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)

or a salt thereof; wherein

R ¹ and R ² are independently selected from hydrogen, halo, CF ₃ , C _1-4 alkyl and allyl;

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, 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;

X represents

wherein when both J and L represent CH, 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;

or when Z is absent or when Z represents OCH ₂ , X may additionally represent

w Therein R ⁷ represents CF ₃ or methyl.

According to a further aspect the present invention provides a compound of formula (IA)

or a salt thereof; wherein

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;

X represents

wherein when E represents CH, 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;

or when Z is absent or represents OCH ₂ , X may additionally represent wherein R ⁷ represents CF ₃ or methyl.

According to a further aspect the present invention provides a compound of formula (IB)

or a salt thereof; wherein

R ¹ and R ² are independently selected from hydrogen, halo, CF ₃ , C _1-4 alkyl and allyl;

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, 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;

X represents

wherein when both J and L represent CH, 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;

or when Z is absent or represents OCH ₂ , X may additionally represent wherein R ⁷ represents CF ₃ or methyl.

As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms. For example, C _1-4 alkyl 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, 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-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-.

In an embodiment, there is provided 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 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 and R ¹² represents hydrogen or Ci _-4 alkyl.

In an embodiment, there is provided 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 _1-4 -alkyl.

In an embodiment, there is provided a compound of formula (I) as defined above or a salt thereof wherein A, J, L, Z, 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 ₃ , C _1-4 alkyl, C _1-4 alkoxy, CN, CONR ¹⁰ R ¹¹ or N ₃ , wherein R ¹⁰ and R ¹¹ are independently selected from hydrogen

In an embodiment, there is provided 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 ₃ , C _1-4 alkyl, C _1-4 alkoxy 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 R ¹ is in a para position relative to the -OCH ₂ - linker. In a further embodiment R ² is in an ortho position relative to the -OCH ₂ - linker. In a further

embodiment 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.

In a further embodiment R ¹ is in an ortho position relative to the bond linking to the pyridine ring. In a further embodiment R ² is in a meta position relative to the -OCH ₂ - linker.

In an embodiment R ¹ and R ² do not both represent C _2-4 alkyl or allyl.

In an embodiment, where one of R ¹ and R ² represents or allyl, the other represents hydrogen.

In an embodiment 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.

In an embodiment, 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.

In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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.

In an embodiment 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.

In an embodiment 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.

In an embodiment R ⁴ represents hydrogen. In a further embodiment R ⁴ represents methyl. In an embodiment, Z is O and R ⁴ is hydrogen. In an embodiment, Z is CH ₂ CH ₂ and R ⁴ is hydrogen.

In an embodiment, Y represents the pyrazole group defined above and R ⁴ is hydrogen or methyl. In an embodiment, Y represents the piperidine group defined above and R ⁴ is hydrogen. In an embodiment, Y represents the pyrrole group defined above and R ⁴ is hydrogen. In an embodiment, Y represents the phenyl group defined above and R ⁴ is hydrogen.

In an embodiment Y represents wherein R ³ represents CF ₃ or methyl.

In a embodiment Y represents wherein R ³ represents CF ₃ .

In an embodiment 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.

In an embodiment R ⁵ represents hydrogen or methyl and R ⁶ represents hydrogen.

In an embodiment, 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.

In an embodiment, when A represents N, R ⁵ and R ⁶ both represent hydrogen.

In an embodiment, 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.

In an embodiment X represents wherein R ⁷ represents methyl.

In an embodiment X represents

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, 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.

In an embodiment X represents

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, 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 alkoxy, CN, or N ₃ .

In an embodiment X represents

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, 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 , 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.

In an embodiment X represents

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, 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. In an embodiment 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 . In an embodiment 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. In an embodiment, when E represents CH, R ⁸ represents chloro in an ortho position relative to the R ⁹ substituent. In an embodiment 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 . In an embodiment 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, CO ₂ H, 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 ⁸ represents hydrogen and R ⁹ is as defined in each of the above embodiments. In an embodiment, when 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. In an embodiment, when 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.

In an embodiment J and L each represent CH.

In an embodiment R ⁸ represents hydrogen. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment R ⁸ represents chloro in an ortho position relative to the R ⁹ substituent. In an embodiment 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. In an embodiment 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. In an embodiment J and L both represent CH and R ⁸ represents methyl in a meta position relative to the R ⁹ substituent. In an embodiment R ⁹ represents hydrogen, chloro, fluoro, CF ₃ , OCF ₃ , CN, CONH ₂ or N ₃ . In an embodiment 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. In an embodiment R ⁸ represents hydrogen and R ⁹ is as defined in each of the above embodiments. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment 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. In an embodiment J and L both represent 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. In an embodiment J and L both represent 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. In an embodiment 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.

In an embodiment, J represents N and L represents CH; R ⁸ represents halo; and R ⁹ represents CF ₃ , C _1-4 alkoxy, halo or CN. In an embodiment, 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. In an embodiment, J represents N and L represents CH; R ⁸ represents chloro; and R ⁹ represents CF ₃ , C _1-4 alkoxy, halo or CN. In an embodiment, J represents N and L represents CH; R ⁸ represents chloro; and R ⁹ represents CF ₃ .

In an embodiment, J represents CH and L represents N; R ⁸ represents hydrogen; and R ,9 ^! represents CF ₃ , Ci _-4 alkoxy, halo or CN. In an embodiment, J represents CH and L represents N; R ⁸ represents hydrogen; and R ⁹ represents C _1-4 alkoxy. In an embodiment, J represents CH and L represents N; R ⁸ represents hydrogen; and R ⁹ represents methoxy.

In an embodiment, 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.

In an embodiment 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.

In an embodiment, Z represents CH ₂ CH ₂ and each of R ⁸ and R ⁹ represent hydrogen.

In an embodiment R ⁹ represents CONR ¹⁰ R ¹¹ wherein R ¹⁰ and R ¹¹ are independently selected from hydrogen and methyl.

In an embodiment R ⁹ represents hydrogen, halo, CF ₃ , OCF ₃ , C _1-4 alkyl, C _1-4 alkoxy, CN, or N ₃ .

In an embodiment R ⁹ represents hydrogen, halo, CF ₃ , OCF ₃ , C _1-4 alkyl, C _1-4 alkoxy 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-y l]-5-trifluoromethyl-pyrazole-4- carboxylic acid;

1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-y l]-5-methyl-pyrazole-4- carboxylic acid;

1-[6-(2-(4-(phenethyl)phenylmethyloxy)-phenyl)pyridin-2-y l]-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)-p henyl)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)-phe nyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-cyanophenyloxy)phenylmethyloxy)-ph enyl)pyridine-2-yl]-piperidine-

4-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-fluorophenyloxy)phenylmethyloxy)-p henyl)pyridine-2-yl]-piperidine- 4-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-trifluoromethylphenyloxy)phenylmet hyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(3,5-difluoro-2-(4-(4-trifluoromethylphenoxy)phenylm ethyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(3,5-difluoro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phe nyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-chloro-2-(4-(4-trifluoromethylphenoxy)phenylmethy loxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-chloro-2-(4-(4-cyanophenoxy)phenylmethyloxy)-phen yl)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)ph enylmethyloxy)-phenyl)pyridin-2- yl]-piperidine-4-carboxylic acid;

1-[6-(3,5-difluoro-2-(4-(5-cyanopyridin-2-yloxy)phenylmet hyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-chloro-2-(4-(5-trifluoromethylpyridin-2-yloxy)phe nylmethyloxy)-phenyl)pyridin-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylp yridin-2-yloxy)phenylmethyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid;

1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl oxy)-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)pyridi n-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)-ph enyl)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)phe nylmethyloxy)-phenyl)pyridin-2-yl]-

5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(4-(5-trifluoromethylpyridin-2-yloxy)phenylmethyl oxy)-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)-phen yl)pyridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(3-chloro-5-trifluoromethylpyridin-2-yloxy)phe nylmethyloxy)-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)phenyl methyloxy)-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)-phe nyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;

1-[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-ph enyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-((6-(4-methoxyphenoxy)pyridine-3-yl)methyloxy)-ph enyl)pyridine-2-yl]-5-methyl- pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-((6-(3,4-dichlorophenoxy)pyridine-3-yl)m ethyloxy)-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)-phen yl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-methoxyphenyl)phenylmethyloxy)-phenyl)pyrid ine-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)pyridin e-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)pyrid ine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-fluorophenyl)phenylmethyloxy)-phenyl)pyridi ne-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin e-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-chlorophenyl)phenylmethyloxy)-phenyl)pyridi ne-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)pyridin e-2-yl]-5-methyl-pyrazole-4- carboxylic acid;

1-[6-(2-(1-(4-(4-methoxyphenyl)phenyl)ethyloxy)-phenyl)py ridine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(3,4-dichlorophenyl)phenylmethyloxy)-phenyl)py ridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-fluoro-2-methylphenyl)phenylmethyloxy)-phen yl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)phenylmethyloxy)-pheny l)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)-phen yl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyl oxy)-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)-pheny l)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)pheny lmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(3-chloro-4-methoxy-phenyl)phenylmeth yloxy)-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)pheny lmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-ethyloxy-3-trifluoromethylphenyl)p henylmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-ethyloxy-3-methylphenyl)phenylmethylo xy)-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)phe nylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(2,4-dimethoxy-phenyl)phenylmethyloxy)-p henyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-methoxy-2-trifluoromethylphenyl)ph enylmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-fluoro-2-methylphenyl)phenylmethyl oxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-methoxy-2-methylphenyl)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-isopropyloxyl-2-methylphenyl)pheny lmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-chloro-2-methoxyphenyl)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid; 1-[6-(2-(2-methyl-4-(4-chloro-2-ethyloxyphenyl)phenylmethylo xy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(2-chloro-4-ethyloxyphenyl)phenylmeth yloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(2-chloro-4-methoxyphenyl)phenylmethy loxy)-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)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methoxy-4-(4-methoxyphenyl)phenylmethyloxy)-ph enyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methoxy-4-(4-methoxy-3-trifluoromethylphenyl)p henylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxyli c acid;

1-[6-(2-(2-methoxy-4-(2-chloro-4-methoxy-phenyl)phenylmet hyloxy)-phenyl)pyridine-2-yl]-

5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methoxy-4-(4-methoxy-2-methylphenyl)phenylmethylo xy)-phenyl)pyridine-2-yl]-

5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-fluorophenyl)phenylm ethyloxy)-phenyl)pyridine-2-yl]-

5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-methoxyphenyl)phenyl methyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-(2-methyl-propyloxy)-4-(4-cyanophenyl)phenylme thyloxy)-phenyl)pyridine-2-yl]-

5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmet hyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-propyloxy-4-(4-cyanophenyl)phenylmethyloxy)-pheny l)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)phenylmeth yloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-(methoxyethyloxy)-4-(4-methoxyphenyl)phenylmet hyloxy)-phenyl)pyridine-2-yl]- δ-trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(2-(2-(methoxyethyloxy)-4-(4-cyanophenyl)phenylmethy loxy)-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)-phe nyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phe nyl)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)-phen yl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(3,5-difluoro-2-(1-(4-(4-methoxyphenyl)phenyl)ethylo xy)-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)pheny l)ethyloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-chloro-2-(4-(4-cyanophenyl)phenylmethyloxy)-pheny l)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)phenylmethyl oxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-trifluoromethylphenyl)phe nylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxy-2-methyl-phenyl)p henylmethyloxy)- 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)p yridine-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)phenylmethylox y)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(2-(2-methyl-4-(5-trifluoromethylpyridin-2-yl)phenylmet hyloxy)-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)phenylmethylox y)-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-carboxyli c acid;

1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylp yridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-5-trifluoromethyl-pyrazole-4-carboxyli c 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)pyridi ne-2-yl]-piperidine-4-carboxylic acid;

1-[6-(2-(4-(4-cyanophenyl)phenylmethyloxy)-phenyl)pyridin e-2-yl]-piperidine-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-trifluoromethylphenyl)phenylmethyl oxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(2-(2-propyloxy-4-(4-trifluoromethylphenyl)phenylmethyl oxy)-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)phenylmethy loxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-chloro-2-(2-methyl-4-(4-cyanophenyl)phenylmethylo xy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(3,5-difluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmet hyloxy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethylox y)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethylo xy)-phenyl)pyridine-2-yl]- piperidine-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyl oxy)-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)phenylmethyl oxy)-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)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-methoxyphenyl)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-cyanophenyl)phenylmethylo xy)-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)ph enylmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(6-chloro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)ph enylmethyloxy)-phenyl)pyridine- 2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(4-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)ph enylmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(6-fluoro-2-(2-methyl-4-(4-trifluoromethoxyphenyl)ph enylmethyloxy)-phenyl)pyridine-

2-yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-iodo-2-(2-methyl-4-(4-trifluoromethylphenyl)phenylme thyloxy)-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)phenylmethyl oxy)-phenyl)Dyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-methoxy-2-methylphenyl)phenylmethy loxy)-phenyl)Dyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-fluoro-2-methylphenyl)phenylmethyl oxy)-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)phenylmethylo xy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-fluoro-4-(4-methoxyphenyl)phenylmethy loxy)-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)phe nylmethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)ph enylmethyloxy)-phenyl)pyridine- 2-yl]-piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(4-cyano-2-methylphenyl)phen ylmethyloxy)-phenyl)pyridine-

2-yl]-piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(4-methoxy-2-trifluoromethyl phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid; 1-[6-(5-methyl-2-(2-methyl-4-(4-chloro-2-trifluoromethylphen yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-propyloxy-4-(4-cyanophenyl)phenylmeth yloxy)-phenyl)pyridine-2-yl]-1- piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(4-(4-cyanophenyl)phenylmethyloxy)-pheny l)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(4-cyanophenyl)phenylmethylo xy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(4-trifluoromethoxyphenyl)ph enylmethyloxy)-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-trifluoromethylp yridin-2-yl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1-piperidine-4-carboxylic acid;

1-[6-(5-methyl-2-(2-methyl-4-(5-cyanopyridin-2-yl)phenylm ethyloxy)-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)phenylm ethyloxy)-phenyl)pyridine-2- yl]-piperidine-4-carboxylic acid;

1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-chloro-2-trif luoromethyl- phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1-piperidine-4 -carboxylic acid;

1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-methyl-4-trif luoromethyl- phenyl)phenylmethyloxy)-phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;

1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(4-cyano-2-methy l-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid;

1-[6-(5-trifluoromethyl-2-(2-propyloxy-4-(2-chloro-4-meth oxy-phenyl)phenylmethyloxy)- phenyl)pyridine-2-yl]-1 -piperidine-4-carboxylic acid; 1-[6-(5-trifluoromethyl-2-(2-methyl-4-(3-chloro-5-trifluorom ethylpyridin-2- yl)phenylmethyloxy)-phenyl)pyridine-2-yl]-piperidine-4-carbo xylic acid;

1-[6-(5-trifluoromethyl-2-(2-methyl-4-(5-cyanopyridin-2-y l)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)-phe nyl)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)pheny lmethyloxy)-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)py ridin-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid; 1-(6-{2-[({6-[(4-carboxyphenyl)oxy]-3-pyridinyl}methyl)oxy]p henyl}-pyridin-2-yl)-5-

(trifluoromethyl)-i H-pyrazole-4-carboxylic acid;

1-[6-(2-(4-(4-carboxyphenyl)phenylmethyloxy)-phenyl)pyrid ine-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylic acid;

1-[6-(2-(2-methyl-4-(4-carboxyphenyl)phenylmethyloxy)-phe nyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-methoxy-4-(4-carboxyphenyl)phenylmethyloxy)-ph enyl)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)phenylmethy loxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid; 1-[6-(5-fluoro-2-(2-fluoro-4-(4-carboxyphenyl)phenylmethylox y)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(5-fluoro-2-(2-methoxy-4-(4-carboxyphenyl)phenylmeth yloxy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(2-(2-fluoro-4-(4-carboxyphenyl)phenylmethyloxy)-phe nyl)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)-phe nyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid;

1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phe nyl)pyridin-2-yl]-2-methyl- pyrrole-3-carboxylic acid;

1-[6-(2-(4-(4-methoxyphenoxy)phenylmethyloxy)-phenyl)pyri din-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)phenylmethylo xy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;

1-[6-(5-fluoro-2-(2-methyl-4-(4-fluorophenyl)phenylmethyl oxy)-phenyl)pyridin-2-yl]-2- methyl-pyrrole-3-carboxylic acid;

1-[6-(2-(4-(4-cyanophenyloxy)phenylmethyloxy)-phenyl)pyri din-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)pyridin e-2-yl]-benzoic acid;

4-[6-(2-(4-(4-trifluoromethylphenyl)phenylmethyloxy)-phen yl)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)pheny lmethyloxy)-phenyl)pyridine-2-yl]- δ-trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(3-propyl-2-(4-(4-trifluoromethylphenyl)phenylmethyl oxy)-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-carboxyli c acid;

1-[6-(3-propyl-2-(2-methyl-4-(4-trifluoromethylphenyl)phe nylmethyloxy)-phenyl)pyridine-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid;

1-[6-(3-(propen-2-yl)-2-(4-(4-methoxyphenyl)phenylmethylo xy)-phenyl)pyridine-2-yl]-5- trifluoromethyl-pyrazole^-carboxylic acid;

1-[6-(3-propyl-2-(4-(4-methoxyphenyl)phenylmethyloxy)-phe nyl)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-trifluo romethyl-pyrazole-4- carboxylic acid

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

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 R ⁴ 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 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. Certain isotopic variations of a compound of the invention, for example, those in which a radioactive isotope such as ³ H or ¹⁴ C is incorporated, 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.

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-trif luoromethyl-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)-ph enyl)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 RR ⁹⁹ rreepprreesseents CN) can be prepared according to the following general synthetic process (Scheme 1 ):

Scheme 1

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)

(Ma)

The compounds of formula (V) wherein R ³ represents CF ₃ or CH ₃ are commercially available (from Aldrich and Orphachem respectively). The compounds of formula (V) wherein R ³ represents C _2-4 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)

(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 R ³ represents CF ₃ is described in the literature (Tetrahedron, 1993, 49(5); 1057-62). The preparation of the compounds of ffoorrmmuullaa ((VVll)) wwhheerreeiinn RR ³³ rreepprreesseennttss CC _22--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)

reflux

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.

Scheme 5: phenyl compounds of formula (Nd)

90 to 110 ⁰ C

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

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.

(II)

Suitable, for example, for R ¹ = Cl and R ² =H R ¹ = R ² = F

R ¹ = CF ₃ and R ² = H

Certain compounds of formula (VIIb) are commercially available, for example, where 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:

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).

Analogous processes may be used to prepare other compounds of formula (VIIb) where R ¹ is C _1-4 alkyl and R ² is as defined above. For example, 2-bromo-4,6-dimethyl phenol is commercially available from Bionet.

Compounds of formula (VIIb) where R ¹ is H and R ² is ethyl, isopropyl or t-butyl in an ortho position relative to the -OCH ₂ - 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 R ² is and R ¹ 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

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 R ⁹ 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, (CH ₂ ) ₂ , or OCH ₂ (although it can also be used wherein Z is absent).

Scheme 8

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 R ⁵ represents F or Cl.

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

(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 OCH ₂ , may be prepared by the following method (Scheme 1Ob) - as an alternative to using Scheme 8 above.

Scheme 10b

(XVIII)

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 R ⁵ represents methyl, the aldehyde group of 4-cyano- 2-methyl benzaldehyde (from Chemstep Product List) may be reduced by standard methods, for example using NaBH ₄ and then a bromination step is carried out typically using PBr ₃ . To prepare a compound of formula (Xl) wherein R ⁴ represents methyl, and R ⁵ and R ⁶ both represent hydrogen, the carbonyl group of 4-acetyl benzonitrile (from Aldrich) may be reduced to the corresponding hydroxyl compound, for example using NaBH ₄ and then a bromination step is carried out typically using PBr ₃ .

To prepare a compound of formula (Xl) wherein A represents N and R ⁴ , R ⁵ and R ⁶ 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 OCH ₂ , 4-hydroxybenzaldehyde (or more generally a compound of formula (XVIII)) is alkylated by chloroacetonitrile, then the aldehyde function is reduced, for example NaBH ₄ , then the resulting hydroxy group is brominated, for example using PBr ₃ .

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 / H ₂ O rt or 60-70 ⁰ C (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 R ⁹ 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 R ⁹ represents CONH ₂ may also be prepared by the following scheme (Scheme 12) from the corresponding nitrile derivatives (of formula (IVa) or (IVb) or (IVc) wherein R ⁹ 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

In Scheme 12, Z is absent or Z represents O.

Compounds of formula (I) wherein both Y represents the pyrrole group defined above and R ⁹ represents CN, or wherein Y is defined as above and R ⁹ = 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.

Scheme 13b

Scheme 13b is particularly suitable to prepare compounds wherein J represents N and L represents CH , and Z is absent.

(XXVI)

Scheme 14

Scheme 14 is particularly suitable to prepare compounds wherein Z is absent or Z represents O, OCH ₂ or CH ₂ CH ₂ .

In respect of the compounds of formula (IX):

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

(IXa)

(XIII)

Certain compounds of formula (XIII) are commercially available; for example:

(a) when A represents N, hal represents Cl; and R ⁵ and R ⁶ both represent H (Aldrich) or R ⁵ represents Me and R ⁶ represents H (Bionet).

(b) when A represents CH, R ⁵ represents H (Aldrich), or R ⁵ represents F (Apollo), or R ⁵ represents Cl (AKSCI).

Compounds of formula (XIII) when A represents CH and R ⁵ represents OCi _-4 alkyl or O(CH ₂ ) _n OMe (wherein n represents 2 or 3) may be prepared by O-alkylation of the compound of formula (XIII) wherein R ⁵ represents OH (commercially available from Apin).

A suitable preparation for compounds of formula (XIII) when A represents CH and R ⁵ represents methyl is described in the literature (Chemical and Pharmaceutical Bulletin; 33(7); 2809-20; 1985).

Scheme 16

When R ⁵ represents Me, OMe or Cl:

(XIVb)

Scheme 17

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

(XV) (IXd)

Certain compounds of formula (XV) are commercially available, for example wherein R ⁵ represents H and R ⁶ represents Me or R ⁵ represents Me and R ⁶ 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

(XIVb)

Preparation of compounds of formula (VIII)

(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.

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 R ⁵ represents Me (Betapharma); A represents CH and R ⁵ represents OMe (Aldrich); A represents CH and R ⁵ represents F (Aldrich). Where R ⁴ represents H and A represents N, note the earlier reference to compounds of formula (XV) in Scheme 18a. Where R ⁴ 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, 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

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.

to rt (VIIIc)

Scheme 20b

When R ⁹ is CN or COOR ¹² and A and J each represent CH and/or R ⁵ /R ⁶ is halogen, Scheme 20b is particularly suitable.

(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.

(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

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.

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 R ⁵ represents H, Me or OMe (Aldrich, Apollo or Apin); or wherein A represents N and R ⁵ and R ⁶ 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 R ⁵ represents Cl or F:

PBr ₃

Compounds of formula (XVIIIb) are commercially available, for example from Aldrich for R ⁵ represents Cl and from Apin for R ⁵ represents F.

Certain compounds of formula (XIX) are commercially available, for example: wherein hal represents Br or Cl, J represents N, R ⁸ represents H, and R ⁹ represents CN, CF ₃ ,

COOR ¹² , Cl or OMe (Aldrich, Fluka or Acros); wherein hal represents Cl, J represents N,

R ⁸ represents Cl, and 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

(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 R ⁵ represents OC _1-4 alkyl or O(CH ₂ ) ₂ - ₃ OMe:

as in pathway B Scheme 21

(VIIIg)

R = C _{1 4} alkyl or (CH ₂ J _n OMe, n= 2 or 3

Synthesis of compounds of formula (VIII) with Z representing OCH ₂ , can be carried out according to Scheme 24.

Scheme 24

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 (CH ₂ ) ₂ , can be carried out according to Scheme 25.

Scheme 25

or rt

(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 OCH ₂ , and X representing a thiazole ring system as defined above, can be carried out according to Scheme 26.

Scheme 26

reflux

(XXIV)

(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 R ⁵ 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 OCH ₂ 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 ( ¹ H 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:

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 40 ⁰ C. 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 40 ⁰ C. 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 40 ⁰ C. 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)

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 50 ⁰ C for 4 hours and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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. ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of ethyl 4-bromo-2-hydroxybenzoate (2g, 8.16mmol) in acetone (50ml) was added Cs ₂ CO ₃ (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 50 ⁰ C for 4 hours and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The title compound was obtained as a colorless oil (2.2g, yield= 90%). ¹ H NMR (300MHz, CDCI ₃ , 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)

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%). ¹ H N MR (300MHz, CDCI ₃ , 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)

To a solution of 2-chloro-5-trifluoromethylpyridine (Aldrich, 4g, 22.04mmol) in DME (80ml) and H ₂ O (10ml) were added Pd(PhP ₃ ) ₄ (1.27g, 1.10mmol), 4-formylphenylboronic acid

(Aldrich, 3.96g, 26.45mmol) and Na ₂ CO ₃ (5.84g, 55.09mmol). The mixture was heated at

90 ⁰ C for 3 hours, cooled and poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. After purification by chromatography on silica gel (CH ₂ CI ₂ / 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:

Description 5a: 4-(4-cyanophenoxy)-benzaldehyde (D5a)

To a solution of 4-hydroxybenzaldehyde (Aldrich, 5.04g, 41.28mmol), in DMF (50ml) was added portionwise Cs ₂ CO ₃ (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 110 ⁰ C for 2 hours, then cooled and poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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:

Description 6: 4-((4-t-butylphenyl)methyloxy)benzaldehyde (D6)

To a solution of 4-hydroxybenzaldehyde (Aldrich, 0.978g, 8mmol) in acetone (30ml) was added CS ₂ CO3 (1.8g, 12mmol) and then 4-t-butylbenzyl bromide (Aldrich, 2g, 8.8mmol) and the mixture was heated at 70 ⁰ C overnight and then poured into water. After extraction

with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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%). ¹ H 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)

To a solution of 4-(4-cyanophenoxy)-benzaldehyde (D5a, 5.2g, 23.32mmol) in MeOH (70ml) was added portionwise NaBH ₄ (0.975g, 29.46mmol). The mixture was stirred at room temperature for 30 minutes and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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:

Description 8a: 4-(4-trifluoromethylphenyl)-benzyl alcohol (D8a)

To a solution of 4-(4-trifluoromethylphenyl)-benzoic acid (Apollo, 3g, 11.27mmol) in THF (100ml) was added dropwise a solution of LiAIH ₄ 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 CH ₂ CI ₂ .

The filtrate was washed with CH ₂ CI ₂ and the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The title compound was obtained as a white solid (1.9g, yield= 66.8%); ¹ H 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)

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)

From ethyl 2-methyl-4-(4-trifluoromethylphenyl)-benzoate (D4j). The title compound was obtained as grey powder (yield = 78%). ¹ H NMR (300MHz, CDCI ₃ , 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)

From ethyl 2-methyl-4-(4-methoxyphenyl)-benzoate (D4k). The title compound was obtained as yellow powder (yield= 67%). ¹ H 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)

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)

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)

From ethyl 4-bromo-2-(2-methylpropyloxy)benzoate (D2), the title compound was obtained as a yellow oil (yield=89.8%). ¹ H NMR (300MHz, CDCI ₃ , 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)

From ethyl 4-bromo-2-(methoxyethyloxy)benzoate (D3) the title compound was obtained as a yellow oil (yield=87.86%). ¹ H NMR (300MHz, CDCI ₃ , 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

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)

To a solution of 4-bromo-2-methyl-benzyl alcohol (D8f, 7g, 34.8mmol) in DME (100ml) and H ₂ O (10ml) were added Pd(PhP ₃ ) ₄ (4g, 3.5mmol), 4-cyanophenylboronic acid (Aldrich, 6.7g, 45.3mmol) and Na ₂ CO ₃ (7.4g, 69.6mmol). The mixture was heated at 110 ⁰ C overnight, cooled and poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. After purification by chromatography on silica gel (CH ₂ CI ₂ ), the residue was triturated with iPr ₂ O and the resulting precipitate was filtered and dried. The title compound was obtained as a yellow solid (6g, yield: 77.2%). ¹ H NMR (300MHz, CDCI ₃ , 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)

4-bromo-2-methyl-benzyl alcohol (D8f, 3Og, 150 mmol), bis(pinacolato)diboron (40 g, 156 mmol), Pd(dppf)CI ₂ (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 N ₂ 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%). ¹ H 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)

To a solution of 4-(4-cyanophenoxy)-benzyl alcohol (D7, 0.9g, 4mmol) in CH ₂ CI ₂ (40ml) cooled in a ice bath, was added dropwise PBr ₃ (solution 1 IWCH ₂ CI ₂ , 1.6ml, 1.6mmol). The mixture was stirred at 0 ⁰ C for 30 minutes, then at room temperature for 1 hour and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The title compound was obtained as a colorless oil which crystallised (1.15g, yield: 99.8%); ¹ H NMR (300MHz, CDCI ₃ , 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:

The following intermediates were similarly prepared as described for D11 :

Description 44a: 4-bromo-2-(2-methylpropyloxy)-benzyl bromide (D44a)

From 4-bromo-2-(2-methylpropyloxy)-benzyl alcohol (D8g) the title compound was obtained as yellow oil (yield=100%). 1 H NMR (300MHz, CDCI ₃ , 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)

From 4-bromo-2-(methoxyethyloxy)-benzyl alcohol (D8h) the title compound was obtained as yellow oil (yield=95%). ¹ H NMR (300MHz, CDCI ₃ , 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)

From 4-bromo-2-methyl-benzyl alcohol (D8f) as a cream oil which solidified (yield= 96.1 %). ¹ H NMR (300MHz, CDCI ₃ , 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)

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)

[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol (D10, 32g, 129 mmol) was dissolved in CH ₂ CI ₂ (300 ml.) and the reaction mixture was cooled to O ⁰ C. PBr ₃ (104 g, 385 mmol) was dropwise added, and the reaction mixture was stirred at O ⁰ C 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 Na ₂ SO ₄ and concentrated to give crude product, which was recrystallized in n-hexane to afford the title compound as a white solid (32 g, 81 %). ¹ H NMR (400 MHz, CDCI ₃ ) 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)

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.), Cs ₂ CO ₃ (17.7g, 54 mmol, 3 equiv.) in water (17ml_), and Pd(Ph ₃ P) 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 CH ₂ CI ₂ . The organic layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting solid was purified by chromatography on silica gel (CH ₂ CI ₂ / 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)

To a suspension of NaN ₃ (5.5 g, 85 mmol, 6eq) in H ₂ O (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 50 ⁰ C 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 Na ₂ SO ₄ , 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)

To a solution of 4-(4-azidophenyl)-toluene (D47, 2.3 g, 1 1 mmol) in CCI ₄ (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 CH ₂ CI ₂ and dried over Na ₂ SO ₄ 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)

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 Cs ₂ CO ₃ (0.535 g, 1.64 mmol). The reaction mixture was stirred at 70 ⁰ C for 48hours. After evaporation of the solvent, the residue was hydrolised and extracted with CH ₂ CI ₂ . The organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ ) 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)

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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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; ¹ H

NMR (300MHz, CDCI ₃ , 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)

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; ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of 2,6-dichloropyridine (Aldrich, 1.257g, 8.5 mmol) in DMF (50ml) was added Cs ₂ CO ₃ (2.34g, 7.18 mmol) and then ethyl 2-methyl-pyrrole-3-carboxylate (1g, 6.53 mmol). The mixture was heated at 130 ⁰ C for 24 hours, then cooled and poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /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; ¹ H NMR (300MHz, CDCI ₃ , 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)

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 80 ⁰ C 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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The remaining solid was triturated in CH ₃ CN, 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)

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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /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; ¹ H NMR (300MHz, CDCI ₃ , 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)

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(Ph ₃ P) ₄ (0.781 g, 0.676 mmole and Na ₂ CO ₃ (3.58g, 33.8 mmol) in water (10ml). The resulting mixture was heated in Microwave (6OW, 30 min, 130 ⁰ C). Water and AcOEt were added to the mixture. The organic phase was dried (Na ₂ SO ₄ ) and concentrated. The residue was purified by chromatography on silicagel (cHex/EtOAc, gradient from 95/5 to 80/20 then CH ₂ CI ₂ ). The title compound was obtained as white solid (3.8%). LC/MS: 248.01 (M+H) Rt= 3.39min; ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of ethyl 1-(6-chloropyridin-2-yl)-5-trifluoromethyl-pyrazole-4-carbox ylate (D50, 3g, 9.39mmol) in DME (30ml) and water (3ml) were added Pd(PPh ₃ ) 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 Na ₂ CO ₃ (2.986g, 28.17 mmol) and the mixture was heated at 90 ⁰ C for 3 hours . After cooling, the mixture was poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /cHex, 4/1 then CH ₂ CI ₂ ) 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; ¹ H NMR (300MHz, CDCI ₃ , 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:

Description 57a: Ethyl 1-(6-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)-5- trifluoromethyl-pyrazole-4-carboxylate (D57a)

To a solution of ethyl 1-(6-(5-chloro-2-methoxyphenyl)pyridin-2-yl)-5-trifluorometh yl- pyrazole-4-carboxylate (D56e, 3.95g, 9.28 mmol) in CH ₂ CI ₂ (80ml) was added dropwise

BBr ₃ (23.21 ml of a solution 1 M in CH ₂ CI ₂ , 23.21 mmol). The mixture was stirred at room temperature overnight and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /cHex, 4/1 ) to give the title compound as a cream solid (2.22g, 58.11 %). ¹ H NMR (300MHz, CDCI ₃ , 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:

Description 58: 1-{6-[2-hydroxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperi dine-4- carboxylic acid (D58)

To a solution of ethyl 1-{6-[2-methoxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperi dine-4- carboxylate (D56n, 3.5 g, 8.57 mmol) was added pyridine hydrochloride (15 g, 130 mmol). The reaction mixture was stirred at 150 ⁰ C for 1 h, then cooled and diluted with

AcOEt. The organic phase was washed with H ₂ O, then a saturated solution of NH ₄ CI . 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)

To a solution of 1-{6-[2-hydroxy-5-trifluoromethylphenyl]pyridin-2-yl}-piperi dine-4- carboxylic acid (D58, 1.5g, 3.48 mmol) in EtOH (50 mL) at 0 ⁰ C was added HCI (gas) during 5min. The reaction mixture was stirred at room temperature for 2h. N ₂ 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

NaHCO ₃ . After extraction with AcOEt, the organic phase was washed with H ₂ O, 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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 1g, 2.65mmol) in acetone (50ml) was added Cs ₂ CO ₃ (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 )

Ethyl 1-{6-[2-(2-propen-1-yloxy)phenyl]pyridin-2-yl}-5-(trifluorom ethyl)-pyrazole-4- carboxylate (D60, 0.66g, 1.58mmol) was heated at 200 ⁰ C for 10 minutes and then cooled. After purification by chromatography on silicagel ( cHex/ CH ₂ CI ₂ , 110/0 to 0/100), the title compound was obtained as a white powder (0.4g, 60.6%). ¹ H 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)

A solution of ethyl 1-{6-[2-hydroxy-3-(2-propen-1-yl)phenyl]pyridin-2-yl}-5-(tri fluoromethyl)- pyrazole-4-carboxylate (D61 , 0.7g, 1.67mmol) in MeOH (35ml) was hydrogenated (H- Cube apparatus, 50 ⁰ C, 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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 1g, 2.65 mmol) in acetone (50ml) was added Cs ₂ CO ₃ (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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH ₂ CI ₂ /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; ¹ H NMR (300MHz, CDCI ₃ , 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)

A mixture of ethyl 1-(6-(2-(4-cyanobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluorom ethyl- 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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ then CH ₂ CI ₂ /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; ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of ethyl 1-(6-(2-(4-(aminothiocarbonyl)-benzyloxy)-phenyl)pyridin-2-y l)-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 CH ₂ CI ₂ , the organic phase was dried

(Na ₂ SO ₄ ), and concentrated under reduced pressure. After trituration with iPr ₂ O , the title compound was obtained as cream solid (0.42g, yield= 71.2%); LC/MS: 565.0 (M+H), Rt = 4.33min; ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 1 g, 2.65 mmol) in acetone (50ml) was added Cs ₂ CO ₃ (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 (Na ₂ SO ₄ ), and concentrated under reduced pressure. The title compound was obtained as a brown solid (1.5g, quantitative yield); ¹ H 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:

Description 67: Ethyl 1 -(6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl)-2-methyl- pyrrole-3-carboxylate (D67)

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%); ¹ H NMR (300MHz, CDCI ₃ , 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)

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:

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)

From ethyl 1-(6-(5-methyl-2-hydroxyphenyl)pyridin-2-yl)-5-trifluorometh yl-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-piperid inecarboxylate (D71)

From ethyl 1-(6-(5-methyl-2-hydroxyphenyl)pyridin-2-yl)-piperidine-4-ca rboxylate (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)

From ethyl 1-(6-(5-trifluoromethyl-2-hydroxyphenyl)pyridin-2-yl)-piperi dine-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)

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 (Na ₂ SO ₄ ) 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-piperid inecarboxylic acid

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-piperid inecarboxylate (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 80 ⁰ C overnight, and then concentrated under reduced pressure. After dilution with H ₂ O, 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)

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-pyridin yl}-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)pyridi n- 2-yl]-5-trifluoromethyl-pyrazole-4-carboxylate (D76)

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(PPh ₃ ) ₄ (0.103g, 0.089mmol), then 4-fluorophenyl boronic acid (0.162g, 1.16mmol) and Na ₂ CO ₃ (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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), 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%). ¹ H NMR (300MHz, CDCI ₃ , 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-carboxylat e (D77)

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 H ₂ O (3ml), were added Pd(PPh ₃ ) ₄ (72mg, 0.062mmol), 4-trifluoromethoxyphenylboronic acid (Avocado, 0.386g, 1.87mmol) and Na ₂ CO ₃ (0.331g, 3.12mmol) and the mixture was heated at 105 ⁰ C overnight and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH ₂ CI ₂ /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. ¹ H NMR (CDCI ₃ , 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)

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 Na ₂ CO ₃ (0.483 ml. of a 1 M solution, 0.483 mmol) in DME (100 ml) was added Pd(Ph ₃ P) 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 H ₂ O, 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. ¹ H 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:

The following intermediates were similarly prepared as described for Description 77:

The following intermediates were similarly prepared as described for Description 77:

Description 156: Ethyl 1 -[6-(2-(4-(4-azidophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D156)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 0.2g, 0.53 mmol) in CH ₃ CN (50 ml) was added K ₂ CO ₃ (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 80 ⁰ C for 24h and to complete the reaction 1.5 eq of all reagents were added. The reaction mixture was stirred at 80 ⁰ C for 48hours before being cooled and concentrated to dryness. The crude mixture was taken up in water and extracted with CH ₂ CI ₂ . The organic layers were dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The resulting solid was purified by chromatography on silica gel (CH ₂ CI ₂ /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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 1.5g, 3.98mmol) in acetone (60ml) was added Cs ₂ CO ₃ (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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was

purified by chromatography on silica gel (CH ₂ CI ₂ ZcHeX, 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; ¹ H NMR (300Mz, CDCI ₃ , 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-carboxylat e (D158)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 0.42g, 1.1 1 mmol) in acetone (30ml) was added Cs ₂ CO ₃ (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 70 ⁰ C overnight and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ ). 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; ¹ H NMR (300Mz, CDCI ₃ , 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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 1.5g, 3.98mmol) in acetone (250ml) was added Cs ₂ CO ₃ (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 70 ⁰ C overnight and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ /cHex, 3/2). The title compound was obtained as a white solid (1.25g, yield= 55%). ¹ H 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-carboxylat e (D160)

To a solution of ethyl 1-(6-(5-chloro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluorometh yl- pyrazole-4-carboxylate (D57a, 0.24g, 0.58mmol) in acetone (1OmI) was added Cs ₂ CO ₃ (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 70 ⁰ C 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%); ¹ H NMR (300Mz, CDCI ₃ , 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-carboxylat e (D161)

To a solution of ethyl 1-(6-(5-fluoro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluorometh yl- pyrazole-4-carboxylate (D57b, 0.25g, 0.63mmol) in acetone (20ml) was added Cs ₂ CO ₃ (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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) 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%); ¹ H NMR (300Mz, CDCI ₃ , 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-carboxylat e (D162)

To a solution of ethyl 1-(6-(3,5-difluoro-2-hydroxyphenyl)pyridin-2-yl)-5-trifluoro methyl- pyrazole-4-carboxylate (D57c, 0.23g, 0.556mmol) in acetone (1 OmI) was added Cs ₂ CO ₃ (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 (Na ₂ SO ₄ ) 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 %); ¹ H NMR (300Mz, CDCI ₃ , 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)

To a solution of ethyl 1-(6-(2-hydroxyphenyl)pyridin-2-yl)-5-trifluoromethyl-pyrazo le-4- carboxylate (D56a, 0.7g, 1.86mmol) in acetone (50ml) was added Cs ₂ CO ₃ (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 70 ⁰ C overnight and then poured into water. After extraction with CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ /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; ¹ H NMR (300Mz, CDCI ₃ , 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:

The following intermediates were similarly prepared as described for Description 157:

The following intermediates were similarly prepared as described for Description 157:

The following intermediates were similarly prepared as described for Description 157:

The following intermediates were similarly prepared as described for Description 157:

Description 240: 1-[6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyr role- 3-carboxylic acid (D240)

To a solution of ethyl 1-(6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl)-2-methyl-pyr role-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%). ¹ H NMR (300MHz, CDCI ₃ , 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)

To a solution of Ethyl 1-[6-( 2-hydroxy-phenyl)pyridin-2-yl]-2-methyl-pyrrole-3-carboxylat e (D56g, 0.6g, 2 mmol) in CH ₃ CN (20 ml), 4-bromo-2-methylbenzyl bromide D44c (0. 647g, 2.45 mmol) and Cs ₂ CO ₃ (0.79g, 2.45 mmol, 1.2 eq) were added. The mixture was refluxed for I Ohours and then poured into water, extracted with CH ₂ CI ₂ and dried over Na ₂ SO ₄ . 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 70 ⁰ C 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)

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)methyl oxy)- phenyl)pyridin-2-yl]-1 -piperidine-4-carboxylic acid (D243)

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:

Prepared by a similar method as described for D56a:

Prepared by a similar method as described for D57a:

Description 254: Ethyl-1-[6-(6-chloro-2-hydroxy-phenyl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D254)

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:

Description 259: Ethyl 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylat e (D259)

Prepared by a similar method as described for D77 from ethyl 1-(6-(2-(4- bromobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyraz ole-4-carboxylate (D66a), the title compound was obtained as a colourless oil (yield = 46.5%). LC/MS: 610.3 (M+Na), Rt = 4.56min; ¹ H NMR (CDCI ₃ , 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-pyr azole-4-carboxylate

(D260)

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-pyr azole-4-carboxylate (D66c), the title compound was obtained as a yellow oil (yield = 28%). LC/MS: 642.3 (M+Na), Rt = 4.66min; ¹ H NMR (CDCI ₃ , 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-triflu oromethyl- pyrazole-4-carboxylic acid

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 H ₂ O (20ml) was added NaOH (18.4ml of a solution 1 N, 18.4mmol) and the mixture was heated at 70 ⁰ C 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): C _3I H ₂₄ F ₃ N ₃ O ₃ Rt= 2.72min, CaIc: 544.1848 (M+H), Found: 544.1883 (M+H); ¹ H 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)pyridi n-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid

To a solution of ethyl 1-[6-(2-(4-(4-trifluoromethylphenyl)benzyloxy)-phenyl)pyridi n-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylate (D158, 0.42g, 0.69mmol) in MeOH (20ml) and H ₂ O (10ml) was added NaOH (3.44ml of a solution 1 N, 3.44mmol) and the mixture was heated at 70 ⁰ C 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): C ₃₀ Hi ₉ F ₆ N ₃ O ₃ , Rt= 2.78min, CaIc: 584.1409 (M+H), Found: 584.1452 (M+H); ¹ H 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

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 80 ⁰ C 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH ₂ CI ₂ /Me0H, 9/1), and after crystallisation from CH ₃ CN, 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): C ₃₀ H ₂₂ F ₃ N ₃ O ₄ , Rt= 2.76 min, CaIc: 544.1484 (M-H), Found: 544.1479 (M-H); ¹ H 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)pyrid in-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid

To a solution of ethyl 1-[6-(5-chloro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyrid in-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 80 ⁰ C 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was triturated with iPr ₂ O, and the precipitate was filtered and dried. The title compound was obtained as white solid (0.105g, yield: 79%). LC-HRMS (a): C ₃₀ H ₂₁ CIiF ₃ N ₃ O ₄ , Rt= 2.81 min, CaIc: 578.1094 (M-H), Found: 578.1072 (M-H); ¹ H NMR (300MHz, CDCI ₃ , 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)pyrid in-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid

To a solution of ethyl 1-[6-(5-fluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)pyrid in-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): C ₃₀ H ₂₁ F ₄ N ₃ O ₄ , Rt= 2.72min, CaIc: 562.1390 (M-H), Found: 562.1429 (M-H); ¹ H 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)p yridin-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid

To a solution of ethyl 1-[6-(3,5-difluoro-2-(4-(4-methoxyphenyl)benzyloxy)-phenyl)p yridin- 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 80 ⁰ C 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was triturated with iPr ₂ O, and the precipitate was filtered and dried. The title compound was obtained as a white powder (0.085g, yield= 50%). LC-HRMS (a): C ₃₀ H ₂₀ F ₅ N ₃ O ₄ , Rt= 2.76min, CaIc: 580.1296(M-H), Found: 580.1276(M-H); ¹ H NMR (CDCI ₃ , 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)pyridi n-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid

To a solution of ethyl 1-[6-(2-(2-methyl-4-(4-fluorophenyl)benzyloxy)-phenyl)pyridi n-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: 221 ⁰ C; LC-HRMS (a): C ₃₀ H ₂₁ F ₄ N ₃ O ₃ , Rt= 2.79 min, CaIc: 546.1441 (M-H), Found: 546.1414 (M-H); ¹ H 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

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 CH ₃ CN, the title compound was obtained as white crystals (0.5g, yield= 63.2%). Mp: 190 ⁰ C; LC-HRMS (a): C ₃₀ H ₁₉ F ₃ N ₄ O ₄ , Rt = 2.65min , CaIc: 555.1281 (M-H), Found: 555.1231 (M-H); ¹ H 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

To a solution of ethyl 1-[6-(2-(2-methyl-4-(4-trifluoromethoxyphenyl)benzyloxy)- phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazole-4-carboxylat e (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 60 ⁰ C 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= 171 ⁰ C; LC-HRMS (a): C _3I H _2I F ₆ N ₃ O ₄ , Rt= 3.26min, CaIc: 612.1358 (M-H), Found: 612.1352 (M- H); ¹ H 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-trifluoromethylpyri din-2- ylJbenzyloxyJ-phenylJpyridin^-y^-S-trifluoromethyl-pyrazole^ -carboxylic acid

To a solution of ethyl 1-[6-(5-methyl-2-(2-methyl-4-(3-chloro-5-trifluoromethylpyri din-2- yl)benzyloxy)-phenyl)pyridin-2-yl]-5-trifluoromethyl-pyrazol e-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 60 ⁰ C 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was triturated with iPr ₂ O and the resulting solid was filtered, washed with iPr ₂ O and dried. The title compound was obtained as a white powder (0.07g, yield= 46.3%). LC-HRMS: C _3i H ₂₁ Ch F ₆ N ₄ O ₃ , Rt= 3.33min, CaIc: 647.1285 (M+H), Found: 647.1313 (M+H); ¹ H 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 R ⁹ ≠ CN or were similarly prepared as described for Example 8 for R ⁹ = CN:

The following Examples were similarly prepared as described for Example 9 for R ⁹ ≠ CN or were similarly prepared as described for Example 8 for R ⁹ = CN:

Example Name

87 1-[6-(3,5-difluoro-2-(4-(4-cyanophenyl)phenylmethyloxy)-phen yl)pyridin-2-yl]-5- trifluoromethyl-pyrazole-4-carboxylic acid

The following Examples were similarly prepared as described for Example 9 for R ⁹ ≠ CN or were similarly prepared as described for Example 8 for R ⁹ = CN:

The following Examples were similarly prepared as described for Example 9 for R ⁹ ≠ CN or were similarly prepared as described for Example 8 for R ⁹ = CN:

The following Examples were similarly prepared as described for Example 9 for R ⁹ ≠ CN or were similarly prepared as described for Example 8 for R ⁹ = CN:

Example 167: 1-[6-(2-(4-(4-cyanophenyl)benzyloxy)-phenyl)pyridin-2-yl]-5- methyl- pyrazole-4-carboxylic acid

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 H ₂ O (20ml) was added NaOH (5.5ml of a solution 1 N, 5.54mmol) and the mixture was heated at 70 ⁰ C 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 CH ₂ CI ₂ /Me0H, 97/3, led after crystallisation from CH ₃ CN to the title compound as white crystals (0.3g, yield= 55.7%). Mp: 202 ⁰ C; LC/MS: 487.1 (M+H), Rt= 3.03min; LC-HRMS (a): C ₃₀ H ₂₂ N ₄ O ₃ , Rt= 2.71 min, CaIc: 487.1770 (M+H), Found: 487.1776 (M+H); ¹ H 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 CH ₂ CI ₂ /Me0H, 93/7, and trituration with iPr ₂ O 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)

Mp: 258°C; LC/MS: 505.1 (M+H), Rt = 2.61 min; LC-HRMS (a): C ₃₀ H ₂₄ N ₄ O ₄ , Rt= 2.30min, CaIc: 505.1876 (M+H), Found: 505.18.63 (M+H); ¹ H 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

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 H ₂ O (10ml) was added NaOH (7.53ml of a solution 1 N, 7.53mmol) and the mixture was heated at 90 ⁰ C 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 (CH ₂ CI ₂ /Me0H, 97/3 then 9/1 )to afford a white solid which was triturated with hot iPr ₂ O. After filtration, the title compound as white solid (0.17g, yield= 39.3%). Mp: 211 ⁰ C; LC/MS: 576.0 (M+H), Rt = 2.75min; LC-HRMS (a): C ₃₀ H ₂₁ F ₃ N ₄ O ₅ , Rt = 2.31 min, CaIc: 575.1542 (M+H), Found: 575.1584 (M+H); ¹ H 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

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-tri fluoromethyl-pyrazole-4- carboxylate (D120) as pale yellow crystals. Mp= 202.5 ⁰ C; LC-HRMS (a): C ₃₀ H ₂₂ F ₃ N ₅ O ₄ , Rt= 2.43min, CaIc: 572.1546 (M-H), Found: 572.1516 (M-H); ¹ H 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

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-piperid inecarboxylic 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 Na ₂ CO ₃ (0.138g, 1.3 mmol) and Pd(Ph ₃ P) 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The solid residue was recrystallised from CH ₃ CN. The title compound was obtained as white crystals ( 0.06g, yield= 17.7%). LC-HRMS (a): C ₃₂ H ₃₀ N ₄ O _{3 ,} Rt= 2.97, CaIc: 519.2396 (M+H), Found: 519.2416 (M+H); ¹ H 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)b enzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid

To a solution of 1-{6-[2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yOphenyOmethylJoxy^δ-^rifluoromethyOphenyO^-pyridinyl^-pipe ridinecarboxylic acid (D75, 0.55g, 0.495 mmol) and 6-bromo-3-pyridinecarbonitrile (0.136 g, 0.743 mmol) in DME (50 ml.) was added Na ₂ CO ₃ (0.743 ml. of a solution 1 N, 0.743 mmol) and Pd(Ph ₃ P) ₄ (11.44 mg, 9.90 μmol). The reaction mixture was heated under reflux for 3 days (0.02eq of Pd(Ph ₃ P) 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 NaHCO ₃ , then H ₂ O. The organic layer was dried (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH ₂ CI ₂ /Me0H 100/0 to 90/10). After recrystallisation from CH ₃ CN, the title compound was obtained as white crystals ( 0.14g, yield= 46.9%). LC-HRMS (a): C ₃₂ H ₂₇ F ₃ N ₄ O _{3 ,} Rt= 3.26min, CaIc: 573.2114 (M+H), Found: 573.2178 (M+H); ¹ H 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

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-piperid inecarboxylic acid (D74, 0.3g, 0.652mmol) in DME (5ml) and H ₂ O (1 ml) was added 2,3-dichloro-5-trifluoromethyl- pyridine (0.183g, 0.847mmol), Pd(PPh ₃ ) ₄ (37.7mg, 0.033mmol) and Na ₂ CO ₃ (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 (Na ₂ SO ₄ ) 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): C ₃₂ H ₂₉ CI ₁ F ₃ N ₃ O ₃ , Rt= 3.49, CaIc: 596.1927, Found: 596.1983; ¹ H 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

To a solution of 1-[6-(2-(4-bromobenzyloxy)-phenyl)pyridin-2-yl]-2-methyl-pyr role-3- carboxylic acid (D240, 0.39g, 0.84mmol) in DME (30ml) was added 4-cyanophenylboronic acid (Aldrich, 0.137g, 0.93mmol), then Na ₂ CO ₃ (0.178g , 1.68mmol) in H ₂ O (5ml) and

Pd(Ph ₃ P) 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 (Na ₂ SO ₄ ) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH ₂ CI ₂ then CH ₂ CI ₂ /Me0H 9/1 ) and the resulting solid was triturated with hot CH ₃ CN 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): C _3I H ₂₃ N ₃ O ₃ , Rt= 3.14min, CaIc: 484.1661 (M-H), Found: 484.1658 (M-H); ¹ H 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

To a solution of 1-[6-(2-(4-bromo-2-methylbenzyloxy)-phenyl)pyridin-2-yl]-2-m ethyl- 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), Cs ₂ CO ₃ ( 652 mg, 2 mmol, 1.2 eq) and Pd(PPh ₃ ) ₄ (94mg, 0.05 eq, 0.084 mmol). The reaction was performed in sealed tube in a microwave Biotage at 130 ⁰ C for 8 minutes. The mixture was poured in water, acidified to pH = 5 with aqueous 1 N HCI, extracted with DCM, and dried over Na ₂ SO ₄ . After filtration and evaporation in vacuo, the remaining oil was purified by chromotagraphy on silica gel (eluent: CH ₂ CI ₂ / MeOH= 95:5). Recristallisation from a mixture of CH ₃ CN/ EtOH afforded the title compound as an orange powder (127 mg, 15.46%). LC-HRMS (a): C ₃₁ H ₂₅ F ₁ N ₂ O _{3 ,} Rt= 3.63min, CaIc: 493.1927 (M+H), Found: 493.1917 (M+H); ¹ H 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:

Example 178: 1 -[6-( 2-(4-(4-cyanophenoxy)benzyloxy)-phenyl)pyridin-2-yl]-2-methy l- pyrrole-3-carboxylic acid

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}benzonitri le (D49,

300mg, 0.71 mmol, 1.1 eq), Cs ₂ CO ₃ ( 229mg, 0.71 mmol, 1.1 eq) and Pd(PPh ₃ ) ₄ (STREM, 41 mg, 0.05eq). The reaction mixture was heated at 130 ⁰ C for 8 minutes in a biotage microwave. The solution was poured in water, acidified to pH 6 and the solid filtered off, dissolved in CH ₂ CI ₂ and washed with water. The organic phase was dried over Na ₂ SO ₄ and filtered on a small pad of silica. After evaporation, the title compound was obtained as a white powder (186mg, 56%). LC-HRMS (b): C ₃ iH ₂₃ N ₃ O ₄ , Rt= 3.10min, CaIc: 502.1767

(M+H), Found: 502.1778 (M+H); ¹ H 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)be nzyloxy)- phenyl)pyridin-2-yl]-piperidine-4-carboxylic acid

To a solution of ethyl 1-[6-(3,5-difluoro-2-(2-methyl-4-bromobenzyloxy)-phenyl)pyri din-2- yl]-piperidine-4-carboxylate (D69a, 0.4g, 0.74mmol) in DME (30ml) and water (3ml) were added Pd(PPh ₃ ) ₄ (0.085g, 0.074mmol), then 4-trifluoromethylphenyl boronic acid (0.18g, 0.95mmol) and Na ₂ CO ₃ (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 CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /Me0H, 98/2) and then preparative HPLC, to give the titled compound as a brown solid (0.05g, 1 1.7%). LC-HRMS (b): C ₃₂ H ₂₇ F ₅ N ₂ O ₃ , Rt= 3.45min, CaIc: 583.2020 (M+H), Found: 583.1992 (M+H); ¹ H 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)benzyl oxy)- phenylJpyridin^-ylJ-S-trifluoromethyl-pyrrazole^-carboxylic acid

Similarly prepared as for Example 179 from ethyl 1-(6-(5-fluoro-2-(2-methyl-4- bromobenzyloxy)-phenyl)pyridin-2-yl)-5-trifluoromethyl-pyraz ole-4-carboxylate (D66c, 0.5g, 0.86mmol) and 4-trifluoromethylphenylboronic acid (0.213g, 1.12mmol). The title compound was obtained, after flash chromatography (CH ₂ CI ₂ /Me0H, 98/2) and then recrystallisation from CH ₃ CN, as white crystals (0.11g, yield= 20.67%). Mp= 237.7°C; LC- HRMS (b): C ₃₁ H ₂₀ F ₇ N ₃ O _{3 ,} Rt = 3.10min, CaIc: 614.1315 (M-H), Found: 614.1315 (M-H); ¹ H 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

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 (CH ₂ CI ₂ ZMeOH, 98/2) and then recrystallisation from CH ₃ CN, as white crystals (0.02g, yield= 4.1 %). Mp= 291.6°C; LC-HRMS (a): C _3I H ₂₈ CI ₁ F ₁ N ₂ O ₃ , Rt= 3.39min, CaIc: 531.1851 (M+H), Found: 531.1798 (M+H); ¹ H NMR (CDCI ₃ , 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)py ridin- 2-yl]-5-trifluoromethyl-pyrrazole-4-carboxylic acid

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(PPh ₃ ) ₄ (0.062g, 0.053mmol), then 3,4-dimethoxyphenyl boronic acid

(0.127g, 0.69mmol) and Na ₂ CO ₃ (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

CH ₂ CI ₂ , the organic phase was dried (Na ₂ SO ₄ ), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH ₂ CI ₂ /Me0H, gradient

100/0 to 95/5). After trituration with Et ₂ O, the title compound was obtained as a brown powder (yield= 1 1.1 %). LC-HRMS (a): C ₃₂ H ₂₆ F ₃ N ₃ O _{5 ,} Rt= 2.80min, CaIc: 588.1746 (M-H),

Found: 588.1759 (M-H); ¹ H 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:

Example 187: 1-[6-(2-(4-(4-methoxy-2-methyl-phenyl)benzyloxy)-phenyl)pyri din-2- yl]-5-trifluoromethyl-pyrazole-4-carboxylic acid

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-tr ifluoromethyl-pyrazole-4- carboxylate (D259), the title compound was obtained as white crystals (yield = 50.4%). LC-HRMS (a): C _3I H ₂₄ F ₃ N ₃ O ₄ , Rt = 2.78min, CaIc: 558.1641 (M-H), Found: 558.1600 (M- H); ¹ H 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)benz yloxy)- phenylJpyridin^-ylJ-S-trifluoromethyl-pyrazole^-carboxylic acid

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)pyridi n-2-yl]-5-trifluoromethyl- pyrazole-4-carboxylate (D260), the title compound was obtained as a grey powder (yield = 58.7%). LC-HRMS (a): C ₃₂ H ₂₅ F ₄ N ₃ O ₄ , Rt = 2.88min, CaIc: 590.1703 (M-H), Found: 590.1676 (M-H); ¹ H 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:

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 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 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)-phe nyl)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.