AU2008338368A1 - 4-imidazolidinones as Kv1.5 potassium channel inhibitors - Google Patents
4-imidazolidinones as Kv1.5 potassium channel inhibitors Download PDFInfo
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Description
WO 2009/079624 PCT/US2008/087397 4-IMIDAZOLIDINONES AS KV1.5 POTASSIUM CHANNEL INHIBITORS FIELD OF THE INVENTION The present invention relates to compounds that are effective as Kv1.5 potassium channel inhibitors. The present invention also relates to compositions comprising 5 certain Kv1.5 potassium channel inhibitors, and to methods for treating cardiac arrhythmia. BACKGROUND OF THE INVENTION Atrial fibrillation (AF) is a frequently encountered cardiac arrhythmia in the clinical setting. It affects nearly 3 million people in the United States and its prevalence 10 increases with the aging of the population. AF is most often treated with class III antiarrhythmic agents, acting at both the atrial and ventricular levels. Commonly used or prescribed antiarrhythmic drugs inhibit various potassium channels, and prolong ventricular repolarization. Prolongation of ventricular repolarization can in turn precipitate the occurrence of life-threatening-ventricular arrhythmias, mainly 15 Torsades de Pointes (TdP). Certain atrial-selective antiarrhythmic agents offer one possibility of increased therapeutic efficacy and safety by minimizing cardiac proarrhythmia inherent in conventional antiarrhythmic therapies. There is an unmetneed to provide certain new compounds that function as effective 20 atrial-selective antiarrhythmic agents and which do not affect ventricular rhythm. In addition, there is an unmet need to provide certain new compounds that function as effective atrial-selective antiarrhythmic agents and that are compatible with other cardiac devices, cardiac protocols, therapies, and medications. References related to Kv1.5 potassium channel include: Brendel, J., et al., Curr. Med. Chem. 2003, 1, 273 25 287; Firth, A. L., et al., 2008, 33, 31-47; Vidaillet, H., et al., Am. J. Med. 2002, 113, 365-370; Tsang, T. S. M., et al., Am. J. Med. 2002, 113, 432-435; Yang, Q., et al., - 1 - WO 2009/079624 PCT/US2008/087397 Expert Opin. Ther. Patents 2007, 17, 1443-1456; Regan, C. P., et al., J. Cardiovasc. Pharmacol. 2007, 49, 236-245; Nattel, S. Physiol. Rev. 2007, 87, 425-456; Tombola, F., et al., Annu. Rev. Cell Dev. Biol. 2006, 22, 23-52; and Wirth, K. J., et al., J. Cardiovasc. Pharmacol. 2007, 49, 197-206. 5 SUMMARY OF THE INVENTION The present invention provides compounds of Formula (I): 0 Ari-(CR 5 R)m N (CR 9
R
1 0
)P-R
3 Ar 2 N R N
(CR
7
R
8 )n-R 2 (I) or pharmaceutically acceptable salts thereof, wherein Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R , R', R 8 , R 9 , R 1 0 , m, n, and p are defined as described herein. The present invention also provides compositions comprising an effective amount of one or more compounds of Formula (I) and one or more excipients. The present invention also provides a method for treating or preventing cardiac 10 arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, the method comprising administering to a subject an effective amount of a compound of Formula (I) according to the present invention. -2- WO 2009/079624 PCT/US2008/087397 The present invention also provides a method for treating or preventing cardiac arrhythmias, for example atrial arrhythmia, including but not limited to, atrial fibrillation and atrial flutter, wherein the method comprises administering to a subject a composition comprising an effective amount of one or more compounds of Formula 5 (I) according to the present invention and one or more excipients. The present invention also provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure. In some embodiments, the methods comprise administering to a subject an effective amount of a compound of Formula 10 (I) according to the present invention. The present invention further provides methods for treating or preventing diseases or conditions associated with cardiac arrhythmias, including but not limited to, thromboembolism, stroke, and heart failure, wherein said method comprises administering to a subject a composition comprising an effective amount of one or 15 more compounds of Formula (I) according to the present invention and one or more excipients. The present invention also provides a method for inducing cardioversion, comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject. 20 The present invention also provides a method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of Formula (I) to the subject. The present invention also provides a method for treating or preventing a disorder associated with inhibition of Kv1.5 potassium channel in a subject comprising 25 administering a therapeutically effective amount of a compound of Formula (I) to the subject. As an example, these compounds are useful in treating atrial arrhythmia, thromboembolism, stroke or cardiac failure. -3- WO 2009/079624 PCT/US2008/087397 These and other objects, features, and advantages will become apparent to those of skilled in the art from a reading of the following detailed description and the appended claims. DETAILED DESCRIPTION OF THE INVENTION 5 Kv1.5 potassium channel inhibitors of the present invention are capable of treating and preventing arrhythmia in the atrial portion of the human heart or in the heart of certain animals. It has been discovered that functional Kv1.5 potassium channels are found in human atrial tissue but not in human ventricular myocytes. Without wishing to be limited by theory, it is believed the inhibition of the Kv1.5 voltage-gated 10 Shaker-like potassium (K+) ion channel can ameliorate, abate, or otherwise cause to be controlled, atrial fibrillation and flutter without prolonging ventricular repolarization. DEFINITIONS As used herein, all percentages, ratios and proportions herein are by weight, unless otherwise specified. All temperatures are in degrees Celsius (0C), unless otherwise 15 specified. All documents cited are in relevant part; the citation of any document is not to be construed as an admission that it is prior art with respect to the present invention. Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, 20 including, or comprising specific process steps, it is contemplated that compositions of the present invention also consist essentially of, or consist of, the recited components, and that the processes of the present teachings also consist essentially of, or consist of, the recited processing steps. In this specification, where an element or component is said to be included in and/or 25 selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components -4- WO 2009/079624 PCT/US2008/087397 and can be selected from a group consisting of two or more of the recited elements or components. The use of the singular herein includes the plural (and vice versa) unless specifically stated otherwise. In addition, where the use of the term "about" is before a 5 quantitative value, the present invention also includes the specific quantitative value itself, unless specifically stated otherwise. It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present teachings remain operable. Moreover, two or more steps or actions can be conducted simultaneously. 10 As used herein, unless otherwise noted, "alkyl" whether used alone or as part of a substituent group refers to saturated straight and branched carbon chains having 1 to 20 carbon atoms or any number within this range, for example, 1 to 6 carbon atoms or 1 to 4 carbon atoms. Designated numbers of carbon atoms (e.g. C1-6) shall refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion 15 of a larger alkyl-containing substituent. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like. Where so indicated, alkyl groups can be optionally substituted. In substituent groups with multiple alkyl groups such as N(Cl_ 6 alkyl) 2 , the alkyl groups may be the same or different. 20 As used herein, unless otherwise noted, "alkoxy" refers to groups of formula -Oalkyl and -Operfluoroalkyl. Designated numbers of carbon atoms (e.g. -OC1-6 and -OC1-6 perfluoroalkyl) shall refer independently to the number of carbon atoms in the alkoxy group. Non-limiting examples of alkyl groups include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, iso-butoxy, tert-butoxy, and the like. Where so 25 indicated, alkoxy groups can be optionally substituted. As used herein, the terms "alkenyl" and "alkynyl" groups, whether used alone or as part of a substituent group, refer to straight and branched carbon chains having 2 or -5- WO 2009/079624 PCT/US2008/087397 more carbon atoms, preferably 2 to 20, having at least one carbon-carbon double bond ("alkenyl") or at least one carbon-carbon triple bond ("alkynyl"). Where so indicated, alkenyl and alkynyl groups can be optionally substituted. Nonlimiting examples of alkenyl groups include ethenyl, 3-propenyl, 1-propenyl (also 2 5 methylethenyl), isopropenyl (also 2-methylethen-2-yl), buten-4-yl, and the like. Nonlimiting examples of alkynyl groups include ethynyl, prop-2-ynyl (also propargyl), propyn-1-yl, and 2-methyl-hex-4-yn-1-yl. As used herein, "cycloalkyl," whether used alone or as part of another group, refers to a non-aromatic hydrocarbon ring including cyclized alkyl, alkenyl, or alkynyl 10 groups, e.g., having from 3 to 14 ring carbon atoms, for example, from 3 to 7 or 3 to 6 ring carbon atoms, and optionally containing one or more (e.g., 1, 2, or 3) double or triple bonds. Cycloalkyl groups can be monocyclic (e.g., cyclohexyl) or polycyclic (e.g., containing fused, bridged, and/or spiro ring systems), wherein the carbon atoms are located inside or outside of the ring system. Any suitable ring position of 15 the cycloalkyl group can be covalently linked to the defined chemical structure. Where so indicated, cycloalkyl rings can be optionally substituted. Nonlimiting examples of cycloalkyl groups include: cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctanyl, decalinyl, octahydropentalenyl, octahydro-1H-indenyl, 20 3a,4,5,6,7,7a-hexahydro-3H-inden-4-yl, decahydroazulenyl; bicyclo[6.2.0]decanyl, decahydronaphthalenyl, and dodecahydro-1H-fluorenyl. The term "cycloalkyl" also includes carbocyclic rings which are bicyclic hydrocarbon rings, non-limiting examples of which include, bicyclo-[2. 1.1 ]hexanyl, bicyclo[2.2. 1]heptanyl, bicyclo[3. 1. 1]heptanyl, 1,3-dimethyl[2.2.1]heptan-2-yl, bicyclo[2.2.2]octanyl, and 25 bicyclo[3.3.3]undecanyl. "Haloalkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen atoms. As used herein, halogen refers to F, Cl, Br and I. Haloalkyl groups include perhaloalkyl groups, wherein all hydrogens of an 30 alkyl group have been replaced with halogens (e.g., -CF 3 , -CF 2
CF
3 ). The halogens can be the same (e.g., CHF 2 , -CF 3 ) or different (e.g., CF 2 CI). Where so indicated, -6- WO 2009/079624 PCT/US2008/087397 haloalkyl groups can optionally be substituted with one or more substituents in addition to halogen. Examples of haloalkyl groups include, but are not limited to, fluoromethyl, dichloroethyl, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl groups. 5 The term "aryl," wherein used alone or as part of another group, is defined herein as an aromatic monocyclic ring of 6 carbons or an aromatic polycyclic ring of from 10 to 14 carbons. Aryl groups include but are not limited to, for example, phenyl or naphthyl (e.g., naphthylen-1-yl or naphthylen-2-yl). Where so indicated, aryl groups may be optionally substituted with one or more substituents. Aryl groups also 10 include, but are not limited to for example, phenyl or naphthyl rings fused with one or more saturated or partially saturated carbon rings (e.g., bicyclo[4.2.0]octa-1,3,5 trienyl, indanyl), which can be substituted at one or more carbon atoms of the aromatic and/or saturated or partially saturated rings. The terms "heterocyclic," "heterocycle," and "heterocyclyl," whether used alone or as 15 part of another group, are defined herein as groups having one or more rings (e.g., 1, 2 or 3 rings) and having from 3 to 20 atoms (e.g., 3 to 10 atoms, 3 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (0), and sulfur (S), and wherein the ring that includes the heteroatom is non-aromatic. In heterocyclyl groups that include 2 or more fused rings, any non 20 heteroatom bearing ring may be aryl (e.g., indolinyl, tetrahydroquinolinyl, chromanyl). Exemplary heterocyclyl groups have from 3 to 14 ring atoms of which from 1 to 5 are heteroatoms independently selected from nitrogen (N), oxygen (0), or sulfur (S). One or more N or S atoms in a heterocyclyl group can be oxidized (e.g., N->O-, S(O),
SO
2 ). Where so indicated, heterocyclyl groups can be optionally substituted. 25 Non-limiting examples of monocyclic heterocyclyl groups include, for example: diazirinyl, aziridinyl, urazolyl, azetidinyl, pyrazolidinyl, imidazolidinyl, oxazolidinyl, isoxazolinyl, isoxazolyl, thiazolidinyl, isothiazolyl, isothiazolinyl oxathiazolidinonyl, oxazolidinonyl, hydantoinyl, tetrahydrofuranyl, pyrrolidinyl, morpholinyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl, piperidin-2-onyl (valerolactam), 30 2,3,4,5-tetrahydro-1H-azepinyl, 2,3-dihydro-1 H-indolyl, and 1,2,3,4-tetrahydro -7- WO 2009/079624 PCT/US2008/087397 quinolinyl. Non-limiting examples of heterocyclic groups having 2 or more rings include, for example: hexahydro-1 H-pyrrolizinyl, 3a,4,5,6,7,7a-hexahydro-1 H benzo[d]imidazolyl, 3a,4,5,6,7,7a-hexahydro-1H-indolyl, 1,2,3,4-tetrahydroquinolinyl, chromanyl, isochromanyl, indolinyl, isoindolinyl, and decahydro-1H 5 cycloocta[b]pyrrolyl. The term "heteroaryl," whether used alone or as part of another group, is defined herein as a single or fused ring system having from 5 to 20 atoms (e.g., 5 to 10 atoms, 5 to 6 atoms) wherein at least one atom in at least one ring is a heteroatom selected from nitrogen (N), oxygen (0), and sulfur (S), and wherein further at least 10 one of the rings that includes a heteroatom is aromatic. In heteroaryl groups that include 2 or more fused rings, any non-heteroatom bearing ring may be a carbocycle (e.g., 6,7-Dihydro-5H-cyclopentapyrimidinyl) or aryl (e.g., benzofuranyl, benzothiophenyl, indolyl). Exemplary heteroaryl groups have from 5 to 14 ring atoms and contain from 1 to 5 ring heteroatoms independently selected from nitrogen (N), 15 oxygen (0), and sulfur (S). One or more N or S atoms in a heteroaryl group can be oxidized (e.g., N->O-, S(O), SO 2 ). Where so indicated, heteroaryl groups can be substituted. Non-limiting examples of monocyclic heteroaryl rings include, for example: 1,2,3,4-tetrazolyl, [1,2,3]triazolyl, [1,2,4]triazolyl, triazinyl, thiazolyl, 1H imidazolyl, oxazolyl, furanyl, thiopheneyl, pyrimidinyl, and pyridinyl. Non-limiting 20 examples of heteroaryl rings containing 2 or more fused rings include: benzofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl, cinnolinyl, naphthyridinyl, phenanthridinyl, 7H-purinyl, 9H-purinyl, 5H-pyrrolo[3,2-d]pyrimidinyl, 7H-pyrrolo[2,3 d]pyrimidinyl, pyrido[2,3-d]pyrimidinyl, 2-phenylbenzo[d]thiazolyl, 1H-indolyl, 4,5,6,7 tetrahydro-1-H-indolyl, quinoxalinyl, 5-methylquinoxalinyl, quinazolinyl, quinolinyl, and 25 isoquinolinyl. One non-limiting example of a heteroaryl group as described above is C1-C5 heteroaryl, which is a monocyclic aromatic ring having 1 to 5 carbon ring atoms and at least one additional ring atom that is a heteroatom (preferably 1 to 4 additional ring atoms that are heteroatoms) independently selected from nitrogen (N), oxygen (0), 30 and sulfur (S). Examples of Cl-C5 heteroaryl include, but are not limited to for example, triazinyl, thiazol-2-yl, thiazol-4-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H -8- WO 2009/079624 PCT/US2008/087397 imidazol-4-yl, isoxazolin-5-yl, furan-2-yl, furan-3-yl, thiophen-2-yl, thiophen-4-yl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyridin-2-yl, pyridin-3-yl, and pyridin-4-yl. For the purposes of the present invention, fused ring groups, spirocyclic rings, 5 bicyclic rings and the like, which comprise a single heteroatom will be considered to belong to the cyclic family corresponding to the heteroatom containing ring. For example, 1,2,3,4-tetrahydroquinoline having the formula: H is, for the purposes of the present invention, considered a heterocyclyl group. 6,7 10 Dihydro-5H-cyclopentapyrimidine having the formula:
NY
is, for the purposes of the present invention, considered a heteroaryl group. When a fused ring unit contains heteroatoms in both a saturated and an aryl ring, the aryl ring will predominate and determine the type of category to which the ring is assigned. 15 For example, 1,2,3,4-tetrahydro-[1,8]naphthyridine having the formula: H N N is, for the purposes of the present invention, considered a heteroaryl group. The terms "treat" and "treating," as used herein, refer to partially or completely alleviating, inhibiting, ameliorating and/or relieving a condition from which a patient is 20 suspected to suffer. -9- WO 2009/079624 PCT/US2008/087397 As used herein, "therapeutically effective" refers to a substance or an amount that elicits a desirable biological activity or effect. Except when noted, the terms "subject" or "patient" are used interchangeably and refer to mammals such as human patients and non-human primates, as well as 5 experimental animals such as rabbits, rats, and mice, and other animals. Accordingly, the term "subject" or "patient" as used herein means any mammalian patient or subject to which the compounds of the invention can be administered. In an exemplary embodiment of the present invention, to identify subject patients for treatment according to the methods of the invention, accepted screening methods 10 are employed to determine risk factors associated with a targeted or suspected disease or condition or to determine the status of an existing disease or condition in a subject. These screening methods include, but are not limited to for example, conventional work-ups to determine risk factors that may be associated with the targeted or suspected disease or condition. These and other routine methods allow 15 the clinician to select patients in need of therapy using the methods and compounds of the present invention. The term "substituted" is used throughout the specification. The term "substituted" is defined herein as a moiety, whether acyclic or cyclic, which has one or more (e.g. 1 10) hydrogen atoms replaced by a substituent as defined herein below. Substituents 20 include those that are capable of replacing one or two hydrogen atoms of a single moiety at a time, and also those that can replace two hydrogen atoms on two adjacent carbons to form said substituent. For example, substituents that replace single hydrogen atoms includes, for example, halogen, hydroxyl, and the like. A two hydrogen atom replacement includes carbonyl, oximino, and the like. Substituents 25 that replace two hydrogen atoms from adjacent carbon atoms include, for example, epoxy, and the like. When a moiety is described as "substituted" any number of its hydrogen atoms can be replaced, as described above. For example, difluoromethyl is a substituted C, alkyl; trifluoromethyl is a substituted C, alkyl; 4-hydroxyphenyl is a substituted aryl ring; (N,N-dimethyl-5-amino)octanyl is a substituted C8 alkyl; 3 30 guanidinopropyl is a substituted C3 alkyl; and 2-carboxypyridinyl is a substituted heteroaryl. - 10- WO 2009/079624 PCT/US2008/087397 At various places in the present specification, substituents of compounds are disclosed in groups or in ranges. It is specifically intended that the description include each and every individual subcombination of the members of such groups and ranges. For example, the term "C_6 alkyl" is specifically intended to individually 5 disclose C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C6, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl. In one aspect, the present invention provides compounds of Formula I: 0 Ar 1 - (CR 5
R
6 )m N (CR 9
R
10
)-R
3 Ar 2 X N R 4 Ri
(CR
7
R
8 )n-R 2 10 (I) or a pharmaceutically acceptable salt thereof, wherein: Ar is selected from C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1 15 5 R" groups; Ar2 is selected from (CH 2 )z-C 6
-C
1 o aryl, wherein z = 0 or 1 and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1-5 R 1 7 groups; - 11 - WO 2009/079624 PCT/US2008/087397
R
1 is selected from H and C1_6 alkyl;
R
2 is selected from H, C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 18 , SR 18 , NR 28
R
29 , S0 2
R
30 , C6-C10 aryl, 5 and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C16 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 16 groups;
R
3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 10 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 1 8 , SR 1 8 , NR 31
R
32 , S0 2
R
30 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C16 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl, aryl, and 15 heteroaryl each is optionally substituted with 1-5 R 16 groups;
R
4 is selected from H and C16 alkyl; each R 5 and R 6 is independently selected from H, C16 alkyl, halogen and NHS0 2
C
1
_
6 alkyl; alternatively, any two R 5 and R 6 , taken together with the carbon to which they are 20 bound, can form a carbonyl group; each R 7 and R 8 is independently selected from H, C16 alkyl, and halogen; alternatively, any two R 7 and R 8 , taken together with the carbon to which they are bound, can form a carbonyl group; each R 9 and R 1 0 is independently are selected from H, C16 alkyl, and halogen; - 12- WO 2009/079624 PCT/US2008/087397 alternatively, any two R 9 and R 1 0 taken together with the carbon to which they are bound, can form a carbonyl group; each R" is independently selected from C16 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 5 heteroatoms selected from N, 0 and S, halogen, CN, OR, SR, NO 2 and NR R 1 4 wherein the C16 alkyl, the C2-6 alkenyl, the C2-6 alkynyl, and the C3-10 cycloalkyl is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R 1 6 groups; each R 1 2 is independently selected from H, C1-6 alkyl, and C1-3 perhaloalkyl; 10 each R 1 3 and R 1 4 is independently selected from H and C1_6 alkyl; each R 1 5 is independently selected from halogen, CN, OH, C1_6 alkoxy, C1-3 perhaloalkoxy, SH, SC 1 -_ alkyl, NH 2 , NH(C 1
_
6 alkyl), and N(C 16 alkyl) 2 ; each R 16 is independently selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OC1_6 alkyl, OC1-3 perhaloalkyl, SH, SC 1 -_ alkyl, NH 2 , NH(C_ 6 alkyl), and N(C_ 6 15 alkyl) 2 ; each R 1 7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NO 2 , C3 10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 1 8 , SR 1 8 , NR 1 9
R
2 0 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 20 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl is optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl is optionally substituted with 1-5 R 22 groups; alternatively, two R 17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, 0 25 and S, and optionally substituted with 1-5 R 22 groups; - 13- WO 2009/079624 PCT/US2008/087397 each R 18 is independently selected from H, C1-6 alkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C16 alkyl optionally is substituted with 1-4 R 23 groups; 5 each R 1 9 and R 2 0 is independently selected from H, C1-6 alkyl, C(O)R 24 , C(O)OR 24
C(=NR
25
)NR
2 6
R
27 , C(O)NR 2 6
R
27 , and SO 2
R
24 ; each R 21 is independently selected from halogen, CN, OH, C1-6 alkoxy, SH, SC 1
-
6 alkyl, NH 2 , NH(Cj_ 6 alkyl), N(C_ 6 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered 10 heteroaryl containing 1-4 heteroatoms selected from N, 0 and S; each R 22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OC1-6 alkyl, C1-3 perhaloalkoxy, SH, SC 1
-
6 alkyl, NH 2 , NH(C 1
-
6 alkyl), -CH 2 heteroaryl and N(C 16 alkyl) 2 ; each R 2 3 is independently is selected from halogen, CN, OH, OC1-6 alkyl, NH 2 , 15 NH(C 1
-
6 alkyl), N(C 1 6 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the cycloheteroalkyl, aryl , and heteroaryl each is optionally substituted with 1-4 groups selected from C1_6 alkyl, C1-3 perhaloalkyl, and halogen; 20 R 24 is C1_6 alkyl optionally substituted with 1-4 groups selected fromhalogen, CN, OH, OC1_6 alkyl, OC1-3 perhaloalkyl, SH, SC 1
-
6 alkyl, NH 2 , NH(C 1
-
6 alkyl), and N(C 16 alkyl) 2 ; each R 25 , R 2 6 and R 27 is independently selected from H and C1_6 alkyl; each R 28 and R 2 9 is independently selected from H, C1_6 alkyl optionally substituted with 1-4 R 3 e groups, C(O)R 3 0 , C(O)OR 30 , C(=NR 25
)NR
2 eR 27 , C(O)NR 2 eR 27 , and 25 SO 2
R
3 0 ; -14- WO 2009/079624 PCT/US2008/087397
R
30 is selected from C1-6 alkyl, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1-4 groups selected from C1-6 alkyl, halogen, CN, OH, OC1-6 alkyl, OC1-3 perhaloalkyl, SH, SC_e alkyl, NH 2 , NH(C_ 6 alkyl), and N(C_ 6 alkyl) 2 ; 5 each R 31 and R 32 is independently selected from H, C1-6 alkyl optionally substituted with 1-4 R 3 6 groups, C3-10 cycloalkyl, C(O)R 3 3 , C(O)OR 33 , C(=NR 25
)NR
2 6
R
27 ,
C(O)NR
3 4
R
35 , SO 2
R
33 , 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S; 10 R 33 is selected from C1-6 alkyl optionally substituted with 1-4 R 3 6 groups, C6-C10 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-4 R 37 groups;
R
34 and R 3 5 each independently is selected from H, C1-6 alkyl optionally substituted 15 with 1-4 R groups, C6-C10 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-4 R 37 groups; each R 3 6 is independently selected from halogen, CN, OH, C16 alkoxy, C1-3 perhaloalkoxy, SH, SC1-6 alkyl, NH 2 , NH(C_ 6 alkyl), N(C 16 alkyl) 2 , C6 or C10 aryl, and 20 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S; each R 37 is independently selected from C16 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, C16 alkoxy, C1-3 perhaloalkoxy, SH, SC1-6 alkyl, NH 2 , NH(C 1
_
6 alkyl), and N(C_ 6 alkyl) 2 ; m is 0, 1 2, 3, or 4; 25 n isO, 1,2, 3,4, 5or6; and - 15- WO 2009/079624 PCT/US2008/087397 p is 0, 1, 2, 3, 4, 5 or 6. In some embodiments, R 1 is H. In some embodiments, R 4 is H or C1-6 alkyl. In some embodiments, m is 0, 1, 2, or 3. In some embodiments, m is 1 and R 5 and 5 R 6 , are each methyl or H (e.g., both R 5 and R 6 are H). In some embodiments, m is 2 and R 5 and R 6 , at each occurrence, are each methyl or H (e.g., R 5 and R 6 , at each occurrence, are each H). In some embodiments, m is 3 and R 5 and R 6 , at each occurrence, are each methyl or H (e.g., R 5 and R 6 , at each occurrence, are each H). In some embodiments, Ar is a C6-C10 aryl ring or a 5-14 membered heteroaryl ring, 10 each aryl or heteroaryl ring having at least one substituent selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH 2 , NH(C 1
-
6 alkyl), N(C 16 alkyl) 2 , NO 2 , C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC1_ 6 alkyl,CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, wherein the C1-6 alkyl group optionally is substituted with R 1 5 and wherein the 3-10 membered cycloheteroalkyl is 15 optionally substituted with R 16 . In some embodiments, Ar is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH 2 , NH(C 1
-
6 alkyl),
N(C
16 alkyl) 2 , NO 2 , C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC 1 -_ alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, 20 wherein the C1_6 alkyl group optionally is substituted with R 1 5 and wherein the 3-10 membered cycloheteroalkyl optionally is substituted with R 16 . In some embodiments, Ar is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, F, Cl, OH, OCH 3 , OCF 3 , SCH 3 , CH 2
N(CH
3
)
2 , and pyrrolidinyl, piperidinyl, piperazinyl, N 25 methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl. - 16- WO 2009/079624 PCT/US2008/087397 In some embodiments, Ar is para-substituted phenyl (e.g., 4-methoxyphenyl). In some embodiments, Ar is selected from pyridine and pyrimidine, each optionally substituted with 1-5 R 11 groups. In some embodiments, Ar 2 is phenyl substituted with 1, 2, or 3 substituents 5 independently selected from halogen, C1-6 alkyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3 10 membered cycloheteroalkyl ring containing 1 to 4 heteroatoms selected from N, 0 and S, and 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl and the C3-10 cycloalkyl are each optionally substituted with 1-5 R 2 1 groups, and wherein the cycloheteroalkyl and heteroaryl 10 each optionally is substituted with 1-5 R 22 groups. In some embodiments, Ar 2 is phenyl substituted with C1-6 alkyl (e.g., 4-(tert butyl)phenyl) or C3-10 cycloalkyl (e.g., 4-cyclopropylphenyl). In some embodiments, Ar 2 is phenyl substituted with 1, 2 or 3 substitutents independently selected from F, Cl, methyl, ethyl, propyl, iso-propyl, butyl, tert-butyl, 15 cyclopropyl, trifluoromethyl, pyrrolidine, piperidine, piperazine N-methylpiperazine, N ethylpiperazine, morpholine, pyridine, imidazole and 2-methylimidazole. In some embodiments, Ar2 is phenyl substituted with 1, 2, or 3 OR" groups. In some embodiments, R 18 is selected from H, C1-6 alkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, and 5-10 20 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl optionally is substituted with 1-4 R 23 groups. In some embodiments, R 1 8 is C1-6 alkyl. In other embodiments, R 1 8 is C1-6 alkyl substituted with 1-4 groups selected from halogen, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, a C6-C10 aryl ring, and a 5-10 membered heteroaryl ring 25 containing 1-4 heteroatoms selected from N, 0 and S. In some embodiments, R 18 is C1-6 alkyl substituted with 1-2 groups selected from F, phenyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl. - 17- WO 2009/079624 PCT/US2008/087397 In some embodiments, Ar2 is phenyl substituted with 1, 2, or 3 NR 1 9
R
20 groups. In some embodiments, R 1 9 and R 20 are selected from H, C1-6 alkyl, C(=NR 25
)NR
2
R
27 , and S0 2
R
24 . In some embodiments, R 1 9 and R 20 are each independently C1-6 alkyl. Examples of these compounds include those wherein Ar 2 is phenyl substituted with 5 NH 2 , N(CH 3
)
2 , N(CH 2
CH
3
)
2 , NHSO 2
CH
3 , N(SO 2
CH
3
)
2 , and NH(C=NH)NH 2 . In some embodiments, Ar 2 is phenyl substituted with two R 1 7 groups, wherein the two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring selected from pyrrolidine, 1,3-dioxolane, 1,4-dioxane, pyrrolidine, piperidine, piperazine and morpholine, each optionally substituted with 1-5 R 22 10 groups. Examples of these compounds include those wherein Ar 2 is benzo[d][1,3]dioxolyl, 2,2-difluorobenzo[d][1,3]dioxolyl, indolinyl, N-methylindolinyl, 2,3-dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, N-methyl-3,4 dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinolinyl, and N-methyl-1,2,3,4 tetrahydroquinolinyl. 15 In some embodiments, Ar 2 is para-substituted phenyl. In some embodiments, Ar 2 is 5-10 membered heteroaryl optionally substituted with 1 5 R 1 7 groups. For example, Ar2 can be selected from furanyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, and quinolinyl, each optionally substituted with 1-5 R 1 7 groups. 20 In some embodiments, R 2 is selected from H, CN, C1-6 alkyl optionally substituted with 1-5 R 1 5 groups, and C2-6 alkenyl optionally substituted with 1-5 R 1 5 groups. In some embodiments, R 2 is C6-C10 aryl (e.g., phenyl) optionally substituted with 1-5
R
1 6 groups. In some embodiments, R 2 is OR. In some embodiments, R 1 is phenyl optionally 25 substituted with 1-4 R 23 groups or 5-10 membered heteroaryl optionally substituted with 1-4 R23 groups. - 18- WO 2009/079624 PCT/US2008/087397 In some embodiments, R 2 is S0 2
R
30 . In some embodiments, R 3 0 is optionally substituted C-C6 alkyl, or optionally substituted 6-10 membered aryl. In some embodiments, R 2 is 5-10 membered heteroaryl (e.g., pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl) optionally substituted with 1-5 R 1 6 groups 5 In some embodiments, R 2 is C3-10 cycloalkyl (e.g., C3-6 cycloalkyl) optionally substituted with 1-5 R 15 groups. In some embodiments, R 2 is 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S (e.g., piperidinyl) optionally substituted with 1 5 R 1 6 groups. 10 In some embodiments, R 2 is NR 28
R
29 . In some embodiments, R 28 is H, and R 2 9 is
C(O)R
30 . R 3 0 can be optionally substituted 5-10 membered heteroaryl (e.g., pyridinyl, imidaziolyl, pyrimidinyl or pyrazinyl). In some embodiments, R 2 8 is H, and R 2 9 is
C(O)OR
30 . R 30 can be C-C6 alkyl. In some embodiments, R 28 and R 2 9 are each independently H or C1-C6 alkyl. In some embodiments, R 28 is H, and R 2 9 is 15 C(O)NR 2 6
R
2 7 . R 28 and R 2 9 can each independently be H or C1-C6 alkyl, wherein the C0-C6 alkyl is optionally substituted with 5-10 membered heteroaryl or 6-10 membered aryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are each optionally and independently substituted with 1-5 R 1 6 groups. In some embodiments, n is 0, 1, 2, 3, or 4. In some embodiments, n is 1 and R 7 and 20 R 8 each is H. In some embodiments, n is 1 and R 7 and R , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 2 and each R 7 and R 8 , at each occurrence, is H. In some embodiments, n is 2 and one R7 and R , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 3 and each R 7 and R 8 , at each occurrence, is H. In some 25 embodiments, n is 3 and one R 7 and R , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, n is 4 and each R 7 and R 8 , at - 19- WO 2009/079624 PCT/US2008/087397 each occurrence, is H. In some embodiments, n is 4 and one R 7 and R , taken together with the carbon to which they are bound, form a carbonyl. In some embodiments, p is 0. In some embodiments, p is 0 and R 3 is H or C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl). In some embodiments, R 4 5 is H. In some embodiments, R 3 and R 4 are each independently H or C1_6 alkyl. In some embodiments, R 3 is C6-C10 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S (e.g., pyrrolyl, imidazolyl, pyridinyl, or pyrimidinyl), each optionally substituted with 1-5 R 1 6 groups. In some embodiments, R 3 is NR 31
R
3 2 . In some embodiments, one of R 31 and R 3 2 is 10 H and the other is S0 2
R
33 . R 3 3 can be C1-6 alkyl optionally substituted with 1-4 R 3 4 groups (e.g., C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S). In some embodiments, R 33 is benzyl or CH 2 -pyridinyl. In some embodiments, R 3 is NR 3 1
R
3 2 and one of R 31 and R 3 2 is H and the other is
C(O)NR
3 4
R
35 . R 3 4 and R 3 5 can each independently be H or C1_6 alkyl. In some 15 embodiments, one of R 34 and R 3 5 is H and the other is C1_6 alkyl. In other embodiments, one of R 34 and R 3 5 is H and the other is C6-C10 aryl (e.g., phenyl) or 5 10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S (e.g., pyridinyl or pyrimidinyl). In some embodiments, one of R 34 and R 35 is C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert-butyl) and the other is C6-C10 aryl or 5-10 20 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S (e.g., phenyl, pyridinyl or pyrimidinyl). In some embodiments, R 3 is NR 3 1
R
3 2 and one of R 31 and R 3 2 is H and the other is
C(O)OR
33 . R 33 can be C16 alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl or tert butyl) optionally substituted with 1-4 R 3 6 groups (e.g., NH 2 , NH(C 1
_
6 alkyl), N(C 16 25 alkyl) 2 , C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S). In some embodiments, R 33 is benzyl. - 20 - WO 2009/079624 PCT/US2008/087397 In some embodiments, R 3 is NR 3 1
R
3 2 and one of R 31 and R 32 is H and the other is C6 or C10 aryl (e.g., phenyl), or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S (e.g., pyridinyl or pyrimidinyl). In some embodiments, R 3 is NR 31
R
32 and each of R 31 and R 3 2 is H. 5 In some embodiments, R 3 is NR 3 1
R
32 and each of R 31 and R 3 2 independently is C1-6 alkyl optionally substituted with 1-4 R 3 6 groups. In some embodiments, each of R 31 and R 32 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, tert butyl, benzyl and CH 2 -pyridinyl. In some embodiments, R 3 is OR 1 8 . R 1 8 can be H or C1-6 alkyl optionally is substituted 10 with 1-4 R23 groups (e.g., R 1 8 can be benzyl or CH 2 -pyridinyl). In some embodiments, R 3 is C6-C10 aryl (e.g., phenyl) or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S (e.g., pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl or quinolinyl), each optionally substituted with 1-5 R 1 6 groups. 15 In some embodiments, p is 1, 2, 3, or 4. In some embodiments, p is 1 and each of R 9 and R 1 0 is H. In some embodiments, p is 1 and R 9 and R 1 0 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 2 and each of R 9 and R 10 , at each occurrence, is H. In some embodiments, p is 2 and one of R 9 and R 1 0 , taken together with the carbon to which they are bound, form 20 a carbonyl group. In some embodiments, p is 3 and each of R 9 and R 10 , at each occurrence, is H. In some embodiments, p is 3 and one of R 9 and R 1 0 , taken together with the carbon to which they are bound, form a carbonyl group. In some embodiments, p is 4 and each of R 9 and R 10 , at each occurrence, is H. In some embodiments, p is 4 and one of R 9 and R 1 0 , taken together with the carbon to which 25 they are bound, form a carbonyl group. - 21 - WO 2009/079624 PCT/US2008/087397 In some embodiments, the compounds of the invention have a structure according to Formula (II): 0 Ar- (CR 5
R
6 ) N (CR 9
R
1 0
)-R
3 Ar 2 Ar2 N R 4 R1
(CR
7
R
8 )n-R 2 (II) 5 or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R', R 8 , R 9 , R 1 0 , n, and p are defined as above. In some embodiments, m is 1 and R 5 and R 6 are each H. In some embodiments, m is 1 and one of R 5 and R 6 is H and the other is C1_6 alkyl. In some embodiments, m is 10 1 and R 5 and R 6 , at each occurrence, are each H. In some embodiments, Ar is para-substituted phenyl (e.g., 4-methoxyphenyl). In some embodiments, the compounds of the invention have a structure according to Formula (Ill): - 22 - WO 2009/079624 PCT/US2008/087397 0 Ar 1
-(CR
5
R
6 )m N (CR 9
R
1
)-R
3 Ar 2 N R N R 4
(CR
7
R
8
)"-R
2 0 (Ill) or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4 or 5 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R', R , R 9 , R 10 , m, 5 and p are defined above. In some embodiments, when m=O, R 4 is methyl, (CR 9
R
0 )p-R 3 forms methyl,
(CR
7
R
8 ) -R 2 forms methyl, Ar 2 is phenyl, and R 1 is H, then Ar cannot be 2,4 dichlorophenyl; In some embodiments, when m=0, R 4 is methyl, and R 1 is H, Ar 2 is phenyl, and one 10 of (CR 9
R
0 )p-R 3 and (CR 7 R 8
)-R
2 forms methyl and the other of (CR 9
R
0 )p-R 3 and
(CR
7
R
8 ) -R 2 forms H, then Ar cannot be 2,4-dichlorophenyl; In some embodiments, when m=0, R 4 is methyl, (CR 9
R
0 )p-R 3 forms methyl,
(CR
7
R
8 ) -R 2 forms t-butyl, Ar 2 is phenyl, and R 1 is H, then Ar cannot be phenyl; In some embodiments, when m=0, R 4 is methyl, (CR 9
R
0 )p-R 3 forms phenyl, 15 (CR 7
R
8 ) -R 2 forms t-butyl, Ar 2 is phenyl, and R 1 is H, then Ar cannot be phenyl; - 23 - WO 2009/079624 PCT/US2008/087397 In some embodiments, when m=0, R 1 is H, Ar2 is phenyl, (CRR 8
)-R
2 forms t-butyl,
(CR
9
R
1 0 )p-R 3 forms methyl, and R 4 is methyl, then Ar cannot be phenyl, 4 methylphenyl, or 4-methoxyphenyl. In some embodiments, when m=0, R 1 is H, Ar2 is phenyl, (CRR 8
)-R
2 forms t-butyl, 5 (CR 9
R
1 0 )p-R 3 forms phenyl, and R 4 is methyl, then Ar cannot be phenyl. In some embodiments, when m=0, R 1 is H, Ar2 is phenyl, (CR 7 R 8
)-R
2 forms ethyl,
(CR
9
R
0 )p-R 3 forms H, and R 4 is H, then Ar cannot be 2-methoxyphenyl. In some embodiments, when m=0, R 1 is H, Ar 2 is phenyl, (CR 7 R 8
)-R
2 forms methyl,
(CR
9
R
0 )p-R 3 forms H, and R 4 is H, then Ar cannot be 4-methoxyphenyl, 4 10 ethoxyphenyl or 4-bromophenyl. In some embodiments, when m=0, R 1 is H, Ar 2 is phenyl, (CR 7 R 8
)-R
2 forms methyl,
(CR
9
R
0 )p-R 3 forms butyl, and R 4 is H, then Ar cannot be phenyl. In some embodiments, when m=0, R 1 is H, Ar 2 is phenyl, (CR 7 R 8
)-R
2 forms H,
(CR
9
R
0 )p-R 3 forms methyl, and R 4 is H, then Ar cannot be 4-chlorophenyl or 2,4, 15 dichlorophenyl. In some embodiments, when m=0, R 1 is H, Ar 2 is phenyl, (CR 7 R 8
)-R
2 forms H,
(CR
9
R
0 )p-R 3 forms methyl, and R 4 is H, then Ar cannot be 2,4,-dichlorophenyl. In some embodiments, when R 1 is H, Ar 2 is phenyl, n is 0 and R 2 is H, p is 1 and R 3 is phenyl, and m is 0, then Ar cannot be 4-methylphenyl or cyclohexyl. In some 20 embodiments, when R 1 is H, Ar 2 is phenyl, n is 0 and R 2 is H, p is 1 and R 3 is phenyl, and m is 1, then Ar cannot be phenyl. In some embodiments, when p is 0 and R 3 is H, R 4 is H, n is 1 and R 2 is phenyl, m is 1 and Ar is phenyl, and R 1 is H, then Ar 2 cannot be 4-chlorophenyl or 4 (dimethylamino)phenyl. -24- WO 2009/079624 PCT/US2008/087397 In some embodiments, each R 1 7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 18 , SR 18 , NR 1 9
R
20 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 5 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 22 groups; alternatively, two R 1 7 groups, together with the carbon atoms to which they are 10 bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, 0 and S, and optionally substituted with 1-5 R 22 groups; Ar2 is selected from C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1 5 R 1 7 groups; 15 each R" is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR, SR , and NR 13 R, wherein the C1-6 alkyl, the C2-6 alkenyl, the C2-6 alkynyl, and the C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl is 20 optionally substituted with 1-5 R 1 6 groups; and each R 22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OC1_6 alkyl, C1-3 perhaloalkoxy, SH, SC 1
-
6 alkyl, NH 2 , NH(C 1
-
6 alkyl), and N(C_ 6 alkyl) 2 . Compounds described herein can contain an asymmetric atom (also referred as a 25 chiral center), and some of the compounds can contain one or more asymmetric atoms or centers, which can thus give rise to optical isomers (enantiomers) and diastereomers. The present teachings and compounds disclosed herein include - 25- WO 2009/079624 PCT/US2008/087397 such enantiomers and diastereomers, as well as the racemic and resolved, enantiomerically pure R and S stereoisomers, as well as other mixtures of the R and S stereoisomers and pharmaceutically acceptable salts thereof. Optical isomers can be obtained in pure form by standard procedures known to those skilled in the art, 5 which include, but are not limited to for example, chiral chromatography, diastereomeric salt formation, kinetic resolution, and asymmetric synthesis. The present invention also includes cis and trans or E/Z isomers of compounds of Formula (I) containing alkenyl moieties (e.g., alkenes and imines). It is also understood that the present teachings encompass all possible regioisomers, and 10 mixtures thereof, which can be obtained in pure form by standard separation procedures known to those skilled in the art, and include, but are not limited to, column chromatography, thin-layer chromatography, and high-performance liquid chromatography. Pharmaceutically acceptable salts of compounds of the present invention, which can 15 have an acidic moiety, can be formed using organic and inorganic bases. Both mono and polyanionic salts are contemplated, depending on the number of acidic hydrogens available for deprotonation. Suitable salts formed with bases include metal salts, such as alkali metal or alkaline earth metal salts, for example sodium, potassium, or magnesium salts; ammonia salts and organic amine salts, such as 20 those formed with morpholine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or tri-lower alkylamine (e.g., ethyl-tert-butyl-, diethyl-, diisopropyl-, triethyl-, tributyl- or dimethylpropylamine), or a mono-, di-, or trihydroxy lower alkylamine (e.g., mono-, di or triethanolamine). Specific non-limiting examples of inorganic bases include NaHCO 3 , Na 2
CO
3 , KHCO 3 , K 2
CO
3 , Cs2CO3, LiOH, NaOH, KOH, NaH 2
PO
4 , Na 2
HPO
4 , 25 and Na 3
PO
4 . Internal salts also can be formed. Similarly, when a compound disclosed herein contains a basic moiety, salts can be formed using organic and inorganic acids. For example, salts can be formed from the following acids: acetic, propionic, lactic, benzenesulfonic, benzoic, camphorsulfonic, citric, tartaric, succinic, dichloroacetic, ethenesulfonic, formic, fumaric, gluconic, glutamic, hippuric, 30 hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, malonic, mandelic, methanesulfonic, mucic, napthalenesulfonic, nitric, oxalic, pamoic, pantothenic, phosphoric, phthalic, propionic, succinic, sulfuric, tartaric, toluenesulfonic, and -26- WO 2009/079624 PCT/US2008/087397 camphorsulfonic, carbonic, as well as other known pharmaceutically acceptable acids. The compounds described herein may be administered to humans and other animals orally, parenterally, sublingually, by aerosolization or inhalation spray, rectally, 5 intracisternally, intravaginally, intraperitoneally, bucally, intrathecally or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. The term parenteral as used herein includes subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, or infusion techniques. Topical administration may also involve 10 the use of transdermal administration such as transdermal patches or ionophoresis devices. Methods of formulation are well known in the art and are disclosed, for example, in Remington: The Science and Practice of Pharmacy, Mack Publishing Company, Easton, Pa., 21st Edition (2005), incorporated herein by reference. 15 Pharmaceutical compositions for use in the present invention can be in the form of sterile, non-pyrogenic liquid solutions or suspensions, coated capsules, suppositories, lyophilized powders, transdermal patches or other forms known in the art. Injectable preparations, for example, sterile injectable aqueous or oleaginous 20 suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending 25 medium. For this purpose any bland fixed oil may be employed including synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. The injectable formulations can be sterilized, for example, - 27 - WO 2009/079624 PCT/US2008/087397 by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. Formulations comprising crystalline forms of the compositions described herein for 5 slow absorption from subcutaneous or intramuscular injection are provided herein. Additionally, delayed absorption of a parenterally administered drug form may be accomplished by dissolving or suspending the compounds in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio 10 of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations may also be prepared by entrapping the drug in liposomes or microemulsions, which are compatible with body tissues. 15 Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, 20 carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, 25 acetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. - 28 - WO 2009/079624 PCT/US2008/087397 Solid compositions of a similar type may also be employed as fillers in soft and hard filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, capsules, pills, and granules can be prepared with 5 coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric 10 substances and waxes. The compounds described herein can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical 15 formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the 20 dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. 25 Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, EtOAc, benzyl 30 alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, - 29 - WO 2009/079624 PCT/US2008/087397 oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, 5 sweetening, flavoring, and perfuming agents. Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives 10 or buffers as may be required. Ophthalmic formulations, ear drops, and the like are also contemplated as being within the scope of this invention. Compositions of the invention may also be formulated for delivery as a liquid aerosol or inhalable dry powder. Liquid aerosol formulations may be nebulized predominantly into particle sizes that can be delivered to the terminal and respiratory 15 bronchioles. Effective amounts of the compounds of the invention generally include any amount sufficient to detectably modulate Kv1.5 potassium channel activity, or to alleviate symptoms of diseases associated with Kv1.5 potassium channel activity or susceptible to Kv1.5 potassium channel activity modulation. 20 The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. It will be understood, however, that the specific dose level for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, 25 sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The therapeutically effective amount for a given situation can be readily determined by routine experimentation and is within the skill and judgment of the ordinary clinician. - 30 - WO 2009/079624 PCT/US2008/087397 In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including directions for treating or preventing atrial arrhythmia, thromboembolism, stroke, or 5 cardiac failure by administering an effective amount of a compound of the present invention. In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including 10 directions for inhibiting Kv1.5 potassium channel by administering an effective amount of a compound of the present invention. In another aspect of the invention, kits that include one or more compounds of the invention are provided. Representative kits include a compound described herein (e.g., a compound of Formula I) and a package insert or other labeling including 15 directions for inducing cardioversion by administering an effective amount of a compound of the present invention. When any variable occurs more than one time in any constituent or in any formula, its definition in each occurrence is independent of its definition at every other occurrence (e.g., in N(C_ 6 alkyl) 2 , each C1-6 alkyl may be the same or different than 20 the other). Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. The Kv1.5 potassium channel inhibitors of the present invention are certain 4 imidazolidinones, and include all enantiomeric and diasteriomeric forms and salts of compounds having the formula (I): - 31 - WO 2009/079624 PCT/US2008/087397 0 Ar 1
-(CR
5
R
6 )m N (CR 9
R
1 0
)-R
3 Ar 2 :X N R 4 Ri
(CR
7
R
8
)"-R
2 (I) wherein the core scaffold is numbered in the following manner, 0 N 4 5 5 For the purposes of the present invention, a compound depicted by the racemic formula, for example: F 0 0 N'~ N N N will stand equally well for any of the four stereoisomers having the formula: - 32 - WO 2009/079624 PCT/US2008/087397 F F FN N F F 0 0 N NH N N N N F F FF F+F 0 0 I O N \ N' NH N NH 7- N\ or or mixtures thereof (or in the case where one or more additional chiral centers are 5 present, all stereoisomers and mixtures thereof). Compounds of the present invention can be prepared in accordance with the procedures outlined herein, from commercially available starting materials, compounds known in the literature, or readily prepared intermediates, by employing standard synthetic methods and procedures known to those skilled in the art. 10 Standard synthetic methods and procedures for the preparation of organic molecules and functional group transformations and manipulations can be readily obtained from the relevant scientific literature or from standard textbooks in the field. It will be appreciated that where typical or preferred process conditions (i.e., reaction temperatures, times, mole ratios of reactants, solvents, pressures, etc.) are given, - 33 - WO 2009/079624 PCT/US2008/087397 other process conditions can also be used unless otherwise stated. Optimum reaction conditions can vary with the particular reactants or solvent used. Those skilled in the art will recognize that the nature and order of the synthetic steps presented can be varied for the purpose of optimizing the formation of the 5 compounds described herein. The processes described herein can be monitored according to any suitable method known in the art. For example, product formation can be monitored by spectroscopic means, such as nuclear magnetic resonance spectroscopy (e.g., 1 H or 13C), infrared spectroscopy, spectrophotometry (e.g., UV-visible), mass spectrometry, or by 10 chromatography such as high-performance liquid chromatograpy (HPLC), gas chromatography (GC), gel-permeation chromatography (GPC), or thin layer chromatography (TLC). Preparation of the compounds can involve protection and deprotection of various chemical groups. The chemistry of protecting groups can be found, for example, in 15 Greene et al., Protective Groups in Organic Synthesis, 4th. Ed. (John Wiley & Sons, 2007), the entire disclosure of which is incorporated by reference herein for all purposes. The reactions or the processes described herein can be carried out in suitable solvents, which can be readily selected by one skilled in the art. Suitable solvents 20 typically are substantially nonreactive with the reactants, intermediates, and/or products at the temperatures at which the reactions are carried out, i.e., temperatures that can range from the solvent's freezing temperature to the solvent's boiling temperature. A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable 25 solvents for a particular reaction step can be selected. The compounds of these teachings can be prepared by methods known in the art. The reagents used in the preparation of the compounds of these teachings can be either commercially obtained or can be prepared by standard procedures described - 34 - WO 2009/079624 PCT/US2008/087397 in the literature. For example, compounds of the present invention can be prepared according to the method illustrated in the General Synthetic Schemes: GENERAL SYNTHETIC SCHEME(S) FOR PREPARATION OF COMPOUNDS. The reagents used in the preparation of the compounds of this invention can be 5 either commercially obtained or can be prepared by standard procedures described in the literature. In accordance with this invention, compounds in the genus may be produced by one of the following reaction schemes. Functionalized amino acid amides (e.g. 1) may be prepared using standard literature procedures. Ring closure to form the 4-imiddazolidinone 3 can be accomplished by 10 heating 1 in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat mixture of the two. Conventional or microwave heating may be employed. O R 3 0 (f Base ,kN "-+'" Solvent Ar 4 Ar2
H
2 N R 4 4 2 0 R 3 0 R 3 PN RBats Ar 1 m Novet Ar _ N Ar N R Ar 2 R 4 3 5 Alternatvely, amino acid amide 4 may be cyclized to imidazolidinone 5 by by heating in the presence of a suitable aldehyde (2) in an appropriate solvent or as a neat 15 mixture of the two. Conventional or microwave heating may be employed. Functionalization in the presence of a base and suitable electrophilic (e.g. alkyl halide, alkyl sulfonate, sulfonyl halide, acid halide) agent provides the desired imidazolidinone. -35- WO 2009/079624 PCT/US2008/087397 o R 3 0 )", ( PBase 10 N+ Solvent Ar 1 mH Ar 2 H
H
2 N R 4 4 2 P R 3 0 R 3 P Baji~ Ar 1 R Ar 1 m R4 M NH R \ Ar 2 Ar3 5 In cases when the amino acid side chain may be modified, such as carboxylic acid side chain examples (e.g. 6) where PG is a suitable protecting group, removal of the protecting group using standard conditions provides imidazolidinone 7. Amide 5 synthesis may then be accomplished using standard literature procedure to provide 8. 0 0 0 AOPG D OH NR 31
R
32 N P Deprotection_ p KAm.ide Arimm N4 4 Ar m N Ar 2 6 2Ar 2 7Ar8R Alternatively, imidazolidinone 7 may be converted to suitably protected amines (9) 10 using methods described in the literature, which may be subsequently deprotected under the appropriate conditions to provide the free amine 10. Side chain functionalization may then be accomplished with a suitable electrophile (e.g. carboxylic acid, carboxylic acid halide, sulfonyl halide, isocyanante) in the presence or absence of a suitable coupling agent (e.g. EDCI) or base (e.g. NEt 3 , DIPEA) to 15 provide 11. - 36 - WO 2009/079624 PCT/US2008/087397 0 OH 0 NHPG 0 NH 2 Ar C O Amide synthesis Ar N PGDeprotection NRH2 N R+Pq , 4 m0 Nk~ Y r -N'2R N, R2 Ar -N RAr 2 10R
A
2 IR Ar 2 Ar2 7 RAr2 9 E 0 NH Electrophile Coupling agent Ar N R 4 Base A 2 Ar 2 11R Reduction of 7 with a suitable reducing agent (e.g. borane) may also be employed to provide alcohol 12. Conversion of the alcohol to a leaving group (e.g. halide or 5 sulfonate) using standard literature procedures followed by displacement with a nucleophile provides 13 where Nu is a suitable alcohol or amine. 0 00 Nu (r OH 0 (OH p Reduction 1) Conversion to Ar mn R4 Arm leaving group Ar N R 4 N 2 N R 4 2) Nucleophile Ar 2
'R
2 Ar y R 2 Ar 1 R 2 13 7 12 1 10 EXAMPLES The following non-limiting examples are presented to illustrate the present teachings. The skilled person will understand that there are numerous equivalents and variations not exemplified but which still form part of the present teachings. CATEGORY I 15 Example 1: 2-(4-tert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin 4-one: - 37 - WO 2009/079624 PCT/US2008/087397 0 H 2 N Br 0 -NH N Br BrH H 0 OO N 0 O Pd / C, H2 0 K 2 C0 3 , CH 3 0H N N N--l N-J N _aCHO H H Step 1: 2-Bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 12.9 mL (148.6 mmol) of bromoacetylbromide in 500 mL of anhydrous methylene chloride at room 5 temperature was added 45.7 mL (312.1 mmol) of 4-methoxyphenethyl amine. The resulting solution was stirred for 12 hours and monitored by TLC. 900 mL of 0.1 N HCI was added and the organic layer was separated in a separatory funnel. The remaining aqueous layer was extracted with methylene chloride (3 x 200 mL) and all organic layers were combined. The organic layers were dried over sodium sulfate, 10 filtered, and the solvent was removed in vacuo to provide 40.0 g (94 % yield) of product as a slightly yellow oil. MW = 272.14; 1 H NMR (300 MHz, CDCla)6 7.20 (d, 2H, J = 6.6 Hz), 6.88 (d, 2H, J = 6.6 Hz), 3.88 (s, 2H), 3.83 (s, 3H), 3.56 (q, 2H, J = 6.7 Hz), 2.81 (t, 2H, J = 6.7 Hz); (MH*) 273; Step 2: 2-(Benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide: To 40 g 15 (147.1 mmol) of 2-bromo-N-[2-(4-methoxyphenyl)ethyl]acetamide in 200 mL of THF at room temperature was added 36 mL (294.2 mmol) of N-methyl benzyl amine. The resulting solution was stirred for 12 hours and was monitored by TLC. The THF was removed in vacuo giving 44 g (100 % yield) of a yellow oil. MW = 312.41; 1 H NMR (300 MHz, CDC13) 6 7.33 (m, 5H), 7.14 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.4 20 Hz), 3.81 (s, 3H), 3.55 (q, 2H, J = 6.7 Hz), 3.52 (s, 2H), 3.03 (s, 2H), 2.80 (t, 2H, J = 6.7 Hz), 2.20 (s, 3H); (MH*) 313; Step 3: N-[2-(4-Methoxyphenyl)ethyl]-2-methylaminoacetamide: To 44 g of 2 (benzylmethylamino)-N-[2-(4-methoxyphenyl)ethyl]acetamide in ethanol at room -38- WO 2009/079624 PCT/US2008/087397 temperature was added 5.0 g of 10% Pd/C and the mixture was put on a hydrogen Parr reduction apparatus (40 psi of H). The resulting mixture was shaken on the Parr reduction machine and recharged with hydrogen gas to maintain the 40 psi of hydrogen gas for 16 hours. The mixture was then filtered through celite, and the 5 solvent removed in vacuo resulting in 31.7 g (100 % yield) of product as a yellow oil. MW = 222.28; 'H NMR (300 MHz, CDC13): .67.16 (d, 2H, J = 8.2 Hz), 6.86 (d, 2H, J = 8.2 Hz), 3.81 (s, 3H), 3.54 (q, 2H, J = 7.5 Hz), 3.22 (s, 2H), 2.79 (t, 2H, J = 7.5 Hz), 2.37 (s, 3H); (MH*) 223. Step 4: 2-(4-tert-Butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4 10 one: To 20.0 g (90.1 mmol) of N-[2-(4-methoxyphenyl)ethyl]-2 methylaminoacetamide in 200 mL of methanol at room temperature was added 13.7 g (99.1 mmol) of potassium carbonate and 13.1 mL (99.1 mmol) of 4-t butylbenzaldehyde. The resulting mixture was stirred at reflux and monitored by HPLC. Upon completion, the solvent was removed in vacuo, and the residue was 15 diluted with 300 mL of methylene chloride, washed with water (3 x 50 mL), dried over sodium sulfate, filtered, and the solvent was removed in vacuo. The residue was purified by Horizon MPLC in 5 g portions with gradiant solvent eluents of 5 % 20 % ethyl acetate in hexanes for 1650 mL followed by 20 %-50 % ethyl acetate in hexanes for 1200 mL. The product containing fractions were combined and the 20 solvent removed in vacuo and the remaining solid was recrystallized in ethyl acetate and hexanes to give 20.0 g (60 % yield) of pure product. MW = 366.50, MP = 121.4 0C; Rf: 0.2 (Hex:EtOAc 4:1); 1 H NMR (300 MHz, CDC13): .67.43 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.41 (s, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1H), 2.78 (m, 2H), 2.50 (m, 1H), 2.26 (s, 3H), 1.36 (m, 9H); 13C NMR (CDC13) 25 .6171.30, 158.48, 153.05, 134.08, 130.92, 130.04, 128.51, 125.87, 114.10, 84.24, 57.75, 55.51, 42.20, 39.04, 34.99, 33.00, 31.58; (MH*) 367; Anal. Calcd. for C23H30N202 with 0.25 H20: C, 74.66; H, 8.29; N, 7.55. Found: C, 74.79; H, 8.10; N, 7.26. Examples 2-48 were prepared according to the procedures described in Example 1 30 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): - 39 - WO 2009/079624 PCT/US2008/087397 Example 2: 2-(4-tert-Butylphenyl)-3-[2-(3-methoxyphenyl)ethyl]- 1 methylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 67.42 (m, 1H), 7.19 (m, 3H), 6.76 (m, 1H), 6.60 (m, 2H), 3.75 (s, 3H), 3.71 (m, 2H), 3.08 (m, 1H), 2.82 (m, 2H), 2.56 (m, 1H), 2.02 (s, 3H), 1.35 (s, 9H); 13C NMR (CDC13) . 170.40, 159.92, 140.50, 5 129.70, 128.53, 125.87, 121.45, 115.52, 114.48, 112.35, 84.26, 66.11, 60.65, 57.73, 55.39, 41.96, 39.00, 34.99; (MH*) 367; Anal. Calcd. for C23H30N202 with 0.6 H20: C, 67.90; H, 7.53; N, 6.71. Found: C, 67.83; H, 7.53; N, 6.71. Example 3: 2-(3,4-Dichlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 methylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.50 (d, 1 H, J = 8.1 Hz), 10 7.34 (m, 1H), 7.15 (m, 1H), 7.02 (d, 2H, J = 8.4 Hz), 6.88 (m, 2H), 4.35 (m, 1H), 3.85 (s, 3H), 3.74 (m, 2H), 3.14 (m, 1H), 2.73 (m, 2H), 2.64 (m, 1H), 2.25 (s, 3H); 13C NMR (CDC13) 6 171.19, 158.66, 137.92, 134.00, 133.02, 130.96, 130.91, 130.69, 130.12, 128.06, 114.26, 83.30, 57.39, 55.52, 42.28, 38.83, 33.21; (MH*) 380; Anal. Calcd. for C19H20Cl2N202: C, 60.17; H, 5.32; N, 7.39. Found: C, 60.20; H, 5.55; 15 N, 7.24. Example 4: 2-(4-tert-Butylphenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin 4-one, 1 H NMR (300 MHz, CDC13) 6 7.41 (d, 2H, J = 6.6 Hz), 7.27 (d, 2H, J = 6.3 Hz), 6.95 (d, 2H, J = 6.6 Hz), 6.80 (d, 2H, J = 6.6 Hz), 4.56 (s, 1H), 3.79 (s, 3H), 3.72 (m, 1H), 3.18 (m, 1H), 3.09 (m, 1H), 2.78 (m, 2H), 2.60 (m, 1H), 2.50 (m, 1H), 20 2.31 (m, 1H), 1.36 (s, 9H), 0.98 (m, 3H); 13C NMR (CDC13) 6171.28, 158.46, 152.86, 134.81, 130.99, 130.04, 128.60, 125.74, 114.09, 82.85, 55.50, 55.09, 46.76, 42.07, 34.96, 33.04, 31.59, 13.43; (MH*) 381; Anal. Calcd. for C24H32N202 with 0.35 H20: C, 74.52; H, 8.52; N, 7.24. Found: C, 74.75; H, 8.13; N, 6.97. Example 5: 2-(4-Cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 25 methylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.21 (d, 2H, J = 7.8 Hz), 7.11 (d, 2H, J = 7.8 Hz), 6.97 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz), 4.4 (s, 1 H), 3.77 (s, 3H), 3.67 (m, 2H), 3.09 (m, 1H), 2.75 (m, 2H), 2.85 (m, 1H), 1.94 (m, 1H), 1.02 (m, 2H), 0.74 (m, 2H); 13C NMR (CDC13) 6 171.36, 158.49, 155.51, 146.08, 130.89, 130.05, 128.81, 126.07, 114.11, 84.27, 57.73, 42.13, 38.87, 33.00, 15.54, - 40 - WO 2009/079624 PCT/US2008/087397 9.92, 9.86; (MH*) 351; Anal. Calcd. for C22H26N202: C, 75.40; H, 7.48; N, 7.99. Found: C, 75.21; H, 7.62; N, 8.03. Example 6: 3-[2-(4-Methoxyphenyl)ethyl]- 1 -methyl-2-(4-trifluoromethylphenyl) imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13) 6 7.67 (d, 2H, J = 7.4 Hz), 7.42 (d, 5 2H, J = 8.4 Hz), 6.97 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.7 Hz), 4.46 (s, 1H), 3.80 (s, 3H), 3.73 (d, 1H, J = 15.0 Hz), 3.70 (m, 1H), 3.15 (d, 1H, J = 14.2 Hz), 2.73 (m, 2H), 2.57 (m, 1H), 2.23 (s, 3H); (MH*) 379. Example 7: 2-(3-Chlorophenyl)-1 -ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4 one trifluoroacetate, 1 H-NMR (300 MHz, CDC13) 6 7.43 (d, 1H, J = 3.1 Hz), 7.38 (t, 10 1H, J = 7.6 Hz), 7.22 (s, 1H), 7.19 (d, 1H, J = 7.7 Hz), 7.00 (d, 2H, J = 6.5 Hz), 6.83 (d, 2H, J = 6.5 Hz), 4.93 (s, 1H), 3.85 (m, 2H), 3.80 (s, 3H), 3.49 (d, 1H, J = 13.5 Hz), 2.78 (m, 2H), 2.62 (m, 1H), 2.59 (q, 2H, J = 7.2 Hz), 1.08 (t, 3H, J = 7.5 Hz); (MH*) 359. Example 8: 2-(3,4-Dichlorophenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin 15 4-one trifluoroacetate, 1 H-NMR (300 MHz, CDC13) 6 7.48 (d, 1H, J = 8.21 Hz), 7.3 (d, 1H, J = 2.0 Hz), 7.13 (dd, 1H, J = 2.1, 8.3 Hz), 7.00 (d, 2H, J = 6.6 Hz), 6.85 (d, 2H, J = 6.6 Hz), 4.63 (s, 1H), 3.81 (s, 3H), 3.78 (m, 2H), 3.27 (d, 1H, J = 13.0 Hz), 2.75 (m, 2H), 2.48 (m, 3H), 1.02 (t, 3H, J = 7.2 Hz); (MH*) 393. Example 9: 2-(3,4-Dimethylphenyl)-1-methyl-3-(3-phenylpropyl)imidazolidin-4-one, 20 1 H NMR (300 MHz, CDC13) 6 7.16 (m, 1H), 7.07 (m, 2H), 6.99 (m, 5H), 4.56 (s, 1H), 3.71 (dd, 1H, J = 2.1 Hz, 14.1 Hz), 3.49 (m, 1H), 3.01 (dd, 1H, J = 2.1 Hz, 14.1 Hz), 2.67 (m, 1H), 2.45 (t, 2H, J = 14.0 Hz), 2.20 (s, 3H), 1.58 (m, 2H), 1.30 (s, 6H) 13C NMR (CDC13) 6172.3, 153.1, 141.7, 138.6, 137.5, 134.7, 134.3, 131.1, 130.2, 129.9, 128.5, 126.5, 114.3, 84.0, 57.9, 40.4, 39.1, 35.1, 33.5, 31.7, 29.2; (MH*) 323. 25 Example 10: 2-(4-tert-Butylphenyl)-1-methyl-3-(3-phenylpropyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.36m, 2H), 7.11 (m, 5H), 6.99 (m, 2H), 4.66 (s, 1H), 3.77 (dd, 1H, J = 2.1 Hz, 14.1 Hz), 3.55 (m, 1H), 3.11 (dd, 1H, J = 2.1 Hz, 14.1 Hz), - 41 - WO 2009/079624 PCT/US2008/087397 2.55 (m, 1H), 2.41 (t, 2H, J = 14.0 Hz), 2.26 (s, 3H), 1.55 (m, 2H), 1.27 (s, 9H); 13C NMR (CDC1 3 ) . 171.2, 153.1, 141.7, 134.3, 134.1, 130.0, 128.7, 128.6, 128.5, 126.2, 126.0, 84.0, 57.9, 40.4, 39.1, 35.1, 33.5, 31.7, 29.2; (MH*) 351. Example 11: 2-(4-tert-Butylphenyl)-3-(4-methoxybenzyl)-1-methylimidazolidin-4 5 one, 1 H NMR: (300 MHz, CDC13) 6 7.5 (d, 2H, J = 8.1 Hz), 7.34 (d, 2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.1 Hz), 6.80 (d, 2H, J = 8.1 Hz), 4.90 (d, 1H, J = 14.1 Hz), 4.50 (s, 1H), 3.81 (s, 3H), 3.44 (d, 1H, J = 14.1 Hz), 2.90 (d, 1H, J = 14.1 Hz), 2.30 (s, 2H), 1.44 (s, 9H); 13C NMR (CDC13) 6 174.0, 159.3, 153.0, 134.1, 130.2, 128.8, 128.7, 125.9, 114.2, 83.1, 58.0, 55.6, 43.5, 39.1, 36.9, 35.1, 31.7; (MH') 353. 10 Example 12: 2-(4-tert-Butylphenyl)-1-methyl-3-phenethylimidazolidin-4-one, 'H NMR (300 MHz, CDC13) 6 7.32 (d, 2H, J = 8.3 Hz), 7.13 (m, 5H), 6.93 (d, 2H, J = 6.4 Hz), 4.31 (s, 1H), 3.58 (m, 2H), 3.01 (dd, 1H, J = 2.3, 14.1 Hz), 2.74 (m, 2H), 2.46 (m, 1H), 2.14 (s, 3H), 1.26 (s, 9H); (MH*) 337. Example 13: 1-Ethyl-3-phenethyl-2-(4-trifluoromethylphenyl)imidazolidin-4-one, 'H 15 NMR (300 MHz, CDC13) 6 7.56 (d, 2H, J = 8.1 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.20 (m, 3H), 6.97 (d, 2H, J = 7.9 Hz), 4.43 (s, 1H), 3.66 (m, 2H), 3.03 (d, 1H, J = 16.5 Hz), 2.68 (m, 2H), 2.51 (m, 1H), 2.40 (m, 1H), 2.25 (m, 1H), 0.87 (t, 3H, J = 7.2 Hz); (MH*) 363. Example 14: 1-Ethyl-3-phenethyl-2-(3-trifluoromethylphenyl)imidazolidin-4-one, 'H 20 NMR (300 MHz, CDC13) 6 7.37 (d, 1H, J = 8.2 Hz), 7.20 (m, 4H), 7.01 (m, 3H), 4.31 (s, 1H), 3.64 (m, 2H), 3.00 (d, 1H, J = 16.5 Hz), 2.63 (m, 3H), 2.39 (m, 1H), 2.24 (m, 1H), 0.87 (t, 3H, J = 7.2 Hz); (MH*) 363. Example 15: 1-Ethyl-2-(4-Ethylphenyl)-3-phenethylimidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.04 (m, 7H), 6.88 (d, 2H, J = 8.1 Hz), 4.77 (s, 1H), 3.60 (m, 2H), 25 3.23 (d, 1H, J = 14.6 Hz), 2.64 (m, 2H), 2.50 (m, 3H), 2.36 (q, 2H, J = 7.2 Hz), 1.06 (t, 3H, J = 7.6 Hz), 0.87 (t, 3H, J = 7.2 Hz); (MH*) 323. - 42 - WO 2009/079624 PCT/US2008/087397 Example 16: R-3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-methylimidazolidin 4-one, 1 H NMR (300 MHz, CDC13) 67.43 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.41 (s, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1H), 2.78 (m, 2H), 2.50 (m, 1H), 2.26 (s, 3H), 1.36 (m, 9H); (MH*) 367. 5 Example 17: S-3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-methylimidazolidin 4-one, 1 H NMR (300 MHz, CDC13) 67.44 (m, 2H), 7.26 (m, 2H), 6.96 (m, 2H), 6.81 (m, 2H), 4.42 (s, 1H), 3.80 (s, 3H), 3.70 (m, 2H), 3.15 (m, 1H), 2.79 (m, 2H), 2.50 (m, 1H), 2.26 (s, 3H), 1.36 (m, 9H); (MH*) 367. Example 18: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-1-methyl 10 imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.44 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.4), 7.12 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 6.6 Hz), 4.14 (s,1H), 3.75 (dd, 1H, J = 1.2, 14.1 Hz), 3.62 (m, 2H), 3.14 (dd, 1H, J = 2.1, 14.1 Hz), 2.85 (m, 2H), 2.55 (m, 1H), 2.26 (s, 3H), 1.37 (s, 9H); (MH*) 421. Example 19: 3-(4-(Trifluoromethoxy)phenethyl)-2-(3,4-dichlorophenyl)-1 -methyl 15 imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.49 (d, 1H, J = 8.4 Hz), 7.38 (d, 1H, J = 2.1 Hz), 7.11 (m, 5H), 4,34 (s, 1H), 3.71 (m, 2H), 3.14 (dd, 1H, J = 2.4, 14.4 Hz), 2.82 (m, 2H), 2.64 (m, 1H), 2.24 (s, 3H); (MH*) 434. Example 20: 3-(4-(Trifluoromethoxy)phenethyl)-1-methyl-2-(4-(trifluoromethyl) phenyl)imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.69 (d, 2H, 8.4 Hz), 7.42 20 (d, 2H, J = 8.4 Hz), 7.16 (d, 2H, J = 7.8 Hz), 7.06 (d, 2H, J = 7.8 Hz), 4.45 (s, 1H), 3.74 (m, 2H), 3.13 (dd, 1H, J = 2.4, 14.4 Hz), 2.81 (m, 2H), 2.63 (m, 1H), 2.45 (s, 3H); (MH*) 433. Example 21: 2-(4-tert-Butylphenyl)-1-methyl-3-(2-phenylpropyl)imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.42 (m, 5H), 7.13 (m,4H), 4.54 (s, 1H), 3.68 (m, 2H), 25 3.21 (m, 1H), 2.50 (m, 3H), 2.24 (s, 3H), 1.36 (s, 9H), 1.22 (d, 3H, J = 6.9 Hz); (MH*) 351 - 43 - WO 2009/079624 PCT/US2008/087397 Example 22: 3-(4-Fluorophenethyl)-2-(4-tert-butylphenyl)-1-methylimidazolidin-4 one, 'H-NMR (300 MHz, CDC13) 6 7.44 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 6.97 (m,4H), 4.44 (s, 1H), 3.68 (m, 2H), 3.18 (m, 2H), 2.95 (m, 2H), 2.26 (s, 3H), 1.37 (s, 9H); (MH*) 355. 5 Example 23: 3-(4-iso-Propylphenethyl)-2-(4-tert-butylphenyl)-1-methylimidazolidin 4-one, 1 H-NMR (300 MHz, CDC13) 6 7.43 (d, 2H, J = 6.6 Hz) 7.27 (d, 2H, J = 6.6 Hz), 7.14 (d, 2H J = 8.4 Hz), 6.97 (d, 2H. J = 8.4 Hz), 4.42 (s, 1H), 3.72 (m, 2H), 3.16 (dd, 1H, J = 2.4, 14.1 Hz), 2.82 (m, 3H), 2.58 (m, 1H), 2.27 (s, 3H), 1.38 (s, 9H) 1.26 (d, 6H, J = 6.9 Hz); (MH*) 379. 10 Example 24: 3-(4-(Trifluoromethyl)phenethyl)-2-(4-tert-butylphenyl)-1-methyl imidazolidin-4-one, 1 H-NMR (300 MHz, CD30D) 6 7.49 (dd, 4H, J = 4.8, 13.0 Hz), 7.3 (d, 2H, J = 8.3 Hz), 7.21 (d, 2H, J = 8.0 Hz), 4.61 (s, 1H), 3.53 (m, 2H), 3.13 (m, 1H), 2.92 (m, 1H), 2.78 (m, 1H), 2.62 (m, 1H), 2.23 (s, 3H), 1.35 (s, 9H); (MH*) 405. Example 25: 3-(3,4-Difluorophenethyl)-2-(3,4-dimethylphenyl)-1-methylimidazolidin 15 4-one, 1 H-NMR (300 MHz, CD30D) 6 7.21 (m, 1H), 7.25 (m, 3H), 6.91 (m, 1H), 6.83 (m, 1H), 4.59 (s, 1H), 3.64 (d, 1H, J = 14.2 Hz), 3.54 (m, 1H), 3.13 (d, 1H, J = 14.0, Hz), 2.91 (m, 1H), 2.68 (m, 1H), 2.55 (m, 1H), 2.33 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H); (MH*) 345. Example 26: 3-(3,4-difluorophenethyl)-2-(3,4-dichlorophenyl)-1-methylimidazolidin 20 4-one: 1 H-NMR (300 MHz, CD30D) 6 7.61 (d, 1H, J = 7.1 Hz), 7.52 (s, 1H), 7.33 (dd, 1H, J = 1.5, 6.8 Hz), 7.13 (q, 1H, J = 8.1 Hz), 7.01 (m, 1H), 6.88 (m, 1H), 4.68 (s, 1H), 3.66 (d, 1H, J = 14.1 Hz), 3.58 (m, 1H), 3.15 (d, 1H, J = 14.0, Hz), 2.91 (m, 1H), 2.66 (m, 2H), 2.27 (s, 3H); (MH*) 385. Example 27: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-1-ethyl 25 imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13) 6 7.50 (d, 2H, 8.4Hz), 7.22 (d, 2H, 8.2Hz), 7.14 (s, 4H), 5.54 (s, 1H), 3.94 (m, 1H), 3.84 (s, 2H), 2.90 (m, 4H), 2.63 (m, 1H), 1.36 (s, 9H), 1.20 (t, 3H, J = 7.1 Hz); 13 C-NMR (CDC13) 5 166.8, 155.5, 136.7, - 44 - WO 2009/079624 PCT/US2008/087397 130.3, 128.6, 126.9, 121.5, 80.6, 51.1, 47.9, 42.4, 32.9, 31.4, 11.0; (MH*) 435; elemental analysis: theory C2 6
H
36
N
2 0 2 + 1.05 mol C 2
HF
3 0 2 C 56.56; H 5.47; N 5.05; found C 56.52, H 5.51, N 5.07. Example 28: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-cyclopropylphenyl)-1-methy 5 imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13) 6 7.01 (m, 8H), 4.31 (s, 1H), 3.65 (m, 2H), 3.16 (d, 1H, J = 14.0 Hz), 2.75 (m, 2H), 2.55 (m, 1H), 2.17 (s, 3H), 1.90 (m, 1H), 1.01 (d, 2H, J = 8.4 Hz) 0.68 (d, 2H, J = 8.4 Hz); (MH*) 405. Example 29: 3-(3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-4-oxoimidazolidin-1 yl)propanenitrile, 1 H NMR (300 MHz, CD30D) 6 7.52 (d, 2H, J = 8.2 Hz), 7.40 (d, 2H, 10 J = 8.2 Hz), 6.95 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.5 Hz), 4.79 (bs, 1H), 3.81 (bs, 1H), 3.77 (s, 3H), 3.48 (m, 1H), 3.24 (m, 1H), 2.75 (m, 4H), 2.50 (m, 3H), 1.37 (s, 9H); (MH*) 406. Example 30: 3-(4-Methoxyphenethyl)-1-allyl-2-(4-tert-butylphenyl)imidazolidin-4 one, 1 H NMR (300 MHz, CD30D) 6 7.5 (d, 2H, J = 8.3 Hz), 7.32 (d, 2H, J = 8.3 Hz), 15 6.95 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 5.72 (m, 1H), 5.20 (m, 2H), 4.74 (s, 1H), 3.77 (s, 3H), 3.59 (m, 2H), 3.32 (m, 2H), 3.15 (m, 1H), 2.86 (m, 2H), 2.46 (m, 1H), 1.36 (s, 9H); (MH*) 393. Example 31: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)- 1 -(3-hydroxypropyl) imidazolidin-4-one, 1 H NMR (300 MHz, CD30D) 6 7.47 (d, 2H, J = 8.1 Hz), 7.25 (d, 20 2H, J = 8.4 Hz), 6.99 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.25 (bs, 2H), 3.94 (m, 1H), 3.81 (s, 3H), 3.77 (m, 1H), 3.61 (m, 2H), 3.46 (m, 1H), 2.81 (m, 4H), 2.61 (m, 1H), 1.75 (m, 2H), 1.36 (s, 9H); (MH*) 411. Example 32: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1 -(2-hydroxyethyl) imidazolidin-4-one, 1 H NMR (300 MHz, CD30D) 6 7.38 (d, 2H, J = 8.3 Hz), 7.25 (d, 25 2H, J = 8.3 Hz), 6.83 (d, 2H, J = 8.6 Hz), 6.70 (d, 2H, J = 8.6 Hz), 4.63 (s, 1H), 3.65 (m, 4H), 3.38 (m, 3H), 3.21 (m, 1H), 2.49 (m, 5H), 1.25 (s, 9H); (MH*) 397. - 45 - WO 2009/079624 PCT/US2008/087397 Example 33: 3-(4-(trifluoromethyl)phenethyl)-2-(3,4-dimethylphenyl)-1-methyl imidazolidin-4-one: ('H-NMR, 300 MHz, CD30D): 6 7.56 (d, 2H, J = 7.1 hz), 7.25 (d, 2H, J = 7.3 hz), 7.22 (m, 1H), 7.09 (m, 2H), 4.59 (s, 1H), 3.61(m, 2H), 3.13 (d, 1H, J = 14.1 hz), 2.91 (m, 1H), 2.79 (m, 1H), 2.66 (m, 1H), 2.32 (s, 3H), 2.31 (s, 3H), 2.22 5 (s, 3H). (MPH) 377. Example 34: (2R,5S)-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5-isopropyl-1 methylimidazolidin-4-one: ('H-NMR, 300 MHz, CD30D): 6 7.47 (d, 2H, J = 7.1 hz), 7.14 (d, 2H, J = 6.8 hz), 7.08 (d, 2H, j = 6.7 hz), 6.81 (d, 2H, J = 7.3 hz), 5.19 (s, 1H), 3.82(m, 1H), 3.78 (s, 3H), 3.38 (m, 1H), 2.71 (m, 3H), 2.13 (m, 1H), 2.07 (s, 10 3H), 1.36 (s, 9H), 1.06 (d, 3H, J = 6.3 hz), 0.95 (d, 3H, J = 6.5 hz). (M*H) 409. Example 35: (2S,5S)-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5-isopropyl-1 methylimidazolidin-4-one: ('H-NMR, 300 MHz, CD30D): 6 7.48 (d, 2H, J = 7.0 hz), 7.13 (d, 2H, J = 6.9 hz), 7.07 (d, 2H, J = 7.0 hz), 6.82 (d, 2H, J = 7.3 hz), 5.18 (s, 1H), 3.82(m, 1H), 3.79 (s, 3H), 3.57 (m, 1H), 2.69 (m, 3H), 2.08 (s, 3H), 2.07 (m, 15 1H), 1.37 (s, 9H), 1.05 (d, 3H, J = 6.3 hz), 0.96 (d, 3H, J = 6.5 hz). (MPH) 409. Example 36: 1-Benzyl-2-(4-dimethylamino-phenyl)-3-phenethyl-imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.16 (m, 1OH), 6.98 (d, 2H, J = 8.2 Hz), 6.65 (d, 2H, J = 8.8 Hz), 4.55 (s, 1H), 3.71 (d, 1H, J = 13.2 Hz), 3.56 (m, 1H), 3.42 (d, 1H, J = 15.2 Hz), 3.19 (d, 1H, J = 13.2 Hz), 2.95 (d, 1H J = 14.2 Hz), 2.91 (s, 6H), 2.75 (m, 2H), 20 2.47 (m, 1H). (MPH) 400. Example 37: 1-Benzyl-3-[2-(4-methoxy-phenyl)-ethyl]-2-(3-trifluoromethyl-phenyl) imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.84 (d, 1H, J = 7.9 Hz), 7.65 (d, 1H, J = 8.0 Hz), 7.59 (t, 1H, J = 7.6 Hz), 7.44 (t, 1H, J = 7.6 Hz), 7.17 (m, 3H), 7.09 (d, 2H, J = 7.8 Hz), 6.98 (d, 2H, J = 8.6 Hz), 6.70 (d, 2H, J = 8.7 Hz ), 5.47 (s, 1H), 25 3.75 (d, 1H, J = 13.1 Hz), 3.68 (s, 3H), 3.47 (d, 1H, J = 15.6 Hz), 3.41 (m, 1H), 3.35 (d, 1H, J = 13.2 Hz), 3.03 (d, 1H J = 16.6 Hz), 2.71 (m, 1H), 2.57 (m, 2H). (MPH) 455. - 46 - WO 2009/079624 PCT/US2008/087397 Example 38: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-quinolin-2-yl-imidazolidin-4 one; compound with trifluoro-acetic acid, 1 H-NMR (300 MHz, CDC13): 6 8.28 (d, 1H, J = 8.5 Hz), 8.22 (d, 1H, J = 8.4 Hz), 7.90 (d, 1H, J = 8.1 Hz), 7.83 (t, 1H, J = 7.7 Hz), 7.67 (t, 1H, J = 7.5 Hz), 7.62 (d, 1H, J = 8.5 Hz), 6.96 (d, 2H, J = 9.5 Hz), 6.73 (d, 5 2H, J = 8.7 Hz), 5.24 (s, 1H), 3.89 (d, 1H, J = 14.4 Hz), 3.82 (m, 1H), 3.75 (s, 3H), 3.34 (d, 1H, J = 15.9 Hz), 2.83 (m, 2H), 2.63 (m, 1H), 2.43 (s, 3H). (M*H) 362. Example 39: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1,5 dimethylimidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.39 (d, J = 8.2 Hz, 2 H), 7.14 (d, J = 8.2 Hz, 2 H), 7.03 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 4.86 (s, 1 10 H), 3.82 (m, 1 H), 3.79 (s, 3 H), 3.54 (m, 1 H), 2.78 (m, 2 H), 2.63 (m, 1 H), 2.10 (s, 3 H), 1.34 (s, 9 H), 1.23 (d, J = 6.7 Hz, 3 H); 13C NMR (75 MHz, CDC13) 5 174.59, 158.62, 152.79, 133.72, 131.05, 130.16, 128.31, 125.96, 114.25, 82.41, 59.59, 55.64, 42.11, 35.09, 34.14, 33.28, 31.67, 13.70; (MH*) 381; elemental analysis: theory C 24
H
32
N
2 0 2 C 75.75; H 8.48; N 7.36; found C 76.02, H 8.15, N 7.06. 15 Example 40: 5-(S)-/sobutyl-2-(R)-(4-iso-propylphenyl)-3-[2-(4-methoxyphenyl) ethyl]-1-methylimidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.30 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 8.1 Hz), 7.06 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.7 Hz), 5.59 (s, 1H), 3.96 (m, 1H), 3.79 (s, 3H), 3.49 (t, 1H, J = 6.3 Hz), 2.95 (m, 1H), 2.77 (m, 3H), 2.24 (s, 3H), 2.01 (m,1H), 1.72 (m, 1H), 1.63 (m, 1H), 1.27 (d, 6H, J = 6.9 Hz), 20 0.97 (d, 3H, J = 6.6 Hz), 0.96 (d, 3H, J = 6.5 Hz); (MH*) 409. Example 41: 2-(S)-(4-Dimethylaminophenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl) ethyl]-1-methylimidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.14 (d, 2H, J = 8.7 Hz), 6.93 (d, 2H, J = 8.6 Hz), 6.83 (d, 2H, J = 8.6 Hz), 6.68 (d, 2H, J = 9.4 Hz), 5.18 (s, 1H), 3.67 (s, 3H), 3.59 (m, 1H), 3.03 (m, 1H), 2.96 (s, 6H), 2.67 (m, 2H), 2.44 (m, 25 1H), 2.21 (s, 3H), 1.91 (m, 1H), 1.69 (m. 1H), 0.87 (d, 3H, J = 6.6 Hz), 0.84 (d, 3H, J = 6.5 Hz); (MH+) 410. Example 42: 2-(R)-(4-Ethylphenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.27 (d,2H, J = 7.7 Hz), - 47 - WO 2009/079624 PCT/US2008/087397 7.15 (d, 2H, J = 8.1 Hz), 7.06 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.9 Hz), 5.42 (s, 1H), 3.93 (m, 1H), 3.79 (s, 3H), 3.74 (d, J = 13.0 Hz, 1H), 3.48 (m, 1H), 2.72 (m, 4H), 2.20 (s, 3H), 1.97 (m, 1H), 1.64 (m, 2H), 1.26 (m, 3H), 0.97 (d, 3H, J = 6.6 Hz), 0.96 (d, 3H, J = 6.6 Hz); (MH*) 395. 5 Example 43: 5-(S)-Benzyl-2-(R)-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.26 (m, 4H), 7.20 (m, 1H), 7.14 (d, 2H, J = 8.0 Hz), 6.97 (d, 2H, J = 8.1 Hz), 6.84 (d, 2H, J = 8.7 Hz), 6.72 (d, 2H, J = 8.7 Hz), 5.01 (s, 1H), 3.77 (m, 1H), 3.73 (s, 3H), 3.70 (m, 1H), 3.18 (d, 1H, J = 14.4 Hz), 3.03 (d, 1H, J = 14.4 Hz), 2.58 (m, 5H), 1.93 (s, 3H), 1.18 (t, 3H, J = 7.6 10 Hz); (MH*) 429. Example 44: 5-(S)-Benzyl-2-(R)-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl] 1-methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.32 (m, 4H), 7.26 (m, 1H), 7.13 (d, J = 8.2 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 6.85 (m, 2H), 6.78 (d, J = 8.7 Hz, 2H), 5.05 (s, 1H), 3.87 (m, 1H), 3.80 (s, 3H), 3.75 (m, 1H), 3.23 (dd, 1H, J = 4.3, 15 14.4 Hz), 3.08 (dd, 1H, J = 6.3, 14.4 Hz), 2.67 (m, 3H), 2.26 (s, 3H), 2.25 (s, 3H), 2.00 (s, 3H); (MH*) 429. Example 45: 2-(R)-(4-Chlorophenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.32 (d, 2H, J = 8.5 Hz), 7.08 (d, 2H, J = 8.5 Hz), 6.96 (d, 2H, J = 8.6 Hz), 6.74 (d, 2H, J = 8.7 Hz), 5.10 (s, 20 1H), 3.85 (m, 1H), 3.71 (s, 3H), 3.38 (t, 1H, J = 7.0 Hz), 2.63 (m, 3H), 2.05 (s, 3H), 1.87 (m, 1H), 1.47 (m, 2H), 0.87 (d, 6H, J = 6.6 Hz); (MH*) 401. Example 46: 2-(S)-(4-Chlorophenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.28 (d, 2H, J = 6.6 Hz), 7.17 (d, 2H, J = 6.6 Hz), 6.87 (d, 2H, J = 6.6 Hz), 6.73 (d, 2H, J = 6.6 Hz), 4.21 (s, 25 1H), 3.71 (s, 3H), 2.92 (m, 1H), 2.66 (m, 2H), 2.41 (m, 1H), 2.12 (s, 3H), 1.94 (m, 1H), 1.55 (m, 1H), 0.91 (d, 3H, J = 6.2 Hz), 0.89 (d, 3H, J = 6.2 Hz); (MH*) 401. - 48 - WO 2009/079624 PCT/US2008/087397 Example 47: 2-(S)-(4-Ethylphenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.24 (s, 4H), 6.94 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.7 Hz), 4.34 (s, 1H), 3.78 (s, 3H), 3.56 (m, 1H), 3.01 (m, 1H), 2.79 (m, 1H), 2.69 (q, 3H, J = 7.6 Hz), 2.46 (m, 1H), 2.23 (s, 3H), 2.03 (m, 1H), 5 1.77 (m, 1H), 1.27 (t, 3H, J = 7.6 Hz), 1.00 (d, 3H, J = 6.5 Hz), 0.98 (d, 3H, J = 6.5 Hz); (MH*) 395. Example 48: 2-(S)-(4-tert-Butylphenyl)-5-(S)-iso-butyl-3-[2-(4-methoxyphenyl) ethyl]-1-methyl-imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13): 6 7.33 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 7.2 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.27 10 (s, 1H), 3.70 (s, 3H), 3.45 (m, 1H), 2.94 (m, 1H), 2.70 (m, 2H), 2.37 (m, 1H), 2.16 (s, 3H), 1.96 (m, 1H), 1.69 (m, 1H), 1.57 (m, 1H), 1.26 (s, 9H), 0.92 (d, 3H, J = 6.8 Hz), 0.90 (d, 3H, J = 6.7 Hz); (MH*) 423. CATEGORY II Example 49: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1 15 methylimidazolidin-4-one Amino amides were prepared as indicated previously. 0 03C 0 N0N N a N N + H F3 ' N H N N 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1-methylimidazolidin 20 4-one: The starting trifluoromethoxy-phenethyl-amino-amide (523 mg, 1.89 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar via pipet. Next, melted 4-diethylaminobenzalde-hdye (2.00 g, 11.3 mmol) was added to the reaction in small portions via pipet. The reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 175 0C for 5 minutes. At this time the reaction - 49 - WO 2009/079624 PCT/US2008/087397 was cooled to room temperature and de-capped. The material was then purified with flash column chromatography to afford a pale orange viscous syrup, 518 mg, chemical yield 62.9%. 'H-NMR (300 MHz, CDC13) 6 7.11 (m, 6H), 6.67 (d, 2H, J = 7.3 Hz), 4.33 (s, 1H), 3.71 (d, 1H, J = 13.9 Hz), 3.62 (m, 1H), 3.40 (m, 4H), 3.08 (d, 5 1H, J = 13.9 Hz), 2.88 (m, 2H), 2.59 (m, 1H), 2.25 (s, 3H), 1.21 (t, 6H, J = 6.6 Hz); 13 C-NMR (CDC13) 5 171.8, 148.3, 137.9, 136.9, 130.4, 129.9, 122.8, 121.2, 111.5, 84.5, 57.8, 44.6, 41.8, 38.8, 33.4, 12.8; (MH*) 436.6; elemental analysis: theory
C
23
H
28
F
3
N
3 0 2 + 0.16 mol H 2 0 C 63.02; H 6.51; N 9.59; found C 63.03, H 6.60, N 9.53. 10 Examples 50-69 were prepared according to the procedures described in Example 49 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 50: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(dimethylamino)phenyl)-1 methylimidazolidin-4-one, 391 mg, chemical yield 52.4%. 'H-NMR (300 MHz, CDC13) 15 6 7.15 (m, 6H), 6.74 (d, 2H, J = 6.9 Hz), 4.37 (s, 1H), 3.72 (d, 1H, J = 14.1 Hz), 3.63 (m, 1H), 3.10 (d, 1H, J = 14.1 Hz), 3.02 (s, 6H), 2.86 (m, 2H), 2.62 (m, 1H), 2.25 (s, 3H); 13 C-NMR (CDC13) 5 171.2, 151.8, 137.9, 130.4, 129.8, 121.3, 112.3, 84.4, 57.8, 44.6, 41.8, 40.7, 38.7, 33.4; (MH*) 408. Elemental analysis: theory C 21
H
24
N
3 0 2 + 0.07 mol H 2 0 C 61.71; H 5.95; N 10.28; found C 61.70, H 5.80, N 10.35. 20 Example 51: 2-(4-Diethylamino-phenyl)-3-[2-(4-methoxy-phenyl)-ethyl]-1-methyl imidazolidin-4-one, 1 H-NMR (300 MHz, CD30D) 6 7.17 (d, 2H, J = 8.7 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 6.73 (d, 2H, J = 8.7 Hz), 4.43 (s, 1H), 3.74 (s, 3H), 3.60 (d, 1H, J = 14.3 Hz), 3.50 (m, 1H), 3.40 (q, 4H, J = 7.0 Hz), 3.07 (dd, 1H, J = 2.3, 14.2 Hz), 2.82 (m, 1H), 2.69 (m, 1H), 2.45 (m, 1H), 2.21 (s, 3H), 1.17 (t, 25 6H, J = 7.0 Hz); (MH*) 382. Example 52: 3-(4-Methoxyphenethyl)-2-(4-(iso-propyl(methyl)amino)phenyl)-1 methylimidazolidin-4-one, 1 H-NMR (300 MHz, CDC13) 6 7.17 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 8.7 Hz), 6.80 (m, 4H), 4.37 (s, 1H), 4.15 (m, 1H), 3.79 (s, 3H), 3.67 (m, - 50 - WO 2009/079624 PCT/US2008/087397 2H), 3.10 (dd, 1H, J = 2.1, 13.8 Hz), 2.82 (m, 3H), 2.78 (s, 3H), 2.56 (m, 3H), 1.22 (d, 6H, J = 6.3 Hz); (MH*) 382. Example 53: 3-(4-(Methoxy)phenethyl)-2-(4-(diethylamino)benzyl)-1 methylimidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.07 (m, 4H), 6.83 (d, 2H, J 5 = 8.8 Hz), 6.65 (d, 2H, J = 8.4 Hz), 4.07 (t, 1H, J = 4.8Hz), 3.90 (m, 1H), 3.79 (s, 3H), 3.52 (d, 1H, J = 15.6 Hz), 3.37 (q, 4H, J = 6.9 Hz), 3.07 (m, 1H), 2.95 (d, 1H, J = 15.2 Hz), 2.79 (d, 2H, J = 4.7 Hz), 2.72 (m, 2H), 2.28 (s, 3H), 1.17 (t, 6H, J = 8.0 Hz); (MH*) 396. Example 54: 3-(4-Methoxyphenethyl)-2-(4-(dimethylamino)phenyl)-1 10 methylimidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.19 (d, 2H, J = 7.1 Hz), 6.96 (d, 2H, J = 6.9 Hz), 6.81 (d, 4H, J = 7.0 Hz), 4.46 (s, 1H), 3.60 (d, 1H, J = 13.9 Hz), 3.52 (m, 1H), 3.19 (d, 1H, J = 14.1 Hz), 3.01 (s, 6H), 2.81 (m, 1H), 2.70 (m, 1H), 2.48 (m, 1H), 1.21 (s, 3H); (MH*) 354. Example 55: 2-(4-Diethylamino-3-fluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1 15 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.03 (m, 3H), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.7 Hz), 4.48 (s, 1H), 3.74 (s, 3H), 3.61 (dd, 1H, J = 1.1, 14.3 Hz), 3.50 (m, 1H), 3.26 (m, 4H), 3.09 (dd, 1H, J = 2.3, 14.3 Hz), 2.82 (m, 1H), 2.68 (m, 1H), 2.48 (m, 1H), 2.22 (s, 3H), 1.10 (t, 6H, J = 7.0 Hz); (MH*) 400. Example 56: 2-(3-Chloro-4-diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1 20 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.36 (d, 1H, J = 1.9 Hz), 7.22 (m, 2H), 6.95 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.50 (s, 1H), 3.75 (s, 3H), 3.64 (dd, 1H, J = 1.2, 14.3 Hz), 3.51 (m, 1H), 3.15 (q, 4H, J = 7.1 Hz), 3.12 (m, 1H), 2.82 (m, 1H), 2.69 (m, 1H), 2.44 (m, 1H), 2.24 (s, 3H), 1.05 (t, 6H, J = 7.1 Hz); (MH*) 416. 25 Example 57: 2-(4-Diethylamino-3,5-difluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 6.97 (m, 4H), 6.82 (d, 2H, J = 8.7 Hz), 4.54 (s, 1H), 3.76 (s, 3H), 3.65 (dd, 1H, J = 14.3, 1.4 Hz), 3.54 (m, 1H), - 51 - WO 2009/079624 PCT/US2008/087397 3.18 (q, 4H, J = 7.1 Hz), 3.13 (m, 1H), 2.85 (m, 1H), 2.70 (m, 1H), 2.49 (m, 1H), 2.25 (s, 3H), 1.04 (t, 6H, J = 7.1 Hz); (MH*) 418. Example 58: 2-(2-Chloro-4-diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1 methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.21 (d, 1H, J = 9.5 Hz), 5 6.98 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.7 Hz), 6.69 (m, 2H), 5.20 (s, 1H), 3.73 (s, 3H), 3.61 (m, 2H), 3.36 (q, 4H, J = 7.1 Hz), 3.09 (dd, 1H, J = 2.2, 14.2 Hz), 2.74 (m, 2H), 2.51 (m, 1H), 2.25 (s, 3H), 1.16 (t, 6H, J = 7.1 Hz); (MH') 416. Example 59: 2-R-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1-methyl imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.17 (d, 2H, J = 8.7 Hz), 6.95 (d, 10 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.43 (s, 1H), 3.72 (s, 3H), 3.60 (d, 1H, J = 14.3 Hz), 3.51 (m, 1H), 3.37 (q, 4H, J = 7.0 Hz), 3.06 (dd, 1H, J = 2.3, 14.2 Hz), 2.82 (m, 1H), 2.69 (m, 1H), 2.43 (m, 1H), 2.19 (s, 3H), 1.15 (t, 6H, J = 7.0 Hz); (MH*) 382. Example 60: 2-S-(4-Diethylaminophenyl)-3-[2-(4-methoxyphenyl)-ethyl]-1-methyl 15 imidazolidin-4-one, 'H-NMR (300 MHz, CD30D) 6 7.17 (d, 2H, J = 8.8 Hz), 6.95 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.8 Hz), 4.43 (s, 1H), 3.73 (s, 3H), 3.60 (d, 1H, J = 14.2 Hz), 3.50 (m, 1H), 3.37 (q, 4H, J = 7.1 Hz), 3.06 (dd, 1H, J = 2.4, 14.1 Hz), 2.82 (m, 1H), 2.69 (m, 1H), 2.44 (m, 1H), 2.19 (s, 3H), 1.15 (t, 6H, J = 7.0 Hz); (MH*) 382. 20 Example 61: 5-(S)-Isobutyl-2-(S)-(4-isopropyl-phenyl)-3-[2-(4-methoxy-phenyl) ethyl]-1-methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 7.31 (s, 4H), 6.91 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.7 Hz), 4.42 (d, 1H, J = 2.3 Hz), 3.74 (s, 3H), 3.44 (m, 1H), 3.02 (m, 1H), 2.95 (m, 1H), 2.82 (m, 1H), 2.67 (m, 1H), 2.37 (m, 1H), 2.19 (s, 3H), 2.01 (m, 1H), 1.71 (m, 1H), 1.66 (m, 1H), 1.29 (s, 3H), 1.26 (s, 3H), 25 1.01 (d, 3H, J = 6.7 Hz), 0.98 (d, 3H, J = 6.6 Hz). (M*H) 409. Example 62: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-(4-piperazin-1-yl-phenyl) imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 7.27 (d, 2H, J = 8.7 Hz), 7.04 (d, - 52 - WO 2009/079624 PCT/US2008/087397 2H, J = 8.7 Hz), 6.96 (d, 2H, J = 8.7 Hz), 6.83 (d, 2H, J = 8.7 Hz), 4.50 (s, 1H), 3.77 (s, 3H), 3.62 (dd, 1H, J = 14.3, 1.0 Hz), 3.54 (m, 1H), 3.23 (m, 4H), 3.11 (dd, 1H, J = 14.2, 2.4 Hz), 3.01 (m, 4H), 2.74 (m, 3H), 2.48 (m, 1H), 2.23 (s, 3H). (M*H) 395. Example 63: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-[4-(pyridin-4-ylmethoxy) 5 phenyl]-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 8.54 (d, 2H, J = 6.1 Hz), 7.54 (d, 2H, J = 5.9 Hz), 7.33 (d, 2H, J = 8.6 Hz), 7.09 (d, 2H, J = 8.6 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.25 (s, 2H), 4.53 (s, 1H), 3.76 (s, 3H), 3.62 (dd, 1H, J = 14.3, 0.9 Hz), 3.51 (m, 1H), 3.11 (dd, 1H, J = 14.3, 2.4 Hz), 2.72 (m, 2H), 2.45 (m, 1H), 2.22 (s, 3H). (M*H) 418. 10 Example 64: 3-[2-(4-Methoxy-phenyl)-ethyl]- 1 -methyl-2-[4-(3-methyl-butoxy) phenyl]-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 7.27 (d, 2H, J = 8.4 Hz), 6.95 (m, 4H), 6.80 (d, 2H, J = 8.4 Hz), 4.50 (s, 1H), 4.03 (t, 2H, J = 6.5 Hz), 3.74 (s, 3H), 3.61 (d, 1H, J = 14.1 Hz), 3.52 (t, 1H, J = 5.7 Hz), 3.09 (dd, 1H, J = 14.3, 2.0 Hz), 2.72 (m, 2H), 2.45 (m, 1H), 2.20 (s, 3H), 1.85 (m, 1H), 1.67 (m, 2H), 0.98 (d, 15 6H, J = 6.6 Hz). (MPH) 397. Example 65: 5-(S)-Benzyl-2-(R)-(4-tert-butyl-phenyl)-3-[2-(4-methoxy-phenyl)-ethyl] 1-methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.36 (d, 2H, J = 8.3 Hz), 7.26 (m, 5H), 7.02 (d, 2H, J = 8.3 Hz), 6.88 (d, 2H, J = 8.7 Hz), 6.76 (d, 2h, J = 8.7 Hz), 5.02 (bs, 1H), 3.85 (m, 1H), 3.79 (s, 3H), 3.74 (m, 1H), 3.21 (dd, 1H, J = 14.3, 20 4.3 Hz), 3.06 (dd, 1H, J = 14.3, 6.1 Hz), 2.73 (m, 1H), 2.57 (m, 2H), 1.99 (s, 3H), 1.31 (s, 9H). (MPH) 457. Example 66: 2-(R)-(4-tert-Butyl-phenyl)-5-(S)-isobutyl-3-[2-(4-methoxy-phenyl) ethyl]-1-imethyl-imidazolidin-4-one, 'H-NMR (300 MHz, CDC13): 6 7.39 (d, 2H, J = 8.3 Hz), 7.11 (d, 2H, J = 8.3 Hz), 7.05 (d, 2H, J = 8.6 Hz), 6.81 (d, 2h, J = 8.6 Hz), 5.08 25 (bs, 1H), 3.90 (m, 1H), 3.78 (s, 3H), 3.44 (dt, 1H, J = 6.0, 1.6 Hz), 2.76 (m, 2H), 2.65 (m, 1H), 2.09 (s, 3H), 1.96 (m, 1H), 1.53 (t, 2H, J = 6.6 Hz), 1.33 (s, 9H), 0.96 (d, 3H, J = 2.8 Hz), 0.93 (d, 3H, J = 2.7 Hz). (MPH) 423. - 53 - WO 2009/079624 PCT/US2008/087397 Example 67: (2-{2-(4-Dimethylamino-phenyl)-1 -[2-(4-methoxy-phenyl)-ethyl]-3 methyl-5-oxo-imidazolidin-4-(S)-yl}-ethyl)-carbamic acid tert-butyl ester, 'H-NMR (300 MHz, CD30D): 6 7.30 (d, 2H, J = 8.4 Hz), 6.96 (m, 4H), 6.82 (d, 2H, J = 8.4 Hz), 4.49 (s, 1H), 3.77 (s, 3H), 3.51 (m, 1H), 3.20 (m, 2H), 3.06 (s, 6H), 2.85 (m, 5 2H), 2.69 (m, 1H), 2.48 (m, 1H), 2.28 (s, 3H), 2.00 (m, 2H), 1.46 (s, 9H). (MPH) 497. Example 68: 2-(R)-(4-Dimethylamino-phenyl)-5-(S)-isobutyl-3-[2-(4-methoxy phenyl)-ethyl]-1-methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 7.09 (m, 4H), 6.83 (m, 4H), 4.97 (d, 1H, J = 2.1 Hz), 3.84 (m, 1H), 3.79 (s, 3H), 3.46 (m, 1H), 10 2.99 (s, 6H), 2.77 (m, 2H), 2.61 (m, 1H), 2.07 (s, 3H), 1.83 (m, 1H), 1.46 (m, 2H), 0.96 (d, 3H, J = 4.8 Hz), 0.93 (d, 3H, J = 4.8 Hz). (MPH) 410. Example 69: 5-(S)-Benzyl-2-(S)-(3,4-dimethyl-phenyl)-3-[2-(4-methoxy-phenyl) ethyl]-1-methyl-imidazolidin-4-one, 'H-NMR (300 MHz, CD30D): 6 7.28 (m, 5H), 7.03 (d, IH, J = 7.5 Hz), 6.91 (d, 2H, J = 9.0 Hz), 6.81 (d, 2H, J = 8.7 Hz), 6.70 (dd, IH, J 15 = 7.8, 1.8 Hz), 6.54 (s, 1H), 4.41 (d, 1H, J = 2.4 Hz), 3.78 (s, 3H), 3.40 (m, 1H), 3.12 (m, 2H), 2.68 (m, 2H), 2.33 (m, 2H), 2.25 (s, 3H), 2.20 (s, 3H), 2.16 (s, 3H). (MPH) 429. CATEGORY III Example 70: 3-(4-Methoxyphenethyl)-1-methyl-2-(1-methyl-1,2,3,4 20 tetrahydroquinolin-6-yl)imidazolidin-4-one 0 00 H 07 A H a / N N N + H ~N N - 54 - WO 2009/079624 PCT/US2008/087397 3-(4-Methoxyphenethyl)-1 -methyl-2-(1 -methyl-1,2,3,4-tetrahydroquinolin-6 yl)imidazolidin-4-one: A solution of N-(4-methoxyphenethyl)-2 (methylamino)acetamide (0.16 g, 0.72 mmol) and 1-methyl-1,2,3,4 tetrahydroquinoline-6-carbaldehyde (0.14 g, 0.78 mmol) in MeCN (1.5 mL) was 5 irradiated in the microwave (CEM, 150 0C) for 5 min. The crude reaction mixture was purified by reverse phase HPLC to yield 0.09 g of the desired product. 1 H NMR (300 MHz, CD30D) 5 6.99 (m, 3H), 6.85 (m, 3H), 6.62 (d, 2H, J = 8.4 Hz), 4.39 (bs, 1H), 3.76 (s, 3H), 3.58 (m, 2H), 3.30 (m, 3H), 3.08 (m, 1H), 2.91 (s, 3H), 2.75 (m, 1H), 2.20 (s, 3H), 1.97 (m, 2H); (MH*) 380. 10 Examples 71-74 were prepared according to the procedures described in Example 69 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 71: 3-[2-(4-Methoxy-phenyl)-ethyl]-1-methyl-2-quinolin-4-yl-imidazolidin-4 one trifluoroacetate, 1 H-NMR (300 MHz, CDC13) 6 9.03 (d, 1H, J = 4.7 Hz), 8.32 (d, 15 1H, J = 8.4 Hz), 8.17 (d, 1H, J = 8.5 Hz), 7.85 (t, 1H, J = 7.2 Hz), 7.66 (t, 1H, J = 7.2 Hz), 7.38 (d, 1H, J = 4.7 Hz), 6.88 (d, 2H, J = 4.5 Hz), 6.78 (d, 2H, J = 4.5 Hz), 5.07 (s, 1H), 3.78 (s, 3H), 3.78 (m, 2H), 3.23 (d, 1H, J = 12.4 Hz), 2.81 (m, 1H, J = 5.8 Hz), 2.58 (m, 2H), 2.27 (s, 3H); (MH*) 362. Example 72: 3-[2-(4-Methoxyphenyl)-ethyl]-1-methyl-2-(1H-pyrrol-2-yl)-imidazolidin 20 4-one trifluoroacetate, 1 H-NMR (300 MHz, CDC13) 6 8.79 (bs, 1H), 6.89 (d, 2H, J = 8.6 Hz), 6.74 (m, 1H), 6.71 (d, 2H, J = 8.6 Hz), 6.18 (m, 1H), 6.08 (d, 1H, J = 8.6 Hz), 4.48 (s, 1H), 3.68 (s, 3H), 3.54 (d, 1H, J = 15.0 Hz), 3.34 (m, 1H), 2.95 (dd, 1H, J = 2.5, 14.0 Hz), 2.85 (m, 1H), 2.61 (m, 1H), 2.28 (m, 1H), 2.19 (s, 3H); (MH*) 300. Example 73: 3-[2-(4-Methoxy-phenyl)ethyl]- 1 -methyl-2-(1 -methyl-1 H-pyrrol-2-yl) 25 imidazolidin-4-one, 1 H-NMR (300 MHz, CDC13) 6 7.00 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 6.45 (t, 1H, J = 2.2 Hz), 6.17 (q, 1H, J = 1.8 Hz), 6.07 (t. 1H, J = 3.1 Hz), 4.59 (s, 1H), 3.78 (s, 3H), 3.67 (m, 2H), 3.60 (s, 3H), 3.03 (dd, 1H, J = 2.6, 14.2 Hz), 2.79 (m, 2H), 2.49 (m, 1H), 2.28 (s, 3H); (MH*) 314. - 55 - WO 2009/079624 PCT/US2008/087397 Example 74: 3-(4-Methoxyphenethyl)-1 -methyl-2-(4-methyl-3,4-dihydro-2H benzo[b][1,4]oxazin-7-yl)imidazolidin-4-one, 1 H NMR (300 MHz, CD30D) 5 6.97 (d, 2H, J = 8.6 Hz), 6.78 (m, 5H), 4.40 (m, 1H), 4.28 (m, 2H), 3.76 (s, 3H), 3.55 (m, 2H), 3.30 (m, 3H), 3.07 (m, 1H), 2.92 (s, 3H), 2.76 (m, 2H), 2.47 (m, 1H), 2.21 (s, 3H); 5 (MH*) 383. Category IV Example 75: 1-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)-2-(4-tert butylphenyl)imidazolidin-4-one
H
2 N Os O O /O N 0 )EDC 0s 2 00 3 H1) EDCI H 2 N Cs2CO3 NH BO'N - OHN BOC OH 2) HCI H O 0 0 NaH O N NH I-N C1 0 10 -0 Step 1: tert-Butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate: To a solution of 2-(tert-butoxycarbonyl)acetic acid (20.0 g, 114.3 mmol) and 2-(4 methoxyphenyl)ethylamine (18.0 mL, 122.9 mmol) in CH 2 Cl 2 (825 mL) was added EDCI (32.9 g, 171.8 mmol). The reaction mixture was stirred at room temperature 15 for 4 days, washed with 0.1 N HCI (2 x 500 mL), dried over Na 2
SO
4 and evaporated to yield 32.4 g of the desired product. 1 H NMR (300 MHz, CD 3 0D) 6 7.86 (bs, 1H), 7.14 (d, 2H, J = 8.5 Hz), 6.9 (d, 2H, J = 8.6 Hz), (s, 3H), 3.66 (s, 2H), 3.39 (m, 2H), 2.74 (t, 2H, J = 7.3 Hz), 1.46 (s, 9H); (MH*) 309. - 56 - WO 2009/079624 PCT/US2008/087397 Step 2: N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride: To a solution of tert-butyl 2-(4-methoxyphenethylamino)-2-oxoethylcarbamate (32.39 g, 105.0 mmol) in MeOH (350 mL) was slowly added a solution of HCI in dioxane (4.0 N, 100 mL, 400.0 mmol). The reaction mixture was stirred at RT for 16 h and evaporated to 5 yield 24.44 g of the desired product. 'H NMR (CD30D) 6 7.16 (d, 2H, J = 8.1 Hz), 6.87 (d, 2H, J = 8.1 Hz), 3.78 (s, 3H), 3.64 (s, 2H), 3.46 (t, 2H, J = 6.9 Hz), 2.78 (t, 2H, J = 7.5 Hz); (MH*) 209. Step 3: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)imidazolidin-4-one: To a solution N-(4-methoxyphenethyl)-2-aminoacetamide hydrochloride (5.1 g, 20.7 10 mmol) and 4-tert-butylbenzaldehyde (3.6 mL, 21.5 mmol) in MeOH (140 mL) was added Cs 2
CO
3 (7.3 g, 22.2 mmol). The reaction mixture was warmed to 60 0C for 17 h followed by evaporation of the MeOH. The crude residue was dissolved in CH 2 Cl 2 , washed with H 2 0 and brine, dried over Na 2
SO
4 and evaporated to yield 6.9 g of the desired product. 1 H NMR (300 MHz, CD30D) 6 7.50 (d, 2H, J = 8.3 Hz), 7.26 (d, 2H, 15 J = 8.3 Hz), 7.01 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.5 Hz), 5.20 (s, 1H), 3.84 (s, 3H), 3.45 (m, 3H), 2.79 (m, 2H), 2.57 (m, 1H), 1.35 (s, 9H); (MH*) 353. Step 4: 1-(4-Methoxybenzyl)-3-(4-methoxyphenethyl)-2-(4-tert butylphenyl)imidazolidin-4-one, To a solution of 3-(4-methoxyphenethyl)-2-(4-tert butylphenyl)imidazolidin-4-one in 100 mL DMF (0.5 g 1.4 mmol) sodium hydride 20 (0.04 g 1.6 mmol) was added and stirred for 10 minutes, followed by the addition of p-methoxybenzyl chloride (02 g 1.6 mmol). The new solution was stirred overnight. 400 mL of water was added and the organic layer was extracted with CH 2 Cl 2 (3x100 mL) and the combined organic layers were dried over MgSO 4 . The organic solvent was boiled off and the resulting residue was purified by chromatography to produce 25 a white solid, 0.3 g, 55.6 % yield. 1 H NMR (300 MHz, CDC13) 6 7.44 (m, 2 H), 7.31 (m, 3 H), 7.15 (m, 2 H), 6.90 (m, 2 H), 6.82 (m, 3 H), 4.70 (s, 1 H), 3.80 (s, 6 H), 3.61 (m, 4 H), 3.16 (m, 1 H), 2.91 (m, 2 H), 2.50 (m, 1 H), 1.38 (m, 9 H); (MH*) 473. Examples 76-85 were prepared according to the procedures described in Example 74 above using the corresponding reagents (e.g., corresponding amino acid, amine, 30 and aldehyde reagents): - 57 - WO 2009/079624 PCT/US2008/087397 Example 76: 1-(4-Methoxybenzyl)-2-(4-chlorophenyl)-3-phenethylimidazolidin-4 one, 'H NMR (300 MHz, CDC13) 6 7.40 (m, 9 H), 7.06 (m, 2 H), 6.85 (m, 2 H), 4.61 (m, 1 H), 3.81 (s, 3 H), 3.70 (m, 1 H), 3.54 (m, 2 H), 3.30 (m, 1 H), 3.10 (m, 1 H), 2.83 (m, 2 H), 2.61 (m, 1 H); (MH*) 421. 5 Example 77: 3-(4-Methoxyphenethyl)-2-(benzo[d][1,3]dioxol-5-yl)-1 benzylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.29 (m, 5 H), 7.20 (m, 2 H), 6.98 (m, 2 H), 6.80 (m, 3 H), 3.03 (m, 2 H), 4.64 (m, 1 H), 3.81 (s, 3 H), 3.78 (m, 1 H), 3.63 (m, 1 H), 3.55 (m, 1 H), 3.33 (d, 1 H, J = 13.2 Hz), 3.06 (m, 1 H), 2.80 (m, 2 H), 2.56 (m, 1 H); (MH*) 431 10 Example 78: 1 -Benzyl-3-[2-(4-methoxyphenyl)-ethyl]-2-(4-trifluoromethylphenyl) imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.57 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.18 (m, 3H), 7.05 (dd, 2H, J = 2.3, 7.6 Hz), 6.88 (d, 2H, J = 8.6 Hz), 6.74 (d, 2H, J = 8.7 Hz), 4.64 (s, 1H), 3.73 (s, 3H), 3.61 (m, 2H), 3.50 (dd, 1H, J = 1.4, 14.4 Hz), 3.31 (d, 1H, J = 13.1 Hz), 3.05 (dd, 1H, J = 2.1, 14.4 Hz), 2.65 (m, 15 2H), 2.48 (m, 1H); (MH*) 455. Example 79: 1-Benzyl-2-(3,4-dichlorophenyl)-3-[2-(4-methoxyphenyl)-ethyl] imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.38 (d, 1H, J = 8.2 Hz), 7.19 (m, 4H), 7.06 (m, 3H), 6.90 (d, 2H, J = 8.6 Hz), 6.76 (d, 2H, J = 8.6 Hz), 4.51 (s, 1H), 3.74 (s, 3H), 3.65 (m, 1H), 3.47 (dd, 1H, J = 1.4, 14.5 Hz), 3.30 (d, 1H, J = 13.1 Hz), 20 3.03 (dd, 1H J = 2.2, 14.4 Hz), 2.66 (m, 3H), 2.48 (m, 1H); (MH+) 455. Example 80: 1 -Benzyl-2-(3-chlorophenyl)-3-[2-(4-methoxyphenyl)-ethyl] imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.28 (m, 2H), 7.19 (m, 5H), 7.07 (d, 2H, J = 7.8 Hz), 6.90 (d, 2H, J = 8.6 Hz), 6.75 (d, 2H, J = 8.6 Hz), 4.57 (s, 1H), 3.73 (s, 3H), 3.65 (d, 1H, J = 12.7 Hz), 3.61 (m, 1H), 3.47 (d, 1H, J = 15.7 Hz), 3.29 (d, 25 1H, J = 13.1 Hz), 3.02 (d, 1H J = 16.5 Hz), 2.67 (m, 2H), 2.44 (m, 1H); (MH+) 421. Example 81: 1 -Benzyl-2-(4-isopropylphenyl)-3-[2-(4-methoxyphenyl)-ethyl] imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.17 (m, 9H), 6.85 (d, 2H, J = 8.7 - 58 - WO 2009/079624 PCT/US2008/087397 Hz), 6.71 (d, 2H, J = 8.7 Hz), 4.63 (s, 1H), 3.69 (s, 3H), 3.69 (m, 1H), 3.49 (m, 2H), 3.25 (d, 1H, J = 13.2 Hz), 2.98 (dd, 1H, J = 14.3, 2.2 Hz), 2.86 (m, 1H), 2.70 (m, 2H), 2.38 (m, 1H), 1.19 (d, 6H, J = 7.1 Hz); (MH*) 429. Example 82: 1-Benzyl-2-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl]-imidazolidin 5 4-one, 'H-NMR (300 MHz, CDC13) 6 7.17 (m, 9H), 6.87 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 11.5 Hz), 4.63 (s, 1H), 3.70 (s, 3H), 3.69 (d, 1H, J = 12.7 Hz), 3.52 (m, 1H), 3.44 (d, 1H, J = 15.5 Hz), 3.24 (d, 1H, J = 13.2 Hz), 2.98 (d, 1H, J = 16.5 Hz), 2.64 (m, 4H), 2.39 (m, 1H), 1.18 (t, 3H, J = 10.6 Hz); (MH*) 415. Example 83: 1 -Benzyl-2-(4-tert-butyl-phenyl)-3-[2-(4-methoxyphenyl)-ethyl] 10 imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.33 (d, 2H, J = 8.4 Hz), 7.24 (d, 2H, J = 8.4 Hz), 7.15 (m, 5H), 6.85 (d, 2H, J = 8.6 Hz), 6.71 (d, 2H, J = 8.6 Hz), 4.63 (s, 1H), 3.69 (s, 3H), 3.69 (m, 1H), 3.47 (m, 2H), 3.25 (d, 1H, J = 13.2 Hz), 2.98 (dd, 1H, J = 2.2, 14.3 Hz), 2.71 (m, 2H), 2.38 (m, 1H), 1.27 (s, 9H); (MH') 443. Example 84: 1 -Benzyl-2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)-ethyl] 15 imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.12 (m, 8H), 6.88 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.7 Hz), 4.59 (s, 1H), 3.70 (s, 3H), 3.66 (m, 1H), 3.56 (m, 1H), 3.43 (dd, 1H, J = 1.4, 14.3 Hz), 3.23 (d, 1H, J = 13.2 Hz), 2.97 (dd, 1H, J = 13.2 Hz), 2.67 (m, 2H), 2.43 (m, 1H), 2.20 (s, 6H); (MH*) 415. Example 85: 1 -Benzyl-2-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)-ethyl] 20 imidazolidin-4-one, 'H-NMR (300 MHz, CDC13) 6 7.51 (m, 2H), 7.43 (m, 3H), 7.28 (m, 4H), 7.12 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.6 Hz), 4.86 (s, 1H), 3.96 (s, 3H), 3.89 (d, 1H, J = 13.1 Hz), 3.80 (m, 1H), 3.71 (d, 1H, J = 15.7 Hz), 3.51 (d, 1H, J = 13.1 Hz), 3.26 (d, 1H, J = 14.4 Hz), 2.91 (m, 2H), 2.66 (m, 1H); (MH') 405. CATEGORY V 25 Example 86: 3-(4-Methoxyphenethyl)-1-(2-(benzyloxy)ethyl)-2-(4-tert butylphenyl)imidazolidin-4-one - 59 - WO 2009/079624 PCT/US2008/087397 N H Br Os 2
C
3
ON
0 0 3-(4-Methoxyphenethyl)-1 -(2-(benzyloxy)ethyl)-2-(4-tert-butylphenyl)imidazolidin-4 one: To a solution of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)imidazolidin-4 5 one (0.55 g, 1.57 mmol) and 1-((2-bromoethoxy)methyl)benzene (0.27 mL, 1.71 mmol) in 1,4-dioxane (15.0 mL) was added Cs2CO3. The reaction mixture was stirred at 65 0C for a total of 3 d followed by filtration and evaporation to yield the crude material. The crude material was purified by reverse phase HPLC to yield 0.18 g of the desired product. 1 H NMR (300 MHz, CDC13) 6 7.45 (d, 2H, J = 8.4 Hz), 10 7.31 (m, 7H), 6.99 (d, 2H, J = 8.7 Hz), 6.38 (d, 2H, J = 8.7 Hz), 4.94 (s, 1H), 4.46 (s, 2H), 3.90 (m, 1H), 3.81 (s, 3H), 3.65 (m, 4H), 2.81 (m, 4H), 2.55 (m, 1H), 1.37 (s, 9H); (MH*) 487. Examples 87-88 were prepared according to the procedures described in Example 85 above using the corresponding reagents (e.g., corresponding amino acid, amine, 15 and aldehyde reagents): Example 87: 3-(4-Methoxyphenethyl)-1-(3-(benzyloxy)propyl)-2-(4-tert butylphenyl)imidazolidin-4-one, 1 H NMR (300 MHz, CD30D) 6 7.72 (d, 2H, J = 8.4 Hz), 7.30 (m, 5H), 7.16 (m, 2H), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 4.67 (bs, 1H), 4.28 (bs, 2H), 3.79 (s, 3H), 3.43 (m, 4H), 3.14 (m, 1H), 2.70 (m, 3H), 20 2.43 (m, 2H), 1.66 (m, 2H), 1.32 (s, 9H); (MH*) 501. Example 88: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-(3-(pyridin-2 ylmethoxy)propyl)imidazolidin-4-one trifluroacetate, 1 H NMR (300 MHz, CDC13) 6 8.84 (d, 1H, J = 5.3 Hz), 8.26 (t, 1H, J = 7.7 Hz), 7.73 (m, 2H), 7.44 (d, 2H, J = 8.3 Hz), 7.27 (d, 2H, J = 8.3 Hz), 6.96 (d, 2H, J = 8.6 Hz), 6.80 (d, 2H, J = 8.6 Hz), 5.09 - 60 - WO 2009/079624 PCT/US2008/087397 (bs, 1H), 4.80 (bs, 2H), 3.95 (m, 1H), 3.76 (m, 4H), 3.56 (m, 3H), 2.84 (m, 4H), 2.58 (m, 1H), 1.86 (m, 2H), 1.31 (s, 9H); (MH*) 502. CATEGORY VI Example 89: 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -[3-(pyridin-3 5 ylmethoxy)propyl]imidazolidin-4-one N OH O NIN 1) MeSO 2 CI, NEtS, THE 2) NaH, Pyridin-3-ylmethanol, DMF Step 1. 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-1 -(3-(pyridin-3 ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(4-methoxyphenethyl)-2-(4 tert-butylphenyl)-1-(3-hydroxypropyl)imidazolidin-4-one (0.2 g, 0.6 mmol) in THF (6.0 10 mL) was added Et 3 N (0.2 mL, 1.2 mmol) followed by methanesulfonyl chloride (0.05 mL, 0.65 mmol). The reaction mixture was stirred at room temperature for 18 hours followed by evaporation of the THF and dilution in methylene chloride. The methylene chloride was washed with 0.1 N HCI (2x), dried over Na 2
SO
4 and evaporated to yield 0.3 g of the desired product. 1 H NMR (300 MHz, CDC13) 6 7.49 15 (d, 2H, J = 8.1 Hz), 7.28 (d, 2H, J = 7.8 Hz), 7.01 (d, 2H, J = 8.4 Hz), 6.84 (d, 2H, J = 8.7 Hz), 4.21 (m, 2H), 3.95 (s, 1H), 3.82 (s, 3H), 3.71 (s, 1H), 3.03 (m, 1H), 2.82 (m, 6H), 2.01 (bs, 2 H), 1.39 (m, 9H); (MH*) 489. Step 2. 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-(3-(pyridin-3 ylmethoxy)propyl)imidazolidin-4-one: To a solution of 3-(3-(4-methoxyphenethyl)-2 20 (4-tert-butylphenyl)-4-oxoimidazolidin-1-yl)propyl methanesulfonate (0.1 g, 0.3 mmol) in THF (7.5 mL) was added NaH (60%, 0.02 g, 0.6 mmol) followed by pyridin 3-ylmethanol (0.04 mL, 0.4 mmol). The reaction mixture was stirred at room temperature for 17 hours at which time additional NaH (60%, 0.06 g, 1.43 mmol) and pyridin-3-ylmethanol (0.12 mL, 1.3 mmol) were added. The reaction mixture was 25 warmed to 50 0C for a total reaction time of 41 hours followed by evaporation to yield - 61 - WO 2009/079624 PCT/US2008/087397 the crude product. The crude material was purified by reverse phase HPLC to yield 0.06 g of the desired product. 1 H NMR (300 MHz, CDC13) 6 8.79 (bs, 1H), 8.67 (d, 1H, J = 5.2 Hz), 8.11 (d, 1H, J = 8.0 Hz), 7.74 (m, 1H), 7.37 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.89 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.6 Hz), 5.11 (s, 1H), 5 4.49 (q, 2 H, J = 9.5, 2.8 Hz), 3.90 (m, 1H), 3.69 (m, 4H), 3.49 (m, 3H), 2.69 (m, 5H), 1.79 (m, 2H), 1.24 (s, 9H); (MH*) 502. Example 90 was prepared according to the procedures described in Examples 88 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): 10 Example 90: N-(3-(3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-4-oxoimidazolidin 1-yl)propyl)nicotinamide, 1 H NMR (300 MHz, CDC13) 6 9.40 (s, 1H), 8.83 (m, 1H), 8.51 (m, 1H), 7.88 (m, 1H), 7.46 (d, 2H, J = 8.3 Hz), 7.25 (d, 2H, J = 8.3 Hz), 6.97 (d, 2H, J = 8.5 Hz), 6.80 (d, 2H, J = 8.6 Hz), 5.23 (s, 1H), 4.08 (m, 1H), 3.81 (m, 2H), 3.75 (s, 3H), 3.43 (m, 3H), 2.73 (m, 5H), 1.95 (t, 2H, J = 6.5 Hz), 1.32 (s, 9H); (MH*) 15 515. CATEGORY VII Example 91: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1 -(methylsulfonyl) imidazolidin-4-one: 0 0 NH 1) NaH N NH N,' 2) CH 3
SO
2 CI 0g\ 20 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-(methylsulfonyl) imidazolidin-4-one: To a solution of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl) imidazolidin-4-one -62- WO 2009/079624 PCT/US2008/087397 (0.2 g 0.6 mmol) sodium hydride (0.02 g (0.7mmol) was added at room temperature in DMF (50 mL) and stirred for 10 minutes. Mesyl chloride was added in a slow steady stream. The resulting solution was monitored by HPLC and stirred overnight. Water was added (100mL) and the organic layer was extracted with methylene 5 chloride (3 x 100 mL). The combined organic layers were dried over MgSO 4 , the organic exract is filtered, and the solvent was boiled off. The residue was purified by chromatography to give 0.08 g of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-1 (methylsulfonyl)imidazolidin-4-one, 31 .7 % yield. 'H NMR (300 MHz, CDC13) 6 7.45 (d, 2H, J = 8.4 Hz), 7.22 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J 10 = 8.7 Hz), 5.64 (s, 1 H), 4.20 (m, 1 H), 4.00 (m, 2 H), 3.80 (s, 3 H), 2.85 (m, 2 H), 2.73 (m, 1 H), 2.42 (s, 3 H), 1.34 (s, 9 H); (MH*) 431. Examples 92-95 were prepared according to the procedures described in Examples 90 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): 15 Example 92: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-(3 fluorophenylsulfonyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.08 (m, 12 H), 5.19 (m, 2 H), 3.89 (m, 2 H), 3.81 (s, 3 H), 2.87 (m, 2 H), 2.68 (m, 1 H), 2.28 (s, 3 H); (MH') 511. Example 93: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1-tosylimidazolidin-4 20 one, 1 H NMR (300 MHz, CDC13) 6 7.41 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 7.8 Hz), 7.19 (d, 2H, J = 8.4 Hz), 7.11 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.79 (d, 2H, J = 8.7 Hz), 5.77 (s, 1 H), 4.11 (m, 2 H), 3.81 (s, 3 H), 3.77 (m, 1 H), 2.71 (m, 2 H), 2.57 (m, 1 H), 2.41 (s, 3 H), 1.34 (s, 9 H); (MH*) 507. Example 94: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1 25 (ethylsulfonyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.44 (d, 2H, J = 8.4), 7.22 (d, 2H, J = 8.7 Hz), 7.06 (d, 2H, J = 8.4 Hz), 6.86 (d, 2H, J = 8.7 Hz), 5.77 (s, 1 H), 4.30 (m, 1 H), 3.96 (m, 2 H), 3.81 (s, 3 H), 2.82 (m, 1 H), 2.60 (m, 2 H), 2.44 (m, 1 H), 1.36 (s, 9 H), 1.10 (t, 3H, J = 7.5 Hz); (MH*) 445. - 63 - WO 2009/079624 PCT/US2008/087397 Example 95: 3-(4-Methoxyphenethyl)-2-(4-tert-butylphenyl)-1 -(4 ethylphenylsulfonyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.44 (d, 2H, J = 8.4 Hz), 7.34 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.7 Hz), 7.11 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz), 6.81 (d, 2H, J = 8.4 Hz), 5.77 (s, 1 H), 4.09 (m, 2 H), 3.81 5 (s, 3 H), 3.78 (m, 1 H), 2.73 (m, 4 H), 2.44 (m, 1 H), 1.36 (s, 9 H), 1.25 (t, 3H, J = 6.6 Hz); (MH*) 521. CATEGORY VIII Example 96: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide
CO
2 Bn
CO
2 Bn CO 2 Bn p-TSA, paraformaldehyde., TFA, EtSiH, 4-trifluoromethoxyphenethyl amine, toluene, reflux, 1.5h Cbz, 0 CHC1 3 , rt, 2 d. EDC-HCI, HOBt, Et 3 N, DMF/CH 2 Cl 2 , rt, CbzHN C0 2 H N CbzN C0 2 H 24 h O Me
F
3 CO
CO
2 Bn O CO2H H 1) Hq, Pd/C, MeOH, rt, 24 h, N CbzN N 2) 4-tert-butylbenzaldehyde' I e Cs 2
CO
3 , MeOH 65 0C, 24 h NCH3
OCF
3
F
3 CO 0 0I O N N CDI, DBU, 3-aminopyridine,, N H rt, 24 h N
CH
3 10 Step 1: (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate: The mixture of Z-Glu(Bzl)-OH (3.7 g, 10.0 mmol), p-toluenesulfonic acid (190 mg, 1.0 mmol), and paraformaldehyde (2.5 g) in toluene (120 mL) was refluxed for 1.5 h. 15 The solution was decanted into a separatory funnel, diluted with ether, washed with 5% NaHCO 3 and brine, and dried over Na 2
SO
4 . The solvent was removed under - 64 - WO 2009/079624 PCT/US2008/087397 reduced pressure to give the crude product as a colorless oil, which was then purified by column chromatography (silica gel, 4:1 Hexanes/ethyl acetate) to yield a colorless oil (3.5 g, 91%). 'H NMR (300 MHz, CDC13) 6 7.36 (m, 10H), 5.53 (bs, 1H), 5.18 (m, 3H), 5.09 (m, 2H), 4.40 (t, 1H, J = 5.7 Hz), 2.51 (m, 2H), 2.36 (m, 1H), 5 2.24 (m, 1H); (MH+) 384. Step2: (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5-oxopentanoic acid: To the solution of (S)-benzyl 4-(3-(benzyloxy)-3-oxopropyl)-5-oxooxazolidine-3-carboxylate (3.5 g, 9.1 mmol) in CHC1 3 at room temperature was added triethylsilane (4.4 mL, 27.4 mmol) followed by trifluoroacetic acid (46 mL). The resultant solution was 10 stirred at room temperature for 2 days. The solvent was removed under reduced pressure to give the crude product as a murky paste, which was purified by HPLC (reversed phase C18, H 2 0/acetonitrile) to give a colorless paste (2.8 g, 81 %). 'H NMR (300 MHz, CDC13, 2 rotamers) 6 7.36 (m, 10H), 5.12 (4H), 4.75 (m, 1H), 2.89 (s, 3H), 2.43 (m, 3H), 2.10 (m, 1H); 13C NMR (75 MHz, CDC13) 5 175.9, 172.6, 15 172.5, 157.3, 156.4, 136.4, 136.3, 135.9, 128.8, 128.7, 128.5, 128.3, 128.0, 68.0, 66.7, 60.7, 58.5, 58.3, 32.0, 31.6, 30.9, 30.7, 24.3, 23.9, 21.2, 14.4; (MH*) 385. Step 3: (S)-benzyl 5-(4-(trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5 oxopentanoate: To the solution of (S)-5-(benzyloxy)-2-(benzyloxycarbonyl)-5 oxopentanoic acid (1.4 g, 3.7 mmol) and trifluoromethoxyphenethylamine 20 hydrochloride (0.84 g, 3.5 mmol) in DMF (30 mL) was added Et 3 N (1.5 mL, 4.7 mmol), HOBt (0.71 g, 5.2 mmol), and EDC*HCI (1.0 g, 5.2 mmol). The resultant suspension was stirred at room temperature overnight. The mixture was concentrated to half of the volume and was then partitioned between ethyl acetate and 1N sodium bisulfate. The layers were separated and the organic solution was 25 washed with water, 5% NaHCO 3 , water, and brine, and dried over Na 2
SO
4 . The solvent was removed under reduced pressure to give the crude product as a yellowish paste, which was purified by HPLC (C18, H 2 0/acetonitrile) to give a colorless paste (1.73 g, 86%). 'H NMR (300 MHz, CDC13) 6 7.35 (m, 10H), 7.11 (m, 4H), 6.17 (bs, 1H), 5.11 (m, 4H), 4.61 (m, 1H), 3.53 (m, 1H), 3.42 (m, 1H), 2.74 (m, 30 5H), 2.32 (m, 3H), 1.98 (m, 1H); (MH*) 573. - 65 - WO 2009/079624 PCT/US2008/087397 Step 4: 3-((4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3-methyl-5 oxoimidazolidin-4-yl)propanoic acid: The mixture of (S)-benzyl 5-(4 (trifluoromethoxy)phenethylamino)-4-(benzyloxycarbonyl)-5-oxopentanoate (1.70 g, 3.0 mmol) and Pd-C (10%, 0.2 g) in 2-propanol (30 mL) was stirred under hydrogen 5 (1 atm) at room temperature overnight. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl ether to give a white solid (0.80 g), which was used without further purification. To the mixture of this crude product (4.9 g, 14 mmol), and Cs2CO3 (4.6 g, 14 mmol) in MeOH (70 mL) was added 4-tert-butylbenzaldehyde (4.6 mL, 27 mmol). The 10 resultant mixture was stirred at reflux overnight. The solvent was removed under reduced pressure and the product was purified by HPLC (C18, water/acetonitrile) to give the products as two diastereomers. Major (trans) isomer: 1 H NMR (300 MHz, CDC13) 6 7.43 (d, 2H, J = 8.4 Hz), 7.19 (m, 4H), 7.09 (d, 2H, J = 8.4 Hz), 5.39 (s, 1H), 4.03 (m, 1H), 3.58 (m, 1H), 2.83 (m, 3H), 2.48 (m, 2H), 2.13 (m, 5H), 1.33 (s, 15 9H); 13C NMR (75 MHz, CDC13) 5 176.8, 170.9, 154.2, 148.4, 137.1, 130.4, 130.2, 128.2, 126.6, 121.6, 120.6 (CF 3 , q, J = 255 Hz), 79.2, 62.7, 42.2, 35.4, 35.2, 33.3, 31.6, 29.9, 23.1; (MH*) 493.2313 (calc'd C26H32F3N204 493.2314); Minor (cis) isomer: 1 H NMR (300 MHz, CDC13) 6 7.42 (d, 2H, J = 8.4 Hz), 7.22 (d, 2H, J = 8.4 Hz), 7.10 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.4 Hz), 4.39 (d, 1H, J = 1.5 Hz), 3.55 20 (m, 1H), 3.22 (m, 1H), 2.93 (m, 1H), 2.76 (m, 1H), 2.54 (m, 3H), 2.23 (m, 5H), 1.34 (s, 9H); 13C NMR (75 MHz, CDC13) 5 178.4, 172.1, 153.6, 148.1, 137.4, 132.6, 130.3, 128.7, 126.0, 121.3, 120.6 (CF 3 , q, J = 255 Hz), 82.9, 65.2, 42.2, 36.9, 35.0, 33.1, 31.5, 29.5, 23.3; (MH*) 493. Step 5: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3-methyl 25 5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)propanamide: To the solution of 3-((4S)-1-(4 (trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3-methyl-5-oxoimidazolidin-4 yl)propanoic acid (240 mg, 0.41 mmol) in THF (2 mL) was added 1,1' carbonyldiimidazole (264 mg, 1.6 mmol) and the resultant mixture was stirred at room temperature for 30 min. A solution of DBU (183 pL, 1.2 mmol) and 3 30 aminopyridine (200 mg, 2.1 mmol) in THF (1.5 mL) was then added and the mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the product was purified by HPLC (C18, H 2 0/acetonitrile) to - 66 - WO 2009/079624 PCT/US2008/087397 give the major isomer as a yellow amorphous powder (84 mg, 37%). 'H NMR (300 MHz, CDC13) 6 9.35 (m, 1H), 8.67 (s, 1H), 8.28 (m, 2H), 7.38 (d, 2H, J = 8.4 Hz), 7.29 (m, 1H), 7.10 (m, 6H), 4.99 (d, 1H, J = 2.1 Hz), 3.93 (m, 1H), 3.55 (m, 1H), 2.84 (m, 2H), 2.70 (m, 1H), 2.43 (m, 2H), 2.21 (m, 1H), 2.05 (s, 3H), 1.88 (m, 1H), 1.31 5 (s, 9H); 13C NMR (75 MHz, CDC13) 5 173.3, 172.1, 153.0, 148.1, 144.1, 140.6, 137.2, 136.0, 132.5, 130.2, 127.8, 127.6, 126.0, 124.0, 121.2, 120.6 (CF 3 , q, J = 255 Hz), 80.4, 62.4, 41.3, 34.9, 34.0, 33.2, 32.7, 31.4, 32.7; 1 9 F-NMR (282 MHz, CDC13) 5104.8; (MH*) 569. Examples 97-101 were prepared according to the procedures described in Example 10 95 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 97: 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(phenylsulfonyl)propanamide, 'H NMR (300 MHz, CDC13) 6 8.10 (m, 2H), 7.55 (m, 3H), 7.42 (d, 2H, J = 8.4 Hz), 7.20 (d, 2H, J = 8.4 15 Hz), 7.09 (m, 4H), 5.25 (s, 1H), 4.07 (m, 1H), 3.45 (m, 1H), 2.82 (m, 3H), 2.02 (m, 7H), 1.34 (s, 9H); 13C NMR (75 MHz, CDC13) 5 171.6, 153.4, 148.2, 140.0, 136.9, 133.5, 131.5, 130.3, 129.0, 128.3, 127.9, 126.2, 121.5, 120.6 (CF 3 , q, J = 255 Hz), 104.1, 79.0, 63.1, 41.3, 35.0, 34.5, 33.4, 33.0, 31.5, 22.8; 1 9 F NMR (282 MHz, CDC13) 5105.2; (MH*) 632. 20 Example 98: 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-3-yl)acetamide, 1 H NMR (300 MHz, CDC13) 6 10.10 (s, 1H), 8.68 (s, 1H), 8.37 (d, 1H, J = 4 Hz), 8.25 (d, 1H, J = 8 Hz), 7.44 (d, 2H, J = 8 Hz), 7.30 (m, 1H), 7.13 (m, 6H), 5.18 (d, 1H, J = 2 Hz), 3.94 (m, 1H), 3.81 (m, 1H), 2.97 (m, 1H), 2.8 (m, 4H), 2.14 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, 25 CDC13) 6 173.3, 169.0, 153.3, 148.2, 144.8, 141.1, 137.0, 135.6, 131.7, 130.1, 127.7, 127.3, 126.2, 123.9, 121.4, 120.6 (CF 3 , q, J = 255 Hz), 80.7, 60.8, 42.2, 38.0, 34.9, 34.7, 33.3, 31.4; 1 9 F NMR (282 MHz, CDC13) 5105.1; (MH*) 555. Example 99: 2-((2S,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-yl)acetamide, 1 H NMR (300 MHz, CDC13) - 67 - WO 2009/079624 PCT/US2008/087397 6 9.80 (s, 1H), 8.19 (d, 1H, J = 4 Hz), 8.12 (d, 1H, J = 8 Hz), 7.58 (m, 1H), 7.26 (d, 2H, J = 8 Hz), 7.13 (d, 2H, J = 8 Hz), 6.88 (m, 5H), 4.28 (d, 1H, J = 2 Hz), 3.44 (m, 1H), 3.31 (m, 1H), 2.83 (m, 2H), 2.69 (m, 2H), 2.38 (m, 1H), 2.18 (s, 3H), 1.21 (s, 9H); 13C NMR (75 MHz, CDC13) 5 172.1, 168.9, 153.5, 151.8, 148.1, 148.0, 138.5, 5 137.5, 133.0, 130.3, 128.9, 125.9, 121.3, 120.6 (CF 3 , q, J = 255 Hz), 119.8, 114.4, 83.1, 63.4, 42.3, 38.6, 37.1, 35.0, 33.2, 31.5; 19 F NMR (282 MHz, CDC13) 5104.8; (MH*) 555. Example 100: 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide, 1H NMR (300 MHz, 10 CD30D) 6 8.50 (d, 1H, J = 4.5 Hz), 7.81 (dt, 1H, J = 7.8, 1.6 Hz), 7.48 (m, 3H), 7.31 (dd, 1H, J = 5.5, 7.1 Hz), 7.17 (m, 6H), 5.16 (d, 1H, J = 2.2 Hz), 4.54 (dd, 2H, J = 16.0, 28.0), 3.96 (m, 1H), 3.75 (m, 1H), 2.79 (m, 5H), 2.10 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CD30D) 5 174.5, 173.1, 159.3, 154.1, 149.9, 149.2, 139.4, 138.9, 134.2, 131.5, 129.3, 127.0, 123.9, 123.2, 122.2, 122.0 (CF 3 , q, J = 255 Hz), 82.0, 15 62.5, 45.7, 43.3, 36.8, 35.7, 34.7, 34.0, 31.8; 1 9 F NMR (282 MHz, CD30D) 5103.4; (MH*) = 569. Example 101: 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)-N-(pyridin-2-ylmethyl)acetamide, 1H NMR (300 MHz, CD30D) 6 8.55 (d, 1H, J = 1.8 Hz), 8.44 (dd, 1H, J = 1.5, 4.8 Hz), 7.84 (m, 1H), 7.48 20 (d, 2H, J = 8.4 Hz), 7.41 (m, 1H), 7.17 (m, 6H), 5.12 (d, 1H, J = 2.1 Hz), 4.46 (dd, 2H, J = 15.0, 34.0 Hz), 3.93 (m, 1H), 3.73 (m, 1H), 2.79 (m, 5H), 2.06 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CD30D) 5 174.5, 173.0, 154.1, 149.6, 149.2, 148.9, 139.5, 137.8, 136.8, 134.3, 131.6, 129.3, 127.0, 125.3, 122.2, 122.0 (CF 3 , q, J = 255 Hz), 82.0, 62.5, 43.3, 41.7, 36.9, 35.7, 34.7, 34.0, 31.8; 1 9 F NMR (282 MHz, CD30D) 25 5103.5; (MH*) = 569. Category IX Example 102: benzyl 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethylcarbamate - 68 - WO 2009/079624 PCT/US2008/087397
F
3 CO F 3 CO 0 CO 2 H O NHCbz N ' 1) DPPA, Et 3 N, toluene, 40 C, 24 h N N
CH
3 2) BnOH, 105 C, 12 h 'CH3
F
3 CO H ON 1) H 2 , Pd/C, MeOH, rt N N 2) 2-picolinic acid, EDC-HCI, N HOBt, Et 3 N, DMF, rt, overnight.
CH
3 A solution of 3-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)propanoic acid (1.86 g, 3.45 mmol), Et 3 N (2.40 mL, 17.2 mmol), and diphenylphosphorylazide (1.70 mL, 7.93 mmol) in toluene (20 mL) 5 was stirred at 40 OC overnight. Benzyl alcohol (3.20 mL, 31.0 mmol) was then added and the resultant mixture was stirred at -105 OC for 12 hours. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and 5% NaHCO 3 . The layers were separated and the organic solution was washed with another portion of 5% NaHCO 3 and brine, and dried over Na 2
SO
4 . The solvent 10 was removed under reduced pressure and the product was purified by column chromatography (silica gel, 4:1 Hexanes/ethyl acetate) to a yellow paste (1.30 g, 63%). 1 H NMR (300 MHz, CDC13) 6 7.28 (m, 7H), 7.03 (m, 4H), 6.94 (d, 2H, J = 8.1 Hz), 5.64 (m, 1H), 5.03 (s, 2H), 4.91 (s, 1H), 3.82 (m, 1H), 3.35 (m, 1H), 3.28 (m, 1H), 3.15 (m, 1H), 2.70 (m, 3H), 1.94 (m, 4H), 1.69 (m, 1H), 1.24 (s, 9H); 13C NMR 15 (75 MHz, CDC13) 5 173.1, 156.6, 152.8, 148.1, 137.4, 137.0, 132.5, 130.2, 128.6, 128.3, 128.2, 127.7, 125.9, 121.3, 120.7 (CF 3 , q, J = 255 Hz), 80.4, 66.7, 62.6, 41.8, 37.9, 34.9, 34.6, 33.4, 31.5, 27.9; 1 9 F NMR (282 MHz, CDC13) 5104.8; (MH*) 598. Example 103: N-(2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethyl)picolinamide: A mixture of benzyl - 69 - WO 2009/079624 PCT/US2008/087397 2-((2R,4S)-1 -(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3-methyl-5 oxoimidazolidin-4-yl)ethylcarbamate (78 mg, 0.13 mmol) and Pd-C (10%, 5 mg) in MeOH/THF (lmL/lmL) was stirred under H 2 (1 atm) for 2 hours at room temperature. The mixture was filtered and the filtrate was concentrated under 5 reduced pressure. The resultant crude amine was dissolved in DMF and to this solution was added Et 3 N (60 pL, 0.43 mmol), picolinic acid (24 mg, 0.20 mmol), HOBt (27 mg, 0.20 mmol), and EDC*HCI (38 mg, 0.20 mmol). The resultant mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was taken up in ethyl acetate and 5% NaHCO 3 . 10 The layers were separated and the organic solution was washed with water and brine, and dried over Na 2
SO
4 . The solvent was removed under reduced pressure and the product was purified by HPLC (C18, H 2 0/acetonitrile) to give a yellow solid (35 mg, 47%). 1 H NMR (300 MHz, CDC13) 6 8.70 (m, 1H), 8.58 (d, 1H, J = 4.2 Hz), 8.21 (d, 1H, J = 7.8 Hz), 7.84 (dd, 1H, J = 1.8, 7.8 Hz), 7.40 (m, 3H), 7.07 (m, 6H), 15 5.05 (d, 1H, J = 1.8 Hz), 3.94 (m, 1H), 3.56 (m, 3H), 2.78 (m, 3H), 2.17 (m, 1H), 2.07 (s, 3H), 1.92 (m, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDC13) 5 172.8, 164.5, 152.7, 150.4, 148.3, 148.0, 137.5, 137.4, 132.8, 130.2, 127.8, 126.1, 125.9, 122.4, 121.2, 120.6 (CF 3 , q, J = 255 Hz), 80.4, 62.4, 41.8, 36.0, 34.9, 34.6, 33.4, 31.5, 27.8; 1 9 F NMR (282 MHz, CDC13) 5104.8; (MH*) 569. 20 Examples 104-105 were prepared according to the procedures described in Example 101 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 104: N-(2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert butylphenyl)-3-methyl-5-oxoimidazolidin-4-yl)ethyl)nicotinamide, 1 H NMR (300 MHz, 25 CDC13) 6 9.10 (d, 1H, J = 1.8 Hz), 8.72 (dd, 1H, J = 1.5, 4.8 Hz), 8.46 (m, 1H), 8.24 (dt, 1H, J = 8.1, 2.1 Hz), 7.39 (m, 3H), 7.07 (m, 6H), 5.09 (d, 1H, J = 2.4 Hz), 3.93 (m, 1H), 3.83 (m, 1H), 3.50 (m, 1H), 3.35 (m, 1H), 2.79 (m, 3H), 2.12 (m, 1H), 2.06 (s, 3H), 1.85 (m, 1H)1.32 (s, 9H); 13C NMR (75 MHz, CDC13) 5 173.9, 165.3, 153.0, 152.1, 148.6, 148.1, 137.2, 135.3, 132.1, 130.3, 130.1, 127.7, 126.1, 123.6, 121.3, 30 120.6 (CF 3 , q, J = 255 Hz), 80.7, 64.0, 41.9, 37.8, 34.9, 34.7, 33.3, 31.4, 27.6; 1 9 F NMR (282 MHz, CDC13) 5105.0; (MH*) 569. - 70 - WO 2009/079624 PCT/US2008/087397 Example 105: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-1 methyl-5-(2-(pyrimidin-2-ylamino)ethyl)imidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 8.31 (d, 2H, J = 4.4 Hz), 7.38 (d, 2H, J = 8.3 Hz), 7.18 (d, 2H, J = 8.6 Hz), 7.06 (m, 4H), 6.68 (bs, 1H), 6.55 (t, 1H, J = 4.8 Hz), 5.22 (s, 1H), 3.99 (m, 1H), 3.67 5 (m, 1H), 3.53 (m, 1H), 3.30 (m, 1H), 2.82 (m, 3H), 2.21 (m, 1H), 2.07 (s, 3H), 1.91 (m, 1H), 1.32 (s, 9H); 13C NMR (75 MHz, CDC13) 5 173.0, 162.1, 158.1, 152.8, 148.1, 137.5, 132.7, 130.2, 127.8, 125.9, 121.2, 120.6 (CF 3 , q, J = 255 Hz), 114.7, 110.3, 80.3, 62.8, 41.7, 38.3, 34.9, 33.3, 31.5, 29.9, 27.5; 1 9 F NMR (282 MHz, CDC13) 5105.0; (MH*) 542. 10 Category X Example 106: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-5-(2 hydroxyethyl)-1-methylimidazolidin-4-one
F
3 CO F 3 CO F 3 CO CH3 O 2 0 OH b NBn N' CO2H a N 'b N N, N N
CH
3
'CH
3 / CH 3 15 To a solution of 2-((2R,4S)-1-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)acetic acid (1.0g, 1.7 mmol) in THF (15 mL) at -78 OC was added BH 3 *THF (5.1 mL, 5.1 mmol). The resulting solution was stirred at -78 OC to room temperature overnight. The mixture was diluted with ethyl acetate and washed with 5% NaHCO 3 and brine. The organic solution was dried over Na 2
SO
4 20 and concentrated under reduced pressure to give the crude product, which was purified by HPLC to yield a colorless oil (770 mg, 98%). 1 H NMR (300 MHz, CDC13) 6 7.41 (d, 2H, J = 8 Hz), 7.17 (m, 4H), 7.03 (d, 2H, J = 8 Hz), 5.05 (d, 1H, J = 2 Hz), - 71 - WO 2009/079624 PCT/US2008/087397 4.45 (bs, 1H), 3.99 (m, 1H), 3.76 (m, 2H), 3.56 (m, 1H), 3.80 (m, 3H), 2.06 (s, 3H), 1.98 (m, 2H), 1.34 (s, 9H); 1 9 F NMR (282 MHz, CDC13) 5105.0; (MH*) 465. Example 107: (2R,5S)-5-(2-(benzyl(methyl)amino)ethyl)-2-(4-tert-butylphenyl)-1 methyl-3-(4-(trifluoromethoxy)phenethyl)imidazolidin-4-one: To a solution of 5 (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-tert-butylphenyl)-5-(2-hydroxyethyl) 1-methylimidazolidin-4-one (130 mg, 0.28 mmol) and Et 3 N (78 pL, 0.56 mmol) in THF (3 mL) was added methanesulfonyl chloride (24 pL, 0.31 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over Na 2
SO
4 . The solvent 10 was removed under reduced pressure to give the crude product as a pale brown oil (157 mg). The crude product (120 mg, 0.22 mmol) was dissolved in THF (1 mL) and N, N'-benzylmethyl amine (286 pL, 2.2 mmol) was added. The resultant mixture was stirred at room temperature for 3 days followed by stirring at 60 OC for another day. The solvent was removed under reduced pressure and the product was 15 purified by HPLC to give a colorless oil (106 mg, 85%). 'H NMR (300 MHz, CDC13) 6 7.43-7.08 (m, 13H), 4.97 (d, 1H, J = 2 Hz), 3.90 (m, 1H), 3.54 (m, 3H), 2.83 (m, 2H), 2.69 (m, 2H), 2.44 (m, 1H), 2.24 (s, 3H), 2.05 (s, 3H), 2.02 (m, 1H), 1.89 (m, 1H), 1.36 (s, 9H); 13C NMR (75 MHz, CDC13) 5 173.4, 152.6, 148.0, 139.3, 137.6, 133.2, 130.2, 129.3, 128.3, 127.8, 127.1, 125.8, 121.2, 120.6 (CF 3 , q, J = 255 Hz), 20 80.6, 62.4, 61.9, 53.3, 42.3, 41.5, 34.8, 34.5, 33.3, 31.4, 26.9; 1 9 F NMR (282 MHz, CDC13) 5105.2; (MH*) 568. Category XI Example 108: (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl) 1 -methyl-5-(2-(pyridin-2-ylmethoxy)ethyl)imidazolidin-4-one: - 72 - WO 2009/079624 PCT/US2008/087397 F 3 C O F 3 C O N 0 OH N - 1) CH 3
SO
2 CI, Et 3 N, THF, rt, 24 h N N'CH 2) NaH, 2-pyridinemethanol, 'CH3 CH3THF, -78 'C rt NN (2R,5S)-3-(4-(trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1-methyl-5-(2 (pyridin-2-ylmethoxy)ethyl)imidazolidin-4-one: To a solution of (5S)-3-(4 (trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-5-(2-hydroxyethyl)-1 5 methylimidazolidin-4-one (413 mg, 0.86 mmol) and Et 3 N (240 pL, 1.7 mmol) in THF (5 mL) was added methanesulfonyl chloride (80 pL, 1.0 mmol). The resulting mixture was stirred at room temperature overnight. The mixture was diluted with ethyl acetate and washed with water and brine, and dried over Na 2
SO
4 . The solvent was removed under reduced pressure to give the crude product as light brown oil 10 (478 mg). The crude product (126 mg, 0.23 mmol) was dissolved in dry THF (1 mL and 1 mL wash) and added to the mixture of 2-pyridinemethanol (44 pL, 0.46 mmol) and NaH (60% dispersion, 18 mg, 0.47 mmol) in THF (1 mL) at -78 OC (prepared from adding NaH to the solution of 2-pyridinemethanol in THF at -78 OC and stirring it for 20 min). The resultant mixture was stirred at -78 OC to room temperature 15 overnight. The mixture was diluted with ethyl acetate and washed with 5% NaHCO 3 , water, and brine, and then dried over Na 2
SO
4 . The solvent was removed under reduced pressure and the trans-isomer was purified by HPLC (C18, water/acetonitrile) followed by washing with 10% Na 2
CO
3 to give the product as a free base (13 mg). 1 H NMR (300 MHz, CD30D) 6 8.47 (d, 1H, J = 4.2 Hz), 7.85 (dt, 20 1H, J = 7.8, 1.5 Hz), 7.55 (d, 1H, J = 7.9 Hz), 7.32 (dd, 1H, J = 5.1, 6.6 Hz), 7.17 (m, 4H), 7.02 (d, 2H, J = 8.7 Hz), 6.71 (d, 2H, J = 8.7 Hz), 5.01 (d, 1H, J = 2.1 Hz), 4.59 (s, 2H), 3.77 (m, 1H), 3.64 (t, 2H, J = 6.6 Hz), 3.56 (m, 1H), 3.39 (q, 4H, J = 6.9 Hz), 2.82 (m, 2H), 2.65 (m, 1H), 2.09 (m, 4H), 1.89 (m, 1H), 1.16 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CD30D) 5 175.3, 159.8, 150.2, 149.7, 149.3, 139.5, 139.0, 131.6, 25 130.5, 124.2, 123.4, 122.7, 122.2, 122.0 (CF 3 , q, J = 255 Hz), 112.8,82.1, 74.3, - 73 - WO 2009/079624 PCT/US2008/087397 68.4, 62.6, 45.5, 42.6, 34.7, 33.9, 29.6, 13.0; 1 9 F NMR (282 MHz, CD30D) 5103.5; (MH*) 571. Examples 109-110 were prepared according to the procedures described in Example 108 above using the corresponding reagents (e.g., corresponding amino 5 acid, amine, and aldehyde reagents): Example 109: (2R,5S)-3-(4-methoxyphenethyl)-5-(benzyloxymethyl)-2-(4 (diethylamino)phenyl)-1-methylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.35 (m, 5H), 7.05 (d, 2H, J = 8.6 Hz), 6.98 (d, 2H, J = 8.5 Hz), 6.75 d, 2H, J = 8.4 Hz), 6.64 (d, 2H, J = 8.4 Hz), 4.97 (d, 1H, J = 1.8 Hz), 4.58 (dd, 2H, J = 12.1, 15.6 Hz), 10 3.84 (m, 7H), 3.37 (q, 4H, J = 6.9 Hz), 2.71 (m, 3H), 2.29 (s, 3H), 1.18 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CDC13) 5 171.6, 158.2, 148.7, 138.4, 131.3, 129.9, 129.6, 128.5, 127.8, 127.7, 123.1, 113.9, 111.4, 82.2, 73.7, 69.5, 64.4, 55.4, 44.5, 42.2, 33.7, 33.1, 12.7; (MH*) 502. Example 110: (2S,5S)-3-(4-methoxyphenethyl)-5-(benzyloxymethyl)-2-(4 15 (diethylamino)phenyl)-1-methylimidazolidin-4-one, 1 H NMR (300 MHz, CDC13) 6 7.36 (m, 5H), 7.19 (d, 2H, J = 8.5 Hz), 7.01 (d, 2H, J = 8.5 Hz), 6.82 d, 2H, J = 8.4 Hz), 6.66 (d, 2H, J = 8.4 Hz), 4.65 (s, 2H), 4.30 (d, 1H, J = 1.8 Hz), 4.01 (dd, 1H, J = 2.4, 10.0 Hz), 3.82 (m, 4H), 3.63 (m, 1H), 3.40 (q, 4H, J = 6.9 Hz), 3.29 (m, 1H), 2.81 (m, 2H), 2.53 (m, 1H), 2.39 (s, 3H), 1.21 (t, 6H, J = 6.9 Hz); 13C NMR (75 MHz, CDC13) 6 20 170.3, 158.3, 148.8, 138.7, 131.1, 130.0, 128.5, 127.7, 127.6, 123.4, 114.0, 111.4, 110.3, 82.9, 73.6, 71.8, 66.7, 55.4, 44.5, 42.1, 38.6, 32.9, 12.8; (MH*) 502. CATEGORY XII Example 111: N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl-5 oxoimidazolidin-4-yl)methyl)methanesulfonamide - 74 - WO 2009/079624 PCT/US2008/087397
H
3 CO
H
3 CO
NHSO
2
CH
3 N N NN / CH 3 / CH 3 Preparation of N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)methanesulfonamide and N-(((2S,4S)-1-(4 methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl-5-oxoimidazolidin-4 5 yl)methyl)methanesulfonamide: (5S)-3-(4-methoxyphenethyl)-5-(aminomethyl)-2-(4 tert-butylphenyl)-1-methylimidazolidin-4-one (105 mg, 0.26 mmol), Et 3 N (73 pL, 0.52 mmol), and methanesulfonyl chloride (30 pL, 0.39 mmol) in THF (2 mL) were stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by HPLC to give the two diastereomers. Major (trans) 10 diastereomer (38 mg): 1 H NMR (300 MHz, CDC13) 6 7.40 (d, 2H, J = 8.4 Hz), 7.06 (m, 4H), 6.85 (d, 2H, J = 8.5 Hz), 5.11 (bs, 1H), 4.95 (m, 1H), 3.96 (m, 1H), 3.80 (s, 3H), 3.51 (m, 2H), 3.89 (m, 1H), 2.88 (s, 3H), 2.78 (m, 3H), 2.03 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CDC13) 5 170.8, 158.6, 153.0, 132.2, 130.3, 129.8, 127.6, 126.1, 114.2, 80.1, 62.9, 55.4, 42.0, 41.1, 40.5, 34.9, 34.6, 32.9, 31.4; (MH*) 474. 15 Minor (cis) diastereomer (8 mg): 1 H NMR (300 MHz, CDC13) 6 7.43 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.7 Hz),6.81 (d, 2H, J = 9.0 Hz), 5.26 (m, 1H), 4.40 (d, 1H, , J = 1.8 Hz), 3.79 (s, 3H), 3.64 (m, 2H), 3.35 (m, 1H), 3.18 (m, 1H), 3.01 (s, 3H), 2.77 (m, 2H), 2.50 (m, 1H), 2.27 (s, 3H), 1.35 (s, 9H); 13C NMR (75 MHz, CDC13) 5 170.7, 158.6, 153.5, 133.3, 130.4, 130.0, 128.5, 126.0, 114.1, 20 82.6, 64.9, 55.5, 42.2, 41.7, 40.7, 37.0, 35.0, 32.8, 31.5; (MH*) 474. Examples 112-115 were prepared according to the procedures described in Example 111 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): - 75 - WO 2009/079624 PCT/US2008/087397 Example 112: N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)propane-1-sulfonamide, 1 H NMR (300 MHz, CDC13) 6 7.39 (d, 2H, J = 8.3 Hz), 7.04 (m, 4H), 6.84 (d, 2H, J = 8.6 Hz), 5.09 (bs, 1H), 4.93 (m, 1H), 3.91 (m, 1H), 3.79 (s, 3H), 3.50 (m, 2H), 3.27 (m, 1H), 2.98 (m, 2H), 2.78 5 (m, 3H), 2.03 (s, 3H), 1.83 (m, 2H), 1.32 (s, 9H), 1.06 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDC13) 5 171.2, 158.8, 153.1, 132.5, 130.5, 130.0, 127.8, 126.2, 114.4, 80.4, 63.0, 55.6, 54.7, 42.4, 41.4, 35.1, 34.9, 33.2, 31.6, 17.7, 13.4; (MH*) 502. Example 113: N-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)propane-1-sulfonamide, 1 H NMR (300 MHz, CDC13) 5 10 7.43 (d, 2H, J = 8.5 Hz), 7.21 (d, 2H, J = 8.5 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.16 (m, 1H), 4.39 (d, 1H, , J = 2.1 Hz), 3.79 (s, 3H), 3.62 (m, 2H), 3.33 (m, 1H), 3.16 (m, 1H), 3.07 (m, 2H), 2.77 (m, 2H), 2.49 (m, 1H), 2.26 (s, 3H), 1.86 (m, 2H), 1.35 (s, 9H), 1.07 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDC13) 5 170.7, 158.6, 153.5, 133.2, 130.5, 130.0, 128.5, 126.0, 114.1, 82.6, 65.1, 55.5, 54.6, 15 42.2, 41.8, 37.0, 35.0, 32.8, 31.5, 17.6, 13.1; (MH') 502. Example 114: N-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)butane-1-sulfonamide, 1 H NMR (300 MHz, CDC13) 6 7.42 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), 6.94 (d, 2H, J = 8.6 Hz), 6.81 (d, 2H, J = 8.6 Hz), 5.16 (m, 1H), 4.39 (d, 1H, , J = 2.1 Hz), 3.79 (s, 3H), 3.63 (m, 2H), 20 3.33 (m, 1H), 3.17 (m, 1H), 3.09 (m, 2H), 2.76 (m, 2H), 2.50 (m, 1H), 2.26 (s, 3H), 1.81 (m, 2H), 1.46 (m, 2H), 1.35 (s, 9H), 0.94 (t, 3H, , J = 7.5 Hz); 13C NMR (75 MHz, CDC13) 5 170.8, 158.6, 153.4, 133.3, 130.5, 130.0, 128.5, 126.0, 114.1, 82.6, 65.1, 55.5, 52.7, 42.2, 41.8, 37.0, 35.0, 32.8, 31.5, 25.9, 21.7, 13.8; (MH*) 516. Example 115: N-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 25 5-oxoimidazolidin-4-yl)methyl)(pyridin-3-yl)methanesulfonamide, 1 H NMR (300 MHz,
CD
3 0D) 6 8.57 (d, IH, J = 1.8 Hz), 8.52 (dd, IH, J = 1.5, 4.8, Hz), 7.91 (dt, IH, J = 7.8, 1.8 Hz), 7.46 (m, 3H), 7.12 (d, 2H, J = 8.4 Hz), 7.05 (d, 2H, J = 8.4 Hz), 6.81 (d, 2H, J = 8.4 Hz), 5.19 (d, 1H, J = 2.4 Hz), 4.30 (m, 2H), 3.82 (m, 1H), 3.73 (s, 3H), 3.51 (m, 1H), 3.40 (m, 2H), 2.74 (m, 3H), 2.07 (s, 3H), 1.33 (s, 9H); 13C NMR (75 30 MHz, CD30D) 5 173.3, 160.2, 154.3, 152.5, 150.2, 141.1, 134.5, 132.2, 131.3, - 76 - WO 2009/079624 PCT/US2008/087397 129.4, 129.1, 127.4, 125.6, 115.5, 81.9, 65.8, 57.0, 56.1, 43.6, 42.9, 36.0, 35.0, 33.9, 32.1; (MH*) 551. Category XIII Example 116: 1-(((4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl-5 5 oxoimidazolidin-4-yl)methyl)-3-ethylurea
H
3 CO
H
3 CO 0 O NH 2 HN N N NH N, Na
CH
3
CH
3 A mixture of (5S)-3-(4-methoxyphenethyl)-5-(aminomethyl)-2-(4-tert-butylphenyl)-1 methylimidazolidin-4-one (98 mg, 0.25 mmol) and ethyl isocyanate (99 pL, 1.25 mmol) in CH 2 Cl 2 (3 mL) were stirred at room temperature overnight. The solvent 10 was removed under reduced pressure and the products were purified by HPLC (C18, water/acetonitrile) followed by washing with 10% Na 2
CO
3 to give the two diastereomers as free bases. Major diastereomer (trans, 65 mg): 1 H NMR (300 MHz, CD30D) 6 7.44 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H, J = 8.4 Hz), 5.15 (d, 1H, J = 2.1 Hz), 3.73 (s, 3H), 3.68 (m, 2H), 15 3.49 (m, 1H), 3.28 (m, 1H), 3.16 (q, 2H, J = 7.2 Hz), 2.76 (m, 2H), 2.60 (m, 1H), 2.09 (s, 3H), 1.31 (s, 9H), 1.10 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CD30D) 5 173.9, 160.9, 159.9, 153.9, 134.4, 131.9, 130.8, 129.1. 126.9, 115.1, 81.9, 65.1, 55.8, 43.5, 39.8, 35.9, 35.7, 34.7, 33.9, 31.9, 15.9; (MH*) 467. Minor diastereomer (cis, 9 mg): 1 H NMR (300 MHz, CD 3 0D) 6 7.37 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.4 Hz), 6.83 20 (d, 2H, J = 8.4 Hz), 6.70 (d, 2H, J = 8.4 Hz), 4.39 (d, 1H, J = 2.1 Hz), 3.65 (s, 3H), 3.42 (m, 3H), 3.04 (m, 3H), 2.63 (m, 2H), 2.32 (m, 1H), 2.16 (s, 3H), 1.24 (s, 9H), 1.00 (t, 3H, J = 7.2 Hz); 13C NMR (75 MHz, CD30D) 5 173.4, 161.4, 160.1, 154.3, - 77 - WO 2009/079624 PCT/US2008/087397 135.5, 131.9, 131.0, 130.0, 126.8, 115.1, 83.7, 67.6, 55.8, 43.5, 40.0, 37.4, 35.9, 35.7, 33.7, 31.9, 15.9; (MH*) 467. Examples 117-121 were prepared according to the procedures described in Example 116 above using the corresponding reagents (e.g., corresponding amino 5 acid, amine, and aldehyde reagents): Example 117: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)-3-(pyrimidin-4-yl)urea, 1 H NMR (300 MHz, CD30D) 6 8.75 (s, 1H), 8.41 (d, 1H, J = 6 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.24 (d, 1H, J = 6 Hz), 7.14 (d, 2H, J = 8.4 Hz), 6.96 (d, 2H, J = 8.4 Hz), 6.70 (d, 2H, J = 8.4 Hz), 5.21 (d, 10 1H, J = 2.1 Hz), 3.78 (m, 3H), 3.69 (s, 3H), 3.61 (m, 1H), 3.51 (m, 1H), 2.74 (m, 2H), 2.59 (m, 1H), 2.14 (s, 3H), 1.33 (s, 9H); 13C NMR (75 MHz, CD30D) 5 173.6, 160.6, 159.9, 158.4, 157.5, 156.5, 154.0, 134.3, 131.7, 130.7, 129.1, 127.1, 115.0, 109.9, 81.9, 65.0, 55.7, 43.4, 39.2, 35.7, 34.7, 33.9, 31.8; (MH*) 517. Example 118: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 15 5-oxoimidazolidin-4-yl)methyl)urea, 1 H NMR (300 MHz, CD30D) 6 7.46 (d, 2H, J = 8.4 Hz), 7.12 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.4 Hz), 6.82 (d, 2H, J = 8.4 Hz), 5.12 (d, 1H, 2.4 Hz), 3.74 (s, 3H), 3.72 (m, 1H), 3.60 (dd, 1H, J = 3.3, 13.8 Hz), 3.49 (m, 1H), 3.30 (m, 1H), 2.78 (m, 2H), 2.60 (m, 1H), 2.10 (s, 3H), 1.32 (s, 9H); 13C NMR (75 MHz, CD30D) 5 173.9, 162.1, 160.0, 154.0, 134.4, 131.9, 130.9, 129.2, 20 127.0, 115.1, 82.0, 65.1, 55.8, 43.6, 39.8, 35.7, 34.7, 34.0, 31.8; (MH*) 439. Example 119: 1-(((2R,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1 H NMR (300 MHz, CDC13) 6 7.38 (d, 2H, J = 8.4 Hz), 7.05 (m, 4H), 6.82 (d, 2H, J = 8.4 Hz), 5.27 (bs, 1H), 5.07 (d, 1H, J = 1.8 Hz), 3.86 (m, 1H), 3.78 (s, 3H), 3.72 (m, 1H), 3.45 (m, 1H), 3.23 (m, 1H), 2.79 25 (m, 2H), 2.77 (d, 3H, J = 4.5 Hz), 2.66 (m, 1H), 2.11 (s, 3H), 1.32 (s, 9H); 13C NMR (75 MHz, CDC13) 5 172.8, 159.3, 158.5, 152.8, 132.7, 130.5, 129.9, 127.8, 125.9, 114.1, 80.6, 63.4, 55.4, 41.9, 39.6, 34.9, 34.6, 33.0, 31.4, 27.3; (MH*) 453. - 78 - WO 2009/079624 PCT/US2008/087397 Example 120: 1-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-3-methyl 5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1 H NMR (300 MHz, CDC13) 6 7.40 (d, 2H, J = 8.4 Hz), 7.21 (d, 2H, J = 8.4 Hz), , 6.93 (d, 2H, J = 8.4 Hz), 6.80 (d, 2H, J = 8.4 Hz), 5.66 (bs, 1H), 5.21 (bs, 1H), 4.50 (s, 1H), 3.78 (m, 4H), 3.60 (m, 1H), 3.30 5 (m, 2H), 2.77 (m, 5H), 2.50 (m, 1H), 2.36 (s, 3H), 1.34 (s, 9H); 13C NMR (75 MHz, CDC13) 5 171.8, 160.0, 158.5, 153.4, 130.5, 130.0, 128.6, 125.9, 114.1, 82.6, 66.1, 55.5, 42.3, 40.5, 37.2, 35.0, 32.8, 31.5, 29.9, 27.4; (MH*) 453. Example 121: 1-(((2S,4S)-1-(4-methoxyphenethyl)-2-(4-cyclopropylphenyl)-3 methyl-5-oxoimidazolidin-4-yl)methyl)-3-methylurea, 1 H NMR (300 MHz, CDC13) 5 10 7.15 (d, 2H, J = 8.1 Hz), 7.04 (d, 2H, J = 8.1 Hz), 6.92 (d, 2H, J = 8.4 Hz), 6.78 (d, 2H, J = 8.1 Hz), 5.57 (bs, 1H), 5.23 (bs, 1H), 4.35 (d, 1H, J = 2.4 Hz), 3.78 (s, 3H), 3.74 (m, 1H), 3.58 (m, 1H), 3.32 (m, 1H), 3.09 (m, 1H), 2.76 (s, 3H), 2.71 (m, 2H), 2.65 (m, 1H), 2.26 (s, 3H), 1.90 (tt, 1H, J = 3.3, 5.1 Hz), 0.99 (m, 2H), 0.70 (m, 2H); 13C NMR (75 MHz, CDC13) 5 172.3, 159.7, 158.5, 146.2, 133.8, 130.5, 129.9, 128.8, 15 126.0, 114.1, 82.6, 66.0, 55.4, 42.0, 40.3, 37.0, 32.8, 27.3, 15.4, 9.9, 9.8; (MH*) 437. Category XIV Example 122: 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5 dimethylimidazolidin-4-one - 79 - WO 2009/079624 PCT/US2008/087397
NH
2 0 H H FDlCI 4-methul morpholinp N N BOC + HO N'BOC HOBT, CH 2 Cl 2 , rt, 18hr o H I TFA, MeOH, rt, 3 h NH H N K CO MeOH. rt H N NH 2 ~-~-- ~-48 h+ 0 N 0 0 NaH, CH 3 1, THF, rt, 18hr 0 N N Step 1: Preparation of tert-butyl 1-(4-methoxyphenethylamino)-2-methyl-1 oxopropan-2-ylcarbamate: The starting BOC-Aib-OH (5.0 g, 24.6 mmol) was dissolved in methylene chloride (200 mL) in a single-neck 500mL flask equipped 5 with a stir bar under an inert N 2 atmosphere. Next, 1-(3-dimethylaminopropyl)-3 ethylcarbodiimide hydrochloride (6.13 g, 32.0 mmol), followed by 1 hydroxybenzotriazole (4.32 g, 32.0 mmol) were added to the mixture and dissolved. 4-methylmorpholine (8.11, 73.8 mmol) was then added to the reaction in one portion via syringe. Lastly, 4-methoxyphenethylamine (3.61 mL, 24.6 mmol) was added to 10 the reaction in one portion also via syringe. The reaction was then vigorously stirred at room temperature for 18 hours then extracted twice with saturated aqueous NaHCO 3 (2 x 250 mL) and d.i. H 2 0 (250 mL). The remaining organic layer was then filtered over anhydrous MgSO 4 , and evaporated to dryness on a rotovap. The product was purified by flash column chromatography using a hexane, HOAc 15 gradient system, whose fractions are concentrated on a roto-evaporator to give a white fluffy powder, 4.71 g, chemical yield 57%. 1 H-NMR (300 MHz, CDC13) 6 7.14 (d, 2H, J = 6.4 Hz), 6.85 (d, 2H, J = 6.4 Hz), 6.46 (bs, 1H), 4.94 (bs, 1H), 3.80 (s, 3H), 3.48 (dd, 2H, J = 6.2, 7.0 Hz), 2.77 (t, 2H, J = 7.0), 1.46 (s, 6H), 1.43 (s, 9H); - 80 - WO 2009/079624 PCT/US2008/087397 13 C-NMR (75 MHz, CDC13) 5 174.8, 158.5, 155.0, 131.2, 129.9, 114.2, 57.0, 55.5, 41.3, 35.0, 28.6, 26.0; (MH') 337.1. Step 2: Preparation of N-(4-methoxyphenethyl)-2-amino-2-methylpropanamide: The tert-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-ylcarbamate, (4.75 5 g, 14.1 mmol) was dissolved with stirring in methylene chloride (50 mL) in a 100mL single-neck flask equipped with a stir bar under an inert N 2 atmosphere. Next, trifluoroacetic acid (10.9 mL, 141 mmol) was added to the reaction in one portion via syringe increasing the concentration to 25% by volume in acid. The reaction was then vigorously stirred at room temperature for 3 hours. After transferring the 10 mixture to a 500 mL Erlenmeyer flask, the reaction was slowly diluted with saturated aqueous NaHCO 3 (100 mL) and d.i. H 2 0 (25 mL). The biphasic mixture was then basified to a constant pH of 9 via the addition of solid KOH. The mixture was separated and the remaining aqueous phase was further extracted with methylene chloride (2 x 100 mL). The combined organic extracts were filtered over anhydrous 15 MgSO 4 , and evaporated to dryness on a roto-evaporator to give a viscous yellow syrup (3.06 g, chemical yield 92%). 'H-NMR (300 MHz, CDC13) 6 7.65 (bs, 1H), 7.09 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 8.8 Hz), 3.76 (s, 3H), 3.41 (dd, 2H, J = 6.6, 7.3 Hz), 2.73 (t, 2H, J = 7.3 Hz), 1.30 (s, 6H); 13 C-NMR (75 MHz, CDC13) 5 177.7, 158.4, 131.4, 129.9, 114.1, 55.4, 40.8, 35.1, 29.4; (MH*) 237.1. 20 Step 3: Preparation of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5 dimethylimidazolidin-4-one: The N-(4-methoxyphenethyl)-2-amino-2 methylpropanamide (1 g, 4.23 mmol) was dissolved in methanol (25 mL) in single neck 100 mL flask equipped with a stir bar under an inert N 2 atmosphere. Next,
K
2
CO
3 (644 mg, 4.66 mmol) was added to the reaction in one portion. Lastly, 4-t 25 butyl benzaldehyde (0.78 mL, 4.66 mmol) was added to the reaction in one portion via syringe. The reaction was then vigorously stirred at room temperature for 48 hours. The reaction was evaporated to dryness on a roto-evaporator. The resulting residue was re-dissolved in methylene chloride (100 mL) and extracted with saturated aqueous NaHCO 3 (3 x 100 mL). The remaining organic layer was filtered 30 over anhydrous MgSO 4 and evaporated a second time to dryness. Subsequent flash column chromatography using a hexane, HOAc gradient system affords a white - 81 - WO 2009/079624 PCT/US2008/087397 solid (935 mg, chemical yield 58%). 1H-NMR (300 MHz, CDC13) 6 7.43 (d, 2H, J = 8.4 Hz), 7.18 (d, 2H, J = 8.4 Hz), 7.04 (d, 2H, J = 8.7 Hz), 6.84 (d, 2H, J = 8.7 Hz), 5.05 (s, 1H), 3.85 (m, 1H), 3.80 (s, 3H), 2.87 (m, 2H), 2.64 (m, 1H), 1.39 (s, 3H), 1.35 (s, 9H), 1.17 (s, 3H); 1 3 C-NMR (75 MHz, CDC13) 5 178.4, 158.6, 152.9, 135.5, 5 130.7, 130.0, 127.16, 126.3, 114.2, 74.2, 59.6, 55.5, 42.0, 35.0, 32.5, 31.5, 25.9, 24.8; (MH*) 381.2; elemental analysis: theory C 24
H
32
N
2 0 2 + 0.41 mol H 2 0 C 74.34; H 8.43; N 7.23; found C 74.31, H 8.15, N 7.37. Example 123: 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-1,5,5 trimethylimidazolidin-4-one: The 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5 10 dimethylimidazolidin-4-one (200 mg, 0.53 mmol) was dissolved in dry tetrahydrofuran (15mL) in a single-neck 25 mL flask equipped with a stir bar under an inert N 2 atmosphere. Next, sodium hydride (13 mg, 0.58 mmol) was added to the reaction and allowed to stir for 15 minutes. Lastly, iodomethane (0.06 mL, 1.16 mmol) was added to the reaction in one portion via syringe. The reaction was 15 vigorously stirred at room for 18 hours. The reaction was evaporated to dryness on a roto-evaporator. The resulting residue was partitioned between methylene chloride (25 mL) and saturated aqueous NaHCO 3 (25 mL) and separated. The remaining aqueous layer was further extracted with methylene chloride (2 x 25mL). The combined organic extracts were then filtered over anhydrous MgSO 4 and 20 evaporated to dryness. Subsequent flash column chromatography using a hexane, HOAc gradient system affords a clear, viscous syrup (87 mg, chemical yield 42%). 'H-NMR (300 MHz, CDC13) 6 7.41 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 7.01 (d, 2H, J = 8.8 Hz), 6.83 (d, 2H, J = 8.8 Hz), 4.42 (s, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 2.78 (m, 2H), 2.54 (m, 1H), 2.10 (s, 3H), 1.36 (s, 3H), 1.35 (s, 3H); 13 C-NMR (75 25 MHz, CDC13) 5 176.5, 158.5, 152.8, 134.5, 130.9, 130.9, 128.6, 125.7, 114.1, 80.2, 61.6, 55.5, 41.4, 35.0, 32.9, 31.6, 30.7, 24.2, 16.7; (MH*) 395.1; elemental analysis: theory C 25
H
34
N
2 0 2 + 0.3 mol H 2 0 C 75.07; H 8.72; N 7.00; found C 75.30, H 8.78, N 6.69. - 82 - WO 2009/079624 PCT/US2008/087397 Examples 124-126 were prepared according to the procedures described in Example 122-123 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 124: 3-(4-Methoxyphenethyl)-2-(4-cyclopropylphenyl)-5,5 5 dimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.11 (m, 4H), 7.06 (m, 2H), 6.82 (m, 2H), 5.00 (s, 1H), 3.86 (m, 1H), 3.79 (s, 3H), 2.81 (m, 2H), 2.62 (m, 1H), 1.91 (m, 1H), 1.88 (bs, 1H), 1.38 (s, 3H), 1.16 (s, 3H), 1.02 (m, 2H), 0.73 (m, 2H); 13 C-NMR (75 MHz, CDC13) 5 178.5, 158.6, 146.0, 135.5, 130.7, 130.0, 127.4, 126.5, 114.2, 74.3, 59.6, 55.5, 42.0, 32.5, 25.9, 24.8, 15.5, 9.9; (MH*) 365.1; elemental 10 analysis: theory C 23
H
28
N
2 0 2 + 0.80 mol H 2 0 C 73.30; H 7.38; N 7.43; found C 73.44, H 7.70, N 7.53. Example 125: 3-(4-Methoxyphenethyl)-1-benzyl-2-(4-tert-butylphenyl)-5,5 dimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.34 (d, 2H, J = 8.4 Hz), 7.25 (d, 2H, J = 8.4 Hz), 7.13 (m, 5H), 7.05 (d, 2H, J = 8.5 Hz), 6.85 (d, 2H, J = 6.6 15 Hz), 4.67 (s, 1H), 3.82 (s, 3H), 3.77 (m, 1H), 3.73 (d, 1H, J = 13.9 Hz), 3.57 (d, 1H, J = 13.9 Hz), 2.79 (m, 2H), 2.54 (s, 1H), 1.35 (s, 9H), 1.17 (s, 3H), 1.11 (s,3H); 13C NMR (75 MHz, CDC13) 5 176.4, 158.5, 152.5, 139.5, 134.8, 130.9, 130.1, 129.0, 128.0, 127.0, 125.5, 114.1, 79.9, 62.2, 55.6, 50.1, 41.5, 34.9, 32.9, 31.6, 26.0, 18.2; (MH*) 471.2; elemental analysis: theory C 31
H
38
N
2 0 2 + 0.42mol H 2 0 C 77.86; H 8.19; 20 N 5.86; found C 77.86, H 7.98, N 5.71. Example 126: 3-(4-Methoxyphenethyl)-1-ethyl-2-(4-tert-butylphenyl)-5,5 dimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.39 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.4 Hz), 7.00 (d, 2H, J = 8.8 Hz), 6.81 (d, 2H, J = 8.4 Hz), 4.56 (s, 1H), 3.79 (m, 3H), 3.63 (m, 1H), 2.73 (m, 3H), 2.46 (m, 2H), 1.42 (s, 3H), 1.36 (s, 25 9H), 1.09 (s, 3H), 0.78 (t, 3H, J = 7.3 Hz); 1 3 C-NMR (75 MHz, CDC13) 5 176.3, 158.4, 152.6, 136.1, 131.0, 130.1, 128.7, 125.5, 114.0, 79.7, 62.0, 55.5, 41.4, 40.5, 34.9, 32.9, 31.6, 26.3, 17.8, 15.9; (MH*) 409; elemental analysis: theory C2 6
H
36
N
2 0 2 + 0.48 mol H 2 0 C 74.85; H 8.53; N 6.71; found C 74.60, H 8.46, N 6.59. Category XV - 83 - WO 2009/079624 PCT/US2008/087397 Example 127: 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1,5,5 trimethylimidazolidin-4-one. H N20NN BOC
NH
2 0 EDCI, HOBT OO S+' HO N, BOC0 4-methylmorpholine,
CH
2 C1 2 , rt, 18 h TFA, MeOH, rt, 3 h 0 0 H N N- HN microwave, N 7j N o" H 175 C, 5 min. N_ Step 1: tert-butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2 yl(methyl)carbamate: The starting N-BOC-a-(methylamino)iso-butryic acid (12.1 g, 55.9 mmol) was dissolved in methylene chloride (300 mL) in a single-neck 500mL 5 flask equipped with a stir bar under an inert N 2 atmosphere. Next, 1-(3 dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (13.9 g, 72.7 mmol), followed by 1-hydroxybenzotriazole (9.82 g, 72.7 mmol) were added to the mixture and dissolved. 4-methylmorpholine (18.4 mL, 168 mmol) was added to the reaction in one portion via syringe. Lastly, 4-methoxyphenethylamine (8.20 mL, 55.9 mmol) 10 was added to the reaction in one portion also via syringe. The reaction was vigorously stirred at room temperature for 18 hours then extracted twice with saturated aqueous NaHCO 3 (2 x 250 mL) and d.i. H 2 0 (250 mL). The remaining organic layer was then filtered over anhydrous MgSO 4 , and evaporated to dryness on a rotovap. The product was purified by flash column chromatography using a 15 hexane, HOAc gradient system, whose fractions are concentrated on a roto evaporator to give a white fluffy powder, 4.71 g, chemical yield 57%. 1 H-NMR (300 MHz, CDC13) 6 7.14 (d, 2H, J = 8.6 Hz), 6.86 (d, 2H, J = 8.6 Hz), 5.85 (bs, 1H), 3.82 - 84 - WO 2009/079624 PCT/US2008/087397 (s, 3H), 3.75 (m, 2H), 2.89 (s, 3H), 2.77 (t, 2H, J = 7.1), 1.44 (s, 9H), 1.40 (s, 6H); 13 C-NMR (75 MHz, CDC13) 5 176.7, 158.4, 131.4, 129.9, 114.2, 59.2, 55.5, 40.7, 35.1, 30.2, 25.3; (MH*) 351.0. Step 2: N-(4-methoxyphenethyl)-2-methyl-2-(methylamino)propanamide: The tert 5 butyl 1-(4-methoxyphenethylamino)-2-methyl-1-oxopropan-2-yl(methyl)carbamate, (12.9g, 36.8 mmol) was dissolved in methylene chloride (105 mL) in a single-neck 500mL flask under an inert N 2 atmosphere. Next, trifluoroacetic acid (35 mL) was added to the reaction mixture via syringe to increase the concentration to 25% acid by volume. The reaction was vigorously stirred at room temperature for 3 hours. 10 After transferring the reaction to an Erlenmeyer flask the mixture was slowly diluted with saturated aqueous NaHCO 3 (500 mL) and de-ionized water (100 mL). While stirring, this biphasic mixture was basified to a constant pH of 9 via the addition of solid KOH. The mixture was then separated. The remaining aqueous phase was further extracted with methylene chloride (2 x 100 mL). The combined organic 15 layers were filtered over anhydrous MgSO 4 , and evaporated to dryness on a roto evaporator to give a viscous yellow syrup, 8.31 g, chemical yield 90%. 1 H-NMR (300 MHz, CDC13) 6 7.41 (bs, 2H), 7.14 (d, 2H, J = 6.4 Hz), 6.86 (d, 2H, J = 6.4 Hz), 3.80 (s, 3H), 3.48 (dd, 2H, J = 6.2, 7.3 Hz), 2.78 (t, 2H, J = 7.0 Hz), 2.22 (s, 3H), 1.27 (s, 6H); 13 C-NMR (75 MHz, CDC13) 5 176.2, 158.4, 131.4, 130.0, 129.9, 114.2, 59.1, 20 55.6, 55.5, 40.7, 35.2, 30.3, 25.3; (MH*) 251.1. Step 3: 3-(4-methoxyphenethyl)-2-(4-(diethylamino)phenyl)-1,5,5 trimethylimidazolidin-4-one: The N-(4-methoxyphenethyl)-2-methyl-2 (methylamino)propanamide, (528 mg, 2.11 mmol) was added to a 2.0 - 5.0 mL Emry's process vial equipped with a stir bar. Next, melted 4-diethylamino 25 benzaldehyde (2.0 g, 11.3 mmol) was added to the reaction via pipet. The reaction was then capped and heated in a Biotage Initiator 60 microwave for 5 minutes at 175 C with stirring. The reaction was then cooled to room temperature, decapped, diluted with methylene chloride (2 mL) and purified via flash column chromatography whose fractions when evaporated to dryness on a rotovap give a viscous pale beige 30 syrup, 628 mg, chemical yield 73%. 1 H-NMR (300 MHz, CDC13) 6 7.14 (d, 2H, J = 8.4 Hz), 7.03 (d, 2H, J = 8.1 Hz), 6.81 (d, 2H, J = 8.4 Hz), 6.65 (d, 2H, J = 8.4 Hz), - 85 - WO 2009/079624 PCT/US2008/087397 4.35 (s, 1 H, J =), 3.78 (s, 3H), 3.72 (m, 1 H), 3.38 (q, 4H, J = 7.0 Hz), 2.77 (m, 2H), 2.52 (m, 1H), 2.09 (s, 3H), 1.33 (s, 3H), 1.19 (t, 6H, J = 7.0), 1.00 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.4, 158.4, 148.9, 131.1, 130.1, 130.0, 123.3, 114.0, 111.5, 80.2, 61.5, 55.5, 44.6, 41.3, 33.0, 30.7, 24.1, 16.4, 12.8; (MH*) 410.1; elemental 5 analysis: theory C 25
H
35
N
3 0 2 + 1.8 mol H 2 0 C 67.93; H 8.80; N 9.50; found C 67.94, H 8.80, N 9.51. Examples 128-133 were prepared according to the procedures described in Example 127 above using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): 10 Example 128: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(dimethylamino)phenyl)-1,5,5 trimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.20 (d, 2H, J = 8.8 Hz), 7.14 (s, 4H), 6.75 (d, 2H, J = 8.8 Hz), 4.37 (s, 1H), 3.77 (m, 1H), 3.02 (s, 3H), 2.82 (m, 2H), 2.59 (m, 1H), 2.09 (s, 3H), 1.34 (s, 3H), 0.99 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.6, 151.6, 137.9, 130.5, 129.8, 124.3, 121.3, 112.3, 80.2, 61.5, 40.9, 15 40.7, 33.3, 30.6, 24.1, 16.3; (MH*) 436.1; elemental analysis: theory C 23
H
28
F
3
N
3 0 2 + 0.94 mol H 2 0 C 61.06; H 6.65; N 9.29; found C 61.18, H 6.60, N 9.33. Example 129: 3-(4-(Trifluoromethoxy)phenethyl)-2-(4-(diethylamino)phenyl)-1,5,5 trimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.15 (d, 2H, J = 8.8 Hz), 7.14 (s, 4H), 6.68 (d, 2H, J = 8.8 Hz), 4.35 (s, 1H), 3.77 (m, 1H), 3.39 (dd, 4H, J = 20 7.1, 14.3 Hz); 2.83 (m, 2H), 2.60 (m, 1H), 2.10 (s, 3H), 1.34 (s, 3H), 1.20 (t, 6H, J = 7.0 Hz), 0.97 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.5, 149.0, 148.0, 137.9, 130.5, 130.0, 123.0, 121.2, 111.5, 80.3, 61.5, 44.6, 40.9, 33.3, 30.6, 24.1, 16.3, 12.9; (MH+)464.2; elemental analysis: theory C 25
H
32
F
3
N
3 0 2 + 0.63 mol H 2 0 C 63.23; H 7.06; N 8.85; found C 63.23, H 7.22, N 8.91. 25 Example 130: 3-(4-Methoxyphenethyl)-2-(2-(diethylamino)pyrimidin-5-yl)-1, 5,5 trimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 8.16 (s, 2H), 7.05 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 4.20 (s, 1H), 3.82 (m, 1H), 3.78 (s, 3H), 3.63 (dd, 4H, J= 7.0, 12.3 Hz), 2.82 (m, 2H), 2.58 (m, 1H), 2.07 (s, 3H), 1.29 (s, 3H), 1.21 (t, 6H, J = 7.1Hz), 0.99 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.4, 162.1, 158.9, - 86 - WO 2009/079624 PCT/US2008/087397 158.6, 130.7, 130.1, 116.8, 114.2, 77.0, 61.4, 55.5, 42.3, 41.3, 33.0, 30.5, 24.1, 16.7, 13.2; (MH*) 412.4; elemental analysis: theory C 23
H
33
N
5 0 2 + 0.50 mol H 2 0 C 65.68; H 8.14; N 16.65; found C 65.68, H 8.34, N 16.68. Example 131: 3-(4-Methoxyphenethyl)-2-(4-(dimethylamino)phenyl)-1,5,5 5 trimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.18 (d, 2H, J = 8.8 Hz), 7.03 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.72 (d, 2H, J = 8.8 Hz), 4.37 (s,1H), 3.80 (s, 3H), 3.76 (m, 1H), 3.00 (s, 6H), 2.76 (m, 2H), 2.53 (m, 1H), 2.09 (s, 3H), 1.34 (s, 3H), 1.02 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.5, 158.4, 151.5, 131.1, 130.1, 129.8, 124.6, 114.0, 112.3, 80.2, 61.5, 55.5, 41.3, 40.7, 33.0, 30.7, 10 24.1, 16.5; (MH*) 382.1; elemental analysis: theory C 23
H
31
N
3 0 2 + 2.08 mol H 2 0 C 65.93; H 8.46; N 10.03; found C 65.93, H 8.15, N 9.91. Example 132: 3-(4-Methoxyphenethyl)-1,5,5-trimethyl-2-(4-(piperidin-1 yl)phenyl)imidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.17 (d, 2H, J = 8.7 Hz), 7.00 (d, 2H, J = 8.6 Hz), 6.92 (d, 2H, J = 8.6 Hz), 6.82 (d, 2H, J = 8.6 Hz), 4.36 (s, 15 1H), 3.78 (s, 3H), 3.72 (m, 2H), 3.21 (t, 4H, J = 5.1 Hz), 2.75 (m, 2H), 2.54 (m, 1H), 2.07 (s, 3H), 1.70 (m, 4H), 1.60 (m, 2H), 1.33 (s, 3H), 1.00 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.4, 158.4, 153.2, 131.0, 130.1, 129.7, 127.2, 116.1, 114.0 80.1, 61.5, 55.5, 50.4, 41.3, 33.0, 30.7, 26.0, 24.6, 24.1, 16.5; (MH*) 422.1; elemental analysis: theory C2 6
H
35
N
3 0 2 + 3.27 mol H 2 0 C 64.99; H 8.71; N 8.75; found C 64.99, 20 H 8.64, N 8.60. Example 133: 3-(4-Methoxyphenethyl)-2-(4-(iso-propyl(methyl)amino)phenyl)-1,5,5 trimethylimidazolidin-4-one: 1 H-NMR (300 MHz, CDC13) 6 7.18 (d, 2H, J = 8.6 Hz), 7.04 (d, 2H, J = 8.6 Hz), 6.84 (d, 2H, J = 8.6 Hz), 6.79 (d, 2H, J = 8.6 Hz), 4.37 (s, 1H), 4.16 (m, 1H), 3.81 (s, 3H), 3.74 (m,1H), 2.79 (m, 5H), 2.55 (m, 1H), 2.10 (s, 25 3H), 1.35 (s, 3H), 1.22 (d, 6H, J = 6.6 Hz), 1.02 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 176.4, 158.4, 131.3, 130.1, 129.9, 112.8, 80.2, 61.6, 55.5, 49.0, 41.3, 33.0, 30.7, 24.1, 19.7, 19.6, 16.5; (MH*) 410.2; elemental analysis: theory C 25
H
35
N
3 0 2 + 0.35 mol H 2 0 C 72.20; H 8.65; N 10.10; found C 72.20, H 8.33, N 10.07. Category XVI - 87 - WO 2009/079624 PCT/US2008/087397 Example 134: 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-diethylimidazolidin 4-one NH H PyBOP DIPEA, N -Fmoc OJ1 0 H H N N, N, .Fmoc N H H' Piperdine NH 2 K2C3. MeH 12 IC 0- H 0 MF rt 3o' MW, 25 min. 0' o1 1 1 0 0 N NH d N 5 Step 1: Preparation of (9H-fluoren-9-yl)methyl)-3-((4 methoxyphenethyl)carbamoyl)pentan-3-ylcarbamate: To a solution of 2-(((9H fluoren-9-yl)methoxy)carbonyl)-2-ethylbutanoic acid (1.76 g, 5.0 mmole) in DMF (15 mL) was added PyBOP (2.6 g, 5.0 mmol). After stirring at room temperature for 10 min, 4-methoxyphenethyl amine (0.76 g, 5.0 mmol) was added, and the solution was 10 stirred for a further 5 min. Finally, diisopropyl amine (6 drops) was added, and the solution was stirred for 2 h at room temperature. The reaction mixture was diluted with EtOAc and washed with aqueous KHSO 4 .(5%), saturated NaHCO 3 , water and dried with Na 2
SO
4 . The solvent was removed in vacuo, and the resulting residue was purified by flash silica column chromatography to provide desired product (1.68 15 g, chemical yield 70%). - 88 - WO 2009/079624 PCT/US2008/087397 Step 2: Preparation of N-(4-methoxyphenethyl)-2-amino-2-ethylbutanamide: To a solution of the (9H-fluoren-9-yl)methyl)-3-((4-methoxyphenethyl)carbamoyl)pentan 3-ylcarbamate (1.40 g, 3.0 mmol) in DMF (10 mL) was added piperdine (1 mL). After stirring at room temperature for 2 h, the white ppt was removed and the filtrate 5 was evaporated in vacuo to give desired product (1.7 g). This compound is used for the next step reactions without further purification Step 3: Preparation of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5 diethylimidazolidin-4-one: To the solution of the N-(4-methoxyphenethyl)-2-amino-2 ethylbutanamide (530 mg, 2.0 mmol in 5 mL of methanol) and K 2
CO
3 (276 mg, 2.0 mmol) in a 2.0 - 5.0 mL Emry's process vial equipped with a stir bar was added 4 tert-butylbenzaldehyde (356 mg, 2.2 mmol). The reaction mixture was then capped, stirred 30 sec. and heated in a Biotage Initiator 60 microwave for 20 minutes at 120 0C. The reaction was then cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water, dried over Na 2
SO
4 and purified via flash column chromatography to give desired product (610 mg, chemical yield 74%). 1 H-NMR (300 MHz, CDC13) 6 7.45 (d, 2H, J = 8.0Hz), 7.25 (d, 2H, J = 8.0Hz), 7.05 (d, 2H, J = 8.5Hz), 6.82 (d, 2H, J = 8.8Hz), 5.21 (s, 1H), 3.82 (m, 1H), 3.79 (s, 3H), 2.83 (m, 1H), 2.67 (m, 2H), 1.81 (m, 2H), 1.60 (m, 2H), 1.56 (s 9H), 0.97 (m, 6H); 13 C-NMR (75 MHz, CDC13) 5 175.0, 158.6, 153.0, 136.2, 130.9, 130.0, 127.4, 126.4, 114.2, 75.2, 66.5, 55.6, 42.2, 35.1, 32.8, 31.6, 31.1, 29.2, 8.9, 8.7; (MH*) 409; elemental analysis: theory C2 6
H
36
N
2 0 2 + 0.4 H 2 0 C 75.11, H 8.92, N 6.74; found C 75.02, H 9.08, N 6.82. Example 135: 1-N-methyl-3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5 diethylimidazolidin-4-one: To a solution of 409 mg (1 mmol) of 1-N-methyl-3-(4 methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-diethylimidazolidin-4-one in 10 mL 10 DMF was added 46 mg (2 mmol) of sodium hydride, followed by 710 mg (5 mmol) of iodomethane. The reaction was stirred at room temperature for 2 days and then stripped of solvent. The residue was dissolved in EtOAc, washed with water, dried over Na 2
SO
4 , filtered and stripped. The residual material was then purified via flash column chromatography to provide the desired product (350 mg, 82%). 1 H-NMR 15 (300 MHz, CDC13) 6 7.43 (d, 2H, J = 8.5Hz), 7.30 (d, 2H, J = 8.8Hz), 7.00 (d, 2H, J = - 89 - WO 2009/079624 PCT/US2008/087397 8.6Hz), 6.79 (d, 2H, J = 8.8Hz), 4.89 (s, 1H), 3.79 (s, 3H), 3.73 (m, 1H), 2.85 (m, 1H), 2.73 (m, 1H), 2.57 (m, 1H), 2.21 (s, 3H), 1.87 (m, 1H), 1.66 (m, 2H), 1.47 (m, 1H), 1.37 (s 9H), 0.97 (t, 3H, J = 7.2Hz), 0.91 (t, 3H, J = 7.4Hz); 13 C-NMR (75 MHz, CDC13) 5 175.0, 158.5, 152.7, 135.9, 131.1, 130.0, 128.7, 125.8, 114.1, 80.9, 68.2, 5 55.6, 41.8, 35.0, 33.3, 31.7, 29.9, 28.0, 27.8, 9.9, 9.6; MH*) 423.2; elemental analysis: theory C 27
H
38
N
2 0 2 + 0.2 H 2 0 C 76.09, H 9.08, N 6.57; found C 75.92, H 9.16, N 6.76. Category XVII Example 136: 3-(4-methoxyphenethyl)-1,5,5-trimethyl-2-(4-(pyrrolidin-1 yl)phenyl)imidazolidin-4-one %N NH N N a 0 N N The starting cyclized 4-imidazolidinone (450 mg, 1.14 mmol) was dissolved with 10 stirring in 2 mL of DMF which was then pipetted into an Emry's 2-5 mL process vial equipped with a stir bar. Next, cesium carbonate (746 mg, 2.29 mmol) was added to the reaction vial in one portion. Lastly, iodomethane (0.23 mL, 4.58 mmol) was added to the vial in one portion via syringe. The process vial was then capped and heated in a Biotage Initiator 60 microwave for 5 minutes at 150 0C. The reaction 15 was cooled to room temperature, de-capped, and diluted in a mixture of 30 mL of de-ionized water and 30 mL of methylene chloride. The bi-phasic fluids were then transferred to a separatory funnel and separated. The remaining aqueous layer was extracted with 2 more 30 mL portions of metyhlene chloride. The combined organic extracts were then filtered over anhydrous MgSO 4 and evaporated to dryness. 20 Subsequent flash column chromatography affords a clear viscous syrup, 103 mg, - 90 - WO 2009/079624 PCT/US2008/087397 chemical yield 22.2%. 'H-NMR (300 MHz, CDC13) 6 7.17 (d, 2H, J = 8.4Hz), 7.04 (d, 2H, J = 8.4Hz), 6.83 (d, 2H, J = 8.6Hz), 6.56 (d, 2H, J = 8.6Hz), 4.37 (s, 1H), 3.80 (s, 3H), 3.74 (m, 1H), 3.33 (t, 4H, J = 6.6Hz), 2.77 (m, 2H), 2.55 (m, 1H), 2.09 (s, 3H), 2.04 (t, 4H, J = 6.4Hz), 1.34 (s, 3H), 1.01 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 5 176.4, 158.4, 148.9, 131.1, 130.1, 130.0, 123.4, 114.0, 111.6, 80.3, 61.5, 55.5, 47.8, 41.3, 33.0, 30.6, 25.8, 24.1, 16.4; (MH*) 408.1; elemental analysis: theory
C
25
H
33
N
3 0 2 + 2.35 mol H 2 0 C 66.74; H 8.44; N 9.34; found C 66.70, H 8.31, N 9.20. Category XVIII Example 137: 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-dimethyl-1 (pyridin-3-ylmethyl)imidazolidin-4-one: N NH N N + Br N C kQ N H-Br Preparation of 3-(4-methoxyphenethyl)-2-(4-tert-butylphenyl)-5,5-dimethyl-1-(pyridin 3-ylmethyl)imidazolidin-4-one: The starting 4-imidazolidone (250 mg, 0.92 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, cesium carbonate (629 mg, 1.93 mmol) was added in one portion to the reaction vial. This was followed by the addition of picolylbromide hydrogen bromide (232 mg, 0.92 mmol). Lastly, the reactants were submerged via the addition of DMF via syringe (2.0 mL). The reaction vial was then capped and heated in a Biotage Initiator 60 microwave for 8.5 minutes at 200 0C. The reaction was then cooled to room temperature and de-capped. The material was purified by flash column chromatography to afford a clear viscous syrup, 65 mg, chemical yield 15.0%. 1
H
NMR (300 MHz, CDC13) 6 8.28 (d, 2H, J = 7.9Hz), 7.30 (m, 1H), 7.25 (d, 2H, J = 8.2Hz), 7.12 (d, 2H, J = 8.2Hz), 7.01 (d, 2H, J = 8.4Hz), 6.96 (m, 1H), 6.83 (d, 2H, J - 91 - WO 2009/079624 PCT/US2008/087397 = 8.6Hz) 4.61 (s, 1H), 3.81 (s, 3H), 3.77 (d, 1H, J = 14.5Hz) 3.74 (m, 1H), 3.50 (d, 1H, J = 14.3Hz), 2.75 (m, 2H), 2.68 (m, 1H), 1.30 (s, 9H), 1.85 (s, 3H), 1.14 (s, 3H); 13 C-NMR (75 MHz, CDC13) 5 175.5, 158.5, 152.6, 150.0, 148.3, 136.6, 134.9, 134.4, 130.8, 130.1, 128.9, 125.6, 123.0, 114.1, 80.0, 62.2, 55.5, 47.8, 41.3, 34.9, 32.8, 31.5, 25.8, 18.3; (MH*) 472.2; elemental analysis: theory C 30
H
37
N
3 0 2 + 1.24 mol
C
2
HF
3 0 2 C 63.64; H 6.29; N 6.85; found C 63.56, H 6.09, N 6.74. Category XIX Example 138: 3-(4-methoxyphenethyl)-2,5,5-trimethyl-2-p-tolylimidazolidin-4-one 0 H 0 ON NH2 + a O - N 1N b N 0, The starting C-5 geminal dimethyl amino-amide (500 mg, 2.12 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, 4 5 methylacetophenone (5.0 mL, 37.4 mmol) was added to the reaction in one portion via syringe. The reaction vial was then capped and heated in a Biotage Initiator 60 microwave at 220 0C for 5 minutes. The reaction was then cooled to room temperature and de-capped. The material was then purified by flash column chromatography to afford a pale yellow viscous syrup, 488 mg, chemical yield 10 65.3%. 'H-NMR (300 MHz, CDC13) 6 7.24 (m, 2H), 7.17 (m, 2H), 7.07 (m, 2H), 6.82 (m, 2H), 3.77 (s, 3H), 3.53 (m, 1H), 3.00 (m, 1H), 2.87 (t, 2H, J = 7.3Hz), 2.35 (s, 3H), 2.14 (br, 1H), 1.71 (s, 3H), 1.42 (s, 3H), 1.29 (s, 3H); 13 C-NMR (75 MHz, CDC13) - 92 - WO 2009/079624 PCT/US2008/087397 5 178.0, 158.5, 141.6, 138.4, 131.3, 130.1, 129.7, 126.0, 114.1, 78.6, 59.0, 55.5, 44.6, 33.7, 28.6, 27.9, 27.0, 21.2; (MH*) 353.1; elemental analysis: theory
C
22
H
28
N
2 0 2 + 0.10 mol H 2 0 C 74.59; H 8.02; N 7.91; found C 74.57, H 7.94, N 7.78. Example 139: 3-(4-methoxyphenethyl)-1,2,5,5-tetramethyl-2-p-tolylimidazolidin-4 5 one: 3-(4-methoxyphenethyl)-2,5,5-trimethyl-2-p-tolylimidazolidin-4-one (301 mg, 0.85 mmol) was added to an Emry's 2 - 5 mL process vial equipped with a stir bar. Next, the material was dissolved in 2 mL of DMF with stirring. This was followed by the addition of cesium carbonate (557 mg, 1.71 mmol). Lastly, iodomethane (0.17 mL, 3.41 mmol) was added to the reaction in one portion via syringe. The reaction 10 vial was then capped and heated in a Biotage Initiator 60 microwave at 150 0C for 5 minutes. The reaction was then cooled to room temperature and de-capped. The reaction mixture was then partitioned between 20 mL of de-ionized water and 20 mL of methylene chloride and separated. The remaining aqueous layer was further extracted with 2 more 20 mL portions of methylene chloride. The combined organic 15 extracts were filtered over anhydrous MgSO 4 and evaporated dryness. The resulting material was purified by flash column chromatography to afford a clear viscous syrup, 256 mg, chemical yield 81.9%. 'H-NMR (300 MHz, CDC13) 6 7.36 (d, 2H, J = 8.0Hz), 7.18 (d, 2H, J = 8.2Hz), 6.97 (d, 2H, J = 8.6Hz), 6.78 (d, 2H, J = 8.4Hz), 3.78 (s, 3H), 3.21 (m, 1H), 3.06 (m, 1H), 2.78 (m, 1H), 2.47 (m, 1H), 2.38 (s, 3H), 2.18 (s, 20 3H), 1.64 (s, 3H), 1.36 (s, 3H), 1.34 (s, 3H); 1 3 C-NMR (75 MHz, CDC13) 5 176.4, 158.3, 139.2, 138.3, 131.5, 130.0, 129.1, 127.7, 114.0, 80.7, 60.8, 55.5, 43.5, 33.8, 27.2, 24.8, 22.7, 21.3, 21.2; (MH*) 367.1; elemental analysis: theory C 23
H
30
N
2 0 2 C 75.37; H 8.25; N 7.64; found C 75.21, H 8.09, N 7.65. Example 140 was prepared according to the procedures described in Example 138 25 139 using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents): Example 140: 3-(4-methoxyphenethyl)-2-(3,4-dimethylphenyl)-1,2,5,5 tetramethylimidazolidin-4-one: 'H-NMR (300 MHz, CDC13) 6 7.15 (m ,4H), 6.99 (d, 2H, J = 8.6Hz), 6.79 (d, 2H, J = 8.4Hz), 3.78 (s, 3H), 3.26 (m, 1H), 3.03 (m, 1H), 30 2.81 (m, 1H), 2.49 (m, 1H), 2.29 (s, 6H), 1.64 (s, 3H), 1.37 (s, 3H), 1.35 (s, 3H); 13C - 93 - WO 2009/079624 PCT/US2008/087397 NMR (75 MHz, CDC13) 5176.5, 158.3, 139.6, 136.9, 136.6, 131.6, 130.0, 129.6, 128.9, 125.1, 114.0, 80.8, 60.8, 55.5, 43.6, 33.8, 27.3, 24.7, 22.8, 21.4, 20.3, 19.7; (MH*) 367.1; elemental analysis: theory C 23
H
30
N
2 0 2 + 0.81 mol H 2 0 C 72.49; H 8.36; N 7.35; found C 72.48, H 8.21, N 7.23. 5 CATEGORY XX Example 141: 2-(4-tert-butylphenyl)-1-(3-cyclohexylpropanoyl)-3-[2-(4- methoxy phenyl)ethyl]imidazolidin-4-one -010 0 /0 N +O EDOI, CH 2
CI
2 . N H N\ & +ECC2 10 Cyclohexaneacetic acid (81 mg, 0.57 mmol) and 2-(4-tert-butylphenyl)-3-(4 methoxyphenethyl)imidazolidin-4-one (158 mg, 0.45 mmol) were dissolved in CH 2
CI
2 (6.0 mL). After stirring briefly, EDCI (137.7 mg , 72 mmol) was added, and the reaction was stirred at room temperature until the starting material was consumed. The reaction was then stripped of solvent and the crude residue was purified by 15 HPLC (CH3CN/H20, 0.1% TFA) to provide 38 mg of the desired product. Examples 142 - 296 were prepared according to the procedures described herein using the corresponding reagents (e.g., corresponding amino acid, amine, and aldehyde reagents). High-performance liquid chromatography (HPLC) was recorded with Column Aquasil C18 (Aquasil C18 HPLC column, 50 mm length x 2 mm ID, 5 20 micron particle) using following conditions: Mobile Phase A: 10 mM NH 4 0AC in 95% water / 5% CAN (Pipette 6.67 mL of 7.5 M NH 4 0AC solution into 4743 mL H 2 0, then add 250 mL of ACN to the solution and mixture). Mobile Phase B: 10 mM NH 4 0AC in 5% water / 95% CAN (Pipette 6.67 mL of 7.5 M NH 4 0AC solution into 243 mL H 2 0. - 94 - WO 2009/079624 PCT/US2008/087397 Then add 4750 mL of ACN to the solution and mixture). Flow Rate: 0.800 mL/min, Column Temperature: 400C, Injection Volume: 5 mL and UV: monitor 214 nm and 254 nm. Gradient Table: 5 Time(min) %B 0.0 0 2.5 100 4.0 100 4.1 0 10 5.5 0 Mass spectra were recorded using Agilent 1200 HPLC/time-of-flight mass spectrometer 3x50 mm, 1.8 micron stable bond C18 column, T = 70 C, linear gradient from 70/30 (A:B) to 5/95 (A:B) over 1.2 minutes; A) water w/ 0.1% formic acid, B) acetonitrile w/ 0.1% formic acid. Mass spectrometer was scanned from m/z 100-1000. 15 Table 1 Structure Name Ion Retention Time 0 + 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-2-(4 pyrrolidin-1 ylphenyl)imidazolidin 142 4-one 394 3.2 F F 2 -(3,4 dichlorophenyl)-1 methyl-3-{2-[4 N (trifluoromethyl)pheny I]ethyl}imidazolidin-4 143 0 one 417 3.4 N-({(2R,4S)-2-(4-tert o NVS butylphenyl)-1-[2-(4 methoxyphenyl)ethyl] 3-methyl-5 oxoimidazolidin-4 yl}methyl)methanesulf 144 onamide 74 3.2 -95- WO 2009/079624 PCT/US2008/087397 0 2-(1-ethyl-1 H-indol-5 N _3_ methoxyphenyl)ethyl] 1,5,5 N trimethylimidazolidin 145 4-one 406 3.2 2-{4-[2 (dimethylamino)ethox y]phenyl}-3-[2-(4 methoxyphenyl)ethyl] 1 -methylimidazolidin 146 4-one 398 3 3-[2-(4 methoxyphenyl)ethyl] 1 -methyl-2-[4-(pyrid in 2 ylmethoxy)phenyl]imi 147 dazolidin-4-one 418 3 0 N-(4-{3-[2-(4 methoxyphenyl)ethyl] 1-methyl-4 oxoimidazolidin-2 yl}phenyl)methanesulf 148 onamide 404 2.6 0 2-(2,2-difluoro-1,3 benzodioxol-5-yl)-3 [2-(4 methoxyphenyl)ethyl] 0 1,5,5 0-7 trimethylimidazolidin 149 F 4-one 419 3.2 N N 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[4-(2 pyrrolidin-1 ylethoxy)phenyl]imida 150 zolidin-4-one 424 3.2 O 2-(4 cyclopropylphenyl)-3 [2-(4 methoxyphenyl)ethyl] 1-(3-pyridin-3 ylpropanoyl)imidazoli 151 din-4-one 470 3.2 -96- WO 2009/079624 PCT/US2008/087397 0 H methoxyphenyl)ethyl] e N 1 -methyl-2-(2-phenyl 1H-imidazol-5 152 yI)imidazolidin-4-one 377 2.7 0 N-(2-{2-(4-tert o butylphenyl)-3-[2-(4 N-S-r methoxyphenyl)ethyl] 0 4-oxoimidazolidin-1 yIlethyl)ethanesulfona 153 mide 488 3.2 0 /00N 2-(4-tert-butylphenyl) 0 1 -butyryl-3-[2-(4 methoxyphenyl )ethyl]i 154 midazolidin-4-one 423 3.3 methoxyphenyl)ethyl] - 1-methyl-2-[4-(2 o morpholin-4 155 ylethoxy)phenyl]imida 155olidin-4-one 440 3.1 0 2-(4-tert-butylphenyl) methoxyphenyl)ethyl] phenylpropyl)imidazol 156 idin-4-one 471 3.8 methoxyphenyl)ethyl] o - 1 -methyl-2-[4 (piperidin-4 157 din-4-one 410 2.9 F F 0 (5S)-5-(2-am inoethyl) 2-(4-tert-butyl phenyl) 1 -methyl-3-{2-[4 (trifl uoromethoxy)phe nyl]ethyllim idazolid in 158 4-one 64 3.3 -97 - WO 2009/079624 PCT/US2008/087397 0 N 2-(4-tert-butylphenyl) 1-isopropyl-3-[2-(4 methoxyphenyl)ethyl]i 159 midazolidin-4-one 395 3.6 0 2-(4-tert-butylphenyl) 3-[3-(4 fluorophenyl)propyl] 1-methylimidazolidin 160 4-one 369 3.5 0 2-{4 N\ [ethyl(isopropyl)amino ]phenyl}-3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 161 4-one 396 3.5 F> 0 -10 3-[(4S)-2-(4-tert butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 162 4-yl]propanoic acid 493 3.2 N-(4-{3-[2-(4 methoxyphenyl)ethyl] N 1-methyl-4 oxoimidazolidin-2 yl}phenyl)-N (methylsulfonyl)metha 163 0 nesulfonamide 482 2.7 NS 0 2-(4-tert-butylphenyl) N 1-methyl-3-{2-[2 (methylthio)pyrimidin 5 yl]ethyl}imidazolidin 164 4-one 385 3.2 0 2-(2,4 N N- dimethoxypyrimidin-5 0yl)-3-[2-(4 NyN methoxyphenyl)ethyl] 0 1-methylimidazolidin 165 4-one 373 2.8 -98- WO 2009/079624 PCT/US2008/087397 0 2-(4-tert-butylphenyl) N methoxyphenyl)ethyl] 1-(pyridin-3 ylacetyl)imidazolidin 166 4-one 472 3.3 O N 2-(4-ted-butylphenyl) 1-hexanoyl-3-[2-(4 methoxyphenyl)ethyl]i 167 midazolidin-4-one 451 3.4 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[1-(pyridin 4-ylmethyl)-1 H-indol 5-yl]imidazolidin-4 168 one 441 3.1 0 2-(4-tert-butylphenyl) N~r 3-[2-(4 methoxyphenyl)ethyl] 1-(pyridin-4 ylacetyl)imidazolidin 169 4-one 472 3.3 0 2-[2 N\ (diethylamino)pyrimidi N' n-5-yl]-3-[2-(4 N methoxyphenyl)ethyl] 1 -methylimidazolidin 170 4-one 384 3.1 0 N tert-butyl (3-{2-(4-tert H butylphenyl)-3-[2-(4 methoxyphenyl)ethyl] 4-oxoimidazolidin-1 171 yl}propyl)carbamate 510 3.6 0 N 2-(2-tert-butyl-1 H imidazol-4-yl)-3-[2-(4 N methoxyphenyl)ethyl] 1 -methylimidazolidin 172 4-one 357 2.8 -99- WO 2009/079624 PCT/US2008/087397 0 N cyclopropylphenyl)-1 methyl-3-(3 phenylpropyl)imidazol 173 idin-4-one 335 3.4 0 2-(4-tert-butylphenyl) N 1-[3 N (diisopropylamino)pro pyl]-3-[2-(4 methoxyphenyl)ethyl]i 174 midazolidin-4-one 494 3.1 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[1-(pyridin 2-ylmethyl)-1 H-indol 5-yl]imidazolidin-4 175 one 441 3.1 2-(2-tet butylpyrimidin-5-yl)-3 [2-(4 methoxyphenyl)ethyl] N 1,5,5 trimethylimidazolidin 176 4-one 397 3.1 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[1-(pyridin 3-ylmethyl)-1 H-indol 5-yl]imidazolidin-4 177 one 441 3.1 (2R,5S)-5-{2 [benzyl(pyridin-3 ylmethyl)amino]ethyl} 2-(4-tert-butylphenyl) 1-methyl-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 178 4-one 645 3.7 0 N methoxyphenyl)ethyl] N 1-methyl-2-quinolin-3 179 ylimidazolidin-4-one 362 3 -100 - WO 2009/079624 PCT/US2008/087397 0 N 2-(4-tert-butylphenyl) 1 -(cyclohexylacetyl) 0 3-[2-(4 methoxyphenyl)ethyl]i 180 midazolidin-4-one 477 3.6 N-({(2R,4S)-2-(4-tert o NH-S butylphenyl)-1-[2-(4 methoxyphenyl)ethyl] N 3-methyl-5 oxoimidazolidin-4 yl}methyl)butane-1 181 sulfonamide 516 3.4 1-({(2S,4S)-2-(4 cyclopropylphenyl)-1 methoxyphenyl)ethyl] 3-methyl-5 oxoimidazolidin-4 182 yl}methyl)urea 423 2.9 3-[(4S)-2-(4-tert F butylphenyl)-3 methyl-5-oxo-1-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 4-yl]-N-pyridin-2 183 ylpropanamide 569 3.5 0 2-(1 H-imidazol-5-yl) N NH methoxyphenyl)ethyl] 1-methylimidazolidin 184 4-one 301 2.3 0 0 N 2-(6-tert-butylpyridin 3-yl)-3-[2-(4 N methoxyphenyl)ethyl] 1 -methylimidazolidin 185 4-one 368 3.1 0 N methoxyphenyl)ethyl] 1-methyl-2-pyridin-3 186 N ylimidazolidin-4-one 312 2.7 - 101 - WO 2009/079624 PCT/US2008/087397 0 0 2-(2-furyl)-3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 187 4-one 301 2.8 0 2-(4-tert-butylphenyl) N 3-[2-(4 methoxyphenyl)ethyl] 1-(3-piperidin-1 ylpropanoyl)imidazoli 188 din-4-one 492 2.9 0 N 2-(4-isobutylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 189 4-one 367 3.4 (5S)-2-(4-tert F F N butylphenyl)-1 0 1 methyl-5-[2-(pyrid i n-2 ylamino)ethyl]-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 190 4-one 541 3.7 0 F- /3-[2-(4 o methoxyphenyl)ethyl] 1-methyl-2-(1-methyl N\ 1H-imidazol-2 191 yl)imidazolidin-4-one 315 2.6 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-(4 morpholin-4 ylphenyl)imidazolidin 192 4-one 396 2.9 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[4-(4 methylpiperazin-1 yl)phenyl]imidazolidin 193 4-one 409 3.2 - 102 - WO 2009/079624 PCT/US2008/087397 F ~ 3-[(4S)-2-(4-tert F F butylphenyl)-3 Fl - methyl-5-oxo-1 -12-[4 N (trifluoromethoxy)phe nyl]ethyllimidazolidin 4-yI]-N-[2 (d imethylami no)ethyl] 194 propanamide 563 3.2 F_~ 2-[(2R, 4S)-2-(4-tert F o H\ butylphenyl)-3 N methyl-5-oxo-1 -{2-[4 e N (trifluoromethoxy)phe nyl]ethyllimidazolidin 4-yI]-N-py rid in-2 195 ylacetamide 555 3.5 0 N N~ 2-(4-tert-butylphenyl) 0 methoxyphenyl)ethyl] / 1-(3-pyrimidin-2 ylpropanoyl)imidazoli 196 din-4-one 487 3.2 0 N N-1-(3-{3-[2-(4 methoxyphenyl)ethyl] NH 1 -methyl-4 197 HN "~H2 oxoimidazolidin-2 yIlphenyl)guanidine 368 2.7 0 N -4 cyclopropyl phenyl)-1 methyl-3-(2 phenoxyethyl)imidazo 198 Iidin-4-one 337 3.2 0 2-(4-ethyl-3,4 N\/ dihydro-2H-1 ,4 -N benzoxazi n-7-y)-3-[2 (4 methoxyphenyl)ethyl] N \-1-methyl im idazol id in 199 4-one 396 3.1 0 N-{2-[2-(4-tert butylphenyl)-3 N methyl-5 NH o ~oxoi midazol id in- 1-y] 1 phenylethyllmethanes 200 ulfonamide 30 3 - 103 - WO 2009/079624 PCT/US2008/087397 0 _ 2-(4-tert-butylphenyl) N3-[2-(6 methoxypyridin-3 yl)ethyl]-1 methylimidazolidin-4 201 one 368 3.3 0 N 2-(4-fluorophenyl)-3 N [2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 202 4-one 329 3 0 2-(4-aminophenyl)-3 [2-(4 methoxyphenyl)ethyl] 1 -methylimidazolidin 203 NH2 4-one 326 2.7 -A 3-[2-(4 methoxyphenyl)ethyl] o r 1 -methyl-2-(4-pyridin 3 ylphenyl)imidazolidin 204 4-one 388 3.1 0 1-{3-[benzyl(pyridin-2 N N ylmethyl)amino]propyl }-2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]i 205 midazolidin-4-one 591 4.2 N0 NN N 2-(4-tert-butylphenyl) 1-methyl-3-[2-(4 pyrrolidin-1 ylphenyl)ethyl]imidazo 206 lidin-4-one 406 3.8 0 2-[4 N\ (diisopropylamino)phe nyl]-3-[2-(4 methoxyphenyl)ethyl] N 1 -methylimidazolidin 207 4-one 410 3.5 - 104 - WO 2009/079624 PCT/US2008/087397 N N 2-[4-(diethylamino)-3 methoxyphenyl]-3-[2 0- (4 methoxyphenyl)ethyl] 20 1-methylimidazolidin 208 4-one 412 3.4 N-(2-{2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl] b 0 4-oxoimidazolidin-1 yl}ethyl)methanesulfo 209 namide 474 3.1 N 3-[2-(4 N methoxyphenyl)ethyl] 1,5-dimethyl-2-(4 methylphenyl)imidazo 210 lidin-4-one 339 3.1 F 1-2-[(4S)-2-(4-tert H H F - butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 4-yl]ethyl}-3-pyridin-3 211 ylurea 584 3.5 0 2-(4-tert-butylphenyl) N3-[2-(4 N methoxyphenyl)ethyl] 1-(2-pyridin-2 ylethyl)imidazolidin-4 212 one 458 3.8 o 2-[4 (diethylamino)phenyl] N II methoxyphenyl)ethyl] 5,5 dimethylimidazolidin 213 4-one 396 3.3 N\ N 3-[2-(4 methoxyphenyl)ethyl] 0- 1-methyl-2-(4-pyridin 2 ylphenyl)imidazolidin 214 4-one 388 3.1 - 105 - WO 2009/079624 PCT/US2008/087397 N N_ 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-(4-pyridin 4 ylphenyl)imidazolidin 215 4-one 388 3.1 0 N 2-(4-tert-butylphenyl) \-N 1-(3 cyclohexylpropanoyl) 0 3-[2-(4 methoxyphenyl)ethyl]i 216 midazolidin-4-one 0 0 2-(1-ethyl-1, 2,3,4 tetrahydroquinolin-6 yl)-3-[2-(4 methoxyphenyl)ethyl] N$ 1-methylimidazolidin 217 4-one 394 3.4 N N 1 -benzyl-3-[2-(4 NH methoxyphenyl)ethyl] 2-(1 H-pyrrol-2 218 yl)imidazolidin-4-one 376 3.2 0N 2-(2,3-dihydro-1,4 N benzodioxin-6-yl)-3 N [2-(4 methoxyphenyl)ethyl] 1 -methylimidazolidin 219 4-one 369 2.9 2-(4-tert-butylphenyl) 0 1-[4 (diethylamino)benzyl] 3-[2-(4 methoxyphenyl)ethyl] 5,5 dimethylimidazolidin 220 4-one 542 4 N 2-(5-tert-butyl-1 N methyl-1 H-imidazol-2 N yl)-3-[2-(4 methoxyphenyl)ethyl] 1 -methylimidazolidin 221 4-one 371 3.1 - 106 - WO 2009/079624 PCT/US2008/087397 0 2-(1-ethyl-2,3 N dihydro-1H-indol-5 yl)-3-[2-(4 methoxyphenyl)ethyl] N 1-methylimidazolidin 222 4-one 380 3.3 2-[2 (dimethylamino)pyrimi din-5-yl]-3-[2-(4 methoxyphenyl)ethyl] 'N 1,5,5 trimethylimidazolidin 223 4-one 384 3 O N 2-(4-tert-butylphenyl) 1 -cyclopropyl-3-[2-(4 methoxyphenyl)ethyl]i 224 midazolidin-4-one 393 3.4 0 N 2-(1-ethyl-1H-indol-5 yl)-3-[2-(4 methoxyphenyl)ethyl] 1 -methylimidazolidin 225 4-one 378 3.2 2-(2-tert butylpyrimidin-5-y)-3 [2-(4 N methoxyphenyl)ethyl] 1 -methylimidazolidin 226 4-one 369 3 0 2-(4-tert-butylphenyl) N-ethyl-3-[2-(4 o methoxyphenyl)ethyl] 4-oxoimidazolidine-1 227 carboxamide 424 3.2 0 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-(4 pyrrolidin-1 CN ylphenyl)imidazolidin 228 4-one 380 3.4 - 107 - WO 2009/079624 PCT/US2008/087397 0 2-[2 (dimethylamino)pyrimi din-5-yl]-3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 229 4-one 356 2.8 (2R,5S)-2-(4-tert ®r, 0 butylphenyl)-1 methyl-5-{2 [methyl(phenyl)amino] ethyl}-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 230 4-one 554 3.8 (2R,5S)-2-(4-tert F butylphenyl)-5-[2 (dimethylamino)ethyl] 1-methyl-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 231 4-one 492 3.3 (2R,5S)-2-(4-tert butylphenyl)-5-(1 H indol-3-ylmethyl)-3-[2 Nz (4 H methoxyphenyl)ethyl] 1 -methylimidazolidin 232 4-one 496 3.5 2-(4-tert-butylphenyl) 4 1-(1H-imidazol-2 ylmethyl)-3-[2-(4 methoxyphenyl)ethyl] 5,5 dimethylimidazolidin 233 4-one 461 3.4 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-1 propylimidazolidin-4 234 one 423 3.7 0 N 2-(4-chlorophenyl)-3 [2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 235 4-one 345 3.2 -108 - WO 2009/079624 PCT/US2008/087397 N 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-1 (pyridin-4 ylmethyl)imidazolidin 236 4-one 472 3.5 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-1 (pyridin-2 ylmethyl)imidazolidin 237 4-one 472 3.6 (2R,5S)-2-(4-tert F> Hbutylphenyl)-1 methyl-5-[2-(pyridin-3 ylamino)ethyl]-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 238 4-one 541 3.3 2-(3-aminophenyl)-3 [2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 239 4-one 326 2.7 0 2-(4-tert-butylphenyl) 3-(2-{4 [(dimethylamino)meth yl]phenyl}ethyl)-1 methylimidazolidin-4 240 one 394 2.7
N
2-[4 (diisopropylamino)phe nyl]-3-[2-(4 methoxyphenyl)ethyl] 1,5,5 trimethylimidazolidin 241 4-one 438 3.6 0 2-(4-tert-butylphenyl) S NH 3-[2-(4 SN methoxyphenyl)ethyl] 0 1-(1H-pyrazol-4 ylcarbonyl)imidazolidi 242 n-4-one 447 3 - 109 - WO 2009/079624 PCT/US2008/087397 0 N N cyclopropylphenyl)-3 (4-methoxyphenyl)-1 methylimidazolidin-4 243 one 323 3 2-[4-(4 hydroxypiperidin-1 yl)phenyl]-3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 244 4-one 410 2.8 o2-[4 (difluoromethoxy)phe nyl]-3-[2-(4 methoxyphenyl)ethyl] 1,5,5 trimethylimidazolidin 245 F 4-one 405 3.1 0 2-(4-tert-butylphenyl) -N 1-[4 (dimethylamino)butan oyl]-3-[2-(4 methoxyphenyl)ethyl]i 246 midazolidin-4-one 466 2.8 0 2-[4-(dimethylamino) 2-methoxyphenyl]-3 [2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 247 4-one 384 3.2 0 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 1-(pyridin-2 ylacetyl)imidazolidin 248 4-one 472 3.3 /0 0 2-[4 (diethylamino)phenyl] 3-(4-methoxyphenyl) N 1-methylimidazolidin 249 4-one 354 3.1 -110- WO 2009/079624 PCT/US2008/087397 \ N 2-(4-tert-butylphenyl) 1-(pyridin-3-ylmethyl) F zo-C,3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 250 4-one 498 3.7 0 2-(4-tert-butylphenyl) 3-(4-methoxyphenyl) 1-methylimidazolidin 251 4-one 339 3.2 0 N) 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-(4 -N nitrophenyl)imidazolid 252 in-4-one 356 3 0 N 2-(1H-indol-5-yl)-3-[2 (4 methoxyphenyl)ethyl] 1-methylimidazolidin 253 H 4-one 350 2.9 0 N N 2-(4-tedt-butylphenyl) 3-[2-(4 0 methoxyphenyl)ethyl] 1-(3-pyridin-3 ylpropanoyl)imidazoli 254 din-4-one 486 3.3 0>_\ N 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 1-(pyridin-3 ylmethyl)imidazolidin 255 4-one 444 3.7 N H 2-(4-tedt-butylphenyl) N H 3-[2-(4 N methoxyphenyl)ethyl] 4-oxo-N pentylimidazolidine-1 256 carboxamide 466 3.4 - 111 - WO 2009/079624 PCT/US2008/087397 2-[4-(1H-imidazol-1 yl)phenyl]-3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 257 4-one 377 2.9 F (2R,5S)-2-(4-tert butylphenyl)-5-{2 [ethyl(phenyl)amino]et N hyl}-1-methyl-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 258 4-one 568 3.9 0 1-cyclopropyl-2-(1H indol-5-yl)-3-[2-(4 methoxyphenyl)ethyl]i 259 NH midazolidin-4-one 376 3 N-{2-[(2R,4S)-2-(4 F 0 Ntert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 4-yl]ethyl}-2 260 methylalaninamide 549 4 (2R,5S)-2-(4-tett F> 0 butylphenyl)-5-[2 (diethylamino)ethyl] N 1-methyl-3-{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 261 4-one 520 3.3 0 1-benzyl-3-[2-(4 N methoxyphenyl)ethyl] 2-pyridin-2 262 ylimidazolidin-4-one 388 3.1 2-[3 (diethylamino)phenyl] 3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 263 4-one 382 3.3 -112- WO 2009/079624 PCT/US2008/087397 0 o3-[2-(4 N methoxyphenyl)ethyl] 1-methyl-2-pyridin-2 264 ylimidazolidin-4-one 312 2.7 0 N N 2-(4-tert-butylphenyl) N-1 3-[2-(4 hydroxyphenyl)ethyl] 1-methylimidazolidin 265 4-one 353 3 N o 2-(2,6 dimethylphenyl)-3-[2 N (4 methoxyphenyl)ethyl] 1-methylimidazolidin 266 4-one 339 3.2 0 N N 2-(2-aminopyridin-3 0- yl)-3-[2-(4 NHt methoxyphenyl)ethyl] N 1-methylimidazolidin 267 4-one 327 2.7 0 2-(4-tert-butylphenyl) N H3-[2-(4 methoxyphenyl)ethyl] 4-oxo-N-pyrimidin-4 ylimidazolidine-1 268 carboxamide 473 3.4 N N N 2-(4-tert-butylphenyl) 3-{2-[4 (dimethylamino)pheny I]ethyl}-1 methylimidazolidin-4 269 one 380 3.6 2-[4-(4-ethylpiperazin 1 -yl)phenyl]-3-[2-(4 N methoxyphenyl)ethyl] 1-methylimidazolidin 270 4-one 23 3.2 -113- WO 2009/079624 PCT/US2008/087397 0 2-(3,4 dimethylphenyl)-3-[2 (4 methoxyphenyl)ethyl] 1-methylimidazolidin 271 4-one 339 3.3 2-[4-(diethylamino)-2 (trifluoromethyl)pheny 1- 1]-3-[2-(4 F methoxyphenyl)ethyl] 1-methylimidazolidin 272 4-one 450 3.3 0 NN methoxyphenyl)ethyl] 1-methyl-2-(2 phenylethyl)imidazolid 273 in-4-one 339 3.3 o2-(4 cyclopropylphenyl)-3 [2-(4 methoxyphenyl)ethyl] 1,5,5 trimethylimidazolidin 274 4-one 379 3.4 0 2-(4 N cyclopropylphenyl)-3 [3-(4 fluorophenyl)propyl] 1-methylimidazolidin 275 4-one 353 3.3 0 N- 0 1-(2-{2-(4-tert N N- butylphenyl)-3-[2-(4 NH methoxyphenyl)ethyl] 4-oxoimidazolidin-1 276 yI}ethyl)-3-ethylurea 67 3.2 0 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[2-(2 methyl-1H-imidazol-1 2 yl)phenyl]imidazolidin 277 4-one 391 3.1 -114- WO 2009/079624 PCT/US2008/087397 2-(4-tert-butylphenyl) 0 N 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-1 (pyrimidin-5 ylmethyl)imidazolidin 278 4-one 473 3.3 N 2-(4-tedt-butylphenyl) N 3-[2-(4 methoxyphenyl)ethyl] 5,5-dimethyl-1-[(1 methyl-1 H-imidazol-2 yl)methyl]imidazolidin 279 4-one 75 3.7 2-(3,4 dimethylphenyl)-3-[2 (4 N methoxyphenyl)ethyl] 1,5 dimethylimidazolidin 280 4-one 353 3.3 0 2-(2-tert-butyl-1 methyl-1 H-imidazol-5 yl)-3-[2-(4 N, N- methoxyphenyl)ethyl] 1 -methylimidazolidin 281 4-one 371 2.9 0 2-(4-tert-butylphenyl) N 3-[2-(4 methoxyphenyl)ethyl] 0 1-(pyrazin-2 ylcarbonyl)imidazolidi 282 n-4-one 459 3.2 N N 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[4-(pyridin 0 3 ylmethoxy)phenyl]imi 283 N dazolidin-4-one 418 3.1 0 N N ~ 2-(4-hydroxyphenyl) 3-[2-(4 methoxyphenyl)ethyl] 1-methylimidazolidin 284 4-one 327 2.6 -115- WO 2009/079624 PCT/US2008/087397 0 2-(4-tert-butylphenyl) 3-[2-(4 methoxyphenyl)ethyl] 1-pentylimidazolidin 285 4-one 423 3.8 O N 2-(4-tert-butylphenyl) 1-methyl-3-[2-(4 piperidin-1 ylphenyl)ethyl]imidazo 286 lidin-4-one 420 3.9 0 methoxyphenyl)ethyl] 1-methyl-4 oxoimidazolidin-2 287 N yl}benzonitrile 336 2.9 0 2-(4-tert-butylphenyl) 1-isonicotinoyl-3-[2 (4 methoxyphenyl)ethyl]i 288 midazolidin-4-one 458 3.2 0 2-(4-tert-butylphenyl) N H 3-[2-(4 N methoxyphenyl)ethyl] 0 N-methyl-4 oxoimidazolidine-1 289 carboxamide 410 3.1 0 2-(4-tert-butylphenyl) 1-methyl-3-(2 phenoxyethyl)imidazo 290 lidin-4-one 353 3.4 0 0 N N 2-(4-tedt-butylphenyl) 1-methyl-3-[2-(4 morpholin-4 ylphenyl)ethyl]imidazo 291 lidin-4-one 22 3.4 -116- WO 2009/079624 PCT/US2008/087397 0 2-(4-tert-butylphenyl) 3 -[2-(4 methoxyphenyl)ethyl] 1-(3-pyridin-2 ylpropyl)imidazolidin 292 4-one 472 3.9 0 1-benzyl-2-[4 (dimethylamino)pheny 1]-3-[2-(4 methoxyphenyl)ethyl]i 293 midazolidin-4-one 430 3.3 3-[(4S)-2-(4-tert F F butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phe nyl]ethyl}imidazolidin 4-yl]-N (phenylsulfonyl)propa 294 namide 632 3.3 0 1-({(2R,4S)-2-(4-tert N - N 0butylphenyl)-1 -[2-(4 H methoxyphenyl)ethy] 3-methyl-5 oxoimidazolidin-4 295 yl}methyl)-3-ethylurea 467 3.1 N N- 3-[2-(4 methoxyphenyl)ethyl] 1-methyl-2-[4-(2 piperidin-1 ylethoxy)phenyl]imida 296 zolidin-4-one 438 3.2 KV1.5 PATCH CLAMP EP Kv1.5 currents are recorded by the whole cell mode of patch clamp 5 electrophysiology. Kv1.5 is stably over expressed in HEK cells. Microelectrodes are pulled from borosilicate glass (TW150) and heat polished (tip resistance, 1.5 to 3 megaohms). The external solution is standard Tyrodes solution. The internal (microelectrode) solution contained: 110 mM KCI, 5 mM K 2 ATP, 5 mM K 4 BAPTA, 1 -117- WO 2009/079624 PCT/US2008/087397 mM MgCl 2 and 10 mM HEPES, adjusted to pH 7.2 with KOH. Command potentials are applied for 1 second to +60mV from a holding potential of -70 mV using Axon software (pClamp 8.1) and hardware (Axopatch 1D, 200B). Compounds are prepared as 10-20mM DMSO stocks and diluted to appropriate test concentrations. After 5 stable currents are achieved, compounds are perfused onto the cells and the cells are pulsed every 5 seconds until no further changes in current are evident at a given compound concentration. Inhibition is measured at the end of the 1 second pulses and expressed relative to controls. Kv1.5 inhibition is estimated by single point determinations done at 1 IM. 10 Generally following this procedure, results for representative compounds according to the present invention are listed in Table 2 below. Table 2 Structure Name Kv1.5 %inhib @1uM 0 0-1 2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 1 methylimidazolidin-4-one 80 --N 2-(4-tert-butylphenyl)-3-[2-(3 methoxyphenyl)ethyl]-1 2 methylimidazolidin-4-one 48 2-(3,4-dichlorophenyl)-3-[2-(4 a methoxyphenyl)ethyl]-1 3 C' methylimidazolidin-4-one 53 -118- WO 2009/079624 PCT/US2008/087397 0 -~ 2-(4-tert-butylphenyl)-1-ethyl-3-[2 (4 methoxyphenyl)ethyl]imidazolidin-4 4 one 80 0 2-(4-cyclopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 5 methylimidazolidin-4-one 59 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[4 F (trifluoromethyl)phenyl]imidazolidin 6 F 4-one 23 00 2-(3-chlorophenyl)-1 -ethyl-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4- 2 7 one 2 00 2-(3,4-dichlorophenyl)-1 -ethyl-3-[2 I (4 8 methoxyphenyl)ethyl]imidazolidin-4 8 one 3 0 N 07;-2-(3,4-dimethylphenyl)-1 -methyl-3- 7 9 (3-phenylpropyl)imidazolidin-4-one 7 0
N
2-(4-tert-butylphenyl)-1 -methyl-3-(3 10 phenylpropyl)imidazolidin-4-one 57 -119- WO 2009/079624 PCT/US2008/087397 0 N 2-(4-tert-butylphenyl)-3-(4 methoxybenzyl)-1 11methylimidazolidin-4-one 53 0 N -6 2-(4-tert-butylphenyl)-1 -methyl-3-(2 12 -phenylethyl)imidazolidin-4-one 23 0 1 -ethyl-3-(2-phenylethyl)-2-[4 F (trifluoromethyl)phenyl]imidazolidin 13 F4-one 35 0 N / F 1 -ethyl-3-(2-phenylethyl)-2-[3 (trifi uoromethyl )phenyl]i midazol id in 14 F 4-one 27 0 1 -ethyl-2-(4-ethylphenyl)-3-(2 15 phenylethyl)imidazolidin-4-one 21 "--- 0\ /N- H (2R)-2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 16 methylimidazolidin-4-one 83 0 (',H /N-k (2S)-2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 17 methylimidazolidin-4-one 87 - 120- WO 2009/079624 PCT/US2008/087397 F -~ 2-(4-tert-butylphenyl)-1-methyl-3-{2 [4 (trifluoromethoxy)phenyl]ethyllimida 18 zolidin-4-one 58 0 F 0- F N 2-(3,4-dichlorophenyl)-1-methyl-3 {2-[4 d (trifluoromethoxy)phenyl]ethyllimida 19 zolidin-4-one 82 0 FN 1-methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyl}-2-[4 F (trifluoromethyl)phenyl]imidazolidin 20 F 4-one 62 0 N 2-(4-tert-butylphenyl)-1 -methyl-3-(2 21 phenylpropyl)imidazolidin-4-one 69 0 N 2-(4-tert-butyl phenyl)-3-[2-(4 -7 fluorophenyl)ethyl]-1 22 methylimidazolidin-4-one 30 0 N 2-(4-tert-butyl phenyl)-3-[2-(4 -7, isopropylphenyl)ethyl]-1 23 methylimidazolidin-4-one 43 F0 FF N 2-(4-tert-butylphenyl)-1 -methyl-3-{2 [4 (trifluoromethyl)phenyl]ethyllimidazo 24 Iidin-4-one 18 - 121 - WO 2009/079624 PCT/US2008/087397 F 0 3-[2-(3,4-difluorophenyl)ethyl]-2 (3,4-dimethylphenyl)-1 25 methylimidazolidin-4-one 26 F X(0 CI 2-(3,4-dichlorophenyl)-3-[2-(3,4 cl difluorophenyl)ethyl]-1 26 CImethylimidazolidin-4-one 21 FF F 2-(4-tert-butylphenyl)-1 -ethyl-3-{2 [4 (trifluoromethoxy)phenyl]ethyllimida 27 zolidin-4-one 91 F 2-(4-cyclopropylphenyl)-1 -methyl-3 {2-[4 (trifluoromethoxy)phenyl]ethyllimida 28 zolidin-4-one 53 -~0 3-{2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-4 29 Noxoimidazolidin-1-yIlpropanenitrile 32 0 N 1 -aIly-2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 30 one 81 0 \-\OH 2-(4-tert-butylphenyl)-1-(3 hyd roxypropyl )-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 31 one 29 - 122- WO 2009/079624 PCT/US2008/087397 0 OH N 2-(4-tert-butylphenyl)-1 -(2 hyd roxyethyl )-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 32 one 47 F 2-(3,4-dimethylphenyl)-1 -methyl-3 N {2-[4 (trifluoromethyl)phenyl]ethyllimidazo 33 Iidin-4-one 30 0o 0 N (2R,5S)-2-(4-tert-butylphenyl)-5 isopropyl-3-[2-(4 methoxyphenyl)ethyl]-1 34 methylimidazolidin-4-one 73 0 N(2 S,5S)-2-(4-tert-butylIpheny1)-5 isopropyl-3-[2-(4 methoxyphenyl)ethyl]-1 35 methylimidazolidin-4-one 23 0 Q 1 -benzyl-2-[4 36 N-- ~~(d im et hyIa m ino) ph eny1]-3-(2 36 h en ylIet hyl1) imid az olIid in-4-o ne 52 N 1 -Benzyl-3-[2-(4-methoxy-phenyl) F ethyl]-2-(3-trifluoromethyl-phenyl) 37 F F imidazolidin-4-one 0 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-quinolin-2-ylimidazolidin-4 38 one 15 - 123- WO 2009/079624 PCT/US2008/087397 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1,5 39 dimethylimidazolidin-4-one 79 (2R, 5S)-5-isobutyl-2-(4 isopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 40 methylimidazolidin-4-one 56 (2S,5S)-2-[4 (dimethylamino)phenyl]-5-isobutyl 41 N-3-[2-(4-methoxyphenyl)ethyl]-1 41methylimidazolidin-4-one 86 0 0 (2R, 5S)-2-(4-ethylphenyl)-5 isobutyl-3-[2-(4 methoxyphenyl)ethyl]-1 42 methylimidazolidin-4-one 40 0 (2R, 5S)-5-benzyl-2-(4-ethylphenyl) 3-[2-(4-methoxyphenyl)ethyl]-1 43 methylimidazolidin-4-one 83 0 0 N (2R,5S)-5-benzyl-2-(3,4 d im ethyl phe nyl)-3-[2-(4 methoxyphenyl)ethyl]-1 44 methylimidazolidin-4-one 82 0 (2R, 5S)-2-(4-chlorophenyl)-5 isobutyl-3-[2-(4 methoxyphenyl)ethyl]-1 45 CI methylimidazolidin-4-one 66 - 124- WO 2009/079624 PCT/US2008/087397 0
N
,N (2S,5S)-2-(4-chlorophenyl)-5 isobutyl-3-[2-(4 cl methoxyphenyl)ethyl]-1 46 CImethylimidazolidin-4-one 74 0 (2S, 5S)-2-(4-ethylphenyl)-5 isobutyl-3-[2-(4 methoxyphenyl)ethyl]-1 47 methylimidazolidin-4-one 79 0 (2S,5S)-2-(4-tert-butylphenyl)-5 isobutyl-3-[2-(4 methoxyphenyl)ethyl]-1 48 methylimidazolidin-4-one 93 0 NFN F; 2-[4-(diethylamino)phenyl]-1 -methyl 0 -2-4 (trifluoromethoxy)phenyl]ethyllimida 49 zolidin-4-one 67 0 N N F F F / -CJ2-[4-(dimethylamino)phenyl]-1 F methyl-3-{2-[4 / (trifluoromethoxy)phenyl]ethyllimida 50 zolidin-4-one 28 N N 2-[4-(diethylamino)phenyl]-3-[2-(4 CN methoxyphenyl)ethyl]-1 51 methylimidazolidin-4-one 96 0 N 14 [isopropyl(methyl)amino]phenyl}-3 [2-(4-methoxyphenyl)ethyl]-1 52 methylimidazolidin-4-one 59 - 125- WO 2009/079624 PCT/US2008/087397 0 2-[4-(diethylamino)benzyl]-3-[2-(4 N methoxyphenyl)ethyl]-1 53 methylimidazolidin-4-one 90 -00 N 2-[4-(dimethylamino)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-1 54 methylimidazolidin-4-one 36 F 2-[4-(diethylamino)-3-fluorophenyl] rN 3-[2-(4-methoxyphenyl)ethyl]-1 55 methylimidazolidin-4-one 45 0 c 2-[3-chloro-4-(diethylamino)phenyl] 56 3-[2-(4-methoxyphenyl)ethyl]-1 56methylimidazolidin-4-one 38 0 2-[4-(diethylamino)-3, 5 d iflIu oroph enyl1]-3-[2-(4 57 methoxyphenyl)ethyl]-1 57methylimidazolidin-4-one 31 0 CH 2-[2-chloro-4-(diethylamino)phenyl] 3-[2-(4-methoxyphenyl)ethyl]-1 58 methylimidazolidin-4-one 62 0 / (2R)-2-[4-(diethylamino)phenyl]-3 [2-(4-methoxyphenyl)ethyl]-1 59 methylimidazolidin-4-one 84 - 126- WO 2009/079624 PCT/US2008/087397 0 (2S)-2-[4-(diethylamino)phenyl]-3 60 [2-(4-methoxyphenyl)ethyl]-1 60methylimidazolidin-4-one 75 N (2S,5S)-5-isobutyl-2-(4 isopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 61 methylimidazolidin-4-one 95 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(4-piperazin-1 62 vylphenyl)imidazolidin-4-one 24 3-[2-(4-methoxyphenyl)ethyl]-1 0 methyl-2-[4-(pyridin-4 6 ylmethoxy)phenyl]imidazolidin-4 63 one 45 0 O-Crr3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[4-(3 64 methylbutoxy)phenyl]imidazolidin-4 64one 51 0 (2R, 5S)-5-benzyl-2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 65 methylimidazolidin-4-one 66 (2R, 5S)-2-(4-tert-butylphenyl)-5 isobutyl-3-[2-(4 methoxyphenyl)ethyl]-1 66 methylimidazolidin-4-one 83 -127- WO 2009/079624 PCT/US2008/087397 / tert-butyl (2-{(4S)-2-[4 N (dimethylamino)phenyl]-1-[2-(4 methoxyphenyl)ethyl]-3-methyl-5 oxoimidazolidin-4 67 yIjethy1) ca rba mate 80 0 (2R,5S)-2-[4 (dimethylamino)phenyl]-5-isobutyl 68 N-3-[2-(4-methoxyphenyl)ethyl]-1 68methylimidazolidin-4-one 53 0 I 0\ N ZN (2S, 5S)-5-benzyl-2-(3,4 d im ethyl phe nyl)-3-[2-(4 methoxyphenyl)ethyl]-1 69 methylimidazolidin-4-one 93 0 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(1 -methyl-1,2,3,4 N \ etrahydroquinolin-6-yI)imidazolidin 70 4-one 56 0 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-quinolin-4-ylimidazolidin-4 71 one 26 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(1 H-pyrrol-2 72 yI)imidazolidin-4-one 26 NX' 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-( 1-methyl-i H-pyrrol-2 73 yI)imidazolidin-4-one 24 - 128- WO 2009/079624 PCT/US2008/087397 0 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(4-methyl-3,4-dihydro-2H LN 1,4-benzoxazin-7-yI)imidazolidin-4 74 one 49 0 -~ 0 2-(4-tert-butylphenyl)-1-(4 methoxybenzyl )-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 75 one 82 0 2-(4-chlorophenyl)-1-(4 761- methoxybenzyl)-3-(2 76 henylethyl)imidazolidin-4-one 83 0 2-( 1,3-benzodioxol-5-y)-1 -benzyl-3 o ~ mLthoxypheny)ethy]imidazolidin-4 77 one 32 1 -benzyl-3-[2-(4 methoxyphenyl)ethyl]-2-[4 F(trifl uoromethyl)phenyl]i midazol id in 78 F4-one 61 1 -benzyl-2-(3,4-d ich lorophenyl)-3 [2-(4 methoxyphenyl)ethyl]i midazol idi n-4 79 CIone 26 1-lbenzyl2-(3-chorophenyl)-3-[2-(4 80 one 61 - 129- WO 2009/079624 PCT/US2008/087397 0 1 -benzyl-2-(4-isopropylphenyl)-3-[2 (4 methoxyphenyl)ethyl]imidazolidin-4 81 one 79 0 -0 1 -benzyl-2-(4-ethylphenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 82 one 75 1 -benzyl-2-(4-tert-butylphenyl)-3-[2 (4 methoxyphenyl)ethyl]imidazolidin-4 83 one 79 1 -be nzyl-2-(3,4-d im ethyl phe nyl1)-3 [2-(4 methoxyphenyl)ethyl]imidazolidin-4 84 one 56 1 -benzyl-2-(4-fluorophenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 85Fone 43 1 -[2-( benzyloxy)ethyl]-2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 86 one 71 0 /1 -[3-(benzyloxy)propyl]-2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 87 one 47 - 130 - WO 2009/079624 PCT/US2008/087397 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -[3-(pyridin 2-ylmethoxy)propyl]imidazolidin-4 88 one 61 0 N- (342-4t-utyl-bu yIp yhn 1)--[-(- ( o methoxyphenyl)ethyl]-1 -[-prdn o-ylmethoyaopyinliiaoldn 90 o 501 co mide2 0 N- H &I\N N- (4 -{r-b4utyIhertnby 1heny )-[2-2-(4 methoxyphenyl)ethyl]-4 91 (methysulfooxo imidazolidin-1-ne8 0 01 2-(4-tert-butyl phenyl)-3-[2( metoxphenyl)ethfoyl]-1 -[-4 91 (methoysulfnyl)eimidazolidin-4- 8 0 N 0 -S ~ 2-(4-tert-butyl phenyl)-1-[( 01 flutophenyl)lfoyl]-l -[2(4 methoyphenyl)ethfoyl]imidazolidin 92 4one 30 0 0 01m ethoxypheonyl)etl- -[(4 methoyphenyl)ulfoyl]imidazolidin-4 93 4one 65 01 1 WO 2009/079624 PCT/US2008/087397 0 N C 2-(4-tert-butylphenyl)-1-[(4 ethylphenyl)sulfonyl]-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 95 one 34 F 0 N 3-[(4S)-2-(4-tert-butylphenyl)-3 F methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]-N-pyridin-3 96 ylpropanamide 72 F F +F O 3-((2R,4S)-1-(4 N rH 0 (trifluoromethoxy)phenethyl)-2-(4 N tert-butylphenyl)-3-methyl-5 oxoimidazolidin-4-yI)-N 97 (phenylsulfonyl)propanamide F 0C N N, N 2-[(2R,4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 98 zolidin-4-yI]-N-pyridin-3-ylacetamide 47 F 0C F~r 0 H F 0 N 2-[(2S,4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 99 zolidin-4-yI]-N-pyridin-2-ylacetamide 31 F 0 F>'-OC 0 O\T2-[(2R, 4S)-2-(4-tert-butyl phenyl)-3 N methyl-5-oxo-1 -2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]-N-(pyridin-2 100 ylmethyl)acetamide 83 F 0C F> 00 H N 2-[(2R,4S)-2-(4-tert-butylphenyl)-3 N methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida olidin-4-yI]-N-(pyridin-3 101 ylmethyl)acetamide 39 - 132 - WO 2009/079624 PCT/US2008/087397 F 0 benzyl {2-[(4S)-2-(4-tert butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 102 zoIid in-4-yI lethyllcarba mate 20 F - N-{2-[(4S)-2-(4-tert-butylphenyl)-3 F methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]ethyllpyridine-2 103 carboxamide 63 N-{2-[(4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 104 zolidin-4-yIlethyllnicotinamide 40 FK-C o (5S)-2-(4-tert-butylphenyl)-1 -methyl N 5-[2-(pyri mid in-2-ylam ino)ethyl]-3 {2-[4 (trifluoromethoxy)phenyl]ethyllimida 105 zolidin-4-one 75 F L0w N (2R,5S)-2-(4-tert-butylphenyl)-5-(2 hydroxyethyl)-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimida 106 zolidin-4-one 79 F 0C F>( 0 F 0 (2R,5S)-5-{2 N [benzyl(methyl)amino]ethyl}-2-(4 tert-butylphenyl)-1-methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimida 107 zolidin-4-one 45 F 0 F o F 0 , o\ N) (2R, 5S)-2-[4-(diethylamino)phenyl] 1 -methyl-5-[2-(pyridin-2 ylmethoxy)ethyl]-3-{2-[4 108 (trifluoromethoxy)phenyl]ethyllimida 108olidin-4-one 67 -133 - WO 2009/079624 PCT/US2008/087397 (2R,5S)-5-[(benzyloxy)methyl]-2-[4 (diethylamino)phenyl]-3-[2-(4 109 methoxyphenyl)ethyl]-1 109methylimidazolidin-4-one 85 (2S,5S)-5-[(benzyloxy)methyl]-2-[4 (diethylamino)phenyl]-3-[2-(4 110 methoxyphenyl)ethyl]-1 110methylimidazolidin-4-one 94 0 NHS-Io <-N N-({(2S,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 111 vImethyl)methanesulfonamide 91 0 0 N N-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 112, yIlmethyl)propane-1 -sulfonamide 87 o N N-({(2S,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 113, yIlmethyl)propane-1 -sulfonamide 94 N N-({(2S,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 114 vIlmethyl)butane-l-sulfonamide 90 0 H [2-(4-methoxyphenyl)ethyl]-3 N\ methyl-5-oxoimidazolidin-4 yIlmethyl)-1 -pyridin-3 115 ylmethanesulfonamide 63 -134 - WO 2009/079624 PCT/US2008/087397 -N HH 1 -({(2S,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 116 yIlmethyl)-3-ethylurea 85 0 0 0 N H N H 1-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 117 yIlmethyl)-3-pyri mid in-4-yl urea 48 o N /0 N N\ NH2 1 -({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 118 yIlmethyl)urea 26 0 N\ H N~ H 1-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 119 yIlmethyl)-3-methylurea 50 0 0 H H 1 -({(2S,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 120 yIlmethyl)-3-methylurea 82
HN
NHN 1 -({(2S,4S)-2-(4-cyclopropylphenyl) 1-[2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 121 yIlmethyl)-3-methylurea 78 0 NH 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5 122 dimethylimidazolidin-4-one 25 -135 - WO 2009/079624 PCT/US2008/087397 0 N, N o 2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1,5,5 123 trimethylimidazolidin-4-one 97 0 2-(4-cyclopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-5,5 124 dimethylimidazolidin-4-one 18 0 0 1 -benzyl-2-(4-tert-butylphenyl)-3-[2 (4-methoxyphenyl)ethyl]-5,5 125 dimethylimidazolidin-4-one 21 2-(4-tert-butylphenyl)-1-ethyl-3-[2 (4-methoxyphenyl)ethyl]-5,5 126 dimethylimidazolidin-4-one 91 N N 2-[4-(diethylamino)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-1,5,5 127 trimethylimidazolidin-4-one 87 0
N-
2-[4-(dimethylamino)phenyl]-1,5,5 F rimethyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyl}imida 128 zolidin-4-one 45 O N F F 2-[4-(diethylamino)phenyl]-1,5,5 F trimethyl-3-{2-[4 N (trifluoromethoxy)phenyl]ethyl}imida 129 zolidin-4-one 58 - 136 - WO 2009/079624 PCT/US2008/087397 0 N 2-[2-(d iethylami no)pyri mid in-5-y]-3 [2-(4-methoxyphenyl)ethyl]-1,5,5 130 trimethylimidazolidin-4-one 25 0 N 2-[4-(dimethylamino)phenyl]-3-[2-(4 /N, methoxyphenyl)ethyl]-1,5,5 131 trimethylimidazolidin-4-one 58 3-[2-(4-methoxyphenyl)ethyl]-1,5,5 0 trimethyl-2-(4-piperidin-1 132 ylphenyl)imidazolidin-4-one 34
ON
[isopropyl(methyl)amino]phenyl}-3 [2-(4-methoxyphenyl)ethyl]-1,5,5 133 trimethylimidazolidin-4-one 58 0 o00 2-(4-tert-butylphenyl)-5, 5-diethyl-3 [2-(4 methoxyphenyl)ethyl]imidazolidin-4 134, one 41 0 2-(4-tert-butylphenyl)-5, 5-diethyl-3 [2-(4-methoxyphenyl)ethyl]-1 135 methylimidazolidin-4-one 74 3-[2-(4-methoxyphenyl)ethyl]-1,5,5 136 rimethyl-2-(4-pyrrolidin-1 136ylphenyl)imidazolidin-4-one 28 -137 - WO 2009/079624 PCT/US2008/087397 0 N 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 1 -(pyridin-3-ylmethyl)imidazolidin-4 137 one 73 N N cr~c3-[2-(4-methoxyphenyl)ethyl]-2, 5,5 trimethyl-2-(4 138 methylphenyl)imidazolidin-4-one 14 0 / N-N / 3-[2-(4-methoxyphenyl)ethyl] 1,2,5,5-tetramethyl-2-(4 139 methylphenyl)imidazolidin-4-one 35 0 0/ N / 2-(3,4-dimethylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1,2,5,5 140 tetramethylimidazolidin-4-one 57 0 2-(4-tert- butylIp he ny1)- 1 -(3 o cyclohexylpropanoyl)-3-[2-(4 m et hoxy ph eny1) et h yI] imidazoIi d in -4 141 one 27 3-[2-(4-methoxyphenyl)ethyl]-5, 5 N ~d im eth yl1-2-(4- py rrolIi d in-1 142 yIp h eny1) im id az oIi d in -4-o ne 13 F F 0 2-(3,4-d ichIo ro ph eny1)- 1 -meth yl1-3 al N {2-[4 (t riflIu oro met hy1) phe n yI]et hyIIi m id az o 143 Il idin-4-one 10 - 138 - WO 2009/079624 PCT/US2008/087397 110 0 NH S N N-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 144 yIlmethyl)methanesulfonamide 69 0
NN
2-(1 -ethyl-1 H-indol-5-yI)-3-[2-(4 N methoxyphenyl)ethyl]-1, 5,5 145 trimethylimidazolidin-4-one 90 (dimethylamino)ethoxy]phenyl}-3-[2 (4-methoxyphenyl)ethyl]-1 146 methylimidazolidin-4-one1 3-[2-(4-methoxyphenyl)ethyl]-1 0 methyl-2-[4-(pyridin-2 147 ylmethoxy)phenyl]imidazolidin-4 147one 24 0 N Nl-(-3-[2-(4-methoxyphenyl)ethyl] 149 1-me5thyl-4-oxoimidazolidin-2-oe 3 0 y3-[2-(4-methoxyphenyl)ethyl] methyl-2-[4-(2-pyrrolidin-1 150 ylethoxy)phenyl]imidazolidin-4-one 0 -139 - WO 2009/079624 PCT/US2008/087397 0 N_ 0 2-(4-cyclopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(3-pyridin-3 151 ylpropanoyl)imidazolidin-4-one 35 0 HN 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(2-phenyl-1 H-imidazol-5 152 yI)imidazolidin-4-one 4 HN- N-(2-{2-(4-tert-butyl phenyl )-3-[2-(4 0 methoxyphenyl)ethyl]-4 XO oxoimidazolidin-1 153 yIlethyl)ethanesulfonamide 32 0 N 2-(4-tert-butylphenyl)-1 -butyryl-3-[2 0 (4 methoxyphenyl)ethyl]imidazolidin-4 154 one 42 o 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[4-(2-morpholin-4 155 ylethoxy)phenyl]imidazolidin-4-one 4 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(3 156 iphenylpropyI)imidazolidin-4-one 21 0 3-2-(4-methoxyphenylethy]-1 157 yloxy)phenyl]imidazolidin-4-one 3 - 140- WO 2009/079624 PCT/US2008/087397 F( NHF, (5S)-5-(2-aminoethyl)-2-(4-tert butylphenyl)-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimida 158 zolidin-4-one 8 2-(4-tert-butyl pheny1)- 1 -iso pro pyl-3 [2-(4 methoxyphenyl)ethyl]imidazolidin-4 159 one 77 0 2-(4-tert-butyl phenyl)-3-[3-(4 fluorophenyl)propyl]-1 160, methylimidazolidin-4-one 59 0 2-{4-[ethylI(iso pro pyl)a min o]ph enyl} N 3-[2-(4-methoxyphenyl)ethyl]-1 161 methylimidazolidin-4-one 49 F 0 -/O F 0 3-[(4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 162 zolidin-4-yIlpropanoic acid 2 0 N\ N-(4-{3-[2-(4-methoxyphenyl)ethyl] 1-methyl-4-oxoimidazolidin-2 0 yIlphenyl)-N zs\: (methylsulfonyl)methanesulfonamid 163 0e 3 N 0
N
N 2-(4-tert-butylphenyl)-1 -methyl-3-{2 -7 [2-(methylthio)pyrimidin-5 164 yI]ethyllimidazolidin-4-one 21 - 141 - WO 2009/079624 PCT/US2008/087397 0 N N Ny-N 2-(2,4-d imethoxypyri mid in-5-yI)-3 O\ [2-(4-methoxyphenyl)ethyl]-1 165 methylimidazolidin-4-one 6 0 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(pyridin-3 166 ylacetyl)imidazolidin-4-one 24 2-(4-tert-butylphenyl)-1 -hexanoyl-3 [2-(4 methoxyphenyl)ethyl]imidazolidin-4 167 one 80 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[1 -(pyridin-4-ylmethyl)-1 H 168 indol-5-yIlimidazolidin-4-one 19 0 N_ 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(pyrid in-4 169 ylacetyl)i midazol id in-4-one 23 0 N N/_ N 2-[2-(d iethylami no)pyri mid in-5-y]-3 170 [2-(4-methoxyphenyl)ethyl]-1 10methyl imidazol idi n-4-one 5 0 N \-\- tert-butyl (3-{2-(4-tert-butylphenyl) 0 0X 3-[2-(4-rnethoxyphenyl)ethyl]-4 11711 lyIpropyl)carbamate 165 - 142- WO 2009/079624 PCT/US2008/087397 0 N FNN 2-(2-tert-butyl-1 H-imidazol-4-yI)-3 T [2-(4-methoxyphenyl)ethyl]-1 172 methylimidazolidin-4-one 5 0 N 2-(4-cyclopropylphenyl)-1 -methyl-3 1731 (3-phenylpropyl)imidazolidin-4-one 37 ' N 2-(4-tert-butylphenyl)-1-[3 (diisopropylamino)propyl]-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 174 one 41 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[1 -(pyridin-2-ylmethyl)-1 H 175 indol-5-yIlimidazolidin-4-one 41 N 2-(2-tert-butyl pyri mid in-5-yI )-3-[2-(4 methoxyphenyl)ethyl]-1,5,5 176 trimethylimidazolidin-4-one 9 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[1 -(pyrid in-3-yl methyl)-1 H 177 indol-5-yI]im idazolid in-4-one 39 F o(2R, 5S)-5-{2-[benzyl(pyrid in-3 yl methyl)am ino]ethyl}-2-(4-tert butylphenyl)-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimida 178 olidin-4-one 5 - 143- WO 2009/079624 PCT/US2008/087397 0 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-quinolin-3-ylimidazolidin-4 179 one 15 2-(4-tert-butylphenyl)-1 (cyclohexylacetyl )-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 180 one 40 0 0 o NH-S N N-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxyphenyl)ethyl]-3 methyl-5-oxoimidazolidin-4 181, yIlmethyl)butane-1 -sulfonamide 6 0 0 NH. 0- - N N 1 -({(2S,4S)-2-(4-cyclopropylphenyl) 1 -[2-(4-methoxyphenyl)ethyl]-3 182 methyl-5-oxoimidazolidin-4 182yIlmethyl)urea 88 F H 3-[(4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]-N-pyridin-2 183 ylpropanamide 9 0 N H 2-(l H-imidazol-5-yI)-3-[2-(4 methoxyphenyl)ethyl]-1 184 methylimidazolidin-4-one1 0 N/ 2-(6-tert-butyl pyrid in-3-yI)-3-[2-(4 methoxyphenyl)ethyl]-1 185 methylimidazolidin-4-one 12 - 144- WO 2009/079624 PCT/US2008/087397 0 ZN-b 3-[2-(4-methoxyphenyl)ethyl]-1 N methyl-2-pyridin-3-ylimidazolidin-4 186 one1 0 0 2-(2-furyl)-3-[2-(4 methoxyphenyl)ethyl]-1 187 methylimidazolidin-4-one 11 0 N 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(3-piperidin 188 1 -ylpropanoyl)imidazolidin-4-one 16 0 0_ N 2-(4-isobutylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 189 methylimidazolidin-4-one 64 F>O 0 Ny ,) Ir N,_' (5 S)-2-(4-tert-butyl ph enyl1)- 1-m ethyl N 5-[2-( pyridin-2-ylamino)ethyl]-3-{2 [4 (trifluoromethoxy)phenyl]ethyllimida 190 zolidin-4-one 19 0 NX' 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(1 -methyl-1 H-imidazol-2 191 yI)imidazolidin-4-one 4 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(4-morpholin-4 192 ylphenyl)imidazolidin-4-one 11 - 145- WO 2009/079624 PCT/US2008/087397 F 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-[4-(4-methylpiperazin-1 193 yI)phenyllimidazolidin-4-one 6 F 0 F 3-[(4S)-2-(4-tert-butylphenyl)-3 F methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]-N-[2 194, (dimethylamino)ethyllpropanamide 2 F 0 F 0 N 2-[(2R,4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 195 zolidin-4-yI]-N-pyridin-2-ylacetamide 4 N 2-(4-tert- butylIphe ny1)-3-[2-(4 methoxyphenyl)ethyl]-1 -(3 pyrimidin-2 196 ylpropanoyl)imidazolidin-4-one 27 0
N
NH 1 -(3-{3-[2-(4-methoxyphenyl)ethyl] HN "H2 1 -methyl-4-oxoimidazolidin-2 197 H H yIlphenyl)guanidine 11 0 N 2-(4-cyclopropylphenyl)-1 -methyl-3 198 (2-phenoxyethyl)imidazolidin-4-one 20 0 0 \ 2-(4-ethyl-3,4-dihydro-2H-1,4 0 benzoxazi n-7-yI )-3-[2-(4 -N \-methoxyphenyl)ethyl]-1 1 1991 methylimidazolidin-4-one 173 - 146- WO 2009/079624 PCT/US2008/087397 0 N NH N-{2-[2-(4-tert- butylI phe nyl1)- 3 m eth ylI-5-oxo im id azoIid in -1 -y I]-l1 200 p h en y Iethy I Imeth a nes u Ifo n am ide 15 N 2-(4-tert- butylI phe nyl1)-3-[2-(6 m et hoxy py ri d in-3-y1) eth yI]- 1 201 m et h yIi m idazoIi d in -4-o ne 9 0 N ) -N\ 2-(4-fluorophenyl)-3-[2-(4 F methoxyphenyl)ethyl]-1 202,F methylimidazolidin-4-one 6 0 2-(4-am inophenyl)-3-[2-(4 NH2 methoxyphenyl)ethyl]-1 203 H methylimidazolidin-4-one 11 / o~crj3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(4-pyridin-3 204 ylphenyl)imidazolidin-4-one 12 0 N NN 1 -{3-[benzyl(pyridin-2 N ylmethyl)amino]propyl}-2-(4-tert butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 205 one 54 CN 0 NN 2-(4-tert-butylphenyl)-1 -methyl-3-[2 (4-pyrrolidin-1 206 ylphenyl)ethyl]imidazolidin-4-one 0 - 147- WO 2009/079624 PCT/US2008/087397 0 N 2-[4-(diisopropylamino)phenyl]-3-[2 N (4-methoxyphenyl)ethyl]-1 207 -methylimidazolidin-4-one 21 2-[4-(diethylamino)-3 methoxyphenyl]-3-[2-(4 208 methoxyphenyl)ethyl]-1 208methylimidazolidin-4-one 7 0 0 N "I'S N-(2-{2-(4-tert-butyl phenyl )-3-[2-(4 0 methoxyphenyl)ethyl]-4 XG oxoimidazolidin-1 209 yIlethyl)methanesulfonamide 20 N N 3-[2-(4-methoxyphenyl)ethyl]-1,5 dimethyl-2-(4 210 methylphenyl)imidazolidin-4-one 52 1-{2-[(4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida 211 zolidin-4-yIlethyl}-3-pyridin-3-ylurea 13 0 IN N 2-(4-tert-butyl phenyl)-3-[2-(4 _ methoxyphenyl)ethyl]-1-(2-pyridin-2 212 vlethyl)imidazolidin-4-one 37 0+ 2-[4-(diethylamino)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-5, 5 213 dimethylimidazolidin-4-one 17 - 148- WO 2009/079624 PCT/US2008/087397 3-[2-(4-methoxyphenyl)ethyl]-1 N methyl-2-(4-pyridin-2 214 vylphenyl)imidazolidin-4-one 12 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(4-pyridin-4 215 ylphenyl)imidazolidin-4-one 2 0 \N 0 2-(4-tert-butylphenyl)-1 -(3 cyclohexylpropanoyl)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 216 one 27 0 2-(l1-ethyl- 1, 2, 3, 4 tetrahydroquinolin-6-y)-3-[2-(4 N$ methoxyphenyl)ethyl]-1 2171 methylimidazolidin-4-one 55 1 -benzyl-3-[2-(4 NH methoxyphenyl)ethyl]-2-(1 H-pyrrol 218 2-yI)imidazolidin-4-one 0 00 100 -N N 0 2-(2, 3-dihydro-1 ,4-benzodioxin-6 co-e yI)-3-[2-(4-methoxyphenyl)ethyl]-1 219 0methylimidazolidin-4-one 36 / 2-(4-tert-butylphenyl)-1 -[4 (diethylamino)benzyl]-3-[2-(4 methoxyphenyl)ethyl]-5, 5 220 dimethylimidazolidin-4-one 8 -149- WO 2009/079624 PCT/US2008/087397 0 N N 2-(5-tert-butyl-1 -methyl-i H-imidazol _00 2-yI)-3-[2-(4-methoxyphenyl)ethyl] 221 1-methylimidazolidin-4-one 5 0 N 2-(l1-ethyl-2, 3-dihydro-1 H-indol-5 N yI)-3-[2-(4-methoxyphenyl)ethyl]-1 222 methylimidazolidin-4-one 23 N 2-[2-(dimethylamino)pyrimidin-5-y] 3-[2-(4-methoxyphenyl)ethyl]-1,5,5 223 trimethylimidazolidin-4-one 8 0y N 2-(4-tert-butyl pheny1)- 1 -cyclo pro pyl k methoxyphenyl)ethyl]imidazolidin-4 224 one 88 0 N /2-(l1-ethy1- 1 H-i nd ol-5-yI)-3-[2-(4 methoxyphenyl)ethyl]-1 225 methylimidazolidin-4-one 82 /1 0 2-(2-tert-butyl pyri mid in-5-yI )-3-[2-(4 methoxyphenyl)ethyl]-1 226 methylimidazolidin-4-one 10 0 N H 0 2-(4-tert-butyl phenyl )-N-ethyl-3-[2 (4-methoxyphenyl)ethyl]-4 227 oxoimidazolidine-1 -carboxamide 15 - 150 - WO 2009/079624 PCT/US2008/087397 0 3-[2-(4-methoxyphenyl)ethyl]-1 N methyl-2-(4-pyrrolidin-1 228 ylphenyl)imidazolidin-4-one 7 0 N -2(imtyain-yiidn5y] N 3-[2-(4-methoxyphenyl)ethyl]-1 229 methylimidazolidin-4-one 4 F (2R,5S)-2-(4-tert-butylphenyl)-1 N methyl-5-{2 [methyl(phenyl)amino]ethyl-3-2-[4 (trifluoromethoxy)phenyl]ethyllimida 230 zolidin-4-one 12 F> 0 (2R, 5S)-2-(4-tert-butylphenyl)-5-[2 N (dimethylamino)ethyl]-1 -methyl-3-{2 [4 (trifluoromethoxy)phenyl]ethyllimida 231 zolidin-4-one 13 0- 0 N (2R,5S)-2-(4-tert-butylphenyl)-5 H (1 H-indol-3-ylmethyl)-3-[2-(4 methoxyphenyl)ethyl]-1 232 methylimidazolidin-4-one 15 0 \ " _N N 0 H 2 -(4 -tert- b utyIp h eny1) -1 -(1 H i m idazol1-2-ylIm et hyl1)- 3 -[2- (4 methoxyphenyl)ethyl]-5, 5 233 dim et h y Iim idaz o Iid in -4 -one 61 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 234 1 -propylimidazolidin-4-one 54 - 151 - WO 2009/079624 PCT/US2008/087397 0 0-N -N 2-(4-chlorophenyl)-3-[2-(4 cl methoxyphenyl)ethyl]-1 235 CImethylimidazolidin-4-one 13 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 1 -(pyridin-4-ylmethyl)imidazolidin-4 236 one 64 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 1 -(pyridin-2-ylmethyl)imidazolidin-4 237 one 73 FH F>0 (2,S-2-(4-tert-butylphenyl)-1 N methyl-5-[2-( pyrid in-3 ylamino)ethyl]-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimida 238 zolidin-4-one 13 0 / 2-(3-aminophenyl)-3-[2-(4 / methoxyphenyl)ethyl]-1 239 methylimidazolidin-4-one 4 0 2-(4-tert-butyl phenyl)-3-(2-{4 [(dimethylamino)methyl]phenyllethy 240 )-l1-methylimidazolidin-4-one 4 2-[4-(diisopropylamino)phenyl]-3-[2 K (4-methoxyphenyl)ethyl]-1,5,5 241 trimethylimidazolidin-4-one 13 - 152 - WO 2009/079624 PCT/US2008/087397 0 -N NH <N 2-(4-tert-butylphenyl)-3-[2-(4 0 methoxyphenyl)ethyl]-1 -(1 H pyrazol-4-ylcarbonyl)imidazolidin-4 242 one 8 0 O-aN N 2-(4-cyclopropylphenyl)-3-(4 , :7$methoxyphenyl)-1 243 -methylimidazolidin-4-one 10 2-[4-(4-hydroxypiperid in-i yI)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-1 244 -methylimidazolidin-4-one 11 0 N4 2-[4-(difluoromethoxy)phenyl]-3-[2 0__(F (4-methoxyphenyl)ethyl]-1,5,5 245 F trimethylimidazolidin-4-one 26 0 N - 02-(4-tertbutylphenyl)-l -4 methoxyphenyl)ethyl]imidazolidin-4 246 one 0 0 2-[4-(dimethylamino)-2 C, methoxyphenyl]-3-[2-(4 N methoxyphenyl)ethyl]-1 247 methylimidazolidin-4-one 11 0 N 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(pyridin-2 248 ylacetyl)imidazolidin-4-one 19 -153 - WO 2009/079624 PCT/US2008/087397 2-[4-(diethylamino)phenyl]-3-(4 N methoxyphenyl)-1 249 methylimidazolidin-4-one 7 0y_ N F z- 2-(4-tert- butylIp he ny1)- 1 -(py rid in -3 F ylmethyl)-3-{2-[4 (t riflIu oro met hoxy) ph en yI]eth y11im id a 250 zolidin-4-one 36 0 2-(4-tert-butyl phe ny1)-3-(4 methoxyphenyl)-1 251 methyl im id azolIid in-4-o ne 11 0 3-[2-(4-methoxyphenyl)ethyl]-1 0-- methyl-2-(4 252 0 -nitrophenyl)imidazolidin-4-one 9 2-(l1 H-indol-5-yI)-3-[2-(4 methoxyphenyl)ethyl]-1 253 H methylimidazolidin-4-one 13 0 00 / 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(3-pyridin-3 254 vlpropanoyl)imidazolidin-4-one 61 0y_ N 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(pyridin-3 255, ylmethyl)imidazolidin-4-one 25 -154 - WO 2009/079624 PCT/US2008/087397 0 N 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-4-oxo-N 256 ipentylimidazolidine-1 -carboxamide 63 2-[4-(l1H-imidazol-1 -yI)phenyl]-3-[2 N ~(4-methoxyphenyl)ethyl]-1 257 methylimidazolidin-4-one 8 (2R, 5S)-2-(4-tert-butylphenyl)-5-2 N [ethyl(phenyl)amino]ethyl}-1 -methyl (trifluoromethoxy)phenyl]ethyllimida 258 zolidin-4-one 3 0 N N 1 -cyclopropyl-2-( 1 H-indol-5-yI)-3-[2 (4 NH methoxyphenyl)ethyl]imidazolidin-4 259 NHone 18 F 0 F - Nylv r 0 N-{2-[(2R,4S)-2-(4-tert-butylphenyl) 3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimida zolidin-4-yI]ethyl}-2 260 methylalaninamide 7 F (2R, 5S)-2-(4-tert-butylphenyl)-5-[2 N (diethylamino)ethyl]-1 -methyl-3-{2 [4 (trifluoromethoxy)phenyl]ethyllimida 261 zolidin-4-one 9 N~ 1-benzyl-3-[2-(4 methoxyphenyl)ethyl]-2-pyrid in-2 262 ylimidazolidin-4-one 13 -155 - WO 2009/079624 PCT/US2008/087397 0 - 0 2-[3-(diethylamino)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-1 263 methylimidazolidin-4-one 58 0 / -N N 3-[2-(4-methoxyphenyl)ethyl]-1 U/N methyl-2-pyridin-2-ylimidazolidin-4 264 one 11 0 N-\ C N-1 2-(4-tert-butyl phenyl)-3-[2-(4 hydroxyphenyl)ethyl]-1 265 methylimidazolidin-4-one 6 0 N 2-(2,6-dimethylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 266 methylimidazolidin-4-one 11 0 / N N N 2-(2-aminopyridin-3-yI)-3-[2-(4 N methoxyphenyl)ethyl]-1 267, methylimidazolidin-4-one 6 0 N _H 2-(4-tert-butyl phenyl)-3-[2-(4 0 N\--N methoxyphenyl)ethyl]-4-oxo-N pyrimidin-4-ylimidazolidine-1 268 carboxamide 0 0/ ( ,N /N 2-(4-tert-butyl phenyl)-3-{2-[4 (dimethylamino)phenyl]ethyl}-1 269 methylimidazolidin-4-one 9 - 156 - WO 2009/079624 PCT/US2008/087397 2-[4-(4-ethylpiperazin-1 -yI)phenyl] 3-[2-(4-methoxyphenyl)ethyl]-1 270 methylimidazolidin-4-one 8 0 0- N 2-(3,4-dimethylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 271 methylimidazolidin-4-one 94 0 F 2-[4-(diethylamino)-2 F 1 (trifluoromethyl)phenyl]-3-[2-(4 methoxyphenyl)ethyl]-1 272 methylimidazolidin-4-one 80 0 N 3-[2-(4-methoxyphenyl)ethyl]-1 methyl-2-(2 273 phenylethyl)imidazolidin-4-one 12 2-(4-cyclopropylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1, 5,5 274 trimethylimidazolidin-4-one 79 0 N 2-(4-cyclopropylphenyl)-3-[3-(4 <( fluorophenyl)propyl]-1 275 methylimidazolidin-4-one 24 0 N- 0 N\ HN4 1 -(2-{2-(4-tert-butyl phenyl )-3-[2-(4 _ /NH methoxyphenyl)ethyl]-4 x C/ oxoimidazolidin-1 -yIlethyl)-3 276 ethylurea 37 -157 - WO 2009/079624 PCT/US2008/087397 0 / -N 3-[2-(4-methoxyphenyl)ethyl]-1 277 /methyl-2-[2-(2-methyl-1 H-imidazol 27 1-yI)phenyllimidazolidin-4-one 19 0 N 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 1 -(pyri mid in-5-ylmethyl)i midazolid in 278 4-one 30 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-5, 5-dimethyl 1 -[(l1-methyl-1 H-imidazol-2 279 yI)methyllimidazolidin-4-one 47 2-(3,4-dimethylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1,5 280 dimethylimidazolidin-4-one 37 0 N N N ~ 2-(2-tert-butyl-1 -methyl-i H-imidazol T - 5-yI)-3-[2-(4-methoxyphenyl)ethyl] 281 1-methylimidazolidin-4-one 4 0 N 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 -(pyrazin-2 282 vlcarbonyl)imidazolidin-4-one 25 3-[2-(4-methoxyphenyl)ethyl]-1 0 methyl-2-[4-(pyridin-3 ylmethoxy)phenyl]imidazolidin-4 283 N ,one 3 - 158 - WO 2009/079624 PCT/US2008/087397 0 N N- N 2-(4-hyd roxyphenyl )-3-[2-(4 methoxyphenyl)ethyl]-1 284 methylimidazolidin-4-one 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-1 285 pentylimidazolidin-4-one 41 N 2-(4-tert-butyl pheny1)- 1 -m ethyl1-3-[2 (4-pi perid in-i 286 yl ph enylI)ethy11i m id azol id in-4-o ne 26 0 4-{3-[2-(4-methoxyphenyl)ethyl]-1 methyl-4-oxoimidazolidin-2 287 NyIlbenzonitrile 6 0 N N 0 ~2-(4-tert-butylphenyl)-1 ison icotinoyl-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 288 one 12 N H 0 2-(4-tert-butyl phenyl)-3-[2-(4 methoxyphenyl)ethyl]-N-methyl-4 289 oxoimidazolidine-1 -carboxamide 8 0 2-(4-tert-butylphenyl)-1 -methyl-3-(2 290 phenoxyethyl)imidazolidin-4-one 17 -159 - WO 2009/079624 PCT/US2008/087397 0 0 N N 2-(4-tert-butylphenyl)-1-methyl-3-[2 (4-morpholin-4 291 ylphenyl)ethyllimidazolidin-4-one 17 0 N N 2-(4-tert-butylphenyl)-3-[2-(4 methoxyphenyl)ethyl]-1-(3-pyridin-2 292 ylpropyl)imidazolidin-4-one 48 0 1-benzyl-2-[4 (dimethylamino)pheny]-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4 293 one 80 F 3-[(4S)-2-(4-tert-butylphenyl)-3 methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyl}imida zolidin-4-yl]-N 294 (phenylsulfonyl)propanamide 32 0 N N H 1-({(2R,4S)-2-(4-tert-butylphenyl)-1 [2-(4-methoxypheny)ethy]-3 methyl-5-oxoimidazolidin-4 295 yl}methyl)-3-ethylurea 56 3-[2-(4-methoxyphenyl)ethy]-1 methyl-2-[4-(2-piperidin-1 296 ylethoxy)phenyl]imidazolidin-4-one 1 Variations, modifications, and other implementations of what is described herein will occur to those skilled in the art without departing from the spirit and the essential characteristics of the present teachings. Accordingly, the scope of the present 5 teachings is to be defined not by the preceding illustrative description but instead by - 160- WO 2009/079624 PCT/US2008/087397 the following claims, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein. Each of the printed publications, including but not limited to patents, patent applications, books, technical papers, trade publications and journal articles 5 described or referenced in this specification are incorporated by reference herein in their entirety. - 161 -
Claims (126)
1. A compound having the Formula (I): 0 Ar 1 -(CR 5 R 6 )m N (CR 9 R 10 )-R 3 Ar 2 :x N R 4 Ri (CR 7 R 8 )n-R
2 (I) 5 or a pharmaceutically acceptable salt thereof, wherein: Ar is selected from C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1 5 R" groups; 10 Ar2 is selected from (CH 2 )z-C 6 -C 1 0 aryl, wherein z = 0 or 1 and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1-5 R 1 7 groups; R 1 is selected from H and C1-6 alkyl; R 2 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 15 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 18 , SR 18 , NR 28 R 29 , S0 2 R 30 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is - 162- WO 2009/079624 PCT/US2008/087397 optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 16 groups; R 3 is selected from H, C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms 5 selected from N, 0 and S, halogen, CN, OR 1 8 , SR 1 8 , NR 31 R 32 , S0 2 R 30 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 16 groups; 10 R 4 is selected from H and C1-6 alkyl; each R 5 and R 6 is independently selected from H, C1-6 alkyl, halogen and NHS02C1- 6 alkyl; or, any two R 5 and R , taken together with the carbon to which they are bound, form a carbonyl group; 15 each R 7 and R 8 is independently selected from H, C1-6 alkyl, and halogen; or, any two R 7 and R , taken together with the carbon to which they are bound, form a carbonyl group; each R 9 and R 1 0 is independently are selected from H, C1-6 alkyl, and halogen; or, any two R 9 and R 1 0 taken together with the carbon to which they are bound, form 20 a carbonyl group; each R" is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR, SR , NO 2 and NR 13 R 1 4 - 163- WO 2009/079624 PCT/US2008/087397 wherein the C1-6 alkyl, the C2-6 alkenyl, the C2-6 alkynyl, and the C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R 1 6 groups; each R 1 2 is independently selected from H, C1-6 alkyl, and C1-3 perhaloalkyl; 5 each R 1 3 and R 1 4 is independently selected from H and C1-6 alkyl; each R 1 5 is independently selected from halogen, CN, OH, C1-6 alkoxy, C1-3 perhaloalkoxy, SH, SC 1 - 6 alkyl, NH 2 , NH(C 1 - 6 alkyl), and N(C_ 6 alkyl) 2 ; each R 1 6 is independently selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OC1-6 alkyl, OC1-3 perhaloalkyl, SH, SC 1 - 6 alkyl, NH 2 , NH(C_ 6 alkyl), and N(C_ 6 10 alkyl) 2 ; each R 1 7 is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, NO 2 , C3 10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 1 8 , SR 1 8 , NR 1 9 R 2 0 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 15 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 22 groups; or, two R 17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, 0 and S, and 20 optionally substituted with 1-5 R 2 2 groups; each R 18 is independently selected from H, C1-6 alkyl, C1_3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl optionally is substituted with 1-4 R 23 groups; - 164- WO 2009/079624 PCT/US2008/087397 each R 1 9 and R 20 is independently selected from H, C1-6 alkyl, C(O)R 24 , C(O)OR 24 C(=NR 25 )NR 2 6 R 27 , C(O)NR 2 6 R 27 , and SO 2 R 24 ; each R 21 is independently selected from halogen, CN, OH, C16 alkoxy, SH, SC 1 - 6 alkyl, NH 2 , NH(C_ 6 alkyl), N(C 16 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 5 1-4 heteroatoms selected from N, 0 and S, a C6-C10 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, 0 and S; each R 22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, OH, OC1-6 alkyl, C1-3 perhaloalkoxy, SH, SC 1 - 6 alkyl, NH 2 , NH(C 1 - 6 alkyl), -CH 2 heteroaryl and N(C 16 alkyl) 2 ; 10 each R 2 3 is independently is selected from halogen, CN, OH, OC1-6 alkyl, NH 2 , NH(C 1 - 6 alkyl), N(C 16 alkyl) 2 , 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the cycloheteroalkyl, aryl , and heteroaryl each is optionally substituted with 1-4 groups selected from C1-6 15 alkyl, C1-3 perhaloalkyl, and halogen; R 24 is C1-6 alkyl optionally substituted with 1-4 groups selected from halogen, CN, OH, OC1-6 alkyl, OC1-3 perhaloalkyl, SH, SC 1 - 6 alkyl, NH 2 , NH(C_ 6 alkyl), and N(C_ 6 alkyl) 2 ; each R 25 , R 2 6 and R 27 is independently are selected from H and C16 alkyl; 20 each R 28 and R 2 9 is independently are selected from H, C16 alkyl optionally substituted with 1-4 R 3 e groups, C(O)R 30 , C(O)OR 30 , C(=NR 25 )NR 2 eR 27 , C(O)NR 2 eR 27 and SO 2 R 3 0 ; R 30 is selected from C16 alkyl, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted - 165- WO 2009/079624 PCT/US2008/087397 with 1-4 groups selected from C1_6 alkyl, halogen, CN, OH, OC1_6 alkyl, OC1-3 perhaloalkyl, SH, SC1_e alkyl, NH 2 , NH(C_ 6 alkyl), and N(C 16 alkyl) 2 ; each R 31 and R 32 is independently selected from H, C16 alkyl optionally substituted with 1-4 R 3 6 groups, C3-10 cycloalkyl, C(O)R 3
3 , C(O)OR 33 , C(=NR 25 )NR 2 6 R 27 , 5 C(O)NR 3
4 R 35 , S0 2 R 33 , 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S; R 33 is selected from C1-6 alkyl optionally substituted with 1-4 R 3 6 groups, C6-C10 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 10 1-4 heteroatoms selected from N, 0 and S and optionally substituted with 1-4 R 37 groups; R 34 and R 3 5 each independently is selected from H, C1-6 alkyl optionally substituted with 1-4 R 3 6 groups, C6-C10 aryl optionally substituted with 1-4 R 37 groups, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S and 15 optionally substituted with 1-4 R 37 groups; each R 3 6 is independently selected from halogen, CN, OH, C16 alkoxy, C1-3 perhaloalkoxy, SH, SC1_6 alkyl, NH 2 , NH(C_ 6 alkyl), N(C 16 alkyl) 2 , C6 or C10 aryl, and
5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S; each R 37 is independently selected from C16 alkyl, C1-3 perhaloalkyl, halogen, CN, 20 OH, C16 alkoxy, OC1-3 perhaloalkoxy, SH, SC1-6 alkyl, NH 2 , NH(C 1 - 6 alkyl), and N(C 16 alkyl) 2 ; m is 0, 1 2, 3, or 4; n isO, 1,2, 3,4,5 or6; and p is 0, 1, 2, 3, 4, 5 or 6. - 166- WO 2009/079624 PCT/US2008/087397 2. The compound of claim 1, wherein R 1 is H. 3. The compound of claim 1 or 2, wherein R 4 is H. 4. The compound of claim 1 or 2, wherein R 4 is C1-6 alkyl. 5. The compound of any one of claims 1 to 4, wherein m is 0 or 1. 5
6. The compound of any one of claims 1 to 4, wherein m is 2.
7. The compound of any one of claims 1 to 4, wherein m is 3.
8. The compound of any one of claims 1 to 7, wherein R 5 and R 6 , at each occurrence, are each methyl or H.
9. The compound of any one of claims 1 to 8, wherein R 5 and R 6 , at each 10 occurrence, are each H.
10. The compound of any one of claims 1 to 9, wherein Ar is a C6-C10 aryl ring or a 5-14 membered heteroaryl ring, each aryl or heteroaryl ring having at least one substituent selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH 2 , NH(C_ 6 alkyl), N(C 16 alkyl) 2 , NO 2 , C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC 1 - 6 alkyl,CN, and 3-10 15 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, wherein the C1-6 alkyl group optionally is substituted with R 1 5 and wherein the 3-10 membered cycloheteroalkyl is optionally substituted with R 16 . - 167- WO 2009/079624 PCT/US2008/087397
11. The compound of any one of claims 1 to 10, wherein Ar is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from C1-6 alkyl, halogen, C1-6 alkoxy, OH, NH 2 , NH(C 1 - 6 alkyl), N(C_ 6 alkyl) 2 , NO 2 , C1-3 haloalkyl, C1-3 haloalkoxy, SH, SC1_ 6 alkyl, CN, and 3-10 membered cycloheteroalkyl containing 1 to 5 4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl group optionally is substituted with R 1 5 and wherein the 3-10 membered cycloheteroalkyl optionally is substituted with R 1 6 .
12. The compound of claim 11, wherein Ar is phenyl optionally substituted with 1, 2 or 3 substituents independently selected from methyl, ethyl, propyl, iso-propyl, butyl, 10 tert-butyl, F, Cl, OH, OCH 3 , OCF 3 , SCH 3 , CH 2 N(CH 3 ) 2 , and pyrrolidinyl, piperidinyl, piperazinyl, N-methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
13. The compound of any one of claims 1 to 12, wherein Ar is para-substituted phenyl.
14. The compound of any one of claims 1 to 13, wherein Ar 1 is 4-methoxyphenyl.
15 15. The compound of any one of claims 1 to 9, wherein Ar is selected from pyridinyl and pyrimidinyl, each optionally substituted with 1-5 R groups.
16. The compound of any one of claims 1 to 15, wherein Ar 2 is phenyl substituted with 1, 2, or 3 substituents independently selected from halogen, C1-6 alkyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl ring containing 1 to 4 20 heteroatoms selected from N, 0 and S, and 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl and the C3-10 cycloalkyl are each optionally substituted with 1-5 R 21 groups, and wherein the cycloheteroalkyl and heteroaryl each optionally is substituted with 1-5 R 22 groups.
17. The compound of claim 16, wherein Ar 2 is phenyl substituted with C1-6 alkyl or 25 C3-10 cycloalkyl. - 168- WO 2009/079624 PCT/US2008/087397
18. The compound of claim 17, wherein Ar 2 is 4-(tert-butyl)phenyl or 4 cyclopropylphenyl.
19. The compound of claim 16, wherein Ar 2 is phenyl substituted with 1, 2 or 3 substitutents independently selected from F, Cl, methyl, ethyl, propyl, iso-propyl, 5 butyl, tert-butyl, cyclopropyl, trifluoromethyl, pyrrolidinyl, piperidinyl, piperazinyl N methylpiperazinyl, N-ethylpiperazinyl, morpholinyl, pyridinyl, imidazolyl and 2 methylimidazolyl.
20. The compound of any one of claims 1 to 15, wherein Ar 2 is phenyl substituted with 1, 2, or 3 OR 18 groups. 10
21. The compound of claim 20, wherein R 18 is selected from H, C1-6 alkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl optionally is substituted with 1-4 R 23 groups. 15
22. The compound of claim 21, wherein R 18 is C1-6 alkyl.
23. The compound of claim 21, wherein R 1 8 is C1-6 alkyl substituted with 1-4 groups selected from halogen, 3-10 membered cycloheteroalkyl containing 1-4 heteroatoms selected from N, 0 and S, a C6-C10 aryl ring, and a 5-10 membered heteroaryl ring containing 1-4 heteroatoms selected from N, 0 and S. 20
24. The compound of claim 23, wherein R 1 8 is C1-6 alkyl substituted with 1-2 groups selected from F, phenyl, pyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, N methylpiperazinyl, N-ethylpiperazinyl, and morpholinyl.
25. The compound of any one of claims 1 to 15, wherein Ar2 is phenyl substituted with 1, 2, or 3 NR 1 9 R 20 groups. - 169- WO 2009/079624 PCT/US2008/087397
26. The compound of claim 25, wherein R 1 9 and R 20 are selected from H, C1-6 alkyl, C(=NR )NR 2 eR 27 , and S0 2 R.
27. The compound according to claim 26, wherein R 1 9 and R 20 are each independently C1-6 alkyl. 5
28. The compound of claim 25, wherein Ar 2 is phenyl substituted with NH 2 , N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , NHSO 2 CH 3 , N(SO 2 CH 3 ) 2 , and NH(C=NH)NH 2 .
29. The compound according to any one of claims 1 to 15, wherein Ar 2 is phenyl substituted with two R 1 7 groups, wherein the two R 1 7 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring selected from 10 pyrrolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl, pyrrolidinyl, piperidinyl, piperazinyl and morpholinyl, each optionally substituted with 1-5 R 22 groups.
30. The compound according to claim 29, wherein Ar2 is benzo[d][1,3]dioxolyl, 2,2-difluorobenzo[d][1,3]dioxolyl, indolinyl, N-methylindolinyl, 2,3 dihydrobenzo[b][1,4]dioxinyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, N-methyl-3,4 15 dihydro-2H-benzo[b][1,4]oxazinyl, 1,2,3,4-tetrahydroquinolinyl, and N-methyl-1,2,3,4 tetrahydroquinolinyl.
31. The compound of any one of claims 1 to 30, wherein Ar 2 is para-substituted phenyl.
32. The compound of any one of claims 1 to 15, wherien Ar 2 is 5-10 membered 20 heteroaryl optionally substituted with 1-5 R 1 7 groups.
33. The compound of claim 32, wherein Ar 2 is selected from furanyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl, and quinolinyl, each optionally substituted with 1-5 R17 groups. - 170 - WO 2009/079624 PCT/US2008/087397
34. The compound of any of claims 1 to 33, wherein R 2 is selected from H, CN, C1-6 alkyl optionally substituted with 1-5 R 1 5 groups, and C2-6 alkenyl optionally substituted with 1-5 R 1 5 groups.
35. The compound of any of claims 1 to 33, wherein R 2 is C6-C10 aryl optionally 5 substituted with 1-5 R 16 groups.
36. The compound of claim 35, wherein R 2 is phenyl optionally substituted with 1 5 R 1 6 groups.
37. The compound of any of claims 1 to 33, wherein R 2 is OR 18 .
38. The compound of claim 37, wherein R 1 8 is phenyl optionally substituted with 10 1-4 R 23 groups.
39. The compound of claim 37, wherein R 1 8 is 5-10 membered heteroaryl optionally substituted with 1-4 R 2 3 groups.
40. The compound of any of claims 1 to 33, wherein R 2 is S0 2 R 30
41. The compound of claim 40, wherein R 30 is optionally substituted C1-C6 alkyl, 15 or optionally substituted 6-10 membered aryl.
42. The compound of any of claims 1 to 33, wherein R 2 is 5-10 membered heteroaryl optionally substituted with 1-5 R 1 6 groups.
43. The compound of claim 42, wherein R 2 is pyridinyl, pyrimidinyl, imidazolyl or pyrazolyl, each of which is optionally substituted with 1-5 R 1 6 groups. 20
44. The compound of any of claims 1 to 33, wherein R 2 is C3-10 cycloalkyl, optionally substituted with 1-5 R 1 5 groups. - 171 - WO 2009/079624 PCT/US2008/087397
45. The compound of claim 44, wherein R 2 is C3-6 cycloalkyl, optionally substituted with 1-5 R 1 5 groups.
46. The compound of any of claims 1 to 33, wherein R 2 is 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, optionally 5 substituted with 1-5 R 1 6 groups.
47. The compound of claim 46, wherein R 2 is piperidinyl optionally substituted with 1-3 R 1 5 groups.
48. The compound of any of claims 1 to 33, wherein R 2 is NR 2 8 R 2 .
49. The compound of claim 48, wherein R 28 is H, and R 2 9 is C(O)R 30 10
50. The compound of claim 49, wherein R 30 is optionally substituted 5-10 membered heteroaryl.
51. The compound of claim 50, wherein R 30 is pyridinyl, imidaziolyl, pyrimidinyl or pyrazinyl, each of which is optionally substituted.
52. The compound of claim 48, wherein R 28 is H, and R 2 9 is C(O)OR 30 15
53. The compound of claim 52, wherein R 3 0 is C1-C6 alkyl.
54. The compound of claim 48, wherein R 28 and R 2 9 are each independently H or C1-C6 alkyl.
55. The compound of claim 48, wherein R 28 is H, and R 2 9 is C(O)NR 2 R.
56. The compound of claim 48, wherein R 28 and R 2 9 are each independently H or 20 C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 5-10 membered - 172 - WO 2009/079624 PCT/US2008/087397 heteroaryl or 6-10 membered aryl, wherein the 6-10 membered aryl and the 5-10 membered heteroaryl are each optionally and independently substituted with 1-5 R 1 6 groups.
57. The compound of any one of claims 1 to 56, wherein n is 0. 5
58. The compound of any one of claims 1 to 56, wherein n is 1.
59. The compound of any one of claims 1 to 56, wherein n is 2.
60. The compound of any one of claims 1 to 56, wherein n is 3.
61. The compound of any one of claims 1 to 56, wherein n is 4.
62. The compound of any one of claims 58 to 61, wherein R 7 and R 8 , at each 10 occurrence, are each H.
63. The compound of any one of claims 58 to 61, wherein one R 7 and R , taken together with the carbon to which they are bound, form a carbonyl.
64. The compound of any one of claims 1 to 63, wherein p is 0.
65. The compound of claim 64, wherein R 3 is H or C1-6 alkyl. 15
66. The compound of claim 65, wherein R 3 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl.
67. The compound of claim 65, wherein R 4 is H.
68. The compound of claim 64, wherein R 3 and R 4 are each H. - 173 - WO 2009/079624 PCT/US2008/087397
69. The compound of claim 64, wherein R 3 and R 4 are each C1-6 alkyl.
70. The compound of any one of claims 1 to 64, wherein R 3 is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each optionally substituted with 1-5 R 1 6 groups. 5
71. The compound of claim 70, wherein R 3 is phenyl.
72. The compound of claim 70, wherein R 3 is selected from pyrrolyl, imidazolyl, pyridinyl, and pyrimidinyl.
73. The compound of any one of claims 1 to 64, wherein R 3 is NR 31 R 3 2
74. The compound of claim 73, wherein one of R 31 and R 3 2 is H and the other is 10 S0 2 R 33
75. The compound of claim 74, wherein R 33 is C1-6 alkyl optionally substituted with 1-4 R 34 groups.
76. The compound of claim 75, wherein R 33 is C1-6 alkyl optionally substituted with C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected 15 from N, O and S.
77. The compound of claim 76, wherein R 33 is benzyl or CH 2 -pyridinyl.
78. The compound of claim 73, wherein one of R 31 and R 3 2 is H and the other is C(O)NR 34 R 3 5
79. The compound of claim 78, wherein R 3 4 and R 3 5 are each H. 20
80. The compound of claim 78, wherein R 34 and R 3 5 are each C16 alkyl. -174 - WO 2009/079624 PCT/US2008/087397
81. The compound of claim 78, wherein one of R 3 4 and R 3 5 is H and the other is C1_6 alkyl.
82. The compound of claim 78, wherein one of R 3 4 and R 3 5 is H and the other is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from 5 N, O and S.
83. The compound of claim 82, wherein one of R 3 4 and R 3 5 is H and the other is selected from phenyl, pyridinyl and pyrimidinyl.
84. The compound of claim 78, wherein one of R 3 4 and R 3 5 is C1-6 alkyl and the other is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms 10 selected from N, 0 and S.
85. The compound of claim 84, wherein one of R 34 and R 3 5 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl, and the other is selected from phenyl, pyridinyl and pyrimidinyl.
86. The compound of claim 73, wherein one of R 31 and R 3 2 is H and the other is 15 C(O)OR 33
87. The compound of claim 86, wherein R 33 is C1-6 alkyl optionally substituted with 1-4 R 3 6 groups.
88. The compound of claim 87, wherein R 33 is selected from methyl, ethyl, propyl, isopropyl, butyl and tert-butyl. 20
89. The compound of claim 87, wherein R 3 3 is C1-6 alkyl substituted with NH 2 , NH(C 1 - 6 alkyl), or N(C 16 alkyl) 2 . -175 - WO 2009/079624 PCT/US2008/087397
90. The compound of claim 87, wherein R 33 is C1_6 alkyl substituted with C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S.
91. The compound of claim 90, wherein R 3 3 is benzyl. 5
92. The compound of claim 73, wherein one of R 31 and R 3 2 is H and the other is C6 or C10 aryl, or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S.
93. The compound of claim 92, wherein one of R 31 and R 3 2 is H and the other is selected from phenyl, pyridinyl and pyrimidinyl. 10
94. The compound of claim 73, wherein each of R 3 1 and R 32 is H.
95. The compound of claim 73, wherein each of R 31 and R 32 independently is C1-6 alkyl optionally substituted with 1-4 R 36 groups.
96. The compound of claim 95, wherein each of R 31 and R 32 independently is selected from methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, benzyl and CH 2 15 pyridinyl.
97. The compound of claim 95, wherein each of R 31 and R 32 independently is selected from benzyl and CH 2 -pyridinyl.
98. The compound of any one of claims 1 to 64, wherein R 3 is OR 18 .
99. The compound of claim 98, wherein R 1 8 is H. 20
100. The compound of claim 98, wherein R 1 8 is C1-6 alkyl optionally is substituted with 1-4 R23 groups. - 176 - WO 2009/079624 PCT/US2008/087397
101. The compound of claim 100, wherein R 1 8 is benzyl or CH 2 -pyridinyl.
102. The compound of any one of claims 1 to 64, wherein R 3 is C6-C10 aryl or 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each optionally substituted with 1-5 R 1 6 groups. 5
103. The compound of claim 102, wherein R 3 is selected from phenyl, pyrrolyl, imidazolyl, pyridinyl, pyrimidinyl, indolyl and quinolinyl.
104. The compound of any one of claims 70 to 103, wherein p is 1.
105. The compound of any one of claims 70 to 103, wherein p is 2.
106. The compound of any one of claims 70 to 103, wherein p is 3. 10
107. The compound of any one of claims 70 to 103, wherein p is 4.
108. The compound of any one of claims 104 to 107, wherein each of R 9 and R 10 , at each occurrence, is H.
109. The compound of any one of claims 104 to 107, wherein one of R 9 and R 10 , taken together with the carbon to which they are bound, form a carbonyl group. 15
110. The compound of claim 1, having the Formula (II): 0 Ar 1 -(CR 5 R 6 )m N (CR 9 R 10 )p-R 3 Ar2 N R N R 4 (CR 7 R 8 )n-R 2 -177 - WO 2009/079624 PCT/US2008/087397 (II) or a pharmaceutically acceptable salt thereof, wherein m is 1, 2 or 3 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R', R 8 , R 9 , R 1 0 , n, and p are defined as in claim 1. 5
111. The compound of claim 110, wherein m is 1 and R 5 and R 6 are each H.
112. The compound of claim 110, wherein m is 1 and one of R 5 and R 6 is H and the other is C1-6 alkyl.
113. The compound of claim 110, wherein m is 1 and R 5 and R 6 , at each occurrence, are each H. 10
114. The compound of any one of claims 110 to 113, wherein Ar is para substituted phenyl.
115. The compound of claim 114, wherein Ar is 4-methoxyphenyl.
116. The compound of claim 1, having the formula (Ill): 0 Ar 1 -(CR 5 R 6 )m N (CR 9 R 10 )p-R 3 Ar 2 N 4 R N (CR 7 R 8 )n-R 2 0 15 (III) - 178 - WO 2009/079624 PCT/US2008/087397 or a pharmaceutically acceptable salt thereof, wherein n is 0, 1, 2, 3, 4 or 5 and Ar 1 , Ar 2 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R', R 8 , R 9 , R 1 0 , m, and p are defined as in claim 1. 5
117. A compound of claim 1 that is 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4-one; 2-(4-tert-butylphenyl)-3-[2-(3-methoxyphenyl)ethyl]-1-methylimidazolidin-4-one;; 2-(3,4-dichlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4-one; 2-(4-tert-butylphenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4-one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(trifluoromethyl)phenyl]imidazolidin-4-one; 2-(3-chlorophenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one; 2-(3,4-dichlorophenyl)-1-ethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one; 2-(3,4-dimethylphenyl)-1-methyl-3-(3-phenylpropyl)imidazolidin-4-one; 2-(4-tert-butylphenyl)-1 -methyl-3-(3-phenylpropyl)imidazolidin-4-one; 2-(4-tert-butylphenyl)-3-(4-methoxybenzyl)-1-methylimidazolidin-4-one; -179 - WO 2009/079624 PCT/US2008/087397 2-(4-tert-butylphenyl)-1 -methyl-3-(2-phenylethyl)imidazolidin-4-oneI 1 -ethyl-3-(2-phenylethyl)-2-[4-(trifluoromethyl)phenyl]imidazolidin-4-oneI 1 -ethyl-3-(2-phenylethyl)-2-[3-(trifluoromethyl)phenyl]imidazolidin-4-oneI 1 -ethyl-2-(4-ethylphenyl)-3-(2-phenylethyl)imidazolidin-4-one;I (2R)-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI (2S)-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-(3,4-dichlorophenyl)-1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyl}-2-[4-(trifluoromethyl)phenyl]imidazolidin-4 one" 2-(4-tert-butylphenyl)-1 -methyl-3-(2-phenylpropyl)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-fluorophenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-isopropylphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -methyl-3-{2-[4-(trifluoromethyl)phenyl]ethyllimidazolidin-4-oneI 3-[2-(3,4-difluorophenyl)ethyl]-2-(3,4-dimethylphenyl)-1 -methylimidazolidin-4-one;I 2-(3,4-dichlorophenyl)-3-[2-(3,4-difluorophenyl)ethyl]-1 -methylimidazolidin-4-one;I - 180 - WO 2009/079624 PCT/US2008/087397 2-(4-tert-butylphenyl)-1 -ethyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-(4-cyclopropylphenyl)-1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 3-{2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph enyl)ethyl ]-4-oxo im idazol id in- 1 -yI11pro pane nitrilIe 1 -aIly-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -(3-hydroxypropyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -(2-hydroxyethyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(3,4-dimethylphenyl)-1 -methyl-3-{2-[4-(trifluoromethyl)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-2-(4-tert-butylphenyl)-5-isopropyl-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin 4-one;I (2S, 5S)-2-(4-tert-butylphenyl)-5-isopropyl-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin 4-one;I 1 -benzyl-2-[4-(dimethylamino)phenyl]-3-(2-phenylethyl)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-quinolin-2-ylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,5-dimethylimidazolidin-4-oneI (2R, 5S)-5-iso butyl-2-(4-iso propyIph enyl)-3-[2-(4-methoxyph enyl)ethy]- 1 -m ethyl imid azolIid in-4 one" (2S, 5S)-2-[4-(dimethylamino)phenyl]-5-isobutyl-3-[2-(4-methoxypheny)ethyl]- methylimidazolidin-4-one;I - 181 - WO 2009/079624 PCT/US2008/087397 (2R, 5S)-2-(4-ethylphenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI (2R, 5S)-5-benzyl-2-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I (2R, 5S)-5-benzyl-2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" (2R, 5S)-2-(4-chlorophenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4 one" (2S,5S)-2-(4-chlorophenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one; (2S,5S)-2-(4-ethylphenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I (2S,5S)-2-(4-tert-butylphenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" 2-[4-(diethylamino)phenyl]-1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-[4-(dimethylamino)phenyl]-1 -methyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin-4 one; 2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-{4-[isopropyl(methyl)amino]phenyl}-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one; 2-[4-(diethylamino)benzyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-[4-(dimethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI - 182 - WO 2009/079624 PCT/US2008/087397 2-[4-(diethylamino)-3-fluorophenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-[3-chloro-4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI 2-[4-(diethylamino)-3, 5-difluorophenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" 2-[2-chloro-4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI (2R)-2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI (2S)-2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-one;I (2S,5S)-5-isobutyl-2-(4-isopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-piperazin-1 -ylphenyl)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[4-(pyridin-4-ylmethoxy)phenyl]imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[4-(3-methylbutoxy)phenyl]imidazolidin-4-oneI (2R, 5S)-5-benzyl-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" (2R, 5S)-2-(4-tert-butylphenyl)-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4 one" tert-butyl (2-{(4S)-2-[4-(d im ethyl am in o)pheny]- 1 -[2-(4-meth oxy ph enyI)ethyl ]-3-methyl-5 oxoimidazolidin-4-yIlethyl)carbamate (2R, 5S)-2-[4-(dimethylamino)phenyl]-5-isobutyl-3-[2-(4-methoxyphenyl)ethyl]- - 183 - WO 2009/079624 PCT/US2008/087397 methylimidazolidin-4-one;I (2S, 5S)-5-benzyl-2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one" 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-( 1-methyl-i 2, 3,4-tetrahydroquinolin-6 yI)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-quinolin-4-ylimidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-( 1 H-pyrrol-2-yI)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-( 1-methyl-i H-pyrrol-2-yI)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-methyl-3,4-dihydro-2H-1 ,4-benzoxazin-7 yI)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -(4-methoxybenzyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-chlorophenyl)-1 -(4-methoxybenzyl)-3-(2-phenylethyl)imidazolidin-4-oneI 2-( 1, 3-benzodioxol-5-y)-1 -benzyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -benzyl-3-[2-(4-methoxyphenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]imidazolidin-4-oneI 1 -benzyl-2-(3,4-dichlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -benzyl-2-(3-chlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -benzyl-2-(4-isopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI - 184 - WO 2009/079624 PCT/US2008/087397 1 -benzyl-2-(4-ethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one;I 1 -benzyl-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -benzyl-2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -benzyl-2-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -[2-(benzyloxy)ethyl]-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 1 -[3-(be nzy loxy) pro pyl ]-2-(4-tert-butyl ph enylI)-3-[2-(4-m eth oxyph eny)ethy]i midazol id in-4-o ne 2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph eny)ethy1-1 -[3-(py rid in-2 ylmethoxy)propyl]imidazolidin-4-one;I 2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph eny)ethy1-1 -[3-(py rid in-3 ylmethoxy)propyl]imidazolidin-4-oneI N-(3-{2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidin-1 yIlpropyl)nicotinamide 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(methylsulfonyl)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -[(3-fluorophenyl)sulfonyl]-3-[2-(4-methoxyphenyl)ethy]imidazolidin-4 one" 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -[(4-methylphenyl)sulfony]imidazolidin-4 one" 2-(4-tert-butylphenyl)-1 -(ethylsulfonyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -[(4-ethylphenyl)sulfonyl]-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4 - 185 - WO 2009/079624 PCT/US2008/087397 one" 3-[(4S)-2-(4-tert-butylphenyl )-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-pyridin-3-ylpropanamide 3-[2-(4-methoxypheny)ethy]-1 -methyl-2-[4-(2-piperidin-1 -ylethoxy)phenyl]imidazolidin-4-oneI 2-[(2R,4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-pyridin-3-ylacetamide 2-[(2S,4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-pyridin-2-ylacetamide 2-[(2R, 4S)-2-(4-tert-butyl phenyl )-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-(pyridin-2-ylmethyl)acetamide 2-[(2R,4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-(pyridin-3-ylmethyl)acetamide benzyl {2-[(4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]ethyllcarbamate N-{2-[(4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (triflu orom ethoxy) ph enyl ]ethylim idazol id in-4-y I]ethyllpyrid ine-2-carboxa mid e N-{2-[(4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]ethyllnicotinamide (5S)-2-(4-tert-butylphenyl)-1 -methyl-5-[2-(pyrimidin-2-ylamino)ethyl]-3-2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-2-(4-tert-butylphenyl)-5-(2-hydroxyethyl)-1 -methyl-3-{2-[4 - 186 - WO 2009/079624 PCT/US2008/087397 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-5-{2-[benzyl(methyl)amino]ethyl}-2-(4-tert-butylphenyl)-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-2-[4-(diethylamino)phenyl]-1 -methyl-5-[2-(pyridin-2-ylmethoxy)ethyl]-3-2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-5-[(benzyloxy)methyl]-2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- methylimidazolidin-4-one;I (2S, 5S)-5-[(benzyloxy)methyl]-2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- methylimidazolidin-4-one;I N-({(2S,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)methanesulfonamide N-({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)propane-1 -sulfonamide N-({(2S,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)propane-1 -sulfonamide N-({(2S,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)butane-1 -sulfonamide N-({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)-1-pyridin-3-ylmethanesulfonamide 1 -({(2S,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)-3-ethylurea - 187 - WO 2009/079624 PCT/US2008/087397 1 -({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)-3-pyrimidin-4-ylurea 1 -({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)u rea 1 -({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlm ethylI)-3-m ethyl urea 1 -({(2S,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlm ethylI)-3-m ethyl urea 1 -(1(2S, 4S)-2-(4-cyclo pro pylIph enyl)- 1 -[2-(4-meth oxy ph enyI)ethyI]-3-m ethy1-5-oxoi mid azoid in 4-yIlmethyl)-3-methylurea 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 '5, 5-trimethylimidazolidin-4-oneI 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethylimidazolidin-4-one;I 1 -benzyl-2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -ethyl-3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethylimidazolidin-4-oneI 2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 '5, 5-trimethylimidazolidin-4-oneI 2-[4-(dimethylamino)phenyl]-1,5, 5-trimethyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-[4-(diethylamino)phenyl]-1,5, 5-trimethyl-3-{2-[4-(trifluoromethoxy)phenyl]ethyllimidazolidin 4-one;I - 188 - WO 2009/079624 PCT/US2008/087397 2-[2-(diethylamino)pyrimidin-5-yI]-3-[2-(4-methoxyphenyl)ethyl]-1 ,5,5-trimethylimidazolidin-4 one" 2-[4-(dimethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1,5, 5-trimethylimidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 '5, 5-trimethyl-2-(4-piperidin-1 -ylphenyl)imidazolidin-4-one;I 2-{4-[isopropyl(methyl)amino]phenyl}-3-[2-(4-methoxyphenyl)ethyl]-1 '5, 5-trimethylimidazolidin 4-one;I 2-(4-tert-butylphenyl)-5, 5-diethyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-5, 5-diethyl-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 ,5,5-trimethyl-2-(4-pyrrolidin-1 -ylphenyl)imidazolidin-4-oneI 2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph eny)ethy]-5,5-d imethyl- 1 -( py rid in-3 ylmethyl)imidazolidin-4-one 3-[2-(4-methoxyphenyl)ethyl]-2, 5, 5-trimethyl-2-(4-methylphenyl)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1,2,5, 5-tetramethyl-2-(4-methylphenyl)imidazolidin-4-oneI 2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,2,5, 5-tetramethylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-1 -(3-cyclohexylpropanoyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4 one; 3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethyl-2-(4-pyrrolidin-1 -ylphenyl)imidazolidin-4-oneI 2-(3,4-dichlorophenyl)-1 -methyl-3-{2-[4-(trifluoromethyl)phenyl]ethyllimidazolidin-4-oneI - 189 - WO 2009/079624 PCT/US2008/087397 N-({(2R,4S)-2-(4-tert-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yl}methyl)methanesulfonamide 2-(1-ethyl-1 H-indol-5-yl)-3-[2-(4-methoxyphenyl)ethyl]-1,5,5-trimethylimidazolidin-4-one; 2-{4-[2-(dimethylamino)ethoxy]phenyl}-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4 one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(pyridin-2-ylmethoxy)phenyl]imidazolidin-4-one; N-(4-{3-[2-(4-methoxyphenyl)ethyl]-1-methyl-4-oxoimidazolidin-2 yl}phenyl)methanesulfonamide 2-(2,2-difluoro-1,3-benzodioxol-5-yl)-3-[2-(4-methoxyphenyl)ethyl]-1,5,5-trimethylimidazolidin 4-one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(2-pyrrolidin-1-ylethoxy)phenyl]imidazolidin-4-one; 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(3-pyridin-3-ylpropanoyl)imidazolidin 4-one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-(2-phenyl-1 H-imidazol-5-yl)imidazolidin-4-one; N-(2-{2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidin-1 yl}ethyl)ethanesulfonamide 2-(4-tert-butylphenyl)-1-butyryl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(2-morpholin-4-ylethoxy)phenyl]imidazolidin-4 one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(3-phenylpropyl)imidazolidin-4-one; - 190 - WO 2009/079624 PCT/US2008/087397 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[4-(piperidin-4-yloxy)phenyl]imidazolidin-4-oneI (5S)-5-(2-aminoethyl)-2-(4-tert-butylphenyl)-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -isopropyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[3-(4-fluorophenyl)propyl]-1 -methylimidazolidin-4-one;I 2-{4-[ethyl(isopropyl)amino]phenyl}-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-oneI 3-[(4S)-2-(4-tert-butylphenyl )-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]propanoic acid N-(4-{3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxoimidazolidin-2-yIlphenyl)-N (methylsulfonyl)methanesulfonamide 2-(4-tert-butylphenyl)-1 -methyl-3-{2-[2-(methylth io)pyri mid in-5-yI]ethylli midazol id in-4-oneI 2-(2,4-dimethoxypyrimidin-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(pyridin-3-ylacetyl)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -hexanoyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[1 -(pyridin-4-ylmethyl)-1 H-indol-5-yI]imidazolidin-4 one" 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(pyridin-4-ylacetyl)imidazolidin-4-oneI 2-[2-(diethylamino)pyrimidin-5-yI]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I - 191 - WO 2009/079624 PCT/US2008/087397 tert-butyl (3-{2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidin-1 yIlpropyl)carbamate 2-(2-tert-butyl-1 H-imidazol-4-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-cyclopropylphenyl)-1 -methyl-3-(3-phenylpropyl)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -[3-(diisopropylamino)propyl]-3-[2-(4-methoxyphenyl)ethyl]imidazolidin 4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[1 -(pyridin-2-ylmethyl)-1 H-indol-5-yI]imidazolidin-4 one" 2-(2-tert-butylpyri mid in-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-, '5, 5-tri methyl imidazol id in-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[1 -(pyridin-3-ylmethyl)-1 H-indol-5-yI]imidazolidin-4 one; (2R, 5S)-5-12-[ be nzyI( py rid in-3-yl methylI)a m ino]ethyl}1-2-(4-tert-butyl ph enyl)- 1 -m ethyl1-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-quinolin-3-ylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -(cyclohexylacetyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI N-({(2R,4S)-2-(4-tert-butylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yIlmethyl)butane-1 -sulfonamide 1 -({(2S,4S)-2-(4-cyclopropylphenyl)-1 -[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin 4-yIlmethyl)urea 3-[(4S)-2-(4-tert-butylphenyl )-3-methyl-5-oxo-1 -12-[4 - 192 - WO 2009/079624 PCT/US2008/087397 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-pyridin-2-ylpropanamide 2-(l1 H-imidazol-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(6-tert-butylIpy rid in-3-y I)-3-[2-(4-meth oxyph enyl)ethyl ]- 1 -m ethyIi m idazolIid in-4-o n e; 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-pyridin-3-ylimidazolidin-4-oneI 2-(2-furyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(3-piperidin-1 -ylpropanoyl)imidazolidin 4-one;I 2-(4-isobutylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I (5S)-2-(4-tert-butylphenyl)-1 -methyl-5-[2-(pyridin-2-ylamino)ethyl]-3-2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-( 1-methyl-i H-imidazol-2-yI)imidazolidin-4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-morpholin-4-ylphenyl)imidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-[4-(4-methylpiperazin-1 -yI)phenyl]imidazolidin-4-oneI 3-[(4S)-2-(4-tert-butylphenyl )-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-[2-(dimethylamino)ethyl]propanamide 2-[(2R, 4S)-2-(4-tert-butyl phenyl )-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]-N-pyridin-2-ylacetamide 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(3-pyrimidin-2-ylpropanoyl)imidazolidin -193 - WO 2009/079624 PCT/US2008/087397 4-one;I 1 -(3-{3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-4-oxoimidazolidin-2-yIlphenyl)guanidine 2-(4-cyclopropylphenyl)-1 -methyl-3-(2-phenoxyethyl)imidazolidin-4-oneI 2-(4-ethyl-3,4-dihydro-2H-1 ,4-benzoxazin-7-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 methylimidazolidin-4-one;I N-{2-[2-(4-tert-butylphenyl)-3-methyl-5-oxoimidazolidin-1 -yI]-l phenylethyllmethanesulfonamide 2-(4-tert-butylphenyl)-3-[2-(6-methoxypyridin-3-y)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-fluorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-aminophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-pyridin-3-ylphenyl)imidazolidin-4-oneI 1 -13-[ benzyl (py rid in-2-yl methyl)a min o]propyl}1-2-(4-tert-butylIphe ny1)-3-[2-(4 methoxyphenyl)ethyl]imidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -methyl-3-[2-(4-pyrrolidin-1 -ylphenyl)ethyl]imidazolidin-4-oneI 2-[4-(diisopropylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4-one;I 2-[4-(diethylamino)-3-methoxyphenyl]-3-[2-(4-methoxyphenyl)ethyl]- -methylimidazolidin-4 one" N-(2-{2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidin-1 -194 - WO 2009/079624 PCT/US2008/087397 yl}ethyl)methanesulfonamide 3-[2-(4-methoxyphenyl)ethyl]-1,5-dimethyl-2-(4-methylphenyl)imidazolidin-4-one; 1-{2-[(4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyl}imidazolidin-4-yl]ethyl}-3-pyridin-3-ylurea 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(2-pyridin-2-ylethyl)imidazolidin-4-one; 2-[4-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-5,5-dimethylimidazolidin-4-one; 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-pyridin-2-ylphenyl)imidazolidin-4-one; 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-pyridin-4-ylphenyl)imidazolidin-4-one; 2-(4-tert-butylphenyl)-1 -(3-cyclohexylpropanoyl)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4 one; 2-(1-ethyl- 1,2,3,4-tetrahydroquinolin-6-yl)-3-[2-(4-methoxyphenyl)ethy]-1 -methylimidazolidin 4-one; 1 -benzyl-3-[2-(4-methoxyphenyl)ethyl]-2-(1 H-pyrrol-2-yl)imidazolidin-4-one; 2-(2,3-dihydro-1,4-benzodioxin-6-yl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one; 2-(4-tert-butylphenyl)-1 -[4-(diethylamino)benzyl]-3-[2-(4-methoxyphenyl)ethyl]-5,5 dimethylimidazolidin-4-one; 2-(5-tert-butyl-1 -methyl-1 H-imidazol-2-yl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin 4-one; -195 - WO 2009/079624 PCT/US2008/087397 2-(l1-ethyl-2, 3-dihydro-1 H-indol-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-[2-(dimethylamino)pyrimidin-5-yI]-3-[2-(4-methoxyphenyl)ethyl]-1,5,5-trimethylimidazolidin-4 one" 2-(4-tert-butylphenyl)-1 -cyclopropyl-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI 2-( 1-ethyl-i H-indol-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(2-tert-butyl pyri mid in-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methyli midazol id in-4-one 2-(4-tert-butylphenyl)-N-ethyl-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidine-1 -carboxamide 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-pyrrolidin-1 -ylphenyl)imidazolidin-4-oneI 2-[2-(dimethylamino)pyrimidin-5-yI]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I (2R, 5S)-2-(4-tert-butylphenyl)-1 -methyl-5-{2-[methyl(phenyl)amino]ethyl-3-2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-2-(4-tert-butylphenyl)-5-[2-(dimethylamino)ethyl]-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI (2R, 5S)-2-(4-tert-butylphenyl)-5-( 1 H-indol-3-ylmethyl)-3-[2-(4-methoxyphenyl)ethyl]-1 methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-1 -(1 H-imidazol-2-ylmethyl)-3-[2-(4-methoxyphenyl)ethyl]-5,5 dimethylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5, 5-dimethyl-1 -propylimidazolidin-4-oneI - 196 - WO 2009/079624 PCT/US2008/087397 2-(4-chlorophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph eny)ethy]-5, 5-d im ethy1- 1 -( py rid in-4 ylmethyl)imidazolidin-4-one 2-(4-tert-butylIph enyl)-3-[2-(4-m ethoxyph eny)ethy]-5,5-d imethyl- 1 -( py rid in-2 ylmethyl)imidazolidin-4-one (2R, 5 S)-2-(4-tert-butylIphe nyl)- 1 -m ethyl1-5-[2-(py rid in-3-y lam ino)ethyl ]-3-2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-(3-aminophenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-(2-{4-[(dimethylamino)methyl]phenyllethyl)- -methylimidazolidin-4 one" 2-[4-(diisopropylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 '5, 5-trimethylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(1 H-pyrazol-4-ylcarbonyl)imidazolidin-4 one" 2-(4-cyclopropylphenyl)-3-(4-methoxyphenyl)-1 -methylimidazolidin-4-one;I 2-[4-(4-hydroxypiperidin-1 -yI)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 one; 2-[4-(difluoromethoxy)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1,5, 5-trimethylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-1 -[4-(dimethylamino)butanoyl]-3-[2-(4-methoxyphenyl)ethyl]imidazolidin 4-one;I 2-[4-(dimethylamino)-2-methoxyphenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4 -197 - WO 2009/079624 PCT/US2008/087397 one" 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(pyridin-2-ylacetyl)imidazolidin-4-oneI 2-[4-(diethylamino)phenyl]-3-(4-methoxyphenyl)-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-1 -(pyridin-3-ylmethyl)-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-(4-methoxyphenyl)-1 -methylimidazolidin-4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(4-nitrophenyl)imidazolidin-4-oneI 2-(l1 H-indol-5-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(3-pyridin-3-ylpropanoyl)imidazolidin-4 one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -(pyridin-3-ylmethyl)imidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-N-pentylimidazolidine- carboxamide 2-[4-(l1 H-imidazol-1 -yI)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I (2R, 5S)-2-(4-tert-butylphenyl)-5-{2-[ethyl(phenyl)amino]ethyl-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI I -cyclopropyl-2-( I H-indol-5-yI)-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-oneI N-{2-[(2R, 4S)-2-(4-tert-butyl phenyl)-3-methyl-5-oxo-1 -{2-[4 - 198 - WO 2009/079624 PCT/US2008/087397 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-yI]ethyl}-2-methylalaninamide (2R, 5S)-2-(4-tert-butylphenyl)-5-[2-(diethylamino)ethyl]-1 -methyl-3-{2-[4 (trifluoromethoxy)phenyl]ethyllimidazolidin-4-oneI 1 -benzyl-3-[2-(4-methoxyphenyl)ethyl]-2-pyridin-2-ylimidazolidin-4-oneI 2-[3-(diethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-pyridin-2-ylimidazolidin-4-oneI 2-(4-tert-butylphenyl)-3-[2-(4-hydroxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(2,6-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(2-aminopyridin-3-yI)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxo-N-pyri mid in-4-yli midazolid ine-1 carboxamide 2-(4-tert-butylphenyl)-3-{2-[4-(dimethylamino)phenyl]ethyl-1 -methylimidazolidin-4-one;I 2-[4-(4-ethylpiperazin-1 -yI)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-oneI 2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1 -methylimidazolidin-4-one;I 2-[4-(diethylamino)-2-(trifluoromethyl)phenyl]-3-[2-(4-methoxyphenyl)ethyl]-1 methylimidazolidin-4-one;I 3-[2-(4-methoxyphenyl)ethyl]-1 -methyl-2-(2-phenylethyl)imidazolidin-4-oneI -199 - WO 2009/079624 PCT/US2008/087397 2-(4-cyclopropylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,5,5-trimethylimidazolidin-4-one; 2-(4-cyclopropylphenyl)-3-[3-(4-fluorophenyl)propyl]-l-methylimidazolidin-4-one; 1-(2-{2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-4-oxoimidazolidin-1-yl}ethyl)-3 ethylurea 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[2-(2-methyl-1 H-imidazol-1-yl)phenyl]imidazolidin-4 one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5,5-dimethyl-1 -(pyrimidin-5 ylmethyl)imidazolidin-4-one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-5,5-dimethyl-1-[(1-methyl-i H-imidazol-2 yl)methyl]imidazolidin-4-one; 2-(3,4-dimethylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1,5-dimethylimidazolidin-4-one; 2-(2-tert-butyl-1-methyl-1 H-imidazol-5-yl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin 4-one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(pyrazin-2-ylcarbonyl)imidazolidin-4-one; 3-[2-(4-methoxyphenyl)ethyl]-1-methyl-2-[4-(pyridin-3-ylmethoxy)phenyl]imidazolidin-4-one; 2-(4-hydroxyphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-methylimidazolidin-4-one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-pentylimidazolidin-4-one; 2-(4-tert-butylphenyl)-1-methyl-3-[2-(4-piperidin-1-ylphenyl)ethyl]imidazolidin-4-one; - 200 - WO 2009/079624 PCT/US2008/087397 4-{3-[2-(4-methoxyphenyl)ethyl]-1-methyl-4-oxoimidazolidin-2-yl}benzonitrile; 2-(4-tert-butylphenyl)-1-isonicotinoyl-3-[2-(4-methoxypheny)ethyl]imidazolidin-4-one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-N-methyl-4-oxoimidazolidine-1 carboxamide; 2-(4-tert-butylphenyl)-1-methyl-3-(2-phenoxyethyl)imidazolidin-4-one; 2-(4-tert-butylphenyl)-1-methyl-3-[2-(4-morpholin-4-ylphenyl)ethyl]imidazolidin-4-one; 2-(4-tert-butylphenyl)-3-[2-(4-methoxyphenyl)ethyl]-1-(3-pyridin-2-ylpropyl)imidazolidin-4-one; 1-benzyl-2-[4-(dimethylamino)phenyl]-3-[2-(4-methoxyphenyl)ethyl]imidazolidin-4-one; 3-[(4S)-2-(4-tert-butylphenyl)-3-methyl-5-oxo-1 -{2-[4 (trifluoromethoxy)phenyl]ethyl}imidazolidin-4-yl]-N-(phenylsulfonyl)propanamide; and 1-({(2R,4S)-2-(4-tert-butylphenyl)-1-[2-(4-methoxyphenyl)ethyl]-3-methyl-5-oxoimidazolidin-4 yl}methyl)-3-ethylurea; or a pharmaceutically acceptable salt thereof.
118. A pharmaceutical composition comprising one or more compounds of any one of claims 1 to 117 and one or more excipients.
119. A method for treating or preventing atrial arrhythmia comprising administering a 5 therapeutically effective amount of a compound of any one of claims 1 to 117 or a pharmaceutical composition of claim 118 to a subject.
120. The method of claim 119, wherein the atrial arrhythmia comprises atrial fibrillation or atrial flutter. - 201 - WO 2009/079624 PCT/US2008/087397
121. A method for or preventing treating thromboembolism, stroke, or cardiac failure comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 117 or a pharmaceutical composition of claim 118 to a subject.
122. The compound of claim 1, wherein each R 1 7 is independently selected from 5 C1_6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 heteroatoms selected from N, 0 and S, halogen, CN, OR 18 , SR 18 , NR 1 9 R 20 , C6-C10 aryl, and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, wherein the C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-10 cycloalkyl each is optionally substituted with 1-5 R 21 groups, and 10 wherein the cycloheteroalkyl, aryl, and heteroaryl each is optionally substituted with 1-5 R 22 groups; alternatively, two R17 groups, together with the carbon atoms to which they are bound, form a 5 or 6 membered ring containing 1-2 heteroatoms selected from N, 0 and S, and optionally substituted with 1-5 R 22 groups; 15 Ar2 is selected from C6-C10 aryl and 5-10 membered heteroaryl containing 1-4 heteroatoms selected from N, 0 and S, each of which is optionally substituted with 1 5 R 1 7 groups; each R is independently selected from C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-10 cycloalkyl, C1-3 perhaloalkyl, 3-10 membered cycloheteroalkyl containing 1 to 4 20 heteroatoms selected from N, 0 and S, halogen, CN, OR, SR , and NR 13 R, wherein the C1-6 alkyl, the C2-6 alkenyl, the C2-6 alkynyl, and the C3-10 cycloalkyl each is optionally substituted with 1-5 R 1 5 groups, and wherein the cycloheteroalkyl is optionally substituted with 1-5 R 1 6 groups; and each R 22 is independently is selected from C1-6 alkyl, C1-3 perhaloalkyl, halogen, CN, 25 OH, OC1_6 alkyl, C1-3 perhaloalkoxy, SH, SC 1 - 6 alkyl, NH 2 , NH(C 1 - 6 alkyl), and N(C 1 - 6 alkyl) 2 . - 202 - WO 2009/079624 PCT/US2008/087397
123. A method for inhibiting Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 117 or a pharmaceutical composition of claim 118 to a subject.
124. A method for treating or preventing a disorder associated with inhibition of 5 Kv1.5 potassium channel in a subject comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 117 or a pharmaceutical composition of claim 118 to a subject.
125. The method of claim 124, wherein the disorder is selected from the group consisting of atrial arrhythmia, thromboembolism, stroke and cardiac failure. 10
126. A method for inducing cardioversion, comprising administering a therapeutically effective amount of a compound of any one of claims 1 to 117 or a pharmaceutical composition of claim 118 to a subject. - 203 -
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US1493707P | 2007-12-19 | 2007-12-19 | |
| US61/014,937 | 2007-12-19 | ||
| US1550507P | 2007-12-20 | 2007-12-20 | |
| US61/015,505 | 2007-12-20 | ||
| PCT/US2008/087397 WO2009079624A1 (en) | 2007-12-19 | 2008-12-18 | 4-imidazolidinones as kv1.5 potassium channel inhibitors |
Publications (1)
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| AU2008338368A1 true AU2008338368A1 (en) | 2009-06-25 |
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| AU2008338368A Abandoned AU2008338368A1 (en) | 2007-12-19 | 2008-12-18 | 4-imidazolidinones as Kv1.5 potassium channel inhibitors |
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| Country | Link |
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| EP (1) | EP2234615A1 (en) |
| JP (1) | JP2011507883A (en) |
| AU (1) | AU2008338368A1 (en) |
| BR (1) | BRPI0820698A2 (en) |
| CA (1) | CA2709186A1 (en) |
| WO (1) | WO2009079624A1 (en) |
| ZA (1) | ZA201005087B (en) |
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| NO3175985T3 (en) | 2011-07-01 | 2018-04-28 | ||
| WO2013112932A1 (en) | 2012-01-27 | 2013-08-01 | Gilead Sciences, Inc. | Combination therapies using late sodium ion channel blockers and potassium ion channel blockers |
| WO2014134419A1 (en) | 2013-03-01 | 2014-09-04 | Gilead Sciences, Inc. | Use of ikach blockers for the treatment of cardiac diseases |
| WO2015193255A1 (en) * | 2014-06-16 | 2015-12-23 | Universite De Lille 2 Droit Et Sante | Compounds, pharmaceutical composition and their use in treating neurodegenerative diseases |
| EP3472376A4 (en) | 2016-06-16 | 2019-12-18 | Richard Edward Watts | Oligonucleotide directed and recorded combinatorial synthesis of encoded probe molecules |
| GB2557931A (en) * | 2016-12-16 | 2018-07-04 | Univ Bristol | Unnatural amino acids |
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| US3442892A (en) * | 1965-06-11 | 1969-05-06 | Nippon Shinyaku Co Ltd | Imidazolidinone derivatives |
| MY125533A (en) * | 1999-12-06 | 2006-08-30 | Bristol Myers Squibb Co | Heterocyclic dihydropyrimidine compounds |
| US20070299072A1 (en) * | 2006-06-20 | 2007-12-27 | Wyeth | Kv1.5 potassium channel inhibitors |
-
2008
- 2008-12-18 AU AU2008338368A patent/AU2008338368A1/en not_active Abandoned
- 2008-12-18 EP EP08861728A patent/EP2234615A1/en not_active Withdrawn
- 2008-12-18 JP JP2010539792A patent/JP2011507883A/en not_active Withdrawn
- 2008-12-18 BR BRPI0820698A patent/BRPI0820698A2/en not_active IP Right Cessation
- 2008-12-18 CA CA2709186A patent/CA2709186A1/en not_active Abandoned
- 2008-12-18 WO PCT/US2008/087397 patent/WO2009079624A1/en active Application Filing
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| WO2009079624A1 (en) | 2009-06-25 |
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| JP2011507883A (en) | 2011-03-10 |
| BRPI0820698A2 (en) | 2019-09-24 |
| EP2234615A1 (en) | 2010-10-06 |
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