FIELD OF THE INVENTION

This invention relates to novel calcium-sensing receptor-active compounds, to said compounds for use in therapy, to pharmaceutical compositions comprising said compounds, to methods of treating diseases with said compounds, and to the use of said compounds in the manufacture of medicaments.

BACKGROUND OF THE INVENTION

The calcium-sensing receptor (CaSR) is a G-protein-coupled receptor (GPCR) that signals through the activation of phospholipase C, increasing levels of inositol 1,4,5-triphosphate and cytosolic calcium. The CaSR belongs to the subfamily C of the GPCR superfamily, which also includes receptors for glutamate, gamma aminobutyric acid (GABA), pheromones and odorants that all possess a very large extra-cellular domain. This domain is highly negatively charged and is involved in binding of calcium and other positively charged molecules. The CaSR is found in the parathyroid glands but has also been identified in the brain, intestine, pituitary, thyroid glands, bone tissue and kidneys [Brown, E. M. Calcium-Sensing Receptor. Primer of the Metabolic Bone Diseases and Disorders of Mineral

Metabolism Fifth Edition, 2003 by American Society for Bone and Mineral

Research, Chapter 17, p. 111. ; Drueke, T. E. Nephrol Dial Transplant (2004) 19, v20-v26].

The calcium sensing receptor (CaSR) detects changes in extra-cellular calcium concentration and initiates the functional response of this cell, which is a modulation of the secretion of the parathyroid hormone (PTH). Secretion of PTH increases extra-cellular calcium ion concentration by acting on various cells, such as bone and kidney cells, and the extra-cellular calcium ion concentration reciprocally inhibits the secretion of PTH by acting on parathyroid cells. The reciprocal relationship between calcium concentration and PTH level is an essential mechanism for calcium homeostasis maintenance.

The calcimimetic activity corresponds to the ability to produce or induce biological responses observed through variations in the concentration of extracellular calcium ions (Ca ²⁺ ) _e and extracellular magnesium ions (Mg ²⁺ ) _e .

(Ca ²⁺ ) _e and (Mg ²⁺ ) _e ions play a major role in the body through their regulation of calcium homeostasis on which many vital functions of the body depend. Thus, hypo- and hypercalcemia, that is to say conditions in which (Ca ²⁺ ) _e ions are below or above the mean threshold, have a major effect on many functions, such as cardiac, renal or intestinal functions. They deeply affect the central nervous system (Chattopadhyay et al. Endocr. Review, Vol.17, 4, pp 289-307 (1996)). It has been shown that Ca ²⁺ and Mg ²⁺ ions, but also Ba ²⁺ ions, within millimolar concentration ranges, stimulate CaSRs. Activation of CaSRs might be induced in the brain by β-amyloid peptides, which are involved in neurodegenerative diseases such as Alzheimer's disease (Ye et al, J. Neurosci., 47, 547-554, Res. 1997). Disturbance of CaSR activity is associated with biological disorders such as primary and secondary hyperparathyroidism, osteoporosis, cardiovascular, gastrointestinal, endocrine and neurodegenerative diseases, or certain cancers in which (Ca ²⁺ ) _e ions are abnormally high. Primary hyperparathyroidism (primary HPT) is characterised by elevated levels of PTH and serum calcium which is typically caused by adenoma of the parathyroid gland. It can result in bone pain and excessive bone resorption.

Secondary hyperparathyroidism (secondary HPT) often develops in patients who have reduced kidney function and is characterised by elevated levels of PTH. The underlying causes are complex, but a reduced ability to convert vitamin D to calcitriol and elevated levels of phosphorus play significant roles in the

development of secondary HPT. If left untreated, the clinical manifestations of secondary HPT include bone and joint pain and limb deformities [Harrington, P.E. and Fotsch, C. Calcium Sensing Receptor Activators: Calcimimetics. Current Medicinal Chemistry, 2007, 14, 3027-3034].

A reduced kidney function or renal failure is also accompanied by renal osteodystrophy, e.g. osteitis fibrosa, osteomalacia, adynamic bone disease, or osteopo- rosis. These disorders are characterized by either high or low bone turnover.

Osteoporosis is a multifactor disease which depends in particular on age and sex. While menopausal women are very greatly affected, osteoporosis is increasingly proving to be a problem in elderly men as well, and, for the moment, no optimal treatment exists. Its social cost may become even heavier in the years to come, particularly as life expectancy is becoming longer. Osteoporosis is currently treated with estrogens, calcitonin or biphosphonates which prevent bone resorption without stimulating bone growth. More recent data demonstrate that intermittent increases in PTH or in derivatives thereof are effective in the treatment of osteoporosis and make it possible to remodel bone by stimulating bone formation (Whitfield et al., Drugs & Aging, 15 (2) pp 117-129 (1999)). This new therapeutic approach for treatment of osteoporosis appears to be very advantageous, although major problems are associated with the use of PTH hormone, such as the route of injection, but also the appearance of tumors, observed recently during clinical trials in humans. Intermittent secretion of endogenous PTH can be obtained by blocking the calcium sensing receptor. The blocking of PTH secretion with CaSR agonists may be followed by a rapid increase in PTH (rebound effect), which is then beneficial in the treatment of osteoporosis. A compound having an activating effect on CaSR (CaSR agonist), that is, a compound which selectively acts on CaSR to mimic or strengthen the action of Ca ²⁺ , is called a calcimimetic. On the other hand, a compound having an antagonistic effect on CaSR (CaSR antagonist, that is, a compound which suppresses or inhibits the action of Ca ²⁺ ), is called a calcilytic.

The calcium-sensing receptor has recently been found to be a potent target for developing novel therapies such as using calcimimetics for treatment of diarrhea. [Osigweh et al, J American Coll. of Surgeons, V201, Issue 3, suppl 1, Sept 2005, pl7.]

Calcimimetics have been shown to be commercially useful for the treatment of hyperparathyroidism (HPT) : The calcimimetic compound Cinacalcet® [Balfour, J. A. B. et al. Drugs (2005) 65(2), 271-281 ; Linberg et. al. J. Am. Soc. Nephrol (2005), 16, 800-807, Clinical Therapeutics (2005), 27(11), 1725-1751] is commercially available for the treatment of secondary HPT in chronic kidney disease patients on dialysis and for the treatment of primary HPT in patients with parathyroid carcinoma. Thus, proof of concept for activators of calcium sensing receptor (CaSR) in humans has been achieved and the clinical relevance is well established.

Other calcimimetic compounds are for example described in WO02/059102, WO98/001417, WO05/065050, WO 05/34928, WO03/099814, WO03/099776, WO00/21910, WO01/34562, WO01/090069, WO97/41090, US6,001,884,

W096/12697, EP1203761, W095/11221, WO93/04373, EP1281702, WO02/12181, WO04/56365, WO04/069793, WO04/094362, US2004242602, WO04/106280, WO04/106295, WO04/106296, WO05/068433, WO05/115975, EP 1757582, WO 2009/051718, WO 2008/019690, WO 2009/065406 and WO2010/021351.

SUMMARY OF THE INVENTION The novel compounds of the present invention are modulators, e.g. activators or agonists of the human calcium sensing receptor (CaSR) and may thus be useful in the treatment or prophylaxis of a number of diseases or physiological disorders involving modulation of CaSR activity.

Accordingly, the present invention relates to a compound of general formula I

[I]

wherein

Ar represents C ₆ -ioaryl, Ci-ioheteroaryl or C ₆ - ₈ heterocycloalkylaryl, wherein said C ₆ - i ₀ aryl, Ci-i ₀ heteroaryl or C ₆ - ₈ heterocycloalkylaryl, is optionally substituted with one or more, same or different substituents independently selected from halogen, hydroxy, Ci _-4 alkyl, trifluoromethyl or Ci _-4 alkoxy ;

X represents -CH- or a nitrogen atom;

Ri represents Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkynyl, hydroxyCi- ₆ alkyl, Ci- ₆ haloalkyl, or C ₃ - ₇ cycloalkyl;

R ₂ represents hydrogen, or is selected from the group consisting of aminoC ₂ - ₆ alkyl, Ci _-6 alkyl, C ₂ - ₆ alkenyl, hydroxyC ₂ - ₆ alkyl, Ci- ₆ alkylaminoC ₂ - ₆ alkyl, hydroxyCi- ₆ alkylaminoC ₂ - ₆ alkyl, Ci- ₃ alkylsulfonylaminoC ₂ - ₆ alkyl, Ci- ₆ alkylcarbonyl, Ci- ₆ alkylaminocarbonyl, Ci- ₃ alkylsulfonylCi _-5 heterocycloalkyl, aminosulfonylCi- ₆ alkyl, Ci _-5 heterocycloalkyl, Ci _-5 heterocycloalkylcarbonyl wherein said Ci _-6 alkyl, C ₂ - ₆ alkenyl, hydroxyC ₂ - ₆ alkyl, Ci- ₆ alkylaminoC ₂ - ₆ alkyl, hydroxyCi- ₆ alkylaminoC ₂ - ₆ alkyl, Ci- ₆ alkylaminocarbonyl, Ci _-5 heterocycloalkyl or Ci _-5 heterocycloalkylcarbonyl is optionally further substituted by one or more substituents selected from halogen, hydroxy, trifluoromethyl, -S(0) ₂ NH ₂ , -S(0) ₂ CH ₃ or -NH ₂ ;

R ₃ represents hydrogen or is selected from the group consisting of Ci _-6 alkyl, C ₂ - ₆ alkenyl, C ₂ - ₆ alkoxy, aminoC ₂ - ₆ alkyl, C _3-7 cycloalkyl, Ci _-5 heterocycloalkyl; or R ₂ and R ₃ together with the adjacent nitrogen form a 4, 5, 6 or 7-membered Ci- ₆ heterocycloalkyl comprising one or more heteroatoms selected from the group consisting of O, S and N, said Ci- ₆ heterocycloalkyl being optionally substituted by oxo, hydroxy, halogen, trifluoromethyl, Ci _-6 alkyl, -NH ₂ , -S(0) ₂ NH ₂ , -S(0) ₂ CH ₃ , Ci- ₆ alkylcarbonyl, hydroxyC _2-6 alkyl, Ci _-6 alkoxy, aminoCi- ₆ alkyl, Ci- ₆ alkylamino, or aminosulfonylCi- ₆ alkylamino; as well as stereoisomers, pharmaceutically acceptable salts, solvates, or hydrates thereof.

The compounds of the present invention may for example be useful in the treatment of complications associated with chronic kidney disease, such as hyperparathyroidism, e.g. primary and/or secondary hyperparathyroidism, or tertiary hyperparathyroidism. Other complications associated with chronic kidney disease are anemia, cardiovascular diseases, and the compounds of the present invention are also believed to have a beneficial effect on these diseases. The compounds of the present invention may furthermore be useful for promoting osteogenesis and treating or preventing osteoporosis, such as steroid induced, senile and post-menopausal osteoporosis; osteomalacia and related bone disorders, or for the prevention of bone loss post renal transplantation, or in rescue therapy pre-parathyroidectomy.

It is presently believed that the compounds of the present invention may have advantageous pharmacokinetic or pharmacodynamic properties, such as prolonged in vivo half-life and prolonged in vivo efficacy, in comparison to known structurally related compounds.

The compounds of formula I, la and lb according to the present invention all contain features that imparts on the molecules a high stability towards human liver microsomes and hepatocytes, as well as increased volumes of distribution in vivo, which may render the compounds of the present invention especially suitable for intravenous or other parenteral administration.

In another aspect, the invention relates to the compound of general formula I, la or lb as defined above for use as a medicament in therapy.

In another aspect, the invention relates to the compound of general formula I, la or lb as defined above for use in the treatment, amelioration or prophylaxis of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

In yet another aspect, the invention relates to a pharmaceutical composition comprising a compound of formula I, la or lb or a pharmaceutically acceptable salt, solvate, or hydrate thereof together with a pharmaceutically acceptable excipient or vehicle.

In a further aspect, the invention relates to a method of preventing, treating or ameliorating parathyroid carcinoma, parathyroid adenoma, primary parathyroid hyperplasia, cardiac, renal or intestinal dysfunctions, diseases of the central nervous system, chronic renal failure, chronic kidney disease, polycystic kidney disorder, podocyte-related diseases, primary hyperparathyroidism, secondary hyperparathyroidism, tertiary hyperparathyroidism, anemia, cardiovascular diseases, renal osteodystrophy, osteitis fibrosa, adynamic bone disease, osteoporosis, steroid induced osteoporosis, senile osteoporosis, post-menopausal osteoporosis, osteomalacia and related bone disorders, bone loss post renal transplantation, cardiovascular diseases, gastrointestinal diseases, endocrine and neurodegenerative diseases, cancer, Alzheimer's disease, IBS, IBD,

malassimilation, malnutrition, abnormal intestinal motility such as diarrhea, vascular calcification, abnormal calcium homeostasis, hypercalcemia, or renal bone diseases, the method comprising administering to a patient in need thereof an effective amount of a compound of general formula I, la or lb, optionally in combination or as supplement with an active vitamin-D sterol or vitamin-D derivative, such as 1-a-hydroxycholecalciferol, ergocalciferol, cholecalciferol, 25- hydroxycholecalciferol, Ι-α-25-dihydroxycholecalciferol, or in combination or as supplement with phosphate binders, estrogens, calcitonin or biphosphonates.

In a still further aspect, the invention relates to intermediate compounds useful for the synthesis of compounds according to formula I, la or lb.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

The term "heteroaryl" is intended to include radicals of (a) heterocyclic aromatic ring(s), comprising 1-10 carbon atoms and 1-4 heteroatoms, such as 1-6 carbon atoms and 1-3 heteroatoms, such as 1-5 carbon atoms and 1-2 heteroatoms, or such as 2-5 carbon atoms and 1-3 heteroatoms, in particular a 5- or 6-membered ring, wherein the heteroatoms selected from O, S and N, e.g. pyridyl, tetrazolyl, thiazolyl, imidazolyl, pyrazolyl, oxazolyl, oxadiazolyl, thiophenyl, 1,2,4-triazolyl, isoxazolyl, thienyl, pyrazinyl, pyrimidinyl, [ l,2,3]triazolyl, quinolyl, indazolyl, isothiazolyl, benzo[b]thiophene or indolyl. The term "cycloalkyl" is intended to indicate a saturated cycloalkane radica l or ring, comprising 3-7 carbon atoms, such as 3-6 carbon atoms, such as 4-5 or 5-6 carbon atoms, e.g . cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and

cycloheptyl . The term "heterocycloalkyl" is intended to indicate a cycloalkyl radical as defined above, in particular 4, 5, 6 or 7-membered rings, including polycyclic radicals, such as a 5-6 membered ring, comprising 1-5 or 1-4 carbon atoms and 1-4 heteroatoms, such as 4-5 carbon atoms and 1-3 heteroatoms, selected from O, N, or S, e.g . morpholino, morpholinyl, piperidyl, and piperazinyl.

The term "heterocycloalkylaryl" is intended to include radicals of heterocycloalkyl rings, in particula r 5- or 6- membered rings, comprising 1-5 carbon atoms and 1-4 hetero atoms (selected from O, S and N), such as 1-4 carbon atoms and 1-3 hetero atoms, preferably 3-4 carbon atoms and 1-2 hetero atoms selected from O, S, or N, the heterocycloalkyl ring being fused with one or more aromatic carbocyclic rings comprising 6- 10 carbon atoms, in particular 6- or 10 membered rings, such as phenyl or naphthyl, e.g . benzodioxolyl .

The term "heterocycloalkylcarbonyl", is intended to indicate a radical of the formula -C(0)-R, wherin R represents heterocycloalkyl as defined above, e.g . piperidylcarbonyl.

The term "aryl" is intended to indicate a radical of aromatic carbocyclic rings comprising 6- 10 carbon atoms, in particular 5- or 6-membered rings, optionally fused carbocyclic rings with at least one aromatic ring, such as phenyl, naphthyl, e.g . 1-na phthyl, indenyl, indanyl and tetrahydro-na phthalene.

The term "ha logen" is intended to indicate a substituent from the 7 ^th main group of the periodic table, prefera bly fluoro, chloro and bromo.

The term "alkyl" is intended to indicate the radical obtained when one hydrogen atom is removed from a hydrocarbon . Said alkyl comprises 1-6, preferably 1-4 or 1-3, such as 2-3, carbon atoms. The term includes the subclasses normal alkyl (n- alkyl), secondary and tertiary alkyl, such as methyl, ethyl, n-propyl, isopropyl, n- butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl and isohexyl.

The term "alkenyl" is intended to indicate a hydrocarbon radical comprising 1-4 C- C double bonds, e.g. 1, 2 or 3 double bonds and 2-6 carbon atoms, in particular 2- 4 carbon atoms, such as 2-3 carbon atoms, e.g. ethenyl, allyl, propenyl, butenyl, pentenyl, or hexenyl.

The term "alkynyl" is intended to indicate a hydrocarbon radical comprising 1-4 C- C triple bonds, e.g. 1, 2 or 3 triple bonds and 2-6 carbon atoms, in particular 2-4 carbon atoms, such as 2-3 carbon atoms, e.g. ethynyl, propynyl, butynyl, or pentynyl.

The term "hydroxyalkyl" is intended to indicate an alkyl radical as defined above, wherein one, two, three or more hydrogen atoms are replaced by hydroxyl, e.g. hydroxymethyl, hydroxyethyl, hydroxypropyl or 2,3-dihydroxypropyl.

The term "haloalkyl" is intended to indicate an alkyl radical as defined above, wherein one, two, three or more hydrogen atoms are replaced by halogen, same or different, such as bromo, chloro and/or fluoro, e.g. fluoromethyl.

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 "aminoalkyl" is intended to indicate a radical of the formula -R-NH ₂ , wherein R represents alkyl as indicated above, e.g. aminomethyl or aminoethyl.

The term "alkylamino" is intended to indicate a radical of the formula -NH-R, wherein R represents alkyl as defined above, e.g. methylamino, ethylamino, or propylamino.

The term "alkylaminoalkyl" is intended to indicate a radical of the formula -R-NH- R, wherein R represents alkyl as defined above, e.g. ethylaminoethyl,

propylaminoethyl or ethylaminopropyl.

The term "hydroxyalkylaminoalkyl" is intended to indicate a radical of the formula -R-NH-R'-OH, wherein R and R' represents alkyl as defined above, e.g.

hydroxyethylaminoethyl, hydroxypropylaminoethyl or hydroxyethylaminopropyl. The term "alkylcarbonyl" is intended to indicate a radical of the formula -C(0)-R, wherein R represents alkyl as defined above, e.g. methylcarbonyl, or

ethylcarbonyl.

The term "alkylaminocarbonyl" is intended to indicate a radical of the formula - C(0)-NH-R, wherein R represents alkyl as defined above, e.g.

methylaminocarbonyl, ethylaminocarbonyl or propylaminocarbonyl. The term "alkylsulfonylaminoalkyl" is intended to indicate a radical of the formula - R-NH-S(0) ₂ -R, wherein R represents alkyl as defined above, e.g.

methylsulfonylaminomethyl, or methylsulfonylaminoethyl.

The term "aminosulfonylalkylamino" is intended to indicate a radical of the formula -NH-R-S(0)2-NH ₂ , wherein R represents alkyl as defined herein, e.g.

aminosulfonylmethylamino, or aminosulfonylethylamino.

The term "hydroxyalkyl" is intended to indicate a radical of the formula -R-OH, wherein R represents alkyl as indicated above, e.g. hydroxymethyl, hydroxyethyl or hydroxypropyl.

The term "aminosulfonylalkyl" is intended to indicate a radical of the formula -R- S(0) ₂ -NH ₂ , wherein R represents alkyl as defined herein, e.g.

methylsulfonylamino, ethylsulfonylamino or propylsulfonylamino.

The term "alkylsulfonylheterocycloalkyl" is intended to indicate a radical of the formula -R'-S(0) ₂ -R, wherein R represents alkyl as defined above, R' represents heterocycloalkyl as defined above, e.g. methylsulfonylpiperidyl or

methylsulfonylpiperazinyl.

The term "pharmaceutically acceptable salt" is intended to indicate salts prepared by reacting a compound of formula I, la or lb with a suitable inorganic or organic acid, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, nitric, phosphoric, formic, acetic, 2,2-dichloroacetic, 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, la or lb may also be prepared by reaction with a suitable base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide, ammonia, 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 N,N'-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, la or lb 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 formula I, la or lb may comprise asymmetrically substituted (chiral) carbon atoms and carbon-carbon double bonds which may give rise to the existence of isomeric forms, e.g. enantiomers, diastereomers and geometric isomers. The present invention includes all such isomers, either in pure form or as mixtures thereof. Pure stereoisomeric forms of the compounds and the

intermediates of this invention may be obtained by the application of procedures known by persons skilled in the art. Diastereomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e. g. liquid chromatography using chiral stationary phases.

Enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereoisomeric forms may also be derived from the corresponding pure stereoisomeric forms of the appropriate starting materials, provided that the reaction occurs stereoselectively or stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereoselective or stereospecific methods of preparation. These methods will advantageously employ chirally pure starting materials. Likewise, pure geometric isomers may be obtained from the corresponding pure geometric isomers of the appropriate starting materials. A mixture of geometric isomers will typically exhibit different physical properties, and they may thus be separated by standard chromatographic techniques well-known in the art.

The present invention further includes prodrugs of compounds of general formula I, la or lb, i.e. derivatives such as esters, ethers, complexes or other derivatives which undergo a biotransformation in vivo before exhibiting their pharmacological effects. The compounds of formula I, la or lb may be obtained in crystalline form either directly by concentration from an organic solvent or by crystallisation or re- crystallisation from an organic solvent or mixture of said solvent and a co-solvent that may be organic or inorganic, such as water. The crystals may be isolated in essentially solvent-free form or as a solvate, such as a hydrate. The invention covers all crystalline modifications and forms and also mixtures thereof.

Embodiments

In an embodiment of the present invention compound I represent la or lb

lb

In an embodiment of the present invention Ri represents methyl. In an embodiment of the present invention X represents -CH-.

In an embodiment of the present invention X represents a nitrogen atom.

In an embodiment of the present invention Ar represents phenyl substituted with one or more, same or different substituents independently selected from fluoro, chloro, methoxy or ethoxy.

In an embodiment of the present invention Ar represents 4-fluoro-3- methoxyphenyl. In an embodiment of the present invention Ar represents naphthyl or

benzodioxolyl. In an embodiment of the present invention R ₃ represents hydrogen.

In an embodiment of the present invention R ₂ and R ₃ together with the adjacent nitrogen atom to which they are attached forms a 6-membered Ci _-5 heterocyclo- alkyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, said Ci _-5 heterocycloalkyl being optionally substituted by oxo, -NH ₂ , -S(0) ₂ NH ₂ , - S(0) ₂ CH _3; hydroxy, halogen, trifluoromethyl, Ci _-6 alkyl, Ci _-6 alkylcarbonyl, Ci- ₆ alkoxy, aminoCi- ₆ alkyl, or Ci _-6 alkylamino. In an embodiment of the present invention R ₂ and R ₃ together with the adjacent nitrogen to which they are attached forms a 6-membered C ₄ - ₅ heterocycloalkyl comprising 1 or 2 heteroatoms selected from the group consisting of O and N, said C ₄ - ₅ heterocyclic ring being optionally substituted by oxo, -NH ₂ , hydroxyC ₂ - ₄ alkyl, - S(0) ₂ CH ₃ or methylcarbonyl, such as piperidyl, aminopiperidyl, methylsulfonyl- piperidyl, morpholinyl, oxopiperazinyl, methylcarbonylpiperazinyl, methylsulfonyl- piperazinyl, hydroxymethylpiperazinyl or piperazinyl.

In an embodiment of the present invention R ₂ represents aminoC ₂ - ₄ alkyl, Ci _-4 alkyl, C ₂ - ₄ alkenyl, hydroxyC ₂ - ₄ alkyl, Ci- ₄ alkylaminoC ₂ - ₄ alkyl, Ci- ₆ alkylcarbonyl, Ci _-4 alkyl- aminocarbonyl, Ci- ₃ alkylsulfonylC ₄ - ₅ heterocycloalkyl, aminosulfonylCi _-4 alkyl, methylsulfonylaminoCi _-4 alkyl, C ₄ - ₅ heterocycloalkyl, or C ₄ - ₅ heterocycloalkylcarbonyl, wherein said Ci _-4 alkyl, C ₂ - ₄ alkenyl, hydroxyC ₂ - ₄ alkyl, Ci- ₄ alkylaminoCi- ₄ alkyl, Ci- ₄ alkylaminocarbonyl, C ₄ - ₅ heterocycloalkyl or C ₄ - ₅ heterocycloalkylcarbonyl is optionally further substituted by one or more substituents selected from hydroxy, -S(0) ₂ NH ₂ , -S(0) ₂ CH ₃ or -NH ₂ , such as hydroxyethylaminoethyl, hydroxypropyl- aminoethyl, aminoethyl, piperidylcarbonyl, aminosulfonylethyl, aminosulfonyl- propyl, methylcarbonyl, di hydroxy propyl, hydroxyethyl, methylsulfonylaminoethyl, methylsulfonylpiperidyl or piperidyl. In an embodiment of the present invention Ri is methyl, Ar is 4-fluoro-3-methoxy- phenyl, R ₃ is hydrogen and X is -CH ₂ -.

Specific examples of compounds of formula I, la or lb may be selected from the group consisting of:

2-[2-[[5-[(lR,3S)-3-[[(lR)-l-(l-Naphthyl)ethyl]amino]cycl opentyl]-2-pyridyl] amino]ethylamino]ethanol; triple formic acid salt (compound 101),

1- [5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]amin o]cyclopentyl]-

2- pyridyl]piperidin-4-amine (compound 102), N-[5-[(lR,3S)-3-[[(lR)-l-(l-Naphthyl)ethyl]amino]cyclopentyl ]-2-pyridyl]ethane -1,2-diamine (compound 103),

N-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]am ino]cyclopentyl]-

2- pyridyl]piperidine-4-carboxamide (compound 104),

(lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6- morpholino-3- pyridyl)cyclopentanamine (compound 105),

(lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6-pip erazin-l-yl-3- pyridyl)cyclopentanamine (compound 106),

5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]amino ]cyclopentyl]-N- (4-piperidyl)pyridin-2-amine (compound 107),

3- [[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]ami no] cyclopentyl]- 2-pyridyl]amino]propane-l-sulfonamide (compound 108),

4- [5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]amin o]cyclopentyl]-

2- pyridyl]piperazin-2-one (compound 109),

2-[2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)e thyl]amino] cyclopentyl]-2-pyridyl]amino]-ethylamino]ethanol; dihydrochloride (compound HO),

3- [2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl] amino] cyclopentyl]-2-pyridyl]amino]-ethylamino]propan-l-ol (compound 111),

5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]am ino]cyclopentyl]-N- (l-methylsulfonyl-4-piperidyl)pyridin-2-amine (compound 112),

2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethy l]amino] cyclopentyl]- 2-pyridyl]amino]-ethanesulfonamide (compound 113),

2- [[5-[(lR,3S)-3-[[(lR)-l-(l,3-Benzodioxol-4-yl)ethyl]amino]cy clopentyl]-2- pyridyl]amino]-ethanesulfonamide (compound 114),

3- [[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]ami no] cyclopentyl]- 2-pyridyl]amino]propane-l,2-diol (compound 115),

1- [4-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]a mino]

cyclopentyl]-2-pyridyl]piperazin-l-yl]ethanone (compound 116),

4-[5-[(lR,3S)-3-[[(lR)-l-(3-Ethoxyphenyl)ethyl]amino]cycl opentyl]-2- pyridyl]piperazin-2-one (compound 117),

(lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-[6-(4- methylsulfonyl- piperazin-l-yl)-3-pyridyl]cyclopentanamine; dihydrochloride salt (compound 118),

2- [[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]ami no] cyclopentyl]- 2-pyridyl]amino]ethanol (compound 119),

2-[2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethy l]amino]-cyclo- pentyl]-2-pyridyl]amino]ethylamino]ethanol; triple formic acid salt (compound 120), 2-[[5-[(lR,3S)-3-[[(lR)-l-(3-Chlorophenyl)ethyl]amino]cyclop entyl]-2-pyridyl]- amino]ethanesulfonamide (compound 121),

2-[2-[[5-[(lR,3S)-3-[[(lR)-l-(l-Naphthyl)ethyl]amino]cyclope ntyl]pyrimidin-2- yl]amino]ethylamino]ethanol (compound 122),

N-[2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)e thyl]amino]cyclo- pentyl]pyrimidin-2-yl]amino]ethyl]methanesulfonamide (compound 123),

2-[4-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)et hyl]amino] cyclopentyl]pyrimidin-2-yl]piperazin-l-yl]ethanol (compound 124),

2-[[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethy l]amino]

cyclopentyl]pyrimidin-2-yl]amino]ethanesulfonamide (compound 125),

4-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl ]amino]

cyclopentyl]pyrimidin-2-yl]piperazin-2-one (compound 126),

1- [4-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]a mino] cyclopentyl]pyrimidin-2-yl]piperazin-l-yl]ethanone; formic acid salt (compound 127) or

N-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]am ino]-cyclopentyl]-

2- pyridyl]acetamide (compound 128).

Specific examples of intermediates for the preparation of compounds of formula I may be selected from the group consisting of:

(3R)-3-(6-Fluoro-3-pyridyl)cyclopentanone (Intermediate 1),

(3R)-3-(6-chloro-3-pyridyl)cyclopentanone (Intermediate 2),

(3R)-3-(6-Iodo-3-pyridyl)cyclopentanone (Intermediate 3),

(lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6-flu oro-3- pyridyl)cyclopentanamine (Intermediate 4),

(lS,3R)-N-[(lR)-l-(l,3-Benzodioxol-4-yl)ethyl]-3-(6-fluoro-3 -pyridyl)

cyclopentanamine (Intermediate 5),

(lS,3R)-N-[(lR)-l-(3-Chlorophenyl)ethyl]-3-(6-fluoro-3-pyrid yl)

cyclopentanamine (Intermediate 6),

(lS,3R)-N-[(lR)-l-(3-Ethoxyphenyl)ethyl]-3-(6-fluoro-3-py ridyl)

cyclopentanamine (Intermediate 7),

(lS,3R)-3-(6-Fluoro-3-pyridyl)-N-[(lR)-l-(l-naphthyl)ethyl]c yclopentanamine (Intermediate 8),

(lS,3R)-3-(6-Chloro-3-pyridyl)-N-[(lR)-l-(l-naphthyl)ethyl]c yclopentanamine (Intermediate 9),

(lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6-iod o-3-pyridyl) cyclopentanamine (Intermediate 10),

(3R)-3-(2-Methylsulfanylpyrimidin-5-yl)cyclopentanone (Intermediate 11), (3R)-3-(2-Methylsulfonylpyrimidin-5-yl)cyclopentanone (Intermediate 12), (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(2-met hylsulfonyl- pyrimidin-5-yl)cyclopentanamine (Intermediate 13), or

(lS,3R)-3-(2-Methylsulfonylpyrimidin-5-yl)-N-[(lR)-l-(l-naph thyl)ethyl] cyclo- pentanamine (Intermediate 14).

Pharmaceutical compositions

For use in therapy, 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, la or lb, optionally together with one or more other therapeutically active compound(s), together with a pharmaceutically acceptable excipient or vehicle. 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.

Pharmaceutical compositions of the invention may be in unit dosage form such as tablets, pills, capsules, powders, granules, elixirs, syrups, emulsions, ampoules, suppositories or parenteral solutions or suspensions; for oral, parenteral, opthalmic, transdermal, intra-articular, topical, pulmonal, nasal, buccal or rectal administration or in any other manner appropriate for the formulation of compounds used in nephrology and in accordance with accepted practices such as those disclosed in Remington: The Science and Practice of Pharmacy, 21 ^st ed.,

2000, Lippincott Williams & Wilkins. In the composition of the invention, the active component may be present in an amount of from about 0.01 to about 99%, such as 0.1% to about 10 % by weight of the composition. For oral administration in the form of a tablet or capsule, a compound of formula I, la or lb may suitably be combined with an oral, non-toxic, pharmaceutically acceptable carrier such as ethanol, glycerol, water or the like. Furthermore, suitable binders, lubricants, disintegrating agents, flavouring agents and colourants may be added to the mixture, as appropriate. Suitable binders include, e.g., lactose, glucose, starch, gelatin, acacia gum, tragacanth gum, sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes or the like. Lubricants include, e.g., sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride or the like. Disintegrating agents include, e.g., starch, methyl cellulose, agar, bentonite, xanthan gum or the like. Additional excipients for capsules include macrogols or lipids.

For the preparation of solid compositions such as tablets, the active compound of formula I, la or lb is mixed with one or more excipients, such as the ones described above, and other pharmaceutical diluents such as water to make a solid preformulation composition containing a homogenous mixture of a compound of formula I, la or lb. The term "homogenous" is understood to mean that the compound of formula I, la or lb is dispersed evenly throughout the composition so that the composition may readily be subdivided into equally effective unit dosage forms such as tablets or capsules. The preformulation composition may then be subdivided into unit dosage forms containing from about 0.05 to about 1000 mg, in particular from about 0.1 to about 500 mg, e.g. 10-200mg, such as 30-180 mg, such as 20-50 mg of the active compound of the invention.

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, la or lb.

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 may be administered either orally, parenterally, intravenously or topically 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 400 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.

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. Liquid formulations for either oral or parenteral administration of the compound of the invention include, e.g., aqueous solutions, syrups, aqueous or oil suspensions and emulsion with edible oils such as 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 or polyvinylpyrolidone.

For parenteral administration, e.g. intramuscular, intraperitoneal, subcutaneous or intravenous injection or infusion, the pharmaceutical composition preferably comprises a compound of formula I, la or lb dissolved or solubilised in an appropriate, pharmaceutically acceptable solvent. For parenteral administration, the composition of the invention may include a sterile aqueous or non-aqueous solvent, in particular water, isotonic saline, isotonic glucose solution, buffer solution or other solvent conventionally used for parenteral administration of therapeutically active substances. The composition may be sterilised by, for instance, filtration through a bacteria-retaining filter, addition of a sterilising agent to the composition, irradiation of the composition, or heating the composition. Alternatively, the compound of the invention may be provided as a sterile, solid preparation, e.g. a freeze-dried powder, which is dissolved in sterile solvent immediately prior to use.

The composition intended for parenteral administration may additionally comprise conventional additives such as stabilisers, buffers or preservatives, e.g. antioxidants such as methyl hydro xybenzoate or the like.

Compositions for rectal administration may be in the form of a suppository incorporating the active ingredient and a carrier such as cocoa butter, or in the form of an enema.

Compositions suitable for intra-articular administration may be in the form of a sterile aqueous preparation of the active ingredient which may be in microcry- stalline form, for example, in the form of an aqueous microcrystalline suspension. Liposomal formulations or biodegradable polymer systems may also be used to present the active ingredient for both intra-articular and ophthalmic administration.

Compositions suitable for topical administration, including ophthalmic treatment, include liquid or semi-liquid preparations such as liniments, lotions, gels, applicants, oil-in-water or water-in-oil emulsions such as creams, ointments or pastes; or solutions or suspensions such as drops. For topical administration, the compound of formula I, la or lb may typically be present in an amount of from 0.01 to 20% by weight of the composition, such as 0.1% to about 10 %, but may also be present in an amount of up to about 50% of the composition. Compositions for ophthalmic treatment may preferably additionally contain a cyclodextrin.

Compositions suitable for administration to the nasal or buccal cavity or for inhalation include powder, self-propelling and spray formulations, such as aerosols and atomizers. Such compositions may comprise a compound of formula I, la or lb in an amount of 0.01-20%, e.g. 2%, by weight of the composition. The composition may additionally comprise one or more other active components conventionally used in the treatment of physiological disorders or diseases associated with disturbances of CaSR activity, such as hyperparathyroidism.

Pharmacological methods

The calcium sensing receptor (CaSR) and its use in identifying or screening for calcimimetic compounds has e.g. been described in EP 637 237, EP 1 296 142, EP 1 100 826, EP 1 335 978, and EP 1 594 446.

In vitro and in vivo methods for testing the compounds of the present invention are well established and may be found in the references listed above, or e.g. in Journal of Biological Chemistry (2004), 279(8), 7254-7263 or in US 5 858 684 and references cited therein.

Biological assay for analysis of in vitro activity

The assay investigates a compound's functional ability to act as a biological positive modulator on the human CaSR. Activation of the receptor expressed on CHO-K1 cells is detected through the G alpha q pathway, the activation of phospholipase C and the accumulation of intracellular inositol phosphate (IP) as described earlier [Sandrine Ferry, Bruno Chatel, Robert H. Dodd, Christine Lair, Danielle Gully, Jean-Pierre Maffrand, and Martial Ruat. Effects of Divalent Cations and of a Calcimimetic on Adrenocorticotropic Hormone Release in Pituitary Tumor Cells. Biochemical and biophysical research Communications 238, 866-873 (1997)]. The human CaSR is stably expressed on a CHO-K1 cell clone, stimulated with a basal level of calcium and challenged with the tested compound. The level of IP1 is determined using the IP-One Terbium htrf kit (Cisbio, France). CHO-K1 cells not transfected with the CaSR fail to elicit an IP1 response upon calcium and/or compound stimulation. Cloning of the human CaSR gene

The ORF coding for the human CaSR (genebank: NM_000388) was acquired from Invitrogen Corp, USA and subsequently cloned into the mammalian expression vector pCDA3.1.

Generation of cell line expressing CaSR

CHO-K1 cells were transfected using Lipofectamine according to manufacturer's protocol (400.000 cells/well were seeded in a 6-well plate and transfected after 24 hours using 2 μg DNA and 5 μΙ lipofectamine). After another 24 hours the cells were detached, seeded and subjected to lmg/ml of G-418. Following 7 days growth single clones were picked, the CaSR expression evaluated using the 5C10 antibody against CaSR, the clones with the highest expression were selected and tested for functional response. The preferred clone was cultured according to standard procedures described in ATCC (American Type Culture Collection) protocols for CHO-K1 with the addition of 500μg/ml G-418.

Functional whole cell assay

On the assay day, cells were thawed, harvested and resuspended to 4*10 ⁶ cells/ml in stimulation buffer (containing : Hepes lOmM, MgCI ₂ 0.5mM, KCI 4.2mM, NaCI 146mM, glucose 5.5mM, LiCI 50 mM, BSA 0.5% at pH 7.4). Ten μΙ cell solution was pipetted into wells of a white 384-well plate (Perkin Elmer Optiplate) containing 2 μΙ compound diluted in assay buffer (containing : Hepes lOmM, MgCI ₂ 0.5mM, KCI 4.2mM, NaCI 146mM, glucose 5.5mM, LiCI 50 mM, CaCI ₂ 11.4 mM at pH 7.4), resulting in a final Ca ²⁺ concentration of 1.9 mM. After compound stimulation for 1 hour at 37 ° C and 15 min at room temperature, 10 ul of IP-One assay detection reagent (prepared as described by the IP-One assay kit

manufacturer) was added and the plate was incubated for another 1 hour at room temperature. Finally the plate was read using a Perkin Elmer EnVision, according to the protocol supplied by the IP-One assay kit manufacturer. The FRET ratio was calculated by dividing the 665 nm emission signal with that of the 615 nm.

The molar concentration of a compound that produces 50% of the maximum agonistic response (the IC50 value) is calculated according to the equation

"General sigmoidal curve with Hill slope, a to d" (Equation 1). This model describes a sigmoidal curve with an adjustable baseline. The equation can be used to fit curves where response is either increasing or decreasing with respect to the independent variable, X.

Equation 1. y = (a - d) / (1 + (x / c) ^A b) + d Parameters:

x = concentration of tested compound

y = response (%)

a = min response as compound concentration approaches 0

d = max response as concentration of tested compound is increasing

c = IC50 for the curve

b = Hill coefficient or curve slope Assay results using compounds of the present invention indicate that compounds of the present invention are potent modulators of CaSR, thus making them potentially useful in the treatment of diseases related to kidneys or bones.

See table 1. Biological assay for analysis of clearance in human liver microsomes

Test compound concentration is 0.5 μΜ, microsome concentration is 0.5 mg/mL and NADPH concentration is 1 mM in the incubation. The described method is performed by the liquid handling system Tecan RSP and is based on a 96-well format.

Control incubations with test compound without NADPH and test compound without microsomes are conducted to investigate non-CYP mediated metabolism and stability in phosphate buffer at 37 °C, respectively. Incubation conditions

The human liver microsomal suspension in phosphate buffer is mixed with NADPH. The mixture is pre-heated (7 min) to 37 °C. Test compound is added, and the mixture is incubated for 30 minutes. Incubations are run in duplicate. Samples are withdrawn at predetermined stop times and mixed with methanol containing internal standard (IS) to terminate all enzyme activity and precipitate proteins. A control without NADPH (to detect problems such as nonspecific protein binding, heat instability or non-CYP mediated metabolism) and a control without microsomes (for assessing compound stability in the absence of any active enzymes) are tested.

The percentage of organic solvent in the incubations is less than 1%. Careful inspections of reagents are performed prior to the start of any experiment to ensure all reagents are in solution. Sample analysis

The 96-well plates are centrifuged. Test compound depletion, using a compound specific LC/MS/MS method, is determined. The logarithm of the peak area ratios of test compound to internal standard (IS) versus incubation time is plotted in a graph.

The rate constant (k) (min ^"1 ) of test compound depletion is calculated from the linear part of the curve and the half-time (ti _/2 ) in minutes can be calculated from the rate constant (Eq. 2).

Intrinsic clearance (Cl _int ) (mL/min/mg protein) is calculated from:

Clint = k / c (Eq . 3)

where c is the microsomal protein concentration in mg/mL.

Intrinsic clearance is the maximum ability of the liver to extract a drug in the absence of blood flow restrictions.

Conversion to apparent clearance (Cl _app ) (mL/min/kg) is done by Eq. 4:

Clapp = Clint x a x b/d (Eq . 4) where a, b and d are the scaling factors for normalizing Cl _int to human body weight.

The following human scaling factors are used :

a : 45 (microsomal protein / liver weight (mg/g))

b: 1500 (liver weight (g))

d : 70 (body weight (kg))

Hepatic clearance (Cl _n ) (mL/min/kg) based on the well-stirred model is described as followed :

Clh = (Cl _app ^■ Q) / (Cl _app + Q) (Eq . 5) where Q is the liver blood flow in mL/min/kg (20 in humans). Dividing hepatic clearance with liver blood flow, the hepatic extraction ratio (%) can be calculated : E _h = Clh / Q ^■ 100 (Eq . 6)

Apparent clearance below approximately 10 mL/min/kg human body weight (corresponding to extraction ratio of approx. 33%) is considered as low clearance (high metabolic stability). Apparent intrinsic clearance above approximately 60 mL/min/kg human body weight (corresponding to extraction ratio of approx. 75%) is considered as high clearance (low metabolic stability).

Results for compounds according to the present invention tested in the above assay are shown in table 1.

Biological assay for analysis of clearance in rat hepatocytes

Test compounds and 4 control compounds are tested in duplicate per run. Test compound concentration is 0.5 μΜ and cell concentration is lxlO ⁶ cells/mL in the incubation. The described method is performed by the liquid handling system Tecan RSP and is based on a 96-well format.

The liver is collected from a male Spraque-Dawley rat. One liver lobe is cut off and flushed with various buffers to loosen the cells. The cell suspension is washed and centrifuged, and the cell density is adjusted to 1.2 x 10 ⁶ cells/mL with Krebs- Henseleit buffer, pH 7.4, containing 0.2% bovine serum albumin (BSA). Only cell suspensions with viability above 80% are used.

Incubation conditions

The cell suspension is pre-heated (20 min) to 37 °C. Test compound is added, and the mixture is incubated for 20 minutes. Incubations are run in duplicate. Samples are withdrawn at predetermined stop times and mixed with methanol containing internal standard (IS) to terminate all enzyme activity and precipitate proteins.

The percentage of organic solvent in the incubations is less than 1%. Careful inspections of reagents are performed prior to the start of any experiment to ensure all reagents are in solution.

Sample analysis The 96-well plates are centrifuged. Test compound depletion, using a compound specific LC/MS/MS method, is determined.

Data analysis

Data analysis is performed as described above in the section "Biological assay for analysis of clearance in human liver microsomes", with the following modifications:

Intrinsic clearance (Cl _int ) (mL/min/10 ⁶ cells) is calculated from : Clint = k/ c where c is the cell concentration in 10 ⁶ cells/mL.

The following scaling factors for rat are used for eq. 4:

a : 120 (cells / liver weight (10 ⁶ cells/g))

b: 10 (liver weight (g))

d : 0.25 (body weight (kg))

Liver blood flow in rats (for eq. 5) :

Q: 55 mL/min/kg

Apparent clearance below approximately 25 mL/min/kg rat body weight

(corresponding to an extraction ratio of approx. 33%) is considered as low clearance (high metabolic stability). Apparent intrinsic clearance above

approximately 165 mL/min/kg rat body weight (corresponding to an extraction ratio of approx. 75%) is considered as high clearance (low metabolic stability).

Results for compounds according to the present invention tested in the above assay are shown in table 1.

Compound Functional whole Clearance (% Eh) in Clearance (% Eh) in number cell assay human liver rat hepatocytes

(modulation of microsomes A: Eh < 33%;

human CaSR) A: Eh < 33%; B: 33% < Eh <

A: <200 nM; B: 33% < Eh < 75%; 75%;

B: 200-1000 nM; C: Eh > 75% C: Eh > 75 %

101 A A B

107 A A A 109 A A A

113 A A A

114 B A -

115 B A A

116 A A A

117 B A -

121 B A -

123 B A -

126 A A B

127 B A A

Table 1. Pharmacokinetic data for compounds according to the present invention.

Methods of preparation

The compounds of general formula I, la and lb can be prepared in a number of ways well known to those skilled in the art of organic synthesis. The compounds of formula I can be synthesised using the methods 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 compounds of formula I, la and lb can be prepared by techniques and procedures readily available to one of ordinary skill in the art, for example by following the procedures as set forth in the following schemes. The reactions are performed 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 recognised by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionalities present on various portions of the starting molecules in a reaction must be compatible with the reagents and reactions proposed. Not all compounds of formula I, la and lb 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 schemes described in this section are not intended to limit the scope of the invention in any way. All substituents, unless otherwise indicated, are previously defined. The reagents and starting materials are either available from commercial suppliers or prepared by methods known to one of ordinary skill in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-22 (John Wiley and Sons, 2004); Rodd's

Chemistry of Carbon Compounds, Volumes 1-5 and Supplements (Elsevier Science Publishers, 2000); Organic Reactions, Volumes 1-64 (John Wiley and Sons, 2004); March's Advanced Organic Chemistry (John Wiley and Sons, 5 ^th Edition) and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1999). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesised, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure. The starting materials and the intermediates of the reactions may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallisation, chromatography and the like. Such materials may be characterised using conventional means, including physical constants and spectral data.

Compounds of general formula I may be obtained by for example substitution or metal catalyzed amination reactions on compounds of general structure V.

V

a. R5 in compound V can be substituted with an appropriate primary or secondary amine, when R5 is F, CI or alkylsulfone. The reaction can be carried out in a solvent like DMSO, DMF or acetonitrile or, when preferred neat with or without a base present eg. triethylamine or DIPEA.

When R5 is CI, Br, OTf, OTs or I, compounds of general formula I may be obtained by metal catalyzed amination reactions. The catalyst may be, but is not limited to, Pd(OAc) ₂ , Pd ₂ (dba) ₃ or Cul, optionally in association with a phosphine or diamine ligand such as, but not limited to, ditert-butyl-(2-phenylphenyl) phosphane, ditert- butyl-[2-(2,4,6-triisopropylphenyl)phenyl]phosphane, trans-N,N'-dimethyl- cyclohexane-l,2-diamine or N,N'-dimethylethane-l,2-diamine as well as a base eg. tBuONa, Cs ₂ C0 ₃ or K ₃ P0 ₄ . The reaction is carried out in solvents like toluene, 1,4-dioxane or DMF either by applying conventional heating or microwave irradiation.

Compounds of general formula V may be obtained by reductive amination between a cyclopentanone of general formula II and an amine of general formula III. The reaction between ketone II and amine III may be carried out either by one-pot reductive amination or with isolation of the imine followed by reduction.

IV a. The formation of the intermediate iminium IV may be promoted by addition of a protic or aprotic acid such as, but not limited to acetic acid, Yb(OAc) ₃ and Ti(Oi- Pr) ₄ respectively. The reducing agent may be but is not limited to Na(CN)BH ₃ , NaBH ₄ , Na(OAc) ₃ BH (for other non-limiting conditions see Org. React. 2002, 59, 1- 714 and references cited therein).

b. The formation of the imine is promoted either by Lewis acids such as TiCI ₄ , ZnCI ₂ , AICI ₃ or by bases such as pyridine, optionally in the presence of a drying agent such as TiCI ₄ or molecular sieve (see Comprehensive Organic Functional Group Transformations 3, 403 (1995) Pergamon).

c. Reduction may be performed by hydrogenation in the presence of a catalyst such as Pd/C, Pt/C or a chiral rhodium complex to perform the reaction in a stereoselective manner or by hydride transfer from a reducing agent such as BH ₃ , NaBH ₄ , NaBH ₃ CN, LiAIH ₄ , L-selectride (see Larock R. C. Comprehensive Organic Transformations 1989, VCH Comprehensive Organic Functional Group

Transformations 2, 268-269 (2005) Pergamon and references cited therein).

e. Coupling reaction with an heteroaryl halide or pseudo halide such as triflate in the presence of a palladium source such as Pd(OAc) ₂ , PdCI ₂ (PPh ₃ ) ₂ , a base such as NEt ₃ , K ₂ C0 ₃ , NaHC0 ₃ , tBuOK, optionally with a phosphine such PPh ₃ , P(o-Tol) ₃ , 1,3- bis(diphenylphosphino)propane (dppp), optionally in the presence of a salt like NBu ₄ CI, AgN0 ₃ in a solvent such as DMF or acetonitrile. Alternatively a decarboxylative Heck-type coupling may be performed using an heteroaryl carboxylic acid (Org. Lett. 2004, 6, 433).

f. Chemospecific reduction of the double bond may be performed under numerous conditions. The hydrogen source may be H ₂ , water, Hantzsch esters. Metal-based catalysts such as Pd/C, Pd(PPh ₃ ) ₄ , supported PdCI ₂ , Rh-, Co-, Cu-, Ir-based catalysts may be used. Stereoselectivity may be achieved by addition of a chiral auxiliary such as but not limited to enantiopure binaphtol phosphate

derivatives/valine, imidazolidinone iminiums, bidentate phosphines.

Alternatively cyclopentenones may be subjected to 1,4-addition.

g. Reaction with an heteroaryl metal in which the metal may be Li, Mg halide, trialkyltin, boronic acid, boronic acid ester, optionally in the presence of a metal complex such as PdCI ₂ , Pd(OAc) ₂ , Pd(PPh ₃ ) ₄ , (acac)Rh(CO) ₂ , Ni(acac) ₂ ,

(COD)Rh(l,4-dihydroquinone)BF ₄ with a ligand typically phosphine-based such as PBu ₃ , PPh ₃ , l,3-bis(diphenylphosphino)propane (dppp), 1,3-hydroquinone or 1,4- hydroquinone in solvents such as DMF, THF, water, toluene, dioxane,

dimethoxyethane. In the presence of a chiral ligand as a pure enantiomer such as BINAP, phosphoramidite, Me-DuPHOS and the like the reaction may be performed stereoselective^.

Diastereomeric mixtures of I and V may be separated using straight phase chromatography on silica gel, preparative HPLC or by chiral HPLC.

Chiral amines of the general formula III are commercially available or may be prepared from more readily available aldehydes by catalytic asymmetric synthesis using tert-butanesulfinamide according to Liu, G. ; Cogan, D.A. ; Ellmann, J. A., J. Amer. Chem. Soc, 1997, 114, 9913.

The invention is described in further detail in the following non-limiting examples which are not in any way intended to limit the scope of the invention as claimed.

EXAMPLES General

For ^X H nuclear magnetic resonance (NMR) spectra (300 MHz) and ¹³ C NMR (75.6 MHz) chemical shift values (δ) (in ppm) are quoted for dimethyl-c/ ₆ sulfoxide (DMSO-c/ ₆ ) or CDCI ₃ solutions relative to internal tetramethylsilane (δ = 0) standard. The value of a multiplet, either defined (doublet (d), triplet (t), quartet (q), doublet of doublets (dd), doublet of triplets (dt)) or not (m) at the approximate mid-point is given unless a range is quoted, (bs) indicates a broad singlet.

The microwave reactor used was the model Initiator™ from Biotage.

The organic solvents used were anhydrous unless otherwise specified. Flash chromatography was performed on silica gel from Fluka Chemie GmbH,

Switzerland.

Chemicals unless otherwise noted were from commercial sources, e.g. Aldrich, Maybridge Chemical, Fluka or ABCR.

The following abbreviations have been used : acac Acetyl acetonate

Boc tert-Butyl oxycarbonyl

BINAP 2,2'-Bis(diphenylphosphino)-l, l'-binaphthyl

COD 1,5-cyclooctadiene

dba dibenzylideneacetone

IPEA Diisopropyl ethylamine

DMF N-Dimethyl formamide

DMSO Dimethylsulfoxid

dppp l,3-bis(diphenylphosphino)propane

Me-DuPHOS 2,2',5,5'-Tetramethyl-l,l'-(o-phenylene)diphospholane

nbd norbornadiene

OAc Acetate

P(o-Tol) ₃ tri-o-tolylphosphine

THF Tetrahydrofurane

Tf Triflate

Ts Tosylate

Flash chromatography was performed on silica gel. Appropriate mixtures of ethyl acetate, dichloromethane, methanol, and heptane were used as eluents unless otherwise noted. [Rh(R-BINAP)(nbd)]BF ₄ was prepared according to the procedure described in Itooka, R. ; Iguchi, Y. ; Miyaura, N. ; J. Org. Chem., 2003, 68, 6000. HPLC purifications of the crude products were performed by using Waters LC-MS system [column : Waters X Terra C18, 5 μΐη or Luna C18 100 A 5 μ; Size: 250 χ 10.00 mm (Phenomenex)]; Sample Manager: Waters 2767; Pump: Waters 2525; Single Quadrupole: Waters ZQ; PDA-detector: Waters 2996), solventsystem: A = 50 mM Ammonium hydrogencarbonate and B = acetonitrile; flow rate = 18 mL/min.

Alternatively, a solvent system consisting of A = water (0.1% formic acid) and B = acetonitrile (0.1% formic acid) was used. Unless otherwise noted, analytical LC/MS was performed on a Dionex APS-system with a P680A analytical pump and a Thermo MSQ Plus mass spectrometer (ionisation mode: ES+/ES-). Column : Waters XBridge, 150 mm x 4.6 mm, 5 μιτι; mobile phase: A = 50 mM NH ₄ HC0 ₃ (aq.) and B = acetonitrile; flow rate = 1.2 mL/min; method (10 min) : Linear gradient method going from 10 % B to 90 % B in 4.5 minutes and staying at 90 % B for another 1.5 minutes.

Table 2. Exemplified compounds of general formula I :

Table 3: Exemplified intermediates:

Intermediate 1: (3R)-3-(6-Fluoro-3-pyridyl)cyclopentanone

A round bottom flask was charged with tBuOK (5.6 g, 50 mmol) and dioxane (150 mL) and the slurry was degassed for 20 min. Cyclopentenone (21.5 g, 250 mmol) was added and degassing continued for 5 min before addition of 2-fluoro-5-

(4,4,5,5-tetramethyl-[l,3,2]-dioxaborolan-2-yl)-pyridine (11.0 g, 50 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (1.1 g, 1.3 mmol), then the reaction mixture was heated on an oilbath at 80 °C for 90 min. The crude was concentrated in vacuo and purified by flash chromatography (eluent: 30 % ethylacetate in heptane) to yield the title compound : 6.2 g (70%).

1H NMR (300 MHz, CDCI3) δ 8.13 (s, 1H), 7.70 (td, J = 8.1, 2.6 Hz, 1H), 6.93 (dd, J = 8.4, 3.0 Hz, 1H), 3.62 - 3.26 (m, 1H), 2.82 - 2.61 (m, 1H), 2.54 - 2.42 (m, 2H), 2.41 - 2.15 (m, 2H), 2.11 - 1.86 (m, 1H). Intermediate 2: (3R)-3-(6-chloro-3-pyridyl)cyclopentanone A 20 mL microwave vial was charged with 2-chlorpyridine-5-boronic acid (1.57 g, 10 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (275 mg, 0.3 mmol), then capped and backfilled with argon. In a second flask 2-cyclopenten-l-one (0.8 mL, 10 mmol) was taken up in dioxane/water 6: 1 (10 mL) and degassed with argon for 15 min before adding triethylamine (1.4 mL, 10 mmol), degassing was continued for 5 min before the solution was transferred to the microwave vial with a syringe. The reaction mixture was heated in a microwave reactor at 80 °C for 15 min.

Extractive workup with brine and ethyl acetate and subsequent concentration under high vacuum to remove deborylated by-product yielded the title compound : 870 mg (48%).

1H NMR (300 MHz, CDCI3) δ 8.32 (d, J = 2.5 Hz, 1H), 7.55 (dd, J = 8.4, 2.6 Hz, 1H), 7.32 (d, J = 8.3 Hz, 1H), 3.58 - 3.31 (m, 1H), 2.84 - 2.63 (m, 1H), 2.62 - 2.43 (m, 2H), 2.43 - 2.16 (m, 2H), 2.12 - 1.88 (m, 1H). Intermediate 3: (3R)-3-(6-Iodo-3-pyridyl)cyclopentanone

A 5 mL microwave vial was charged with Intermediate 2 (1 g, 5.1 mmol) in propionitrile (1.0 mL), then chlorotrimethyl silane (2.0 mL, 10.2 mmol) followed by sodium iodide (3.0 g, 25.6 mmol) was added. The reaction mixture was heated in a microwave reactor at 130 °C for 1.5 h, then quenched with 10% aq. Na ₂ C0 ₃ (50 mL) and extracted with ethyl acetate (2 x 50 mL). The combined organic layers were dried and concentrated in vacuo. The residue was purified using flash chromatography (30% ethyl acetate/heptane) and further purified by preparative HPLC to afford the title compound as a solid (420 mg, 39%).

1H NMR (300 MHz, CDCI3) δ 8.31 (d, J = 2.6 Hz, 1H), 7.71 (d, J = 8.1 Hz, 1H), 7.23 (dd, J = 8.1, 2.6 Hz, 1H), 3.48 - 3.28 (m, 1H), 2.78 - 2.61 (m, 1H), 2.56 - 2.42 (m, 2H), 2.41 - 2.20 (m, 2H), 2.05 - 1.87 (m, 1H).

General procedure 1 : reductive amination (GP1) Intermediate 4: (lS,3R)-N-[( lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3- (6-fluoro-3-pyridyl)cyclopentanamine

In a round-bottom flask Intermediate 1 (179 mg, 1.0 mmol) and (lR)-l-(4-fluoro- 3-methoxyphenyl)ethylamine hydrochloride (206 mg, 1.0 mmol) was suspended in CH ₃ CN (4 mL), sodium triacetoxyborohydride (279 mg, 1.4 mmol) followed by acetic acid (60 μί) was added and the reaction mixture stirred at room

temperature for 16h. Saturated NaHC0 ₃ , aq (3 mL) was added and the product was extracted with CH ₂ CI ₂ . The combined organic phases were concentrated and purified by flash chromatography (eluent: 50-100% EtOAc in heptane) to yield the title compound : 72 mg (22%). 1H NMR (300 MHz, CDCI3) δ 8.03 (d, J = 2.4 Hz, 1H), 7.62 (td, J = 8.1, 2.6 Hz, 1H), 7.06 - 6.94 (m, 2H), 6.86 - 6.78 (m, 2H), 3.90 (s, 3H), 3.83 (q, J = 6.6 Hz, 1H), 3.16 - 3.02 (m, 1H), 3.02 - 2.87 (m, 1H), 2.27 - 2.14 (m, 1H), 2.11 - 1.92 (m, 2H), 1.81 - 1.56 (m, 2H), 1.42 - 1.31 (m, 4H).

Intermediate 5: (lS,3R)-N-[(lR)-l-(l,3-Benzodioxol-4-yl)ethyl]-3-(6- fluoro-3-pyridyl)cyclopentanamine

Prepared according to GPl from Intermediate 1 (400 mg, 2.2 mmol) and 1-(2H- benzo[d] l,3-dioxolen-4-yl)(lR)ethylamine-hydrochloride (495 mg, 2.5 mmol) yielding the title compound : 198 mg (27%).

1H NMR (300 MHz, CDCI3) δ 8.02 (d, J = 1.9 Hz, 1H), 7.65 (td, J = 8.2, 2.5 Hz, 1H), 6.88 - 6.70 (m, 4H), 5.95 (s, 2H), 3.98 (q, J = 6.6 Hz, 1H), 3.22 - 3.06 (m, 1H), 3.03 - 2.86 (m, 1H), 2.30 - 2.16 (m, 1H), 2.08 - 1.89 (m, 3H), 1.82 - 1.62 (m, 2H), 1.44 (d, J = 6.7 Hz, 3H).

Intermediate 6: (lS,3R)-N-[(lR)-l-(3-Chlorophenyl)ethyl]-3-(6-fluoro-3- pyridyl)cyclopentanamine

Prepared according to GPl from Intermediate 1 (400 mg, 2.2 mmol) and (R)-l-(3- chlorophenyl)ethanamine (382 mg, 2.5 mmol) yielding the title compound : 228 mg (32%).

1H NMR (300 MHz, CDCI3) δ 8.02 (d, J = 2.3 Hz, 1H), 7.66 - 7.59 (m, 1H), 7.33 (bs, 1H), 7.28 - 7.19 (m, 3H), 6.82 (dd, J = 8.5, 3.0 Hz, 1H), 3.85 (q, J = 6.6 Hz, 1H), 3.14 - 3.02 (m, 1H), 2.99 - 2.87 (m, 1H), 2.26 - 2.16 (m, 1H), 2.10 - 1.93 (m, 2H), 1.81 - 1.59 (m, 3H), 1.39 (d, J = 6.5 Hz, 3H).

Intermediate 7: (lS,3R)-N-[(lR)-l-(3-Ethoxyphenyl)ethyl]-3-(6-fluoro-3- pyridyl)cyclopentanamine

Prepared according to GPl from Intermediate 1 (400 mg, 2.2 mmol) and (R)-l-(3- ethoxyphenyl)ethanamine (495 mg, 2.5 mmol) yielding the title compound : 200 mg (27%).

1H NMR (300 MHz, CDCI3) δ 8.01 (d, J = 2.3 Hz, 1H), 7.66 - 7.58 (m, 1H), 7.30 - 7.20 (m, 1H), 6.99 - 6.85 (m, 2H), 6.85 - 6.74 (m, 2H), 4.06 (q, J = 7.0 Hz, 2H), 3.93 - 3.76 (m, 1H), 3.17 - 3.04 (m, 1H), 2.99 - 2.84 (m, 1H), 2.57 - 2.18 (m, 2H), 2.09 - 1.88 (m, 3H), 1.83 - 1.67 (m, 2H), 1.50 - 1.37 (m, 5H).

Intermediate 8: (lS,3R)-3-(6-Fluoro-3-pyridyl)-N-[(lR)-l-(l- naphthyl)ethyl]cyclopentanamine Prepared according to GPl from Intermediate 1 (400 mg, 2.2 mmol) and R(+)-l- (l-naphthyl)ethylamin (420 mg, 2.5 mmol) yielding the title compound : 267 mg (36%).

1H NMR (300 MHz, CDCI3) δ 8.20 (d, J = 7.7 Hz, 1H), 8.01 (d, J = 2.1 Hz, 1H), 7.92 - 7.84 (m, 1H), 7.76 (d, J = 8.1 Hz, 1H), 7.70 - 7.57 (m, 2H), 7.57 - 7.44 (m, 3H), 6.82 (dd, J = 8.4, 3.0 Hz, 1H), 4.74 (q, J = 6.6 Hz, 1H), 3.28 - 3.14 (m, 1H), 2.99 - 2.84 (m, 1H), 2.34 - 2.20 (m, 1H), 2.10 - 1.90 (m, 2H), 1.83 - 1.66 (m, 2H), 1.66 - 1.55 (m, 1H), 1.52 (d, J = 6.6 Hz, 3H). Intermediate 9: (lS,3R)-3-(6-Chloro-3-pyridyl)-N-[(lR)-l-(l- naphthyl )ethyl]cyclopentanamine

Prepared according to GPl from Intermediate 2 (430 mg, 2.2 mmol) and R(+)-l- (l-naphthyl)ethylamin (376 mg, 2.2 mmol) yielding the title compound : 231 mg (30%).

1H NMR (300 MHz, DMSO) δ 8.29 (d, J = 7.8 Hz, 1H), 8.26 (d, J = 2.5 Hz, 1H), 7.95 - 7.88 (m, 1H), 7.82 - 7.68 (m, 3H), 7.57 - 7.45 (m, 3H), 7.40 (d, J = 8.3 Hz, 1H), 4.66 (q, J = 6.3 Hz, 1H), 3.17 (d, J = 4.5 Hz, 1H), 3.09 - 2.97 (m, 1H), 2.97 - 2.84 (m, 1H), 2.38 - 2.29 (m, 1H), 2.22 - 2.10 (m, 1H), 1.98 - 1.83 (m, 1H), 1.79 - 1.62 (m, 3H), 1.38 (d, J = 6.6 Hz, 3H).

Intermediate 10: (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]- 3-(6-iodo-3-pyridyl)cyclopentanamine

Prepared according to GPl from Intermediate 3 (1.10 g, 4.0 mmol) and (lR)-l-(4- fluoro-3-methoxyphenyl)ethylamine hydrochloride (824 mg, 4.0 mmol) yielding the title compound : 500 mg (28%).

1H NMR (300 MHz, CDCI3) δ 8.21 (d, J = 2.5 Hz, 1H), 7.60 (d, J = 8.1 Hz, 1H), 7.18 (dd, J = 8.1, 2.6 Hz, 1H), 7.06 - 6.92 (m, 2H), 6.81 (ddd, J = 8.2, 4.3, 2.0 Hz, 1H), 3.90 (s, 3H), 3.82 (q, J = 6.6 Hz, 1H), 3.20 - 3.01 (m, 1H), 2.96 - 2.81 (m, 1H), 2.30 - 2.12 (m, 1H), 2.11 - 1.90 (m, 2H), 1.83 - 1.53 (m, 3H), 1.35 (d, J = 6.6 Hz, 4H).

General procedure 2: substitution of the fluoro pyridine (GP2)

Example 1: 2-[2-[[5-[( lR,3S)-3-[[( lR)-l-(l-Naphthyl)ethyl]amino] cyclopentyl]-2-pyridyl]amino]ethylamino]ethanol; triple formic acid (compound 101)

A 0.5 mL microwave vial was charged with Intermediate 8 (15 mg, 0.04 mmol), then DMSO (0.5 mL) was added followed by N-(2-hydroxyethyl)ethylendiamine (40 mg, 0.40 mmol) and DIPEA (65 μΙ_, 0.40 mmol). The vial was capped and heated in a microwave reactor at 160 °C for 20 min. The reaction mixture was diluted with saturated NaHC0 ₃ and extracted with CH ₂ CI ₂ . Concentrated and purified by preparative HPLC (basic system : NH ₄ HC0 ₃ ) to yield the title compound 2.1 mg (13%).

1H NMR (300 MHz, DMSO) δ 8.29 (d, J = 7.8 Hz, 1H), 8.14 (s, 2H), 7.99 - 7.84 (m, 1H), 7.82 - 7.65 (m, 2H), 7.65 - 7.42 (m, 3H), 6.78 (t, J = 5.8 Hz, 1H), 4.66 (q, J = 6.5 Hz, 1H), 4.42 (bs, 1H), 3.65 - 3.50 (m, 1H), 3.50 - 3.39 (m, 2H), 3.29 - 3.22 (m, 2H), 3.05 - 2.89 (m, J = 7.1 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.19 - 1.98 (m, 2H), 1.92 - 1.76 (m, 1H), 1.77 - 1.55 (m, 2H), 1.37 (d, J = 6.5 Hz, 3H), 1.34 - 1.22 (m, 1H).

General Procedure 3: substitution of fluoro pyridine with subsequent Boc deprotection of an amine (GP3) Example 2: l-[5-[( lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl] amino]cyclopentyl]-2-pyridyl]piperidin-4-amine (compound 102)

Prepared according to GP 3 from Intermediate 4 and Boc-4-aminopiperidine, after extractive workup the crude was concentrated and redissolved in 4N HCI in dioxane. Heated at 60 °C for 1 h, then concentrated and purified by preparative HPLC (basic system: NH ₄ HC0 ₃ ) to yield the title compound.

1H NMR (600 MHz, DMSO) δ 7.95 (d, J = 2.4 Hz, 1H), 7.43 (dd, J = 8.8, 2.5 Hz, 1H), 7.16 (dd, J = 8.6, 1.8 Hz, 1H), 7.10 (dd, J = 11.5, 8.2 Hz, 1H), 6.88 (ddd, J = 8.1, 4.3, 1.9 Hz, 1H), 6.80 (d, J = 8.8 Hz, 1H), 4.25 - 4.19 (m, 2H), 3.82 (s, 3H), 3.76 (q, J = 6.4 Hz, 1H), 3.19 - 3.11 (m, 1H), 2.92 - 2.86 (m, 1H), 2.85 - 2.79 (m, 2H), 2.79 - 2.72 (m, 1H), 2.02 - 1.95 (m, 1H), 1.89 - 1.81 (m, 2H), 1.81 - 1.73 (m, 2H), 1.64 - 1.51 (m, 2H), 1.43 - 1.33 (m, 2H), 1.30 - 1.25 (m, 1H), 1.24 (d, J = 6.6 Hz, 3H).

General Procedure 4: substitution of chloro pyridine (GP4)

Example 3: N-[5-[(lR,3S)-3-[[( lR)-l-(l-Naphthyl)ethyl]amino] cyclopentyl]-2-pyridyl]ethane-l,2-diamine (compound 103)

A 4 mL vial was charged with Intermediate 9 (64 mg, 0.2 mmol) and

ethylenediamine (0.2 mL, 2.0 mmol), capped and heated on a shaker at 120 °C for 48 h. After extractive work up with water and CH ₂ CI ₂ , the resulting residue was purified by preparative HPLC (basic system : NH ₄ HC0 ₃ ) to yield the title compound. 1H NMR (300 MHz, DMSO) δ 8.28 - 8.25 (m, 1H), 7.96 - 7.88 (m, 1H), 7.79 (s, 1H), 7.78 - 7.69 (m, 2H), 7.56 - 7.44 (m, 3H), 7.36 - 7.27 (m, 1H), 6.63 - 6.52 (m, 1H), 6.44 (d, J = 8.5 Hz, 1H), 4.68 (q, J = 6.6 Hz, 1H), 3.42 - 3.37 (m, 2H), 3.09 - 2.95 (m, 1H), 2.90 (t, J = 6.0 Hz, 2H), 2.76 - 2.66 (m, 1H), 2.10 - 2.00 (m, 1H), 1.88 - 1.52 (m, 4H), 1.39 (d, J = 6.5 Hz, 3H), 1.35 - 1.23 (m, 1H).

General Procedure 5: cupper catalyzed amination of iodo pyridine (GP5)

Example 4: N-[5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino]cyclopentyl]-2-pyridyl]piperidine-4-carbo xamide (compound 104)

A 4 mL vial was charged with Intermediate 10 (15 mg, 0.03 mmol) and dissolved in DMF (150 μΙ_). Then piperidine-4-carboxamide (13 mg, 0.1 mmol) followed by cupper iodide (3 mg, 0.02 mmol), K ₃ P0 ₄ (14 mg, 0.07 mmol) and trans-N,N'- dimethyl-cyclohexane-l,2-diamine (3 mg, 0.02 mmol) was added and the reaction mixture heated on a shaker at 90 °C over night. Purified by preparative HPLC (basic system: NH ₄ HC0 ₃ ) to yield the title compound.

1H NMR (300 MHz, DMSO) δ 10.22 (s, 1H), 8.13 (s, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.63 (dd, J = 8.6, 2.3 Hz, 1H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.6, 8.2 Hz, 1H), 6.92 - 6.84 (m, 1H), 3.82 (s, 3H), 3.75 (q, J = 6.5 Hz, 1H), 2.96 - 2.77 (m, 4H), 2.12 - 1.83 (m, 3H), 1.83 - 1.53 (m, 5H), 1.53 - 1.38 (m, 2H), 1.37 - 1.28 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H).

Example 5: (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6- morpholino-3-pyridyl)cyclopentanamine (compound 105)

Prepared according to GP2 from Intermediate 4 and morpholine.

1H NMR (300 MHz, DMSO) δ 7.97 (d, J = 2.3 Hz, 1H), 7.45 (dd, J = 8.7, 2.5 Hz, 1H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.6, 8.3 Hz, 1H), 6.88 (ddd, J = 8.2, 4.5, 2.0 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H), 3.75 (q, J = 6.5 Hz, 1H), 3.70 - 3.65 (m, 4H), 3.40 - 3.32 (m, 4H), 2.94 - 2.83 (m, 1H), 2.83 -

2.69 (m, 1H), 2.07 - 1.95 (m, 1H), 1.91 - 1.71 (m, 2H), 1.66 - 1.49 (m, 2H), 1.34 - 1.25 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H).

Example 6: (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-(6- piperazin-l-yl-3-pyridyl)cyclopentanamine (compound 106)

Prepared according to GP2 from Intermediate 4 and piperazine.

1H NMR (300 MHz, DMSO) δ 7.93 (d, J = 2.2 Hz, 1H), 7.43 - 7.36 (m, 1H), 7.15 (d, J = 8.6 Hz, 1H), 7.09 (dd, J = 11.6, 8.2 Hz, 1H), 6.93 - 6.81 (m, 1H), 6.71 (d, J = 8.7 Hz, 1H), 3.82 (s, 3H), 3.79 - 3.69 (m, 1H), 2.97 - 2.80 (m, 1H), 2.78 -

2.70 (m, 5H), 2.05 - 1.93 (m, 1H), 1.89 - 1.68 (m, 2H), 1.68 - 1.48 (m, 2H), 1.33 - 1.25 (m, 1H), 1.23 (d, J = 6.4 Hz, 3H). (m, 4H is hidden under the water peak at 3.33) Example 7: 5-[(lR,3S)-3-[[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl] amino]cyclopentyl]-N-(4-piperidyl)pyridin-2-amine (compound 107)

Prepared according to GP3 from Intermediate 4 and 4-amino-l-Boc-piperidine. 1H NMR (600 MHz, DMSO) δ 7.92 (d, J = 2.4 Hz, 1H), 7.39 (dd, J = 8.8, 2.5 Hz, 1H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.88 (ddd, J = 8.2, 4.4, 1.9 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H), 4.14 - 4.07 (m, 2H), 3.82 (s, 3H), 3.74 (q, J = 6.6 Hz, 1H), 2.91 - 2.84 (m, 1H), 2.84 - 2.70 (m, 4H), 2.04 - 1.93 (m, 1H), 1.84 - 1.75 (m, 2H), 1.74 - 1.68 (m, 2H), 1.63 - 1.50 (m, 2H), 1.35 - 1.24 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H), 1.21 - 1.12 (m, 2H).

Example 8: 3-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino]cyclopentyl]-2-pyridyl]amino]propane-l-su lfonamide (compound 108)

Prepared according to GP2 from Intermediate 4 and 3-aminopropane-l- sulfonamide hydrochloride.

1H NMR (600 MHz, DMSO) δ 7.78 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 8.6, 2.4 Hz, 1H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.87 (ddd, J = 8.2, 4.4, 1.9 Hz, 1H), 6.76 (s, 2H), 6.43 - 6.35 (m, 2H), 3.82 (s, 3H), 3.74 (q, J = 6.5 Hz, 1H), 3.31 - 3.27 (m, 2H), 3.03 - 2.97 (m, 2H), 2.92 - 2.81 (m, 1H), 2.77 - 2.65 (m, 1H), 2.01 - 1.94 (m, 1H), 1.94 - 1.86 (m, 2H), 1.85 - 1.71 (m, 2H), 1.61 - 1.51 (m, 2H), 1.28 - 1.17 (m, 4H).

Example 9: 4-[5-[( lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl] amino]cyclopentyl]-2-pyridyl]piperazin-2-one (compound 109)

Prepared according to GP2 from Intermediate 4 and 2-oxypiperazine.

1H NMR (300 MHz, DMSO) δ 8.00 (bs, 1H), 7.97 (d, J = 2.1 Hz, 1H), 7.47 (dd, J = 8.7, 2.3 Hz, 1H), 7.15 (d, J = 7.1 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.88 (dd, J = 6.5, 4.5 Hz, 1H), 6.76 (d, J = 8.7 Hz, 1H), 3.92 (s, 2H), 3.82 (s, 3H), 3.78 - 3.72 (m, 1H), 3.69 - 3.62 (m, 2H), 3.28 - 3.22 (m, 2H), 2.96 - 2.83 (m, 1H), 2.82 - 2.70 (m, 1H), 2.05 - 1.94 (m, 1H), 1.90 - 1.69 (m, 2H), 1.68 - 1.50 (m, 2H), 1.33 - 1.25 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H).

Example 10: 2-[2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]-2-pyridyl]amino]ethylamino]ethanol;

dihydrochloride (compound 110)

Prepared according to GP2 from Intermediate 4 and N-(2- hydroxyethyl)ethylendiamine. IH NMR (300 MHz, DMSO) δ 10.12 (bs, IH), 9.71 (bs, IH), 9.07 (bs, 2H), 7.97 (d, J = 8.5 Hz, IH), 7.77 (s, IH), 7.67 (d, J = 8.4 Hz, IH), 7.26 (dd, J = 11.3, 8.3 Hz, IH), 7.21 - 7.05 (m, 2H), 4.49 - 4.26 (m, IH), 3.88 (s, 3H), 3.82 - 3.73 (m, 2H),

3.74 - 3.64 (m, 2H), 3.31 - 3.26 (m, IH), 3.24 - 3.14 (m, 2H), 3.14 - 3.01 (m, 3H), 3.01 - 2.88 (m, IH), 2.36 - 2.19 (m, IH), 2.19 - 2.03 (m, IH), 2.03 - 1.70

(m, 4H), 1.63 (d, J = 6.7 Hz, 3H).

Example 11: 3-[2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]-2-pyridyl]amino]ethylamino]propan-l -ol (compound 111)

Prepared according to GP2 from Intermediate 4 and N-(3-hydroxypropyl)- ethylendiamine.

IH NMR (600 MHz, DMSO) δ 7.77 (d, J = 2.3 Hz, IH), 7.26 (dd, J = 8.6, 2.4 Hz, IH), 7.15 (dd, J = 8.6, 1.8 Hz, IH), 7.09 (dd, J = 11.5, 8.2 Hz, IH), 6.87 (ddd, J = 8.1, 4.3, 1.9 Hz, IH), 6.40 (d, J = 8.6 Hz, IH), 6.16 (t, J = 5.6 Hz, IH), 3.82 (s, 3H), 3.74 (q, J = 6.5 Hz, IH), 3.45 (t, J = 6.3 Hz, 2H), 3.27 - 3.21 (m, 2H), 2.92 - 2.81 (m, IH), 2.73 - 2.65 (m, IH), 2.65 - 2.61 (m, 2H), 2.56 (t, J = 6.9 Hz, 2H), 2.00 - 1.93 (m, IH), 1.86 - 1.78 (m, IH), 1.78 - 1.71 (m, IH), 1.69 - 1.51 (m, 5H), 1.22 (d, J = 6.6 Hz, 3H).

Example 12: 5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl] amino]cyclopentyl]-N-( l-methylsulfonyl-4-piperidyl)pyridin-2-amine (compound 112)

Prepared according to GP2 from Intermediate 4 and l-methylsulfonylpiperidin-4- amine hydrochloride.

IH NMR (600 MHz, DMSO) δ 7.78 (d, J = 2.3 Hz, IH), 7.27 (dd, J = 8.6, 2.4 Hz, IH), 7.15 (dd, J = 8.6, 1.9 Hz, IH), 7.09 (dd, J = 11.5, 8.2 Hz, IH), 6.87 (ddd, J = 8.2, 4.4, 1.9 Hz, IH), 6.41 (d, J = 8.6 Hz, IH), 6.27 (d, J = 7.6 Hz, IH), 3.82 (s, 3H), 3.80 - 3.76 (m, IH), 3.74 (q, J = 6.7 Hz, IH), 3.53 - 3.45 (m, 2H), 2.93 - 2.80 (m, 7H), 2.76 - 2.63 (m, IH), 2.02 - 1.91 (m, 3H), 1.85 - 1.78 (m, IH),

1.75 (ddd, J = 13.8, 9.4, 4.9 Hz, IH), 1.60 - 1.50 (m, 2H), 1.47 - 1.38 (m, 2H), 1.23 (d, J = 6.6 Hz, 3H).

Example 13: 2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl )ethyl]amino]cyclopentyl]-2-pyridyl]amino]ethanesulfonamide (compound 113)

Prepared according to GP2 from Intermediate 4 and 2-aminoethanesulfonamide hydrochloride. 1H NMR (300 MHz, DMSO) δ 7.83 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 8.6, 2.4 Hz, 1H), 7.20 (dd, J = 8.6, 1.9 Hz, 1H), 7.13 (dd, J = 11.5, 8.3 Hz, 1H), 6.97 - 6.88 (m, 1H), 6.85 (s, 2H), 6.47 - 6.36 (m, 2H), 3.90 - 3.84 (m, 1H), 3.83 (s, 3H), 3.65 - 3.55 (m, 2H), 3.25 - 3.14 (m, 2H), 3.04 - 2.88 (m, 1H), 2.82 - 2.64 (m, 1H), 2.10 - 1.95 (m, 1H), 1.90 - 1.71 (m, 2H), 1.68 - 1.54 (m, 2H), 1.36 - 1.20 (m, 4H).

Example 14: 2-[[5-[(lR,3S)-3-[[( lR)-l-( l,3-Benzodioxol-4-yl)ethyl] amino]cyclopentyl]-2-pyridyl]amino]ethanesulfonamide (compound 114) Prepared according to GP2 from Intermediate 5 and 2-aminoethanesulfonamide hydrochloride.

1H NMR (600 MHz, DMSO) δ 7.82 (d, J = 2.3 Hz, 1H), 7.31 (dd, J = 8.6, 2.4 Hz, 1H), 6.91 (dd, J = 7.8, 1.1 Hz, 1H), 6.83 - 6.78 (m, 1H), 6.77 - 6.74 (m, 1H), 6.44 - 6.37 (m, 2H), 6.05 (bs, 1H), 5.98 - 5.94 (m, 2H), 3.91 (q, J = 6.7 Hz, 1H), 3.63 - 3.57 (m, 2H), 3.21 - 3.15 (m, 2H), 2.97 - 2.89 (m, 1H), 2.80 - 2.69 (m, 1H), 2.04 - 1.96 (m, 1H), 1.87 - 1.78 (m, 1H), 1.78 - 1.70 (m, 1H), 1.62 - 1.49 (m, 2H), 1.26 (d, J = 6.7 Hz, 3H), 1.24 - 1.17 (m, 1H).

Example 15: 3-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino]cyclopentyl]-2-pyridyl]amino]propane-l,2- diol (compound 115)

Prepared according to GP2 from Intermediate 4 and 3-amino-l,2-propanediol. 1H NMR (300 MHz, DMSO) δ 8.24 (s, 2H), 7.76 (d, J = 2.2 Hz, 1H), 7.35 - 7.24 (m, 2H), 7.19 (dd, J = 11.5, 8.3 Hz, 1H), 6.99 (ddd, J = 8.2, 4.4, 1.9 Hz, 1H), 6.49 (d, J = 8.6 Hz, 1H), 6.34 - 6.19 (m, 1H), 4.06 (q, J = 6.5 Hz, 1H), 3.84 (s, 3H), 3.62 - 3.52 (m, 1H), 3.41 - 3.23 (m, 3H), 3.21 - 3.03 (m, 2H), 2.86 - 2.66 (m, 1H), 2.18 - 2.00 (m, 1H), 1.95 - 1.67 (m, 3H), 1.67 - 1.54 (m, 1H), 1.51 - 1.42 (m, 1H), 1.40 (d, J = 6.7 Hz, 3H). Example 16: l-[4-[5-[( lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl )ethyl]amino]cyclopentyl]-2-pyridyl]piperazin-l-yl]ethanone (compound 116)

Prepared according to GP2 from Intermediate 4 and acetylpiperazine.

1H NMR (300 MHz, DMSO) δ 7.97 (d, J = 2.4 Hz, 1H), 7.45 (dd, J = 8.8, 2.5 Hz, 1H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.3 Hz, 1H), 6.87 (ddd, J = 8.2, 4.5, 2.0 Hz, 1H), 6.79 (d, J = 8.8 Hz, 1H), 3.82 (s, 3H), 3.75 (q, J = 6.5 Hz, 1H), 3.57 - 3.34 (m, 8H), 2.96 - 2.83 (m, 1H), 2.83 - 2.70 (m, 1H), 2.03 (s, 3H), 2.01 - 1.93 (m, 1H), 1.93 - 1.68 (m, 2H), 1.68 - 1.48 (m, 2H), 1.32 - 1.25 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H). Example 17: 4-[5-[(lR,3S)-3-[[( lR)-l-(3-Ethoxyphenyl)ethyl]amino] cyclopentyl]-2-pyridyl]piperazin-2-one (compound 117)

Prepared according to GP2 from Intermediate 7 and 2-oxypiperazine.

IH NMR (600 MHz, DMSO) δ 8.02 (s, IH), 7.97 (d, J = 2.4 Hz, IH), 7.47 (dd, J = 8.8, 2.4 Hz, IH), 7.18 (t, J = 7.8 Hz, IH), 6.93 - 6.90 (m, IH), 6.88 (d, J = 7.6 Hz, IH), 6.76 (d, J = 8.8 Hz, IH), 6.75 - 6.72 (m, IH), 4.00 (q, J = 7.0 Hz, 2H), 3.92 (s, 2H), 3.71 (q, J = 6.6 Hz, IH), 3.68 - 3.64 (m, 2H), 3.28 - 3.23 (m, 2H), 2.92 - 2.85 (m, IH), 2.82 - 2.73 (m, IH), 2.04 - 1.96 (m, IH), 1.88 - 1.80 (m, IH), 1.78 - 1.71 (m, IH), 1.64 - 1.52 (m, 2H), 1.31 (t, J = 7.0 Hz, 3H), 1.29 - 1.23 (m, IH), 1.22 (d, J = 6.6 Hz, 3H).

Example 18: (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]-3-[6- (4-methylsulfonylpiperazin-l-yl)-3-pyridyl]cyclopentanamine;

dihydrochloride salt (compound 118)

Prepared according to GP2 from Intermediate 4 and l-(methylsulfonyl)piperazine hydrochloride.

IH NMR (600 MHz, DMSO) δ 10.28 (bs, IH), 9.84 (bs, IH), 8.06 (bs, IH), 7.88 (d, J = 1.8 Hz, IH), 7.74 (dd, J = 8.3, 1.8 Hz, IH), 7.44 - 7.37 (m, IH), 7.26 (dd, J = 11.3, 8.3 Hz, IH), 7.18 (ddd, J = 8.2, 4.1, 2.0 Hz, IH), 4.41 (dq, J = 13.7, 6.7 Hz, IH), 3.89 (s, 3H), 3.87 - 3.79 (m, 4H), 3.32 - 3.22 (m, 5H), 3.07 - 2.97 (m, IH), 2.94 (s, 3H), 2.35 - 2.22 (m, IH), 2.22 - 2.11 (m, IH), 1.99 - 1.78 (m, 4H), 1.65 (d, J = 6.7 Hz, 3H). Example 19: 2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino]cyclopentyl]-2-pyridyl]amino]ethanol (compound 119)

Prepared according to GP4 from Intermediate 4 and ethanolamine.

IH NMR (300 MHz, DMSO) δ 8.21 (s, IH), 7.77 (d, J = 2.3 Hz, IH), 7.26 (dd, J = 8.6, 2.4 Hz, IH), 7.19 (dd, J = 8.6, 1.9 Hz, IH), 7.12 (dd, J = 11.5, 8.3 Hz, IH), 6.97 - 6.83 (m, IH), 6.43 (d, J = 8.6 Hz, IH), 6.21 (t, J = 5.7 Hz, IH), 3.92 - 3.77 (m, 4H), 3.49 (t, J = 6.0 Hz, 2H), 3.31 - 3.21 (m, 2H), 3.02 - 2.86 (m, IH), 2.81 - 2.66 (m, IH), 2.06 - 1.94 (m, IH), 1.88 - 1.73 (m, 2H), 1.64 - 1.51 (m, 2H), 1.33 - 1.24 (m, 4H).

Example 20: 2-[2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino]cyclopentyl]-2-pyridyl]amino]ethylamino]e thanol; triple formic acid salt (compound 120) Prepared according to GP2 from Intermediate 4 and N-(2-hydroxyethyl) ethylendiamine.

1H NMR (600 MHz, DMSO) δ 7.77 (d, J = 2.2 Hz, 1H), 7.26 (dd, J = 8.6, 2.4 Hz, 1H), 7.15 (dd, J = 8.6, 1.8 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.87 (ddd, J = 8.1, 4.3, 1.9 Hz, 1H), 6.40 (d, J = 8.6 Hz, 1H), 6.18 (t, J = 5.6 Hz, 1H), 4.45 (bs, 1H), 3.82 (s, 3H), 3.74 (q, J = 6.5 Hz, 1H), 3.43 (t, J = 5.7 Hz, 2H), 3.27 - 3.22 (m, 2H), 2.92 - 2.81 (m, 1H), 2.74 - 2.68 (m, 1H), 2.66 (t, J = 6.3 Hz, 2H), 2.58 (t, J = 5.7 Hz, 2H), 2.00 - 1.93 (m, 1H), 1.85 - 1.78 (m, 1H), 1.78 - 1.71 (m, 1H), 1.60 - 1.50 (m, 2H), 1.27 - 1.18 (m, 4H).

Example 21: 2-[[5-[(lR,3S)-3-[[( lR)-l-(3-Chlorophenyl)ethyl]amino] cyclopentyl]-2-pyridyl]amino]ethanesulfonamide (compound 121)

Prepared according to GP2 from Intermediate 6 and 2-aminoethanesulfonamide hydrochloride.

1H NMR (600 MHz, DMSO) δ 7.81 (d, J = 2.3 Hz, 1H), 7.43 - 7.39 (m, 1H), 7.36 - 7.30 (m, 4H), 7.28 - 7.22 (m, 1H), 6.46 - 6.39 (m, 2H), 3.77 (q, J = 6.6 Hz, 1H), 3.63 - 3.59 (m, 2H), 3.22 - 3.17 (m, 2H), 2.90 - 2.81 (m, 1H), 2.76 - 2.68 (m, 1H), 2.00 - 1.94 (m, 1H), 1.86 - 1.78 (m, 1H), 1.78 - 1.71 (m, 1H), 1.62 - 1.49 (m, 2H), 1.29 - 1.20 (m, 4H).

Intermediate 11: (3R)-3-(2-Methylsulfanylpyrimidin-5-yl)cyclopentanone

A 20 mL microwave vial was charged with 2-(methylthio)pyrimidine-5-boronic acid (2.75 g, 16.2 mmol) and [Rh((R)-BINAP)(nbd)] tetrafluoroborate (904 mg, 0.6 mmol), then capped and backfilled with argon. In a second flask 2-cyclopenten-l- one (7.0 mL, 81 mmol) was taken up in MeOH (6 mL) and degassed with argon for 15 min before adding triethylamine (2.3 mL, 16.2 mmol), degassing was continued for 5 min before the solution was transferred to the microwave vial with a syringe. The reaction mixture was heated in a microwave reactor at 80 °C for 15 min. Extractive workup with brine and ethyl acetate and subsequent purification by flash chromatography (eluent: 0-50 % ethylacetate in heptane) yielded the title compound : 592 mg (20%).

1H NMR (300 MHz, CDCI3) δ 8.46 (s, 2H), 3.46 - 3.21 (m, 1H), 2.83 - 2.62 (m, 1H), 2.58 (s, 3H), 2.55 - 2.41 (m, 2H), 2.41 - 2.20 (m, 2H), 2.05 - 1.90 (m, 1H). Intermediate 12: (3R)-3-(2-Methylsulfonylpyrimidin-5-yl)cyclo pentanone

In a round-bottom flask Intermediate 11 (586 mg, 2.8 mmol) was taken up in dry CH ₂ CI ₂ (50 mL), then cooled on an icebath to 5 °C before adding 3- chloroperbenzoic acid (1.21 g, 7.0 mmol). The icebath was removed and the reaction mixture allowed warming to room temperature. After 3h the oxidation was complete and saturated NaHC0 ₃ , aq (50 mL) was added. The organic phase was concentrated and purified by flash chromatography (eluent: 25-100% EtOAc in heptane) to yield the title compound : 230 mg (79%).

1H NMR (300 MHz, MeOH) δ 7.77 (s, 2H), 2.64 - 2.25 (m, 1H), 2.15 (s, 3H), 1.60 - 1.45 (m, 1H), 1.41 - 1.09 (m, 4H), 0.98 - 0.80 (m, 1H).

Intermediate 13: (lS,3R)-N-[(lR)-l-(4-Fluoro-3-methoxy-phenyl)ethyl]- 3-(2-methylsulfonylpyrimidin-5-yl)cyclopentanamine

Prepared according to GP1 from Intermediate 12 (141 mg, 0.58 mmol) and (1R)- l-(4-fluoro-3-methoxyphenyl)ethylamine hydrochloride (133 mg, 0.65 mmol) yielding the title compound : 49 mg (21%).

1H NMR (300 MHz, CDCI3) δ 8.80 (s, 2H), 7.07 - 6.93 (m, 2H), 6.82 (ddd, J = 8.2, 4.3, 2.0 Hz, 1H), 3.90 (s, 3H), 3.88 - 3.73 (m, 1H), 3.34 (s, 3H), 3.23 - 2.97 (m, 2H), 2.34 - 2.09 (m, 2H), 2.09 - 1.96 (m, 1H), 1.92 - 1.64 (m, 2H), 1.52 - 1.39 (m, 1H), 1.37 (d, J = 6.6 Hz, 3H).

Intermediate 14: ( lS,3R)-3-(2-Methylsulfonylpyrimidin-5-yl )-N-[( 1R)-1- ( l-naphthyl)ethyl]cyclopentanamine

Prepared according to GP1 from Intermediate 12 (470 mg, 1.96 mmol) and R(+)- l-(l-naphthyl)ethylamine (369 mg, 2.15 mmol) yielding the title compound : 371 mg (47%).

1H NMR (300 MHz, CDCI3) δ 8.77 (s, 2H), 8.18 (d, J = 7.7 Hz, 1H), 7.93 - 7.86 (m, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.71 - 7.62 (m, 1H), 7.57 - 7.45 (m, 4H), 4.87 - 4.71 (m, 1H), 3.33 (s, 3H), 3.30 - 3.20 (m, 1H), 3.07 - 2.92 (m, 1H), 2.39 - 2.24 (m, 1H), 2.17 - 2.05 (m, 1H), 2.02 - 1.78 (m, 4H), 1.57 (d, J = 6.4 Hz, 3H).

General procedure 6: substitution of the sulfonyl group (GP6)

Exampel 22: 2-[2-[[5-[(lR,3S)-3-[[( lR)-l-( l-Naphthyl)ethyl]amino] cyclopentyl] pyrimidin-2-yl]amino]ethylamino]ethanol (compound 122)

A 0.5 mL microwave vial was charged with Intermediate 14 (15 mg, 0.04 mmol), then DMSO (0.5 mL) was added followed by N-(2-hydroxyethyl)ethylendiamine (40 mg, 0.40 mmol) and DIPEA (65 μί, 0.40 mmol). The vial was capped and heated in a microwave reactor at 160 °C for 20 min. The reaction mixture was diluted with saturated NaHC0 ₃ and extracted with CH ₂ CI ₂ . Concentrated and purified by preparative HPLC (basic system : NH ₄ HC0 ₃ ) to yield the title compound 2.1 mg (13%).

1H NMR (300 MHz, DMSO) δ 8.29 (d, J = 7.8 Hz, 1H), 8.14 (s, 2H), 7.99 - 7.84 (m, 1H), 7.82 - 7.65 (m, 2H), 7.65 - 7.42 (m, 3H), 6.78 (t, J = 5.8 Hz, 1H), 4.66 (q, J = 6.5 Hz, 1H), 4.42 (bs, 1H), 3.65 - 3.50 (m, 1H), 3.50 - 3.39 (m, 2H), 3.29 - 3.22 (m, 2H), 3.05 - 2.89 (m, J = 7.1 Hz, 2H), 2.66 (t, J = 6.4 Hz, 2H), 2.57 (t, J = 5.8 Hz, 2H), 2.19 - 1.98 (m, 2H), 1.92 - 1.76 (m, 1H), 1.77 - 1.55 (m, 2H),

I .37 (d, J = 6.5 Hz, 3H), 1.34 - 1.22 (m, 1H).

Example 23: N-[2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]pyrimidin-2- yl]amino]ethyl]methanesulfonamide (compound 123)

Prepared according to GP6 from Intermediate 13 and N-(2- aminoethyl)methanesulfonamide.

1H NMR (600 MHz, DMSO) δ 8.24 (s, 2H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.87 (ddd, J = 8.2, 4.4, 1.9 Hz, 1H), 4.42 (t, J = 5.4 Hz, 1H), 3.82 (s, 3H), 3.78 - 3.68 (m, 1H), 3.70 - 3.60 (m, 4H), 3.52 (dd, J =

I I.7, 6.1 Hz, 2H), 2.99 - 2.82 (m, 1H), 2.78 - 2.67 (m, 1H), 2.47 - 2.42 (m, 4H), 2.42 - 2.38 (m, 2H), 2.25 - 2.11 (m, 1H), 2.07 - 1.98 (m, 1H), 1.91 - 1.82 (m,

1H), 1.80 - 1.69 (m, 1H), 1.66 - 1.51 (m, 2H), 1.31 - 1.24 (m, 1H), 1.23 (d, J = 6.6 Hz, 2H).

Example 24: 2-[4-[5-[( lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl )ethyl]amino]cyclopentyl]pyrimidin-2-yl]piperazin-l-yl]ethan ol (compound 124)

Prepared according to GP6 from Intermediate 13 and N-hydroxyethyl-piperazine. 1H NMR (600 MHz, DMSO) δ 8.17 (s, 2H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 7.06 (bs, 1H), 6.94 (bt, J = 6.0 Hz, 1H), 6.87 (ddd, J = 8.2, 4.4, 1.9 Hz, 1H), 3.82 (s, 3H), 3.74 (q, J = 6.5 Hz, 1H), 3.41 - 3.34 (m, 2H), 3.15 - 3.05 (m, 2H), 2.88 (s, 3H), 2.88 - 2.83 (m, 1H), 2.77 - 2.65 (m, 1H), 2.17 (bs, 1H), 2.06 - 1.99 (m, 1H), 1.89 - 1.81 (m, 1H), 1.78 - 1.70 (m, 1H), 1.65 - 1.53 (m, 2H), 1.30 - 1.24 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H). Example 25: 2-[[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]pyrimidin-2-yl]amino]ethanesulfonami de

(compound 125)

Prepared according to GP6 from Intermediate 13 and 2-amino-ethanesulfonic acid amide hydrochloride.

1H NMR (600 MHz, DMSO) δ 8.19 (s, 2H), 7.15 (dd, J = 8.6, 1.9 Hz, 1H), 7.09

(dd, J = 11.5, 8.2 Hz, 1H), 6.99 (t, J = 6.0 Hz, 1H), 6.93 - 6.85 (m, 3H), 3.82 (s, 3H), 3.74 (q, J = 6.5 Hz, 1H), 3.67 - 3.60 (m, 2H), 3.20 (dd, J = 8.1, 6.4 Hz, 2H), 2.91 - 2.83 (m, 1H), 2.76 - 2.67 (m, 1H), 2.25 - 2.12 (m, 1H), 2.06 - 1.97 (m, 1H), 1.93 - 1.81 (m, 1H), 1.80 - 1.71 (m, 1H), 1.66 - 1.51 (m, 2H), 1.32 - 1.24 (m, 1H), 1.23 (d, J = 6.6 Hz, 2H).

Example 26: 4-[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]pyrimidin-2-yl]piperazin-2-one (compound 126)

Prepared according to GP6 from Intermediate 13 and piperazin-2-one.

1H NMR (300 MHz, DMSO) δ 8.30 (s, 2H), 8.03 (bs, 1H), 7.15 (dd, J = 8.7, 2.0 Hz, 1H), 7.09 (dd, J = 11.5, 8.3 Hz, 1H), 6.87 (ddd, J = 8.2, 4.5, 2.0 Hz, 1H), 4.12 (s, 2H), 3.89 - 3.83 (m, 2H), 3.82 (s, 3H), 3.74 (q, J = 6.4 Hz, 1H), 3.29 - 3.19 (m, 2H), 2.99 - 2.82 (m, 1H), 2.82 - 2.65 (m, 1H), 2.11 - 1.96 (m, 1H), 1.96 - 1.80 (m, 2H), 1.80 - 1.69 (m, 1H), 1.69 - 1.51 (m, 2H), 1.38 - 1.26 (m, 1H), 1.23 (d, J = 6.6 Hz, 3H).

Example 27: l-[4-[5-[( lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy-phenyl) ethyl]amino]cyclopentyl]pyrimidin-2-yl]piperazin-l-yl]ethano ne; formic acid salt (compound 127)

Prepared according to GP6 from Intermediate 13 and 1-acetylpiperazine.

1H NMR (300 MHz, DMSO) δ 8.28 (s, 2H), 8.23 (s, 1H), 7.22 (dd, J = 8.6, 1.9 Hz, 1H), 7.14 (dd, J = 11.5, 8.3 Hz, 1H), 6.93 (ddd, J = 8.2, 4.4, 2.0 Hz, 1H), 3.96 - 3.85 (m, 1H), 3.83 (s, 3H), 3.76 - 3.69 (m, 4H), 3.52 - 3.42 (m, 4H), 3.06 - 2.91 (m, 1H), 2.85 - 2.68 (m, 1H), 2.16 - 2.06 (m, 1H), 2.04 (s, 3H), 1.96 - 1.75 (m, 2H), 1.72 - 1.57 (m, 2H), 1.45 - 1.34 (m, 1H), 1.31 (d, J = 6.6 Hz, 3H).

Example 28: N-[5-[(lR,3S)-3-[[( lR)-l-(4-Fluoro-3-methoxy- phenyl)ethyl]amino] -cyclopentyl]-2-pyridyl]acetamide (compound 128)

Prepared according to GP5 from Intermediate 10 and acetamide.

1H NMR (300 MHz, DMSO) δ 10.34 (s, 1H), 8.13 (d, J = 2.0 Hz, 1H), 7.96 (d, J = 8.6 Hz, 1H), 7.64 (dd, J = 8.6, 2.4 Hz, 1H), 7.16 (dd, J = 8.6, 1.9 Hz, 1H), 7.09 (dd, J = 11.5, 8.2 Hz, 1H), 6.88 (ddd, J = 8.3, 4.5, 2.0 Hz, 1H), 3.82 (s, 3H), 3.75 (q, J = 6.4 Hz, 1H), 2.98 - 2.80 (m, 2H), 2.25 - 2.00 (m, 5H), 1.98 - 1.52 (m, 4H), 1.39 - 1.18 (m, 4H).