HK1233250A1 - New pyridinyloxy- and phenyloxy-pyrazolyl compounds - Google Patents

Description

novel pyridyloxy-and phenyloxy-pyrazolyl compounds

The present invention relates to organic compounds useful for the treatment or prevention in mammals, and in particular to aldosterone synthase inhibitors useful for the treatment or prevention of chronic kidney disease (chronic kidney disease), congestive heart failure (congestive heart failure), hypertension (hypertension), primary aldosteronism (primary aldosteronism) and Cushing syndrom.

The present invention provides novel compounds of formula (I)

Wherein

R¹Is substituted phenyl or substituted pyridyl, wherein substituted phenyl and substituted pyridyl are substituted with one to three substituents independently selected from cyano, halogen, haloalkyl, alkoxy, and alkyl;

R²is a ring system selected from the group consisting of groups A, B, C, D, E, F, G and H.

R³And R⁷Independently selected from the group consisting of H, alkyl, alkoxy, halo, haloalkoxy, carboxy, alkoxycarbonyl, substituted phenylalkoxy, substituted heteroarylalkoxy, substituted heteroarylalkyl, substituted heteroaryloxyalkyl, and substituted heterocycloalkoxy, wherein substituted phenylalkoxy, substituted heteroarylalkoxy, substituted heteroarylalkyl, substituted heteroaryloxyalkyl, and substituted heterocycloalkoxy are substituted with one to three substituents independently selected from the group consisting of H, alkyl, and halo;

R⁴is H, hydroxy, hydroxyalkyl, alkoxy, alkoxycarbonyl, halogen, phenylalkoxy, heterocycloalkylcarbonyl substituted with one to three substituents independently selected from H, alkylcarbonylalkylsulfonyl and hydroxyalkyl, heteroarylalkoxy substituted with one to three substituents independently selected from H, alkyl and halogen, heteroaryloxyalkyl substituted with one to three substituents independently selected from H and halogen, heteroarylalkyl substituted with one to three substituents independently selected from H and hydroxy, heterocycloalkoxy substituted with one to three substituents independently selected from H and alkylcarbonyl, or heterocycloalkylalkyl substituted with one to three substituents independently selected from H, halogen and hydroxyalkyl;

R⁶is H or halogen;

R⁵is H, halogen, alkoxy, alkylsulfonyl, alkylthio or haloalkyl；

R⁸Is alkyl or phenylalkyl;

R⁹is H, alkylcarbonyl or heteroarylcarbonyl substituted with one to three substituents independently selected from H and alkyl;

n is 0, 1 or 2;

and pharmaceutically acceptable salts thereof.

The inventors herein describe inhibitors of aldosterone synthase that have the potential to protect against organ/tissue damage caused by absolute or relative excess of aldosterone. Hypertension affects approximately 20% of the adult population in developed countries. In the population over the age of 60, this percentage rises to above 60%. Hypertensive patients show an increased risk of other physiological complications including stroke, myocardial infarction, atrial fibrillation, heart failure, peripheral vascular disease, and renal injury. The renin angiotensin aldosterone system is a pathway that has been linked to hypertension, (blood) mass and salt balance, and more recently to direct contribution to peripheral organ damage at the late stages of heart failure or renal disease. ACE inhibitors and Angiotensin Receptor Blockers (ARBs) have been successfully used to improve the duration and quality of a patient's life. These drugs do not give maximum protection. In a larger number of patients ACE and ARB lead to so-called aldosterone breakthrough, a phenomenon in which aldosterone levels return to pathological levels after first initially dropping. It has been shown that the detrimental effects of unfavorably elevated aldosterone levels (related to salt intake/levels) can be minimized by aldosterone blockade with a mineralocorticoid receptor antagonist. Direct inhibition of aldosterone synthesis is expected to provide even better protection as it will also reduce the non-genomic impact of aldosterone.

The effect of aldosterone on Na/K transport results in increased sodium and water reabsorption and potassium secretion in the kidney. Overall this leads to an increased blood volume and thus to an increased blood pressure. In addition to its role in regulating renal sodium reabsorption, aldosterone can exert deleterious effects on the kidney, heart and vascular system, particularly in "high sodium" conditions. It has been shown that: in this case, aldosterone causes increased oxidative stress, which may ultimately contribute to organ damage. Aldosterone injection into kidney-injured rats (either by high salinity treatment or by unilateral nephrectomy) induced extensive damage to the kidney, including glomerular expansion, podocyte injury, interstitial inflammation, mesangial cell proliferation and fibrosis, which is reflected by proteinuria. More specifically, aldosterone has been shown to increase the expression of the adhesion molecule ICAM-1 in the kidney. ICAM-1 is critically involved in glomerulonephritis. Similarly, aldosterone has been shown to increase the expression of inflammatory cytokines such as the interleukins IL-1b and IL-6, MCP-1 and osteopontin. At the cellular level, it was demonstrated that aldosterone increased the expression of type I collagen mRNA, a mediator of fibrosis, in vascular fibroblasts. Aldosterone also stimulates collagen type IV accumulation in rat mesangial cells and induces plasminogen activator inhibitor-1 (PAI-1) expression in smooth muscle cells. In summary, aldosterone has emerged as a key hormone involved in renal damage. Aldosterone plays an equally important role in mediating cardiovascular risk.

There is a lot of preclinical evidence as follows: MR-antagonists (spironolactone and eplerenone) improve blood pressure, heart and kidney function in various preclinical models.

Recent preclinical studies have highlighted the important contribution of CYP11B2 to cardiovascular and renal morbidity and mortality. The CYP11B2 inhibitor FAD286 and the MR antagonist spironolactone were evaluated in a rat model of chronic kidney disease (high angiotensin II exposure; high salt and mononephrectomy). Angiotensin II and high salinity treatments result in proteinuria, azotemia, renal vascular hypertrophy, glomerular injury, increased PAI-1, and osteopontin mRNA expression, as well as tubulointerstitial fibrosis. Both drugs prevent these renal effects and attenuate hypertrophy of the heart and the inner aorta. Plasma aldosterone decreased after 4 weeks of treatment with FAD286, while spironolactone increased aldosterone at 4 and 8 weeks of treatment. Similarly, only spironolactone, but not FAD286, increased angiotensin II and salinity-stimulated PAI-1mRNA expression in the aorta and heart. In other studies, the CYP11B2 inhibitor FAD286 improved blood pressure and cardiovascular function and structure in rats with experimental heart failure. In the same study, FAD286 was shown to improve kidney function and morphology.

Administration of an orally active CYP11B2 inhibitor, LCI699, to a patient with primary aldosteronism led to the following conclusions: it effectively inhibits CYP11B2 in patients with primary aldosteronism, resulting in significantly lower circulating aldosterone levels, and it corrects hypokalemia and mildly lowers blood pressure. The effect on the glucocorticoid axis is consistent with poor selectivity of the compound and potential inhibition of cortisol synthesis. Taken together, these data support the concept that CYP11B2 inhibitors can reduce undesirably high aldosterone levels. Obtaining good selectivity relative to CYP11B1 is important for the absence of undesirable side effects on the HPA axis and will distinguish different CYP11B2 inhibitors.

The compounds of the invention according to formula (I) are potent inhibitors of CYPB11B2 and exhibit increased selectivity for CYP11B2, in combination with improved metabolic stability, relative to CYP11B 1.

Objects of the present invention are the compounds of formula (I) and their above-mentioned salts and esters and their use as therapeutically active substances, processes for preparing said compounds, intermediates, pharmaceutical compositions, medicaments containing said compounds, their pharmaceutically acceptable salts or esters, the use of said compounds, salts or esters for the treatment or prophylaxis of illnesses, especially for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom, and the use of said compounds, salts or esters for the preparation of medicaments for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The term "alkoxy" denotes a group of formula R '-O-, wherein R' is alkyl. Examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxy groups include methoxy.

The term "alkoxycarbonyl" denotes a group of formula-C (O) -R ', wherein R' is alkoxy. Examples of alkoxycarbonyl groups include groups of the formula-C (O) -R ', wherein R' is methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy and tert-butoxy. Particular alkoxycarbonyl groups are groups of the formula-C (O) -R ', where R' is methoxy or ethoxy.

The term "alkyl" denotes a monovalent straight or branched chain saturated hydrocarbon group of 1 to 12 carbon atoms. In particular embodiments, the alkyl group has from 1 to 7 carbon atoms, and in more particular embodiments from 1 to 4 carbon atoms. Examples of alkyl groups include methyl, ethyl, propyl and isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. A particular alkyl group is methyl.

The term "alkylcarbonyl" denotes a group of formula-c (o) -R ', wherein R' is alkyl. Examples of alkylcarbonyl groups include groups of the formula-c (o) -R ', wherein R' is methyl or ethyl. Particular alkylcarbonyl groups are groups of the formula-c (o) -R ', wherein R' is methyl.

The term "alkylthio" denotes a group of formula R '-S-, wherein R' is alkyl. Examples of alkylthio are radicals in which R' is methyl, ethyl, propyl and isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particular alkylthio groups are those wherein R' is methyl.

The term "alkylsulfonyl" denotes the formula R' -S (O)₂-wherein R' is alkyl. Examples of alkylsulfonyl are groups in which R' is methyl, ethyl, propyl and isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl. Particular alkylsulfonyl groups are those wherein R' is methyl.

The term "carbonyl" denotes the group-C (O) -.

The term "cyano" denotes a-C ≡ N group.

The term "haloalkoxy" denotes an alkoxy group wherein at least one hydrogen atom of the alkoxy group is replaced by the same or different halogen atom. The term "perhaloalkoxy" denotes an alkoxy group wherein all of the hydrogen atoms of the alkoxy group have been replaced by the same or different halogen atoms. Examples of haloalkoxy groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, trifluoromethylethoxy, trifluorodimethylethoxy and pentafluoroethoxy. Particular haloalkoxy groups are difluoromethoxy and trifluoromethoxy. A more particular haloalkoxy group is difluoromethoxy.

The term "haloalkyl" denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group has been replaced by the same or a different halogen atom. The term "perhaloalkyl" denotes an alkyl group wherein all of the hydrogen atoms of the alkyl group have been replaced by the same or different halogen atoms. Examples of the haloalkyl group include a fluoromethyl group, a difluoromethyl group, a trifluoromethyl group, a trifluoroethyl group, a trifluoromethylethyl group and a pentafluoroethyl group. A particular haloalkyl group is trifluoromethyl.

The terms "halogen" and "halo" are used interchangeably herein and denote fluorine, chlorine, bromine, or iodine. Particular halogens are chlorine and fluorine. More particularly halogen is chlorine.

The term "heteroaryl" denotes a mono-or bicyclic ring system of a monovalent aromatic heterocycle of 5 to 12 ring atoms, comprising 1,2,3 or 4 heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of heteroaryl groups include pyrrolyl, furyl, thienyl, imidazolyl, and the like,Oxazolyl, thiazolyl, triazolyl,Oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrazolyl, pyridazinyl, pyrimidinyl, triazinyl, azaRadical diazaBasic group, heteroAzolyl, benzofuranyl, isothiazolyl, benzothienyl, indolyl, isoindolyl, isobenzofuranyl, benzimidazolylAzolyl, benzisoylAzolyl, benzothiazolyl, benzisothiazolyl, benzoOxadiazolyl, benzothiadiazolyl, benzotriazolyl, purinyl, quinolinyl, isoquinolinyl, quinazolinyl, and quinoxalinyl groups. Particular heteroaryl groups are triazolyl, pyrazolyl, imidazolyl, pyridyl and pyrazolyl.

The term "heteroarylalkoxy" denotes an alkoxy group wherein one of the hydrogen atoms of the alkoxy group is replaced by a heteroaryl group. Particular heteroarylalkoxy groups are heteroarylmethoxy groups in which the heteroaryl group is pyrazolyl, triazolyl or pyridyl.

The term "heteroarylalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by an aryl group. A particular heteroarylalkyl group is a heteroarylmethyl group, wherein the heteroaryl group is a pyridonyl group.

The term "heteroarylcarbonyl" denotes a compound of formula-c (o) -R ', wherein R' is heteroaryl. Particular heteroarylcarbonyl groups are groups of the formula-c (o) -R ', wherein R' is pyrazolyl or pyridinyl.

The term "heteroaryloxyalkyl" denotes a radical of formula R '-O-alkyl wherein R' is heteroaryl. Particular heteroaryloxyalkyl radicals are those of the formula R '-O-methyl, where R' is pyridyl.

The term "heterocycloalkanesThe radical "denotes a monovalent saturated or partially unsaturated mono-or bicyclic ring system of 3 to 9 ring atoms, comprising 1,2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. In particular embodiments, heterocycloalkyl is a monovalent saturated monocyclic ring system of 4 to 7 ring atoms, comprising 1,2, or 3 ring heteroatoms selected from N, O and S, the remaining ring atoms being carbon. Examples of monocyclic saturated heterocycloalkyl groups are aziridinyl, oxetanyl, azetidinyl, oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydro-thienyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinyl, morpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl and thiazinanyl (thiazinanyl). An example of a bicyclic saturated heterocycloalkyl is 8-aza-bicyclo [3.2.1]Octyl, quinuclidinyl, 8-oxa-3-aza-bicyclo [3.2.1]Octyl, 9-aza-bicyclo [3.3.1]Nonyl, 3-oxa-9-aza-bicyclo [3.3.1]Nonyl, 3-thia-9-aza-bicyclo [3.3.1]Nonyl and 2, 6-diaza-spiro [3.3]A heptalkyl group. Examples of partially unsaturated heterocycloalkyl are dihydrofuranyl, imidazolinyl, dihydro-Oxazolyl, tetrahydro-pyridyl, or dihydropyranyl. More specific examples of heterocycloalkyl groups are pyrrolidinyl, pyrazolidinyl, imidazolidinyl,oxazolidinyl, isoOxazolidinyl, thiazolidinyl, piperidinyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperazinylMorpholinyl, thiomorpholinyl, 1, 1-dioxo-thiomorpholin-4-yl, azepanyl, diazepanyl, homopiperazinyl, oxazepanyl, thiazinanyl and 2, 6-diaza-spiro [3.3]A heptalkyl group.

The term "heterocycloalkylalkyl" denotes an alkyl group wherein one of the hydrogen atoms of the alkyl group is replaced by a heterocycloalkyl group. A particular heterocycloalkyl alkyl group is heteroarylmethyl, wherein heterocycloalkyl is azetidinyl or morpholinyl.

The term "heterocycloalkylcarbonyl" refers to the formula-C (O) -R ', wherein R' is heterocycloalkyl. Particular heterocycloalkylcarbonyl groups are of the formula-C (O) -R ', where R' is azetidinyl, morpholinyl or piperazinyl.

The term "heterocycloalkoxy" denotes a group of formula R '-O-, wherein R' is heterocycloalkyl. Particular heterocycloalkoxy groups are groups of the formula R '-O-, wherein R' is pyrrolidinyl.

The term "hydroxy" denotes an-OH group.

The term "hydroxyalkyl" denotes an alkyl group wherein at least one hydrogen atom of the alkyl group is replaced by a hydroxyl group. Examples of hydroxyalkyl groups include hydroxymethyl, hydroxyethyl, hydroxypropyl, hydroxymethylpropyl and dihydroxypropyl. A particular example is hydroxymethyl.

The term "phenylalkoxy" denotes an alkoxy group wherein one hydrogen atom of the alkoxy group is replaced by a phenyl group. Examples of phenylalkoxy are phenylmethoxy and phenylethoxy. A particular example of a phenylalkoxy group is phenylmethoxy.

The term "pharmaceutically acceptable salts" refers to those salts that retain the biological effectiveness and properties of the free base or free acid, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, particularly hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by the addition of an inorganic or organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium salts, and the like. Salts derived from organic bases include, but are not limited to, salts of: primary, secondary and tertiary amines, substituted amines, including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Particular pharmaceutically acceptable salts of the compounds of formula (I) are the hydrochloride, mesylate and citrate salts.

By "pharmaceutically acceptable ester" is meant that the compound of formula (I) may be derivatised at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Examples of such compounds include physiologically acceptable and metabolically labile ester derivatives such as methoxymethyl ester, methylthiomethyl ester and pivaloyloxymethyl ester. Furthermore, any physiologically acceptable equivalent of a compound of formula (I) that is similar to the metabolically labile ester and is capable of producing the parent compound of formula (I) in vivo is within the scope of the invention.

The term "protecting group" (PG) denotes a group: in the meaning conventionally associated therewith in synthetic chemistry, a reactive site in a polyfunctional compound is selectively blocked so that a chemical reaction can be selectively carried out at another unprotected reactive site. The protecting group may be removed at an appropriate point in time. Exemplary protecting groups are amino-protecting groups, carboxy-protecting groups or hydroxy-protecting groups. Particular protecting groups are tert-butoxycarbonyl (Boc), benzyloxycarbonyl (Cbz), fluorenylmethoxycarbonyl (Fmoc) and benzyl (Bn). Still more particular protecting groups are tert-butoxycarbonyl (Boc) and fluorenylmethoxycarbonyl (Fmoc). A more specific protecting group is tert-butoxycarbonyl (Boc).

The abbreviation uM denotes micromolar concentration and is equivalent to the marker μ M.

The compounds of the present invention may also be formulated as suchThe compounds contain unnatural proportions of atomic isotopes at one or more atoms. For example, the invention also includes isotopically-labeled variants of the invention, which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the predominant atomic mass or mass number usually found in nature for the atom. All isotopes of any particular atom or element as specifically recited are contemplated within the scope of the compounds of the present invention and uses thereof. Exemplary isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine and iodine, such as²H(“D”)，³H(“T”)，¹¹C，¹³C，¹⁴C，¹³N，¹⁵N，¹⁵O，¹⁷O，¹⁸O，³²P，³³P，³⁵S，¹⁸F，³⁶Cl，¹²³I and¹²⁵I. certain isotopically-labeled compounds of the invention (e.g., with³H or¹⁴C-labeled ones) can be used in compound and/or substrate tissue distribution assays. Tritium-labeled (³H) And carbon-14 (¹⁴C) Isotopes are useful for their ease of preparation and detectability. Further with heavier isotopes such as deuterium (i.e.,²H) substitution may provide certain therapeutic benefits due to better metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and may therefore be preferred in some circumstances. Positron emitting isotopes such as¹⁵O，¹³N，¹¹C, and¹⁸f can be used in Positron Emission Tomography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of the present invention can generally be prepared by following procedures analogous to those disclosed in the schemes and/or in the examples below, by substituting an isotopically labeled reagent for a non-isotopically labeled reagent. In particular, in which one or more H atoms have been replaced²Compounds of formula (I) wherein the H atom is replaced are also embodiments of the present invention.

The compounds of formula (I) may contain several asymmetric centers and may exist as: optically pure enantiomers, mixtures of enantiomers, such as, for example, racemates, optically pure diastereomers, mixtures of diastereomers, diastereomeric racemates or mixtures of diastereomeric racemates.

According to Cahn-Ingold-Prelog Convention, the asymmetric carbon atoms may be in either the "R" or "S" configuration.

Furthermore, embodiments of the present invention are compounds according to formula (I) as described herein and pharmaceutically acceptable salts or esters thereof, in particular, compounds according to formula (I) as described herein and pharmaceutically acceptable salts thereof, more in particular, compounds according to formula (I) as described herein.

Furthermore, a particular embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is¹Is phenyl substituted with one to three substituents independently selected from cyano and halogen.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is a ring system selected from the group consisting of groups A, B, C, D, E and F.

A further particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is a ring system selected from the group consisting of groups A, B and C.

A more particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is²Is a ring system group A.

Furthermore, an embodiment of the invention is a compound according to formula (I) as described herein, wherein n is zero.

Furthermore, an embodiment of the present invention is a compound according to formula (I) as described herein, wherein R is⁷Is H.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is³Is a radical of H, an alkoxy group,halogen, haloalkoxy or heteroarylalkoxy substituted with one to three substituents independently selected from H and alkyl.

Furthermore, a particular embodiment of the present invention is a compound according to formula (I) as described herein, wherein R is⁴Is H, hydroxy, heteroarylalkoxy or heterocycloalkylalkyl.

A further particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁴Is H.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁵Is H.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁶Is H.

Another particular embodiment of the invention are compounds according to formula (I) as described herein, wherein R is⁷Is H.

Another embodiment of the present invention are compounds according to formula (I) as described herein, wherein R is⁹Is heteroarylcarbonyl substituted with one alkyl group.

Particular examples of compounds of formula (I) as described herein are selected from

4- (4-chlorophenoxy) -5- (2, 3-difluorophenyl) -1H-pyrazole;

3- (4-chlorophenyl) -4- (4-methoxyphenoxy) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (4-chlorophenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (2-methoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (2, 4-dimethoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2-chlorophenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (trifluoromethoxy) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (difluoromethoxy) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2-fluorophenyl) -1H-pyrazole;

3- (5-chloro-2-methoxyphenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

5- (4-chloro-2-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- (4-chlorophenoxy) -5- (4-methylsulfonylphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- [4- (trifluoromethyl) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2, 4-difluorophenyl) -1H-pyrazole;

5- (4-methylsulfonylphenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

5- (2-chloro-4-methylthiophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (4-methylsulfonylphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

2-chloro-5- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] pyridine;

5- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -2-methylpyridine;

2- [ [5- (2, 4-dichlorophenyl) -1H-pyrazol-4-yl ] oxy ] -6-fluoropyridine;

2- [ [3- (2, 4-dichlorophenyl) -1H-pyrazol-4-yl ] oxy ] -6-methylpyridine;

5- (2-chlorophenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

4- (4-chloro-2-fluorophenoxy) -5- (2-chlorophenyl) -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chloro-4-methylthiophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (4-chloro-2-fluorophenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -3-fluorobenzonitrile;

4- [ [5- (2, 3-difluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (3-chloro-2-fluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (3-chloro-2-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (3-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

3- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoic acid methyl ester;

5- (2-chloro-3-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (2-chloro-3-fluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (3-phenylmethoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chloropyridin-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

3- [4- (4-cyano-2-fluorophenoxy) -1H-pyrazol-3-yl ] benzoic acid methyl ester;

ethyl 2- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoate;

2- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoic acid;

4- [ [5- (2-phenylmethoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (2-chloro-4-methylsulfonylphenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (2-chloro-4-methylsulfonylphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholine-4-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (4-methylsulfonylpiperazine-1-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [3- (hydroxymethyl) azetidine-1-carbonyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (hydroxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-2-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-3-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (3-methyl-1, 2-)Azol-5-yl) methoxy]Phenyl radical]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile;

4- [ [3- [3- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (2-chloropyridin-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (1-methylpyrazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- (3-pyrrolidin-3-yloxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [3- (1-acetylpyrrolidin-3-yl) oxyphenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (3-butoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (2-methoxyphenyl) ethyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- (1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (pyridine-3-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (pyridine-2-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-methyl-1, 3-thiazol-5-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (1-methylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (1-benzylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (6-fluoropyridin-2-yl) oxymethyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-3-yloxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

1- [ [3- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]Pyridine-1--3-alkoxides;

4- [ [3- [3- [ (4-oxopyridin-1-yl) methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (6-chloropyridin-2-yl) oxymethyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl ] methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholin-4-ylmethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-3-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-2-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (1-methylpyrazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-3-yloxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (4-oxopyridin-1-yl) methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 2-fluoro-3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (2-chloropyridin-4-yl) methoxy ] -2-fluorophenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (piperazin-1-ylmethyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- [ [4- (1-methylpyrazole-4-carbonyl) piperazin-1-yl ] methyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- [ [5- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 3-chloro-2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- (3- (1-nicotinoylpiperidin-3-yl) -1H-pyrazol-4-yloxy) benzonitrile;

and pharmaceutically acceptable salts thereof.

More particular examples of compounds of formula (I) as described herein are selected from

4- (4-chlorophenoxy) -3- (2-methoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (difluoromethoxy) phenyl ] -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -3-fluorobenzonitrile;

4- [ [3- [2- (2-methoxyphenyl) ethyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholin-4-ylmethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 2-fluoro-3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- [ [4- (1-methylpyrazole-4-carbonyl) piperazin-1-yl ] methyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- [ [5- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

and pharmaceutically acceptable salts thereof.

A process for the preparation of a compound of formula (I) as described herein is an object of the present invention.

The preparation of the compounds of formula (I) according to the invention can be carried out sequentially or via convergent routes. The synthesis of the present invention is shown in the following general scheme. The techniques required to carry out the reaction and the purification of the resulting product are known to those skilled in the art. If a mixture of enantiomers or diastereomers is produced during the course of the reaction, these enantiomers or diastereomers may be separated by methods described herein or known to those skilled in the art, such as, for example, chiral chromatography or crystallization. The substituents and symbols used in the following description of the process have the meanings given herein.

The following abbreviations are used herein:

AcOH ═ acetic acid, BOC ═ tert-butoxycarbonyl, BuLi ═ butyllithium, CDI ═ 1, 1-carbonyldiimidazole, DCM ═ dichloromethane, DBU ═ 2,3,4,6,7,8,9, 10-octahydro-pyrimido [1,2-a ] or a salt thereof]Aza derivativesDCE ═ 1, 2-dichloroethane, DIBALH ═ diisobutylaluminum hydride, DCC ═ N, N '-dicyclohexylcarbodiimide, DMA ═ N, N-dimethylacetamide, DMAP ═ 4-dimethylaminopyridine, DMF ═ N, N-dimethylformamide, EDCI ═ N- (3-dimethylaminopropyl) -N' -ethylcarbodiimide hydrochloride, EtOAc ═ ethyl acetate, EtOH ═ ethanol, Et ═ dimethyl carbodiimide₂Diethyl ether, Et₃Triethylamine, eq ═ equivalent, HATU ═ O- (7-azabenzotriazol-1-yl) -1,1,3, 3-tetramethylureaHexafluorophosphate, HPLC ═ high performance liquid chromatography, HOBT ═ 1-hydroxybenzotriazole, Huenig's base ═ iPr₂NEt ═ N-ethyldiisopropylamine, IPC ═ process quality control, LAH ═ lithium aluminum hydride, LDA ═ lithium diisopropylamide, LiBH₄Lithium borohydride, MeOH-methanol, NaBH₃CN, sodium cyanoborohydride, NaBH₄Sodium borohydride, NaI ═ sodium iodide, Red-Al ═ bis (2-methoxyethoxy) sodium aluminum hydride, RT ═ room temperature, TBDMSCl ═ tert-butyldimethylsilyl chloride, TFA ═ trifluoroacetic acid, THF ═ tetrahydrofuran, quant ═ quantitative.

In the presence of an acid, such as, for example, aqueous hydrochloric acid, in a solvent, such as tetrahydrofuran, bisIn an alkane, methanol, ethanol or mixtures thereof, dimethylamino-alkene 1 or hydroxy-alkene compound 2 (scheme 1) is reacted with hydrazine hydrate at elevated temperatures, e.g., about 50 ℃ to the reflux temperature of the solvent, to form pyrazole compound 3 (step a).

Scheme 1

Protected pyrazole compounds 51 bearing triflate, bromine or iodine functionality (scheme 2) with boronic acid or ester compounds 52 or 56 using Suzuki conditions, e.g. in the presence of a catalyst such as tri-o-tolylphosphine/palladium (II) acetate, tetrakis- (triphenylphosphine) -palladium, bis (triphenylphosphine) palladium (II) chloride or dichloro [1,1' -bis (diphenylphosphino) -ferrocene]Palladium (II) (optionally in the form of dichloromethane complex (1: 1)) and in the presence of a base, such as aqueous or non-aqueous potassium phosphate, sodium carbonate or potassium carbonate, in a solvent, such as dimethyl sulfoxide, toluene, ethanol, dimethyl sulfoxideAlkane, tetrahydrofuranOr N, N-dimethylformamide and in an inert atmosphere such as argon or nitrogen at a temperature preferably in the range of room temperature to about 130 c to give pyrazole 54 or 57 (step a).

Scheme 2

X is halogen or OSO₂CF₃

R^2aIs aryl or heteroaryl

R¹⁰¹And R¹⁰²Both of which are OH or, for example, form together with the boron atom to which they are bound

Alternatively, protected pyrazole compound 51 bearing a triflate, bromine or iodine functionality (scheme 2) is reacted with alkyne-1-hydrocarbon compound 53 under Sonagashira reaction conditions with copper (I) iodide and tetrakis- (triphenylphosphine) -palladium (0) in piperidine, upon treatment at room temperature to about 100 ℃, to give alkyne pyrazole compound 55 (step b). Catalytic hydrogenation converts compounds 55 and 57 to pyrazoles 59 and 58 (step c). Subsequent removal of the protecting groups in compounds 54, 58 and 59 gives free pyrazoles 60 and 61 (e.g., treatment with trifluoroacetic acid under microwave conditions at a temperature of about 100 ℃ can be used to remove the p-methoxy-benzyl protecting groups, with bis-benzyl in MeOH at about room temperatureTreatment with 4M HCl in an alkane may be used to remove the THP protecting group, step d).

Scheme 3

X is halogen orOSO₂CF₃

R¹⁰¹And R¹⁰²Both of which are OH or, for example, form together with the boron atom to which they are bound

Hydroxypyrazole 102 may be prepared from pyrazole-boronic acid or ester compounds 101 bearing suitable protecting groups by oxidation with hydrogen peroxide in the presence of an acid such as acetic acid in a solvent such as THF, preferably at about 0 ℃ (step a, scheme 3). Formylation of hydroxypyrazole 102 can be achieved, for example, by reaction with paraformaldehyde, manganese (II) chloride, TEA in a solvent such as acetonitrile at a temperature of about 80 ℃ (step b). Reductive amination with a suitable piperazine derivative at about room temperature using, for example, sodium triacetoxyborohydride, acetic acid in a solvent such as dichloroethane affords the piperazinylmethyl substituted hydroxypyrazole 104 (step c). Reaction of a piperazinylmethyl substituted hydroxypyrazole 104 with a suitable haloaryl compound in the presence of potassium carbonate in a solvent such as N-methylpyrrolidone at elevated temperature (up to 150 ℃) and optionally with microwave radiation to give an aryloxy-pyrazole 105 (step d); alternatively, the aryloxy-pyrazole 105 can be in a solvent such as 1, 4-bisFrom hydroxypyrazole 104 and haloaryl compounds in alkanes in the presence of ketone (I) iodide, potassium carbonate or cesium carbonate, chelating 1, 2-diamino compounds such as N, N' -dimethylethylenediamine or trans-1, 2-diamino-hexane at elevated temperatures, preferably with the aid of microwave heating. Removal of the protecting function affords pyrazole 106 (step e.).

Carbon-linked halo-aromatic, halo-heteroaromatic or halo-heterocyclic compounds 108 (preferably X equals bromine or iodine) can undergo halo-metal exchange when treated with a metal such as magnesium or lithium in a solvent such as tetrahydrofuran at a temperature range of-78 ℃ to 0 ℃, and then reacted with an aldehyde 107 (prepared from hydroxypyrazole 103 as described in step d), preferably at a temperature range of-78 ℃ to room temperature, to give hydroxy compounds 109 (scheme 3, step f). The hydroxyl group in compound 109 can be removed and replaced by hydrogen by, for example, treatment with a reagent such as triethylsilane in a solvent such as trifluoroacetic acid, preferably at 0 ℃ to room temperature, to give pyrazole 110 (step g) and protecting group-removed pyrazole 111 (step h).

Dimethylamino-alkene 1 or hydroxy-alkene compound 2 are known or can be prepared e.g. as described in scheme 4:

scheme 4

X is halogen

R²Is aryl or heteroaryl

Oxirane compound 202 (scheme 4), is known or can be prepared by methods well known in the art, such as, for example, epoxidizing olefin precursor 201 in a solvent such as dichloromethane using m-chloroperbenzoic acid (step a). The appropriate hydroxy-heterocycle is reacted with ethylene oxide 202 in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate or sodium hydride in a solvent such as tetrahydrofuran, dimethyl sulfoxide, N-dimethylformamide or 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU) at a temperature of from room temperature to about 100 ℃ to give adduct 203 (step b). Adduct 203 can be oxidized to ketone compound 206 (oxalyl chloride, dimethyl sulfoxide, triethylamine in dichloromethane at-78 ℃ to room temperature, step c), for example, using Swern conditions. Alternatively, the ketone compound 206 can be derived from the arylacetyl compound 204 by i) at CH₃Partial halogenation of CO (for example by reaction with trimethylphenyl ammonium tribromide in dichloromethane at room temperature), followed by ii) reaction with a suitable hydroxy-heterocycle in the presence of a base such as sodium carbonate, potassium carbonate or cesium carbonate or sodium hydride in a solvent such as tetrahydrofuran, dimethyl sulfoxide, N, N-dimethylformamide or 1, 3-dimethyl-3, 4,5, 6-tetrahydro-2 (1H) -pyrimidinone (DMPU) at a temperature of from room temperature to about 100 ℃ (steps, d, e). Aryloxy-ketone 206i) is reacted with 1, 1-dimethoxy-N, N-dimethyl-methylamine in N, N-dimethylformamide at a temperature of about 50 ℃ to about 180 ℃, preferably under microwave heating to form dimethylamino adduct 1 or ii) is reacted with alkyl formate and a base such as sodium alkylate in an alcoholic solvent at a temperature of about 0 ℃ to room temperature to give hydroxy-alkene compound 2 (step f).

Scheme 5

X is halogen or OSO₂CF₃

R is alkyl

Pyrazole 51 bearing halogen or triflate moieties are known and can be prepared by methods known in the art or as described in scheme 5. Aryloxy-ester compound 251i) is reacted with 1, 1-dimethoxy-N, N-dimethyl-methylamine in N, N-dimethylformamide at a temperature of about 50 ℃ to about 180 ℃, preferably with microwave heating, to form dimethylamino adduct 252 or ii) is reacted with alkyl formate and a base such as sodium alkyl in an alcoholic solvent at a temperature of about 0 ℃ to room temperature to give hydroxy-olefin compound 253 (scheme 5, step a). Dimethylamino-olefin compound 252 or hydroxy-olefin compound 253 is reacted with hydrazine hydrate in the presence of an acid such as, for example, aqueous hydrochloric acid in a solvent such as tetrahydrofuran, dioxaneAn alkane, methanol, ethanol or mixtures thereof, at an elevated temperature, e.g., between about 50 c to the reflux temperature of the solvent, to form pyrazole compound 254 (step b). Introduction of a protecting group, such as a THP group, into pyrazole compound 254 (treatment with 3, 4-dihydro-2H-pyran and p-toluenesulfonic acid monohydrate in DCM at room temperature) affords protected pyrazole 255 (step c). Can be prepared, for example, by treatment with trifluoromethanesulfonic anhydride in DCM in the presence of triethylamine, preferably at room temperature, or in a solvent such as pyridine, preferably at elevated temperatureThe hydroxy-pyrazole 255 is converted to pyrazole 51 bearing a halogen or triflate moiety by phospho-oxychlorination (step d).

Further, an embodiment of the present invention is a method for preparing the compound of formula (I) described above, which comprises reacting a compound of formula (II) or (III) in the presence of hydrazine hydrate;

wherein R is¹And R²Described herein, and n is zero.

In particular, in the presence of an acid, especially aqueous hydrochloric acid, in a solvent such as tetrahydrofuran, bisAlkane, methanol, ethanol or mixtures thereof, at elevated temperature, in particular between about 50 ℃ to the reflux temperature of the solvent.

Furthermore, an object of the present invention are compounds according to formula (I) as described herein for use as therapeutically active substances.

Also, an object of the present invention is a pharmaceutical composition comprising a compound according to formula (I) as described herein and a therapeutically inert carrier.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of diabetic nephropathy.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of renal or cardiac fibrosis.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of chronic kidney disease.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of congestive heart failure.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of hypertension.

The invention also relates to the use of a compound according to formula (I) as described herein for the treatment or prevention of primary aldosteronism.

A particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

Furthermore, a particular embodiment of the present invention is a compound according to formula (I) as described herein for use in the treatment or prevention of diabetic nephropathy.

Another particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of renal or cardiac fibrosis.

Furthermore, a particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of chronic kidney disease.

Furthermore, a particular embodiment of the invention is a compound according to formula (I) as described herein for use in the treatment or prevention of congestive heart failure.

Furthermore, a particular embodiment of the present invention is a compound according to formula (I) as described herein for use in the treatment or prevention of hypertension.

Furthermore, a particular embodiment of the present invention is a compound according to formula (I) as described herein for use in the treatment or prevention of primary aldosteronism.

The invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

The invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of diabetic nephropathy.

The invention also relates to the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of renal or cardiac fibrosis.

Furthermore, an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of chronic kidney disease.

Furthermore, an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of congestive heart failure.

Furthermore, an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of hypertension.

Furthermore, an embodiment of the present invention is the use of a compound according to formula (I) as described herein for the preparation of a medicament for the treatment or prevention of primary aldosteronism.

Furthermore, an object of the present invention is a method for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom, which method comprises administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, an object of the present invention is a method for the treatment or prevention of diabetic nephropathy, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, an object of the present invention is a method for the treatment or prevention of renal or cardiac fibrosis, said method comprising administering an effective amount of a compound according to formula (I) as described herein.

Furthermore, an embodiment of the invention is a method of treating or preventing chronic kidney disease, comprising administering an effective amount of a compound according to formula (I) as described herein.

Further, an embodiment of the invention is a method of treating or preventing congestive heart failure, which method comprises administering an effective amount of a compound according to formula (I) described herein.

Furthermore, an embodiment of the invention is a method of treating or preventing hypertension, comprising administering an effective amount of a compound according to formula (I) described herein.

Furthermore, an embodiment of the invention is a method of treating or preventing primary aldosteronism, comprising administering an effective amount of a compound according to formula (I) as described herein.

Further, an embodiment of the invention is a compound of formula (I) as described herein, prepared according to any one of the methods.

Test program

The inventors herein determined the use of the G-402 cell line as a host cell for ectopic expression (transiently or stably) of an enzyme of the CYP11 family. In particular, the inventors developed stable G-402 cells that ectopically express human CYP11B1, human CYP11B2, human CYP11a1, cynomolgus monkey CYP11B1 or cynomolgus monkey CYP11B2 enzyme activity. Importantly, the established cell line G-402 expressed cofactors (corticotoxin and corticotoxin reductase) important for the activity of the CYP11 family and no relevant enzyme activity of the CYP11 family (compared to H295R cells) was detected in these cells. The G-402 cell line is therefore uniquely suited as a host cell for ectopic expression of enzymes from the CYP11 family.

G-402 cells can be obtained from ATCC (CRL-1440) and originally derived from renal leiomyoma.

The expression plasmid contains the ORF for human/cynomolgus (cyno) CYP11B1 or CYP11B2 under the control of a suitable promoter (CMV-promoter) and a suitable resistance marker (neomycin). The expression plasmid is transfected into G-402 cells using standard techniques, and these cells are then selected for expression of a given resistance marker. Individual cell-clones were then selected and evaluated for exhibiting the desired enzyme activity using 11-deoxycorticosterone (Cyp11B2) or 11-deoxycorticosterol (Cyp11B1) as substrates.

G-402 cells expressing the CYP11 construct were established as described above and maintained in McCoy5a Modified Medium (Medium Modified), ATCC Catalog No. (Catalog No.)30-2007 containing 10% FCS and 400. mu.g/ml G418 (Geneticin)) under an atmosphere of 5% CO 2/95% air at 37 ℃. The cellular enzyme assay was performed in DMEM/F12 medium containing 2.5% charcoal-treated FCS and appropriate concentrations of substrate (0.3-10uM 11-deoxycorticosterone, 11-deoxycorticosterol or corticosterone). For testing enzyme activity, cells were seeded onto 96-well plates and incubated for 16 h. Aliquots of the supernatant were then transferred and analyzed for the concentration of the expected product (aldosterone for CYP11B 2; cortisol for CYP11B 1). The concentrations of these steroids can be determined using HTRF tests from CisBio that analyze aldosterone or cortisol.

Inhibition of the release of the produced steroid can be used as a measure of the individual enzyme inhibition of the test compound added during the cellular enzyme test. The dose-dependent inhibition of enzyme activity by compounds was calculated by plotting the added inhibitor concentration (x-axis) against the measured steroid/product levels (y-axis). Inhibition was then calculated by fitting the following 4-parameter sigmoid function (Morgan-Mercer-flodin (mmf) model) to the raw data points using the least squares method:

where A is the maximum y value, B is the EC50 factor determined using XLFit, C is the minimum y value and D is the slope value.

The maximum value a corresponds to the amount of steroid produced in the absence of inhibitor and the value C corresponds to the amount of steroid detected when the enzyme is completely inhibited.

EC50 values for the compounds claimed herein were determined using the described G402-based test system. Cyp11B2 enzyme activity was measured in the presence of 1 μ M deoxycorticosterone and various amounts of inhibitor; cyp11B1 enzyme activity was measured in the presence of 1 μ M deoxycorticosterol and various amounts of inhibitor.

The compounds of formula (I) and pharmaceutically acceptable salts or esters thereof as described herein have an EC of between 0.000001uM and 1000uM₅₀(CYP11B2) values, particular compounds have an EC between 0.00005uM and 500uM₅₀(CYP11B2) values, more particularly compounds having an EC between 0.0005uM and 50uM₅₀(CYP11B2) values, yet particular compounds have an EC between 0.0005uM and 5uM₅₀(CYP11B2) value. These results have been obtained by using the enzyme test.

The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (e.g. in the form of pharmaceutical preparations). The pharmaceutical preparations can be administered internally, such as orally (for example in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays) or rectally (for example in the form of suppositories). However, administration may also be carried out parenterally, such as intramuscularly or intravenously (e.g. in the form of ampoules).

The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert, inorganic or organic adjuvants for the preparation of tablets, coated tablets, dragees and hard gelatine capsules. As such excipients for tablets, dragees and hard gelatine capsules, lactose, corn starch or derivatives thereof, talc, stearic acid or salts thereof and the like may be used, for example.

Suitable excipients for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid substances and liquid polyols and the like.

Suitable adjuvants for the preparation of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

Suitable excipients for injectable preparations are, for example, water, alcohols, polyols, glycerol, vegetable oils, etc.

Suitable excipients for suppositories are, for example, natural or hardened oils, waxes, fats, semi-solid or liquid polyols, etc.

In addition, the pharmaceutical preparations can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavors, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They may also contain additional therapeutically valuable substances.

The dosage can vary within wide limits and will of course be adapted to the individual requirements in each particular case. In general, in the case of oral administration, the following should be appropriate: a daily dose of about 0.1mg to 20mg/kg body weight, preferably about 0.5mg to 4mg/kg body weight (e.g. about 300 mg/person), is divided into preferably 1-3 individual doses, which may for example consist of the same amount. However, it is clear that the upper limit given herein can be exceeded when the presentation necessitates.

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention of aldosterone-mediated diseases.

The compounds of formula (I) herein, or pharmaceutically acceptable salts and esters thereof, are inhibitors of CYP11B 2. The compounds of formula (I) herein, or pharmaceutically acceptable salts and esters thereof, also exhibit variable inhibition of CYP11B1, but exhibit improved selectivity for CYP11B2 over CYP11B 1. Such compounds may be used for the treatment or prevention of conditions which show excessive cortisol production/levels or both cortisol and aldosterone levels (e.g. Cushing's syndrome, burn trauma patients, depression, post-traumatic stress disorder, chronic stress, adrenocorticotropic adenoma, Cushing's disease (Morbus Cushing)).

According to the present invention, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of cardiovascular disorders (including hypertension and heart failure), vascular disorders, endothelial dysfunction, baroreceptor dysfunction, renal disorders, liver disorders, fibrotic disorders, inflammatory disorders, retinopathy, neuropathy (such as peripheral neuropathy), pain, insulinopathy, edema, depression and the like.

Cardiovascular conditions include congestive heart failure, coronary heart disease, cardiac arrhythmia, arterial fibrillation, cardiac damage, decreased ejection fraction, diastolic and systolic cardiac dysfunction, fibrinoid necrosis of coronary arteries, cardiac fibrosis, hypertrophic cardiomyopathy, impaired arterial compliance, impaired diastolic filling, ischemia, left ventricular hypertrophy, myocardial and vascular fibrosis, myocardial infarction, myocardial necrotic lesions, cardiac arrhythmias, prevention of sudden cardiac death, restenosis, stroke, vascular damage.

Renal conditions include acute and chronic renal failure, nephropathy, end-stage renal disease, diabetic nephropathy, decreased creatinine clearance, decreased glomerular filtration rate, expansion of reticuloendothelial matrix with or without significant hypercytosis, focal thrombosis of glomerular capillaries, global (global) fibrinoid necrosis, glomerulosclerosis, ischemic lesions, malignant nephrosclerosis (e.g., ischemic contraction, microalbuminuria, proteinuria, decreased renal blood flow, renal arteriopathy, swelling and proliferation of the cells within the capillaries (endothelium and mesangium) and/or outside the capillaries (crescents)).

Renal disorders also include glomerulonephritis (e.g., diffuse hyperplasia, focal hyperplasia, mesangial hyperplasia, membranous hyperplasia, minimally-altered membranous glomerulonephritis), lupus nephritis, non-immune basement membrane abnormalities (e.g., Alport syndrome), renal fibrosis, and glomerulosclerosis (e.g., nodular or global and focal segmental glomerulosclerosis).

Liver disorders include, but are not limited to, hepatic steatosis, nonalcoholic steatohepatitis, cirrhosis, hepatic ascites, hepatic congestion, and the like.

Vascular conditions include, but are not limited to, thrombotic vascular disease (e.g., parietal fibroid necrosis, extravasation and fragmentation of red blood cells, and luminal and/or parietal thrombosis), proliferative arterial disease (e.g., thickening of swollen endomysial (myointimal) cells and nodules surrounded by mucinous extracellular matrix), atherosclerosis, decreased vascular compliance (e.g., stiffness, decreased ventricular compliance, and decreased vascular compliance), endothelial dysfunction, and the like.

Inflammatory disorders include, but are not limited to, arthritis (e.g., osteoarthritis), inflammatory airway diseases (e.g., Chronic Obstructive Pulmonary Disease (COPD)), and the like.

Pain includes, but is not limited to, acute pain, chronic pain (e.g., joint pain), and the like.

Edema includes, but is not limited to, edema in peripheral tissues, liver congestion, liver ascites, spleen congestion, respiratory or pulmonary congestion, and the like.

Insulinopathies include, but are not limited to, insulin resistance, type I diabetes, type II diabetes, glucose sensitivity, pre-diabetic conditions, pre-diabetes, syndrome X, and the like.

Fibrotic diseases include, but are not limited to, cardiac and intrarenal fibrosis, renal interstitial fibrosis and liver fibrosis.

Furthermore, compounds of formula (I) as described herein or their pharmaceutically acceptable salts and esters may also be used for the treatment or prevention of cardiovascular disorders selected from the group consisting of: hypertension, heart failure (especially post-myocardial infarction heart failure), left ventricular hypertrophy, and stroke.

In another embodiment, the cardiovascular disorder is hypertension.

In particular embodiments, the cardiovascular disorder is anti-therapeutic hypertension.

In another embodiment, the cardiovascular disorder is heart failure.

In another embodiment, the cardiovascular disorder is left ventricular hypertrophy.

In another embodiment, the cardiovascular disorder is congestive heart failure, more particularly in patients with preserved left ventricular ejection fraction.

In another embodiment, the cardiovascular disorder is stroke.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of renal disorders.

In another embodiment, the renal disorder is nephropathy.

In another embodiment, the renal disorder is autoimmune glomerulonephritis.

In another embodiment, the chronic kidney disease is diabetic nephropathy.

In another embodiment, the fibrotic disorder is renal or cardiac fibrosis.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of type II diabetes.

In another embodiment, the compounds of formula (I) or their pharmaceutically acceptable salts and esters may be used for the treatment or prevention of type I diabetes.

In another embodiment compounds of formula (I) or their pharmaceutically acceptable salts and esters can be used for the treatment or prevention of diabetic nephropathy.

The invention is illustrated below by means of examples, which do not have limiting characteristics.

In the case of the preparation examples which result in a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as, for example, chiral chromatography or crystallization.

Examples

All examples and intermediates were prepared under argon atmosphere if not otherwise stated.

Pyrazoles which carry a hydrogen substituent at either of the two nitrogen atoms and which have no symmetrical substituents at 3 carbon atoms always exist in two tautomeric forms. The structural formulae and names describe either of the two forms.

Intermediate A-1

(Z and/or E) -2- (4-chlorophenoxy) -1- (2, 3-difluorophenyl) -3- (dimethylamino) prop-2-en-1-one

[A]2-bromo-1- (2, 3-difluorophenyl) ethanone

To a solution of 2, 3-difluoroacetophenone (0.6g, 3.84mmol) in DCM (10mL) was added trimethylphenyl ammonium tribromide (1.59g, 4.23mmol) in portions and the reaction mixture was stirred at room temperature overnight. The mixture was diluted with DCM, poured into water (10mL) and the aqueous layer extracted with DCM (2 × 20 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 20% EtOAc-heptane gradient) to give the title compound (0.868g, 96%) as a colorless oil.

[B]2- (4-chlorophenoxy) -1- (2, 3-difluorophenyl) ethanone

To a solution of 2-bromo-1- (2, 3-difluorophenyl) ethanone (0.1g, 0.425mmol) in DMF (1mL) was added 4-chloro-phenol (0.055g, 0.425mmol) followed by K₂CO₃(0.147g, 1.06mmol) and then the reaction mixture was stirred at room temperature for 2.5 h. The mixture was diluted with EtOAc, poured into 1N aqueous HCl (2mL) and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 30% EtOAc-heptane gradient) to give the title compound (0.055g, 44%) as an off-white solid.

[C](Z and/or E) -2- (4-chlorophenoxy) -1- (2, 3-difluorophenyl) -3- (dimethylamino) prop-2-en-1-one- Ketones

In a microwave vial, 2- (4-chlorophenoxy) -1- (2, 3-difluorophenyl) ethanone (0.055g, 0.195mmol) and DMF-DMA (0.046g, 0.389mmol) were dissolved in DMF (1mL) and then the reaction mixture was heated to 80 ℃ under microwave radiation for 15 min. The mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography (eluting with a 10 to 60% EtOAc-heptane gradient) to give the title compound (0.034g, 52%) as an off-white solid. MS:338.1(M + H)⁺)。

In analogy to the procedure described for the preparation of intermediate a-1, by using the appropriate starting materials, the following intermediates listed in table 1 were prepared:

TABLE 1

Intermediate B-1

(rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl ] benzoic acid

[A](rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Benzoic acid methyl ester

To 3- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl group]To a suspension of methyl benzoate (example 33) (0.207g, 0.616mmol) in DCM (10mL) was added 3, 4-dihydro-2H-pyran (0.104g, 1.23mmol) followed by p-toluenesulfonic acid monohydrate (0.023g, 0.123mmol) and the reaction mixture was then stirred at room temperature for 48H. The mixture was diluted with DCM, poured into water (20mL) and the aqueous layer extracted with DCM (2 × 40 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was then purified by silica gel flash chromatography (eluting with a 0 to 40% EtOAc-heptane gradient) to give the title compound (0.215g, 82%) as a pale yellow amorphous solid. MS:404.3(M + H)⁺)。

[B](rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Benzoic acid

To (rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]To a solution of methyl benzoate (0.215g, 0.532mmol) in THF (10 mL)/water (5mL) was added LiOH (0.038g, 1.6mmol) and the reaction mixture was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, poured into 1M aqueous HCl (10mL) and the aqueous layer extracted with EtOAc (2 × 40 mL). The combined organics were washed with brine, over Na₂SO₄Drying, filtration and evaporation to dryness gave the title compound (0.218g, 95%) as a pale yellow amorphous solid. MS 390.3(M + H)⁺)。

Intermediate B-2

(rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl ] trifluoromethanesulfonate

[A]2- (4-Cyanophenoxy) acetic acid ethyl ester

To a solution of 4-hydroxybenzonitrile (0.636g, 5.34mmol) in acetone (10mL) was added K₂CO₃(0.738g, 5.34mmol) followed by the addition of ethyl 2-chloroacetate (0.687g, 5.61mmol) and heating of the reaction mixture at reflux overnight. The solvent was evaporated, the residue taken up in EtOAc, then poured into water (20mL) and the aqueous layer extracted with EtOAc (50 mL). The combined organics were washed with brine, over Na₂SO₄Dry, filter and evaporate to dryness to give the title compound (1.046g, 95%) as a white solid, which was used in the next step without further purification.

[B](E and/or Z) -2- (4-cyanophenoxy) -3-hydroxy-prop-2-enoic acid ethyl ester

To a suspension of 60% NaH (0.245g, 6.12mmol) in THF (3mL) in mineral oil cooled to 0 deg.C (ice bath) was added a solution of ethyl 2- (4-cyanophenoxy) acetate (1.046g, 5.1mmol) and ethyl formate (0.415g, 5.61mmol) in THF (5mL) and the reaction mixture was stirred at room temperature overnight. The mixture was quenched with MeOH (2.5mL) and then evaporated to dryness. The residue was triturated in DCM and the solvent was decantedA viscous solid was obtained. The material was then dissolved in MeOH and evaporated to dryness to give the title compound (1.19g, 95%) as a yellow oil, which was used as the crude mixture in the next step. MS:232.2 (M-H)⁺)。

[C]4- [ (3-hydroxy-1H-pyrazol-4-yl) oxy]Benzonitrile

To a solution of (E and/or Z) -ethyl 2- (4-cyanophenoxy) -3-hydroxy-prop-2-enoate (1.2g, 5.15mmol) in MeOH (15ml) was added hydrazine hydrate (0.309g, 6.17mmol) and the reaction mixture was heated to 65 ℃ for 1 h. The mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 10% MeOH-DCM) to give the title compound (0.637g, 61%) as an orange solid. MS:202.1(M + H)⁺)。

[D](rac) -4- (3-hydroxy-1-tetrahydropyran-2-yl-pyrazol-4-yl) oxybenzonitrile

To 4- [ (3-hydroxy-1H-pyrazol-4-yl) oxy]To a suspension of benzonitrile (0.2g, 0.994mmol) in DCM (10mL) was added p-toluenesulfonic acid monohydrate (0.038g, 0.199mmol), followed by 3, 4-dihydro-2H-pyran (0.1g, 1.19mmol) and the reaction mixture was stirred at room temperature overnight. The solid precipitate was filtered off. Evaporating the mother liquor to dryness; the residue was triturated in DCM, filtered and combined with the first solid precipitate. The two materials were further dried to give the title compound (0.248g, 85%) as a colorless solid. MS:286.2(M + H)⁺)。

[E](rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate ester

To a solution of (rac) -4- (3-hydroxy-1-tetrahydropyran-2-yl-pyrazol-4-yl) oxybenzonitrile (0.115g, 0.403mmol) in DCM (1.5mL) was added TEA (0.061g, 0.605mmol), followed by triflic anhydride (0.125g, 0.443mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, the mixture was diluted with DCM, poured into water (10mL) and the aqueous layer was extracted with DCM (2 × 20 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 30% EtOAc-heptane gradient) to give the title compound (0.153g, 91%) as a colorless oil. 417.1 (M)⁺)。

Intermediate B-3

(rac) -4- [ [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl ] methyl ] piperazine-1-carboxylic acid tert-butyl ester

[A](rac) -1-tetrahydropyran-2-yl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan- 2-yl) pyrazoles

To a solution of 4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole (1g, 5.15mmol) in DCE (25mL) was added pTsOH (0.098g, 0.515mmol) followed by 3, 4-dihydro-2H-pyran (0.867g, 10.3mmol) and the reaction mixture was heated to 40 ℃ for 3H. The mixture was diluted with DCM and saturated NaHCO was poured in₃Solution (50mL) and the aqueous layer was extracted with DCM (2 × 75 mL).The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 60% EtOAc-heptane gradient) to give the title compound (0.818g, 57%) as a colorless solid. MS:279.2(M + H)⁺)。

[B](rac) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol

To a solution of (rac) -1-tetrahydropyran-2-yl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) pyrazole (0.818g, 2.94mmol) in THF (15mL) cooled to 0 deg.C with an ice bath was added acetic acid (0.265g, 4.41mmol) followed by fractional addition of H₂O₂(0.343g, 3.53mmol) while maintaining the temperature below 5 ℃. The reaction mixture was allowed to warm to room temperature and then stirred for 2 h. The mixture was neutralized by addition of concentrated NaOH solution at 0 ℃, and the turbid solution was decanted and evaporated to dryness. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 10% MeOH-DCM) to give the title compound (0.396g, 80%) as a colorless oil. MS:169.1(M + H)⁺)。

[C](rac) -4-hydroxy-1-tetrahydropyran-2-yl-pyrazole-3-carbaldehyde

To a solution of (rac) -1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-4-ol (0.1g, 0.595mmol) in acetonitrile (1mL) was added manganese (II) chloride (0.15g, 1.19mmol) and TEA (0.12g, 1.19mmol), followed by paraformaldehyde (0.054g, 1.78mmol), and the reaction mixture was heated to 80 ℃ for 2H. The mixture was diluted with EtOAc, poured into 1M HCl solution (5mL) and the aqueous layer extracted with EtOAc (2 × 20 mL). The combined organics were passed over Na₂SO₄Dried, filtered and evaporated to dryness to give the title compound (0.045g, 39%) as a pale yellow oil. The crude product was used in the next step without further purification. MS:195.1 (M-H)^-)。

[D](rac) -4- [ (4-hydroxy-1-tetrahydropyran-2-yl-pyrazol-3-yl) methyl]Piperazine-1-carboxylic acid tert-butyl ester Esters

To a solution of (rac) -4-hydroxy-1-tetrahydropyran-2-yl-pyrazole-3-carbaldehyde (0.045g, 0.229mmol) in DCE (1.5mL) was added piperazine-1-carboxylic acid tert-butyl ester (0.064g, 0.344mmol) and acetic acid (0.016g, 0.275 mmol). The reaction mixture was stirred at room temperature for 30min, then sodium triacetoxyborohydride (0.146g, 0.688mmol) was added and stirring continued for 1.5 h. The mixture was diluted with EtOAc and poured into H₂O (10mL) and the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 15% MeOH-DCM) to give the title compound (0.032g, 38%) as a light yellow oil. MS:367.3(M + H)⁺)。

[E](rac) -4- [ [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Methyl radical]Piperazine- 1-Carboxylic acid tert-butyl ester

(rac) -4- [ (4-hydroxy-1-tetrahydropyran-2-yl-pyrazol-3-yl) methyl group in a microwave vial]Piperazine-1-carboxylic acid tert-butyl ester (0.03g, 0.082mmol), 4-fluorobenzonitrile (0.02g, 0.164mmol) and K₂CO₃(0.025g, 0.18mmol) was mixed in NMP (0.6mL) and heated in a microwave at 150 ℃ for 20 min. The reaction was evaporated to dryness. Passing the residue through siliconGel flash chromatography (purification eluting with a 0 to 40% EtOAc-heptane gradient) afforded the title compound (0.012g, 31%) as a colorless oil. MS:468.3(M + H)⁺)。

Example 1

4- (4-chlorophenoxy) -5- (2, 3-difluorophenyl) -1H-pyrazole

To a solution of (Z and/or E) -2- (4-chlorophenoxy) -1- (2, 3-difluorophenyl) -3- (dimethylamino) prop-2-en-1-one (intermediate A-1) (0.034g, 0.101mmol) in EtOH (1mL) was added hydrazine monohydrate (0.01g, 0.201mmol) followed by 4M HCl in bisAn alkane solution (0.028ml, 0.111mmol) was then heated to 65 ℃ for 3 h. The mixture was evaporated to dryness and the residue was purified by preparative HPLC (Gemini NX 3u column, gradient 1% aqueous formic acid/acetonitrile) to give the title compound (0.021g, 68%) as a colorless waxy solid. MS 307.4(M + H)⁺)。

The following examples listed in table 2 were prepared by using the indicated starting materials analogously to the procedure described for the preparation of example 1:

TABLE 2

Example 42

5- (2-chloro-4-methylsulfonylphenyl) -4- (4-chlorophenoxy) -1H-pyrazole

Sodium bicarbonate (0.115g, 1.37mmol) in water (1mL) was added to 5- (2-chloro-4-methylthiophenyl) -4- (4-chlorophenoxy) -1H-pyrazole (example 17) (0.06g, 0.171 mmol) at 0 deg.C (ice bath)) In a solution in acetone (1 mL). A solution of oxone (0.147g, 0.239mmol) in water (1.5mL) was then added dropwise to the mixture while maintaining the temperature below 5 ℃ and stirring at this temperature was continued for 2 h. The mixture was quenched by the addition of 40% sodium bisulfite solution (2mL) at 0 ℃. The resulting suspension was diluted with EtOAc, acidified with 25% aqueous HCl and the resulting aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 100% EtOAc-heptane gradient) to give the title compound (0.036g, 55%) as a colorless amorphous solid. MS:383.3(M + H)⁺)。

Example 43

4- [ [5- (2-chloro-4-methylsulfonylphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

In analogy to the procedure described in example 42, 4- [ [5- (2-chloro-4-methylthiophenyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile (example 26) was oxidized with oxone to give the title compound as a colorless amorphous solid. MS 374.5(M + H)⁺)。

Example 44

4- [ [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl]-1-tetrahydropyran-2-yl-pyrazole- 4-radical]Oxybenzonitrile

To (rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]To a solution of benzoic acid (intermediate B-1) (0.035g, 0.09mmol) in DCM (2mL) was added 1- (piperazin-1-yl) ethanone (0.011g, 0.09mmol), triethylamine (0.027g, 0.27mmol) and TBTU (0.035g, 0.108 mmol). The reaction mixture was then stirred at room temperature for 1.5 h. The mixture was diluted with DCM, poured into water (10mL) and the aqueous layer extracted with DCM (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dry, filter and evaporate to dryness to give the title compound (0.048g) as a yellow oil which was used in the next step without further purification. MS:500.3(M + H)⁺)。

[B]4- [ [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile

To (rac) -4- [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]To a solution of oxybenzonitrile (0.048g, 0.097mmol) in MeOH (1mL) was added 4M HCl bisAlkane solution (0.121mL, 0.483mmol) and the reaction mixture was stirred at rt for 3 h. The mixture was evaporated to dryness and the residue was taken up in saturated NaHCO₃The solution (2mL) was treated and then extracted with EtOAc (2 × 10 mL). Subjecting the organic layer to Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 10% MeOH-DCM) to give the title compound (0.02g, 47%) as a colorless solid. MS 416.3(M + H)⁺)。

In analogy to the procedure described for the preparation of example 44, the following examples listed in table 3 were prepared by coupling (rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl ] benzoic acid (intermediate B-1) with the indicated amine and subsequently removing the THP protecting group.

TABLE 3

Example 48

4- [ [3- (3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- (3-benzyloxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile

Analogously to intermediate B-1[ A]4- [ [5- (3-Phenylmethoxyphenyl) -1H-pyrazol-4-yl ] as described for the preparation of]Oxy radical]Benzonitrile (example 36) was reacted with dihydro-pyran to give the title compound as a pale yellow solid. MS:452.3(M + H)⁺)。

[B](rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile

To (rac) -4- [3- (3-benzyloxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl purged with argon]To a solution of oxybenzonitrile (0.127g, 0.282mmol) in MeOH (20mL) was added 10% Pd/C (0.03g, 0.028 mmol). The reaction mixture is then reacted in H₂Stirring for 2h under atmosphere (balloon). The reaction mixture was filtered through a glass microfiber filter and the filtrate evaporated to dryness. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0% to 40% EtOAc-heptane) to give the title compound as a colourless amorphous solid (0.092g, 86%). MS:362.3(M + H)⁺)。

[C]4- [ [3- (3-hydroxyphenyl) -1H-pyrazol-4-yl ] amino acids]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless solid. MS:278.2(M + H)⁺)。

Example 49

4- [ [3- [3- (hydroxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- [3- (hydroxymethyl) -methyl) Phenyl radical]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxy benzene Nitrile (A) to methyl cyanide

To the cooled to 0 deg.C (ice bath) (rac) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl ester]Benzoic acid (intermediate B-1[ B ]]) (0.053g, 0.123mmol) in THF (1mL) a 1M solution of borane-THF complex in THF (0.247mL, 0.247mmol) was added dropwise and the reaction mixture was stirred at room temperature overnight. The mixture was quenched by slow addition of 1M aqueous HCl (5mL) and extracted with EtOAc (2 × 25 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated to dryness. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0% to 10% MeOH-DCM) to give the title compound (0.048g, 93%) as a light yellow oil. MS:376.3(M + H)⁺)。

[B]4- [ [3- [3- (hydroxymethyl) phenyl group]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- [3- (hydroxymethyl) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a yellow oil. MS:292.2(M + H)⁺)。

Example 50

4- [ [3- [3- (pyridin-2-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- [3- (2-pyridylmethoxy) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl] Oxybenzonitrile

To (rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile (example 48[ B ]]) (0.033g, 0.091mmol) in DMF (1mL) was added 2- (bromomethyl) pyridine hydrobromide (0.023g, 0.091mmol) and K₂CO₃(0.038g, 0.272 mmol). The reaction mixture was then stirred at room temperature for 8 h. The mixture was diluted with EtOAc, poured into 1M aqueous HCl (5mL) and the aqueous layer extracted with EtOAc (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dry, filter and evaporate to dryness to give the title compound (0.047g) as a pale yellow oil, which was used in the next step without further purification. MS:453.3(M + H)⁺)。

[B]4- [ [3- [3- (pyridin-2-ylmethoxy) phenyl ] phenyl]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- [3- (2-pyridylmethoxy) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a yellow solid. MS:369.2(M + H)⁺)。

In analogy to the procedure described for the preparation of example 50, the following examples listed in table 4 were prepared by reacting (rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl ] oxybenzonitrile (example 48[ B ]) with a halo-methyl heterocyclic compound and subsequently with an acid.

TABLE 4

Example 57

(rac) -4- [ [3- (3-pyrrolidin-3-yloxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac, diastereomer) -3- [3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-one- Base of]Phenoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester

To the cooled to 0 deg.C (ice bath) (rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile (example 48[ B ]])(0.1g, 0.277mmol) and tert-butyl 3-hydroxypyrrolidine-1-carboxylate (0.062g, 0.332mmol) in THF (2mL) was added (E) -diazene-1, 2-diylbis (piperidin-1-ylmethanone) (0.14g, 0.553mmol) followed by dropwise addition of tri-n-butylphosphine (0.073g, 0.089 mmol). The reaction mixture was then stirred at room temperature overnight. The mixture was diluted with EtOAc, poured into water (5mL) and the aqueous layer extracted with EtOAc (2 × 20 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated to dryness. The crude material was washed with Et₂Triturate O, filter the solids and evaporate the mother liquor. The residue was purified by silica gel flash chromatography (eluting with a 0% to 100% EtOAc-heptane gradient) to give the title compound (0.043g, 28%) as a yellow oil (two racemic diastereomers). MS:529.5 (M-H)⁺)。

[B](rac) -4- [ [3- (3-pyrrolidin-3-yloxyphenyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac, diastereomer) -3- [3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Phenoxy radical]Pyrrolidine-1-carboxylic acid tert-butyl ester with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless oil. MS:347.2(M + H)⁺)。

Example 58

(rac) -4- [ [3- [3- (1-acetylpyrrolidin-3-yl) oxyphenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

To 4- [ [3- (3-pyrrolidin-3-yloxyphenyl) -1H-pyrazol-4-yl]Oxy radical]To a solution of benzonitrile (example 57) (0.022g, 0.057mmol) in DCM (2mL) was added triethylamine (0.017g, 0.172mmol), acetic acid (0.003g, 0.057mmol) and TBTU (0.022g, 0.069 mmol). The reaction mixture was stirred at room temperature for 1 h. The mixture was then evaporated to dryness, the residue was dissolved in water (5mL) and extracted with EtOAc (2 × 10 mL). The residue was purified by preparative HPLC (Gemini NX 3u column, gradient 1% aqueous formic acid/acetonitrile) to give the title compound (0.012g, 43%) as a colorless amorphous solid. MS:389.3(M + H)⁺)。

Example 59

4- [ [5- (3-butoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- (3-butoxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile

Analogously to example 57[ A ]](rac) -4- [3- (3-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile (example 48[ B ]]) And tert-butyl 3-hydroxyazetidine-1-carboxylate was reacted with (E) -diazen-1, 2-diylbis (piperidin-1-ylmethanone) and tri-n-butylphosphine in THF to give the title compound as a colorless oil. MS:418.4(M + H)⁺)。

[B]4- [ [5- (3-butoxyphenyl) -1H-pyrazol-4-yl ] amino acids]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- (3-butoxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless oil. MS:334.2(M + H)⁺)。

Example 60

4- [ [3- [2- (2-methoxyphenyl) ethyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- [2- (2-methoxyphenyl) ethynyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl] Oxybenzonitrile

(rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl is introduced into a sealed tube]Triflate (intermediate B-2) (0.075g, 0.180mmol), 1-ethynyl-2-methoxybenzene (0.028g, 0.216mmol) and TEA (0.091g, 0.899mmol) were combined in DMF (1.5 mL). Then, bis (triphenylphosphine) palladium (II) chloride (0.013g, 0.018mmol) and ketone (I) iodide (0.007g, 0.036mmol) were added and the reaction mixture was heated to 80 ℃ for 2 h. The mixture was diluted with EtOAc, poured into water (5mL) and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Drying, filtering and evaporating. The residue was purified by silica gel flash chromatography (eluting with a 0 to 40% EtOAc-heptane gradient) to give the title compound (0.01g, 14%) as a colorless oil. MS:316.2(M-THP + H)⁺)。

[B](rac) -4- [3- [2- (2-methoxyphenyl) ethyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxygen gas Cyanobenzene radical

To (rac) -4- [3- [2- (2-methoxyphenyl) ethynyl purged with argon]-1-tetrahydropyran-2-yl-pyrazol-4-yl]To a solution of oxybenzonitrile (0.01g, 0.025mmol) in EtOH (2mL) was added 10% Pd/C (0.003g, 0.0025 mmol). The reaction mixture is then reacted in H₂Stirring for 5h (under balloon). The mixture was diluted with MeOH, filtered through a glass microfiber filter and the filtrate evaporated to dryness to give the title compound (0.007g, 69%) as a yellow oil, which was used in the next step without further purification. MS:404.3(M + H)⁺)。

[C]4- [ [3- [2- (2-methoxyphenyl) ethyl]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) 4- [3- [2- (2-methoxyphenyl) ethyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) was reacted in MeOH to give the title compound as a yellow oil. MS:320.2(M + H)⁺)。

Example 61

(rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -5- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]-3, 6-dihydro- 2H-pyridine-1-carboxylic acid tert-butyl ester

(rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl is introduced into a microwave vial]Triflate (intermediate B-2) (0.125g, 0.3mmol) and 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylic acid tert-butyl ester (0.102g, 0.329mmol) were combined in DMF (2 mL). The vial was purged with argon and then bis (triphenylphosphine) palladium (II) chloride (0.021g, 0.03mmol) and 1M Na were added₂CO₃Aqueous solution (0.749mL, 0.749mmol) and then the reaction mixture was heated to 120 ℃ for 15min under microwave irradiation. The mixture was diluted with EtOAc, poured into water (10mL) and the aqueous layer extracted with EtOAc (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a 0 to 70% EtOAc-heptane gradient) to give the title compound (0.095g, 70%) as a light yellow oil. MS:451.4(M + H)⁺)。

[B](rac, diastereomer) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl] Piperidine-1-carboxylic acid tert-butyl ester

Analogously to example 60[ B ]](rac) -5- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Hydrogenation of tert-butyl-3, 6-dihydro-2H-pyridine-1-carboxylate gave the title compound as a colorless oil. MS:453.4(M + H)⁺)。

[C](rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac, diastereomer) -3- [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Piperidine-1-carboxylic acid tert-butyl ester with HCl (4M bisAlkane solution) in MeOH to give the title compound as a pale yellow oil. MS:269.2(M + H)⁺)。

Example 62

(rac) -4- [ [3- (1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [ 1-acetyl-3- (1-acetyl-3-piperidinyl) pyrazol-4-yl]Oxybenzonitrile

To the cooled to 0 deg.C (ice bath) (rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl group)]Oxy radical]Benzonitrile (example 61) (0.04g, 0.149mmol) in DMF (0.6mL) was added TEA (0.07g, 0.745mmol) followed by acetyl chloride (0.035g, 0.447mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was diluted in EtOAc and poured into H₂O (2.5mL) and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated to give the title compound (0.052g) as a yellow oil which was used in the next step without further purification. MS:353.2(M + H)⁺)。

[B](rac) -4- [ [3- (1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile

To (rac) -4- [ 1-acetyl-3- (1-acetyl-3-piperidinyl) pyrazol-4-yl]Oxybenzonitrile (0.05g, 0.142mmol) in bisTo a solution in an alkane (0.5mL) was added 4M aqueous NaOH (0.177mL, 0.709mmol) and the reaction mixture was stirred at room temperature for 1 h. The mixture was evaporated to dryness and the residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 10% MeOH-DCM) to give the title compound (0.006g, 16%) as a colorless solid. MS 311.2(M + H)⁺)。

Example 63

(rac) -4- [ [3- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

To (rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl group]Oxy radical]Benzonitrile (example)61) (0.04g, 0.149mmol) to a solution in DMF (0.6mL) was added 1-methyl-1H-pyrazole-4-carboxylic acid (0.021g, 0.164mmol) and TEA (0.06g, 0.596mmol) followed by HATU (0.068g, 0.179mmol) and the reaction mixture stirred at room temperature for 5H. The mixture was diluted with EtOAc, poured into water (5mL) and the aqueous layer extracted with EtOAc (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0 to 10% MeOH-DCM) to give the title compound (0.015g, 27%) as a colorless amorphous solid. MS:377.3(M + H)⁺)。

Example 64

(rac) -4- [ [3- [1- (pyridine-3-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

To (rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl group]Oxy radical]To a solution of benzonitrile (example 61) (0.029g, 0.087mmol) in DMF (0.5mL) was added nicotinic acid (0.011g, 0.087mmol) and TEA (0.026g, 0.262mmol), followed by TBTU (0.034g, 0.105mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc, poured into water (5mL) and the aqueous layer extracted with EtOAc (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by preparative HPLC (Gemini NX 3u column, gradient 1% aqueous formic acid/acetonitrile) to give the title compound (0.004g, 10%) as an orange oil. MS 374.3(M + H)⁺)。

Example 65

(rac) -4- [ [3- [1- (pyridine-2-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

In analogy to the procedure described for the preparation of example 64, (rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile (example 61) was reacted with pyridine-2-carboxylic acid and TBTU to give the title compound as a colorless solid. MS:374.2(M + H)⁺)。

Example 66

4- [ [3- (2-methyl-1, 3-thiazol-5-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 61[ A]And example 44[ B ]]The procedure described in (rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (intermediate B-2) was reacted with 2-methyl-5- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) thiazole and subsequently with HCl (bis of 4M)Alkane solution) in MeOH to give the title compound as a pale yellow oil. MS:283.1(M + H)⁺)。

Example 67

4- [ [3- (1-methylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 61[ A]And examples44[B]The procedure described in (rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (intermediate B-2) with 1-methyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole followed by HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless oil. MS:266.2(M + H)⁺)。

Example 68

4- [ [5- (1-benzylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 61[ A]And example 44[ B ]]The procedure described in (rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (intermediate B-2) was reacted with 1-benzyl-4- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -1H-pyrazole and then with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless oil. MS:342.1(M + H)⁺)。

Example 69

4- [ [3- [3- [ (6-fluoropyridin-2-yl) oxymethyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3-, [2 ]3- (chloromethyl) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxy-benzyl Nitrile

To (rac) -4- [3- [3- (hydroxymethyl) phenyl ] cooled to 0 DEG C]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile (example 49[ A ]]) (0.13g, 0.329mmol) to a solution in DMF (2mL) was added 2,4, 6-trimethylpyridine (0.064g, 0.527mmol), methanesulfonyl chloride (0.64g, 0.56mmol) and lithium chloride (0.028g, 0.658 mmol). The reaction mixture was stirred at 0 ℃ for 10min and then at room temperature for 1 h. The mixture was diluted with EtOAc and poured into saturated NaHCO₃Solution (5mL) and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Drying, filtration and evaporation gave the title compound (0.144g, 100%) as a colourless oil. The crude product was used in the next step without further purification. MS 394.2(M + H)⁺)。

[B](rac) -4- [3- [3- [ (6-fluoro-2-pyridinyl) oxymethyl]Phenyl radical]-1-tetrahydropyran-2-yl-pyri dine Azol-4-yl]Oxybenzonitrile

To (rac) -4- [3- [3- (chloromethyl) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]To a solution of oxybenzonitrile (0.038g, 0.088mmol) in DMF (1mL) was added 6-fluoropyridin-2-ol (0.01g, 0.088mmol) and K₂CO₃(30.4mg, 0.22 mmol). The reaction mixture was heated to 60 ℃ overnight. The mixture was diluted with EtOAc, poured into 1m hcl solution and the aqueous layer extracted with EtOAc (2 × 10 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0% to 40% EtOAc-heptane) to give the title compoundThis was a colorless oil (0.047g, 85%). MS:471.2(M + H)⁺)。

[C]4- [ [3- [3- [ (6-fluoropyridin-2-yl) oxymethyl group]Phenyl radical]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- [3- [ (6-fluoro-2-pyridinyl) oxymethyl]Phenyl radical]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless amorphous solid. MS:387.2(M + H)⁺)。

In analogy to the procedure described for the preparation of examples 69[ B ] and [ C ], the following examples listed in table 5 were prepared by reacting (rac) -4- [3- [3- (chloromethyl) phenyl ] -1-tetrahydropyran-2-yl-pyrazol-4-yl ] oxybenzonitrile with the indicated heterocycle and subsequent treatment with acid.

TABLE 5

Example 74

4- [ [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl ] methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) -4- [3- (3-formylphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile

To (rac) -4- [3- [3- (hydroxymethyl) phenyl]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile (example 49[ A ]]) (0.159g, 0.403mmol) in IITo a solution in alkane (5mL) was added manganese dioxide (0.421g, 4.84mmol) and the reaction mixture was heated to 60 ℃ for 3 h. The mixture was diluted with EtOAc, filtered through Dicalite and washed with EtOAc. The solvent was evaporated and the residue was purified by silica gel flash chromatography (eluting with a 0% to 20% EtOAc-heptane gradient) to give the title compound (0.115g, 73%) as a colorless oil. MS:290.1(M + H-THP)⁺)。

[B](rac) -4- [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl]Methyl radical]Phenyl radical]-1- Tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile

To (rac) -4- [3- (3-formylphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]To a solution of oxybenzonitrile (0.065g, 0.164mmol) in DCE (1mL) was added 3-fluoroazetidin-3-yl) methanol (0.017g, 0.164mmol) and acetic acid (0.012mg, 0.197 mmol). The reaction mixture was stirred at room temperature for 30min, then sodium triacetoxyborohydride (0.104g, 0.493mmol) was added and stirring was continued for 2 h. The mixture was diluted with EtOAc, poured into water (5mL) and the aqueous layer extracted with EtOAc (2 × 10mL)And (6) taking. The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by silica gel flash chromatography (eluting with a gradient of 0% to 15% MeOH-DCM) to give the title compound (0.019g, 20%) as a colorless oil. MS:463.3(M + H)⁺)。

[C]4- [ [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl)]Methyl radical]Phenyl radical]-1H-pyrazole-4- Base of]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) -4- [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl]Methyl radical]Phenyl radical]-1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a brown solid. MS 379.2(M + H)⁺)。

Example 75

4- [ [3- [3- (morpholin-4-ylmethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

In analogy to the procedure described for the preparation of example 74, (rac) -4- [3- (3-formylphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with morpholine and then with HCl (4M bisAlkane solution) in MeOH to give the title compound as a yellow oil. MS:361.2(M+H⁺)。

Example 76

4- [ [3- [2- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 48[ A ]]And 48[ B ]]And example 50[ A ]]And 50[ B ]]From 4- [ [5- (2-phenylmethoxyphenyl) -1H-pyrazol-4-yl group]Oxy radical]Benzonitrile (example 41) the title compound is prepared by the following reaction sequence i) reaction with dihydro-pyran; ii) removing benzyl groups by catalytic hydrogenation; iii) alkylation with 4- (bromomethyl) pyridine hydrobromide, potassium carbonate; iv) removing the protecting group; it was obtained as a colorless amorphous solid. MS:369.1(M + H)⁺)。

In analogy to the procedure described for the preparation of example 50, the following examples listed in table 6 were prepared by reacting (rac) -4- [3- (2-hydroxyphenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl ] oxybenzonitrile (example 76, step ii) reaction product) with a halo-methyl heterocyclic compound and subsequently with an acid.

TABLE 6

In analogy to the procedure described for the preparation of examples 69[ B ] and [ C ], (rac) -4- [3- [2- (chloromethyl) phenyl ] -1-tetrahydropyran-2-yl-pyrazol-4-yl ] oxybenzonitrile (via i) was reacted with dihydro-pyran; ii) reduction with borane tetrahydrofuran complex; iii) preparation from 2- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoic acid (example 40) by treatment with methanesulfonyl chloride, LiCl, 2,4, 6-trimethylpyridine, DMF) with the indicated heterocycle and subsequent reaction with acid the following examples listed in Table 7 were prepared.

TABLE 7

Example 84

4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

[A](rac) - [4- [3- (2-fluoro-3-hydroxy-phenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxy benzene Nitrile (A) to methyl cyanide

(rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl is introduced into a microwave vial]Triflate (intermediate B-2) (0.296g, 0.674mmol) and 2-fluoro-3-hydroxyphenylboronic acid (0.105g, 0.674mmol) were combined in DMF (3.0 mL). The mixture was purged with argon, then bis (triphenylphosphine) palladium (II) chloride (0.047g, 0.067mmol) was added followed by 1M Na₂CO₃Aqueous solution (2mL, 2.02 mmol). The reaction mixture was then heated immediately to 80 ℃ in a microwave for 5 min. The mixture was washed with EtOAcDilute, pour into 1M aqueous HCl and extract the aqueous layer with EtOAc (2 × 15 mL). The combined organics were washed with brine, over Na₂SO₄Dried, filtered and evaporated. The residue was purified by preparative HPLC (Gemini NX 3u column, gradient 1% aqueous formic acid/acetonitrile) to give the title compound (0.031g, 10%) as a colorless oil. MS:380.2(M + H)⁺)。

[B]4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile

Analogously to example 44[ B](rac) - [4- [3- (2-fluoro-3-hydroxy-phenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl]Oxybenzonitrile with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless solid. MS:296.1(M + H)⁺)。

In analogy to the procedure described for the preparation of example 50, the following examples listed in table 8 were prepared by reacting (rac) - [4- [3- (2-fluoro-3-hydroxy-phenyl) -1-tetrahydropyran-2-yl-pyrazol-4-yl ] oxybenzonitrile (example 84[ a ]) with a halo-methyl heterocyclic compound and then with an acid.

TABLE 8

Example 87

4- [ [5- (piperazin-1-ylmethyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 44[ B](rac) -4- [ [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Methyl radical]Piperazine-1-carboxylic acid tert-butyl ester (intermediate B-3) with HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless oil. MS 284.2(M + H)⁺)。

Example 88

4- [ [5- [ [4- (1-methylpyrazole-4-carbonyl) piperazin-1-yl ] methyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

In analogy to the procedure described for the preparation of example 64, 4- [ [5- (piperazin-1-ylmethyl) -1H-pyrazol-4-yl]Oxy radical]Benzonitrile (example 87) was reacted with 1-methyl-1H-pyrazole-4-carboxylic acid and TBTU to give the title compound as a colorless amorphous solid. MS:392.2(M + H)⁺)。

Example 89

(rac) -3-fluoro-4- [ [5- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

The title compound was prepared by the following reaction sequence: i) analogously to example 61[ A](rac) - [4- (4-cyano-2-fluoro-phenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (prepared analogously to the procedure described for intermediate B-2, but replacing 4-hydroxybenzonitrile with 3-fluoro-4-hydroxy-benzonitrile) was reacted with tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate; ii) analogously to example 60[ B]The steps described for the preparation of (1) catalytic hydrogenation; iii) analogously to [ B ] for example 44]The protecting group is removed in the step; iv) in analogy to the procedure described for the preparation of example 64, coupling with 1-methyl-1H-pyrazole-4-carboxylic acid with the aid of TBTU; the title compound was obtained as a colorless amorphous solid. MS 395.2(M + H)⁺)。

Example 90

4- [ [3- [ 3-chloro-2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

Analogously to example 61[ A]Example 50[ A]And example 44[ B ]]The procedure described in (rac) - [4- (4-cyanophenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (intermediate B-2) was reacted with 3-chloro-2-hydroxyphenylboronic acid, followed by 5- (chloromethyl) -1-methyl-1H-1, 2, 3-triazole, and then HCl (4M bisAlkane solution) in MeOH to give the title compound as a colorless amorphous solid. MS:407.1(M + H)⁺)。

Example 91

(rac) -3-fluoro-4- [ [3- [1- (pyridine-3-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile

The title compound was prepared by the following reaction sequence: i) analogously to example 61[ A](rac) - [4- (4-cyano-2-fluoro-phenoxy) -1-tetrahydropyran-2-yl-pyrazol-3-yl]Triflate (prepared analogously to the procedure described for the preparation of intermediate B-2, but replacing 4-hydroxybenzonitrile with 3-fluoro-4-hydroxy-benzonitrile) was reacted with tert-butyl 3- (4,4,5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -5, 6-dihydropyridine-1 (2H) -carboxylate; ii) analogously to example 60[ B]The steps described for the preparation of (1) catalytic hydrogenation; iii) analogously to [ B ] for example 44]The step (2) removing the protecting group; iv) coupling with nicotinic acid with the aid of TBTU analogously to the procedure described for the preparation of example 64; the title compound was obtained as a brown oil. MS:392.2(M + H)⁺)。

Example A

The compounds of formula (I) can be used in a manner known per se as active ingredients in the preparation of tablets of the following composition:

example B

The compounds of formula (I) can be used in a manner known per se as active ingredients in the preparation of capsules of the following composition:

Claims (25)

1. A compound of formula (I)

Wherein

R¹Is substituted phenyl or substituted pyridyl, wherein substituted phenyl and substituted pyridyl are substituted with one to three substituents independently selected from cyano, halogen, haloalkyl, alkoxy, and alkyl;

R²is selected fromRing systems of groups A, B, C, D, E, F, G and H,

R³and R⁷Independently selected from the group consisting of H, alkyl, alkoxy, halo, haloalkoxy, carboxy, alkoxycarbonyl, substituted phenylalkoxy, substituted heteroarylalkoxy, substituted heteroarylalkyl, substituted heteroaryloxyalkyl, and substituted heterocycloalkoxy, wherein substituted phenylalkoxy, substituted heteroarylalkoxy, substituted heteroarylalkyl, substituted heteroaryloxyalkyl, and substituted heterocycloalkoxy are substituted with one to three substituents independently selected from the group consisting of H, alkyl, and halo;

R⁴is H, hydroxy, hydroxyalkyl, alkoxy, alkoxycarbonyl, halogen, phenylalkoxy, heterocycloalkylcarbonyl substituted with one to three substituents independently selected from H, alkylcarbonyl, alkylsulfonyl and hydroxyalkyl, heteroarylalkoxy substituted with one to three substituents independently selected from H, alkyl and halogen, heteroaryloxyalkyl substituted with one to three substituents independently selected from H and halogen, heteroarylalkyl substituted with one to three substituents independently selected from H and hydroxy, heterocycloalkoxy substituted with one to three substituents independently selected from H and alkylcarbonyl, or heterocycloalkylalkyl substituted with one to three substituents independently selected from H, halogen and hydroxyalkyl;

R⁶is H or halogen;

R⁵is H, halogen, alkoxy, alkylsulfonyl, alkylthio or haloalkyl;

R⁸is alkyl or phenylalkyl;

R⁹is H, alkylcarbonyl or heteroarylcarbonyl substituted with one to three substituents independently selected from H and alkyl;

n is 0, 1 or 2;

and pharmaceutically acceptable salts thereof.

2. According to claim1 wherein R is¹Is phenyl substituted with one to three substituents independently selected from cyano and halogen.

3. The compound according to any one of claims 1 and 2, wherein R²Is a ring system selected from the group consisting of groups A, B, C, D, E and F.

4. A compound according to any one of claims 1 to 3, wherein R²Is a ring system selected from the group consisting of groups A, B and C.

5. A compound according to any one of claims 1 to 4, wherein R²One is a ring system group A.

6. The compound according to any one of claims 1 to 5, wherein n is 0.

7. A compound according to any one of claims 1 to 6, wherein R⁷Is H.

8. A compound according to any one of claims 1 to 7, wherein R³Is H, alkoxy, halogen, haloalkoxy or heteroarylalkoxy substituted with one to three substituents independently selected from H and alkyl.

9. A compound according to any one of claims 1 to 8, wherein R⁴Is H, hydroxy, heteroarylalkoxy or heterocycloalkylalkyl.

10. According to the claimsThe compound of any one of claims 1 to 9, wherein R⁴Is H.

11. The compound according to any one of claims 1 to 10, wherein R⁵Is H.

12. The compound according to any one of claims 1 to 11, wherein R⁶Is H.

13. The compound according to any one of claims 1 to 12, wherein R⁷Is H.

14. The compound according to any one of claims 1 to 13, wherein R⁹Is heteroarylcarbonyl substituted with one alkyl group.

15. A compound according to any one of claims 1 to 14 selected from

4- (4-chlorophenoxy) -5- (2, 3-difluorophenyl) -1H-pyrazole;

3- (4-chlorophenyl) -4- (4-methoxyphenoxy) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (4-chlorophenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (2-methoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -3- (2, 4-dimethoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2-chlorophenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (trifluoromethoxy) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (difluoromethoxy) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2-fluorophenyl) -1H-pyrazole;

3- (5-chloro-2-methoxyphenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

5- (4-chloro-2-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- (4-chlorophenoxy) -5- (4-methylsulfonylphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [ 2-fluoro-4- (trifluoromethyl) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- [4- (trifluoromethyl) phenyl ] -1H-pyrazole;

4- (4-chlorophenoxy) -5- (2, 4-difluorophenyl) -1H-pyrazole;

5- (4-methylsulfonylphenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

5- (2-chloro-4-methylthiophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (4-methylsulfonylphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

2-chloro-5- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] pyridine;

5- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -2-methylpyridine;

2- [ [5- (2, 4-dichlorophenyl) -1H-pyrazol-4-yl ] oxy ] -6-fluoropyridine;

2- [ [3- (2, 4-dichlorophenyl) -1H-pyrazol-4-yl ] oxy ] -6-methylpyridine;

5- (2-chlorophenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

4- (4-chloro-2-fluorophenoxy) -5- (2-chlorophenyl) -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chloro-4-methylthiophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (4-chloro-2-fluorophenyl) -4- [4- (trifluoromethyl) phenoxy ] -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -3-fluorobenzonitrile;

4- [ [5- (2, 3-difluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (3-chloro-2-fluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (3-chloro-2-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (3-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

3- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoic acid methyl ester;

5- (2-chloro-3-fluorophenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (2-chloro-3-fluorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (3-phenylmethoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chloropyridin-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

3- [4- (4-cyano-2-fluorophenoxy) -1H-pyrazol-3-yl ] benzoic acid methyl ester;

ethyl 2- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoate;

2- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] benzoic acid;

4- [ [5- (2-phenylmethoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

5- (2-chloro-4-methylsulfonylphenyl) -4- (4-chlorophenoxy) -1H-pyrazole;

4- [ [5- (2-chloro-4-methylsulfonylphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (4-acetylpiperazine-1-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholine-4-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (4-methylsulfonylpiperazine-1-carbonyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [3- (hydroxymethyl) azetidine-1-carbonyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (hydroxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-2-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-3-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (3-methyl-1, 2-)Azol-5-yl) methoxy]Phenyl radical]-1H-pyrazol-4-yl]Oxy radical]Benzonitrile;

4- [ [3- [3- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (2-chloropyridin-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (1-methylpyrazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- (3-pyrrolidin-3-yloxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [3- (1-acetylpyrrolidin-3-yl) oxyphenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (3-butoxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (2-methoxyphenyl) ethyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [5- (3-piperidinyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- (1-acetylpiperidin-3-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (pyridine-3-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (pyridine-2-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-methyl-1, 3-thiazol-5-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (1-methylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (1-benzylpyrazol-4-yl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (6-fluoropyridin-2-yl) oxymethyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (pyridin-3-yloxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

1- [ [3- [4- (4-cyanophenoxy) -1H-pyrazol-3-yl ] amino acid]Phenyl radical]Methyl radical]Pyridine-1--3-alkoxides;

4- [ [3- [3- [ (4-oxopyridin-1-yl) methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (6-chloropyridin-2-yl) oxymethyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ [ 3-fluoro-3- (hydroxymethyl) azetidin-1-yl ] methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholin-4-ylmethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-3-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-2-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (1-methylpyrazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- (pyridin-3-yloxymethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (4-oxopyridin-1-yl) methyl ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 2-fluoro-3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- [ (2-chloropyridin-4-yl) methoxy ] -2-fluorophenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (piperazin-1-ylmethyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- [ [4- (1-methylpyrazole-4-carbonyl) piperazin-1-yl ] methyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- [ [5- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 3-chloro-2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- (3- (1-nicotinoylpiperidin-3-yl) -1H-pyrazol-4-yloxy) benzonitrile;

and pharmaceutically acceptable salts thereof.

16. A compound according to any one of claims 1 to 15 selected from

4- (4-chlorophenoxy) -3- (2-methoxyphenyl) -1H-pyrazole;

4- (4-chlorophenoxy) -5- [2- (difluoromethoxy) phenyl ] -1H-pyrazole;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- (2-chlorophenyl) -1H-pyrazol-4-yl ] oxy ] -3-fluorobenzonitrile;

4- [ [3- [2- (2-methoxyphenyl) ethyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -4- [ [3- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [3- (morpholin-4-ylmethyl) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [2- [ (3-methyltriazol-4-yl) methoxy ] phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- (2-fluoro-3-hydroxyphenyl) -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [3- [ 2-fluoro-3- (pyridin-4-ylmethoxy) phenyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

4- [ [5- [ [4- (1-methylpyrazole-4-carbonyl) piperazin-1-yl ] methyl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

(rac) -3-fluoro-4- [ [5- [1- (1-methylpyrazole-4-carbonyl) piperidin-3-yl ] -1H-pyrazol-4-yl ] oxy ] benzonitrile;

and pharmaceutically acceptable salts thereof.

17. A process for the preparation of a compound according to any one of claims 1 to 16, comprising the reaction of a compound of formula (II) or (III) in the presence of hydrazine hydrate;

wherein R is¹And R²As defined in any one of claims 1 to 14 and n is 0.

18. A compound according to any one of claims 1 to 16 for use as therapeutically active substance.

19. A pharmaceutical composition comprising a compound according to any one of claims 1 to 16 and a therapeutically inert carrier.

20. The use of a compound according to any one of claims 1 to 16 for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

21. A compound according to any one of claims 1 to 16 for use in the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

22. The use of a compound according to any one of claims 1 to 16 for the preparation of a medicament for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom.

23. A method for the treatment or prophylaxis of chronic kidney disease, congestive heart failure, hypertension, primary aldosteronism and cushing syndrom, which method comprises administering an effective amount of a compound according to any one of claims 1 to 16.

24. A compound according to any one of claims 1 to 16, when manufactured according to a process of claim 17.

25. The invention as hereinbefore described.