WO2009068652A1

WO2009068652A1 - 2, 6-disubstituted pyridines and 2, 4-disubstituted pyrimidines as soluble guanylate cyclase activators

Info

Publication number: WO2009068652A1
Application number: PCT/EP2008/066444
Authority: WO
Inventors: Thierry Boyer; Nerina Dodic; Brian Evans; Barrie Edward Kirk
Original assignee: Smithkline Beecham Corporation
Priority date: 2007-11-30
Filing date: 2008-11-28
Publication date: 2009-06-04

Abstract

Disclosed are compounds of formula (I): wherein n represents 1 or 2; each R1 independently represents halo or trifluoromethyl; wherein halo represents fluoro, chloro or bromo; R2 represents hydrogen or C1-3alkyl; X represents N or CH; wherein -Z- represents a group selected from: (A), (B) or (C), wherein R3 represents trifluoromethyl or C1-3alkyl; and R4 represents hydrogen, trifluoromethyl or C1-3alkyl; with the proviso that where Z represents a thiophene group and X represents N, R2 cannot represent C1-3alkyl; and when X represents CH, -Z- can additionally represent a group selected from: (D) or (E) or salts thereof which activate soluble guanylate cyclase (sGC) pharmaceutical compositions containing them, their use is medicine, and processes for their preparation.

Description

2,6-DISUBSTITUTED PYRIDINES AND 2 , 4-DISUBSTITUTED PYRIMIDINES AS SOLUBLE GUANYLATE CYCLASE ACTIVATORS

The present invention relates to novel compounds, pharmaceutical compositions containing them, to their use in medicine, and to processes for their preparation. In particular the present invention relates to compounds which, when administered to a patient, activate soluble guanylate cyclase (sGC) and to the use of such compounds for the activation of sGC in patients for a therapeutic effect.

sGC is a member of a family of related enzymes which share homologous catalytic domains but are activated in different ways. This family includes the adenylate cyclases, a class of membrane bound enzymes that convert ATP to cAMP, which are regulated by G proteins, and the membrane-bound guanylate cyclases that make cyclic guanosine monophosphate (cGMP) in response to hormone signals via an extracellular ligand binding domain.

Whilst not wishing to be bound by theory, it is considered that the active enzyme contains one heme unit in a heterodimer arrangement, composed of one alpha and one beta-subunit. Several subtypes of subunits have been described, which differ from each other with respect to sequence and tissue-specific distribution. The subtypes alpha-1 and beta-1 are thought to be mainly expressed in the brain and the lung but have also been shown to be expressed in heart, kidney, liver, skeletal muscle, placenta, colon, uterus, prostate, spleen, pancreas, platelets and isolated blood vessels. Alpha-2 subunits have been detected in the brain, placenta, uterus and pancreas, while beta-2 subunits seem to be expressed in the liver and kidney.

The enzyme is thought to be a principal receptor for the ubiquitous signalling molecule, nitric oxide (NO), forming a NO-sGC-cGMP signal transduction axis. It is believed that soluble guanylate cyclase is a heme sensor protein that selectively binds NO at the heme iron, which activates the enzyme to convert guanosine triphosphate (GTP) to cGMP. It is thought that cGMP subsequently mediates a number of important physiological processes, including smooth muscle relaxation and neurotransmission. It has been suggested that cGMP is a critical component involved in the regulation of various (patho)physiological processes, for example in cardiovascular, respiratory, gastrointestinal, urogenital, nervous and immune systems including, neuronal excitability and particularly smooth muscle tone, thereby controlling, among other things, blood pressure, gastro-intestinal motility and genital erection.

Due to its ubiquitous nature, activation of this enzyme is likely to have significant pathological implications. This is particularly true of the cardiovascular system in which dysfunction of NO-sGC-cGMP signalling is thought to be involved in diseases and conditions such as atherosclerosis, stroke and sepsis. Thus, novel drugs based on selective activation of the enzyme have the potential for therapeutic benefit.

For a review of NO-independent activation of sGC see Oleg V. Evgenov et al.; Nature Reviews, Vol. 5, September 2006, pp755-768. Reference is made therein to the compounds BAY 58-2667 (see also WO01/19780) and HMR-1766 (see also WO00/02851 ) as sGC activators. The following more recent article discusses BAY 58-2667 in the context of treatment of congestive heart failure: Hypertension, 2007, 49, 1128-1133.

The novel compounds are activators of sGC and consequently may have application in the treatment of one or more diseases or conditions, which include: cardiovascular diseases and conditions, such as angina (including stable and unstable angina pectoris), low cardiac output, cerebral ischemia, cardiac ischemia, myocardial infarction, coronary reperfusion injury, arterial hypertension (including pulmonary arterial hypertension), congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), heart failure with preserved ejection fraction, acute heart failure syndromes (AHFS), cardiac hypertrophy, acute coronary syndrome, thromboses (including arterial or venous thrombosis), atherosclerosis, peripheral vascular disease, glomerulonephritis, restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement), Raynaud's disease, vascular complications of diabetes or of obesity, stroke, hereditary cerebral haemorrhage, endothelial dysfunction, and other inflammatory cardiovascular disorders; erectile dysfunction; female sexual arousal disorder, respiratory failure, acute respiratory distress syndrome, gall bladder dysfunction, sickle cell disease, osteoporosis, inflammation, wound healing, chronic kidney insufficiency, renal fibrosis, renal failure, glomerulonephritis, chronic renal disease, cardiorenal syndrome, hepatorenal syndrome, liver cirrhosis, diabetes, metabolic syndrome, male pattern baldness; neuro-function disorders (including diseases or conditions displaying neuroinflammation pathology and neurodegenerative diseases, particularly chronic neurodegenerative conditions) such as Alzheimer's disease, dementia, age-related memory dysfunction, mild cognitive impairment, cognitive deficit, corticobasal degeneration, frontotemporal dementia, diffuse Lewis body type of Alzheimer's disease, and apoptotic insults caused by beta-amyloid treatment, epilepsy; pain of neuropathic origin including neuralgias, Parkinson's disease, subacute sclerosing panencephalitic Parkinsonism, postencephalitic Parkinsonism, guam Parkinsonism-dementia complex, progressive supranuclear palsy, pugilistic encephalitis, Pick's disease, Huntingdon's disease, AIDS-associated dementia; multiple sclerosis, amyotrophic lateral sclerosis; sleep disorders (including narcolepsy and sleep deficits associated with Parkinson's disease), and ALS (motor neuron disease).

Thus representative diseases and conditions for which the novel compounds may be useful include arterial hypertension (including pulmonary arterial hypertension), angina, cardiac ischemia, myocardial infarction, congestive heart failure (for example due to systolic and/or diastolic cardiac dysfunction, low cardiac output or high systemic vascular resistance), cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome and restenosis (for example following percutaneous vascular intervention, vascular angioplasty or stent placement).

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

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

or a salt thereof; wherein n represents 1 or 2; each R¹ independently represents halo or trifluoromethyl; wherein halo represents fluoro, chloro or bromo;

R² represents hydrogen or C_1-3alkyl;

X represents N or CH; wherein -Z- represents a group selected from:

wherein R³ represents trifluoromethyl or Ci_-3alkyl; andr R⁴\ represents hydrogen, trifluoromethyl or Ci_₃alkyl;

with the proviso that where Z represents a thiophene group and X represents N, R² cannot represent Ci_-3alkyl;

and when X represents CH, -Z- can additionally represent a group selected from:

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 3, carbon atoms and examples include methyl, ethyl, n-propyl, and isopropyl.

In an embodiment there is provided a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

In an embodiment there is provided a compound of formula (I) as defined above.

In an embodiment there is provided a pharmaceutically acceptable salt of a compound of formula (I) as defined above.

As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use.

In an embodiment each R¹ independently represents halo. In an embodiment n represents 2 and both R¹ groups independently represent halo. In an embodiment n represents 2 and both R¹ groups represent chloro.

In an embodiment each R¹ independently represents trifluoromethyl. In an embodiment n represents 2 and both R¹ groups represent trifluoromethyl. In an embodiment n represents 1 and the R¹ group represents trifluoromethyl.

In an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, or 3,5-dichlorophenyl.

In an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, or 4-bromo-3-fluorophenyl.

In an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.

In an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 3,4-dichlorophenyl.

In an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 3-trifluoromethylphenyl.

In an embodiment R² represents hydrogen or methyl.

In an embodiment X represents CH and R² represents hydrogen or methyl. In an embodiment X represents N and R² represents hydrogen.

In an embodiment R³ represents trifluoromethyl.

In an embodiment R⁴ represents hydrogen or methyl.

In an embodiment Z represents the pyrazole group illustrated above. In an embodiment Z represents the pyrazole group illustrated above, X represents CH or N, R² represents hydrogen, R³ represents trifluoromethyl and the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, A- trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.

In an embodiment Z represents the pyrrole group illustrated above. In an embodiment Z represents the pyrrole group illustrated above, X represents CH or N, R² represents hydrogen or methyl, R⁴ represents hydrogen or methyl, and the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5- dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, A- trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl; in an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 3,4-dichlorophenyl.

In an embodiment Z represents the thiophene group illustrated above. In an embodiment Z represents the thiophene group illustrated above, X represents CH or N, R² represents hydrogen, and the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3- chloro-4-fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3- trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl; in an embodiment the R¹ group(s) together with the phenyl ring to which they are attached represent 3-trifluoromethylphenyl.

In an embodiment Z represents the piperidine group illustrated above. In an embodiment Z represents the piperidine group illustrated above, X represents CH, R² represents hydrogen, and the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl.

In an embodiment Z represents the phenoxy group illustrated above. In an embodiment Z represents the phenoxy group illustrated above, X represents CH, R² represents hydrogen, and the R¹ group(s) together with the phenyl ring to which they are attached represent 2,3- dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 3,4-difluorophenyl, 3-chloro-4- fluorophenyl, 4-bromo-3-fluorophenyl, 4-trifluoromethylphenyl, 3-trifluoromethylphenyl, or 3,5-bis(trifluoromethyl)phenyl. In an embodiment there is provided a compound of formula (I) as defined above selected from:

^^-(S^-Dichlorophenyl^-pyridinyO-S-^rifluoromethyO-I H-pyrazole-^carboxylic acid; 1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(2,3-Dichlorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid;

1-{6-[3-(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(3,4-Difluorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-{6-[3,5-bis(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1H-pyrazole-4-carboxylic acid;

^^-(S-Chloro^-fluorophenyl^-pyridiny^-S-^rifluoromethy^-I H-pyrazole^-carboxylic acid;

1-[6-(4-Bromo-3-fluorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(3,5-Dichlorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(3,4-Dichlorophenyl)-4-methyl-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

In an embodiment there is provided a compound of formula (I) as defined above selected from: 1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-pyrrole-3-carboxylic acid;

1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-2-methyl-pyrrole-3-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

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

1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-piperidine-4-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

4-(6-(3-trifluoromethylphenyl)-pyridin-2-yloxy)-benzoic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

5-(6-(3-trifluoromethylphenyl)-pyridin-2-yl)-thiophene-2-carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

5-(2-(3-trifluoromethylphenyl)-pyrimidin-4-yl)-thiophene-2-carboxylic acid; ^^(S^-dichlorophenyl^-pyrimidiny^-S-^rifluoromethy^-I H-pyrazole^-carboxylic acid; S-^rifluoromethyO-i^-tS-^rifluoromethyOphenyO^-pyrimidinylϊ-I H-pyrazole-^carboxylic acid; or a salt thereof, in an embodiment a pharmaceutically acceptable salt thereof.

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.

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 or associated solvents 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. Also included within the scope of the invention are solvates (including hydrates) of salts of the compounds of formula (I). The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of formula (I).

Typically, a salt may be readily prepared by using a desired acid or base as appropriate. The salt may precipitate from solution and be collected by filtration or may be recovered by evaporation of the solvent. Suitable pharmaceutically acceptable salts can include acid addition salts or base addition salts and will be apparent to those skilled in the art. A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic acid such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric or phosphoric acid; or with a suitable organic acid such as succinic, maleic, malic, mandelic, formic, acetic, propionic, hexanoic, fumaric, glutamic, lactic, citric, tartaric, benzoic, salicylic, aspartic, benzenesulfonic, p-toluenesulfonic, methanesulfonic, ethanesulfonic or naphthalenesulfonic acid. Other non-pharmaceutically acceptable salts such as oxalates, may be used, for example in the isolation of compounds of formula (I) and are included within the scope of this invention. A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of formula (I) with a suitable inorganic or organic base, including salts of primary, secondary and tertiary amines, such as ammonia, isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexyl amine, N-methyl-D-glucamine triethylamine, triethanolamine, choline, arginine, lysine or histidine. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline-earth-metal salts such as sodium, potassium, calcium or magnesium salts; in particular pharmaceutically acceptable metal salts of the carboxylic acid moiety that is present in the compound of formula (I). Since the compounds of formula (I) include a carboxylic acid moiety together with one or more basic nitrogen atom(s) they have the possibility to also form internal salts (including zwitterionic salts), which salts are also included within the scope of the present invention.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolised in the body to form a compounds of formula (I) which is pharmacologically active. Such derivatives may therefore be described as "prodrugs". All such prodrugs of compounds of formula (I) are included within the scope of the invention. Examples of pro-drug functionality suitable for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). In particular the carboxylic acid function attached to the group Y may be a suitable candidate for pro-drug functionality, for example by formation of appropriate esters or amides. It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of formula (I)-

Hereinafter, a compound of formula (I) (whether in solvated or unsolvated form) or a pharmaceutically acceptable salt thereof (whether in solvated or unsolvated form) defined in any aspect of the invention (except intermediate compounds in chemical processes) are referred to as "a compound of the invention".

Also included within the scope of the invention are alternative crystalline or non-crystalline forms, including polymorphic forms, of a compound of formula (I) or a salt thereof.

The invention also includes all suitable isotopic variations of a compound of the invention. An isotopic variation of a compound of the invention is defined as one in which at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into 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 a compound of the invention, as an activator of sGC, may be useful in the treatment of a disease or condition which is mediated by sGC activity.

According to a further aspect, the invention provides a pharmaceutical composition comprising a compound of the invention, together with one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s). The carrier(s), diluent(s) and/or excipient(s) must each be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

According to a further aspect there is provided a pharmaceutical composition comprising a) 0.1 mg to 1000 mg of a compound of the invention and b) 0.1g to 2g of one or more pharmaceutically acceptable carrier(s), diluents(s) and/or excipient(s).

According to a further aspect the invention provides a compound of the invention as defined above for use in therapy; in an embodiment the therapy is human therapy.

According to a further aspect, the invention provides a pharmaceutical composition as defined above for use in therapy; in an embodiment the therapy is human therapy. According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of a disease or condition mediated by sGC activity.

According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition comprising a compound of the invention for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

According to a further aspect the invention provides a compound of the invention or a pharmaceutical composition as defined above for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.

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

According to a further aspect the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

According to a further aspect the invention provides the use of a compound of the invention for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.

According to a further aspect the invention provides a method of treatment of a disease or condition which is mediated by the activity of sGC, in an embodiment arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis, comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition as defined above.

According to a further aspect the invention provides a method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of the invention, or of a pharmaceutical composition comprising a compound of the invention.

A compound of the invention may also be used in combination with other therapeutic agents. The invention thus provides, in a further aspect, a combination comprising a compound of the invention or a pharmaceutically acceptable derivative thereof together with a further therapeutic agent.

When a compound of the invention or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same disease state the dose of each compound may differ from that when the compound is used alone.

The compounds of the present invention may for example be used in combination with antihypertensive drugs such as diuretics (for example epitizide, bendroflumethiazide, chlortalidone, chlorthiazide, hydrochlorthiazide, indapamide, metolazone), ACE inhibitors (such as benzapril, captopril, enalapril, fosinopril, lisinopril, preindopril, quinapril, ramipril, trandopril), angiotensin receptor blockers (such as candesartan, irbesartan, losartan, telmisartan, valsartan), calcium channel inhibitors (such as amlodipine, felodipine, isradapine, nifedipine, niimodipine, nitrendipine, diltiazem, verapamil), α-adrenergic receptor antagonists (such as doxazosin, prazosin, terazosin, phentolamine, indoramin, phenoxybenzamine, tolazoline), β-adrenergic receptor antagonists (such as atenolol, metoprolol, nadolol, oxprenolol, pindolol, propanolol, timolol), mixed α/β-adrenergic receptor antagonists (such as bucindalol, carvedilol, labetolol) or may be used in combination with PDE5 inhibitors (such as sildenafil, tadalafil, vardenafil), or may be used in combination with cholesterol-lowering or lipid-lowering drugs, for example statins (such as atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin), fibrates (such as bezafibrate, ciprofibrate, gemfibrozil, fenofibrate), or nicotinic acid.

The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier or excipient comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations by any convenient route.

When administration is sequential, either the compound of the invention or the second therapeutic agent may be administered first. When administration is simultaneous, the combination may be administered either in the same or different pharmaceutical composition.

When combined in the same formulation it will be appreciated that the two compounds must be stable and compatible with each other and the other components of the formulation. When formulated separately they may be provided in any convenient formulation, conveniently in such manner as are known for such compounds in the art.

It will be appreciated that references herein to "treat", "treating" or "treatment" extend to prevention of recurrence of symptoms (whether mild, moderate or severe) and to suppression or amelioration of symptoms (whether mild, moderate or severe) as well as the treatment of established conditions.

The compound of the invention may be administered as the raw chemical but the active ingredient is preferably presented as a pharmaceutical formulation.

The compound of the invention may be administered in conventional dosage forms prepared by combining a compound of the invention with one or more standard pharmaceutical excipients, carriers or diluents, according to conventional procedures well known in the art. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation.

The pharmaceutical compositions of the invention may be formulated for administration by any route, and include those in a form adapted for oral, topical or parenteral administration to mammals including humans.

The compositions may be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

The topical formulations of the present invention may be presented as, for instance, ointments, creams or lotions, eye ointments and eye or ear drops, impregnated dressings and aerosols, and may contain appropriate conventional additives such as preservatives, solvents to assist drug penetration and emollients in ointments and creams.

The formulations may also contain compatible conventional carriers, such as cream or ointment bases and ethanol or oleyl alcohol for lotions. Such carriers may be present as from about 1% up to about 98% of the formulation. More usually they will form up to about 80% of the formulation.

Tablets and capsules for oral administration may be in unit dose presentation form, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatine, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrants, for example potato starch; or acceptable wetting agents such as sodium lauryl sulphate. The tablets may be coated according to methods well known in normal pharmaceutical practice. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives, such as suspending agents, for example sorbitol, methyl cellulose, glucose syrup, gelatine, hydroxyethyl cellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats, emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, oily esters such as glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and, if desired, conventional flavouring or colouring agents.

Suppositories typically contain conventional suppository bases, e.g. cocoa-butter or other glyceride.

For parenteral administration, fluid unit dosage forms are prepared utilising the compound and a sterile vehicle, water being preferred. The compound, depending on the vehicle and concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter-sterilised before filling into a suitable vial or ampoule and sealing.

Advantageously, agents such as a local anaesthetic, preservative and buffering agents can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum. The dry lyophilised powder is then sealed in the vial and an accompanying vial of water for injection may be supplied to reconstitute the liquid prior to use. Parenteral suspensions are prepared in substantially the same manner except that the compound is suspended in the vehicle instead of being dissolved and sterilisation cannot be accomplished by filtration. The compound can be sterilised by exposure to ethylene oxide before suspending in the sterile vehicle. Advantageously, a surfactant or wetting agent is included in the composition to facilitate uniform distribution of the compound.

The pharmaceutical compositions of the invention may be formulated, for administration to mammals including humans, by any route, and include those in a form adapted for oral, topical or parenteral administration. The compositions may, for example, be in the form of tablets, capsules, powders, granules, lozenges, creams or liquid preparations, such as oral or sterile parenteral solutions or suspensions.

Thus in one aspect the invention provides a pharmaceutical composition for oral administration such as an oral suspension or liquid, for example an aqueous based fluid formulation, or a solid dosage formulation such as a tablet or capsule.

The compositions may contain from 0.1% by weight, preferably from 10-60% by weight, of the active material, depending on the method of administration. It will be recognised by one of skill in the art that the optimal quantity and spacing of individual doses of a compound of the invention will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the age and the condition of the patient and will be ultimately at the discretion of the attendant physician, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e. the number of doses of a compound of the invention given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

Each dosage unit for oral administration typically contains for example from 0.5 to 250 mg (and for parenteral administration contains for example from 0.05 to 25 mg) of a compound of the invention calculated as the compound of formula (I).

A compound of the invention will normally be administered in a daily dosage regimen (for an adult patient) of, for example, an oral dose of between 1 mg and 1000 mg, for example between 1 mg and 500 mg, e.g. between 5 and 250 mg or an intravenous, subcutaneous, or intramuscular dose of between 0.1 mg and 100 mg, for example between 0.1 mg and 50 mg, e.g. between 1 and 25 mg of the compound of formula (I) or a salt thereof calculated as the compound of formula (I), the compound of the invention being administered 1 to 4 times per day, for example 1 to 2 times a day. In one embodiment, a compound of the invention may be administered once a day.

Suitably a compound of the invention will be administered for a period of continuous therapy, for example for a week or more.

Since the compounds of formula (I) are intended for use in pharmaceutical compositions it will readily be understood that they are each suitably provided in substantially pure form, for example at least 60% pure, for example at least 75% pure, for example at least 85%, for example at least 98% pure (% are on a weight for weight basis). Impure preparations of the compounds may be used for preparing the more pure forms used in the pharmaceutical compositions; these less pure preparations of the compounds typically contain at least 1 %, for example at least 5%, for example from 10 to 59% of a compound of the invention.

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.

It will be appreciated that all novel intermediates used to prepare a compound of the invention form yet a further aspect of the present invention. Compounds of formula (IA) wherein Z represents the pyrazole group as defined above can be prepared by deprotection of a compound of formula (II)

wherein

R¹, R², R³, X, and n are as defined above and P represents a carboxylic acid protecting group, for example Ci_-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.

Suitable protecting groups and deprotection methods are, for example given in T. W. Greene, 'Protective Groups in Organic Synthesis' (J. Wiley and Sons, 1991 ). Alkyl ester carboxylic acid protection can be removed, for example, by treatment with mineral base such a potassium hydroxide at an elevated temperature such as reflux in a suitable solvent, for example an alcohol such as ethanol.

Compounds of formula (II) may be prepared by reaction of a compound of formula (III)

wherein

R², R³, X and P' are as defined above and L is halo, such as chlorine or bromine, with a compound of formula (IV)

wherein R¹ and n are as defined above.

The reaction is typically carried out under nitrogen in a suitable solvent, such as dioxan and water, in the presence of a base, such as sodium carbonate, and a suitable catalyst, such as tetrakis(triphenylphosphine)palladium(0) or trans dichloro(tricyclohexylphosphine)palladium(l l) at elevated temperature, suitably 100⁰C.

Compounds of formula (I I I) may be prepared by reaction of a compound of formula (V),

wherein R², X and L are as defined above, with a compound of formula (Vl)

wherein

R³ and P' are as defined above and R⁶ is C_h alky!.

The reaction is typically carried out by adding a solution of compound (Vl) in a suitable solvent (for example anhydrous tetrahydrofuran; adding dropwise under nitrogen at -15⁰C) to a solution of compound (V) in a suitable solvent (for example anhydrous tetrahydrofuran) followed by stirring at room temperature, suitably for between 4 to 24 hours.

Compounds of formula (V) are either commercially available or are prepared from compounds of formula (VII)

wherein R², X and L are as defined above and L' is a halogen atom, such as chlorine or bromine. Compounds of formula (IV), formula (VII) and formula (Vl) are either commercially available or can be readily prepared using known methodology.

Compounds of formula (IB) wherein Z represents the pyrrole group as defined above can be prepared by deprotection of a compound of formula (NB) (similarly to that described previously for the compound of formula (II)):

wherein

R¹, R², R⁴, X, and n are as defined above and P represents a carboxylic acid protecting group, for example C_1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.

Compounds of formula (NB) may be prepared by reaction of a compound of formula (NIB)

wherein

R², R⁴, X and P' are as defined above and L is halo, such as chlorine or bromine, with a compound of formula (VIII) wherein R⁴ is defined above.

The reaction is typically carried out under nitrogen in a suitable solvent, such as dioxane and water, in the presence of a base, such as tripotasium phosphate or sodium carbonate, and a suitable catalyst, such as [1 ,1 '-Bis(diphenylphosphino)ferrocene] dichloropalladium(ll) or tetrakis(triphenylphosphine)palladium(0) at elevated temperature, suitably 100⁰C up to 150⁰C. Compounds of formula (HIB) may be prepared by reaction of a compound of formula (VII), wherein R², X and L are as defined above and L' is a halogen atom, such as chlorine or bromine, with a compound of formula (VIII) wherein R⁴ and P' are as defined above.

The reaction is typically carried out in a suitable solvent, such as DMF, in the presence of a base, such as sodium carbonate or cesium carbonate, at elevated temperature, suitably 100⁰C up to 130⁰C.

Compounds of formula (IC) wherein Z represents the thiophene group and X represents CH as defined above can be prepared by reaction of 5-carboxy-thiophene-2-boronic acid with a compound of formula (NIC). The reaction is typically carried out under nitrogen in a suitable solvent, such as dimethoxyethane and water, in the presence of a base, such as sodium carbonate and a suitable catalyst, such as tetrakis(triphenylphosphine) palladium(O) at elevated temperature, suitably 100⁰C.

Compounds of formula (ID) wherein Z represents the thiophene group, X is N and R² is H can be prepared by deprotection of a compound of formula (ND)

wherein R¹ and n are as defined above and P represents a carboxylic acid protecting group, for example Ci_s alkyl, such that together with the carboxylic acid residue an ester is formed. Compounds of formula (ND) may be prepared by reaction of compounds of formula (IX), lic acid protecting group, for example Ci_-6 alkyl,

with a compound of formula (X), wherein R¹ and n are as defined above.

Compounds of formula (IX) are first treated with dimethylformamide dimethylacetal at 100⁰C, the resulting enaminone was then reacted with compounds of formula (X) in a suitable solvent, such as ethanol, in the presence of sodium ethylate at elevated temperature, suitably 8O⁰C.

Compounds of formula (IE) wherein Z represents the phenoxy group as defined above can be prepared by deprotection of a compound of formula (NE) (similarly to that described previously for the compound of formula (II)):

wherein R¹, R², X, and n are as defined above and P represents a carboxylic acid protecting group, for example C_1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed.

Compounds of formula (NE) may be prepared by reaction of a compound of formula (NIE), wherein R², X and L are as defined above and L is a halogen atom, such as chlorine or bromine, with a compound of formula (IV) wherein R¹ and n are as defined above.

Compounds of formula (NIE) may be prepared by reaction of a compound of formula (Xl), wherein P is defined above, with a compound of formula (VII) wherein R², X and L are as defined above and L' is a halogen atom, such as chlorine or bromine.

The reaction is typically carried out in a suitable solvent, such as dimethylformamide, in the presence of a base, such as cesium carbonate, at elevated temperature, suitably 12O⁰C.

Compounds of formula (IF) wherein X represents CH and Z represents the piperidinyl group as defined above can be prepared by deprotection of a compound of formula (NF) (similarly to that described previously for the compound of formula (II)):

wherein

R¹, R² and n are as defined above, and P represents a carboxylic acid protecting group, for example C_1-6 alkyl or benzyl, such that together with the carboxylic acid residue an ester is formed. Compounds of formula (NF) can be prepared by reaction of compounds of formula (IMF) wherein R², L and P are defined above, with a compound of formula (IV) wherein R¹ and n are as defined above.

Compounds of formula (IMF) may be prepared by reaction of a compound of formula (XIII), wherein P is defined above, with a compound of formula (VII) wherein X represents CH, and wherein R² and L are as defined above and L' is a halogen atom, such as chlorine or bromine.

Supporting Examples and Descriptions

The invention is illustrated by the Examples described below.

In the procedures that follow, after each starting material, reference to a Description by number is typically provided. This is provided merely for assistance to the skilled chemist. The starting material may not necessarily have been prepared from the batch referred to.

Where reference is made to the use of a "similar" procedure, as will be appreciated by those skilled in the art, such a procedure may involve variations known to those skilled in the art, for example reaction temperature, reagent/solvent amount, reaction time, work-up conditions or chromatographic purification conditions.

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

LCMS (Liquid Chromatography Mass Spectroscopy) Method A: LCMS was conducted using a Waters ZQ mass spectrometer operating in positive ion or negative ion electrospray mode, mass range 100-1000 amu. UV wavelength: 215- 330nm; column: 3.3cm x 4.6mm ID, 3μm ABZ+PLUS; flow rate: 3ml/min; injection volume: 5μl. Solvent A: 95% acetonitrile + 5% of a 1% v/v solution of formic acid in water. Solvent B: 0.1% v/v solution of formic acid in 1 OmM aqueous ammonium acetate. Gradient: mixtures of Solvent A and Solvent B are used according to the following gradient profiles (expressed as % Solvent A in the mixture): 0% A/0.7min, 0-100% A/3.5min, 100% A/1.1 min, 100-0% A/0.2min.

For mass directed automated preparation, the preparative column used was typically a Supelcosil ABZplus (10cm x 2.12cm internal diameter; particle size 5μm); UV detection wavelength: 200-320nm; flow rate: 20ml/min; injection volume: 0.5ml. Solvent A: 0.1% v/v solution of formic acid in water. Solvent B: 95% acetonitrile + 5% of a 1 % v/v solution of formic acid in water

Method B : 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 HPLC was conducted on a X-terra MS C18 column (3 x 30 mm internal diameter, particule size 2,5 μm), eluting with 0,01 M ammonium acetate in water (solvent A) and 100% acetonitrile using the following elution gradient: 0-4 minutes, 5 to 100% B; 4-5 minutes, 100%B at a flow rate of 1 ,1 mL/min at 40⁰C.

LC-HRMS (Liquid Chromatography - High-resolution mass spectroscopy) Analytical HPLC was conducted on a LUNA 3u C18 column (30 x 3 mm internal diameter, particule size 2,5 μm). 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 to 100%B; 3,5-4 minutes, 100%B; 4-4,5 minutes, 100 to 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.

Proton Magnetic Resonance (¹H NMR) spectra were recorded using a Brucker DPX 400MHz spectrometer. 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:

Description 1 : 6-Hvdroxy-4-methyl-2(1H)-pyridinone hydrochloride (D1)

Cone, HCI, Δ

6-Hydroxy-4-methyl-2-oxo-1 ,2-dihydro-3-pyridinecarbonitrile (Aldrich, 5g, 33.31 mmol) was stirred and heated under reflux in concentrated hydrochloric acid (60ml) for 5 days. A further quantity (150ml) of acid was added and heating was continued for a further 7 days. The mixture was evaporated to give the title compound (8.287g) as a pale brown solid. LCMS (method A): single peak, Rt = 0.75mins; MH⁺ 126 (free base). Description 2: 2, 6-Dibromo-4-methylpyridine (D2)

θ-Hydroxy^-methyl^-oxo-i ^-dihydro-S-pyridinecarbonitrile hydrochloride (D1 , 5g, 30.94mmol) and phosphorus oxybromide (25g, 87.2mmol) were heated together at 13O⁰C for 6 hours. The mixture was cooled in ice and water was added cautiously and the mixture was then basified with 2M sodium hydroxide solution and extracted with dichloromethane. The organic phase was separated and evaporated to give a pale brown solid. This was purified by silica gel chromatography (CombiFlash Companion, Redisep 8Og silica gel column) eluting with cyclohexane-dichloromethane mixtures (100%-70% cyclohexane). Fractions which contained the major component were combined and evaporated to give the title compound (1.279g, 16%) as a colourless solid. LCMS (method A): single peak, Rt = 3.09mins; MH⁺ 250, 252, 254.

Description 3: 2-Bromo-6-hvdrazino-4-methylpyridine (D3)

2,6-Dibromo-4-methylpyridine (D2, 1.279g, 5.098mmol) was dissolved in anhydrous dimethylsulfoxide (12ml) and stirred at room temperature. Hydrazine monohydrate (0.99ml, 20.39mmol, 4eq.) was added slowly and the mixture was then stirred at room temperature for 3 hours and then at 12O⁰C for 18 hours. The mixture was cooled to room temperature and poured into water and the resulting precipitate was collected by filtration, washed with water and dried to give the title compound (881 mg, 85%) as a beige coloured solid. LCMS (method A): major peak, Rt = 1.60mins; MH⁺ 202, 204. Description 4: Ethyl (2£/Z)-3-r2-(6-bromo-4-methyl-2-pyridinyl)hvdrazino1-2-

(trifluoroacetyl)-2-propenoate (D4)

A solution of ethyl 2-(ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (Aldrich, 1.047g, 4.36mmol, 0.85ml) in anhydrous tetrahydrofuran (11 ml) was added dropwise, under nitrogen, to a stirred solution of 6-bromo-4-methyl-2(1 H)-pyridinone hydrazone (D3, 881 mg, 4.36mmol) at -15⁰C. When the addition was complete the solution was allowed to attain room temperature and stirred for 4 hours. The mixture was evaporated under reduced pressure to give the title compound as an orange-brown oil. LCMS (method A): 2 peaks, Rt = 3.51 mins and 3.54mins; MH⁺ 396, 398 (1^st peak), MH⁺ 396, 398 (2^nd peak).

Description 5: 2-Bromo-6-hvdrazinopyridine (D5)

A mixture of 2,6-dibromopyridine (Aldrich; 2.37g, 0.01 mol) and hydrazine hydrate (0.53 ml) in ethanol (50 ml) was heated at 80⁰C for 2 hours. A further portion of hydrazine hydrate (2.65 ml) was added and the mixture was heated under reflux for 4 days. The reaction was evaporated to give a cream solid. This was purified by chromatography on silica (isolute 5Og) using dichloromethane-ethanol-ammonia (300:8:1 ) as eluant. Appropriate eluates were collected and evaporated to a pale cream solid. Crystallisation from ethyl acetate- cyclohexane gave the title compound as a white fluffy solid (1.5g, 80%). LCMS (method A): Rt = 0.68 mins; MH⁺ 188, 190 Description 6: Ethyl 1-(6-bromo-2-pyridinyl)-5-(trifluoromethyl)-1H-pyrazole-4- carboxylate (D6)

Ethyl (2Z)-3-(ethyloxy)-2-(trifluoroacetyl)-2-propenoate (Aldrich, 1.32g, 0.0055 mol) was added in a solution of ethanol (25 ml) to a solution of 2-bromo-6-hydrazinopyridine (D5, 0.94g, 0.005 mol) in ethanol (25 ml) containing diisopropylethylamine (0.92 ml, 0.0055 mol) at -2O⁰C over a 30 minute period. The solution was allowed to slowly warm to room temperature and stirred for a further 2 hours. The orange solution was evaporated to an orange-red gum. This was purified by chromatography on silica (5Og; lsolute cartridge) using dichloromethane-ethanol-ammonia (1000:8:1 ) as eluant. Appropriate eluates were collected and evaporated to yield the product as a pale yellow oil (1.35g, 74%). This solidified on standing. LCMS (method A): single Peak, Rt = 3.41 mins; MH⁺ 364, 366.

Description 7: Ethyl 1 -r6-(3,4-dichlorophenyl)-2-pyridinyll-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylate (D7)

A mixture of ethyl 1-(6-bromo-2-pyridinyl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (D6, 0.364g, 0.001 mol), 3,4-dichlorophenyl boronic acid (0.209g, 0.0011 mol), sodium carbonate (0.106g, 0.001 mol) and tetrakis triphenylphosphine palladium (0.057g, 0.00005 mol) in degassed dioxan (10 ml) and water (10 ml) was heated at 100⁰C for 2 hrs. The dark mixture was poured into ethyl acetate (50 ml) and brine (50 ml). The organic phase was dried (Na₂SO₄) and evaporated to a yellow-brown gum. This was purified on silica (5Og; lsolute cartridge) using dichloromethane-ethanol-ammonia (1000:8:1 ) as eluant. Appropriate eluates were collected and evaporated to yield the title compound as a white solid (0.42g, 97%). LCMS (method A): Rt= 4.13 mins; MH⁺ 430, 432, 434. Description 8: Ethyl 1 -(6-chloro-2-pyridinyl)-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylate (D8)

A solution of Ethyl (2Z)-3-(ethyloxy)-2-(trifluoroacetyl)-2-propenoate (Aldrich,1.2g, 0.005 mol) in dry tetrahydrofuran (10ml) was added to a solution of 2-chloro-6-hydrazinopyridine (Bionet Research Intermediates, 0.715g, 0.005 mol) in dry tetrahydrofuran (10ml) at -2O⁰C over 15 minutes. When the addition was complete, the solution was allowed to slowly warm to room temperature. After 2 hours, the solution was evaporated and the residue was purified by chromatography on silica (5Og; lsolute cartridge) using dichloromethane-ethanol-ammonia (1000:8:1 ) as eluant. Appropriate eluates were collected and evaporated to give a pale- yellow oil (1.35g, 85%). Crystallisation from 40-60 petrol gave the title compound as a white powder (1.1g). LCMS (method A): single peak, Rt = 3.38 mins; MH⁺ 320, 322.

Description 9: Ethyl 1 -(6-bromo-4-methyl-2-pyridinyl)-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylate (D9)

p-toluenesulfonic acid

toluene, Δ

Ethyl (2£/Z)-3-[2-(6-bromo-4-methyl-2-pyridinyl)hydrazino]-2-(trifluoroacetyl)-2-propenoate (D4, 1.611g, 4.066mmol) and p-tolenesulfonic acid monohydrate (30mg) were stirred and heated under reflux in anhydrous toluene (20ml) for 18 hours. The mixture was diluted with toluene and poured into saturated sodium hydrogen carbonate solution and the mixture stirred. The organic phase was separated, dried (MgSO₄) and evaporated to give the title compound (1.225g) as a brown oil. LCMS (method A): single peak, Rt = 3.49 mins; MH⁺ 378, 380. Description 10: Ethyl 1-(6-chloropyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D10)

To a solution of 2,6-dichloropyridine (Aldrich, 1.257g, 8.5 mmol) in DMF (50ml) was added cesium carbonate (2.34g, 7.18 mmol) and then ethyl 2-methyl-pyrrole-3-carboxylate (1g,

6.53 mmol). The mixture was heated at 130⁰C for 24 hours , then cooled and poured into water. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH₂CI₂/cHex,

3/2 then 4/1 ) to give the titled compound as a colorless oil which crystallised (0.55g, 31.8%); LC/MS (method B): Rt= 3.30 min; MH+ 265.1.

H¹ NMR (300MHz, CDCI₃, ppm): 7.8 (t, 1 H), 7.35 (d, 1 H), 7.25 (d, 1 H), 6.95 (d, 1 H), 6.7 (d, 1 H), 4.3 (q, 2H), 2.7 (s, 3H), 1.4 (t, 3H).

Using a similar procedure to that of Description 10, the following compound was prepared:

Description 11 : Ethyl i-fG-chloropyridin-Σ-vD-pyrrole-S-carboxylate (D11)

H¹ NMR (300MHz, CDCI₃, ppm): 8.1 (s, 1 H), 7.75 (t, 1 H), 7.45 (d, 1 H), 7.3 (d, 1 H), 7.2 (d, 1 H), 6.75 (d, 1 H), 4.35 (q, 2H), 1.4 (t, 3H)

Description 12: Ethyl 1-(6-chloropyridin-2-yl)-piperidine-4-carboxylate (D12)

To a solution of 2,6-dichloropyridine (Aldrich, 4g, 27.03mmol) in EtOH (50ml) was added ethyl piperidine-4-carboxylate (Emka-Chemie, 10.41 ml, 67.57 mmol) . The mixture was heated under reflux for 24 hours and then poured into water. . After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography (CH₂CI₂/cHex, 3/2 then 4/1 ) to give the titled compound as a colorless oil (3.93g, 54.15%). LC/MS (method B): Rt= 3.54 min; MH⁺ 269.1 ; H¹ NMR (300MHz, CDCI₃, ppm): 7.3 (t, 1 H), 6.5 (d, 1 H), 6.4 (d, 1 H), 4.05 (m, 4H), 2.9 (m, 2H), 2.45 (m, 1 H), 1.9 (m, 2H), 1.7 (m, 2H), 1.2 (t, 3H).

Description 13: 6-chloro-2-(3-trifluoromethylphenyl)-pyridine (D13)

To a solution of 2,6-dichloropyridine (Aldrich, 2g, 13.5mmol) in DME (30ml) were added Pd(PPh₃)₄ (1.56g, 1.35mmol), then 3-trifluoromethylphenylboronic acid (3.85g, 20.27mmol) and Na₂CO₃ (13.5ml of a solution 2M, 27mmol) and the mixture was heated at 105⁰C for 18 hours. After cooling, the mixture was poured into water. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄), and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient CH₂CI₂/cHex, 3/7 to CH₂CI₂ 100%) to give the titled compound as a colorless oil (1.31g, 37.7%). LC/MS (method B): Rt= 3.68 min; MH⁺ 258.16 .

Description 14: Ethyl-1 -(6-(3,4-dichlorophenyl)-pyridin-2-yl)-2-methyl-pyrrole-3- carboxylate (D14)

PdCI₂(dppf)-CH₂CI₂-adduct microwave (100W)

To a solution of intermediate ethyl 1-(6-chloropyridin-2-yl)-2-methyl-pyrrole-3-carboxylate (D10, 0.3g, 1.13mmol) in 1 ,4-dioxane (10ml), were added 3,4-dichlorophenylboronic acid (0.324g, 1.7mmol), potassium phosphate tribasic (0.481 g, 2.267mmol) in water (2ml) and PdCI₂(dppf)-CH₂CI₂-adduct (0.093g, 0.1 13mmol). The mixture was heated under microwave (100W) for 40 minutes. The mixture was then filtered over celite, and the filtrate was extracted with EtOAc/H₂O, the organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH₂CI₂). The title compound was obtained as white powder (0.195g, yield= 45.9%). H¹ NMR ( CDCI₃, ppm): 8.1 (s, 1 H), 7.85 (m, 2H), 7.65 (d, 1 H), 7.45 (d, 1 H), 7.2 (d, 1 H), 6.9 (d, 1 H), 6.65 (d, 1 H), 4.25 (q, 2H), 2.7 (s, 3H), 1.3 (t, 3H)

Description 15: Ethyl-1-(6-(3.4-dichlorophenyl)-pyridin-2-yl)-piperidine-4-carboxylate (D15)

To a solution of ethyl 1-(6-chloropyridin-2-yl)-piperidine-4-carboxylate (D12, 0.5g, 1.86mmol) in DME (20ml) and water (2ml) were added Pd(PPh₃)₄ (0.215g, 0.186mmol), then 3,4- dichlorophenylboronic acid (0.355g, 1.86mmol) and Cs₂CO₃ (0.606g, 1.86 mmol) and the mixture was heated at 100⁰C for 18 hours . 3,4-dichlorophenylboronic acid (0.177g,

0.93mmol) and Pd(PhP₃)₄ (0.215g, 0.186mmol) were added and the mixture was heated at

100⁰C for 18 hours. After cooling, the mixture was poured into water. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄), and concentrated under reduced pressure.

The residue was purified by flash chromatography (gradient CH₂CI₂/cHex, 3/7 to

CH₂CI₂ 100%) to give the titled compound as a colorless gum (0.14g, 19.8%). LC/MS

(method B) Rt= 4.37 min; MH⁺ 379.1. H¹ NMR (300MHz, CDCI₃, ppm): 8.05 (s, 1 H), 7.75 (d,

1 H), 7.45 (d, 1 H), 7.4 (t, 1 H), 6.95 (d, 1 H), 6.6 (d, 1 H), 4.25 (Id, 2H), 4.05 (q, 2H), 2.95 (t, 2H), 2.5 (m, 1 H), 1.95 (m, 2H), 1.75 (m, 2H), 1.25 (t, 3H)

Description 16: 2-Chloro-4-hvdrazinopyrimidine (D16A) and 4-chloro-2- hydrazinopyrimidine (D16B)

2,4-Dichloropyrimidine (Aldrich, 4.47g, 30mmol), triethylamine (6.06g,60mmol, 8.34ml) and hydrazine monohydrate (1.507g, 30mmol, 1.46ml) were stirred in ethanol (60ml) at room temperature for 24 hours. The mixture was poured into water and portioned with dichloromethane. The organic extracts were evaporated to give a mixture of the title compounds (986mg) as a colourless solid. LCMS (method A): Single peak, Rt = 0.56 mins; MH⁺ 145. Description 17: Ethyl 1-(2-chloro-4-pyrimidinyl)-5-(trifluoromethyl)-1H- Pyrazole-4-carboxylate (D17)

2. Chromatography

A mixture of 2-chloro-4-hydrazinopyrimidine and 4-chloro-2-hydrazinopyrimidine (D16A and D16B, 2.8g, 0.02mol) was stirred in anhydrous tetrahydrofuran (80ml). Triethylamine (0.022mol, 3ml) was added, followed by the dropwise addition of a solution of ethyl 2- (ethoxymethylene)-4,4,4-trifluoro-3-oxobutyrate (Aldrich, 5g, 0.021 mol). The mixture was stirred at room temperature for 30minut.es and the solution hydrolysed with water. The oragic phase was extracted with dichloromethane, dried over Na₂SO₄ and evaporated. The residue was purified by chromatography on silica gel eluting with (CH₂CI₂ / cHex, 8:2 then CH₂CI₂ 100%) to give the title compound as an oil which crystallizes (2.9g, 45.2%). LCMS (method B): single peak, Rt = 3.27 min; MH⁺ 321

Description 18: Ethyl -5-(2-(3-trifluoromethylphenyl)-pyrimidin-4-yl)-thiophene-2- carboxylate (D18)

A solution of ethyl δ-acetyl-thiophene^-carboxylate (0.5g, 2.52mmol) in DMF.DMA (2ml) was heated at 100⁰C for I hour, then cooled and concentrated under reduced pressure. The solid residue was dissolved in EtOH (20ml). Then 3-trifluoromethylbenzamidine.HCI (Interchim, 0.567g, 2.52mmol) and EtONa (0.206g, 3.03mmol) were added and the mixture was heated at 80⁰C for 16 hours and then poured into water. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography on silica gel (CH₂CI₂). The title compound was obtained as a white solid (0.69g, yield= 72%). LC/MS (method B): Rt= 4.35mins; MH⁺ 379.1 ; H¹ NMR (300MHz, CDCI₃, ppm): 8.86 (d, 1 H), 8.82 (s, 1 H), 8.76 (d, 1 H), 7.85 (d, 1 H), 7.8 (m, 2H), 7.67 (t, 1 H), 7.55 (d, 1 H), 4.42 (q, 2H), 1.45 (t, 3H).

Description 19: Ethyl 4-(6-chloropyridin-2-yloxy)-benzoate (D19)

To a solution of methyl 4-hydroxybenzoate (Aldrich, 1.13g, 7.43mmol) in DMF (30ml) was added Cs₂CO₃ (2.64g, 8.1 1 mmol) and the mixture was stirred at room temperature for 10 minutes. Then 2,6-dichloropyridine (1 g, 6.76mmol) was added and the mixture was heated at 120°C for 3 hours and then poured into water. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄), and concentrated under reduce pressure. The residue was purified by flash chromatography (CH₂CI₂/cHex, 3/2) to give the title compound as a colorless oil (1.2g, 67.4%). LC/MS (method B): Rt= 3.24mins; MH⁺ 264.15 ; H¹ NMR (300MHz, CDCI₃, ppm): 8.1 (d, 2H), 7.7 (t, 1 H), 7.2 (d, 2H), 7.15 (d, 1 H), 6.9 (d, 1 H), 3.95 (s, 3H).

Example 1 : 1 -f6-(3,4-dichlorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid

A mixture of ethyl 1 -[6-(3,4-dichlorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylate (D7, 0.36g, 0.000837mol) and sodium hydroxide (0.067g, 0.00168 mol) in dioxan (2ml) and water (2ml) was stirred at room temperature for 18 hours. The solution was evaporated and the residue was dissolved in DMSO-Water (1 :1 ; 4ml). The solution was applied in 6 runs to mass directed auto preparation. Appropriate fractions were combined and evaporated to give a white solid. Crystallisation from acetonitrile gave the product as a white powder (0.204g, 61 %). LCMS (method A): single Peak, Rt = 4.04 mins; MH⁺ 402, 404, 406. ¹H NMR (d₆-DMSO) δ (ppm) 7.8-7.9 (2H,m), 8.1 (1 H, dd), 8.25-8.37 (4H, m), 1 1.7 (1 H, broad s). Example 2: 1 -f6-f4-(trifluoromethyl)phenvn-2-pyridinyl)-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

Ethyl 1-(6-bromo-2-pyridinyl)-5-(trifluoromethyl)-1/-/-pyrazole-4-carboxylate (D6, 100mg, 0.275mmol) and 4-(trifluoromethyl)phenylboronic acid (Aldrich, 52mg, 0.275mmol) were stirred in dioxan (1.5ml). A solution of sodium carbonate (58mg, 0.549mmol) in water (1.5ml) was added and the solution degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (20mg) was added and the mixture stirred and heated at 100⁰C for 18 hours, under nitrogen. The mixture was cooled to room temperature, filtered and blown dry under nitrogen. The residue was portioned between chloroform and water and the pH adjusted to pH4 with 2M hydrochloric acid. The organic phase was separated and blown down under nitrogen. The residue was purified by mass directed autopreparation and appropriate filtrates were evaporated to give the title compound (46.5mg). LCMS (method A): single peak, Rt = 3.77mins; MH⁺ 402.

Using a similar procedure to that of Example 2, using the appropriately substituted phenylboronic acid (all available from Aldrich with the exception of 4-bromo-3-fluorophenyl boronic acid which is available from Lancaster Synthesis Ltd), the following Examples 3 to 9 were prepared.

Example 3: 1 -f6-(2,3-dichlorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid

LCMS (method A): single peak, Rt = 3.67mins; MH⁺ 402, 404. Example 4: 1 -f6-f3-(trifluoromethyl)phenvn-2-pyridinyl)-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

LCMS (method A): single peak, Rt = 3.73mins; MH⁺ 402.

Example 5: 1 -r6-(3,4-difluorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1H-pyrazole-4- carboxylic acid

LCMS (method A): single peak, Rt = 3.61 mins; MH⁺ 370.

Example 6: 1 -f6-r3.5-bis(trifluoromethyl)phenvn-2-pyridinyl)-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

LCMS (method A): Single peak, Rt = 3.97mins, MH⁺ 470. Example 7: 1 -f6-(3-chloro-4-fluorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

LCMS (method A): single peak, Rt = 3.82mins; MH⁺ 386.

Example 8: 1 -f6-(4-bromo-3-fluorophenyl)-2-pyridinvn-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

LCMS (method A): single peak, Rt = 3.89min; MH⁺ 430, 433.

Example 9: 1 -r6-(3,5-dichlorophenyl)-2-pyridinyll-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid

Pd(CI)₂(P(cyclohexyl)₃)₂

A mixture of ethyl 1-(6-chloro-2-pyridinyl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (D8, 0.16g, 0.0005 mol), 3,5-dichlorobenzene boronic acid (Aldrich, 0.105g, 0.00055 mol), sodium carbonate (0.053g, 0.0005 mol) and the palladium catalyst (0.037g, 0.00005 mol) in degassed dioxan (10 ml) and water (5 ml) was heated under reflux for 2 hours. To the cooled solution was added 2M sodium hydroxide solution (0.75 ml) and the suspension was stirred for 1 hour. The suspension was filtered and the filtrate was evaporated. The residue was purified by mass directed auto preparation and appropriate filtrates were evaporated. Crystallisation from acetonitrile gave the title compound as an off-white powder (0.018g, 9%). LCMS (method A): single peak, Rt = 4.18mins; MH⁺ 402, 404, 406.

Example 10: 1 -f6-(3,4-dichlorophenyl)-4-methyl-2-pyridinvn-5-(trifluoromethyl)-1 H- pyrazole-4-carboxylic acid

Ethyl 1-(6-bromo-4-methyl-2-pyridinyl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (D9, 1.221g, 3.229mmol) and 3,4-dichlorophenylboronic acid (Aldrich, 0.616g, 3.229mmol) were stirred in dioxan (25ml). A solution of sodium carbonate (0.684g, 6.458mmol) in water (20ml) was added and the solution degassed with nitrogen. Tetrakis(triphenylphosphine)palladium (0) (0.2g) was added and the mixture stirred and heated at 100⁰C, under nitrogen, for 18 hours. The mixture was cooled to room temperature, poured into brine and extracted with ethyl acetate. The mixture was filtered and the organic phase was separated, dried (MgSO₄) and evaporated to give a light brown solid (0.924g). A portion (0.09g) of this solid was purified by mass directed autopreparation to give the title compound (0.029g) as a pale brown solid. LCMS (method A): single peak, Rt = 4.26mins, MH⁺ 416, 418.

Example 11 : i-fG-OΛ-dichlorophenvD-pyridin-Σ-vD-pyrrole-S-carboxylic acid

PdCI₂(dppf)-CH₂CI₂-adduct microwave (100W) 2- NaOH

EtOH/H₂O , reflux

To a solution of ethyl 1-(6-chloro-2-pyridinyl)-1 H-pyrrole-3-carboxylate (D1 1 , 0.3g, 1.2mmol) in 1 ,4-dioxane (10ml), were added 3,4-dichlorophenylboronic acid (0.23g, 1.2mmol), potassium phosphate tribasic (0.511g, 2.41 mmol) in water (2ml) and PdCI₂(dppf)-CH₂CI₂- adduct (0.098g, 0.12mmol). The mixture was heated under microwave (100W) for 40 minutes. The mixture was then filtered over celite, and the filtrate was extracted with AcOEtVH₂O, the organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The residue was purified by chromatography on silicagel (CH₂CI₂). The resulting solid was dissolved in EtOH (30ml). A solution 1 N of NaOH (3.2ml) and the mixture was heated under reflux for 18 hours. EtOH was evaporated under reduced pressure and the aquous phase was acidified to pH=6 with a solution 1 N of HCI. The resulting precipitate was filtered, washed with water , then iPr₂O then with hot CH₃CN. The title compound was obtained as an off-white powder (0.08g, yield = 31%). H¹ NMR ( DMSO d6, ppm): 8.4 (s, 1 H), 8.2 (d, 1 H), 7.95 (m, 3H), 7.8 (m, 2H), 7.7 (s, 1 H), 6.55 (s, 1 H); LC-HRMS: Target Mass calculated for C₁₆H₁₀CI₂N₂O₂ :331.0041 (M-H), Found: 331.0056 (M-H), Rt= 2.50 mins.

Example 12: i-fG-OΛ-dichlorophenvD-pyridin-Σ-vD-Σ-methyl-pyrrole-S-carboxylic acid

To a solution of ethyl 1-[6-(3,4-dichlorophenyl)-2-pyridinyl]-2-methyl-1 H-pyrrole-3-carboxylate (D14, 0.19g, 0.506mmol) in EtOH (10ml) was added NaOH ( 2.53ml of a solution 1 N, 2.53mmol) and the mixture was heated under reflux for 18 hours. The EtOH was evaporated under reduced pressure and tha aquous residue was acidified to pH=6 with a solution 1 N of HCI, then extracted with AcOEt. The organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The title compound was obtained as an off-white powder (0.055g, yield= 31.3%). H¹ NMR ( CDCI₃, ppm): 8.2 (s, 1 H), 7.95 (m, 2H), 7.8 (d, 1 H), 7.6 (d, 1 H), 7.35 (d, 1 H), 7.1 (d, 1 H), 6.85 (d, 1 H), 2.8 (s, 3H); LC-HRMS: Target Mass calculated for C₁₇H₁₂CI₂N₂O₂ :345.0198 (M-H), Found: 345.0213 (M-H), Rt= 2.90 mins.

The following Examples were prepared by a similar method as described for Example 12 using the appropriate starting materials:

Example 13 : i-fG-O^-dichlorophenvD-pyridin-Σ-vD-piperidine^-carboxylic acid

H¹ NMR ( CDCI₃, ppm): 8.15 (s, 1 H), 7.85 (d, 1 H), 7.6 (t, 1 H), 7.55 (d, 1 H), 7.05 (d, 1 H), 6.7 (d, 1 H), 4.4 (Id, 2H), 3.1 (t, 2H), 2.65 (m, 1 H), 2.1 (m, 2H), 1.85 (m, 2H) LC-HRMS: Target Mass calculated for C₁₇H₁₆CI₂N₂O₂ :351.0667 (M+H), Found: 351.0682 (M+H), Rt= 2.61 mins. Example 14: 4-(6-(3-trifluoromethylphenyl)-pyridin-2-yloxy)-benzoic acid

H¹ NMR ( DMSO d6, ppm): 8.2 (m, 2H), 8.05 (m, 3H), 7.95 (d, 1 H), 7.8 (d, 1 H), 7.7 (t, 1 H), 7.35 (d, 2H), 7.15 (d, 1 H)

LC-HRMS: Target Mass calculated for Ci₉H₁₂F₃N₁O₃ : 360.0847 (M+H), Found: 360.0861 (M+H), Rt= 2.41 mins.

Example 15: 5-(6-(3-trifluoromethylphenyl)-pyridin-2-yl)-thiophene-2-carboxylic acid

98°C

To a solution of 6-chloro-2-(3-trifluoromethylphenyl)-pyridine (D13,1.31 g, 5mmol) in DME (20ml) were added Pd(PPh₃)₄ (0.59g, 0.5mmol), 5-carboxy-thiophene-2-boronic acid (1.3g, 7.6mmol) and Na₂CO₃ (5.09ml of a solution 2N, lOmmol) and the mixture was heated at 98°C for 48 hours and then poured into water. The aquous phase was washed with CH₂CI₂ and then acidified to pH 5 with a solution of HCI 1 N. After extraction with CH₂CI₂, the organic phase was dried (Na₂SO₄) and concentrated under reduced pressure. The title compound was obtained as a cream solid (0.21 g, 12%). ¹H NMR (300MHz, DMSO d6, ppm): 13.3 (s, 1 H), 8.5 (Is, 2H), 8.07 (m, 3H), 7.93 (d, 1 H), 7.85 (t, 1 H), 7.78 (m, 2H); LC-HRMS: Target Mass calculated for C₁₇H₁₀F₃N₁O₂S₁ : 350.0462 (M+H), Found: 350.0456 (M+H), Rt= 2.25 mins.

Example 16: 1 -r2-(3,4-dichlorophenyl)-4-pyrimidinvn-5-(trifluoromethyl)-1H-pyrazole-4- carboxylic acid

To a solution of ethyl 1-(2-chloro-4-pyrimidinyl)-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylate (D17, 0.32g, 1 mmol) in a mixture of DME (10ml) and EtOH (2ml), were added 3,4- dichlorophenylboronic acid (Aldrich, 1.1 mmol), Pd(PPh₃)₄ (0.035g, 0.03mmol) and a solution of cesium carbonate (0.392g, 1.2mmol) in water (2ml). The reaction mixture was stirred at 7O⁰C for 1 hour. The solvent was evaporated to dryness and the residue was portioned between dichloromethane and water, the organic phase was separated and dried over Na₂SO₄ The resulting residue was treated with sodium hydroxide (solution 1 N, 5ml) in EtOH (10ml) at 70⁰C for 12hours. The solvent was evaporated and the residue was acidified with a solution of HCI N to pH 4-5 to give after filtration the title compound as a beige powder (180mg, 45%). ¹H NMR (300MHz, DMSO d6, ppm): 9.2 (d, 1 H), 8.5 (s, 1 H), 8.45 (s, 1 H), 8.3 (d, 1 H), 8.00 (d, 1 H), 7.85 (d, 1 H).; LC-HRMS: Target Mass calculated for C₁₅H₇CI₂F₃N₄O₂: 369.0366 (M+H), Found: 369.0300 (M+H), Rt= 2.36 mins.

The following Examples were prepared by a similar method as described for Example 16, using the appropriate starting materials:

Example 17: 5-(trifluoromethyl)-1 -{2-r3-(trifluoromethyl)phenvn-4-pyrimidinyl)-1H- pyrazole-4-carboxylic acid

H1 NMR (DMSO d6, ppm): 9.25 (d, 1 H), 8.70 (m, 2H), 8.45 (s, 1 H), 8.0 (m,2H), 7.85 (m, 1 H). LC-HRMS Target Mass calculated for C₁₆H₈F₆N₄O₂: 403.0629 (M+H), Found: 403.0611 (M+H), Rt= 2.29 mins; LC/MS (method B): Rt=2.77 mins; MH⁺ 403 Example 18: 5-(2-(3-trifluoromethylphenyl)-pyrimidin-4-yl)-thiophene-2-carboxylic acid

1 H NMR (300MHz, DMSO d6, ppm): 8.9 (d, 1 H), 8.72 (m, 2H), 8 (d, 1 H), 7.93 (m, 2H), 7.83 (t, 1 H), 7.36 (d, 1 H); LC-HRMS Target Mass calculated for C₁₆H₉F₃N₂O₂S₁: 351.0415 (M+H), Found: 351.0441 (M+H), Rt= 2.19 mins.

Biological Assay The activity of soluble guanylate cyclase (sGC) can be tested in an assay based on measuring the fluorescence polarisation (FP) signal of fluorescently labelled cGMP. FP of this fluorescent molecule increases on interaction with an anti-cGMP antibody as the mobility of the molecule is reduced. Newly produced cGMP displaces this interaction giving rise to a decrease in polarisation and FP signal which can be equated to enzyme activity.

Compounds are incubated with human sGC, anti-cGMP antibody, the GTP substrate and fluorescently labelled cGMP. After a period of one hour the assay is stopped with the addition of EDTA and after a further hour the assay is read.

Assay procedure

Human sGC is thawed and resuspended in assay buffer (10OmM TRIS, 1 OmM MgCI₂, 0.2mM Tween 20, pH7.4, containing 1 :100 dilution of sheep anti-cGMP) to give a final concentration of 1 nM in the well. A substrate solution is prepared containing GTP and 8- fluo-cGMP in de-ionized water to a final concentration of 25μM and 5OnM respectively. Assay plates containing 5μl_ of various test compounds and of a standard agonist (50μM - 5OnM) in 1 % DMSO as 6 point, four fold dilutions across a 96 well plate are used in the assay. The plate also contains 6 wells of DMSO (1%) to produce high control and a cGMP standard curve (14nM to 10μM) to convert FP data to cGMP concentration. 25μl_ of enzyme mix and 20μl of substrate mix described above are added to each well of the plate. Samples are mixed on an orbital shaker and then incubated at room temperature for 1 hour. After this incubation period 5μl of 0.5M EDTA is added to all wells and the plates are incubated for a further hour at room temperature prior to reading the FP signal in an appropriate reader. For data handling FP data are converted to cGMP concentrations and then fitted using ActivityBase software. The activity of a test compound is determined as the pEC500 value which is the concentration able to increase by 5-fold basal cGMP. The compounds of Examples 1 to 18 gave pEC500 values of greater than 5. In an embodiment the compounds of the invention give a pEC500 value of ≥ 5.5 when tested in this assay. In an embodiment the compounds of the invention give a pEC500 value of ≥ 6 when tested in this assay.

The following compounds were also prepared by similar methods to those described above: 1-[6-(2,4-dichlorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; and 1- [2-(4-chlorophenyl)-4-pyrimidinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid. When tested in the assay described above both of these compounds gave pEC500 values of < 5 i.e. below the detectable limit of the assay.

Claims

1. A compound of formula (I)

R² represents hydrogen or C_1-3alkyl;

X represents N or CH; wherein -Z- represents a group selected from:

wherein R³ represents trifluoromethyl or C_1-3alkyl; and R⁴ represents hydrogen, trifluoromethyl or C_1-3alkyl;

with the proviso that where Z represents a thiophene group and X represents N, R² cannot represent C_1-3alkyl;

and when X represents CH, -Z- can additionally represent a group selected from:

2. A compound of formula (I) as defined in claim 1 or a salt thereof wherein n represents 2 and both R¹ groups independently represent halo.

3. A compound of formula (I) as defined in claim 1 or a salt thereof wherein each R¹ independently represents trifluoromethyl.

4. A compound of formula (I) as defined in any one of claims 1 to 3 or a salt thereof wherein X represents CH and R² represents hydrogen or methyl.

5. A compound of formula (I) as defined in any one of claims 1 to 3 or a salt thereof wherein X represents N and R² represents hydrogen.

6. A compound of formula (I) as defined in any one of claims 1 to 5 or a salt thereof wherein R³ represents trifluoromethyl.

7. A compound of formula (I) as defined in any one of claims 1 to 5 or a salt thereof wherein R⁴ represents hydrogen or methyl.

8. A compound of formula (I) as defined in claim 1 selected from: i-tθ-^^-Dichlorophenyl^-pyridinyll-δ-^rifluoromethy^-I H-pyrazole^-carboxylic acid; 1-{6-[4-(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(2,3-Dichlorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; 1-{6-[3-(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

1-[6-(3,4-Difluorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid; 1-{6-[3,5-bis(Trifluoromethyl)phenyl]-2-pyridinyl}-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid;

1-[6-(3-Chloro-4-fluorophenyl)-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4-carboxylic acid;

^^-(S^-Dichlorophenyl^-pyridinyO-S-^rifluoromethyO-I H-pyrazole^-carboxylic acid; 1-[6-(3,4-Dichlorophenyl)-4-methyl-2-pyridinyl]-5-(trifluoromethyl)-1 H-pyrazole-4- carboxylic acid; or a pharmaceutically acceptable salt thereof.

9. A compound of formula (I) as defined in claim 1 selected from: 1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-pyrrole-3-carboxylic acid; 1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-2-methyl-pyrrole-3-carboxylic acid; or a pharmaceutically acceptable salt thereof.

10. A compound of formula (I) as defined in claim 1 selected from: 1-(6-(3,4-dichlorophenyl)-pyridin-2-yl)-piperidine-4-carboxylic acid; 4-(6-(3-trifluoromethylphenyl)-pyridin-2-yloxy)-benzoic acid; 5-(6-(3-trifluoromethylphenyl)-pyridin-2-yl)-thiophene-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

11. A compound of formula (I) as defined in claim 1 selected from: 5-(2-(3-trifluoromethylphenyl)-pyrimidin-4-yl)-thiophene-2-carboxylic acid; ^^(S^-dichlorophenyl^-pyrimidinyO-S-^rifluoromethyO-I H-pyrazole^-carboxylic acid; 5-(trifluoromethyl)-1-{2-[3-(trifluoromethyl)phenyl]-4-pyrimidinyl}-1 H-pyrazole-4- carboxylic acid; or a pharmaceutically acceptable salt thereof.

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

13. A compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for use in therapy.

14. A pharmaceutical composition as claimed in claim 12 for use in therapy.

15. A compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 12, for use in the treatment of a disease or condition mediated by the activity of sGC.

16. A compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 12, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

17. A compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition as defined in claim 12, for use in the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.

18. Use of a compound of formula (I) as defined in any one of claims 1 to 11 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 defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis.

20. Use of a compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure or peripheral vascular disease.

21. A method of treatment of a disease or condition mediated by the activity of sGC comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof, or of a pharmaceutical composition as claimed in claim 12.

22. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, cardiac ischemia, myocardial infarction, congestive heart failure, cardiac hypertrophy, acute coronary syndrome, atherosclerosis, peripheral vascular disease, cardiorenal syndrome, hepatorenal syndrome or restenosis comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition as claimed in claim 12.

23. A method of treatment of arterial hypertension, pulmonary arterial hypertension, angina, congestive heart failure, or peripheral vascular disease comprising administration to a human subject in need of such treatment of a therapeutically effective amount of a compound of formula (I) as defined in any one of claims 1 to 1 1 or a pharmaceutically acceptable salt thereof or of a pharmaceutical composition as claimed in claim 12.