Compounds as calcium channel blockers

The present application relates to calcium channel inhibitors containing compounds of formula (I)wherein Ar1, Ar2, L1, L2, n, R1, R4, X and Y are as defined in the specification. The present application also relates to compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

TECHNICAL FIELD

The present application relates to compounds that are calcium channel blockers, compositions comprising such compounds, and methods of treating conditions and disorders using such compounds and compositions.

BACKGROUND OF THE INVENTION

Voltage-gated calcium channels (VGCC) play an integral role in the regulation of membrane ion conductance, neurotransmitter release, and cellular excitability. VGCC are composed of the pore-forming α1 subunit and auxiliary α2δ and β subunits that modulate channel expression and functional properties (Dolphin, A. C. A short history of voltage-gated calcium channels. British Journal of Pharmacology 2006, 147 (Suppl. 1), S56-S62). These channels can be classified into low-voltage activated (LVA; T-type or Cav3.x) and high-voltage activated (HVA; L-type or Cav1.x and N-, P/Q- and R-types or Cav2.x) channels. N-, P/Q and R channels typically activate at more positive membrane potentials (˜−30 mV) and are involved in “presynaptic” neurotransmission (McGivern J. G. Targeting N-type and T-type calcium channels for the treatment of pain. Drug Discovery Today 2006, 11, 245-253). T-type channels are activated at relatively negative membrane potentials (˜−60 mV) and are primarily involved in “postsynaptic” excitability (Shin, H.-S.; Cheong, E.-J.; Choi, S.; Lee, J.; Na, H. S. T-type Ca2+channels as therapeutic targets in the nervous system. Curr. Opin. in Pharmacology 2008, 8, 33-41).

N-type channel αδsubunits are encoded by a single gene (α1B or Cav2.2) in contrast to pharmacologically defined L- and T-type currents that are encoded by multiple α1-subunit genes. A diversity of N-type channels arises due to extensive alternative splicing of the α subunit gene that generates variants with different expression patterns and GPCR-modulated biophysical properties (Gray, A. C.; Raingo, J.; Lipscombe, D. Neuronal calcium channels: splicing for optimal performance. Cell Calcium, 2007, 42(4-5), 409-417). The primary sequence for Cav2.2 is highly conserved across species (rat and human share 91% identity at the amino acid level).

Pain is the most common symptom of disease and the most frequent complaint with which patients present to physicians. Inadequate pain management across the spectrum of pain etiologies remains a major public health problem. Going forward, the development of novel therapeutics with new mechanisms of action for the treatment of pain including calcium channel blockade will have a significant impact on the ongoing struggle to balance efficacy and safety for those patients most in need. The compounds of the present invention are novel calcium channel blockers that have utility in treating pain, amongst other conditions.

SUMMARY OF THE INVENTION

The invention is directed to compounds of formula (I)

or a pharmaceutically acceptable salt thereof, wherein

is a single or double bond;

n, at each occurrence, is independently 1 or 2;

Rc, at each occurrence, is independently alkyl or haloalkyl;

q, at each occurrence, is independently 1, 2, or 3;

y at each occurrence, is independently 1, 2, or 3;

z at each occurrence, is independently 0, 1, 2, or 3;

Riiat each occurrence, is independently oxo or alkyl;

one of A6, A7, A8, A9, and A10is C and the others are each independently CH or N;

R2and R3taken together with the carbon atom to which they are attached form a cycloalkyl;

R3and R5taken together are —(CH2)p— or —O—(CH2)p—; or

R4and R5taken together are a bond, —(CH2)s—, or —O—(CH2)s—; whereins, at each occurrence, is independently 1 or 2; or

R4and R6taken together are —CH2—; or

L1-L2Y taken together are S(O)r;

with the provisos that

Ar2is other than a pyrazole substituted with 1 or 2 groups independently selected from aryl and heteroaryl; or

when Ar1is phenyl, R1is hydrogen or methyl, X is CH2, n is 1, L1-L2Y taken together are S(O)r, r is 2, then Ar2is other than 4-methylphenyl; or

when the bond connecting L2to Y is a double bond, Y is CR2; or

when X is other than CH2, n is 2.

Another aspect of the invention relates to pharmaceutical compositions comprising therapeutically effective amount of compound(s) of the invention or pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carrier. Such compositions can be administered in accordance with a method of the invention, typically as part of a therapeutic regimen for treatment or prevention of conditions and disorders related to calcium channels. More particularly, the method is useful for treating conditions related to a method of treating pain in a subject in need thereof. The method comprises administering to the subject a therapeutically suitable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Conditions related to pain include acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, cancer pain, allodynia, fibromyalgia, sciatica, back pain, and headache pain including migraine, or combinations thereof.

Another aspect of the invention provides a method of treating disorders of the central nervous system in a subject in need thereof. The method comprising the step of: administering a therapeutically suitable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. The disorders of the central nervous system include stroke, epilepsy, manic depression, bipolar disorders, depression, anxiety, schizophrenia, migraine, and psychoses; neural degenerative disorders including Alzheimer's disease, AIDS related dementia, Parkinson's disease, neuropathy caused by head injury, and dementia caused by cerebrovascular disorders; disorders of the lower urinary tract including overactive bladder, prostatis, prostadynia, interstitial cystitis, and benign prostatic hyperplasia; disorders caused by psychogenic stress including bronchial asthma, unstable angina, and hypersensitive colon inflammation; cardiovascular disorders including hypertension, atherosclerosis, heart failure, and cardiac arrhythmias; drug addiction withdrawal symptoms, including ethanol addiction withdrawal symptoms; skin disorders including pruritis and allergic dermatitis, inflammatory bowel disease; cancer; diabetes; and infertility and sexual dysfunction, or combinations thereof.

The compounds, compositions comprising the compounds, and methods for treating or preventing conditions and disorders by administering the compounds are further described herein.

These and other objects of the invention are described in the following paragraphs. These objects should not be deemed to narrow the scope of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of formula (I) are disclosed in this invention

wherein Ar1, Ar2, L1, L2, n, R1, R4, X and Y are as defined above in the Summary of the Invention. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

In various embodiments, the present invention provides at least one variable that occurs more than one time in any substituent or in the compound of the invention or any other formulae herein. Definition of a variable on each occurrence is independent of its definition at another occurrence. Further, combinations of substituents are permissible only if such combinations result in stable compounds. Stable compounds are compounds, which can be isolated from a reaction mixture.

As used in the specification and the appended claims, unless specified to the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched hydrocarbon chain containing from 2 to 10 carbons and containing at least one carbon-carbon double bond formed by the removal of two hydrogens. Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and 3-decenyl.

The term “alkenylene” denotes a divalent group derived from a straight or branched chain hydrocarbon of 2 to 4 carbon atoms and contains at least one carbon-carbon double. Representative examples of alkylene include, but are not limited to, —CH═CH— and —CH2CH═CH—.

The term “alkylene” denotes a divalent group derived from a straight or branched chain hydrocarbon 1 to 10 carbon atoms. Representative examples of alkylene include, but are not limited to, —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2—, and —CH2CH(CH3)CH2—.

The term “aryl” as used herein, means phenyl or a bicyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to a monocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl. Representative examples of the aryl groups include, but are not limited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, and tetrahydronaphthalenyl. The bicyclic aryl is attached to the parent molecular moiety through any carbon atom contained within the bicyclic ring system. The aryl groups of the present invention can be unsubstituted or substituted.

The term “cycloalkyl” or “cycloalkane” as used herein, means a monocyclic, a bicyclic, or a tricyclic cycloalkyl. The monocyclic cycloalkyl is a carbocyclic ring system containing three to eight carbon atoms, zero heteroatoms and zero double bonds. Examples of monocyclic ring systems include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. The bicyclic cycloalkyl is a monocyclic cycloalkyl fused to a monocyclic cycloalkyl ring, or a bridged monocyclic ring system in which two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge containing one, two, three, or four carbon atoms. Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane. Tricyclic cycloalkyls are exemplified by a bicyclic cycloalkyl fused to a monocyclic cycloalkyl, or a bicyclic cycloalkyl in which two non-adjacent carbon atoms of the ring systems are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms. Representative examples of tricyclic-ring systems include, but are not limited to, tricyclo[3.3.1.03,7]nonane (octahydro-2,5-methanopentalene or noradamantane), and tricyclo[3.3.1.13,7]decane (adamantane). The monocyclic, bicyclic, and tricyclic cycloalkyls can be unsubstituted or substituted, and are attached to the parent molecular moiety through any substitutable atom contained within the ring system.

The term “cycloalkenyl” or “cycloalkene” as used herein, means a monocyclic or a bicyclic hydrocarbon ring system. The monocyclic cycloalkenyl has four-, five-, six-, seven- or eight carbon atoms and zero heteroatoms. The four-membered ring systems have one double bond, the five- or six-membered ring systems have one or two double bonds, and the seven- or eight-membered ring systems have one, two or three double bonds. Representative examples of monocyclic cycloalkenyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl. The bicyclic cycloalkenyl is a monocyclic cycloalkenyl fused to a monocyclic cycloalkyl group, or a monocyclic cycloalkenyl fused to a monocyclic cycloalkenyl group. The monocyclic or bicyclic cycloalkenyl ring may contain one or two alkylene bridges, each consisting of one, two or three carbon atoms, each linking two non-adjacent carbon atoms of the ring system. Representative examples of the bicyclic cycloalkenyl groups include, but are not limited to, 4,5,6,7-tetrahydro-3aH-indene, octahydronaphthalenyl and 1,6-dihydro-pentalene. The monocyclic and bicyclic cycloalkenyl can be attached to the parent molecular moiety through any substitutable atom contained within the ring systems, and can be unsubstituted or substituted.

The term “halo” or “halogen” as used herein, means Cl, Br, I, or F.

The term “haloalkyl” as used herein, means an alkyl group, as defined herein, in which one, two, three, four, five or six hydrogen atoms are replaced by halogen. Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, trifluoromethyl, difluoromethyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and trifluoropropyl such as 3,3,3-trifluoropropyl.

The term “heterocycle” or “heterocyclic” as used herein, means a monocyclic heterocycle, a bicyclic heterocycle, or a tricyclic heterocycle. The monocyclic heterocycle is a three-, four-, five-, six-, seven-, or eight-membered ring containing at least one heteroatom independently selected from the group consisting of O, N, and S. The three- or four-membered ring contains zero or one double bond, and one heteroatom selected from the group consisting of O, N, and S. The five-membered ring contains zero or one double bond and one, two or three heteroatoms selected from the group consisting of O, N and S. The six-membered ring contains zero, one or two double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. The seven- and eight-membered rings contains zero, one, two, or three double bonds and one, two, or three heteroatoms selected from the group consisting of O, N, and S. Representative examples of monocyclic heterocycles include, but are not limited to, azetidinyl, azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl, isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl, morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl, pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyridinyl, tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl, thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclic heterocycle fused to a phenyl group, or a monocyclic heterocycle fused to a monocyclic cycloalkyl, or a monocyclic heterocycle fused to a monocyclic cycloalkenyl, or a monocyclic heterocycle fused to a monocyclic heterocycle, or a bridged monocyclic heterocycle ring system in which two non adjacent atoms of the ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Representative examples of bicyclic heterocycles include, but are not limited to, benzopyranyl, benzothiopyranyl, chromanyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, azabicyclo[2.2.1]heptyl (including 2-azabicyclo[2.2.1]hept-2-yl), 2,3-dihydro-1H-indolyl, isoindolinyl, octahydrocyclopenta[c]pyrrolyl, octahydropyrrolopyridinyl, and tetrahydroisoquinolinyl. Tricyclic heterocycles are exemplified by a bicyclic heterocycle fused to a phenyl group, or a bicyclic heterocycle fused to a monocyclic cycloalkyl, or a bicyclic heterocycle fused to a monocyclic cycloalkenyl, or a bicyclic heterocycle fused to a monocyclic heterocycle, or a bicyclic heterocycle in which two non adjacent atoms of the bicyclic ring are linked by an alkylene bridge of 1, 2, 3, or 4 carbon atoms, or an alkenylene bridge of two, three, or four carbon atoms. Examples of tricyclic heterocycles include, but not limited to, octahydro-2,5-epoxypentalene, hexahydro-2H-2,5-methanocyclopenta[b]furan, hexahydro-1H-1,4-methanocyclopenta[c]furan, aza-adamantane (1-azatricyclo[3.3.1.13,7]decane), and oxa-adamantane (2-oxatricyclo[3.3.1.13,7]decane). The monocyclic, bicyclic, and tricyclic heterocycles are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the rings, and can be unsubstituted or substituted.

The term “heteroaryl” as used herein, means a monocyclic heteroaryl or a bicyclic heteroaryl. The monocyclic heteroaryl is a five- or six-membered ring. The five-membered ring contains two double bonds. The five-membered ring may contain one heteroatom selected from O or S; or one, two, three, or four nitrogen atoms and optionally one oxygen or sulfur atom. The six-membered ring contains three double bonds and one, two, three or four nitrogen atoms. Representative examples of monocyclic heteroaryl include, but are not limited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, 1,3-oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, 1,3-thiazolyl, thienyl, triazolyl, and triazinyl. The bicyclic heteroaryl consists of a monocyclic heteroaryl fused to a phenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or a monocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclic heteroaryl fused to a monocyclic heterocycle. Representative examples of bicyclic heteroaryl groups include, but are not limited to, benzofuranyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzoxadiazolyl, 6,7-dihydro-1,3-benzothiazolyl, benzotriazolyl, imidazo[1,2-a]pyridinyl, indazolyl, indolyl, isoindolyl, isoquinolinyl, naphthyridinyl, pyridoimidazolyl, quinolinyl, thiazolo[5,4-b]pyridin-2-yl, thiazolo[5,4-d]pyrimidin-2-yl, and 5,6,7,8-tetrahydroquinolin-5-yl. The monocyclic and bicyclic heteroaryl groups of the present invention can be substituted or unsubstituted and are connected to the parent molecular moiety through any carbon atom or any nitrogen atom contained within the ring systems.

The term “heteroatom” as used herein, means a nitrogen, oxygen, or sulfur atom.

The term “hydroxyl” or “hydroxy” as used herein, means an —OH group.

The term “oxo” as used herein, means a ═O group.

Compounds of the invention have the formula (I) as described above.

Particular values of variable groups in compounds of formula (I) are as follows. Such values may be used where appropriate with any of the other values, definitions, claims or embodiments defined hereinbefore or hereinafter.

More particularly, compounds of formula (I) can include, but are not limited to compounds wherein X is CH2, NC(O)OtBu, NH, or N-alkyl; and n is 1 or 2.

In another embodiment, Ar1is aryl or heteroaryl; and R1is aryl, heteroaryl, alkyl or hydrogen, wherein aryl and heteroaryl at each occurrence are independently substituted with 0, 1, 2, or 3, haloalkyl, halogen or —ORa, wherein Rais alkyl.

In another embodiment, L1is —(CH2)pC(O)—, wherein p is 1; L2is —N(R5)— or —N(R5)—(CH2)q; and Y is a bond or CR2R3; wherein R5is hydrogen or alkyl; q is 1 or 2; R2is hydrogen or phenyl; R3is hydrogen, alkyl, or cycloalkyl; or R2and R3taken together with the carbon atom to which they are attached form a cycloalkyl.

Yet in another embodiment, L1is —(CH2)p—; L2is —N(R5)—, —N(R5)—(CH2)q—, or —N(R5)—CH2CH(OH)CH2—; p is 2; q is 3; and Y is O or C(O).

In another embodiment, L1is —(CH2)pC(O); L2is —N(R5)—, —N(R5)—(CH2)q—, —NH—CH(R5)—(CH2)q—, —NH—CH(R5)—; p is 1, 2, or 3; q is 1, 2, or 3; Y is a bond, CR2, CH2CR2R3, or CR2R3; R2is hydrogen or phenyl, wherein the phenyl is either unsubstituted or further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, and haloalkyl; and R3and R5taken together are —(CH2)p—.

In yet another embodiment, L1is —(CH2)pC(O)—; L2is —N(R5)—, —N(R5)—(CH2)q—, —NH—CH(R5)—(CH2)q—, —NH—CH(R5)—; p is 1, 2, or 3; q is 1, 2, or 3; Y is a bond, CR2, CH2CR2R3, or CR2R3; R2is hydrogen or phenyl, wherein the phenyl is either unsubstituted or further substituted with 1, 2, or 3 substituents selected from the group consisting of alkyl, halogen, and haloalkyl; R4and R5taken together are a bond or —(CH2)s—; and s is 1.

In one embodiment, L1is —(CH2)p—; —N(R5)—(CH2)q—; p is 1, 2, or 3; q is 1 or 2; Y is a bond or CR2R3; R4and R5taken together are —(CH2)s—; and s is 1.

In another embodiment, L1is —(CH2)p—; —N(R5)—CH(R6)—; p is 1, 2, or 3; Y is a bond or CR2R3; R4and R6taken together are CH2; R5is hydrogen or alkyl.

Yet in another embodiment, L1is —(CH2)p—; L2is —N(R5)— or —N(R5)—(CH2)q—; p is 2 or 3; q is 1 or 3; R5is hydrogen or alkyl; and Y is O or CR2R3, wherein R2and R3are each hydrogen.

In one embodiment, L1is —(CH2)pC(O)—, wherein p is 1; L2is —N(R5)—, —N(R5)—(CH2)q— or —NH—CH(R5)—(CH2)q—; p is 1, 2, 3 or 4; q is 1, 2, or 3; R5is hydrogen, alkyl, or G1; Y is a bond, CR2R3, O, or S(O)2; R2is hydrogen or phenyl, wherein the phenyl is either unsubstituted or further substituted with 1, 2, or 3 halogen substituents; R3is hydrogen, alkyl, or hydroxyl; or R4and R5taken together are a bond or —(CH2)s— or —O—(CH2)s—, wherein s is 1.

In another embodiment, L1is —(CH2)p—, wherein in p is 1, 2 or 3; L2is —N(R5)—CH(R6)—; Y is a bond or CR2R3, wherein R2and R3are each hydrogen; R5is alkyl; and R4and R6taken together are CH2. In another embodiment, L1is —(CH2)p—, wherein in p is 1, 2 or 3; L2is (x); Y is a bond, CR2R3, CH2CR2R3, or CR2R3O, wherein R2and R3are each hydrogen. In one embodiment, L1-L2Y taken together are S(O)r, wherein r is 1 or 2.

In another embodiment, L1-L2Y taken together are S(O)2.

Specific embodiments of compounds contemplated as part of the invention include, but are not limited to:1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-{[6-(trifluoromethyl)pyridin-3-yl]methyl}acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-(1,3-thiazol-2-ylmethyl)acetamide;N-[(1-methyl-1H-pyrazol-3-yl)methyl]-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-(5-chloropyridin-2-yl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-benzyl-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-[3-(trifluoromethyl)benzyl]acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-[4-(trifluoromethyl)benzyl]acetamide;N-[cyclopropyl(phenyl)methyl]-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-(1-phenylcyclobutyl)acetamide;N-(4-fluorobenzyl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-(3,3-diphenylpropyl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-benzhydryl-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-(2,2-diphenylethyl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-(2,2-diphenylpropyl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;1-[2-(3,3-diphenylpyrrolidin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-[2-(3-benzylpiperazin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}-3,3-diphenylpyrrolidin-2-one;1-[2-oxo-2-(3-phenylpyrrolidin-1-yl)ethyl]-3,3-diphenylpyrrolidin-2-one;N-2,3-dihydro-1H-inden-2-yl-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;1-[2-(2,2-diphenylmorpholin-4-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-[2-(3,3-diphenylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-[2-(4,4-diphenylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-1,2,3,4-tetrahydronaphthalen-1-ylacetamide;4-[(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetyl]-1-[3-(trifluoromethyl)benzyl]piperazin-2-one;1-benzhydryl-4-[(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetyl]piperazin-2-one;1-[2-(4-benzhydrylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(diphenylmethylene)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[bis(4-fluorophenyl)(hydroxy)methyl]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(hydroxy {bis[3-(trifluoromethyl)phenyl]}methyl)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(5-methoxy-1H-indol-3-yl)-3,6-dihydropyridin-1(2H)-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(2,6-dichlorobenzyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-(2-oxo-2-{4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(4-fluorobenzyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;N-[(1-benzylpyrrolidin-3-yl)methyl]-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;N-(1-benzyl-3-methylpyrrolidin-3-yl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-{1-[3-(trifluoromethyl)benzyl]piperidin-4-yl}acetamide;1-[2-oxo-2-(4-{[3-(trifluoromethyl)benzyl]amino}piperidin-1-yl)ethyl]-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(2,4-dichlorobenzyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-[2-oxo-2-(4-{1-[3-(trifluoromethyl)phenyl]ethyl}piperazin-1-yl)ethyl]-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[(4-fluorophenyl)(phenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[(4-chlorophenyl)(phenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;N-(1-benzhydrylpiperidin-4-yl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;1-{2-[(2R)-4-benzhydryl-2-methylpiperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[(4aS,7aS)-6-benzhydryloctahydro-1H-pyrrolo[3,4-b]pyridin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[(4aR,7aR)-6-benzhydryloctahydro-1H-pyrrolo[3,4-b]pyridin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-(2-{4-[(2,2-diphenylethyl)amino]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(4-fluorophenyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-oxo-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}-3,3-diphenylpyrrolidin-2-one;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-{(3 aS*,4S*,6aR*)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-{(3 aS*,4R*,6aR*)-2-[3-(trifluoromethyl)benzyl]octahydrocyclopenta[c]pyrrol-4-yl}acetamide;1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-(2,2-diphenylpropyl)acetamide;3,3-bis(4-fluorophenyl)-1-(2-oxo-2-{4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)pyrrolidin-2-one;1-[2-(3,3-diphenylpyrrolidin-1-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;3,3-diphenyl-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;1-{2-[4-(3,5-dimethoxybenzyl)piperazin-1-yl]ethyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;4-benzhydryl-1-[2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)ethyl]piperazin-2-one;3,3-dimethyl-1-[2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)ethyl]-4-(thien-2-ylmethyl)piperazin-2-one;1-benzhydryl-4-[2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)ethyl]piperazin-2-one;3,3-diphenyl-1-{2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}pyrrolidin-2-one;1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;1-[2-(2,2-diphenylmorpholin-4-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;1-[2-oxo-2-(2-phenylmorpholin-4-yl)ethyl]-3,3-diphenylpiperidin-2-one;1-[2-(3,3-diphenylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;1-[2-(4,4-diphenylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;1-{2-[2-(4-fluorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{2-[2-(4-fluorophenyl)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;N-(6-fluoro-3,4-dihydro-2H-chromen-4-yl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-[2-(4-benzhydrylpiperidin-1-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;N-(2,2-diphenylpropyl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-(2-{4-[hydroxy(diphenyl)methyl]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;1-(2-oxo-2-{4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;1-(2-oxo-2-{4-[4-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;1-{2-[4-(3-chlorobenzyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;1-benzhydryl-4-[(2-oxo-3,3-diphenylpiperidin-1-yl)acetyl]piperazin-2-one;1-[2-oxo-2-(4-{[3-(trifluoromethyl)phenyl]sulfonyl}piperazin-1-yl)ethyl]-3,3-diphenylpiperidin-2-one;N-(1-benzhydrylpiperidin-4-yl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;N-(1-benzhydryl-3-methylpyrrolidin-3-yl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-{2-[4-(benzhydrylamino)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{2-[(4aS,7aS)-1-benzhydryloctahydro-6H-pyrrolo[3,4-b]pyridin-6-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;N-(1-benzyl-3-methylpyrrolidin-3-yl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)piperidin-2-one;1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3-phenylpiperidin-2-one;1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3-phenylpiperidin-2-one;1-(2-oxo-2-{4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)-3-phenylpiperidin-2-one;1-{2-[4-(2,4-dichlorobenzyl)piperazin-1-yl]-2-oxoethyl}-3-phenylpiperidin-2-one;1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-phenylpiperidin-2-one;1-{2-oxo-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}-3-phenylpiperidin-2-one;N-[1-(4-fluorophenyl)cyclobutyl]-2-(2-oxo-3-phenylpiperidin-1-yl)acetamide;1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-methyl-3-phenylpiperidin-2-one;3,3-diphenyl-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;tert-butyl 4-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3-oxo-2-phenylpiperazine-1-carboxylate;1-[2-(4-benzhydrylpiperazin-1-yl)-2-oxoethyl]-3-phenylpiperazin-2-one;1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-3-phenylpiperazin-2-one;1-(2-{4-[bis(4-fluorophenyl)methyl]piperazin-1-yl}-2-oxoethyl)-4-methyl-3-phenylpiperazin-2-one;1-{2-[[3-(3,5-dimethoxyphenoxy)propyl](methyl)amino]ethyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;1-{2-[[2-hydroxy-3-(quinolin-5-yloxy)propyl](methyl)amino]ethyl}-3,3-bis(4-methoxyphenyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[[2-hydroxy-3-(2-{(E)-2-[3-(methoxymethyl)isoxazol-5-yl]vinyl}phenoxy)propyl](methyl)amino]ethyl}pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[[2-hydroxy-3-(quinolin-5-yloxy)propyl](methyl)amino]ethyl}pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[4-(3,4,5-trimethoxybenzyl)piperazin-1-yl]ethyl}pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{3-[4-(3,4,5-trimethoxybenzyl)piperazin-1-yl]propyl}pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)pyrrolidin-2-one;N-{2-[3,3-bis(4-methoxyphenyl)-2-oxopyrrolidin-1-yl]ethyl}benzamide;1-{2-[2,3-dihydro-1H-inden-2-yl(methyl)amino]ethyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{3-[2,3-dihydro-1H-inden-2-yl(methyl)amino]propyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;1-{2-[[3-(3,5-dimethoxyphenoxy)propyl](methyl)amino]ethyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{3-[[3-(3,5-dimethoxyphenoxy)propyl](methyl)amino]propyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{3-[methyl(2-phenylethyl)amino]propyl}-3,3-diphenylpiperidin-2-one;1-{2-[[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino]ethyl}-3,3-diphenylpiperidin-2-one;1-{3-[[2-(3,5-dimethoxyphenyl)ethyl](methyl)amino]propyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[[2-(3-methoxyphenyl)ethyl](methyl)amino]ethyl}piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{3-[[2-(3-methoxyphenyl)ethyl](methyl)amino]propyl}piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[methyl(2-phenylethyl)amino]ethyl}piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{3-[methyl(2-phenylethyl)amino]propyl}piperidin-2-one;3,3-bis(4-methoxyphenyl)-1-{2-[[2-(3-methoxyphenyl)ethyl](methyl)amino]ethyl}piperidin-2-one;3,3-bis(4-methoxyphenyl)-1-{3-[[2-(3-methoxyphenyl)ethyl](methyl)amino]propyl}piperidin-2-one;1-{2-[[2-(2,4-dimethoxyphenyl)ethyl](methyl)amino]ethyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{3-[(3,5-dimethoxybenzyl)(methyl)amino]propyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;3-isopropyl-3-(3-methoxyphenyl)-1-{3-[[2-(3-methoxyphenyl)ethyl](methyl)amino]propyl}piperidin-2-one;1-{3-[[2-(4-fluorophenyl)ethyl](methyl)amino]propyl}-3-isopropyl-3-(3-methoxyphenyl)piperidin-2-one;3-isopropyl-3-(3-methoxyphenyl)-1-{2-[[2-(4-methoxyphenyl)ethyl](methyl)amino]ethyl}piperidin-2-one;1-{3-[4-(3,5-dimethoxybenzyl)piperazin-1-yl]propyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{2-[4-(3,5-dimethoxybenzyl)piperazin-1-yl]ethyl}-3,3-bis(4-methoxyphenyl)piperidin-2-one;1-{3-[4-(3,5-dimethoxybenzyl)piperazin-1-yl]propyl}-3-isopropyl-3-(3-methoxyphenyl)piperidin-2-one;3,3-diphenyl-1-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]piperidin-2-one;3,3-bis(4-fluorophenyl)-1-[3-(4-pyrimidin-2-ylpiperazin-1-yl)propyl]piperidin-2-one;3,3-bis(4-fluorophenyl)-1-[2-(4-pyrimidin-2-ylpiperazin-1-yl)ethyl]piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-[4-(2-methoxyphenyl)piperazin-1-yl]ethyl}piperidin-2-one;3,3-bis(4-fluorophenyl)-1-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propyl}piperidin-2-one;3,3-bis(4-fluorophenyl)-1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)piperidin-2-one;3,3-diphenyl-1-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)piperidin-2-one;3,3-diphenyl-1-(2-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}ethyl)piperidin-2-one;3,3-bis(4-fluorophenyl)-1-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)piperidin-2-one;N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methyl-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;3,3-diphenyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{[3-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-2-one;3,3-diphenyl-1-{[3-(trifluoromethyl)phenyl]sulfonyl}piperidin-2-one;1-[(3-{[(cis-2,6-dimethylmorpholin-4-yl]carbonyl}phenyl)sulfonyl]-3,3-diphenylpyrrolidin-2-one;3,3-diphenyl-1-{[2-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-2-one;3,3-diphenyl-1-{[4-(trifluoromethyl)phenyl]sulfonyl}pyrrolidin-2-one;N-cyclopropyl-3-[(2-oxo-3,3-diphenylpyrrolidin-1-yl)sulfonyl]benzamide;1-{[2-chloro-4-(trifluoromethyl)phenyl]sulfonyl}-3,3-diphenylpyrrolidin-2-one;1-[2-(7-benzyl-2,7-diazaspiro[3.5]non-2-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-(2-oxo-2-{7-[4-(trifluoromethyl)benzyl]-2,7-diazaspiro[3.5]non-2-yl}ethyl)pyrrolidin-2-one;1-{[3-(1H-indazol-5-yl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;3,3-diphenyl-1-(3-{3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}propyl)pyrrolidin-2-one;1-({4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-3,3-diphenylpyrrolidin-2-one;1-({4-methyl-2-[3-(trifluoromethyl)phenyl]-1,3-thiazol-5-yl}methyl)-3,3-diphenylpyrrolidin-2-one;1-{2-[4-(4-chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{2-[4-(3-chlorophenoxy)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{2-[4-(3,4-difluorophenoxy)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{2-[4-(4-methoxyphenoxy)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-(2-oxo-2-{4-[3-(trifluoromethyl)phenoxy]piperidin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;1-(2-{4-[(benzyloxy)imino]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;1-(2-oxo-2-{4-[5-(trifluoromethyl)-1H-1,2,3-benzotriazol-1-yl]piperidin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-piperidin-4-yl-N-[4-(trifluoromethyl)phenyl]acetamide;1-{2-[3-(3,4-dimethoxybenzyl)-3-methylpiperazin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;N-(1,3-oxazol-2-ylmethyl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;1-{2-[4-(2,4-dichlorobenzyl)piperazin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;1-(2-{4-[bis(4-fluorophenyl)methylene]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;1-[2-(3,3-diphenylpyrrolidin-1-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)piperidin-2-one;1-[2-(4,4-diphenylpiperidin-1-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)piperidin-2-one;1-[2-(3,3-diphenylpyrrolidin-1-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;3,3-bis(4-fluorophenyl)-1-(2-oxo-2-{-4-[3-(trifluoromethyl)benzyl]piperazin-1-yl}ethyl)piperidin-2-one;N-(1-benzhydrylazetidin-3-yl)-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;3,3-diphenyl-1-({3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}-3-phenylpiperidin-2-one;3,3-diphenyl-1-({3-[3-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-{1-[3-(trifluoromethyl)benzyl]azetidin-3-yl}acetamide;3-phenyl-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;benzyl 4-[(2-oxo-3,3-diphenylpiperidin-1-yl)acetyl]piperazine-1-carboxylate;N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]piperidin-4-yl}-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-(2-{4-[4-fluoro-3-(trifluoromethyl)benzyl]piperazin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-{(3S)-1-[3-(trifluoromethyl)benzyl]pyrrolidin-3-yl}acetamide;2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-{(3R)-1-[3-(trifluoromethyl)benzyl]pyrrolidin-3-yl}acetamide;(3S)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-phenylpiperidin-2-one;(3R)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-phenylpiperidin-2-one;3-(4-fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;N-(5-chloropyridin-2-yl)-2-(2-oxo-3-phenylpiperidin-1-yl)acetamide;1-{[3-(4-chlorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;1-{[3-(4-fluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;1-{[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;3,3-diphenyl-1-({5-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-3-yl}methyl)pyrrolidin-2-one;N-methyl-2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-{1-[3-(trifluoromethyl)benzyl]piperidin-4-yl}acetamide;N-{1-[4-fluoro-3-(trifluoromethyl)benzyl]azetidin-3-yl}-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;3,3-diphenyl-1-({3-[4-(trifluoromethoxy)phenyl]-1,2,4-oxadiazol-5-yl}methyl)piperidin-2-one;2-(2-oxo-3,3-diphenylpiperidin-1-yl)-N-{1-[3-(trifluoromethyl)benzyl]piperidin-4-yl}acetamide;N-{1-[2-fluoro-3-(trifluoromethyl)benzyl]azetidin-3-yl}-2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetamide;1-{[3-(4-tert-butylphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[3,3-bis(4-fluorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-3,3-diphenylpyrrolidin-2-one;1-{2-[3,3-bis(4-fluorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;1-{2-[3,3-bis(4-fluorophenyl)pyrrolidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-{[3-(4-hydroxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;1-{[3-(4-chlorobenzyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-{1-[3-(trifluoromethyl)benzyl]piperidin-4-yl}acetamide;1-{[3-(4-isobutoxyphenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpiperidin-2-one;3,3-bis(4-fluorophenyl)-1-(2-oxo-2-{(4aS,7aS)-1-[3-(trifluoromethyl)benzyl]octahydro-6H-pyrrolo[3,4-b]pyridin-6-yl}ethyl)pyrrolidin-2-one;3,3-diphenyl-1-({3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-({3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;1-({3-[2-(4-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-3,3-diphenylpiperidin-2-one;1-{[3-(6-chloropyridin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;1-{[3-(3,5-difluorophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;3-(4-fluorophenyl)-1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}pyrrolidin-2-one;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]acetamide;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[4-(trifluoromethyl)phenyl]acetamide;3,3-diphenyl-1-({3-[5-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3,3-diphenyl-1-({3-[4-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3,3-diphenyl-1-[(3-pyridin-3-yl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidin-2-one;3,3-diphenyl-1-[(3-pyridin-4-yl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidin-2-one;1-{4-oxo-4-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]butyl}-3,3-diphenylpyrrolidin-2-one;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-(5-chloropyridin-2-yl)acetamide;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[6-(trifluoromethyl)pyridin-2-yl]acetamide;1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-(4-fluorophenyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}pyrrolidin-2-one;2-[3-(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-[5-(trifluoromethyl)pyridin-2-yl]acetamide;3,3-diphenyl-1-[(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidin-2-one;tert-butyl 5-{5-[(2-oxo-3,3-diphenylpyrrolidin-1-yl)methyl]-1,2,4-oxadiazol-3-yl}pyridin-2-ylcarbamate;3,3-bis(4-fluorophenyl)-1-[(3-pyrazin-2-yl-1,2,4-oxadiazol-5-yl)methyl]pyrrolidin-2-one;1-{[3-(4-bromophenyl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;1-{[3-(6-aminopyridin-3-yl)-1,2,4-oxadiazol-5-yl]methyl}-3,3-diphenylpyrrolidin-2-one;4-(5-{[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]methyl}-1,2,4-oxadiazol-3-yl)benzonitrile;(3S)-3-(4-fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;(3R)-3-(4-fluorophenyl)-1-({3-[4-(trifluoromethyl)phenyl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;3-(4-fluorophenyl)-1-({3-[6-(trifluoromethyl)pyridin-3-yl]-1,2,4-oxadiazol-5-yl}methyl)pyrrolidin-2-one;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-{1-[3-fluoro-4-(trifluoromethyl)benzyl]azetidin-3-yl}acetamide;1-(2-oxo-2-{3-[4-(trifluoromethyl)phenyl]azetidin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;4-{1-[(2-oxo-3,3-diphenylpiperidin-1-yl)acetyl]azetidin-3-yl}benzonitrile;N-(1-benzylazetidin-3-yl)-2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]acetamide;1-(2-oxo-2-{4-[3-(trifluoromethyl)phenyl]piperidin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;1-{2-[4-(4-fluorophenyl)piperidin-1-yl]-2-oxoethyl}-3,3-diphenylpiperidin-2-one;1-(2-oxo-2-{4-[4-(trifluoromethyl)phenyl]piperidin-1-yl}ethyl)-3,3-diphenylpiperidin-2-one;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-[6-(trifluoromethyl)pyridin-2-yl]acetamide;2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide;N-[3-chloro-5-(trifluoromethyl)pyridin-2-yl]-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;1-(2-{4-[4-chloro-3-(trifluoromethyl)phenyl]-4-hydroxypiperidin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one;N-(5-cyanopyridin-2-yl)-2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetamide;2-[3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl]-N-(5-cyanopyridin-2-yl)acetamide;1-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3-(4-fluorophenyl)pyrrolidin-2-one;3-(4-fluorophenyl)-1-{2-oxo-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}pyrrolidin-2-one;1-[2-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3-(4-fluorophenyl)pyrrolidin-2-one;1-[2-(7-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3-(4-fluorophenyl)pyrrolidin-2-one;1-[2-(6-chloro-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3-(4-fluorophenyl)pyrrolidin-2-one;1-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;3,3-bis(4-fluorophenyl)-1-{2-oxo-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}pyrrolidin-2-one;1-[2-(3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl]-3,3-diphenylpiperidin-2-one;1-{2-oxo-2-[7-(trifluoromethyl)-3,4-dihydroisoquinolin-2(1H)-yl]ethyl}-3,3-diphenylpiperidin-2-one;1-({3-[2-(2-chlorophenyl)ethyl]-1,2,4-oxadiazol-5-yl}methyl)-3,3-diphenylpiperidin-2-one;1-({3-[(4-chlorophenoxy)methyl]-1,2,4-oxadiazol-5-yl}methyl)-3,3-diphenylpiperidin-2-one;(+)-3-(4-fluorophenyl)-1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}pyrrolidin-2-one;(−)-3-(4-fluorophenyl)-1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}pyrrolidin-2-one;1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]-3-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}-3-[4-(trifluoromethyl)phenyl]pyrrolidin-2-one;3-(2-chloro-4-fluorophenyl)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]pyrrolidin-2-one;3-(2-chloro-4-fluorophenyl)-1-{2-oxo-2-[5-(trifluoromethyl)-1,3-dihydro-2H-isoindol-2-yl]ethyl}pyrrolidin-2-one;3-(3,4-dichlorophenyl)-1-[2-(5-fluoro-1,3-dihydro-2H-isoindol-2-yl)-2-oxoethyl]pyrrolidin-2-one;1-(2-{4-[bis(4-fluorophenyl)(hydroxy)methyl]piperidin-1-yl}-2-oxoethyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one;1-(2-{4-[bis(4-fluorophenyl)(hydroxy)methyl]piperidin-1-yl}-2-oxoethyl)-3,3-diphenylpiperidin-2-one; or1-(2-(4-(bis(4-fluorophenyl)methyl)piperazin-1-yl)-2-oxoethyl)-4-isopropyl-3-phenylpiperazin-2-one.

Compounds of the present application may exist as stereoisomers wherein, asymmetric or chiral centers are present. These stereoisomers are “R” or “S” depending on the configuration of substituents around the chiral carbon atom. The terms “R” and “S” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30.

On occasion, the relative stereochemistry of an enantiomeric pair is known, however, the absolute configuration is not known. In that circumstance, the relative stereochemistry descriptor terms “R*” and “S*” are used. The terms “R*” and “S*” used herein are defined in Eliel, E. L.; Wilen, S. H. Stereochemistry of Organic Compounds; John Wiley & Sons, Inc.: New York, 1994; pp 119-120 and 1206. In a particular enantiomeric pair, the relative descriptors are reversed to indicate that this pair of enantiomers is of unknown absolute stereochemistry.

The present application contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this application. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of compounds of the present application may be prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution which is well known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.

Geometric isomers may exist in the present compounds. The invention contemplates the various geometric isomers and mixtures thereof resulting from the disposition of substituents around a carbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkyl group, or a heterocycle group. Substituents around a carbon-carbon double bond or a carbon-nitrogen bond are designated as being of Z or E configuration and substituents around a cycloalkyl or a heterocycle are designated as being of cis or trans configuration.

Within the present invention it is to be understood that compounds disclosed herein may exhibit the phenomenon of tautomerism.

Thus, the formulae drawings within this specification can represent only one of the possible tautomeric or stereoisomeric forms. It is to be understood that the invention encompasses any tautomeric or stereoisomeric form, and mixtures thereof, and is not to be limited merely to any one tautomeric or stereoisomeric form utilized within the naming of the compounds or formulae drawings.

Compounds of this invention can exist in an isotopic form containing one or more atoms having an atomic mass or mass number different from the atomic mass or mass number most abundantly found in nature. Isotopes of atoms such as hydrogen, carbon, phosphorous, sulfur fluorine, chlorine, and iodine include, but are not limited to2H,3H,11C,14C,32P,35S,18F,36Cl, and125I, respectively. Compounds that contain other isotopes of these and/or other atoms are within the scope of this invention. Compounds containing tritium (3H) and14C radioisotopes are preferred in general for their ease in preparation and detectability for radiolabeled compounds. Isotopically labeled compounds of this invention can be prepared by the general methods well known to persons having ordinary skill in the art. Such Isotopically labeled compounds can be conveniently prepared by carrying out the procedures disclosed in the Examples and Schemes below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

C. BIOLOGICAL DATA

Abbreviations which have been used in the descriptions of Biological Data that follow are: EDTA for ethylenediaminetetraacetic acid; FBS for fetal bovine serum; FLIPR for fluorometric imaging plate reader; HBSS for Hank's balanced salt solution; HEPES for 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid; i.p. for intraperitoneal; MEM for minimum essential medium; MEM NEAA for minimum essential medium non-essential amino acid; p.o. for per orem (by mouth).

(i) In Vitro Methods—Assessment of Calcium Channel Activity Using FLIPR:

IMR32 cells endogenously expressing human Cav2.2 were assayed for Ca2+influx using a no-wash calcium indicator dye (Calcium 4 dye: Molecular Probes) and FLIPR technology (Lubin, M. L.; Reitz, T. L.; Todd, M. J.; Flores, C. M.; Qin, N.; Xin, H. A nonadherent cell-based HTS assay for N-type calcium channel using calcium 3 dye. Assay and Drug Development Technologies 2006, 4(6), 689-694). The IMR32 cells were maintained in MEM media containing 10% (v/v) FBS, 1% (v/v) antibiotic/antimitotic, 1% (v/v) sodium pyruvate and 1% (v/v) MEM NEAA. Following dissociation in 0.05% (v/v) trypsin/EDTA, cells were seeded into black 1×96-well plates (Corning Cellbind) at a density of 1-1.2×105cells/well and incubated in the maintenance media above for 48 hours at 37° C. Immediately prior to performing the assay the media was removed and cells were loaded for 1.5 hours with 1× Calcium 4 dye prepared in HBSS (137 mM NaCl, 5.4 mM KCl, 0.25 mM Na2HPO4, 0.44 mM KH2PO4, 1.3 mM CaCl2, 1 mM MgSO4, 4.2 mM NaHCO3) containing HEPES pH 7.4 at room temperature. After dye loading and a subsequent 60 minute pre-incubation with compounds (full log dilutions from 10 μM to 0.1 nM) in the presence of 1.3 mM CaCl2and 2 μM nifedipine to block endogenous L-type channels, the external Ca2+concentration was increased to 5 mM CaCl2and the cells concomitantly depolarized with 80 mM KCl to assay channel activity. To determine the IC50values, the percent inhibition of the compound at each concentration was determined relative to the activity in the absence of inhibitor, and data was fitted using non-linear regression sigmoidal dose response curve analysis with GraphPad Prism®.

Sprague Dawley rats were briefly restrained, and capsaicin was administered at 10 μg in 10 μL of vehicle by intraplantar injection into the center of the right hind paw. Secondary mechanical hyperalgesia (SMH) was measured at the heel away from the site of injection 180 minutes following capsaicin exposure. Compounds and gabapentin (positive control), were administered p.o. 60 minutes before testing (2 hours after capsaicin) or i.p. 30 minutes before testing (2.5 hours after capsaicin). SMH was measured using calibrated von Frey filaments (Stoelting, Woodale, Ill.). Following the 1 hour habituation in the testing room, rats were moved to individual plexiglass chambers that sit on top of a wire mesh to allow for access for stimulation of the plantar surface of the hind paws. Rats were allowed to acclimate to the new chambers for 15 minutes before the onset of testing. The paw withdrawal threshold was determined by increasing and decreasing stimulus intensity (force: g) and calculated using Dixon's up-down method (Chaplan, S. R.; Bach, F. W.; Pogrel, J. W.; Chung, J. M.; Yaksh, T. L.; Quantitative assessment of tactile allodynia in the rat paw. J. Neuroscience Methods 1994, 53(1), 55-63). The filaments (maximum force of 15.0 g) were held in place for 8 seconds or until there was a withdrawal response from the mechanical stimulation.

D. METHODS OF USING THE COMPOUNDS

One embodiment of the present invention provides a method of treating pain in a subject in need thereof. The method comprises administering to the subject, including a mammal, such as a human, a therapeutically suitable amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof. Conditions related to pain include acute pain, chronic pain, neuropathic pain, inflammatory pain, visceral pain, cancer pain, allodynia, fibromyalgia, sciatica, back pain, and headache pain including migraine, or combinations thereof. Preferably, the method comprises administering to the mammal a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof. In certain embodiments, the method comprises administering to the mammal a therapeutically effective amount of any of the compounds as described herein, or a pharmaceutically acceptable salt thereof, in combination with one or more of the following: nonsteroidal anti-inflammatory drug (NSAID), opioid analgesic, barbiturate, benzodiazapine, histamine antagonist, sedative, skeletal muscle relaxant, transient receptor potential ion channel antagonist, α-adrenergic, tricyclic antidepressant, anticonvulsant, tachykinin antagonist, muscarinic antagonist, cyclooxygenase-2 selective inhibitor, neuroleptic, vanilloid receptor agonist, vanilloid receptor antagonist, β-adrenergic, local anesthetic, corticosteroid, 5-HT receptor agonist, 5-HT receptor antagonist, 5-HT2Areceptor antagonist, cholinergic analgesic, α2δ ligand such as gabapentin or pregabalin, cannabinoid receptor ligand, metabotropic glutamate subtype 1 receptor antagonist, serotonin reuptake inhibitor, norepinephrine reuptake inhibitor, dual serotonin-noradrenaline reuptake inhibitor, Rho kinase inhibitor, inducible nitric oxide synthase inhibitor, acetylcholinesterase inhibitor, prostaglandin E2subtype 4 antagonist, leukotriene B4 antagonist, 5-lipoxygenase inhibitor, sodium channel blocker, 5-HT3 antagonist, N-methyl-D-aspartic acid receptor antagonist, and phosphodiesterase V inhibitor.

Yet another embodiment of the present invention relates to a method for providing a method for treating disorders of the central nervous system including stroke, epilepsy, manic depression, bipolar disorders, depression, anxiety, schizophrenia, migraine, and psychoses; neural degenerative disorders including Alzheimer's disease, AIDS related dementia, Parkinson's disease, neuropathy caused by head injury, and dementia caused by cerebrovascular disorders; disorders of the lower urinary tract including overactive bladder, prostatis, prostadynia, interstitial cystitis, and benign prostatic hyperplasia; disorders caused by psychogenic stress including bronchial asthma, unstable angina, and hypersensitive colon inflammation; cardiovascular disorders including hypertension, atherosclerosis, heart failure, and cardiac arrhythmias; drug addiction withdrawal symptoms, including ethanol addiction withdrawal symptoms; skin disorders including pruritis and allergic dermatitis, inflammatory bowel disease; cancer; diabetes; and infertility and sexual dysfunction in a mammal in need of such treatment. This method comprises administering to the mammal (including human) a therapeutically effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.

An increase in intracellular calcium concentration has been correlated with seizure activity (Heinemann, U.; Lux, H. D.; Gutnick, M. J. Extracellular free calcium and potassium during paroxysmal activity in the cerebral cortex of the cat. Exp. Brain Res. 1977, 27, 237-243). Several studies have indicated that calcium channel blockers produce anticonvulsant activity (Vezzani, A.; Wu, H. Q.; Stasi, M. A.; Angelico, P.; Samanin, R. Effects of various calcium channel blockers on three different models of limbic seizures in rats. Neuropharmacology 1988, 27(5), 451-458. Otoom, S.; Hasan, Z. Nifedipine inhibits picrotoxin-induced seizure activity: further evidence on the involvement of L-type calcium channel blockers in epilepsy. Fundamental & Clinical Pharmacology 2006, 20, 115-119).

Calcium channel blockers have been evaluated in the treatment of bipolar disorders and manic depression for decades. There are suggestions that the calcium channel subtype has influence on efficacy of these disorders (Gitlin, M. Treatment-resistant bipolar disorder. Molecular Psychiatry 2006, 11, 227-240. Levy, N. A.; Janicak, P. G. Bipolar Disorders 2000, 2, 108-119).

Calcium channel blockers have also been associated with the treatment of anxiety and depression (Saade, S.; Balleine, B. W.; Minor, T. R. The L-type calcium channel blocker nimodipine mitigates “learned helplessness” in rats. Pharmacology, Biochemistry and Behavior 2003, 74, 269-278).

Several cardiac disorders are treated with calcium channel blockers. Atherosclerosis may be reduced by a decrease in free radical-mediated damage as a result of influence on the biophysical properties of membranes (Mason, R. P.; Mak, I. T.; Walter, M. F.; Tulenko, T. N.; Mason, P. E. Antioxidant and cytoprotective activities of the calcium channel blocker mibefradil. Biochemical Pharmacology 1998, 55, 1843-1852). Hypertension and angina are both successfully treated with calcium channel blockers (Croom, K. F.; Wellington, K. Modified-release nifedipine: A review of the use of modified-release formulations in the treatment of hypertension and angina pectoris. Drugs 2006, 66(4), 497-528).

Ion channels including calcium channels play an important role in sperm physiology and fertilization (Darszon, A.; Labarca, P.; Hishigaki, T.; Espinosa, F. Ion channels in sperm physiology. Physiological Reviews 1999, 79(2), 481-510).

Increased calcium levels in neurones has been implicated in Alzheimer's disease. Two suggested mechanisms of increased calcium influx are that β-amyloid may form calcium permeable channels (Bhatia, R.; Lin, H.; Lal, R. Fresh and globular amyloid beta protein (1-42) induces rapid cellular degeneration: evidence for AβP channel-mediated cellular toxicity. FASEB J. 2000, 14(9), 1233-1243) or a G-protein-coupled receptor may be activated by β-amyloid (Lorton, D. β-Amyloid induced IL-1β release from an activated human monocyte cell line is calcium- and G-protein-dependent. Mech. Ageing Dev. 1997, 94(1-3), 199-211).

Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention can be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

Compounds of the invention can also be administered as a pharmaceutical composition comprising the compounds of interest in combination with one or more pharmaceutically acceptable carriers. The phrase “therapeutically effective amount” of the compound of the invention means a sufficient amount of the compound to treat disorders, at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well-known in the medical arts. For example, it is well within the skill of the art to start doses of the compound at levels lower than required to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.

The total daily dose of the compounds of this invention administered to a human or other animal range from about 0.01 mg/kg body weight to about 100 mg/kg body weight. More preferable doses can be in the range of from about 0.01 mg/kg body weight to about 30 mg/kg body weight. If desired, the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions may contain such amounts or submultiples thereof to make up the daily dose.

The present invention further provides pharmaceutical compositions that comprise compounds of the present invention or a pharmaceutically acceptable salt or solvate thereof. The pharmaceutical compositions comprise compounds of the present invention that may be formulated together with one or more non-toxic pharmaceutically acceptable carriers.

The pharmaceutical compositions of this invention can be administered to humans and other mammals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally or as an oral or nasal spray. The term “parenterally” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.

Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such carriers as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned carriers.

Besides inert diluents, the oral compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfuming agents.

Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating carriers or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers or propellants which may be required. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.

The compounds of the present invention can be used in the form of pharmaceutically acceptable salts derived from inorganic or organic acids. The phrase “pharmaceutically acceptable salt” means those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like and are commensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al. describe pharmaceutically acceptable salts in detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable organic acid. Representative acid addition salts include, but are not limited to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate (isothionate), lactate, malate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as, but not limited to, methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as, but not limited to, decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides; arylalkyl halides like benzyl and phenethyl bromides and others. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which can be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and such organic acids as acetic acid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinic acid and citric acid.

Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as, but not limited to, the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as, but not limited to, lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium, trimethylammonium, triethylammonium, diethylammonium, ethylammonium and the like. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as used herein, represents those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use.

The present invention contemplates compounds of the invention formed by synthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well as solvated forms, including hydrated forms, such as hemi-hydrates. In general, the solvated forms, with pharmaceutically acceptable solvents such as water and ethanol among others are equivalent to the unsolvated forms for the purposes of the invention.

F. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention when prepared by synthetic processes or by metabolic processes. Preparation of the compounds by metabolic processes includes those occurring in the human or animal body (in vivo) or processes occurring in vitro.

The compounds of the invention may be prepared by a variety of processes well known for the preparation of compounds of this class. For example, the compounds of the invention wherein the groups Ar1, Ar2, L1, L2, n, R1, R4, X, and Y, have the meanings as set forth in the summary section unless otherwise noted, can be synthesized as shown in Schemes 1-16.

Abbreviations which have been used in the descriptions of the Schemes and the Examples that follow are: Boc for t-butoxy carbonyl; Bu for butyl; Et for ethyl, EtOH for ethanol; DMF or N,N-dimethylformamide; DMSO for dimethyl sulfoxide; KOtBu for potassium tert-butoxide; MeOH for methanol; NEt3for triethylamine; Ph for phenyl; psi for pounds per square inch; tBu for tert-butyl; and THF for tetrahydrofuran.

Compounds of formula (3), wherein Ar1, Ar2, L2, n, p, R1, R4, X and Y are as defined in formula (I), may be prepared as illustrated in Scheme 1. The treatment of compounds of formula (1) with Br(CH2)pCOEt in the presence of a base such as potassium t-butoxide, potassium hydride, or sodium ethoxide in a solvent such as tetrahydrofuran or dioxane at a temperatures of 20-100° C. for 4 to 24 hours supplies the corresponding alkylated lactam. Subsequent treatment with a base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide in a mixture of ethanol and water at 20-100° C. for 1 to 12 hours provides the corresponding carboxylic acid of formula (2). Coupling of carboxylic acid (2) with H-L2Y—Ar2—R4, wherein the H is a hydrogen on a nitrogen atom contained on a primary or secondary amine or as part of a heterocyclic ring, forms an amide bond and yields compounds of formula (3) which are representative of compounds of formula (I). Examples of conditions known to generate amides from a mixture of a carboxylic acid and an amine include but are not limited to adding a coupling reagent such as but not limited to N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (EDCI), 1,3-dicyclohexylcarbodiimide (DCC), bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU), O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate (TBTU), and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (HBTU). The coupling reagents may be added as a solid, a solution or as the reagent bound to a solid support resin. In addition to the coupling reagents, auxiliary-coupling reagents may facilitate the coupling reaction. Auxiliary coupling reagents that are often used in the coupling reactions include but are not limited to N,N-dimethylpyridin-4-amine (DMAP), 1-hydroxy-7-azabenzotriazole (HOAT) and 1-hydroxybenzotriazole hydrate (HOBT). The reaction may be carried out optionally in the presence of a base such as triethylamine or diisopropylethylamine. The coupling reaction may be carried out in solvents such as but not limited to tetrahydrofuran, N,N-dimethylformamide, dichloromethane, and ethyl acetate. The reaction may be conducted at ambient or elevated temperatures.

Alternatively, compounds of formula (3) may be prepared from compounds of formula (2) by first forming the corresponding acid chloride. Compounds of formula (2), may be treated with oxalyl chloride or thionyl chloride in a solvent such as dichloromethane or toluene at room temperature over 1 to 12 hours to form the intermediate acid chloride. Subsequent treatment with H-L2Y—Ar2—R4affords compounds of formula (3). Less reactive amines may require elevated temperatures to achieve complete reaction, and this can be realized in a solvent such as dichloroethane or toluene at temperatures of 30-100° C. over 1-12 hours.

Compounds of formula (5) wherein Ar1and R1are as described in formula (I) which are representative of compounds of formula (1) are prepared with the following procedures. Furanones of formula (4) can be treated with ammonia and zinc chloride in an autoclave at temperatures of 150-250° C. for 12 to 36 hours to produce compounds of formula (5) wherein RAis hydrogen. Alternatively, treatment of compounds of formula (4) with a primary amine such as 2-aminoethanol or 3-aminopropanol at 80-120° C. for 8 to 24 hours supplies compounds of formula (5) wherein RAis a group such as hydroxyethyl or hydroxypropyl.

Compounds of formula (5) wherein RAis hydrogen, can also be prepared by combining compounds of formula (6) and formula (7) at or near 0° C., wherein RBis methyl or ethyl, in the presence of a base such as lithium diisopropylamide or the sodium salt of triphenylmethane in a solvent such as tetrahydrofuran as described in the literature (Stamm, H.; Woderer, A.; Wiesert, W. Chem. Ber. 1981, 114, 32-48) and gradually allowed to warm to room temperature.

Compounds of formula (9) wherein Ar1and R1are as described in formula (I) which are representative of compounds of formula (1) are prepared by the following sequence. Compounds of formula (7), wherein R1is aryl or heteroaryl, are dissolved in a base such as tetrahydrofuran or dioxane, cooled to a temperature less than −40° C., and treated with a base such as lithium bis(trimethylsilyl)amide or lithium diisopropylamine. After warming to or near 0° C., the reaction mixture is cooled to less than −40° C., and then a solution of bromoacetonitrile is added. After gradually warming to room temperature over 2 or more hours, compounds of formula (8) are obtained. Compounds of formula (8) are hydrogenated (15-100 pounds per square inch) for 4 to 24 hours in a solvent such as acetic acid or ethanol, in the presence of a catalyst such as platinum oxide to supply compounds of formula (9). Alternatively, the reduction and subsequent cyclization from compounds of formula (8) to compounds of formula (9) can be accomplished with hydrogen and a catalyst such as Raney®-nickel in a solvent mixture of ammonia in methanol.

Compounds of formula (11) wherein Ar1and R1are as described in formula (I) which are representative of compounds of formula (1) are prepared by the following sequence. Compounds of formula (7), wherein R1is alkyl, aryl, or heteroaryl, are dissolved in ethanol and treated with sulfuric acid at reflux over 4-16 hours. The intermediate ester can be dissolved in a solvent such as dioxane or tetrahydrofuran and treated with a base such as sodium ethoxide, sodium methoxide, or sodium t-butoxide for 30 minutes to 2 hours at a temperature of 20 to 60° C. Addition of acrylonitrile with continued heating at 40-80° C. for an additional 30 minutes to 2 hours furnishes compounds of formula (10). The reduction and subsequent cyclization from compounds of formula (10) to compounds of formula (11) can be accomplished by hydrogenation (15-50 pounds per square inch) in the presence of a catalyst such as Raney®-nickel in a solvent mixture of ammonia in methanol.

Compounds of formula (14), (15), and (16), wherein Ar1, Ar2, L2, p, R4, and Y are as defined in formula (I) may be prepared as illustrated in Scheme 5. Compounds of formula (12) can be converted to the corresponding carbamate of formula (13) by treating with di-tert-butyl dicarbonate in the presence of a base such as triethylamine in a solvent such as dichloromethane. Compounds of formula (13) are converted to compounds of formula (14) by the methods described in Scheme 1. Compounds of formula (14) give compounds of formula (15) when treated with trifluoroacetic acid in methylene chloride or hydrochloric acid in dioxane. Compounds of formula (16) are prepared from compounds of formula (15) by reacting with an aldehyde or ketone in a solvent such as methanol in the presence of sodium cyanoborohydride or sodium triacetoxyborohydride and an acid such as acetic acid. Compounds of formulas (14), (15), and (16) are representative of compounds of formula (I).

Compounds of formula (19), wherein Ar1, Ar2, L2, n, R1, R4, and Y are as defined in formula (I) and j is 1, 2 or 3 may be prepared as illustrated in Scheme 6. Compounds of formula (17) which may be prepared which can be prepared as described in Scheme 2 are treated with carbon tetrabromide in the presence of triphenylphosphine in a solvent such as dichloromethane to provide compounds of formula (18). Compounds of formula (18) may be treated with H-L2Y—Ar2—R4, wherein the H is a hydrogen on a nitrogen atom contained on a primary or secondary amine or as part of a heterocyclic ring, in the presence of a base such as sodium hydride, triethylamine, or potassium carbonate optionally with a catalytic amount of potassium iodide in a solvent such as N,N-dimethylformamide, acetonitrile, toluene or ether optionally heated to provide compounds of formula (19). Compounds of formula (19) are representative of compounds of formula (I).

Compounds of formula (19), wherein Ar1, Ar2, L2, n, R1, R4, and Y are as defined in formula (I) and j is 1, 2 or 3 may be prepared as illustrated in Scheme 7. Compounds of formula (17) which can be prepared as described in Scheme 2 are treated with an oxidant such as Dess-Martin periodinane in a solvent such as dichloromethane or under Swern oxidation conditions to give aldehydes of formula (20). Compounds of formula (20) are transformed to compounds of formula (19) by treating with H-L2Y—Ar2—R4, wherein the H is a hydrogen on a nitrogen atom contained on a primary or secondary amine or as part of a heterocyclic ring, in the presence of a reducing agent such as sodium cyanoborohydride or sodium triacetoxyborohydride and optionally in the presence of an acid such as acetic acid in a solvent such as methanol. Compounds of formula (19) are representative of compounds of formula (I).

Compounds of formula (26), wherein Ar1, Ar2, L2, n, R1, R2, R3, R4, and X are as defined in formula (I) and j is 1, 2 or 3 can be prepared as illustrated in Scheme 8. Compounds of formula (21); wherein L2has a primary amine, secondary amine, or amine contained in a heterocycle protected as a carbamate; when treated with carbon tetrabromide in the presence of triphenylphosphine in a solvent such as dichloromethane or tetrahydrofuran provide compounds of formula (22). Compounds of formula (22) can be reacted with compounds of formula (1) in the presence of a base such as potassium t-butoxide in a solvent such as tetrahydrofuran at a temperature of 60-75° C. for 8 to 24 hours to supply compounds of formula (23). The t-butoxy carbonyl protecting group can then be removed with acid (trifluoroacetic acid/dichloromethane or hydrochloric acid/dioxane) to supply compounds of formula (24). Compounds of formula (24) can be reacted with compounds of formula (25) in a solvent such as methanol, dichloromethane or a mixture thereof in the presence of acetic acid and sodium cyanoborohydride, sodium triacetoxyborohydride, or resin-bound-cyanoborohydride at a temperature of 20-50° C. for 8 to 24 hours to supply compounds of formula (26). Compounds of formula (26) are representative of compounds of formula (I).

Compounds of formula (26), wherein Ar1, Ar2, L2, n, R1, R2, R3, R4, and X are as defined in formula (I) and j is 1, 2 or 3 can be prepared as illustrated in Scheme 9. Compounds of formula (24); wherein the H is attached to L2as either part of a primary amine, secondary amine, or amine contained in a heterocycle protected as a carbamate; can be heated with bromides of formula (27) in the presence of a base such as sodium carbonate in a solvent such as 2-butanone in a sealed vessel for 24-36 hours to give compounds of formula (26). Compounds of formula (26) are representative of compounds of formula (I).

Compounds of formula (29), wherein Ar2, R2, R3and R4are as defined in formula (I), can be prepared from compounds of formula (28). Compounds of formula (28) are heterocycles with a pendant amine functionality protected as a carbamate. Compounds of formula (28) can be treated with compounds of formula (27) in the presence of a base such as potassium carbonate optionally with a catalytic amount of potassium iodide present in a solvent such as N,N-dimethylformamide. Subsequent removal of the t-butoxy carbonyl protecting group under acid conditions such as trifluoroacetic acid in dichloromethane or hydrochloric acid in dioxane supplies compounds of formula (29). Compounds of formula (29) can be used in Schemes 1, 5, 6, or 7.

Compounds of formula (31) and (33), wherein Ar2, R2, R3and R4are as defined in formula (I), can be prepared from compounds of formula (30). Compounds of formula (30) represent monocyclic or bicyclic heterocycles such as for example piperazine or octahydropyrrolo[3,4-b]pyridine wherein one of the amine moieties is protected as a t-butoxy carbamate. Compounds of formula (30) can be reductively aminated with compounds of formula (25) as described in Scheme 8. Removal of the protecting group under the acidic conditions described in Scheme 10 supplies compounds of formula (31).

Compounds of formula (30) can be reacted with sulfonyl chlorides of formula (32) in the presence of a base such diisopropylethylamine or triethylamine in solvent such as dichloromethane. Removal of the protecting group under the acidic conditions described in Scheme 10 supplies compounds of formula (33).

Compounds of formula (31) and (33) can be used in Schemes 1, 5, 6, or 7.

Compounds of formula (35), wherein Ar1, Ar2, n, p, R1, R4, X, and Y are as defined in formula (I), are prepared as described in Scheme 12. Compounds of formula (2) can be reacted with a compound of formula (34) in the presence of a dehydrating agent such as N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride in a solvent such as dichloroethane initially at room temperature for 1 to 4 hours and then heated for 8 to 24 hours to supply compounds of formula (35). Compounds of formula (35) are representative of compounds of formula (I).

Compounds of formula (37), wherein Ar1, Ar2, L2, n, R1, R4, and X are as defined in formula (I) and j is 1, 2 or 3 can be prepared as illustrated in Scheme 13. Compounds of formula (24); wherein the H is attached to L2as either part of a primary amine, secondary amine, or amine contained in a heterocycle may be coupled with compounds of formula (36) using the amide bond forming reaction conditions described in Scheme 1. Compounds of formula (37) are representative of compounds of formula (I).

Compounds of formulas (41) and (42), wherein Ar1, Ar2, n, R1, and R4are as defined in formula (I) and j at each occurrence is independently 1, 2 or 3 can be prepared as illustrated in Scheme 14. Compounds of formula (38) can be treated with compounds of formula (39) in the presence of a base such as sodium methoxide in optionally heated N,N-dimethylformamide. The phthalimide group is subsequently removed by treatment with hydrazine in a heated mixture of ethanol and water to provide compounds of formula (40). Compounds of formula (40) can be treated with compounds of formula (18) in the presence of a base such as potassium carbonate in a heated acetonitrile solution to give compounds of formula (41). Compounds of formula (41) can be reacted with formaldehyde under the reductive amination conditions described in Scheme 5 to provide compounds of formula (42) which are representative of compounds of formula (I).

Compounds of formulas (44), (46), and (48), wherein A1, A2, A3, A4, A5, A6, A7, A8, A9, A10, Ar1, Ar2, L2, n, R1, R4, X, and Y are as defined in formula (I) can be prepared as illustrated in Scheme 15. Compounds of formula (1) can be reacted with compounds of formulas (43), (44), or (47); wherein LG is a leaving group such as chlorine, bromine, iodine, trifluoromethanesulfonate, or p-toluenesulfonate; in the presence of a base such as sodium hydride, potassium hydride, or potassium t-butoxide in solvents such as tetrahydrofuran or N,N-dimethylformamide to give compounds of formulas (44), (46), or (48), respectively, which are representative of compounds of formula (I).

Compounds of formulas (50), wherein Ar1, Ar2, n, R1, R4, and X are as defined in formula (I) can be prepared as illustrated in Scheme 16. Compounds of formula (1) can be reacted with compounds of formula (49) in the presence of a base such as potassium t-buoxide in a solvent such as tetrahydrofuran to give compounds of formula (50) which are representative of compounds of formula (I).

It will be appreciated that the synthetic schemes and specific examples as illustrated in the Examples section are illustrative and are not to be read as limiting the scope of the invention as it is defined in the appended claims. All alternatives, modifications, and equivalents of the synthetic methods and specific examples are included within the scope of the claims.

Optimum reaction conditions and reaction times for each individual step may vary depending on the particular reactants employed and substituents present in the reactants used. Unless otherwise specified, solvents, temperatures and other reaction conditions may be readily selected by one of ordinary skill in the art. Specific procedures are provided in the Examples section. Reactions may be worked up in the conventional manner, e.g. by eliminating the solvent from the residue and further purified according to methodologies generally known in the art such as, but not limited to, crystallization, distillation, extraction, trituration and chromatography. Unless otherwise described, the starting materials and reagents are either commercially available or may be prepared by one skilled in the art from commercially available materials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of the reaction conditions, reagents and sequence of the synthetic route, protection of any chemical functionality that may not be compatible with the reaction conditions, and deprotection at a suitable point in the reaction sequence of the method are included in the scope of the invention. Suitable protecting groups and the methods for protecting and deprotecting different substituents using such suitable protecting groups are well known to those skilled in the art; examples of which may be found in T. Greene and P. Wuts, Protecting Groups in Chemical Synthesis (3rded.), John Wiley & Sons, NY (1999), which is incorporated herein by reference in its entirety. Synthesis of the compounds of the invention may be accomplished by methods analogous to those described in the synthetic schemes described hereinabove and in specific examples.

Starting materials, if not commercially available, may be prepared by procedures selected from standard organic chemical techniques, techniques that are analogous to the synthesis of known, structurally similar compounds, or techniques that are analogous to the above described schemes or the procedures described in the synthetic examples section.

Similarly, when a pure geometric isomer of a compound of the invention is required, it may be obtained by carrying out one of the above procedures using a pure geometric isomer as a starting material, or by resolution of a mixture of the geometric isomers of the compound or intermediates using a standard procedure such as chromatographic separation.

The compounds and processes of the present application will be better understood by reference to the following Examples, which are intended as an illustration of and not a limitation upon the scope of the application. Compounds of the application were named by ACD/ChemSketch version 5.01 (developed by Advanced Chemistry Development, Inc., Toronto, ON, Canada) or were given names consistent with ACD nomenclature or were named by Stuct=Name naming algorithm in ChemDraw Ultra 9.0.7 (developed by CambridgeSoft, Cambridge, Mass., USA).

3,3-Diphenyldihydrofuran-2(3H)-one (3.98 g, 16.70 mmol) and zinc chloride (0.080 g) were placed in an autoclave. Ammonia (8 mL) was added, and the reactor was sealed and heated at 225° C. for 21 hours under an argon atmosphere at an equilibrium pressure of 800 pounds per square inch. The vessel was cooled, the ammonia was vented, and a mixture of solids was obtained. The solid was treated with ethanol (100 mL), filtered and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave the title compound. MS (DCI+) m/z 238.1 (M+H)+.

To a solution of the product from Example 1A (1.0 g, 4.21 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 6.3 mL, 6.3 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.47 mL, 4.21 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 324.2 (M+H)+.

The product from Example 1B (0.92 g, 2.84 mmol) was dissolved in ethanol (20 mL).

A solution of lithium hydroxide (0.57 g, 23.8 mmol) in water (5 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and then concentrated to give the title compound. MS (DCI+) m/z 296.1 (M+H)+.

In a 500 mL flask containing 3,3-diphenylpyrrolidine-2-one (5.00 g, 21 mmol; Example 1A) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 M in tetrahydrofuran, 24 mL, 48 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad of diatomaceous earth. The organic phase was separated, concentrated, and the residue purified over silica gel eluting with 95:5 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 224 (M+H)+.

To tert-butyl 2-benzylpiperazine-1-carboxylate (0.052 g, 0.190 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (Example 1C, 0.051 g, 0.173 mmol) and 2-(1H-benzo[d][1,2,3]triazol-1-yl)-1,1,3,3-tetramethylisouronium hexafluorophosphate(V) (0.069 g, 0.181 mmol) in dichloromethane (0.5 mL) was added diisopropylethylamine (0.045 mL, 0.259 mmol), and the reaction was stirred a room temperature. After stirring overnight, the reaction was concentrated, loaded onto a silica gel column (Analogix® SF15-12, Burlington, Wis.) and eluted with a gradient of 5% to 100% ethyl acetate/hexanes. To the resulting product was added HCl (2.0 Min diethyl ether, 3.57 μl, 0.117 mmol), and the reaction was stirred at room temperature overnight. The reaction was centrifuged, and the solvent was decanted away from the solid. Diethyl ether (1 mL) was added, and the suspension was sonicated to give a fine suspension. The reaction was centrifuged, the solvent was decanted and the resulting solid dried to give the title compound as the hydrochloride salt.1H NMR (300 MHz, pyridine-d5) δ ppm 7.05-7.50 (m, 15H), 4.65-4.80 (m, 2H), 4.25-4.55 (m, 2H), 3.95-4.15 (m, 2H), 3.40-3.75 (m, 5H), 2.95-3.27 (m, 2H), 2.75-2.85 (m, 2H); MS (DCI+) m/z 454.2 (M+H)+.

In a 500 mL flask containing 3,3-diphenylpiperidin-2-one (3.77 g, 15 mmol; Example 68C) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 Min tetrahydrofuran, 15 mL, 30 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad or diatomaceous earth. The organic phase was separated, concentrated, and the residue was purified over silica gel eluting with 95:5 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 238 (M+H)+.

To a solution of tert-butyl 3-oxopiperazine-1-carboxylate (0.75 g, 3.75 mmol) in N,N-dimethylformamide (3 mL) was added a 60% dispersion of sodium hydride in oil (0.18 g, 4.5 mmol). The mixture was stirred at ambient temperature for 1 hour. To the resulting suspension was added bromodiphenylmethane (1.02 g, 4.12 mmol) and stirring was continued at room temperature overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, concentrate in vacuo, and chromatographed on silica gel eluting with 20% ethyl acetate/hexane to yield 0.5 g of the t-butoxycarbonyl-protected title compound. The protected material was dissolved in methanol (10 mL) and treated with 4 N HCl/dioxane solution (2 mL) at ambient temperature for 3 hours. Diethyl ether was added to the solution to precipitate the title compound as the hydrochloride salt.1H NMR (300 MHz, DMSO-d6) δ ppm 9.49 (s, 1H), 7.41 (m, 6H), 7.20 (d, J=6.44 Hz, 4H), 6.92 (s, 1H), 3.88 (s, 2H), 3.43 (m, 2H), 3.19 (m, 2H); MS (DCI) m/z 267 (M+H)+.

To a solution of 4-bromopyridine (0.78 g, 5.0 mmol) in tetrahydrofuran (5 mL) was added isopropylmagnesium chloride (2.0 Min tetrahydrofuran, 2.5 mL, 5.0 mmol) via syringe under nitrogen at room temperature. The reaction mixture was stirred for one hour. To the reaction mixture was then added bis(4-fluorophenyl)methanone (0.98 g, 4.5 mmol) dissolved in tetrahydrofuran (7 mL) via syringe. The reaction mixture was stirred overnight, quenched with a saturated aqueous solution of ammonium chloride (10 mL), and extracted with diethyl ether. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. Silica gel chromatography eluting with 5% methanol/dichloromethane gave bis(4-fluorophenyl)(pyridin-4-yl)methanol on (0.73 g, 2.45 mmol).

The product from the Example 41A (0.14 g) was dissolved in methanol (5 mL) and treated with a 4 N solution of HCl in dioxane (1 mL) at room temperature for 2 hours. The reaction mixture was concentrated to yield the dihydrochloride salt of the title compound. MS (DCI) m/z 259 (M+H)+.

A suspension of 1-(3-(trifluoromethyl)phenyl)ethanone (0.100 g, 0.532 mmol), tert-butyl piperazine-1-carboxylate (0.148 g, 0.797 mmol), acetic acid (0.046 mL, 0.797 mmol) and sodium cyanoborohydride (0.050 g, 0.797 mmol) in ethanol (0.5 mL) was heated under nitrogen at 75° C. After stirring overnight the reaction was concentrated, saturated sodium bicarbonate (0.7 mL) was added, and the product was extracted into ethyl acetate (2×0.7 mL). The combined organic layers were concentrated, dissolved in a minimal amount of dichloromethane, loaded directly onto a SF15-12 silica gel column (Analogix®, Burlington, Wis.), and the title compound was eluted using a gradient of 2% to 20% ethyl acetate/hexanes over 20 minutes (flow=30 mL/minute).

The product from Example 44A (0.071 g, 0.198 mmol) was added to HCl (2.0 Min dioxane) (0.991 mL, 1.981 mmol), and methanol was added dropwise until the reaction became nearly homogeneous. As the reaction was stirred, a precipitate formed. The reaction was concentrated to give the title compound (0.066 g, 0.256 mmol) as the dihydrochloride salt. MS (APCI) m/z 259 (M+H)+.

A solution of the dihydrochloride of R-methylpiperazine (Tetrahedron Lett. 1994, 35, 16, 2533-2536)(0.42 g, 2.42 mmol) in N,N-dimethylformamide (3 mL) was treated with bromodiphenylmethane (0.6 g, 2.42 mmol), potassium carbonate (1.17 g, 8.5 mmol), and a catalytic amount of potassium iodide. The resultant reaction mixture was then stirred at ambient temperature overnight. Then the reaction mixture was concentrated and partitioned between water/methylene chloride. The organic layer was dried over magnesium sulfate, concentrated and the residue was purified by preparative HPLC on a Waters Nova-Pak® HR C18 6 um 60 Å Prep-Pak® cartridge column (40 mm×100 mm) using a gradient of 10% to 100% acetonitrile in 10 mM aqueous ammonium acetate over 12 minutes at a flow rate of 70 mL/min to provide the title compound.

To a solution of (4aS,7aS)-6-benzyloctahydro-1H-pyrrolo[3,4-b]pyridine dihydrochloride (CAS 151213-39-7) in methylene chloride was added di-tert-butyl dicarbonate and triethylamine. The reaction mixture was stirred at room temperature overnight, and then it was washed with saturated sodium bicarbonate solution. The organic layer was separated and dried over MgSO4, concentrated, and then chromatographed on silica gel eluting with 30% ethyl acetate/hexane to give the title compound.

The product from Example 50A (0.15 g, 0.5 mmol) in methanol (80 mL) was hydrogenated (4 pounds per square inch) in the presence of palladium hydroxide on carbon (0.42 g) for 3 hours at room temperature. The reaction mixture was filtered and concentrated to yield the title compound. MS (DCI) m/z 227 (M+H)+.

The product from Example 50C (0.15 g, 0.38 mmol) was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (1 mL) at ambient temperature for 1 hour. The reaction mixture was concentrated to yield the title compound as the trifluoroacetic acid salt. MS (ESI+) m/z 292 (M+H)+.

Formaldehyde (4.08 g, 50.2 mmol) was dissolved in methanol (2.032 mL, 50.2 mmol). The reaction was cooled to 0° C. (ice bath) and N-(3-(trifluoromethyl)benzyl)-1-(trimethylsilyl)methanamine (Example 56A, 10.94 g, 41.9 mmol) was added dropwise via addition funnel over 30 minutes. Potassium carbonate (4.63 g, 33.5 mmol) was added, and the mixture was stirred at 0° C. for 2 hours. The reaction solution was decanted from the potassium carbonate. The solution was treated with more potassium carbonate and decanted again. The potassium carbonate solids were sequentially washed with ether and these washes were added to the reaction solution. The solvent was removed in vacuo to give the title compound.

Hydroxylamine hydrochloride (3.47 g, 50.0 mmol) and sodium acetate (4.27 g, 52.0 mmol) were dissolved in water (15 mL) and added to a solution of 2-(3-(trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one (Example 56C, 11.33 g, 40 mmol) in ethanol (80 mL). The reaction was brought to reflux and then allowed to cool to 70° C. After 1 hour, the solvent was removed in vacuo to give the title compound.

2-(3-(Trifluoromethyl)benzyl)hexahydrocyclopenta[c]pyrrol-4(5H)-one oxime (Example 56D, 11.9 g, 39.9 mmol) in 20% ammonia/methanol (115 mL) was added to methanol-washed Raney®-nickel, water-wet (38.52 g, 295 mmol) in a 500 mL pressure bottle. The vessel was pressurized with hydrogen (30 pounds per square inch), and the mixture was shaken for 16 hours at room temperature. The mixture was filtered through a nylon membrane, the solvent removed in vacuo, and the crude oil adsorbed onto silica gel. Chromatography using an SF65-400 silica gel column (Analogix®, Burlington, Wis.) with 1-10% methanol (2 N NH3)/dichloromethane gave:

To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (0.28 g, 1.00 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (1.00 mL, 1.00 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (0.69 mL, 1.00 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 333 (M+NH4)+.

A solution of the product from Example 58A (20 mg, 0.063 mmol) in acetic acid (4 mL) was added to PtO2(4.00 mg, 0.018 mmol) in a 50 mL pressure bottle and stirred at room temperature for 12 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 274 (M+H)+.

To a solution of the product from Example 58B (0.82 g, 3.00 mmol) in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran, 4.5 mL, 4.5 mmol) via syringe under nitrogen followed by ethyl 2-bromoacetate (0.33 mL, 3.00 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated and then diluted with ethyl acetate. The reaction mixture was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The residue was purified with silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (APCI+) m/z 359.9 (M+H)+.

The product from Example 58C (0.90 g, 2.50 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.57 g, 23.97 mmol) in water (5 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and concentrated to supply the title compound. MS (APCI+) m/z 332.2 (M+H)+.

tert-Butyl 4-(2-hydroxyethyl)piperazine-1-carboxylate (5.76 g, 25.0 mmol) was dissolved in dry tetrahydrofuran (100 mL) and carbon tetrabromide (9.12 g, 27.5 mmol). A solution of triphenyl phosphine (6.62 g, 25.3 mmol) in dry tetrahydrofuran (25 mL) was added dropwise, and the mixture was stirred for 20 hours. The reaction was diluted with n-hexane (100 mL) and washed with a saturated NaHCO3solution, water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexanes 1:4 gave the title compound. MS (DCI) m/z 295 (M+H)+.

To a solution of 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 1.37 g, 5.00 mmol) in tetrahydrofuran (30 mL) was added potassium t-butoxide (1.0 M in tetrahydrofuran) (7.5 mL, 7.5 mmol) followed by the product from Example 63A (1.47 g, 5.00 mmol). The reaction mixture was heated at 75° C. for 18 hours. The reaction was concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. The residue was purified with silica gel chromatography eluting with 3% methanol/dichloromethane to give the title compound. MS (DCI) m/z 486.3 (M+H)+.

The product from Example 63B (2.00 g, 4.12 mmol) was dissolved in dichloromethane (40 mL) and treated with trifluoroacetic acid (7.40 g, 64.9 mmol) at 0° C. The reaction was allowed to come to room temperature and stirred for 1 hour. The reaction was neutralized with triethylamine and concentrated. The residue was taken into ethyl acetate, and then it was washed with water and brine, dried with MgSO4, filtered and concentrated to give the title compound. MS (DCI) m/z 386.2 (M+H)+.

To a solution of the product from Example 63C (1.85 g, 4.80 mmol) in methanol/dichloromethane (50 mL) was added 3,5-dimethoxybenzaldehyde (0.80 g, 4.80 mmol), macroporous-cyanoborohydride resin (8.09 g, 4.80 mmol, 2.24 mol/g) and acetic acid (1.6 mL, 4.80 mmol). The reaction was stirred at 40° C. for 18 hours under an atmosphere of nitrogen. The reaction was cooled to room temperature, filtered and concentrated. Silica gel chromatography eluting with 3% methanol/dichloromethane gave the title compound. The title compound was dissolved in methanol (10 mL) and treated with HCl (1.25 M in methanol, 5.1 mL), concentrated and dried under vacuum to give the title compound as the corresponding hydrochloride salt. MS (DCI) m/z 536.3 (M+H)+.

To a solution of Dess-Martin periodinane (8.03 g, 18.92 mmol) in dichloromethane (100 mL) was added a solution of the product from Example 67A (4.84 g, 17.20 mmol) in dichloromethane (50 mL) at room temperature. After 30 minutes at room temperature, the reaction is diluted with diethyl ether, filtered and concentrated. Chromatography eluting with a gradient of 50% to 100% ethyl acetate/hexanes using a SF25-40 g (Analogix®, Burlington, Wis.) column gave the title compound. MS (DCI+) m/z 280.1 (M+H)+.

2,2-Diphenylacetic acid (50 g) was dissolved in ethanol (350 mL). Concentrated sulfuric acid (3 mL) was added, and the mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated and diluted with diethyl ether. The organic solvent solution was then extracted with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried with magnesium sulfate, filtered, and concentrated to obtain the title compound. MS (DCI+) m/z 241 (M+H)+.

The product of Example 68A (5.58 g) was dissolved in anhydrous dioxane (15 mL). Sodium ethoxide (1.58 g) was added and the mixture was heated to 40-50° C. for 30 minutes. Acrylonitrile (1.44 mL) was added dropwise with stirring. The mixture was heated at 60-70° C. for one hour. The dioxane was removed in vacuo, and the residue was taken up in diethyl ether, washed with water and brine, dried with magnesium sulfate, filtered, and concentrated. The crude material was purified by silica gel chromatography (3-10% ethyl acetate/hexane) to obtain the title compound. MS (DCI+) m/z 311 (M+NH4)+.

The product of Example 68B (14.4 g, 49.1 mmol) and 7 M ammonia in methanol (150 mL) were added to solvent-washed Raney®-nickel (72.0 g, 1227 mmol), and the mixture was stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane. The reaction mixture was concentrated. The residue was dissolved in dichloromethane/methanol (1:1) and filtered through a pad of diatomaceous earth to remove a greenish residue. The filtrate was concentrated to obtain a solid which was slurried in methanol, filtered, and dried to obtain the title compound. MS (DCI+) m/z 251 (M+H)+.

To a solution of the product of Example 68C (2.51 g, 10.00 mmol) in tetrahydrofuran (100 mL) was added potassium tert-butoxide (1.35 g, 12.00 mmol) under nitrogen followed by ethyl 2-bromoacetate (1.22 mL, 11.00 mmol). The reaction mixture was heated to 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (20:80) gave the title compound. MS (DCI+) m/z 338 (M+H)+.

The product from Example 68D (1.70 g, 5.04 mmol) was dissolved in ethanol (40 mL). A solution of lithium hydroxide (1.20 g, 50.10 mmol) in water (10 mL) was added, and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI+) m/z 310 (M+H)+.

To tert-butyl piperazine-1-carboxylate (1.39 g, 7.46 mmol) and diisopropylethylamine (1.955 mL, 11.19 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzene-1-sulfonyl chloride (1.196 mL, 7.46 mmol) dropwise. The reaction was stirred overnight. Thin layer chromatography indicated formation of a new product (hexanes/ethyl acetate 1:1). The reaction was diluted with dichloromethane (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound.

The product from Example 84A (2.75 g, 6.97 mmol) was dissolved in dioxane (10 mL) with sonication. To the solution was added hydrochloric acid (4.0 Min dioxane) (5.23 mL, 20.92 mmol), and the reaction was allowed to stir at room temperature. After stirring for 4 hours, the reaction was concentrated. This residue was triturated with diethyl ether with sonication to give a solid which was collected by filtration to give the title compound as the hydrochloride salt.

The product from Example 87A was dissolved in methylene chloride (5 mL) and treated with trifluoroacetic acid (2 mL) at room temperature for 1 hour. Then the reaction mixture was concentrated, partitioned between methylene chloride and an aqueous solution of sodium bicarbonate. The organic layer was separated, dried over magnesium sulfate, and concentrated to yield the title compound. MS (ESI+) m/z 391 (M+H)+.

The product from Example 88A was dissolved in methylene chloride and reacted with trifluoroacetic acid at ambient temperature for 1 hour. The reaction mixture was concentrated to yield the trifluoroacetic salt of the title compound. m/z 418 (M+H)+.

To a solution of ethyl 2,2-bis(4-fluorophenyl)acetate (1.55 g, 5.64 mmol) in anhydrous dioxane (10 mL) was added sodium ethoxide (0.38 g, 5.61 mmol), and the reaction was stirred at a temperature between 40-50° C. for 30 minutes. Acrylonitrile (0.35 mL, 5.61 mmol) was added dropwise with stirring, and the reaction was heated at 60-70° C. for an additional 1 hour. The dioxane was removed in vacuo, and the residue was taken up in ether, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with a gradient of 3% to 10% ethyl acetate/hexane gave the title compound. MS (DCI) m/z 342 (M+NH4)+.

The product from Example 90A (560 mg, 1.700 mmol) as a solution in 7 M ammonia/methanol (20 mL) was added to solvent-washed Raney®-nickel (2800 mg, 47.7 mmol) in a 250 mL stainless steel pressure bottle and stirred at room temperature for 24 hours under hydrogen (30 pounds per square inch). The mixture was filtered through a nylon membrane and was concentrated. The residue was dissolved in methanol/dichloromethane (1:1), filtered and concentrated to give a solid which was slurried in methanol, filtered and dried to give the title compound. MS (DCI) m/z 288 (M+H)+.

To the product from Example 90B (0.43 g, 1.50 mmol) as a solution in tetrahydrofuran (20 mL) was added potassium tert-butoxide (1.0 M in tetrahydrofuran) (1.80 mL, 1.80 mmol) via syringe under nitrogen followed by the addition of ethyl 2-bromoacetate (0.18 mL, 1.65 mmol). The reaction mixture heated at 80° C. and stirred overnight. The reaction mixture was cooled to room temperature, concentrated, diluted with ethyl acetate, washed with water and brine, dried with MgSO4, filtered and concentrated. Silica gel chromatography eluting with ethyl acetate/hexane (1:4) gave the title compound. MS (DCI) m/z 374 (M+H)+.

The product from Example 90C (0.40 g, 1.07 mmol) was dissolved in ethanol (20 mL). A solution of lithium hydroxide (0.21 g, 8.57 mmol) in water (5 mL) was added and the reaction was heated to 80° C. for 2 hours. The reaction mixture was cooled to room temperature, concentrated, neutralized with 2 N HCl, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered, and then concentrated to give the title compound. MS (DCI) m/z 346 (M+H)+.

3-Methyl-3-phenylpiperidin-2-one is prepared using the procedures described in Examples 91A and 91B substituting ethyl 2-phenylpropionate for ethyl 2-phenylacetate. To 3-methyl-3-phenylpiperidin-2-one (1.01 g, 5.34 mmol) in tetrahydrofuran (3 mL) was added potassium t-butoxide (1.0 Min tetrahydrofuran, 6.40 mL, 6.40 mmol), and the mixture was allowed to stir at room temperature for 30 minutes. To the mixture was added ethyl 2-bromoacetate (0.591 mL, 5.34 mmol). The reaction was heated to 60° C. and stirred for 2 hours. The reaction was cooled, diluted with ethyl acetate (50 mL), washed with 1 N HCl (25 mL) and brine (25 mL), dried over magnesium sulfate and concentrated. The residue was loaded directly onto a SF25-40 silica gel column (Analogix®, Burlington, Wis.), and the intermediate ethyl ester was eluted using a gradient of 5% ethyl acetate/hexanes to 75% ethyl acetate over 30 minutes (flow=30 mL/minute). The ethyl ester was dissolved in ethanol (10 mL) and sodium hydroxide (2.0 M, 5.34 mL, 10.67 mmol) was added. After stirring for 30 minutes, thin layer chromatography (100% ethyl acetate) showed complete consumption of the starting material. The reaction was diluted with ethyl acetate (50 mL), washed with 1 N HCl (50 mL) and brine (50 mL), dried over magnesium sulfate, and concentrated to give the title compound.1H NMR (300 MHz, CDCl3) δ ppm 7.42-7.11 (m, 5H), 4.28 (d, J=16.7, 1H), 4.12 (d, J=16.7, 1H), 3.59-3.33 (m, 2H), 2.23 (dt, J=4.5, 13.5, 1H), 2.07-1.89 (m, 1H), 1.85-1.66 (m, 2H), 1.61 (s, 3H); MS (APCI+) m/z 248 (M+H)+.

To a solution of 3-phenylpiperazin-2-one (CAS 5368-28-5, 0.5 g, 2.84 mmol) in methylene chloride (30 mL) was added di-tert-butyl dicarbonate (0.74 g, 3.4 mmol) and triethylamine (0.6 mL, 4.26 mmol) and the reaction mixture was stirred at ambient temperature overnight. The reaction mixture was diluted with methylene chloride and washed with saturated aqueous NaHCO3solution. The organic layer was separated, dried over MgSO4and concentrated to yield the title compound. MS (ESI+) m/z 488 (M+H)+.

The following examples, Examples 105-143, can be prepared by the methodologies described in the preceding Examples and Schemes or by methods familiar to once skilled in the art:

3,3-bis(4-fluorophenyl)-1-(3-{4-[3-(trifluoromethyl)phenyl]piperazin-1-yl}propyl)piperidin-2-one; and

1-(2-(7-Benzyl-2,7-diazaspiro[3.5]nonan-2-yl)-2-oxoethyl)-3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 152, 0.185 g, 0.349 mmol) and ethanol (20 mL) were added to 20% Pd(OH)2—C, wet (0.037 g, 0.263 mmol) in a 50 mL pressure bottle and stirred for 1 hour at 30 psi and 50° C. The mixture was filtered through a nylon membrane and concentrated to give the title compound.

To a suspension of 3,3-diphenylpyrrolidin-2-one (2.00 g, 8.43 mmol; Example 1A) in tetrahydrofuran (10 mL) was added potassium 2-methylpropan-2-olate (9.27 mL, 9.27 mmol). After stirring for 30 minutes, the reaction was a suspension so the reaction was heated to 40° C. The reaction was cooled to ambient temperature, and then tert-butyl 4-bromobutanoate (2.068 g, 9.27 mmol) as a solution in tetrahydrofuran (3 mL) was added. The reaction was stirred for 3 hours, then poured into ethyl acetate/1 N HCl (1:1, 300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was loaded onto a GraceResolv™ 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 40% ethyl acetate/hexanes (Flow=40 mL/minute) over 30 minutes. The product was dissolved in 5 mL of dichloromethane then 5 mL of trifluoroacetic acid was added. After stirring for 3 hours, the reaction was concentrated to give the title compound.1H NMR (300 MHz, CDCl3) δ 7.36-7.22 (m, 10H), 3.45 (m, 4H), 2.79 (t, J=6.5, 2H), 2.31 (t, J=7.1, 2H), 1.89 (p, J=7.0, 2H); MS (ESI+) m/z 324.0 (M+H)+.

A solution of tert-butyl 4-oxopiperidine-1-carboxylate (524 mg, 2.63 mmol) and O-benzylhydroxylamine hydrochloride (504 mg, 3.16 mmol) in pyridine (5 mL) was stirred at ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between ether and H2O. The separated organic phase was washed with 1 N aqueous HCl and brine, dried over MgSO4, filtered, and concentrated in vacuo to yield 816 mg of crude N-tert-butoxycarbonyl intermediate. This material was taken up in CH2Cl2(5 mL), followed by addition of trifluoroacetic acid (5.0 mL, 65.0 mmol) via syringe. After stirring for 30 minutes at ambient temperature, the reaction was cooled to 0° C. and quenched by slow addition of 2 N aqueous NaOH solution (35 mL). The mixture was diluted with 75 mL CH2Cl2and the phases were separated. The organic layer was washed with 1 N aqueous NaOH solution and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound.1H NMR (300 MHz, CDCl3) δ ppm 7.39-7.27 (m, 5H), 5.07 (s, 2H), 3.02-2.94 (m, 2H), 2.94-2.86 (m, 2H), 2.63-2.54 (m, 2H), 2.33-2.23 (m, 2H), 1.58 (bs, 1H); MS (DCI+) m/z 205 (M+H)+.

Trifluoroacetic acid (3.0 mL, 39 mmol) was added to a solution of the product of Example 166C (279 mg, 0.439 mmol) in CH2Cl2(3 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then cooled to 0° C., diluted with CH2Cl2(25 mL) and quenched by slow addition of 2 N aqueous NaOH solution (25 mL). The mixture was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Ether was added to the residue which caused a solid to form, which was collected by vacuum filtration and washed with minimal ether and air-dried. The material was then chromatographed on silica gel (Analogix® Intelliflash™ 280; SF10-8 g column; 10% methanol/CH2Cl2) to afford the title compound.1H NMR (300 MHz, CDCl3) δ ppm 7.68 (d, J=8.3, 2H), 7.36 (d, J=8.2, 2H), 7.32-7.15 (m, 10H), 4.85-4.69 (m, 1H), 3.68 (s, 2H), 3.45 (t, J=6.4, 2H), 3.17-3.06 (m, 2H), 2.76 (td, J=12.4, 1.9, 2H), 2.66-2.56 (m, 2H), 2.00-1.65 (m, 5H), 1.40-1.21 (m, 2H); MS (DCI+) m/z 536 (M+H)+.

To a solution of tert-butyl azetidin-3-ylcarbamate (0.34 g, 2 mmol) in dichloroethane was added 3-(trifluoromethyl)benzaldehyde (0.45 g, 2.6 mmol) and sodium triacetoxyborohydride (0.64 g, 3 mmol). The resultant mixture was stirred at room temperature for 16 hours, and then the mixture was diluted with dichloromethane and washed with aqueous NaHCO3solution. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 30-70% ethyl acetate/hexane to yield the title compound.

The title compound was obtained by the procedure described in Examples 41A and 41B, replacing 3-(trifluoromethyl)benzaldehyde with 4-fluoro-3-(trifluoromethyl)benzaldehyde. MS (DCI) m/z 263 (M+H)+.

The title compound was obtained as described in Example 180B using product from Example 184A. MS (DCI) m/z 263 (M+H)+.

To a solution of (S)-tert-butyl pyrrolidin-3-ylcarbamate (0.25 g, 1.34 mmol) in dichloromethane (10 mL) was added 3-(trifluoromethyl)benzaldehyde (0.3 g, 1.745 mmol) and sodium triacetoxyborohydride (0.43 g, 2.01 mmol). The mixture was stirred at room temperature for 16 hours. Then the reaction mixture was diluted with dichloromethane and washed with NaHCO3solution. The organic layer was dried with MgSO4, concentrated, and purified by flash chromatography, eluting with 50% ethyl acetate/hexane to yield the title compound.

To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated to give a brownish foam. The foam was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2over 20 minutes gave the title compound as the second eluting enantiomer.1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.

To lithium bis(trimethylsilyl)amide (1.0 Min tetrahydrofuran) (18.73 mL, 18.73 mmol) at −78° C. was added methyl 2-(4-fluorophenyl)acetate (3.00 g, 17.84 mmol) as a solution in tetrahydrofuran (5 mL) dropwise. During the addition, a white solid precipitated. After the addition, the reaction was placed in an ice bath and stirred for 1 hour. 2-Bromoacetonitrile (2.354 g, 19.62 mmol) was added as a solution in tetrahydrofuran (2 mL) and the reaction was allowed to stir for an additional 1 hour. The reaction was poured into a mixture of 1 N HCl (50 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with brine (50 mL), dried over magnesium sulfate and concentrate. The resulting reside was chromatographed over silica gel (SF40-115, Analogix®) eluting with a gradient of 5% to 50% ethyl acetate/hexanes (Flow=85 mL/minute) to provide the title compound.1H NMR (300 MHz, CDCl3) δ 7.31-7.19 (m, 2H), 7.13-7.01 (m, 2H), 3.93 (t, J=7.6, 1H), 3.73 (s, 3H), 3.02 (dd, J=7.2, 16.8, 1H), 2.81 (dd, J=8.0, 16.9, 1H).

In a 500 mL flask containing 3,3-bis(4-fluorophenyl)pyrrolidin-2-one (Example 58B, 4.1 g, 15 mmol) as a suspension in ether (300 mL) was added lithium aluminum hydride (2.0 Min tetrahydrofuran, 15 mL, 30 mmol) slowly via syringe under nitrogen. The reaction was refluxed overnight, cooled to room temperature, and then carefully quenched by the slow addition of 1 N NaOH (60 mL). The reaction was diluted with ethyl acetate (200 mL) and filtered through a pad of diatomaceous earth. The organic phase was separated, concentrated, and the residue purified over silica gel eluting with 97:3 dichloromethane/methanol to give the title compound. MS (DCI+) m/z 260 (M+H)+.

3-(4-Chlorophenyl)propanenitrile (0.477 g, 2.88 mmol), hydroxylamine hydrochloride (0.300 g, 4.32 mmol) and sodium hydrogencarbonate (1.210 g, 14.40 mmol) were stirred together in methanol (4 mL) and heated to 60° C. for 16 hours. The reaction was cooled, filtered and concentrated. The reside was dissolved in minimal dichloromethane/methanol and loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 50% ethyl acetate/hexanes to 100% ethyl acetate (Flow=30 mL/minute) over 20 minutes to supply the title compound.

To a suspension of 3-(4-fluorophenyl)pyrrolidin-2-one (Example 189B, 1.36 g, 7.59 mmol) in tetrahydrofuran was added potassium 2-methylpropan-2-olate (8.35 ml, 8.35 mmol). The reaction was allowed to stir for 30 minutes, during which time a yellow solution resulted. To the reaction was added ethyl 2-bromoacetate (0.92 ml, 8.35 mmol) and stirring was continued at room temperature. After stirring for 3 hours, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was separated, washed with brine (100 mL), dried over magnesium sulfate and concentrated. The residue was dissolved in minimal dichloromethane and loaded onto a GraceResolv 40 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 40 minutes. The resulting ethyl ester intermediate was dissolved in methanol (10 mL) and treated with sodium hydroxide (7.59 mL, 15.18 mmol). After stirring for 1 hour, the reaction was poured into a 1:1 mixture of ethyl acetate/1 N HCl (300 mL). The organic layer was washed with brine (100 mL), dried over magnesium sulfate and concentrated to give the title compound.1H NMR (300 MHz, DMSO-d6) δ 12.87 (s, 1H), 7.34-7.26 (m, 2H), 7.20-7.10 (m, 2H), 4.00 (s, 2H), 3.71 (t, J=9.0, 1H), 3.52-3.43 (m, 2H), 2.59-2.35 (m, 1H), 2.07-1.91 (m, 1H).

To a suspension of 2-(3,3-bis(4-fluorophenyl)-2-oxopyrrolidin-1-yl)acetic acid (0.200 g, 0.604 mmol; Example 58D) and 5-(trifluoromethyl)isoindoline hydrobromide (0.178 g, 0.664 mmol) in dichloromethane (0.5 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (0.160 mL, 0.905 mmol) and the reaction stirred for 3 days. The reaction was loaded onto a GraceResolv™ 12 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 50% ethyl acetate/hexanes (Flow=20 mL/minute) over 30 minutes to give the title compound. MS (ESI+) m/z 501.1 (M+H)+.

A solution of (Z)-tert-butyl 5-(N-hydroxycarbamimidoyl)pyridin-2-ylcarbamate (0.131 g, 0.5 mmol), 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (0.153 g, 0.5 mmol; Example 1C) and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (0.199 g, 1.0 mmol) were stirred together in dichloroethane (7.0 mL) at room temperature for 2 hours. The reaction was then heated to 85° C. and stirred overnight. The reaction was cooled, loaded onto a SF25-40 column (Analogix®) and the product eluted using a gradient of 10% ethyl acetate/hexanes to 70% ethyl acetate over 30 minutes (Flow=30 mL/minute) to supply the title compound.

To a suspension of 2-(2-oxo-3,3-diphenylpyrrolidin-1-yl)acetic acid (1.477 g, 5.0 mmol; Example 1C) in dichloromethane (20 mL) was added catalytic amount of N,N-dimethylformamide followed by oxalyl dichloride (2.0 Min dichloromethane, 3.75 mL, 7.5 mmol). After stirring for 60 minutes, the reaction was concentrated, dried under high vacuum overnight. The resulting material was taken for further reactions without additional purification.

A mixture of the product of Example 262A (180 mg, 0.91 mmol), the product of Example 68E (280 mg, 0.901 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (347 mg, 1.81 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3.5 hours and then heated to reflux for 16 hours. The cooled reaction mixture was diluted with CH2Cl2, washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel twice using ethyl acetate/hexanes as eluant, then finally purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). The dried down fractions were taken up in CH2Cl2and combined and concentrated in vacuo. Hexane was added to the residue, which caused the product to solidify. The resulting material was collected by vacuum filtration and dried in the vacuum oven at 50° C. for 4 hours to give the title compound.1H NMR (300 MHz, DMSO-d6) δ ppm 7.46-7.41 (m, 1H), 7.35-7.16 (m, 13H), 4.83 (s, 2H), 3.56 (t, J=6.3, 2H), 3.20-3.10 (m, 2H), 3.09-3.00 (m, 2H), 2.62-2.55 (m, 2H), 1.79-1.67 (m, 2H); MS (ESI+) m/z 472 (M+H)+.

A mixture of the product of Example 263A (148 mg, 0.738 mmol), the product of Example 68E (228 mg, 0.738 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (283 mg, 1.48 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3 hours, then heated to reflux for 24 hours. The cooled reaction mixture was diluted with CH2Cl2(100 mL) and washed with 1 N aqueous HCl (2×30 mL) and saturated aqueous NaHCO3solution and brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel (Analogix® Intelliflash™ 280; SF15-24 g column; 40% ethyl acetate/hexanes) to give a viscous oil which was left standing overnight. Methanol (1 mL) was then added causing a solid to form which was collected by vacuum filtration, washed with hexanes, and air-dried to give the title compound.1H NMR (300 MHz, DMSO-d6) δ ppm 7.40-7.33 (m, 2H), 7.31-7.07 (m, 12H), 5.32 (s, 2H), 4.87 (s, 2H), 3.58 (t, J=6.3, 2H), 2.62-2.54 (m, 2H), 1.78-1.67 (m, 2H); MS (ESI+) m/z 474 (M+H)+.

2-(4-(Trifluoromethyl)phenyl)acetic acid (5.0 g, 24.49 mmol) was dissolved in ethanol (100 mL). Concentrated sulfuric acid (1 mL) was added, and the mixture was refluxed overnight. After cooling to room temperature, the reaction mixture was concentrated and diluted with diethyl ether. The organic solvent solution was then extracted with water, saturated aqueous sodium bicarbonate solution, and brine. The organic layer was then dried with magnesium sulfate, filtered, and concentrated to obtain the title compound. MS (DCI+) m/z 250 (M+NH4)+.

To a solution of the product from Example 266A (5.25 g, 23.0 mmol) in dry tetrahydrofuran at −78° C. was added lithium bis(trimethylsilyl)amide (1.0 M in hexane) (23.00 mL, 23.0 mmol) dropwise via syringe under nitrogen. The reaction was brought to 0° C. and stirred for one hour. The reaction was re-cooled to −78° C. and then bromoacetonitrile (1.56 mL, 23.0 mmol) was added as a solution in tetrahydrofuran (10 mL). The reaction was stirred for 2 hours while the temperature was allowed to reach room temperature. The reaction was quenched with saturated aqueous ammonium chloride solution and extracted with diethyl ether. The organics were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (10% ethyl acetate/hexanes), to obtain the title compound. MS (DCI+) m/z 289 (M+NH4)+.

A solution of the product from Example 266B (4.1 g, 15.12 mmol) in methanol (10 mL) was added to 7 M ammonia in methanol (5.00 mL) and Raney® nickel, water wet, A-7000 (12.30 g, 210 mmol) in a 250 mL stainless steel pressure bottle and stirred for 16 hours under hydrogen (30 psi) at room temperature. The mixture was filtered through a nylon membrane and then concentrated to obtain solid. The solid was slurried in 5% ethyl acetate/hexanes, filtered and dried to give the title compound. MS (DCI+) m/z 247 (M+NH4)+.

To a solution of the product from Example 266C (3.1 g, 13.00 mmol) in tetrahydrofuran (40 mL) was added potassium tert-butoxide (1.0 Min tetrahydrofuran, 15.7 mL, 15.7 mmol) via syringe under nitrogen, and the resultant mixture was stirred for 15 minutes. Then ethyl 2-bromoacetate (1.59 mL, 14.4 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated and then diluted with ethyl acetate, washed with water and brine, dried over magnesium sulfate, filtered and concentrated. The resulting residue was dissolved in ethanol/water (4:1, 60 mL) and treated with lithium hydroxide (1.254 g, 52.4 mmol). After stirring for 2 hours at reflux, the reaction was concentrated, diluted with ice/water (150 mL) and neutralized with 2 N HCl. The precipitate formed was filtered, washed with water (50 mL), and dried under vacuum to obtain the title compound. MS (DCI+) m/z 288.1 (M+H)+.

The title compound was prepared using the procedures described in Examples 266A through Example 266D substituting 2-(2-chloro-4-fluorophenyl)acetic acid for 2-(4-(trifluoromethyl)phenyl)acetic acid in the procedure described in Example 266A. MS (DCI) m/z 272.0 (M+H)+.

The title compound was prepared using the procedures described in Examples 266A through Example 266D substituting 2-(3,4-dichlorophenyl)acetic acid for 2-(4-(trifluoromethyl)phenyl)acetic acid in the procedure described in Example 266A. MS (DCI) m/z 289.1 (M+H)+.

Many variations in the invention will suggest themselves to those skilled in the art in light of the foregoing detailed description. All such obvious variations are within the full intended scope of the appended claims.