WO2010039913A1 - Calcilytic compounds - Google Patents

Abstract

Novel calcilytic compounds, pharmaceutical compositions, methods of synthesis and methods of using them are provided.

Description

CALCILYTIC COMPOUNDS

FIELD OF THE INVENTION

The present invention relates to novel calcilytic compounds, pharmaceutical compositions containing these compounds, processes for their preparation and their use as calcium receptor antagonists.

BACKGROUND OF THE INVENTION

In mammals, extracellular Ca^+ is under rigid homeostatic control and regulates various processes such as blood clotting, nerve and muscle excitability, and proper bone formation. Extracellular Ca^+ inhibits the secretion of parathyroid hormone ("PTH") from parathyroid cells, inhibits bone resorption by osteoclasts, and stimulates secretion of calcitonin from C-cells. Calcium receptor proteins enable certain specialized cells to respond to changes in extracellular Ca^+ concentration.

PTH is the principal endocrine factor regulating Ca^+ homeostasis in the blood and extracellular fluids. PTH, by acting on bone and kidney cells, increases the level of Ca^+ in the blood. This increase in extracellular Ca^+ then acts as a negative feedback signal, depressing PTH secretion. The reciprocal relationship between extracellular Ca^+ and PTH secretion forms an important mechanism maintaining bodily Ca^+ homeostasis.

Extracellular Ca^⁺ acts directly on parathyroid cells to regulate PTH secretion.

The existence of a parathyroid cell surface protein which detects changes in extracellular Ca 2+ has been confirmed. See Brown et al., Nature 366:574, 1993. In parathyroid cells, this protein, the calcium receptor, acts as a receptor for extracellular Ca , detects changes in the ion concentration of extracellular Ca^+, and initiates a functional cellular response, PTH secretion.

Extracellular Ca^⁺ influences various cell functions, reviewed in Nemeth et al., Cell Calcium 11 :319, 1990. For example, extracellular Ca^+ plays a role in parafollicular (C-cells) and parathyroid cells. See Nemeth, Cell Calcium 11 :323, 1990. The role of extracellular Ca^+ on bone osteoclasts has also been studied. See Zaidi, Bioscience Reports 10:493, 1990. Various compounds are known to mimic the effects of extra-cellular Ca^⁺ on a calcium receptor molecule. Calcilytics are compounds able to inhibit calcium receptor activity, thereby causing a decrease in one or more calcium receptor activities evoked by extracellular Ca^+. Calcilytics are useful as lead molecules in the discovery, development, design, modification and/or construction of useful calcium modulators, which are active at Ca^+ receptors. Such calcilytics are useful in the treatment of various disease states characterized by abnormal levels of one or more components, e.g., polypeptides such as hormones, enzymes or growth factors, the expression and/or secretion of which is regulated or affected by activity at one or more Ca^+ receptors. Target diseases or disorders for calcilytic compounds include diseases involving abnormal bone and mineral homeostasis.

Abnormal calcium homeostasis is characterized by one or more of the following activities: an abnormal increase or decrease in serum calcium; an abnormal increase or decrease in urinary excretion of calcium; an abnormal increase or decrease in bone calcium levels (for example, as assessed by bone mineral density measurements); an abnormal absorption of dietary calcium; an abnormal increase or decrease in the production and/or release of messengers which affect serum calcium levels such as PTH and calcitonin; and an abnormal change in the response elicited by messengers which affect serum calcium levels. Thus, calcium receptor antagonists offer a unique approach towards the pharmacotherapy of diseases associated with abnormal bone or mineral homeostasis, such as hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia associated with malignancy and bone fracture, osteopenia, and osteoporosis.

SUMMARY OF THE INVENTION

The present invention is directed to novel compounds according to Formula (I):

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring;

R² is selected from the group consisting of hydrogen, -NR⁴R⁵, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring; or R¹ and R² together form a 5-8 membered ring, optionally containing one to three heteroatoms selected from N, O, and S;

R³ is selected from the group consisting of (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring;

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (Ci-C₈)cycloalkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, heteroaryl, -C(O)R⁶, -SO₂((Ci-C₄)alkyl), (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, aryl(Ci-C₈)alkyl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring; or R⁴ and R⁵ taken together with the nitrogen to which they are attached represent a 5- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur; each R⁶ is independently selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, heteroaryl(Ci-C₈)alkyl, -CO((Ci-C₄)alkyl), -CO(aryl), and -CO(heteroaryl), wherein any heterocycloalkyl is a 3-8 membered ring; any aryl or heteroaryl group of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted by -O-(Ci-C₂)alkyl-O-; and wherein any R¹, R², R³, R⁴, R⁵, or R⁶ is unsubstituted or, where possible, is substituted with one to three substituents independently selected from halogen, cyano, nitro, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -CONR⁴R⁵, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -SO₂NR⁴R⁵, -N(R⁴)C(O)R⁶, -N(R⁴)C(O)OR⁶, -N(R⁴)C (O)NR⁴R⁵, (Ci-C₆)alkyl, halo(Ci-C₄)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl group is optionally substituted one to three times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, said heterocycloalkyl is a 5-6 membered ring, and R⁴, R⁵, and R⁶ are the same as defined above; or a salt thereof.

The present invention is also directed to formulations comprising compounds of Formula (I), or a salt thereof, and their use as calcium receptor antagonists in the treatment of a variety of diseases associated with abnormal bone or mineral homeostasis, including but not limited to hypoparathyroidism, osteosarcoma, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget' s disease, humoral hypercalcemia associated with malignancy and bone fracture, osteopenia, and osteoporosis.

The present invention further provides a method for antagonizing calcium receptors in a mammal, including a human, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I), or a salt thereof. The present invention further provides a method for increasing serum parathyroid levels in a mammal, including a human, which comprises administering to a mammal in need thereof an effective amount of a compound of Formula (I), or a salt thereof. DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term "alkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms. As used herein, the terms

and "(C₁-C8)alkyl" refer to an alkyl group having at least 1 and up to 4 or 8 carbon atoms respectively. Examples of such branched or straight-chained alkyl groups useful in the present invention include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, n-hexyl, n-heptyl, n-octyl, and branched analogs of the latter 3 normal alkanes. As used herein, the term "haloalkyl" refers to a straight- or branched-chain hydrocarbon radical having the specified number of carbon atoms substituted by one or more halogens. Included within the scope of the present invention are mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, and bromine, and specifically fluorine. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl, trifluoroethyl, pentafluoroethyl, and hexafluoroisopropyl. As used herein, the term "alkenyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon double bonds. Examples include ethenyl and propenyl.

As used herein, the term "alkynyl" refers to straight or branched hydrocarbon chains containing the specified number of carbon atoms and at least 1 and up to 3 carbon- carbon triple bonds. Examples include ethynyl and propynyl.

As used herein, the term "cycloalkyl" refers to a non-aromatic, saturated, cyclic hydrocarbon ring containing the specified number of carbon atoms. The term "C3-C8 cycloalkyl" refers to a non-aromatic cyclic hydrocarbon ring having from three to eight carbon atoms. Exemplary "C3-C8 cycloalkyl" groups useful in the present invention include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

"Alkoxy" means an alkyl radical containing the specified number of carbon atoms attached through an oxygen linking atom. The term "(Ci-C₄)alkoxy" refers to a straight- or branched-chain hydrocarbon radical having at least 1 and up to 4 carbon atoms attached through an oxygen linking atom. Exemplary "(Ci-C₄)alkoxy" groups useful in the present invention include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, 5-butoxy, and t-butoxy. "Heterocycloalkyl" means a non-aromatic heterocyclic ring containing 3-8 or 5-6 ring atoms, being saturated or having one or more degrees of unsaturation and containing one or more heteroatom substitutions selected from O, S, and/or N. Such a ring may be optionally fused to one or more other heterocycloalkyl ring(s) or cycloalkyl ring(s). Examples of "heterocycloalkyl" moieties include, but are not limited to, aziridinyl, thiiranyl, oxiranyl, azetidinyl, oxetanyl, thietanyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, 1 ,4-dioxanyl, 1,3-dioxanyl, piperidinyl, piperazinyl, 2,4- piperazinedionyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, pyrazolidinyl, pyrazolinyl, morpholinyl, thiomorpholinyl, tetrahydrothiopyranyl, tetrahydrothienyl, and the like. "Aryl" refers to optionally substituted monocyclic or fused polycarbocyclic groups having 6 to 14 carbon atoms and having at least one aromatic ring that complies with Hϋckel's Rule. Examples of "aryl" groups are phenyl, naphthyl, anthracenyl, phenanthrenyl, and the like. Preferably aryl refers to optionally substituted phenyl.

"Heteroaryl" means an optionally substituted aromatic monocyclic ring or fused polycarbocyclic ring system wherein at least one ring complies with Hϋckel's Rule, has the specified number of ring atoms, and that ring contains at least one heteroatom selected from N, O, and/or S. Examples of 5-membered "heteroaryl" groups include furanyl, thienyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, and isothiazolyl. Examples of 6-membered "heteroaryl" groups include oxo-pyridyl, pyridinyl, pyridazinyl, pyrazinyl, and pyrimidinyl. Examples of

6,6-fused "heteroaryl" groups include quinolinyl, isoquinolinyl, quinoxalinyl, cinnolinyl, phthalazinyl, quinazolinyl, 1,5-naphthyridinyl, 1 ,6-naphthyridinyl, 1 ,7-naphthyridinyl, 1,8-naphthyridinyl, and pteridinyl. Examples of 6,5-fused "heteroaryl" groups include benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, indolizinyl, indolyl, isoindolyl, and indazolyl.

"Optionally substituted" indicates that a group, such as alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, or heteroaryl, may be unsubstituted, or the group may be substituted with one or more substituent(s) as defined.

As used herein, "halogen" or "halo" refers to F, Cl, Br, or I. Suitably, R¹ is selected from the group consisting of hydrogen, halogen, cyano,

-NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl (e.g. any heterocycloalkyl moiety of the groups heterocycloalkyl or heterocycloalkyl(Ci-C₈)alkyl) is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C2)alkyl-O- bridging two adjacent ring atoms (e.g. to form a 1,3-benzodioxole or 2,3-dihydro-l,4-benzodioxin group), and wherein any R¹ moiety is optionally substituted one to three times independently by halogen, cyano, nitro, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -CONR⁴R⁵, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -SO₂NR⁴R⁵, -N(R⁴)C(O)R⁶, -N(R⁴)C(O)OR⁶, -N(R⁴)C(O)NR⁴R⁵, (Ci-C₆)alkyl, halo(Ci-C₄)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any aryl or heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and wherein said heterocycloalkyl is a 5-6 membered ring. In another embodiment, R¹ is selected from the group consisting of (Ci-Ce)alkyl,

(C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-Ce)alkyl, heteroaryl, and heteroaryl(Ci-Ce)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R¹ moiety is optionally substituted one to three times independently by halogen, cyano, amino,

(Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, -C(O)O(C i-C₄)alkyl, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl, wherein said aryl or heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl.

In another embodiment, R¹ is selected from the group consisting of (Ci-Ce)alkyl, phenyl, and 5-6 membered heteroaryl, optionally substituted, one to three times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, phenyl, or 5-6 membered heteroaryl, wherein any phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl. In a further embodiment, R¹ is a 5-membered heteroaryl group, optionally substituted one to two times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, phenyl, or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl. In yet a further embodiment, R¹ is thienyl or thiazolyl, optionally substituted one to two times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, phenyl, or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and wherein the 5-6 membered heteroaryl group is selected from furanyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, and pyrimidinyl.

Specifically, R¹ is thienyl, optionally substituted one to two times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, phenyl, or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C4)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and wherein the 5-6 membered heteroaryl group is selected from furanyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, and pyrimidinyl. In selected embodiments, R¹ is 5-methyl-2-thienyl, 4-(5-methyl-l,3,4-oxadiazol-2-yl)-2- thienyl, 5-methyl-4-(2-pyridinyl)-2-thienyl, or phenethyl.

Suitably, R² is selected from the group consisting of hydrogen, -NR⁴R⁵, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R² moiety is optionally substituted one to three times independently by halogen, cyano, nitro, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -CONR⁴R⁵, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -SO₂NR⁴R⁵, -N(R⁴)C(O)R⁶, -N(R⁴)C(O)OR⁶, -N(R⁴)C(O)NR⁴R⁵, (Ci-C₆)alkyl, halo(Ci-C₄)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein any heterocycloalkyl is a 5-6 membered ring.

In another embodiment, R² is selected from the group consisting of (Ci-Ce)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-C₆)alkyl, heteroaryl, and heteroaryl(Ci-C₆)alkyl, wherein any heterocycloalkyl is a 5-6 membered ring, and any aryl group is optionally substituted by -O-(Ci-C2)alkyl-O-, and wherein any R² moiety is optionally substituted one to three times independently by halogen, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl.

In another embodiment, R² is selected from the group consisting of (Ci-Ce)alkyl, phenyl, and 5-6 membered heteroaryl, optionally substituted, one to three times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, phenyl, or 5-6 membered heteroaryl. In a further embodiment, R² is (Ci-C₆)alkyl. In a specific embodiment, R² is methyl.

Suitably, R³ is selected from the group consisting of (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C2)alkyl-O-, and wherein any R moiety is optionally substituted one to three times independently by halogen, cyano, nitro, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -CONR⁴R⁵, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -SO₂NR⁴R⁵, -N(R⁴)C(O)R⁶, -N(R⁴)C(O)OR⁶, -N(R⁴)C(O)NR⁴R⁵, (Ci-C₆)alkyl, halo(Ci-C₄)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, aryl, or heteroaryl, wherein said heterocycloalkyl is a 5-6 membered ring.

In another embodiment, R³ is selected from the group consisting of (Ci-Ce)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl(Ci-Ce)alkyl, and heteroaryl(Ci-Ce)alkyl, wherein said heteroaryl or heterocycloalkyl is a 5-6 membered ring, and said aryl is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R moiety is optionally substituted one to three times independently by halogen, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkyl, -CF3, or (Ci-C₄)alkoxy.

In a further embodiment, R³ is a phenyl(Ci-C₂)alkyl group, optionally substituted one to two times, independently, by F, Cl, (Ci-C₄)alkyl, (Ci-C₄)alkoxy, -O-(Ci-C₂)alkyl-O-, or -CF₃. Specifically, R is phenethyl, optionally substituted one to two times, independently, by F, Cl, (Ci-C₄)alkyl, (Ci-C₄)alkoxy, or -CF₃. In a selected embodiment, R³ is phenethyl. In another selected embodiment, R³ is cyclohexylethyl.

One particular embodiment of the invention is a compound of Formula (I) wherein:

R¹ is selected from the group consisting of (Ci-Ce)alkyl, (C₃-Ce)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-C₆)alkyl, heteroaryl, and heteroaryl(Ci-C₆)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R¹ moiety is optionally substituted one to three times independently by halogen, cyano, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, -C(O)O(C i-C₄)alkyl, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl, wherein said aryl or heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl;

R² is selected from the group consisting of (Ci-Ce)alkyl, (C₃-C₆)CyC loalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-Ce)alkyl, heteroaryl, and heteroaryl(Ci-C₆)alkyl, wherein any heterocycloalkyl is a 5-6 membered ring, and any aryl group is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R² moiety is optionally substituted one to three times independently by halogen, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl; and

R³ is selected from the group consisting of (Ci-Ce)alkyl, (C₃-C₆)CyC loalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl(Ci-C₆)alkyl, and heteroaryl(Ci-C₆)alkyl, wherein said heteroaryl or heterocycloalkyl is a 5-6 membered ring, and said aryl is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R³ moiety is optionally substituted one to three times independently by halogen, amino,

(Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkyl, -CF₃, or (Ci-C₄)alkoxy; or a salt thereof. Another particular embodiment of the invention is a compound of Formula (I) wherein:

R¹ is thienyl, optionally substituted one to two times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, phenyl, or 5-6 membered heteroaryl, wherein said phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C4)alkyl, -CF₃, amino, (Ci-C4)alkylamino, (Ci-C4)alkyl(Ci-C4)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and wherein the 5-6 membered heteroaryl group is selected from furanyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, and pyrimidinyl; R² is (Ci-C₆)alkyl; and

R³ is phenethyl, optionally substituted one to two times, independently, by F, Cl, (Ci-C₄)alkyl, (Ci-C₄)alkoxy, or -CF₃; or a salt thereof.

Specific compounds exemplified herein are:

2-(3-hydroxy-2-pyridinyl)-6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)- 4(3H)-pyrimidinone;

2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[4-(5-methyl-l,3,4-oxadiazol-2-yl)-2- thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone; 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2-pyridinyl)-2-thienyl]-3-(2- phenylethyl)-4(3H)-pyrimidinone;

2-(3-hydroxy-2-pyridinyl)-6-methyl-3,5-bis(2-phenylethyl)-4(3H)-pyrimidinone; and

3-(2-cyclohexylethyl)-2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2- pyridinyl)-2-thienyl]-4(3H)-pyrimidinone.

Processes for preparing the compounds of Formula (I) are also within the ambit of this invention. To illustrate, process for preparing a compound of Formula (I)

wherein R¹, R², and R³ are the same as defined above for Formula (I), the process comprising treating a compound of Formula A:

with an appropriate reagent, such as thionyl chloride, followed by addition of an optionally substituted 3-amino-2-propenoate, such as methyl 3-amino-2-butenoate, to the intermediate acid chloride, in an appropriate solvent, such as dichloromethane, to form a compound of Formula B:

wherein R is the same as in Formula (I), which may then be treated with an appropriate amine, such as phenethylamine, along with an appropriate Lewis acid, such as trimethylaluminum, in an appropriate solvent, such as 1,2-dichloroethane, optionally with heating, to form a compound of Formula C:

wherein R² and R³ are the same as for those groups in Formula (I), which is then brominated with an appropriate reagent, such as N-bromosuccinimide, in an appropriate solvent, such as N,Λ/-dimethylformamide, followed by coupling under either Suzuki conditions with an appropriate boronic acid, such as (5-methyl-2-thienyl)boronic acid, an appropriate base, such as sodium carbonate, an appropriate catalyst, such as bis(tri-t- butylphosphine)palladium(O), all in an appropriate solvent or solvent mixture, such as toluene/ethanol/water, with heating or Stille conditions with an appropriate stannane, such as 2-methyl-5-[5-(trimethylstannanyl)-3-thienyl]-l,3,4-oxadiazole, an appropriate reagent, such as cesium fluoride, an appropriate catalyst, such as bis(tή-t- butylphosphine)palladium(O), all in an appropriate solvent, such as 1,4-dioxane, with heating, and ultimately deprotection with an appropriate reagent, such as hydrobromic acid, in an appropriate solvent, such as acetic acid, or under hydrogenation conditions under H₂ pressure with an appropriate catalyst, such as palladium on charcoal, in an appropriate solvent or solvent mixture, such as ethyl acetate/ethanol, to form a compound of Formula (I), from which a salt may optionally be formed.

The term "solvate" refers to a complex of variable stoichiometry formed by a solute and a solvent. Such solvents for the purpose of the invention may not interfere with the biological activity of the solute. Examples of suitable solvents include, but are not limited to, water, methanol, ethanol and acetic acid. Preferably, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include, without limitation, water, ethanol and acetic acid. Solvates wherein water is the solvent molecule are typically referred to as "hydrates". Hydrates include compositions containing stoichiometric amounts of water, as well as compositions containing variable amounts of water. Solvates, particularly hydrates, of the compounds of Formula (I) and salts thereof, are within the scope of the invention. When a disclosed compound or its salt is named or depicted by structure, it is to be understood that the compound or salt, including solvates (particularly, hydrates) thereof, may exist in crystalline forms, non-crystalline forms or a mixture thereof. The compound or salt, or solvates (particularly, hydrates) thereof, may also exhibit polymorphism (i.e. the capacity to occur in different crystalline forms). These different crystalline forms are typically known as "polymorphs." It is to be understood that when named or depicted by structure, the disclosed compound, or solvates (particularly, hydrates) thereof, also include all polymorphs thereof. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. One of ordinary skill in the art will appreciate that different polymorphs may be produced, for example, by changing or adjusting the conditions used in crystallizing/recrystallizing the compound.

The invention also includes various isomers of the compounds of Formula (I) and mixtures thereof. "Isomer" refers to compounds that have the same composition and molecular weight but differ in physical and/or chemical properties. The structural difference may be in constitution (geometric isomers) or in the ability to rotate the plane of polarized light (stereoisomers). With regard to stereoisomers, the present compounds may have one or more asymmetric carbon atom and may occur as racemates, racemic mixtures, and as individual enantiomers or diastereomers. All such isomeric forms are included within the present invention, including mixtures thereof.

Because of their potential use in medicine, the salts of the compounds of Formula (I) are preferably pharmaceutically acceptable. Suitable pharmaceutically acceptable salts can include acid or base addition salts. As used herein, the term "pharmaceutically acceptable" means a compound which is suitable for pharmaceutical use. Salts and solvates (e.g. hydrates and hydrates of salts) of the compounds of the invention which are suitable for use in medicine are those wherein the counterion or associated solvent is pharmaceutically acceptable. However, salts and solvates having non-pharmaceutically acceptable counterions or associated solvents are within the scope of the present invention, for example, for use as intermediates in the preparation of other compounds of the invention and their salts and solvates.

A pharmaceutically acceptable acid addition salt can be formed by reaction of a compound of Formula (I) containing a basic moiety with a suitable inorganic or organic acid (such as acetic, aspartic, benzenesulfonic, benzoic, bicarbonic, camphorsulfonic, carbonic, citric, dodecyl sulfonic, 1 ,2-ethanedisulfonic, ethanesulfonic, formic, fumaric, (3i?,45^*,5i?,6i?)-2,3,4,5,6,7-hexahydroxyheptanoic acid, galacturonic, gluconic, glutamic, hexanoic, hydrobromide, hydrochloride, 2-hydroxyethanesulfonic, hydroxynaphthoic, lactic, lactobionic, malic, maleic, mandelic, methanesulfonic, mucic, naphthalene-2- sulfonic, nitric, pamoic, pantoic, phosphoric/diphosphoric, polygalacturonic, propionic, salicylic, stearic, succinic, sulfonic, tannic, tartaric, or/?-toluenesulfonic acid), optionally in a suitable solvent such as an organic solvent, to give the salt which is usually isolated for example by crystallization and filtration. Pharmaceutically acceptable acid addition salts of a compound of Formula (I) include acetate, aspartate, benzenesulfonate, benzoate, bicarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, formate, fumarate, galacturonate, gluceptate, gluconate, glutamate, glycollylarsanilate, hexanoate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylsulfate, mucate, napsylate, nitrate, pamoate, pantothenate, phosphate/diphosphate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, teoclate, or tosylate salts.

A pharmaceutically acceptable base addition salt can be formed by reaction of a compound of Formula (I) containing an acidic moiety with a suitable inorganic or organic base (e.g. triethylamine, ethanolamine, triethanolamine, choline, arginine, lysine, or histidine), optionally in a suitable solvent such as an organic solvent, to give the base addition salt which is usually isolated for example by crystallization and filtration. Other suitable pharmaceutically acceptable salts include pharmaceutically acceptable metal salts, for example pharmaceutically acceptable alkali-metal or alkaline- earth-metal salts such as sodium, potassium, calcium, or magnesium salts; in particular pharmaceutically acceptable metal salts of one or more carboxylic acid moieties that may be present in the compound of Formula (I).

Other non-pharmaceutically acceptable salts, e.g. trifluoroacetate, may be used, for example in the isolation of compounds of the invention, and are included within the scope of this invention. The invention includes within its scope all possible stoichiometric and non-stoichiometric forms of the salts of the compounds of Formula (I). The free base form of a compound of Formula (I) may be prepared from any salt form by any suitable method known to the art, including treatment of the salt with an inorganic or organic base, suitably an inorganic or organic base having a higher pKa than the free base form of the compound.

In order to use a compound of Formula (I) or a salt thereof for the treatment of humans and other mammals, it is normally formulated in accordance with standard pharmaceutical practice as a pharmaceutical composition.

The calcilytic compounds can be administered by different routes including intravenous, intraperitoneal, subcutaneous, intramuscular, oral, topical (transdermal), or transmucosal administration. For systemic administration, oral administration is preferred. For oral administration, for example, the compounds can be formulated into conventional oral dosage forms such as capsules, tablets, and liquid preparations such as syrups, elixirs, and concentrated drops.

Alternatively, the calcilytic compounds can be administered by injection (parenteral administration), e.g., for intramuscular, intravenous, intraperitoneal, and subcutaneous administration. For injection, the compounds of the invention are formulated in liquid solutions, preferably, in physiologically compatible buffers or solutions, such as saline solution, Hank's solution, or Ringer's solution. In addition, the compounds may be formulated in solid form and redissolved or suspended immediately prior to use. Lyophilized forms can also be produced.

Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, bile salts and fusidic acid derivatives. In addition, detergents may be used to facilitate permeation. Transmucosal administration, for example, may be through nasal sprays, rectal suppositories, or vaginal suppositories.

For topical administration, the compounds of the invention can be formulated into ointments, salves, gels, or creams, as is generally known in the art.

While it is possible that, for use in therapy, a compound of Formula (I), as well as salts, solvates and the like, may be administered as a neat preparation, i.e. no additional carrier, the more usual practice is to present the active ingredient confected with a carrier or diluent. Accordingly, the invention further provides pharmaceutical compositions, which comprise a compound of Formula (I) and salts, solvates, and the like, and one or more pharmaceutically acceptable carriers, diluents, or excipients. The compounds of Formula (I) and salts, solvates, etc., are as described above. The carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of the Formula (I), or salts, solvates, etc., with one or more pharmaceutically acceptable carriers, diluents or excipients.

It will be appreciated by those skilled in the art that certain protected derivatives of compounds of Formula (I), which may be made prior to a final deprotection stage, may not possess pharmacological activity as such, but may, in certain instances, be administered orally or parenterally and thereafter metabolized in the body to form compounds of the invention which are pharmacologically active. Such derivatives may therefore be described as "prodrugs". Further, certain compounds of the invention may act as prodrugs of other compounds of the invention. All protected derivatives and prodrugs of compounds of the invention are included within the scope of the invention. Examples of suitable pro-drugs for the compounds of the present invention are described in Drugs of Today, Volume 19, Number 9, 1983, pp 499 - 538 and in Topics in Chemistry, Chapter 31 , pp 306 - 316 and in "Design of Prodrugs" by H. Bundgaard, Elsevier, 1985, Chapter 1 (the disclosures in which documents are incorporated herein by reference). It will further be appreciated by those skilled in the art, that certain moieties, known to those skilled in the art as "pro-moieties", for example as described by H. Bundgaard in "Design of Prodrugs" (the disclosure in which document is incorporated herein by reference) may be placed on appropriate functionalities when such functionalities are present within compounds of the invention. Preferred "pro-moieties" for compounds of the invention include: ester, carbonate ester, hemi-ester, phosphate ester, nitro ester, sulfate ester, sulfoxide, amide, carbamate, azo-, phosphamide, glycoside, ether, acetal, and ketal derivatives of the compounds of Formula (I).

The amounts of various calcilytic compounds to be administered can be determined by standard procedures taking into account factors such as the compound IC₅₀, EC50, the biological half-life of the compound, the age, size, and weight of the patient, and the disease or disorder associated with the patient. The importance of these and other factors to be considered are known to those of ordinary skill in the art.

Amounts administered also depend on the routes of administration and the degree of oral bioavailability. For example, for compounds with low oral bioavailability, relatively higher doses will have to be administered.

Preferably, the composition is in unit dosage form. For oral application, for example, a tablet, or capsule may be administered, for nasal application, a metered aerosol dose may be administered, for transdermal application, a topical formulation or patch may be administered and for transmucosal delivery, a buccal patch may be administered. In each case, dosing is such that the patient may administer a single dose.

Each dosage unit for oral administration contains suitably from 0.01 to 500 mg/kg, and preferably from 0.1 to 50 mg/kg, of a compound of Formula (I) or a salt thereof, calculated as the free base. The daily dosage for parenteral, nasal, oral inhalation, transmucosal or transdermal routes contains suitably from 0.01 mg to 100 mg/kg, of a compound of Formula (I). A topical formulation contains suitably 0.01 to 5.0% of a compound of Formula (I). The active ingredient may be administered, for example, from 1 to 6 times per day, preferably once, sufficient to exhibit the desired activity, as is readily apparent to one skilled in the art.

As used herein, "treatment" of a disease includes, but is not limited to prevention, retardation, and prophylaxis of the disease.

Diseases and disorders which might be treated or prevented, based upon the affected cells, include bone and mineral-related diseases or disorders; hypoparathyroidism; those of the central nervous system such as seizures, stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage, such as occurs in cardiac arrest or neonatal distress, epilepsy, neurodegenerative diseases such as Alzheimer's disease, Huntington's disease and Parkinson's disease, dementia, muscle tension, depression, anxiety, panic disorder, obsessive-compulsive disorder, post-traumatic stress disorder, schizophrenia, neuroleptic malignant syndrome, and Tourette's syndrome; diseases involving excess water reabsorption by the kidney, such as syndrome of inappropriate ADH secretion (SIADH), cirrhosis, congestive heart failure, and nephrosis; hypertension; preventing and/or decreasing renal toxicity from cationic antibiotics (e.g., aminoglycoside antibiotics); gut motility disorders such as diarrhea and spastic colon; GI ulcer diseases; GI diseases with excessive calcium absorption such as sarcoidosis; autoimmune diseases and organ transplant rejection; squamous cell carcinoma; and pancreatitis.

In a preferred embodiment of the present invention, the present compounds are used to increase serum parathyroid hormone ("PTH") levels. Increasing serum PTH levels can be helpful in treating diseases such as hypoparathyroidism, osteosarcoma, periodontal disease, fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia malignancy, osteopenia, and osteoporosis.

Another aspect of the present invention describes a method of treating a human comprising administering to said human a therapeutically effective amount of a compound of Formula (I), or a salt thereof, to increase the serum PTH level. Preferably, the method is carried out by administering an amount of the compound effective to cause an increase in duration and/or quantity of serum PTH level sufficient to have a therapeutic effect.

In various embodiments, the compound administered to a human causes an increase in serum PTH for a period of time of up to one hour, about one to about twenty- four hours, about one to about twelve hours, about one to about six hours, about one to about five hours, about one to about four hours, about two to about five hours, about two to about four hours, or about three to about six hours.

In an alternative embodiment of the present invention, the compound administered to a patient causes an increase in serum PTH for a period of more than about twenty- four hours provided that it is co-administered with an anti resorptive agent.

In additional different embodiments, the compound administered to a patient causes an increase in serum PTH of up to two fold, two to five fold, five to ten fold, and at least 10 fold, greater than peak serum PTH in the patient. The peak serum level is measured with respect to a patient not undergoing treatment. In a selected embodiment of the present invention, a compound of Formula (I), or a salt thereof, is co-administered with an anti-resorptive agent. Suitable anti-resorptive agents for co-administration include, but are not limited to, estrogens, lα,25-(OH)₂D₃, lα- (OH)D₃, calcitonin, denosumab, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.

Examples of selective estrogen receptor modulators which can be used in combination with a compound of Formula (I), or a salt thereof, include, but are not limited to, lasofoxifene (Oporia^®), raloxifene (Evista^®), arzoxifene, bazedoxifene, ospemifene, Chiesi's CHF-4227, and Prostrakan's PSK-3471. Examples of bisphosphonates which can be used in combination with a compound of Formula (I), or a salt thereof, include, but are not limited to, tiludronate (Skelid^®), clondronate (Bonefos^®), etidronate (Didronel^®), alendronate (Fosamax^®), risedronate (Actonel^®), ibandronate (Boniva^®), zoledronate (Zometa^®), minodronate (Onobis^®), neridronate, and pamidronate. Examples of estrogens which can be used in combination with a compound of Formula (I), or a salt thereof, include, but are not limited to, estradiol, conjugated equine estrogens (Premarin^®), or other estrogens. Examples of cathepsin K inhibitors which can be used in combination with a compound of Formula (I), or a salt thereof, include, but are not limited to, Novartis's AAE- 581, balicatib, GlaxoSmithKline's SB-462795 and odanacatib. The calcitonin that is used in combination with a compound of Formula (I), or a salt thereof, may be used as an injectable or intranasal formulation, such as Miacalcin^®, Miacalcic^®, Calcitonia^®, Fortical^®, or Elcitonin^®, or as an oral formulation, such as Novartis' SMC-021, Bone Medical's BN-002 (Capsitonin^®), or Nobex's NCT-025 (Oratonin^®).

Pharmaceutical compositions comprising a compound of Formula (I), or a salt thereof, which is active when given orally, can be formulated as syrups, tablets, capsules and lozenges. A syrup formulation will generally consist of a suspension or solution of the compound or salt in a liquid carrier for example, ethanol, peanut oil, olive oil, glycerine or water with a flavoring or coloring agent. Where the composition is in the form of a tablet, any pharmaceutical carrier routinely used for preparing solid formulations may be used. Examples of such carriers include magnesium stearate, terra alba, talc, gelatin, acacia, stearic acid, starch, lactose and sucrose. Where the composition is in the form of a capsule, any routine encapsulation is suitable, for example using the aforementioned carriers in a hard gelatin capsule shell. Where the composition is in the form of a soft gelatin shell capsule, any pharmaceutical carrier routinely used for preparing dispersions or suspensions may be considered, for example aqueous gums, celluloses, silicates or oils, and are incorporated in a soft gelatin capsule shell. Typical parenteral compositions consist of a solution or suspension of a compound or salt in a sterile aqueous or non-aqueous carrier optionally containing a parenterally acceptable oil, for example polyethylene glycol, polyvinylpyrrolidone, lecithin, arachis oil or sesame oil.

Typical compositions for inhalation are in the form of a solution, suspension or emulsion that may be administered as a dry powder or in the form of an aerosol using a conventional propellant such as dichlorodifluoromethane or trichlorofluoromethane.

A typical suppository formulation comprises a compound of Formula (I) or a salt thereof which is active when administered in this way, with a binding and/or lubricating agent, for example polymeric glycols, gelatins, cocoa-butter or other low melting vegetable waxes or fats or their synthetic analogs.

Typical dermal and transdermal formulations comprise a conventional aqueous or non-aqueous vehicle, for example a cream, ointment, lotion or paste or are in the form of a medicated plaster, patch or membrane.

Preferably the composition is in unit dosage form, for example a tablet, capsule or metered aerosol dose, so that the patient may administer a single dose.

No unacceptable toxo logical effects are expected when compounds of the present invention are administered in accordance with the present invention.

The biological activity of the compounds of Formula (I) is demonstrated by the following tests: (I) Calcium Receptor Inhibitor Assay: Method A:

Calcilytic activity was measured by determining the IC50 of the test compound for blocking increases of intracellular Ca^+ elicited by extracellular Ca^+ in HEK 293 4.0-7 cells stably expressing the human calcium receptor. HEK 293 4.0-7 cells were constructed as described by Rogers et al, J. Bone Miner. Res. 10 Suppl. 1 :S483, 1995 (hereby incorporated by reference herein). Intracellular Ca^+ increases were elicited by increasing extracellular Ca^⁺ from 1 to 1.75 mM. Intracellular Ca^+ was measured using fluo-3, a fluorescent calcium indicator.

The procedure was as follows:

1. Cells were maintained in T- 150 flasks in selection media (DMEM supplemented with 10% fetal bovine serum and 200 μg/mL hygromycin B), under 5% Cθ2:95% air at 37

⁰C and were grown up to 90% confluency.

2. The medium was decanted and the cell monolayer was washed twice with phosphate-buffered saline (PBS) kept at 37 ⁰C. After the second wash, 6 mL of 0.02% EDTA in PBS was added and incubated for 4 minutes at 37 ⁰C. Following the incubation, cells were dispersed by gentle agitation.

3. Cells from 2 or 3 flasks were pooled and pelleted (100 x g). The cellular pellet was resuspended in 10-15 mL of SPF-PCB+ and pelleted again by centrifugation. This washing was done twice.

Sulfate- and phosphate-free parathyroid cell buffer (SPF-PCB) contains 20 mM Na-Hepes, pH 7.4, 126 mM NaCl, 5 mM KCl, and 1 mM MgC^. SPF-PCB was made up and stored at 4 ⁰C. On the day of use, SPF-PCB was supplemented with 1 mg/mL of D-glucose and 1 mM CaCl2 and then split into two fractions. To one fraction, bovine serum albumin. (BSA; fraction V, ICN) was added at 5 mg/mL (SPF-PCB+). This buffer was used for washing, loading and maintaining the cells. The BSA-free fraction was used for diluting the cells in the cuvette for measurements of fluorescence.

4. The pellet was resuspended in 10 mL of SPF-PCB+ containing 2.2 μM fluo-3 (Molecular Probes) and incubated at room temperature for 35 minutes.

5. Following the incubation period, the cells were pelleted by centrifugation. The resulting pellet was washed with SPF-PCB+. After this washing, cells were resuspended in SPF-PCB+ at a density of 1 -2 x 10⁶ cells/mL.

6. For recording fluorescent signals, 300 μL of cell suspension were diluted in 1.2 mL of SPF buffer containing 1 mM CaCl2 and 1 mg/mL of D-glucose. Measurements of fluorescence were performed at 37 ⁰C with constant stirring using a spectrofluorimeter. Excitation and emission wavelengths were measured at 485 and 535 nm, respectively. To calibrate fluorescence signals, digitonin (5 mg/mL in ethanol) was added to obtain Fmax, and the apparent Fmin. was determined by adding Tris-EGTA (2.5 M Tris-Base, 0.3 M EGTA). The concentration of intracellular calcium was calculated using the following equation:

Intracellular calcium = (F-F_mm/F_max) x K^; where K^ = 400 nM. 7. To determine the potential calcilytic activity of test compounds, cells were incubated with test compound (or vehicle as a control) for 90 seconds before increasing the concentration of extracellular Ca^+ from 1 to 2mM. Calcilytic compounds were detected by their ability to block, in a concentration-dependent manner, increases in the concentration of intracellular Ca^+ elicited by extracellular Ca^+. Method B: 48 hours prior to running the CaSR assay, frozen HEK293 CaRec4.0-cl7 cells are thawed, counted, and diluted to 3e5/mL (15K/50 μL). The cell medium used to dilute the cells consists of DMEM/F12 (HAM'S) 1 :1 with L-Glutamine, 15mM HEPES, phenol red, 10% Fetal Bovine Serum, and 1% Penicillin-Streptomycin solution. Cell solution is seeded at 15K cells/50 μL/well in Greiner Poly-D-Lysine coated 384well, black, clear bottom, tissue culture plates and left at room temperature for one hour to reduce edge effect. After the first hour at room temperature, cell plates are then placed into a 37 ⁰C, 5% CO₂ incubator for 48 hours.

On the day of the experiment, plate confluency is first checked via microscope. Wells should be -100% confluent in an even cell monolayer. Assay reagents are prepared fresh. Dye load buffer consists of Hank's Buffered Saline Solution with .75 mM Calcium, without Magnesium, without Sodium Bicarbonate, with 20 mM Hepes, Probenecid (2.5 mM final concentration), Fluo4 (2 μM final concentration), and Brilliant Black (500 μM final concentration). Compound dilution buffer consists of Hank's Buffered Saline Solution without Calcium, without Magnesium (without Sodium Bicarbonate) and CHAPS (0.01% final concentration). A ligand curve plate is also prepared fresh. A 16 pt curve is dispensed into a Greiner 384 well polypropylene plate. The top concentration of the ligand, CaCl is 2.875 mM (final concentration) and the lowest concentration is .375 mM (final concentration). An ECgo value is generated from the curve data.

The CaSR assay begins when the cell media is aspirated from the cell plate using a Tecan Plate Washer, leaving nothing but the cell monolayer. Dye Load Buffer is added to the cell plate at 20 μL/well using a Multidrop and the loaded plate incubates for 45 minutes at 37 ⁰C, 5% CO₂ . Compound plates are received with 1 μL of compound stamped at 5 niM-top concentration (25 μM final cone, in cell plate). Compound Dilution Buffer is added to columns 1-24 in the compound plate at 65 μL/well using a Multidrop. Column 6 is pre-stamped with 1 μL DMSO to represent the high control, and column 18 receives 65 μL of buffer as the low control. The compound addition takes place on a Cybi Well dispenser when 10 μL of diluted compound is added to the dye loaded cell plate. The cell plate with compound is then incubated at room temperature for 5 minutes. The Antagonist addition takes place on the FLIPR when 10 μL of ECso challenge is added to the cell plate and fluorescence imagining proceeds for 65 sec. Column 18 of the ECso challenge plate contains only buffer to represent a low control or tool antagonist. The compounds of Examples 1-5 were tested according to the above assay conditions and each demonstrated an IC50 of < 1 μM. (II) Calcium Receptor Binding Assay Method A:

HEK 293 4.0-7 cells stably transfected with the Human Parathyroid Calcium Receptor ("HuPCaR") were scaled up in T 180 tissue culture flasks. Plasma membrane is obtained by polytron homogenization or glass douncing in buffer (50 mM Tris-HCl pH 7.4, 1 mM EDTA, 3 mM MgCl2) in the presence of a protease inhibitor cocktail containing 1 μM Leupeptin, 0.04 μM Pepstatin, and 1 mM PMSF. Aliquoted membrane was snap frozen and stored at -80 ⁰C. ³H labeled compound was radiolabeled to a radiospecific activity of 44 Ci/mmole and was aliquoted and stored in liquid nitrogen for radiochemical stability.

A typical reaction mixture contains 2 nM -1H compound ((R,R)-N-4'-Methoxy-t-3- 3'-methyl-r-ethylphenyl-l-(l-naphthyl)ethylamine), or ³H compound (R)-N- [2-Hy droxy- 3-(3-chloro-2-cyanophenoxy)propyl]- 1 , 1 -dimethyl-2-(4-methoxyphenyl)ethylamine 4-10 ug membrane in homogenization buffer containing 0.1% gelatin and 10% EtOH in a reaction volume of 0.5 mL. Incubation is performed in 12 x 75 polyethylene tubes in an ice water bath. To each tube 25 μL of test sample in 100% EtOH is added, followed by 400 μL of cold incubation buffer, and 25 μL of 40 nM ³H-compound in 100% EtOH for a final concentration of 2 nM. The binding reaction is initiated by the addition of 50 μL of 80-200 ug/mL HEK 293 4.0-7 membrane diluted in incubation buffer, and allowed to incubate at 4 ⁰C for 30 min. Wash buffer is 50 mM Tris-HCl containing 0.1% PEL Nonspecific binding is determined by the addition of 100-fold excess of unlabeled homologous ligand, and is generally 20% of total binding. The binding reaction is terminated by rapid filtration onto 1% PEI pretreated GF/C filters using a Brandel Harvester. Filters are placed in scintillation fluid and radioactivity assessed by liquid scintillation counting. Method B:

Ligand binding assays were performed in a 96-well filtration plate assembly (MADVN65, Millipore Corporation). The wells were pre -blocked with 1% PEI in 50 mM Tris/HCl, pH 7.4. Membranes prepared from HEK293 expressing calcium receptors were incubated with [³H] compound (2-(2-hydroxyphenyl)-6-methyl-5-(2-methylpropyl)-3-(2- phenylethyl)-4(3H)-pyrimidinone) in the absence or presence of various concentrations of unlabeled ligand or compound in 50 mM Tris/HCl, pH 7.4, 3 mM MgCl₂, 1 mM EDTA containing 0.1% PEI for 1 hour at 4 ⁰C. After the incubation, membrane -bound radio labeled ligand was separated from the unbound by filtration using a Millipore filtration manifold, followed by washing with ice-cold buffer (2 X 0.1 mL). Bound radioactivity remaining on the filters was determined in 1 mL Bio-Safe (Research Products international Corp. Order No. 111195) in a liquid scintillation counter. The data was analyzed with GraphPad PRISM software.

The compounds of Examples 1-5 were tested according to the above assay conditions and each demonstrated an IC50 of < 1 μM. For instance, the compound of example 2 demonstrated an IC₅₀ in a ligand binding assay of approximately 0.062 μM.

Definitions: d - day(s), h - hour(s), min. - minute(s), sat. - saturated, aq. - aqueous, rt - room temperature,

Δ - heat, g - gram(s), mg - milligram(s),

L - liter(s), niL - milliliter(s), mmol - millimole(s),

M - molar,

Ar- argon gas, H₂- hydrogen gas,

Na₂SO₄ - sodium sulfate,

MgSO₄ - magnesium sulfate,

K2CO3 - potassium carbonate,

Na₂CO₃ - sodium carbonate, NaHCO₃ - sodium bicarbonate,

CsF - cesium fluoride,

KF - potassium fluoride,

AlMe₃ - trimethylaluminum,

Ti(Oz-Pr)₄ - titanium(IV) isopropoxide, SOCl₂ - thionyl chloride,

POCl₃ - phosphorus oxychloride,

H₂O₂ - hydrogen peroxide,

Br₂ - bromine,

NBS - Λ/-bromosuccinimide, BnBr - benzyl bromide,

MeI - methyl iodide,

AcOH - acetic acid,

HBr - hydrobromic acid,

HCl - hydrochloric acid, NaOH - sodium hydroxide,

Pd[P(^-Bu)₃J₂ - έώ(tri-t-butylphosphine)palladium(0),

Me₆Sn₂ - hexamethylditin

Pd/C - palladium on charcoal,

DMF - Λf,Λ/-dimethylformamide, DCE - 1,2-dichloroethane,

THF - tetrahydrofuran,

CH₂Cl₂ - dichloromethane, MeOH - methanol, EtOH - ethanol, Et₂O - diethyl ether, EtOAc - ethyl acetate.

Chemical Background:

The compounds of this invention may be made by a variety of methods, including Standard chemistry. Any previously defined variable will continue to have the previously defined meaning unless otherwise indicated. Illustrative general synthetic methods are set out below and then specific compounds of the invention as prepared are given in the examples.

Compounds of general Formula (I) may be prepared by methods known in the art of organic synthesis as set forth in part by the following synthetic scheme. In the scheme described below, it is well understood that protecting groups for sensitive or reactive groups are employed where necessary in accordance with general principles of chemistry. Protecting groups are manipulated according to standard methods of organic synthesis (T. W. Green and P. G. M. Wuts (1991) Protecting Groups in Organic Synthesis, John Wiley & Sons). These groups are removed at a convenient stage of the compound synthesis using methods that are readily apparent to those skilled in the art. The selection of processes, as well as the reaction conditions and order of their execution, shall be consistent with the preparation of compounds of Formula (I). Those skilled in the art will recognize if a stereocenter exists in compounds of Formula (I). Accordingly, the present invention includes both possible stereoisomers and includes not only racemic compounds but the individual enantiomers as well. When a compound is desired as a single enantiomer, it may be obtained by stereospecific synthesis or by resolution of the final product or any convenient intermediate. Resolution of the final product, an intermediate, or a starting material may be effected by any suitable method known in the art. See, for example, Stereochemistry of Organic Compounds by E. L. Eliel, S. H. Wilen, and L. N. Mander (Wiley-Interscience, 1994). The compounds described herein may be made from commercially available starting materials or synthesized using known organic, inorganic, and/or enzymatic processes. Illustrated Methods of preparation Schemes

Included in the present invention is a process according to Scheme 1 for the synthesis of the compounds:

a) K₂CO₃, BnBr, acetone/DMF, Δ; δJ 6 M aq. NaOH, methanol/H₂O; c) SOCl₂, Δ; d) R²C(NH₂)=CHCO₂Me, CH₂Cl₂; e) R³NH₂, AlMe₃, DCE, A;β NBS, DMF; g) R¹B(OH)₂, Na₂CO₃, Pd[P(t-Bu)₃]₂, toluene/EtOH/H₂O, Δ; or R¹SnMe₃, CsF, Pd[P(>Bu)₃]₂, 1,4-dioxane, Δ ; h) HBr, AcOH; or H₂, Pd/C, EtOAc/EtOH.

Examples Nuclear magnetic resonance spectra were recorded at either 300 or 400 MHz using, respectively, a Bruker ARX 300 or Bruker AVANCE 400 spectrometer. CHLOROFORM- d is deuteriochloroform and DMSO-ύfø is hexadeuteriodimethylsulfoxide. Chemical shifts are reported in parts per million (δ) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet of doublets, dt=doublet of triplets, app=apparent, br=broad. J indicates the NMR coupling constant measured in Hertz. Fourier transform infrared

(FTIR) spectra were recorded on a Nicolet 510 infrared spectrometer. FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm'l). Mass spectra were taken on either a SCIEX5 or Micromass instruments, using electrospray (ES) ionization techniques. Elemental analyses were obtained using a Perkin- Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Celsius. Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel. Analytical and preparative HPLC were carried out on Rainin or Beckman chromatographs. ODS refers to an octadecylsilyl derivatized silica gel chromatographic support. 5 μ Apex-ODS indicates an octadecylsilyl derivatized silica gel chromatographic support having a nominal particle size of 5 μ, made by Jones Chromatography, Littleton, Colorado. YMC ODS-AQ^® is an ODS chromatographic support and is a registered trademark of YMC Co. Ltd., Kyoto, Japan. PRP- 1^® is a polymeric (styrene-divinylbenzene) chromatographic support, and is a registered trademark of Hamilton Co., Reno, Nevada. Celite^® is a filter aid composed of acid- washed diatomaceous silica, and is a registered trademark of Manville Corp., Denver, Colorado.

The following examples are intended to be illustrative only and not limiting in any way: Example 1

2-(3-Hvdroxy-2-pyridinvπ-6-methyl-5-(5-methyl-2-thienvπ-3-(2-phenylethvπ-4(3H)- pyrimidinone a) Phenylmethyl 3-r(phenylmethyl)oxy^"|-2-pyridinecarboxylate To a solution of 3-hydroxypicolinic acid (7.83 g, 56.3 mmol) in acetone:DMF (200 mL:20 mL) was added powdered K₂CO₃ (23.3 g, 169 mmol) followed by BnBr (15.4 mL, 129.5 mmol). The mixture was heated to 60 ⁰C overnight, then filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography

(EtOAc/Ηexanes: 10-60%) to yield the title compound (8.60 g, 48%). ¹H NMR (400 MHz, MeOD) δ ppm 5.23 (s, 2 H), 5.40 (s, 2 H), 7.29 - 7.37 (m, 6 H), 7.39 - 7.44 (m, 4 H), 7.53 (dd, J=8.59, 4.55 Hz, 1 H), 7.71 (dd, J=8.72, 1.14 Hz, 1 H), 8.19 (dd, J=4.67, 1.14 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 320. b) 3-r(Phenylmethyl)oxy1-2-pyridinecarboxylic acid To a solution of phenylmethyl 3-[(phenylmethyl)oxy]-2-pyridinecarboxylate (3.0 g,

9.40 mmol) in MeOH:THF (8 mL:3 mL) at 0 ⁰C was added 6 M aq. NaOH (2.19 niL, 13.2 mmol). The cooling bath was removed and the reaction mixture was stirred at rt for 3h. The solvent was thoroughly evaporated and the remaining residue was diluted with water (70 mL) then extracted with EtOAc (2 x 70 mL). The aqueous layer was cooled with ice, acidified to pH -2.5 with 6 M aq. HCl, and then extracted with EtOAc (3 x 7OmL). The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo to yield the title compound as a white solid (2.0 g, 93%). ¹H NMR (400 MHz, DMSO-J₆) δ ppm 5.24 (s, 2 H), 7.30 - 7.50 (m, 6 H), 7.66 (d, J=7.83 Hz, 1 H), 8.16 (dd, J=4.55, 1.01 Hz, 1 H), 13.18 (br. s., 1 H). LC/MS (m/z): [M+H]⁺ =230. c) Methyl-3-|Y {3-[(phenylmethyl)oxy^"|-2-pyridinyl| carbonyl)amino^"|-2- butenoateenamide

A solution of 3-[(phenylmethyl)oxy]-2-pyridinecarboxylic acid (0.650 g, 2.84 mmol) in SOCl₂ (7 mL) was heated to 85 ⁰C in a sealed tube for 22 min. The mixture was concentrated in vacuo and the residue was azeotroped thrice with toluene. The resultant acid chloride was diluted with CH₂Cl₂ (11.0 mL) and cooled to 0 ⁰C. A solution of methyl 3-amino-2-butenoate (0.981 g, 8.52 mmol) in CH₂Cl₂ (10.0 mL) was added, the ice-bath was removed, and the mixture was stirred overnight at rt. The mixture was diluted with CH₂Cl₂, then washed with sat. aq. NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexanes: 0-40%) to yield the title compound (0.390 g, 42.1% for 2 steps). ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 2.60 (s, 3 H), 3.75 (s, 3 H), 5.04 (d, J=LOl Hz, 1 H), 7.30 - 7.43 (m, 6 H), 7.47 - 7.52 (m, 2 H), 8.32 - 8.38 (m, 1 H), 12.69 - 12.85 (m, 1 H). LC/MS (m/z): [M+H]⁺ =327. d) 6-Methyl-3-(2-phenylethv0-2- {3-r(phenylmethyl)oxyl-2-pyridinyl} -4(3H)- pyrimidinone

To a solution of phenethylamine (432 mg, 3.57mmol) in DCE (10 mL) at 0 ⁰C was added AlMe₃ (2 M solution in toluene, 1.78 mL, 3.57 mmol). The cooling bath was removed and the mixture was stirred at rt for 30 min., then recooled in an ice-bath. To the reaction mixture was added a solution of methyl-3-[({3-[(phenylmethyl)oxy]-2- pyridinyl}carbonyl)amino]-2-butenoateenamide (388 mg, 1.19 mmol) in DCE (10 mL) using a syringe. The mixture was stirred for 30 min. at rt then heated to 90 ⁰C overnight in an oil bath. The final mixture was diluted with CH₂Cl₂, then washed with sat. aq.

NaHCθ3, dried over Na₂SO₄, and filtered through Celite^®. The residue obtained after concentration in vacuo was purified by flash column chromatography (EtOAc/Hexanes: 20-65%) to yield the title compound (174 mg, 37%). ¹H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.37 (s, 3 H), 2.85 - 2.98 (m, 2 H), 3.86 - 4.07 (m, 2 H), 5.15 (s, 2 H), 6.36 - 6.44 (s, 1 H), 6.83 - 6.96 (m, 2 H), 7.13 - 7.37 (m, 8 H), 7.40 - 7.50 (m, 2 H), 8.36 - 8.44 (m, 1 H). LC/MS (m/z): [M+H]⁺ =398. e) 5-Bromo-6-methyl-3-(2-phenylethvD-2- {3-r(phenylmethyl)oxy^"|-2-pyridinvU - 4(3H)-pyrimidinone

To a solution of 6-methyl-3-(2-phenylethyl)-2-{3-[(phenylmethyl)oxy]-2- pyridinyl}-4(3H)-pyrimidinone (85 mg, 0.214 mmol) in DMF (2.0 mL) at 0 ⁰C was added NBS (45.7 mg, 0.257 mmol). The cooling bath was removed and the reaction mixture was stirred overnight at rt, then the solvent was evaporated under reduced pressure and the resulting residue was diluted with CH₂Cl₂ and washed with sat. aq. NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexanes: 10-70%) to yield the title compound (86 mg, 84%). ¹H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.58 (s, 3 H), 2.91 - 2.98 (m, 2 H), 3.95 - 4.03 (m, 2 H), 5.16 (s, 2 H), 6.89 - 6.93 (m, 2 H), 7.17 - 7.23 (m, 3 H), 7.26 - 7.34 (m, 5 H), 7.44 - 7.46 (m, 2 H), 8.39 (dd, J=3.92, 1.89 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 476, 478.

f) 6-Methyl-5-(5-methyl-2-thienvπ-3-(2-phenylethvπ-2-(3-r(phenylmethvπoxy1-2- pyridinvU -4(3H)-pyrimidinone

To a suspension of 5-bromo-6-methyl-3-(2-phenylethyl)-2-{3-[(phenylmethyl)- oxy]-2-pyridinyl}-4(3H)-pyrimidinone (86 mg, 0.181 mmol), (5-methyl-2-thienyl)boronic acid (51.3 mg, 0.361mmol), and Na₂CO₃ (38.3 mg, 0.361 mmol) in toluene (3.0 mL) was added EtOH (0.012 mL) and deionized water (0.012 mL). The mixture was degassed for 10 min. by bubbling it with a dry nitrogen stream. Finally, Pd[P(?-Bu)3]₂ (13.84 mg, 0.027 mmol) was added and the mixture was heated in a pre -heated oil bath at 100 ⁰C for 60 min. The reaction mixture was filtered, concentrated in vacuo, and the remaining residue was purified by flash column chromatography (EtOAc/Ηex: 20-55 %) to yield the title compound as a white solid (37 mg, 43 %). ¹U NMR (400 MHz, CHLOROFORM-J) δ ppm 2.55 (s, 3 H), 2.57 (s, 3 H), 2.94 - 3.02 (m, 2 H), 3.94 - 4.04 (m, 2 H), 5.19 (s, 2 H), 6.79 - 6.82 (m, 1 H), 6.90 - 6.94 (m, 2 H), 7.04 - 7.06 (m, 1 H), 7.17 - 7.20 (m, 3 H), 7.27 - 7.34 (m, 5 H), 7.44 (s, 2 H), 8.40 - 8.42 (m,l H). LC/MS (m/z): [M+H]⁺ = 494. g) 2-(3-Hvdroxy-2-pyridinvπ-6-methyl-5-(5-methyl-2-thienvπ-3-(2-phenylethvπ-

4(3H)-pyrimidinone

To a cooled solution of 6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-{3- [(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (37 mg, 0.075 mmol) in AcOH (0.50 mL) was slowly added 1.0 mL HBr in AcOH (33% w/w). After 3 d at rt, the reaction mixture was quenched by pouring it into ice-cold water. The pH of the mixture was adjusted using 6N NaOH to pH -7.0, then it was extracted with CH₂Cl₂ (2 x 50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (CH₂C1₂/Hexanes: 45-100%) to give the title compound (8.0 mg, 26.5%, plus 14.0 mg recovered starting material). ¹H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.57 (s, 6 H), 3.27 - 3.35 (m, 2 H), 4.91 - 5.00 (m, 2 H), 6.81 - 6.83 (m, 1 H), 7.07 - 7.10 (m, 1 H), 7.21 - 7.44 (m, 7 H), 8.32 - 8.35 (m, 1 H), 13.86 (s, 1 H). LC/MS (m/z): [M+H]⁺ = 404. Example 2

2-(3-Hvdroxy-2-pyridinv0-6-methyl-5-r4-(5 -methyl- 1.3.4-oxadiazol-2-yr)-2-thienyll-3-(2- phenylethyl)-4(3H)-pyrimidinone a) 5-Bromo-thiophene-3-carboxylic acid

To a solution of thiophene-3-carboxylic acid (50 g, 390 mmol) in AcOH (200 mL) at rt was added Br₂ (22.11 mL, 429 mmol) as a solution in AcOH (150 mL) over 25 min. The resulting solution was stirred at rt for 6 d. The resulting orange suspension was poured into 1 L of cold water. A voluminous white precipitate formed and was isolated by vacuum filtration. The material was re-suspended in cold water and isolated by vacuum filtration to give a white solid, which was dried in a vacuum oven at 60 ⁰C for 4 d to give the title compound (74.5 g, 92%) containing <10% contamination from the di-brominated material. LCMS (m/z): [M+Η]⁺ = 207/209. b) Ethyl 5-bromo-thiophene-3-carboxylate To a solution of 5-bromo-thiophene-3-carboxylic acid (74.5 g, 360 mmol) in EtOH

(300 mL) at rt was added HCl (4 M solution in 1,4-dioxane, 36.0 mL, 144 mmol). The resulting solution was stirred at reflux overnight. The reaction mixture was concentrated to an oil and brought up in CH₂Cl₂ and 5% aq. NaHCOs. The layers were separated, and the aqueous phase was extracted with another portion of CH₂Cl₂. The combined organic portions were washed with brine, dried over MgSO₄, filtered, and concentrated to a tan oil. ¹H NMR indicates the presence of the correct product with a small amount of impurity present (from di-brominated product). (In a previous reaction, the reaction mixture was purified by flash column chromatography (5 - 50 % CH₂C1₂/Hexanes) to give the desired product as a yellow oil and the remainder as a 1 :1 mixture of the 2 products, mono and di- brominated esters.) LCMS (m/z): [M+H]⁺ = 235/237. c) 5 -Bromo-3 -thiophenecarbohydrazide

To a solution of ethyl 5-bromo-thiophene-3-carboxylate (50 g, 213 mmol) in EtOH (53.2 mL) at rt was added anhydrous hydrazine (33.4 mL, 1063 mmol). The resulting solution stirred at reflux for 4 h. The reaction mixture was concentrated to remove EtOH, and then poured into water/ice to form a white precipitate. The solid was isolated by filtration and subsequently dried under vacuum to give the title compound (37.35 g, 79%) as a white solid. LCMS (m/z): [M+H]⁺ = 221/223. d) 2-(5 -Bromo-3 -thienvO-5 -methyl- 1 ,3,4-oxadiazole

To a mixture of 5 -bromo-3 -thiophenecarbohydrazide (4.70 g, 21.26 mmol) and AcOH (5.48 mL, 96 mmol) in CH₂Cl₂ (70 mL) was added (under nitrogen)

POCl₃ (9.91 mL, 106 mmol). The mixture was heated to 85 ⁰C for 60 min. The solvent was evaporated and the remaining residue was dissolved in EtOAc and carefully washed with sat. aq. NaHCO_β. The organic layer was dried over Na₂SO₄, filtered, and then purified by flash column chromatography (EtOAc/Hexanes: 10-50%) to yield the title compound (2.94 g, 56.4%). ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 2.61 (s, 3 H), 7.62 (d, J=I.52 Hz, 1 H), 7.89 (d, J=I.77 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 246. e) 2-Methyl-5-[5-(trimethylstannanyl)-3-thienyl]-l,3,4-oxadiazole

To degassed 1,4-dioxane (12 mL) was added 2-(5 -bromo-3 -thienyl)-5 -methyl- 1 ,3,4-oxadiazole (474 mg, 1.934 mmol), Pd[P(?-Bu)₃]₂ (99 mg, 0.193 mmol) then Me₆Sn₂ (0.493 mL, 2.379 mmol). The reaction mixture was heated for 50 min. The reaction mixture was filtered, concentrated in vacuo, and the residue was purified by flash column chromatography (EtOAc/Hexanes: 5-30 %) to yield the title compound as a white solid (420 mg, 66%). ¹H NMR (400 MHz, CHLOROFORM-^) δ ppm 0.44 (s, 9 H), 2.61 (s, 3 H), 7.68 - 7.77 (m, 1 H), 8.22 - 8.29 (m, 1 H). LC/MS (m/z): [M+H]⁺ = 331. f) 6-Methyl-5-[4-(5 -methyl- 1.3.4-oxadiazol-2-yl)-2-tMenyll-3-(2-phenylethyl)-2-

{3-r(phenylmethyl)oxyl-2-pyridinvU-4(3H)-pyrimidinone

To a suspension of 5-bromo-6-methyl-3-(2-phenylethyl)-2-{3-[(phenylmethyl)- oxy]-2-pyridinyl}-4(3H)-pyrimidinone (100 mg, 0.210 mmol) in degassed 1,4-dioxane (6.0 mL) was added CsF (96 mg, 0.630 mmol) and Pd[P(?-Bu)₃]₂ (10.73 mg, 0.021 mmol) followed by 2-methyl-5-[5-(trimethylstannanyl)-3-thienyl]-l,3,4-oxadiazole (97 mg, 0.294 mmol). The reaction mixture was heated to 110 ⁰C in a preheated oil bath for 60 min. The mixture was filtered, concentrated in vacuo and then purified by flash column chromatography (EtOAc/Hexanes, 30-95%) to yield the title compound (86 mg, 73%). LC/MS (m/z): [M+H]⁺ = 562. g) 2-(3-Hydroxy-2-pyridinyl)-6-methyl-5-[4-(5-methyl-l,3,4-oxadiazol-2-yl)-2- thienyll -3 -(2-phenylethyl)-4(3H)-pyrimidinone Debenzylation was achieved by hydrogenation using the Η-CUBE^® instrument at ambient temperature with pre-packed Pd/C (5% w/w) at 1 bar hydrogen pressure and a flow rate of 1.2 mL/min. The sample, 6-methyl-5-[4-(5-methyl-l,3,4-oxadiazol-2-yl)-2- thienyl] -3 -(2-phenylethyl)-2- {3 - [(phenylmethyl)oxy] -2-pyridinyl} -4(3H)-pyrimidinone, (69 mg, 0.123 mmol) was dissolved in 10 mL EtOAc:EtOΗ (1 :1) and allowed to hydrogenate for 1.0 h. The solvent was concentrated under reduced pressure and the remaining residue was purified by flash column chromatography (EtOAc/Hexanes: 10- 70%) to yield the title compound (25 mg, 43%). ¹H NMR (400 MHz, CHLOROFORM-J) δ ppm 2.64 (s, 3 H), 2.65 (s, 3 H), 3.28 - 3.34 (m, 2 H), 4.96 - 5.04 (m, 2 H), 7.22 - 7.46 (m, 7 H), 7.81 (d, J=I.26 Hz, 1 H), 8.16 (d, J=I.26 Hz, 1 H), 8.35 (dd, J=4.04, 1.77 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 472.

2-(3-Hvdroxy-2-pyridinyl)-6-methyl-5-r5-methyl-4-(2-pyridinyl)-2-thienyll-3-(2- phenylethyl)-4(3H)-pyrimidinone hydrochloride a) 5-(4-Bromo-5-methyl-2-thienvπ-6-methyl-3-(2-phenylethvπ-2-{3- lYphenylmethyl) oxy^"|-2-pyridinyl) -4(3H)-pyrimidinone

To a solution of 6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-2-{3- [(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (152 mg, 0.308 mmol) in 1 ,4-dioxane (5.0 mL) was added H₂O₂ (aq. 30% wt., 45.4 mg, 0.40 mmol) and HBr (aq. 48% wt., 78.0 mg, 0.462 mmol). After stirring for 2 d at rt the mixture was diluted with CH₂Cl₂ (50 mL) and then washed with sat. aq. NaHCO₃. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexanes: 10-40%) to yield the title compound as a yellow foam (141.0 mg, 80 %). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 2.48 (s, 3 H), 2.57 (s, 3 H), 2.92 - 3.01 (m, 2 H), 3.94 - 4.06 (m, 2 H), 5.19 (s, 2 H), 6.89 - 6.95 (m, 2 H), 7.07 (s, 1 H), 7.16 - 7.23 (m, 3 H), 7.32 (d, J=2.02 Hz, 5 H), 7.43 - 7.49 (m, 2 H), 8.38 - 8.44 (m, 1 H). LC/MS (m/z): [M+H]⁺ =572. b) 6-Methyl-5-r5-methyl-4-(2-pyridinvπ-2-thienyl1-3-(2-phenylethvπ-2-(3- r(phenylmethyl)oxyl-2-pyridinvU-4(3H)-pyrimidinone

To a solution of 5-(4-bromo-5-methyl-2-thienyl)-6-methyl-3-(2-phenylethyl)-2-{3- [(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (143.0 mg, 0.250 mmol) in degassed 1,4-dioxane (8.0 mL) was added CsF (114 mg, 0.749 mmol), Pd[P(?-Bu)₃]₂ (12.76 mg, 0.025 mmol), and 2-(tributylstannanyl)pyridine (153 mg, 0.375 mmol). The mixture was heated to 110 ⁰C in a preheated oil bath for 3.0 h. The mixture was cooled to rt and then quenched with 10% aq. KF solution (20 mL) and allowed to stir for 30 min. The mixture was diluted with EtOAc (50 mL) and then filtered through Celite^®. The organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The remaining residue was purified by flash column chromatography (EtOAc/Ηexanes: 40-90%) to yield the title compound (78.3 mg, 54.9 %). ¹H NMR (400 MHz, MeOD) δ ppm 2.55 (s, 3 H), 2.71 (s, 3 H), 2.84 - 2.94 (m, 2 H), 3.93 - 4.06 (m, 2 H), 6.85 - 6.93 (m, 2 H), 7.14 - 7.21 (m, 3 H), 7.26 - 7.47 (m, 7 H), 7.63 - 7.73 (m, 2 H), 7.82 - 7.98 (m, 2 H), 8.36 - 8.43 (m, 1 H), 8.61 - 8.69 (m, 1 H). LC/MS (m/z): [M+H]⁺ = 571. c) 2-(3-Hvdroxy-2-pyridinyl)-6-methyl-5-r5-methyl-4-(2-pyridinyl)-2-thienyll-3- (2-phenylethyl)-4(3H)-pyrimidinone hydrochloride

To a solution of 6-methyl-5-[5-methyl-4-(2-pyridinyl)-2-thienyl]-3-(2- phenylethyl)-2-{3-[(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (78.0 mg, 0.137 mmol) in EtOAcMeOH (1.0 mL:1.5 mL) was added 10% Pd/C (18.62 mg, 0.017 mmol). H₂ was supplied to the mixture using a balloon. The reaction was stirred overnight but found to be incomplete by tic and LCMS. Additional Pd/C was added (15.0 mg) and the mixture was stirred another 18 h. The mixture was filtered, concentrated in vacuo, and purified by flash column chromatography (MeOH/CH₂Cl₂: 0-1.0%) to yield 2-(3-hydroxy- 2-pyridinyl)-6-methyl-5-[5-methyl-4-(2-pyridinyl)-2-thienyl]-3-(2-phenylethyl)-4(3H)- pyrimidinone (42 mg, 59.5%, as a free base). The free base form was then dissolved in CH₃CN/CH₂C1₂ (2.0 mL:1.0 niL) and treated with a solution of HCl (2.0 M solution in Et₂O, 0.243 mL, 0.486 mmol) and stirred for 20 min. The solvent was evaporated and the residue was azeotroped using toluene (2 x 5 mL) to yield the final salt form: 47.0 mg, yellow solid. ¹H NMR (400 MHz, DMSO-J₆) δ ppm 2.53 (s, 3 H), 2.71 (s, 3 H), 2.82 - 2.90 (m, 2 H), 3.95 - 4.02 (m, 2 H), 6.90 (m, 2 H), 7.23 (m, 3 H), 7.52 (m, 2 H), 7.57 - 7.68 (m, 2 H), 7.90 - 7.96 (m, 1 H), 8.16 - 8.28 (m, 2 H), 8.76 - 8.81 (m, 1 H), 10.97 (br. s., 1 H). LC/MS (m/z): [M+H]⁺ = 481.

Example 4

2-(3-Hvdroxy-2-pyridinyl)-6-methyl-3,5-bis(2-phenylethyl)-4(3H)-pyrimidinone a) 6-Methyl-3-(2-phenylethyl)-5-(phenylethynyl)-2-{3-[(phenylmethyl)oxyl-2- pyridinyl) -4(3H)-pyrimidinone

To a suspension of 5-bromo-6-methyl-3-(2-phenylethyl)-2-{3-[(phenylmethyl)- oxy]-2-pyridinyl}-4(3H)-pyrimidinone (200 mg, 0.420 mmol) in degassed 1,4-dioxane (4.0 mL) was added CsF (128 mg, 0.840 mmol), Pd[P(?-Bu)₃]₂ (10.8 mg, 0.021 mmol), and tributyl(phenylethynyl)stannane (0.221 mL, 0.630 mmol). The reaction mixture was heated to 150 ⁰C under microwave irradiation for 30 min. The mixture was filtered through a 0.2 μM microfϊlter, concentrated in vacuo and then purified by flash column chromatography (EtOAc/Ηexanes, 20-60%) to yield the title compound (160 mg, 77%). ¹H NMR (400 MHz, CDCl₃): δ ppm 2.65 (3H, s); 2.98-3.00 (2H, m); 3.97-4.05 (2H, m); 5.16 (2H, s); 6.91-6.94 (2H, m); 7.15-7.23 (3H, m); 7.28-7.40 (8H, m); 7.44-7.48 (2H, m); 7.62-7.65 (2H, m); 8.40-8.41 (IH, m). LC/MS (m/z): [M+H]⁺ = 498. b) 2-(3-Hydroxy-2-pyridinyl)-6-methyl-3,5-bis(2-phenylethyl)-4(3H)-pyrimidinone To 10% Pd/C (34.2 mg, 0.032 mmol) was added a solution of 6-methyl-3-(2- phenylethyl)-5-(phenylethynyl)-2-{3-[(phenylmethyl)oxy]-2-pyridinyl}-4(3H)- pyrimidinone (160 mg, 0.322 mmol) in EtOH (10.0 mL). H₂ was supplied to the mixture using a balloon. The reaction was stirred at rt for 6 h. The mixture was filtered through a 0.2 μM microfilter, concentrated in vacuo, and purified by reverse phase HPLC (CH₃CN/H₂O (0.1% TFA): 10-90%) to yield the title compound (80 mg, 95%). ¹H NMR (400 MHz, CDC13): δ ppm 2.18 (3H, s); 2.91(4H, m); 3.16-3.20(2H, m), 4.77-4.81(2H, m); 7.24-7.46 (12H, m); 8.31-8.32 (IH, d, J=3.28); 12.02 (IH, br. s). LC/MS (m/z): [M+H]⁺ = 412.

Example 5

3-(2-Cyclohexylethyl)-2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2-pyridinyl)-2- thienyll -4(3H)-pyrimidinone hydrochloride a) 2-(2,5-Dibromo-3-thienyl)pyridine

To a solution of 2-(3-thienyl)pyridine (9.00 g, 55.8 mmol) in DMF (90.0 mL) at 0 ⁰C was added NBS (26.8 g, 150.7 mmol) portionwise over 30 min. The reaction was stirred at rt overnight. The reaction mixture was poured into water (100 mL) and extracted with EtOAc (2 x 150 mL). The combined organic layers were washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Ηexanes: 0-5%) to yield the title compound (13.5 g, 76%). LC/MS (m/z): [M+Η]⁺ = 320. b) 2-(5-Bromo-2-methyl-3-thienyl)pyridine To a solution of 2-(2,5-dibromo-3-thienyl)pyridine (13.0 g, 41.00 mmol) in THF

(150 mL) at -78 ⁰C was added /?-BuLi (1.6 M solution in hexanes, 30.75 mL, 49.2 mmol) at a slow dropwise rate over 3 min. The reaction was stirred at -78 ⁰C for 10 min, and then MeI (8.84 mL, 61.45 mmol) was added. The reaction mixture was allowed to warm to rt over several hours. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (150 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexanes: 0-4%) to yield the title compound (6.5 g, 63%). ¹H NMR (400 MHz, CHLOROFORM- d) δ ppm 2.61 (s, 3 H), 7.20 (ddd, J=I.5, 4.9, 1.0 Hz, 1 H), 7.28 (s, 1 H), 7.41 (d, J=7.8 Hz, 1 H), 7.73 (td, J=7.8, 1.9 Hz, 1 H), 8.66 (d, J=4.0 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 254/256. c) Λ/-(2-Cyclohexylethyl)-3 -oxobutanamide To a solution of (2-cyclohexylethyl)amine hydrochloride (1.7 g, 10.39 mmol) in

CH₂Cl₂ (51.9 mL) at 0 ⁰C was added diketene (0.881 mL, 11.42 mmol) dropwise via syringe. The reaction mixture was stirred for 10 min. at 0 ⁰C, followed by heating to reflux overnight. Upon cooling, the solution was washed with 1 M aq. HCl. The aqueous layer was extracted with CH₂Cl₂, and the combined organics were washed with brine, dried over dried over Na₂SO₄, filtered, and concentrated in vacuo to afford the title compound (2.5 g, >100%, contained some residual solvent) as an orange glass. d) 3 - [(pheny lmethy Doxy 1 -2 -pyridinecarboxamide

To a solution of 3-[(phenylmethyl)oxy]-2-pyridinecarboxylic acid (1.00 g, 4.36 mmol) in THF (4.36 mL) was added triethylamine (0.669 mL, 4.80 mmol) and the reaction mixture was cooled to 0 ⁰C. Ethyl chloroformate (0.440 mL, 4.58 mmol) was added dropwise via syringe. The reaction mixture was stirred for 5 min. at 0 ⁰C, and then raised to rt. The reaction mixture was stirred for 10 min. at rt, followed by the addition of a solution OfNH₄OH (2.55 mL, 65.4 mmol) in THF (4 mL). After stirring for 1 h at rt, the reaction mixture was concentrated in vacuo, diluted with water and extracted twice with CH₂Cl₂. The combined organics were washed with sat. aq. NaHCO₃ and brine, dried over dried over MgSO₄, filtered, and concentrated in vacuo to afford the title compound (792 mg, 80%) as a tan solid. LC/MS (m/z): [M+H]⁺ = 229. e) 3-(2-Cyclohexylethyl)-6-methyl-2- {3-[(phenylmethyl)oxy^"|-2-pyridinyll -4(3H)- pyrimidinone

To 3-[(phenylmethyl)oxy]-2-pyridinecarboxamide (2.074 g, 9.09 mmol) and JV-(2- cyclohexylethyl)-3-oxobutanamide (1.6 g, 7.57 mmol) under Ar was added Ti(Oz-Pr)₄ (8.87 mL, 30.3 mmol). The reaction mixture was heated to 150 ⁰C overnight (-21 h), followed by removal of excess Ti(Oz-Pr)₄ by vacuum distillation. Upon cooling to rt, the resultant residue was diluted with toluene and quenched with 2 M aq. HCl. The mixture was stirred for 2 h, the layers were separated, and the aqueous phase was extracted three times with toluene. The combined organics were washed with brine, dried over dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was combined with the crude reaction mixture from another batch (run on 2.37 mmol scale - limiting reagent) for purification by flash column chromatography (EtOAc/Ηexanes: 0-100%) to afford the title compound (240 mg, 6% - combined yield) as a brown oil. LC/MS (m/z): [M+Η]⁺ = 404. f) 5-Bromo-3-(2-cvclohexylethyl)-6-methyl-2-{3-r(phenylmethyl)oxyl-2- pyridinyl) -4(3H)-pyrimidinone

To a solution of 3-(2-cyclohexylethyl)-6-methyl-2-{3-[(phenylmethyl)oxy]-2- pyridinyl}-4(3H)-pyrimidinone (237 mg, 0.587 mmol) in DMF (3.92 mL) at 0 ⁰C was added NBS (110 mg, 0.617 mmol). The reaction mixture was stirred for 5 min. at 0 ⁰C, followed by warming to rt and stirring for 2.5 h. The reaction was quenched with sat. aq. NaΗCθ3 and diluted with Et₂O. The layers were separated and the aqueous phase was extracted three times with Et₂O. The combined organics were washed with brine, dried over dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (EtOAc/Hexanes: 0-50%) to yield the title compound (186 mg, 66%). ¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 0.60 - 0.69 (m, 2 H), 1.06 - 1.11 (m, 4 H), 1.25 - 1.40 (m, 3 H), 1.45 - 1.54 (m, 4 H), 2.54 (s, 3 H), 3.83 (br s, 2 H),

5.17 (s, 2 H), 7.30 - 7.43 (m, 7 H), 8.33 (dd, J=4.04, 2.00 Hz, 1 H). LC/MS (m/z): [M+H]⁺ = 484/486. g) 3-(2-Cvclohexylethvπ-6-methyl-5-r5-methyl-4-(2-pyridinvπ-2-thienyl1-2-(3- [(phenylmethyl)oxyl-2-pyridinyll-4(3H)-pyrimidinone To a degassed solution of 2-(5-bromo-2-methyl-3-thienyl)pyridine (0.176 g, 0.691 mmol) in 1,4-dioxane (2.61 mL) was added

(18 mg, 0.035 mmol) followed by Me₆Sn₂ (0.150 mL, 0.726 mmol). The reaction mixture was again degassed with Ar and then heated to 150 ⁰C for 75 min. under microwave irradiation. The crude reaction mixture was transferred via syringe to a flask containing 5-bromo-3-(2-cyclohexylethyl)-6- methyl-2-{3-[(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (186 mg, 0.386 mmol), CsF (117 mg, 0.771 mmol), and Pd[P(?-Bu)₃]₂ (9.85 mg, 0.019 mmol), and the solution was degassed with Ar bubbling for 10 min. The vessel was then heated to 150 ⁰C for 90 min. under microwave irradiation. Upon cooling, the reaction mixture was filtered through Celite^® and concentrated in vacuo. The residue was purified by flash column chromatography (Acetone/CF^Cb: 0-10%) to yield the title compound (135 mg, 61%) as a yellow oil which expanded to a yellow foam upon drying under high vacuum. LC/MS (m/z): [M+Η]⁺ = 577. h^ S-ri-CvclohexylethylVl-O-hydroxy-l-pyridinvπ-ό-methyl-S-rS-methyl^-ri- pyridinyl)-2-thienvH-4(3H)-pyrimidinone

To a solution of 3-(2-cyclohexylethyl)-6-methyl-5-[5-methyl-4-(2-pyridinyl)-2- thienyl]-2-{3-[(phenylmethyl)oxy]-2-pyridinyl}-4(3H)-pyrimidinone (135 mg, 0.234 mmol) in EtOAc (1.56 mL) under an Ar atmosphere was added 10% Pd/C (37.4 mg, 0.035 mmol) followed by MeOH (3.12 mL). The Ar atmosphere was removed under low vacuum and replaced with H₂ by balloon three times. The reaction was stirred overnight at rt. Additional Pd/C (37.4 mg, 0.035 mmol) was added and the mixture was stirred another 1 h while bubbling through H₂. Additional Pd/C (37.4 mg, 0.035 mmol) was added and the mixture was stirred another 5 h while bubbling through H₂. Additional Pd/C (37.4 mg, 0.035 mmol) was added and the mixture was stirred another 80 min. while bubbling through H₂. Additional Pd/C (37.4 mg, 0.035 mmol) was added and the mixture was stirred another 90 min. while bubbling through H₂. The reaction mixture was filtered through Celite^®, rinsed through with 1 : 1 MeOH/EtOAc followed by CH₂Cl₂, and concentrated in vacuo to afford the title compound (98.8 mg, 87%) as a bright yellow solid. LC/MS (m/z): [M+H]⁺ = 487. π 3-(2-Cvclohexylethyl)-2-(3-hvdroxy-2-pyridinvπ-6-methyl-5-r5-methyl-4-(2- pyridinvD-2-thienvπ -4(3H)-pyrimidinone hydrochloride

To a solution of 3-(2-cyclohexylethyl)-2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5- methyl-4-(2-pyridinyl)-2-thienyl]-4(3H)-pyrimidinone (98.8 mg, 0.203 mmol) in CH₂Cl₂ (4.06 mL) was added HCl (1 M solution in Et₂O, 1.015 mL, 1.015 mmol) followed by additional HCl (1 M solution in Et₂O, 1.015 mL, 1.015 mmol). The reaction mixture was stirred at RT for 10 min. followed by concentration in vacuo to afford the title compound (105.8 mg, 95%) as a bright yellow solid. ¹U NMR (400 MHz, CHLOROFORM-d) δ ppm 0.86 - 0.98 (m, 4 H), 1.06 - 1.23 (m, 4 H), 1.30 - 1.38 (m, 2 H), 1.67 - 1.77 (m, 3 H), 2.80 (s, 3 H), 2.88 (s, 3 H), 2.55 (br s, 2 H), 7.45 (dd, J=3.80, 8.00 Hz, 1 H), 7.74 (d, J=7.04 Hz, 1 H), 7.81 - 7.86 (m, 1 H), 7.96 (d, J=6.56 Hz, 1 H), 8.04 - 8.10 (m, 1 H), 8.26 (d, J=4.04 Hz, 1 H), 8.41 - 8.47 (m, 1 H), 8.92 - 8.98 (m, 1 H). LC/MS (m/z): [M+H]⁺ = 487.

Example 6

Pharmaceutical formulations:

Tablet Formulation

An exemplary tablet formulation is formed by tableting the following mixture:

Ingredient Wt%

Compound* 50.8

Povidone K30 2.2

Microcrystalline cellulose 40.7

Croscarmellose sodium 5.3

Magnesium Stearate 1.0

* Compound is a compound of this invention

Parenteral formulation

A pharmaceutical composition for parenteral administration is prepared by dissolving an appropriate amount of a compound of Formula (I) in polyethylene glycol with heating. This solution is then diluted with water for injections (to 100 mL). The solution is then rendered sterile by filtration through a 0.22 micron membrane filter and sealed in sterile containers.

All publications, including but not limited to patents and patent applications cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference as though fully set forth.

Claims

What is claimed is:

1. A compound according to Formula (I):

wherein:

R¹ is selected from the group consisting of hydrogen, halogen, cyano, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring;

R² is selected from the group consisting of hydrogen, -NR⁴R⁵, -C(O)R⁶, -C(O)OR⁶, -C(O)NR⁴R⁵, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring; or R¹ and R² together form a 5-8 membered ring, optionally containing one to three heteroatoms selected from N, O, and S;

R³ is selected from the group consisting of (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring;

R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (Ci-C₈)cycloalkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, heteroaryl, -C(O)R⁶, -SO₂((Ci-C₄)alkyl), (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, aryl(Ci-C₈)alkyl, and heteroaryl(Ci-C₈)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring; or R⁴ and R⁵ taken together with the nitrogen to which they are attached represent a 5- to 7-membered saturated ring optionally containing one other heteroatom which is oxygen, nitrogen, or sulfur; each R⁶ is independently selected from the group consisting of hydrogen, (Ci-C₈)alkyl, (C₂-C₈)alkenyl, (C₂-C₈)alkynyl, (C₃-C₈)cycloalkyl, (C₃-C₈)cycloalkyl(Ci-C₈)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₈)alkyl, aryl, aryl(Ci-C₈)alkyl, heteroaryl, heteroaryl(Ci-C₈)alkyl, -CO((Ci-C₄)alkyl), -CO(aryl), and -CO(heteroaryl), wherein any heterocycloalkyl is a 3-8 membered ring; and wherein any aryl or heteroaryl group of R¹, R², R³, R⁴, R⁵, or R⁶ is optionally substituted by -O-(d-C₂)alkyl-O-; any R¹, R², R³, R⁴, R⁵, or R⁶ is unsubstituted or, where possible, is substituted with one to three substituents independently selected from halogen, cyano, nitro, -NR⁴R⁵, -OR⁶, -C(O)R⁶, -C(O)OR⁶, -CONR⁴R⁵, -SR⁶, -S(O)R⁶, -S(O)₂R⁶, -SO₂NR⁴R⁵, -N(R⁴)C(O)R⁶, -N(R⁴)C(O)OR⁶, -N(R⁴)C(O)NR⁴R⁵, (Ci-C₆)alkyl, halo(Ci-C₄)alkyl, (C₂-C₆)alkenyl, (C₂-C₆)alkynyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, aryl, and heteroaryl, wherein said aryl or heteroaryl group is optionally substituted one to three times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, said heterocycloalkyl is a 5-6 membered ring, and R⁴, R⁵, and R⁶ are the same as defined above; or a salt thereof.

2. The compound or salt according to Claim 1, wherein:

R¹ is selected from the group consisting of (Ci-Ce)alkyl, (C₃-C₆)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-C₆)alkyl, heteroaryl, and heteroaryl(Ci-C₆)alkyl, wherein any heterocycloalkyl is a 3-8 membered ring, and any aryl group is optionally substituted by -O-(Ci-C₂)alkyl-O-, and wherein any R¹ moiety is optionally substituted one to three times independently by halogen, cyano, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, -C(O)O(Ci-C₄)alkyl, (Ci-C₄)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl, wherein said aryl or heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl; R² is selected from the group consisting of (Ci-Ce)alkyl, (C₃-Ce)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl, aryl(Ci-C₆)alkyl, heteroaryl, and heteroaryl(Ci-C₆)alkyl, wherein any heterocycloalkyl is a 5-6 membered ring, and any aryl group is optionally substituted by -O-(Ci-C2)alkyl-O-, and wherein any R² moiety is optionally substituted one to three times independently by halogen, amino, (Ci-C4)alkylamino, (Ci-C4)alkyl(Ci-C4)alkylamino, (Ci-C4)alkyl, -CF₃, (Ci-C₄)alkoxy, aryl, or heteroaryl; and

R³ is selected from the group consisting of (Ci-Ce)alkyl, (C₃-Ce)cycloalkyl, (C₃-C₆)cycloalkyl(Ci-C₆)alkyl, heterocycloalkyl(Ci-C₆)alkyl, aryl(Ci-C₆)alkyl, and heteroaryl(Ci-C₆)alkyl, wherein said heteroaryl or heterocycloalkyl is a 5-6 membered ring, and said aryl is optionally substituted by -O-(Ci-C2)alkyl-O-, and wherein any R³ moiety is optionally substituted one to three times independently by halogen, amino, (Ci-C₄)alkylamino, (Ci-C₄)alkyl(Ci-C₄)alkylamino, (Ci-C₄)alkyl, -CF₃, or (Ci-C₄)alkoxy.

3. The compound or salt according to any one of Claims 1-2, wherein R¹ is thienyl, optionally substituted one to two times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, phenyl, or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl group is optionally substituted one to two times independently by halogen, (Ci-C₄)alkyl, -CF₃, amino, (Ci-C4)alkylamino, (Ci-C4)alkyl(Ci-C4)alkylamino, (Ci-C4)alkoxy, hydroxy(Ci-C₄)alkyl, or (Ci-C₄)alkoxy(Ci-C₄)alkyl, and wherein the 5-6 membered heteroaryl group is selected from furanyl, thiazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrazinyl, and pyrimidinyl.

4. The compound or salt according to any one of Claims 1-3, wherein R² is selected from the group consisting of (Ci-Ce)alkyl, phenyl, and 5-6 membered heteroaryl, optionally substituted, one to three times, independently, by halogen, (Ci-C₄)alkyl, -CF₃, (Ci-C4)alkoxy, phenyl, or 5-6 membered heteroaryl.

5. The compound or salt according to any one of Claims 1-4, wherein R is phenethyl, optionally substituted one to two times, independently, by F, Cl, (Ci-C₄)alkyl,

(Ci-C₄)alkoxy, or -CF₃.

6. A compound which is: 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-(5-methyl-2-thienyl)-3-(2-phenylethyl)-

4(3H)-pyrimidinone;

2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[4-(5-methyl-l,3,4-oxadiazol-2-yl)-2- thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone;

2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2-pyridinyl)-2-thienyl]-3-(2- phenylethyl)-4(3H)-pyrimidinone;

2-(3 -hydroxy-2-pyridinyl)-6-methyl-3 ,5-bis(2-phenylethyl)-4(3H)-pyrimidinone; or 3-(2-cyclohexylethyl)-2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2- pyridinyl)-2-thienyl]-4(3H)-pyrimidinone; or a salt thereof.

7. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-(5-methyl-2-thienyl)- 3-(2-phenylethyl)-4(3H)-pyrimidinone.

8. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[4-(5-methyl-l ,3,4- oxadiazol-2-yl)-2-thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone.

9. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2- pyridinyl)-2-thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone.

10. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2- pyridinyl)-2-thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone hydrochloride.

11. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-(5-methyl-2-thienyl)- 3-(2-phenylethyl)-4(3H)-pyrimidinone or a pharmaceutically acceptable salt thereof.

12. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[4-(5-methyl-l ,3,4- oxadiazol-2-yl)-2-thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone or a pharmaceutically acceptable salt thereof.

13. A compound which is 2-(3-hydroxy-2-pyridinyl)-6-methyl-5-[5-methyl-4-(2- pyridinyl)-2-thienyl]-3-(2-phenylethyl)-4(3H)-pyrimidinone or a pharmaceutically acceptable salt thereof.

14. A process for the preparation of the compound or salt according to any one of Claims 1-13, which process comprises treating a compound of Formula A:

with thionyl chloride, followed by addition of an optionally substituted 3-amino-2- propenoate, to form a compound of Formula B:

wherein R² is the same as in Formula (I), which is then treated with an amine, along with a Lewis acid, to form a compound of Formula C:

wherein R² and R³ are the same as for those groups in Formula (I), which is then brominated, followed by Palladium catalyzed coupling, and deprotection, to form a compound of Formula (I) from which a salt may optionally be formed.

15. A pharmaceutical composition which comprises the compound or salt according to any one of Claims 1-13, and a pharmaceutically acceptable diluent, carrier and/or excipient.

16. A process for preparing the composition as defined in claim 15, the process comprising mixing the compound or salt as defined in claim 1 with a pharmaceutically acceptable diluent, carrier, and/or excipient.

17. A method of antagonizing a calcium receptor, which comprises administering to a human in need thereof, an effective amount of the compound or salt according to any one of Claims 1-13.

18. A method of treating a disease or disorder characterized by an abnormal bone or mineral homeostasis, which comprises administering to a human in need thereof, an effective amount of the compound or salt according to any one of Claims 1-13.

19. A method according to claim 18 wherein the abnormal bone or mineral homeostasis disease or disorder is selected from the group consisting of osteosarcoma, periodontal disease, bone fracture, osteoarthritis, rheumatoid arthritis, Paget's disease, humoral hypercalcemia, malignancy, osteopenia, and osteoporosis.

20. A method according to claim 19 wherein the bone or mineral disease or disorder is osteoporosis.

21. A method of increasing serum parathyroid levels which comprises administering to a human in need thereof, an effective amount of the compound or salt according to any one of Claims 1-13.

22. A method according to claim 19 wherein the compound according to Formula (I) is co-administered with an anti-resorptive agent.

23. A method according to claim 22 wherein the anti-resorptive agent is selected from the group consisting of estrogens, 101,25-(OH)₂Ds, lα-(0H)U₃, calcitonin, denosumab, selective estrogen receptor modulators, vitronectin receptor antagonists, V-H+-ATPase inhibitors, src SH2 antagonists, bisphosphonates and cathepsin K inhibitors.

24. A method according to claim 23 wherein the selective estrogen receptor modulator is selected from the group consisting of lasofoxifene, raloxifene, arzoxifene, bazedoxifene, and ospemifene.

25. A method according to claim 23 wherein the bisphosphonate is selected from the group consisting of tiludronate, clondronate, etidronate, alendronate, risedronate, ibandronate, zoledronate, minodronate, neridronate, and pamidronate.