WO2010015652A2

WO2010015652A2 - Thiazole compounds as activators of soluble guanylate cyclase

Info

Publication number: WO2010015652A2
Application number: PCT/EP2009/060145
Authority: WO
Inventors: Anne Marie Jeanne Bouillot; Nerina Dodic; Francoise Jeanne Gellibert; Olivier Mirguet
Original assignee: Smithkline Beecham Corporation
Priority date: 2008-08-07
Filing date: 2009-08-05
Publication date: 2010-02-11
Also published as: WO2010015652A3

Abstract

Disclosed are compounds of formula (I) wherein R¹ and R² are independently selected from hydrogen, halo, C_1-4alkyl, C_1-4alkoxy, CF₃ and OCF₃; -Y- represents formula (IA) R³ represents hydrogen, fluoro, chloro or C_1-4alkyl; R^4a and R^4b each independently represent hydrogen, C_1-4alkyl, C_1-4alkoxy, CF₃ or halo; and R⁵ represents a group Z-X; wherein Z is absent or represents (CH₂)₂ or O; and X represents formula (IB) wherein: 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, R⁶ represents hydrogen, halo, CF₃, C_1-4alkyl or C_1-4alkoxy in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, OCF₃, C_1-4alkyl, C_1-4alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; or when one of J or L represents N, R⁶ represents hydrogen or halo in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, C_1-4alkyl, C_1-4alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; and R⁸ and R⁹ are independently selected from hydrogen and C_1-4alkyl; or salts thereof which activate soluble guanylate cyclase (sGC), pharmaceutical compositions containing them, their use in medicine, and processes for their preparation.

Description

THIAZOLE COMPOUNDS AS ACTIVATORS OF SOLUBLE GUANYLATE CYCLASE

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 of the invention 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 compounds of the invention 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 compounds of the invention may be useful is congestive heart failure. Another particular disease or condition for which the compounds of the invention may be useful is peripheral vascular disease. Another particular disease or condition for which the compounds of the invention may be useful is arterial hypertension (also known as systemic hypertension). Another particular disease or condition for which the compounds of the invention may be useful is pulmonary arterial hypertension. Another particular disease or condition for which the compounds of the invention may be useful is angina.

According to one aspect the present invention provides a compound of formula (I)

or a salt thereof wherein

R¹ and R² are independently selected from hydrogen, halo,

Ci_-4alkoxy, CF₃ and OCF₃;

-Y- represents

R³ represents hydrogen, fluoro, chloro or

R^4a and R^4b each independently represent hydrogen,

CF₃ or halo; and

R⁵ represents a group Z-X; wherein Z is absent or represents (CH₂)₂ or O; and X represents

wherein: 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, R⁶ represents hydrogen, halo, CF₃, C_1-4alkyl or C_1-4alkoxy in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, OCF₃, C_1-4alkyl, C_1-4alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; or when one of J or L represents N, R⁶ represents hydrogen or halo in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, C_1-4alkyl, C_1-4alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; and R⁸ and R⁹ are independently selected from hydrogen and C_1-4alkyl.

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

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, C_1-4alkoxy 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 R¹ and R² are independently selected from hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, CF₃, OCF₃ or OCH₃. In a further embodiment R¹ represents hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, CF₃, OCF₃ or OCH₃. In a further embodiment R² represents hydrogen, methyl, fluoro or OCF₃.

In a further embodiment R¹ is in a para position relative to the -OCH₂- linker. In a further embodiment R² is in an ortho position relative to the -OCH₂- linker. In a further embodiment R¹ is in a para position relative to the -OCH₂- linker and R² is in an ortho position relative to the - OCH₂- linker.

In a further embodiment R¹ is in an ortho position relative to the bond linking to the thiazole ring. In a further embodiment R² is in a meta position relative to the -OCH₂- linker.

In a further embodiment R¹ represents hydrogen and R² represents hydrogen, methyl or CF₃, in a further embodiment with R² in an ortho position relative to the -OCH₂- linker. In a further embodiment R² represents hydrogen and R¹ represents hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, methoxy, CF₃ or OCF₃, in a further embodiment with R¹ in a para position relative to the -OCH₂- linker. In a further embodiment R¹ represents fluoro and R² represents fluoro, in a further embodiment with R¹ in a para position relative to the -OCH₂- linker and R² in an ortho position relative to the -OCH₂- linker.

In a further embodiment R¹ represents hydrogen and R² represents methyl, in a further embodiment with R² in a meta position relative to the -OCH₂- linker. In a further embodiment R¹ represents fluoro and R² represents hydrogen, in a further embodiment with R¹ in an ortho position relative to the bond linking to the thiazole ring. In a further embodiment R² represents hydrogen and R¹ represents hydrogen, methyl, ethyl, fluoro, chloro or CF₃, with R¹ in a para position relative to the -OCH₂- linker.

In an embodiment R³ represents hydrogen. In a further embodiment R³ represents methyl. In a further embodiment R³ represents chloro.

In an embodiment R^4a and R^4b each independently represent hydrogen, C_1-4alkyl, C_1-4alkoxy or halo. In an embodiment R^4a represents hydrogen. In an embodiment R^4b represents hydrogen, methyl, methoxy, propoxy, fluoro or chloro. In an embodiment R^4a represents hydrogen and R^4b represents hydrogen, methyl, methoxy, propoxy, fluoro or chloro.

In an embodiment R^4a represents hydrogen and R^4b represents methyl.

In an embodiment Z is absent.

In an embodiment R⁶ is in a meta-position relative to the R⁷ substituent.

In an embodiment J and L both represent CH.

In an embodiment J represents N and L represents CH.

In an embodiment J represents CH and L represents N.

In an embodiment J and L both represent CH and R⁶ represents hydrogen, halo, CF₃, C-^alkoxy or C_1-4alkyl in a meta or ortho position relative to the R⁷ substituent. In an embodiment J and L both represents CH and R⁶ represents hydrogen, halo, CF₃ or C_1-4alkyl in a meta position relative to the R⁷ substituent. In an embodiment J and L both represents CH and R⁶ represents C_1-4alkoxy in an ortho position relative to the R⁷ substituent. In an embodiment J and L both represent CH and R⁶ represents hydrogen, methyl, chloro or CF₃ in a meta position relative to the R⁷ substituent. In an embodiment J and L both represents CH and R⁶ represents methoxy in an ortho position relative to the R⁷ substituent.

In an embodiment one of J and L represents N and R⁶ represents hydrogen or chloro in a meta or ortho position relative to the R⁷ substituent.

In an embodiment R⁷ represents hydrogen, halo, CN, OCF₃, CF₃, C^alkoxy, CH₂OH, CONR⁸R⁹ or CO₂H; wherein R⁸ and R⁹ are independently selected from hydrogen and C_1-4alkyl. In an embodiment R⁷ represents hydrogen, fluoro, chloro, CN, CF₃, OCF₃, methoxy, CH₂OH, CO₂H, CO₂NH₂ or CO₂N(CH₃),.

In an embodiment J and L both represent CH, R⁶ represents hydrogen and R⁷ represents hydrogen, fluoro, chloro, methoxy, CN, CF₃, CH₂OH, CO₂H, CO₂NH₂ or CO₂N(CH₃)₂. In an embodiment J and L both represent CH, R⁷ represents CF₃ and R⁶ represents halo, C_1-4alkyl or CF₃. In an embodiment J and L both represent CH, R⁷ represents CF₃ and R⁶ represents chloro, methyl or CF₃. In an embodiment J and L both represent CH, R⁷ represents CN and R ,6¹ represents C_1-4alkyl. In an embodiment J and L both represent CH, R⁷ represents CN and R^b represents methyl. In an embodiment J and L both represent CH, R⁶ represents CF₃ and R⁷ represents C_1-4alkoxy. In an embodiment J and L both represent CH, R⁶ represents CF₃ and R⁷ represents methoxy. In an embodiment J and L both represent CH, R⁶ represents methoxy and R⁷ represents hydrogen.

In an embodiment J and L both represent CH, R⁶ represents hydrogen and R⁷ represents CF₃.

In an embodiment one of J and L represents N and the other represents CH, R⁷ represents CF₃ and R⁶ represents halo. In an embodiment one of J and L represents N and the other represents CH, R⁷ represents CF₃ and R⁶ represents chloro. In an embodiment J represents N, L represents CH, R⁷ represents CF₃ and R⁶ represents halo. In an embodiment J represents N, L represents CH, R⁷ represents CF₃ and R⁶ represents chloro.

In an embodiment one of J and L represents N and the other represents CH, R⁷ represents C_1- ₄alkoxy and R⁶ represents hydrogen. In an embodiment one of J and L represents N and the other represents CH, R⁷ represents methoxy and R⁶ represents hydrogen. In an embodiment J represents CH, L represents N, R⁷ represents methoxy and R⁶ represents hydrogen.

In an embodiment one of J and L represents N and the other represents CH, R⁶ represents halo and R⁷ represents CN. In an embodiment J represents N and L represents CH, R⁶ represents halo and R⁷ represents CN. In an embodiment J represents N and L represents CH, R⁶ represents chloro and R⁷ represents 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-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-ethylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4'-cyano-2'-methyl-3-(propyloxy)-4-biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid; i^-p-^P'-chloro-S-methyl^'-^rifluoromethylH-biphenylyOmethylϊoxy^δ-methylphenyO-I .S- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[2-({[3'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid; 1-{4-[2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid; 1-{4-[2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-({[3-methyl-4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-({[3-fluoro-4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-3-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1-(4-{2-[({4-[(4-chlorophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-[4-(2-{[(4-{[4-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-fluorophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-carboxy-3-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid; 1-{4-[2-({[3,4'-bis(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4-{[4-(methyloxy)phenyl]oxy}phenyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-({[4'-cyano-3-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-({[3-chloro-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-({[3-chloro-4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid; 1-[4-(2-{[(3-chloro-4'-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-({[3-(methyloxy)-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}-3_!5-difluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1-(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]-3,5-difluorophenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-{4-[3,5-difluoro-2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid; 1-(4-{2-[({2-methyl-4-[6-(methyloxy)-3-pyridinyl]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-{4-[2-({[4'-(hydroxymethyl)-3-methyl-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-fluoro-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[5-chloro-4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1 -{5-chloro-4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-(5-chloro-4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-{5-methyl-4-[2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[3_!5-difluoro-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-5-methyl-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1 -(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]phenyl}-5-methyl-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3_!5-difluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-({[4'-(aminocarbonyl)-3-methyl-4-biphenylyl]methyl}oxy)-3,5-difluorophenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}-5-fluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-fluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1-{4-[2-({[2\3-dimethyl-4^l-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-3,5-difluorophenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-chloro-2-({[2\3-dimethyl-4^l-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid;

1-[4-(5-chloro-2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-2'_!3-dimethyl-4-biphenylyl)methyl]oxy}-3_!5-difluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid; 1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-[(trifluoromethyl)oxy]phenyl}-1 ,3-thiazol-

2-yl)-4-piperidinecarboxylic acid; 1-(4-{5-methyl-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3-thiazol-

2-yl)-4-piperidinecarboxylic acid;

1-(4-{2-[({4'-[(dimethylamino)carbonyl]-3-methyl-4-biphenylyl}methyl)oxy]-5-methylphenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-(4-{5-chloro-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3-thiazol- 2-yl)-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-{4-[5-(methyloxy)-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid; 1 -(4-{5-(methyloxy)-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(methyloxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(1-methylethyl)phenyl]-1 ,3-thiazol-2-yl}- 4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-ethylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[5-(1-methylethyl)-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 _!3- thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[3-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-(4-{2-[({4-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-2-methylphenyl}methyl)oxy]-5- methylphenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid;

1-(4-{2-[({4-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-2-methylphenyl}methyl)oxy]-5-ethylphenyl}- 1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[5-ethyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-(4-{5-ethyl-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3-thiazol-2- yl)-4-piperidinecarboxylic acid; i^-p-^^-methyl^'-^rifluoromethylH-biphenylyllmethylJoxy^S-^rifluoromethyOphenyO-I .S- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3-(trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; i^-p-t^-tS-chloro-S-^rifluoromethyl^-pyridinyO^-methylphenylJmethy^oxyl-δ-

(trifluoromethyOphenyO-i ^-thiazol^-yl^-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-3-(trifluoromethyl)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid; 1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-4'-(methyloxy)-2'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-

1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[5-ethyl-2-({[3-methyl-2'_!4'-bis(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-(propyloxy)-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-

2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-2'_!4'-bis(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol- 2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-5-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[2'-chloro-3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-3-

(trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1 -{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-3,5-dimethylphenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylic acid; and

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3_!5-dimethylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

1-{4-[4-chloro-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid;

1-{4-[2-fluoro-6-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}- 4-piperidinecarboxylic acid;

1-{4-[4-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-

4-piperidinecarboxylic acid; and i^-p-t^-^-chloro-δ-^rifluoromethyl^-pyridinyO^-methylphenylϊmethyOoxyl-S-

(trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

In an embodiment there is provided a salt of a compound of formula (I) as defined above selected from:

1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}- 4-piperidinecarboxylic acid 2-aminoethanol (1 :1 ); sodium 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylate; and

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid 2-aminoethanol (1 :1 ).

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. Separation of individual enantiomers of the compounds of formula (I) (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. For certain compounds of formula (I), for example certain compounds where J or L represents nitrogen, 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. Since the compound of formula (I) contains a CO₂H group, 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 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) can include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts, which salts are also included within the scope of the present invention.

In an embodiment, there is a provided a sodium salt of a compound of formula (I).

In an embodiment there is provided an ethanolamine salt of a compound of formula (I), in a further embodiment a 1 :1 ethanolamine salt.

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 compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". All such prodrugs of compounds of the invention 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). 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 the invention.

Hereinafter, compounds of formula (I) (whether in solvated or unsolvated form) or their pharmaceutically acceptable salts (whether in solvated or unsolvated form) are referred to as "compounds of the invention".

Also included within the scope of the invention are polymorphs of a compound of the invention.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulphur, fluorine and chlorine such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁷O, ¹⁸O, ³¹P, ³²P, ³⁵S, ¹⁸F and ³⁶CI, respectively. Certain isotopic variations of the invention, for example, those in which a radioactive isotope such as ³H or ¹⁴C is incorporated, are useful in drug and/or substrate tissue distribution studies. Tritiated, i.e., ³H, and carbon-14, i.e., ¹⁴C, isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with isotopes such as deuterium, i.e., ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements and hence may be preferred in some circumstances. Isotopic variations of the compounds 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 compounds of the invention, as activators 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 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 the use of a compound of the invention for the manufacture of a medicament for treating a disease or condition mediated by sGC activity.

According to a further aspect the invention provides a compound of the invention for use in the treatment of a disease or condition mediated by sGC activity.

According to a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, in association with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). The carrier, diluent and/or excipient must 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 the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC such as one or more of the diseases described above, for example arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease 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 comprising a compound of the invention.

According to a further aspect the invention provides a method of treatment of cardiorenal syndrome or hepatorenal syndrome 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. The compounds 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. Appropriate doses will be readily appreciated by those skilled in the art. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician or veterinarian.

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 "treatment" extend to prophylaxis, prevention of recurrence and 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. Where the compositions comprise dosage units, each unit will typically contain from 5-1000 mg of the active ingredient.

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 particular mammal being treated, 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.

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.

Compounds 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.

Compounds of general formula (I) may be prepared according to reaction scheme 1 by saponification of compounds of formula (II) in a presence of base such as NaOH or LiOH in a suitable solvent such as ethanol at 40⁰C or reflux.

Scheme 1

Compounds of formula (II) may be prepared according to reaction scheme 2 by reacting compounds of formula (III) and compound of formula (IV) in the presence of base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux.

Scheme 2

Compounds of formula (III) may be prepared according to reaction scheme 3 by reacting the alpha bromo ketone of formula (V) and ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate (Vl) in a suitable solvent such as ethanol or DMF at reflux, or under microwave conditions in ethanol at 120⁰C.

Scheme 3

(V)

Compounds of formula (III) where R³ represents hydrogen may also be prepared according to reaction scheme 4a by Suzuki coupling using the boronic acid of formula (VII) and ethyl 1-(4- bromo-1 ,3-thiazol-2-yl)-4-piperidinecarboxylate of formula (VIII) with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux.

Scheme 4a

(VIII) (III)

(VII)

The compound of formula (VIII) may be prepared according to reaction scheme 4b.

Scheme 4b

(Villa) (VIIIb) (VlIl)

In respect of the compounds of formula (VII), certain compounds are commercially available, for example 2-hydroxyphenyl boronic acid (from Aldrich) and 5-fluoro-2-hydroxyphenyl boronic acid (from Apollo or Combi Blocks). Other compounds of formula (VII) which are not commercially available may be prepared by standard methods well-known to the person skilled in the art.

For example, compounds of formula (VII) may be prepared from the corresponding methyl derivatives of formula (Vila) according to Scheme 4b.

Scheme 4b

Suitable, for example, for

R¹ = Cl and R² =H

R¹ = R² = F

R¹ = CH₃ and R² = H

R¹ = CF, and R² = H

The compound of formula (Vila) where R¹ is ethyl and R² is hydrogen may be prepared as described in WO2005019151.

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

Compounds of formula (Vila) where R¹ is propyl and R² is hydrogen may be prepared from the corresponding 4-propyl-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. Analogous processes may be used to prepare other compounds of formula (Vila) where R¹ is C_1-4alkyl and R² is as defined above. For example, 2-bromo-4,6-dimethyl phenol is commercially available from Bionet.

Compounds of formula (Vila) where R¹ is H and R² is ethyl, isopropyl or t-butyl 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 (Vila) where R² is and R¹ is as defined above.

Certain compounds of formula (V) are commercially available, for example where R¹ represents methyl, ethyl, isopropyl in the ortho position relative to the OH substitutent and R² represents hydrogen.

In a general process, compounds of general formula (V) which are not commercially available may be prepared according to reaction scheme 5 by reacting the alkyl ketone of formula (IX) with a suitable brominating agent such as copper (II) bromide in a suitable solvent such as a mixture of EtOAc and chloroform or a bromine polymer supported reagent in THF.

Scheme 5

brominating agent

(IX) (V)

When R¹ = CF₃ and R² = H, compounds of formula (IXa) may be prepared according to reaction scheme 6 starting from (i) the commercially available 4-(trifluoromethyl)phenol with methyl iodide in a solvent such as acetonitrile at reflux with a suitable base such as potassium carbonate, followed by (ii) reaction with acetic anhydride in trifluorosulfonic acid at 30⁰C, and (iii) demethylation using boron tribromide in a suitable solvent such as DCM at -8O⁰C.

Scheme 6

(IXa)

The compound of formula (Vl) may be prepared according to reaction scheme 7 in two steps by first reacting fluorenylmethyloxycarbonyl chloride and potassium thiocyanate in a suitable solvent such as ethyl acetate, to afford the non isolated 9H-fluoren-9-ylmethyl isothiocyanatidocarbonate, followed by reaction with ethyl 4-piperidinecarboxylate in a suitable solvent such as chloroform.

Scheme 7

(Vl)

The compound of formula (X) may be prepared according to reaction schemes 8 to 10.

(X)

The compound of formula (Xa) may be prepared according to reaction scheme 8, starting from reduction of the carboxylic acid of formula (Xl) using borane dimethyl sulphide in THF at 75°C, followed by bromation of alcohol (XII) with phosphorus tribromide in dichloromethane at room temperature.

Scheme 8

Certain compounds of formula (Xl) are commercially available; others may be prepared by standard methods well-known to the person skilled in the art.

The compound of formula (Xb) may be prepared according to reaction scheme 9. The alcohol of formula (Xl) can be also prepared from esterification of the carboxylic acid of formula (X) using sulphuric acid in methanol at reflux, followed by reduction of (XII) with lithium aluminium hydride in THF at 0⁰C. The borolane derivative of formula (XV) may be prepared by reacting the compound of formula (Xl) with bis(pinacolato)diboron with Pd(dppf)CI₂(N) and potassium acetate in a suitable solvent such as 1 ,4-dioxane at reflux. Compound (Xb) may be finally obtained from compound (XV) by bromination with phosphorus tribromide in DCM at 0⁰C. Scheme 9

(XV) (Xb)

Certain compounds of formula (XIV) or the corresponding carboxylic acids of formula (XIII) are commercially available: 4-bromo-2-methylbenzoic acid, 4-bromo-2-chlorobenzoic acid or methyl 4-bromo-2-methoxybenzoate (from Aldrich); or may be prepared by standard methods well- known to the person skilled in the art.

Where R^4a represents C_1-4alkoxy, the compound of formula (Xc) may be prepared according to reaction scheme 10, starting from alkylation of the benzaldehyde of formula (XVIa) using a base such as sodium hydride in a suitable solvent, such as THF/DMF followed by reduction of the aldehyde (XVIb) with sodium borohydride in methanol at room temperature. Bromination of the alcohol with phosphorus tribromide in dichloromethane at room temperature provides the compound (Xc).

Scheme 10

1- NaBH₄, MeOH, rt

(XVIa) (XVIb) (Xc)

Where R⁵ represents a group Z-X wherein Z is absent, compound (IVa) may be prepared according to reaction scheme 1 1 , namely by Suzuki reaction from the alcohol of formula (XV) and the corresponding halo derivative of formula (XVII), for example reacting with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux, followed by bromination, for example with phosphorus tribromide in DCM at 0⁰C. Scheme 11

(XV)

Certain compounds of formula (XVII) are commercially available, for example: wherein hal represents Br or Cl, J represents N, R⁶ represents H, and R⁷ represents CN, CF₃, COOH, Cl or OMe (Aldrich, Fluka or Acros); wherein hal represents Cl, J represents N, R⁶ represents Cl, and R⁷ represents CF₃ (Aldrich); wherein J represents CH, hal represents F, R⁶ represents H, F, Cl, OMe, Me, or CF₃, and R⁷ represents CN or COOH (Aldrich, Acros, Apin). Other compounds of formula (XVII) may be prepared by standard methods well-known to the person skilled in the art.

Where R⁵ represents a group Z-X wherein Z is absent, compound (IVa) may also be prepared according to reaction scheme 12, namely by Suzuki reaction from the alcohol of formula (XII) and the corresponding boronic acid derivative of formula (XVIII), for example reacting with palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux followed by bromination with phosphorus tribromide in DCM at O⁰C.

Scheme 12

(XII)

Compounds of formula (XVIII) are either commercially available or can be prepared by standard methods well-known to the person skilled in the art.

Compounds of formula (Na) wherein Z is absent may be also prepared according to reaction schemes 13 and 14.

Following reaction scheme 13, compounds of formula (XIX) may be prepared from reaction of a compound of formula (III) with the corresponding alkylating reagent of formula (X) in the presence of a base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux. Suzuki coupling with the corresponding boronic acid of formula (XVIII) using palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux provides the compound of formula (Na). Scheme 13

Following reaction scheme 14, compounds of formula (XX) may be prepared from alkylation of a compound of formula (III) with the corresponding alkylating reagent of formula (Xb) in the presence of base such as potassium carbonate or cesium carbonate in a suitable solvent such as acetonitrile or acetone at reflux. After Suzuki coupling with the corresponding halide of formula (XVII) using palladium tetrakis with a base such as cesium carbonate in a suitable solvent such as DME at reflux provides the compound of formula (Na).

Scheme 14

Compounds of formula (lib) wherein Z represents O may be also prepared according to reaction scheme 15 by reacting a compound of formula (III) and a compound of formula (IVb).

Scheme 15

Compounds of formula (IVb) may be prepared according to reaction scheme 16 by reacting the commercially available aldehyde of formula (XX) and the compound of formula (XXI) in the presence of base such as cesium carbonate in a suitable solvent such as DMF at 85°C. The aldehyde function of compounds of formula (XXII) may be reduced down to the corresponding alcohol function of compounds of formula (XXIII) in the presence of reducing agent such as lithium aluminium hydride in a suitable solvent such as THF at room temperature. Finally, compounds of formula (IVb) may be prepared from compounds of formula (XXIII) in the presence of a brominating agent such as phosphorus tribromide in a suitable solvent such as DCM at room temperature.

Scheme 16

DMF

LiAIH₄ THF, RT

(IVb) (XXIII)

Phenol derivatives of formula (XXI) are commercially available or may be prepared by standard methods well-known to the person skilled in the art.

Compounds of formula (NIb) where R³ represents fluoro or chloro may be prepared according to reaction scheme 17 by reacting compounds of formula (Ilia) where R³ represents hydrogen in the presence of a halogenating agent, such as Selectfluor in a suitable solvent such as DMF, or N-chlorosuccinimide in a suitable solvent such as acetonitrile at 60⁰C.

Scheme 17

Compounds of formula (lie) wherein Z represents CH₂CH₂ may be also prepared according to reaction scheme 18 by reacting using a Heck reaction between the compound of formula (XIX) and the compound of formula (XXIV) followed by a reduction with hydrogen on Pd/C in a suitable solvent such as ethanol.

Scheme 18

Certain compounds of formula (XXIV) are commercially available. Other compounds of formula (NIV) may be prepared by methods as described in Tetrahedron (2007), 63(23), 5088-5094 or in Journal of Organic Chemistry (2007), 72(1 ), 144-149 or may be prepared by standard methods well-known to the person skilled in the art.

Alternatively, compounds of formula (lie) with Z representing (CH₂^, can be prepared according to Scheme 19.

Scheme 19

Compounds of formula (IVc) may be prepared according to Scheme 20.

Scheme 20

or rt

(XXVI)

(4-phenethyl)benzyl aldehyde is commercially available (from Alfa or ABCR). Other compounds of formula (XXVI) may be prepared by methods as described in Tetrahedron Letters, 1999, 40(11 ), 2075-2078 or in Tetrahedron Letters, 2006, 62(51 ), 11925-11932, or may be prepared by standard methods well-known to the person skilled in the art.

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 an "analogous" procedure, as will be appreciated by those skilled in the art, such a procedure may involve minor variation, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

Compounds are named using ACD/Name PRO 6.02 chemical naming software (Advanced Chemistry Development Inc., Toronto, Ontario, M5H2L3, Canada).

In the reporting of Proton Magnetic Resonance (¹H NMR) spectral data, chemical shifts are reported in ppm (δ) using tetramethylsilane as the internal standard. Splitting patterns are designed as s, singlet; d, doublet; 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 40⁰C. The mass spectra (MS) were recorded on a Micromass ZQ-LC mass spectrometer using electrospray positive ionisation [ES+ve to give MH⁺ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)^" molecular ion] modes. Analytical LC-HRMS Methods:

(a) Analytical HPLC was conducted on a LUNA 3u C18 column (2,5 μm 30^*3 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0 ^■* 0.5 minutes, 5%B; 0.5 ^■* 3.5 minutes, 5%B ^■* 100%B; 3.5 ^■* 4 minutes, 100%B; 4 ^■* 4.5 minutes, 100%B ^■* 5%B; 4.5 ^■* 5.5 minutes, 5%B at a flowrate of 1.3 mL/min with a temperature of 40⁰C. The mass spectra (MS) were recorded on a Micromass LCT mass spectrometer using electrospray positive ionisation [ES+ve to give MH⁺ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)^" molecular ion] modes.

(b) Analytical HPLC was conducted on a X-Bridge C18 column (2,5 μm 30^*3 mm id) eluting with 0.01 M ammonium acetate in water (solvent A) and 100% acetonitrile (solvent B) using the following elution gradient: 0 ^■* 0.5 minutes, 5%B; 0.5 ^■* 3.5 minutes, 5%B ^■* 100%B; 3.5 ^■* 4 minutes, 100%B; 4 ^■* 4.5 minutes, 100%B ^■* 5%B; 4.5 ^■* 5.5 minutes, 5%B at a flowrate of 1.3 mL/min with a temperature of 40⁰C. The mass spectra (MS) were recorded on a Micromass LCT mass spectrometer using electrospray positive ionisation [ES+ve to give MH⁺ molecular ion] or electrospray negative ionisation [ES-ve to give (M-H)^" molecular ion] modes.

Intermediate 1 : 2-bromo-1 -(2-hydroxy-5-methylphenyl)ethanone

To a solution of commercially available 1-(2-hydroxy-5-methylphenyl)ethanone (3 g, 19.98 mmol) in a mixture of chloroform (60 ml) and ethyl acetate (60 ml) was added copper(ll) bromide (8.92 g, 40.0 mmol) and the reaction was stirred at 100 °C for 18 hours. After cooling, the white solid (CuBr) was filtered and the filtrate was concentrated under reduced pressure.

The title compound, 2-bromo-1-(2-hydroxy-5-methylphenyl)ethanone (4.15 g, 73% yield) was obtained as an orange oil. LC: Rt= 3.01 min. ¹H NMR (CDCI₃): δ 7.55 (d, 1 H), 7.35 (dd, 1 H),

6.95 (d, 1 H), 4.45 (s, 2H), 2.3 (s, 3H).

The following Intermediate was prepared by an analogous method to that described for

Intermediate 1.

Intermediate 3: 1 -(methyloxy)-4-(trifluoromethyl)benzene

To a solution of commercially available 4-(trifluoromethyl)phenol (25 g, 154 mmol) in Acetonitrile (500 ml.) was added the potassium carbonate (63.9 g, 463 mmol) and the iodomethane (57.6 ml_, 925 mmol). The reaction was reluxed overnight. After cooling, the potassium carbonate was filtered and the filtrate was concentrated under reduced pressure. The title compound, 1- (methyloxy)-4-(trifluoromethyl)benzene (23.4 g, 133 mmol, 86 % yield) was obtained as a pale yellow oil. ¹H NMR (CDCI₃): £7.50 (d, 2H), 6.85 (d, 2H), 3.75 (s, 3H).

Intermediate 4: 1-[2-(methyloxy)-5-(trifluoromethyl)phenyl]ethanone

At 0⁰C, to the trifluoromethane sulfonic acid (30.9 ml, 348 mmol), was added dropwise a solution of 1-(methyloxy)-4-(trifluoromethyl)benzene, intermediate 3, (12.25 g, 69.5 mmol) in acetic anhydride

(13.15 ml, 139 mmol). The temperature was maintained under 30⁰C. The reaction was then stirred at room temperature for one night. The reaction was gently hydrolysed with addition of ice and extracted with Et₂O. The combined organic phases were washed with a saturated solution of hydrogeno sodium carbonate, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography (cHex/EtOAc: 90/10 to 60/40) to give the title compound 1-[2-(methyloxy)-5-(trifluoromethyl)phenyl]ethanone (8.968 g, 41.1 mmol, 59.1 % yield) as a yellow oil. ¹H NMR (CDCI₃) £7.95 (d, 1 H), 7.6 (dd, 1 H), 6.95 (d, 1 H), 3.95 (s, 3H), 2.55 (s, 3H). Intermediate 5: 1 -[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone

At -80⁰C, to a solution of 1-[2-(methyloxy)-5-(trifluoromethyl)phenyl]ethanone, Intermediate 4, (8.968 g, 41.1 mmol) in dichloromethane (150 ml) was added dropwise a 1 M solution of boron tribromide in dichloromethane (41.1 ml, 41.1 mmol). The reaction was stirred at -80⁰C for 1 hour. The reaction was quenched with addition of water/ ice and the aqueous phase was extracted with dichloromethane. The combined organic phases were washed twice with a 1 N NaOH solution, dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography (cHex and cHex /Dichloromethane 50/50) to give the title compound 1-[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone (1.394 g, 6.83 mmol, 16.61 % yield) as an orange oil. LC/MS: m/z 203 [M-H]⁺, Rt 3.08 min. ¹H NMR (CDCI₃) £8.05 (d, 1 H), 7.75 (dd, 1 H), 7.05 (d, 1 H), 2.75 (s, 3H).

Intermediate 6: 2-bromo-1 -[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone

To as solution of 1 1-[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone, Intermediate 5, (1.394 g, 6.83 mmol), in a mixture of chloroform (20 ml) and ethyl acetate (20 ml) was added copper(ll) bromide (2.97 g, 13.32 mmol) and the reaction was stirred at 100 ⁰C for 23 hours. After cooling, the white solid (CuBr) was filtered and the filtrate was concentrated under reduced pressure.The title compound 2-bromo-1-[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone (2.046 g), was obtained as a brown oil and was used in the subsequent step without futher purification. ¹H NMR (CDCI₃) £7.9 (d, 1 H), 7.65 (dd, 1 H), 7. (d, 1 H), 4.4 (s, 2H).

Intermediate 7: 9H-fluoren-9-ylmethyl isothiocyanatidocarbonate

Fluorenylmethyloxycarbonyl chloride (1 Kg, 3.86 mol; in 5 batches, 200g^*5) was dissolved in anhydrous ethyl acetate (300ml^*5). This solution was added dropwise to a suspension of dry potassium thiocyanate (82.6 g^*5, 4.25 mol) in anhydrous ethyl acetate (1.5 L^*5) at 0⁰C under N₂ atmosphere. The solution was allowed to warm to RT and stirred overnight. The reaction was monitored by thin layer chromatography. The reaction mixture was passed through a celite pad to remove residual salts and the ethyl acetate was removed by evaporation under reduce pressure to afford a total of 1.08 Kg (200g^*5) of crude product, (yield= 100%). The crude product was used for the subsequent step without futher purification.

Intermediate 8: ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate

Fluorenylmethyloxycarbonyl isothiocyanate, intermediate 7, (1.08 Kg, 3.86 mol, in 5 batches, 200g^*5) was dissolved in chloroform (1.5 L^*5) and a solution of commercially available piperidine-4-carboxylic acid ethyl ester (133.7 g^*5, 4.25 mol) in chloroform was added. Then the mixture was stirred at RT for 3 hours. The mixture was concentrated in vacuo and residue was washed with Et₂O, filtered and the solid was dissolved in dichloromethane (1.5 L^*5) then piperidine (329.1 g^*5, 19 mol) was added. The mixture was stirred at RT overnight. The reaction mixture was concentrated. The residue was purified by flash chromatography (EtOAc/pentane=1/10-1/2) to afford the title compound ethyl 1-(aminocarbonothioyl)-4- piperidinecarboxylate, (195 g, 30% yield in 2 steps). 1H NMR: (CDCI₃, 400MHz) δ 5.85 (s, 2H), 4.30 (s, 2H), 4.12 (dd, 2H), 3.25 (t, 2H), 2.48-2.56 (m, 1 H), 1.91-1.95 (m, 2H), 1.73-1.79 (m, 2H), 1.19 (t, 3H).

Intermediate 9: ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate

A solution of 2-bromo-1-(2-hydroxy-5-methylphenyl)ethanone, Intermediate 1 , (4.15 g, 13.23 mmol) and ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate, Intermediate s, (2.86 g, 13.23 mmol) in ethanol (100 ml) was stirred at 80 ⁰C for 5 hours. The reaction was concentrated under reduce pressure and the residue was dissolved in dichloromethane, washed with water and a saturated solution of hydrogeno sodium carbonate, dried over sodium sulfate and evaporated in vacuo. The crude compound was purified by flash chromatography (cHex and cHex /EtOAc: 50/50) to give the title compound ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2- yl]piperidine-4-carboxylate (4.3 g, 12.41 mmol, 94 % yield) as an orange solid. LC/MS: m/z 347 [M+H]+, Rt 3.83 min. ¹H NMR (CDCI₃,) £7.35 (d, 1 H), 7 (dd, 1 H), 6.85 (d, 1 H), 6.75 (s, 1 H), 4.2 (q, 2H), 3.95 (m, 2H), 3.2 (m, 2H), 2.55 (m, 1 H), 2.3 (s, 3H), 2.05 (m, 2H), 1.85 (m, 2H), 1.3 (t, 3H).

Intermediate 10: ethyl 1-[4-(5-ethyl-2-hydroxyphenyl)-1,3-thiazol-2-yl]-4- piperidinecarboxylate

To a solution of 2-bromo-1-(5-ethyl-2-hydroxyphenyl)ethanone, intermediate 2, (1 g, 4.11 mmol), in ethanol (15 mL) was added the ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate, intermediate 8, (1.068 g, 4.94 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial high to 120 ⁰C for 20 min. The solvent was evaporated in vacuo and the crude compound was purified by flash chromatography (dichloromethane/ cHex 50/50 and dichloromethane/ cHex: 90/10) to give the title compound, ethyl 1-[4-(5-ethyl-2-hydroxyphenyl)- 1 ,3-thiazol-2-yl]-4-piperidinecarboxylate (785 mg, 2.178 mmol, 52.9 % yield) as light yellow solid. LC/MS: m/z 361 [M+H]+, Rt 4.01 min. ¹H NMR (CDCI₃,) £7.35 (d, 1 H), 7.05 (dd, 1 H), 6.9 (d, 1 H), 6.75 (s, 1 H), 4.2 (q, 2H), 3.95 (m, 2H), 3.2 (m, 2H), 2.7-2.5 (m, 3H), 2.1 (m, 2H), 1.9 (m, 2H), 1.55 (brs, 1 H), 1.35-1.15 (2t, 6H).

Intermediate 11 : ethyl 1-{4-[2-hydroxy-5-(trifluoromethyl)phenyl]-1,3-thiazol-2-yl}-4- piperidinecarboxylate E^t

To a solution of 2-bromo-1-[2-hydroxy-5-(trifluoromethyl)phenyl]ethanone, Intermediate 6, (2g, 7.07 mmol), in ethanol (15 mL) was added ethyl 1-(aminocarbonothioyl)-4- piperidinecarboxylate, Intermediate 8, (1.834 g, 8.48 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial high to 120 ⁰C for 20 min. The solvent was evaporated in vacuo and the crude compound was purified by flash chromatography (DCM/cyclohexane 50/50 and DCM) to give the title compound, ethyl 1-{4-[2-hydroxy-5-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylate (1.993 g, 4.98 mmol, 70.4 % yield) as light yellow solid. LC/MS: m/z 401 [M+H]+, Rt 3.98 min.¹H NMR (DMSO, d⁶,) J8.2 (d, 1 H), 7.55 (s, 1 H), 7.45 (dd, 1 H), 7.05 (d, 1 H), 4.1 (q, 2H), 3.85 (m, 2H), 3.2 (m, 2H), 2.65 (m, 1 H), 2 (m, 2H), 1.75-1.55 (m, 2H), 1.2 (t, 3H). Intermediate 12: (4-bromo-2-methylphe ol

To a solution of commercially available 4-bromo-2-methylbenzoic acid (250 g, 1.16 mol, in 4 batches, 62.5 g^*4) in THF (300ml^*4) was added a solution of borane-dimethyl sulfide (44.2g ^*4, 0.58 mol^*4) in THF (75 ml^*4) at 0⁰C. After addition, the reaction mixture was stirred for 5 min, then the mixture was heated to 75°C for 48hours. The reaction mixture was cooled to RT and then a saturated solution of K₂CO₃ was added to the reaction mixture. The separated organic layer was dried over sodium sulphate and concentrated in vacuo. The crude of 4 batches were purified together by flash chromatography (pentane/ AcOEt:5/1 ) to give the title compound (4- bromo-2-methylphenyl)methanol,. (190 g, 81% yield). ¹H NMR: (d6-DMSO, 400MHZ) δ 7.30 (d,

2H), 7.25 (d, 1 H), 5.10 (t, 1 H), 4.39 (d, 2H), 2.17 (s, 3H) .

Intermediate 13: 4-bromo-1-(bromomethvl)-2-methylbenzene

To a solution of (4-bromo-2-methylphenyl) methanol, intermediate 12, (100 g, 0. 5mol) in dicholoromethane (1 L) was added dropwise phosphorus tribromine (54.2 g, 0.2 mol) at 0 ⁰C. After addition, the reaction mixture was stirred for 2 hours at RT. The mixture was adjusted to pH=7 with a saturated solution of NaHCO₃. The separated organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product (4-bromo-2- methylphenyl)methanol, (128 g, 97% yield). ¹H NMR: (400 MHZ, CDCI₃) δ 7.43 (t, 1 H), 7.32- 7.37 (m, 2H), 4.67 (s, 2H), 2.33 (s, 3H).

Intermediate 14: methyl 4-bromo-2-methylbenzoate

To a solution of commercially available 4-bromo-2-methylbenzoic acid (200 g, 0.87 mol) in methanol (500 ml.) was added sulphuric acid (98%, 10 ml_). The reaction mixture was heated to reflux overnight. After cooling, the reaction mixture was concentrated, and then water and ethyl acetate were added. The organic layers were separated, dried over sodium sulfate and concentrated in vacuo to give the title compound, methyl 4-bromo-2-methylbenzoate as red oil (190 g, 90%), which was used for next step without purification and characterization.

Intermediate 15: (4-bromo-2-methylphenyl)methanol

LiAIH₄ (30 g, 0.79 moL) was dissolved in THF (500 ml_), and the mixture was cooled to O⁰C. A solution of intermediate 14, methyl 4-bromo-2-methylbenzoate (70 g, 0.29 mol) in THF (200 ml.) was dropwise added at O⁰C, and the reaction mixture was stirred at room temperature overnight. After cooling with ice-bath, water (30 g) was dropwise added, followed by aqueous NaOH solution (15%, 90 g). The solid was filtered and washed with THF (500 ml_). The filtrate was concentrated in vacuo to give a red solid, which was recrystallized from petroleum ether/EtOAc (30:1 ) to give the title compound (4-bromo-2-methylphenyl)methanol as a white solid (40 g, 65% yield). ¹H NMR (400 MHz, CDCI₃) £ 7.32 (m, 2H), 7.23 (m, 1 H), 4.61 (s, 2H), 2.30 (s, 3H).

Intermediate 16: r2-methvl-4-(4,4.5,5-tetramethyl-1 ,3,2-dioxaborolan-2-vl)phenyllmethanol

A solution of intermediate 15, (4-bromo-2-methylphenyl)methanol, (30 g, 150 mmol), bis(pinacolato)diboron (40 g, 156 mmol), Pd(dppf)CI₂(N) (8 g, 10 mmol), and potassium acetate (44 g, 448 mmol) in 1 ,4-dioxane (600 ml.) was heated to reflux under N₂ for 4 hours. After cooling, the reaction mixture was filtered, and the filtrate was concentrated in vacuo. Purification by flash chromatography (petroleum ether/ EtOAc: 5/1 ) gave the title compound [2- methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol as a red oil (34 g, 90%yield). ¹H NMR (400 MHz, DMSO-d₆) J7.50-7.38 (m, 3H), 5.14 (t, 1 H), 4.51 (d, 2H), 2.22 (s, 3H), 1.28 (s, 12H). Intermediate 17: 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of intermediate 16, [2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methanol , (32 g, 129 mmol) in dichloromethane (300 mL) was cooled to O⁰C. Phosphorus tribromide (104 g, 385 mmol) was dropwise added, and the reaction mixture was stirred at O⁰C for 45 min. The reaction mixture was poured into ice water, and the organic layer was washed with aqueous sodium carbonate solution until the pH=7. The organic layer was dried over sodium sulfate and concentrated in vacuo. After reystallization from n-hexane, the title compound, 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane, was obtained as a white solid (32 g, 81%yield). ¹H NMR (400 MHz, CDCI₃) £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).

Intermediate 18: ethyl 1 -{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-1,3-thiazol-2-yl}-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, intermediate 9, (4.3 g, 12.41 mmol) in acetonitrile (20 mL) was added cesium carbonate (12.13 g, 37.2 mmol) and 2-[4-(bromomethyl)-3-methylphenyl]-4,4,5,5-tetramethyl-1 ,3-dioxolane, intermediate 17, (3.86 g, 12.41 mmol). The reaction mixture was stirred at 70⁰C for 72 hours before being cooled and filtrated. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (DichloromethaneCM/cHex 30/70 and Dichloromethane) to give the title compound ethyl 1-{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylate (1.3 g, 2.255 mmol, 18.17 %) as a yellow solid. LC/MS: m/z 577 [M+H]+, Rt 4.83 min. ¹H NMR (CHCI₃,) £8.05 (d, 1 H), 7.65 (m, 2H), 7.5 (dd, 1 H), 7.15 (s, 1 H), 7.05 (m, 1 H), 6.9 (d, 1 H), 5.15 (s, 2H), 4.2 (q, 2H), 4.05 (m, 2H), 3.15 (m, 2H), 2.55 (m, 1 H), 2.4-2.35 (2s, 6H), 2.05 (m, 2H), 1.95-1.75 (m, 2H), 1.4 (s, 12H),1.3 (t, 3H). The following Intermediates were prepared by an analogous method to that described for Intermediate 18.

Intermediate 21 : ethyl 1 -[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5- methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate, Intermediate 18, (600 mg, 1.041 mmol) in DME (50 ml.) and some drops of water was added successively the commercially available 4-bromo-3-methylbenzonitrile (408 mg, 2.081 mmol,), cesium carbonate (1020 mg, 3.13 mmol,) and tetrakis(triphenylphosphine)palladium(0) (35 mg , 0.030 mmol,). The reaction mixture was then heated at 110⁰C for 18 hours before being cooled and concentrated under reduced pressure. The crude was taken up in water and extracted with Et₂O. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (cHex to cHex/EtOAc: 20/80) to give the title compound ethyl 1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)- 1 ,3-thiazol-2-yl]-4-piperidinecarboxylate (205 mg, 0.362 mmol, 34.8 %) as a orange oil. LCMS : (M+H)⁺= 566, Rt= 4.60 min. ¹H NMR (CDCI₃) S 7.95 (d, 1 H), 7.55-7.4 (m, 3H), 7.25 (d, 1 H), 7.1 (m, 3H), 6.95 (dd, 1 H), 6.85 (d, 1 H), 5.05 (s, 2H), 4.1 (q, 2H), 3.95 (m, 2H), 3.05 (m, 2H), 2.45 (m, 1 H), 2.35 (s, 3H), 2.3 (s, 3H), 2.25 (s, 3H), 2.05-1.9 (m, 2H), 1.85-1.7 (m, 2H), 1.15 (t, 3H).

The following Intermediates were prepared by an analogous method to that described for Intermediate 21.

Intermediate 24: 4-bromo-2-(propyloxy)benzaldehyde

To a solution of commercially available 4-bromo-2-hydroxybenzaldehyde, (7g, 34.8 mmol) in Tetrahydrofuran (75 ml.) and N,N-Dimethylformamide (25 mL) was added portionwise sodium hydride (0.919 g, 38.3 mmol) and the mixture was stirred at room temperature for 15 minutes. Then 1-bromopropane (4.11 mL, 45.3 mmol) was added and the reaction mixture was heated at 60⁰C for 5 hours and then poured into water. After extraction with dichloromethane, the organic phase was dried over sodim sulfate and concentrated under reduced pressure. The product was obtained as a cream powder (8.4g, 34.6 mmol, 99 %) and was used in the next step without futher purification. LCMS : (M+H)⁺= 246, Rt= 3.41 min.¹H NMR (CDCI₃) δ 10.37 (s, 1 H), 7.65 (dd, 1 H), 7.05 (dd, 1 H), 7 (s, 1 H), 3.95 (t, 2H), 1.75 (m, 2H), 1.05 (t, 3H).

Intermediate 25: [4-bromo-2-(propyloxy)phenyl]methanol

To a solution of 4-bromo-2-(propyloxy)benzaldehyde, intermediate 24, (8.4 g, 34.6 mmol) in methanol (100 mL) was added portionwise sodium borohydride (1.444 g, 38.0 mmol) and the reaction mixture was stirred at room temperature for 30 minutes and then poured into water.

After extraction with dichloromethane, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The title product, [4-bromo-2-(propyloxy)phenyl]methanol was obtained as a pale yellow oil (8.35 g, 34.1 mmol, 99 %). LCMS: Rt= 3.06 min., no mass found. ¹H NMR (CDCI₃) £7.05 (dd, 1 H), 6.95 (dd, 1 H), 6.9 (s, 1 H), 4.6 (d, 2H), 3.9 (t, 2H), 2.2 (t,

1 H), 1.75 (m, 2H), 1.05 (t, 3H).

Intermediate 26: 4-bromo-1-(bromomethvl)-2-(propyloxv)benzene

To a solution of [4-bromo-2-(propyloxy)phenyl]methanol, intermediate 25,(1.5 g, 6.12 mmol), in dichloromethane (50 mL), was added phosphorus tribromide (1.732 mL, 18.36 mmol). The reaction was stirred at room temperature for 4 hours. Water (100 mL) was dropwise added, completed with addition of a 1 N NaOH solution (50 mL). The aqueous phase was extracted with Et₂O. The combined organic phases were dried over sodium sulfate and concentrated under reduce pressure. The title compound, 4-bromo-1-(bromomethyl)-2-(propyloxy)benzene, (1.8 g, 5.84 mmol, 95 %) was obtained as an oil. ¹H NMR (CDCI₃) δ l .2 (dd, 1 H), 7.05 (dd, 1 H), 7 (s, 1 H), 4.5 (s, 2H), 3.95 (t, 2H), 1.9 (m, 2H), 1.1 (t, 3H).

Intermediate 27: ethyl 1 -[4-(2-{[(4-bromo-2-methylphenyl)methyl]oxy}-5-methylphenyl)- 1,3-thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, intermediate 9, (400 mg, 1.155 mmol), in acetonitrile (20 ml.) were added cesium carbonate (1129 mg, 3.46 mmol) and 4-bromo-1-(bromomethyl)-2-methylbenzene, intermediate 13, (320 mg, 1.212 mmol). The reaction mixture was stirred at 70⁰C for 4 hours before being cooled and filtrated. The filtrate was concentrated under reduced pressure and the crude product was purified by flash chromatography (dichloromethane/cHex 30/70 and dichloromethane) to give the title compound ethyl 1-[4-(2-{[(4-bromo-2-methylphenyl)methyl]oxy}-5-methylphenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate (570 mg, 1.077 mmol, 93 %) as a white solid. LCMS : (M+H)⁺= 530, Rt= 4.68 min. ¹H NMR (CDCI₃) £7.95 (d, 1 H), 7.35-7.2 (m, 3H), 7 (s, 1 H), 6.95 (dd, 1 H), 6.8 (d, 1 H), 4.9 (s, 2H), 4.1 (q, 2H), 3.95 (m, 2H), 3.05 (m, 2H), 2.45 (m, 1 H), 2.3 (s, 3H), 2.25 (s, 3H), 1.95 (m, 2H), 1.85-1.7 (m, 2H), 1.2 (t, 3H).

The following Intermediate was prepared by a method analogous to that described for Intermediate 27.

Intermediate 29: ethyl 1-{4-[2-({[2'<:hloro-3-methyl-4χtrifluoromethyl)-4- biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate.

To a solution of ethyl 1-[4-(2-{[(4-bromo-2-methylphenyl)methyl]oxy}-5-methylphenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate, intermediate 27, (400 mg, 0.755 mmol), in 1 ,2-

Dimethoxyethane (5OmL), were added the commercially available [2-chloro-4-

(trifluoromethyl)phenyl]boronic acid, (340 mg, 1.515 mmol), PalladiumTetrakis (30 mg, 0.026 mmol), cesium carbonate (740 mg, 2.271 mmol). The reaction vessel was sealed and heated in

Biotage Initiator using initial high to 120 ⁰C for 20 min. The solvent was then evaporated in vacuo and the residue was dissolved in Et₂O and washed with water. The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The crude product was purified by flash chromatography (cHex to dichloromethane) to give the title compound ethyl 1-

{4-[2-({[2'-chloro-3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylate (310 mg, 0.493 mmol, 65.2 %) as an oil. LCMS : (M+H)⁺ 630, Rt= 7.4 min. ¹H NMR (CDCI₃) £ 8.1 (d, 1 H), 7.8 (d, 1 H), 7.7-7.5 (m, 4H), 7.25-7.2 (m, 2H),

7.1 (dd, 1 H), 6.95 (d, 1 H), 5.2 (s, 2H), 4.2 (q, 2H), 4.1 (m, 2H), 3.15 (m, 2H), 2.6 (m, 1 H), 2.5 (s,

3H), 2.4 (s, 3H), 2.1 (m, 2H), 2-1.8 (m, 2H), 1.7 (t, 3H).

The following Intermediate was prepared by a method analogous to that described for Intermediate 29.

Intermediate 31 : Ethyl 1-(4-bromo-1 ,3-thiazol-2-yl)-4-piperidinecarboxylate

A mixture of the commercially available 2,4-dibromo-1 ,3-thiazole (7.3 g, 30 mmol), ethyl 4- piperidinecarboxylate (6.9 ml_, 45 mmol, 1.5 equiv.) and triethylamine (9.2 ml_, 66 mmol, 2.2 equiv.) in DMF (70 ml.) was stirred at 8O⁰C overnight before being concentrated to dryness. The crude product was taken up in EtOAc and washed successively with a saturated NH₄CI solution and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (cyclohexane/EtOAc: 100/0 to 80/20) to give the title compound (8.2 g, 86% yield) as a colorless oil. ¹H NMR (DMSO d6) J6.84 (s, 1 H), 4.08 (q, J = 7.1 Hz, 2H), 3.77 (m, 2H), 3.09 (m, 2H), 2.59 (m, 1 H), 1.91 (m, 1 H), 1.59 (m, 2H), 1.18 (t, J = 7.0 Hz, 3H). LCMS: (M+H)⁺= 319, 321 , Rt= 3.24 min.

Intermediate 32: Ethyl 1 -[4-(2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-(4-bromo-1 ,3-thiazol-2-yl)-4-piperidinecarboxylate (Intermediate 31 , 8.22 g, 25 mmol) in DME was added the commercially available (2-hydroxyphenyl)boronic acid (5.3 g, 33.6 mmol, 1.5 equiv.). The mixture was then degassed with argon for 10 min and cesium carbonate (2.3 g, 75 mmol, 3 equiv.) and tetrakis(triphenylphosphine)palladium(0) (1 g, 0.9 mmol, 0.03 equiv.) were added under argon. Finally, water (30 ml.) was added and the reaction mixture was stirred at 80⁰C overnight before being cooled and diluted with EtOAc. The organic layer was washed successively with a saturated NH₄CI solution (pH adjusted to 3 by adding a 1 N HCI solution) and brine. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (cyclohexane/EtOAc: 100/0 to 85/15) to give the title compound (6.3 g, 75% yield) as a white solid. ¹H NMR (DMSO d6, 400 MHz) δ 11.25 (s, 1 H), 7.80 (dd, J = 7.9 and 1.5 Hz, 1 H), 7.34 (s, 1 H), 7.14 (m, 1 H), 6.88-6.80 (m, 2H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (m, 2H), 3.20 (m, 2H), 2.64 (m, 1 H), 1.98 (m, 2H), 1.66 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). LCMS : (M+H)⁺= 333, Rt= 3.71 min.

Intermediate 33 : Ethyl 1-[5-chloro-4-(2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate (Intermediate 32, 2 g, 6 mmol) in acetonitrile (200 ml.) was added N-chlorosuccinimide (880 mg, 6.6 mmol, 1.1 equiv.). The reaction mixture was then stirred at 60 ⁰C for 16h before being cooled and concentrated to dryness. The residue was taken up in water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was recrystallised from MeOH to give the title compound (1.2 g, 55% yield) as a beige solid. ¹H NMR (DMSO d6, 300 MHz) δ 10.13 (s, 1 H), 7.51 (dd, J = 7.8 and 1.8 Hz, 1 H), 7.23 (m, 1 H), 6.93-6.81 (m, 2H), 4.10 (q, J = 7.0 Hz, 2H), 3.75 (m, 2H), 3.15 (m, 2H), 2.63 (m, 1 H), 1.94 (m, 2H), 1.63 (m, 2H), 1.19 (t, J = 7.0 Hz, 3H). LCMS : (M+H)⁺= 367, Rt= 3.96 min.

Intermediate 34: 4'-formyl-4-biphenvlcarbonitrile

To a solution of the commercially available 4-bromobenzaldehyde (3 g, 16.21 mmol) in DME (80 ml) and H₂O (10 mL) were added Pd(PhP₃)₄ (0.937 g, 0.05 equiv.), (4-cyanophenyl)boronic acid (2.859 g, 1.2 equiv.) and Na₂CO₃ (4.296 g, 2.5 equiv.). The mixture was heated at 90⁰C for 3 hours, cooled and poured into water. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. After purification by chromatography on silicagel (CH₂CI₂ / cHex, 4/1 ), the title compound was obtained as a beige solid (3 g, yield: 89.39%). LC: Rt= 2.99 min. H¹ NMR (300MHz, CDCI₃, ppm): 10 (s, 1 H), 8.05 (d, 2H), 7.8 ( m, 6H).

The following Intermediate was prepared by an analogous method to that described for Intermediate 34:

Intermediate 36: 4'-(hydroxymethyl)-4-biphenylcarbonitrile

To a solution of 4'-formyl-4-biphenylcarbonitrile (Intermediate 34, 1.5 g, 7.24 mmol) in MeOH was added portionwise NaBH₄ (0.0.303g, 1.1 equiv.). The mixture was stirred at room temperature for 30 minutes and then poured into water. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a cream solid (1.49 g, 98.4%). H¹ NMR (300MHz, CDCI₃, ppm): 7.65 (q, 4H), 7.55 (d, 2H), 7.45 (d, 2H), 4.7 (s, 2H).

The following Intermediate was prepared by an analogous method to that described for Intermediate 36:

Intermediate 38: 4'-(bromomethyl)-4-biphenvlcarbonitrile

To a solution of 4'-(hydroxymethyl)-4-biphenylcarbonitrile (Intermediate 36, 1.49 g, 7.2 mmol) in CH₂CI₂ (4OmL) cooled in a ice bath, was added dropwise PBr₃ (solution 1 M/CH₂CI₂, 3.56 ml_, 0.5 equiv.). The mixture was stirred at 0⁰C for 30 minutes, then at room temperature for 1 hour and then poured into water. After extraction with CH₂CI₂, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a cream solid (1.8 g, yield: 92.82%). LC/MS: (M+H)= 273, Rt= 3.53min

Intermediate 38.

Intermediate 40: 4-(4-cyanophenoxy)-benzaldehyde

To a solution of the commercially available 4-hydroxybenzaldehyde (5.04 g, 41.28 mmol), in DMF (5OmL) was added portionwise Cs₂CO₃ (14.79 g, 45.41 mmol) and the mixture was stirred at room temperature for 10 minutes. Then 4-fluorobenzonitrile (5 g, 41.28 mmol) was added and the mixture was heated at 110⁰C for 2 hours, then cooled and poured into water. After extraction with dichloromethane, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. After purification by chromatography on silicagel (CH₂CI₂ / cHex, 3/2, then 4/1 ), the title compound was obtained as a white solid (5.25 g, yield: 57%). LC/MS: 224.1 (M+H) , Rt= 3.07min.

Intermediate 41 : 4-(4-cvanophenoxv)-benzyl alcohol

To a solution of 4-(4-cyanophenoxy)-benzaldehyde (Intermediate 40, 5.2 g, 23.32 mmol) in MeOH (70 ml.) was added portionwise NaBH₄ (0.975 g, 29.46 mmol). The mixture was stirred at room temperature for 30 minutes and then poured into water. After extraction with CH₂CI₂, the organic phase was dried over sodium sulfate and concentrated under reduced pressure. The title compound was obtained as a colorless oil which crystallised (5.13 g, yield: 97.8%). LC/MS: 224.1 (M-H) , Rt=2.82 min

Intermediate 42: 4-(4-cvanophenoxv)-benzvl bromide

To a solution of 4-(4-cyanophenoxy)-benzyl alcohol (Intermediate 41 , 0.9 g, 4 mmol) in CH₂CI₂ (40 mL) cooled in a ice bath, was added dropwise PBr₃ (solution 1 IWCH₂CI₂, 1.6ml, 1.6mmol). The mixture was stirred at 0⁰C for 30 minutes, then at room temperature for 1 hour and then poured into water. After extraction with CH₂CI₂, the organic phase was dried over sodium and concentrated under reduced pressure. The title compound was obtained as a colorless oil which crystallised (1.15g, yield: 99.8%). H¹ NMR (300MHz, CDCI₃, ppm): 7.65 (d, 2H), 7.45 (d, 2H), 7.1 (d, 2H), 7 (d, 2H), 4.55 (s, 2H)

Intermediate 43: Ethyl 1 -[5-chloro-4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-[5-chloro-4-(2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, (Intermediate 33, 200 mg, 0.55 mmol) in acetonitrile was added cesium carbonate (270 mg, 0.8 mmol, 1.5 equiv.) and 4'-(bromomethyl)-4-biphenylcarbonitrile, intermediate 38 (180 mg, 0.65 mmol, 1.2 equiv.). The reaction mixture was stirred at 80⁰C for 48h before being cooled and concentrated to dryness. The crude mixture was taken up in water and extracted with dichoromethane. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The resulting solid was recrystallised in MeOH to give the desired compound (200 mg, 67% yield) as a beige solid. ¹H NMR (CDCI₃, 300 MHz) δ 7.74 (d, J = 8.6

Hz, 2H), 7.70 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.5 Hz, 2H), 7.45 (dd, J =

7.6 and 1.7 Hz, 2H), 7.04 (m, 1 H), 5.19 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.92 (m, 2H), 3.10 (m,

2H), 2.53 (m, 1 H), 2.02 (m, 2H), 1.94 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). LCMS : (M+H)⁺= 558, Rt= 4.38 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 43 using the appropriate alkylating agent.

Intermediate 46: 2-bromo-1 -(2-hydroxyphenyl)-1 -propanone

To a solution of commercially available 1-(2-hydroxyphenyl)-1 -propanone (4.5 ml. , 33 mmol) in THF was added bromine on polymer support (17.5 g, 31.6 mmol) and the reaction was stirred at room temperature for 16 hours. After filtration, the filtrate was concentrated under reduced pressure and the title compound (2.1 g, 28% yield) was obtained as an oil. The compound was used in the next step without further purification.

Intermediate 47: ethyl 1-[4-(2-hydroxyphenyl)-5-methyl-1,3-thiazol-2-yl]-4- piperidinecarboxylate

A solution of 2-bromo-1-(2-hydroxyphenyl)-1 -propanone (Intermediate 46, 2.1 g, 9.25 mmol) and ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate (Intermediate 8, 2 g, 9.25 mmol) in DMF (25 ml.) was stirred at room temperature for 18 hours. The reaction was concentrated under reduced pressure and the residue was taken up in MeOH. The solid was filtered to give the title compound (800 mg, 25 % yield) as a white solid. ¹H NMR (CDCI₃, 300 MHz) £7.41 (d, J = 7.8 and 1.5 Hz, 1 H), 7.22 (m, 1 H), 7.00 (dd, J = 8.2 and 1.1 Hz, 1 H), 6.89 (m, 1 H), 4.18 (q, J = 7.2 Hz, 2H), 3.91 (m, 2H), 3.16 (m, 2H), 2.55 (m, 1 H), 2.50 (s, 3H), 2.05 (m, 2H), 1.87 (m, 2H), 1.28 (t, J = 7.2 Hz, 3H).

Intermediate 48: ethyl 1 -{5-methyl-4-[2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxyphenyl)-5-methyl-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, (Intermediate 47, 200 mg, 0.58 mmol) in acetonitrile (10 ml.) was added cesium carbonate (280 mg, 0.58 mmol, 1.5 equiv.) and 4'-(bromomethyl)-4-biphenylyl methyl ether (Intermediate 39, 177 mg, 0.64 mmol, 1.1 equiv.). The reaction mixture was stirred at room temperature for 52h before being concentrated to dryness. The crude mixture was taken up in water and extracted with dichloromethane. The organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on silica using cyclohexane/EtOAc as eluant to give the desired compound (170 mg, 54% yield) as a colorless oil. ¹H NMR (CDCI₃, 300 MHz) δ 7.57-7.49 (m, 4H), 7.46-7.39 (m, 3H), 7.29 (m, 1 H), 7.07-6.95 (m, 4H), 5.1 1 (s, 2H), 4.16 (q, J = 7.1 Hz, 2H), 3.96 (m, 2H), 3.86 (s, 3H), 3.06 (m, 2H), 2.50 (m, 1 H), 2.18 (s, 3H), 2.02 (m, 2H), 1.89 (m, 2H), 1.26 (t, J = 7.1 Hz, 3H). LCMS : (M+H)⁺= 543, Rt= 4.39 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 48 using the appropriate alkylating agent.

Intermediate 52: 4-{[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde

To a solution of the commercially available of 4-(trifluoromethyl)phenol (9.1 g, 56 mmol, 1.2 equiv.) in DMF (100 mL) was added successively cesium carbonate (22.8 g, 70 mmol, 1.5 equiv.) and 4-fluorobenzaldehyde (5 mL, 46.6 mmol) at room temperature. The reaction mixture was then stirred at 85°C for 16h before being cooled and filtered. The resulting filtrate was concentrated to dryness and the crude oil was purified by flash chromatography (SiO₂, cyclohexane/ethyl acetate 70/30) to give the title compound (9.0 g, 73% yield) as a colorless oil. 1H NMR (CDCI₃) δ 9.97 (s, 1 H), 7.91 (m, 2H), 7.67 (d, J = 8.6 Hz, 2H), 7.20-7.11 (m, 4H). LCMS: (M+H)⁺ = 267, Rt= 3.53 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 52 using the appropriate phenol.

Intermediate 56: (4-{r4-(Trifluoromethvl)phenvlloxy}phenvl)methanol (FCAF/U1555/180/1)

To a solution of 4-{[4-(Trifluoromethyl)phenyl]oxy}benzaldehyde (Intermediate 52, 9 g, 34 mmol) in THF at 0⁰C was added drop wise LiAIH₄ (17 mL, 1 M in THF, 17 mmol, 0.7 equiv.). After the addition was complete, the reaction mixture was allowed to warm to RT for 4h before being quenched with wet Na₂SO₄. Water was added and the aqueous layer was extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (9 g, 99% yield) as a white powder. ¹H NMR (CDCI₃) δ 7.58 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.06 (d, J = 8.2 Hz, 2H), 7.05 (d, J = 8.6 Hz, 2H), 4.72 (s, 2H). LCMS : (M-H)= 267, Rt= 3.24 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 56 using the appropriate aldehyde:

Intermediate 60: 1 -(Bromomethyl)-4-{[4-(trifluoromethyl)phenyl]oxy}benzene

To a solution of (4-{[4-(trifluoromethyl)phenyl]oxy}phenyl)methanol (Intermediate 56, 9 g, 33.6 mmol) in dichloromethane (100 mL) at 0⁰C was added dropwise PBr₃ (13 mL, 1 M in DCM, 1 mmol, 0.4 equiv.). The reaction mixture was allowed to warm to room temperature for 16h before being quenched with water. The aqueous layer was extracted with dichloromethane and the organic layer was washed with saturated NaHCO₃, dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (10.2 g, 92% yield) as a colorless oil that crystallize on standing. ¹H NMR (CDCI₃) J7.60 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 7.8 Hz, 2H), 7.08 (d, J = 8.4 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 4.53 (s, 2H). LC: Rt= 4.00 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 60 using the appropriate alcohol.

Intermediate 64: 4-bromo-1 -(bromomethyl)-2-(methyloxy)benzene

To a solution of the commercially available [4-bromo-2-(methyloxy)phenyl]methanol (5 g, 23 mmol) in dichloromethane (100 mL) at 0⁰C was added dropwise PBr₃ (9 mL, 1 M in DCM, 9 mmol, 0.4 equiv.). The reaction mixture was allowed to warm to room temperature for 16 hours before being quenched with water. The aqueous layer was extracted with Dichloromethane and the organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give the title compound (6.3 g, 98% yield) as a white solid. ¹H NMR (CDCI₃) J7.25 (d, 1 H), 7.15- 7.0 (m, 2H), 4.5 (s, 2H), 3.95 (s, 3H). LC: Rt= 3.47 min. Intermediate 65: ethyl 1 -{4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate (Intermediate 32, 60 mg, 0.18 mmol) in acetonitrile (10 mL) was added cesium carbonate (70 mg, 0.22 mmol, 1.2 equiv.) and the commercially available 1-(chloromethyl)-4-(2- phenylethyl)benzene (46 mg, 0.27 mmol, 1.5 equiv.). The reaction mixture was stirred at 80⁰C for 48h before being cooled and concentrated to dryness. The crude mixture was taken up in water and extracted with EtOAc. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica using cyclohexane/EtOAc as eluant to give the desired compound (20 mg, 21% yield) as a colorless oil. ¹H NMR (CDCI₃, 300 MHz) S8.24 (m, 1 H), 7.40 (m, 2H), 7.35- 7.14 (m, 9H), 7.10-6.98 (m, 2H), 5.16 (s, 2H), 4.18 (q, J = 7.1 Hz, 2H), 4.06 (m, 2H), 3.15 (m, 2H), 2.95 (s, 4H), 2.54 (m, 1 H), 2.06 (m, 2H), 1.88 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). LC/MS: m/z 527 [M+H]⁺, Rt 4.60 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 65 using the appropriate alkylating agent.

Intermediate 75: ethyl 1 -{4-[2-({[3'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-{[(4-bromophenyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate (Intermediate 66, 333 mg, 0.66 mmol) in DME (50 mL) was added successively [3-methoxyphenyl]boronic acid (151 mg, 0.99 mmol, 1.5 equiv.), cesium carbonate (0.8 mL, 2.5M in water, 2.0 mmol, 3 equiv.) and tetrakis(triphenylpnosphine)palladium(0) (40 mg, 33 μmol, 0.05 equiv.). The reaction mixture was then heated to reflux for 24 h before being cooled and saturated NH₄CI was added. The mixture was then extracted with EtOAc and the organic layer was washed with brine, dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude product was purified by chromatography on silica using cyclohexane/EtOAc as eluant to give the desired compound (67 mg, 19% yield) as a beige solid. ¹H NMR (CDCI₃, 300 MHz) £8.21 (d, J = 7.7 Hz, 1 H), 7.63 (d, J = 8.0 Hz, 2H), 7.55 (d, J =

8.0 Hz, 2H), 7.38 (dd, J = 8.1 and 7.7 Hz, 2H), 7.31-7.19 (m, 3H), 7.15 (br s, 1 H), 7.06 (dd, J =

8.1 and 8.1 Hz, 2H), 6.92 (m, 1 H), 5.24 (s, 2H), 4.17 (q, J = 7.0 Hz, 2H), 4.09 (m, 2H), 3.89 (s, 3H), 3.19 (m, 2H), 2.55 (m, 1 H), 2.06 (m, 2H), 1.89 (m, 2H), 1.28 (t, J = 7.0 Hz, 3H). LC/MS: m/z 529 [M+H]⁺, Rt 4.54 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 75 using the appropriate boronic acid.

Intermediate ,4b

Prepared from Analytical data No.

Intermediate 66 ¹H NMR (CDCI₃) £8.23 (d, J = 7.1 and 4- Hz, 1 H), 7.63-7.47 (m, 6H), 7.25 methoxyphenyl]b (m, 2H), 7.10-6.95 (m, 4H), 5.24

78 (s, 2H), 4.17 (m, 2H), 4.07 (m, oronic acid H

2H), 3.17 (m, 2H), 2.54 (m, 1 H), 2.05 (m, 2H), 1.88 (m, 2H), 1.28 (m, 3H). LC/MS: m/z 529 [M+H]⁺, Rt 4.54 min.

Intermediate 66 ¹H NMR (CDCI₃) £ 8.19 (m, 1 H), and 4- 7.76-7.68 (m, 4H), 7.64 (d, J = 8.4 trifluoromethylph Hz, 2H), 7.59 (d, J = 8.4 Hz, 2H), 7.31-7.16 (m, 2H), 7.1 1-7.00 (m, enyl]boronic acid

79 H 2H), 5.25 (s, 2H), 4.17 (q, J = 7.1

Hz, 2H), 4.1 1 (m, 2H), 3.22 (m, 2H), 2.56 (m, 1 H), 2.06 (m, 2H), 1.89 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H). LC/MS: m/z 567 [M+H]⁺, Rt 4.71 min.

Intermediate 66 ¹H NMR (CDCI₃) £ 8.21 (m, 1 H), and 4- 7.76 (d, J = 8.4 Hz, 2H), 7.71 (d, J cyanophenyl] = 8.4 Hz, 2H), 7.64 (d, J = 8.6 Hz, 2H), 7.60 (d, J = 8.6 Hz, 2H), boronic acid 7.30-7.16 (m, 2H), 7.1 1-7.00 (m,

80 H 2H), 5.26 (s, 2H), 4.17 (q, J = 7.1

Hz, 2H), 4.08 (m, 2H), 3.20 (m, 2H), 2.55 (m, 1 H), 2.06 (m, 2H), 1.89 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). LC/MS: m/z 524 [M+H]⁺, Rt 4.40 min.

Intermediate 67 ¹H NMR (CDCI₃) £ 8.23 (m, 1 H), and 4- 7.77-7.67 (m, 2H), 7.56 (m, 2H), trifluoromethyl 7.51-7.40 (m, 2H), 7.28 (m, 1 H), 7.19-7.03 (m, 3H), 5.21 (s, 2H), phenyl]

81 Me 4.17 (q, J = 7.1 Hz, 2H), 4.07 (m, boronic acid

2H), 3.17 (m, 2H), 2.54 (m, 1 H), 2.46 (s, 3H), 2.05 (m, 2H), 1.88 (m, 2H), 1.28 (t, J = 7.1 Hz, 3H). LC/MS: m/z 581 [M+H]⁺, Rt 4.88 min.

Intermediate 88: (3-Methyl-4'trifluoromethyl-biphenyl-4-yl)-methanol

To a solution of (4-bromophenyl)-methanol, (Intermediate 15, 80 g, 0.4 mol) and the commercially available 4-trifluoromethyl-phenyl boronic acid (91.2 g, 0.48 mol) in 1 ,4-dioxane (1.6 L) was added a solution of sodium carbonate (106 g, 1 mol) in water (240 ml), then Pd(PPh₃)₄ (23.0 g, 0.02 mol) was added under nitrogen, after completion of the addition, the reaction mixture was heated at 1 10⁰C overnight. LC/MS showed disappearance of starting material, then cooled to RT and filtered. The filtrate was purified by column chromatography on silica gel eluted with (pentane: EtOAc = 20:1-10:1 ) to give the desired product. (65 g, Yield: 61.4%). ¹H NMR: (d6-DMSO, 400MHZ) δ 7.88-7.82 (m, 4H), 7.53-7.44 (m, 3H), 5.12 (t, J=5.2Hz 1 H), 4.50 (d, J=5.2Hz, 2H), 2.28 (s, 3H).

The following Intermediate was prepared by a method analogous to that described for Intermediate 88 using the appropriate boronic acids.

Intermediate 90: 4-Bromomethvl-3-methvl-4'trifluoromethyl-biphenvl

To a solution of (3-methyl-4'-(trifluoromethyl)biphenyl-4-yl)methanol, (Intermediate 88, 65 g, 0.244 mol) in dichloromethane (650 ml.) was added dropwise PBr₃ (26.5 g, 0.1 mol) at 0⁰C. After completion of the addition, the reaction mixture was warmed to RT and stirred for 2h. 200 ml. of water were added, and the pH was adjusted to 7 with addition of a saturated aqueous NaHCO₃ solution. The mixture was extracted with dichloromethane and the organic layer was dried over sodium sulphate, filtered and concentrated in vacuo to give the desired product. (75 g, Yield: 93.2%). ¹H NMR: (CDCI₃, 400MHZ) δ 7.63-7.67 (m, 4H), 7.39 (t, J=4Hz, 3H), 4.54 (s, 2H), 2.47 (s, 3H).

The following Intermediate was prepared by a method analogous to that described for Intermediate 90.

Intermediate _R4b Prepared from

R⁵ Analytical data No.

¹H NMR: (CDCI₃, 400MHZ) δ 7.68 (dd,

J₁= 6.6Hz, J₂=8.4Hz, 2H), 7.63 (d,

91 Me Intermediate 89 CN J=6.8Hz, 2H), 7.38 (dd, J₁=SHz,

J₂=12.4Hz, 3H), 4.53 (s, 2H), 2.47 (s,

3H)

Intermediate 92: ethyl 1 -[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5- methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-hydroxy-5-methylphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, (Intermediate 9, 350 mg, 1.010 mmol) in acetonitrile (20 ml.) was added cesium carbonate (1g, 3.07 mmol) and 4-(bromomethyl)-3-methyl-4'-(trifluoromethyl)biphenyl, intermediate 90, (370 mg, 1.124 mmol). The reaction mixture was stirred at 70⁰C for 18h filtered and. The crude mixture was taken up in isopropyl ether, filtered and the filtrate was concentrated to dryness. The crude product was purified by chromatography on silica using DCM, DCM/MEOH, 99/1 as eluant to give the desired compound (280 mg, 46.6% yield) as a white solid. LC/MS: m/z 595 [M+H]+, Rt 4.81 min. ¹H NMR (CDCI_3, 400MHz) δ 8.05 (d, 1 H), 7.75 (m, 4H), 7.55 (d, 1 H), 7.45 (m, 2H), 7.20 (s, 1 H), 7.05 (d, 1 H), 6.95 (d, 1 H), 5.15 (s, 2H), 4.15 (q, 2H), 4.05 (m, 2H), 3.15 (m, 2H), 2.55 (m, 1 H), 2.45 (s, 3H), 2.35 (s, 3H), 2.05 (m, 2H),1.85 (m, 2H), 1.20 (t, 3H).

The following Intermediate was prepared by a method analogous to that described for Intermediate 92.

The following Intermediates were prepared by an analogous method to that described for Intermediate 1.

The following Intermediate was prepared by an analogous method to that described for Intermediate 1.

The following Intermediates were prepared by an analogous method to that described for Intermediate 1 1.

Intermediate 103: Ethyl 1-[4-(5-fluoro-2-hydroxyphenyl)-1,3-thiazol-2-yl]-4- iperidinecarboxylate

To a solution of commercially available 2-bromo-1-(5-fluoro-2-hydroxyphenyl)ethanone (2.1g, 9.3 mmol), in DMF (100 ml.) was added ethyl 1-(aminocarbonothioyl)-4-piperidinecarboxylate, (Intermediate 8, 2 g, 9.3 mmol). The reaction mixture was stirred at RT for 18h before being concentrated to dryness. The crude compound was recrystallised in MeOH to give the title compound (2.8 g, 86 % yield) as white solid. ¹H NMR (DMSO-d⁶,) δ 7.65 (dd, J = 10.4 and 3.1 Hz, 1 H), 7.46 (s, 1 H), 6.99 (ddd, J = 8.9, 8.2 and 3.1 Hz, 1 H), 6.87 (dd, J = 8.9 and 4.9 Hz, 1 H), 4.09 (q, J = 7.1 Hz, 2H), 3.87 (m, 2H), 3.20 (m, 2H), 2.64 (m, 1 H), 1.97 (m, 2H), 1.66 (m, 2H), 1.19 (t, J = 7.1 Hz, 3H). LC/MS: m/z 351 [M+H]+, Rt 3.73 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 103 using ethanol at 80⁰C instead of DMF.

Intermediate 106: (4-bromo-2-chlorophenyl)methanol

To a solution of commercially available 4-bromo-2-chlorobenzoic acid (10 g, 42.5 mmol) in THF (150 ml.) was added a solution of lithium aluminium hydride in THF (42.5 ml_, 1 M in THF, 42.5 mmol) at 0⁰C. After addition, the reaction mixture was allowed to stir from 0⁰C to RT for 48 h before being quenched with wet sodium sulphate and filtered through Celite. The filtrate was concentrated in vacuo to give the title compound (4-bromo-2-chlorophenyl)methanol (6.9 g, 74% yield). ¹H NMR: (CDCI₃, 300MHZ) δ 7.55-7.35 (m, 2H), 7.28 (m, 1 H), 4.74 (s, 2H).

Intermediate 107: 4-bromo-1 -(bromomethyl)-2-chlorobenzene

To a solution of (4-bromo-2-chlorophenyl)methanol, intermediate 106, (6.9 g, 31 mmol) in dicholoromethane (200 ml.) was added dropwise a solution of phosphorus tribromide in DCM (12.5 ml_, 1 M in DCM, 12.5 mmol, 0.4 equiv.) at 0 ⁰C. After addition, the reaction mixture was stirred for 16 hours at RT. Water was added and the mixture was extracted with DCM. The organic layer was dried over sodium sulfate, filtered, concentrated in vacuo to give the title product 4-bromo-1-(bromomethyl)-2-chlorobenzene (8.1 g, 99% yield). ¹H NMR: (300 MHZ, CDCI₃) δ 7.52 (m, 1 H), 7.35 (m, 1 H), 7.22 (m, 1 H), 4.48 (s, 2H). The following Intermediates were prepared by an analogous method to that described for Intermediate 18.

Intermediate 110: 1 -{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

To a solution of ethyl 1-{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate (Intermediate 18, 500 mg, 0.867 mmol), in methanol (50 ml_), was added a 1 N solution of lithium hydroxyde (7.80 ml_, 7.80 mmol). The reaction was stirred at 80⁰C for 4 hours. The reaction was concentrated in vacuo and neutralized with a 1 N HCI solution. The aquous phase was extracted with DCM and the organic phase was dried over sodium sulphate and concentrated in vacuo. A mixture of 1-{4-[2- ({[4-(dihydroxyboranyl)-2-methylphenyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid (268 mg, 0.575 mmol, 66.3% yield) and 1-{4-[5-methyl-2-({[2-methyl- 4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid (132 mg, 0.241 mmol, 27.8 % yield) was obtained as a white solid. The crude mixture was used directly in subsequent steps without purification. LC/MS: 2 peaks m/z 467 [M+H]+, Rt 2.66 min and m/z 549 [M+H]+, Rt 3.62 min.

The following Intermediate was prepared by a similar method to that described for Intermediates 110.

The following Intermediate was prepared by a similar method to that described for Intermediate 21.

The following Intermediate was prepared by an analogous method to that described for Intermediate 27.

The following Intermediates were prepared by an analogous method to that described for Intermediate 29

Intermediate 29.

Intermediate 122: (3,5-difluoro-2-hydroxyphenyl)boronic acid

A solution of boron tribromide (1 12 ml_, 1 M in DCM, 112 mmol, 3 equiv.) was added to a solution of commercially available [3,5-difluoro-2-(methyloxy)phenyl]boronic acid (7 g, 37.4 mmol) in DCM (100 ml.) at 0⁰C. The reaction mixture was stirred at this temperature for 2h before being poured into iced water (150 ml_). The aqueous layer was extracted with DCM and the resulting organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude compound was triturated in cyclohexane to give the title compound (4.7 g, 72% yield) as a off-white solid. 1 H NMR (CD₃OD, 300 MHz) δ 6.86 (m, 1 H), 6.66 (m, 1 H). LCMS: m/z 173, (M-H)^", Rt 2.30 min.

Intermediate 123: ethyl 1 -[4-(3,5-difluoro-2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate

To a solution of ethyl 1-(4-bromo-1 ,3-thiazol-2-yl)-4-piperidinecarboxylate (Intermediate 31 , 6.6 g, 21 mmol) in DME (80 mL) was added (3,5-difluoro-2-hydroxyphenyl)boronic acid, (Intermediate 122, 4.7 g, 31 mmol, 1.5 equiv.). The mixture was then degassed with argon for 10 min and a solution of cesium carbonate (20.3 g, 63 mmol, 3 equiv.) in water (25 mL) and tetrakis(triphenylphosphine)palladium(0) (1.2 g, 1.0 mmol, 0.05 equiv.) were added under argon. The reaction mixture was stirred at reflux for 72h before being cooled and diluted with EtOAc and water. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography (cyclohexane/EtOAc: 100/0 to 70/30) to give the title compound (1.25 g, 16% yield) as a white solid. ¹H NMR (DMSO d6, 300 MHz) δ 11.54 (s, 1 H), 7.55 (s, 1 H), 7.54 (m, 1 H), 7.19 (m, 1 H), 4.10 (q, J = 7.1 Hz, 2H), 3.84 (m, 2H), 3.21 (m, 2H), 2.64 (m, 1 H), 1.98 (m, 2H), 1.66 (m, 2H), 1.20 (t, J = 7.1 Hz, 3H). LCMS: m/z 369 (M+H)⁺, Rt= 3.89 min.

Intermediate 124: Ethyl 1-[4-(2-hydroxy-3-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate

To a solution of the commercially available (2-hydroxy-3-methylphenyl)boronic acid (381 mg, 2.506 mmol), in DME (10 mL) and water (some drops), were added ethyl 1-(4-bromo-1 ,3- thiazol-2-yl)-4-piperidinecarboxylate, (Intermediate 31 , 400 mg, 1.253 mmol.), PalladiumTetrakis (45 mg, 0.039 mmol), and cesium carbonate (820 mg, 2.52 mmol). The reaction vessel was sealed and heated in Biotage Initiator using initial normal to 160 ⁰C for 15 min. After cooled, the reaction was diluted in Et₂O and the organic phase was dried over sodium sulfate and concentrated in vacuo. After purification by flash chromatography with Chex 70% / EtOAc 30% to Chex 20% / EtOAc 80% the title compound was obtained as a beige solid, (320 mg, 73.7 % yield). LC/MS: m/z 347 [M+H]+, Rt 3.88 min.¹H NMR (CDCI₃,300MHz) J7.31 (d, 1 H), 7.02-6.98 (m, 2H), 6.64 (s, 1 H), 4.08 (q, 2H), 3.86 (m, 2H), 3.08 (m, 2H), 2.45 (m, 1 H), 2.21 (s, 3H), 1.93 (m, 2H), 1.79 (m, 2H), 1.19 (t, 3H).

The following Intermediate was prepared by an analogous method to that described for Intermediate 124.

Intermediate 124.

Intermediate 127: ethyl 1-[4-(4-chloro-2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylate

To a solution of ethyl 1-{4-[4-chloro-2-(methyloxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylate, intermediate 126 (1.6g, 4.20 mmol) in DCM (30 ml.) at 0°c under N₂, was added dropwise BBr₃ (1 M in solution in DCM), (8.40 ml_, 8.40 mmol) for 10 min. The reaction mixture was then stirred for 4 hours at RT. Water was added slowly followed by a saturated solution of NaHCO₃ and the aqueous solution was extracted with DCM (2x30ml). The combined organic layers were washed with water (1 x 20 ml.) then dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was used in subsequent steps without more purification. LC/MS: m/z 367 [M+H]+, Rt 3.94 min.

The following Intermediate was prepared by an analogous method to that described for Intermediate 65 using the appropriate alkylating agent.

The following Intermediate was prepared by an analogous methods to that described for Intermediate 65 using the appropriate alkylating agent.

The following Intermediate was prepared by an analogous method to that described for Intermediate 88 using the appropriate boronic acid.

The following Intermediate was prepared by an analogous method to that described for Intermediate 90.

Intermediate _R4b Prepared from R⁵ Analytical data No.

156 Me Intermediate 155 OCF₃ LC: Rt 4.20 min. ¹H NMR: (CDCI₃,

400MHZ) δ 7.61 (d, 2H), 7 .44-7.41

(m_! 3H), 7.32( d_! 2H), 4.60 (s, 2H),

2.53 (s, 3H).

The following Intermediates were prepared by an analogous method to that described for Intermediate 92.

Intermediate

R¹ Prepared from Analytical data No.

163 MeO Intermediate 98 and LC/MS: m/z 627 [IVH-H]⁺, Rt 4.83 min. Intermediate 156 ¹H NMR (CDCI₃, 400MHz) J7.76 (br s, 1 H), 7.54 (d, 2H), 7.42 (d, 1 H), 7.34 (m, 2H), 7.20 (m, 2H), 7.14 (s,

1 H), 6.90 (d, 1 H), 6.73 (d, 1 H), 5.04 (s, 2H), 4.10 (q, 2H), 3.95 (m, 2H), 3.77 (s, 3H), 3.06 (m, 2H), 2.44 (m, 1 H), 2.35 (s, 3H), 1.94 (m, 2H), 1.80 (m, 2H), 1 .20 (t, 3H).

164 MeO Intermediate 98 and LC/MS: m/z 568 [M+H]⁺, Rt 4.46 min. Intermediate 91 ¹H NMR (CDCI₃, 400MHz) J7.83 (br s, 1 H), 7.74 (m, 4H), 7.57 (m, 1 H), 7.47 (m, 2H), 7.19 (s, 1 H), 6.99 (d,

1 H), 6.83 (d, 1 H), 5.15 (s, 2H), 4.19 (q, 2H), 4.08 (m, 2H), 3.88 (s, 3H), 3.20 (m, 2H), 2.56 (m, 1 H), 2.46 (s, 3H), 2.06 (m, 2H), 1.91 (m, 2H), 1.29 (t, 3H).

165 iPr Intermediate 99 and LC/MS: m/z 580 [M+H]⁺, Rt 4.67 Intermediate 91 min.¹H NMR (DMSO-d6, 300MHz) δ 7.92 (m, 4H), 7.66 (s, 1 H), 7.57 (m, 3 H), 7.16 (m, 3H), 5.26 (s, 2H), 4.08

(q, 2H), 3.87 (m, 2H), 3.12 (m, 2H), 2.88 (m, 1 H), 2.58(m, 1 H), 2.42 (s, 3H), 1.94 (m, 2H), 1.66 (m, 2H), 1.20 (m, 9H)

166 iPr Intermediate 99 and LC/MS: m/z 6.23 [M+H]⁺, Rt 7.44 Intermediate 90 min. ¹H NMR (CDCI₃, 300MHz) δ 7.92 (m, 4H), 8.0 (m, 1 H), 7.63 (m, 3H), 7.47 (d, 1 H), 7.36 (m, 2 H),

7.08-7.04 (m, 3H), 6.91 (d, 1 H), 5.10 (s, 2H), 4.09 (q, 2H), 3.97 (m, 2H), 3.07 (m, 2H), 2.88 (m, 1 H), 2.46 (m, 1 H), 2.37 (s, 3H), 1.96 (m, 2H), 1.81 (m, 2H), 1 .22-1.18 (m, 9H)

Intermediate 168: [2',3-dimethyl-4'-(trifluoromethyl)-4-biphenylyl]methanol

To a solution of (4-bromophenyl)-methanol (Intermediate 15, 2.0 g, 9.8 mmol) and the commercially available [2-methyl-4-(trifluoromethyl)phenyl]boronic acid (2 g, 9.8 mmol) in DME was added a 1 M solution of sodium carbonate (20 ml_, 2 equiv.) then Pd(PPh₃)₄ (120 mg, 0.01 equiv.) was added and the reaction mixture was heated at 80⁰C for 18 hours. The reaction was filtered on Celite and washed with Et₂O. The filtrate was then washed with water and a NaHCO₃ solution, dried over sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluted with DCM and DCM/MeOH 95/5 to give the title compound. (2.3 g, yield: 84%). ¹H NMR: (CDCI₃) δ 7.60-7.4 (m, 3H), 7.35 (d, 1 H), 7.2-7.1 (m, 2H), 4.75 (s, 1 H), 2.45 (s, 3H), 2.35 (s, 3H).

Intermediate 169: 4'-(bromomethyl)-2,3'-dimethyl-4-(trifluoromethyl)biphenyl

To a solution of [2',3-dimethyl-4'-(trifluoromethyl)-4-biphenylyl]methanol (Intermediate 168, 2.3 g, 8.2 mmol) in dichloromethane was added dropwise PBr₃ (1.55 ml_, 2 equiv.). After completion of the addition, the reaction mixture was stirred at RT for 18h. 200 ml. of water were added, and the organic phase was decanted and dried over sodium sulfate and concentrated in vacuo. Purification by column chromatography on silica gel eluted with DCM/cHex 50/50 to

DCM gave the title compound as an oil. (1.81 g, yield: 64%). LC: Rt 4.62 min.¹H NMR: (CDCI₃) δ 7.6-7.5 (m, 2H), 7.40 (d, 1 H), 7.5 (d, 1 H), 7.2-7.1 (m, 2H), 4.65 (s, 2H), 2.55 (s, 3H), 2.35 (s,

3H). Intermediate 170: Ethyl 1-{4-[5-chloro-2-({[2',3-dimethyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(5-chloro-2-hydroxyphenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, (Intermediate 101 , 130 mg, 0.36 mmol) in acetonitrile (10 mL) was added cesium carbonate (0.139 g, 1.2 equiv.) and 4'-(bromomethyl)-2,3'-dimethyl-4-(trifluoromethyl)biphenyl, (Intermediate 169, 0.122 g, 1 equiv.). The reaction mixture was stirred at 70⁰C overnight, filtered and concentrated to dryness. The crude product was purified by chromatography on silica using DCM as eluant to give the desired compound (195 mg, 87% yield) as an oil. LC/MS: m/z 629 [M+H]+, Rt 4.91 min.

The following Intermediates were prepared by an analogous method to that described for Intermediate 170 using the appropriate alkylating agent.

Intermediate 173: Ethyl 1 -[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-3,5- difluorophenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate

To a solution of ethyl 1-[4-(2-{[(4-bromo-2-methylphenyl)methyl]oxy}-3,5-difluorophenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylate (Intermediate 135, 0.07 g, 0.127 mmol) and (4-cyano-2- methylphenyl)boronic acid (0.041 g, 0.254 mmol) in acetonitrile (20 ml) was added cesium carbonate (0.083 g, 0.254 mmol) and Palladium tetrakis (7.33 mg, 6.35 μmol). The reaction was then stirred to reflux during one night. TLC (Chex /EtOAc: 80/20) showed that the reaction was incomplete. (4-cyano-2-methylphenyl)boronic acid (0.041 g, 0.254 mmol) and Palladium tetrakis (7.33 mg, 6.35 μmol) was added and the reaction was stirred to reflux during five hours and stirred at room temperature for 48 hours. The reaction was incomplete but treated. The crude reaction was filtered on celite and concentrated in vacuo. Purifcation by flash chromatography on silica was carried out using DCM/MeOH 99/1 gave the title compound (0.06 g, 0.102 mmol, 80 % yield) as an oil. LC/MS: m/z 588 [M+H]⁺, Rt 4.66 min. ¹H NMR (CDCI₃, 300 MHz) δl.10) (d, 1 H), 7.59-7.52 (m, 3H), 7.35-7.28 (d, 3H), 7.16 (brs 1 H), 6.83 (m, 1 H), 5.05 (s, 2H), 4.19 (q, 2H), 4.04 (m, 2H), 3.17 (m, 2H), 2.57 (m, 1 H), 2.47 (s, 3H), 2.33 (s, 3H), 2.06 (m, 2H), 1.90 (m, 2H), 1.30 (t, 3H).

The following Intermediates were prepared by an analogous method to that described for Intermediate 173.

Intermediate 177: {4-r3-chloro-5-(trifluoromethvl)-2-pyridinvn-2-methvlphenvl)methanol

To a solution of [2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]methanol (Intermediate 16, 5 g, 20.2 mmol) in dioxane (50 ml.) and H₂O (50 ml.) were added 2,3-dichloro- 5-trifluoromethylpyridine (5.2 g, 24 mmol), Pd(PPh₃)₄ (0.69 g, 0.6 mmol) and K₂CO₃ (8.3 g, 60.5 mmol) and the mixture was heated at 100⁰C overnight. Dioxane was removed under reduced pressure and AcOEt and water were added. The organic phase was washed with brine, then water, dried over sodium sulfate and concentrated in vacuo. Purification by chromatography on silicagel (petroleum ether/AcOEt, 5/1 ) afforded the title compound (4 g, yield: 65.9%). LC/MS: 301.7 (M+H), Rt= 1.7min

Example 1 : 1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)- 1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid.

To a solution of ethyl 1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)- 1 ,3-thiazol-2-yl]-4-piperidinecarboxylate, intermediate 21 , (205 mg, 0.362 mmol) in ethanol (20 ml.) was added a 1 N solution of lithium hydroxide (1.1 ml_, 1.100 mmol). The reaction was stirred at 80 ⁰C for 4 hours. The reaction was then concentrated in vacuo, dissolved in water and neutralised with a 1 N HCI solution. The compound was extracted with dichloromethane, and the organic phases were dried over sodium sulfate and concentrated under reduce pressure. After recrystallization from ethanol, the title compound, 1-[4-(2-{[(4'-cyano-2',3- dimethyl^-biphenylyOmethyOoxyϊ-δ-methylphenyO-i ^-thiazol^-yO^-piperidinecarboxylic acid (80 mg, 0.149 mmol, 41.1 %) was obtained as a white solid. Mp = 100⁰C (gummy). LC/MS: m/z 538 [M+H]⁺, Rt 3.56 min. LC/HRMS (M+H)⁺ calc for C₃₂H_3IN₃O₃S 538.2164; found 538.2147; Rt 3.16 min. ¹H NMR (CDCI₃) J¹H NMR J8.05 (d, 1 H), 7.6-7.5 (m, 3H), 7.5 (d, 1 H), 7.25-7.15 (m, 3H), 7.1 (dd, 1 H), 7.7 (d, 1 H), 5.20 (s, 2H), 4.1 (m, 2H), 3.15 (m, 2H), 2.15 (m, 1 H), 2.45 (s, 3H), 2.35 (s, 3H), 2.3 (s, 3H), 2.15 (m, 2H), 2.0-1.8 (m, 2H).

The following Examples were prepared by methods analogous to that described for Example 1 :

Example 5: ^{^^-({^'-chloro-S-methyl-^^trifluoromethylJ^-biphenylylJmethy^oxyJ-S- methylphenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

To a solution of ethyl ethyl 1-{4-[2-({[2'-chloro-3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate, intermediate 29, (310 mg, 0.493 mmol), in ethanol (50 mL) was added a 1 N solution of sodium hydroxide (4.93 ml, 4.93 mmol). The reaction was stirred at 90 ⁰C for 2 hours. The reaction was then concentrated in vacuo, dissolved in water and treated with a 1 N HCI solution until PH=5. The compound was extracted with Et₂O, and the organic phase was dried over sodium sulfate and concentrated under reduce pressure. The crude product was purified by flash chromatography (dichloromethane to dichloromethane/MeOH, 95/5). After recrystallization from acetonitrile, the title compound, 1-{4-[2-({[2'-chloro-3-methyl-4'- (trifluoromethyl)-4-biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid (130 mg, 0.216 mmol, 43.9 %) was obtained as a white powder. Mp = 172°C. LC/MS: m/z 601 [M+H]⁺, Rt 3.96 min. LC/HRMS (M+H)⁺ calc for C_3IH₂₈CIF₃N₂O₃S 601.1539; found 601.1550. Rt 3.76 min.¹H NMR (CDCI₃) J ¹H NMR 8.05 (d, 1 H), 7.8 (s, 1 H), 7.6-7.4 (m, 3H), 7.3 (m, 3H), 7.1 (dd, 1 H), 6.95 (d, 1 H), 5.20 (s, 2H), 4.1 (m, 2H), 3.2 (m, 2H), 2.15 (m, 1 H), 2.45 (s, 3H), 2.35 (s, 3H), 2.1 (m, 2H), 2.0-1.8 (m, 2H).

Example 6: 1 -{4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid

1 N sodium hydroxide (0.4 mL, 10 equiv.) was added to a solution of ethyl 1 -{4-[2-({[4-(2- phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate (Intermediate 65, 20 mg, 38 μmol) in EtOH (4 mL) and the reaction mixture was refluxed for 72h. The mixture was then acidified with 1 N HCI and extracted with EtOAc. The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure. The resulting solid was triturated with Et₂O and filtered to give the desired compound (10 mg, 60% yield) as a off-white solid. Mp = 137°C. ¹H NMR (DMSO d6) £ 12.33 (br s, 1 H), 8.1 1 (m, 1 H), 7.40 (d, J = 8.0 Hz, 2H), 7.31- 7.13 (m, 10H), 6.99 (m, 1 H), 5.21 (s, 2H), 3.89 (m, 2H), 3.11 (m, 2H), 2.88 (s, 4H), 2.51 (m, 1 H), 1.94 (m, 2H), 1.62 (m, 2H). LC/MS: m/z 499 [M+H]⁺, Rt 3.48 min. LC/HRMS (M+H)⁺ calc for C₃₀H₃₁N₂O₃S 499.2055; found 499.2034. Rt 3.18 min.

The following Examples were prepared by an analogous method to that described for Example 6 starting from the corresponding ester:

The following Example was prepared by an analogous method to that described for Example 6 starting from the corresponding ester.

Example 1-{4-[4-chloro-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 36 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

Example 38: 1 -[5-chloro-4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]- 4-piperidinecarboxylic acid

1 N sodium hydroxide (0.4 ml_, 1 equiv.) was added to a solution of ethyl 1-[5-chloro-4-(2-{[(4'- cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylate (Intermediate 43, 200 mg, 0.36 mmol) in a MeOH/THF (2/1 ) mixture (20 ml.) and the reaction mixture was refluxed for 1Oh. The mixture was then quenched with 1 N HCI (0.4 mL) and concentrated to dryness. The resulting solid was recrystallised in a MeOH/water (9/1 ) mixture to give the desired compound (10 mg, 5% yield) as a white solid. ¹H NMR (DMSO d6, 300 MHz) J¹H NMR (DMSO d6) δ 12.36 (br s, 1 H), 7.93 (d, J = 9.1 Hz, 2H), 7.90 (d, J = 9.1 Hz, 2H), 7.76 (d, J = 8.3 Hz, 2H), 7.57 (d, J = 8.3 Hz, 2H), 7.39 (m, 1 H), 7.33 (dd, J = 7.6 and 1.5 Hz, 1 H), 7.19 (d, J = 8.3 Hz, 1 H), 7.02 (m, 1 H), 5.23 (s, 2H), 3.78 (m, 2H), 3.11 (m, 2H), 2.54 (m, 1 H), 1.92 (m, 2H), 1.60 (m, 2H). LCMS : (M+H)⁺= 530, Rt= 3.21 min.

The following Examples were prepared by an analogous method to that described for Example 38 starting from the corresponding ester .

Example 41 : 1 -{5-methyl-4-[2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid

1 N sodium hydroxide (1.6 ml_, 5 equiv.) was added to a solution of ethyl 1-{5-methyl-4-[2-({[4'- (methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate (Intermediate 48, 170 mg, 0.3 mmol) in MeOH (10 ml.) and the reaction mixture was refluxed for 24h. The mixture was then quenched with 1 N HCI (1.6 ml.) and concentrated to dryness. The resulting solid was recrystallised in a MeOH/water (9/1 ) mixture to give the desired compound (130 mg, 84% yield) as a white solid. ¹H NMR (DMSO d6, 300 MHz) J7.66-7.57 (m, 2H), 7.60 (d, J = 8.2 Hz, 2H), 7.46 (d, J = 8.2 Hz, 2H), 7.36-7.26 (m, 2H), 7.16 (d, J = 7.8 Hz, 1 H), 7.05-6.95 (m, 3H), 5.14 (s, 2H), 3.79 (s, 3H), 3.74 (m, 2H), 2.97 (m, 2H), 2.11 (m, 1 H), 2.08 (s, 3H), 1.82 (m, 2H), 1.58 (m, 2H). HRMS : calculated for C₃₀H_3IN₂O₄S (M+H)⁺ : 515.2004; found : 515.1960.

The following Example was prepared by an analogous method to that described for Example 6 starting from the corresponding ester:

Example 1-{4-[3,5-difluoro-2-({[3-methyl-4'-(trifluoromethyl)-4- 42 biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

The following Examples were prepared by an analogous method to that described for Example 41 starting from the corresponding ester.

Example 1-{4-[2-fluoro-6-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 44 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

The following Examples were prepared by an analogous method to that described for Example 6 starting from the corresponding ester.

The following Examples were prepared by a similar method to that described for Example 54 starting from the corresponding ester.

Example 1-[4-(2-{[(4'-cyano-2\3-dimethyl-4-biphenylyl)methyl]oxy}-3,5-difluorop 53 thiazol-2-yl]-4-piperidinecarboxylic acid

Example 54: 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1,3-thiazol-2-yl}-4-piperidinecarboxylic acid

To a solution of ethyl 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate (Intermediate 92, 280mg, 0.471 mmol) in ethanol (50 ml.) was added a 1 N solution of sodium hydroxide (2.4 ml, 2.4 mmol). The reaction was stirred at 100 ⁰C for 2 hours. The reaction was then concentrated in vacuo, dissolved in water and treated with a 1 N HCI solution (pH = 4.5). The compound was extracted with dichloromethane, and the organic phases were dried over sodium sulfate and concentrated under reduce pressure. After recrystallization from acetonitrile, the title compound, 1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid (220 mg, 0.388 mmol, 82 %) was obtained as a white powder. Mp = 215°C. LC/MS: m/z 567 [M+H]⁺, Rt 3.87 min. LC/HRMS (M+H)⁺ calc for C₃₁H₂₉F₃N₂O₃S 567.1929; found 538.2147; Rt 3.70 min. ¹H NMR (d⁶, DMSO 400MHz) δ 7.95 (m, 3H), 7.85 (m, 2H), 7.65 (s, 1 H), 7.6-7.5 (m, 2H), 7.20 (s, 1 H), 7.15-7.05 (m, 2H), 5.25 (s, 2H), 3.9 (m, 2H), 3.15 (m, 2H), 2.55 (m, 1 H), 2.40 (s, 3H), 2.30 (s, 3H), 1.95 (m, 2H), 1.70-1.60 (m, 2H).

Example 55: 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid-2- aminoethanol (1 :1)

To a solution of 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 1 ,3-thiazol-2-yl}-4-pipeιϊdinecarboxylic acid (Example 54, 400 mg, 0.706 mmol) in dichloromethane (20 ml.) was added ethanolamine (0.043 ml_, 0.706 mmol). The reaction was concentrated in vacuo. The compound was recrystallized from acetonitrile to give the title compound 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid-2-aminoethanol (1 :1 ) (330 mg, 0.526 mmol, 74.5 % yield) as a white powder. ¹H NMR (d⁶, DMSO, 300MHz) δ 7.95 (m, 3H), 7.85 (m, 2H), 7.65 (s, 1 H), 7.6-7.5 (m, 2H), 7.20 (s, 1 H), 7.2-7.0 (m, 2H), 5.25 (s, 2H), 3.85 (m, 2H), 3.5 (t, 2H), 3.10 (m, 2H), 2.70 (t, 2H), 2.45 (m, 1 H), 2.40 (s, 3H), 2.25 (s, 3H), 1.90 (m, 2H), 1.70-1.50 (m, 2H).

Example 56i sodium 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1,3-thiazol-2-yl}-4-piperidinecarboxylate

Na

To a solution of 1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid (Example 54, 840 mg, 1.413 mmol) in ethanol (50 ml.) was added a 1 N sodium hydroxide solution (7.06 ml, 7.06 mmol). The reaction was heated at 100 ⁰C for 2 hours. The solution was evaporated in vacuo and the residue was taken up in water. The precipitate was filtered and dried. The compound was recrystallized from a mixture of acetonitrile and methanol to give the title compound sodium 1-{4-[5-methyl-2-({[3-methyl-4'- (trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylate as a white solid (70 mg, 0.119 mmol). Most of the compound was dissolved in the filtrate. The compound had the same analytical data as was obtained for Example 54. The following Example was prepared by a method analogous to that described for Example 54 but using lithium hydroxide as base.

Example 1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol- 57 2-yl]-4-piperidinecarboxylic acid

The following Example was prepared by a method analogous to that described for Example 55.

Example 1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol- 58 2-yl]-4-piperidinecarboxylic acid 2-aminoethanol (1 :1 )

Example 1-(4-{2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5- 59 [(trifluoromethyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid

The following Examples were prepared by methods analogous to that described for Example 54 starting from the corresponding ester.

The following Example was prepared by a similar method to that described for Example 54 starting from the corresponding ester. Example 1-(4-{5-chloro-2-[({3-methyl-44(trifluoromethyl)oxy]-4- 62 biphenylyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid

The following Example was prepared by an analogous method to that described for Example 1 starting from the corresponding ester.

Example 1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(trifluoromethyl)phenyl]- 63 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

The following Examples were prepared by methods analogous to that described for Example 6 (or as described for Example 1 in the case of Examples 68, 72, 73, 74, 75 and 79; in some cases, sodium hydroxide was used instead of lithium hydroxide) starting from the corresponding ester.

Example 81 : GSK2236881A 1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-5- methylphenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid (N7106-76-1 )

To a solution of Intermediate 1 10 1-{4-[5-methyl-2-({[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-pipeιϊdinecarboxylic acid (190 mg, 0.407 mmol) in DME (50 ml_), were added 6-bromo-3-pyridinecarbonitrile (150 mg, 0.820 mmol), PalladiumTetrakis (15 mg, 0.013 mmol), and cesium carbonate (400 mg, 1.228 mmol). The reaction was stirred at 110⁰C for 18 hours and concentrated in vacuo and triturated with a 1 N HCI solution (pH = 7). The precipitate was filtered, washed with water and methanol to give the title compound as a pale yellow solid (90 mg, 42.1%). Mp = 129°C. LC/MS: m/z 525 [M+H]⁺, Rt 3.23 min. LC/HRMS (M+H)⁺ calc for C₃₀H₂₈N₄O₃S 525.1960; found 525.1909. Rt 2.92 min. ¹H NMR (DMSO-d6, 300MHz) £ 12.33 (brs, 1 H), 9.00 (s, 1 H), 8.40 (d, 1 H), 8.23 (d, 1 H), 8.08 (s, 1 H), 8.00 (d, 1 H), 7.91 (s, 1 H), 7.59 (d, 1 H), 7.18 (s, 1 H), 7.08 (m, 2H), 5.29 (s, 2H), 3.90 (m, 2H), 3.10 (m, 2H), 2.55 (m, 1 H), 2.43 (s, 3H), 2.29 (s, 3H), 1.93 (m, 2H), 1.63 (m, 2H).

The following Examples were prepared by a method analogous to that described for Example 1 but in some cases sodium hydroxide was used instead of lithium hydroxide (or by a method analogous to that described for Example 6 in the case of Example 87; or by a method analogous to that described for Example 54 in the case of Example 82; or by a method analogous to that described for Example 81 for Example 86) starting from the corresponding ester.

Example Name

89 1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3, 5-dimethylphenyl)-1 ,3- thiazol-2-yl]-4-piperidinecarboxylic acid

Example 1-{4-[4-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 90 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid

Biological Assay The activity of soluble guanylate cyclase (sGC) can be tested in an assay based on measuring the fluorescent polarisation (FP) signal of fluorescently labelled cGMP. FP increases on interaction with an anti-cGMP antibody as the motility of the molecule is reduced. Newly produced cGMP displaces the interaction giving rise to a decrease in polarisation and FP signal which can be equated to enzyme activity. Compounds are incubated with human sGC, anti- cGMP antibody, the GTP substrate and fluorescently labelled cGMP. After a period of one hour the assay is stopped with the addition of EDTA and after a further hour the assay is read.

Human sGC is thawed and resuspended in assay buffer (10OmM TRIS, 1 OmM MgCI₂, 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give 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 90 were tested in the assay described above and gave pEC500 values of greater than 5.0. In an embodiment the compounds of the invention give a pEC500 value of ≥6.0 when tested in this assay. In a further embodiment the compounds of the invention give a pEC500 value of ≥7.0 when tested in this assay.

The compounds 1 -{5-methyl-4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}- 4-piperidinecarboxylic acid and 1-(4-{5-(1-methylethyl)-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4- biphenyly^methy^oxylpheny^-i ^-thiazol^-yl^-piperidinecarboxylic acid were also prepared by analogous methods to those described above. These two compounds were tested in the assay described above and gave pEC500 values of < 5.0 i.e. below the detectable limit of the assay.

The application of which this description and claims forms part may be used as a basis for priority in respect of any subsequent application. The claims of such subsequent application may be directed to any feature or combination of features described herein. They may take the form of product, composition, process, or use claims and may include, by way of example and without limitation, the following claims.

Claims

1. A compound of formula (I)

or a salt thereof wherein

R¹ and R² are independently selected from hydrogen, halo, Ci_-4alkyl, Ci_-4alkoxy, CF₃ and OCF₃;

-Y- represents

R³ represents hydrogen, fluoro, chloro or C_1-4alkyl;

R^4a and R^4b each independently represent hydrogen, C_1-4alkyl, C_1-4alkoxy, CF₃ or halo; and

R⁵ represents a group Z-X; wherein Z is absent or represents (CH₂^ or O; and X represents

wherein: 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, R⁶ represents hydrogen, halo, CF₃, C_1- ₄alkyl or C_1-4alkoxy in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, OCF₃, C_1-4alkyl, C_1-4alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; when one of J or L represents N, R⁶ represents hydrogen or halo in a meta or ortho position relative to the R⁷ substituent and R⁷ represents hydrogen, halo, CF₃, C_1-4alkyl, C_1- ₄alkoxy, CH₂OH, CN, CONR⁸R⁹ or CO₂H; and R⁸ and R⁹ are independently selected from hydrogen and C_1-4alkyl.

2. A compound of formula (I) or a salt thereof as claimed in claim 1 wherein: R¹ represents hydrogen and R² represents hydrogen, methyl or CF₃, with R² in an ortho position relative to the -OCH₂- linker; or R² represents hydrogen and R¹ represents hydrogen, methyl, ethyl, isopropyl, fluoro, chloro, methoxy, CF₃ or OCF₃, with R¹ in a para position relative to the -OCH₂- linker; or R¹ represents fluoro and R² represents fluoro, with R¹ in a para position relative to the -OCH₂- linker and R² in an ortho position relative to the -OCH₂- linker.

3. A compound of formula (I) or a salt thereof as claimed in claim 1 or claim 2 wherein R² represents hydrogen and R¹ represents hydrogen, methyl, ethyl, fluoro, chloro or CF₃, with R¹ in a para position relative to the -OCH₂- linker.

4. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 3 wherein R³ represents hydrogen.

5. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 4 wherein R^4a represents hydrogen and R^4b represents hydrogen, methyl, methoxy, propoxy, fluoro or chloro.

6. A compound of formula (I) or a salt thereof as claimed in claim 5 wherein R^4a represents hydrogen and R^4b represents methyl.

7. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 6 wherein Z is absent.

8. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 7 wherein J and L both represent CH.

9. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 8 wherein R⁶ is in a meta-position relative to the R⁷ substituent.

10. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 9 wherein J and L both represent CH; and R⁶ represents hydrogen or R⁶ represents methyl, chloro or CF₃ in a meta position relative to the R⁷ substituent.

11. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 9 wherein: J and L both represent CH, R⁶ represents hydrogen and R⁷ represents hydrogen, fluoro, chloro, methoxy, CN, CF₃, CH₂OH, CO₂H, CO₂NH₂ or CO₂N(CH₃)₂; or J and L both represent CH, R⁷ represents CF₃ and R⁶ represents chloro, methyl or CF₃; or J and L both represent CH, R⁷ represents CN and R⁶ represents methyl; or J and L both represent CH, R⁶ represents CF₃ and R⁷ represents methoxy.

12. A compound of formula (I) or a salt thereof as claimed in any one of claims 1 to 9 wherein J and L both represent CH, R⁶ represents hydrogen and R⁷ represents CF₃.

13. A compound of formula (I) as claimed in claim 1 selected from:

1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2- yl]-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-ethylphenyl)-1 ,3-thiazol-2-yl]-

4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-2',3-dimethyl-4-biphenylyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4'-cyano-2'-methyl-3-(propyloxy)-4-biphenylyl]methyl}oxy)-5-methylphenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[2'-chloro-3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-5-methylphenyl]-

1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-({[3'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid;

1-{4-[2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4-piperidinecarboxylic acid;

1-{4-[2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1-{4-[2-({[3-methyl-4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-chloro-3-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-chlorophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-{4-[2-({[3,4'-bis(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[2-({[3-chloro-4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-[4-(2-{[(3-chloro-4'-fluoro-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{4-[2-({[3-(methyloxy)-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}-3,5-difluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]-3,5-difluorophenyl}-1 ,3-thiazol-2-yl)- 4-piperidinecarboxylic acid;

1-{4-[3,5-difluoro-2-({[4'-(methyloxy)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-(4-{2-[({2-methyl-4-[6-(methyloxy)-3-pyridinyl]phenyl}methyl)oxy]phenyl}-1 ,3-thiazol-2- yl)-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-fluoro-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; 1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-[5-chloro-4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-{5-chloro-4-[2-({[4-(2-phenylethyl)phenyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4- piperidinecarboxylic acid;

1-{4-[3,5-difluoro-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-4-biphenylyl)methyl]oxy}phenyl)-5-methyl-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-[({4-[(4-cyanophenyl)oxy]phenyl}methyl)oxy]phenyl}-5-methyl-1 ,3-thiazol-2-yl)-4- piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3,5-difluorophenyl)-1 ,3-thiazol-2-yl]- 4-piperidinecarboxylic acid;

1-{4-[2-({[4'-(aminocarbonyl)-3-methyl-4-biphenylyl]methyl}oxy)-3,5-difluorophenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-fluorophenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; i^-p-^P'.S-dimethyl^'-^rifluoromethylH-biphenylyllmethylloxyJ-S.S-difluorophenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-chloro-2-({[2'_!3-dimethyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-2'_!3-dimethyl-4-biphenylyl)methyl]oxy}-3_!5-difluorophenyl)-1 ,3-thiazol- 2-yl]-4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid;

1-(4-{2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-[(trifluoromethyl)oxy]phenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-(4-{5-methyl-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-(4-{2-[({4'-[(dimethylamino)carbonyl]-3-methyl-4-biphenylyl}methyl)oxy]-5- methylphenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid; 1-(4-{5-chloro-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-(methyloxy)-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-(4-{5-(methyloxy)-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}- 1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(methyloxy)phenyl]-1 ,3-thiazol-2- yl}-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-5-(1-methylethyl)phenyl]-1 ,3-thiazol- 2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-(1-methylethyl)-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[3-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-(4-{2-[({4-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-2-methylphenyl}methyl)oxy]-5- methylphenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid; 1-(4-{2-[({4-[3-chloro-5-(trifluoromethyl)-2-pyridinyl]-2-methylphenyl}methyl)oxy]-5- ethylphenyl}-1 ,3-thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[5-ethyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol- 2-yl}-4-piperidinecarboxylic acid;

1-(4-{5-ethyl-2-[({3-methyl-4'-[(trifluoromethyl)oxy]-4-biphenylyl}methyl)oxy]phenyl}-1 ,3- thiazol-2-yl)-4-piperidinecarboxylic acid;

1-{4-[2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-3-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3-methylphenyl)-1 ,3-thiazol-2-yl]-4- piperidinecarboxylic acid; i^-p-f^-fS-chloro-S-^rifluoromethyl^-pyridinyll^-methylphenylJmethyl^xyl-S- (trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[2-{[(4'-cyano-2'_!3-dimethyl-4-biphenylyl)methyl]oxy}-3-(trifluoromethyl)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-5-methylphenyl]-1 ,3-thiazol- 2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-4'-(methyloxy)-2'-(trifluoromethyl)-4- biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[5-ethyl-2-({[3-methyl-2',4'-bis(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[5-methyl-2-({[3-(propyloxy)-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[5-methyl-2-({[3-methyl-2'_!4'-bis(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-5-(trifluoromethyl)phenyl]- 1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-({[2'-chloro-3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)-3- (trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; 1-{4-[2-({[4-(5-cyano-2-pyridinyl)-2-methylphenyl]methyl}oxy)-3,5-dimethylphenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-[4-(2-{[(4'-cyano-3-methyl-4-biphenylyl)methyl]oxy}-3,5-dimethylphenyl)-1 ,3-thiazol-2- yl]-4-piperidinecarboxylic acid;

1-{4-[4-chloro-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid;

1-{4-[2-fluoro-6-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3-thiazol- 2-yl}-4-piperidinecarboxylic acid;

1-{4-[4-methyl-2-({[3-methyl-4'-(trifluoromethyl)-4-biphenylyl]methyl}oxy)phenyl]-1 ,3- thiazol-2-yl}-4-piperidinecarboxylic acid; and i^-p-t^-^-chloro-S-^rifluoromethyl^-pyridinyll^-methylphenylJmethyl^xyl-S- (trifluoromethyl)phenyl]-1 ,3-thiazol-2-yl}-4-piperidinecarboxylic acid; or a salt thereof.

14. A pharmaceutical composition comprising a compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).

15. A compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14, for use in therapy.

16. A compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14, for use in the treatment of a disease or condition mediated by the activity of sGC.

17. A compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as claimed in claim 14, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

18. Use of a compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disease or condition mediated by the activity of sGC.

19. Use of a compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

20 A method of treatment of a disease or condition mediated by the activity of sGC comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as claimed in claim 14.

21. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as claimed in any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as claimed in claim 14.