WO2009071504A1 - 2,6-disubstituted pyridines as soluble guanylate cyclase activators - Google Patents

2,6-disubstituted pyridines as soluble guanylate cyclase activators Download PDF

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Publication number
WO2009071504A1
WO2009071504A1 PCT/EP2008/066514 EP2008066514W WO2009071504A1 WO 2009071504 A1 WO2009071504 A1 WO 2009071504A1 EP 2008066514 W EP2008066514 W EP 2008066514W WO 2009071504 A1 WO2009071504 A1 WO 2009071504A1
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Prior art keywords
methyl
compound
phenyl
formula
trifluoromethyl
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PCT/EP2008/066514
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French (fr)
Inventor
Anne Marie Jeanne Bouillot
Nerina Dodic
Francoise Jeanne Gellibert
Olivier Mirguet
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Smithkline Beecham Corporation
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Priority claimed from GB0723629A external-priority patent/GB0723629D0/en
Priority claimed from GB0813714A external-priority patent/GB0813714D0/en
Priority claimed from GB0816960A external-priority patent/GB0816960D0/en
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Publication of WO2009071504A1 publication Critical patent/WO2009071504A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • 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
    • 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
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Definitions

  • the present invention relates to novel compounds, pharmaceutical compositions containing them, to their use in medicine, and to processes for their preparation.
  • the present invention relates to compounds which, when administered to a patient, activate soluble guanylate cyclase (sGC) and to the use of such compounds for the activation of sGC in patients for a therapeutic effect.
  • sGC soluble guanylate cyclase
  • sGC is a member of a family of related enzymes which share homologous catalytic domains but are activated in different ways.
  • This family includes the adenylate cyclases, a class of membrane bound enzymes that convert ATP to cAMP, which are regulated by G proteins, and the membrane-bound guanylate cyclases that make cyclic guanosine monophosphate (cGMP) in response to hormone signals via an extracellular ligand binding domain.
  • cGMP cyclic guanosine monophosphate
  • the active enzyme contains one heme unit in a heterodimer arrangement, composed of one alpha and one beta- subunit.
  • Several subtypes of subunits have been described, which differ from each other with respect to sequence and tissue-specific distribution.
  • the subtypes alpha-1 and beta- 1 are thought to be mainly expressed in the brain and the lung but have also been shown to be expressed in heart, kidney, liver, skeletal muscle, placenta, colon, uterus, prostate, spleen, pancreas, platelets and isolated blood vessels.
  • Alpha-2 subunits have been detected in the brain, placenta, uterus and pancreas, while beta-2 subunits seem to be expressed in the liver and kidney.
  • the enzyme is thought to be a principal receptor for the ubiquitous signalling molecule, nitric oxide (NO), forming a NO-sGC-cGMP signal transduction axis. It is believed that soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission.
  • NO ubiquitous signalling molecule
  • soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission.
  • cGMP is a critical component involved in the regulation of various (patho)physiological processes, for example in cardiovascular, respiratory, gastrointestinal, urogenital, nervous and immune systems including, neuronal excitability and particularly smooth muscle tone, thereby controlling, among other things, blood pressure, gastro-intestinal motility and genital erection.
  • the novel compounds are activators of sGC and consequently may have application in the treatment of one or more diseases or conditions, which include: cardiovascular diseases and conditions, such as angina (including stable and unstable angina pectoris), low cardiac output, cerebral ischemia, cardiac ischemia, myocardial infarction, coronary reperfusion injury, arterial hypertension (including pulmonary arterial hypertension), congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), heart failure with preserved ejection fraction, acute heart failure syndromes (AHFS), cardiac hypertrophy, acute coronary syndrome, thromboses (including arterial or venous thrombosis), atherosclerosis, peripheral vascular disease, glomerulonephritis, restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement), Raynaud's disease, vascular complications of diabetes or of obesity, stroke, hereditary cerebral haemorrhage, endothelial dysfunction,
  • cardiovascular hypertension including pulmonary arterial hypertension
  • cardiac ischemia myocardial infarction
  • congestive heart failure for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance
  • cardiac hypertrophy acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome and restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement).
  • a particular disease or condition for which the novel compounds may be useful is congestive heart failure. Another particular disease or condition for which the novel compounds may be useful is peripheral vascular disease. Another particular disease or condition for which the novel compounds may be useful is arterial hypertension (also known as systemic hypertension). Another particular disease or condition for which the novel compounds may be useful is pulmonary arterial hypertension. Another particular disease or condition for which the novel compounds may be useful is angina.
  • the present invention provides a compound of formula (I)
  • R 1 and R 2 are independently selected from hydrogen, halo, CF 3 , C 1-4 alkyl and allyl;
  • R 3 represents CF 3 or C 1-4 alkyl; and R 3a represents CF 3 or C 1-4 alkyl;
  • R 4 represents hydrogen or methyl
  • Z is absent or represents (CH 2 ) 2 , O or OCH 2 ;
  • A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; when A represents CH, R 5 is selected from hydrogen, methyl, Ci -4 alkoxy, methoxy-C 2- 3 alkoxy-, chloro or fluoro and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl;
  • R 8 represents hydrogen, chloro, fluoro, CF 3 , C 1- 4 alkyl or C 1-4 alkoxy in a meta or ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents hydrogen or halo; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN, CONR 10 R 11 , CO 2 R 12 or N 3 , wherein R 10 and R 11 are independently selected from hydrogen and C 1-4 alkyl, and R 12 represents hydrogen or C 1-4 alkyl;
  • X may additionally represent
  • R 7 represents CF 3 or methyl.
  • the present invention provides a compound of formula (IA)
  • R 1 and R 2 are independently selected from hydrogen, chloro and fluoro
  • Y represents wherein R 3 represents CF 3 or C 1-4 alkyl; and R 3a represents CF 3 or C 1-4 alkyl;
  • R 4 represents hydrogen or methyl
  • Z is absent or represents (CH 2 ) 2 , O or OCH 2 ;
  • a and E both represent CH; or one of A and E represents CH and the other represents N; when A represents CH, R 5 is selected from hydrogen, methyl, C 1-4 alkoxy, methoxy- C 2-3 -alkoxy-, chloro or fluoro and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl;
  • R 8 represents hydrogen, chloro, fluoro, C 1-4 alkyl or C 1- 4 alkoxy in a meta or ortho position relative to the R 9 substituent; or when E represents N, R 8 represents hydrogen; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1- 4 alkoxy, CN, CONR 10 R 11 , CO 2 R 12 or N 3 , wherein R 10 and R 11 are independently selected from hydrogen and C 1-4 alkyl, and R 12 represents hydrogen or C 1-4 alkyl;
  • X may additionally represent wherein R 7 represents CF 3 or methyl.
  • R 1 and R 2 are independently selected from hydrogen, halo, CF 3 , C 1-4 alkyl and allyl;
  • R 3 represents CF 3 or C 1-4 alkyl; and R 3a represents CF 3 or C 1-4 alkyl;
  • R 4 represents hydrogen or methyl
  • Z is absent or represents (CH 2 ) 2 , O or OCH 2 ;
  • A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; when A represents CH, R 5 is selected from hydrogen, methyl, C 1-4 alkoxy, methoxy-C 2-3 - alkoxy-, chloro or fluoro and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl;
  • R 8 represents hydrogen, chloro, fluoro, CF 3 , Ci- 4 alkyl or Ci -4 alkoxy in a meta or ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents hydrogen or halo; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C ⁇ alkyl, Ci -4 alkoxy, CN, CONR 10 R 11 , CO 2 R 12 or N 3 , wherein R 10 and R 11 are independently selected from hydrogen and Ci -4 alkyl, and R 12 represents hydrogen or Ci -4 alkyl;
  • X may additionally represent wherein R 7 represents CF 3 or methyl.
  • alkyl refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms.
  • C 1-4 alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms.
  • alkyl as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.
  • alkoxy refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example, means a straight or branched alkoxy group containing at least 1 , and at most 4, carbon atoms.
  • alkoxy as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2- oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, or 2-methylprop-2-oxy.
  • halo refers to the elements fluorine, chlorine, bromine and iodine. In an embodiment halo represents bromine, fluorine and chlorine. In a further embodiment halo represents fluorine and chlorine.
  • a methoxy-C 2- 3alkoxy- group represents a group MeO (C H 2 ) 2 -30- i.e. where the C 2 -3alkoxy component is straight-chained.
  • Suitable examples include methoxy- ethoxy- or methoxy-n-propoxy-.
  • R 3 represents CF 3 or methyl; and R 3a represents methyl; when A represents CH, R 5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl; X is as defined above, wherein R 7 represents
  • R 8 represents hydrogen, methyl, methoxy, ethoxy, CF 3 or chloro; or when one of J and L represents N, R 8 represents hydrogen or chloro; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , Ci -4 alkyl,
  • a compound of formula (I) as defined above or a salt thereof wherein A, E, Z, R 1 , R 2 and R 4 are as defined above for formula (IA); Y is as defined above, in which R 3 represents CF 3 or methyl; and R 3a represents methyl; when A represents CH, R 5 is selected from hydrogen, methyl, methoxy, propyloxy, isobutyloxy or methoxyethoxy and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl; X is as defined above, wherein R 7 represents CF 3 or methyl; R 8 represents hydrogen or chloro; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , Ci -4 -alkyl, CN, CONR 10 R 11 , CO 2 R 12 or N 3 , wherein R 10 and R 11 are independently selected from hydrogen and C 1-4 -alkyl, and R 12 represents hydrogen or C
  • a compound of formula (I) as defined above or a salt thereof wherein A, J, L, Z, R 1 , R 2 and R 4 are as defined above for formula (I) or formula (IB); Y is as defined above, in which R 3 represents CF 3 or methyl; and R 3a represents methyl; when A represents CH, R 5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl; X is as defined above, wherein R 7 represents CF 3 or methyl; when both J and L represent CH, R 8 represents hydrogen, methyl, methoxy, ethoxy, CF 3 or chloro; or when one of J and L represents N, R 8 represents hydrogen or chloro; and R 9 represents hydrogen, halo, CF 3 , OCF
  • R 3 represents CF 3 or methyl; and R 3a represents methyl; when A represents CH, R 5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R 6 represents hydrogen; or when A represents N, R 5 and R 6 each represent hydrogen or one of R 5 and R 6 represents hydrogen and the other represents methyl; X is as defined above, wherein R 7 represents
  • R 8 represents hydrogen, methyl, methoxy, ethoxy, CF 3 or chloro; or when one of J and L represents N, R 8 represents hydrogen or chloro; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy or
  • pharmaceutically acceptable means a compound which is suitable for pharmaceutical use.
  • A represents CH. In an embodiment A and E both represent CH. In an embodiment one of A and E represent CH and the other represents N.
  • R 1 is in a para position relative to the -OCH 2 - linker.
  • R 2 is in an ortho position relative to the -OCH 2 - linker.
  • R 1 is in a para position relative to the -OCH 2 - linker and R 2 is in an ortho position relative to the -OCH 2 - linker.
  • R 1 is in an ortho position relative to the bond linking to the pyridine ring.
  • R 2 is in a meta position relative to the -OCH 2 - linker.
  • R 1 and R 2 do not both represent C 2-4 alkyl or allyl.
  • R 1 and R 2 represents or allyl
  • the other represents hydrogen
  • R 1 and R 2 each represent hydrogen. In an embodiment R 1 and R 2 each represent fluoro, in a further embodiment with R 1 in a para position relative to the - OCH 2 - linker and R 2 in an ortho position relative to the -OCH 2 - linker. In an embodiment R 1 represents chloro or fluoro and R 2 represents hydrogen, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker, and in a yet further embodiment with R 1 in an ortho position relative to the bond linking to the pyridine ring.
  • R 2 represents chloro or fluoro and R 1 represents hydrogen, in a further embodiment with R 2 in a meta position relative to the -OCH 2 - linker.
  • R 1 represents C 1-4 alkyl and R 2 represents hydrogen, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker.
  • R 1 represents methyl and R 2 represents hydrogen, in a further embodiment with R 1 in a para position relative to the -OCH 2 - linker.
  • R 1 represents hydrogen and R 2 represents C 1-4 alkyl, in a further embodiment with R 2 in an ortho position relative to the - OCH 2 - linker.
  • R 1 represents hydrogen and R 2 represents n-propyl, in a further embodiment with R 2 in an ortho position relative to the -OCH 2 - linker.
  • R 1 represents hydrogen and R 2 represents allyl, in a further embodiment with R 2 in an ortho position relative to the -OCH 2 - linker.
  • R 1 represents CF 3 and R 2 represents hydrogen, in a further embodiment with R 2 in an ortho position relative to the -OCH 2 - linker.
  • R 3 represents methyl or CF 3 . In a further embodiment R 3 represents CF 3 . In an embodiment R 3a represents methyl or CF 3 . In a further embodiment R 3a represents methyl.
  • R 4 represents hydrogen. In a further embodiment R 4 represents methyl.
  • Z is O and R 4 is hydrogen.
  • Z is CH 2 CH 2 and R 4 is hydrogen.
  • Y represents the pyrazole group defined above and R 4 is hydrogen or methyl.
  • Y represents the piperidine group defined above and R 4 is hydrogen.
  • Y represents the pyrrole group defined above and R 4 is hydrogen.
  • Y represents the phenyl group defined above and R 4 is hydrogen.
  • Y represents wherein R 3 represents CF 3 or methyl.
  • Y represents wherein R 3 represents CF 3 .
  • Z is absent or represents O or CH 2 CH 2 . In an embodiment Z is absent or represents O. In an embodiment Z is absent. In an embodiment Z represents O.
  • R 5 represents hydrogen or methyl and R 6 represents hydrogen.
  • R 5 when A represents CH, R 5 represents hydrogen, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy, methoxyethoxy, fluoro or chloro. In an embodiment, when A represents CH, R 5 represents hydrogen, methyl, methoxy, fluoro or chloro. In an embodiment, when A represents CH, R 5 represents hydrogen, methyl, methoxy or fluoro.
  • R 5 and R 6 both represent hydrogen.
  • R 9 represents hydrogen, halo, CF 3 , OCF 3 , CN or N 3 . In a further embodiment R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1- 4 alkoxy or CN.
  • X represents wherein R 7 represents methyl.
  • J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R 8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF 3 in a meta position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents hydrogen or halo in a meta position relative to the R 9 substituent; or when both J and L represent CH, R 8 represents methyl, methoxy, CF 3 or halo in an ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents halo in an ortho position relative to the R 9 substituent; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , Ci -4 alkyl, Ci -4 alkoxy, CN, CONR 10 R 11 , CO 2 R 12 , or N 3 , wherein R 10 and R 11 each independently represent hydrogen or C 1-4 alkyl, and R 12 represents hydrogen or C 1-4 alkyl.
  • J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R 8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF 3 in a meta position relative to the R 9 substituent; or when one of J and L represents
  • R 8 represents hydrogen or halo in a meta position relative to the R 9 substituent; or when both J and L represent CH, R 8 represents methyl, methoxy, CF 3 or halo in an ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents halo in an ortho position relative to the R 9 substituent; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , Ci -4 alkoxy, CN, or N 3 .
  • J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R 8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF 3 in a meta position relative to the R 9 substituent; or when one of J and L represents
  • R 8 represents hydrogen or halo in a meta position relative to the R 9 substituent; or when both J and L represent CH, R 8 represents methyl, methoxy, CF 3 or halo in an ortho position relative to the R 9 substituent; or when one of J and L represents N, R 8 represents halo in an ortho position relative to the R 9 substituent; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C ⁇ alkyl, Ci -4 alkoxy, CN, CONR 10 R 11 or N 3 , wherein R 10 and R 11 each independently represent hydrogen or Ci -4 alkyl.
  • X represents
  • E represents CH or N; when E represents CH, R 8 represents hydrogen or methyl in a meta position relative to the R 9 substituent or halo in an ortho position relative to the R 9 substituent; or when E represents N, R 8 represents hydrogen; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN, CONR 10 R 11 , CO 2 R 12 , or N 3 , wherein R 10 and R 11 each independently represent hydrogen or C 1-4 alkyl, and R 12 represents hydrogen or C 1-4 alkyl.
  • X is as defined above wherein E represents CH or N; when E represents CH, R 8 represents hydrogen or methyl in a meta position relative to the R 9 substituent or halo in an ortho position relative to the R 9 substituent; or when E represents N, R 8 represents hydrogen; and R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1- 4 alkyl, C 1-4 alkoxy, CN or N 3 .
  • R 8 represents hydrogen or, when E represents CH, R 8 represents chloro or fluoro in an ortho position relative to the R 9 substituent.
  • E represents CH when E represents CH, R 8 represents chloro in an ortho position relative to the R 9 substituent.
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN, CO 2 H, CONH 2 or N 3 .
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN or N 3 .
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , t-butyl, methoxy, CN, CO 2 H, CONH 2 or N 3 .
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , t-butyl, methoxy, CN or N 3 .
  • R 8 represents hydrogen and R 9 is as defined in each of the above embodiments.
  • E represents CH each of R 8 and R 9 represent halo, suitably chloro or fluoro, with R 8 being in an ortho position relative to the R 9 substituent.
  • E represents CH each of R 8 and R 9 represent chloro, with R 8 being in an ortho position relative to the R 9 substituent.
  • J and L each represent CH.
  • R 8 represents hydrogen.
  • J and L both represent CH and R 8 represents methyl, methoxy, CF 3 , chloro or fluoro in an ortho position relative to the R 9 substituent.
  • one of J and L represents CH and the other represents N and R 8 represents chloro or fluoro in an ortho position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, methoxy, ethoxy, CF 3 , chloro or fluoro in a meta position relative to the R 9 substituent.
  • one of J and L represents CH and the other represents N and R 8 represents chloro or fluoro in a meta position relative to the R 9 substituent.
  • R 8 represents chloro in an ortho position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, methoxy, ethoxy, CF 3 or chloro in a meta position relative to the R 9 substituent.
  • one of J and L represents CH and the other represents N and R 8 represents chloro in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl in a meta position relative to the R 9 substituent.
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , CN, CONH 2 or N 3 .
  • R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN or N 3 . In an embodiment R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , t-butyl, methoxy, CN, CONH 2 or N 3 . In an embodiment R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , t-butyl, methoxy, CN or N 3 . In an embodiment R 9 represents hydrogen, chloro, fluoro, CF 3 , OCF 3 , t-butyl, methoxy or CN. In an embodiment R 9 represents OCF 3 or CN.
  • R 8 represents hydrogen and R 9 is as defined in each of the above embodiments.
  • J and L both represent CH and each of R 8 and R 9 represent methoxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • J and L both represent CH and each of R 8 and R 9 represent methoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, and R 9 represents halo, suitably fluoro or chloro, or methoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, and R 9 represents fluoro or methoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, and R 9 represents Ci- 4 alkoxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents methyl, and R 9 represents isopropyloxy or ethoxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • R 8 represents chloro, and R 9 represents C 1-4 alkoxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • R 8 represents chloro, and R 9 represents methoxy, ethoxy or isopropyloxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • R 8 represents chloro, and R 9 represents C 1-4 alkoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • R 8 represents chloro, and R 9 represents methoxy, ethoxy or isopropyloxy, with R 8 being in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents CF 3 and R 9 represents C 1-4 alkoxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents CF 3 and R 9 represents methoxy, ethoxy or isopropyloxy, with R 8 being in an ortho position relative to the R 9 substituent.
  • CH and R 8 represents CF 3 and R 9 represents halo or Ci -4 alkoxy, with R 8 being in a meta position relative to the R 9 substituent.
  • CH and R 8 represents CF 3 and R 9 represents chloro, methoxy, ethoxy or isopropyloxy, with R 8 being in a meta position relative to the R 9 substituent.
  • J and L both represent CH and R 8 represents CF 3 and R 9 represents chloro or methoxy with R 8 being in a meta position relative to the R 9 substituent.
  • J represents N and L represents CH; R 8 represents halo; and R 9 represents CF 3 , C 1-4 alkoxy, halo or CN.
  • J represents N and L represents CH; R 8 represents chloro or fluoro; and R 9 represents CF 3 , Ci -4 alkoxy, halo or CN.
  • J represents N and L represents CH; R 8 represents chloro; and R 9 represents CF 3 , C 1-4 alkoxy, halo or CN.
  • J represents N and L represents CH; R 8 represents chloro; and R 9 represents CF 3 .
  • J represents CH and L represents N; R 8 represents hydrogen; and R ,9 ! represents CF 3 , Ci -4 alkoxy, halo or CN.
  • J represents CH and L represents N; R 8 represents hydrogen; and R 9 represents C 1-4 alkoxy.
  • J represents CH and L represents N; R 8 represents hydrogen; and R 9 represents methoxy.
  • E represents N; R 8 represents H and R 9 represents CF 3 , C 1-4 alkoxy, halo or CN. In an embodiment E represents N; R 8 represents H and R 9 represents CF 3 , methoxy, chloro, fluoro or CN.
  • J and L each represent CH and R 8 represents hydrogen, methyl, methoxy, ethoxy, CF 3 or chloro. In another embodiment one of J and L represents N and the other represents CH and R 8 represents hydrogen or chloro.
  • Z represents CH 2 CH 2 and each of R 8 and R 9 represent hydrogen.
  • R 9 represents CONR 10 R 11 wherein R 10 and R 11 are independently selected from hydrogen and methyl.
  • R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy, CN, or N 3 .
  • R 9 represents hydrogen, halo, CF 3 , OCF 3 , C 1-4 alkyl, C 1-4 alkoxy or CN.
  • a compound of formula (I) as defined above selected from: 1-[6-(5-fluoro-2-(4-(4-methoxyphenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
  • a compound of formula (I) as defined above selected from: 1-[6-(3,5-difluoro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2- yl]-piperidine-4-carboxylic acid;
  • a compound of formula (I) as defined above selected from: 1-[6-(2-(2-methyl-4-(4-methoxy-3-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
  • a compound of formula (I) as defined above selected from: 1-[6-(2-(2-methoxy-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
  • 4-carboxylic acid or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
  • a compound of formula (I) as defined above selected from: 1 -[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
  • a compound of formula (I) as defined above selected from: 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;
  • a compound of formula (I) as defined above selected from: 1 -[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
  • a compound of formula (I) as defined above selected from: 1-[6-(3-(propen-2-yl)-2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- ⁇ -trifluoromethyl-pyrazole ⁇ -carboxylic acid;
  • the compound of formula (I) will include a chiral centre at the carbon atom bearing that substituent. Separation of the individual enatiomers of the relevant compounds (e.g. from racemic mixtures produced) may be carried out by standard methods well-known to the person skilled in the art, for example by chiral chromatography.
  • Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable.
  • salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
  • Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention.
  • the term "solvate” refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent.
  • solute in this invention, a compound of formula (I) or a salt thereof
  • solvents for the purpose of the invention may not interfere with the biological activity of the solute.
  • suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid.
  • the solvent used is a pharmaceutically acceptable solvent.
  • suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid.
  • the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
  • the salts of the compounds of formula (I) will be pharmaceutically acceptable.
  • the invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).
  • a salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
  • Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts and will be apparent to those skilled in the art.
  • a pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid; or with a suitable organic acid such as succinic, maleic, malic, mandelic, formic, acetic, propionic, hexanoic, fumaric, glutamic, lactic, citric, tartaric, benzoic, salicylic, aspartic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acid.
  • a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid
  • a pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, including salts of primary, secondary and tertiary amines, such as ammonia, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N- methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine.
  • a suitable inorganic or organic base including salts of primary, secondary and tertiary amines, such as ammonia, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N- methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine.
  • suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of the carboxylic acid moiety that is present in the compound of formula (I). Since the compounds of formula (I) include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts (including zwitterionic salts), which salts are also included within the scope of the present invention.
  • the carboxylic acid function attached to the group Y may be a suitable candidate for pro-drug functionality, for example by formation of appropriate esters or amides.
  • certain moieties known to those skilled in the art as “pro-moieties”, for example as described by H. Bundgaard in "Design of Prodrugs” (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I).
  • a compound of formula (I) (whether in solvated or unsolvated form) or a pharmaceutically acceptable salt thereof (whether in solvated or unsolvated form) defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "a compound of the invention".
  • the invention also includes all suitable isotopic variations of a compound of the invention.
  • An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature.
  • isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2 H, 3 H, 13 C, 14 C, 15 N, 17 0, 18 0, 31 P, 32 P, 35 S, 18 F and 36 CI, respectively.
  • isotopic variations of a compound of the invention are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3 H, and carbon-14, i.e., 14 C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
  • a compound of the invention as an activator of sGC, may be useful in the treatment of a disease or condition which is mediated by sGC activity.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of the invention, together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the carrier(s), diluent(s) and/or excipient(s) must each be "acceptable” in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
  • a pharmaceutical composition comprising a) 0.1 mg to 1000 mg of a compound of the invention and b) 0.1g to 2g of one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • a pharmaceutical composition comprising 1-[6-(2-(4- (4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • composition comprising 1-[6- (2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
  • the invention provides a compound of the invention as defined above for use in therapy; in an embodiment the therapy is human therapy.
  • the invention provides a pharmaceutical composition as defined above for use in therapy; in an embodiment the therapy is human therapy.
  • the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of a disease or condition mediated by sGC activity.
  • the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
  • the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for treating a disease or condition mediated by sGC activity.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
  • the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
  • the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC, in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis, comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition as defined above.
  • sGC in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis
  • the invention provides a method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition comprising a compound of the invention.
  • a compound of the invention may also be used in combination with other therapeutic agents.
  • the invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
  • each compound may differ from that when the compound is used alone.
  • the compounds of the present invention may for example be used in combination with antihypertensive drugs such as diuretics (for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone), ACE inhibitors
  • diuretics for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone
  • ACE inhibitors for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone
  • angiotensin receptor blockers such as candesartan, irbesartan, losartan, telmisartan, valsartan
  • calcium channel inhibitors such as amlodipine, felodipine, isradapine, nifedipine, niimodipine, nitrendipine, diltiazem, verapamil
  • ⁇ -adrenergic receptor antagonists such as doxazosin, prazosin, terazosin, phentolamine, indoramin, phenoxybenzamine, tolazoline
  • ⁇ -adrenergic receptor antagonists such as atenolol, metoprolol, nadolol, oxpren
  • compositions comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention.
  • the individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
  • either the compound of the invention or the second therapeutic agent may be administered first.
  • the combination may be administered either in the same or different pharmaceutical composition.
  • the two compounds When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
  • references herein to "treat”, “treating” or “treatment” extend to prevention of recurrence of symptoms (whether mild, moderate or severe) and to suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
  • the compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
  • the compound of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with one or more standard pharmaceutical excipients, carriers or diluents, according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.
  • compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.
  • the compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
  • the formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • suitable conventional carriers such as cream or ointment bases and ethanol or oleyl alcohol for lotions.
  • Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
  • Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate.
  • the tablets may be coated according to methods well known in normal pharmaceutical practice.
  • Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use.
  • Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
  • suspending agents for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate
  • Suppositories typically contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
  • fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred.
  • the compound depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle.
  • the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.
  • agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle.
  • the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use.
  • Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration.
  • the compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle.
  • a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
  • compositions of the invention may be formulated, for administration to mammals including humans, by any route, and include those in a form adapted for oral, topical or parenteral administration.
  • the compositions may, for example, be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
  • the invention provides a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.
  • a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.
  • compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
  • the optimal quantity and spacing of individual doses of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
  • Each dosage unit for oral administration typically contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the compound of formula (I).
  • a compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 1000 mg, for example between 1 mg and 500 mg, e.g. between 5 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of formula (I) or a salt thereof calculated as the compound of formula (I), the compound of the invention being administered 1 to 4 times per day, for example 1 to 2 times a day.
  • a compound of the invention may be administered once a day.
  • a compound of the invention will be administered for a period of continuous therapy, for example for a week or more.
  • the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each suitably provided in substantially pure form, for example at least 60% pure, for example at least 75% pure, for example at least 85%, for example at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds typically contain at least 1 %, for example at least 5%, for example from 10 to 59% of a compound of the invention.
  • a compound of the invention may be prepared in a variety of ways. These processes form further aspects of the present invention.
  • step (i) the intermediate compounds of formula (II) can be prepared according to the processes set out in Schemes 2 to 5.
  • Ethyl isonipecotate is commercially available (from Aldrich).
  • the compound of formula (lie) can also be prepared in a solvent such as acetone, CH 3 CN or THF in the presence of a base such as Na 2 CO 3 , K 2 CO 3 or Cs 2 CO 3 , under reflux.
  • step (ii) the intermediate compounds of formula (III) can be prepared according to the processes set out in Schemes 6 and 7.
  • 2-hydroxyphenyl boronic acid is commercially available (from Aldrich) as is 5-fluoro-2- hydroxyphenyl boronic acid (from Apollo or Combi Blocks).
  • the compounds of formula (NIb) can be prepared from the boronic acids of formula (VIIb); these are either commercially available or can be prepared by standard methods well- known to the person skilled in the art.
  • Compounds of formula (VIIb) where R 1 is ethyl, propyl or allyl in a para position relative to the -OCH 2 - linker and R 2 is hydrogen may be prepared from the corresponding 4-ethyl, 4-propyl or 4-allyl-anisole by (i) bromination in the position ortho to the methoxy group and (ii) conversion of the bromine to a boronic acid group by standard methods (for example, as described in WO2005019151 : bromination p142 and conversion of bromine to boronic acid pp365, 373 or 419).
  • step (iii) the following two general synthetic schemes can be used (Schemes 88 aanndd 99)),, eexxcceepptt iinn tthhee ccaassee ooff ccoommppoouunnddss wwhheerrein both Y represents pyrrole and R 9 represents CN (for which see Schemes 13 and 14).
  • the subsequent step (iv) may be carried out according to Scheme 11.
  • the temperature used in this ester hydrolysis reaction will depend on the nature of the compound and the length of time for which the reaction is performed; this will be well appreciated by the person skilled in the art.
  • ester hydrolysis reaction is instead suitably carried out using LiOH at room temperature to avoid hydrolysis of the cyano group to an amide group.
  • Scheme 13a is particularly suitable to prepare compounds wherein J represents CH and L represents CH or N , and Z is absent.
  • Scheme 13b is particularly suitable to prepare compounds wherein J represents N and L represents CH , and Z is absent.
  • Scheme 14 is particularly suitable to prepare compounds wherein Z is absent or Z represents O, OCH 2 or CH 2 CH 2 .
  • hal' may represent chloro or bromo where such compounds are commercially available. If the compound is not commercially available, then hal' will represent bromo and the compound may be prepared by standard methods. 2-chloro-5-chloromethylpyridine and 4- bromo-2-fluoro-benzyl bromide are both commercially available (from Aldrich). Other compounds of formula (IX) may generally be prepared by the following methods (Schemes Schemes 15, 16, 17 and 18) or by other standard methods well-known to the person skilled in the art.
  • Scheme 19 is particularly suitable for compounds wherein one of A , J or L represents N.
  • Pathway A is thus typically used where A represents N or L represents N; and pathway B is typically used where J represents N.
  • Compounds of formula (X) are either commercially available or can be prepared by standard methods well-known to the person skilled in the art.
  • 2-methoxypyridine-5-boronic acid is available from Aldrich and 2-cyanopyridine-5- boronic acid and 2-trifluoromethylpyridine-5-boronic acid are available from Frontier.
  • Certain compounds of formula (XVII) are commercially available, for example: wherein J represents N, R 8 represents H and R 9 represents CN, CF 3 , COOR 12 , Cl or OMe (Aldrich, Fluka or Acros); wherein J represents N, R 8 represents Cl and R 9 represents CF 3 (Aldrich).
  • Other compounds of formula (XVII) may be prepared by standard methods well- known to the person skilled in the art.
  • Pathway B is also typically used where J and L both represent CH where hal represents Br.
  • Scheme 20a is particularly suitable.
  • Scheme 20b is particularly suitable.
  • Scheme 20c is particularly suitable.
  • Pathway A is thus typically used for J represents N and/or R 9 represents CN, COOR 12 and/or R 5 represents H, Me, OMe.
  • Pathway B is thus typically used for A represents N or for A represents CH and hal represents F and R 5 represents H, Me, or OMe.
  • Phenol derivatives of formula (XXI) are commercially available or may be prepared by standard methods well-known to the person skilled in the art.
  • R 5 represents Cl or F:
  • R 8 represents Cl
  • R 9 represents CF 3 (Aldrich); wherein J represents CH, hal represents F, R 8 represents H, F, Cl, OMe, Me, or CF 3 , and R 9 represents CN or COOR 12
  • R 5 represents OC 1-4 alkyl or O(CH 2 ) 2 - 3 OMe: as in pathway B Scheme 21
  • MS mass spectra
  • Example 1 1 -[6-(2-(4-phenethyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid
  • Example 10 1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- ylJbenzyloxyJ-phenylJpyridin ⁇ -y ⁇ -S-trifluoromethyl-pyrazole ⁇ -carboxylic acid
  • Example 168 1 -[6-( 2-(4-(4-carboxamidophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- methyl-pyrazole-4-carboxylic acid as a white solid (0.08g)
  • Example 170 1 -[6-(2-(2-methyl-4-(5-carboxamidopyridin-2-yl)benzyloxy)- phenylJpyridin ⁇ -ylJ-S-trifluoromethyl-pyrazole ⁇ -carboxylic acid
  • Example 172 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
  • Example 173 1-[6-( 5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- yl)benzyloxy)-phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
  • Example 175 1 -[6-( 2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid
  • Example 178 1 -[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid
  • Example 179 1-[6-(3,5-difluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
  • Example 180 1-[6-(5-fluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)benzyloxy)- phenylJpyridin ⁇ -ylJ-S-trifluoromethyl-pyrrazole ⁇ -carboxylic acid
  • Example 179 Similarly prepared as for Example 179 from ethyl 1-(6-(5-fluoro-2-(2-methyl-4- bromobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D66c, 0.5g, 0.86mmol) and 4-trifluoromethylphenylboronic acid (0.213g, 1.12mmol).
  • Example 181 1 -[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
  • Example 182 1 -[6-(2-(2-methyl-4-(3,4-dimethoxyphenyl)benzyloxy)-phenyl)pyridin- 2-yl]-5-trifluoromethyl-pyrrazole-4-carboxylic acid
  • Example 187 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)benzyloxy)-phenyl)pyridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid
  • Example 188 1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl-phenyl)benzyloxy)- phenylJpyridin ⁇ -ylJ-S-trifluoromethyl-pyrazole ⁇ -carboxylic acid
  • sGC soluble guanylate cyclase
  • FP fluorescence polarisation
  • Compounds are incubated with human sGC, anti-cGMP antibody, the GTP substrate and fluorescently labelled cGMP. After a period of one hour the assay is stopped with the addition of EDTA and after a further hour the assay is read.
  • Human sGC is thawed and resuspended in assay buffer (10OmM TRIS, 1 OmM MgCI 2 , 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give a final concentration of 1 nM in the well.
  • assay buffer (10OmM TRIS, 1 OmM MgCI 2 , 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give a final concentration of 1 nM in the well.
  • a substrate solution is prepared containing GTP and 8- fluo-cGMP in de-ionized water to a final concentration of 25 ⁇ M and 5OnM respectively.
  • Assay plates containing 5 ⁇ l_ of various test compounds and of a standard agonist (50 ⁇ M - 5OnM) in 1 % DMSO as 6 point, four fold dilutions across a 96 well plate are used in the assay.
  • the plate also contains 6 wells of DMSO (1%) to produce high control and a cGMP standard curve (14nM to 10 ⁇ M) to convert FP data to cGMP concentration.
  • 25 ⁇ l_ of enzyme mix and 20 ⁇ l of substrate mix described above are added to each well of the plate.
  • Samples are mixed on an orbital shaker and then incubated at room temperature for 1 hour. After this incubation period 5 ⁇ l of 0.5M EDTA is added to all wells and the plates are incubated for a further hour at room temperature prior to reading the FP signal in an appropriate reader.
  • FP data are converted to cGMP concentrations and then fitted using ActivityBase software.
  • the activity of a test compound is determined as the pEC500 value which is the concentration able to increase by 5-fold basal cGMP.
  • Examples 1 to 191 were tested in the assay described above and each gave pEC500 values of greater than 5.0.
  • a compound of the invention gives a pEC500 value of ⁇ 6.0 when tested in the assay described above.
  • a compound of the invention gives a pEC500 value of ⁇ 7.0 when tested in the assay described above

Abstract

Disclosed are compounds of formula (I) wherein R1 and R2 are independently selected from hydrogen, halo, CF3, C1-4alkyl and allyl; Y represents (II), (III), (IV) or (V) wherein R3 represents CF3 or C1-4alkyl; and R3a represents CF3 or C1-4alkyl.

Description

COMPOUNDS
The present invention relates to novel compounds, pharmaceutical compositions containing them, to their use in medicine, and to processes for their preparation. In particular the present invention relates to compounds which, when administered to a patient, activate soluble guanylate cyclase (sGC) and to the use of such compounds for the activation of sGC in patients for a therapeutic effect.
sGC is a member of a family of related enzymes which share homologous catalytic domains but are activated in different ways. This family includes the adenylate cyclases, a class of membrane bound enzymes that convert ATP to cAMP, which are regulated by G proteins, and the membrane-bound guanylate cyclases that make cyclic guanosine monophosphate (cGMP) in response to hormone signals via an extracellular ligand binding domain.
Whilst not wishing to be bound by theory, it is considered that the active enzyme contains one heme unit in a heterodimer arrangement, composed of one alpha and one beta- subunit. Several subtypes of subunits have been described, which differ from each other with respect to sequence and tissue-specific distribution. The subtypes alpha-1 and beta- 1 are thought to be mainly expressed in the brain and the lung but have also been shown to be expressed in heart, kidney, liver, skeletal muscle, placenta, colon, uterus, prostate, spleen, pancreas, platelets and isolated blood vessels. Alpha-2 subunits have been detected in the brain, placenta, uterus and pancreas, while beta-2 subunits seem to be expressed in the liver and kidney.
The enzyme is thought to be a principal receptor for the ubiquitous signalling molecule, nitric oxide (NO), forming a NO-sGC-cGMP signal transduction axis. It is believed that soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission. It has been suggested that cGMP is a critical component involved in the regulation of various (patho)physiological processes, for example in cardiovascular, respiratory, gastrointestinal, urogenital, nervous and immune systems including, neuronal excitability and particularly smooth muscle tone, thereby controlling, among other things, blood pressure, gastro-intestinal motility and genital erection.
Due to its ubiquitous nature, activation of this enzyme is likely to have significant pathological implications. This is particularly true of the cardiovascular system in which dysfunction of NO-sGC-cGMP signalling is thought to be involved in diseases and conditions such as atherosclerosis, stroke and sepsis. Thus, novel drugs based on selective activation of the enzyme have the potential for therapeutic benefit. For a review of NO-independent activation of sGC see Oleg V. Evgenov et al.; Nature Reviews, Vol. 5, September 2006, pp755-768. Reference is made therein to the compounds BAY 58-2667 (see also WO01/19780) and HMR-1766 (see also WO00/02851 ) as sGC activators. The following more recent article discusses BAY 58- 2667 in the context of treatment of congestive heart failure: Hypertension, 2007, 49, 1128- 1133.
The novel compounds are activators of sGC and consequently may have application in the treatment of one or more diseases or conditions, which include: cardiovascular diseases and conditions, such as angina (including stable and unstable angina pectoris), low cardiac output, cerebral ischemia, cardiac ischemia, myocardial infarction, coronary reperfusion injury, arterial hypertension (including pulmonary arterial hypertension), congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), heart failure with preserved ejection fraction, acute heart failure syndromes (AHFS), cardiac hypertrophy, acute coronary syndrome, thromboses (including arterial or venous thrombosis), atherosclerosis, peripheral vascular disease, glomerulonephritis, restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement), Raynaud's disease, vascular complications of diabetes or of obesity, stroke, hereditary cerebral haemorrhage, endothelial dysfunction, and other inflammatory cardiovascular disorders; erectile dysfunction; female sexual arousal disorder, respiratory failure, acute respiratory distress syndrome, gall bladder dysfunction, sickle cell disease, osteoporosis, inflammation, wound healing, chronic kidney insufficiency, renal fibrosis, renal failure, glomerulonephritis, chronic renal disease, cardiorenal syndrome, hepatorenal syndrome, liver cirrhosis, diabetes, metabolic syndrome, male pattern baldness; neuro-function disorders (including diseases or conditions displaying neuroinflammation pathology and neurodegenerative diseases, particularly chronic neurodegenerative conditions) such as Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, corticobasal degeneration, frontotemporal dementia, diffuse Lewis body type of Alzheimer's disease, and apoptotic insults caused by beta-amyloid treatment, epilepsy; pain of neuropathic origin including neuralgias, Parkinson's disease, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, guam Parkinsonism-dementia complex, progressive supranuclear palsy, pugilistic encephalitis, Pick's disease, Huntingdon's disease, AIDS-associated dementia; multiple sclerosis, amyotrophic lateral sclerosis; sleep disorders (including narcolepsy and sleep deficits associated with Parkinson's disease), and ALS (motor neuron disease).
Thus representative diseases and conditions for which the novel compounds may be useful include arterial hypertension (including pulmonary arterial hypertension), angina, cardiac ischemia, myocardial infarction, congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome and restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement).
A particular disease or condition for which the novel compounds may be useful is congestive heart failure. Another particular disease or condition for which the novel compounds may be useful is peripheral vascular disease. Another particular disease or condition for which the novel compounds may be useful is arterial hypertension (also known as systemic hypertension). Another particular disease or condition for which the novel compounds may be useful is pulmonary arterial hypertension. Another particular disease or condition for which the novel compounds may be useful is angina.
According to one aspect the present invention provides a compound of formula (I)
Figure imgf000005_0001
or a salt thereof; wherein
R1 and R2 are independently selected from hydrogen, halo, CF3, C1-4alkyl and allyl;
Y represents
Figure imgf000005_0002
wherein R3 represents CF3 or C1-4 alkyl; and R3a represents CF3 or C1-4 alkyl;
R4 represents hydrogen or methyl;
Z is absent or represents (CH2)2, O or OCH2; A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; when A represents CH, R5 is selected from hydrogen, methyl, Ci-4alkoxy, methoxy-C2- 3alkoxy-, chloro or fluoro and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl;
X represents
Figure imgf000006_0001
wherein when both J and L represent CH, R8 represents hydrogen, chloro, fluoro, CF3, C1- 4alkyl or C1-4alkoxy in a meta or ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents hydrogen or halo; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and C1-4alkyl, and R12 represents hydrogen or C1-4alkyl;
or when Z is absent or when Z represents OCH2, X may additionally represent
w Therein R7 represents CF3 or methyl.
According to a further aspect the present invention provides a compound of formula (IA)
Figure imgf000006_0002
or a salt thereof; wherein
R1 and R2 are independently selected from hydrogen, chloro and fluoro;
Y represents
Figure imgf000007_0001
wherein R3 represents CF3 or C1-4alkyl; and R3a represents CF3 or C1-4alkyl;
R4 represents hydrogen or methyl;
Z is absent or represents (CH2)2, O or OCH2;
A and E both represent CH; or one of A and E represents CH and the other represents N; when A represents CH, R5 is selected from hydrogen, methyl, C1-4alkoxy, methoxy- C2-3-alkoxy-, chloro or fluoro and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl;
X represents
Figure imgf000007_0002
wherein when E represents CH, R8 represents hydrogen, chloro, fluoro, C1-4alkyl or C1- 4alkoxy in a meta or ortho position relative to the R9 substituent; or when E represents N, R8 represents hydrogen; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1- 4alkoxy, CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and C1-4alkyl, and R 12 represents hydrogen or C1-4alkyl;
or when Z is absent or represents OCH2, X may additionally represent
Figure imgf000007_0003
wherein R7 represents CF3 or methyl.
According to a further aspect the present invention provides a compound of formula (IB)
Figure imgf000007_0004
or a salt thereof; wherein
R1 and R2 are independently selected from hydrogen, halo, CF3, C1-4alkyl and allyl;
Y represents
Figure imgf000008_0001
wherein R3 represents CF3 or C1-4alkyl; and R3a represents CF3 or C1-4alkyl;
R4 represents hydrogen or methyl;
Z is absent or represents (CH2)2, O or OCH2;
A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; when A represents CH, R5 is selected from hydrogen, methyl, C1-4alkoxy, methoxy-C2-3- alkoxy-, chloro or fluoro and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl;
X represents
Figure imgf000008_0002
wherein when both J and L represent CH, R8 represents hydrogen, chloro, fluoro, CF3, Ci- 4alkyl or Ci-4alkoxy in a meta or ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents hydrogen or halo; and R9 represents hydrogen, halo, CF3, OCF3, C^alkyl, Ci-4alkoxy, CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and Ci-4alkyl, and R12 represents hydrogen or Ci-4alkyl;
or when Z is absent or represents OCH2, X may additionally represent
Figure imgf000008_0003
wherein R7 represents CF3 or methyl.
As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C1-4alkyl means a straight or branched alkyl containing at least 1 , and at most 4, carbon atoms. Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.
As used herein, the term "alkoxy" refers to a straight or branched alkoxy group containing the specified number of carbon atoms. For example,
Figure imgf000009_0001
means a straight or branched alkoxy group containing at least 1 , and at most 4, carbon atoms. Examples of "alkoxy" as used herein include, but are not limited to, methoxy, ethoxy, propoxy, prop-2- oxy, butoxy, but-2-oxy, 2-methylprop-1-oxy, or 2-methylprop-2-oxy.
As used herein, the term "halo" refers to the elements fluorine, chlorine, bromine and iodine. In an embodiment halo represents bromine, fluorine and chlorine. In a further embodiment halo represents fluorine and chlorine.
In an embodiment, a methoxy-C2-3alkoxy- group represents a group MeO (C H 2)2-30- i.e. where the C2-3alkoxy component is straight-chained. Suitable examples include methoxy- ethoxy- or methoxy-n-propoxy-.
In an embodiment, there is provided a compound of formula (I) as defined above or a salt thereof wherein A, J, L, Z, R1, R2 and R4 are as defined above for formula (I) or formula
(IB); Y is as defined above, in which R3 represents CF3 or methyl; and R3a represents methyl; when A represents CH, R5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl; X is as defined above, wherein R7 represents
CF3 or methyl; when both J and L represent CH, R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro; or when one of J and L represents N, R8 represents hydrogen or chloro; and R9 represents hydrogen, halo, CF3, OCF3, Ci-4alkyl,
Figure imgf000009_0002
CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and
Figure imgf000009_0003
and R12 represents hydrogen or Ci-4alkyl.
In an embodiment, there is provided a compound of formula (I) as defined above or a salt thereof wherein A, E, Z, R1, R2 and R4 are as defined above for formula (IA); Y is as defined above, in which R3 represents CF3 or methyl; and R3a represents methyl; when A represents CH, R5 is selected from hydrogen, methyl, methoxy, propyloxy, isobutyloxy or methoxyethoxy and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl; X is as defined above, wherein R7 represents CF3 or methyl; R8 represents hydrogen or chloro; and R9 represents hydrogen, halo, CF3, OCF3, Ci-4-alkyl,
Figure imgf000009_0004
CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and C1-4-alkyl, and R12 represents hydrogen or C1-4-alkyl. In an embodiment, there is provided a compound of formula (I) as defined above or a salt thereof wherein A, J, L, Z, R1, R2 and R4 are as defined above for formula (I) or formula (IB); Y is as defined above, in which R3 represents CF3 or methyl; and R3a represents methyl; when A represents CH, R5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl; X is as defined above, wherein R7 represents CF3 or methyl; when both J and L represent CH, R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro; or when one of J and L represents N, R8 represents hydrogen or chloro; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, CONR10R11 or N3, wherein R10 and R11 are independently selected from hydrogen
Figure imgf000010_0001
In an embodiment, there is provided a compound of formula (I) as defined above or a salt thereof wherein A, J, L, Z, R1, R2 and R4 are as defined above for formula (I) or formula
(IB); Y is as defined above, in which R3 represents CF3 or methyl; and R3a represents methyl; when A represents CH, R5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl; X is as defined above, wherein R7 represents
CF3 or methyl; when both J and L represent CH, R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro; or when one of J and L represents N, R8 represents hydrogen or chloro; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy or
CN.
In an embodiment there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above.
In an embodiment there is provided a pharmaceutically acceptable salt of a compound of formula (I) as defined above.
As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use.
In an embodiment A represents CH. In an embodiment A and E both represent CH. In an embodiment one of A and E represent CH and the other represents N.
In an embodiment R1 is in a para position relative to the -OCH2- linker. In a further embodiment R2 is in an ortho position relative to the -OCH2- linker. In a further embodiment R1 is in a para position relative to the -OCH2- linker and R2 is in an ortho position relative to the -OCH2- linker.
In a further embodiment R1 is in an ortho position relative to the bond linking to the pyridine ring. In a further embodiment R2 is in a meta position relative to the -OCH2- linker.
In an embodiment R1 and R2 do not both represent C2-4alkyl or allyl.
In an embodiment, where one of R1 and R2 represents
Figure imgf000011_0001
or allyl, the other represents hydrogen.
In an embodiment R1 and R2 each represent hydrogen. In an embodiment R1 and R2 each represent fluoro, in a further embodiment with R1 in a para position relative to the - OCH2- linker and R2 in an ortho position relative to the -OCH2- linker. In an embodiment R1 represents chloro or fluoro and R2 represents hydrogen, in a further embodiment with R1 in a para position relative to the -OCH2- linker, and in a yet further embodiment with R1 in an ortho position relative to the bond linking to the pyridine ring.
In an embodiment, R2 represents chloro or fluoro and R1 represents hydrogen, in a further embodiment with R2 in a meta position relative to the -OCH2- linker.
In an embodiment R1 represents C1-4alkyl and R2 represents hydrogen, in a further embodiment with R1 in a para position relative to the -OCH2- linker. In an embodiment R1 represents methyl and R2 represents hydrogen, in a further embodiment with R1 in a para position relative to the -OCH2- linker. In an embodiment R1 represents hydrogen and R2 represents C1-4alkyl, in a further embodiment with R2 in an ortho position relative to the - OCH2- linker. In an embodiment R1 represents hydrogen and R2 represents n-propyl, in a further embodiment with R2 in an ortho position relative to the -OCH2- linker. In an embodiment R1 represents hydrogen and R2 represents allyl, in a further embodiment with R2 in an ortho position relative to the -OCH2- linker.
In an embodiment R1 represents CF3 and R2 represents hydrogen, in a further embodiment with R2 in an ortho position relative to the -OCH2- linker.
In an embodiment R3 represents methyl or CF3. In a further embodiment R3 represents CF3. In an embodiment R3a represents methyl or CF3. In a further embodiment R3a represents methyl.
In an embodiment R4 represents hydrogen. In a further embodiment R4 represents methyl. In an embodiment, Z is O and R4 is hydrogen. In an embodiment, Z is CH2CH2 and R4 is hydrogen. In an embodiment, Y represents the pyrazole group defined above and R4 is hydrogen or methyl. In an embodiment, Y represents the piperidine group defined above and R4 is hydrogen. In an embodiment, Y represents the pyrrole group defined above and R4 is hydrogen. In an embodiment, Y represents the phenyl group defined above and R4 is hydrogen.
In an embodiment Y represents wherein R3 represents CF3 or methyl.
In a embodiment Y represents
Figure imgf000012_0001
wherein R3 represents CF3.
In an embodiment Z is absent or represents O or CH2CH2. In an embodiment Z is absent or represents O. In an embodiment Z is absent. In an embodiment Z represents O.
In an embodiment R5 represents hydrogen or methyl and R6 represents hydrogen.
In an embodiment, when A represents CH, R5 represents hydrogen, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy, methoxyethoxy, fluoro or chloro. In an embodiment, when A represents CH, R5 represents hydrogen, methyl, methoxy, fluoro or chloro. In an embodiment, when A represents CH, R5 represents hydrogen, methyl, methoxy or fluoro.
In an embodiment, when A represents N, R5 and R6 both represent hydrogen.
In an embodiment, R9 represents hydrogen, halo, CF3, OCF3,
Figure imgf000012_0002
CN or N3. In a further embodiment R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1- 4alkoxy or CN.
In an embodiment X represents
Figure imgf000012_0003
wherein R7 represents methyl.
In an embodiment X represents
Figure imgf000012_0004
wherein either J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF3 in a meta position relative to the R9 substituent; or when one of J and L represents N, R8 represents hydrogen or halo in a meta position relative to the R9 substituent; or when both J and L represent CH, R8 represents methyl, methoxy, CF3 or halo in an ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents halo in an ortho position relative to the R9 substituent; and R9 represents hydrogen, halo, CF3, OCF3, Ci-4alkyl, Ci-4alkoxy, CN, CONR10R11, CO2R12, or N3, wherein R10 and R11 each independently represent hydrogen or C1-4alkyl, and R12 represents hydrogen or C1-4alkyl.
In an embodiment X represents
Figure imgf000013_0001
wherein either J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF3 in a meta position relative to the R9 substituent; or when one of J and L represents
N, R8 represents hydrogen or halo in a meta position relative to the R9 substituent; or when both J and L represent CH, R8 represents methyl, methoxy, CF3 or halo in an ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents halo in an ortho position relative to the R9 substituent; and R9 represents hydrogen, halo, CF3, OCF3,
Figure imgf000013_0002
Ci-4alkoxy, CN, or N3.
In an embodiment X represents
Figure imgf000013_0003
wherein either J and L both represent CH or one of J and L represents CH and the other represents N; when both J and L represent CH, R8 represents hydrogen, halo, methyl, methoxy, ethoxy or CF3 in a meta position relative to the R9 substituent; or when one of J and L represents
N, R8 represents hydrogen or halo in a meta position relative to the R9 substituent; or when both J and L represent CH, R8 represents methyl, methoxy, CF3 or halo in an ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents halo in an ortho position relative to the R9 substituent; and R9 represents hydrogen, halo, CF3, OCF3, C^alkyl, Ci-4alkoxy, CN, CONR10R11 or N3, wherein R10 and R11 each independently represent hydrogen or Ci-4alkyl. In an embodiment X represents
Figure imgf000014_0001
wherein E represents CH or N; when E represents CH, R8 represents hydrogen or methyl in a meta position relative to the R9 substituent or halo in an ortho position relative to the R9 substituent; or when E represents N, R8 represents hydrogen; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, CONR10R11 , CO2R12, or N3, wherein R10 and R11 each independently represent hydrogen or C1-4alkyl, and R12 represents hydrogen or C1-4alkyl. In an embodiment X is as defined above wherein E represents CH or N; when E represents CH, R8 represents hydrogen or methyl in a meta position relative to the R9 substituent or halo in an ortho position relative to the R9 substituent; or when E represents N, R8 represents hydrogen; and R9 represents hydrogen, halo, CF3, OCF3, C1- 4alkyl, C1-4alkoxy, CN or N3. In an embodiment R8 represents hydrogen or, when E represents CH, R8 represents chloro or fluoro in an ortho position relative to the R9 substituent. In an embodiment, when E represents CH, R8 represents chloro in an ortho position relative to the R9 substituent. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, CO2H, CONH2 or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy, CN, CO2H, CONH2 or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy, CN or N3. In an embodiment R8 represents hydrogen and R9 is as defined in each of the above embodiments. In an embodiment, when E represents CH each of R8 and R9 represent halo, suitably chloro or fluoro, with R8 being in an ortho position relative to the R9 substituent. In an embodiment, when E represents CH each of R8 and R9 represent chloro, with R8 being in an ortho position relative to the R9 substituent.
In an embodiment J and L each represent CH.
In an embodiment R8 represents hydrogen. In an embodiment J and L both represent CH and R8 represents methyl, methoxy, CF3, chloro or fluoro in an ortho position relative to the R9 substituent. In an embodiment one of J and L represents CH and the other represents N and R8 represents chloro or fluoro in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, methoxy, ethoxy, CF3, chloro or fluoro in a meta position relative to the R9 substituent. In an embodiment one of J and L represents CH and the other represents N and R8 represents chloro or fluoro in a meta position relative to the R9 substituent. In an embodiment R8 represents chloro in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, methoxy, ethoxy, CF3 or chloro in a meta position relative to the R9 substituent. In an embodiment one of J and L represents CH and the other represents N and R8 represents chloro in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl in a meta position relative to the R9 substituent. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3,
Figure imgf000015_0001
CN, CONH2 or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy, CN, CONH2 or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy, CN or N3. In an embodiment R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy or CN. In an embodiment R9 represents OCF3 or CN. In an embodiment R8 represents hydrogen and R9 is as defined in each of the above embodiments. In an embodiment J and L both represent CH and each of R8 and R9 represent methoxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and each of R8 and R9 represent methoxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, and R9 represents halo, suitably fluoro or chloro, or methoxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, and R9 represents fluoro or methoxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, and R9 represents Ci- 4alkoxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents methyl, and R9 represents isopropyloxy or ethoxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment R8 represents chloro, and R9 represents C1-4alkoxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment R8 represents chloro, and R9 represents methoxy, ethoxy or isopropyloxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment R8 represents chloro, and R9 represents C1-4alkoxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment R8 represents chloro, and R9 represents methoxy, ethoxy or isopropyloxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents CF3 and R9 represents C1-4alkoxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents CF3 and R9 represents methoxy, ethoxy or isopropyloxy, with R8 being in an ortho position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents CF3 and R9 represents halo or Ci-4alkoxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents CF3 and R9 represents chloro, methoxy, ethoxy or isopropyloxy, with R8 being in a meta position relative to the R9 substituent. In an embodiment J and L both represent CH and R8 represents CF3 and R9 represents chloro or methoxy with R8 being in a meta position relative to the R9 substituent.
In an embodiment, J represents N and L represents CH; R8 represents halo; and R9 represents CF3, C1-4alkoxy, halo or CN. In an embodiment, J represents N and L represents CH; R8 represents chloro or fluoro; and R9 represents CF3, Ci-4alkoxy, halo or CN. In an embodiment, J represents N and L represents CH; R8 represents chloro; and R9 represents CF3, C1-4alkoxy, halo or CN. In an embodiment, J represents N and L represents CH; R8 represents chloro; and R9 represents CF3.
In an embodiment, J represents CH and L represents N; R8 represents hydrogen; and R ,9! represents CF3, Ci-4alkoxy, halo or CN. In an embodiment, J represents CH and L represents N; R8 represents hydrogen; and R9 represents C1-4alkoxy. In an embodiment, J represents CH and L represents N; R8 represents hydrogen; and R9 represents methoxy.
In an embodiment, E represents N; R8 represents H and R9 represents CF3, C1-4alkoxy, halo or CN. In an embodiment E represents N; R8 represents H and R9 represents CF3, methoxy, chloro, fluoro or CN.
In an embodiment J and L each represent CH and R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro. In another embodiment one of J and L represents N and the other represents CH and R8 represents hydrogen or chloro.
In an embodiment, Z represents CH2CH2 and each of R8 and R9 represent hydrogen.
In an embodiment R9 represents CONR10R11 wherein R10 and R11 are independently selected from hydrogen and methyl.
In an embodiment R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, or N3.
In an embodiment R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy or CN.
For the avoidance of doubt, the term "independently" means that where more than one substituent is selected from a number of possible substituents, those substituents may be the same or different.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-methyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3-carboxylic acid; 1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(4-(t-butyl)phenylmethyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(5-fluoro-2-(4-(4-methoxyphenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-
4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-fluorophenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine- 4-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-trifluoromethylphenyloxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4-trifluoromethylphenoxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(3,5-difluoro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-trifluoromethylphenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-piperidine-4- carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(3,5-difluoro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2- yl]-piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(5-cyanopyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(phenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-[6-(3,5-difluoro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-iodo-phenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-chloro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- methyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-chloropyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-((6-(3,4-dichlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-((6-(4-chlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-((6-(4-chlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1-[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-((6-(3,4-dichlorophenoxy)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(4-azidophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1 -[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl-pyrazole-4- carboxylic acid;
1-[6-(2-(4-(4-t-butylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-chlorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl-pyrazole-4- carboxylic acid;
1-[6-(2-(1-(4-(4-methoxyphenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(3,4-dichlorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-fluoro-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-iodophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(2-(2-methyl-4-(4-methoxy-3-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-4-methoxy-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3,4-dichloro-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-4-isopropyloxylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-ethyloxy-3-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-ethyloxy-3-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3,4-dimethoxy-phenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(2-methyl-4-(4-chloro-2-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(2,4-dimethoxy-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxy-2-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-fluoro-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxy-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-isopropyloxyl-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-chloro-2-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-chloro-2-ethyloxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(2-chloro-4-ethyloxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(2-chloro-4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(2-(2-methoxy-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-methoxy-3-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(2-chloro-4-methoxy-phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methoxy-4-(4-methoxy-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-propyloxy-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(2-(methoxyethyloxy)-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-(methoxyethyloxy)-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- δ-trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(2-(2-(methoxyethyloxy)-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-chloro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(3,5-difluoro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(1-(4-(4-methoxyphenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(1-(4-(4-cyanophenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(1-(4-(4-trifluoromethylphenyl)phenyl)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-chloro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl-phenyl)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-trifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-cyanopyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-[6-(2-(4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid; 1-[6-(2-((6-(4-methoxyphenyl)pyridine-3-yl)methyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-methylthiazol-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl-pyrazole-
4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(2-methyl-4-(6-methoxypyridin-3-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(5-trifluoromethylpyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-chloropyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-methoxypyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(4-chlorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-chloro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(5-chloro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(3,5-difluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-chloro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(4-chloro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(6-chloro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine- 2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(4-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(6-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-iodo-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-
5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-fluoro-2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)Dyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(4-(4-methoxy-2-methylphenyl)phenylmethyloxy)-phenyl)Dyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-fluoro-2-methylphenyl)phenylmethyloxy)-phenyl)Dyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-fluoro-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-fluoro-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-fluoro-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1 -[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridine- 2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-cyano-2-methylphenyl)phenylmethyloxy)-phenyl)pyridine-
2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-methoxy-2-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid; 1-[6-(5-methyl-2-(2-methyl-4-(4-chloro-2-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-propyloxy-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1- piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-
2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1-piperidine-4-carboxylic acid;
1-[6-(5-methyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)phenylmethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-chloro-2-trifluoromethyl- phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1-piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-methyl-4-trifluoromethyl- phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-cyano-2-methyl-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-chloro-4-methoxy-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid; 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;
1-[6-(5-trifluoromethyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(4-aminocarbonylphenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-(aminocarbonyl)phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(5-(aminocarbonyl)pyridine-2-yl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
1-[6-(2-(4-(4-carboxyphenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-(6-{2-[({6-[(4-carboxyphenyl)oxy]-3-pyridinyl}methyl)oxy]phenyl}-pyridin-2-yl)-5-
(trifluoromethyl)-i H-pyrazole-4-carboxylic acid;
1-[6-(2-(4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;
1-[6-(2-(2-methyl-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-methoxy-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(3,5-difluoro-2-(4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(5-chloro-2-(2-methyl-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-fluoro-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(5-fluoro-2-(2-methoxy-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(2-(2-fluoro-4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1 -[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
1-[6-(2-(2-methyl-4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid;
1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid;
1-[6-(2-(4-(4-methoxyphenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid;
1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid; 1-[6-(2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;
1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;
1-[6-(2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from:
4-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-benzoic acid;
4-[6-(2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-benzoic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-[6-(3-(propen-2-yl)-2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]- δ-trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(3-propyl-2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(3-(propen-2-yl)-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-propyl-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;
1-[6-(3-(propen-2-yl)-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;
1-[6-(3-propyl-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.
In an embodiment there is provided a compound of formula (I) which is 1-[6-(2-(4-(4- cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid
Figure imgf000028_0001
or a pharmaceutically acceptable salt thereof.
In an embodiment there is provided 1-[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid.
In an embodiment there is provided a compound of formula (I) which is 1-[6-(2-(2-methyl- 4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid
Figure imgf000028_0002
or a pharmaceutically acceptable salt thereof.
In an embodiment there is provided 1-[6-(2-(2-methyl-4-(4- trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid. To the extent that certain compounds of formula (I) may exist in stereoisomeric forms (e.g. they may contain one or more asymmetric carbon atoms), the individual stereoisomers (enantiomers and diastereomers) and mixtures of these are included within the scope of the present invention. Similarly the invention also extends to conformational isomers of compounds of formula (I) and any geometric {cis and/or trans) isomers of said compounds. Likewise, it is understood that if the compounds of formula (I) may exist in tautomeric forms other than that shown above, then these tautomers are also included within the scope of the present invention.
Where R4 represents methyl, the compound of formula (I) will include a chiral centre at the carbon atom bearing that substituent. Separation of the individual enatiomers of the relevant compounds (e.g. from racemic mixtures produced) may be carried out by standard methods well-known to the person skilled in the art, for example by chiral chromatography.
Salts of compounds of formula (I) which are suitable for use in medicine are those wherein the counterion is pharmaceutically acceptable. However, salts having non- pharmaceutically acceptable counterions are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of formula (I) and their pharmaceutically acceptable salts.
Solvates of the compounds of formula (I) and solvates of the salts of the compounds of formula (I) are included within the scope of the present invention. As used herein, the term "solvate" refers to a complex of variable stoichiometry formed by a solute (in this invention, a compound of formula (I) or a salt thereof) and a solvent. Those skilled in the art of organic chemistry will appreciate that many organic compounds can form such complexes with solvents in which they are reacted or from which they are precipitated or crystallized. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Most preferably the solvent used is water. Where the solvent used is water such a solvate may then also be referred to as a hydrate.
Because of their potential use in medicine, in one embodiment the salts of the compounds of formula (I) will be pharmaceutically acceptable. Reference is made to Berge et al. J. Pharm. ScL, 1977, 66, 1-19, which is incorporated herein by reference. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I). Typically, a salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent.
Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts and will be apparent to those skilled in the art. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid; or with a suitable organic acid such as succinic, maleic, malic, mandelic, formic, acetic, propionic, hexanoic, fumaric, glutamic, lactic, citric, tartaric, benzoic, salicylic, aspartic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acid. Other non-pharmaceutically acceptable salts such as oxalates may be used, for example in the isolation of compounds of formula (I), and are included within the scope of this invention. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, including salts of primary, secondary and tertiary amines, such as ammonia, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N- methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of the carboxylic acid moiety that is present in the compound of formula (I). Since the compounds of formula (I) include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts (including zwitterionic salts), which salts are also included within the scope of the present invention.
It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form a compounds of formula (I) which is pharmacologically active. Such derivatives may therefore be described as "prodrugs". All such prodrugs of compounds of formula (I) are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). In particular the carboxylic acid function attached to the group Y may be a suitable candidate for pro-drug functionality, for example by formation of appropriate esters or amides. It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I).
Hereinafter, a compound of formula (I) (whether in solvated or unsolvated form) or a pharmaceutically acceptable salt thereof (whether in solvated or unsolvated form) defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "a compound of the invention".
Also included within the scope of the invention are alternative crystalline or non-crystalline forms, including polymorphic forms, of a compound of formula (I) or a salt thereof.
The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into a compound of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as 2H, 3H, 13C, 14C, 15N, 170, 180, 31P, 32P, 35S, 18F and 36CI, respectively. Certain isotopic variations of a compound of the invention, for example, those in which a radioactive isotope such as 3H or 14C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., 3H, and carbon-14, i.e., 14C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., 2H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of a compound of the invention can generally be prepared by conventional procedures such as by the illustrative methods or by the preparations described in the Examples hereafter using appropriate isotopic variations of suitable reagents.
As discussed above, it is believed that a compound of the invention, as an activator of sGC, may be useful in the treatment of a disease or condition which is mediated by sGC activity.
According to a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). The carrier(s), diluent(s) and/or excipient(s) must each be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.
According to a further aspect there is provided a pharmaceutical composition comprising a) 0.1 mg to 1000 mg of a compound of the invention and b) 0.1g to 2g of one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). In an embodiment there is provided a pharmaceutical composition comprising 1-[6-(2-(4- (4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
In a further embodiment there is provided a pharmaceutical composition comprising 1-[6- (2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
According to a further aspect the invention provides a compound of the invention as defined above for use in therapy; in an embodiment the therapy is human therapy.
According to a further aspect, the invention provides a pharmaceutical composition as defined above for use in therapy; in an embodiment the therapy is human therapy.
According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of a disease or condition mediated by sGC activity.
According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
According to a further aspect the invention provides the use of a compound of the invention for the preparation of a medicament for treating a disease or condition mediated by sGC activity.
According to a further aspect the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
According to a further aspect the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
According to a further aspect the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC, in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis, comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition as defined above.
According to a further aspect the invention provides a method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition comprising a compound of the invention.
A compound of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.
When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.
The compounds of the present invention may for example be used in combination with antihypertensive drugs such as diuretics (for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone), ACE inhibitors
(such as benzapril, captopril, enalapril, fosinopril, lisinopril, preindopril, quinapril, ramipril, trandopril), angiotensin receptor blockers (such as candesartan, irbesartan, losartan, telmisartan, valsartan), calcium channel inhibitors (such as amlodipine, felodipine, isradapine, nifedipine, niimodipine, nitrendipine, diltiazem, verapamil), α-adrenergic receptor antagonists (such as doxazosin, prazosin, terazosin, phentolamine, indoramin, phenoxybenzamine, tolazoline), β-adrenergic receptor antagonists (such as atenolol, metoprolol, nadolol, oxprenolol, pindolol, propanolol, timolol), mixed α/β-adrenergic receptor antagonists (such as bucindalol, carvedilol, labetolol) or may be used in combination with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil), or may be used in combination with cholesterol-lowering or lipid-lowering drugs, for example statins (such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibrates (such as bezafibrate, ciprofibrate, gemfibrozil, fenofibrate), or nicotinic acid.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.
When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.
When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.
It will be appreciated that references herein to "treat", "treating" or "treatment" extend to prevention of recurrence of symptoms (whether mild, moderate or severe) and to suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.
The compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.
The compound of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with one or more standard pharmaceutical excipients, carriers or diluents, according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.
The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans. The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.
The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.
Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.
Suppositories typically contain conventional suppository bases, e.g. cocoa-butter or other glyceride.
For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing. Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.
The pharmaceutical compositions of the invention may be formulated, for administration to mammals including humans, by any route, and include those in a form adapted for oral, topical or parenteral administration. The compositions may, for example, be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.
Thus in one aspect the invention provides a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.
The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration.
It will be recognised by one of skill in the art that the optimal quantity and spacing of individual doses of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.
Each dosage unit for oral administration typically contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the compound of formula (I).
A compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 1000 mg, for example between 1 mg and 500 mg, e.g. between 5 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of formula (I) or a salt thereof calculated as the compound of formula (I), the compound of the invention being administered 1 to 4 times per day, for example 1 to 2 times a day. In one embodiment, a compound of the invention may be administered once a day.
Suitably a compound of the invention will be administered for a period of continuous therapy, for example for a week or more.
Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each suitably provided in substantially pure form, for example at least 60% pure, for example at least 75% pure, for example at least 85%, for example at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds typically contain at least 1 %, for example at least 5%, for example from 10 to 59% of a compound of the invention.
A compound of the invention may be prepared in a variety of ways. These processes form further aspects of the present invention.
Throughout the specification, general formulae are designated by Roman numerals (I), (II), (III), (IV) etc.
It will be appreciated that all novel intermediates used to prepare a compound of the invention form yet a further aspect of the present invention, in particular intermediate compounds of formulae (III), (IV), (VIII), (XII), (XXV), and (XXVI) as defined herein.
Compounds of formula (I) (other than those wherein both Y represents the pyrrole group ddeeffiinneedd aabboovvee aanndd RR99 rreepprreesseents CN) can be prepared according to the following general synthetic process (Scheme 1 ):
Scheme 1
Figure imgf000038_0001
In respect of step (i) the intermediate compounds of formula (II) can be prepared according to the processes set out in Schemes 2 to 5.
Scheme 2: pyrazole compounds of formula (Na)
Figure imgf000038_0002
(Ma)
The compounds of formula (V) wherein R3 represents CF3 or CH3 are commercially available (from Aldrich and Orphachem respectively). The compounds of formula (V) wherein R3 represents C2-4 alkyl can be prepared according to the process described in US2005096353 (see Scheme 6 at page 17 and the Examples). Scheme 3: pyrrole compounds of formula (lib)
Figure imgf000039_0001
(Hb)
The preparation of ethyl 2-methyl-pyrrole-3-carboxylate is described in the literature (Tet. Lett, (2006), 47(13), 2151-2154; or J. Org. Chem., (2005), 70(12), 4751-4761 ). The preparation of the compound of formula (Vl) wherein R3 represents CF3 is described in the literature (Tetrahedron, 1993, 49(5); 1057-62). The preparation of the compounds of ffoorrmmuullaa ((VVll)) wwhheerreeiinn RR33 rreepprreesseennttss CC22--44 aallkkyyll iis also described in the literature (Canadian Journal of Chemistry; 1970, 48(1 1 ); 1689-97).
Scheme 4: piperidine compound of formula (lie)
Figure imgf000039_0002
reflux
Figure imgf000039_0003
Ethyl isonipecotate is commercially available (from Aldrich). The compound of formula (lie) can also be prepared in a solvent such as acetone, CH3CN or THF in the presence of a base such as Na2CO3, K2CO3 or Cs2CO3, under reflux.
Scheme 5: phenyl compounds of formula (Nd)
Figure imgf000039_0004
90 to 1100C
The boronic acid is commercially available (from Aldrich). In respect of step (ii) the intermediate compounds of formula (III) can be prepared according to the processes set out in Schemes 6 and 7.
Scheme 6
Figure imgf000040_0001
2-hydroxyphenyl boronic acid is commercially available (from Aldrich) as is 5-fluoro-2- hydroxyphenyl boronic acid (from Apollo or Combi Blocks).
Scheme 7a
The compounds of formula (NIb) can be prepared from the boronic acids of formula (VIIb); these are either commercially available or can be prepared by standard methods well- known to the person skilled in the art.
Figure imgf000040_0002
(II)
Suitable, for example, for R1 = Cl and R2 =H R1 = R2 = F
R1 = CF3 and R2 = H
Certain compounds of formula (VIIb) are commercially available, for example, where R1 is in a para position relative to the -OCH2- linker and R2 is in an ortho position relative to the -OCH2- linker:
Figure imgf000041_0001
Compounds of formula (VIIb) where R1 is ethyl, propyl or allyl in a para position relative to the -OCH2- linker and R2 is hydrogen may be prepared from the corresponding 4-ethyl, 4-propyl or 4-allyl-anisole by (i) bromination in the position ortho to the methoxy group and (ii) conversion of the bromine to a boronic acid group by standard methods (for example, as described in WO2005019151 : bromination p142 and conversion of bromine to boronic acid pp365, 373 or 419).
Analogous processes may be used to prepare other compounds of formula (VIIb) where R1 is C1-4alkyl and R2 is as defined above. For example, 2-bromo-4,6-dimethyl phenol is commercially available from Bionet.
Compounds of formula (VIIb) where R1 is H and R2 is ethyl, isopropyl or t-butyl in an ortho position relative to the -OCH2- linker may be prepared from the corresponding 2-ethyl- anisole, 2-isopropyl-anisole or 2-t-butyl-anisole, by
(i) bromination in the position ortho to the methoxy group using NBS and diisopropylethylamine (by a method as described in US2004235852, page 29, compound (0231 )), and (ii) conversion of the bromine to a boronic acid group by standard methods.
Analogous processes may be used to prepare other compounds of formula (VIIb) where R2 is and R1 is as defined above.
The compounds of formula (NId) and Ie) can be prepared according to the processes set out in Scheme 7b.
Scheme 7b
Figure imgf000042_0001
In respect of step (iii), the following two general synthetic schemes can be used (Schemes 88 aanndd 99)),, eexxcceepptt iinn tthhee ccaassee ooff ccoommppoouunnddss wwhheerrein both Y represents pyrrole and R9 represents CN (for which see Schemes 13 and 14).
The synthesis described in Scheme 8 is particularly suitable for compounds wherein either J or L represents N or Z represents O, (CH2)2, or OCH2 (although it can also be used wherein Z is absent).
Scheme 8
Figure imgf000042_0002
Scheme 9
The synthesis described in Scheme 9 relates to compounds wherein Z is absent and both J and L represent CH or J represents CH and L represents N and is particularly suitable for compounds wherein R5 represents F or Cl.
Figure imgf000043_0001
Compounds of formula (X) are either commercially available or can be prepared by standard methods well-known to the person skilled in the art.
Compounds of formula (IVc) wherein A represents CH, Z is absent, J represents N and L represents CH, may be prepared by the following method (Scheme 1Oa) - as an alternative to using Scheme 8 above.
Scheme 10a
Figure imgf000044_0001
(IVc)
Compounds of formula (IVd) wherein A represents CH or N, X represents a thiazole ring system as defined above, and Z is absent or represents OCH2, may be prepared by the following method (Scheme 1Ob) - as an alternative to using Scheme 8 above.
Scheme 10b
Figure imgf000044_0002
(XVIII)
Figure imgf000044_0003
Certain compounds of formula (Xl) wherein A represents CH, are commercially available, for example 4-cyanobenzyl bromide (from Aldrich), 4-cyano-2-fluorobenzyl bromide (from Apollo), and 4-cyano-2-methoxybenzyl bromide (from Carbocore). To prepare a compound of formula (Xl) wherein R5 represents methyl, the aldehyde group of 4-cyano- 2-methyl benzaldehyde (from Chemstep Product List) may be reduced by standard methods, for example using NaBH4 and then a bromination step is carried out typically using PBr3. To prepare a compound of formula (Xl) wherein R4 represents methyl, and R5 and R6 both represent hydrogen, the carbonyl group of 4-acetyl benzonitrile (from Aldrich) may be reduced to the corresponding hydroxyl compound, for example using NaBH4 and then a bromination step is carried out typically using PBr3.
To prepare a compound of formula (Xl) wherein A represents N and R4, R5 and R6 each represent H, bromination of the methyl group of 5-methylpyridine-2-carbonitrile (from Fluorochem) is carried out typically using N-bromosuccinimide.
To prepare a compound of formula (Xl) wherein A represents CH and Z represents OCH2, 4-hydroxybenzaldehyde (or more generally a compound of formula (XVIII)) is alkylated by chloroacetonitrile, then the aldehyde function is reduced, for example NaBH4, then the resulting hydroxy group is brominated, for example using PBr3.
Other compounds of formula (Xl) can be prepared by standard methods well known to the person skilled in the art.
The subsequent step (iv) may be carried out according to Scheme 11.
Scheme 11
NaOH or LiOH MeOH / H2O rt or 60-700C (IVa) or (IVb) or (IVc) or (IVd) *■ (Ia) or (Ib) or (Ic) or (Id) respectively
The temperature used in this ester hydrolysis reaction will depend on the nature of the compound and the length of time for which the reaction is performed; this will be well appreciated by the person skilled in the art.
Where R9 represents CN, the ester hydrolysis reaction is instead suitably carried out using LiOH at room temperature to avoid hydrolysis of the cyano group to an amide group.
Certain compounds of formula (I) wherein R9 represents CONH2 may also be prepared by the following scheme (Scheme 12) from the corresponding nitrile derivatives (of formula (IVa) or (IVb) or (IVc) wherein R9 represents CN synthesised as described in Schemes 8, 9 or 10a above). Such a synthesis can also apply to the corresponding compounds wherein Y represent a pyrrole group as defined above.
Scheme 12
Figure imgf000046_0001
In Scheme 12, Z is absent or Z represents O.
Compounds of formula (I) wherein both Y represents the pyrrole group defined above and R9 represents CN, or wherein Y is defined as above and R9 = CN can be prepared according to the following general synthetic processes (Scheme 13a, Scheme 13b or Scheme 14).
Scheme 13a Scheme 13a is particularly suitable to prepare compounds wherein J represents CH and L represents CH or N , and Z is absent.
Figure imgf000046_0002
Scheme 13b
Scheme 13b is particularly suitable to prepare compounds wherein J represents N and L represents CH , and Z is absent.
Figure imgf000047_0001
(XXVI)
Scheme 14
Scheme 14 is particularly suitable to prepare compounds wherein Z is absent or Z represents O, OCH2 or CH2CH2.
Figure imgf000047_0002
In respect of the compounds of formula (IX):
Figure imgf000048_0001
hal' may represent chloro or bromo where such compounds are commercially available. If the compound is not commercially available, then hal' will represent bromo and the compound may be prepared by standard methods. 2-chloro-5-chloromethylpyridine and 4- bromo-2-fluoro-benzyl bromide are both commercially available (from Aldrich). Other compounds of formula (IX) may generally be prepared by the following methods (Schemes Schemes 15, 16, 17 and 18) or by other standard methods well-known to the person skilled in the art.
Scheme 15
Figure imgf000048_0002
(IXa)
(XIII)
Certain compounds of formula (XIII) are commercially available; for example:
(a) when A represents N, hal represents Cl; and R5 and R6 both represent H (Aldrich) or R5 represents Me and R6 represents H (Bionet).
(b) when A represents CH, R5 represents H (Aldrich), or R5 represents F (Apollo), or R5 represents Cl (AKSCI).
Compounds of formula (XIII) when A represents CH and R5 represents OCi-4 alkyl or O(CH2)nOMe (wherein n represents 2 or 3) may be prepared by O-alkylation of the compound of formula (XIII) wherein R5 represents OH (commercially available from Apin).
A suitable preparation for compounds of formula (XIII) when A represents CH and R5 represents methyl is described in the literature (Chemical and Pharmaceutical Bulletin; 33(7); 2809-20; 1985).
Scheme 16
When R5 represents Me, OMe or Cl:
Figure imgf000049_0001
(XIVb)
Scheme 17
Figure imgf000049_0002
Compounds of formula (XIVa, XIVb, XIVc and XIVe) are commercially available: 4-bromo- 2-methylbenzoic acid, 4-bromo-2-chlorobenzoic acid, methyl 4-bromo-2-methoxybenzoate (from Aldrich) or 4-bromo-2-hydroxybenzoic acid (from Apin) and 4-bromo-2- hydroxybenzaldehyde (from Apin); or may be prepared by standard methods well-known to the person skilled in the art.
Scheme 18a
Figure imgf000049_0003
(XV) (IXd) Certain compounds of formula (XV) are commercially available, for example wherein R5 represents H and R6 represents Me or R5 represents Me and R6 represents H (from Asymchem). Other compounds of formula (XV) may be prepared by standard methods well-known to the person skilled in the art.
Scheme 18b
Figure imgf000050_0001
(XIVb)
Preparation of compounds of formula (VIII)
Figure imgf000050_0002
(VIII) may be carried out according to the following Schemes 19 to 25.
Synthesis of biphenyl compounds of formula (VIII) wherein Z is absent can be carried out according to Schemes 19 or 20.
Scheme 19
Scheme 19 is particularly suitable for compounds wherein one of A , J or L represents N.
Figure imgf000051_0001
Pathway A is thus typically used where A represents N or L represents N; and pathway B is typically used where J represents N. Compounds of formula (X) are either commercially available or can be prepared by standard methods well-known to the person skilled in the art. 2-methoxypyridine-5-boronic acid is available from Aldrich and 2-cyanopyridine-5- boronic acid and 2-trifluoromethylpyridine-5-boronic acid are available from Frontier.
Certain compounds of formula (XVI) are commercially available, for example: where A represents CH and R5 represents Me (Betapharma); A represents CH and R5 represents OMe (Aldrich); A represents CH and R5 represents F (Aldrich). Where R4 represents H and A represents N, note the earlier reference to compounds of formula (XV) in Scheme 18a. Where R4 represents methyl, note the earlier reference to compounds of formula (XIII) in Scheme 15. Other compounds of formula (XVI) may be prepared by standard methods well-known to the person skilled in the art.
Certain compounds of formula (XVII) are commercially available, for example: wherein J represents N, R8 represents H and R9 represents CN, CF3, COOR12, Cl or OMe (Aldrich, Fluka or Acros); wherein J represents N, R8 represents Cl and R9 represents CF3 (Aldrich). Other compounds of formula (XVII) may be prepared by standard methods well- known to the person skilled in the art.
Pathway B is also typically used where J and L both represent CH where hal represents Br. Scheme 20a
When R is other than CN or COOR and A and J each represent CH and R /R is other than halogen, Scheme 20a is particularly suitable.
Figure imgf000052_0001
to rt
Figure imgf000052_0002
Figure imgf000052_0003
(VIIIc)
Scheme 20b
When R9 is CN or COOR12 and A and J each represent CH and/or R5/R6 is halogen, Scheme 20b is particularly suitable.
Figure imgf000052_0004
(VIIIc)
Scheme 20c
When R is CN or COOR and A represents CH, and J represents N and/or R /R is halogen, Scheme 20c is particularly suitable.
Figure imgf000053_0001
(VIIId)
Synthesis of compounds of formula (VIII) with Z representing O, can be carried out according to Schemes 21 , 22 or 23.
Scheme 21
rt
Figure imgf000053_0002
Pathway A is thus typically used for J represents N and/or R9 represents CN, COOR12 and/or R5 represents H, Me, OMe. Pathway B is thus typically used for A represents N or for A represents CH and hal represents F and R5 represents H, Me, or OMe.
Compounds of formula (XVIIIa) are commercially available, for example: 4-hydroxy-2- methylbenzaldehyde (Interchim), 4-hydroxy-2-methoxybenzaldehyde (Fluka or Acros), and 4-hydroxybenzaldehyde (Aldrich). In respect of the compounds of formula (XX), note the earlier reference to compounds of formula (XV) in Scheme 18a. Certain compounds of formula (XX) are commercially available, for example: wherein A represents CH and R5 represents H, Me or OMe (Aldrich, Apollo or Apin); or wherein A represents N and R5 and R6 each represents H (Aldrich). Other compounds of formula (XX) may be prepared by standard methods well- known to the person skilled in the art.
Phenol derivatives of formula (XXI) are commercially available or may be prepared by standard methods well-known to the person skilled in the art.
Scheme 22
Where R5 represents Cl or F:
Figure imgf000054_0001
PBr3
Figure imgf000054_0002
Compounds of formula (XVIIIb) are commercially available, for example from Aldrich for R5 represents Cl and from Apin for R5 represents F.
Certain compounds of formula (XIX) are commercially available, for example: wherein hal represents Br or Cl, J represents N, R8 represents H, and R9 represents CN, CF3,
COOR12, Cl or OMe (Aldrich, Fluka or Acros); wherein hal represents Cl, J represents N,
R8 represents Cl, and R9 represents CF3 (Aldrich); wherein J represents CH, hal represents F, R8 represents H, F, Cl, OMe, Me, or CF3, and R9 represents CN or COOR12
(Aldrich, Acros, Apin). Other compounds of formula (XIX) may be prepared by standard methods well-known to the person skilled in the art.
Scheme 23
Where R5 represents OC1-4alkyl or O(CH2)2-3OMe: as in pathway B Scheme 21
(VIIIg)
Figure imgf000055_0001
R = C1 4alkyl or (CH2JnOMe, n= 2 or 3
Synthesis of compounds of formula (VIII) with Z representing OCH2, can be carried out according to Scheme 24.
Scheme 24
Figure imgf000055_0002
Compounds of formula (XXII) are either commercially available or may be prepared by standard methods well-known to the person skilled in the art.
Synthesis of compounds of formula (VIII) with Z representing (CH2)2, can be carried out according to Scheme 25.
Scheme 25
or rt
Figure imgf000055_0003
Figure imgf000055_0004
(4-phenethyl)benzyl aldehyde is commercially available (from Alfa or ABCR). Other compounds of formula (XXIII) may be prepared by methods as described in Tetrahedron Letters, 1999, 40(1 1 ), 2075-2078 or in Tetrahedron Letters, 2006, 62(51 ), 1 1925-11932, or may be prepared by standard methods well-known to the person skilled in the art. Synthesis of compounds of formula (VIII) with Z being absent or representing OCH2, and X representing a thiazole ring system as defined above, can be carried out according to Scheme 26.
Scheme 26
Figure imgf000056_0001
reflux
(XXIV)
Figure imgf000056_0002
(VII Ij)
Certain compounds of formula (XXIV) are commercially available, for example where Z is absent, ethyl or methyl 4-cyanobenzoate and 2-fluoro-4-cyanobenzoic acid as well as 6- cyanonicotinic acid. To prepare compounds of formula (XXIV) wherein A represents CH, Z is absent and R5 is other than H and F, the bromo substituent of a compound of formula (XIV) (see Schemes 16 and 17) may be replaced by cyano according to standard methods well-known to the person skilled in the art. To prepare compounds of formula (XXIV) wherein Z represents OCH2 one may begin from the appropriate 4-hydroxy benzoic acid or 6-hydroxynicotinic acid or a suitable benzoate or nicotinoate (either commercially available or able to be prepared by standard methods well-known to the person skilled in the art), and O-alkylate with chloroacetonitrile.
Supporting Examples and Descriptions
The invention is illustrated by the Examples described below.
In the procedures that follow, after each starting material, reference to a Description by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.
Where reference is made to the use of a "similar" procedure, as will be appreciated by those skilled in the art, such a procedure may involve variations known to those skilled in the art, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.
Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada). In the reporting of Proton Magnetic Resonance (1H NMR) spectral data, chemical shifts are reported in ppm (δ) using tetramethylsilane as the internal standard. Splitting patterns are designed as s, singlet; d, doublet; Id, large doublet; t, triplet; q, quartet; m, multiplet.
The following table lists the used abbreviations:
Figure imgf000057_0001
Figure imgf000058_0001
Analytical method LC-MS
Analytical HPLC was conducted on a X-terra MS C18 column (2,5 μm 3*30 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent
B) using the following elution gradient: 0 -^ 4 minutes, 5%B -> 100%B; 4 -^ 5 minutes,
100%B at a flowrate of 1.1 mL/min with a temperature of 400C. The mass spectra (MS) were recorded on a Micromass ZQ-LC mass spectrometer using electrospray positive ionisation [ES+ve to give MH+ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)" molecular ion] modes.
Analytical LC-HRMS Methods:
(a) Analytical HPLC was conducted on a LUNA 3u C18 column (2,5 μm 30*3 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent
B) using the following elution gradient: 0 -> 0.5 minutes, 5%B; 0.5 -> 3.5 minutes, 5%B -» 100%B; 3.5 -» 4 minutes, 100%B; 4 -» 4.5 minutes, 100%B -» 5%B; 4.5 -» 5.5 minutes, 5%B at a flowrate of 1.3 mL/min with a temperature of 400C. The mass spectra (MS) were recorded on a Micromass LCT mass spectrometer using electrospray positive ionisation [ES+ve to give MH+ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)" molecular ion] modes.
(b) Analytical HPLC was conducted on a X-Bridge C18 column (2,5 μm 30*3 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0 ^ 0.5 minutes, 5%B; 0.5 ^ 3.5 minutes, 5%B -» 100%B; 3.5 -» 4 minutes, 100%B; 4 -» 4.5 minutes, 100%B -» 5%B; 4.5 -» 5.5 minutes, 5%B at a flowrate of 1.3 mL/min with a temperature of 400C. The mass spectra (MS) were recorded on a Micromass LCT mass spectrometer using electrospray positive ionisation [ES+ve to give MH+ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)" molecular ion] modes.
Description 1 : 4-bromo-2-propyloxy-benzaldehyde (D1)
Figure imgf000059_0001
To a solution of 4-bromo-2-hydroxybenzaldehyde (Apin, 5g, 24.87mmol) in DMF (80ml) was added portionwise NaH (60% in mineral oil, 1.19g, 29.85mmol) and the mixture was stirred at room temperature for 30 minutes. Then 1-bromopropane (2.71 ml, 29.85mmol) was added and the mixture was heated at 500C for 4 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with cHex, and the resulting precipitate was filtered and dried . The title compound was obtained as a cream powder (3.7g, yield= 61.2%). LC/MS: 245 (M+H), Rt= 3.43min. 1H NMR (300MHz, CDCI3, ppm): 7.7 (d, 1 H), 7.2 (d + s, 2H), 4.05 (t, 2H), 1.9 (m, 2H), 1.1 (t, 3H).
Description 2: ethyl 4-bromo-2-(2-methylpropyloxy)benzoate (D2)
Figure imgf000059_0002
To a solution of ethyl 4-bromo-2-hydroxybenzoate (2g, 8.16mmol) in acetone (50ml) was added Cs2CO3 (4g, 12.24mmol) and the mixture was stirred at room temperature for 10 minutes. Then 1-bromo-2-methylpropane (1.11g, 8.98mmol) was added and the mixture was heated at 500C for 4 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a colorless oil (2.2g, yield= 90%). 1H NMR (300MHz, CDCI3, ppm): 7.59 (d, 1 H), 7.02 (dd, 1 H), 7.01 (bs, 1 H), 4.28 (q, 2H), 3.70 (d, 2H), 2.07 (m, 1 H), 1.30 (t, 3H), 0.99 (d, 6H)
Description 3: ethyl 4-bromo-2-(methoxyethyloxy)benzoate (D3)
Figure imgf000059_0003
Prepared according to a similar procedure as described for D2 from ethyl 4-bromo-2- hydroxybenzoate, the title compound was obtained as a white solid (yield = 77%). 1H N MR (300MHz, CDCI3, ppm): 7.68 (d, 1 H), 7.15 (m, 2H), 4.34 (q, 2H), 4.19 (t, 2H), 3.81 (t, 2H), 3.48 (s, 3H), 1.39 (t, 3H)
Description 4a: 4-(5-trifluoromethylpyridin-2-yl)-benzaldehyde (D4a)
Figure imgf000060_0001
To a solution of 2-chloro-5-trifluoromethylpyridine (Aldrich, 4g, 22.04mmol) in DME (80ml) and H2O (10ml) were added Pd(PhP3)4 (1.27g, 1.10mmol), 4-formylphenylboronic acid
(Aldrich, 3.96g, 26.45mmol) and Na2CO3 (5.84g, 55.09mmol). The mixture was heated at
900C for 3 hours, cooled and poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. After purification by chromatography on silica gel (CH2CI2 / cHex, 4/1 ), the title compound was obtained as a pale yellow solid (3.8g, yield: 68.7%). LC/MS: 252.2 (M+H) , Rt= 3.27min
The following intermediates were similarly prepared:
Figure imgf000060_0002
Figure imgf000061_0001
Description 5a: 4-(4-cyanophenoxy)-benzaldehyde (D5a)
Figure imgf000062_0001
To a solution of 4-hydroxybenzaldehyde (Aldrich, 5.04g, 41.28mmol), in DMF (50ml) was added portionwise Cs2CO3 (14.79g, 45.41 mmol) and the mixture was stirred at room temperature for 10 minutes. Then 4-fluorobenzonitrile (Aldrich, 5g, 41.28mmol) was added and the mixture was heated at 1100C for 2 hours, then cooled and poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. After purification by chromatography on silica gel (CH2CI2 / cHex, 3/2, then 4/1 ), the title compound was obtained as a white solid(5.25g, yield: 57.0%); LC/MS: 224.1 (M+H) , Rt = 3.07min
The following intermediates were similarly prepared:
Figure imgf000062_0002
Figure imgf000063_0001
Description 6: 4-((4-t-butylphenyl)methyloxy)benzaldehyde (D6)
Figure imgf000063_0002
To a solution of 4-hydroxybenzaldehyde (Aldrich, 0.978g, 8mmol) in acetone (30ml) was added CS2CO3 (1.8g, 12mmol) and then 4-t-butylbenzyl bromide (Aldrich, 2g, 8.8mmol) and the mixture was heated at 700C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure to leave a solid which was recrystallised from MeOH. The title compound was obtained as cream crystals (0.64g, 29.8%). 1H NMR (300MHz, DMSO d6, ppm): 9.9 (s, 1 H), 7.9 (d, 2H), 7.45 (m, 4H), 7.2 (d, 2H), 5.2 (s, 2H), 1.3 (s, 9H)
Description 7 : 4-(4-cyanophenoxy)-benzyl alcohol (D7)
Figure imgf000064_0001
To a solution of 4-(4-cyanophenoxy)-benzaldehyde (D5a, 5.2g, 23.32mmol) in MeOH (70ml) was added portionwise NaBH4 (0.975g, 29.46mmol). The mixture was stirred at room temperature for 30 minutes and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a colorless oil which crystallised (5.13g, yield: 97.8%); LC/MS: 224.1 (M-H) , Rt=2.82min
The following intermediates were similarly prepared:
Figure imgf000064_0002
Figure imgf000065_0001
Figure imgf000066_0001
Description 8a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D8a)
Figure imgf000067_0001
To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH4 1 M in THF (1 1.3ml, 11.27mmol) and the mixture was stirred at room temperature for 30 minutes. Water (50ml) was then added dropwise. The insoluble material was filtered on a Celite pad and washed with CH2CI2.
The filtrate was washed with CH2CI2 and the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%); 1H NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.7 (d,
2H), 7.45 (d, 2H), 5.3 (t, 1 H), 4.55 (d, 2H).
The following intermediates were similarly prepared:
Description 8b: 4-(4-chlorophenyl)-benzyl alcohol (D8b)
Figure imgf000067_0002
From 4-(4-chlorophenyl)-benzoic acid (Apollo, 3g, 12.9mmol). The title compound was obtained as white solid (2.6g, yield= 92.2%); LC/MS: 217.4 (M-H), Rt = 3.15min
Description 8c: 2-methyl-4-(4-trifluoromethylphenyl)-benzyl alcohol (D8c)
Figure imgf000067_0003
From ethyl 2-methyl-4-(4-trifluoromethylphenyl)-benzoate (D4j). The title compound was obtained as grey powder (yield = 78%). 1H NMR (300MHz, CDCI3, ppm): 7.71 (bs, 4H), 7.49 (m, 2H), 7.44 (bs, 1 H), 4.79 (s, 2H), 2.46 (s, 3H).
Description 8d : 2-methyl-4-(4-methoxyphenyl)-benzyl alcohol (D8d)
Figure imgf000067_0004
From ethyl 2-methyl-4-(4-methoxyphenyl)-benzoate (D4k). The title compound was obtained as yellow powder (yield= 67%). 1H NMR (300MHz, DMSO d6, ppm): 7.58 (d, 2H), 7.9 (d, 2H), 7.40 (m, 3H), 7.00 (d, 2H), 5.07 (t, 1 H), 4.51 (d, 2H), 3.8 (s, 3H), 2.30 (s, 3H).
Description 8e : 2-methyl-4-(4-trifluoromethoxyphenyl)-benzyl alcohol (D8e)
Figure imgf000068_0001
From ethyl 2-methyl-4-(4-trifluoromethoxyphenyl)-benzoate (D4I). The title compound was obtained as a pale grey powder (yield= 88%). LC/MS: 281.1 (M-H), Rt = 3.44min.
Description 8f: 4-bromo-2-methyl -benzyl alcohol (D8f)
Figure imgf000068_0002
From 4-bromo-2-methylbenzoic acid (Aldrich) as a white powder (yield= 59.9%). LC/MS: Rt = 2.59min.
Description 8g: 4-bromo-2-(2-methylpropyloxy)-benzyl alcohol (8g)
Figure imgf000068_0003
From ethyl 4-bromo-2-(2-methylpropyloxy)benzoate (D2), the title compound was obtained as a yellow oil (yield=89.8%). 1H NMR (300MHz, CDCI3, ppm): 7.09 (d, 1 H), 7.00 (dd, 1 H), 6.92 (sd, 1 H), 4.58 (s, 2H), 3.69 (d, 2H), 2.05 (m, 1 H), 0.97 (d, 6H).
Description 8h: 4-bromo-2-(methoxyethyloxy)-benzyl alcohol (D8h)
Figure imgf000068_0004
From ethyl 4-bromo-2-(methoxyethyloxy)benzoate (D3) the title compound was obtained as a yellow oil (yield=87.86%). 1H NMR (300MHz, CDCI3, ppm): 7.15 (d, 1 H), 7.11 (dd, 1 H), 7.04 (sd, 1 H), 4.63 (s, 2H), 4.2 (t, 2H), 3.76 (t, 2H), 3.45 (s, 3H). Description 8i: 4-bromo-2-(propyloxy)-benzyl alcohol
Figure imgf000069_0001
Prepared by an analogous method as described for Description 7 from 4-bromo-2- propyloxy-benzaldehyde (D1 ). The title compound was obtained as a yellow oil (yield = 99%). LC: Rt= 3.06min.
Description 9: 2-methyl-4-(4-cyanophenyl)-benzyl alcohol (D9)
Figure imgf000069_0002
To a solution of 4-bromo-2-methyl-benzyl alcohol (D8f, 7g, 34.8mmol) in DME (100ml) and H2O (10ml) were added Pd(PhP3)4 (4g, 3.5mmol), 4-cyanophenylboronic acid (Aldrich, 6.7g, 45.3mmol) and Na2CO3 (7.4g, 69.6mmol). The mixture was heated at 1100C overnight, cooled and poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. After purification by chromatography on silica gel (CH2CI2), the residue was triturated with iPr2O and the resulting precipitate was filtered and dried. The title compound was obtained as a yellow solid (6g, yield: 77.2%). 1H NMR (300MHz, CDCI3, ppm): 7.72 (q, 4H), 7.51 (d, 1 H), 7.45 (dd, 1 H), 7.43 (bs, 1 H), 4.79 (s, 2H), 2.45 (s, 3H)
Description I^ [2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanol (D10)
Figure imgf000069_0003
4-bromo-2-methyl-benzyl alcohol (D8f, 3Og, 150 mmol), bis(pinacolato)diboron (40 g, 156 mmol), Pd(dppf)CI2(ll) (8 g, 10 mmol), and potassium acetate (44 g, 448 mmol) were dissolved in 1 ,4-dioxane (600 ml_), and the reaction mixture was heated to reflux under N2 for 4 h. After cooling, the reaction mixture was filtered, and the filtrate was concentrated. Purification by column chromatography (silica gel; petroleum ether: ethyl acetate = 5:1 ) afforded the title compound as a red oil (34 g, yield: 90%). 1H NMR (400 MHz, DMSO-c/6) J7.50-7.38 (m, 3H), 5.14 (t, 1 H), 4.51 (d, 2H), 2.22 (s, 3H), 1.28 (s, 12H). Description 11 : 4-(4-cyanophenoxy)-benzyl bromide (D11)
Figure imgf000070_0001
To a solution of 4-(4-cyanophenoxy)-benzyl alcohol (D7, 0.9g, 4mmol) in CH2CI2 (40ml) cooled in a ice bath, was added dropwise PBr3 (solution 1 IWCH2CI2, 1.6ml, 1.6mmol). The mixture was stirred at 00C for 30 minutes, then at room temperature for 1 hour and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a colorless oil which crystallised (1.15g, yield: 99.8%); 1H NMR (300MHz, CDCI3, ppm): 7.65 (d, 2H), 7.45 (d, 2H), 7.1 (d, 2H), 7 (d, 2H), 4.55 (s, 2H).
The following intermediates were similarly prepared:
Figure imgf000070_0002
Figure imgf000071_0001
Figure imgf000072_0001
Figure imgf000073_0001
The following intermediates were similarly prepared as described for D11 :
Description 44a: 4-bromo-2-(2-methylpropyloxy)-benzyl bromide (D44a)
Figure imgf000073_0002
From 4-bromo-2-(2-methylpropyloxy)-benzyl alcohol (D8g) the title compound was obtained as yellow oil (yield=100%). 1 H NMR (300MHz, CDCI3, ppm): 7.2 (d, 1 H), 7.06 (dd, 1 H), 7.01 (sd, 1 H), 4.52 (s, 2H), 3.8 (d, 2H), 2.18 (m, 1 H), 1.1 (d, 6H).
Description 44b: 4-bromo-2-(methoxyethyloxy)-benzyl bromide (D44b)
Figure imgf000073_0003
From 4-bromo-2-(methoxyethyloxy)-benzyl alcohol (D8h) the title compound was obtained as yellow oil (yield=95%). 1H NMR (300MHz, CDCI3, ppm): 7.21 (d, 1 H), 7.09 (dd, 1 H), 7.05 (sd, 1 H), 4.54 (s, 2H), 4.2 (t, 2H), 3.83 (t, 2H), 3.49 (s, 3H).
Description 44c: 4-bromo-2-methyl-benzyl bromide (D44c)
Figure imgf000074_0001
From 4-bromo-2-methyl-benzyl alcohol (D8f) as a cream oil which solidified (yield= 96.1 %). 1H NMR (300MHz, CDCI3, ppm): 7.37 (bs, 1 H), 7.32 (d, 1 H), 7.19 (d, 1 H), 4.47 (s, 2H), 2.41 (s, 3H).
Description 44d: 4-bromo-2-propyloxy-benzyl bromide (D44d)
Figure imgf000074_0002
From 4-bromo-2-propyloxy-benzyl alcohol (D8i) as a cream oil (yield= 98%). LC: Rt = 3.88min.
Description 45: 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (D45)
Figure imgf000074_0003
[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol (D10, 32g, 129 mmol) was dissolved in CH2CI2 (300 ml.) and the reaction mixture was cooled to O0C. PBr3 (104 g, 385 mmol) was dropwise added, and the reaction mixture was stirred at O0C for 45 min. The reaction mixture was poured into ice water, and the organic layer was washed with aqueous sodium carbonate solution until the pH reached 7. The organic layer was dried over Na2SO4 and concentrated to give crude product, which was recrystallized in n-hexane to afford the title compound as a white solid (32 g, 81 %). 1H NMR (400 MHz, CDCI3) J :7.62 (d, 1 H), 7.31 (d, 1 H), 7.26 (d, 1 H), 4.51 (s, 2H), 2.42 (s, 3H), 1.34 (s, 12H). LC-MS: 31 1 (M+H).
Description 46: 4-(4-methylphenyl)-aniline (D46)
Figure imgf000074_0004
To a solution of 4-bromoaniline (3g, 17.4 mmol) in toluene (45 ml.) was added successively (4-methylphenyl)boronic acid (2.81 g, 21 mmol, 1.2 equiv.), Cs2CO3 (17.7g, 54 mmol, 3 equiv.) in water (17ml_), and Pd(Ph3P)4 (300 mg, 0.2 mmol, 0.01 equiv.). The reaction mixture was then heated to reflux for 24 hours before being cooled and concentrated under reduced pressure. The crude product was taken up in water and extracted with CH2CI2. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was purified by chromatography on silica gel (CH2CI2 / MeOH, 98/2) to give the title compound as a white solid (2.6 g, 81% yield).
LCMS (a): (M+H)+= 184, Rt = 3.09 min.
Description 47: 4-(4-azidophenyl)-toluene (D47)
Figure imgf000075_0001
To a suspension of NaN3 (5.5 g, 85 mmol, 6eq) in H2O (4 ml_), were added at rt tBuOH
(20 ml_), 4-(4-methylphenyl)-aniline (D7, 2.6 g, 14.2 mmol) and tBuONO (20.3 ml_, 0.17 mol, 24 eq). The reaction mixture was stirred for 18 hours and to complete the reaction was then heated to 500C for 48 hours. The mixture was taken up in water and extracted with AcOEt. The organic layers were washed with HCI (1 N), dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound as a brown oil (2.3 g, yield: 78%). LC/MS: 200.4 (M+H) , Rt = 3.93 min
Description 48: 4-(4-azidophenyl)-benzyl bromide (D48)
Figure imgf000075_0002
To a solution of 4-(4-azidophenyl)-toluene (D47, 2.3 g, 1 1 mmol) in CCI4 (10OmL) was added N-bromosuccinimide (2.9 g,16.5 mmol, 1.5 eq.) and AIBN (180 mg, 1.1 mmol, 0.1 eq). The mixture was stirred to reflux for 34 hours and after cooling water was added. The organic layer was extracted with CH2CI2 and dried over Na2SO4 to give after evaporation, the title compound as a brown powder (3.5 g, quantitative yield). LC/MS: 279-280 (M+H) , Rt = 3.90 min Description 49i 4-{[4-({2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyloxy}methyl)phenyloxy}benzonitrile (D49)
Figure imgf000076_0001
To a solution of 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (Aldrich, 0.3g, 1.36 mmol,) in acetone (20ml) were added 4-(4-cyanophenoxy)-benzyl bromide (D1 1 , 0.472 g, 1.64 mmol) and Cs2CO3 (0.535 g, 1.64 mmol). The reaction mixture was stirred at 700C for 48hours. After evaporation of the solvent, the residue was hydrolised and extracted with CH2CI2. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2) to give the title compound as a white solid (0.5g, 86%). LC/MS : 445 (M+H) Rt = 4.16
Description 50: Ethyl 1-(6-chloropyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D50)
Figure imgf000076_0002
To a solution of 2,6-dichloropyridine (Aldrich, 5g, 33.78 mmol) in EtOH (80ml) was added dropwise hydrazine hydrate (Aldrich, 8.2ml, 169 mmol). The mixture was heated under reflux during 4 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was dissolved in EtOH (100ml) and ethyl-2-(ethoxymethylene)-4,4,4-trifluoro-3-oxo-butyrate
(Aldrich, 6.9ml, 35.47 mmol) was added dropwise. The mixture was heated under reflux during 3 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure to give the titled compound as a cream oil which crystallised (10.2g, 94.5%). LC/MS: 320.1 (M+H) , Rt = 3.35 min; 1H
NMR (300MHz, CDCI3, ppm): 8.05 (s, 1 H), 7.8 (t, 1 H), 7.5 (d, 1 H), 7.4 (d, 1 H), 4.3 (q, 2H),
1.3 (t, 3H).
Description 51 : Ethyl 1-(6-chloropyridin-2-yl)-5-methyl-pyrazole-4-carboxylate (D51)
Figure imgf000076_0003
Similarly prepared to Description 50 starting from 2,6-dichloropyridine (Aldrich, 7g, 47.3 mmol), hydrazine hydrate (11.47ml, 236.5 mmol), and then ethyl-2-(ethoxymethylene)-3- oxo-butyrate (Orphachem, 8.79g, 47.3 mmol) the title compound was obtained as an ocre solid (12.4g, 98.75%). LC/MS: 266.1 (M+H), Rt = 3.28 min; 1H NMR (300MHz, CDCI3, ppm): 8.05 (s, 1 H), 7.85 (m, 2H), 7.35 (m, 1 H), 4.35 (q, 2H), 2.95 (s, 3H), 1.35 (t, 3H).
Description 52: Ethyl 1-(6-chloropyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D52)
Figure imgf000077_0001
To a solution of 2,6-dichloropyridine (Aldrich, 1.257g, 8.5 mmol) in DMF (50ml) was added Cs2CO3 (2.34g, 7.18 mmol) and then ethyl 2-methyl-pyrrole-3-carboxylate (1g, 6.53 mmol). The mixture was heated at 1300C for 24 hours, then cooled and poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/cHex, 3/2 then 4/1 ) to give the titled compound as a colorless oil which crystallised (0.55g, 31.8%); LC/MS: 265.1 (M+H) , Rt= 3.30 min; 1H NMR (300MHz, CDCI3, ppm): 7.8 (t, 1 H), 7.35 (d, 1 H), 7.25 (d, 1 H), 6.95 (d, 1 H), 6.7 (d, 1 H), 4.3 (q, 2H), 2.7 (s, 3H), 1.4 (t, 3H).
Description 53: i-fθ-chloropyridin^-ylJ^-methyl-pyrrole-S-carboxylic acid (D53)
Figure imgf000077_0002
To a solution of ethyl 1-(6-chloropyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D52, 0.5g, 1.9mmol) in EtOH (10ml) were added NaOH (solution 1 N, 8ml, 7.6 mmol). The reaction mixture was heated at 800C for 18hours. After evaporation of the organic solvent, the residue was diluted in 100 ml of water and the pH was adjusted to 5 with 1 N HCI solution. After extraction with CH2CI2, the organic phase was dried (Na2SO4 ), and concentrated under reduced pressure. The remaining solid was triturated in CH3CN, filtered and dried under vaccum to give the title compound as a white powder (387mg, 86%). LC/MS: 237 (M+H) Rt = 1.86 min
Description 54: Ethyl 1-(6-chloropyridin-2-yl)-piperidine-4-carboxylate (D54)
Figure imgf000077_0003
To a solution of 2,6-dichloropyridine (Aldrich, 4g, 27.03mmol) in EtOH (50ml) was added ethyl piperidine-4-carboxylate (Emka-Chemie, 10.41 ml, 67.57 mmol). The mixture was heated under reflux for 24 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/cHex, 3/2 then 4/1 ) to give the titled compound as a colorless oil (3.93g, 54.15%). LC/MS: 269.1 (M+H) Rt = 3.54 min; 1H NMR (300MHz, CDCI3, ppm): 7.3 (t, 1 H), 6.5 (d, 1 H), 6.4 (d, 1 H), 4.05 (m, 4H), 2.9 (m, 2H), 2.45 (m, 1 H), 1.9 (m, 2H), 1.7 (m, 2H), 1.2 (t, 3H).
Description 55: Methyl 4-(6-chloropyridin-2-yl)-benzoate (D55)
Figure imgf000078_0001
To a solution of 2,6-dichloropyridine (5g, 33.8 mmol) in DME (120ml) were added 4- methoxycarbonylphenyl boronic acid (1.52g, 8.45 mmol), Pd(Ph3P)4 (0.781 g, 0.676 mmole and Na2CO3 (3.58g, 33.8 mmol) in water (10ml). The resulting mixture was heated in Microwave (6OW, 30 min, 1300C). Water and AcOEt were added to the mixture. The organic phase was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silicagel (cHex/EtOAc, gradient from 95/5 to 80/20 then CH2CI2). The title compound was obtained as white solid (3.8%). LC/MS: 248.01 (M+H) Rt= 3.39min; 1H NMR (300MHz, CDCI3, ppm): 8.15 (m, 4H), 7.75 (m, 2H), 7.35 (dd, 1 H), 4 (s, 3H).
Description 56a: Ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D56a)
Figure imgf000078_0002
To a solution of ethyl 1-(6-chloropyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D50, 3g, 9.39mmol) in DME (30ml) and water (3ml) were added Pd(PPh3)4 (0.542g, 0.47mmol), then 2-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenol (2.56ml, 12,21 mmol) and Na2CO3 (2.986g, 28.17 mmol) and the mixture was heated at 900C for 3 hours . After cooling, the mixture was poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/cHex, 4/1 then CH2CI2) to give the titled compound as a yellow oil which crystallised (3.37g, 95.2%). LC/MS: 378.1 (M+H) Rt = 3.54 min; 1H NMR (300MHz, CDCI3, ppm): 8.1 (s, 1 H), 7.95 (m, 2H), 7.75 (d, 1 H), 7.45 (d, 1 H), 7.3 (t, 1 H), 6.95 (d, 1 H), 6.85 (t, 1 H), 4.3 (q, 2H), 1.3 (t, 3H). In subsequent tables a bond V simply illustrates the attachment point for the group concerned and does not represent any specific stereochemical orientation.
The following intermediates were similarly prepared:
Figure imgf000079_0001
Figure imgf000079_0002
Figure imgf000080_0001
Figure imgf000081_0001
Figure imgf000082_0002
Description 57a: Ethyl 1-(6-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D57a)
Figure imgf000082_0001
To a solution of ethyl 1-(6-(5-chloro-2-methoxyphenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D56e, 3.95g, 9.28 mmol) in CH2CI2 (80ml) was added dropwise BBr3 (23.21 ml of a solution 1 M in CH2CI2, 23.21 mmol). The mixture was stirred at room temperature overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/cHex, 4/1 ) to give the title compound as a cream solid (2.22g, 58.11 %). 1H NMR (300MHz, CDCI3, ppm ) δ: 8.15 (s, 1 H), 8.1 (t, 1 H), 7.95 (d, 1 H), 7.75 (sd, 1 H), 7.55 (d, 1 H), 7.3 (dd, 1 H), 6.95 (d, 1 H)4.35 (q, 2H), 1.4 (t, 3H); LC/MS: 412.0 (M+H), Rt= 3.89min.
The following intermediates were similarly prepared:
Figure imgf000083_0001
Figure imgf000083_0002
Figure imgf000084_0001
Description 58: 1-{6-[2-hydroxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperidine-4- carboxylic acid (D58)
Figure imgf000085_0001
To a solution of ethyl 1-{6-[2-methoxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperidine-4- carboxylate (D56n, 3.5 g, 8.57 mmol) was added pyridine hydrochloride (15 g, 130 mmol). The reaction mixture was stirred at 1500C for 1 h, then cooled and diluted with
AcOEt. The organic phase was washed with H2O, then a saturated solution of NH4CI . The organic phase was dried (I^^SO^ and concentrated under reduced pressure. The residue was triturated with pentane. The resulting solid was filtered, washed with pentane, and dried. The title compound was obtained as a light yellow powder (1.5g, yield= 40.6%). LC/MS: 367.0 (M+H), Rt = 2.75min.
Description 59: Ethyl 1-{6-[2-hydroxy-5-trifluoromethylphenyl]pyridin-2-yl}- piperidine-4-carboxylate (D59)
Figure imgf000085_0002
To a solution of 1-{6-[2-hydroxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperidine-4- carboxylic acid (D58, 1.5g, 3.48 mmol) in EtOH (50 mL) at 00C was added HCI (gas) during 5min. The reaction mixture was stirred at room temperature for 2h. N2 was bubbled in the solution to eliminate HCI(g) and the reaction solution was concentrated. Water (50ml) was added to the residue and the mixture was basified with a saturated solution of
NaHCO3. After extraction with AcOEt, the organic phase was washed with H2O, then a saturated solution of NaCI, then dried (Na2SO4\, and concentrated under reduced pressure. The title compound was obtained as a brown oil (2g, yield= 95%). LC/MS: 395.1 (M+H), Rt = 4.07min.
Description 6th ethyl 1-{6-[2-(2-propen-1-yloxy)phenyl]pyridin-2-yl}-5-
(trifluoromethyl)-pyrazole-4-carboxylate (D60)
Figure imgf000085_0003
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 1g, 2.65mmol) in acetone (50ml) was added Cs2CO3 (0.95g,
2.92mmol) and the mixture was stirred at room temperature for 10 minutes. Then allyl bromide (0.337g, 2.78mmol) was added and the mixture was heated under reflux for 2 hours and then cooled. After filtration of the insoluble material, the filtrate was concentrated under reduced pressure. After trituration of the oily residue with pentane, and filtration of the resulting precipitate, the title compound was obtained as a white powder (0.66g, yield= 59.7%). LC/MS: 418 (M+H), Rt = 3.97min
Description 61 : ethyl 1 -{6-[2-hydroxy-3-(2-propen-1 -yl)phenyl]pyridin-2-yl}-5- (trifluoromethyl)-pyrazole-4-carboxylate (D61 )
Figure imgf000086_0001
Ethyl 1-{6-[2-(2-propen-1-yloxy)phenyl]pyridin-2-yl}-5-(trifluoromethyl)-pyrazole-4- carboxylate (D60, 0.66g, 1.58mmol) was heated at 2000C for 10 minutes and then cooled. After purification by chromatography on silicagel ( cHex/ CH2CI2, 110/0 to 0/100), the title compound was obtained as a white powder (0.4g, 60.6%). 1H NMR (300MHz, DMSO d6, ppm): 12.10 (s, 1 H), 8.44 (s, 1 H), 8.42 (d, 1 H), 8.33 (t, 1 H), 7.94 (dd, 1 H), 7.79 (d, 1 H), 7.25 (dd, 1 H), 6.95 (t, 1 H), 5.98 (m, 1 H), 5.04 (m, 2H), 4.35 (q, 2H), 3.37 (d, 2H), 1.32 (t, 3H).
Description 62: ethyl 1-{6-[2-hydroxy-3-propylphenyl]pyridin-2-yl}-5-
(trifluoromethyl)-pyrazole-4-carboxylate (D62)
Figure imgf000086_0002
A solution of ethyl 1-{6-[2-hydroxy-3-(2-propen-1-yl)phenyl]pyridin-2-yl}-5-(trifluoromethyl)- pyrazole-4-carboxylate (D61 , 0.7g, 1.67mmol) in MeOH (35ml) was hydrogenated (H- Cube apparatus, 500C, 30bar). After evaporation of the solvent under reduced pressure, the title compound was obtained as a colorless oil (0.6g, 85%). LC/MS: 420.0 (M+H), Rt = 4.19min.
Description 63: Ethyl 1-(6-(2-(4-cyanobenzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D17)
Figure imgf000086_0003
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 1g, 2.65 mmol) in acetone (50ml) was added Cs2CO3 (1 -12g, 3.45 mmol) and the mixture was stirred at room temperature during 10 minutes. 4-cyanobenzyl bromide (Aldrich, 0.55g, 2.78 mmol) was then added and the mixture was heated under reflux for 1 hour and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2/cHex, 4/1 ). The title compound was obtained as a yellow oil which crystallised (1.33g, quantitative yield); LC/MS: 493.1 (M+H), Rt = 4.01 min; 1H NMR (300MHz, CDCI3, ppm) : 8.05 (s, 1 H), 7.95 (d, 1 H), 7.85 (t, 2H), 7.6 (d, 2H), 7.5 (d, 1 H), 7.4 (d, 2H), 7.3 (t, 1 H), 7.1 (t, 1 H), 6.95 (d, 1 H), 5.15 (s, 2H), 4.3 (q, 2H), 1.35 (t, 3H).
Description 64: Ethyl 1 -(6-(2-(4-(aminothiocarbonyl)-benzyloxy)-phenyl)pyridin-2-yl)- 5-trifluoromethyl-pyrazole-4-carboxylate (D64)
Figure imgf000087_0001
A mixture of ethyl 1-(6-(2-(4-cyanobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D63, 0.8g, 1.63mmol), diethyl dithiophosphate (Aldrich, 0.41 ml, 2.44mmol) and a drop of water was stirred at room temperature for 24 hours and then water was added. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2 then CH2CI2/Me0H, 98/2). The title compound was obtained as a yellow solid (0.57g, yield= 66.6%). LC/MS: 527.1 (M+H), Rt = 3.81 min; 1H NMR (300MHz, CDCI3, ppm): 8.15 (s, 1 H), 8.1 (d, 1 H), 7.95 (m, 2H), 7.85 (m, 2H), 7.75 (Is, 1 H), 7.65 (d, 1 H), 7.4 (d+ls, 3H), 7.15 (t, 1 H), 7.05 (d, 1 H), 5.2 (s, 2H), 4.4 (q, 2H), 1.45 (t, 3H).
Description 65: Ethyl 1 -(6-(2-(4-(4-methyl-thiazol-2-yl)-benzyloxy)-phenyl)pyridin-2- yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D65)
Figure imgf000087_0002
To a solution of ethyl 1-(6-(2-(4-(aminothiocarbonyl)-benzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D64, 0.55g, 1.05mmol) in EtOH (50ml) was added chloroacetone (0.17ml, 2.1 mmol) and the mixture was heated under reflux for 3 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. After trituration with iPr2O , the title compound was obtained as cream solid (0.42g, yield= 71.2%); LC/MS: 565.0 (M+H), Rt = 4.33min; 1H NMR (300MHz, CDCI3, ppm) : 8.05 (s+d, 2H), 7.85 (m, 4H), 7.45 (d, 1 H), 7.35 (d, 2H), 7.4 (dd, 1 H), 7.05 (t, 1 H), 6.95 (d, 1 H), 6.8 (s, 1 H), 5.1 (s, 2H), 4.3 (q, 2H), 2.45 (s, 3H), 1.35 (t, 3H).
Description 66a: Ethyl 1-(6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D66a)
Figure imgf000088_0001
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 1 g, 2.65 mmol) in acetone (50ml) was added Cs2CO3 (1.3g, 4 mmol) and the mixture was stirred at room temperature during 10 minutes. 4-bromobenzyl bromide (Aldrich, 0.73g, 2.9 mmol) was then added and the mixture was heated under reflux during 2 hours and then poured into water. After extraction with EtOAc, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The title compound was obtained as a brown solid (1.5g, quantitative yield); 1H NMR (300MHz, DMSO d6, ppm) : 8.4 (s, 1 H), 8.15 (Is, 2H), 7.75 (dd, 2H), 7.6 (d, 2H), 7.45 (t, 1 H), 7.4 (d, 2H), 7.25 (d, 1 H), 7.1 (t, 1 H), 5.25 (s, 2H), 4.35 (q, 2H), 1.35 (t, 3H).
The following intermediates were similarly prepared:
Figure imgf000088_0002
Figure imgf000088_0003
Figure imgf000089_0001
Figure imgf000090_0001
Figure imgf000091_0001
Description 67: Ethyl 1 -(6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl)-2-methyl- pyrrole-3-carboxylate (D67)
Figure imgf000092_0001
Prepared similarly as described for Description 66a from ethyl 1-(6-(2- hydroxyphenyl)pyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D56g) as colorless oil (yield= 100%); 1H NMR (300MHz, CDCI3, ppm): 7.85 (d, 2H), 7.75 (t, 1 H), 7.4 (d, 2H), 7.3 (t, 1 H), 7.15 (m, 3H), 7.05 (t, 1 H), 6.95 (d, 1 H), 6.9 (d, 1 H), 6.65 (d, 1 H), 5.05 (s, 2H), 4.25 (q, 2H), 2.65 (s, 3H), 1.3 (t, 3H).
Description 68: Ethyl 1-(6-( 2-(4-bromo-2-methyl-benzyloxy)-phenyl)pyridin-2-yl)-2- methyl-pyrazole-3-carboxylate (D68)
Figure imgf000092_0002
Prepared similarly as described for Description 66a from ethyl 1-(6-(2- hydroxyphenyl)pyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D56g) as a yellow oil (yield = 57%). LCMS: 505 (M+H), Rt= 4.41 min.
The following intermediates were similarly prepared:
Figure imgf000092_0003
Figure imgf000092_0004
Figure imgf000093_0002
Similarly prepared as described for D66a :
Description 70: ethyl 1 -{6-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-pyridin-2-yl}-5-(trifluoromethyl)-1H- pyrazole-4-carboxylate (D70)
Figure imgf000093_0001
From ethyl 1-(6-(5-methyl-2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D57d) and 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (D45) as a white powder (yield = 53.5%). LC/MS : 622.1 (M+H), Rt= 4.76min
Description 71 : ethyl 1 -{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-methylphenyl]-2-pyridinyl}-4-piperidinecarboxylate (D71)
Figure imgf000094_0001
From ethyl 1-(6-(5-methyl-2-hydroxyphenyl)pyridin-2-yl)-piperidine-4-carboxylate (D57h) and 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (D45) as a colorless oil (yield = 82%). LC/MS : 571.2 (M+H), Rt = 4.68min
Description 72: ethyl 1 -{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-(trifluoromethyl)phenyl]-2-pyridinyl}-4- piperidinecarboxylate (D72)
Figure imgf000094_0002
From ethyl 1-(6-(5-trifluoromethyl-2-hydroxyphenyl)pyridin-2-yl)-piperidine-4-carboxylate (D59) and 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (D45) as a white gum (yield = 93%). LC/MS : 625.3 (M+H), Rt = 4.83min
Description 73: ethyl 1 -{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1H-pyrazole-4- carboxylate (D73)
Figure imgf000094_0003
To a solution of ethyl 1-(6-(2-(4-bromo-2-methylbenzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D66b, 2.5g, 4.5mmol) in DMF (50ml) were added bis(pinacolato)diboron (1.25g, 4.9mmol), Pd(OAc)2 (0.03g, 0.13mmol) and potassium acetate (0.66g, 6.69mmol) and the mixture was heated at 85°C overnight and then poured into water. After extraction with AcOEt, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (cHex/AcOEt from 100/0 to 80/20). The title compound was obtained as a colorless oil which crystallised (1.4g, yield = 52%). LC/MS : 608.1 (M+H), Rt = 4.77min
Description 74: 1 -{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-methylphenyl]-2-pyridinyl}-4-piperidinecarboxylic acid
Figure imgf000095_0001
To a solution of ethyl 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-methylphenyl]-2-pyridinyl}-4-piperidinecarboxylate (D71 , 1g, 1.753mmol) in EtOH (25ml) was added NaOH (8.76ml of a 1 N solution, 8.76mmol) and the reaction mixture was heated at 800C overnight, and then concentrated under reduced pressure. After dilution with H2O, the mixture was acidified with a solution of HCI 1 N and the resulting precipitate was filtered, washed with water and dried. The title compound was obtained as a white solid (0.807g, quantitative yield). LC/MS: 461.1 (M+H), Rt = 2.71 min
Description 75: 1 -{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- ylJphenyllmethyl^xyJ-S-ttrifluoromethylJphenyll^-pyridinyl^-piperidinecarboxylic acid (D76)
Figure imgf000095_0002
To a yellow solution of ethyl 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan- 2-yl)phenyl]methyl}oxy)-5-(trifluoromethyl)phenyl]-2-pyridinyl}-4-piperidinecarboxylate (D72, 0.6 g, 0.961 mmol) in EtOH (50 ml) / THF (10 ml) was added NaOH (3 ml of a solution 1 N, 3.00 mmol) and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated in vacuo, diluted with water, acidified with a solution of HCI 1 N (pH~6), and then extracted with AcOEt. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The title compound was obtained as a white amorphous solid (0.5g, yield =87.2%). LC/MS : 597.2 (M+H), Rt = 3.84min. Description 76: Ethyl 1-[6-(2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridin- 2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D76)
Figure imgf000096_0001
To a solution of ethyl 1-(6-(2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D66b, 0.5g, 0.89mmol) in DME (50ml) and water (5ml) were added Pd(PPh3)4 (0.103g, 0.089mmol), then 4-fluorophenyl boronic acid (0.162g, 1.16mmol) and Na2CO3 (0.19g, 1.78mmol) and the mixture was heated under reflux for 2 hours . After cooling, the mixture was poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (cHex 100% to cHex/EtOAc 8/2) to give the title compound as a yellow solid (0.38g, yield= 74.0%). 1H NMR (300MHz, CDCI3, ppm): 8.05 (m, 2H), 7.9 (d, 1 H), 7.8 (t, 1 H), 7.5 (m, 3H), 7.35 (m, 4H), 7.05 (m, 4H), 5.1 (s, 2H), 4.3 (q, 2H), 2.3 (s, 3H), 1.35 (t, 3H).
Description 77: Ethyl 1-[6-( 2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D77)
Figure imgf000096_0002
To a solution of ethyl 1-(6-(2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D66b, 0.7g, 1.25mmol) in DME (30ml) and H2O (3ml), were added Pd(PPh3)4 (72mg, 0.062mmol), 4-trifluoromethoxyphenylboronic acid (Avocado, 0.386g, 1.87mmol) and Na2CO3 (0.331g, 3.12mmol) and the mixture was heated at 1050C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2/cHex, 4/1 ). The title compound was obtained as a colorless oil (0.58g, yield= 72.4%). LC/MS: 641.9 (M+H), Rt = 4.71 min. 1H NMR (CDCI3, ppm): 8.05 (s+d, 2H), 7.9 (dd, 1 H), 7.8 (t, 1 H), 7.55 (d, 2H), 7.5 (d, 1 H), 7.8 (m, 3H), 7.2 (m, 2H), 7.05 (m, 2H), 6.75 (d, 1 H), 5.1 (s, 2H), 4.3 (q, 2H), 2.3 (s, 3H), 1.35 (t, 3H). Description 78: Ethyl 1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5- trifluoromethylpyridin-2-yl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylate (D78)
Figure imgf000097_0001
To a solution of ethyl 1-{6-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-pyridin-2-yl}-5-(trifluoromethyl)-1 /-/-pyrazole- 4-carboxylate (D70, 0.200 g, 0.322 mmol), 2,3-dichloro-5-trifluoromethyl-pyridine (0.104 g, 0.483 mmol) and Na2CO3 (0.483 ml. of a 1 M solution, 0.483 mmol) in DME (100 ml) was added Pd(Ph3P)4 (7.44 mg, 6.44 μmol). The mixture was stirred under microwave irradiation for 20 min at 140 °C.The reaction mixture was cooled and extratcted twice with
AcOEt (50ml). The organic layer was washed with H2O, then a saturated solution of NaCI , then dried (Na2SO4 \ and concentrated under reduced pressure. After chromatography on silicagel (cHex / AcOEt 100/0 to 80/20 gradient), the title compound was obtained as a colorless gum (0.15g, yield = 69%). LC/MS : 675.0 (M+H), Rt = 4.66min. 1H NMR (DMSO d6, ppm): 9.03 (s, 1 H), 8.59 (s, 1 H), 8.36 (s, 1 H), 8.13 (m, 2H), 7.72 (dd, 1 H), 7.55 (m, 4H), 7.27 (m, 2H), 5.29 (s, 2H), 4.33 (q, 2H), 2.32 (s, 3H), 2.31 (s, 3H), 1.31 (t, 3H)
The following intermediates were similarly prepared to Description 77:
Figure imgf000098_0001
Figure imgf000099_0001
Figure imgf000100_0001
Figure imgf000101_0001
Figure imgf000102_0001
Figure imgf000103_0001
Figure imgf000104_0001
Figure imgf000105_0001
Figure imgf000107_0001
Figure imgf000108_0001
Figure imgf000109_0002
The following intermediates were similarly prepared as described for Description 77:
Figure imgf000109_0001
Figure imgf000109_0003
Figure imgf000110_0001
Figure imgf000111_0001
Figure imgf000112_0001
Figure imgf000113_0001
Figure imgf000114_0001
The following intermediates were similarly prepared as described for Description 77:
Figure imgf000115_0001
Figure imgf000115_0002
Figure imgf000116_0001
Figure imgf000117_0001
Figure imgf000118_0003
Description 156: Ethyl 1 -[6-(2-(4-(4-azidophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D156)
Figure imgf000118_0001
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 0.2g, 0.53 mmol) in CH3CN (50 ml) was added K2CO3 (0.11g, 0.79 mmol, 1.5 equiv.) and 4-(4-azidophenyl)-benzyl bromide (D48, 0.23g, 0.79 mmol, 1.5 equiv.). The reaction mixture was stirred at 800C for 24h and to complete the reaction 1.5 eq of all reagents were added. The reaction mixture was stirred at 800C for 48hours before being cooled and concentrated to dryness. The crude mixture was taken up in water and extracted with CH2CI2. The organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting solid was purified by chromatography on silica gel (CH2CI2/Me0H, 98/2) to give the title compound as a yellow oil (0.16g, yield: 53%); LC/MS: 585.17 (M+H), Rt = 4.63min
Description 157: Ethyl 1-[6-(2-(4-phenethyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D157)
Figure imgf000118_0002
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 1.5g, 3.98mmol) in acetone (60ml) was added Cs2CO3 (1.94g, 5.97mmol) and the mixture was stirred at room temperature for 10 minutes. 4-(phenethyl)- benzyl bromide (Alfa Aesar, 1g, 4.38mmol) was added and the mixture was heated at 70°C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2ZcHeX, 3/2). The title compound was obtained as a colorless oil (2.1g, yield= 92.4%); LC/MS: 572.1 (M+H) Rt = 4.59 min; 1H NMR (300Mz, CDCI3, ppm): 8.2 (m, 2H), 8 (d, 1 H), 7.9 (t, 1 H), 7.55 (d, 1 H), 7.4 (dd, 1 H), 7.3 (m, 4H), 7.2 (m, 6H), 7.15 (t, 1 H), 5.15 (s, 2H), 4.4 (q, 2H), 2.95 (s, 4H), 1.45 (t, 3H).
Description 158: Ethyl 1-[6-( 2-(4-(4-trifluoromethylphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D158)
Figure imgf000119_0001
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 0.42g, 1.1 1 mmol) in acetone (30ml) was added Cs2CO3 (0.544g, 1.67mmol) and the mixture was stirred at room temperature for 10 minutes. 4-(4- trifluoromethylphenyl)-benzyl bromide (D18, 0.368g, 1.17mmol) was added and the mixture was heated at 700C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2). The title compound was obtained as a yellow oil which crystallised (0.42g, yield= 61.7%); LC/MS: 612.1 (M+H) Rt= 4.60 min; 1H NMR (300Mz, CDCI3, ppm): 8.1 (d, 1 H), 8.05 (s, 1 H), 7.9 (d, 1 H), 7.8 (t, 1 H), 7.65 (Is, 4H), 7.5 (m, 3H), 7.6 (d, 2H), 7.3 (dd, 1 H), 7.05 (m, 2H), 5.15 (s, 2H), 4.3 (q, 2H), 1.35 (t, 3H).
Description 159: Ethyl 1 -[6-(2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylate (D159)
Figure imgf000119_0002
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 1.5g, 3.98mmol) in acetone (250ml) was added Cs2CO3 (1.55g, 4.77mmol) and the mixture was stirred at room temperature for 30 minutes. 4-(4- methoxyphenyl)-benzyl bromide (D16, 1.1g, 3.98mmol) was added and the mixture was heated at 700C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2/cHex, 3/2). The title compound was obtained as a white solid (1.25g, yield= 55%). 1H NMR (300Mz, DMSO d6, ppm): 8.35 (s, 1 H), 8.2 (m, 2H), 7.75 (t, 2H), 7.6 (dd, 4H), 7.5 (d, 2H), 7.45 (dd, 1 H), 7.3 (d, 1 H), 7.1 (t, 1 H), 7 (d, 2H), 5.3 (s, 2H), 4.35 (q, 2H), 3.8 (s, 3H), 1.3 (t, 3H).
Description 160: Ethyl 1-[6-(5-chloro-2-(4-(4-methoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D160)
Figure imgf000120_0001
To a solution of ethyl 1-(6-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D57a, 0.24g, 0.58mmol) in acetone (1OmI) was added Cs2CO3 (0.19g, 0.58mmol) and the mixture was stirred at room temperature for 10 minutes. 4-(4- methoxyphenyl)-benzyl bromide (D16, 0.162g, 0.58mmol) was added and the mixture was heated at 700C for 18 hours. The solid material was filtered off, washed with acetone, and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cHex 100% to cHex/EtOAc 8/2). The title compound was obtained as a white amorphous powder (0.14g, yield= 40%); 1H NMR (300Mz, CDCI3, ppm): 8.2 (d, 1 H), 8.15 (s, 1 H), 8 (s, 1 H), 7.9 (t, 1 H), 7.55 (m, 5H), 7.4 (d, 2H), 7.35 (dd, 1 H), 7 (m, 3H), 5.2 (s, 2H), 4.4 (q, 2H), 3.9 (s, 3H), 1.4 (t, 3H).
Description 161 : Ethyl 1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D161)
Figure imgf000120_0002
To a solution of ethyl 1-(6-(5-fluoro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D57b, 0.25g, 0.63mmol) in acetone (20ml) was added Cs2CO3 (0.31 g, 0.95mmol) and the mixture was stirred at room temperature for 10 minutes. 4-(4- methoxyphenyl)-benzyl bromide (D16, 0.21 g, 0.76mmol) was added and the mixture was heated at 65°C for 2 hours and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cHex 100% to cHex/EtOAc 8/2). The title compound was obtained as a white solid (0.34g, yield= 90.9%); 1H NMR (300Mz, CDCI3, ppm): 8.25 (d, 1 H), 8.15 (s, 1 H), 7.95 (t, 1 H), 7.8 (dd, 1 H), 7.55 (m, 5H), 7.45 (d, 2H), 7.1 (m, 2H), 7 (d, 2H), 5.2 (s, 2H), 4.4 (q, 2H), 3.9 (s, 3H), 1.45 (t, 3H). Description 162 : Ethyl 1-[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D162)
Figure imgf000121_0001
To a solution of ethyl 1-(6-(3,5-difluoro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl- pyrazole-4-carboxylate (D57c, 0.23g, 0.556mmol) in acetone (1 OmI) was added Cs2CO3 (0.181g, 0.556mmol) and the mixture was stirred at room temperature for 10 minutes. 4- (4-methoxyphenyl)-benzyl bromide (D16, 0.154g, 0.556mmol) was added and the mixture was stirred at room temperature for 18 hours and then poured into water. After extraction with AcOEt, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (cHex 100% to cHex/EtOAc 7/3). The title compound was obtained as a colorless oil (0.18g, yield= 53.1 %); 1H NMR (300Mz, CDCI3, ppm): 8 (d+s, 2H), 7.8 (t, 1 H), 7.55 (d, 1 H), 7.35 (m, 5H), 7.15 (m, 2H), 6.9 (m, 3H), 4.85 (s, 2H), 4.35 (q, 2H), 3.8 (s, 3H), 1.3 (t, 3H).
Description 163: Ethyl 1-[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylate (D163)
Figure imgf000121_0002
To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4- carboxylate (D56a, 0.7g, 1.86mmol) in acetone (50ml) was added Cs2CO3 (0.91 g, 2.78mmol) and the mixture was stirred at room temperature for 10 minutes. 4-(4- cyanophenoxy)-benzyl bromide (D11 , 0.59g, 2.04mmol) was added and the mixture was heated at 700C overnight and then poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2/cHex, 4/1 ). The title compound was obtained as a colorless oil (0.83g, yield= 76.5%). LC/MS: 585.0 (M+H) Rt= 4.36 min; 1H NMR (300Mz, CDCI3, ppm): 8.05 (m, 2H), 7.85 (dd, 1 H), 7.8 (t, 1 H), 7.55 (d, 2H), 7.5 (d, 1 H), 7.35 (m, 3H), 7.1 (t, 1 H), 6.95 (m, 5H), 5.1 (s, 2H), 4.35 (q, 2H), 1.35 (t, 3H)
The following intermediates were similarly prepared as described for Description 157:
Figure imgf000122_0001
Figure imgf000123_0001
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
The following intermediates were similarly prepared as described for Description 157:
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0002
The following intermediates were similarly prepared as described for Description 157:
Figure imgf000135_0001
Figure imgf000136_0002
The following intermediates were similarly prepared as described for Description 157:
Figure imgf000136_0003
Figure imgf000136_0001
Figure imgf000137_0002
The following intermediates were similarly prepared as described for Description 157:
Figure imgf000137_0001
Figure imgf000137_0003
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Description 240: 1-[6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole- 3-carboxylic acid (D240)
Figure imgf000144_0001
To a solution of ethyl 1-(6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl)-2-methyl-pyrrole-3- carboxylate (D67, 0.46g, 0.996mmol) in EtOH (50ml) was added NaOH (solution 1 N, 20ml). The mixture was heated under reflux for 18 hours then cooled and neutralised by addition of a solution of HCI 1 N. After evaporation of EtOH , the resulting precipitate was filtered , washed with water and dried. The title compound was obtained as yellow solid (0.39g, yield = 90%). 1H NMR (300MHz, CDCI3, ppm): 7.85 (m, 2H), 7.75 (t, 1 H), 7.4 (d, 2H), 7.3 (t, 1 H), 7.2 (m, 3H), 7.05 (t, 1 H), 6.95 (d, 1 H), 6.9
Description 241 : 1-[6-( 2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid (D241)
Figure imgf000144_0002
To a solution of Ethyl 1-[6-( 2-hydroxy-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3-carboxylate (D56g, 0.6g, 2 mmol) in CH3CN (20 ml), 4-bromo-2-methylbenzyl bromide D44c (0. 647g, 2.45 mmol) and Cs2CO3 (0.79g, 2.45 mmol, 1.2 eq) were added. The mixture was refluxed for I Ohours and then poured into water, extracted with CH2CI2 and dried over Na2SO4. The organic phase was concentrated under reduced pressure to leave a yellow oil which was dissolved in EtOH (70ml )and a few drops of THF. 1 N NaOH solution was added (6ml_, 5.85 mmol) and the mixture was heated at 700C for 48hours. After evaporation of the organic solvents in vacuo, the reaction mixture was acidified to pH= 5 with 1 N HCI solution. The resulting precipitate was filtered, washed with water and dried to give the title compound as a cream powder (0.56g, 62.9%). LC/MS: 479 (M+H) Rt = 3.54 min.
Description 242: 1 -[6-( 5-fluoro-2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2-yl]- 2-methyl-pyrrole-3-carboxylic acid (D242)
Figure imgf000144_0003
Prepared as described for Description 241 from ethyl 1-[6-(5-fluoro-2-hydroxy- phenyl)pyridin-2-yl]-2-methyl-pyrrole-3-carboxylate (D56h).
Description 243 : 1-[6-(5-trifluoromethyl-2-((2-propyloxy-4-bromophenyl)methyloxy)- phenyl)pyridin-2-yl]-1 -piperidine-4-carboxylic acid (D243)
Figure imgf000145_0001
Prepared by a similar method as described for D66a from ethyl 1-{6-[2-hydroxy-5- trifluoromethylphenyl]pyridin-2-yl}-piperidine-4-carboxylate (D59) and 4-bromo-2- propyloxy-benzyl bromide (D44d). The title compound was obtained as an orange oil (yield = 82%). LC/MS: 623.0 (M+H), Rt= 4.90min.
Prepared by a similar method as described for D77:
Figure imgf000145_0002
Figure imgf000145_0003
Figure imgf000146_0002
Prepared by a similar method as described for D56a:
Figure imgf000146_0001
Figure imgf000146_0003
Prepared by a similar method as described for D57a:
Figure imgf000147_0001
Figure imgf000147_0004
Description 254: Ethyl-1-[6-(6-chloro-2-hydroxy-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D254)
Figure imgf000147_0002
Prepared by a similar method as described for D56a from 1-(6-chloropyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D50). The title compound was obtained as a yellow oil (yield= 93%). LC/MS: 412.1 (M+H), Rt= 3.62min.
Prepared by a similar method as described for D157:
Figure imgf000147_0003
Figure imgf000147_0005
Figure imgf000148_0001
Description 259: Ethyl 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D259)
Figure imgf000149_0001
Prepared by a similar method as described for D77 from ethyl 1-(6-(2-(4- bromobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D66a), the title compound was obtained as a colourless oil (yield = 46.5%). LC/MS: 610.3 (M+Na), Rt = 4.56min; 1H NMR (CDCI3, ppm): 8.22 (d, 1 H), 8.15 (s, 1 H), 8.01 (dd, 1 H), 7.91 (t, 1 H), 7.57 (d, 1 H), 7.43 (m, 3H), 7.32 (d, 2H), 7.17 (m, 3H), 6.83 (m, 2H), 5.23 (s, 2H), 4.41 (q, 2H), 3.86 (s, 3H), 2.29 (s, 3H), 1.42 (t, 3H).
Description 260: Ethyl 1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl- phenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate
(D260)
Figure imgf000149_0002
Prepared by a similar method as described for D77 from ethyl 1-(6-(5-fluoro-2-(4-bromo-2- methyl-benzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D66c), the title compound was obtained as a yellow oil (yield = 28%). LC/MS: 642.3 (M+Na), Rt = 4.66min; 1H NMR (CDCI3, ppm): 8.12 (d, 1 H), 8.06 (s, 1 H), 7.81 (t, 1 H), 7.68 (dd, 1 H), 7.50 (d, 1 H), 7.28 (d, 1 H), 7.19 (s, 1 H), 7.08 (m, 2H), 7.03 (m, 2H), 6.73 (m, 2H), 5.05 (s, 2H), 4.32 (q, 2H), 3.77 (s, 3H), 2.25 (s, 3H), 2.20 (s, 3H), 1.33 (t, 3H).
Example 1 : 1 -[6-(2-(4-phenethyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid
Figure imgf000150_0001
To a solution of ethyl 1-[6-(2-(4-phenethyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D157, 2.1 g, 3.68mmol) in MeOH (50ml) and H2O (20ml) was added NaOH (18.4ml of a solution 1 N, 18.4mmol) and the mixture was heated at 700C for 3 hours and then poured into water. The solution was neutralised by addition of a solution 1 N of HCI. After cooling, the resulting precipitate was filtered, washed with water, then pentane and dried. The title compound was obtained as a white solid (1.77g, yield = 88.6%). Mp: 157°C; LC/MS: 544.1 (M+H), Rt= 3.38min; LC-HRMS (a): C3IH24F3N3O3 Rt= 2.72min, CaIc: 544.1848 (M+H), Found: 544.1883 (M+H); 1H NMR (DMSO, d6, ppm): 8.35 (s, 1 H), 8.15 (m, 2H), 7.75 (m, 2H), 7.45 (dd, 1 H), 7.35 (d, 2H), 7.2 (m, 8H), 7.1 (t, 1 H), 5.2 (s, 2H), 2.9 (s, 4H).
Example 2: 1-[6-(2-(4-(4-trifluoromethylphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000150_0002
To a solution of ethyl 1-[6-(2-(4-(4-trifluoromethylphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D158, 0.42g, 0.69mmol) in MeOH (20ml) and H2O (10ml) was added NaOH (3.44ml of a solution 1 N, 3.44mmol) and the mixture was heated at 700C for 3 hours and then poured into water. The solution was neutralised by addition of a solution 1 N of HCI. After cooling, the resulting precipitate was filtered, washed with water, then pentane and dried. The title compound was obtained as a white solid (0.38g, yield= 94.8%). Mp: 189°C; LC/MS: 584.14 (M+H), Rt= 3.45min; LC-HRMS (a): C30Hi9F6N3O3 , Rt= 2.78min, CaIc: 584.1409 (M+H), Found: 584.1452 (M+H); 1H NMR (DMSO d6, ppm): 8.35 (s, 1 H), 8.2 (m, 2H), 7.9 (d, 2H), 7.8 (d, 2H), 7.7 (m, 4H), 7.55 (d, 2H), 7.45 (dd, 1 H), 7.3 (d, 1 H), 7.1 (t, 1 H), 5.35 (s, 2H) Example 3^ 1-[6-(2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000151_0001
To a solution of ethyl 1-[6-(2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D159, 1.25g, 2.18mmol) in EtOH (40ml) and THF (10ml) was added NaOH (10.9ml of a solution 1 N, 10.9mmol) and the mixture was heated at 800C for 1 hour and then EtOH was evaporated. The aquous residue was made slightly acid with a solution 1 N of HCI and was extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2/Me0H, 9/1), and after crystallisation from CH3CN, the title compound was obtained as a white crystals (1.1g, yield= 92%) LC/MS: 546.13 (M+H), Rt= 3.21 min, LC-HRMS (a): C30H22F3N3O4 , Rt= 2.76 min, CaIc: 544.1484 (M-H), Found: 544.1479 (M-H); 1H NMR (DMSO, d6, ppm): 8.3 (s, 1 H), 8.15 (m, 2H), 7.75 (m, 2H), 7.6 (d, 3H), 7.5 (d, 2H), 7.45 (m, 1 H), 7.3 (d, 2H), 7.15 (t, 1 H), 7 (d, 2H), 5.3 (s, 2H), 3.85 (s, 3H)
Example 4: 1-[6-(5-chloro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000151_0002
To a solution of ethyl 1-[6-(5-chloro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D160, 0.14g, 0.23mmol) in EtOH (40ml) was added NaOH (1.15ml of a solution 1 N, 1.15mmol) and the mixture was heated at 800C for 2 hours and then EtOH was evaporated. The aquous residue was made slightly acid with a solution 1 N of HCI and was extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with iPr2O, and the precipitate was filtered and dried. The title compound was obtained as white solid (0.105g, yield: 79%). LC-HRMS (a): C30H21CIiF3N3O4 , Rt= 2.81 min, CaIc: 578.1094 (M-H), Found: 578.1072 (M-H); 1H NMR (300MHz, CDCI3, ppm): 8.15 (s+d, 2H), 7.95 (sd, 1 H), 7.85 (t, 1 H), 7.5 (m, 5H), 7.35 (d, 2H), 7.25 (dd, 1 H), 6.95 (m, 3H), 5.15 (s, 2H), 3.85 (s, 3H) Example 5: 1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000152_0001
To a solution of ethyl 1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D161 , 0.34g, 0.57mmol) in MeOH (20ml) was added NaOH (1.72ml of a solution 1 N, 1.72mmol) and the mixture was heated under reflux overnight and then cooled. The solution was neutralised by addition of a solution 1 N of HCI. After evaporation of MeOH under reduced pressure , the resulting precipitate was filtered, washed with water, then pentane and dried. The title compound was obtained as a white solid (0.29g, yield= 89.6%). Mp: 187°C; LC-HRMS (a): C30H21F4N3O4, Rt= 2.72min, CaIc: 562.1390 (M-H), Found: 562.1429 (M-H); 1H NMR (DMSO, d6, ppm): 8.35 (s, 1 H), 8.25 (d, 1 H), 8.15 (t, 1 H), 7.8 (d, 1 H), 7.65 (m, 5H), 7.5 (d, 2H), 7.35 (m, 2H), 7.05 (d, 2H), 5.3 (s, 2H), 3.85 (s, 3H)
Example 6: 1-[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000152_0002
To a solution of ethyl 1-[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyridin- 2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D162, 0.18g, 0.295mmol) in EtOH (50ml) was added NaOH (1.47ml of a solution 1 N, 1.47mmol) and the mixture was heated at 800C for 1 hour and then EtOH was evaporated. The aquous residue was made slightly acid with a solution 1 N of HCI and was extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with iPr2O, and the precipitate was filtered and dried. The title compound was obtained as a white powder (0.085g, yield= 50%). LC-HRMS (a): C30H20F5N3O4, Rt= 2.76min, CaIc: 580.1296(M-H), Found: 580.1276(M-H); 1H NMR (CDCI3, ppm): 8.1 (s, 1 H), 8.05 (d, 1 H), 7.85 (t, 1 H), 7.55 (d, 1 H), 7.4 (m, 5H), 7.15 (d, 2H), 6.9 (d+m, 3H), 4.9 (s, 2H), 3.8 (s, 3H). Example 7: 1-[6-(2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000153_0001
To a solution of ethyl 1-[6-(2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylate (D76, 0.38g, 0.66mmol) in MeOH (20ml) was added NaOH (1.98ml of a solution 1 N, 1.98mmol) and the mixture was heated under reflux overnight and then cooled. The solution was neutralised by addition of a solution 1 N of HCI. After evaporation of MeOH under reduced pressure, the resulting precipitate was filtered, washed with water, then pentane and dried. The title compound was obtained as a white solid (0.28g, yield= 77.5%). Mp: 2210C; LC-HRMS (a): C30H21F4N3O3 , Rt= 2.79 min, CaIc: 546.1441 (M-H), Found: 546.1414 (M-H); 1H NMR (DMSO, d6, ppm): 8.3 (s, 1 H), 8.1 (m, 2H), 7.7 (m, 4H), 7.45 (m, 4H), 7.4 (d, 1 H), 7.3 (t, 2H), 7.1 (t, 1 H), 5.3 (s, 2H), 2.35 (s, 3H)
Example 8i 1-[6-(2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000153_0002
To a solution of ethyl 1-[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D163, 0.83g, 1.42mmol) in EtOH (30ml) and THF (30ml) was added LiOH (2.84ml of a solution 1 N, 2.84mmol) and the mixture was stirred at room temperature overnight. The solution was adjusted to pH4 with a 1 N solution of HCI and the organic solvents were evaporated under reduced pressure. The resulting precipitate was filtered and dried. After crystallisation from CH3CN, the title compound was obtained as white crystals (0.5g, yield= 63.2%). Mp: 1900C; LC-HRMS (a): C30H19F3N4O4 , Rt = 2.65min , CaIc: 555.1281 (M-H), Found: 555.1231 (M-H); 1H NMR (300MHz, DMSO d6, ppm): 8.3 (s, 1 H), 8.15 (m, 2H), 7.85 (d, 2H), 7.75 (t, 2H), 7.55 (d, 2H), 7.45 (t, 1 H), 7.32 (d, 1 H), 7.15 (m, 5H), 5.3 (s, 2H). Example 9^ 1 -[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)- phenylJpyridin^-y^-S-trifluoromethyl-pyrazole^-carboxylic acid
Figure imgf000154_0001
To a solution of ethyl 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D77, 0.55g, 0.86mmol) in MeOH (20ml), THF (20ml) and water (10ml) was added NaOH (4.3ml of a solution 1 N, 4.3mmol) and the mixture was heated at 600C for 2 hours. The solution was made slightly acid with a solution 1 N of HCI and the organic solvents were evaporated under reduced pressure. The resulting precipitate was filtered, washed with water, then pentane and dried. The title compound was obtained as a white powder (yield=88.8%). Mp= 1710C; LC-HRMS (a): C3IH2IF6N3O4 , Rt= 3.26min, CaIc: 612.1358 (M-H), Found: 612.1352 (M- H); 1H NMR (DMSO d6), ppm): 8.3 (s, 1 H), 8.1 (m, 2H), 7.8 (d, 2H), 7.75 (m, 2H), 7.55 (s, 1 H), 7.45 (m, 5H), 7.35 (d, 1 H), 7.15 (t, 1 H), 5.3 (s, 2H), 2.3 (s, 3H).
Example 10: 1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- ylJbenzyloxyJ-phenylJpyridin^-y^-S-trifluoromethyl-pyrazole^-carboxylic acid
Figure imgf000154_0002
To a solution of ethyl 1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- yl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D78, 0.150 g, 0.222 mmol) in EtOH (20 ml) and THF (5 ml) was added NaOH (0.700 ml of a solution 1 N, 0.700 mmol) and the mixture was stirred at 600C for 4 hours. The reaction mixture was concentrated under reduced pressure, diluted with water, acidified with HCI 1 N (pH~6), and extracted with AcOEt. The organic phase was dried (Na2SO4) and concentrated under reduced pressure. The residue was triturated with iPr2O and the resulting solid was filtered, washed with iPr2O and dried. The title compound was obtained as a white powder (0.07g, yield= 46.3%). LC-HRMS: C3i H21 Ch F6N4O3 , Rt= 3.33min, CaIc: 647.1285 (M+H), Found: 647.1313 (M+H); 1H NMR (DMSO d6), ppm): 9.03 ( s, 1 H), 8.58 (s, 1 H), 8.3 (s, 1 H), 8.13 (m, 2H), 7.71 (dd, 1 H), 7.55 (m, 4H), 7.27 (m, 2H), 5.29 (s, 2H), 2.33 (s, 3H), 2.31 (s, 3H). The following Examples were similarly prepared as described for Example 9 for R9 ≠ CN or were similarly prepared as described for Example 8 for R9 = CN:
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0002
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
The following Examples were similarly prepared as described for Example 9 for R9 ≠ CN or were similarly prepared as described for Example 8 for R9 = CN:
Example Name
87 1-[6-(3,5-difluoro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000178_0001
Figure imgf000179_0002
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Figure imgf000189_0001
Figure imgf000190_0001
Figure imgf000191_0001
Figure imgf000192_0002
The following Examples were similarly prepared as described for Example 9 for R9 ≠ CN or were similarly prepared as described for Example 8 for R9 = CN:
Figure imgf000192_0003
Figure imgf000192_0001
Figure imgf000192_0004
The following Examples were similarly prepared as described for Example 9 for R9 ≠ CN or were similarly prepared as described for Example 8 for R9 = CN:
Figure imgf000193_0001
Figure imgf000194_0001
Figure imgf000194_0002
Figure imgf000195_0001
The following Examples were similarly prepared as described for Example 9 for R9 ≠ CN or were similarly prepared as described for Example 8 for R9 = CN:
Figure imgf000195_0002
Figure imgf000196_0001
Figure imgf000197_0002
Figure imgf000197_0001
Figure imgf000197_0003
Figure imgf000198_0001
Figure imgf000200_0001
Figure imgf000201_0001
Figure imgf000202_0001
Figure imgf000203_0001
Figure imgf000204_0001
Figure imgf000205_0001
Figure imgf000206_0001
Figure imgf000207_0001
Figure imgf000208_0001
Figure imgf000209_0001
Figure imgf000210_0001
Example 167: 1-[6-(2-(4-(4-cyanophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-methyl- pyrazole-4-carboxylic acid
Figure imgf000211_0001
To a solution of ethyl 1-[6-(2-(4-(4-cyanophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-methyl- pyrazole-4-carboxylate (D168, 0.57g, 1.1 1 mmol) in MeOH (20ml) and H2O (20ml) was added NaOH (5.5ml of a solution 1 N, 5.54mmol) and the mixture was heated at 700C for 3 hours and then poured into water. The solution was neutralised by addition of a solution 1 N of HCI. After cooling, the resulting precipitate was filtered, washed with water, then pentane and dried. The solid was purified by chromatography on silica gel . Elution with CH2CI2/Me0H, 97/3, led after crystallisation from CH3CN to the title compound as white crystals (0.3g, yield= 55.7%). Mp: 2020C; LC/MS: 487.1 (M+H), Rt= 3.03min; LC-HRMS (a): C30H22N4O3 , Rt= 2.71 min, CaIc: 487.1770 (M+H), Found: 487.1776 (M+H); 1H NMR (DMSO, d6, ppm):8.05 (m, 3H), 7.9 (m, 4H), 7.75 (m, 4H), 7.6 (d, 2H), 7.45 (dd, 1 H), 7.3 (d, 1 H), 7.15 (t, 1 H), 5.35 (s, 2H), 2.85 (s, 3H).
Then elution with CH2CI2/Me0H, 93/7, and trituration with iPr2O led to
Example 168: 1 -[6-( 2-(4-(4-carboxamidophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- methyl-pyrazole-4-carboxylic acid as a white solid (0.08g)
Figure imgf000211_0002
Mp: 258°C; LC/MS: 505.1 (M+H), Rt = 2.61 min; LC-HRMS (a): C30H24N4O4 , Rt= 2.30min, CaIc: 505.1876 (M+H), Found: 505.18.63 (M+H); 1H NMR (DMSO, d6, ppm): 8.05 (m, 4H), 7.95 (d, 2H), 7.85 (dd, 1 H), 7.25 (m, 5H), 7.55 (d, 2H), 7.45 (dd, 1 H), 7.4 (s, 1 H), 7.3 (d, 1 H), 7.15 (t, 1 H), 5.3 (s, 2H), 2.9 (s, 3H). Example 169: 1 -[6-( 2-(4-(4-carboxamidophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000212_0001
To a solution of ethyl 1-[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D163, 0.44g, 0.75mmol) in MeOH (20ml) and H2O (10ml) was added NaOH (7.53ml of a solution 1 N, 7.53mmol) and the mixture was heated at 900C for 24 hours and then poured into water. The solution was neutralised by addition of a solution 1 N of HCI. After cooling, the resulting precipitate was filtered, washed with water, then pentane and dried. The solid was purified by chromatography on silicagel (CH2CI2/Me0H, 97/3 then 9/1 )to afford a white solid which was triturated with hot iPr2O. After filtration, the title compound as white solid (0.17g, yield= 39.3%). Mp: 2110C; LC/MS: 576.0 (M+H), Rt = 2.75min; LC-HRMS (a): C30H21F3N4O5 , Rt = 2.31 min, CaIc: 575.1542 (M+H), Found: 575.1584 (M+H); 1H NMR (DMSO, d6, ppm): 8.3 (s, 1 H), 8.15 (m, 2H), 7.95 (d+m, 3H), 7.75 (m, 2H), 7.55 (d, 2H), 7.5 (m, 1 H), 7.35 (s+d, 2H), 7.15 (m, 1 H), 7.1 (d, 2H), 7.05 (d, 2H), 5.25 (s, 2H).
Example 170: 1 -[6-(2-(2-methyl-4-(5-carboxamidopyridin-2-yl)benzyloxy)- phenylJpyridin^-ylJ-S-trifluoromethyl-pyrazole^-carboxylic acid
Figure imgf000212_0002
Prepared similarly to the method described for Example 164 from ethyl 1-[6-(2-(2-methyl- 4-(5-cyanopyridin-2-yl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylate (D120) as pale yellow crystals. Mp= 202.50C; LC-HRMS (a): C30H22F3N5O4 , Rt= 2.43min, CaIc: 572.1546 (M-H), Found: 572.1516 (M-H); 1H NMR (300MHz, DMSO d6, ppm): 9.1 (bs, 1 H), 8.31 (m, 2H), 8.24 (bs, NH), 8.16 to 8.06 (m, 3H), 8.02 (bs, 1 H), 7.94 (d, 1 H), 7.74 (t, 2H), 7.62 (bs, NH), 7.5 (m, 2H), 7.37 (d, 1 H), 7.13 (t, 1 H), 5.31 (s, 2H), 2.35 (s, 3H). Example 171 : 1-[6-(5-methyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
Figure imgf000213_0001
To a solution of 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-methylphenyl]-2-pyridinyl}-4-piperidinecarboxylic acid (D74, 0.3g, 0.65 mmol) and 6-bromo-3-pyridinecarbonitrile (0.155 g, 0.85 mmol) in DME (5 ml.) and water (1 ml), were added Na2CO3 (0.138g, 1.3 mmol) and Pd(Ph3P)4 (37.7 mg, 0.033mmol). The reaction mixture was heated under reflux overnight and then poured into water. After extraction with AcOEt, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The solid residue was recrystallised from CH3CN. The title compound was obtained as white crystals ( 0.06g, yield= 17.7%). LC-HRMS (a): C32H30N4O3 , Rt= 2.97, CaIc: 519.2396 (M+H), Found: 519.2416 (M+H); 1H NMR (300MHz, DMSO d6, ppm): 9.08 (s, 1 H), 8.38 (d, 1 H), 8.2 (d, 1 H), 8.03 (s, 1 H), 7.97 (d, 1 H), 7.52 (m, 3H), 7.15 (bs, 2H), 7.09 (d, 1 H), 6.75 (d, 1 H), 5.19 (s, 2H), 4.25 (Id, 2H), 2.92 (t, 2H), 2.46 (m, 1 H), 2.36 (s, 3H), 2.3 (s, 3H), 1.88 (m, 2H), 1.55 (m, 2H)
Example 172: 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
Figure imgf000213_0002
To a solution of 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yOphenyOmethylJoxy^δ-^rifluoromethyOphenyO^-pyridinyl^-piperidinecarboxylic acid (D75, 0.55g, 0.495 mmol) and 6-bromo-3-pyridinecarbonitrile (0.136 g, 0.743 mmol) in DME (50 ml.) was added Na2CO3 (0.743 ml. of a solution 1 N, 0.743 mmol) and Pd(Ph3P)4 (11.44 mg, 9.90 μmol). The reaction mixture was heated under reflux for 3 days (0.02eq of Pd(Ph3P)4 and 0.5 eq 6-bromo-3-pyridinecarbonitrile were added once each day until completion of the reaction). After cooling, the mixture was filtered through celite and concentrated. The residue was taken in AcOEt and washed with a saturated solution of NaHCO3, then H2O. The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH2CI2/Me0H 100/0 to 90/10). After recrystallisation from CH3CN, the title compound was obtained as white crystals ( 0.14g, yield= 46.9%). LC-HRMS (a): C32H27F3N4O3 , Rt= 3.26min, CaIc: 573.2114 (M+H), Found: 573.2178 (M+H); 1H NMR (300MHz, DMSO d6, ppm): 9.09 (s, 1 H), 8.39 (d, 1 H), 8.2 (d, 1 H), 8.02 (m, 3H), 7.75 (d, 1 H), 7.56 (m, 2H), 7.47 (d, 1 H), 7.18 (d, 1 H), 6.83 (d, 1 H), 5.37 (s, 2H), 4.24 (Id, 2H), 2.96 (t, 2H), 2.55 (m, 1 H), 2.4 (s, 3H), 1.87 (m, 2H), 1.54 (m, 2H).
Example 173: 1-[6-( 5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyridin-2- yl)benzyloxy)-phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
Figure imgf000214_0001
To a solution of 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)-5-methylphenyl]-2-pyridinyl}-4-piperidinecarboxylic acid (D74, 0.3g, 0.652mmol) in DME (5ml) and H2O (1 ml) was added 2,3-dichloro-5-trifluoromethyl- pyridine (0.183g, 0.847mmol), Pd(PPh3)4 (37.7mg, 0.033mmol) and Na2CO3 (0.138g, 1.303mmol) and the reaction mixture was heated under reflux overnight and then poured into water. After extraction with AcOEt, the organic phase was dried (Na2SO4) and concentrated under reduced pressure. The sample was purified by Mass Directed AutoPrep. The title compound was obtained as a white powder (0.04g, yield= 10.3%). LC- HRMS (a): C32H29CI1F3N3O3 , Rt= 3.49, CaIc: 596.1927, Found: 596.1983; 1H NMR (300MHz, DMSO d6, ppm): 9.02 (bs, 1 H), 8.57 (bs, 1 H), 7.53 (m, 4H), 7.49 (bs, 1 H), 7.16 (bs, 2H), 7.10 (d, 1 H), 6.77 (d, 1 H), 5.2 (s, 2H), 4.25 (m, 2H), 2.93 (m, 2H), 2.47 (m, 1 H), 2.35 (s, 3H), 2.31 (s, 3H), 1.89 (m, 2H), 1.55 (m, 2H).
Example 174: 1-[6-(2-(4-(4-cyanophenyl)benzyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid
Figure imgf000214_0002
To a solution of 1-[6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3- carboxylic acid (D240, 0.39g, 0.84mmol) in DME (30ml) was added 4-cyanophenylboronic acid (Aldrich, 0.137g, 0.93mmol), then Na2CO3 (0.178g , 1.68mmol) in H2O (5ml) and
Pd(Ph3P)4 (0.048g, 0.042mmol). The mixture was heated under reflux overnight , then cooled and filtered on a celite pad and the precipitate washed with EtOAc. The filtrate was washed with water, then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH2CI2 then CH2CI2/Me0H 9/1 ) and the resulting solid was triturated with hot CH3CN and then filtered. The title compound was obtained as white solid (0.035g, yield= 9%). LC/MS: 486.0 (M+H) , Rt= 3.46min; LC- HRMS (a): C3IH23N3O3 , Rt= 3.14min, CaIc: 484.1661 (M-H), Found: 484.1658 (M-H); 1H NMR (300MHz, DMSO d6, ppm): 8.05 (m, 2H), 7.95 (q, 4H), 7.8 (m, 3H), 7.6 (d, 2H), 7.5 (d, 1 H), 7.45 (m, 1 H), 7.3 (d, 1 H), 7.2 (d, 1 H), 7.15 (t, 1 H), 6.55 (d, 1 H), 5.35 (s, 2H), 2.65 (s, 3H).
Example 175: 1 -[6-( 2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid
Figure imgf000215_0001
To a solution of 1-[6-(2-(4-bromo-2-methylbenzyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid (D241 , 797 mg, 1.67 mmol) in DME (5ml_) and a few drops of EtOH were added (4-fluorophenyl)boronic acid ( 280 mg, 2 mmol, 1.2eq), Cs2CO3 ( 652 mg, 2 mmol, 1.2 eq) and Pd(PPh3)4 (94mg, 0.05 eq, 0.084 mmol). The reaction was performed in sealed tube in a microwave Biotage at 1300C for 8 minutes. The mixture was poured in water, acidified to pH = 5 with aqueous 1 N HCI, extracted with DCM, and dried over Na2SO4. After filtration and evaporation in vacuo, the remaining oil was purified by chromotagraphy on silica gel (eluent: CH2CI2/ MeOH= 95:5). Recristallisation from a mixture of CH3CN/ EtOH afforded the title compound as an orange powder (127 mg, 15.46%). LC-HRMS (a): C31H25F1N2O3 , Rt= 3.63min, CaIc: 493.1927 (M+H), Found: 493.1917 (M+H); 1H NMR ( DMSO-d6, ppm): 8.0 (t, 1 H) 7.9 (d, 1 H) 7.8 (d, 1 H) 7.7 (m, 2H) 7.5 (m, 4H) 7.3 (m, 4H) 7.1 (m, 2H) 6.5 (s, 1 H) 5.2 (s, 2H) 2.6 (s, 3H) 2.3 (s, 3H).
Prepared similarly to the method as described for Example 174:
Figure imgf000215_0002
Figure imgf000216_0001
Figure imgf000216_0003
Example 178: 1 -[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid
Figure imgf000216_0002
To a solution of 1-(6-chloropyridin-2-yl)-2-methyl-pyrrole-3-carboxylic acid (D53, 168 mg, 60.64 mmol) in DME (3.5 mL) and EtOH (0.5mL) were added 4-{[4-({2-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyloxy}methyl)phenyloxy}benzonitrile (D49,
300mg, 0.71 mmol, 1.1 eq), Cs2CO3 ( 229mg, 0.71 mmol, 1.1 eq) and Pd(PPh3)4 (STREM, 41 mg, 0.05eq). The reaction mixture was heated at 1300C for 8 minutes in a biotage microwave. The solution was poured in water, acidified to pH 6 and the solid filtered off, dissolved in CH2CI2 and washed with water. The organic phase was dried over Na2SO4 and filtered on a small pad of silica. After evaporation, the title compound was obtained as a white powder (186mg, 56%). LC-HRMS (b): C3iH23N3O4 , Rt= 3.10min, CaIc: 502.1767 (M+H), Found: 502.1778 (M+H); 1H NMR ( DMSO-d6, ppm): 8.0 (m, 2H) 7.9 (m, 2H) 7.8 (m, 1 H) 7.5 (m, 4H) 7.3 (d, 1 H) 7.1 (m, 6H) 6.5 (s, 1 H) 5.25 (s, 2H) 2.6 (s, 3H).
Example 179: 1-[6-(3,5-difluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
Figure imgf000217_0001
To a solution of ethyl 1-[6-(3,5-difluoro-2-(2-methyl-4-bromobenzyloxy)-phenyl)pyridin-2- yl]-piperidine-4-carboxylate (D69a, 0.4g, 0.74mmol) in DME (30ml) and water (3ml) were added Pd(PPh3)4 (0.085g, 0.074mmol), then 4-trifluoromethylphenyl boronic acid (0.18g, 0.95mmol) and Na2CO3 (0.157g, 1.47 mmol) and the mixture was heated under reflux for 3 days. After cooling, the mixture was poured into water. After extraction with CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/Me0H, 98/2) and then preparative HPLC, to give the titled compound as a brown solid (0.05g, 1 1.7%). LC-HRMS (b): C32H27F5N2O3 , Rt= 3.45min, CaIc: 583.2020 (M+H), Found: 583.1992 (M+H); 1H NMR (300MHz, DMSO d6, ppm): 7.9 (d, 2H), 7.85 (d, 2H), 7.55 (m, 3H), 7.4 (m, 2H), 7.3 (d, 1 H), 7.1 (d, 1 H), 6.85 (d, 1 H), 4.95 (s, 2H), 4.2 (Id, 2H), 2.9 (t, 2H), 2.4 (m, 1 H), 2.3 (s, 3H), 1.85 (Id, 2H), 1.55 (m, 2H).
Example 180: 1-[6-(5-fluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)benzyloxy)- phenylJpyridin^-ylJ-S-trifluoromethyl-pyrrazole^-carboxylic acid
Figure imgf000217_0002
Similarly prepared as for Example 179 from ethyl 1-(6-(5-fluoro-2-(2-methyl-4- bromobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carboxylate (D66c, 0.5g, 0.86mmol) and 4-trifluoromethylphenylboronic acid (0.213g, 1.12mmol). The title compound was obtained, after flash chromatography (CH2CI2/Me0H, 98/2) and then recrystallisation from CH3CN, as white crystals (0.11g, yield= 20.67%). Mp= 237.7°C; LC- HRMS (b): C31H20F7N3O3 , Rt = 3.10min, CaIc: 614.1315 (M-H), Found: 614.1315 (M-H); 1H NMR (DMSO d6, ppm): 8.3 (s, 1 H), 8.15 (Is, 2H), 7.9 (d, 2H), 7.8 (m, 3H), 7.55 (m, 4H), 7.45 (m, 1 H), 7.35 (m, 1 H), 5.3 (s, 2H), 2.35 (s, 3H). Example 181 : 1 -[6-(5-chloro-2-(2-methyl-4-(4-fluorophenyl)benzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid
Figure imgf000218_0001
Similarly prepared from ethyl 1-[6-(5-chloro-2-(2-methyl-4-bromobenzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylate (D69b, 0.5g, 0.92mmol) and 4- fluorophenylboronic acid (0.168g, 1.19mmol). The title compound was obtained, after flash chromatography (CH2CI2ZMeOH, 98/2) and then recrystallisation from CH3CN, as white crystals (0.02g, yield= 4.1 %). Mp= 291.6°C; LC-HRMS (a): C3IH28CI1F1N2O3 , Rt= 3.39min, CaIc: 531.1851 (M+H), Found: 531.1798 (M+H); 1H NMR (CDCI3, ppm): 7.85 (s, 1 H), 7.45 (m, 2H), 7.35 (t, 2H), 7.3 (Is, 2H), 7.2 (m, 2H), 7.05 (t, 2H), 6.95 (d, 1 H), 6.55 (d, 1 H), 5.05 (s, 2H), 4.25 (Id, 2H), 2.95 (t, 2H), 2.55 (m, 1 H), 2.3 (s, 3H), 1.95 (m, 2H), 1.75 (m, 2H).
Example 182: 1 -[6-(2-(2-methyl-4-(3,4-dimethoxyphenyl)benzyloxy)-phenyl)pyridin- 2-yl]-5-trifluoromethyl-pyrrazole-4-carboxylic acid
Figure imgf000218_0002
To a solution of ethyl 1-[6-(2-(4-bromo-2-methylbenzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrrazole-4-carboxylate (D66b, 0.3g, 0.53mmol) in DME (50ml) and water
(5ml) were added Pd(PPh3)4 (0.062g, 0.053mmol), then 3,4-dimethoxyphenyl boronic acid
(0.127g, 0.69mmol) and Na2CO3 (0.112g, 1.06mmol) and the mixture was heated under reflux for 2 days . After cooling, the mixture was poured into water. After extraction with
CH2CI2, the organic phase was dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH2CI2/Me0H, gradient
100/0 to 95/5). After trituration with Et2O, the title compound was obtained as a brown powder (yield= 1 1.1 %). LC-HRMS (a): C32H26F3N3O5 , Rt= 2.80min, CaIc: 588.1746 (M-H),
Found: 588.1759 (M-H); 1H NMR (300MHz, DMSO d6, ppm): 8.3 (s, 1 H), 8.1 (m, 2H),
7.75 (t, 2H), 7.5 (s, 1 H), 7.4 (m, 3H), 7.35 (d, 1 H), 7.2 (m, 2H), 7.15 (t, 1 H), 7 (d, 1 H), 5.25 (s, 2H), 3.85 (s, 3H), 3.8 (s, 3H), 2.3 (s, 3H).
Prepared by a similar method as described for Example 9:
Figure imgf000219_0002
Figure imgf000219_0003
Figure imgf000219_0001
Figure imgf000220_0002
Example 187: 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)benzyloxy)-phenyl)pyridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000220_0001
Prepared by a similar method as described for Example 9 from ethyl 1-[6-(2-(4-(4- methoxy-2-methyl-phenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylate (D259), the title compound was obtained as white crystals (yield = 50.4%). LC-HRMS (a): C3IH24F3N3O4, Rt = 2.78min, CaIc: 558.1641 (M-H), Found: 558.1600 (M- H); 1H NMR (300MHz, DMSO, ppm): 8.31 (s, 1 H), 8.19 (t, 1 H), 8.14 (m, 1 H), 7.74 (m, 2H), 7.46 (m, 3H), 7.31 (m, 3H), 7.12 (m, 2H), 6.86 (sd, 1 H), 6.82 (dd, 1 H), 5.30 (s, 2H), 3.77 (s, 3H), 2.21 (s, 3H). Example 188: 1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl-phenyl)benzyloxy)- phenylJpyridin^-ylJ-S-trifluoromethyl-pyrazole^-carboxylic acid
Figure imgf000221_0001
Prepared by a similar method as described for Example 9 from ethyl 1-[6-(5-fluoro-2-(2- methyl-4-(4-methoxy-2-methyl-phenyl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylate (D260), the title compound was obtained as a grey powder (yield = 58.7%). LC-HRMS (a): C32H25F4N3O4 , Rt = 2.88min, CaIc: 590.1703 (M-H), Found: 590.1676 (M-H); 1H NMR (300MHz, DMSO, ppm): 8.31 (s, 1 H), 8.16 (m, 2H), 7.77 (dd, 1 H), 7.55 (dd, 1 H), 7.43 to 7.32 (m, 3H), 7.13 (s, 1 H), 7.10 (m, 2H), 6.85 (sd, 1 H), 6.81 (dd, 1 H), 5.26 (s, 2H), 3.77 (s, 3H), 2.28 (s, 3H), 2.21 (s, 3H).
The following Examples were also prepared from appropriate starting materials by similar methods to those described above:
Figure imgf000221_0002
Figure imgf000222_0001
Biological Assay
The activity of soluble guanylate cyclase (sGC) can be tested in an assay based on measuring the fluorescence polarisation (FP) signal of fluorescently labelled cGMP. FP of this fluorescent molecule increases on interaction with an anti-cGMP antibody as the mobility of the molecule is reduced. Newly produced cGMP displaces this interaction giving rise to a decrease in polarisation and FP signal which can be equated to enzyme activity.
Compounds are incubated with human sGC, anti-cGMP antibody, the GTP substrate and fluorescently labelled cGMP. After a period of one hour the assay is stopped with the addition of EDTA and after a further hour the assay is read.
Human sGC is thawed and resuspended in assay buffer (10OmM TRIS, 1 OmM MgCI2, 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give a final concentration of 1 nM in the well. A substrate solution is prepared containing GTP and 8- fluo-cGMP in de-ionized water to a final concentration of 25μM and 5OnM respectively. Assay plates containing 5μl_ of various test compounds and of a standard agonist (50μM - 5OnM) in 1 % DMSO as 6 point, four fold dilutions across a 96 well plate are used in the assay. The plate also contains 6 wells of DMSO (1%) to produce high control and a cGMP standard curve (14nM to 10μM) to convert FP data to cGMP concentration. 25μl_ of enzyme mix and 20μl of substrate mix described above are added to each well of the plate. Samples are mixed on an orbital shaker and then incubated at room temperature for 1 hour. After this incubation period 5μl of 0.5M EDTA is added to all wells and the plates are incubated for a further hour at room temperature prior to reading the FP signal in an appropriate reader. For data handling FP data are converted to cGMP concentrations and then fitted using ActivityBase software. The activity of a test compound is determined as the pEC500 value which is the concentration able to increase by 5-fold basal cGMP.
The compounds of Examples 1 to 191 were tested in the assay described above and each gave pEC500 values of greater than 5.0. In an embodiment a compound of the invention gives a pEC500 value of ≥6.0 when tested in the assay described above. In a further embodiment a compound of the invention gives a pEC500 value of ≥7.0 when tested in the assay described above
The compound 1-[6-(2-((6-(4-carboxy-phenyloxy)pyridin-3-yl)methyloxy)-phenyl)pyridin-2- yl]-5-methyl-pyrazole-4-carboxylic acid was also prepared and when tested in the assay described above gave a pEC500 value of < 5.0 i.e. below the detectable limit of the assay.

Claims

Claims
1. A compound of formula (I)
Figure imgf000224_0001
or a salt thereof; wherein
R1 and R2 are independently selected from hydrogen, halo, CF3,
Figure imgf000224_0002
and allyl;
Y represents
Figure imgf000224_0003
wherein R represents CF3 or Ci-4 alkyl; and R represents CF3 or Ci-4 alkyl;
R4 represents hydrogen or methyl;
Z is absent or represents (CH2)2, O or OCH2;
A, J and L each represent CH; or one of A, J and L represents N and the other two each represents CH; when A represents CH, R5 is selected from hydrogen, methyl, d^alkoxy, methoxy- C2-3alkoxy-, chloro or fluoro and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl;
X represents
Figure imgf000225_0001
wherein when both J and L represent CH, R8 represents hydrogen, chloro, fluoro, CF3, Ci-4alkyl or
Figure imgf000225_0002
in a meta or ortho position relative to the R9 substituent; or when one of J and L represents N, R8 represents hydrogen or halo; and R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C^alkoxy, CN, CONR10R11, CO2R12 or N3, wherein R10 and R11 are independently selected from hydrogen and Ci-4alkyl, and R12 represents hydrogen or Ci-4alkyl;
or when Z is absent or represents OCH2, X may additionally represent
Figure imgf000225_0003
wherein R7 represents CF3 or methyl.
2. A compound of formula (I) as defined in claim 1 or a salt thereof wherein R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy, CN, or N3.
3. A compound of formula (I) as defined in claim 1 or claim 2 or a salt thereof wherein R9 represents hydrogen, halo, CF3, OCF3, C1-4alkyl, C1-4alkoxy or CN.
4. A compound of formula (I) as defined in any one of claims 1 to 3 or a salt thereof wherein Y is as defined in claim 1 , wherein R3 represents CF3 or methyl; and R3a represents methyl; and when A represents CH, R5 is selected from hydrogen, fluoro, methyl, methoxy, propyloxy, isopropyloxy, isobutyloxy or methoxyethoxy and R6 represents hydrogen; or when A represents N, R5 and R6 each represent hydrogen or one of R5 and R6 represents hydrogen and the other represents methyl;
X is as defined in claim 1 , wherein R7 represents CF3 or methyl; and when both J and L represent CH, R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro; or when one of J and L represents N, R8 represents hydrogen or chloro; and R9 represents hydrogen, halo, CF3, OCF3,
Figure imgf000225_0004
or CN.
5. A compound of formul ed in any one of claims 1 to 4 or a salt thereof
wherein Y represents
Figure imgf000225_0005
, wherein R3 represents CF3 or methyl.
6. A compound of formul ed in any one of claims 1 to 5 or a salt thereof
wherein Y represents
Figure imgf000226_0001
, wherein RJ represents CF3.
7. A compound of formula (I) as defined in any one of claims 1 to 6 or a salt thereof wherein R1 and R2 each represent hydrogen.
8. A compound of formula (I) as defined in any one of claims 1 to 7 or a salt thereof wherein R4 represents hydrogen.
9. A compound of formula (I) as defined in any one of claims 1 to 8 or a salt thereof wherein A represents CH.
10. A compound of formula (I) as defined in any one of claims 1 to 9 or a salt thereof wherein R5 represents hydrogen or methyl and R6 represents hydrogen.
11. A compound of formula (I) as defined in any one of claims 1 to 10 or a salt thereof wherein Z is absent.
12. A compound of formula (I) as defined in any one of claims 1 to 10 or a salt thereof wherein Z represents O.
13. A compound of formula (I) as defined in any one of claims 1 to 12 or a salt thereof wherein J and L each represent CH.
14. A compound of formula (I) as defined in any one of claims 1 to 13 or a salt thereof wherein when J and L each represent CH, R8 represents hydrogen, methyl, methoxy, ethoxy, CF3 or chloro; or when one of J and L represents N and the other represents CH, R8 represents hydrogen or chloro.
15. A compound of formula (I) as defined in any one of claims 1 to 14 or a salt thereof wherein R8 represents hydrogen.
16. A compound of formula (I) as defined in any one of claims 1 to 15 or a salt thereof wherein R9 represents hydrogen, chloro, fluoro, CF3, OCF3, t-butyl, methoxy or CN.
17. A compound of formula (I) as defined in any one of claims 1 to 16 or a salt thereof wherein R9 represents OCF3 or CN.
18. A compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.
19. A compound of formula (I) which is 1-[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid
Figure imgf000227_0001
or a pharmaceutically acceptable salt thereof.
20. 1-[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid.
21. A compound of formula (I) which is 1-[6-(2-(2-methyl-4-(4- trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid
Figure imgf000227_0002
or a pharmaceutically acceptable salt thereof.
22. 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid.
23. A pharmaceutical composition comprising a compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
24. A pharmaceutical composition comprising 1-[6-(2-(4-(4- cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4- carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
25. A pharmaceutical composition comprising 1-[6-(2-(2-methyl-4-(4- trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).
26. A compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for use in therapy.
27. A pharmaceutical composition as claimed in claim 23 for use in therapy.
28. 1-[6-(2-(4-(4-cyanophenoxy)phenylmethyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof for use in therapy.
29. 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethyloxy)-phenyl)pyridin-2-yl]- 5-trifluoromethyl-pyrazole-4-carboxylic acid or a pharmaceutically acceptable salt thereof for use in therapy.
30. A pharmaceutical composition as defined in claim 24 or claim 25 for use in therapy.
31. A compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 23 to 25, for use in the treatment of a disease or condition mediated by the activity of sGC.
32. A compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in any one of claims 23 to 25, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
33. A compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 23, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
34. A compound as defined in any one of claims 19 to 22, or a pharmaceutical composition as defined in claim 24 or claim 25, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
35. Use of a compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of a disease or condition mediated by the activity of sGC.
36. Use of a compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.
37. Use of a compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
38. Use of a compound as defined in any one of claims 19 to 22 for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.
39. A method of treatment of a disease or condition mediated by the activity of sGC comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as claimed in any one of claims 23 to 25.
40. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 17, 19 to 22 or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition as claimed in any one of claims 23 to 25.
41. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure, or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition as claimed in claim 23.
42. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure, or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound as defined in any one of claims 19 to 22 or of a pharmaceutical composition as claimed in claim 24 or claim 25.
PCT/EP2008/066514 2007-12-03 2008-12-01 2,6-disubstituted pyridines as soluble guanylate cyclase activators WO2009071504A1 (en)

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GB0813714.3 2008-07-25
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