.g. 2-thienyl & 3-thienyl
  • furan e.g. 2-furyl & 3-furyl
  • indole e.g. 3-indolyl & 4-indolyl
  • benzofuran e.g. 3-benzofuranyl & 4-benzo
  • the aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyi, 3-benzofuranyl and 4-benzofurany! rings, each optionally substituted by one or more substituent groups R 2 .
  • Ar 2 are optionally substituted phenyl rings.
  • Ar 2 is selected from (i) optionally substituted 5-membered heteroaryl rings containing 1 or 2 heteroatom ring members (more preferably 2 nitrogen heteroatom ring members), at least one of which is nitrogen; and (ii) optionally substituted 9-membered bicyclic heteroaryl groups containing 1 to 3 heteroatom ring members (more preferably 1 or 2 nitrogen heteroatom ring members) of which at least 1 is nitrogen.
  • preferred heteroaryl rings are selected from optionally substituted indole, indazole, pyrrolopyridine and pyrazole rings.
  • heteroaryl rings can be selected from indazol-4-yl, indazol-5-yl, indol-4-yl, indol-5-yl, pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrazol-2-yl and pyrazol-3-yl, each optionally substituted as defined herein.
  • the heteroaryl rings can be selected from unsubsituted indazol-4-yl, unsubsituted indazol-5-yl, unsubsituted indol-4-yl, unsubsituted indol-5-yl, unsubsituted pyrrolo[2,3-b]pyridin-4-yl, unsubsituted pyrrolo[2,3-b]pyridin-5-yl, 1-benzylpyrazol-2-yl and 1-benzylpyrazol-3-yl.
  • the aryl or heteroaryl ring Ar 2 can be optionally substituted by by one or more substituents R 2 .
  • each aryl or heteroaryl ring is substituted by 0, 1 , 2 or 3 substituents R 2 .
  • each aryl or heteroaryl ring is substituted by 0, 1 or 2 substituents R 2 .
  • each aryl or heteroaryl ring is unsubstituted.
  • each aryl or heteroaryl ring is substituted by 1 substituent R 2 .
  • each aryl or heteroaryl ring is substituted by 2 substituents R 2 .
  • R 2 is halogen; cyano; nitro; or a group R a -R d ; wherein R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X 1 , X 1 C(X 2 )X 1 , S, SO, SO 2 , NR C , SO 2 NR 0 or NR 0 SO 2 ; and
  • R d is hydrogen; a Ci -4 aikyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C 1-4 alkyl and C- ⁇ - 4 alkoxy, and wherein the C 1-4 alkyl and C 1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms.
  • R 2 is halogen; cyano; nitro; or a group R a -R d ; where R a is a bond, O, CO, X 1 C(X 2 ), C(X 2 )X ⁇ X 1 C(X 2 JX 1 , S, SO, SO 2 , NR 0 , SO 2 NR 0 or NR 0 SO 2 ; and R d is hydrogen or a Ci -4 alkyl group optionally substituted by one or more fluorine atoms.
  • the moiety R a may be as set out in the General Preferences and Definitions section above.
  • R 2 is absent or is selected from halogen; Ci -4 alkyl optionally substituted with one or more fluorine atoms; Ci -4 alkoxy optionally substituted with one or more fluorine atoms; cyclopropyl; cyclopropoxy; cyano; CONH 2 ; Ci -4 alkylsulphonyl; C 1-4 acylamino; C 1-4 alkylsulphonylamino; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, Ci -4 alkyl and C 1-4 alkoxy.
  • R 2 is absent or is selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; and methylsulphonylamino; and a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from chlorine, fluorine, cyano, methyl and methoxy.
  • Ar 2 is a phenyl group, preferably it is unsubstituted or substituted by 1 , 2 or 3 substituents selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; and methylsulphonylamino.
  • substituent When one substituent is present on the phenyl ring, it is preferred that the substituent is present at an orf/?o-position on the ring. When two substituents are present on the phenyl ring, it is preferred that at least one, and preferably both are located at an o/f ⁇ o-position on the ring.
  • Ar 2 which are unsubstituted except where specified consists of phenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2- chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 3-indolyl, 4-indolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thienyl and 3-thienyl.
  • Ar 2 which are unsubstituted except where specified
  • Ar 2 may be other than a phenyl group bearing a substituent at the meta- position thereof wherein the substituent is an optionally substituted alkyl group, an optionally substituted amino group or a group containing the moiety C(O)-N where the carbon atom of the carbonyl group is attached to the mefa-position of the phenyl group.
  • substituent is an optionally substituted alkyl group, an optionally substituted amino group or a group containing the moiety C(O)-N where the carbon atom of the carbonyl group is attached to the mefa-position of the phenyl group.
  • optionally substituted amino group in this context includes any group (apart from nitro) containing a nitrogen atom wherein the said nitrogen atom is attached to the mef ⁇ -position of the phenyl group.
  • the compound of the formula (1) may be other than a compound wherein T is O, b is 0 and Ar 2 is a 4-methylphenyl group.
  • the compound of the formula (1) may be other than a compound wherein b is 0 and Ar 2 is a bicyclic group containing at least one nitrogen ring member, the said nitrogen ring member being attached directly to the ring containing the moiety T.
  • the compound of formula (1) may be other than: 2-(3-chlorophenyl)-4-(4-methoxyphenyl)-1 H-imidazole-5-carboxamide; and/or 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide; and/or 2-(2,6-difluorophenyl)-4-(3-(hydroxymethyl)phenyl)-1 H-imidazole-5-carboxamide; and/or 2-(furan-3-yl)-4-(thiophen-2-yl)-1H-imidazole-5-carboxamide; and/or 2-(benzo[b]thiophen-3-yl)-5-(thiophen-2-yl)oxazole-4-carboxamide; and/or 2-(benzo[b]thiophen-3-yl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(1
  • the compound of formula (1) may be other than any one or more (in any combination) of:
  • One preferred sub-group of compounds is the group of compounds represented by the formula (5):
  • G 1 is C(O), C(O)NH or HNC(O);
  • G 2 is selected from OH and a group Het where Het is a 5 to 7 membered non-aromatic heterocyclic ring containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the group Het being linked to the C(O) group by a nitrogen ring member and being optionally substituted by one or two substituents selected from C 1-4 alkyl, hydroxy-C 1-4 alkyl, hydroxy, amino-C 1-4 alkyl, and mono- or di-Ci -2 -alkylamino-C 1-4 alkyl; or
  • G 2 is selected from: ⁇ a 5 to 8 membered non-aromatic heterocyclic ring Het' containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the heterocyclic ring being optionally substituted by one or two substituents selected from C 1-4 alkyl, hydroxy-Ci -4 alkyl, hydroxy, amino-C 1-4 alkyl, and mono- or di-C 1-2 -alkylamino-C 1-4 alkyl; and
  • one sub-group of compounds is the sub-group wherein Ar 2 is an optionally substituted phenyl ring as hereinbefore defined.
  • Particularly preferred compounds are those wherein Ar 2 is a 2,6-difluorophenyl ring or a 2-fluoro-6- chlorophenyl ring.
  • the various functional groups and substituents making up the compounds of the formula (1 ) are typically chosen such that the molecular weight of the compound of the formula (1) does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
  • a reference to a particular compound also includes ionic, salt, solvate, and protected forms thereof, for example, as discussed below.
  • salts for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulphonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (1) include the salt forms of the compounds.
  • Salt forms may be selected and prepared according to methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
  • Acid addition salts may be formed with a wide variety of acids, both inorganic and organic.
  • acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g.
  • salts consist of salts formed from hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
  • 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 FV, NHR 3 + , NR 4 + ).
  • Examples of some 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(CHa) 4 + .
  • the compounds of the formula (1) contain an amine function
  • these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person.
  • Such quaternary ammonium compounds are within the scope of formula (1).
  • the salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol. 66, pp. 1- 19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
  • Compounds of the formula (1) containing an amine function may also form N-oxides.
  • a reference herein to a compound of the formula (1) that contains an amine function also includes the N-oxide.
  • N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
  • N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4 th Edition, Wiley Interscience, pages 1200-12-1. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
  • MCPBA m- chloroperoxybenzoic acid
  • the imidazole group may take either of the following two tautomeric forms A and B.
  • the general formula (1) illustrates form A but the formula is to be taken as embracing both tautomeric forms.
  • references to compounds of the formula (1) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
  • optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, lngold and Prelog, see Advanced Organic Chemistry by Jerry March, 4 th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, lngold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.
  • Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art.
  • compounds of the formula (1) exist as two or more optical isomeric forms
  • one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity.
  • the invention provides compositions containing a compound of the formula (1) having one or more chiral centres, wherein at least 55% (e.g.
  • the compound of the formula (1) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
  • the compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element.
  • a reference to hydrogen includes within its scope 1 H, 2 H (D), and 3 H (T).
  • references to carbon and oxygen include within their scope respectively 12 C, 13 C and 14 C and 16 O and 18 O.
  • the isotopes may be radioactive or non-radioactive.
  • the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use.
  • the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
  • formula (1) Also encompassed by formula (1) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds, and pro-drugs of the compounds.
  • solvates e.g. hydrates
  • complexes e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals
  • pro-drugs is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1).
  • esters of the active compound e.g., a physiologically acceptable metabolically labile ester.
  • acyloxymethyl e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;
  • prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.).
  • the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
  • Compounds of the invention have activity as inhibitors of FLT3 kinase and are useful in the prophylaxis or treatment of autoimmue diseases and in particular multiple sclerosis.
  • the invention provides: • The use of a compound of the formula (1) or any sub-groups or examples thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of an autoimmune disease such as multiple sclerosis.
  • a method for the prophylaxis or treatment of an autoimmune disease such as multiple sclerosis which method comprises administering to a subject in need thereof a compound of the formula (1) or any sub-groups or examples thereof as defined herein.
  • the activity of the compounds of the invention as inhibitors of FLT3 kinase can be measured using the assays set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC 50 value.
  • Preferred compounds of the present invention are compounds having an IC 50 value of less than 10 ⁇ M, more preferably less than 1 ⁇ M.
  • EAE Experimental autoimmune encephalomyelitis
  • TMEV-IDD Theiler's murine encephalitis virus-induced demyelinating disease
  • MS multiple sclerosis
  • treating and “treatment” as used herein in the context of multiple sclerosis include any one or more of:
  • ⁇ modifying the progression of the disease; ⁇ providing symptomatic relief, e.g. by eliminating or reducing the severity of one or more symptoms;
  • Symptoms of multiple sclerosis that may be eliminated or reduced in severity in accordance with the invention include any one or more symptoms, in any combination, selected from:
  • the compound may be used in a prophylactic sense during periods of remission in order to prevent or reduce the likelihood or severity of relapses or it may be used to treat patients who are suffering from a relapse. Preferably it is used in a prophylactic sense.
  • the compound of formula (1) will generally be administered to a subject in need of such administration, for example a human patient.
  • the compound will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic.
  • the benefits of administering a compound of the invention may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
  • a typical daily dose of the compound can be up to 1000 mg per day, for example in the range from 0.01 milligrams to 10 milligrams per kilogram of body weight, more usually from 0.025 milligrams to 5 milligrams per kilogram of body weight, for example up to 3 milligrams per kilogram of bodyweight, and more typically 0.15 milligrams to 5 milligrams per kilogram of bodyweight although higher or lower doses may be administered where required.
  • an initial starting dose of 12.5 mg may be administered 2 to 3 times a day.
  • the dosage can be increased by 12.5 mg a day every 3 to 5 days until the maximal tolerated and effective dose is reached for the individual as determined by the physician.
  • the quantity of compound administered will be commensurate with the nature of the disease or physiological condition being treated and the therapeutic benefits and the presence or absence of side effects produced by a given dosage regimen, and will be at the discretion of the physician.
  • the compound of the formula (1) or a pharmaceutically acceptable salt thereof may be used as the sole therapeutic agent or it may be used in conjunction with other therapeutic agents such as steroids or interferons.
  • the compound of the formula (1) or pharmaceutically acceptable salt thereof is used as the sole therapeutic agent.
  • the compounds for use in accordance with the invention can be prepared by the processes described in PCT/GB2008/001612 and the examples therein.
  • R x is hydrogen or a C 1-4 alkyl group (preferably methyl or ethyl), with ammonia under conditions suitable for forming a primary amide group;
  • LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent (e.g. an organotin reagent) suitable for introduction of a group Ar 1 , in the presence of a metal catalyst and in particular a palladium catalyst (for example under Suzuki coupling or Stille reaction conditions); or
  • a boronic acid or boronate ester or organometallic reagent e.g. an organotin reagent
  • LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH 2 -Ar 1 , in the presence of a metal catalyst and in particular a palladium catalyst; or
  • LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent (e.g. an organotin reagent) suitable for introduction of a group Ar 2 , in the presence of a metal catalyst and in particular a palladium catalyst; or
  • LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH 2 -Ar 2 , in the presence of a metal catalyst and in particular a palladium catalyst; and
  • the (carbethoxymethylene)triphenyl phosporane 12 is reacted with the aroyl or heteroaroyl chloride 11 to give the triphenylphosporanylidene derivative 13.
  • the reaction is typically carried out in a non-protic solvent such as dichloromethane at a low temperature, for example at around 0 0 C, in the presence of the trimethylsilylating agent ⁇ /,O-fc/s(trimethylsilyl)acetamide.
  • the triphenylphosporanylidene moiety is then oxidatively cleaved using an oxidising agent such as potassium peroxymonosulphate (Oxone ® ) in water/THF to give the substituted dioxopropionate ester 14.
  • the ester 14 is then reacted with an aryl or heteroaryl aldehyde Ai ⁇ -CHO and ammonium acetate in acetic acid at an elevated temperature in excess of 100 0 C (e.g. up to about 160 0 C) in order to form the imidazole ester 15.
  • Treatment of the imidazole ester 15 with aqueous ammonia at an elevated temperature gives the imidazolyl carboxamide 16.
  • Hydrolysis of the imidazolyl ester 15 may conveniently be carried out in standard manner using an alkali metal hydroxide such as aqueous potassium hydroxide with moderate heating, for example to a temperature in the range 50-60 0 C.
  • an alkali metal hydroxide such as aqueous potassium hydroxide with moderate heating, for example to a temperature in the range 50-60 0 C.
  • the carboxylic acid 17 can be converted to the carboxamide 15 by reaction with ammonia in the presence of a reagent of the type commonly used in the formation of amide bonds.
  • a reagent of the type commonly used in the formation of amide bonds examples include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan ⁇ t al, J. Amer. Chem Soc. 1955, 77, 1067), 1-ethyl-3-(3'- dimethylaminopropyl)-carbodiimide (EDAC) (Sheehan et al, J. Org. Chem.
  • DCC 1,3-dicyclohexylcarbodiimide
  • EDAC 1-ethyl-3-(3'- dimethylaminopropyl)-carbodiimide
  • uronium-based coupling agents such as O-(7-azabenzotriazol-1-yl)- ⁇ /, ⁇ /,N', ⁇ /'- tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters (1990) 31, 205).
  • Carbodiimide-based coupling agents are advantageously used in combination with 1 -hydroxy-7- azabenzotriazole (HOAt) (Carpino, J. Amer. Chem. Soc.
  • a preferred coupling reagent is EDAC in combination with HOAt or HOBt.
  • the coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide, dichloromethane, dimethylformamide or N- methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co-solvents.
  • a non-aqueous, non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide, dichloromethane, dimethylformamide or N- methylpyrrolidine
  • aqueous solvent optionally together with one or more miscible co-solvents.
  • the ⁇ -keto-ester 18 which is either commercially available or can be made according to standard methods, is reacted with nitrous acid to give the the oxime 19.
  • the nitrous acid can be generated in known fashion from sodium nitrite and an acid such as acetic acid.
  • the oxime 19 is converted to the imidazolyl ester 15 by reaction with an aryl or heteroaryl aldehyde Ai ⁇ -CHO and ammonium acetate in acetic acid at an elevated temperature in excess of 100 0 C (e.g. up to about 160 0 C).
  • the imidazoyl ester 15 is then converted to the carboxamide 16 by the series of reactions illustrated in Scheme 2 above.
  • the ⁇ -keto-ester 18 is brominated using pyridinium bromide perbromide in ethanol in the presence of triethylamine to give the ⁇ -bromo- ⁇ -keto-ester 20 which is then reacted with an alkali metal (e.g. sodium) salt of an aryl or heteroaryl carboxylic acid Ai ⁇ -COaH in ethanol at a temperature in excess of 100 0 C (e.g. up to about 120 0 C) to give the diester 21.
  • the diester 21 is cyclised to the oxazole ester 22 by treatment with ammonium acetate in acetic acid with heating (e.g. to reflux).
  • the oxazole ester 22 is then hydrolysed using an alkali metal hydroxide (e.g. lithium hydroxide) in an aqueous solvent (e.g. aqueous THF) to give the carboxylic acid 23 which is converted to the carboxamide 24 by reaction with ammonia in the presence of EDAC and HOBt under conditions of the type described above.
  • an alkali metal hydroxide e.g. lithium hydroxide
  • aqueous solvent e.g. aqueous THF
  • the N-(diphenylmethylene)glycine ethyl ester 25 is treated with a base such as potassium terf-butoxide in a dry solvent such as THF with cooling to a low temperature (e.g. a temperature of about -78 0 C), followed by reaction with the acid chloride 11.
  • the resulting ⁇ -amino- ⁇ -keto-ester 26 is converted to the amide 27 by reaction with a carboxylic acid Ai ⁇ -CO 2 H in the presence of EDAC and HOBt under the amide forming conditions described above.
  • the amide 27 is converted to the oxazole ester 22 by a cyclodehydration reaction brought about by heating with POCI 3 .
  • the oxazole ester 22 can then be hydrolysed (e.g. by using potassium hydroxide) to the carboxylic acid 23 and converted to the amide 24 as described above in relation to Scheme 4.
  • aminomaiononitrile 29 is reacted with the aroyl or heteroaroyl chloride 28 in a high boiling polar aprotic solvent such as N-methylpyrrolidone at an elevated temperature above 100 0 C (e.g. up to 120 0 C) to give the amino-cyano-oxazole 30 which is converted to the corresponding bromo-compound 31 by treatment with copper bromide and ferf-butyl nitrite in dry acetonitrile. The nitrile group is then partially hydrolysed in concentrated sulphuric acid to give the the bromo-oxazolyl carboxamide 32.
  • a high boiling polar aprotic solvent such as N-methylpyrrolidone
  • the aryl or heteroaryl group Ar 1 can be added by reacting the oxazolyl carboxamide 32 with a suitable aryl or heteroaryl boronic acid Ar 1 -B(OH) 2 or boronate ester Ar 1 -B(OR) 2 (where R is an alkyl group or the two groups R combine to form a linked divalent group such as a pinacol residue) under Suzuki coupling conditions or with an aryl or heteroaryl tin compound Ar 1 -SnR 3 (where R is an alkyl group) under Stille reaction conditions.
  • a suitable aryl or heteroaryl boronic acid Ar 1 -B(OH) 2 or boronate ester Ar 1 -B(OR) 2 where R is an alkyl group or the two groups R combine to form a linked divalent group such as a pinacol residue
  • Suzuki coupling conditions or with an aryl or heteroaryl tin compound Ar 1 -SnR 3 (where R is an alkyl group) under Still
  • the bromo-oxazolyl carboxamide 32 may be reacted with a suitable aryl or heteroaryl boronate or boronic acid Ar 1 -B(OH) 2 or boronate ester Ar 1 -B(OR) 2 in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis (1 ,1'- ⁇ /s(diphenylphosphino)-ferrocene) palladium dichloride (Pd(dppf) 2 CI 2 ) and a base (e.g. a carbonate such as potassium carbonate).
  • a palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis (1 ,1'- ⁇ /s(diphenylphosphino)-ferrocene) palladium dichloride (Pd(dppf) 2 CI 2
  • a base e.g. a carbonate such as potassium carbonate
  • the reaction may be carried out in a polar solvent, for example acetonitrile or an aqueous solvent such as aqueous ethanol, or an ether such as dimethoxyethane, and the reaction mixture is typically subjected to heating, for example to a temperature of 80 0 C or more, e.g. a temperature in excess of 100 0 C, for example a temperature of up to about 150 0 C.
  • a polar solvent for example acetonitrile or an aqueous solvent such as aqueous ethanol, or an ether such as dimethoxyethane
  • boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA. Where the boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by Miyaura and Suzuki, Chem. Rev. (1995) 95, 2457. Thus, boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester. The resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid.
  • the Stille reaction with an aryl or heteroaryl tin compound Ar 1 -SnR 3 is typically carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium, in solvents and under conditions generally similar to those used for Suzuki coupling reactions.
  • a palladium catalyst for example tetrakis(triphenylphosphine)palladium
  • ethyl isocyanoacetate 33 is reacted with the aroyl or heteroaroyl chloride 11 to give the oxazole ester 34.
  • the reaction is typically carried out in a polar aprotic solvent such as acetonitrile in the presence of a non-interfering base such as triethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU), usually with heating, for example to a temperature in excess of 100 0 C.
  • a polar aprotic solvent such as acetonitrile
  • a non-interfering base such as triethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU)
  • the oxazole ester 34 is then converted to the iodo-oxazole ester 35 by reaction with lithium ⁇ /s(trimethylsilyl)amide in THF at low temperature (e.g. -78 0 C) followed by iodine.
  • the iodo-oxazole 35 is then used as substrate for a Suzuki coupling reaction with a boronic acid Ai ⁇ -B(OH) 2 or boronate Ar ⁇ -B(OR) 2 under the conditions described above to give the oxazole ester 22.
  • the oxazole ester 22 is then converted via the carboxylic acid 23 to the carboxamide 24 in the manner described above.
  • the iodo-oxazole ester 35 is hydrolysed to the carboxylic acid 36 and then converted to the carboxamide 37 before the Suzuki coupling step, as shown in Scheme 8.
  • 2-amino diethylmalonate 38 is acylated using the acid chloride 28 in a non-protic solvent such as dichloromethane in the presence of non-interfering base such as triethylamine or diisopropylethylamine, to give the amide 39.
  • Amide 39 is then cyclised to the ethoxy-oxazole ester 40 by treatment with trifluoroacetic anhydride in trifluorotoluene at an elevated temperature, e.g. a temperature in excess of 100 0 C, for example a temperature of up to about 160 0 C.
  • the ethoxy-oxazole ester 40 is hydrolysed using aqueous potassium hydroxide to give an intermediate carboxylic acid (not shown) which is then reacted with an aryl or heteroaryl amine Ar 1 -NH 2 in the presence of HOBt and a carbodiimide derivative such as a PS-carbodiimide resin to give the amide 41.
  • the heteroarylamino-oxazole ester 42 is hydrolysed to the carboxylic acid 43, using a metal hydroxide (advantageously trimethyltin hydroxide in dichloroethane) and the carboxylic acid 43 is then converted to the carboxamide 44 by reaction with ammonia in the presence of EDAC and HOBt under conditions analogous to those described above.
  • a metal hydroxide advantageousously trimethyltin hydroxide in dichloroethane
  • the bromo-oxazolyl carboxamide 32 (see Scheme 6 above) is subjected to a palladium catalysed amination by reaction with Ar 1 -NH 2 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)/ t»/s(diphenylphosphino)-1 ,1"-binaphthalene and sodium terf-butoxide to give the product 44.
  • the amination reaction is typically carried out at an elevated temperature, e.g. a temperature up to about 160 0 C, in a high boiling solvent such as trifluorotoluene.
  • the iodo-oxazole ester 35 (see Scheme 8) is subjected to amination by reaction with Ar ⁇ -NH 2 in the presence of a palladium catalyst to give an intermediate ester (not shown).
  • the ester is then hydrolysed using an alkali metal hydroxide such as potassium hydroxide as described above to give the oxazole carboxylic acid 46.
  • the oxazole carboxylic acid 46 is then reacted with ammonia in the presence of EDAC and HOBt to give the amide product 47.
  • the starting material is the bromo-oxazole 48 which is reacted with 4- hydroxyphenylboronic acid in the presence of a palladium catalyst such as as 1,1 '- 6/s(diphenylphosphino)ferrocene-palladium(ll)dichloride and a base such as sodium carbonate in a polar solvent such as acetonitrile to give the hydroxyphenyloxazole compound 49.
  • the hydroxyphenyloxazole compound 49 is then reacted with an alkylene dichloride CI-(CH 2 ) n -CI where n is 2 or more (e.g. 2, 3 or 4) to give the chloroalkoxy compound SO.
  • the chloroalkoxy compound is then reacted with an amine NR 111 R" 1 in the presence of a non-interfering base such as triethylamine to give the product 51.
  • the reaction may be carried out in a polar organic solvent such as a butanol: dioxane mixture in the presence of a base (e.g. an alkali metal carbonate such as caesium carbonate), typically with heating to a temperature in excess of 100 0 C.
  • a base e.g. an alkali metal carbonate such as caesium carbonate
  • Compound 54 can then be treated with acid (e.g sulphuric acid) to hydrolyse the nitrile group to a carboxamide group to give a compound of the formula 56.
  • the compound of formula 56 can then be reacted under amide-forming conditions (see Scheme 2 above) with an amine of the formula HNR U R U' where R u and R u' are the same or different and each is hydrogen or a substituent or NR U R U' forms a cyclic amine such as piperidine or morpholine, to give an amide of the formula 57.
  • the compound of formula 54 can be reacted under amide-forming conditions with an amine of the formula HNR U R U> to give a compound of formula 55 which is then treated with acid to hydrolyse the nitrile group to a carboxamide group to give a compound of the formula 57.
  • the amine 59 can be reacted with a carboxylic acid R 6 CO 2 H under amide forming conditions as described above.
  • R b is a cyclic amine linked to the carbonyl group via a nitrogen atom (e.g. as in 1-piperidinyl, 4- morpholinyl or 4-piperazinyl)
  • the amine 59 can be reacted with the cyclic amine in the presence of 1 ,1'-carbonyldiimidazole.
  • the reaction is typically carried out at room temperature in a solvent such as dichloromethane in the presence of a non-interfering base such as triethylamine or diisopropylethylamine.
  • the resulting intermediate, compound 60 is then treated with acid (e.g. sulphuric acid) as described above to hydrolyse the nitrile group to a carboxamide group thus giving the compound of formula 61
  • the substituted benzaldehyde 62 is subjected to reductive amination with an amine HNR 2 R 2' in the presence of a borohydride reducing agent (such as sodium triacetoxyborohydride) in a chlorinated hydrocarbon solvent (such as 1 ,2-dichloroethane) containing acetic acid to give the substituted aminomethylphenyl oxazole compound 63 in which NR 2 R 2 can be, for example, a dialkylamino group or an optionally susbtituted cyclic amino group such as a morpholinyl, piperidinyl or piperazinyl group.
  • the reductive amination reaction is typically carried out at room temperature.
  • the compounds of the invention can be isolated and purified according to standard techniques well known to the person skilled in the art.
  • One technique of particular usefulness in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column.
  • Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein.
  • the methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS.
  • Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds.
  • 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 of the invention 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 comprising a compound of the formula (1) or any sub-groups or examples thereof as defined herein and a pharmaceutically acceptable carrier.
  • pharmaceutically acceptable refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problems 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.
  • compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration.
  • compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
  • the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
  • the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.
  • the pharmaceutical composition is in a form suitable for oral administration.
  • Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
  • compositions containing compounds of the formula (1) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
  • tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g.
  • swellable crosslinked polymers such as crosslinked carboxymethylcellulose
  • lubricating agents e.g. stearates
  • preservatives e.g. parabens
  • antioxidants e.g. BHT
  • buffering agents for example phosphate or citrate buffers
  • effervescent agents such as citrate/bicarbonate mixtures.
  • Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form.
  • Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
  • the solid dosage forms can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating.
  • a protective film coating e.g. a wax or varnish
  • the coating e.g. a Eudragit TM type polymer
  • the coating can be designed to release the active component at a desired location within the gastrointestinal tract.
  • the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or duodenum.
  • the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • a release controlling agent for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract.
  • the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract.
  • the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art.
  • Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts
  • compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
  • compositions for parenteral administration may be formulated for administration as discrete dosage units or may be formulated for administration by infusion.
  • formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
  • compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known.
  • the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
  • a formulation intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams.
  • the active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
  • Solvent A 0.02% Ammonia and 5% Solvent B in acetonitrile
  • Solvent B 0.02% Ammonia and 0.063% ammonium formate in water.
  • UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 120-1000 amu.
  • Solvent A 0.02% Ammonia and 5% Solvent B in acetonitrile.
  • Solvent B 0.02% Ammonia and 0.063% ammonium formate in water.
  • UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 80-1000 amu.
  • Solvent B 0.02% Ammonia and 0.063% ammonium formate in water.
  • UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionization was by positive or negative ion electrospray. Molecular weight scan range was 120 -1000 amu.
  • Microwave mediated reactions were performed in a Biotage Sixty microwave reactor at the temperature and times specified in the experimental section.
  • TBS - frvs-buffered saline Eu-N 1 - europium N1 chelate The reagent is the Eu 3+ -chelate of N 1 -(p-iodoacetamido- benzyl)diethylenetriamine-N 1
  • Examples A-1 to A-20 were prepared using General Method A which comprises the sequence of reactions set out in Scheme 1 above.
  • Step a Ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate.
  • Step c Ethyl 4-(4 ⁇ methoxyphenyl)-2-phenyl-1 H-imidazole-5-carboxylate
  • Step b 2-(4-bromo-2,6-difluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5- carboxamide
  • aqueous phase was then acidified by the addition of acetic acid and purified by SPE using MP-TsOH cartridges (2x1000mg) to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5- carboxylic acid (0.09Og) as an orange oil which was used without further purification.
  • Step b 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H-imidazole-5-carboxamide
  • Step b ethyl 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxylate
  • Step b 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate
  • Step c ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate
  • Step b ethyl 2-(2,6-difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate
  • Step c ethyl 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylate
  • Step a fert-butyl 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl) benzylcarbamate
  • Step b 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
  • N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (0.006g, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 1-(2-chloroethyl)-piperidine (0.05Og, 0.3mmol) in MeCN (2ml) to 11O 0 C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the product as a white solid (0.009g, 0.027mmol). LCMS (3) 2.50min; m/z (ES+) 331.
  • Step b 2-(2,6-difluorophenyl)-5-(4-(2-(piperidin-1-yl)ethylamino)phenyl)oxazole-4- carboxamide
  • Step a N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine
  • N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (0.006g, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 2-dimethylaminoethyl chloride hydrochloride (0.043g, 0.3mmo! in MeCN (2ml) to 11O 0 C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the desired compound as a white solid, (0.025g, 0.086mmol). LCMS (3) 2.12min; m/z (ES+) 291
  • Step b 2-(2,6-difluorophenyl)-5-(4-(2-(dimethylamino)ethylamino)phenyl)oxazole-4- carboxamide
  • Step a N-(2-morpholinoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine
  • N-(2-morpholinoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4 J 4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (O.OO ⁇ g, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 2- N-(2-chloroethyl)morpholine hydrochloride (0.056g, 0.3mmol) in MeCN (2ml) to 11O 0 C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the desired compound as an off-white solid (0.03Og, 0.090mmol).
  • LCMS (3) 1.91min; m/z (ES+) 333
  • Step b 2-(2,6-difluorophenyl)-5-(4-(2-morpholinoethylamino)phenyl)oxazole-4- carboxamide
  • Step a ferf-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzyl)pipera2ine- 1-carboxylate
  • Example F- 1 Prepared in a similar manner to the procedure outlined for the synthesis of Example F- 1 using te/f-butyl 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)piperazine-1- carboxylate synthesised as described above. The product obtained was used without further purification.
  • Step b 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide

Abstract

The invention provides a compound for use in the treatment of an autoimmune disease such as multiple sclerosis, the compound being a compound of the formula (1) or a salt, solvate, N-oxide or tautomer thereof; wherein a is 0 or 1; b is 0 or 1 : provided that the sum of a and b is 0 or 1; T is O or NH; Ar1 is an optionally substituted monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group; and Ar2 is an optionally substituted monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group; provided that, when b is 0, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T.

Description

PHARMACEUTICAL COMPOUNDS
This invention relates to compounds for use in the prophylaxis or treatment of automimmune diseases and in particular multiple sclerosis.
Background of the Invention
Multiple Sclerosis
Multiple Sclerosis (MS) is a disabling neurological condition characterised by gradual destruction of the myelin sheath, a protective fatty layer that surrounds nerve fibres of the central nervous system. As a consequence of the damage to the myelin sheath, the nerve fibres can no longer effectively conduct electrical signals and this gives rise to a variety of symptoms, including changes in sensation, visual problems, muscle weakness, depression, difficulties with coordination and speech, severe fatigue, cognitive impairment, problems with balance, overheating, pain, and urinary and faecal incontinence. In more severe cases, MS will cause impaired mobility and disability.
MS is generally categorized as an autoimmune disease which results from attacks by an individual's immune system on the nervous system.
Multiple sclerosis can be categorised into three types, relapsing-remitting MS, secondary progressive MS and primary progressive MS. In around 80% of MS sufferers, the MS starts off as a relapsing and remitting condition which means that there are periods of relapse, when symptoms flare up, often quite suddenly, and then periods of remission, when symptoms improve. The periods between relapses can be highly unpredictable and often several years may pass between relapses.
After an initial period of relapsing-remitting MS, patients may progress to secondary progressive MS which involves the gradual accumulation of neurological disability, without remission, despite a reduction in the frequency of relapse . About half of people who have relapsing-remitting MS go on to the secondary progressive stage in the first 10 years.
The third type of MS, primary progressive MS, afflicts about 10% of MS patients. With this type of MS, there are no periods of remission and the disease gets gradually worse from the start. This causes increasing disability, and can reduce life expectancy. There is currently no cure for multiple sclerosis but a number of different types of drugs are used to control or manage the symptoms, of which the most popular are antiinflammatory steroids such as methyl prednisolone. Steroids are typically used to treat relapses but are not believed to alter the course of the disease. Largely because of the side effects, it is generally recommended not to use steroids for more than about three weeks at a time and for no more than about three courses per year. Side effects caused by steroids include stomach irritation, such as indigestion and heartburn, stomach ulcers, mood changes or mood swings, insomnia, nausea, bone-thinning osteoporosis, cataracts, weight gain, swelling and obesity, acne and diabetes. Steroids are generally suitable for treating only about 10-20% of relapses.
Non-steroidal anti-inflammatory drugs (NSAIDs) have been used to alleviate or manage some of the symptoms of MS but, again, they have no effect on the course of the disease. Moreover, they have well known side effects such as gastric irritation and can cause gastric bleeding and stomach ulcers.
A number of treatments, including β-interferon and Copaxone, have been licensed as "disease modifying" therapies reducing the frequency of MS relapses and providing a modest benefit in terms of disability progression. However, at present, there remains a need for alternative, more effective symptomatic and disease modifying treatments for MS that lack the side effects associated with existing drug treatments.
Autoimmune diseases such as multiple sclerosis often result from inappropriate or unregulated activation of autoreactive T cells. Traditional approaches to treatment of autoimmune diseases through immunosuppression have focused on direct inhibition of T cells.
Whartenby et al. Proc. Natl. Acad. ScL U S A. (2005) Nov 15; 102(46): 16741 -6, (Inhibition of FLT3 signaling targets DCs to ameliorate autoimmune disease) examined the targeted inhibition of antigen-presenting cells as a means of downregulating immune responses and treating autoimmune disease. Dendritic cells (DCs) are the central antigen-presenting cells for the initiation of T cell responses, including autoreactive T cell responses. A large proportion of DCs are derived from hematopoietic progenitors that express the FLT3 receptor (CD135). Stimulation of the receptor via FLT3 ligand either in vivo or in vitro is known to drive expansion and differentiation of these progenitors toward a DC phenotype. Whartenby et al. hypothesized that inhibition of FLT3 signalling would produce an inhibition of DC-induced stimulation of T cells, thereby inhibiting autoimmune responses. To test this hypothesis, they examined the effects of FLT3 kinase inhibitors on DCs and their role in the promulgation of autoimmune disease, and were able to show that inhibition of FLT3 signalling induces apoptosis in both mouse and human DCs, and therefore is a potential target for immune suppression. Thy found also that targeted inhibition of FLT3 significantly improved the course of established disease in a model for multiple sclerosis (experimental autoimmune encephalomyelitis) suggesting a potential avenue for treating autoimmune disease.
It has recently been reported that a selective FLT3 kinase inhibitor (the imidazoacridinone Symadex™ from Xanthus Pharmaceuticals, Inc.) was able to reverse the course of the disease in mouse models of both acute and chronic multiple sclerosis. The results were presented in a poster session by Stephen J. Karlik, Ph.D., Professor of Diagnostic Radiology at the University of Western Ontario, London, Ontario, together with researchers from Xanthus at the 60th American Academy of Neurology Meeting in Chicago, IL. Using the experimental autoimmune encephalomyelitis (EAE) model, the Xanthus researchers evaluated the effect of Symadex during both the acute and chronic phases of EAE in the mouse models. A partial, concentration-dependant decrease in clinical signs was observed in the acute prevention experiment, and chronic treatment resulted in a dose-dependent reduction of clinical scores. The researchers examined Symadex-treated versus control animals for changes in several circulating biomarkers known to be relevant to autoimmune disease. Symadex was found to bring elevated levels of monocyte- and macrophage-related biomarkers associated with disease back to normal. MRI imaging showed that macrophage function was inhibited in areas of inflammation.
FLT3 Kinase
Protein kinases constitute a large family of structurally related enzymes that are responsible for the control of a wide variety of signal transduction processes within the cell (Hardie and Hanks (1995) The Protein Kinase Facts Book. I and II, Academic Press, San Diego, CA). The kinases may be categorized into families by the substrates they phosphorylate (e.g., protein-tyrosine, protein-serine/threonine, lipids, etc.). Sequence motifs have been identified that generally correspond to each of these kinase families (e.g., Hanks and Hunter, FASEB J., (1995) 9. 576-596; Knighton, et a/., Science, (1991) 253, 407-414; Hiles, et al., Cell, (1992) 70, 419-429; Kunz, et al., Cell, (1993) 73, 585-596; Garcia-Bustos, et al., EMBO J., (1994) 13, 2352-2361). Protein kinases may be characterized by their regulation mechanisms. These mechanisms include, for example, autophosphorylation, transphosphorylation by other kinases, protein-protein interactions, protein-lipid interactions, and protein-polynucleotide interactions. An individual protein kinase may be regulated by more than one mechanism.
Kinases regulate many different cell processes including, but not limited to, proliferation, differentiation, apoptosis, motility, transcription, translation and other signalling processes, by adding phosphate groups to target proteins. These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. Phosphorylation of target proteins occurs in response to a variety of extracellular signals (hormones, neurotransmitters, growth and differentiation factors, etc.), cell cycle events, environmental or nutritional stresses, etc. The appropriate protein kinase functions in signalling pathways to activate or inactivate (either directly or indirectly), for example, a metabolic enzyme, regulatory protein, receptor, cytoskeletal protein, ion channel or pump, or transcription factor. Uncontrolled signalling due to defective control of protein phosphorylation has been implicated in a number of diseases, including, for example, inflammation, cancer, allergy/asthma, disease and conditions of the immune system, disease and conditions of the central nervous system, and angiogenesis.
FMS-like tyrosine kinase 3 (FLT3) is a receptor tyrosine kinase involved in the proliferation, differentiation and apoptosis of hematopoietic and non-hematopoietic cells (Scheijen and Griffin, Oncogene (2002) 21, 3314-3333 and Reilly, British Journal of Haematology (2002) 116, 744-757). As a result of the natural ligand (FL) binding, the FLT3 receptor dimerises resulting in activation of its tyrosine kinase domain, receptor autophosphorylation and recruitment of downstream signalling molecules such as the p85 subunit of PI3K (phosphatidylinositol 3 kinase), PLC-gamma (Phospholipase-C gamma), STAT5a (signal transducer and activator of transcription 5a), and SRC family tyrosine kinases (Gilliland and Griffin, Blood (2002) 100(5), 1532-42; Drexler, Leukemia (1996) 10(4), 588-99 and Ravandi et al., CHn Cancer Res. (2003) 9(2), 535-50).
J. Lykkeberg et al., Acta Chemica Scandinavica, Series B: Organic Chemistry and Biochemistry (1975) B29(7), 793-5 describes the preparation of some 2,4-disubstituted imidazole-5-carboxamides by thermolysis of β-substituted α-(1-tetrazolyl)acrylamides. Amongst the compounds disclosed in the article are 2,5-diphenyl-1 H-imidazole-4- carboxylic acid amide and 2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide.
Ponomarev et a/., Zhurnal Fizicheskoi Khimii (1990) 64(10), 2723-9 (Chem Abs. 114:100938) describes the electronic absorption spectra of fused oxazole compounds. Amongst the compounds disclosed in the article is 2,5-diphenyl-oxazole-4-carboxylic acid amide.
Ozaki et a/., Chem. Pharm. Bull. (1983) 31(12), 4417-24 discloses a series of 2- substituted oxazole compounds as blood platelet aggregation inhibitors. One of the compounds exemplified in the article is 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4- carboxylic acid amide.
JP 63-10767 and JP 86-155456 (Yoshitomi) disclose diaryl imidazoles as analgesic and anti-inflammatory agents. The compound 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H- imidazole-4-carboxylic acid amide is specifically disclosed.
WO 2006/095159 (AstraZeneca) discloses imidazolyl-anilino-pyrimidines as cell proliferation inhibitors.
WO 02/00649 (AstraZeneca) discloses substituted quinazolines as Aurora kinase inhibitors.
WO 2004/005283 (Vertex) discloses pyridyl and pyrimidinyl substituted oxazoles, thiazoles and imidazoles as protein kinase inhibitors.
WO 2007/043400 (Kissei) discloses aryl and heteroaryl pyrazole derivatives as xanthine oxidase inhibitors. The compound 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide is specifically disclosed as a chemical intermediate.
WO 2005/040139 (AB Science et al.) and WO 2007/131953 (AB Science) disclose 2- phenylamino-oxazoles as inhibitors of various tyrosine kinases.
WO 2008/024980 (Serenex Inc.) discloses pyrrole, thiophene, furan, imidazole, oxazole and thiazole derivatives that have Hsp90 inhibiting activity and which are useful for treating a range of diseases including cancer. Our earlier patent application PCT/GB2008/001612 (the contents of which are incorporated herein by reference) discloses aryl- and heteroaryl-substituted oxazoles and imidazoles as inhibitors or various kinases, including FLT3 kinase.
Summary of the Invention
The invention provides compounds of the type disclosed in our earlier application PCT/GB2008/001612 for use in the prophylaxis or treatment of autoimmune diseases and in particular multiple sclerosis.
The compounds for use in accordance with the invention are defined and described below and in the claims appended hereto.
Accordingly, in one aspect, the invention provides a compound for use in the treatment of an autoimmune disease, and in particular multiple sclerosis, the compound being a compound of the formula (1):
Figure imgf000007_0001
or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1 ; b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
T is O or NH
Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S1 and being optionally substituted by one or more substituents R1; provided that, when b is 0, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T;
Ar2Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2;
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by one or more substituents R3; Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X\ S, SO, SO2, NR0, SO2NR0 or NR0SO2;
Rb is:
• hydrogen; or
• a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by one or more substituents R3; or
• a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R°)2; and 3 to 8-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by one or more substituents R3; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O1 CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
Rc is hydrogen or a C1-4 hydrocarbon group;
X1 is O, S or NR0;
X2 is =0, =S or =NR°;
R2 is halogen; cyano; nitro; or a group Ra-Rd;
Rd is hydrogen; a C1-4 alkyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the C1-4 alkyl and C1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms;
R3 is X2; halogen; cyano; nitro; a group Ra-Re; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms (e.g. up to 2 heteroatoms) selected from O, N and S and being optionally substituted by a group R4;
Re is:
- hydrogen; or
- a C1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°)2; wherein one to three but not all of the carbon atoms of the C1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X1 or X1C(X2)X1; or - a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the C1.4 alkyl and Ci-4 alkoxy groups are each optionally substituted with one or more fluorine atoms; and R4 is selected from halogen, cyano, nitro and a group Ra-Rd; provided that when a is 0, Ar1 is other than a 2-aminopyridin-4-y! or 2-amino-pyrimidin-4- yl group wherein the 2-amino moiety is optionally substituted; and that neither Ar2-(NH)b- nor Ar1-(NH)a- form an optionally substituted quinoxalin-4-ylamino group; and that when when a is 1 and b is 0, then Ar2 is other than a bicyclic group containing a pyrrole or pyrazole ring fused to a non-aromatic six-membered carbocyclic ring wherein the point of attachment of Ar2 is a nitrogen atom of the pyrrole or pyrazole ring.
In one general embodiment, the compounds of formula (1) are as defined above provided that they are other than the compounds: 2,5-diphenyl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide; and 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
In one embodiment, the compound is an amide of the formula (1a):
Figure imgf000009_0001
or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1 ; b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
T is O or NH Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1;
Ar2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; provided that, when b is O, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T;
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3;
Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
Rb is:
• hydrogen; or
• a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; or
• a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R°)2; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X1C(X2), C(X2)X\ X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
R° is hydrogen or a Ci-4 hydrocarbon group;
X1 is O, S or NR0;
X2 is =0, =S or =NR°;
R2 is halogen; cyano; nitro; or a group Ra-Rd;
Rd is hydrogen or a Ci-4 alkyl group optionally substituted by one or more fluorine atoms;
R3 is X2; halogen; cyano; nitro; a group Ra-Re; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R4;
Re is: - hydrogen; or
- a C-I-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°)2; wherein one to three but not all of the carbon atoms of the C1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X1 or X1C(X2)X1; and
R4 is selected from halogen, cyano, nitro and a group Ra-Rd; provided that when a is 0, Ar1 is other than a 2-aminopyridin-4-yl or 2-amino- pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted; and that neither Ar2-(NH)b- nor Ar1-(NH)a- form an optionally substituted quinoxalin-4-ylamino group; but optionally excluding the compounds:
2,5-diphenyl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide; and 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
In each of the foregoing formulae, when b is 0 and the group Ar2 is attached directly to the 5-membered ring containing the moiety T, the attachment of the 5-membered ring is to a carbon atom of the moiety Ar2. Thus, the general formulae exclude from theiur scope compounds of the type disclosed in WO 2008/024980.
In one sub-group of compounds, a and b are both 0 and therefore the compound is an amide of the formula (2):
Figure imgf000011_0001
(2) or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a); but optionally excluding the compounds:
2,5-diphenyl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluoropheπyl)-5-(4-methoxyphenyl)-1H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide; and 2-(4-methylphenyl)-5~phenyl-oxazole- 4-carboxylic acid amide.
Within formula (2), one group of compounds consists of amides of the formula (2a):
Figure imgf000012_0001
(2a) and salts, solvates, N-oxides and tautomers thereof; wherein Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a), but optionally excluding the compounds 2, 5-diphenyl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; and 2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof.
Another group of compounds consists of amides of the formula (2b):
Figure imgf000012_0002
(2b) and salts, solvates, N-oxides and tautomers thereof; wherein Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a), but optionally excluding the compounds 2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide and 2-(4-methylphenyl)-5-phenyl-oxazole- 4-carboxylic acid amide.
A further group of compounds for use in accordance with the invention consists of amides of the formula (2c):
Figure imgf000013_0001
(2c) and salts, solvates, N-oxides and tautomers thereof; wherein Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a).
In another subgroup of compounds for use according to the invention, a is 1 and b is 0 and therefore the compound is an amide of the formula (3):
Figure imgf000013_0002
or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a).
Within formula (3), one group of compounds consists of amides of the formula (3a):
Figure imgf000013_0003
(3a) and salts, solvates, N-oxides and tautomers thereof; wherein Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a).
In a further sub-group of compounds, a is 0 and b is 1 and therefore the compound is an amide of the formula (4):
Figure imgf000013_0004
(4) or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a).
Within formula (4), one group of compounds for use in accordance with the invention consists of amides of the formula (4a):
Figure imgf000014_0001
(4a) and salts, solvates, N-oxides and tautomers thereof; wherein Ar1 and Ar2 are as hereinbefore defined in each of formulae (1) and (1a).
General Preferences and Definitions
In this specification, references to formula (1) include not only formula (1) perse but also formulae (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) and sub-groups, examples or embodiments thereof, unless the context requires otherwise.
Thus for example, references to therapeutic uses, pharmaceutical formulations and processes for making compounds, where they refer to formula (1), are also to be taken as referring to formulae (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) and subgroups, examples or embodiments thereof.
Similarly, where preferences, embodiments and examples are given for compounds of the formula (1), they are also applicable to formulae (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) unless the context requires otherwise.
As used herein, the term "modulation", as applied to the activity of FLT3 kinase, is intended to define a change in the level of biological activity of the kinase(s). Thus, modulation encompasses physiological changes which effect an increase or decrease in the relevant kinase activity. In the latter case, the modulation may be described as "inhibition".
The term "upregulation" as used herein in relation to the kinase is defined as including elevated expression or over-expression of the kinase, including gene amplification (i.e. multiple gene copies) and increased expression by a transcriptional effect, and hyperactivity and activation of the kinase, including activation by mutations.
The following general preferences and definitions shall apply to each of the moieties T, Ar1, Ar2, R1 to R4 and any sub-definition, sub-group or embodiment thereof, unless the context indicates otherwise.
The term "halogen" as used herein refers to fluorine, chlorine, bromine and iodine and does not include astatine.
The term "aryl" as used herein refers to a carbocyclic ring or group having aromatic character and the term "heteroaryl" is used herein to denote a heterocyclic group having aromatic character. The terms "aryl" and "heteroaryl" (e.g. as used in relation to the moieties Ar1 and Ar2) embrace aromatic monocyclic ring systems and polycyclic (e.g. bicyclic) ring systems containing one or more aromatic rings. The term covers polycyclic ring systems in which all of the fused rings are aromatic as well as ring systems where one or more rings are non-aromatic, provided that at least one ring is aromatic. In polycyclic systems containing both aromatic and non-aromatic rings fused together, the group may be attached to another moiety (e.g. the five membered ring containing N and T) by the aromatic ring, or by a non-aromatic ring.
Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to ten ring members. The heteroaryl group can be, for example, a five membered or six membered monocyclic ring or a bicyclic structure formed from fused five and six membered rings or two fused six membered rings or two fused five membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulphur and oxygen. The heteroaryl ring will contain up to 4 heteroatoms, more typically up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.
Examples of five membered heteroaryl groups include but are not limited to pyrrole, furan, thiophene, imidazole, furazan, oxazole, oxadiazole, oxatriazole, isoxazole, thiazole, isothiazole, pyrazole, triazole and tetrazole groups. Examples of six membered heteroaryl groups include but are not limited to pyridine, pyrazine, pyridazine, pyrimidine and triazine.
A bicyclic heteroaryl group may be, for example, a group selected from: a) a benzene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; b) a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; c) a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; d) a pyrrole ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; e) a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; f) an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; g) an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; h) an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; i) a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; j) an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; k) a thiophene ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms;
I) a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; m) a cyclohexyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; and n) a cyclopentyl ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms.
Particular examples of bicyclic heteroaryl groups containing a five membered ring fused to another five membered ring include but are not limited to imidazothiazole (e.g. imidazo[2,1-b]thiazole) and imidazoimidazole (e.g. imidazo[1,2-a]imidazole).
Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzofuran, benzothiophene, benzimidazole, benzoxazole, isobenzoxazole, benzisoxazole, benzothiazole, benzisothiazole, isobenzofuran, indole, isoindole, indolizine, indoiine, isoindoline, purine (e.g., adenine, guanine), indazole, pyrazolopyrimidine (e.g. pyrazolo[1 ,5-a]pyrimidine), benzodioxole and pyrazolopyridine (e.g. pyrazolo[1,5-a]pyridine) groups. A further example of a six membered ring fused to a five membered ring is a pyrrolopyridine group such as a pyrrolo[2,3-b]pyridine group.
Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinoline, isoquinoline, chroman, thiochroman, chromene, isochromene, isochroman, benzodioxan, quinolizine, benzoxazine, benzodiazine, pyridopyridine, quinoxaline, quinazoline, cinnoline, phthalazine, naphthyridine and pteridine groups.
Examples of polycyclic aryl and heteroaryl groups containing an aromatic ring and a non-aromatic ring include tetrahydronaphthalene, tetrahydroisoquinoline, tetrahydroquinoline, dihydrobenzothiophene, dihydrobenzofuran, 2,3-dihydro- benzo[1,4]dioxine, benzo[1,3]dioxole, 4,5,6,7-tetrahydrobenzofuran, indoiine, isoindoline and indane groups.
Examples of carbocyclic aryl groups include phenyl, naphthyl, indenyl, and tetrahydronaphthyl groups.
References to "carbocyclic" and "heterocyclic" rings or groups as used herein (for example in relation to the substituent group R3) shall, unless the context indicates otherwise, include both aromatic and non-aromatic ring systems. Thus, for example, the term "carbocyclic and heterocyclic" includes within its scope aromatic, non-aromatic, unsaturated, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The carbocyclic or heterocyclic rings or groups can be aryl or heteroaryl rings or groups as hereinbefore defined
The term "non-aromatic group" embraces unsaturated ring systems without aromatic character, partially saturated and fully saturated carbocyclic and heterocyclic ring systems. The terms "unsaturated" and "partially saturated" refer to rings wherein the ring structure(s) contains atoms sharing more than one valence bond i.e. the ring contains at least one multiple bond e.g. a C=C, C≡C or N=C bond. The term "fully saturated" refers to rings where there are no multiple bonds between ring atoms. Saturated carbocyclic groups include cycloalkyl groups as defined below. Partially saturated carbocyclic groups include cycloalkenyl groups as defined below, for example cyclopentenyl, cycloheptenyl and cyclooctenyl. A further example of a cycloalkenyl group is cyclohexenyl.
Examples of non-aromatic heterocyclic groups include heterocyclic groups having from 3 to 7 ring members, typically 4 to 7 ring members, and more usually from 5 to 6 ring members. Such groups typically have 1 , 2, 3 or 4 heteroatom ring members selected from nitrogen, oxygen and sulphur.
Further examples of non-aromatic heterocyclic rings include bridged bicyclic ring systems such as bicycloalkanes and azabicycloalkanes. By "bridged ring systems" is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged ring systems include bicyclo[2.2.1]heptane, aza- bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, aza-bicyclo[2.2.2]octane (e.g. quinuclidine), bicyclo[3.2.1]octane and aza-bicyclo[3.2.1]octane. Particular examples of bridged bicyclic ring systems are quinuclidine and 8-methyl-8-aza-bicyclo[3.2.1]octane.
When sulphur is present, it may, where the nature of the adjacent atoms and groups permits, exist as -S-, -S(O)- or -S(O)2-.
The heterocyclic groups can contain, for example, cyclic ether moieties (e.g. as in tetrahydrofuran and dioxane), cyclic thioether moieties (e.g. as in tetrahydrothiophene and dithiane), cyclic amine moieties (e.g. as in pyrrolidine), cyclic amide moieties (e.g. as in pyrrolidone), cyclic thioamides, cyclic thioesters, cyclic ester moieties (e.g. as in butyrolactone), cyclic sulphones (e.g. as in sulpholane and sulpholene), cyclic sulphoxides, cyclic sulphonamides and combinations thereof (e.g. morpholine and thiomorpholine and its S-oxide and S,S-dioxide), and cyclic ureas (e.g. as in imidazolidin-2-one).
Examples of monocyclic non-aromatic heterocyclic groups include 4, 5, 6 and 7- membered monocyclic heterocyclic groups. Particular examples include azetidine, pyrrolidine (e.g. 1-pyrrolidinyl, 2-pyrrolidinyl and 3-pyrrolidinyl), piperidine (e.g. 1- piperidinyl, 2-piperidinyl, 3-piperidinyl and 4-piperidinyl), azepine, pyrrolidone, pyran (2H- pyran or 4H-pyran), dihydrothiophene, dihydropyran, dihydrofuran, dihydrothiazole, tetrahydrofuran, tetrahydrothiophene, dioxane, tetrahydropyran (e.g. 4-tetrahydro pyranyl), imidazoline, imidazolidinone, oxazoline, thiazoline, 2-pyrazoline, pyrazolidine, morpholine, piperazine, N-alkyl piperazines such as N-methyl piperazine, thiomorpholine and its S-oxide and S,S-dioxide, piperidone, piperazone, and N-alkyl piperidines such as N-methyl piperidine.
One sub-set of non-aromatic heterocyclic groups consists of saturated groups such as azetidine, pyrrolidine, piperidine, morpholine, thiomorpholine, thiomorpholine S1S- dioxide, piperazine, N-alkyl piperazines, and N-alkyl piperidines.
Examples of non-aromatic carbocyclic groups include cycloalkane groups such as cyclohexyl and cyclopentyl, cycloalkenyl groups such as cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl, as well as cyclohexadienyl, cyclooctatetraene, tetrahydronaphthenyl and decalinyl.
Preferred non-aromatic carbocyclic groups are saturated monocyclic rings. Typical examples are 3, 4, 5 and 6 membered saturated carbocyclic rings, e.g. optionally substituted cyclopentyl and cyclohexyl rings.
One sub-set of non-aromatic carbocyclic groups includes monocyclic groups and particularly saturated monocyclic groups, e.g. cycloalkyl groups. Examples of such cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl; more typically cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, particularly cyclohexyl.
Further examples of non-aromatic cyclic groups include bridged ring systems such as bicycloalkanes and azabicycloalkanes although such bridged ring systems are generally less preferred. By "bridged ring systems" is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 131-133, 1992. Examples of bridged ring systems include bicyclo[2.2.1]heptane, aza-bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, aza- bicyclo[2.2.2]octane, bicyclo[3.2.1]octane and aza-bicyclo[3.2.1]octane. A particular example of a bridged ring system is the 1-aza-bicyclo[2.2.2]octan-3-yl group.
In the definition of the compounds of the formula (1) above and as used hereinafter, the term "hydrocarbon" is used in its conventional sense to denote aliphatic, alicyclic and aromatic groups having an all-carbon backbone and consisting of carbon and hydrogen atoms, except where otherwise stated.
In certain cases, as defined herein, one or more of the carbon atoms making up the carbon backbone may be replaced by a specified atom or group of atoms.
Examples of hydrocarbon groups include alkyl, cycloalkyl, cycloalkenyl, carbocyclic aryl, alkenyl, alkynyl, cycloalkylalkyl, cycloalkenylalkyl, and carbocyclic aralkyl, aralkenyl and aralkynyl groups. Such groups can be unsubstituted or, where stated, substituted by one or more substituents as defined herein. The examples and preferences expressed below apply to each of the hydrocarbon substituent groups or hydrocarbon-containing substituent groups referred to in the various definitions of substituents for compounds of the formula (1) unless the context indicates otherwise.
The term "acyclic hydrocarbon group" as used herein (e.g. in the phrase "Ci-I2 acyclic hydrocarbon group") encompasses alkyl, alkenyl, alkynyl and mixed alkenyl-alkynyl groups.
Preferred non-aromatic hydrocarbon groups are saturated groups such as alkyl and cycloalkyl groups.
Generally by way of example, the hydrocarbon groups can have up to twelve carbon atoms, unless the context requires otherwise. Subsets of hydrocarbon groups are C1-S hydrocarbon groups, C1-6 hydrocarbon groups, C1-4 hydrocarbon groups, C1-3 hydrocarbon groups and C1-2 hydrocarbon groups, specific examples being any individual value or combination of values selected from Ci, C2, C3, C4, C5, C6, C7 and C8 hydrocarbon groups.
The term "alkyl" covers both straight chain and branched chain alkyl groups. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, terf-butyl, n- pentyl, 2-pentyl, 3-pentyl, 2-methyl butyl, 3-methyl butyl, and n-hexyl and its isomers. Subsets of alkyl groups are C1-8 alkyl groups, C1-6 alkyl groups, C1-4 alkyl groups, C1-3 alkyl groups and C1-2 alkyl groups.
Examples of cycloalkyl groups are those derived from cyclopropane, cyclobutane, cyclopentane, cyclohexane and cycloheptane. Within the sub-set of cycloalkyl groups the cycloalkyl group will have from 3 to 8 carbon atoms, particular examples being C3-6 cycloalkyl groups.
Examples of alkenyl groups include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2- propenyl (allyl), isopropenyl, butenyl, buta-1 ,4-dienyl, pentenyl, and hexenyl. Within the sub-set of alkenyl groups, the alkenyl group may have 2 to 8 carbon atoms, particular examples being C2-6 alkenyl groups, such as C2-4 alkenyl groups.
Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl and cyclohexenyl. Within the sub-set of cycloalkenyl groups, the cycloalkenyl groups may have from 3 to 8 carbon atoms, and particular examples are C3-6 cycloalkenyl groups.
Examples of alkynyl groups include, but are not limited to, ethynyl and 2-propynyl (propargyl) groups. Within the sub-set of alkynyl groups the alkynyl groups may have 2 to 8 carbon atoms, particular examples being C2-6 alkynyl groups and C2-4 alkynyl groups.
Examples of carbocyclic aryl groups include substituted and unsubstituted phenyl groups.
Examples of cycloalkylalkyl, cycloalkenylalkyl, carbocyclic aralkyl, aralkenyl and aralkynyl groups include phenethyl, benzyl, styryl, phenylethynyl, cyclohexylmethyl, cyclopentylmethyl, cyclobutylmethyl, cyclopropylmethyl and cyclopentenylmethyl groups.
Where stated, 1 to 3 carbon atoms of a hydrocarbon group may optionally be replaced by O, S, SO, SO2, NRC, X1C(X2), C(X2)X1 orX1C(X2)X1 (or a sub-group thereof) wherein X1 and X2 are as hereinbefore defined, provided that at least one carbon atom of the hydrocarbon group remains. For example, 1 , 2, 3 or 4 carbon atoms of the hydrocarbon group may be replaced by one of the atoms or groups listed, and the replacing atoms or groups may be the same or different. In general, the number of linear or backbone carbon atoms replaced will correspond to the number of linear or backbone atoms in the group replacing them. Examples of groups in which one or more carbon atom of the hydrocarbon group have been replaced by a replacement atom or group as defined above include ethers and thioethers (C replaced by O or S), amides, esters, thioamides and thioesters (C-C replaced by X1C(X2) or C(X2)X1), sulphones and sulphoxides (C replaced by SO or SO2), amines (C replaced by NR0). Further examples include ureas, carbonates and carbamates (C-C-C replaced by X1C(X2)X1).
The term "aza-cycloalkyl" as used herein refers to a cycloalkyl group in which one of the carbon ring members has been replaced by a nitrogen atom. Thus examples of aza- cycloalkyl groups include piperidine and pyrrolidine. The term "oxa-cycloalkyl" as used herein refers to a cycloalkyl group in which one of the carbon ring members has been replaced by an oxygen atom. Thus examples of oxa-cycloalkyl groups include tetrahydrofuran and tetrahydropyran. In an analogous manner, the terms "diaza- cycloalkyl", "dioxa-cycloalkyl" and "aza-oxa-cycloalkyl" refer respectively to cycloalkyl groups in which two carbon ring members have been replaced by two nitrogen atoms, or by two oxygen atoms, or by one nitrogen atom and one oxygen atom.
The definition "Ra-Rb" as used herein, either with regard to substituents present on a carbocyclic or heterocyclic moiety, or with regard to other substituents present at other locations on the compounds of the formula (1), includes inter alia compounds wherein Ra is selected from a bond, O, CO, OC(O), SC(O), NR0C(O), OC(S), SC(S), NR0C(S), OC(NR0), SC(NRC), NR0C(NR0), C(O)O, C(O)S, C(O)NR0, C(S)O, C(S)S, C(S) NR0, C(NR°)O, C(NR°)S, C(NR°)NRC, OC(O)O, SC(O)O, NR0C(O)O, OC(S)O, SC(S)O, NR0C(S)O, OC(NR°)O, SC(NR°)O, NRCC(NR°)O, OC(O)S, SC(O)S, NR0C(O)S, OC(S)S, SC(S)S, NR0C(S)S, OC(NR°)S, SC(NR°)S, NR°C(NRC)S, OC(O)NR0, SC(O)NR0, NR0C(O) NR0, OC(S)NR0, SC(S) NR0, NR0C(S)NR0, OC(NRC)NR°, SC(NR°)NR°, NR0C(NR0NR0, S, SO, SO2, NR0, SO2NR0 and NR0SO2 wherein R0 is as hereinbefore defined.
The moiety Rbcan be hydrogen or it can be a group selected from carbocyclic and heterocyclic groups having from 3 to 7 ring members (usually 4 to 7 and more usually 5 to 6), and a C1-12 hydrocarbon group optionally substituted as defined. Examples of hydrocarbon, carbocyclic and heterocyclic groups are as set out above.
When Ra is O and Rb is a C1-12 hydrocarbon group, Ra and Rb together form a hydrocarboxy group. Preferred hydrocarboxy groups include saturated hydrocarboxy such as alkoxy (e.g. Ci-6 alkoxy, more usually C1-4 alkoxy such as ethoxy and methoxy, particularly methoxy), cycloalkoxy (e.g. C3-e cycloalkoxy such as cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy) and cycloalkylalkoxy (e.g. C3-6 cycloalkyl-C1-2 alkoxy such as cyclopropylmethoxy).
The hydrocarboxy groups can be substituted by various substituents as defined herein. For example, the alkoxy groups can be substituted by halogen (e.g. as in difluoromethoxy and trifluoromethoxy), hydroxy (e.g. as in hydroxyethoxy), C1-2 alkoxy (e.g. as in methoxyethoxy), hydroxy-C1-2 alkyl (as in hydroxyethoxyethoxy) or a cyclic group (e.g. a cycloalkyl group or non-aromatic heterocyclic group as hereinbefore defined). Examples of alkoxy groups bearing a non-aromatic heterocyclic group as a substituent are those in which the heterocyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, C1-4-alkyl-piperazines, C3-7-cycloalkyl- piperazines, tetrahydropyran or tetrahydrofuran and the alkoxy group is a C1-4 alkoxy group, more typically a Ci-3 alkoxy group such as methoxy, ethoxy or n-propoxy.
Alkoxy groups substituted by a monocyclic group such as pyrrolidine, piperidine, morpholine and piperazine and N-substituted derivatives thereof such as N-benzyl, N- C1-4 acyl and N-C1-4 alkoxycarbonyl. Particular examples include pyrrolidinoethoxy, piperidinoethoxy and piperazinoethoxy.
When Ra is a bond and Rb is a Cw2 hydrocarbon group, examples of hydrocarbon groups Ra-Rb are as hereinbefore defined. The hydrocarbon groups may be saturated groups such as cycloalkyl and alkyl and particular examples of such groups include methyl, ethyl and cyclopropyl. The hydrocarbon (e.g. alkyl) groups can be substituted by various groups and atoms as defined herein. Examples of substituted alkyl groups include alkyl groups substituted by one or more halogen atoms such as fluorine and chlorine (particular examples including bromoethyl, chloroethyl and trifluoromethyl), or hydroxy (e.g. hydroxymethyl and hydroxyethyl), Ci-8 acyloxy (e.g. acetoxymethyl and benzyloxymethyl), amino and mono- and dialkylamino (e.g. aminoethyl, methylaminoethyl, dimethylaminomethyl, dimethylaminoethyl and terf-butylaminomethyl), alkoxy (e.g. C1-2 alkoxy such as methoxy - as in methoxyethyl), and cyclic groups such as cycloalkyl groups, aryi groups, heteroaryl groups and non-aromatic heterocyclic groups as hereinbefore defined).
Particular examples of alkyl groups substituted by a cyclic group are those wherein the cyclic group is a saturated cyclic amine such as morpholine, piperidine, pyrrolidine, piperazine, Ci-4-alkyl-piperazines, C3-7-cycloalkyl-piperazines, tetrahydropyran or tetrahydrofuran and the alkyl group is a Ci-4 alkyl group, more typically a C1-3 alkyl group such as methyl, ethyl or n-propyl. Specific examples of alkyl groups substituted by a cyclic group include pyrrolidinomethyl, pyrrolidinopropyl, morpholinomethyl, morpholinoethyl, morpholinopropyl, piperidinylmethyl, piperazinomethyl and N- substituted forms thereof as defined herein.
Particular examples of alkyl groups substituted by aryl groups and heteroaryl groups include benzyl and pyridylmethyl groups.
When Ra is SO2NR0, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbon group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb where Ra is SO2NR0 include aminosulphonyl, C1-4 alkylaminosulphonyl and di-C-ι-4 alkylaminosulphonyl groups, and sulphonamides formed from a cyclic amino group such as piperidine, morpholine, pyrrolidine, or an optionally N-substituted piperazine such as N-methyl piperazine.
Examples of groups Ra-Rb where Ra is SO2 include alkylsulphonyl, heteroarylsulphonyl and arylsulphonyl groups, particularly monocyclic aryl and heteroaryl sulphonyl groups. Particular examples include methylsulphonyl, phenylsulphonyl and toluenesulphonyl.
When Ra is NR0, Rb can be, for example, hydrogen or an optionally substituted C1-8 hydrocarbon group, or a carbocyclic or heterocyclic group. Examples of Ra-Rb where Ra is NR0 include amino, C1-4 alkylamino (e.g. methylamino, ethylamino, propylamino, isopropylamino, terf-butylamino), di-C1-4 alkylamino (e.g. dimethylamino and diethylamino) and cycloalkylamino (e.g. cyclopropylamino, cyclopentylamino and cyclohexylamino).
In one general embodiment, when T is N and a is 0, Ar1 may be other than a pyrimidin-4- yl group bearing a substituent at the 2-position thereof.
Specific Embodiments of and Preferences for Ar1, Ar2, and R1 to R4
In this section, the various definitions of Ar1, Ar2, and R1 to R4 set out below apply to each of the general formulae (1), (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5) unless the context indicates otherwise. Each of the various definitions of Ar1, Ar2, and R1 to R4 set out below may be combined with each other and with each of the general formulae (1), (1a), (2), (2a), (2b), (2c), (3), (3a), (4), (4a) and (5).
Ar1 Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 (more preferably up to 3, for example up to 2) heteroatoms selected from O, IM and S, and being optionally substituted by one or more substituents R1.
The 5- to 10-membered aryl or heteroaryl groups may be as set out above in the General Preferences and Definitions section.
Preferred aryl and heteroaryl groups are monocyclic 5- and 6-membered rings containing up to 2 and more preferably up to 1 heteroatom selected from O, N and S.
Particular aryl and heteroaryl rings are optionally substituted phenyl, thiophene (e.g. 2- thienyl & 3-thienyl), furan (e.g. 2-furyl & 3-furyl), pyridine (e.g. 2-pyridyl, 3-pyridyl & 4- pyridyl), and pyrazole (e.g. 3-pyrazolyl & 4-pyrazolyl) rings.
More particularly, the aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3- thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl rings, each optionally substituted by one or more substituent groups R1.
El
The aryl or heteroaryl ring Ar1 can be optionally substituted by one or more substituents R1.
Typically, each aryl or heteroaryl ring is substituted by 0, 1, 2 or 3 substituents R1.
More typically, each aryl or heteroaryl ring is substituted by 0, 1 or 2 substituents R1 and more preferably by 0 or 1 substituents.
In one embodiment, the aryl or heteroaryl ring is unsubstituted.
In another embodiment, the aryl or heteroaryl ring is substituted by 1 substituent R1.
In another embodiment, the aryl or heteroaryl ring is substituted by 2 substituents R1.
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 8-membered (e.g. 3 to 7-membered) carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3. The definitions of halogen, Ra-Rb; and 3 to 8-membered (e.g. 3 to 7-membered) carbocyclic or heterocyclic rings may be as set out above in the General Preferences and Definitions section.
In a preferred group of compounds, R1 is halogen; cyano; or a group Raa-Rbb;
Raa is a bond, O, CO, OC(O), C(O)O, NRCCC(O), C(O)NRCC, NRCO, OC(O)O, NR00C(O)O, OC(O)NR00, NR00C(O) NRC0, S, SO, SO2, SO2NR00 or NR00SO2 wherein
Rbb is:
• hydrogen; or
• a 3 to 8-membered non-aromatic carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a 5- or 6-membered aryl or heteroaryl group containing up to 4 (e.g up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a C1-I2 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(R°°)2; o 3 to 8-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g. up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, OC(O), NR00C(O), OC(NR00), C(O)O, C(O)NR00, NR00, OC(O)O, NR00C(O)O, OC(NR00)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2 , NR00, SO2NR00 and NR00SO2; R00 is hydrogen or a saturated C1-4 hydrocarbon group; R3a is oxo; halogen; cyano; a group Raa-Ree; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C1-4 alkyl, CM acyl, Ci-4 alkoxycarbonyl or C1-4 alkylsulphonyl;
Ree is:
■ hydrogen; or
■ a C1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(ROC)2; or
■ a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the C1-4 alkyl and C1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms.
In another preferred group of compounds, R1 is halogen; cyano; or a group Raa-Rbb';
Raa is a bond, O, CO, OC(O), C(O)O1 NR00C(O), C(O)NR00, NRCC, OC(O)O, NR00C(O)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2, SO2NR00 or NR00SO2 wherein
Rbb' is:
• hydrogen; or
• a 3 to 7-membered non-aromatic carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a 5- or 6-membered aryl or heteroaryl group containing up to 4 (e.g up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(RCC)2; o 3 to 7-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g. up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; wherein one to three but not all of the carbon atoms of the Ci-12 acyclic hydrocarbon group may optionally be replaced by O, CO, OC(O), NR00C(O), OC(NR00), C(O)O, C(O)NR00, NR00, OC(O)O, NR00C(O)O, OC(NRC0)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2 , NR00, SO2NR00 and NR00SO2;
R00 is hydrogen or a saturated C^ hydrocarbon group;
R3a is oxo; halogen; cyano; a group Raa-Ree'; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C1-4 alkyl, C1-4 acyl, C1-4 alkoxycarbonyl or C1-4 alkylsulphonyl;
Ree' is hydrogen; or a C1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(R00)2.
In the foregoing definitions of Rbb and Rbb', the the C1-12 acyclic hydrocarbon group may be unsubstituted or substituted. Where it is substituted, preferably it bears no more than 3 substituents, and preferably no more than one of the substituents is a cyclic group.
In the foregoing definitions of Rbb and Rbb , the 3 to 8-membered (e.g. 3 to 7-membered) non-aromatic carbocyclic or heterocyclic ring (whether attached directly to Raa or via the C1-I2 acyclic hydrocarbon group) is preferably selected from azetidine, pyrrolidine, piperidine, piperazine, tetrahydropyran, tetrahydrothiopyran, morpholine, thiomorpholine (and the S-oxide and the S,S-dioxides thereof) each optionally substituted by up to 2, and more preferably up to 1 substituents R3a.
In an alternative embodiment within Rbb, the 3 to 8-membered non-aromatic carbocyclic or heterocyclic ring (whether attached directly to Raa or via the C1--I2 acyclic hydrocarbon group) is a bridged bicyclic ring such as an aza-bicyclo[2.2.2]octane or aza- bicyclo[3.2.1]octane group, each optionally substituted by one or two C1-4 alkyl (e.g. methyl) groups.
In another preferred group of compounds, R1 is selected from: halogen;
CO2R5 wherein R5 is hydrogen or C1-6 alkyl;
SO2R5;
C1-4 alkyl optionally substituted by hydroxy or C1-2 alkoxy or one or more fluorine atoms;
C1-4 alkoxy optionally substituted by hydroxy or Ci-2 alkoxy or one or more fluorine atoms; or a group Q, C(O)NHQ, HNC(O)Q, C(O)NH-AIk-Q, HNC(O)-AIk-Q, NH-AIk-Q, CH2Q,
S(O)Q, SO2Q, C(O)Q or O-Alk(OH)p-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH; and Q is selected from: a saturated or partially unsaturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, Ci-4 alkyl, hydroxy- Ci-4 alkyl, amino-Ci-4 alkyl, mono- or di-C1-4 alkylamino-Ci-4 alkyl, amino, mono- or di-C1-4 alkylamino, Ci-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9 wherein the C1-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C1-4 alkylamino or phenyl;
O-Alk-Q' where AIk is as defined above and Q' is an optionally substituted saturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 as hereinbefore defined or a group NR7R8;
O-Q" where Q" is a saturated or partially unsaturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-C1-4 alkyl, mono- or di- C1-4 alkylamino-C1-4 alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and CJi-C1-4 alkylaminocarbonyl; a 5- or 6- membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF3, C1-4 alkyl, hydroxy-C1-4 alkyl,
Figure imgf000030_0001
alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or di-Ci-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di- C1-4 alkylaminocarbonyl; and
R9 is C1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C1-4 alkyl, halogen, Ci-4 alkoxy or cyano.
In a more preferred group of compounds, R1 is selected from: halogen;
CO2R53 wherein R5a is C1-6 alkyl; SO2R5;
Ci-4 alkyl optionally substituted by hydroxy or C1-2 alkoxy; C1-4 alkoxy optionally substituted by hydroxy or Ci-2 alkoxy; or a group Q, CH2Q, S(O)Q, SO2Q, C(O)Q or O-Alk(OH)p-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH; and Q is selected from: a saturated or partially unsaturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-Ci-4 alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9 wherein the Ci-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C1-4 alkylamino or phenyl;
O-Alk-Q' where AIk is as defined above and Q' is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het1 as hereinbefore defined or a group NR7R8;
O-Q" where Q" is a saturated or partially unsaturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, Ci-4 alkyl, hydroxy- C1-4 alkyl, amino-Ci-4 alkyl, mono- or di-C-M alkylamino-C^ alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C^4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; a 5- or 6- membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF3, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-Ci-4 alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di- C1-4 alkylaminocarbonyl; and
R9 is C1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C1-4 alkyl, halogen, C1-4 alkoxy or cyano.
In another preferred group of compounds, R1 is selected from: halogen;
CO2R5a wherein R5a is C1-6 alkyl;
SO2R5; C1-4 alkyl optionally substituted by hydroxy or C1-2 alkoxy;
C1-4 alkoxy optionally substituted by hydroxy or C1-2 alkoxy; or a group Q, CH2Q, S(O)Q, SO2Q, C(O)Q or O-Alk-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms provided that there are at least 2 carbon atoms in line between O and Q; and Q is selected from: a saturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or Ci-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9;
O-Alk-Q' where AIk is as defined above and Q' is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het1 as hereinbefore defined or a group NR7R8; and
R9 is C1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryi groups are optionally substituted by C1-4 alkyl, halogen, C1-4 alkoxy or cyano.
When R1 is a group O-Alk-Q, the moiety AIk may typically be selected from CH2CH2, CH2CH2CH2, CH2CH(Me), CH2CMe2, CH2CH2CH(Me) and CH2CH2CMe2, and preferably is selected from CH2CH2 and CH2CH2CH2.
In one embodiment, the group Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl;
SO2R5a; hydroxy; and
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9; where R9 is as hereinbefore defined.
In another embodiment, the group Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from Ci-4 alkyl, Ci-4 acyl, Ci-4 alkoxycarbonyl, Ci-4 alkylsulphonyl, aminocarbonyl, and mono- and di-Ci-4 alkylaminocarbonyl; hydroxy; and
NR7R8 where R7 is hydrogen or Ci-4 alkyl; and R8 is hydrogen, Ci-4 alkyl, SO2R9 or COR9; where R9 is as hereinbefore defined.
One preferred group of substituents R1 is represented by the formula:
Figure imgf000033_0001
where the asterisk indicates the point of attachment to the group Ar1;
Y is a bond, 0-AIk- (where AIk is as hereinbefore defined), or a C1-3 alkylene group; and
B is O, NH, CH2 or a group NR10; and
R10 is selected from Ci-4 alkyl, Ci-4 acyl, carbamoyl, mono- and di-Ci.4 alkylcarbamoyl,
Ci-4 alkoxycarbonyl and Ci-4 alkylsulphonyl.
When Ar1 is a phenyl or other 6-membered aromatic ring such as pyridyl, it is preferred that a substituent R1 is present at the para or 4-position of the ring. It is further preferred that only a single substituent R1 is present and that the said single substituent is located at the para or 4-position of the ring.
Particular groups R1 are those found in the compounds set out below in the Examples section of this application.
Ar2 Ar2Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 (more preferably up to 3, for example up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2.
The 5- to 10-membered aryl or heteroaryl rings may be as set out above in the General Preferences and Definitions section.
Preferred aryl and heteroaryl rings are monocyclic 5- and 6-membered rings containing up to 3 and more preferably 1 or 2 heteroatoms selected from O, N and S, and bicyclic 6.5 fused rings containing up to 3 heteroatoms and more preferably 1 or 2 heteroatoms selected from O, N and S.
In one embodiment, the aryl and heteroaryl rings are selected from phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine, pyrrolopyridine and pyrazole rings, each optionally substituted by one or more substituents R2. In another embodiment, the aryl and heteroaryl rings are selected from phenyl, thiophene, furan, indole, indazole, pyrrolopyridine, benzoimidazole, benzofuran, pyridine and pyrazole rings, each optionally substituted by one or more substituents R2. For example, in another embodiment, the aryl and heteroaryl rings can be selected from phenyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4-pyrazole, 5-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyl, 5-indolyl, 6-indolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6- indazolyl, benzimidazol-4-yl, 3-benzofuranyl, 4-benzofuranyl and pyrrolo[2,3-b]pyridine (e.g. pyrrolo[2,3-b]pyridin-4-yl) rings, each optionally substituted by one or more substituent groups R2.
In another embodiment, the aryl and heteroaryl rings can be selected from phenyl, 2- thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3- indolyl, 4-indolyl, 3-indazolyl, 4-indazolyl, benzimidazol-4-yl, 3-benzofuranyl and A- benzofuranyl rings, each optionally substituted by one or more substituent groups R2.
In another embodiment, the aryl and heteroaryl rings are optionally substituted phenyl, thiophene (e.g. 2-thienyl & 3-thienyl), furan (e.g. 2-furyl & 3-furyl), indole (e.g. 3-indolyl & 4-indolyl), benzofuran (e.g. 3-benzofuranyl & 4-benzofuranyl), pyridine (e.g. 2-pyridyl, 3- pyridyl & 4-pyridyl), and pyrazole (e.g. 3-pyrazolyl & 4-pyrazolyl) rings. More particularly, within this embodiment, the aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazolyl, 4-pyrazolyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyi, 3-benzofuranyl and 4-benzofurany! rings, each optionally substituted by one or more substituent groups R2.
In one subset of compounds, particularly preferred groups Ar2 are optionally substituted phenyl rings.
In another embodiment, Ar2 is selected from (i) optionally substituted 5-membered heteroaryl rings containing 1 or 2 heteroatom ring members (more preferably 2 nitrogen heteroatom ring members), at least one of which is nitrogen; and (ii) optionally substituted 9-membered bicyclic heteroaryl groups containing 1 to 3 heteroatom ring members (more preferably 1 or 2 nitrogen heteroatom ring members) of which at least 1 is nitrogen.
Within this embodiment, preferred heteroaryl rings are selected from optionally substituted indole, indazole, pyrrolopyridine and pyrazole rings.
More particularly, the heteroaryl rings can be selected from indazol-4-yl, indazol-5-yl, indol-4-yl, indol-5-yl, pyrrolo[2,3-b]pyridin-4-yl, pyrrolo[2,3-b]pyridin-5-yl, pyrazol-2-yl and pyrazol-3-yl, each optionally substituted as defined herein.
For example, the heteroaryl rings can be selected from unsubsituted indazol-4-yl, unsubsituted indazol-5-yl, unsubsituted indol-4-yl, unsubsituted indol-5-yl, unsubsituted pyrrolo[2,3-b]pyridin-4-yl, unsubsituted pyrrolo[2,3-b]pyridin-5-yl, 1-benzylpyrazol-2-yl and 1-benzylpyrazol-3-yl.
The aryl or heteroaryl ring Ar2 can be optionally substituted by by one or more substituents R2.
Typically, each aryl or heteroaryl ring is substituted by 0, 1 , 2 or 3 substituents R2.
More typically, each aryl or heteroaryl ring is substituted by 0, 1 or 2 substituents R2.
In one embodiment, each aryl or heteroaryl ring is unsubstituted.
In another embodiment, each aryl or heteroaryl ring is substituted by 1 substituent R2.
In a further embodiment, each aryl or heteroaryl ring is substituted by 2 substituents R2.
R2 is halogen; cyano; nitro; or a group Ra-Rd; wherein Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NRC, SO2NR0 or NR0SO2; and
Rd is hydrogen; a Ci-4 aikyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C-ι-4 alkoxy, and wherein the C1-4 alkyl and C1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms.
In one subgroup of compounds, R2 is halogen; cyano; nitro; or a group Ra-Rd; where Ra is a bond, O, CO, X1C(X2), C(X2)X\ X1C(X2JX1, S, SO, SO2, NR0, SO2NR0 or NR0SO2; and Rd is hydrogen or a Ci-4 alkyl group optionally substituted by one or more fluorine atoms.
The moiety Ra may be as set out in the General Preferences and Definitions section above.
More typically, R2 is absent or is selected from halogen; Ci-4 alkyl optionally substituted with one or more fluorine atoms; Ci-4 alkoxy optionally substituted with one or more fluorine atoms; cyclopropyl; cyclopropoxy; cyano; CONH2; Ci-4 alkylsulphonyl; C1-4 acylamino; C1-4 alkylsulphonylamino; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, Ci-4 alkyl and C1-4 alkoxy.
More preferably, R2 is absent or is selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; and methylsulphonylamino; and a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from chlorine, fluorine, cyano, methyl and methoxy.
When Ar2 is a phenyl group, preferably it is unsubstituted or substituted by 1 , 2 or 3 substituents selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; and methylsulphonylamino.
When one substituent is present on the phenyl ring, it is preferred that the substituent is present at an orf/?o-position on the ring. When two substituents are present on the phenyl ring, it is preferred that at least one, and preferably both are located at an o/fΛo-position on the ring.
One sub-set of particularly preferred groups Ar2 (which are unsubstituted except where specified) consists of phenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2- chloro-6-fluorophenyl, 2,6-dichlorophenyl, 2,6-dimethylphenyl, 3-indolyl, 4-indolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thienyl and 3-thienyl.
Another sub-set of particularly preferred groups Ar2 (which are unsubstituted except where specified) consists of phenyl, 2,6-difluorophenyl, 2-chloro-6-fluorophenyl, 2- chlorophenyl, 2-fluorophenyl, 3-indolyl, 4-indolyl, 2-pyrazolyl, 5-pyrazolyl, 2-thienyl and 3-thienyl.
When b is 1 , Ar2 may be other than a phenyl group bearing a substituent at the meta- position thereof wherein the substituent is an optionally substituted alkyl group, an optionally substituted amino group or a group containing the moiety C(O)-N where the carbon atom of the carbonyl group is attached to the mefa-position of the phenyl group. The term "optionally substituted amino group" in this context includes any group (apart from nitro) containing a nitrogen atom wherein the said nitrogen atom is attached to the mefø-position of the phenyl group.
The compound of the formula (1) may be other than a compound wherein T is O, b is 0 and Ar2 is a 4-methylphenyl group.
Alternatively or additionally, the compound of the formula (1) may be other than a compound wherein b is 0 and Ar2 is a bicyclic group containing at least one nitrogen ring member, the said nitrogen ring member being attached directly to the ring containing the moiety T.
Alternatively, or additionally, the compound of formula (1) may be other than: 2-(3-chlorophenyl)-4-(4-methoxyphenyl)-1 H-imidazole-5-carboxamide; and/or 2-(4-chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide; and/or 2-(2,6-difluorophenyl)-4-(3-(hydroxymethyl)phenyl)-1 H-imidazole-5-carboxamide; and/or 2-(furan-3-yl)-4-(thiophen-2-yl)-1H-imidazole-5-carboxamide; and/or 2-(benzo[b]thiophen-3-yl)-5-(thiophen-2-yl)oxazole-4-carboxamide; and/or 2-(benzo[b]thiophen-3-yl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(1 H-benzo[d]imidazol-2-yl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(2-methoxyphenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(3-cyanophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(4-(dimethylamino)phenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 5-(4-methoxyphenyl)-2-(quinolin-3-yl)oxazole-4-carboxamide; and/or 2-(3-methoxyphenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2,5-ib/s(4-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(2,6-difluorophenyl)-5-(3-methoxyphenyl)oxazole-4-carboxamide; and/or 2-(2,6-difluorophenyl)-5-(2-methoxyphenyl)oxazole-4-carboxamide; and/or teAf-butyl 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzylcarbamate.
Alternatively, or additionally, the compound of formula (1) may be other than any one or more (in any combination) of:
2-(2,6-difluorophenyl)-5-(2,4-dimethoxyphenyl)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(2-fluoro-4-methoxyphenyl)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(3,4,5-trimethoxyphenyl)oxazole-4-carboxamide;
2-(2,6-difluorophenyl)-5-(2,4-dimethoxyphenylamino)oxazole-4-carboxamide; and
2-(2,6-difluorophenyl)-5-(4-(piperidin-1-yl)phenyl)oxazole-4-carboxamide.
Preferred Sub-groups of Compounds
One preferred sub-group of compounds is the group of compounds represented by the formula (5):
Figure imgf000038_0001
(5) or salts, solvates or tautomers thereof; wherein G1 is C(O), C(O)NH or HNC(O); and
(i) when G1 is C(O), then G2 is selected from OH and a group Het where Het is a 5 to 7 membered non-aromatic heterocyclic ring containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the group Het being linked to the C(O) group by a nitrogen ring member and being optionally substituted by one or two substituents selected from C1-4 alkyl, hydroxy-C1-4 alkyl, hydroxy, amino-C1-4 alkyl, and mono- or di-Ci-2-alkylamino-C1-4 alkyl; or
(ii) when G1 is C(O)NH or HNC(O), then G2 is selected from: ■ a 5 to 8 membered non-aromatic heterocyclic ring Het' containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the heterocyclic ring being optionally substituted by one or two substituents selected from C1-4 alkyl, hydroxy-Ci-4 alkyl, hydroxy, amino-C1-4 alkyl, and mono- or di-C1-2-alkylamino-C1-4 alkyl; and
■ C1-4 alkyl substituted by a group Het' or a group NR7R8, where R7 and R8 are the same or different and each is hydrogen or C1-4 alkyl; and Het' is as hereinbefore defined.
Within formula (5), one sub-group of compounds is the sub-group wherein Ar2 is an optionally substituted phenyl ring as hereinbefore defined. Particularly preferred compounds are those wherein Ar2 is a 2,6-difluorophenyl ring or a 2-fluoro-6- chlorophenyl ring.
General
For the avoidance of doubt, it is to be understood that each general and specific preference, embodiment and example of the groups Ar1 may be combined with each general and specific preference, embodiment and example of the group Ar2 as defined herein and that all such combinations are embraced by this application.
The various functional groups and substituents making up the compounds of the formula (1 ) are typically chosen such that the molecular weight of the compound of the formula (1) does not exceed 1000. More usually, the molecular weight of the compound will be less than 750, for example less than 700, or less than 650, or less than 600, or less than 550. More preferably, the molecular weight is less than 525 and, for example, is 500 or less.
Particular compounds of the invention are as illustrated in the examples below.
Salts, Solvates, Tautomers, Isomers, N-Oxides. Esters, Prodrugs and Isotopes
Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvate, and protected forms thereof, for example, as discussed below.
Many compounds of the formula (1) can exist in the form of salts, for example acid addition salts or, in certain cases salts of organic and inorganic bases such as carboxylate, sulphonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds of the formula (1) include the salt forms of the compounds.
Salt forms may be selected and prepared according to methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002.
Acid addition salts may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L- ascorbic), L-aspartic, benzenesulphonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulphonic, (+)-(1 S)-camphor-10-sulphonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulphuric, ethane-1 ,2-disulphonic, ethanesulphonic, 2- hydroxyethanesulphonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), α-oxoglutaric, glycolic, hippuric, hydrobromic, hydrochloric, hydriodic, isethionic, (+)-L-lactic, (±)-DL-lactic, lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulphonic, naphthalene-2-sulphonic, naphthalene-1,5-disulphonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, L-pyroglutamic, salicylic, 4-amino-salicyiic, sebacic, stearic, succinic, sulphuric, tannic, (+)-L-tartaric, thiocyanic, p-toluenesulphonic, undecylenic and valeric acids, as well as acylated amino acids and cation exchange resins.
One particular group of salts consists of salts formed from hydrochloric, hydriodic, phosphoric, nitric, sulphuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulphonic, toluenesulphonic, methanesulphonic, ethanesulphonic, naphthalenesulphonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids.
For example, if the compound is anionic, or has a functional group which may be anionic (e.g., -COOH may be -COO"), then a salt may be formed with a suitable cation. Examples of suitable inorganic cations include, but are not limited to, alkali metal ions such as Na+ and K+, alkaline earth cations such as Ca2+ and Mg2+, and other cations such as Al3+. Examples of suitable organic cations include, but are not limited to, ammonium ion (i.e., NH4 +) and substituted ammonium ions (e.g., NH3R+, NH2FV, NHR3 +, NR4 +). Examples of some 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(CHa)4 +.
Where the compounds of the formula (1) contain an amine function, these may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to the skilled person. Such quaternary ammonium compounds are within the scope of formula (1).
The salt forms of the compounds of the invention are typically pharmaceutically acceptable salts, and examples of pharmaceutically acceptable salts are discussed in Berge et al., 1977, "Pharmaceutically Acceptable Salts," J. Pharm. ScL, Vol. 66, pp. 1- 19. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.
Compounds of the formula (1) containing an amine function may also form N-oxides. A reference herein to a compound of the formula (1) that contains an amine function also includes the N-oxide.
Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N- oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle.
N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as hydrogen peroxide or a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4th Edition, Wiley Interscience, pages 1200-12-1. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m- chloroperoxybenzoic acid (MCPBA), for example, in an inert solvent such as dichloromethane.
Compounds of the formula (1) may exist in a number of different geometric isomeric, and tautomeric forms and references to compounds of the formula (1) include all such forms. For the avoidance of doubt, where a compound can exist in one of several geometric isomeric or tautomeric forms and only one is specifically described or shown, all others are nevertheless embraced by formula (1).
For example, in compounds of the formula (1) wherein T is NH, the imidazole group may take either of the following two tautomeric forms A and B. For simplicity, the general formula (1) illustrates form A but the formula is to be taken as embracing both tautomeric forms.
Figure imgf000042_0001
Where compounds of the formula (1) contain one or more chiral centres, and can exist in the form of two or more optical isomers, references to compounds of the formula (1) include all optical isomeric forms thereof (e.g. enantiomers, epimers and diastereoisomers), either as individual optical isomers, or mixtures (e.g. racemic mixtures) or two or more optical isomers, unless the context requires otherwise.
The optical isomers may be characterised and identified by their optical activity (i.e. as + and - isomers, or d and / isomers) or they may be characterised in terms of their absolute stereochemistry using the "R and S" nomenclature developed by Cahn, lngold and Prelog, see Advanced Organic Chemistry by Jerry March, 4th Edition, John Wiley & Sons, New York, 1992, pages 109-114, and see also Cahn, lngold & Prelog, Angew. Chem. Int. Ed. Engl., 1966, 5, 385-415.
Optical isomers can be separated by a number of techniques including chiral chromatography (chromatography on a chiral support) and such techniques are well known to the person skilled in the art. Where compounds of the formula (1) exist as two or more optical isomeric forms, one enantiomer in a pair of enantiomers may exhibit advantages over the other enantiomer, for example, in terms of biological activity. Thus, in certain circumstances, it may be desirable to use as a therapeutic agent only one of a pair of enantiomers, or only one of a plurality of diastereoisomers. Accordingly, the invention provides compositions containing a compound of the formula (1) having one or more chiral centres, wherein at least 55% (e.g. at least 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%) of the compound of the formula (1) is present as a single optical isomer (e.g. enantiomer or diastereoisomer). In one general embodiment, 99% or more (e.g. substantially all) of the total amount of the compound of the formula (1) may be present as a single optical isomer (e.g. enantiomer or diastereoisomer).
The compounds of the invention include compounds with one or more isotopic substitutions, and a reference to a particular element includes within its scope all isotopes of the element. For example, a reference to hydrogen includes within its scope 1H, 2H (D), and 3H (T). Similarly, references to carbon and oxygen include within their scope respectively 12C, 13C and 14C and 16O and 18O.
The isotopes may be radioactive or non-radioactive. In one embodiment of the invention, the compounds contain no radioactive isotopes. Such compounds are preferred for therapeutic use. In another embodiment, however, the compound may contain one or more radioisotopes. Compounds containing such radioisotopes may be useful in a diagnostic context.
Also encompassed by formula (1) are any polymorphic forms of the compounds, solvates (e.g. hydrates), complexes (e.g. inclusion complexes or clathrates with compounds such as cyclodextrins, or complexes with metals) of the compounds, and pro-drugs of the compounds. By "prodrugs" is meant for example any compound that is converted in vivo into a biologically active compound of the formula (1).
For example, 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. Such 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 of the formula -C(=O)OR wherein R is:
C1-7alkyl
(e.g., -Me, -Et, -nPr, -iPr, -nBu, -sBu, -iBu, -tBu);
C1-7aminoalkyl
(e.g., aminoethyl; 2-(N,N-diethylamino)ethyl; 2-(4-morpholino)ethyl); and acyloxy-C1-7alkyl
(e.g., acyloxymethyl; acyloxyethyl; pivaloyloxymethyl; acetoxymethyl;
1-acetoxyethyl;
1 -(1 -methoxy-1 -methyl)ethyl-carbonyloxyethyl;
1-(benzoyloxy)ethyl; isopropoxy-carbonyloxymethyl;
1-isopropoxy-carbonyloxyethyl; cyclohexyl-carbonyloxymethyl;
1 -cyclohexyl-carbonyloxyethyl; cyclohexyloxy-carbonyloxymethyl;
1-cyclohexyloxy-carbonyloxyethyl;
(4-tetrahydropyranyloxy)carbonyloxymethyl;
1-(4-tetrahydropyranyloxy)carbonyloxyethyl;
(4-tetrahydropyranyl)carbonyloxymethyl; and
1-(4-tetrahydropyranyl)carbonyloxyethyl).
Also, some prodrugs are activated enzymatically to yield the active compound, or a compound which, upon further chemical reaction, yields the active compound (for example, as in ADEPT, GDEPT, LIDEPT, etc.). For example, the prodrug may be a sugar derivative or other glycoside conjugate, or may be an amino acid ester derivative.
Biological Activity and Therapeutic Uses
Compounds of the invention have activity as inhibitors of FLT3 kinase and are useful in the prophylaxis or treatment of autoimmue diseases and in particular multiple sclerosis.
Therefore, in further aspects, the invention provides: • The use of a compound of the formula (1) or any sub-groups or examples thereof as defined herein for the manufacture of a medicament for the prophylaxis or treatment of an autoimmune disease such as multiple sclerosis.
• A method for the prophylaxis or treatment of an autoimmune disease such as multiple sclerosis, which method comprises administering to a subject in need thereof a compound of the formula (1) or any sub-groups or examples thereof as defined herein.
The activity of the compounds of the invention as inhibitors of FLT3 kinase can be measured using the assays set forth in the examples below and the level of activity exhibited by a given compound can be defined in terms of the IC50 value. Preferred compounds of the present invention are compounds having an IC50 value of less than 10 μM, more preferably less than 1 μM.
Experimental autoimmune encephalomyelitis (EAE) and Theiler's murine encephalitis virus-induced demyelinating disease (TMEV-IDD) are two clinically relevant murine models of multiple sclerosis (MS) (see (i) Raine CS: Biology of disease. The analysis of autoimmune demyelination: its impact upon multiple sclerosis. Lab Invest 1984, 50:608- 635; (ii) Steinman L: Assessment to the utility of animal models for MS and demyelinating disease in the design of rational therapy. Neuron 1999, 24:511-514; and (iii) Kevin G. Fuller et al., Mouse Models of Multiple Sclerosis: Experimental Autoimmune Encephalomyelitis and Theiler's Virus-Induced Demyelinating Disease, Autoimmunity: Methods and Protocols, (Series; Methods in Molecular Medicine), Volume: 102 , 2004, 339-361)
The usefulness of the compounds of formula (1) in treating multiple sclerosis can he demonstrated using either of the above models and in particular the experimental autoimmune encephalomyelitis (EAE) model described in the examples below.
The terms "treating" and "treatment" as used herein in the context of multiple sclerosis include any one or more of:
■ halting the progression of the disease;
■ slowing the progression of the disease;
■ modifying the progression of the disease; ■ providing symptomatic relief, e.g. by eliminating or reducing the severity of one or more symptoms;
■ extending periods of remission;
■ preventing relapses;
■ reducing the severity of relapses; and
■ preventing or slowing the progression from an initial period of relapsing-remitting MS to secondary progressive MS.
Symptoms of multiple sclerosis that may be eliminated or reduced in severity in accordance with the invention include any one or more symptoms, in any combination, selected from:
■ weakness and/or numbness in one or more extremities;
■ tingling of the extremities;
■ tight band-like sensations around the trunk or limbs;
■ tremor of one or more extremities;
■ dragging or poor control of one or both legs;
■ spastic or ataxic paraparesis;
■ paralysis of one or more extremities;
■ hyperactive tendon reflexes;
■ disappearance of abdominal reflexes;
■ Lhermitte's sign;
■ retrobulbar or optic neuritis;
■ unsteadiness in walking;
■ problems with balance,
■ increased muscle fatigue;
■ brain stem symptoms (diplopia, vertigo, vomiting);
■ disorders of micturition;
■ hemiplegia;
■ trigeminal neuralgia; ■ other pain syndromes;
■ nystagmus and ataxia;
■ cerebellar-type ataxia;
■ Charcot's triad; diplopia;
■ bilateral internuclear ophthalmoplegia;
■ myokymia or paralysis of facial muscles;
■ deafness;
■ tinnitus;
■ unformed auditory hallucinations (because of involvement of cochlear connections);
■ transient facial anesthesia or of trigeminal neuralgia;
■ urinary and/or faecal incontinence
■ bladder dysfunction euphoria;
■ depression;
■ fatigue;
■ dementia;
« dull, aching pain in the low back;
■ sharp, burning, poorly localized pains in a limb;
■ abrupt attacks of neurologic deficit;
■ dysarthria and ataxia;
■ paroxysmal pain and dysesthesia in a limb;
■ flashing lights;
■ paroxysmal itching;
■ tonic seizures;
■ changes in sensation;
■ visual problems;
■ muscle weakness; ■ difficulties with coordination and speech;
■ cognitive impairment;
■ overheating; and
■ impaired mobility and disability.
The compound may be used in a prophylactic sense during periods of remission in order to prevent or reduce the likelihood or severity of relapses or it may be used to treat patients who are suffering from a relapse. Preferably it is used in a prophylactic sense.
The compound of formula (1) will generally be administered to a subject in need of such administration, for example a human patient.
The compound will typically be administered in amounts that are therapeutically or prophylactically useful and which generally are non-toxic. However, in certain situations, the benefits of administering a compound of the invention may outweigh the disadvantages of any toxic effects or side effects, in which case it may be considered desirable to administer compounds in amounts that are associated with a degree of toxicity.
A typical daily dose of the compound can be up to 1000 mg per day, for example in the range from 0.01 milligrams to 10 milligrams per kilogram of body weight, more usually from 0.025 milligrams to 5 milligrams per kilogram of body weight, for example up to 3 milligrams per kilogram of bodyweight, and more typically 0.15 milligrams to 5 milligrams per kilogram of bodyweight although higher or lower doses may be administered where required.
By way of example, an initial starting dose of 12.5 mg may be administered 2 to 3 times a day. The dosage can be increased by 12.5 mg a day every 3 to 5 days until the maximal tolerated and effective dose is reached for the individual as determined by the physician. Ultimately, the quantity of compound administered will be commensurate with the nature of the disease or physiological condition being treated and the therapeutic benefits and the presence or absence of side effects produced by a given dosage regimen, and will be at the discretion of the physician. The compound of the formula (1) or a pharmaceutically acceptable salt thereof may be used as the sole therapeutic agent or it may be used in conjunction with other therapeutic agents such as steroids or interferons.
In one general embodiment of the invention, the compound of the formula (1) or pharmaceutically acceptable salt thereof is used as the sole therapeutic agent.
Methods for the Preparation of Compounds of the formula (1)
The compounds for use in accordance with the invention can be prepared by the processes described in PCT/GB2008/001612 and the examples therein.
The processes described in PCT/GB2008/001612 comprise: (a) the reaction of a compound of the formula (6A):
Figure imgf000049_0001
wherein Rx is hydrogen or a C1-4 alkyl group (preferably methyl or ethyl), with ammonia under conditions suitable for forming a primary amide group; or
(b) the partial hydrolysis of a compound of the formula (6B):
Figure imgf000049_0002
or
(c) when a is 0, the reaction of a compound of the formula (6C):
Figure imgf000049_0003
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent (e.g. an organotin reagent) suitable for introduction of a group Ar1, in the presence of a metal catalyst and in particular a palladium catalyst (for example under Suzuki coupling or Stille reaction conditions); or
(d) when a is 1 , the reaction of a compound of the formula (6C):
Figure imgf000050_0001
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH2-Ar1, in the presence of a metal catalyst and in particular a palladium catalyst; or
(e) when b is 0, the reaction of a compound of the formula (6D):
Figure imgf000050_0002
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with a boronic acid or boronate ester or organometallic reagent (e.g. an organotin reagent) suitable for introduction of a group Ar2, in the presence of a metal catalyst and in particular a palladium catalyst; or
(f) when b is 1 , the reaction of a compound of the formula (6D):
Figure imgf000050_0003
wherein LG is chlorine, bromine, iodine or trifluoromethanesulphonate; with an amine of the formula NH2-Ar2, in the presence of a metal catalyst and in particular a palladium catalyst; and
(g) optionally converting one compound of the formula (1) into another compound of the formula (1). Compounds in which a and b are both 0 and T is NH can be prepared by the sequence of reactions shown in Scheme 1.
Figure imgf000051_0001
Figure imgf000051_0002
Scheme 1
As shown in Scheme 1 , the (carbethoxymethylene)triphenyl phosporane 12 is reacted with the aroyl or heteroaroyl chloride 11 to give the triphenylphosporanylidene derivative 13. The reaction is typically carried out in a non-protic solvent such as dichloromethane at a low temperature, for example at around 0 0C, in the presence of the trimethylsilylating agent Λ/,O-fc/s(trimethylsilyl)acetamide. The triphenylphosporanylidene moiety is then oxidatively cleaved using an oxidising agent such as potassium peroxymonosulphate (Oxone®) in water/THF to give the substituted dioxopropionate ester 14. The ester 14 is then reacted with an aryl or heteroaryl aldehyde Ai^-CHO and ammonium acetate in acetic acid at an elevated temperature in excess of 100 0C (e.g. up to about 160 0C) in order to form the imidazole ester 15. Treatment of the imidazole ester 15 with aqueous ammonia at an elevated temperature (e.g. up to about 150 0C) gives the imidazolyl carboxamide 16.
As an alternative to forming the carboxamide group by reacting the imidazolyl ester 15 with ammonia, it may instead be hydrolysed to the carboxylic acid 17 which is then converted to the carboxamide 16 as shown in Scheme 2.
Figure imgf000052_0001
Scheme 2
Hydrolysis of the imidazolyl ester 15 may conveniently be carried out in standard manner using an alkali metal hydroxide such as aqueous potassium hydroxide with moderate heating, for example to a temperature in the range 50-60 0C.
The carboxylic acid 17 can be converted to the carboxamide 15 by reaction with ammonia in the presence of a reagent of the type commonly used in the formation of amide bonds. Examples of such reagents include 1,3-dicyclohexylcarbodiimide (DCC) (Sheehan θt al, J. Amer. Chem Soc. 1955, 77, 1067), 1-ethyl-3-(3'- dimethylaminopropyl)-carbodiimide (EDAC) (Sheehan et al, J. Org. Chem. (1961) 26, 2525), uronium-based coupling agents such as O-(7-azabenzotriazol-1-yl)-Λ/,Λ/,N',Λ/'- tetramethyluronium hexafluorophosphate (HATU) and phosphonium-based coupling agents such as 1-benzo-triazolyloxytris-(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) (Castro et al, Tetrahedron Letters (1990) 31, 205). Carbodiimide-based coupling agents are advantageously used in combination with 1 -hydroxy-7- azabenzotriazole (HOAt) (Carpino, J. Amer. Chem. Soc. (1993) 115, 4397) or 1- hydroxybenzotriazole (HOBt) (Konig et al, Chem. Ber., (1970) 103, 708, 2024-2034). A preferred coupling reagent is EDAC in combination with HOAt or HOBt.
The coupling reaction is typically carried out in a non-aqueous, non-protic solvent such as acetonitrile, dioxan, dimethylsulphoxide, dichloromethane, dimethylformamide or N- methylpyrrolidine, or in an aqueous solvent optionally together with one or more miscible co-solvents. The reaction can be carried out at room temperature.
An alternative synthetic route to compounds of the formula (1) where a and b are both 0 and T is NH is illustrated in Scheme 3.
Figure imgf000053_0001
Figure imgf000053_0002
Scheme 3
In Scheme 3, the β-keto-ester 18, which is either commercially available or can be made according to standard methods, is reacted with nitrous acid to give the the oxime 19. The nitrous acid can be generated in known fashion from sodium nitrite and an acid such as acetic acid. The oxime 19 is converted to the imidazolyl ester 15 by reaction with an aryl or heteroaryl aldehyde Ai^-CHO and ammonium acetate in acetic acid at an elevated temperature in excess of 100 0C (e.g. up to about 160 0C). The imidazoyl ester 15 is then converted to the carboxamide 16 by the series of reactions illustrated in Scheme 2 above.
Compounds in which a and b are both 0 and T is O can be prepared by the sequence of reactions shown in Scheme 4, which is based on the synthetic route described in J. Org. Chem. (1960) 25, 1151-1154.
Figure imgf000054_0001
Figure imgf000054_0002
Scheme 4
In Scheme 4, the β-keto-ester 18 is brominated using pyridinium bromide perbromide in ethanol in the presence of triethylamine to give the α-bromo-β-keto-ester 20 which is then reacted with an alkali metal (e.g. sodium) salt of an aryl or heteroaryl carboxylic acid Ai^-COaH in ethanol at a temperature in excess of 100 0C (e.g. up to about 120 0C) to give the diester 21. The diester 21 is cyclised to the oxazole ester 22 by treatment with ammonium acetate in acetic acid with heating (e.g. to reflux). The oxazole ester 22 is then hydrolysed using an alkali metal hydroxide (e.g. lithium hydroxide) in an aqueous solvent (e.g. aqueous THF) to give the carboxylic acid 23 which is converted to the carboxamide 24 by reaction with ammonia in the presence of EDAC and HOBt under conditions of the type described above.
An alternative route to compounds in which a and b are both 0 and T is O is shown in Scheme 5.
Figure imgf000055_0001
Figure imgf000055_0002
Scheme 5
In Scheme 5, the N-(diphenylmethylene)glycine ethyl ester 25 is treated with a base such as potassium terf-butoxide in a dry solvent such as THF with cooling to a low temperature (e.g. a temperature of about -78 0C), followed by reaction with the acid chloride 11. The resulting α-amino-β-keto-ester 26 is converted to the amide 27 by reaction with a carboxylic acid Ai^-CO2H in the presence of EDAC and HOBt under the amide forming conditions described above. The amide 27 is converted to the oxazole ester 22 by a cyclodehydration reaction brought about by heating with POCI3. The oxazole ester 22 can then be hydrolysed (e.g. by using potassium hydroxide) to the carboxylic acid 23 and converted to the amide 24 as described above in relation to Scheme 4.
A further route to compounds of the formula 1 wherein a and b are both O and T is O is shown in Scheme 6.
Figure imgf000055_0003
Figure imgf000055_0004
Scheme 6
In Scheme 6, aminomaiononitrile 29 is reacted with the aroyl or heteroaroyl chloride 28 in a high boiling polar aprotic solvent such as N-methylpyrrolidone at an elevated temperature above 100 0C (e.g. up to 120 0C) to give the amino-cyano-oxazole 30 which is converted to the corresponding bromo-compound 31 by treatment with copper bromide and ferf-butyl nitrite in dry acetonitrile. The nitrile group is then partially hydrolysed in concentrated sulphuric acid to give the the bromo-oxazolyl carboxamide 32.
The aryl or heteroaryl group Ar1 can be added by reacting the oxazolyl carboxamide 32 with a suitable aryl or heteroaryl boronic acid Ar1-B(OH)2 or boronate ester Ar1-B(OR)2 (where R is an alkyl group or the two groups R combine to form a linked divalent group such as a pinacol residue) under Suzuki coupling conditions or with an aryl or heteroaryl tin compound Ar1 -SnR3 (where R is an alkyl group) under Stille reaction conditions.
Thus, for example, the bromo-oxazolyl carboxamide 32 may be reacted with a suitable aryl or heteroaryl boronate or boronic acid Ar1 -B(OH)2 or boronate ester Ar1-B(OR)2 in the presence of a palladium catalyst such as tetrakis(triphenylphosphine)palladium or bis (1 ,1'-ό/s(diphenylphosphino)-ferrocene) palladium dichloride (Pd(dppf)2CI2) and a base (e.g. a carbonate such as potassium carbonate). The reaction may be carried out in a polar solvent, for example acetonitrile or an aqueous solvent such as aqueous ethanol, or an ether such as dimethoxyethane, and the reaction mixture is typically subjected to heating, for example to a temperature of 80 0C or more, e.g. a temperature in excess of 100 0C, for example a temperature of up to about 150 0C.
Many boronates suitable for use in preparing compounds of the invention are commercially available, for example from Boron Molecular Limited of Noble Park, Australia, or from Combi-Blocks Inc, of San Diego, USA. Where the boronates are not commercially available, they can be prepared by methods known in the art, for example as described in the review article by Miyaura and Suzuki, Chem. Rev. (1995) 95, 2457. Thus, boronates can be prepared by reacting the corresponding bromo-compound with an alkyl lithium such as butyl lithium and then reacting with a borate ester. The resulting boronate ester derivative can, if desired, be hydrolysed to give the corresponding boronic acid. The Stille reaction with an aryl or heteroaryl tin compound Ar1 -SnR3 is typically carried out in the presence of a palladium catalyst, for example tetrakis(triphenylphosphine)palladium, in solvents and under conditions generally similar to those used for Suzuki coupling reactions.
Figure imgf000057_0001
Figure imgf000057_0002
Scheme 7
In Scheme 7, ethyl isocyanoacetate 33 is reacted with the aroyl or heteroaroyl chloride 11 to give the oxazole ester 34. The reaction is typically carried out in a polar aprotic solvent such as acetonitrile in the presence of a non-interfering base such as triethylamine or diazabicyclo[5.4.0]undec-7-ene (DBU), usually with heating, for example to a temperature in excess of 100 0C. The conditions for this reaction step may be as described in Organic Letters (2006) 8, 5231-5234. The oxazole ester 34 is then converted to the iodo-oxazole ester 35 by reaction with lithium ό/s(trimethylsilyl)amide in THF at low temperature (e.g. -78 0C) followed by iodine.
The iodo-oxazole 35 is then used as substrate for a Suzuki coupling reaction with a boronic acid Ai^-B(OH)2 or boronate Ar^-B(OR)2 under the conditions described above to give the oxazole ester 22. The oxazole ester 22 is then converted via the carboxylic acid 23 to the carboxamide 24 in the manner described above.
In a variation on the route described in Scheme 7 above, the iodo-oxazole ester 35 is hydrolysed to the carboxylic acid 36 and then converted to the carboxamide 37 before the Suzuki coupling step, as shown in Scheme 8.
Figure imgf000058_0001
Figure imgf000058_0002
Scheme 8
Compounds of the formula 1 wherein a is 1, b is 0 and T is O can be prepared by the route illustrated in Scheme 9.
Figure imgf000058_0003
Figure imgf000058_0004
Scheme 9 In Scheme 9, the synthesis of the key intermediate ethyl 2-aryl-5-(arylamino)oxazole-4- carboxylate 42 is based upon the method described in Tetrahedron (2006) 62, 4698- 4707.
Thus, 2-amino diethylmalonate 38 is acylated using the acid chloride 28 in a non-protic solvent such as dichloromethane in the presence of non-interfering base such as triethylamine or diisopropylethylamine, to give the amide 39. Amide 39 is then cyclised to the ethoxy-oxazole ester 40 by treatment with trifluoroacetic anhydride in trifluorotoluene at an elevated temperature, e.g. a temperature in excess of 100 0C, for example a temperature of up to about 160 0C.
The ethoxy-oxazole ester 40 is hydrolysed using aqueous potassium hydroxide to give an intermediate carboxylic acid (not shown) which is then reacted with an aryl or heteroaryl amine Ar1-NH2 in the presence of HOBt and a carbodiimide derivative such as a PS-carbodiimide resin to give the amide 41. Heating the amide 41 in a high boiling inert solvent such as trifluorotoluene to an elevated temperature in excess of 160 0C (e.g. up to about 180 0C) leads to rearrangement of the amide to give the arylamino or heteroarylamino-oxazole ester 42.
The heteroarylamino-oxazole ester 42 is hydrolysed to the carboxylic acid 43, using a metal hydroxide (advantageously trimethyltin hydroxide in dichloroethane) and the carboxylic acid 43 is then converted to the carboxamide 44 by reaction with ammonia in the presence of EDAC and HOBt under conditions analogous to those described above.
An alternative route to compounds of the formula 1 wherein a is 1 , b is 0 and T is O is illustrated in Scheme 10.
Figure imgf000059_0001
Scheme 10
In Scheme 10, the bromo-oxazolyl carboxamide 32 (see Scheme 6 above) is subjected to a palladium catalysed amination by reaction with Ar1 -NH2 in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0)/ t»/s(diphenylphosphino)-1 ,1"-binaphthalene and sodium terf-butoxide to give the product 44. The amination reaction is typically carried out at an elevated temperature, e.g. a temperature up to about 160 0C, in a high boiling solvent such as trifluorotoluene.
A variation on the amination reaction sequence of Scheme 10 is illustrated in Scheme 11.
Figure imgf000060_0001
Scheme 11
In Scheme 11, the bromo-compound 31 (see Scheme 6) is subjected to a palladium catalysed amination by reaction with Ar1-NH2 in the presence of a palladium catalyst to give the intermediate nitrile 45 which is then partially hydrolysed using acidic conditions such as concentrated sulphuric acid or basic conditions such as aqueous potassium hydroxide (typically with microwave heating) to give the product 44.
Compounds of the formula 1 wherein b is 1 , a is 0 and T is O can be prepared by the reaction sequence set out in Scheme 12.
Figure imgf000060_0002
Scheme 12
In Scheme 12, the iodo-oxazole ester 35 (see Scheme 8) is subjected to amination by reaction with Ar^-NH2 in the presence of a palladium catalyst to give an intermediate ester (not shown). The ester is then hydrolysed using an alkali metal hydroxide such as potassium hydroxide as described above to give the oxazole carboxylic acid 46. The oxazole carboxylic acid 46 is then reacted with ammonia in the presence of EDAC and HOBt to give the amide product 47. Compounds of the formula (1) wherein T is O, b is 0, a is 0 and Ar1 is a phenyl group substituted by an aminoalkoxy substituent -(CH2)R-NR111R'" (where each R'" is hydrogen or alkyl or NR111R1" forms a cyclic group) can be prepared according to the synthetic route shown in Scheme 13.
Figure imgf000061_0001
Scheme 13
In Scheme 13, the starting material is the bromo-oxazole 48 which is reacted with 4- hydroxyphenylboronic acid in the presence of a palladium catalyst such as as 1,1 '- 6/s(diphenylphosphino)ferrocene-palladium(ll)dichloride and a base such as sodium carbonate in a polar solvent such as acetonitrile to give the hydroxyphenyloxazole compound 49. The hydroxyphenyloxazole compound 49 is then reacted with an alkylene dichloride CI-(CH2)n-CI where n is 2 or more (e.g. 2, 3 or 4) to give the chloroalkoxy compound SO. The chloroalkoxy compound is then reacted with an amine NR111R"1 in the presence of a non-interfering base such as triethylamine to give the product 51.
Compounds of the formula (1) wherein wherein T is O, b is 0, a is 0 and Ar1 is a phenyl group substituted by an amino(hydroxy)alkoxy substituent can be prepared according to the synthetic route shown in Scheme 14.
Figure imgf000061_0002
Scheme 14 In Scheme 14, the hydroxyphenyloxazole compound 49 is treated with a base such as potassium carbonate followed by epichlorohydrin. The reaction is typically carried out in a polar solvent such as DMF at an elevated temperature (e.g. up to or in excess of 100 0C). The resulting oxirane 52 is then reacted with an amine HNR'"R'" in a polar solvent such as methanol at an elevated temperature (e.g. up to or in excess of 100 0C) to give the product 53.
Compounds of the formula (1) wherein wherein T is O, b is 0, a is 1 and Ar1 is a benzoic acid amide group can be prepared according to the synthetic route shown in Scheme 15.
Figure imgf000062_0001
Figure imgf000062_0002
Scheme 15
In Scheme 15, the bromo-cyano-oxaxole 31 (see Scheme 6) is subjected to a palladium catalysed amination by reaction with an aminobenzoic acid (4-aminobenzoic acid is specifically illustrated in the reaction scheme but the 2- and 3-isomers could be used instead) in the presence of a palladium catalyst such as fr/s(dibenzylideneacetone)dipalladium(0) in combination with 9,9-dimethyl-4,5- jb/s(diphenylphosphino)xanthene to give the substituted oxazolylaminobenzoic acid compound 54. The reaction may be carried out in a polar organic solvent such as a butanol: dioxane mixture in the presence of a base (e.g. an alkali metal carbonate such as caesium carbonate), typically with heating to a temperature in excess of 100 0C. Compound 54 can then be treated with acid (e.g sulphuric acid) to hydrolyse the nitrile group to a carboxamide group to give a compound of the formula 56. The compound of formula 56 can then be reacted under amide-forming conditions (see Scheme 2 above) with an amine of the formula HNRURU' where Ru and Ru' are the same or different and each is hydrogen or a substituent or NRURU' forms a cyclic amine such as piperidine or morpholine, to give an amide of the formula 57.
Alternatively, the compound of formula 54 can be reacted under amide-forming conditions with an amine of the formula HNRURU> to give a compound of formula 55 which is then treated with acid to hydrolyse the nitrile group to a carboxamide group to give a compound of the formula 57.
The reverse amides of the compounds of formula 57 (i.e. compounds of the formula (1) in which T is O, b is 0, a is 1 and Ar1 is an acylamino-phenyl group can be prepared according to the synthetic route shown in Scheme 16.
Figure imgf000063_0001
Figure imgf000063_0002
Scheme 16
In Scheme 16, the bromo-cyano-oxaxole 31 (see Scheme 6) is subjected to a palladium catalysed amination under conditions as described for Scheme 15 above, using a nitroaniline as the amine (the 4-nitroaniline is illustrated but other isomers could be used instead) to give the nitrophenylamine 58. The nitro group of the nitrophenylamine 58 is reduced to an amino group, for example by catalytic hydrogenation over palladium on carbon, to give the amine 59. The amine 59 can be converted to the acylamino compound 60 (where Rb is as hereinbefore defined) by any of a variety of well known methods. For example, the amine 59 can be reacted with a carboxylic acid R6CO2H under amide forming conditions as described above. Alternatively, when Rb is a cyclic amine linked to the carbonyl group via a nitrogen atom (e.g. as in 1-piperidinyl, 4- morpholinyl or 4-piperazinyl), the amine 59 can be reacted with the cyclic amine in the presence of 1 ,1'-carbonyldiimidazole. The reaction is typically carried out at room temperature in a solvent such as dichloromethane in the presence of a non-interfering base such as triethylamine or diisopropylethylamine. The resulting intermediate, compound 60, is then treated with acid (e.g. sulphuric acid) as described above to hydrolyse the nitrile group to a carboxamide group thus giving the compound of formula 61
Compounds of the formula (1) wherein T is O, b is 0, a is 0 and Ar1 is a substituted aminomethyl-phenyl group can be prepared according to the synthetic route shown in Scheme 17.
Figure imgf000064_0001
Scheme 17
In Scheme 17, the bromo-oxazole carboxamide 32 (see Scheme 6 above) is reacted with a formyl-phenyl boronic acid (the 3-formyl-phenyl boronic acid is shown in the Scheme but the 2- or 4- isomers could be used instead) under Suzuki coupling conditions (see Scheme 6 above) to give the substituted benzaldehyde 62. The substituted benzaldehyde 62 is subjected to reductive amination with an amine HNR2R2' in the presence of a borohydride reducing agent (such as sodium triacetoxyborohydride) in a chlorinated hydrocarbon solvent (such as 1 ,2-dichloroethane) containing acetic acid to give the substituted aminomethylphenyl oxazole compound 63 in which NR2R2 can be, for example, a dialkylamino group or an optionally susbtituted cyclic amino group such as a morpholinyl, piperidinyl or piperazinyl group. The reductive amination reaction is typically carried out at room temperature.
Once formed, many compounds of the formula (1) can be converted into other compounds of the formula (1) using standard functional group interconversions.
Examples of functional group interconversions and reagents and conditions for carrying out such conversions can be found in, for example, Advanced Organic Chemistry, by Jerry March, 4th edition, 119, Wiley Interscience, New York, Fiesers' Reagents for Organic Synthesis, Volumes 1-17, John Wiley, edited by Mary Fieser (ISBN: 0-471- 58283-2), and Organic Syntheses, Volumes 1-8, John Wiley, edited by Jeremiah P. Freeman (ISBN: 0-471-31192-8).
In many of the reactions described above, it may be necessary to protect one or more groups to prevent a reaction from taking place at an undesirable location on the molecule. Examples of protecting groups, and methods of protecting and deprotecting functional groups, can be found in Protective Groups in Organic Synthesis (T. Green and P. Wuts; 3rd Edition; John Wiley and Sons, 1999).
The compounds of the invention can be isolated and purified according to standard techniques well known to the person skilled in the art. One technique of particular usefulness in purifying the compounds is preparative liquid chromatography using mass spectrometry as a means of detecting the purified compounds emerging from the chromatography column.
Preparative LC-MS is a standard and effective method used for the purification of small organic molecules such as the compounds described herein. The methods for the liquid chromatography (LC) and mass spectrometry (MS) can be varied to provide better separation of the crude materials and improved detection of the samples by MS. Optimisation of the preparative gradient LC method will involve varying columns, volatile eluents and modifiers, and gradients. Methods are well known in the art for optimising preparative LC-MS methods and then using them to purify compounds. Such methods are described in Rosentreter U, Huber U.; Optimal fraction collecting in preparative LC/MS; J Comb Chem.; 2004; 6(2), 159-64 and Leister W, Strauss K, Wisnoski D, Zhao Z, Lindsley C, Development of a custom high-throughput preparative liquid chromatography/mass spectrometer platform for the preparative purification and analytical analysis of compound libraries; J Comb Chem.; 2003; 5(3); 322-9.
Pharmaceutical Formulations
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 of the invention 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. Accordingly, in another aspect, the invention provides a pharmaceutical composition comprising a compound of the formula (1) or any sub-groups or examples thereof as defined herein and a pharmaceutically acceptable carrier.
The term "pharmaceutically acceptable" as used herein refers to compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a subject (e.g. human) without excessive toxicity, irritation, allergic response, or other problems or complication, commensurate with a reasonable benefit/risk ratio. Each carrier, excipient, etc. must also be "acceptable" in the sense of being compatible with the other ingredients of the formulation.
The pharmaceutical compositions can be in any form suitable for oral, parenteral, topical, intranasal, ophthalmic, otic, rectal, intra-vaginal, or transdermal administration. Where the compositions are intended for parenteral administration, they can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration or for direct delivery into a target organ or tissue by injection, infusion or other means of delivery.
In one embodiment, the pharmaceutical composition is in a form suitable for i.v. administration, for example by injection or infusion.
In another embodiment, the pharmaceutical composition is in a form suitable for subcutaneous (s.c.) administration.
In a further embodiment, the pharmaceutical composition is in a form suitable for oral administration.
Pharmaceutical dosage forms suitable for oral administration include tablets, capsules, caplets, pills, lozenges, syrups, solutions, powders, granules, elixirs and suspensions, sublingual tablets, wafers or patches and buccal patches.
Pharmaceutical compositions containing compounds of the formula (1) can be formulated in accordance with known techniques, see for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA.
Thus, tablet compositions can contain a unit dosage of active compound together with an inert diluent or carrier such as a sugar or sugar alcohol, eg; lactose, sucrose, sorbitol or mannitol; and/or a non-sugar derived diluent such as sodium carbonate, calcium phosphate, calcium carbonate, or a cellulose or derivative thereof such as methyl cellulose, ethyl cellulose, hydroxypropyl methyl cellulose, and starches such as corn starch. Tablets may also contain such standard ingredients as binding and granulating agents such as polyvinylpyrrolidone, disintegrants (e.g. swellable crosslinked polymers such as crosslinked carboxymethylcellulose), lubricating agents (e.g. stearates), preservatives (e.g. parabens), antioxidants (e.g. BHT), buffering agents (for example phosphate or citrate buffers), and effervescent agents such as citrate/bicarbonate mixtures. Such excipients are well known and do not need to be discussed in detail here.
Capsule formulations may be of the hard gelatin or soft gelatin variety and can contain the active component in solid, semi-solid, or liquid form. Gelatin capsules can be formed from animal gelatin or synthetic or plant derived equivalents thereof.
The solid dosage forms (e.g. tablets, capsules etc.) can be coated or un-coated, but typically have a coating, for example a protective film coating (e.g. a wax or varnish) or a release controlling coating. The coating (e.g. a Eudragit ™ type polymer) can be designed to release the active component at a desired location within the gastrointestinal tract. Thus, the coating can be selected so as to degrade under certain pH conditions within the gastrointestinal tract, thereby selectively releasing the compound in the stomach or in the ileum or duodenum.
Instead of, or in addition to, a coating, the drug can be presented in a solid matrix comprising a release controlling agent, for example a release delaying agent which may be adapted to selectively release the compound under conditions of varying acidity or alkalinity in the gastrointestinal tract. Alternatively, the matrix material or release retarding coating can take the form of an erodible polymer (e.g. a maleic anhydride polymer) which is substantially continuously eroded as the dosage form passes through the gastrointestinal tract. As a further alternative, the active compound can be formulated in a delivery system that provides osmotic control of the release of the compound. Osmotic release and other delayed release or sustained release formulations may be prepared in accordance with methods well known to those skilled in the art. Compositions for topical use include ointments, creams, sprays, patches, gels, liquid drops and inserts (for example intraocular inserts). Such compositions can be formulated in accordance with known methods.
Compositions for parenteral administration are typically presented as sterile aqueous or oily solutions or fine suspensions, or may be provided in finely divided sterile powder form for making up extemporaneously with sterile water for injection.
Compositions for parenteral administration may be formulated for administration as discrete dosage units or may be formulated for administration by infusion.
Examples of formulations for rectal or intra-vaginal administration include pessaries and suppositories which may be, for example, formed from a shaped moldable or waxy material containing the active compound.
Compositions for administration by inhalation may take the form of inhalable powder compositions or liquid or powder sprays, and can be administrated in standard form using powder inhaler devices or aerosol dispensing devices. Such devices are well known. For administration by inhalation, the powdered formulations typically comprise the active compound together with an inert solid powdered diluent such as lactose.
The compounds of the inventions will generally be presented in unit dosage form and, as such, will typically contain sufficient compound to provide a desired level of biological activity. For example, a formulation intended for oral administration may contain from 0.1 milligrams to 2 grams of active ingredient, more usually from 10 milligrams to 1 gram, for example, 50 milligrams to 500 milligrams.
The active compound will be administered to a patient in need thereof (for example a human or animal patient) in an amount sufficient to achieve the desired therapeutic effect.
EXAMPLES
The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Liquid Chromatography - Mass spectrometry (LC-MS) Methods
LC-MS (1) analyses were performed on a Micromass ZQ mass spectrometer / Waters Alliance 2795 HT HPLC with a Phenomenex Gemini 3 μm, C18, 30 mm x 3 mm i.d. column at a temperature of 35°C and a flow rate of 1.2 mL/rninute using the following solvent gradient:
Solvent A: 0.02% Ammonia and 5% Solvent B in acetonitrile
Solvent B: 0.02% Ammonia and 0.063% ammonium formate in water.
0.00 - 2.50 minutes: 5% A / 95% B to 95% A / 5% B, 1.2mL/minute
2.50 - 2.75 minutes: 95% A / 5% B, 1.2mL/minute
2.75 - 3.65 minutes: 95% A / 5% B, 2.0 mL/minute
3.65 - 4.00 minutes: 95% A / 5% B to 5% A / 95% B, 2.0 mL/minute
UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 120-1000 amu.
LC-MS (2) analyses were performed on a Micromass ZQ mass spectrometer / Waters Alliance 2795 HT HPLC with a Phenomenex Gemini 5 μm, C18, 30 mm x 4.6 mm Ld. column at a temperature of 35°C and a flow rate of 2 mL/minute using the following solvent gradient:
Solvent A: 0.02% Ammonia and 5% Solvent B in acetonitrile.
Solvent B: 0.02% Ammonia and 0.063% ammonium formate in water.
0.00 - 4.25 minutes: 5% A / 95% B to 95% A / 5% B.
4.25 - 5.80 minutes: 95% A / 5% B.
5.80 - 5.90 minutes: 95% A / 5% B to 5% A / 95% B.
5.90 - 7.00 minutes: 5% A / 95% B.
UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionisation was by positive or negative ion electrospray. Molecular weight scan range was 80-1000 amu.
LC-MS (3) analyses were performed on a Micromass ZQ mass spectrometer / Waters Alliance 2795 HT HPLC with a XBridge C18 2.5μm 3.0x30mm i.d. column at a temperature of 350C and a flow rate of 1 mL/minute using the following solvent gradient: Solvent A: 0.02% Ammonia and 5% Solvent B in acetonitrile.
Solvent B: 0.02% Ammonia and 0.063% ammonium formate in water.
0.00 - 2.5 minutes: 5% A / 95% B to 95% A / 5% B, flow rate 1 mL/min.
2.5 - 2.75 minutes: 95% A / 5% B, flow rate 1 mL/min to 1.66mLΛnin.
2.75 - 3.55 minutes: 95% A / 5% B, flow rate 1.66ml_/min.
3.55 - 3.65 minutes: 95% A / 5% B to 5% A / 95% B1 flow rate 1.66mL/min.
3.65 - 4.00 minutes: 5% A / 95% B, flow rate 1.66mL/min to 1 mL/min.
UV detection was at 220-400 nm using a Waters 996 photodiode array UV detector and ionization was by positive or negative ion electrospray. Molecular weight scan range was 120 -1000 amu.
1H NMR spectra were obtained using a Bruker DPX-400 spectrometer.
Microwave mediated reactions were performed in a Biotage Sixty microwave reactor at the temperature and times specified in the experimental section.
Glossary of Terms
Et2O - diethyl ether
MgSO4 - magnesium sulphate
MeOH - methanol
SPE - solid-phase extraction
MP - macroporous
TsOH - toluene sulphonic acid
HPLC - high performance liquid chromatography
EtOH - ethanol
HCI - hydrogen chloride
EtOAc - ethyl acetate
CDCI3 - deuterated chloroform
DMSO - dimethylsulphoxide
CD3OD - deuterated methanol
THF - tetrahydrofuran
H2O - water d - doublet dd - double doublet s - singlet br. s - broad singlet t - triplet q - quartet m - multiplet
DMF - dimethylformamide
LCMS — liquid chromatography-mass spectrometry
NMR - nuclear magnetic resonance
NMP - N-methylpyrrolidine
DCE - dichloroethane
DCM - dichloromethane
N2 - nitrogen
H2SO4 - sulphuric acid
MP-SH - macroporous thiol
MP-CO3 - macroporous carbonate
Pd(dppf)2CI2 - [1 ,1'-ib/s(diphenylphosphino)ferrocene]dichloropalladium (II)
PS - polymer supported uL or μl_ - microlitre mL - millilitre mg - milligramme nM - nanomolar nm - nanometre uM or μM - micromolar mM - millimolar pM - picomolar
Kda - kilo Daltons
ATP - adenosine triphosphate
MgCI2 - magnesium chloride
MnCI2 - manganese (II) chloride
GST - glutathione S-transferase
HEPES - 4-(2-hydroxyethyl)-1-piperazineethanesulphonic acid
DTT - dithiothreitol
EDTA - ethylenediaminetetraacetic acid
BSA - bovine serum albumin
TBS - frvs-buffered saline Eu-N1 - europium N1 chelate. The reagent is the Eu3+-chelate of N1-(p-iodoacetamido- benzyl)diethylenetriamine-N1
General Method A
Examples A-1 to A-20 were prepared using General Method A which comprises the sequence of reactions set out in Scheme 1 above.
The tricarbonyl intermediate 14 in Scheme 1 was prepared following a procedure outlined in J. Org. Chem. (1995) 60, 8231-8235.
Example A-1 4-(4-methoxyphenyl)-2-phenyl-1H-imidazole-5-carboxamide
Step a - Ethyl 3-(4-methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate.
Figure imgf000072_0001
To a stirred solution of (carbethoxymethylene)triphenylphosphorane (0.50Og, 1.44mmol) in DCM (7ml) under an N2 atmosphere was added N, O-jb/s(trimethylsilyl)acetamide (0.42ml, 1.7mmol). The solution was then cooled to O0C and p-anisoylchloride (0.25Og, 1.47mmol) was added. The reaction mixture was then gradually warmed to room temperature and stirred overnight. The reaction was quenched by the addition of H2O (3ml) and the aqueous phase was extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford ethyl 3-(4- methoxyphenyl)-3-oxo-2-(triphenylphosphoranylidene)propionate. (0.637g, 1.32mmol, 92%) as an off white solid which was used without further purification. 1H NMR (CDCI3) δ 0.62 (3H1 1), 3.69 (2H, q), 3.82 (3H, s), 6.86 (2H, d), 7.43-7.55 (9H, m), 7.71-7.80 (8H, m). LCMS (2) Rt: 3.65min; m/z 483.
Step b - Ethyl 3-(4-methoxyphenyl)-2,3-dioxopropanoate
Figure imgf000072_0002
To a solution of ethyl 3-(4-methoxyphenyl)-3-oxo-2- (triphenylphosphoranylidene)propionate. (0.51Og, 1.1mmol) in THF (10ml) was added water (10ml) followed by oxone (0.974g, 1.6mmol) in portions and the resulting mixture was stirred at room temperature overnight. The solid was removed by filtration and filtrate concentrated in vacuo and extracted with DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford crude ethyl 3-(4- methoxyphenyl)-2,3-dioxopropanoate as a yellow oil (0.50Og) as a mixture with triphenylphosphine oxide which was used without further purification. LCMS (2) 2.38min; m/z 237.
Step c - Ethyl 4-(4~methoxyphenyl)-2-phenyl-1 H-imidazole-5-carboxylate
Figure imgf000073_0001
A mixture of crude ethyl 3-(4-methoxyphenyl)-2,3-dioxopropanoate (0.05Og, approximately 0.11mmol), ammonium acetate (0.082g, 10.6mmol) and benzaldehyde (11μl, 0.11mmol) in acetic acid (0.5ml) was heated in the microwave at 16O0C for 5 minutes. The reaction mixture was diluted with MeOH and purified by SPE using a MP- TsOH cartridge (1000mg). The solvent was removed in vacuo to afford ethyl 4-(4- methoxyphenyl)-2-phenyl-1 H-imidazole-5-carboxylate (0.022g, 0.07mmo!) which was used without further purification. LCMS (2) Rt: 3.29; m/z 323.
Step d - 4-(4-methoxyphenyl)-2-phenyl-1 H-imidazole-5-carboxamide
Figure imgf000073_0002
A suspension of ethyl 4-(4-methoxyphenyl)-2-phenyl-1 H-imidazole-5-carboxylate (0.078g, 0.23mmol) in aqueous (28%) ammonia (4.5ml) was heated in the microwave for 35 minutes at 15O0C. The solvent was then removed in vacuo and the residue was purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-phenyl-1 H-imidazole-5- carboxamide (0.0109g, 0.04mmol, 16%) as a white solid. 1H NMR (DMSO) δ 3.82 (3H, s), 7.01 (2H, d), 7.10 (1H1 br. s), 7.39-7.43 (2H, m), 7.49 (2H, dd), 7.85 (2H, d), 8.10 (2H, m). LCMS (2) Rt: 2.46min; m/z (ES+) 294. In a similar manner as described in example A-1 , but using the appropriate aryl or heteroaryl aldehyde in place of benzaldehyde in Step c, the compounds described in examples A-2 to A-20 were prepared.
Example A-2 2-(2-chlorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000074_0001
1H NMR (DMSO) δ 3.82 (3H, s), 7.00 (2H, d) 7.08 (1H, br. s), 7.33 (1H, br. s), 7.45-7.53 (2H, m), 7.62 (1H, m), 7.75 (1 H, m), 7.86 (2H, d). LCMS (2) Rt: 2.55min; m/z (ES+) 328/330.
Example A-3 2-(2-methoxyphenyl)-4-(4-methoxyphenyl)-1H-lmidazole-5-carboxamide
Figure imgf000074_0002
1H NMR (DMSO) δ 3.82 (3H1 s), 3.91 (3H1 s), 7.00 (2H, d), 7.03 (1H, br. s), 7.07 (1H, m), 7.17 (1H1 m), 7.39 (1H1 br. s), 7.42 (1H1 m), 7.80 (2H, d), 7.97 (1H, dd), 11.97 (1H, br. s). LCMS (2) Rt: 2.63min; m/z (ES+) 324.
Example A-4 2-(3-methoxyphenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000074_0003
1H NMR (DMSO) δ 3.82 (3H, s), 3.84 (3H1 s), 6.97 (1H1 ddd), 7.01 (2H, d), 7.08 (1H1 br. s), 7.39 (1H, dd), 7.43 (1H1 br. s), 7.67-7.71 (2H1 m), 7.83 (2H1 d), 12.70 (1H, br. s). LCMS (2) Rt: 2.48min; m/z (ES+) 324. Example A-5 2,4-bis(4-methoxyphenyl)-1H-imidazo!e-5-carboxamide
Figure imgf000075_0001
1H NMR (DMSO) δ 3.82 (3H, S)1 3.82 (3H, s), 7.01 (2H, d), 7.05 (3H, m), 7.38 (1H, br. s), 7.84 (2H, d), 8.03 (2H, d), 12.55 (1H, br. s). LCMS (2) Rt: 2.41 min; m/z (ES+) 324.
Example A-6 4-(4-methoxyphenyl)-2-o-tolyl-1H-imidazole-5-carboxamide
Figure imgf000075_0002
1H NMR (DMSO) δ 2.57 (3H, s), 3.82 (3H, s), 7.00 (2H, d), 7.04 (1H, br. s), 7.28-7.35 (4H, m), 7.67 (1H, d), 7.87 (2H, d), 12.55 (1H, br. s). LCMS (2) Rt: 2.51 min; m/z 308.
Example A-7 4-(4-methoxyphenyl)-2-m-tolyl-1H-imidazole-5-carboxamide
Figure imgf000075_0003
1H NMR (DMSO) δ 2.39 (3H1 s), 3.82 (3H, s), 7.01 (2H, d), 7.08 (1H, br. s), 7.22 (1H1 d), 7.37 (1 H, dd), 7.40 (1 H1 br. s), 7.84 (2H1 d), 7.89 (1H, d), 7.95 (1 H1 s). LCMS (2) Rt: 2.64min; m/z (ES+) 308.
Example A-8 4-(4-methoxyphenyl)-2-p-tolyl-1H-imidazole-5-carboxamide
Figure imgf000076_0001
1H NMR (DMSO) δ 2.35 (3H, s), 3.81 (3H, s), 7.00 (2H, d), 7.04 (1H, br. s), 7.29 (2H1 d), 7.38 (1H, br. s), 7.83 (2H, d), 7.98 (2H, d), 12.63 (1 H, br. s). LCMS (2) Rt: 2.62min; m/z (ES+) 308.
Example A-9 2-(4-bromo-2-fluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamϊde
Figure imgf000076_0002
1H NMR (DMSO) δ 3.82 (3H, s), 7.00 (2H, d), 7.12 (1H, br. s), 7.38 (1H, br. s), 7.58 (1H, dd), 7.75 (1H1 dd), 7.81 (2H1 d), 7.92 (1H1 dd), 12.70 (1 H1 br. s). LCMS (2) Rt: 2.81 min; m/z (ES+) 390/392.
Example A-10 2-(2,6-dichlorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000076_0003
1H NMR (DMSO) δ 3.81 (3H, s), 7.00 (2H1 d), 7.06 (1H1 br. s), 7.38 (1H, br. s), 7.58 (1H, dd), 7.64 (1H1 d), 7.66 (1H1 d), 7.87 (2H, d). LCMS (2) Rt: 2.34; m/z (ES+) 362/364/366.
Example A-11 2-(2-fluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000077_0001
1H NMR (DMSO) 5 3.82 (3H, s), 7.00 (2H, d), 7.11 (1 H, br. s), 7.33 - 7.41 (3H, m), 7.50 (1H, m), 7.82 (2H, d), 7.95 (1H, m), 12.63 (1H, br. s).
Example A-12 4-(4-methoxyphenyl)-2-(pyridin-3-yl)-1H-imidazole-5-carboxamide
Figure imgf000077_0002
1H NMR (DMSO) δ 3.83 (3H, s), 7.03 (2H1 d), 7.14 (1H1 br. s), 7.50 (1H, br. s), 7.53 (1H, dd), 7.85 (2H, d), 8.41 (1H, ddd), 8.60 (1H, dd), 9.28 (1H, d), 12.94 (1H, br. s).
Example A-13 2-(1H-indol-3-yl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000077_0003
1H NMR (DMSO) δ 3.83 (3H, s), 7.02 (2H, d), 7.05 (1H, br. s), 7.11-7.20 (2H, m), 7.45 (1 H, d), 7.47 (1H, br. s), 7.88 (2H, d), 8.06 (1H, d), 8.51 (1 H, d), 11.41 (1H, br. s), 12.34 (1H, br. s).
Example A-14 2-(4-bromo-2,6-difluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Step a - 4-bromo-2,6-difluorobenzaldehyde
Figure imgf000077_0004
To a solution of 4-bromo-2,6-difluorobenzylalcohol (0.20Og, 0.9mmol) in DCM (4ml) and DMSO (0.440ml) was added triethylamine (1ml, 0.72mmol) and sulfur trioxide pyridine complex (0.57Og, 3.6mmol) and the resulting solution was stirred at room temperature for 3 hours. The solution was diluted with Et2O and washed with 0.5M aqueous HCI, 1 M sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 4-bromo-2,6-difluorobenza!dehyde (0.166g, 0.75mmol, 84%) as a white solid. 1H NMR (CDCI3) δ 7.22 (2H, d), 10.29 (1H, br. s). LCMS (2) Rt: 2.74min.
Step b - 2-(4-bromo-2,6-difluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5- carboxamide
Figure imgf000078_0001
The title compound was prepared according to the procedure described in example A-1 using 4-bromo-2,6-difluorobenzaldehyde in place of benzaldehyde in Step c. 1H NMR (DMSO) δ 3.81 (3H, s), 7.01 (2H, d), 7.12 (1H1 br. s), 7.35 (1H, br. s), 7.72 (2H, d), 7.81 (2H, d), 13.03 (1H, br. s). LCMS (2) Rt: 2.59min; m/z (ES+) 408/410.
Example A-15 2-(2-chloro-6-fluorophenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000078_0002
1H NMR (DMSO) δ 3.81 (3H, s), 7.00 (2H, d), 7.08 (1 H, br. s), 7.37 (1H, br. s), 7.43 (1 H, dd), 7.52 (1H, d), 7.61 (1H, m), 7.85 (2H, d), 12.98 (1H, br. s). LCMS (2) Rt: 2.08min; m/z (ES+) 346/348.
Example A-16 2-(2,6-difluorophenyl)-4-(thiophen-2-yl)-1H-imidazole-5-carboxamide
Figure imgf000079_0001
LCMS (2) Rt: 192min; m/z (ES+) 306.
Example A-17 2-(3,5-dimethoxyphenyl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamicle
Figure imgf000079_0002
1H NMR (DMSO) δ 3.82 (9H, s), 6.83 (1H, t), 7.02 (2H, d), 7.07 (1H, br. s), 7.32 (2H, d), 7.47 (1H, br. s), 7.81 (2H, d), 12.68 (1H, br. s). LCMS (2) Rt: 2.55min; m/z (ES+) 354.
Example A-18 2-(2,6-difluorophenyl)-4-(2-fIuorophenyl)-1H-imidazole-5-carboxamide
Figure imgf000079_0003
LCMS (2) Rt: 1.97min; m/z (ES+) 318.
Example A-19 2-(2,6-difluorophenyl)-4-phenyl-1H-imidazole-5-carboxamide
Figure imgf000079_0004
LCMS (2) Rt: 1.97min; m/z (ES+) 300.
Example A-20 2-(2,6-difluorophenyl)-4-(3-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000080_0001
1H NMR (DMSO) δ 3.80 (3H1 s), 6.95 (1H, ddd), 7.20 (1H, br. s), 7.31 (2H, t), 7.36 (1H, d), 7.41 (1H, br. s), 7.44 (1H1 m), 7.56 (1H, m), 7.63 (1H, m). LCMS (2) Rt: 2.11min; m/z (ES+) 330.
General Method B
General Method B comprises the series of reactions set out in Scheme 2 above.
Example B-1 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5-carboxamide
Step a - 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H-imidazole-5-carboxylic acid
Figure imgf000080_0002
To a solution of ethyl 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H-imidazole-5-carboxylate (0.089g, 0.28mmol, prepared (using pyridine-4-carboxaldehyde in place of benzaldehyde) according to the method outlined in Example A-1 , step c), in methanol was added 1M aqueous potassium hydroxide (5ml, δ.Ommol) and the resulting mixture stirred at 550C for 48 hours. The solution was cooled to room temperature, neutralised by the addition of 0.5M aqueous HCI and extracted with DCM. The aqueous phase was then acidified by the addition of acetic acid and purified by SPE using MP-TsOH cartridges (2x1000mg) to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1H-imidazole-5- carboxylic acid (0.09Og) as an orange oil which was used without further purification. LCMS (2) Rt: 1.20min; m/z (ES+) 296.
Step b - 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H-imidazole-5-carboxamide
Figure imgf000081_0001
To a solution of 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H-imidazole-5-carboxylic acid (0.09Og, 0.3mmol) and hydroxybenzotriazole monohydrate (0.047g, 0.3mmol) in DMF (2.5ml) was added 0.5M ammonia in dioxane (2ml, LOmmol) and the resulting solution stirred at room temperature for 10 minutes. 1-[3-(Dimethylamino)propyl]-3- ethylcarbodiimide (0.064g, 0.33mmol) was added and the reaction mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 4-(4-methoxyphenyl)-2-(pyridin-4-yl)-1 H- imidazole-5-carboxamide (0.025g, O.Oδmmol, 67%). 1H NMR (DMSO) δ 3.83 (3H, s), 7.03 (2H1 d), 7.20 (1H, br. s), 7.50 (1H, br. s), 7.84 (2H, d), 8.03 (2H, dd), 8.68 (2H, dd), 13.12 (1 H, br. s). LCMS (2) Rt 1.68min; m/z (ES+) 295.
In a similar manner as described in example B-1 the compounds described in examples B-2 to B-6 were prepared.
Example B-2 2-(5-methoxy-1H-indol-3-yl)-4-(4-methoxyphenyl)-1H-imida2θle-5-carboxamϊde
Figure imgf000081_0002
1H NMR (DMSO) δ 3.82 (3H, s), 3.85 (3H, s), 6.82 (1H, dd), 7.02 (2H, d), 7.06 (1H, br. s), 7.34 (1H1 d), 7.42 (1H, br. s), 7.87 (2H, d), 7.92 (1 H, d), 8.01 (1 H, d), 11.30 (1 H, br. s), 12.32 (1 H, br. s). LCMS (2) Rt: 2.25min; m/z (ES+) 363.
Example B-3 2-(benzo[b]thiophen-3-yl)-4-(4-methoxyphenyl)-1H-imidazole-5-carboxamide
Figure imgf000082_0001
1H NMR (DMSO) δ 3.83 (3H, s), 7.04 (2H, d), 7.16 (1H, br. s), 7.50 (2H, m), 7.57 (1H, br. s), 7.87 (2H, d), 8.06 (1H, d), 8.41 (1 H, s), 9.12 (1H, d), 12.84 (1H, br. s). LCMS (2) Rt: 2.77min; m/z (ES+) 350.
Example B-4
4-(4-methoxyphenyl)-2-(1 -methyl-1 H-indol-3-yl)-1 H-imidazole-5-carboxamide
Figure imgf000082_0002
LCMS (2) Rt: 2.55min; m/z (ES+) 347.
Example B-5
2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)-1 H-imidazole-5-carboxamide
Figure imgf000082_0003
1H NMR (DMSO) 0 3.84 (3H, s), 7.10 (2H, d), 7.39 (2H, t), 7.66 (1H, br. s), 7.67 (1H, br. s), 7.73 (1H, m), 8.24 (2H, d). LCMS (2) Rt: 2.99min; m/z (ES+) 331.
Example B-6
4-(4-methoxyphenyl)-2-(pyridin-2-yl)-1 H-imidazole-5-carboxamide
Figure imgf000082_0004
1H NMR (DMSO) δ 3.81 (3H, s), 6.97 (2H, d), 7.14 (1H, br. s), 7.43 (1H, ddd), 7.47 (1H, br. s), 7.85 (2H, d), 7.95 (1 H1 ddd), 8.17 (1H, d), 8.65 (1H1 d), 13.24 (1H, br. s). LCMS (2) Rt: 1.99min; m/z (ES+) 295.
General Method C
General Method C comprises the series of reactions set out in Scheme 3 above.
Example C-1 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxamide
Step a - ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate
Figure imgf000083_0001
To a stirred solution of ethyl picolinoylacetate (0.50Og, 2.6mmo!) in acetic acid (0.5mL) was added a solution of sodium nitrite (0.238g, 3.4mmol) in water (O.δmL), dropwise. The resulting solution was stirred at room temperature for 2 hours after which water (O.δmL) was added and the reaction was stirred for a further 2 hours. The mixture was extracted with Et2O and the combined organic phase was washed with water, saturated sodium bicarbonate solution and brine, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.353g, 1.6mmol, 61%) as a white solid. 1H NMR (DMSO) δ 1.17 (3H, t), 4.22 (2H, q), 7.74 (1H, m), 8.04-8.11 (2H, m), 8.74 (1H, m), 12.87 (1 H, s). LCMS (2) Rt: 1.09min; m/z (ES+) 223.
Step b - ethyl 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxylate
Figure imgf000083_0002
A mixture of ethyl 2-(hydroxyimino)-3-oxo-3-(pyridin-2-yl)propanoate (0.30Og, 1.4mmol), ammonium acetate (0.104g, 1.4mmol) and 2,6-difluorobenzaldehyde (0.145mL, 1.3mmol) in acetic acid (6mL) was heated in the microwave at 16O0C for 2 minutes. The reaction mixture was diluted with MeOH and purified by SPE using a MP-TsOH resin cartridge (2500mg). The crude mixture obtained was purified by preparative HPLC to afford ethyl 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1 H-imidazole-5-carboxylate (0.029g, 0.09mmol, 7%) as a pale solid. LCMS (2) Rt: 2.46min; m/z (ES+) 330.
Step c - 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1 H-imidazole-5-carboxamide
Figure imgf000084_0001
Prepared according to the method outlined in example B-1 from ethyl 2-(2,6- difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxylate (0.029g, 0.09mmol) to afford 2-(2,6-difluorophenyl)-4-(pyridin-2-yl)-1H-imidazole-5-carboxamide (0.0025g, O.OOδmmol, 9%). 1H NMR (DMSO) δ 7.27 (2H, t), 7.43 (1H, dd), 7.62 (1H, m), 7.86 (1 H, br. s), 7.98 (1 H, br. dd), 8.29 (1H, br. d), 8.65 (1H, ddd), 11.38 (1H, br. s), 13.28 (1H, br. s). LCMS (2) Rt: 2.28min; m/z 301.
General Method D
General Method D comprises the series of reactions set out in Scheme 4 above. The reaction sequence is based on a route to diaryl substituted oxazoles described in J. Org. Chem. (1960) 25, 1151-1154.
Sodium 2,6-difluorobenzoate
Figure imgf000084_0002
To a solution of 2,6-difluorobenzoic acid (1.0Og, 6.3mmol) in EtOH and water (5:1, 6OmL) was added 1N aqueous sodium hydroxide solution (6.33mL, 6.3mmol). The reaction mixture was stirred for 10 minutes at room temperature and then solvents were removed in vacuo to yield sodium 2,6-difluorobenzoate (1.22g, 6.3mmol, quantitative) as an off white solid. 1H NMR (DMSO) δ 6.89 (2H, m), 7.15 (1H, m).
Example D-1 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxamide
Step a - ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate
Figure imgf000085_0001
To a solution of ethyl p-anisoylacetate (1.0Og, 4.5mmol) in ethanol (14mL) at 5O0C was added triethylamine (0.63mL, 4.5mmol) followed by pyridinium hydrobromide perbromide (1.44g, 4.5mmol) and the resulting mixture was then stirred at 5O0C for 2 hours. The reaction was cooled to room temperature and poured into EtOAc. The organic phase was then washed with saturated sodium bicarbonate solution and 0.5M aqueous HCI, dried over MgSO4 and the solvent removed in vacuo to afford ethyl 2-bromo-3-(4- methoxyphenyl)-3-oxopropanoate (1.209g, 4.0mmol, 89%) which was used without further purification. 1H NMR (CDCI3) δ 1.26 (3H, t), 3.89 (3H, s), 4.28 (2H, q), 5.62 (1H, s), 6.96 (2H1 d), 7.98 (2H, d). LCMS (2) Rt: 3.06min; m/z (ES+) 301/303.
Step b - 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate
Figure imgf000085_0002
A solution of ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate (0.09Og, 0.3mmol) and sodium 2,6-difluorobenzoate (0.054g, 0.30mmol) in ethanol (2mL) was heated at 12O0C in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc (25mL) and water (25mL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0 - 40% EtOAc in hexanes to afford 3- ethoxy-1-(4-methoxyphenyl)-1 ,3-dioxopropan-2-yl 2,6-difluorobenzoate (0.108g, 0.29mmol, 96%) as a clear film. 1H NMR (CDCI3) δ 1.27 (3H, t), 3.89 (3H, s), 4.30 (2H, m), 6.47 (1H, s), 6.97 (4H, m), 7.46 (1H, m), 8.06 (2H, d). LCMS (1) Rt: 2.26min; m/z (ES+) 379.
Step c - ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate
Figure imgf000086_0001
To a stirred solution of 3-ethoxy-1-(4-methoxyphenyl)-1 ,3-dioxopropan-2-yl 2,6- difluorobenzoate (0.082g, 0.22mmol) in acetic acid (3 ml.) was added ammonium acetate (0.125g, 1.62mmol) and the reaction mixture heated to reflux for 3 hours. A further portion of ammonium acetate (0.017g, 0.22mmol) was added the reaction mixture heated to reflux for 1 hour. The reaction was diluted with water and extracted with EtOAc. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 15% EtOAc in hexanes as eluent to afford ethyl 2-(2,6- difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylate (0.041g, 0.11mmol, 53%) as a white crystalline solid. 1H NMR (CDCI3) δ 1.41 (3H, t), 3.87 (3H, s), 4.43 (2H, q), 6.99 (2H1 d), 7.07 (2H, t), 7.49 (1H, m), 8.15 (2H, d). LCMS (1) Rt: 2.46min; m/z (ES+) 360.
Step d - 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid
Figure imgf000086_0002
To a stirred solution of ethyl 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5- carboxylate (0.03Og, O.Oδmmol) in THF and H2O (1:1, 3mL) was added lithium hydroxide hydrate (0.008g, 0.33mmol) and the reaction mixture stirred at room temperature for 2.5 hours. The THF was removed in vacuo and 1N aqueous HCI was added and the resultant precipitate collected by filtration to afford 2-(2,6-difluorophenyl)- 4-(4-methoxyphenyl)oxazole-5-carboxy!ic acid (0.027g, O.Oδmmol, 98%) as a white solid which was used without further purification. LCMS (1) Rt: 1.24min; m/z (ES+) 332.
Step e - 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxamide
Figure imgf000087_0001
To a solution of 2-(2,6-difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxylic acid (0.026g, 0.08mmol) and hydroxybenzotriazole monohydrate (0.012g, O.Oδmmol) in DMF (3mL) was added 0.5M ammonia in dioxane (0.471 mL, 0.24mmol) and the reaction mixture stirred at room temperature for 10 minutes. 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide (0.015g, 0.08mmol) was then added and the resulting reaction mixture stirred at room temperature overnight. After a further addition of hydroxybenzotriazole monohydrate (O.OOδg, 0.05mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.01Og, O.Oδmmol) and 0.5M ammonia in dioxane (0.315ml_, 0.1116mmo!) the reaction mixture was stirred at room temperature for 4 hours. The solvent was evaporated in vacuo, and the residue was partitioned between DCM (1OmL) and water (1OmL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6- difluorophenyl)-4-(4-methoxyphenyl)oxazole-5-carboxamide (0.018g, O.Oδmmol, 69%) as a white solid. 1H NMR (CD3OD) δ 3.88 (3H, s), 7.03 (2H, d), 7.25 (2H, t), 7.68 (1H, m), 8.21 (2H, d). LCMS (2) Rt: 2.80; m/z (ES+) 331.
General Method E
General Method E comprises the series of reactions set out in Scheme 5 above.
Example E-1 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxamide
Step a - ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (see J. Am. Chem. Soc. (2005) 127, 5784-5785)
Figure imgf000087_0002
To a stirred solution of potassium ferf-butoxide (0.84g, 7.5mmol) in dry THF (5.25mL) under an N2 atmosphere at -780C was added a cooled (-780C) solution of N- (diphenylmethylene)glycine ethyl ester (2.0Og, 7.5mmol) in dry THF (3mL), dropwise. The resulting solution was stirred at -780C for 30 minutes when it was added via canula to a stirred solution of 2-thiophene carbonyl chloride (0.8OmL, 7.5mmol) in dry THF (3mL) under an N2 atmosphere at -78°C. The resulting mixture was stirred at -780C for 1 hour. The reaction was warmed to room temperature, 3N aqueous HCI (7.5mL) was then added and the mixture stirred for 15 minutes. The resulting mixture was then concentrated in vacuo, diluted with water and washed with Et2O. The aqueous phase was evaporated to dryness to afford ethyl 2-amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (1.345g) as a pale solid which was used without further purification. LCMS (2) Rt: 1.44min; m/z (ES+) 214.
Step b - ethyl 2-(2,6-difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate
Figure imgf000088_0001
To a stirred mixture of crude ethyl 2~amino-3-oxo-3-(thiophen-2-yl)propanoate hydrochloride (0.44g), hydroxybenzotriazole monohydrate (0.417g, 2.7mmol) and 2,6- difluorobenzoic acid (0.431 g, 2.7mmol) in DMF (5.5mL) was added triethylamine (0.38mL, 5.2mmol) followed by 1~(3-(dimethylamino)propyl)-3-ethyl-carbodiirnide hydrochloride (0.575g, 3.0mmol). The resulting mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was partitioned between water and DCM. The organic phase was separated, washed with water, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 20% EtOAc in hexane as eluant to afford ethyl 2-(2,6- difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate (0.123g, 0.35mmol, 20%). 1H NMR (CDCI3) δ 1.27 (3H, t), 4.28 (2H, m), 6.21 (1H, d), 7.00 (2H, t), 7.26 (1H, dd), 7.44 (2H, m), 7.83 (1H, dd), 8.20 (1H, dd). LCMS (1) Rt: 2.10min; m/z (ES+) 354.
Step c - ethyl 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylate
Figure imgf000088_0002
A solution of ethyl 2-(2,6-difluorobenzamido)-3-oxo-3-(thiophen-2-yl)propanoate (0.12Og, 0.34mmol) in phosphorous oxychloride (0.4ml_, 4.29mmol) was stirred at 750C overnight. The reaction was cooled to room temperature and then poured into ice-water. The resultant mixture was basified with solid sodium bicarbonate and then extracted with EtOAc. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylate (0.096g, 0.29mmol, 84%) as a brown solid. 1H NMR (CDCI3) δ 1.40 (3H, t), 4.23 (2H, q), 7.00 (2H, t), 7.11 (1 H, dd), 7.40 (1H, m), 7.45 (1H1 dd), 8.07 (1H, dd). LCMS (1) Rt: 2.58min; m/z (ES+) 336.
Step d - 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylic acid
Figure imgf000089_0001
To a solution of ethyl 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylate (0.096g, 0.29mmol) in MeOH (6ml_) was added 1M potassium hydroxide solution (8mL, δ.Ommol) and the resulting mixture stirred at 550C overnight. The reaction was cooled to room temperature, acidified with 4N HCI and extracted with DCM. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6- difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylic acid (0.078g, 0.25mmol, 89%) as an off white solid which was used without further purification. LCMS (1 ) Rt: 1.41 min; m/z (ES+) 308.
Step e - 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxamide
Figure imgf000089_0002
To a solution of 2-(2,6-difluorophenyl)-5-(thiophen-2-yl)oxazole-4-carboxylic acid (0.078g, 0.25mmol) and hydroxybenzotriazole monohydrate (0.039g, 0.25mmol) in DMF (2mL) was added a 0.5M ammonia in dioxane solution (1.5mL, 0.75mmol) and the reaction mixture was stirred at room temperature for 10 minutes. 1-(3- (Dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.054g, 0.28mmol) was then added and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6- difluorophenyl)-5-(thiophen-2-yI)oxazole-4-carboxamide (0.0031g, 0.01 mmol, 4%) as a white solid. 1H NMR (DMSO) δ 7.25 (1H1 dd), 7.40 (2H, t), 7.69 - 7.76 (3H, m), 7.84 (1H, dd), 8.17 (1H, dd). LCMS (2) Rt: 2.73min; m/z (ES+) 307.
In a similar manner as described in example E-1 the compounds described in examples E-2 to E-4 were prepared.
Example E-2 2-(2,6-dJfluorophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000090_0001
1H NMR (DMSQ) δ 3.84 (3H, s), 7.10 (2H, d), 7.39 (2H, t), 7.66 (1H, br. s), 7.67 (1H, br. s), 7.73 (1H1 m), 8.24 (2H, d). LCMS (2) Rt: 2.99min; m/z (ES+) 331.
Example E-3 2-(1H-indol-3-yl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000090_0002
1H NMR (DMSO) δ 3.85 (3H, s), 7.09 (2H, d), 7.25 (2H, m), 7.52 (1H, dd), 7.59 (1H, br. s), 7.79 (1H, br. s), 8.23 (1H, d), 8.39 (3H, m), 11.96 (1H, br. s). LCMS (2) Rt: 2.73min; m/z (ES+) 334.
Example E-4 2-(1H-indol-3-yl)-5-(thiophen-2-yl)oxazole-4-carboxamide
Figure imgf000090_0003
1H NMR (DMSO) δ 7.21-7.29 (3H, m), 7.53 (1H, dd), 7.64 (1H, br. s), 7.76 (1H, dd), 7.80 (1H1 br.s ), 8.20 (1H, dd), 8.22 (1H1 d), 8.39 (1H, dd), 11.99 (1H, br. s). LCMS (2) Rt: 2.73min; m/z (ES+) 310.
General Method F
General Method F comprises the series of reactions set out in Scheme 6 above.
Boronic acid synthesis
4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid
Figure imgf000091_0001
A mixture of 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (0.12Og, 0.55mmol), 1-(2-chloroethyl)piperidine hydrochloride (0.10Og, 0.54mmol), potassium carbonate (0.226g, 1.64mmol) and 18-crown-6 (0.072g, 0.27mmol) in MeCN (3mL) was heated in the microwave at 18O0C for 10 minutes. The mixture was diluted with MeOH and a small amount of water and purified by SPE using a MP-TsOH resin (1000mg) cartridge. The solvent was removed in vacuo to afford 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid (0.129g, 0.52mmol, 95%) which was used without further purification. LCMS (1) Rt: 1.55; m/z (ES+) 250.
4-(2-(dimethylamino)ethoxy)phenylboronic acid
Figure imgf000091_0002
Prepared in a manner similar to that described for the preparation of 4-(2-(piperidin-1 ■ yl)ethoxy)phenylboronic acid. LCMS (1) Rt: 1.19; m/z (ES+) 210.
4-(2-morpholinoethoxy)phenylboronic acid
Figure imgf000091_0003
Prepared in a manner similar to that described for the preparation of 4-(2-(piperidin-1- yl)ethoxy)phenylboronic acid. LCMS (1) Rt: 1.18; m/z (ES+) 252. 4-((4-acetylpiperazin-1 -yl)methyl)phenylboronic acid
Figure imgf000092_0001
To a stirred mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (0.12Og, 0.4mmol) and potassium carbonate (0.056g, 0.4mmol) in DMF (3ml_) was added N-acetylpiperazine (0.052g, 0.4mmol) and the resulting reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo. The residue was suspended in MeOH and purified by SPE using an MP-TsOH resin (1000mg) cartridge to afford 4-((4-acetylpiperazin-1-yl)methyl)phenylboronic acid as an oil which was used without further purification. LCMS (1) Rt: 1.04min; m/z (ES+) 263.
4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid
Figure imgf000092_0002
Prepared in a manner similar to that described for the preparation of 4-((4- acetylpiperazin-1-yl)methyl)phenylboronic acid. LCMS (1) Rt: 0.91 min; m/z (ES+) 235.
4-((2-morpholinoethoxy)methyl)phenylboronic acid
Figure imgf000092_0003
Prepared in a manner similar to that described for the preparation of 4-((4- acetylpiperazin-1-yl)methyl)phenylboronic acid. LCMS (1) Rt: 0.27min; m/z (ES+) 266.
tert-butyl 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)piperazine-1 - carboxylate
Figure imgf000092_0004
To a stirred mixture of 2-(4-bromophenyl)-4,4,5,5-tetramethyi-1,3,2-clioxaborolane (0.114g, 0.4mmol) and potassium carbonate (0.06Og, 0.43mmol) in DMF (3ml_) was added te/f-Butyl 1-piperazinecarboxylate (0.071 g, 0.4mmol) and the resulting reaction mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the crude te/f-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl)piperazine- 1-carboxylate obtained was used without further purification. LCMS (1) Rt: 2.56min; m/z (ES+) 403.
Example F-1 2-(2,6-difluorophenyl)-5-phenyloxazole-4-carboxamide
Step a - 5-amino-2-(2,6-difluorophenyl)oxazole-4-carbonitrile
Figure imgf000093_0001
To a solution of aminomaiononitriie p-toluenesulfonate (0.05Og, 0.2mmol) in NMP (0.5mL) was added 2,6-difluorobenzoyl chloride (27ul, 0.21 mmol) and the resulting solution heated in the microwave at 1200C for 5 minutes. The solution was diluted with EtOAc and water. The organic phase was washed with water and brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-amino-2-(2,6- difluorophenyl)oxazole-4-carbonitrile (0.03Og, 0.14mmol, 69%) as an off-white solid. 1H NMR (DMSO) δ 7.30 (2H, t), 7.61 (1H1 m), 8.14 (2H, br. s). LCMS (1) Rt: 1.59 min; m/z (ES+) 222.
Step b - 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile
Figure imgf000093_0002
To a stirred solution of copper bromide (2.02g, 9.0mmol) in dry acetonitrile (64mL) under an N2 atmosphere at O0C was added terf-butyl nitrite (0.6OmL, δ.Ommol). 5-Amino-2- (2,6-difluorophenyl)oxazole-4-carbonitrile was then added in portions. The resulting solution was stirred at O0C for 30 minutes and then warmed to room temperature and stirred for a further 30 minutes. The reaction was partitioned between water and Et2O. The organic layer was washed with 1 M HCI and the combined aqueous phases extracted with Et2O. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel chromatography using a gradient of 0-20% EtOAc in hexane to afford 5-bromo-2-(2,6-difluorophenyl)oxazole-4- carbonitrile (0.487g, 1.7mmol, 38%) as a white solid. 1H NMR (CDCI3) δ 7.02 (2H, t), 7.47 (1 H, m). LCMS (1) Rt: 2.20min.
Step c - 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000094_0001
A solution of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.01Og, 0.04mmol) in concentrated H2SO4 (0.4mL) was stirred at room temperature for 4 hours. The reaction was neutralised with saturated sodium bicarbonate solution and extracted with EtOAc. The organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 5- bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.01Og, 0.03mmol, 94%) as a white solid. 1H NMR (CDCI3) δ 5.79 (1H, br. s), 6.95 (1 H, br. s), 7.07 (2H1 1), 7.49 (1H, m). LCMS (1) Rt: 1.59min; m/z (ES+) 303/305.
Step d - 2-(2,6-difluorophenyl)-5-phenyloxazole-4-carboxamide
Figure imgf000094_0002
A mixture of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.06Og, 0.2mmol), phenyl boronic acid (0.048g, 0.4mmol), Pd(dppf)2CI2 (O.OOδg, 0.01 mmol) and 1M sodium carbonate solution (0.395mL, 0.4mmol) in acetonitrile (4mL) was heated in the microwave at 150°C for 15 minutes. The reaction mixture was partitioned between 1M sodium hydroxide solution and EtOAc and the aqueous phase washed with EtOAc. The organic phase was passed through a MP-SH resin cartridge (0.5g) and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6- difluorophenyl)-5-phenyloxazole-4-carboxamide (0.0047g, 0.02mmol, 8%) as a white solid. 1H NMR (DMSO) δ 7.40 (2H, t,), 7.54 (3H, m), 7.75 (3H, m), 8.24 (2H, m). LCMS (2) Rt: 2.89min; m/z (ES+) 301. Example F-2 2-(2,6-difIuorophenyl)-5-(pyridin-2-yl)oxazole-4-carboxamide
Figure imgf000095_0001
A mixture of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.05Og, 0.16mmol), tri-n-butyl(2-pyridyl)tin (0.12Og, 0.32mmol) and tetrakis(triphenylphosphine)palladium(0) (0.01Og, O.OOβmmol) in acetonitrile (2.5mL) was heated in the microwave for 15 minutes at 1500C. The reaction was diluted with MeOH and passed through a MP-SH resin cartridge (0.5g), then purified by SPE using a MP-TsOH resin (500mg) cartridge and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2- (2,6-difluorophenyl)-5-(pyridin-2-yl)oxazole-4-carboxamide (0.029g, O.IOmmol, 58%) as a white solid. 1H NMR (DMSO) δ 7.41 (2H, t), 7.55 (1H, ddd), 7.76 (1H, m), 7.88 (1 H, br. s), 8.06 (1H, ddd), 8.32 (1H, dt), 8.77 (1H, ddd), 9.10 (1H, br. s). LCMS (2) Rt: 2.23min; m/z (ES+) 302.
In a similar manner as described in example F- 1 the compounds described in examples F-3 to F-37 were prepared.
Example F-3 2-(2,6-difluorophenyl)-5-(4-(dimethylamino)phenyl)oxazole-4-carboxamide
Figure imgf000095_0002
1H NMR (DMSO) δ 3.01 (6H, s), 6.81 (2H, d), 7.38 (2H, t), 7.57 (1H, br. s), 7.58 (1H, br, s), 7.71 (1H, m), 8.16 (2H, d). LCMS (2) Rt: 3.16min; m/z (ES+) 344.
Example F-4 2-(2,6-difluorophenyl)-5-(4-morpholinophenyl)oxazole-4-carboxamide
Figure imgf000096_0001
1H NMR (DMSO) δ 3.28 (4H, m), 3.76 (4H, m), 7.07 (2H, d), 7.38 (2H, t), 7.63 (1H, br. s), 7.64 (1 H, br. s), 7.72 (1H1 m), 8.17 (2H, d). LCMS (2) Rt: 2.90min; m/z (ES+) 386.
Example F-5 2-(2,6-difluorophenyl)-5-(thiophen-3-yl)oxazole-4-carboxamide
Figure imgf000096_0002
1H NMR (DMSO) δ 7.40 (2H, t), 7.73 (4H, m), 7.87 (1H, dd), 8.68 (1H, dd). LCMS (2) Rt: 2.90min; m/z (ES+) 307.
Example F-6 2-(2,6-difluorophenyl)-5-(4-(methylsulfonyl)phenyl)oxazole-4-carboxamide
Figure imgf000096_0003
1H NMR (DMSO) δ 3.30 (3H, s), 7.42 (2H, t), 7.77 (1 H, m), 7.90 (2H, br. s), 8.09 (2H, d), 8.48 (2H, d). LCMS (2) Rt: 2.46min; m/z (ES+) 379.
Example F-7 2-(2,6-difluorophenyl)-5-(6-(dimethylamino)pyridin-3-yl)oxazole-4-carboxamide
Figure imgf000096_0004
1H NMR (DMSO) δ 3.11 (6H, s), 6.77 (1 H, d), 7.38 (2H, t), 7.62 (1H1 br. s), 7.65 (1H, br. S), 7.71 (1H, m), 8.34 (1H, dd), 8.95 (1H1 dd). LCMS (2) Rt: 2.37 min; m/z (ES+) 345.
Example F-8 2-(2,6-difluorophenyl)-5-(pyridin-4-yl)oxazole-4-carboxamide
Figure imgf000097_0001
1H NMR (DMSO) δ 7.42 (2H, t), 7.77 (1H, m), 7.92 (1H, br. s), 7.94 (1H, br. s), 8.21 (2H, dd), 8.76 (2H, dd). LCMS (2) Rt: 2.18min; m/z (ES+) 302.
Example F-9 2-(2,6-difluorophenyl)-5-(pyridin-3-yl)oxazole-4-carboxamide
Figure imgf000097_0002
1H NMR (DMSO) δ 7.41 (2H, t), 7.59 (1H, ddd), 7.76 (1H1 m), 7.85 (2H, br. s), 8.60 (1H, ddd), 8.67 (1H, dd), 9.32 (1H, dd). LCMS (2) Rt: 2.18min; m/z (ES+) 302.
Example F-10
2-(2,6-difluorophenyl)-5-(4-((4-methylpiperazin-1-yl)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000097_0003
The title compound was prepared using 4-((4-methylpiperazin-1-yl)methyl)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 2.15 (3H, s), 2.35 (8H, m), 3.52 (2H, s), 7.40 (2H, t), 7.45 (2H, d), 7.74 (3H, m), 8.18 (2H, d). LCMS (2) Rt: 2.58min; m/z (ES+) 413.
Example F-11 5-(4-((4-acetylpiperazin-1-yl)methyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000098_0001
The title compound was prepared using 4-((4-acetylpiperazin-1-yl)methyl)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 1.91 (3H, s), 2.33 (2H, m), 2.40 (2H, m), 3.44 (4H, m), 3.57 (2H, s), 7.40 (2H, t), 7.48 (2H, d), 7.74 (3H, m), 8.20 (2H, d). LCMS (2) Rt: 2.44min; m/z (ES+) 441.
Example F-12
2-(2,6-difluorophenyl)-5-(4-((2-morpholinoethoxy)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000098_0002
The title compound, prepared using 4-((2-morpholinoethoxy)methyl)phenylboronic acid synthesised as described above, was isolated as the formate salt. 1H NMR (DMSO) δ 3.53 (6H, m), 4.03 (6H, m), 4.89 (2H, s), 7.42 (2H, t), 7.75 (3H, m), 7.86 (2H, s), 8.38 (2H, d), 8.50 (1H, s). LCMS (2) Rt: 2.46min; m/z (ES+) 443.
Example F-13 2-(2,6-difluorophenyl)-5-(4-(2-morpholinoethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000098_0003
The title compound was prepared using 4-(2-morpholinoethoxy)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 2.48 (4H, t), 2.72 (2H, t), 3.58 (4H, t), 4.17 (2H, t), 7.10 (2H, d), 7.39 (2H, t), 7.68 (1 H, br. s), 7.69 (1H, br. s), 7.72 (1H, m), 8.22 (2H, d). LCMS (2) Rt: 2.69min; m/z (ES+) 430.
Example F-14 2-(2,6-difluorophenyl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000099_0001
The title compound was prepared using 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 1.39 (2H, m), 1.76 (4H1 m), 2.45 (4H1 m), 2.68 (2H, m), 4.15 (2H, t), 7.10 (2H, d), 7.39 (2H, t), 7.68 (1 H, br. s), 7.69 (1H, br, s), 7.73 (1H, m), 8.22 (2H, d). LCMS (2) Rt: 3.38min; m/z (ES+) 428.
Example F-15
2-(2,6-difluorophenyJ)-5-(4-(2-(dimethylamino)ethoxy)phenyI)oxazole-4- carboxamide
Figure imgf000099_0002
The title compound was prepared using 4-(2-(dimethylamino)ethoxy)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 2.22 (6H, s), 2.64 (2H, t), 4.13 (2H, t), 7.10 (2H, d), 7.39 (2H, t), 7.68 (1H, br. s), 7.69 (1H, br. s), 7.72 (1 H, m), 8.22 (2H, d). LCMS (2) Rt: 2.86min; m/z (ES+) 388.
Example F-16 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Step a - fert-butyl 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl) benzylcarbamate
Figure imgf000100_0001
1H NMR (DMSO) δ 1.41 (9H, s), 4.19 (2H, d), 7.38 (2H, d), 7.40 (2H, t), 7.51 (1H, t), 7.74 (3H, m), 8.17 (2H, d). LCMS (2) Rt: 3.14min; m/z (ES+) 430.
Step b - 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000100_0002
To a solution of terf-butyl 4-(4-carbamoyl~2-(2,6-difluorophenyl)oxazol-5- yl)benzylcarbamate (0.11Og, 0.26mmol) in DCM (1OmL) was added 4M HCI in dioxane (1.5mL, δ.Ommol) and the resulting mixture stirred at room temperature overnight. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(aminomethyl)pheny!)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.0366g, 0.11mmol, 43%) as a white solid as the formate salt. 1H NMR (DMSO) δ 3.95 (2H, s), 7.40 (2H, t), 7.55 (2H, d), 7.74 (3H, m), 8.21 (2H, d), 8.33 (1 H1 s). LCMS (2) Rt: 2.30min; m/z (ES+) 330.
Example F-17 5-(4-carbamoylphenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000100_0003
1H NMR (DMSO) δ 7.41 (2H, t), 7.53 (1H, br. s), 7.75 (1 H1 m), 7.81 (2H, br. s), 8.01 (2H, d), 8.12 (1H, br. s), 8.32 (2H, d). LCMS (2) Rt: 2.08min; m/z (ES+) 344.
Example F-18 2-(2,6-difluorophenyl)-5-(6-methoxypyridin-3-yl)oxazole-4-carboxamide
Figure imgf000101_0001
1H NMR (DMSO) δ 3.94 (3H, s), 7.01 (1 H, d), 7.40 (2H, t), 7.70-7.80 (3H, m), 8.51 (1H, dd), 9.01 (1H1 dd). LCMS (2) Rt: 2.74min; m/z (ES+) 332.
Example F-19 2-(2,6-difluorophenyl)-5-(6-morpholinopyridin-3-yl)oxazole-4-carboxamide
Figure imgf000101_0002
1H NMR (DMSO) δ 3.60 (4H, m), 3.71 (4H, m), 6.98 (1H, d), 7.39 (2H1 1), 7.66 (1H, br. s), 7.68 (1H1 br. s), 7.72 (1H, m), 8.39 (1H, dd), 8.97 (1H, d). LCMS (2) Rt: 2.64min; m/z (ES+) 387.
Example F-20 2-(2,6-difluorophenyl)-5-(4-(morpholinomethyl)phenyl)oxazole-4-carboxamide
Figure imgf000101_0003
1H NMR (DMSO) δ 2.38 (4H, br. t), 3.53 (2H, s), 3.59 (4H, t), 7.40 (2H, t), 7.47 (2H, d), 7.74 (3H, m), 8.19 (2H, d). LCMS (2) Rt: 2.67min; m/z (ES+) 400.
Example F-21 5-(4-benzenesulfonamide)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000102_0001
1H NMR (DMSO) δ 7.41 (2H, t), 7.52 (2H, s), 7.76 (1H, m), 7.84 (2H, br. s), 7.96 (2H, d), 8.40 (2H, d). LCMS (2) Rt: 2.25min; m/z (ES+) 380.
Example F-22 5-(4-aminophenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000102_0002
1H NMR (DMSO) δ 5.78 (2H, br. s), 6.64 (2H, d), 7.37 (2H, t), 7.54 (2H, br. s), 7.70 (1H1 m), 8.01 (2H, d). LCMS (2) Rt: 2.36min; m/z (ES+) 316.
Example F-23 5-(4-acetamidophenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000102_0003
1H NMR (DMSO) δ 2.09 (3H, s), 7.39 (2H, t), 7.70-7.74 (5H, m), 8.21 (2H, d), 10.24 (1H, br. s). LCMS (2) Rt: 2.28min; m/z (ES+) 358.
Example F-24
2-(2-chloro-6-fluorophenyl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000103_0001
The title compound was prepared using 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid synthesised as described above. After purification by preparative HPLC the compound was purified by SPE using a MP-TsOH (500mg) cartridge. 1H NMR (DMSO) δ 1.38 (2H, m), 1.50 (4H, quin), 2.44 (4H, br. t), 2.68 (2H, t), 4.15 (2H, t), 7.09 (2H, d), 7.52 (1H, ddd), 7.61 (1H, d), 7.64 (1 H, br. s), 7.70-7.76 (2H, m), 8.22 (2H, d). LCMS (2) Rt: 3.45min; m/z (ES+) 444/446.
Example F-25 2-(2,6-dichlorophenyl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000103_0002
The title compound was prepared using 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid synthesised as described above. After purification by preparative HPLC the compound was purified by SPE using a MP-TsOH (500mg) cartridge. 1H NMR (DMSO) δ 1.39 (2H, m), 1.50 (4H1 quin), 2.44 (4H, br. t), 2.67 (2H, t), 4.15 (2H, t), 7.08 (2H, d), 7.63 (1H, br. s), 7.68-7.76 (3H, m), 7.78 (1H, br. s), 8.21 (2H, d). LCMS (2) Rt: 3.60min; m/z 460/462/464.
Example F-26 2-(2-fluorophenyl)-5-(4-(2-(piperidin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000103_0003
The title compound was prepared using 4-(2-(piperidin-1-yl)ethoxy)phenylboronic acid synthesised as described above. 1H NMR (DMSO) δ 1.36-1.42 (2H, m), 1.51 (4H, quin), 2.47 (4H, br s), 2.70 (2H, t), 4.16 (2H, t), 7.10 (2H, d), 7.41-7.49 (2H, m), 7.62-7.68 (2H, m), 7.71 (1H, br s), 8.17 (1H, ddd), 8.30 (2H, d). LCMS (2) Rt: 3.31min; m/z 410.
Example F-27 2-(2-fluorophenyl)-5-(4-(2-morpholinoethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000104_0001
1H NMR (DMSO) δ 2.49 (4H, m), 2.73 (2H, t), 3.59 (4H, t), 4.18 (2H, t), 7.11 (2H, d), 7.41-7.49 (2H, m), 7.43 (1H, ddd), 7.47 (1H, ddd), 7.62-7.68 (2H, m), 7.72 (1H, br s), 8.18 (1 H, ddd), 8.30 (2H, d). LCMS (2) Rt: 2.67min; m/z 412.
Example F-28 2-(2,6-difluorophenyl)-5-(3,4-dimethoxyphenyl)oxazole-4-carboxamide
Figure imgf000104_0002
1H NMR (CDCI3) δ 3.95 (3H, s), 4.00 (3H, s), 5.53 (1H, br s), 6.67 (1H, d), 7.08 (2H, t), 7.26 (1H, br s), 7.47 (1H, tt), 7.92 (1H, dd), 8.35 (1 H, d). LCMS (2) Rt: 2.68min; m/z (ES+) 361.
Example F-29 5-(benzo[d][1,3]dioxol-5-yl)-2-(2J6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000104_0003
1H NMR (CDCI3) 5 5.53 (1H, br s), 6.03 (2H, s), 6.92 (1 H, d), 7.08 (2H, t), 7.22 (1H, br s), 7.47 (1H, quin), 7.96 (1H, s), 8.01 (1H, d). LCMS (2) Rt: 2.84min; m/z (ES+) 345.
Example F-30 2-(2)6-Difluorophenyl)-5-(3-(morpholine-4-carbonyl)phenyl)oxazole-4-carboxamide
Figure imgf000105_0001
1H NMR (DMSO) δ 3.41 (2H, br s), 3.64 (6H, br m), 7.40 (2H, t), 7.53-7.56 (1H, m), 7.63 (1H, t), 7.71-7.79 (3H, m)r 8.24-8.26 (1 H, m), 8.33 (1H, t). LCMS (2) Rt: 2.27min; m/z (ES+) 414.
Example F-31 2-(2,6-Difluorophenyl)-5-(3-(piperidine-1-carbonyl)phenyl)oxazole-4-carboxamide
Figure imgf000105_0002
1H NMR (DMSO) δ 1.50-1.63 (6H, br m), 3.32 (2H, br m), 3.61 (2H, br m), 7.41 (2H, t), 7.50-7.51 (1 H, m), 7.62 (1H, t), 7.71-7.80 (3H, m), 8.23-8.27 (1H, m), 8.31 (1 H, s). LCMS (2) Rt: 2.71min; m/z (ES+) 412.
Example F-32
2-(2,6-difluorophenyl)-5-(4-(2-(piperidin-1-yl)ethylamino)phenyl)oxazole-4- carboxamide Step a - N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzenamine
Figure imgf000106_0001
N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (0.006g, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 1-(2-chloroethyl)-piperidine (0.05Og, 0.3mmol) in MeCN (2ml) to 11O0C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the product as a white solid (0.009g, 0.027mmol). LCMS (3) 2.50min; m/z (ES+) 331.
Step b - 2-(2,6-difluorophenyl)-5-(4-(2-(piperidin-1-yl)ethylamino)phenyl)oxazole-4- carboxamide
Figure imgf000106_0002
The title compound was prepared from N-(2-(piperidin-1-yl)ethyl)-4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)benzenamine synthesised as described in Step a above. 1H NMR (DMSO) δ 1.35-1.45 (2H, m), 1.49-1.58 (4H, m), 2.35-2.45 (4H, m), 2.45-2.55 (2H, m), 3.21 (2H, q), 6.15 (1H, t), 6.70 (2H, d), 7.39 (2H, t), 7.55 (2H, br. s), 7.65-7.75 (1H, m), 8.08 (2H, d). LCMS (2) 3.19min; m/z (ES+) 427.
Example F-33
2-(2,6-difluorophenyl)-5-(4-(2-(dimethylamino)ethylamino)phenyl)oxazole-4- carboxamide
Step a - N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine
Figure imgf000107_0001
N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (0.006g, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 2-dimethylaminoethyl chloride hydrochloride (0.043g, 0.3mmo!) in MeCN (2ml) to 11O0C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the desired compound as a white solid, (0.025g, 0.086mmol). LCMS (3) 2.12min; m/z (ES+) 291
Step b - 2-(2,6-difluorophenyl)-5-(4-(2-(dimethylamino)ethylamino)phenyl)oxazole-4- carboxamide
Figure imgf000107_0002
Prepared from N-(2-(dimethylamino)ethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine synthesised as described in Step a above. 1H NMR (DMSO) δ 2.20 (6H, s), 2.48 (2H, t), 3.19 (2H, q), 6.15 (1H, t), 6.70 (2H, d), 7.39 (2H, t), 7.55 (2H, br. s), 7.65-7.75 (1H, m), 8.08 (2H, d). LCMS (2) 2.65min; m/z (ES+) 387.
Example F-34
2-(2,6-difluorophenyl)-5-(4-(2-morpholinoethylamino)phenyl)oxazole-4- carboxamide
Step a: N-(2-morpholinoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine
Figure imgf000107_0003
N-(2-morpholinoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine was prepared by heating 4-(4J4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzenamine (0.219g, 1mmol), potassium iodide (O.OOδg, 0.03mmol), potassium carbonate (0.06Og, 0.4mmol) and 2- N-(2-chloroethyl)morpholine hydrochloride (0.056g, 0.3mmol) in MeCN (2ml) to 11O0C by microwave irradiation for 10 minutes. The crude reaction was purified by preparative HPLC to give the desired compound as an off-white solid (0.03Og, 0.090mmol). LCMS (3) 1.91min; m/z (ES+) 333
Step b: 2-(2,6-difluorophenyl)-5-(4-(2-morpholinoethylamino)phenyl)oxazole-4- carboxamide
Figure imgf000108_0001
Prepared from N-(2-morpholinoethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)benzenamine synthesised as described in Step a above. 1H NMR (DMSO) δ 2.4-2.5 (4H, m), 2.52 (2H, t), 3.21 (2H, q), 3.6 (4H, t), 6.15 (1H, t), 6.70 (2H, d), 7.39 (2H, t), 7.55 (2H, br. s), 7.65-7.75 (1 H, m), 8.08 (2H, d). LCMS (2) 2.57min; m/z (ES+) 429.
Example F-35 2-(2,6-difluorophenyl)-5-(naphthalen-1-yl)oxazole-4-carboxamide
Figure imgf000108_0002
1H NMR (DMSO) δ 7.34-7.40 (2H, m), 7.48 (1H, br s), 7.56 (1H, br s), 7.58-7.62 (2H, m), 7.63-7.68 (1 H, m), 7.69-7.77 (1H, m), 7.82-7.86 (1H, m), 7.87-7.91 (1H, m), 8.04-8.08 (1H, m), 8.12-8.16 (1H, m). LCMS (2) 2.97min; m/z (ES+) 351.
Example F-36 2-(2,6-difluorophenyl)-5-(1H-indol-4-yl)oxazole-4-carboxamide
1H NMR (DMSO) δ 6.82 (1H, s), 7.42 (1H, t), 7.35-7.42 (2H1 m), 7.48-7.59 (4H, m), 7.70- 7.80 (1 H, m), 8.19 (1 H, d), 11.32 (1 H, br. s). LCMS (2) 2.49min; m/z (ES+) 340.
Example F-37 2-(2,6-difluorophenyl)-5-(quinolin-8-yl)oxazole-4-carboxamide
Figure imgf000109_0002
1H NMR (DMSO) δ 7.33-7.40 (3H, m), 7.47 (1H, br. s), 7.61 (1H, dd), 7.68-7.78 (2H, m), 8.06 (1H, dd), 8.19 (1 H, dd), 8.48 (1H, dd), 8.90 (1 H, dd). LCMS (2) 2.35min; m/z (ES+) 352.
General Methods G-J
Figure imgf000110_0001
Method H
Figure imgf000110_0002
Figure imgf000110_0003
Method J
Figure imgf000110_0005
Figure imgf000110_0004
Example G-1 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide
Step a - ferf-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)benzyl)pipera2ine- 1-carboxylate
Figure imgf000110_0006
Prepared in a similar manner to the procedure outlined for the synthesis of Example F- 1 using te/f-butyl 4-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzyl)piperazine-1- carboxylate synthesised as described above. The product obtained was used without further purification. LCMS (2) Rt: 3.52min; m/z (ES+) 499.
Step b - 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide
Figure imgf000111_0001
To a solution of te/f-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5- yl)benzyl)piperazine-1 -carboxylate (0.10Og1 0.2mmol) in DCM (3mL) was added 4M HCI in dioxane (2mL, δ.Ommol) and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-ylmethyl)phenyl)oxazole-4- carboxamide (0.043g, O.immol, 50%) as a white solid as the formate salt. 1H NMR (DMSO) δ 2.44 (4H, m), 2.88 (4H1 m), 3.55 (2H, s), 7.40 (2H, t), 7.47 (2H, d), 7.75 (3H, m), 8.19 (2H, d), 8.32 (1H, s). LCMS (2) Rt: 2.63min; m/z (ES+) 399.
Example G-2
2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide dihydrochloride
Step a - te/f-butyl 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2- yl)piperazine-1 -carboxylate
Figure imgf000111_0002
Prepared in a similar manner to the procedure outlined for the synthesis of Example F-1. The product was purified by silica gel column chromatography using a gradient of 30- 75% EtOAc in hexanes. 1H NMR (CDCI3) δ 1.49 (9H, s), 3.56 (4H1 m), 3.67 (4H, m), 5.55 (1H, br. d), 6.70 (1H, d), 7.07 (2H, t), 7.18 (1H, br. d), 7.46 (1H, m), 8.69 (1H, dd), 9.01 (1H, dd). LCMS (1) Rt: 2.31 min; m/z (ES+) 486. Step b - 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4-carboxamide
Figure imgf000112_0001
A mixture of te/f-butyl 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2- yl)piperazine-1-carboxylate (0.227g, 0.47mmol) in DCM (3mL) and 4N HCI in dioxane (2mL, δ.Ommol) was stirred at room temperature for 48 hours. The solvent was removed in vacuo to give 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole- 4-carboxamide (0.211g, 0.46mmol, 98%) as a white solid as the dihydrochloride salt. 1H NMR (DMSO) δ 3.20 (4H, m), 3.90 (4H, t), 7.11 (1H, d), 7.39 (2H, t), 7.73 (3H, m), 8.44 (1H, dd), 9.0 (1H, d), 9.24 (1 H, br. s), 9.30 (1H, br. s). LCMS (2) Rt: 2.38min; m/z (ES+) 386.
Example G-3 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000112_0002
Prepared in a similar manner to the method described in Example G-2. The final product was suspended in saturated sodium bicarbonate solution and extracted with EtOAc and DCM. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4- carboxamide as a yellow solid. 1H NMR (DMSO) δ 2.84 (4H, m), 3.20 (4H, m), 7.03 (2H, d), 7.38 (2H, t), 7.61 (1H1 br. s), 7.62 (1H, br. s), 7.72 (1H, m), 8.15 (2H, d). LCMS (2) Rt: 2.60min; m/z (ES+) 385.
Example G-4 2-(2-fluorophenyl)-5-(4-(piρerazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000113_0001
Prepared according to the method described for Example G-3. 1H NMR (DMSO) δ 2.85 (4H, t), 3.21 (4H, t), 7.04 (2H, d), 7.40-7.50 (2H, m), 7.60-7.66 (3H, m), 8.16 (1H1 m), 8.22 (2H, d). LCMS (2) Rt: 2.32min; m/z 367.
Example G-5 2-(2-chloro-6-fluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000113_0002
Prepared according to the method described for Example G-3. 1H NMR (DMSO) δ 2.84 (4H, m), 3.20 (4H, m), 7.02 (2H, d), 7.52 (1H, ddd), 7.58 (1 H, br. s). 7.60 (1H, m), 7.67 (1H, br. s), 7.12 (1 H, m), 8.14 (2H, d). LCMS (2) Rt: 2.59min; m/z (ES+) 401/403.
Example H-1 2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000113_0003
To a stirred suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4~ carboxamide (0.025g, 0.065mmol) in DCE (2mL) under an N2 atmosphere at room temperature was added formaldehyde 37% solution (1OuL, 0.12mmol) followed by sodium triacetoxyborohydride (0.066g, 0.31 mmol) and the resulting mixture stirred at room temperature for 2 hours. The reaction mixture was diluted with DCM and washed with saturated sodium bicarbonate solution. The aqueous phase was extracted with DCM and the combined organic phases dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5~(4-(4-methylpiperazin-1-yl)phenyl)oxazole-4- carboxamide (0.019g, 0.048mmol, 72%) as a white solid. 1H NMR (CDCI3) δ 2.36 (3H, s), 2.57 (4H, t), 3.34 (4H, t), 5.49 (1H, br. s), 6.97 (2H, d), 7.07 (2H, t), 7.19 (1 H, br. s), 7.45 (1 H, m), 8.31 (2H, d). LCMS (2) Rt: 2.75min; m/z (ES+) 399.
Example H-2
2-(2,6-difluorophenyl)-5-(6-(4-methyIpiperazin-1-yl)pyridin-3-yl)oxazole-4- carboxamide
Figure imgf000114_0001
Prepared in a similar manner to that described in Example H-1 except that triethylamine (2.6 equivalents) was added to the reaction prior to the formaldehyde addition. 1H NMR (CDCI3) δ 2.35 (3H, s), 2.52 (4H, t), 3.70 (4H1 1), 5.12 (1 H, br. s), 6.70 (1H, d), 7.07 (2H, t), 7.18 (1H, br. s), 7.46 (1 H, m), 8.68 (1H, dd), 8.99 (1H, d). LCMS (2) Rt: 2.54min; m/z (ES+) 400.
Example 1-1 5-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000114_0002
To a solution of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4- carboxamide (0.029g, 0.075mmol) in DCM (3mL) was added triethylamine (12uL, 0.086mmol) followed by acetyl chloride (6uL, 0.084mmol). The resulting solution was stirred at room temperature for 2 hours when further portion of triethylamine (12uL, 0.086mmol) and acetyl chloride (6uL, 0.084mmol) were added and the reaction stirred at room temperature for 1 hour. The solvent was then removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-(4-acetylpiperazin-1-yl)phenyl)-2-(2,6- difluorophenyl)oxazole-4-carboxamide (0.025g, 0.059mmol, 78%) as a white solid. 1H NMR (DMSO) δ 2.06 (3H, s), 3.28 (2H, m), 3.56 (2H1 m, masked by water), 3.59 (4H, m), 7.08 (2H, d), 7.38 (2H, t), 7.63 (1H, br. s), 7.64 (1H, br. s), 7.72 (1H, m), 8.18 (2H, d). LCMS (2) Rt: 2.52min; m/z (ES+) 427.
Example I-2
5-(6-(4-acetylpiperazin-1-yl)pyridin-3-yl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000115_0001
Prepared in a similar manner to that described in Example 1-1 except that triethylamine (3.3 equivalents) was initially added to the reaction. 1H NMR (DMSO) δ 2.06 (3H, s), 3.56 (4H, m), 3.63 (2H, m), 3.71 (2H, m), 7.00 (1H, d), 7.39 (2H, t), 7.67 (1 H, br. s), 7.69 (1H, br. s), 7.72 (1 H, m), 8.39 (1 H, dd), 8.97 (1H, d), LCMS (2) Rt: 2.34min; m/z (ES+) 428.
Example J-1
4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)phenyl)-N-methylpiperazine-1- carboxamide
Figure imgf000115_0002
To a suspension of 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4- carboxamide (0.029g, 0.075mmol) in DCM (3mL) was added methyl isocyanate (8uL, 0.136mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo to afford 4-(4-(4-carbamoyI-2-(2,6~difluorophenyl)oxazol- 5-yl)phenyl)-N-methylpiperazine-1-carboxamide (0.026g, 0.059mmol, 79%) as a yellow solid. 1H NMR (DMSO) δ 2.85 (3H, d), 3.34 (4H, m), 3.56 (4H1 m), 4.46 (1H, br. q), 5.49 (1H, br. s), 6.95 (2H, d), 7.07 (2H, t), 7.20 (1H, br. s), 7.46 (1 H, m), 8.32 (2H, d). LCMS (2) Rt: 2.43min; m/z (ES+) 442.
Example J -2
4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)pyridin-2-yl)-N- methylpiperazine-1 -carboxamide
Figure imgf000116_0001
To a suspension of 2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-yl)oxazole-4- carboxamide dihydrochloride (0.06Og, 0.13mmol) in DCM (3mL) was added triethylamine (4OuL, 0.29mmol) followed by methyl isocyanate (12uL, 0.20mmol). The resulting solution was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was purified by preparative HPLC and then by SPE using a MP- TsOH resin (500mg) cartridge to afford 4-(5-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol- 5-yl)pyridin-2-yl)-N-methyipiperazine-1-carboxamide (0.0057g, 0.013mmol, 10%) as a yellow solid. 1H NMR (DMSO) δ 2.58 (3H, d), 3.40 (4H, m), 3.61 (4H, m), 6.54 (1H, br. q), 6.99 (1 H, d), 7.38 (2H, t), 7.65 (1 H, br. s), 7.67 (1H, br. s), 7.72 (1 H, m), 8.37 (1H, dd), 8.95 (1H, d). LCMS (2) Rt: 2.27min; m/z (ES+) 443.
Example J-3
4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyl)-N- methy lpiperazine-1 -carboxamide
Figure imgf000117_0001
Prepared according to the method described in example J-1 from 2-(2,6-difluorophenyl)- 5-(4-(piperazin-1-yl)phenylamino)oxa2θle-4-carboxamide. 1H NMR (DMSO) δ 2.58 (3H, d), 3.03 (4H, t), 3.40 (4H1 1), 6.53 (1H, q), 6.96 (2H, d), 7.28 (2H, br. s), 7.29 - 7.34 (4H, m), 7.62 (1H, m), 9.12 (1H, s). LCMS (2) Rt: 2.13min; m/z 457.
General Methods K and L
Method K
Figure imgf000117_0003
Figure imgf000117_0002
Figure imgf000117_0004
Example K-1
2-(2,6-difluorophenyl)-5-(4-((4-fluorophenylsulfonamido)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000118_0001
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide hydrochloride (0.03Og1 0.082mmol) in DCM (2ml_) was added triethylamine (25uL, 0.18mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016g, 0.082mmol) and the resulting mixture stirred at room temperature overnight. Triethylamine (13uL, 0.093mmol) followed by 4-fluorobenzenesulfonyl chloride (0.016g, 0.082mmol) was then added and the reaction stirred for a further 3 hours. After 2 hours triethylamine (6uL, 0.043mmol) and 4-fluorobenzenesulfonyl chloride (0.008g, 0.041 mmol) was added. The solvent was removed in vacuo and the residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-((4-fluorophenylsulfonamido)methyl)phenyl)oxazole-4- carboxamide (0.023Og, 0.047mmot, 57%) as a white solid. 1H NMR (DMSO) δ 4.07 (2H, d), 7.39 (6H, m), 7.74 (3H, m), 7.85 (2H, m), 8.13 (2H, d), 8.32 (1H, t). LCMS (2) Rt: 3.07min; m/z (ES+) 488.
In a similar manner as described in example K-1 the compound described in example K- 2 was prepared.
Example K-2
2-(2,6-difluorophenyl)-5-(4-(phenyIsulfonamidomethyl)phenyl)oxazole-4- carboxamide
Figure imgf000118_0002
1H NMR (DMSO) δ 4.06 (2H, d), 7.38 (2H, d), 7.40 (2H, t), 7.56 - 7.66 (3H, m), 7.73 (3H, m), 7.82 (2H, m), 8.13 (2H, d), 8.28 (1 H, t). LCMS (2) Rt: 3.02min; m/z (ES+) 470.
Example L-1 5-(4-(benzamidomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000119_0001
To a suspension of 5-(4-(aminomethyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide hydrochloride (0.03Og, O.Oδmmol) in DCM (2m L) was added triethylamine (25uL) followed by benzoyl chloride (11uL) and the resulting mixture stirred at room temperature for 2 hours The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-(benzamidomethyl)phenyl)-2-(2,6- difluorophenyl)oxazole-4-carboxamide (0.0128g, 0.03mmol, 36%). 1H NMR (DMSO) δ 4.54 (2H, d), 7.40 (2H, t), 7.49 (4H, m), 7.55 (1H, m), 7.74 (3H, m), 7.92 (2H, m), 8.18 (2H, d), 9.15 (1H, t). LCMS (2) Rt: 2.82min; m/z (ES+) 434.
In a similar manner as described in example L-1 the compounds described in examples L-2 to L-3 were prepared.
Example L-2
2-(2,6-difluorophenyl)-5-(4-((4-fluorobenzamido)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000119_0002
1H NMR (DMSO) δ 4.54 (2H, d), 7.32 (2H, t), 7.39 (2H, t), 7.47 (2H, d), 7.73 (3H, m), 7.99 (2H, dd), 8.18 (2H, d), 9.17 (1H, t). LCMS (2) Rt: 2.91min; m/z (ES+) 452.
Example L-3
2-(2,6-difluorophenyl)-5-(4-((thiophene-2-carboxamido)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000120_0001
1H NMR (DMSO) δ 4.52 (2H, d), 7.17 (1H1 dd), 7.39 (2H, t), 7.46 (2H, d), 7.73 (3H, m), 7.79 (1H, d), 7.83 (1H, d), 8.19 (2H, d), 9.14 (1 H, t). LCMS (2) Rt: 2.78min; m/z (ES+) 440.
General Method M
General Method M comprises the series of reactions set out in Scheme 7 above.
Example M-1 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxamide
Step a - ethyl 5-(4-methoxyphenyl)oxazo!e-4-carboxylate (see Org. Lett. (2006) 8, 5231-5234)
Figure imgf000120_0002
A solution of ethyl isocyanoacetate (2.126ml_, 19.5mmol) and p-anisole chloride (2.765g, 16.2mmol) in acetonitrile (2OmL) was stirred for 20 minutes. 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (7.329mL, 48.6mmol) was then added and the reaction heated in the microwave at 11O0C for 10 minutes. The solvent was then removed in vacuo and the residue purified by silica gel column chromatography using 35% EtOAc in hexane as eluant to afford ethyl 5-(4-methoxyphenyl)oxazole-4-carboxylate (1.211g, 4.9mmol, 30%). 1H NMR (CDCI3) δ 1.41 (3H, t), 3.87 (3H, s), 4.41 (2H, q), 6.99 (2H, d), 7.85 (1H, s), 8.07 (2H, d). LCMS (1) Rt: 1.90min; m/z (ES+) 248.
Step b - ethyl 2-iodo-5-(4-methoxypheny!)oxazole-4-carboxylate
Figure imgf000121_0001
To a solution of ethyl 5-(4-methoxyphenyl)oxazole~4-carboxylate (2.75g, 11.1mmol) in anhydrous THF (20 mL) under an N2 atmosphere at -780C was added 1M lithium ιb/s(trimethylsilyl)amide in THF (18mL, 18mmol), dropwise. The reaction mixture was stirred at -780C for one hour. A solution of iodine (5.Og, 19.7mmol) in anhydrous THF (10 mL) was added dropwise and the reaction stirred at -780C for a further 1 hour. The mixture was then warmed to -1O0C and 10% sodium thiosulfate solution and EtOAc was added. The aqueous phase was extracted with EtOAc and the combined organic phase was washed with brine, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 10 - 40% EtOAc in hexanes gradient to afford ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (3.33g, 8.9mmol, 80%) as a white solid. 1H NMR (CDCI3) δ 1.40 (3H1 1), 3.87 (3H, s), 4.41 (2H, q), 6.98 (2H, d), 8.01 (2H, d). LCMS (1) Rt: 2.13min; m/z (ES+) 374.
Step c - 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxamide
Figure imgf000121_0002
To a mixture of ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (0.10Og, 0.27mmol) and 2-thiophenyl boronic acid (0.069g, 0.54mmol) in acetonitrile (2 mL) was added a solution of Pd(dppf)2CI2 (0.01Og, 0.012mmo!) in acetonitrile (0.2mL) followed by 1M aqueous sodium carbonate solution (0.535mL, 0.54mmol). The resulting reaction mixture was heated at 1500C in the microwave for 15 minutes and the solvent was then removed in vacuo. The residue was purified by silica gel column chromatography using a gradient of 4 - 90% EtOAc in hexanes to afford ethyl 5-(4-methoxyphenyl)-2-(thiophen- 2-yl)oxazole-4-carboxylate which was used without further purification. LCMS (1) Rt: 2.45min; m/z (ES+) 330.
To a solution of ethyl 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylate in MeOH (2mL) and DCM (0.5mL) was added 1M aqueous lithium hydroxide solution (2mL, 2mmol). The reaction mixture was stirred at 5O0C overnight and then 2M aqueous HCI (0.125mL) was added and the solvent removed in vacuo to afford 5-(4-methoxyphenyl)- 2-(thiophen-2-yl)oxazole-4-carboxylic acid which was used without further purification. LCMS (1) Rt: 1.34min; m/z (ES+) 302.
To a solution of 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4-carboxylic acid in DCM (2mL) and DMF (1mL) was added hydroxybenzotriazole monohydrate (0.022g, 0.14mmol) followed by 0.5M ammonia in dioxane (1.3mL, 0.65mmol). A solution of 1-(3- (dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.078g, 0.41 mmol) in DMF/DCM (4:1 , 0.5mL) was added and the reaction stirred at room temperature overnight. The solvents were removed in vacuo and the residue was purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4- carboxamide (0.0128g, 0.04mmol, 15%) as a white solid. 1H NMR (CDCI3) δ 3.85 (3H, S)1 5.53 (1H, br. s), 7.00 (2H, d), 7.16 (1H, dd), 7.17 (1H, br. s), 7.48 (1H, dd), 7.74 (1H, dd), 8.32 (2H, d). LCMS (2) Rt: 2.90min; m/z (ES+) 301.
Example M-2 5-(4-methoxyphenyl)-2-phenyloxazole-4-carboxamide
Figure imgf000122_0001
To a solution of 5-(4-methoxyphenyl)-2-phenyloxazole-4-carboxylic acid (prepared according to the method described for 5-(4-methoxyphenyl)-2-(thiophen-2-yl)oxazole-4- carboxylic acid in Example M-1 , 0.032g, 0.11 mmol) and hydroxybenzotriazole monohydrate (0.02g, 0.13mmol) in DCM (2mL) and DMF (1mL) was added 0.5M ammonia in dioxane (1mL, O.δmmol), followed by PS-carbodiimide resin. The resulting mixture was stirred at room temperature overnight. The mixture was passed through a MP-CO3 resin cartridge and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 5-(4-rnethoxyphenyl)-2-phenyloxazole-4-carboxamide (O.OOδg, 0.03mmol, 27%) as a white solid. 1H NMR (DMSO) δ 3.85 (3H, s), 7.10 (2H, d), 7.60 (3H, m), 7.66 (1 H, br. s), 7.78 (1H1 br. s), 8.14 (2H, m), 8.37 (2H, d). LCMS (2) Rt: 3.16min; m/z (ES+) 295.
In a similar manner as described in example M-1 the compounds described in examples M-3 to M-11 were prepared.
Example M-3 2-(2-fluorophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000123_0001
1H NMR (CDCI3) δ 3.90 (3H, s), 5.58 (1H, br. s), 7.03 (2H, d), 7.24-7.34 (3H1 m), 7.51 (1H, m), 8.11 (1H, m), 8.41 (2H, d). LCMS (2) Rt: 3.02min; m/z (ES+) 313.
Example M-4 2-(1H-indol-4-yl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000123_0002
1H NMR (DMSO) δ 3.86 (3H, s), 7.12 (2H, d), 7.28 (1H, dd), 7.37 (1H, m), 7.60 (1H, dd), 7.63 (1H, d), 7.67 (1H, br. s), 7.88 (2H1 m), 8.40 (2H, d), 11.53 (1H, s). LCMS (2) Rt: 2.84min; m/z (ES+) 334.
Example M-5 5-(4-methoxyphenyl)-2-(thiophen-3-yl)oxazole-4-carboxamide
Figure imgf000123_0003
1H NMR (CDCI3) δ 3.88 (3H, s), 5.54 (1H, br. s), 7.00 (2H, d), 7.19 (1H, br. s), 7.44 (1 H, dd), 7.65 (1H, dd), 8.01 (1H, dd), 8.32 (2H, d). LCMS (2) Rt: 2.88min; m/z (ES+) 301.
Example M -6 2-(2-carbamoylphenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000124_0001
Prepared using 2-cyanophenyl boronic acid which hydrolysed to the amide under the reaction conditions. 1H NMR (DMSO) δ 3.84 (3H, s), 7.07 (2H, d), 7.55 (1H, dd), 7.62 (2H, m), 7.68 (2H, br. s), 7.72 (1 H1 br. s), 8.04 (2H, m), 8.30 (2H, d). LCMS (2) Rt: 1.96min; m/z (ES+) 338.
Example M-7 2-(3-fluorophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000124_0002
1H NMR (CDCI3) δ 3.91 (3H, s), 5.56 (1 H1 br. s), 7.04 (2H, d), 7.19-7.23 (2H, m), 7.50 (1H, m), 7.80 (1H, ddd), 7.90 (1 H, m), 8.37 (2H, d). LCMS (2) Rt: 3.15min; m/z (ES+) 313.
Example M-8 2-(4-fluorophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000124_0003
1H NMR (CDCI3) δ 3.88 (3H, s), 5.56 (1 H, br. s), 7.01 (2H, d), 7.17-7.22 (3H, m), 8.09 (2H, dd), 8.33 (2H, d). LCMS (2) Rt: 3.11min; m/z (ES+) 313.
Example M-9 2-(4-cyanophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000125_0001
1H NMR (DMSO) δ 3.82 (3H, s), 7.10 (2H, d), 7.72 (1H, br. s), 7.87 (1H1 br. s), 8.08 (2H, d), 8.30 (2H, d), 8.40 (2H, d). LCMS (2) Rt: 2.92min; m/z (ES+) 342 (M+Na+).
Example NMO 2-(2,4-difluorophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000125_0002
1H NMR (CDCI3) δ 3.88 (3H, s), 5.56 (1H, br. s), 6.96-7.06 (4H, m), 7.21 (1H, br. s), 8.09 (1H, m), 8.36 (2H, d). LCMS (2) Rt: 3.11min; m/z (ES+) 331.
Example M-11 5-(4-methoxyphenyl)-2-(4-(methylsulfonyl)phenyl)oxazole-4-carboxamide
Figure imgf000125_0003
1H NMR (DMSO) δ 3.31 (3H, s), 3.85 (3H, s), 7.10 (2H, d), 7.71 (1 H, br. s), 7.87 (1H, br. s), 8.13 (2H, d), 8.36 (2H, d), 8.38 (2H, d). LCMS (2) Rt: 2.47min; m/z (ES+) 373.
Example M-12 2-(1H-indol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Step a - ethyl 5-(4-bromophenyl)oxazole-4-carboxylate
Figure imgf000126_0001
Prepared from 4-bromobenzoyl chloride according to the procedure outlined for ethyl 5- (4-methoxyphenyl)oxazole-4-carboxylate in example M-1. 1H NMR (DMSO) δ 1.42 (3H, t), 4.42 (2H, q), 7.61 (2H, d), 7.92 (1 H, s), 7.99 (2H1 d). LCMS (1) Rt: 2.10min; m/z (ES+) 268/270 MH+ - Et.
Step b - terf-butyl 4-(4-(4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate
Figure imgf000126_0002
A solution of fr7s(dibenzylideneacetone)dipalladium(0) (0.079g, 0.09mmol), 9,9-dimethyl- 4,5-jb/s(diphenylphosphino)xanthene (0.10Og, 0.17mmol), ethyl 5-(4- bromophenyl)oxazole-4-carboxylate (0.50Og, 1.69mmol), ferf-butyl 1- piperazinecarboxylate (0.409g, 2.20mmol) and cesium carbonate (0.786g, 2.41 mmol) in dioxane (25ml) and t-butanol (25ml) was degassed, placed under a nitrogen atmosphere and heated under reflux overnight. The solvent was removed in vacuo and the residue partitioned between water and DCM. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 50% EtOAc in hexane as eluant to afford terf-butyl 4-(4-(4- (ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.34Og, 0.85mmol, 50%) of a yellow solid. 1H NMR (CDCI3) δ 1.42 (3H, t), 1.49 (9H, s), 3.28 (4H, br. t), 3.59 (4H, br. t), 4.42 (2H, q), 6.95 (2H, d), 7.83 (1H, s), 8.05 (2H, d). LCMS (1) Rt: 2.37min; m/z (ES+) 402.
Step c - fø/f-buty! 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1- carboxylate
Figure imgf000127_0001
Prepared from terf-butyl 4-(4-(4-(ethoxycarbonyl)oxazol-5-yl)phenyi)piperazine-1- carboxylate using the procedure described for the synthesis of ethyl 2-iodo-5-(4- methoxyphenyl)oxazole-4-carboxyiate in example M-1. 1H NMR (DMSO) δ 1.40 (3H, t), 1.57 (9H, s), 3.29 (4H, br. t), 3.59 (4H, br. t), 4.41 (2H, q), 6.93 (2H, d), 7.99 (2H, d). LCMS (1) Rt: 2.58min; m/z (ES+) 528.
Step d - 2-(1H-indol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000127_0002
A mixture of ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (0.08Og, 0.15mmol), indole-4-boronic acid (0.048g, 0.30mmol), Pd(dppf)2CI2 (0.006g, 0.007mmol) and 1M aq. sodium carbonate (0.31ml, 0.31 mmol) in acetonitrile (2.5ml) was heated in the microwave at 1500C for 15 minutes. The reaction mixture was diluted with DCM and washed with 1M NaOH. The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo to afford terf-butyl 4-(4-(4- (ethoxycarbonyl)-2-(1 H-indol-4-yl)oxazol-5-yl)phenyl)piperazine-1 -carboxylate which was used without further purification. LCMS (1) Rt: 2.61 min; m/z (ES+) 517. To a solution of terf-butyl 4-(4-(4-(ethoxycarbonyl)-2~(1H-indol-4-yl)oxazol-5- yl)phenyl)piperazine-1 -carboxylate in MeOH (10ml) was added 1M aq KOH (3ml) and the resulting mixture stirred at 550C for 3 hours. The reaction was cooled to room temperature and the methanol removed in vacuo. The reaction mixture was then partitioned between DCM and water and the resulting precipitate collected by filtration to afford 5-(4-(4-(te/f-butoxycarbonyl)piperazin-1 -yl)phenyl)-2-(1 H-indol-4-yl)oxazole-4- carboxylic acid as the potassium salt (0.045g, 0.09mmol, 57% two steps). LCMS (1) Rt: 1.66min; m/z (ES+) 489. To a solution of 5-(4-(4-(te/t-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1 H-indol-4- yl)oxazole-4-carboxylic acid potassium salt (0.045, 0.09mmol) in DCM (0.9ml) and DMF (0.7ml) was added hydroxybenzotriazole monohydrate (0.018g, 0.12mmol), 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.027g, 0.14mmol) and 0.5M ammonia in dioxane (0.9ml, 0.45mmol) and the resultant mixture stirred overnight at room temperature. The solvent was then removed in vacuo and the residue purified by preparative HPLC to afford te/ϊ-butyl 4~(4-(4-carbamoyl-2-(1 H-indoi-4-yl)oxazol-5- yl)phenyl)piperazine-1-carboxylate (0.027g, 0.06mmol, 65%). LCMS (2) Rt: 3.33min; m/z (ES+) 488.
To a suspension of terf-butyl 4-(4-(4-carbamoyl-2-(1 H-indol-4-yl)oxazol-5- yl)phenyl)piperazine-1-carboxylate (0.027g, O.Oδmmol) in DCM (1ml) was added 4M HCI in dioxane (0.5ml, 2.0mmol) and the reaction stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH cartridge (500mg) to afford 2-(1H-indol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4- carboxamide (0.0078g, 0.02mmol, 36%). 1H NMR (DMSO) δ 2.86 (4H, br. t), 3.22 (4H, br. t), 7.06 (2H, d), 7.21 (1H, t), 7.35 (1H, br. t), 7.56-7.60 (2H, m), 7.62 (1H, d), 7.79 (1H, br. s), 7.86 (1H, dd), 8.30 (2H, d), 11.51 (1H, br. s). LCMS (2) Rt: 2.36min; m/z (ES+) 388.
Example M-13 5-(4-(piperazin-1-yl)phenyl)-2-(pyridin-3-yl)oxazole-4-carboxamide
Figure imgf000128_0001
Prepared according to the method described in example M-12. 1H NMR (DMSO) δ 2.85 (4H, m), 3.21 (4H, m), 7.03 (2H, d), 7.61-7.64 (2H, m), 7.76 (1H, br. s), 8.29 (2H, d), 8.45 (1H, ddd), 8.75 (1H, dd), 9.30 (1H, dd). LCMS (2) Rt: 1.74min; m/z (ES+) 350.
Example M-14 5-(4-(piperazin-1-yl)phenyl)-2-(pyridin-4-yl)oxazole-4-carboxamide
Figure imgf000129_0001
Prepared according to the method described for example M-12, except that during the NaOH mediated hydrolysis the reaction was worked up by acidifying the aqueous phase and extracting the product into DCM. 1H NMR (DMSO) δ 2.86 (4H, t), 3.23 (4H, t), 7.04 (2H, d), 7.62 (1H, br. s), 7.76 (1H, br. s), 8.01 (2H1 d), 8.29 (2H, d), 8.79 (2H, d). LCMS (2) Rt: 1.80min; m/z (ES+) 350.
Example M-15 2-(1H-indol-5-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000129_0002
Prepared according to the method described in example M-12. 1H NMR (CD3OD) δ 3.03 (4H1 m), 3.31 (4H1 m), 6.61 (1H, d), 7.06 (2H1 d), 7.36 (1 H, d), 7.53 (1H, d), 7.92 (1 H, dd), 8.25 (2H1 d), 8.37 (1H, d). LCMS (1) 2.31 min; m/z (ES+) 388.
Example M-16 2-(1H-indol-6-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000129_0003
5-(4-(4-(fert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-6-yl)oxazole-4-carboxylic acid was prepared according to the method described for the synthesis of 5-(4-(4-(terf- butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1 H-indol-4-yl)oxazole-4-carboxylic acid in example M-12, except that during the NaOH mediated hydrolysis the reaction was worked up by acidifying the aqueous phase and extracting the product in DCM. To a solution of 5-(4-(4-(te/f-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(1H-indol-6- yl)oxazole-4-carboxylic acid (0.038g, O.Oδmmol) in DMF (1ml) was added O-(7- azabenzotriazoM-yO-N.^N'.N'-tetramethyluronium hexafluorophosphate (0.036g, 0.09mmol) and diisopropylethylamine (0.016ml, 0.09mmol). The solution was stirred at room temperature for 5 minutes and then 0.5M ammonia in dioxane (0.31ml, 0.16mmol) was added and the resultant mixture stirred at room temperature for 2 hours. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford tert-butyl 4-(4-(4-carbamoyl-2-(1H-indol-6-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.018g, 0.04mmol, 46%). LCMS (2) Rt: 3.39min; m/z (ES+) 488. A solution of terf-butyl 4-(4-(4-carbamoyl-2-(1H-indol~6-yl)oxazol-5-yl)phenyl)piperazine- 1-carboxylate (0.018g, 0.04mmol) in MeOH was loaded onto a MP-TsOH cartridge (500mg). The cartridge was washed with MeOH and allowed to stand for 2 hours. The cartridge was then washed with 2M ammonia in MeOH and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(1 H-indol-6-yl)-5-(4- (piperazin-1-yl)phenyl)oxazole-4-carboxamide (0.006g, 0.02mmol, 50%). 1H NMR (DMSO) δ 2.85 (4H, t), 3.20 (4H, t), 6.55 (1H, m), 7.04 (2H, d), 7.55 (1H, br. s), 7.56 (1 H, m), 7.68 (1H, br. s), 7.71 (1 H, d), 7.77 (1H1 dd), 8.15 (1 H1 s), 8.26 (2H, d), 11.48 (1H, br. s). LCMS (2) Rt: 2.32min; m/z (ES+) 388.
Example M-17 2-(1H-indazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Step a - ferf-butyl 4-(4-(4-(ethoxycarbonyl)-2-(1 H-indazol-4-yl)oxazol-5- yl)phenyl)piperazine-1-carboxylate
Figure imgf000130_0001
To a mixture of terf-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1- carboxylate (0.08Og, 0.15mmol), 4-(4,4,5,5-tetramethyl-[1 ,3,2]-dioxaborolan-2-yl)-1H- indazole (0.08Og, 0.33mmol) and sodium carbonate (0.048g, 0.45mmol) in toluene (0.81ml), ethanol (0.49ml) and water (0.23ml) was added
6/s(triphenylphosphine)palladium (II) chloride (0.005g, 0.007mmol) and the resulting mixture heated in the microwave at 12O0C for 60 minutes followed by an additional 45 minutes. The reaction mixture was diluted with EtOAc and washed with 1M NaOH. The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 10-100% EtOAc in hexane gradient to afford terf-butyl 4-(4-(4- (ethoxycarbonyl)-2-(1H-indazol-4-yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.037g, 0.07mmol, 47%) as a yellow solid. LCMS (2) Rt: 3.57min; m/z (ES+) 518.
Step b - 2-(1H-indazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000131_0001
Prepared from te/if-butyl 4-(4-(4-(ethoxycarbonyl)-2-(1 H-indazol-4-yl)oxazol-5- yl)phenyl)piperazine-1-carboxylate according to the method described in example M-16 except that the final acid mediated Boc group removal is performed as described in example M-12 with 4M HCI in dioxane. 1H NMR (DMSO) δ 2.87 (4H, t), 3.23 (4H, t), 7.06 (2H, d), 7.54 (1H, t), 7.59 (1H, br s), 7.76 (1H, d), 7.93 (1 H, d), 8.01 (1H, br s), 8.33 (2H, d), 8.98 (1H, s), 13.43 (1 H, br s). LCMS (2) Rt: 1.99min; m/z (ES+) 389.
Example M-18 2-(1H-indazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Step a - 4-chloro-1H-pyrrolo[2,3-b]pyridine
Figure imgf000131_0002
Prepared from 7-Azaindole according to the procedure outlined in the patent WO 03/082289. LCMS (3) Rt: 1.89min; m/z (ES+) 153/155.
Step b - 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H-pyrrolo[2,3-b]pyridine
Figure imgf000132_0001
A solution of 2-(dicyclohexylphosphino)biphenyl (0.287g, 0.819mmol), jb/s(pinacolato)diboron (0.915g, 3.60mmol), Acetic acid potassium salt (0.965g, 9.83mmol), fr7s(dibenzylideneacetone)dipalladium(0) (0.03Og1 0.032mmol) and 4-chloro- 1H-pyrrolo[2,3-b]pyridine (0.50Og, 3.28mmol) in dioxane (10ml) was degassed, placed under a nitrogen atmosphere and heated under reflux for 3 hours. The solvent was removed in vacuo. The residue was taken up in MeOH and loaded onto a MP-TsOH cartridge (2500rng). The cartridge was washed with MeOH then with 2M ammonia in MeOH and the solvent reduced in vacuo to afford 4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (0.394g, 1.62mmol, 48%) of a brown solid. LCMS (2) Rt: 1.39min; m/z (ES+) 245.
Step c - ferf-butyl 4-(4-(4-(ethoxycarbonyl)-2-(1H-pyrrolo[2,3-b]pyridin-4-yl)oxazol-5- yl)phenyl)piperazine-1-carboxylate
Figure imgf000132_0002
To a mixture of terf-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1- carboxylate (0.08Og, 0.15mmol), 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1H- pyrrolo[2,3-b]pyridine (0.093g, 0.38mmol) and sodium carbonate (0.048g, 0.45mmol) in toluene (0.81ml), ethanol (0.49ml) and water (0.23ml) was added jb/s(tιϊphenylphosphine)palladium (II) chloride (0.005g, 0.007mmol) and the resulting mixture irradiated in the microwave at 12O0C for 60 minutes. The reaction mixture was diluted with EtOAc and washed with H2O. The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford te/t-butyl 4-(4-(4-(ethoxycarbonyl)-2-(1 H-pyrrolo[2,3-b]pyridin-4- yl)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.07Og, 0.123mmol, 81%) as a yellow solid. 1H NMR (CDCI3) δ 1.46 (3H, t), 1.49 (9H, s), 3.31 (4H, m), 3.61 (4H, m), 4.47 (2H, q), 7.00 (2H, d), 7.24 (1H, m), 7.55 (1H, m), 7.90 (1H, d), 8.18 (2H, d), 8.46 (1H, d), 10.68 (1H, br s). LCMS (3) Rt: 2.63min; m/z (ES+) 518.
Step d - 5-(4-(piperazin-1-yl)phenyl)-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl)oxazole-4- carboxamide
Figure imgf000133_0001
Prepared from te/f-buty! 4-(4-(4-(ethoxycarbonyl)-2-(1 H-pyrrolo[2,3-b]pyridin-4-yl)oxazol- 5-yl)phenyl)piperazine-1-carboxylate according to the method described in example M- 12 step d from the hydrolysis using KOH onwards. The final product was purified using preparative HPLC to yield the desired compound as the formate salt. 1H NMR (DMSO) δ 2.87 (4H, m), 3.24 (4H1 m), 7.06 (2H, d), 7.30 (1H, m), 7.59 (1 H, m), 7.71 (1H, m), 7.76 (1H, d), 7.87 (1H, m), 8.31 (3H, m), 8.40 (1 H, d), 12.02 (1 H, s). LCMS (2) Rt: 1.88min; m/z (ES+) 389. General Method N
General Method N comprises the series of reactions set out in Scheme 8 above.
Example N-1 5-(4-methoxyphenyl)-2-(1H-pyrazol-5-yl)oxazole-4-carboxamide
Step a - 2-iodo-5-(4-methoxypheny])oxazole-4-carboxylic acid
Figure imgf000134_0001
To a solution of ethyl 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylate (1.0Og, 2.7mmol) in DCE (25ml_) was added trimethyl tin hydroxide (1.7Og, 9.4mmol) and the resultant mixture stirred at 8O0C for 3 hours. Trimethyl tin hydroxide (0.24g, 1.3mmol) was then added and the reaction stirred at 8O0C overnight. The reaction was cooled to room temperature and extracted with DCM. The organic phase was washed with 1 M aqueous HCI and brine, dried over MgSO4 and the solvent removed in vacuo to give 2- iodo-5-(4-methoxyphenyl)oxazole-4-carboxylic acid (0.92g, 2.7mmol, 99%) as a white solid which was used without further purification. 1H NMR (CDCI3) δ 3.88 (3H, s), 6.99 (2H, d), 8.13 (2H1 d). LCMS (1) Rt: 1.03min; m/z (ES+) 346.
Step b - 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000134_0002
To a solution 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxylic acid (0.92g, 2.7mmol) in DCM (2OmL) and DMF (1OmL) was added hydroxybenzotriazole monohydrate (0.44g, 2.9mmol) followed by 0.5M ammonia in dioxane (22mL, H .Ommol) and 1-(3- (dimethylamino)propyl)-3-ethyl-carbodiimide hydrochloride (0.77g, 4.0mmol) and the reaction stirred at room temperature overnight. EtOAc was then added and the mixture washed with brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using gradient of 0 - 50% EtOAc in DCM to afford 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide (0.66g. 1.9mmol, 70%) as a yellow solid. 1H NMR (CDCI3) δ 3.79 (3H, s), 5.47 (1 H, br. s), 6.90 (2H, d), 6.94 (1H, br. s), 8.14 (2H, d). LCMS (1) Rt: 1.84min; m/z (ES+) 345.
Step c - 5-(4-methoxyphenyl)-2-(1 H-pyrazol-5-yl)oxazole-4-carboxamide
Figure imgf000134_0003
To a mixture of 2-iodo-5-(4-methoxyphenyl)oxazole-4-carboxamide (0.025g, 0.07mmol), 1 H-pyrazole-5-boronic acid (0.02Og, 0.18mmol) and [1 ,1'- ό/s(diphenylphosphino)ferrocene]dichloropalladium(ll) (0.003g, 0.004mmol) in acetonitrile (2mL) and DMSO (0.5mL) was added a 1M sodium carbonate solution (0.1 ml_, O.immol) and the reaction heated in the microwave at 15O0C for 15 minutes. A further portion of [1,1'-/j/s(diphenylphosphino)ferrocene]dichloro-palladium(ll) (0.003g, 0.004mmol) was added and the mixture heated at 15O0C for a further 10 minutes in the microwave. The reaction was diluted with EtOAc and washed 1 M sodium carbonate solution. The aqueous phase was extracted with EtOAc and the combined organic phases were washed with brine, dried over MgSO4 and passed through a MP-SH resin cartridge (500mg). The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2-(1H-pyrazol-5-yl)oxazole-4- carboxamide (0.008g, 0.03mmol, 38%) as a white solid. 1H NMR (DMSO) δ 3.84 (3H, s), 6.90 (1H, br. d), 7.09 (2H, d), 7.62 (1H, br. s), 7.67 (1H, br. s), 7.97 (1H, br. s), 8.27 (2H, br. d), 13.50 (1H, br. s). LCMS (2) Rt: 1.98min; m/z (ES+) 285.
In a similar manner as described in example N-1 the compounds described in examples N-2 to N-10 were prepared.
Example N-2 5-(4-methoxyphenyl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamide
Figure imgf000135_0001
Prepared using 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester which deprotected under the reaction conditions. 1H NMR (DMSO) δ 3.84 (3H, s), 7.07 (2H, d), 7.59 (1H, br. s), 7.62 (1H, br. s), 8.09 (1 H, br. s), 8.30 (2H, d), 8.50 (1H, br. s), 13.49 (1 H, br. s). LCMS (2) Rt: 1.91min; m/z (ES+) 285.
Example N -3 2-(3-acetamidophenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000136_0001
1H NMR (DMSO) δ 2.09 (3H, s), 3.85 (3H, s), 7.11 (2H1 d), 7.51 (1H, t), 7.66 (1 H, br. s), 7.71 (1H, br. s), 7.76 (1 H, CkJd)1 7.80 (1H, dt), 8.30 (2H, d), 8.36 (1H, br. t), 10.23 (1H, s). LCMS (2) Rt: 2.43min; m/z (ES+) 352.
Example N-4 5-(4-methoxyphenyl)-2-(4-(trifluoromethyl)phenyl)oxazole-4-carboxamide
Figure imgf000136_0002
LCMS (2) Rt: 3.41 min; m/z 363.
Example N-5 2-(2-fluoro-4-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000136_0003
LCMS (2) Rt: 3.31 min; m/z 381.
Example N-6 2-(2-fluoro-5-(trifluoromethyI)phenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000136_0004
LCMS (2) Rt: 3.34min; m/z 381. Example N-7 2-(2-fluoro-3-(trifluoromethyl)phenyl)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000137_0001
LCMS (2) Rt: 3.33min; m/z 381.
Example N-δ 5-(4-methoxyphenyl)-2-(3-(trifluoromethyl)phenyl)oxazole-4-carboxamide
Figure imgf000137_0002
1H NMR (DMSO) δ 3.85 (3H, s), 7.10 (2H, d), 7.67 (1H, br. s), 7.85 (1H, t), 7.90 (1H, br. s), 7.96 (1H, d), 8.40-8.44 (4H, m). LCMS (2) Rt: 3.38min; m/z 363.
Example N-9 5-(4-methoxyphenyl)-2-p-tolyloxazole-4-carboxamide
Figure imgf000137_0003
LCMS (2) Rt: 3.22min; m/z 309.
Example N-10 5-(4-methoxyphenyl)-2-m-tolyloxazole-4-carboxamide
Figure imgf000138_0001
1H NMR (DMSO) δ 2.43 (3H, s), 3.85 (3H, s), 7.09 (2H, d), 7.40 (1H, d), 7.48 (1H, t), 7.64 (1H, br. s), 7.76 (1H, br. s), 7.93 (1 H1 d), 7.97 (1H, s), 8.37 (2H, d). LCMS (2) Rt: 3.23min; m/z 309.
General Method O
General Method O comprises the series of reactions set out in Scheme 9 above.
Example O-1 2-(2,6-difluorophenyl)-5-(pheny!amino)oxazole-4-carboxamide
Step a - diethyl 2-(2,6-difluorobenzamido)malonate
Figure imgf000138_0002
To a stirred suspension of 2-amino diethylmalonate hydrochloride (5.0Og, 23.6mmol) in DCM (20OmL) at O0C was added diisopropylethylamine (4.0OmL, 49.1mmol). To the resulting solution at O0C was added a solution of 2,6-difluorobenzoyl chloride (3.0OmL, 25.5mmol) in DCM (5OmL), dropwise, and the reaction warmed to room temperature and stirred for 1 hour. The solution was washed with 1M aqueous HCI, brine, saturated aqueous sodium bicarbonate and brine, dried over MgSO4 and the solvent removed in vacuo to afford diethyl 2-(2,6-dif!uorobenzamido)malonate (7.1Og, 22.5mmol, 95%) as a white solid. 1H NMR (CDCI3) δ 1.32 (6H, t), 4.31 (4H, m), 5.35 (1H, d), 6.97 (2H, t), 7.06 (1H, br. d), 7.41 (1H, m).
Step b - ethyl 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate
Figure imgf000139_0001
A solution of diethyl 2-(2,6-difluorobenzamido)malonate (5.0Og, 15.9mmol) in trifluorotoluene (16mL) and trifluoroacetic anhydride (8.33mL, 129.7mmol) was heated in the microwave at 16O0C for 5 minutes. The solvent was removed in vacuo and the residue purified by silica gel column chromatography using a gradient of 0 - 90% EtOAc in hexanes to afford ethyl 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate (2.11g, 7.1mmol, 45%) as a white solid which was used without further purification. 1H NMR (CDCI3) δ 1.39 (3H, t), 1.53 (3H, t), 4.39 (2H, q), 4.58 (2H, q), 7.02 (2H, t), 7.41 (1H, m).
Step c - 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylic acid
Figure imgf000139_0002
A suspension of ethyl 2~(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylate (2.1Og, 7.1mmol) in 1M aqueous potassium hydroxide and heated to 1000C for 6 hours. The mixture was then cooled to O0C and acidified to pH 3 by 2M aqueous HCI. The resulting white solid was filtered, washed with water and dried in a vacuum oven to afford 2-(2,6- difluorophenyl)-5-ethoxyoxazole-4-carboxylic acid (1.28g, 4.8mmol, 67%). 1H NMR (CD3OD) δ 1.52 (3H, t), 4.61 (2H, q), 7.19 (2H, t), 7.61 (1H, m). LCMS (1) Rt: 1.09min; m/z (ES+) 270.
Step d - 2-(2,6-difluorophenyl)-5-ethoxy-N-phenyloxazole-4-carboxamide
Figure imgf000139_0003
To a solution of 2-(2,6-difluorophenyl)-5-ethoxyoxazole-4-carboxylic acid (0.1Og1 0.37mmol) and hydroxybenzotriazole monohydrate (0.06g, 0.39mmol) in DCM (4mL) was added PS-carbodiimide resin (0.36g, 0.45mmol, 1.25mmol/g) followed by aniline (39uL, 0.43mmol). The resulting mixture was stirred at room temperature for 4 hours when a further portion of aniline (7uL, O.Oδmmol) was added and the reaction stirred at room temperature overnight. The mixture was filtered through a silica-carbonate cartridge, followed by a MP-TsOH resin cartridge which was rinsed with DCM and MeOH to afford 2-(2,6-difluorophenyl)-5-ethoxy-N-phenyloxazole-4-carboxamide (0.13g) which was used without further purification. LCMS (1) Rt: 2.30; m/z (ES+) 345.
Step e - ethyl 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylate
Figure imgf000140_0001
A solution of 2-(2,6-difluorophenyl)-5-ethoxy-N-phenyloxazole-4-carboxamide (0.13g, 0.38mmol) in trifluorotoluene was heated at 18O0C for 5 minutes in the microwave. The solvent was removed in vacuo to give ethyl 2-(2,6-difluorophenyl)-5- (phenylamino)oxazole-4-carboxylate (0.13g) as a brown solid which was used without further purification. LCMS (1) Rt: 2.40min; m/z (ES+) 345.
Step f - 2-(2,6-dif!uorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid
Figure imgf000140_0002
To a solution of ethyl 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylate (0.08Og, 0.23mmol) in DCE (8mL) was added trimethyltin hydroxide (0.300g, 1.66mmol) and the resulting solution stirred at 8O0C overnight. A further portion of trimethyltin hydroxide (0.168g, 0.93mmol) was added and the solution stirred at 8O0C overnight. The reaction was diluted with DCM and washed with 1 M aqueous HCI and brine. The organic phase was dried over MgSO4 and solvent removed in vacuo. The residue was purified by silica gel column chromatography using an 8% to 50% EtOAc in hexanes gradient followed by a 5% to 50% MeOH in DCM gradient to afford 2-(2,6- difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.03Og, 0.095mmol, 41% three steps). LCMS (1) Rt: 1.46min; m/z (ES+) 317.
Step g - 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxamide
Figure imgf000141_0001
To a solution of 2-(2,6-difluorophenyl)-5-(phenylamino)oxazole-4-carboxylic acid (0.03Og, 0.095mmol) in DCM (3mL) was added hydroxybenzotriazole monohydrate (0.015g, 0.098mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (0.02Og, O.IOmmol) and 0.5M ammonia in dioxane (0.9mL, 0.45mmol). The reaction mixture was stirred at room temperature overnight. Further 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide (0.007g, 0.038mmol) and ammonia in dioxane (0.57mL, 0.29mmol) were added and the reaction stirred for 3 hours at room temperature. The solvent was evaporated in vacuo and the residue purified by preparative HPLC to afford 2-(2,6- difluorophenyl)-5-(phenylamino)oxazole-4-carboxamide (0.006g, 0.019mmol, 20%) as a white solid. 1H NMR (DMSO) δ 7.03 (1 H, dd), 7.35 (4H, m), 7.38 (2H, br. s), 7.43 (2H, m), 7.64 (1H, m), 9.34 (1H, br. s). LCMS (2) Rt 2.87min; m/z (ES+) 338 (M+Na), 299 (M-NH2).
General Method P
General Method P comprises the series of steps set out in Scheme 10 above.
Example P-1 2-(2,6-difluorophenyl)-5-(4-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000141_0002
To a stirred, degassed solution of 5-bromo-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.125g, 0.41 mmol) in trifluorotoluene (10.5mL) was added f/7s(dibenzylideneacetone)dipalladium(0) (0.019g, 0.02mmol), (±)-2,2"- Jb/s(diphenylphosphino)-1 ,1"-binaphthalene (0.026g, 0.04mmol), and sodium tert- butoxide (0.059g, 0.62mmol). This was followed by addition of p-anisidine (0.076g, 0.62mmol) after approximately 3 minutes stirring. The resulting reaction mixture was degassed, placed under an N2 atmosphere and heated in the microwave at 16O0C for 20 minutes. The solution was then washed with 2M aqueous HCI and brine, dried over MgSO4 and then passed through a MP-SH resin cartridge (500mg). The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 2-(2,6- difluorophenyl)-5-(4-methoxyphenylamino)oxazole-4-carboxamide (0.0037g, 0.01 mmol, 8%) as a white solid. 1H NMR (DMSO) δ 3.74 (3H, s), 6.93 (2H, d), 7.29 (2H, br. s), 7.32 (2H, t), 7.37 (2H, d), 7.62 (1H, m), 9.17 (1H, br. s). LCMS (2) Rt: 2.80min; m/z (ES+) 346.
General Method Q
General Method Q comprises the series of reactions set out in Scheme 11 above.
Example Q-1 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carbonitrile
Figure imgf000142_0001
A solution of palladium acetate (0.0057g, 0.025mmol) and (±)-2,2"- ό/s(diphenylphosphino)-1 ,1"-binaphthalene (0.015g, 0.024mmol) in DMF (7.1mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6-difluorophenyl)oxazole- 4-carbonitrile (0.10Og, 0.35mmol), 4-morpholinoaniline (0.25Og, 1.40mmol) and potassium phosphate tribasic (0.149g, 0.70mmol) were added and the mixture heated in the microwave for 3 minutes at 18O0C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through a MP-SH resin cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a gradient 10-100% EtOAc in hexanes to afford 2- (2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carbonitrile (0.035g, O.OQmmol, 26%) as an off white solid. 1H NMR (DMSO) δ 3.08 (4H, t), 3.74 (4H, t), 6.97 (2H, d), 7.24 (2H, d), 7.33 (2H, t), 7.64 (1 H, m), 10.58 (1H, s). LCMS (2) Rt: 2.92min; m/z (ES+) 383. Step b - 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carboxamide
Figure imgf000143_0001
A solution of 2-(2,6-difluoropheny!)-5-(4-morpholinophenylamino)oxazole-4-carbonitrile (0.035g, 0.09mmol) in concentrated sulfuric acid (1.7mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was extracted with EtOAc. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carboxamide (0.031g, 0.077mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 3.06 (4H, t), 3.73 (4H, t), 6.94 (2H, d), 7.28 (2H, br. s), 7.32 (4H, m), 7.62 (1 H, m), 9.13 (1H, s). LCMS (2) Rt: 2.60min; m/z (ES+) 401.
Example Q-2 2-(2,6-difluorophenyl)-5-(3-morpholinophenylamino)oxazole-4-carboxamide
Figure imgf000143_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.12 (4H, t), 3.75 (4H, t), 6.64 (1H, dd), 6.90 (1H, dd), 7.02 (1H, t), 7.18 (1H, t), 7.34 (2H, t), 7.36 (2H, br. s), 7.63 (1 H, m), 9.20 (1 H, s). LCMS (2) Rt: 2.59mins; m/z (ES+) 401.
Example Q-3 2-(2,6-difluorophenyl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carboxamide
Figure imgf000144_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.18 (3H, s), 7.35 (2H, t), 7.49 (2H, br. s), 7.58 (2H, d), 7.67 (1H, m), 7.83 (2H, d), 9.86 (1H, s). LCMS (2) Rt: 2.20min; m/z (ES+) 394.
Example Q-4 2-(2,6-difluorophenyl)-5-(3-(methylsulfonyl)phenylamino)oxazole-4-carboxamide
Figure imgf000144_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.21 (3H, s), 7.34 (2H, t), 7.43 (2H, br. s), 7.53 (1H, d), 7.60 (1H, t, dd), 7.65 (1H, m), 7.73 (1H, d), 7.98 (1H, s), 9.74 (1H, s). LCMS (2) Rt: 2.21 min; m/z 394.
Example Q-5 2-(2J6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000144_0003
To a suspension of 2-(2,6-difluorophenyl)-5-(2~methoxyphenylamino)oxazole-4- carbonitrile (0.018g, 0.055mmol, prepared according to the procedure described for Q-1 step a) in water (4.5mL) was added 1M aqueous potassium hydroxide (0.27mL, 0.27mmol) and the resulting mixture stirred at 14O0C in the microwave for 15 minutes. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(2-methoxyphenylamino)oxazole-4-carboxamide (0.0104g, 0.030mmol, 55%). 1H NMR (DMSO) δ 3.92 (3H, s), 6.99 (1H, ddd), 7.04 (1H, ddd), 7.12 (1H, dd), 7.35 (2H, t), 7.42 (2H, br. s), 7.64 (1H, m), 7.68 (1H, dd), 9.48 (1H, s). LCMS (2) Rt: 2.86min; m/z (ES+) 346.
Example Q-6 2-(2,6-difluorophenyl)-5-(3-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000145_0001
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 3.76 (3H, s), 6.61 (1H, dd), 7.00 (1 H, dd), 7.07 (1H, t), 7.24 (1 H, t), 7.34 (2H, t), 7.38 (2H, br. s), 7.63 (1 H, m), 9.31 (1H, s). LCMS (2) Rt: 2.71 min; m/z (ES+) 346.
Example Q-7
2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenylamino)oxazole-4- carboxamide
Step a - 1-methyl-4-(4-nitrophenyl)piperazine
Figure imgf000145_0002
To a solution of 1-methylpiperazine (0.605ml, 5.45mmol) in DMF (6.25ml) was added 4- fluoronitrobenzene (0.750ml, 7.07mmol) and potassium carbonate (1.13g, 8.18mmol) and the reaction mixture stirred at 9O0C overnight. The reaction was then cooled to room temperature, diluted with DCM and washed with water. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel silica chromatography using a 0-10% MeOH in DCM gradient to afford 1-methyl-4-(4- nitrophenyl)piperazine (1.03g, 4.66mmol, 85%) as a yellow solid. 1H NMR (DMSO) δ 2.37 (3H, s), 2.58 (4H, t), 3.45 (4H, t), 6.82 (2H, d), 8.12 (2H, d). LCMS (1) Rt: 1.63min; m/z (ES+) 222.
Step b - 4-(4-methylpiperazin-1-yl)benzenamine
Figure imgf000146_0001
A solution of 1-methyl-4-(4-nitrophenyl)piperazine (1.03g, 4.66mmol) in MeOH (100ml) was hydrogenated at 2O0C at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford 4-(4-methylpiperazin-1-yl)benzenamine (0.82g, 4.29mmol, 92%) as an off-white solid. 1H NMR (CDCI3) δ 2.37 (3H, s), 2.62 (4H1 1), 3.09 (4H, t), 3.40 (2H, br. s), 6.65 (2H, d), 6.82 (2H, d). LCMS (1) Rt: 0.98min; m/z (ES+) 192.
Step c - 2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazin-1-yl)phenylamino)oxazole-4- carboxamide
Figure imgf000146_0002
4-(4-Methylpiperazin-1 -yl)benzenamine and 5-bromo-2-(2,6-difluorophenyl)oxazole-4- carbonitrile were reacted together following the procedure set out in example Q-1 to give an intermediate nitrile which was hydrolysed to give the title compound by the method of step b in example Q-1. 1H NMR (DMSO) δ 2.21 (3H, s), 2.44 (4H, t), 3.08 (4H, t), 6.92 (2H, d), 7.26 - 7.34 (6H, m), 7.60 (1 H, m), 9.10 (1H, s). LCMS (2) Rt: 2.39min; m/z (ES+) 414.
Example Q-8 2-(2,6-difluoropheny[)-5-(4-(2-morpholinoethoxy)phenylamino)oxazole-4- carboxamide
Figure imgf000147_0001
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 2.46 (4H, m), 2.67 (2H, t), 3.58 (4H, t), 4.06 (2H, t), 6.93 (2H, d), 7.30 (2H, br. s), 7.32- 7.36 (4H, m), 7.62 (1 H, m), 9.14 (1H, br. s). LCMS (2) Rt: 2.42min; m/z (ES+) 445.
Example Q-9
5-(4-(4-acetylpiperazin-1-yI)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Step a - 1-(4-(4-aminophenyl)piperazin-1-yl)ethanone
Figure imgf000147_0002
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine. 1H NMR (CDCI3) δ 2.13 (3H, s), 3.00 (4H, m), 3.61 (2H1 1), 3.76 (2H, t), 3.20-3.80 (2H, br. s), 6.66 (2H, d), 6.82 (2H, d). LCMS (1) Rt 0.94min; m/z (ES+) 220.
Step b - 5-(4-(4-acetylpiperazin-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000148_0001
1-(4-(4-Aminophenyl)piperazin-1-yl)ethanone and 5-bromo-2-(2,6- difluorophenyl)oxazole-4-carbonitrile were reacted together following the procedure set out in example Q-1 to give an intermediate nitrile which was hydrolysed to give the title compound by the method of step b in example Q-1. 1H NMR (DMSO) δ 2.04 (3H, s), 3.04 (2H, t), 3.11 (2H, t), 3.57 (4H, m), 6.96 (2H, d), 7.29 (2H, br. s), 7.30-7.34 (4H, m), 7.62 (1H, m), 9.14 (1 H, s). LCMS (2) Rt: 2.21 min; m/z (ES+) 442.
Example Q-10
2-(2,6-difluorophenyl)-5-(3-(2-morpholinoethoxy)phenylamino)oxazole-4- carboxamide
Figure imgf000148_0002
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 2.47 (4H, br. t), 2.69 (2H, t), 3.58 (4H, t), 4.09 (2H, t), 6.61 (1H, dd), 7.00 (1H, dd), 7.08 (1H, t), 7.22 (1 H, t), 7.33 (2H, t), 7.39 (2H, br. s), 7.64 (1H, m), 9.31 (1H, s). LCMS (2) Rt: 2.54min; m/z (ES+) 445.
Example Q-11 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenylamino)oxazole-4-carboxamide
Step a - terf-butyl 4-(4-aminophenyl)piperazine-1-carboxylate
Figure imgf000149_0001
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine. 1H NMR (CDCI3) δ 1.48 (9H, s), 3.00 (4H, m), 3.61 (4H, m), 6.66 (2H, d), 6.87 (2H, d). LCMS (1) Rt: 1.75min; m/z (ES+) 222, 178.
Step b - 2-(2,6-difluorophenyl)-5-(4-(piperazin-1-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000149_0002
The title compound was prepared according to the procedure described in example Q-1 from terf-butyl 4-(4-aminophenyl)piperazine-1-carboxylate. Boc deprotection occurred during the acid mediated nitrile hydrolysis. 1H NMR (DMSO) δ 2.84 (4H, t), 3.01 (4H, m), 6.91 (2H, d), 7.27-7.34 (6H, m), 7.62 (1H, m), 9.10 (1H, br. s). LCMS (2) Rt: 2.09min; m/z (ES+) 400.
Example Q-12
2-(2,6-difluorophenyl)-5-(3-(piperazin-1-yl)phenylamϊno)oxazole-4-carboxamide formate salt
Step a - terf-butyl 4-(3-aminophenyl)piperazine-1-carboxylate
Figure imgf000149_0003
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine. The final product was purified by silica gel column chromatography using a 10-100% EtOAc in hexane gradient. 1H NMR (CDCI3) δ 1.48 (9H, s), 3.11 (4H, t), 3.57 (4H, t), 6.26 (1H, ddd), 6.30 (1 H, m), 6.37 (1 H, ddd), 7.06 (1H, t).
Step b - 2-(2,6-difluorophenyl)-5-(3-(piperazin-1-yl)phenylamino)oxazole-4-carboxamide formate salt
Figure imgf000150_0001
The title compound was prepared according to the procedure described in example Q-1 from fe/t-butyl 4-(3-aminophenyl)piperazine-1-carboxylate. Boc deprotection occurred during the acid mediated nitrile hydrolysis and the final product was isolated as the formate salt following preparative HPLC. 1H NMR (DMSO) δ 2.95 (4H, m), 3.16 (4H, m), 6.64 (1H, dd), 6.89 (1 H1 dd), 7.02 (1 H, t), 7.17 (1 H, t), 7.34 (2H, t), 7.38 (2H, br. s), 7.63 (1H, m), 8.27 (1 H, s, formate), 9.20 (1 H, br. s). LCMS (2) Rt: 2.25min; m/z (ES+) 400.
Example Q-13 2-(2,6-difluorophenyl)-5-(4-(piperidin-1-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000150_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 1.55 (6H, m), 3.07 (4H, t), 6.91 (2H, d), 7.29 (6H, m), 7.61 (1H1 m), 9.07 (1 H, br. s). LCMS (2) Rt: 3.27min; m/z (ES+) 399.
Example Q-14 2-(2,6-difluorophenyl)-5-(4-(4-methylpiperazine-1-carbonyl)phenylamino) oxazole- 4-carboxamide
Figure imgf000151_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 2.19 (3H, s), 2.31 (4H, m), 3.49 (4H, m), 7.40 (8H, m), 7.65 (1 H, m), 9.54 (1H, br. s). LCMS (2) Rt: 2.07min; m/z (ES+) 442.
Example Q-15 5-(4-(1,4-diazepan-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Ste a - fe/f-butyl 4-(4-aminophenyl)-1 ,4-diazepane-1-carboxylate
Figure imgf000151_0002
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yI)benzenamine. LCMS (1) Rt: 1.85min; m/z (ES+) 292.
Step b - 5-(4-(1 ,4-diazepan-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000151_0003
The title compound was prepared from te/Y-butyl 4-(4-aminophenyl)-1 ,4-diazepane-1- carboxylate according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 1.93 (2H, m), 2.86 (2H, m), 3.06 (2H1 m), 3.56 (4H, m), 5.60 (1 H, br.s), 6.62 (1 H, br.s), 6.69 (2H, d), 7.03 (2H, t), 7.27 (2H1 d), 7.37 (1H, m), 8.63 (1 H, br.s). LCMS (2) Rt: 5 2.56min; m/z (ES+) 414.
Example Q-16 2-(2,6-difluorophenyl)-5-(4-(piperidin-4-yloxy)phenylamino)oxazole-4-carboxamide
Figure imgf000152_0001
Prepared according to the procedure described in example Q-5, except the Boc group ) was removed by treatment with 4M HCI in dioxane, prior to the base hydrolysis of the nitrile. 1H NMR (CDCI3) δ 1.63 (2H, m), 1.96 (2H, m), 2.70 (2H, m), 3.09 (2H, m), 4.27 (1 H, m), 5.31 (1 H, br.s), 5.98 (1 H1 br.s), 6.46 (1H1 br.s), 6.84 (2H, d), 6.97 (2H, m), 7.23 (2H, d), 7.33 (1 H, m), 8.62 (1 H, br.s). LCMS (2) Rt: 2.54min; m/z (ES+) 415.
Example Q-17 i 5-(4-(4-aminopiperidin-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Step a - ferf-butyl 1-(4-aminopheny!)piperidin-4-ylcarbamate
Figure imgf000152_0002
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine, except that the nitro group reduction was carried out in methanol using 20% w/w of 5% Pd/C under a hydrogen atmosphere for 4h at room temperature. LCMS (2) Rt: 2.26min; m/z (ES+) 292. Step b - 5-(4-(4-aminopiperidin-1-yI)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000153_0001
The title compound was prepared from terf-butyl 1-(4-aminophenyl)piperidin-4- ylcarbamate according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 1.45 (2H, m), 1.85 (2H, m), 2.71 (3H, m), 3.52 (2H, m), 5.28 (1H, br.s), 6.43 (1 H, br.s), 6.87 (2H, d), 6.96 (2H, t), 7.22 (2H, d), 7.31 (1 H, m), 8.59 (1 H, br.s). LCMS (2) Rt: 2.30min; m/z (ES+) 414.
Example Q-18 5-(4-(4-(aminomethyl)piperidin-1 -yl)phenylamino)-2-(2,6-dif luorophenyl) oxazole-4- carboxamide
Step a - ferf-butyl (1-(4-aminophenyl)piperidin-4-yI)methylcarbamate
Figure imgf000153_0002
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine. 1H NMR (CDCI3) δ 1.10 (1 H, m), 1.47 (9H, s), 1.79 (4H, m), 2.36 (1 H, dd), 2.60 (1H, m), 3.11 (2H, m), 3.36 (2H, m), 4.62 (1 H, br.s), 6.67 (2H, d), 6.84 (2H, d). LCMS (2) Rt: 2.45min; m/z (ES+) 306.
Step b - 5-(4-(4-(aminomethyl)piperidin-1-yl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000154_0001
The title compound was prepared from ferf-butyl (1-(4-aminophenyl)piperidin-4- yl)methylcarbamate according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 1.00 (1 H, m), 1.72 (4H, m), 2.34 (1H, dd), 2.60 (3H, m), 3.44 (1 H, m), 3.56 (1H, m), 5.37 (1H1 br.s), 6.49 (1H, br.s), 6.88 (2H, d), 6.96 (2H, t), 7.22 (2H, d), 7.30 (1H, m), 8.60 (1 H, br.s). LCMS (2) Rt: 2.49min; m/z (ES+) 428.
Example Q-19
2-(2,6-difluorophenyl)-5-(4-(3-oxopiperazin-1-yl)phenylamino)oxazole-4- carboxamide
Step a - 4-(4-aminophenyl)piperazin-2-one
Figure imgf000154_0002
The title compound was prepared according to the procedure described for the synthesis of 4-(4-methylpiperazin-1-yl)benzenamine, except that the nitro reduction was carried out in methanol using 20% w/w of 5% Pd/C under a hydrogen atmosphere for 4h at room temperature. 1H NMR (DMSO) δ 3.14 (2H, m), 3.24 (2H, m), 3.45 (2H, s), 4.09 (2H, br.s), 6.52 (2H, d), 6.71 (2H, d), 7.93 (1 H, br.s). LCMS (2) Rt: 0.78min; m/z (ES+) 192.
Step b - 2-(2,6-difluorophenyl)-5-(4-(3-oxopiperazin-1-yl)phenylamino)oxazoIe-4- carboxamide
Figure imgf000155_0001
The title compound was prepared from 4-(4-aminophenyl)piperazin-2-one according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.30 (4H, m), 3.66 (2H, s), 6.94 (2H, d), 7.31 (6H, m), 7.62 (1H, m), 8.03 (1H, br.s), 9.13 (1H, s). LCMS (2) Rt: 2.08min; m/z (ES+) 414.
Example Q-20
2-(2,6-difluorophenyl)-5-(4-(dimethylcarbamoyl)phenylamino)oxazole-4- carboxamide
Figure imgf000155_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 2.96 (6H, s), 7.41 (8H, m), 7.65 (1H, m), 9.53 (1H, s). LCMS (2) Rt: 2.24min; m/z (ES+) 387.
Example Q-21
2-(2,6-difluorophenyl)-5-(4-(piperidine-1-carbonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000156_0001
Prepared according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 1.70 (6H, br. m), 3.57 (4H1 br. m), 5.50 (1 H, br.s), 6.60 (1 H, br.s), 7.09 (2H, t), 7.43 (5H, m), 9.00 (1H, s). LCMS (2) Rt: 2.68min; m/z (ES+) 427.
Example Q-22
2-(2,6-difluorophenyl)-5-(4-(piperazine-1-carbonyl)phenylamino)oxazole-4- carboxamide
Step a - ferf-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate
Figure imgf000156_0002
4-Nitrobenzoic acid (1.00g, δ.OOmmol), te/f-butyl 1-piperazinecarboxyIate (1.1Og, 6.00mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.7Og, 9.00mmol) and /V-methylmorpholine (1.30ml, 12.00mmol) were dissolved in dichloromethane (10ml) and the reaction mixture stirred at 200C for 5h. The reaction was then washed with saturated sodium bicarbonate solution and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-50% EtOAc in hexane gradient to afford te/f-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.88g, 5.60mmol, 94%) as a white solid. LCMS (1) Rt: 2.01 min; m/z (ES+) No M + H+, but 280 (-tBu) and 236 (-Boc).
Step b - fe/f-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate
Figure imgf000157_0001
A solution of te/f-butyl 4-(4-nitrobenzoyl)piperazine-1-carboxylate (1.0Og, 3.00mmol) in MeOH (60ml) was hydrogenated at 2O0C at atmospheric pressure using an H-Cube (flow rate at 1 ml/min and full hydrogen mode) using a Pd/C cartridge. The solvent was removed in vacuo to afford terf-butyl 4-(4-aminobenzoyl)piperazine-1-carboxylate (0.85g, 2.79mmol, 93%) as a white solid. 1H NMR (CDCI3) δ 1.41 (9H, s), 3.38 (4H, m), 3.53 (4H, m), 4.07 (2H, br. s), 6.55 (2H, d), 7.17 (2H, d). LCMS (2) Rt: 2.14min; m/z (ES+) 306.
Step c - 2-(2,6-difluorophenyI)-5-(4-(piperazine-1-carbonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000157_0002
The title compound was prepared from te/t-butyl 4-(4-aminobenzoyl)piperazine-1- carboxylate according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 2.91 (4H, m), 3.61 (4H, m), 5.44 (1 H, br.s), 6.62 (1 H, br.s), 7.09 (2H, t), 7.45 (5H, m), 9.02 (1 H, s). LCMS (2) Rt: 1.91min; m/z (ES+) 428.
Example Q-23 2-(2-Fluorophenyl)-5-(4-morpholinophenylamino)oxazole-4-carboxamide
Figure imgf000157_0003
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.07 (4H, br t), 3.74 (4H, brt), 6.90 (2H1 d), 7.27 (2H, br s), 7.34-7.42 (4H, m), 7.50-7.55 (1H, m), 7.93 (1H, ddd), 9.08 (1 H, s). LCMS (2) Rt: 2.59min; m/z 383.
Example Q-24 5-(4-(1H-imidazol-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000158_0001
Prepared according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 5.42 (1H, br s), 6.61 (1 H, br s), 7.08 (2H, dd), 7.20 (1 H1 s), 7.25 (1 H, m), 7.39 (2H, d), 7.45 (1H, m), 7.50 (2H, d), 7.85 (1H, s), 9.00 (1H, s). LCMS (2) Rt: 2.33min; m/z 382.
Example Q-25 2-(2,6-difluorophenyl)-5-(4-(sulfonamide)phenylamino)oxazole-4-carboxamide
Figure imgf000158_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 7.23 (2H, s), 7.34 (2H, t), 7.44 (2H1 s), 7.52 (2H, d), 7.65 (1 H, m), 7.74 (2H, d), 9.70 (1H, s). LCMS (2) Rt: 2.05min; m/z 395.
Example Q-26
2-(2,6-difluorophenyl)-5-(4-(N',N1-dimethylsulfonamide)phenylamino)oxazole-4- carboxamide
Figure imgf000159_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 2.58 (6H, s), 7.34 (2H, t), 7.48 (2H, s), 7.58 (2H, d), 7.67 (3H, m), 9.83 (1 H, s). LCMS (2) Rt: 2.60min; m/z 423.
Example Q-27
2-(2,6-difluorophenyl)-5-(4-(N'-methylsulfonamide)phenylamino)oxazole-4- carboxamide
Figure imgf000159_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 2.39 (3H, d), 7.28 (1 H, q), 7.33 (2H1 1), 7.45 (2H, s), 7.54 (2H, d), 7.67 (3H, m), 9.76 (1H, s). LCMS (2) Rt: 2.30min; m/z 409.
Example Q-28
2-(2,6-difluorophenyl)-5-(4-(piperidin-1-ylsulfonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000160_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 1.33 (2H, m), 1.52 (4H, m), 2.84 (4H, m), 7.33 (2H, t), 7.47 (2H, s), 7.56 (2H, d), 7.63 (3H1 m), 9.82 (1 H, s). LCMS (2) Rt: 3.01 min; m/z 463.
Example Q-29
2-(2,6-difluorophenyl)-5-(4-(morpholinosulfonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000160_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 2.83 (4H, t), 3.61 (4H, t), 7.34 (2H, t), 7.48 (2H, s), 7.62 (5H1 m), 9.86 (1H, s). LCMS (2) Rt: 2.55min; m/z 465.
Example Q-30
5-(4-(1H-1,2,4-triazol-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000161_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 7.34 (2H, t), 7.40 (2H1 br s), 7.61 (3H, m), 7.80 (2H, d), 8.21 (1 H, s), 9.22 (1H, s), 9.57 (1 H, br s). LCMS (2) Rt: 2.31 min; m/z 383.
Example Q-31 5-(4-(1H-tetrazol-1-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000161_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 7.39 (2H, t), 7.44 (2H1 br s), 7.65 (3H, m), 7.85 (2H, d), 9.70 (1 H, br s), 10.02 (1 H, s). LCMS (2) Rt: 2.39min; m/z 384.
Example Q-32
2-(2,6-difluorophenyl)-5-(4-(5-oxo-4,5-dihydro-1H-pyrazol-3- yl)phenylamino)oxazole-4-carboxamide
Figure imgf000162_0001
Prepared according to the procedure described in example Q-1. LCMS (2) Rt: 1.58min; m/z 398.
Example Q-33
2-(2,6-difIuorophenyl)-5-(4-(5-(hydroxymethyl)isoxazol-3-yl)phenylamino)oxazole- 4-carboxamide
Figure imgf000162_0002
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 4.58 (2H, d), 5.70 (1 H, t), 6.89 (1 H, s), 7.35 (2H, t), 7.41 (2H, br s), 7.53 (2H, d), 7.65 (1 H, m), 7.82 (2H, d) 9.58 (1 H, br s). LCMS (2) Rt: 2.38min; m/z 413.
Example Q-34 5-(4-(1H-tetrazol-5-yl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000163_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 7.35 (2H1 1), 7.43 (2H, br s), 7.57 (2H, d), 7.65 (1 H, m), 7.96 (2H, d), 9.63 (1H1 br s). LCMS (2) Rt: 1.53min; m/z 383.
Example Q-35 2-(2,6-dichlorophenyl)-5-(4-(piperazin-1-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000163_0002
Prepared according to the procedure described in example Q-11. 1H NMR (DMSO) δ 2.88 (4H, t), 3.02 (4H, t), 6.90 (2H, d), 7.20 (3H, m), 7.40 (1H, br s), 7.61-7.70 (3H, m), 9.05 (1 H, br s). LCMS (2) Rt: 2.57min; m/z 432.
Example Q-36
2-(2-chloro-6-fluorophenyl)-5-(4-(piperazin-1-yl)phenylamino)oxazole-4- carboxamide
Figure imgf000164_0001
Prepared according to the procedure described in example Q-11. 1H NMR (DMSO) δ 2.88 (4H, t), 3.03 (4H, t), 6.91 (2H, d), 7.25 (3H, m), 7.35 (1H, br s), 7.46 (1H, t), 7.54 (1H, d), 7.64 (1H, m), 9.08 (1H, br s). LCMS (2) Rt: 2.44min; m/z 416.
Example Q-37 2-(2,6-dimethylphenyl)-5-(4-(pϊperazin-1-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000164_0002
Prepared according to the procedure described in example Q-11. 1H NMR (CD3OD) δ
2.35 (6H, s), 3.35 (8H, m, obscured by CD3OD peak), 7.06 (2H, d), 7.20 (2H, d), 7.30-
7.36 (3H, m), 8.56 (1 H, br s). LCMS (2) Rt: 2.64min; m/z 392.
Example Q-38 5-(1H-benzo[d]imidazol-1-yl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000164_0003
Prepared according to the method described in example Q-1 , except that the Buchwald coupling was performed at 15O0C for 5 minutes. 1H NMR (DMSO) δ 7.37-7.44 (4H, m), 7.72-7.78 (2H, m), 7.80-7.83 (1H, m), 7.85 (1H, br. s), 7.88 (1 H, br. s), 8.87 (1 H1 s). LCMS (2) Rt: 2.40min; m/z (ES+) 341.
Example Q-39 2-(2,6-difluorophenyl)-5-(3,4-dimethoxyphenylamino)oxazole-4-carboxamide
Figure imgf000165_0001
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 3.73 (3H1 s), 3.77 (3H, s), 6.92 (1 H, d), 6.98 (1 H, dd), 7.14 (1 H, d), 7.31 (2H, br s), 7.32 (2H, t), 7.61 (1 H, tt), 9.16 (1 H, s). LCMS (2) Rt: 2.53min; m/z (ES+) 376.
Example Q-40 2-(2,6-difluorophenyl)-5-(3,4,5-trimethoxyphenylamino)oxazole-4-carboxamide
Figure imgf000165_0002
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 3.62 (3H1 s), 3.78 (6H, s), 6.84 (2H, s), 7.33 (2H, t), 7.36 (2H, br s), 7.61 (1H, tt), 9.22 (1 H, s). LCMS (2) Rt: 2.61 min; m/z (ES+) 406.
Example Q-41 5-(benzo[d][1,3]dioxol-5-ylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000166_0001
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 6.01 (2H, s), 6.89 (2H, s), 7.10 (1H1 s), 7.31 (2H, br s), 7.32 (2H, t), 7.62 (1H, tt), 9.20 (1 H, s). LCMS (2) Rt: 2.69min; m/z (ES+) 360.
Example Q-42 2-(2,6-difluorophenyl)-5-(4-(trifluoromethoxy)phenylamino)oxazole-4-carboxamide
Figure imgf000166_0002
Prepared according to the procedure described in example Q-5. 1H NMR (DMSO) δ 7.34 (2H, t), 7.38 (2H, d), 7.40 (2H, br s), 7.52 (2H, d), 7.64 (1H, tt), 9.53 (1H, s). LCMS (2) Rt: 3.28min; m/z (ES+) 400.
Example Q-43
2-(2,6-difluorophenyl)-5-(2-fluoro-4-(methylsulfonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000166_0003
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO)
5 3.25 (3H, S)1 7.37 (2H, t), 7.62 (2H, br s), 7.68 (1H, tt), 7.77 (1H, dd), 7.82 (1 H, t), 7.88
(1H, dd), 9.80 (1H, s). LCMS (2) Rt: 2.40min; m/z (ES+) 412.
Example Q-44
2-(2,6-difluorophenyl)-5-(2-fluoro-5-(methylsulfonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000167_0001
Prepared according to the procedure described in example Q-1. 1H NMR (DMSO) δ 3.24 (3H, s), 7.35 (2H, t), 7.56-7.70 (5H, m), 8.18 (1 H, d), 9.67 (1H, s). LCMS (2) Rt: 2.30min; m/z (ES+) 412.
Example Q-45 2-(2,6-difluorophenyl)-5-(pyridin-3-ylamino)oxazole-4-carboxamide
Figure imgf000167_0002
The title compound was prepared according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 5.49 (1 H, br.s), 6.56 (1H1 br.s), 7.00 (2H, t), 7.22 (1 H, dd), 7.35 (1H, m), 7.72 (1 H, m), 8.25 (1H, dd), 8.61 (1H, d), 8.83 (1 H, br.s). LCMS (2) Rt: 2.09min; m/z (ES+) 317.
Example Q-46 2-(2,6-difluorophenyl)-5-(4-(piperidin-4-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000168_0001
The title compound was prepared according to the procedure described in example Q-1 from te/ϊ-butyl 4-(4-aminophenyl)piperidine-1-carboxylate. Boc deprotection occurred during the acid mediated nitrile hydrolysis. 1H NMR (CD3OD) δ 1.79 (2H1 m), 1.98 (2H, m), 2.79 (1H, m), 3.03 (2H, m), 3.39 (2H, m), 7.09 (2H, t), 7.18 (2H, d), 7.31 (2H, d), 7.46 (1 H, m), 8.44 (1H, s). LCMS (2) Rt: 2.13min; m/z (ES+) 399.
Example Q-47
2-(2,6-difluorophenyl)-5-(6-(piperazin-1-yl)pyridin-3-ylamino)oxazole-4- carboxamide
Figure imgf000168_0002
The title compound was prepared according to the procedure described in example Q-1 from te/f-butyl 4-(5-aminopyridin-2-yl)piperazine-1-carboxylate. Boc deprotection occurred during the acid mediated nitrile hydrolysis. 1H NMR (CD3OD) δ 3.30 (4H, m), 3.74 (4H, m), 6.97 (1H, dd), 7.18 (2H, t), 7.55 (1H1 m), 7.76 (1H, dd), 8.33 (1H, dd), 8.55 (1 H, s). LCMS (2) Rt: 1.93min; m/z (ES+) 401.
Example Q-48 2-(2,6-difluorophenyl)-5-(6-morpholinopyridin-3-ylamino)oxazole-4-carboxamide
Figure imgf000169_0001
The title compound was prepared according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 3.46 (4H, m), 3.84 (4H, m), 6.69 (1 H, d), 7.05 (2H, t), 7.40 (1 H, m), 7.64 (1 H, dd), 8.31 (1 H, d). LCMS (2) Rt: 2.33min; m/z (ES+) 402.
Example Q-49
2-(2,6-difluorophenyl)-5-(6-(4-methylpiperazin-1-yl)pyridin-3-ylamino)oxazole-4- carboxamide
Figure imgf000169_0002
The title compound was prepared according to the procedure described in example Q-1. 1H NMR (CDCI3) δ 2.43 (3H, s), 2.68 (4H, m), 3.58 (4H, m), 6.70 (1 H, d), 7.04 (2H, t), 7.40 (1 H, m), 7.62 (1 H, dd), 8.29 (1 H, d). LCMS (2) Rt: 2.21 min; m/z (ES+) 415.
Example Q-50
5-(4-((piperidin-4-ylmethyl)carbamoyl)phenyIamino)-2-(2,6-difluorophenyl)oxazole- 4-carboxamide
Step a - terf-butyl 4-((4-arninobenzamido)methyl)piperidine-1-carboxylate
Figure imgf000169_0003
To a solution of 4-(aminomethyl)-Boc-piperidine (0.313g, 1.458mmol), 4-aminobenzoic acid (0.20Og, 1.458mmol) and N-methyl morpholine (0.242mL, 2.187mmol) in dichloromethane (2ml_) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.422g, 2.187mmol) and the reaction mixture stirred at room temperature overnight. The reaction was then washed with water and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using a 0-100% EtOAc in hexane gradient to afford tert- butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.91min; m/z (ES+) 334.
Step b - fert-butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido) methyl)piperidine-1 -carboxylate
Figure imgf000170_0001
A solution of fr/s(dibenzylideneacetone)dipalladium(0) (0.019g, 0.021 mmol) and 9,9- dimethyl-4,5-ib/s(diphenylphosphino)xanthene (0.011g, 0.021 mmol) in nBuOH:dioxane (1 :1) (5mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6- difluorophenyl)oxazole-4-carbonitrile (0.08Og, 0.281 mmol), fenf-butyl 4-((4- aminobenzamido)methyl)piperidine-1-carboxylate (0.25Og, 1.40mmol) and cesium carbonate (0.108g, 0.561 mmol) were added and the mixture heated in the microwave for 3 minutes at 14O0C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through a thiol resin cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford tert- butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5- ylamino)benzamido)methyl)piperidine-1 -carboxylate (0.035g, 0.09mmol, 26%) as a light yellow solid. LCMS (2) Rt: 3.09min; m/z (ES+) 538.
Step c - 5-(4-((piperidin-4-ylmethyI)carbamoyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000171_0001
A solution of terf-butyl 4-((4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5- ylamino)benzamido)methyl)piperidine-1-carboxylate (0.028g, 0.052mmol) in concentrated sulfuric acid (1mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 with 5M NaOH and extracted with EtOAc. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo to afford 5-(4~((piperidin-4-ylmethyl)carbamoyl)phenylamino)-2-(2,6- difluorophenyl)oxazole-4-carboxamide (0.003g, O.OOTmmol, 14%) as a yellow solid. 1H NMR (CD3OD) δ 1.51 (2H, m), 2.00 (3H, m), 2.99 (2H, t), 3.35 (2H, m), 3.45 (2H, m), 7.22 (2H, t), 7.53 (2H, d), 7.60 (1 H, m), 7.87 (2H, d), 8.55 (1H, br s). LCMS (2) Rt: 1.85min; m/z (ES+) 456.
Example Q-51
5-(4-((3-aminopropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazoIe-4- carboxamide
Step a - terf-butyl 3-(4-aminobenzamido)propylcarbamate
Figure imgf000171_0002
The title compound was prepared according to the procedure described for the synthesis of fe/t-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.69min; m/z (ES+) 294.
Step b - 5-(4-((3-aminopropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000172_0001
Prepared according to the procedure described in example Q-50 (steps b and c). 1H NMR (CD3OD) δ 1.97 (2H, quin), 3.01 (2H, t), 3.52 (2H, t), 7.22 (2H, t), 7.52 (2H, d), 7.60 (1 H, m), 7.88 (2H, d), 8.57 (1H, br s). LCMS (2) Rt: 1.74min; m/z (ES+) 416.
Example Q-52
5-(4-((2-aminoethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyI)oxazole-4- carboxamide
Step a - te/t-butyl 2-(4-aminobenzamido)ethylcarbamate
Figure imgf000172_0002
The title compound was prepared according to the procedure described for the synthesis of terf-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxyIate. LCMS (3) Rt: 1.60min; m/z (ES+) 280.
Step b - 5-(4-((2-aminoethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000173_0001
Prepared according to the procedure described in example Q-50 (steps b and c). 1H NMR (CD3OD) δ 3.17 (2H, t), 3.67 (2H, t), 7.22 (2H, t), 7.53 (2H1 d), 7.60 (1H, m), 7.91 (2H, d), 8.56 (1H1 s). LCMS (2) Rt: 1.74min; m/z (ES+) 402.
Example Q-53
(R)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4- carboxamide
Step a - (R)-tert-buty\ 3-(4-aminobenzamido)piperidine-1-carboxylate
Figure imgf000173_0002
The title compound was prepared according to the procedure described for the synthesis of terf-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.88min; m/z (ES+) 320.
Step b - (R)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole- 4-carboxamide
Figure imgf000174_0001
Prepared according to the procedure described in example Q-50 (steps b and c). 1H NMR (DMSO) δ 1.50 (2H1 1), 1.71 (1H, m), 1.84 (1H, m), 2.57 (1H, m), 2.92 (1H, d), 3.07 (1H, d), 3.90 (2H, m), 7.34 (2H, t), 7.43 (2H, br s), 7.47 (2H, d), 7.64 (1 H, m), 7.83 (2H, d), 8.14 (1 H, d), 8.32 (1H, s). LCMS (2) Rt: 1.96min; m/z (ES+) 442.
Example Q-54
(S)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole-4- carboxamide
Step a - (S)-terf-butyl 3-(4-aminobenzamido)piperidine-1-carboxylate
Figure imgf000174_0002
The title compound was prepared according to the procedure described for the synthesis of terf-butyl 4-((4-aminobenzamido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.89min; m/z (ES+) 320.
Step b - (S)-2-(2,6-difluorophenyl)-5-(4-(piperidin-3-ylcarbamoyl)phenylamino)oxazole- 4-carboxamide
Figure imgf000175_0001
Prepared according to the procedure described in example Q-50 (steps b and c). 1H NMR (DMSO) δ 1.50 (2H, t), 1.72 (1H, m), 1.84 (1H, m), 2.57 (1H, m), 2.91 (1H, d), 3.07 (1H, d), 3.92 (2H, m), 7.34 (2H, t), 7.43 (2H, br s), 7.47 (2H, d), 7.64 (1 H, m), 7.83 (2H, d), 8.15 (1H, d), 8.31 (1H, s). LCMS (2) Rt 1.95min; m/z (ES+) 442.
Example Q-55
(f?)-5-(4-((piperidin-3-ylmethyl)carbamoyl)phenylannino)-2-(2,6- difluorophenyl)oxazole-4-carboxamide
Step a - (R)-fe/f-butyl 3-((4-aminobenzamido)methyl)piperidine-1-carboxylate
Figure imgf000175_0002
The title compound was prepared according to the procedure described for the synthesis of te/f-butyl 4-((4-aminobenzarnido)methyl)piperidine-1-carboxylate. LCMS (3) Rt: 1.93min; m/z (ES+) 334.
Step b - (f?)-5-(4-((piperidin-3-ylmethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000176_0001
Prepared according to the procedure described in example Q-50 (steps b and c). 1H NMR (CD3OD) δ 1.46 (2H, m), 1.74 (1H, m), 1.96 (2H, m), 2.10 (1 H, m), 2.75 (1H, t), 2.92 (1H, t), 3.36 (3H, m), 7.21 (2H, t), 7.51 (2H, d), 7.58 (1 H, m), 7.86 (2H, d), 8.52 (1H, br s). LCMS (2) Rt: 1.85min; m/z (ES+) 456.
Example Q-56
2-(2,6-difluorophenyl)-5-(4-(piperidin-1-yImethyl)phenylamino)oxazole-4- carboxamide
Figure imgf000176_0002
Prepared according to the procedure described in example (steps b and c). 1H NMR (CD3OD) δ 1.55 (2H, m), 1.71 (4H1 quin), 2.79 (4H, m), 3.82 (2H, br s), 7.19 (2H, t), 7.39 (2H, d), 7.45 (2H, d), 7.56 (1 H1 m). LCMS (2) Rt: 3.12min; m/z (ES+) 413.
Example Q-57
2-(2-chloro-6-fluorophenyl)-5-(4-(1-methylpiperazine-4- carbonyl)phenylamino)oxazole-4-carbonitrile
Figure imgf000177_0001
Prepared according to the method described for example Q-1. 1H NMR (CD3OD) δ 2.35 (3H, s), 2.45-2.55 (4H, m), 3.60-3.70 (4H, br. s), 7.28-7.35 (1H, m), 7.40-7.50 (5H, m), 7.55-7.61 (1H1 m). LCMS (2) 2.14min; m/z (ES+) 458, 460.
Example Q-58 2-(1H-indazol-4-yl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carboxamide
Step a - mixture of methyl 1-(4-methoxybenzyl)-1H-indazole-4-carboxylate and methyl 2-(4-methoxybenzyl)-2H-indazole-4-carboxylate
Figure imgf000177_0002
To a solution of methyl 1 H-indazole-4-carboxylate (0.9Og, 5.11mmol) in anhydrous DMF (40ml) was added NaH, as a 60% suspension in mineral oil (0.31g, 5.11mmol). After stirring at room temperature for 5 minutes, 4-methoxybenzyl chloride (1.15ml, 5.11mmol) was added and the reaction stirred for a further hour. The reaction was then diluted with DCM and washed with water and brine before being dried over Na2SO4 and concentrated to a clear oil. Flash chromatography on silica gel, using a gradient of 0- 35% EtOAc in hexanes as eluant, gave 1.22g (4.12mmol, 81%) of an approximate one to one mixture of the two regioisomers. LCMS (3) 2.31 and 2.41 min; m/z (ES+) 297.
Step b - mixture of 1-(4-methoxybenzyl)-1H-indazole-4-carboxylic acid and 2-(4- methoxybenzyl)-2H-indazole-4-carboxylic acid
Figure imgf000177_0003
A mixture of methyl 1-(4-methoxybenzyl)-1H-indazole-4-carboxyIate and methyl 2-(4- methoxybenzyl)-2H-indazole-4-carboxylate (1.22g, 4.12mmol) was taken up in MeOH (13ml) and to the solution were added THF (6.5ml) and 1 M aqueous NaOH solution (6.5ml). The reaction was stirred at room temperature overnight then acidified to pH1 with 2M HCI and the resulting precipitate filtered off and dried under vacuum to give 1.07g (3.79mmol, 92%) of white solid. LCMS (3) 1.32 and 1.47 min; m/z (ES-) 281.
Step c - mixture of 2-(1-(4-methoxybenzyI)-1H-indazol-4-yl)-5-aminooxazole-4- carbonitrile and 2-(2-(4-methoxybenzyl)-2H-indazol-4-yl)-5-aminooxazole-4-carbonitrile
Figure imgf000178_0001
A mixture of 1-(4-methoxybenzyl)-1 H-indazole-4-carboxylic acid and 2-(4- methoxybenzyl)-2H-indazole-4-carboxylic acid (1.07g, 3.79mmol) was taken up in a mixture of DCM (10ml) and DMF (100μl) and then oxalyl chloride (0.38ml, 4.55mmol) was added dropwise. After stirring at room temperature for 2 hours the solvent was removed in vacuo and the residue dissolved in NMP (5ml). To this solution was added aminomalononitrile tosylate (1.15g, 4.55mmol) and the reaction heated to 12O0C under microwave irradiation for a period of 5 minutes. The reaction mixture was then diluted with DCM and washed with water. The resulting white precipitate was filtered off and dried in vacuo to give 1.1g (3.20mmol, 84%) of a white powdery solid containing a mixture of the two regioisomers. LCMS (3) 2.15 and 2.25 min; m/z (ES-) 344.
Step d - mixture of 2-(1-(4-methoxybenzyl)-1H-indazol-4-yl)-5-bromooxazole-4- carbonitrile and 2-(2-(4-methoxybenzyl)-2H-indazol-4-yl)-5-bromooxazole-4-carbonitrile
Figure imgf000178_0002
Copper (II) bromide (1.4Og, 6.40mmol) was suspended in anhydrous acetonitrile (30ml) under a nitrogen atmosphere at O0C. Terf-butyl nitrite (0.87ml, 3.52mmol) was added, followed by the portionwise addition of a mixture of 2-(1-(4-methoxybenzyl)-1H-indazol- 4-yl)-5-aminooxazole-4-carbonitrile and 2-(2-(4-methoxybenzyl)-2H-indazoI-4-yl)-5- aminooxazole-4-carbonitrile (1.1g, 3.20mmol). The reaction was stirred at O0C for 30 minutes and then warmed to room temperature and stirred for a further 30 minutes. The reaction was diluted with diethyl ether and washed with 2M HCI and brine before being dried over Na2SO4, concentrated in vacuo and purified by flash chromatography (silica gel, 10-50% EtOAc in hexanes as eluant) to give the desired mixture of regioisomers as a yellow solid, 0.50Og (1.2mmol, 38%). LCMS (3) broad peak at 2.66 min; m/z (ES-) 408.
Step e - mixture of 2-(1-(4-methoxybenzyl)-1H-indazol-4-yl)-5-(4~ (methylsulfonyl)phenylamino)oxazole-4-carbonitrile and 2-(2-(4-methoxybenzyl)-2H- indazol-4-yl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carbonitrile
Figure imgf000179_0001
Palladium acetate (O.OOδg, 0.026mmo!) and BINAP (0.016mmol, 0.026mmol) were dissolved in DMF (5ml) and stirred at RT for 5 minutes. 2-(1-(4-Methoxybenzyl)-1H- indazol-4-yl)-5-bromooxazole-4-carbonitrile and 2-(2-(4-methoxybenzyl)-2H-indazol-4- yl)-5-bromooxazole-4-carbonitrile (0.15Og, 0.37mmol), 4-(methylsulfonyl)benzenamine (0.063g, 0.37mmol) and potassium phosphate tribasic (0.16Og, 0.73mmol) were then added and the reaction heated under microwave irradiation to 14O0C for a period of 5 minutes. The crude reaction mixture was purified by prep-HPLC to give a mixture of the two regioisomers as a yellow powder, 0.024g (0.044mmol, 12%). LCMS (3) 2.24 min (broad peak); m/z (ES-) 498.
Step f - 2-(3a,7a-dihydro-1 H-indazol-4-yl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4- carboxamide
Figure imgf000180_0001
A mixture of 2-(1-(4-methoxybenzyl)-1 H-indazol-4-yl)-5-(4- (methylsulfonyl)phenylamino)oxa2ole-4-carbonitrile and 2-(2-(4-methoxybenzyl)-2H- indazol-4-yl)-5-(4-(methylsulfonyl)phenylamino)oxazole-4-carbonitrile (0.024g, 0.044mmol) was taken up in TFA (1ml) and heated to 14O0C under microwave irradiation for a period of 30 minutes. The TFA was then removed in vacuo and the residue purified by prep-HPLC to furnish the title compound as a yellow solid (0.0027g, 0.0068mmol, 15%), 1H NMR (CD3OD) δ 3.20 (3H, s), 7.40-7.55 (2H, m), 7.6-7.8 (3H, m), 7.80-7.95 (2H, m), 8.92 (1 H, s), 13.35 (1H, s) LCMS (2) 1.99min; m/z (ES+) 397.
Example Q-59 2-(1H-indazol-4-yl)-5-(4-(piperazin-1-yl)phenylamino)oxazole-4-carboxamide
Figure imgf000180_0002
The title compound was prepared according to the procedure for Q-58 above. 1H NMR (DMSO) δ 2.85-2.95 (4H, m), 3.05-3.15 (4H, m), 6.85-6.95 (2H, m), 7.35 (2H, br. s), 7.40-7.50 (1H, m), 7.55-7.70 (4H, m), 8.28 (1 H, s), 9.35 (1 H, s) LCMS (2) 1.90min; m/z (ES+) 404.
Example Q-60
2-(1H-indazol-4-yl)-5-(4-(4-(2,2,2-trifluoroacetyl)piperazin-1- yl)phenylamino)oxazole-4-carboxamide
Figure imgf000181_0001
The title compound was isolated as a byproduct from the synthesis of 2-(1H-indazol-4- yl)-5-(4-(piperazin-1-yI)phenyIamino)oxazole-4-carboxamide, described in Q-59 above. 1H NMR (DMSO) δ 2.90-3.00 (4H, m), 3.05-3.15 (4H, m), 6.95-7.05 (2H, m), 7.25 (1H, br. s), 7.38-7.52 (4H, m), 7.55-7.65 (2H, m), 8.28 (1H, s), 8.85 (1H, s) LCMS (2) 1.84min; m/z (ES+) 500.
General Method R
General Method R comprises the series of steps set out in Scheme 12 above.
Example R-1 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxamide
Step a - 5-(4-methoxyphenyl)~2-(phenylamino)oxazole-4-carboxylic acid
Figure imgf000181_0002
To a mixture of ethyl 2-iodo-5-(4-methoxyphenyl)oxazo!e-4-carboxylate (0.03Og, O.OδOmmol), fr/s(dibenzylideneacetone)dipalladium(0) (0.004g, 0.004mmol), 2- dicyclohexylphosphino^'^'.δ'-tri-iso-propyM J'-biphenyl (O.OOδg, 0.013mmol) and potassium carbonate (0.04Og, 0.29mmol) in anhydrous DMF (1mL) was added aniline (0.041 g, 0.44mmol). The resulting mixture was stirred and degassed at room temperature for 5 minutes and then heated in the microwave at 15O0C for 10 minutes. The crude reaction mixture was passed through a MP-SH resin cartridge and then purified by SPE using a MP-TsOH resin cartridge to afford, after eluting with 2M ammonia in MeOH, ethyl 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylate which was used without further purification. LCMS (1) 2.30min; m/z (ES+) 339. To a stirred solution of ethyl 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylate in MeOH (5mL) at 550C was added 1M aqueous potassium hydroxide solution (2.075ml_, 2.08mmol) and the reaction mixture stirred at 550C overnight. The reaction was cooled to room temperature and the MeOH removed in vacuo. The remaining solution was diluted with water and washed with DCM. The aqueous phase was acidified with 2M aqueous HCI (2ml_) and extracted with EtOAc. The combined organic phase was washed with brine, dried over MgSO4 and the solvent removed in vacuo to afford 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylic acid (0.012g, 0.039mmol, 48%) as a white solid which was used without further purification. LCMS (1) Rt: 1.44min; m/z (ES+) 311.
Step b - 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxamide
Figure imgf000182_0001
To a stirred solution of 5-(4-methoxyphenyl)-2-(phenylamino)oxazole-4-carboxylic acid (0.012g, 0.039mmol), 1-hydroxybenzotriazole hydrate (0.009g, 0.059mmol) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.011g, 0.057mmol) in DMF (5mL) was added a 0.5M ammonia in dioxane solution (0.116ml_, 0.058mmol) and the resulting mixture stirred at room temperature overnight. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford 5-(4-methoxyphenyl)-2- (phenylamino)oxazole-4-carboxamide (0.0045g, 0.015mmol, 38%). 1H NMR (DMSO) δ 3.82 (3H, s), 6.98 (1 H, t), 7.04 (2H, d), 7.33 (2H, t), 7.51 (1 H, br, s), 7.60 (1H, br, s), 7.73 (2H, d), 8.16 (2H, d), 10.40 (1H, s). LCMS (2) Rt: 2.67min; m/z (ES+) 310.
In a similar manner as described in example R-1 the compounds described in examples R-2 to R-9 were prepared.
Example R-2 5-(4-methoxyphenyl)-2-(2-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000183_0001
1H NMR (DMSO) δ 3.81 (3H, s), 3.86 (3H, s), 7.00 (3H, m), 7.02 (2H, d), 7.48 (1H, br, s), 7.55 (1 H, br, s) 8.19 (2H, d), 8.30 (1 H, d), 9.30 (1 H, s). LCMS (2) Rt: 2.84min; m/z (ES+) 340.
Example R-3 5-(4-methoxyphenyl)-2-(3-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000183_0002
1H NMR (DMSO) δ 3.77 (3H, s), 3.82 (3H, s), 6.57 (1 H, m), 7.04 (2H, d), 7.22 (1 H, m), 7.25 (1H, m), 7.33 (1H, d), 7.48 (1 H, br, s), 7.51 (1 H, br, s), 8.14 (2H, d), 10.40 (1H, s). LCMS (2) Rt: 2.69min; m/z (ES+) 340.
Example R-4 5-(4-methoxyphenyl)-2-(4-methoxyphenylamino)oxazole-4-carboxamide
Figure imgf000183_0003
1H NMR (DMSO) δ 3.73 (3H, s), 3.81 (3H, s), 6.90 (2H, d), 7.02 (2H1 d), 7.48 (1 H, br, s), 7.53 (1 H, br, s) 7.64 (2H, d), 8.14 (2H, d), 10.17 (1H, s). LCMS (2) Rt: 2.62min; m/z (ES+) 340.
Example R-5 2-(o-toluidino)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000183_0004
1H NMR (DMSO) δ 2.30 (3H1 s), 3.80 (3H1 s), 7.00 (1H, t), 7.01 (2H, d), 7.21 (2H, m), 7.38 (1H, br, s), 7.48 (1H br, s), 7.98 (1H, d), 7.40 (2H, d), 9.33 (1H, s). LCMS (2) Rt: 2.78min; m/z (ES+) 324.
Example R-6 2-(m-toIuidino)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000184_0001
1H NMR (DMSO) δ 2.31 (3H, s), 3.80 (3H, s), 6.78 (1H1 d), 7.02 (2H1 d), 7.19 (1H1 1), 7.44 (1H, br, s), 7.51 (1 H, s), 7.55 (1H, d), 7.57 (1H, br, s), 8.13 (2H, d), 10.29 (1H, s). LCMS (2) Rt: 2.83min; m/z (ES+) 324.
Example R-7 2-(p-toluidino)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000184_0002
1H NMR (DMSO) δ 2.26 (3H, s), 3.81 (3H, s), 7.02 (2H, d), 7.12 (2H, d), 7.51 (1H, br, s), 7.57 (1H, br, s), 7.60 (2H, d), 8.14 (2H, d), 10.27 (1H, s). LCMS (2) Rt: 2.82min; m/z (ES+) 324.
Example R-8 2-(2-fluorophenylamino)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000184_0003
1H NMR (DMSO) δ 3.81 (3H, s), 7.04 (3H, m), 7.21 (2H, m), 7.51 (1 H, br s), 7.59 (1H, br s), 8.17 (2H, d), 8.42 (1H, m), 10.15 (1H, s). LCMS (2) Rt: 2.77min; m/z 328.
Example R-9 2-(2,6-difluorophenylamino)-5-(4-methoxyphenyl)oxazole-4-carboxamide
Figure imgf000185_0001
For this example the catalyst system employed during step a was fr/s(dibenzylideneacetone)dipalladium(0) and 9,9-dimethyl-4,5- ό/s(diphenylphosphino)xanthene with cesium carbonate as a base. The reaction mixture was irradiated in the microwave for 15 minutes at 15O0C. 1H NMR (DMSO) δ 3.79 (3H, s), 7.00 (2H, d), 7.14 (1H, br s), 7.32 (2H, t), 7.35 (1 H1 m), 7.43 (1H1 br s), 8.02 (2H, d), 9.84 (1H1 br s). LCMS (2) Rt: 1.84min; m/z 346.
Example R-10 2-(o-toluidino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Step a - fert-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine- 1 -carboxylate
Figure imgf000185_0002
A mixture of tert-buty\ 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1- carboxylate (O.Oδg, 0.11mmol), o-toluidine (0.061ml, 0.57mmol), f/7s(dibenzylideneacetone)dipalladium(0) (0.005g, O.OOδmrnol), 2- (dicyclohexylphosphinoj-^'.δ'-tri-i-propyl-i.i'-biphenyl (0.011g, 0.02mmol) and potassium carbonate (0.063g, 0.46mmol) in DMF (1.5ml) was degassed and heated in the microwave at 15O0C for 20 minutes. The reaction mixture was diluted with EtOAc and washed with water (x2). The organic phase was passed through a MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by silica gel column chromatography using 10-90% EtOAc in hexane as gradient to afford te/f-butyl 4-(4-(2-(o-toluidino)-4~(ethoxycarbonyl)oxazol-5-yl)phenyl)piperazine- 1-carboxylate (0.03Og, O.OΘmmol, 52%). LCMS (1) Rt: 2.63min; m/z (ES+) 507.
Step b - 2-(o-toluidino)-5-(4-(4-(ferf-butoxycarbonyl)piperazin-1-yI)phenyI)oxazole-4- carboxylic acid
Figure imgf000186_0001
To a solution of ferf-butyl 4-(4-(2-(o-toluidino)-4-(ethoxycarbonyl)oxazol-5- yl)phenyl)piperazine-1-carboxylate (0.042g, O.Oδmmol) in DCE (2ml) was added trimethyltin hydroxide (0.14Og, 0.77mmol) and the resulting mixture was heated at 8O0C overnight. The reaction was cooled to room temperature and diluted with DCM. The organic phase was washed with water. The combined aqueous phase was extracted with DCM and the combined organic phase dried over MgSO4 and the solvent removed in vacuo to afford 2-(o-toluidino)-5-(4-(4-(te/ϊ-butoxycarbonyl)piperazin-1- yl)phenyl)oxazole-4-carboxylic acid (0.038g, O.Oδmmol, 96%). LCMS (1) Rt: 1.89min; m/z (ES+) 479.
Step c - fe/f-butyl 4-(4-(2-(o~toluidino)-4-carbamoyloxazol-5-yI)phenyl)piperazine-1- carboxylate
Figure imgf000186_0002
To a solution of 2-(o-toluidino)-5-(4-(4-(te/if-butoxycarbonyl)piperazin-1- yl)phenyI)oxazole-4-carboxylic acid (0.038, O.Oδmmol) in DCM (0.8ml) and DMF (0.6ml) was added hydroxybenzotriazole monohydrate (0.016g, O.IOmmol), 1-[3- (dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.024g, 0.13mmol) and 0.5M ammonia in dioxane (0.8ml, 0.4mmol) and the resultant mixture stirred overnight at room temperature. A further portion each of hydroxybenzotriazole monohydrate (0.016g, O.IOmmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.024g, 0.13mmol) and 0.5M ammonia in dioxane (0.8ml, 0.4mmol) was added and the resultant mixture stirred for 5 hours at room temperature, followed by the addition of hydroxybenzotriazole monohydrate (0.008g, O.Oδmmol), 1-[3-(dimethylamino)propyl]-3- ethylcarbodiimide hydrochloride (0.012g, 0.065mmol) and 0.5M ammonia in dioxane (0.4ml, 0.2mmol) and the reaction mixture was stirred overnight. The solvent was then removed in vacuo and the residue purified by preparative HPLC to afford terf-butyl 4-(4- (2-(o-toluidino)-4-carbamoyloxazol-5-yl)phenyl)piperazine-1-carboxylate (0.012g, 0.025mmol, 32%). LCMS (2) Rt: 3.41 min; m/z (ES+) 478.
Step d - 2-(o-toluidino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000187_0001
To a solution of ferf-butyl 4-(4-(2-(o-toluidino)-4-carbamoyloxazol-5-yl)phenyl)piperazine- 1-carboxylate (0.012g, 0.025mmol) in DCM (0.5ml) was added 0.5M HCI in dioxane (0.25ml, 0.125mmol) and the resulting solution stirred at room temperature for 2 hours. The mixture was then diluted with MeOH and purified by SPE using a MP-TsOH (500mg) cartridge to afford 2-(o-toluidino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4- carboxamide (0.0087g, 0.023mmol, 92%). 1H NMR (DMSO) δ 2.30 (3H, s), 2.84 (4H, m), 3.15 (4H, m), 6.97-7.01 (3H, m). 7.19-7.23 (2H, m), 7.32 (1H, br. d), 7.41 (1H, br. d), 7.99 (1H, dd), 8.07 (2H, d), 9.26 (1 H, s). LCMS (2) Rt: 2.32min; m/z (ES+) 378.
Example R-11 2-(2-methoxyphenylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000188_0001
Prepared according to the method described in example R-10. 1H NMR (DMSO) δ 2.87 (4H, m), 3.18 (4H, m), 3.87 (3H1 s), 6.94-7.05 (5H1 m), 7.43 (1H, br. d), 7.51 (1H, br. d), 8.12 (2H, d), 8.31 (1 H, m), 9.26 (1H, s). LCMS (2) Rt: 2.36min; m/z (ES+) 394.
Example R-12 2-(3-methoxyphenylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000188_0002
Prepared according to the method described in example R-10. 1H NMR (DMSO) δ 2.86 (4H, t), 3.18 (4H, t), 3.77 (3H, s), 6.56 (1H, dd), 6.99 (2H, d), 7.21 (1 H, d), 7.25 (1H, m), 7.32 (1H, dd), 7.41 (1H, br. s), 7.43 (1H, br. s), 8.06 (2H, d), 10.32 (1H, s). LCMS (2) Rt: 2.31min; m/z (ES+) 394.
Example R-13 2-(2,6-difluorophenylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000188_0003
Prepared according to the method described in example R-10 with the exception that in step a 9,9-dimethyl-4,5-£>/s(diphenylphosphino)xanthene was used in place of 2- (dicyclohexylphosphino)-2\4\6^ri-i-propyl-1 J'-biphenyl. 1H NMR (CD3OD) δ 3.01 (4H, m), 3.26 (4H, m), 6.98 (2H, d), 7.09 (2H, t), 7.29 (1 H, m), 8.00 (2H, d). LCMS (2) Rt: 1.95min; m/z (ES+) 400.
Example R-14 5-(4-(piperazin-1-yl)phenyl)-2-(pyridin-3-ylamino)oxazole-4-carboxamide
Figure imgf000189_0001
Prepared according to the method described in example R-13 with the exception that step c was performed as follows:
To a solution of 5-(4-(4-(te/f-butoxycarbonyl)piperazin-1-yl)phenyl)-2-(pyridin-3- ylamino)oxazole-4-carboxylic acid (0.046g, O.immol) in DMF (1ml) was added O-(7- azabenzotriazol-1-yI)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.065g, 0.17mmol), diisopropylethylamine (0.03ml, 0.17mmol) and 0.5M NH3 in dioxane (0.6ml, 0.3mmol) and the resultant mixture stirred at room temperature overnight. A further portion of O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.02Og, 0.05mmol), diisopropylethylamine (0.01ml, 0.056mmol) and 0.5M NH3 in dioxane (0.2ml, O.immol) was added and the reaction stirred for 1 hour. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford terf-butyl 4-(4-(4-carbamoyl-2-(pyridin-3-ylamino)oxazol-5-yl)phenyl)piperazine-1-carboxylate (0.006g, 0.013mmol, 13%). LCMS (2) Rt: 2.64min; m/z (ES+) 465. 1H NMR (DMSO) δ 2.84 (4H, t), 3.16 (4H, t), 6.99 (2H, d), 7.35 (1 H, dd), 7.44 (1 H, br s), 7.66 (1H, br s), 8.07 (2H, d), 8.19 (1 H, dd), 8.35 (1H, dd), 8.77 (1 H, d), 10.60 (1 H, br s). LCMS (2) Rt: 1.62min; m/z (ES+) 365.
Example R-15 2-(1H-indazol-5-ylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000190_0001
Prepared according to the method described in example R-14 from 1-Boc-5- aminoindazole (the Boc group was removed under the Buchwald coupling conditions). 1H NMR (DMSO) δ 3.17 (4H, m), 3.41 (4H, m), 7.07 (2H, d), 7.45-7.50 (2H, m), 7.52 (1 H, br s), 7.64 (1H, br. s), 8.01 (1H, s), 8.13 (2H, d), 8.37 (1H, dd), 10.30 (1H, s), 12.94 (1H, br. s). LCMS (2) Rt: 1.75min; m/z (ES+) 404.
Example R-16 2-(1H-indazol-6-ylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000190_0002
Prepared according to the method described in example R-14 from 1-Boc-6- aminoindazole (the Boc group was removed under the Buchwald coupling conditions). 1H NMR (DMSO) δ 3.06 (4H, m), 3.32 (4H, m), 7.05 (2H, d), 7.26 (1H, dd), 7.41 (1H, br. s), 7.62 (1 H, br. s), 7.67 (1 H, d), 7.96 (1 H, s), 8.11 (3H, m), 10.54 (1 H1 s), 12.74 (1H, br. s). LCMS (2) Rt: 1.83min; m/z (ES+) 404.
Example R-17
2-(1 -benzyl-1 H-pyrazol-4-ylamino)-5-(4-(piperazin-1 -yl)phenyl)oxazole-4- carboxamide
Figure imgf000191_0001
Prepared according to the method described for R-14. 1H NMR (DMSO) δ 2.84 (4H, t), 3.15 (4H, m), 5.29 (2H, s), 6.97 (2H, d), 7.23 (2H, m), 7.29 (1 H, m), 7.35 (2H, m), 7.44 (1 H, br. d), 7.49 (1H, d), 7.59 (1 H1 br. d), 8.05 (2H, d), 8.30 (1 H, d), 10.06 (1 H, s). LCMS (2) Rt: 2.15min; m/z (ES+) 444.
Example R-18
2-(1 -benzyl-1 H-pyrazol-5-ylamino)-5-(4-(piperazin-1 -yl)phenyl)oxazole-4- carboxamide
Figure imgf000191_0002
Prepared according to the method described for R-14 using 1 -benzyl-1 H-pyrazol-5- amine (see Chem. Ber. 1968, 101 , 3265-3277). 1H NMR (DMSO) δ 2.84 (4H, t), 3.15 (4H, m), 5.38 (2H, s), 6.62 (1H, d), 6.96 (2H, d), 7.09 (2H, m), 7.23 (1 H, m), 7.30 (2H, m), 7.36 (1 H, br. s), 7.38 (1 H, br. s), 7.41 (1 H, d), 8.01 (2H, d). LCMS (2) Rt: 2.06min; m/z (ES+) 444.
Example R-19 2-(1H-pyrazol-4-ylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Step a - terf-butyl 4-amino-1 H-pyrazole-1-carboxylate
Figure imgf000191_0003
To a stirred mixture of 4-nitro-1 H-pyrazole (2.1Og, 19mmol, see WO2006/044821) and 4- dimethylaminopyridine (0.23g, 2mmol) in DCM (210ml) was added di-fe/f- butyldicarbonate (4.86g, 22mmol) and the resulting solution stirred at room temperature for 1 hour. The reaction mixture was washed with 1M HCl, dried over MgSO4 and the solvent removed in vacuo to afford terf-butyl 4-nitro-1H-pyrazole-1-carboxylate (4.03g, 19mmol, 100%) as a white solid. 1H NMR (DMSO) δ 1.61 (9H1 s), 8.54 (1H, s), 9.32 (1 H, s). LCMS (2) Rt: 2.46min.
A solution of fe/f-butyl 4-nitro-1H-pyrazole-1-carboxylate (1.Og, 4.7mmol) in MeOH (120ml) was passed through the H-Cube with full hydrogen mode at 6O0C and 1 bar with a 10% Pd/C cartridge using 1ml/min flow rate. The solution was then passed through the H-Cube for a second time using identical conditions and the solvent removed in vacuo to afford ferf-butyl 4-amino-1 H-pyrazole-1-carboxylate (0.82g, 4.5mmol, 95%). 1H NMR (DMSO) δ 1.54 (9H, s), 4.42 (2H, s), 7.33 (1H, s), 7.35 (1H, s). LCMS (2) Rt: 1.45min; m/z (ES+) 206 M+Na+.
Step b - 2-(1H-pyrazol-4-ylamino)-5-(4-(4-(terf-butoxycarbonyl)piperazin-1- yl)phenyl)oxazole-4-carboxylic acid
Figure imgf000192_0001
A mixture of terf-butyl 4-(4-(4-(ethoxycarbonyl)-2-iodooxazol-5-yl)phenyl)piperazine-1- carboxylate (0.15Og, 0.28mmol), terf-butyl 4-amino-1H-pyrazole-1-carboxylate (0.261g, 1.42mmol), cesium carbonate (0.462g, 2.39mmol), fr7s(dibenzylideneacetone)dipalladium(0) (0.012g, 0.013mmol) and 9,9-dimethyl-4,5- jb/s(diphenylphosphino)xanthene (0.0165g, 0.029mmol) in 1BuOH (4.5ml) and dioxane (4.5ml) was degassed, placed under a nitrogen atmosphere and then stirred under reflux overnight. The reaction mixture was passed through a MP-SH cartridge and the solvent removed in vacuo. The residue was partitioned between water and EtOAc and the aqueous phase extracted with EtOAc and DCM. The combined organic phases were dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(1 H-pyrazol-4-ylamino)-5-(4-(4-(terf- butoxycarbonylJpiperazin-i-yOphenyOoxazole^-carboxylic acid (0.033g, 0.073mmol, 26%). LCMS (2) Rt: 1.68 min; m/z (ES+) 455. Step c - 2-(1H-pyrazol-4-ylamino)-5-(4-(piperazin-1-yl)phenyl)oxazole-4-carboxamide
Figure imgf000193_0001
Prepared as described in steps c and d of example R-14 from 2-(1 H-pyrazol-4-ylamino)- 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)oxazole-4-carboxylic acid. 1H NMR (CD3OD) δ 2.91 (4H, m), 3.20 (4H, m, part obscured by CD3OD peak), 6.93 (2H, d), 7.47 (1H, S)1 7.72 (1H, s), 8.08 (2H, d). LCMS (2) Rt: 1.42min; m/z (ES+) 354.
General Method S
General Method S comprises the series of steps set out in Scheme 13 above.
Example S-1
2-(2,6-difluorophenyl)-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide
Figure imgf000193_0002
To a mixture of 5-bromo-2-(2,6~difluorophenyl)oxazole-4-carboxamide (0.06Og, 0.20mmol), 4-hydroxyphenylboronic acid (0.055g, 0.40mmol) and 1 ,1'- /)/s(diphenylphosphino)ferrocene-palladium(ll)dichloride (O.OOδg, 0.01 mmol) in MeCN (4ml) was added 1 M aqueous Na2CO3 (0.4ml, 0.4mmol). The reaction was heated Wa microwave irradiation to 1500C and held at this temperature for 15 minutes. The reaction was then diluted with EtOAc and washed with 2M HCI. The organic layer was dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 5-70% EtOAc in hexane as eluant to furnish 2- (2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.05Og, 0.16mmol, 80%) as an off white powder. LCMS (1) 1.73min; m/z (ES-) 315. Step b - 5-(4-(2-chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000194_0001
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.10Og, 0.316mmol) in DMF (5ml) were added potassium carbonate (0.22Og, 1.58mmol) and 1 ,2-dichloroethane (0.50ml, 6.32mmol). The reaction was heated to 1300C via microwave irradiation and held at that temperature for 1 hour. The reaction was then diluted with EtOAc, washed with water and brine and dried over Na2SO4 before being concentrated in vacuo. The resulting residue was purified by silica gel flash chromatography using 0-50% EtOAc in hexane as eluant to afford 5-(4-(2- chloroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4-carboxamide (0.11g, 0.29mmol, 92%) as a white solid. LCMS (1) 2.25min; m/z (ES+) 379/381.
Step c - 2-(2,6-difluorophenyI)-5-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000194_0002
To a solution of 5-(4-(2-chIoroethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide (0.02Og, 0.053mmol) in DMSO (1ml) were added N-methylpiperazine (11 μl, 0.10δmmol) and triethylamine (12μl, 0.10θmmol). The reaction was heated to 15O0C via microwave irradiation and held at that temperature for 25 minutes. Purification was performed by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(2-(4- methylpiperazin-1-yl)ethoxy)phenyl)oxazole-4-carboxamide (0.0024g, 0.0054mmol, 10%) as an off white powder. 1H NMR (CD3OD) δ 2.57 (3H, s), 2.76-2.96 (1OH, m), 4.24 (2H, t), 7.06 (2H, m), 7.22 (2H, m), 7.64 (1 H, m), 8.26 (2H, m). LCMS (2) 2.25min; m/z (ES+) 443.
The compounds described in examples S-2 to S-11 were prepared in a similar manner as described in example S-1 Example S-2
2-(2-fluoro-6-(4-methylpiperazin-1-yl)phenyl)-5-(4-(2-(4-methylpiperazin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000195_0001
Isolated as a by-product from the synthesis of example S-1. 1H NMR (CD3OD) δ 2.56 (3H, s), 2.70 (3H, s), 2.82-2.96 (1OH, m), 3.06-3.14 (4H, br, s), 3.20 (4H, t), 4.22 (2H, t), 6.98-7.12 (4H, m), 7.54 (1H, m), 8.23 (2H, m). LCMS (2) 2.34min; m/z (ES+) 523.
Example S-3
2-(2-fluoro-6-(4-hydroxypiperidin-1-yl)phenyl)-5-(4-(2-(4-hydroxypiperidin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000195_0002
Isolated as a by-product from the synthesis of example S-4. 1H NMR (CD3OD) δ 1.51 (2H, m), 1.84 (4H, m), 2.06 (2H, m), 2.82 (2H1 m), 3.08 (2H, m), 3.23 (2H, m), 3.41 (4H, m), 3.67 (1H, m), 3.92 (1H, m), 4.41 (2H, t), 6.91 (1 H, m), 7.05 (1 H, d), 7.12 (2H, m), 7.52 (1H, m), 8.3 (2H, m). LCMS (2) 2.27min; m/z (ES+) 525.
Example S-4
2-(2,6-difluorophenyl)-5-(4-(2-(4-hydroxypiperidin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000196_0001
1H NMR (CD3OD) δ 1.80-1.90 (2H, m), 2.06-2.14 (2H, m), 3.10-3.20 (2H1 br. m), 3.42- 3.50 (4H, m), 3.90-3.98 (1 H1 br. m), 4.44 (2H, t), 7.12-7.16 (2H, m), 7.20-7.27 (2H1 m), 7.60-7.70 (1H, m), 8.28-8.32 (2H, m). LCMS (2) 2.40min; m/z (ES+) 444.
Example S-5
(S)-2-(2,6-difluorophenyl)-5-(4-(2-(2-(hydroxymethyI)pyrrolidin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000196_0002
1H NMR (CD3OD) δ 1.82-1.92 (1H, m), 1.96-2.12 (2H, m), 2.14-2.24 (1H, m), 3.10-3.18 (1H, m), 3.40-3.52 (2H, m), 3.63-3.70 (1 H, m), 3.71-3.86 (3H, m), 4.41 (2H, t), 7.12-7.16 (2H, m), 7.20-7.27 (2H, m), 7.61-7.69 (1H, m), 8.28-8.32 (2H, m). LCMS (2) 2.68min; m/z (ES+) 444.
Example S-6
(R)-2-(2,6-difluorophenyl)-5-(4-(2-(2-(hydroxymethyl)pyrrolidin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000196_0003
1H NMR (CD3OD) δ 1.82-1.92 (1H, m), 1.96-2.12 (2H1 m), 2.14-2.24 (1 H, m), 3.10-3.18 (1H1 m), 3.40-3.52 (2H1 m), 3.63-3.70 (1H, m), 3.71-3.86 (3H, m), 4.41 (2H, t), 7.12-7.16 (2H1 m), 7.20-7.27 (2H1 m), 7.61-7.69 (1H1 m), 8.28-8.32 (2H, m). LCMS (2) 2.67min; m/z (ES+) 444.
Example S-7 2-(2,6-difluorophenyl)-5-(4-(2-(4-(2-hydroxyethyl)piperazin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000197_0001
1H NMR (CD3OD) δ 2.88-2.96 (4H, br, s), 2.99 (4H, q), 3.06-3.14 (4H, br, s), 3.82 (2H, t), 4.27 (2H, t), 7.06-7.11 (2H, m), 7.20-7.26 (2H, m), 7.60-7.68 (1H, m), 8.24-8.30 (2H1 m). LCMS (2) 2.22min; m/z (ES+) 473.
Example S-8
2-(2,6-difluorophenyl)-5-(4-(2-((2- hydroxyethyl)(methyl)amino)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000197_0002
1H NMR (CD3OD) δ 2.84 (3H, s), 3.18 (2H, t), 3.46 (2H, t), 3.87 (2H, t), 4.40 (2H, t), 7.12-7.16 (2H, m), 7.20-7.26 (2H, m), 7.60-7.68 (1H, m), 8.26-8.31 (2H, m). LCMS (2) 2.43min; m/z (ES+) 418.
Example S-9
2-(2,6-difluorophenyl)-5-(4-(2-(3-oxopiperazin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000197_0003
1H NMR (CD3OD) δ 2.87 (2H, t), 2.96 (2H, t), 3.30 (2H1 s), 3.37 (2H, t), 4.26 (2H, t), 7.07-7.11 (2H, m), 7.20-7.26 (2H, m), 7.60-7.68 (1 H, m), 8.24-8.29 (2H, m). LCMS (2) 2.20min; m/z (ES+) 443. Example S-10
1-(2-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-yl)phenoxy)ethyl)piperidine-4- carboxamide
Figure imgf000198_0001
1H NMR (CD3OD) δ 1.82-1.98 (4H, m), 2.32-2.42 (1H, m), 2.48-2.58 (2H, m), 3.10 (2H, t), 3.27-3.32 (2H, br. s), 4.31 (2H, t), 7.08-7.14 (2H, m), 7.20-7.27 (2H, m), 7.60-7.68 (1H, m), 8.26-8.30 (2H, m). LCMS (2) 2.33min; m/z (ES+) 471.
Example S-11
5-(4-(2-(benzyl(methyl)amino)ethoxy)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000198_0002
1H NMR (CD3OD) δ 2.41 (3H, s), 2.94 (2H, t), 3.73 (2H, s), 4.24 (2H, t), 7.02-7.08 (2H1 m), 7.16-7.40 (7H, m), 7.60-7.68 (1H, m), 8.23-8.28 (2H, m). LCMS (2) 3.63min; m/z (ES+) 464.
Example S-12
2-(2,6-difluorophenyl)-5-(4-(3-(piperidin-1-yl)propoxy)phenyl)oxazole-4- carboxamide
Figure imgf000198_0003
1H NMR (DMSO) δ 1.36-1.44 (2H, m) 1.53 (4H, quin), 1.92 (2H, quin), 2.42-2.48 (4H, br. s), 3.51 (2H, t), 4.10 (2H, t), 7.06-7.11 (2H, m), 7.35-7.42 (2H, m), 7.66 (2H, br. s), 7.70- 7.77 (1 H, m), 8.21-8.25 (2H, m). LCMS (2) 3.38min; m/z (ES+) 442.
Example S-13 2-(2,6-difluorophenyl)-5-(4-(3-morpholinopropoxy)phenyl)oxazole-4-carboxamide
Figure imgf000199_0001
1H NMR (DMSO) δ 1.90 (2H, quin), 2.34-2.40 (4H, br. s), 2.44 (2H, t), 3.58 (4H, t), 4.10 (2H, t), 7.06-7.11 (2H, m), 7.36-7.42 (2H, m), 7.66 (1 H, br. s), 7.68 (1 H, br, s), 7.69-7.76 (1 H, m), 8.20-8.25 (2H, m). LCMS (2) 2.82min; m/z (ES+) 444.
Example S-14 2-(2,6-difluorophenyl)-5-(4-(piperidin-4-ylmethoxy)phenyI)oxazole-4-carboxamide
Figure imgf000199_0002
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4- hydroxyphenyl)oxazole-4-carboxamide with benzyl 4-(bromomethyI)piperidine-1- carboxylate according to the procedure described in example S-1 , step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1ml/min, 2O0C, 0.05M in MeOH). 1H NMR (DMSO) δ 1.30-1.50 (2H, m), 1.85 (2H, d), 1.90-2.10 (1 H, m), 2.71-2.81 (2H,m), 3.21 (2H, d), 3.92 (2H, d), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 3.13min; m/z (ES+) 414.
Example S-15 2-(2,6-difluorophenyl)-5-(4-(morpholin-2-ylmethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000200_0001
The title compound was prepared by alkylation of 2-(2,6-difluorophenyl)-5-(4- hydroxyphenyl)oxazole-4-carboxamide with 2-chloromethyl-4-benzylmorpholine, according to the procedure described in example S-1 , step b, followed by subsequent deprotection using the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1ml/min, 0.05M in MeOH, 7O0C). 1H NMR (DMSO) δ 2.59-2.70 (2H, m), 2.90-3.00 (2H, m), 3.41-3.51 (1H, m), 3.69-3.79 (2H, m), 4.00 (2H, d), 7.05-7.15 (2H1 m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.21-8.30 (2H, m). LCMS (2) 2.38min; m/z (ES+) 416.
Example S-16
2-(2,6-difluorophenyl)-5-(4-(2-((2- hydroxyethyl)(propyl)amino)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000200_0002
1H NMR (DMSO) δ 0.85 (3H1 1), 1.42 (2H1 sextet), 2.50 (2H, t), 2.60 (2H1 1), 2.88 (2H, t), 3.48 (2H, t), 4.11 (2H1 1), 7.05-7.15 (2H1 m), 7.35-7.45 (2H1 m), 7.60-7.80 (3H, m), 8.20- 8.30 (2H1 m). LCMS (2) 2.94min; m/z (ES+) 446.
Example S-17
2-(2,6-difluorophenyl)-5-(4-(2-(3-hydroxypiperidin-1-yl)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000200_0003
1H NMR (DMSO) δ 1.00-1.11 (1H1 m), 1.35-1.50 (1H1 m), 1.57-1.65 (1H, m), 1.75-1.85 (2H, m), 1.90-2.00 (1H, m), 2.70-2.80 (3H, m), 2.90-2.98 (1H1 m), 3.40-3.52 (1 H, m), 4.15 (2H, t), 4.62 (1H, br. s), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.51 min; m/z (ES+) 444.
Example S-18
2-(2,6-difluorophenyl)-5-(4-(2-(4-(hydroxymethyl)piperidin-1- yl)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000201_0001
1H NMR (DMSO) δ 1.08-1.20 (2H, m), 1.28-1.40 (1 H, m), 1.60-1.70 (2H, m), 2.00 (2H, t), 2.70 (2H, t), 2.90-3.00 (2H, m), 3.22 (2H, d), 4.15 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.57min; m/z (ES+) 458.
Example S-19
2-(2,6-difluorophenyl)-5-(4-(2-(ethyl(2-hydroxyethyl)amino)ethoxy)phenyl)oxazole-
4-carboxamide
Figure imgf000201_0002
1H NMR (DMSO) δ 0.98 (3H, t), 2.57-2.64 (4H, m), 2.87 (2H, t), 3.48 (2H, t), 4.11 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H1 m), 8.20-8.30 (2H, m). LCMS (2) 2.66min; m/z (ES+) 432.
Example S-20 2-(2,6-difluorophenyl)-5-(4-(2-(methylamino)ethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000201_0003
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6- difluorophenyl)oxazole-4-carboxamide with N-methylbenzylamine, according to the procedure described in example S-1 , step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1ml/min, 6O0C, 0.05M in MeOH). 1H NMR (DMSO) δ 2.35 (3H, s), 2.87 (2H, t), 4.10 (2H, t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.55min; m/z (ES+) 374.
Example S-21
2-(2,6-difluorophenyl)-5-(4-(2-(2-hydroxyethylamino)ethoxy)phenyl)oxazole-4- carboxamide
Figure imgf000202_0001
The title compound was prepared by reaction of 5-(4-(2-chloroethoxy)phenyl)-2-(2,6- difluorophenyl)oxazole-4-carboxamide with 2-(benzylamino)ethanol, according to the procedure described in example S-1 , step c, followed by deprotection with the H-cube hydrogenation system (full H2 mode, 10% Pd\C catalyst, 1ml/min, 6O0C, 0.05M in MeOH). 1H NMR (DMSO) δ 2.79 (2H, t), 3.17 (2H, t), 3.55 (2H, t), 4.20 (2H. t), 7.05-7.15 (2H, m), 7.35-7.45 (2H, m), 7.60-7.80 (3H, m), 8.20-8.30 (2H, m). LCMS (2) 2.17min; m/z (ES+) 404.
General Method T
General Method T comprises the series of steps set out in Scheme 14 above.
Example T-1
2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)oxazole-4- carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide
Figure imgf000202_0002
To a solution of 2-(2,6-difluorophenyl)-5-(4-hydroxyphenyl)oxazole-4-carboxamide (0.10Og, 0.316mmol) in DMF (5ml) was added K2CO3 (0.066g, 0.474mmol). The resulting mixture was stirred at room temperature for 30 minutes, after which time epichlorohydrin (0.044g, 0.474mmol) was added. The reaction was heated to 1000C, stirred at this temperature for 2h and then diluted with EtOAc before being washed with water and brine. Drying over Na2SO4 and removal of solvent under vacuum gave 2-(2,6- difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4-carboxamide (0.102g, 0.274mmol, 87%) as a golden oil. LCMS (1) 2.00min; m/z (ES+) 374.
Step b - 2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(piperidin-1-yl)propoxy)phenyl)oxazole- 4-carboxamide
Figure imgf000203_0001
To a solution of 2-(2,6-difluorophenyl)-5-(4-(oxiran-2-ylmethoxy)phenyl)oxazole-4- carboxamide (0.025g, 0.0671 mmol) in MeOH (1ml) was added piperidine (0.017g, 0.201 mmol). The reaction was heated to 1000C via microwave irradiation and held at this temperature for 15 minutes. The crude reaction was then purified by preparative HPLC to give 2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(piperidin-1- yl)propoxy)phenyl)oxazole-4-carboxamide (0.0036g, 0.0079mmol, 12%) as an off white powder. 1H NMR (DMSO) δ 1.34-1.41 (2H, m), 1.46-1.54 (4H, m), 2.35-2.48 (6H, m), 3.92-4.01 (2H, m), 4.04-4.08 (1H, m), 7.08-7.12 (2H, m), 7.34-7.41 (2H, m), 7.66 (1H, br. s), 7.68 (1H, br, s), 7.69-7.76 (1 H, m), 8.20-8.24 (2H, m). LCMS (2) 3.06min; m/z (ES+) 458.
In a similar manner as described in example T- 1 the compounds described in examples T-2 to T-4 were prepared.
Example T-2
2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-morpholinopropoxy)phenyl)oxazole-4- carboxamide
Figure imgf000204_0001
1H NMR (DMSO) δ 2.35-2.50 (6H, m), 3.56 (4H, t), 3.94-4.02 (2H, m), 4.05-4.10 (1 H, m), 7.08-7.12 (2H, m), 7.36-7.42 (2H, m), 7.66 (1 H, br. s), 7.68 (1H, br, s), 7.70-7.76 (1H, m), 8.20-8.26 (2H, m). LCMS (2) 2.44min; m/z (ES+) 460.
Example T-3
2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(4-methylpiperazin-1- yl)propoxy)phenyl)oxazole-4-carboxamide
Figure imgf000204_0002
1H NMR (DMSO) δ 2.16 (3H, s), 2.28-2.40 (6H, m), 2.40-2.50 (4H, m), 3.92-4.00 (2H, m), 4.03-4.09 (1H, m), 7.07-7.12 (2H, m), 7.34-7.42 (2H, m), 7.66 (1 H, br. s), 7.68 (1H, br, s), 7.70-7.76 (1H, m), 8.20-8.26 (2H, m). LCMS (2) 2.37min; m/z (ES+) 473.
Example T-4
2-(2,6-difluorophenyl)-5-(4-(2-hydroxy-3-(4-hydroxypiperidin-1- yl)propoxy)phenyl)oxazole-4-carboxamide
Figure imgf000204_0003
1H NMR (DMSO) δ 1.36-1.46 (2H, m), 1.68-1.76 (2H, m), 2.15-2.26 (3H, m), 2.40-2.46 (1 H, m), 2.76-2.86 (2H, m), 3.42-3.50 (1H1 m), 3.92-4.02 (2H1 m), 4.03-4.08 (1 H, m), 7.07-7.12 (2H, m), 7.34-7.41 (2H1 m), 7.66 (2H, br s), 7.68-7.76 (1 H1 m), 8.20-8.25 (2H, m). LCMS (2) 2.28min; m/z (ES+) 474.
General Method U
General Method U comprises the series of steps set out in Scheme 15 above.
Example U-1 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid
Step a - 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid
Figure imgf000205_0001
A solution of fr/s(dibenzylideneacetone)dipalladium(0) (0.337g, 0.368mmol) and 9,9- dimethyl-4,5-jb/s(diphenylphosphino)xanthene (0.213g, 0.368mmol) in n-butanol:dioxane (1 :1) (5mL) was stirred at room temperature for 3 minutes. Then 5-bromo-2-(2,6- difluorophenyl)oxazole-4-carbonitrile (1.5Og, 5.262mmol), 4-aminobenzoic acid (2.165g, 15.787mmol) and cesium carbonate (3.429g, 10.525mmol) were added and the mixture heated in the microwave for 3 minutes at 14O0C. The reaction was diluted with EtOAc and washed with water. The organic phase was passed through an MP-SH cartridge, dried over MgSO4 and the solvent removed in vacuo. The residue was purified by column chromatography using a 20-45% EtOAc:hexane gradient then further purified by trituration of the solid in DCM:hexane (1 :1) to afford 4-(4-cyano-2-(2,6- difluorophenyl)oxazol-5-ylamino)benzoic acid (0.251 g, 0.735mmol, 14%) as a light yellow solid. 1H NMR (DMSO) δ 7.34 (2H, t), 7.40 (2H, d), 7.66 (1 H, m), 7.92 (2H, d), 11.16 (1 H, br s), 12.76 (1H, br s). LCMS (3) Rt: 1.53min; m/z (ES+) 342.
Step b - 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid
Figure imgf000206_0001
A solution of 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.962g, 2.819mmol) in concentrated sulfuric acid (5mL) was stirred at room temperature for 1.5 hours. The reaction mixture was added to ice water and a precipitate formed. The precipitate was isolated by filtration and the remaining aqueous layer extracted with ethyl acetate. The organic layer was combined with the precipitate and reduced in vacuo to yield 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.58Og, 1.614mmol, 57%) as a yellow solid. 1H NMR (DMSO) δ 7.35 (2H, t), 7.46 (4H, m), 7.65 (1 H, m), 7.87 (2H, d), 9.71 (1H, s), 12.64 (1H, br s). LCMS (2) Rt: 1.37min; m/z (ES+) 360.
Example U -2
2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4- carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4- carbonitrile
Figure imgf000206_0002
To a solution of 4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.02Og, 0.059mmol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.022g, 0.059mmol), and diisopropylethylamine (0.02OmL, 0.117mmol) in N,N-dimethylformide (2mL) was added morpholine (0.005mL, 0.059mmol) and the reaction mixture stirred at room temperature for 16 hours. The reaction was then diluted with EtOAc washed with 1 M HCI, water and brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(morpholine-4- carbonyl)phenylamino)oxazole-4-carbonitrile (0.009g, 0.022ITImOl, 37%) as a yellow solid. LCMS (2) Rt: 2.38 min; m/z (ES+) 411.
Step b - 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxa2ole-4- carboxamide
Figure imgf000207_0001
A solution of 2-(2,6-difluorophenyl)-5-(4-(morpholine-4-carbonyl)phenylamino)oxazole-4- carbonitrile (0.009g, 0.022mmol) in concentrated sulfuric acid (0.5mL) was stirred at room temperature for 1.5 hours. The solution was neutralised by pouring into saturated sodium bicarbonate solution. The aqueous phase was then basified to pH14 using 5M NaOH and extracted with EtOAc. The combined organic phase was dried over MgSO4 and the solvent removed in vacuo to afford 2-(2,6-difluorophenyl)-5-(4-(morpholine-4- carbonyl)phenylamino)oxazole-4-carboxamide (0.007g, 0.017mmol, 77%) as a yellow solid. 1H NMR (DMSO) δ 3.51 (4H, m), 3.58 (4H, m), 7.32-7.47 (8H, m), 7.64 (1H, m), 9.55 (1H, s). LCMS (2) Rt: 2.14min; m/z (ES+) 429.
Example U-3
5-(4-((2-(methylamino)ethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000207_0002
Prepared according to the procedure described in example U-2. 1H NMR (DMSO) δ 2.30 (3H, s), 2.64 (2H, t), 3.32 (2H, t), 7.34 (2H, t), 7.39 (2H, br s), 7.45 (2H, d), 7.64 (1H, m), 7.81 (2H, d), 8.28 (1H, t). LCMS (2) Rt: 2.00min; m/z (ES+) 416.
Example U-4 5-(4-((3-(methylamino)propyl)carbamoyl)phenylamino)-2-(2,6-dif[uorophenyl) oxazole-4-carboxam ide
Figure imgf000208_0001
Prepared according to the procedure described in example U-2. 1H NMR (DMSO) δ 1.65 (2H, quin), 2.29 (3H, s), 2.53 (2H, m), 3.28 (2H, m), 7.33 (2H, t), 7.45 (2H, d), 7.51 (2H, br s), 7.63 (1 H, m), 7.79 (2H, d), 8.40 (1H, t). LCMS (2) Rt: 2.07min; m/z (ES+) 430.
Example U -5
5-(4-(((4-benzylmorpholin-2-yl)methyl)carbamoyl)phenylamino)-2-(2,6- difluorophenyl)oxazole-4-carboxamide
Figure imgf000208_0002
Prepared according to the procedure described in example U-2. 1H NMR (DMSO) δ 1.83 (1 H, t), 2.05 (1 H, t), 2.57 (1 H, d), 2.78 (1 H, d), 3.28 (2H, m), 3.52-3.59 (3H, m), 3.61 (1H, m), 3.78 (1 H, d), 7.23 (1 H, m), 7.29-7.37 (6H1 m), 7.45 (4H, m), 7.65 (1 H, m), 7.80 (2H, d), 8.42 (1H, t), 9.60 (1 H, s). LCMS (2) Rt: 2.72min; m/z (ES+) 548.
Example U-6
(R)-2-(2,6-difluorophenyl)-5-(4-(pyrrolidin-3-ylcarbamoyl)phenylamino)oxazole-4- carboxamide
Figure imgf000208_0003
Prepared according to the procedure described in example U-2. 1H NMR (DMSO) δ 1.68 (1H, m), 1.98 (1H, m), 2.71 (1H, m), 2.78 (1H, m), 2.96 (2H1 m), 4.31 (1H, m), 7.34 (2H, t), 7.37-7.52 (4H, m), 7.63 (1H, m), 7.82 (2H, d), 8.21 (1 H1 d). LCMS (2) Rt: 2.04min; m/z (ES+) 428.
Example U-7
(S)-2-(2,6-difluorophenyl)-5-(4-(pyrroIidin-3-ylcarbamoyI)phenylamino)oxazole-4- carboxamide
Figure imgf000209_0001
Prepared according to the procedure described in example U-2. 1H NMR (DMSO) δ 1.68 (1H, m), 1.98 (1H, m), 2.71 (1H, m), 2.78 (1H, m), 2.96 (2H, m), 4.31 (1H, m), 7.34 (2H, t), 7.37-7.52 (4H1 m), 7.63 (1H, m), 7.82 (2H, d), 8.21 (1 H, d). LCMS (2) Rt: 2.05min; m/z (ES+) 428.
Example U -8
5-(4-((2-(dimethylamino)ethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000209_0002
Prepared according to the procedure described in example U-2. 1H NMR (CD3OD) δ 2.40 (6H1 d), 2.68 (2H, t), 3.56 (2H, t), 7.20 (2H, t), 7.51 (2H, d), 7.58 (1 H, m), 7.86 (2H, d). LCMS (2) Rt: 2.14min; m/z (ES+) 430.
Example U-9
5-(4-((2-morpholinoethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000210_0001
Prepared according to the procedure described in example U-2. 1H NMR (CD3OD) δ 2.45 (4H, m), 2.51 (2H1 1), 3.45 (2H1 1), 3.61 (4H, t), 7.11 (2H, t), 7.41 (2H, d), 7.47 (1 H1 m), 7.76 (2H1 d). LCMS (2) Rt: 2.03min; m/z (ES+) 472.
Example LMO
2-(2,6-difluorophenyl)-5-(4-(qulnuclidin-3-ylcarbamoyl)phenylamino)oxazole-4- carboxamide
Figure imgf000210_0002
Prepared according to the procedure described in example U-2. 1H NMR (CD3OD) δ 1.63 (1H1 m), 1.84 (2H, m), 1.98 (1H, m), 2.11 (1H, m), 2.85-3.02 (4H, m); 3.10 (1H, m), 3.41 (1H, m), 4.19 (1 H, m), 7.20 (2H1 1), 7.52 (2H1 d), 7.58 (1H1 m), 7.88 (2H1 d). LCMS (2) Rt: 2.27min; m/z (ES+) 468.
Example U-11
5-(4-((8-methyl-8-aza-bicyclo[3.2.1]octan-3-yl)carbamoyl)phenylamino)-2-(2,6- difluorophenyl)oxazole-4-carboxamide
Figure imgf000210_0003
Prepared according to the procedure described in example U-2. 1H NMR (CD3OD) δ 2.10-2.33 (8H1 m), 2.53 (3H1 s), 3.48 (2H, m), 4.09 (1H1 1), 7.24 (2H1 1), 7.55 (2H1 d), 7.61 (1H1 m), 7.83 (2H1 d). LCMS (2) Rt: 2.28min; m/z (ES+) 482. Example U-12
(/?)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl) phenylamino)oxazole-4-carboxamide
Figure imgf000211_0001
To a solution of 4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoic acid (0.04Og, 0.111 mmol), 0-(7-Azabenzotriazol-1-yl)-N,N,N',Nl-tetramethyluronium hexafluorophosphate (0.042g, 0.111mmol), and diisopropylethylamine (0.038mL, 0.222mmol) in DMF (0.35ml_) was added D-prolinol (0.011mL, 0.111 mmol) and the reaction mixture stirred at room temperature for 6 hours. The reaction was reduced in vacuo. The residue was purified by preparative HPLC to afford the white solid (f?)-2- (2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)phenylamino)oxazole- 4-carboxamide (0.018g, 0.040mmol, 36%). 1H NMR (DMSO) δ 1.68 (1 H, m), 1.90 (3H, m), 3.61-3.32 (4H, m), 4.13 (1H, br s), 4.75 (1H, t), 7.50-7.31 (8H, m), 7.64 (1H1 m), 9.50 (1H, br s). LCMS (2) Rt: 2.10min; m/z (ES+) 443.
Example U-13
(S)-2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)pyrrolidine-1-carbonyl) phenylamino)oxazole-4-carboxamide
Figure imgf000211_0002
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.68 (1 H, m), 1.90 (3H, m), 3.61-3.32 (4H, m), 4.13 (1 H, br s), 4.75 (1 H, t), 7.50-7.31 (8H, m), 7.64 (1 H, m), 9.50 (1H, br s). LCMS (2) Rt: 2.11min; m/z (ES+) 443.
Example U-14
2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)piperidine-1-carbonyl)phenylamino) oxazole-4-carboxamide
Figure imgf000212_0001
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.74-1.30 (6H, m), 2.92 (1H, m), 3.49 (1 H, m), 3.61 (1 H, m), 4.10 (2H, br m), 4.75 (1 H, t), 7.41-7.31 (6H, m), 7.43 (2H, d), 7.64 (1H, m), 9.41 (1 H, br s). LCMS (2) Rt: 2.21min; m/z (ES+) 457.
Example U-15
2-(2,6-difluorophenyl)-5-(4-(3-hydroxypiperidine-1-carbonyl)phenylamino)oxazole-
4-carboxamide
Figure imgf000212_0002
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.40 (2H, m), 1.69 (1 H, m), 1.86 (1H, m), 3.08-2.75 (2H, m), 3.49 (1 H, m), 4.06 (2H, br m), 4.87 (1 H, br s), 7.38-7.31 (6H, m), 7.43 (2H, d), 7.64 (1H, m), 9.48 (1 H, br s). LCMS (2) Rt: 2.03min; m/z (ES+) 443.
Example U-16
5-(4-((2-hydroxyethyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000212_0003
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 3.31 (2H, q), 3.49 (2H, q), 4.72 (1 H, t), 7.34 (2H, t), 7.42 (2H, br s), 7.46 (2H, d), 7.64 (1 H, m), 7.83 (2H, d), 8.31 (1 H, br t), 9.57 (1 H, br s). LCMS (2) Rt: 1.83min; m/z (ES+) 403.
Example U-17
5-(4-((3-hydroxypropyl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl)oxazole-4- carboxamide
Figure imgf000213_0001
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.66 (2H, quin), 3.30 (2H, q), 3.45 (2H, q), 4.45 (1H, t), 7.34 (2H, t), 7.39 (2H, br s), 7.48 (2H, d), 7.64 (1H, m), 7.81 (2H1 d), 8.29 (1H, br t), 9.55 (1H, br s). LCMS (2) Rt: 1.90min; m/z (ES+) 417.
Example U-18
5-(4-((1-methylpiperidin-4-yl)carbamoyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000213_0002
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.58 (2H, q), 1.75 (2H, d), 1.97 (2H, t), 2.18 (3H1 s), 2.78 (2H, d), 3.72 (1H, br m), 7.34 (2H, t), 7.40 (2H, br s), 7.47 (2H, d), 7.65 (1H, m), 7.84 (2H, d), 8.11 (1 H, d). LCMS (2) Rt: 2.09min; m/z (ES+) 456.
Example U-19
2-(2,6-difluorophenyl)-5-(4-(3-(hydroxymethyl)morpholine-4-carbonyl) phenylamino)oxazole-4-carboxamide
Figure imgf000214_0001
Prepared according to the procedure described in example U-12. 1H NMR (CD3OD) δ 3.31 (2H, m), 3.53 (1H, m), 3.63 (1H, m), 3.86 (5H, m), 7.20 (2H, t), 7.50 (4H, m), 7.56 (1 H, m). LCMS (2) Rt: 1.92min; m/z (ES+) 459.
Example U-20 te/t-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido) piperidine-1 -carboxylate
Figure imgf000214_0002
Prepared according to the procedure described in example U-12. 1H NMR (DMSO) δ 1.41 (11 H, m), 1.75 (2H, d), 2.83 (2H, br m), 3.94 (3H, m), 7.34 (2H, t), 7.42 (2H, br s), 7.46 (2H1 d), 7.64 (1H, m), 7.82 (2H, d), 8.14 (1H, d), 9.57 (1H, br s). LCMS (2) Rt: 2.83min; m/z (ES+) 542.
Example U-21
2-(2,6-difluorophenyl)-5-(4-(piperidin-4-ylcarbamoyl)phenylamino)oxazole-4- carboxamide
Figure imgf000214_0003
To terf-butyl 4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzamido) piperidine-1 -carboxylate (0.019g, 0.036mmol) was added 1M HCI in dioxane and the reaction mixture stirred at room temperature for 2 hours. The reaction mixture was reduced in vacuo, taken up in methanol and purified by SPE using a MP-TsOH cartridge (500mg) to generate 2-(2,6-difluorophenyl)-5-(4-(piperidin-4-yIcarbamoyl)phenylamino) oxazole-4-carboxamide (0.014g, 0.031 mmol, 98%) as a white solid. 1H NMR (DMSO) δ 1.45 (2H, q), 1.75 (2H, d), 2.58 (2H, t), 3.00 (2H, d), 3.84 (1 H, m), 7.33 (2H, t), 7.40 (2H, br s), 7.46 (2H, d), 7.64 (1 H, m), 7.83 (2H, d), 8.11 (1 H, d). LCMS (2) Rt: 1.87min; m/z (ES+) 442.
Example U -22 tert-butyl (4-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)benzoyl) morpholin-2-yl)methylcarbamate
Figure imgf000215_0001
Prepared according to the procedure described in example U-12. 1H NMR (CD3OD) δ 1.38 (11 H, br m), 2.98 (2H, br m), 3.15 (2H, m), 3.51 (1H, m), 3.58 (1 H, m), 3.94 (1 H, br m), 7.21 (2H, t), 7.47 (2H, d), 7.53 (2H, d), 7.59 (1H, m). LCMS (2) Rt: 2.54min; m/z (ES+) 558.
Example U -23
5-(4-(2-(aminomethyl)morpholine-4-carbonyl)phenylamino)-2-(2,6-difluorophenyl) oxazole-4-carboxamide
Figure imgf000215_0002
Prepared according to the procedure described in example U-21. 1H NMR (DMSO) δ 2.76 (1H, br m), 2.84 (1H, br m), 3.10 (1H1 br m), 3.53-3.45 (3H, m), 3.69 (2H, m), 3.89 (1H, br m), 7.34 (2H, t), 7.42-7.37 (4H, m), 7.47 (2H, d), 7.65 (1 H, m). LCMS (2) Rt: 1.86min; m/z (ES+) 458.
Example U -24 2-(2,6-difluorophenyl)-5-(4-(2-(2-hydroxyethyl)-1-methylpiperazine-4- carbonyl)phenylamino)oxazole-4-carboxamide
Figure imgf000216_0001
2-(1-methylpiperazin-2-yl)ethanol was prepared by dissolving methyl 2-(1-methyl-3- oxopiperazin-2-yl)acetate (0.50Og, 2.50mmol, prepared according to Abelman et al., Tetrahedron Letters, 44 (2003), 1823-1826) in THF (10ml) followed by addition of LiAIH4 (2M in THF, 3.12ml, 6.24mmol). The resulting solution was refluxed for 2h, concentrated in vacuo, basified to pH12 with 1 M NaOH solution and filtered through a celite pad. The filtrate was purified by SPE using a TsOH cartridge to give 2-(1-methylpiperazin-2- yl)ethanol as a golden oil (0.125g, 0.87mmol). 2-(2,6-difluorophenyl)-5-(4-(2-(2- hydroxyethyl)-1-methylpiperazine-4-carbonyl)phenylamino)oxazole-4-carboxamide was then prepared using the method described in example U-12. 1H NMR (CD3OD) δ 1.35- 1.40 (1 H, m), 1.92-2.05 (1 H, m), 2.10-2.20 (2H, m), 2.36 (3H, s), 2.30-2.38 (1H, m), 2.85-2.95 (2H, m), 3.25-3.35 (2H, m), 3.55-3.65 (2H, br. s), 7.15-7.25 (2H, m), 7.42-7.48 (2H, m), 7.50-7.60 (3H, m) LCMS (2) 1.96min; m/z (ES+) 486.
Example U-25
2-(2,6-difluorophenyl)-5-(4-(2-(hydroxymethyl)-1-methylpiperazine-4- carbonyl)phenylamino)oxazole-4-carboxamide
Figure imgf000217_0001
The above compound was synthesised by the method given in example U-12 using (1- methylpiperazin-2-yl)methanol (cf. WO 2005/026152) as a starting material. 1H NMR (CD3OD) δ 1.45-1.52 (2H, m), 2.40-2.50 (1H, m), 2.50-2.60 (4H, m), 2.95-3.08 (1 H, m), 3.10-3.30 (2H, m), 3.65-3.80 (2H, m), 7.18-7.25 (2H, m), 7.48-7.55 (4H, m), 7.56-7.65 (1H, m). LCMS (2) 1.82min; m/z (ES+) 472.
Example U -26
(f?)-2-(2,6-difluorophenyl)-5-(4-(3-(hydroxymethyl)-1-methylpiperazine-4- carbonyl)phenylamino)oxazole-4-carboxamide
Figure imgf000217_0002
The above compound was synthesised by the method given in example U-12 using (R)- (4-methylpiperazin-2-yl)methanol (cf. Falomi and Giacomelli, SYNLETT, 1996, p143- 144) as a starting material. 1H NMR (CD3OD) δ 2.22 (1H, dt), 2.30-2.40 (4H, m), 2.90- 3.00 (1 H, m), 3.05-3.15 (1 H, m), 3.25-3.35 (3H, m, partially obscured by solvent peak), 3.75-3.85 (1H, br. s), 3.89-3.98 (1H, m), 7.18-7.25 (2H, m), 7.48-7.54 (4H, m), 7.56-7.62 (1H, m) LCMS (2) 1.94min; m/z (ES+) 472.
Example U-27 (S)-2-(2,6-difluorophenyl)-5-(4-(3-(hydroxymethyl)-1-methyIpiperazine-4- carbonyl)phenylamino)oxazoIe-4-carboxamide
Figure imgf000218_0001
The above compound was synthesised by the method given in example U-12 using (S)- (4-methylpiperazin-2-yl)methanol (cf. Falomi and Giacomelli, SYNLETT1 1996, p143- 144) as a starting material. 1H NMR (CD3OD) δ 2.22 (1 H, dt), 2.30-2.40 (4H, m), 2.90- 3.00 (1H, m), 3.05-3.15 (1H, m), 3.25-3.35 (3H, m, partially obscured by solvent peak), 3.75-3.85 (1 H, br. s), 3.89-3.98 (1 H, m), 7.18-7.25 (2H, m), 7.48-7.54 (4H1 m), 7.56-7.62 (1H, m) LCMS (2) 1.94min; m/z (ES+) 472.
General Method V
General Method V comprises the series of steps set out in Scheme 16 above.
Example V- 1 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(4-nitrophenylamino)oxazole-4-carbonitrile
Figure imgf000218_0002
Prepared according to the procedure described in example U-1 , step a. LCMS (2) Rt: 2.70min; m/z (ES+) 343.
Step b - 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile
Figure imgf000219_0001
A solution of 2-(2,6-difluorophenyl)-5-(4-nitrophenylamino)oxazole-4-carbonitrile (0.435g, 1.271mmol) in 50:50 MeOH:EtOAc (10ml) was hydrogenated using a 10% Pd/C catalyst at 3O0C at atmospheric pressure using the Thales H-Cube at a flow rate of 1ml/min. The organic layer was then reduced in vacuo to yield 5-(4-aminophenylamino)-2-(2,6- difluorophenyl)oxazole-4-carbonitrile (0.36Og, 1.153mmol, 90%). 1H NMR (CD3OD) δ 6.74 (2H, d), 7.10 (2H, d), 7.14 (2H, t), 7.55 (1H, m). LCMS (2) Rt: 2.47min; m/z (ES+) 313.
Step c - 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carboxamide
Figure imgf000219_0002
Prepared according to the procedure described in example Q-50, part c. 1H NMR (DMSO) δ 4.94 (2H, br s), 6.53 (2H, d), 7.07 (2H, d), 7.21 (2H, br s), 7.29 (2H, t), 7.59 (1H, m), 8.87 (1H, br s). LCMS (2) Rt: 2.14min; m/z (ES+) 331.
Example V-2
N-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyl)-4-methyl p iperazine-1 -carboxamide
Step a - N-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyl)-4- methylpiperazine-1 -carboxamide
Figure imgf000220_0001
To a solution of 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole-4-carbonitrile (0.02Og, 0.064mmol), and diisopropylethylamine (0.011mL, 0.064mmol) in DCM (1mL) was added 1 ,1"-carbonyldiimidazole (0.031 g, 0.192mmol) and the reaction mixture stirred at room temperature for 15 minutes. To the reaction mixture was then added N- methyl piperazine (0.025mL, 0.192mmol) and the reaction mixture stirred for 1 hour. The reaction mixture was partitioned between water and DCM. The organic layer was reduced in vacuo to yield N-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyl)- 4-methylpiperazine-1-carboxamide (0.019g, 0.042mmol, 66%). LCMS (2) Rt: 2.32 min; m/z (ES+) 439.
Step b - N-(4-(4-carbamoyl-2-(2,6-difluorophenyI)oxazol-5-ylamino)phenyl)-4-methyl piperazine-1 -carboxamide
Figure imgf000220_0002
Prepared according to the procedure described in example Q-50, part c. 1H NMR (DMSO) δ 2.20 (3H, s), 2.31 (4H, t), 3.42 (4H, t), 7.34-7.27 (6H, m), 7.41 (2H, d), 7.62 (1 H, m), 8.47 (1 H, br s), 9.18 (1 H, br s). LCMS (2) Rt: 2.05min; m/z (ES+) 457.
Example V-3
2-(2,6-difluorophenyl)-5-(4-(3-(methylamino)propanamido)phenylamino)oxazoIe-4- carboxamide Step a - ferf-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyIamino)-3- oxopropyl(methyl)carbamate
Figure imgf000221_0001
To a solution of N-^ΘAf-butoxycarbony^-S-methylaminopropanoic acid (0.022g, O.Hmmol) in DMF (1.25ml) were added 0-(7-azabenzotriazol-1-yl)-N,N,N',N'- tetramethyluronium hexafluorophosphate (0.04Og, 0.11mmol) and diisopropylethylamine (0.018ml, 0.11mmol) followed by 5-(4-aminophenylamino)-2-(2,6-difluorophenyl)oxazole- 4-carbonitrile (0.03Og, O.IOmmol) and the resultant mixture stirred at room temperature overnight. A further portion of N-(teAf-butoxycarbonyl)-3-methylaminopropanoic acid (0.022g, 0.1 Immol), 0-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (0.04Og, 0.1 Immol) and diisopropylethylamine (0.018ml, 0.1 Immol) was added and the reaction stirred for 2 hours at room temperature. The solvent was removed in vacuo and the residue purified by preparative HPLC to afford terf-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5-yIamino)phenylamino)-3- oxopropyl(methyl)carbamate (0.021 g, 0.04mmol, 44%) as a white solid. LCMS (2) Rt: 3.03min; m/z (ES+) 498.
Step b - 2-(2,6-difluorophenyl)-5-(4-(3-(methylamino)propanamido)phenyIamino)oxazole- 4-carboxamide
Figure imgf000221_0002
A solution of te/f-butyl 3-(4-(4-cyano-2-(2,6-difluorophenyl)oxazol-5- ylamino)phenylamino)-3-oxopropyl(methyl)carbamate (0.021 g, 0.04mmol) in concentrated sulfuric acid (1 ml) was stirred at room temperature overnight. The reaction was basified by addition to sat. sodium bicarbonate and then addition of 6M NaOH (to ~pH12). The aqueous phase was then extracted with EtOAc, the combined organic phases dried over MgSO4 and the solvent removed in vacuo. The residue was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(4-(3-
(methylamino)propanamido)phenylamino)oxazoIe-4-carboxamide (0.0038g, 0.009mmol, 22%). 1H NMR (CD3OD) δ 2.64 (3H, s), 2.73 (2H, t), 3.20 (2H, masked by CD3OD peak), 7.08 (2H, t), 7.29 (2H, d), 7.45 (1H, m), 7.48 (2H, d), 8.45 (1H, br. s). LCMS (2) Rt: 2.28min; m/z (ES+) 416.
Example V-4
N-(4-(4-carbamoyl-2-(2,6-difluorophenyl)oxazol-5-ylamino)phenyl)piperidine-3- carboxamide
Figure imgf000222_0001
Prepared according to the procedure descried in example V-2. LCMS (2) Rt: 2.40min; m/z (ES+) 442.
General Method X
General Method X comprises the series of steps set out in Scheme 17 above.
Example X-1 2-(2,6-Difluorophenyl)-5-(3-(morpholinomethyl)phenyl)oxazole-4-carboxamide
Step a - 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide
Figure imgf000222_0002
Prepared according to the method desribed in example F-1. 1H NMR (DMSO) δ 7.39- 7.43 (2H, m), 7.74-7.83 (4H1 m), 8.03-8.05 (1 H, m), 8.59 (1H, m), 8.72-8.73 (1H, m), 10.10 (1 H, s). LCMS (3) Rt: 2.18min; m/z (ES+) 329.
Step b - 2-(2,6-Difluorophenyl)-5-(3-(morpholinomethyl)phenyI)oxazo!e-4-carboxamide
Figure imgf000223_0001
To a solution of 2-(2,6-difluorophenyl)-5-(3-formylphenyl)oxazole-4-carboxamide(0.050g, 0.152mmol), morpholine (0.027ml_, 0.305mmol) and sodium triacetoxyborohydride (0.014g, 0.228mmol) in 1 ,2-dichloroethane (6mL) was added acetic acid (0.013ml_, 0.228mmol) at room temperature. The resulting mixture was stirred at room temperature for 2h and then quenched with saturated sodium bicarbonate. The aqueous layer was extracted with ethyl acetate and the combined organic extracts dried over MgSO4 and concentrated in vacuo to give a residue that was purified by preparative HPLC to afford 2-(2,6-difluorophenyl)-5-(3~(morpholinomethyl)phenyl)oxazole-4-carboxamide (0.022g, 0.056mmol, 37%) as a white solid. 1H NMR (DMSO) δ 2.39 (4H, br m), 3.54 (2H, br m), 3.59 (4H, t), 7.38-7.45 (3H1 m), 7.50 (1H, t), 7.71-7.78 (3H, m), 8.13-8.17 (2H, m). LCMS (2) Rt: 2.62min; m/z (ES+) 400.
In a similar manner as described in example X- 1 the compounds described in examples X-2 to X-4 were prepared.
Example X-2
2-(2,6-Difluorophenyl)-5-(3-((3-oxopiperazin-1-yl)methyl)phenyl)oxazole-4- carboxamide
Figure imgf000224_0001
1H NMR (DMSO) δ 2.57 (2H, br t), 2.96 (2H, s), 3.15-3.18 (2H, m), 3.62 (2H, s), 7.38- 7.46 (3H1 m), 7.49-7.53 (1H, m), 7.71-7.78 (4H, m), 8.15-8.18 (2H, m). LCMS (2) Rt: 2.18min; m/z (ES+) 413.
Example X-3
2-(2,6-Difluorophenyl)-5-(3-(piperazin-1-ylmethyl)phenyl)oxazole-4-carboxamide formate salt
Figure imgf000224_0002
Modified procedure; Prepared using 1-boc-piperazine, with the following modification to the procedure used in example X- 1 : the crude reaction was passed through MP-TsOH cartridge and washed with methanol. After 3h the cartridge was washed with 2M ammonia solution in methanol. The methanol solution was concentrated to give a residue that was purified by preparative HPLC to afford the product as the formate salt. 1H NMR (DMSO) δ 2.42 (4H, br m), 2.83 (4H, t), 3.54 (2H, s), 7.38-7.43 (3H, m), 7.47- 7.51 (1 H, m), 7.72-7.78 (2H, m), 8.11-8.15 (2H, m), 8.35 (2H, s). LCMS (2) Rt: 2.18min; m/z (ES+) 399.
Example X-4
5-(3-((2-(Aminomethyl)morpholino)methyl)phenyl)-2-(2,6-difluorophenyl)oxazole-4- carboxamide formate salt
Figure imgf000225_0001
Prepared using 1- ferf-butyl morpholin-2-ylmethylcarbamate according to the procedure described in example X-3 to afford the product as the formate salt. 1H NMR (DMSO) δ 1.87 (1H, t), 2.11-2.17 (1H, m), 2.67-2.70 (3H, m), 2.78-2.82 (1 H, m), 3.48-3.53 (2H1 m), 3.55-3.60 (2H, m), 3.80-3.83 (1 H, m), 7.38-7.40 (2H, m), 7.43-7.46 (1 H, m), 7.48-7.52 (1 H, m), 7.60 (2H, br s), 7.70-7.76 (1H, m), 8.12-8.15 (2H, m), 8.34 (1 H, br s). LCMS (2) Rt: 2.21 mins; m/z (ES+) 429.
BIOLOGICAL ACTIVITY FLT3 Enzyme Inhibition FLT3 Enzyme:
A GST - kinase fusion protein of 70 KDa was produced using sf9 baculovirus expression system, with a construct expressing the human FLT3 (564 -993) with an amino terminal GST tag. The protein was purified by one-step affinity chromatography using glutathione-agarose.
FLT3 Kinase Assay:
FLT3 enzyme activity is determined using a Dissociation Enhanced Lanthanide Fluorescent Immunoassay (DELFIA) with a peptide substrate derived from the Gastrin Precursor (Tyr 87) peptide LEEEEEAYGWMDFGRRS with a core sequence: EAYGW.
The amount of phosphorylated peptide produced is detected by means of a phospho- Tyrosine specific Europium-labelled antibody using Time-Resolved Fluorescence at Excitation 360-35nm and Emission 620-35nm.
Enzyme reaction:
Assay reactions are set up in a 25uL final volume on a 96 well plate. FLT3-GST enzyme (Sareum) at 9nM is incubated with varying concentrations of inhibitor in 2.5% DMSO, 0.25uM peptide: Biotin -LEEEEEAYGWMDFGRRS and 3OuM ATP in 6OmM HEPES pH 7.5, 8OmM MgCI2, 8OmM MnCI2, 1.25mM DTT and 0.01% Triton X-100. The reaction is allowed to proceed for 30 minutes at room temperature before stopping with 100μl_ Stop solution comprising of 10OmM EDTA, 1x BSA blocker in TBS (Perbio) and 0.05% Surfact-Amps20 (Perbio).
Detection step:
The stopped reaction is transferred to a black 96-well Neutravidin-coated plate (Perbio) and incubated for 30 minutes to capture the biotinylated peptide substrate. After washing wells 3 times with 20OuL TBS/T buffer, Anti-Phospho-Tyr-100 antibody labelled with Eu- N1 (Perkin Elmer AD0159) is added to all wells for 60 minutes at room temperature. After a repeat washing step, DELFIA Enhancement solution (Perkin Elmer) is added to all wells for 5 minutes and the fluorescence measured on a plate reader Analyst HT (Molecular Devices).
The % inhibition of the activity is calculated and plotted in order to determine the concentration of test compound required to inhibit 50% of the enzyme activity (ICS0).
By means of the protocol set out above, it was found that the compounds of Examples B-2, F-13, F-14, F-15, F-22, F-24, F-25, F-26, F-27, G-2, G-3, G-4, G-5, H-1 , H-2, 1-1 , I- 2, J-1 , J-2, J-3, M-4, M-12, M-17, P-1 , Q-1 , Q-2, Q-3, Q-7, Q-8, Q-9, Q-10, Q-11 , Q-12, Q-13, Q-14, Q-15, Q-16, Q-19, Q-20, Q-21 , Q-22, Q-26, Q-23, Q-24, Q-25, Q-27, Q-29, Q-31, Q-32, Q-34, Q-35, Q-36, Q-37, Q-47, Q-56, Q-57, Q-58, Q-60, R-1, R-2, R-3, R-5, R-8, R-11, R-12, R-13, R-14, R-15, R-16, R-17, S-6, S-7, S-8, S-9, S-10, S-11 , S-12, S- 13, T-1 , T-2, T-3, T-4 and U-1 , U-5, U-12, U-13, U-14, U-15, U-16, U-17, U-18, U-19, U- 20, U-21, U-22, U-23, U-24, U-25, U-26, U-27, V-2, V-3 and V-4 each have IC50 values less than 10 μM or exhibit greater than 50% inhibition at a concentration of 10μM, whereas the compounds of Examples E-3, E-4, F-2, F-7, F-9, F-10, F-11, F-12, F-16, F- 19, G-1, M-2, M-3, M-9, M-11 , N-2, N-3, N-7, N-8, Q-28, Q-30, Q-33, S-1 , S-2, S-3, S-4 and S-5 each have an IC50 value of less than 100 μM or exhibit greater than 50% inhibition at a concentration of 100 μM.
Examination of the effect of compound of formula (1) in an experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis
The usefulness of the compounds of formula (1) in treating multiple sclerosis can be determined using an experimental autoimmune encephalomyelitis (EAE) mouse model. Groups of mice are challenged with mouse spinal cord homogenate (SCH) in complete Freund's adjuvant (CFA) in order to induce EAE. Treatments are given according to the schedule below.
Treatment (n mice per group)
Group A - vehicle control
Group B - Compound of formula (1) 30 mg/kg days -1 to 10 once daily by oral gavage
Group C - Compound of formula (1) 10 mg/kg days -1 to 10 twice daily by oral gavage
Group D - Positive control drug
A solution of SCH in PBS is prepared and mixed in an equal volume with CFA. The mixture is sonicated and then homogenised and an amount of 1mg in 100 μl is administered per mouse by subcutaneous injection at the base of the tail. In addition, mice are given 200 ng pertussis toxin in 0.5ml by intraperitoneal (ip) injection on day 0 and again 48 hours later.
Mice are treated as described above according to the outline above from day -1 to day 10. The compound of formula (1) is prepared daily by dissolving 15 mg of the compound (stored at -20 0C) in sterile distilled water to give 6 mg/ml solution. A dose of 100 μl is given by oral gavage daily to the group B mice (equivalent to 30 mg/kg per 2Og mouse). For group C mice, 1 ml of the 6 mg/kg stock is further diluted 1 :3 in sterile distilled water, and a dose of 100 μl is given orally twice daily (equivalent to 2 x 10 mg/kg per 2Og mouse). Distilled water is used as the vehicle control for the mice in group A. Group D mice are given a dose of 5 mg/kg dexamethasone (100 μg in 100 μl per 2Og mouse) on days 3-7 and days 10-12.
Moribund animals are euthanised according to Home Office regulations and all remaining animals are euthanized at day 28 post-induction. At termination, brains and spinal cords are taken from all animals and fixed for histopathology examination.
Mice are weighed prior to EAE induction (Day 0) and then daily from day 5 until termination. Clinical disease is monitored from day 5 and scored according the following system:
0 normal
0.5 weight loss without clinical symptoms
1 flaccid paralysis of tail 1.5 impairment of the righting reflex
2 single hind limb paralysis
3 bilateral hind limb paralysis
4 hind limb and forelimb paralysis
5 moribund
PHARMACEUTICAL FORMULATIONS
EXAMPLE
(i) Tablet Formulation
A tablet composition containing a compound of the formula (1) is prepared by mixing 50mg of the compound with 197mg of lactose (BP) as diluent, and 3mg magnesium stearate as a lubricant and compressing to form a tablet in a known manner.
(ii) Capsule Formulation
A capsule formulation is prepared by mixing 100mg of a compound of the formula (1) with 100mg lactose and filling the resulting mixture into standard opaque hard gelatin capsules.
(iii) Injectable Formulation I
A parenteral composition for administration by injection can be prepared by dissolving a compound of the formula (1 ) (e.g. in a salt form) in water containing 10% propylene glycol to give a concentration of active compound of 1.5% by weight. The solution is then sterilised by filtration, filled into an ampoule and sealed.
(iv) Injectable Formulation Il
A parenteral compositon for injection is prepared by dissolving in water a compound of the formula (1) (e.g. in salt form) (2mg/mL) and mannitol (50mg/mL), sterile filtering the solution and filling into sealable 1mL vials or ampoules.
(iv) Subcutaneous Injection Formulation
A composition for sub-cutaneous administration is prepared by mixing a compound of the formula (1) with pharmaceutical grade corn oil to give a concentration of 5mg/mL The composition is sterilised and filled into a suitable container. Equivalents
The foregoing examples are presented for the purpose of illustrating the invention and should not be construed as imposing any limitation on the scope of the invention. It will readily be apparent that numerous modifications and alterations may be made to the specific embodiments of the invention described above and illustrated in the examples without departing from the principles underlying the invention. All such modifications and alterations are intended to be embraced by this application.

Claims

1. A compound for use in the treatment of an autoimmune disease, the compound being a compound of the formula (1):
Figure imgf000230_0001
or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1 ; b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
T is O or NH
Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1;
Ar2 Js a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; provided that, when b is 0, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T;
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3;
Ra is a bond, O, CO, X1C(X2), C(X2)X\ X1C(X2)X1, S, SO, SO2, NRC, SO2NR0 or NR0SO2;
Rb is:
• hydrogen; or
• a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; or
• a Ci-I2 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(R°)2; and 3 to 8-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
R0 is hydrogen or a C1-4 hydrocarbon group; X1 is O, S or NRC; X2 is =0, =S or =NRC;
R2 is halogen; cyano; nitro; or a group Ra-Rd;
Rd is hydrogen; a C1-4 alkyl group optionally substituted by one or more fluorine atoms; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the C1-4 alkyl and C1-4 alkoxy substituents on the benzene ring are each optionally substituted with one or more fluorine atoms;
R3 is X2; halogen; cyano; nitro; a group Ra-Re; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R4; Re is:
- hydrogen; or
- a C1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°)2; wherein one to three but not all of the carbon atoms of the C1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X1 or X1C(X2)X1; or
- a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the C1-4 alkyl and C1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms; and
R4 is selected from halogen, cyano, nitro and a group Ra-Rd; provided that when a is O, Ar1 is other than a 2-aminopyridin-4-yl or 2-amino- pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted; and that neither A^-(NHJb- nor Ar1-(NH)a- form an optionally substituted quinoxalin-4-ylamino group; and that when a is 1 and b is 0, then Ar2 is other than a bicyclic group containing a pyrrole or pyrazole ring fused to a non-aromatic six-membered carbocyclic ring wherein the point of attachment of Ar2 is a nitrogen atom of the pyrrole or pyrazole ring; but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide; and 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
2. A compound for use according to claim 1 which is an amide of the formula (1a):
Figure imgf000232_0001
or a salt, solvate, N-oxide or tautomer thereof; wherein: a is 0 or 1 ; b is 0 or 1 : provided that the sum of a and b is 0 or 1 ;
T is O or NH
Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1;
Ar2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; provided that, when b is 0, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T;
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; Ra is a bond, O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2; Rb is:
• hydrogen; or
• a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; or
• a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(RC)2; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X1C(X2), C(X2)X1, X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
R° is hydrogen or a C1-4 hydrocarbon group; X1 is O, S or NR0; X2 is =O, =S or =NR°;
R2 is halogen; cyano; nitro; or a group Ra-Rd;
Rd is hydrogen or a C1-4 alkyl group optionally substituted by one or more fluorine atoms;
R3 is X2; halogen; cyano; nitro; a group Ra-Re; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by a group R4; Re is: hydrogen; or
- a C1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°)2; wherein one to three but not all of the carbon atoms of the C-i-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X1 or X1C(X2JX1; and R4 is selected from halogen, cyano, nitro and a group Ra-Rd; provided that when a is O, Ar1 is other than a 2-aminopyridin-4-yl or 2- amino-pyrimidin-4-yl group wherein the 2-amino moiety is optionally substituted; and that neither Ar2^N H)b- nor Ar1-(NH)a- form an optionally substituted quinoxalin-4-ylamino group; but excluding the compounds:
2,5-diphenyl-1H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4-carboxylic acid amide; and 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
3. A compound for use according to claim 2 wherein : a is O or 1; b is 0 or 1: provided that the sum of a and b is 0 or 1 ;
T is O or NH
Ar1 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S, and being optionally substituted by one or more substituents R1;
Ar2 is a monocyclic or bicyclic 5- to 10-membered aryl or heteroaryl group containing up to 4 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R2; provided that, when b is 0, a carbon atom of Ar2 is attached directly to the 5-membered ring containing the moiety T;
R1 is halogen; cyano; nitro; a group Ra-Rb; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3;
Ra is a bond, O, CO, X1C(X2), C(X2)X\ X1C(X2)X1, S, SO, SO2, NR0, SO2NR0 or NR0SO2;
Rb is:
• hydrogen; or
• a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; or • a C1-I2 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; N(RC)2; and 3 to 7-membered carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3; wherein one to three but not all of the carbon atoms of the C1-12 acyclic hydrocarbon group may optionally be replaced by O, CO, X1C(X2), C(X2)X1, X1C(X2)X\ S, SO, SO2, NR0, SO2NR0 or NR0SO2;
R° is hydrogen or a Ci-4 hydrocarbon group; X1 is O, S or NR0; X2 is =0, =S or =NR°;
R2 is halogen; cyano; nitro; or a group Ra-Rd;
Rd is hydrogen or a C1-4 alkyl group optionally substituted by one or more fluorine atoms;
R3 is X2; halogen; cyano; nitro; a group Ra-Re; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by a group R4; Re is: hydrogen; or
- a C1-6 acyclic hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; nitro; carboxy; amino; and N(R°)2; wherein one to three but not all of the carbon atoms of the C1-6 acyclic hydrocarbon group may optionally be replaced by O, S, SO, SO2, NR0, X1C(X2), C(X2)X1 or X1C(X2)X1; and R4 is selected from halogen, cyano, nitro and a group Ra-Rd.
4. A compound for use according to any one of claims 1 to 3 which is an amide of the formula (2):
Figure imgf000235_0001
(2) or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as defined in claim 1 or claim 2 or claim 3; but excluding the compounds:
2,5-diphenyl-1 H-imidazole-4-carboxyIic acid amide and tautomers thereof;
2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof;
2-phenyl-5-(3,4,5-trimethoxy-phenyl)-oxazole-4-carboxylic acid amide;
2,5-diphenyl-oxazole-4-carboxylic acid amide; and
2-(4-methylphenyl)- 5-phenyl-oxazole-4-carboxylic acid amide.
5. A compound for use according to claim 4 which is an amide of the formula (2a):
Figure imgf000236_0001
(2a) or a salt, solvate, N-oxide or tautomer thereof; wherein Ar1 and Ar2 are as defined 5 in claim 4, but excluding the compounds 2,5-diphenyI-1 H-imidazole-4-carboxylic acid amide and tautomers thereof; 2-(4-fluorophenyl)-5-(4-methoxyphenyl)-1 H- imidazole-4-carboxylic acid amide and tautomers thereof; and 2-phenyl-5-thiophen-2-yl-1 H-imidazole-4-carboxylic acid amide and tautomers thereof.
) 6. A compound for use according to claim 4 which is an amide of the formula (2b):
Figure imgf000236_0002
(2b) or a salt, solvate, N-oxide or tautomer thereof; wherein Ar1 and Ar2 are as hereinbefore defined in claim 4, but excluding the compounds 2-phenyl-5-(3,4,5- trimethoxy-phenyl)-oxazole-4-carboxylic acid amide; 2,5-diphenyl-oxazole-4- carboxylic acid amide; and 2-(4-methylphenyl)-5-phenyl-oxazole-4-carboxylic acid amide.
7. A compound for use according to claim 4 which is an amide of the formula (2c):
Figure imgf000237_0001
(2c) or a salt, solvate, N-oxide or tautomer thereof; wherein Ar1 and Ar2 are as defined in claim 4.
8. A compound for use according to any one of claims 1 to 3 which is an amide of the formula (3):
Figure imgf000237_0002
(3) or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as defined in claim 1 or claim 2 or claim 3.
9. A compound for use according to claim 8 which is an amide of the formula (3a):
Figure imgf000237_0003
(3a) or a salt, solvate, N-oxide or tautomer thereof; wherein Ar1 and Ar2 are as defined in claim 8.
10. A compound for use according to any one of claims 1 to 3 which is an amide of the formula (4):
Figure imgf000238_0001
(4) or a salt, solvate, N-oxide or tautomer thereof; wherein T, Ar1 and Ar2 are as defined in claim 1 or claim 2 or claim 3.
11. A compound for use according to claim 10 which is an amide of the formula (4a):
Figure imgf000238_0002
(4a) or a salt, solvate, N-oxide or tautomer thereof; wherein Ar1 and Ar2 are as defined in claim 10.
12. A compound for use according to any one of claims 1 to 11 wherein Ar1 is selected from substituted monocyclic 5- and 6-membered aryl and heteroaryl rings containing up to 2 heteroatoms selected from O, N and S, each of the aryl and heteroaryl rings being optionally substituted by one or more substituents R1.
13. A compound for use according to claim 12 wherein the optionally substituted monocyclic 5- and 6-membered aryl and heteroaryl rings contain up to 1 heteroatom selected from O, N and S.
14. A compound for use according to claim 13 wherein Ar1 is selected from optionally substituted phenyl, thiophene, furan, pyridine and pyrazole rings.
15. A compound for use according to claim 14 wherein Ar1 is selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 2-pyridyl, 3-pyridyl and 4-pyridyl rings, each optionally substituted by one or more substituent groups R1.
16. A compound for use according to claim 14 wherein Ar1 is phenyl optionally substituted by one or more substituent groups R1.
17. A compound for use according to any one of the preceding claims wherein the aryl or heteroaryl group Ar1 is substituted by 0, 1 or 2 substituents R1.
18. A compound for use according to claim 17 wherein the aryl or heteroaryl group Ar1 is substituted by 0 or 1 substituents R1.
19. A compound for use according to any one of the preceding claims wherein R1 is selected from halogen; cyano; or a group Raa-Rbb;
Raa is a bond, O, CO, OC(O), C(O)O, NRCCC(O), C(O)NRCC, NRC0, OC(O)O, NR00C(O)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2, SO2NR00 or NR00SO2 wherein
Rbb is:
• hydrogen; or
• a 3 to 8-membered non-aromatic carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a 5- or 6-membered aryl or heteroaryl group containing up to 4 (e.g up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(R00J2; o 3 to 8-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g. up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; wherein one to three but not all of the carbon atoms of the CM2 acyclic hydrocarbon group may optionally be replaced by O, CO, OC(O), NRCCC(O), OC(NRCC), C(O)O, C(O)NR00, NRCC, OC(O)O, NRCCC(O)O, OC(NR00P, OC(O)NR00, NR00C(O) NR00, S, SO, SO2, NR00, SO2NR00 and NR00SO2;
R00 is hydrogen or a saturated C1-4 hydrocarbon group; R3a is oxo; halogen; cyano; a group Raa-Ree; or a 3 to 8-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C1-4 alkyl, Ci-4 acyl, Ci-4 alkoxycarbonyl or C1-4 alkylsulphonyl; Ree is:
■ hydrogen; or
■ a C1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(R0C)2; or
■ a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy, and wherein the Ci-4 alkyl and C1-4 alkoxy groups are each optionally substituted with one or more fluorine atoms.
20. A compound for use according to claim 19 wherein R1 is selected from halogen; cyano; or a group Raa-Rbb>;
Raa is a bond, O, CO, OC(O), C(O)O, NR00C(O), C(O)NR00, NR00, OC(O)O, NR00C(O)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2, SO2NR00 or NR00SO2 wherein Rbb' is:
• hydrogen; or
• a 3 to 7-membered non-aromatic carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or
• a 5- or 6-membered aryl or heteroaryl group containing up to 4 (e.g. up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; or • a C1-12 acyclic hydrocarbon group optionally substituted by one or more substituents selected from: o hydroxy; o oxo; o halogen; o cyano; o carboxy; o N(RCC)2; o 3 to 7-membered non-aromatic carbocyclic or heterocyclic rings containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; o 5- or 6-membered aryl or heteroaryl groups each containing up to 4 (e.g. up to 2) heteroatoms selected from O, N and S and being optionally substituted by one or more substituents R3a; wherein one to three but not all of the carbon atoms of the C1--I2 acyclic hydrocarbon group may optionally be replaced by O, CO, OC(O), NRCCC(O), OC(NRCC), C(O)O, C(O)NRCC, NRCC, OC(O)O, NR00C(O)O, OC(NRC0)O, OC(O)NR00, NR00C(O) NR00, S, SO, SO2 , NR00, SO2NR00 and NR00SO2;
R00 is hydrogen or a saturated C1-4 hydrocarbon group; R3a is oxo; halogen; cyano; a group Raa-Ree'; or a 3 to 7-membered carbocyclic or heterocyclic ring containing up to 2 heteroatoms selected from O, N and S and being optionally substituted by C1-4 alkyl, C1-4 acyl, C1-4 alkoxycarbonyl or C1-4 alkylsulphonyl;
Re8' is hydrogen; or a C1-6 acyclic saturated hydrocarbon group optionally substituted by one or more substituents selected from hydroxy; oxo; halogen; cyano; carboxy; and N(RCC)2.
21. A compound for use according to any one of the preceding claims wherein R1 is selected from: halogen;
CO2R5 wherein R5 is hydrogen or C1-6 alkyl; SO2R5; C1-4 alkyl optionally substituted by hydroxy or C1-2 alkoxy or one or more fluorine atoms;
C1-4 alkoxy optionally substituted by hydroxy or C1-2 alkoxy or one or more fluorine atoms; or a group Q, C(O)NHQ, HNC(O)Q, C(O)NH-AIk-Q, HNC(O)-AIk-Q, NH-AIk-Q, CH2Q, S(O)Q, SO2Q, C(O)Q or O-Alk(OH)p-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or O and OH; and Q is selected from: a saturated or partially unsaturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-C1-4 alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or CJi-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or Ci-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9 wherein the C1-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C1-4 alkylamino or phenyl;
O-Alk-Q' where AIk is as defined above and Q' is an optionally substituted saturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 as hereinbefore defined or a group NR7R8;
0-Q" where Q" is a saturated or partially unsaturated 4 to 8 membered (e.g. 4 to 7 membered) heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy- C1-4 alkyl, alkyl, mono- or di-C-M alkylamino-C1-4 alkyl, amino, mono- or di-Ci-4 alkylamino, C1-4 acyl, Ci-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; a 5- or 6- membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF3, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-C1.4 alkyl, mono- or CIi-C1-4 alkylamino-C1-4 alkyl, amino, mono- or CIi-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, CM alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; and
R9 is Ci-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C1-4 alkyl, halogen, C1-4 alkoxy or cyano.
22. A compound for use according to any one of the preceding claims wherein
R1 is selected from: halogen;
CO2R5 wherein R5 is C1-6 alkyl;
SO2R5;
C1-4 alkyl optionally substituted by hydroxy or C1-2 alkoxy;
C1-4 alkoxy optionally substituted by hydroxy or C1-2 alkoxy; or a group Q, CH2Q, S(O)Q, SO2Q, C(O)Q or O-Alk(OH)p-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms and p is O or 1 provided that there are at least 2 carbon atoms in line between O and Q, or OH and Q, or
O and OH; and Q is selected from: a saturated or partially unsaturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy-C^ alkyl, amino-C1-4 alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or Cu-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9 wherein the C1-4 alkyl moieties in each case are optionally substituted by OH, amino, mono- or di-C1-4 alkylamino or phenyl;
O-Alk-Q' where AIk is as defined above and Q1 is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het1 as hereinbefore defined or a group NR7R8;
0-Q" where Q" is a saturated or partially unsaturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from =0, OH, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-C1-4 alkyl, mono- or di-C1-4 alkylamino-C1-4 alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; a 5- or 6- membered monocyclic heteroaryl ring containing 1 to 4 heteroatom ring members selected from O, N and S, of which at least one is N, the heteroaryl ring being optionally substituted by one or more substituents selected from OH, halogen, CN, CF3, C1-4 alkyl, hydroxy-C1-4 alkyl, amino-C1-4 alkyl, mono- or di-C-ι-4 alkylamino-C1-4 alkyl, amino, mono- or di-C1-4 alkylamino, C1-4 acyl, C1-4 alkoxycarbonyl, d.4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; and
R9 is C1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by C1-4 alkyl, halogen, Ci.4 alkoxy or cyano.
23. A compound for use according to claim 21 or claim 22 wherein R1 is selected from: halogen;
CO2R5a wherein R5a is C1-6 alkyl;
SO2R5a;
C1-4 alkyl optionally substituted by hydroxy or Ci-2 alkoxy;
C1-4 alkoxy optionally substituted by hydroxy or C1-2 alkoxy; or a group Q, CH2Q, S(O)Q, SO2Q, C(O)Q or O-Alk-Q where AIk is a straight or branched chain alkylene group of 2 to 5 carbon atoms provided that there are at least 2 carbon atoms in line between O and Q; and Q is selected from: a saturated 4 to 7 membered heterocyclic ring Het1 containing a nitrogen ring member and optionally a further heteroatomic ring member selected from O, N and S, wherein the heterocyclic ring Het1 is optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 acyl, d.4 alkoxycarbonyl, Ci-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; hydroxy;
NR7R8 where R7 is hydrogen or Ci-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9;
O-Alk-Q' where AIk is as defined above and Q' is an optionally substituted saturated 4 to 7 membered heterocyclic ring Het1 as hereinbefore defined or a group NR7R8; and
R9 is C1-4 alkyl optionally substituted by a 5- or 6-membered aryl or heteroaryl group containing up to 2 heteroatoms selected from O, N and S and wherein the aryl and heteroaryl groups are optionally substituted by Ci-4 alkyl, halogen, Ci-4 alkoxy or cyano.
24. A compound for use according to any one of claims 21 to 23 wherein R1 is a group O-Alk(OH)p-Q.
25. A compound for use according to claim 24 wherein p is 1.
26. A compound for use according to claim 24 wherein p is O.
27. A compound for use according to claim 26 wherein R1 is a group O-Alk-Q, and the moiety AIk is selected from CH2CH2, CH2CH2CH2, CH2CH(Me), CH2CMe2, CH2CH2CH(Me) and CH2CH2CMe2.
28. A compound for use according to claim 27 wherein the moiety AIk is selected from CH2CH2 and CH2CH2CH2.
29. A compound for use according to any one of claims 21 to 28 wherein Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 acyl, C1-4 alkoxycarbonyl, C1-4 alkylsulphonyl, aminocarbonyl, and mono- and di-C1-4 alkylaminocarbonyl; SO2R5; hydroxy; and
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9.
30. A compound for use according to claim 29 wherein Q is selected from: a saturated 5 or 6 membered heterocyclic ring selected from pyrrolidine, morpholine, piperidine and piperazine, each being optionally substituted by one or more substituents selected from C1-4 alkyl, C1-4 acyl, Ci-4 alkoxycarbonyl, Ci-4 alkylsulphonyl, aminocarbonyl, and mono- and Ui-C1-4 alkylaminocarbonyl; hydroxy; and
NR7R8 where R7 is hydrogen or C1-4 alkyl; and R8 is hydrogen, C1-4 alkyl, SO2R9 or COR9.
31. A compound for use according to any one of the preceding claims wherein R1 is a moiety having the formula:
Figure imgf000246_0001
where the asterisk indicates the point of attachment to the group Ar .1.; Y is a bond, O-Alk- (where AIk is as hereinbefore defined), or a C1-3 alkylene group; and
B is O, NH, CH2 or a group NR10; and
R10 is selected from C1-4 alkyl, C1-4 acyl, carbamoyl, mono- and di-C1-4 alkylcarbamoyl, C1-4 alkoxycarbonyl and C1-4 alkylsulphonyl.
32. A compound for use according to any one of the preceding claims wherein Ar2 is selected from optionally substituted monocyclic 5- and 6-membered aryl and heteroaryl rings containing up to 3 heteroatoms selected from O, N and S, and optionally substituted bicyclic 6.5 fused rings containing up to 3 heteroatoms selected from O, N and S.
33. A compound for use according to claim 32 wherein the optionally substituted monocyclic 5- and 6-membered aryl and heteroaryl rings and optionally substituted bicyclic 6.5 fused rings each contain 1 or 2 heteroatoms selected from O, N and S.
34. A compound for use according to claim 33 wherein the aryl and heteroaryl rings are selected from:
(a) the group consisting of phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine, pyrrolopyridine and pyrazole rings, each optionally substituted by one or more substituents R2; or
(b) the group consisting of phenyl, thiophene, furan, indole, indazole, benzoimidazole, benzofuran, pyridine and pyrazole rings, each optionally substituted by one or more substituents R2.
35. A compound for use according to claim 34 wherein the aryl and heteroaryl rings are selected from:
(a) the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3- pyrazole, 4-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyl, 3- indazolyl, 4-indazolyl, benzimidazol-4-yl, 3-benzofuranyl and 4-benzofuranyl rings, each optionally substituted by one or more substituent groups R2; or
(b) the group consisting of phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3- pyrazole, 4-pyrazole, 5-pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4- indolyl, 5-indolyl, 6-indolyl, 3-indazolyl, 4-indazolyl, 5-indazolyl, 6-indazolyl, benzimidazol-4-yl, 3-benzofuranyl, 4-benzofuranyl and pyrrolo[2,3-b]pyridine rings, each optionally substituted by one or more substituent groups R2.
36. A compound for use according to claim 34 wherein the aryl and heteroaryl rings are selected from phenyl, thiophene, furan, indole, benzofuran, pyridine and pyrazole rings, each optionally substituted by one or more substituents R2.
37. A compound for use according to claim 36 wherein the aryl and heteroaryl rings are selected from phenyl, 2-thienyl, 3-thienyl, 2-furyl, 3-furyl, 3-pyrazole, 4- pyrazole, 2-pyridyl, 3-pyridyl, 4-pyridyl, 3-indolyl, 4-indolyl, 3-benzofuranyl and 4- benzofuranyl rings, each optionally substituted by one or more substituent groups R2.
38. A compound for use according to any one of claims 32 to 37 wherein Ar2 is an optionally substituted phenyl ring.
39. A compound for use according to any one of claims 1 to 31 wherein Ar2 is selected from (i) optionally substituted 5-membered heteroaryl groups containing 1 or 2 heteroatom ring members (more preferably 2 nitrogen heteroatom ring members), at least one of which is nitrogen; and (ii) optionally substituted 9- membered bicyclic heteroaryl groups containing 1 to 3 heteroatom ring members (more preferably 1 or 2 nitrogen heteroatome ring members) of which at least 1 is nitrogen.
40. A compound for use according to claim 39 wherein Ar2 is selected from optionally substituted indole, pyrrolopyridine, indazole and pyrazole groups.
41. A compound for use according to claim 40 wherein Ar2 is selected from optionally substituted indazol-4-yl, indazol-5-yl, indol-4-yl, indol-5-yl, pyrrolo[2,3-b]pyridin-4- yl, pyrrolo[2,3-b]pyridin-5-yl, pyrazol-2-yl and pyrazol-3-yl,
42. A compound for use according to claim 32 wherein Ar2 is an optionally substituted 1 H-pyrrolo[2,3-b]pyridine group.
43. A compound for use according to any one of the preceding claims wherein the aryl or heteroaryl ring Ar2 is substituted by 0, 1 or 2 substituents R2.
44. A compound for use according to claim 43 wherein the aryl or heteroaryl ring is unsubstituted.
45. A compound for use according to claim 43 wherein the aryl or heteroaryl ring is substituted by 1 substituent R2.
46. A compound for use according to claim 43 wherein the aryl or heteroaryl ring is substituted by 2 substituents R2.
47. A compound for use according to any one of the preceding claims wherein R2 is halogen; cyano; nitro; or a group Ra-Rd; where Ra is a bond, O, CO, X1C(X2), C(X2)X\ X1C(X2)X\ S, SO, SO2, NRC, SO2NR0 or NR0SO2; and Rd is hydrogen or a C1-4 alkyl group optionally substituted by one or more fluorine atoms.
48. A compound for use according to claim 47 wherein R2 is absent or is selected from halogen; C1-4 alkyl optionally substituted with one or more fluorine atoms; CL4 alkoxy optionally substituted with one or more fluorine atoms; cyclopropyl; cyclopropoxy; cyano; CONH2; C1-4 alkylsulphonyl; Ci-4 acylamino; C1-4 alkylsulphonylamino; or a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from halogen, cyano, C1-4 alkyl and C1-4 alkoxy.
49. A compound for use according to claim 48 wherein R2 is absent or is selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; methylsulphonylamino; and a benzyl group wherein the benzene ring of the benzyl group is optionally substituted with one to three substituents selected from chlorine, fluorine, cyano, methyl and methoxy.
50. A compound for use according to any one of claims 1 to 38 and 43 to 49 wherein Ar2 is a phenyl group which is unsubstituted or substituted by 1 , 2 or 3 substituents selected from fluorine; chlorine; bromine; methyl optionally substituted with one or more fluorine atoms; methoxy optionally substituted with one or more fluorine atoms; cyano; methylsulphonyl; acetylamino; and methylsulphonylamino.
51. A compound for use according to claim 50 wherein one substituent is present on the phenyl ring and the substituent is present at an orffto-position on the ring.
52. A compound for use according to claim 50 wherein two substituents are present on the phenyl ring and at least one is located at an oAf/70-position on the ring.
53. A compound for use according to claim 50 wherein both substituents are located at an orffto-position on the ring.
54. A compound for use according to claim 50 wherein Ar2 is selected from phenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 2-chloro-6-fluorophenyl, 2,6- dichlorophenyl, 2,6-dimethylphenyl, 3-indolyl, 4-indolyl, 3-pyrazolyl, 4-pyrazolyl, 2-thienyl and 3-thienyl.
55. A compound for use according to claim 54 wherein Ar2 is selected from phenyl, 2,6-difluorophenyl, 2-chlorophenyl, 2-fluorophenyl, 3-indolyl, 4-indolyl, 3- pyrazolyl, 4-pyrazolyl, 2-thienyl and 3-thienyl.
56. A compound for use according to claim 49 wherein Ar2 is selected from unsubsituted indazol-4-yl, unsubsituted indazol-5-yl, unsubsituted indol-4-yl, unsubsituted indol-5-yl, unsubsituted pyrrolo[2,3-b]pyridin-4-yl, unsubsituted pyrrolo[2,3-b]pyridin-5-yl, 1-benzylpyrazol-2-yl and 1-benzylpyrazol-3-yl.
57. A compound for use according to claim 8 having the formula (5):
Figure imgf000250_0001
(5) or salts, solvates or tautomers thereof; wherein Ar2 is as defined in any one of the preceding claims; G1 is C(O), C(O)NH or HNC(O); and
(i) when G1 is C(O), then G2 is selected from OH and a group Het where Het is a 5 to 7 membered non-aromatic heterocyclic ring containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the group Het being linked to the C(O) group by a nitrogen ring member and being optionally substituted by one or two substituents selected from C1-4 alkyl, hydroxy-C1-4 alkyl, hydroxy, amino-Ci.4 alkyl, and mono- or di-C1-2- alkylamino-C1-4 alkyl; or
(ii) when G1 is C(O)NH or HNC(O), then G2 is selected from: ■ a 5 to 8 membered non-aromatic heterocyclic ring Het' containing a nitrogen atom ring member and optionally one further heteroatom ring member selected from O, N and S: the heterocyclic ring being optionally substituted by one or two substituents selected from C1-4 alkyl, hydroxy- C1-4 alkyl, hydroxy, amino-C^ alkyl, and mono- or di-Ci-2-alkylamino-C1-4 alkyl; and
■ C1-4 alkyl substituted by a group Het' or a group NR7R8, where R7 and R8 are the same or different and each is hydrogen or Ci-4 alkyl; and Het' is as hereinbefore defined.
58. A compound for use according to any one of the preceding claims in the form of a salt.
59. A compound for use according to any one of the preceding claims in the form of a solvate.
60. A compound for use according to any one of the preceding claims in the form of an N-oxide.
61. A compound for use according to any one of claims 1 to 57 and 59 which is neither a salt nor an N-oxide.
62. A compound for use according to any one of claims 1 to 61 wherein the compound is in the form of a pharmaceutical composition.
63. A compound for use as defined in any one of claims 1 to 61 wherein the autoimmune disease is multiple sclerosis.
64. The use of a compound as defined in any one of claims 1 to 61 for the manufacture of a medicament for the the prophylaxis or treatment of an autoimmune disease.
65. The use according to claim 61 wherein the autoimmune disease is multiple sclerosis.
66. A method for the prophylaxis or treatment of an autoimmune disease, which method comprises administering to a subject in need thereof a compound as defined in any one of claims 1 to 61.
67. A method according to claim 66 wherein the autoimmune disease is multiple sclerosis.
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