WO2014009296A1 - Imidazopyrazine derivatives as modulators of tnf activity - Google Patents

Imidazopyrazine derivatives as modulators of tnf activity Download PDF

Info

Publication number
WO2014009296A1
WO2014009296A1 PCT/EP2013/064332 EP2013064332W WO2014009296A1 WO 2014009296 A1 WO2014009296 A1 WO 2014009296A1 EP 2013064332 W EP2013064332 W EP 2013064332W WO 2014009296 A1 WO2014009296 A1 WO 2014009296A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
heteroaryl
optionally substituted
heterocycloalkyl
substituents
Prior art date
Application number
PCT/EP2013/064332
Other languages
French (fr)
Inventor
Jonathan Mark Bentley
Daniel Christopher Brookings
Julien Alistair Brown
Thomas Paul CAIN
Laura Jane GLEAVE
Alexander Heifetz
Victoria Elizabeth JACKSON
Craig Johnstone
Deborah LEIGH
James Madden
John Robert Porter
Matthew Duncan Selby
Zhaoning Zhu
Original Assignee
Ucb Pharma S.A.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ucb Pharma S.A. filed Critical Ucb Pharma S.A.
Priority to JP2015520937A priority Critical patent/JP6259824B2/en
Priority to EP13734128.5A priority patent/EP2872511B1/en
Priority to EA201500133A priority patent/EA028041B1/en
Priority to ES13734128T priority patent/ES2711131T3/en
Priority to BR112015000790-2A priority patent/BR112015000790B1/en
Priority to US14/414,299 priority patent/US9475820B2/en
Priority to CA2877543A priority patent/CA2877543C/en
Priority to CN201380037284.5A priority patent/CN104470924B/en
Publication of WO2014009296A1 publication Critical patent/WO2014009296A1/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
    • C07D491/107—Spiro-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4985—Pyrazines or piperazines ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
    • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of fused imidazole derivatives, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted imidazo[l,2-a]pyrazine derivatives. These compounds are modulators of the signalling of TNFa, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders,
  • cardiovascular disorders cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
  • TNFa is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death.
  • TNF Tumour Necrosis Factor
  • One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors.
  • TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.
  • Typical macromolecular TNFa inhibitors include anti-TNFa antibodies; and soluble TNFa receptor fusion proteins.
  • anti-TNFa antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab
  • chimeric antibodies such as infliximab (Remicade®), and pegylated Fab' fragments such as certulizumab pegol (Cimzia®).
  • An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®).
  • TNF superfamily members including TNFa itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M.G. Tansey & D.E. Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088; and F.S. Carneiro et al., J. sexual Medicine, 2010, 7, 3823-3834).
  • the compounds in accordance with the present invention being potent modulators of human TNFa activity, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders;
  • cardiovascular disorders cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.
  • the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds.
  • certain compounds of this invention may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilised in assays (e.g. a fluorescence polarisation assay) for detecting pharmacologically active compounds.
  • the compounds in accordance with the present invention potently neutralise the activity of TNFa in a commercially available HEK-293 derived reporter cell line known as HEK-BlueTM CD40L.
  • This cell line is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a concentration-dependent manner by TNFa.
  • the compounds of the present invention When tested in the HEK-293 bioassay, the compounds of the present invention exhibit an IC 50 value of 50 ⁇ or less, generally of 20 ⁇ or less, usually of 5 ⁇ or less, typically of 1 ⁇ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC 50 figure denotes a more active compound).
  • the present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
  • E represents a covalent bond; or E represents -0-, -S-, -S(O)-, -S(0) 2 - or -N(R 4 )-; or E represents an optionally substituted straight or branched Ci_ 4 alkylene chain;
  • Q represents a covalent bond; or Q represents -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-,
  • Ci_ 6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -;
  • Y represents C 3 _ 7 cycloalkyl, aryl, C 3 _ 7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
  • Z represents hydrogen, halogen or trifluoromethyl; or Z represents Ci_ 6 alkyl, C 3 _ 7 cycloalkyl, aryl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents - ⁇ - ⁇ or -Z 1 -C(0)-Z 2 , either of which moieties may be optionally substituted by one or more substituents;
  • Z 1 represents a divalent radical derived from an aryl, C 3 _ 7 heterocycloalkyl or heteroaryl group
  • Z 2 represents aryl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkenyl or heteroaryl;
  • R 1 , R 2 and R 3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifiuoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -SF 5 , -NR b R c , -NR c COR d , -NR c C0 2 R d , -NHCONR b R c , -NR c S0 2 R e , -N(S0 2 R e ) 2 , -NHS0 2 NR b R c , -COR d , -C0 2 R d , -CONR b R c , -CON(OR a )R b or -S0 2
  • R 4 and R 5 independently represent hydrogen or Ci_ 6 alkyl
  • R a represents Ci_ 6 alkyl, aryl, aryl(Ci_ 6 )alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents;
  • R b and R c independently represent hydrogen or trifluoromethyl; or Ci_ 6 alkyl, C 3 -7 cycloalkyl, C 3 -7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_ 6 )alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
  • R b and R c when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents;
  • R d represents hydrogen; or Ci_ 6 alkyl, C 3 -7 cycloalkyl, aryl, C 3 -7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
  • R e represents Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • the present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated.
  • the present invention provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
  • the present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a
  • the present invention provides a method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
  • any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
  • Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid.
  • suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
  • solvates of the compounds of formula (I) above include within its scope solvates of the compounds of formula (I) above.
  • Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate.
  • the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
  • the present invention also includes co-crystals within its scope.
  • co-crystal is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio.
  • the preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physico chemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co- crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012).
  • pharmaceutical ingredient include Z-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide.
  • the present invention includes within its scope prodrugs of the compounds of formula (I) above.
  • prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I).
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
  • Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched Ci_ 6 alkyl groups, for example Ci_ 4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as "Ci_ 6 alkoxy", “Ci_6 alkylthio", "Ci_ 6 alkylsulphonyl” and "Ci_ 6 alkylamino" are to be construed accordingly.
  • Ci_ 4 alkylene chain refers to a divalent straight or branched alkylene chain containing 1 to 4 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.
  • Suitable C 2 _ 6 alkenyl groups include vinyl and allyl.
  • Suitable C 2 _ 6 alkynyl groups include ethynyl and propargyl.
  • Suitable C3-7 cycloalkyl groups which may comprise benzo-fused analogues thereof, include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
  • Suitable C 4 _ 7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl,
  • Suitable aryl groups include phenyl and naphthyl, preferably phenyl.
  • Suitable aryl(Ci_6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
  • C3_ 7 heterocycloalkyl refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkyl groups include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, diazepanyl, thiadiazepanyl and azocanyl.
  • Additional values include oxetanyl, dihydrobenzothienyl, isoindolinyl and isothiazolidinyl.
  • C 3 _ 7 heterocycloalkenyl refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof.
  • Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1,2,3,6-tetrahydropyridinyl.
  • Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 8-azabicyclo- [3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl and 3,9-diazabicyclo[4.2.1]nonanyl.
  • Additional values include 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 3- azabicyclo[3.2.1]octanyl and 3,6-diazabicyclo[3.2.2]nonanyl.
  • Typical heterobicycloalkenyl groups include 8-azabicyclo[3.2.1]octenyl.
  • Suitable spiroheterocycloalkyl groups include 2-oxa-6-azaspiro[3.3]heptanyl, 2- oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl and 2-oxa-7-azaspiro[3.5]- nonanyl. Additional values include 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl and 7-oxa-2-azaspiro[3.5]nonanyl.
  • Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-3 ⁇ 4]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo[4,5- £]pyridinyl, purinyl, imidazo[l,2-a]pyrimidiny
  • Additional values include thieno[2,3-c]pyrazolyl, thieno[3,4-£][l,4]dioxinyl, pyrrolo[3,4-3 ⁇ 4]pyridinyl and imidazo[2,l-3 ⁇ 4]thiazolyl.
  • halogen as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
  • each individual atom present in formula (I), or in the formulae depicted hereinafter may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred.
  • each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter may be present as a 1H, 2 H (deuterium) or 3 H (tritium) atom, preferably 1H.
  • each individual carbon atom present in formula (I), or in the formulae depicted hereinafter may be present as a 12 C, 13 C or 14 C atom, preferably 12 C.
  • the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
  • Q represents -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- or -N(R 5 )S(0) 2 -; or Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain optionally comprising one, two or three heteroatom- containing linkages independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -; Z represents C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl,
  • E, Y, R 1 , R 2 , R 3 , R 5 , Z 1 and Z 2 are as defined above.
  • the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
  • R 1 represents halogen or cyano; or Ci_ 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C 3 -7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci_6)alkyl, C 3 -7 heterocycloalkenyl, C4-9 heterobicycloalkyl, C 4 _9 heterobicyclo alkenyl, heteroaryl, heteroaryl(Ci_6)alkyl, (C 3 -7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C 3 -7)heterocycloalkyl-,
  • E, Q, Y, Z, R 2 and R 3 are as defined above.
  • the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
  • R 1 represents halogen or cyano; or Ci_ 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl, C 3 -7 cycloalkyl, C4-7 cycloalkenyl, C 3 -7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci_6)alkyl, C 3 -7 heterocycloalkenyl, C4-9 heterobicycloalkyl, heteroaryl, heteroaryl(Ci_6)alkyl, (C 3 -7)heterocycloalkyl(Ci_6)alkyl- aryl- , hetero aryl(C 3 _7)hetero cyclo alkyl- , (C 4 _7)cyclo alkenyl- hetero aryl- ,
  • E, Q, Y, Z, R 2 and R 3 are as defined above.
  • typical values thereof include methylene (-CH 2 -), (methyl)methylene, ethylene (-CH 2 CH 2 -), (ethyl)methylene, (dimethyl)- methylene, (methyl)ethylene, propylene (-CH 2 CH 2 CH 2 -), (propyl)methylene and
  • chains may be optionally substituted by one or more substituents.
  • such chains are unsubstituted, monosubstituted or disubstituted.
  • such chains are unsubstituted or monosubstituted.
  • such chains are unsubstituted.
  • such chains are monosubstituted.
  • such chains are disubstituted.
  • Examples of typical substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, oxo, hydroxy, Ci_ 6 alkoxy, trifluoromethoxy, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, carboxy, tetrazolyl, amino carbonyl, Ci_ 6 alkylamino carbonyl and di(Ci_6)alkylamino- carbonyl.
  • Suitable substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, hydroxy, Ci_6 alkoxy, amino, carboxy and tetrazolyl, especially hydroxy or Ci_ 6 alkoxy.
  • substituents on the alkylene chain which may be present in a compound in accordance with the invention include fluoro, trifluoromethyl, hydroxy, methoxy, amino, carboxy and tetrazolyl, especially hydroxy or methoxy.
  • E represents a covalent bond, whereby the integer Y is attached directly to the imidazo[l,2-a]pyrazine nucleus.
  • E represents -0-, -S-, -S(O)-, -S(0) 2 - or -N(R 4 )-.
  • E represents -0-.
  • E represents -S-.
  • E represents -S(O)-.
  • E represents -S(0) 2 -.
  • E represents -N(R 4 )-.
  • E represents an optionally substituted straight or branched Ci_4 alkylene chain.
  • E represents an optionally substituted methylene (-CH 2 -) linkage.
  • E represents an optionally substituted (methyl)methylene linkage.
  • E represents an optionally substituted (ethyl)methylene linkage.
  • E represents a covalent bond; or E represents -N(R 4 )-; or E represents an optionally substituted straight or branched Ci_ 4 alkylene chain.
  • E represents -N(R 4 )-; or E represents an optionally substituted straight or branched Ci_ 4 alkylene chain.
  • E represents a covalent bond; or E represents -N(R 4 )-; or E represents methylene (-CH 2 -), (methyl)methylene or (ethyl)methylene, any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of typical substituents on the linkage represented by E include halogen, trifluoromethyl, hydroxy, Ci_ 6 alkoxy, trifluoromethoxy, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, carboxy and tetrazolyl, especially hydroxy or Ci_ 6 alkoxy.
  • substituents on the linkage represented by E include fluoro, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, carboxy and tetrazolyl, especially hydroxy or methoxy.
  • a particular example of a typical substituent on E is hydroxy.
  • Another example of a typical substituent on E is methoxy.
  • Typical values of E include -N(R 4 )-, -CH 2 -, -CH(OH)-, -CH(CH 3 )- and
  • E may represent a covalent bond. Additional values of E include -CH(OCH 3 )- and -C(CH 3 )(OH)-.
  • Suitable values of E include -CH 2 - and -CH(OH)-. Additional values include -CH(OCH 3 )-, -CH(CH 3 )- and -C(CH 3 )(OH)-.
  • E represents -CH 2 -.
  • E represents -CH(OH)-.
  • E represents -CH(OCH 3 )-.
  • E represents -CH(CH 3 )-.
  • the -CH(CH 3 )- linkage represented by E is in the (S) stereochemical configuration.
  • E represents -C(CH 3 )(OH)-.
  • Q represents a covalent bond, whereby the integer Z is attached directly to the imidazo[l ,2-a]pyrazine nucleus.
  • Q represents -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-,
  • Q represents -0-.
  • Q represents -S-.
  • Q represents -S(O)-.
  • Q represents -S(0) 2 -.
  • Q represents -N(R 5 )-.
  • Q represents -C(0)N(R 5 )-.
  • Q represents -N(R 5 )C(0)-.
  • Q represents -S(0) 2 N(R 5 )-.
  • Q represents -N(R 5 )S(0) 2 -.
  • Q represents -N(R 5 )S(0) 2 -.
  • Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -.
  • Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain.
  • Q represents an optionally substituted straight or branched Ci_6 alkylene chain comprising one heteroatom-containing linkage independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -.
  • Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain comprising two heteroatom- containing linkages independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -.
  • Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain comprising three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0) 2 -, -N(R 5 )-, -C(0)N(R 5 )-, -N(R 5 )C(0)-, -S(0) 2 N(R 5 )- and -N(R 5 )S(0) 2 -.
  • Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -N(R 5 )-, -C(0)N(R 5 )- and -N(R 5 )C(0)-.
  • Q represents a covalent bond; or Q represents -S(0)- or -S(0) 2 -; or Q represents an optionally substituted straight or branched Ci_ 6 alkylene chain optionally comprising one or two heteroatom-containing linkages selected from -0-, -S-, -N(R 5 )-, -C(0)N(R 5 )-, and -N(R 5 )C(0)-.
  • Selected examples of typical substituents on the linkage represented by Q include halogen, trifiuoromethyl, hydroxy, Ci_ 6 alkoxy and amino.
  • substituents on the linkage represented by Q include fluoro, trifiuoromethyl, hydroxy, methoxy and amino.
  • Q represents a covalent bond; or Q represents -S(O)- or -S(0) 2 -; or Q represents -CH 2 -, -CH(F)-, -CF 2 -, -CH(CH 3 )-, -CH(OH)-, -CH(OCH 3 )-, -CH(NH 2 )-, -CH 2 CH 2 -, -CH(OH)CH 2 -, -CH(OH)CF 2 -, -CH(OCH 3 )CH 2 -, -CH 2 0-, -CH(CH 3 )0-, -C(CH 3 ) 2 0-, -CH(CH 2 CH 3 )0-, -CH(CF 3 )0-, -CH 2 S-, -CH 2 N(R 5 )-, -CH 2 CH 2 CH 2 -, -CH(OH)CH 2 CH 2 -, -CH(OCH 3 )CH 2 CH 2 -, -CH 2 CH
  • -CH 2 OCH 2 C(0)N(R 5 )- or -CH 2 OCH 2 CH 2 OCH 2 -. Additional values include -N(R 5 )-, -CH(CH 2 OH)-, -CH 2 S(0)-, -CH 2 S(0) 2 -, -CH 2 S(0)CH 2 -, -CH 2 S(0) 2 CH 2 - and
  • Q represents -CH 2 -, -CH 2 0-, -CH 2 S- and -CH 2 OCH 2 -.
  • Q represents -CH 2 -.
  • Q represents -CH 2 0-.
  • Q represents -CH 2 S-.
  • Q represents
  • Y represents C 3 _ 7 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • Y represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
  • Y represents optionally substituted C 3 _ 7 cycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C 3 _ 7 cycloalkyl. In another aspect of that embodiment, Y represents mono substituted C 3 _ 7 cycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C 3 _ 7 cycloalkyl.
  • Y represents optionally substituted aryl. In one aspect of that embodiment, Y represents unsubstituted aryl. In another aspect of that embodiment, Y represents monosubstituted aryl. In a further aspect of that embodiment, Y represents disubstituted aryl.
  • Y represents optionally substituted C 3 _ 7 heterocycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C 3 _ 7 heterocycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C 3 _ 7 heterocycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C 3 _ 7 heterocycloalkyl.
  • Y represents optionally substituted heteroaryl. In one aspect of that embodiment, Y represents unsubstituted heteroaryl. In another aspect of that embodiment, Y represents monosubstituted heteroaryl. In a further aspect of that embodiment, Y represents disubstituted heteroaryl.
  • Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
  • Y represents phenyl, which may be optionally substituted by one or more substituents.
  • optional substituents which may be present on the moiety Y include one, two or three substituents independently selected from halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulfinyl, Ci_ 6 alkylsulfonyl, amino, Ci_ 6 alkylamino, di(Ci_ 6 )alkyl- amino, arylamino, C 2 _ 6 alkylcarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, C 2 _ 6 alkylcarbonyl, C 3 -6 cycloalkylcarbonyl, C 3 -6 heterocycloalkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, amino carbonyl, Ci_ 6 alkylamino carbonyl, di(Ci_6)alky
  • Typical examples of optional substituents on the moiety Y include halogen and difluoromethoxy.
  • substituents on the moiety Y include fluoro, chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, methylamino, tert- butylamino, dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinyl- carbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, aminosulfonyl, methylaminos
  • Typical examples of particular substituents on the moiety Y include chloro and difluoromethoxy.
  • Typical values of Y include benzocyclobutenyl, phenyl, fluorophenyl (including 2-fluorophenyl, 3 -fluorophenyl and 4-fluorophenyl), chlorophenyl (including 2-chloro- phenyl, 3 -chlorophenyl and 4-chlorophenyl), difluorophenyl (including 2,6-difluoro- phenyl), (chloro)(fluoro)phenyl (including 5-chloro-2-fluorophenyl and 2-chloro-5- fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyl and 2,6-dichlorophenyl), methylphenyl (including 4-methylphenyl), dimethylphenyl (including 2,5-dimethylphenyl and 2,6-dimethylphenyl), (trifluoromethyl)phenyl [including 2-(trifluoromethyl)phenyl], (chloro)(
  • Suitable values of Y include dichlorophenyl and (difluoromethoxy)phenyl.
  • Y represents 2,5-dichlorophenyl.
  • Y represents 2-(difluoromethoxy)phenyl.
  • Z represents hydrogen
  • Z is other than hydrogen
  • Z represents hydrogen; or Z represents Ci_ 6 alkyl, C3-7 cycloalkyl, aryl, C 3 _7 heterocycloalkyl, C 3 _7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents - ⁇ - ⁇ or -Z 1 -C(0)-Z 2 , either of which moieties may be optionally substituted by one or more substituents.
  • Z represents Ci_ 6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl, C 3 _7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Z l -Z 2 or -Z 1 -C(0)-Z 2 , either of which moieties may be optionally substituted by one or more substituents.
  • Z represents hydrogen, fluoro or trifluoromethyl; or Z represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, tetrahydropyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, morpholinyl, azocanyl, thiazolinyl, furyl, thienyl, pyrazolyl, 4,5,6,7-tetrahydroindazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, [l,
  • the moiety Z 1 represents a divalent radical derived from an aryl, C 3 _ 7 heterocyclo- alkyl or heteroaryl group, any of which groups may be optionally substituted by one or more substituents.
  • the moiety Z 1 represents a divalent radical derived from a phenyl, pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl or pyridinyl group, any of which groups may be optionally substituted by one or more substituents.
  • Typical values of the moiety Z 1 include the groups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh) and (Zj):
  • moiety Z 1 includes the groups of formula (Za), (Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above.
  • the moiety Z 2 represents aryl, C 3 _ 7 heterocycloalkyl, C 3 _ 7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more
  • Z 2 represents phenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl, imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
  • Examples of optional substituents which may be present on the moiety Z, Z 1 or Z 2 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, oxo, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy, difluoro- methoxy, trifluoromethoxy, Ci_ 3 alkylenedioxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkyl, C 2 -6 alkylcarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, C 2 -6 alkylcarbonyl, carboxy, C 2 -6 alkoxycarbonyl, aminocarbonyl, Ci_ 6 alkyla
  • Typical examples of optional substituents on the moiety Z, Z 1 or Z 2 include halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, oxo, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 3 alkylenedioxy, Ci_ 6 alkylsulfonyl, amino, di(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkyl, C 2 -6 alkylcarbonylamino, Ci_ 6 alkylsulfonylamino, formyl, carboxy, C 2 -6 alkoxycarbonyl, aminocarbonyl, Ci_ 6 alkylamino- carbonyl, di(Ci_6)alkylaminocarbonyl, amino carbonylamino and hydrazino carbonyl.
  • Examples of particular substituents on the moiety Z, Z 1 or Z 2 include f uoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylenedioxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, dimethylaminomethyl, dimethylamino ethyl, acetylamino, methylsulfonyl- amino, formyl, acetyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylami
  • Typical examples of particular substituents on the moiety Z, Z 1 or Z 2 include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylenedioxy, methylsulfonyl, amino, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, acetylamino, methylsulfonylamino, formyl, carboxy, methoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminocarbonylamino and hydrazinocarbonyl.
  • Typical values of Z 2 include phenyl, hydroxyphenyl, oxopyrrolidinyl, dioxo- pyrrolidinyl, (hydroxy)(oxo)pyrrolidinyl, (amino)(oxo)pyrrolidinyl, (oxo)oxazolidinyl, oxoimidazolidinyl, morpholinyl, imidazolinyl, methylthiazolyl, formylthiazolyl, imidazolyl, tetrazolyl and pyridinyl.
  • Z 2 include oxopyrrolidinyl and (oxo)oxazolidinyl.
  • Z 2 represents oxopyrrolidinyl.
  • Z 2 represents (oxo)oxazo lidinyl.
  • Typical values of Z include hydrogen, fluoro, trifluoromethyl, methyl, ethyl, n- propyl, isopropyl, isobutyl, tert-bvXy ⁇ , cyclopropyl, cyclopentyl, cyclohexyl, oxo- cyclohexyl, phenyl, bromophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, difluoro- methoxyphenyl, trifluoromethoxyphenyl, methylenedioxyphenyl, methylsulfonylphenyl, dimethylaminophenyl, acetylaminophenyl, methylsulfonylaminophenyl, carboxyphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl, dimethylaminocarbonylphenyl, aminocarbonylaminophenyl, tetrahydro
  • oxopyrrolidinylphenyl dioxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl, (amino)(oxo)pyrrolidinylphenyl, (oxo)oxazolidinylphenyl, oxoimidazolidinylphenyl, imidazolinylphenyl, methylthiazolylphenyl, formylthiazolylphenyl, imidazolylphenyl, tetrazolylphenyl, phenylpyrrolidinyl, hydroxyphenylpiperazinyl, (methyl)(phenyl)- pyrazolyl, oxoimidazolidinylthiazolyl, hydroxyphenyltriazolyl, morpholinyltetrazolyl, oxopyrrolidinylpyridinyl, (oxo)oxazolidinylpyridin
  • Z include hydrogen, methyl, methylsulfonylphenyl, pyridinyl, oxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl.
  • Z represents hydrogen.
  • Z represents methyl.
  • Z represents methylsulfonylphenyl.
  • Z represents 3-(methylsulfonyl)phenyl.
  • Z represents pyridinyl.
  • Z represents pyridin-4-yl.
  • Z represents oxopyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxopyrrolidin-l-yl)phenyl. In a sixth embodiment, Z represents (hydroxy)(oxo)pyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(3- hydroxy-2-oxopyrrolidin-l-yl)phenyl. In another aspect of that embodiment, Z represents 3-(4-hydroxy-2-oxopyrrolidin-l-yl)phenyl. In a seventh embodiment, Z represents (oxo)oxazolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxo- oxazolidinyl-3-yl)phenyl.
  • R 1 , R 2 and R 3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifiuoromethyl, trifluoromethoxy, -OR a , -SR a , -SOR a , -S0 2 R a , -SF 5 , -NR b R c , -NR c COR d , -NR c C0 2 R d , -NHCONR b R c , -NR c S0 2 R e , -N(S0 2 R e ) 2 , -NHS0 2 NR b R c , -COR d , -C0 2 R d , -CONR b R c , -CON(OR a )R b or -S0 2 NR b R c ; or Ci_ 6 alkyl, C 2 _ 6 alkenyl, C 2 _6 alkynyl,
  • heterocycloalkenyl C 4 _9 heterobicycloalkyl, heteroaryl, heteroaryl(Ci_6)alkyl,
  • R 1 , R 2 and R 3 independently represent hydrogen, halogen, cyano or -C0 2 R d ; or Ci_6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, heteroaryl, (C 3 -7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C 3 -7)heterocycloalkyl-,
  • R 1 , R 2 and R 3 may independently represent C 4 _9 heterobicycloalkenyl or (C 3 _7)cycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
  • R 1 , R 2 or R 3 examples include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_ 6 )- alkyl, nitro, Ci_ 6 alkyl, trifluoromethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_ 3 alkylenedioxy, Ci_ 6 alkoxy(Ci_ 6 )- alkyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N-
  • Additional examples include halo(Ci_6)alkyl, difluoromethyl, difluoro ethyl, hydroxy(Ci_6)alkyl, Ci_ 6 alkylsulphinyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkylamino,
  • R 1 , R 2 or R 3 may be substituted by a carboxylic acid isostere or prodrug moiety.
  • carboxylic acid isostere or prodrug moiety is meant any functional group, structurally distinct from a carboxylic acid moiety, that will be recognised by a biological system as being similar to, and thus capable of mimicking, a carboxylic acid moiety, or will be readily convertible by a biological system in vivo into a carboxylic acid moiety.
  • a synopsis of some common carboxylic acid isosteres is presented by N.A. Meanwell in J. Med. Chem., 2011, 54, 2529-2591 (cf. in particular Figures 25 and 26).
  • suitable carboxylic acid isostere or prodrug moieties include the functional groups of formula (i) to (xli):
  • asterisk (*) represents the site of attachment to the remainder of the molecule; n is zero, 1 or 2;
  • X represents oxygen or sulphur
  • R f represents hydrogen, Ci_ 6 alkyl or -CH 2 CH(OH)CH 2 OH;
  • R g represents Ci_ 6 alkyl, trifluoromethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CF 3 ;
  • R h represents hydrogen, cyano or -C0 2 R d , in which R d is as defined above; and R represents hydrogen or halogen.
  • n is zero. In another embodiment, n is 1. In a further embodiment, n is 2.
  • X represents oxygen. In another embodiment, X represents sulphur.
  • R f represents hydrogen. In another embodiment, R f represents Ci_6 alkyl, especially methyl. In a further embodiment, R is -CH 2 CH(OH)CH 2 OH.
  • R g represents Ci_ 6 alkyl, especially methyl.
  • R g represents trifluoromethyl, -CH 2 CH 2 F, -CH 2 CHF 2 , -CH 2 CF 3 or -CF 2 CF 3 .
  • R g represents trifluoromethyl.
  • R g represents -CH 2 CH 2 F.
  • R g represents -CH 2 CHF 2 .
  • R g represents -CH 2 CF 3 .
  • R g represents -CF 2 CF 3 .
  • R h is hydrogen. In another embodiment, R h represents cyano.
  • R h represents -C0 2 R d , especially methoxycarbonyl.
  • R represents hydrogen. In another embodiment, R represents halogen, especially chloro.
  • ⁇ represents tetrazolyl, especially a C-linked tetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, in particular a group of formula (xxiv) as depicted above.
  • ⁇ represents Ci_ 6 alkylsulphonylaminocarbonyl, i.e. a moiety of formula (iii) as depicted above wherein R g represents Ci_ 6 alkyl.
  • ⁇ represents Ci_ 6 alkylaminosulphonyl, i.e. a moiety of formula (x) as depicted above wherein R g represents Ci_ 6 alkyl.
  • ⁇ represents (Ci_6)alkylcarbonylaminosulphonyl, i.e. a moiety of formula (v) as depicted above wherein R g represents Ci_ 6 alkyl.
  • Suitable carboxylic acid isostere or prodrug moieties represented by ⁇ include the functional group of formula (xlii):
  • the asterisk (*) represents the site of attachment to the remainder of the molecule.
  • Suitable examples of optional substituents which may be present on R 1 , R 2 or R 3 include one, two or three substituents independently selected from halogen, cyano, Ci_ 6 alkyl, hydroxy, Ci_ 6 alkoxy, Ci_ 6 alkylsulphonyl, oxo, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl and amino sulphonyl. Additional examples include hydroxy(Ci_6)alkyl, (C3-7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
  • R 1 , R 2 or R 3 examples include fluoro, chloro, bromo, cyano, cyano ethyl, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, methyl- sulphonylethyl, oxo, amino, methylamino, dimethylamino, methoxyethylamino, N- (hydroxyethyl)-N-(methyl)amino, acetylamino, methoxy carbonylamino, ethoxycarbonyl- amino, ethylamino carbonylamino, butylamino carbon
  • Additional examples include isopropyl, isobutyl, difluoromethyl, difluoro ethyl, hydroxymethyl, hydro xyethyl, hydro xyisopropyl, methoxyethyl, methylsulphinyl, ethylamino,
  • hydroxy ethylamino hydroxypropylamino, (hydroxy)(methyl)propylamino, (hydroxy)- (methoxy)(methyl)propylamino, (hydroxy)(methylthio)butylamino, dimethylaminoethyl- amino, (dimethylamino)(methyl)propylamino, N-(dimethylaminoethyl)-N-(hydroxyethyl)- amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)- (hydroxy)propylamino, tetrahydrofuranylamino, morpholinylethylamino, oxopyrrolidinyl- methylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethylamino, methylpyr
  • Suitable examples of particular substituents on R 1 , R 2 or R 3 include fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl, tert-butoxycarbonyl and amino sulphonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranylamino, tetrazolylmethyl and aminocarbonylmethyl.
  • R 1 represents hydrogen, halogen, cyano or -C0 2 R d ; or Ci_ 6 alkyl, aryl, C 3 _7 heterocycloalkyl, C 3 _7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl- (Ci_6)alkyl-aryl-, heteroaryl(C 3 _7)heterocycloalkyl-, (C 4 _7)cycloalkenyl-heteroaryl-, (C 3 _7)heterocycloalkyl-heteroaryl-, (C 3 _7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-,
  • R 1 may represent (C 4 -9)- heterobicycloalkenyl- or (C 3 _7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen, cyano or -C0 2 R d ; or Ci_ 6 alkyl, aryl, C3-7 heterocycloalkyl, C 3 _7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C 3 _7)heterocycloalkyl-, (C 4 _7)cycloalkenyl-heteroaryl-,
  • R 1 may represent (C 4 -9)- heterobicycloalkenyl- or (C 3 _7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen or cyano; or Ci_ 6 alkyl, aryl, C3-7
  • heterocycloalkyl C 3 _7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl- aryl- , hetero aryl(C 3 _7)hetero cyclo alkyl- , (C 4 _7)cyclo alkeny 1-hetero aryl- ,
  • R 1 may represent (C 4 -9)- heterobicycloalkenyl- or (C 3 _7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen or cyano; or Ci_ 6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C 3 _7)heterocycloalkyl-, (C 3 _7)heterocycloalkyl-heteroaryl-,
  • R 1 may represent (C 4 -9)- heterobicycloalkenyl- or (C 3 _7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
  • R 1 represents halogen; or aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, (C 4 _9)heterobicycloalkenyl-, heteroaryl, (C 3 _7)cycloalkyl- heteroaryl-, (C 3 _7)heterocycloalkyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl- or (C 4- c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents heteroaryl or (C 3 _7)heterocycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R 1 may represent aryl, C 3 -7 heterocycloalkyl, C 3 -7
  • R 1 may represent halogen.
  • R 1 represents hydrogen
  • R 1 represents halogen. In one aspect of that embodiment, R 1 represents bromo.
  • R 1 represents cyano
  • R 1 represents -C0 2 R d .
  • R 1 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 1 represents optionally substituted ethyl.
  • R 1 represents optionally substituted aryl. In one aspect of that embodiment, R 1 represents optionally substituted phenyl. In a seventh embodiment, R 1 represents optionally substituted C3-7
  • R 1 represents optionally substituted piperidinyl.
  • R 1 represents optionally substituted C3-7
  • R 1 represents optionally substituted dihydropyranyl. In a second aspect of that embodiment, R 1 represents optionally substituted dihydrothiopyranyl. In a third aspect of that embodiment, R 1 represents optionally substituted 1,2,3,6-tetrahydropyridinyl.
  • R 1 represents optionally substituted (C 4- c>)- heterobicycloalkenyl-. In one aspect of that embodiment, R 1 represents optionally substituted 8-azabicyclo[3.2.1 Joctenyl.
  • R 1 represents optionally substituted heteroaryl.
  • R 1 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-aryl-.
  • R 1 represents optionally substituted pyrrolidinylmethylphenyl-.
  • R 1 represents optionally substituted piperazinylmethylphenyl-.
  • R 1 represents optionally substituted heteroaryl(C3_7)- heterocycloalkyl-. In one aspect of that embodiment, R 1 represents optionally substituted pyridinylpiperazinyl- .
  • R 1 represents optionally substituted (C 3 _7)cycloalkyl- heteroaryl-. In one aspect of that embodiment, R 1 represents optionally substituted cyclohexylpyrimidinyl-.
  • R 1 represents optionally substituted (C 4-7 )- cycloalkenyl-heteroaryl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl- heteroaryl-.
  • R 1 represents optionally substituted morpholinylthiazolyl-.
  • R 1 represents optionally substituted pyrrolidinylpyridinyl-.
  • R 1 represents optionally substituted piperidinylpyridinyl-.
  • R 1 represents optionally substituted piperazinylpyridinyl-.
  • R 1 represents optionally substituted morpholinylpyridinyl-.
  • R 1 represents optionally substituted thiomorpholinyl- pyridinyl-. In a seventh aspect of that embodiment, R 1 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R 1 represents optionally substituted pyrrolidinylpyrimidinyl-. In a ninth aspect of that embodiment, R 1 represents optionally substituted piperidinylpyrimidinyl-. In a tenth aspect of that embodiment, R 1 represents optionally substituted piperazinylpyrimidinyl-. In an eleventh aspect of that embodiment, R 1 represents optionally substituted morpholinylpyrimidinyl-.
  • R 1 represents optionally substituted thiomorpholinyl- pyrimidinyl-. In a thirteenth aspect of that embodiment, R 1 represents optionally substituted diazepanylpyrimidinyl-. In a fourteenth aspect of that embodiment, R 1 represents optionally substituted thiadiazepanylpyrimidinyl-.
  • R 1 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-heteroaryl-.
  • R 1 represents optionally substituted morpholinylmethylthienyl-.
  • R 1 represents optionally substituted morpholinylethylpyrazolyl-.
  • R 1 represents optionally substituted (C 3-7 )- hetero cyclo alkeny 1-hetero aryl- .
  • R 1 represents optionally substituted (C4-9)- heterobicycloalkyl-heteroaryl-.
  • R 1 represents optionally substituted (C 4- c>)- spiroheterocycloalkyl-heteroaryl-.
  • R 1 represents hydrogen, bromo, cyano or -C0 2 R d ; or ethyl, phenyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzoiuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinyl- piperazinyl, pyrrolidinylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,
  • R 1 may represent chloro, trifluoromethyl, -OR a , -S0 2 R a or -CONR b R c ; or methyl, dihydropyranyl, dihydrothiopyranyl, 8-azabicyclo[3.2.1]octenyl, dihydrothieno [3,4- ?][l ,4] dioxinyl, dihydropyrrolo [3 ,4-£]pyridinyl, imidazolylmethyl, triazolylmethyl, pyridinylmethyl, morpholinylmethylphenyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexenyl- pyrimidinyl, morpholinylthiazolyl, azetidinylpyridinyl, isothiazolidinylpyridinyl
  • R 1 represents bromo; or phenyl, piperidinyl, dihydropyranyl, dihydrothiopyranyl, 1 ,2,3,6-tetrahydropyridinyl, 8-azabicyclo[3.2.1]octenyl, indolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclohexylpyrimidinyl, morpholinylthiazolyl, piperidinylpyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, pyrrolidinylpyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, diazepanyl- pyrimidinyl, 3 -azabicyclo [3.1.0]hexanylpyrimidinyl, 3 -azabicyclo [4.1.0]heptanyl- pyr
  • R 1 represents pyridinyl, piperazinylpyrimidinyl or diazepanyl- pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_ 6 )alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoro ethyl, C 2 - 6 alkenyl, hydroxy, Ci_ 6 alkoxy, trifluoroethoxy, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, di(Ci_6)alkylamino,
  • Additional examples include halo(Ci_6)alkyl, difluoromethyl, difluoroethyl, hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylsulphinyl, amino(Ci_6)- alkyl, Ci_ 6 alkylamino, hydroxy(Ci_6)alkylamino, [(Ci_6)alkoxy](hydroxy)(Ci_6)alkylamino, [(C i _ 6 )alkylthio] (hydro xy)(C i _ 6 )alkylamino , di(C i _ 6 )alkylamino(C i _ 6 )alkylamino , N- [di(C i _ 6 )alkylamino(C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , hydro x
  • alkoxycarbonyl(C 1 _ 6 )alkylamino N- [(C 1 _6)alkyl] -N- [(C 1 _6)alkylsulphonyl] amino , (C 1 _ 6 )- alkylsulphonylamino(Ci_6)alkyl, formyl, (C 3 -7)cycloalkylcarbonyl, phenylcarbonyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl, Ci_ 6 alkylamino carbonyl, hydro xy(Ci _ 6 )- alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl and amino sulphonyl.
  • R 1 Selected examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, cyano, Ci_ 6 alkyl, hydroxy, Ci_ 6 alkoxy, Ci_6 alkylsulphonyl, oxo, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl and C 2 _ 6 alkoxy- carbonyl. Additional examples include hydroxy(Ci_6)alkyl, (C 3 _7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl and aminosulphonyl.
  • Suitable examples of optional substituents on R 1 include one, two or three substituents independently selected from Ci_ 6 alkoxy and oxo.
  • substituents on R 1 include one, two or three substituents independently selected from fluoro, chloro, cyano, cyanoethyl, methyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, trifluoroethoxy, methylsulphonyl, methylsulphonylethyl, oxo, amino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, methylsulphonylamino, acetyl, carboxy, carboxy- methyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, tetrazolyl, aminocarbonyl and methylsulphonyl- aminocarbonyl.
  • Additional examples include ethyl, isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methoxymethyl, methoxy- ethyl, methylsulphinyl, ethylamino, hydroxyethylamino, hydroxypropylamino, (hydroxy)- (methyl)propylamino, (hydroxy)(methoxy)(methyl)propylamino, (hydroxy)(methylthio)- butylamino, dimethylaminoethylamino, (dimethylamino)(methyl)propylamino, N- (dimethylaminoethyl)-N-(hydroxyethyl)amino, hydro xymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)(hydroxy)propylamino, tetrahydrofurany
  • Selected examples of particular substituents on R 1 include one, two or three substituents independently selected from fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl and tert-butoxycarbonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranyl- amino, tetrazolylmethyl, aminocarbonylmethyl and aminosulphonyl.
  • Suitable examples of particular substituents on R 1 include one, two or three substituents independently selected from methoxy and oxo.
  • R 1 include hydrogen, bromo, cyano, -C0 2 R d , methoxycarbonyl- ethyl, ethoxycarbonylethyl, chlorophenyl, hydro xyphenyl, acetylphenyl, amino carbonyl- phenyl, oxopiperidinyl, methylsulphonylpiperazinyl, morpholinyl, tert-butoxycarbonyl- 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, methylindazolyl, dimethylisoxazolyl, methylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl, methylpyridinyl, (cyano)(methyl)pyridinyl, dimethyl- pyridinyl, chlor
  • oxopyrimidinyl aminopyrimidinyl, dimethylaminopyrimidinyl, methoxyethylamino- pyrimidinyl, hydroxypyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, pyrrolidinylpyridinyl, hydroxypyrrolidinylpyridinyl, piperidinyl- pyridinyl, acetylpiperidinylpyridinyl, piperazinylpyridinyl, (methyl)(piperazinyl)- pyridinyl, cyanoethylpiperazinylpyridinyl, trifluoroethylpiperazinylpyridinyl,
  • Additional values include chloro, trifluoromethyl, -OR a , -S0 2 R a , -CONR b R c , N-isopropyl- carbonyl-N-methylaminomethyl, N-cyclopropylcarbonyl-N-methylaminomethyl, methylsulphinylphenyl, methylsulphonylphenyl, (methyl)(methylsulphonyl)phenyl, ethenylcarbonylaminophenyl, tert-butoxycarbonylaminophenyl, phenylcarbonylphenyl, aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, isopropyl- carbonylpiperidinyl, cyclobutylcarbonylpiperidinyl, methoxycarbonylpiperidinyl, tert- butoxycarbonylpiperidinyl, dihydropyranyl
  • R 1 Definitive values of R 1 include bromo, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, methylpyrazolyl, cyanopyridinyl, methoxypyridinyl, oxopyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, carboxypiperidinylpyrimidinyl, piperazinyl- pyrimidinyl, methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl, oxodiazepanylpyrimidinyl and 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl.
  • Additional values include aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1 ,2,3 ,6-tetrahydropyridinyl, methylsulphonyl-8- azabicyclo[3.2.1 Joctenyl, tert-butoxycarbonyl-8-azabicyclo[3.2.1 Joctenyl, oxoindolyl, hydroxyisopropylpyrimidinyl, tetrahydrofuranylaminopyrimidinyl, carboxycyclohexyl- pyrimidinyl, morpholinylthiazolyl, carboxypiperidinylpyridinyl, (carboxy)(
  • R 1 examples include methoxypyridinyl, oxopyridinyl,
  • R 2 represents hydrogen, halogen or optionally substituted Ci_ 6 alkyl.
  • Typical examples of optional substituents on R 2 include C 2 _ 6 alkoxycarbonyl.
  • Typical examples of particular substituents on R 2 include ethoxycarbonyl.
  • R 2 represents hydrogen. In a second embodiment, R 2 represents halogen. In one aspect of that embodiment, R 2 represents fluoro. In a third embodiment, R 2 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 2 represents mono substituted methyl or mono substituted ethyl.
  • R 2 include hydrogen, fluoro and ethoxycarbonylethyl.
  • R 3 represents hydrogen
  • R 4 represents hydrogen or methyl.
  • R 4 represents hydrogen. In a second embodiment, R 4 represents Ci_ 6 alkyl, especially methyl.
  • R 5 represents hydrogen, methyl or ethyl.
  • R 5 represents hydrogen.
  • R 5 represents Ci_ 6 alkyl, especially methyl or ethyl.
  • R 5 represents methyl.
  • R 5 represents ethyl.
  • Suitable substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_ 6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, hydroxy, hydroxy(Ci_6)alkyl, amino(Ci_6)alkyl, cyano, trifluoromethyl, oxo, C 2 _6 alkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkylcarbonyloxy, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, phenylamino, pyridinylamino, C 2 _ 6
  • Typical examples of specific substituents on R a , R b , R c , R d or R e , or on the heterocyclic moiety -NR b R c include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydro xymethyl, hydro xyethyl, amino methyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl,
  • R a represents Ci_ 6 alkyl, aryl(Ci_ 6 )alkyl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected values of R a include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R a Selected examples of suitable substituents on R a include Ci_ 6 alkoxy and oxo.
  • R a Selected examples of specific substituents on R a include methoxy and oxo.
  • R a represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R a ideally represents unsubstituted Ci_ 6 alkyl, especially methyl. In another aspect of that embodiment, R a ideally represents substituted Ci_ 6 alkyl, e.g.
  • R a represents optionally substituted aryl.
  • R a represents unsubstituted aryl, especially phenyl.
  • R a represents monosubstituted aryl, especially methylphenyl.
  • R a represents optionally substituted aryl(Ci_6)alkyl, ideally unsubstituted aryl(Ci_6)alkyl, especially benzyl.
  • R a represents optionally substituted heteroaryl.
  • R a represents optionally substituted heteroaryl(Ci_6)alkyl, e.g. dioxoisoindolylpropyl.
  • R a examples include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.
  • R b represents hydrogen or trifluoromethyl; or Ci_ 6 alkyl, C 3 -7 cycloalkyl, C 3 -7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or Ci_ 6 alkyl, aryl(Ci_ 6 )alkyl, C 3 -7 heterocycloalkyl or C 3 -7 heterocycloalkyl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
  • R b examples include hydrogen and Ci_ 6 alkyl.
  • R b represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl,
  • pyrrolidinylpropyl thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
  • R b include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
  • R b Selected examples of suitable substituents on R b include Ci_ 6 alkoxy, Ci_ 6 alkylthio, Ci_6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, hydroxy, cyano, C 2 _ 6 alkoxycarbonyl, di- (Ci_6)alkylamino and C 2 _ 6 alkoxy carbonylamino.
  • R b Selected examples of specific substituents on R b include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxy carbonylamino.
  • R b include hydrogen, methyl, methoxyethyl, methylthio ethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino - ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
  • R b represents hydrogen. In another embodiment, R b represents Ci_ 6 alkyl, especially methyl.
  • R c include hydrogen; or Ci_ 6 alkyl, C 3 -7 cycloalkyl or C 3 -7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R c represents hydrogen, Ci_ 6 alkyl or C 3 -7 cycloalkyl.
  • Representative values of R c include hydrogen; or methyl, eye lo butyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
  • R c Selected examples of suitable substituents on R c include C 2 _ 6 alkylcarbonyl and C 2 _6 alkoxycarbonyl.
  • R c Selected examples of specific substituents on R c include acetyl and tert- butoxycarbonyl.
  • R c include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
  • R c represents hydrogen or Ci_ 6 alkyl. In one embodiment, R c is hydrogen.
  • R c represents Ci_ 6 alkyl, especially methyl or ethyl, particularly methyl.
  • R c represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
  • the moiety -NR b R c may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin- l-yl, homopiperidin-l-yl,
  • homomorpholin-4-yl or homopiperazin-l-yl any of which groups may be optionally substituted by one or more substituents.
  • Selected examples of suitable substituents on the heterocyclic moiety -NR b R c include Ci_ 6 alkyl, Ci_ 6 alkylsulphonyl, hydroxy, hydroxy(Ci_ 6 )alkyl, amino(Ci_6)alkyl, cyano, oxo, C 2 _ 6 alkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, amino, C 2 _ 6 alkylcarbonyl- amino, C 2 _ 6 alkylcarbonylamino(Ci_6)alkyl, C 2 _ 6 alkoxycarbonylamino, Ci_ 6 alkyl- sulphonylamino and aminocarbonyl.
  • Selected examples of specific substituents on the heterocyclic moiety -NR b R c include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
  • R c Specific values of the moiety -NR b R c include azetidin-l-yl, hydroxyazetidin-l-yl, hydro xymethylazetidin- 1 -yl, (hydro xy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin-l-yl, cyano azetidin-l-yl, carboxyazetidin- l-yl, amino azetidin-l-yl,
  • R d represents hydrogen; or Ci_ 6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
  • R d examples include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
  • R d Selected examples of suitable substituents on R d include halogen, Ci_ 6 alkyl, Ci_ 6 alkoxy, oxo, C 2 _ 6 alkylcarbonyloxy and di(Ci_6)alkylamino.
  • R d Selected examples of particular substituents on R d include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
  • R d represents hydrogen. In another embodiment, R d represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R d ideally represents unsubstituted Ci_ 6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, R d ideally represents substituted Ci_ 6 alkyl, e.g. substituted methyl or substituted ethyl, including
  • R d represents optionally substituted aryl.
  • R d represents unsubstituted aryl, especially phenyl.
  • R d represents monosubstituted aryl, especially methylphenyl.
  • R d represents disubstituted aryl, e.g. dimethoxyphenyl.
  • R d represents optionally substituted heteroaryl, e.g. thienyl, chloro thienyl, methylthienyl, methylimidazolyl or thiazolyl.
  • R d represents optionally substituted C3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl.
  • R d represents optionally substituted C3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.
  • R d selected examples include hydrogen, methyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
  • R e represents Ci_ 6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
  • R e Selected examples of suitable substituents on R e include Ci_ 6 alkyl, especially methyl.
  • R e represents optionally substituted Ci_ 6 alkyl, ideally unsubstituted Ci_ 6 alkyl, e.g. methyl or propyl, especially methyl.
  • R e represents optionally substituted aryl.
  • R e represents unsubstituted aryl, especially phenyl.
  • R e represents monosubstituted aryl, especially methylphenyl.
  • R e represents optionally substituted heteroaryl.
  • Selected values of R e include methyl, propyl and methylphenyl.
  • One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • R 1 1 represents halogen or cyano; or Ci_ 6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, (C 4 _9)heterobicycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)- alkyl-aryl-, heteroaryl-(C 3 _7)heterocycloalkyl-, (C 3 _7)cycloalkyl-heteroaryl-,
  • R 15 and R 16 independently represent hydrogen, halogen, cyano, nitro, Ci_ 6 alkyl, trifluoromethyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_ 6 alkylthio, Ci_6 alkylsulfmyl, Ci_ 6 alkylsulfonyl, amino, Ci_ 6
  • R 1 1 represents halogen or cyano; or Ci_ 6 alkyl, aryl, C 3 -7
  • heterocycloalkyl C 3 -7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl-(C 3 -7)heterocycloalkyl-, (C 4 -7)cycloalkenyl-heteroaryl-, (C 3-7 )- heterocycloalkyl-heteroaryl-, (C 3 -7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C 3-7 )- heterocycloalkenyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl- or (C 4- c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 1 1 represents halogen or cyano; or Ci_ 6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 _7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl- (C 3 _7)heterocycloalkyl-, (C 3 _7)heterocycloalkyl-heteroaryl-, (C 3 _7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl- or (C 4 _9)spiroheterocyclo- alkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R 1 1 may represent (C 4 -9)heterobicycloalkenyl- or (C 3-7 )- cycl
  • R 11 examples include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, nitro, Ci_ 6 alkyl, trifluoromethyl, trifluoro ethyl, C 2 _ 6 alkenyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_3 alkylenedioxy, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylthio, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, Ci_ 6 alkylamino, di(C 1 _ 6 )alkylamino , (C 1 _6)alkoxy(C 1 _ 6 )alkylamino , N- [(C 1 _6)alkyl] -N- [
  • Additional examples include difluoromethyl, difluoroethyl, hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkylsulphinyl, hydroxy(C i _ 6 )alkylamino, [(C i _ 6 )alkoxy](hydroxy)(C i _ 6 )alkylamino, [(C i _ 6 )alkylthio] - (hydroxy)(C i _6)alkylamino, di(C i _6)alkylamino(C i _6)alkylamino, N- [di(C i _6)alkylamino- (C i _6)alkyl] -N- [hydroxy(C i _ 6 )alkyl] amino, hydroxy(C i _6)alkyl(C3_7)cyclo alkylamino , (hydroxy) [(C3-7)cycloalkyl(C i _6)alkyl] amino
  • Suitable examples of optional substituents which may be present on R 11 include one, two or three substituents independently selected from halogen, cyano, Ci_ 6 alkyl, hydroxy, Ci_ 6 alkoxy, Ci_ 6 alkylsulphonyl, oxo, C 2 _6 alkylcarbonyl, carboxy, carboxy(Ci_ 6 )- alkyl, C 2 - 6 alkoxycarbonyl and aminosulphonyl. Additional examples include hydroxy- (Ci_6)alkyl, (C3_7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)- alkyl.
  • R 11 examples include fiuoro, chloro, bromo, cyano, cyanoethyl, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, trifiuoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, difiuoromethoxy, trifluoromethoxy, trifiuoroethoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, methyl- sulphonylethyl, oxo, amino, methylamino, dimethylamino, methoxy ethylamino, N- (hydroxyethyl)-N-(methyl)amino, acetylamino, methoxy carbonylamino, ethoxycarbonyl- amino, ethylamino carbonylamino, butylamino
  • Additional examples include isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydro xyethyl, hydro xyisopropyl, methoxyethyl, methylsulphinyl, ethylamino,
  • hydroxy ethylamino hydroxypropylamino, (hydroxy)(methyl)propylamino, (hydroxy)- (methoxy)(methyl)propylamino, (hydroxy)(methylthio)butylamino, dimethylaminoethyl- amino, (dimethylamino)(methyl)propylamino, N-(dimethylaminoethyl)-N-(hydroxyethyl)- amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)- (hydroxy)propylamino, tetrahydrofuranylamino, morpholinylethylamino, oxopyrrolidinyl- methylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethylamino, methylpyr
  • Suitable examples of particular substituents on R 11 include fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl, tert-butoxycarbonyl and amino sulphonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranylamino, tetrazolylmethyl and aminocarbonylmethyl.
  • R 11 represents Ci_ 6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7
  • R 11 may represent (C 4 _9)heterobicycloalkenyl- or (C 3 _7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R 11 may represent halogen.
  • R 11 represents Ci_ 6 alkyl, aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, heteroaryl, (C 3 _7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl- (C 3 _7)heterocycloalkyl-, (C 3 _7)heterocycloalkyl-heteroaryl-, (C 3 _7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl- or (C 4 _9)spirohetero- cycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 11 may represent (C 4 -9)heterobicycloalkenyl- or (C 3-7 )- cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R 11 may represent halogen.
  • R 11 represents halogen; or aryl, C 3 -7 heterocycloalkyl, C 3 -7 heterocycloalkenyl, (C 4 _9)heterobicycloalkenyl-, heteroaryl, (C 3 _7)cycloalkyl-heteroaryl-, (C 3 _7)heterocycloalkyl-heteroaryl-, (C 4 _9)heterobicycloalkyl-heteroaryl- or (C 4- c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
  • R 11 represents heteroaryl or (C 3 _7)heterocycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R 11 may represent aryl, C 3 -7 heterocycloalkyl, C 3 -7
  • R 11 may represent halogen.
  • R 11 represents halogen. In one aspect of that embodiment, R 11 represents bromo.
  • R 11 represents cyano
  • R 11 represents optionally substituted Ci_ 6 alkyl. In one aspect of that embodiment, R 11 represents optionally substituted ethyl.
  • R 11 represents optionally substituted aryl. In one aspect of that embodiment, R 11 represents optionally substituted phenyl.
  • R 11 represents optionally substituted C 3 _7 heterocycloalkyl. In one aspect of that embodiment, R 11 represents optionally substituted piperidinyl.
  • R 11 represents optionally substituted C 3 -7
  • R 11 represents optionally substituted dihydropyranyl. In a second aspect of that embodiment, R 11 represents optionally substituted dihydrothiopyranyl. In a third aspect of that embodiment, R 11 represents optionally substituted 1,2,3,6-tetrahydropyridinyl.
  • R 11 represents optionally substituted (C 4 -9)- heterobicycloalkenyl-. In one aspect of that embodiment, R 11 represents optionally substituted 8-azabicyclo[3.2. ljoctenyl.
  • R 11 represents optionally substituted heteroaryl.
  • R 11 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
  • R 11 represents optionally substituted
  • R 11 represents optionally substituted pyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R 11 represents optionally substituted piperazinylmethylphenyl-.
  • R 11 represents optionally substituted heteroaryl(C 3 _7)- heterocycloalkyl-. In one aspect of that embodiment, R 11 represents optionally substituted pyridinyl-piperazinyl- .
  • R 11 represents optionally substituted (C 3 _7)cycloalkyl- heteroaryl-. In one aspect of that embodiment, R 11 represents optionally substituted cyclohexylpyrimidinyl-.
  • R 11 represents optionally substituted
  • R 11 represents optionally substituted (C 3-7 )- heterocycloalkyl-heteroaryl-.
  • R 11 represents optionally substituted morpholinylthiazolyl-.
  • R 11 represents optionally substituted pyrrolidinylpyridinyl-.
  • R 11 represents optionally substituted piperidinylpyridinyl-.
  • R 11 represents optionally substituted piperazinylpyridinyl-.
  • R 11 represents optionally substituted morpholinyl- pyridinyl-.
  • R 11 represents optionally substituted thiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R 11 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R 11 represents optionally substituted pyrrolidinylpyrimidinyl-. In a ninth aspect of that embodiment, R 11 represents optionally substituted piperidinylpyrimidinyl-. In a tenth aspect of that embodiment, R 11 represents optionally substituted piperazinylpyrimidinyl-. In an eleventh aspect of that embodiment, R 11 represents optionally substituted morpholinylpyrimidinyl-.
  • R 11 represents optionally substituted thiomorpholinylpyrimidinyl-. In a thirteenth aspect of that embodiment, R 11 represents optionally substituted diazepanylpyrimidinyl-. In a fourteenth aspect of that embodiment, R 11 represents optionally substituted
  • R 11 represents optionally substituted (C 3-7 )- heterocycloalkyl(Ci_6)alkyl-heteroaryl-.
  • R 11 represents optionally substituted morpholinylmethylthienyl-.
  • R 11 represents optionally substituted morpholinylethylpyrazolyl-.
  • R 11 represents optionally substituted (C 3-7 )- hetero cyclo alkeny 1-hetero aryl- .
  • R 11 represents optionally substituted (C 4 -9)- heterobicycloalkyl-heteroaryl- .
  • R 11 represents optionally substituted (C 4 -9)- spiroheterocycloalkyl-heteroaryl-.
  • R 11 represents bromo or cyano; or ethyl, phenyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinyl- piperazinyl, pyrrolidinylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,
  • R 11 may represent chloro, trifluoromethyl, -OR a , -S0 2 R a or -CONR b R c ; or methyl, dihydropyranyl, dihydrothiopyranyl, 8-azabicyclo[3.2.1]octenyl, dihydrothieno [3,4- ?][l ,4] dioxinyl, dihydropyrrolo [3 ,4-£]pyridinyl, imidazo lylmethyl, triazolylmethyl, pyridinylmethyl, morpholinylmethylphenyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexenyl- pyrimidinyl, morpholinylthiazolyl, azetidinylpyridinyl, isothiazolidinylpyridin
  • R 1 1 represents bromo; or phenyl, piperidinyl, dihydropyranyl, dihydrothiopyranyl, 1 ,2,3,6-tetrahydropyridinyl, 8-azabicyclo[3.2.1]octenyl, indolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclohexylpyrimidinyl, morpholinylthiazolyl, piperidinylpyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, pyrrolidinylpyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, diazepanyl- pyrimidinyl, 3 -azabicyclo [3.1.0]hexanylpyrimidinyl, 3 -azabicyclo [4.1.0]heptanyl-
  • R 1 1 represents pyridinyl, piperazinylpyrimidinyl or diazepanyl- pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
  • Typical examples of optional substituents on R 1 1 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoro ethyl, C 2 _ 6 alkenyl, hydroxy, Ci_ 6 alkoxy, trifluoroethoxy, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, di(Ci_6)alkylamino,
  • Additional examples include difluoromethyl, difluoro ethyl, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy(Ci_6)alkyl, Ci_ 6 alkylsulphinyl, Ci_ 6 alkylamino, hydro xy(C i _ 6 )alkylamino , [(C i _6)alkoxy] (hydro xy)(C i _ 6 )alkylamino , [(C i _ 6 )alkylthio] - (hydroxy)(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkylamino, N-[di(Ci_6)alkylamino- (C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , hydro xy(C i _6)alkyl(C 3 -7)cyclo alkylamino
  • R 1 Selected examples of optional substituents on R 1 include one, two or three substituents independently selected from halogen, cyano, Ci_ 6 alkyl, hydroxy, Ci_ 6 alkoxy, Ci_6 alkylsulphonyl, oxo, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl and C 2 _ 6 alkoxy- carbonyl. Additional examples include hydroxy(Ci_6)alkyl, (C 3 _7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl and aminosulphonyl.
  • Suitable examples of optional substituents on R 1 1 include one, two or three substituents independently selected from Ci_ 6 alkoxy and oxo.
  • substituents on R 1 1 include one, two or three substituents independently selected from fluoro, chloro, cyano, cyanoethyl, methyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, trifluoroethoxy, methylsulphonyl, methylsulphonylethyl, oxo, amino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, methylsulphonylamino, acetyl, carboxy, carboxy- methyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, tetrazolyl, aminocarbonyl and methylsulphonyl- aminocarbonyl.
  • Additional examples include ethyl, isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methoxymethyl, methoxy- ethyl, methylsulphinyl, ethylamino, hydroxyethylamino, hydroxypropylamino, (hydroxy)- (methyl)propylamino, (hydroxy)(methoxy)(methyl)propylamino, (hydroxy)(methylthio)- butylamino, dimethylaminoethylamino, (dimethylamino)(methyl)propylamino, N- (dimethylaminoethyl)-N-(hydroxyethyl)amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)(hydroxy)propylamino, tetrahydrofuranyl-
  • Selected examples of particular substituents on R 11 include one, two or three substituents independently selected from fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl and tert-butoxycarbonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranyl- amino, tetrazolylmethyl, amino carbonylmethyl and aminosulphonyl.
  • Suitable examples of particular substituents on R 11 include one, two or three substituents independently selected from methoxy and oxo.
  • R 11 selected values include bromo, cyano, methoxycarbonylethyl, ethoxy- carbonylethyl, chlorophenyl, hydroxyphenyl, acetylphenyl, aminocarbonylphenyl, oxopiperidinyl, methylsulphonylpiperazinyl, morpholinyl, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, methylpyrazolyl, dimethyl- pyrazolyl, methylindazolyl, dimethylisoxazolyl, methylimidazolyl, pyridinyl, fluoro- pyridinyl, cyanopyridinyl, methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl, trifluoromethylpyridinyl, e
  • Additional values include chloro, N-isopropylcarbonyl-N-methylaminomethyl, N-cyclopropylcarbonyl-N- methylaminomethyl, methylsulphinylphenyl, methylsulphonylphenyl, (methyl)- (methylsulphonyl)phenyl, ethenylcarbonylaminophenyl, tert-butoxycarbonylamino- phenyl, phenylcarbonylphenyl, aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, isopropylcarbonylpiperidinyl, cyclobutylcarbonylpiperidinyl, methoxycarbonylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydro
  • aminocarbonyl (methyl)pyridinyl, methylaminocarbonylpyridinyl, hydroxyethylamino- carbonylpyridinyl, dimethylaminocarbonylpyridinyl, (isopropyl)(methyl)pyrimidinyl, (isobutyl)(methyl)pyrimidinyl, hydroxyisopropylpyrimidinyl, (methoxymethyl)(methyl)- pyrimidinyl, (methoxyethyl)(methyl)pyrimidinyl, methylsulphonylpyrimidinyl, dioxopyrimidinyl, ethylaminopyrimidinyl, hydroxyethylaminopyrimidinyl,
  • hydroxypropylaminopyrimidinyl (hydroxy)(methyl)propylaminopyrimidinyl, (hydroxy)- (methoxy)(methyl)propylaminopyrimidinyl, (hydroxy)(methylthio)butylamino- pyrimidinyl, dimethylaminoethylaminopyrimidinyl, (dimethylamino)(methyl)propyl- aminopyrimidinyl, N-(dimethylaminoethyl)-N-(hydroxyethyl)aminopyrimidinyl, hydroxymethylcyclopentylaminopyrimidinyl, hydroxycyclobutylmethylamino- pyrimidinyl, (cyclopropyl)(hydroxy)propylaminopyrimidinyl, tetrahydrofuranylamino- pyrimidinyl, morpholinylethylaminopyrimidinyl, oxopyrrolidinylmethylamino- pyrimi
  • dioxoisothiazolidinylpyrimidinyl hydroxytetrahydropyranylpyrimidinyl, difluoro- piperidinylpyrimidinyl, hydroxypiperidinylpyrimidinyl, hydroxymethylpiperidinyl- pyrimidinyl, methoxypiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl, (carboxy)- (methyl)piperidinylpyrimidinyl, (carboxy)(hydroxy)piperidinylpyrimidinyl, (amino)- (carboxy)piperidinylpyrimidinyl, (ethoxycarbonyl)(methyl)piperidinylpyrimidinyl, aminocarbonylpiperidinylpyrimidinyl, hydroxyethylpiperazinylpyrimidinyl, (methyl)- (oxopiperazinyl)pyrimidinyl, carboxymethylpiperazinylpyrimidinyl
  • R 11 Definitive values of R 11 include bromo, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, methylpyrazolyl, cyanopyridinyl, methoxypyridinyl, oxopyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, carboxypiperidinylpyrimidinyl, piperazinyl- pyrimidinyl, methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl, oxodiazepanylpyrimidinyl and 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl.
  • Additional values include aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1 ,2,3 ,6-tetrahydropyridinyl, methylsulphonyl-8- azabicyclo[3.2.1 Joctenyl, tert-butoxycarbonyl-8-azabicyclo[3.2.1 Joctenyl, oxoindolyl, hydroxyisopropylpyrimidinyl, tetrahydrofuranylaminopyrimidinyl, carboxycyclohexyl- pyrimidinyl, morpholinylthiazolyl, carboxypiperidinylpyridinyl, (carboxy)(
  • R 11 examples include methoxypyridinyl, oxopyridinyl,
  • R 15 and R 16 may independently represent hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, isopropyl, trifiuoromethyl, hydroxy, methoxy, difluoro- methoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methyl- amino, tert-butylamino, dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinyl- carbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, amino- carbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, tri
  • R 15 Illustrative values of R 15 include halogen and difluoromethoxy.
  • R 15 represents hydrogen. In a second embodiment, R 15 represents halogen. In a first aspect of that embodiment, R 15 represents fluoro. In a second aspect of that embodiment, R 15 represents chloro. In a third embodiment, R 15 represents Ci_ 6 alkyl. In one aspect of that embodiment, R 15 represents methyl. In a fourth embodiment, R 15 represents trifluoromethyl. In a fifth embodiment, R 15 represents Ci_6 alkoxy. In one aspect of that embodiment, R 15 represents methoxy. In a sixth embodiment, R 15 represents difluoromethoxy. In a seventh embodiment, R 15 represents trifluoromethoxy.
  • Selected values of R 15 include hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.
  • Suitable values of R 15 include chloro and difluoromethoxy.
  • Typical values of R 16 include hydrogen, halogen, Ci_ 6 alkyl, trifluoromethyl, difluoromethoxy and amino.
  • R 16 Illustrative values of R 16 include hydrogen and halogen.
  • R 16 represents hydrogen. In a second embodiment, R 16 represents halogen. In a first aspect of that embodiment, R 16 represents fluoro. In a second aspect of that embodiment, R 16 represents chloro. In a third embodiment, R 16 represents Ci_ 6 alkyl. In one aspect of that embodiment, R 16 represents methyl. In a fourth embodiment, R 16 represents trifluoromethyl. In a fifth embodiment, R 16 represents difluoromethoxy. In a seventh embodiment, R 16 represents amino.
  • Selected values of R 16 include hydrogen, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy and amino.
  • Suitable values of R 16 include hydrogen and chloro.
  • R 16 is attached at the /?ara-position of the phenyl ring relative to the integer R 15 .
  • a particular sub-group of the compounds of formula (IIA) above is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • V represents C-R 22 or N
  • R 21 represents hydrogen, halogen, halo(Ci_ 6 )alkyl, cyano, Ci_ 6 alkyl, trifluoro- methyl, C 2 _ 6 alkenyl, C 2 _ 6 alkynyl, hydroxy, hydroxy(Ci_6)alkyl, Ci_ 6 alkoxy, difluoro- methoxy, trifluoromethoxy, trifluoroethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, amino, amino(Ci_6)alkyl, Ci_ 6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N- [hydro xy(Ci_6)alkyl] amino, (C 3 -7)heterocycloalkylamino, C 2 _ 6 alkyl- carbonylamino, (C 2 _6)alkyl
  • R 22 represents hydrogen, halogen, cyano or Ci_ 6 alkyl
  • R 23 represents hydrogen or Ci_ 6 alkyl
  • V represents C-R 22 . In another embodiment, V represents N.
  • R 21 represents hydrogen, halogen, cyano, Ci_ 6 alkyl, trifluoromethyl, C 2 _6 alkenyl, C 2 _ 6 alkynyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, amino, Ci_ 6 alkylamino, di(C ⁇ alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N-[(Ci_6)alkyl]-N-[hydroxy(Ci_6)alkyl]amino, C 2 _ 6 alkylcarbonylamino, C 2 _ 6 alkoxycarbonylamino, Ci_ 6 alkylsulphonylamino, formyl, C 2 _ 6 alkylcarbonyl, carboxy, C 2 _ 6 alkoxycarbonyl, aminocarbonyl, Ci_ 6
  • R 21 represents hydroxy(Ci_ 6 )alkyl, Ci_ 6 alkoxy or (C 3 _7)heterocycloalkyl- amino; or R 21 represents (C 3 _7)cycloalkyl, (C 3 _7)heterocycloalkyl, (C 4 -9)heterobicycloalkyl or (C 4 _9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 represents hydrogen, halogen, cyano, Ci_ 6 alkyl, trifluoromethyl, C 2 -6 alkenyl, hydroxy, Ci_ 6 alkoxy, trifluoroethoxy, amino, di(Ci_6)alkylamino, (Ci_ 6 )- alkoxy(Ci_6)alkylamino, N-[(Ci_6)alkyl]-N-[hydroxy(Ci_6)alkyl]amino, Ci_ 6 alkylsulphonyl- amino or carboxy; or R 21 represents (C 3 _7)heterocycloalkyl, (C 4 _9)heterobicycloalkyl or (C 4 -9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R 21 may represent hydroxy(Ci_6)alkyl or (C 3-7 )- heterocycloalkylamino; or R 21 may represent optionally substituted (C 3
  • R 21 represents hydroxy or Ci_ 6 alkoxy; or R 21 represents
  • R 21 may represent hydroxy(Ci_6)alkyl or (C 3 _7)heterocycloalkylamino; or R 21 may represent (C 3 _7)cycloalkyl or (C 4 -9)spiroheterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 3 _7)cycloalkyl group
  • typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 4 _7)cycloalkenyl group
  • typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 3 _7)heterocycloalkyl group
  • typical values include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepanyl and thiadiazepanyl, any of which groups may be optionally substituted by one or more substituents.
  • Additionalvalues include oxetanyl, azetidinyl, tetrahydrofuranyl, isothiazolidinyl, imidazolidinyl and tetrahydropyranyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 3 _7)heterocycloalkenyl group
  • a typical value is optionally substituted 1 ,2,3,6-tetrahydropyridinyl.
  • Additionalvalues include dihydropyranyl and dihydrothiopyranyl, either of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 4 -9)heterobicycloalkyl group
  • typical values include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diaza- bicyclo[3.2.1]octanyl and 3,9-diazabicyclo[4.2.1]nonanyl, any of which groups may be optionally substituted by one or more substituents.
  • Additional values include 3- azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.2.1]octanyl and 3,6-diazabicyclo[3.2.2]octanyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 represents an optionally substituted (C 4 -9)spiroheterocycloalkyl group
  • typical values include 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa- 6-azaspiro[3.5]nonanyl and 2-oxa-7-azaspiro[3.5]nonanyl, any of which groups may be optionally substituted by one or more substituents.
  • Additional values include 5-azaspiro- [2.4]heptanyl, 2-azaspiro[3.3]heptanyl and 7-oxa-2-azaspiro[3.5]nonanyl, any of which groups may be optionally substituted by one or more substituents.
  • R 21 examples include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_ 6 )alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoroethyl, C 2 _ 6 alkenyl, hydroxy, Ci_ 6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphonyl, (Ci_ 6 )alkyl- sulphonyl(Ci_6)alkyl, oxo, amino, Ci_ 6 alkylamino, di(Ci_6)alkylamino, C 2 _ 6 alkylcarbonyl- amino, C 2 _ 6 alkoxycarbonylamino, Ci_ 6 alkylsulphonylamino, formyl, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)al
  • di(Ci_6)alkylaminosulphonyl examples include tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
  • Suitable examples of optional substituents on R 21 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, cyanomethyl, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulphonyl, methyl- sulphonylmethyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxy- carbonylamino, ethoxy carbonylamino, tert-butoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbon
  • R 21 Definitive examples of optional substituents which may be present on R 21 include one, two or three substituents independently selected from halogen, Ci_ 6 alkyl, hydroxy, Ci_6 alkoxy, Ci_ 6 alkylsulphonyl, oxo, carboxy, carboxy(Ci_6)alkyl and C 2 _ 6 alkoxy- carbonyl. Additional examples include tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
  • R 21 Selected examples of optional substituents on R 21 include one, two or three substituents independently selected from cyano(Ci_ 6 )alkyl, trifluoroethyl, hydroxy, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl and Ci_6 alkylsulphonylamino carbonyl.
  • R 21 Selected examples of particular substituents on R 21 include one, two or three substituents independently selected from fluoro, methyl, hydroxy, methoxy,
  • Additional examples include tetrazolylmethyl and aminocarbonylmethyl.
  • R 21 examples include one, two or three substituents independently selected from cyanoethyl, trifluoroethyl, hydroxy, methylsulphonyl, methylsulphonylethyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolyl and methylsulphonylammocarbonyl.
  • R 21 may be substituted by oxo.
  • R 21 represents hydrogen, fluoro, cyano, methyl, trifluoromethyl, ethenyl, hydroxy, methoxy, isopropoxy, trif uoroethoxy, amino, dimethylamino, methoxyethyl- amino, N-(hydroxyethyl)-N-(methyl)amino, carboxy, pyrrolidinyl, hydro xypyrrolidinyl, piperidinyl, acetylpiperidinyl, carboxypiperidinyl, piperazinyl, cyanoethylpiperazinyl, trif uoroethylpiperazinyl, methylsulphonylpiperazinyl, methylsulphonylethylpiperazinyl, oxopiperazinyl, acetylpiperazinyl, tert-butoxycarbonylpiperazinyl, carboxymethyl- piperazinyl, carboxy ethyl
  • R 21 may represent hydroxy- isopropyl, tetrahydrofuranylamino, carboxycyclohexyl, methoxypyrrolidinyl, carboxypyrrolidmyl, difluoropiperidmyl, (carboxy)(methyl)piperidinyl, (carboxy)(hydroxy)- piperidinyl, (ethoxycarbonyl)(methyl)piperidinyl, tetrazolylmethylpiperazinyl, amino- carbonylmethylpiperazinyl, dimethylmorpholinyl, carboxy-3-azabicyclo[3.1.0]hexanyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl, carboxy-3-azabicyclo[4.1.0]heptanyl, oxo- 3,6-diazabicyclo[3.2.2]nonanyl or carboxy-2-azaspiro[3.3]heptanyl.
  • R 21 includes cyano, methoxy, carboxypiperidinyl, piperazinyl, methylsulphonylpiperazinyl, oxopiperazinyl, carboxymethylpiperazinyl, carboxyethyl- piperazinyl, morpholinyl, oxodiazepanyl and 2-oxa-6-azaspiro[3.3]heptanyl.
  • Additional values include hydroxyisopropyl, tetrahydrofuranylamino, carboxycyclohexyl, methoxypyrrolidinyl, carboxypyrrolidinyl, difluoropiperidmyl, (carboxy)(methyl)piperidinyl, (carboxy)(hydroxy)piperidinyl, (ethoxycarbonyl)(methyl)piperidinyl, tetrazolylmethylpiperazinyl, aminocarbonylmethylpiperazinyl, dimethylmorpholinyl, carboxy-3- azabicyclo[3.1.0]hexanyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl, carboxy-3- azabicyclo[4.1.0]heptanyl, oxo-3,6-diazabicyclo[3.2.2]nonanyl and carboxy-2- azaspiro[3.3]heptanyl.
  • R 21 examples include hydroxy, methoxy, piperazinyl, oxopiperazinyl and oxodiazepanyl.
  • R 21 represents hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R 21 represents hydroxyisopropyl, especially 2-hydroxyprop-2-yl.
  • R 22 represents hydrogen or Ci_ 6 alkyl.
  • R 22 represents hydrogen, chloro, cyano or methyl.
  • R 22 represents hydrogen or cyano.
  • R 22 represents hydrogen or methyl.
  • R 22 represents hydrogen. In another embodiment, R 22 represents Ci_ 6 alkyl, especially methyl. In a further embodiment, R 22 represents cyano. In an additional embodiment, R 22 represents halogen, especially chloro.
  • R 23 represents hydrogen or methyl.
  • R 23 represents hydrogen. In another embodiment, R 23 represents Ci_ 6 alkyl, especially methyl.
  • T represents -CH 2 - or -CH 2 CH 2 -;
  • U represents C(O) or S(0) 2 ;
  • W represents O, S, S(O), S(0) 2 , N(R 31 ) or C(R 32 )(R 33 );
  • R 31 represents hydrogen, cyano(Ci_ 6 )alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoro- ethyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C 2 _ 6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl(Ci_6)alkyl, amino carbonyl, aminocarbonyl(Ci_6)alkyl, Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl, Ci_ 6 alkylaminosulphonyl or di(Ci_6)alkyl- aminosulphonyl; R represents halogen, Ci_ 6 alkoxy, carboxy, carb
  • alkoxycarbonyl C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl or aminocarbonyl;
  • R 33 represents hydrogen, halogen, Ci_ 6 alkyl, hydroxy or amino
  • V, E, Q, Z, R 15 , R 16 and R 23 are as defined above.
  • T represents -CH 2 -. In a second embodiment, T represents -CH 2 CH 2 -.
  • U represents C(O). In a second embodiment, U represents
  • W represents O, S, S(O), S(0) 2 , N(R 31 ), CF 2 , CH(C0 2 H) or
  • W represents O, N(R 31 ) or C(R 32 )(R 33 ).
  • W represents O, S, S(O), S(0) 2 , N(R 31 ) or CH(C0 2 H).
  • W represents O, S(0) 2 , N(R 31 ) or CH(C0 2 H).
  • W represents O. In a second embodiment, W represents S. In a third embodiment, W represents S(O). In a fourth embodiment, W represents S(0) 2 . In a fifth embodiment, W represents N(R 31 ). In a sixth embodiment, W represents C(R 32 )(R 33 ). In a first aspect of the sixth embodiment, W represents CF 2 . In a second aspect of the sixth embodiment, W represents CH(C0 2 H). In third aspect of the sixth embodiment, W represents CH(tetrazolyl).
  • R 31 represents hydrogen, cyano(Ci_6)alkyl, Ci_ 6 alkyl, trifluoromethyl, trifluoro ethyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C 2 _ 6 alkyl- carbonyl, carboxy, carboxy(Ci_6)alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)- alkyl, aminocarbonyl, Ci_ 6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, amino- sulphonyl, Ci_6 alkylamino sulphonyl or di(Ci_6)alkylaminosulphonyl.
  • R 31 represents hydrogen, cyano(Ci_ 6 )alkyl, trifluoroethyl, Ci_ 6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, C 2 _ 6 alkylcarbonyl, carboxy(Ci_6)alkyl, C 2 _6 alkoxycarbonyl or C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl. Additionally, R 31 may represent tetrazolyl(Ci_6)alkyl or aminocarbonyl(Ci_6)alkyl.
  • R 31 represents hydrogen, Ci_ 6 alkylsulphonyl or carboxy(Ci_6)alkyl. Additionally, R 31 may represent tetrazolyl(Ci_6)alkyl or aminocarbonyl(Ci_6)alkyl.
  • Typical values of R 31 include hydrogen, cyanoethyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl, methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Additional values include tetrazolylmethyl and ammocarbonylmethyl.
  • Selected values of R 31 include hydrogen, cyanoethyl, trifluoroethyl, methyl- sulphonyl, methylsulphonylethyl, acetyl, carboxymethyl, carboxyethyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl and ethoxycarbonylethyl. Additional values include tetrazolylmethyl and aminocarbonylmethyl.
  • R 31 Definitive values of R 31 include hydrogen, methylsulphonyl, carboxymethyl and carboxyethyl. Additional values include tetrazolylmethyl and aminocarbonylmethyl.
  • R 31 is hydrogen.
  • R 32 represents halogen, Ci_ 6 alkoxy, carboxy, carboxy(Ci_ 6 )alkyl, C 2 _ 6 alkoxycarbonyl, C 2 _ 6 alkoxycarbonyl(Ci_6)alkyl or tetrazolyl.
  • R 32 represents halogen, carboxy or C 2 _ 6 alkoxycarbonyl.
  • Typical values of R 32 include fluoro, methoxy, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl,
  • R 32 include fluoro, carboxy and ethoxycarbonyl.
  • R 32 represents carboxy
  • R 33 represents hydrogen, halogen, Ci_ 6 alkyl or hydroxy.
  • R 33 represents hydrogen. In a second embodiment, R 33 represents halogen. In one aspect of that embodiment, R 33 represents fluoro. In a third embodiment, R 33 represents Ci_ 6 alkyl. In one aspect of that embodiment, R 33 represents methyl. In a fourth embodiment, R 33 represents hydroxy. In a fifth embodiment, R 33 represents amino.
  • Another sub-group of the compounds of formula (IIB) above is represented by the compounds of formula (IIF) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • R 34 represents hydrogen, halogen, halo(Ci_ 6 )alkyl, hydroxy, Ci_ 6 alkoxy, Ci_ 6 alkylthio, Ci_ 6 alkylsulphinyl, Ci_ 6 alkylsulphonyl, amino, Ci_ 6 alkylamino, di(Ci_ 6 )alkyl- amino, (C 2 -6)alkylcarbonylamino, (C 2 -6)alkylcarbonylamino(Ci_6)alkyl, (Ci_6)alkyl- sulphonylamino, or (Ci_6)alkylsulphonylamino(Ci_6)alkyl; and
  • E, Q, Z, V, W, R 15 , R 16 and R 23 are as defined above.
  • R 34 represents hydrogen. In a second embodiment, R 34 represents halogen. In one aspect of that embodiment, R 34 represents fluoro. In a third embodiment, R 34 represents halo(Ci_6)alkyl. In one aspect of that embodiment, R 34 represents fluoromethyl. In a fourth embodiment, R 34 represents hydroxy. In a fifth embodiment, R 34 represents Ci_ 6 alkoxy, especially methoxy. In a sixth embodiment, R 34 represents Ci_ 6 alkylthio, especially methylthio. In a seventh embodiment, R 34 represents Ci_6 alkylsulphinyl, especially methylsulphinyl. In an eighth embodiment, R 34 represents Ci_6 alkylsulphonyl, especially methylsulphonyl.
  • R 34 represents amino.
  • R 34 represents Ci_ 6 alkylamino, especially methylamino.
  • R 34 represents di(Ci_6)alkylamino, especially dimethylamino.
  • R 34 represents (C 2 -6)alkylcarbonylamino, especially acetylamino.
  • R 34 represents (C 2 -6)alkylcarbonylamino(Ci_6)alkyl, especially acetylaminomethyl.
  • R 34 represents (Ci_6)alkylsulphonyl- amino, especially methylsulphonylamino.
  • R 34 represents (Ci_6)alkylsulphonylamino(Ci_6)alkyl, especially methylsulphonylaminomethyl.
  • R 34 represents hydrogen, halogen, halo(Ci_ 6 )alkyl, hydroxy or
  • Selected values of R 34 include hydrogen, fluoro, fluoromethyl, hydroxy, methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino, methylamino, dimethylamino and acetylaminomethyl.
  • Particular values of R include hydrogen, fluoro, fluoromethyl, hydroxy and acetylaminomethyl.
  • R 34 represents hydrogen or hydroxy.
  • a further sub-group of the compounds of formula (IIB) above is represented by the compounds of formula (IIG) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
  • E, Q, Z, V, W, R 15 , R 16 and R 23 are as defined above.
  • the compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
  • Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders.
  • Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, polymyositis, scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligo articular and polyarticular forms thereof), anaemia of chronic disease (ACD), Still's disease (juvenile and/or adult onset), Beliefs disease and Sjogren's syndrome.
  • SLE systemic lupus erythematosus
  • psoriasis psoriatic arthropathy
  • vasculitis polymyositis
  • scleroderma multiple sclerosis
  • Autoimmune endocrine disorders include thyroiditis.
  • Organ-specific autoimmune disorders include Addison's disease, haemolytic or pernicious anaemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis,
  • osteoporosis osteopenia, osteopenia, erosive bone disease, chondritis, cartilage degeneration and/or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy) and organ transplant rejection (including kidney allograft rejection).
  • COPD chronic obstructive pulmonary disease
  • Neurological and neurodegenerative disorders include Alzheimer's disease,
  • Parkinson's disease Huntington's disease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.
  • Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders
  • Modulators of TNFa function may also be of use in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).
  • Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.
  • Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularisation (including corneal vascularisation and neovascularisation), retinal vein occlusion, and various forms of uveitis and keratitis.
  • retinopathy including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity
  • macular oedema including diabetic macular oedema
  • vascularisation including corneal vascularisation and neovascularisation
  • retinal vein occlusion and various forms of uveitis and keratitis.
  • Oncological disorders which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia and anaemia).
  • proliferative disorders especially cancer
  • cancer-associated complications including skeletal complications, cachexia and anaemia.
  • cancer-associated complications including skeletal complications, cachexia and anaemia.
  • haematological malignancy including leukaemia and lymphoma
  • non-haematological malignancy including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma.
  • Chronic leukaemia may be myeloid or lymphoid. Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplasia syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia.
  • CML chronic myelogenous leukaemia
  • CLL chronic lymphocytic/lymphoid leukaemia
  • ALL acute lymphoblastic
  • lymphoma Varieties of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALTl lymphoma and marginal zone lymphoma.
  • Varieties of non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle.
  • Modulators of TNFa function may also be used to increase the safety of the potent anticancer effect of TNF (see F.V. Hauwermeiren et al., J. Clin. Invest., 2013, 123, 2590-2603).
  • the present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
  • compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
  • compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium glycollate
  • wetting agents e.g. sodium lauryl sulphate.
  • the tablets may be coated by methods well known in the art.
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives.
  • the preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
  • Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
  • compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion.
  • Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials.
  • the compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
  • the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
  • the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • a suitable propellant e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack or dispensing device may be accompanied by instructions for administration.
  • the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water.
  • the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers.
  • Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
  • the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • a bactericidal or fungicidal agent for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
  • ophthalmic administration compounds may be formulated in an ointment such as petrolatum.
  • the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component.
  • suitable non- irritating excipient include, for example, cocoa butter, beeswax and polyethylene glycols.
  • daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
  • a compound in accordance with the present invention may be co- administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.
  • another pharmaceutically active agent e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.
  • the compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
  • E, Q, Y, Z, R 1 , R 2 and R 3 are as defined above, and L 1 represents a suitable leaving group.
  • the leaving group L 1 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a Ci_ 4 alkanol such as ethanol, or a cyclic ether such as 1 ,4-dioxane.
  • a suitable solvent e.g. a Ci_ 4 alkanol such as ethanol, or a cyclic ether such as 1 ,4-dioxane.
  • the leaving group L 2 is typically a halogen atom, e.g. bromo.
  • the reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a Ci_ 4 alkanol such as ethanol.
  • a suitable solvent e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a Ci_ 4 alkanol such as ethanol.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a Ci_ 4 alkanol such as methanol.
  • a suitable solvent e.g. a hydrocarbon solvent such as toluene, or a Ci_ 4 alkanol such as methanol.
  • the halogen atom Hal is typically bromo.
  • reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • a suitable solvent e.g. a cyclic ether such as tetrahydrofuran.
  • reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
  • a suitable solvent e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
  • the sulfonic acid derivative of use in the foregoing reaction is suitably an organic sulfonic acid derivative such as methanesulfonic acid.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.
  • the intermediates of formula (X) above may be prepared by treating a compound of formula (IX) as defined above with formaldehyde.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.
  • R z represents a Ci_ 4 alkyl group, e.g. methyl; with a reducing agent.
  • the reducing agent of use in the foregoing reaction is suitably an alkali metal borohydride such as lithium borohydride.
  • the reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or a Ci_ 4 alkanol such as methanol, or a mixture thereof.
  • the reducing agent of use in the foregoing reaction may suitably be diisobutylaluminium hydride.
  • the reaction is conveniently effected at a temperature in the region of 0°C in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
  • the compounds of formula (I) above wherein E represents -N(H)- may be prepared by a process which comprises reacting a compound of formula (III) as defined above with an isocyanide derivative of formula Y-NC and an aldehyde derivative of formula
  • the transition metal catalyst of use in the foregoing reaction is suitably a zirconium derivative, e.g. a zirconium halide such as zirconium(IV) chloride.
  • the reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a Ci_ 4 alkanol such as n-butanol.
  • the starting materials of formula (III), (IV), (VI), (VII), (XI) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
  • any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art.
  • a compound of formula (I) wherein E represents -C(O)- may be converted into the corresponding compound wherein E represents -CH(OH)- by treatment with a reducing agent such as sodium borohydride.
  • a compound of formula (I) wherein E represents -CH(OH)- may be converted into the corresponding compound wherein E represents -CH 2 - by heating with elemental iodine and phosphinic acid in acetic acid; or by treating with triethylsilane and an acid, e.g. an organic acid such as trifluoro acetic acid, or a Lewis acid such as boron trifluoride diethyl etherate; or by a two-step procedure which comprises: (i) treatment with thionyl bromide; and (ii) treatment of the product thereby obtained with a transition metal catalyst, e.g.
  • a compound of formula (I) which contains a hydroxy group may be alkylated by treatment with the appropriate alkyl halide in the presence of a base, e.g. sodium hydride, or silver oxide.
  • a compound of formula (I) wherein -Q-Z represents -CH 2 OH may be arylated in a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with the appropriate aryl or heteroaryl hydroxide.
  • a compound of formula (I) wherein -Q-Z represents -CH 2 OH may be converted into the corresponding compound of formula (I) wherein -Q-Z represents -CH 2 S-Z via a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with a compound of formula Z-SH, typically in the presence of a base, e.g. an inorganic base such as potassium carbonate.
  • a compound of formula (I) which contains hydroxy may be converted into the corresponding fluoro-substituted compound by treatment with diethylamino sulfur trifluoride (DAST).
  • a compound of formula (I) which contains hydroxy may be converted into the corresponding difluoro-substituted compound via a two-step procedure which comprises: (i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii) treatment of the carbonyl-containing compound thereby obtained with DAST.
  • an oxidising agent e.g. manganese dioxide
  • a compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl halide, typically at an elevated temperature in an organic solvent such as acetonitrile.
  • the reaction may be effected at ambient temperature in an organic solvent such as N,N-dimethylformamide, in the presence of a base, e.g. an inorganic base such as cesium carbonate or potassium carbonate.
  • a compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl tosylate in the presence of a base, e.g. an inorganic base such as sodium hydride, or an organic base such as l,8-diazabicyclo[5.4.0]undec-7- ene (DBU).
  • a base e.g. an inorganic base such as sodium hydride, or an organic base such as l,8-diazabicyclo[5.4.0]undec-7- ene (DBU).
  • a compound of formula (I) which contains an N-H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by C 2 _ 6 alkyl- carbonyl, e.g. acetyl, by treatment with the appropriate acyl anhydride, e.g. acetic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine.
  • acyl anhydride e.g. acetic anhydride
  • a compound of formula (I) which contains an N-H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by Ci_ 6 alkyl- sulphonyl, e.g.
  • Ci_ 6 alkylsulphonyl halide e.g. a Ci_ 6 alkylsulphonyl chloride such as methanesulphonyl chloride
  • Ci_ 6 alkylsulphonic anhydride e.g. methanesulphonic anhydride
  • a base e.g. an organic base such as triethylamine
  • a compound of formula (I) containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(O)- by treatment with 3-chloroperoxy- benzoic acid.
  • a compound of formula (I) containing the moiety -S(O)- may be converted into the corresponding compound containing the moiety -S(0) 2 - by treatment with 3-chloroperoxybenzoic acid.
  • a compound of formula (I) containing an aromatic nitrogen atom may be converted into the corresponding N-oxide derivative by treatment with 3-chloroperoxybenzoic acid.
  • a bromophenyl derivative of formula (I) may be converted into the corresponding optionally substituted 2-oxopyrrolidin-l-ylphenyl or 2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-one or oxazolidin-2-one, or an appropriately substituted analogue thereof.
  • the reaction is conveniently effected at an elevated temperature in the presence of copper(I) iodide, trans-N,N'-dimethylcyclohexane-l,2- diamine and an inorganic base such as potassium carbonate.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted aryl or heteroaryl moiety by treatment with the appropriately substituted aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1 ,3-propanediol or neopentyl glycol.
  • the reaction is typically effected in the presence of a transition metal catalyst, e.g.
  • a base e.g. an inorganic base such as sodium carbonate or potassium carbonate, or potassium phosphate.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted aryl, heteroaryl or heterocycloalkenyl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately functionalised halo- or tosyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivative.
  • halogen e.g. bromo
  • Step (i) is conveniently effected in the presence of a transition metal catalyst such as [ ⁇ , -bis- (diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex.
  • a transition metal catalyst such as [ ⁇ , -bis- (diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex.
  • Step (ii) is conveniently effected in the presence of a transition metal catalyst such as tetrakis- (triphenylphosphine)palladium(O), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 - yljiron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a transition metal catalyst such as tetrakis- (triphenylphosphine)palladium(O), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 - yljiron-dichloropalladium-dichloromethane complex
  • a base e.g. an inorganic base such as sodium carbonate or potassium carbonate.
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents an optionally substituted imidazol-l-yl moiety by treatment with the appropriately substituted imidazole derivative, typically in the presence of copper(II) acetate and an organic base such as N,N,N',N'-tetramethy lethy lenediamine (TMED A) .
  • TMED A N,N,N',N'-tetramethy lethy lenediamine
  • a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R 1 represents 2-(methoxycarbonyl)- ethyl via a two-step procedure which comprises: (i) reaction with methyl acrylate; and (ii) catalytic hydrogenation of the alkenyl derivative thereby obtained, typically by treatment with a hydrogenation catalyst, e.g. palladium on charcoal, under an atmosphere of hydrogen gas.
  • Step (i) is typically effected in the presence of a transition metal catalyst, e.g. palladium(II) acetate or bis(dibenzylideneacetone)palladium(0), and a reagent such as tri(ortAo-tolyl)phosphine.
  • a compound of formula (I) wherein R 1 represents 6-methoxypyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 2-oxo-l,2-dihydro- pyridin-5-yl by treatment with pyridine hydrochloride; or by heating with a mineral acid such as hydrochloric acid.
  • a compound of formula (I) wherein R 1 represents 6-methoxy-4-methylpyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 4-methyl-2-oxo-l,2-dihydropyridin-5-yl; and a compound of formula (I) wherein R 1 represents 6-methoxy-5-methylpyridin-3-yl may be converted into the corresponding compound wherein R 1 represents 3-methyl-2- oxo- 1 ,2-dihydropyridin-5-yl.
  • a compound of formula (I) wherein R 1 represents 2-oxo-l,2-dihydropyridin-5-yl may be converted into the corresponding compound wherein R 1 represents 2-oxopiperidin- 5-yl by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as platinum(IV) oxide.
  • a compound of formula (I) containing a carbon-carbon double bond may be converted into the corresponding compound containing a carbon-carbon single bond by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal.
  • a compound of formula (I) containing an ester moiety e.g. a C 2 _ 6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may be converted into the
  • the transformation may be effected by treatment with a base, typically an inorganic base such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.
  • a base typically an inorganic base such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.
  • a compound of formula (I) containing an N-(tert-butoxycarbonyl) moiety may be converted into the corresponding compound containing an N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • an acid e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
  • a compound of formula (I) wherein R 1 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom may be prepared by reacting a compound of formula (I) wherein R 1 represents halogen, e.g. bromo, with the appropriate compound of formula R'-H [e.g. 1- (pyridin-3-yl)piperazine].
  • R'-H e.g. 1- (pyridin-3-yl)piperazine
  • a compound of formula (IIB) wherein R 21 represents ethenyl may be prepared by reacting a compound of formula (IIB) wherein R 21 represents halogen, e.g. chloro, with potassium vinyl trifluoroborate.
  • the reaction is typically effected in the presence of a transition metal catalyst, e.g. [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, e.g. an organic base such as triethylamine.
  • a compound of formula (IIB) wherein R 21 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (IIB) wherein R 21 represents halogen, e.g. chloro, with the appropriate compound of formula R 21 -H [e.g.
  • a base e.g. an organic base such as triethylamine or l-methyl-2- pyrrolidinone.
  • the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
  • the diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt.
  • a racemate of formula (I) may be separated using chiral HPLC.
  • a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above.
  • a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
  • any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3 rd edition, 1999.
  • the protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
  • the compounds in accordance with this invention potently inhibit TNF - induced NF-KB activation in the following assay. Inhibition of TNFa-induced NF- ⁇ activation
  • HEK-293 cells Stimulation of HEK-293 cells by TNFa leads to activation of the NF- ⁇ pathway.
  • the reporter cell line used to determine TNFa activity was purchased from InvivoGen.
  • HEK-BlueTM CD40L is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a dose-dependent manner by TNFa (0.5 ng/mL).
  • Compounds were diluted from 10 mM DMSO stocks (final assay concentration 0.3%) to generate a 10-point 3-fold serial dilution curve (30,000 nM to 2 nM final concentration).
  • Si0 2 silica h: hour
  • Pd(PPli 3 )4 tetrakis(triphenylphosphine)palladium(0)
  • Solvent A 0.1% formic acid/water
  • Solvent B 0.1% formic acid/acetonitrile
  • UV detection wavelength 215 nm
  • Solvent A 0.1% formic acid/water
  • Solvent B 0.1% formic acid/acetonitrile
  • UV detection wavelength 215 nm
  • Solvent A 0.1% formic acid/water
  • Solvent B 0.1% formic acid/acetonitrile
  • UV detection wavelength 215 nm
  • UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
  • Solvent A 0.1% formic acid/water
  • Solvent B 0.1% formic acid/acetonitrile
  • UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
  • Solvent A 2 nM ammonium hydrogencarbonate in water
  • UV detection wavelength 215 nm
  • UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
  • Inlet method LC7 40ml 7030 tubes.w60 Method Gradient: Time (min) % A % B
  • Inlet method LC7 40ml 9010 tubes. w60
  • ACD Flow 2 mL/minute (acetonitrile with 0.1% formic acid) throughout run.
  • Potassium hydroxide 105 g, 1872 mmol was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately -20°C.
  • l-(2- Hydroxyphenyl)ethanone 11.28 mL, 93.7 mmol was added dropwise, followed by diethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes.
  • the reaction mixture was heated at 90°C for 4 h, then cooled to room temperature and partitioned between water (200 mL) and EtOAc (300 mL). The organic layer was separated, dried over MgS0 4 and concentrated in vacuo. The brown residue was triturated with acetonitrile (50 mL), yielding the title compound (3.52 g, 61%) as a brown solid.
  • the reaction was heated at 90°C for 8.5 h in a sealed tube under nitrogen.
  • the mixture was diluted with EtOAc (20 mL) and washed with water (15 mL).
  • the aqueous phase was diluted with water (15 mL) and extracted with EtOAc (20 mL).
  • the combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum.
  • the crude product was purified by column chromatography, eluting with heptanes: ethyl acetate 1 :0 to 1 : 1 , to yield the title compound (81 mg, 50%).
  • the mixture was heated at 90°C for 4 h in a sealed tube, then left to stand at r.t. for 4 days.
  • the mixture was heated at 90°C for 2 h, then at 100°C for a total of 8 h.
  • the mixture was partitioned between EtOAc (20 mL) and water (15 mL).
  • the aqueous layer was diluted with water ( ⁇ 15 mL) and extracted with EtOAc (20 mL).
  • the combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum.
  • the residue was purified by FCC, eluting with 0-100%
  • Example 9 (700 mg, 1.48 mmol) was suspended in 4M HC1 in 1,4-dioxane (3.7 mL) and the mixture was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure and dried under vacuum, to afford the title compound (595 mg, 98%>) as a sticky beige solid.
  • Method B HPLC-MS: MH+ mlz 373, RT 1.21 minutes.
  • a second reaction batch was prepared whereby a 4M solution of HCl in dioxane (10.4 mL, 4 mmol) was added to a solution of 3-(tert-butyl) 6- ethyl 3-azabicyclo[4.1.0]heptane-3,6-dicarboxylate (1 g, 4 mmol) in ethanol (40 mL) and the reaction mixture was warmed to 75°C, then stirred at this temperature overnight. The reaction mixture was cooled to r.t., then concentrated under vacuum in combination with the first batch, to afford the title compound (3.1 g) as a pale yellow solid.
  • Example 8 (700 mg, 1.49 mmol) was suspended in 4M HC1 in 1,4-dioxane (3.72 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dried under vacuum to afford the title compound (600 mg, 99%) as an off-white solid.
  • Method B HPLC-MS: MH+ mlz 371, RT 1.29 minutes.
  • Example 13 (270 mg, 0.54 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL, 8.15 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum to afford the title compound (220 mg, 75%) as a yellow powder.
  • Method B HPLC-MS: MH+ mlz 397, RT 0.89 minutes.
  • Example 3 (44 mg, 0.06 mmol) was dissolved in 1,4-dioxane (1 mL) and 6M HC1 in water (0.18 mL) was added. The mixture was heated under reflux at 70°C for 9 h. The mixture was diluted with EtOAc (10 mL) and neutralised with 1M aqueous NaOH solution. Water (10 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with 0-10% MeOH in DCM, to afford an off-white solid. This material was suspended in minimal DCM and filtered to yield the title compound (15 mg, 35%) as a white solid. Method A HPLC-MS: MH+ mlz 383, RT 3.37 minutes.
  • Example 8 (900 mg, 1.91 mmol) was dissolved in ethanol (50 mL), then palladium on carbon (10% w/w, 204 mg) was added. The suspension was degassed using vacuum/ nitrogen and the reaction mixture was stirred under hydrogen at ambient temperature and pressure for 14 h. The reaction mixture was then degassed using vacuum/nitrogen and filtered through celite, washing with MeOH (15 mL). The solvent was removed under reduced pressure and the residue was purified by FCC, eluting with 10-15% DCM in MeOH, to afford the title compound (571 mg, 63%>) as a pale yellow oil.
  • Pd(PPh 3 ) 4 (16 mg, 0.01 mmol) was added to a thoroughly degassed mixture of Intermediate 6 (50 mg, 0.14 mmol) and (4-sulfamoylphenyl)boronic acid (41 mg, 0.2 mmol) in 2M aqueous sodium carbonate solution (0.44 mL) and 1 ,2-dimethoxyethane (2.2 mL). The mixture was heated in a sealed tube at 90°C under nitrogen for 2 h.
  • the mixture was heated at 90°C in a sealed tube under a nitrogen atmosphere for 2 h, then cooled and diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with 1 :9 DMSO/ acetonitrile (20 mL) and filtered. The solid residue was washed with acetonitrile (10 mL) to afford the title compound (76 mg, 21%) as a white solid.

Abstract

A series of imidazo[1,2-α]pyrazine derivatives, being potent modulators of human TNFα activity, are accordingly of benefit in the treatment and/or prevention of various human ailments, including autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.

Description

IMIDAZOPYRAZINE DERIVATIVES AS MODULATORS OF TNF
ACTIVITY
The present invention relates to a class of fused imidazole derivatives, and to their use in therapy. More particularly, this invention is concerned with pharmacologically active substituted imidazo[l,2-a]pyrazine derivatives. These compounds are modulators of the signalling of TNFa, and are accordingly of benefit as pharmaceutical agents, especially in the treatment of adverse inflammatory and autoimmune disorders, neurological and neurodegenerative disorders, pain and nociceptive disorders,
cardiovascular disorders, metabolic disorders, ocular disorders, and oncological disorders.
TNFa is the prototypical member of the Tumour Necrosis Factor (TNF) superfamily of proteins that share a primary function of regulating cell survival and cell death. One structural feature common to all known members of the TNF superfamily is the formation of trimeric complexes that bind to, and activate, specific TNF superfamily receptors. By way of example, TNFa exists in soluble and transmembrane forms and signals through two receptors, known as TNFR1 and TNFR2, with distinct functional endpoints.
Various products capable of modulating TNFa activity are already commercially available. All are approved for the treatment of inflammatory and autoimmune disorders such as rheumatoid arthritis and Crohn's disease. All currently approved products are macromolecular and act by inhibiting the binding of human TNFa to its receptor. Typical macromolecular TNFa inhibitors include anti-TNFa antibodies; and soluble TNFa receptor fusion proteins. Examples of commercially available anti-TNFa antibodies include fully human antibodies such as adalimumab (Humira®) and golimumab
(Simponi®), chimeric antibodies such as infliximab (Remicade®), and pegylated Fab' fragments such as certulizumab pegol (Cimzia®). An example of a commercially available soluble TNFa receptor fusion protein is etanercept (Enbrel®).
TNF superfamily members, including TNFa itself, are implicated in a variety of physiological and pathological functions that are believed to play a part in a range of conditions of significant medical importance (see, for example, M.G. Tansey & D.E. Szymkowski, Drug Discovery Today, 2009, 14, 1082-1088; and F.S. Carneiro et al., J. Sexual Medicine, 2010, 7, 3823-3834). The compounds in accordance with the present invention, being potent modulators of human TNFa activity, are therefore beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders;
neurological and neurodegenerative disorders; pain and nociceptive disorders;
cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
In addition, the compounds in accordance with the present invention may be beneficial as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents. Thus, in one embodiment, the compounds of this invention may be useful as radioligands in assays for detecting pharmacologically active compounds. In an alternative embodiment, certain compounds of this invention may be useful for coupling to a fluorophore to provide fluorescent conjugates that can be utilised in assays (e.g. a fluorescence polarisation assay) for detecting pharmacologically active compounds.
The compounds in accordance with the present invention potently neutralise the activity of TNFa in a commercially available HEK-293 derived reporter cell line known as HEK-Blue™ CD40L. This cell line is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a concentration-dependent manner by TNFa. When tested in the HEK-293 bioassay, the compounds of the present invention exhibit an IC50 value of 50 μΜ or less, generally of 20 μΜ or less, usually of 5 μΜ or less, typically of 1 μΜ or less, suitably of 500 nM or less, ideally of 100 nM or less, and preferably of 20 nM or less (the skilled person will appreciate that a lower IC50 figure denotes a more active compound).
The present invention provides a compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000003_0001
(I) wherein
E represents a covalent bond; or E represents -0-, -S-, -S(O)-, -S(0)2- or -N(R4)-; or E represents an optionally substituted straight or branched Ci_4 alkylene chain;
Q represents a covalent bond; or Q represents -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-,
-C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- or -N(R5)S(0)2-; or Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-;
Y represents C3_7 cycloalkyl, aryl, C3_7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents Ci_6 alkyl, C3_7 cycloalkyl, aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Ί}-Ί} or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents;
Z1 represents a divalent radical derived from an aryl, C3_7 heterocycloalkyl or heteroaryl group;
Z2 represents aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl; R1, R2 and R3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifiuoromethoxy, -ORa, -SRa, -SORa, -S02Ra, -SF5, -NRbRc, -NRcCORd, -NRcC02Rd, -NHCONRbRc, -NRcS02Re, -N(S02Re)2, -NHS02NRbRc, -CORd, -C02Rd, -CONRbRc, -CON(ORa)Rb or -S02NRbRc; or Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C4_7 cycloalkenyl, C3_7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3_7 heterocycloalkyl, C3_7 heterocycloalkyl(Ci_6)alkyl, C3_7 heterocycloalkenyl, C4_9 heterobicycloalkyl, C4_9 heterobicyclo alkenyl, heteroaryl, heteroaryl(Ci_6)alkyl,
(C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C3_7)heterocycloalkyl-,
(C3_7)cycloalkyl-heteroaryl-, (C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl- heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl- heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents;
R4 and R5 independently represent hydrogen or Ci_6 alkyl; Ra represents Ci_6 alkyl, aryl, aryl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents;
Rb and Rc independently represent hydrogen or trifluoromethyl; or Ci_6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
Rb and Rc, when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents;
Rd represents hydrogen; or Ci_6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
Re represents Ci_6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
The present invention also provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated.
In another aspect, the present invention provides a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
The present invention also provides a method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a
pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof. In another aspect, the present invention provides a method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
Where any of the groups in the compounds of formula (I) above is stated to be optionally substituted, this group may be unsubstituted, or substituted by one or more substituents. Typically, such groups will be unsubstituted, or substituted by one or two substituents.
For use in medicine, the salts of the compounds of formula (I) will be
pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of the compounds of use in the invention or of their pharmaceutically acceptable salts. Suitable pharmaceutically acceptable salts of the compounds of use in this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of use in the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid or phosphoric acid. Furthermore, where the compounds of use in the invention carry an acidic moiety, e.g. carboxy, suitable pharmaceutically acceptable salts thereof may include alkali metal salts, e.g. sodium or potassium salts; alkaline earth metal salts, e.g. calcium or magnesium salts; ammonium salts; and salts formed with suitable organic ligands, e.g. quaternary ammonium salts.
The present invention includes within its scope solvates of the compounds of formula (I) above. Such solvates may be formed with common organic solvents, e.g. hydrocarbon solvents such as benzene or toluene; chlorinated solvents such as chloroform or dichloromethane; alcoholic solvents such as methanol, ethanol or isopropanol; ethereal solvents such as diethyl ether or tetrahydrofuran; or ester solvents such as ethyl acetate. Alternatively, the solvates of the compounds of formula (I) may be formed with water, in which case they will be hydrates.
The present invention also includes co-crystals within its scope. The technical term "co-crystal" is used to describe the situation where neutral molecular components are present within a crystalline compound in a definite stoichiometric ratio. The preparation of pharmaceutical co-crystals enables modifications to be made to the crystalline form of an active pharmaceutical ingredient, which in turn can alter its physico chemical properties without compromising its intended biological activity (see Pharmaceutical Salts and Co- crystals, ed. J. Wouters & L. Quere, RSC Publishing, 2012). Typical examples of co- crystal formers, which may be present in the co-crystal alongside the active
pharmaceutical ingredient, include Z-ascorbic acid, citric acid, glutaric acid, urea and nicotinamide.
The present invention includes within its scope prodrugs of the compounds of formula (I) above. In general, such prodrugs will be functional derivatives of the compounds of formula (I) which are readily convertible in vivo into the required compound of formula (I). Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985.
Suitable alkyl groups which may be present on the compounds of use in the invention include straight-chained and branched Ci_6 alkyl groups, for example Ci_4 alkyl groups. Typical examples include methyl and ethyl groups, and straight-chained or branched propyl, butyl and pentyl groups. Particular alkyl groups include methyl, ethyl, n- propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, 2,2-dimethylpropyl and 3- methylbutyl. Derived expressions such as "Ci_6 alkoxy", "Ci_6 alkylthio", "Ci_6 alkylsulphonyl" and "Ci_6 alkylamino" are to be construed accordingly.
The expression "Ci_4 alkylene chain" refers to a divalent straight or branched alkylene chain containing 1 to 4 carbon atoms. Typical examples include methylene, ethylene, methylmethylene, ethylmethylene and dimethylmethylene.
Suitable C2_6 alkenyl groups include vinyl and allyl.
Suitable C2_6 alkynyl groups include ethynyl and propargyl.
Suitable C3-7 cycloalkyl groups, which may comprise benzo-fused analogues thereof, include cyclopropyl, cyclobutyl, benzocyclobutenyl, cyclopentyl, indanyl, cyclohexyl and cycloheptyl.
Suitable C4_7 cycloalkenyl groups include cyclobutenyl, cyclopentenyl,
cyclohexenyl and cycloheptenyl.
Suitable aryl groups include phenyl and naphthyl, preferably phenyl. Suitable aryl(Ci_6)alkyl groups include benzyl, phenylethyl, phenylpropyl and naphthylmethyl.
The term "C3_7 heterocycloalkyl" as used herein refers to saturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable heterocycloalkyl groups include azetidinyl, tetrahydrofuranyl, dihydrobenzofuranyl, pyrrolidinyl, indolinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, tetrahydropyranyl, chromanyl, tetrahydrothiopyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, 1,2,3,4- tetrahydroisoquinolinyl, piperazinyl, 1,2,3,4-tetrahydroquinoxalinyl, homopiperazinyl, morpholinyl, benzoxazinyl, thiomorpholinyl, diazepanyl, thiadiazepanyl and azocanyl.
Additional values include oxetanyl, dihydrobenzothienyl, isoindolinyl and isothiazolidinyl.
The term "C3_7 heterocycloalkenyl" as used herein refers to monounsaturated or polyunsaturated monocyclic rings containing 3 to 7 carbon atoms and at least one heteroatom selected from oxygen, sulphur and nitrogen, and may comprise benzo-fused analogues thereof. Suitable heterocycloalkenyl groups include thiazolinyl, imidazolinyl, dihydropyranyl, dihydrothiopyranyl and 1,2,3,6-tetrahydropyridinyl.
Typical heterobicycloalkyl groups include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5- azabicyclo[2.2.1]heptanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 8-azabicyclo- [3.2.1]octanyl, 3,8-diazabicyclo[3.2.1]octanyl and 3,9-diazabicyclo[4.2.1]nonanyl.
Additional values include 6-azabicyclo[3.2.0]heptanyl, 3-azabicyclo[4.1.0]heptanyl, 3- azabicyclo[3.2.1]octanyl and 3,6-diazabicyclo[3.2.2]nonanyl.
Typical heterobicycloalkenyl groups include 8-azabicyclo[3.2.1]octenyl.
Suitable spiroheterocycloalkyl groups include 2-oxa-6-azaspiro[3.3]heptanyl, 2- oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]nonanyl and 2-oxa-7-azaspiro[3.5]- nonanyl. Additional values include 2-azaspiro[3.3]heptanyl, 5-azaspiro[2.4]heptanyl and 7-oxa-2-azaspiro[3.5]nonanyl.
Suitable heteroaryl groups include furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, dibenzothienyl, pyrrolyl, indolyl, pyrrolo[2,3-¾]pyridinyl, pyrrolo[3,2- c]pyridinyl, pyrazolyl, pyrazolo[l,5-a]pyridinyl, pyrazolo[3,4-d]pyrimidinyl, indazolyl, 4,5,6,7-tetrahydroindazolyl, oxazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, isothiazolyl, imidazolyl, benzimidazolyl, imidazo[l,2-a]pyridinyl, imidazo[4,5- £]pyridinyl, purinyl, imidazo[l,2-a]pyrimidinyl, imidazo[l,2-a]pyrazinyl, oxadiazolyl, thiadiazolyl, triazolyl, [l,2,4]triazolo[l,5-a]pyrimidinyl, benzotriazolyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyridazinyl, cinnolinyl, phthalazinyl, pyrimidinyl, quinazolinyl, pyrazinyl, quinoxalinyl, pteridinyl, triazinyl and chromenyl groups. Additional values include thieno[2,3-c]pyrazolyl, thieno[3,4-£][l,4]dioxinyl, pyrrolo[3,4-¾]pyridinyl and imidazo[2,l-¾]thiazolyl.
The term "halogen" as used herein is intended to include fluorine, chlorine, bromine and iodine atoms, typically fluorine, chlorine or bromine.
Where the compounds of formula (I) have one or more asymmetric centres, they may accordingly exist as enantiomers. Where the compounds of use in the invention possess two or more asymmetric centres, they may additionally exist as diastereomers. The invention is to be understood to extend to the use of all such enantiomers and diastereomers, and to mixtures thereof in any proportion, including racemates. Formula (I) and the formulae depicted hereinafter are intended to represent all individual stereoisomers and all possible mixtures thereof, unless stated or shown otherwise. In addition, compounds of formula (I) may exist as tautomers, for example keto (CH2C=0)<→enol (CH=CHOH) tautomers or amide (NHC=0)<→ hydro xyimine (N=COH) tautomers.
Formula (I) and the formulae depicted hereinafter are intended to represent all individual tautomers and all possible mixtures thereof, unless stated or shown otherwise.
It is to be understood that each individual atom present in formula (I), or in the formulae depicted hereinafter, may in fact be present in the form of any of its naturally occurring isotopes, with the most abundant isotope(s) being preferred. Thus, by way of example, each individual hydrogen atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 1H, 2H (deuterium) or 3H (tritium) atom, preferably 1H. Similarly, by way of example, each individual carbon atom present in formula (I), or in the formulae depicted hereinafter, may be present as a 12C, 13C or 14C atom, preferably 12C.
In one aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
Q represents -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- or -N(R5)S(0)2-; or Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one, two or three heteroatom- containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-; Z represents C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Zl-Z2 or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents; and
E, Y, R1, R2, R3, R5, Z1 and Z2 are as defined above.
In another aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
R1 represents halogen or cyano; or Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci_6)alkyl, C3-7 heterocycloalkenyl, C4-9 heterobicycloalkyl, C4_9 heterobicyclo alkenyl, heteroaryl, heteroaryl(Ci_6)alkyl, (C3-7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-,
(C3-7)cycloalkyl-heteroaryl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)heterocycloalkyl- heteroaryl-, (C3-7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl- heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents; and
E, Q, Y, Z, R2 and R3 are as defined above.
In another aspect, the present invention provides a compound of formula (I) as depicted above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, wherein
R1 represents halogen or cyano; or Ci_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci_6)alkyl, C3-7 heterocycloalkenyl, C4-9 heterobicycloalkyl, heteroaryl, heteroaryl(Ci_6)alkyl, (C3-7)heterocycloalkyl(Ci_6)alkyl- aryl- , hetero aryl(C3 _7)hetero cyclo alkyl- , (C4_7)cyclo alkenyl- hetero aryl- ,
(C3-7)heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or
(C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents; and
E, Q, Y, Z, R2 and R3 are as defined above. Where the compounds in accordance with the invention comprise an optionally substituted straight or branched alkylene chain, typical values thereof include methylene (-CH2-), (methyl)methylene, ethylene (-CH2CH2-), (ethyl)methylene, (dimethyl)- methylene, (methyl)ethylene, propylene (-CH2CH2CH2-), (propyl)methylene and
(dimethyl)ethylene, any of which chains may be optionally substituted by one or more substituents. Suitably, such chains are unsubstituted, monosubstituted or disubstituted. Typically, such chains are unsubstituted or monosubstituted. In one embodiment, such chains are unsubstituted. In another embodiment, such chains are monosubstituted. In a further embodiment, such chains are disubstituted.
Examples of typical substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, oxo, hydroxy, Ci_6 alkoxy, trifluoromethoxy, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, carboxy, tetrazolyl, amino carbonyl, Ci_6 alkylamino carbonyl and di(Ci_6)alkylamino- carbonyl.
Examples of suitable substituents on the alkylene chain which may be present in a compound in accordance with the invention include halogen, trifluoromethyl, hydroxy, Ci_6 alkoxy, amino, carboxy and tetrazolyl, especially hydroxy or Ci_6 alkoxy.
Specific examples of suitable substituents on the alkylene chain which may be present in a compound in accordance with the invention include fluoro, trifluoromethyl, hydroxy, methoxy, amino, carboxy and tetrazolyl, especially hydroxy or methoxy.
In a first embodiment, E represents a covalent bond, whereby the integer Y is attached directly to the imidazo[l,2-a]pyrazine nucleus.
In a second embodiment, E represents -0-, -S-, -S(O)-, -S(0)2- or -N(R4)-. In a first aspect of that embodiment, E represents -0-. In a second aspect of that embodiment, E represents -S-. In a third aspect of that embodiment, E represents -S(O)-. In a fourth aspect of that embodiment, E represents -S(0)2-. In a fifth aspect of that embodiment, E represents -N(R4)-.
In a third embodiment, E represents an optionally substituted straight or branched Ci_4 alkylene chain. In a first aspect of that embodiment, E represents an optionally substituted methylene (-CH2-) linkage. In a second aspect of that embodiment, E represents an optionally substituted (methyl)methylene linkage. In a third aspect of that embodiment, E represents an optionally substituted (ethyl)methylene linkage. Generally, E represents a covalent bond; or E represents -N(R4)-; or E represents an optionally substituted straight or branched Ci_4 alkylene chain.
Typically, E represents -N(R4)-; or E represents an optionally substituted straight or branched Ci_4 alkylene chain.
Suitably, E represents a covalent bond; or E represents -N(R4)-; or E represents methylene (-CH2-), (methyl)methylene or (ethyl)methylene, any of which groups may be optionally substituted by one or more substituents.
Selected examples of typical substituents on the linkage represented by E include halogen, trifluoromethyl, hydroxy, Ci_6 alkoxy, trifluoromethoxy, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, carboxy and tetrazolyl, especially hydroxy or Ci_6 alkoxy.
Specific examples of typical substituents on the linkage represented by E include fluoro, trifluoromethyl, hydroxy, methoxy, trifluoromethoxy, amino, methylamino, dimethylamino, carboxy and tetrazolyl, especially hydroxy or methoxy.
A particular example of a typical substituent on E is hydroxy. Another example of a typical substituent on E is methoxy.
Typical values of E include -N(R4)-, -CH2-, -CH(OH)-, -CH(CH3)- and
-CH(CH2CH3)-; or E may represent a covalent bond. Additional values of E include -CH(OCH3)- and -C(CH3)(OH)-.
Suitable values of E include -CH2- and -CH(OH)-. Additional values include -CH(OCH3)-, -CH(CH3)- and -C(CH3)(OH)-.
In a first embodiment, E represents -CH2-.
In a second embodiment, E represents -CH(OH)-.
In a third embodiment, E represents -CH(OCH3)-.
In a fourth embodiment, E represents -CH(CH3)-. In a particular aspect of that embodiment, the -CH(CH3)- linkage represented by E is in the (S) stereochemical configuration.
In a fifth embodiment, E represents -C(CH3)(OH)-.
In a first embodiment, Q represents a covalent bond, whereby the integer Z is attached directly to the imidazo[l ,2-a]pyrazine nucleus.
In a second embodiment, Q represents -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-,
-C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- or -N(R5)S(0)2-. In a first aspect of that embodiment, Q represents -0-. In a second aspect of that embodiment, Q represents -S-. In a third aspect of that embodiment, Q represents -S(O)-. In a fourth aspect of that embodiment, Q represents -S(0)2-. In a fifth aspect of that embodiment, Q represents -N(R5)-. In a sixth aspect of that embodiment, Q represents -C(0)N(R5)-. In a seventh aspect of that embodiment, Q represents -N(R5)C(0)-. In an eighth aspect of that embodiment, Q represents -S(0)2N(R5)-. In a ninth aspect of that embodiment, Q represents -N(R5)S(0)2-.
In a third embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-. In a first aspect of that embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain. In a second aspect of that embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain comprising one heteroatom-containing linkage independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-. In a third aspect of that embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain comprising two heteroatom- containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-. In a fourth aspect of that embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain comprising three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-. In a fifth aspect of that embodiment, Q represents an optionally substituted straight or branched Ci_6 alkylene chain comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -N(R5)-, -C(0)N(R5)- and -N(R5)C(0)-.
Typically, Q represents a covalent bond; or Q represents -S(0)- or -S(0)2-; or Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one or two heteroatom-containing linkages selected from -0-, -S-, -N(R5)-, -C(0)N(R5)-, and -N(R5)C(0)-.
Selected examples of typical substituents on the linkage represented by Q include halogen, trifiuoromethyl, hydroxy, Ci_6 alkoxy and amino.
Specific examples of typical substituents on the linkage represented by Q include fluoro, trifiuoromethyl, hydroxy, methoxy and amino.
Suitably, Q represents a covalent bond; or Q represents -S(O)- or -S(0)2-; or Q represents -CH2-, -CH(F)-, -CF2-, -CH(CH3)-, -CH(OH)-, -CH(OCH3)-, -CH(NH2)-, -CH2CH2-, -CH(OH)CH2-, -CH(OH)CF2-, -CH(OCH3)CH2-, -CH20-, -CH(CH3)0-, -C(CH3)20-, -CH(CH2CH3)0-, -CH(CF3)0-, -CH2S-, -CH2N(R5)-, -CH2CH2CH2-, -CH(OH)CH2CH2-, -CH(OCH3)CH2CH2-, -CH2CH20-, -CH2OCH2-, -CH2OCH(F)-, -CH2OCF2-, -CH2OCH(CH3)-, -CH(CH3)OCH2-, -CH2OC(CH3)2-, -C(CH3)2OCH2-, -CH2SCH2-, -CH2CH2N(R5)-, -CH2N(R5)CH2-, -CH2CH2OCH2-, -CH2CH2N(R5)C(0)-, -CH2OCH2CH2-, -CH2OCH2CF2-, -CH2OCH2CH(CH3)-, -CH2OCH(CH3)CH2-,
-CH2OC(CH3)2CH2-, -CH2OCH2CH(CH3)CH2-, -CH2OCH2CH20-,
-CH2OCH2C(0)N(R5)- or -CH2OCH2CH2OCH2-. Additional values include -N(R5)-, -CH(CH2OH)-, -CH2S(0)-, -CH2S(0)2-, -CH2S(0)CH2-, -CH2S(0)2CH2- and
-CH2N(R5)C(0)-.
Particular values of Q include -CH2-, -CH20-, -CH2S- and -CH2OCH2-. In a first embodiment, Q represents -CH2-. In a second embodiment, Q represents -CH20-. In a third embodiment, Q represents -CH2S-. In a fourth embodiment, Q represents
-CH2OCH2-.
Generally, Y represents C3_7 cycloalkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Typically, Y represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents.
In a first embodiment, Y represents optionally substituted C3_7 cycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C3_7 cycloalkyl. In another aspect of that embodiment, Y represents mono substituted C3_7 cycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C3_7 cycloalkyl.
In a second embodiment, Y represents optionally substituted aryl. In one aspect of that embodiment, Y represents unsubstituted aryl. In another aspect of that embodiment, Y represents monosubstituted aryl. In a further aspect of that embodiment, Y represents disubstituted aryl.
In a third embodiment, Y represents optionally substituted C3_7 heterocycloalkyl. In one aspect of that embodiment, Y represents unsubstituted C3_7 heterocycloalkyl. In another aspect of that embodiment, Y represents monosubstituted C3_7 heterocycloalkyl. In a further aspect of that embodiment, Y represents disubstituted C3_7 heterocycloalkyl.
In a fourth embodiment, Y represents optionally substituted heteroaryl. In one aspect of that embodiment, Y represents unsubstituted heteroaryl. In another aspect of that embodiment, Y represents monosubstituted heteroaryl. In a further aspect of that embodiment, Y represents disubstituted heteroaryl.
Suitably, Y represents benzocyclobutenyl, phenyl, thienyl, thiazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
Appositely, Y represents phenyl, which may be optionally substituted by one or more substituents.
Examples of optional substituents which may be present on the moiety Y include one, two or three substituents independently selected from halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_6 alkylthio, Ci_6 alkylsulfinyl, Ci_6 alkylsulfonyl, amino, Ci_6 alkylamino, di(Ci_6)alkyl- amino, arylamino, C2_6 alkylcarbonylamino, Ci_6 alkylsulfonylamino, formyl, C2_6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, C3-6 heterocycloalkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, amino carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, aminosulfonyl, Ci_6 alkylaminosulfonyl and di(Ci_6)alkylaminosulfonyl.
Typical examples of optional substituents on the moiety Y include halogen and difluoromethoxy.
Examples of particular substituents on the moiety Y include fluoro, chloro, bromo, cyano, nitro, methyl, isopropyl, trifluoromethyl, hydroxy, methoxy, difluoromethoxy, trifluoromethoxy, methylthio, methylsulfmyl, methylsulfonyl, amino, methylamino, tert- butylamino, dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinyl- carbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, amino carbonyl, methylamino carbonyl, dimethylamino carbonyl, aminosulfonyl, methylaminosulfonyl and dimethylaminosulfonyl.
Typical examples of particular substituents on the moiety Y include chloro and difluoromethoxy.
Typical values of Y include benzocyclobutenyl, phenyl, fluorophenyl (including 2-fluorophenyl, 3 -fluorophenyl and 4-fluorophenyl), chlorophenyl (including 2-chloro- phenyl, 3 -chlorophenyl and 4-chlorophenyl), difluorophenyl (including 2,6-difluoro- phenyl), (chloro)(fluoro)phenyl (including 5-chloro-2-fluorophenyl and 2-chloro-5- fluorophenyl), dichlorophenyl (including 2,5-dichlorophenyl and 2,6-dichlorophenyl), methylphenyl (including 4-methylphenyl), dimethylphenyl (including 2,5-dimethylphenyl and 2,6-dimethylphenyl), (trifluoromethyl)phenyl [including 2-(trifluoromethyl)phenyl], (chloro)(trifluoromethyl)phenyl [including 5-chloro-2-(trifluoromethyl)phenyl], (methyl)- (trifluoromethyl)phenyl [including 2-methyl-5-(trifluoromethyl)phenyl], bis(trifluoro- methyl)phenyl [including 2,5-bis(trifluoromethyl)phenyl], methoxyphenyl (including 2- methoxyphenyl), (difluoromethoxy)phenyl [including 2-(difluoromethoxy)phenyl and 3- (difluoromethoxy)phenyl], (difluoromethoxy)(fluoro)phenyl [including 2-(difluoro- methoxy)-5-fluorophenyl and 5-(difluoromethoxy)-2-fluorophenyl], (chloro)- (difluoromethoxy)phenyl [including 5-chloro-2-(difluoromethoxy) phenyl and 6-chloro-2- (difluoromethoxy)phenyl], (trifluoromethoxy)phenyl [including 2-(trifluoromethoxy)- phenyl], (amino)(chloro)phenyl (including 5-amino-2-chlorophenyl), methylthienyl (including 3-methylthien-2-yl), methylthiazolyl (including 2-methyl-l,3-thiazol-4-yl), (chloro)(methyl)thiazolyl (including 5-chloro-2-methyl-l,3-thiazol-4-yl), dimethyl- thiazolyl (including 2,4-dimethyl-l,3-thiazol-5-yl) and pyridinyl (including pyridin-3-yl and pyridin-4-yl).
Suitable values of Y include dichlorophenyl and (difluoromethoxy)phenyl.
In one embodiment, Y represents 2,5-dichlorophenyl.
In a particular embodiment, Y represents 2-(difluoromethoxy)phenyl.
In one embodiment, Z represents hydrogen.
In another embodiment, Z is other than hydrogen.
In a selected embodiment, Z represents hydrogen; or Z represents Ci_6 alkyl, C3-7 cycloalkyl, aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Ί}-Ί} or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents.
In a further embodiment, Z represents Ci_6 alkyl, C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Zl-Z2 or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents.
Typically, Z represents hydrogen, fluoro or trifluoromethyl; or Z represents methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, tetrahydrofuranyl, pyrrolidinyl, indolinyl, tetrahydropyranyl, piperidinyl, 1,2,3,4-tetrahydroquinolinyl, morpholinyl, azocanyl, thiazolinyl, furyl, thienyl, pyrazolyl, 4,5,6,7-tetrahydroindazolyl, benzoxazolyl, isoxazolyl, thiazolyl, benzothiazolyl, imidazolyl, benzimidazolyl, [l,2,4]triazolo[l,5-a]- pyrimidinyl, tetrazolyl, pyridinyl, quinolinyl, isoquinolinyl, phthalazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Zl-7? or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents.
The moiety Z1 represents a divalent radical derived from an aryl, C3_7 heterocyclo- alkyl or heteroaryl group, any of which groups may be optionally substituted by one or more substituents. Typically, the moiety Z1 represents a divalent radical derived from a phenyl, pyrrolidinyl, piperazinyl, pyrazolyl, thiazolyl, triazolyl, tetrazolyl or pyridinyl group, any of which groups may be optionally substituted by one or more substituents. Typical values of the moiety Z1 include the groups of formula (Za), (Zb), (Zc), (Zd), (Ze), (Zf), (Zg), (Zh) and (Zj):
Figure imgf000017_0001
wherein
the symbols # represent the points of attachment of the moiety Z1 to the remainder of the molecule; and
the asterisks (*) represent the site of attachment of optional substituents.
Particular values of the moiety Z1 include the groups of formula (Za), (Zc), (Ze), (Zf), (Zg), (Zh) and (Zj) as depicted above. The moiety Z2 represents aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more
substituents. Typically, Z2 represents phenyl, pyrrolidinyl, oxazolidinyl, imidazolidinyl, morpholinyl, imidazolinyl, thiazolyl, imidazolyl, tetrazolyl or pyridinyl, any of which groups may be optionally substituted by one or more substituents.
Examples of optional substituents which may be present on the moiety Z, Z1 or Z2 include one, two or three substituents independently selected from halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, oxo, hydroxy, hydroxy(Ci_6)alkyl, Ci_6 alkoxy, difluoro- methoxy, trifluoromethoxy, Ci_3 alkylenedioxy, Ci_6 alkylthio, Ci_6 alkylsulfmyl, Ci_6 alkylsulfonyl, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkyl, C2-6 alkylcarbonylamino, Ci_6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylamino- carbonyl, aminosulfonyl, Ci_6 alkylaminosulfonyl, di(Ci_6)alkylaminosulfonyl, amino carbonylamino and hydrazino carbonyl.
Typical examples of optional substituents on the moiety Z, Z1 or Z2 include halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, oxo, hydroxy, hydroxy(Ci_6)alkyl, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_3 alkylenedioxy, Ci_6 alkylsulfonyl, amino, di(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkyl, C2-6 alkylcarbonylamino, Ci_6 alkylsulfonylamino, formyl, carboxy, C2-6 alkoxycarbonyl, aminocarbonyl, Ci_6 alkylamino- carbonyl, di(Ci_6)alkylaminocarbonyl, amino carbonylamino and hydrazino carbonyl.
Examples of particular substituents on the moiety Z, Z1 or Z2 include f uoro, chloro, bromo, cyano, nitro, methyl, ethyl, isopropyl, trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylenedioxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methylamino, tert-butylamino, dimethylamino, dimethylaminomethyl, dimethylamino ethyl, acetylamino, methylsulfonyl- amino, formyl, acetyl, carboxy, methoxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylaminosulfonyl, dimethylaminosulfonyl, aminocarbonylamino and hydrazino carbonyl.
Typical examples of particular substituents on the moiety Z, Z1 or Z2 include fluoro, chloro, bromo, cyano, nitro, methyl, ethyl, trifluoromethyl, oxo, hydroxy, hydroxymethyl, methoxy, difluoromethoxy, trifluoromethoxy, methylenedioxy, methylsulfonyl, amino, dimethylamino, dimethylaminomethyl, dimethylaminoethyl, acetylamino, methylsulfonylamino, formyl, carboxy, methoxycarbonyl, tert- butoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminocarbonylamino and hydrazinocarbonyl.
Typical values of Z2 include phenyl, hydroxyphenyl, oxopyrrolidinyl, dioxo- pyrrolidinyl, (hydroxy)(oxo)pyrrolidinyl, (amino)(oxo)pyrrolidinyl, (oxo)oxazolidinyl, oxoimidazolidinyl, morpholinyl, imidazolinyl, methylthiazolyl, formylthiazolyl, imidazolyl, tetrazolyl and pyridinyl.
Selected values of Z2 include oxopyrrolidinyl and (oxo)oxazolidinyl. In one embodiment, Z2 represents oxopyrrolidinyl. In another embodiment, Z2 represents (oxo)oxazo lidinyl.
Typical values of Z include hydrogen, fluoro, trifluoromethyl, methyl, ethyl, n- propyl, isopropyl, isobutyl, tert-bvXy\, cyclopropyl, cyclopentyl, cyclohexyl, oxo- cyclohexyl, phenyl, bromophenyl, cyanophenyl, nitrophenyl, methoxyphenyl, difluoro- methoxyphenyl, trifluoromethoxyphenyl, methylenedioxyphenyl, methylsulfonylphenyl, dimethylaminophenyl, acetylaminophenyl, methylsulfonylaminophenyl, carboxyphenyl, aminocarbonylphenyl, methylaminocarbonylphenyl, dimethylaminocarbonylphenyl, aminocarbonylaminophenyl, tetrahydrofuranyl, oxopyrrolidinyl, dimethylamino- pyrrolidinyl, tert-butoxycarbonylpyrrolidinyl, indolinyl, tetrahydropyranyl, piperidinyl, ethylpiperidinyl, tert-butoxycarbonylpiperidinyl, aminocarbonylpiperidinyl, 2-oxo-3,4- dihydroquinolinyl, morpholinyl, azocanyl, oxothiazolinyl, furyl, hydroxymethylfuryl, thienyl, methylpyrazolyl, dimethylpyrazolyl, 4,5,6,7-tetrahydroindazolyl, benzoxazolyl, methylisoxazolyl, dimethylisoxazolyl, methylthiazolyl, aminothiazolyl, benzothiazolyl, methylbenzothiazolyl, aminobenzothiazolyl, imidazolyl, methylimidazolyl, methyl- benzimidazolyl, dimethyl[l,2,4]triazolo[l,5-a]pyrimidinyl, dimethylaminoethyltetrazolyl, pyridinyl, fluoropyridinyl, chloropyridinyl, cyanopyridinyl, methylpyridinyl, (cyano)- (methyl)pyridinyl, trifluoromethylpyridinyl, oxopyridinyl, methoxypyridinyl, dimethyl- aminomethylpyridinyl, acetylaminopyridinyl, carboxypyridinyl, methoxycarbonyl- pyridinyl, aminocarbonylpyridinyl, (aminocarbonyl)(fluoro)pyridinyl, methylamino- carbonylpyridinyl, dimethylaminocarbonylpyridinyl, hydrazinocarbonylpyridinyl, quinolinyl, isoquinolinyl, (methyl)(oxo)phthalazinyl, pyrimidinyl, pyrazinyl,
oxopyrrolidinylphenyl, dioxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl, (amino)(oxo)pyrrolidinylphenyl, (oxo)oxazolidinylphenyl, oxoimidazolidinylphenyl, imidazolinylphenyl, methylthiazolylphenyl, formylthiazolylphenyl, imidazolylphenyl, tetrazolylphenyl, phenylpyrrolidinyl, hydroxyphenylpiperazinyl, (methyl)(phenyl)- pyrazolyl, oxoimidazolidinylthiazolyl, hydroxyphenyltriazolyl, morpholinyltetrazolyl, oxopyrrolidinylpyridinyl, (oxo)oxazolidinylpyridinyl, oxoimidazo lidinylpyridinyl, pyridinylthiazolyl, pyridinyltetrazolyl and morpholinylcarbonylphenyl.
Particular values of Z include hydrogen, methyl, methylsulfonylphenyl, pyridinyl, oxopyrrolidinylphenyl, (hydroxy)(oxo)pyrrolidinylphenyl and (oxo)oxazolidinylphenyl. In a first embodiment, Z represents hydrogen. In a second embodiment, Z represents methyl. In a third embodiment, Z represents methylsulfonylphenyl. In one aspect of that embodiment, Z represents 3-(methylsulfonyl)phenyl. In a fourth embodiment, Z represents pyridinyl. In one aspect of that embodiment, Z represents pyridin-4-yl. In a fifth embodiment, Z represents oxopyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxopyrrolidin-l-yl)phenyl. In a sixth embodiment, Z represents (hydroxy)(oxo)pyrrolidinylphenyl. In one aspect of that embodiment, Z represents 3-(3- hydroxy-2-oxopyrrolidin-l-yl)phenyl. In another aspect of that embodiment, Z represents 3-(4-hydroxy-2-oxopyrrolidin-l-yl)phenyl. In a seventh embodiment, Z represents (oxo)oxazolidinylphenyl. In one aspect of that embodiment, Z represents 3-(2-oxo- oxazolidinyl-3-yl)phenyl.
Generally, R1, R2 and R3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifiuoromethyl, trifluoromethoxy, -ORa, -SRa, -SORa, -S02Ra, -SF5, -NRbRc, -NRcCORd, -NRcC02Rd, -NHCONRbRc, -NRcS02Re, -N(S02Re)2, -NHS02NRbRc, -CORd, -C02Rd, -CONRbRc, -CON(ORa)Rb or -S02NRbRc; or Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3-7 cycloalkyl, C4-7 cycloalkenyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl- (Ci_6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci_6)alkyl, C3-7
heterocycloalkenyl, C4_9 heterobicycloalkyl, heteroaryl, heteroaryl(Ci_6)alkyl,
(C3-7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-,
(C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl- heteroaryl- or (C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
Typically, R1, R2 and R3 independently represent hydrogen, halogen, cyano or -C02Rd; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C3-7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C3-7)heterocycloalkyl-,
(C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-,
(C3-7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3-7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1, R2 and R3 may independently represent C4_9 heterobicycloalkenyl or (C3_7)cycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
Examples of optional substituents which may be present on R1, R2 or R3 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)- alkyl, nitro, Ci_6 alkyl, trifluoromethyl, trifluoroethyl, C2_6 alkenyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_3 alkylenedioxy, Ci_6 alkoxy(Ci_6)- alkyl, Ci_6 alkylthio, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N- [hydro xy- (Ci_6)alkyl] amino, C2_6 alkylcarbonylamino, C2_6 alkoxycarbonylamino, Ci_6 alkylamino- carbonylamino, Ci_6 alkylsulphonylamino, formyl, C2_6 alkylcarbonyl, carboxy, carboxy- (Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl, amino- carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, Ci_6 alkylsulphonylamino carbonyl, aminosulphonyl, Ci_6 alkylamino sulphonyl and di(Ci_6)alkylamino- sulphonyl. Additional examples include halo(Ci_6)alkyl, difluoromethyl, difluoro ethyl, hydroxy(Ci_6)alkyl, Ci_6 alkylsulphinyl, amino(Ci_6)alkyl, hydroxy(Ci_6)alkylamino,
[(C i _6)alkoxy] (hydro xy)(C i _6)alkylamino , [(C i _6)alkylthio] (hydro xy)(C i _6)alkylamino , di(C i _6)alkylamino(C i _6)alkylamino , N- [di(C i _6)alkylamino(C i _6)alkyl] -N- [hydro xy(C i _6)- alkyl] amino , hydro xy(C i _6)alkyl(C3-7)cycloalkylamino , (hydroxy) [(C3-7)cycloalkyl(C i _6)- alkyljamino, (C3_7)heterocycloalkylamino, (C3_7)heterocycloalkyl(Ci_6)alkylamino, oxo- (C3_7)heterocycloalkyl(C i _6)alkylamino , (C i _6)alkylheteroarylamino , heteroaryl(C i _6)alkyl- amino , (C i _6)alkylheteroaryl(C i _6)alkylamino , N- [(C i _6)alkyl] -N- [(C2_6)alkylcarbonyl] - amino, (C2_6)alkylcarbonylamino(Ci_6)alkyl, C3_6 alkenylcarbonylamino, bis[(C3_6)alkenyl- carbonyl] amino , N- [(C i _6)alkyl] -N- [(C3-7)cycloalkylcarbonyl] amino , N- [carboxy(C i _6)- alkyl]-N-[(Ci_6)alkyl] amino, C2_6 alkoxycarbonyl(Ci_6)alkylamino, N-[(Ci_6)alkyl]-N- [(C i _6)alkylsulphonyl] amino , (C i _6)alkylsulphonylamino(C i _6)alkyl, (C3-7)cycloalkyl- carbonyl, phenylcarbonyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl and hydroxy- (Ci_6)alkylaminocarbonyl.
In particular, R1, R2 or R3 may be substituted by a carboxylic acid isostere or prodrug moiety. By the expression "carboxylic acid isostere or prodrug moiety" is meant any functional group, structurally distinct from a carboxylic acid moiety, that will be recognised by a biological system as being similar to, and thus capable of mimicking, a carboxylic acid moiety, or will be readily convertible by a biological system in vivo into a carboxylic acid moiety. A synopsis of some common carboxylic acid isosteres is presented by N.A. Meanwell in J. Med. Chem., 2011, 54, 2529-2591 (cf. in particular Figures 25 and 26). Typical examples of suitable carboxylic acid isostere or prodrug moieties include the functional groups of formula (i) to (xli):
Figure imgf000022_0001
(ϋ) (iii) (iv)
Figure imgf000022_0002
(ix) (x) (xi) (xii) (xiii)
Figure imgf000022_0003
(xiv) (xvi) (xvii)
Figure imgf000022_0004
(xviii) (xix) (XX) (xxi)
Figure imgf000023_0001
(xxii) (xxiii) (xxiv) (xxv)
Figure imgf000023_0002
xxvi) (xxvii) (xxviii) (xxix)
Figure imgf000023_0003
xxx) (xxxi) (xxxii) (xxxiii)
Figure imgf000023_0004
(xxxviii) (xl) (xli) wherein
the asterisk (*) represents the site of attachment to the remainder of the molecule; n is zero, 1 or 2;
X represents oxygen or sulphur;
Rf represents hydrogen, Ci_6 alkyl or -CH2CH(OH)CH2OH;
Rg represents Ci_6 alkyl, trifluoromethyl, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3; Rh represents hydrogen, cyano or -C02Rd, in which Rd is as defined above; and R represents hydrogen or halogen.
In one embodiment, n is zero. In another embodiment, n is 1. In a further embodiment, n is 2.
In one embodiment, X represents oxygen. In another embodiment, X represents sulphur.
In one embodiment, R f represents hydrogen. In another embodiment, R f represents Ci_6 alkyl, especially methyl. In a further embodiment, R is -CH2CH(OH)CH2OH.
In one embodiment, Rg represents Ci_6 alkyl, especially methyl. In another embodiment, Rg represents trifluoromethyl, -CH2CH2F, -CH2CHF2, -CH2CF3 or -CF2CF3. In a first aspect of that embodiment, Rg represents trifluoromethyl. In a second aspect of that embodiment, Rg represents -CH2CH2F. In a third aspect of that embodiment, Rg represents -CH2CHF2. In a fourth aspect of that embodiment, Rg represents -CH2CF3. In a fifth aspect of that embodiment, Rg represents -CF2CF3.
In one embodiment, Rh is hydrogen. In another embodiment, Rh represents cyano.
In a further embodiment, Rh represents -C02Rd, especially methoxycarbonyl.
In one embodiment, R represents hydrogen. In another embodiment, R represents halogen, especially chloro.
In a selected embodiment, Ω represents tetrazolyl, especially a C-linked tetrazolyl moiety of formula (xxiv) or (xxv) as depicted above, in particular a group of formula (xxiv) as depicted above.
In another embodiment, Ω represents Ci_6 alkylsulphonylaminocarbonyl, i.e. a moiety of formula (iii) as depicted above wherein Rg represents Ci_6 alkyl.
In another embodiment, Ω represents Ci_6 alkylaminosulphonyl, i.e. a moiety of formula (x) as depicted above wherein Rg represents Ci_6 alkyl.
In a further embodiment, Ω represents (Ci_6)alkylcarbonylaminosulphonyl, i.e. a moiety of formula (v) as depicted above wherein Rg represents Ci_6 alkyl.
Additional examples of suitable carboxylic acid isostere or prodrug moieties represented by Ω include the functional group of formula (xlii):
Figure imgf000025_0001
wherein
the asterisk (*) represents the site of attachment to the remainder of the molecule.
Suitable examples of optional substituents which may be present on R1, R2 or R3 include one, two or three substituents independently selected from halogen, cyano, Ci_6 alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylsulphonyl, oxo, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl and amino sulphonyl. Additional examples include hydroxy(Ci_6)alkyl, (C3-7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
Examples of particular substituents on R1, R2 or R3 include fluoro, chloro, bromo, cyano, cyano ethyl, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, methyl- sulphonylethyl, oxo, amino, methylamino, dimethylamino, methoxyethylamino, N- (hydroxyethyl)-N-(methyl)amino, acetylamino, methoxy carbonylamino, ethoxycarbonyl- amino, ethylamino carbonylamino, butylamino carbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolyl, amino- carbonyl, methylamino carbonyl, dimethylammocarbonyl, methylsulphonylammocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Additional examples include isopropyl, isobutyl, difluoromethyl, difluoro ethyl, hydroxymethyl, hydro xyethyl, hydro xyisopropyl, methoxyethyl, methylsulphinyl, ethylamino,
hydroxy ethylamino, hydroxypropylamino, (hydroxy)(methyl)propylamino, (hydroxy)- (methoxy)(methyl)propylamino, (hydroxy)(methylthio)butylamino, dimethylaminoethyl- amino, (dimethylamino)(methyl)propylamino, N-(dimethylaminoethyl)-N-(hydroxyethyl)- amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)- (hydroxy)propylamino, tetrahydrofuranylamino, morpholinylethylamino, oxopyrrolidinyl- methylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethylamino, methylpyrazolylmethylamino, N-acetyl-N- methylamino, N-isopropylcarbonyl-N-methylamino, ethenylcarbonylamino,
bis(ethenylcarbonyl)amino, N-cyclopropylcarbonyl-N-methylamino, N-(carboxymethyl)- N-methylamino, N-(carboxyethyl)-N-methylamino, tert-butoxycarbonylamino, methoxycarbonylethylamino, N-methyl-N-(methylsulphonyl)amino, isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, tetrazolylmethyl, amino carbonylmethyl and hydroxyethylaminocarbonyl.
Suitable examples of particular substituents on R1, R2 or R3 include fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl, tert-butoxycarbonyl and amino sulphonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranylamino, tetrazolylmethyl and aminocarbonylmethyl.
Typically, R1 represents hydrogen, halogen, cyano or -C02Rd; or Ci_6 alkyl, aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl- (Ci_6)alkyl-aryl-, heteroaryl(C3_7)heterocycloalkyl-, (C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-,
(C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or
(C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent (C4-9)- heterobicycloalkenyl- or (C3_7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
Suitably, R1 represents halogen, cyano or -C02Rd; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3_7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C3_7)heterocycloalkyl-, (C4_7)cycloalkenyl-heteroaryl-,
(C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-,
(C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or
(C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent (C4-9)- heterobicycloalkenyl- or (C3_7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
Generally, R1 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7
heterocycloalkyl, C3_7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl- aryl- , hetero aryl(C3 _7)hetero cyclo alkyl- , (C4_7)cyclo alkeny 1-hetero aryl- ,
(C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or
(C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent (C4-9)- heterobicycloalkenyl- or (C3_7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
More generally, R1 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl(C3_7)heterocycloalkyl-, (C3_7)heterocycloalkyl-heteroaryl-,
(C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent (C4-9)- heterobicycloalkenyl- or (C3_7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
Still more generally, R1 represents halogen; or aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, (C4_9)heterobicycloalkenyl-, heteroaryl, (C3_7)cycloalkyl- heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4-c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
Even more generally, R1 represents heteroaryl or (C3_7)heterocycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent aryl, C3-7 heterocycloalkyl, C3-7
heterocycloalkenyl, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent halogen.
In a first embodiment, R1 represents hydrogen.
In a second embodiment, R1 represents halogen. In one aspect of that embodiment, R1 represents bromo.
In a third embodiment, R1 represents cyano.
In a fourth embodiment, R1 represents -C02Rd.
In a fifth embodiment, R1 represents optionally substituted Ci_6 alkyl. In one aspect of that embodiment, R1 represents optionally substituted ethyl.
In a sixth embodiment, R1 represents optionally substituted aryl. In one aspect of that embodiment, R1 represents optionally substituted phenyl. In a seventh embodiment, R1 represents optionally substituted C3-7
heterocycloalkyl. In one aspect of that embodiment, R1 represents optionally substituted piperidinyl.
In an eighth embodiment, R1 represents optionally substituted C3-7
heterocycloalkenyl. In a first aspect of that embodiment, R1 represents optionally substituted dihydropyranyl. In a second aspect of that embodiment, R1 represents optionally substituted dihydrothiopyranyl. In a third aspect of that embodiment, R1 represents optionally substituted 1,2,3,6-tetrahydropyridinyl.
In a ninth embodiment, R1 represents optionally substituted (C4-c>)- heterobicycloalkenyl-. In one aspect of that embodiment, R1 represents optionally substituted 8-azabicyclo[3.2.1 Joctenyl.
In a tenth embodiment, R1 represents optionally substituted heteroaryl. In selected aspects of that embodiment, R1 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents.
In an eleventh embodiment, R1 represents optionally substituted (C3-7)- heterocycloalkyl(Ci_6)alkyl-aryl-. In a first aspect of that embodiment, R1 represents optionally substituted pyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R1 represents optionally substituted piperazinylmethylphenyl-.
In a twelfth embodiment, R1 represents optionally substituted heteroaryl(C3_7)- heterocycloalkyl-. In one aspect of that embodiment, R1 represents optionally substituted pyridinylpiperazinyl- .
In a thirteenth embodiment, R1 represents optionally substituted (C3_7)cycloalkyl- heteroaryl-. In one aspect of that embodiment, R1 represents optionally substituted cyclohexylpyrimidinyl-.
In a fourteenth embodiment, R1 represents optionally substituted (C4-7)- cycloalkenyl-heteroaryl-.
In a fifteenth embodiment, R1 represents optionally substituted (C3-7)- heterocycloalkyl- heteroaryl-. In a first aspect of that embodiment, R1 represents optionally substituted morpholinylthiazolyl-. In a second aspect of that embodiment, R1 represents optionally substituted pyrrolidinylpyridinyl-. In a third aspect of that embodiment, R1 represents optionally substituted piperidinylpyridinyl-. In a fourth aspect of that embodiment, R1 represents optionally substituted piperazinylpyridinyl-. In a fifth aspect of that embodiment, R1 represents optionally substituted morpholinylpyridinyl-. In a sixth aspect of that embodiment, R1 represents optionally substituted thiomorpholinyl- pyridinyl-. In a seventh aspect of that embodiment, R1 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R1 represents optionally substituted pyrrolidinylpyrimidinyl-. In a ninth aspect of that embodiment, R1 represents optionally substituted piperidinylpyrimidinyl-. In a tenth aspect of that embodiment, R1 represents optionally substituted piperazinylpyrimidinyl-. In an eleventh aspect of that embodiment, R1 represents optionally substituted morpholinylpyrimidinyl-. In a twelfth aspect of that embodiment, R1 represents optionally substituted thiomorpholinyl- pyrimidinyl-. In a thirteenth aspect of that embodiment, R1 represents optionally substituted diazepanylpyrimidinyl-. In a fourteenth aspect of that embodiment, R1 represents optionally substituted thiadiazepanylpyrimidinyl-.
In a sixteenth embodiment, R1 represents optionally substituted (C3-7)- heterocycloalkyl(Ci_6)alkyl-heteroaryl-. In a first aspect of that embodiment, R1 represents optionally substituted morpholinylmethylthienyl-. In a second aspect of that embodiment, R1 represents optionally substituted morpholinylethylpyrazolyl-.
In a seventeenth embodiment, R1 represents optionally substituted (C3-7)- hetero cyclo alkeny 1-hetero aryl- .
In an eighteenth embodiment, R1 represents optionally substituted (C4-9)- heterobicycloalkyl-heteroaryl-.
In a nineteenth embodiment, R1 represents optionally substituted (C4-c>)- spiroheterocycloalkyl-heteroaryl-.
Appositely, R1 represents hydrogen, bromo, cyano or -C02Rd; or ethyl, phenyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzoiuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinyl- piperazinyl, pyrrolidinylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,
morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl, pyrrolidinylpyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl, morpholinylmethylthienyl, morpholinylethylpyrazolyl, 2-oxa-5-azabicyclo[2.2.1]- heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]- octanylpyrimidinyl, 2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl or 2-oxa-7-azaspiro[3.5]- nonanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 may represent chloro, trifluoromethyl, -ORa, -S02Ra or -CONRbRc; or methyl, dihydropyranyl, dihydrothiopyranyl, 8-azabicyclo[3.2.1]octenyl, dihydrothieno [3,4- ?][l ,4] dioxinyl, dihydropyrrolo [3 ,4-£]pyridinyl, imidazolylmethyl, triazolylmethyl, pyridinylmethyl, morpholinylmethylphenyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexenyl- pyrimidinyl, morpholinylthiazolyl, azetidinylpyridinyl, isothiazolidinylpyridinyl, imidazolidinylpyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl, tetrahydrofuranyl- pyrimidinyl, isothiazolidinylpyrimidinyl, tetrahydropyranylpyrimidinyl, azetidinylmethyl- pyridinyl, piperazinylmethylpyridinyl, morpholinylmethylpyridinyl, thiomorpholinyl- methylpyridinyl, morpholinylmethylpyrimidinyl, 3-azabicyclo[3.1.0]hexanylpyrimidinyl, 3-azabicyclo[4.1.0]heptanylpyrimidinyl, 3-azabicyclo[3.2.1 Joctanylpyrimidinyl, 3,6- diazabicyclo[3.2.2]nonanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]octanylpyridinyl, 2- azaspiro[3.3]heptanylpyrimidinyl, 5-azaspiro[2.4]heptanylpyrimidinyl or 7-oxa-2- azaspiro[3.5]nonanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Definitively, R1 represents bromo; or phenyl, piperidinyl, dihydropyranyl, dihydrothiopyranyl, 1 ,2,3,6-tetrahydropyridinyl, 8-azabicyclo[3.2.1]octenyl, indolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclohexylpyrimidinyl, morpholinylthiazolyl, piperidinylpyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, pyrrolidinylpyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, diazepanyl- pyrimidinyl, 3 -azabicyclo [3.1.0]hexanylpyrimidinyl, 3 -azabicyclo [4.1.0]heptanyl- pyrimidinyl, 3 ,6-diazabicyclo [3.2.2]nonanylpyrimidinyl, 2-azaspiro [3.3 Jheptanyl- pyrimidinyl or 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Illustratively, R1 represents pyridinyl, piperazinylpyrimidinyl or diazepanyl- pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Typical examples of optional substituents on R1 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoro ethyl, C2-6 alkenyl, hydroxy, Ci_6 alkoxy, trifluoroethoxy, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, di(Ci_6)alkylamino,
(C i _6)alkoxy(C i _6)alkylamino , N- [(C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , C i _6 alkylsulphonylamino, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxy- carbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl, aminocarbonyl and Ci_6 alkyl- sulphonylaminocarbonyl. Additional examples include halo(Ci_6)alkyl, difluoromethyl, difluoroethyl, hydroxy(Ci_6)alkyl, Ci_6 alkoxy(Ci_6)alkyl, Ci_6 alkylsulphinyl, amino(Ci_6)- alkyl, Ci_6 alkylamino, hydroxy(Ci_6)alkylamino, [(Ci_6)alkoxy](hydroxy)(Ci_6)alkylamino, [(C i _6)alkylthio] (hydro xy)(C i _6)alkylamino , di(C i _6)alkylamino(C i _6)alkylamino , N- [di(C i _6)alkylamino(C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , hydro xy(C i _6)alkyl- (C3_7)cyclo alkylamino , (hydroxy) [(C3-7)cycloalkyl(C i _6)alkyl] amino , (C3-7)- heterocycloalkylamino, (C3_7)heterocycloalkyl(Ci_6)alkylamino, oxo(C3_7)- heterocycloalkyl(Ci_6)alkylamino, (Ci_6)alkylheteroarylamino, heteroaryl(Ci_6)alkylamino, (Ci_6)alkylheteroaryl(Ci_6)alkylamino, C2_6 alkylcarbonylamino, (C2_6)alkylcarbonylamino- (Ci_6)alkyl, N-[(Ci_6)alkyl]-N-[(C2_6)alkylcarbonyl] amino, C3-6 alkenylcarbonylamino, bis[(C3-6)alkenylcarbonyl] amino , N- [(C 1 _6)alkyl] -N- [(C3-7)cycloalkylcarbonyl] -amino , N- [carboxy(Ci_6)alkyl]-N-[(Ci_6)alkyl] amino, C2_6 alkoxycarbonylamino, C2_6
alkoxycarbonyl(C 1 _6)alkylamino , N- [(C 1 _6)alkyl] -N- [(C 1 _6)alkylsulphonyl] amino , (C 1 _6)- alkylsulphonylamino(Ci_6)alkyl, formyl, (C3-7)cycloalkylcarbonyl, phenylcarbonyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl, Ci_6 alkylamino carbonyl, hydro xy(Ci _6)- alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl and amino sulphonyl.
Selected examples of optional substituents on R1 include one, two or three substituents independently selected from halogen, cyano, Ci_6 alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylsulphonyl, oxo, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl and C2_6 alkoxy- carbonyl. Additional examples include hydroxy(Ci_6)alkyl, (C3_7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl and aminosulphonyl.
Suitable examples of optional substituents on R1 include one, two or three substituents independently selected from Ci_6 alkoxy and oxo.
Typical examples of particular substituents on R1 include one, two or three substituents independently selected from fluoro, chloro, cyano, cyanoethyl, methyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, trifluoroethoxy, methylsulphonyl, methylsulphonylethyl, oxo, amino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, methylsulphonylamino, acetyl, carboxy, carboxy- methyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, tetrazolyl, aminocarbonyl and methylsulphonyl- aminocarbonyl. Additional examples include ethyl, isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methoxymethyl, methoxy- ethyl, methylsulphinyl, ethylamino, hydroxyethylamino, hydroxypropylamino, (hydroxy)- (methyl)propylamino, (hydroxy)(methoxy)(methyl)propylamino, (hydroxy)(methylthio)- butylamino, dimethylaminoethylamino, (dimethylamino)(methyl)propylamino, N- (dimethylaminoethyl)-N-(hydroxyethyl)amino, hydro xymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)(hydroxy)propylamino, tetrahydrofuranyl- amino, morpholinylethylamino, oxopyrrolidinylmethylamino, ethyloxadiazolylamino, methylthiadiazolylammo, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethyl- amino, methylpyrazolylmethylamino, acetylamino, N-acetyl-N-methylamino, N-isopropyl- carbonyl-N-methylamino, ethenylcarbonylamino, bis(ethenylcarbonyl)amino, N- cyclopropylcarbonyl-N-methylamino, N-(carboxymethyl)-N-methylamino, N- (carboxyethyl)-N-methylamino, tert-butoxycarbonylamino, methoxycarbonylethylamino, N-methyl-N-(methylsulphonyl)amino, formyl, isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, tetrazolylmethyl, aminocarbonylmethyl, methylaminocarbonyl, hydroxyethylamino-carbonyl, dimethylaminocarbonyl and aminosulphonyl.
Selected examples of particular substituents on R1 include one, two or three substituents independently selected from fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl and tert-butoxycarbonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranyl- amino, tetrazolylmethyl, aminocarbonylmethyl and aminosulphonyl.
Suitable examples of particular substituents on R1 include one, two or three substituents independently selected from methoxy and oxo.
Selected values of R1 include hydrogen, bromo, cyano, -C02Rd, methoxycarbonyl- ethyl, ethoxycarbonylethyl, chlorophenyl, hydro xyphenyl, acetylphenyl, amino carbonyl- phenyl, oxopiperidinyl, methylsulphonylpiperazinyl, morpholinyl, tert-butoxycarbonyl- 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, methylpyrazolyl, dimethylpyrazolyl, methylindazolyl, dimethylisoxazolyl, methylimidazolyl, pyridinyl, fluoropyridinyl, cyanopyridinyl, methylpyridinyl, (cyano)(methyl)pyridinyl, dimethyl- pyridinyl, trifluoromethylpyridinyl, ethenylpyridinyl, methoxypyridinyl, (methoxy)- (methyl)pyridinyl, isopropoxypyridinyl, trifluoroethoxypyridinyl, (methyl)(trifluoro- ethoxy)pyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl, (dimethyl)(oxo)pyridinyl, aminopyridinyl, dimethylaminopyridinyl, methoxyethylaminopyridinyl, N- (hydroxyethyl)-N-(methyl)aminopyridinyl, methylsulphonylaminopyridinyl, carboxy- pyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl, methoxypyrimidinyl,
oxopyrimidinyl, aminopyrimidinyl, dimethylaminopyrimidinyl, methoxyethylamino- pyrimidinyl, hydroxypyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, pyrrolidinylpyridinyl, hydroxypyrrolidinylpyridinyl, piperidinyl- pyridinyl, acetylpiperidinylpyridinyl, piperazinylpyridinyl, (methyl)(piperazinyl)- pyridinyl, cyanoethylpiperazinylpyridinyl, trifluoroethylpiperazinylpyridinyl,
methylsulphonylpiperazinylpyridinyl, methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl, acetylpiperazinylpyridinyl, (tert-butoxycarbonylpiperazinyl)- (methyl)pyridinyl, carboxymethylpiperazinylpyridinyl, carboxyethylpiperazinylpyridinyl, ethoxycarbonylmethylpiperazinylpyridinyl, ethoxycarbonylethylpiperazinylpyridinyl, morpholinylpyridinyl, thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl, dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl, hydroxypyrrolidinylpyrimidinyl, carboxypiperidinylpyrimidinyl, piperazinylpyrimidinyl, methylsulphonylpiperazinyl- pyrimidinyl, oxopiperazinylpyrimidinyl, tert-butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, oxodiazepanylpyrimidinyl, dioxothiadiazepanylpyrimidinyl, morpholinylmethylthienyl, morpholinylethylpyrazolyl, 2-oxa-5-azabicyclo[2.2.1 Jheptanylpyrimidinyl, 2-oxa-6- azaspiro[3.3]heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]octanylpyrimidinyl, 2-oxa-6- azaspiro[3.5]nonanylpyrimidinyl and 2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl.
Additional values include chloro, trifluoromethyl, -ORa, -S02Ra, -CONRbRc, N-isopropyl- carbonyl-N-methylaminomethyl, N-cyclopropylcarbonyl-N-methylaminomethyl, methylsulphinylphenyl, methylsulphonylphenyl, (methyl)(methylsulphonyl)phenyl, ethenylcarbonylaminophenyl, tert-butoxycarbonylaminophenyl, phenylcarbonylphenyl, aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, isopropyl- carbonylpiperidinyl, cyclobutylcarbonylpiperidinyl, methoxycarbonylpiperidinyl, tert- butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1 ,2,3 ,6-tetrahydropyridinyl, methylsulphonyl-8- azabicyclo[3.2.1 Joctenyl, tert-butoxycarbonyl-8-azabicyclo[3.2.1 Joctenyl, methylthienyl, dihydrothieno[3,4-¾][l,4]dioxinyl, oxoindolyl, oxodihydropyrrolo[3,4-¾]pyridinyl, hydroxyisopropylpyridinyl, methylsulphonylpyridinyl, (difluoromethyl)(oxo)pyridinyl, (oxo)(trifluoromethyl)pyridinyl, (methoxy)(oxo)pyridinyl, acetylaminopyridinyl, bis(ethenylcarbonyl)aminopyridinyl, N-methyl-N-(methylsulphonyl)aminopyridinyl, formylpyridinyl, aminocarbonylpyridinyl, (aminocarbonyl)(methyl)pyridinyl, methylaminocarbonylpyridinyl, hydroxyethylaminocarbonylpyridinyl, dimethylamino- carbonylpyridinyl, (isopropyl)(methyl)pyrimidinyl, (isobutyl)(methyl)pyrimidinyl, hydroxyisopropylpyrimidinyl, (methoxymethyl)(methyl)pyrimidinyl, (methoxyethyl)- (methyl)pyrimidinyl, methylsulphonylpyrimidinyl, dioxopyrimidinyl, ethylamino- pyrimidinyl, hydroxyethylaminopyrimidinyl, hydroxypropylaminopyrimidinyl,
(hydroxy)(methyl)propylaminopyrimidinyl, (hydroxy)(methoxy)(methyl)propylamino- pyrimidinyl, (hydroxy)(methylthio)butylaminopyrimidinyl, dimethylaminoethylamino- pyrimidinyl, (dimethylamino)(methyl)propylaminopyrimidinyl, N-(dimethylaminoethyl)- N-(hydroxyethyl)aminopyrimidinyl, hydroxymethylcyclopentylaminopyrimidinyl, hydroxycyclobutylmethylaminopyrimidinyl, (cyclopropyl)(hydroxy)propylamino- pyrimidinyl, tetrahydrofuranylaminopyrimidinyl, morpholinylethylaminopyrimidinyl, oxopyrrolidinylmethylaminopyrimidinyl, ethyloxadiazolylaminopyrimidinyl, methyl- thiadiazolylaminopyrimidinyl, thiazolylmethylaminopyrimidinyl, thiazolylethylamino- pyrimidinyl, pyrimidinylmethylaminopyrimidinyl, methylpyrazolylmethylamino- pyrimidinyl, acetylaminopyrimidinyl, N-acetyl-N-methylaminopyrimidinyl, N- (carboxymethyl)-N-methylaminopyrimidinyl, N-(carboxyethyl)-N-methylamino- pyrimidinyl, methoxycarbonylethylaminopyrimidinyl, N-methyl-N-(methylsulphonyl)- aminopyrimidinyl, pyrazinyl, methylimidazolylmethyl, triazolylmethyl, methylpyridinyl- methyl, methoxypyridinylmethyl, morpholinylmethylphenyl, (cyclopropyl)(methyl)- pyrimidinyl, hydroxycyclobutylpyrimidinyl, (cyclopentyl)(methyl)pyrimidinyl, carboxy- cyclohexylpyrimidinyl, carboxycyclohexenylpyrimidinyl, morpholinylthiazolyl, oxopyrrolidinylpyridinyl, dioxoisothiazolidinylpyridinyl, oxoimidazolidinylpyridinyl, (hydroxy)(methyl)piperidinylpyridinyl, carboxypiperidinylpyridinyl, (carboxy)(methyl)- piperidinylpyridinyl, (chloro)(piperazinyl)pyridinyl, difluoroethylpiperazinylpyridinyl, (methyl)(oxopiperazinyl)pyridinyl, (methyl)(morpholinyl)pyridinyl, oxomorpholinyl- pyridinyl, (methyl)(thiomorpholinyl)pyridinyl, (methyl)(oxothiomorpholinyl)pyridinyl, hydroxyoxetanylpyrimidinyl, hydroxyazetidinylpyrimidinyl, hydroxymethylazetidinyl- pyrimidinyl, (tert-butoxycarbonyl)(hydroxy)azetidinylpyrimidinyl, (methyl)- (tetrahydrofuranyl)pyrimidinyl, hydroxymethylpyrrolidinylpyrimidinyl, methoxy- pyrrolidinylpyrimidinyl, methoxymethylpyrrolidinylpyrimidinyl, oxopyrrolidinyl- pyrimidinyl, (methyl)(oxo)pyrrolidinylpyrimidinyl, dimethylaminopyrrolidinyl- pyrimidinyl, carboxypyrrolidinylpyrimidinyl, dioxoisothiazolidinylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl, difluoropiperidinylpyrimidinyl, hydroxypiperidinylpyrimidinyl, hydroxymethylpiperidinylpyrimidinyl, methoxy- piperidinylpyrimidinyl, oxopiperidinylpyrimidinyl, (carboxy)(methyl)piperidinyl- pyrimidinyl, (carboxy)(hydroxy)piperidinylpyrimidinyl, (amino)(carboxy)piperidinyl- pyrimidinyl, (ethoxycarbonyl)(methyl)piperidinylpyrimidinyl, aminocarbonylpiperidinyl- pyrimidinyl, hydroxyethylpiperazinylpyrimidinyl, (methyl)(oxopiperazinyl)pyrimidinyl, carboxymethylpiperazinylpyrimidinyl, carboxyethylpiperazinylpyrimidinyl, tetrazolyl- methylpiperazinylpyrimidinyl, aminocarbonylmethylpiperazinylpyrimidinyl, methyl- morpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl, oxomorpholinylpyrimidinyl, hydroxymethylazetidinylcarbonylpyridinyl, piperazinylcarbonylpyridinyl, methyl- piperazinylcarbonylpyridinyl, morpholinylcarbonylpyridinyl, thiomorpholinylcarbonyl- pyridinyl, dioxothiomorpholinylcarbonylpyridinyl, (methyl)(morpholinylmethyl)- pyrimidinyl, carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl, ethoxycarbonyl-3- azabicyclo[3.1.0]hexanylpyrimidinyl, carboxy-3-azabicyclo[4.1.0]heptanylpyrimidinyl, carboxy-3-azabicyclo[3.2.1 Joctanylpyrimidinyl, methoxycarbonyl-3-azabicyclo[3.2.1]- octanylpyrimidinyl, oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl, oxo-2-oxa-6- azaspiro[3.4]octanylpyridinyl, difluoro-5-azaspiro[2.4]heptanylpyrimidinyl, carboxy-2- azaspiro [3.3 Jheptanylpyrimidinyl and 7-oxa-2-azaspiro [3.5 Jnonanylpyrimidinyl.
Definitive values of R1 include bromo, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, methylpyrazolyl, cyanopyridinyl, methoxypyridinyl, oxopyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, carboxypiperidinylpyrimidinyl, piperazinyl- pyrimidinyl, methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl, oxodiazepanylpyrimidinyl and 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl. Additional values include aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1 ,2,3 ,6-tetrahydropyridinyl, methylsulphonyl-8- azabicyclo[3.2.1 Joctenyl, tert-butoxycarbonyl-8-azabicyclo[3.2.1 Joctenyl, oxoindolyl, hydroxyisopropylpyrimidinyl, tetrahydrofuranylaminopyrimidinyl, carboxycyclohexyl- pyrimidinyl, morpholinylthiazolyl, carboxypiperidinylpyridinyl, (carboxy)(methyl)- piperidinylpyridinyl, (methyl)(oxopiperazinyl)pyridinyl, methoxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl, difluoropiperidinylpyrimidinyl, (carboxy)(methyl)- piperidinylpyrimidinyl, (carboxy)(hydroxy)piperidinylpyrimidinyl, (ethoxycarbonyl)- (methyl)piperidinylpyrimidinyl, carboxymethylpiperazinylpyrimidinyl, carboxyethyl- piperazinylpyrimidinyl, tetrazolylmethylpiperazinylpyrimidinyl, aminocarbonylmethyl- piperazinylpyrimidinyl, dimethylmorpholinylpyrimidinyl, carboxy-3-azabicyclo[3.1.0]- hexanylpyrimidinyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl, carboxy-3- azabicyclo[4.1.0]heptanylpyrimidinyl, oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl and carboxy-2-azaspiro[3.3]heptanylpyrimidinyl.
Illustrative values of R1 include methoxypyridinyl, oxopyridinyl,
piperazinylpyrimidinyl, oxopiperazinylpyrimidinyl and oxodiazepanylpyrimidinyl.
Typically, R2 represents hydrogen, halogen or optionally substituted Ci_6 alkyl.
Typical examples of optional substituents on R2 include C2_6 alkoxycarbonyl.
Typical examples of particular substituents on R2 include ethoxycarbonyl.
In a first embodiment, R2 represents hydrogen. In a second embodiment, R2 represents halogen. In one aspect of that embodiment, R2 represents fluoro. In a third embodiment, R2 represents optionally substituted Ci_6 alkyl. In one aspect of that embodiment, R2 represents mono substituted methyl or mono substituted ethyl.
Selected values of R2 include hydrogen, fluoro and ethoxycarbonylethyl.
In a particular embodiment, R3 represents hydrogen.
Suitably, R4 represents hydrogen or methyl.
In a first embodiment, R4 represents hydrogen. In a second embodiment, R4 represents Ci_6 alkyl, especially methyl.
Suitably, R5 represents hydrogen, methyl or ethyl.
In a first embodiment, R5 represents hydrogen. In a second embodiment, R5 represents Ci_6 alkyl, especially methyl or ethyl. In one aspect of that embodiment, R5 represents methyl. In another aspect of that embodiment, R5 represents ethyl.
Typical examples of suitable substituents on Ra, Rb, Rc, Rd or Re, or on the heterocyclic moiety -NRbRc, include halogen, Ci_6 alkyl, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_6 alkoxy(Ci_6)alkyl, Ci_6 alkylthio, Ci_6 alkylsulphinyl, Ci_6 alkylsulphonyl, hydroxy, hydroxy(Ci_6)alkyl, amino(Ci_6)alkyl, cyano, trifluoromethyl, oxo, C2_6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, C2_6 alkylcarbonyloxy, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, phenylamino, pyridinylamino, C2_6 alkylcarbonylamino, C2_6 alkylcarbonylamino(Ci_6)alkyl, C2_6 alkoxycarbonylamino, Ci_6 alkylsulphonylamino, amino carbonyl, Ci_6 alkylamino carbonyl and di(Ci_6)alkylaminocarbonyl.
Typical examples of specific substituents on Ra, Rb, Rc, Rd or Re, or on the heterocyclic moiety -NRbRc, include fluoro, chloro, bromo, methyl, ethyl, isopropyl, methoxy, isopropoxy, difluoromethoxy, trifluoromethoxy, methoxymethyl, methylthio, ethylthio, methylsulphinyl, methylsulphonyl, hydroxy, hydro xymethyl, hydro xyethyl, amino methyl, cyano, trifluoromethyl, oxo, acetyl, carboxy, methoxycarbonyl,
ethoxycarbonyl, tert-butoxycarbonyl, acetoxy, amino, methylamino, ethylamino, dimethylamino, phenylamino, pyridinylamino, acetylamino, tert-butoxycarbonylamino, acetylaminomethyl, methylsulphonylamino, amino carbonyl, methylamino carbonyl and dimethylaminocarbonyl.
Suitably, Ra represents Ci_6 alkyl, aryl(Ci_6)alkyl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Selected values of Ra include methyl, ethyl, benzyl and isoindolylpropyl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on Ra include Ci_6 alkoxy and oxo.
Selected examples of specific substituents on Ra include methoxy and oxo.
In one embodiment, Ra represents optionally substituted Ci_6 alkyl. In one aspect of that embodiment, Ra ideally represents unsubstituted Ci_6 alkyl, especially methyl. In another aspect of that embodiment, Ra ideally represents substituted Ci_6 alkyl, e.g.
methoxyethyl. In another embodiment, Ra represents optionally substituted aryl. In one aspect of that embodiment, Ra represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Ra represents monosubstituted aryl, especially methylphenyl. In another embodiment, Ra represents optionally substituted aryl(Ci_6)alkyl, ideally unsubstituted aryl(Ci_6)alkyl, especially benzyl. In a further embodiment, Ra represents optionally substituted heteroaryl. In a further embodiment, Ra represents optionally substituted heteroaryl(Ci_6)alkyl, e.g. dioxoisoindolylpropyl.
Specific values of Ra include methyl, methoxyethyl, benzyl and dioxoisoindolylpropyl.
In a particular aspect, Rb represents hydrogen or trifluoromethyl; or Ci_6 alkyl, C3-7 cycloalkyl, C3-7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3-7 heterocycloalkyl, C3-7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Selected values of Rb include hydrogen; or Ci_6 alkyl, aryl(Ci_6)alkyl, C3-7 heterocycloalkyl or C3-7 heterocycloalkyl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents.
Typical values of Rb include hydrogen and Ci_6 alkyl. Illustratively, Rb represents hydrogen or trifluoromethyl; or methyl, ethyl, n-propyl, isopropyl, n-butyl, 2-methylpropyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, phenylethyl, azetidinyl, tetrahydrofuryl,
tetrahydrothienyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl,
azetidinylmethyl, tetrahydrofurylmethyl, pyrrolidinylmethyl, pyrrolidinylethyl,
pyrrolidinylpropyl, thiazolidinylmethyl, imidazolidinylethyl, piperidinylmethyl, piperidinylethyl, tetrahydroquinolinylmethyl, piperazinylpropyl, morpholinylmethyl, morpholinylethyl, morpholinylpropyl, pyridinyl, indolylmethyl, pyrazolylmethyl, pyrazolylethyl, imidazolylmethyl, imidazolylethyl, benzimidazolylmethyl, triazolylmethyl, pyridinylmethyl or pyridinylethyl, any of which groups may be optionally substituted by one or more substituents.
Representative values of Rb include hydrogen; or methyl, ethyl, n-propyl, benzyl, pyrrolidinyl or morpholinylpropyl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on Rb include Ci_6 alkoxy, Ci_6 alkylthio, Ci_6 alkylsulphinyl, Ci_6 alkylsulphonyl, hydroxy, cyano, C2_6 alkoxycarbonyl, di- (Ci_6)alkylamino and C2_6 alkoxy carbonylamino.
Selected examples of specific substituents on Rb include methoxy, methylthio, methylsulphinyl, methylsulphonyl, hydroxy, cyano, tert-butoxycarbonyl, dimethylamino and tert-butoxy carbonylamino.
Specific values of Rb include hydrogen, methyl, methoxyethyl, methylthio ethyl, methylsulphinylethyl, methylsulphonylethyl, hydroxyethyl, cyanoethyl, dimethylamino - ethyl, tert-butoxycarbonylaminoethyl, dihydroxypropyl, benzyl, pyrrolidinyl, tert- butoxycarbonylpyrrolidinyl and morpholinylpropyl.
In one embodiment, Rb represents hydrogen. In another embodiment, Rb represents Ci_6 alkyl, especially methyl.
Selected values of Rc include hydrogen; or Ci_6 alkyl, C3-7 cycloalkyl or C3-7 heterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
In a particular aspect, Rc represents hydrogen, Ci_6 alkyl or C3-7 cycloalkyl. Representative values of Rc include hydrogen; or methyl, eye lo butyl, cyclopentyl, cyclohexyl, tetrahydropyranyl and piperidinyl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on Rc include C2_6 alkylcarbonyl and C2_6 alkoxycarbonyl.
Selected examples of specific substituents on Rc include acetyl and tert- butoxycarbonyl.
Specific values of Rc include hydrogen, methyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydropyranyl, acetylpiperidinyl and tert-butoxycarbonylpiperidinyl,
Suitably, Rc represents hydrogen or Ci_6 alkyl. In one embodiment, Rc is hydrogen.
In another embodiment, Rc represents Ci_6 alkyl, especially methyl or ethyl, particularly methyl. In a further embodiment, Rc represents C3-7 cycloalkyl, e.g. cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.
Alternatively, the moiety -NRbRc may suitably represent azetidin-l-yl, pyrrolidin- 1-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-1- yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin- l-yl, homopiperidin-l-yl,
homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on the heterocyclic moiety -NRbRc include Ci_6 alkyl, Ci_6 alkylsulphonyl, hydroxy, hydroxy(Ci_6)alkyl, amino(Ci_6)alkyl, cyano, oxo, C2_6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, amino, C2_6 alkylcarbonyl- amino, C2_6 alkylcarbonylamino(Ci_6)alkyl, C2_6 alkoxycarbonylamino, Ci_6 alkyl- sulphonylamino and aminocarbonyl.
Selected examples of specific substituents on the heterocyclic moiety -NRbRc include methyl, methylsulphonyl, hydroxy, hydroxymethyl, aminomethyl, cyano, oxo, acetyl, carboxy, ethoxycarbonyl, amino, acetylamino, acetylaminomethyl, tert-butoxy- carbonylamino, methylsulphonylamino and aminocarbonyl.
Specific values of the moiety -NRbRc include azetidin-l-yl, hydroxyazetidin-l-yl, hydro xymethylazetidin- 1 -yl, (hydro xy)(hydroxymethyl)azetidin- 1 -yl, aminomethyl- azetidin-l-yl, cyano azetidin-l-yl, carboxyazetidin- l-yl, amino azetidin-l-yl,
aminocarbonylazetidin-l-yl, pyrrolidin-l-yl, aminomethylpyrrolidin-l-yl, oxopyrrolidin-1- yl, acetylaminomethylpyrrolidin-l-yl, tert-butoxycarbonylaminopyrrolidin-l-yl, oxo- oxazolidin-3-yl, hydroxyisoxazolidin-2-yl, thiazolidin-3-yl, oxothiazolidin-3-yl, dioxo- isothiazolidin-2-yl, piperidin-l-yl, hydroxypiperidin-l-yl, hydroxymethylpiperidin-l-yl, aminopiperidin- 1 -yl, acetylaminopiperidin- 1 -yl, tert-butoxycarbonylaminopiperidin- 1 -yl, methylsulphonylaminopiperidin-l-yl, morpholin-4-yl, piperazin-l-yl, methylpiperazin-1- yl, methylsulphonylpiperazin-l-yl, oxopiperazin-l -yl, acetylpiperazin-l-yl,
ethoxycarbonylpiperazin- 1 -yl and oxohomopiperazin- 1 -yl.
Suitably, Rd represents hydrogen; or Ci_6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable values for Rd include hydrogen, methyl, ethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, thiazolidinyl, thienyl, imidazolyl and thiazolyl, any of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on Rd include halogen, Ci_6 alkyl, Ci_6 alkoxy, oxo, C2_6 alkylcarbonyloxy and di(Ci_6)alkylamino.
Selected examples of particular substituents on Rd include fluoro, methyl, methoxy, oxo, acetoxy and dimethylamino.
In one embodiment, Rd represents hydrogen. In another embodiment, Rd represents optionally substituted Ci_6 alkyl. In one aspect of that embodiment, Rd ideally represents unsubstituted Ci_6 alkyl, e.g. methyl, ethyl, isopropyl, 2-methylpropyl or tert- butyl, especially methyl. In another aspect of that embodiment, Rd ideally represents substituted Ci_6 alkyl, e.g. substituted methyl or substituted ethyl, including
acetoxymethyl, dimethylaminomethyl and trifluoro ethyl. In another embodiment, Rd represents optionally substituted aryl. In one aspect of that embodiment, Rd represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Rd represents monosubstituted aryl, especially methylphenyl. In a further aspect of that embodiment, Rd represents disubstituted aryl, e.g. dimethoxyphenyl. In a further embodiment, Rd represents optionally substituted heteroaryl, e.g. thienyl, chloro thienyl, methylthienyl, methylimidazolyl or thiazolyl. In another embodiment, Rd represents optionally substituted C3-7 cycloalkyl, e.g. cyclopropyl or cyclobutyl. In a further embodiment, Rd represents optionally substituted C3-7 heterocycloalkyl, e.g. thiazolidinyl or oxo- thiazolidinyl.
Selected examples of specific values for Rd include hydrogen, methyl, acetoxymethyl, dimethylaminomethyl, ethyl, trifluoroethyl, isopropyl, 2-methylpropyl, tert-butyl, cyclopropyl, cyclobutyl, phenyl, dimethoxyphenyl, thiazolidinyl, oxothiazolidinyl, thienyl, chlorothienyl, methylthienyl, methylimidazolyl and thiazolyl.
Suitably, Re represents Ci_6 alkyl or aryl, either of which groups may be optionally substituted by one or more substituents.
Selected examples of suitable substituents on Re include Ci_6 alkyl, especially methyl.
In one embodiment, Re represents optionally substituted Ci_6 alkyl, ideally unsubstituted Ci_6 alkyl, e.g. methyl or propyl, especially methyl. In another embodiment, Re represents optionally substituted aryl. In one aspect of that embodiment, Re represents unsubstituted aryl, especially phenyl. In another aspect of that embodiment, Re represents monosubstituted aryl, especially methylphenyl. In a further embodiment, Re represents optionally substituted heteroaryl.
Selected values of Re include methyl, propyl and methylphenyl.
One sub-class of compounds according to the invention is represented by the compounds of formula (IIA) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
Figure imgf000041_0001
(IIA) wherein
R1 1 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, (C4_9)heterobicycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)- alkyl-aryl-, heteroaryl-(C3_7)heterocycloalkyl-, (C3_7)cycloalkyl-heteroaryl-,
(C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl- heteroaryl- or (C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents; R15 and R16 independently represent hydrogen, halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_6 alkylthio, Ci_6 alkylsulfmyl, Ci_6 alkylsulfonyl, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, arylamino, C2_6 alkylcarbonylamino, Ci_6 alkylsulfonylamino, formyl, C2_6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, C3-6 heterocycloalkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, amino carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, aminosulfonyl, Ci_6 alkylaminosulfonyl or di(Ci_6)alkylaminosulfonyl; and
E, Q and Z are as defined above.
Suitably, R1 1 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7
heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl- aryl-, heteroaryl-(C3-7)heterocycloalkyl-, (C4-7)cycloalkenyl-heteroaryl-, (C3-7)- heterocycloalkyl-heteroaryl-, (C3-7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3-7)- heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4-c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
Aptly, R1 1 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3_7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl- (C3_7)heterocycloalkyl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocyclo- alkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R1 1 may represent (C4-9)heterobicycloalkenyl- or (C3-7)- cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
Examples of optional substituents which may be present on R11 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, nitro, Ci_6 alkyl, trifluoromethyl, trifluoro ethyl, C2_6 alkenyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_3 alkylenedioxy, Ci_6 alkoxy(Ci_6)alkyl, Ci_6 alkylthio, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, Ci_6 alkylamino, di(C 1 _6)alkylamino , (C 1 _6)alkoxy(C 1 _6)alkylamino , N- [(C 1 _6)alkyl] -N- [hydro xy(C 1 _6)alkyl] - amino, C2_6 alkylcarbonylamino, C2_6 alkoxycarbonylamino, Ci_6 alkylamino carbonyl- amino, Ci_6 alkylsulphonylamino, formyl, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl, amino carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, Ci_6 alkylsulphonylamino carbonyl, aminosulphonyl, Ci_6 alkylaminosulphonyl and di(Ci_6)alkylaminosulphonyl. Additional examples include difluoromethyl, difluoroethyl, hydroxy(Ci_6)alkyl, Ci_6 alkylsulphinyl, hydroxy(C i _6)alkylamino, [(C i _6)alkoxy](hydroxy)(C i _6)alkylamino, [(C i _6)alkylthio] - (hydroxy)(C i _6)alkylamino, di(C i _6)alkylamino(C i _6)alkylamino, N- [di(C i _6)alkylamino- (C i _6)alkyl] -N- [hydroxy(C i _6)alkyl] amino, hydroxy(C i _6)alkyl(C3_7)cyclo alkylamino , (hydroxy) [(C3-7)cycloalkyl(C i _6)alkyl] amino , (C3-7)heterocycloalkylamino , (C3-7)- heterocycloalkyl(C i _6)alkylamino , oxo(C3_7)heterocycloalkyl(C i _6)alkylamino , (C i _6)alkyl- heteroarylamino, heteroaryl(Ci_6)alkylamino, (Ci_6)alkylheteroaryl(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N-[(C2-6)alkylcarbonyl] amino, C3_6 alkenylcarbonylamino, bis[(C3_6)alkenyl- carbonyl] amino , N- [(C i _6)alkyl] -N- [(C3-7)cycloalkylcarbonyl] amino , N- [carboxy(C i _6)- alkyl]-N-[(Ci_6)alkyl] amino, C2-6 alkoxycarbonyl(Ci_6)alkylamino, N-[(Ci_6)-alkyl]-N- [(Ci_6)alkylsulphonyl] amino, (C3-7)cycloalkylcarbonyl, phenylcarbonyl, tetrazolyl(Ci_6)- alkyl, aminocarbonyl(Ci_6)alkyl and hydroxy(Ci_6)alkylaminocarbonyl.
Suitable examples of optional substituents which may be present on R11 include one, two or three substituents independently selected from halogen, cyano, Ci_6 alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylsulphonyl, oxo, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)- alkyl, C2-6 alkoxycarbonyl and aminosulphonyl. Additional examples include hydroxy- (Ci_6)alkyl, (C3_7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)- alkyl.
Examples of particular substituents on R11 include fiuoro, chloro, bromo, cyano, cyanoethyl, nitro, methyl, ethyl, tert-butyl, trifluoromethyl, trifiuoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, difiuoromethoxy, trifluoromethoxy, trifiuoroethoxy, methylenedioxy, ethylenedioxy, methoxymethyl, methylthio, methylsulphonyl, methyl- sulphonylethyl, oxo, amino, methylamino, dimethylamino, methoxy ethylamino, N- (hydroxyethyl)-N-(methyl)amino, acetylamino, methoxy carbonylamino, ethoxycarbonyl- amino, ethylamino carbonylamino, butylamino carbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolyl, amino- carbonyl, methylamino carbonyl, dimethylammocarbonyl, methylsulphonylammocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Additional examples include isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydro xyethyl, hydro xyisopropyl, methoxyethyl, methylsulphinyl, ethylamino,
hydroxy ethylamino, hydroxypropylamino, (hydroxy)(methyl)propylamino, (hydroxy)- (methoxy)(methyl)propylamino, (hydroxy)(methylthio)butylamino, dimethylaminoethyl- amino, (dimethylamino)(methyl)propylamino, N-(dimethylaminoethyl)-N-(hydroxyethyl)- amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)- (hydroxy)propylamino, tetrahydrofuranylamino, morpholinylethylamino, oxopyrrolidinyl- methylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethylamino, methylpyrazolylmethylamino, N-acetyl-N- methylamino, N-isopropylcarbonyl-N-methylamino, ethenylcarbonylamino,
bis(ethenylcarbonyl)amino, N-cyclopropylcarbonyl-N-methylamino, N-(carboxymethyl)- N-methylamino, N-(carboxyethyl)-N-methylamino, tert-butoxycarbonylamino, methoxycarbonylethylamino, N-methyl-N-(methylsulphonyl)amino, isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, tetrazolylmethyl, aminocarbonylmethyl and hydroxyethylaminocarbonyl.
Suitable examples of particular substituents on R11 include fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl, tert-butoxycarbonyl and amino sulphonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranylamino, tetrazolylmethyl and aminocarbonylmethyl.
Generally, R11 represents Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7
heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl- (C3_7)heterocycloalkyl-, (C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent (C4_9)heterobicycloalkenyl- or (C3_7)cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent halogen.
More generally, R11 represents Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl- (C3_7)heterocycloalkyl-, (C3_7)heterocycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spirohetero- cycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent (C4-9)heterobicycloalkenyl- or (C3-7)- cycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent halogen. Still more generally, R11 represents halogen; or aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, (C4_9)heterobicycloalkenyl-, heteroaryl, (C3_7)cycloalkyl-heteroaryl-, (C3_7)heterocycloalkyl-heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4-c>)- spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents.
Even more generally, R11 represents heteroaryl or (C3_7)heterocycloalkyl- heteroaryl-, either of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent aryl, C3-7 heterocycloalkyl, C3-7
heterocycloalkenyl, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent halogen.
In a first embodiment, R11 represents halogen. In one aspect of that embodiment, R11 represents bromo.
In a second embodiment, R11 represents cyano.
In a third embodiment, R11 represents optionally substituted Ci_6 alkyl. In one aspect of that embodiment, R11 represents optionally substituted ethyl.
In a fourth embodiment, R11 represents optionally substituted aryl. In one aspect of that embodiment, R11 represents optionally substituted phenyl.
In a fifth embodiment, R11 represents optionally substituted C3_7 heterocycloalkyl. In one aspect of that embodiment, R11 represents optionally substituted piperidinyl.
In a sixth embodiment, R11 represents optionally substituted C3-7
heterocycloalkenyl. In a first aspect of that embodiment, R11 represents optionally substituted dihydropyranyl. In a second aspect of that embodiment, R11 represents optionally substituted dihydrothiopyranyl. In a third aspect of that embodiment, R11 represents optionally substituted 1,2,3,6-tetrahydropyridinyl.
In a seventh embodiment, R11 represents optionally substituted (C4-9)- heterobicycloalkenyl-. In one aspect of that embodiment, R11 represents optionally substituted 8-azabicyclo[3.2. ljoctenyl.
In an eighth embodiment, R11 represents optionally substituted heteroaryl. In selected aspects of that embodiment, R11 represents benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl or pyrazinyl, any of which groups may be optionally substituted by one or more substituents. In a ninth embodiment, R11 represents optionally substituted
(C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-. In a first aspect of that embodiment, R11 represents optionally substituted pyrrolidinylmethylphenyl-. In a second aspect of that embodiment, R11 represents optionally substituted piperazinylmethylphenyl-.
In a tenth embodiment, R11 represents optionally substituted heteroaryl(C3_7)- heterocycloalkyl-. In one aspect of that embodiment, R11 represents optionally substituted pyridinyl-piperazinyl- .
In an eleventh embodiment, R11 represents optionally substituted (C3_7)cycloalkyl- heteroaryl-. In one aspect of that embodiment, R11 represents optionally substituted cyclohexylpyrimidinyl-.
In a twelfth embodiment, R11 represents optionally substituted
(C4_7)cycloalkenyl-heteroaryl- .
In a thirteenth embodiment, R11 represents optionally substituted (C3-7)- heterocycloalkyl-heteroaryl-. In a first aspect of that embodiment, R11 represents optionally substituted morpholinylthiazolyl-. In a second aspect of that embodiment, R11 represents optionally substituted pyrrolidinylpyridinyl-. In a third aspect of that embodiment, R11 represents optionally substituted piperidinylpyridinyl-. In a fourth aspect of that embodiment, R11 represents optionally substituted piperazinylpyridinyl-. In a fifth aspect of that embodiment, R11 represents optionally substituted morpholinyl- pyridinyl-. In a sixth aspect of that embodiment, R11 represents optionally substituted thiomorpholinylpyridinyl-. In a seventh aspect of that embodiment, R11 represents optionally substituted diazepanylpyridinyl-. In an eighth aspect of that embodiment, R11 represents optionally substituted pyrrolidinylpyrimidinyl-. In a ninth aspect of that embodiment, R11 represents optionally substituted piperidinylpyrimidinyl-. In a tenth aspect of that embodiment, R11 represents optionally substituted piperazinylpyrimidinyl-. In an eleventh aspect of that embodiment, R11 represents optionally substituted morpholinylpyrimidinyl-. In a twelfth aspect of that embodiment, R11 represents optionally substituted thiomorpholinylpyrimidinyl-. In a thirteenth aspect of that embodiment, R11 represents optionally substituted diazepanylpyrimidinyl-. In a fourteenth aspect of that embodiment, R11 represents optionally substituted
thiadiazepanylpyrimidinyl- .
In a fourteenth embodiment, R11 represents optionally substituted (C3-7)- heterocycloalkyl(Ci_6)alkyl-heteroaryl-. In a first aspect of that embodiment, R11 represents optionally substituted morpholinylmethylthienyl-. In a second aspect of that embodiment, R11 represents optionally substituted morpholinylethylpyrazolyl-.
In a fifteenth embodiment, R11 represents optionally substituted (C3-7)- hetero cyclo alkeny 1-hetero aryl- .
In a sixteenth embodiment, R11 represents optionally substituted (C4-9)- heterobicycloalkyl-heteroaryl- .
In a seventeenth embodiment, R11 represents optionally substituted (C4-9)- spiroheterocycloalkyl-heteroaryl-.
Appositely, R11 represents bromo or cyano; or ethyl, phenyl, piperidinyl, piperazinyl, morpholinyl, 1,2,3,6-tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, indazolyl, isoxazolyl, imidazolyl, pyridinyl, quinolinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinyl- piperazinyl, pyrrolidinylpyridinyl, piperidinylpyridinyl, piperazinylpyridinyl,
morpholinylpyridinyl, thiomorpholinylpyridinyl, diazepanylpyridinyl, pyrrolidinyl- pyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, diazepanylpyrimidinyl, thiadiazepanylpyrimidinyl, morpholinylmethylthienyl, morpholinylethylpyrazolyl, 2-oxa-5-azabicyclo[2.2.1]- heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]- octanylpyrimidinyl, 2-oxa-6-azaspiro[3.5]nonanylpyrimidinyl or 2-oxa-7-azaspiro[3.5]- nonanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R11 may represent chloro, trifluoromethyl, -ORa, -S02Ra or -CONRbRc; or methyl, dihydropyranyl, dihydrothiopyranyl, 8-azabicyclo[3.2.1]octenyl, dihydrothieno [3,4- ?][l ,4] dioxinyl, dihydropyrrolo [3 ,4-£]pyridinyl, imidazo lylmethyl, triazolylmethyl, pyridinylmethyl, morpholinylmethylphenyl, cyclopropylpyrimidinyl, cyclobutylpyrimidinyl, cyclopentylpyrimidinyl, cyclohexylpyrimidinyl, cyclohexenyl- pyrimidinyl, morpholinylthiazolyl, azetidinylpyridinyl, isothiazolidinylpyridinyl, imidazolidinylpyridinyl, oxetanylpyrimidinyl, azetidinylpyrimidinyl, tetrahydrofuranyl- pyrimidinyl, isothiazolidinylpyrimidinyl, tetrahydropyranylpyrimidinyl, azetidinylmethyl- pyridinyl, piperazinylmethylpyridinyl, morpholinylmethylpyridinyl, thiomorpholinyl- methylpyridinyl, morpholinylmethylpyrimidinyl, 3-azabicyclo[3.1.0]hexanylpyrimidinyl, 3-azabicyclo[4.1.0]heptanylpyrimidinyl, 3-azabicyclo[3.2. ljoctanylpyrimidinyl, 3,6- diazabicyclo[3.2.2]nonanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]octanylpyridinyl, 2- azaspiro[3.3]heptanylpyrimidinyl, 5-azaspiro[2.4]heptanylpyrimidinyl or 7-oxa-2- azaspiro[3.5]nonanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Definitively, R1 1 represents bromo; or phenyl, piperidinyl, dihydropyranyl, dihydrothiopyranyl, 1 ,2,3,6-tetrahydropyridinyl, 8-azabicyclo[3.2.1]octenyl, indolyl, pyrazolyl, pyridinyl, pyrimidinyl, cyclohexylpyrimidinyl, morpholinylthiazolyl, piperidinylpyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, pyrrolidinylpyrimidinyl, piperidinylpyrimidinyl, piperazinylpyrimidinyl, morpholinylpyrimidinyl, diazepanyl- pyrimidinyl, 3 -azabicyclo [3.1.0]hexanylpyrimidinyl, 3 -azabicyclo [4.1.0]heptanyl- pyrimidinyl, 3 ,6-diazabicyclo [3.2.2]nonanylpyrimidinyl, 2-azaspiro [3.3 Jheptanyl- pyrimidinyl or 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Illustratively, R1 1 represents pyridinyl, piperazinylpyrimidinyl or diazepanyl- pyrimidinyl, any of which groups may be optionally substituted by one or more substituents.
Typical examples of optional substituents on R1 1 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoro ethyl, C2_6 alkenyl, hydroxy, Ci_6 alkoxy, trifluoroethoxy, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, amino, di(Ci_6)alkylamino,
(C i _6)alkoxy(C i _6)alkylamino , N- [(C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , C i _6 alkylsulphonylamino, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxy- carbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl, aminocarbonyl and Ci_6 alkyl- sulphonylaminocarbonyl. Additional examples include difluoromethyl, difluoro ethyl, hydroxy(Ci_6)alkyl, Ci_6 alkoxy(Ci_6)alkyl, Ci_6 alkylsulphinyl, Ci_6 alkylamino, hydro xy(C i _6)alkylamino , [(C i _6)alkoxy] (hydro xy)(C i _6)alkylamino , [(C i _6)alkylthio] - (hydroxy)(Ci_6)alkylamino, di(Ci_6)alkylamino(Ci_6)alkylamino, N-[di(Ci_6)alkylamino- (C i _6)alkyl] -N- [hydro xy(C i _6)alkyl] amino , hydro xy(C i _6)alkyl(C3-7)cyclo alkylamino , (hydroxy) [(C3-7)cycloalkyl(C i _6)alkyl] amino , (C3-7)heterocycloalkylamino , (C3-7)- heterocycloalkyl(C i _6)alkylamino , oxo(C3_7)heterocycloalkyl(C i _6)alkylamino , (C i _6)alkyl- heteroarylamino, heteroaryl(Ci_6)alkylamino, (Ci_6)alkylheteroaryl(Ci_6)alkylamino, C2_6 alkylcarbonylamino, N-[(Ci_6)alkyl]-N-[(C2_6)alkylcarbonyl] amino, C3_6 alkenylcarbonyl- amino , bis[(C3-6)alkenylcarbonyl] amino , N- [(C i _6)alkyl] -N- [(C3-7)cycloalkylcarbonyl] - amino, N-[carboxy(Ci_6)alkyl]-N-[(Ci_6)alkyl]amino, C2_6 alkoxycarbonylamino, C2_6 alkoxycarbonyl(C i _6)alkylamino , N- [(C i _6)alkyl] -N- [(C i _6)alkylsulphonyl] amino , formyl, (C3_7)cycloalkylcarbonyl, phenylcarbonyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl, Ci_6 alkylaminocarbonyl, hydroxy(Ci_6)alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl and aminosulphonyl.
Selected examples of optional substituents on R1 include one, two or three substituents independently selected from halogen, cyano, Ci_6 alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylsulphonyl, oxo, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl and C2_6 alkoxy- carbonyl. Additional examples include hydroxy(Ci_6)alkyl, (C3_7)heterocycloalkylamino, tetrazolyl(Ci_6)alkyl, aminocarbonyl(Ci_6)alkyl and aminosulphonyl.
Suitable examples of optional substituents on R1 1 include one, two or three substituents independently selected from Ci_6 alkoxy and oxo.
Typical examples of particular substituents on R1 1 include one, two or three substituents independently selected from fluoro, chloro, cyano, cyanoethyl, methyl, trifluoromethyl, trifluoro ethyl, ethenyl, hydroxy, methoxy, isopropoxy, trifluoroethoxy, methylsulphonyl, methylsulphonylethyl, oxo, amino, dimethylamino, methoxyethylamino, N-(hydroxyethyl)-N-(methyl)amino, methylsulphonylamino, acetyl, carboxy, carboxy- methyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, ethoxy- carbonylmethyl, ethoxycarbonylethyl, tetrazolyl, aminocarbonyl and methylsulphonyl- aminocarbonyl. Additional examples include ethyl, isopropyl, isobutyl, difluoromethyl, difluoroethyl, hydroxymethyl, hydroxyethyl, hydroxyisopropyl, methoxymethyl, methoxy- ethyl, methylsulphinyl, ethylamino, hydroxyethylamino, hydroxypropylamino, (hydroxy)- (methyl)propylamino, (hydroxy)(methoxy)(methyl)propylamino, (hydroxy)(methylthio)- butylamino, dimethylaminoethylamino, (dimethylamino)(methyl)propylamino, N- (dimethylaminoethyl)-N-(hydroxyethyl)amino, hydroxymethylcyclopentylamino, hydroxycyclobutylmethylamino, (cyclopropyl)(hydroxy)propylamino, tetrahydrofuranyl- amino, morpholinylethylamino, oxopyrrolidinylmethylamino, ethyloxadiazolylamino, methylthiadiazolylamino, thiazolylmethylamino, thiazolylethylamino, pyrimidinylmethyl- amino, methylpyrazolylmethylamino, acetylamino, N-acetyl-N-methylamino, N-isopropyl- carbonyl-N-methylamino, ethenylcarbonylamino, bis(ethenylcarbonyl)amino, N- cyclopropylcarbonyl-N-methylamino, N-(carboxymethyl)-N-methylamino, N- (carboxyethyl)-N-methylamino, tert-butoxycarbonylamino, methoxycarbonylethylamino, N-methyl-N-(methylsulphonyl)amino, formyl, isopropylcarbonyl, cyclobutylcarbonyl, phenylcarbonyl, tetrazolylmethyl, amino carbonylmethyl, methylaminocarbonyl, hydroxyethylamino-carbonyl, dimethylaminocarbonyl and aminosulphonyl. Selected examples of particular substituents on R11 include one, two or three substituents independently selected from fluoro, cyano, methyl, hydroxy, methoxy, methylsulphonyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, ethoxycarbonyl and tert-butoxycarbonyl. Additional examples include hydroxyisopropyl, tetrahydrofuranyl- amino, tetrazolylmethyl, amino carbonylmethyl and aminosulphonyl.
Suitable examples of particular substituents on R11 include one, two or three substituents independently selected from methoxy and oxo.
Selected values of R11 include bromo, cyano, methoxycarbonylethyl, ethoxy- carbonylethyl, chlorophenyl, hydroxyphenyl, acetylphenyl, aminocarbonylphenyl, oxopiperidinyl, methylsulphonylpiperazinyl, morpholinyl, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, benzofuryl, thienyl, indolyl, pyrazolyl, methylpyrazolyl, dimethyl- pyrazolyl, methylindazolyl, dimethylisoxazolyl, methylimidazolyl, pyridinyl, fluoro- pyridinyl, cyanopyridinyl, methylpyridinyl, (cyano)(methyl)pyridinyl, dimethylpyridinyl, trifluoromethylpyridinyl, ethenylpyridinyl, methoxypyridinyl, (methoxy)(methyl)- pyridinyl, isopropoxypyridinyl, trifluoroethoxypyridinyl, (methyl)(trifluoroethoxy)- pyridinyl, oxopyridinyl, (methyl)(oxo)pyridinyl, (dimethyl)(oxo)pyridinyl, amino- pyridinyl, dimethylaminopyridinyl, methoxyethylaminopyridinyl, N-(hydroxyethyl)-N- (methyl)aminopyridinyl, methylsulphonylaminopyridinyl, carboxypyridinyl, quinolinyl, hydroxypyridazinyl, pyrimidinyl, methoxypyrimidinyl, oxopyrimidinyl, amino- pyrimidinyl, dimethylaminopyrimidinyl, methoxyethylaminopyrimidinyl, hydroxy- pyrazinyl, pyrrolidinylmethylphenyl, piperazinylmethylphenyl, pyridinylpiperazinyl, pyrrolidinylpyridinyl, hydroxypyrrolidinylpyridinyl, piperidinylpyridinyl, acetyl- piperidinylpyridinyl, piperazinylpyridinyl, (methyl)(piperazinyl)pyridinyl, cyanoethyl- piperazinylpyridinyl, trifluoroethylpiperazinylpyridinyl, methylsulphonylpiperazinyl- pyridinyl, methylsulphonylethylpiperazinylpyridinyl, oxopiperazinylpyridinyl, acetyl- piperazinylpyridinyl, (tert-butoxycarbonylpiperazinyl)(methyl)pyridinyl, carboxymethyl- piperazinylpyridinyl, carboxyethylpiperazinylpyridinyl, ethoxycarbonylmethyl- piperazinylpyridinyl, ethoxycarbonylethylpiperazinylpyridinyl, morpho linylpyridinyl, thiomorpholinylpyridinyl, oxothiomorpholinylpyridinyl, dioxothiomorpholinylpyridinyl, oxodiazepanylpyridinyl, hydroxypyrrolidinylpyrimidinyl, carboxypiperidinylpyrimidinyl, piperazinylpyrimidinyl, methylsulphonylpiperazinylpyrimidinyl, oxopiperazinyl- pyrimidinyl, tert-butoxycarbonylpiperazinylpyrimidinyl, morpholinylpyrimidinyl, thiomorpholinylpyrimidinyl, dioxothiomorpholinylpyrimidinyl, oxodiazepanyl- pyrimidinyl, dioxothiadiazepanylpyrimidinyl, morpholinylmethylthienyl, morpholinyl- ethylpyrazolyl, 2-oxa-5-azabicyclo[2.2.1 Jheptanylpyrimidinyl, 2-oxa-6-azaspiro[3.3]- heptanylpyrimidinyl, 2-oxa-6-azaspiro[3.4]octanylpyrimidinyl, 2-oxa-6-azaspiro[3.5]- nonanylpyrimidinyl and 2-oxa-7-azaspiro[3.5]nonanylpyrimidinyl. Additional values include chloro, N-isopropylcarbonyl-N-methylaminomethyl, N-cyclopropylcarbonyl-N- methylaminomethyl, methylsulphinylphenyl, methylsulphonylphenyl, (methyl)- (methylsulphonyl)phenyl, ethenylcarbonylaminophenyl, tert-butoxycarbonylamino- phenyl, phenylcarbonylphenyl, aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, isopropylcarbonylpiperidinyl, cyclobutylcarbonylpiperidinyl, methoxycarbonylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1,2,3,6- tetrahydropyridinyl, methylsulphonyl-8-azabicyclo[3.2. ljoctenyl, tert-butoxycarbonyl-8- azabicyclo[3.2.1]octenyl, methylthienyl, dihydrothieno[3,4-£][l,4]dioxinyl, oxoindolyl, oxodihydropyrrolo [3 ,4-£]pyridinyl, hydroxyisopropylpyridinyl, methylsulphonyl- pyridinyl, (difluoromethyl)(oxo)pyridinyl, (oxo)(trifluoromethyl)pyridinyl, (methoxy)- (oxo)pyridinyl, acetylaminopyridinyl, bis(ethenylcarbonyl)aminopyridinyl, N-methyl-N- (methylsulphonyl)aminopyridinyl, formylpyridinyl, aminocarbonylpyridinyl,
(aminocarbonyl)(methyl)pyridinyl, methylaminocarbonylpyridinyl, hydroxyethylamino- carbonylpyridinyl, dimethylaminocarbonylpyridinyl, (isopropyl)(methyl)pyrimidinyl, (isobutyl)(methyl)pyrimidinyl, hydroxyisopropylpyrimidinyl, (methoxymethyl)(methyl)- pyrimidinyl, (methoxyethyl)(methyl)pyrimidinyl, methylsulphonylpyrimidinyl, dioxopyrimidinyl, ethylaminopyrimidinyl, hydroxyethylaminopyrimidinyl,
hydroxypropylaminopyrimidinyl, (hydroxy)(methyl)propylaminopyrimidinyl, (hydroxy)- (methoxy)(methyl)propylaminopyrimidinyl, (hydroxy)(methylthio)butylamino- pyrimidinyl, dimethylaminoethylaminopyrimidinyl, (dimethylamino)(methyl)propyl- aminopyrimidinyl, N-(dimethylaminoethyl)-N-(hydroxyethyl)aminopyrimidinyl, hydroxymethylcyclopentylaminopyrimidinyl, hydroxycyclobutylmethylamino- pyrimidinyl, (cyclopropyl)(hydroxy)propylaminopyrimidinyl, tetrahydrofuranylamino- pyrimidinyl, morpholinylethylaminopyrimidinyl, oxopyrrolidinylmethylamino- pyrimidinyl, ethyloxadiazolylaminopyrimidinyl, methylthiadiazolylaminopyrimidinyl, thiazolylmethylaminopyrimidinyl, thiazolylethylaminopyrimidinyl, pyrimidinylmethyl- aminopyrimidinyl, methylpyrazolylmethylaminopyrimidinyl, acetylaminopyrimidinyl, N- acetyl-N-methylaminopyrimidinyl, N-(carboxymethyl)-N-methylaminopyrimidinyl, N- (carboxyethyl)-N-methylaminopyrimidinyl, methoxycarbonylethylaminopyrimidinyl, N- methyl-N-(methylsulphonyl)aminopyrimidinyl, pyrazinyl, methylimidazolylmethyl, triazolylmethyl, methylpyridinylmethyl, methoxypyridinylmethyl, morpholinylmethyl- phenyl, (cyclopropyl)(methyl)pyrimidinyl, hydroxycyclobutylpyrimidinyl, (cyclopentyl)- (methyl)pyrimidinyl, carboxycyclohexylpyrimidinyl, carboxycyclohexenylpyrimidinyl, morpholinylthiazolyl, oxopyrrolidinylpyridinyl, dioxoisothiazolidinylpyridinyl, oxoimidazolidinylpyridinyl, (hydroxy)(methyl)piperidinylpyridinyl, carboxypiperidinyl- pyridinyl, (carboxy)(methyl)piperidinylpyridinyl, (chloro)(piperazinyl)pyridinyl, difluoroethylpiperazinylpyridinyl, (methyl)(oxopiperazinyl)pyridinyl, (methyl)- (morpholinyl)pyridinyl, oxomorpholinylpyridinyl, (methyl)(thiomorpholinyl)pyridinyl, (methyl)(oxothiomorpholinyl)pyridinyl, hydroxyoxetanylpyrimidmyl, hydroxyazetidinyl- pyrimidinyl, hydroxymethylazetidinylpyrimidinyl, (tert-butoxycarbonyl)(hydroxy)- azetidinylpyrimidinyl, (methyl)(tetrahydrofuranyl)pyrimidinyl, hydroxymethyl- pyrrolidinylpyrimidinyl, methoxypyrrolidinylpyrimidinyl, methoxymethylpyrrolidinyl- pyrimidinyl, oxopyrrolidinylpyrimidinyl, (methyl)(oxo)pyrrolidinylpyrimidinyl, dimethylaminopyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl,
dioxoisothiazolidinylpyrimidinyl, hydroxytetrahydropyranylpyrimidinyl, difluoro- piperidinylpyrimidinyl, hydroxypiperidinylpyrimidinyl, hydroxymethylpiperidinyl- pyrimidinyl, methoxypiperidinylpyrimidinyl, oxopiperidinylpyrimidinyl, (carboxy)- (methyl)piperidinylpyrimidinyl, (carboxy)(hydroxy)piperidinylpyrimidinyl, (amino)- (carboxy)piperidinylpyrimidinyl, (ethoxycarbonyl)(methyl)piperidinylpyrimidinyl, aminocarbonylpiperidinylpyrimidinyl, hydroxyethylpiperazinylpyrimidinyl, (methyl)- (oxopiperazinyl)pyrimidinyl, carboxymethylpiperazinylpyrimidinyl, carboxyethyl- piperazinylpyrimidinyl, tetrazolylmethylpiperazinylpyrimidinyl, aminocarbonylmethyl- piperazinylpyrimidinyl, methylmorpholinylpyrimidinyl, dimethylmorpholinylpyrimidinyl, oxomorpholinylpyrimidinyl, hydroxymethylazetidinylcarbonylpyridinyl, piperazinyl- carbonylpyridinyl, methylpiperazinylcarbonylpyridinyl, morpholinylcarbonylpyridinyl, thiomorpholinylcarbonylpyridinyl, dioxothiomorpholinylcarbonylpyridinyl, (methyl)- (morpholinylmethyl)pyrimidinyl, carboxy-3-azabicyclo[3.1.0]hexanylpyrimidinyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl, carboxy-3-azabicyclo[4.1.0]- heptanylpyrimidinyl, carboxy-3-azabicyclo[3.2. ljoctanylpyrimidinyl, methoxycarbonyl- 3-azabicyclo[3.2.1]octanylpyrimidinyl, oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl, oxo-2-oxa-6-azaspiro[3.4]octanylpyridinyl, difluoro-5-azaspiro[2.4]heptanylpyrimidinyl, carboxy-2-azaspiro[3.3]heptanylpyrimidinyl and 7-oxa-2-azaspiro[3.5]nonanyl- pyrimidinyl.
Definitive values of R11 include bromo, tert-butoxycarbonyl-1,2,3,6- tetrahydropyridinyl, methylpyrazolyl, cyanopyridinyl, methoxypyridinyl, oxopyridinyl, piperazinylpyridinyl, morpholinylpyridinyl, carboxypiperidinylpyrimidinyl, piperazinyl- pyrimidinyl, methylsulphonylpiperazinylpyrimidinyl, oxopiperazinylpyrimidinyl, oxodiazepanylpyrimidinyl and 2-oxa-6-azaspiro[3.3]heptanylpyrimidinyl. Additional values include aminosulphonylphenyl, methylsulphonylpiperidinyl, acetylpiperidinyl, tert-butoxycarbonylpiperidinyl, dihydropyranyl, dihydrothiopyranyl, methylsulphonyl- 1 ,2,3 ,6-tetrahydropyridinyl, acetyl- 1 ,2,3 ,6-tetrahydropyridinyl, methylsulphonyl-8- azabicyclo[3.2.1 Joctenyl, tert-butoxycarbonyl-8-azabicyclo[3.2.1 Joctenyl, oxoindolyl, hydroxyisopropylpyrimidinyl, tetrahydrofuranylaminopyrimidinyl, carboxycyclohexyl- pyrimidinyl, morpholinylthiazolyl, carboxypiperidinylpyridinyl, (carboxy)(methyl)- piperidinylpyridinyl, (methyl)(oxopiperazinyl)pyridinyl, methoxypyrrolidinylpyrimidinyl, carboxypyrrolidinylpyrimidinyl, difluoropiperidinylpyrimidinyl, (carboxy)(methyl)- piperidinylpyrimidinyl, (carboxy)(hydroxy)piperidinylpyrimidinyl, (ethoxycarbonyl)- (methyl)piperidinylpyrimidinyl, carboxymethylpiperazinylpyrimidinyl, carboxyethyl- piperazinylpyrimidinyl, tetrazolylmethylpiperazinylpyrimidinyl, aminocarbonylmethyl- piperazinylpyrimidinyl, dimethylmorpholinylpyrimidinyl, carboxy-3-azabicyclo[3.1.0]- hexanylpyrimidinyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanylpyrimidinyl, carboxy-3- azabicyclo[4.1.0]heptanylpyrimidinyl, oxo-3,6-diazabicyclo[3.2.2]nonanylpyrimidinyl and carboxy-2-azaspiro[3.3]heptanylpyrimidinyl.
Illustrative values of R11 include methoxypyridinyl, oxopyridinyl,
piperazinylpyrimidinyl, oxopiperazinylpyrimidinyl and oxodiazepanylpyrimidinyl.
Typically, R15 and R16 may independently represent hydrogen, fluoro, chloro, bromo, cyano, nitro, methyl, isopropyl, trifiuoromethyl, hydroxy, methoxy, difluoro- methoxy, trifluoromethoxy, methylthio, methylsulfinyl, methylsulfonyl, amino, methyl- amino, tert-butylamino, dimethylamino, phenylamino, acetylamino, methylsulfonylamino, formyl, acetyl, cyclopropylcarbonyl, azetidinylcarbonyl, pyrrolidinylcarbonyl, piperidinyl- carbonyl, piperazinylcarbonyl, morpholinylcarbonyl, carboxy, methoxycarbonyl, amino- carbonyl, methylaminocarbonyl, dimethylaminocarbonyl, aminosulfonyl, methylamino- sulfonyl and dimethylaminosulfonyl. Typical values of R15 include hydrogen, halogen, Ci_6 alkyl, trifluoromethyl, Ci_6 alkoxy, difluoromethoxy and trifluoromethoxy.
Illustrative values of R15 include halogen and difluoromethoxy.
In a first embodiment, R15 represents hydrogen. In a second embodiment, R15 represents halogen. In a first aspect of that embodiment, R15 represents fluoro. In a second aspect of that embodiment, R15 represents chloro. In a third embodiment, R15 represents Ci_6 alkyl. In one aspect of that embodiment, R15 represents methyl. In a fourth embodiment, R15 represents trifluoromethyl. In a fifth embodiment, R15 represents Ci_6 alkoxy. In one aspect of that embodiment, R15 represents methoxy. In a sixth embodiment, R15 represents difluoromethoxy. In a seventh embodiment, R15 represents trifluoromethoxy.
Selected values of R15 include hydrogen, fluoro, chloro, methyl, trifluoromethyl, methoxy, difluoromethoxy and trifluoromethoxy.
Suitable values of R15 include chloro and difluoromethoxy.
Typical values of R16 include hydrogen, halogen, Ci_6 alkyl, trifluoromethyl, difluoromethoxy and amino.
Illustrative values of R16 include hydrogen and halogen.
In a first embodiment, R16 represents hydrogen. In a second embodiment, R16 represents halogen. In a first aspect of that embodiment, R16 represents fluoro. In a second aspect of that embodiment, R16 represents chloro. In a third embodiment, R16 represents Ci_6 alkyl. In one aspect of that embodiment, R16 represents methyl. In a fourth embodiment, R16 represents trifluoromethyl. In a fifth embodiment, R16 represents difluoromethoxy. In a seventh embodiment, R16 represents amino.
Selected values of R16 include hydrogen, fluoro, chloro, methyl, trifluoromethyl, difluoromethoxy and amino.
Suitable values of R16 include hydrogen and chloro.
In a particular embodiment, R16 is attached at the /?ara-position of the phenyl ring relative to the integer R15.
A particular sub-group of the compounds of formula (IIA) above is represented by the compounds of formula (IIB) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
Figure imgf000055_0001
(IIB) wherein
V represents C-R22 or N;
R21 represents hydrogen, halogen, halo(Ci_6)alkyl, cyano, Ci_6 alkyl, trifluoro- methyl, C2_6 alkenyl, C2_6 alkynyl, hydroxy, hydroxy(Ci_6)alkyl, Ci_6 alkoxy, difluoro- methoxy, trifluoromethoxy, trifluoroethoxy, Ci_6 alkylthio, Ci_6 alkylsulphonyl, amino, amino(Ci_6)alkyl, Ci_6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N- [hydro xy(Ci_6)alkyl] amino, (C3-7)heterocycloalkylamino, C2_6 alkyl- carbonylamino, (C2_6)alkylcarbonylamino(Ci_6)alkyl, C2_6 alkoxycarbonylamino, Ci_6 alkylsulphonylamino, (Ci_6)alkylsulphonylamino(Ci_6)alkyl, formyl, C2_6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, aminocarbonyl, Ci_6 alkylamino carbonyl, di(C ^alkylamino carbonyl, aminosulphonyl, Ci_6 alkylamino sulphonyl or di(Ci_6)alkylamino- sulphonyl; or R21 represents (C3-7)cycloalkyl, (C4-7)cycloalkenyl, (C3-7)heterocycloalkyl, (C3-7)heterocycloalkenyl, (C4_9)heterobicyclo alkyl or (C4-9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;
R22 represents hydrogen, halogen, cyano or Ci_6 alkyl;
R23 represents hydrogen or Ci_6 alkyl; and
E, O, Z, R15 and R16 are as defined above.
In one embodiment, V represents C-R22. In another embodiment, V represents N.
Generally, R21 represents hydrogen, halogen, cyano, Ci_6 alkyl, trifluoromethyl, C2_6 alkenyl, C2_6 alkynyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_6 alkylthio, Ci_6 alkylsulphonyl, amino, Ci_6 alkylamino, di(C ^alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N-[(Ci_6)alkyl]-N-[hydroxy(Ci_6)alkyl]amino, C2_6 alkylcarbonylamino, C2_6 alkoxycarbonylamino, Ci_6 alkylsulphonylamino, formyl, C2_6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, aminocarbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl, Ci_6 alkylaminosulphonyl or di(Ci_6)alkyl- aminosulphonyl; or R21 represents (C4_7)cyclo alkenyl, (C3-7)heterocycloalkyl, (C3_7)heterocycloalkenyl, (C4_9)heterobicycloalkyl or (C4-9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
Ideally, R21 represents hydroxy(Ci_6)alkyl, Ci_6 alkoxy or (C3_7)heterocycloalkyl- amino; or R21 represents (C3_7)cycloalkyl, (C3_7)heterocycloalkyl, (C4-9)heterobicycloalkyl or (C4_9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents.
Typically, R21 represents hydrogen, halogen, cyano, Ci_6 alkyl, trifluoromethyl, C2-6 alkenyl, hydroxy, Ci_6 alkoxy, trifluoroethoxy, amino, di(Ci_6)alkylamino, (Ci_6)- alkoxy(Ci_6)alkylamino, N-[(Ci_6)alkyl]-N-[hydroxy(Ci_6)alkyl]amino, Ci_6 alkylsulphonyl- amino or carboxy; or R21 represents (C3_7)heterocycloalkyl, (C4_9)heterobicycloalkyl or (C4-9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents. Additionally, R21 may represent hydroxy(Ci_6)alkyl or (C3-7)- heterocycloalkylamino; or R21 may represent optionally substituted (C3_7)cycloalkyl.
Suitably, R21 represents hydroxy or Ci_6 alkoxy; or R21 represents
(C3-7)heterocycloalkyl or (C4_9)heterobicycloalkyl, either of which groups may be optionally substituted by one or more substituents. Additionally, R21 may represent hydroxy(Ci_6)alkyl or (C3_7)heterocycloalkylamino; or R21 may represent (C3_7)cycloalkyl or (C4-9)spiroheterocycloalkyl, either of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C3_7)cycloalkyl group, typical values include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, any of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C4_7)cycloalkenyl group, typical values include cyclobutenyl, cyclopentenyl, cyclohexenyl and cycloheptenyl, any of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C3_7)heterocycloalkyl group, typical values include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, diazepanyl and thiadiazepanyl, any of which groups may be optionally substituted by one or more substituents. Additionalvalues include oxetanyl, azetidinyl, tetrahydrofuranyl, isothiazolidinyl, imidazolidinyl and tetrahydropyranyl, any of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C3_7)heterocycloalkenyl group, a typical value is optionally substituted 1 ,2,3,6-tetrahydropyridinyl. Additionalvalues include dihydropyranyl and dihydrothiopyranyl, either of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C4-9)heterobicycloalkyl group, typical values include 3-azabicyclo[3.1.0]hexanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, quinuclidinyl, 2-oxa-5-azabicyclo[2.2.2]octanyl, 8-azabicyclo[3.2.1]octanyl, 3,8-diaza- bicyclo[3.2.1]octanyl and 3,9-diazabicyclo[4.2.1]nonanyl, any of which groups may be optionally substituted by one or more substituents. Additional values include 3- azabicyclo[4.1.0]heptanyl, 3-azabicyclo[3.2.1]octanyl and 3,6-diazabicyclo[3.2.2]octanyl, any of which groups may be optionally substituted by one or more substituents.
Where R21 represents an optionally substituted (C4-9)spiroheterocycloalkyl group, typical values include 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa- 6-azaspiro[3.5]nonanyl and 2-oxa-7-azaspiro[3.5]nonanyl, any of which groups may be optionally substituted by one or more substituents. Additional values include 5-azaspiro- [2.4]heptanyl, 2-azaspiro[3.3]heptanyl and 7-oxa-2-azaspiro[3.5]nonanyl, any of which groups may be optionally substituted by one or more substituents.
Examples of optional substituents which may be present on R21 include one, two or three substituents independently selected from halogen, cyano, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoroethyl, C2_6 alkenyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, Ci_6 alkylthio, Ci_6 alkylsulphonyl, (Ci_6)alkyl- sulphonyl(Ci_6)alkyl, oxo, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, C2_6 alkylcarbonyl- amino, C2_6 alkoxycarbonylamino, Ci_6 alkylsulphonylamino, formyl, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl, amino carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, Ci_6 alkylsulphonylaminocarbonyl, aminosulphonyl, Ci_6 alkylamino sulphonyl and
di(Ci_6)alkylaminosulphonyl. Additional examples include tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
Suitable examples of optional substituents on R21 include one, two or three substituents independently selected from fluoro, chloro, bromo, cyano, cyanomethyl, methyl, ethyl, trifluoromethyl, trifluoroethyl, ethenyl, hydroxy, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, methylthio, methylsulphonyl, methyl- sulphonylmethyl, oxo, amino, methylamino, dimethylamino, acetylamino, methoxy- carbonylamino, ethoxy carbonylamino, tert-butoxycarbonylamino, methylsulphonylamino, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, tetrazolyl, amino- carbonyl, methylamino carbonyl, dimethylammocarbonyl, methylsulphonylammocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Additional examples include tetrazolylmethyl and aminocarbonylmethyl.
Definitive examples of optional substituents which may be present on R21 include one, two or three substituents independently selected from halogen, Ci_6 alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylsulphonyl, oxo, carboxy, carboxy(Ci_6)alkyl and C2_6 alkoxy- carbonyl. Additional examples include tetrazolyl(Ci_6)alkyl and aminocarbonyl(Ci_6)alkyl.
Selected examples of optional substituents on R21 include one, two or three substituents independently selected from cyano(Ci_6)alkyl, trifluoroethyl, hydroxy, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, oxo, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl and Ci_6 alkylsulphonylamino carbonyl.
Selected examples of particular substituents on R21 include one, two or three substituents independently selected from fluoro, methyl, hydroxy, methoxy,
methylsulphonyl, oxo, carboxy, carboxymethyl, carboxyethyl and ethoxycarbonyl.
Additional examples include tetrazolylmethyl and aminocarbonylmethyl.
Examples of particular substituents on R21 include one, two or three substituents independently selected from cyanoethyl, trifluoroethyl, hydroxy, methylsulphonyl, methylsulphonylethyl, oxo, acetyl, carboxy, carboxymethyl, carboxyethyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolyl and methylsulphonylammocarbonyl.
Suitably, R21 may be substituted by oxo.
Typically, R21 represents hydrogen, fluoro, cyano, methyl, trifluoromethyl, ethenyl, hydroxy, methoxy, isopropoxy, trif uoroethoxy, amino, dimethylamino, methoxyethyl- amino, N-(hydroxyethyl)-N-(methyl)amino, carboxy, pyrrolidinyl, hydro xypyrrolidinyl, piperidinyl, acetylpiperidinyl, carboxypiperidinyl, piperazinyl, cyanoethylpiperazinyl, trif uoroethylpiperazinyl, methylsulphonylpiperazinyl, methylsulphonylethylpiperazinyl, oxopiperazinyl, acetylpiperazinyl, tert-butoxycarbonylpiperazinyl, carboxymethyl- piperazinyl, carboxy ethylpiperazinyl, ethoxycarbonylmethylpiperazinyl, ethoxycarbonyl- ethylpiperazinyl, morpholinyl, thiomorpholinyl, oxothiomorpholinyl, dioxo- thiomorpholinyl, oxodiazepanyl, dioxothiadiazepanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 2-oxa-6-azaspiro[3.3]heptanyl, 2-oxa-6-azaspiro[3.4]octanyl, 2-oxa-6-azaspiro[3.5]- nonanyl or 2-oxa-7-azaspiro[3.5]nonanyl. Additionally, R21 may represent hydroxy- isopropyl, tetrahydrofuranylamino, carboxycyclohexyl, methoxypyrrolidinyl, carboxypyrrolidmyl, difluoropiperidmyl, (carboxy)(methyl)piperidinyl, (carboxy)(hydroxy)- piperidinyl, (ethoxycarbonyl)(methyl)piperidinyl, tetrazolylmethylpiperazinyl, amino- carbonylmethylpiperazinyl, dimethylmorpholinyl, carboxy-3-azabicyclo[3.1.0]hexanyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl, carboxy-3-azabicyclo[4.1.0]heptanyl, oxo- 3,6-diazabicyclo[3.2.2]nonanyl or carboxy-2-azaspiro[3.3]heptanyl.
Selected values of R21 include cyano, methoxy, carboxypiperidinyl, piperazinyl, methylsulphonylpiperazinyl, oxopiperazinyl, carboxymethylpiperazinyl, carboxyethyl- piperazinyl, morpholinyl, oxodiazepanyl and 2-oxa-6-azaspiro[3.3]heptanyl. Additional values include hydroxyisopropyl, tetrahydrofuranylamino, carboxycyclohexyl, methoxypyrrolidinyl, carboxypyrrolidinyl, difluoropiperidmyl, (carboxy)(methyl)piperidinyl, (carboxy)(hydroxy)piperidinyl, (ethoxycarbonyl)(methyl)piperidinyl, tetrazolylmethylpiperazinyl, aminocarbonylmethylpiperazinyl, dimethylmorpholinyl, carboxy-3- azabicyclo[3.1.0]hexanyl, ethoxycarbonyl-3-azabicyclo[3.1.0]hexanyl, carboxy-3- azabicyclo[4.1.0]heptanyl, oxo-3,6-diazabicyclo[3.2.2]nonanyl and carboxy-2- azaspiro[3.3]heptanyl.
Illustrative values of R21 include hydroxy, methoxy, piperazinyl, oxopiperazinyl and oxodiazepanyl.
In a particular embodiment, R21 represents hydroxy(Ci_6)alkyl. In one aspect of that embodiment, R21 represents hydroxyisopropyl, especially 2-hydroxyprop-2-yl.
Generally, R22 represents hydrogen or Ci_6 alkyl.
Suitably, R22 represents hydrogen, chloro, cyano or methyl.
Appositely, R22 represents hydrogen or cyano.
Typically, R22 represents hydrogen or methyl.
In one embodiment, R22 represents hydrogen. In another embodiment, R22 represents Ci_6 alkyl, especially methyl. In a further embodiment, R22 represents cyano. In an additional embodiment, R22 represents halogen, especially chloro.
Typically, R23 represents hydrogen or methyl.
In one embodiment, R23 represents hydrogen. In another embodiment, R23 represents Ci_6 alkyl, especially methyl.
Particular sub-groups of the compounds of formula (IIB) above are represented by the compounds of formula (IIC), (IID) and (HE) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
Figure imgf000060_0001
T represents -CH2- or -CH2CH2-;
U represents C(O) or S(0)2;
W represents O, S, S(O), S(0)2, N(R31) or C(R32)(R33);
R31 represents hydrogen, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoro- ethyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl(Ci_6)alkyl, amino carbonyl, aminocarbonyl(Ci_6)alkyl, Ci_6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl, Ci_6 alkylaminosulphonyl or di(Ci_6)alkyl- aminosulphonyl; R represents halogen, Ci_6 alkoxy, carboxy, carboxy(Ci_6)alkyl, C2_6
alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl or aminocarbonyl;
R33 represents hydrogen, halogen, Ci_6 alkyl, hydroxy or amino; and
V, E, Q, Z, R15, R16 and R23 are as defined above.
In a first embodiment, T represents -CH2-. In a second embodiment, T represents -CH2CH2-.
In a first embodiment, U represents C(O). In a second embodiment, U represents
S(0)2.
Generally, W represents O, S, S(O), S(0)2, N(R31), CF2, CH(C02H) or
CH(tetrazolyl).
Appositely, W represents O, N(R31) or C(R32)(R33).
Suitably, W represents O, S, S(O), S(0)2, N(R31) or CH(C02H).
Typically, W represents O, S(0)2, N(R31) or CH(C02H).
In a first embodiment, W represents O. In a second embodiment, W represents S. In a third embodiment, W represents S(O). In a fourth embodiment, W represents S(0)2. In a fifth embodiment, W represents N(R31). In a sixth embodiment, W represents C(R32)(R33). In a first aspect of the sixth embodiment, W represents CF2. In a second aspect of the sixth embodiment, W represents CH(C02H). In third aspect of the sixth embodiment, W represents CH(tetrazolyl).
Generally, R31 represents hydrogen, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoro ethyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C2_6 alkyl- carbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)- alkyl, aminocarbonyl, Ci_6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, amino- sulphonyl, Ci_6 alkylamino sulphonyl or di(Ci_6)alkylaminosulphonyl.
Suitably, R31 represents hydrogen, cyano(Ci_6)alkyl, trifluoroethyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, C2_6 alkylcarbonyl, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl or C2_6 alkoxycarbonyl(Ci_6)alkyl. Additionally, R31 may represent tetrazolyl(Ci_6)alkyl or aminocarbonyl(Ci_6)alkyl.
Definitively, R31 represents hydrogen, Ci_6 alkylsulphonyl or carboxy(Ci_6)alkyl. Additionally, R31 may represent tetrazolyl(Ci_6)alkyl or aminocarbonyl(Ci_6)alkyl.
Typical values of R31 include hydrogen, cyanoethyl, methyl, ethyl, isopropyl, trifluoromethyl, trifluoroethyl, methylsulphonyl, methylsulphonylethyl, formyl, acetyl, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, aminocarbonyl, methylamino- carbonyl, dimethylaminocarbonyl, aminosulphonyl, methylaminosulphonyl and dimethylaminosulphonyl. Additional values include tetrazolylmethyl and ammocarbonylmethyl.
Selected values of R31 include hydrogen, cyanoethyl, trifluoroethyl, methyl- sulphonyl, methylsulphonylethyl, acetyl, carboxymethyl, carboxyethyl, tert-butoxy- carbonyl, ethoxycarbonylmethyl and ethoxycarbonylethyl. Additional values include tetrazolylmethyl and aminocarbonylmethyl.
Definitive values of R31 include hydrogen, methylsulphonyl, carboxymethyl and carboxyethyl. Additional values include tetrazolylmethyl and aminocarbonylmethyl.
A particular value of R31 is hydrogen.
Suitably, R32 represents halogen, Ci_6 alkoxy, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl or tetrazolyl.
Typically, R32 represents halogen, carboxy or C2_6 alkoxycarbonyl.
Typical values of R32 include fluoro, methoxy, carboxy, carboxymethyl, carboxyethyl, methoxycarbonyl, ethoxycarbonyl, methoxycarbonylmethyl,
methoxycarbonylethyl, ethoxycarbonylmethyl, ethoxycarbonylethyl, tetrazolyl and aminocarbonyl.
Particular values of R32 include fluoro, carboxy and ethoxycarbonyl.
In a selected embodiment, R32 represents carboxy.
Suitably, R33 represents hydrogen, halogen, Ci_6 alkyl or hydroxy.
In a first embodiment, R33 represents hydrogen. In a second embodiment, R33 represents halogen. In one aspect of that embodiment, R33 represents fluoro. In a third embodiment, R33 represents Ci_6 alkyl. In one aspect of that embodiment, R33 represents methyl. In a fourth embodiment, R33 represents hydroxy. In a fifth embodiment, R33 represents amino.
Another sub-group of the compounds of formula (IIB) above is represented by the compounds of formula (IIF) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
Figure imgf000063_0001
wherein
R34 represents hydrogen, halogen, halo(Ci_6)alkyl, hydroxy, Ci_6 alkoxy, Ci_6 alkylthio, Ci_6 alkylsulphinyl, Ci_6 alkylsulphonyl, amino, Ci_6 alkylamino, di(Ci_6)alkyl- amino, (C2-6)alkylcarbonylamino, (C2-6)alkylcarbonylamino(Ci_6)alkyl, (Ci_6)alkyl- sulphonylamino, or (Ci_6)alkylsulphonylamino(Ci_6)alkyl; and
E, Q, Z, V, W, R15, R16 and R23 are as defined above.
In a first embodiment, R34 represents hydrogen. In a second embodiment, R34 represents halogen. In one aspect of that embodiment, R34 represents fluoro. In a third embodiment, R34 represents halo(Ci_6)alkyl. In one aspect of that embodiment, R34 represents fluoromethyl. In a fourth embodiment, R34 represents hydroxy. In a fifth embodiment, R34 represents Ci_6 alkoxy, especially methoxy. In a sixth embodiment, R34 represents Ci_6 alkylthio, especially methylthio. In a seventh embodiment, R34 represents Ci_6 alkylsulphinyl, especially methylsulphinyl. In an eighth embodiment, R34 represents Ci_6 alkylsulphonyl, especially methylsulphonyl. In a ninth embodiment, R34 represents amino. In a tenth embodiment, R34 represents Ci_6 alkylamino, especially methylamino. In an eleventh embodiment, R34 represents di(Ci_6)alkylamino, especially dimethylamino. In a twelfth embodiment, R34 represents (C2-6)alkylcarbonylamino, especially acetylamino. In a thirteenth embodiment, R34 represents (C2-6)alkylcarbonylamino(Ci_6)alkyl, especially acetylaminomethyl. In a fourteenth embodiment, R34 represents (Ci_6)alkylsulphonyl- amino, especially methylsulphonylamino. In a fifteenth embodiment, R34 represents (Ci_6)alkylsulphonylamino(Ci_6)alkyl, especially methylsulphonylaminomethyl.
Typically, R34 represents hydrogen, halogen, halo(Ci_6)alkyl, hydroxy or
(C2-6)alkylcarbonylamino(Ci_6)alkyl.
Selected values of R34 include hydrogen, fluoro, fluoromethyl, hydroxy, methoxy, methylthio, methylsulphinyl, methylsulphonyl, amino, methylamino, dimethylamino and acetylaminomethyl. Particular values of R include hydrogen, fluoro, fluoromethyl, hydroxy and acetylaminomethyl.
Suitably, R34 represents hydrogen or hydroxy.
A further sub-group of the compounds of formula (IIB) above is represented by the compounds of formula (IIG) and N-oxides thereof, and pharmaceutically acceptable salts and solvates thereof, and glucuronide derivatives thereof, and co-crystals thereof:
Figure imgf000064_0001
wherein
E, Q, Z, V, W, R15, R16 and R23 are as defined above.
Specific novel compounds in accordance with the present invention include each of the compounds whose preparation is described in the accompanying Examples, and pharmaceutically acceptable salts and solvates thereof.
The compounds in accordance with the present invention are beneficial in the treatment and/or prevention of various human ailments. These include autoimmune and inflammatory disorders; neurological and neurodegenerative disorders; pain and nociceptive disorders; cardiovascular disorders; metabolic disorders; ocular disorders; and oncological disorders.
Inflammatory and autoimmune disorders include systemic autoimmune disorders, autoimmune endocrine disorders and organ-specific autoimmune disorders. Systemic autoimmune disorders include systemic lupus erythematosus (SLE), psoriasis, psoriatic arthropathy, vasculitis, polymyositis, scleroderma, multiple sclerosis, systemic sclerosis, ankylosing spondylitis, rheumatoid arthritis, non-specific inflammatory arthritis, juvenile inflammatory arthritis, juvenile idiopathic arthritis (including oligo articular and polyarticular forms thereof), anaemia of chronic disease (ACD), Still's disease (juvenile and/or adult onset), Beliefs disease and Sjogren's syndrome. Autoimmune endocrine disorders include thyroiditis. Organ-specific autoimmune disorders include Addison's disease, haemolytic or pernicious anaemia, acute kidney injury (AKI; including cisplatin- induced AKI), diabetic nephropathy (DN), obstructive uropathy (including cisplatin- induced obstructive uropathy), glomerulonephritis (including Goodpasture's syndrome, immune complex-mediated glomerulonephritis and antineutrophil cytoplasmic antibodies (ANCA)-associated glomerulonephritis), lupus nephritis (LN), minimal change disease, Graves' disease, idiopathic thrombocytopenic purpura, inflammatory bowel disease (including Crohn's disease, ulcerative colitis, indeterminate colitis and pouchitis), pemphigus, atopic dermatitis, autoimmune hepatitis, primary biliary cirrhosis, autoimmune pneumonitis, autoimmune carditis, myasthenia gravis, spontaneous infertility,
osteoporosis, osteopenia, erosive bone disease, chondritis, cartilage degeneration and/or destruction, fibrosing disorders (including various forms of hepatic and pulmonary fibrosis), asthma, rhinitis, chronic obstructive pulmonary disease (COPD), respiratory distress syndrome, sepsis, fever, muscular dystrophy (including Duchenne muscular dystrophy) and organ transplant rejection (including kidney allograft rejection).
Neurological and neurodegenerative disorders include Alzheimer's disease,
Parkinson's disease, Huntington's disease, ischaemia, stroke, amyotrophic lateral sclerosis, spinal cord injury, head trauma, seizures and epilepsy.
Cardiovascular disorders include thrombosis, cardiac hypertrophy, hypertension, irregular contractility of the heart (e.g. during heart failure), and sexual disorders
(including erectile dysfunction and female sexual dysfunction). Modulators of TNFa function may also be of use in the treatment and/or prevention of myocardial infarction (see J.J. Wu et al., JAMA, 2013, 309, 2043-2044).
Metabolic disorders include diabetes (including insulin-dependent diabetes mellitus and juvenile diabetes), dyslipidemia and metabolic syndrome.
Ocular disorders include retinopathy (including diabetic retinopathy, proliferative retinopathy, non-proliferative retinopathy and retinopathy of prematurity), macular oedema (including diabetic macular oedema), age-related macular degeneration (ARMD), vascularisation (including corneal vascularisation and neovascularisation), retinal vein occlusion, and various forms of uveitis and keratitis.
Oncological disorders, which may be acute or chronic, include proliferative disorders, especially cancer, and cancer-associated complications (including skeletal complications, cachexia and anaemia). Particular categories of cancer include
haematological malignancy (including leukaemia and lymphoma) and non-haematological malignancy (including solid tumour cancer, sarcoma, meningioma, glioblastoma multiforme, neuroblastoma, melanoma, gastric carcinoma and renal cell carcinoma).
Chronic leukaemia may be myeloid or lymphoid. Varieties of leukaemia include lymphoblastic T cell leukaemia, chronic myelogenous leukaemia (CML), chronic lymphocytic/lymphoid leukaemia (CLL), hairy-cell leukaemia, acute lymphoblastic leukaemia (ALL), acute myelogenous leukaemia (AML), myelodysplasia syndrome, chronic neutrophilic leukaemia, acute lymphoblastic T cell leukaemia, plasmacytoma, immunoblastic large cell leukaemia, mantle cell leukaemia, multiple myeloma, acute megakaryoblastic leukaemia, acute megakaryocytic leukaemia, promyelocytic leukaemia and erythroleukaemia. Varieties of lymphoma include malignant lymphoma, Hodgkin's lymphoma, non-Hodgkin's lymphoma, lymphoblastic T cell lymphoma, Burkitt's lymphoma, follicular lymphoma, MALTl lymphoma and marginal zone lymphoma.
Varieties of non-haematological malignancy include cancer of the prostate, lung, breast, rectum, colon, lymph node, bladder, kidney, pancreas, liver, ovary, uterus, cervix, brain, skin, bone, stomach and muscle. Modulators of TNFa function may also be used to increase the safety of the potent anticancer effect of TNF (see F.V. Hauwermeiren et al., J. Clin. Invest., 2013, 123, 2590-2603).
The present invention also provides a pharmaceutical composition which comprises a compound in accordance with the invention as described above, or a pharmaceutically acceptable salt or solvate thereof, in association with one or more pharmaceutically acceptable carriers.
Pharmaceutical compositions according to the invention may take a form suitable for oral, buccal, parenteral, nasal, topical, ophthalmic or rectal administration, or a form suitable for administration by inhalation or insufflation.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets, lozenges or capsules prepared by conventional means with
pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methyl cellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogenphosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents, emulsifying agents, non-aqueous vehicles or preservatives. The preparations may also contain buffer salts, flavouring agents, colouring agents or sweetening agents, as appropriate.
Preparations for oral administration may be suitably formulated to give controlled release of the active compound.
For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
The compounds of formula (I) may be formulated for parenteral administration by injection, e.g. by bolus injection or infusion. Formulations for injection may be presented in unit dosage form, e.g. in glass ampoules or multi-dose containers, e.g. glass vials. The compositions for injection may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilising, preserving and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g. sterile pyrogen-free water, before use.
In addition to the formulations described above, the compounds of formula (I) may also be formulated as a depot preparation. Such long-acting formulations may be administered by implantation or by intramuscular injection.
For nasal administration or administration by inhalation, the compounds according to the present invention may be conveniently delivered in the form of an aerosol spray presentation for pressurised packs or a nebuliser, with the use of a suitable propellant, e.g. dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas or mixture of gases.
The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack or dispensing device may be accompanied by instructions for administration.
For topical administration the compounds of use in the present invention may be conveniently formulated in a suitable ointment containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, liquid petroleum, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax and water. Alternatively, the compounds of use in the present invention may be formulated in a suitable lotion containing the active component suspended or dissolved in one or more pharmaceutically acceptable carriers. Particular carriers include, for example, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, benzyl alcohol, 2-octyldodecanol and water.
For ophthalmic administration the compounds of use in the present invention may be conveniently formulated as micronized suspensions in isotonic, pH-adjusted sterile saline, either with or without a preservative such as a bactericidal or fungicidal agent, for example phenylmercuric nitrate, benzylalkonium chloride or chlorhexidine acetate.
Alternatively, for ophthalmic administration compounds may be formulated in an ointment such as petrolatum.
For rectal administration the compounds of use in the present invention may be conveniently formulated as suppositories. These can be prepared by mixing the active component with a suitable non- irritating excipient which is solid at room temperature but liquid at rectal temperature and so will melt in the rectum to release the active component. Such materials include, for example, cocoa butter, beeswax and polyethylene glycols.
The quantity of a compound of use in the invention required for the prophylaxis or treatment of a particular condition will vary depending on the compound chosen and the condition of the patient to be treated. In general, however, daily dosages may range from around 10 ng/kg to 1000 mg/kg, typically from 100 ng/kg to 100 mg/kg, e.g. around 0.01 mg/kg to 40 mg/kg body weight, for oral or buccal administration, from around 10 ng/kg to 50 mg/kg body weight for parenteral administration, and from around 0.05 mg to around 1000 mg, e.g. from around 0.5 mg to around 1000 mg, for nasal administration or administration by inhalation or insufflation.
If desired, a compound in accordance with the present invention may be co- administered with another pharmaceutically active agent, e.g. an anti-inflammatory molecule such as methotrexate or prednisolone.
The compounds of formula (I) above may be prepared by a process which comprises reacting a compound of formula (III) with a compound of formula (IV):
Figure imgf000069_0001
wherein E, Q, Y, Z, R1, R2 and R3 are as defined above, and L1 represents a suitable leaving group.
The leaving group L1 is typically a halogen atom, e.g. bromo.
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a Ci_4 alkanol such as ethanol, or a cyclic ether such as 1 ,4-dioxane.
The compounds of formula (I) above wherein E represents -C(O)- may be prepared by a process which comprises reacting a compound of formula (V) with a compound of formula (VI):
Figure imgf000069_0002
(V) (VI) wherein Q, Y, Z, R1, R2 and R3 are as defined above, Rx represents a Ci_4 alkyl group, e.g. methyl, and L2 represents a suitable leaving group.
The leaving group L2 is typically a halogen atom, e.g. bromo.
The reaction is conveniently effected at ambient or elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide, a hydrocarbon solvent such as toluene, or a Ci_4 alkanol such as ethanol.
The intermediates of formula (V) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (VII):
Figure imgf000070_0001
(VII) wherein Q, Z and Rx are as defined above, and Ry represents a Ci_4 alkyl group, e.g. methyl.
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a hydrocarbon solvent such as toluene, or a Ci_4 alkanol such as methanol.
The compounds of formula (I) above wherein E represents -CH(OH)- may be prepared by a process which comprises reacting a compound of formula Y-MgHal with a compound of formula (VIII):
Figure imgf000070_0002
(VIII) wherein Q, Y, Z, R1, R2 and R3 are as defined above, and Hal represents a halogen atom.
The halogen atom Hal is typically bromo.
The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
The intermediates of formula (VIII) above may be prepared by treating a compound of formula (IX):
Figure imgf000071_0001
wherein Q, Z, R1, R2 and R3 are as defined above; with (chloromethylene)dimethyl- iminium chloride (Vilsmeier reagent).
The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a dipolar aprotic solvent such as N,N-dimethylformamide.
The compounds of formula (I) above wherein E represents -CH2- and Y represents optionally substituted aryl or heteroaryl may be prepared by a process which comprises reacting a compound of formula Y!-H with a compound of formula (X):
Figure imgf000071_0002
(X) wherein Q, Z, R1, R2 and R3 are as defined above, and Y1 represents aryl or heteroaryl, either of which groups may be optionally substituted by one or more substituents; in the presence of a sulfonic acid derivative.
The sulfonic acid derivative of use in the foregoing reaction is suitably an organic sulfonic acid derivative such as methanesulfonic acid. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.
The intermediates of formula (X) above may be prepared by treating a compound of formula (IX) as defined above with formaldehyde. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. water.
The intermediates of formula (IX) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (XI):
Figure imgf000072_0001
wherein Q, Z and L1 are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).
The compounds of formula (I) above wherein -Q-Z represents -CH2OH may be prepared by a process which comprises treating a compound of formula (XII):
Figure imgf000072_0002
wherein E, Y, R1, R2 and R3 are as defined above, and Rz represents a Ci_4 alkyl group, e.g. methyl; with a reducing agent.
The reducing agent of use in the foregoing reaction is suitably an alkali metal borohydride such as lithium borohydride. The reaction is conveniently effected at ambient temperature in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran, or a Ci_4 alkanol such as methanol, or a mixture thereof.
Alternatively, the reducing agent of use in the foregoing reaction may suitably be diisobutylaluminium hydride. The reaction is conveniently effected at a temperature in the region of 0°C in a suitable solvent, e.g. a cyclic ether such as tetrahydrofuran.
The intermediates of formula (XII) above may be prepared by reacting a compound of formula (III) as defined above with a compound of formula (XIII):
Figure imgf000073_0001
(ΧΠΙ) wherein E, Y, Rz and L1 are as defined above; under conditions analogous to those described above for the reaction between compounds (III) and (IV).
The compounds of formula (I) above wherein E represents -N(H)- may be prepared by a process which comprises reacting a compound of formula (III) as defined above with an isocyanide derivative of formula Y-NC and an aldehyde derivative of formula
OHC-Q-Z; in the presence of a transition metal catalyst.
The transition metal catalyst of use in the foregoing reaction is suitably a zirconium derivative, e.g. a zirconium halide such as zirconium(IV) chloride. The reaction is conveniently effected at an elevated temperature in a suitable solvent, e.g. a Ci_4 alkanol such as n-butanol.
Where they are not commercially available, the starting materials of formula (III), (IV), (VI), (VII), (XI) and (XIII) may be prepared by methods analogous to those described in the accompanying Examples, or by standard methods well known from the art.
It will be understood that any compound of formula (I) initially obtained from any of the above processes may, where appropriate, subsequently be elaborated into a further compound of formula (I) by techniques known from the art. By way of example, a compound of formula (I) wherein E represents -C(O)- may be converted into the corresponding compound wherein E represents -CH(OH)- by treatment with a reducing agent such as sodium borohydride.
A compound of formula (I) wherein E represents -CH(OH)- may be converted into the corresponding compound wherein E represents -CH2- by heating with elemental iodine and phosphinic acid in acetic acid; or by treating with triethylsilane and an acid, e.g. an organic acid such as trifluoro acetic acid, or a Lewis acid such as boron trifluoride diethyl etherate; or by a two-step procedure which comprises: (i) treatment with thionyl bromide; and (ii) treatment of the product thereby obtained with a transition metal catalyst, e.g. (2,2'-bipyridine)dichlororuthenium(II) hydrate, in the presence of diethyl l,4-dihydro-2,6- dimethyl-3,5-pyridinedicarboxylate (Hantzsch ester) and a base, e.g. an organic base such as N,N-diisopropylethylamine.
A compound of formula (I) which contains a hydroxy group may be alkylated by treatment with the appropriate alkyl halide in the presence of a base, e.g. sodium hydride, or silver oxide. A compound of formula (I) wherein -Q-Z represents -CH2OH may be arylated in a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with the appropriate aryl or heteroaryl hydroxide. A compound of formula (I) wherein -Q-Z represents -CH2OH may be converted into the corresponding compound of formula (I) wherein -Q-Z represents -CH2S-Z via a two-step procedure which comprises: (i) treatment with thionyl chloride; and (ii) treatment of the chloro derivative thereby obtained with a compound of formula Z-SH, typically in the presence of a base, e.g. an inorganic base such as potassium carbonate. A compound of formula (I) which contains hydroxy may be converted into the corresponding fluoro-substituted compound by treatment with diethylamino sulfur trifluoride (DAST). A compound of formula (I) which contains hydroxy may be converted into the corresponding difluoro-substituted compound via a two-step procedure which comprises: (i) treatment with an oxidising agent, e.g. manganese dioxide; and (ii) treatment of the carbonyl-containing compound thereby obtained with DAST.
A compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl halide, typically at an elevated temperature in an organic solvent such as acetonitrile. Alternatively, the reaction may be effected at ambient temperature in an organic solvent such as N,N-dimethylformamide, in the presence of a base, e.g. an inorganic base such as cesium carbonate or potassium carbonate.
Alternatively, a compound of formula (I) which contains an N-H moiety may be alkylated by treatment with the appropriate alkyl tosylate in the presence of a base, e.g. an inorganic base such as sodium hydride, or an organic base such as l,8-diazabicyclo[5.4.0]undec-7- ene (DBU).
A compound of formula (I) which contains an N-H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by C2_6 alkyl- carbonyl, e.g. acetyl, by treatment with the appropriate acyl anhydride, e.g. acetic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine. A compound of formula (I) which contains an N-H moiety may be converted into the corresponding compound wherein the nitrogen atom is substituted by Ci_6 alkyl- sulphonyl, e.g. methylsulphonyl, by treatment with the appropriate Ci_6 alkylsulphonyl halide, e.g. a Ci_6 alkylsulphonyl chloride such as methanesulphonyl chloride, or with the appropriate Ci_6 alkylsulphonic anhydride, e.g. methanesulphonic anhydride, typically at ambient temperature in the presence of a base, e.g. an organic base such as triethylamine.
A compound of formula (I) containing the moiety -S- may be converted into the corresponding compound containing the moiety -S(O)- by treatment with 3-chloroperoxy- benzoic acid. Likewise, a compound of formula (I) containing the moiety -S(O)- may be converted into the corresponding compound containing the moiety -S(0)2- by treatment with 3-chloroperoxybenzoic acid.
A compound of formula (I) containing an aromatic nitrogen atom may be converted into the corresponding N-oxide derivative by treatment with 3-chloroperoxybenzoic acid.
A bromophenyl derivative of formula (I) may be converted into the corresponding optionally substituted 2-oxopyrrolidin-l-ylphenyl or 2-oxooxazolidin-3-ylphenyl derivative by treatment with pyrrolidin-2-one or oxazolidin-2-one, or an appropriately substituted analogue thereof. The reaction is conveniently effected at an elevated temperature in the presence of copper(I) iodide, trans-N,N'-dimethylcyclohexane-l,2- diamine and an inorganic base such as potassium carbonate.
A compound of formula (I) wherein R1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1 represents an optionally substituted aryl or heteroaryl moiety by treatment with the appropriately substituted aryl or heteroaryl boronic acid or a cyclic ester thereof formed with an organic diol, e.g. pinacol, 1 ,3-propanediol or neopentyl glycol. The reaction is typically effected in the presence of a transition metal catalyst, e.g. [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), tetrakis(triphenylphosphine)palladium(0), or bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron-dichloropalladium-dichloro methane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate, or potassium phosphate.
A compound of formula (I) wherein R1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1 represents an optionally substituted aryl, heteroaryl or heterocycloalkenyl moiety via a two-step procedure which comprises: (i) reaction with bis(pinacolato)diboron or bis(neopentyl glycolato)diboron; and (ii) reaction of the compound thereby obtained with an appropriately functionalised halo- or tosyloxy-substituted aryl, heteroaryl or heterocycloalkenyl derivative. Step (i) is conveniently effected in the presence of a transition metal catalyst such as [Ι, -bis- (diphenylphosphino)ferrocene]dichloropalladium(II), or bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron-dichloropalladium-dichloromethane complex. Step (ii) is conveniently effected in the presence of a transition metal catalyst such as tetrakis- (triphenylphosphine)palladium(O), or bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 - yljiron-dichloropalladium-dichloromethane complex, and a base, e.g. an inorganic base such as sodium carbonate or potassium carbonate.
A compound of formula (I) wherein R1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1 represents an optionally substituted imidazol-l-yl moiety by treatment with the appropriately substituted imidazole derivative, typically in the presence of copper(II) acetate and an organic base such as N,N,N',N'-tetramethy lethy lenediamine (TMED A) .
A compound of formula (I) wherein R1 represents halogen, e.g. bromo, may be converted into the corresponding compound wherein R1 represents 2-(methoxycarbonyl)- ethyl via a two-step procedure which comprises: (i) reaction with methyl acrylate; and (ii) catalytic hydrogenation of the alkenyl derivative thereby obtained, typically by treatment with a hydrogenation catalyst, e.g. palladium on charcoal, under an atmosphere of hydrogen gas. Step (i) is typically effected in the presence of a transition metal catalyst, e.g. palladium(II) acetate or bis(dibenzylideneacetone)palladium(0), and a reagent such as tri(ortAo-tolyl)phosphine.
A compound of formula (I) wherein R1 represents 6-methoxypyridin-3-yl may be converted into the corresponding compound wherein R1 represents 2-oxo-l,2-dihydro- pyridin-5-yl by treatment with pyridine hydrochloride; or by heating with a mineral acid such as hydrochloric acid. By utilising similar methodology, a compound of formula (I) wherein R1 represents 6-methoxy-4-methylpyridin-3-yl may be converted into the corresponding compound wherein R1 represents 4-methyl-2-oxo-l,2-dihydropyridin-5-yl; and a compound of formula (I) wherein R1 represents 6-methoxy-5-methylpyridin-3-yl may be converted into the corresponding compound wherein R1 represents 3-methyl-2- oxo- 1 ,2-dihydropyridin-5-yl.
A compound of formula (I) wherein R1 represents 2-oxo-l,2-dihydropyridin-5-yl may be converted into the corresponding compound wherein R1 represents 2-oxopiperidin- 5-yl by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as platinum(IV) oxide.
More generally, a compound of formula (I) containing a carbon-carbon double bond may be converted into the corresponding compound containing a carbon-carbon single bond by catalytic hydrogenation, typically by treatment with gaseous hydrogen in the presence of a hydrogenation catalyst such as palladium on charcoal.
A compound of formula (I) containing an ester moiety, e.g. a C2_6 alkoxycarbonyl group such as methoxycarbonyl or ethoxycarbonyl, may be converted into the
corresponding compound containing a carboxy (-C02H) moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid. Alternatively, the transformation may be effected by treatment with a base, typically an inorganic base such as an alkali metal hydroxide, e.g. sodium hydroxide or lithium hydroxide; or an organic base such as sodium methoxide or sodium ethoxide.
A compound of formula (I) containing an N-(tert-butoxycarbonyl) moiety may be converted into the corresponding compound containing an N-H moiety by treatment with an acid, e.g. a mineral acid such as hydrochloric acid, or an organic acid such as trifluoroacetic acid.
A compound of formula (I) wherein R1 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (I) wherein R1 represents halogen, e.g. bromo, with the appropriate compound of formula R'-H [e.g. 1- (pyridin-3-yl)piperazine]. The reaction is conveniently effected with the assistance of a transition metal catalyst, e.g. tris(dibenzylideneacetone)dipalladium(0), in the presence of an amination ligand such as 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl (XPhos) and a base, e.g. an inorganic base such as sodium tert-butoxide.
A compound of formula (IIB) wherein R21 represents ethenyl may be prepared by reacting a compound of formula (IIB) wherein R21 represents halogen, e.g. chloro, with potassium vinyl trifluoroborate. The reaction is typically effected in the presence of a transition metal catalyst, e.g. [l, -bis(diphenylphosphino)ferrocene]dichloropalladium(II), and a base, e.g. an organic base such as triethylamine.
A compound of formula (IIB) wherein R21 represents a substituent containing at least one nitrogen atom, which substituent is linked to the remainder of the molecule via a nitrogen atom, may be prepared by reacting a compound of formula (IIB) wherein R21 represents halogen, e.g. chloro, with the appropriate compound of formula R21-H [e.g. 2- methoxyethylamine, pyrrolidin-3-ol, piperazine, l-(methylsulfonyl)piperazine, piperazin- 2-one, morpholine, thiomorpholine, thiomorpholine 1,1 -dioxide, l,4-diazepan-5-one, 2- oxa-5-azabicyclo[2.2.1]heptane or an appropriately substituted azaspiroalkane], optionally in the presence of a base, e.g. an organic base such as triethylamine or l-methyl-2- pyrrolidinone.
Where a mixture of products is obtained from any of the processes described above for the preparation of compounds according to the invention, the desired product can be separated therefrom at an appropriate stage by conventional methods such as preparative HPLC; or column chromatography utilising, for example, silica and/or alumina in conjunction with an appropriate solvent system.
Where the above-described processes for the preparation of the compounds according to the invention give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques. In particular, where it is desired to obtain a particular enantiomer of a compound of formula (I) this may be produced from a corresponding mixture of enantiomers using any suitable conventional procedure for resolving enantiomers. Thus, for example, diastereomeric derivatives, e.g. salts, may be produced by reaction of a mixture of enantiomers of formula (I), e.g. a racemate, and an appropriate chiral compound, e.g. a chiral base. The diastereomers may then be separated by any convenient means, for example by crystallisation, and the desired enantiomer recovered, e.g. by treatment with an acid in the instance where the diastereomer is a salt. In another resolution process a racemate of formula (I) may be separated using chiral HPLC. Moreover, if desired, a particular enantiomer may be obtained by using an appropriate chiral intermediate in one of the processes described above. Alternatively, a particular enantiomer may be obtained by performing an enantiomer-specific enzymatic biotransformation, e.g. an ester hydrolysis using an esterase, and then purifying only the enantiomerically pure hydrolysed acid from the unreacted ester antipode.
Chromatography, recrystallisation and other conventional separation procedures may also be used with intermediates or final products where it is desired to obtain a particular geometric isomer of the invention.
During any of the above synthetic sequences it may be necessary and/or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry, ed. J.F.W. McOmie, Plenum Press, 1973; and T.W. Greene & P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 3rd edition, 1999. The protecting groups may be removed at any convenient subsequent stage utilising methods known from the art.
The following Examples illustrate the preparation of compounds according to the invention.
The compounds in accordance with this invention potently inhibit TNF - induced NF-KB activation in the following assay. Inhibition of TNFa-induced NF-κΒ activation
Stimulation of HEK-293 cells by TNFa leads to activation of the NF-κΒ pathway. The reporter cell line used to determine TNFa activity was purchased from InvivoGen. HEK-Blue™ CD40L is a stable transfectant expressing SEAP (secreted alkaline phosphatase) under the control of the IFNP minimal promoter fused to five NF-KB binding sites. Secretion of SEAP by these cells is stimulated in a dose-dependent manner by TNFa (0.5 ng/mL). Compounds were diluted from 10 mM DMSO stocks (final assay concentration 0.3%) to generate a 10-point 3-fold serial dilution curve (30,000 nM to 2 nM final concentration). They were mixed with cells and stimulating ligand in a 384-well microtitre plate and incubated for 18 h. SEAP activity was determined in the supernatant using the colorimetric substrate QUANTI-Blue™ (InvivoGen). Percentage inhibitions for compound dilutions were calculated between a DMSO control and maximum inhibition (by excess control compound) and an IC50 calculated using XLfit™ (4 parameter logistic model) in ActivityBase.
When tested in the above assay, the compounds of the accompanying Examples were all found to exhibit IC50 values of 50 μΜ or better.
EXAMPLES
Abbreviations
DCM: dichloromethane EtOAc: ethyl acetate
DMF: N,N-dimethylformamide MeOH: methanol
DMSO: dimethylsulfoxide TFA: trifluoroacetic acid
THF: tetrahydrofuran DIPEA: N,N-diisopropylethyl MeCN: acetonitrile EtOH: ethanol
Si02: silica h: hour
r. : room temperature RT: retention time
br: broad M: mass
FCC: flash column chromatography
HPLC: High Performance Liquid Chromatography
LCMS: Liquid Chromatography Mass Spectrometry
ES+: Electrospray Positive Ionisation
Pd(PPli3)4 : tetrakis(triphenylphosphine)palladium(0)
Pd(dppf)Cl2 : [1,1 '-bis(diphenylphosphino)ferrocene]dichloropalladium(II)
Hantzsch ester: diethyl l,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate
Nomenclature
Compounds were named with the aid of ACD/Name Batch (Network) version 11.01, and/or Accelrys Draw 4.0.
Analytical Conditions
All NMR spectra were obtained either at 250 MHz or at 500 MHz. Analytical HPL C
Method A
Column: Waters Atlantis dC18 (2.1 x 100 mm, 3 μιη column)
Flow rate: 0.6 mL/minute
Solvent A: 0.1% formic acid/water
Solvent B: 0.1% formic acid/acetonitrile
Injection volume: 3
Column temperature: 40°C
UV detection wavelength: 215 nm
Eluent: 0.00-5.00 minutes, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5.00-5.40 minutes, 100% solvent B; 5.40-5.42 minutes, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 5.42-7.00 minutes, 95% solvent A + 5% solvent B. Method B
Column: Waters Atlantis dC18 (2.1 x 50 mm, 3 μιη column)
Flow rate: 1.0 mL/minute
Solvent A: 0.1% formic acid/water
Solvent B: 0.1% formic acid/acetonitrile
Injection volume: 3 μΐ,
UV detection wavelength: 215 nm
Eluent: 0.00-2.50 minutes, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 2.50-2.70 minutes, 100% solvent B; 2.71-3.00 minutes, 95% solvent A + 5% solvent B.
Method C
Column: Waters Atlantis dC18 (2.1 x 30 mm, 3 μιη column)
Flow rate: 1.0 mL/minute
Solvent A: 0.1% formic acid/water
Solvent B: 0.1% formic acid/acetonitrile
Injection volume: 3 μΐ,
UV detection wavelength: 215 nm
Eluent: 0.00-1.50 minutes, constant gradient from 95% solvent A + 5% solvent B to 100%) solvent B; 1.50-1.60 minutes, 100% solvent B; 1.60-1.61 minutes, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B; 1.61-2.00 minutes, 95% solvent A + 5% solvent B.
MS detection using Waters LCT or LCT Premier, or ZQ or ZMD.
UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
Method D (uPLC)
Column: Phenomenex, Kinetex-XB C18 (2.1 mm x 100 mm, 1.7 μιη column) Flow rate: 0.6 mL/minute
Solvent A: 0.1% formic acid/water
Solvent B: 0.1% formic acid/acetonitrile
Injection volume: 3 μΐ,
Column temperature: 40°C UV detection wavelength: 215 nm
Eluent: 0.00-5.30 minutes, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5.30-5.80 minutes, 100% solvent B; 5.80-5.82 minutes, constant gradient from 100% solvent B to 95% solvent A + 5% solvent B.
MS detection using Waters LCT or LCT Premier, or ZQ or ZMD.
UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
Method E (high pH)
Column: Phenomenex, Gemini CI 8 (2.0 mm x 100 mm, 3 μιη column)
Flow rate: 0.5 mL/minute
Solvent A: 2 nM ammonium hydrogencarbonate in water
Solvent B: acetonitrile
Injection volume: 3
Column temperature: 50°C
UV detection wavelength: 215 nm
Eluent: 0.00-5.50 minutes, constant gradient from 95% solvent A + 5% solvent B to 100% solvent B; 5.50-5.90 minutes, 100% solvent B.
MS detection using Waters LCT or LCT Premier, or ZQ or ZMD.
UV detection using Waters 2996 photodiode array or Waters 2787 UV or Waters 2788 UV.
Preparative HPLC
Preparative Method A
Flow rate: 40 mL/minute
Mobile Phase A: water with 0.1% formic acid
Mobile Phase B: acetonitrile with 0.1% formic acid
Column: Waters Sunfire, C18, 30 mm x 100 mm
Particle Size: 10 μιη
Runtime: 25.5 minutes
Inlet method: LC7 40ml 7030 tubes.w60 Method Gradient: Time (min) % A % B
0.00 75 25
2.00 75 25
2.50 70 30
18.50 0 100
21.50 0 100
22.50 99 1
23.00 99 1 ACD Flow: 2 mL/minute (acetonitrile with 0.1% formic acid) throughout run.
Primary wavelength (collection) : 215 nm
Equipment: Gilson 215 Liquid Handler with 819 valve, Gilson 307 pump (at
Column Dilution), Waters 2487 Detector (prep cell), Waters FC II (waste collection), Knauer degasser, Waters 600 pump/controller (No. 3 pump heads).
Software: Masslynx v4.0 sp4
Preparative Method B
Flow rate: 40 mL/minute
Mobile Phase A: water with 0.1% formic acid
Mobile Phase B: acetonitrile with 0.1% formic acid
Column: Waters Sunfire, CI 8, 30 mm x 100 mm
Particle Size: 10 μιη
Runtime: 25.5 minutes
Inlet method: LC7 40ml 9010 tubes. w60
Method Gradient: Time (min) % A % B
0.00 95 5
2.00 95 5
2.50 90 10
18.50 0 100
21.50 0 100
22.50 95 5 23.00 95
ACD Flow: 2 mL/minute (acetonitrile with 0.1% formic acid) throughout run.
Primary wavelength (collection) : 215 nm
Equipment: Gilson 215 Liquid Handler with 819 valve, Gilson 307 pump (at
Column Dilution), Waters 2487 Detector (prep cell), Waters FC II (waste collection), Knauer degasser, Waters 600 pump/controller (No. 3 pump heads).
Software: Masslynx v4.0 sp4
Preparative Method C
Flow rate: 20 mL/minute
Mobile Phase A: water
Mobile Phase B: acetonitrile
Column: Waters Sunfire, CI 8, 30 mm x 100 mm
Particle Size: 5 μιη
Runtime: 19 minutes
Method Gradient: Time (min) % A % B
0.00 95 5
2.00 95 5
2.50 90 10
14.50 0 100
16.50 0 100
17.00 95 5
19.00 95 5
Primary wavelength (collection): 215 nm
Secondary wavelength : 254 nm
Equipment: Gilson 215 Liquid Handler, Gilson 321 Pumps, Gilson 151 UV/Vis
Detector.
Software: Gilson Unipoint V5.11 Preparative Method D (high pH)
Flow rate: 40 mL/minute
Mobile Phase A: acetonitrile + 0.2% ammonium hydroxide
Mobile Phase B: acetonitrile + 0.2% ammonium hydroxide
Column: Waters Sunfire, CI 8, 30 mm x 100 mm
Particle Size: 5 μιη
Runtime: 15.5 minutes
Time (min) % A %
0.00 95 5
2.00 85 15
12.00 70 30
12.50 5 95
15.00 5 95
15.50 95 5
Primary wavelength (collection) : 215 nm
Secondary wavelength: 254 nm INTERMEDIATE 1
1 -[2-(Difluoromethoxy)phenyllethan- 1 -one
Potassium hydroxide (105 g, 1872 mmol) was suspended in a mixture of acetonitrile (200 mL) and water (200 mL) and cooled to approximately -20°C. l-(2- Hydroxyphenyl)ethanone (11.28 mL, 93.7 mmol) was added dropwise, followed by diethyl [bromo(difluoro)methyl]phosphonate (33.27 mL, 187.3 mmol) over 15 minutes.
The mixture was then allowed to warm to room temperature over 1 hour. The mixture was extracted with ethyl acetate (3 x 200 mL), then the combined organic layers were washed with brine (50 mL), dried over magnesium sulfate and concentrated under vacuum. The mixture was purified by flash chromatography to afford the title compound
(16.0 g, 92%) as a colourless oil. Method B HPLC-MS: MH+ mlz 187, RT 1.77 minutes. INTERMEDIATE 2
2-Bromo- 1 -[2-(difluoromethoxy)phenyllethan- 1 -one
A solution of bromine (1.25 mL, 24.44 mmol) in glacial acetic acid (20 mL) was added dropwise over 60 minutes to a stirring solution of Intermediate 1 (4.6 g, 24.4 mmol) in glacial acetic acid (20 mL) in the dark. When the addition was complete the reaction was diluted with DCM (200 mL) and washed with water (200 mL). The aqueous layer was then extracted with DCM (50 mL). To the combined organic layers was added saturated aqueous sodium carbonate solution (100 mL), and further solid sodium carbonate was added portionwise with vigorous stirring until the mixture was neutralised. The organic phase was separated and the aqueous layer was extracted with DCM (2 x 50 mL). The combined organic layers were washed with brine (50 mL), dried over sodium sulphate, filtered and concentrated under vacuum to afford the title compound (6.48 g, 82%) as a light yellow oil. δΗ (500 MHz, CDC13) 7.83 (m, 1H), 7.58 (td, J 8.3, 1.7 Hz, 1H), 7.34 (m, 1H), 7.20 (d, J 8.3 Hz, 1H), 6.64 (t, J 72.9 Hz, 1H), 4.53 (s, 2H). Method C HPLC-MS: MH+ mlz 265/267, RT 1.32 minutes.
INTERMEDIATE 3 (E)-Nf-(5-Bromopyrazin-2-yl)-N,N-dimethylethenimidamide
2 Amino-5-bromopyrazine (10 g, 57.5 mmol) was suspended in toluene (250 mL). l,l-Dimethoxy-N,N-dimethylethylamine (12.6 mL, 86.2 mmol) was added and the reaction mixture was stirred at 80°C for 16 h. The reaction mixture was concentrated under vacuum and diluted with ethyl acetate (60 mL). The resulting material was washed with saturated aqueous sodium bicarbonate solution (40 mL), water (3 x 40 mL) and brine (40 mL), dried over sodium sulfate, filtered and concentrated under vacuum, to afford a brown oil. Purification by flash chromatography, eluting with heptane:EtOAc 1 :0 to 2:8, afforded the title compound (11.61 g, 83%) as an off-white solid. 5H (250 MHz, CDC13) 8.29 (d, J 1.4 Hz, 1H), 7.90 (s, 1H), 3.11 (s, 6H), 2.06 (s, 3H). Method A HPLC-MS: MH+ mlz 243/245, eluting in the solvent front. INTERMEDIATE 4
6-Bromo-3-([2-(difluoromethoxy)phenyllca^
Intermediate 3 (17.9 g, 70.1 mmol) and Intermediate 2 (11.5 g, 41.2 mmol) were taken up in anhydrous DMF (100 mL) and stirred at room temperature for 60 minutes, then stirred at 60-70°C for a total of 2 h. The reaction mixture was allowed to cool to room temperature before being partitioned between ethyl acetate (350 mL) and water (100 mL). The organic phase was then washed with 5% w/v aqueous citric acid (4 x 60 mL), saturated aqueous sodium bicarbonate solution (40 mL) and brine (40 mL), then dried over sodium sulfate and concentrated under vacuum to afford a brown solid. This material was rinsed with 5% EtOAc in heptane (40 mL), then heptane (3 x 20 mL), then dried under vacuum to afford a light brown solid. This material was triturated twice with ethyl acetate/heptane to afford the title compound (15.75 g, 53%) as a light brown solid. δΗ (500 MHz, CDCls) 9.74 (d, J 1.3 Hz, IH), 8.99 (d, J 1.2 Hz, IH), 7.60 (ddd, J 8.3, 7.2, 2.1 Hz, IH), 7.43 (m, 2H), 7.35 (d, J 8.2 Hz, IH), 6.50 (t, J73.1 Hz, IH), 2.13 (s, 3H). Method A HPLC-MS: MH+ mlz 382/384, RT 1.33 minutes.
INTERMEDIATE 5 (6-Bromo-2-methylimidazo[l,2-alpyrazin-3-yl)[2-(difluoromethoxy)phenyllmethanol
Intermediate 4 (2.64 g, 6.9 mmol) was dissolved in 2: 1 THF/MeOH (15 mL) and cooled to 0°C. Sodium borohydride (261 mg, 6.9 mmol) was then added, and the reaction mixture was stirred under nitrogen for 30 minutes. The reaction mixture was quenched by the addition of water (20 mL), then filtered. The resulting brown precipitate was washed with water (2 x 5 mL), then cold MeOH (3 x 3 mL). The resulting material was dried under high vacuum to afford the title compound (2.65 g, 84%>) as an off-white solid. δΗ (250 MHz, CDCI3) 8.79 (d, J 1.2 Hz, IH), 8.43 (d, J 1.3 Hz, IH), 7.61 (d, J 7.4 Hz, IH), 7.37 (ddd, J 16.4, 8.2, 6.7 Hz, 2H), 7.11 (d, J8.0 Hz, IH), 6.52 (m, 2H), 3.27 (s, IH), 2.45 (s, 3H). Method A HPLC-MS: MH+ mlz 384/386, RT 1.15 minutes. INTERMEDIATE 6
6-Bromo-3-[2-(difluoromethoxy)benzyll-2-methylimidazo[l,2-alpyrazine
Intermediate 5 (4.1 g, 10.7 mmol) was suspended in DCM (50 mL) and cooled to 0°C under nitrogen. Thionyl bromide (1.08 mL, 13.9 mmol) was added dropwise, and the reaction mixture was allowed to warm to room temperature and was stirred for 1 h. The reaction mixture was concentrated under vacuum to afford a brown foam, which was then dissolved in anhydrous DMF (30 mL). DIPEA (5.8 mL, 33.1 mmol) was added, followed by (2,2'-bipyridine)dichlororuthenium(II) hydrate (200 mg, 0.267 mmol) and Hantzsch ester (2.97 g, 11.7 mmol). The reaction mixture was degassed by bubbling through nitrogen for approximately 5 minutes. The reaction was then sealed, placed
approximately 8-10 cm from an 11 watt fluorescent lamp, and stirred for approximately 1 h. The reaction mixture was partitioned between ethyl acetate (100 mL) and water (100 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2 x 30 mL). The combined organic layers were washed with brine (20 mL), dried over sodium sulfate, filtered and concentrated under vacuum to afford a yellow solid. The material obtained was purified by flash chromatography on silica, eluting with a heptane:ethyl acetate gradient from 1 :0 to 9: 1 to 7:3 to 4:6, to afford the title compound (2.4 g) as an off-white solid. Further product was obtained by combining mixed fractions, and concentrating under vacuum. The mixture obtained was suspended in ethyl acetate (5 mL) then sonicated. A fine precipitate formed. The mother liquor was separated and the precipitate was washed with ethyl acetate (2 x 2 mL). The precipitate was then dried under vacuum to afford a light brown solid (485 mg). Combined yield = 2.9 g (74%). 5H (500 MHz, CDCls) 8.80 (s, 1H), 7.93 (s, 1H), 7.30 (m, 1H), 7.14 (m, 2H), 6.89 (d, J 7.2 Hz, 1H), 6.62 (t, J73.4 Hz, 1H), 4.27 (s, 2H), 2.54 (s, 3H). Method A HPLC-MS: MH+ mlz 368/370, RT 1.31 minutes.
INTERMEDIATE 7
2-Bromo- 1 -(2,5-dichlorophenyl)ethanone
2,5-Dichloroacetophenone (20.9 g, 0.11 mol) was dissolved in diethyl ether (300 mL) and the reaction mixture was cooled to 0°C. Bromine (5.66 mL, 0.11 mol) was added slowly dropwise and the reaction mixture was allowed to warm to room temperature over 20 minutes. The reaction mixture was treated with saturated aqueous NaHC03 solution (250 mL). The organic layer was separated, dried over MgSC^ and concentrated in vacuo, yielding the title compound (20.0 g, 68%) as a yellow oil. 5H (d6- DMSO) 7.94 (dd, J2.2, 0.3 Hz, 1H), 7.61 (m, 2H), 4.88 (s, 2H).
INTERMEDIATE 8
(6-Bromo-2-methylimidazo[l,2-alpyrazin-3-yl)(2,5-dichlorophenyl)methanone
Intermediate 3 (5.02 g, 20.65 mmol) was dissolved in ethanol (10 mL) and Intermediate 7 (7.17 g, 26.85 mmol) was added. The reaction mixture was heated at 80°C overnight. The reaction mixture was concentrated in vacuo, and the residue was redissolved in EtOAc (100 mL) and partitioned with saturated aqueous NaHC03 solution (100 mL). The organic layer was extracted, dried over MgSC^ and concentrated in vacuo. The residue was triturated with methanol, yielding the title compound (1.0 g, 12%) as a brown solid. LCMS (ES+) 386.0 (M+H)+.
INTERMEDIATE 9
5-[3-(2,5-Dichlorobenzoyl)-2-methylimidazo[ 1 ,2-a]pyrazin-6-yll- lH-pyridin-2-one
Intermediate 8 (1.00 g, 2.68 mmol) was dissolved in a mixture of 1,4-dioxane (4 mL) and water (1 mL), and was added to a microwave vial. [l, -Bis(di-tert-butyl- phosphino)ferrocene]dichloropalladium(II) (84 mg, 0.13 mmol), 5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)-lH-pyridin-2-one (592 mg, 2.68 mmol) and 2M aqueous sodium carbonate solution (1 mL) were added. The reaction mixture was heated under microwave irradiation at 100°C for 1 h. The reaction mixture was quenched with water (5 mL) and partitioned with DCM (10 mL). The organic layer was extracted, dried over MgS04 and concentrated in vacuo. The residue was purified by column chromatography (SiC"2, 0-100%) EtOAc/hexane), yielding the title compound (125 mg, 12%>) as a yellow solid. 5H (d6-DMSO) 11.98 (s, 1H), 9.67 (d, J 1.4 Hz, 1H), 9.31 (d, J 1.4 Hz, 1H), 8.12 (d, J2.6 Hz, 1H), 8.07 (dd, J 9.6, 2.7 Hz, 1H), 7.75 (m, 3H), 6.52 (d, J 9.6 Hz, 1H) 2.00 (s, 3H). LCMS (ES+) 400.0 (M+H)+. INTERMEDIATE 10
5 - (3 - [(2,5 -Dichlorophenyl)(hydroxy)methyl] -2-methylimidazo [ 1 ,2-a]pyrazin-6-yl| - 1H- pyridin-2-one
Intermediate 9 (120 mg, 0.30 mmol) was dissolved in ethanol (2 mL) and sodium borohydride (11 mg, 0.30 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes, then quenched with saturated aqueous NH4C1 solution (5 mL). The precipitate was filtered off, washed with diethyl ether and dried under suction, yielding the title compound (144 mg, 95%) as a cream solid. 5H (d6-DMSO) 12.15 (s, IH), 9.09 (s, IH), 8.96 (s, IH), 8.23 (d, J 9.0 Hz, IH), 8.15 (s, IH), 8.01 (s, IH), 7.48 (s, IH), 7.48-7.45 (m, IH), 6.74 (s, IH), 6.55 (s, IH), 6.49 (d, J9.3 Hz, IH) 1.88 (s, 3H). LCMS (ES+) 401.0 (M+H)+.
INTERMEDIATE 11
5 -(6-Methoxypyridin-3 -yl)pyrazin-2-amine
2-Amino-5-bromopyrazine (5.00 g, 28.7 mmol), [l, -bis(diphenylphosphino)- ferrocene]palladium(II) dichloride dichloromethane adduct (0.48 g, 0.58 mmol) and 6- methoxypyridin-3-ylboronic acid (5.27 g, 34.5 mmol) were dissolved in 1,4-dioxane (100 mL) under a nitrogen atmosphere and 2M aqueous potassium carbonate solution (16 mL, 32 mmol) was added. The reaction mixture was heated at 90°C for 4 h, then cooled to room temperature and partitioned between water (200 mL) and EtOAc (300 mL). The organic layer was separated, dried over MgS04 and concentrated in vacuo. The brown residue was triturated with acetonitrile (50 mL), yielding the title compound (3.52 g, 61%) as a brown solid. δΗ (dg-DMSO) 8.69 (d, J2.1 Hz, IH), 8.48 (d, J 1.4 Hz, IH), 8.19 (dd, J 8.7, 2.5 Hz, IH), 7.96 (d, J 1.4 Hz, IH), 6.87 (d, J 8.7 Hz, IH), 6.54 (s, 2H), 3.89 (s, 3H). LCMS (ES+) 203.0 (M+H)+.
INTERMEDIATE 12
N'- [5 -(6-Methoxypyridin-3 -yl)pyrazin-2-yl] -N,N-dimethylacetamidine
Intermediate 11 (1.0 g, 4.9 mmol) was suspended in methanol (5 mL) and N,N- dimethylacetamide dimethyl acetal (3.7 g, 4.1 mL, 25 mmol) was added. The reaction mixture was heated at 80°C overnight. The reaction mixture was concentrated in vacuo, then the residue was dissolved in EtOAc (20 mL) and partitioned with saturated aqueous NaHCC"3 solution (50 mL). The organic layer was extracted, dried over MgSC^ and concentrated in vacuo. The residue was purified by column chromatography (Si02, 0- 100% EtOAc/hexane), yielding the title compound (0.91 g, 68%>) as a yellow solid. 5H (dg-DMSO) 8.82 (m, 2H), 8.31 (dd, J 8.7, 2.5 Hz, IH), 8.08 (s, IH), 6.92 (d, J 8.7 Hz, IH), 3.91 (s, 3H), 3.08 (s, 6H), 2.07 (s, 3H). LCMS (ES+) 272.0 (M+H)+.
INTERMEDIATE 13
[2-(Difluoromethoxy)phenyll[6-(6-methoxypyridin-3-yl)-2-methylimidazo[l,2-alpyrazin- 3-yllmethanone
Intermediate 12 (0.91 g, 3.38 mmol) and Intermediate 2 (0.895 g, 3.38 mmol) were dissolved in ethanol (5 mL) and heated to reflux for 18 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between saturated aqueous
NaHCC"3 solution (20 mL) and EtOAc (50 mL). The organic layer was separated, dried over MgS04 and concentrated in vacuo. The residue was purified by column
chromatography (Si02, 0-100%) EtOAc/hexane), yielding the title compound (0.18 g, 13%) as an orange oil. δΗ (CDC13) 9.92 (d, J 1.4 Hz, IH), 9.26 (d, J 1.4 Hz, IH), 8.87 (d, J2.3 Hz, IH), 8.25 (dd, J 8.7, 2.5 Hz, IH), 7.61 (m, IH), 7.48 (m, IH), 7.41 (m, 2H), 6.92 (d, J 8.7 Hz, IH), 6.35 (s, IH), 4.05 (s, 3H), 2.15 (s, 3H). LCMS (ES+) 411.0 (M+H)+.
INTERMEDIATE 14 tert-Butyl 4-(5- (3-[2-(difluoromethoxy)benzyll-2-methylimidazo[l ,2-a]pyrazin-6- yl|pyrimidin-2-yl)piperazine- 1 -carboxylate
Intermediate 6 (100 mg, 0.27 mmol) and tert-bvXy\ 4-[5-(4,4,5,5-tetramethyl- 1, 3, 2-dioxaborolan-2-yl)pyrimidin-2-yl]piperazine-l -carboxylate (88 mg, 0.225 mmol) were dissolved in 1,4-dioxane (4 mL) and 2M aqueous potassium carbonate solution (475 μί) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron; dichloromethane; dichloro- palladium (11.1 mg, 0.01 mmol) was added. The reaction was heated at 90°C for 8.5 h in a sealed tube under nitrogen. The mixture was diluted with EtOAc (20 mL) and washed with water (15 mL). The aqueous phase was diluted with water (15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography, eluting with heptanes: ethyl acetate 1 :0 to 1 : 1 , to yield the title compound (81 mg, 50%). δΗ (250 MHz, CDC13) 9.07 (s, 1H), 8.76 (s, 2H), 7.95 (d, J 1.4 Hz, 1H), 7.31 (d, J 7.4 Hz, 1H), 7.13 (m, 2H), 6.94 (m, 1H), 6.64 (t, J29 Hz, 1H), 4.33 (s, 2H), 3.87 (m, 4H), 3.51 (m, 4H), 2.58 (s, 3H), 1.49 (s, 9H). Method A HPLC-MS: MH+ mlz 552, RT 5.01 minutes.
INTERMEDIATE 15
[2-(3-Oxopiperazin- 1 -yl)pyrimidin-5-yllboronic acid
(2-Chloropyrimidin-5-yl)boronic acid (1.0 g, 6.32 mmol) and piperazin-2-one (1.6 g, 16.0 mmol) were suspended in 1,4-dioxane (10 mL) and the mixture was heated at
100°C under microwave irradiation for 45 minutes. The supernatant liquid was decanted from the suspension and the residue was triturated with methanol and diethyl ether. The resultant solids were filtered off and dried under vacuum to afford the title compound (706 mg, 30%) as a pale pink solid. LCMS: MH+ 223.
INTERMEDIATE 16
[2-(5-Oxo- 1 ,4-diazepan- 1 -yl)pyrimidin-5-yllboronic acid
(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and l,4-diazepan-5- one (288 mg, 2.53 mmol) were suspended in 1,4-dioxane (3 mL) and the mixture was heated at 100°C under microwave irradiation for 45 minutes. The resulting slurry was concentrated under vacuum and triturated with MeOH to afford the title compound as a cream precipitate, which was used without further purification. LCMS: MH+ 237. INTERMEDIATE 17 fert-Butyl 4-(4,4,5 ,5-tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- 1 ,2,3 ,6-tetrahydropyridine- 1 - carboxylate
tert- utyl 4-[(trifluoromethane)sulfonyloxy]- 1 ,2,3,6-tetrahydropyridine- 1 - carboxylate (500 mg, 1.51 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (460 mg, 1.81 mmol), 1 , -bis(diphenyl- phosphanyl)ferrocene (25 mg, 0.05 mmol) and potassium acetate (444 mg, 4.53 mmol) were dissolved in 1,4-dioxane (10 mL) and degassed for 5 minutes. Bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (37 mg, 0.05 mmol) was added and the mixture was heated at 80°C for 3 h. The mixture was filtered through celite and concentrated under reduced pressure. The residue was purified by FCC (eluting with EtOAc in heptanes) to afford the title compound (332 mg, 71%) as a white solid. δΗ (500 MHz, CDC13) 6.46 (s, 1H), 3.95 (q, J2.8 Hz, 2H), 3.43 (t, J 5.6 Hz, 2H), 2.22 (dq, J 5.5, 2.8 Hz, 2H), 1.46 (s, 9H), 1.26 (s, 12H).
INTERMEDIATE 18
2-Chloro-5-(3-([2-(difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6- yDpyridine
Intermediate 6 (200 mg, 0.54 mmol), (6-chloropyridin-3-yl)boronic acid (90 mg, 0.57 mmol) and 2M aqueous potassium carbonate solution (0.95 mL) were combined in 1,4-dioxane (8 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l -yljiron dichloropalladium dichloromethane complex (22 mg, 0.03 mmol) was added. The mixture was heated at 90°C for 8.5 h. The mixture was partitioned between EtOAc (20 mL) and water (15 mL) and the phases were separated. The aqueous phase was diluted with water (~15 mL) and extracted with EtOAc (20 mL). The combined organic phases were washed with brine (10 mL) and dried over magnesium sulfate, then concentrated under vacuum. The residue was purified by FCC, eluting with 0-100% EtOAc in heptanes, to afford the title compound (92.6 mg, 38%) as an off-white solid. The crude material was used without further purification. Method C HPLC-MS: MH+ mlz 401, RT 1.30 minutes. INTERMEDIATE 19 tert-Butyl 3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-8-azabicyclo[3.2.11oct-2-ene- 8-carboxylate
tert-Butyl 3-[(trifluoromethane)sulfonyloxy]-8-azabicyclo[3.2. l]oct-2-ene-8- carboxylate (100 mg, 0.28 mmol), 4,4,5, 5-tetramethyl-2-(4,4,5,5-tetramethyl-l, 3,2- dioxaborolan-2-yl)-l,3,2-dioxaborolane (85 mg, 0.36 mmol), 1 , -bis(diphenyl- phosphanyl)ferrocene (5 mg, 0.01 mmol) and potassium acetate (82 mg, 0.84 mmol) were dissolved in 1,4-dioxane (2 mL) and degassed for 5 minutes. Bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (7 mg, 0.01 mmol) was added and the mixture was heated at 80°C for a total of 3 h. The reaction mixture was cooled and filtered over celite. The solid was washed with EtOAc (2 x 10 mL) and the combined filtrate was concentrated under vacuum. The crude product was purified using FCC, eluting with a gradient of 0-50% EtOAc in heptanes, to afford the title compound (86.8 mg, 89%) as a colourless oil. 5H (500 MHz, CDC13) 6.76 (s, 1H), 4.33 (d, J29.8 Hz, 2H), 2.79 (d, J 17.5 Hz, 1H), 2.12 (dd, J 13.3, 7.3 Hz, 1H), 1.92 (m, 2H), 1.65 (m, 2H), 1.46 (d, J 7.1 Hz, 9H), 1.26 (d, J 6.3 Hz, 12H).
INTERMEDIATE 20
Methyl 2- (4- [5 -(3- {[2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 12- \- pyrazin-6-yl)pyrimidin-2-yllpiperazin- 1 -yl| acetate
The hydrochloride salt of Example 4 (200 mg, 0.41 mmol) was dissolved in DMF (4 mL) and caesium carbonate (401 mg, 1.23 mmol) was added. The resulting mixture was stirred under nitrogen for 5 minutes, then methyl bromoacetate (35 μί, 0.37 mmol) was added and the reaction mixture was stirred under nitrogen for 2.5 h. The reaction mixture was diluted with water (10 mL) and extracted with EtOAc (20 mL). The organic layer was washed with brine (2 x 10 mL), dried over sodium sulfate and concentrated to dryness. The residue was triturated with DCM to yield the title compound (118 mg, 55%). δΗ (500 MHz, CD3OD) 8.92 (s, 1H), 8.84 (s, 2H), 8.52 (s, 1H), 7.37-7.30 (m, 1H), 7.26-7.16 (m, 3H), 6.93 (t, J 73.9 Hz, 1H), 4.47 (s, 2H), 3.97-3.91 (m, 4H), 3.75 (s, 3H), 3.34 (s, 2H), 2.71-2.65 (m, 4H), 2.47 (s, 3H). INTERMEDIATE 21 fert-Butyl 4- [5 -(3 - ( [2-(difluoromethoxy)phenyll (hydroxy)methyll -2-methylimidazo [ 1 ,2- alpyrazin-6-yl)pyridin-2-yllpiperazine- 1 -carboxylate
tert- utyl 4-[5-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyridin-2-yl]- piperazine-1 -carboxylate (101 mg, 0.26 mmol) and Intermediate 5 (100 mg, 0.26 mmol) were added to degassed 1,4-dioxane (1.5 mL) in a sealed tube. Degassed 1M aqueous sodium carbonate solution (0.781 mL, 0.781 mmol) was added, followed by
bis(triphenylphosphine)palladium(II) dichloride (9 mg, 0.013 mmol), and the reaction mixture was heated under nitrogen at 100°C for 8 h. The reaction mixture was diluted with EtOAc (15 mL) and the organic layer was washed with saturated aqueous sodium bicarbonate solution (6 mL) followed by brine (6 mL), then dried over sodium sulfate and concentrated. The residue was purified by FCC, eluting with a gradient of 0-2.5% (7M NH3 in MeOH) in DCM, to afford the title compound (117 mg, 77%) as a light brown glass. δΗ (500 MHz, CDC13) 8.80 (m, 1H), 8.39 (d, J2.3 Hz, 1H), 8.35 (m, 1H), 7.91 (m, 2H), 7.33 (m, 2H), 7.04 (m, 1H), 6.63 (d, J 8.9 Hz, 1H), 6.38 (m, 2H), 5.50 (s, 1H), 3.53 (m, 8H), 2.28 (s, 3H), 1.47 (s, 9H).
INTERMEDIATE 22
1 - [5 -(Dihydroxyboranyl)pyrimidin-2-yllpiperidine-4-carboxylic acid
(2-Chloropyrimidin-5-yl)boronic acid (1 g, 6.32 mmol) was dissolved in EtOH (15 mL) and piperidine-4-carboxylic acid (816 mg, 6.32 mmol) was added, followed by triethylamine (881 μί, 6.32 mmol). The reaction mixture was heated at 80°C for a total of 4 h. The reaction mixture was concentrated to dryness and 10 mL of water was added. The resulting suspension was cooled to 0°C for 30 minutes, then filtered, and the solid was washed with minimal water. Only a trace amount of precipitate was isolated so this was recombined with the filtrate and concentrated to dryness to afford the title compound. The crude product was used without purification. Method C HPLC-MS: MH+ mlz 252, RT 0.70 minutes. INTERMEDIATE 23
(2-[(li?,56',6r)-6-(Ethoxycarbonyl)-3-azabicyclo[3.1.01hexan-3-yllpyrimidin-5-yl|- boronic acid
(2-Chloropyrimidin-5-yl)boronic acid (250 mg, 1.58 mmol), ethyl (lR,5S,6r)-3- azabicyclo[3.1.0]hexane-6-carboxylate hydrochloride (303 mg, 1.58 mmol) and triethyl- amine (0.22 mL, 1.58 mmol) were dissolved in ethanol (8 mL) and stirred at 80°C overnight. The reaction mixture was cooled and concentrated under vacuum. Water (30 mL) was added, and the solid was filtered and dried, to afford the title compound (253 mg, 58%) as a pale brown solid. Method B HPLC-MS: MH+ mlz 278, RT 1.35 minutes.
INTERMEDIATE 24
(2-[4-(Ethoxycarbonyl)piperidin-l-yllpyrimidin-5-yl|boronic acid
(2-Chloropyrimidin-5-yl)boronic acid (2 g, 12.63 mmol) and ethyl piperidine-4- carboxylate (1.94 mL, 12.63 mmol) were dissolved in 1,4-dioxane (20 mL) and heated at 60°C under microwave irradiation for 1 h. The reaction mixture was concentrated to dryness and partitioned between EtOAc and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated to dryness, to afford the title compound (1.79 g, 51%) as a yellow gum. Method C HPLC-MS: MH+ mlz 280, RT 0.94 minutes.
INTERMEDIATE 25 Ethyl (li?,56',6r)-3-[5-(3-([2-(difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-al- pyrazin-6-yl)pyrimidin-2-yll-3-azabicyclo[3.1.01hexane-6-carboxylate
Intermediate 6 (120 mg, 0.32 mmol), Intermediate 23 (117 mg, 0.42 mmol) and 2M aqueous potassium carbonate solution (0.51 mL) were stirred in 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (13 mg, 0.01 mmol). The mixture was heated at 100°C for 15 h. The reaction mixture was cooled to r.t. and EtOAc (10 mL) was added. The solution was washed with water (2 x 10 mL) and brine (10 mL), dried over sodium sulfate, then concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-7% MeOH in DCM, to afford the title compound (122 mg, 72%) as a pale orange oil. δΗ (500 MHz, CDC13) 9.04 (s, IH), 8.74 (d, J5.7 Hz, 2H), 7.91 (s, IH), 7.31-7.26 (m, IH), 7.17 (d, J 8.0 Hz, IH), 7.12 (t, J 7.5 Hz, IH), 6.93 (d, J 7.6 Hz, IH), 6.63 (t, J 73.5 Hz, IH), 4.32 (s, 2H), 4.14 (q, J 7.1 Hz, 2H), 4.03 (d, J 11.5 Hz, 2H), 3.70-3.64 (m, 2H), 2.57 (s, 3H), 2.29-2.22 (m, 2H), 1.59- 1.52 (m, IH), 1.26 (t, J7.3 Hz, 3H). Method D HPLC-MS: MH+ mlz 520, RT 3.32 minutes.
INTERMEDIATE 26
(2-[4-(Ethoxycarbonyl)-4-methylpiperidin- 1 -yllpyrimidin-5-yl|boronic acid
(2-Chloropyrimidin-5-yl)boronic acid (321 mg, 2.03 mmol) and ethyl 4-methyl- piperidine-4-carboxylate (347 mg, 2.03 mmol) were stirred in 1,4-dioxane (6 mL) and the mixture was degassed with nitrogen for 5 minutes. The tube was sealed and heated under microwave irradiation for 30 minutes at 65°C. Further (2-chloropyrimidin-5-yl)boronic acid (36 mg, 0.23 mmol) was added and the mixture was heated under microwave irradiation for 30 minutes at 65°C. The mixture was concentrated to afford the title compound, which was used without further purification. Method C HPLC-MS: MH+ mlz 294, RT 1.09 minutes.
INTERMEDIATE 27
{2-[4-Hydroxy-4-(methoxycarbonyl)piperidin- 1 -yllpyrimidin-5-yl|boronic acid
(2-Chloropyrimidin-5-yl)boronic acid (0.25 g, 1.579 mmol) and methyl 4- hydro xypiperidine-4-carboxylate (0.528 g, 3.315 mmol) were dissolved in DMSO (5 mL) and heated at 70°C under microwave irradiation for 50 minutes. The mixture was diluted with EtOAc (45 mL) and washed with saturated aqueous ammonium chloride solution (3 x 6 mL), water (6 mL) and brine (10 mL), then dried over sodium sulfate and
concentrated, to afford the title compound (230 mg, 48%) as a brown gum. Method C HPLC-MS: MH+ mlz 282, RT 0.70 minutes. INTERMEDIATE 28
1 - {6-Bromo-2-methylimidazo[ 1 ,2-a"|pyrazin-3-yl| - 1 -[2-(difluoromethoxy)phenyllethanol Intermediate 4 (924 mg, 2.42 mmol) was dissolved in THF (10 mL) and cooled to 0°C under nitrogen. Methylmagnesium bromide in THF/toluene (3.11 mL of a 1.4M solution) was added at 0°C under nitrogen and the reaction mixture was stirred for 1 h at 0°C under nitrogen. Further methylmagnesium bromide in THF/toluene (1.55 mL of a 1.4M solution) was added at 0°C under nitrogen and the reaction mixture was stirred at 0°C under nitrogen for 10 minutes. The reaction mixture was carefully quenched by addition of saturated aqueous ammonium chloride solution (15 mL) at 0°C, and extracted into EtOAc (25 mL). The organic layer was separated, washed with brine (15 mL), dried over sodium sulfate and concentrated to dryness. The residue was triturated with DCM (5 mL) to afford an off- white solid. The filtrate was purified by FCC, eluting with 20-100% EtOAc in heptanes, to afford the title compound (360 mg, 37%) as a yellow gum. 5H (500 MHz, CD3OD) 8.65 (s, 1H), 8.35 (d, J 1.3 Hz, 1H), 8.17-8.11 (m, 1H), 7.44-7.37 (m, 2H), 7.10-7.04 (m, 1H), 6.71-6.37 (m, 1H), 2.66 (s, 3H), 2.13 (s, 3H). Method C HPLC-MS: MH+ mlz 398/400, RT 1.19 minutes.
INTERMEDIATE 29
Ethyl 1 -|"5-(3- ( 1 -[2-(difluoromethoxy)phenyll- 1 -hydroxy ethyl I -2-methylimidazo[ 12- \- pyrazin-6-yl)pyrimidin-2-yllpiperidine-4-carboxylate
Intermediate 28 (180 mg, 0.45 mmol), Intermediate 24 (189.24 mg, 0.68 mmol) and 2M aqueous potassium carbonate solution (0.9 mL) were suspended in 1,4-dioxane (10 mL). The mixture was purged with nitrogen for 5 minutes, then bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (18 mg, 0.02 mmol) was added and the mixture was heated at 100°C for 4 h. The mixture was cooled to r.t, filtered through celite and concentrated under reduced pressure. The residue was purified by preparative HPLC to afford the title compound (85 mg, 34%) as a pale yellow solid. δΗ (500 MHz, DMSO-dg) 8.94 (d, J 1.1 Hz, 1H), 8.55 (s, 2H), 8.27 (d, J 1.1 Hz, 1H), 8.22 (dd, J7.8, 1.6 Hz, 1H), 7.51-7.25 (m, 2H), 7.15-6.70 (m, 2H), 6.47 (s, 1H), 4.55 (d, J 13.4 Hz, 2H), 4.08 (q, J7.1 Hz, 2H), 3.26-2.98 (m, 2H), 2.70-2.62 (m, 1H), 2.61 (s, 3H), 2.07 (s, 3H), 1.90 (d, J 10.2 Hz, 2H), 1.50 (q, J 11.1 Hz, 2H), 1.19 (t, J 7.1 Hz, 3H). Method B HPLC-MS: MH+ mlz 553, RT 1.95 minutes.
INTERMEDIATE 30
Ethyl 1 -[5-(3- ( 1 -[2-(difluoromethoxy)phenyllethenyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yllpiperidine-4-carboxylate
Intermediate 29 (80 mg, 0.14 mmol) and 4-methylbenzenesulfonic acid monohydrate (6 mg, 0.03 mmol) were dissolved in toluene (3 mL) and the mixture was heated at 80°C for 4 h, then at 120°C for 2 h. The mixture was concentrated under reduced pressure and purified by preparative HPLC to afford the title compound (25 mg, 32%) as an off-white solid. δΗ (500 MHz, CDC13) 9.03 (d, J 14.9 Hz, 1H), 8.59 (s, 2H), 7.73 (s, 1H), 7.49-7.37 (m, 2H), 7.36-7.30 (m, 1H), 7.14 (d, J 8.3 Hz, 1H), 6.18 (t, J 73.4 Hz, 1H), 5.99 (s, 1H), 5.76 (s, 1H), 4.69 (dt, J 13.5, 3.5 Hz, 2H), 4.15 (q, J7.1 Hz, 2H), 3.17-3.00 (m, 2H), 2.58 (tt, J 11.0, 3.9 Hz, 1H), 2.46 (s, 3H), 1.99 (dd, J 13.5, 3.3 Hz, 2H), 1.71 (qd, J 11.4, 4.1 Hz, 2H), 1.26 (t, J 7.1 Hz, 3H). Method B HPLC-MS: MH+ mlz 535, RT 2.35 minutes.
INTERMEDIATE 31
Ethyl 1 -[5-(3- ( 1 -[2-(difluoromethoxy)phenyllethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yllpiperidine-4-carboxylate
Intermediate 30 (25 mg, 0.05 mmol) was dissolved in ethanol (50 mL), then palladium on carbon (10% w/w, 5 mg) was added. The suspension was degassed using vacuum/nitrogen and the mixture was stirred under hydrogen at r.t. for 14 h. The reaction mixture was then degassed using vacuum/nitrogen and filtered through celite, washing with MeOH (15 mL). The solvent was removed under reduced pressure to afford the title compound (25 mg) as a pale yellow sticky solid. LCMS showed that the conversion had not gone to completion, and the crude product was used without purification. Method B HPLC-MS: MH+ mlz 537, RT 2.25 minutes. INTERMEDIATE 32
6-Bromo-3 - ( [2-(difluoromethoxy)phenyll (methoxy)methyl| -2-methylimidazo [ 1 ,2- ] - pyrazine
Intermediate 5 (1.44 g, 3.75 mmol) was stirred in anhydrous DCM (50 mL) under nitrogen and the mixture was cooled with an ice bath. Thionyl bromide (0.38 mL, 4.87 mmol) was added slowly, then the mixture was allowed to warm to r.t. and stirred for 1 h. The mixture was then cooled with an ice bath and anhydrous MeOH (15.43 mL, 0.38 mol) was added slowly. The mixture was stirred for 30 minutes. The mixture was reduced to dryness under vacuum and the flask was flushed with nitrogen. Anhydrous DCM (50 mL) was added, the mixture was cooled and thionyl bromide (0.1 mL, 1.3 mmol) was added. The mixture was stirred at r.t. for 1 h before being quenched with MeOH and concentrated under vacuum to afford the title compound (1.06 g, 71%).
Method C HPLC-MS: MH+ mlz 398/400, RT 1.35 minutes.
INTERMEDIATE 33
(2-{7-Oxo-3,6-diazabicyclo[3.2.21nonan-3-yl|pyrimidin-5-yl)boronic acid triethyl- azanium chloride
(2-Chloropyrimidin-5-yl)boronic acid (1.13 g, 7.14 mmol) and (15',5i?)-3,6-diaza- bicyclo[3.2.2]nonan-7-one (1.00 g, 7.13 mmol) were mixed together in ethanol (15 mL) and triethylamine (1.00 mL, 7.10 mmol) was added. The mixture was heated to 80°C for 3 days. The mixture was concentrated in vacuo to afford the title compound (2.70 g, UV purity 94.7%) as an off-white solid, which was used in subsequent coupling reactions without any further purification. δΗ (300 MHz, DMSO-d6) 10.54-9.53 (br s, 2H), 8.08 (s, 2H), 4.88-4.74 (m, 2H), 3.65-3.53 (m, 1H), 3.48-3.39 (m, 1H), 3.24-3.11 (m, 2H), 3.03 (q, J 7.3 Hz, 6H), 2.59-2.52 (m, 1H), 1.78-1.53 (m, 4H), 1.19 (t, J 7.3 Hz, 9H). INTERMEDIATE 34 fert-Butyl 4- [5 -(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin- 6-yl)pyridin-2-yllpiperazine- 1 -carboxylate
Intermediate 6 (100 mg, 0.27 mmol) and tert-butyl 4-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyridin-2-yl]piperazine-l-carboxylate (159 mg, 0.41 mmol) were combined in 1 ,4-dioxane (7 mL) and the mixture was degassed before the addition of 2M aqueous potassium carbonate solution (0.473 mL) and bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (11 mg, 0.014 mmol). The mixture was heated at 90°C for 4 h in a sealed tube, then left to stand at r.t. for 4 days. The mixture was heated at 90°C for 2 h, then at 100°C for a total of 8 h. The mixture was partitioned between EtOAc (20 mL) and water (15 mL). The aqueous layer was diluted with water (~15 mL) and extracted with EtOAc (20 mL). The combined organic layers were washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-100%
EtOAc in heptanes. The residue was then twice purified by FCC, eluting with mixtures of MeOH in DCM, to afford the title compound (35 mg, 22%) as a white solid. Method B HPLC-MS: MH+ mlz 551, RT 2.10 minutes.
INTERMEDIATE 35
4-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- piperidine hydrochloride
Example 9 (700 mg, 1.48 mmol) was suspended in 4M HC1 in 1,4-dioxane (3.7 mL) and the mixture was stirred at r.t. for 2 h. The mixture was concentrated under reduced pressure and dried under vacuum, to afford the title compound (595 mg, 98%>) as a sticky beige solid. Method B HPLC-MS: MH+ mlz 373, RT 1.21 minutes. INTERMEDIATE 36
3-([2-(Difluoromethoxy)phenyl]methyl|-6-^
imidazo[l ,2-a]pyrazine
Intermediate 6 (600 mg, 1.63 mmol) and (6-fluoro-4-methylpyridin-3-yl)boronic acid (375 mg, 2.42 mmol) were dissolved in a mixture of 1 ,4-dioxane (3 mL) and 2M aqueous potassium carbonate solution (2.5 mL). The mixture was flushed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (100 mg, 0.12 mmol) was added and the mixture was heated at 90°C for 15 h. The mixture was diluted with EtOAc (20 mL), then washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting dark brown solid was purified by FCC, eluting with 70-100% EtOAc in heptanes followed by 0-10% MeOH in DCM, to afford the title compound (422 mg, 65%) as a light pink solid. δΗ (500 MHz, CD3OD) 8.95 (d, J 1.2 Hz, 1H), 8.33 (d, J 1.2 Hz, 1H), 8.13 (s, 1H), 7.35-7.28 (m, 1H), 7.23-7.14 (m, 3H), 7.06 (s, 1H), 6.86 (t, J 74.0 Hz, 1H), 4.44 (s, 2H), 2.48 (s, 3H), 2.36 (s, 3H). Method D HPLC- MS: MH+ mlz 399, RT 3.29 minutes.
INTERMEDIATE 37
5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-2- fluoropyridine
A mixture of Intermediate 6 (50 mg, 0.14 mmol), (6-fluoropyridin-3-yl)boronic acid (29 mg, 0.2 mmol) and 2M aqueous sodium carbonate solution (0.10 mL) in acetonitrile (1.0 mL) was purged with nitrogen for 5 minutes. Bis[3-(diphenyl- phosphanyl)cyclopenta-2,4-dien-l -yljiron dichloropalladium dichloromethane complex (3 mg, 2.5 mol %) was added, then the reaction mixture was heated at 150°C under microwave irradiation for 30 minutes. The reaction mixture was partitioned between EtOAc (5 mL) and water (3 mL). The aqueous layer was separated and extracted with EtOAc (5 mL). The combined organic extracts were washed with brine (5 mL), dried over sodium sulfate and evaporated. The residue was purified by FCC, eluting with 20- 100%) EtOAc in heptanes, to afford the title compound (41 mg, 79%) as a yellow solid. δΗ (500 MHz, CD3OD) 8.97 (d, J 1.2 Hz, 1H), 8.76 (d, J 2.4 Hz, 1H), 8.70 (d, J 1.4 Hz, IH), 8.53-8.44 (m, IH), 7.37-7.28 (m, IH), 7.26-7.15 (m, 4H), 7.07-6.69 (m, IH), 4.48 (s, 2H), 2.46 (s, 3H). Method B HPLC-MS: MH+ mlz 385, RT 1.94 minutes.
INTERMEDIATE 38
Ethyl 1 -[5-(3- ([2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyridin-2-yl"|piperidine-4-carboxylate
A mixture of Intermediate 37 (38 mg, 0.1 mmol) and ethyl piperidine-4- carboxylate (30.5 μί, 0.2 mmol) in pyridine (0.5 mL) was heated at 180°C under microwave irradiation for a total of 3 h. The reaction mixture was evaporated and the residue was purified by FCC, eluting with 50-100% EtOAc in heptanes, to afford the title compound (38 mg, 74%) as an off-white solid. δΗ (500 MHz, CD3OD) 8.90 (d, J 1.4 Hz, IH), 8.60 (d, J2.2 Hz, IH), 8.41 (d, J 1.4 Hz, IH), 8.04 (dd, J 9.0, 2.5 Hz, IH), 7.38-7.27 (m, IH), 7.19 (td, J 8.0, 6.2 Hz, 3H), 7.11-6.67 (m, 2H), 4.45 (s, 2H), 4.28 (dt, J 13.4, 3.6 Hz, 2H), 4.15 (q, J7.1 Hz, 2H), 3.12-3.01 (m, 2H), 2.64 (tt, J 11.0, 3.9 Hz, IH), 2.47 (s, 3H), 2.05-1.95 (m, 2H), 1.72 (qd, J 11.3, 4.0 Hz, 2H), 1.27 (t, J 7.1 Hz, 3H). Method B HPLC-MS: MH+ mlz 522, RT 1.87 minutes.
INTERMEDIATE 39
Ethyl 1 -[5-(3- ([2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyridin-2-yll-4-methylpiperidine-4-carboxylate
A mixture of Intermediate 37 (200 mg, 0.52 mmol) and ethyl 4-methylpiperidine- 4-carboxylate hydrochloride (216 mg, 1.04 mmol) in pyridine (0.5 mL) was heated at 180°C under microwave irradiation for 4 h. The reaction mixture was concentrated and the residue was purified by FCC, eluting with 20-100%) EtOAc in heptanes, to afford the title compound (131 mg, 47%) as an off-white solid. δΗ (500 MHz, CD3OD) 8.88 (d, J 1.4 Hz, IH), 8.57 (d, J2.3 Hz, IH), 8.37 (d, J 1.4 Hz, IH), 8.01 (dd, J9.0, 2.5 Hz, IH), 7.31 (ddd, J 8.6, 6.8, 2.3 Hz, IH), 7.26-7.11 (m, 3H), 7.08-6.71 (m, 2H), 4.43 (s, 2H), 4.19 (q, J7.1 Hz, 2H), 4.01 (dt, J 13.7, 4.2 Hz, 2H), 3.18 (ddd, J 13.6, 10.7, 2.9 Hz, 2H), 2.46 (s, 3H), 2.17 (d, J 13.6 Hz, 2H), 1.51 (ddd, J 14.1, 10.7, 4.0 Hz, 2H), 1.27 (t, J7.1 Hz, 3H), 1.23 (s, 3H). Method B HPLC-MS: MH+ mlz 536, RT 1.96 minutes. INTERMEDIATE 40
(2,5-Dichlorophenyl)[2-methyl-6-n-methy
methanone
To Intermediate 8 (1 g, 2.68 mmol) in 1,4-dioxane (4 mL) and water (1 mL) were added l-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrazole (556 mg, 2.68 mmol), dichloro[l, -bis(di-tert-butylphosphino)]ferrocenepalladium(II) (84 mg, 0.13 mmol) and aqueous sodium carbonate solution (2M, 1 mL) and the reaction mixture was heated under microwave irradiation at 100°C for 1 h. The cooled reaction mixture was partitioned between water and DCM, then the organic layer was dried over magnesium sulfate and concentrated in vacuo. The crude residue was purified by column
chromatography (Si02, EtOAc:DCM, 0 to 100%) to afford the title compound (254 mg, 25%) as a cream solid. δΗ (400 MHz, DMSO-d6) 9.63 (d, J 1.5 Hz, 1H), 9.29 (d, J 1.4 Hz, 1H), 8.41 (s, 1H), 8.03 (d, J 0.5 Hz, 1H), 7.80-7.79 (m, 1H), 7.73 (d, J l .l Hz, 2H), 3.93 (s, 3H), 1.99 (s, 3H). HPLC-MS: MH+ mlz 386.0, RT 2.22 minutes.
INTERMEDIATE 41
(2,5-Dichlorophenyl)[2-methyl-6-(l-methylpyrazol-4-yl)imidazo[l,2-alpyrazin-3-yll- methanol
To Intermediate 40 (254 mg, 0.66 mmol) in ethanol (5 mL) and DCM (2 mL) was added sodium borohydride (25 mg, 0.66 mmol). The reaction mixture was stirred at r.t. for 15 minutes. Saturated aqueous ammonium chloride solution and DCM were added to the reaction mixture. The organic layer was separated by passing through a phase separator, then concentrated, to afford the title compound (183 mg, 71%) as a white solid which was used without further purification. The material could be further purified by preparative HPLC. δΗ (400 MHz, DMSO-de) 8.93 (d, J 1.2 Hz, 1H), 8.85 (d, J 1.2 Hz, 1H), 8.24 (s, 1H), 8.05 (s, 1H), 7.99 (s, 1H), 7.48 (d, J 1.3 Hz, 2H), 6.61 (d, J 3.5 Hz, 1H), 6.48 (s, 1H), 3.90 (s, 3H), 1.97 (s, 3H). HPLC-MS: MH+ mlz 388.6, RT 1.99 minutes. INTERMEDIATE 42
Ethyl 3-azabicyclo[4.1.0"|heptane-6-carboxylate hydrochloride
A 4M solution of HCl in 1,4-dioxane (2.07 mL, 8 mmol) was added to a solution of 3-(tert-butyl) 6-ethyl 3-azabicyclo[4.1.0]heptane-3,6-dicarboxylate (1 g, 4 mmol) in ethanol (10 mL) at r.t. The mixture was stirred at r.t. for 2.5 h. An additional aliquot of ethanol (10 mL) and a 4M solution of HCl in 1,4-dioxane (4.14 mL, 16 mmol) were added, and the mixture was heated at 50°C for 1.5 h. The reaction mixture was cooled and evaporated under vacuum. A second reaction batch was prepared whereby a 4M solution of HCl in dioxane (10.4 mL, 4 mmol) was added to a solution of 3-(tert-butyl) 6- ethyl 3-azabicyclo[4.1.0]heptane-3,6-dicarboxylate (1 g, 4 mmol) in ethanol (40 mL) and the reaction mixture was warmed to 75°C, then stirred at this temperature overnight. The reaction mixture was cooled to r.t., then concentrated under vacuum in combination with the first batch, to afford the title compound (3.1 g) as a pale yellow solid. 5H (250 MHz, DMSO-dg) 9.07 (d, J37.9 Hz, 2H), 4.05 (q, J 7.1 Hz, 2H), 3.08 (d, J 13.1 Hz, 1H), 2.83 (s, 2H), 2.61 (dt, J 13.7, 6.5 Hz, 1H), 2.00-1.81 (m, 1H), 1.71 (q, J 7.0 Hz, 1H), 1.36-1.22 (m, 2H), 1.18 (q, J 7.1, 6.4 Hz, 3H).
INTERMEDIATE 43
Ethyl 3 - [5 -(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yl"|-3-azabicyclo[4.1.0]heptane-6-carboxylate
(2-Chloropyrimidin-5-yl)boronic acid (231 mg, 1.46 mmol) and Intermediate 42 (300 mg, 1.46 mmol) were dissolved in DMF (5 mL) and potassium carbonate (302 mg, 2.19 mmol) was added. The mixture was heated at 80°C in a sealed tube for 3.5 h. The reaction mixture was cooled down to r.t., then Intermediate 6 (347 mg, 0.94 mmol), a 2M solution of potassium carbonate in water (1.39 mL) and 1,4-dioxane (6 mL) were added. The mixture was degassed with nitrogen, then Pd(dppf)Cl2.DCM (39 mg, 0.048 mmol) was added. The mixture was heated at 80°C in a sealed tube for 3 h. The reaction mixture was cooled down to r.t. and concentrated under vacuum. The resulting brown residue was partitioned between EtOAc (5 mL) and water (3 mL). The organic phase was washed with water (3 x 3 mL), then the aqueous washes were combined and extracted with EtOAc (3 x 3 mL). The organic extracts were combined, dried over sodium sulfate, filtered and evaporated. The resulting crude brown oil was purified by FCC (Si02, heptanes:EtOAc 7.5:2.5 to 2:8) to afford a solid which was further purified by trituration in diethyl ether, then dissolved in a mixture of DMSO and water. The solid which precipitated out of solution was filtered and washed with diethyl ether, to afford the title compound (55 mg, 11%). Method C HPLC-MS: MH+ mlz 535, RT 1.46 minutes.
INTERMEDIATE 44
Ethyl 4- [5 -(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yll cyclohex-3 -ene- 1 -carboxylate
A mixture of Intermediate 6 (0.3 g, 0.815 mmol), ethyl 4-[5-(4,4,5,5-tetramethyl- l,3,2-dioxaborolan-2-yl)pyrimidin-2-yl]cyclohex-3-ene-l-carboxylate (0.38 g, l .O mmol), and a 2M solution of potassium carbonate in water (1.22 mL, 2.0 mmol), in DMF (5 mL) and 1,4-dioxane (5 mL), was degassed by bubbling nitrogen through the mixture for 30 minutes. Pd(dppf)Cl2 complex with dichloromethane (0.03 g, 0.04 mmol) was added and the mixture was heated at 80°C in a pressure tube for 4 h. The mixture was cooled and stored in a freezer for 7 days. The reaction mixture was diluted with EtOAc (20 mL), then washed with water (3 x 10 mL). The aqueous washes were combined and extracted with EtOAc (10 mL). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under vacuum. The resulting crude residue was purified by
FCC (heptane: EtOAc 7.5:2.5 to 2.5:7.5) to afford the title compound (339 mg, 80%) as an off-white solid. δΗ (500 MHz, CDC13) 9.14 (d, J 6.9 Hz, 3H), 8.17 (s, 1H), 7.38 (s, 1H), 7.36-7.30 (m, 1H), 7.23-7.13 (m, 2H), 7.01 (d, J 7.5 Hz, 1H), 6.66 (t, J 73.5 Hz, 1H), 4.38 (s, 2H), 4.20 (qd, J 7.1, 1.6 Hz, 2H), 2.92 (d, J 17.0 Hz, 1H), 2.72-2.51 (m, 7H), 2.33-2.22 (m, 1H), 1.94-1.83 (m, 1H), 1.31 (t, J 7.1 Hz, 3H). Method B HPLC-MS: MH+ mlz 520, RT 2.27 minutes.
INTERMEDIATE 45
Ethyl 4- [5 -(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yllcyclohexane- 1 -carboxylate
Intermediate 44 (165 mg, 0.32 mmol) was dissolved in ethanol (5 mL), then EtOAc (5 mL) and triethylamine (0.047 mL, 0.349 mmol) were added. Palladium on carbon (10% w/w, 67.6 mg, 0.063 mmol) was added. The reaction mixture was flushed with nitrogen (3 times) and hydrogen (3 times), then stirred successively under hydrogen for 6 h and 50 minutes, under nitrogen for 2 days, under hydrogen for 6 h, under nitrogen overnight, and under hydrogen for 3 h. The reaction mixture was filtered through Kieselguhr and washed through with EtOAc, then the filtrate was concentrated. The resulting yellow gum was purified by column chromatography (Si02, 0-3% MeOH in DCM), to afford the title compound (158 mg, 98%>) as a mixture of cis trans isomers (65:35) as a yellow/orange gum. Method D HPLC-MS: MH+ mlz 522, RT 3.78 and 3.73 minutes.
INTERMEDIATE 46
4-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- 1 ,2,3,6-tetrahydropyridine hydrochloride
Example 8 (700 mg, 1.49 mmol) was suspended in 4M HC1 in 1,4-dioxane (3.72 mL) and stirred at room temperature for 2 h. The mixture was concentrated under reduced pressure and dried under vacuum to afford the title compound (600 mg, 99%) as an off-white solid. Method B HPLC-MS: MH+ mlz 371, RT 1.29 minutes. INTERMEDIATE 47
3-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-8- azabicyclo[3.2.1 ]oct-2-ene hydrochloride
Example 13 (270 mg, 0.54 mmol) was dissolved in a 4M solution of hydrogen chloride in 1,4-dioxane (2 mL, 8.15 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum to afford the title compound (220 mg, 75%) as a yellow powder. Method B HPLC-MS: MH+ mlz 397, RT 0.89 minutes. EXAMPLE 1
5-[3-(2,5-Dichlorobenzyl)-2-methylimidazo[ 1 ,2-a]pyrazin-6-yll- lH-pyridin-2-one
Intermediate 10 (189 mg, 0.47 mmol) was dissolved in acetic acid (2 mL). Iodine (119 mg, 0.47 mmol) and phosphinic acid (0.1 mL) were added. The reaction mixture was heated at 100°C for 2 h. The reaction mixture was quenched with 2M aqueous NaOH solution (5 mL) and partitioned with DCM. The organic layer was extracted, dried over MgS04 and concentrated in vacuo. The residue was purified by preparative HPLC, yielding the title compound (6 mg, 3%) as a white solid. 5H (d6-DMSO) 11.83 (s, IH), 8.96 (d, J 1.1 Hz, IH), 8.78 (d, J 1.0 Hz, IH), 8.14 (dd, J 9.6, 2.7 Hz, IH), 8.08 (m, IH), 7.55 (m, IH), 7.39 (dd, J 8.6, 2.5 Hz, IH), 7.05 (d, J2.4 Hz, IH), 6.48 (d, J 9.5 Hz, IH), 4.50 (s, 2H), 2.24 (s, 3H). LCMS (ES+) 386.0 (M+H)+.
EXAMPLE 2
[2-(Difluoromethoxy)phenyll[6-(6-methoxypyridin-3-yl)-2-methylimidazo[l,2-alpyrazin- 3-yllmethanol
Intermediate 13 (0.18 g, 0.44 mmol) and sodium borohydride (0.016 g, 0.44 mmol) were dissolved in ethanol (5 mL) and stirred at room temperature for 1 h. 2M aqueous NaOH solution (5 mL) was added to the reaction mixture, and the mixture was extracted with DCM (20 mL). The organic layers were separated, dried over MgS04, and concentrated in vacuo. The residue was triturated with DCM, and the precipitate was filtered off, washing with DCM/MeOH, and dried in vacuo, yielding the title compound (0.100 g, 55%) as a white solid. δΗ (dg-DMSO) 9.01 (d, J 1.3 Hz, IH), 8.88 (d, J 1.4 Hz, IH), 8.76 (d, J2.1 Hz, IH), 8.28 (dd, J 8.7, 2.5 Hz, IH), 8.05 (dd, J 5.7, 3.8 Hz, IH), 7.40 (dd, J5.9, 3.4 Hz, 2H), 7.13 (dd, J 5.7, 3.6 Hz, IH), 7.08 (s, IH), 6.97 (m, IH), 6.57 (d, J 4.2 Hz, IH), 6.34 (d, J4.2 Hz, IH), 3.93 (s, 3H), 2.22 (s, 3H). LCMS (ES+) 413.0 (M+H)+. EXAMPLE 3
5- (3-[2-(Difluoromethoxy)benzyll-2-methylimidazo[ 1 ,2-a"|pyrazin-6-yl| -2-methoxy- pyridine
Intermediate 6 (100 mg, 0.272 mmol) and 6-methoxypyridin-3-ylboronic acid (62 mg, 0.41 mmol) were dissolved in 1,4-dioxane (7 mL), and a 2M solution of potassium carbonate in water (0.5 mL) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron; dichloro- methane; dichloropalladium (11 mg, 0.014 mmol) was added. The mixture was heated at 90°C in a sealed tube for 5 h. The mixture was diluted with EtOAc (20 mL) and water
(15 mL), then the organic layer was dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by column chromatography, eluting with EtOAc in heptanes (0-100%), to yield the title compound (44 mg, 40%) as an off-white solid. 5H (250 MHz, CDCls) 9.04 (d, J 1.3 Hz, 1H), 8.60-8.43 (m, 1H), 8.12-7.92 (m, 2H), 7.29- 7.20 (m, 1H), 7.15-7.01 (m, 2H), 6.92-6.84 (m, 1H), 6.77 (dd, J 8.7, 0.7 Hz, 1H), 6.58 (t, J29.4 Hz, 1H), 4.27 (s, 2H), 3.91 (s, 3H), 2.52 (s, 3H). Method C HPLC-MS: MH+ mlz 397, RT 1.24 minutes.
EXAMPLE 4
5- (3-[2-(Difluoromethoxy)benzyll-2-methylimidazo[ 1 ,2-a"|pyrazin-6-yl| -2-(piperazin- 1 - yOpyrimidine
Intermediate 14 (93%>, 81 mg, 136 μιηοΐ) was dissolved in DCM (0.2 mL). TFA (0.2 mL) was added and the reaction mixture was stirred at ambient temperature for 30 minutes. The reaction mixture was concentrated under vacuum. The crude product was loaded onto an SCX-2 cartridge and washed with MeOH. The product was then eluted with 7M ammonia in MeOH and concentrated under vacuum. The crude product was purified by column chromatography, eluting with DCM:(7M ammonia in MeOH) 1 :0 to 95:5, to afford the title compound (46 mg, 73%) as a pale pink solid. 5H (250 MHz, CDCI3) 8.93 (s, 1H), 8.67 (s, 2H), 7.84 (d, J 1.3 Hz, 1H), 7.19 (m, 1H), 7.06 (m, 2H), 6.85 (m, 1H), 6.57 (t, J29 Hz, 1H), 4.25 (s, 2H), 3.81 (m, 4H), 2.89 (m, 4H), 2.49 (s, 3H). Method A HPLC-MS: MH+ mlz 452, RT 2.98 minutes. EXAMPLE 5
5-(3-[2-(Difluoromethoxy)benzyl]-2-methyU^
one
Example 3 (44 mg, 0.06 mmol) was dissolved in 1,4-dioxane (1 mL) and 6M HC1 in water (0.18 mL) was added. The mixture was heated under reflux at 70°C for 9 h. The mixture was diluted with EtOAc (10 mL) and neutralised with 1M aqueous NaOH solution. Water (10 mL) was added, the organic layer was separated and the aqueous layer was extracted with EtOAc (3 x 10 mL). The organic layers were combined, dried over magnesium sulfate and concentrated under reduced pressure. The crude product was purified by column chromatography, eluting with 0-10% MeOH in DCM, to afford an off-white solid. This material was suspended in minimal DCM and filtered to yield the title compound (15 mg, 35%) as a white solid. Method A HPLC-MS: MH+ mlz 383, RT 3.37 minutes.
EXAMPLE 6
4-(5-(3-[2-(Difluoromethoxy)benzyll-2-methylimidazo[l,2-alpyrazin-6-yl|pyrimidin-2- yl)piperazin-2-one
A solution of Intermediate 6 (256 mg, 0.69 mmol) and Intermediate 15 (386 mg,
1.04 mmol) in 2M aqueous K2CO3 solution (1.1 mL) and 1,4-dioxane (7 mL) was degassed under nitrogen. Pd(dppf)Ci2 complex with DCM (28.4 mg, 0.03 mmol) was added and the mixture was heated at 100°C for 4 h. The mixture was diluted with water (15 mL) and extracted with 1 :1 chloroform/isopropanol (2 x 20 mL), followed by 1 :5 methanol/DCM. The combined organic extracts were dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with methanol (20 mL) and the remaining solids were filtered off, washed with diethyl ether (20 mL) and dried under vacuum, to afford the title compound (186 mg, 57%>) as an off-white solid. 5H (500 MHz, MeOD) 8.93 (s, 1H), 8.91 (s, 2H), 8.56 (s, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.25-7.15 (m, 3H), 6.91 (t, J74.0 Hz, 1H), 4.46 (s, 2H), 4.43 (s, 2H), 4.14-4.07 (m, 2H), 3.45 (t, J 5.3 Hz, 2H), 2.46 (s, 3H). HPLC-MS: MH+ mlz 466. EXAMPLE 7 l-(5-(3-[2-(Difluoromethoxy)benzyl]-2-meth^
yl)- 1 ,4-diazepan-5-one
A solution of Intermediate 16 (133 mg, 0.56 mmol) and Intermediate 6 (207 mg,
0.56 mmol) in 1,4-dioxane (4 mL) and DMSO (0.5 mL) was degassed under nitrogen. To this solution was added a nitrogen-degassed 2M aqueous solution of K2C03 (986 μί) followed by Pd(dppf)Cl2 complex with DCM (23 mg, 0.03 mmol). The reaction mixture was sealed under nitrogen and stirred at 120°C for 16 h. EtOAc (10 mL) and water (5 mL) were added and the organic phase was separated, then the aqueous layer was further extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The crude product was purified by Biotage (SNAP lOg cartridge), eluting with 0-100% EtOAc in heptanes, followed by 0-10% (7N NH3 in MeOH) in DCM, to afford a brown solid. This material was triturated with MeOH to afford the title compound (47 mg, 18%) as a white precipitate. δΗ (250 MHz, CDC13) 9.16 (s, 1H), 8.78 (s, 2H), 8.01 (d, J 1.4 Hz, 1H), 7.30 (m, 1H), 7.15 (m, 2H), 6.96 (d, J 10.5 Hz, 1H), 6.65 (t, J29 Hz, 1H), 6.04 (s, 1H), 4.34 (s, 2H), 4.12 (m, 4H), 3.39 (d, J5.5 Hz, 2H), 2.71 (m, 2H), 2.61 (s, 3H). LCMS: MH+ 480/481.
EXAMPLE 8 tert-Butyl 4-(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin-6- yl)- 1 ,2,3 ,6-tetrahydropyridine- 1 -carboxylate
A mixture of Intermediate 6 (100 mg, 0.27 mmol), Intermediate 17 (126 mg, 0.41 mmol) and aqueous potassium carbonate solution (2M, 0.54 mL) in 1,4-dioxane (4 mL) was purged with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron dichloropalladium dichloromethane complex (11 mg, 0.01 mmol) was added and the mixture was heated at 90°C for 2 h. The mixture were filtered through celite, concentrated under reduced pressure and purified by preparative HPLC, to afford the title compound (67.4 mg, 53%) as a beige solid. δΗ (500 MHz, CDC13) 8.91 (s, 1H), 7.65 (s, 1H), 7.28 (d, J 7.4 Hz, 1H), 7.16 (d, J 8.1 Hz, 1H), 7.10 (t, J7.5 Hz, 1H), 6.91 (t, J 8.4 Hz, 1H), 6.78-6.43 (m, 2H), 4.27 (s, 2H), 4.16-4.06 (m, 2H), 3.63 (s, 2H), 2.53 (s, - I l l -
3H), 2.41 (s, 2H), 1.47 (s, 9H). Method D HPLC-MS: MH+ mlz 471, RT 3.52 minutes.
EXAMPLE 9 tert-Butyl 4-(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2- methylimidazo [ 1 ,2-a]pyrazin-6- yDpiperidine- 1 -carboxylate
Example 8 (900 mg, 1.91 mmol) was dissolved in ethanol (50 mL), then palladium on carbon (10% w/w, 204 mg) was added. The suspension was degassed using vacuum/ nitrogen and the reaction mixture was stirred under hydrogen at ambient temperature and pressure for 14 h. The reaction mixture was then degassed using vacuum/nitrogen and filtered through celite, washing with MeOH (15 mL). The solvent was removed under reduced pressure and the residue was purified by FCC, eluting with 10-15% DCM in MeOH, to afford the title compound (571 mg, 63%>) as a pale yellow oil. 5H (500 MHz, CDCls) 9.09 (br s, 1H), 7.65 (s, 1H), 7.32 (t, J7.2 Hz, 1H), 7.15 (t, J 8.8 Hz, 2H), 6.97 (d, J 7.4 Hz, 1H), 6.62 (t, J 73.5 Hz, 1H), 4.28 (s, 4H), 2.83 (s, 2H), 2.60 (s, 3H), 1.92 (d, J 12.3 Hz, 2H), 1.72-1.56 (m, 3H), 1.47 (s, 9H). Method D HPLC-MS: MH+ mlz 474, RT 3.22 minutes.
EXAMPLE 10
4-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- benzene- 1 -sulfonamide
Pd(PPh3)4 (16 mg, 0.01 mmol) was added to a thoroughly degassed mixture of Intermediate 6 (50 mg, 0.14 mmol) and (4-sulfamoylphenyl)boronic acid (41 mg, 0.2 mmol) in 2M aqueous sodium carbonate solution (0.44 mL) and 1 ,2-dimethoxyethane (2.2 mL). The mixture was heated in a sealed tube at 90°C under nitrogen for 2 h.
Further (4-sulfamoylphenyl)boronic acid (41 mg, 0.2 mmol) and 2M aqueous sodium carbonate solution (0.44 mL) were added and the mixture was heated at 90°C for a further 2 h. The reaction mixture was cooled, diluted with DCM (10 mL), and washed with saturated aqueous sodium hydro gencarbonate solution (10 mL) followed by brine, then dried over sodium sulfate and concentrated under vacuum. The crude residue was triturated with a minimum of chloroform, to afford the title compound (12 mg, 19%) as a pale yellow solid. δΗ (500 MHz, DMSO-d6) 9.06-9.00 (m, 2H), 8.28-8.22 (m, 2H), 7.95- 7.89 (m, 2H), 7.48-7.10 (m, 7H), 4.48 (s, 2H), 2.34 (s, 3H). Method D HPLC-MS: MH+ mlz 445, RT 2.59 minutes.
EXAMPLE 11
4- [5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyridin-2-yllmorpholine
Intermediate 18 (90% pure, 92.6 mg, 0.21 mmol) and morpholine (60 mg, 0.69 mmol) were stirred in l-methyl-2-pyrrolidinone (2 mL) in a microwave tube. The reaction mixture was heated to 200°C under microwave irradiation for a total of 2.5 h.
The mixture was loaded onto an SCX cartridge, which was washed with MeOH followed by 7M ammonia in MeOH. The ammonia fractions were concentrated under vacuum and purified by FCC, eluting with 0-10% (7M ammonia in MeOH) in DCM. The crude material was further purified by FCC, eluting with 50-100% EtOAc in heptanes, to afford the title compound (29.6 mg, 30%) as an off-white solid. δΗ (250 MHz, CDC13) 9.02 (d, J 1.4 Hz, 1H), 8.57 (d, J2.0 Hz, 1H), 8.06 (dd, J 8.9, 2.5 Hz, 1H), 7.98 (d, J 1.4 Hz, 1H), 7.32-7.24 (m, 1H), 7.20-7.06 (m, 2H), 6.95-6.34 (m, 3H), 4.32 (s, 2H), 3.86-3.81 (m, 4H), 3.61-3.55 (m, 4H), 2.56 (s, 3H). Method A HPLC-MS: MH+ mlz 452, RT 3.43 minutes. EXAMPLE 12
5- (3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-2-[4- (methanesulfonyDpiperazin- 1 -yllpyrimidine
A mixture of (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 1- (methylsulfonyl)piperazine (311 mg, 1.89 mmol) was heated under microwave irradiation at 100°C for 1 h. Intermediate 6 (153 mg, 0.42 mmol), 2M aqueous sodium carbonate solution (1.52 mL) and 1 ,2-dimethoxyethane (4 mL) were added. The mixture was thoroughly degassed with nitrogen, then Pd(PPh3)4 (73 mg, 0.06 mmol) was added. The mixture was heated at 90°C in a sealed tube under a nitrogen atmosphere for 2 h, then cooled and diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was triturated with 1 :9 DMSO/ acetonitrile (20 mL) and filtered. The solid residue was washed with acetonitrile (10 mL) to afford the title compound (76 mg, 21%) as a white solid. 5H (250 MHz, CDC13) 9.06 (d, J 1.2 Hz, 1H), 8.76 (s, 2H), 7.99 (d, J 1.4 Hz, 1H), 7.35-7.25 (m, 1H), 7.20-7.07 (m, 2H), 6.99-6.32 (m, 2H), 4.32 (s, 2H), 4.09-3.95 (m, 4H), 3.35-3.22 (m, 4H), 2.79 (s, 3H), 2.57 (s, 3H). Method D HPLC-MS: MH+ mlz 530, RT 2.91 minutes.
EXAMPLE 13 tert-Butyl 3 -(3 - ( [2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a]pyrazin-6- yl)-8-azabicyclo[3.2.1"|oct-2-ene-8-carboxylate
Intermediate 6 (50 mg, 0.136 mmol), Intermediate 19 (68 mg, 0.20 mmol) and 2M aqueous sodium carbonate solution (0.43 mL) were combined in 1 ,2-dimethoxy ethane (2.2 mL) and degassed thoroughly under nitrogen. Pd(PPh3)4 (16 mg, 0.01 mol) was added and the mixture was heated at 90°C in a sealed tube for 2 h. The reaction mixture was cooled to r. , then diluted with DCM (10 mL). The mixture was washed using saturated aqueous sodium bicarbonate solution (2 x 5 mL) and brine (10 mL). The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with a gradient of 0-100% EtOAc in heptanes. The material was further purified by preparative HPLC, to afford the title compound (14.4 mg, 21%) as a white solid. δΗ (500 MHz, CDC13) 8.94 (s, 1H), 7.61 (s, 1H), 7.28 (dd, J 13.0, 5.5 Hz, 1H), 7.16 (d, J 8.1 Hz, 1H), 7.11 (t, J 7.5 Hz, 1H), 6.91 (d, J7.6 Hz, 1H), 6.63 (t, J 73.5 Hz, 1H), 4.55 (s, 2H), 4.27 (s, 2H), 3.00 (s, 1H), 2.54 (s, 3H), 2.15 (d, J48.4 Hz, 2H), 2.08-1.92 (m, 3H), 1.66-1.61 (m, 1H), 1.42 (s, 9H). Method A HPLC-MS: MH+ mlz 497, RT 4.64 minutes. EXAMPLE 14
2- (4- [5 -(3- {[2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo [1 ,2-a"|pyrazin-6-yl)- pyrimidin-2-yl]piperazin-l-yl| acetic acid, formate salt
Intermediate 20 (118 mg, 0.23 mmol) was suspended in THF (2 mL) and 4M aqueous sodium hydroxide solution (59 μί) was added. The reaction mixture was stirred for 1 h. MeOH (1 mL) was added and the mixture was heated gently with a heat gun until a solution was obtained. The resulting mixture was stirred for 45 minutes. Further 4M aqueous sodium hydroxide solution (30 μί) was added, and the reaction mixture was heated at 50°C for 1 h. Further 4M aqueous sodium hydroxide solution (30 μί) was added, and the reaction mixture was heated at 50°C for 30 minutes, then maintained at r.t. overnight. The reaction mixture was neutralised with 4M HC1 to pH ~6 and was concentrated to dryness. The residue was dissolved in MeOH and loaded onto a SAX column. The column was flushed with MeOH, then a 1 :9 mixture of 1M aqueous HC1/ MeOH. All fractions contained product and impurities, so all of the material was recombined and concentrated to dryness. The residue was purified by preparative HPLC to yield the title compound (23.4 mg, 19%). δΗ (500 MHz, DMSO-d6) 8.98 (s, 1H), 8.96 (s, 2H), 8.79 (s, 1H), 7.42-7.06 (m, 5H), 4.42 (s, 2H), 3.88-3.81 (m, 4H), 3.26 (s, 2H), 2.72-2.63 (m, 4H), 2.33 (s, 3H). Method D HPLC-MS: MH+ mlz 509, RT 1.91 minutes.
EXAMPLE 15
2- (4- [5 -(3- {[2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-q"|pyrazin-6-yl)- pyrimidin-2-yllpiperazin- 1 -yl| acetamide
The hydrochloride salt of Example 4 (126 mg, 0.26 mmol) was dissolved in DMF (3 mL), then caesium carbonate (252 mg, 0.77 mmol) and 2-bromoacetamide (37 mg, 0.27 mmol) were added, and the reaction mixture was stirred for a total of 20 h. The reaction mixture was concentrated to dryness and triturated with water (3 mL), to afford the title compound (111.6 mg, 85%) as an off-white solid. δΗ (500 MHz, DMSO-d6) 8.98 (s, 1H), 8.95 (s, 2H), 8.79 (s, 1H), 7.42-7.12 (m, 7H), 4.42 (s, 2H), 3.90-3.80 (m, 4H), 2.92 (s, 2H), 2.55-2.50 (m, 4H), 2.33 (s, 3H). Method D HPLC-MS: MH+ mlz 508, RT 1.68 minutes. EXAMPLE 16
[2-(Difluoromethoxy)phenyll (2-methyl-6-[6-(piperazin-l-yl)pyridin-3-yllimidazo[l,2-al- pyrazin-3 -yl| methanol
Intermediate 21 (117 mg, 0.207 mmol) was dissolved in a mixture of DCM (5 mL) and trifluoro acetic acid (1 mL) and stirred at r.t. overnight. The reaction mixture was concentrated under vacuum, redissolved in DCM (20 mL), washed with saturated aqueous sodium bicarbonate solution (2 x 10 mL) followed by brine (10 mL), then dried over sodium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-2.5% (7M NH3 in MeOH) in DCM. The resulting material was further purified by preparative HPLC. The product fractions were combined and extracted with DCM (4 x 10 mL). The organic layer was washed with brine (10 mL), dried over sodium sulfate and concentrated under vacuum, to afford the title compound (50 mg, 52%) as a white solid. δΗ (250 MHz, CDC13) 8.85 (d, J 1.1 Hz, 1H), 8.66 (dd, J 4.1, 1.9 Hz, 2H), 8.15 (m, 1H), 8.05 (dd, J 8.9, 2.4 Hz, 1H), 7.40 (m, 2H), 7.16 (d, J 8.6 Hz, 1H), 6.80 (m, 3H), 3.54 (m, 4H), 2.87 (m, 4H), 2.34 (s, 3H). Method D HPLC-MS: MH+ m/z 467, RT 1.43 minutes. EXAMPLE 17
5 -(3 - ( [2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-a"|pyrazin-6-yl)-N- (oxolan-3 -yl)pyrimidin-2-amine
(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4- dioxane (1 mL) and tetrahydrofuran-3-amine hydrochloride (117 mg, 0.95 mmol) was added, followed by sodium carbonate (117.13 mg, 1.11 mmol). The reaction mixture was heated at 100°C under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1 ,2-dimethoxyethane (2 mL). Intermediate
6 (58 mg, 0.16 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction mixture was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added, and the mixture was heated at 90°C for 2 h. The reaction mixture was diluted with EtOAc (15 mL), washed with water (10 mL) and brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC, to afford the title compound (22 mg, 15%>) as a white solid. 5H (500 MHz, CD3OD) 8.91 (s, 1H), 8.80 (d, J4.1 Hz, 2H), 8.50 (s, 1H), 7.32 (t, J 7.7 Hz, 1H), 7.24-7.14 (m, 3H), 6.91 (t, J 73.9 Hz, 1H), 4.60-4.52 (m, 1H), 4.45 (s, 2H), 4.03-3.94 (m, 2H), 3.90-3.82 (m, 1H), 3.72 (dd, J9.1, 3.7 Hz, 1H), 2.45 (s, 3H), 2.35-2.27 (m, 1H), 1.98 (m, J4.9 Hz, 1H). Method D HPLC-MS: MH+ mlz 453, RT 2.51 minutes. EXAMPLE 18
5-(3-([2-(Difluoromethoxy)phenyllmeth^
difluoropiperidin- 1 -yOpyrimidine
(2-Chloropyrimidin-5-yl)boronic acid (200 mg, 1.26 mmol) and 4,4-difluoro- piperidine hydrochloride (239 mg, 1.52 mmol) were suspended in 1,4-dioxane (3 mL) and heated for 1 h at 100°C under microwave irradiation. The mixture was filtered and concentrated under vacuum. Intermediate 6 (200 mg, 0.54 mmol) and 1,4-dioxane (4 mL) were added, and the mixture was degassed for 5 minutes. Degassed 2M aqueous potassium carbonate solution (0.81 mL) and bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron dichloropalladium dichloromethane complex (31 mg, 0.04 mmol) were added and the mixture was heated at 100°C for 16 h. The mixture was partitioned between EtOAc (30 mL) and water (20 mL) and the aqueous phase was extracted with further EtOAc (20 mL). The organic layers were combined and washed with brine, dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with a gradient of 0-5% ammonia/MeOH in DCM. The material was then triturated in hot MeOH, and the solids were filtered, to afford the title compound (124 mg, 47%) as a pale peach solid. δΗ (250 MHz, CDC13) 9.16 (s, 1H), 8.78 (s, 2H), 8.00 (s, 1H), 7.30 (d, J 8.4 Hz, 1H), 7.16 (dd, J 12.3, 7.4 Hz, 2H), 7.01-6.34 (m, 2H), 4.34 (s, 2H), 4.10-3.99 (m, 4H), 2.62 (s, 3H), 2.03 (tt, J 13.6, 5.8 Hz, 4H). Method A HPLC-MS: MH+ mlz 487, RT 4.55 minutes.
EXAMPLE 19 6-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yl]-2-oxa-6-azaspiro[3.31heptane
(2-Chloropyrimidin-5-yl)boronic acid (150 mg, 0.95 mmol) and 2-oxa-6-azaspiro- [3.3]heptane oxalate (239 mg, 1.26 mmol) were suspended in 1,4-dioxane (6 mL) and triethylamine (0.18 mL, 1.26 mmol) was added. The mixture was heated at 100°C under microwave irradiation for 1 h. The mixture was diluted with MeOH (20 mL), then concentrated. To the resulting orange oil were added Intermediate 6 (228 mg, 0.62 mmol), 2M aqueous potassium carbonate solution (1.4 mL) and 1,4-dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis[3-(diphenylphosphanyl)- cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (36 mg, 0.04 mmol), then the mixture was heated at 100°C for 15 h. EtOAc (10 mL) was added, then the mixture was washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with a gradient of 0-7% MeOH in DCM. The resulting material was further purified by preparative HPLC, to afford the title compound (21.2 mg, 5%) as a white solid. δΗ (500 MHz, CDC13) 9.04 (d, J 4.5 Hz, IH), 8.74 (s, 2H), 7.93 (s, IH), 7.28 (t, J 7.9 Hz, IH), 7.17 (d, J 8.2 Hz, IH), 7.12 (t, J 7.5 Hz, IH), 6.94 (d, J 7.6 Hz, IH), 6.63 (t, J 73.5 Hz, IH), 4.87 (s, 4H), 4.35 (s, 4H), 4.32 (s, 2H), 2.57 (s, 3H). Method A HPLC-MS: MH+ mlz 465, RT 3.59 minutes.
EXAMPLE 20
4-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yll-2,6-dimethylmorpholine
(2-Chloropyrimidin-5-yl)boronic acid (50 mg, 0.32 mmol) was dissolved in 1,4- dioxane (1 mL) and 2,6-dimethylmorpholine (117 μί, 0.95 mmol) was added. The reaction mixture was heated at 100°C under microwave irradiation for 1 h. The reaction mixture was transferred to a pressure tube and diluted with 1 ,2-dimethoxyethane (2 mL). Intermediate 6 (77 mg, 0.21 mmol) was added, followed by 2M aqueous sodium carbonate solution (0.76 mL), and the reaction was degassed with nitrogen for 5 minutes. Pd(PPh3)4 (36 mg, 0.03 mmol) was added and the mixture was heated at 90°C for 100 minutes. The reaction mixture was diluted with EtOAc (15 mL) and washed with water (10 mL), followed by brine (10 mL), then dried over sodium sulfate and concentrated to dryness. The residue was purified by preparative HPLC to afford the title compound
(17.6 mg, 12%) as a white solid. δΗ (500 MHz, CD3OD) 8.90 (d, J 1.3 Hz, IH), 8.83 (s, 2H), 8.50 (d, J 1.3 Hz, IH), 7.36-7.28 (m, IH), 7.24-7.14 (m, 3H), 6.91 (t, J 74.0 Hz, IH), 4.64 (d, J 11.8 Hz, 2H), 4.45 (s, 2H), 3.71-3.58 (m, 2H), 2.62 (dd, J 13.3, 10.6 Hz, 2H), 2.45 (s, 3H), 1.24 (d, J 6.1 Hz, 6H). Method D HPLC-MS: MH+ mlz 481, RT 3.42 minutes. EXAMPLE 21 l-[5-(3-([2-(Difluoromethoxy)phenyllm
pyrimidin-2-yllpiperidine-4-carboxylic acid
Intermediate 6 (120 mg, 0.326 mmol) and Intermediate 22 (164 mg, 0.424 mmol) were charged to a sealed tube with 1,4-dioxane (1 mL) and 1 ,2-dimethoxyethane (1 mL), and the mixture was degassed. Aqueous sodium carbonate solution (2M, 0.815 mL, 1.63 mmol) and Ρά(ΡΡ1¾)4 (19 mg, 0.016 mmol) were added, and the mixture was stirred at 90°C under nitrogen for 3 h. Further Intermediate 22 (164 mg, 0.424 mmol) and 2M aqueous sodium carbonate solution (0.815 mL, 1.63 mmol) were added, the mixture was degassed, and Pd(PPh3)4 (19 mg, 0.016 mmol) was added. The mixture was then stirred at 90°C under nitrogen for 4 h. The mixture was diluted with water (10 mL) and DCM (10 mL). The organic phase was separated and the aqueous phase was extracted with DCM (2 x 5 mL), then the combined organic layers were discarded. The aqueous layer was adjusted to pH 1 by the addition of 0.5N HC1 (10 mL). The resultant white suspension was filtered, and the filter pad was washed with water (2 x 4 mL) and MeOH (4 mL). The resulting solid was suspended in MeOH (20 mL) and heated to reflux, then allowed to cool to r.t. before being filtered, to afford the title compound (50 mg, 31%) as a white solid. δΗ (500 MHz, CD3OD) 8.90 (s, 1H), 8.81 (s, 2H), 8.48 (s, 1H), 7.35-7.28 (m, 1H), 7.23-7.14 (m, 3H), 6.89 (t, J 74.0 Hz, 1H), 4.68 (d, J 13.5 Hz, 2H), 4.44 (s, 2H), 3.19-3.09 (m, 2H), 2.63 (tt, J 10.9, 3.9 Hz, 1H), 2.44 (s, 3H), 2.04-1.93 (m, 2H), 1.71- 1.56 (m, 2H). Method D HPLC-MS: MH+ mlz 495, RT 2.73 minutes.
EXAMPLE 22
(li?,56',6r)-3-(5-(3-[2-(Difluoromethoxy)benzyll-2-methylimidazo[l,2-alpyrazin-6-yl|- pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylic acid
Intermediate 25 (100 mg, 0.19 mmol) was dissolved in THF (2 mL), then 2M aqueous NaOH solution (0.29 mL) was added and the mixture was stirred at 50°C overnight. Further 2M aqueous NaOH solution (0.5 mL) was added and the mixture was heated at 80°C for 6 h and then overnight. The reaction mixture was concentrated and adjusted to pH 5 using 1M aqueous HC1 solution. The aqueous layer was extracted with 1 : 1 isopropanol/chloroform (2 xlO mL), then the organic layer was washed with brine (10 niL), dried over sodium sulfate and concentrated. The resultant solids were suspended in MeCN/MeOH/DMSO and filtered, to afford the title compound (7.7 mg, 8%) as a white solid. δΗ (500 MHz, DMSO-de) 12.27 (s, 1H), 8.97 (d, J 1.0 Hz, 1H), 8.92 (s, 2H), 8.76 (s, 1H), 7.41-7.11 (t, J 75.6 Hz, 1H), 7.34-7.28 (m, 1H), 7.17 (dd, J 18.5, 7.6 Hz, 3H), 4.41 (s, 2H), 3.91 (d, J 11.6 Hz, 2H), 3.60 (d, J 10.9 Hz, 2H), 2.33 (s, 3H), 2.18 (d, J 15.4 Hz, 2H), 1.40 (t, J3.0 Hz, 1H). Method D HPLC-MS: MH+ mlz 493, RT 2.52 minutes.
EXAMPLE 23 Ethyl 1 -[5-(3- ([2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yll-4-methylpiperidine-4-carboxylate
Intermediate 6 (150 mg, 0.41 mmol) and Intermediate 26 (80% pure, 164.21 mg, 0.45 mmol) were dissolved in 1,4-dioxane (2 mL) and 2M aqueous potassium carbonate solution (713 L, 1.426 mmol) was added. The reaction mixture was degassed with nitrogen for 5 minutes, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) was added. The reaction mixture was heated at 90°C for 18 h in a sealed tube under nitrogen. Further Intermediate 26 (50 mg), 2M aqueous potassium carbonate solution (240 μί) and bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (5 mg) were added and the mixture was heated for a further 2 h. Further
Intermediate 26 (50 mg), 2M aqueous potassium carbonate solution (240 μί) and bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (5 mg) were added and the mixture was heated for a further 3 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 10 mL). The organic layer was washed with brine (10 mL), dried over magnesium sulfate and concentrated under vacuum. The residue was purified by FCC, eluting with 0-100% EtOAc in heptanes followed by 0-30% MeOH in DCM, to afford the title compound (170 mg, 78%). δΗ (250 MHz, CDCls) 9.15 (s, 1H), 8.75 (s, 2H), 7.96 (d, J 1.3 Hz, 1H), 7.33 (d, J 8.7 Hz, 1H), 7.16 (dd, J 13.4, 7.2 Hz, 2H), 6.99-6.35 (m, 2H), 4.42 (d, J 13.9 Hz, 2H), 4.33 (s, 2H), 4.20 (q, J 7.1 Hz, 2H), 3.39-3.27 (m, 2H), 2.61 (s, 3H), 2.20 (d, J 13.6 Hz, 2H), 1.52-1.40 (m, 2H), 1.32-1.25 (m, 6H). Method D HPLC-MS: MH+ mlz 537, RT 3.91 minutes. EXAMPLE 24 l-[5-(3-([2-(Difluoromethoxy)phenyllm
pyrimidin-2-yll -4-methylpiperidine-4-carboxylic acid
Example 23 (160 mg, 0.30 mmol) was stirred in THF (7 mL), 2M aqueous NaOH solution (1.49 mL) was added and the mixture was heated at 80°C for 3 h. Lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added and the mixture was heated for a further 1.5 h. The temperature was then increased to 110°C and the mixture was stirred for 19 h. Further lithium hydroxide monohydrate (25 mg, 0.60 mmol) was added and the mixture was heated at 110°C for 6.5 h. The reaction mixture was concentrated, dissolved in water (10 mL) and acidified by dropwise addition of 6M HC1 until a white precipitate formed at pH 1. The precipitate was filtered and dried, to afford the title compound (112.3 mg, 73%) as a white solid. δΗ (250 MHz, DMSO-d6) 9.08 (s, 1H), 8.95 (s, 2H), 8.87 (s, 1H), 7.59-6.95 (m, 5H), 4.45 (s, 2H), 4.29 (d, J 13.1 Hz, 2H), 3.33 (t, J 10.8 Hz, 2H), 2.35 (s, 3H), 2.01 (d, J 13.7 Hz, 2H), 1.40 (t, J 9.6 Hz, 2H), 1.18 (s, 3H). Method D HPLC-MS: MH+ mlz 509, RT 2.99 minutes.
EXAMPLE 25 5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-2-(3- methoxypyrrolidin- 1 -yDpyrimidine
(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.632 mmol) and 3-methoxy- pyrrolidine (64 mg, 0.63 mmol) were suspended in 1,4-dioxane (3 mL), triethylamine (0.09 mL, 0.632mmol) was added and the mixture was heated at 60°C under microwave irradiation for 45 minutes. The reaction mixture was concentrated under vacuum, dissolved in DCM (20 mL) and washed with water (2 x 10 mL). The aqueous layer was concentrated under vacuum. To the resulting off-white solid were added Intermediate 6 (173 mg, 0.47 mmol), 2M aqueous potassium carbonate solution (1.09 mL) and 1,4- dioxane (5 mL). The mixture was thoroughly degassed before the addition of bis [3- (diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (27 mg, 0.034 mmol). The mixture was heated at 100°C overnight. Ρά(ΡΡ1¾)4 (0.034 mmol) was added and the mixture was heated at 100°C overnight. EtOAc (10 mL) was added and the mixture was washed with water (2 x 10 mL) and brine (10 mL). The organic fraction was dried over sodium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-7% MeOH in DCM. The material was then further purified by preparative HPLC to afford the title compound (7.3 mg, 2%) as a yellow solid. δΗ (500 MHz, CDC13) 9.06 (s, 1H), 8.76 (s, 2H), 7.91 (s, 1H), 7.29 (t, J 7.8 Hz, 1H), 7.17 (d, J 8.1 Hz, 1H), 7.12 (t, J 7.5 Hz, 1H), 6.93 (d, J 7.7 Hz, 1H), 6.81-6.45 (m, 1H), 4.32 (s, 2H), 4.16-4.05 (m, 1H), 3.85-3.74 (m, 2H), 3.74-3.62 (m, 2H), 3.38 (s, 3H), 2.58 (s, 3H), 2.25-2.16 (m, 1H), 2.10 (m, 1H). Method D HPLC-MS: MH+ mlz 466, RT 2.77 minutes. EXAMPLE 26
2-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yll-2-azaspiro[3.31heptane-6-carboxylic acid
(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-azaspiro[3.3]- heptane-6-carboxylic acid hydrochloride (113 mg, 0.64 mmol) were dissolved in DMF (2 mL), then potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80°C in a sealed tube for 2 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4- dien-l-yl]iron dichloropalladium dichloromethane complex (17 mg, 0.02 mmol) was added. The mixture was heated at 80°C in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were acidified to pH 4 by the addition of 6M hydrochloric acid. The mixture was left to stand for 10 minutes and the resultant precipitate was collected by filtration. The solids were washed with water (5 mL) and DCM (5 mL), and dried under vacuum, to afford the title compound (50.9 mg, 25%) as a pale pink solid. δΗ (500 MHz, CD3OD) 8.92 (s, 1H), 8.83 (s, 2H), 8.54 (s, 1H), 7.32 (t, J 7.0 Hz, 1H), 7.23-7.15 (m, 3H), 6.90 (t, J 73.9 Hz, 1H), 4.61 (s, 1H), 4.46 (s, 2H), 4.20 (s, 2H), 4.13 (s, 2H), 3.06-3.01 (m, 1H), 2.56-2.47 (m, 4H), 2.45 (s, 3H). Method D HPLC-MS: MH+ mlz 507, RT 2.51 minutes. EXAMPLE 27 l-[5-(3-([2-(Difluoromethoxy)phenyll^
pyrimidin-2-yll -4-hydroxypiperidine-4-carboxylic acid
Intermediate 6 (120 mg, 0.326 mmol) and Intermediate 27 (164 mg, 0.424 mmol) were charged to a sealed tube with 1,4-dioxane (1 mL) and 1 ,2-dimethoxy ethane (1 mL) and degassed. Aqueous sodium carbonate solution (2M, 0.815 mL, 1.63 mmol) was added, followed by Pd(PPh3)4 (19 mg, 0.016 mmol). The mixture was stirred at 90°C for 3 h. Further Intermediate 27 (164 mg, 0.424 mmol) was added and the mixture was degassed, then further Pd(PPh3)4 (19 mg, 0.016 mmol) was added and the reaction mixture was stirred at 90°C under nitrogen for 3 h. The mixture was diluted with water (10 mL) and washed with DCM (2 x 5 mL), then the aqueous layer was acidified to pH 1- 2 by the addition of 1M aqueous HC1. The aqueous layer was extracted with DCM (3 x 10 mL). A brown residue, that dissolved in neither layer, was collected and purified by preparative HPLC, to afford the title compound (25 mg, 20%) as a white solid. 5H (500 MHz, CD3OD) 8.94 (s, 1H), 8.84 (s, 2H), 8.52 (s, 1H), 7.38-7.30 (m, 1H), 7.27-7.17 (m, 3H), 6.93 (t, J 74.0 Hz, 1H), 4.57 (d, J 13.3 Hz, 2H), 4.47 (s, 2H), 3.54-3.41 (m, 2H), 3.37 (s, 3H), 2.10-1.99 (m, 2H), 1.77 (d, J 13.2 Hz, 2H). Method D HPLC-MS: MH+ mlz 511, RT 2.41 minutes.
EXAMPLE 28
(3S)- 1 -[5-(3- ([2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yllpiperidine-3 -carboxylic acid
(2-Chloropyrimidin-5-yl)boronic acid (65 mg, 0.41 mmol), (35)-piperidine-3- carboxylic acid (56 mg, 0.431 mmol) and potassium carbonate (57 mg, 0.41 mmol) were charged to a sealed tube with DMF (2 mL) under nitrogen. The reaction mixture was stirred at 80°C for 60 minutes. To the mixture were added Intermediate 6 (100 mg, 0.271 mmol), 1,4-dioxane (2 mL) and 2M aqueous sodium carbonate solution (0.16 mL, 1.231 mmol). The mixture was degassed, bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l- yljiron dichloropalladium dichloromethane complex (17 mg, 0.021 mmol) was added and the mixture was stirred at 80°C under nitrogen for 6 h. The mixture was partitioned between DCM (20 mL) and water (10 mL), and the aqueous fraction was washed with DCM (10 mL). The aqueous layer was acidified to pH 1, then extracted with DCM (3 x 15 mL). The combined extracts were washed with brine (10 mL), dried over sodium sulfate and concentrated. The residue was purified by preparative HPLC to afford the title compound (30 mg, 15%) as a light brown solid. δΗ (500 MHz, DMSO-d6) 8.98 (s, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.44-7.10 (m, 5H), 4.78-4.70 (m, 1H), 4.52 (d, J 13.0 Hz, 1H), 4.42 (s, 2H), 3.18-3.10 (m, 1H), 3.05 (t, J 11.0 Hz, 1H), 2.44-2.35 (m, 1H), 2.34 (s, 3H), 2.01 (d, J 9.4 Hz, 1H), 1.79-1.59 (m, 2H), 1.44 (q, J 11.9 Hz, 1H). Method D HPLC-MS: MH+ mlz 495, RT 2.84 minutes.
EXAMPLE 29
5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-2-[4- ( \H- 1 ,2,3 ,4-tetrazol-5-ylmethyl)piperazin- 1 -yllpyrimidine formate
Example 4 (132 mg, 0.29 mmol) and potassium carbonate (40 mg, 0.29 mmol) were stirred in DMF (2 mL) for 10 minutes before the addition of 5-(chloromethyl)-lH- 1,2,3,4-tetrazole (35 mg, 0.29 mmol) in two portions, 30 minutes apart. The mixture was stirred for 6 h at r.t., then allowed to stand over the weekend. The mixture was diluted with EtOAc, washed with water followed by brine, dried over magnesium sulfate and concentrated. The residue was purified by FCC, eluting with 10-50% MeOH in DCM. The resulting material was further purified by preparative HPLC to afford the title compound (20.9 mg, 13%). δΗ (250 MHz, DMSO-d6) 8.97 (d, J 6.2 Hz, 3H), 8.79 (s, 1H), 7.57-6.95 (m, 6H), 4.42 (s, 2H), 3.97 (s, 2H), 3.84 (s, 4H), 2.58 (s, 4H), 2.33 (s, 3H). Method D HPLC-MS: MH+ mlz 534, RT 2.02 minutes.
EXAMPLE 30
(3R)- 1 -[5-(3- ([2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin-6- yl)pyrimidin-2-yl"|piperidine-3 -carboxylic acid
(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and (3i?)-piperidine- 3 -carboxylic acid (82 mg, 0.63 mmol) were suspended in DMF (2 mL) and stirred for 2 h at 80°C. To the mixture were added Intermediate 6 (120 mg, 0.32 mmol), 2M aqueous potassium carbonate solution (0.48 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (13 mg, 0.016 mmol) was added. The mixture was heated at 80°C in a sealed tube for 15 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were acidified to pH 4 by the addition of 6M hydrochloric acid. The mixture was left to stand for 10 minutes and the resultant precipitate was collected by filtration. The solids were washed with water (5 mL) and dried under vacuum, to afford the title compound (50.6 mg, 31%) as a brown solid. 5H (500 MHz, DMSO-dg) 12.33 (s, IH), 8.96 (s, IH), 8.94 (s, 2H), 8.78 (s, IH), 7.41-7.12 (t, J 74.2 Hz, IH), 7.31 (t, J 6.4 Hz, IH), 7.22-7.13 (m, 3H), 4.72 (d, J 10.6 Hz, IH), 4.50 (d, J 12.9 Hz, IH), 4.39 (s, 2H), 3.17 (t, J 11.8 Hz, IH), 3.07 (t, J 11.0 Hz, IH), 2.41 (t, J 10.5 Hz, 1H), 2.34 (s, 3H), 2.01 (d, J 9.8 Hz, IH), 1.68 (dt, J23.0, 12.2 Hz, 2H), 1.44 (d, J 12.2 Hz, IH). Method D HPLC-MS: MH+ mlz 495, RT 2.84 minutes.
EXAMPLE 31
1 -[5-(3- ( 1 -[2-(Difluoromethoxy)phenyll- 1 -hydroxyethyll -2-methylimidazo[ 1 ,2-a]- pyrazin-6-yl)pyrimidin-2-yllpiperidine-4-carboxylic acid
Intermediate 29 (85 mg, 0.15 mmol) was suspended in THF (3 mL), then 2M aqueous NaOH solution (0.77 mL) was added and the mixture was heated at 80°C for 7 h. The mixture was concentrated under reduced pressure and acidified with IN aqueous HCl solution to pH 4-5. The mixture was extracted with 1 : 1 isopropanol/chloroform (2 x 25 mL) and the organic layer was washed with water (2 x 10 mL), then dried over sodium sulfate and concentrated under reduced pressure, to afford the title compound (68 mg, 76%) as a beige solid. δΗ (500 MHz, CD3OD) 9.47 (s, IH), 9.14 (s, 2H), 8.95 (s, IH), 8.86 (dd, J 7.8, 1.6 Hz, IH), 8.06 (t, J 7.4 Hz, IH), 8.00 (td, J 7.9, 1.6 Hz, IH), 7.66 (d, J 8.0 Hz, IH), 7.11 (t, J73.9 Hz, IH), 5.34-5.20 (m, 2H), 3.83-3.67 (m, 2H), 3.31 (s, 3H), 3.25 (tt, J 11.0, 3.9 Hz, IH), 2.77 (s, 3H), 2.60 (dd, J 13.4, 3.2 Hz, 2H), 2.25 (q, J 10.9 Hz, 2H), 1.90 (s, IH). Method D HPLC-MS: MH+ mlz 524, RT 2.50 minutes. EXAMPLE 32
1 -[5-(3- ( 1 -[2-(Difluoromethoxy)phenyllethyl| -2-methylimidazo[l ,2-alpyrazin-6-yl)- pyrimidin-2-yllpiperidine-4-carboxylic acid formate
Intermediate 31 (47% pure, 25 mg, 0.02 mmol) was suspended in THF (5 mL), then 2M aqueous NaOH solution (0.11 mL) was added and mixture was heated at 80°C for 2 h. The mixture was concentrated under reduced pressure and acidified with IN aqueous HC1 solution to pH 3-4. The mixture was extracted with 1 : 1 isopropanol/ chloroform (2 x 25 mL), concentrated under reduced pressure and purified by preparative HPLC, to afford the title compound (5.2 mg, 47%) as an off-white solid. 5H (500 MHz, CD3OD) 8.96-8.86 (m, 1H), 8.82 (s, 2H), 8.52 (s, 1H), 8.49 (s, 1H), 7.74-7.60 (m, 1H), 7.42-7.27 (m, 2H), 7.16 (d, J 7.7 Hz, 1H), 6.73 (t, J 74.0 Hz, 1H), 5.08 (q, J 7.3 Hz, 1H), 4.73 (d, J 13.4 Hz, 2H), 3.21-3.12 (m, 2H), 2.66-2.56 (m, 1H), 2.38 (s, 3H), 2.06-1.98 (m, 2H), 1.84 (d, J 7.4 Hz, 3H), 1.74-1.62 (m, 2H). Method D HPLC-MS: MH+ mlz 509, RT 2.83 minutes.
EXAMPLE 33
1 -[5-(3- ([2-(Difluoromethoxy)phenyll(methoxy)methyl| -2-methylimidazo[ 1 ,2-a]- pyrazin-6-yl)pyrimidin-2-yllpiperidine-4-carboxylic acid
Intermediate 32 (63 mg, 0.158 mmol) and Intermediate 22 (79 mg, 0.208 mmol) were charged to a sealed tube with 1,4-dioxane (1 mL) and 1 ,2-dimethoxy ethane (1 mL) and the mixture was degassed. Degassed 2M aqueous sodium carbonate solution (0.395 mL, 0.791 mmol) and Ρά(ΡΡ1¾)4 (9 mg, 0.01 mmol) were added and the reaction mixture was stirred under nitrogen at 90°C for 3 h. Further Intermediate 22 (79 mg, 0.208 mmol) was added and the mixture was degassed. Degassed 2M aqueous sodium carbonate solution (0.395 mL, 0.791 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol) were then added and the reaction mixture was stirred under nitrogen at 90°C for 3 h. Further Intermediate 22 (79 mg, 0.208 mmol) was added and the mixture was degassed. Degassed 2M aqueous sodium carbonate solution (0.395 mL, 0.791 mmol) and Pd(PPh3)4 (9 mg, 0.01 mmol) were then added and the reaction was stirred under nitrogen at 90°C for 3 h. The mixture was diluted with DCM (15 mL) and water (10 mL), the organic layer was separated and the aqueous layer was washed with DCM (10 mL). The aqueous layer was adjusted to pH 1-2 by the addition of 0.5M aqueous HC1 solution (10 mL), then extracted with DCM (3 x 10 mL). The combined organic layers were washed with brine (10 mL), dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (20 mg, 24%) as an off-white solid. 5H (500 MHz, CDC13) 9.05 (d, J l. l Hz, 1H), 8.73 (s, 2H), 8.32 (d, J 1.2 Hz, 1H), 7.73 (dd, J 7.2, 2.0 Hz, 1H), 7.41-7.30 (m, 2H), 7.08 (d, J 7.6 Hz, 1H), 6.44 (t, J 73.7 Hz, 1H), 5.99 (s, 1H), 4.71 (d, J 13.5 Hz, 2H), 3.40 (s, 3H), 3.23-3.11 (m, 2H), 2.67 (m, 1H), 2.56 (s, 3H), 2.12- 2.01 (m, 2H), 1.85-1.70 (m, 2H). Method D HPLC-MS: MH+ mlz 525, RT 3.00 minutes. EXAMPLE 34
1 -[5-(3- ([2-(Difluoromethoxy)phenyll(methoxy)methyl| -2-methylimidazo[ 1 ,2-a]- pyrazin-6-yl)pyrimidin-2-yl"|- 1 ,4-diazepan-5-one
A mixture of Intermediate 16 (90% pure, 120 mg, 0.46 mmol) and Intermediate 32 (200 mg, 0.5 mmol) was stirred in 1,4-dioxane (4 mL) and DMSO (0.5 mL) and the mixture was degassed with nitrogen. Aqueous potassium carbonate solution (2M, 800 μί) was added, followed by bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]iron dichloropalladium dichloromethane complex (19 mg, 0.02 mmol), and the reaction mixture was heated at 100°C for 4 h. EtOAc (10 mL) and water (5 mL) were added and the solution was stirred vigorously for 5 minutes. The aqueous layer was extracted with EtOAc, and the combined organic extracts were washed with water (10 mL) and brine (10 mL). The aqueous phase was further extracted with DCM (3 x 20 mL). The combined organic layers were dried over magnesium sulfate and concentrated under vacuum. The crude residue was purified by FCC, eluting with 0-6% (7M NH3 in MeOH) in DCM, to afford the title compound (107 mg, 46%>) as a cream solid. 5H (500 MHz, CDC13) 9.13 (s, 1H), 8.77 (s, 2H), 8.38 (s, 1H), 7.75 (d, J 7.3 Hz, 1H), 7.37 (dq, J 15.0, 7.3, 6.6 Hz, 2H), 7.09 (d, J7.7 Hz, 1H), 6.46 (t, J 73.6 Hz, 1H), 6.05 (s, 1H), 6.00 (s, 1H), 4.13 (d, J5.6 Hz, 4H), 3.42 (s, 3H), 3.38 (t, J 6.5 Hz, 2H), 2.78-2.68 (m, 2H), 2.59 (s, 3H). Method D HPLC-MS: MH+ mlz 510, RT 2.61 minutes. EXAMPLE 35 l-[5-(3-([2-(Difluoromethoxy)phenyll^
pyrimidin-2-yllpyrrolidine-3 -carboxylic acid
A mixture of (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 3- carboxypyrrolidin-l-ium trifluoroacetate (200 mg, 0.87 mmol) was heated under microwave irradiation at 100°C for 1 h. Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous sodium carbonate solution (0.65 mL) and 1 ,2-dimethoxyethane (4 mL) were added. The mixture was thoroughly degassed, then Pd(PPh3)4 (50 mg, 0.04 mmol) was added. The mixture was heated at 90°C in a sealed tube under nitrogen for 2 h. The mixture was cooled to r.t., then diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (8.9 mg, 5%) as a tan solid. 5H (250 MHz, DMSO-dg) 8.93 (d, J 1.2 Hz, 1H), 8.90 (s, 2H), 8.73 (s, 1H), 7.53-6.93 (m, 5H), 4.38 (s, 2H), 3.73-3.65 (m, 2H), 3.55 (q, J6.9 Hz, 2H), 3.19-3.12 (m, 1H), 2.29 (s, 3H), 2.21-2.09 (m, 2H). Method D HPLC-MS: MH+ mlz 481, RT 2.44 minutes.
EXAMPLE 36
2- (4-[5-(3- ([2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a"|pyrazin-6-yl)- pyrimidin-2-yllpiperazin- 1 -yllpropanoic acid
(2-Chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and 2-(piperazin-l- yl)propanoic acid (100 mg, 0.63 mmol) were dissolved in DMF (2 mL) and potassium carbonate (131 mg, 0.95 mmol) was added. The mixture was heated at 80°C in a sealed tube for 6 h. To the mixture were added Intermediate 6 (150 mg, 0.41 mmol), 2M aqueous potassium carbonate solution (0.6 mL) and 1,4-dioxane (3 mL). The mixture was degassed with nitrogen, then bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l-yl]- iron dichloropalladium dichloromethane complex (25 mg, 0.03 mmol) was added. The mixture was heated at 80°C in a sealed tube for 4 h. The mixture was diluted with DCM (20 mL) and extracted with water (10 mL), followed by 2M aqueous potassium carbonate solution (10 mL). The combined aqueous layers were extracted with 1 : 1 isopropanol/ chloroform (20 mL), then the organic layer was separated and concentrated under vacuum. The residue was purified by preparative HPLC to afford the title compound (43.8 mg, 21%). δΗ (500 MHz, DMSO-d6) 8.97 (d, J 1.1 Hz, 1H), 8.94 (s, 2H), 8.78 (s, 1H), 7.33-7.29 (m, 1H), 7.26 (t, J 15 Hz, 1H), 7.18 (d, J 8.1 Hz, 1H), 7.16 (d, J 6.2 Hz, 2H), 4.41 (s, 2H), 3.79 (dt, J 14.1, 6.9 Hz, 4H), 3.24 (q, J 7.0 Hz, 1H), 2.65 (dt, J 16.1, 4.3 Hz, 4H), 2.32 (s, 3H), 1.19 (d, J 7.0 Hz, 3H). Method A HPLC-MS: MH+ mlz 524, RT 3.15 minutes.
EXAMPLE 37 4-[5-(3-([2-(Difluoromethoxy)phenyll(hydroxy)methyl|-2-methylimidazo[l,2-alpyrazin- 6-yl)pyrimidin-2-yllpiperazin-2-one
A mixture of (2-chloropyrimidin-5-yl)boronic acid (100 mg, 0.63 mmol) and piperazin-2-one (63 mg, 0.632 mmol) was heated in 1,4-dioxane (2 mL) under microwave irradiation at 100°C for 1 h. Intermediate 5 (160 mg, 0.417 mmol), 2M aqueous sodium carbonate solution (1.516 mL, 3.03 mmol) and 1 ,2-dimethoxyethane (1 mL) were added. The mixture was thoroughly degassed, then Pd(PPh3)4 (73 mg, 0.06 mmol) was added. The mixture was heated at 90°C in a sealed tube under nitrogen for 8 h. The mixture was diluted with EtOAc (20 mL) and saturated aqueous sodium bicarbonate solution (10 mL). The organic phase was separated and washed with brine (10 mL), then dried over sodium sulfate and concentrated under vacuum. The residue was suspended in hot DMSO (2 mL), allowed to cool and filtered. The solids were washed with MeOH (2 x 2 mL), and the combined filtrates were purified preparative HPLC, to afford the title compound (10 mg, 3%) as a white solid. δΗ (500 MHz, DMSO-de) 8.98 (m, 3H), 8.91-8.85 (m, 1H), 8.15 (s, 1H), 8.04 (dd, J 5.7, 3.7 Hz, 1H), 7.38 (dt, J 7.4, 3.7 Hz, 2H), 7.23-6.88 (m, 2H), 6.55 (d, J4.1 Hz, 1H), 6.34 (d, J4.2 Hz, 1H), 4.25 (s, 2H), 4.05-3.90 (m, 2H), 3.31 (t, J 6.5 Hz, 2H), 2.19 (s, 3H). Method D HPLC-MS: MH+ mlz 482, RT 2.05 minutes.
EXAMPLE 38 3-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yll-3,6-diazabicyclo[3.2.21nonan-7-one
To a solution of Intermediate 33 (0.33 g, 0.815 mmol) were added Intermediate 6 (0.3 g, 0.81 mmol), 2M aqueous potassium carbonate solution (4.07 mL) and 1,4-dioxane (20 mL). The mixture was degassed with nitrogen for 15 minutes, then bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (34 mg, 0.04 mmol) was added. The mixture was heated at 80°C for 18 h. Upon cooling to r.t., the mixture was evaporated to dryness and the residue was purified by FCC, eluting with a gradient of 0-100% MeOH in DCM. The crude residue was triturated with hot MeOH, then the resulting precipitate was filtered and dried, to afford the title compound (47.3 mg, 10%) as an off-white solid. δΗ (500 MHz, DMSO-d6) 8.97 (d, J 1.3 Hz, IH), 8.94 (s, 2H), 8.78 (d, J 1.3 Hz, IH), 8.10 (d, J5.7 Hz, IH), 7.42-7.09 (m, 5H), 4.89-4.81 (m, 2H), 4.41 (s, 2H), 3.68-3.61 (m, IH), 3.29 (d, J 14.1 Hz, IH), 3.22-3.16 (m, IH), 2.61-2.55 (m, IH), 2.32 (s, 3H), 1.81-1.57 (m, 4H). Method D HPLC-MS: MH+ mlz 506, RT 2.51 minutes.
EXAMPLE 39 l-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyridin-2-yllpiperazine
Intermediate 34 (35 mg, 0.06 mmol) was stirred in DCM (0.2 mL) and
trifluoro acetic acid (0.2 mL) was added. The mixture was stirred at r.t. for 30 minutes, before being purified using a SCX cartridge, to afford the title compound (26.2 mg, 90%>) as a pale yellow glassy solid. δΗ (250 MHz, CDC13) 8.99 (s, IH), 8.54 (d, J 2.3 Hz, IH), 8.03-7.92 (m, 2H), 7.26 (m, IH), 7.19-7.05 (m, 2H), 6.94-6.33 (m, 3H), 4.31 (s, 2H), 3.62 (s, 4H), 3.03 (s, 4H), 2.54 (s, 3H). Method D HPLC-MS: MH+ mlz 451, RT 1.62 minutes. EXAMPLE 40
3-([2-(Difluoromethoxy)phenyllmethyl|-6-(3,6-dihydro-2H-pyran-4-yl)-2-methyl- imidazo[l ,2-a]pyrazine
Intermediate 6 (200 mg, 0.54 mmol) and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (170 mg, 0.81 mmol) were dissolved in 1,4-dioxane (5 mL) and 2M potassium carbonate in water (0.8 mL) was added. The mixture was flushed with nitrogen and bis[3-(diphenylphosphanyl)cyclopenta-2,4-dien-l -yljiron dichloropalladium dichloromethane complex (20 mg, 0.02 mmol) was added. The mixture was heated at 90°C for 16 h. The mixture was diluted with EtOAc (30 mL), then washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over sodium sulfate and concentrated under vacuum. The resulting dark orange solid was purified by FCC, eluting with 0-100% EtOAc in heptanes followed by 0-10% MeOH in EtOAc, to afford the title compound (159 mg, 79%) as a peach solid. δΗ (250 MHz, CDC13) 8.87 (d, J 1.1 Hz, IH), 7.62 (s, IH), 7.17-7.01 (m, 3H), 6.93-6.29 (m, 3H), 4.32 (q, J2.5 Hz, 2H), 4.24 (s, 2H), 3.88 (t, J 5.5 Hz, 2H), 2.50 (s, 3H), 2.43-2.32 (m, 2H). Method A HPLC-MS: MH+ mlz 372, RT 3.74 minutes. EXAMPLE 41 l-[4-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- piperidin- 1 -yl] ethan- 1 -one
Intermediate 35 (100 mg, 0.24 mmol) was dissolved in DCM (5 mL), then triethylamine (0.07 mL, 0.49 mmol) and acetic anhydride (23.12 μί, 0.24 mmol) were added at r.t. The mixture was stirred at r.t. for 2 h, then concentrated under reduced pressure and purified by preparative HPLC, to afford the title compound (56 mg, 55%) as a brown sticky solid. δΗ (500 MHz, CDC13) 9.04 (s, IH), 7.60 (s, IH), 7.34-7.27 (m, IH), 7.22-7.08 (m, 2H), 6.93 (d, J 7.4 Hz, IH), 6.62 (t, J 73.6 Hz, IH), 4.78 (t, J 13.4 Hz, IH), 4.27 (s, 2H), 3.94 (d, J 13.6 Hz, IH), 3.80-3.60 (m, IH), 3.18 (td, J 13.3, 2.5 Hz, IH),
2.65 (td, J 13.1, 2.6 Hz, IH), 2.56 (s, 3H), 2.12 (s, 3H), 2.07-1.99 (m, IH), 1.92 (d, J 13.0 Hz, IH), 1.67 (dtd, J25.5, 12.6, 6.2 Hz, 2H). Method D HPLC-MS: MH+ mlz 415, RT 2.10 minutes. EXAMPLE 42
4-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-4- methylpyridin-2-yllpiperazin-2-one
Intermediate 36 (100 mg, 0.25 mmol) was added to piperazin-2-one (75 mg, 0.75 mmol) in l-methyl-2-pyrrolidinone (2.5 mL) in a microwave tube. The mixture was stirred at 200°C under microwave irradiation for 1.5 h, then at 220°C for 1 h. The mixture was purified using a SCX cartridge, then further purified by preparative HPLC, to afford the title compound (61.2 mg, 51%) as an off-white solid. δΗ (250 MHz, CDC13) 9.01 (s, 1H), 8.06 (s, 1H), 7.69 (d, J 1.2 Hz, 1H), 7.26 (s, 1H), 7.17-7.05 (m, 2H), 6.91-6.26 (m, 3H), 4.29 (s, 2H), 4.13 (s, 2H), 3.90 (t, J 5.1 Hz, 2H), 3.49 (br s, 2H), 2.54 (s, 3H), 2.28 (s, 3H). Method A HPLC-MS: MH+ mlz 479, RT 3.02 minutes. EXAMPLE 43
6-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-2,3- dihydro- lH-indol-2-one
A mixture of Intermediate 6 (300 mg, 0.81 mmol), (2-oxo-2,3-dihydro-lH-indol- 6-yl)boronic acid (216.29 mg, 1.22 mmol) and 2M aqueous potassium carbonate solution (1.63 mL) in 1,4-dioxane (10 mL) was purged with nitrogen for 5 minutes, then bis[3- (diphenylphosphanyl)cyclopenta-2,4-dien- 1 -yljiron dichloropalladium dichloromethane complex (33 mg, 0.04 mmol) was added and the mixture was heated at 100°C for 3 h. The mixture was cooled to r.t., filtered through celite and concentrated under reduced pressure. The residue was purified by FCC, then recrystallized from MeOH, to afford the title compound (39 mg, 10%) as a beige solid. δΗ (500 MHz, DMSO-d6) 10.54 (s, 1H), 8.98 (d, J 1.2 Hz, 1H), 8.76 (d, J 1.2 Hz, 1H), 7.58 (dd, J 7.8, 1.5 Hz, 1H), 7.50 (s, 1H), 7.42-7.27 (m, 2H), 7.27-7.08 (m, 4H), 4.45 (s, 2H), 3.52 (s, 2H), 2.34 (s, 3H). Method D HPLC-MS: MH+ mlz 421, RT 2.48 minutes.
EXAMPLE 44 l-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyridin-2-yl"|piperidine-4-carboxylic acid
Intermediate 38 (38 mg, 0.07 mmol) was dissolved in ethanol (1.5 mL) and 2M aqueous potassium hydroxide solution (36.5 μί) was added. The reaction mixture was heated at 80°C for 5 h, then heating was continued overnight. The cooled reaction mixture was filtered. A solid was collected, which was washed with ethanol (10 mL) and dried under vacuum to afford an off-white solid. The filtrate was evaporated to afford an off-white solid. This material was triturated with hot EtOAc to afford an off-white solid. All the solids and filtrate were combined and purified by preparative HPLC to afford the title compound (8.5 mg, 23%) as a white solid. δΗ (500 MHz, DMSO-d6) 8.95 (s, 1H), 8.73 (d, J2.3 Hz, 1H), 8.67 (s, 1H), 8.10 (dd, J 8.9, 2.4 Hz, 1H), 7.45-7.07 (m, 5H), 6.94 (d, J 9.0 Hz, IH), 4.42 (s, 2H), 4.26 (d, J 13.3 Hz, 2H), 2.99 (t, J 11.2 Hz, 2H), 2.33 (s, 3H), 1.87 (d, J 10.7 Hz, 2H), 1.53 (q, J 11.2 Hz, 2H), plus one signal obscured by DMSO peak. Method D HPLC-MS: MH+ mlz 494, RT 2.10 minutes. EXAMPLE 45
Potassium 1 -[5-(3- ([2-(difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a]pyrazin- 6-yl)pyridin-2-yll-4-methylpiperidine-4-carboxylate
Intermediate 39 (65 mg, 0.08 mmol) was dissolved in ethanol (3 mL) and 2M aqueous potassium hydroxide solution (61 μί) was added. The reaction mixture was heated at 80°C for 2 h. Further 2M aqueous potassium hydroxide solution (0.24 mL) was added and the reaction mixture was heated at 80°C for 1.5 h. Further 2M aqueous potassium hydroxide solution (0.30 mL) was added and the reaction mixture was heated at 80°C for 2 h. The cooled reaction mixture was acidified with 2M hydrochloric acid to pH 2. The mixture was partitioned between 1 : 10 isopropanol/chloroform (6 mL) and water (3 mL). The aqueous layer was separated and further extracted into 1 : 10 isopropanol/chloroform (2 x 6 mL). The combined organic extracts were washed with brine (6 mL), dried over sodium sulfate and evaporated, to give a yellow solid (55 mg). A second portion of Intermediate 39 (45 mg, 0.12 mmol) was hydrolysed using the foregoing procedure to afford a yellow solid (32 mg). The batches were dissolved in 1 : 10 isopropanol/chloroform (3 mL), combined and evaporated. The resulting yellow solid (82 mg) was dissolved in ethanol (5 mL), then 2M aqueous potassium hydroxide solution (79 μί) was added. The mixture was stirred at r.t. for 1 h, before being heated at 50°C for 2 h, then at 80°C for 2 h. The reaction mixture remained a suspension. The cooled mixture was evaporated, and the resulting solid was dissolved in a mixture of isopropanol (7 mL) and water (3 mL) by warming with a heat gun. The resultant solution was stirred at r.t. for 20 minutes, then evaporated, to afford the title compound (80 mg, 71%) as a yellow solid. δΗ (500 MHz, DMSO-de) 8.93 (d, J 1.3 Hz, IH), 8.70 (d, J 2.5 Hz, IH), 8.64 (d, J 1.2 Hz, IH), 8.06 (dd, J9.0, 2.5 Hz, IH), 7.41-7.06 (m, 5H), 6.89 (d, J 9.1 Hz, IH), 4.41 (s, 2H), 4.00-3.90 (m, 2H), 3.19-3.15 (m, 2H), 2.33 (s, 3H), 2.00 (d, J 13.2 Hz, 2H), 1.30- 1.21 (m, 2H), 1.07 (s, 3H). Method D HPLC-MS: MH+ mlz 508, RT 2.27 minutes. EXAMPLE 46
3-[(2,5-Dichlorophenyl)methyl]-2-mem^
pyrazine
A mixture of Intermediate 41 (183 mg, 0.47 mmol), iodine (119 mg, 0.47 mmol), phosphinic acid (0.1 mL) and acetic acid (2 mL) was heated at 100°C for 2 h. To the cooled reaction mixture were added aqueous NaOH solution (2M) and DCM, then the organic layer was dried over magnesium sulfate and concentrated. The crude residue was purified by column chromatography (Si02, EtOAc:hexanes, 0 to 100%, then MeOH: EtOAc, 0 to 20%), then further purified by preparative HPLC, to afford the title compound (17 mg, 10%) as a white solid. δΗ (400 MHz, DMSO-d6) 8.94 (d, J 0.9 Hz, 1H), 8.64 (d, J 0.8 Hz, 1H), 8.20 (s, 1H), 7.96 (s, 1H), 7.56 (d, J 8.5 Hz, 1H), 7.40 (dd, J 8.5, 2.4 Hz, 1H), 7.08 (d, J2.4 Hz, 1H), 4.47 (2H, s), 3.89 (3H, s), 2.25 (3H, s). HPLC- MS: MH+ mlz 372, RT 2.15 minutes.
EXAMPLE 47
3-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yl]-3-azabicyclo[4.1.0]heptane-6-carboxylic acid
To a solution of Intermediate 43 (55.5 mg, 0.104 mmol) was added a 2M solution of potassium hydroxide in water (0.052 mL, 0.104 mmol) at r.t. The reaction mixture was stirred at 60°C for 24 h and left standing at r.t. for 48 h. Further 2M solution of potassium hydroxide in water (0.052 mL, 0.104 mmol) was added and the reaction mixture was stirred at 60°C for a further 24 h. The reaction mixture was cooled to r.t. and the mixture was concentrated to ~2 mL, then the resulting solid was filtered and washed with diethyl ether. The solid was dissolved in water/DMSO (~6 mL) by sonication and heating. The precipitated solid was discarded, and the filtrate was concentrated under vacuum to yield a solid which was triturated in DMSO/water. The resulting solid was filtered, washed with water and discarded. The new filtrate was washed with diethyl ether (2 x 2 mL). The aqueous extract was acidified to pH 5 using a 1M aqueous solution of HC1, then extracted with diethyl ether (1 x 2 mL) and isopropanol: chloroform (2 x 2 mL). The organic extracts were combined and evaporated. The resulting solid was further purified by trituration in EtOAc, to afford the title compound (11 mg, 19%>) as a beige solid. 5H (500 MHz, DMSO-dg) 12.28 (s, IH), 8.97 (d, J 1.2 Hz, IH), 8.93 (s, 2H), 8.76 (d, J 1.2 Hz, IH), 7.41-7.10 (m, 5H), 4.41 (s, 2H), 4.26 (dd, J 13.7, 2.3 Hz, IH), 3.91 (dd, J 13.7, 4.7 Hz, IH), 3.78 (dt, J 12.1, 5.8 Hz, IH), 3.39 (ddd, J 13.6, 8.5, 5.4 Hz, 2H), 2.33 (s, 3H), 1.86-1.71 (m, 2H), 1.28 (dd, J9.1, 4.2 Hz, IH), 0.78-0.70 (m, IH). Method D HPLC-MS: MH+ mlz 507, RT 2.80 minutes.
EXAMPLE 48
2-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- pyrimidin-2-yllpropan-2-ol
A mixture of Intermediate 6 (0.5 g, 1.36 mmol), 2-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)pyrimidin-2-yl]propan-2-ol (0.5 g, 1.89 mmol), [l, -bis(diphenyl- phosphino)ferrocene]dichloropalladium(II) dichloromethane complex (30 mg, 0.037 mmol) and 2M aqueous sodium carbonate solution (3 mL) in 1,4-dioxane (12 mL) was degassed and stirred at 110°C for 2 h. The cooled reaction mixture was diluted with
EtOAc and washed with brine. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The crude residue was purified by column chromatography (Si02, EtOAc:hexanes, 80 to 100%). The resulting material was triturated in diethyl ether, filtered, washed with diethyl ether and dried, to give the title compound (64 mg, 10%) as a beige solid. δΗ (400 MHz, DMSO-d6) 9.37 (s, 2H), 9.09 (m, 2H), 7.26 (m, 5H), 5.15 (s, IH), 4.47 (s, 2H), 2.35 (s, 3H), 1.55 (m, 6H). HPLC-MS: MH+ mlz 426, RT 1.99 minutes.
EXAMPLE 49
(li?,4 ?)-4-[5-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin- 6-yl)pyrimidin-2-yl"|cyclohexane- 1 -carboxylic acid
Intermediate 45 (158 mg, 0.3 mmol) was dissolved in ethanol (5 mL), sodium ethoxide (62 mg, 0.91 mmol) was added and the reaction mixture was heated at 70°C for 18 h. Water (4 mL) was added, and the mixture was stirred at 70°C for 22 h. A 6M aqueous solution of sodium hydroxide (0.25 mL) was added and the reaction was stirred for 2 h. The reaction mixture was allowed to cool, then diluted with a 1M aqueous solution of sodium hydroxide (10 mL) and washed with EtOAc (20 mL). The organic phase was discarded. The aqueous phase was acidified to pH 5 using 6M aqueous hydrogen chloride solution to give a cloudy solution, which was extracted with a mixture of 2-propanol/chloroform (3 x 20 mL). The organic extracts were combined, dried over sodium sulfate and concentrated. The crude residue was purified by preparative HPLC. The resulting material (30 mg) was dissolved in 1,4-dioxane (3 mL) and water (3 mL). A 1M aqueous solution of potassium hydroxide (70 μί) was added, and the mixture was sonicated until a solution was obtained. The solution was concentrated to dryness, water (1 mL) was added and the solution was dried, to afford the title compound (29 mg, 88%) as a white solid. δΗ (500 MHz, DMSO-dg) 9.28 (s, 2H), 9.05 (s, 2H), 7.43-7.08 (m, 5H), 4.45 (s, 2H), 2.76 (tt, J 12.0, 3.5 Hz, 1H), 2.33 (s, 3H), 1.97-1.87 (m, 4H), 1.79-1.70 (m, 1H), 1.60-1.48 (m, 2H), 1.40-1.28 (m, 2H). Method A HPLC-MS: MH+ mlz 494, RT 2.82 minutes.
EXAMPLE 50
5 -(3 - ( [2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-q"|pyrazin-6-yl)- pyridine-2-carbonitrile
Tetrakis(triphenylphosphine)palladium(0) (16 mg, 0.01 mmol) was added to a thoroughly degassed mixture of Intermediate 6 (50 mg, 0.14 mmol) and 5-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyridine-2-carbonitrile (47 mg, 0.2 mmol) in 2M aqueous sodium carbonate solution (0.22 mL) and 1 ,2-dimethoxy ethane (1.1 mL). The mixture was heated in a sealed tube at 90°C under a nitrogen atmosphere for 2 h. The reaction mixture was allowed to cool to room temperature and diluted with DCM (10 mL). The mixture was washed with saturated aqueous sodium bicarbonate solution (10 mL) and brine, then dried over sodium sulphate and concentrated under vacuum. The residue was purified by FCC, eluting with a 0-2% gradient of methanol in DCM. The crude product was further purified by preparative HPLC, to afford the title compound (24 mg, 45%) as an off-white solid. δΗ (250 MHz, CDC13) 9.18-9.05 (m, 2H), 8.40 (dd, J 8.2, 2.3 Hz, 1H), 8.32 (d, J 1.4 Hz, 1H), 7.78 (dd, J 8.2, 0.7 Hz, 1H), 7.36-7.27 (m, 1H), 7.22- 7.09 (m, 2H), 7.01 (dd, J 7.6, 1.5 Hz, 1H), 6.66 (t, J 73.5 Hz, 1H), 4.37 (s, 2H), 2.61 (s, 3H). Method D HPLC-MS: MH+ mlz 392, RT 3.13 minutes. EXAMPLE 51
5 -(3 - ( [2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo [ 1 ,2-alpyrazin-6-yl)- pyridine-3 -carbonitrile
Tetrakis(triphenylphosphine)palladium(0) (31.4 mg, 0.03 mmol) was added to a thoroughly degassed mixture of Intermediate 6 (100 mg, 0.27 mmol) and (5-cyano- pyridin-3-yl)boronic acid (60.27 mg, 0.41 mmol) in a 2M solution of sodium carbonate in water (0.65 mL) and 1 ,2-dimethoxyethane (3.3 mL). The mixture was heated in a sealed tube at 90°C overnight under a nitrogen atmosphere. The reaction mixture was allowed to cool to room temperature and diluted with dichloromethane (20 mL). The mixture was washed with a saturated aqueous solution of sodium bicarbonate (20 mL) and brine, then dried over sodium sulfate, filtered and concentrated in vacuo. The resulting crude mixture was purified by preparative HPLC to afford the title compound (8 mg, 6%) as a pale yellow solid. δΗ (250 MHz, CDC13) 9.21 (d, J2.2 Hz, 1H), 9.06 (d, J 1.4 Hz, 1H), 8.86 (d, J2.0 Hz, 1H), 8.54 (t, J2.1 Hz, 1H), 8.27 (d, J 1.4 Hz, 1H), 7.36-7.27 (m, 1H), 7.22-7.09 (m, 2H), 7.04-6.35 (m, 2H), 4.36 (s, 2H), 2.59 (s, 3H). Method D HPLC-MS: MH+ mlz 392, RT 2.98 minutes.
EXAMPLE 52 l-[4-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)- 1 ,2,3 ,6-tetrahydropyridin- 1 -yl]ethan- 1 -one
Triethylamine (0.07 mL, 0.49 mmol) and acetic anhydride (23.23 μί, 0.25 mmol) were added to a suspension of Intermediate 46 (100 mg, 0.25 mmol) in dichloromethane (5 mL) at room temperature. The mixture was stirred at room temperature for 2 h, then concentrated under reduced pressure. The crude residue was purified by preparative HPLC (Method C) to afford the title compound (55.5 mg, 55%) as a brown oil. 5H (500 MHz, CDC13) 8.96 (s, 1H), 7.69 (d, J 10.4 Hz, 1H), 7.27 (d, J 14.4 Hz, 1H), 7.19-7.07 (m, 2H), 6.94 (t, J 8.5 Hz, 1H), 6.82-6.42 (m, 2H), 4.28 (d, J 5.8 Hz, 3H), 4.18 (d, J2.8 Hz, 1H), 3.82 (t, J 5.7 Hz, 1H), 3.66 (t, J 5.7 Hz, 1H), 2.56 (d, J 1.8 Hz, 3H), 2.54 (s, 1H), 2.41 (s, 1H), 2.15 (d, J 19.0 Hz, 3H). Method D HPLC-MS: MH+ mlz 413, RT 2.31 minutes. EXAMPLE 53
4-(3- ([2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-alpyrazin-6-yl)- 1 - (methanesulfonyDpiperidine
Intermediate 35 (100 mg, 0.24 mmol) was suspended in dichloromethane (3 mL) at room temperature and triethylamine (0.07 mL, 0.49 mmol) was added, followed by methanesulfonic anhydride (42.6 mg, 0.24 mmol). The mixture was stirred for 2 h, then concentrated under reduced pressure. The residue was purified by HPLC (Method C) to afford the title compound (83 mg, 75%) as a beige solid. δΗ (500 MHz, CDC13) 9.04 (s, 1H), 7.62 (s, 1H), 7.31 (t, J 7.8 Hz, 1H), 7.14 (dd, J 16.7, 8.2 Hz, 2H), 6.95 (d, J7.5 Hz, 1H), 6.63 (t, J 73.6 Hz, 1H), 4.28 (s, 2H), 3.94 (d, J 12.0 Hz, 2H), 3.85-3.56 (m, 1H), 2.82 (d, J 6.0 Hz, 5H), 2.57 (s, 3H), 2.08 (d, J 12.3 Hz, 2H), 1.81 (qd, J 12.5, 4.0 Hz, 2H). Method D HPLC-MS: MH+ mlz 451, RT 2.35 minutes. EXAMPLE 54
3-(3-([2-(Difluoromethoxy)phenyllmethyl|-2-methylimidazo[l,2-alpyrazin-6-yl)-8- (methanesulfonyl)-8-azabicyclo[3.2.1 ]oct-2-ene
Intermediate 47 (80% purity, 110 mg, 0.2 mmol) was stirred in dichloromethane (5 mL) and triethylamine (42 μί, 0.3 mmol) was added. After cooling to 0°C, methanesulfonyl chloride (47 μί, 0.61 mmol) was added slowly. The reaction mixture was allowed to warm slowly to room temperature and stirred for 2 h. The reaction mixture was washed with water (5 mL), saturated sodium bicarbonate solution (10 mL) and brine (10 mL). The organic phase was dried over sodium sulfate and concentrated. The crude yellow oil was purified by chromatography on silica (Biotage, lOg cartridge), eluting with 0 to 50% dichloromethane in a 10% methanol solution in dichloromethane, to afford the title compound (62 mg, 64%) as a dark orange oil. 5H (500 MHz, CDCI3) 8.90 (s, 1H), 7.66 (s, 1H), 7.28 (dd, J 13.9, 6.1 Hz, 1H), 7.16 (d, J 8.2 Hz, 1H), 7.12 (t, J 7.5 Hz, 1H), 7.05 (d, J5.5 Hz, 1H), 6.64 (t, J 73.6 Hz, 1H), 4.52 (q, J6.3 Hz, 2H), 4.27 (s, 2H), 2.97 (dd, J 16.7, 4.0 Hz, 1H), 2.91 (s, 3H), 2.54 (s, 3H), 2.35-2.24 (m, 2H), 2.17 (ddd, J 17.8, 11.8, 6.3 Hz, 1H), 2.12-1.98 (m, 2H), 1.77-1.68 (m, 1H). Method D HPLC- MS: MH+ mlz 475, RT 2.73 minutes. EXAMPLE 55
4-[5-(3-([2-(Difluoromethoxy)phenyll
thiazol-2-yllmorphoiine
Intermediate 6 (150 mg, 0.41 mmol) and 4-[5-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)-l,3-thiazol-2-yl]morpholine (180 mg, 0.61 mmol) were dissolved in 1,4-dioxane (3 mL) and a 2M solution of potassium carbonate in water (0.6 mL) was added. The mixture was flushed with nitrogen, then Pd(dppf)Ci2 complex with dichloromethane (30 mg, 0.04 mmol) was added. The mixture was heated at 90°C for 16 h, then at 100°C for 4 h. The mixture was diluted with ethyl acetate (20 mL), then washed with water (2 x 10 mL) and brine (10 mL). The organic layer was dried over magnesium sulfate and concentrated under vacuum. The resulting dark green crude solid was successively purified by chromatography on silica, eluting with 0 to 100% ethyl acetate in heptane and 0 to 10% methanol in ethyl acetate, then by preparative HPLC (Method A), to afford the title compound (45 mg, 24%) as an off-white solid. 5H (250 MHz, CDCls) 8.90 (d, J 1.3 Hz, 1H), 7.91 (d, J 1.3 Hz, 1H), 7.49 (s, 1H), 7.26 (s, 1H), 7.19-7.06 (m, 2H), 6.98-6.33 (m, 2H), 4.28 (s, 2H), 3.89-3.74 (m, 4H), 3.58-3.44 (m, 4H), 2.53 (s, 3H). Method A HPLC-MS: MH+ mlz 458, RT 3.81 minutes.
EXAMPLE 56
3-([2-(Difluoromethoxy)phenyllmethyl|-6-(3,6-dihydro-2H-thiopyran-4-yl)-2-methyl- imidazo[l ,2-a]pyrazine
Intermediate 6 (50 mg, 0.136 mmol), 2-(3,6-dihydro-2H-thiopyran-4-yl)-4,4,5,5- tetramethyl-l,3,2-dioxaborolane (46.07 mg, 0.2 mmol) and a 2M solution of sodium bicarbonate in water (0.43 mL) were combined in 1 ,2-dimethoxy ethane (2.2 mL) and the mixture was degassed thoroughly under nitrogen. Tetrakis(triphenylphosphine)- palladium(O) (16 mg, 0.014 mmol) was added and the mixture was heated at 90°C in a sealed tube for 2 h. The reaction mixture was cooled to room temperature and diluted using dichloromethane (10 mL). The mixture was washed using an aqueous saturated solution of sodium bicarbonate (2 x 5 mL) and brine (10 mL). The organic phase was dried over sodium sulfate and concentrated in vacuo. The crude orange oil was purified by chromatography on silica (Biotage, lOg cartridge), eluting with 0 to 100%) ethyl acetate in heptane, to afford the title compound (23.5 mg, 45%) as a yellow solid. 5H (500 MHz, CDCls) 8.94 (s, 1H), 7.74-7.66 (m, 1H), 7.32-7.27 (m, 1H), 7.16 (d, J 8.1 Hz, 1H), 7.11 (t, J7.5 Hz, 1H), 6.93-6.89 (m, 1H), 6.88 (t, J4.4 Hz, 1H), 6.63 (t, J 73.6 Hz, 1H), 4.28 (s, 2H), 3.39 (dd, J 12.7, 10.5 Hz, 2H), 2.88 (t, J 5.8 Hz, 2H), 2.69-2.61 (m, 2H), 2.55 (s, 3H). Method D HPLC-MS: MH+ mlz 388, RT 3.06 minutes.
EXAMPLE 57
6-Bromo-3-[2-(difluoromethoxy)benzyll-2-methylimidazo[l,2-alpyrazine
See Intermediate 6.
EXAMPLES 58 & 59
1 -[5-(3- ([2-(Difluoromethoxy)phenyll(methoxy)methyl| -2-methylimidazo[ 1 ,2-a]- pyrazin-6-yl)pyrimidin-2-yll-l,4-diazepan-5-one (Isomers A and B)
Example 34 (96 mg) was separated into its component enantiomers using SFC on Chiralcel OD-H, eluting with 12%> isopropanol : 88%> C02, to afford Isomer A (40.5 mg) as a pale solid and Isomer B (37.9 mg) as a pale solid.
Isomer A (Example 58): δΗ (250 MHz, CDC13) 9.06 (s, 1H), 8.77 (s, 2H), 8.36 (s, 1H), 7.74 (m, 1H), 7.35 (m, 2H), 7.09 (d, J 8.7 Hz, 1H), 6.46 (t, J73.6 Hz, 1H), 6.25 (s, 1H), 6.00 (s,lH), 4.13 (m, 4H), 3.42 (s, 3H), 3.39 (m, 2H), 2.72 (m, 2H), 2.57 (s, 3H).
Isomer B (Example 59): δΗ (250 MHz, CDC13) 9.06 (s, 1H), 8.76 (s, 2H), 8.36 (s, 1H), 7.73 (m, 1H), 7.35 (m, 2H), 7.09 (d, J 8.7 Hz, 1H), 6.45 (t, J73.6 Hz, 1H), 6.25 (s, 1H), 6.00 (s, 1H), 4.12 (m, 4H), 3.41 (s, 3H), 3.38 (m, 2H), 2.72 (m, 2H), 2.57 (s, 3H).
EXAMPLES 60 & 61
4-[5-(3-([2-(Difluoromethoxy)phenyll(hydroxy)methyl|-2-methylimidazo[l,2-alpyrazin- 6-yl)pyrimidin-2-yllpiperazin-2-one (Isomers A and B)
Example 37 (130 mg) was separated into its component enantiomers using HPLC on Chiralcel OD-H 25 cm, eluting with MeOH + 0.1% diethylamine, to afford Isomer A (10 mg) as a light brown solid and Isomer B (12 mg) as a light brown solid. Isomer A {Example 60): δΗ (500 MHz, DMSO-d6) 8.98 (m, 3H), 8.89 (s,lH), 8.15 (s, 1H), 8.05 (dd, J 5.6, 3.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.23-6.91 (m, 2H), 6.55 (s, 1H), 4.25 (s, 2H), 4.01-3.95 (m, 2H), 3.16 (s, 2H), 2.19 (s, 3H).
Isomer B (Example 61): δΗ (500 MHz, DMSO-d6) 8.98 (m, 3H), 8.89 (s, 1H), 8.15 (s, 1H), 8.05 (dd, J 5.7, 3.7 Hz, 1H), 7.41-7.35 (m, 2H), 7.22-6.90 (m, 2H), 6.55 (s, 1H), 4.25 (s, 2H),4.01-3.95 (m, 2H), 3.16 (s, 2H), 2.19 (s, 3H).
EXAMPLE 62 [2-(Difluoromethoxy)phenyll (2-meth^^
pyrazin-3-yl| methanol (Isomer B)
Example 16 (150 mg) was separated into its component enantiomers using HPLC on Chiralcel OD-H 25cm, eluting with 15% EtOH:85% heptanes + 0.1% diethylamine, to afford the title compound (36 mg) as a light brown solid. 5H (500 MHz, acetone-d6) 8.85 (d, J 1.3 Hz, 1H), 8.67 (dd, J 10.2, 1.8 Hz, 2H), 8.15 (dd, J 7.0, 2.1 Hz, 1H), 8.06 (dd, J 8.9, 2.5 Hz, 1H), 7.41 (ddt, J 10.6, 7.3, 3.3 Hz, 2H), 7.17 (d, J 8.0 Hz, 1H), 7.05-6.71 (m, 2H), 6.67 (s, 1H), 3.59-3.50 (m, 4H), 2.93-2.84 (m, 4H + water), 2.34 (s, 3H).
EXAMPLE 63
Ethyl (li?,56',6r)-3-(5-(3-[2-(difluoromethoxy)benzyll-2-methylimidazo[l,2-alpyrazin-6- yl|pyrimidin-2-yl)-3-azabicyclo[3.1.0]hexane-6-carboxylate
See Intermediate 25. EXAMPLE 64
4-(3- ([2-(Difluoromethoxy)phenyllmethyl| -2-methylimidazo[ 1 ,2-a] pyrazin-6-yl)- 1 - (methanesulfonyl)- 1 ,2,3 ,6-tetrahydropyridine
Intermediate 46 (100 mg, 0.25 mmol) was suspended in DCM (3 mL) at room temperature, then triethylamine (0.07 mL, 0.49 mmol) was added, followed by methanesulfonic anhydride (43 mg, 0.25 mmol). The mixture was stirred for 2 h, then concentrated under reduced pressure and purified by HPLC (Method C), to afford the title compound (52 mg, 47%) as an off white solid. δΗ (250 MHz, CDC13) 8.93 (s, 1H), 7.71 (s, IH), 7.26 (s, IH), 7.19-7.05 (m, 2H), 6.94 (d, J7.6 Hz, IH), 6.82-6.40 (m, 2H), 4.28 (s, 2H), 4.00 (d, J2.9 Hz, 2H), 3.52 (t, J5.7 Hz, 2H), 2.84 (s, 3H), 2.60-2.56 (m, 2H), 2.55 (s, 3H). Method D HPLC-MS: MH+ mlz 449, RT 2.60 minutes.
5

Claims

Claims:
1. A compound of formula (I) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000143_0001
(I) wherein
E represents a covalent bond; or E represents -0-, -S-, -S(O)-, -S(0)2- or -N(R4)-; or E represents an optionally substituted straight or branched Ci_4 alkylene chain;
Q represents a covalent bond; or Q represents -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- or -N(R5)S(0)2-; or Q represents an optionally substituted straight or branched Ci_6 alkylene chain optionally comprising one, two or three heteroatom-containing linkages independently selected from -0-, -S-, -S(O)-, -S(0)2-, -N(R5)-, -C(0)N(R5)-, -N(R5)C(0)-, -S(0)2N(R5)- and -N(R5)S(0)2-;
Y represents C3-7 cycloalkyl, aryl, C3-7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents;
Z represents hydrogen, halogen or trifluoromethyl; or Z represents Ci_6 alkyl, C3-7 cycloalkyl, aryl, C3_7 heterocycloalkyl, C3_7 heterocycloalkenyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; or Z represents -Ί}-Ί} or -Z1-C(0)-Z2, either of which moieties may be optionally substituted by one or more substituents;
Z1 represents a divalent radical derived from an aryl, C3_7 heterocycloalkyl or heteroaryl group;
Z2 represents aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl or heteroaryl; R1, R2 and R3 independently represent hydrogen, halogen, cyano, nitro, hydroxy, trifluoromethyl, trifluoromethoxy, -ORa, -SRa, -SORa, -S02Ra, -SF5, -NRbRc, -NRcCORd, -NRcC02Rd, -NHCONRbRc, -NRcS02Re, -N(S02Re)2, -NHS02NRbRc, -CORd, -C02Rd, -CONRbRc, -CON(ORa)Rb or -S02NRbRc; or Ci_6 alkyl, C2_6 alkenyl, C2_6 alkynyl, C3_7 cycloalkyl, C4_7 cycloalkenyl, C3_7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3_7 heterocycloalkyl, C3_7 heterocycloalkyl(Ci_6)alkyl, C3_7 heterocycloalkenyl, C4_g heterobicycloalkyl, C4_9 heterobicycloalkenyl, heteroaryl, heteroaryl(Ci_6)alkyl,
(C3_7)heterocycloalkyl(Ci_6)alkyl-aryl-, heteroaryl(C3_7)heterocycloalkyl-,
(C3_7)cycloalkyl-heteroaryl-, (C4_7)cycloalkenyl-heteroaryl-, (C3_7)heterocycloalkyl- heteroaryl-, (C3_7)heterocycloalkyl(Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl- heteroaryl-, (C4_9)heterobicycloalkyl-heteroaryl- or (C4_9)spiroheterocycloalkyl- heteroaryl-, any of which groups may be optionally substituted by one or more substituents;
R4 and R5 independently represent hydrogen or Ci_6 alkyl;
Ra represents Ci_6 alkyl, aryl, aryl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents;
Rb and Rc independently represent hydrogen or trifluoromethyl; or Ci_6 alkyl, C3_7 cycloalkyl, C3_7 cycloalkyl(Ci_6)alkyl, aryl, aryl(Ci_6)alkyl, C3_7 heterocycloalkyl, C3_7 heterocycloalkyl(Ci_6)alkyl, heteroaryl or heteroaryl(Ci_6)alkyl, any of which groups may be optionally substituted by one or more substituents; or
Rb and Rc, when taken together with the nitrogen atom to which they are both attached, represent azetidin-l-yl, pyrrolidin-l-yl, oxazolidin-3-yl, isoxazolidin-2-yl, thiazolidin-3-yl, isothiazolidin-2-yl, piperidin-l-yl, morpholin-4-yl, thiomorpholin-4-yl, piperazin-l-yl, homopiperidin-l-yl, homomorpholin-4-yl or homopiperazin-l-yl, any of which groups may be optionally substituted by one or more substituents;
Rd represents hydrogen; or Ci_6 alkyl, C3_7 cycloalkyl, aryl, C3_7 heterocycloalkyl or heteroaryl, any of which groups may be optionally substituted by one or more substituents; and
Re represents Ci_6 alkyl, aryl or heteroaryl, any of which groups may be optionally substituted by one or more substituents.
2. A compound as claimed in claim 1 wherein
Y represents phenyl or thiazolyl, either of which groups may be optionally substituted by one or more substituents; R1 represents heteroaryl or (C3_7)heterocycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents; and
E, Q, Z, R2 and R3 are as defined in claim 1.
3. A compound of formula (IIA) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000145_0001
(IIA) wherein
R11 represents halogen or cyano; or Ci_6 alkyl, aryl, C3-7 heterocycloalkyl, C3-7 heterocycloalkenyl, (C4_9)heterobicycloalkenyl, heteroaryl, (C3_7)heterocycloalkyl(Ci_6)- alkyl-aryl-, heteroaryl-(C3_7)heterocycloalkyl-, (C3_7)cycloalkyl-heteroaryl-,
(C4_7)cycloalkenyl- heteroaryl-, (C3_7)heterocycloalkyl- heteroaryl-, (C3_7)heterocycloalkyl- (Ci_6)alkyl-heteroaryl-, (C3_7)heterocycloalkenyl-heteroaryl-, (C4_9)heterobicycloalkyl- heteroaryl- or (C4_9)spiroheterocycloalkyl-heteroaryl-, any of which groups may be optionally substituted by one or more substituents;
R15 and R16 independently represent hydrogen, halogen, cyano, nitro, Ci_6 alkyl, trifluoromethyl, hydroxy, Ci_6 alkoxy, difluoromethoxy, trifluoromethoxy, Ci_6 alkylthio, Ci_6 alkylsulfmyl, Ci_6 alkylsulfonyl, amino, Ci_6 alkylamino, di(Ci_6)alkylamino, arylamino, C2-6 alkylcarbonylamino, Ci_6 alkylsulfonylamino, formyl, C2-6 alkylcarbonyl, C3-6 cycloalkylcarbonyl, C3-6 heterocycloalkylcarbonyl, carboxy, C2-6 alkoxycarbonyl, amino carbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkylaminocarbonyl, aminosulfonyl, Ci_6 alkylaminosulfonyl or di(Ci_6)alkylaminosulfonyl; and
E, Q and Z are as defined in claim 1.
4. A compound as claimed in claim 3 wherein R11 represents heteroaryl or (C3_7)heterocycloalkyl-heteroaryl-, either of which groups may be optionally substituted by one or more substituents.
5. A compound as claimed in claim 3 represented by formula (IIB) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000146_0001
(IIB) wherein
V represents C-R22 or N;
R21 represents hydrogen, halogen, halo(Ci_6)alkyl, cyano, Ci_6 alkyl, trifluoro- methyl, C2_6 alkenyl, C2_6 alkynyl, hydroxy, hydroxy(Ci_6)alkyl, Ci_6 alkoxy, difluoro- methoxy, trifluoromethoxy, trifluoroethoxy, Ci_6 alkylthio, Ci_6 alkylsulphonyl, amino, amino(Ci_6)alkyl, Ci_6 alkylamino, di(Ci_6)alkylamino, (Ci_6)alkoxy(Ci_6)alkylamino, N- [(Ci_6)alkyl]-N- [hydro xy(Ci_6)alkyl] amino, (C3-7)heterocycloalkylamino, C2_6 alkyl- carbonylamino, (C2_6)alkylcarbonylamino(Ci_6)alkyl, C2_6 alkoxycarbonylamino, Ci_6 alkylsulphonylamino, (Ci_6)alkylsulphonylamino(Ci_6)alkyl, formyl, C2_6 alkylcarbonyl, carboxy, C2_6 alkoxycarbonyl, aminocarbonyl, Ci_6 alkylamino carbonyl, di(Ci_6)alkyl- aminocarbonyl, aminosulphonyl, Ci_6 alkylamino sulphonyl or di(Ci_6)alkylamino- sulphonyl; or R21 represents (C3-7)cycloalkyl, (C4-7)cycloalkenyl, (C3-7)heterocycloalkyl, (C3-7)heterocycloalkenyl, (C4_9)heterobicyclo alkyl or (C4-9)spiroheterocycloalkyl, any of which groups may be optionally substituted by one or more substituents;
R22 represents hydrogen, halogen, cyano or Ci_6 alkyl;
R23 represents hydrogen or Ci_6 alkyl;
E, Q and Z are as defined in claim 1 ; and
R15 and R16 are as defined in claim 3.
6. A compound as claimed in claim 5 wherein R21 represents hydroxy(Ci_6)alkyl.
7. A compound as claimed in claim 5 represented by formula (IIC), (IID) or or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000147_0001
Figure imgf000147_0002
Figure imgf000147_0003
wherein
T represents -CH2- or -CH2CH2-;
U represents C(O) or S(0)2;
W represents O, S, S(O), S(0)2, N(R31) or C(R32)(R33);
R31 represents hydrogen, cyano(Ci_6)alkyl, Ci_6 alkyl, trifluoromethyl, trifluoro- ethyl, Ci_6 alkylsulphonyl, (Ci_6)alkylsulphonyl(Ci_6)alkyl, formyl, C2_6 alkylcarbonyl, carboxy, carboxy(Ci_6)alkyl, C2_6 alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl(Ci_6)alkyl, aminocarbonyl, aminocarbonyl(Ci_6)alkyl, Ci_6 alkylaminocarbonyl, di(Ci_6)alkylaminocarbonyl, aminosulphonyl, Ci_6 alkylaminosulphonyl or di(Ci_6)alkyl- aminosulphonyl;
R32 represents halogen, Ci_6 alkoxy, carboxy, carboxy(Ci_6)alkyl, C2_6
alkoxycarbonyl, C2_6 alkoxycarbonyl(Ci_6)alkyl, tetrazolyl or aminocarbonyl;
R33 represents hydrogen, halogen, Ci_6 alkyl, hydroxy or amino;
E, Q and Z are as defined in claim 1 ;
R15 and R16 are as defined in claim 3; and
V and R23 are as defined in claim 5.
8. A compound as claimed in claim 5 represented by formula (IIF) or (II G) or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof:
Figure imgf000148_0001
Figure imgf000148_0002
wherein
R34 represents hydrogen, halogen, hydroxy, Ci_6 alkoxy, Ci_6 alkylthio, Ci_6 alkylsulphinyl, Ci_6 alkylsulphonyl, amino, Ci_6 alkylamino or di(Ci_6)alkylamino;
E, Q and Z are as defined in claim 1 ;
R15 and R16 are as defined in claim 3; V and R are as defined in claim 5; and
W is as defined in claim 7.
9. A compound as claimed in claim 8 wherein R34 represents hydrogen or hydroxy.
10. A compound as claimed in any one of the preceding claims wherein E represents -CH2- or -CH(CH3)-.
11. A compound as claimed in any one of claims 3 to 10 wherein R15 represents difluoromethoxy.
12. A compound as claimed in claim 1 as herein specifically disclosed in any one of the Examples.
13. A compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated.
14. A compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, for use in the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder.
15. A pharmaceutical composition comprising a compound of formula (I) as defined in claim 1 or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof, in association with a pharmaceutically acceptable carrier.
16. A pharmaceutical composition as claimed in claim 15 further comprising an additional pharmaceutically active ingredient.
17. A method for the treatment and/or prevention of disorders for which the administration of a modulator of TNFa function is indicated which comprises
administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N-oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
18. A method for the treatment and/or prevention of an inflammatory or autoimmune disorder, a neurological or neurodegenerative disorder, pain or a nociceptive disorder, a cardiovascular disorder, a metabolic disorder, an ocular disorder, or an oncological disorder, which comprises administering to a patient in need of such treatment an effective amount of a compound of formula (I) as defined above or an N- oxide thereof, or a pharmaceutically acceptable salt or solvate thereof, or a glucuronide derivative thereof, or a co-crystal thereof.
PCT/EP2013/064332 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of tnf activity WO2014009296A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
JP2015520937A JP6259824B2 (en) 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of TNF activity
EP13734128.5A EP2872511B1 (en) 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of tnf activity
EA201500133A EA028041B1 (en) 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of tnf activity
ES13734128T ES2711131T3 (en) 2012-07-13 2013-07-05 Imidazopyrazine Derivatives as Modulators of TNF Activity
BR112015000790-2A BR112015000790B1 (en) 2012-07-13 2013-07-05 IMIDAZOPYRAZINE DERIVATIVES AS ACTIVITY MODULATORS
US14/414,299 US9475820B2 (en) 2012-07-13 2013-07-05 Substituted imidazo[1,2-a]pyrazines as TNF activity modulators
CA2877543A CA2877543C (en) 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of tnf activity
CN201380037284.5A CN104470924B (en) 2012-07-13 2013-07-05 Imidazopyrazines derivant as TNF active regulator

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1212513.4A GB201212513D0 (en) 2012-07-13 2012-07-13 Therapeutic agents
GB1212513.4 2012-07-13

Publications (1)

Publication Number Publication Date
WO2014009296A1 true WO2014009296A1 (en) 2014-01-16

Family

ID=46799593

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/064332 WO2014009296A1 (en) 2012-07-13 2013-07-05 Imidazopyrazine derivatives as modulators of tnf activity

Country Status (11)

Country Link
US (1) US9475820B2 (en)
EP (1) EP2872511B1 (en)
JP (1) JP6259824B2 (en)
CN (1) CN104470924B (en)
BR (1) BR112015000790B1 (en)
CA (1) CA2877543C (en)
EA (1) EA028041B1 (en)
ES (1) ES2711131T3 (en)
GB (1) GB201212513D0 (en)
TR (1) TR201901652T4 (en)
WO (1) WO2014009296A1 (en)

Cited By (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015086505A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Purine derivatives as modulators of tnf activity
WO2015086519A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
WO2015086499A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyrimidine derivatives as modulators of tnf activity
WO2015086501A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridazine derivatives as modulators of tnf activity
WO2015086507A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
WO2015086502A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Pyrazolopyridine derivatives as modulators of tnf activity
WO2015086498A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of tnf activity
WO2015086503A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazotriazine derivatives as modulators of tnf activity
WO2015086496A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Triazolopyridine derivatives as modulators of tnf activity
WO2015086509A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
WO2015086513A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Tetrahydrobenzimidazole derivatives as modulators of tnf activity
WO2015086526A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused tricyclic imidazole derivatives as modulators of tnf activity
WO2015086504A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazothiazole derivatives as modulators of tnf activity
WO2015086506A1 (en) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of tnf activity
WO2015086511A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Triazolopyridazine derivatives as modulators of tnf activity
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
WO2016050975A1 (en) * 2014-10-03 2016-04-07 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives
WO2016149437A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds useful as inhibitors of tnf
WO2016149439A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Heterocyclic compounds useful as inhibitors of tnf
WO2016149436A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Substituted tricyclic heterocyclic compounds
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
WO2016198401A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Indazole derivatives as modulators of tnf activity
WO2016198398A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Fused tricyclic imidazo pyrazines as modulators of tnf activity
WO2016198400A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Benzoxazinone derivatives and analogues thereof as modulators of tnf activity
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
WO2017023905A1 (en) 2015-08-03 2017-02-09 Bristol-Myers Squibb Company Heterocyclic compounds useful as modulators of tnf alpha
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
JP2017520570A (en) * 2014-06-25 2017-07-27 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Imidazo [1,2-a] pyrazin-1-ylbenzamide compounds for treating spinal muscular atrophy
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
WO2017167993A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
WO2017167994A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
WO2017167996A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
WO2017167995A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused hexacyclic imidazole derivatives as modulators of tnf activity
US9815797B2 (en) 2013-12-09 2017-11-14 Ucb Biopharma Sprl Fused bicyclic heteroaromatic derivatives as modulators of TNF activity
US9834553B2 (en) 2013-12-09 2017-12-05 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
WO2017216292A1 (en) * 2016-06-16 2017-12-21 Janssen Pharmaceutica Nv Bicyclic pyridine, pyrazine, and pyrimidine derivatives as pi3k beta inhibitors
US9856253B2 (en) 2015-04-17 2018-01-02 Abbvie, Inc. Tricyclic modulators of TNF signaling
US9879016B2 (en) 2015-04-17 2018-01-30 Abbvie Inc. Indazolones as modulators of TNF signaling
US9890154B2 (en) 2013-12-09 2018-02-13 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
US9890174B2 (en) 2013-12-09 2018-02-13 Ucb Biopharma Sprl Fused Tricyclic imidazole derivatives as modulators of TNF activity
US9932334B2 (en) 2013-12-09 2018-04-03 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
US9932343B2 (en) 2013-12-09 2018-04-03 Ucb Biopharma Sprl Fused tricyclic benzimidazoles derivatives as modulators of TNF activity
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9957255B2 (en) 2013-12-09 2018-05-01 Ucb Biopharma Sprl Benzotriazole derivatives as modulators of TNF activity
US10004737B2 (en) 2013-12-09 2018-06-26 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of TNF activity
WO2018167176A1 (en) * 2017-03-15 2018-09-20 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
US10160748B2 (en) 2015-04-17 2018-12-25 Abbvie Inc. Indazolones as modulators of tnf signaling
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10335392B2 (en) 2015-08-03 2019-07-02 Bristol-Myers Squibb Company Cyclic compounds useful as modulators of TNF α
US10526316B2 (en) 2015-10-09 2020-01-07 Janssen Pharmaceutica Nv Quinoxaline and pyridopyrazine derivatives as PI3Kβ inhibitors
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10705094B2 (en) 2015-06-18 2020-07-07 UCB Biopharma SRL TNF receptor signaling modulator assay
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11130751B2 (en) 2017-03-29 2021-09-28 Janssen Pharmaceutica Nv Quinoxaline and pyridopyrazine derivatives as PI3K-beta inhibitors
US11174311B2 (en) 2016-12-21 2021-11-16 UCB Biopharma SRL Antibody against trimeric TNFα complex
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3939980B1 (en) * 2017-04-25 2023-07-26 UCB Biopharma SRL Process for preparing fused pentacyclic imidazole derivatives and uses thereof as modulators of tnf activity
CN107365248A (en) * 2017-07-25 2017-11-21 上海应用技术大学 Diphenylethane and trans stilbene derivative of difluoro-methoxy substitution and its preparation method and application
CN113967214A (en) * 2021-11-30 2022-01-25 广东药科大学 Application of imidazopyrazine cyclopropane carboxamide compound

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064674A1 (en) * 2000-03-01 2001-09-07 Janssen Pharmaceutica N.V. 2,4-disubstituted thiazolyl derivatives
US20040220189A1 (en) * 2003-02-20 2004-11-04 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhbitors
US20050009832A1 (en) * 2003-02-20 2005-01-13 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
WO2011022439A1 (en) * 2009-08-17 2011-02-24 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2011100502A1 (en) * 2010-02-11 2011-08-18 OSI Pharmaceuticals, LLC 7-aminofuropyridine derivatives
WO2013034048A1 (en) * 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP3648763B2 (en) * 1994-08-23 2005-05-18 日本油脂株式会社 Cypridina luciferin derivative and sugar hydrolase determination method
HUP0301801A2 (en) * 2000-07-14 2003-09-29 Bristol-Myers Squibb Pharma Company Imidazo[1,2-a]pyrazine derivatives and pharmaceutical compositions containing them
EP1945644A2 (en) * 2005-11-10 2008-07-23 Schering Corporation Imidazopyrazines as protein kinase inhibitors
EP2103614A1 (en) * 2008-03-18 2009-09-23 Santhera Pharmaceuticals (Schweiz) AG Substituted imidazopyrimidine, imidazopyrazine and imidazopyridazine derivatives as melanocortin-4 receptor modulators
CA2731357A1 (en) * 2008-07-24 2010-01-28 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Fluorescently or spin-labeled kinases for rapid screening and identification of novel kinase inhibitor scaffolds
WO2010088518A2 (en) * 2009-01-31 2010-08-05 Kalypsys, Inc. Heterocyclic modulators of gpr119 for treatment of disease
EP2651945A1 (en) * 2010-12-17 2013-10-23 Bayer Intellectual Property GmbH 6-substituted imidazopyrazines for use as mps-1 and tkk inhibitors in the treatment of hyperproliferative disorders

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001064674A1 (en) * 2000-03-01 2001-09-07 Janssen Pharmaceutica N.V. 2,4-disubstituted thiazolyl derivatives
US20040220189A1 (en) * 2003-02-20 2004-11-04 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhbitors
US20050009832A1 (en) * 2003-02-20 2005-01-13 Sugen, Inc. Use of 8-amino-aryl-substituted imidazopyrazines as kinase inhibitors
WO2011022439A1 (en) * 2009-08-17 2011-02-24 Intellikine, Inc. Heterocyclic compounds and uses thereof
WO2011100502A1 (en) * 2010-02-11 2011-08-18 OSI Pharmaceuticals, LLC 7-aminofuropyridine derivatives
WO2013034048A1 (en) * 2011-09-08 2013-03-14 Merck Sharp & Dohme Corp. Substituted benzofuran compounds and methods of use thereof for the treatment of viral diseases

Non-Patent Citations (14)

* Cited by examiner, † Cited by third party
Title
"Design of Prodrugs", 1985, ELSEVIER
"Pharmaceutical Salts and Co- crystals", 2012, RSC PUBLISHING
"Protective Groups in Organic Chemistry", 1973, PLENUM PRESS
CABALLERO, JULIO ET AL: "Docking and quantitative structure-activity relationship studies for imidazo[1,2-a]pyrazines as inhibitors of checkpoint kinase-1", MEDICINAL CHEMISTRY RESEARCH , 21(8), 1912-1920 CODEN: MCREEB; ISSN: 1054-2523, 2012, XP002714719 *
F.S. CARNEIRO ET AL., J. SEXUAL MEDICINE, vol. 7, 2010, pages 3823 - 3834
F.V. HAUWERMEIREN ET AL., J. CLIN. INVEST., vol. 123, 2013, pages 2590 - 2603
J.J. WU ET AL., JAMA, vol. 309, 2013, pages 2043 - 2044
M. MACCOSS ET AL: "Synthesis and biological evaluation of nucleosides containing 8-amino-imidazo[1,2-[alpha]]pyrazine as an isosteric replacement for adenine", JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 30, no. 5, 1 October 1993 (1993-10-01), pages 1213 - 1220, XP055083835, ISSN: 0022-152X, DOI: 10.1002/jhet.5570300508 *
M.G. TANSEY; D.E. SZYMKOWSKI, DRUG DISCOVERY TODAY, vol. 14, 2009, pages 1082 - 1088
MATTHEWS T P ET AL: "Design and evaluation of 3,6-di(hetero)aryl imidazo[1,2-a]pyrazines as inhibitors of checkpoint and other kinases", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, PERGAMON, vol. 20, no. 14, 15 July 2010 (2010-07-15), pages 4045 - 4049, XP027103981, ISSN: 0960-894X, [retrieved on 20100527] *
MICHAEL A. LYON ET AL: "Glyoxylic Acid and MP-Glyoxylate:? Efficient Formaldehyde Equivalents in the 3-CC of 2-Aminoazines, Aldehydes, and Isonitriles", ORGANIC LETTERS, vol. 6, no. 26, 1 December 2004 (2004-12-01), pages 4989 - 4992, XP055083816, ISSN: 1523-7060, DOI: 10.1021/ol0478234 *
N.A. MEANWELL, J. MED. CHEM., vol. 54, 2011, pages 2529 - 2591
SANKAR K. GUCHHAIT ET AL: "C-H Bond Functionalization Under Metalation-Deprotonation Process: Regioselective Direct Arylation of 3-Aminoimidazo[1,2- a ]pyrazine", THE JOURNAL OF ORGANIC CHEMISTRY, vol. 77, no. 18, 21 September 2012 (2012-09-21), pages 8321 - 8328, XP055083819, ISSN: 0022-3263, DOI: 10.1021/jo301065s *
T.W. GREENE; P.G.M. WUTS: "Protective Groups in Organic Synthesis", 1999, JOHN WILEY & SONS

Cited By (160)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9273043B2 (en) 2011-06-22 2016-03-01 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US9630959B2 (en) 2011-06-22 2017-04-25 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10450308B2 (en) 2011-06-22 2019-10-22 Purdue Pharma L.P. TRPV1 antagonists including dihydroxy substituent and uses thereof
US10273247B2 (en) 2013-12-09 2019-04-30 Ucb Biopharma Sprl Imidazothiazole derivatives as modulators of TNF activity
US9969728B2 (en) 2013-12-09 2018-05-15 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
WO2015086502A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Pyrazolopyridine derivatives as modulators of tnf activity
WO2015086498A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of tnf activity
WO2015086503A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazotriazine derivatives as modulators of tnf activity
WO2015086496A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Triazolopyridine derivatives as modulators of tnf activity
US9902720B2 (en) 2013-12-09 2018-02-27 Ucb Biopharma Sprl Pyrazolopyridine derivatives as modulators of TNF activity
WO2015086513A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Tetrahydrobenzimidazole derivatives as modulators of tnf activity
WO2015086526A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused tricyclic imidazole derivatives as modulators of tnf activity
WO2015086504A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazothiazole derivatives as modulators of tnf activity
WO2015086506A1 (en) * 2013-12-09 2015-06-18 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of tnf activity
WO2015086511A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Triazolopyridazine derivatives as modulators of tnf activity
WO2015086501A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridazine derivatives as modulators of tnf activity
US9890174B2 (en) 2013-12-09 2018-02-13 Ucb Biopharma Sprl Fused Tricyclic imidazole derivatives as modulators of TNF activity
US9890154B2 (en) 2013-12-09 2018-02-13 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
US9932334B2 (en) 2013-12-09 2018-04-03 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
US9873703B2 (en) 2013-12-09 2018-01-23 Ucb Biopharma Sprl Imidazopyridazine derivatives as modulators of TNF activity
US9868749B2 (en) 2013-12-09 2018-01-16 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of TNF activity
WO2015086519A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
US9932342B2 (en) 2013-12-09 2018-04-03 Ucb Biopharma Sprl Imidazopyrimidine derivatives as modulators of TNF activity
WO2015086499A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyrimidine derivatives as modulators of tnf activity
US9850240B2 (en) 2013-12-09 2017-12-26 Ucb Biopharma Sprl Triazolopyridine derivatives as modulators of TNF activity
US9932343B2 (en) 2013-12-09 2018-04-03 Ucb Biopharma Sprl Fused tricyclic benzimidazoles derivatives as modulators of TNF activity
US9920052B2 (en) 2013-12-09 2018-03-20 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
US9834553B2 (en) 2013-12-09 2017-12-05 Ucb Biopharma Sprl Tetrahydroimidazopyridine derivatives as modulators of TNF activity
WO2015086509A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
US9926313B2 (en) 2013-12-09 2018-03-27 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
US10093652B2 (en) 2013-12-09 2018-10-09 Ucb Biopharma Sprl Tetrahydrobenzimidazole derivatives as modulators of TNF activity
US10087179B2 (en) 2013-12-09 2018-10-02 Ucb Biopharma Sprl Fused tricyclic imidazole derivatives as modulators of TNF activity
US10053464B2 (en) 2013-12-09 2018-08-21 Ucb Biopharma Sprl Triazolopyridazine derivatives as modulators of TNF activity
US9714251B2 (en) 2013-12-09 2017-07-25 Ucb Biopharma Sprl Imidazotriazine derivatives as modulators of TNF activity
US9815797B2 (en) 2013-12-09 2017-11-14 Ucb Biopharma Sprl Fused bicyclic heteroaromatic derivatives as modulators of TNF activity
US10004737B2 (en) 2013-12-09 2018-06-26 Ucb Biopharma Sprl Fused imidazole and pyrazole derivatives as modulators of TNF activity
US9957255B2 (en) 2013-12-09 2018-05-01 Ucb Biopharma Sprl Benzotriazole derivatives as modulators of TNF activity
US9988383B2 (en) 2013-12-09 2018-06-05 Ucb Biopharma Sprl Purine derivatives as modulators of TNF activity
US9969729B2 (en) 2013-12-09 2018-05-15 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of TNF activity
WO2015086505A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Purine derivatives as modulators of tnf activity
WO2015086507A1 (en) 2013-12-09 2015-06-18 Ucb Biopharma Sprl Imidazopyridine derivatives as modulators of tnf activity
US10513493B2 (en) 2014-02-13 2019-12-24 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493442B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9527835B2 (en) 2014-02-13 2016-12-27 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10300051B2 (en) 2014-02-13 2019-05-28 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9994546B2 (en) 2014-02-13 2018-06-12 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9493450B2 (en) 2014-02-13 2016-11-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10676457B2 (en) 2014-02-13 2020-06-09 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11155532B2 (en) 2014-02-13 2021-10-26 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US11247992B2 (en) 2014-02-13 2022-02-15 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10717737B2 (en) 2014-02-13 2020-07-21 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US10174030B2 (en) 2014-02-13 2019-01-08 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
US9670210B2 (en) 2014-02-13 2017-06-06 Incyte Corporation Cyclopropylamines as LSD1 inhibitors
JP2017520570A (en) * 2014-06-25 2017-07-27 エフ．ホフマン−ラ ロシュ アーゲーＦ． Ｈｏｆｆｍａｎｎ−Ｌａ Ｒｏｃｈｅ Ａｋｔｉｅｎｇｅｓｅｌｌｓｃｈａｆｔ Imidazo [1,2-a] pyrazin-1-ylbenzamide compounds for treating spinal muscular atrophy
US9695167B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted triazolo[1,5-a]pyridines and triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10047086B2 (en) 2014-07-10 2018-08-14 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10138249B2 (en) 2014-07-10 2018-11-27 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
US10125133B2 (en) 2014-07-10 2018-11-13 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyridines and substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US10112950B2 (en) 2014-07-10 2018-10-30 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9695168B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,5-α]pyridines and imidazo[1,5-α]pyrazines as LSD1 inhibitors
US10640503B2 (en) 2014-07-10 2020-05-05 Incyte Corporation Imidazopyridines and imidazopyrazines as LSD1 inhibitors
US10556908B2 (en) 2014-07-10 2020-02-11 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US10968221B2 (en) 2014-07-10 2021-04-06 Incyte Corporation Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors
US9695180B2 (en) 2014-07-10 2017-07-04 Incyte Corporation Substituted imidazo[1,2-a]pyrazines as LSD1 inhibitors
US9758523B2 (en) 2014-07-10 2017-09-12 Incyte Corporation Triazolopyridines and triazolopyrazines as LSD1 inhibitors
JP2017531648A (en) * 2014-10-03 2017-10-26 ユーシービー バイオファルマ エスピーアールエル Fused five-membered imidazole derivatives
WO2016050975A1 (en) * 2014-10-03 2016-04-07 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives
CN107108672A (en) * 2014-10-03 2017-08-29 Ucb生物制药私人有限公司 The five rings imdazole derivatives of fusion
US11912721B2 (en) 2014-10-03 2024-02-27 UCB Biopharma SRL Fused pentacyclic imidazole derivatives
KR20170068503A (en) * 2014-10-03 2017-06-19 유씨비 바이오파마 에스피알엘 Fused pentacyclic imidazole derivatives
AU2015326798B2 (en) * 2014-10-03 2020-01-02 Sanofi Fused pentacyclic imidazole derivatives
EA032839B1 (en) * 2014-10-03 2019-07-31 Юсб Байофарма Спрл Fused pentacyclic imidazole derivatives
US10202405B2 (en) 2014-10-03 2019-02-12 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives
US10906919B2 (en) 2014-10-03 2021-02-02 UCB Biopharma SRL Fused pentacyclic imidazole derivatives
KR102442235B1 (en) 2014-10-03 2022-09-08 유씨비 바이오파마 에스알엘 Fused pentacyclic imidazole derivatives
CN107108672B (en) * 2014-10-03 2019-11-08 Ucb生物制药私人有限公司 Condensed five rings imdazole derivatives
WO2016149439A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Heterocyclic compounds useful as inhibitors of tnf
WO2016149437A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds useful as inhibitors of tnf
US10308652B2 (en) 2015-03-18 2019-06-04 Bristol-Myers Squibb Company Tricyclic heterocyclic compounds useful as inhibitors of TNF
US10189840B2 (en) 2015-03-18 2019-01-29 Bristol-Myers Squibb Company Substituted tricyclic heterocyclic compounds
US10112944B2 (en) 2015-03-18 2018-10-30 Bristol-Myers Squibb Company Heterocyclic compounds useful as inhibitors of TNF
WO2016149436A1 (en) 2015-03-18 2016-09-22 Bristol-Myers Squibb Company Substituted tricyclic heterocyclic compounds
US11401272B2 (en) 2015-04-03 2022-08-02 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10800779B2 (en) 2015-04-03 2020-10-13 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US9944647B2 (en) 2015-04-03 2018-04-17 Incyte Corporation Heterocyclic compounds as LSD1 inhibitors
US10266532B2 (en) 2015-04-17 2019-04-23 Abbvie Inc. Tricyclic modulators of TNF signaling
US10273238B2 (en) 2015-04-17 2019-04-30 Abbvie Inc. Indazolones as modulators of TNF signaling
US9856253B2 (en) 2015-04-17 2018-01-02 Abbvie, Inc. Tricyclic modulators of TNF signaling
US10160748B2 (en) 2015-04-17 2018-12-25 Abbvie Inc. Indazolones as modulators of tnf signaling
US9879016B2 (en) 2015-04-17 2018-01-30 Abbvie Inc. Indazolones as modulators of TNF signaling
US10287299B2 (en) 2015-06-08 2019-05-14 Ucb Biopharma Sprl Substituted benzo[b][1,4]oxazines and pyrido[3,2-b][1,4]oxazines as modulators of tumor necrosis factor activity
JP2018521022A (en) * 2015-06-08 2018-08-02 ユーシービー バイオファルマ エスピーアールエル Fused tricyclic imidazopyrazines as modulators of TNF activity
WO2016198398A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Fused tricyclic imidazo pyrazines as modulators of tnf activity
EA036289B1 (en) * 2015-06-08 2020-10-22 Юсб Байофарма Спрл Fused tricyclic imidazo pyrazines as modulators of tnf activity
US10472362B2 (en) 2015-06-08 2019-11-12 Ucb Biopharma Sprl Fused tricyclic imidazo pyrazines as modulators of TNF activity
WO2016198401A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Indazole derivatives as modulators of tnf activity
WO2016198400A1 (en) 2015-06-08 2016-12-15 Ucb Biopharma Sprl Benzoxazinone derivatives and analogues thereof as modulators of tnf activity
CN107690434B (en) * 2015-06-08 2021-07-30 Ucb生物制药私人有限公司 Fused tricyclic imidazopyrazine derivatives as modulators of TNF activity
CN107690434A (en) * 2015-06-08 2018-02-13 Ucb生物制药私人有限公司 Fused tricyclic Imidazopyrazines derivative as TNF active regulators
US10775385B2 (en) 2015-06-18 2020-09-15 UCB Biopharma SRL Treatment of autoimmune and inflammatory disorders with asymmetric TNF alpha trimers
US11674967B2 (en) 2015-06-18 2023-06-13 UCB Biopharma SRL Method of identifying potential inhibitors of APO TNFα trimers
US11448655B2 (en) 2015-06-18 2022-09-20 UCB Biopharma SRL Method for identifying a modulator of the TNFα or CD40L interaction with their cognate receptors
US10883996B2 (en) 2015-06-18 2021-01-05 UCB Biopharma SRL Methods of identifying signaling modulators of the trimeric TNFa
US10705094B2 (en) 2015-06-18 2020-07-07 UCB Biopharma SRL TNF receptor signaling modulator assay
US10969393B2 (en) 2015-06-18 2021-04-06 UCB Biopharma SRL Complexes between anti-TNF antibodies, trimeric TNF proteins and organic molecules binding them
US11022614B2 (en) 2015-06-18 2021-06-01 UCB Biopharma SRL Antibodies binding to trimeric TNF alpha epitopes
WO2017023905A1 (en) 2015-08-03 2017-02-09 Bristol-Myers Squibb Company Heterocyclic compounds useful as modulators of tnf alpha
US10335392B2 (en) 2015-08-03 2019-07-02 Bristol-Myers Squibb Company Cyclic compounds useful as modulators of TNF α
US11498900B2 (en) 2015-08-12 2022-11-15 Incyte Corporation Salts of an LSD1 inhibitor
US10329255B2 (en) 2015-08-12 2019-06-25 Incyte Corporation Salts of an LSD1 inhibitor
US10723700B2 (en) 2015-08-12 2020-07-28 Incyte Corporation Salts of an LSD1 inhibitor
US10526316B2 (en) 2015-10-09 2020-01-07 Janssen Pharmaceutica Nv Quinoxaline and pyridopyrazine derivatives as PI3Kβ inhibitors
US11407749B2 (en) 2015-10-19 2022-08-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11572366B2 (en) 2015-11-19 2023-02-07 Incyte Corporation Heterocyclic compounds as immunomodulators
US11866435B2 (en) 2015-12-22 2024-01-09 Incyte Corporation Heterocyclic compounds as immunomodulators
US11535615B2 (en) 2015-12-22 2022-12-27 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2017167996A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
WO2017167995A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused hexacyclic imidazole derivatives as modulators of tnf activity
WO2017167993A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
US10654861B2 (en) 2016-04-01 2020-05-19 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
US10669286B2 (en) 2016-04-01 2020-06-02 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
WO2017167994A1 (en) 2016-04-01 2017-10-05 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
US10766906B2 (en) 2016-04-01 2020-09-08 UCB Biopharma SRL Fused hexacyclic imidazole derivatives as modulators of TNF activity
US10793578B2 (en) 2016-04-01 2020-10-06 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
US10166221B2 (en) 2016-04-22 2019-01-01 Incyte Corporation Formulations of an LSD1 inhibitor
US11608337B2 (en) 2016-05-06 2023-03-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11673883B2 (en) 2016-05-26 2023-06-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US10894793B2 (en) 2016-06-16 2021-01-19 Janssen Pharmaceutica Nv Bicyclic pyridine, pyrazine, and pyrimidine derivatives as PI3K beta inhibitors
EA037361B1 (en) * 2016-06-16 2021-03-18 Янссен Фармацевтика Нв Bicyclic pyridine, pyrazine, and pyrimidine derivatives as pi3k beta inhibitors
WO2017216292A1 (en) * 2016-06-16 2017-12-21 Janssen Pharmaceutica Nv Bicyclic pyridine, pyrazine, and pyrimidine derivatives as pi3k beta inhibitors
KR102472453B1 (en) * 2016-06-16 2022-11-29 얀센 파마슈티카 엔.브이. Bicyclic Pyridine, Pyrazine, and Pyrimidine Derivatives as PI3K Beta Inhibitors
KR20190016954A (en) * 2016-06-16 2019-02-19 얀센 파마슈티카 엔.브이. Bicyclic pyridine, pyrazine, and pyrimidine derivatives as PI3K beta inhibitors
US11873309B2 (en) 2016-06-20 2024-01-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US11718605B2 (en) 2016-07-14 2023-08-08 Incyte Corporation Heterocyclic compounds as immunomodulators
US11613536B2 (en) 2016-08-29 2023-03-28 Incyte Corporation Heterocyclic compounds as immunomodulators
US11174311B2 (en) 2016-12-21 2021-11-16 UCB Biopharma SRL Antibody against trimeric TNFα complex
US10308644B2 (en) 2016-12-22 2019-06-04 Incyte Corporation Heterocyclic compounds as immunomodulators
US11566026B2 (en) 2016-12-22 2023-01-31 Incyte Corporation Heterocyclic compounds as immunomodulators
US10800768B2 (en) 2016-12-22 2020-10-13 Incyte Corporation Heterocyclic compounds as immunomodulators
US11465981B2 (en) 2016-12-22 2022-10-11 Incyte Corporation Heterocyclic compounds as immunomodulators
US10806785B2 (en) 2016-12-22 2020-10-20 Incyte Corporation Immunomodulator compounds and methods of use
US11339149B2 (en) 2016-12-22 2022-05-24 Incyte Corporation Heterocyclic compounds as immunomodulators
US10793565B2 (en) 2016-12-22 2020-10-06 Incyte Corporation Heterocyclic compounds as immunomodulators
US11787793B2 (en) 2016-12-22 2023-10-17 Incyte Corporation Heterocyclic compounds as immunomodulators
WO2018167176A1 (en) * 2017-03-15 2018-09-20 Ucb Biopharma Sprl Fused pentacyclic imidazole derivatives as modulators of tnf activity
US10953019B2 (en) 2017-03-15 2021-03-23 UCB Biopharma SRL Fused pentacyclic imidazole derivatives as modulators of TNF activity
US11130751B2 (en) 2017-03-29 2021-09-28 Janssen Pharmaceutica Nv Quinoxaline and pyridopyrazine derivatives as PI3K-beta inhibitors
US10669271B2 (en) 2018-03-30 2020-06-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US11124511B2 (en) 2018-03-30 2021-09-21 Incyte Corporation Heterocyclic compounds as immunomodulators
US11414433B2 (en) 2018-05-11 2022-08-16 Incyte Corporation Heterocyclic compounds as immunomodulators
US10906920B2 (en) 2018-05-11 2021-02-02 Incyte Corporation Heterocyclic compounds as immunomodulators
US10618916B2 (en) 2018-05-11 2020-04-14 Incyte Corporation Heterocyclic compounds as immunomodulators
US11512064B2 (en) 2018-08-31 2022-11-29 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US10968200B2 (en) 2018-08-31 2021-04-06 Incyte Corporation Salts of an LSD1 inhibitor and processes for preparing the same
US11753406B2 (en) 2019-08-09 2023-09-12 Incyte Corporation Salts of a PD-1/PD-L1 inhibitor
US11401279B2 (en) 2019-09-30 2022-08-02 Incyte Corporation Pyrido[3,2-d]pyrimidine compounds as immunomodulators
US11866451B2 (en) 2019-11-11 2024-01-09 Incyte Corporation Salts and crystalline forms of a PD-1/PD-L1 inhibitor
US11780836B2 (en) 2020-11-06 2023-10-10 Incyte Corporation Process of preparing a PD-1/PD-L1 inhibitor
US11760756B2 (en) 2020-11-06 2023-09-19 Incyte Corporation Crystalline form of a PD-1/PD-L1 inhibitor
US11866434B2 (en) 2020-11-06 2024-01-09 Incyte Corporation Process for making a PD-1/PD-L1 inhibitor and salts and crystalline forms thereof

Also Published As

Publication number Publication date
GB201212513D0 (en) 2012-08-29
JP2015525752A (en) 2015-09-07
US20150191482A1 (en) 2015-07-09
CA2877543C (en) 2020-09-22
JP6259824B2 (en) 2018-01-10
EA028041B1 (en) 2017-09-29
BR112015000790B1 (en) 2022-07-19
BR112015000790A2 (en) 2017-06-27
US9475820B2 (en) 2016-10-25
EA201500133A1 (en) 2015-07-30
CN104470924A (en) 2015-03-25
TR201901652T4 (en) 2019-02-21
CN104470924B (en) 2016-11-09
ES2711131T3 (en) 2019-04-30
CA2877543A1 (en) 2014-01-16
EP2872511B1 (en) 2019-01-16
EP2872511A1 (en) 2015-05-20

Similar Documents

Publication Publication Date Title
CA2877543C (en) Imidazopyrazine derivatives as modulators of tnf activity
EP3080120B1 (en) Fused imidazole and pyrazole derivatives as modulators of tnf activity
EP3080110B1 (en) Tetrahydroimidazopyridine derivatives as modulators of tnf activity
CA2877550C (en) Imidazopyridine derivatives as modulators of tnf activity
EP3080121B1 (en) Fused tricyclic benzimidazoles derivatives as modulators of tnf activity
EP3080128B1 (en) Imidazopyridazine derivatives as modulators of tnf activity
EP3080112B1 (en) Imidazopyridine derivatives as modulators of tnf activity
EP3080127A1 (en) Imidazopyrimidine derivatives as modulators of tnf activity
EP3080114A1 (en) Fused tricyclic imidazole derivatives as modulators of tnf activity
EP3080126A1 (en) Purine derivatives as modulators of tnf activity
WO2015086496A1 (en) Triazolopyridine derivatives as modulators of tnf activity
EP3080117A1 (en) Imidazopyridine derivatives as modulators of tnf activity
EP3080130A1 (en) Triazolopyridazine derivatives as modulators of tnf activity
CN107690434B (en) Fused tricyclic imidazopyrazine derivatives as modulators of TNF activity

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13734128

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2877543

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2015520937

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14414299

Country of ref document: US

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2013734128

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 201500133

Country of ref document: EA

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112015000790

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112015000790

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20150113