WO2013082751A1

WO2013082751A1 - Phosphate transport inhibitors i

Info

Publication number: WO2013082751A1
Application number: PCT/CN2011/083521
Authority: WO
Inventors: Morten Dahl SOERENSEN; Jens Christian Hoejland Larsen; Bjarne Noerremark; Xifu Liang; Guoxiang Huang
Original assignee: Leo Pharma A/S
Priority date: 2011-12-06
Filing date: 2011-12-06
Publication date: 2013-06-13

Abstract

Compounds according to formula (I) are useful in the treatment of phosphate homeostasis.

Description

PHOSPHATE TRANSPORT INHIBITORS I Field of the invention

The present invention relates to novel heteroaromatic compounds, to said compounds for use as a medicament, to pharmaceutical compositions comprising said compounds, to methods of preventing, treating or ameliorating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.

Background of the invention

Phosphate is an essential component of life and fulfils both structural and metabolic roles. Cells obtain phosphorus in the form of negatively charged inorganic phosphate (P,) from the extracellular environment by means of secondary-active transport. In vertebrates, P, transporters use the inwardly directed electrochemical gradient of Na ⁺ ions, established by the Na⁺- K⁺ -ATPase, to drive P, influx. Defects in P, homeostasis may result in severe pathologies. Thus, phosphate retention has been shown to play a major role in the progression of renal failure and induction of uremic bone disease and secondary hyperparathyroidism. Diabetes patients are especially at risk, and their number is increasing rapidly. Hyperphosphatemia associated with chronic kidney disease (CKD) is linked tightly to increased risk of cardiovascular morbidity and mortality.

Elevated serum phosphate concentrations within the high normal range in individuals with functional kidneys also are correlated with increased cardiovascular risk and mortality. Thus, elevated serum phosphate is an emerging health risk (J Am Soc

Nephrol, 2009, 20(11), 2348-2358).

In the prior art, to alleviate these clinical conditions, ingestion of a low-phosphate diet and the use of a phosphate adsorbent having the function of adsorbing/precipitating phosphate released from the diet have been carried out from the viewpoint of reducing the amount of phosphate available for intestinal absorption. However, a low-phosphate diet has a low compliance due to bad taste and may also lead to nutritional disorders, for example due to lack of ingestion of other nutrients. Representative examples of oral phosphate adsorbents include calcium preparations, magnesium preparations, lanthanum preparations, and aluminum preparations. However, calcium preparations and magnesium preparations induce hypercalcemia and hypermagnesia, respectively, and tissue accumulation of lanthanum with unknown long-term consequences has been observed for lanthanum preparations. Aluminum preparations induce aluminum osteopathy, aluminum cerebropathy, and dialysis dementia and their use is thus restricted to short-term salvage therapy, i.e. rapid reduction of serum phosphate concentrations. Also various anion exchange resins have been developed as the oral phosphate adsorbents. Since, however, these anion exchange resins have lower phosphate adsorption capacity than the above group of compounds, a high level of dosage is necessary for phosphate absorption reduction purposes leading to poor patient compliance.

Intestinal phosphate absorption occurs through both a paracellular mechanism involving tight junctions and an active transcellular mechanism involving the type II sodium- dependent phosphate cotransporter Npt2b (SLC34a2) (J Am Soc Nephrol, 2009, supra). It was shown that Npt2b is largely responsible for intestinal phosphate absorption and contributes to the maintenance of systemic phosphate homeostasis. Thus inhibition of intestinal phosphate absorption by inhibition of the sodium-dependent phosphate transporter Npt2b by a small molecule would be a desirable method to control serum phosphate levels in patients with chronic renal disease or undergoing dialysis.

US 2006/017426 discloses compounds inhibiting in vivo phosphorus transport and medicine containing the same.

WO 01/05398 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a N-aryl-2- sulfonamidobenzamide compound.

WO 01/82924 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a dihydroxybenzamide compound.

WO 01/87294 discloses a method of inhibiting sodium-dependent phosphate transport by administering to a subject in need thereof a safe and effective amount of a N-aryl-2- sulfonamidobenzamide compound.

WO 02/28353 discloses thiophene compounds, useful for treatment of chronic renal failure and uremic bone disease.

WO 03/048134 discloses triazole compounds and medicinal use thereof as sodium- phosphate cotransporter inhibitors.

WO 04/085382 discloses compounds which suppress the concentration of phosphorous in serum.

WO 06/0217426 discloses compounds inhibiting in vivo phosphorus transport and medicine containing same.

Object of the invention

It is an object of embodiments of the invention to provide compounds and

pharmaceutical compositions that can effectively prevent or treat diseases induced by an increase in the phosphate concentration of serum by effectively suppressing the phosphate concentration of serum.

Summary of the invention

It has been found by the present inventors that novel heteroaromatic compounds may inhibit sodium-dependent phosphate transport into cells and may inhibit sodium- dependent phosphate uptake in the small intestine. The present inventors have also found that the novel heteroaromatic compounds may inhibit the sodium-dependent intestinal Npt2b transporter. The inventors have also found that compounds of the present invention may reduce the increase in serum levels of phosphate of mammals to which phosphate have been administered orally.

Compounds of the present invention may have improved pharmacokinetic properties such as improved solubility, absorption or stability in comparison to known structurally related compounds. A particular advantage of some of the compounds of the present invention is that they show higher chemical stability in comparison to known structurally related compounds.

So, in a first aspect the present invention relates to a compound according to formula I

wherein

Ri, R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, COOH, (d-C₄)alkyl, halo(Ci-C₄)alkyl, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy, halo(Ci-C₄)alkoxy, cycloalkyl and heterocycloalkyl; R₄ is selected from the group consisting of hydrogen, halogen, (Ci-C₄)alkyl and heterocycloalkyl;

R₅ is selected from the group consisting of hydrogen, COOH, (d-C₆)alkyl,

heterocycloalkyl(Ci-C₆)alkyl, aryl(Ci-C₆)alkyl and heteroaryl(Ci-C₆)alkyl, said (Ci- C₆)alkyl, aryl(Ci-C₆)alkyl, heterocycloalkyl(Ci-C₆)alkyl and heteroaryl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from R₆;

R₆ is selected from the group consisting of halogen, -ORa, -SRa, -S(0)Ra, -S(0)₂Ra, - NRaRb, -N⁺RaRbRc, -OC(0)Ra, -P(0)(OH)₂, (Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl, aryl and a heterocyclic ring; said (Ci-C₆)alkyl, heterocycloalkyl, cycloalkyl, aryl and heterocyclic ring optionally being substituted by one or more substituents selected from R₇; Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, alkoxy(Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and

heterocycloalkyl(Ci-C₆)alkyl; said (Ci-C₆)alkyl, alkoxy(Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and heterocycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from R₇;

R₇ is selected from the group consisting of hydroxyl, -COOH, -ORd, -NRdRe, -N⁺RdReRf, and -S0₂OH;

Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl and heterocycloalkyl(Ci-C₆)alkyl; said (Ci- C₆)alkyl, cycloalkyl, heterocycloalkyl and heterocycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from halogen, hydroxyl, or cyano;

X and Y are selected from the group consisting of CH and N with the proviso that when X represents CH, Y represents N; and with the proviso that when X represents N, Y represents CH; and pharmaceutically acceptable and physiologically cleavable esters, pharmaceutically acceptable salts, hydrates, N-oxides or solvates thereof.

In another aspect, the invention relates to a compound according to formula

wherein R₂, R₃, R₄, X and Y are as defined above and wherein A represents a (C₂-C₈) alkylene chain ;

wherein R₈ is selected from the group consisting of hydrogen and (Ci-C₆)alkyl ; and wherein each occurrence of Ri, R₂, R3, R₄, X and Y, respectfully, is identical to any other occurrence of said substituent in the compound of the formula Γ. In another aspect, the invention relates to a compound according to the invention for use as a medicament.

In another aspect, the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of phosphate homeostasis.

In another aspect, the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of age-related arteriosclerosis, anemia, angina pectoris, anomaly of saccharometabolism, arthralgia, bone deformity, calciphylaxis, cardiac induction, cardiovascular calcification, cardiovascular events, chronic kidney disease, diabetic vasculopathy, ectopic calcification, fracture, growth retardation, heart conduction disturbance, heart failure induced by cardiac murmur or valvular disease, hyperlipidemia, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, immune deficiency, metabolic bone disease, metabolic osteopathy, metastatic calcification, muscle damage, myalgia, myoca rdiopathy, nervous system damage induced by PTH increase or Vitamin D lowering, osteoalgia, osteoporosis, progression of renal failure, pruritus cutaneous, pulmonary diffusing impairment, renal failure, renal osteodystrophy, secondary hyperparathyroidism, sexual dysfunction, skin ischemic ulcer, soft tissue calcification, tendon rupture, and uremic bone disease.

In another aspect, the invention relates to a compound according to the invention for use in the prophylaxis, treatment or amelioration of calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary

hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease.

In another aspect, the invention relates to a pharmaceutical composition comprising a compound according to the invention together with a pharmaceutically acceptable vehicle of excipient or pharmaceutically acceptable carrier(s). In another aspect, the invention relates to a use of a compound according to the invention in the manufacture of a medicament for the prophylaxis, treatment or amelioration of calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease.

In another aspect, the invention relates to a method of preventing, treating or ameliorating calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease, the method comprising administering to a person suffering from at least one of said diseases or conditions an effective amount of one or more compounds according to the invention, optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

Detailed disclosure of the invention

Definitions The term "hydrocarbon radical" is intended to indicate a radical containing only hydrogen and carbon atoms, it may contain one or more double and/or triple carbon-carbon bonds, and it may comprise cyclic moieties in combination with branched or linear moieties. Said hydrocarbon comprises 1- 10 carbon atoms, and prefera bly comprises 1-8, e.g . 1-6, e.g . 1-4, e.g. 1-3, e.g . 1-2, eg . 2-3 carbon atoms. The term includes alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkynyl and aryl, as indicated below.

The term "aryl" is intended to indicate a radical of aromatic carbocyclic rings comprising 6- 14carbon atoms, such as 6- 10 carbon atoms or 6-9 ca rbon atoms, in particular 5- or 6-membered rings, including fused ca rbocyclic rings with at least one aromatic ring, such as phenyl, naphthyl, indenyl and indanyl .

The term "heteroaryl" is intended to indicate radicals of heterocyclic aromatic rings comprising 1-6 heteroatoms (selected from O, S and N) and 1 - 14 carbon atoms, such as 1-5 heteroatoms and 1- 12 carbon atoms, such as 1-5 heteroatoms and 1-6 carbon atoms, such as 1-4 heteroatoms and 1-3 carbon atoms, in particular 5- or 6-membered rings with 1-4 heteroatoms selected from 0, S a nd N, including fused bicyclic rings with 1-4 heteroatoms, and wherein at least one ring is aromatic, e.g . pyridyl, quinolyl, isoquinolyl, indolyl, thiadiazolyl, oxodiazolyl, tetrazolyl, furanyl, thiazolyl, benzooxazolyl, imidazolyl, pyrazolyl, triazolyl, oxazolyl, isoxazolyl, thienyl, pyrazinyl, isothiazolyl, benzimidazolyl, benzofuranyl and 6,7,8,9-tetrahydropyrido[2,3-b] [ l,6] naphthyridine.

In the present context, the term "alkyl" is intended to indicate a radical obtained when one hyd rogen atom is removed from a hydrocarbon . Said alkyl comprises 1 - 10, preferably 1-8, such as 1-6, such as 1-4, such as 1-3, such as 1-2 carbon atoms or 2-3 carbon atoms. The term includes the subclasses normal alkyl (/7-alkyl), secondary and tertiary alkyl, such as methyl, ethyl, /7-propyl, isopropyl, /7-butyl, isobutyl, sec -butyl, tert. -butyl, pentyl, isopentyl, hexyl and isohexyl . The prefix "(C_a-_b)" wherein a and b are integers, indicates that the subsequent group comprises from a to b carbon atoms, such as 1-8, 1-6, 1-4, 1-3, 1-2 carbon atoms.

The term "alkylene" is intended to indicate a divalent saturated aliphatic hydrocarbyl group preferably having from 2 to 8 carbon atoms that are either straight-chained or branched . This term is exemplified by groups such as ethylene (-CH₂CH₂-) or n- propylene (-CH₂CH₂CH₂-) . The term "cycloalkyl" is intended to indicate a saturated cycloalkane radical comprising 3-12 carbon atoms, preferably 3-10 carbon atoms, in particular 3-8 carbon atoms, such as 3-6 carbon atoms or 3-5 carbon atoms , including fused bicyclic rings or bridged bicyclic or tricyclic rings, e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl.

The term "heterocycloalkyl" is intended to indicate a cycloalkane radical as described above, wherein one or more carbon atoms are replaced by heteroatoms, comprising 1 - 14 carbon atoms, e.g. 2-5 or 2-4 carbon atoms, further comprising 1-6 heteroatoms, preferably 1, 2, or 3 heteroatoms, selected from 0, N, or S, e.g. piperidinyl, pyrrolidinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl, piperazinyl, [ l,3]dioxolanyl and

[ l,3]dioxolyl, or including fused bicyclic rings with 1-4 heteroatoms, wherein at least one ring comprises a heteroatom, and wherein the other ring may for example be a carbocyclic ring, or including bridged carbocyclic rings, such as e.g. 1,4- diazabicyclo[2.2.2]octane or l,6-diazabicyclo[4.2.2]decane.

The term "halogen" is intended to indicate a substituent from the 7^th main group of the periodic table, such as fluoro, chloro, bromo and iodo. The term "haloalkyl" is intended to indicate an alkyl group as defined above substituted with one or more halogen atoms as defined above, e.g. fluoro or chloro, such as difluoromethyl, or trifluoromethyl.

The term "alkoxy" is intended to indicate a radical of the formula -OR', wherein R' is alkyl as indicated above, e.g. methoxy, ethoxy, n-propoxy, isopropoxy, butoxy, etc.

The term "haloalkoxy" is intended to indicate a radical of the formula -OR', wherein R' is haloalkyl as indicated above, e.g. trifluoromethoxy or difluoromethoxy. The term "hydroxyalkyl" is intended to indicate an alkyl group as defined above substituted with one or more hydroxy, e.g. hydroxymethyl, hydroxyethyl,

hydroxypropyl.

The term "heterocyclic ring" is intended to include the definitions heteroaryl and heterocycloalkyl as defined above, including annelated ring systems with each other or with cyclic hydrocarbons, e.g. 2,5-dihydrobenzo(b)dioxocine, 2,3,5,8-tetrahydro- [ l,4]dioxocine, 5,8-dihydro-[ l,4]dioxocine, 2,3-dihydro-lH-isoindole, 1,2,3,4- tetrahydropyrido[4,3-b]-[ l,8]-naphthyridine.

The term "arylalkyl" is intended to indicate an alkyl radical as defined above, which is substituted with an aryl radical as defined above, e.g. benzyl, phenylethyl etc.

The term "heteroarylalkyl" is intended to indicate an alkyl radical as defined above, which is substituted with a heteroaryl radical as defined above, e.g. imidazolylmethyl, pyridinylethyl, etc.

The term "heterocycloalkylalkyl" is intended to indicate an alkyl radical as defined above, which is substituted with a heterocycloalkyl radical as defined above, e.g.

tetrahydropyranylmethyl, piperazinylmethyl, piperidinylmethyl, etc. The term "alkoxyalkyl" is intended to indicate an alkyl radical as defined above, which is substituted with an alkoxy radical as defined above, i.e. -R'-O-R', wherein each R' is alkyl, same or different, as indicated above, e.g. methoxymethyl, ethoxymethyl.

The term "pharmaceutically acceptable salt" is intended to indicate salts prepared by reacting a compound of formula I comprising a basic moiety with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroaetic, adipic, ascorbic, L-aspartic, L-glutamic, galactaric, lactic, maleic, L-malic, phthalic, citric, propionic, benzoic, glutaric, gluconic, D- glucuronic, methanesulfonic, salicylic, succinic, malonic, tartaric, benzenesulfonic, ethane-l,2-disulfonic, 2-hydroxy ethanesulfonic acid, toluenesulfonic, sulfamic or fumaric acid. Pharmaceutically acceptable salts of compounds of formula I comprising an acidic moiety may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, silver hydroxide, ammonia or the like, or suitable non-toxic amines, such as lower alkylamines, for example triethylamine, hydroxy-lower alkylamines, for example 2- hydroxyethylamine, bis-(2-hydroxyethyl)-amine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example Ν,Ν'-dibenzylethylenediamine, and dibenzylamine, or L-arginine or L-lysine.

The term "solvate" is intended to indicate a species formed by interaction between a compound, e.g. a compound of formula I, and a solvent, e.g. alcohol, glycerol or water, wherein said species are in a solid form. When water is the solvent, said species is referred to as a hydrate.

Compounds of the invention which comprise free hydroxyl groups or free carboxylic acid groups may also exist in the form of pharmaceutically acceptable, physiologically cleavable esters, and as such are included within the scope of the present invention. Such pharmaceutically acceptable esters are preferably prodrug ester derivatives, such being convertible by solvolysis or cleavage under physiologically conditions to the corresponding compounds of the invention which comprise free hydroxyl groups or free carboxylic acid groups respectively, e.g. in-vivo hydrolysable.

Specific embodiments of the invention

In one or more embodiments of the present invention R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, (Ci-C₄)alkoxy, halo(Ci-C₄)alkoxy and heterocycloalkyl.

In one or more embodiments of the present invention R^ R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, cyano, methyl, ethyl, trifluoroalkyl, methoxy, and morpholinyl.

In one or more embodiments of the present invention R₃ is hydrogen.

In one or more embodiments of the present invention Ri is trifluoromethyl, R₂ is chloro and R₃ is hydrogen.

In one or more embodiments of the present invention R₄ is selected from the group consisting of halogen and heterocycloalkyl.

In one or more embodiments of the present invention R₄ is selected from the group consisisting of chloro, bromo and piperidinyl .

In one or more embodiments of the present invention R5 is selected from the group consisting of hydrogen, COOH,(Ci-C₆)alkyl, and heterocycloalkyl(Ci-C₆)alkyl.

In one or more embodiments of the present invention R₅ is methyl or ethyl. In one or more embodiments of the present invention R₅ is selected from the group consisting of piperazinylalkyl, piperidinylalkyl, and morpholinylalkyl.

In one or more embodiments of the present invention R₅ is selected from the group consisting of piperazinylmethyl, piperidinylmethyl, and morpholinylmethyl.

In one or more embodiments of the present invention R6 is selected from the group consisting of halogen, -ORa, -SRa, -S(0)Ra, -NRaRb, -N⁺RaRbRc, -OC(0)Ra, - P(=0)(OH)₂, (Ci-C₆)alkyl, and heterocycloalkyl.

In one or more embodiments of the present invention R₆ is selected from the group consisting of CI, -ORa, -SRa, -S(0)Ra, -NRaRb, -N⁺RaRbRc, -OC(0)Ra, methyl, ethyl, morpholinyl, piperidinyl and piperazinyl. In one or more embodiments of the present invention Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, heterocycloalkyl, heteroaryl, and heterocycloalkyl(Ci-C₆)alkyl.

In one or more embodiments of the present invention Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranylmethyl, and triazolyl.

In one or more embodiments of the present invention R₇ is selected from the group consisting of hydroxyl, -COOH, -NH₂, -N(CH)₃ ⁺, and -S0₂OH.

In one or more embodiments of the present invention Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (d-C₆)alkyl and

heterocycloalkyl(Ci-C₆)alkyl; said (Ci-C₆)alkyl and heteroycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more hydroxyl.

In one or more embodiments of the present invention Rd, Re and Rf each independently are selected from the group consisting of hydrogen, methyl and

tetrahydropyranylmethyl.

In particular compounds of the formula I according to the invention may be selected from : N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (chloromethyl)benzamide;

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (1 -pi peridyl) phenyl] benzamide;

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (chloromethy I) benzamide;

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] imidazole-4-carbonyl] phenyl] -3- (chloromethy I) benzamide;

3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl] phenyl] methyl -methyl-ami no] propanoic acid;

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- [ [4-( 1-pi peridyl) -1-piperidyl] methyl] benzamide;

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (morpholinomethyl) benzamide;

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (tetrahydrofuran-3-yloxy methyl) benzamide;

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (piperazin-l-yl methyl) benzamide;

3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl]phenyl]methylsulfanyl]propanoic acid;

3-[[3-[[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- pi peridyl) phenyl]carbamoyl] phenyl] methylsulfany I] propanoic acid ;

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- pi peridyl) phenyl] -3-(lH-l, 2, 4-triazol-3-ylsulfany I methyl) benzamide;

3-[[bis(2-hydroxyethyl)amino]methyl]-N-[2-[ l-[4-chloro-3-

(trifluoromethyl) phenyl] pyrazole-4-carbonyl]-4-( 1-pi peridyl) phenyl] benzamide;

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- pi peridyl) phenyl] -3-(2-hydroxyethoxy methyl) benzamide;

3-[[3-[[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- pi peridyl) phenyl]carbamoyl] phenyl] methyl -methyl-ami no] propanoic acid ;

N- [2- [ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbonyl]-4-( 1- pi peridyl) phenyl] -3-(piperazin-l-yl methyl) benzamide;

N- [4-bromo-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (8, 9-dihydro-6H-pyrido[2,3-b] [ l, 6] naphthyridin-7-yl methyl) benzamide;

N- [4-bromo-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3-(2- hydroxyethoxymethy I) benzamide; and N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] imidazole-4-carbonyl] phenyl] -3- (piperazin-l-yl methyl) benzamide.

In one or more embodiments of the present invention a compound of the formula I or I ^' according to the invention may be used in the prophylaxis, treatment or amelioration of cardiovascular calcification, chronic kidney disease, primary hyperparathyroidism, secondary hyperparathyroidism, hyperphosphatemia or progression of renal failure.

For use in prophylaxis, therapy or amelioration, compounds of the present invention are typically in the form of a pharmaceutical composition. The invention therefore relates to a pharmaceutical composition comprising a compound of formula I, optionally together with one or more other therapeutically active compound(s), together with a

pharmaceutically acceptable excipient, vehicle or carrier(s). The excipient must be "acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof.

Conveniently, the active ingredient comprises from 0.05-99.9% by weight of the formulation. In the form of a dosage unit, the compound may be administered one or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner. Conveniently, a dosage unit of a formulation contain between 0.1 mg and 1000 mg, preferably between 1 mg and 100 mg, such as 5-50 mg of a compound of formula I.

A suitable dosage of the compound of the invention will depend, inter alia, on the age and condition of the patient, the severity of the disease to be treated and other factors well known to the practising physician. The compound is preferably administered orally according to different dosing schedules, e.g. daily or with weekly intervals. In general a single dose will be in the range from 0.01 to 100 mg/kg body weight. The compound may be administered as a bolus (i.e. the entire daily dosis is administered at once) or in divided doses two or more times a day.

It is also envisaged that in certain treatment regimes, administration with longer intervals, e.g. every other day, every week, or even with longer intervals may be beneficial. If the treatment involves administration of another therapeutically active compound it is recommended to consult Goodman & Gilman's The Pharmacological Basis of

Therapeutics, 9^th Ed., J.G. Hardman and L. E. Limbird (Eds.), McGraw-Hill 1995, for useful dosages of said compounds.

The administration of a compound of the present invention with one or more other active compounds may be either concomitantly or sequentially.

The formulations include e.g. those in a form suitable for oral (including sustained or timed release) administration.

The formulations may conveniently be presented in dosage unit form and may be prepared by any of the methods well known in the art of pharmacy, e.g. as disclosed in Remington, The Science and Practice of Pharmacy, 21ed ed., 2005. All methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing the active ingredient into association with a liquid carrier or a finely divided solid carrier or both, and then, if necessary, shaping the product into the desired formulation.

Formulations of the present invention suitable for oral administration may be in the form of discrete units as capsules, sachets, tablets or lozenges, each containing a predetermined amount of the active ingredient; in the form of a powder or granules; in the form of a solution or a suspension in an aqueous liquid or non-aqueous liquid, such as ethanol or glycerol; or in the form of an oil-in-water emulsion or a water-in-oil emulsion. Such oils may be edible oils, such as e.g. cottonseed oil, sesame oil, coconut oil or peanut oil. Suitable dispersing or suspending agents for aqueous suspensions include synthetic or natural gums such as tragacanth, alginate, acacia, dextran, sodium carboxymethylcellulose, gelatin, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carbomers and polyvinylpyrrolidone. The active ingredients may also be administered in the form of a bolus, electuary or paste.

A tablet may be made by compressing or moulding the active ingredient optionally with one or more accessory ingredients. Compressed tablets may be prepared by

compressing, in a suitable machine, the active ingredient(s) in a free-flowing form such as a powder or granules, optionally mixed by a binder, such as e.g. lactose, glucose, starch, gelatine, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, polyethylene glycol, waxes or the like; a lubricant such as e.g. sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like; a disintegrating agent such as e.g. starch, methylcellulose, agar, bentonite, croscarmellose sodium, sodium starch glycollate, crospovidone or the like or a dispersing agent, such as polysorbate 80.

Moulded tablets may be made by moulding, in a suitable machine, a mixture of the powdered active ingredient and suitable carrier moistened with an inert liquid diluent.

In addition to the aforementioned ingredients, the formulations of a compound of formula I Or may include one or more additional ingredients such as diluents, buffers, flavouring agents, colourant, surface active agents, thickeners, preservatives, e.g.

methyl hydroxy benzoate (including anti-oxidants), emulsifying agents and the like.

When the active ingredient is administered in the form of salts with pharmaceutically acceptable non-toxic acids or bases, preferred salts are for instance easily water-soluble or slightly soluble in water, in order to obtain a particular and appropriate rate of absorption.

METHODS OF PREPARATION

The compounds of the present invention can be prepared in a number of ways well known to those skilled in the art of synthesis. The compounds of formula I may for example be prepared using the reactions and techniques outlined below together with methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. The reactions are carried out in solvents appropriate to the reagents and materials employed and suitable for the transformations being effected. Also, in the synthetic methods described below, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of experiment and work-up procedures, are chosen to be conditions of standard for that reaction, which should be readily recognized by one skilled in the art. Not all compounds falling into a given class may be compatible with some of the reaction conditions required in some of the methods described. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternative methods can be used. The compounds of the present invention or any intermediate may be purified if required using standard methods well known to a synthetic organist chemist, e.g. methods described in "Purification of Laboratory Chemicals", 5^th ed. 2003. Starting materials are either known compounds, commercially available, or they may be prepared by routine synthetic methods well known to a person skilled in the art.

GENERAL PROCEDURES, PREPARATIONS AND EXAMPLES

*H nuclear magnetic resonance (NMR) spectra were usually recorded at 300 MHz, 500 MHz or 600 MHz and ¹³C NMR spectra at 75.6 MHz. Chemical shift values (δ, in ppm) are quoted in the specified solvent relative to internal tetramethylsilane (δ = 0.00) or chloroform (δ = 7.25) or deuteriochloroform (δ = 76.81 for ¹³C NMR) standards. The value of a multiplet, either defined (doublet (d), triplet (t), quartet (q)) or not (m) at the approximate mid point is given unless a range is quoted , (bs) indicates a broad singlet. The organic solvents used were usually anhydrous. Chromatography was performed on Merck silica gel 60 (0.040 - 0-063 mm). The solvent ratios indicated refer to v:v unless otherwise noted.

The following abbreviations have been used throughout

AcOH Acetic acid

AUC Area under the curve

DCE dichloroethane DCM dichloromethane

DIPEA Diisopropylethyl amine

DMF Ν,Ν'-Dimethylformamide

DMSO dimethyl sulfoxide

EA Ethyl acetate

Et ethyl

h hour(s)

L litre

m milli

M mol/L

Me methyl

NIS N-Iodosuccinimide

NMR nuclear magnetic resonance

PE Petroleum ether

rt room temperature

RT Retention Time

tBuOK Potassium tertiary-butoxide

THF tetrahydrofuran

v volume

Tris 2-Amino-2-hydroxymethyl-propane-l,3-diol

C5H 140NCI 2-hydroxy-/V,/V,/V-trimethylethanaminium chloride

SGLT1 Sodium-dependent glucose cotransporter 1

hSGLTl Human sodium-dependent glucose cotransporter 1

SLC5A1 Solute carrier family 5 member 1

HEPES 4-(2-hydroxyethyl)-l-piperazineethanesulfonic acid

C7H 17N05 (2R,3R,4R,5S)-6-Methylaminohexane-l,2,3,4,5-pentol

Preparative HPLC/MS Method Al : Preparative HPLC/MS was performed on Gilson 281. Column : Shimadzu cl8 19mm x 250mm, 15 μιη x 2; solventsystem : A = water (0.1 % formic acid) and B = acetonitrile; flow rate = 30 mL/min; method (8 min) : Linear gradient method going from 30 % B to 65 % B in 8 minutes and staying at 95 % B for another 3 minutes. The fractions were collected based on ion traces of relevant ions and PDA signal (214/254 nm).

Method A2 : Preparative HPLC/MS was performed on a Dionex APS-system with two Shimadzu PP150 prep, pumps and a Thermo MSQ Plus mass spectrometer. Column : Waters XTerra C-18, 150 mm x 19 mm, 5 μιη; solventsystem : A = water (0.1 % formic acid) and B = acetonitrile (0.1 % formic acid); flow rate = 18 mL/min; method (10 min) : Linear gradient method going from 10 % B to 100 % B in 6 minutes and staying at 100 % B for another 2 minutes. The fractions were collected based on ion traces of relevant ions and PDA signal (240-400 nm) .

General Methods and Examples:

Some compounds of the invention may for example be prepared according to the following non-limiting general methods and examples:

Scheme 1

Scheme 2

Compounds of general formula I, wherein X = N and Y = CH may be prepared as depicted in Scheme 1 or 2. Step A: Deprotection of the triphenylmethyl protecting group is for example performed under acidic conditions, for example by using 90% AcOH / 10% H₂0 and microwave heating for an appropriate time and temperature.

Step B: N-arylation of pyrazole is for example performed under mild copper catalyzed conditions, for example Cul in the presence of sodium ascorbate, (lR,2R)-(-)-l,2- Bis(Methylamino)cyclohexane and DMSO.

Step C: R₄, wherein R₄ is nitrogen-containing heterocycloalkyl, is introduced by nucleophile aromatic substitution using an appropriate base, for example DiPEA, NaH or ButOK, and appropriate solvent, for example DMSO, DMF or CH3CN. The reaction is for example performed under elevated temperature.

Step Dl : Reduction of the nitrogroup to give the corresponding aniline can for example be performed using NH4CI and Zn or Fe and AcOH or using H₂ in the presence of Pd on carbon.

Step D2: Reduction of the nitrogroup in the present of triphenylmethyl protecting group can for example be performed using Zn and NH4CI or Fe and AcOH as reducing agents. Step E: Amide coupling can for example be performed by reacting benzoylchloride with an aniline in the presence of a base, for example DIPEA or K2C03, using for example CH2CL2 or DMF as solvent.

Step F: R₅, wherein R₅ represents -ORa, -SRa, -NRaRb or heterocycloalkyl, is for example introduced by nucleophilic substitution. The benzylic chloride is for example substituted by an amine in the presence of a base, for example K₂C0₃, DIPEA or CsC0₃, using an appropriate solvent, for example DMSO, DMF, or CH₂CI₂ as solvent.

Alternatively, some compounds of formula I with Ri equal to CF₃, R₂ equal to CI , and R₄ equal to CI may for example be prepared according to the method outlined in scheme 3.

Scheme 3

Starting materials are either commercially available or are prepared from commercially available molecules by synthetic transformations according to standard procedures known to a chemist skilled in the art of organic synthesis.

Furthermore, some compounds of formula I with Ri equal to CF₃, R₂ equal to CI, and R₄ equal to CI and X equal to CH and Y equal to N may for example be prepared according to the method outlined in scheme 4.

INTERMEDIATES Intermediate 1.1 :

(5-chloro-2-nitro-phenyl)-(l-tritylpyrazol-4-yl)metha

Intermediate 1.1 can be prepared as described in EP0574781, example 2, compound 13.

Intermediate 1.2 :

1 - [4-chloro-3-(trifluoromethy I) phenyl] -4-iodo-pyrazole

sodium ascorbate

DMSO

A mixture of aryl bromide (5.2 g, 20 mmol), pyrazole (2.72 g, 40 mmol), sodium ascorbate (200 mg,l mmol), Cul (380 mg, 2 mmol), trans-N,N'-dimethyl-cyclohexane- 1,2-diamine (430 mg, 3 mmol), and Na₂C0₃ (4.0 g, 40 mmol) in DMSO was degassed by using argon and stirred at 140 °C for 4 h and at 100 °C for two days. The reaction mixture was then poured into H₂0/Et₂0. After phase separation, the aqueous phase was extracted twice with Et20. The combined organic phases were washed with brine, dried over Na2S04 and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with CH₂CI₂, giving the intermediate l-[4-chloro-3- (trifluoromethyl) phenyl] pyrazole.

A mixture of l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole (3.5 g, 14.19 mmol) and NIS (4.4 g, 19.56 mmol) in AcOH (25 mL) was microwaved at 150 °C for 15 min. The solution was concentrated to remove AcOH . The residue was taken up in 10% NaHS0₃ solution/Et₂0. After phase separation, the aqueous phase was extracted twice with Et₂0. The combined organic phases were washed with aqueous NaHC03 solution, dried over Na2S04, and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with PE/CH₂CI₂ 2 : 1, giving the title compound as a solid.

1H NMR (DMSO-d6, 300 MHz) δ 8.94 (s, 1H), 8.27 (s, 1H), 8.16 (d, 1H), 7.93 (s, 1H), 7.88 (d, 1H).

Intermediate 1.3 :

(5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-4-yl] methanol

To a solution of l-[4-chloro-3-(trifluoromethyl)phenyl]-4-iodo-pyrazole (2 g, 6.28 mmol) in THF (20 mL) was added dropwise isopropylmagnesiumchloride (2 M in THF, 3.5 mL, 7.00 mL) at -20 °C. The reaction solution was stirred at 0°C for 1 h. To this solution was added 5-chloro-2-nitro-benzaldehyde (1.40 g, 7.53 mmol). The solution was stirred at ambient temperature for 2 h. The reaction was quenched with aqueous NH₄CI solution. The mixture was extracted twice with Et₂0. The combined organic phases were dried and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with PE/ethyl acetate 8 : 1 → 4: 1, giving the title compound, which was not pure, but used directly to the next step without further purification. 1H NMR (DMSO-d6, 300 MHz) δ 8.54 (s, 1H), 8.23 (d, 1H), 8.15 (dd, 1H), 8.04 (d, 1H), 7.97 (d, 1H), 7.82 (d, 1H), 7.74 (s, 1H), 7.66 (dd, 1H), 6.33 (d, 1H), 6.26 (d, 1H) .

Intermediate 1.4 :

(5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-4- yl]methanone

To a solution of (5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl)phenyl]pyrazol-4-yl]methanol (2.1 g) in CH₂CI₂ (30 ml_) was added Dess-Martin periodinane (3.0 g, 7.00 mmol) in portions at room temperature. The obtained mixture was stirred at room temperature for 1 h. The mixture was then filtered through a short pad of silica gel and washed with CH₂CI₂. The filtrated was concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with PE/ethyl acetate 8 : 1, giving a solid after evaporation. The solid was washed with small amount of MeOH, giving the title compound.

1H NMR (CDCI₃, 300 MHz) δ 8.32 (s, 1H), 8.20 (d, 1H), 8.07 (d, 1H), 7.96 (d, 1H), 7.83 (dd, 1H), 7.71 - 7.60 (m, 2H), 7.51 (d, 1H).

Intermediate 1.5 :

(2-amino-5-chloro-phenyl)-[ l-[4-chloro-3-(trifluoromethy I) phenyl] pyrazol-4- yl]methanone

To a suspension of (5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl) phenyl] pyrazol-4-yl]metha none

(1.7 g, 3.96 mmol) in CH₃COOH (80 mL) and H₂0 (20 mL) was heated to 50 °C, then Fe (1.1 g, 19.8 mmol) was added. The reaction was stirred at 50 °C for 2 h. After cooling to room temperature, filtrated to remove the solid present, the filtrate was extracted with CH₂CI₂. The combined organic layer was washed by saturated aqueous sodium carbonate (200 mL) and brine (300 mL), dried over anhydrous sodium sulfate. The solvent was distilled off in vacuo. The residue was purified by chromatography on silica gel, eluting with PE/ethyl acetate 10 : 1→ 3 : 1, giving the title compound as a yellow solid

1H NMR (DMSO-d6, 300 MHz), δ 9.26 (s, 1H), 8.41 (d, 1H), 8.30 (dd, 1H), 8.21 (s, 1H), 7.92 (d, 1H), 7.65 (d, 1H), 7.33 (dd, 1H), 7.01 (s, 2H), 6.89 (d, 1H).

Example 1 (Compound 1)

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (chloromethyl)benzamide

To a solution of (2-amino-5-chloro-phenyl)-[ l-[4-chloro-3- (trifluoromethyl)phenyl]pyrazol-4-yl]methanone (6 g, 15 mmol) and N- ethyldiisopropylamine (9.68 mL, 75mmol, 5eq) in CH₂CI₂ (10 mL) was added dropwise 3-(chloromethyl)benzoyl chloride (4.25 mL, 22.5 mmol,1.5eq) at 0 °C. The mixture was stirred at 0 °C for 15 minutes before it was diluted with CH₂CI₂ (100 mL) and washed with water. The aqueous phase was extracted 3 times with CH₂CI₂ and the combined organic phases were dried over MgS04. Evaporation to dryness afforded the title compound.

1H NMR (CDCI3 300 MHz) δ 11.60 (s, 1H), 8.83 (d, 1H), 8.48 (s, 1H), 8.17 (s, 1H), 8.14 (d, 1H), 8.05 (t, 1H), 7.95 (dt, 1H), 7.91 - 7.83 (m, 2H), 7.72 - 7.48 (m, 4H), 4.68 (s, 2H).

Intermediate 2.1 :

[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-4-yl]-[2-nitro-5-(l- piperidyl) phenyl] metha none

A suspension of (5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl)phenyl]pyrazol-4-yl]methanone (786 mg, 1.82 mmol) in piperidine (10 mL) was stirred at 90 °C for 20 min. The obtained solution was concentrated in vacuo and the residue was taken up in H₂0/CH₂Cl₂. After phase separation, the aqueous phase was extracted twice with CH₂CI₂. The combined organic phases were dried over MgS04 and concentrated in vacuo. The residue was purified by filtration through a short column of silica gel, eluting with CH2CI₂, giving the title compound as a yellow solid . 1H NMR (DMSO-d6, 300 MHz), δ 9.15 (s, 1H), 8.35 (d, 1H), 8.27 (dd, 1H), 8.20 (s, 1H), 8.10 (d, 1H), 7.89 (d, 1H), 7.11 (dd, 1H), 6.91 (d, 1H), 3.60 - 3.47 (m, 4H), 1.73 - 1.47 (m, 2H).

Intermediate 2.2 :

[2-amino-5-(l-piperidyl) phenyl] -[ 1- [4-chloro-3-(trifluoromethy I) phenyl] pyrazol -4- yl]methanone

A mixture of [ l-(4-chloro-3-trifluoromethyl-phenyl)-pyrazol-4-yl]-(2-nitro-5-(l- piperidyl)phenyl)-methanone (625 mg, 1.3 mmol), NH₄CI (349 mg, 6.5 mmol), and Zn (850 mg, 13.0 mmol) in MeOH (25 mL) was refluxed for 2 h. The mixture was filtered . The filtrate was concentrated in vacuo. Column chromatography on silica gel, eluting with 2% of MeOH in CH₂CI₂, afforded the title compound as a solid. 1H NMR (DMSO-d6, 300 MHz), δ 9.24 (s, 1H), 8.39 (d, 1H), 8.30 (dd, 1H), 8.18 (s, 1H), 7.92 (d, 1H), 7.21 - 7.07 (m, 1H), 6.79 (d, 1H), 6.66 - 6.42 (m, 2H), 3.03 - 2.80 (m, 4H), 1.59 (d, 4H), 1.46 (d, 2H).

Example 2 (Compound 2)

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (1 -pi peridyl) phenyl] benzamide

To a solution of (2-amino-5-(l-pipendyl)phenyl)-[ l-(4-chloro-3-tnfluoromethyl-phenyl)- pyrazol-4-yl]-methanone (730 mg, 1.62 mmol) and N-ethyldiisopropylamine (0.85 ml_, 4.90 mmol) in CH₂CI₂ (10 mL) was added dropwise 3-(chloromethyl)benzoyl chloride (0.3 mL, 2.11 mmol) at 0 °C. The mixture was stirred at room temperature for 1 h and then quenched with saturated aqueous solution of NaHC03 and H₂0 (1/1). After phase separation, the aqueous phase was extracted with CH₂CI₂. The combined organic phases were dried over Na₂S0₄ and concentrated in vacuo. The residue was purified by chromatography on silica gel, eluting with 20% to 40 % of ethyl acetate in PE, giving a solid after evaporation. The solid was washed with small amount of hexane, giving the title compound

1H NMR (DMSO-d6, 300 MHz), δ 10.46 (s, 1H), 9.17 (s, 1H), 8.32 (d, 1H), 8.24 (dd, 1H), 8.14 (s, 1H), 7.90 (d, 1H), 7.79 (s, 1H), 7.71 (d, 1H), 7.59 (t, 2H), 7.44 (t, 1H), 7.24 (dd, 1H), 7.14 (d, 1H), 4.74 (s, 2H), 3.30 (s, 1H), 3.24 - 3.12 (m, 3H), 1.82 - 1.41 (m, 6H).

Intermediate 3.1

(5-bromo-2-nitro-pheny I)- [ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-4-yl] methanol

To a solution of l-[4-chloro-3-(trifluoromethyl)phenyl]-4-iodo-pyrazole (4,86g, 13 mmol) in THF (40 mL) was added dropwise isopropylmagnesiumchloride (1,3 M in THF, 11 mL) at 0 °C. The reaction solution was stirred at 0°C for 75 min. To this solution was added 5-bromo-2-nitro-benzaldehyde (3,0 g, 13 mmol). The solution was stirred at ambient temperature for 1,5 h. The reaction was quenched with aqueous NH₄CI solution. The mixture was extracted twice with EtOAC. The combined organic phases were dried and concentrated in vacuo. Purification of the residue by chromatography on silica gel, eluting with Heptane/ethyl acetate 100 : 0→ 0: 100, afforded the title compound.

1HNMR (CDCI3, 300MHz), δ 8.12 (d, 1H), 8.00 (d, 1H), 7.93 - 7.86 (m, 2H), 7.76 (dd, 1H), 7.66 (s, 1H), 7.62 (dd, 1H), 7.57 (d, 1H), 6.54 (s, 1H).

Intermediate 3.2 : (2-amino-5-bromo-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl) phenyl] pyrazol-4-yl]metha none

To a solution of (5-bromo-2-nitro-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl)phenyl]pyrazol-4-yl]methanol (4,91 g) in CH₂CI₂ (50 ml_) was added Dess-Martin periodinane (4,63 g, 10.92 mmol) in portions at room temperature. The obtained mixture was stirred at room temperature for 2 h. The mixture was extracted with saturated Na₂C0₃, H₂0 and brine. The organic fraction was dried, filtered, and evaporated. The compound was used without further purification.

(5-bromo-2-nitro-phenyl)-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazol-4- yl]methanone was suspended in MeOH and NH4CI was added. Zn powder was added in small portions at rt. The reaction was heated to reflux until the reaction was completed . The reaction was filtered, evaporated and purified by chromatography on silica gel, eluting with Heptane 100% to Heptane/EtOAc 25/75, to afford the title compound . 1HNMR (CDCI3, 300MHz), δ 8.39 (s, 1H), 8.13 (d, 1H), 8.10 (s, 1H), 7.87 (dd, 1H), 7.83 (d, 1H), 7.65 (d, 1H), 7.39 (dd, 1H), 6.66 (d, 1H), 5.94 (s, 2H).

Example 3 (Compound 3)

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbony I] phenyl] -3- (chloromethyl)benzamide

To a solution of (2-amino-5-bromo-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl)phenyl]pyrazol-4-yl]methanone (1,65 g, 3,71 mmol) and Et3N (1,55 mL, 11,13 mmol) in CH₂CI₂ (15 mL) was added a solution of 3-(chloromethyl)benzoyl chloride (0.68 mL, 4.82 mmol) in CH₂CI₂ (4ml) at 0 °C. The mixture was stirred at room temperature. After 18 h 3-(chloromethyl)benzoyl chloride (0.68 mL, 4.82 mmol) was added. The reaction was stirred at rt until the reaction was completed .

The reaction was quenched with H₂0, the aqueous was extracted with CH₂CI₂. The combined organic phases were dried over Na2S04 and concentrated in vacuo.

The solid was washed with CH₂CI₂ to afford the title compound.

1HNMR (DMSO-d6, 300MHz), δ 10.75 (s, 1H), 9.24 (s, 1H), 8.34 (d, 1H), 8.24 (dd, 1H), 8.18 (s, 1H), 7.90 (d, 1H), 7.88 - 7.78 (m, 3H), 7.77 - 7.70 (m, 2H), 7.65 - 7.57 (m, 1H), 7.47 (t, 1H), 4.75 (s, 2H) .

Intermediate 4.1 :

(5-chloro-2-nitro-phenyl)-(lH-imidazol-4-yl) methanol

To a solution of 4-iodo-lH-imidazole (2 g, 10.3 mmol) in THF (20 mL) was added dropwise isopropylmagnesiumchloride (2 M in THF, 12 mL, 23.7 mmol) at room temperature. The reaction solution was stirred at rt for 2 h. To this solution was added 5-chloro-2-nitro-benzaldehyde (2.9 g, 15.5 mmol) in 10 mL THF. The solution was stirred at room temperature for 2 h. The reaction was quenched with aqueous NH₄CI solution. The mixture was extracted twice with EA. The combined organic phases were dried and concentrated in vacuo. The residue was purified silica gel chromatography column (PE/EA, 3/1 to 1/1) to give the title compound as a brown solid. Intermediate 4.2 :

(5-chloro-2-nitro-phenyl)-(lH-imidazol-4-yl)methanone

To a solution of (5-chloro-2-nitro-phenyl)-(lH-imidazol-4-yl)methanol (2.1 g, 8.3 mmol) in dichloroethane (40 mL) was added Mn0₂ (5.8 g, 66.2 mmol). The reaction solution was stirred at 80 °C for 3 h. The insoluble material was filtered off, and the filtrate was concentrated in vacuo to afford crude target compound.

Intermediate 4.3 :

(5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-(trifluoromethyl)phenyl]imidazol-4-

A mixture of (5-chloro-2-nitro-phenyl)-(lH-imidazol-4-yl)methanone (500 mg, 1.99 mmol), 4-bromo-l-chloro-2-(trifluoromethyl)benzene (1.03 g, 3.97 mmol), Cul (38 mg, 0.20 mmol), trans-N,N'-dimethyl-cyclohexane-l,2-diamine (42 mg, 0.30 mmol) and Cs₂C0₃ (1.30 g, 3.97 mmol) in DMSO (10 mL, which has been degassed with argon) was heated with microwaves for 50 minutes at 120 °C. Water and EA was added, and the organic phase was isolated and evaporated to dryness. The resulting mixture was purified by silica gel chromatography column (PE/EA, 5/1 to 2/1) to obtain the title compound as a yellow oil .

Intermediate 4.4 :

(2-amino-5-chloro-phenyl)-[ l-[4-chloro-3-(trifluoromethy I) phenyl] imidazol-4- yl]methanone

A solution of (5-chloro-2-nitro-phenyl)-[ l-[4-chloro-3-(tnfluoromethyl)phenyl]imidazol- 4-yl]methanone (140 mg, 0.33 mmol) in AcOH (10 mL) was heated to 60°C, then Fe (182 mg, 3.30 mmol) was added. The reaction mixture was stirred at 60°C for 3 h. The mixture was filtered. The filtrate was concentrated in vacuo. The resulting mixture was poured into saturated Na₂C0₃ (10 mL), extracted with EA (3* 10 mL). The combined organic layers were dried and concentrated in vacuo to afford the title compound as a yellow solid .

Example 4 (Compound 4)

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]imidazole-4-carbonyl]phenyl]-3- (chloromethyl)benzamide

To a mixture of (2-amino-5-chloro-phenyl)-[ l-[4-chloro-3-

(trifluoromethyl)phenyl]imidazol-4-yl]methanone (120 mg, 0.30 mmol) and DIPEA (78 mg, 0.60 mmol) in CH₂CI₂ (5 mL) was added dropwise 3-(chloromethyl)benzoyl chloride (85 mg, 0.45 mmol). The reaction solution was stirred at rt for 3 h. The resulting mixture was poured into water (10 mL), extracted with CH₂CI₂ (3* 10 mL). The combined organic layers were dried and concentrated in vacuo to afford crude title compound .

Example 5 (Compound 5)

3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl] phenyl] methyl -methyl-ami no] propanoic acid

Step 1.

A mixture of N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]-3-(chloromethyl)benzamide (Compound 1) (100 mg, 0.18 mmol), Cs₂C0₃ (237 mg, 0.73 mmol) and ethyl 3-aminopropanoate hydrochloride (56 mg, 0.36 mmol) in MeCN (5 ml_) was stirred at 50 °C overnight (tested by TLC) . Then the reaction mixture was filtered and the filtrate was concentrated to get crude product, which was purified by prep-TLC (PE/EA/MeOH = 1/1/0.1) to obtain a yellow residue.

Step 2.

A solution of ethyl 3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl]phenyl]methylamino]propanoate (40 mg, 0.063 mmol), NaBH₃CN (40 mg, 0.63 mmol) and HCHO (103 mg, 1.26 mmol, 37% water solution) in AcOH (5 ml.) was stirred at 30 °C for 3h (tested by TLC). Then water (10 mL) was added and the solution was concentrated to get crude product, which was used for next step without further purification.

Step 3.

A mixture of ethyl 3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl]phenyl]methyl-methyl-amino]propanoate (150 mg, crude), LiOH (6mL, 10% water solution) and THF (2 mL) was stirred at 40 °C for 2h (tested by TLC). Then the reaction mixture was acidified with concentrated HCI and extracted with CH₂CI₂ (20 mL, 3 times). The CH₂CI2 phase was dried with Na2S0₄ and concentrated to get crude product, which was purified by preparative HPLC/MS_method Al to obtain the title compound as a yellow solid. 1H NMR (CDCI3, 500MHz) δ= 2.50 (3H, s), 2.69-2.70 (2H, m), 3.03-3.04 (2H, m), 4.00 (2H, s ), 7.56-7.67 (4H, m), 7.84-7.99 (4H, m), 8.13-8.17 (2H, m), 8.63 ( 1H, s), 8.76 ( 1H, d), 11.66 ( 1 H, s) . Example 6 (Compound 6)

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- [ [4-( 1-pi peridyl) - 1-piperidy I] methyl] benzamide

A mixture of N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl] pyrazole-4- carbonyl] phenyl]-3-(chloromethyl)benzamide (Compound 1) (600 mg, 1.09 mmol), K2C0₃ (450 mg, 10.9 mmol) and l-(4-piperidyl)piperidine (276 mg, 1.63 mmol) in MeCN (60 ml_) was stirred at 60 °C overnight. Then the mixture was filtered and the filtrate was concentrated to get a residue, which was purified by prepa rative HPLC/MS method Al to obtain the title compound as a yellow solid .

1H NMR (CDCI3, 500MHz) δ= 1..58 (s, 2H), 1.83- 1.92 (m, 6H), 2.02-2.04 (d, 2H), 2. 11 ~2.15 (m, 2H ), 3.0~3.2(m, 6H),3.62(s. 2H), 7.46-7.51 (m, 2H), 7.61-7.68 (dd, 2H), 7.88~7.94(dd, 4H), ,8.14(s, l H),8.17~8.18(d, lH),8.51(s, l H),8.59(s, 1H), 8.81 ~8.83(dd, 1 H), 11.54 (s, 1 H) .

Example 7 (Compound 7)

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (morpholinomethyl) benzamide

A mixture of N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]-3-(chloromethyl)benzamide (Compound 1) (1.0 g, 1.8 mmol), K2C0₃ (1 g, 7.3 mmol) and morpholine (316 mg, 3.6 mmol) in MeCN (80 mL) was stirred at 60 °C overnight. Then the mixture was filtered and the filtrate was concentrated to get a residue, which was purified by preparative HPLC/MSjnethod Al to obtain the title compound as a white solid.

1HNMR (CDCI3, 500MHz) δ= 2.54-2.55 (m, 4H), 3.66 (s, 2H), 3.77-3.78 (m, 4H), 7.48- 7.69 (m, 4H), 7.85-7.91 (m, 3H), 8.01 (s, 1H), 8.13-8.17 (m, 2H), 8.47 (s, 1H), 8.83 (d, 1H), 11.57 (s, 1H).

Example 8 (Compound 8)

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (tetrahydrofuran-3-yloxy methyl) benzamide

A mixture of N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]-3-(chloromethyl)benzamide (Compound 1) (60 mg, 0.11 mmol), tetrahydrofuran-3-ol (20 mg, 0.22mmol), and tBuOK (24 mg, 0.22 mmol) in DMF (3 mL) was heated in a microwave oven for 1 hour at 120 °C. The mixture was poured into H₂0 (10 mL), extracted with EA (3 x 20 mL), dried and concentrated . The resulting mixture was purified by preparative HPLC/MS_method Al to obtain the title compound as a light yellow solid. 1HNMR (CDCI3, 500MHz) 5= 11.62 (s, IH), 8.84 (d, IH), 8.53 (s, IH), 8.16 (s, 2H), 8.02 (s, IH), 7.92 (d, IH), 7.90 (dd, IH), 7.86 (d, IH), 7.67 (d, IH), 7.62 (dd, IH), 7.55 (d, IH), 7.51 (t, IH), 4.65-4.59 (m, 2H), 4.29-4.27 (m, IH), 4.01-3.95 (m, 2H), 3.88-3.84 (m, 2H), 2.13-2.03 (m, 2H).

Example 9 (Compound 9)

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (piperazin-l-yl methyl) benzamide

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (chloromethyl)benzamide (Compound 1) (25 mg, 0.045 mmol) was dissolved in dry DMF (500 μΙ_) followed by addition of DIPEA (31 μΙ_, 0.18 mmol) and piperazine (12 mg,

0.136 mmol). The mixture was heated in a microwave oven for 15 minutes at 150 °C, followed by HPLC purification method A2(eluting with 50% to 100 % MeCN), to afford the title compound as a white solid. 1HNMR (CDCI3, 500MHz) δ= 11.64 (s, IH), 8.86 (d, IH), 8.77 (s, IH), 8.22 (d, IH), 8.13 (s, IH), 8.06 (s, IH), 7.99 (dd, IH), 7.96 - 7.90 (m, IH), 7.85 (d, IH), 7.68 - 7.60 (m, 2H), 7.55 - 7.45 (m, 2H), 3.69 (s, 2H), 3.25 (s, 4H), 2.74 (s, 4H).

Example 10 (Compound 10)

3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl]phenyl]methylsulfanyl]propanoic acid

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (chloromethyl)benzamide (Compound 1) (43 mg, 0.078 mmol) was dissolved in dry DMF (800 μΙ_) followed by addition of DIPEA (80 μΙ_, 0.45 mmol) and mercaptopropanoicacid (30 μΙ_, 0.345 mmol). The mixture was heated in a microwave oven for 15 minutes at 150 °C, followed by HPLC purification method A2 (eluting with 40% to 100 % MeCN), to afford the title compound as a white solid .

1HNMR (CDCI3, 500MHz), δ 11.59 (s, 1H), 8.82 (d, 1H), 8.55 (s, 1H), 8.19 - 8.12 (m, 2H), 7.94 (s, 1H), 7.92 - 7.86 (m, 2H), 7.85 (d, 1H), 7.67 (d, 1H), 7.63 (dd, 1H), 7.55 (d, 1H), 7.49 (t, 1H), 7.26 (s, 1H), 3.84 (s, 2H), 2.72 (dd, 2H), 2.65 (dd, 2H).

Example 11 (Compound 11)

3-[[3-[[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- i peridyl)phenyl]carbamoyl] phenyl] methylsulfany I] propanoic acid

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (l-piperidyl)phenyl]benzamide (Compound 2) (50 mg, 0.083 mmol) was dissolved in dry DMF followed by addition of DIPEA (59 μΙ_, 0.336 mmol) and mercaptopropanoicacid (15 μΙ_, 0.167 mmol). The mixture was heated in a microwave oven for 15 minutes at 100 °C, followed by HPLC purification method A2 (eluting with 30% to 100 % MeCN), to afford the title compound. IHNMR (DMSO-d6, 600MHz), δ 10.54 - 10.44 (m, IH), 9.18 (s, IH), 8.33 (d, IH), 8.24 (dd, IH), 8.16 (s, IH), 7.90 (d, IH), 7.70 (s, IH), 7.66 (d, IH), 7.64 (d, IH), 7.47 (d, IH), 7.39 (dd, IH), 7.24 (dd, IH), 7.16 (d, IH), 3.74 (s, 2H), 3.19 (dd, 4H), 2.53 (dd, 2H), 2.47 (dd, 2H), 1.69 - 1.60 (m, 4H), 1.59 - 1.50 (m, 2H).

Example 12 (Compound 12)

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- iperidyl) phenyl] -3-(lH-l, 2, 4-triazol-3-ylsulfany I methyl) benzamide

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (l-piperidyl)phenyl]benzamide (Compound 2) (20 mg, 0.033 mmol) was mixed with 1H- l,2,4-triazole-3-thiol (3 mg, 0.033 mmol) and K2C0₃ (9 mg, 0.067 mmol) and dissolved in DMF (0.5ml_). The mixture was heated in a microwave oven for 5 minutes at 100 °C, followed by prep. HPLC purification method A2, to afford the title compound.

IHNMR (DMSO-d6, 300MHz) IH NMR, δ 10.46 (s, IH), 9.17 (s, IH), 8.41 (s, IH), 8.32 (d, IH), 8.23 (dd, IH), 8.15 (s, IH), 7.88 (d, IH), 7.77 (s, IH), 7.70 - 7.58 (m, 2H), 7.55 - 7.47 (m, IH), 7.36 (t, IH), 7.23 (dd, IH), 7.15 (d, IH), 4.34 (s, 2H), 3.22 - 3.16 (m, 4H), 1.70 - 1.48 (m, 6H).

Example 13 (Compound 13)

3-[[bis(2-hydroxyethyl)amino]methyl]-N-[2-[ l-[4-chloro-3-

(trifluoromethyl) phenyl] pyrazole-4-carbonyl]-4-(l-piperidyl) phenyl] benzamide

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (l-piperidyl)phenyl]benzamide (Compound 2) (200 mg, 0.33 mmol) was dissolved in dry DMF (4 mL) followed by addition of 2-(2-hydroxyethylamino)ethanol (105 mg, 0.998 mmol) and K₂C0₃ (92 mg, 0.665 mmol). The mixture was heated in a microwave oven for 15 minutes at 120 °C. The reaction was added water and extracted 3 times by Et₂0 and 2 times by CH₂CI₂. The combined organic fractions was evaporated and purified by chromatography on silica gel, eluting with 98% CH₂CI₂ / 2%Et₃N to 80%CH₂CI₂ / 18% MeOH / 2% Et₃N, to afford the title compound .

1HNMR (CDCI3, 300MHz), δ 11.53 (s, 1H), 8.78 (s, 1H), 8.67 (d, 1H), 8.27 - 8.16 (m, 2H), 8.14 (s, 1H), 8.05 - 7.87 (m, 2H), 7.66 (d, 1H), 7.46 (d, 2H), 7.42 - 7.35 (m, 1H), 7.31 - 7.26 (m, 1H), 3.88 (s, 2H), 3.74 (dd, 4H), 3.17 (dd, 4H), 2.83 (dd, 4H), 1.78 - 1.69 (m, 4H), 1.64 - 1.56 (m, 2H).

Example 14 (Compound 14)

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- piperidyl) phenyl] -3-(2-hydroxyethoxymethy I) benzamide

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (l-piperidyl)phenyl]benzamide (Compound 2) was dissolved in ethylene glycol (0.5 mL). The mixture was shaken at 125 °C for an appropriate time and purified by prep. HPLC. 1HNMR (DMSO-d6, 300MHz), δ 10.47 (s, IH), 9.17 (s, IH), 8.32 (d, IH), 8.23 (dd, IH), 8.15 (s, IH), 7.90 (d, IH), 7.76 - 7.55 (m, 3H), 7.55 - 7.33 (m, 2H), 7.24 (dd, IH), 7.15 (d, IH), 4.62 (s, IH), 4.47 (s, 2H), 3.61 - 3.48 (m, 2H), 3.46 - 3.41 (m, 2H), 3.22 - 3.15 (m, 4H), 1.90 - 1.35 (m, 6H).

Example 15 (Compound 15)

3-[[3-[[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- piperidyl)phenyl]carbamoyl] phenyl] methyl -methyl-ami no] propanoic acid

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4- (l-piperidyl)phenyl]benzamide (Compound 2) (20 mg, 0.033 mmol) was dissolved in dry DMF (400 μΙ_) followed by addition of 3-(methylamino)propanoic acid hydrochloride (14 mg, 0.0997 mmol) and K₂C0₃ (23 mg, 0.165 mmol). The mixture was heated in a microwave oven for 15 minutes at 150 °C, followed by prep. HPLC purification method A2 (eluting with 40% to 100 % MeCN), to afford the title compound.

1HNMR (DMSO-d6, 300MHz), δ 10.44 (s, IH), 9.15 (s, IH), 8.31 (d, IH), 8.23 (dd, IH),

8.14 (s, IH), 7.90 (d, IH), 7.68 - 7.60 (m, 3H), 7.47 - 7.34 (m, 2H), 7.24 (dd, IH),

7.15 (d, IH), 3.47 (s, 2H), 3.22 - 3.16 (m, 4H), 2.66 - 2.56 (m, 2H), 2.44 - 2.36 (m, 2H), 2.07 (s, 3H), 1.72 - 1.47 (m, 6H).

Example 16 (Compound 16)

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- piperidyl) phenyl] -3-(piperazin-l-yl methyl) benzamide

3-(chloromethyl)-N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-

(l-piperidyl)phenyl]benzamide (Compound 2) (3.8 g, 6.4 mmol) was suspended in MeCN (10 ml_). Piperazine (64 mmol) was added and the mixture was briefly heated to reflux with a heatgun. The solution was refluxed for approx. 2 minutes and then cooled to rt. Precipitation was observed and water (50 ml_) was slowly added. Filtration and subsequent washings with water afforded the title compound.

IHNMR (DMSO-d6, 300MHz), δ 10.45 (s, IH), 9.14 (s, IH), 8.30 (d, IH), 8.22 (dd, IH), 8.14 (s, IH), 7.89 (d, IH), 7.72 - 7.55 (m, 3H), 7.47 - 7.31 (m, 2H), 7.24 (dd, IH), 7.15 (d, IH), 3.35 (s, 2H), 3.22 - 3.18 (m, 4H), 2.70 - 2.57 (m, 4H), 2.32 - 2.13 (m, 4H), 1.73 - 1.42 (m, 6H).

Example 17 (Compound 17)

N- [4-bromo-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (8,9-dihydro-6H-pyrido[2,3-b] [ l,6]naphthyridin-7-ylmethyl)benzamide

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]phenyl]-3- (chloromethyl)benzamide (Compound 3) (50 mg, 0.084 mmol) was dissolved in dry DMF (1 ml.) followed by addition of DIPEA (29 μΙ_, 0.167 mmol) and 6,7,8,9- tetrahydropyrido[2,3-b] [ l,6]naphthyridine (46 mg, 0.25 mmol). The mixture was heated in a microwave oven for 15 minutes at 120 °C, followed by HPLC purification method A2 (eluting with 40% to 100 % MeCN), to afford the title compound as a brown solid.

IHNMR (DMSO-d6, 300MHz), δ= 10.98 (s, IH), 9.29 - 9.23 (m, 2H), 8.83 (dd, IH), 8.62 (s, IH), 8.35 (d, IH), 8.28 (dd, IH), 8.22 - 8.17 (m, 2H), 8.03 - 7.72 (m, 9H), 7.60 (t, IH), 4.64 (d, 4H), 3.57 (s, 4H).

Example 18 (Compound 18)

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbony I] phenyl] -3-(2- hydroxyethoxymethyl)benzamide

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbony I] phenyl] -3- (chloromethyl)benzamide (Compound 3) (100 mg, 0.168 mmol) was dissolved in dry DMF (1 ml_) and ethylene glycol (1 ml_). The mixture was heated in a microwave oven for 15 minutes at 150 °C. Additional Ethylene glycol (1 ml_) was added and the reaction was heated in a microwave oven for 15 minutes at 150 °C. The mixture was purified by HPLC (Method A2) followed by chromatography on silica gel, eluting with Pe/EtOAc 9: 1 to Pe/EtOAc 1 : 1, to afford the title compound.

IHNMR (DMSO-d6, 300MHz), δ 10.74 (s, IH), 9.23 (s, IH), 8.34 (d, IH), 8.25 (dd, IH), 8.18 (s, IH), 7.91 (d, IH), 7.88 - 7.81 (m, 2H), 7.77 (d, IH), 7.74 - 7.65 (m, 2H), 7.51 (d, IH), 7.43 (t, IH), 4.48 (s, 2H), 3.57 - 3.50 (m, 2H), 3.47 - 3.42 (m, 2H).

Example 19 (Compound 19)

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] imidazole-4-carbonyl] phenyl] -3- (piperazin-l-yl methyl) benzamide

A mixture of N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]imidazole-4- carbonyl]phenyl]-3-(chloromethyl)benzamide (Compound 4)

(160 mg, crude) and piperazine (258 mg, 30 mmol) in MeCN (5 mL) was stirred at reflux for 4 h. The mixture was concentrated, and the resulting material was purified by preparative HPLC/MSjnethod Al to afford the title compound as a yellow solid.

1HNMR (CDCI3) δ= 12.06 (s, 1H), 8.89 (d, 1H), 8.63 (d, 1H), 8.46 (brs, 1H), 8.28 (s, 1H), 8.06 (s, 1H), 7.98-7.96 (m, 2H), 7.85 (d, 1H), 7.73-7.66 (m, 2H), 7.60 (dd, 2H), 7.48 ( d, 2H), 3.68 (s, 2H), 3.21 (s, 4H), 2.74 (s, 4H).

Example 20 (Compound 20)

N-[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- iperidyl) phenyl] -3-(2-hydroxyethylsulfanyl methyl) benzamide

(l-piperidyl)phenyl]benzamide (Compound 2) (80 mg, 0.133 mmol) was dissolved in dry

DMF (5 mL) followed by addition of 2-mercapto-ethanol (28 μί, 0.399 mmol) and K₂C0₃

(37 mg, 0.266 mmol). The mixture was heated in a microwave oven for 10 mi nutes at 100 °C, followed by prep. HPLC purification method A2 (eluting with 30% to 100 %

MeCN), to afford the title compound. IHNMR (DMSO-d6, 300MHz), δ 10.47 (s, IH), 9.17 (s, IH), 8.33 (d, IH), 8.24 (dd, IH), 8.15 (s, IH), 7.90 (d, IH), 7.78 - 7.58 (m, 3H), 7.51 - 7.42 (m, IH), 7.38 (t, IH), 7.24 (dd, IH), 7.16 (d, IH), 4.75 (t, IH), 3.49 (td, 2H), 3.19 (t, 4H), 2.45 (t, 2H), 1.71 - 1.39 (m, 7H).

Example 21

Npt2B phosphate uptake assay

CHO cells stably expressing full-length human Npt2B (hNpt2B, GenBank accession no. NM_006424) or rat Npt2B (ratNpt2B, GenBank accession no. BC070898) were used to evaluate compounds for their inhibitory activity against sodium-dependent transport of radiolabeled (33P) phosphate. For this purpose, test and negative control wells, respectively, on a 96-well plate were incubated with 100 ul assay buffer containing sodium (137 mM NaCI, 5.4 mM KCI, 2.8 mM CaCI₂, 1.2 mM MgS0₄, 14 mM Tris HCI, 0.1 mM KH₂P0₄, pH 7.4) and 1 uCi/ml 33P-labeled phosphate. Positive control wells were incubated with 100 ul assay buffer containing choline instead of sodium ( 137 mM

C5H 140NCI, 5.4 mM KCI, 2.8 mM CaCI₂, 1.2 mM MgS0₄, 14 mM Tris HCI, 0.1 mM

KH₂P0₄, pH 7.4) and 1 uCi/ml 33P-labeled phosphate. Immediately thereafter, various concentrations of test compound were loaded to their designated wells. As vehicle control, DMSO was loaded to the negative and positive control wells, resulting in a final DMSO concentration of 1% v/v in all 96 wells. After that, the plate was gently agitated at 600 rpm for 1 min and then incubated for 30 min at 30 ° C, followed by 4-times washing with each 150 ul/well ice cold washing buffer (137 mM NaCI, 14 mM Tris HCI, pH 7.4). Cells were then lysed with 20 ul/well lysis buffer (0.5% Triton X-100) and agitated at 900 rpm for 5 min. Finally, 80 ul/well of scintillation buffer (Microscint 40) were added and radioactivity was analysed with a scintillation counter (Microbeta Trilux). All experiments were performed in duplicate.

The relative IC50 value, a measure of the potency of the compound in inhibiting the human or rat Npt2B, was obtained from a 4 parameter curve fit and defined as the concentration of compound giving a response midway between the minimal and maximal inhibition. The absolute IC50 value was calculated as the concentration of test compound at which 50% of maximal inhibition of the positive control (sodium replaced by choline,

0% Npt2B activity) was observed.

The effect, a decrease in cellular uptake of 33P-labeled phosphate was measured as a decrease in scintillation counts and calculated for each concentration of a compound as

% inhibition using the following equation : % Inhibition = [ l-(Sx-Sc)/(So-Sc)]*100%

Sx = scintillation counts in presence of tested compound

SO = scintillation counts in presence of negative control (137 mM sodium; 100% Npt2B activity)

Sc = scintillation counts in presence of positive control (137 mM choline; 0% Npt2B activity)

The compounds of the present invention were tested in the Npt2B phosphate uptake assays. The absolute IC50 values of the compounds are shown in table 1 Npt2B IC50 ranges:

* indicates that IC50 values are > 1000nM

** indicates that IC50 values are > 100nM and < 1000nM

*** indicates that IC50 values are < 100nM

Compound no. rNpt2B IC50 hNpt2B IC50

1 - _**

2 - _**

3 _***

5 - _**

6 _** _**

7 - _***

8 - _***

9 _** _**

10 _*** _***

11 _*** _***

12 _*** _***

13 - _***

14 _** _***

15 - _**

16 _** _**

17 _** _***

18 _** _**

19 _** _**

20 _** _** Example 22

Inhibitory Acivity Against P Absorption from Intestinal Tract

Male Sprague Dawley rats were fed a low phosphate diet (<0.1% Pi) for 5 days. Animals were fasted overnight before dosing. The following day animals were dosed orally with compound or vehicle. All animals were dosed p.o with 10 MBq/kg 32P 15-30 minutes after administration of compound. Blood samples were drawn 15, 30, 45 and 60 minutes after 32P bolus had been administered. Samples were analyzed for radioactivity on a Packard Tri-Carb 2900TR Liquid Scintillation Counter and reduction in phosphate was estimated by change in average AUC compared against vehicle control.

P data

One-way ANOVA, Dunnett's post test was used for a significance test of the average AUC difference of blood radioactivity. For all compounds, a significant difference was observed as compared with the group with the administration of vehicle at p < 0.05.

Example 23

Test of chemical stability

A stock solution of the compound in organic solvent was diluted 1 : 3 using the wanted buffers (pH 2, pH 5, pH 7,4 and/or pH 9) to a concentration of app. 30 mg/ml. The solutions were then portioned out in a number of vials, which remained in the autosampler at room temperature during analysis on HPLC (using a gradient programme and UV-detection).

Stability of the compound over time was evaluated using the decrease of Area and Area % of the compound in the chromatograms, whereupon the recovery of the compound was estimated.

(Compound 372 in US 2006/0217426)

N-[2-[ l-[4-chloro-3- >95% >95% >95% >95%

(trifluoromethyl) phenyl] pyrazole-4-ca rbonyl]-4-( 1- piperidyl)phenyl] -3-(2- hydroxyethylsulfanyl methyl) benzamide

(compound 20)

Claims

1. A compound according to formula I

wherein

Ri, R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, hydroxyl, cyano, COOH, (Ci-C₄)alkyl, halo(Ci-C₄)alkyl, hydroxy(Ci-C₄)alkyl, (Ci-C₄)alkoxy, halo(Ci-C₄)alkoxy, cycloalkyl and heterocycloalkyl;

R₄ is selected from the group consisting of hydrogen, halogen, (Ci-C₄)alkyl and heterocycloalkyl; R₅ is selected from the group consisting of hydrogen, COOH, (Ci-C₆)alkyl,

heterocycloalkyl(Ci-C₆)alkyl, aryl(d-C₆)alkyl and heteroaryl(Ci-C₆)alkyl, said (Ci- C₆)alkyl, aryl(Ci-C₆)alkyl, heterocycloalkyl(Ci-C₆)alkyl and heteroaryl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from R₆; R₆ is selected from the group consisting of halogen, -ORa, -SRa, -S(0)Ra, -S(0)₂Ra, - NRaRb, -N⁺RaRbRc, -OC(0)Ra, -P(0)(OH)₂, (Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl, aryl and a heterocyclic ring; said (Ci-C₆)alkyl, heterocycloalkyl, cycloalkyl, aryl and heterocyclic ring optionally being substituted by one or more substituents selected from R₇;

Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, alkoxy(Ci-C₆)alkyl, cycloalkyl, heterocycloalkyl, heteroaryl and

heterocycloalkyl(Ci-C₆)alkyl; said (Ci-C₆)alkyl, alkoxy(Ci-C₆)alkyl, cycloalkyl, heterocycloalkyi, heteroaryl and heterocycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from R₇;

Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, cycloalkyl, heterocycloalkyi and heterocycloalkyl(d-C₆)alkyl; said (Ci- C₆)alkyl, cycloalkyl, heterocycloalkyi and heterocycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more substituents selected from halogen, hydroxyl, or cyano;

2. The compound according to claim 1, wherein R^ R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, cyano, (Ci-C₄)alkyl, halo(Ci-

C₄)alkyl, (Ci-C₄)alkoxy, halo(Ci-C₄)alkoxy and heterocycloalkyi.

3. The compound according to claim 1 or 2, wherein Ri, R₂ and R₃ each independently are selected from the group consisting of hydrogen, halogen, cyano, methyl, ethyl, trifluoroalkyl, methoxy, and morpholinyl.

4. The compound according to any of the preceding claims , wherein R₃ is hydrogen.

5. The compound according to any of the preceding claims, wherein Ri is trifluoromethyl, R₂ is chloro and R₃ is hydrogen.

6. The compound according to any of the preceding claims, wherein R₄ is selected from the group consisting of halogen and heterocycloalkyi.

7. The compound according to any of the preceding claims, wherein R₄ is selected from the group consisisting of chloro, bromo and piperidinyl.

8. The compound according to any of the preceding claims, wherein R₅ is selected from the group consisting of hydrogen, COOH, (Ci-C₆)alkyl, and heterocycloalkyl(Ci-C₆)alkyl .

9. The compound according to claim 8, wherein R₅ is methyl or ethyl .

10. The compound accordi ng to claim 8, wherein R₅ is selected from the group consisting of piperazinylalkyl, piperidinylalkyl, and morpholinylalkyl .

11. The compound according to claim 10, wherein R₅ is selected from the group consisting of piperazinylmethyl, piperidinylmethyl, and morpholinylmethyl .

12. The compound according to any of the preceding claims, wherein R6 is selected from the group consisting of halogen, -ORa, -SRa, -S(0)Ra, -NRaRb, -N⁺RaRbRc, -OC(0)Ra, - P(=0)(OH)₂, (d-CeJalkyl, and heterocycloalkyl .

13. The compound according to claim 12, wherein R₆ is selected from the group consisting of CI, -ORa, -SRa, -S(0)Ra, -NRaRb, -N⁺RaRbRc, -OC(0)Ra, methyl, ethyl, morpholinyl, piperidinyl and piperazinyl .

14. The compound according to claim 13, wherein Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, heterocycloalkyl, heteroaryl, and heterocycloalkyl(Ci-C₆)alkyl .

15. The compound according to claim 14, wherein Ra, Rb and Rc each independently are selected from the group consisting of hydrogen, methyl, ethyl, propyl, butyl, isobutyl, pentyl, hexyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyranylmethyl, and triazolyl .

16. The compound according to any of the preceding claims, wherein R₇ is selected from the group consisting of hydroxyl, -COOH, -N H₂, -N⁺(CH)₃, and -S0₂OH .

17. The compound according to any of the preceding claims, wherein Rd, Re and Rf each independently are selected from the group consisting of hydrogen, (Ci-C₆)alkyl, and heterocycloalkyl(Ci-C₆)alkyl ; said (Ci-C₆)alkyl and heteroycloalkyl(Ci-C₆)alkyl optionally being substituted by one or more hydroxyl .

18. The compound according to claim 17, wherein Rd, Re and Rf each independently are selected from the group consisting of hydrogen, methyl and tetrahydropyranylmethyl.

19. The compound according to claim 1 selected from

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3- (chloromethy I) benzamide;

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbony I] phenyl] -3-

[ [4-(l-pi peridyl) -1-piperidy I] methyl] benzamide; N-[4-chloro-2-[ l-[4-chloro-3-

(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3-(morpholinomethy I) benzamide;

N-[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbony I] phenyl] -3- (tetrahydrofuran-3-yloxy methyl) benzamide;

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbonyl] phenyl] -3-

(piperazin-l-yl methyl) benzamide;

3-[[3-[[4-chloro-2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4- carbonyl]phenyl]carbamoyl]phenyl]methylsulfanyl]propanoic acid ;

3-[[bis(2-hydroxyethyl)amino]methyl]-N-[2-[ l-[4-chloro-3- (trifluoromethyl) phenyl] pyrazole-4-carbonyl]-4-(l-pi peridyl) phenyl] benzamide;

3-[[3-[[2-[ l-[4-chloro-3-(trifluoromethyl)phenyl]pyrazole-4-carbonyl]-4-(l- pi peridyl) phenyl]carbamoyl] phenyl] methyl -methyl-ami no] propanoic acid;

N- [2- [ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-ca rbonyl]-4-( 1- pi peridyl) phenyl] -3-(piperazin-l-yl methyl) benzamide; N- [4-bromo-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3- (8,9-dihydro-6H-pyrido[2,3-b] [ l,6] naphthyridin-7-ylmethyl)benzamide;

N-[4-bromo-2-[ l-[4-chloro-3-(trifluoromethyl) phenyl] pyrazole-4-carbony I] phenyl] -3-(2- hydroxyethoxymethyl)benzamide; and

N- [4-chloro-2-[ l- [4-chloro-3-(trifluoromethyl) phenyl] imidazole-4-carbonyl] phenyl] -3- (piperazin- l-yl methyl) benzamide.

20. A compound according to formula

r

Wherein R_lr R₂, R₃, R₄, X and Y are as defined in claim 1 and wherein A represents a (C₂- C₈) alkylene chain ;

wherein R₈ is selected from the group consisting of hydrogen and (Ci-C₆)alkyl ; and wherein each occurrence of Ri, R₂, R3, R₄, X and Y, respectfully, is identical to any other occurrence of said substituent in the compound of the formula I ^' .

21. A compound according to any one of claims 1-20 for use as a medicament.

22. A compound according to any of claims 1 -20 for use in the prophylaxis, treatment or amelioration of phosphate homeostasis.

23. A compound according to any of claims 1 -20 for use in the prophylaxis, treatment or amelioration of calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperpa rathyroidism, soft tissue calcification or uremic bone disease.

24. A pharmaceutical composition comprising a compound according to any one of claims 1-20 together with a pharmaceutically acceptable vehicle of excipient or pharmaceutically acceptable carrier(s).

25. The pharmaceutical composition according to claim 24 together with one or more other therapeutically active compound(s).

26. A use of a compound according to any one of claims 1-20 in the manufacture of a medicament for the prophylaxis, treatment or amelioration of calciphylaxis,

cardiovascular calcification, cardiovascular events, chronic kidney disease, primary hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease.

27. The use according to claim 26, wherein the disease or condition is selected from the group consisting of cardiovascular calcification, chronic kidney disease, primary hyperparathyroidism, secondary hyperparathyroidism, hyperphosphatemia or

progression of renal failure.

28. A method of preventing, treating or ameliorating calciphylaxis, cardiovascular calcification, cardiovascular events, chronic kidney disease, primary

hyperparathyroidism, hyperphosphatemia, hypoparathyroidism, metabolic bone disease, metabolic osteopathy, osteoporosis, progression of renal failure, renal failure, renal osteodystrophy, secondary hyperparathyroidism, soft tissue calcification or uremic bone disease,, the method comprising administering to a person suffering from at least one of said diseases or conditions an effective amount of one or more compounds according to any one of claims 1-20, optionally together with a pharmaceutically acceptable carrier or one or more excipients, optionally in combination with other therapeutically active compounds.

29. The method according to claim 28, wherein the disease or condition is selected from the group consisting of cardiovascular calcification, chronic kidney disease, primary hyperparathyroidism, secondary hyperparathyroidism, hyperphosphatemia or

progression of renal failure.