Classifications

• • 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
  • C07D471/04—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P13/00—Drugs for disorders of the urinary system
  • A61P13/12—Drugs for disorders of the urinary system of the kidneys
• • 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
• • 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
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• • 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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

• the present invention relates to pyridyl and pyrimidinyl derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy.
• the invention relates to compounds and compositions that are capable of decreasing HIF prolyl hydroxylase (HPH) enzyme activity, also referred to as prolyl hydroxylase domain (PHD) protein, thereby increasing the stability and/or activity and/or levels of hypoxia inducible factor (HIF) and/or altering other hypoxia-induced reactions independent of HIF.
• HPH prolyl hydroxylase
• HIF hypoxia inducible factor
• HIF mediates changes in gene expression in response to changes in cellular oxygen concentration.
• HIF is a heterodimer having an oxygen-regulated subunit (HIF- ) and a constitutively expressed subunit (HIF- ⁇ ).
• HIF-a is hydroxylated at conserved proline residues by prolyl-hydroxylase (PHD) resulting in its rapid degradation.
• PLD prolyl-hydroxylase
• HIF-a is hydroxylated at conserved proline residues by prolyl-hydroxylase
• hypooxia hypooxia
• HIF-a which triggers an increase in glycolysis to compensate for energy loss due to reduced oxidative phosphorylation and upregulation of erythropoiesis and angiogenesis to achieve more efficient oxygen utilization.
• Other HIF-independent signalling pathways also respond to hypoxia and contribute to oxygen availability increase.
• PHD exists in three isoforms referred to as PHD1, PHD2 and PHD3 which function as oxygen sensors and in the regulation of cell metabolism in response to oxygen content in cells. Due to the central role of PHD in oxygen sensing, PHD inhibitors would be expected to be useful in treating cardiovascular disorders such as ischemic events, hematological disorders such as anemia, pulmonary disorders, brain disorders, and kidney disorders.
• Patent Document 1 describes certain triazolopyrimidine derivative compounds that are said to be useful as pest control agents.
• Patent Document 2 describes certain pyridyl triazolopyrimidine derivative compounds that are said to be useful as harmful organism control agents.
• Patent Document 3 describes triazolopyrimidine compounds that are said to be useful for treating of inhibiting the growth of cancerous tumour cells and associated diseases.
• Patent Document 4 describes certain triazolopyrimidine compounds that are said to be useful as anxiolytic agents.
• Non-Patent Documents 1 and 2 describe triazolopyrimidine compounds.
• Patent Document 1 WO2010/018868
• Patent Document 2 WO2010/018853
• Patent Document 3 WO02/02563
• Patent Document 4 US4209621
• Non-Patent Document 1 Aurora Screening Library January 2015 Cat. K08.258.458
• Non-Patent Document 2 Ambinter Stock Screening Collection September 2014 Cat.
• the present invention provides inhibitors of PHD.
• X , X , X and Y each independently represent C, CH or N, provided that (i) at least
• X one of X , X , X and Y represents N, and (ii) if Y represents N, then X represents C;
• R 1 represents hydrogen, halogen, Q-Cg alkyl, C3-C6 cycloalkyl,
• n 0 or 1 ;
• p is 0 or 1 ;
• R represents hydrogen, Ci-Cg alkyl (unsubstituted, or substituted by at least one substituent independently selected from halogen, hydroxyl, C1-C6 haloalkyl, Ci ⁇ alkoxy,
• C3-C6 cycloalkyl C6-C 10 aryl, NR R , oxetanyl, oxolanyl and oxanyl
• C3-C6 cycloalkyl unsubstituted, or substituted by at least one substituent independently selected from halogen, cyano and C1-C6 alkyl
• C6-Cio aryl C6-Cio aryl
• a 4- to 7-membered heterocyclyl unsubstituted, or substituted by at least one Cj-Cg alkyl
• R 5 and R 6 each independently represent hydrogen, Cj-C6 alkyl (unsubstituted, or substituted by at least one substituent independently selected from halogen, hydroxyl, Cj-C6
• R 5 and R 6 may together with the nitrogen atom to which they are attached form a 4- to
• R and R each independently represent a hydrogen atom or a C ⁇ -C(, alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and C j-Cg alkoxy;
• R and R each independently represent a hydrogen atom or a C -C ⁇ alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and C ⁇ -C(, alkoxy;
• R and R each independently represent a hydrogen atom or a Cj-Cg alkyl or C3-C6 cycloalkyl group
• Y represents C or N
• R represents a hydrogen or halogen atom, or a C1-C3 alkyl or
• R represents a group of formula (II) to (VIII)
• n is 0 or an integer from 1 to 4
• Z represents CH or N
• R a represents halogen, cyano, Ci-Cgalkyl, C2-Cg alkenyl, C2-C6 alkynyl or C3-C6 b e d G
• each of R , R , R andR independently represents hydrogen, halogen, ⁇ -C ⁇ alkyl, C]-C6 alkoxy, Cj-C6 haloalkyl, C3-C6 cycloalkyl or NR 13 R 14 , and each R f independently represents halogen, Cj-Cg alkyl, C1-C6 alkoxy, Cj-Cg haloalkyl, C3-C6
• R and R each independently represent a hydrogen atom or a C ⁇ -C ⁇ alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and C1-C6 alkoxy;
• R represents a group of formula (II) and R represents
• an "alkyl”, “alkenyl” or “alkynyl” substituent group or an “alkyl”, “alkenyl” or “alkynyl” moiety in a substituent group may be linear or branched.
• Ci-Cg alkyl groups/moieties include methyl, ethyl, propyl, 2 -methyl- 1 -propyl,
• alkenyl substituent group or an alkenyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon double bonds.
• C2-C6 alkenyl groups/moieties examples include ethenyl, propenyl, 1-butenyl, 2-butenyl,
• alkynyl substituent group or an alkynyl moiety in a substituent group refers to an unsaturated alkyl group or moiety having one or more carbon-carbon triple bonds.
• Examples of C2-C6 alkynyl groups/moieties include ethynyl, 2-propynyl, 1-butynyl, 2-butynyl,
• a “cycloalkyl” substituent group or a “cycloalkyl” moiety in a substituent group refers to a saturated hydrocarbyl ring containing, for example, from 3 to 8 carbon atoms, examples of which include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
• haloalkyl substituent group or a “haloalkyl” moiety in a substituent group refers to an alkyl group or moiety in which one or more, e.g. one, two, three, four or five, hydrogen atoms are replaced independently by halogen atoms, i.e. by fluorine, chlorine, bromine or iodine atoms.
• haloalkyl groups/moieties include fluoromethyl, difluoromethyl, trifluoromethyl and 2,2,2-trifluoroethyl.
• a “hydroxyalkyl” substituent group or a “hydroxyalkyl” moiety in a substituent group refers to an alkyl group or moiety in which one or more, e.g. one, two or three hydrogen atoms are replaced by hydroxyl groups, examples of which include -
• oxo refers to an oxygen atom doubly bonded to the carbon atom to which it is attached to form the carbonyl of a ketone or aldehyde.
• halogen includes fluorine, chlorine, bromine and iodine.
• heterocyclyl substituent group or a “heterocyclyl” moiety in a substituent group refers to a 4- to 9-membered ring system which may be monocyclic or bicyclic (in which the two rings are fused, bridged or spiro), wherein the ring system is saturated and contains from 1 to 4 ring heteroatoms independently selected from, nitrogen, oxygen and sulphur. It should be understood that a heterocyclyl group/moiety can be attached to the rest of the molecule through any suitable ring carbon or ring nitrogen atom.
• heterocyclyl groups include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, oxazolidinyl, oxetanyl, oxolanyl (tetrahydrofuranyl), oxanyl (tetrahydropyranyl),
• aryl substituent group or an “aryl” moiety in a substituent group refers to a monocyclic or bicyclic aromatic hydrocarbon ring, examples of which include phenyl and naphthyl.
• heteroaryl substituent group or a “heteroaryl” moiety in a substituent group refers to an aryl group in which from 1 to 4 ring carbon atoms are replaced by heteroatoms independently selected from nitrogen, oxygen and sulphur.
• the heteroaryl group/moiety can be attached to the rest of the molecule through any suitable ring carbon or ring nitrogen atom.
• heteroaryl groups include pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, triazinyl, thienyl, furyl, furazanyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, tetrazinyl, quinoxalinyl, benzothiazolyl, benzoxazolyl, quinolinyl, quinazolinyl, indolyl, 7-azaindolyl, indolizinyl, indazolyl, imidazo[l ,2-a]pyridinyl, l ,3-thiazolo[5,4-b]pyridinyl, l ,3-thiazolo[5,4-c
• heterocyclyl, aryl and heteroaryl groups it should be understood that the invention does not encompass any unstable ring structures or any O-O, O-S or S-S bonds and that if the heterocyclyl, aryl or heteroaryl group is substituted, the substituent may be attached to any suitable ring atom.
• the heterocyclic ring may contain one or more (e.g. one or two) further ring heteroatoms (e.g. nitrogen, oxygen or sulphur atoms) in addition to the nitrogen atom to which 5 and R 6 , or R and R , or R and R , or R and R , are attached.
• further ring heteroatoms e.g. nitrogen, oxygen or sulphur atoms
• the invention does not encompass any unstable ring structures or any O-O, 0-S or S-S bonds.
• a substituent is present on the ring, it may be attached to any suitable ring atom.
• heterocyclic rings include azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, azepanyl and 1 ,4-oxaazepanyl.
• alkoxyalkyl For the purposes of the present invention, where a combination of moieties is referred to as one group, for example, alkoxyalkyl, alkylcarbonyl or, alkoxycarbonyl, the last mentioned moiety contains the atom by which the group is attached to the rest of the molecule.
• An example of an alkoxyalkyl group is 3-methoxypropyl (-CH2CH2CH2OCH3).
• X , X , X and Y each independently represent C, CH or N, provided that (i) at least
• ⁇ , ⁇ , ⁇ and Y represents N, and (ii) if Y represents N, then X represents C.
• At least two of X , X , X and Y represent N.
• X and X both represent N, X represents C and Y represents CH.
• At least three of X , X , X and Y represent N.
• each of X , X , X and Y represent N.
• R represents one of the following groups:
• halogen e.g. fluorine, chlorine, bromine or iodine
• Ci-C 6 or C1-C4, or Ci-C 2 alkyl
• Ci-C 6 alkoxyCi-C 6 alkyl e.g. C 1 -C3 alkoxyCi-C 6 alkyl or C1-C3 alkoxyC] -C 4 alkyl
• substituents e.g. one, two, three or four substituents independently selected from oxo, C 1 -Cg, or C 1 -C4, or C ⁇ -C 2 alkyl,
• R represents:
• R 1 represents:
• heteroatoms independently selected from nitrogen and oxygen which is either unsubstituted or is substituted by one or two substituents independently selected from oxo, C1-C4, or C1-C3, or Cj-C 2 alky 1 (e.g. methyl, ethyl, n-propyl or n-butyl),
• Ci-C 2 alkylcarbonyl Ci-C 2 alkoxy, cyclopropyl, C1-C4, or C1-C3, or
• the R 1 heterocyclyl group is selected from azetidinyl, pyrrolidinyl, piperidinyl, morpholinyl, oxazolidinyl, piperazinyl, azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.3]heptanyl and 2,6-diazaspiro[3.3]heptanyl.
• R represents hydrogen, Cj-Cg, or C1-C4, or C1-C2 alkyl (unsubstituted, or substituted by at least one substituent, e.g.
• substituents independently selected from halogen, hydroxyl, C ⁇ -C , or C1-C4, or C1-C2 haloalkyl, C ⁇ -C , or Q-C4, or C1-C2 alkoxy,
• C1-C2 alkyl C6-Cio aryl, or a 4- to 7-membered heterocyclyl (unsubstituted, or substituted by at least one, e.g. one, two, three or four independently selected, C]-C6, or
• R represents hydrogen, C1-C4, or C1-C3, or C1-C2 alkyl
• substituent e.g. one, two, three or four substituents, independently selected from fluorine, chlorine, cyano and C1-C2 alkyl
• phenyl, or a 4- to 7-membered heterocyclyl unsubstitute
• the R heterocyclyl group represents a 4- to 6-membered heterocyclyl comprising one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur.
• the 4- to 6-membered heterocyclyl comprises a single ring nitrogen or a single ring oxygen atom, examples of which include pyrrolidinyl, oxetanyl, oxolanyl and oxanyl.
• R represents hydrogen, C1-C3 alkyl
• R 5 and R 6 each independently represent
• each of the aryl, heteroaryl and heterocyclyl groups being optionally substituted with at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen, C ⁇ -C ⁇ , or C1 -C4, or C1-C2 alkyl, C1 -C6, or C1-C4, or C1-C2 alkoxy, and Cj -C6, or C1-C4, or C1-C2 alkylcarbonyl, or R and R may together with the nitrogen atom to which they are attached form a 4- to 6- or 7-membered saturated heterocyclic ring unsubstituted, or substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from halogen, hydroxyl, oxo and Cj-C6, or C1-C4, or C1-C2 alkoxy.
• substituent e.g. one, two, three or four substituents, independently selected from halogen,
• the R 5 or R 6 heteroaryl groups or moieties are 5- to 6- membered monocyclic rings comprising one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur.
• the or R ⁇ heteroaryl groups or moieties are 5- to 6-membered monocyclic rings comprising one or two ring nitrogen atoms, examples of which include imidazolyl, pyrazolyl, pyridazinyl and pyrimidinyl.
• the R 5 or R 6 heterocyclyl groups or moieties are 4- to 6- membered monocyclic rings comprising one or two ring heteroatoms independently selected from nitrogen, oxygen and sulphur.
• the R 5 or R 6 heterocyclyl groups or moieties are 4- to 6-membered monocyclic rings comprising one or two ring heteroatoms independently selected from nitrogen and oxygen, examples of which include azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, oxetanyl, oxolanyl and oxanyl.
• 5 and R 6 each independently represent
• Ci Ci to C2, C3, C4 or C5 alkyl (unsubstituted, or substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from fluorine, chlorine,
• each of the aryl, heteroaryl and heterocyclyl groups being optionally substituted with at least one substituent, e.g. one, two, three or four substituents, independently selected from fluorine, chlorine, C1-C2 alkyl, C1-C2 alkoxy, and C1-C2 alkylcarbonyl.
• substituents e.g. one, two, three or four substituents, independently selected from fluorine, chlorine, C1-C2 alkyl, C1-C2 alkoxy, and C1-C2 alkylcarbonyl.
• Ci Ci to C2, C3, C4 or C5 alkyl (unsubstituted, or substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from fluorine, hydroxyl,
• each of the aryl, heteroaryl and heterocyclyl groups being optionally substituted with at least one substituent, e.g. one, two, three or four substituents, independently selected from methyl, methoxy, and C1-C2 alkylcarbonyl.
• R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring unsubstituted, or substituted by at least one substituent, e.g. one, two, three or four substituents, independently selected from fluorine, chlorine, hydroxyl, oxo and C1-C2 alkoxy.
• the saturated heterocyclic ring may contain a single ring heteroatom (being the nitrogen atom to which R 5 and R 6 are attached).
• the saturated heterocyclic ring may contain a second ring heteroatom selected from nitrogen or oxygen.
• R 5 and R 6 together with the nitrogen atom to which they are attached form an azetidinyl or pyrrolidinyl ring optionally substituted by one or two substituents independently selected from fluorine, hydroxyl and methoxy.
• R 5 and R 6 together with the nitrogen atom to which they are attached form an azetidinyl ring substituted by a methoxy group.
• R and R each independently represent a hydrogen atom or a C Cg, or C1-C4, or
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, hydroxyl, oxo and Ci-Cg, or C1-C4, or C1-C2 alkoxy.
• substituent e.g. one, two, three or four substituents
• the saturated heterocyclic ring may contain a single ring heteroatom (being the
• the saturated heterocyclic ring may contain a second ring heteroatom selected from nitrogen or oxygen.
• R and R each independently represent a hydrogen atom or a Cj-Cg, or C1-C4, or C1-C2 alkyl, particularly methyl, group.
• R and R together with the nitrogen atom to which they are attached form a pyrrolidinyl ring which is unsubstituted or substituted as hereinbefore described.
• R and R each independently represent a hydrogen atom or a C1-C6, or C1-C4, or
• R and R may together with the nitrogen atom to which they are attached form a 4- to 6- or 7-membered saturated heterocyclic ring optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, hydroxyl, oxo and C ⁇ -C ⁇ , or C1-C4, or C1-C2 alkoxy.
• substituents e.g. one, two, three or four substituents
• the saturated heterocyclic ring may contain a single ring heteroatom (being the
• the saturated heterocyclic ring may contain a second ring heteroatom selected from nitrogen or oxygen.
• R and R each independently represent a hydrogen atom or a C]-C6,
• R and R both represent a methyl group.
• R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring (e.g. azetidinyl, pyrrolidinyl or piperidinyl) optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from fluorine, chlorine, hydroxyl, oxo and C1-C2 alkoxy.
• substituent e.g. one, two, three or four substituents
• R and R together with the nitrogen atom to which they are attached form a 4- to 6-membered saturated heterocyclic ring (e.g ⁇ azetidinyl, pyrrolidinyl or piperidinyl) optionally substituted by one or two substituents independently selected from fluorine, chlorine, hydroxyl, oxo and methoxy, in particular oxo.
• azetidinyl e.g ⁇ azetidinyl, pyrrolidinyl or piperidinyl
• substituents independently selected from fluorine, chlorine, hydroxyl, oxo and methoxy, in particular oxo.
• R and R each independently represent a hydrogen atom or a C 1 -C ⁇ , or C 1 -C4, or C1-C2 alkyl or C3-C6 cycloalkyl group.
• R and R each independently represent a hydrogen atom or a C ⁇ -Cg
• R and R both represent a methyl group.
• Y represents C and R represents a hydrogen or halogen atom (e.g. fluorine or chlorine), or a C1-C3 alkyl (e.g. methyl) or amino ( ⁇ 3 ⁇ 4) group.
• R represents a hydrogen or halogen atom (e.g. fluorine or chlorine), or a C1-C3 alkyl (e.g. methyl) or amino ( ⁇ 3 ⁇ 4) group.
• Y represents C and R represents a hydrogen or fluorine atom or a methyl or amino group.
• Y represents N and R is absent.
• R represents a group of formula (II) to (VIII)
• n is 0 or an integer 1, 2, 3 or 4, Z represents CH or N,
• R a represents halogen, cyano, Cj-C6, or C1-C4, or C1-C2 alkyl, C2-C6 or C2-C4 alkenyl,
• each of R , R , R and R independently represents hydrogen, halogen, C 1 -C6, or C1-C4, or C1-C2 alkyl, Cj-Cg, or C1-C4, or
• each R independently represents halogen, Cj-Cg, or C1-C4, or C1-C2 alkyl, C1-C6, or C1-C4, or C1-C2 alkoxy, C1-C6, or Q-C4, or C1-C2 haloalkyl, C3-C6 cycloalkyl or
• R represents halogen, cyano or C 2 -Cg or C 2 - C4 alkynyl.
• R represents fluorine, chlorine, cyano or C 2 -C4 alkynyl.
• R represents chlorine, cyano or ethynyl.
• each of R , R , R and R independently represents hydrogen, halogen, C 1 -C 2 alkyl, C 1 -C 2 alkoxy, C 1 -C 2 haloalkyl (e.g. trifluoromethyl) or
• each of R , R , R and R independently represents hydrogen
• each R independently represents halogen, C 1 -C 2 alkyl,
• each R independently represents fluorine, chlorine, bromine,
• n is 0 in formula (VIII) so that R is absent.
• R represents a group of formula (II) in which R , R , R , d e
• R and R are as hereinbefore defined.
• R represents a group of formula (II) in which R represents cyano b e d c
• each of R , R , R and R independently represents hydrogen, fluorine, chlorine,
• R represents a group of formula (II) in which R represents c b d c
• R represents methyl, and each of R , R and R independently represents hydrogen, fluorine or methyl.
• R represents a group of formula (II) in which R represents c b d c
• R represents methyl, and each of R , R and R represents hydrogen.
• R and R each independently represent a hydrogen atom or a C1-C6, or C1-C4, or
• R and R may together with the nitrogen atom to which they are attached form a 4- to 6- or 7-membered saturated heterocyclic ring optionally substituted by at least one substituent (e.g. one, two, three or four substituents) independently selected from halogen, hydroxyl, oxo and C]-C6, or Q-C4, or Q-C2 alkoxy.
• substituent e.g. one, two, three or four substituents
• the saturated heterocyclic ring may contain a single ring heteroatom (being the
• the saturated heterocyclic ring may contain a second ring heteroatom selected from nitrogen or oxygen.
• R and R each independently represent a hydrogen atom or a C ⁇ -C(>,
• R and R each independently
• R 13 14 represent a hydrogen atom or a methyl group.
• R and R both represent a hydrogen atom.
• the invention provides compounds of formula (la)
• R 1 represents NHC(0)R 4 or NR 5 R 6 ;
• E is a nitrogen atom or CR ;
• R and R each independently represent a hydrogen or fluorine atom
• R and R each independently represent a hydrogen, fluorine or chlorine atom or a methyl group
• R , R and R are as defined above.
• R in formula (la) represents NHC(0)R in which R represents a C1 -C3 alkyl or C3-C6 cycloalkyl group.
• R in formula (la) represents NR R in which R and R each represent a hydrogen atom.
• Examples of compounds of the invention include:
• the present invention further provides a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined above which comprises
• L represents a leaving group (e.g. a halogen atom, tributyl stannyl, boronic acid
• a palladium catalyst e.g. palladium (II) chloride, palladium (II) acetate,
• n, Z, R and R are as defined above;
• Process (i) is conveniently carried out under a nitrogen atmosphere, in an organic solvent such as dioxane, tetrahydrofuran, acetonitrile or N-methylpyrrolidone and at a temperature in the range of, for example, 20°C to 120°C.
• organic solvent such as dioxane, tetrahydrofuran, acetonitrile or N-methylpyrrolidone
• Process (ii) is conveniently carried out in an organic solvent such as dimethylsulphoxide, N-methylpyrrolidone, ethanol, isopropyl alcohol, acetonitrile or tetrahydrofuran and at a temperature in the range of, for example, 20°C to 180°C.
• organic solvent such as dimethylsulphoxide, N-methylpyrrolidone, ethanol, isopropyl alcohol, acetonitrile or tetrahydrofuran
• a compound of formula (I) may be converted into another compound of formula (I).
• carbonyl group, -C(0)OR may be converted into a corresponding compound of formula (I) in which R 1 represents a hydroxymethyl group by reacting the former with a reducing agent such as lithium borohydride in the presence of a polar solvent such as tetrahydrofuran at a temperature in the range from 0°C to 20° or 25°C.
• a compound of formula (I) in which R represents a carboxyl group may be converted into a corresponding compound of formula (I) in which R 1 represents an amide group, -C(0)NR 5 R 6 , by reacting the former with an amine of formula (XX), HNR 5 R 6 , where R 5 and R 6 are as hereinbefore defined,
• a compound of formula (I) in which R 1 represents a halogen atom may be converted to a corresponding compound of formula (I) in which R ⁇ represents -NR ⁇ R ⁇ , by reacting the former with an amine of formula (XX), HNR 5 R 6 , (a) in a polar solvent such as ethanol under a nitrogen atmosphere and at elevated temperature, e.g. in the range from 70°C to 180°C, or (b) in the presence of an organopalladium catalyst, e.g.
• a compound of formula (I) in which R 1 represents a halogen atom may be converted to a
• a compound of formula (I) in which R 1 represents a halogen atom may be converted to a
• a compound of formula (I) in which R 1 represents a halogen atom may be converted to a
• compounds of formula (I) in which R represents a group, -NHC(0)R may be prepared by reacting compounds of formula (I) in which R ⁇ represents an amino group
• HATU l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3- oxid hexafluorophosphate
• the compounds of formula (I) above may be converted to a pharmaceutically acceptable salt thereof, preferably an acid addition salt such as a formate, hemi-formate, hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate, citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate, oxalate, 1 -hydroxy-2-napthoate
• an acid addition salt such as a formate, hemi-formate, hydrochloride, hydrobromide, benzenesulphonate (besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate, nitrate, phosphate, acetate, fumarate, maleate, tart
• compounds of formula (I) may bear one or, more radiolabels.
• radiolabels may be introduced by using radiolabel-containing reagents in the synthesis of the compounds of formula (I), or may be introduced by coupling the compounds of formula (I) to chelating moieties capable of binding to a radioactive metal atom.
• radiolabeled versions of the compounds may be used, for example, in diagnostic imaging studies.
• any atom specified herein may also be an isotope of said atom.
• hydrogen encompasses H, H and H.
• carbon atoms are to be understood to include 12 C, 13 C and 14 C
• nitrogen atoms are to be understood to include 14 N and N
• oxygen atoms are to be understood to include O, O and O.
• compounds of formula (I) may be isotopically labelled.
• an "isotopically labelled" compound is one in which the abundance of a particular nuclide at a particular atomic position within the molecule is increased above the level at which it occurs in nature.
• Compounds of formula (I) and their salts may be in the form of hydrates or solvates which form an aspect of the present invention. Such solvates may be formed with common organic solvents, including but not limited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.
• Compounds of formula (I) and their salts may be amorphous or in a polymorphic form or a mixture of any of these, each of which forms an aspect of the present invention.
• the compounds of formula (I) and their pharmaceutically acceptable salts have activity as pharmaceuticals and may be used for the treatment of conditions associated with hypoxia inducible factor (HIF) and/or other hypoxia-induced alterations independent of HIF.
• HIF hypoxia inducible factor
• the present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined for use in therapy, in particular for the treatment of conditions associated with hypoxia inducible factor and/or other hypoxia- induced alterations independent of HIF.
• the present invention also provides the use of a compound of formula (I) or a
• the present invention still further provides a method of treating a condition associated with hypoxia inducible factor and/or other hypoxia-induced alterations independent of HIF which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined.
• a method of treating a condition associated with hypoxia inducible factor and/or other hypoxia-induced alterations independent of HIF which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined. Examples of preferred embodiments of the present invention are as described below.
• X represents N; X represents N; X represents C; Y represents CH;
• R 1 represents hydrogen, halogen, C J -CG alkyl, C3-C6 cycloalkyl,
• n 0 or 1 ;
• p O or l ;
• R represents hydrogen, Cj-Cg alkyl (unsubstituted, or substituted by at least one substituent independently selected from halogen, hydroxyl, Cj -Cg haloalkyl, C j -Cg alkoxy,
• C3-C6 cycloalkyl Cg-Cio aryl, 5- to 10-membered heteroaryl, 4- to 7-membered heterocyclyl, each of the aryl, heteroaryl and heterocyclyl groups being optionally substituted with at least one substituent independently selected from halogen, C ⁇ -C ⁇ alkyl,
• R 5 and R 6 may together with the nitrogen atom to which they are attached form a
• R and R each independently represent a hydrogen atom or a Cj-C6 alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and C]-C6 alkoxy;
• R and R each independently represent a hydrogen atom or a C ⁇ -C ⁇ alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and Cj-Cg alkoxy;
• R and R each independently represent a hydrogen atom or a Q-Cg alkyl or C3-C6 cycloalkyl group
• Y represents C or N
• R represents a hydrogen or halogen atom, or a C1-C3 alkyl or amino group; when Y represents N, R is absent;
• R represents a group of formula (II) to (VIII)
• R a represents halogen, cyano, Cj-Cg alkyl, C2-Cg alkenyl, C2-C6 alkynyl or C3-C6
• each of R , R , R and R independently represents hydrogen, halogen, C ⁇ -C ⁇ alkyl, C1-C6 alkoxy, Cj-Cg haloalkyl, C3-C6 cycloalkyl or NR , 3 R 14 , and each R f independently represents halogen, ⁇ -C ⁇ alkyl, Q-Cg alkoxy, C 1-C6 haloalkyl, C3-C6
• R and R each independently represent a hydrogen atom or a Cj-C6 alkyl or C3-C6
• R and R may together with the nitrogen atom to which they are attached form a 4- to 7-membered saturated heterocyclic ring optionally substituted by at least one substituent independently selected from halogen, hydroxyl, oxo and C i ⁇ C6 alkoxy; or a pharmaceutically acceptable salt thereof.
• C1-C4 alkyl C1 -C2 alkylcarbonyl, Ci-C2 alkoxy, cyclopropyl, C1-C4 alkoxycarbonyl, -(CH 2 ) p NR 7 R 8 and C(0)NR 7 R 8 .
• C1-C3 alkyl (unsubstituted, or substituted by one, two or three substituents independently selected from fluorine, hydroxyl, trifluoromethyl, Ci-C 2 alkoxy, cyclopropyl, phenyl, 9 10
• NR R oxetanyl, oxolanyl and oxanyl
• C3-C4 cycloalkyl unsubstituted, or substituted by one or two substituents independently selected from fluorine, cyano and C]-C 2 alkyl
• phenyl or a 4- to 6-membered heterocyclyl (unsubstituted, or substituted by one or two C1-C6 alkyl groups).
• 1 1 12 independently selected from fluorine, hydroxyl, methoxy, cyclopropyl, NR R , phenyl, 5- to 6-membered heteroaryl and 4- to 6-membered heterocyclyl, each of the aryl, heteroaryl and heterocyclyl substituents being optionally substituted with one, two, three, or four substituents independently selected from fluorine, chlorine, oxo, methyl, methoxy, C1-C4 alkoxycarbonyl, and phenyl),
• each of the aryl, heteroaryl and heterocyclyl groups (groups (v), (vi) and (vii) above) being optionally substituted with one, two, three or four substituents independently selected from methyl, methoxy, and C1-C2 alkylcarbonyl.
• R 1 represents NHC(0)R 4 or NR 5 R 6 ;
• E is a nitrogen atom or CR b ;
• R and R each independently represent a hydrogen or fluorine atom
• R and R each independently represent a hydrogen, fluorine or chlorine atom or a methyl group
• R represents a C1-C3 alkyl or C3-C6 cycloalkyl group; and R 5 and R 6 each represent a hydrogen atom.
• a pharmaceutical composition comprising a compound of formula (I) or a
• decompensated heart failure heart failure following a heart attack or peripheral artery disease.
• a method for inhibiting PHD in a patient comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a
• a method for treating acute kidney injury, chronic kidney disease, acute decompensated heart failure, heart failure following a heart attack or peripheral artery disease which comprises administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, as defined in the above [1].
• Prophylaxis is expected to be particularly relevant to the treatment of persons who have suffered a previous episode of, or are otherwise considered to be at increased risk of, the disorder or condition in question.
• Persons at risk of developing a particular disorder or condition generally include those having a family history of the disorder or condition, or those who have been identified by genetic testing or screening to be particularly susceptible to developing the disorder or condition or those in the prodromal phase of a disorder.
• treat include improvement of the conditions described herein.
• the terms “treat”, “treatment” and “treating” include all processes providing slowing, interrupting, arresting, controlling, or stopping of the state or progression of the conditions described herein, but does not necessarily indicate a total elimination of all symptoms or a cure of the condition.
• the terms “treat”, “treatment,” and “treating” are intended to include therapeutic as well as prophylactic treatment of such conditions.
• condition relate to any unhealthy or abnormal state.
• condition associated with hypoxia inducible factor and/or other hypoxia-induced alterations independent of HIF includes conditions, disorders and diseases in which the inhibition of PHD, in particular PHD1, provides a therapeutic benefit, such as hypoxic or ischaemic conditions, examples of which include:
• Cardiovascular and Metabolic disorders stroke; myocardial infarction including acute myocardial infarction; congestive heart failure; atherosclerosis; chronic venous insufficiency; cardiac cirrhosis; diabetes; acute decompensated heart failure; heart failure following a heart attack; peripheral artery disease; and occlusive artery disease;
• Pulmonary disorders chronic obstructive pulmonary disease; pulmonary embolism; mountain sickness; acute repiratory failure; and interstitial lung diseases (ILD) including idiopathic ILD, such as idiopathic pulmonary fibrosis, desquamative interstitial pneumonia, nonspecific interstitial pneumonia, cryptogenic organizing pneumonia, respiratory
• ILD interstitial lung diseases
• bronchiolitis-associated interstitial lung disease acute interstitial pneumonia or lymphoid interstitial pneumonia;
• Kidney disorders acute kidney failure; acute kidney injury; chronic kidney disease; and renal ischaemia reperfusion injury;
• leukaemia chronic myelogenous leukaemia and chronic lymphocytic leukaemia
• breast cancer genitourinary cancer
• skin cancer bone cancer
• prostate cancer liver cancer
• brain cancer cancer of the larynx, gall bladder, rectum, parathyroid, thyroid, adrenal, neural tissue, bladder, head, neck, stomach, bronchi, and kidneys
• basal cell carcinoma squamous cell carcinoma, metastatic skin carcinoma, osteosarcoma, Ewing's sarcoma, veticulum cell sarcoma, and Kaposi's sarcoma
• myeloma giant cell tumour, islet cell tumour, acute and chronic lymphocytic and granulocytic tumours
• hairy-cell tumour adenoma, medullary carcinoma, pheochromocytoma, mucosal neuromas, intestinal ganglioneuromas, hyperplastic corneal nerve tumuor, marfanoid habitus tumuor
• Liver disorders hepatic ischemia reperfusion injury.
• the compound may be useful for preventing or treating, for example, such diseases as cardiac diseases (cardiac hypertrophy, acute heart failure and chronic heart failure including congestive heart failure, cardiomyopathy, angina, myocarditis, arrhythmia, tachycardia, myocardial infarction, etc.), myocardial ischemia, venous insufficiency, post-myocardial infarction transition to heart failure, hypertension, cor pulmonale, arteriosclerosis including atherosclerosis (aneurysm, coronary arterial sclerosis, cerebral arterial sclerosis, peripheral arterial sclerosis, etc.), intervention (percutaneous coronary angioplasty, stent placement, coronary angioscopy, intravascular ultrasound, coronary thrombolytic therapy, etc.)- and heart transplantation-related vascular thickening/occlusion/organ damages, vascular reocclusion/restenosis after bypass surgery, respiratory diseases (cold syndrome, pneumonia, asthma, pulmonary hypertension, pulmonary thrombus/
• cerebrovascular damage e.g., malignant mastocytosis, exogenous obesity, hyperinsulinar obesity, hyperplasmic obesity, hypophyseal adiposity, hypoplasmic obesity, hypothyroid obesity, hypothalamic obesity, symptomatic obesity, infantile obesity, upper body obesity, alimentary obesity, hypogonadal obesity, systemic mastocytosis, simple obesity, central obesity, etc.), hyperphagia, hyperlipidemia, hypercholesterolemia, impaired glucose tolerance, etc.), insulin resistant syndrome, syndrome X, vesceral obesity syndrome, male or female sexual dysfunction, cerebrovascular damage (asymptomatic cerebrovascular damage, transient cerebral ischemia attack, stroke, cerebrovascular dementia, hypertensive
• encephalopathy cerebral infarction, etc.
• cerebral edema cerebral circulatory disturbance
• recurrence and aftereffects of cerebrovascular damages neurological symptoms, mental symptoms, subjective symptoms, impairment of activities of daily living, etc.
• kidney diseases nephritis, glomerulonephritis, glomerulosclerosis, renal failure, thrombotic microangiopathy, diabetic nephropathy, nephrotic syndrome, hypertensive nephrosclerosis, complications of dialysis, organ damage including nephropathy by irradiation, etc.), ocular disorders (glaucoma, ocular hypertension, etc.), thrombosis, multiple organ failure, endothelial dysfunction, other circulatory diseases (ischemic cerebral circulatory disturbance, Raynaud's disease, Buerger's disease, etc.), chronic occlusive pulmonary diseases, interstitial pneumonia, carinii pneumonia, connective tissue disorders (e.g., systemic erythematosus,
• hematological/hematopoietic disorders erythrocytosis, vascular purpura, autoimmune hemolytic anemia, disseminated intravascular coagulation syndrome, multiple myelosis, etc.
• solid tumor tumors (malignant melanoma, malignant lymphoma, digestive organs (e.g., stomach, intestine, etc.) cancers, etc.), cancers and cachexia associated therewith, cancer metastases, endocrine disorders (Addison's disease, Cushing's syndrome,
• pheochromocytoma primary aldosteronism, etc.
• urological/male genital diseases cystitis, prostatic enlargement, prostate cancer, sexually transmitted diseases, etc.
• gynecological disorders menopausal disorders, pregnancy toxemia, endometriosis, uterine fibroid, ovarian diseases, mammary gland diseases, sexually transmitted diseases, etc.
• infectious diseases viral infectious diseases of, for example, cytomegalovirus, influenza virus and herpesvirus, rickettsial infectious diseases, bacterial infectious diseases, etc.
• toxemia septicemia, septic shock, endotoxic shock, gram-negative septicemia, toxin shock syndrome, etc.
• cutaneous diseases keloid, hemangioma, psoriasis, etc.
• the daily dosage of the compound of the invention if inhaled, may be in the range from 0.05 micrograms per kilogram body weight ⁇ g/kg) to 100 micrograms per kilogram body weight ⁇ g/kg).
• the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight ⁇ g/kg) to 100 milligrams per kilogram body weight (mg/kg).
• the compounds of formula (I) and pharmaceutically acceptable salts thereof may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a pharmaceutical composition in which the formula (I) compound/salt (active ingredient) is in association with a
• the present invention further provides a pharmaceutical composition
• a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined, in association with a pharmaceutically acceptable adjuvant, diluent or carrier.
• the present invention still further provides a process for the preparation of a pharmaceutical composition of the invention which comprises mixing a compound of formula (I) or a pharmaceutically acceptable salt thereof as hereinbefore defined with a pharmaceutically acceptable adjuvant, diluent or carrier.
• compositions of the invention are those conventionally employed in the field of pharmaceutical formulation, and include, but are not limited to, sugars, sugar alcohols, starches, ion exchangers, alumina, aluminium stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycerine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulphate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium
• carboxymethylcellulose polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.
• compositions of the present invention may be administered orally, parenterally, by inhalation spray, rectally, nasally, buccally, vaginally or via an implanted reservoir. Oral administration is preferred.
• the pharmaceutical compositions of the invention may contain any conventional non-toxic pharmaceutically acceptable adjuvants, diluents or carriers.
• parenteral as used herein includes subcutaneous,
• the pharmaceutical compositions may be in the form of a sterile injectable preparation, for example, as a sterile injectable aqueous or oleaginous suspension.
• the suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents (such as, for example, Tween 80) and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
• suitable diluents and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural
• oils such as olive oil or castor oil, especially in their
• oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.
• compositions of this invention may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, powders, granules, and aqueous suspensions and solutions. These dosage forms are prepared according to techniques well-known in the art of pharmaceutical formulation. In the case of tablets for oral use, carriers which are commonly used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. For oral administration in a capsule form, useful diluents include lactose and dried corn starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavouring and/or colouring agents may be added.
• compositions of the invention may also be administered in the form of suppositories for rectal administration.
• These compositions can be prepared by mixing the active ingredient with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active ingredient.
• suitable non-irritating excipient include, but are not limited to, cocoa butter, beeswax and polyethylene, glycols.
• compositions of this invention may be administered by nasal aerosol or inhalation.
• Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and/or other solubilising or dispersing agents known in the art.
• the pharmaceutical composition will preferably comprise from 0.05 to 99 %w (per cent by weight), more preferably from 0.05 to 80 %w, still more preferably from 0.10 to 70 %w, and even more preferably from 0.10 to 50 %w, of active ingredient, all percentages by weight being based on total composition.
• the compounds of the invention may also be administered in conjunction with other compounds used for the treatment of the above conditions.
• the invention therefore further relates to combination therapies wherein a compound of the invention or a pharmaceutical composition or formulation comprising a compound of the invention is administered with another therapeutic agent or agents for the treatment of one or more of the conditions previously indicated.
• therapeutic agents may be selected from the following:
• Angiotensin II receptor blockers such as Candesartan, Losartan, Valsartan, Irbesartan, Telmisartan, Olmisartan or Azilsartan;
• Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent within approved dosage ranges.
• Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz or 300 MHz as stated and at 300.3K unless otherwise stated; the chemical shifts ( ⁇ ) are reported in parts per million. Spectra were recorded using a Bruker 400 AVANCE instrument fitted with a 5mm BBFO probe with instrument controlled by Bruker TopSpin 2.1 software, or by a Bruker 400
• Mass spectra were recorded with a Waters SQD single quadrupole mass spectrometer using electrospray ionization.
• Mobile phase consisted of 5 mM ammonium acetate or 0.1% formic acid in water and acetonitrile using Acquity UPLC BEH or HSS CI 8 columns (2.1 mm id x 50 mm long).
• Preparative HPLC was performed using one or more of the following:
• Mobile phases typically consisted of acetonitrile or methanol mixed with water containing either 0.1% formic acid or 0.1% ammonia, unless stated otherwise.
• Rt in the following examples means the temperature ranging from 20°C to 25°C.

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